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Advances in Understanding the Pathophysiology of Rheumatoid Arthritis

Key Points

  • TNFα antagonists and costimulatory modulators have significantly improved the outlook for RA therapy
  • New therapeutic options are still sought for patients with poor response to current therapy. The ultimate goal for RA therapy would be to achieve disease remission.
  • A patient nonresponsive to one TNFα antagonist may respond to another TNFα antagonist or to an agent with a different mechanism of action
  • Emerging T-cell therapies directly target T-cell activity or indirectly target T-cell activity via proinflammatory cytokines

Despite the availability of new treatments and therapeutic strategies, rheumatoid arthritis (RA) continues to adversely affect societal health and individual well-being. The cost to patients and society is significant, with more than 9 million doctor visits and a quarter-million hospitalizations due to RA each year. (1-3) Patients suffering from RA do obtain relief from current therapy, but loss of response or lack of response to RA treatments is still problematic, leaving room for new therapeutic options.

The benefit of earlier intervention with aggressive and combination therapies is evident. A “window of opportunity” may exist within the first 2 years of RA diagnosis, during which the early use of disease-modifying antirheumatic drugs (DMARDs) can lead to less erosion and joint damage. Early intervention alters the course of RA by slowing progression or inducing or sustaining remission. Delay of therapy can result in irreversible joint damage and loss of function. (4-9)

The observation that both proinflammatory and anti-inflammatory cytokines and their soluble receptors were upregulated in synovial membrane cell cultures led to the rational development of current TNFα antagonist therapies. Specific cytokines and other regulatory molecules involved in the inflammatory response became potential therapeutic targets. (10) TNFα antagonists were the first available drugs to target a specific cytokine by blocking the proinflammatory cytokine, TNFα. TNFα antagonism ameliorates the inflammatory response and has also been shown to restore regulatory CD4+CD25+ T-cell (TREG) function (Table 1), the goal being a return to immune tolerance. (10,11)

Table 1. Effects of TNFα Antagonism

TNFα Blockade
• Downregulates other proinflammatory cytokines, IL-1, IL-6, IL-8, MCP-1, and VEGF
• Decreases recruitment and decreases cellular activation of immune and inflammatory cells into joints
• Reduces angiogenesis
• Decreases serum levels of degradative enzymes MMP-1 and -3
Restoration of TREG Function
• Confers a suppressive phenotype on T cells
• Inhibits T-cell proliferation and cytokine production

TNFα=tumor necrosis factor α; IL-1=interleukin 1; IL- 6=interleukin 6; IL-8 =interleukin 8 ; MCP-1=monocyte chemoattractant protein; VEGF=vascular endothelial growth factor; MMP-1=matrix metalloproteinase 1; MMP-3=matrix metalloproteinase 3.

In addition to anticytokine therapies, targeting the proximal T cell has also been studied in RA. Early T-cell depletion strategies were clinically disappointing, and synovial T cells remained elevated despite significant systemic lymphopenia. Use of cM-T412, an anti-CD4 monoclonal antibody, alone or combined with methotrexate, significantly depleted peripheral CD4+ T cells but did not provide relief from RA symptoms. (12,13) Alemtuzumab, a monoclonal antibody that selectively binds CD52 on T and B cells, depleted peripheral T cells. Even so, a significant number of both T and B cells infiltrated synovial tissues, and CD4+ T cells were found throughout the synovial infiltrate. (14) There are also reports of patients with coexistent HIV and active RA, even with HIV-dependent depletion of peripheral CD4+ T cells, suggesting that the pathogenesis of RA is at least partly due to factors that are independent of CD4+ T-cell involvement. (15,16) Despite these results, selective inhibition of T cells using costimulatory blockade with abatacept has shown that T-cell modulation is an effective strategy for patients with RA.

