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Musculoskeletal & Immunologic Disorders David B. Hellmann, MD, MACP John B. Imboden, Jr., MD

``Diagnosis & Evaluation A. Examination of the Patient In the patient with arthritis, the two clinical clues most helpful for diagnosis are the joint pattern and the presence or absence of extra-articular manifestations. The joint pattern is defined by the answers to three questions: (1) Is inflammation present? (2) How many joints are involved? and (3) What joints are affected? Joint inflammation manifests as redness, warmth, swelling, and morning stiffness of at least 30 minutes’ duration. Both the number of affected joints and the specific sites of involvement affect the differential diagnosis (Table 20–1). Some diseases— gout, for example—are characteristically monarticular, whereas other diseases, such as rheumatoid arthritis, are usually polyarticular. The location of joint involvement can also be distinctive. Only two diseases frequently cause prominent involvement of the distal interphalangeal (DIP) joint: osteoarthritis and psoriatic arthritis. Extra-articular manifestations such as fever (eg, gout, Still disease, endocarditis), rash (eg, systemic lupus erythematosus, psoriatic arthritis, Still disease), nodules (eg, rheumatoid arthritis, gout), or neuropathy (eg, polyarteritis nodosa, granulomatosis with polyangiitis [formerly Wegener granulomatosis]) narrow the differential diagnosis further.

B. Arthrocentesis and Examination of Joint Fluid If the diagnosis is uncertain, synovial fluid should be examined whenever possible (Table 20–2). Most large joints are easily aspirated, and contraindications to arthrocentesis are few. The aspirating needle should never be passed through an overlying cellulitis or psoriatic plaque because of the risk of introducing infection. For patients who are receiving long-term anticoagulation therapy with warfarin, joints can be aspirated with a small-gauge needle (eg, 22F) if the international normalized ratio (INR) is < 3.0.

1. Types of studies A. Gross examination—Clarity is an approximate guide to the degree of inflammation. Noninflammatory fluid is transparent, mild inflammation produces translucent fluid, and purulent effusions are opaque. Bleeding disorders,

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trauma, and traumatic taps are the most common causes of bloody effusions.

B. Cell count—The synovial fluid white cell count discriminates between noninflammatory (< 2000 white cells/ mcL), inflammatory (2000–75,000 white cells/mcL), and purulent (> 100,000 white cells/mcL) joint effusions.

Synovial fluid glucose and protein levels add little information and should not be ordered.

C. Microscopic examination—Compensated polarized light microscopy identifies and distinguishes monosodium urate (gout, negatively birefringent) and calcium pyrophosphate (pseudogout, positive birefringent) crystals.

Gram stain has specificity but limited sensitivity (50%) for septic arthritis.

D. Culture—Bacterial cultures as well as special studies for gonococci, tubercle bacilli, or fungi are ordered as appropriate.

2. Interpretation—Synovial fluid analysis is diagnostic in infectious or microcrystalline arthritis. Although the severity of inflammation in synovial fluid can overlap among various conditions, the synovial fluid white cell count is a helpful guide to diagnosis (Table 20–3). cc

DEGENERATIVE & CRYSTAL-INDUCED Arthritis DEGENERATIVE JOINT DISEASE (Osteoarthritis) ``

A degenerative disorder with minimal articular inflammation.

No systemic symptoms.

Pain relieved by rest; morning stiffness brief.

Radiographic findings: narrowed joint space, osteophytes, increased density of subchondral bone, bony cysts.

``

`` `` ``

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Chapter 20 not increase the incidence of osteoarthritis, but participation in competitive contact sports does. Jobs requiring frequent bending and carrying increase the risk of knee osteoarthritis.

Table 20–1. Diagnostic value of the joint pattern.

Characteristic Inflammation

Status Present Absent Monarticular

Number of involved joints

Oligoarticular (2–4 joints) Polyarticular (≥ 5 joints) Distal interphalangeal Metacarpophalangeal, wrists

Site of joint involvement

First metatarsal phalangeal

Representative Disease Rheumatoid arthritis, systemic lupus erythematosus, gout Osteoarthritis Gout, trauma, septic arthritis, Lyme disease, osteoarthritis Reactive arthritis, psoriatic arthritis, inflammatory bowel disease Rheumatoid arthritis, systemic lupus erythematosus Osteoarthritis, psoriatic arthritis (not rheumatoid arthritis) Rheumatoid arthritis, systemic lupus erythematosus, calcium pyrophosphate deposition disease (not osteoarthritis) Gout, osteoarthritis

``General Considerations Osteoarthritis, the most common form of joint disease, is chiefly a disease of aging. Ninety percent of all people have radiographic features of osteoarthritis in weightbearing joints by age 40. Symptomatic disease also increases with age. Gender is also a risk factor, because osteoarthritis develops in women more frequently than in men.

This arthropathy is characterized by degeneration of cartilage and by hypertrophy of bone at the articular margins. Inflammation is usually minimal. Hereditary and mechanical factors may be involved in the pathogenesis.

Obesity is a risk factor for osteoarthritis of the knee, hand, and probably of the hip. Recreational running does

``Clinical Findings A. Symptoms and Signs Degenerative joint disease is divided into two types: (1) primary, which most commonly affects some or all of the following: the DIP and the proximal interphalangeal (PIP) joints of the fingers, the carpometacarpal joint of the thumb, the hip, the knee, the metatarsophalangeal (MTP) joint of the big toe, and the cervical and lumbar spine; and (2) secondary, which may occur in any joint as a sequela to articular injury resulting from either intra-articular (including rheumatoid arthritis) or extra-articular causes.

The injury may be acute, as in a fracture; or chronic, as that due to occupational overuse of a joint, metabolic disease (eg, hyperparathyroidism, hemochromatosis, ochronosis), or neurologic disorders (syringomyelia; see below).

The onset is insidious. Initially, there is articular stiffness, seldom lasting more than 15 minutes; this develops later into pain on motion of the affected joint and is made worse by activity or weight bearing and relieved by rest.

Flexion contracture or varus deformity of the knee is not unusual, and bony enlargements of the DIP (Heberden nodes) and PIP (Bouchard nodes) are occasionally prominent (Figure 20–1). There is no ankylosis, but limitation of motion of the affected joint or joints is common. Crepitus may often be felt over the knee. Joint effusion and other articular signs of inflammation are mild. There are no systemic manifestations.

B. Laboratory Findings Osteoarthritis does not cause elevation of the erythrocyte sedimentation rate (ESR) or other laboratory signs of inflammation. Synovial fluid is noninflammatory.

Table 20–2. Examination of joint fluid.

Measure

(Normal)

Group I (Noninflammatory)

Group II (Inflammatory)

Group III (Purulent)

Volume (mL) (knee)

< 3.5

Often > 3.5

Often > 3.5

Often > 3.5

Clarity

Transparent

Transparent

Translucent to opaque

Opaque

Color

Clear

Yellow

Yellow to opalescent

Yellow to green

WBC (per mcL)

< 200

< 2000

2000–75,000

Polymorphonuclear leukocytes

< 25%

< 25%

50% or more

75% or more

Culture

Negative

Negative

Negative

Usually positive2

1

> 100,0002

Gout, rheumatoid arthritis, and other inflammatory conditions occasionally have synovial fluid WBC counts > 75,000/mcL but rarely > 100,000/mcL. 2 Most purulent effusions are due to septic arthritis. Septic arthritis, however, can present with group II synovial fluid, particularly if infection is caused by organisms of low virulence (eg, Neisseria gonorrhoeae) or if antibiotic therapy has been started.

WBC, white blood cell count.

1

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Table 20–3. Differential diagnosis by joint fluid groups.

Group I (Noninflammatory) (< 2000 white cells/mcL) Degenerative joint disease Trauma1 Osteochondritis dissecans Osteochondromatosis Neuropathic arthropathy1 Subsiding or early inflammation Hypertrophic osteoarthropathy2 Pigmented villonodular synovitis1

Group II (Inflammatory) (2000–75,000 white cells/mcL) Rheumatoid arthritis Acute crystal-induced synovitis (gout and pseudogout) Reactive arthritis Ankylosing spondylitis Rheumatic fever2 Tuberculosis

Group III (Purulent) (> 100,000 white cells/mcL) Pyogenic bacterial infections

Hemorrhagic Hemophilia or other hemorrhagic diathesis Trauma with or without fracture Neuropathic arthropathy Pigmented villonodular synovitis Synovioma Hemangioma and other benign neoplasms

1

May be hemorrhagic.

Noninflammatory or inflammatory group.

Reproduced, with permission, from Rodnan GP (editor). Primer on the rheumatic diseases, 7th ed. JAMA. 1973;224(Suppl):662.

2

C. Imaging Radiographs may reveal narrowing of the joint space; osteophyte formation and lipping of marginal bone; and thickened, dense subchondral bone. Bone cysts may also be present.

``Differential Diagnosis Because articular inflammation is minimal and systemic manifestations are absent, degenerative joint disease should seldom be confused with other arthritides. The distribution of joint involvement in the hands also helps distinguish osteoarthritis from rheumatoid arthritis. Osteoarthritis chiefly affects the DIP and PIP joints and spares the wrist and metacarpophalangeal (MCP) joints; rheumatoid arthritis involves the wrists and MCP joints and spares the DIP joints. Furthermore, the joint enlargement is bony-hard and

cool in osteoarthritis but spongy and warm in rheumatoid arthritis. Skeletal symptoms due to degenerative changes in joints—especially in the spine—may cause coexistent metastatic neoplasia, osteoporosis, multiple myeloma, or other bone disease to be overlooked.

``Prevention Weight reduction reduces the risk of developing symptomatic knee osteoarthritis. Correcting leg length discrepancy of > 1 cm with shoe modification may prevent knee osteoarthritis from developing in the shorter leg. Maintaining normal vitamin D levels may reduce the occurrence and progression of osteoarthritis, in addition to being important for bone health.

``Treatment A. General Measures For patients with mild to moderate osteoarthritis of weight-bearing joints, moderate physical activity (eg, a supervised walking program, hydrotherapy classes, or Tai Chi classes), and use of assistive devices (eg, a cane on the contralateral side) may result in clinical improvement of functional status without aggravating the joint pain. Weight loss can also improve the symptoms.

B. Analgesic and Anti-inflammatory Drugs

s Figure 20–1. Osteoarthritis with bony enlargement of the distal interphalangeal (DIP) joints (Heberden nodes) and proximal interphalangeal (PIP) joints (Bouchard nodes). (Courtesy of Richard P. Usatine, MD; used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)

Nonsteroidal anti-inflammatory drugs (NSAIDs) (see Table 5–3) are more effective (and more toxic) than acetaminophen for osteoarthritis of the knee or hip. Their superiority is most convincing in persons with severe disease. Patients with mild disease should start with acetaminophen (2.6–4 g/d). NSAIDs should be considered for patients who do not respond to acetaminophen. (See discussion of NSAID toxicity in the section on treatment of rheumatoid arthritis.) High doses of NSAIDs, as used in the inflammatory arthritides, are unnecessary. A topical NSAID—diclofenac gel 1% is approved by the US Food and Drug Administration (FDA) for treatment of osteoarthritis; the recommended dose is 4 g applied to the affected

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joint four times daily. Topical diclofenac appears more effective than placebo for knee and hand osteoarthritis.

Rates of systemic side effects are lower with topical than with oral diclofenac. Few studies have compared the efficacy of oral and topical NSAIDs. Chondroitin sulfate and glucosamine, alone or in combination, are no better than placebo in reducing pain in patients with knee or hip osteoarthritis.

For many patients, it is possible eventually to reduce the dosage or limit use of drugs to periods of exacerbation. For patients with knee osteoarthritis and effusion, intra-articular injection of triamcinolone (20–40 mg) may obviate the need for analgesics or NSAIDs. Corticosteroid injections up to four times a year appear to be safe. Intra-articular injections of sodium hyaluronate reduce symptoms moderately in some patients. Capsaicin cream 0.025–0.075% applied three or four times a day can also reduce knee pain without NSAIDs.

CRYSTAL DEPOSITION ARTHRITIS

C. Surgical Measures

``General Considerations

Total hip and knee replacements provide excellent symptomatic and functional improvement when involvement of that joint severely restricts walking or causes pain at rest, particularly at night. Arthroscopic surgery for knee osteoarthritis is ineffective.

Gout is a metabolic disease of a heterogeneous nature, often familial, associated with abnormal amounts of urates in the body and characterized early by a recurring acute arthritis, usually monarticular, and later by chronic deforming arthritis. The associated hyperuricemia is due to overproduction or underexcretion of uric acid—sometimes both. The disease is especially common in Pacific islanders, eg, Filipinos and Samoans. Primary gout has a heritable component, and genome-wide surveys have linked risk of gout to several genes whose products regulate urate handling by the kidney. Secondary gout, which may have a heritable component, is related to acquired causes of hyperuricemia, eg, medication use (especially diuretics, lowdose aspirin, cyclosporine, and niacin), myeloproliferative disorders, multiple myeloma, hemoglobinopathies, chronic kidney disease, hypothyroidism, psoriasis, sarcoidosis, and lead poisoning (Table 20–4). Alcohol ingestion promotes hyperuricemia by increasing urate production and decreasing the renal excretion of uric acid. Finally, hospitalized patients frequently suffer attacks of gout because of changes in diet, fluid intake, or medications that lead either to rapid reductions or increases in the serum urate level.

About 90% of patients with primary gout are men, usually over 30 years of age. In women, the onset is typically postmenopausal. The characteristic lesion is the tophus, a nodular deposit of monosodium urate monohydrate crystals with an associated foreign body reaction. Tophi are found in cartilage, subcutaneous and periarticular tissues, tendon, bone, the kidneys, and elsewhere. Urates have been demonstrated in the synovial tissues (and fluid) during acute arthritis; indeed, the acute inflammation of gout is believed to be initiated by the ingestion of uncoated urate crystals by monocytes and synoviocytes. Once inside the cells, the gout crystals are processed through Toll-like receptors and activate NALP-3 inflammasomes which in turn release a variety of chemotactic agents and cytokines capable of mediating inflammation. The precise relationship of hyperuricemia to gouty arthritis is still obscure, since chronic hyperuricemia is found in people who never

``Prognosis Marked disability is less common in patients with osteoarthritis than in those with rheumatoid arthritis, but symptoms may be quite severe and limit activity considerably (especially with involvement of the hips, knees, and cervical spine).

``When to Refer • Refer patients to an orthopedic surgeon when recalcitrant symptoms or functional impairment, or both, warrant consideration of joint replacement surgery of the hip or knee.

Altman R et al. Topical therapy for osteoarthritis: clinical and pharmacologic perspectives. Postgrad Med. 2009 Mar; 121(2):139–47. [PMID: 19332972] Aran S et al. A double-blind randomized controlled trial appraising the symptom-modifying effects of colchicine on osteoarthritis of the knee. Clin Exp Rheumatol. 2011 May–Jun; 29(3):513–8. [PMID: 21640042] Chan FK et al. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet. 2010 Jul 17;376(9736): 173–9. Erratum in: Lancet. 2011 Jul 16;378(9787):228. [PMID: 20638563] Harvey WF et al. Association of leg-length inequality with knee osteoarthritis: a cohort study. Ann Intern Med. 2010 Mar 2; 152(5):287–95. [PMID: 20194234] Losina E et al. Impact of obesity and knee osteoarthritis on morbidity and mortality in older Americans. Ann Intern Med. 2011 Feb 15;154(4):217–26. [PMID: 21320937] Wandel S et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network metaanalysis. BMJ. 2010 Sep 16;341:c4675. [PMID: 20847017]

1. Gouty Arthritis ``

E s s en t ia l S o f dia g n o s i s

Acute onset, usually monarticular, recurring attacks, often involving the first MTP joint.

Polyarticular involvement more common in patients with long-standing disease.

Identification of urate crystals in joint fluid or tophi is diagnostic.

Dramatic therapeutic response to NSAIDs. With chronicity, urate deposits in subcutaneous tissue, bone, cartilage, joints, and other tissues.

``

``

``

`` ``

Musculoskeletal & Immunologic Disorders

Table 20–4. Origin of hyperuricemia.

Primary hyperuricemia A. Increased production of purine 1. Idiopathic 2. Specific enzyme defects (eg, Lesch-Nyhan syndrome, glycogen storage diseases) B. Decreased renal clearance of uric acid (idiopathic) Secondary hyperuricemia A. Increased catabolism and turnover of purine 1. Myeloproliferative disorders 2. Lymphoproliferative disorders 3. Carcinoma and sarcoma (disseminated) 4. Chronic hemolytic anemias 5. Cytotoxic drugs 6. Psoriasis B. Decreased renal clearance of uric acid 1. Intrinsic kidney disease 2. Functional impairment of tubular transport a. Drug-induced (eg, thiazides, low-dose aspirin) b. Hyperlacticacidemia (eg, lactic acidosis, alcoholism) c. Hyperketoacidemia (eg, diabetic ketoacidosis, starvation) d. Diabetes insipidus (vasopressin-resistant) e. Bartter syndrome Modified, with permission, from Rodnan GP. Gout and other crystalline forms of arthritis. Postgrad Med. 1975 Oct;58(5):6–14.

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joint (“podagra”), although others, especially those of the feet, ankles, and knees, are commonly affected. Gouty attacks may develop in periarticular soft tissues such as the arch of the foot. Hips and shoulders are rarely affected. More than one joint may occasionally be affected during the same attack; in such cases, the distribution of the arthritis is usually asymmetric. As the attack progresses, the pain becomes intense. The involved joints are swollen and exquisitely tender and the overlying skin tense, warm, and dusky red. Fever is common and may reach 39°C. Local desquamation and pruritus during recovery from the acute arthritis are characteristic of gout but are not always present. Tophi may be found in the external ears, feet, olecranon and prepatellar bursae, and hands (Figure 20–2). They usually develop years after the initial attack of gout.

Asymptomatic periods of months or years commonly follow the initial acute attack. After years of recurrent severe monarthritis attacks of the lower extremities and untreated hyperuricemia, gout can evolve into a chronic, deforming polyarthritis of upper and lower extremities that mimics rheumatoid arthritis.

B. Laboratory Findings The serum uric acid is elevated (> 7.4 mg/dL) in 95% of patients who have serial measurements during the course of an attack. However, a single uric acid determination is normal in up to 25% of cases, so it does not exclude gout,

develop gout or uric acid stones. Rapid fluctuations in serum urate levels, either increasing or decreasing, are important factors in precipitating acute gout. The mechanism of the late, chronic stage of gouty arthritis is better understood. This is characterized pathologically by tophaceous invasion of the articular and periarticular tissues, with structural derangement and secondary degeneration (osteoarthritis).

Uric acid kidney stones are present in 5–10% of patients with gouty arthritis. Hyperuricemia correlates highly with the likelihood of developing stones, with the risk of stone formation reaching 50% in patients with a serum urate level > 13 mg/dL. Chronic urate nephropathy is caused by the deposition of monosodium urate crystals in the renal medulla and pyramids. Although progressive chronic kidney disease occurs in a substantial percentage of patients with chronic gout, the role of hyperuricemia in causing this outcome is controversial, because many patients with gout have numerous confounding risk factors for chronic kidney disease (eg, hypertension, alcohol use, lead exposure, and other risk factors for vascular disease).

``Clinical Findings A. Symptoms and Signs Acute gouty arthritis is sudden in onset and frequently nocturnal. It may develop without apparent precipitating cause or may follow rapid increases or decreases in serum urate levels. Common precipitants are alcohol excess (particularly beer), changes in medications that affect urate metabolism, and, in the hospitalized patient, fasting before medical procedures. The MTP joint of the great toe is the most susceptible

s Figure 20–2. Acute gouty arthritis superimposed on tophaceous gout. (Courtesy of the Western Journal of Medicine and JM Geiderman, MD; used, with permission, from Usatine RP, Smith MA, Mayeaux EJ, Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGrawHill, 2009.)

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especially in patients taking urate-lowering drugs. During an acute attack, the peripheral blood white cell count is frequently elevated. Identification of sodium urate crystals in joint fluid or material aspirated from a tophus establishes the diagnosis. The crystals, which may be extracellular or found within neutrophils, are needle-like and negatively birefringent when examined by polarized light microscopy.

C. Imaging Early in the disease, radiographs show no changes. Later, punched-out erosions with an overhanging rim of cortical bone (“rat bite”) develop. When these are adjacent to a soft tissue tophus, they are diagnostic of gout.

``Differential Diagnosis Acute gout is often confused with cellulitis. Bacteriologic studies usually exclude acute pyogenic arthritis. Pseudogout is distinguished by the identification of calcium pyrophosphate crystals (positive birefringence) in the joint fluid, usually normal serum uric acid, and the radiographic appearance of chondrocalcinosis.

Chronic tophaceous arthritis may resemble chronic rheumatoid arthritis; gout is suggested by an earlier history of monarthritis and is established by the demonstration of urate crystals in a suspected tophus. Likewise, hips and shoulders are generally spared in tophaceous gout.

Biopsy may be necessary to distinguish tophi from rheumatoid nodules. A radiographic appearance similar to that of gout may be found in rheumatoid arthritis, sarcoidosis, multiple myeloma, hyperparathyroidism, or Hand-Schüller-Christian disease. Chronic lead intoxication may result in attacks of gouty arthritis (saturnine gout).

``Treatment A. Asymptomatic Hyperuricemia Asymptomatic hyperuricemia should not be treated; uric acid–lowering drugs need not be instituted until arthritis, renal calculi, or tophi become apparent.

B. Acute Attack Arthritis is treated first and hyperuricemia weeks or months later, if at all. Sudden reduction of serum uric acid often precipitates further episodes of gouty arthritis.

1. NSAIDs—These drugs (see Table 5–3) are the treatment of choice for acute gout. Traditionally, indomethacin has been the most frequently used agent, but all of the other newer NSAIDs are probably equally effective. Indomethacin is initiated at a dosage of 25–50 mg orally every 8 hours and continued until the symptoms have resolved (usually 5–10 days). Active peptic ulcer disease, impaired kidney function, and a history of allergic reaction to NSAIDs are contraindications. For patients at high risk for upper gastrointestinal bleeding, celecoxib (200 mg twice a day on day 1 then 100 mg twice daily until resolution), a cyclooxygenase type 2 (COX-2) inhibitor, may be an appropriate first choice for management of an acute gout attack. Long-term

use of COX-2 inhibitors is not advised because of the association with increased risk of cardiovascular events, which has led to the removal of some drugs (eg, rofecoxib and valdecoxib) from the US market.

2. Colchicine—Neither oral nor intravenous colchicine should be used for the treatment of acute gout flares. A patient who is taking prophylactic doses of colchicine may continue it through the flare. The use of oral colchicine during the intercritical period to prevent gout attacks is discussed below.

3. Corticosteroids—Corticosteroids often give dramatic symptomatic relief in acute episodes of gout and will control most attacks. They are most useful in patients with contraindications to the use of NSAIDs. Corticosteroids may be given intravenously (eg, methylprednisolone, 40 mg/d tapered over 7 days) or orally (eg, prednisone, 40–60 mg/d tapered over 7 days). If the patient’s gout is monarticular, intra-articular administration (eg, triamcinolone, 10–40 mg depending on the size of the joint) is very effective. Because gouty and septic arthritis can coexist, albeit rarely, joint aspiration and Gram stain with culture of synovial fluid should be performed when intra-articular corticosteroids are given.

4. Anakinra—Uncontrolled studies suggest that this interleukin-1 receptor antagonist has efficacy for the management of acute gout.

C. Management between Attacks Treatment during symptom-free periods is intended to minimize urate deposition in tissues, which causes chronic tophaceous arthritis, and to reduce the frequency and severity of recurrences. Patients with a single episode of gout who are willing to lose weight and stop drinking alcohol are at low risk for another attack and unlikely to benefit from long-term medical therapy. In contrast, older individuals with mild chronic kidney disease who require diuretic use and have a history of multiple attacks of gout are more likely to benefit from pharmacologic treatment.

In general, the higher the uric acid level and the more frequent the attacks, the more likely that long-term medical therapy will be beneficial.

1. Diet—Potentially reversible causes of hyperuricemia are a high-purine diet, obesity, alcohol consumption, and use of certain medications (see below). Beer consumption appears to confer a higher risk of gout than does whiskey or wine. Higher levels of meat and seafood consumption are associated with increased risks of gout, whereas a higher level of dairy products consumption is associated with a decreased risk. Although dietary purines usually contribute only 1 mg/dL to the serum uric acid level, moderation in eating foods with high purine content is advisable (Table 20–5). A high liquid intake and, more importantly, a daily urinary output of 2 L or more will aid urate excretion and minimize urate precipitation in the urinary tract.

2. Avoidance of hyperuricemic medications—Thiazide and loop diuretics inhibit renal excretion of uric acid and

Musculoskeletal & Immunologic Disorders

Table 20–5. The purine content of foods.1 Low-purine foods Refined cereals and cereal products, cornflakes, white bread, pasta, flour, arrowroot, sago, tapioca, cakes Milk, milk products, and eggs Sugar, sweets, and gelatin Butter, polyunsaturated margarine, and all other fats Fruit, nuts, and peanut butter Lettuce, tomatoes, and green vegetables (except those listed below) Cream soups made with low-purine vegetables but without meat or meat stock Water, fruit juice, cordials, and carbonated drinks High-purine foods All meats, including organ meats, and seafood Meat extracts and gravies Yeast and yeast extracts, beer, and other alcoholic beverages Beans, peas, lentils, oatmeal, spinach, asparagus, cauliflower, and mushrooms 1 The purine content of a food reflects its nucleoprotein content and turnover. Foods containing many nuclei (eg, liver) have many purines, as do rapidly growing foods such as asparagus.

The consumption of large amounts of a food containing a small concentration of purines may provide a greater purine load than consumption of a small amount of a food containing a large concentration of purines.

Reproduced, with permission, from Emmerson BT. The management of gout. N Engl J Med. 1996 Feb 15;334(7):445–51.

should be avoided in patients with gout. Similarly, low doses of aspirin aggravate hyperuricemia, as does niacin.

3. Colchicine—There are two indications for daily colchicine administration. First, colchicine can be used to prevent future attacks. For the person who has mild hyperuricemia and occasional attacks of gouty arthritis, long-term colchicine prophylaxis may be all that is needed.

Second, colchicine can also be used when uricosuric drugs or allopurinol (see below) are started, to suppress attacks precipitated by abrupt changes in the serum uric acid level.

For either indication, the usual dose is 0.6 mg either once or twice a day. Colchicine is renally cleared. Patients who have coexisting moderate chronic kidney disease should take colchicine only once a day or once every other day in order to avoid the peripheral neuromyopathy and other complications of colchicine toxicity.

4. Reduction of serum uric acid—Indications for a urate lowering intervention include frequent acute arthritis not controlled by colchicine prophylaxis, tophaceous deposits, or kidney damage. Hyperuricemia with infrequent attacks of arthritis may not require treatment. If instituted, the goal of medical treatment is to maintain the serum uric acid at or below 6 mg/dL, which allows urate crystals to solubilize.

Three classes of agents may be used to lower the serum uric acid—the uricosuric drugs, xanthine oxidase inhibitors (allopurinol or febuxostat), and uricase (pegloticase); none is of value in the treatment of acute gout. Choosing between uricosuric drugs and allopurinol depends on the

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result of a 24-hour urine uric acid determination. A value under 800 mg/d indicates undersecretion of uric acid, which is amenable to uricosuric agents if kidney function is preserved or to a xanthine oxidase inhibitor (allopurinol or febuxostat) if kidney function is limited. Patients with > 800 mg of uric acid in a 24-hour urine collection are overproducers and require a xanthine oxidase inhibitor.

The uricase, pegloticase, requires intravenous administration and is indicated only in patients with chronic gout refractory to other treatments.

A. Uricosuric drugs—Uricosuric drugs, which block the tubular reabsorption of filtered urate thereby reducing the metabolic urate pool, prevent the formation of new tophi and reduce the size of those already present. When administered concomitantly with colchicine, they may lessen the frequency of recurrences of acute gout. The indication for uricosuric treatment is the increasing frequency or severity of acute attacks. Uricosuric agents are ineffective in patients with an estimated glomerular filtration rate of < 60 mL/min.

The following uricosuric drugs may be used: (1) Probenecid, 0.5 g orally daily initially, with gradual increase to 1–2 g daily; or (2) sulfinpyrazone, 50–100 mg orally twice daily initially, with gradual increase to 200–400 mg twice daily. Hypersensitivity to either with fever and rash occurs in 5% of cases; gastrointestinal complaints are observed in 10%. Probenecid also inhibits the excretion of penicillin, indomethacin, dapsone, and acetazolamide.

Precautions with uricosuric drugs include maintaining a daily urinary output of 2000 mL or more in order to minimize the precipitation of uric acid in the urinary tract.

This can be further prevented by giving alkalinizing agents (eg, potassium citrate, 30–80 mEq/d orally) to maintain a urine pH of > 6.0. Uricosuric drugs should not be used in patients with a history of uric acid nephrolithiasis. Aspirin in moderate doses antagonizes the action of uricosuric agents, but low doses (325 mg or less per day) do not; doses of aspirin > 3 g daily are themselves uricosuric.

B. Xanthine oxidase inhibitors—The xanthine oxidase inhibitors promptly lower plasma urate and urinary uric acid concentrations and facilitate tophus mobilization.

Inhibitors of xanthine oxidase are of special value in uric acid overproducers; in tophaceous gout; in patients unresponsive to the uricosuric regimen; and in gouty patients with uric acid renal calculi. Asymptomatic hyperuricemia should not be treated. Two xanthine oxidase inhibitors are available for treating chronic gout: allopurinol and febuxostat. One or the other should be chosen; allopurinol and febuxostat are not to be used together. The most frequent adverse effect with either medication is the precipitation of an acute gouty attack; thus, patients generally should be receiving prophylactic doses of colchicine and should not be experiencing an acute flare when xanthine oxidase inhibitors are initiated. Hypersensitivity to allopurinol occurs in 2% of cases and can be life-threatening. The most common sign of hypersensitivity is a pruritic rash that may progress to toxic epidermal necrolysis, particularly if allopurinol is continued; vasculitis and hepatitis are other manifestations. Patients should be instructed to stop

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allopurinol immediately if a rash develops. Febuxostat apparently does not cause the hypersensitivity reactions seen with allopurinol and can be given without dose adjustment to patients with mild to moderate renal disease.

However, 2–3% of patients taking febuxostat may develop abnormal liver function tests. In addition, one clinical study showed that febuxostat was associated with a slightly higher rate of fatal and non-fatal cardiovascular events than allopurinol (0.97 vs 0.58 per 100 patient-years).

The initial daily dose of allopurinol is 300 mg/d orally for most patients who have normal kidney function; the dose of allopurinol should be increased in 100-mg increments to achieve the desired serum uric acid level of ≤ 6.0 mg/dL. Successful treatment usually requires a dose of 300–400 mg of allopurinol daily. The maximum daily dose is 800 mg. Allopurinol can be used in chronic kidney disease, but the dose must be reduced to decrease the chance of side effects. For patients with renal impairment, the initial dose should be 50–100 mg daily.

Allopurinol interacts with other drugs. The combined use of allopurinol and ampicillin causes a drug rash in 20% of patients. Allopurinol can increase the half-life of probenecid, while probenecid increases the excretion of allopurinol. Thus, a patient taking both drugs may need to use slightly higher than usual doses of allopurinol and lower doses of probenecid. The initial dose of febuxostat is 40 mg/d orally. If the target serum uric acid is not reached within 2 weeks, then the dose of febuxostat can be increased to its maximum of 80 mg/d.

C. Uricase—Nonprimate mammals do not develop gout because they have an enzyme—uricase—that ensures that purine metabolism does not end with urate but the much more soluble metabolite, allantoin. In humans, the gene for uricase has been inactivated by a missense mutation, so purine metabolism dead ends with the production of uric acid, which becomes insoluble above a level of 6.8 mg/dL. Pegloticase, a recombinant uricase that must be administered intravenously (8 mg every 2 weeks), is indicated for the rare patient with chronic tophaceous gout who is refractory to all other therapies. Pegloticase carries a “Black Box Warning,” which advises administering the drug only in healthcare settings and by healthcare professionals prepared to manage anaphylactic and other serious infusion reactions.

contraindicated because of underlying chronic kidney disease; intravenous colchicine should not be used because of its narrow therapeutic index (particularly in kidney dysfunction); and corticosteroids are already being used.

Often the best approach for monarticular gout—after excluding infection—is injecting corticosteroids into the joint (see above). For polyarticular gout, increasing the dose of systemic corticosteroid may be the only alternative.

Since transplant patients often have multiple attacks of gout, long-term relief requires lowering the serum uric acid with allopurinol or febuxostat. (Kidney dysfunction seen in many transplant patients makes uricosuric agents ineffective.) Both allopurinol and febuxostat inhibit the metabolism of azathioprine and should be avoided in patients who must take azathioprine.

``Prognosis Without treatment, the acute attack may last from a few days to several weeks. The intervals between acute attacks vary up to years, but the asymptomatic periods often become shorter if the disease progresses. Chronic gouty arthritis occurs after repeated attacks of acute gout, but only after inadequate treatment. The younger the patient at the onset of disease, the greater the tendency to a progressive course. Destructive arthropathy is rarely seen in patients whose first attack is after age 50.

Patients with gout are anecdotally thought to have an increased incidence of hypertension, kidney disease (eg, nephrosclerosis, interstitial nephritis, pyelonephritis), diabetes mellitus, hypertriglyceridemia, and atherosclerosis.

Burns CM et al. Gout therapeutics: new drugs for an old disease.

Lancet. 2011 Jan 8;377(9760):165–77. [PMID: 20719377] Choi HK et al. Fructose-rich beverages and risk of gout in women.

JAMA. 2010 Nov 24;304(20):2270–8. [PMID: 21068145] Neogi T. Clinical practice. Gout. N Engl J Med. 2011 Feb 3; 364(5): 443–52. [PMID: 21288096] Stamp LK et al. Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. Arthritis Rheum.

2011 Feb;63(2):412–21. [PMID: 21279998] Sundy J et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011 Aug 17;306(7):711–20. [PMID: 21846852]

D. Chronic Tophaceous Arthritis With rigorous medical compliance, allopurinol or febuxostat or pegloticase shrinks tophi and in time can lead to their disappearance. Resorption of extensive tophi requires maintaining a serum uric acid below 6 mg/dL. Surgical excision of large tophi offers mechanical improvement in selected deformities.

E. Gout in the Transplant Patient Hyperuricemia and gout commonly develop in many transplant patients because they have decreased kidney function and require drugs that inhibit uric acid excretion (especially cyclosporine and diuretics). Treating acute gout in these patients is challenging: NSAIDs are usually

2. Chondrocalcinosis & Pseudogout Chondrocalcinosis is the presence of calcium-containing salts in articular cartilage. Diagnosed radiologically, it may be familial and is commonly associated with a wide variety of metabolic disorders (eg, hemochromatosis, hyperparathyroidism, ochronosis, diabetes mellitus, hypothyroidism, Wilson disease, and gout). Pseudogout (also called calcium pyrophosphate dihydrate [CPPD] deposition disease) is most often seen in persons age 60 or older, is characterized by acute, recurrent and rarely chronic arthritis involving large joints (most commonly the knees and the wrists) and is almost always accompanied by chondrocalcinosis of the affected joints. Other joints frequently affected are the

Musculoskeletal & Immunologic Disorders MCPs, hips, shoulders, elbows, and ankles. Involvement of the DIP and PIP joints is no more common in CPPD deposition disease than in other age-matched controls.

Pseudogout, like gout, frequently develops 24–48 hours after major surgery. Identification of calcium pyrophosphate crystals in joint aspirates is diagnostic of pseudogout.

