Antibody response is reduced following vaccination with 7‐valent conjugate pneumococcal vaccine in adult methotrexate‐treated patients with established arthritis,but not those treated with tumor necrosis factor inhibitors

Objective

To study the influence of antiinflammatory treatments, including methotrexate (MTX) and tumor necrosis factor (TNF) inhibitors, on antibody response following vaccination using a 7‐valent conjugate pneumococcal vaccine in adult patients with established arthritis.

Methods

Patients with rheumatoid arthritis (RA) or spondylarthropathy (SpA) (including psoriatic arthritis) were vaccinated (n = 505). All patients were stratified into 6 prespecified groups based on diagnosis and treatment (RA patients receiving MTX, RA patients receiving anti‐TNF agents and MTX, RA patients receiving TNF inhibitors as monotherapy, SpA patients receiving anti‐TNF agents and MTX, SpA patients receiving TNF inhibitors as monotherapy, and SpA patients receiving nonsteroidal antiinflammatory drugs [NSAIDs] and/or analgesics). SpA patients receiving only NSAIDs/analgesics served as a control group. All patients received 1 dose (0.5 ml) of vaccine intramuscularly. Levels of IgG antibodies against 23F and 6B serotypes were measured at vaccination and at 4–6 weeks following vaccination, using standardized enzyme‐linked immunosorbent assays.

Results

Positive antibody response was defined as an antibody response ratio (ARR) (i.e., ratio of post‐ to prevaccination antibody levels) of ≥2. The ARR differed significantly between the groups. A better ARR was seen among patients in the control group compared to those in groups treated with MTX or MTX in combination with TNF inhibitors. Among patients treated with TNF inhibitors as monotherapy, ARRs for both serotypes were lower numerically, but were not significantly different, compared to those in controls. Ongoing MTX treatment was predictive of reduced response (odds ratio 0.41 [95% confidence interval 0.24–0.68], P = 0.001). Higher age was associated with impaired positive antibody response. Concomitant prednisolone treatment elicited better positive antibody response in patients with RA.

Conclusion

Treatment with MTX and higher age were predictive of an impaired antibody response to the 7‐valent conjugate pneumococcal vaccine in this cohort of patients with chronic arthritis. TNF inhibitors did not significantly affect antibody responses.

     

Effect of rituximab on physical function and quality of life in patients with rheumatoid arthritis previously untreated with methotrexate

Objective

To assess the effect of rituximab plus methotrexate (MTX) compared with MTX alone on patient‐reported outcomes (PROs) and health‐related quality of life (HRQOL) in patients with active early rheumatoid arthritis (RA) previously untreated with MTX.

Methods

Patients with active early RA were randomized to groups receiving placebo, rituximab 500 mg, or rituximab 1,000 mg. Rituximab was given by intravenous infusion on days 1 and 15. From week 24, patients with a Disease Activity Score in 28 joints–erythrocyte sedimentation rate of ≥2.6 were eligible for retreatment. Physical function was assessed by Health Assessment Questionnaire (HAQ) disability index (DI) and Short Form 36 (SF‐36) scores. Patients achieving a minimal clinically important difference (MCID) for PROs were determined. Additional PROs, including fatigue and pain, were assessed.

Results

A total of 748 patients were randomized and received the study drug. Patient characteristics were well balanced. At week 52, treatment with rituximab in both dose groups showed significant improvements in the HAQ DI compared to the MTX alone group (?0.905 and ?0.916 in the rituximab 500 mg plus MTX and 1,000 mg plus MTX groups, respectively, versus ?0.628 in the MTX alone group; P < 0.0001). Higher proportions of patients achieved MCID in the HAQ DI in the rituximab plus MTX groups compared to MTX alone. Treatment with rituximab plus MTX led to a significant reduction in the SF‐36 physical component summary for both rituximab dose groups, but did not show statistically significant differences in the SF‐36 mental component summary. Compared to the MTX alone group, both doses of rituximab plus MTX were associated with significant reductions in the patient global assessment of disease activity and pain, and a significantly higher improvement in Functional Assessment of Chronic Illness Therapy–Fatigue scores from baseline to 52 weeks.

