The impact of new biologicals in the treatment of rheumatoid arthritis

Transcription

1 Rheumatology 2004;43(Suppl. 3):iii17 iii23 The impact of new biologicals in the treatment of rheumatoid arthritis doi: /rheumatology/keh203 The past decade has seen a shift in the paradigm for RA management. DMARDs have been introduced at earlier stages of disease in an effort to slow or stop radiographic disease progression before irreversible joint damage, work disability, functional decline and other adverse outcomes are seen. Although often effective, DMARDs have been limited in treatment durability over the long term due to side-effects and declining efficacy. Combination regimens, often involving weekly methotrexate as the anchor drug, have been used increasingly to overcome the limitations of DMARD monotherapy. The advent of biological therapies that specifically target key proinflammatory cytokines, believed to be important in disease pathogenesis, provides several new treatment options. In controlled clinical trials, the IL-1 blocker anakinra (r-methuil-1ra) significantly reduced the clinical signs and symptoms of RA when used alone or in combination with weekly methotrexate. The TNF inhibitors etanercept, infliximab and adalimumab have shown similar efficacy; indeed, higher response rates for clinical and radiological parameters have been seen with the TNF blockers. Importantly, each of these biological response modifiers significantly reduced radiographic disease progression in 6- to 12-month studies, and some radiographic data extend to 24 months. Despite these promising findings, it remains to be determined whether slowing radiographic progression will translate into significant improvements in long-term outcomes. KEY WORDS: Rheumatoid arthritis, Radiographic progression, Biological therapy, Anakinra, Etanercept, Infliximab, Adalimumab, Disease-modifying antirheumatic drugs, Methotrexate, Leflunomide. The treatment of RA has changed considerably within the past decade, moving from a conservative approach designed to control clinical symptoms to a more aggressive approach designed to limit joint destruction. Instead of delaying treatment with DMARDs, such as methotrexate, sulphasalazine and hydroxychloroquine, these drugs are being used increasingly in the treatment of earlystage disease as well as in more aggressive combination regimens. This evolution in patient management recognizes that the sideeffects associated with RA severe functional declines, joint destruction, work disability, comorbid diseases and premature mortality are generally considerably greater than the side-effects associated with DMARDs and corticosteroids [1, 2]. Despite the toxicities of these medications, the natural history of RA suggests that the risks of using these drugs is much lower than the risks associated with insufficient treatment. Within the first 2 yr of disease, many patients have radiographic evidence of substantial bone erosions, but, more importantly, radiographic progression of disease occurs in almost all patients over time [3 6]. In most patients with serious RA, progression of bone erosions is best described by a first-order model in which approximately 50% of detectable radiographic damage occurs during the first 5 yr of disease [7]. By providing only symptomatic treatment of early-stage disease, the processes inherent to radiographic progression remain unchecked. In the conservative approach to RA treatment, extensive joint damage is often present by the time DMARDs and corticosteroids are finally introduced. Conversely, by introducing these medications, as well as the newly developed biological therapies, in early-stage disease, it may be possible to limit or slow damage within the joint. Risks of delaying aggressive treatment The goal of early aggressive treatment is to improve long-term outcomes. Work disability is an important adverse outcome, representing one of the major societal costs of RA. The National Health Interview Survey found that only 56% of adult male RA patients under age 65 were still working compared with 89% of males without arthritis [8]. Among women, only 31% of RA patients were still working compared with 62% of those without the disease. Notably, many patients who became work-disabled due to RA first obtained medical treatment after they were already disabled. These findings underscore the need to educate the public that early RA treatment may reduce severe outcomes, such as work disability. RA reduces the lifespan by approximately 10 yr when it is managed conservatively according to the strategies used in the 1970s and 1980s [9 11]. The risk of premature mortality is associated with markers of severe disease, including high scores for functional disability and greater numbers of joints involved. After