Clinical Trial Results: TNFα Antagonists

Etanercept

Etanercept is a p75 TNF-R Fc fusion protein that competitively binds to the TNFα membrane receptor to inactivate TNFα.10 The efficacy of etanercept was established in studies of patients with refractory RA who received etanercept with or without methotrexate. Etanercept resulted in rapid, sustained reduction in RA disease activity over 3–6 months. (17-19) Evidence that earlier use of methotrexate prevented or slowed joint damage led to a comparative study of etanercept and methotrexate in patients with early, active RA. (20) Compared with weekly methotrexate, etanercept and methotrexate more rapidly improved the signs and symptoms of RA and significantly reduced joint damage after 6 months of treatment.

The Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes (TEMPO) is a 3-year study of etanercept and methotrexate, either alone or as combination therapy. In this study, patients had longstanding RA and a previously unsatisfactory response to a DMARD other than methotrexate. Two-year results show that compared with either drug alone, etanercept plus methotrexate significantly improved the mean Disease Activity Score (DAS), along with the numbers of patients achieving either remission (DAS <1.6) or a clinically meaningful increase in Health Assessment Questionnaire (HAQ) score. Combined etanercept and methotrexate also reduced radiographic progression as measured by erosion score and total Sharp score (TSS). (21,22)

Results from another comparative study, of etanercept plus methotrexate vs methotrexate alone, support the idea that remission is an achievable goal with the early use of aggressive treatment. The 2-year Combination of Methotrexate and Etanercept (COMET) study enrolled methotrexate-naive patients who had had active RA for 2 years or less. The primary endpoint of this study was DAS28 remission (<2.6) at 52 weeks. (23) Fifty percent of patients taking etanercept and methotrexate achieved remission at 1 year compared with 28% of those taking single-agent methotrexate (P<0.001). Low disease activity (DAS28 ≤3.2) was reported more frequently in the etanerceptmethotrexate group than in the methotrexate group (64% vs 41%, respectively; P<0.001).

Infliximab

Infliximab is a chimeric monoclonal antibody to human TNFα that binds to soluble and transmembrane forms of TNFα in vitro. Loss of TNFα activity results from binding to the soluble receptor, while binding to transmembrane forms initiates a cytotoxic response; it is not known which is important to the action of infliximab. TNFα inhibition by infliximab reduces serum levels of inflammatory mediators and vascular endothelial growth factor (VEGF), decreases chemokine expression in synovial tissue, and reduces lymphocyte migration into joints. (24) Repeated administration of infliximab and methotrexate over 2 years in patients with a previous inadequate response to methotrexate significantly improved several measures of RA activity, including ACR response, HAQ, and quality of life, along with slowing of radiographic progression. (25) The onset of clinical response was rapid and sustained throughout the 2-year study period.

The Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) trial combined methotrexate with infliximab or placebo in patients with an RA duration of 3 years or less who were naive to methotrexate or TNFα antagonists. (26) The primary endpoint was the percentage of ACR improvement (ACR-N). Infliximab and methotrexate significantly improved the week 54 median ACR-N compared with methotrexate alone, effectively reducing the signs and symptoms of RA disease activity. Combined infliximab and methotrexate also significantly inhibited radiographic progression as measured by the Sharp/van der Heijde Score (SHS) and significantly improved physical function measured by HAQ. A long-term assessment at 4 years of follow-up shows that infliximab maintained initial rapid improvements in DAS28, with a further decrease of 0.2 units in DAS28 score per year. (27)

Adalimumab

Adalimumab, a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody to TNFα, blocks TNFα interaction with p55 and p75 cell surface TNF receptors. Adalimumab lyses surface TNFα-expressing cells in vitro in the presence of complement, and modulates TNFα-induced biologic responses, such as altering levels of adhesion molecules that facilitate leukocyte migration. Adalimumab does not inactivate lymphotoxin (TNFβ). (28) Several randomized controlled trials show that adalimumab given every other week significantly reduced disease activity at 24 weeks, either as monotherapy or in combination with DMARDs including methotrexate. (29-31) Improvement was noted as early as week 1.31 In a long-term extension trial, almost one-half of patients at 4 years had achieved a clinical remission (DAS28 <2.6), and 22% reported a HAQ equal to zero. (32)

