05 Rheumatology

SECTION 5

Rheumatology 35.

Approach to Arthritis Liyakat Ali Gauri, BR Ajay, Asim Khan, Nadeem Liyakat, Qadir Fatima

157

36.

Approach to Seronegative Arthritis Harminder Singh Pannu, Harpreet Kaur, Anmol Singh, Piyush Harchand

166

37.

Pre-clinical Rheumatoid Arthritis - Identification and Implication Rohini Handa

171

38.

Remission in Rheumatoid Arthritis: A Reality in 2017 Shankar Subramanian

175

39.

Gout in 2017 Arup Kumar Kundu, Abhishek Kundu

179

40.

The Future of Systemic Lupus Erythematosus Satyabrata Ganguly, Anish Kar

183

41.

Pulmonary Renal Syndrome Yojana Gokhale, Raosaheb Rathod

186

42.

Antiphospholipid Syndrome Vikram Londhey

191

Approach to Arthritis

C H A P T E R

35

Liyakat Ali Gauri, BR Ajay, Asim Khan, Nadeem Liyakat, Qadir Fatima

ABSTRACT

Arthritis is the inflammation of the joints which is a term derived from Greek in which arthro- means joint and –itis means inflammation. Once the source of pain is confirmed as originating from joint then decide whether the disease is inflammatory or non-inflammatory in nature. Patients with an inflammatory arthritis are more likely to have palpable synovitis and morning stiffness; if the condition is severe, they may have fever, weight loss, and fatigue.

Then evaluate the temporal pattern of the disorder; especially acute versus chronic duration. Then classify the arthritis according to the spatial pattern: primarily, monoarthritis or poly arthritis and the presence of axial involvement. Then search for the existence of extraarticular and/or systemic manifestations.

Arthritis is the inflammation of the joints which is a term derived from Greek in which arthro- means joint and– itis means inflammation. 12th October has been declared as World Arthritis day. Musculoskeletal diseases are among the most common reasons for which medical help is sought. Anywhere between 25% and 30% individuals will have a musculoskeletal complaint in their life

Fig. 1: Stress pain and restriction at the wrist – there is no pain in the neutral ‘loose-pack’ position, but progressive pain and some restriction as the wrist moves towards full extension or full flexion

Table 1 : Distinctive features of regional syndromes Periarticular pain

Articular pain

Neurogenic pain

Referred pain

Enquiry

Only a few selective movements are painful

All joint movements are painful

Dysaesthesic; aggravated by compression of nerve or movement of the spine

Unrelated to movement; ‘visceral’ timing; poorly localised, may be improved by rubbing

Pain on motion

Active> passive; selected movements

Active~passive; several directions

Normal; if root pain: pain on movement of the affected spine segment

Normal

Range of motion

Active movement may be limited by pain; passive movement: full

May be limited equally for both active and passive movement

Normal

Normal

Resisted active movement

Pain on specific manoeuvres

No effect

No effect

No effect

Local palpation

Tenderness over affected periarticular structure (away from joint line)

Possible tenderness over joint line, crepitus, capsular swelling, effusion, increased heat

Normal

Normal

Neurological examination

Normal

Normal

May be abnormal

Normal

RHEUMATOLOGY

158

Table 2: Differences between inflamed and damaged joints

Table 4: Diagnostic Clues in Patients Presenting with Joint Pain

Inflamed joint

Damaged joint

Early morning stiffness

Prolonged

Brief

Clues from history and physical examination

Diagnoses to consider

Inactivity stiffness

Prolonged

Brief

Sudden onset of pain in seconds or minutes

Increased warmth

+

−

Fracture, internal derangement, Trauma, loose body

Stress pain

Yes

No

Onset of pain over several hours or one to two days

+

–

Infection, crystal deposition disease, other inflammatory arthritic condition

+++

+/−

Insidious onset of pain over days to weeks

−

+++

Indolent infection, osteoarthritis, infiltrative disease, tumor

+/−

−

Septic arthritis

Malalignment/ deformity

−

+/−

Intravenous drug use, immunosuppression

Instability

−

+/−

Previous acute attacks in any joint, with spontaneous resolution

Crystal deposition disease, other inflammatory arthritic condition

Recent prolonged course of corticosterioid therapy

Infection, avascular necrosis

Coagulopathy, use of anticoagulants

Hemarthrosis

Urethritis, conjunctivitis, diarrhea, and rash

Reactive arthritis

Psoriatic patches or nail changes such as pitting

Psoriatic arthritis

Use of diuretics, presence of tophi, history of renal stones or alcoholic binges

Gout

Eye inflammation, low back pain

Ankylosing spondylitis

Capsular softtissue swelling Effusion Coarse crepitus Erythema

Table 3: Shows a broad classification of the causes of arthritis with a focus on major causes of monoarthritis Acute arthritis

Chronic arthritis Inflammatory

Monoarthritis

Monoarthritis

Crystal induced arthritis (gout and pseudogout)

Tubercular arthritis

Septic arthritis

Other infections (e.g Brucellosis)

Gonococcal arthritis

Fungal arthritis

Acute onset of Immunoinflammatory inflammatory polyarthritis arthritis (like RA, SLE) Crystal induced arthritis Polyarthritis (e.g., acute onset of polyarthritis, reactive arthritis)

Polyarthritis (e.g., RA, psoriatic arthritis, spondyloarthritis)

Non-inflammatory Monoarthritis

Monoarthritis

Hemarthrosis

Single joint osteoarthritis

Trauma

Neuropathic arthropathy Osteonecrosis Pigmented villo nodular synovitis

Polyarthritis

Polyarthritis (e.g., osteoarthritis)

time.1,2 A significant proportion of patients who present with musculoskeletal complaints have in fact systemic illness such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) etc. which may be potentially lifethreatening if not detected, correctly diagnosed and treated. These conditions have to be distinguished from other musculoskeletal conditions, which have no systemic component. The evaluation should proceed to ascertain if the complaint is (1) articular or non-articular in origin, (2)

Gonococcal arthritis Young adulthood, migratory polyarthralgias, inflammation of the tendon sheaths of hands and feet, dermatitis Hilar adenopathy, erythema nodosum

Sarcoidosis

inflammatory or non-inflammatory in nature, (3) acute or chronic in duration, and (4) localized (monoarticular) or widespread (polyarticular) in distribution.

ARTICULAR VERSUS NONARTICULAR

The first step in approach to a patient with arthritis is to confirm that the origin of pain is from the joint. (anatomical basis).3 Questioning and examination will allow the distinction of four main origins (Table 1): a.

Articular pain

b.

Extra articular pain:

•

periarticular pain

•

neurogenic pain

•

referred pain.

Articular structures include the synovium, synovial fluid,

159

Patient has arthralgia limited to one or a very few joints

Elicit complete history and perform physical examination

Does patient have significant trauma or focal bone pain?

Yes

Perform radiography

Abnormal

Patient has fracture, tumor, or metabolic bone disease

No

Unsuccessful

Perform joint aspiration

Yes

Does patient have effusion or signs of inflammation?

Does patient have point tenderness or trigger points?

No

Successful Reevaluate

Aspirate is bloody

Aspirate contains bone marrow elements

Patient has coagulopathy, pseudogout, tumor, trauma, or Charcot joint (check PT, PTT, platelet count, and bleeding time)

Patient has intra-articular fracture

Does aspirate contain > 2,000/mm3 WBCs and > 75% PMNs?

No

Yes

Patient has bursitis, tendinitis, or firbomyalgia

No

Patient has osteoarthritis, internal derangement, soft tissue injury, or viral infection

Yes

Crystals are present in joint fluid

Patient has gout (monosodium urate crystals)

Normal

Patient has pseudogout (calcium pyrophosphate dihydrate crystals)

Cultures are positive

Joint fluid is sterile

Patient has infectious arthritis

Patient may have rheumatoid arthritis, juvenile rheumatoid arthritis, viral infection, systemic lupus erythematosus, Lyme disease, sarcoidosis, or spondyloarthropathy (check CBC, ESR and RF level; consider testing for HLA-B27 and ANA and liver function testing, Lyme disease serology, and pelvic radiography)

Fig. 2: Diagnosing Acute Monoarthritis articular cartilage, intraarticular ligaments, joint capsule, and juxta-articular bone. Non articular (or periarticular) structures, such as supportive extra articular ligaments, tendons, bursae, muscle, fascia, bone, nerve, and overlying skin, may be involved in the pathologic process.

Arthropathies – that is, diseases affecting the joints – are at the heart of rheumatology.

As the first step we have to recognise that this is an articular syndrome. Once this is done four fundamental features of the articular pattern should be defined: 1.

Whether the disease is inflammatory or noninflammatory in nature.

2.

The temporal pattern of the disorder; especially acute versus chronic duration.

3.

The spatial pattern: primarily, monoarthritis or polyarticular arthritis and the presence of axial involvement.

4.

The existence of extra-articular and/or systemic manifestations.

INFLAMMATORY VERSUS NON-INFLAMMATORY DISORDERS

Determine the nature of the underlying pathologic process and whether inflammatory or non-inflammatory findings exist. Inflammatory Disorders may be infectious (Neisseria gonorrhoeae or Mycobacterium tuberculosis), crystal-induced (gout, pseudogout), immune-related (rheumatoid arthritis [RA], systemic lupus erythematosus [SLE]), reactive(rheumatic fever, reactive arthritis), or idiopathic. Non-inflammatory disorders may be related to trauma (rotator cuff tear), repetitive use (bursitis, tendinitis), degeneration or ineffective repair (Osteoarthritis), neoplasm (pigmented villonodular synovitis) or pain amplification (fibromyalgia).

The most important goal is to differentiate the features of joint damage, predominantly caused by OA, from those of inflammatory joint disease (Table 2).

CHAPTER 35

Patient probably has inflammatory process

RHEUMATOLOGY

160

Table 5: Synovial Fluid Characteristics in the Clinical Situations, with Imaging and Investigation Techniques Best Used to Identify the Cause Diagnosis

Cells

Microorganisms Appearance

Imaging Modality

Comments

Bacterial arthritis

Neutrophils 10,000-100,000

Gram stain usually positive

Aspiration to dryness: may need ultrasound

Systemic symptoms.

Gram stain

Aspiration to dryness; may need ultrasound

Systemic symptoms, Gram stain

XR,CPPD

Presence of appropriate crystals

Gonococcal arthritis

Crystal arthritis

Neutrophils 10,000-100,000

Gram stain usually positive

Neutrophils 10,000-100,000

Turbid/pus

Turbid/pus

Turbid/pus

Blood and synovial fluid culture

Blood and synovial fluid culture

Acute serum urate unreliable Tuberculous arthritis

Mononuclear 5000-50,000

Acid-fast stain often negative

Inflammatory Neutrophils moioarthropathies 5000-50,000

Turbid/pus

At-risk population Ziehl-Neelsen stain biopsy may be necessary

Slightly turbid Ultrasound/ MRIfor early synovitis and erosions

Serum autoantibodies such as RF, AC PA, ANA

Osteoarthritis

Mononuclear 0-2000

—

Clear

XR changes

Usually noninflammatory CPPD may be present

Internal derangement

Red blood cells

—

Clear/turbid

MRI

Arthroscopy may be necessary

Trauma

Red blood cells

Clear/turbid

XR

Tc bone scan may aid diagnosis if radiograph normal

—

MRI in early disease

XR abnormal only in advanced cases

CXR

Ischemic necrosis Rarer Causes Sarcoidosis

Mononuclear 5000-20,000

—

PVNS

Red blood cells

—

Charcot’s

Mononuclear

—

Turbid

Ultrasound and Synovial biopsy essential MRI XR

CPPD may be present

0-2000 Lyme disease

Neutrophils 0-5000

Clear/turbid

SF eosinophilia may be found Serology for Barmlia

Amyloid

Mononuclear 2000-10,000

Turbid

Synovial biopsy for Congo red stain

ACPA, anticitrullinated protein antibody; ANA, antinuclear antibody; CPPD, calcium pyrophosphate dehydrate deposition; CXR, chest radiograph; MRI, magnetic resonance imaging; PVNS, pigmented villonodular synovitis; RF, rheumatoid factor; SF, synovial fluid; XR, radiograph.

Inflammatory disorders may be identified by any of the four cardinal signs of inflammation (erythema, warmth, pain, or swelling). In active inflammatory disease pain is worst in the morning (often waking the patient up a little early) and is relieved as they get up and start to move their joints. Morning stiffness is often prolonged, lasting

for more than 30 min and sometimes for several hours.

Stiffness after rest may persist for more than 5 min. With inflammatory disease sufficient to trigger the acute phase response, the patient may additionally complain of nonspecific features such as fatigability, weight loss, night sweats (the commonest symptom of pyrexia

Table 6: Algorithm for assessing initial history and examination. CMC, carpometacarpal; CTD, connective tissue disease; DIP, distal interphalangeal; JIA, juvenile idiopathic arthritis; MCTD, mixed connective tissue disease; PIP, proximal interphalangeal Musculoskeletal complaint Distribution

Inflammatory

Bursitis/tendinitis Polymyalgia rheumatica

Noninflammatory

Acute

Inflammatory

Polyarthritis (≥4 joints)

Mono/ oligoarthritis (1-3 joints)

Chronic

Acute

Chronic

Meniscal tear (internal derangement) Osteoarthritis flare Reflex sympathetic dystrophy

Osteoarthritis (hip or knee) Osteonecrosis Neuropathic arthritis Hemochromatosis Pigmented villonodular synovitis

Hemoglobinopathies Amyloid arthropathies

Osteoarthritis (DIP, PIP, CMC1)

Infectious arthritis Gout Pseudogout Reactive arthritis Chlamydial arthritis

Psoriatic arthritis Spondyloarthropathies Pauciarticular JIA Indolent infectious arthritis*

Viral arthritis Serum sickness Drug-induced arthritis Early onset of CTD Rheumatic fever Palindromic rheumatism RS3PE

Rheumatoid arthritis Undifferentiated polyarthritis Inflammatory osteoarthritis MCTD Lupus Scleroderma Polyarticular JIA Adult Still’s disease

Joint damage/OA is typically associated with pain that increases with repeated use of the joint, which is relieved by rest, and which is often worst towards the end of the day. Patients may describe pain and stiffness(gelling) that increases again after resting that subsides after just a few minutes. Early morning stiffness in OA is ‘worn off’ in well under 30 minutes. Although OA signs may be detected in many joints on examination (many being asymptomatic), OA usually causes pain in just one or a few joints at any one time. Extra-articular manifestations (eg, anterior uveitis, skin lesions, lung or bowel problems) are not associated with OA, which is purely a condition of the joints, although age-related co-morbidities (eg, obesity, hypertension, depression) may commonly occur in older patients with OA and contribute to their participation restriction.

It is noteworthy that people with OA may suffer ‘flares’ of pain which may relate to minor inflammation or be biomechanically initiated. During such pain exacerbations patients may have more prolonged morning and activity stiffness. However, inflammation is not a prominent clinical feature and OA does not trigger the acute phase response. Conversely, longstanding but ‘inactive’ inflammatory arthritis will be associated with ‘mechanical’ pain reflecting joint damage caused by their inflammatory disease.

Physical examination will support joint damage/OA if there is coarse crepitus, joint-line tenderness (often localised rather than universal as in inflammatory

In inflammatory diseases the synovium becomes inflamed, engorged and eventually hypertrophied and the volume of synovial fluid increases. Causing intraarticular hypertension leading to pain, stiffness and restriction of movement. A joint with intra-articular hypertension is most comfortable in the position that minimises the pressure increase. This position, generally mild to mid flexion, and is termed the ‘loose-pack’ position, in which the capsule is normally at its loosest and therefore can accommodate an increase in fluid and soft tissue. Conversely, the positions in which the capsule is naturally tight – the ‘tight-pack’ positions at the extremes of range of movement – are the positions that are the first to be painful when synovitis is developing, and the first movements to become restricted.

