RETRACTED. The treatment of rheumatoid arthritis. Lee S. Simon* MD

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1 4 The treatment of rheumatoid arthritis Lee S. Simon* MD Best Practice & Research Clinical Rheumatology Vol. 18, No. 4, pp , 2004 doi: /j.berh available online at Associate Clinical Professor of Medicine Beth Israel Deaconess Medical Center, Harvard Medical School, 110 Francis St Suite 4B, Boston, MA 02215, USA The treatment of rheumatoid arthritis has changed dramatically in the last 10 years and in parallel the definition and expectations of patients and clinicians of the effects of disease-modifying antirheumatic agents has changed as well. Current expectations of efficacy now include improvement of signs and symptoms of disease activity as well as slowing, if not complete inhibition, of disease progression as measured by X-ray progression along with significant improvement in patient physical function. In addition, clinicians assess the safety profile of these agents more critically in an attempt to improve the risk:benefit profile. Drugs, such as methotrexate, sulfasalazine and leflunomide have provided patients with substantial relief of symptoms and improvement in terms of X-ray progression, but they have been hampered by the occurrence of significant adverse events along with the inability to maintain benefit for prolonged periods of time. With the increased understanding of the basic biological mechanisms of the disease process, there has been the introduction of four biological disease modifying therapies and other drugs into clinical practice, which have altered aspects of the risk:benefit ratio for patients with various rheumatic diseases. Key words: disease modifying anti-rheumatic drugs; methotrexate; leflunomide; sulfasalazine; biological response modifiers; etanercept; infliximab; anakinra; adalimumab. Rheumatoid arthritis (RA) is a disease that affects people in their prime of life, predominantly between the ages of years of age, with a clear preference for women. The disease is quite heterogeneous with an unpredictable course. However, in general it leads, if unchecked, to the destruction of the tissues within joints and consequent physical disability in the great majority. Therapy has been targeted towards the treatment of the signs and symptoms of the disease as well as towards changing its natural history. Without disease modifying therapy patients with this disease do not enjoy an adequate health-related quality of life nor a normal life span. Unfortunately, although there are drugs that have been shown to improve signs and symptoms, alter the natural history of the disease and improve quality of life there is still no cure. In addition, these available therapies are associated with risks including the potential risk of death or irreversible organ damage. The challenge for society is to balance these * Tel.: þ ; Fax: þ address: lsimon@bidmc.harvard.edu (L.S. Simon) /$ - see front matter Q 2004 Published by Elsevier Ltd.

2 508 L. S. Simon known potential risks of therapy with the acknowledged benefits despite the fact that these drugs do not lead to a cure. Prior to 1998 there was a limited repertoire of therapies available that fulfilled the characteristics of a disease-modifying anti-rheumatic drug (DMARD). Those therapies included cyclophosphamide, intramuscular gold, anti-malarial therapy, sulfasalazine, azathioprine, 6-mercaptopurine and methotrexate (MTX). Although available as a chemotherapeutic agent for many years, it was not until 1988 that MTX was popularised at relatively low dose (7.5 mg per week) as a chronic treatment for RA. Approval of methotrexate for improving the signs and symptoms of RA soon followed, but it was within the development programme for leflunomide that both sulfasalzine and MTX have been most rigorously studied. All of the available therapies to treat RA possess potential inherent risks. The nonselective non-steroidal anti-inflammatory drugs (NSAIDs), which are not presently thought to have important effects on the natural history of the disease, are known to induce significant damage to the upper and lower gastrointestinal tract, which is related to the primary biological mechanism of action of the drugs. DMARDs similarly possess risks. These risks are mostly related to the inherent mode of action of the drug such as bone marrow suppression with cytotoxic therapies, although idiosyncratic events or direct effects of a specific drug on an organ, such as heavy metal damage to the kidneys associated with gold therapy, might be observed. Data accumulated during the period before 1998 demonstrated that few patients were tolerant and therapeutically responsive for long periods of time. Thus, it was common for patients to require various agents during the life of their active disease. With the advent of MTX patients began to stay on therapy for longer periods. However, even the relatively low dose of MTX used to treat RA was associated with significant risks including infection, infiltrative pulmonary disease, particularly in those patients who suffered from obesity or diabetes mellitus, or chronic progressive cirrhosis with or without antecedent drug-induced hepatitis. Other risks associated with specific therapies included (1) cyclophosphamide-induced leukaemia, urinary tract cancers, or bone marrow suppression leading to infection; (2) IM gold-induced heavy metal kidney damage, skin reactions, bowel disease, vasculitis; or (3) sulfasaslazine-induced skin reactions and/or hepatitis. Thus, the use of DMARDs is important and should be considered as early as possible once a diagnosis has been confirmed, the available therapies require chronic use and are not without potential toxic effects. This chapter will review the approach to the patient with RA and the various drugs that are considered to be DMARDs. Not all of these drugs are available throughout the world and several, particularly the biological disease modifiers (or Biological Response Modifiers (BRMs)) are prohibitively expensive. The evaluation of the available therapies is limited by the outcome measures and the design of the clinical trials used to achieve regulatory approval throughout the world. Typically, we are reliant on studies that compare a new therapy against the effects of standard of care (SOC) in patients who have been poor responders up until entering the inception cohort of the study. This generates a study design that requires patients to be given either SOC plus placebo versus the study drug plus SOC. This combination study approach significantly limits the understanding of risk and benefit of the study drug. Furthermore, the benefit of drugs such as the BRMs may not be adequately measured by the usual outcome measures. The American College of Rheumatology (ACR) 20 measure is a per patient composite responder score that requires a 20% improvement in the assessed tender and swollen joint count as well as three out of the following five measures: (1) the physician