A study of adalimumab and methotrexate in early aggressive RA (the PREMIER study) was the first to compare the efficacy of a TNFα antagonist, methotrexate, alone or in combination in methotrexate-naive RA patients. (9) The primary endpoints were a 50% improvement in ACR50 and a 50% mean change in TSS from baseline. At 1 year, the proportion of patients achieving an ACR50 response was significantly greater for the combined-therapy group than either drug alone; this effect was sustained through the second year of treatment. Similar results were observed for ACR20, ACR70, and ACR90 responses. There was also significantly less radiographic progression at 1 and 2 years, with a mean increase of 1.3 and 1.9 Sharp units, respectively, for patients taking combination therapy compared with an increase of 3 or more Sharp units for patients taking monotherapy. Almost one-half of patients taking combination therapy were in remission at 2 years (DAS28 <2.8).

Two additional products specific for human TNFα are under evaluation. In a dose-ranging, comparative trial of methotrexate-refractory patients, golimumab (CNTO 148) combined with methotrexate resulted in significantly improved ACR and DAS responses at week 16, which were maintained through week 52. (33) No safety concerns were noted with golimumab in this study. Golimumab is now under study in phase 3 trials in patients with RA who either are methotrexate naive, have a suboptimal response to methotrexate, or have been previously treated with a TNF antagonist. In some of these trials, ACR50 is a primary endpoint.

Certolizumab pegol (CDP870) is a fully humanized, anti- TNF antibody Fab’ fragment that neutralizes TNFα. The Fab’ fragment retains the affinity and potency of the monoclonal antibody but lacks the Fc portion of the parent IgG4 antibody. (34) In two phase 3 studies (RAPID 1 and RAPID 2), certolizumab added to ongoing methotrexate35-39 resulted in significant improvements in TSS, ACR20, ACR50, and ACR70 at week 24 (RAPID 1 and RAPID 2) and also at week 52 (RAPID 1). The proportion of patients with an ACR50 response at week 52 was just less than 40%, and the proportion of patients with an ACR70 response was slightly more than 20%. Patients also sustained significant improvements in their HAQ Disability Index and a quality-oflife measure. Adverse effects associated with certolizumab were generally mild to moderate and did not result in higher discontinuation rates. Long-term, phase 3, openlabel studies are ongoing to assess response, radiographic progression, and safety.

TNFα Antagonist Safety

TNFα antagonists were generally well tolerated in clinical trials. Mild injection-site reactions were noted with etanercept (17-20) and adalimumab. (28,30) Infusion reactions (or hypersensitivity reactions) have been reported with infliximab. (26) These usually occur during or within 2 hours of the infliximab infusion, and symptoms might include urticaria, dyspnea, or hypotension. (40)

Antibody development to etanercept appears to be absent or minimal, and the presence of antibodies was not correlated with either a lack of response or adverse effects in clinical trials. (18,20) Infliximab use results in antibody formation in some patients. Antibody formation may be associated with development of some hypersensitivity reactions (40) and has been associated with decreased trough levels of infliximab. (41) Further study is needed to fully understand the impact antibody formation has on treatment with infliximab.

Serious bacterial infections also occur in more patients taking a TNFα antagonist (0.07–0.09 per patient year) than other DMARDs (0.01–0.06 per patient year). It is not known if this increase might be dose-related (eg, increased incidence with higher TNFα antagonist doses) or what contribution glucocorticoid use might have to the increased risk of infection. (42) Patients should not start therapy in the presence of an active infection and should be monitored if a new infection is contracted. Therapy should also be discontinued in the face of a serious infection. (28,40,43) The safety of TNFα antagonists during surgery remains to be elucidated. (42)

As a class, TNFα antagonists are also associated with an increased risk of tuberculosis. The risk of newly acquired or activation of latent tuberculosis is raised with DMARD use, and the risk appears to be further increased with TNFα antagonists. While numerically more cases of tuberculosis were reported with infliximab or adalimumab than etanercept, definitive data are lacking on the comparative risk of tuberculosis between the TNFα antagonists. (42) Tuberculosis screening should be part of the pretreatment regimen with all TNFα antagonists (44); the optimal tuberculosis prophylaxis/treatment regimen has not yet been identified. (42)

Lymphoma and solid tumors have been reported with TNFα antagonist use; however, the risk of developing lymphoma is reportedly higher in RA patients compared with the general population. Whether TNFα antagonists further increase this risk is still unclear. It is unknown whether patients with a history of lymphoma or solid tumors should use TNFα antagonists. (42)

Continued vigilance is needed to fully understand the safety profiles of the TNFα antagonists. (42,45) Data from a variety of sources, such as clinical trial data (including long-term extension studies), patient registries, and spontaneous reporting systems, will be useful in understanding the risk of infection, malignancy, and other adverse events in the RA population.