With light microscopy, the rhomboid-shaped crystals differ from the needle-shaped gout crystals. A red compensator is used for positive identification, since pseudogout crystals are blue when parallel and yellow when perpendicular to the axis of the compensator. Urate crystals give the opposite pattern. X-ray examination shows not only calcification (usually symmetric) of cartilaginous structures but also signs of degenerative joint disease (osteoarthritis).

Unlike gout, pseudogout is usually associated with normal serum urate levels.

NSAIDs (salicylates, indomethacin, naproxen, and other drugs) are helpful in the treatment of acute episodes.

Patients at increased risk for upper gastrointestinal bleeding may use a COX-2 inhibitor to treat acute attacks of pseudogout. Long-term use of COX-2 inhibitors is not advised because of the association with increased risk of cardiovascular events. Colchicine, 0.6 mg orally twice daily, is more effective for prophylaxis than for acute attacks.

Aspiration of the inflamed joint and intra-articular injection of triamcinolone, 10–40 mg, depending on the size of the joint, are also of value in resistant cases.

Pascual E et al. Synovial fluid analysis for crystals. Curr Opin Rheumatol. 2011 Mar;23(2):161–9. [PMID: 21285711] Richette P et al. An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease. Rheumatology (Oxford). 2009 Jul;48(7):711–5. [PMID: 19398486]

cc

PAIN SYNDROMES

NECK PAIN ``

E s s en t ia l S o f dia g n o s i s

Most chronic neck pain is caused by degenerative joint disease and responds to conservative approaches.

Whiplash is the most common type of traumatic injury to the neck.

Serious erosive disease of the atlantoaxial joint (C1–2) may lead to neurologic complications in patients with rheumatoid arthritis and ankylosing spondylitis.

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neck, shoulder girdle, and upper extremity. Diagnostic differentiation may be difficult. Some represent primary disorders of the cervicobrachial region; others are local manifestations of systemic disease. It is frequently not possible to make a specific diagnosis.

``Clinical Findings A. Symptoms and Signs Neck pain may be limited to the posterior region or, depending on the level of the symptomatic joint, may radiate segmentally to the occiput, anterior chest, shoulder girdle, arm, forearm, and hand. It may be intensified by active or passive neck motions. The general distribution of pain and paresthesias corresponds roughly to the involved dermatome in the upper extremity. Radiating pain in the upper extremity is often intensified by hyperextension of the neck and deviation of the head to the involved side.

Limitation of cervical movements is the most common objective finding. Neurologic signs depend on the extent of compression of nerve roots or the spinal cord. Compression of the spinal cord may cause paraparesis or paraplegia.

B. Imaging The radiographic findings depend on the cause of the pain; many plain radiographs are completely normal in patients who have suffered an acute cervical strain. Loss of cervical lordosis is often seen but is nonspecific. In osteoarthritis, comparative reduction in height of the involved disk space is a frequent finding. The most common late radiographic finding is osteophyte formation anteriorly, adjacent to the disk; other chronic abnormalities occur around the apophysial joint clefts, chiefly in the lower cervical spine.

Use of advanced imaging techniques is indicated in the patient who has severe pain of unknown cause that fails to respond to conservative therapy or in the patient who has evidence of myelopathy. MRI is more sensitive than CT in detecting disk disease, extradural compression, and intramedullary cord disease. CT is preferable for demonstration of fractures.

``Differential Diagnosis & Treatment

``

``

``

``General Considerations At any point in time, about 15% of adults are experiencing neck pain, which develops more commonly in women than in men. The prevalence of neck pain peaks at age 50. A large group of articular and extra-articular disorders are characterized by pain that may involve simultaneously the

The causes of neck pain include acute and chronic cervical strain or sprains, herniated nucleus pulposus, osteoarthritis, ankylosing spondylitis, rheumatoid arthritis, fibromyalgia, osteomyelitis, neoplasms, polymyalgia rheumatica, compression fractures, pain referred from visceral structures (eg, angina), and functional disorders.

A. Nonspecific Neck Pain In the absence of trauma or evidence of infection, malignancy, neurologic findings, or systemic inflammation, the patient can be treated conservatively. Conservative therapy can include rest, analgesics, or physical therapy.

B. Acute Cervical Musculotendinous Strain Cervical strain is generally caused by mechanical postural disorders, overexertion, or injury (eg, whiplash). Acute

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episodes are associated with pain, decreased cervical spine motion, and paraspinal muscle spasm, resulting in stiffness of the neck and loss of motion. Muscle trigger points can often be localized. After whiplash injury, patients often experience not only neck pain but also shoulder girdle discomfort and headache. Management includes administration of analgesics. Soft cervical collars are commonly recommended, but evidence suggests they may delay recovery. Acupuncture, manipulation, or physical therapy can help some patients, but the precise role of these treatments is not well established. Corticosteroid injection into cervical facet joints is ineffective. Gradual return to full activity is encouraged.

C. Herniated Nucleus Pulposus Rupture or prolapse of the nucleus pulposus of the cervical disks into the spinal canal causes pain radiating at a C6–7 level. When intra-abdominal pressure is increased by coughing, sneezing, or other movements, symptoms are aggravated, and cervical muscle spasm may occur.

Neurologic abnormalities include decreased reflexes of the deep tendons of the biceps and triceps and decreased sensation and muscle atrophy or weakness in the forearm or hand. Cervical traction, bed rest, and other conservative measures are usually successful. Radicular symptoms usually respond to conservative therapy, including NSAIDs, activity modification, intermittent cervical traction, and neck immobilization. Cervical epidural corticosteroid injections may help those who fail conservative therapy.

Surgery is indicated for unremitting pain and progressive weakness despite a full trial of conservative therapy and if a surgically correctable abnormality is identified by MRI or CT myelography. Surgical decompression achieves excellent results in 70–80% of such patients.

D. Arthritic Disorders Cervical spondylosis (degenerative arthritis) is a collective term describing degenerative changes that occur in the apophysial joints and intervertebral disk joints, with or without neurologic signs. Osteoarthritis of the articular facets is characterized by progressive thinning of the cartilage, subchondral osteoporosis, and osteophytic proliferation around the joint margins. Degeneration of cervical disks and joints may occur in adolescents but is more common after age 40. Degeneration is progressive and is marked by gradual narrowing of the disk space, as demonstrated by radiography. Osteocartilaginous proliferation occurs around the margin of the vertebral body and gives rise to osteophytic ridges that may encroach upon the intervertebral foramina and spinal canal, causing compression of the neurovascular contents.

Osteoarthritis of the cervical spine is often asymptomatic but may cause diffuse neck pain. A minority of patients with neck pain also suffer from radicular pain or myelopathy. Myelopathy develops insidiously and is manifested by sensory dysfunction and clumsy hands. Some patients also complain of unsteady walking, urinary frequency and urgency, or electrical shock sensations with neck flexion or extension (Lhermitte sign). Weakness, sensory loss, and

spasticity with exaggerated reflexes develop below the level of spinal cord compression. Amyotrophic lateral sclerosis, multiple sclerosis, syringomyelia, spinal cord tumors, and tropical spastic paresis from HTLV-1 infection can mimic myelopathy from cervical arthritis. The mainstay of conservative therapy is immobilizing the cervical spine with a collar. With moderate to severe neurologic symptoms, surgical treatment is indicated.

Atlantoaxial subluxation may occur in patients with either rheumatoid arthritis or ankylosing spondylitis.

Inflammation of the synovial structures resulting from erosion and laxity of the transverse ligament can lead to neurologic signs of spinal cord compression. Treatment may vary from use of a cervical collar or more rigid bracing to operative treatment, depending on the degree of subluxation and neurologic progression. Surgical treatment for stabilization of the cervical spine is a last resort.

E. Other Disorders Osteomyelitis and neoplasms are discussed below.

Osteoporosis is discussed in Chapter 26.

Aas RW et al. Workplace interventions for neck pain in workers.

Cochrane Database Syst Rev. 2011 Apr 13;(4):CD008160.

[PMID: 21491405] Benyamin RM et al. Systematic review of the effectiveness of cervical epidurals in the management of chronic neck pain. Pain Physician. 2009 Jan–Feb;12(1):137–57. [PMID: 19165300] Eubanks JD. Cervical radiculopathy: nonoperative management of neck pain and radicular symptoms. Am Fam Physician.

2010 Jan 1;81(1):33–40. [PMID: 20052961] Goode AP et al. Prevalence, practice patterns, and evidence for chronic neck pain. Arthritis Care Res (Hoboken). 2010 Nov; 62(11):1594–601. [PMID: 20521306] Haines T et al; Cervical Overview Group (COG). A Cochrane review of patient education for neck pain. Spine J. 2009 Oct; 9(10):859–71. [PMID: 19596214]

THORACIC OUTLET SYNDROMES Thoracic outlet syndromes result from compression of the neurovascular structures supplying the upper extremity.

Symptoms and signs arise from intermittent or continuous pressure on elements of the brachial plexus (> 90% of cases) or the subclavian or axillary vessels (veins or arteries) by a variety of anatomic structures of the shoulder girdle region. The neurovascular bundle can be compressed between the anterior or middle scalene muscles and a normal first thoracic rib or a cervical rib. Most commonly thoracic outlet syndromes are caused by scarred scalene neck muscle secondary to neck trauma or sagging of the shoulder girdle resulting from aging, obesity, or pendulous breasts. Faulty posture, occupation, or thoracic muscle hypertrophy from physical activity (eg, weight-lifting, baseball pitching) may be other predisposing factors.

Thoracic outlet syndromes present in most patients with some combination of four symptoms involving the upper extremity, namely pain, numbness, weakness, and swelling. The predominant symptoms depend on whether the compression chiefly affects neural or vascular structures. The onset of symptoms is usually gradual but can be

Musculoskeletal & Immunologic Disorders sudden. Some patients spontaneously notice aggravation of symptoms with specific positioning of the arm. Pain radiates from the point of compression to the base of the neck, the axilla, the shoulder girdle region, arm, forearm, and hand. Paresthesias are common and distributed to the volar aspect of the fourth and fifth digits. Sensory symptoms may be aggravated at night or by prolonged use of the extremities. Weakness and muscle atrophy are the principal motor abnormalities. Vascular symptoms consist of arterial ischemia characterized by pallor of the fingers on elevation of the extremity, sensitivity to cold, and, rarely, gangrene of the digits or venous obstruction marked by edema, cyanosis, and engorgement.

The symptoms of thoracic outlet syndromes can be provoked within 60 seconds over 90% of the time by having a patient elevate the arms in a “stick-em-up” position (ie, abducted 90 degrees in external rotation). Reflexes are usually not altered. Obliteration of the radial pulse with certain maneuvers of the arm or neck, once considered a highly sensitive sign of thoracic outlet obstruction, does not occur in most cases.

Chest radiography will identify patients with cervical rib (although most patients with cervical ribs are asymptomatic). MRI with the arms held in different positions is useful in identifying sites of impaired blood flow. Intraarterial or venous obstruction is confirmed by angiography. Determination of conduction velocities of the ulnar and other peripheral nerves of the upper extremity may help localize the site of their compression.

Thoracic outlet syndrome must be differentiated from osteoarthritis of the cervical spine, tumors of the superior pulmonary sulcus, cervical spinal cord, or nerve roots, and periarthritis of the shoulder.

Treatment is directed toward relief of compression of the neurovascular bundle. Greater than 95% of patients can be treated successfully with conservative therapy consisting of physical therapy and avoiding postures or activities that compress the neurovascular bundle. Some women will benefit from a support bra. Operative treatment, required by < 5% of patients, is more likely to relieve the neurologic rather than the vascular component that causes symptoms.

Brooke BS et al. Contemporary management of thoracic outlet syndrome. Curr Opin Cardiol. 2010 Nov;25(6):535–40. [PMID: 20838336] Fugate MW et al. Current management of thoracic outlet syndrome. Curr Treat Options Cardiovasc Med. 2009 Apr;11(2): 176–83. [PMID: 19289030] Povlsen B et al. Treatment for thoracic outlet syndrome.

Cochrane Database Syst Rev. 2010 Jan 20;(1):CD007218.

[PMID: 20091624]

LOW BACK PAIN Up to 80% of the population experience low back pain at some time. The differential diagnosis is broad and includes muscular strain, primary spine disease (eg, disk herniation, degenerative arthritis), systemic diseases (eg, metastatic cancer), and regional diseases (eg, aortic aneurysm). A

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precise diagnosis cannot be made in the majority of cases.

Even when anatomic defects—such as vertebral osteophytes or a narrowed disk space—are present, causality cannot be assumed since such defects are common in asymptomatic patients. Most patients with acute onset of low back pain will improve in 1–4 weeks and need no evaluation beyond the initial history and physical examination. The diagnostic challenge is to identify those patients who require more extensive or urgent evaluation. In practice, this means identifying those patients with pain caused by (1) infection, (2) cancer, (3) inflammatory back disease such as ankylosing spondylitis, or (4) pain referred from abdominal or pelvic processes, such as an expanding aortic aneurysm. Significant or progressive neurologic deficits also require identification. If there is no evidence of these problems, conservative therapy is called for.

1. Clinical Approach to Diagnosis ``General History & Physical Examination Low back pain is a final common pathway of many processes; the pain of vertebral osteomyelitis, for example, is not very different in quality and intensity from that due to back strain of the weekend gardener. Historical factors of importance include smoking, weight loss, age over 50, and cancer, all of which are risk factors for vertebral body metastasis. Osteomyelitis most frequently occurs in adults with a history of recurrent urinary tract infections and is especially common in diabetics and injection drug users. A history of a cardiac murmur should raise concern about endocarditis, since back pain is not an uncommon manifestation. A background of renal calculi might indicate another cause of referred back pain.

``History of Back Pain Certain qualities of a patient’s pain can indicate a specific diagnosis. Low back pain radiating down the buttock and below the knee suggests a herniated disk causing nerve root irritation. Other conditions—including sacroiliitis, facet joint degenerative arthritis, spinal stenosis, or irritation of the sciatic nerve from a wallet—also cause this pattern.

The diagnosis of disk herniation is further suggested by physical examination (see below) and confirmed by imaging techniques. Disk herniation can be asymptomatic, so its presence does not invariably link it to the symptom.

Low back pain at night, unrelieved by rest or the supine position, suggests the possibility of malignancy, either vertebral body metastasis (chiefly from prostate, breast, lung, multiple myeloma, or lymphoma) or a cauda equina tumor. Similar pain can also be caused by compression fractures (from osteoporosis or myeloma).

Symptoms of large or rapidly evolving neurologic deficits identify patients who need urgent evaluation for possible cauda equina tumor, epidural abscess or, rarely, massive disk herniation. When a herniated disk impinges a nerve root, pain is the most prominent symptom; numbness and weakness are less common and, when present, are of the magnitude consistent with compression of a single

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nerve root. Symptoms of bilateral leg weakness (from multiple lumbar nerve root compressions) or of saddle area anesthesia, bowel or bladder incontinence, or impotence (indicating multiple sacral nerve root compressions) indicate a cauda equina process.

Low back pain that worsens with rest and improves with activity is characteristic of ankylosing spondylitis or other seronegative spondyloarthropathies, especially when the onset is insidious and begins before age 40. Most degenerative back diseases produce precisely the opposite pattern, with rest alleviating and activity aggravating the pain. Low back pain causing the patient to writhe occurs in renal colic but can also indicate a leaking aneurysm. The pain associated with pseudoclaudication from lumbar spinal stenosis is discussed below.

``Physical Examination of the Back Several physical findings should be sought because they help identify those few patients who need more than conservative management.

Neurologic examination of the lower extremities will detect the small deficits produced by disk disease and the large deficits complicating such problems as cauda equina tumors. A positive straight leg raising test indicates nerve root irritation. The examiner performs the test on the supine patient by passively raising the patient’s ipsilateral leg. The test is positive if radicular pain is produced with the leg raised 60 degrees or less. It has a specificity of 40% but is 95% sensitive in patients with herniation at the L4–5 or L5–S1 level (the sites of 95% of disk herniations). It can be falsely negative, especially in patients with herniation above the L4–5 level. The crossed straight leg sign is positive when raising the contralateral leg reproduces the sciatica. It has a sensitivity of 25% but is 90% specific for disk herniation.

Detailed examination of the sacral and lumbar nerve roots, especially L5 and S1, is essential for detecting neurologic deficits associated with back pain. Disk herniation produces deficits predictable for the site involved (Table 20–6).

Deficits of multiple nerve roots suggest a cauda equina tumor or an epidural abscess, both requiring urgent evaluation and treatment.

Measurement of spinal motion in the patient with acute pain is rarely of diagnostic utility and usually simply confirms that pain limits motion. An exception is the decreased range of motion in multiple regions of the spine (cervical, thoracic, and lumbar) in a diffuse spinal disease such as

Table 20–6. Neurologic testing of lumbosacral nerve disorders.

Nerve Root

Motor

Reflex

Sensory Area

L4

Dorsiflexion of foot

Knee jerk

Medial calf

L5

Dorsiflexion of great toe

None

Medial forefoot

S1

Plantar flexion of foot

Ankle jerk

Lateral foot

ankylosing spondylitis. By the time the patient has such limits, however, the diagnosis is usually straightforward.

If back pain is not severe and does not itself limit motion, the modified Schober test of lumbar motion is helpful in early diagnosis of ankylosing spondylitis. To perform this test, two marks are made with the patient upright: one 10 cm above the sacral dimples and another 5 cm below. The patient then bends forward as far as possible, and the distance between the points is measured. Normally, the distance increases from 15 cm to at least 20 cm. Anything less indicates reduced lumbar motion.

Palpation of the spine usually does not yield diagnostic information. Point tenderness over a vertebral body is reported to suggest osteomyelitis, but this association is uncommon. A step-off noted between the spinous process of adjacent vertebral bodies may indicate spondylolisthesis, but the sensitivity of this finding is extremely low. Tenderness of the soft tissues overlying the greater trochanter of the hip is a manifestation of trochanteric bursitis.

Inspection of the spine is not often of value in identifying serious causes of low back pain. The classic posture of ankylosing spondylitis is a late finding. Scoliosis of mild degree is not associated with an increased risk of clinical back disease. Cutaneous neurofibromas can identify the rare patient with nerve root encasement.

Examination of the hips should be part of the complete examination. While hip arthritis usually produces pain chiefly in the groin area, some patients have buttock or low back symptoms.

``Further Examination If the history and physical examination do not suggest the presence of infection, cancer, inflammatory back disease, major neurologic deficits, or pain referred from abdominal or pelvic disease, further evaluation can be deferred while conservative therapy is tried. The great majority of patients will improve with conservative care over 1–4 weeks.

Regular radiographs of the lumbosacral spine give 20 times the radiation dose of a chest radiograph and provide limited, albeit important, information. Oblique films double the radiation dose and are not routinely needed.

Radiographs can provide evidence of vertebral body osteomyelitis, cancer, fractures, or ankylosing spondylitis.

Degenerative changes in the lumbar spine are ubiquitous in patients over 40 and do not prove clinical disease. Plain radiographs have very low sensitivity or specificity for disk disease. Thus, plain radiographs are warranted promptly for patients suspected of having infection, cancer, or fractures; selected other patients who do not improve after 2–4 weeks of conservative therapy are also candidates. The Agency for Healthcare Research and Quality guidelines for obtaining lumbar radiographs are summarized in Table 20–7.

MRI provides exquisite anatomic detail but is reserved for patients who are considering surgery or have evidence of a systemic disease. For example, MRI is needed urgently for any patient in whom an epidural mass or cauda equina tumor is suspected but not for a patient believed to have a routine disk herniation, since most will improve over 4–6 weeks of conservative therapy. Noncontrast CT does not

Musculoskeletal & Immunologic Disorders

Table 20–7. AHRQ criteria for lumbar radiographs in patients with acute low back pain.

Possible fracture Major trauma Minor trauma in patients > 50 years Long-term corticosteroid use Osteoporosis > 70 years Possible tumor or infection > 50 years < 20 years History of cancer Constitutional symptoms Recent bacterial infection Injection drug use Immunosuppression Supine pain Nocturnal pain AHRQ, Agency for Healthcare Research and Quality.

Reproduced, with permission, from Suarez-Almazor et al. Use of lumbar radiographs for the early diagnosis of low back pain.

Proposed guidelines would increase utilization. JAMA. 1997 Jun; 277:1782–6.

image cauda equina tumors or other intradural lesions, and if used instead of MRI it must include intrathecal contrast.

Radionuclide bone scanning has limited usefulness. It is most useful for early detection of vertebral body osteomyelitis or osteoblastic metastases. The bone scan is normal in multiple myeloma because lytic lesions do not take up isotope.

2. Management While any management plan must be individualized, key elements of most conservative treatments for back pain include analgesia and education. Analgesia can usually be provided with NSAIDs (see Table 5–3), but severe pain may require opioids (see Table 5–4). Rarely does the need for opioids extend beyond 1–2 weeks.

Diazepam, cyclobenzaprine, carisoprodol, and methocarbamol have been prescribed as muscle relaxants, though their sedative effects may limit their use. They should be reserved for patients who do not respond to NSAIDs and usually are needed only for 1–2 weeks, which reduces the chance of dependence. Their use should be avoided in older patients, who are at risk for falling. All patients should be taught how to protect the back in daily activities—ie, not to lift heavy objects, to use the legs rather than the back when lifting, to use a chair with arm rests, and to rise from bed by first rolling to one side and then using the arms to push to an upright position. Back manipulation for benign, mechanical low back pain appears safe and as effective as therapies provided by clinicians.

Rest and back exercises, once thought to be cornerstones of conservative therapy, are now known to be ineffective for acute back pain. Advice to rest in bed is less effective than advice to remain active. No bed rest with

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continuation of ordinary activities as tolerated is superior to 2 days of bed rest, 7 days of bed rest, and back mobilizing exercises. Similarly, for acute back pain, exercise therapy is not effective. The value of corsets or traction is dubious.

Epidural corticosteroid injections can provide short-term relief of sciatica but do not improve functional status or reduce the need for surgery. In double-blind studies, repeated injections have been no more effective than a single injection. For chronic low back pain, yoga is as effective as a back exercise program and more effective than a self-care book. Corticosteroid injections into facet joints are ineffective for chronic low back pain. Massage therapy is effective for treatment of chronic back pain, with benefits lasting at least 6 months.

Surgical consultation is needed urgently for any patient with a major or evolving neurologic deficit. Randomized controlled trials have shown that for sciatica caused by disk herniation, conservative treatment and surgery achieve similar 1-year outcomes; however, pain relief and perceived recovery were obtained more quickly with surgery. Surgery tends to ameliorate leg pain more quickly and fully than back pain.

Complaints without objective findings suggest a psychological role in symptom formation. Treatment includes reassurance and nonopioid analgesics.

``When to Refer • Suspected malignancy.

• Inflammatory low back pain.

``When to Admit • Neurologic signs indicative of cauda equina syndrome.

• Vertebral osteomyelitis.

Cherkin DC et al. A comparison of the effects of 2 types of massage and usual care on chronic low back pain: a randomized, controlled trial. Ann Intern Med. 2011 Jul 5;155(1):1–9.

[PMID: 21727288] Chou R et al; Clinical Guidelines Committee of the American College of Physicians. Diagnostic imaging for low back pain: advice for high-value health care from the American College of Physicians. Ann Intern Med. 2011 Feb 1;154(3):181–9.

[PMID: 21282698] Chou R et al. Nonsurgical interventional therapies for low back pain: a review of the evidence for an American Pain Society clinical practice guideline. Spine (Phila Pa 1976). 2009 May 1;34(10):1078–93. [PMID: 19363456] Chou R et al. Will this patient develop persistent disabling low back pain? JAMA. 2010 Apr 7;303(13):1295–302. [PMID: 20371789] Hildreth CJ et al. JAMA patient page. Sciatica. JAMA. 2009 Jul 8;302(2):216. [PMID: 19584353] Weinstein JN et al. Surgical compared with nonoperative treatment for lumbar degenerative spondylolisthesis: four-year results in the Spine Patient Outcomes Research Trial (SPORT) randomized and observational cohorts. J Bone Joint Surg Am. 2009 Jun;91(6):1295–304. [PMID: 19487505] Wilkens P et al. Effect of glucosamine on pain-related disability in patients with chronic low back pain and degenerative lumbar osteoarthritis: a randomized controlled trial. JAMA. 2010 Jul 7;304(1):45–52. [PMID: 20606148]

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LUMBAR SPINAL STENOSIS ``

E s s en t ia l S o f dia g n o s i s

Most patients are older than 60 years.

Presenting symptom is often back pain radiating to the buttocks and thighs.

Pain often interferes with walking, worsens with lumbar extension, and improves with lumbar flexion.

Back and leg pain often associated with numbness and paresthesias.

Preservation of pedal pulses helps exclude vascular claudication.

Diagnosis best confirmed by MRI.

`` ``

``

``

``

``

``Differential Diagnosis The onset of symptoms with standing, the location of the maximal discomfort to the thighs, and the preservation of pedal pulses help distinguish the “pseudoclaudication” of spinal stenosis from true claudication caused by vascular insufficiency. Distinguishing spinal stenosis from disk herniation can be challenging since both conditions can produce pain radiating down the back of the leg. Features that favor spinal stenosis are the gradual onset of symptoms, the marked exacerbation with walking, and the amelioration of symptoms with sitting or lumbar flexion. Complaints of bilateral aching in the buttocks associated with stiffness may make some practitioners consider the diagnosis of polymyalgia rheumatica. However, patients with lumbar spinal stenosis do not have the shoulder or neck symptoms characteristic of polymyalgia rheumatica.

``Treatment ``General Considerations Lumbar spinal stenosis, defined as narrowing of the spinal canal with compression of the nerve roots, may be congenital or (more commonly) acquired. It most frequently results from enlarging osteophytes at the facet joints, hypertrophy of the ligamentum flavum, and protrusion or bulging of intervertebral disks. Lumbar spinal stenosis may produce symptoms by directly compressing nerve roots or by compressing nutrient arterioles that supply the nerve roots.

``Clinical Findings A. Symptoms and Signs Most patients with lumbar spinal stenosis are over 60 years old and complain of either leg pain or trouble walking. The pain may originate in the low back but will extend below the buttock into the thigh in nearly 90% of patients. In approximately 50% of patients, the pain will extend below the knee.

The pain is often a combination of aching and numbness, which characteristically worsens with walking. The pain can also be brought on by prolonged standing. Not infrequently the symptoms are bilateral. Many patients are more troubled by poor balance, unsteadiness of gait, or leg weakness that develops as they walk. Some describe these neuroclaudication symptoms as developing “spaghetti legs” or “walking like a drunk sailor.” Because the lumbar spinal canal volume increases with back flexion and decreases with extension, some patients observe that they have fewer symptoms walking uphill than down. The back and lower extremity examination in patients with lumbar spinal stenosis is often unimpressive. Less than 10% have a positive straight leg raise sign, 25% have diminished deep tendon reflexes, and 60% have slight proximal weakness. Walking with the patient may reveal unsteadiness, although usually the patient’s perception of gait disturbance is greater than that of an observer.

B. Imaging The diagnosis of spinal stenosis in a patient with symptoms is best confirmed by MRI.

Weight loss and exercises aimed at reducing lumbar lordosis, which aggravates symptoms of spinal stenosis, can help.

Lumbar epidural corticosteroid injections provide some immediate relief for about 50% of patients and more sustained relief for approximately 25%. When disabling symptoms persist, surgery will reduce pain and improve function substantially in approximately 75% of patients at 1 and 2 years; only about 25% of patients treated conservatively will experience a similar improvement.

Genevay S et al. Lumbar spinal stenosis. Best Pract Res Clin Rheumatol. 2010 Apr;24(2):253–65. [PMID: 20227646] Tran de QH et al. Lumbar spinal stenosis: a brief review of the nonsurgical management. Can J Anaesth. 2010 Jul;57(7): 694–703. [PMID: 20428988] Weinstein JN et al. Surgical compared with nonoperative treatment for lumbar degenerative spondylolisthesis: four-year results in the Spine Patient Outcomes Research Trial (SPORT) randomized and observational cohorts. J Bone Joint Surg Am. 2009 Jun;91(6):1295–304. [PMID: 19487505]

FIBROMYALGIA ``

E s s en t ia l S o f dia g n o s i s

Most frequent in women aged 20–50.

Chronic widespread musculoskeletal pain syndrome with multiple tender points.

Fatigue, headaches, numbness common.

Objective signs of inflammation absent; laboratory studies normal.

`` ``

`` ``

``General Considerations Fibromyalgia is one of the most common rheumatic syndromes in ambulatory general medicine affecting 3–10% of the general population. It shares many features with the chronic fatigue syndrome, namely, an increased frequency

Musculoskeletal & Immunologic Disorders among women aged 20–50, absence of objective findings, and absence of diagnostic laboratory test results. While many of the clinical features of the two conditions overlap, musculoskeletal pain predominates in fibromyalgia whereas lassitude dominates the chronic fatigue syndrome.

The cause is unknown, but aberrant perception of painful stimuli, sleep disorders, depression, and viral infections have all been proposed. Fibromyalgia can be a rare complication of hypothyroidism, rheumatoid arthritis or, in men, sleep apnea.

``Clinical Findings The patient complains of chronic aching pain and stiffness, frequently involving the entire body but with prominence of pain around the neck, shoulders, low back, and hips.

Fatigue, sleep disorders, subjective numbness, chronic headaches, and irritable bowel symptoms are common.

Even minor exertion aggravates pain and increases fatigue.

Physical examination is normal except for “trigger points” of pain produced by palpation of various areas such as the trapezius, the medial fat pad of the knee, and the lateral epicondyle of the elbow.

``Differential Diagnosis Fibromyalgia is a diagnosis of exclusion. A detailed history and repeated physical examination can obviate the need for extensive laboratory testing. Rheumatoid arthritis and systemic lupus erythematosus (SLE) present with objective physical findings or abnormalities on routine testing.

Thyroid function tests are useful, since hypothyroidism can produce a secondary fibromyalgia syndrome. Polymyositis produces weakness rather than pain. The diagnosis of fibromyalgia probably should be made hesitantly in a patient over age 50 and should never be invoked to explain fever, weight loss, or any other objective signs. Polymyalgia rheumatica produces shoulder and pelvic girdle pain, is associated with anemia and an elevated ESR, and occurs after age 50.

Hypophosphatemic states, such as oncogenic osteomalacia, should also be included in the differential diagnosis of musculoskeletal pain unassociated with physical findings. In contrast to fibromyalgia, oncogenic osteomalacia usually produces pain in only a few areas and is associated with a low serum phosphate level.

``Treatment A multidisciplinary approach is most effective. Patient education is essential. Patients can be comforted that they have a diagnosable syndrome treatable by specific though imperfect therapies and that the course is not progressive. Cognitive behavioral therapy, including programs that emphasize mindfulness meditation is often helpful. There is modest efficacy of amitriptyline, fluoxetine, duloxetine, milnacipran, chlorpromazine, cyclobenzaprine, pregabalin, or gabapentin. Amitriptyline is initiated at a dosage of 10 mg orally at bedtime and gradually increased to 40–50 mg depending on efficacy and toxicity. Less than 50% of the patients experience a sustained improvement. Exercise programs are also beneficial. NSAIDs are generally ineffective. Tramadol and

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acetaminophen combinations have ameliorated symptoms modestly in short-term trials. Opioids and corticosteroids are ineffective and should not be used to treat fibromyalgia.

Acupuncture is also ineffective.

``Prognosis All patients have chronic symptoms. With treatment, however, many do eventually resume increased activities. Progressive or objective findings do not develop.

Arnold LM et al. Flexible dosed duloxetine in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled trial. J Rheumatol. 2010 Dec;37(12):2578–86. [PMID: 20843911] Häuser W et al. Efficacy of multicomponent treatment in fibromyalgia syndrome: a meta-analysis of randomized controlled clinical trials. Arthritis Rheum. 2009 Feb 15;61(2):216–24.

[PMID: 19177530] Moore RA et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD007938. [PMID: 21412914] van Koulil S et al. Tailored cognitive-behavioral therapy and exercise training for high-risk patients with fibromyalgia.

Arthritis Care Res (Hoboken). 2010 Oct;62(10):1377–85.

[PMID: 20521308]

CARPAL TUNNEL SYNDROME ``

E s s en t ia l S o f dia g n o s i s

Begins as pain, burning, and tingling in the distribution of the median nerve.

Symptoms initially most bothersome at night.

Weakness or atrophy, especially of the thenar eminence, appears later.

Common in occupations that require repetitive wrist motion and in pregnancy, diabetes, and rheumatoid arthritis.

``

`` ``

``

``General Considerations An entrapment neuropathy, carpal tunnel syndrome is a painful disorder caused by compression of the median nerve between the carpal ligament and other structures within the carpal tunnel. The contents of the tunnel can be compressed by synovitis of the tendon sheaths or carpal joints, recent or malhealed fractures, tumors, and occasionally congenital anomalies. Even though no anatomic lesion is apparent, flattening or even circumferential constriction of the median nerve may be observed during operative section of the ligament. The disorder may occur in pregnancy, is seen in individuals with a history of repetitive use of the hands, and may follow injuries of the wrists. There is a familial type of carpal tunnel syndrome in which no etiologic factor can be identified.

Carpal tunnel syndrome can also be a feature of many systemic diseases: rheumatoid arthritis and other rheumatic disorders (inflammatory tenosynovitis); myxedema,

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localized amyloidosis in chronic kidney disease, sarcoidosis, and leukemia (tissue infiltration); acromegaly; and hyperparathyroidism.

``Clinical Findings The initial symptoms are pain, burning, and tingling in the distribution of the median nerve (the palmar surfaces of the thumb, the index and long fingers, and the radial half of the ring finger). Aching pain may radiate proximally into the forearm and occasionally proximally to the shoulder and over the neck and chest. Pain is exacerbated by manual activity, particularly by extremes of volar flexion or dorsiflexion of the wrist. It is most bothersome at night.

Impairment of sensation in the median nerve distribution may or may not be demonstrable. Subtle disparity between the affected and opposite sides can be shown by testing for two-point discrimination or by requiring the patient to identify different textures of cloth by rubbing them between the tips of the thumb and the index finger. Tinel or Phalen sign may be positive. (Tinel sign is tingling or shock-like pain elicited by tapping the volar surface of the wrist; Phalen sign is pain or paresthesia in the distribution of the median nerve when the patient flexes both wrists to 90 degrees for 60 seconds.) The carpal compression test, in which numbness and tingling are induced by the direct application of pressure over the carpal tunnel, may be more sensitive and specific than the Tinel and Phalen tests.

Muscle weakness or atrophy, especially of the thenar eminence, appears later than sensory disturbances. Specific examinations include electromyography and determinations of segmental sensory and motor conduction delay.

Sensory conduction delay is evident before motor delay.

``Differential Diagnosis This syndrome should be differentiated from other cervicobrachial pain syndromes, from compression syndromes of the median nerve in the forearm or arm, and from mononeuritis multiplex. When left-sided, it may be confused with angina pectoris.

``Treatment Treatment is directed toward relief of pressure on the median nerve. When a causative lesion is discovered, it is treated appropriately. Otherwise, patients in whom carpal tunnel syndrome is suspected should modify their hand activities and have the affected wrist splinted for 2–6 weeks.

NSAIDs can also be added. Patients should be referred to a specialist for injection of corticosteroid into the carpal tunnel or for operation when they do not improve or when thenar muscle atrophy or weakness develops. Muscle strength returns gradually, but complete recovery cannot be expected when atrophy is pronounced.

``When to Refer • Refer to a hand surgeon if symptoms persist despite the use of wrist splints.