3 The treatment of rheumatoid arthritis 509 global analysis of response, (2) a patient global analysis of response, (3) a visual analogue scale that measures pain at the moment of measure, (4) applying the results of a patient reported outcome: the Health Assessment Questionaire Disability Index (HAQ DI), and (5) either an erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) value. The tumour necrosis factor alpha (TNF-a) inhibitors are particularly good therapies for improving the overall sense of illness and fatigue, neither of which are measured in the ACR 20 responder index. RA is a systemic inflammatory disease of unknown cause with much of its pathobiology being manifested within the joint tissues. It is believed that in the right genetic host, some environmental event, perhaps a common virus, will precipitate a series of responses which culminate in the initiation of a serious inflammatory disease primarily invested in the joint, but with many systemic features. This process is highly complex and may lead to elaboration of a series of cells and cytokines that, ultimately, leads to the destruction of soft tissues, bone and cartilage within the joint and significant disability in the untreated or undertreated patient. These changes are now known to be time-dependant, so there is an imperative to establish the correct diagnosis so that the appropriate aggressive therapies can be considered. Untreated, the disease is characterised by a chronic, symmetrical progressive polyarthritis that typically affects synovial joints. It has systemic effects including fatigue, low-grade fever, the development of anaemia of chronic disease and, occasionally, serositis and a systemic vasculitis. 1 RA has been described worldwide with an approximate prevalence of 1% in the adult population. The age distribution is unimodal with the peak age at onset being between the third and sixth decades of life. Women are twice as likely to have the disease. 2,3 Mortality is increased in patients with RA 4,5, with the mean life expectancy being shortened by 7 years in males and 3 years in females. 6 Death most often results from infection, heart disease, respiratory failure, renal failure and gastrointestinal disease, although it is possible that some of these fatal events may be enhanced due to choice of therapy. Patients are prone to premature atherosclerosis. 7 As a chronic disabling condition, one of the most important economic outcomes is work disability, with rates of work disability in the USA and Europe ranging from 22 to 85% and 31 to 80%, respectively. 8 Historically, clinicians were relegated to using palliative agents to decrease pain and inflammation, but with an improved understanding of the basic pathobiology, targeted therapies have been developed that not only improve the signs and symptoms of the disease but also alter its natural history in many patients. Now, the primary goals of management of RA not only include the alleviation of pain, the reduction of inflammation, but they also require early preservation of joint function, prevention of joint damage and maintenance of a stable or improved health-related quality of life. 9 This approach reverses the concept of a traditional treatment pyramid. It was believed that a conservative approach was appropriate given the poor ability to diagnose and the knowledge that early disease modifying therapies were potentially quite toxic. Thus the benefit to risk ratio only warranted many of these drugs to be administered to the sicker patients. However, we have therapies with significantly improved benefit to risk ratios thus warranting more aggressive use earlier in the disease course, thus inverting the classic treatment pyramid. DMARDs are drugs that, in randomized controlled trials, have been demonstrated to alter not only pain, evidence of inflammation but also to inhibit X-ray progression and improve physical function. 10 Many of these therapies have been also shown to be useful in combination thus targeting different aspects of the complex inflammatory

4 510 L. S. Simon cascade. Some of these therapies have been termed BRMs and are DMARDs. With their development they have altered the overall landscape of therapy. For many years the traditional pyramidal approach to the treatment of RA was to provide symptomatic relief with aspirin or non-steroidal anti-inflammatory drugs (NSAIDs). As the disease progressed, usually after an average of 4 years, physicians would add traditional DMARDs and/or various doses of glucocorticoids. These later, powerful, anti-inflammatory agents were thought initially to be miracle drugs and may well be classic DMARDs, but the risk of their use over the longer term at significant dose is not warranted. The NSAIDs were developed to replace glucocorticoids and, although efficacious, they did not alter the natural history of the disease and were identified with a unique series of adverse events including a significant risk of gastrointestinal bleeding and resultant death. The most commonly used early DMARDs included parenteral gold, sulfasalazine, MTX and, more recently, leflunomide. This chapter will first examine the efficacy of individual DMARD therapies, then when used in combination with other drugs. It is not that NSAIDs or their conjoiners should not be used. Rather, since they do not alter the natural history of the disease and we now know that aggressive early therapy with the appropriate drugs that do alter the disease progression will alter the ultimate outcome, then this chapter will review the evidence for the benefit to risk ratio of DMARDs, whether as drugs or biological modifiers. First will be a review of efficacy and then a review of safety for each therapy. Furthermore, given the newly available targeted biological therapies, the chapter will separately review drugs and biological BRMs. EFFICACY Available drug monotherapy Gold therapy Parenteral organic gold compounds have been used since the 1920s for the treatment of rheumatoid arthritis. 10 They were commonly used to treat certain bacterial infections and the aetiology of RA was considered to probably be associated with such an infection. Its clinical efficacy has been shown in double-blind studies 11,12 and its radiographical efficacy was demonstrated 12,13 by a decrease in Total Sharp Score (TSS), a measure of X-ray damage. 14,15 The dilemma was that some patients did benefit but, on balance, it was used with great care. Even today there are patients maintained on this relatively inexpensive therapy. Requiring weekly intramuscular injections with a test dose of 10 mg followed by 25 mg the next week, with several months at least of 50 mg a week until either toxicity ensues or a response was achieved. At that point either the drug was stopped or if responsive, then the patient would be converted slowly to achieve a monthly maintenance injection. As noted below, this approach required weekly blood and urine tests for at least the first 6 months. Due to these potential problems, an oral gold drug was developed. Unfortunately, this was not very efficacious and although the safety signals were improved, the drug benefit to risk ratio did not warrant continued use. Sulfasalazine Early uncontrolled trials in the late 1940s demonstrated the efficacy of sulfasalazine, a condensation product of a salicylate moiety and a sulpha-containing

