Artritis reumatoide modificadores

REVIEW ARTICLE

Drugs Aging 2009; 26 (4): 273-293 1170-229X/09/0004-0273/$49.95/0

ª 2009 Adis Data Information BV. All rights reserved.

Guidelines for the Use of Conventional and Newer Disease-Modifying Antirheumatic Drugs in Elderly Patients with Rheumatoid Arthritis Alejandro Dı´az-Borjo´n Department of Medicine, Division of Rheumatology, Hospital Angeles Lomas, Huixquilucan, Estado de Me´xico, Mexico

Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. General Considerations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.1 Pharmacokinetics and Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1.2 Immunization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2. Conventional (Synthetic) Disease-Modifying Antirheumatic Drugs (DMARDs) . . . . . . . . . . . . . . . . . . .

2.1 Methotrexate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.2 Antimalarials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.3 Sulfasalazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.4 Leflunomide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.5 Other Synthetic DMARDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.5.1 Gold Salts . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.5.2 Penicillamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.5.3 Minocycline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.5.4 Ciclosporin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2.5.5 Azathioprine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3. Biologic DMARDs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.1 Tumour Necrosis Factor-a Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.2 Interleukin-1 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.3 B-Cell Depletion Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3.4 Co-Stimulation Blockade . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4. Discussion and Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abstract

273 275 275 275 276 276 278 279 280 281 281 282 282 283 283 283 283 284 284 286 287

Treatment strategies in the management of rheumatoid arthritis (RA) have significantly changed in the past decade. The early use of diseasemodifying antirheumatic drugs (DMARDs) is the basis of this new treatment strategy. Because these agents alter the natural disease course of RA, early aggressive intervention results in better outcomes with respect to future structural damage and disability. The arrival of the ‘biologic agents’ era in rheumatology has further improved the therapeutic options in patients with RA. A significant portion of individuals with this ailment are elderly, with approximately one-third of patients experiencing their first symptoms

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after the age of 60 years. Yet, many elderly patients with RA do not receive optimal treatment. Although the reasons for this have not been completely defined, it seems clinicians are reluctant to use DMARDs in the elderly because of uncertainty regarding their efficacy and safety in this population. The aging process is associated with important changes in drug pharmacokinetics and pharmacodynamics. It appears that the former, mainly through decreased renal clearance, is responsible for an increased incidence of adverse effects with some DMARDs. The old are also more susceptible to infection than the young, making prevention of infectious disease through vaccination of particular importance; however, healthcare professionals should be aware that some DMARDs, including biologic agents, may interfere with responses to vaccination. The available data, although limited, suggest that DMARDs, including some biologic agents, are similarly effective in the old and the young, while maintaining very good adverse effect profiles. Therefore, the elderly with RA should not be excluded from receiving optimal treatment with these medications. At the same time, clinicians must be aware of the possible increased risk of drug toxicities, recognize the need to adjust therapy to match individual patient characteristics (i.e. renal function, co-morbidities, concomitant medication use or polypharmacy), and use the lowest possible effective dosage. This review describes the special considerations to be taken into account when administering conventional (synthetic) or biologic DMARDs to elderly patients with RA.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that primarily affects the joints and is associated with significant morbidity, mortality and disability.[1-3] The incidence and prevalence of RA increase with age[4,5] and up to one-third of cases begin their disease course after age 60 years,[6,7] an entity known as elderlyonset RA (EORA).[8] It is important to note that this subdivision of RA by age is completely empirical with no specific physiological rationale for it, although some clinical differences have been described.[9-11] Additionally, a significant portion of patients with younger-onset RA (YORA) will ‘graduate’ to the elderly population, resulting in a large number of patients with RA belonging to this age group. Whether EORA carries a better or poorer prognosis than YORA is still debatable.[11,12] Co-morbidities associated with the elderly (e.g. heart disease, chronic lung disease, malignancies, etc.) may contribute to a perception of worse outcomes[12] as well as predisposing this population to adverse drug effects and toxicities. Additionally, elderly YORA patients may ª 2009 Adis Data Information BV. All rights reserved.

have other co-morbid conditions secondary to longstanding disease.

Based on compelling evidence that early aggressive management of RA provides better outcomes in regards to quality of life and disability, treatment strategies for RA have shifted from the conservative ‘wait and see’ approach used 15 years ago. Current treatment guidelines emphasize use of disease-modifying antirheumatic drugs (DMARDs) early in the disease, specifically within 3 months of diagnosis.[13,14] The arrival of newer therapies, including biologic agents, the use of combination DMARD therapy and the resurgence of low-dose corticosteroid therapy have also improved outcomes in clinical trials. Therefore, use of DMARD combination therapy or DMARD(s) plus a biologic agent with or without low-dose corticosteroids is relatively common in current clinical practice. In spite of this, a recent study showed that most elderly patients with RA do not receive DMARD therapy.[15] The same study, however, acknowledges an increase in DMARD prescription to the Drugs Aging 2009; 26 (4)

Use of DMARDs in Elderly Patients with RA

elderly RA population in the last few years, particularly by rheumatologists.[15] Nonetheless, there seems to be a bias towards prescribing DMARDs less frequently in older patients with RA even amongst rheumatology specialists.[16] Other authors have found that older patients with RA are prescribed biologic agents and DMARD combination therapy less frequently than their younger counterparts.[17] Furthermore, although some trials include patients up to 70 years of age, the elderly population is under-represented in RA therapy clinical trials, and specific trials in this age group are lacking; therefore, data about the efficacy and toxicity of DMARDs and biologic agents in the elderly are scarce.

The goal of aggressive treatment strategies in RA is to modify the natural disease course, thereby alleviating pain, decreasing inflammation, improving functional status and preventing joint deformity and disability. In general, all patients with RA should be offered optimal management of their disease (pharmacological and non-pharmacological). Elderly patients should not be excluded from the benefits of DMARD or biologic therapy; however, additional considerations, as well as closer monitoring for adverse medication effects, toxicities and drugdrug interactions may be required. This article reviews the considerations that need to be taken into account when prescribing conventional DMARDs or newer biologic therapies to elderly patients with RA. While nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat RA and can have significant adverse effects in the elderly (e.g. cardiovascular, gastrointestinal, etc.), these agents do not have disease-modifying properties, and therefore are not discussed in this review. In contrast, corticosteroids have been shown not only to improve the signs and symptoms of RA but also to slow radiographic damage in patients with RA.[18] However, these medications belong to a different class of drugs and are not currently considered DMARDs. The use, efficacy and toxicity (e.g. cardiovascular, metabolic, bone, etc.) of corticosteroids in the elderly deserve a separate review, and therefore are not discussed in detail in this article. ÂŞ 2009 Adis Data Information BV. All rights reserved.

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1. General Considerations 1.1 Pharmacokinetics and Pharmacodynamics

It is well known that pharmacokinetics (the actions of the body on a drug) change during the aging process. This is particularly relevant since most clinical trials of medications, including DMARDs, have included few or no elderly patients.[19] The frequent phenomenon of polypharmacy in the old may contribute to altered DMARD metabolism and a higher incidence of toxicities or adverse effects. However, in general, there is a lack of information about DMARD pharmacokinetics in the elderly population.[20] The pharmacokinetics process is comprised of several steps: absorption, distribution, metabolism and elimination. Although the elderly have significant physiological changes in the gastrointestinal tract (decreased saliva and gastric acid production, decreased motility), drug absorption is usually not affected.[20] Unlike absorption, changes in all other steps in the pharmacokinetic process may contribute to the appearance of adverse events. Drug distribution may be affected by increased body fat and by decreases in total body water, cardiac output, hepatic and renal blood flow and albumin concentration.[19-22] Decreased hepatic blood flow and protein synthesis contribute to reduced metabolic drug clearance. Finally, decreased glomerular filtration rate associated with aging results in decreased drug elimination.[20,21] In contrast to pharmacokinetics, changes in pharmacodynamics (the action of a drug in the body) have not been well studied in the elderly, but there may be decreased or altered responses to drugs in this age group.[20] In summary, age-related changes in drug metabolism and elimination are important to consider when prescribing DMARDs, including biologic agents, to patients aged >60 years, mainly because of a potential for increased risk of adverse effects and toxicities.

1.2 Immunization

Aging is accompanied by an increased risk of morbidity and mortality due to infections.

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RA itself, and its treatment, may also increase susceptibility to infections,[23] emphasizing the need to take infectious disease prevention in the elderly seriously. Even though data concerning immunization during DMARD therapy are scant, vaccination following the recommended adult immunization schedule guidelines, which may vary from country to country, is encouraged in all patients with RA, including the elderly; however, special care should be taken when considering vaccination in patients taking DMARDs or biologic agents. Immunization with live vaccines (measles/mumps/rubella, varicella zoster and intranasal influenza) is not contraindicated in patients with RA per se. However, it is contraindicated in individuals taking immunosuppressant medications,[24] which some DMARDs (e.g. methotrexate, leflunomide, ciclosporin [cyclosporine], azathioprine) and all biologic agents are considered to be. Other vaccine types may be administered,[24] and are in fact recommended in recently released guidelines from the American College of Rheumatology (ACR);[25] however, the clinician must be aware of concerns about diminished vaccine efficacy, particularly with patients taking tumour necrosis factor-a (TNFa) inhibitors and/or methotrexate. Patients taking methotrexate monotherapy may have an impaired response to pneumococcal vaccines[26,27] but respond well to influenza immunization, whereas treatment regimens that include TNFa blockers and methotrexate are associated with lower response rates to influenza vaccination.[26,28] One of the newer biologic agents, rituximab, has also been shown to be associated with a decreased response to influenza vaccine.[29] The author is unaware of studies focusing on the effect of DMARDs or biologic therapy on vaccination in the elderly.

In conclusion, clinicians are encouraged to follow the recommended adult immunization schedules provided by the Advisory Committee on Immunization Practices (ACIP) in the US or its equivalent in other countries. Immunization with non-live vaccines can be undertaken at any time regardless of treatment but should be considered before initiating therapy with methotrexate and/or certain biologic agents if possible to improve the chances of a good response. ª 2009 Adis Data Information BV. All rights reserved.

According to the ACIP guidelines, live vaccines are contraindicated in patients taking immunosuppressants; therefore, when such vaccines are required, they should be administered before initiating or after stopping this type of therapy. In general, further study is needed to evaluate the effect of DMARDs and biologic agents on immunization efficacy and safety, particularly in the elderly.

