Clinical study findings of recent years support the notion that patients with rheumatoid arthritis (RA) should be treated earlier and more aggressively. Monotherapy with disease-modifying antirheumatic drugs (DMARDs) is effective in some cases, but triple DMARD therapy is superior to double therapy or monotherapy in early or late RA. Leflunomide is at least as effective as methotrexate (MTX) and sulfasalazine and more effective than placebo.
ABSTRACT: Clinical study findings of recent years support the notion that patients with rheumatoid arthritis (RA) should be treated earlier and more aggressively. Monotherapy with disease-modifying antirheumatic drugs (DMARDs) is effective in some cases, but triple DMARD therapy is superior to double therapy or monotherapy in early or late RA. Leflunomide is at least as effective as methotrexate (MTX) and sulfasalazine and more effective than placebo. Tumor necrosis factor α antagonists are effective in patients with early or late RA, especially in combination with MTX. Anakinra is more effective than placebo as monotherapy or when combined with MTX. Rituximab and abatacept are useful as monotherapy but are more effective when used in combination with other DMARDs.
Clinical studies conducted during the past 10 to 20 years have shown that rheumatoid arthritis (RA), which affects about 1% of the US population, is a progressive disease that can cause significant morbidity and mortality.1,2 These findings have contributed to an increased realization that patients with RA should be treated early and aggressively.3,4 Since the late 1990s, use of combination therapy has increased, and a surge of new medications has greatly expanded the treatment options. In this article, we review the efficacy and safety of these new and improved therapies.
A disease-modifying antirheumatic drug (DMARD) or a biologic agent used in the treatment of patients with RA should decrease the number of swollen and tender joints, improve laboratory measurements of inflammation, slow radiographic disease progression, and maintain a patient's physical functioning, as well as have an acceptable safety profile. Controlled clinical trials evaluate the efficacy of a new medication in patients who have RA by assessing multiple outcomes.
The American College of Rheumatology (ACR) core set of disease activity measures for improvement in RA during trials is used frequently in US trials.5 The measures determine a medication's efficacy by specifying a response to treatment as at least a 20% (ACR 20) improvement in both swollen and tender joint counts and in 3 of the 5 remaining ACR core measures. Other cutoffs, including ACR 50 and ACR 70 (50% and 70% improvement, respectively) have been developed from each of the same core measures.
In many trials, efficacy is measured by the Disease Activity Score (DAS) developed by the European League Against Rheumatism (EULAR). The DAS is a validated index that combines tender and swollen joint counts, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level, and a general health measure (range, 0 to 10).6
The 28-joint Disease Activity Score (DAS 28) is the most frequently used tool for measuring the severity of RA.7 DAS 28 scores higher than 5.1 are considered severe, scores between 3.2 and 5.1 are moderate, scores between 2.6 and 3.2 are low, and scores lower than 2.6 indicate "remission." A good EULAR response is a DAS improvement greater than 1.2; a moderate response is between 0.6 and 1.2, depending on the baseline DAS.
The modified van der Heijde–Sharp (vdH-S) score is the most frequently used method to assess the ability of an antirheumatic drug to alter radiographic progression.8 It measures the number of erosions and the degree of joint-space narrowing in 16 joints of each hand and wrist and 6 joints of each foot. The maximum possible modified vdH-S score is 448. The average untreated patient with RA progresses at a rate of 5 total Sharp units per year-equivalent to the destruction of 1 small joint of the hand or foot. When patients have a modified vdH-S score higher than 50, usually they are experiencing some disability, frequently as a result of both small- and large-joint involvement.9
Clinical trials also measure the effect the medication has on a patient's functional capacity and overall health status. The Health Assessment Questionnaire Disability Index (HAQ-DI) is a simple, short (10-question), and validated questionnaire that assesses patient function in 8 categories of activities of daily living within the previous week.10
The HAQ-DI produces a score between 0 (no disability) and 3 (serious disability). A score higher than 1 correlates with some disability; typically, poorly medicated patients progress at the rate of 0.05 to 0.1 units a year. The minimum clinically important change that a patient can discern when taking a new medication is 0.22 to 0.25 units. The health-related quality of life Short Form 36 (SF-36), a validated tool for assessing overall health status, contains 36 items within 8 subscales and 2 summary scales for physical and mental components.11 The minimum clinically important difference for each SF-36 subscale is 5 to 10 units; for overall summary scores, it is 2.5 to 5 units.
Clinical experience in treating patients with RA has shown that monotherapy with DMARDs often is ineffective and may not lead to a sustained clinical remission.12,13 Therefore, multiple controlled clinical trials have assessed whether combining DMARDs that have differing toxicities might be more effective.14 Several trials have assessed the value of methotrexate (MTX) in combination with other DMARDs in early RA (less than 1 to 3 years of disease) and late RA (more than 3 years of disease).