• Refer to a hand surgeon if weakness or thenar atrophy develops.

Atroshi I et al. Incidence of physician-diagnosed carpal tunnel syndrome in the general population. Arch Intern Med. 2011 May 23;171(10):943–4. [PMID: 21606100] Huisstede BM et al. Carpal tunnel syndrome. Part I: effectiveness of nonsurgical treatments—a systematic review. Arch Phys Med Rehabil. 2010 Jul;91(7):981–1004. [PMID: 20599038] Huisstede BM et al. Carpal tunnel syndrome. Part II: effectiveness of surgical treatments—a systematic review. Arch Phys Med Rehabil. 2010 Jul;91(7):1005–24. [PMID: 20599039] Jarvik JG et al. Surgery versus non-surgical therapy for carpal tunnel syndrome: a randomised parallel-group trial. Lancet.

2009 Sep 26;374(9695):1074–81. [PMID: 19782873]

DUPUYTREN CONTRACTURE This relatively common disorder is characterized by hyperplasia of the palmar fascia and related structures, with nodule formation and contracture of the palmar fascia.

The cause is unknown, but the condition has a genetic predisposition and occurs primarily in white men over 50 years of age. The incidence is higher among alcoholic patients and those with chronic systemic disorders (especially cirrhosis). It is also associated with systemic fibrosing syndrome, which includes Peyronie disease, mediastinal and retroperitoneal fibrosis, and Riedel struma. The onset may be acute, but slowly progressive chronic disease is more common.

Dupuytren contracture manifests itself by nodular or cord-like thickening of one or both hands, with the fourth and fifth fingers most commonly affected. The patient may complain of tightness of the involved digits, with inability to satisfactorily extend the fingers, and on occasion there is tenderness. The resulting cosmetic problems may be unappealing, but in general the contracture is well tolerated since it exaggerates the normal position of function of the hand. Fasciitis involving other areas of the body may lead to plantar fibromatosis (10% of patients) or Peyronie disease (1–2%).

If the palmar nodule is growing rapidly, injections of triamcinolone or collagenase into the nodule may be of benefit. Surgical intervention is indicated in patients with significant flexion contractures, depending on the location, but recurrence is not uncommon.

Hurst LC et al; CORD I Study Group. Injectable collagenase clostridium histolyticum for Dupuytren’s contracture. N Engl J Med. 2009 Sep 3;361(10):968–79. [PMID: 19726771]

COMPLEX REGIONAL PAIN SYNDROME Complex regional pain syndrome (formerly called reflex sympathetic dystrophy) is a rare disorder of the extremities characterized by autonomic and vasomotor instability. The cardinal symptoms and signs are pain localized to an arm or leg, swelling of the involved extremity, disturbances of color and temperature in the affected limb, dystrophic changes in the overlying skin and nails, and limited range of motion. Strikingly, the findings are not limited to the distribution of a single peripheral nerve. Most cases are preceded by direct physical trauma, often of relatively

Musculoskeletal & Immunologic Disorders minor nature, to the soft tissues, bone, or nerve. Early mobilization after injury or surgery reduces the likelihood of developing the syndrome. Vitamin C, 500 mg/d orally, is effective in reducing the risk of complex regional pain syndrome following wrist fracture. Any extremity can be involved, but the syndrome most commonly occurs in the hand and is associated with ipsilateral restriction of shoulder motion (shoulder-hand syndrome). The syndrome proceeds through phases: pain, swelling, and skin color and temperature changes develop early and, if untreated, lead to atrophy and dystrophy. The swelling in complex regional pain syndrome is diffuse (“catcher’s mitt hand”) and not restricted to joints. Pain is often burning in quality, intense, and often greatly worsened by minimal stimuli such as light touch. The shoulder-hand variant of this disorder sometimes complicates myocardial infarction or injuries to the neck or shoulder. Complex regional pain syndrome may occur after a knee injury or after arthroscopic knee surgery. There are no systemic symptoms. In the early phases of the syndrome, bone scans are sensitive, showing diffuse increased uptake in the affected extremity.

Radiographs eventually reveal severe generalized osteopenia. In the posttraumatic variant, this is known as Sudeck atrophy. Symptoms and findings are bilateral in some. This syndrome should be differentiated from other cervicobrachial pain syndromes, rheumatoid arthritis, thoracic outlet obstruction, and scleroderma, among others.

Early treatment offers the best prognosis for recovery.

For mild cases, NSAIDs (eg, naproxen 250–500 mg twice daily orally) can be effective. For more severe cases associated with edema, prednisone, 30–60 mg/d orally for 2 weeks and then tapered over 2 weeks, can be effective. Pain management is important and facilitates physical therapy, which plays a critical role in efforts to restore function.

Some patients will also benefit from antidepressant agents (eg, nortriptyline initiated at a dosage of 10 mg orally at bedtime and gradually increased to 40–75 mg at bedtime) or from anticonvulsants (eg, gabapentin 300 mg three times daily orally). Bisphosphonates, calcitonin, intravenous immunoglobulin, regional nerve blocks and dorsalcolumn stimulation have also been demonstrated to be helpful. Patients who have restricted shoulder motion may benefit from the treatment described for scapulohumeral periarthritis. The prognosis partly depends on the stage in which the lesions are encountered and the extent and severity of associated organic disease.

Bruehl S. An update on the pathophysiology of complex regional pain syndrome. Anesthesiology. 2010 Sep;113(3):713–25.

[PMID: 20693883] Goebel A et al. Intravenous immunoglobulin treatment of the complex regional pain syndrome: a randomized trial. Ann Intern Med. 2010 Feb 2;152(3):152–8. [PMID: 20124231]

BURSITIS Inflammation of bursae—the synovium-like cellular membranes overlying bony prominences—may be secondary to trauma, infection, or arthritic conditions such as gout, rheumatoid arthritis, or osteoarthritis. The most common

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s Figure 20–3. Aseptic olecranon bursitis secondary to repetitive trauma. (Courtesy of Richard P. Usatine, MD; used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)

locations are the subdeltoid, olecranon (Figure 20-3), ischial, trochanteric, semimembranous-gastrocnemius (Baker cyst), and prepatellar bursae.

There are several ways to distinguish bursitis from arthritis. Bursitis is more likely than arthritis to cause focal tenderness and swelling and less likely to affect range of motion of the adjacent joint. Olecranon bursitis, for example, causes an oval (or, if chronic, bulbous) swelling at the tip of the elbow and does not affect elbow motion, whereas an elbow joint inflammation produces more diffuse swelling and reduces range of motion. Similarly, a patient with prepatellar bursitis has a small focus of swelling over the kneecap but no distention of the knee joint itself and preserved knee motion. A patient with trochanteric bursitis will have tenderness over the greater trochanter and normal internal rotation of the hip; a patient with hip arthritis usually will have reduced internal rotation. Bursitis caused by trauma responds to local heat, rest, NSAIDs, and local corticosteroid injections.

Bursitis can result from infection. The two most common sites are the olecranon and prepatellar bursae. Acute swelling and redness at either of these two sites calls for aspiration to rule out infection. The absence of fever does not exclude infection; one-third of those with septic olecranon bursitis are afebrile. A bursal fluid white blood cell count of > 1000/mcL indicates inflammation from infection, rheumatoid arthritis, or gout. In septic bursitis, the white cell count averages over 50,000/mcL. Most cases are caused by Staphylococcus aureus; the Gram stain is positive in two-thirds. Treatment involves antibiotics and aspiration for tense effusions.

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Chronic, stable olecranon bursa swelling usually does not require aspiration. Aspiration of the olecranon bursa runs the risk of creating a chronic drainage site, which can be reduced by using a “zig-zag” approach with a small needle (25-gauge if possible) and pulling the skin over the bursa before introducing it. Applying a pressure bandage may also help prevent chronic drainage. Surgical removal of the bursa is indicated only for cases in which repeated infections occur. Repetitive minor trauma to the olecranon bursa should be eliminated by avoiding resting the elbow on a hard surface or by wearing an elbow pad.

A bursa can also become symptomatic when it ruptures.

This is particularly true for Baker cyst, whose rupture can cause calf pain and swelling that mimic thrombophlebitis.

Ruptured Baker cysts are imaged easily by sonography or MRI. In most cases, imaging is unnecessary because the cyst and an associated knee effusion are detectable on physical examination. It may be important to exclude a deep venous thrombosis, which can be mimicked by a ruptured Baker cyst. Treatment of a ruptured cyst includes rest, leg elevation, and injection of triamcinolone, 20–40 mg into the knee anteriorly (the knee compartment communicates with the cyst). Rarely, Baker cyst can compress vascular structures and cause leg edema and true thrombophlebitis.

Rowand M et al. Clinical inquiries. How should you treat trochanteric bursitis? J Fam Pract. 2009 Sep;58(9):494–500.

[PMID: 19744419]

cc

AUTOIMMUNE DISEASES

RHEUMATOID ARTHRITIS ``

arthritis can begin at any age, but the peak onset is in the fourth or fifth decade for women and the sixth to eighth decades for men. The cause is not known. Susceptibility to rheumatoid arthritis is genetically determined with multiple genes contributing. Inheritance of class II HLA molecules with a distinctive five-amino-acid sequence known as the “shared epitope” is the best characterized genetic risk factor. Untreated, rheumatoid arthritis causes joint destruction with consequent disability and shortens life expectancy. Early, aggressive treatment is the standard of care.

The pathologic findings in the joint include chronic synovitis with formation of a pannus, which erodes cartilage, bone, ligaments, and tendons. In the acute phase, effusion and other manifestations of inflammation are common. In the late stage, organization may result in fibrous ankylosis; true bony ankylosis is rare.

``Clinical Findings A. Symptoms and Signs 1. Joint symptoms—The clinical manifestations of rheumatoid disease are highly variable, but joint symptoms usually predominate. Although acute presentations may occur, the onset of articular signs of inflammation is usually insidious, with prodromal symptoms of vague periarticular pain or stiffness. Symmetric swelling of multiple joints with tenderness and pain is characteristic. Monarticular disease is occasionally seen initially. Stiffness persisting for > 30 minutes (and usually many hours) is prominent in the morning.

Stiffness may recur after daytime inactivity and be much more severe after strenuous activity. Although any diarthrodial joint may be affected, PIP joints of the fingers, MCP joints (Figure 20–4), wrists, knees, ankles, and MTP joints

E s s en t ia l S o f dia g n o s i s

Usually insidious onset with morning stiffness and pain in affected joints.

Symmetric polyarthritis with predilection for small joints of the hands and feet; deformities common with progressive disease.

Radiographic findings: juxta-articular osteoporosis, joint erosions, and joint space narrowing.

Rheumatoid factor and antibodies to cyclic citrullinated peptides (anti-CCP) are present in 70–80%.

Extra-articular manifestations: subcutaneous nodules, interstitial lung disease, pleural effusion, pericarditis, splenomegaly with leukopenia, and vasculitis.

``

``

``

``

``

``General Considerations Rheumatoid arthritis is a chronic systemic inflammatory disease whose major manifestation is synovitis of multiple joints. It has a prevalence of 1% and is more common in women than men (female:male ratio of 3:1). Rheumatoid

s Figure 20–4. Rheumatoid arthritis with ulnar deviation at the metacarpophalangeal (MCP) joints.

(Courtesy of Richard P. Usatine, MD; used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine.

McGraw-Hill, 2009.)

Musculoskeletal & Immunologic Disorders are most often involved. Synovial cysts and rupture of tendons may occur. Entrapment syndromes are not unusual— particularly of the median nerve at the carpal tunnel of the wrist. Rheumatoid arthritis can affect the neck but spares the other components of the spine and does not involve the sacroiliac joints. In advanced disease, atlantoaxial (C1–C2) subluxation can lead to myelopathy.

2. Rheumatoid nodules—Twenty percent of patients have subcutaneous rheumatoid nodules, most commonly situated over bony prominences but also observed in the bursae and tendon sheaths (Figure 20–5). Nodules are occasionally seen in the lungs, the sclerae, and other tissues.

Nodules correlate with the presence of rheumatoid factor in serum (“seropositivity”), as do most other extra-articular manifestations.

3. Ocular symptoms—Dryness of the eyes, mouth, and other mucous membranes is found especially in advanced disease (see Sjögren syndrome). Other ocular manifestations include episcleritis, scleritis, and scleromalacia due to scleral nodules.

4. Other symptoms—Interstitial lung disease is not uncommon (estimates of prevalence vary widely according to method of detection) and manifests clinically as cough and progressive dyspnea. Pericarditis and pleural disease, when present, are usually silent clinically. Patients with active joint disease often have palmar erythema.

Occasionally, a small vessel vasculitis develops and manifests as tiny hemorrhagic infarcts in the nail folds or finger pulps. Although necrotizing arteritis is well reported, it is

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rare. A small subset of patients with rheumatoid arthritis have Felty syndrome, the occurrence of splenomegaly and neutropenia, usually in the setting of severe, destructive arthritis. Felty syndrome must be distinguished from the large granular lymphocyte syndrome, with which it shares many features.

Aortitis is a rare late complication that can result in aortic regurgitation or rupture and is usually associated with evidence of rheumatoid vasculitis elsewhere in the body.

B. Laboratory Findings Anti-CCP antibodies and rheumatoid factor, an IgM antibody directed against the Fc fragment of IgG, are present in 70–80% of patients with established rheumatoid arthritis but have sensitivities of only 50% in early disease. AntiCCP antibodies are the most specific blood test for rheumatoid arthritis (specificity ~95%). Rheumatoid factor can occur in other autoimmune disease and in chronic infections, including hepatitis C, syphilis, subacute bacterial endocarditis, and tuberculosis. The prevalence of rheumatoid factor positivity also rises with age in healthy individuals. Approximately 20% of rheumatoid patients have antinuclear antibodies.

The ESR and levels of C-reactive protein are typically elevated in proportion to disease activity. A moderate hypochromic normocytic anemia is common. The white cell count is normal or slightly elevated, but leukopenia may occur, often in the presence of splenomegaly (eg, Felty syndrome). The platelet count is often elevated, roughly in proportion to the severity of overall joint inflammation.

Initial joint fluid examination confirms the inflammatory nature of the arthritis. (See Table 20–2.) Arthrocentesis is needed to diagnose superimposed septic arthritis, which is a common complication of rheumatoid arthritis and should be considered whenever a patient with rheumatoid arthritis has one joint inflamed out of proportion to the rest.

C. Imaging

s Figure 20–5. Rheumatoid nodules over the extensor surface of the forearm. (Courtesy of Richard P. Usatine, MD; used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)

Of all the laboratory tests, radiographic changes are the most specific for rheumatoid arthritis. Radiographs obtained during the first 6 months of symptoms, however, are usually normal. The earliest changes occur in the wrists or feet and consist of soft tissue swelling and juxta-articular demineralization. Later, diagnostic changes of uniform joint space narrowing and erosions develop. The erosions are often first evident at the ulnar styloid and at the juxtaarticular margin, where the bony surface is not protected by cartilage. Diagnostic changes also occur in the cervical spine, with C1–2 subluxation, but these changes usually take many years to develop. Although both MRI and ultrasonography are more sensitive than radiographs in detecting bony and soft tissue changes in rheumatoid arthritis, their value in early diagnosis relative to that of plain radiographs has not been established.

``Differential Diagnosis The differentiation of rheumatoid arthritis from other joint conditions and immune-mediated disorders can be difficult.

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In 2010, the American College of Rheumatology updated their classification criteria for rheumatoid arthritis. In contrast to rheumatoid arthritis, osteoarthritis spares the wrist and the MCP joints. Osteoarthritis is not associated with constitutional manifestations, and the joint pain is characteristically relieved by rest, unlike the morning stiffness of rheumatoid arthritis. Signs of articular inflammation, prominent in rheumatoid arthritis, are usually minimal in degenerative joint disease. CPPD deposition disease can cause a degenerative arthropathy of the MCPs and wrists; radiographs are usually diagnostic. Although gouty arthritis is almost always intermittent and monarticular in the early years, it may evolve with time into a chronic polyarticular process that mimics rheumatoid arthritis. Gouty tophi can resemble rheumatoid nodules both in typical location and appearance. The early history of intermittent monarthritis and the presence of synovial urate crystals are distinctive features of gout. Spondyloarthropathies, particularly earlier in their course, can be a source of diagnostic uncertainty; predilection for lower extremities and involvement of the spine and sacroiliac joints point to the correct diagnosis.

Chronic Lyme arthritis typically involves only one joint, most commonly the knee, and is associated with positive serologic tests (see Chapter 34). Human parvovirus B19 infection in adults can mimic early rheumatoid arthritis.

However, arthralgias are more prominent than arthritis, fever is common, IgM antibodies to parvovirus B19 are present, and the arthritis usually resolves within weeks. Infection with hepatitis C can cause a chronic nonerosive polyarthritis associated with rheumatoid factor; tests for anti-CCP antibodies are negative.

Malar rash, photosensitivity, discoid skin lesions, alopecia, high titer antibodies to double-stranded DNA, glomerulonephritis, and central nervous system abnormalities point to the diagnosis of SLE. Polymyalgia rheumatica occasionally causes polyarthralgias in patients over age 50, but these patients remain rheumatoid factorâ&#x20AC;&#x201C;negative and have chiefly proximal muscle pain and stiffness, centered on the shoulder and hip girdles. Rheumatic fever is characterized by the migratory nature of the arthritis, an elevated antistreptolysin titer, and a more dramatic and prompt response to aspirin; carditis and erythema marginatum may occur in adults, but chorea and subcutaneous nodules virtually never do. Finally, a variety of cancers produce paraneoplastic syndromes, including polyarthritis. One form is hypertrophic pulmonary osteoarthropathy most often produced by lung and gastrointestinal carcinomas, characterized by a rheumatoidlike arthritis associated with clubbing, periosteal new bone formation, and a negative rheumatoid factor. Diffuse swelling of the hands with palmar fasciitis occurs in a variety of cancers, especially ovarian carcinoma.

``Treatment The primary objectives in treating rheumatoid arthritis are reduction of inflammation and pain, preservation of function, and prevention of deformity. Success requires early, effective pharmacologic intervention. Disease-modifying antirheumatic drugs (DMARDs) should be started as soon as the diagnosis of rheumatoid disease is certain and then

adjusted with the aim of suppressing disease activity. The American College of Rheumatology recommends using standardized assessments, such as the Disease Activity Score 28 Joints (DAS28), to gauge therapeutic responses, with the target of mild disease activity or remission by these measures. In advanced disease, surgical intervention may help improve function of damaged joints and to relieve pain.

A. Nonsteroidal Anti-inflammatory Drugs NSAIDs provide some symptomatic relief in rheumatoid arthritis but do not prevent erosions or alter disease progression. They are not appropriate for monotherapy and should only be used in conjunction with DMARDs. A large number of NSAIDs are available; all appear equivalent in terms of efficacy (see Table 5â&#x20AC;&#x201C;3).

Celecoxib, a selective COX-2 inhibitor, is FDA-approved for the treatment of osteoarthritis and rheumatoid arthritis. Compared with traditional NSAIDs, COX-2 inhibitors are as effective for treating rheumatoid arthritis but less likely in some circumstances to cause upper gastrointestinal tract adverse events (eg, obstruction, perforation, hemorrhage, or ulceration). Long-term use of COX-2 inhibitors, particularly in the absence of concomitant aspirin use, has been associated with an increased risk of cardiovascular events, leading to the removal of some COX-2 inhibitors from the US market and intense scrutiny of all drugs in that class.

1. Gastrointestinal side effectsâ&#x20AC;&#x201D;For traditional NSAIDs that inhibit both COX-1 and COX-2, gastrointestinal side effects, such as gastric ulceration, perforation, and gastrointestinal hemorrhage, are the most common serious side effects. The overall rate of bleeding with NSAID use in the general population is low (1:6000 users or less) but is increased by long-term use, higher NSAID dose, concomitant corticosteroids or anticoagulants, the presence of rheumatoid arthritis, history of peptic ulcer disease or alcoholism, and age over 70. Twenty-five percent of all hospitalizations and deaths from peptic ulcer disease result from traditional NSAID therapy. Each year, 1:1000 patients with rheumatoid arthritis will require hospitalization for NSAID-related gastrointestinal bleeding or perforation.

Although all traditional NSAIDs can cause massive gastrointestinal bleeding, the risk may be higher with indomethacin and piroxicam, probably because these drugs preferentially inhibit COX-1 in the stomach.

One approach to reducing the gastrointestinal toxicity of traditional NSAIDs is to add a proton pump inhibitor (eg, omeprazole 20 mg orally daily). Sucralfate, antacids, and H2-blockers (such as ranitidine) either do not work or do not work as well as proton pump inhibitors. The expense of proton pump inhibitors and misoprostol dictates that their use should be reserved for patients with risk factors for NSAID-induced gastrointestinal toxicity (noted above). Patients who have recently recovered from an NSAID-induced bleeding gastric ulcer appear to be at high risk for rebleeding (about 5% in 6 months) when an NSAID is reintroduced, even if prophylactic measures such as proton pump inhibitors are used. NSAIDs can also affect

Musculoskeletal & Immunologic Disorders the lower intestinal tract, causing perforation or aggravating inflammatory bowel disease.

Acute liver injury from NSAIDs is rare, occurring in about 1 of every 25,000 patients using these agents. Having rheumatoid arthritis or taking sulindac may increase the risk.

2. Renal side effects—All of the NSAIDs, including aspirin and the COX-2 inhibitors, can produce renal toxicity, including interstitial nephritis, nephrotic syndrome, prerenal azotemia, and aggravation of hypertension.

Hyperkalemia due to hyporeninemic hypoaldosteronism may also be seen rarely. The risk of renal toxicity is low but is increased by age over 60, a history of kidney disease, congestive heart failure, ascites, and diuretic use. COX-2 inhibitors appear to cause as much nephrotoxicity as traditional NSAIDs. 3. Platelet effects—All NSAIDs except the nonacetylated salicylates and the COX-2 inhibitors interfere with platelet function and prolong bleeding time. For all older NSAIDs except aspirin, the effect on bleeding time resolves as the drug is cleared. Aspirin irreversibly inhibits platelet function, so the bleeding time effect resolves only as new platelets are made. Concomitant administration of a traditional NSAID can interfere with the ability of aspirin to acetylate platelets and thus may interfere with the cardioprotective effects of low-dose aspirin. COX-2 inhibitors, which differ from other NSAIDs in not inhibiting platelet function, do not increase the risk of bleeding with surgical procedures as most NSAIDs do. Unfortunately, this failure to inhibit platelets is now known to lead to increased risks of myocardial infarction and stroke, particularly when the medications are used in high doses for prolonged periods of time.

Patients requiring low-dose aspirin who are not compliant have a greater risk of developing a thrombotic event while taking a COX-2 inhibitor than while taking a traditional NSAID. Whether combination therapy with low-dose aspirin and a COX-2 inhibitor maintains the gastrointestinal advantage of selective COX-2 inhibitors is not yet known.

Although groups of patients with rheumatoid arthritis respond similarly to NSAIDs, individuals may respond differently—an NSAID that works for one patient may not work for another. Thus, if the first NSAID chosen is not effective after 2–3 weeks of use, another should be tried.

B. Corticosteroids Low-dose corticosteroids (eg, oral prednisone 5–10 mg daily) produce a prompt anti-inflammatory effect in rheumatoid arthritis and slow the rate of articular erosion. However, their multiple side effects limit their longterm use.

Low-dose corticosteroids often are used as a “bridge” to reduce disease activity until the slower acting DMARDs take effect or as adjunctive therapy for active disease that persists despite treatment with DMARDs. No more than 10 mg of prednisone or equivalent per day is appropriate for articular disease. Many patients do reasonably well on 5–7.5 mg daily. (The use of 1 mg tablets, to facilitate doses of < 5 mg/d, is encouraged.) Higher doses are used to manage serious extra-articular manifestations (eg, pericarditis,

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necrotizing scleritis). When the corticosteroids are to be discontinued, they should be tapered gradually on a planned schedule appropriate to the duration of treatment.

All patients receiving long-term corticosteroid therapy should take measures to prevent osteoporosis.

Intra-articular corticosteroids may be helpful if one or two joints are the chief source of difficulty. Intra-articular triamcinolone, 10–40 mg depending on the size of the joint to be injected, may be given for symptomatic relief but not more than four times a year.

C. Synthetic DMARDs 1. Methotrexate—Methotrexate is usually the initial synthetic DMARD of choice for patients with rheumatoid arthritis. It is generally well tolerated and often produces a beneficial effect in 2–6 weeks. The usual initial dose is 7.5 mg of methotrexate orally once weekly. If the patient has tolerated methotrexate but has not responded in 1 month, the dose can be increased to 15 mg orally once per week.

The maximal dose is usually 20–25 mg/wk. The most frequent side effects are gastric irritation and stomatitis.

Cytopenia, most commonly leukopenia or thrombocytopenia but rarely pancytopenia, due to bone marrow suppression is another important potential problem. The risk of developing pancytopenia is much higher in patients with elevation of the serum creatinine (≥ 2 mg/dL).

Hepatotoxicity with fibrosis and cirrhosis is an important toxic effect that correlates with cumulative dose and is uncommon with appropriate monitoring of liver function tests. Methotrexate is contraindicated in a patient with any form of chronic hepatitis. Heavy alcohol use increases the hepatotoxicity, so patients should be advised to drink alcohol in extreme moderation, if at all. Diabetes, obesity, and kidney disease also increase the risk of hepatotoxicity. Liver function tests should be monitored at least every 12 weeks, along with a complete blood count. The dose of methotrexate should be reduced if aminotransferase levels are elevated, and the drug should be discontinued if abnormalities persist despite dosage reduction. Gastric irritation, stomatitis, cytopenias, and hepatotoxicity are reduced by prescribing either daily folate (1 mg orally) or weekly leucovorin calcium (2.5–5 mg taken orally 24 hours after the dose of methotrexate). Hypersensitivity to methotrexate can cause an acute or subacute interstitial pneumonitis that can be life-threatening but which usually responds to cessation of the drug and institution of corticosteroids.

Because methotrexate is teratogenic, women of childbearing age as well as men must use effective contraception while taking the medication. Methotrexate is associated with an increased risk of B cell lymphomas, some of which resolve following the discontinuation of the medication.

The combination of methotrexate and other folate antagonists, such as trimethoprim-sulfamethoxazole, should be used cautiously, since pancytopenia can result. Probenecid should also be avoided since it increases methotrexate drug levels and toxicity.

2. Sulfasalazine—This drug is a second-line agent for rheumatoid arthritis. It is usually introduced at a dosage of 0.5 g orally twice daily and then increased each week by

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0.5 g until the patient improves or the daily dose reaches 3 g. Side effects, particularly neutropenia and thrombocytopenia, occur in 10–25% and are serious in 2–5%.

Sulfasalazine also causes hemolysis in patients with glucose-6phosphate dehydrogenase (G6PD) deficiency, so a G6PD level should be checked before initiating sulfasalazine.

Patients with aspirin sensitivity should not be given sulfasalazine. Patients taking sulfasalazine should have complete blood counts monitored every 2–4 weeks for the first 3 months, then every 3 months.

3. Leflunomide—Leflunomide, a pyrimidine synthesis inhibitor, is also FDA-approved for treatment of rheumatoid arthritis and is administered as a single oral daily dose of 20 mg. The most frequent side effects are diarrhea, rash, reversible alopecia, and hepatotoxicity. Some patients experience dramatic unexplained weight loss. The drug is carcinogenic, teratogenic, and has a half-life of 2 weeks.

Thus, it is contraindicated in premenopausal women or in men who wish to father children.

4. Antimalarials—Hydroxychloroquine sulfate is the antimalarial agent most often used against rheumatoid arthritis. Monotherapy with hydroxychloroquine should be reserved for patients with mild disease because only a small percentage will respond and in some of those cases only after 3–6 months of therapy. Hydroxychloroquine is often used in combination with other conventional DMARDs, particularly methotrexate and sulfasalazine. The advantage of hydroxychloroquine is its comparatively low toxicity, especially at a dosage of 200–400 mg/d orally (not to exceed 6.5 mg/kg/d). The most important reaction, pigmentary retinitis causing visual loss, is rare at this dose.

Ophthalmologic examinations every 12 months are required when this drug is used for long-term therapy.

Other reactions include neuropathies and myopathies of both skeletal and cardiac muscle, which usually improve when the drug is withdrawn.

5. Minocycline—Minocycline is more effective than placebo for rheumatoid arthritis. It is reserved for early, mild cases, since its efficacy is modest, and it works better during the first year of rheumatoid arthritis. The mechanism of action is not clear, but tetracyclines do have anti-inflammatory properties, including the ability to inhibit destructive enzymes such as collagenase. The dosage of minocycline is 200 mg orally daily. Adverse effects are uncommon except for dizziness, which occurs in about 10%.

D. Biologic DMARDs 1. Tumor necrosis factor inhibitors—Inhibitors of tumor necrosis factor (TNF)—a pro-inflammatory cytokine—are fulfilling the aim of targeted therapy for rheumatoid arthritis. These medications are frequently added to the treatment of patients who have not responded adequately to methotrexate and are increasingly used as initial therapy in combination with methotrexate for patients with poor prognostic factors.

Five inhibitors are in use: etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. Etanercept, a soluble recombinant TNF receptor:Fc fusion protein, is

usually administered at a dosage of 50 mg subcutaneously once per week. Infliximab, a chimeric monoclonal antibody, is administered at a dosage of 3–10 mg/kg intravenously; infusions are repeated after 2, 6, 10, and 14 weeks and then are administered every 8 weeks. Adalimumab, a human monoclonal antibody that binds to TNF, is given at a dosage of 40 mg subcutaneously every other week. The dose for golimumab, a human anti-TNF monoclonal antibody, is 50 mg subcutaneously once monthly. Certolizumab pegol is a PEGylated monoclonal antibody TNF inhibitor; the dose is 200–400 mg subcutaneously every 2 to 4 weeks.

Each drug produces substantial improvement in more than 60% of patients. Each is usually very well tolerated. Minor irritation at injection sites is the most common side effect of etanercept and adalimumab. Rarely, nonrecurrent leukopenia develops in patients. TNF plays a physiologic role in combating many types of infection; TNF inhibitors have been associated with a several-fold increased risk of serious bacterial infections and a striking increase in granulomatous infections, particularly reactivation of tuberculosis.

Screening for latent tuberculosis (see Chapter 9) is mandatory before the initiation of TNF blockers. It is prudent to suspend TNF blockers when a fever or other manifestations of a clinically important infection develops in a patient. Demyelinating neurologic complications that resemble multiple sclerosis have been reported rarely in patients taking etanercept, but the true magnitude of this risk—likely quite small—has not been determined with precision. While there are conflicting data with respect to increased risk of malignancy, in 2009, the FDA issued a safety alert about case reports of malignancies, including leukemias, in patients treated with TNF inhibitors. Contrary to expectation, TNF inhibitors were not effective in the treatment of congestive heart failure. The use of infliximab, in fact, was associated with increased morbidity in a congestive heart failure trial. Consequently, TNF inhibitors should be used with extreme caution in patients with congestive heart failure. Infliximab can rarely cause anaphylaxis and induce anti-DNA antibodies (but rarely clinically evident SLE). A final concern about TNF inhibitors is the expense, which is more than $10,000 per year.

2. Abatacept—Abatacept, a recombinant protein made by fusing a fragment of the Fc domain of human IgG with the extracellular domain of a T cell inhibitory receptor (CTLA4), blocks T-cell costimulation. It is approved by the FDA for use in rheumatoid arthritis and produces clinically meaningful responses in approximately 50% of individuals whose disease is active despite the combination of methotrexate and a TNF inhibitor.

3. Rituximab—Rituximab is a humanized mouse monoclonal antibody that depletes B cells. It is approved by the FDA to be used in combination with methotrexate for patients whose disease has been refractory to treatment with a TNF inhibitor.

4. Tocilizumab—Tocilizumab is a monoclonal antibody that blocks the receptor for IL-6, an inflammatory cytokine involved in the pathogenesis of rheumatoid arthritis. It also is approved by the FDA to be used in combination with

Musculoskeletal & Immunologic Disorders methotrexate for patients whose disease has been refractory to treatment with a TNF inhibitor.

E. DMARD Combinations As a general rule, DMARDs have greater efficacy when administered in combination than when used individually.

Currently, the most commonly used combination is that of methotrexate with one of the TNF inhibitors, which clearly is superior to methotrexate alone. The urge to use combination therapies with TNF inhibitors as the initial treatment for rheumatoid arthritis, however, has been tempered by concerns about their safety and cost. The American College of Rheumatology has published detailed recommendations on the initiation of DMARD combinations.

``Course & Prognosis After months or years, deformities may occur; the most common are ulnar deviation of the fingers, boutonnière deformity (hyperextension of the DIP joint with flexion of the PIP joint), “swan-neck” deformity (flexion of the DIP joint with extension of the PIP joint), valgus deformity of the knee, and volar subluxation of the MTP joints. The excess mortality associated with rheumatoid arthritis is largely due to cardiovascular disease that is unexplained by traditional risk factors and that appears to be a result of deleterious effects of chronic systemic inflammation on the vascular system.

``When to Refer Early referral to a rheumatologist is essential for appropriate diagnosis and the timely introduction of effective pharmacologic and nonpharmacologic (physical and occupational) therapy.

Aletaha D et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum.

2010 Sep;62(9):2569–81. [PMID: 20872595] Chan FK et al. Celecoxib versus omeprazole and diclofenac in patients with osteoarthritis and rheumatoid arthritis (CONDOR): a randomised trial. Lancet. 2010 Jul 17;376(9736): 173–9. Erratum in: Lancet. 2011 Jul 16;378(9787):228. [PMID: 20638563] Emery P et al; Combination of Methotrexate and Etanercept in Early Rheumatoid Arthritis Trial Group. Two-year clinical and radiographic results with combination etanercept-methotrexate therapy versus monotherapy in early rheumatoid arthritis: a two-year, double-blind, randomized study. Arthritis Rheum.

2010 Mar;62(3):674–82. Erratum in: Arthritis Rheum. 2010 Oct;62(10):3005. [PMID: 20187135] Huizinga TW et al. In the clinic. Rheumatoid arthritis. Ann Intern Med. 2010 Jul 6;153(1):ITC1–15. [PMID: 20621898] Klarenbeek NB et al. Discontinuing treatment in patients with rheumatoid arthritis in sustained clinical remission: exploratory analyses from the BeSt study. Ann Rheum Dis. 2011 Feb;70(2):315–9. [PMID: 21068104] van Vollenhoven RF et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet. 2009 Aug 8; 374(9688):459–66. [PMID: 19665644]

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ADULT STILL DISEASE Still disease is a systemic form of juvenile chronic arthritis in which high spiking fevers are much more prominent, especially at the outset, than arthritis. This syndrome also occurs in adults. Most adults are in their 20s or 30s; onset after age 60 is rare. The fever is dramatic, often with daily spikes to 40°C, associated with sweats and chills, and then plunging to normal or several degrees below normal in the absence of antipyretics. Many patients initially complain of sore throat. An evanescent salmon-colored nonpruritic rash, chiefly on the chest and abdomen, is a characteristic feature. The rash can easily be missed since it often appears only with the fever spike. Many patients also have lymphadenopathy and pericardial effusions. Joint symptoms are mild or absent in the beginning, but a destructive arthritis, especially of the wrists, may develop months later. Anemia and leukocytosis, with white blood counts sometimes exceeding 40,000/mcL, are the rule. Ferritin levels are exceptionally high (> 3000 mg/mL) in more than 70% of cases of adult Still disease—for reasons that are not clear. A low percentage (< 20%) of serum ferritin that is glycosylated may be even more specific for adult Still disease.