2. Conventional (Synthetic) DiseaseModifying Antirheumatic Drugs (DMARDs) Medications that have been shown to alter the natural course of RA (e.g. delay or prevent joint damage and/or improve functionality) are known as DMARDs. These agents vary widely in their type, mechanism of action, onset of efficacy and toxicity profiles. Since the change to a more aggressive treatment strategy for RA in the late 1990s, use of conventional DMARDs in general has increased, although the use of certain drugs of this type (gold salts, penicillamine) has decreased.

Use of combination DMARD therapy, with or without corticosteroids, has been shown to be superior to monotherapy in some studies,[30-36] and is therefore common practice today.

2.1 Methotrexate

Aminopterin, the precursor to methotrexate, was initially synthesized as an agent for the treatment of leukaemia and was used successfully to treat RA for the first time in the early 1950s.[20,37,38] However, it was not until the 1980s that several clinical trials corroborated the efficacy and safety of methotrexate in the treatment of RA,[39-43] and since then, methotrexate has become the most widely used DMARD worldwide for managing this disorder. Methotrexate has the advantage of having a fast onset of action when compared with other DMARDs and slows radiographic (e.g. erosions) disease progression.[44] The efficacy of methotrexate in the elderly has been studied by some investigators and by analysis of pooled data from multiple clinical trials; these data show that methotrexate is at least as good Drugs Aging 2009; 26 (4)

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Table I. Toxic and adverse effects of methotrexate, and guidelines for monitoring its use in patients with rheumatoid arthritis System/organ

Adverse/toxic effect

Baseline evaluation

Monitoring

Gastrointestinal (most common)

Oral ulcers, nausea, vomiting, abdominal pain/discomfort, diarrhoea, hepatotoxicity

Pulmonary

Interstitial pneumonitis, pulmonary nodulosis

Haematological

Leukopenia, thrombocytopenia, megaloblastic anaemia, non-Hodgkin’s lymphoma (Epstein-Barr virusassociated)

Chest x-ray, liver function tests (including albumin), blood urea nitrogen, creatinine, complete blood count (including platelet count) and hepatitis B and C serology

Complete blood count (including platelet count), liver function tests (including albumin), blood urea nitrogen and creatinine every 4-8 weeks

Renal

Decreased creatinine clearance

Skin

Nodulosis, alopecia

Reproductive

Teratogenesis, oligospermia

Metabolic

Hyperhomocysteinaemia

Nervous system

Headache, neurotoxicity, seizures (very rare)

in elderly patients as in the young,[45,46] while tending to require lower dosages.[47] Methotrexate is an antimetabolite that prevents production of purines and pyrimidines through dihydrofolate reductase inhibition with subsequent impairment of DNA synthesis and, thus, cell proliferation. Although this may explain the mechanism of action of methotrexate in oncology as well as some of its toxicities,[48] its main anti-inflammatory effects in RA seem to be due to other means, specifically through promotion of adenosine release by inhibition of aminoimidazolecarboxamido ribonucleotide transformylase.[48-51] The overall effect translates into decreased synthesis of pro-inflammatory cytokines such as TNFa, interleukin (IL)-6 and interferon-g, as well as increased production of IL-10, a potent antiinflammatory cytokine.

Methotrexate can be administered orally, subcutaneously or intramuscularly, with good bioavailability. It is metabolized by the liver and intracellularly into active metabolites that may remain in tissues for prolonged periods of time and can be converted back to methotrexate.[51] At the low doses used to treat RA, methotrexate has a terminal half-life of 3–10 hours, with most of the drug being eliminated by renal excretion and the rest through bile. Some investigators have ª 2009 Adis Data Information BV. All rights reserved.

assessed methotrexate pharmacokinetic changes in the elderly, and found a significant decrease in its elimination that was closely related to diminished creatinine clearance.[52] No other significant changes were seen when comparing methotrexate pharmacokinetics in old versus young subjects.

Discontinuation of therapy due to toxicity or adverse events rather than lack of efficacy is a major issue with methotrexate use,[53] with approximately only 30% of patients adhering to therapy after 10 years.[54] The adverse and toxic effects of methotrexate as well as guidelines for monitoring its use are presented in table I. A meta-analysis of clinical trials pointed to decreased renal function rather than age itself as a determinant of methotrexate toxicity in the elderly population.[55] Thus, methotrexate dosage should be adjusted according to renal function, which declines in older individuals. Old age and mild renal insufficiency have been reported to be associated with CNS toxicity symptoms such as mood alteration, memory impairment and unpleasant cranial sensations.[56] Bone mineral density decreases with age, and RA itself is a risk factor for osteoporosis; in addition, while methotrexate alone does not cause bone loss, it does seem to potentiate the decalcification effects of Drugs Aging 2009; 26 (4)

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corticosteroids.[57] There is no clear cut evidence that age itself is a risk factor for other toxicities of methotrexate. As previously mentioned, some adverse effects or toxicities are due to methotrexate acting as a folic acid antagonist and therefore their incidence and severity can be prevented or ameliorated by folic acid supplementation with little effect on efficacy; this strategy may actually decrease discontinuation rates.[58-60] It is recommended that all patients receiving methotrexate for RA be supplemented with folic acid.[58,61] No dosage for folic acid supplementation in patients taking methotrexate for RA has been specified; however, administration of 1 mg/day of folic acid is common practice, although some authors recommend at least 5 mg folic acid given once weekly starting the morning after methotrexate is ingested.[58] Use of other significant folic acid antagonists such as trimethoprim should be avoided because of increased potential for toxicity.

In summary, limited evidence suggests that methotrexate is safe and effective in the treatment of elderly patients with RA, as long as the dosage is adjusted according to renal function.

Folic acid supplementation should also be provided. Even with these precautions, careful follow-up and strict monitoring for toxicities is encouraged.

2.2 Antimalarials

Two antimalarials, hydroxychloroquine and chloroquine, are commonly used in the treatment of RA. They were first used for this purpose in the early 1950s; however, reports of ocular toxicity limited their use for many years.[20,62] Use of these medications was not popular until the rarity of this adverse effect was recognized. The efficacy of antimalarials to treat RA has been demonstrated in retrospective studies[63] and clinical trials.[64-66] Hydroxychloroquine seems to have slightly less efficacy and less toxicity than chloroquine.[67] However, these compounds have not been convincingly shown to decrease radiographic progression in RA,[68] and have a very slow onset of action (3–6 months) compared with other DMARDs.[69] Therefore, monotherapy with either ª 2009 Adis Data Information BV. All rights reserved.

drug is usually reserved for mild, non-erosive disease. Nevertheless, antimalarials have additive effects to other DMARDs, particularly to treatment regimens containing methotrexate.[31,70] Hence, combination therapies that include antimalarials are commonly used in clinical practice.

Although the precise mechanism of action of antimalarials has not been elucidated, these alkaline substances accumulate in lysosomes, raising their pH and stabilizing them.[71] This prevents protein degradation by acidic hydrolases in these vacuoles, resulting in impaired macromolecule assembly in endosomes and protein modification in the Golgi apparatus. The overall effect appears to be a decreased formation of major histocompatibility complex class II (MHC II) molecules necessary for antigen-presenting cells to stimulate CD4+ T lymphocytes.[71,72] Both hydroxychloroquine and chloroquine are readily absorbed in the gastrointestinal tract, and have a large volume of distribution with predilection for pigmented tissues such as the skin and retina. They are partially metabolized by the liver and have long half-lives (1–2 months).

The primary form of elimination is through the urine.[73] The antimalarials are the best tolerated of the DMARDs because of their few serious adverse effects (table II). Indeed, serious adverse effects are so rare that no routine laboratory workup is recommended. Even so, retinal toxicity remains the most feared adverse effect. Fortunately, several studies have established the exceptional occurrence of this potentially blinding toxicity if the recommended maximum medication dosages are not exceeded (<3 mg/kg/day for chloroquine and <6.5 mg/kg/day for hydroxychloroquine).[74] Moreover, several risk factors that predispose patients to this toxic effect have been identified, such as renal[75,76] or hepatic dysfunction,[76] increased body fat (dosage should be adjusted to the lean bodyweight, not the total bodyweight),[74,76,77] pre-existing keratopathy,[77] age >60 years and treatment duration >5 years.[74] Given the increased risk of senile macular degeneration in the elderly,[78] close follow-up of these individuals is indicated.

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Table II. Toxic and adverse effects of antimalarials, and guidelines for monitoring their use in patients with rheumatoid arthritis System/organ

Adverse/toxic effect

Baseline evaluation

Monitoring

Eye (rare)

Retinal toxicity, corneal deposits Nausea/vomiting, abdominal pain, diarrhoea

Ophthalmological examination if age >40 years or pre-existing eye disease, liver function tests and creatinine

Ophthalmological evaluation yearly

Gastrointestinal (most common) Neuromuscular (rare)

Myopathy

Haematological (rare)

Aplastic anaemia, agranulocytosis, thrombocytopenia

Skin

Pigmentation of skin and mucosa (very long-term use), hair bleaching, pruritus

Cardiovascular (rare)

Cardiomyopathy, heart block

Nervous system

Headache and dizziness (common), ototoxicity, seizures (very rare)

2.3 Sulfasalazine

Sulfasalazine was the first medication created specifically to treat RA. Its creator, Nanna Svartz, reported its efficacy for treating this condition in the late 1940s;[79,80] however, concomitant reports of inefficacy[81] prevented sulfasalazine from gaining popularity until the drug was revisited and found to be effective more than 30 years later.[82] The disease-modifying properties of sulfasalazine, including its ability to slow radiographic progression, have been corroborated in several randomized clinical trials and observational studies,[83-87] and its efficacy is comparable to that of methotrexate,[88] leflunomide,[89] injectable gold salts and penicillamine.[90] Sulfasalazine has been found to have greater radiographic progression slowing properties and a faster onset of action than hydroxychloroquine.[87,91] Combined analysis of five prospective studies of sulfasalazine for the treatment of RA showed that this medication is as effective in the elderly as in the young.[92] Combination therapy of sulfasalazine and methotrexate[88,93] has shown a modest trend towards better efficacy than either agent alone, and the combination of sulfasalazine, methotrexate and hydroxychloroquine[31] has demonstrated significantly better efficacy than any of these agents used as monotherapy.