Conclusions

Rituximab plus MTX was associated with significant improvement in physical function and HRQOL outcomes compared with MTX alone in patients previously untreated with MTX.

     

Studies of cell‐mediated immune responses to influenza vaccination in systemic lupus erythematosus

Objective

Both antibody and cell‐mediated responses are involved in the defense against influenza. In patients with systemic lupus erythematosus (SLE), a decreased antibody response to subunit influenza vaccine has been demonstrated, but cell‐mediated responses have not yet been assessed. This study was therefore undertaken to assess cell‐mediated responses to influenza vaccination in patients with SLE.

Methods

Fifty‐four patients with SLE and 54 healthy control subjects received subunit influenza vaccine. Peripheral blood mononuclear cells and sera were obtained before and 1 month after vaccination. Cell‐mediated responses to A/H1N1 and A/H3N2 vaccines were evaluated using an interferon‐γ (IFNγ) enzyme‐linked immunospot assay and flow cytometry. Antibody responses were measured using a hemagglutination inhibition test.

Results

Prior to vaccination, patients with SLE had fewer IFNγ spot‐forming cells against A/H1N1 compared with control subjects and a lower frequency of IFNγ‐positive CD8+ T cells. After vaccination, the number of IFNγ spot‐forming cells increased in both patients and control subjects, although the number remained lower in patients. In addition, the frequencies of CD4+ T cells producing tumor necrosis factor and interleukin‐2 were lower in patients after vaccination compared with healthy control subjects. As expected for a subunit vaccine, vaccination did not induce a CD8+ T cell response. For A/H3N2‐specific responses, results were comparable. Diminished cell‐mediated responses to influenza vaccination were associated with the use of prednisone and/or azathioprine. The increase in A/H1N1‐specific and A/H3N2‐specific antibody titers after vaccination was lower in patients compared with control subjects.

Conclusion

In addition to a decreased antibody response, cell‐mediated responses to influenza vaccination are diminished in patients with SLE, which may reflect the effects of the concomitant use of immunosuppressive drugs. This may render these patients more susceptible to (complicated) influenza infections.

     

Immunization responses in rheumatoid arthritis patients treated with rituximab: Results from a controlled clinical trial

Objective

To examine immunization responses in patients with rheumatoid arthritis (RA) treated with rituximab and to investigate the effects of rituximab‐induced CD20+ B cell depletion on immune responses to tetanus toxoid (T cell–dependent antigen), pneumococcal polysaccharide (T cell–independent antigen), and keyhole limpet hemocyanin (KLH) (neoantigen) and on delayed‐type hypersensitivity (DTH).

Methods

In a controlled trial, we enrolled 103 patients with active RA receiving a stable dose of methotrexate (MTX). Tetanus toxoid, pneumococcal polysaccharide, and KLH vaccines as well as a Candida albicans skin test were administered to 1 group of patients receiving rituximab plus MTX (called rituximab‐treated patients) for 36 weeks and to 1 group of patients receiving MTX alone for 12 weeks. The primary end point was the proportion of patients with a ≥4‐fold rise in antitetanus IgG levels. Antitetanus, antipneumococcal, and anti‐KLH serum IgG levels were measured prior to and 4 weeks following vaccine administration. The DTH response to C albicans was measured 2–3 days following placement.

Results

Responses to tetanus toxoid vaccine (≥4‐fold rise) were similar in both groups (39.1% of rituximab‐treated patients and 42.3% of patients treated with MTX alone). The ability to maintain a positive DTH response to the C albicans skin test was comparable in both groups (77.4% of rituximab‐treated patients and 70% of patients treated with MTX alone), showing no effect of rituximab treatment. Rituximab‐treated patients had decreased responses to pneumococcal polysaccharide vaccine (57% of patients had a 2‐fold rise in titer in response to ≥1 serotype, compared with 82% of patients treated with MTX alone) and to KLH vaccine (47% of patients had detectable anti‐KLH IgG, compared with 93% of patients treated with MTX alone).