A combination therapy that has been most studied in recent years is triple-DMARD therapy using MTX, sulfasalazine (SSZ), and hydroxychloroquine; occasionally, corticosteroids are added. In the Finnish Rheumatoid Arthritis Combination Therapy (FIN-RACo) trial, triple- DMARD therapy and prednisone (5 to 10 mg/d) was superior to a single-drug strategy in DMARD-naive patients with early RA.15 A 5-year follow-up study of this patient population showed improvement in work productivity and less disability in patients who were receiving combination therapy.16
In the United States, O'Dell and colleagues17 showed that triple- DMARD therapy is more effective than double therapy or monotherapy in patients with established late RA. Calguneri and associates18 confirmed these findings. Radiographic progression was examined in both the FIN-RACo trial and the Calguneri study; it was shown to be less in patients who were receiving triple-DMARD therapy than in those who were receiving monotherapy.15,18
The Combinatietherapie Bij Reumatoide Artritis (COBRA) study used a step-down design to evaluate combination therapy.19 DMARD-naive patients with early RA were randomized to the combination of MTX, SSZ, and high-dose (60 mg) prednisolone or to SSZ alone.
Prednisone was tapered during the subsequent weeks and discontinued by week 28. MTX was stopped by week 40; subsequently, patients continued taking SSZ alone. Not surprisingly, patients receiving combination therapy improved significantly and more rapidly than those receiving monotherapy. By week 56, however, both groups of patients were symptomatically the same. At 5 years of follow-up, however, the combination-therapy group had sustained reduction in the rate of radiological progression; this result suggested that early, aggressive therapy could lessen subsequent joint destruction.20
Other controlled trials have examined different DMARD combinations. Kremer and coworkers21 reported a 24-week trial using a step-up design in which patients who had persistently active RA-despite receiving 6 months of MTX therapy-were randomized to MTX plus leflunomide or MTX plus placebo. The combination-therapy group showed clinical benefit (52% of patients achieved an ACR 20 response, 26% an ACR 50 response, and 10% an ACR 70 response) but experienced more liver toxicity. As such, if MTX is used in combination with leflunomide, tests for liver injury must be performed and patients monitored closely.
Tugwell and colleagues22 conducted a 6-month controlled trial that compared the combination of MTX plus cyclosporine with MTX plus placebo in patients who had active late RA despite having had partial responses to previous MTX treatment. After 6 months, patients receiving combination therapy showed greater clinical improvement than patients receiving MTX alone.
However, other trials in patients with early or late RA have not confirmed a clinical advantage for the combination of MTX and cyclosporine over MTX alone: combination therapy does slow radiographic progression but is more toxic than MTX alone.23,24 A trial by Willkens and associates25 did not show that the combination of azathioprine plus MTX is more effective than either drug alone.
This is a prodrug, converted after oral administration to the active metabolite, A77-1726. This metabolite is a competitive inhibitor of dihydroorotate dehydrogenase, the rate-limiting enzyme required for de novo pyrimidine synthesis. Leflunomide is indicated for patients who have moderate to severe RA in both early and late disease. Because it has a long half-life, a loading dosage of 100 mg/d for 3 days may be used to reach a steady state more quickly. However, because of toxicity concerns, a loading dose often is skipped and treatment is started with the usual daily maintenance dose of 20 mg. Maximum effectiveness is achieved by 4 months.
In clinical trials of 12 to 24 months' duration, leflunomide was at least as effective (52% of patients achieved an ACR 20 response, 34% an ACR 50 response, and 20% an ACR 70 response) as MTX and SSZ and more effective than placebo in RA.26,27 There was no decrease in the efficacy of leflunomide in patients who had received the drug for 5 years compared with the efficacy after 1 year of treatment.28
In addition, the slowing of radiographic progression over 24 months with leflunomide is similar to that with MTX or SSZ; 72% of patients had no change in erosion and joint-space narrowing scores from baseline to 24 months.29 Clinically meaningful improvement in measures of function (HAQ-DI) and the health-related quality of life (SF-36) and work productivity were seen with leflunomide treatment compared with placebo.30
If patients cannot tolerate 20 mg/d of leflunomide, are older, or are also taking MTX, the maintenance dosage should be started at 10 mg/d. Because of its higher cost, leflunomide is best tried after MTX. It may be given to patients who are intolerant of low-dose MTX and may be effective in up to 40% of patients in whom MTX has not succeeded.
