Efforts to develop more effective treatment strategies for patients with RA hinge on understanding the role of inflammatory mediators in the disease process. Interleukin (IL)-1, IL-6, and TNF-α inhibitors have been identified as key cytokines that drive the inflammatory process in RA.36 Additional agents target B-cell depletion and T-cell costimulation.37
TNF-α inhibitors currently FDA-approved are infliximab(Drug information on infliximab), etanercept(Drug information on etanercept), adalimumab(Drug information on adalimumab), golimumab, and certolizumab. Of these agents, adalimumab, certolizumab, etanercept, and golimumab are approved as monotherapy for RA, but they also have been used successfully in conjunction with other DMARDs and more often are used as combination therapy.38
Infliximab. This is a chimeric human-mouse anti–TNF-α monoclonal antibody.39 Infliximab used in combination with MTX in patients with early RA has been shown to inhibit progression of structural damage and radiographic progression.40 Infliximab is the only TNF-α inhibitor currently in use that is administered as an infusion.
Etanercept. This recombinant human TNF receptor-Fc soluble fusion protein has been shown to reduce disease activity in patients with RA.41 The use of etanercept in combination with MTX in patients with early, moderate to severe RA showed outcomes superior to those with MTX monotherapy with regard to clinical remission at 1 year (50% compared with 28%) and radiographic nonprogression (80% compared with 59%).35
Adalimumab. This is a recombinant fully human IgG1 monoclonal antibody. Combination therapy with MTX and adalimumab was superior to adalimumab monotherapy in improving signs and symptoms in patients with early, aggressive RA at 1 year (ACR 50 response was achieved in 62% and 41% of patients, respectively), effecting clinical remission and inhibition of radiographic progression.42
Certolizumab and golimumab. These are the newer anti–TNF-α agents. Certolizumab pegol, a PEGylated TNF-α inhibitor, has been shown to be beneficial for patients with active RA; more patients achieved ACR 20 response than those who received placebo or they had less radiographic progression.43 Golimumab, a human monoclonal TNF antibody, has been studied for use in patients with ongoing disease activity who had been treated with a TNF-α inhibitor (but therapy was discontinued because of loss of efficacy, intolerance, or lack of accessibility).44 In clinical trials, ACR 20 response at week 14 was achieved in a larger number of treated patients than patients given placebo (up to 38% vs 18% of patients).44
In patients who do not respond to one TNF-α inhibitor, switching to an alternative TNF-α inhibitor may be attempted or use of a biologic agent with an alternative treatment target may be considered. The response rate to TNF-α inhibitor switching varies among patients.
Anakinra. This IL-1 receptor antagonist has been FDA-approved for use in patients with moderate to severe RA who have been unresponsive to initial DMARD therapy.43 A recent systematic review concluded that the degree of improvement noted was less than that seen in studies of other biologic agents,45 and this agent is used less widely than anti–TNF-α agents.
Abatacept. This selective T-cell costimulation modulator is another alternative to the TNF-α inhibitors. Patients with active RA who had an inadequate response to TNF-α inhibitor therapy were randomized to receive abatacept or placebo in addition to at least 1 DMARD; at 6 months, they had ACR 50 response rates of 20% compared with 4% and more patients in the abatacept group had clinically meaningful improvement in physical function.46
Rituximab. This is a genetically engineered chimeric anti-CD20 antibody that targets peripheral B cells, which have been shown to play a role at various levels in the inflammatory pathway.47 Rituximab has been FDA-approved for management of moderate to severe RA given with MTX for patients for whom at least 1 TNF-α–blocking agent has resulted in an inadequate response.48 In current practice, patients in whom treatment with one TNF-α inhibitor was not successful often try an alternative TNF-α inhibitor before initiation of rituximab(Drug information on rituximab) therapy.