Conclusion

Recall responses to the T cell–dependent protein antigen tetanus toxoid as well as DTH responses were preserved in rituximab‐treated RA patients 24 weeks after treatment. Responses to neoantigen (KLH) and T cell–independent responses to pneumococcal vaccine were decreased, but many patients were able to mount responses. These data suggest that polysaccharide and primary immunizations should be administered prior to rituximab infusions to maximize responses.

     

Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: A double‐blind,randomized, placebo‐controlled trial

Objective

To determine whether patients with undifferentiated arthritis (UA; inflammatory, nontraumatic arthritis that cannot be diagnosed using current classification criteria) benefit from treatment with methotrexate (MTX).

Methods

The PRObable rheumatoid arthritis: Methotrexate versus Placebo Treatment (PROMPT) study was a double‐blind, placebo‐controlled, randomized, multicenter trial involving 110 patients with UA who fulfilled the American College of Rheumatology (ACR) 1958 criteria for probable RA. Treatment started with MTX (15 mg/week) or placebo tablets, and every 3 months the dosage was increased if the Disease Activity Score was >2.4. After 12 months, the study medication was tapered and discontinued. Patients were followed up for 30 months. When a patient fulfilled the ACR criteria for RA (primary end point), the study medication was changed to MTX. Joint damage was scored on radiographs of the hands and feet.

Results

In 22 of the 55 patients (40%) in the MTX group, UA progressed to RA compared with 29 of 55 patients (53%) in the placebo group. However, in the MTX group, patients fulfilled the ACR criteria for RA at a later time point than in the placebo group (P = 0.04), and fewer patients showed radiographic progression over 18 months (P = 0.046).

Conclusion

This study provides evidence for the efficacy of MTX treatment in postponing the diagnosis of RA, as defined by the ACR 1987 criteria, and retarding radiographic joint damage in UA patients.

     

Tumor necrosis factor therapy and the risk of serious infection and malignancy in patients with early rheumatoid arthritis: A meta‐analysis of randomized controlled trials

Objective

To conduct a meta‐analysis of the rates of serious infection and malignancy in patients with early rheumatoid arthritis (RA) who have started anti–tumor necrosis factor (anti‐TNF) therapy and had not received treatment with disease‐modifying antirheumatic drugs (DMARDs) or methotrexate (MTX).

Methods

A systematic literature search was conducted through the summer of 2009. All studies included were randomized, double‐blind, placebo‐controlled trials involving patients with early RA who were started on anti‐TNF therapy without prior DMARD/MTX use. Six trials met the inclusion criteria for the meta‐analysis, comprising a total of 2,183 patients receiving biologic therapy and 1,236 patients receiving MTX. The data extracted were from published trials.

Results

A pooled odds ratio (OR) (determined using Mantel‐Haenszel methods, with a continuity correction designed for sparse data) was calculated for serious infections (requiring hospitalization) and malignancies, comparing anti‐TNF therapy to MTX control. The pooled OR for serious infections was 1.28 (95% confidence interval [95% CI] 0.82–2.00) and that for malignancies was 1.08 (95% CI 0.50–2.32). There was no significant difference in either the rate of serious infections or the rate of malignancies between the anti‐TNF therapy group and the control group.

Conclusion

Whereas other meta‐analyses have shown an increased risk of serious infection and malignancy in patients receiving anti‐TNF therapy, the results of the present meta‐analysis show that there is not an increased risk when the patients have early disease and have not previously been treated with DMARDs and/or MTX.