Lessons from synthetic DMARD clinical trials
Clinical trial experience has taught several lessons about the use of DMARDs in patients with RA:
•All DMARDs work best in patients who have early RA and should be started as early as possible, preferably within the first 3 to 6 months after disease onset.
•MTX is the most effective synthetic DMARD, although there is variability in patients' individual responses; in some patients, the maximum effect is achieved only when they receive up to 25 mg/wk subcutaneously.
•Triple-DMARD therapy works better than monotherapy without a significant increase in toxicity.17
•Low-dose corticosteroid therapy in RA may retard radiographic progression.31,32
•Early therapy may slow radiographic progression and prevent disability in patients who are able to achieve a remission.
The last lesson was supported by the Tight Control for Rheumatoid Arthritis (TICORA) trial.33 This study demonstrated that early and aggressive treatment of patients who have RA that involves escalating therapy from monotherapy to combination DMARDs to high-dose DMARD therapy to achieve disease remission may significantly improve disease activity and decrease radiographic disease progression, as well as improve physical function and quality of life. However, many patients with RA do not respond to or cannot tolerate DMARD therapy. For patients with RA who do not respond to DMARDs maximally, are intolerant of them, or have poor prognostic factors, biologic therapy (tumor necrosis factor a [TNF-α] antagonists, abatacept and rituximab) should be considered.
The TNF-α antagonists
Controlled trials using TNF-α antagonists have confirmed that these biologic agents are effective in patients with early or late RA. Each TNF-α antagonist works best in combination with MTX. Clinical experience has shown that other DMARDs, such as leflunomide, may be used with effectiveness equal to that of MTX when used in combination with the TNF-α antagonists.34 Use of these biologic therapies is most cost-effective in patients who have moderate or severe disease activity and poor prognostic signs. Currently, 5 TNF-α antagonists are available for clinical use: etanercept, infliximab, adalimumab, golimumab, and certolizumab.
Etanercept. This is a soluble TNF-receptor fusion protein that binds both TNF-α and TNF-β, thereby preventing each from interacting with its receptor. A regimen of 50 mg by subcutaneous injection once weekly is as effective as 25 mg twice weekly, although some patients may benefit from one regimen more than another.35
Etanercept monotherapy is more effective than placebo in reducing disease activity in patients with late RA.36 The Early RA (ERA) trial and follow-up studies demonstrated that etanercept monotherapy could reduce disease activity more quickly and as effectively as high-dose MTX in patients with early RA.21,37 In the Trial of Etanercept and Methotrexate With Radiographic Patient Outcomes (TEMPO), the combination of etanercept and MTX was superior to either agent alone in a cohort of patients with late RA.38
Infliximab. This is a chimeric, IgG1, anti–TNF-α, monoclonal antibody that binds both soluble and membrane-bound TNF-α with high affinity. It impairs the binding of TNF-α to its receptor and lyses cells that express TNF-α through both antibody- and complement-dependent cytotoxicity.
Clinical trials have demonstrated that after a loading regimen of 3 mg/kg taken intravenously at 0, 2, and 6 weeks, subsequent dosing at 3 mg/kg every 8 weeks is the minimally effective regimen. Patients who do not respond or maintain a response may be escalated to a dosage of 5 to 10 mg/kg every 4 weeks.
Early monotherapy studies demonstrated that monotherapy with infliximab is superior to placebo, but the frequent development of human antichimeric antibodies (HACAs) led to the combination of infliximab with MTX. Pivotal trials include the Active Controlled Study of Patients Receiving Infliximab for Treatment of RA of Early Onset (ASPIRE) and the Anti-Tumor Necrosis Factor Trial in RA With Concomitant Therapy (ATTRACT), which demonstrated that infliximab plus MTX is clinically and radiographically superior to MTX monotherapy in patients with early and late RA, respectively.39,40 In addition, the results of the Behandel-Strategien (BeSt) study have shown that early treatment of RA with combination therapy with infliximab and MTX results in improved outcomes when compared with monotherapy or combination therapy with nonbiologic DMARDs.3,41,42
Adalimumab. This is a recombinant, human IgG1, monoclonal antibody that binds to human TNF-α with high affinity; it impairs cytokine binding to its receptor and lyses cells expressing TNF-α on their membranes. The usual dosage is 40 mg taken subcutaneously every other week, although up to 20% of patients require weekly dosing.
A combination of adalimumab with MTX appears to lessen the need to escalate dosing from every other week to weekly. Pivotal trials-the PREMIER study and the Anti-TNF Research Study Program of the Monoclonal Antibody Adalimumab (ARMADA)-demonstrated that adalimumab plus MTX is clinically superior to MTX monotherapy in patients with early and late RA, respectively.43-45 In 2009, 2 additional TNF-α antagonists have been approved for RA treatment, golimumab and certolizumab.