adjusting for age, sex, disease duration and formal education level, the 5-yr mortality risk in patients with severe RA, characterized by poor function or high joint counts, was four to six times higher than the risk in patients with less severe disease [12]. Notably, the mortality risk associated with severe RA is as great as that seen for hypertension, hypercholesterolaemia or cigarette smoking in the Multiple Risk Factor Intervention Trial (MRFIT), which followed white males [13]. The use of methotrexate and other DMARDs has been found to be effective in ameliorating the negative effects of RA disease progression, albeit with certain limitations, as will be discussed below. DMARD therapy, nevertheless, has altered clinical expectations with respect to the improvements to be achieved by new RA therapies. An analogy may be drawn between RA and cardiovascular and metabolic disorders, such as hypertension and diabetes. Each of these disorders is associated with dysregulation of a normal physiological process and each is incurable. Treatment of hypertension and diabetes is designed to normalize blood pressure and blood glucose respectively, in order to prevent end-organ damage and its associated morbidity and mortality. Similarly, RA University of Nebraska Medical Center, Omaha, Nebraska, USA. Correspondence to:, 9914 Weavers Point, Pequot Lakes, MN 56472, USA. weaver2a@tds.net iii17 Rheumatology Vol. 43 Suppl. 3 ß British Society for Rheumatology 2004; all rights reserved

2 iii18 treatment should be provided to control inflammation and synovial hypertrophy in order to limit further damage to the joint, and thereby minimize work disability, functional declines and premature mortality. Unfortunately, patients with early RA are much less likely to receive aggressive treatment than those presenting with high blood pressure or elevated serum cholesterol. As a first step, a consultation with a rheumatologist should be obtained for those with evidence of RA in order to better define the clinical situation and design an appropriate treatment plan. It is important to recognize that clinical signs and symptoms of inflammatory joint disease may improve or go unchanged during treatment over 5 to 10 yr, but measures of joint damage may still show significant disease progression over the same period. For example, in a study of RA patients over time, joint tenderness and swelling, ESR, RF titre, morning stiffness, and various patient questionnaire measures were unchanged or improved somewhat over a 5-yr period [14]. However, radiographic scores, joint deformity, limited motion, grip strength and walk time showed evidence that disease had progressed during the same period. Accordingly, partial control of inflammation at a level consistent with an ACR20 response may not be sufficient for preventing joint damage [15]. This level of response is defined by reductions in swollen and tender joint counts of at least 20% and improvements of at least 20% in three or more of the following parameters: physical disability, pain score, investigator s global assessment, patient s global assessment, and acute-phase reactant (either ESR or CRP) [16]. In order to confirm that treatment has significantly affected disease progression, it is important to include radiographic and other measures of joint damage in addition to the standard clinical assessment. Patients with favourable measures of joint damage generally have favourable long-term outcomes, but it remains to be demonstrated whether preventing or slowing joint damage will result in better outcomes. Combination DMARD therapy During the last 15 yr, DMARDs have been introduced at earlier stages of disease, and although effective their durability in treatment over the long-term has been poor [17]. More than 50% of RA patients discontinue DMARD therapy within 2 yr, due to either a reduction in the effectiveness of these agents or the appearance of significant side-effects. On the basis of our greater understanding of the immunopathogenesis of RA, it is possible to identify and target key effector mechanisms, with the goal of downregulating these processes. By combining drugs with distinct but complementary mechanisms, it may be possible to achieve greater therapeutic efficacy while minimizing the toxicity associated with individual drugs. Combination therapy has emerged as a realistic strategy in RA due to the availability of methotrexate as an anchor drug. When administered in low weekly doses, methotrexate is effective and its toxicity can be managed effectively. Moreover, patient retention on methotrexate (62% by 5 yr) tends to be longer than with other DMARDs [17]. Many early studies were largely unsuccessful in showing the superiority of combination DMARD therapy over single-agent therapy [18 20]. In these studies, agents were used at low doses or in combinations that caused significant toxicity. Notably, the combination DMARD regimen used most frequently in clinical practice today methotrexate plus hydroxychloroquine was not evaluated. It is important to recognize, however, that the design used in some studies may not have been amenable for showing the benefit of combination therapy. Starting two DMARDs in parallel and comparing this combination with the individual agents may not be an appropriate design. Instead, it is much easier to measure the incremental benefit of adding a second drug compared with placebo to symptomatic patients on an existing DMARD regimen, such as methotrexate mg weekly. This design has been used successfully in a number of studies of combination DMARD therapy, as well as in clinical trials of the new biological agents. A number of well-controlled clinical trials demonstrate that combination DMARD therapy can be administered safely, providing superior disease control and slowing radiographic progression relative to a single DMARD. For example, in a 6- month double-blind study of 148 patients with active RA, adding cyclosporin to methotrexate therapy allowed 48% of patients to achieve ACR20 responses compared with 16% of those receiving methotrexate alone (P<0.001) [21]. The methotrexate cyclosporin combination was also significantly superior to methotrexate alone in swollen and tender joint counts (P 0.02), patient and physician global assessments (P<0.0001) and degree of disability (P<0.001). Adverse events did not differ significantly between the two treatment arms, but hypertrichosis, tremor, numbness and nausea tended to occur more frequently with combination therapy. Leflunomide is the newest non-biological DMARD to receive approval for RA treatment. This agent inhibits dihydro-orotate dehydrogenase, a key enzyme in the de novo synthesis of the pyrimidine nucleotide uridine monophosphate [22]. In a 24-week study of 263 patients with active RA, leflunomide or placebo was added to existing methotrexate therapy [23]. Patients in this study had a mean disease duration of 11 yr, with high ESR and CRP levels. All patients received background folate therapy. The leflunomide methotrexate combination was effective in 46% of patients compared with 20% of those receiving methotrexate alone. Combination therapy was associated with a higher incidence of several adverse events, including hypertension, oedema, liver function test abnormalities and weight loss. Finally, the benefit of combination DMARD therapy has also been shown in several studies [24 26], although a recent study raises doubts of the long-term benefits of combination therapy relative to treatment with a single DMARD [27]. In a randomized, three-arm study of 102 patients with active RA and poor responses to previous DMARD therapy, the patients were randomly assigned to receive single-agent methotrexate, combination sulphasalazine hydroxychloroquine, or triple therapy involving each of these agents [24]. After 9 months, nearly half the patients achieved a 50% improvement in composite arthritis symptoms without evidence of major drug-related toxicity. These responses were maintained for the duration of the 2-yr study. Notably, these responses were significantly more common with triple therapy (77%) than with methotrexate monotherapy (33%, P<0.001) or sulphasalazine hydroxychloroquine therapy (40%, P ¼ 0.003). In a Finnish study, the rates of remission (the primary outcome) after 1 and 2 yr were 25% (24/97, P ¼ 0.011) and 37% (36/97, P ¼ 0.003) respectively among patients receiving triple combination therapy (methotrexate, sulphasalazine, hydroxychloroquine) vs 11% (11/98) and 18% (18/98) with single-drug therapy [25]. An ACR50 response after 1 yr was achieved by 75% of patients receiving combination therapy vs 60% of patients receiving a single agent (P ¼ 0.028). After 2 yr, an ACR50 response was seen in 71 and 58% of the combination and single-agent groups respectively (P ¼ 0.058). In a US study (n ¼ 171), an ACR20 response (primary outcome) was achieved after 2 yr by 78% of patients receiving triple therapy vs 60% of patients receiving methotrexate and hydroxychloroquine (P ¼ 0.05) and 49% of patients receiving methotrexate and sulphasalazine (P ¼ 0.002) [26]. An ACR50 response was seen in 55, 40 and 29% of the respective treatment groups (P ¼ for the triple combination group vs the methotrexate sulphasalazine group). However, a French study suggests that any initial benefits of combination therapy (methotrexate and sulphasalazine) in patients with early RA may not be sustained over the long term [27]. In this study, the patients followup treatment was left to the discretion of their rheumatologist during the 4 yr after their participation in a 1-yr study evaluating combination therapy. After 5 yr of follow-up there was no difference in inflammatory, disability and structural measures