Although there must be exclusion of other causes of fever, the diagnosis of adult Still disease is strongly suggested by the fever pattern, sore throat, and the classic rash. About half of the patients respond to high-dose aspirin (eg, 1 g three times orally daily) or other NSAIDs, and half require prednisone, sometimes in doses > 60 mg/d orally. TNF inhibitors may be helpful for some patients with refractory adult Still disease, but most patients treated with these agents achieve only partial remissions. More complete and dramatic responses have been achieved with the IL-1 receptor antagonist anakinra.

Bagnari V et al. Adult-onset Still’s disease. Rheumatol Int. 2010 May;30(7):855–62. [PMID: 20020138]

SYSTEMIC LUPUS ERYTHEMATOSUS ``

Occurs mainly in young women.

Rash over areas exposed to sunlight.

Joint symptoms in 90% of patients. Multiple system involvement.

Anemia, leukopenia, thrombocytopenia.

Glomerulonephritis, central nervous system disease, and complications of antiphospholipid antibodies are major sources of disease morbidity.

Serologic findings: antinuclear antibodies (100%), anti–double-stranded DNA antibodies (approximately two-thirds), and low serum complement levels (particularly during disease flares).

`` `` ``

`` ``

``

E s s en t ia l S o f dia g n o s i s

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Chapter 20

``General Considerations SLE is an inflammatory autoimmune disorder characterized by autoantibodies to nuclear antigens. It can affect multiple organ systems. Many of its clinical manifestations are secondary to the trapping of antigen-antibody complexes in capillaries of visceral structures or to autoantibody-mediated destruction of host cells (eg, thrombocytopenia). The clinical course is marked by spontaneous remission and relapses. The severity may vary from a mild episodic disorder to a rapidly fulminant, life-threatening illness.

The incidence of SLE is influenced by many factors, including gender, race, and genetic inheritance. About 85% of patients are women. Sex hormones appear to play some role; most cases develop after menarche and before menopause. Among older individuals, the gender distribution is more equal. Race is also a factor, as SLE occurs in 1:1000 white women but in 1:250 black women.

Familial occurrence of SLE has been repeatedly documented, and the disorder is concordant in 25–70% of identical twins. If a mother has SLE, her daughters’ risks of developing the disease are 1:40 and her sons’ risks are 1:250. Aggregation of serologic abnormalities (positive antinuclear antibody) is seen in asymptomatic family members, and the prevalence of other rheumatic diseases is increased among close relatives of patients. The importance of specific genes in SLE is emphasized by the high frequency of certain HLA haplotypes, especially DR2 and DR3, and null complement alleles.

Before making a diagnosis of SLE, it is imperative to ascertain that the condition has not been induced by a drug (Table 20–8). Procainamide, hydralazine, and isoniazid are the best-studied drugs. While antinuclear antibody tests

Table 20–8. Drugs associated with lupus erythematosus.

Definite association Chlorpromazine Hydralazine Isoniazid Methyldopa

Minocycline Procainamide Quinidine

Possible association β-Blockers Captopril Carbamazepine Cimetidine Ethosuximide Levodopa Lithium Methimazole

Nitrofurantoin Penicillamine Phenytoin Propylthiouracil Sulfasalazine Sulfonamides Trimethadione

Unlikely association Allopurinol Chlorthalidone Gold salts Griseofulvin Methysergide Oral contraceptives

Penicillin Phenylbutazone Reserpine Streptomycin Tetracyclines

Modified and reproduced, with permission, from Hess EV et al.

Drug-related lupus. Bull Rheum Dis. 1991;40(4):1–8.

and other serologic findings become positive in many persons receiving these agents, clinical manifestations occur in only a few.

Four features of drug-induced lupus separate it from SLE: (1) the sex ratio is nearly equal; (2) nephritis and central nervous system features are not ordinarily present; (3) hypocomplementemia and antibodies to doublestranded DNA are absent; and (4) the clinical features and most laboratory abnormalities usually revert toward normal when the offending drug is withdrawn.

The diagnosis of SLE should be suspected in patients having a multisystem disease with a positive test for antinuclear antibodies. Differential diagnosis includes rheumatoid arthritis, systemic vasculitis, scleroderma, inflammatory myopathies, viral hepatitis, sarcoidosis, acute drug reactions, and drug-induced lupus.

The diagnosis of SLE can be made with reasonable probability if 4 of the 11 criteria set forth in Table 20–9 are met. These criteria, developed as guidelines for the inclusion of patients in research studies, do not supplant clinical judgment in the diagnosis of SLE.

``Clinical Findings A. Symptoms and Signs The systemic features include fever, anorexia, malaise, and weight loss. Most patients have skin lesions at some time;

Table 20–9. Criteria for the classification of SLE. (A patient is classified as having SLE if any 4 or more of 11 criteria are met.)

1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Arthritis 6. Serositis 7. Kidney disease a. > 0.5 g/d proteinuria, or b. ≥ 3+ dipstick proteinuria, or c. Cellular casts 8. Neurologic disease a. Seizures, or b. Psychosis (without other cause) 9. Hematologic disorders a. Hemolytic anemia, or b. Leukopenia (< 4000/mcL), or c. Lymphopenia (< 1500/mcL), or d. Thrombocytopenia (< 100,000/mcL) 10. Immunologic abnormalities a. Positive LE cell preparation, or b. Antibody to native DNA, or c. Antibody to Sm, or d. False-positive serologic test for syphilis 11. Positive ANA ANA, antinuclear antibody; SLE, systemic lupus erythematosus.

Modified and reproduced, with permission, from Tan EM et al.

The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982 Nov;25(11):1271–7.

Musculoskeletal & Immunologic Disorders the characteristic “butterfly” (malar) rash affects less than half of patients. Other cutaneous manifestations are, discoid lupus, typical fingertip lesions, periungual erythema, nail fold infarcts, and splinter hemorrhages. Alopecia is common. Mucous membrane lesions tend to occur during periods of exacerbation. Raynaud phenomenon, present in about 20% of patients, often antedates other features of the disease.

Joint symptoms, with or without active synovitis, occur in over 90% of patients and are often the earliest manifestation.

The arthritis can lead to reversible swanneck deformities, but erosive changes are almost never noted on radiographs.

Subcutaneous nodules are rare.

Ocular manifestations include conjunctivitis, photophobia, transient or permanent monocular blindness, and blurring of vision. Cotton-wool spots on the retina (cytoid bodies) represent degeneration of nerve fibers due to occlusion of retinal blood vessels.

Pleurisy, pleural effusion, bronchopneumonia, and pneumonitis are frequent. Restrictive lung disease can develop. Alveolar hemorrhage is rare but life-threatening.

The pericardium is affected in the majority of patients.

Cardiac failure may result from myocarditis and hypertension. Cardiac arrhythmias are common. Atypical verrucous endocarditis of Libman-Sacks is usually clinically silent but occasionally can produce acute or chronic valvular incompetence—most commonly mitral regurgitation.

Mesenteric vasculitis occasionally occurs in SLE and may closely resemble polyarteritis nodosa, including the presence of aneurysms in medium-sized blood vessels.

Abdominal pain (particularly postprandial), ileus, peritonitis, and perforation may result.

Neurologic complications of SLE include psychosis, cognitive impairment, seizures, peripheral and cranial neuropathies, transverse myelitis, and strokes. Severe depression and

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psychosis are sometimes exacerbated by the administration of large doses of corticosteroids.

Several forms of glomerulonephritis may occur, including mesangial, focal proliferative, diffuse proliferative, and membranous (see Chapter 22). Some patients may also have interstitial nephritis. With appropriate therapy, the survival rate even for patients with serious chronic kidney disease (proliferative glomerulonephritis) is favorable, albeit a substantial portion of patients with severe lupus nephritis still eventually require renal replacement therapy.

B. Laboratory Findings (Tables 20–10 and 20–11.) SLE is characterized by the production of many different autoantibodies. Antinuclear antibody tests based on immunofluorescence assays are sensitive but not specific for SLE—ie, they are positive in virtually all patients with lupus but are positive also in many patients with nonlupus conditions such as rheumatoid arthritis, autoimmune thyroid disease, scleroderma, and Sjögren syndrome. False-negative results can occur with tests for antinuclear antibodies based on enzymelinked immunosorbent assays (ELISA). Therefore, SLE should not be excluded on the basis of a negative ELISA for antinuclear antibodies. Antibodies to double-stranded DNA and to Sm are specific for SLE but not sensitive, since they are present in only 60% and 30% of patients, respectively. Depressed serum complement—a finding suggestive of disease activity—often returns toward normal in remission. Anti-double-stranded DNA antibody levels also correlate with disease activity in some patients; anti-Sm levels do not.

Three types of antiphospholipid antibodies occur (Table 20–11). The first causes the biologic false-positive tests for syphilis; the second is the lupus anticoagulant, which despite

Table 20–10. Frequency (%) of autoantibodies in rheumatic diseases.1 ANA

AntiNative DNA

Rheumatoid Factor

AntiSm

AntiSS-A

AntiSS-B

AntiSCL-70

AntiCentromere

AntiJo-1

ANCA

Rheumatoid arthritis

30–60

0–5

70

0

0–5

0–2

0

0

0

0

Systemic lupus erythematosus

95–100

60

20

10–25

15–20

5–20

0

0

0

0–1

Sjögren syndrome

95

0

75

0

65

65

0

0

0

0

Diffuse scleroderma

80–95

0

30

0

0

0

33

1

0

0

Limited scleroderma (CREST syndrome)

80–95

0

30

0

0

0

20

50

0

0

Polymyositis/ dermatomyositis

80–95

0

33

0

0

0

0

0

20–30

0

Granulomatosis with polyangiitis (formerly Wegener granulomatosis)

0–15

0

50

0

0

0

0

0

0

93–961

1 Frequency for generalized, active disease.

ANA, antinuclear antibodies; Anti-Sm, anti-Smith antibody; anti-SCL-70, anti-scleroderma antibody; ANCA, antineutrophil cytoplasmic antibody; CREST, calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia.

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Table 20–11. Frequency (%) of laboratory abnormalities in systemic lupus erythematosus.

Anemia

60%

Leukopenia

45%

Thrombocytopenia

30%

Biologic false-positive tests for syphilis

25%

Antiphospholipid antibodies Lupus anticoagulant

7%

Anti-cardiolipin antibody

25%

Direct Coombs-positive

30%

Proteinuria

30%

Hematuria

30%

Hypocomplementemia ANA

60% 95–100%

Anti-native DNA

50%

Anti-Sm

20%

ANA, antinuclear antibody; Anti-Sm, anti-Smith antibody.

Modified and reproduced, with permission, from Hochberg MC et al.

Systemic lupus erythematosus: a review of clinicolaboratory features and immunologic matches in 150 patients with emphasis on demographic subsets. Medicine (Baltimore). 1985 Sep;64(5):285–95.

its name is a risk factor for venous and arterial thrombosis and for miscarriage. The lupus anticoagulant often causes prolongation of the activated partial thromboplastin time, and its presence is confirmed by an abnormal Russell viper venom time (RVVT) that corrects with the addition of phospholipid but not normal plasma. Anticardiolipin antibodies are the third type of antiphospholipid antibodies. In many cases, the “antiphospholipid antibody” appears to be directed at a serum cofactor (β2-glycoprotein-I) rather than at phospholipid itself. Abnormality of urinary sediment is almost always found in association with renal lesions. Showers of red blood cells, with or without casts, and proteinuria (varying from mild to nephrotic range) are frequent during exacerbation of the disease.

``Treatment Patient education and emotional support, are especially important for patients with lupus. Since the various manifestations of SLE affect prognosis differently and since SLE activity often waxes and wanes, drug therapy—both the choice of agents and the intensity of their use—must be tailored to match disease severity. Patients with photosensitivity should be cautioned against sun exposure and should apply a protective lotion to the skin while out of doors. Skin lesions often respond to the local administration of corticosteroids. Minor joint symptoms can usually be alleviated by rest and NSAIDs. Antimalarials (hydroxychloroquine) may be helpful in treating lupus rashes or joint symptoms and appear to reduce the incidence of severe disease flares. The dose of

hydroxychloroquine is 200 or 400 mg/d orally and should not exceed 6.5 mg/kg/d; annual monitoring for retinal changes is recommended. Drug-induced neuropathy and myopathy may be erroneously ascribed to the underlying disease. The androgenic corticosteroid danazol may be effective therapy for thrombocytopenia not responsive to corticosteroids. Although dehydroepiandrosterone (DHEA) can improve a patient’s sense of well being, the drug is not used often because it has little to no impact on other measures of disease activity and frequently causes troubling side effects (particularly acne and hirsutism).

Corticosteroids are required for the control of certain complications. (Systemic corticosteroids are not usually given for minor arthritis, skin rash, leukopenia, or the anemia associated with chronic disease.) Glomerulonephritis, hemolytic anemia, pericarditis or myocarditis, alveolar hemorrhage, central nervous system involvement, and thrombotic thrombocytopenic purpura all require corticosteroid treatment and often other interventions as well.

Forty to 60 mg of oral prednisone is often needed initially; however, the lowest dose of corticosteroid that controls the condition should be used. Central nervous system lupus may require higher doses of corticosteroids than are usually given; however, corticosteroid psychosis may mimic lupus cerebritis, in which case reduced doses are appropriate. Immunosuppressive agents such as cyclophosphamide, mycophenolate mofetil, and azathioprine are used in cases resistant to corticosteroids. Treatment of severe lupus nephritis includes an induction phase and a maintenance phase. Cyclophosphamide, which improves renal survival but not patient survival, has been for many years the standard treatment for both phases of lupus nephritis.

Mycophenolate mofetil appears to be an effective alternative treatment for many patients with lupus nephritis. Very close follow-up is needed to watch for potential side effects when immunosuppressants are given; these agents should be administered by clinicians experienced in their use.

When cyclophosphamide is required, gonadotropin-releasing hormone analogs can be given to protect a woman against the risk of premature ovarian failure. Belimumab, a monoclonal antibody that inhibits the activity of a B cell growth factor, has received FDA approval for treating antibodypositive SLE patients with active disease who have not responded to standard therapies (eg, NSAIDs, antimalarials, or immunosuppressive therapies). However, the precise indications for its use have not been defined, and its efficacy in severe disease activity is unknown. Belimumab appears less effective in blacks. While observations studies suggested that rituximab was effective in SLE, one large randomized-controlled trial demonstrated it was no more effective than placebo. For patients with the antiphospholipid syndrome—the presence of antiphospholipid antibodies and compatible clinical events—anticoagulation is the treatment of choice (see Antiphospholipid Antibody Syndrome, below). Moderate intensive anticoagulation with warfarin to achieve an INR of 2.0–3.0 is as effective as more intensive regimens. Pregnant patients with recurrent fetal loss associated with antiphospholipid antibodies should be treated with low-molecular-weight heparin plus aspirin.

Musculoskeletal & Immunologic Disorders

``Course & Prognosis Ten-year survival rates exceeding 85% are routine. In most patients, the illness pursues a relapsing and remitting course. Prednisone, often needed in doses of 40 mg/d orally or more during severe flares, can usually be tapered to low doses (5–10 mg/d) when the disease is inactive. However, there are some in whom the disease pursues a virulent course, leading to serious impairment of vital structures such as lung, heart, brain, or kidneys, and the disease may lead to death. With improved control of lupus activity and with increasing use of corticosteroids and immunosuppressive drugs, the mortality and morbidity patterns in lupus have changed. Mortality in SLE shows a bimodal pattern. In the early years after diagnosis, infections—especially with opportunistic organisms—are the leading cause of death, followed by active SLE, chiefly due to kidney or central nervous system disease. In later years, accelerated atherosclerosis, linked to chronic inflammation, becomes a major cause of death. Indeed, the incidence of myocardial infarction is five times higher in persons with SLE than in the general population. Therefore, it is especially important for SLE patients to avoid smoking and to minimize other conventional risk factors for atherosclerosis (eg, hypercholesterolemia, hypertension, obesity, and inactivity). Patients with SLE should receive influenza vaccination every year and pneumococcal vaccination every 5 years. Since SLE patients have a higher risk of developing malignancy (especially lymphoma, lung cancer, and cervical cancer), preventive cancer screening recommendations should be followed assiduously. With more patients living longer, it has become evident that avascular necrosis of bone, affecting most commonly the hips and knees, is responsible for substantial morbidity. Nonetheless, the outlook for most patients with SLE has become increasingly favorable.

``When to Refer • Appropriate diagnosis and management of SLE requires the active participation of a rheumatologist.

• The severity of organ involvement dictates referral to other subspecialists, such as nephrologists and pulmonologists.

``When to Admit • Rapidly progressive glomerulonephritis, pulmonary hemorrhage, transverse myelitis, and other severe organthreatening manifestations of lupus usually require inpatient assessment and management.

• Severe infections, particularly in the setting of immunosuppressant therapy, should prompt admission.

Dooley MA et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011 Nov 17;365(20):1886–95. [PMID: 22087680] Haque S et al. Risk factors for clinical coronary heart disease in systemic lupus erythematosus: the lupus and atherosclerosis evaluation of risk (LASER) study. J Rheumatol. 2010 Feb; 37(2):322–9. [PMID: 19955047]

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Lateef A et al. Biologics in the treatment of systemic lupus erythematosus. Curr Opin Rheumatol. 2010 Sep;22(5):504–9.

[PMID: 20502332] Merrill JT et al. Efficacy and safety of rituximab in moderatelyto-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010 Jan; 62(1):222–33. [PMID: 20039413] Navarra SV et al; BLISS-52 Study Group. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet.

2011 Feb 26;377(9767):721–31. [PMID: 21296403] Petri M et al. High-dose cyclophosphamide versus monthly intravenous cyclophosphamide for systemic lupus erythematosus: a prospective randomized trial. Arthritis Rheum. 2010 May;62(5):1487–93. [PMID: 20131296]

ANTIPHOSPHOLIPID SYNDROME ``

E s s en t ia l S o f dia g n o s i s

Hypercoagulability, with recurrent thromboses in either the venous or arterial circulation.

Thrombocytopenia is common.

Pregnancy complications, specifically pregnancy losses after the first trimester.

Lifelong anticoagulation with warfarin is recommended currently for patients with serious complications of this syndrome because recurrent events are common.

``

`` ``

``

``General Considerations A primary antiphospholipid syndrome (APS) is diagnosed in patients who have venous or arterial occlusions, recurrent fetal loss, or thrombocytopenia in the presence of persistent antiphospholipid antibodies but not other features of SLE. In < 1% of patients with antiphospholipid antibodies, a potentially devastating syndrome known as the “catastrophic antiphospholipid syndrome” occurs, leading to diffuse thromboses, thrombotic microangiopathy, and multiorgan system failure.

``Clinical Findings A. Symptoms and Signs Patients are often asymptomatic until suffering a thrombotic complication of this syndrome or a pregnancy loss.

Thrombotic events may occur in either the arterial or venous circulations. Thus, deep venous thromboses, pulmonary emboli, cerebrovascular accidents are typical clinical events among patients with the APS. Budd-Chiari syndrome, cerebral sinus vein thrombosis, myocardial or digital infarctions, and other thrombotic events also occur.

A variety of other symptoms and signs are often attributed to the APS, including mental status changes, livedo reticularis, skin ulcers, microangiopathic nephropathy, and cardiac valvular dysfunction—typically mitral regurgitation

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that may mimic Libman-Sacks endocarditis. Livedo reticularis is strongly associated with the subset of patients with APS in whom arterial ischemic events develop. Pregnancy losses that are associated with APS include unexplained fetal death after the first trimester, one or more premature births before 34 weeks because of eclampsia or preeclampsia, or three or more unexplained miscarriages during the first trimester.

B. Laboratory Findings As noted in the discussion of SLE, three types of antiphospholipid antibody are believed to contribute to this syndrome: (1) anti-cardiolipin antibodies; (2) a “lupus anticoagulant” that prolongs certain coagulation tests (see below); and (3) an antibody associated with a biologic falsepositive test for syphilis. Anti-cardiolipin antibodies are typically measured with enzyme immunoassays for either IgG or IgM. In general, IgG anti-cardiolipin antibodies are believed to be more pathologic than IgM. A clue to the presence of a lupus anticoagulant, which may occur in individuals who do not have SLE, may be detected by a prolongation of the partial thromboplastin time (which, paradoxically, is associated with a thrombotic tendency rather than a bleeding risk). A finding more sensitive for a lupus anticoagulant, however, is prolongation of the coagulation assay known as the Russell viper venom time (RVVT). In the presence of a lupus anticoagulant, the RVVT is prolonged and does not correct with mixing studies but does with the addition of excess phospholipid. With the last type of antiphospholipid antibody, the patient has a positive rapid plasma reagin (RPR), but negative specific anti-treponemal assays.

``Differential Diagnosis The exclusion of other autoimmune disorders, particularly those in the SLE spectrum, is essential because such disorders may be associated with additional complications requiring alternative treatments. Other genetic or acquired conditions associated with hypercoagulability such as protein C, protein S, factor V Leiden, and antithrombin deficiency should be excluded. Catastrophic APS has a broad differential, including sepsis, pulmonary-renal syndromes, systemic vasculitis, disseminated intravascular coagulation, and thrombotic thrombocytopenic purpura.

``Treatment Present recommendations for anticoagulation are to treat patients with warfarin to maintain an INR of 2.0–3.0.

Patients who have recurrent thrombotic events on this level of anticoagulation may require higher INRs (> 3.0), but the bleeding risk increases substantially with this degree of anticoagulation. Guidelines indicate that patients with APS should be treated with anticoagulation for life. Because of the teratogenic effects of warfarin, subcutaneous heparin and low dose aspirin (81 mg) is the usual approach to prevent pregnancy complications in women with APS. In patients with catastrophic APS, a three-pronged approach is taken in the acute setting: intravenous heparin, high doses of corticosteroids, and either intravenous immune globulin or plasmapheresis.

Cervera R. Update on the diagnosis, treatment, and prognosis of the catastrophic antiphospholipid syndrome. Curr Rheumatol Rep. 2010 Feb;12(1):70–6. [PMID: 20425537] Ruiz-Irastorza G et al. Antiphospholipid syndrome. Lancet. 2010 Oct 30;376(9751):1498–509. [PMID: 20822807] Ziakas PD et al. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet Gynecol. 2010 Jun;115(6):1256–62.

[PMID: 20502298] Zuily S et al. Increased risk for heart valve disease associated with antiphospholipid antibodies in patients with systemic lupus erythematosus: meta-analysis of echocardiographic studies.

Circulation. 2011 Jul 12;124(2):215–24. [PMID: 21690492]

RAYNAUD PHENOMENON ``

E s s en t ia l S o f dia g n o s i s

Paroxysmal bilateral digital pallor and cyanosis followed by rubor.

Precipitated by cold or emotional stress; relieved by warmth.

Primarily affects young women.

Primary form benign; secondary form can cause digital ulceration or gangrene.

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``

`` ``

``General Considerations Raynaud phenomenon (RP) is a syndrome of paroxysmal digital ischemia, most commonly caused by an exaggerated response of digital arterioles to cold or emotional stress. The initial phase of RP, mediated by excessive vasoconstriction, consists of well-demarcated digital pallor or cyanosis; the subsequent (recovery) phase of RP, caused by vasodilation, leads to intense hyperemia and rubor. Although RP chiefly affects fingers, it can also affect toes and other acral areas such as the nose and ears. RP is classified as primary (idiopathic or Raynaud disease) or secondary. Nearly one-third of the population reports being “sensitive to the cold” but does not experience the paroxysms of digital pallor, cyanosis, and erythema characteristic of RP. Primary RP occurs in 2–6% of adults, is especially common in young women, and poses more of a nuisance than a threat to good health. In contrast, secondary RP is less common, is chiefly associated with rheumatic diseases (especially scleroderma), and is frequently severe enough to cause digital ulceration or gangrene.

``Clinical Findings In early attacks of RP, only one or two fingertips may be affected; as it progresses, all fingers down to the distal palm may be involved. The thumbs are rarely affected. During recovery there may be intense rubor, throbbing, paresthesia, pain, and slight swelling. Attacks usually terminate spontaneously or upon returning to a warm room or putting the extremity in warm water. The patient is usually asymptomatic between attacks. Sensory changes that often accompany vasomotor manifestations include numbness, stiffness, diminished sensation, and aching pain.

Musculoskeletal & Immunologic Disorders Primary RP appears first between ages 15 and 30, almost always in women. It tends to be mildly progressive and, unlike secondary RP (which may be unilateral and may involve only one or two fingers), symmetric involvement of the fingers of both hands is the rule. Spasm becomes more frequent and prolonged. Unlike secondary RP, primary RP does not cause digital pitting, ulceration, or gangrene.

Nailfold capillary abnormalities are among the earliest clues that a person has secondary rather than primary RP. The nailfold capillary pattern can be visualized by placing a drop of grade B immersion oil at the patient’s cuticle and then viewing the area with an ophthalmoscope set to 20–40 diopters. Dilation or dropout of the capillary loops indicates the patient has a secondary form of RP, most commonly scleroderma (Table 20–12). While highly specific for secondary RP, nailfold capillary changes have a low sensitivity.

Digital pitting or ulceration or other abnormal physical findings (eg, skin tightening, loss of extremity pulse, rash, swollen joints) can also provide evidence of secondary RP. Primary RP must be differentiated from the numerous causes of secondary RP (Table 20–12). The history and examination may suggest the diagnosis of systemic sclerosis (including its CREST variant), SLE, and mixed connective tissue disease; RP is occasionally the first manifestation of these disorders. The diagnosis of many of these rheumatic diseases can be confirmed with specific serologic tests (see Table 20–10).

Table 20–12. Causes of secondary Raynaud ­phenomenon.

Rheumatic diseases Scleroderma Systemic lupus erythematosus Dermatomyositis/polymyositis Sjögren syndrome Vasculitis (polyarteritis nodosa, Takayasu disease, Buerger disease) Neurovascular compression and occupational Carpal tunnel syndrome Thoracic outlet obstruction Vibration injury Medications Serotonin agonists (sumatriptan) Sympathomimetic drugs (decongestants) Chemotherapy (bleomycin, vinblastine) Ergotamine Caffeine Nicotine Hematologic disorders Cryoglobulinemia Polycythemia vera Paraproteinemia Cold agglutinins Endocrine disorders Hypothyroidism Pheochromocytoma Miscellaneous Atherosclerosis Embolic disease Migraine Exposure to epoxy resins Sequela of frostbite

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RP may occur in patients with the thoracic outlet syndromes. In these disorders, involvement is generally unilateral, and symptoms referable to brachial plexus compression tend to dominate the clinical picture. Carpal tunnel syndrome should also be considered, and nerve conduction tests are appropriate in selected cases.

A particularly severe form of RP occurs in up to onethird of patients receiving bleomycin and vincristine in combination, often for testicular cancer. Treatment is unsuccessful, and the problem persists even with discontinuation of the drugs.

``Differential Diagnosis The differentiation from Buerger disease (thromboangiitis obliterans) is usually not difficult, since thromboangiitis obliterans is generally a disease of men, particularly smokers; peripheral pulses are often diminished or absent; and, when RP occurs in association with thromboangiitis obliterans, it is usually in only one or two digits.

In acrocyanosis, cyanosis of the hands is permanent and diffuse; the sharp and paroxysmal line of demarcation with pallor does not occur with acrocyanosis. Frostbite may lead to chronic RP. Ergot poisoning, particularly due to prolonged or excessive use of ergotamine, must also be considered but is unusual.

RP may be mimicked by type I cryoglobulinemia, in which a monoclonal antibody cryoprecipitates in the cooler distal circulation. Type I cryoglobulinemia is usually associated with multiple myeloma or with lymphoproliferative disorders.

Erythromelalgia can mimic the rubor phase of RP; exacerbation by heat and relief with cold readily distinguish erythromelalgia from RP.

``Treatment A. General Measures Patients should wear gloves or mittens whenever outside in temperatures that precipitate attacks. Keeping the body warm is also a cornerstone of initial therapy. Wearing warm shirts, coats, and hats will help prevent the exaggerated vasospasm that causes RP and that is not prevented by warming only the hands. The hands should be protected from injury at all times; wounds heal slowly, and infections are consequently hard to control. Softening and lubricating lotion to control the fissured dry skin should be applied to the hands frequently. Smoking should be stopped and sympathomimetic drugs (eg, decongestants, diet pills, and amphetamines) should be avoided. For most patients with primary RP, general measures alone are sufficient to control symptoms. Medical or surgical therapy should be considered in patients who have severe symptoms or are experiencing tissue injury from digital ischemia.

B. Medications Calcium channel blockers are first-line therapy for RP. Calcium channel blockers produce a modest benefit and are more effective in primary RP than secondary RP. Slow release nifedipine (30–180 mg/d orally), amlodipine (5–20 mg/d orally), felodipine, or nisoldipine are popular and more effective than verapamil and diltiazem. Other medications that are sometimes effective in treating RP

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include angiotensin-converting enzyme inhibitors, sympatholytic agents (eg, prazosin), topical nitrates, phosphodiesterase inhibitors (eg, sildenafil, tadalafil, and vardenafil), selective serotonin reuptake inhibitors (fluoxetine), endothelin-receptor inhibitors (ie, bosentan), statins, parenteral prostaglandins (prostaglandin E1), and oral prostaglandins (misoprostol).

``General Considerations

``When to Admit

Scleroderma (systemic sclerosis) is a rare chronic disorder characterized by diffuse fibrosis of the skin and internal organs. Symptoms usually appear in the third to fifth decades, and women are affected two to three times as frequently as men.

Two forms of scleroderma are generally recognized: limited (80% of patients) and diffuse (20%). In limited scleroderma, which is also known as the CREST syndrome (representing calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia), the hardening of the skin (scleroderma) is limited to the face and hands. In contrast, in diffuse scleroderma, the skin changes also involve the trunk and proximal extremities. Tendon friction rubs over the forearms and shins occur uniquely (but not universally) in diffuse scleroderma. In general, patients with limited scleroderma have better outcomes than those with diffuse disease, largely because kidney disease or interstitial lung disease rarely develops in patients with limited disease. Cardiac disease is also more characteristic of diffuse scleroderma. Patients with limited disease, however, are more susceptible to digital ischemia, leading to finger loss, and to life-threatening pulmonary hypertension. Small and large bowel hypomotility, which may occur in either form of scleroderma, can cause constipation alternating with diarrhea, malabsorption due to bacterial overgrowth, pseudoobstruction, and severe bowel distension with rupture.

• Patients with severe digital ischemia as evidenced by demarcation should be admitted for intensive therapy.

``Clinical Findings

C. Surgical Measures Sympathectomy may be indicated when attacks have become frequent and severe, when they interfere with work and well being, and particularly when trophic changes have developed and medical measures have failed. Cervical sympathectomy is modestly effective for primary but not secondary RP. Digital sympathectomy may improve secondary RP.

``Prognosis Primary RP is benign and largely a nuisance for affected individuals who are exposed to cold winters or excessive air conditioning. The prognosis of secondary RP depends on the severity of the underlying disease. Unfortunately, severe pain from ulceration and gangrene are not rare with scleroderma, especially the CREST variant.

``When to Refer • Appropriate management of patients with secondary RP often requires consultation with a rheumatologist.

A. Symptoms and Signs Chatterjee S. Management of Raynaud’s phenomenon in the patient with connective tissue disease. Curr Treat Options Cardiovasc Med. 2010 Apr;12(2):185–204. [PMID: 20842555] Huisstede BM et al. Effectiveness of interventions for secondary Raynaud’s phenomenon: a systematic review. Arch Phys Med Rehabil. 2011 Jul;92(7):1166–80. [PMID: 21704799] Shenoy PD et al. Efficacy of tadalafil in secondary Raynaud’s phenomenon resistant to vasodilator therapy: a double blind randomized cross-over trial. Rheumatology (Oxford). 2010 Dec;49(12):2420–8. [PMID: 20837499]

Scleroderma (Systemic Sclerosis) ``

Limited disease (80% of patients): thickening of skin confined to the face, neck, and distal extremities.

Diffuse disease (20%): widespread thickening of skin, including truncal involvement, with areas of increased pigmentation and depigmentation.

Raynaud phenomenon and antinuclear antibodies are present in virtually all patients.

Systemic features of gastroesophageal reflux, hypomotility of gastrointestinal tract, pulmonary fibrosis, pulmonary hypertension, and renal involvement.

``

``

``

``

E s s en t ia l S o f dia g n o s i s

Raynaud phenomenon is usually the initial manifestation and can precede other signs and symptoms by years in cases of limited scleroderma. Polyarthralgia, weight loss, and malaise are common early features of diffuse scleroderma but are infrequent in limited scleroderma.

Cutaneous disease usually, but not always, develops before visceral involvement and can manifest initially as non-pitting subcutaneous edema associated with pruritus. With time the skin becomes thickened and hidebound, with loss of normal folds. Telangiectasia, pigmentation, and depigmentation are characteristic.

Ulceration about the fingertips and subcutaneous calcification are seen. Dysphagia and symptoms of reflux due to esophageal dysfunction are common and result from abnormalities in motility and later from fibrosis. Fibrosis and atrophy of the gastrointestinal tract cause hypomotility. Large-mouthed diverticuli occur in the jejunum, ileum, and colon. Diffuse pulmonary fibrosis and pulmonary vascular disease are reflected in restrictive lung physiology and low diffusing capacities. Cardiac abnormalities include pericarditis, heart block, myocardial fibrosis, and right heart failure secondary to pulmonary hypertension. Scleroderma renal crisis, resulting from intimal proliferation of smaller renal arteries and usually associated with hypertension, is a marker for a poor outcome even though many cases can be treated effectively with angiotensin-converting enzyme inhibitors.

Musculoskeletal & Immunologic Disorders B. Laboratory Findings

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Early in its course, scleroderma can cause diagnostic confusion with other causes of Raynaud phenomenon, particularly SLE, mixed connective tissue disease, and the inflammatory myopathies. Scleroderma can be mistaken for other disorders characterized by skin hardening.

Eosinophilic fasciitis is a rare disorder presenting with skin changes that resemble diffuse scleroderma. The inflammatory abnormalities, however, are limited to the fascia rather than the dermis and epidermis. Moreover, patients with eosinophilic fasciitis are distinguished from those with scleroderma by the presence of peripheral blood eosinophilia, the absence of Raynaud phenomenon, the good response to prednisone, and an association (in some cases) with paraproteinemias. Diffuse skin thickening and visceral involvement are features of scleromyxedema; the presence of a paraprotein, the absence of Raynaud phenomenon, and distinct skin histology point to scleromyxedema. Diabetic cheiropathy typically develops in long-standing, poorly controlled diabetes and can mimic sclerodactyly. Nephrogenic fibrosing dermopathy produces thickening and hardening of the skin of the trunk and extremities in patients with chronic kidney disease; exposure to gadolinium may play a pathogenic role. Morphea and linear scleroderma cause sclerodermatous changes limited to circumscribed areas of the skin and usually have excellent outcomes.

Raynaud syndrome may respond to calcium channel blockers, eg, long-acting nifedipine, 30–120 mg/d orally, or to losartan, 50 mg/d orally, or to sildenafil 50 mg orally twice daily. Patients with esophageal disease should take medications in liquid or crushed form. Esophageal reflux can be reduced and the risk of scarring diminished by avoidance of late-night meals and by the use of proton pump inhibitors (eg, omeprazole, 20–40 mg/d orally), which achieve nearcomplete inhibition of gastric acid production and are remarkably effective for refractory esophagitis. Patients with delayed gastric emptying maintain their weight better if they eat small, frequent meals and remain upright for at least 2 hours after eating. Long-term octreotide (0.1 mg subcutaneously twice daily), a somatostatin analog, helps some patients with bacterial overgrowth and pseudoobstruction.