Golimumab. This is a recombinant, fully human monoclonal antibody with a mechanism of action similar to that of infliximab and adalimumab. The approved dose is 50 mg taken subcutaneously every 4 weeks. Two large, randomized controlled trials have shown that golimumab in combination with MTX is more effective than MTX or golimumab monotherapy in patients with early RA who were MTX-naive (GO-BEFORE) or in patients with established RA who were MTX-incomplete responders (GO-FORWARD).46,47 In addition, golimumab was more effective than placebo in patients who had been unsuccessful with or intolerant of 1 or more anti–TNF-α antagonists (GO-AFTER).48
Certolizumab pegol. This is a PEGylated Fab' fragment derived from a high-affinity humanized anti–TNF-α monoclonal antibody. It lacks the Fc portion of immunoglobulin and consequently does not participate in complement- or antibody-dependent cytotoxicity, although it still blocks the action of membrane-bound and soluble TNF-α. The approved dose of certolizumab is 400 mg taken subcutaneously at weeks 0, 2, and 4, then 200 mg subcutaneously every other week. Alternatively, after loading, certolizumab may be dosed at 400 mg subcutaneously every 4 weeks.
Several clinical trials have demonstrated the efficacy of certolizumab in RA. Keystone and associates49 showed in a 52-week study that certolizumab dosed at 200 or 400 mg every 2 weeks after loading dose (see above) in conjunction with MTX is superior to MTX alone, in terms of clinical response as well as radiographic erosions. Similar clinical efficacy results were reported by Smolen and colleagues50 in the RAPID 2 study (patients treated with certolizumab 200 or 400 mg every 2 weeks after loading plus MTX versus patients treated with MTX alone). Certolizumab as monotherapy dosed 400 mg every 4 weeks was also effective in patients who previously had an inadequate response to 1 or more DMARDs (FAST4WARD study).51
Other outcome measures from TNF-α antagonists used in RA
Each TNF-α antagonist has been examined for its effects on radiographic progression, improvement in function, and health-related quality of life measures. Each reduces radiographic progression, as measured by a change in radiographic erosion scores; decreases HAQ-DI scores; and improves SF-36 scores significantly better than MTX monotherapy in patients with early or late RA. In addition, long-term extension studies for each of the TNF-α antagonists demonstrate sustained clinical response with these agents for up to 10 years of use in patients with RA who continue receiving these agents.
Practical points on use of TNF-α antagonists
Because of cost and safety considerations, not all patients with RA can or should be treated with a TNF-α antagonist. However, TNF-α antagonist therapy can be supported in a patient with poor prognostic features and moderate to severe disease activity, especially after a DMARD, such as MTX, has not been successful.
Based on extrapolation from analysis of the ASPIRE data, patients with RA who are most likely to benefit from early biologic therapy are those who have an initial ESR greater than 50 mm/h (or a CRP level higher than 3 mg/dL), evidence of early joint erosions and a modified Sharp score higher than 10, and more than 13 swollen joints after 12 weeks of aggressive MTX therapy.39 If disability is reduced and the patient remains employed, the cost of TNF-α antagonist therapy may be justified.52
There has been discussion about differences in safety profiles among the TNF-α antagonists. Overall, however, the TNF-α antagonists have fairly similar efficacy and toxicity profiles; the number needed to treat to achieve an ACR 50 response compared with MTX monotherapy is 3 to 5 patients.53
TNF-α inhibitors may be used alone or in combination with DMARDs. However, controlled clinical trials have shown that the combination of a TNF-α antagonist with MTX is more effective in all measures than monotherapy with a TNF-α inhibitor alone. This may be because of the combined effect of multiple agents on RA-related inflammation, although reduction of adverse immune responses (such as HACAs) to the TNF-α antagonist by MTX (or other DMARD) also may play a role.54
Trials and clinical experience have indicated that failure of one TNF-α antagonist may not predict the failure of another.55,56 This finding may be related to differences in mechanism of action between the TNF-α antagonists or immune reactions against these agents. For example, patients with RA not responding to etanercept may respond to infliximab or adalimumab because those anti–TNF-α agents may not only interfere with TNF-α binding to its receptor but also lyse cells expressing TNF-α on their cell surfaces. Also, HACAs may have developed in patients who initially responded to infliximab but later lost that response or who had infusion reactions. Switching these patients to adalimumab or etanercept may restore a clinical response.