Sulfasalazine is comprised of two molecules, a sulfa moiety (sulfapyridine) and 5-aminosalicylic acid (5-ASA). When Pullar et al.[94] compared the ÂŞ 2009 Adis Data Information BV. All rights reserved.

efficacy of sulfapyridine and 5-ASA in the treatment of RA, they found that the former is likely to be responsible for the DMARD activity of sulfasalazine. However, an effect exerted by the parent compound cannot be excluded.[95] The mechanism of action of sulfasalazine, although unknown, may be attributable to its weak antifolate properties but seems more likely to be related to anti-inflammatory and immunomodulatory effects such as inhibition of prostaglandin and leukotriene synthesis, decreases in immunoglobulin and rheumatoid factor levels, inhibition of neutrophil and lymphocyte function, decreased T and B lymphocyte proliferation, and reductions in the levels of several cytokines, including IL-1, IL-6, IL-12 and TNFa. Sulfasalazine also promotes release of adenosine, a property it shares with methotrexate.[96] After oral administration, sulfasalazine is poorly absorbed in the small intestine (10â&#x20AC;&#x201C;30%).[97,98] This absorbed portion undergoes significant enterohepatic circulation and is excreted in the bile; consequently, most of the medication reaches the colon unchanged. In the large intestine, coliform bacteria reduce sulfasalazine to sulfapyridine and 5-ASA, the two active moieties, using an azoreductase. Most of the sulfapyridine is absorbed in the colon, whereas 5-ASA is almost completely excreted in the faeces. The absorbed sulfapyridine and to a lesser extent unchanged sulfasalazine are metabolized in the liver by hydroxylation and Drugs Aging 2009; 26 (4)

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Table III. Toxic and adverse effects of sulfasalazine, and guidelines for monitoring its use in patients with rheumatoid arthritis System/organ

Adverse/toxic effect

Baseline evaluation

Monitoring

Gastrointestinal (most common)

Nausea/vomiting, dyspepsia, diarrhoea, hepatotoxicity (rare)

Skin

Rash, photosensitivity, pruritus

Systemic

Fever

Complete blood count, liver function tests, blood urea nitrogen and creatinine every 2-4 weeks for 3 months, then every 3 months

Haematological (rare)

Haemolytic anaemia (in glucose-6-phosphate dehydrogenase deficiency), aplastic anaemia, agranulocytosis

Complete blood count, liver function tests, blood urea nitrogen, creatinine, and consider glucose-6phosphate dehydrogenase levels

Renal

Nephrotoxicity, crystalluria, haematuria

Nervous system

Headache, anorexia

Reproductive

Oligospermia

acetylation; therefore the half-lives of these components are increased in slow acetylators. However, although such individuals may have increased incidence of nausea and vomiting, there is no evidence of increased risk of serious toxicity or lesser efficacy.[99,100] Sulfapyridine and sulfasalazine are eliminated mainly by the kidneys and therefore dosage should be adjusted according to renal function. The pharmacokinetics of sulfasalazine in the elderly have been studied,[101] and researchers have concluded that age has only a minor effect in the handling of this drug, with the main effect being a prolonged elimination half-life.

Table III summarizes the adverse and toxic effects of sulfasalazine. These can be diminished by slow initiation of the drug with gradual increase in dosage. Increasing age does not affect the frequency or nature of these adverse effects.[92] It is unknown whether the weak antifolate properties of sulfasalazine may influence the appearance of haematological adverse effects, but since folate deficiency is common in the elderly,[102] special caution is advised in this population.

Overall, sulfasalazine may be a safe alternative to methotrexate therapy in elderly patients with RA. As with methotrexate, the dosage should be adjusted according to renal function.

2.4 Leflunomide

After the creation of sulfasalazine, more than 4 decades were to pass before another agent was ª 2009 Adis Data Information BV. All rights reserved.

designed specifically to treat RA. Bartlett and Schleyerbach developed leflunomide in the 1980s[103] and used it successfully in experimental models of inflammatory arthritis. Results from several controlled clinical trials have confirmed the usefulness of leflunomide in RA,[104-107] and its efficacy is comparable to that of sulfasalazine[89] and methotrexate.[105] Combination therapy of leflunomide with methotrexate has been proven to be safe and effective in patients with insufficient response to methotrexate alone,[30] although this combination has not been specifically studied in the elderly.

Leflunomide is an isoxazol derivative that exerts its mechanism of action through inhibition of dihydroorate dehydrogenase, thereby effectively preventing de novo production of pyrimidine, a basic element necessary for DNA synthesis.[103] The end result is decreased proliferation and differentiation of T lymphocytes. Other possible significant mechanisms of action have been described, including inhibition of nuclear factor-kB transcription, cyclo-oxygenase-2 activity and metalloproteinases, together with increasing levels of transforming growth factor-b.

When ingested, leflunomide is well absorbed and achieves good bioavailability. It is rapidly metabolized into its active metabolite, A77 1726, which almost completely binds to plasma proteins.[103] Leflunomide is metabolized by the liver, and is in part eliminated in the bile, with significant enterohepatic circulation; the remainder is Drugs Aging 2009; 26 (4)

Use of DMARDs in Elderly Patients with RA

cleared by the kidneys. Leflunomide has a prolonged half-life of approximately 2 weeks; however, active metabolites may be detected up to 2 years after treatment has stopped because of biliary recycling.

As with most DMARDs, leflunomide may have serious adverse effects (table IV). Because of the long half-life of leflunomide, if severe toxicity occurs or if pregnancy is desired, a colestyramine elimination procedure is required. This consists of taking 8 g of colestyramine orally three times daily for 11 days. There are no studies specifically addressing use of leflunomide in the elderly; notwithstanding, some experts recommend not using the usual loading dose regimen of this drug in such individuals, and considering alternate day dosing.[108] Some authors have reported that the elderly may be at higher risk for pancytopenia, particularly if there is concomitant use of methotrexate.[109] Hypertension (new onset or exacerbation) is a common adverse effect of leflunomide, and may be of particular concern in elderly individuals with co-morbidities such as heart failure and chronic renal disease, which may be exacerbated.

2.5 Other Synthetic DMARDs

Multiple other substances have been shown to be of benefit in the treatment of RA. Two of these, gold salts and penicillamine, are older, classic DMARDs, while others such as minocycline and ciclosporin are used mainly for other purposes. However, these compounds are not very commonly used in todayâ&#x20AC;&#x2122;s clinical practice,

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mainly because of their unfavourable toxicity profiles or unfamiliarity with their use. Nonetheless, these medications have been proven useful, and thus should be considered in cases of intolerance to or inefficacy of more popular DMARDs. The most important of these agents are discussed below. Their most important adverse effects, together with guidelines for their use, are outlined in table V. 2.5.1 Gold Salts

Gold salts have been used to treat RA since the early part of the 20th century and are one of the oldest DMARDs, although their use has significantly decreased in recent decades mainly because of the appearance of other therapies with more favourable toxicity profiles. Chrysotherapy (treatment with gold salts) is available in oral and parenteral (intramuscular administration) forms.

Parenteral gold has been shown to have clinical efficacy in multiple studies,[65,110,111] has been compared with other DMARDs,[65,111] and has been shown to prevent joint erosions.[112] Its oral counterpart (auranofin), although effective,[113] seems to be somewhat weaker in efficacy but has a lower incidence of severe toxicities.[114] Furthermore, in a double-blind, placebo-controlled trial, auranofin was found to be safe and effective in patients with EORA and to also demonstrate a corticosteroid sparing effect.[115] The mechanism of action of gold salts is unknown, although they have been shown to decrease immunoglobulin and rheumatoid factor levels, and to inhibit lymphoproliferation.[116,117] Severe adverse reactions

Table IV. Toxic and adverse effects of leflunomide, and guidelines for monitoring its use in patients with rheumatoid arthritis System/organ

Adverse/toxic effect

Baseline evaluation

Monitoring

Gastrointestinal (most common)

Diarrhoea, nausea, abdominal pain, hepatotoxicity

Cardiovascular

Hypertension (new onset or exacerbation)

Complete blood count and liver function tests (including albumin) every 4-8 weeks, BP monitoring at every visit

Skin

Alopecia, rash

Complete blood count, liver function tests (including albumin) and hepatitis B and C serology

Nervous system

Anorexia, headache, peripheral neuropathy

Haematological (rare)

Agranulocytosis, thrombocytopenia, pancytopenia

Pulmonary (very rare)

Interstitial pneumonitis

BP = blood pressure.

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Table V. Toxic and adverse effects of other conventional (synthetic) disease-modifying antirheumatic drugs (DMARDs), and guidelines for monitoring use of these drugs in patients with rheumatoid arthritis DMARD

Adverse/toxic effect

Baseline evaluation

Monitoring

Gold salts (intramuscular)

Stomatitis, rash, nitritoid reactions, nausea, vomiting, hepatotoxicity, myelosuppression, nephrotoxicity, pneumonitis

CBCa, BUN, creatinine and urinalysis; consider LFTs

CBCa and urinalysis every 2 weeks while on weekly injections, then with each injection; consider LFTs, BUN and creatinine every 3 months

Auranofin (oral gold)

Nausea, vomiting, abdominal pain, diarrhoea rash, stomatitis, dysgeusia, hepatotoxicity, pneumonitis, nephrotoxicity, myelosuppression

CBCa, BUN, creatinine, LFTs and urinalysis

CBCa, BUN, creatinine, LFTs and urinalysis every 4-8 weeks

Penicillamine

Myelosuppression, pneumonitis, nephrotoxicity, hepatotoxicity, SLElike syndrome

CBCa, urinalysis, BUN and creatinine; consider LFTs

CBCa and urinalysis every 2 weeks for 6 months, then every month; consider BUN, creatinine and LFTs every 1-3 months

Minocycline

Nausea, vomiting, diarrhoea, abdominal discomfort, dizziness, vertigo, headache, skin hyperpigmentation, cytopenias, hepatotoxicity (rare)

CBCa, BUN, creatinine and LFTs

No specific recommendations; consider CBCa and LFTs periodically

Ciclosporin

Hypertension, nausea, vomiting, hirsutism, headache, nephrotoxicity, hepatotoxicity, hyperglycaemia, dyslipidaemia, hyperuricaemia (and gout), electrolyte abnormalities, cytopenias, anaemia

BP, CBCa, BUN, creatinine, LFTs and uric acid

BP at every visit; BUN and creatinine every 2 weeks until dose stable, then every month; CBCa, LFTs and electrolytes (potassium) periodically. Consider lipid panel

Azathioprine

Nausea, vomiting (treatment limiting), myelosuppression, hepatotoxicity, hypersensitivity, malignancy (including lymphoma)

CBCa, BUN, creatinine and LFTs; consider TPMT genotyping/ phenotyping

CBCa every 1–2 weeks with dose changes, then every 1–3 months along with LFTs

a

Including platelet count.