This uneven distribution of pain, maximal in all tight pack positions, is called ‘universal stress pain’ – the most sensitive sign of synovitis, occurring even before there is visible swelling or restricted movement (Figure 1). Joint damage is associated with a more even spread of pain throughout the range of movement.

Joint inflammation may also cause increased warmth palpable over the capsular contour. The summated features that allow distinction between joint damage and joint inflammation are shown in table. Age is also an important factor. Joint conditions before the age of 40 are likely to be inflammatory if not traumatic. Inflammatory arthritis will usually establish itself in a matter of days to weeks or months, whereas patients with OA tend to present to doctors only after years of variable but very slowly increasing pain.

THE SPATIAL PATTERN

Monoarthritis

Monoarthritis which is arthritis of a single joint can either be acute(of < 6 weeks duration) or chronic (of > 6 weeks duration) or be either inflammatory or non-inflammatory as given in the Table 3. Acute monoarthritis in adults can have many but crystals, trauma, and infection are the most common. Prompt diagnosis of joint infection, which often is acquired hematogenously, is crucial because of its destructive course (Figure 2). A prospective, threeyear study4 found that the most important risk factors for septic arthritis are a prosthetic hip or knee joint, skin infection, joint surgery, rheumatoid arthritis, age greater than 80 years, and diabetes mellitus. Intravenous drug use and large-vein catheterization are predisposing factors for sepsis in unusual joints (e.g., sternoclavicular joint).4 Gonococcal arthritis is the most common type of non-traumatic acute monoarthritisin young, sexually active persons in the United States. It is three to four times more common in women than in men.4,5 Nongonococcal septic arthritis, the most destructive type, generally is monoarticular (80 percent of cases) and most often affects the knee (50 percent of cases).4,7 Staphylococcus aureus is the most common pathogen in non-gonococcal

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Noninflammatory

Nonarticular Trauma Fracture Fibromyalgia Reflex sympathetic dystrophy

arthritis) and/or bony swelling (osteophyte) along the joint margin. Deformity may also be present in later stages of joint damage and OA.

RHEUMATOLOGY

162

Table 7 : Distinguishing Different Causes of Polyarthritis Arthritis

Patient Profile

History/Onset

Joints Involved

Type of Arthritis

Supportive Tests

GC

F > M, young, active sexually

Fever, acute oligoarthritis or polyarthritis

Wrist, knee, tenosynovitis

Inflammatory

ESR/CRP, WBC

Gout

Men, postmenopausal women

Intermittent oligoarticular early, polyarticular later

MTP, toes, ankle, knee [hands late]

Acute sudden onset severe pain with attacks

CRP, WBC Normal uric acid in 40% acutely

HHC

M > F. mean age, 50

Intermittent oligoarticular or polyarticular

MCP, hip, knee, Intermittent feet or chronic inflammatory

OA

F > M. Age men w/ knee or hip

Additive oligoartictlar or polyarticular

DIP, PIP, first CMC1, knee, hip, MTP, spine

PMR

M= F, older white Prolonged AM stiffness or soreness, weight loss

Inflammatory, Girdle (hip, shoulder) chronic muscles; seldom synovitis

Anemia, ESR/ CRP, LFTs

PsA

Long history of psoriasis

Insidious, additive

DIP, PIP, knees, feet, spine

Inflammatory, asymmetric oligoarticjular

CRP/ESR, negative RF, HLA-B27, Uric acid

Pseudogout

M = F, older patients

Intermittent oligoarticular or polyarticular

Knee, wrist finger, MTP

Intermittent or chronic inflammatory

CRP, WBC

RA

F>M. 35-50 yr

Insidious, additive

PIP, MCP, wrist MTP, knee, ankle

Symmetric inflammatory

CRP/ESR, +RF, +CCP

UPA

F>M

Insidious, one to four joints

Same as RA

Inflammatory

CRP/ESR

Viral (HBV. HCV)

Hepatitis risk factors

Acute, additive polyarthritis

PIP, MCP, wrist, knee, ankle

Inflammatory

ESR/CRP, LFTs, +HCWHBV serologies

Noninflammatory asymmetric or symmetric, bony swelling

ESR/CRP, LFTs, HFE gene, x-rays— chondrocalcinosis and osteophytosis Normal laboratory results

CCP, cyclic citrullinated protein; CMC, carpometacarpal; CRP, C-reactive protein; DIP, distal interphalangeal; ESR, erythrocyte sedimentation rate; GC, gonococcal arthritis; HBV, hepatitis B virus; HCV, hepatitis C virus; HHC, hereditary hemochromatosis; LFT, liver function test; MCP, metacarpophalangeal; MTP, metatarsophalangeal; OA, osteoarthritis; PIP, proximal interphalangeal; PMR, polymyalgia rheumatica; PsA, psoriatic arthritis; RA, rheumatoid arthritis; RF, rheumatoid factor; UPA, undifferentiated polyarthritis; WBC, white blood cell; SLE = systemic lupus erythematosus; IBD = inflammatory bowel disease; RA = rheumatoid arthritis; PAN = polyarteritis nodosa; DIP = distal interphalangeal; PIP = proximal interphalangeal. *—The clues listed in this table are not, in themselves, diagnostic or complete; they are presented for illustrative purposes only.

septic arthritis (60 percent in some series), but non– group-A beta-hemolytic streptococci, gram-negative bacteria, and Streptococcus pneumoniae can be present.3 Anaerobic and gram-negative infections are common in immunocompromised persons. Inflammation of a single large joint, especially the knee, may be present in Lyme disease. Mycobacterial, fungal, and viral infections are rare. Monoarticular inflammation can be the initial manifestation of human immunodeficiency virus (HIV) infection.8 Many types of crystals can trigger acute monoarthritis, but monosodium urate (which causes gout) and calcium pyrophosphate dihydrate (CPPD,

which causes pseudogout) are the most common.

Calcium oxalate (especially in patients who are receiving renal dialysis), apatite, and lipid crystals9 also elicit acute monoarthritis (Table 4). Transient arthritis sometimes results from intra-articular injection of corticosteroids.

Osteoarthritis may worsen suddenly and manifest as pain and effusion. Spontaneous osteonecrosis may occur in patients with risk factors such as alcoholism or chronic corticosteroid use. Aseptic loosening is often the source of pain in a prosthetic joint. Infection, commonly from a skin source, is also possible and requires urgent attention.

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Table 8: Selected Extra-Articular Manifestations Associated with Conditions that Result in Polyarticular Joint Pain* Physical finding

Diagnoses to consider

Skin and mucous membranes Rash Erythema infectiosum Reticulated (lacy) rash

Human parvovirus B19 infection

Facial exanthem (slapped cheek)

Human parvovirus B19 infection

Plaques (scalp, navel, gluteal cleft)

Diagnoses to consider

Skin and mucous membranes continued.

Telangiectasia

Scleroderma

Thickened skin

Scleroderma, amyloidosis, eosinophilic fasciitis

Hair thinning

Hypothyroidism, SLE

Musculoskeletal system SLE, human parvovirus Tender points B19 infection, Lyme disease, rosacea, seborrhea, Heberden’s nodes (DIP joints), Bouchard’s nodes dermatomyositis (PIP joints) Psoriasis

Fibromyalgia

CHAPTER 35

Malar rash

Physical finding

Osteoarthritis

Boutonniere and swanneck deformities

RA, SLE, Ehlers-Danlos syndrome

Heliotrope

Dermatomyositis

Erythema chronicum migrans

Lyme disease

Dactylitis (“sausage digits”)

Spondyloarthropathies

Erythema marginatum rheumaticum

Rheumatic fever

Bursitis and enthesitis

Spondyloarthropathies

Erythema nodosum

Sarcoidosis, Crohn’s disease

Pyoderma gangrenosum

IBD, RA, SLE, anklyosing spondylitis, sarcoidosis, Wegener’s granulomatosis

Palpable purpura

Hypersensitivity vasculitis, Bradycardia Schonlein-Henoch Cardiovascular system purpura, PAN Mitral regurgitation and Antiphospholipidstenosis antibody syndrome,

Livedo reticularis

vasculitis, cholesterol emboli

Constitutional conditions Fever

Reactive arthritis, psoriatic arthritis

Discoid skin lesions

Discoid lupus erythematosus, SLE, sarcoidosis

Gottron’s papules or plaques

Dermatomyositis

Vesicopustule on erythematous base

Gonococcal arthritis

Eyes Iritis or uveitis

Spondyloarthropathies, sarcoidosis, Wegener’s granulomatosis

Conjunctivitis

Spondyloarthropathies, SLE, Wegener’s granulomatosis

Cytoid bodies (retinal exudates)

SLE

Hypothyroidism Rheumatic fever

Aortic regurgitation

Ankylosing spondylitis, rheumatic fever, relapsing polychondritis, reactive arthritis, Marfan syndrome, Takayasu’s arteritis

Cardiomyopathies

Viral infection, amyloidosis, sarcoidosis, SLE, polymyositis

New murmur, fever

Bacterial endocarditis, rheumatic fever

Diminished peripheral pulses

Giant cell arteritis, Takayasu’s arteritis

Lesions Keratoderma blennorrhagicum

Bacterial or viral infection, Still’s disease, subacute bacteria endocarditis, neoplasm

Gastrointestinal system Splenomegaly

Felty’s syndrome, tumorassociated arthritis

Hepatomegaly

Whipple’s disease, hemochromatosis, amyloidosis, Wilson’s disease

Contd..

164

Table 8: Selected Extra-Articular Manifestations Associated with Conditions That Result in Polyarticular Joint Pain* Physical finding

Diagnoses to consider

Physical finding

Diagnoses to consider

Scleritis

RA, relapsing polychondritis

IBD

Ischemic optic neuritis

Giant cell arteritis, Wegener’s granulomatosis

Positive fecal occult blood test

RHEUMATOLOGY

Ears, nose and throat

Genitourinary system Prostatis

Reactive arthritis, ankylosing spondylitis

Oral ulcers

SLE, Behcet’s syndrome, reactive arthritis, Wegener’s granulomatosis

Urethritis or cervicitis

Reactive arthritis, gonococcal arthritis

Parotid enlargement

Sjogren’s syndrome, sarcoidosis

Scrotal or vulvar ulcers

Behcet’s syndrome

Macroglossia

Amyloidosis

Hypogonadism

Hemochromatosis

Scalp tenderness

Giant cell arteritis

Balanitis circinata

Reactive arthritis

Bloody or severe sinusitis

Wegener’s granulomatosis

Neurologic system

Inflammation of ear lobe

Relapsing polychondritis

Entrapment neuropathies

RA, hypothyroidism, hyperparathyroidism

Onycholysis

Psoriatic arthritis, hyperthyroidism

Facial palsy

Lyme disease

Pitting

Psoriatic arthritis

Peripheral neuropathy

SLE, amyloidosis

Clubbing

IBD, Whipple’s disease, hyperthyroidism

Chorea

Nodules

RA, gout, Whipple’s disease, rheumatic fever, amyloidosis, sarcoidosis

Antiphospholipidantibody syndrome, SLE, rheumatic fever

Mononeuritis multiplex

RA, SLE, Lyme disease, vasculitis (e.g., PAN)

Tophi

Gout

Seizures

SLE

Jaundice

Hepatitis, hemochromatosis

Lymphadenopathy

Tumor-associated arthritis, SLE

Hyperpigmentation

Whipple’s disease, hemochromatosis

Nails

SLE = systemic lupus erythematosus; IBD = inflammatory bowel disease; RA = rheumatoid arthritis; PAN = polyarteritis nodosa; DIP = distal interphalangeal; PIP = proximal interphalangeal. *—The clues listed in this table are not, in themselves, diagnostic or complete; they are presented for illustrative purposes only.

Joint aspiration is necessary in monoarthritis. Synovial fluid characteristics are given in Table 5.

POLYARTICULAR ARTHRITIS

Polyarticular joint pain (i.e., pain in more than 4 joints) poses a diagnostic challenge because of the extensive differential diagnosis (Tables 6 & 7). Because many rheumatologic laboratory tests lack the desired specificity, results should be interpreted in the clinical context and with caution. The differential diagnosis can be narrowed through investigation of six clinical factors: disease chronology, inflammation, distribution, extraarticular manifestations (Table 8), disease course, and patient demographics. Algorithm 1 gives the summary of approach to arthritis.

REFERENCE

1.

2.

Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ 2003; 81:646-56.

Woolf AD, Akesson K. Understanding the burden of musculoskeletal conditions. The burden is huge and not

3.

4.

5.

6.

7.

8.

9.

reflected in national health priorities. BMJ 2001; 322:107980.

Malaviya AN. A patient with musculoskeletal (MSK) painsclinical approach. Bull Kuwait Inst Med Spec 2004; 3:73-82.

Goldenberg DL. Septic arthritis. Lancet 1998; 351: 197-2 O’Brien JP, Goldenberg DL, Rice PA. Disseminated gonococcal infection: a prospective analysis of 49 patients and a review of pathophysiology and immune mechanisms.

Medicine [Baltimore] 1983; 62:395-406.

Cucurull E, Espinoza LR. Gonococcal arthritis. Rheum Dis Clin North Am 1998; 24:305-22.

Mikhail IS, Alarcon GS. Nongonococcal bacterial arthritis.

Rheum Dis Clin North Am 1993; 19:311-31.

Berman A, Cahn P, Perez H, Spindler A, Lucero E, Paz S, et al. Human immunodeficiency virus infection associated arthritis: clinical characteristics. J Rheumatol 1999; 26:115862.

Reginato AJ, Schumacher HR, Allan DA, Rabinowitz JL. Acute monoarthritis associated with lipid liquid crystals.

Ann Rheum Dis 1985; 44:537-43.

Conclusion

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Musculoskeletal Complaint Initial rheumatic history and physical exam to determine 1. Is it articular?

2. Is it acute or chronic 3. Is inflammation present?

4. How many/which joints are involved?

CHAPTER 35

Nonarticular condition Consider ● Trauma/fracture ● Fibromyalgia ● Polymyalgia rheumatica ● Bursitis ● Tendinitis

Is it articular?

No

Yes Is complaint > 6 wk?

Yes

No

Chronic

Acute

Is inflammation present?

1. Is there prolonged morning stiffness?

2. Is there soft tissue swelling?

3. Are there systemic symptoms?

4. Is the ESR or CRP elevated?

Consider ● Acute arthritis ● Infectious arthritis ● Gout ● Pseudogout ● Reactive arthritis ● Initial presentation of chronic arthritis

No

Chronic noninflammatory arthritis

Yes Chronic inflammatory arthritis

How many joints involved?

1-3 Are DIP, CMC1, hip or knee joints involved?

No

Unlikely to be osteoarthritis Consider ● Osteonecrosis ● Charcot arthritis

Yes

Osteoarthritis

Chronic inflammatory mono/oligoarthritis Consider ● Indolent infection ● Psoriatic arthritis ● Reactive arthritis ● Pauciarticular JA

>3

Chronic inflammatory polyarthritis Is involvement symmetric?

No

Consider ● Psoriatic arthritis ● Reactive arthritis

Are PIP, MCP, or MTP joints involved?

No

Unlikely to be rheumatoid arthritis Consider ● SLE ● Scleroderma ● Polymyositis

Algorithm 1: Approach to arthritis

Yes

Yes

Rheumatoid arthritis

C H A P T E R

36

Approach to Seronegative Arthritis Harminder Singh Pannu, Harpreet Kaur, Anmol Singh, Piyush Harchand

INTRODUCTION

The term arthritis literally means joint pains associated with joint inflammation, synovial thickening and eventually joint erosions leading to a deforming and debilitating disease. The classic example we see in our day to day practice is Rheumatoid Arthritis (RA). It was recognized in the early part of the 20th century that not all cases of inflammatory arthritis were homogeneous in presentation. The ability to apply the rheumatoid factor (RF) test more widely in the 1950s helped confirm that not all inflammatory arthritis were seropositive.