In addition, patient preferences about dosing route or interval may dictate which TNF-α antagonist is used clinically, or the structure or formulation of the agent may lead to differences in injection tolerability. Overall, however, patients with RA who do not respond to 1 or 2 TNF-α antagonists probably will not respond to other agents in this class and should be switched to a biologic agent that has a different mechanism of action.57,58
Although TNF-α antagonists have revolutionized RA therapy, many patients will not respond to these agents. Randomized controlled trials show that, on average, patients with RA have improvements in ACR response criteria as follows: ACR 20, about 60%; ACR 50, about 40%; ACR 70, about 20%. This indicates that a substantial percentage of patients will not have adequate response to a TNF-α antagonist and may require alternative therapy.
Interleukin-1 receptor antagonist (IL-1RA)
Anakinra is a recombinant form of human IL-1RA that targets the type 1 IL-1 receptor. A regimen of 100 mg/d taken by subcutaneous injection is effective in a subset of patients with RA.
Several studies have demonstrated that anakinra is more effective than placebo as monotherapy or when combined with MTX.59,60 In general, anakinra has not been shown to be as effective as the TNF-α antagonists in clinical trials of patients with late RA (ACR 20 response rates, 38% vs 43%; ACR 50 response rates, 11% vs 24%; and ACR 70 response rates, 1% vs 10%). Trials of anakinra have shown a reduction in radiographic progression and in the HAQ-DI scores.61 Withdrawal rates in clinical trials have ranged from 12% to 27%; adverse effects, in particular injection site reactions, were the reason for most withdrawals.59-61
The role of anakinra in RA is unclear. Initially, some investigators had hoped that if a patient did not respond to a TNF-a antagonist, the patient would be more likely to respond to an IL-1RA. This has not been shown clinically, although a small subset of patients may respond very well. Notably, patients with adult-onset Still disease may have a dramatic improvement when treated with anakinra.62
Other biologic therapies: rituximab and abataceptAbatacept. This is a soluble fusion protein that consists of the extracellular domain of human cytotoxic T-lymphocyte–associated antigen 4 linked to the modified Fc portion of human IgG1. This agent works as a selective co-stimulation modulator that inhibits T-cell activation by binding to CD80/86, thereby blocking its interaction with CD28. This blockage prevents the co-stimulatory signal that is necessary for full activation of T lymphocytes. It is approved for use in RA after failure of initial DMARD therapy.
Clinical trials have shown that optimal dosing of abatacept is a loading regimen of about10 mg/kg (typically 500 mg for weight less than 60 kg, 750 mg for weight 60 to 100 kg, 1000 mg for weight more than 100 kg) given intravenously at 0, 2, and 4 weeks. The subsequent dosing is given monthly as a 30-minute infusion.
Controlled trials using abatacept have confirmed its clinical efficacy in RA. The Abatacept in Inadequate Response to Methotrexate (AIM) trial showed that abatacept improves disease activity and slows radiographic progression in patients with RA for whom MTX monotherapy was not successful.63 In patients with RA who had an inadequate response to TNF-α antagonists (Abatacept Trial in Treatment of Anti-TNF Inadequate Responders [ATTAIN]), abatacept led to a better clinical response than did placebo when added to a current DMARD regimen.64 Responses to abatacept could be observed within 2 weeks of therapy in some patients, but responses were not usually for 2 to 4 months, so most authors recommend trials of 3 to 6 months before abatacept treatment in RA is deemed a failure. Abatacept should not be added to anti–TNF-α therapy because of an increased risk of infection.
Rituximab. This is a chimeric IgG1 monoclonal antibody that binds to CD20 molecules on B cells. This binding results in destruction of B cells through various mechanisms and a severe depletion of peripheral B cells.
Stem cells and plasma cells lack CD20 on their surface and are not depleted with this therapy. Consequently, serum immunoglobulin levels are largely maintained and infection risk is not excessive.
Established in clinical trials, the typical dosing regimen for rituximab in RA is 1000 mg intravenously dosed day 0 and day 14, with repeated dosing given on average 6 to 8 months after the last infusion because of recurring symptoms. Because of possible infusion reactions, patients typically are premedicated with methylprednisolone, 100 mg intravenously; acetaminophen, 1000 mg orally; and an oral antihistamine; however, studies have shown that methylprednisolone often is not needed at the second infusion because infusion reactions are rare. Rituximab is approved for use in RA after failure (or contraindication) of an anti–TNF-α agent.