     

Propensity‐adjusted association of methotrexate with overall survival in rheumatoid arthritis

Objective

While medications used to treat rheumatoid arthritis (RA) may affect survival in RA, few studies take into account the propensity for medication use, which may reflect selection bias in treatment allocation in survival models. We undertook this study to examine the relationship between methotrexate (MTX) use and mortality in RA, after controlling for individual propensity scores for MTX use.

Methods

We studied 5,626 RA patients prospectively for 25 years to determine the risk of death associated with MTX use, modeled in time‐varying Cox regression models. We used the random forest method to generate individual propensity scores for MTX use at study entry and during followup in a time‐varying manner; these scores were included in the multivariate model. We also investigated whether selective discontinuation of MTX immediately prior to death altered the risk of mortality, and we examined the association of duration of MTX use with survival.

Results

During followup, 666 patients (12%) died. MTX use was associated with reduced risk of death (adjusted hazard ratio 0.30 [95% confidence interval 0.09–1.03]). Selective MTX cessation immediately before death did not account for the protective association of MTX use with mortality. Only MTX use for >1 year was associated with lower risks of mortality, but associations were not stronger with longer durations of use.

Conclusion

MTX use was associated with a 70% reduction in mortality in RA.

     

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

Objective

To compare the efficacy of combination therapy with methotrexate (MTX) and hydroxychloroquine (HCQ), MTX and sulfasalazine (SSZ), and MTX, HCQ, and SSZ in patients with rheumatoid arthritis (RA).

Methods

RA patients (n = 171) who had not previously been treated with combinations of the study medications were randomized to receive 1 of the 3 treatment combinations in this 2‐year, double‐blind, placebo‐controlled protocol. HCQ was given at a dosage of 200 mg twice a day. The dosage of MTX was accelerated from 7.5 mg/week to 17.5 mg/week in all patients who were not in remission. Similarly, the dosage of SSZ was escalated from 500 mg twice a day to 1 gm twice a day in patients who were not in remission. The primary end point of the study was the percentage of patients who had a 20% response to therapy according to the American College of Rheumatology (ACR) criteria at 2 years.

Results

Intent‐to‐treat analysis revealed that patients receiving the triple combination responded best, with 78% achieving an ACR 20% response at 2 years, compared with 60% of those treated with MTX and HCQ (P = 0.05) and 49% of those treated with MTX and SSZ (P = 0.002). Similar trends were seen for the ACR 50% response, with 55%, 40%, and 29% of patients in the 3 treatment groups, respectively, achieving these results at 2 years (P = 0.005 for the triple combination group versus the MTX and SSZ group). All combination treatments were well‐tolerated. Fourteen patients (evenly distributed among the 3 groups) withdrew from the protocol because of symptoms that were potentially related to the study medication.

Conclusion

The triple combination of MTX, SSZ, and HCQ is well‐tolerated, and its efficacy is superior to that of the double combination of MTX and SSZ and is marginally superior to that of the double combination of MTX and HCQ.

     

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

Objective

To evaluate the efficacy and safety of anakinra in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA).

Methods

Patients with moderate‐to‐severe active RA who were receiving MTX for 6 consecutive months, with stable doses for ≥3 months (those with disease duration of >6 months but <12 years) were randomized into 6 groups: placebo or 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra administered in a single, daily, subcutaneous injection. The primary efficacy end point was the proportion of subjects who met the American College of Rheumatology 20% improvement criteria (attained an ACR20 response) at week 12.