BP = blood pressure; BUN = blood urea nitrogen; CBC = complete blood count; LFTs = liver function tests; SLE = systemic lupus erythematosus; TPMT = thiopurine methyltransferase.

are uncommon but may be fatal. The nitritoid reactions associated with intramuscular gold administration are vasomotor responses characterized by diaphoresis, hypotension, nausea, vomiting and syncope, which may be of particular concern in elderly patients. There may be some association between this adverse effect and use of ACE inhibitors in elderly individuals.[118] 2.5.2 Penicillamine

Penicillamine has been used for RA since the 1970s; however, its use has declined greatly. Penicillamine has a disease-modifying effect[65,119,120] but has never been proven to slow radiographic progression. Its mechanism of action involves the drug’s chelating and antioxidant properties, inhibition of leukocyte enzymatic activity (e.g. myeloperoxidases, collagenases, etc.), lymphocyte ª 2009 Adis Data Information BV. All rights reserved.

proliferation and function,[121] and decreases in rheumatoid factor levels.[122] The efficacy and toxicity of penicillamine in the elderly are no different to those in the young.[123] Because penicillamine can induce pyridoxine deficiency, some clinicians advocate pyridoxine supplementation in patients taking this medication. Because the elderly are known to be prone to nutritional and vitamin deficiencies, pyridoxine supplementation should therefore be considered in this age group.

2.5.3 Minocycline

Although tetracyclines had been used previously in the treatment of RA, it was not until recently that their efficacy in the treatment of this disorder was demonstrated in clinical trials.[124-127] When O’Dell et al.[128] compared the efficacy of minocycline and hydroxychloroquine in patients with Drugs Aging 2009; 26 (4)

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early seropositive RA, they found minocycline to be superior to hydroxychloroquine in achieving ACR 50 responses (50% improvement) after 2 years of therapy while also exhibiting a prednisone sparing effect.[128] However, minocycline does not seem to slow radiographic progression.[129] Minocycline has anti-inflammatory properties exerted through its ability to inhibit phosphoplipase A2 activity, thereby decreasing prostaglandin, leukotriene and nitric oxide production.[130] The drug also suppresses chemotaxis and leukocyte phagocytosis while decreasing the proliferation and activation of lymphocytes and synovial cells. Effects on metalloproteinases and collagenases as well as its chelating properties may also help explain the therapeutic properties of minocycline.[131] To the authorâ&#x20AC;&#x2122;s knowledge, there are no studies evaluating long-term use of oral minocycline for the treatment of RA in the elderly. Minocycline can induce vestibular vertigo,[132] which may be a significant added risk for falls and subsequent fractures in this age group.

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azathioprine seems to be higher and more serious than that of other DMARDs,[141] whereas the efficacy of the drug is less than that of methotrexate,[142,143] and its use is therefore not popular in the treatment of RA. Nevertheless, azathioprine can be useful in patients with systemic vasculitis associated with RA.[144] Azathioprine is a purine analogue that inhibits DNA synthesis; its mechanism of action in RA may be secondary to its immunosuppressive properties on T lymphocytes.[145] There are no specific studies addressing use of this medication in elderly individuals with RA and azathioprine therapy in this population should therefore be undertaken with caution.

Azathioprine may be involved in significant drug interactions that may require dosage adjustments or the use of alternative medications. One such interaction occurs with allopurinol,[146] which is commonly used to treat gout, a somewhat common form of arthritis among the elderly.

3. Biologic DMARDs

2.5.4 Ciclosporin

Although ciclosporin is mainly used as an immunosuppressant in the solid organ transplantation field, it is effective in the treatment of RA when administered at low dosages. Furthermore, ciclosporin can slow radiographic progression.[133,134] Its combination with methotrexate is safe and effective in patients with severe RA who do not respond satisfactorily to methotrexate alone.[135] The mechanism of action of ciclosporin in RA is not clear but may be related to its immunosuppressive effects on T cells. Although the pharmacokinetics of ciclosporin are not influenced by age, they may be modified by polypharmacy, which is common in the elderly population.[136] Accordingly, some authors recommend using lower doses in this age group.[108] Use of ciclosporin by rheumatologists has been limited mainly because of its high cost and toxicity profile, particularly nephrotoxicity and hypertension.[137] Both are of particular concern in the elderly.

2.5.5 Azathioprine

Evidence supporting the efficacy of azathioprine in RA derives mainly from studies with small numbers of subjects.[133,138-140] Toxicity from ÂŞ 2009 Adis Data Information BV. All rights reserved.

Biologic DMARDs, also known as biologic response modifiers, are the newest form of therapy available not only for RA but also for other rheumatic diseases as well. These agents are partially or fully humanized, protein-based substances designed specifically to interfere with immune responses that may be involved in RA pathogenesis. At the time of writing, four different types of biologic DMARDs are available and have been approved for use in RA: TNFa inhibitors, IL-1 inhibitors, B-cell depletion therapy, and co-stimulation blockade. Multiple other biologic agents are currently being evaluated for the treatment of RA. Some biologics, particularly TNFa inhibitors, may be associated with an increased risk for lymphoma, and although it is unclear if these agents increase the risk of other types of malignancies, routine screening (e.g. cervical smear, mammography, screening colonoscopy) and monitoring of skin lesions are warranted, particularly in the elderly.

3.1 Tumour Necrosis Factor-a Inhibitors

Three TNFa inhibitors are currently being used in RA: etanercept, infliximab and adalimumab.

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In general, they share a common mechanism of action, but differ in their structure and pharmacokinetic properties. Infliximab is partially humanized, whereas etanercept and adalimumab are fully humanized proteins. Infliximab and adalimumab are monoclonal antibodies directed against TNFa, while etanercept is a soluble TNFa receptor bound to the crystallizable fragment (Fc) portion of an immunoglobulin.

All three agents are administered parenterally, with etanercept and adalimumab being injected subcutaneously and infliximab intravenously.

The half-lives of these agents differ significantly, that is, approximately 100 hours for etanercept, 7–12 days for infliximab and 2 weeks for adalimumab.[147-149] The mechanism of elimination of TNFa inhibitors is not entirely clear. There are no formal studies addressing age-related changes in pharmacokinetics of TNFa inhibitors.

The mechanism of action of these agents involves inhibition of the actions of TNFa, a powerful pro-inflammatory cytokine thought to play a major role in the inflammatory process characteristic of RA. Evidence from clinical trials supports their usefulness in RA,[150-153] with all having similar efficacy profiles. It is recommended that infliximab be administered with methotrexate to prevent or diminish the formation of human antichimeric antibodies that decrease its efficacy.[154] In contrast, etanercept and adalimumab can be used as monotherapy, although the clinical and radiological benefits of each are increased when these agents are used in combination with other DMARDs, particularly methotrexate.[155,156] Subset analysis from clinical trials of etanercept has provided insight that this agent is efficacious and safe for use in elderly patients,[157-159] although there may be a higher incidence of severe infections in patients aged >65 years.[159] Data on infliximab and adalimumab use in the elderly are lacking; however, some investigators have found infliximab to be effective but associated with a possible increased risk of treatment withdrawal because of severe infections.[160] It is important to note, however, that this study is limited by the small number of patients available for analysis. Other investigators have not found an increased risk of serious ª 2009 Adis Data Information BV. All rights reserved.

infections in elderly patients receiving TNFa inhibitors compared with those taking methotrexate.[161] Thus, the issue of a possible increased risk of serious infections in elderly subjects taking TNFa inhibitors remains debatable and requires further study. Nevertheless, clinicians must be cautious and should consider administering appropriate vaccinations before initiating this type of medication. Age-related co-morbidities such as previous or current malignancy, heart failure and chronic lung disease may preclude the use of TNFa inhibitors in some elderly patients. The most common and serious adverse effects of TNFa inhibitors are outlined in table VI. 3.2 Interleukin-1 Inhibitors

Anakinra is a recombinant human IL-1 receptor antagonist (rhIL-1ra) designed specifically to block the pro-inflammatory properties of the cytokine IL-1. Anakinra was initially proven to be effective in the treatment of experimental arthritis, and although it is effective in human RA,[162,163] including producing a reduction in radiographic damage, its effects may be considered modest when indirectly compared with other biologic DMARDs. Anakinra is administered by daily subcutaneous injection, has a very short half-life of 4–6 hours and is mainly eliminated in the urine.[164] Therefore, its dosage needs to be adjusted according to renal function. There are no studies evaluating the pharmacokinetics, efficacy or toxicity of anakinra in elderly subjects. The most important adverse effects of the drug are listed in table VII. Special care should be taken when prescribing anakinra in patients with chronic obstructive pulmonary disease or asthma because of an increased risk of respiratory tract infections.[165] Combining anakinra with TNFa inhibitors is contraindicated because of a lack of improved efficacy and a higher incidence of adverse events, particularly serious infections.[166] 3.3 B-Cell Depletion Therapy

B cells appear to participate in RA pathogenesis through different mechanisms such as cytokine and chemokine production, their ability to form organized lymphoid tissue within the synovia and, Drugs Aging 2009; 26 (4)

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Table VI. Toxic and adverse effects of tumour necrosis factor-a inhibitors, and guidelines for their use in patients with rheumatoid arthritis System/organ

Adverse/toxic effect

Baseline evaluation

Monitoring

Skin

Injection site reactions (etanercept, adalimumab), rash Infection (including serious), opportunistic infection (tuberculosis most common), anaphylaxis, malignancy (rare), lupus-like illness, infusion reactions (infliximab)

Purified protein derivative of tuberculin, complete blood count, liver function tests and creatinine; consider chest x-ray and hepatitis B and C serology if not already done

None specifically recommended. When used in combination with synthetic DMARDs (e.g. methotrexate), perform monitoring accordingly

Systemic

Haemolymphatic

Myelosuppression, lymphoma

Cardiovascular

Congestive heart failure exacerbation

Nervous system

Headache, demyelinating disease (rare), optic neuritis (rare), seizures (rare)

Respiratory

Upper respiratory tract infection symptoms

Gastrointestinal

Nausea, vomiting, abdominal discomfort, dyspepsia, hepatotoxicity (rare), hepatitis B reactivation

DMARD = disease-modifying antirheumatic drug.

most notably, their function as highly efficient antigen-presenting cells (APCs).[167,168] Hence, B-cell targeted therapy in RA would seem viable.