3 Biologicals in rheumatoid arthritis iii19 between patients who initially received dual-dmard therapy and those who received a single DMARD. Advent of biological therapy Biological therapy selectively targets mediators believed to be involved in the pathogenesis of RA, specifically IL-1 and TNF [28, 29]. These cytokines share many of the same activities. They regulate expression of cell adhesion molecules, thereby controlling the movement of leucocytes from blood into the synovium. They increase expression of several proinflammatory mediators, including prostaglandin E 2 and nitric oxide, and they stimulate synovial fibroblasts and chondrocytes to secrete matrix metalloproteinases and other enzymes that degrade cartilage. They also stimulate the differentiation and activation of osteoclasts, which are the cell type responsible for bone resorption. The actions of IL-1 and TNF are normally maintained in balance by a variety of anti-inflammatory and immunoregulatory cytokines; however, in RA an imbalance favouring the proinflammatory cytokines appears to be present [30]. Several biologicals have been evaluated in patients with active RA, including the IL-1 receptor antagonist anakinra, the soluble TNF receptor etanercept and the anti-tnf monoclonal antibodies infliximab and adalimumab (Table 1). Anakinra is an exogenous recombinant human IL-1 receptor antagonist (r-methuil-1ra), which is identical to the non-glycosylated form of natural IL-1Ra except for a terminal methionine. Monotherapy with anakinra was evaluated in a controlled clinical trial of 472 patients with active RA, who discontinued any previous DMARD therapy before enrolment [31]. Patients were randomly assigned to receive anakinra 30, 75 or 150 mg or placebo, administered daily via a subcutaneous injection. After 24 weeks of treatment, an ACR20 response was achieved by 43% of the anakinra 150 mg group vs 27% of the placebo group (P ¼ 0.02). In addition, in the anakinra 150 mg group the number of swollen joints was reduced by 9.5 vs 5.7 in the placebo group (P ¼ 0.009), the Health Assessment Questionnaire (HAQ) score was reduced by 0.3 vs 0.0 points (P ¼ ), CRP was reduced by 1.0 vs 0.4 mg/dl (P ¼ ) and ESR was reduced by 10.3 mm/h vs an increase of 0.9 mm/h in the placebo group (P<0.0001). Perhaps more importantly, anakinra significantly slowed radiographic progression relative to placebo when evaluated by either the Larsen method (P ¼ 0.03) or a modified Sharp method (P ¼ ) [32]. Notably, the rate of joint space narrowing remained reduced when anakinra therapy was continued for an additional 24 weeks (during which patients initially assigned to placebo were randomly assigned to one of the three anakinra groups), whereas the rate of bone erosions was slowed even further with continued therapy. Etanercept, a recombinant fusion protein derived from the human soluble TNF receptor, has been evaluated as monotherapy in two multicentre studies. In the first, 234 patients with active RA were randomly assigned to receive etanercept 10 or 25 mg or placebo administered subcutaneously twice per week [33]. The mean disease duration of patients in this study was 12 yr. After 6 months, both etanercept doses were significantly more effective than placebo in producing ACR20 and ACR50 responses. At the higher etanercept dose, ACR20 and ACR50 responses were achieved by 59 and 40% of patients respectively, compared with 11 and 5% of patients with placebo. In another study, etanercept was compared with methotrexate in RA patients with disease duration of less than 3 yr [34]. In this study, 24% of patients were using a DMARD at screening, but they discontinued these agents for 4 weeks before being randomized to treatment. Within the first 4 months of therapy, etanercept 25 mg tended to produce higher ACR response rates than methotrexate, suggesting that this biological agent may have a faster onset of action (Fig. 1). However, the treatments did not differ significantly in terms of ACR response rates after 5 months. On radiographic analysis, both agents slowed disease progression compared with the rate predicted from baseline erosions and disease duration. Patients treated with etanercept 25 mg showed smaller mean increases in erosion score compared with those given methotrexate at the 6- month (etanercept, 0.30; methotrexate, 0.68; P ¼ 0.001) and 12- month assessments (etanercept, 0.47; methotrexate, 1.03; P ¼ 0.002). Notably, the majority of patients receiving etanercept 25 mg (72%, vs 60% of patients receiving methotrexate; P ¼ 0.007) did not develop new or worsening erosions during the 1-yr treatment