Therefore, the term, seronegative variants of rheumatoid arthritis, was introduced. Our aim in this chapter is to provide concise information about the various types of seronegative arthritis and to focus on the approach for its evaluation.

ETIOLOGY OF SERONEGATIVE ARTHRITIS

Although no clear-cut definition exists, the following differential diagnoses should be considered: 1.

Seronegative rheumatoid arthritis

2.

The Spondyloarthritides

3.

Crystalline arthropathies

4.

Infectious diseases

5.

Neoplastic/paraneoplastic arthritis

6.

Inflammatory/ connective tissue disease

Seronegative arthritis may be differentiated into inflammatory versus non-inflammatory. Furthermore seronegative inflammatory arthritis may be divided into monoarthritis (single joint involvement), oligoarthritis (2, 3 or 4 joints involved) or polyarthritis (> 5 joints).

SERONEGATIVE RHEUMATOID ARTHRITIS

IgM, IgG and IgA isotypes of RF occur in sera from patients with RA, although the IgM isotype is the one most frequently assessed. Around 20-25 % of RA patients may test negative for RF and yet have the full clinical picture with the potential for poor prognosis when not treated.

It is important to remember that some patients with RA may take 18-24 months to become seropositive. In 2010, a collaborative effort between the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) revised the 1987 ACR classification criteria for RA in an effort to improve early diagnoses with the goal of identifying patients who would benefit from early introduction of disease modifying therapy.

The new criteria include a positive test for serum anti-CCP

antibodies (ACPA), which carries greater specificity for the diagnosis of RA than a positive test for RF. In early RA, the specificity of ACPA ranges from 94-100%, compared with RF in which the specificity ranges from 23-96%. By the same rule patients should also be negative for ACPA in order to be labeled as seronegative RA. Seronegative patients are often regarded as having a milder set of symptoms compared to seropositive patients. Generally, seronegative patients donâ&#x20AC;&#x2122;t develop rheumatoid nodules as these are commonly displayed in seropositive patients.

This is never a certainty, however, and each patientâ&#x20AC;&#x2122;s symptoms and progression will differ. We know that seropositive RA has strong association with HLA- DR4 but its relation in seronegative RA is controversial.

THE SPONDYLOARTHRITIDES

This group of disorders encompass ankylosing spondylitis (AS), psoriatic arthritis, reactive arthritis, enteropathic arthritis, juvenile onset spondyloarthritis (SpA) and undifferentiated spondyloarthropathy. Some of the important differentiating features amongst these are listed in Table 1.

All of these have some distinct as well as some overlapping features, characteristic axial involvement and a negative rheumatoid factor. Involvement of peripheral joints is usually oligoarticular but rarely polyarthritis may be present.

The typical characteristic features of these seronegative SpAs are: 1.

Asymmetric peripheral arthritis predominantly of lower limbs and inflammatory back pain (IBP).

2.

Radiographic spondylitis

3.

Enthesopathy.

4.

Absence of rheumatoid factor or other features of RA

5.

Anterior uveitis

6.

Increased familial incidence

7.

Presence of dactylitis

8.

Association with HLA B27- The incidence and prevalence of AS generally mirrors the frequency of HLA-B27 in the population. The risk of developing AS in healthy HLA-B27 positive subjects is approximately 6% in various population groups.

sacroiliitis

with

or

without

In India, the prevalence was found to be 0.6% in a study done in South India.

167

Table 1: Features of spondyloarthritides Ankylosing spondylitis

Reactive arthritis

Psoriatic arthritis

Enteropathic arthritis

Age of onset

20-30 years

20-30 years

35-45 years

Any age

Male:female ratio

3:1

5:1

1:1

1:1

Peripheral arthritis

Asymmetrical lower extremities

Asymmetrical lower extremities

Any joints

Asymmetrical lower extremities

Spine involvement

Symmetrical sacroiliitis (100%), delicate marginal Syndesmophytes : lumbar spine and lower thoracic spine involved initially

Asymmetrical sacroiliitis, bulky marginal syndesmophytes

Asymmetrical sacroiliitis, bulky marginal syndesmophytes: cervical spine involvement most commonly

Symmetrical sacroiliitis, delicate marginal syndesmophytes

Enthesitis

Uncommon

Common

Common

Less Common

Dactylitis

Uncommon

Common

Common

Uncommon

Dermatological manifestations

Non-specific

Keratoderma blennorrhagica, circinate balanitis

Psoriasis

Erythema nodosum, pyoderma gangrenosum

Uveitis

Occasional

Common

Occasional

Occasional

Other extra-articular manifestations

Aortic regurgitation, conduction defects, upper lobe pulmonary fibrosis, lgA nephropathy

Aortic regurgitation

Aortic regurgitation

Aortic regurgitation

Familial aggregation Common

Common

Common

Common

HLA B27

80%

40%

30%

90%

Table 2: Criteria for Ankylosing Spondylitis Adapted from the Modified New York criteria 1984 for ankylosing spondylitis Clinical criteria • Low back pain and stiffness for longer than 3 months, which improve with exercise, but are not relieved by rest • Restriction of motion of the lumbar spine in both the sagittal and frontal planes • Restriction of chest expansion relative to normal values correlated for age and sex Radiological criterion • Sacroiliitis grade ≥2 bilaterally, or grade 3–4 unilaterally Progressive damage due to continuous inflammation and osteoproliferation rather than osteodestruction leads to loss of spinal mobility which can be assessed by Schober’s test. Syndesmophytes, ankylosis and eventually fibrosis are the most characteristic features of this disease.

Definite ankylosing spondylitis is present if the radiological criterion is associated with at least one clinical criterion (Table 2).

The characteristic radiological features of AS are shown in Figure 1.

CRYSTALLINE ARTHROPATHIES

Gout is the most common of the crystal induced arthritis. It is usually a chronic disease with acute flares.

Underexcretion is the cause in 85 – 90% patients (excretion < 330 mg/dl) whereas overproduction is the cause in 10% people with hyperuricemia (HU). Prevalence of HU ranges between 2.6% to 47.2% worldwide. Asymptomatic hyperuricemia is present when serum uric acid (SUA) is higher than 6.8 mg/dl (>7mg/dl in adult males and >6mg/ dl in adult females). Only 10% of patients with HU will develop gout and the incidence increases with increasing levels of SUA and the duration for which they remain elevated. At the end of 5 years incidence increases by 10% and 22% if the SUA levels are respectively above 8mg/dl and 9mg/dl. As the duration and levels increase, inflammation and gradually structural damage occurs in the joints (F1igure 2).

Typical clinical presentation is acute monoarthritis involving first metatarsophalangeal joint typically called Podagra. However gout may present as oligoarthritis involving the midtarsal, ankle, knee, wrist or elbow joints. The oligoarticular subacute presentation is usual in elderly and may make the diagnosis confusing, serum uric acid (SUA) is elevated but may be even normal in 30 % of the acute gout cases and should be repeated after 2 weeks. Synovial fluid (SF) aspiration showing monosodium urate (MSU) crystals which are negatively birefringent on polarizing microscope is the definitive

CHAPTER 36

Features

RHEUMATOLOGY

168

Fig. 1: X-ray of patient with AS showing Syndesmophytes (arrows) (left) and middle resulting in bamboo spine. Right sided T2 weighted MRI image showing spondylitis and spondylodiscitis Inflammation

hyperuricemia

Urate crystals in tissues

Acute gouty arthritis

Chronic tophaceous gout

Structural damage

Fig. 2: Gout occurring via four sequence of changes from hyperuricemia evidence of gout. A diagnoses of tophaceous gout may be suggested by classic erosions with overhanging edges in plain x-rays. The presence of chondrocalcinosis at the triangular fibrocartilage or menisci of knees is suggestive of calcium pyrophosphate deposition disease (CPPD).

Synovial calcification may also be seen at the MCP and MTP joints, wrist and knees.

INFECTIOUS DISEASE

Infectious arthritis should be considered in any acute monoarticular joint involvement, especially in the presence of fever. Risk factors include: >80 years of age, diabetes mellitus, rheumatoid arthritis, joint surgery, hip or knee prosthesis, skin infection, and human immunodeficiency virus infection.

Staphylococcus aureus is still the most common organism associated with septic arthritis. With increase of intravenous drug abuse, we are seeing more of Methicillin Resistant Staphylococcus aureus (MRSA).

Streptococcus spp, Neisseria gonorrhoeae, Klebsiella

pneumoniae, Pseudomonas, Fusobacterium necrophorum mycobacteria, spirochetes, fungi, and viruses are the other organisms isolated. The major consequence of bacterial invasion is damage to articular cartilage by bacterial proteases as well as host response by leucocyte invasion.

Bacterial septic arthritis usually involves one large joint of the body especially knee or hip. Polyarticular disease is only seen in 10 â&#x20AC;&#x201C; 20% patients, usually those with underlying RA. Acute septic arthritis presents with a single hot, swollen, red and tender joint is shown in Figure 3.

Gonococcal infection is by far the most common cause of monoarthritis or oligoarthritis in young sexually active adults, with a female/male ratio of 3:1. Gonococcal arthritis results from blood dissemination of Neisseria gonorrhoeae from primary sexually acquired mucosal infection. It has a characteristic clinical triad of migratory polyarthralgia, dermatologic lesions (presenting as macules and papules) and tenosynovitis often affecting multiple joints simultaneously (particularly wrists, fingers, ankles, and toes), as well as systemic inflammatory symptoms. Clinical characteristics of gonococcal and nongonococcal arthritis are summarized in Table 3.

Diagnostic clue may be provided by acute phase reactants, leucocytosis but definitive diagnosis needs joint aspiration and direct identification of the culprit bacteria. Blood cultures should be taken. In bacterial septic arthritis, synovial fluid is turbid with high leucocyte count and low glucose. Both aerobic and anaerobic cultures of SF

169

Local soft-tissue infection Diagnostic or therapeutic procedures

Adjacent osteomyelitis

Hematogenous route Penetrating trauma

CHAPTER 36 Fig. 3: Showing a typical red, hot and swollen knee joint (left) and internal structure of that joint (right) in a patient with septic arthritis Table 3: Clinical characteristics of gonococcal and nongonococcal arthritis Characteristics

Gonococcal

Patient profile

Sexually active young adults, mainly Newborns or adults with chronic women disease (diabetes, RA, OA)

Presentation

Migratory polyarthralgias dermatitis, tenosynovitis

Single joint involvement

Pattern of joint involvement

Usually mono or oligoarticular

Rarely Oligoarticular or polyarticular

Culture positivity

Less than 50%

Nearly 90%

Prognosis

Good with adequate antibiotic therapy

Usually bad prognosis, needs good antibiotics plus joint drainage

are gold standards for diagnosis. Imaging studies can identify acute or chronic osteomyelitis.

Septic arthritis is an emergency requiring aggressive approach with early antibiotics and drainage of the purulent material. Early team approach can prevent permanent deformity, disability and mortality which in monoarthritis is as high as 11 percent.

Apart from pyogenic septic arthritis it is important to remember that musculoskeletal involvement could be because of tuberculosis in 1% - 3% of all cases and almost half of them involve the spine. Osteoarticular lesions occur due to hematogenous spread from primary focus.

Arthritis related to hepatitis B virus (HBV) infection may present as acute polyarthritis related to acute infection.

Hepatitis C virus (HCV) infection commonly causes polyarthralgia but is often associated with a positive RF. Parvovirus B19 infection presents acutely with polyarticular symmetric arthralgia without significant swelling. Before highly active antiretroviral therapy (HAART), rheumatic manifestations of HIV infection included HIV- associated arthritis, reactive arthritis, psoriatic arthritis, and painful articular syndrome.

However, the spectrum of disease has significantly changed with HAART therapy, and a syndrome

Nongonococcal

resembling rheumatoid arthritis, SLE, or polymyositis may emerge de novo.

NEOPLASTIC / PARANEOPLASTIC ARTHRITIS

Primary tumors and tumor like disorders of synovium are uncommon but should be considered in the differential diagnoses of monoarticular joint disease. In addition, metastases to bone and primary bone tumors adjacent to a joint may produce joint symptoms. Pigmented villonodular synovits (PVNS) is characterized by the slowly progressive, exuberant, benign proliferation of synovial tissue usually involving a single joint. Clinically it presents as insidious onset of arthritis usually involving the knees. Synovial chondromatosis is another disorder characterized by multiple focal metaplastic growths of cartilage in the synovium or tendon sheaths.

Paraneoplastic arthritis has been described and may occur in several patterns: asymmetric disease involving the lower extremity joints and symmetric polyarthritis with hand joint involvement. It is most commonly seen with breast, colon, lung, ovarian, gastric cancers and lymphoproliferative disorders.

INFLAMMATORY / CONNECTIVE TISSUE DISORDERS

Most people with systemic lupus erythematosis (SLE) have intermittent polyarthritis characterized by soft tissue

170

Table 4: Differential diagnosis of Seronegative Arthritis Symptom or sign

Differential diagnosis

Temperature >40 C (>1040F)

Juvenile-onset or adultonset idiopathic arthritis, bacterial arthritis, SLE

Fever preceding arthritis

Viral arthritis, Lyme arthritis, reactive arthritis, juvenile-onset or adultonset idiopathic arthritis, bacterial endocarditis

RHEUMATOLOGY

0

Migratory arthritis

Rheumatic fever, disseminated gonococcal or meningococcal infection, viral arthritis, SLE

Pain out of proportion to effusion

Rheumatic fever, acute leukemia, AIDS

Effusion greater than pain

Tuberculous arthritis, subacute bacterial endocarditis, enteropathic arthritis, giant cell arteritis, Lyme disease

Leukopenia

SLE, viral arthritis

Episodic recurrences

Lyme disease, crystalinduced arthritis, enteropathic arthritis, Whipple’s disease, juvenile-onset or adultonset idiopathic arthritis, SLE

swelling and tenderness most commonly in hands, wrists and knees. Joint deformities develop in only 10%. Some individuals have rheumatoid like arthritis with erosions

and fulfill criteria for both RA and SLE (rhupus); they may be labeled as having both diseases.

Varied presentation involving the musculoskeletal systems may be seen in other multisystemic diseases like polymyositis, scleroderma, overlap syndromes, sarcoidosis and systemic vasculitis.

On the basis of clinical symptoms and signs, Table 4 shows some of the common differential diagnosis.

REFERENCES

Handa R. Approach to Seronegative Arthritis. JIACM 2003; 4:190-192.

2. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III et al. 2010 Rheumatoid Arthritis Classification Criteria. An American Collage of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis Rheum 2010; 62:2569-2581.

3. Garcia- Arias M, Perez – Esteban S and Castaneda S. Septic Arthritis and Tuberculosis Arthritis. J Arthritis 2012; 1:102.

4. Garcia – De da Torre L, Nava – Zavala A. Gonococcal and Nongonococcal arthritis. Rheum Dis Clin North Am 2009; 35:63–73.

5. Tuli SM. General Principles of Osteoarticular Tuberculosis.

Clin Orthop n Relat Res 2002; 11–19.

6. Garg RK and Somvanshi DS. Spinal Tuberculosis: A Reviw.

J Spinal Cord Med 2011; 34:440–454.

7. Saigal R and Agrawal A. Pathogenesis and Clinical Management of Gouty Arthritis. J Assoc Physicians India 2015; 63:56-63.