Rituximab, a chimeric (mouse-human) antiCD20 monoclonal antibody developed to treat B-cell lymphomas, has been shown to have high efficacy and a good safety profile in the treatment of such tumours. CD20 expression is restricted to mature B cells and pre-B cells, and is absent in earlier B-cell precursors, including haematopoietic stem cells, and mature plasma cells.[169] Use of rituximab in RA is recent, with clinical trials supporting its efficacy and safety.[170,171] It has been proven useful even in patients with RA that is refractory to anti-TNFa therapy.[171] Rituximab effectively and specifically depletes circulating mature B cells through three different

possible mechanisms: (i) antibody dependent cellmediated cytotoxicity; (ii) induction of apoptosis; and (iii) complement-mediated cell damage.[172,173] Rituximab is administered by two intravenous injections separated by 2 weeks. Its halflife varies according to the number of infusions and according to changes in CD20 positive B cells.[174] The metabolism and elimination mechanisms of rituximab have not been completely defined.

Although there are no data available specifically evaluating use of rituximab in elderly patients with RA, there is considerable experience in the use of this medication in B-cell lymphoma within the elderly population.[175] Recently, guidelines for the use of rituximab and other biologics in RA have been published;[176,177] these emphasize that use of

Table VII. Toxic and adverse effects of anakinra, and guidelines for monitoring its use in patients with rheumatoid arthritis System/organ

Adverse/toxic effect

Baseline evaluation

Monitoring

Skin

Injection site reactions

Systemic

Infection (including serious), hypersensitivity

Screen for asthma, blood urea nitrogen, creatinine, complete blood count and liver function tests; consider hepatitis B and C serology if not already done

Complete blood count monthly for 3 months then every 3 months

Gastrointestinal

Nausea, diarrhoea, abdominal pain

Haematological

Neutropenia, thrombocytopenia

Respiratory

Upper respiratory tract infection symptoms

Nervous system

Headache

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rituximab should be reserved for patients with at least moderate disease activity and insufficient response to conventional therapy. Rituximab has not been clearly associated with opportunistic infections, but screening for tuberculosis, if not already done, should be considered prior to initiating therapy. These guidelines also suggest administering hepatitis B, pneumococcal and influenza vaccinations when considering use of rituximab. As previously mentioned, infectious disease prevention in the elderly is of particular concern. The most important adverse effects of rituximab are summarized in table VIII. In conclusion, use of rituximab in the elderly population is well documented to be safe and efficacious in the treatment of B-cell lymphomas, but experience with its use in RA is still lacking.

Therefore, use of this agent should be reserved for those elderly patients with RA who are unresponsive to other therapies.

3.4 Co-Stimulation Blockade

Antigen presentation by the APC and its identification by the T-cell receptor in such lymphocytes is only the initial step leading to activation of the T lymphocyte. Co-stimulation through surface molecules between these two cell types is a crucial and required process to achieve

T-cell activation. One such interaction occurs between the CD28 molecule in T cells and the CD80 and CD86 molecules on APCs.[178] Abatacept is a fully humanized recombinant fusion protein conformed by cytotoxic T-lymphocyte antigen 4 (CTLA-4) [CD152] linked to the Fc fragment of human IgG and thus is also known as CTLA-4 Ig. Abatacept binds with high affinity to the CD80/CD86 molecules on APCs, preventing interaction with the CD28 molecule on T cells, effectively inhibiting co-stimulation with consequent impairment of T-cell activation and blockade of downstream immune responses.[179] Some authors have proposed a possible role for co-stimulation in the pathogenesis of autoimmune disease.[180] Abatacept is the latest type of medication to become available for the treatment of RA, and its efficacy is supported by evidence from clinical trials,[181,182] in some cases including patients who have disease that is refractory to TNFa inhibitors.[183] Abatacept is administered by intravenous infusion and has a half-life of 13.1 days.[184] Its exact metabolism and elimination mechanisms are unknown. Since use of abatacept in RA is quite recent, it is not surprising that there are no studies evaluating its pharmacokinetics, efficacy or safety in the elderly population. Serious and

Table VIII. Toxic and adverse effects of rituximab, and guidelines for monitoring its use in patients with rheumatoid arthritis System/organ

Adverse/toxic effect

Baseline evaluation

Monitoring

Systemic

Asthenia, fever, chills, infection (including serious), infusion reactions, hypersensitivity

Gastrointestinal

Nausea, vomiting, abdominal pain, hepatitis B reactivation

Haematological

Anaemia, neutropenia, lymphopenia, thrombocytopenia

Complete blood count, liver function tests, creatinine and hepatitis B serology; consider hepatitis C serology, immunoglobulin levels, lymphocyte subtypes and tuberculosis screening if not already done

No specific recommendation; consider ECG during and after infusion if history of arrhythmia or significant heart disease; consider lymphocyte subtypes and immunoglobulin levels before re-treatment

Cardiovascular

Hypertension, arrhythmia, peripheral oedema

Respiratory

Bronchospasm, pneumonitis, pulmonary infiltrates, acute respiratory distress syndrome (rare)

Musculoskeletal

Arthralgias, myalgias

Skin

Rash, urticaria

Nervous system

Headache, dizziness, progressive multifocal leukoencephalopathy (rare)

ª 2009 Adis Data Information BV. All rights reserved.

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Table IX. Toxic and adverse effects of abatacept, and guidelines for monitoring its use in patients with rheumatoid arthritis System/organ

Adverse/toxic effect

Baseline evaluation

Monitoring

Systemic

Infection (including serious), infusion reactions, hypersensitivity Nausea, dyspepsia

Complete blood count, liver function tests, creatinine, hepatitis B and C serology, and tuberculosis screening if not already done

No specific recommendation

Gastrointestinal Cardiovascular

Hypertension

Respiratory

Cough, upper respiratory tract infection symptoms

Musculoskeletal

Back pain

Skin

Rash

Nervous system

Headache, dizziness

common adverse events of abatacept are listed in table IX. As with anakinra, combination therapy with TNFa inhibitors is contraindicated because of a higher risk of serious adverse events, including infections, with no significant clinical benefit.[185] 4. Discussion and Conclusion With up to one-third of patients with RA experiencing the first manifestations of the disorder in their older years, and many more who experienced disease onset in their younger years reaching age >60, the elderly represent a significant portion of the whole RA population. The most recent RA treatment guidelines emphasize the importance of early intervention in the disease course using DMARDs to improve functional disability outcomes. There is no specific recommendation regarding age as a limiting factor for use of these agents in the elderly population, and the available evidence suggests that most of these patients do not receive optimal therapy.

Limited available data suggest that some synthetic and biologic DMARDs are as effective in the old as in the young, with little increase in adverse events, especially serious events.

However, pharmacokinetic changes associated with aging, particularly decreased renal function and certain types of drug metabolism, may increase the risk of certain DMARDs. Clinical studies addressing the safety or efficacy of these medications in this age group are lacking, especially studies evaluating the ‘real’ elderly ª 2009 Adis Data Information BV. All rights reserved.

patient with multiple co-morbid conditions and taking numerous medications. For these reasons, special care needs to be taken when prescribing DMARDs to RA patients within this population. This may be of special importance when considering the use of the newer biologic agents as long-term safety data are limited (i.e.

TNFa inhibitors) or non-existent (i.e. abatacept).

Elderly patients with RA should, like their younger counterparts, benefit from early and optimal management of their disease. However, it is becoming increasingly evident that clinical studies in this age group need to be performed before physicians can prescribe synthetic and biologic DMARDs confidently to such patients.

Acknowledgements No sources of funding were used to assist in the preparation of this review. The author has no conflicts of interest that are directly relevant to the content of this review. The author thanks Dr Ine´s Colmegna for her assistance in researching some of the references.

References 1. Sherrer YS, Bloch DA, Mitchell DM, et al. The development of disability in rheumatoid arthritis. Arthritis Rheum 1986 Apr; 29 (4): 494-500 2. Mitchell DM, Spitz PW, Young DY, et al. Survival, prognosis, and causes of death in rheumatoid arthritis.

Arthritis Rheum 1986 Jun; 29 (6): 706-14 3. Michaud K, Wolfe F. Comorbidities in rheumatoid arthritis. Best Pract Res Clin Rheumatol 2007 Oct; 21 (5): 885-906 4. Gabriel SE, Crowson CS, O’Fallon WM. The epidemiology of rheumatoid arthritis in Rochester, Minnesota, 1955-1985. Arthritis Rheum 1999 Mar; 42 (3): 415-20

Drugs Aging 2009; 26 (4)

288

5. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part I. Arthritis Rheum 2008 Jan; 58 (1): 15-25 6. Linos A, Worthington JW, O’Fallon WM, et al. The epidemiology of rheumatoid arthritis in Rochester, Minnesota: a study of incidence, prevalence, and mortality. Am J Epidemiol 1980 Jan; 111 (1): 87-98 7. Terkeltaub R, Esdaile J, Decary F, et al. A clinical study of older age rheumatoid arthritis with comparison to a younger onset group. J Rheumatol 1983 Jun; 10 (3): 418-24 8. van Schaardenburg D, Breedveld FC. Elderly-onset rheumatoid arthritis. Semin Arthritis Rheum 1994 Jun; 23 (6): 367-78 9. Deal CL, Meenan RF, Goldenberg DL, et al. The clinical features of elderly-onset rheumatoid arthritis: a comparison with younger-onset disease of similar duration.

Arthritis Rheum 1985 Sep; 28 (9): 987-94 10. Ferraccioli GF, Cavalieri F, Mercadanti M, et al. Clinical features, scintiscan characteristics and X-ray progression of late onset rheumatoid arthritis. Clin Exp Rheumatol 1984 Apr-Jun; 2 (2): 157-61 11. van der Heijde DM, van Riel PL, van Leeuwen MA, et al.

Older versus younger onset rheumatoid arthritis: results at onset and after 2 years of a prospective follow-up study of early rheumatoid arthritis. J Rheumatol 1991 Sep; 18 (9): 1285-9 12. Tutuncu Z, Kavanaugh A. Rheumatic disease in the elderly: rheumatoid arthritis. Rheum Dis Clin North Am 2007 Feb; 33 (1): 57-70 13. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum 2002 Feb; 46 (2): 328-46 14. O’Dell JR. Therapeutic strategies for rheumatoid arthritis.