In a prospective cohort study, patients who had previously discontinued at least 1 TNF-α inhibitor as a result of lack of efficacy showed clinically significant improvement with rituximab compared with switching to an alternative TNF-α inhibitor.49 The presence of the anti-CCP antibodies, rheumatoid factor positivity, and elevated IgG levels predict favorable response to rituximab in patients with refractory RA.50
Tocilizumab. Overproduction of IL-6 has been shown to play a pathogenetic role in RA. Tocilizumab is a humanized anti–IL-6 receptor monoclonal antibody51 that when used with MTX is effective in inducing remission, sustaining clinical improvement, and improving function.52
Disease activity measures (the DAS 28 and CDAI) at 3 months are significantly related to disease activity at 1 year. Therefore, the 3-month mark serves as a good assessment point for reevaluation, because patients who do not achieve moderate or low levels of disease activity at 3 months after the start of DMARDs are unlikely to be in remission or have low disease activity states at 1 year. Alternative treatment strategies should be pursued both in patients with early RA who have not previously been exposed to DMARDs and in those with established disease and an inadequate response to MTX.20 Our approach to the management of early RA is summarized in Tables 1 and 2.
For the management of more established cases beyond the first year of disease, disease activity targets are reassessed at follow-up.53,54 If the target is attained, the DMARD regimen may be continued with tapering of prednisone(Drug information on prednisone) for patients in remission. If there is sustained remission, consider de-escalation of therapy. For patients with low disease activity, the DMARD regimen should be continued. If the target is not attained, consider adding SSZ and HCQ and, in patients not receiving biologic agents, adding a TNF-α inhibitor or abatacept.
Preventive strategies are important in caring for patients with RA. Along with disease activity measures, they should be assessed periodically at follow-up.53,55-57
Increased use of biologic agents has been accompanied by appropriate vigilance about possible adverse effects, including the risk of serious infections and malignancy. One early meta-analysis of harmful effects associated with anti–TNF-α antibody therapy use in RA showed an increased risk of serious infection and malignancy58; more recent meta-analyses with longer patient follow-up have suggested that the risk of serious infection is only minimally higher than at baseline for patients with RA who are receiving MTX therapy alone, and the overall risk of malignancy is not increased, other than the risk of nonmelanotic skin cancer.59
A recent meta-analysis that compared rates of serious infections for biologic agents with placebo did not reveal significant increases in the risk of serious infections in patients with RA during treatment with rituximab or abatacept.60 Although there is no direct evidence of a causal relationship, cases of progressive multifocal leukoencephalopathy associated with rituximab use have been reported.61
Recognition of the possibility of an increased risk of malignancy and infections is important in the clinician’s selection of treatment strategies. Such recognition also is important for informing patients in shared decision making.
TARGETS IN DEVELOPMENT
Ofatumumab. This anti-CD20 monoclonal antibody has been shown in phase 1 and 2 studies to be beneficial in the treatment of patients with active RA who have not been responsive to at least 1 DMARD.62 Phase 3 trials currently are under way.63,64
Belimumab. This fully human anti–B-lymphocyte stimulator monoclonal antibody65 was FDA-approved in 2011 for treatment of patients with systemic lupus erythematosus. Studies of this agent in RA have been disappointing.66
Atacicept. This recombinant fusion protein binds to the B-lymphocyte stimulator receptor (BLyS, CD257) and a proliferation-inducing ligand (APRIL, CD256), which are stimulators of B-cell maturation, proliferation, and survival.67,68 A study of atacicept in anti–TNF-α–naive patients with moderate to severe active RA and an inadequate response to MTX was done, but the results have not yet been published.69
Tofacitinib. Janus kinase (JAK) 3, an intracellular molecule, plays a critical role in signal transduction of the receptors for IL-2, IL-4, IL-7, IL-19, IL-15, and IL-21 (related to lymphocyte activation, function, and proliferation).70 The oral JAK inhibitor tofacitinib has been shown in phase 2a trials to be effective in patients with active RA; ACR 20 response rates of up to 81% were achieved, and the agent was shown to result in improved pain and physical function compared with placebo.71,72
R788. A recent 6-month, double-blind, placebo-controlled trial of an oral tyrosine kinase inhibitor (R788) in patients who had active RA in spite of receiving long-term MTX therapy showed ACR 20 response rates of up to 67% for patients receiving R788 compared with 35% for placebo patients.73 Diarrhea, upper respiratory tract infections, and elevated blood pressure were noted.
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