8. Harrison`s Principles of Internal Medicine 19th Ed. McGraw- Hill Education, 2015; 2246-2247.

9. Malaviya AN, Sawney S, Mehra NK and Kanga U. Seronegative Arthritis in South Asia: An Up-to-date Review. Curr Rheumatol Rep 2014; 16:413.

10. Londhey V, Satija T. Hyperuricemia: Relevance in Clinical practice. Medicine Update 2016; 1:103–106.

1.

C H A P T E R

37

Pre-clinical Rheumatoid Arthritis Identification and Implication

INTRODUCTION

It is now abundantly clear that time is of utmost essence in Rheumatoid Arthritis (RA) since irreversible damage occurs within the first few years of disease onset. The rate of progression in the first year of disease is significantly higher than in later years. Patients with longer duration of disease do not respond as well to treatment compared with patients with early disease. Apart from the clinical and radiological benefits, early DMARD therapy also favorably influences mortality, which has been shown to be lower in patients who present early compared to those who present late.1,2 This has led to the concept of ‘window period’ in RA- a period of time early in course of RA when the disease is more responsive to therapy. Other reasons that have been advanced in favour of early recognition and treatment of RA include:3 1.

Nothing is gained by waiting. More than 90% of RA patients eventually receive a second line drug in the first 3 years. So deferring the decision on therapy does not lead to avoidance of drugs, it just delays the introduction.

2.

The inflammation is at its peak at disease onset.

3.

The final functional status is determined by the duration of symptoms before initiation of therapy.

4.

Patients in early disease are relatively well and, therefore, more likely to better tolerate drugs.

In light of the arguments advanced above, the paradigm in RA has shifted to ‘early’ disease identification. I shall be discussing the concept of early RA before talking about pre-clinical RA. It is appropriate to add a caveat herepatients in India often present late. Treatment should not be denied to late presenters. It is never too late to start treatment, though earlier is better.

EARLY RA- THE TRANSITION FROM 1987 CLASSIFICATION CRITERIA TO 2010 CRITERIA

The 1987 ARA criteria for RA were developed using cases and controls attending hospital clinics.4 The patients included had longstanding disease (mean disease duration 7.7 years). These criteria (Table 1) incorporated the typical features of symmetric inflammatory polyarthritis and did away with the categories of definite, possible and probable. These criteria were simple to use and required only one laboratory test, rheumatoid factor, and only one set of radiographs, posteroanterior view of hands and wrists. The 1987 criteria were widely adopted all over the world and paved the way for uniformity in

Rohini Handa

case inclusion. These criteria had a sensitivity of 91-94% and specificity of 89% when comparing RA with non-RA. These criteria served their purpose admirably well for several years. Over a period of time a few shortcomings became apparent. The first was the poor performance characteristics of 1987 criteria in early RA. This coincided with a shift in the focus in RA from ‘established’ to ‘early disease’. Two things have fuelled interest in early RA: an explosion of targeted biologic therapies and the growing realization that time to treat is a key driver of outcome.

When applied to early inflammatory polyarthritis, the 1987 ARA criteria for RA had a low ability to discriminate between patients who developed persistent, disabling, or erosive disease and those who did not.5 Studies have shown that the 1987 ACR criteria, when applied to early RA, have a sensitivity ranging from 40 to 90% and specificity from 50 to 90%. The second drawback of 1987 criteria was the inclusion of radiographic features. The radiologic criterion of erosions is encountered in a very small proportion (~13%) of patients in the first 3 months of disease onset limiting its utility.6 However, as many as 50-70% patients may have erosive disease by 2 years thereby underscoring the importance of early treatment.7 Over the past few years anti-citrullinated peptide antibodies (ACPA), also known as anti-cyclic citrullinated peptide antibodies (anti-CCP), have emerged as an important serologic marker for RA. These predict erosive disease and are poor prognostic markers.8 These antibodies obviously do not find mention in the 1987 criteria which were formulated prior to the advent of ACPA. The latest attempt in classification, the 2010 criteria, aim to rectify many of these shortcomings.

The 2010 criteria emerged as a joint initiative of American and European workers and were published simultaneously in the ACR and EULAR journals.9,10 The major aim was to permit early identification of poor prognosis arthritis much before the classic features of

Table 1: The 1987 Criteria for RA 1. Morning stiffness 2. Arthritis in 3 or more joints 3. Arthritis of hand joints 4. Symmetric arthritis 5. Rheumatoid nodules 6. Rheumatoid factor 7. Radiographic changes

172

Table 2: The 2010 ACR/EULAR classification criteria for rheumatoid arthritis Domain: Joint involvement

Domain: Duration of synovitis

1 large joint (0 points)

Less than 6 weeks (0 points)

2-10 large joints (1 point)

6 weeks or longer (1 point)

1-3 small joints (2 points) 4-10 small joints (3 points)

RHEUMATOLOGY

>10 joints [at least 1 small joint] (5 points) Domain: Serology

Domain: Acute phase reactants

RF/CCP negative (0 points)

Normal ESR/CRP (0 points)

RF or CCP positive at low titer, <3 times ULN (2 points)

Abnormal ESR/CRP (1 point)

RF or CCP positive at high titer, defined as >3 times ULN (3 points) ULN= upper limit of normal; Joint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of synovitis. Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are excluded from assessment; “Large joints” refers to shoulders, elbows, hips, knees, and ankles. “Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb interphalangeal joints, and wrists.

florid disease became apparent. These criteria, listed in Table 2, are meant to be applied to patients newly presenting with undifferentiated inflammatory synovitis.

These incorporate factors that best discriminate between those patients who are and those who were not at high risk for persistent and/or erosive disease—this being the appropriate current paradigm underlying the disease construct ‘RA’.9,10 The gold standard for diagnosis of RA was methotrexate initiation by the physician. This was used to identify clinical and laboratory variables which were then subjected to consensus-based, decision science informed approach leading to the evolution of a scoring system. The criteria were satisfied in 87-97% of the patients where physicians instituted methotrexate.

In the new criteria set, classification as ‘definite RA’ is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0–5), serological abnormality (range 0–3), elevated acutephase response (range 0–1) and symptom duration (two levels; range 0–1). These criteria have done away with features that are typical of late disease, namely symmetry, rheumatoid nodules and radiographic changes. There is no longer insistence on a disease duration of 6 weeks. The criterion of morning stiffness has been dispensed with and the serologic marker of ACPA included. This practically means that a patient with 1 small joint involvement (2 points), high levels of RF/ACPA (3 points) and high ESR/CRP (1 point) can be classified as RA even on day 1 of symptoms. These criteria have a provision whereby some patients can be classified as RA even if they do not fulfill the criteria. These include patients with erosive disease typical of RA with a history compatible with prior fulfillment of the 2010 criteria and patients with long-standing disease, including those whose disease is inactive (with or without treatment) who, based on

retrospectively available data, have previously fulfilled the 2010 criteria.

Over diagnosis, however, remains an area of concern with the 2010 criteria. More patients whose disease eventually resolved without ever requiring DMARD were classified at baseline as RA according to the 2010 criteria than with the 1987 criteria (8%) vs. 2%; p=0.01) in a study from UK.11 Similar concerns have been voiced from India especially in context of infectious arthritis where patients with Chikungunya arthritis may easily satisfy the 2010 criteria.12 Clearly, the quest for early detection and ideal classification criteria of RA is far from over. The 2010 criteria for RA represent a significant advance but may need refinement in different populations and as new knowledge becomes available.

EARLY VERSUS ESTABLISHED RA

The cut offs between ‘early’ and ‘established’ RA have progressively decreased over the years. ‘Early RA’ is traditionally defined as a disease duration less that 1 year while ‘established RA’ refers to a disease duration >1 year. The recent ACR recommendations for management of RA, however, peg the limit for early RA as 6 months.13

EARLY RA TO PRE-CLINICAL RA

Moving a step forwards, what is dubbed as ‘early RA’ by clinicians is actually an ‘immunologically advanced’ disease where immunological events precede clinical events by years to decades. The advent of clinical disease, even in early stages, represents the culmination and not the beginning of events. There is, thus, considerable interest in picking up RA in its pre-clinical stage when the disease is immunologically nascent. A plethora of terms have been used to describe the earliest phases of RA. These include pre-RA, preclinical RA, autoantibody positive arthralgia, early RA, very early RA, and extremely early RA. In order to develop and promote consistency in this field, the EULAR (European League against Rheumatism)

173

(b)

(a)

Genetic risk factors

Environmental

risk factors

(c) Systemic autoimmunity (RF, ACPA)

(d)

Symptoms

without arthritis

(e)

Undifferentiated

arthritis

(f) Rheumatoid Arthritis

CHAPTER 37

Fig. 1: Pre-clinical RA to RA

Preclinical RA Early RA (2010 Criteria) Established RA (1987 Criteria)

Primordial Prevention

Primary Prevention

Secondary Prevention

Fig. 2: Evolution of concepts over time Standing Committee for Investigative Rheumatology established the Study Group for Risk Factors for RA.14 It was recommended (Figure 1) that, in prospective studies, individuals at risk of developing RA would be described as having: a.

Genetic risk factors for RA

b.

Environmental risk factors for RA

c.

Systemic autoimmunity associated with RA

d.

Symptoms without clinical arthritis

e.

Unclassified arthritis

f.

RA

The term ‘arthritis’ is used to denote clinically apparent soft tissue swelling or fluid (not bony overgrowth alone).

These phases can exist in combination as in some patients who have autoantibodies and arthralgia. Thus (a) to (e) can be used in a combinatorial manner for example, an individual may have (a)+(b), or (a)+(b)+(c) or (a)+(b)+(d), etc. The prefix ‘pre-RA with:’ can be used before any/

any combination of (a) to (e) but only to describe retrospectively a phase an individual was in once it is known that they have developed RA. Several variations are possible in the proposed schema. Not all individuals may pass through all phases. Seronegative patients may develop arthritis without autoantibodies. The order may also change like some patients develop rheumatoid factor after the onset of arthritis.15 It needs to be reiterated that pre-clinical RA is a retrospective label in a patient who has developed RA. For example a patient who tests positive for rheumatoid factor and anti-citrullinated peptide antibodies in the year 2012 but develops RA in 2016 would not be designated pre-RA in 2010. It is only in 2016 that one would apply the term pre-clinical RA to the period of 2010-2016. The term preclinical RA cannot and should not be used prospectively.

Evolution is not inevitable and resolution is well known.

Some patients may never progress to clinical disease.

Research is currently centring on genetic predisposition and environmental risk factors in RA- things that may lend themselves to manipulation and modulation.16,17 Genome wide association study analyses have identified various RA-associated genes, such as HLA-DRB1, PADI4, PTPN22, TNFAIP3, STAT4 and CCR6.16 However, the contribution of these individual risk loci to the development of RA is variable. Environmental risk factors include smoking which increases the risk of ACPApositive RA. A detailed exposition of these is beyond the scope of this introductory article.

CONCLUSIONS

RA is a ‘time critical illness’ where early treatment fetches the best dividends. Pre-clinical RA is an exciting concept that stimulates identification of preclinical disease. It cannot and should not be used as a prospective clinical label. It may only be applied as a retrospective designation.

As our ability to predict disease improves, the pendulum

174

in future will likely shift from control to prevention in the disease that is RA.

REFERENCES

1.

RHEUMATOLOGY

2.

Symmons DP, Jones MA, Scott DL, Prior P. Long term mortality outcome in patients with rheumatoid arthritis: Early presenters continue to do well. J Rheumatol 1998; 25:1072-7.

Nell VP, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS. Benefit of very early referral and very early therapy with disease modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology 2004; 43:906–14.

3.

Emery P, Salmon M. Early rheumatoid arthritis : time to aim for remission. Ann Rheum Dis 1995; 54:944-7.

4.

Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31:315–24.

5.

Harrison BJ, Symmons DP, Barrett EM, Silman AJ. The performance of the 1987 ARA classification criteria for rheumatoid arthritis in a population based cohort of patients with early inflammatory polyarthritis. American Rheumatism Association. J Rheumatol 1998; 25:2324-30.

6.

Machold KP, Stamm TA, Eberl GJ, Nell VK, Dunky A, Uffmann M, et al. Very recent onset arthritis: clinical, laboratory and radiological findings during the first year of disease. J Rheumatol 2002; 29:2278–87.

7.

Plant MJ, Jones PW, Saklatvala J, Ollier WE, Dawes PT. Patterns of radiological progression in rheumatoid arthritis: results of an 8 year prospective study. J Rheumatol 1998; 25:417–26.

8.

Shankar S, Grover R, Handa R. Role of anti cyclic citrullinated peptide antibodies in erosive disease in patients with rheumatoid arthritis. Indian J Med Res 2006; 124:689-96.

9.

Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III , et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010; 69:1580-8.

10. Aletaha D, Neogi T, Silman A, Funovits J, Felson DT, Bingham CO III, et al. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

Arthritis Rheum 2010; 62:2569–81.

11. Cader MZ, Filer A, Hazlehurst J, de Pablo P, Buckley CD, Raza K. Performance of the 2010 ACR/EULAR criteria for rheumatoid arthritis: comparison with 1987 ACR criteria in a very early synovitis cohort. Ann Rheum Dis 2011; 70:94955.

12. Chopra A. A perspective from India on the 2010 rheumatoid arthritis classification criteria: comment on the article by Aletaha et al. Arthritis Rheum 2011; 63:570.

13. Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

Arthritis Rheumatol 2016;68:1-26.

14. Gerlag DM, Raza K, van Baarsen LG, Brouwer E, Buckley CD, Burmester GR, et al. EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis. Ann Rheum Dis 2012; 71:638–41.

15. Raza K, Gerlag DM. Preclinical inflammatory rheumatic diseases- an overview and relevant nomenclature. Rheum Dis Clin N Am 2014; 40: 569–580.

16. Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al.

Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 2014;506:376-81.

17. Gerlag DM, Norris JM, Tak PP. Towards prevention of autoantibody positive rheumatoid arthritis: from lifestyle modification to preventive treatment. Rheumatology 2016; 55:607-14.

Remission in Rheumatoid Arthritis: A Reality in 2017

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38

Shankar Subramanian

REMISSION IN RA

Remission was an unheard of term in Rheumatoid arthritis (RA). Developments in the last decade or so that have looked a combination of factors have changed all that. Remission while on treatment is being achieved in a significant percentage of patients and drug free remission is being documented in a noteworthy subset. In the words of Prof Rohini Handa, the letters “6T” model captures the essence of all this development. (Figure 1)

TIME TO TREAT

The earlier we control of inflammation in RA, the better is the outcome. The current treatment strategy is to make diagnosis early, be aggressive with therapy after establishing the diagnosis, and aim to reach clinical remission. “Hit early, hit hard” should be the motto.

The therapeutic response in the first 3 months of therapy predicts the potential of reaching remission later. Many studies have shown that aggressive treatment in the early phase of the disease leads to excellent improvement and sustained benefit. The early phase of disease thus presents a “Window of Opportunity” that is characterized by reversible autoimmunity offering an increasing chance of remisison.

Currently we have a vast repertoire of synthetic (sDMARD) and biological disease modifying antirheumatic drugs (bDMARD) that can enable us to achieve remarkable improvement is achievable in clinical outcomes, including remission.

The ACR/EULAR 2010 criteria to diagnose RA enable early diagnosis within a few weeks of onset of disease that was not possible with the earlier 1987 crtieria. The American College of Rheumatology (ACR) 2015 guidelines for the management of RA have laid down a evidence based blueprint for effective RA management that can help in achieving this aim.