5 The treatment of rheumatoid arthritis 511 Table 1. Summary of ACR response rates for leflunomide, sulfasalzine and methotrexate. Study and treatment group ACR 20% ACR 50% ACR 70% Placebo-controlled studies US301 (12 months) Leflunomide ðn ¼ 178Þ a 52.2 b 34.3 b 20.2 b Placebo ðn ¼ 118Þ a Methotrexate ðn ¼ 180Þ MN301(6 months) Leflunomide ðn ¼ 130Þ a 54.6 b 33.1 b 10.0 c Placebo ðn ¼ 91Þ a Sulfasalazine ðn ¼ 132Þ a Non-placebo active-controlled studies MN302 (12 months) Leflunomide ðn ¼ 495Þ a Methotrexate ðn ¼ 489Þ a Intent to treat (ITT) analysis using last observation carried forward (LOCF) technique for patients who discontinued early. a n is the number of ITT patients for whom adequate data were available to calculate the indicated rates. b P, 0:001 leflunomide versus placebo. c P, 0:02 leflunomide versus placebo. antibiotic, which was later confirmed in controlled trials More recently, two of these trials 26,27 showed delay of radiographical progression when compared to placebo. In a meta-analysis 28, sulfasalazine was comparable in efficacy to gold, D-Penicillamine and MTX. The exact mechanism of action is unknown, but it is known that it alters folate metabolism thus altering cell activity. Although initially developed for use in RA, early efficacy trials were not supportive and this drug was then developed for use in inflammatory bowel disease. With few drugs available, the drug was first resurrected in Europe where it has been used in early mild cases of RA. Although not well defined, there are two ways to dose this drug. One would be to begin at a higher dose of between 3 and 4 g in 24 hour in a split dose and then to decrease to a maintenance dose of 2 g per day. Table 1 shows data from some of the most rigorous studies of sulfasalazine comparing the effects with either MTX or leflunomide. Immunomodulatory, immunosuppressant and anti-metabolite therapies In the early 1960s there was significant interest in developing drugs that had been used in cancer treatment to treat patients with RA. Cyclophosphamide, azathioprine and chlorambucil were all considered and demonstrated variable efficacy results but quite impressive tolerability problems and safety signals. MTX was a more complex drug with similar effects at high dose as the previously named therapies, but at low weekly doses it had much fewer potentially adverse effects with interesting anti-inflammatory and DMARD actions. Four double-blind, randomised, placebo controlled trials with oral or intra-muscular MTX showed superior efficacy to placebo Many other studies have confirmed its efficacy It has become the gold standard by which all new DMARD therapies for RA are judged A meta-analysis showed that MTX is superior in efficacy to hydroxychloroquine and oral gold and comparable to sulfasalazine,

6 512 L. S. Simon intra-muscular gold, D-Penicillamine and leflunomide in efficacy. 28,42 Healing of erosions as well as slowing of disease progression has been documented with MTX. Prospective long-term studies have shown that MTX is better tolerated and more efficacious than the older DMARDs. In addition, a higher percentage of patients remain 40,51 53 on MTX for a longer period of time when compared to these other DMARDs. At the time of these studies there were few alternatives available to patients who had a partial response to MTX but still had active disease. Recent studies have shown that the durability of MTX is approximately 1 year. 42 The dose that has been used has changed significantly over time. Initially, a low dose of 7.5 mg was used, but more aggressive dosing as early as possible has been linked with better outcomes. Thus, patients are now more often started at 10 mg or higher, with rapid escalation to oral or parenteral doses of mg per week. Table 1 shows data from some of the most rigorous studies of MTX comparing its effects with either sulfasalazine or leflunomide. The mechanism of action remains unclear, although MTX is known to competitively inhibit the actions of folic acid as well as to inhibit adenosine. As noted below, the concomitant use of folic acid at low dose (1 mg per day) may decrease many of the tolerability problems associated with chronic MTX use while decreasing efficacy only minimally. Leflunomide Leflunomide is an immunomodulatory drug that was developed in the early 1980s. It affected the immune response though inhibiting cell activation by altering the enzymes important for the activation of T cells. Leflunomide was studied in the last series of randomized clinical trials (RCTs) that included a true placebo (Table 1). Three pivotal trials were designed and carried out in Europe and in the USA. These studies evaluated patients with various different disease courses. In addition, in the USA, the patients studied were DMARD naïve typically with less than 3 years of disease. Furthermore, folic acid supplementation for the MTX treated patients was included as a requirement in the USA (US 301), but this was not done in the European trials. One placebocontrolled trial compared leflunomide, MTX and placebo for 52 weeks. 42 ACR response rates of 52, 48 and 26% and ACR 50 response rates of 34, 23 and 8% for leflunomide, MTX and placebo, respectively, were seen. The responses with leflunomide and MTX were statistically equivalent and significantly greater than placebo. Several multinational trials have confirmed these results A 24-week double-blind, randomised, controlled trial comparing leflunomide, sulfasalazine and placebo showed ACR 20 response rates of 55, 56 and 29% and ACR 50 response rates of 33, 30 and 14% for leflunomide, sulfasalazine and placebo, respectively. 56 Leflunomide treated patients had improved function as assessed by the HAQ when compared to sulfasalazine or MTX. Leflunomide, sulfasalazine and MTX all significantly retarded X-ray progression compared with placebo, with the degree of X-ray progression being significantly less with leflunomide than with MTX or sulfasalazine. 50,59,60 Two trials explored the combination of leflunomide with MTX. Both showed a significant clinical improvement when using the combination in those patients who were partial responders initially to MTX alone. 61,62 Glucocorticoid therapy As described above, when synthetic glucocorticoids were applied to patients with intractable RA, the patient response was considered to be a miracle. Unfortunately, with long term use the potentially adverse effects are thought to be, on balance,