period. After the blinded phase of this trial, 512 patients continued on their original therapy in an open-label extension for up to 1 yr. After 24 months, patients receiving etanercept 25 mg showed significantly less radiographic progression than patients receiving methotrexate, as the mean change from baseline in the total Sharp score was 1.3 points in the etanercept 25 mg group vs 3.2 points in the methotrexate group (P ¼ 0.001). Additionally, no increase in the total Sharp score was seen in 63% of the etanercept 25 mg group vs 51% of the methotrexate group (P ¼ 0.017), and no increase in erosions was seen in 70% of the etanercept 25 mg group vs 58% of the methotrexate group (P ¼ 0.012), sustaining the 1-yr results. Use of biologicals in combination with methotrexate Each of the biologicals has been evaluated in patients who remained symptomatic despite methotrexate therapy. Anakinra was evaluated in a 24-week controlled clinical study of 419 patients who had active disease despite receiving methotrexate mg TABLE 1. Comparisons among biological therapies for RA Anakinra Etanercept Infliximab Adalimumab Molecular target IL-1 TNF TNF TNF Drug type Recombinant human Recombinant TNF Chimeric human murine IL-1Ra protein receptor Fc fusion protein anti-tnf monoclonal antibody Clinical trials reported Monotherapy vs placebo Yes Yes No No Monotherapy vs methotrexate No Yes No No Fully human anti-tnf monoclonal antibody Combination therapy Yes Yes Yes Yes ( methotrexate) Recommended dose 100 mg s.c. 25 mg s.c. 3 mg/kg i.v. 40 mg s.c. Dosing schedule Daily Twice weekly Weeks 0, 2 and 6; Every other week then every 8 weeks Recommended use in RA Monotherapy Yes Yes No Yes Combination therapy with methotrexate Yes Yes Yes Yes

4 iii Effect of Etanercept and Methotrexate on ACR Responses at 1 year in Patients With Early RA ACR 20 % Patients ACR ACR 70 Etanercept 25 mg MTX 0 P < Months FIG. 1. Comparison of etanercept with methotrexate with respect to ACR response rates in patients with early RA. Adapted from Bathon et al. [34]. weekly for at least 6 months [36]. Patients were randomly assigned to receive one of five anakinra doses ( mg/kg) or placebo in addition to continuing on their regular methotrexate therapy. On average, patients had disease for about 7 yr. After 24 weeks, anakinra 1.0 mg/kg plus methotrexate provided significantly higher ACR20 (42 vs 23%, P ¼ 0.018), ACR50 (24 vs 4%) and ACR70 (10 vs 0%, P ¼ 0.032) response rates than methotrexate alone. Moreover, the two highest anakinra doses significantly improved many of the components of the ACR response, including the disability score on the HAQ, as well as the investigator and patient global assessments of disease status. Etanercept 25 mg was similarly evaluated in a 24-week study of 89 patients with active disease who had received stable methotrexate therapy at doses of mg weekly for 6 months [37]. Patients in this trial had long-standing disease, as evidenced by a mean duration of 13 yr. After 24 weeks, combination etanercept methotrexate therapy resulted in significantly higher ACR20 (71 vs 27%, P<0.001), ACR50 (39 vs 3%, P<0.001) and ACR70 (15 vs 0%, P ¼ 0.03) response rates compared with the addition of placebo to existing methotrexate therapy. As in the anakinra study, addition of etanercept significantly improved many components of the ACR response. Infliximab, a chimeric (mouse human) antibody against TNF-, was evaluated in combination with methotrexate in a randomized controlled trial of 428 patients with active RA [38]. Patients in this trial had received stable doses of methotrexate of at least 12.5 mg weekly for at least 4 weeks, and they had had RA for a mean duration of approximately 8.4 yr. Patients were randomly assigned to one of two infliximab doses (3 or 10 mg/kg) given according to one of two schedules (once every 4 or 8 weeks). A fifth group received placebo in addition to continuing their stable methotrexate dose. After 30 weeks, the groups receiving combination infliximab methotrexate therapy had ACR20 response rates of 50 58% compared with 20% of those receiving placebo in addition to continuing on methotrexate (all P<0.001). Similarly, ACR50 responses favoured the infliximab groups relative to the placebo group (26 31% vs 5%; P<0.001). After 54 weeks, the groups receiving a combination infliximab methotrexate therapy had ACR % (P<0.001), compared with placebo and methotrexate 17%; ACR % (P ¼ to <0.001), compared with placebo and methotrexate 8%; ACR % (P ¼ 0.04 to <0.001) compared with placebo (plus methotrexate) 2% [39]. Radiographic progression was also evaluated in this study. Both joint space narrowing and erosions increased with methotrexate alone, whereas these parameters did not change appreciably with combination therapy (P<0.001). Among