Results

A total of 419 patients were randomized in the study. Patient demographics and disease status were similar in the 6 treatment groups. The ACR20 responses at week 12 in the 5 active treatment plus MTX groups demonstrated a statistically significant (P = 0.001) dose‐response relationship compared with the ACR20 response in the placebo plus MTX group. The ACR20 response rate in the anakinra 1.0‐mg/kg (46%; P = 0.001) and 2.0‐mg/kg (38%; P = 0.007) dose groups was significantly greater than that in the placebo group (19%). The ACR20 responses at 24 weeks were consistent with those at 12 weeks. Similar improvements in anakinra‐treated subjects were noted in individual ACR components, erythrocyte sedimentation rate, onset of ACR20 response, sustainability of ACR20 response, and magnitude of ACR response. Anakinra was safe and well tolerated. Injection site reaction was the most frequently noted adverse event, and this led to premature study withdrawal in 7% (1.0‐mg/kg group) to 10% (2.0‐mg/kg group) of patients receiving higher doses.

Conclusion

In patients with persistently active RA, the combination of anakinra and MTX was safe and well tolerated and provided significantly greater clinical benefit than MTX alone.

     

The anti‐CD20 antibody rituximab reduces the Th17 cell response

Objective

Rituximab has been shown to be successful in the treatment of rheumatoid arthritis (RA), and this unexpected finding indicates that B cells have an important role in this disease. The present study was undertaken to investigate the mechanism of action of rituximab in RA.

Methods

Twelve patients with active RA were treated with rituximab. Disease activity was evaluated using the 28‐joint Disease Activity Score. Synovial biopsy samples obtained at baseline and 12 weeks after treatment initiation were analyzed by microarray, quantitative polymerase chain reaction, and immunohistochemistry. Peripheral blood mononuclear cells (PBMCs) from healthy volunteers and from 4 patients with X‐linked agammaglobulinemia were stimulated with the Th17‐inducing stimulus Candida albicans, and the response in the presence and absence of rituximab was examined.

Results

In RA patients, rituximab reduced expression of retinoic acid–related orphan receptor γt and interleukin‐22 (IL‐22) and numbers of Th17‐positive cells in synovial tissue, and this correlated with better clinical outcome. Rituximab did not affect tumor necrosis factor α (TNFα), Th1 cell, or Treg cell responses. Rituximab strongly reduced in vitro IL‐17 and IL‐22 production induced by C albicans. This effect was not observed in PBMCs from patients with X‐linked agammaglobulinemia.

Conclusion

Rituximab reduced the local Th17 response in RA patients, whereas it did not influence Th1 cell, Treg cell, or TNFα responses. The decreased Th17 response was associated with reduced inflammation and better clinical outcome. Moreover, inhibition of the Th17 response by rituximab was lost in the absence of B cells, providing evidence that the effects of rituximab are due to B cell depletion. These data demonstrate an unexpected role of B cells in the development of Th17 responses, which could possibly lead to B cell–based strategies for the treatment of Th17‐related autoimmune diseases.

     

The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: Results of a phase IIB randomized,double‐blind,placebo‐controlled,dose‐ranging trial

Objective

To examine the efficacy and safety of different rituximab doses plus methotrexate (MTX), with or without glucocorticoids, in patients with active rheumatoid arthritis (RA) resistant to disease‐modifying antirheumatic drugs (DMARDs), including biologic agents.

Methods

A total of 465 patients were randomized into 9 treatment groups: 3 rituximab groups (placebo [n = 149], 500 mg [n = 124], or 1,000 mg [n = 192] on days 1 and 15) each also taking either placebo glucocorticoids, intravenous methylprednisolone premedication, or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10–25 mg/week); no other DMARDs were permitted.

Results

Significantly more patients who received 2 500‐mg or 2 1,000‐mg infusions of rituximab met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 24 (55% and 54%, respectively) compared with placebo (28%; P < 0.0001). ACR50 responses were achieved by 33%, 34%, and 13% of patients, respectively (P < 0.001), and ACR70 responses were achieved by 13%, 20%, and 5% of patients (P < 0.05). Changes in the Disease Activity Score in 28 joints (−1.79, −2.05, −0.67; P < 0.0001) and moderate to good responses on the European League Against Rheumatism criteria (P < 0.0001) reflected the ACR criteria responses. Glucocorticoids did not contribute significantly to the primary efficacy end point, ACR20 response at 24 weeks. Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion–associated events; oral glucocorticoids conferred no additional safety benefit. Rituximab was well tolerated; the type and severity of infections was similar to those for placebo.