Malabsorption due to bacterial overgrowth also responds to antibiotics, eg, tetracycline, 500 mg four times orally daily, often prescribed cyclically. The hypertensive crises associated with systemic sclerosis renal crisis must be treated early and aggressively (in the hospital) with angiotensin-converting enzyme inhibitors, eg, captopril, initiated at 25 mg orally every 6 hours and titrated up as tolerated to a maximum of 100 mg every 6 hours. Apart from the patient with myositis, prednisone has little or no role in the treatment of scleroderma; high doses (> 15 mg daily) have been associated with scleroderma renal crisis. Cyclophosphamide improves dyspnea and pulmonary function tests modestly in patients with severe interstitial lung disease; this highly toxic drug should only be administered by physicians familiar with its use.

Mycophenolate mofetil, 1 g twice daily, stabilized lung function in small, uncontrolled studies of patients with interstitial lung disease. Bosentan, an endothelin receptor antagonist, improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension and helps prevent digital ulceration. Sildenafil or prostaglandins (delivered by continuous intravenous infusion or intermittent inhalation) may also be useful in treating pulmonary hypertension. At an experimental level, immunoablative therapy with or without stem cell rescue has achieved promising results for some patients with severe, rapidly progressive diffuse scleroderma.

The 9-year survival rate in scleroderma averages approximately 40%. The prognosis tends to be worse in those with diffuse scleroderma, in blacks, in males, and in older patients.

Lung disease—in the form of pulmonary fibrosis or pulmonary arterial hypertension—is now the number one cause of mortality. Death from advanced heart failure or chronic kidney disease is also common. Those persons in whom severe internal organ involvement does not develop in the first 3 years have a substantially better prognosis, with 72% surviving at least 9 years. Breast and lung cancer may be more common in patients with scleroderma.

``Treatment

``When to Refer

Treatment of scleroderma is symptomatic and supportive and focuses on the organ systems involved. There is no effective therapy for the underlying disease process. However, interventions for management of specific organ manifestations of this disease have improved substantially. Severe

• Appropriate management of scleroderma requires frequent consultations with a rheumatologist.

• Severity of organ involvement dictates referral to other subspecialists, such as pulmonologists or gastroenterologists.

Mild anemia is often present. In scleroderma renal crisis, the peripheral blood smear shows findings consistent with a microangiopathic hemolytic anemia (due to mechanical damage to red cells from diseased small vessels). Elevation of the ESR is unusual. Proteinuria appears in association with renal involvement. Antinuclear antibody tests are nearly always positive, frequently in high titers (Table 20–10). The scleroderma antibody (anti-SCL-70), directed against topoisomerase III, is found in one-third of patients with diffuse systemic sclerosis and in 20% of those with CREST syndrome. Although present in only a small number of patients with diffuse scleroderma, anti-SCL-70 antibodies may portend a poor prognosis, with a high likelihood of serious internal organ involvement (eg, interstitial lung disease). Anticentromere antibodies are seen in 50% of those with CREST syndrome and in 1% of individuals with diffuse scleroderma (Table 20–10). Anticentromere antibodies are highly specific for limited scleroderma, but they also occur occasionally in overlap syndromes. Anti-RNA polymerase III antibodies develop in 10–20% of scleroderma patients overall and correlate with the development of diffuse skin disease and renal hypertensive crisis.

``Differential Diagnosis

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Manno R et al. Immunotherapy of systemic sclerosis.

Immunotherapy. 2010 Nov;2(6):863–78. [PMID: 21091117] Ong VH et al. Innovative therapies for systemic sclerosis. Curr Opin Rheumatol. 2010 May;22(3):264–72. [PMID: 20190640] Simeón-Aznar CP et al. Effect of mycophenolate sodium in scleroderma-related interstitial lung disease. Clin Rheumatol.

2011 Nov;30(11):1393–8. [PMID: 21881859]

IDIOPATHIC INFLAMMATORY MYOPATHIES (Polymyositis & Dermatomyositis) ``

E s s en t ia l S o f dia g n o s i s

Bilateral proximal muscle weakness.

Characteristic cutaneous manifestations in dermatomyositis (Gottron papules, heliotrope rash).

Diagnostic tests: elevated creatine kinase, muscle biopsy, electromyography, MRI. Increased risk of malignancy, particularly in dermatomyositis.

Inclusion body myositis can mimic polymyositis but is less responsive to treatment.

`` ``

``

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``

``General Considerations Polymyositis and dermatomyositis are systemic disorders of unknown cause whose principal manifestation is muscle weakness. Although their clinical presentations (aside from the presence of certain skin findings in dermatomyositis, some of which are pathognomonic) and treatments are similar, the two diseases are pathologically quite distinct.

They affect persons of any age group, but the peak incidence is in the fifth and sixth decades of life. Women are affected twice as commonly as men, and the diseases (particularly polymyositis) also occur more often among blacks than whites. There is an increased risk of malignancy in adult patients with dermatomyositis. Indeed, up to one patient in four with dermatomyositis has an occult malignancy. Malignancies may be evident at the time of presentation with the muscle disease but may not be detected until months afterward in some cases. Rare patients with dermatomyositis have skin disease without overt muscle involvement, a condition termed “dermatomyositis sine myositis.” Myositis may also be associated with other connective tissue diseases, especially scleroderma, lupus, mixed connective tissue disease, and Sjögren syndrome.

gravis, polymyositis and dermatomyositis do not cause facial or ocular muscle weakness. Pain and tenderness of affected muscles occur in one-fourth of cases, but these are rarely the chief complaints. About one-fourth of patients have dysphagia. In contrast to scleroderma, which affects the smooth muscle of the lower esophagus and can cause a “sticking” sensation below the sternum, polymyositis or dermatomyositis involves the striated muscles of the upper pharynx and can make initiation of swallowing difficult. Muscle atrophy and contractures occur as late complications of advanced disease. Clinically significant myocarditis is uncommon even though there is often creatine kinase-MB elevation. Patients who are bed-bound from myositis should be screened for respiratory muscle weakness that can be severe enough to cause CO2 retention and can progress to require mechanical ventilation.

The characteristic rash of dermatomyositis is dusky red and may appear in a malar distribution mimicking the classic rash of SLE. Facial erythema beyond the malar distribution is also characteristic of dermatomyositis.

Erythema also occurs over other areas of the face, neck, shoulders, and upper chest and back (“shawl sign”).

Periorbital edema and a purplish (heliotrope) suffusion over the eyelids are typical signs (Figure 20–6). Coloration of the heliotrope and other rashes of dermatomyositis can be affected by skin tone. In blacks, the rashes may appear more hyperpigmented than erythematous or violaceous.

Periungual erythema, dilations of nailbed capillaries, and scaly patches over the dorsum of PIP and MCP joints (Gottron sign) are highly suggestive. Scalp involvement by dermatomyositis may mimic psoriasis. Infrequently, the cutaneous findings of this disease precede the muscle inflammation by weeks or months. Diagnosing polymyositis in patients over age 70 years can be difficult because weakness may be overlooked or attributed erroneously to idiopathic frailty. Polymyositis can remain undiagnosed or will be misdiagnosed as hepatitis because of elevations in alanine aminotransferase (ALT) and aspartate

``Clinical Findings A. Symptoms and Signs Polymyositis may begin abruptly, but the usual presentation is one of gradual and progressive muscle weakness. The weakness chiefly involves proximal muscle groups of the upper and lower extremities as well as the neck. Leg weakness (eg, difficulty in rising from a chair or climbing stairs) typically precedes arm symptoms. In contrast to myasthenia

s Figure 20–6. Heliotrope (violaceous) rash around the eyes in a patient with dermatomyositis. (Courtesy of Richard P. Usatine, MD; used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)

Musculoskeletal & Immunologic Disorders aminotransferase (AST) levels. A subset of patients with polymyositis and dermatomyositis develop the “antisynthetase syndrome,” a group of findings including inflammatory arthritis, fever, Raynaud phenomenon, “mechanic’s hands” (hyperkeratosis along the radial and palmar aspects of the fingers) interstitial lung disease, and often severe muscle disease associated with certain autoantibodies (eg, anti-Jo1 antibodies).

B. Laboratory Findings Measurement of serum levels of muscle enzymes, especially creatine kinase and aldolase, is most useful in diagnosis and in assessment of disease activity. Anemia is uncommon. The ESR and C-reactive protein are often normal and are not reliable indicators of disease activity.

Rheumatoid factor is found in a minority of patients.

Antinuclear antibodies are present in many patients, especially those who have an associated connective tissue disease (Table 20–10). A number of autoantibodies are seen exclusively in patients with myositis and are associated with distinctive clinical features. The most common myositisspecific antibody, anti-Jo-1 antibody, is seen in the subset of patients who have associated interstitial lung disease (Table 20–10). The other myositis-specific autoantibodies are anti-Mi-2, associated with dermatomyositis; anti-SRP (anti-signal recognition particle), associated with rapidly progressive, severe polymyositis, and dysphagia; and anti-155/140, strongly associated with dermatomyositis with malignancy (malignancy in 71% with versus 11% without this antibody). In the absence of the anti-synthetase syndrome, chest radiographs are usually normal.

Electromyographic abnormalities consisting of polyphasic potentials, fibrillations, and high-frequency action potentials point toward a myopathic, rather than a neurogenic, cause of weakness. MRI can detect early and patchy muscle involvement, can guide biopsies, and often is more useful than electromyography. The malignancies most commonly associated with dermatomyositis in descending order of frequency are ovarian, lung, pancreatic, stomach, colorectal, and non-Hodgkin lymphoma. The search for an occult malignancy should begin with a history and physical examination, supplemented with a complete blood count, comprehensive biochemical panel, serum protein electrophoresis, and urinalysis, and should include age- and riskappropriate cancer screening tests. Given the especially strong association of ovarian carcinoma and dermatomyositis, transvaginal ultrasonography, CT scanning, and CA-125 levels may be useful in women. No matter how extensive the initial screening, some malignancies will not become evident for months after the initial presentation.

C. Muscle Biopsy Biopsy of clinically involved muscle is the only specific diagnostic test. The pathology findings in polymyositis and dermatomyositis are distinct. Although both include lymphoid inflammatory infiltrates, the findings in dermatomyositis are localized to perivascular regions and there is evidence of humoral and complement-mediated destruction of microvasculature associated with the

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muscle. In addition to its vascular orientation, the inflammatory infiltrate in dermatomyositis centers on the interfascicular septa and is located around, rather than in, muscle fascicles. A pathologic hallmark of dermatomyositis is perifascicular atrophy. In contrast, the pathology of polymyositis characteristically includes endomysial infiltration of the inflammatory infiltrate. Owing to the sometimes patchy distribution of pathologic abnormalities, however, false-negative biopsies sometimes occur in both disorders.

``Differential Diagnosis Muscle inflammation may occur as a component of SLE, scleroderma, Sjögren syndrome, and overlap syndromes. In those cases, associated findings usually permit the precise diagnosis of the primary condition.

Inclusion body myositis, because of its tendency to mimic polymyositis, is a common cause of “treatmentresistant polymyositis.” In contrast to the epidemiologic features of polymyositis, however, the typical inclusion body myositis patient is white, male, and over the age of 50. The onset of inclusion body myositis is more insidious than that of polymyositis or dermatomyositis (eg, occurring over years rather than months), and asymmetric distal motor weakness is common in inclusion body myositis. Creatine kinase levels in inclusion body myositis are often minimally elevated and are normal in 25%.

Electromyography may show a mixed picture of myopathic and neurogenic abnormalities. Muscle biopsy shows characteristic intracellular vacuoles by light microscopy and either tubular or filamentous inclusions in the nucleus or cytoplasm by electron microscopy. Inclusion body myositis is less likely to respond to therapy.

Hypothyroidism is a common cause of proximal muscle weakness associated with elevations of serum creatine kinase. Hyperthyroidism and Cushing disease may both be associated with proximal muscle weakness with normal levels of creatine kinase. Patients with polymyalgia rheumatica are over the age of 50 and—in contrast to patients with polymyositis—have pain but no objective weakness; creatine kinase levels are normal. Disorders of the peripheral and central nervous systems (eg, chronic inflammatory polyneuropathy, multiple sclerosis, myasthenia gravis, EatonLambert disease, and amyotrophic lateral sclerosis) can produce weakness but are distinguished by characteristic symptoms and neurologic signs and often by distinctive electromyographic abnormalities. A number of systemic vasculitides (polyarteritis nodosa, microscopic polyangiitis, the Churg-Strauss syndrome, granulomatosis with polyangiitis, and mixed cryoglobulinemia) can produce profound weakness through vasculitic neuropathy. The muscle weakness associated with these disorders, however, is typically distal and asymmetric, at least in the early stages.

Many drugs, including corticosteroids, alcohol, clofibrate, penicillamine, tryptophan, and hydroxychloroquine, can produce proximal muscle weakness. Long-term use of colchicine at doses as low as 0.6 mg twice a day in patients with moderate chronic kidney disease can produce a mixed neuropathy-myopathy that mimics polymyositis. The weakness and muscle enzyme elevation reverse

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with cessation of the drug. Polymyositis can occur as a complication of HIV or HTLV-1 infection and with zidovudine therapy as well.

HMG-CoA reductase inhibitors can cause myopathy and rhabdomyolysis. Although only about 0.1% of patients taking a statin drug alone develop myopathy, concomitant administration of other drugs (especially gemfibrozil, cyclosporine, niacin, macrolide antibiotics, azole antifungals, and protease inhibitors) increases the risk. Statin use has also been linked to the development of an autoimmunemediated necrotizing myositis, which persists after the statin has been discontinued and is associated with autoantibodies to HMG-CoA reductase.

``Treatment Most patients respond to corticosteroids. Often a daily dose of 40–60 mg or more of oral prednisone is required initially. The dose is then adjusted downward while monitoring muscle strength and serum levels of muscle enzymes.

Long-term use of corticosteroids is often needed, and the disease may recur or reemerge when they are withdrawn.

Patients with an associated neoplasm have a poor prognosis, although remission may follow treatment of the tumor; corticosteroids may or may not be effective in these patients. In patients resistant or intolerant to corticosteroids, therapy with methotrexate or azathioprine may be helpful. Intravenous immune globulin is effective for dermatomyositis resistant to prednisone. Mycophenolate mofetil (1–1.5 g orally twice daily) may be useful as a steroidsparing agent. Rituximab has achieved encouraging results in some patients with inflammatory myositis unresponsive to prednisone. Since the rash of dermatomyositis is often photosensitive, patients should limit sun exposure.

Hydroxychloroquine (200–400 mg/d orally not to exceed 6.5 mg/kg) can also help ameliorate the skin disease.

Mixed CONNECTIVE TISSUE DISEASE & OVERLAP SYNDROMES Many patients with symptoms and signs compatible with a connective tissue disease have features consistent with more than one type of rheumatic disease. Special attention has been drawn to antinuclear antibody–positive patients who have overlapping features of SLE, scleroderma, and inflammatory myopathy together with autoantibodies to ribonuclear protein (RNP). Some consider these patients to have a distinct entity (“mixed connective tissue disease”), and others view this as a subset of SLE characterized by a higher prevalence of Raynaud phenomenon, polyarthritis, myositis, and pulmonary hypertension and a lower incidence of renal involvement. Other patients have features of more than one connective tissue disease (eg, rheumatoid arthritis and SLE, SLE and scleroderma) in the absence of anti-RNP antibodies and are referred to as having an “overlap syndrome.” Treatments are guided more by the distribution and severity of patients’ organ system involvement than by therapies specific to these overlap syndromes.

Tsai YY et al. Fifteen-year experience of pediatric-onset mixed connective tissue disease. Clin Rheumatol. 2010 Jan;29(1): 53–8. [PMID: 19756834]

SJÖGREN SYNDROME ``

Women are 90% of patients; the average age is 50 years.

Dryness of eyes and dry mouth (sicca components) are the most common features; they occur alone or in association with rheumatoid arthritis or other connective tissue disease.

Rheumatoid factor and other autoantibodies are common.

Increased incidence of lymphoma.

``

``

``When to Refer • Appropriate management of myositis usually requires frequent consultations with a rheumatologist or neurologist.

• Severe lung disease may require consultation with a pulmonologist.

E s s en t ia l S o f dia g n o s i s

``

``

``When to Admit

``General Considerations

• Signs of rhabdomyolysis.

• Respiratory insufficiency with hypoxia or carbon dioxide retention.

Sjögren syndrome is a systemic autoimmune disorder whose clinical presentation is usually dominated by dryness of the eyes and mouth due to immune-mediated dysfunction of the lacrimal and salivary glands. The disorder is predominantly seen in women, with a ratio of 9:1; most cases develop between the ages of 40 and 60 years. Sjögren syndrome can occur in isolation (“primary” Sjögren syndrome) or in association with another rheumatic disease. Sjögren syndrome is most frequently associated with rheumatoid arthritis but also occurs with SLE, primary biliary cirrhosis, scleroderma, polymyositis, Hashimoto thyroiditis, polyarteritis, and interstitial pulmonary fibrosis.

Katzap E et al. Antisynthetase syndrome. Curr Rheumatol Rep. 2011 Jun;13(3):175–81. [PMID: 21455765] Labirua A et al. Interstitial lung disease and idiopathic inflammatory myopathies: progress and pitfalls. Curr Opin Rheumatol. 2010 Nov;22(6):633–8. [PMID: 20827201] Mammen AL et al. Autoantibodies against 3-hydroxy-3-methylglutaryl-coenzyme A reductase in patients with statin-associated autoimmune myopathy. Arthritis Rheum. 2011 Mar; 63(3): 713–21. [PMID: 21360500]

Musculoskeletal & Immunologic Disorders

``Clinical Findings A. Symptoms and Signs Keratoconjunctivitis sicca results from inadequate tear production caused by lymphocyte and plasma cell infiltration of the lacrimal glands. Ocular symptoms are usually mild.

Burning, itching, and the sensation of having a foreign body or a grain of sand in the eye occur commonly. For some patients, the initial manifestation is the inability to tolerate wearing contact lenses. Many patients with more severe ocular dryness notice ropy secretions across their eyes, especially in the morning. Photophobia may signal corneal ulceration resulting from severe dryness. For most patients, symptoms of dryness of the mouth (xerostomia) dominate those of dry eyes. Patients frequently complain of a “cotton mouth” sensation and difficulty swallowing foods, especially dry foods like crackers, unless they are washed down with liquids. The persistent oral dryness causes most patients to carry water bottles or other liquid dispensers from which they sip constantly. A few patients have such severe xerostomia that they have difficulty speaking. Persistent xerostomia results often in rampant dental caries; caries at the gum line strongly suggest Sjögren syndrome. Some patients are most troubled by loss of taste and smell. Parotid enlargement, which may be chronic or relapsing, develops in one-third of patients. Desiccation may involve the nose, throat, larynx, bronchi, vagina, and skin.

Systemic manifestations include dysphagia, small vessel vasculitis, pleuritis, obstructive airways disease and interstitial lung disease (in the absence of smoking), neuropsychiatric dysfunction (most commonly peripheral neuropathies), and pancreatitis; they may be related to the associated diseases noted above. Renal tubular acidosis (type I, distal) occurs in 20% of patients. Chronic interstitial nephritis, which may result in impaired kidney function, may be seen.

B. Laboratory Findings Laboratory findings include mild anemia, leukopenia, and eosinophilia. Polyclonal hypergammaglobulinemia, rheumatoid factor positivity (70%), and antinuclear antibodies (95%) are all common findings. Antibodies against the cytoplasmic antigens SS-A and SS-B (also called Ro and La, respectively) are often present in primary Sjögren syndrome and tend to correlate with the presence of extraglandular manifestations (Table 20–10). Thyroid-associated autoimmunity is a common finding among patients with Sjögren syndrome.

Useful ocular diagnostic tests include the Schirmer test, which measures the quantity of tears secreted. Lip biopsy, a simple procedure, reveals characteristic lymphoid foci in accessory salivary glands. Biopsy of the parotid gland should be reserved for patients with atypical presentations such as unilateral gland enlargement that suggest a neoplastic process.

``Differential Diagnosis Isolated complaints of dry mouth are most commonly due to medication side effects. Chronic hepatic C can cause sicca symptoms and rheumatoid factor positivity. Minor

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salivary gland biopsies reveal lymphocytic infiltrates but not to the extent of Sjögren syndrome, and tests for antiSS-A and anti-SS-B are negative. Diffuse infiltration of CD8 T cells producing parotid gland enlargement can develop in HIV-infected individuals. Involvement of the lacrimal or salivary glands, or both in sarcoidosis can mimic Sjögren syndrome; biopsies reveal noncaseating granulomas. Rarely, amyloid deposits in the lacrimal and salivary glands produce sicca symptoms. IgG4-related systemic disease (characterized by high serum IgG4 levels and infiltration of tissues with IgG4+ plasma cells) can result in lacrimal and salivary gland enlargement that mimics Sjögren syndrome.

``Treatment & Prognosis Treatment of sicca symptoms is symptomatic and supportive. Artificial tears applied frequently will relieve ocular symptoms and avert further desiccation. Topical ocular 0.05% cyclosporine also improves ocular symptoms and signs of dryness. The mouth should be kept well lubricated.

Sipping water frequently or using sugar-free gums and hard candies usually relieves dry mouth symptoms.

Pilocarpine (5 mg orally four times daily) and the acetylcholine derivative cevimeline (30 mg orally three times daily) may improve xerostomia symptoms. Atropinic drugs and decongestants decrease salivary secretions and should be avoided. A program of oral hygiene, including fluoride treatment, is essential in order to preserve dentition. If there is an associated rheumatic disease, its systemic treatment is not altered by the presence of Sjögren syndrome.

Although Sjögren syndrome may compromise patients’ quality of life significantly, the disease is usually consistent with a normal life span. Poor prognoses are influenced mainly by the presence of systemic features associated with underlying disorders, the development in some patients of lymphocytic vasculitis, the occurrence of a painful peripheral neuropathy, and the complication (in a minority of patients) of lymphoma. Severe systemic inflammatory manifestations are treated with prednisone or various immunosuppressive medications. The patients (3–10% of the total Sjögren population) at greatest risk for developing lymphoma are those with severe exocrine dysfunction, marked parotid gland enlargement, splenomegaly, vasculitis, peripheral neuropathy, anemia, and mixed monoclonal cryoglobulinemia.

``When to Refer • Presence of systemic symptoms or signs.

• Symptoms or signs of ocular dryness not responsive to artificial tears.

``When to Admit • Presence of severe systemic signs such as vasculitis unresponsive to outpatient management.

Chai J et al. Neurological manifestations of primary Sjögren’s syndrome. Curr Opin Neurol. 2010 Oct;23(5):509–13.

[PMID: 20689426]

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Kokosi M et al. Pulmonary involvement in Sjögren syndrome.

Clin Chest Med. 2010 Sep;31(3):489–500. [PMID: 20692541] Ramos-Casals M et al. Treatment of primary Sjögren syndrome: a systematic review. JAMA. 2010 Jul 28;304(4):452–60.

[PMID: 20664046]

RHABDOMYOLYSIS ``

E s s en t ia l S o f dia g n o s i s

Associated with crush injuries to muscle, prolonged immobility, drug toxicities, hypothermia, and other causes.

Massive acute elevations of muscle enzymes that peak quickly and usually resolve within days once the inciting injury has been identified and removed.

``

``

``General Considerations Rhabdomyolysis is a syndrome of acute necrosis of skeletal muscle associated with myoglobinuria and markedly elevated creatine kinase levels. Acute tubular necrosis is a common complication of rhabdomyolysis and is due to the toxic effects of filtering excessive quantities of myoglobin in the setting of hypovolemia (See Acute Tubular Necrosis in Chapter 22). Many patients in whom rhabdomyolysis develops are volume-contracted and, therefore, oliguric renal failure is encountered routinely.

Rhabdomyolysis was first recognized as a complication of crush injuries to muscle among victims of the London Blitz during the World War II. Cocaine use and alcohol intoxication, particularly in the setting of prolonged immobility and exposure hypothermia, are leading causes of admissions due to rhabdomyolysis on the medical services of inner city hospitals. Use of statins is another important cause of rhabdomyolysis. The presence of compromised kidney and liver function, diabetes mellitus, and hypothyroidism as well as concomitant use of other medications increase the risk of rhabdomyolysis in patients taking statins. The cytochrome P450 liver enzymes metabolize all statins except for pravastatin and rosuvastatin. Drugs that block the action of cytochrome P450 include protease inhibitors, erythromycin, itraconazole, clarithromycin, diltiazem, and verapamil. Use of these drugs concomitantly with the statins (but not pravastatin or rosuvastatin) can increase the risk of development of rhabdomyolysis. The likelihood of rhabdomyolysis also increases when statins are used with niacin and fibric acids (gemfibrozil, clofibrate, and fenofibrate). Rhabdomyolysis is an uncommon complication of polymyositis, dermatomyositis, and the myopathy of hypothyroidism, despite the high levels of creatine kinase often seen in these conditions.

Often there is little evidence for muscle injury on clinical assessment of the patients with rhabdomyolysis— specifically, myalgias and weakness are usually absent. The first clue to muscle necrosis in such individuals may be a

urinary dipstick testing positive for “blood” (actually myoglobin) in the absence of red cells in the sediment. This positive finding is due to myoglobinuria, which results in a false-positive reading for hemoglobin. Such an abnormality should prompt determination of the serum creatine kinase level, which invariably is elevated (usually markedly so). Other commonly encountered laboratory abnormalities in rhabdomyolysis include elevated serum levels of ALT and lactate dehydrogenase due to release of these enzymes from skeletal muscle.

``Treatment Vigorous fluid resuscitation (4–6 L/d, with careful monitoring for volume overload) is indicated. Infusion of mannitol (100 mg/d) and urine alkalinization (to minimize precipitation of myoglobin within tubules) have been recommended as measures to reduce kidney injury, but definitive evidence for the efficacy of these measures is lacking. Myopathic complications of statins usually resolve within several weeks of discontinuing the drug.

Bosch X et al. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009 Jul 2;361(1):62–72. [PMID: 19571284] Cervellin G et al. Rhabdomyolysis: historical background, clinical, diagnostic and therapeutic features. Clin Chem Lab Med. 2010 Jun;48(6):749–56. [PMID: 20298139]

cc

VASCULITIS SYNDROMES

“Vasculitis” is a heterogeneous group of disorders characterized by inflammation within the walls of affected blood vessels. The major forms of primary systemic vasculitis are listed in Table 20–13. The first consideration in classifying cases of vasculitis is the size of the major vessels involved: large, medium, or small. The presence of the clinical signs and symptoms shown in Table 20–14 help distinguish among these three groups. After determining the size of the major vessels involved, other issues that contribute to the classification include the following: • Does the process involve arteries, veins, or both?

• What are the patient’s demographic characteristics (age, gender, ethnicity, smoking status)?

• Which organs are involved?

• Is there hypocomplementemia or other evidence of immune complex deposition?

• Is there granulomatous inflammation on tissue biopsy?

• Are antineutrophil cytoplasmic antibodies (ANCA) present?

In addition to the disorders considered to be primary vasculitides, there are also multiple forms of vasculitis that are associated with other known underlying conditions.

These “secondary” forms of vasculitis occur in the setting of chronic infections (eg, hepatitis B or C, subacute bacterial endocarditis), connective tissue disorders, inflammatory bowel disease, malignancies, and reactions to medications. Only the major primary forms of vasculitis are discussed here.

Musculoskeletal & Immunologic Disorders

Table 20–13. Classification scheme of primary ­vasculitides according to size of predominant blood vessels involved.

Predominantly large-vessel vasculitides Takayasu arteritis Giant cell arteritis (temporal arteritis) Behçet disease1 Predominantly medium-vessel vasculitides Polyarteritis nodosa Buerger disease Primary angiitis of the central nervous system Predominantly small-vessel vasculitides Immune-complex mediated Cutaneous leukocytoclastic angiitis (“hypersensitivity vasculitis”) Henoch-Schönlein purpura Essential cryoglobulinemia2 “ANCA-associated” disorders3 Granulomatosis with polyangiitis (formerly Wegener granulomatosis)2 Microscopic polyangiitis2 Churg-Strauss syndrome2 1

May involve small, medium, and large-sized blood vessels.

Frequent overlap of small and medium-sized blood vessel involvement.

3 Not all forms of these disorders are always associated with ANCA. ANCA, antineutrophil cytoplasmic antibodies.

2

Langford CA. Vasculitis. J Allergy Clin Immunol. 2010 Feb;125 (2 Suppl 2):S216–25. [PMID: 19932919]

POLYMYALGIA RHEUMATICA & GIANT CELL ARTERITIS ``

E s s en t ia l S o f dia g n o s i s

Age over 50 years.

Giant cell (temporal) arteritis is characterized by headache, jaw claudication, polymyalgia rheumatica, visual abnormalities, and a markedly elevated ESR. The hallmark of polymyalgia rheumatica is pain and stiffness in shoulders and hips lasting for several weeks without other explanation.

`` ``

``

``General Considerations Polymyalgia rheumatica and giant cell arteritis probably represent a spectrum of one disease: Both affect the same population (patients over the age of 50), show preference for the same HLA haplotypes, and show similar patterns of cytokines in blood and arteries. Polymyalgia rheumatica and giant cell arteritis also frequently coexist. The important differences between the two conditions are that polymyalgia rheumatica alone does not cause blindness and responds to low-dose (10–20 mg/d orally) prednisone

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Table 20–14. Typical clinical manifestations of large-, medium-, and small-vessel involvement by vasculitis.

Large

Medium

Small

Constitutional symptoms: fever, weight loss, malaise, arthralgias/arthritis Limb claudication Asymmetric blood pressures Absence of pulses Bruits Aortic dilation

Cutaneous nodules Ulcers Livedo reticularis Digital gangrene Mononeuritis multiplex Microaneurysms

Purpura Vesiculobullous lesions Urticaria Glomerulonephritis Alveolar hemorrhage Cutaneous extravascular necrotizing granulomas Splinter hemorrhages Uveitis Episcleritis Scleritis

therapy, whereas giant cell arteritis can cause blindness and large artery complications and requires high-dose (40–60 mg/d) prednisone.

``Clinical Findings A. Polymyalgia Rheumatica Polymyalgia rheumatica is a clinical diagnosis based on pain and stiffness of the shoulder and pelvic girdle areas, frequently in association with fever, malaise, and weight loss. In approximately two-thirds of cases, polymyalgia occurs in the absence of giant cell arteritis. Because of the stiffness and pain in the shoulders, hips, and lower back, patients have trouble combing their hair, putting on a coat, or rising from a chair. In contrast to polymyositis and polyarteritis nodosa, polymyalgia rheumatica does not cause muscular weakness either through primary muscle inflammation or secondary to nerve infarction. A few patients have joint swelling, particularly of the knees, wrists, and sternoclavicular joints.

B. Giant Cell Arteritis Giant cell arteritis is a systemic panarteritis affecting medium-sized and large vessels in patients over the age of 50. The incidence of this disease increases with each decade of life. The mean age at onset is approximately 79 years.

Giant cell arteritis is also called temporal arteritis because that artery is frequently involved, as are other extracranial branches of the carotid artery. About 50% of patients with giant cell arteritis also have polymyalgia rheumatica. The classic symptoms suggesting that a patient has arteritis are headache, scalp tenderness, visual symptoms (particularly amaurosis fugax or diplopia), jaw claudication, or throat pain. Of these symptoms, jaw claudication has the highest positive predictive value. The temporal artery is usually normal on physical examination but may be nodular, enlarged, tender, or pulseless. Blindness usually results from the syndrome of anterior ischemic optic neuropathy, caused by occlusive arteritis of the posterior ciliary branch

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of the ophthalmic artery. The ischemic optic neuropathy of giant cell arteritis may produce no funduscopic findings for the first 24–48 hours after the onset of blindness.

Asymmetry of pulses in the arms, a murmur of aortic regurgitation, or bruits heard near the clavicle resulting from subclavian artery stenoses identify patients in whom giant cell arteritis has affected the aorta or its major branches. Clinically evident large vessel involvement— characterized chiefly by aneurysm of the thoracic aorta or stenosis of the subclavian, vertebral, carotid, and basilar arteries—occurs in approximately 25% of patients with giant cell arteritis, sometimes years after the diagnosis.

Subclinical large artery disease is the rule: positron emission tomography scans reveal inflammation in the aorta and its major branches in nearly 85% of untreated patients.

Forty percent of patients with giant cell arteritis have nonclassic symptoms at presentation, chiefly respiratory tract problems (most frequently dry cough), mononeuritis multiplex (most frequently with painful paralysis of a shoulder), or fever of unknown origin. Giant cell arteritis accounts for 15% of all cases of fever of unknown origin in patients over the age of 65. The fever can be as high as 40°C and is frequently associated with rigors and sweats. In contrast to patients with infection, patients with giant cell arteritis and fever usually have normal white blood cell counts (before prednisone is started). Thus, in an older patient with fever of unknown origin, marked elevations of acute phase reactants, and a normal white blood count, giant cell arteritis must be considered even in the absence of specific features such as headache or jaw claudication. In some cases, instead of having the well-known symptom of jaw claudication, patients complain of vague pain affecting other locations, including the tongue, nose, or ears. Indeed, unexplained head or neck pain in an older patient may signal the presence of giant cell arteritis.

C. Laboratory Findings 1. Polymyalgia rheumatica—Anemia and elevated acute phase reactants (often markedly elevated ESRs, for example) are present in the most cases, but cases of polymyalgia rheumatica occurring with normal acute phase reactants are well documented.

2. Giant cell arteritis—Nearly 90% of patients with giant cell arteritis have ESRs > 50 mm/h. The ESR in this disorder is often > 100 mm/h, but cases in which the ESR is low or even normal do occur. In one series, 5% of patients with biopsy-proven giant cell arteritis had ESRs < 40 mm/h.

Although the C-reactive protein is slightly more sensitive, patients with biopsy-proven giant cell arteritis with normal C-reactive proteins have also been described. Most patients also have a mild normochromic, normocytic anemia and thrombocytosis. The alkaline phosphatase (liver source) is elevated in 20% of patients with giant cell arteritis.

``Differential Diagnosis The differential diagnosis of malaise, anemia, and striking acute phase reactant elevations includes rheumatic diseases (such as rheumatoid arthritis, other systemic vasculitides,

multiple myeloma, and other malignant disorders) and chronic infections (such as bacterial endocarditis and osteomyelitis).

``Treatment A. Polymyalgia Rheumatica Patients with isolated polymyalgia rheumatica (ie, those not having “above the neck” symptoms of headache, jaw claudication, scalp tenderness, or visual symptoms) are treated with prednisone, 10–20 mg/d orally. If the patient does not experience a dramatic improvement within 72 hours, the diagnosis should be revisited. Usually after 2–4 weeks of treatment, slow tapering of the prednisone can be attempted. Most patients require some dose of prednisone for a minimum of approximately 1 year; 6 months is too short in most cases. Disease flares are common (50% or more) as prednisone is tapered. The addition of weekly methotrexate may increase the chance of successfully tapering prednisone in some patients.

B. Giant Cell Arteritis The urgency of early diagnosis and treatment in giant cell arteritis relates to the prevention of blindness. Once blindness develops, it is usually permanent. Therefore, when a patient has symptoms and findings suggestive of temporal arteritis, therapy with prednisone (60 mg/d orally) should be initiated immediately and a temporal artery biopsy performed promptly. For patients who seek medical attention for visual loss, intravenous pulse methylprednisolone (eg, 1 g daily for 3 days) has been advocated; unfortunately, few patients recover vision no matter what the initial treatment.