N Engl J Med 2004 Jun 17; 350 (25): 2591-602 15. Schmajuk G, Schneeweiss S, Katz JN, et al. Treatment of older adult patients diagnosed with rheumatoid arthritis: improved but not optimal. Arthritis Rheum 2007 Aug 15; 57 (6): 928-34 16. Fraenkel L, Rabidou N, Dhar R. Are rheumatologists’ treatment decisions influenced by patients’ age? Rheumatology (Oxford) 2006 Dec; 45 (12): 1555-7 17. Tutuncu Z, Reed G, Kremer J, et al. Do patients with older-onset rheumatoid arthritis receive less aggressive treatment? Ann Rheum Dis 2006 Sep; 65 (9): 1226-9 18. Kirwan JR, Bijlsma JW, Boers M, et al. Effects of glucocorticoids on radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev 2007 (1): CD006356 19. Beyth RJ, Shorr RI. Principles of drug therapy in older patients: rational drug prescribing. Clin Geriatr Med 2002 Aug; 18 (3): 577-92 20. Ranganath VK, Furst DE. Disease-modifying antirheumatic drug use in the elderly rheumatoid arthritis patient.

Rheum Dis Clin North Am 2007 Feb; 33 (1): 197-217 21. Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol 2003 Aug; 38 (8): 843-53 22. Percy LA, Fang MA. Geropharmacology for the rheumatologist. Rheum Dis Clin North Am 2000 Aug; 26 (3): 433-54, v-vi

ª 2009 Adis Data Information BV. All rights reserved.

Dı´az-Borjo´n

23. Ravikumar R, Anolik J, Looney RJ. Vaccine responses in patients with rheumatoid arthritis. Curr Rheumatol Rep 2007 Oct; 9 (5): 407-15 24. Recommended adult immunization schedule: United States, October 2007-September 2008. Ann Intern Med 2007 Nov 20; 147 (10): 725-9 25. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008 May 30; 59 (6): 762-84 26. Brezinschek HP, Hofstaetter T, Leeb BF, et al. Immunization of patients with rheumatoid arthritis with antitumor necrosis factor alpha therapy and methotrexate. Curr Opin Rheumatol 2008 May; 20 (3): 295-9 27. Visvanathan S, Keenan GF, Baker DG, et al. Response to pneumococcal vaccine in patients with early rheumatoid arthritis receiving infliximab plus methotrexate or methotrexate alone. J Rheumatol 2007 May; 34 (5): 952-7 28. Kapetanovic MC, Saxne T, Nilsson JA, et al. Influenza vaccination as model for testing immune modulation induced by anti-TNF and methotrexate therapy in rheumatoid arthritis patients. Rheumatology (Oxford) 2007 Apr; 46 (4): 608-11 29. Oren S, Mandelboim M, Braun-Moscovici Y, et al. Vaccination against influenza in rheumatoid arthritis patients: the effect of rituximab on the humoral response. Ann Rheum Dis 2008 Jul; 67 (7): 937-41 30. Kremer JM, Genovese MC, Cannon GW, et al. Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized, double-blind, placebo-controlled trial.

Ann Intern Med 2002 Nov 5; 137 (9): 726-33 31. O’Dell JR, Haire CE, Erikson N, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 1996 May 16; 334 (20): 1287-91 32. O’Dell JR. Combination DMARD therapy for rheumatoid arthritis: a step closer to the goal. Ann Rheum Dis 1996 Nov; 55 (11): 781-3 33. O’Dell JR, Haire C, Erikson N, et al. Efficacy of triple DMARD therapy in patients with RA with suboptimal response to methotrexate. J Rheumatol Suppl 1996 Mar; 44: 72-4 34. Boers M, Verhoeven AC, Markusse HM, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997 Aug 2; 350 (9074): 309-18 35. Mottonen T, Hannonen P, Leirisalo-Repo M, et al.

Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial.

FIN-RACo trial group. Lancet 1999 May 8; 353 (9164): 1568-73 36. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, 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 Nov; 52 (11): 3381-90

Drugs Aging 2009; 26 (4)

Use of DMARDs in Elderly Patients with RA

37. Gubner R, August S, Ginsberg V. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am J Med Sci 1951 Feb; 221 (2): 176-82 38. Gubner R. Therapeutic suppression of tissue reactivity: I. Comparison of the effects of cortisone and aminopterin.

Am J Med Sci 1951 Feb; 221 (2): 169-75 39. Thompson RN, Watts C, Edelman J, et al. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J Rheumatol 1984 Dec; 11 (6): 760-3 40. Andersen PA, West SG, O’Dell JR, et al. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double-blind study.

Ann Intern Med 1985 Oct; 103 (4): 489-96 41. Weinblatt ME. Toxicity of low dose methotrexate in rheumatoid arthritis. J Rheumatol Suppl 1985 Dec; 12 Suppl. 12: 35-9 42. Weinblatt ME, Coblyn JS, Fox DA, et al. Efficacy of lowdose methotrexate in rheumatoid arthritis. N Engl J Med 1985 Mar 28; 312 (13): 818-22 43. Williams HJ, Willkens RF, Samuelson Jr CO, et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthritis Rheum 1985 Jul; 28 (7): 721-30 44. Alarcon GS, Lopez-Mendez A, Walter J, et al. Radiographic evidence of disease progression in methotrexate treated and nonmethotrexate disease modifying antirheumatic drug treated rheumatoid arthritis patients: a meta-analysis. J Rheumatol 1992 Dec; 19 (12): 1868-73 45. The effect of age and renal function on the efficacy and toxicity of methotrexate in rheumatoid arthritis.

Rheumatoid Arthritis Clinical Trial Archive Group.

J Rheumatol 1995 Feb; 22 (2): 218-23 46. Wolfe F, Cathey MA. The effect of age on methotrexate efficacy and toxicity. J Rheumatol 1991 Jul; 18 (7): 973-7 47. Bologna C, Viu P, Jorgensen C, et al. Effect of age on the efficacy and tolerance of methotrexate in rheumatoid arthritis. Br J Rheumatol 1996 May; 35 (5): 453-7 48. Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis 2007; 65 (3): 168-73 49. Cronstein BN. The mechanism of action of methotrexate.

Rheum Dis Clin North Am 1997 Nov; 23 (4): 739-55 50. Cronstein BN. Molecular mechanism of methotrexate action in inflammation. Inflammation 1992 Oct; 16 (5): 411-23 51. Drosos A. Methotrexate intolerance in elderly patients with rheumatoid arthritis: what are the alternatives?

Drugs Aging 2003; 20 (10): 723-36 52. Bressolle F, Bologna C, Kinowski JM, et al. Total and free methotrexate pharmacokinetics in elderly patients with rheumatoid arthritis: a comparison with young patients.

J Rheumatol 1997 Oct; 24 (10): 1903-9 53. Sandoval DM, Alarcon GS, Morgan SL. Adverse events in methotrexate-treated rheumatoid arthritis patients.

Br J Rheumatol 1995 Nov; 34 Suppl. 2: 49-56 54. Alarcon GS, Tracy IC, Strand GM, et al. Survival and drug discontinuation analyses in a large cohort of methotrexate

ª 2009 Adis Data Information BV. All rights reserved.

289

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

treated rheumatoid arthritis patients. Ann Rheum Dis 1995 Sep; 54 (9): 708-12 Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis: a metaanalysis of published clinical trials. Arthritis Rheum 1992 Oct; 35 (10): 1117-25 Wernick R, Smith DL. Central nervous system toxicity associated with weekly low-dose methotrexate treatment.

Arthritis Rheum 1989 Jun; 32 (6): 770-5 Buckley LM, Leib ES, Cartularo KS, et al. Effects of low dose methotrexate on the bone mineral density of patients with rheumatoid arthritis. J Rheumatol 1997 Aug; 24 (8): 1489-94 Whittle SL, Hughes RA. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review.

Rheumatology (Oxford) 2004 Mar; 43 (3): 267-71 Ortiz Z, Shea B, Suarez Almazor M, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev 2000; (2): CD000951 Harten P. Reducing toxicity of methotrexate with folic acid [in German]. Z Rheumatol 2005 Jun; 64 (5): 353-8 Morgan SL, Baggott JE, Lee JY, et al. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during longterm, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention. J Rheumatol 1998 Mar; 25 (3): 441-6 Tett S, Cutler D, Day R. Antimalarials in rheumatic diseases. Baillieres Clin Rheumatol 1990 Dec; 4 (3): 467-89 Adams EM, Yocum DE, Bell CL. Hydroxychloroquine in the treatment of rheumatoid arthritis. Am J Med 1983 Aug; 75 (2): 321-6 Clark P, Casas E, Tugwell P, et al. Hydroxychloroquine compared with placebo in rheumatoid arthritis: a randomized controlled trial. Ann Intern Med 1993 Dec 1; 119 (11): 1067-71 Jessop JD, O’Sullivan MM, Lewis PA, et al. A long-term five-year randomized controlled trial of hydroxychloroquine, sodium aurothiomalate, auranofin and penicillamine in the treatment of patients with rheumatoid arthritis. Br J Rheumatol 1998 Sep; 37 (9): 992-1002 Davis MJ, Dawes PT, Fowler PD, et al. Should diseasemodifying agents be used in mild rheumatoid arthritis?

Br J Rheumatol 1991 Dec; 30 (6): 451-4 Avina-Zubieta JA, Galindo-Rodriguez G, Newman S, et al. Long-term effectiveness of antimalarial drugs in rheumatic diseases. Ann Rheum Dis 1998 Oct; 57 (10): 582-7 Sanders M. A review of controlled clinical trials examining the effects of antimalarial compounds and gold compounds on radiographic progression in rheumatoid arthritis. J Rheumatol 2000 Feb; 27 (2): 523-9 Runge LA. Risk/benefit analysis of hydroxychloroquine sulfate treatment in rheumatoid arthritis. Am J Med 1983 Jul 18; 75 (1A): 52-6 Trnavsky K, Gatterova J, Linduskova M, et al. Combination therapy with hydroxychloroquine and methotrexate in rheumatoid arthritis. Z Rheumatol 1993 Sep-Oct; 52 (5): 292-6

Drugs Aging 2009; 26 (4)

290

71. Fox RI. Mechanism of action of hydroxychloroquine as an antirheumatic drug. Semin Arthritis Rheum 1993 Oct; 23 (2 Suppl. 1): 82-91 72. Fox RI, Kang HI. Mechanism of action of antimalarial drugs: inhibition of antigen processing and presentation.