Conclusion

Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA. The primary end point (ACR20 response) was independent of glucocorticoids, although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion.

     

Adalimumab,a fully human anti–tumor necrosis factor α monoclonal antibody,for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The ARMADA trial

Objective

To evaluate the efficacy and safety of adalimumab (D2E7), a fully human monoclonal tumor necrosis factor α antibody, in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite treatment with MTX.

Methods

In a 24‐week, randomized, double‐blind, placebo‐controlled study, 271 patients with active RA were randomly assigned to receive injections of adalimumab (20 mg, 40 mg, or 80 mg subcutaneously) or placebo every other week while continuing to take their long‐term stable dosage of MTX. The primary efficacy end point was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks.

Results

An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20‐mg, 40‐mg, and 80‐mg adalimumab plus MTX groups (47.8%, 67.2%, and 65.8%, respectively) than in the placebo plus MTX group (14.5%) (P < 0.001). ACR50 response rates with the 20‐mg, 40‐mg, and 80‐mg adalimumab dosages (31.9%, 55.2%, and 42.5%, respectively) were significantly greater than that with placebo (8.1%) (P = 0.003, P < 0.001, and P < 0.001, respectively). The 40‐mg and 80‐mg doses of adalimumab were associated with an ACR70 response (26.9% and 19.2%, respectively) that was statistically significantly greater than that with placebo (4.8%) (P < 0.001 and P = 0.020). Responses were rapid, with the greatest proportion of adalimumab‐treated patients achieving an ACR20 response at the first scheduled visit (week 1). Adalimumab was safe and well tolerated; comparable numbers of adalimumab‐treated patients and placebo‐treated patients reported adverse events.

Conclusion

The addition of adalimumab at a dosage of 20 mg, 40 mg, or 80 mg administered subcutaneously every other week to long‐term MTX therapy in patients with active RA provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo.

     

Cytokine response in pediatric patients with pandemic influenza H1N1 2009 virus infection and pneumonia: comparison with pediatric pneumonia without H1N1 2009 infection

Objectives

We investigated serum cytokine levels in pediatric patients with pandemic influenza H1N1 2009 virus (H1N1) infection‐pneumonia and in pediatric patients with pneumonia but without H1N1 infection, and examined correlations between cytokine levels and clinical/laboratory findings.

Methods

Fifty‐seven cases of infection by H1N1 were confirmed by RT‐PCR and enrolled. Of these 57 cases, 26 had a severe H1N1 infection (group 1), and 31 had a mild H1N1 infection (group 2). Sera from 18 cases with pneumonia without H1N1 infection (group 3) were used as controls. The serum levels of 10 cytokines were determined by multiplex assay.

Results

The serum levels of IFN‐α, IL‐6, and IP‐10 were significantly higher in H1N1 infected cases than in group 3, and levels of IL‐6 and IP‐10 were significantly higher in group 1 than in group 2. The level of IL‐10 was significantly higher in groups 1 and 3 than in group 2. However, levels of IFN‐γ and IL‐17 were not significantly different between the three groups. IL‐1β, IL‐4, and MIP‐1α were not detectable in most patients. IP‐10 and IL‐6 levels were found to show negative correlations with lymphocyte count and oxygen saturation.

Conclusions

We found higher levels of cytokines (IFN‐α, IL‐6, IP‐10) of innate immunity than those of acquired immunity in pediatric H1N1 infection. Of the cytokines found to be increased in cases with H1N1 infection, IP‐10 and IL‐6 were found to be correlated with disease severity (lymphopenia and hypoxia). IP‐10 and IL‐6 may be important markers in pediatric H1N1 infection. Pediatr Pulmonol. 2011; 46: 1233–1239. © 2011 Wiley Periodicals, Inc.