patients receiving methotrexate alone, the joint space narrowing score increased by 2.9 points from baseline, while in the groups receiving the combinations of infliximab plus methotrexate the increases ranged from 0.0 to 1.1 points. The erosion score increased by 3.0 points in the methotrexate-only group, and ranged from a decrease of 0.7 points to an increase of 0.3 points in the groups receiving the combination of infliximab and methotrexate. Interestingly, radiographic progression was significantly slowed with combination therapy among patents who achieved ACR20 responses, as well as among those who did not (Fig. 2). No radiographic data have been published yet for adalimumab, the biological agent most recently approved for treatment of RA. Adalimumab is a fully human antibody against TNF-. The combination of adalimumab and methotrexate was studied in a 24- week trial enrolling 271 patients who had failed therapy with as many as four DMARDs and whose response to methotrexate had been inadequate [40]. Patients were randomized to adalimumab 20, 40 or 80 mg every other week or placebo, in addition to their usual dose of methotrexate. After 24 weeks, the ACR20, ACR50 and ACR70 response rates were greatest among patients receiving adalimumab 40 mg (67, 55 and 27% respectively). These response rates were statistically significantly greater than those in the placebo group (14, 8 and 5% respectively) (P<0.01 for all comparisons). The new biological response modifiers, as well as several non-biological DMARDs, have been shown to slow radiographic progression. However, based on available clinical data, the activities of the individual biological agents on radiographic progression cannot be compared directly, owing to differences in trial design and patient populations (Table 2). Accordingly, these clinical studies provide evidence that the new biologicals, like certain DMARDs, can slow radiographic progression, but they do not allow differentiation of the efficacy of one agent vs another. Interestingly, radiographic progression was reduced in patients

5 Biologicals in rheumatoid arthritis iii21 FIG. 2. Effects of combination infliximab methotrexate therapy and methotrexate alone on radiographic progression according to ACR 20% responses. Shown are the mean changes from baseline to week 54 in the total radiographic score for patients who achieved (left panel) and did not achieve (right panel) ACR 20% responses. Infliximab was added to methotrexate at two doses (3 or 10 mg/kg) and according to two different schedules (every 4 or 8 weeks). Data from Lipsky et al. [39]. TABLE 2. Differences in design of radiographic studies of biological agents Anakinra Etanercept Infliximab Study Bresnihan et al., 1998 [31] Jiang et al., 2000 [32] Bathon et al., 2000 [34] Genovese et al., 2002 [35] Enrolment criteria Active RA Active RA Early RA, Early RA, methotrexate-naive methotrexate-naive Length of study 24 weeks 24 weeks, plus 1 yr 2 yr (1-yr open-label 24-wk extension extension of (placebo group Bathon study) randomized to anakinra) Lipsky et al., 2000 [39] Active RA despite prior methotrexate 54 weeks Duration of RA at baseline yr yr months months 9 12 yr Comparator arm(s) Placebo 0 24 weeks: Placebo Methotrexate Methotrexate Methotrexate weeks: None Previous DMARD use 66 71% 66 71% 39 46% 39 46% 100% Other DMARDs used None None None None Methotrexate during study Percentage of patients in radiographic substudy (n/n) 75% (347/472) 24 weeks: 75% (347/472) 48 weeks: 81% 92% (583/632) 81% (512/632) 82% (349/428) (248/305) Radiographic scoring method Larsen Larsen, Genant Modified Sharp Modified Sharp Modified Sharp Mean total radiographic score Larsen: at baseline (range of Genant: treatment groups) who achieved ACR20 responses, as well as in those who did not meet these clinical response criteria. This finding suggests that control of the clinical signs and symptoms of RA, such as swollen and tender joint counts, pain and acute-phase reactants, does not reflect whether progressive joint damage has been arrested. On the basis of ACR20 response rates from clinical trials of the IL-1 and TNF blockers, it is unlikely that inhibition of only one cytokine will be the answer for all patients. RA disease activity may depend more on TNF in some patients, more on IL-1 in other patients, and perhaps more on other cytokines in the remaining patients. By using appropriate drugs in combination, it will hopefully be possible to control the signs and symptoms of RA as well as to slow or prevent further radiographic progression in a large percentage of patients. However, it should be noted that coadministration of anakinra and a TNF blocker is not recommended, owing to an increased risk of serious infections. In clinical trials involving concurrent administration of anakinra and etanercept, the rate of serious infections, 7%, was higher than when either agent was used alone, and the combination of both drugs provided no further clinical advantage over monotherapy