7 not worth the benefit. This is despite accumulated evidence that glucocorticoids are DMARDs even at a low dose, which would decrease the potential for adverse events. Today glucocorticoids are used in combination therapy with other drugs and are used typically at doses of less than 10 mg per day. However, some investigators have argued that giving high dose glucocorticoids initially, with a relatively rapid taper would be even more efficacious. 63 Combination drug therapy Various different combination therapies have been tried with variable success. These might include combining hydroxychloroquine with MTX and glucocorticoids or some variation of these three therapies. In some constructs only two drugs are combined, for example MTX with leflunomide. The COBRA Study uniquely approached the question with initially aggressive therapy that was then tapered to a maintenance approach. In a double-blind, randomised, step-down design trial, the combination of sulfasalazine 500 mg/day (increased to 2000 mg/day over 3 weeks), MTX 7.5 mg/week and a prednisolone taper was compared with sulfasalazine alone in 155 patients with early RA. 63 After 40 weeks, patients were treated solely with sulfasalazine, since prednisolone was discontinued after 28 weeks and MTX after 40 weeks. A total of 72% of the patients in the combination therapy group achieved an ACR 20, compared with 49% in the sulfasalazine group. Radiological evaluation after 28 weeks of treatment showed that 31% of patients in the combination group had a stable Sharp s score compared to only 13% in the sulfasalazine group. TARGETED THERAPIES WITH BIOLOGICAL RESPONSE MODIFIERS Introduction The treatment of rheumatoid arthritis 513 It has become clear that TNF-a and interleukin-1 (IL-1) play pivotal roles in the inflammation and joint damage of RA. 64 High levels of TNF-a and IL-1 are found in the synovial fluid of RA patients. These cytokines have been shown to stimulate resorption of cartilage and inhibit synthesis of proteoglycan Both are potent stimulators of the synovial fibroblasts, chondrocytes and osteoclastogenesis that is associated with the release of matrix metalloproteinases and both inhibit the production of tissue inhibitors of metalloproteinases by synovial fibroblasts. These effects contribute to progressive damage to the joint along with consequent loss of function. TNF-a probably also stimulates the production of IL-11 and the RANK ligand, inducing the development of osteoclastogenesis and further activating the generated osteoclasts thus leading to increased systemic bone resorption as well as bone destruction in the joint. 69 In addition, TNF-a stimulates the expression of adhesion molecules such as intercellular adhesion molecule 1(ICAM-1), resulting in increased transport of leukocytes into the joint. 70 IL-1 is produced by monocytes, macrophages, endothelial cells, B cells and activated T cells. Injection of IL-1 into the knee joints of rabbits results in the degradation of cartilage. 70 TNF-a has a central role in the cascade of RA, since it has been shown that in cultures of synovial cells from RA patients that were treated with TNF-a antibodies, there was a significant reduction in IL-1, IL-6 and IL-8 as well as in granulocytemonocyte colony stimulating factor. 71

8 514 L. S. Simon Anakinra Anakinra is a recombinant human IL-1 receptor antagonist. By binding with the IL-1 receptor, it prevents the binding of IL-1 to the receptor and its accessory protein, thereby preventing target cell signalling. It has an extremely short half-life, a few hours only, and must occupy virtually all of the IL-1 receptors to be effective. 72 As a result daily injections are required and it is significantly limited in its efficacy even if only one molecule of IL-1 binds to its receptor. The efficacy of anakinra has been evaluated as a monotherapy as well as in combination with other drugs. In a placebo-controlled study, patients received placebo or anakinra at 30, 75 or 150 mg/day. 73 In the 150-mg/day group, 43% of patients obtained an ACR 20 response, compared with 27% of patients in the placebo group. It was also shown that anakinra therapy produced a clinically significant improvement in patient function. The clinical response to anakinra was maintained over a period of 76 weeks. 74 Evaluation of X-ray benefit using the Modified Sharp score analysis demonstrated a 58% slowing in the rate of progression of joint space narrowing and a 38% slowing in the rate of joint erosion. 75 A combination therapy of MTX at a maintenance dose of mg weekly and anakinra at several doses (0.1, 0.4, 1.0 and 2.0 mg/kg/day) was compared with MTX plus placebo in a placebo-controlled study. 76 After 12 weeks of therapy, 46% ðp ¼ 0:001Þ of patients receiving 1 mg/kg per day and 38% ðp ¼ 0:007Þ of patients at the 2 mg/kg per day dose obtained an ACR 20 response, compared with only 19% of patients in the placebo group. A confirmatory study 77 compared anakinra 100 mg/day to placebo in patients who were on concomitant MTX at mg per week. At 52 weeks the patients on MTX plus placebo had an ACR 20 of 21% versus 37% in the patients on anakinra plus MTX ðp, 0:001Þ: The primary endpoint was reduction in progression of the TSS. Those patients who were treated with the combination of anakinra plus MTX demonstrated a decreased TSS at 24 weeks of 38% ðp ¼ 0:012Þ and 36% at 52 weeks ðp, 0:001Þ: The anakinra-treated patients had a clinically significant improvement in patient function. Table 2 reviews the accumulated evidence that led to regulatory approval in the USA. Infliximab Infliximab is a chimeric IgG1 monoclonal antibody that neutralises the biological activity of TNF-a by binding with high affinity to soluble and transmembrane forms of TNF-a thereby inhibiting the binding of TNF-a to its receptors 78,79 and thus preventing cell signalling. Infliximab was the first generally used anti-tnf-a agent in patients with RA in whom previous DMARD therapy had failed. 80 A placebo-controlled trial confirmed the efficacy of infliximab in RA with a 60 70% decrease in measures of disease activity. 81 There was a decreased duration of benefit with repeated infusions, particularly in the lower dose group, which was eventually ascribed to an immune response caused by the development of human anti-chimeric antibodies (HACAs). It was found that the development of a HACA response could be mitigated by the co-administration of MTX at doses as low as 7.5 mg per week. The concomitant therapy with MTX may also provide synergistic benefit in terms of treating the RA. It has also recently been reported that patients who do demonstrate a HACA response still had an equal ACR 20 and 50 response rate, when compared with patients who did not develop a HACA, if those patients were treated with concomitant MTX. 82