One study—too small and too preliminary to change the standard therapy recommendations mentioned above— suggested that initiating treatment with intravenous pulse methylprednisolone may increase the chance that a patient with giant cell arteritis will achieve remission and be able to taper off of prednisone. Retrospective studies suggest that low-dose aspirin (~81 mg/d orally) may reduce the chance of visual loss or stroke in patients with giant cell arteritis and should be added to prednisone in the initial treatment.

Although it is prudent to obtain a temporal artery biopsy as soon as possible after instituting treatment, diagnostic findings of giant cell arteritis may still be present 2 weeks (or even considerably longer) after starting corticosteroids.

Typically, a positive biopsy shows inflammatory infiltrate in the media and adventitia with lymphocytes, histiocytes, plasma cells, and giant cells. An adequate biopsy specimen is essential (at least 2 cm in length is ideal), because the disease may be segmental. Unilateral temporal artery biopsies are positive in approximately 80–85% of patients, but bilateral biopsies add incrementally to the yield (10–15% in some studies, less in others). Ultrasonography can detect abnormalities in inflamed temporal arteries, but it has not displaced temporal artery biopsy as the gold standard for diagnosis in most cases because results are highly operator dependent. Temporal artery biopsy is abnormal in only 50% of patients with large artery disease (eg, arm claudication and unequal upper extremity blood pressures). In these

Musculoskeletal & Immunologic Disorders patients, magnetic resonance angiography or CT angiography will establish the diagnosis by demonstrating long stretches of narrowing of the subclavian and axillary arteries.

Prednisone should be continued in a dosage of 60 mg/d orally for about 1 month before tapering. When only the symptoms of polymyalgia rheumatica are present, temporal artery biopsy is not necessary.

After 1 month of high-dose prednisone, almost all patients will have a normal ESR. When tapering and adjusting the dosage of prednisone, the ESR (or C-reactive protein) is a useful but not absolute guide to disease activity. A common error is treating the ESR rather than the patient.

The ESR often rises slightly as the prednisone is tapered, even as the disease remains quiescent. Because elderly individuals often have baseline ESRs that are above the normal range, mild ESR elevations should not be an occasion for renewed treatment with prednisone in patients who are asymptomatic. Unfortunately, no highly effective prednisonesparing therapy has been identified. Methotrexate was modestly effective in one double-blind, placebo-controlled treatment trial but ineffective in another. Anti-TNF therapies do not work in giant cell arteritis. Thoracic aortic aneurysms occur 17 times more frequently in patients with giant cell arteritis than in normal individuals and can result in aortic regurgitation, dissection, or rupture. The aneurysms can develop at any time but typically occur 7 years after the diagnosis of giant cell arteritis is made.

Gonzalez-Gay MA et al. Medical management of polymyalgia rheumatica.ExpertOpinPharmacother.2010May;11(7):1077–87.

[PMID: 20367535] Scheurer RA et al. Treatment of vision loss in giant cell arteritis.

Curr Treat Options Neurol. 2012 Feb;14(1):84-92. [PMID: 22037998]

POLYARTERITIS NODOSA ``

E s s en t ia l S o f dia g n o s i s

Medium-sized arteries are always affected; smaller arterioles are sometimes involved; lung is spared but kidney often affected, causing renin-mediated hypertension.

Clinical findings depend on the arteries involved.

Common features include fever, abdominal pain, extremity pain, livedo reticularis, mononeuritis multiplex, anemia, and elevated acute phase reactants (ESR or C-reactive protein or both).

Associated with hepatitis B (10% of cases).

``

`` ``

``

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decades, numerous subtypes of vasculitis have been recognized, greatly narrowing the spectrum of vasculitis called polyarteritis nodosa. Currently, the term is reserved for necrotizing arteritis of medium-sized vessels that has a predilection for involving the skin, peripheral nerves, mesenteric vessels (including renal arteries), heart, and brain, but polyarteritis nodosa can actually involve almost any organ. Polyarteritis nodosa is relatively rare, with a prevalence of about 30 per 1 million people. Approximately 10% of cases of polyarteritis nodosa are caused by hepatitis B. Most cases of hepatitis B–associated disease occur within 6 months of hepatitis B infection.

``Clinical Findings A. Symptoms and Signs The clinical onset is usually insidious, with fever, malaise, weight loss, and other symptoms developing over weeks to months. Pain in the extremities is often a prominent early feature caused by arthralgia, myalgia (particularly affecting the calves), or neuropathy. The combination of mononeuritis multiplex (with the most common finding being footdrop) and features of a systemic illness is one of the earliest specific clues to the presence of an underlying vasculitis.

Polyarteritis nodosa is among the forms of vasculitis most commonly associated with vasculitic neuropathy.

In polyarteritis nodosa, the typical skin findings— livedo reticularis, subcutaneous nodules, and skin ulcers— reflect the involvement of deeper, medium-sized blood vessels. Digital gangrene is not an unusual occurrence. The most common cutaneous presentation is lower extremity ulcerations, usually occurring near the malleoli. Involvement of the renal arteries leads to a renin-mediated hypertension (much less characteristic of vasculitides involving smaller blood vessels). For unclear reasons, classic polyarteritis nodosa seldom (if ever) involves the lung, with the occasional exception of the bronchial arteries.

Abdominal pain—particularly diffuse periumbilical pain precipitated by eating—is common but often difficult to attribute to mesenteric vasculitis in the early stages.

Nausea and vomiting are common symptoms. Infarction compromises the function of major viscera and may lead to acalculous cholecystitis or appendicitis. Some patients present dramatically with an acute abdomen caused by mesenteric vasculitis and gut perforation or with hypotension resulting from rupture of a microaneurysm in the liver, kidney, or bowel.

Subclinical cardiac involvement is common in polyarteritis nodosa, and overt cardiac dysfunction occasionally occurs (eg, myocardial infarction secondary to coronary vasculitis, or myocarditis).

B. Laboratory Findings

``General Considerations Polyarteritis nodosa, described in 1866, is acknowledged widely as the first form of vasculitis reported in the medical literature. For many years, all forms of inflammatory vascular disease were termed “polyarteritis nodosa.” In recent

Most patients with polyarteritis nodosa have a slight anemia, and leukocytosis is common. Acute phase reactants are often (but not always) strikingly elevated. A major challenge in making the diagnosis of polyarteritis nodosa, however, is the absence of a disease-specific serologic test (eg, an autoantibody). Patients with classic polyarteritis nodosa are

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ANCA-negative and may have low titers of rheumatoid factor or antinuclear antibodies, both of which are nonspecific findings. In patients with polyarteritis nodosa, appropriate serologic tests for active hepatitis B infection must be performed.

C. Biopsy and Angiography The diagnosis of polyarteritis nodosa requires confirmation with either a tissue biopsy or an angiogram. Biopsies of symptomatic sites such as skin (from the edge of an ulcer or the center of a nodule), nerve, or muscle have sensitivities of approximately 70%. The least invasive tests should usually be obtained first, but biopsy of an involved organ is essential. If performed by experienced clinicians, tissue biopsies normally have high benefit-risk ratios because of the importance of establishing the diagnosis.

Patients in whom polyarteritis nodosa is suspected—eg, on the basis of mesenteric ischemia or new-onset hypertension occurring in the setting of a systemic illness—may be diagnosed by the angiographic finding of aneurysmal dilations in the renal, mesenteric, or hepatic arteries. Angiography must be performed cautiously in patients with baseline renal dysfunction.

de Menthon M et al. Treating polyarteritis nodosa: current state of the art. Clin Exp Rheumatol. 2011 Jan–Feb;29(1 Suppl 64): S110–6. [PMID: 21586205] Morgan AJ et al. Cutaneous polyarteritis nodosa: a comprehensive review. Int J Dermatol. 2010 Jul;49(7):750–6. [PMID: 20618492] Pagnoux C et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis Rheum.

2010 Feb;62(2):616–26. [PMID: 20112401]

GRANULOMATOSIS WITH POLYANGIITIS (Formerly Wegener Granulomatosis) ``

For polyarteritis nodosa, corticosteroids in high doses (up to 60 mg of oral prednisone daily) may control fever and constitutional symptoms and heal vascular lesions. Pulse methylprednisolone (eg, 1 g intravenously daily for 3 days) may be necessary for patients who are critically ill at presentation. Immunosuppressive agents, especially cyclophosphamide, lower the risk of disease-related death and morbidity among patients who have severe disease. For patients with polyarteritis nodosa associated with hepatitis B, the preferred treatment regimen is a short course of prednisone accompanied by antiviral therapy and plasmapheresis (three times a week for up to 6 weeks).

``Prognosis Without treatment, the 5-year survival rate in these disorders is poor—on the order of 10%. With appropriate therapy, remissions are possible in many cases and the 5-year survival rate has improved to 60–90%. Poor prognostic factors are chronic kidney disease with serum creatinine > 1.6 mg/dL, proteinuria > 1 g/d, gastrointestinal ischemia, central nervous system disease, and cardiac involvement. In the absence of any of these five factors, 5-year survival is nearly 90%. Survival at 5 years drops to 75% with one poor prognostic factor present and to about 50% with two or more factors. Substantial morbidity and even death may result from adverse effects of cyclophosphamide and corticosteroids. Consequently, these therapies require careful monitoring and expert management. In contrast to many other forms of systemic vasculitis, disease relapses in polyarteritis following the successful induction of remission are the exception rather than the rule, occurring in only about 20% of cases.

Classic triad of upper and lower respiratory tract disease and glomerulonephritis.

Suspect if mild respiratory symptoms (eg, nasal congestion, sinusitis) are refractory to usual treatment.

Pathology defined by the triad of small vessel vasculitis, granulomatous inflammation, and necrosis.

ANCAs, usually directed against proteinase-3 (less commonly against myeloperoxidase present in severe, active disease) (90% of patients).

Kidney disease often rapidly progressive without treatment.

``

``

``

``Treatment

E s s en t ia l S o f dia g n o s i s

``

``

``General Considerations Granulomatosis with polyangiitis, which has an estimated incidence of approximately 12 cases per million individuals per year, is the prototype of diseases associated with antineutrophil cytoplasmic antibodies (ANCA). (Other “ANCAassociated vasculitides” include microscopic polyangiitis and the Churg-Strauss syndrome.) Granulomatosis with polyangiitis is characterized in its full expression by vasculitis of small arteries, arterioles, and capillaries, necrotizing granulomatous lesions of both upper and lower respiratory tract, glomerulonephritis, and other organ manifestations.

Without treatment, generalized disease is invariably fatal, with most patients surviving < 1 year after diagnosis. It occurs most commonly in the fourth and fifth decades of life and affects men and women with equal frequency.

``Clinical Findings A. Symptoms and Signs The disorder usually develops over 4–12 months. Upper respiratory tract symptoms develop in 90% of patients and lower respiratory tract symptoms develop in 60% of patients; some patients may have both upper and lower respiratory tract symptoms. Upper respiratory tract symptoms can include nasal congestion, sinusitis, otitis media, mastoiditis, inflammation of the gums, or stridor due to subglottic stenosis. Since many of these symptoms are common, the

Musculoskeletal & Immunologic Disorders

s Figure 20–7. Scleritis in a patient with granulomatosis with polyangiitis (formerly Wegener granulomatosis). (Courtesy of Everett Allen, MD; used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)

underlying disease is not often suspected until the patient develops systemic symptoms or the original problem is refractory to treatment. The lungs are affected initially in 40% and eventually in 80%, with symptoms including cough, dyspnea, and hemoptysis. Other early symptoms can include a migratory oligoarthritis with a predilection for large joints; a variety of symptoms related to ocular disease (unilateral proptosis from orbital pseudotumor; red eye from scleritis [Figure 20–7], episcleritis, anterior uveitis, or peripheral ulcerative keratitis); purpura or other skin lesions; and dysesthesia due to neuropathy. Renal involvement, which develops in three-fourths of the cases, may be subclinical until kidney disease is advanced. Fever, malaise, and weight loss are common.

Physical examination can be remarkable for congestion, crusting, ulceration, bleeding, and even perforation of the nasal septum. Destruction of the nasal cartilage with “saddle nose” deformity occurs late. Otitis media, proptosis, scleritis, episcleritis, and conjunctivitis are other common findings.

Newly acquired hypertension, a frequent feature of polyarteritis nodosa, is rare in granulomatosis with polyangiitis. Venous thrombotic events (eg, deep venous thrombosis and pulmonary embolism) are a common occurrence in granulomatosis with polyangiitis, at least in part because of the tendency of the disease to involve veins as well as arteries. Although limited forms of granulomatosis with polyangiitis have been described in which the kidney is spared initially, kidney disease will develop in the majority of untreated patients.

B. Laboratory Findings 1. Serum tests and urinalysis—Most patients have slight anemia, mild leukocytosis, and elevated acute phase reactants.

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If there is renal involvement, there is proteinuria and the urinary sediment contains red cells, with or without white cells, and often has red cell casts.

Serum tests for ANCA help in the diagnosis of granulomatosis with polyangiitis and related forms of vasculitis (Table 20–10). Several different types of ANCA are recognized, but the two subtypes relevant to systemic vasculitis are those directed against proteinase-3 (PR3) and myeloperoxidase (MPO). Antibodies to these two antigens are termed “PR3-ANCA” and “MPO-ANCA,” respectively. The cytoplasmic pattern of immunofluorescence (c-ANCA) caused by PR3-ANCA has a high specificity (> 90%) for either granulomatosis with polyangiitis or a closely related disease, microscopic polyangiitis (or, less commonly, the Churg-Strauss syndrome). In the setting of active disease, particularly cases in which the disease is severe and generalized to multiple organ systems, the sensitivity of PR3ANCA is > 95%. A substantial percentage of patients with “limited” granulomatosis with polyangiitis—disease that does not pose an immediate threat to life and is often confined to the respiratory tract—are ANCA-negative.

Although ANCA testing may be very helpful when used properly, it does not eliminate the need in most cases for confirmation of the diagnosis by tissue biopsy.

Furthermore, ANCA levels correlate erratically with disease activity, and changes in titer should not dictate changes in therapy in the absence of supporting clinical data. The perinuclear (p-ANCA) pattern, caused by MPOANCA, is more likely to occur in microscopic polyangiitis or Churg-Strauss but may also be found in granulomatosis with polyangiitis. Approximately 10–25% of patients with classic granulomatosis with polyangiitis have MPO-ANCA. All positive immunofluorescence assays for ANCA should be confirmed by enzyme immunoassays for the specific autoantibodies directed against PR3 or MPO. 2. Histologic findings—Histologic features of granulomatosis with polyangiitis include vasculitis, granulomatous inflammation, geographic necrosis, and acute and chronic inflammation. The full range of pathologic changes is usually evident only on thoracoscopic lung biopsy. Granulomas, observed only rarely in renal biopsy specimens, are found much more commonly on lung biopsy specimens. Nasal biopsies often do not show vasculitis but may show chronic inflammation and other changes which, interpreted by an experienced pathologist, can serve as convincing evidence of the diagnosis. Renal biopsy discloses a segmental necrotizing glomerulonephritis with multiple crescents; this is characteristic but not diagnostic. Pathologists characterize the renal lesion of granulomatosis with polyangiitis (and other forms of “ANCA-associated vasculitis”) as a pauciimmune glomerulonephritis because of the relative absence (compared with immune complex–mediated disorders) of immunoreactants—IgG, IgM, IgA, and complement proteins—within glomeruli.

C. Imaging Chest CT is more sensitive than chest radiography; lesions include infiltrates, nodules, masses, and cavities. Pleural effusions are uncommon. Often the radiographs prompt

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concern about lung cancer. Hilar adenopathy is unusual in granulomatosis with polyangiitis; if present, sarcoidosis, tumor, or infection is more likely. Other common radiographic abnormalities include extensive sinusitis and even bony sinus erosions.

``Differential Diagnosis In most patients with granulomatosis with polyangiitis, refractory sinusitis or otitis media is initially suspected.

When upper respiratory tract inflammation persists and is accompanied by additional systemic inflammatory signs (eg, red eye from scleritis, joint pain and swelling), the diagnosis of granulomatosis with polyangiitis should be considered.

Rheumatoid arthritis will wrongly be suspected in a substantial minority of patients who chiefly complain of joint pain. Arriving at the correct diagnosis is aided by awareness that rheumatoid arthritis typically involves small joints of the hand, whereas granulomatosis with polyangiitis favors large joints, such as the hip, knee, elbow, and shoulder. Lung cancer may be the first diagnostic consideration for some middle-aged patients in whom cough, hemoptysis, and lung masses are presenting symptoms and signs; typically, evidence of glomerulonephritis, a positive ANCA or, ultimately, the lung biopsy findings will point to the proper diagnosis.

Granulomatosis with polyangiitis shares with SLE, anti– glomerular basement membrane disease, and microscopic polyangiitis the ability to cause an acute pulmonary-renal syndrome. Approximately 10–25% of patients with classic granulomatosis with polyangiitis have MPO-ANCA. Owing to involvement of the same types of blood vessels, similar patterns of organ involvement, and the possibility of failing to identify granulomatous pathology on tissue biopsies because of sampling error, granulomatosis with polyangiitis is often difficult to differentiate from microscopic polyangiitis. The crucial distinctions between the two disorders are the tendencies for granulomatosis with polyangiitis to involve the upper respiratory tract (including the ears) and to cause granulomatous inflammation.

``Treatment Early treatment is crucial in preventing the devastating endorgan complications of this disease, and often in preserving life. While granulomatosis with polyangiitis may involve the sinuses or lung for months, once proteinuria or hematuria develops, progression to advanced chronic kidney disease can be rapid (over several weeks). For patients with severe disease, the combination of cyclophosphamide and prednisone is the standard of care. Remissions can be induced in more than 90% of patients treated with prednisone (1 mg/kg daily) plus cyclophosphamide (2 mg/kg/d orally with adjustments required for renal insufficiency and age > 70 years old). Cyclophosphamide is best given daily by mouth; intermittent high-dose intravenous cyclophosphamide is less effective. The current approach to remission induction in severe cases is to use cyclophosphamide for 3–6 months, followed by a switch to a regimen more likely to be tolerated well. Unfortunately, disease relapses occur in a substantial proportion of those patients who achieve remission. In

patients with remission induced by 3–6 months of cyclophosphamide and corticosteroids, azathioprine (up to 2 mg/ kg/d orally) has been shown to be as effective as cyclophosphamide in maintaining disease remissions (at least for up to 12–15 months). Before the institution of azathioprine, patients should be tested (through a commercially available blood test) for deficiencies in the level of thiopurine methyltransferase, an enzyme essential to the metabolism of azathioprine. Another option for remission maintenance is methotrexate, 20–25 mg/wk (administered either orally or intramuscularly). Because of its superior side-effect profile, methotrexate is viewed as an appropriate substitute for cyclophosphamide for initial treatment in patients who do not have significant renal dysfunction (of any cause) or immediately life-threatening disease. Treatment with TNF inhibitors, particularly etanercept, is not effective.

Rituximab, a B-cell-depleting monoclonal antibody, has been shown to be as effective as cyclophosphamide for patients who have never been treated and may be more effective than cyclophosphamide for treating relapses.

However, rituximab’s high cost, its undefined long-term health effects, and its association with opportunistic infections (including progressive multifocal leukoencephalopathy [PML]) indicate that defining rituximab’s precise role in treating ANCA-associated vasculitis requires additional study.

Hiemstra TF et al; European Vasculitis Study Group (EUVAS).

Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA. 2010 Dec 1; 304(21):2381–8. [PMID: 21060104] Stone JH et al. Rituximab versus cyclophosphamide for ANCAassociated vasculitis. N Engl J Med. 2010 Jul 15;363(3):221–32.

[PMID: 20647199] Walsh M et al; European Vasculitis Study Group. Risk factors for relapse of ANCA associated vasculitis. Arthritis Rheum. 2012 Feb; 64(2):542–8. [PMID: 21953279]

MICROSCOPIC POLYANGIITIS ``

E s s en t ia l S o f dia g n o s i s

Necrotizing vasculitis of small- and medium-sized arteries and veins.

Most common cause of pulmonary-renal syndrome: diffuse alveolar hemorrhage and glomerulonephritis.

Associated with ANCA in 75% of cases, usually anti-myeloperoxidase antibodies (MPO-ANCA) that cause a p-ANCA pattern on immunofluorescence testing. ANCA directed against proteinase-3 (PR3-ANCA) can also be observed.

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``

``

``General Considerations Microscopic polyangiitis is a pauci-immune nongranulomatous necrotizing vasculitis that (1) affects small blood vessels (capillaries, venules, or arterioles), (2) often causes

Musculoskeletal & Immunologic Disorders glomerulonephritis and pulmonary capillaritis, and (3) is often associated with ANCA on immunofluorescence testing (directed against MPO, a constituent of neutrophil granules). Because microscopic polyangiitis may involve medium-sized as well as small blood vessels and because it tends to affect capillaries within the lungs and kidneys, its spectrum overlaps those of both polyarteritis nodosa and granulomatosis with polyangiitis.

In rare instances, medications, particularly propylthiouracil, hydralazine, allopurinol, penicillamine, minocycline, and sulfasalazine, induce a systemic vasculitis associated with high titers of MPO-ANCA and features of microscopic polyangiitis.

``Clinical Findings A. Symptoms and Signs A wide variety of findings suggesting vasculitis of small blood vessels may develop in microscopic polyangiitis.

These include “palpable” (or “raised”) purpura and other signs of cutaneous vasculitis (ulcers, splinter hemorrhages, vesiculobullous lesions).

Microscopic polyangiitis is the most common cause of pulmonary-renal syndromes, being several times more common than anti–glomerular basement membrane disease. Interstitial lung fibrosis that mimics usual interstitial pneumonitis is the presenting condition. Pulmonary hemorrhage may occur. The pathologic findings in the lung are typically those of capillaritis.

Vasculitic neuropathy (mononeuritis multiplex) is also common in microscopic polyangiitis.

B. Laboratory Findings As noted, three-fourths of patients with microscopic polyangiitis are ANCA-positive. Elevated acute phase reactants are also typical of active disease. Microscopic hematuria, proteinuria, and red blood cell casts in the urine may occur.

The renal lesion is a segmental, necrotizing glomerulonephritis, often with localized intravascular coagulation and the observation of intraglomerular thrombi upon renal biopsy.

``Differential Diagnosis Distinguishing this disease from granulomatosis with polyangiitis may be challenging in some cases. Microscopic polyangiitis is not associated with the chronic destructive upper respiratory tract disease often found in granulomatosis with polyangiitis. Moreover, as noted, a critical difference between the two diseases is the absence of granulomatous inflammation in microscopic polyangiitis. Because their treatments may differ, microscopic polyangiitis must also be differentiated from polyarteritis nodosa.

``Treatment In microscopic polyangiitis, patients are likely to require prednisone and cyclophosphamide because of the urgency in treating pulmonary hemorrhage and glomerulonephritis.

Cyclophosphamide may be administered either in an oral

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daily regimen or via intermittent (usually monthly) intravenous pulses. Whenever cyclophosphamide is used, Pneumocystis jiroveci prophylaxis with either single-strength oral trimethoprim-sulfamethoxazole or dapsone 100 mg/d is essential. Following the induction of remission, azathioprine is a reasonable choice to replace cyclophosphamide. In cases of drug-induced MPO-ANCA- associated vasculitis, the offending medication should be discontinued; significant organ involvement (eg, pulmonary hemorrhage, glomerulonephritis) requires immunosuppressive therapy.

Rituximab has been shown to be as effective as cyclophosphamide in treating ANCA-associated vasculitis.

``Prognosis The key to effecting good outcomes is early diagnosis.

Compared with patients who have granulomatosis with polyangiitis, those who have microscopic polyangiitis are more likely to have significant fibrosis on renal biopsy because of later diagnosis. The likelihood of disease recurrence following remission in microscopic polyangiitis is about 33%.

Corral-Gudino L et al. Overall survival, renal survival and relapse in patients with microscopic polyangiitis: a systematic review of current evidence. Rheumatology (Oxford). 2011 Aug;50(8):1414–23. [PMID: 21406467] Silva F et al. Mycophenolate mofetil for induction and maintenance of remission in microscopic polyangiitis with mild to moderate renal involvement–a prospective, open-label pilot trial. Clin J Am Soc Nephrol. 2010 Mar;5(3):445–53. [PMID: 20093349]

CRYOGLOBULINEMIA Cryoglobulinemia can be associated with an immunecomplex mediated, small-vessel vasculitis. Chronic infection with hepatitis C is the most common underlying condition; cryoglobulinemic vasculitis also can occur in the setting of other chronic infections, such as subacute bacterial endocarditis and osteomyelitis, and with connective tissues diseases, especially Sjögren syndrome. The cryoglobulins associated with vasculitis are cold-precipitable immune complexes consisting of rheumatoid factor and IgG (rheumatoid factor is an autoantibody to the constant region of IgG). The rheumatoid factor component can be monoclonal (type II cryoglobulins) or polyclonal (type III cryoglobulins). (Type I cryoglobulins are cryoprecipitable monoclonal proteins that lack rheumatoid factor activity; these cause cold-induced hyperviscosity syndromes, not vasculitis, and are associated with lymphoproliferative disease.)

``Clinical Findings Cryoglobulinemic vasculitis typically manifests as recurrent palpable purpura and peripheral neuropathy. A proliferative glomerulonephritis can develop and can manifest as rapidly progressive glomerulonephritis. Abnormal liver function tests, abdominal pain, and pulmonary disease may also occur. The diagnosis is based on a compatible

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clinical picture and a positive serum test for cryoglobulins.

The presence of a disproportionately low C4 level can be a diagnostic clue to the presence of cryoglobulinemia.

``Treatment Asymptomatic cryoglobulinemia is common in hepatitis C–infected individuals and does not in itself warrant treatment. The optimal approach to treatment of hepatitis C–associated cryoglobulinemic vasculitis is viral suppression with pegylated forms of interferon-α and ribavirin.

Because immunosuppressive agents may facilitate viral replication, corticosteroids, cyclophosphamide, and other interventions (including plasmapheresis) should be reserved for organ-threatening complications. B cell depletion using rituximab appears to be a promising avenue of therapy.

Ferri C et al. Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: results of multicenter cohort study and review of the literature. Autoimmun Rev. 2011 Nov;11(1):48–55. [PMID: 21821153] Iannuzzella F et al. Management of hepatitis C virus-related mixed cryoglobulinemia. Am J Med. 2010 May;123(5):400–8.

[PMID: 20399313]

HENOCH-SCHöNLEIN PURPURA Henoch-Schönlein purpura, the most common systemic vasculitis in children, occurs in adults as well. Typical features are palpable purpura (Figure 20–8), arthritis, and hematuria. Abdominal pain occurs less frequently in adults than in children. Pathologic features include leukocytoclastic vasculitis with IgA deposition. The cause is not known.

The purpuric skin lesions are typically located on the lower extremities but may also be seen on the hands, arms, trunk, and buttocks. Joint symptoms are present in the majority of patients, the knees and ankles being most commonly involved. Abdominal pain secondary to vasculitis of the intestinal tract is often associated with gastrointestinal bleeding. Hematuria signals the presence of a renal lesion that is usually reversible, although it occasionally may progress to chronic kidney disease. Children tend to have more frequent and more serious gastrointestinal vasculitis, whereas adults more often suffer from chronic kidney disease. Biopsy of the kidney reveals segmental glomerulonephritis with crescents and mesangial deposition of IgA. Chronic courses with persistent or intermittent skin disease are more likely to occur in adults than in children. The value of corticosteroids has been controversial. In children or adults, prednisone (1 mg/kg/d orally) may benefit those with severe extrarenal manifestations and with evidence of kidney disease. The incremental efficacy of steroid-sparing drugs such as azathioprine and mycophenolate mofetil—often used in the setting of kidney disease—is not known.

Jithpratuck W et al. The clinical implications of adult-onset Henoch-Schönlein purpura. Clin Mol Allergy. 2011 May 27; 9(1):9. [PMID: 21619657] McCarthy HJ et al. Clinical practice: diagnosis and management of Henoch-Schönlein purpura. Eur J Pediatr. 2010 Jun;169(6): 643–50. [PMID: 20012647]

s Figure 20–8. Palpable purpura in a woman with leukocytoclastic vasculitis. (Courtesy of Eric Kraus, MD; used, with permission, from Usatine RP, Smith MA, Mayeaux EJ Jr, Chumley H, Tysinger J. The Color Atlas of Family Medicine. McGraw-Hill, 2009.)

RELAPSING POLYCHONDRITIS This disease is characterized by inflammatory destructive lesions of cartilaginous structures, principally the ears, nose, trachea, and larynx. Nearly 40% of cases are associated with another disease, especially either other immunologic disorders (such as SLE, rheumatoid arthritis, or Hashimoto thyroiditis) or cancers (such as multiple myeloma) or hematologic disorders (such as myelodysplastic syndrome). The disease, which is usually episodic, affects males and females equally.

The cartilage is painful, swollen, and tender during an attack and subsequently becomes atrophic, resulting in permanent deformity. Biopsy of the involved cartilage shows inflammation and chondrolysis. Noncartilaginous manifestations of the disease include fever, episcleritis, uveitis, deafness, aortic insufficiency, and rarely glomerulonephritis. In 85% of patients, a migratory, asymmetric, and seronegative arthropathy occurs, affecting both large and small joints and the costochondral junctions. Diagnosing this uncommon disease is especially difficult since the signs of cartilage inflammation (such as red ears or nasal pain) may be more subtle than the fever, arthritis, rash, or other systemic manifestations.

Prednisone, 0.5–1 mg/kg/d orally, is often effective.

Dapsone (100–200 mg/d orally) or methotrexate (7.5–20 mg orally per week) may also have efficacy, sparing the need for long-term high-dose corticosteroid treatment. Involvement

Musculoskeletal & Immunologic Disorders of the tracheobronchial tree, leading to tracheomalacia, may lead to difficult management issues.

Lahmer T et al. Relapsing polychondritis: An autoimmune disease with many faces. Autoimmun Rev. 2010 Jun;9(8):540–6.

[PMID: 20215048] Yoo JH et al. Relapsing polychondritis: systemic and ocular manifestations, differential diagnosis, management, and prognosis. Semin Ophthalmol. 2011 Jul–Sep;26(4–5):261–9.

[PMID: 21958172]

BEHçET SYNDROME ``

E s s en t ia l S o f dia g n o s i s

Most commonly occurs among persons of Asian, Turkish, or Middle Eastern background, but may affect persons of any demographic profile.

Recurrent, painful aphthous ulcers of the mouth and genitals.

Erythema nodosum–like lesions; a follicular rash; and the pathergy phenomenon (formation of a sterile pustule at the site of a needle stick).

Either anterior or posterior uveitis. Posterior uveitis may be asymptomatic until significant damage to the retina has occurred.

Variety of neurologic lesions that can mimic multiple sclerosis, particularly through involvement of the white matter of the brainstem.

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``General Considerations Named after the Turkish dermatologist who first described it, this disease is of unknown cause. Its protean manifestations are believed to result from vasculitis that may involve all types of blood vessels: small, medium, and large, on both the arterial and venous side of the circulation.

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(unless the patient is asked); in this phenomenon, sterile pustules develop at sites where needles have been inserted into the skin (eg, for phlebotomy) in some patients.

A nonerosive arthritis occurs in about two-thirds of patients, most commonly affecting the knees and ankles.

Eye involvement may be one of the most devastating complications of Behçet disease. Posterior uveitis, in essence a retinal venulitis, may lead to the insidious destruction of large areas of the retina before the patient becomes aware of visual problems. Anterior uveitis, associated with photophobia and a red eye, is intensely symptomatic. This complication may lead to a hypopyon, the accumulation of pus in the anterior chamber. If not treated properly with mydriatic agents to dilate the pupil and corticosteroid eyedrops to diminish inflammation, the anterior uveitis may lead to synechial formation between the iris and lens, resulting in permanent pupillary distortion.

Central nervous system involvement is another cause of major potential morbidity. The central nervous system lesions that may mimic multiple sclerosis radiologically often result in serious disability or death. Findings include sterile meningitis (recurrent meningeal headaches associated with a lymphocytic pleocytosis), cranial nerve palsies, seizures, encephalitis, mental disturbances, and spinal cord lesions. Aphthous ulcerations of the ileum and cecum and other forms of gastrointestinal involvement develop in approximately a quarter of patients. Large vessel vasculitis can lead to pulmonary artery aneurysms and life-threatening pulmonary hemorrhage. Finally, patients have a hypercoagulable tendency that may lead to complicated venous thrombotic events, particularly multiple deep venous thrombosis, pulmonary emboli, cerebral sinus thrombosis, and other problems associated with clotting.

The clinical course may be chronic but is often characterized by remissions and exacerbations.

B. Laboratory Findings

``Clinical Findings

There are no pathognomonic laboratory features of Behçet disease. Although acute phase reactants are often elevated, there is no autoantibody or other assay that is distinctive.

No markers of hypercoagulability specific to Behçet have been identified.

A. Symptoms and Signs

``Treatment

The hallmark of Behçet disease is painful aphthous ulceration in the mouth (see Figure 8–7). These lesions, which usually occur multiply, may be found on the tongue, gums, and inner surfaces of the oral cavity. Genital lesions, similar in appearance, are also common but do not occur in all patients. Other cutaneous lesions of Behçet disease include tender, erythematous, papular lesions that resemble erythema nodosum. (On biopsy, however, many of these lesions are shown to be secondary to vasculitis rather than septal panniculitis.) These erythema nodosum–like lesions have a tendency to ulcerate, a major difference between the lesions of Behçet disease and the erythema nodosum seen in cases of sarcoidosis and inflammatory bowel disease. An erythematous follicular rash that occurs frequently on the upper extremities may be a subtle feature of the disease.

The pathergy phenomenon is frequently underappreciated

Corticosteroids (1 mg/kg/d of oral prednisone) are a mainstay of therapy for severe disease manifestations.

Azathioprine (2 mg/kg/d orally) may be an effective steroidsparing agent. Cyclophosphamide (2 mg/kg/d orally) or chlorambucil (0.1–0.2 mg/kg/d orally) is indicated for severe ocular and central nervous system complications of Behçet disease. Both colchicine (0.6 mg once to three times daily orally) and thalidomide (100 mg/d orally) help ameliorate the mucocutaneous findings. TNF inhibition and interferon alfa-2a demonstrates some promise as a therapeutic approach, but large studies are lacking to date.

Ideguchi H et al. Behçet disease: evolution of clinical manifestations. Medicine (Baltimore). 2011 Mar;90(2):125–32. [PMID: 21358436]

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PRIMARY ANGIITIS OF THE CENTRAL NERVOUS SYSTEM Primary angiitis of the central nervous system is a syndrome with several possible causes that produces small and medium-sized vasculitis limited to the brain and spinal cord.