The pivotal Randomized Evaluation of Long-term Efficacy of Rituxan in RA (REFLEX) trial showed that rituximab is significantly more effective than placebo (ACR 20, 51%; ACR 50, 27%; and ACR 70, 12%, all at 6 months of therapy).65 The dosing regimen for this trial was 1000 mg of rituximab given intravenously at weeks 0 and 2, along with weekly oral MTX. Other ongoing trials have reported that rituximab therapy can be repeated (on average every 6 to 8 months) with similar efficacy in patients with RA who subsequently relapse.66
Longer-term follow-up of patients with RA treated with rituximab shows improved bone erosion scores, suggesting that rituximab may lead to decreased structural damage.67 Limited observational studies suggest that if rituximab use does not result in long-term improvement of RA, the use of other biologic therapies (such as TNF-α antagonists) after B-cell depletion may result in improvement in RA without a substantial increase in morbidity or increased mortality.68
Practical points on the use of abatacept and rituximab in RA
Abatacept has efficacy similar to that of TNF-α antagonists in patients with RA for whom MTX has not succeeded (ACR 20, about 60%; ACR 50, about 40%; and ACR 70, about 20%). Because of different mechanisms of action, both abatacept and rituximab may be effective in patients with RA for whom TNF-α antagonists have not succeeded (ACR 20 responses, about 50%; ACR 50, about 30%; and ACR 70, 10% to 15%).
Rituximab may be more effective in seropositive than in seronegative RA. The agent also may be safer to use than other biologic agents in patients who have mycobacterial exposures; chronic infections, such as osteomyelitis; or malignancy. However, because there is a risk of infection if B-cell depletion leads to decreased immunoglobulin levels, the levels should be assessed in patients who receive multiple courses of rituximab. As with all biologic agents, patients should be screened for latent infections (tuberculosis, hepatitis B) and given immunizations with nonlive vaccines before therapy is started.
Choosing optimal RA treatment
With the treatment options for patients with RA having increased substantially over the past decade, clinicians face the dilemma of how to choose the best therapy for their patient. Currently, there are no serological or synovial biomarkers that tell the clinician which treatment will be most effective for a specific patient.
However, it is now well established that all patients with RA should be treated early (within 6 months of symptomatic disease). Also, those with poor prognostic factors (multiple swollen joints, high levels of inflammatory markers, early erosions, or significant disability) should be considered for more aggressive therapy. Use of a disease activity measure, such as DAS 28, should help guide therapy to attain tight control of inflammation in RA.
The results from the BeSt study have provided insight into direct comparison of treatment approaches in RA.42,69 In that study, patients with RA were treated with 1 of 4 approaches: group 1, sequential monotherapy; group 2, combination DMARDs; group 3, initial combination with MTX, SSZ, and tapering prednisone; and group 4, combination therapy with MTX and infliximab.
About 30% of patients responded well to MTX alone. However, overall, patients in the initial combination-therapy groups (groups 3 and 4) showed earlier clinical improvement and less radiographic damage compared with patients treated with MTX monotherapy. Also, after 3 years of therapy, 20% to 25% of those in groups 1 and 2, 50% in group 3, and 75% in group 4 were still on their initial treatment regimen, suggesting that many patients in groups 1 and 2 had to switch therapy because of ineffectiveness or toxicity. Notably, the overall remission rate in this study was 43%; 13% of the participants stopped taking all rheumatic drugs, and 48% of patients in group 4 were able to stop anti–TNF-α therapy with sustained clinical response.41
Many patients with RA do not respond or only partially respond to the medications currently available, including biologic therapies. This point emphasizes that these agents may be unable to fully suppress RA-related inflammation. In addition, intolerable adverse effects to the medications may develop in some patients.
However, new agents that target multiple aspects of the inflammatory pathways important in RA are being investigated, with the hope that these newer agents may prove more effective and better tolerated than currently available therapies. Some of these therapies, including anti–IL-6 therapy (tocilizumab), additional anti–B-cell therapies, and agents that inhibit the JAK pathway, are in late-stage clinical trials and may soon be approved for use in RA; others are early in the development process.
The newer RA therapies, especially the biologic therapies, have brought about a substantial improvement in the ability to treat patients with RA. However, until head-to-head comparison trials between the existing biologic therapies are performed, which of the available agents are best will not be known (most data suggest that the efficacy of each of the biologic agents is similar overall; the TNF-α antagonists perhaps have a more rapid onset of efficacy than other approved biologics).
Not all patients with RA respond well to the therapies currently available. ACR 20 or ACR 50 responses are no longer satisfactory, and clinicians should strive continually for low disease activity scores or remission. Therefore, new agents are needed to allow for adequate treatment of all patients with RA as well as better prediction models using biomarkers or genetic factors to know which patients will respond to which agents. In addition, with the knowledge that aggressive management of RA soon after the onset of symptoms results in improved outcomes, future research should be directed at not only discovering new agents for RA treatment but also learning how best to identify patients with RA early and using the agents already established most effectively.