9 Response A placebo-controlled trial of repeated treatment cycles of infliximab combined with MTX in patients who had an inadequate response to MTX confirmed efficacy and safety and demonstrated that MTX protects against the development of an immune response (HACA) to the monoclonal antibody. 83 A subsequent 102 week placebo-controlled trial investigated the clinical response (at week 30), X-ray progression (at week 54) and change in patient function of infliximab (at week 102) in a population of RA patients with an incomplete response to MTX At week 54, patients treated with infliximab and MTX had a marked decrease of radiographical progression when compared with MTX alone, as assessed by the modified Sharp score, which was maintained over 2 years. This same study also demonstrated that infliximab at 3 or 10 mg every 4 or 8 weeks also significantly improved patient function as measured by a clinically significant decrease in the HAQ score. 86 There was significant durability with this therapy; about 60% of patients treated with infliximab remained on therapy at 2 years. 87 Table 3 reviews the overall data used for regulatory approval in the USA. A small study including 20 patients who had less than 1 year of RA and were DMARD naïve compared the effects of infliximab 3 mg/kg plus MTX to MTX alone (unknown dose) over 1 year. 88 Synovitis as demonstrated by magnetic resonance imaging (MRI) was the primary outcome. At the end of 54 weeks, there was significantly greater improvement in MRI scored synovitis in the infliximab treated group ðp, 0:05Þ: At 54 weeks, 77% of the infliximab treated patients achieved an ACR 50 versus 40% in the MTX group ðp, 0:05Þ: After 1 year of infliximab therapy, patients were continued on MTX alone. At 35 weeks after cessation of infliximab, no patient flared and all maintained their ACR 50 response. 89 Etanercept Table 2. Percentage of patients with ACR responses in Studies 1 and 3. Study 1 (Patients on MTX) Placebo ðn ¼ 251Þ (%) Kinerete, 100 mg/day ðn ¼ 250Þ (%) Placebo, 150 mg/day ðn ¼ 115Þ (%) Study 3 (No DMARDs) Kinerete, 75 mg/day ðn ¼ 119Þ (%) ðn ¼ 115Þ (%) ACR 20 Month a Month b a ACR 50 Month c Month c ACR 70 Month a Month a a P, 0:05; Kinerete versus placebo. b P, 0:01; Kinerete versus placebo. c P, 0:001; Kinerete versus placebo. The treatment of rheumatoid arthritis 515 Etanercept is a soluble TNF-receptor fusion protein that binds to circulating and cell bound TNF, blocking the cytokine s interaction with cell-surface receptors, thus acting

10 516 L. S. Simon Table 3. Percentage of patients who achieved an ACR response at weeks 30 and 54 with infliximab. Response Placebo ^MTX ðn ¼ 88Þ (%) At 8 weeks ðn ¼ 86Þ (%) Remicade þ MTX 3 mg/kg a 10 mg/kg a At 4 weeks ðn ¼ 86Þ (%) At 8 weeks ðn ¼ 87Þ (%) At 4 weeks ðn ¼ 81Þ (%) ACR 20 Week Week ACR 50 Week Week ACR 70 Week Week MTX, methotrexate. a P, 0:05 for each outcome compared to placebo. as a TNF inhibitor. It is a recombinant protein consisting of human p75 tumour necrosis factor receptor (TNFR) fused to the Fc fragment of human immunoglobulin G1. It is a dimer, formed by combining two identical TNFR moieties with the Fc moiety (TNFR: Fc). Compared with the naturally occurring monomeric stnfr, the etanercept molecule has increased TNF binding affinity, a longer half-life and more potent TNF inhibitory activity in vitro and in vivo. 90 Positive results in a preliminary safety and dose-finding trial in 22 patients with refractory RA 91, led to the development of a 3 month, randomised, double-blind, placebo-controlled trial of etanercept in patients with active, refractory RA. 92 Patients were treated with placebo, 0.25, 2 or 16 mg of etanercept per m 2 of body surface injected twice weekly (b.i.w) subcutaneously (s.c.). There was a significant doseresponse relationship with ACR 20 scores of 14, 33, 46 and 75% in the placebo and 0.25, 2 and 16 mg per m 2 groups, respectively. Eight weeks after cessation of therapy, all evidence of disease returned to baseline values, which suggested that etanercept must be continued to suppress disease activity. Subsequently, a 6 month controlled trial was conducted. 93 Patients were randomly assigned to placebo, 10 or 25 mg of etanercept s.c. b.i.w. The ACR 20 response again indicated a dose-response relationship favouring higher doses of etanercept with responses of 11, 51 and 59% in the placebo, 10 and 25 mg group, respectively. These patients were offered a long-term open-label study 94, which demonstrated that 51% of these patients remained in the study for at least 4 years and there was maintenance of the ACR 20, 50 and 70 responses. There was significant interest in understanding the effects of combination therapy with etanercept and MTX. A 24 week randomised study was conducted in 89 patients who had persistently active disease despite at least 6 months therapy with MTX at a stable, relatively aggressive dose of mg per week. 95 Etanercept was effective, demonstrating an ACR 20 response in 27% of patients treated with MTX alone compared with 71% in patients treated with a combination of etanercept and MTX.