Biopsy-proved cases have predominated in men who have a history of weeks to months of headaches, encephalopathy, and multifocal strokes. Systemic signs and symptoms are absent, and routine laboratory tests are usually normal. MRI of the brain is almost always abnormal, and the spinal fluid often reveals a mild lymphocytosis and a modest increase in protein level. Angiograms classically reveal a “string of beads” pattern produced by alternating segments of arterial narrowing and dilation. However, neither the MRI nor the angiogram appearance is specific for vasculitis. Indeed, in one study, none of the patients who had biopsy-proved central nervous system vasculitis had an angiogram showing “the string of beads,” and none of the patients with the classic angiographic findings had a positive brain biopsy for vasculitis. Many conditions, including vasospasm, can produce the same angiographic pattern as vasculitis. Definitive diagnosis requires a compatible clinical picture; exclusion of infection, neoplasm, or metabolic disorder or drug exposure (eg, cocaine) that can mimic primary angiitis of the central nervous system; and a positive brain biopsy. In contrast to biopsy-proved cases, patients with angiographically defined central nervous system vasculopathy are chiefly women who have had an abrupt onset of headaches and stroke (often in the absence of encephalopathy) with normal spinal fluid findings. Many patients who fit this clinical profile may have reversible cerebral vasoconstriction rather than true vasculitis. Such cases may best be treated with calcium channel blockers (such as nimodipine or verapamil) and possibly a short course of corticosteroids. Biopsy-proved cases usually improve with prednisone therapy and often require cyclophosphamide. In recent years, cases of central nervous system vasculitis associated with cerebral amyloid angiopathy have been reported. These cases often respond well to corticosteroids, albeit the long-term natural history remains poorly defined.

Secondary livedo reticularis occurs in association with a variety of diseases that cause vascular obstruction or inflammation. Of particular importance is the link with antiphospholipid antibody syndrome. Livedo reticularis is the presenting manifestation of 25% of patients with antiphospholipid antibody syndrome and is strongly associated with the subgroup that has arterial thromboses, including those with Sneddon syndrome (livedo reticularis and cerebrovascular events). Other underlying causes of livedo reticularis include the vasculitides (particularly polyarteritis nodosa), cholesterol emboli syndrome, thrombocythemia, cryoglobulinemia, cold agglutinin disease, primary hyperoxaluria (due to vascular deposits of calcium oxalate), and disseminated intravascular coagulation.

Frances C. Dermatological manifestations of Hughes’ antiphospholipid antibody syndrome. Lupus. 2010 Aug;19(9):1071–7.

[PMID: 20693200]

cc

SERONEGATIVE SPONDYLOARTHROPATHIES The seronegative spondyloarthropathies are ankylosing spondylitis, psoriatic arthritis, reactive arthritis, the arthritis associated with inflammatory bowel disease, and undifferentiated spondyloarthropathy. These disorders are noted for male predominance, onset usually before age 40, inflammatory arthritis of the spine and sacroiliac joints, asymmetric oligoarthritis of large peripheral joints, enthesopathy (inflammation of where ligaments, tendons, and joint capsule insert into bone), uveitis in a significant minority, the absence of autoantibodies in the serum, and a striking association with HLA-B27. Present in only 8% of normal whites and 4% of normal blacks, HLA-B27 is positive in 90% of patients with ankylosing spondylitis and 75% with reactive arthritis. HLA-B27 also occurs in 50% of the psoriatic and inflammatory bowel disease patients who have sacroiliitis.

Patients with only peripheral arthritis in these latter two syndromes do not show an increase in HLA-B27.

ANKYLOSING SPONDYLITIS

Berlit P. Diagnosis and treatment of cerebral vasculitis. Ther Adv Neurol Disord. 2010 Jan;3(1):29–42. [PMID: 21180634] ``

LIVEDO RETICULARIS Livedo reticularis produces a mottled, purplish discoloration of the skin with reticulated cyanotic areas surrounding paler central cores. This distinctive “fishnet” pattern is caused by spasm or obstruction of perpendicular arterioles, combined with pooling of blood in surrounding venous plexuses. Livedo reticularis can be idiopathic or a manifestation of a serious underlying condition.

Idiopathic livedo reticularis is a benign condition that worsens with cold exposure, improves with warming, and primarily affects the extremities. Apart from cosmetic concerns, it is usually asymptomatic. Systemic symptoms or the development of cutaneous ulcerations point to the presence of an underlying disease.

Chronic low backache in young adults, generally worst in the morning.

Progressive limitation of back motion and of chest expansion.

Transient (50%) or persistent (25%) peripheral arthritis.

Anterior uveitis in 20–25%.

Diagnostic radiographic changes in sacroiliac joints.

Negative serologic tests for rheumatoid factor and anti-CCP antibodies.

HLA-B27 testing is most helpful when there is an intermediate probability of disease.

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Musculoskeletal & Immunologic Disorders

``General Considerations Ankylosing spondylitis is a chronic inflammatory disease of the joints of the axial skeleton, manifested clinically by pain and progressive stiffening of the spine. The age at onset is usually in the late teens or early 20s. The incidence is greater in males than in females, and symptoms are more prominent in men, with ascending involvement of the spine more likely to occur.

``Clinical Findings A. Symptoms and Signs The onset is usually gradual, with intermittent bouts of back pain that may radiate into the buttocks. The back pain is worse in the morning and usually associated with stiffness that lasts hours. The pain and stiffness improve with activity, in contrast to back pain due to mechanical causes and degenerative disease, which improves with rest and worsens with activity. As the disease advances, symptoms progress in a cephalad direction, and back motion becomes limited, with the normal lumbar curve flattened and the thoracic curvature exaggerated. Chest expansion is often limited as a consequence of costovertebral joint involvement. In advanced cases, the entire spine becomes fused, allowing no motion in any direction. Transient acute arthritis of the peripheral joints occurs in about 50% of cases, and permanent changes in the peripheral joints— most commonly the hips, shoulders, and knees—are seen in about 25%. Enthesopathy, a hallmark of the spondyloarthropathies, can manifest as swelling of the Achilles tendon at its insertion, plantar fasciitis (producing heel pain), or “sausage” swelling of a finger or toe (less common in ankylosing spondylitis than in psoriatic arthritis).

Anterior uveitis is associated in as many as 25% of cases and may be a presenting feature. Spondylitic heart disease, characterized chiefly by atrioventricular conduction defects and aortic regurgitation occurs in 3–5% of patients with long-standing severe disease. Constitutional symptoms similar to those of rheumatoid arthritis are absent in most patients.

B. Laboratory Findings The ESR is elevated in 85% of cases, but serologic tests for rheumatoid factor and anti-CCP antibodies are negative.

Anemia may be present but is often mild. HLA-B27 is found in 90% of white patients and 50% of black patients with ankylosing spondylitis. Because this antigen occurs in 8% of the healthy white population (and 2% of healthy blacks), it is not a specific diagnostic test.

C. Imaging The earliest radiographic changes are usually in the sacroiliac joints. In the first 2 years of the disease process, the sacroiliac changes may be detectable only by MRI. Later, erosion and sclerosis of these joints are evident on plain radiographs; the sacroiliitis of ankylosing spondylitis is bilateral and symmetric. Inflammation where the annulus fibrosus attaches to the vertebral bodies initially causes

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sclerosis (“the shiny corner sign”) and then characteristic squaring of the vertebral bodies. The term “bamboo spine” describes the late radiographic appearance of the spinal column in which the vertebral bodies are fused by vertically oriented, bridging syndesmophytes formed by the ossification of the annulus fibrosus and calcification of the anterior and lateral spinal ligaments. Fusion of the posterior facet joints of the spine is also common.

Additional radiographic findings include periosteal new bone formation on the iliac crest, ischial tuberosities and calcanei, and alterations of the pubic symphysis and sternomanubrial joint similar to those of the sacroiliacs.

Radiologic changes in peripheral joints, when present, tend to be asymmetric and lack the demineralization and erosions seen in rheumatoid arthritis.

``Differential Diagnosis Low back pain due to mechanical causes, disk disease, and degenerative arthritis is very common. Onset of back pain prior to age 30 and an “inflammatory” quality of the back pain (ie, morning stiffness and pain that improve with activity) should raise the possibility of ankylosing spondylitis. In contrast to ankylosing spondylitis, rheumatoid arthritis predominantly affects multiple, small, peripheral joints of the hands and feet. Rheumatoid arthritis spares the sacroiliac joints and only affects the cervical component of the spine. Bilateral sacroiliitis indistinguishable from ankylosing spondylitis is seen with the spondylitis associated with inflammatory bowel disease. Sacroiliitis associated with reactive arthritis and psoriasis, on the other hand, is often asymmetric or even unilateral. Osteitis condensans ilii (sclerosis on the iliac side of the sacroiliac joint) is an asymptomatic, postpartum radiographic finding that is occasionally mistaken for sacroiliitis. Diffuse idiopathic skeletal hyperostosis (DISH) causes exuberant osteophytes of the spine that occasionally are difficult to distinguish from the syndesmophytes of ankylosing spondylitis. The osteophytes of DISH are thicker and more anterior than the syndesmophytes of ankylosing spondylitis, and the sacroiliac joints are normal in DISH.

``Treatment NSAIDs remain first-line treatment of ankylosing spondylitis and may slow radiographic progression of spinal disease. Because individual patients differ in their response to particular NSAIDs, empiric trials of several different NSAIDs are warranted if the response to any given NSAID is not satisfactory. TNF inhibitors have established efficacy for NSAID-resistant axial disease; responses are often substantial and durable. Etanercept (50 mg subcutaneously once a week), adalimumab (40 mg subcutaneously every other week), or infliximab (5 mg/kg every other month by intravenous infusion) is reasonable for patients whose symptoms are refractory to NSAIDs. Sulfasalazine (1000 mg orally twice daily) is sometimes useful for peripheral arthritis but lacks effectiveness for spinal and sacroiliac joint disease. Corticosteroids have minimal impact on the arthritis—particularly the spondylitis—of ankylosing spondylitis and can worsen osteopenia. All patients should

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be referred to a physical therapist for instruction in postural exercises.

``Prognosis Almost all patients have persistent symptoms over decades; rare individuals experience long-term remissions. The severity of disease varies greatly, with about 10% of patients having work disability after 10 years. Developing hip disease within the first 2 years of disease onset presages a worse prognosis. The availability of TNF inhibitors has provided symptomatic relief and improved quality of life for many patients with ankylosing spondylitis.

Heldmann F et al. The European ankylosing spondylitis infliximab cohort (EASIC): a European multicentre study of long term outcomes in patients with ankylosing spondylitis treated with infliximab. Clin Exp Rheumatol. 2011 Jul–Aug;29(4): 672–80. [PMID: 21906431] Jang JH et al. Ankylosing spondylitis: patterns of radiographic involvement—a re-examination of accepted principles in a cohort of 769 patients. Radiology. 2011 Jan;258(1):192–8.

[PMID: 20971774]

3. A pattern of disease in which the DIP joints are primarily affected. Early, this may be monarticular, and often the joint involvement is asymmetric. Pitting of the nails and onycholysis frequently accompany DIP involvement.

4. A severe deforming arthritis (arthritis mutilans) in which osteolysis is marked.

5. A spondylitic form in which sacroiliitis and spinal involvement predominate; 50% of these patients are HLA-B27-positive.

Arthritis is at least five times more common in patients with severe skin disease than in those with only mild skin findings. Occasionally, however, patients may have a single patch of psoriasis (typically hidden in the scalp, gluteal cleft, or umbilicus) and are unaware of its presence. Thus, a detailed search for cutaneous lesions is essential in patients with arthritis of new onset. Also, the psoriatic lesions may have cleared when arthritis appears—in such cases, the history is most useful in diagnosing previously unexplained cases of mono- or oligoarthritis. Nail pitting is sometimes a clue. “Sausage” swelling of one or more digits is a common manifestation of enthesopathy in psoriatic arthritis.

B. Laboratory Findings

PSORIATIC ARTHRITIS ``

E s s en t ia l S o f dia g n o s i s

Psoriasis precedes onset of arthritis in 80% of cases.

Arthritis usually asymmetric, with “sausage” appearance of fingers and toes but a polyarthritis that resembles rheumatoid arthritis also occurs.

Sacroiliac joint involvement common; ankylosis of the sacroiliac joints may occur.

Radiographic findings: osteolysis; pencil-in-cup deformity; relative lack of osteoporosis; bony ankylosis; asymmetric sacroiliitis and atypical syndesmophytes.

``

``

``

``

``General Considerations Although psoriasis usually precedes the onset of arthritis, arthritis precedes (by up to 2 years) or occurs simultaneously with the skin disease in approximately 20% of cases.

``Clinical Findings A. Symptoms and Signs The patterns or subsets of psoriatic arthritis include the following: 1. A symmetric polyarthritis that resembles rheumatoid arthritis. Usually, fewer joints are involved than in rheumatoid arthritis.

2. An oligoarticular form that may lead to considerable destruction of the affected joints.

Laboratory studies show an elevation of the ESR, but rheumatoid factor is not present. Uric acid levels may be high, reflecting the active turnover of skin affected by psoriasis.

There is a correlation between the extent of psoriatic involvement and the level of uric acid, but gout is no more common than in patients without psoriasis. Desquamation of the skin may also reduce iron stores.

C. Imaging Radiographic findings are most helpful in distinguishing the disease from other forms of arthritis. There are marginal erosions of bone and irregular destruction of joint and bone, which, in the phalanx, may give the appearance of a sharpened pencil. Fluffy periosteal new bone may be marked, especially at the insertion of muscles and ligaments into bone. Such changes will also be seen along the shafts of metacarpals, metatarsals, and phalanges. Psoriatic spondylitis causes asymmetric sacroiliitis and syndesmophytes, which are coarser than those seen in ankylosing spondylitis.

``Treatment NSAIDs are usually sufficient for mild cases. Methotrexate (7.5–20 mg orally once a week) is generally considered the drug of choice for patients who have not responded to NSAIDs; methotrexate can improve both the cutaneous and arthritic manifestations. For cases with disease that is refractory to methotrexate, the addition of TNF inhibitors (at doses similar to the treatment of ankylosing spondylitis) is usually effective for both arthritis and psoriatic skin disease. Corticosteroids are less effective in psoriatic arthritis than in other forms of inflammatory arthritis and may precipitate pustular psoriasis during tapers.

Antimalarials may also exacerbate psoriasis. Successful treatment directed at the skin lesions alone (eg, by PUVA

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therapy) occasionally is accompanied by an improvement in peripheral articular symptoms.

Gladman DD et al. Risk factors for radiographic progression in psoriatic arthritis: subanalysis of the randomized controlled trial ADEPT. Arthritis Res Ther. 2010;12(3):R113. [PMID: 20537151] McGonagle D et al. The early phase of psoriatic arthritis. Ann Rheum Dis. 2011 Mar;70 (Suppl 1):i71–6. [PMID: 21339224] Mease PJ. Psoriatic arthritis: update on pathophysiology, assessment and management. Ann Rheum Dis. 2011 Mar;70(Suppl 1):i77–84. [PMID: 21339225]

REACTIVE ARTHRITIS (Formerly Reiter Syndrome) ``

E s s en t ia l S o f dia g n o s i s

Fifty to eighty percent of patients are HLA-B27positive.

Oligoarthritis, conjunctivitis, urethritis, and mouth ulcers most common features.

Usually follows dysentery or a sexually transmitted infection.

s Figure 20–9. Circinate balanitis due to reactive arthritis (Reiter syndrome). (Courtesy of Susan Lindsley, Dr. M. F. Rein, Public Health Image Library, CDC.)

``

``

``

``General Considerations Reactive arthritis is precipitated by antecedent gastrointestinal and genitourinary infections and manifests as an asymmetric sterile oligoarthritis, typically of the lower extremities. It is frequently associated with enthesitis.

Extra-articular manifestations are common and include urethritis, conjunctivitis, uveitis, and mucocutaneous lesions. Reactive arthritis occurs most commonly in young men and is associated with HLA-B27 in 80% of white patients and 50–60% of blacks.

observed in at least 20% of patients, especially after frequent recurrences. Systemic symptoms including fever and weight loss are common at the onset of disease. The mucocutaneous lesions may include balanitis (Figure 20–9), stomatitis, and keratoderma blennorrhagicum (Figure 20–10), indistinguishable from pustular psoriasis. Involvement of the fingernails in reactive arthritis also mimics psoriatic changes.

When present, conjunctivitis is mild and occurs early in the disease course. Anterior uveitis, which can develop at any time in HLA-B27-positive patients, is a more clinically significant ocular complication. Carditis and aortic regurgitation may occur. While most signs of the disease disappear within days or weeks, the arthritis may persist for several months or become chronic. Recurrences involving any combination of the clinical manifestations are common and are sometimes followed by permanent sequelae, especially in the joints (eg, articular destruction).

``Clinical Findings A. Symptoms and Signs Most cases of reactive arthritis develop within 1–4 weeks after either a gastrointestinal infection (with Shigella, Salmonella, Yersinia, Campylobacter) or a sexually transmitted infection (with Chlamydia trachomatis or perhaps Ureaplasma urealyticum). Whether the inciting infection is sexually transmitted or dysenteric does not affect the subsequent manifestations but does influence the gender ratio: The ratio is 1:1 after enteric infections but 9:1 with male predominance after sexually transmitted infections.

Synovial fluid from affected joints is culture-negative. A clinically indistinguishable syndrome can occur without an apparent antecedent infection, suggesting that subclinical infection can precipitate reactive arthritis or that there are other, as yet unrecognized, triggers.

The arthritis is most commonly asymmetric and frequently involves the large weight-bearing joints (chiefly the knee and ankle); sacroiliitis or ankylosing spondylitis is

s Figure 20–10. Keratoderma blennorrhagica of the soles due to reactive arthritis (Reiter syndrome).

(Courtesy of Susan Lindsley, Public Health Image Library, CDC.)

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B. Imaging Radiographic signs of permanent or progressive joint disease may be seen in the sacroiliac as well as the peripheral joints.

``Differential Diagnosis Gonococcal arthritis can initially mimic reactive arthritis, but the marked improvement after 24–48 hours of antibiotic administration and the culture results distinguish the two disorders. Rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis must also be considered. By causing similar oral, ocular, and joint lesions, Behçet disease may also mimic reactive arthritis. The oral lesions of reactive arthritis, however, are typically painless, in contrast to those of Behçet disease.

The association of reactive arthritis and HIV has been debated, but evidence now indicates that it is equally common in sexually active men regardless of HIV status.

``Treatment NSAIDs have been the mainstay of therapy. Antibiotics given at the time of a nongonococcal sexually transmitted infection reduce the chance that the individual will develop this disorder. For chronic reactive arthritis associated with chlamydial infection, combination antibiotics taken for 6 months are more effective than placebo. Patients who do not respond to NSAIDs may respond to sulfasalazine, 1000 mg orally twice daily, or to methotrexate, 7.5–20 mg orally per week. For those patients with recent-onset disease that is refractory to NSAIDs and these DMARDs, anti-TNF agents, which are effective in the other spondyloarthropathies, may be effective.

Meyer A et al; Club Rhumatisme et Inflammation. Safety and efficacy of anti-tumor necrosis factor α therapy in ten patients with recent-onset refractory reactive arthritis. Arthritis Rheum.

2011 May;63(5):1274–80. [PMID: 21538314]

ARTHRITIS & INFLAMMATORY INTESTINAL DISEASES One-fifth of patients with inflammatory bowel disease have arthritis, which complicates Crohn disease somewhat more frequently than it does ulcerative colitis. In both diseases, two distinct forms of arthritis occur. The first is peripheral arthritis—usually a nondeforming asymmetric oligoarthritis of large joints—in which the activity of the joint disease parallels that of the bowel disease. The arthritis usually begins months to years after the bowel disease, but occasionally the joint symptoms develop earlier and may be prominent enough to cause the patient to overlook intestinal symptoms. The second form of arthritis is a spondylitis that is indistinguishable by symptoms or radiographs from ankylosing spondylitis and follows a course independent of the bowel disease. About 50% of these patients are HLA-B27-positive.

Controlling the intestinal inflammation usually eliminates the peripheral arthritis. The spondylitis often requires

NSAIDs, which need to be used cautiously since these agents may activate the bowel disease in a few patients.

Range-of-motion exercises as prescribed for ankylosing spondylitis can be helpful.

About two-thirds of patients with Whipple disease experience arthralgia or arthritis, most often an episodic, large-joint polyarthritis. The arthritis usually precedes the gastrointestinal manifestations by years. In fact, the arthritis resolves as the diarrhea develops. Thus, Whipple disease should be considered in the differential diagnosis of unexplained episodic arthritis.

Papamichael K et al. Low prevalence of antibodies to cyclic citrullinated peptide in patients with inflammatory bowel disease regardless of the presence of arthritis. Eur J Gastroenterol Hepatol. 2010 Jun;22(6):705–9. [PMID: 19525851]

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INFECTIOUS Arthritis*

NONGONOCOCCAL ACUTE BACTERIAL (Septic) ARTHRITIS ``

E s s en t ia l S o f dia g n o s i s

Acute onset of inflammatory monoarticular arthritis, most often in large weight-bearing joints and wrists.

Common risk factors include previous joint damage and injection drug use.

Infection with causative organisms commonly found elsewhere in body.

Joint effusions are usually large, with white blood counts commonly > 50,000/mcL.

``

``

``

``

``General Considerations Nongonococcal acute bacterial arthritis is often a disease that occurs when there is an underlying abnormality. The key risk factors are bacteremia (eg, injection drug use, endocarditis, infection at other sites), damaged or prosthetic joints (eg, rheumatoid arthritis), compromised immunity (eg, diabetes, advanced chronic kidney disease, alcoholism, cirrhosis, and immunosuppressive therapy), and loss of skin integrity (eg, cutaneous ulcer or psoriasis). Staphylococcus aureus is the most common cause of nongonococcal septic arthritis, accounting for about 50% of all cases. Methicillinresistant S aureus (MRSA) and group B streptococcus have become increasing frequent and important causes of septic arthritis. Gram-negative septic arthritis causes about 10% of cases and is especially common in injection drug users and in immunocompromised persons. Escherichia coli and Pseudomonas aeruginosa are the most common gram-negative

∗

Lyme disease is discussed in Chapter 34.

Musculoskeletal & Immunologic Disorders isolates in adults. Pathologic changes include varying degrees of acute inflammation, with synovitis, effusion, abscess formation in synovial or subchondral tissues, and, if treatment is not adequate, articular destruction.

``Clinical Findings A. Symptoms and Signs The onset is usually acute, with pain, swelling, and heat of the affected joint worsening over hours. The knee is most frequently involved; other commonly affected sites are the hip, wrist, shoulder, and ankle. Unusual sites, such as the sternoclavicular or sacroiliac joint, can be involved in injection drug users. Chills and fever are common but are absent in up to 20% of patients. Infection of the hip usually does not produce apparent swelling but results in groin pain greatly aggravated by walking. More than one joint is involved in 15% of cases of septic arthritis; risk factors for multiple joint involvement include rheumatoid arthritis, associated endocarditis, and infection with group B streptococci.

B. Laboratory Findings Synovial fluid analysis is critical for diagnosis. The leukocyte count of the synovial fluid usually exceeds 50,000/mcL and often is > 100,000/mcL, with 90% or more polymorphonuclear cells (Table 20–2). Gram stain of the synovial fluid is positive in 75% of staphylococcal infections and in 50% of gram-negative infections. Synovial fluid cultures are positive in 70–90% of cases; administration of antibiotics prior to arthrocentesis reduces the likelihood of a positive culture result. Blood cultures are positive in approximately 50% of patients.

C. Imaging Imaging tests generally add little to the diagnosis of septic arthritis. Indeed, other than demonstrating joint effusion, radiographs are usually normal early in the disease; in fact, evidence of demineralization may develop within days of onset. MRI and CT are more sensitive in detecting fluid in joints that are not accessible to physical examination (eg, the hip). Bony erosions and narrowing of the joint space followed by osteomyelitis and periostitis may be seen within 2 weeks.

``Differential Diagnosis Gout and pseudogout can cause acute, very inflammatory monoarticular arthritis and high-grade fever; the failure to find crystals on synovial fluid analysis excludes these diagnoses. A well-recognized but uncommon initial presentation of rheumatoid arthritis is an acute inflammatory monoarthritis (“pseudoseptic”). Acute rheumatic fever commonly involves several joints; Still disease may mimic septic arthritis, but laboratory evidence of infection is absent. Pyogenic arthritis may be superimposed on other types of joint disease, notably rheumatoid arthritis. Indeed, septic arthritis must be excluded (by joint fluid examination)

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in any patient with rheumatoid arthritis who has a joint strikingly more inflamed than the other joints.

``Prevention There is no evidence that patients with prosthetic joints undergoing procedures should receive antibiotic prophylaxis to prevent joint infection. However, the topic remains controversial. The American Academy of Orthopedic Surgeons advocates prescribing antibiotic prophylaxis for any patient with a prosthetic joint replacement undergoing a procedure that can cause bacteremia.

``Treatment The effective treatment of septic arthritis requires appropriate antibiotic therapy together with drainage of the infected joint. Hospitalization is always necessary. If the likely causative organism cannot be determined clinically or from the synovial fluid Gram stain, treatment should be started with broad-spectrum antibiotic coverage effective against staphylococci, streptococci, and gram-negative organisms. The recommendation for initial treatment is to give a third-generation cephalosporin: ceftriaxone, 1 g intravenously daily (or every 12 hours if concomitant meningitis or endocarditis is suspected); or cefotaxime, 1 g intravenously every 8 hours; or ceftizoxime, 1 g intravenously every 8 hours. Vancomycin (1 g intravenously every 12 hours, adjusted for age, weight, and renal function) should be used whenever MRSA is reasonably likely. Antibiotic therapy should be adjusted when culture results become available; the duration of antibiotic therapy is usually 4–6 weeks.

Early orthopedic consultation is essential. Effective drainage is usually achieved through early arthroscopic lavage and debridement together with drain placement. Open surgical drainage should be performed when conservative treatment fails, when there is concomitant osteomyelitis requiring debridement, or when the involved joint (eg, hip, shoulder, sacroiliac joint) cannot be drained by more conservative means.

Immobilization with a splint and elevation are used at the onset of treatment. Early active motion exercises within the limits of tolerance will hasten recovery.

``Prognosis The outcome of septic arthritis depends largely on the antecedent health of the patient, the causative organism (eg, S aureus bacterial arthritis is associated with a poor functional outcome in about 40% of cases), and the promptness of treatment. Five to 10 percent of patients with an infected joint die of respiratory complications of sepsis. The mortality rate is 30% for patients with polyarticular sepsis. Bony ankylosis and articular destruction commonly also occur if treatment is delayed or inadequate.

Galloway JB et al. Risk of septic arthritis in patients with rheumatoid arthritis and the effect of anti-TNF therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis. 2011 Oct;70(10):1810–4. [PMID: 21784730] Mathews CJ et al. Bacterial septic arthritis in adults. Lancet. 2010 Mar 6;375(9717):846–55. [PMID: 20206778]

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GONOCOCCAL ARTHRITIS ``

E s s en t ia l S o f dia g n o s i s

Prodromal migratory polyarthralgias.

Tenosynovitis is the most common sign.

Purulent monarthritis in 50%.

Characteristic skin lesions.

Most common in young women during menses or pregnancy.

Symptoms of urethritis frequently absent.

Dramatic response to antibiotics.

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``General Considerations In contrast to nongonococcal bacterial arthritis, gonococcal arthritis usually occurs in otherwise healthy individuals.

Host factors, however, influence the expression of the disease: gonococcal arthritis is two to three times more common in women than in men, is especially common during menses and pregnancy, and is rare after age 40. Gonococcal arthritis is also common in men who have sex with men, whose high incidence of asymptomatic gonococcal pharyngitis and proctitis predisposes them to disseminated gonococcal infection. Recurrent disseminated gonococcal infection should prompt testing of the patient’s CH50 level to evaluate for a congenital deficiency of a terminal complement component (C5, C6, C7, or C8).

``Clinical Findings A. Symptoms and Signs One to 4 days of migratory polyarthralgias involving the wrist, knee, ankle, or elbow are common at the outset.

Thereafter, two patterns emerge. The first pattern is characterized by tenosynovitis that most often affects wrists, fingers, ankles, or toes and is seen in 60% of patients. The second pattern is purulent monarthritis that most frequently involves the knee, wrist, ankle, or elbow and is seen in 40% of patients. Less than half of patients have fever, and less than one-fourth have any genitourinary symptoms. Most patients will have asymptomatic but highly characteristic skin lesions that usually consist of two to ten small necrotic pustules distributed over the extremities, especially the palms and soles.

B. Laboratory Findings The peripheral blood leukocyte count averages about 10,000 cells/mcL and is elevated in less than one-third of patients. The synovial fluid white blood cell count usually ranges from 30,000 to 60,000 cells/mcL. The synovial fluid Gram stain is positive in one-fourth of cases and culture in less than half. Positive blood cultures are uncommon.

Urethral, throat, cervical, and rectal cultures should be done in all patients, since they are often positive in the absence of local symptoms. Urinary nucleic acid amplification tests have excellent sensitivity and specificity for the detection of Neisseria gonorrhoeae in genitourinary sites.

C. Imaging Radiographs are usually normal or show only soft tissue swelling.

``Differential Diagnosis Reactive arthritis can produce acute monarthritis, urethritis, and fever in a young person but is distinguished by negative cultures and failure to respond to antibiotics. Lyme disease involving the knee is less acute, does not show positive cultures, and may be preceded by known tick exposure and characteristic rash. The synovial fluid analysis will exclude gout, pseudogout, and nongonococcal bacterial arthritis. Rheumatic fever and sarcoidosis can produce migratory tenosynovitis but have other distinguishing features. Infective endocarditis with septic arthritis can mimic disseminated gonococcal infection. Meningococcemia occasionally presents with a clinical picture that resembles disseminated gonococcal infection; blood cultures establish the correct diagnosis.

``Treatment In most cases, patients in whom gonococcal arthritis is suspected should be admitted to the hospital to confirm the diagnosis, to exclude endocarditis, and to start treatment. While outpatient treatment has been recommended in the past, the rapid rise in gonococci resistant to penicillin makes initial inpatient treatment advisable.

Approximately 4–5% of all gonococcal isolates produce a β-lactamase that confers penicillin resistance. An additional 15–20% of gonococcal species have chromosomal mutations that result in relative resistance to penicillin. The recommendation for initial treatment is to give a thirdgeneration cephalosporin: ceftriaxone, 1 g intravenously daily (or every 12 hours if concomitant meningitis or endocarditis is suspected); or cefotaxime, 1 g intravenously every 8 hours; or ceftizoxime, 1 g intravenously every 8 hours. Once improvement from parenteral antibiotics has been achieved for 24–48 hours, patients can be switched to cefixime, 400 mg orally twice daily, or cefpodoxime, 400 mg orally twice daily, to complete a 7- to 10-day course.

Recently, however, cephalosporin-resistant strains of gonococci have been identified; treatment with gentamicin or the new fluoroketolide, solithromycin (not yet approved by the United States FDA) has been suggested. Fluoroquinolone antibiotics are also not recommended for the initial treatment of gonococcal infections unless because of drug resistance culture results show antibiotic sensitivity.

``Prognosis Generally, gonococcal arthritis responds dramatically in 24–48 hours after initiation of antibiotics, and drainage of the infected joint(s) is required infrequently. Complete recovery is the rule.

Bolan GA et al. The emerging threat of untreatable gonococcal infection. N Engl J Med. 2012 Feb 9; 366(6):485–7.

García-De La Torre I et al. Gonococcal and nongonococcal arthritis. Rheum Dis Clin North Am. 2009 Feb;35(1):63–73.

[PMID: 19480997]

Musculoskeletal & Immunologic Disorders

RHEUMATIC MANIFESTATIONS OF HIV INFECTION Infection with HIV has been associated with various rheumatic disorders, most commonly arthralgias and arthritis.

HIV painful articular syndrome causes severe arthralgias in an oligoarticular, asymmetric pattern that resolve within 24 hours; the joint examination is normal. HIV-associated arthritis is an asymmetric oligoarticular process with objective findings of arthritis and a self-limited course that ranges from weeks to months. Psoriatic arthritis and reactive arthritis occur in HIV-infected individuals and can be severe; it remains uncertain whether the incidence of these disorders is increased in HIV-infected populations. These spondyloarthropathies can respond to NSAIDs, though many cases are unresponsive. In the era of highly active antiretroviral therapies, immunosuppressive medications can be used if necessary in HIV patients, though with caution. Muscle weakness associated with an elevated creatine kinase can be due to nucleoside reverse transcriptase inhibitor-associated myopathy or HIV-associated myopathy; the clinical presentations of each resemble idiopathic polymyositis but the muscle biopsies show minimal inflammation. Less commonly, an inflammatory myositis indistinguishable from idiopathic polymyositis occurs.

Ezzat WM et al. Anti-cyclic citrullinated peptide antibodies as a discriminating marker between rheumatoid arthritis and chronic hepatitis C-related polyarthropathy. Rheumatol Int. 2011 Jan;31(1):65–9. [PMID: 19882340]

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Arthralgias occur frequently in the course of acute infections with many viruses, but frank arthritis is uncommon.

A notable exception is acute parvovirus B19 infection, which leads to acute polyarthritis in 50–60% of adult cases (infected children develop the febrile exanthem known as “slapped cheek fever”). The arthritis can mimic rheumatoid arthritis but is almost always self-limited and resolves within several weeks. The diagnosis is established by the presence of IgM antibodies specific for parvovirus B19.

Self-limited polyarthritis is also common in acute hepatitis B infection and typically occurs before the onset of jaundice. Urticaria or other types of skin rash may be present. Indeed, the clinical picture resembles that of serum sickness (see Atopic Disease below). Serum transaminase levels are elevated, and tests for hepatitis B surface antigen are positive. Serum complement levels are often low during active arthritis and become normal after remission of arthritis. The incidence of hepatitis B–associated polyarthritis has fallen substantially with the introduction of hepatitis B vaccination. Effective vaccination programs in the United States have eliminated acute rubella infections, formerly a common cause of virally induced polyarthritis.

Changes in the rubella vaccine (an attenuated live vaccine) have greatly reduced the incidence of rubella vaccine–induced polyarthritis as well.

Chronic infection with hepatitis C is associated with chronic polyarthralgia in up to 20% of cases and with

INFECTIONS OF BONES

ACUTE PYOGENIC OSTEOMYELITIS

E s s en t ia l S o f dia g n o s i s

Fever and chills associated with pain and tenderness of involved bone.

Diagnosis usually requires culture of bone biopsy.

ESR often extremely high (eg, > 100 mm/h).

Radiographs early in the course are typically negative.

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chronic polyarthritis in 3–5%. Both can mimic rheumatoid arthritis, and the presence of rheumatoid factor in most hepatitis C–infected individuals leads to further diagnostic confusion. Indeed, hepatitis C–associated arthritis is frequently misdiagnosed as rheumatoid arthritis. Distinguishing hepatitis C–associated arthritis/arthralgias from the cooccurrence of hepatitis C and rheumatoid arthritis can be difficult. Rheumatoid arthritis always causes objective arthritis (not just arthralgias) and can be erosive (hepatitis C–associated arthritis is nonerosive). The presence of antiCCP antibodies points to the diagnosis of rheumatoid arthritis.

``

Kaddu-Mukasa M et al. Rheumatic manifestations among HIV positive adults attending the Infectious Disease Clinic at Mulago Hospital. Afr Health Sci. 2011 Mar;11(1):24–9. [PMID: 21572853]

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``General Considerations Osteomyelitis is a serious infection that is often difficult to diagnose and treat. Infection of bone occurs as a consequence of (1) hematogenous dissemination of bacteria, (2) invasion from a contiguous focus of infection, and (3) skin breakdown in the setting of vascular insufficiency.

``Clinical Findings A. Symptoms and Signs 1. Hematogenous osteomyelitis—Osteomyelitis resulting from bacteremia is a disease associated with sickle cell disease, injection drug users, diabetes mellitus, or the elderly.