Lupus 1993 Feb; 2 Suppl. 1: S9-12 73. Furst DE. Pharmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases.

Lupus 1996 Jun; 5 Suppl. 1: S11-5 74. Marmor MF, Carr RE, Easterbrook M, et al. Recommendations on screening for chloroquine and hydroxychloroquine retinopathy: a report by the American Academy of Ophthalmology. Ophthalmology 2002 Jul; 109 (7): 1377-82 75. Bernstein HN. Ocular safety of hydroxychloroquine.

Ann Ophthalmol 1991 Aug; 23 (8): 292-6 76. Mackenzie AH. Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials. Am J Med 1983 Jul 18; 75 (1A): 40-5 77. Araiza-Casillas R, Cardenas F, Morales Y, et al. Factors associated with chloroquine-induced retinopathy in rheumatic diseases. Lupus 2004; 13 (2): 119-24 78. Ferris 3rd FL. Senile macular degeneration: review of epidemiologic features. Am J Epidemiol 1983 Aug; 118 (2): 132-51 79. Taggart AJ. Sulphasalazine in arthritis: an old drug rediscovered. Clin Rheumatol 1987 Sep; 6 (3): 378-83 80. Svartz N. Sulfasalazine: II. Some notes on the discovery and development of salazopyrin. Am J Gastroenterol 1988 May; 83 (5): 497-503 81. Sinclair RJG, Duthie JJR. Salazopyrin in the treatment of rheumatoid arthritis. Ann Rheum Dis 1949; 8 (3): 226-31 82. McConkey B, Amos RS, Durham S, et al. Sulphasalazine in rheumatoid arthritis. BMJ 1980 Feb 16; 280 (6212): 442-4 83. Weinblatt ME, Reda D, Henderson W, et al. Sulfasalazine treatment for rheumatoid arthritis: a metaanalysis of 15 randomized trials. J Rheumatol 1999 Oct; 26 (10): 2123-30 84. Sulfasalazine in early rheumatoid arthritis. The Australian Multicentre Clinical Trial Group. J Rheumatol 1992 Nov; 19 (11): 1672-7 85. Hannonen P, Mottonen T, Hakola M, et al. Sulfasalazine in early rheumatoid arthritis: a 48-week double-blind, prospective, placebo-controlled study. Arthritis Rheum 1993 Nov; 36 (11): 1501-9 86. Pincus T, Ferraccioli G, Sokka T, et al. Evidence from clinical trials and long-term observational studies that disease-modifying anti-rheumatic drugs slow radiographic progression in rheumatoid arthritis: updating a 1983 review. Rheumatology (Oxford) 2002 Dec; 41 (12): 1346-56 87. van der Heijde DM, van Riel PL, Nuver-Zwart IH, et al.

Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis.

Lancet 1989 May 13; 1 (8646): 1036-8 88. Haagsma CJ, van Riel PL, de Jong AJ, et al. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial. Br J Rheumatol 1997 Oct; 36 (10): 1082-8

ª 2009 Adis Data Information BV. All rights reserved.

Dı´az-Borjo´n

89. Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet 1999 Jan 23; 353 (9149): 259-66 90. Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis: results of two metaanalyses. Arthritis Rheum 1990 Oct; 33 (10): 1449-61 91. Nuver-Zwart IH, van Riel PL, van de Putte LB, et al.

A double blind comparative study of sulphasalazine and hydroxychloroquine in rheumatoid arthritis: evidence of an earlier effect of sulphasalazine. Ann Rheum Dis 1989 May; 48 (5): 389-95 92. Wilkieson CA, Madhok R, Hunter JA, et al. Toleration, side-effects and efficacy of sulphasalazine in rheumatoid arthritis patients of different ages. Q J Med 1993 Aug; 86 (8): 501-5 93. Dougados M, Combe B, Cantagrel A, et al. Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis 1999 Apr; 58 (4): 220-5 94. Pullar T, Hunter JA, Capell HA. Which component of sulphasalazine is active in rheumatoid arthritis? BMJ (Clin Res Ed) 1985 May 25; 290 (6481): 1535-8 95. Bird HA. Sulphasalazine, sulphapyridine or 5-aminosalicylic acid: which is the active moiety in rheumatoid arthritis?

Br J Rheumatol 1995 Nov; 34 Suppl. 2: 16-9 96. Morabito L, Montesinos MC, Schreibman DM, et al.

Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5’-nucleotidasemediated conversion of adenine nucleotides. J Clin Invest 1998 Jan 15; 101 (2): 295-300 97. Tett SE. Clinical pharmacokinetics of slow-acting antirheumatic drugs. Clin Pharmacokinet 1993 Nov; 25 (5): 392-407 98. Rains CP, Noble S, Faulds D. Sulfasalazine: a review of its pharmacological properties and therapeutic efficacy in the treatment of rheumatoid arthritis. Drugs 1995 Jul; 50: 137-56 99. Pullar T, Hunter JA, Capell HA. Effect of acetylator phenotype on efficacy and toxicity of sulphasalazine in rheumatoid arthritis. Ann Rheum Dis 1985 Dec; 44 (12): 831-7 100. Kitas GD, Farr M, Waterhouse L, et al. Influence of acetylator status on sulphasalazine efficacy and toxicity in patients with rheumatoid arthritis. Scand J Rheumatol 1992; 21 (5): 220-5 101. Taggart AJ, McDermott B, Delargy M, et al. The pharmacokinetics of sulphasalazine in young and elderly patients with rheumatoid arthritis. Scand J Rheumatol Suppl 1987; 64: 29-36 102. Figlin E, Chetrit A, Shahar A, et al. High prevalences of vitamin B12 and folic acid deficiency in elderly subjects in Israel. Br J Haematol 2003 Nov; 123 (4): 696-701 103. Bartlett RR, Schleyerbach R. Immunopharmacological profile of a novel isoxazol derivative, HWA 486, with potential antirheumatic activity: I. Disease modifying action on adjuvant arthritis of the rat. Int J Immunopharmacol 1985; 7 (1): 7-18

Drugs Aging 2009; 26 (4)

Use of DMARDs in Elderly Patients with RA

104. Mladenovic V, Domljan Z, Rozman B, et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis: results of a randomized, placebo-controlled, phase II study. Arthritis Rheum 1995 Nov; 38 (11): 1595-603 105. Strand V, Cohen S, Schiff M, et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 1999 Nov 22; 159 (21): 2542-50 106. Emery P, Breedveld FC, Lemmel EM, et al. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2000 Jun; 39 (6): 655-65 107. Cohen S, Cannon GW, Schiff M, et al. Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group. Arthritis Rheum 2001 Sep; 44 (9): 1984-92 108. Olivieri I, Palazzi C, Peruz G, et al. Management issues with elderly-onset rheumatoid arthritis: an update. Drugs Aging 2005; 22 (10): 809-22 109. Chan J, Sanders DC, Du L, et al. Leflunomide-associated pancytopenia with or without methotrexate. Ann Pharmacother 2004 Jul-Aug; 38 (7-8): 1206-11 110. Williams HJ, Ward JR. Comparison of oral and parenteral gold therapy and placebo in the treatment of rheumatoid arthritis. Scand J Rheumatol Suppl 1983; 51: 92-9 111. Ward JR, Williams HJ, Boyce E, et al. Comparison of auranofin, gold sodium thiomalate, and placebo in the treatment of rheumatoid arthritis: subsets of responses.

Am J Med 1983 Dec 30; 75 (6A): 133-7 112. Jones G, Brooks PM. Injectable gold compounds: an overview. Br J Rheumatol 1996 Nov; 35 (11): 1154-8 113. Katz WA, Alexander S, Bland JH, et al. The efficacy and safety of auranofin compared to placebo in rheumatoid arthritis. J Rheumatol Suppl 1982 Jul-Aug; 8: 173-8 114. Tozman EC, Gottlieb NL. Adverse reactions with oral and parenteral gold preparations. Med Toxicol 1987 May-Jun; 2 (3): 177-89 115. Glennas A, Kvien TK, Andrup O, et al. Auranofin is safe and superior to placebo in elderly-onset rheumatoid arthritis. Br J Rheumatol 1997 Aug; 36 (8): 870-7 116. Bluhm GB. The mechanisms of action of conventional chrysotherapy. J Rheumatol Suppl 1982 Jul-Aug; 8: 10-7 117. Lorber A, Jackson WH, Simon TM. Effects of chrysotherapy on cell mediated immune response. J Rheumatol Suppl 1982 Jul-Aug; 8: 37-45 118. Nixon J, Pande I. Gold, nitritoid reactions and angiotensinconverting enzyme inhibitors. Rheumatology (Oxford) 2006 Jan; 45 (1): 118-9 119. Munthe E, Kass E. Penicillamine in rheumatic diseases: a prospective study of tolerance and efficacy. J Rheumatol Suppl 1981 Jan-Feb; 7: 107-11 120. Williams HJ, Ward JR, Reading JC, et al. Low-dose D-penicillamine therapy in rheumatoid arthritis: a controlled, double-blind clinical trial. Arthritis Rheum 1983 May; 26 (5): 581-92

ª 2009 Adis Data Information BV. All rights reserved.

291

121. Lipsky PE, Ziff M. Inhibition of human helper T cell function in vitro by D-penicillamine and CuSO4. J Clin Invest 1980 May; 65 (5): 1069-76 122. Jaffe IA. Comparison of the effect of plasmapheresis and penicillamine on the level of circulating rheumatoid factor. Ann Rheum Dis 1963 Mar; 22: 71-6 123. Dahl SL, Samuelson CO, Williams HJ, et al. Second-line antirheumatic drugs in the elderly with rheumatoid arthritis: a post hoc analysis of three controlled trials.

Pharmacotherapy 1990; 10 (2): 79-84 124. Kloppenburg M, Breedveld FC, Terwiel JP, et al. Minocycline in active rheumatoid arthritis: a double-blind, placebo-controlled trial. Arthritis Rheum 1994 May; 37 (5): 629-36 125. Tilley BC, Alarcon GS, Heyse SP, et al. Minocycline in rheumatoid arthritis: a 48-week, double-blind, placebocontrolled trial. MIRA Trial Group. Ann Intern Med 1995 Jan 15; 122 (2): 81-9 126. O’Dell JR, Haire CE, Palmer W, et al. Treatment of early rheumatoid arthritis with minocycline or placebo: results of a randomized, double-blind, placebo-controlled trial.