6T Time to Treat Treat to Target Targeted Therapy Fig. 1: 6T model to manage RA effectively

TREAT TO TARGET: STRATEGY VS CHOICE OF DRUGS

In addition to the advent of bDMARDs, the last decade witnessed many “Strategy” trials. These studies looked more at reaching a predefined target rather than focus on the drugs used to achieve these targets. Trials like the TICORA, Dutch DAS-driven care, and CAMERA trials were predominantly strategy trials that compared a protocol-driven intensive strategy to usual care. Other trials like BeSt, CIMESTRA, TICORA 2, Step-down versus step-up, and TEAR trials were hybrid in nature, in that an initial parallel design was supplemented with incremental protocol-driven intensification of treatment.

All of these trials showed that a strategy of aiming for low disease activity or remission appears more important than the choice of a specific agent. The key lesson being that routine monitoring with an index should be the norm in patient care at each visit. The choice of the index is not of much importance. One may use DAS28, CDAI, SDAI or any of the several others.

TARGETED THERAPY: THE PROMISE OF REMISSION

The advent of bDMARDs has redefined our expectations of disease management. Table 1 summarises some studies that looked at remission in RA. Registry data support the above observation. In the Norwegian­DMARD registry, about 40% of patients with RA achieved remission. In the ESPOIR cohort, 50% of the patients with early RA were in DAS28 remission 5 years after disease onset and 65% in LDA. Rapidity of response is much better with biological DMARDs than csDMARDs.

DEFINING REMISSION

Remission has been defined variously using different indices, some quite strict like the American Rheumatism Association (ARA) definition, SDAI or CDAI while others are quite loose like DAS, DAS28, modified ARA and MDA. A few indices are based purely on patient reported outcomes (PRA).

Remission is a basically a state characterized by absence of disease activity. The new ACR-EULAR 2011 definition (Figure 2) is a comprehensive attempt to define remission.

A recent systematic review looked at 18 studies and identified factors that best predicted remission in RA (Table 2)

BIOLOGIC FREE AND DRUG FREE REMISSION

Early treatment offers the best chance of drug free remission. In the BeSt study, 48 % of patients were in

176

Table1: Studies that looked at remission in RA with biologics

RHEUMATOLOGY

S No

Included

What it did

Findings

1

BeSt (Behandel­ Compared Strategieën) 4 strategies for inducing remission

Study

Type

Early RA

In patients with sustained remission for over 6 months, DMARDs tapered and finally stopped

Arm with methotrexate and infliximab achieved highest drug free remission in > 25%

2

PRIZE

RCT : methotrexate plus etanercept Vs standard of care

Early RA

to achieve remission

60% achieved remission, At 1 year 40% : Etanercept free remission 23% all drug free remission

3

STRASS

Spacing of RA TNF­blocker injections in RA

DAS­driven spacing out of TNF blockers in 137 patients according to the treat­to ­target paradigm

39% could stop TNF inhibitor in the tapering arm while maintaining the remission

4

RRR study (Remission induction by Remicade in RA)

Follow up study

RA patients in remission as well as LDA over 24 weeks

Evaluate DAS 28 in 102 patients at 1 year after stopping Infliximab

55% (n=56) had DAS 28 < 3.2 with 43% (n=44) in remission with no radiologic progression

5

HONOR study

Follow up study

RA patients in remission after stopping adalimumab

Evaluate DAS 28 in RA patients at 1 year after stopping adalimumab

Adalimumab could be discontinued without flaring in 79% patients with deep remission. 48% maintained remission at 1 year

Table 2: Factors associated favourably with remission • Male sex

• MTHFR 677T alleles and 1298C alleles in the methotrexate (MTX)–treated patients

• young age

• early treatment with s DMARD combinations

• late-onset RA

• the use of anti–tumor necrosis factor (anti-TNF)

• short disease duration • nonsmoker • low baseline disease activity • mild functional impairment • low baseline radiographic damage

• the concurrent use of DMARDs in anti-TNF–treated patients • moderate or good response to treatments at the first 6 months

• absence of rheumatoid factor and anti– citrullinated peptide • low serum level of acute-phase reactant, interleukin-2, and RANKL at baseline

ACR-EULAR 2011 Definition of Remission For clinical trials

For clinical practice

• Boolean • Boolean - SJC, TJS, PtGA, CRP all ≤ 1 - SJC, TJC, PtGA all ≤ 1 • Index-based - SDAI ≤ 3.3 SDAI = SJC + TJC + PhGA + PtGA + CRP (mg/dl)

Active disease

Remission While on drugs

Remission off drugs

• Index-based - CDAI ≤ 2.8 CDAI = SJC + TJC + PhGA + PtGA

Fig. 2: ACR-EULAR definition of remission

Fig. 3: A schematic representation of remission

remission and 14 % in drug-free remission after 5 years.

Drug free remission is what patients associate with “Cure”. (Figure 3) Though currently this number is modest (being under 20%) in most studies however, the future seems promising with our better understanding of RA pathogenesis, better strategies and newer molecules.

ECONOMICS: THE WINDS OF CHANGE

Two factors are driving the winds of change of pricing of biologics. The first one is the emergence of biosimilars.

As more and more biologics go off patent, biosimilars are entering the market and driving the pricing down, almost by 40-70%.

A aspect not easily visible is the enormous amount of research on small molecules targeting various intracellular pathways like Janus-associated kinases (JAKs), spleen tyrosine kinase (SYK), and Bruton’s tyrosine kinase (BTK). Tofacitinib is the most visible face of this army and studies have shown excellent efficacy in RA. In 2022, Tofacitinib will go off patent. Thereafter, we will have a host of small molecules that will go off patent sequentially.

How does that matter? Well, Tofacitinib and the other small molecules are ordinary chemicals and the ease of Drug free Remission Halting the Radiolog...

Rapidity of action

Cost

Combination DMARDs Biologic DMARDs

Cure

Fig. 4: Radar chart showing a comparative analysis of csDMARDs and bDMARDs

Once the drugs go off patent, generics are likely to be priced closer to conventional DMARDs and biologics would have to further revise their pricing. It can be expected that by the year 2023-2025, the conventional DMARDs and small molecules would be almost similarly priced while biologics will all be available at an order of magnitude lesser than what it is now. The winds of change are already visible in India and the rate will only accelerate in the next few years.

HOW WOULD WE BE TREATING RA A DECADE FROM NOW?

In less than a decade, we would structure a regimen for RA in a personalised way. The patient would have a high probability of achieving remission within a few months and would have a good chance of even reaching drug free remission. This would be a very cost effective regimen whichever way we choose to analyse the data as an intense protocol in the beginning with bDMARDs would make cure a reality.

As of today, a large percentage of patents come well outside the window of opportunity. When we treat patients rather late in disease, we can hope at best to control the disease and remission and cure are usually out of reach. Also, the current pricing of bDMARDs makes it out of reach of a vast majority of Indians. In this scenario, bDMARDs may not offer any great advantage over conventional csDMARDs. However, as the promise of remission and cure becomes more and more real, as the prices come down due to the combination of multiple factors and as patients get diagnosed earlier in the disease, remission becomes a reality.

REFERENCES

1.

Goekoop-Ruiterman YPM, De Vries-Bouwstra JK, Allaart CF, Van Zeben D, Kerstens PJSM, Hazes JMW, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 2005; 52:3381–90.

Fig. 5: Small molecules Vs Biologics: Complexity of manufacturing compared

177

CHAPTER 38

Biologics hold an edge over conventional DMARDs, esp in the promise of inducing drug free remission. (Figure 4). They are however priced almost a 100 times more (Rs 5000 Vs Rs 4-500000 per annum) and are currently unaffordable to the majority. The next decade is likely to witness a better price rationalization due to a variety of factors making biologics accessible to many.

manufacturing Vs that of biologicals is akin to difficulty in manufacturing of an ordinary bicycle Vs a Boeing 747 (with all its avionics) respectively (Figure 5).

178

2.

3.

RHEUMATOLOGY

4.

Tanaka Y, Takeuchi T, Mimori T, Saito K, Nawata M, Kameda H, et al RRR study investigators. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Ann Rheum Dis. 2010 Jul;69(7):128691 Katchamart W, Johnson S, Lin HJ, Phumethum V, Salliot C, Bombardier C. Predictors for remission in rheumatoid arthritis patients: A systematic review. Arthritis Care Res (Hoboken) 2010; 62:1128-43.

Nagy G, van Vollenhoven RF. Sustained biologic-free and drug-free remission in rheumatoid arthritis, where are we now? Arthritis Res Ther 2015; 17:181.

5.

Tanaka Y, Hirata S. Is it possible to withdraw biologics from therapy in rheumatoid arthritis? Clin Ther 2013; 35:2028-35.

6.

Pincus T, Castrejรณn I. Evidence that the strategy is more important than the agent to treat rheumatoid arthritis.

Data from clinical trials of combinations of non-biologic DMARDs, with protocol-driven intensification of therapy for tight control or treat-to-target. Bull Hosp Jt Dis 2013; 71:S33-40.

7.

Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

Arthritis Rheumatol 2016; 68:1-26.

C H A P T E R

39

INTRODUCTION

Gout is the commonest crystal arthropathy seen in day to day clinical practice though it is one of the medical ailments which is shrouded in mystery and plagued by misconception. Hyperuricemia is defined as serum uric acid level >6.8 mg/dL, while gout is the inflammatory response to monosodium urate (MSU) crystals formed secondary to hyperuricemia. All hyperuricemic patients do not suffer from gout and approximately one-tenth exhibit gout in the long run. In the last decade, there is an increasing trend of incidence of gout, especially in the elderly (Table 1). Gout usually affects the joints, periarticular soft tissues and kidneys. Articular gout usually has three distinct stages: acute gouty arthritis,

Gout in 2017 Arup Kumar Kundu, Abhishek Kundu

intercritical (interval) gout and chronic tophaceous gout.

Patients with long-standing hyperuricemia generally develops into acute gouty arthritis, which is usually monoarticular (the first attack is in metatarsophalangial joint of great toe in 75% patients – ‘podagra’) though it may be oligoarticular (2-4 joints) or polyarticular (>5 joints).

Intercritical gout is the asymptomatic phases between acute gouty flares, which may last for several months to years. Chronic tophaceous gout usually develops after approximately 10 years of recurrent acute gouty arthritis with deposition of MSU crystals in tendons (tendo Achilles), ligaments, bursae, with concomitant tophi formation in fingers, toes, upper part of forearm and ears (Figures 1 to 4). In many of the patients, the second attack

Table 1: Increase in prevalence of gout and comorbidities in recent years • Increased longevity • Dietary trends (e.g., increased alcohol consumption) • Systemic hypertension • Epidemic of obesity and metabolic syndrome • Rampant use of diuretics and low dose aspirin therapy • Increased survival in congestive heart failure and coronary arterial disease (CAD) • Increased chronic kidney disease and end-stage renal disease • Major organ transplantations (need use of cyclosporin A or tacrolimus)

Fig. 1: Gouty tophi over proximal interphalangeal joint of thumb and distal interphalangeal joint of index finger (black arrows) along with deformity of hand in chronic gout

Fig. 2: White MSU crystals deposited in soft tissue of thigh in a patient of acute on chronic gout. The patient had acute arthritis in different joints too

Fig. 3: Gouty tophi over pinna of left ear (black arrow)

RHEUMATOLOGY

180

Fig. 5: The Double contour (DC) sign (white arrows). The DC sign is a hyperechoic delineation of the cartilage, caused by urate crystal deposits on the surface of the cartilage in chronic gout

Fig. 4: A patient of chronic tophaceous gout with affection of first metatarsophalangeal joints of both feet (black arrows) never occurs or occurs after many years. Gout is usually known as a chronic disease with recurrent acute flare. The renal involvement in gout may take three forms: acute uric acid nephropathy (precipitation of uric acid in the renal tubules or collecting tubules), urate nephropathy (deposition of urate crystals in the renal interstitium and pyramids) and uric acid stones (urolithiasis); it needs to be appreciated that other contributory factors for renal involvement in gout are hypertension, diabetes and longcontinued use of nonsteroidal anti-inflammatory drugs (NSAIDs).

Differential diagnoses of gout in clinical practices are septic arthritis, trauma, cellulitis, reactive arthritis, psoriatic arthritis, palindromic rheumatoid arthritis and pseudogout.

DIAGNOSIS

A classical clinical presentation (Dr. Thomas Sydenham’s classical description) clinches the presumptive diagnosis of acute gout (sudden appearance of red, hot, swollen and acutely tender joint at midnight). A rapid therapeutic response to NSAID or colchicine is often diagnostic but the gold standard for diagnosis of acute gout is demonstration of strongly negative birefringent needle- and rod-shaped crystals of MSU in the synovial fluid under polarized light microscopy. Ordinary light microscope can pick up MSU crystals but polarized microscopy for detection of birefringence characteristic is ideal. Joint effusions in acute gout is inflammatory (>2000 cells/ µl, mostly

polymorphs) in nature. Gram stain, cell culture, and cell count with differentials of the aspirated fluid are often required to exclude septic arthritis and cellulitis (gout mimickers). Serum uric acid (SUA) is usually raised (>10 mg/dL) but it is prudent to remember that up to 40% patients may have normal or low SUA during the acute attack as stress-induced liberation of ACTH and diseaseinduced secretion of cytokines are uricosuric. On the other way, a patient with acute arthritis and raised SUA may have many other diseases (Table 2); thus, a diagnosis of gout should never be based only on SUA level. To differentiate ‘overproducers’ from ‘under excretors’ (see Classification below), estimation of 24-hours urinary uric acid is sometimes required (normal value is < 800 mg on a regular diet). The ESR and CRP are typically elevated with a mild elevation of total WBC count. Complete blood count, urea and creatinine, lipid profile and glucose are important screens for comorbidities. Ordinary radiograph has little contribution in acute gout (only soft tissue swelling; in chronic gout, it may reveal ‘punched-out’ lesions with overhanging edges with or without severe joint destruction – “Martel’s sign”) but ultrasonography of the affected joint may exhibit ‘Double contour sign’ (Figure 5), which is often pathognomonic of acute gout.

Dual-energy CT scan can identify uric acid accumulations but it is not routinely done.

CLASSIFICATION

In over 90% patients, the main abnormality is reduced excretion of uric acid by renal tubules and in around 10% patients, overproduction of uric acid is attributed to the cause of hyperuricemia. Gout is classified into primary (of unknown cause) and secondary gout (having an underlying illness). Primary gout is likely to be due to a genetic defect in renal urate handling. Secondary gout is due to: A.

Over-production of uric acid (overproducers) – Myeloproliferative and lymphoproliferative

Table 2: Differentials of arthritis with raised SUA level • Gout • Psoriasis • Chronic hemolytic anemia • Sarcoidosis • Lymphoma, malignancy, myeloproliferative diseases • Application of cytotoxic drugs

B.

Diminished renal excretion (under excretors) – Renal failure, lactic acidosis, lead poisoning, sarcoidosis, Down’s syndrome, alcohol, metabolic syndrome and drugs (thiazides, low-dose aspirin, pyrazinamide, cyclosporine, nicotinic acid).

MANAGEMENT

A.

Acute Gout – The drugs used are NSAID, colchicines, corticosteroids (intra-articular / systemic), and majority of patients response.

According to researchers in this field, IL-1 inhibitors like anakinra, rilonacept or canakinumab (all are very expensive) may be used in ‘acute’ gouty patients unresponsive to NSAID or colchicines.

Urate lowering therapy (ULT) is generally initiated when the patient is stable i.e., after 2-4 weeks after the acute attack, and continued lifelong. It is judicious to initiate ULT after the 2nd or 3rd attack of gouty arthritis if it occurs within a year. The target uric acid level is <6 mg/dL in general and <5 mg/dL in patients with tophi.

B.

Chronic Gout – The drugs (ULT) are categorised into three groups:

1.

Uricostatic drugs (xanthine oxidase inhibitors) – Allopurinol (100-800 mg/day in single morning dose), oxypurinol, febuxostat (40-120 mg/day, single dose).