11 About 50% of these patients have been followed for up to 5 years with approximately 80% maintaining an ACR 20 response. 96 Etanercept has also been studied in patients with less than 3 years of rheumatoid arthritis who were naïve to MTX in a 24-month study with the primary endpoint of efficacy at 6 months. X-ray was the primary endpoint at 1 year with a subsequent 12-month open-label extension. 97,98 The study was maintained as a double-blind until the last patient completed the 12 month X-ray evaluation and, at that time, patients who were not on etanercept 25 mg b.i.w. were switched to the drug. The study compared MTX aggressively dosed to 20 mg/week, etanercept 10 and 25 mg s.c. b.i.w.. In the first 4 months of the trial, MTX was dosed at a lower level for the first 8 weeks to allow the patients to improve their tolerance of this therapy. During that time, etanercept 25 mg was statistically superior to MTX with respect to the percentage of patients who reached an ACR 20, 50 and 70. At 6 and 12 months, once the dose of MTX was raised and constant, there was no statistically significant difference between the two groups with ACR 20 scores of 65, 60 and 72% in the MTX, 10 and 25 mg groups, respectively at 12 months. However, at the next landmark time-point, 24 months, which was not an unblinded analysis, there was a statistically significant difference between the two groups. This suggested that those patients on etanercept maintained their efficacy while there was an apparent loss of efficacy in the patients on MTX. 99 All of the trials of etanercept in RA demonstrated a significant decrease in patient reported outcomes, such as HAQ scores and, as with other therapies including MTX, the earlier application of etanercept therapy, the greater the decrease in HAQ Of those patients randomised to etanercept in clinical trials, 81% continued therapy for at least 1 year, 73% continued therapy for at least 2 years, 52% continued therapy for at least 3 years while 52% continued therapy for at least 4 years. 87 The overall efficacy of etanercept is summarised in Table 4. Adalimumab The treatment of rheumatoid arthritis 517 Adalimumab is a fully human monoclonal antibody to TNF. Genetically engineered by phage display technology, adalimumab is indistinguishable in structure and function from naturally occurring human IgG-1. It has a terminal half-life of approximately 2 weeks and a high specificity and affinity for TNF. Its therapeutic effects are mediated by blocking the interaction of TNF with the p55 and p75 TNF cell surface receptors. 103 Unfortunately, even though engineered to be no different than the human molecule, clinical studies have demonstrated the developed of an immunological antibody (HACA) response. The approach to the approval of this therapy was to study the efficacy of adalimumab in patients who had failed previous DMARD therapy. It was assessed in a randomised, double-blind, placebo-controlled trial that compared placebo and either 20 or 40 mg of adalimumab given either weekly or every other week over a 6 month period. 104 A doseresponse relationship was seen with all doses being significantly more efficacious than placebo (P, 0:01 for all doses). ACR 20 responses were 19, 36, 39, 46 and 53% in the placebo, adalimumab 20 mg/every other week, 20 mg/week, 40 mg/every other week and 40 mg/week, respectively. Significant differences were also noted for ACR 50 and 70 at 6 months. Long term results were reported from the continuation of a placebocontrolled double-blind study for 12 weeks, which was then continued as an open label extension for an additional 40 weeks in which patients originally treated with placebo were crossed over to therapy and treated with adalimumab 40 mg per week. This study investigated doses of 20, 40 and 80 mg per week or placebo. The study was continued into the 2nd year for the patients who had responded to adalimumab in the first

12 518 L. S. Simon Response Placebo ðn ¼ 80Þ Table 4. The ACR 20, 50 and 70 responses with etanercept. Placebo controlled Active controlled Study I Study II Study III Enbrel a ðn ¼ 78Þ MTX/Placebo ðn ¼ 30Þ MTX/Enbrel a ðn ¼ 59Þ MTX ðn ¼ 217Þ Enbrel a ðn ¼ 207Þ ACR 20 Month 3 23% 62% b 33% 66% b 56% 62% Month 6 11% 59% b 27% 71% b 58% 65% Month 12 NA NA NA NA 65% 72% ACR 50 Month 3 8% 41% b 0% 42% b 24% 29% Month 6 5% 40% b 3% 39% b 32% 40% Month 12 NA NA NA NA 43% 49% ACR 70 Month 3 4% 15% b 0% 15% b 7% 13% c Month 6 1% 15% b 0% 15% b 14% 21% c Month 12 NA NA NA NA 22% 25% a 25 mg Enbrel sub-cutaneously twice weekly. b P, 0:01; Enbrel versus placebo. c P, 0:05; Enbrel versus methotrezate (MTX). 12 months. In this completer s analysis (thus only those patients who responded), the patients were treated with adalimumab 40 mg s.c. per week. At 24 months, 76% of patients achieved an ACR 20, 52% achieved an ACR 50 and 24% achieved an ACR As with other such inhibitors, it was determined that it was important to understand the effect of added MTX. On careful analysis of lower intermittent doses, 12% of patients developed neutralising antibodies. Thus, three trials were completed that combined adalimumab with MTX. The first study 106 evaluated 54 patients treated with a mean MTX dose of 15 mg per week who were also treated with adalimumab 1 mg/kg intravenously (i.v.), 1 mg/kg s.c. or with placebo. Patients were treated with a second injection by the same route when response was lost but no sooner than 4 weeks. Subsequent injections were performed in an open label observation extension at 1 mg/kg s.c. every 2 weeks. Response was a decrease in Disease Activity Score (DAS) of at least 1.2 units. After a single injection, 72, 67 and 28% had a response when treated with i.v., s.c. or placebo, respectively. At 1 year 107, 83% of patients exhibited a response with 69% of patients showing an ACR 20 response and 30% an ACR 50 response. This group of patients has been followed for 3 years with demonstrated maintenance of clinical response. A phase III trial compared patients who were on a mean dose of MTX of 16.8 mg per week and were treated either with placebo or adalimumab 20, 40 or 80 mg every other week for 24 weeks. ACR 20 responses were 15, 48, 66 and 66% in each of these groups, respectively. ACR 50 responses were 8, 32, 54 and 43%, respectively (P, 0:0001 for all groups versus placebo). 108 A subsequent 6 month open label study was conducted in which all patients were treated with adalimumab 40 mg every other week. 109 The ACR 20 response was 71%; the ACR 50 response was 51% and the ACR 70 response was 26%.