Clinical Trial Results: Selective Costimulatory Modulators

Abatacept

Abatacept is the first available biologic drug approved for RA that acts directly against T cells. First known as cytotoxic T-lymphocyte–associated antigen 4-IgG1 (CTLA-4-Ig), abatacept is a costimulation blocker of T-cell activation and proliferation, binding to CD80/CD86 on antigen-presenting cells (APCs), blocking the T-cell CD28 costimulatory T-cell activation signal. (46,47) The Abatacept in Methotrexate (AIM) failures study (46) was a 1-year, randomized, controlled trial to evaluate a once-monthly fixed dose of abatacept (for 6 months) in methotrexate-refractory patients with active RA. Patients continued to receive methotrexate while receiving abatacept. The primary endpoint was the proportion of patients achieving an ACR20 at 6 months. Abatacept resulted in significantly more patients achieving an ACR20, from month 2 through month 6, compared with placebo (60% vs 35.3%, respectively; P<0.001). While significantly more patients taking abatacept also had ACR50 and ACR70 responses at 6 months, the proportion of patients benefiting from the greater reduction in disease activity remained modest (ACR50, 36.5%; ACR70, 16.5%).

The Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN) (47) compared abatacept with placebo in patients who were refractory to either etanercept or infliximab. Patients continued to take at least one DMARD (other than a TNFα antagonist) while in the study. After 6 months, the proportion of patients with an ACR20, ACR50, or ACR70 response was significantly higher in the abatacept group. More patients taking abatacept also had a significant improvement in physical function, measured by at least a 0.3 improvement over baseline HAQ.

Additional phase 3 trials of abatacept in patients with an inadequate response to methotrexate are under way. These studies will evaluate the early effect of abatacept on inflammation and structural damage through MRI, bone mineral density, and biologic markers.

Selective Costimulatory Modulator Safety

In clinical trials, the overall safety profile of abatacept was similar to that of placebo. The most commonly reported adverse events in 10% or more of patients on abatacept included headache, upper respiratory tract infection, nasopharyngitis, and nausea. (48) In both AIM and ATTAIN, CTLA-4-Ig–specific antibodies arose rarely in patients treated with abatacept. (46,47)

In placebo-controlled trials, infection occurred more often in abatacept-treated patients. Infection was the adverse event most frequently requiring clinical intervention. Serious infection occurred in 3.0% of abatacept-treated patients compared with 1.9% of placebo-treated patients, with pneumonia being the most frequent serious infection. (48) Notably, the rate of serious infections increased to 4.4% (vs 1.5% in controls) when abatacept was combined with a TNFα antagonist, and their combined use is not recommended. (42) Abatacept should be used with caution in patients with chronic obstructive pulmonary disease (COPD), as these patients had an increased rate of adverse events, including exacerbation of COPD and related symptoms. Patients should not receive a live vaccine during or within 3 months of stopping abatacept. It is unknown whether abatacept affects vaccine efficacy. As with all immunomodulators, prescreening for tuberculosis is advised, and use during infection is not recommended. Because abatacept is a newer biologic agent, fewer patients have been exposed to it, and the long-term risk of malignancies and other adverse events is unclear. Longer trials in various RA populations are also required to confirm the lack of infection-related adverse events associated with its use.