2.

Uricosuric agents – Probenecid (500-2000 mg/ day), sulfinpyrazone, benzbromarone, losartan, fenofibrate, amlodipine (cyclosporine-induced hyperuricemia), vitamin C (500 mg/day).

3.

Uricolytic drugs – Uricase, rasburicase, pegloticase.

Along with pharmacotherapy, dietary restrictions [avoid alcohol, red meat, sea foods and fructose but protein restriction is not necessary; intake of low-fat dairy products, vitamin C (500 mg/day) and coffee reduces SUA level], lifestyle modifications (overweight patients should restrict calorie and cholesterol) and controlling comorbid conditions are ‘target to treat’ chronic gout.

Acute on chronic flare can be treated by Colchicine (0.6 mg/day for 6 months, or NSAID for one month) along with ULT. ULT dissolves preformed crystals and prevent

181

Lesinurad is a novel uricosuric agent (urate transporter inhibitor), which prevents uric acid reuptake and increases its secretion. It was approved by FDA in late 2015. It is given in addition to either allopurinol or febuxostat if the target SUA level is not attained by taking one of those drugs; lesinurad should not be used alone.

Benzbromarone, sulphinpyrazone, lesinurad and IL-1 inhibitors are not available in India. Rasburicase, by shortterm IV, is used for prevention of tumour lysis syndrome in haematological malignancy, and IV pegloticase (pegylated uricase) is helpful in severe, recalcitrant gout for debulking incapacitating tophi.

COMPLICATED GOUT

•

Polyarticular Gout – Gout is basically a monoarticular disease but polyarticular affection is common in elderly, postmenopausal women on diuretics, in transplant patients and chronic tophaceous gout. Initial acute gouty attack may be polyarticular in 3-14% patients.

•

Gout in the Elderly – Usually above 65 years with a male: female ratio of 1:1. The gouty attack may be polyarticular and the patient may have history of diuretic overuse with or without renal insufficiency; tophi formation is early. Comorbidities (obesity, hypertension, alcohol abuse) are usually not associated with.

•

Organ Transplant Related Gout – Transplant patients (cardiac or kidney transplant) are treated by anti-rejection therapy (cyclosporine), often with diuretics. Approximately 10% develop gout with a mean SUA level of 12 mg/dL where the presentation is atypical, polyarticular, with extensive tophi formation along with involvement of upper extremity and occasionally the spine.

These patients are resistant to therapy. Many a time glucocorticoid, present in immunosuppressive regimen, delays overt inflammation of gout. It is important to remember that allopurinol has severe drug interaction with azathioprine, which is metabolized by zanthine oxidase.

•

Gout in the Women – Above the age of 50 years, gout is the most common cause of inflammatory arthritis in men; gout is rare in children and premenopausal women. After the menopause, excretion of uric acid is reduced due to lack of oestrogen; and thus 50% gouty patients above 60 years of age are women.

•

Gout in Renal Failure – Urate nephropathy may lead to chronic renal failure (CRF) and endstage renal disease (ESRD). In CRF, NSAID and colchicine are avoided. Systemic (in polyarticular disease) and intra-articular (in monoarticular disease) corticosteroid are helpful. Colchicineinduced myelosuppression and myopathy may develop; colchicines-induced side effects are managed by granulocyte colony stimulating factor (for nutropenia), simvastatin, erythromycin and

CHAPTER 39

disorders, psoriasis, glycogen storage disease, haemolytic diseases, high purine diet, alcohol, tumour lysis syndrome, Lesch-Nyhan syndrome, glucose-6-phosphatase deficiency and phosphoribosyl pyrophosphate synthetase overactivity.

new crystal formation, which should be intimated to the patients for proper motivation of their chronic treatment.

cyclosporine. Allopurinol may be used in CRF in a reduced dose of 50-100 mg/day to twice weekly; instead febuxostat can be used safely.

RHEUMATOLOGY

182

•

Gout and Hepatic Disorder – Gout and alcohol are inseperable. NSAID (G.I. hemorrhage), alcohol and even colchicine (with a loading dose) are very unsafe in this situation. Allopurinol in prophylaxis, and parenteral corticosteroids are relatively safe in acute attack. Stoppage of alcohol intake is crucial and life-saving. Febuxostat should better be avoided in severe hepatic dysfunction.

•

Gout in Active Peptic Ulcer Disease – NSAIDs are contraindicated and if nothing is allowed per mouth (e.g., in recent upper G.I. hemorrhage), intraarticular or systemic corticosteroid can be tried in a desperate situation. Supportive measures like misoprostol or proton-pump inhibitors should be continued; specific cox-2 inhibitor (e.g., etoricoxib) can be used cautiously for a short period with allopurinol (for prophylaxis).

•

Asymptomatic Hyperuricemia – It has been shown to be associated with increased cardiovascular morbidity though many authorities are in the opinion that increased morbidity is due to the presence of other cardiovascular risk factors rather than high SUA level. Controversy still persists whether asymptomatic hyperuricemia should be treated or not but consensus is in favour of initiation of treatment if it is associated with arthritis, renal calculi, tophi, tumour lysis syndrome, with very strong family history of gout, patients to receive chemo- or radiotherapy, and with very high SUA level (i.e., men >12mg/dL and women >10 mg/dL).

•

Normouricemic Gout – Around 40% patients may have normal or low SUA during acute attack. The fall in the SUA often precipitates acute episodes due to tophi dissolution. Demonstration of urate crystals in joint fluid makes the diagnosis.

Otherwise a classical history, a positive family history and therapeutically favourable response to colchicine establish the diagnosis.

•

Gout and Metabolic Syndrome – Hyperuricemia occurs as a part of metabolic syndrome (obesity, hypertension, diabetes, hyperlipidemia and CAD) and in this situation, drug interaction is of major concern. Colchicine increases the toxicity of statins by developing rabdomyolysis or myoglobinuria.

Allopurinol prolongs the half life of warfarin though febuxostat has no interaction with warfarin. Diuretics are better avoided; losartan and amlodipine are chosen for treating hypertension, and fenofibrate for hypertriglyceridemia (all are uricosurics). Aspirin in the range of 600-2400 mg/ day cause uric acid retention while doses >4000 mg/day are uricosuric; and thus a very low dose aspirin (75-150 mg/day) used for cardiovascular prophylaxis may not have clinically meaningful untoward effects, and may be continued if needed.

•

Gout in Patients Hypersensitive to Allopurinol – Around 1-2% patients on allopurinol develop hypersensitivity reactions (in 2nd -3rd week), and 20% of them may develop vasculitis or renal failure. This occurs in patients who are on diuretics, or allergic to penicillin/ampicillin/sulphonamides, or is an Asian expressing HLA-B*5801. The other choices for the patient are attempt at desensitization to allopurinol, or addition of febuxostat, probenecid, losartan or uricase. It is always better to start with low dose allopurinol depending on the creatinine clearance to avoid hypersensitivity reactions.

•

Non-rheumatological Controversial Associations – Renal involvement, bursitis, tendonitis, enthesitis and carpal tunnel syndrome are recognised nonarthritic manifestations of gout.

Though uric acid is the most abundant natural antioxidant in human body, hyperuricemia may be a true independent risk factor for CAD. Hyperuricemia is a strong marker of endothelial dysfunction and insulin resistance, and an independent risk factor for systemic hypertension. Associations among hyperuricemia, and atherosclerosis and/or dyslipidemia remain controversial.

CONCLUSION

Presence of gout in a patient should be taken very cautiously. It is the duty of a physician to try to recognise the conditions associated with gout, particularly in the presence of growing evidences that gout increases the risk of cardiovascular diseases.

REFERENCES

Jordan KM. Up-to-date management of gout. Curr Opin Rheumatology 2012; 24:149-51.

2. Kundu AK. Hyperuricemia revisited. Postgraduate Medicine. 2009; XXIII: 257-63.

3. Choi HK. Gout. Rheum Dis Clin North Am, vol 32, Saunders (Elsevier), 2006: 275-400.

4. Paul BJ. Crystal arthritis – past, present and future. JK Science 2006; 8:232-4.

5. So A, Busso N. A magic bullet for gout. Ann Rheum Dis 2009; 68:1517-9.

6. Doherty M, Jansen TL, Nuki G, et al. Gout: why is this curable disease so seldom cured? Ann Rheum Dis 2012; 71:1765-70.

7. Edward NL, So A. Emerging therapies for gout. Rheum Dis Clin North Am, vol 40, Saunders (Elsevier), 2014: 375-87.

8. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 ACR guidelines for management of gout. Part 2: Therapy and anti-inflammatory prophylaxis of acute gouty arthritis.

Arthritis Care Res (Hoboken) 2012; 64:1447-61.

9. Richette P, Bardin T. Gout. Lancet 2010; 375:318-28.

10. Chao J, Terkeltaub R. A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout. Curr Rheumatol Rep 2009; 11:135-40.

1.

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The Future of Systemic Lupus Erythematosus Satyabrata Ganguly, Anish Kar

Systemic lupus erythematosus had a past-a past drenched with “blood’, “sweat” and “tears”. But what is its future-a gloomy future, or is there any silver lining?

Before any therapeutic plan to any disease first we will have to know who the culprit is.

•

Therapeutic Targeting of B Cells

A central role for B cells in SLE pathogenesis has long been accepted although definitive evidence in support of such a conclusion is limited to mouse studies. Genetic depletion of B cells from lupusprone MRI Lpr or N2M 2328 mice completely protects them from developing the disease.1

B cells in patients with SLE can be conceptually divided into three functional groups-

1.

Autoreactive B cells – responsible for autoimmune disease

2.

Protective B cells-that help to promote and effect immunity against foreign antigens.

3.

Regulatory B cells (Breg) -that help to keep immune responses, both pathological and protective, in check.

So an ideal therapeutic approach will be to kill only the autoreactive or “bad” B cells.

In principle, B cells can be targeted directly or indirectly; B cells itself are targeted directly by therapeutic agents or indirectly by targeting cytokines released by B cells.

-

B cell depletion and inactivation

•

CD20-targeted therapy

CD 20 is a surface marker specific for the B cell lineage.

Rituximab is a monoclonal antibody (mAb) and triggers B cell death via antibody-dependent cell mediated cytotoxicity (ADCC) .2 The initial open label experience with rituximab in SLE was encouraging.3 But two double-blinded phase II/III randomised placebo-controlled trials (RCTs) with rituximab in SLE or lupus nephritis (n=257 and n=144 respectively) failed to meet their primary or secondary endpoints.4

Ocrelizumab, a second anti-CD20 mAb has also been tested in a double-blinded phase III RCT in lupus nephritis (n=381). Although there was a trend towards greater renal responses among

ocrelizumab treated patients than among placebo treated patients, the frequency of serious and opportunistic infections in the ocrelizumab group was sufficiently great, so the sponsor had to discontinue dosing.

•

CD19-targeted therapy

CD19 is also a surface marker for B-lineage cells, being expressed from the pro-B cell stage until the plasma cell stage.

Two atucosylated anti-CVD19 mAbs, MEDI-551 and MDX-1342, have been developed that can deplete human B cells in vitro and monkey B cells and human CD19-expressing mouse B cells in vivo.5

•

CD22-targeted therapy

Two phase III double-blinded RCTs in SLE with epratuzumab at cumulative dose are currently underway6, so important information regarding the efficacy and safety of CD22 targeted therapy should emerge in the near future.

•

FcδRIID-targeted therapy

B cell function can be downregulated without depletion of B cells by FcδRIID-directed therapeutics.

-

Generation of Breg cells

Breg cells are IL-10 producing B cells that were initially identified by their ability to downregulate experimental autoimmune encephalomyelitis and intestinal inflammation in mice.7

CD40- directed stimulation of Breg cells promotes their expansion, increases their production of IL-10 and enhances suppressor activity.

No clinical trials with anti-CD40 mAbs in SLE are currently underway. Some limited experience with anti-CD40 is being obtained in human inflammatory disorders, namely a phase II trial with an anti-CD40 mAb , ASKP 1240 in patients with moderate- to- severe plaque psoriasis8 is going on. Favourable results from this trail might spur interest in testing anti-CD40 mAbs in human SLE.

•

Therapeutic Targeting of T Cells

Rationale

Like B cells, an important role for T cells in

SLE pathogenesis has long been appreciated. A thymic BWF1 mice (which lack functional T cells) do not develop lupus, and disease can be fully reconstituted following engraftment of a thymus.9

RHEUMATOLOGY

184

•

T-cell tolerance

T cells can be conceptually divided into 3 functional groups-

1.

Pathogenic T cells

2.

Protective T cells

3.

Regulatory T cells

In contrast to the great interest in B-cell depletion as a therapeutic approach , Pan-T-cell depletion or CD4+ T-cell depletion as a therapeutic approach has received little consideration.

Making the autoreactive T cells immunologically unresponsive to the relevant self antigens might represent a safer and hence more prudent approach.

-

Blockade of T cell activation and differentiation

CD28 targeted therapy i.e., Abatacept showed efficacy in a mouse lupus model but results from clinical tials of abatacept in human SLE have been disappointing

-

T-cell trafficking and Integrin-targeted therapy

Even if pathogenic T cells do succeed in becoming fully activated and differentiated they would remain incapable of triggering and effecting end organ damage if prevented from reaching the end organ. Substantial efficacy was achieved in patients with severe recalcitrant discoid lupus with off-label use of efalizumab, a mAb specific for αL integrin that inhibits T cell migration into target tissues.

•

Therapeutic Targeting of Cytokines:targeting Baff (Beta Cell Activating Factor)

Despite the success of the phase III trials with intravenous belimumab and its outstanding safety profile, belimumab remains far from being a panacea for SLE. Strikingly enough, patients with severe active nephritis or central nervous system disease were excluded from these phase III trials.

So, ironically, we have no information yet regarding the efficacy or safety of belimumab in those patients who arguably have the greatest unmet therapeutic need.

Despite targeting B-cells and T-cells from different angles our success to conquer SLE is far from satisfactory. So, is there any other culprit?

•

Dendritic Cells (DC)

Blood contains 2 DC subsets-

1.

A CD11c (-) one

2.

A CD11C (+) one

The CD11c (-) subset, called plasmacytoid DC (PDCs)

comes from an independent, possibly lymphoid related, differentiation pathway and secretes interferon-γ.

The CD11c (+) subset follows a myeloid differentiation pathway-hence called myeloid DC (MDCs) -where monocytes serve as the reservoir of precursors.

SLE appears as a disease with major alteration in DC subset homeostasis-while one DC subset i.e., PDC is dramatically reduced in the blood (possibly due to accelerated migration into tissue) and the normally quiescent monocytes act as MDC.Thus unabated DC induction may drive the autoimmune response in SLE and this may be controlled by targeting IFN-α.

•

IFN-α in the Pathogenesis of SLE

The release of IFNα by PDC induces monocytes to differentiate into DCs.These cells efficiently capture apoptotic cells and nucleosomes, present in large amounts in SLE blood.These antigen-loaded DC are further activated by IFNα and present self antigens to autoreactive T-cells and B-cells.Such a “ménage a trois” generates a high number of plasma cells producing antibodies, which form immune complexes that may sustain IFNγ production.10 Furthermore high IFN levels explain T and B-cell lymphopenia.

CONCLUSION

Current treatment approaches in SLE are based on nonspecific immunosupression. Current disease models propose IFNγ at the centre of the immunological abnormalities observed in SLE, and poses IFNγ and IFNαproducing cells as novel targets for therapy in this disease.

It is now necessary to develop clinically relevant agents that would block either IFNα production or its biological activity.One of the potential therapeutic targets could be BDCA-2, a novel plasmacytoid dendritic cell-specific type II C lectin, which blocks the induction of type I interferons

by PDCs.11 Our greatest hope is that blocking type I IFN will bring SLE patients the relief that blocking TNF is bringing to patients with rheumatoid arthritis.