Arthritis Rheum 1997 May; 40 (5): 842-8 127. O’Dell JR, Paulsen G, Haire CE, et al. Treatment of early seropositive rheumatoid arthritis with minocycline: four-year followup of a double-blind, placebo-controlled trial. Arthritis Rheum 1999 Aug; 42 (8): 1691-5 128. O’Dell JR, Blakely KW, Mallek JA, et al. Treatment of early seropositive rheumatoid arthritis: a two-year, double-blind comparison of minocycline and hydroxychloroquine. Arthritis Rheum 2001 Oct; 44 (10): 2235-41 129. Bluhm GB, Sharp JT, Tilley BC, et al. Radiographic results from the Minocycline in Rheumatoid Arthritis (MIRA) Trial. J Rheumatol 1997 Jul; 24 (7): 1295-302 130. Amin AR, Attur MG, Thakker GD, et al. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci U S A 1996 Nov 26; 93 (24): 14014-9 131. Alarcon GS. Tetracyclines for the treatment of rheumatoid arthritis. Expert Opin Investig Drugs 2000 Jul; 9 (7): 1491-8 132. Fanning WL, Gump DW. Distressing side-effects of minocycline hydrochloride. Arch Intern Med 1976 Jul; 136 (7): 761-2 133. Jones G, Halbert J, Crotty M, et al. The effect of treatment on radiological progression in rheumatoid arthritis: a systematic review of randomized placebo-controlled trials. Rheumatology (Oxford) 2003 Jan; 42 (1): 6-13 134. Pasero G, Priolo F, Marubini E, et al. Slow progression of joint damage in early rheumatoid arthritis treated with cyclosporin A. Arthritis Rheum 1996 Jun; 39 (6): 1006-15 135. Tugwell P, Pincus T, Yocum D, et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. The Methotrexate-Cyclosporine Combination Study Group. N Engl J Med 1995 Jul 20; 333 (3): 137-41 136. Kovarik JM, Koelle EU. Cyclosporin pharmacokinetics in the elderly. Drugs Aging 1999 Sep; 15 (3): 197-205 137. Gremese E, Ferraccioli GF. Benefit/risk of cyclosporine in rheumatoid arthritis. Clin Exp Rheumatol 2004 Sep-Oct; 22 (5 Suppl. 35): S101-7

Drugs Aging 2009; 26 (4)

Dı´az-Borjo´n

292

138. Urowitz MB, Gordon DA, Smythe HA, et al. Azathioprine in rheumatoid arthritis: a double-blind, cross over study.

Arthritis Rheum 1973 May-Jun; 16 (3): 411-8 139. Gordon DA, Urowitz MB. Use of azathioprine for rheumatoid arthritis. Arthritis Rheum 1982 Oct; 25 (10): 1269-70 140. van Wanghe P, Dequeker J. Compliance and long-term effect of azathioprine in 65 rheumatoid arthritis cases.

Ann Rheum Dis 1982; 41 Suppl. 1: 40-3 141. Suarez-Almazor ME, Spooner C, Belseck E. Azathioprine for treating rheumatoid arthritis. Cochrane Database Syst Rev 2000 (4): CD001461 142. Jeurissen ME, Boerbooms AM, van de Putte LB, et al.

Methotrexate versus azathioprine in the treatment of rheumatoid arthritis: a forty-eight-week randomized, double-blind trial. Arthritis Rheum 1991 Aug; 34 (8): 961-72 143. Sambrook PN, Champion GD, Browne CD, et al.

Comparison of methotrexate with azathioprine or 6-mercaptopurine in refractory rheumatoid arthritis: a life-table analysis. Br J Rheumatol 1986 Nov; 25 (4): 372-5 144. Heurkens AH, Westedt ML, Breedveld FC. Prednisone plus azathioprine treatment in patients with rheumatoid arthritis complicated by vasculitis. Arch Intern Med 1991 Nov; 151 (11): 2249-54 145. Elion GB. The George Hitchings and Gertrude Elion Lecture: the pharmacology of azathioprine. Ann N Y Acad Sci 1993; 685: 400-7 146. Kennedy DT, Hayney MS, Lake KD. Azathioprine and allopurinol: the price of an avoidable drug interaction.

Ann Pharmacother 1996 Sep; 30 (9): 951-4 147. Zhou H. Clinical pharmacokinetics of etanercept: a fully humanized soluble recombinant tumor necrosis factor receptor fusion protein. J Clin Pharmacol 2005 May; 45: 490-7 148. Klotz U, Teml A, Schwab M. Clinical pharmacokinetics and use of infliximab. Clin Pharmacokinet 2007; 46 (8): 645-60 149. Weisman MH, Moreland LW, Furst DE, et al. Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study. Clin Ther 2003 Jun; 25 (6): 1700-21 150. Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein.

N Engl J Med 1997 Jul 17; 337 (3): 141-7 151. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999 Mar 16; 130 (6): 478-86 152. Elliott MJ, Maini RN, Feldmann M, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994 Oct 22; 344 (8930): 1105-10 153. van de Putte LB, Atkins C, Malaise M, et al. Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modify-

ª 2009 Adis Data Information BV. All rights reserved.

154.

155.

156.

157.

158.

159.

160.

161.

162.

163.

164.

165.

166.

167.

ing antirheumatic drug treatment has failed. Ann Rheum Dis 2004 May; 63 (5): 508-16 Maini RN, Feldmann M. How does infliximab work in rheumatoid arthritis? Arthritis Res 2002; 4 Suppl. 2: S22-8 Klareskog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004 Feb 28; 363 (9410): 675-81 Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, randomized, doubleblind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006 Jan; 54 (1): 26-37 Bathon JM, Fleischmann RM, Van der Heijde D, et al.

Safety and efficacy of etanercept treatment in elderly subjects with rheumatoid arthritis. J Rheumatol 2006 Feb; 33 (2): 234-43 Fleischmann RM, Baumgartner SW, Tindall EA, et al.

Response to etanercept (Enbrel) in elderly patients with rheumatoid arthritis: a retrospective analysis of clinical trial results. J Rheumatol 2003 Apr; 30 (4): 691-6 Fleischmann R, Baumgartner SW, Weisman MH, et al.

Long term safety of etanercept in elderly subjects with rheumatic diseases. Ann Rheum Dis 2006 Mar; 65 (3): 379-84 Chevillotte-Maillard H, Ornetti P, Mistrih R, et al. Survival and safety of treatment with infliximab in the elderly population. Rheumatology (Oxford) 2005 May; 44 (5): 695-6 Schneeweiss S, Setoguchi S, Weinblatt ME, et al. Antitumor necrosis factor alpha therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis Rheum 2007 Jun; 56 (6): 1754-64 Bresnihan B, Alvaro-Gracia JM, Cobby M, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998 Dec; 41 (12): 2196-04 Cohen S, Hurd E, Cush J, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002 Mar; 46 (3): 614-24 Kineret (anakinra) [summary of product characteristics].

Stockholm: Biovitrum AB (publ), 2003 Cush JJ. Safety overview of new disease-modifying antirheumatic drugs. Rheum Dis Clin North Am 2004 May; 30 (2): 237-55, v Genovese MC, Cohen S, Moreland L, et al. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 2004 May; 50 (5): 1412-9 Weyand CM, Goronzy JJ, Takemura S, et al. Cell-cell interactions in synovitis: interactions between T cells and B cells in rheumatoid arthritis. Arthritis Res 2000; 2 (6): 457-63

Drugs Aging 2009; 26 (4)

Use of DMARDs in Elderly Patients with RA

168. Martin F, Chan AC. B cell immunobiology in disease: evolving concepts from the clinic. Annu Rev Immunol 2006; 24: 467-96 169. Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy.

Arthritis Rheum 2003 Jun; 48 (6): 1484-92 170. Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004 Jun 17; 350 (25): 2572-81 171. Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.

Arthritis Rheum 2006 Sep; 54 (9): 2793-806 172. Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994 Jan 15; 83 (2): 435-45 173. Mathas S, Rickers A, Bommert K, et al. Anti-CD20- and B-cell receptor-mediated apoptosis: evidence for shared intracellular signaling pathways. Cancer Res 2000 Dec 15; 60 (24): 7170-6 174. Wood AM. Rituximab: an innovative therapy for nonHodgkin’s lymphoma. Am J Health Syst Pharm 2001 Feb 1; 58 (3): 215-29 175. Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005 Jun 20; 23 (18): 4117-26 176. Furst DE, Breedveld FC, Kalden JR, et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2007. Ann Rheum Dis 2007 Nov; 66 Suppl. 3: iii2-22 177. Soriano ER, Galarza-Maldonado C, Cardiel MH, et al.

Use of rituximab for the treatment of rheumatoid

ª 2009 Adis Data Information BV. All rights reserved.

293

178.

179.

180.

181.

182.

183.

184.

185.

arthritis: the Latin American context. Rheumatology (Oxford) 2008 Jul; 47 (7): 1097-9 Linsley PS, Ledbetter JA. The role of the CD28 receptor during T cell responses to antigen. Annu Rev Immunol 1993; 11: 191-212 Dumont FJ. Technology evaluation: abatacept, BristolMyers Squibb. Curr Opin Mol Ther 2004 Jun; 6 (3): 318-30 Reiser H, Stadecker MJ. Costimulatory B7 molecules in the pathogenesis of infectious and autoimmune diseases.

N Engl J Med 1996 Oct 31; 335 (18): 1369-77 Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003 Nov 13; 349 (20): 1907-15 Moreland LW, Alten R, Van den Bosch F, et al. Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion. Arthritis Rheum 2002 Jun; 46 (6): 1470-9 Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005 Sep 15; 353 (11): 1114-23 Orencia (abatacept) [product information]. Princeton (NJ): Bristol-Myers Squibb Company, 2008 Apr Weinblatt M, Schiff M, Goldman A, et al. Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial. Ann Rheum Dis 2007 Feb; 66 (2): 228-34

Correspondence: Dr Alejandro Dı´az-Borjo´n, Vialidad de la Barranca s/n, cons. 860, Col. Valle de las Palmas, C.P. 52787, Huixquilucan, Edo. Me´x., Me´xico.

E-mail: adiazborjon@hotmail.com

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