13 Response Table 5. ACR responses in placebo-controlled trials of Humira (percentage of patients). Placebo ðn ¼ 110Þ Study II monotherapy (26 weeks) Humira 40 mg every other week ðn ¼ 113Þ Humira 40 mg weekly ðn ¼ 103Þ Study III methotrexate combination (24 and 52 weeks) Placebo/MTX ðn ¼ 200Þ Humira/MTX 40 mg every other week ðn ¼ 207Þ ACR20 Month 6 19% 46% 53% a 30% 63% a Month 12 NA NA NA 24% 59% a ACR50 Month 6 8% 22% a 35% a 10% 39% a Month 12 NA NA NA 10% 42% a ACR70 Month 6 2% 12% a 18% a 3% 21% a Month 12 NA NA NA 5% 23% a MTX, methotrexate. a P, 0:01; Humira versus placebo. The treatment of rheumatoid arthritis 519 A 52 week study was completed in patients who were on a mean dose of MTX of 16.6 mg per week and still had active disease. Patients were treated with placebo or adalimumab either 20 mg per week or 40 mg every other week. Both efficacy and radiological outcomes were the primary outcomes of the trial. At week 52, ACR 20 responses were 24, 55 and 59%, respectively (P, 0:001 adalimumab versus placebo). The mean change in TSS was 2.7, 0.8 and 0.1 units over the 52 weeks (P, 0:001 versus placebo for both adalimumab groups, which suggests that adalimumab in conjunction with MTX significantly slows X-ray progression. 110 All the studies of adalimumab in which patient function was measured, showed a clinically significant decrease in the HAQ score, thus a significant improvement in physical function. A summary of these results are shown in Table 5. There were a total of about 2500 patients entered into clinical trials of adalimumab. Of these patients, 81% continued on therapy for at least 1 year, 70% at least 2 years, 62% at least 3 years, 56% at least 4 years and 46% at least 5 years. 87 Safety signals in the treatment of RA including DMARDs and BRMs The decision to use any therapy is governed by its benefit to risk ratio. In earlier approaches to disease modification in RA patients, most of the drugs were not necessarily developed for use in RA. There was great pressure to improve this benefit to risk ratio. There now follows a review of the safety of these agents. Gold Adverse reactions including mucocutaneous reactions, proteinuria and cytopaenias as well as other heavy metal damage have limited the use of gold therapy. 10 In patients treated with gold, careful monitoring of renal function and complete blood counts need to be continued at monthly intervals for the duration of therapy. Most patient s

14 520 L. S. Simon discontinue therapy at about 1 year due to toxicity or loss of effectiveness and it has been estimated that, after 5 years, only 15 20% of patients treated with parental gold will remain on therapy. About 60% of treatment discontinuations have been attributed to toxicity. 40,51,111 Sulfasalazine As a drug product with two different components, a sulfa and a salicylate, sulfasalazine has a wide range of potential toxic effects. These include gastro-intestinal side effects (including elevation of liver transaminases suggesting drug-induced hepatitis), rash, neutropaenia, aplastic anaemia, agranulocytosis, haemolysis, an unusual yellowish discoloration of skin, urine and contact lenses as well as reversible infertility in men. 112 Serious skin reactions may lead to death. In an analysis of six placebo-controlled trials, adverse event-related withdrawals were approximately threefold greater with sulfasalazine compared with placebo. 28 Approximately 30% of patients discontinue sulfasalazine because of adverse events. 24 In the USA, patients treated with sulfasalazine typically maintain therapy for an average of 18 months before discontinuing for lack of efficacy or adverse events. 40,51 In the development programme for leflunomide, sulfasalzine efficacy and safety was comparable to that of leflunomide, with more than 50% of patients discontinuing therapy with sulfasalazine before 12 months. 56 Methotrexate There are numerous safety signals, including potentially serious adverse events as well as other less important signals, but for patients there are often intolerable toxic effects associated with MTX. The adverse events related to tolerability include nausea or vomiting for about 24 hour after an oral or parenteral dose, alopecia, or non-specific gastro-intestinal intolerance. More worrisome effects include stomatitis and bone marrow suppression (all may be responsive to folic acid supplementation). In addition, there may be idiosyncratic allergic-like lung injury (non-infectious pulmonary infiltrates associated with fever and, which is more commonly seen in obese or diabetic patients) and severe liver damage characterised by either overt drug-induced hepatitis or more occult cirrhosis, especially in patients who use alcoholic beverages or who suffer from diabetes. Liver failure may result in death. There is also a rare risk for occult fibrosis elsewhere including the lung or retroperitoneum. The medication has been associated with potentially fatal opportunistic infections and must be withheld in patients with serious infections. In addition, it has been associated with lymphomas and occasionally with severe skin reactions. Rarely has vasculitis been reported. MTX is excreted primarily in the kidneys and should be used cautiously and at low dose in patients with renal insufficiency. Since MTX is non-dialysable, it should never be given to a patient with renal failure on dialysis. It is an abortifacient and may cause fetal death as well as congenital abnormalities. Conception should be avoided on this medication and both 28 41, males and females should employ appropriate contraceptive measures. Given the venerable nature of MTX, very little post-marketing data has been accumulated about serious or other adverse event rates in real-world usage. Leflunomide Leflunomide is an immunomodulator. Common side effects of leflunomide include diarrhoea, abdominal pain, elevation of liver transaminases, hypertension, rash, reversible alopecia and headaches. 42,55 58 Overt liver failure is a rare event, but if