References1. Gabriel SE, Crowson CS, Kremers HM, et al. Survival in rheumatoid arthritis: a population-based analysis of trends over 40 years. Arthritis Rheum. 2003;48:54-58.
2. Scott DL, Smith C, Kingsley G. Joint damage and disability in rheumatoid arthritis: an updated systematic review. Clin Exp Rheumatol. 2003;21(5 suppl 31):S20-S27.
3. Allaart CF, Breedveld FC, Dijkmans BA. Treatment of recent-onset rheumatoid arthritis: lessons from the BeSt study. J Rheumatol Suppl. 2007;80:25-33.
4. Cush JJ. Early rheumatoid arthritis-is there a window of opportunity? J Rheumatol Suppl. 2007;80:1-7.
5. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology: preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995;38:727-735.
6. van Gestel AM, Prevoo ML, van't Hof MA, et al. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum. 1996;39:34-40.
7. Prevoo ML, van't Hof MA, Kuper HH, et al. Modified disease activity scores that include twenty-eight-joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38:44-48.
8. van der Heijde D. How to read radiographs according to the Sharp/van der Heijde method. J Rheumatol. 1999;26:743-745.
9. Welsing PM, van Gestel AM, Swinkels HL, et al. The relationship between disease activity, joint destruction, and functional capacity over the course of rheumatoid arthritis. Arthritis Rheum. 2001;44:2009-2017.
10. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum. 1980;23:137-145.
11. Kvien TK, Kaasa S, Smedstad LM. Performance of the Norwegian SF-36 Health Survey in patients with rheumatoid arthritis, II: a comparison of the SF-36 with disease-specific measures. J Clin Epidemiol. 1998;51:1077-1086.
12. Pincus T, Yazici Y, Sokka T, et al. Methotrexate as the "anchor drug" for the treatment of early rheumatoid arthritis. Clin Exp Rheumatol. 2003;21(5, suppl 31):S179-S185.
13. van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, et al. Limited efficacy of conventional DMARDs after initial methotrexate failure in patients with recent onset rheumatoid arthritis treated according to the disease activity score. Ann Rheum Dis. 2007;66:1356-1362.
14. Goekoop YP, Allaart CF, Breedveld FC, Dijkmans BA. Combination therapy in rheumatoid arthritis. Curr Opin Rheumatol. 2001;13:177-183.
15. MÃ¶ttÃ¶nen 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;353:1568-1573.
16. Korpela M, Laasonen L, Hannonen P, et al; FIN-RACo Trial Group. Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: five-year experience from the FIN-RACo study. Arthritis Rheum. 2004;50:2072-2081.
17. O'Dell JR, Leff R, Paulsen G, et al. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002;46:1164-1170.
18. Calguneri M, Pay S, Caliskaner Z, et al. Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis. Clin Exp Rheumatol. 1999;17:699-704.
19. 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 [published correction appears in Lancet. 1998;351:220]. Lancet. 1997;350:309-318.
20. LandewÃ© RB, Boers M, Verhoeven AC, et al. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum. 2002;46:347-356.
21. 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;137:726-733.
22. 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;333:137-141.
23. Marchesoni A, Battafarano N, Arreghini M, et al. Radiographic progression in early rheumatoid arthritis: a 12-month randomized controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone. Rheumatology (Oxford). 2003;42:1545-1549.
24. Gerards AH, LandewÃ© RB, Prins AP, et al. Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomised placebo controlled trial. Ann Rheum Dis. 2003;62:291-296.
25. Willkens RF, Urowitz MB, Stablein DM, et al. Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthritis Rheum. 1992;35:849-856.
26. 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;44:1984-1992.
27. 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;159:2542-2550.
28. Kalden JR, Schattenkirchner M, SÃ¶rensen H, et al. The efficacy and safety of leflunomide in patients with active rheumatoid arthritis: a five-year followup study. Arthritis Rheum. 2003;48:1513-1520.
29. 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;39:655-665.
30. Tugwell P, Wells G, Strand V, et al. Clinical improvement as reflected in measures of function and health-related quality of life following treatment with leflunomide compared with methotrexate in patients with rheumatoid arthritis: sensitivity and relative efficiency to detect a treatment effect in a twelve-month, placebo-controlled trial. Leflunomide Rheumatoid Arthritis Investigators Group [published correction appears in Arthritis Rheum. 2000;43:1345]. Arthritis Rheum. 2000;43:506-514.
31. van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med. 2002;136:1-12.
32. Kirwan JR. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group. N Engl J Med. 1995;333:142-146.
33. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364:263-239.
34. Hansen KE, Cush J, Singhal A, et al. The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthritis. Arthritis Rheum. 2004;51:228-232.