6 iii22 [41]. The US package inserts for all the biological agents contain warnings about the increased risk of infections associated with their use [42 44], and the package inserts for infliximab and adalimumab bear prominent black box warnings that call attention to the risk of tuberculosis and, in the case of infliximab, other opportunistic infections. Role of the rheumatologist in patient management A window of opportunity for controlling RA may exist very early in the course of disease. Whereas X-rays often provide evidence of joint damage within the first 2 yr, MRI suggests that changes in joint structure are evident as early as 2 months after disease onset [45]. Accordingly, there may be a need to initiate aggressive treatment very soon after RA diagnosis, before a significant amount of irreversible joint damage has occurred. Several barriers to early intervention must be overcome, however, including a lack of recognition of early disease in the primary care setting, failure to refer patients for rheumatology consultations, and difficulties in monitoring disease and predicting outcomes. In order to ensure aggressive treatment of early-stage RA, it will be critical to increase awareness about RA and the recent advances in its treatment among primary care physicians. However, when rheumatologists are considering using the new biologicals, the potential of these medications to increase the risk of infection must be taken into consideration, and rheumatologists must take care to instruct patients and primary care physicians in this respect. A consultation with a rheumatologist should be considered for patients presenting with symptoms of active synovitis, extraarticular features or radiographic evidence of erosions [46]. Patients with RA refractory to available medications should also be referred to a rheumatologist, but ideally such patients should already have been seen by a rheumatologist before reaching a refractory state. Referrals should be considered for several reasons: to confirm a diagnosis of RA; to identify an appropriate treatment plan; to initiate an aggressive treatment regimen or to use experimental agents within clinical trials; to assess the need for occupational or physical therapy or an orthopaedic consultation; or to monitor disease activity and drug-related toxicity. The impact of aggressive treatment of early-stage RA on disease outcomes remains to be established. Similarly, outcome assessments in clinical practice are needed to allow physicians to track the progress of individual patients and to select appropriate medications. Notably, outcome assessments will be needed to establish the cost-effectiveness of aggressive therapy, which will be particularly important considering the relatively high acquisition cost of biological therapy. In calculating costs, the impact of treatment on indirect and intangible costs will need to be considered. By achieving better disease control with early aggressive interventions, various indirect costs associated with work disability, early retirement and lower household income should be reduced. In addition, better disease control should reduce the intangible costs associated with pain and suffering, changes in family structure and poor quality of life. Ultimately, the costeffectiveness of these new RA medications will depend on how patients and society view the importance of patient improvement compared with alternative uses of the same scarce resources. Rheumatology Key messages Early aggressive treatment of RA is important. IL-1 and TNF are the two proinflammatory cytokines targeted by the currently available agents. The new biological agents slow radiographic progression of RA. Dr Weaver has financial interest/relationship or affiliation with one more organizations, including grant research support, consultant status, medical advisory boards and speakers bureaus. These companies include Abbott, Abginex, Amgen, Aventis, Boehringer-Ingelheim, Bristol-Myers-Squibb, Centocor, Connetics, Forrest Laboratories, Fugisawa, Helsinn, Hoffman- LaRoche, Immunex, Lilly, Merck, Merckle, Novartis, Ortho- McNiel, Park-Davis, Pfizer, Pharmacia, Proctor & Gamble, Prometheus, Tap, Takeda, Theraquest and Wyeth. Dr Weaver is also on the board of directors of MGI Pharma and Boston Healthcare. References 1. Pincus T. Long-term outcomes in rheumatoid arthritis. Br J Rheumatol 1995;34(Suppl. 2): Pincus T, Callahan LF. The side effects of rheumatoid arthritis: joint destruction, disability and early mortality. 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