15 present there is a risk of death. A significant number of patients in combination trials with MTX and leflunomide had elevated serum transaminases but no patient sustained liver failure. 61,62 In the clinical trials of leflunomide 42,55 58, approximately 50% of patients remained on leflunomide at 1 year with withdrawals predominantly being due to a lack of efficacy or an adverse event. These data have been expanded through pharmacovigilence assessments of the post-approval marketing experience. 116 Many of the cases of liver adverse events were associated with confounding factors such as other concomitant hepatotoxic medications, history of alcohol abuse and existing liver function disturbance. It is recommended that liver enzyme levels are monitored monthly for the first 6 months of treatment and every 8 weeks thereafter and that alcohol consumption be avoided during leflunomide therapy. Haematological reactions have also been observed with leflunomide in post-marketing analyses. It has been suggested that a complete blood count be performed prior to treatment initiation, every 2 weeks during the first 6 months of therapy and every 8 weeks thereafter. 115 There are other reports, however, which suggest that the rate of hepatic reactions and other bone marrow effects is similar to the rate observed with MTX, other DMARDs and NSAIDs. 117,118 SAFETY OF BIOLOGICAL RESPONSE MODIFIERS The treatment of rheumatoid arthritis 521 The availability of drugs that would modulate specific targets has been an exciting development in the treatment of patients with RA. The problem, of course, is that any change in the complex series of events that characterises the inflammatory cascade of RA may have untoward unexpected effects. A discussion of these problems needs to recognise that there are differences in our understanding of these effects in the BRMs. This is partly due to the relatively small size of the development programmes for infliximab and etanercept prior to approval. As a result, there were significant limitations in understanding, through controlled trials, the various safety signals, which are hard to tease out in post-marketing pharmacovigilence evaluations. To understand a rare event it is necessary to study at least 3000 patients (an event rate of about 0.1%) and ideally with an active control as a comparator. Early studies with the BRMs often studied patients who were concomitantly being treated with MTX. Safety studies were often done in a naturalistic environment and without consistent active controls it is hard to determine what was the cause of an adverse event. The three TNF-a inhibitors, infliximab, etanercept and adalimumab, have been associated with rare cases of exacerbation of clinical signs and symptoms of a multiple sclerosis-like syndrome and/or radiographical evidence of demyelinating disease. Caution should be employed in considering the use of anti-tnf agents in patients with pre-existing or recent onset central nervous system demylinating disorders If such an event develops, the therapy should be discontinued and the patients should be evaluated carefully. There is little data available from the clinical studies with respect to vaccinations or secondary transmission of infection by live vaccines in patients receiving any of the BRMs. It is recommended that live vaccines not be given to patients while they are being treated with anakinra, infliximab, etanercept or adalimumab. The clinical studies performed with the BRMs did not enroll patients if they were planning a pregnancy, were pregnant or breast feeding. Animal studies have shown no 119, maternal toxicity, embryo toxicity, or teratogenecity with any of these agents. These compounds should be given to pregnant females only if clearly needed and it

16 522 L. S. Simon is unknown whether it is safe for a mother to nurse an infant if she is being treated with any of these medications. There continues to be concern about serious infections in patients treated with each of the BRMs including anakinra, infliximab, etanercept and adalimumab, singly or in combination, since there have been post-marketing reports with infliximab and etanercept of sepsis and death. The Food and Drug Administration (FDA) approved labels for each of these medications now includes warnings about the use of these drugs in patients with active infections, a history of recurring infections, or underlying co-morbidities, such as advanced or poorly controlled diabetes, which may increase the risk of infections. Some of these infections began within only a few weeks of starting a BRM. Many of the patients had underlying conditions, which may have placed them at increased risk for such events, including diabetes, congestive heart failure and/or a history of active or chronic infections prior to the initiation of the BRM. The types of infection seen in post-marketing reports include viral, bacterial, fungal and protozoan organisms Patients who have undergone joint replacement and still sustain active RA should be especially careful given the presence of artificial material that is potentially exposed chronically to bacteraemias. 124 Anakinra The analysis of the safety of anakinra is predominantly dependant on the accumulated data from five randomised, placebo-controlled trials involving a total of 2932 patients. 73,76,77,122,125,126 These data included a prospective safety study of about 1400 patients, treated with anakinra at a dose of 100 mg/day. 125 Across the five placebo-controlled trials, there were no significant differences between anakinra #100 mg/day and placebo with respect to the development of adverse events (88 92% versus 85%), serious adverse events ( % versus 6.5%), death ( % versus 0.1%) or withdrawal due to adverse events ( % versus 11.6%). Injection site reactions (ISRs) were the most common cause for withdrawal with any dose of anakinra, with about 7.3% of patients receiving anakinra 100 mg/day withdrawing due to ISRs, compared with 1.3% of patients who received placebo. The most common reason for withdrawal in the placebo group was worsening of RA, which occurred in 6.2% of patients compared with 1.8% in the anakinra 100 mg/day group. Unexpected infectious illness occurred in 36.2% of placebo-treated patients and 39.8% of patients receiving anakinra at 100 mg/day. Of these infections, 0.7% of those in the placebo group and 1.8% in the anakinra 100 mg/day group were considered to be serious. 122 In all five studies, the rate of serious infection following anakinra treatment did not appear to be higher than that seen in the placebo group or that previously reported in the general population. 123 The overall incidence of serious adverse events (SAEs) was not markedly different between anakinra 100 mg/day (7.1%) and placebo (6.5%). In the anakinra 100 mg/day group, the SAEs that occurred in more than 0.5% of patients were worsening of RA (0.7%) and pneumonia (0.7%). 122 The latter was the most common serious infection experienced by patients receiving anakinra. 122,125,126 History of asthma or prior pneumonia and use of glucocorticoids appeared to be risk factors for the development of pneumonia. 122,125,126 Unusual or opportunistic infections such as tuberculosis, histoplasmosis, listeriosis and aspergillosis, were not observed in any of the anakinra placebo-controlled studies. 122,125,126 Malignancies occurred in the anakinra-treated patients at the same rate as in the National Cancer Institute s Surveillance, Epidemiology, and End Results (SEER) programme. 122,127