35. Keystone EC, Schiff MH, Kremer JM, et al. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50:353-363.
36. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med. 1999;130:478-486.
37. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis [published corrections appear in N Engl J Med. 2001;344:76, 240]. N Engl J Med. 2000;343:1586-1593.
38. Klareskog L, van der Heijde D, de Jager JP, et al; TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study investigators. 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;363:675-681.
39. St Clair EW, van der Heijde DM, Smolen JS, et al; Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum. 2004;50:3432-3443.
40. Lipsky PE, van der Heijde D, St Clair EW, et al, for the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med. 2000;343:1594-1602.
41. 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. 2008;58(2 suppl):S126-S135.
42. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2007;146:406-415.
43. Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, randomized, double-blind 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;54:26-37.
44. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial [published correction appears in Arthritis Rheum. 2003;48:855]. Arthritis Rheum. 2003;48:35-45.
45. Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50:1400-1411.
46. Emery P, Fleischmann RM, Moreland LW, et al. Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum. 2009;60:2272-2283.
47. Keystone EC, Genovese MC, Klareskog L, et al. Golimumab, a human antibody to tumour necrosis factor alpha given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate ther-apy: the GO-FORWARD Study. Ann Rheum Dis. 2009;68:789-796.
48. Smolen JS, Kay J, Doyle MK, et al. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet. 2009;374:210-221.
49. Keystone E, Heijde D, Mason D Jr, et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study [published correction appears in Arthritis Rheum. 2009;60:1249]. ArthritisRheum. 2008;58:3319-3329.
50. Smolen J, LandewÃ© RB, Mease P, et al. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study: a randomised controlled trial. Ann Rheum Dis. 2009;68:797-804.
51. Fleischmann R, Vencovsky J, van Vollenhoven RF, et al. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis. 2009;68:805-811.
52. Chen YF, Jobanputra P, Barton P, et al. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. Health Technol Assess. 2006;10:iii-iv, xi-xiii, 1-229.
53. Scott DL, Cope A. New tumour necrosis factor inhibitors for rheumatoid arthritis: are there benefits from extending choice? Ann Rheum Dis. 2009;68:767-769.
54. van der Bijl AE, Breedveld FC, Antoni CE, et al. An open-label pilot study of the effectiveness of adalimumab in patients with rheumatoid arthritis and previous infliximab treatment: relationship to reasons for failure and anti-infliximab antibody status. Clin Rheumatol. 2008;27:1021-1028.
55. Erickson AR, Mikuls TR. Switching anti-TNF-alpha agents: what is the evidence? Curr Rheumatol Rep. 2007;9:416-420.
56. Rubbert-Roth A, Finckh A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis Res Ther. 2009;(11 suppl 1):S1.
57. Brulhart L, Ciurea A, Finckh A, et al. Efficacy of B cell depletion in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor alpha agents: an open-label observational study. Ann Rheum Dis. 2006;65:1255-1257.
58. Finckh A, Ciurea A, Brulhart L, et al. Which subgroup of rheumatoid arthritis patients benefits from switching to rituximab versus alternative anti-TNF agents after previous failure to anti-TNF agent? Ann Rheum Dis. 2009 May 15; [Epub ahead of print].
59. Bresnihan B, Cobby M. Clinical and radiological effects of anakinra in patients with rheumatoid arthritis. Rheumatology (Oxford). 2003;(42, suppl 2):ii22-iiS28.
60. 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;46:614-624.
61. Jiang Y, Genant HK, Watt I, et al. A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum. 2000;43:1001-1009.
62. LequerrÃ© T, Quartier P, Rosellini D, et al; SociÃ©tÃ© Francophone pour la Rhumatologie et les Maladies Inflammatoires en PÃ©diatrie (SOFREMIP); Club Rhumatismes et Inflammation (CRI). Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis. 2008;67:302-308.
63. Kremer JM, Genant HK, Moreland LW, et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2006;144:865-876.
64. Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition [published correction appears in N Engl J Med. 2005;353:2311]. N Engl J Med. 2005; 353:1114-1123.
65. 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;54:2793-2806.
66. Cohen SB. Updates from B cell trials: efficacy. J Rheumatol Suppl. 2006;77:12-17.
67. Keystone E, Emery P, Peterfy CG, et al. Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitor therapies. Ann Rheum Dis. 2009;68:216-221.
68. Genovese MC, Breedveld FC, Emery P, et al. Safety of biologic therapies following rituximab treatment in rheumatoid arthritis patients. Ann Rheum Dis. 2009 Jan 20; [Epub ahead of print].
69. 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;52:3381-3390.