Clinical Trial Results: B-Cell Depletion

Rituximab

Rituximab selectively targets CD20+ B cells and is indicated for use in RA in combination with methotrexate when there has been an inadequate response to TNFα antagonist therapy. B cells act at multiple steps in the inflammatory cascade via induction of proinflammatory cytokines and autoantibody production. (49) Rituximab also affects T-cell function indirectly through its effect on B cells. Within the synovium, B cells also exist in lymphoid aggregates, acting as APCs to provide costimulatory signals that promote T-cell expansion (50) and involve the costimulatory molecules CD80 and CD86. (51) Two studies, the Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) and the Dose-Ranging Assessment: International Clinical Evaluation of Rituximab in Rheumatoid Arthritis (DANCER), showed that rituximab added to ongoing methotrexate significantly improved multiple endpoints for RA. (49,52) REFLEX and DANCER will be covered in more detail in the third newsletter of this series.

Clinical Trial Results: Emerging Therapies

The introduction of currently available biologic therapies represents an important advance in RA treatment, but new treatment choices are still needed to help the substantial number of patients achieving either a minimal response or a good but incomplete response to current therapy.

IL-6 and IL-15, two proinflammatory cytokines, are targets for new drug therapy. IL-6 regulates the immune response, inflammation, hematopoiesis, and bone metabolism. Elevated serum and synovial fluid levels of IL-6 are detected in RA patients, and IL-6 serum levels are associated with indicators of disease activity and joint damage. (53) Tocilizumab, or MRA, is a targeted therapy for IL-6, a humanized anti–IL-6 receptor monoclonal antibody. In phase 2 studies in refractory RA, tocilizumab significantly improved disease activity compared with placebo when given monthly for 3 months. (53) Combination therapy with tocilizumab and methotrexate was superior to either tocilizumab or methotrexate alone for ACR20 response measured at 16 weeks. Only the highest tocilizumab dose (8 mg/kg) combined with methotrexate significantly improved the proportion of patients attaining an ACR50 or ACR70 response, and the 8 mg/kg dose of tocilizumab was also associated with the maximum reduction in DAS. (54) In addition to improving the signs and symptoms of RA, tocilizumab monotherapy resulted in significantly less radiographic progression measured by 52-week TSS compared with conventional DMARDs. (55) Adverse effects appear to be mild to moderate (53,54); treatment-emergent events in the combined tocilizumab/methotrexate trial included infection and musculoskeletal, gastrointestinal, or dermatologic reactions. (54) Phase 3 trials are planned or are under way to further assess the safety and efficacy of tocilizumab combined with methotrexate or methotrexate alone in patients with moderate-to-severe RA who have had an inadequate response to methotrexate or TNFα antagonists.

IL-15 is a pleiotropic cytokine detectable in inflamed synovial tissues that has signal effector pathways distinct from TNFα. IL-15 is involved in multiple proinflammatory pathways, including the recruitment and activation of T cells, maintenance of T-cell memory, and impeding apoptosis of fibroblast-like synoviocytes. (56) HuMax–IL-15 (AMG 714) is a fully human IgG1 anti–IL-15 monoclonal antibody that binds to receptor-bound IL-15 and neutralizes IL-15 activity. A phase 1–2, 12-week study in patients with active RA taking no other DMARDs resulted in 63% of patients achieving an ACR20, although fewer than one-half reached ACR50 or ACR70 at week 8. Treatment was well-tolerated; single doses of HuMax–IL-15 were associated with flu-like symptoms and multiple doses with minor injection-site reactions. Further study is needed to assess the effect of HuMax–IL-15 on natural killer cells and CD8+ T-cell activity. (56)

Alefacept, another costimulatory modulator, is a soluble fusion protein that blocks CD2, a costimulatory site on T cells that binds to CD (58). Blocking CD2 results in inhibition of T-cell activation through depletion of CD45RO+ memoryeffector T cells. (57) Alefacept is currently approved for psoriasis (57) and has shown activity in psoriatic arthritis in combination with methotrexate, reducing disease activity compared with placebo. (58) In patients with active RA, alefacept plus methotrexate was significantly more active than methotrexate, with 67% of patients taking alefacept achieving an ACR20 response at any point during the 12-week study. (59)

Efalizumab is a humanized recombinant antibody against CD11a; CD11a is involved with T-cell adhesion and activation. Efalizumab has been shown to interfere with T-cell activation, and, like alefacept, is approved for psoriasis. (57) However, a phase 2 study of efalizumab for use in RA was unsuccessful and was stopped early because of lack of clinical benefit.