REFERENCES

1.

Shlomchik.M.J.Madalo, M.R.N.D Trounstein.M & Huzsar.D-The role of B cells in Lpr/Lpr- induced autoimmunity. J Exp Med 1994;180:1295-1306.

2.

Cragg.M.S., Walshe C.A., Ivanov.A.O. and Glennie.M.J.The biology of CD20 and its potential as a target for mAb therapy.Curr Dir Autoimmun 2005;8:140-174

3.

Leandro. M.J.Edwards, J.C.Cambridge, G.Ehrenstein.M.R. and Isenberg D.A.-An open study of B lymphocyte depletion in Systemic Lupus Erythematosus. Arthritis Rheum 2002; 46:2673-2677.

4.

Merrill J.T et al.-Efficacy and safety of rituximab in moderateto-severe active systemic lupus erythematosus:The randomised , double-blind phase II/III Systemic lupus erythematosus evaluation of rituximab trial.Arthritis Rheum 62, 222-233 (2010).

5.

Herbst R. et al-B cell depletion in-vitro and in-vivo with an atucosylated anti-Cd19 antibody. J Pharmacol Exp Ther 2010; 335:213-222.

and requirement for T cells in the development of autoimmune disease, as evidenced by an analysis of the athymic nude individuals. J Immunol 1988; 141:85-90.

6.

US National Library of Medicine, clinicaltrials.gov http// clinical trials.gov/ct2/show/NCT01262365.

7.

Fillatreau, S, Sweenie, C.H.McGeachy.M.J.Gray-B cells regulate autoimmunity provision of IL-10. Nat Immuno 2002; 13:944-950.

10. Vallin H, Perers A, Alm GV, Ronnblom L.-Anti-double stranded DNA antibodies and immunostimulatory plasmid DNA in combination mimics the endogenous IFNalpha inducer in SLE. J Immunol 1999; 163:6306.

8.

US National Library of Medicine-clinicaltrials.gov (online) http//clinicaltrials.gov/ct2/show/NCT015852338.

9.

Mihana M, et al. Immunologic abnormality in N2B/N2W F1 mice:thymus independent occurrence of B cell abnormality

185

11. Dzionek A., Sohma Y., Nagafume S. et al-BDCA-2, a novel plasmacytoid dendritic cell specific type II C-type lectin, mediates antigen capture and is a potent inhibitor of interferon alpha/beta induction. J Exp Medical 2001; 194:1823.

CHAPTER 40

C H A P T E R

41

Pulmonary Renal Syndrome

INTRODUCTION

1.

Pulmonary Renal Syndrome (PRS), is a combination of diffuse alveolar haemorrhage (DAH) and glomerulonephritis (GN), occurring simultaneously.

2.

DAH should be suspected in a patients with breathlessness, haemoptysis, alveolar opacities (on chest x-ray), anemia, hypoxemia. Look for RBCs in the urine of a patient of haemoptysis to detect associated renal involvement. And vice a versa ask for history of haemoptysis in patients of nephritis/ RPGN. This will lead to detection of PRS.

3.

4.

5.

PRS is not a single disease, it has a differential diagnosis (Table 1) of its own, most common cause being ANCA positive vasculitis.

Timely diagnosis of PRS is important, considering high mortality (25-50%), need for ventilator support (35-50%) an­d dialysis dependence at 1 year in over 70%.

PRS may be confused with pneumonia, ARDS, pulmonary oedema, pulmonary tuberculosis, thus delaying instituting steroids and immunosuppressants.

HISTORIC BACKGROUND

Combination of pulmonary haemorrhage and glomerulonephritis (GN) was first described by Goodpasture in 1919. The term Goodpasture syndrome was adopted in 1958 to define these patients and pathogenic role of anti-glomerular basement membrane (anti-GBM) antibodies in some cases of pulmonary haemorrhage and GN was proven 10 years later. In an interesting study from Massachusetts General Hospital1, out of 88 patients’ sera, sent for anti-GBM antibodies in the setting of PRS, 48 tested positive for ANCAs, 6 for anti-GBM and 7 for both, whereas in 27 patients unrelated renal and pulmonary diseases were found.

CLINICAL FEATURES OF PRS

The classic clinical presentation of DAH is (a triad) haemoptysis, abrupt fall in haemoglobin and new pulmonary infiltrates (bilateral alveolar infiltrates with apical sparing) and dyspnoea. Some patients present with severe respiratory distress and some with pulmonary infiltrates which resolve and recur. However each of these features is variable and may be absent. Haemoptysis may be absent in 1/3rd patients. Chest radiograph may be normal in 20%, or show unilateral infiltrates in some.

Yojana Gokhale, Raosaheb Rathod

DAH may precede GN by weeks to months. But when they occur simultaneously patient has features of nephritis (oedema, hypertension, haematuria, with or without rising creatinine). PRS has a wide clinical spectrum (Figure 1) and a wide range of severity of presentation from the general outpatient clinic to the ICU setting. Two

Table 1: Differential Diagnosis of PRS Clinical entities classified according to the pathogenetic mechanism (2/3rd cases of PRS are ANCA positive) ANCA-positive systemic vasculitis Wegener’s granulomatosis Microscopic polyangitia Churg-Strauss syndrome Associated with anti-GBM antibodies: Goodpasture’s syndrome ANCA-negative systemic vasculitis Henoch–Schönlein purpura, mixed cryoglobuninaemia, Behcet’s disease, IgA nephropathy ANCA-positive PRS without systemic vasculitis: idiopathic PRS Pauci-immune necrotic glomerulonephritis and pulmonary capillaritis In drug-associated ANCA-positive vasculitis Propylthiouracil, D- Penicillamine, Hydralazine, Allopurinol, Sulfasalazine Anti-GBM-postive and ANCA-positive patients Autoimmune rheumatic diseases (immune complexes and/or ANCA mediated) Systemic lupus erythematosus Scleroderma (ANCA?) Polymyositis Rheumatoid arthritis Mixed collagen vascular disease PRS in thrombotic microangiopathy Antiphospholipid syndrome Thrombotic thrombocytopenic purpura Infections Neoplasms Diffuse alveolar haemorrhage complicating idiopathic pauci-immune glomerulonephritis

187

Fig. 3: Chest x-ray of case 1, bilateral alveolar shadows with apical sparing, S/O DAH

Fig. 2: Chest x-ray of case 1, depicting clear lung fields, when he had haemoptysis illustrative cases are given below for better understanding of the spectrum of PRS.

CASE 1

M/43, presented to his family doctor in December 2004 with malaise, anorexia, haemoptysis. After baseline x-ray (Figure 2), he was started on anti tuberculosis treatment (ATT). Patient kept getting recurrent haemoptysis for which repeated x-ray chest were performed (Figure 3).

In January 2006 he got admitted to our hospital with haempotysis and breathlessness. On examination, pulse-96/min, blood pressure- 180/100, respiratory rate20/ min, he was pale, had no oedema, raised jugular venous pressure or cyanosis. There were bilateral fine crepitations on auscultation of chest. As per his old records his serum creatinine in August 2005 was 2mg/ dl. His investigations at our hospital were as follows: Hemoglobin- 4.5gm/dl, WBC- 12000/cumm, ESR- 115mm at 1 hour, Urine Proteins2+, 15-20RBCs/hpf, x-ray chest revealed bilateral alveolar shadows with sparing of apices (Figure 4), ultrasound kidneys was reported as small contracted kidneys. Patient was clinically diagnosed as â&#x20AC;&#x2DC;Pulmonary renal syndromeâ&#x20AC;&#x2122; and treated with Inj. Methyl Prednosolone 1gm daily for 3 days followed by oral Prednisolone 1mg/kg, Dialysis, pulse Cyclophosphmide.

Plasma exchange, could not be performed in him due to lack of funds. He tested positive for p-ANCA (by immunoflurosecnce) and antibodies to myeloperoxidase

Fig. 4: Chest x-ray of case 1, DAH on admission (MPO by ELISA). Anti- GBM and anti nuclear anti body, cryoglobulins, HBsAg, and anti-HCV, were negative.

Thus he was ANCA positive small vessel vasculitismicroscopic poly angitis presenting as PRS. His kidney biopsy revealed crescentic GN (>50% crescents). He was discharged on oral Cyclophospamide (dose adjusted for creatinine clearance), with serum creatinine 2mg/dl, Hb- 7.5gm. At 6 months creatinine 2.3 mg/dl, Hb-10gm without dialysis. At 9 months creatinine 3.8 mg/dl. Patient was then lost to follow up.

Regarding PRS clinical presentation all investigators have reported a prodrome and an acute presentation.

The prodrome consists of non-specific constitutional symptoms like malaise, fatigue, Fever, weight loss, Arthralgias, myalgias, Episcleritis, purpuric rash that precede acute presentation by an average of 3 months. Up to 8-12 months of prodrome has been reported.

Can we diagnose these patients before acute presentation?

Say during the so called prodrome!

The occurrence of prodromal illness of significant duration in most cases indicates a need and opportunity for earlier diagnosis.

CHAPTER 41

Fig. 1: Clinical spectrum of PRS

188

CASE 2

RHEUMATOLOGY

F/45, had respiratory symptoms for 8 months, initially upper respiratory (sneezing, nasal discharge and stuffiness of nose) which were diagnosed as allergic rhinitis by her doctor, later for her episodic cough and shortness of breath she was investigated and diagnosed as ‘probable Interstitial Lung Disease’ and treated with a short course of steroids on the basis of lung function tests, chest x ray (which was normal) and High resolution CT scan of chest (Figure 5) After 8 months of treatment in private when she was admitted with us in November 1997, she had severe fatigue, with great difficulty doing her daily chores like cooking. But other than a tired look on her face and blood pressure 150/90, rest of the general and systemic examination was normal. Respiratory physician who was treating her, had told her husband that she had a lot of functional element… BUT as per her records her ESR was 135mm and urine examination revealed 120 RBCs /hpf!!! We suspected PRS and sent her blood for ANCA, ANA, ANTI-GBM antibodies. She was c-ANCA positive. Haemoglobin 8.5, WBC- 11,500/ cumm, Serum creatinine 1mg/dl, Ca- 9mg/dl, P- 3.5mg/dl. Her kidney biopsy (Figure 6) revealed ‘multiple glomeruli, most were sclerosed, only 14 relatively preserved and showed fibrinoid necrosis and crescents. Biopsy consistent with the diagnosis of Wegener’s Granulomatosis in end

stage renal disease.’ As her creatinine was 1mg/dl, we monitored her GFR. It was 30ml/min. She was treated with Steroids (Oral Prednisolone 1mg/kg for a month then tapered) and Cyclophosphamide (100 mg daily) for two years. Her GFR remained between 30-35 ml/min for next 5 years. In 2003 ie after 5 years GFR was 50ml and now 19 years later also it is maintained at 50 ml/min while she is taking Prednisolone 2.5mg/day and Methotreaxate 10mg per week. This patients is an excellent example of severity of renal damage (as per kidney biopsy and GFR) within just 8 months from onset of symptoms, and importance of timely adequate immunosuppression to salvage renal function.

Those cases of pulmonary-renal syndrome not related to Goodpasture’s, syndrome usually have clinical features suggesting such diagnoses as vasculitis, acute synovitis, multiplex mononeuritis or previous history of SLE. PRS can be a presenting feature of ANCA positive vasculitis , but it’s rare for SLE to presents as PRS. PRS is reported in 2% patients of SLE. It’s known, patients of SLE who develops the complication. In PRS due to infectious causes (eg Leptospirosis) features of underlying disease (like jaundice) are present.

INVESTIGATIONS AND DIAGNOSIS IN PRS

What are the problems with timely diagnosis? (Clinical, Chest x-ray, serology(ANCA-ANA-anti-GBM antibodyCryoglobulins), HRCT chest, DLCO, Bronchoscopy – BAL, biopsy) Problems are mainly in the diagnosis of DAH.

Fig. 5: HRCT chest of case 2, Ground glass opacities and fibrosis

a

1.

On chest x-ray DAH may be misdiagnosed as infections like bronchopneumonia or tuberculosis or ARDS due sepsis, even raised creatinine may be attributed to MSOF, or it may also be misdiagnosed as pulmonary oedema due to renal failure.

2.

Patient may be asymptomatic for DAH, haemoptysis may be absent in 1/3rd patients. In such cases x-ray chest may not be asked for.

3.

Normal chest x-ray is reported in 20% patients with DAH.

Chest-CT is indicated in patients with hemoptysis with normal chest x-ray or with focal abnormality, atypical for

b

Fig. 6 (a, b): Kidney biopsy case 2, H&E, sclerosed glomeruli, fibrinoid necrosis & crescent (b)

TB. But HRCT chest plays a limited role in the assessment of patients with DAH . On HRCT, early DAH produces ground glass opacity and later fibrosis, a pattern that is seen in many conditions. In fact it generally gets reported as ILD and then one may not consider DAH as a diagnostic possibility.

BAL is more sensitive than any other criteria for the diagnosis of DAH. Fiberoptic bronchoscopy will show haemorrhages from many bronchopulmonary segments.

It may show grossly pink/ red BAL in acute cases or haemosiderine laden macrophages (>30%).

A firm diagnosis of PRS is obtained by clinical presentation, serologic results and histological results although obtaining material for the latter may present practical difficulty in a critically ill patient. Tissue diagnosis should be obtained when cause of DAH is not confirmed by clinical/serological and bronchoscopic evaluation. Open lung biopsy is preferred over trans bronchoscopic lung biopsy. Lung biopsy shows RBCs/ hemosiderin laden macrophages in alveolar spaces. Evidence of capillaritis in the form of alveolar wall distruction and neutrophillic infiltration is rare. Diagnosis of GN is not a problem in presence of active urinary sediment and rising creatinine.

Gold standard for diagnosis of PRS are lung/ kidney biopsy.

Author’s personal suggestion is, treating physician should suspect DAH in a given clinical setting and chest x-ray abnormalities. In absence of fever, start Inj. Methyl prednisolone and daily repeat chest x-ray. The alveolar infiltrates of DAH disappear within 24-48 hours. When in doubt may give steroids under cover of higher antibiotics.

But remember radiological improvement is not as fast in infection as in DAH, so, fast radiological improvement favours the diagnosis of DAH. Remember, majority cases of PRS are due to ANCA positive vasculitis, in which patients get leucocytosis, which may be mistaken to be due to infection. If there is confusion about DAH Vs pulmonary oedema (due to raised creatinine &/or hypertension) give injection Frusemide and look for clinical and radiologic improvement after few hours. If expected improvement does not occur, do consider DAH. It is also important to perform urine examination at the time of admission, before putting urinary catheter. Presence of proteinuria and haematuria rather than leucocytes or nitrites in urine should suggest GN over urosepsis, especially in

189

TREATEMENT OF PRS

1.

Steroids and cyclophosphamide for all.

2.

Add plasma exchange (7-14 days) in severe cases, Creatinine > 5.7mg/dl to improve long term renal outcome, severe DAH, Good Pasture syndrome, Cryoglobulinaemia.

3.

Ventilatory support, if in respiratory distress, hypoxia.

4.

Add novel therapies (activated Factor VII, ECMO for DAH, Rituximab, IVIG) for refractory cases.

Immunosuppression is the cornerstone of treatment in ANCA associated PRS. Standard induction remission regimens include pulse intravenous methylprednisolone (500–1,000 mg) for 3–5 days. As the life threatening features subside, the dose can be reduced to 1 mg/kg prednisone daily for the first month, tapered over the next 3–4 months. Glucocorticoid therapy is combined with cytotoxic agents. Cyclophosphamide is the treatment of choice, at a dose of 0.5–1 gm/m2 administered intravenously as a pulse per month or orally (1–2 mg/ kg/day). Transition to maintenance therapy is done 6–12 months after the initiation of induction therapy or after clinical remission. The maintenance therapy includes low-dose corticosteroids coupled with cytotoxic agents.