Patients with this form of osteomyelitis often present with sudden onset of high fever, chills, and pain and tenderness of the involved bone. The site of osteomyelitis and the causative organism depend on the host. Among patients with hemoglobinopathies such as sickle cell anemia, osteomyelitis is caused most often by salmonellae; S aureus is the second most common cause. Osteomyelitis in injection drug users develops most commonly in the spine. Although in this setting S aureus is most common, gram-negative infections, especially P aeruginosa and Serratia species, are also frequent pathogens. Rapid progression to epidural abscess causing

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fever, pain, and sensory and motor loss is not uncommon. In older patients with hematogenous osteomyelitis, the most common sites are the thoracic and lumbar vertebral bodies.

Risk factors for these patients include diabetes, intravenous catheters, and indwelling urinary catheters. These patients often have more subtle presentations, with low-grade fever and gradually increasing bone pain.

2. Osteomyelitis from a contiguous focus of infection—Prosthetic joint replacement, decubitus ulcer, neurosurgery, and trauma most frequently cause soft tissue infections that can spread to bone. S aureus and Staphylococcus epidermidis are the most common organisms. Localized signs of inflammation are usually evident, but high fever and other signs of toxicity are usually absent. Septic arthritis and cellulitis can also spread to contiguous bone.

3. Osteomyelitis associated with vascular insufficiency— Patients with diabetes and vascular insufficiency are susceptible to developing a very challenging form of osteomyelitis.

The foot and ankle are the most commonly affected sites.

Infection originates from an ulcer or other break in the skin that is usually still present when the patient presents but may appear disarmingly unimpressive. Bone pain is often absent or muted by the associated neuropathy. Fever is also commonly absent. Two of the best bedside clues that the patient has osteomyelitis are the ability to easily advance a sterile probe through a skin ulcer to bone and an ulcer area > 2 cm2.

B. Imaging and Laboratory Findings The plain film is the most readily available imaging procedure to establish the diagnosis of osteomyelitis, but it can be falsely negative early. Early radiographic findings may include soft tissue swelling, loss of tissue planes, and periarticular demineralization of bone. About 2 weeks after onset of symptoms, erosion of bone and alteration of cancellous bone appear, followed by periostitis.

MRI, CT, and nuclear medicine bone scanning are more sensitive than conventional radiography. MRI is the most sensitive and is particularly helpful in demonstrating the extent of soft tissue involvement. Radionuclide bone scanning is most valuable when osteomyelitis is suspected but no site is obvious. Nuclear medicine studies may also detect multifocal sites of infection. Ultrasound is useful in diagnosing the presence of effusions within joints and extraarticular soft tissue fluid collections but not in detecting bone infections.

Identifying the offending organism is a crucial step in selection of antibiotic therapy. Bone biopsy for culture is required except in those with hematogenous osteomyelitis, who have positive blood cultures. Cultures from overlying ulcers, wounds, or fistulas are unreliable.

``Differential Diagnosis Acute hematogenous osteomyelitis should be distinguished from suppurative arthritis, rheumatic fever, and cellulitis.

More subacute forms must be differentiated from tuberculosis or mycotic infections of bone and Ewing sarcoma or, in the case of vertebral osteomyelitis, from metastatic tumor.

When osteomyelitis involves the vertebrae, it commonly traverses the disk—a finding not observed in tumor.

``Complications Inadequate treatment of bone infections results in chronicity of infection, and this possibility is increased by delaying diagnosis and treatment. Extension to adjacent bone or joints may complicate acute osteomyelitis. Recurrence of bone infections often results in anemia, a markedly elevated ESR, weight loss, weakness and, rarely, amyloidosis or nephrotic syndrome. Pseudoepitheliomatous hyperplasia, squamous cell carcinoma, or fibrosarcoma may occasionally arise in persistently infected tissues.

``Treatment Most patients require both debridement of necrotic bone and prolonged administration of antibiotics. Patients with vertebral body osteomyelitis and epidural abscess may require urgent neurosurgical decompression. Depending on the site and extent of debridement, surgical procedures to stabilize, fill in, cover, or revascularize may be needed.

Oral therapy with quinolones (eg, ciprofloxacin, 750 mg twice daily) for 6–8 weeks has been shown to be as effective as standard parenteral antibiotic therapy for chronic osteomyelitis with susceptible organisms. When treating osteomyelitis caused by S aureus, quinolones are usually combined with rifampin, 300 mg orally twice daily.

``Prognosis If sterility of the lesion is achieved within 2–4 days, a good result can be expected in most cases if there is no compromise of the patient’s immune system. However, progression of the disease to a chronic form may occur. It is especially common in the lower extremities and in patients in whom circulation is impaired (eg, diabetics).

Howell WR et al. Osteomyelitis: an update for hospitalists. Hosp Pract (Minneap). 2011 Feb;39(1):153–60. [PMID: 21441771] Zimmerli W. Clinical practice. Vertebral osteomyelitis. N Engl J Med. 2010 Mar 18;362(11):1022–9. [PMID: 20237348]

MYCOTIC INFECTIONS OF BONES & JOINTS Fungal infections of the skeletal system are usually secondary to a primary infection in another organ, frequently the lungs (see Chapter 36). Although skeletal lesions have a predilection for the cancellous portions of long bones and vertebral bodies, the predominant lesion—a granuloma with varying degrees of necrosis and abscess formation— does not produce a characteristic clinical picture.

Differentiation from other chronic focal infections depends on culture studies of synovial fluid or tissue obtained from the local lesion. Serologic tests provide presumptive support of the diagnosis.

1. Candidiasis Candidal osteomyelitis most commonly develops in debilitated, malnourished patients undergoing prolonged

Musculoskeletal & Immunologic Disorders hospitalization for cancer, neutropenia, trauma, complicated abdominal surgical procedures, or injection drug use.

Infected intravenous catheters frequently serve as a hematogenous source. Prosthetic joints can also be infected by Candida.

For susceptible Candida species, fluconazole, 200 mg orally twice daily, is probably as effective as amphotericin B (see Chapter 36).

Dailey NJ et al. Candida glabrata spinal osteomyelitis. Am J Med Sci. 2011 Jan;341(1):78–82. [PMID: 21030857]

Coccidioidomycosis of bones and joints is usually secondary to primary pulmonary infection. Arthralgia with periarticular swelling, especially in the knees and ankles, occurring as a nonspecific manifestation of systemic coccidioidomycosis, should be distinguished from actual bone or joint infection. Osseous lesions commonly occur in cancellous bone of the vertebrae or near the ends of long bones at tendinous insertions. These lesions are initially osteolytic and thus may mimic metastatic tumor or myeloma.

The precise diagnosis depends on recovery of Coccidioides immitis from the lesion or histologic examination of tissue obtained by open biopsy. Rising titers of complement-fixing antibodies also provide evidence of the disseminated nature of the disease.

Oral azole antifungal agents (fluconazole 200–400 mg daily, or itraconazole 200 mg twice daily) are the treatment of choice for bone and joint coccidioidomycosis. Chronic infection is rarely cured with antifungal agents and may require operative excision of infected bone and soft tissue; amputation may be the only solution for stubbornly progressive infections. Immobilization of joints by plaster casts and avoidance of weight bearing provide benefit.

Synovectomy, joint debridement, and arthrodesis are reserved for more advanced joint infections.

Ampel NM. Coccidioidomycosis: a review of recent advances.

Clin Chest Med. 2009 Jun;30(2):241–51. [PMID: 19375631] Blair JE. State-of-the-art treatment of coccidioidomycosis skeletal infections. Ann N Y Acad Sci. 2007 Sep;1111:422–33.

[PMID: 17395727]

3. Histoplasmosis Focal skeletal or joint involvement in histoplasmosis is rare and generally represents dissemination from a primary focus in the lungs. Skeletal lesions may be single or multiple and are not characteristic.

Kauffman CA. Histoplasmosis. Clin Chest Med. 2009 Jun;30(2): 217–25. [PMID: 19375629] Knox KS et al. Histoplasmosis. Proc Am Thorac Soc. 2010 May; 7(3):169–72. [PMID: 20463244]

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TUBERCULOSIS OF BONES & JOINTS Spinal tuberculosis (Pott Disease) ``

E s s en t ia l S o f dia g n o s i s

Seen primarily in immigrants from developing countries or immunocompromised patients.

Back pain and gibbus deformity.

Radiographic evidence of vertebral involvement.

Evidence of Mycobacterium tuberculosis in aspirates or biopsies of spinal lesions.

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`` `` ``

2. Coccidioidomycosis

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``General Considerations In the developing world, children primarily bear the burden of musculoskeletal tuberculosis. In the United States, however, musculoskeletal infection is more often seen in adult immigrants from countries where tuberculosis is prevalent, or it develops in the setting of immunosuppression (eg, HIV infection, therapy with TNF inhibitors).

Spinal tuberculosis (Pott disease) accounts for about 50% of musculoskeletal infection due to M tuberculosis (see Chapter 9). Seeding of the vertebrae may occur through hematogenous spread from the respiratory tract at the time of primary infection, with clinical disease developing years later as a consequence of reactivation. The thoracic and lumbar vertebrae are the most common sites of spinal involvement; vertebral infection is associated with paravertebral cold abscesses in 75% of cases.

``Clinical Findings A. Symptoms and Signs Patients complain of back pain, often present for months and sometimes associated with radicular pain and lower extremity weakness. Constitutional symptoms are usually absent, and < 20% have active pulmonary disease.

Destruction of the anterior aspect of the vertebral body can produce the characteristic gibbus deformity.

B. Laboratory Findings Most patients have a positive reaction to purified protein derivative (PPD) or a positive interferon-gamma release assay. Cultures of paravertebral abscesses and biopsies of vertebral lesions are positive in up to 70–90%. Biopsies reveal characteristic caseating granulomas in most cases.

Isolation of M tuberculosis from an extraspinal site is sufficient to establish the diagnosis in the proper clinical setting.

C. Imaging Radiographs can reveal lytic and sclerotic lesions and bony destruction of vertebrae but are normal early in the disease course. CT scanning can demonstrate paraspinal soft tissue extensions of the infection; MRI is the imaging technique of choice to detect compression of the spinal cord or cauda equina.

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``Differential Diagnosis Spinal tuberculosis must be differentiated from subacute and chronic spinal infections due to pyogenic organisms, Brucella, and fungi as well as from malignancy.

``Complications Paraplegia due to compression of the spinal cord or cauda equina is the most serious complication of spinal tuberculosis.

``Treatment Antimicrobial therapy should be administered for 6–9 months, usually in the form of isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months followed by isoniazid and rifampin for an additional 4–7 months (see also Chapter 9).

Medical management alone is often sufficient. Surgical intervention, however, may be indicated when there is neurologic compromise or severe spinal instability.

Jain AK. Tuberculosis of the spine: a fresh look at an old disease. J Bone Joint Surg Br. 2010 Jul;92(7):905–13. [PMID: 20595106] Kumar R et al. Role of interferon gamma release assay in the diagnosis of Pott disease. J Neurosurg Spine. 2010 May;12(5): 462–6. [PMID: 20433293]

and ankles are most commonly involved, but any joint may be affected. Distribution of joint involvement is usually polyarticular and symmetric. The arthritis is commonly selflimited, resolving after several weeks or months and rarely resulting in chronic arthritis, joint destruction, or significant deformity. Sarcoid arthropathy is often associated with erythema nodosum, but the diagnosis is contingent on the demonstration of other extra-articular manifestations of sarcoidosis and, notably, biopsy evidence of noncaseating granulomas. Despite the clinical appearance of an inflammatory arthritis, synovial fluid often is noninflammatory (ie, < 2000 leukocytes/mcL). In chronic arthritis, radiographs show typical changes in the bones of the extremities with intact cortex and cystic changes.

Treatment of arthritis in sarcoidosis is usually symptomatic and supportive. Colchicine may be of value. A short course of corticosteroids may be effective in patients with severe and progressive joint disease.

Sweiss NJ et al. Rheumatologic manifestations of sarcoidosis.

Semin Respir Crit Care Med. 2010 Aug;31(4):463–73. [PMID: 20665396] Gnanasegaran G et al. Multislice SPECT/CT in benign and malignant bone disease: when the ordinary turns into the extraordinary. Semin Nucl Med. 2009 Nov;39(6):431–42.

[PMID: 19801222]

TUBERCULOUS ARTHRITIS Infection of peripheral joints by M tuberculosis usually presents as a monoarticular arthritis lasting for weeks to months (or longer), but less often, it can have an acute presentation that mimics septic arthritis. Any joint can be involved; the hip and knee are most commonly affected. Constitutional symptoms and fever are present in only a small number of cases. Tuberculosis also can cause a chronic tenosynovitis of the hand and wrist. Joint destruction occurs far more slowly than in septic arthritis due to pyogenic organisms. Synovial fluid is inflammatory but not to the degree seen in pyogenic infections, with synovial white cell counts in the range of 10,000–20,000 cells/mcL. Smears of synovial fluid are positive for acid-fast bacilli in a minority of cases; synovial fluid cultures, however, are positive in 80% of cases. Because culture results may take weeks, the diagnostic procedure of choice usually is synovial biopsy, which yields characteristic pathologic findings and positive cultures in > 90%.

Antimicrobial therapy is the mainstay of treatment. Rarely, a reactive, sterile polyarthritis associated with erythema nodosum (Poncet disease) develops in patients with active pulmonary tuberculosis.

Shu CC et al. Mycobacterial arthritis of large joints. Ann Rheum Dis. 2009 Sep;(9):1504–5. [PMID: 19674984]

ARTHRITIS IN SARCOIDOSIS The frequency of arthritis among patients with sarcoidosis is variously reported between 10% and 35%. It is usually acute in onset, but articular symptoms may appear insidiously and often antedate other manifestations of the disease. Knees

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OTHER RHEUMATIC DISORDERS

RHEUMATIC MANIFESTATIONS OF CANCER Rheumatologic syndromes may be the presenting manifestations for a variety of cancers. Dermatomyositis in adults, for example, is often associated with cancer (see Table 39–2). Hypertrophic pulmonary osteoarthropathy, which is characterized by the triad of polyarthritis, new onset of clubbing, and periosteal new bone formation, is associated with both malignant diseases (eg, lung and intrathoracic cancers) and nonmalignant ones (eg, cyanotic heart disease, cirrhosis, and lung abscess). Cancer-associated polyarthritis is rare, has both oligoarticular and polyarticular forms, and should be considered when “seronegative rheumatoid arthritis” develops abruptly in an elderly patient.

Palmar fasciitis manifests as bilateral palmar swelling with finger contractures and may be the first indication of cancer, particularly ovarian carcinoma. Remitting seronegative synovitis with non-pitting edema (“RS3PE”) presents with a symmetric small joint polyarthritis associated with nonpitting edema of the hands; it can be idiopathic or associated with malignancy. Palpable purpura due to leukocytoclastic vasculitis may be the presenting complaint in myeloproliferative disorders. Hairy cell leukemia can be associated with medium-sized vessel vasculitis such as polyarteritis nodosa. Acute leukemia can produce joint pains that are disproportionately severe in comparison to the minimal swelling and heat that are present. Leukemic arthritis complicates approximately 5% of cases. Rheumatic manifestations of myelodysplastic syndromes include cutaneous vasculitis, lupus-like syndromes, neuropathy, and episodic

Musculoskeletal & Immunologic Disorders intense arthritis. Erythromelalgia, a painful warmth and redness of the extremities that (unlike Raynaud) improves with cold exposure or with elevation of the extremity, is often associated with myeloproliferative diseases, particularly essential thrombocythemia.

Naschitz JE et al. Musculoskeletal syndromes associated with malignancy (excluding hypertrophic osteoarthropathy). Curr Opin Rheumatol. 2008 Jan;20(1):100–5. [PMID: 18281865]

NEUROGENIC ARTHROPATHY (Charcot Joint) Neurogenic arthropathy is joint destruction resulting from loss or diminution of proprioception, pain, and temperature perception. Although initially described in the knees of patients with tabes dorsalis, it is more frequently seen in association with diabetic neuropathy (foot and ankle) or syringomyelia (shoulder). As normal muscle tone and protective reflexes are lost, secondary degenerative joint disease ensues, resulting in an enlarged, boggy, relatively painless joint with extensive cartilage erosion, osteophyte formation, and multiple loose joint bodies. Radiographs can reveal striking osteolysis that mimics osteomyelitis or dramatic destruction of the joint with subluxation, fragmentation of bone, and bony sclerosis.

Treatment is directed toward the primary disease; mechanical devices are used to assist in weight bearing and prevention of further trauma. In some instances, amputation becomes unavoidable.

Thompson P et al. Diabetic foot: Charcot neuropathic osteoarthropathy. Adv Skin Wound Care. 2009 Feb;22(2):72–3.

[PMID: 19155710]

PALINDROMIC RHEUMATISM Palindromic rheumatism is a disease of unknown cause characterized by frequent recurring attacks (at irregular intervals) of acutely inflamed joints. Periarticular pain with swelling and transient subcutaneous nodules may also occur. The attacks cease within several hours to several days.

The knee and finger joints are most commonly affected, but any peripheral joint may be involved. Systemic manifestations other than fever do not occur. Although hundreds of attacks may take place over a period of years, there is no permanent articular damage. Laboratory findings are usually normal. Palindromic rheumatism must be distinguished from acute gouty arthritis and an atypical acute onset of rheumatoid arthritis. In some patients, palindromic rheumatism is a prodrome of rheumatoid arthritis.

Symptomatic treatment with NSAIDs is usually all that is required during the attacks. Hydroxychloroquine may be of value in preventing recurrences.

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dysbaric syndromes (eg, “the bends”), knee menisectomy, and infiltrative diseases (eg, Gaucher disease). The most commonly affected sites are the proximal and distal femoral heads, leading to hip or knee pain. Other commonly affected sites include the ankle, shoulder, and elbow.

Osteonecrosis of the jaw has been rarely associated with use of bisphosphonate therapy, almost always when the bisphosphonate is used for treating metastatic cancer or multiple myeloma rather than osteoporosis. Initially, radiographs are often normal; MRI, CT scan, and bone scan are all more sensitive techniques. Treatment involves avoidance of weight bearing on the affected joint for at least several weeks. The value of surgical core decompression is controversial. For osteonecrosis of the hip, a variety of procedures designed to preserve the femoral head have been developed for early disease, including vascularized and nonvascularized bone grafting procedures. These procedures are most effective in avoiding or forestalling the need for total hip arthroplasty in young patients who do not have advanced disease. Without a successful intervention of this nature, the natural history of avascular necrosis is usually progression of the bony infarction to cortical collapse, resulting in significant joint dysfunction. Total hip replacement is the usual outcome for all patients who are candidates for that procedure.

Babis GC et al. Osteonecrosis of the femoral head. Orthopedics.

2011 Jan;34(1):39. [PMID: 21210589] Smith TO et al. The clinical and radiological outcomes of hip resurfacing versus total hip arthroplasty: a meta-analysis and systematic review. Acta Orthop. 2010 Dec;81(6):684–95.

[PMID: 21067432] Turun S et al. A systematic review of rivaroxaban versus enoxaparin in the prevention of venous thromboembolism after hip or knee replacement. Thromb Res. 2011 Jun;127(6):525–34.

[PMID: 21397931]

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ALLERGIC DISEASES

Allergy is an immunologically mediated hypersensitivity reaction to a foreign antigen manifested by tissue inflammation and organ dysfunction. These responses have a genetic basis, but the clinical expression of disease depends on both immunologic responsiveness and antigen exposure. Allergic disorders may be local or systemic. Because the allergen is foreign (ie, environmental), the skin and respiratory tract are the organs most frequently involved in allergic disease. Allergic reactions may also localize to the vasculature, gastrointestinal tract, or other visceral organs.

Anaphylaxis is the most extreme form of systemic allergy.

``Immunologic Classification An immunologic classification for hypersensitivity reactions serves as a rational basis for diagnosis and treatment.

The classification follows.

OSTEONECROSIS (Avascular Necrosis of Bone)

A. Type I—IgE-Mediated (Immediate) Hypersensitivity

Osteonecrosis is a complication of corticosteroid use, alcoholism, trauma, SLE, pancreatitis, gout, sickle cell disease,

IgE antibodies occupy receptor sites on mast cells. Within minutes after exposure to the allergen, a multivalent

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antigen links adjacent IgE molecules, activating and degranulating mast cells. Clinical manifestations depend on the effects of released mediators on target end organs.

Both preformed and newly generated mediators cause vasodilation, visceral smooth muscle contraction, mucous secretory gland stimulation, vascular permeability, and tissue inflammation. Arachidonic acid metabolites, cytokines, and other mediators induce a late-phase inflammatory response that appears several hours later. There are two clinical subgroups of IgE-mediated allergy: atopy and anaphylaxis.

1. Atopy—The term “atopy” is applied to a group of diseases (allergic rhinitis, allergic asthma, atopic dermatitis, and allergic gastroenteropathy) occurring in persons with an inherited tendency to develop antigen-specific IgE reaction to environmental allergens or food antigens.

Aeroallergens such as pollens, mold spores, animal danders, and house dust mite antigen are common triggers for allergic conjunctivitis, allergic rhinitis, and allergic asthma.

The allergic origin of atopic dermatitis is less well understood, but some patients’ symptoms can be triggered by exposure to dust mite antigen and ingestion of certain foods.

There is a strong familial tendency toward the development of atopy.

2. Anaphylaxis—Certain allergens—especially drugs, insect venoms, latex, and foods—may induce an IgE antibody response, causing a generalized release of mediators from mast cells and resulting in systemic anaphylaxis. This is characterized by (1) hypotension or shock from widespread vasodilation, (2) bronchospasm, (3) gastrointestinal and uterine muscle contraction, and (4) urticaria or angioedema. The condition is potentially fatal and can affect both nonatopic and atopic persons. Isolated urticaria and angioedema are cutaneous forms of anaphylaxis, are much more common, and have a better prognosis.

B. Type II—Antibody-Mediated (Cytotoxic) Hypersensitivity Cytotoxic reactions involve the specific reaction of either IgG or IgM antibody to cell-bound antigens. This results in activation of the complement cascade and the destruction of the cell to which the antigen is bound. Examples include immune hemolytic anemia and Rh hemolytic disease in the newborn.

C. Type III—Immune Complex-Mediated Hypersensitivity Immune complex-mediated reactions occur when antigen and IgG or IgM antibodies form circulating immune complexes. Deposition of these complexes in tissues or in vascular endothelium can produce immune complexmediated tissue injury through activation of the complement cascade, anaphylatoxin generation, and chemotaxis of polymorphonuclear leukocytes. Serum sickness is the classic example of type III hypersensitivity. Immune complex disease also can develop in the setting of chronic infections such as subacute bacterial endocarditis and hepatitis B.

D. Type IV—T Cell–Mediated Hypersensitivity (Delayed Hypersensitivity, Cell-Mediated Hypersensitivity) Type IV delayed hypersensitivity is mediated by activated T cells, which accumulate in areas of antigen deposition. The most common expression of delayed hypersensitivity is allergic contact dermatitis, which develops when a lowmolecular-weight sensitizing substance haptenates with dermal proteins, becoming a complete antigen. Sensitized T cells release cytokines, activating macrophages and promoting the subsequent dermal inflammation; this occurs 1–2 days after the time of contact. Common topical agents associated with allergic contact dermatitis include nickel, formaldehyde, potassium dichromate, thiurams, mercaptos, parabens, quaternium-15, and ethylenediamine. Rhus (poison oak and ivy) contact dermatitis is caused by cutaneous exposure to oils from the toxicodendron plants.

Acute contact dermatitis is characterized by erythema and induration with vesicle formation, often with pruritus, with exudation and crusting in more severe cases. Chronic allergic contact dermatitis may be associated with fissuring, lichenification, or dyspigmentation and may be mistaken for other forms of dermatitis. To diagnose allergic contact dermatitis, patch testing can be performed. cc

ATOPIC DISEASE

Clinical manifestations resembling allergic hypersensitivity can also occur in the absence of an immunologic mechanism. Therefore, the diagnosis of allergy requires answers to the following questions: (1) What is the nature of the disease? (2) Is the disease caused by an IgE-mediated mechanism? (3) What specific allergens are responsible?

The relevant history includes a survey of allergen exposure associated with home, work, hobbies, and habits as well as medications. Physical examination is most useful if performed during exposure. Demonstration of allergic hypersensitivity by in vivo or in vitro testing confirms clinical suspicions of allergic disease.

``Specific IgE Antibody Tests To maximize the positive predictive value of allergy testing, a positive test result must be correlated with the history.

Patients selected for testing include those with moderate to severe disease, those who are potential candidates for allergen immunotherapy, and those with strong predisposing factors for atopic diatheses, eg, a strong family history of atopy or ongoing exposure to potential sources of allergen.

Since the development of rhinitis precedes the presentation of asthma in over half of cases, early intervention may decrease the risk of more severe clinical allergic disease. The type of immune response must be consistent with the nature of the disease. IgE antibody causes allergic rhinitis but not allergic contact dermatitis. IgE antibodies are detected by in vivo (skin tests) or in vitro methods.

Bischoff SC. Food allergy and eosinophilic gastroenteritis and colitis. Curr Opin Allergy Clin Immunol. 2010 Jun;10(3): 238–45. [PMID: 20431371]

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Novak N. New insights into the mechanism and management of allergic diseases: atopic dermatitis. Allergy. 2009 Feb;64(2): 265–75. [PMID: 19178406] Ong PY. Emerging drugs for atopic dermatitis. Expert Opin Emerg Drugs. 2009 Mar;14(1):165–79. [PMID: 19216704] Sicherer SH et al. Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2008. J Allergy Clin Immunol. 2009 Feb;123(2):319–27.

[PMID: 19203656]

Serum Sickness ``

E s s en t ia l S o f dia g n o s i s

Fever, pruritic rash, arthralgias, and arthritis; nephritis in severe cases.

Occurs 7–10 days following administration of an exogenous antigen (eg, heterologous gamma globulin) when specific IgG antibodies develop against the antigen.

Immune complex–mediated small vessel vasculitis and tissue injury.

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``

``General Considerations Serum sickness occurs when an antibody response to exogenously administered antigens results in the formation of immune complexes. Deposition of these complexes in vascular endothelium and tissues produces immune complex– mediated small vessel vasculitis and tissue injury through activation of complement, generation of anaphylatoxins, and chemoattraction of polymorphonuclear leukocytes.

The skin, joints, and kidneys are commonly affected. It is self-limited and resolves after the antigen is cleared. First observed in the preantibiotic era when heterologous serum preparations were used for passive immunization, serum sickness is now less common but still occurs with the use of heterologous anti-thymocyte globulin for transplant rejection and, infrequently, after the administration of murine monoclonal antibodies or even non-protein drugs.

``Clinical Findings A. Symptoms and Signs Sustained high fever (> 101°F) is typical. The earliest manifestation is often a maculopapular or urticarial pruritic rash. Angioedema can occur. Polyarthralgias, frank polyarthritis, and lymphadenopathy are common.

Nephritis is usually mild but can progress to acute renal failure.

B. Laboratory Findings The ESR is increased, and leukocytosis is common. Other nonspecific laboratory findings include elevated hepatic aminotransferases. When nephritis is present, the urinalysis

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reveals proteinuria, hematuria, and red cell casts.

Hypocomplementemia is usually present in cases due to administration of heterologous gamma globulin but not in milder cases precipitated by non-protein drugs. Circulating immune complexes may be found, but current assays are limited in sensitivity.

``Treatment This disease is self-limited, and treatment is usually conservative for mild cases. NSAIDs help relieve the arthralgias, and antihistamines and topical corticosteroids can be of benefit for the skin manifestation. A high-dose course of corticosteroids is administered for serious reactions, especially those complicated by glomerulonephritis and other manifestations of vasculitis. Plasma exchange may be of benefit for cases refractory to corticosteroids.

PSEUDOALLERGIC REACTIONS These reactions resemble immediate hypersensitivity reactions but are not mediated by allergen-IgE interaction. Instead, direct mast cell activation occurs. Examples of pseudoallergic or “anaphylactoid” reactions include radiocontrast reactions, direct mast cell activation by opioids, and the now rare “red man syndrome” from rapid infusion of vancomycin. In contrast to IgE-mediated reactions, these can often be prevented by prophylactic medical regimens.

Radiocontrast Media Reactions Reactions to radiocontrast media do not appear to be mediated by IgE antibodies, yet clinically they are similar to anaphylaxis. If a patient has had an anaphylactoid reaction to conventional radiocontrast media, the risk for a second reaction upon reexposure may be as high as 30%. Patients with asthma or those being treated with β-adrenergic blocking medications may be at increased risk. The management of patients at risk for radiocontrast medium reactions includes use of the low-osmolality contrast preparations and prophylactic administration of prednisone (50 mg orally every 6 hours beginning 18 hours before the procedure) and diphenhydramine (25–50 mg intramuscularly 60 minutes before the procedure). The use of the lower-osmolality radiocontrast media in combination with the pretreatment regimen decreases the incidence of reactions to < 1%.

Liccardi G et al; Cardarelli Hospital Radiocontrast Media and Anesthetic-Induced Anaphylaxis Prevention Working Group.

Strategies for the prevention of asthmatic, anaphylactic and anaphylactoid reactions during the administration of anesthetics and/or contrast media. J Investig Allergol Clin Immunol. 2008;18(1):1–11. [PMID: 18361095] Vermeire S et al. Serum sickness, encephalitis and other complications of anti-cytokine therapy. Best Pract Res Clin Gastroenterol. 2009;23(1):101–12. [PMID: 19258190]

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PRIMARY IMMUNODEFICIENCY DISORDERS The primary immunologic deficiency diseases include congenital and acquired disorders of humoral immunity (B cell function) or cell-mediated immunity (T cell function). Most of these diseases are rare and, because they are genetically determined, usually present in childhood.

Nonetheless, several immunodeficiency disorders can present in adulthood, most notably selective IgA deficiency and common variable immunodeficiency.

COMMON VARIABLE IMMUNODEFICIENCY ``

SELECTIVE IMMUNOGLOBULIN A DEFICIENCY Selective IgA deficiency is the most common primary immunodeficiency disorder and is characterized by serum IgA levels < 15 mg/dL with normal levels of IgG and IgM; its prevalence is about 1:500 individuals. Most persons are asymptomatic because of compensatory increases in secreted IgG and IgM. Some affected patients have frequent and recurrent infections, such as sinusitis, otitis, and bronchitis. Some cases of IgA deficiency may spontaneously remit. When IgG2 subclass deficiency occurs in combination with IgA deficiency, affected patients are more susceptible to encapsulated bacteria and the degree of immune impairment can be more severe. Patients with a combined IgA and IgG subclass deficiency should be assessed for functional antibody responses to glycoprotein antigen immunization.

Atopic disease and autoimmune disorders can be associated with IgA deficiency. Occasionally, a sprue-like syndrome with steatorrhea has been associated with an isolated IgA deficit. Treatment with commercial immune globulin is ineffective, since IgA and IgM are present only in trace quantities in these preparations.

Individuals with selective IgA deficiency may have high titers of anti-IgA antibodies and are at risk for anaphylactic reactions following exposure to IgA through infusions of plasma (or blood transfusions). These antiIgA antibodies develop in the absence of prior exposure to human plasma or blood, possibly due to crossreactivity to bovine IgA in cow’s milk or prior sensitization to maternal IgA in breast milk.

Yel L. Selective IgA deficiency. J Clin Immunol. 2010 Jan;30(1): 10–6. [PMID: 20101521]

Defect in terminal differentiation of B cells, with absent plasma cells and deficient synthesis of secreted antibody.

Frequent sinopulmonary infections secondary to humoral immune deficiency.

Confirmation by evaluation of serum immunoglobulin levels and deficient functional antibody responses.

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Arason GJ et al. Primary immunodeficiency and autoimmunity: lessons from human diseases. Scand J Immunol. 2010 May; 71(5):317–28. [PMID: 20500682] Bussone G et al. Autoimmune manifestations in primary immune deficiencies. Autoimmun Rev. 2009 Feb;8(4):332–6.

[PMID: 19028607] Fried AJ et al. Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections. Clin Microbiol Rev. 2009 Jul;22(3):396–414. [PMID: 19597006] Slatter MA et al. Primary immunodeficiency syndromes. Adv Exp Med Biol. 2010;685:146–65. [PMID: 20687503]

E s s en t ia l S o f dia g n o s i s

``General Considerations The most common cause of panhypogammaglobulinemia in adults is common variable immunodeficiency, a heterogeneous immunodeficiency disorder clinically characterized by an increased incidence of recurrent infections, autoimmune phenomena, and neoplastic diseases. The onset generally is during adolescence or early adulthood but can occur at any age. The prevalence of common variable immunodeficiency is about 1:80,000 in the United States. Most cases are sporadic; 10–20% are familial.

``Clinical Findings A. Symptoms and Signs Increased susceptibility to pyogenic infections is the hallmark of the disease. Virtually all patients suffer from recurrent sinusitis, with bronchitis, otitis, pharyngitis, and pneumonia also being common infections. Infections may be prolonged or associated with unusual complications such as meningitis or sepsis.

Gastrointestinal disorders are commonly associated with common variable immunodeficiency, and a sprue-like syndrome, with diarrhea, steatorrhea, malabsorption, protein-losing enteropathy, and hepatosplenomegaly, may develop in patients. Paradoxically, there is an increased incidence of autoimmune disease (20%), although patients may not display the usual serologic markers. Autoimmune cytopenias are most common, but autoimmune endocrinopathies, seronegative rheumatic disease, and gastrointestinal disorders are also commonly seen. Lymph nodes may be enlarged in these patients, yet biopsies show marked reduction in plasma cells. Noncaseating granulomas are frequently found in the spleen, liver, lungs, or skin.

There is an increased propensity for the development of B cell neoplasms (50- to 400-fold increase risk of lymphoma), gastric carcinomas, and skin cancers.

B. Laboratory Findings The pattern of immunoglobulin isotype deficiency is variable. Most patients present with significantly depressed IgG levels, but over time all antibody classes (IgG, IgA, and IgM) may be affected. Diagnosis is confirmed in patients

Musculoskeletal & Immunologic Disorders with recurrent infections by demonstration of functional or quantitative defects in antibody production. Serum IgG levels are usually < 250 mg/dL; serum IgA and IgM levels are also subnormal. Decreased to absent functional antibody responses to protein antigen immunizations establish the diagnosis.

The causes of the panhypogammaglobulinemia in common variable immunodeficiency patients include intrinsic B cell defects that prevent terminal maturation into antibody-secreting plasma cells. The absolute B cell count in the peripheral blood in most patients, despite the underlying cellular defect, is normal. A subset of these patients have concomitant T cell immunodeficiency with increased numbers of activated CD8 cells, splenomegaly, and decreased delayed-type hypersensitivity.

``Treatment Patients may be treated aggressively with antibiotics at the first sign of infection. Since antibody deficiency predisposes patients to high-risk pyogenic infections, antibiotic coverage should be sure to cover encapsulated bacteria.

CMDT 2013

869

Only after the development of bronchiectasis or after sinus surgery do patients become significantly affected by more virulent organisms such as S aureus or P aeruginosa.

Maintenance intravenous immune globulin therapy is indicated, with infusions of 300–500 mg/kg of intravenous immune globulin given at about monthly intervals.

Adjustment of dosage or of the infusion interval is made on the basis of clinical responses and steady-state trough serum IgG levels. Such therapy is effective in decreasing the incidence of potentially life-threatening infections and increasing quality of life. The yearly cost of monthly infusions can be in excess of $20,000–$30,000.

Deane S et al. Common variable immunodeficiency: etiological and treatment issues. Int Arch Allergy Immunol. 2009; 150(4):311–24. Erratum in: Int Arch Allergy Immunol.

2010;151(4):284. [PMID: 19571563] van de Ven AA et al. B-cell defects in common variable immunodeficiency: BCR signaling, protein clustering and hardwired gene mutations. Crit Rev Immunol. 2011;31(2):85–98.

[PMID: 21542788]