Eculizumab (h5G1.1-mAb), a humanized anti-C5 antibody, previously shown to inhibit activation of complement component C5 into its proinflammatory elements C5a and C5b-9, (60) was studied in patients with active RA despite treatment with methotrexate or leflunomide. Weekly eculizumab added to a DMARD for 5 weeks, followed by monthly administration of eculizumab, significantly reduced erythrocyte sedimentation rate (ESR) and improved the proportion of patients achieving an ACR20 vs placebo (eculizumab 34%, placebo 22%; P=0.04). Eculizumab was well tolerated during this 6-month study. (61)

Recent findings about T-cell–mediated tissue damage suggest that type 1 CD4+ T helper cells (T helper type 1 cells, TH1) are not the sole mediator of events leading to tissue damage. (62) A model involving the T cells that produce IL-17 (TH17) and their production of IL-17 has been identified as a major factor in the regulation of tissue damage defined by delayed-type sensitivity reactions; IL-17 is known to also have a role in autoimmune and allergic conditions. As tissue damage progresses, TH1 may antagonize TH17. The full effect of TH17 has not been completely elucidated, but greater understanding of the pathways mediating tissue damage could lead to new RA therapies.

Nonresponse to TNFα Antagonists

Through a new mechanism of action, the TNFα antagonists have afforded relief to patients who have had a poor response to therapy with methotrexate. Even so, as the numbers of patients receiving TNFα antagonists grows, it is apparent that a substantial number of patients, up to 40%, also have a poor response to TNFα antagonists. (63) The factors involved in nonresponse to TNFα antagonists are poorly understood. Definitions of nonresponse differ and have included a failure to achieve a reduction in DAS28 score by 1.2 or failure to achieve an ACR20 response.

Nonresponse after treatment initiation has been described as primary nonresponse, which may be linked directly to the TNFα antagonist or may indicate the presence of a distinct subtype of RA. Secondary nonresponse is described as the loss of initial response to a TNFα antagonist, and may indicate interindividual differences in pharmacokinetics of RA therapies or signal the development of antibodies. Other reasons for a lack of observed clinical benefit include: a delay in response as opposed to a lack of response; response dependence on the instrument used to measure response (ie, a patient may be nonresponsive by ACR criteria but exhibit radiologic improvement); or the disease may be TNFα independent.64 Nonresponse does not preclude therapy with another TNFα antagonist, since patients failing to respond to one TNFα antagonist have responded to another. (63)

Reliable predictors of response are not yet available to aid the clinician in selecting therapy. C-reactive protein (CRP) levels, (64) synoviolin expression, (65) circulating TNFα activity, (66) genotyping, (67) and anti-CCP titers (68) have all been studied as potential predictors of response to infliximab. Genetic markers have been assessed for infliximab (69) and etanercept, (70) baseline HAQ has been studied for infliximab (71) and etanercept, (71) and pretreatment IgA rheumatoid factor levels have been assessed for infliximab, etanercept, and adalimumab. (72) Table 2 presents the results of these investigations.

An exploratory analysis of the ASPIRE study considered whether joint damage, as measured by changes in Sharp score, would identify predictors of radiographic progression to determine which patients might benefit from infliximab. (73) At week 54, the change in Sharp score was significantly greater in patients taking methotrexate alone vs infliximab and methotrexate. High baseline CRP, elevated ESR, or persistent disease activity were associated with greater radiographic progression in the methotrexate-only group. Little radiographic progression was observed in patients receiving both infliximab and methotrexate, regardless of abnormal baseline CRP and ESR.

It is not understood what pathogenic mechanisms underlie the patterns of response observed in these studies; further study is needed to fully establish their predictive value in therapy. Studies continue to assess potential markers for the three available TNFα antagonists.