Despite rigorous treatment, many of patients with smallvessel vasculitis and PRS need renal transplantation within less than 4 years of initial presentation.

For CAPS related PRS anticoagulation is the main stay of treatment.

PERSONAL EXPERIENCE AND INDIAN DATA (PARTLY PRESENTED IN IRACON 2008)

I personally managed 13 PRS in my unit over 15 years.

Gave MD thesis topic to PG student, who collected 12 PRS from 6 medical units, MICU, IRCU and AKD, in 30 months (Jul 2013-Dec 2015). Out of 25 PRS patients, there were 7 WG, 4 MPO, 1 CSS, 1 Good Pasture, 5 SLE, 7 infection related (Leptospirosis, dengue). All patients, other than those with infectious etiology were treated with steroids and Cyclophspamide, 1 Rituximab, 1 PE, 3 were dialysed, 14 required ventilator support (3 invasive, 11 NIV to start with but 5 had to be shifted to invasive ventilator), Overall survival was 68%, mortality 32%. In those who were on ventilator, mortality was 57% (all on NIV survived, all who eventually needed invasive ventilator, 8/14 died). In 2008, 1st author had collected Indian data on PRS by sending questionnaire to 61 rheumatologists, 12 had responded.

Results were as follows : Total cases :113, (Rheumatic

CHAPTER 41

Diagnostic criteria used for DAH are not uniform in all reports. Hemoptysis, alveolar opacities, anemia, hypoxemia, and/or elevated carbon monoxide transfer factor (DLCO) have been used to define DAH in many series. Carbon monoxide diffusion capacity (DLCO) is used as an adjunctive test to diagnose DAH. DLCO increases in DAH due to presence of haemoglobin in alveoli. If performed in the 1st 48 hours of DAH, an increase in DLCO of 30% over baseline or a value of > 130% predicted is reported to be suggestive of DAH and is observed in 25% patients of DAH. Obtaining DLCO measurement is not practical at night and in critically ill patient.

presence of new onset hypertension. Urine routine is poor man’s kidney biopsy! Also the later may not be possible in critically ill and those with serum creatinine more than 3mg/dl. Recommended treatment in acute nephritis/RPGN is immunosupression with Inj. MPS and Cyclophosphamide, with which improvement in Urine picture occurs rapidly, though fall in creatinine takes a little longer.

RHEUMATOLOGY

190

diseases 97, Lepto-13, Dengue-3) WG : 45, MPA : 15, SLE : 30, APLA : 1, Goodpasture : 1, Other : 5 (PSS,CSS,TTP).

Steroids + Cyc : all but infections, PE : 21, Ventilator : 37, Dialysis : 33, Other : Ritux. 5, IVIg 2, Death : 34 (38.4%), Dialysis dependence : 14. On an average rheumatologists with institutional attachment had seen 0-2 cases per year, and 0-25 cases over practice as 20 years of practice (average 8 PRS cases by individual rheumatologist over 20 years).

In 30 months of PRS data collection by my PG student, all admitted patients with haemoptysis with breathlessness and alveolar shadows on chest film were subjected to urine routine examination, to detect simultaneous GN (In 12/25 patients presenting with respiratory complaints renal involvement was detected on investigations). And all admissions for GN and RPGN were specifically asked for history of haemoptysis in previous few months.

This strategy, we believe, helped in detecting more PRS patients, who would otherwise probably be missed.

of immunosuppressants and prevention of secondary infection is important in successful management of PRS, in ICU setting.

CONCLUSION

Considering the heterogeneity of severity of presentation, early recognition of PRS depends on a high index of clinical suspicion combined with a full assessment of the clinical picture, available serology, radiology and histology, and exclusion of alternative diagnoses. Timely institution

REFERENCES

1.

Syndrome of lung haemorrhage and Nephritis is usually an ANCA-associated condition, Arch Int Med 1996; 156:440445

2.

Bench-to-bedside review: Pulmonary–renal syndromes – an update for the intensivist, Critical Care 2007; 11:213

3.

Frankel SK, Cosgrove GP, Fischer A, Meehan RT, Brown KK. Update in the Diagnosis and Management of Pulmonary Vasculitis. Chest 2006; 129:452-465

4.

Long-term outcome of anti-glomerular basement membrane antibody disease treated with plasma exchange and immunosupresion, Ann Intern med 2001; 134:1033-1042, Med 2001; 134:1033-1042.

5.

Pulmonary-renal syndrome: A 4-year, Experience, Am J Kidney Dis 2002; 39:42-47.

6.

Pulmonary-renal syndromes: An update for respiratory physicians, Respiratory Medicine 2011; 105:1413-1421

7.

Pulmonary-renal syndromes: Experience from an Indian Intensive Care Unit, Indian J Critical care medicine 2015;31625

single-center

C H A P T E R

42

Antiphospholipid Syndrome

Antiphospholipid antibody syndrome (APS) is an acquired prothrombotic state characterized by the presence of one of the clinical criteria of either vascular thrombosis in the arterial or venous tree and recurrent pregnancy losses; supported by the laboratory criteria of presence of antiphospholipid antibodies namely anticardiolipin antibody(ACLA), lupus anticoagulant(LAC) or β2 glycoprotein I(β2GPI) antibody. It is also called as Hughes syndrome. Table 1 gives the revised Sapporo classification criteria for APS. The term APS is not synonymous with antiphospholipid antibody (APLA). There can be presence of the circulating APLA without any clinical manifestations. The presence of APLA may not always mandate therapy whereas APS mandates treatment.

Antiphospholipid antibodies (APLA) are directed against phosphatidyl choline, phosphatidyl serine, phosphatidyl glycerol and phosphatidyl ethanolamine. Anticardiolipin antibody is directed against diphosphatidyl glycerol.

Table 1: Revised Sapporo Classification Criteria for APS • Clinical Criteria 1. Vascular thrombosis

Vikram Londhey

ACLA causes more arterial thrombosis whereas LAC causes more venous thrombosis. APLA may be detected even in healthy individuals, advancing age, lymphoproliferative diseases, syphilis, HIV, Lyme disease, infectious mononucleosis, tuberculosis, certain drugs like phenytoin, valproate, phenothiazines, procainamide, chlorpromazine and hydralazine.

APS can be primary or secondary. Secondary APS is seen in conditions like SLE, RA, autoimmune hypothyroidism, malignancies, HIV and drugs. SLE is the most common rheumatological condition associated with secondary APS. In all patients of SLE with systemic involvement, there is a high association with APS. Hence, it is recommended to screen these patients with APLA. However, in cases of cutaneous lupus without systemic involvement, this screening is not recommended.

PATHOGENESIS

The exact role of the antibodies in the pathogenesis of thromboembolism is not clearly understood. Following mechanisms are the most accepted ones: 1.

It is postulated that endothelium, platelets, trophoblasts, prothrombin, activated protein C, annexin-V, antithrombin 3 and tissue factor have a definite role in the pathogenesis of thrombosis.

The activation or apoptosis of these cells causes migration of negatively charged phospholipids to the outer cell membrane, which otherwise is electrically neutral. β2GPI binds to these negatively charged phospholipids which in turn forms a complex (dimer). This complex activates complement cascade which favours proinflammatory mediators which induce the process of thrombosis.

2.

The oxidant-mediated endothelium by APLA.

3.

By interference or modulation of phospholipid binding proteins which are involved in the regulation of normal coagulation pathway; the procoagulant effect is exerted by APLA.

One or more clinical episodes of arterial, venous or small vessel thrombosis in any tissue or organ

2. Pregnancy morbidity a. One or more unexplained deaths of a morphologically normal fetus at or beyond 10th week of gestation b. One or more premature births of a morphologically normal neonate before 34th wk of gestation because of recognized features of placental insufficiency or c. 3 or more unexplained consecutive spontaneous abortions before 10th wk of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded • Laboratory Criteria 1. Lupus Anticoagulant present in plasma 2. Anticardiolipin antibody of IgG or IgM isotype in serum or plasma, present in medium or high titre(> 40GPL or MPL or more than 99th percentile)by ELISA 3. Anti ß2 glycoprotein I antibody of IgG or IgM isotype in serum or plasma(in titre > 99th percentile)

by ELISA (detection of 1 of the above antibodies on 2 or more occasions at least 12 wk apart)

damage

to

vascular

CLINICAL FEATURES

Thromboembolic phenomena can occur anywhere in the vascular tree. Hence, the clinical features of APS can be seen in any part of the body. The commonest manifestations according to the system involved are mentioned below.

I.

Central Nervous System: Young stroke presenting

192

Table 2: Differential diagnosis of CAPS

Table 3: Treatment of APS related Bad Obstetrics History

Factor V Leiden mutation

Clinical Circumstance

Recommendation

Hyperhomocysteinaemia

>1 Fetal or >3 preembryonic losses, no thrombosis, APLA but no SLE

Prophylactic LMWH 0.5mg/kg/day + Low dose Aspirin 75mg/day throughout Pregnancy and 6-12 weeks postpartum

>1 Fetal or >3 preembryonic losses, no thrombosis, APLA with SLE

Prophylactic LMWH 0.5mg/kg/day +

Prior Thrombosis, regardless of pregnancy loss, APLA but no SLE

Therapeutic LMWH1.5mg/kg/day Or LMWH 1mg/kg/ twice a day + Low dose Aspirin 75mg/day throughout Pregnancy and 6-12 weeks postpartum; Warfarin after 12 weeks

Prior Thrombosis, regardless of pregnancy loss, APLA with SLE

Therapeutic LMWH1.5mg/kg/day Or LMWH 1mg/kg/ twice a day + Low dose Aspirin 75mg/day throughout Pregnancy and 6-12 weeks postpartum+ Prednisolone + Hydroxychloroquine

Vasculitis e.g. Classical Polyarteritis nodosa Infective Endocarditis with embolic phenomena Thrombotic thrombocytopenic purpura (TTP) Cholesterol embolism

RHEUMATOLOGY

Malignancy Hemolytic Uremic syndrome (HUS) Sepsis Disseminated Intravascular Coagulation (DIC) as hemiplegia, cortical sinus thrombosis presenting as paraparesis or seizures, multi-infarct dementia, migraine headache, Guillain Barre syndrome, chorea and optic neuritis.

II.

Obstetrics: Recurrent foetal losses usually after 10th week of gestation, early eclampsia, HELLP syndrome, IUGR, IUFD, thrombocytopenia.

Placental vessel thrombosis causing poor placental perfusion is the cause of these symptoms.

Normally, Annexin V has anticoagulant activity.

This annexin V is reduced on placental villi in APS, which favours a procoagulant state and therefore thrombosis.

III.

Renal: Proteinuria, hematuria, nephritic syndrome, severe hypertension, renal vein thrombosis, renal failure or end stage renal disease are the manifestations.

IV.

Cardiac: Valvular thickening, valvular regurgitation, stenosis, myocardial infarction, intracardiac emboli. Sometimes, a patient may need valve replacement surgery.

V.

Pulmonary: Pulmonary embolism, chronic pulmonary thromboembolism, ARDS, intraalveolar hemorrhages and pulmonary hypertension.

VI.

Skin: Livedo reticularis, ulcerations, digital gangrene, subungual splinter hemorrhages, superficial thrombophlebitis and deep vein thrombosis (DVT). Skin manifestations are commonly seen in CAPS.

VII. ENT: Autoimmune sensorineural hearing loss presenting as bilateral progressive deafness may be one of the rarer symptoms of APS.

CATASTROPHIC APS (CAPS)

It is one of the rheumatological emergencies which is life-threatening. It can present as multiorgan failure.

Kidney is the most commonly affected organ in CAPS followed by lungs, CNS, heart, adrenals and skin. The clinical presentation consists of stroke, respiratory failure, deranged liver and renal functions requiring dialysis.

DIC, gut ischemia causing abdominal pain can also be the presenting features. The factors which precipitate CAPS are infections, surgical procedures, dental

Low dose Aspirin 75mg/day throughout Pregnancy and 6-12 weeks postpartum+ Prednisolone + Hydroxychloroquine

Warfarin after 12 weeks Only Antibody Positivity,no thrombosis, no SLE

Low dose Aspirin 75 mg/day throughout pregnancy

extraction, stoppage of anticoagulants or consumption of oral contraceptive pills. Sometimes pregnancy can be complicated by CAPS. The presence of CAPS during pregnancy can cause maternal as well as foetal mortality.

The conditions which closely mimic CAPS are listed in Table 2.

LABORATORY INVESTIGATIONS

CBC shows thrombocytopenia, Direct Coomb’s test may be positive. Detecting β2GPI dependant ACLA is the gold standard for ACLA. LAC should be checked by dilute Russell Viper venom time. The presence of one of the antibodies from ACLA, LAC or anti β2 glycoprotein-I is enough to make the diagnosis. Multiple or triple positivity predicts the risk for recurrent disease. Histopathological evidence of multiple vessel occlusions in addition to APLA usually in high titres and clinical evidence of multiorgan failure is needed to diagnose CAPS. Thus kidney biopsy, skin biopsy, lung biopsy or biopsy of the small intestine may be needed in confirming the diagnosis of CAPS. The demonstration of any one of the antibodies 12 weeks apart is needed for the confirmation of the diagnosis of APS. However in resource limited settings due to

financial constraints, demonstration of the test only once may be sufficient to diagnose and treat the patient as a case of APS. Cases of secondary APS need other tests like ANA, thyroid function test, HIV, radiological tests like X rays, CT/MRI/USG in suspected cases of infection or malignancy.

the pregnancy morbidity and mortality is changing to have a favourable pregnancy outcome. The treatment of recurrent pregnancy loss is depicted in Table 3.

4.

Patients with APS who have thrombocytopenia, if platelet count is less than 50000, prednisolone and IVIG is recommended. If the platelet count is more than 50000, no treatment is needed.

5.

CAPS needs to be treated aggressively with anticoagulation, steroids and IVIG or plasmapheresis.

TREATMENT

Patients who test positive only for the antibodies without any symptoms should be left alone. They do not need any treatment. There is no reported literature which supports prophylaxis with aspirin in primary prevention.

2.

Patients with arterial or venous thrombosis need to be treated with heparin for acute thrombosis and warfarin to prevent the recurrence of thrombosis. It is necessary to maintain the INR between 2 to 3 for the patients who are on warfarin.

3.

Since SLE is the most common rheumatological condition associated with secondary APS, the treatment of APS with and without SLE needs to be mentioned specially. Both the conditions, SLE and APS whether presenting in isolation or occurring together have a poor pregnancy outcome. Although with the increasing awareness about these conditions and its treatment options,

REFERENCES

1.

2.

3.

4.

5.

Debashish Danda. Antiphospholipid syndrome. Manual of Rheumatology 3rd Edition, published by IRA 2009.

Duruk Erkan, Jane E Salmon, Michael D Lockshin.

Antiphospholipid Syndrome. Kelleyâ&#x20AC;&#x2122;s Textbook of Rheumatology 9th Edition, 2013.

Vittorio Pengo, et al. Diagnosis and therapy of APS. Review Article. Polish Archives of Internal Medicine 2015; 125:672677.

Rezk M, Dawood R, Badr H. Maternal and Fetal outcome in women with antiphospholipid syndrome: a three year observational study. J Matern fetal Neonatal Med 2016; 3:1-5.

Forasteiro R. Multiple Antiphospholipid antibody positivity and Antiphospholipid syndrome criteria reevaluation. Lupus 2014; 12:1252-4.

CHAPTER 42

1.

193