Table 2. Potential Predictors of Response for TNFα Antagonists

Predictor TNFα Antagonist Response
CRP (64) Infliximab • Failure to suppress CRP at wk 2 linked to nonresponse at wk 12
• CRP suppression at wk 12 linked to clinical response at wk 24
• Failure to suppress CRP at week 12 linked to future etanercept response
Synoviolin expression (65) Infliximab • No change between wk 0 and wk 22 synoviolin expression was linked to nonresponse
Circulating TNFα activity (66) Infliximab • Good responders had higher initial IL-6 levels and greater reduction in IL-6 levels after first infliximab infusion
Anti-CCP titers (68) Infliximab • Lower baseline anti-CCP titers linked to response
Genotyping (67,70) Infliximab • Downregulation of 8 selected PBMC transcripts at 3 mo linked to nonresponse
Genetic markers (69,70) Infliximab, etanercept • Certain HLA genotypes associated with response
HAQ (71) Infliximab, etanercept • Higher baseline HAQ linked to decreased response
• Lower baseline HAQ and concurrent use of NSAIDs predictive for remission
IgA rheumatoid factor levels (72) Infliximab, etanercept, adalimumab • Higher pretreatment IgA levels linked to nonresponse

Anti-CCP=anti-cyclic citrullinated peptide; CRP=C-reactive protein; HAQ=Health Assessment Questionnaire; HLA=human leukocyte antigen; PBMC=peripheral blood mononuclear cells.

Combination Therapies and Switching Agents in Nonresponders

TNFα antagonists have been successfully added to continuing methotrexate therapy following an inadequate response to methotrexate alone. (19,31,74,75) Rapid and sustained ACR20 responses in approximately one-half to threequarters of patients were noted, but at least one-half of patients in these studies still failed to meet the more stringent ACR50 or ACR70 response criteria. Adalimumab or infliximab added to existing methotrexate therapy also resulted in less long-term radiographic progression, (74,75) and adalimumab was associated with significantly improved 52-week HAQ. (75) Similar results are noted with the addition of abatacept to a stable methotrexate regimen in patients with a suboptimal methotrexate response. A majority of patients (63%–73%) achieved an ACR20 at 12 months, in addition to significant improvements in HAQ and slowing of radiographic progression. (46,76,77)

Patients who are nonresponsive to a TNFα antagonist may later respond to a different TNFα antagonist. In a retrospective analysis of patients who had switched to etanercept or infliximab due to nonresponse (29 patients), 19 responded to the alternate drug (infliximab or etanercept) as measured by DAS at 3 months. At the median duration of follow-up (11.5 months), 8 of 19 patients with an initial response had stopped because of lack of efficacy. (78) Response to adalimumab has also been noted in patients failing either infliximab or etanercept; 6 months of adalimumab therapy appeared to restore the previous clinical response in a majority of patients. (79) Abatacept has also shown activity in patients who were nonresponsive to infliximab, etanercept, or adalimumab, with one-half of patients attaining an ACR20 and meaningful improvement in HAQ after 6 months of abatacept therapy. (47) Rituximab has also been studied in TNFα failures. In the REFLEX study, significantly more patients taking rituximab achieved an ACR20, ACR50, or ACR70 response than patients taking placebo. Details of the REFLEX study will be covered in detail in the third newsletter of this series. (49)

Combined use of abatacept and a TNFα antagonist is not recommended. In a comparative trial of abatacept or placebo added to a nonbiologic DMARD (eg, methotrexate) or a biologic DMARD (eg, a TNFα antagonist), patients receiving abatacept and a biologic DMARD had more adverse events and more serious adverse events, serious infections, and discontinuations than the placebo group. (80)

Summary

TNFα antagonists have proven to be potent inhibitors of inflammation along multiple pathways in the pathogenesis of RA. Even with these potent biologic agents, a significant proportion of patients with RA show a lack of response to TNFα antagonists or are unable to take this therapy. Early evaluations of broad T-cell inhibition were disappointing; however, abatacept shows great promise in the treatment of RA, including patients who are TNFα naive or who had a poor response to methotrexate. T-cell–directed therapy via costimulatory blockade is an effective strategy in the treatment of RA. Understanding these strategies is extremely important in the management of patients with RA.

Post Test

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