     

Comparison of the response to infliximab or etanercept monotherapy with the response to cotherapy with methotrexate or another disease‐modifying antirheumatic drug in patients with rheumatoid arthritis: Results from the British Society for Rheumatology Biologics Register

Objective

To compare outcome at 6 months in unselected “real‐world” patients with rheumatoid arthritis treated with etanercept or infliximab as either monotherapy, cotherapy with methotrexate (MTX), or cotherapy with another disease‐modifying antirheumatic drug (DMARD).

Methods

A total of 2,711 subjects starting treatment with their first biologic agent (1,453 infliximab and 1,258 etanercept) were followed up for 6 months. Outcome was assessed using the European League Against Rheumatism (EULAR) response criteria. Ordinal regression was used to model the response in the MTX and other DMARD cotherapy groups relative to the monotherapy group separately for the 2 anti–tumor necrosis factor α agents, after adjusting for baseline differences.

Results

Etanercept‐treated patients had an increased likelihood of achieving a higher EULAR response category with cotherapy with MTX (odds ratio [OR] 2.0, 95% confidence interval [95% CI] 1.5–2.7) and with another DMARD (OR 1.2, 95% CI 0.9–1.6) as compared with monotherapy. For infliximab‐treated patients, the likelihoods were 1.4 (95% CI 0.9–2.0) for MTX and 1.3 (95% CI 0.8–2.1) for other DMARDs versus monotherapy. Cotherapy with MTX or another DMARD produced significantly higher rates of remission with etanercept (12% and 11%, respectively) as compared with etanercept monotherapy (5%). Infliximab‐treated patients showed similar remission rates in the MTX and other DMARD cotherapy groups (8% and 5%, respectively) as in the monotherapy group (7%).

Conclusion

In this study of real‐world patients, the use of MTX and, to a lesser extent, other DMARDs as cotherapy with etanercept was associated with a higher likelihood of response. Although the infliximab guidelines suggest that MTX be used as cotherapy, in clinical practice, both monotherapy and cotherapy with DMARDs other than MTX are used. These data suggest that either of the latter strategies may be useful in patients who are intolerant to MTX.

     

B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: A six‐month,national, multicenter,open‐label study

Objective

To examine whether serum B cell markers can predict response to rituximab, a B cell–depleting monoclonal antibody, in patients with refractory rheumatoid arthritis (RA).

Methods

This rituximab re‐treatment dose study (SMART [eSsai MAbthera sur la dose de Re‐Traitement]) involved 208 patients with refractory RA. Serum markers of B cell activation (anti–cyclic citrullinated peptide [anti‐CCP] antibodies, rheumatoid factor [RF], serum IgG, IgA, and IgM levels, serum κ and λ free light chains, and serum BAFF) were assessed before the first rituximab cycle (1,000 mg on days 1 and 15). Univariate and multivariate analyses were performed to identify factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks.

Results

There were 149 responders (72%). Two baseline factors were associated with a EULAR response at 24 weeks in multivariate analysis: the presence of anti‐CCP antibodies or RF (odds ratio 3.5 [95% confidence interval 1.6–7.6]) and a serum IgG concentration above normal (odds ratio 2.11 [95% confidence interval 1.02–4.33]), with synergy between them (odds ratio 6.0 [95% confidence interval 2.2–16.2]).

Conclusion

The presence of RF or anti‐CCP antibodies and elevated IgG are 2 simple biomarkers that can be used routinely before therapy to predict response to rituximab in patients with refractory RA.

     

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

Objective

To compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX monotherapy or adalimumab monotherapy in patients with early, aggressive rheumatoid arthritis (RA) who had not previously received MTX treatment.

Methods

This was a 2‐year, multicenter, double‐blind, active comparator–controlled study of 799 RA patients with active disease of <3 years' duration who had never been treated with MTX. Treatments included adalimumab 40 mg subcutaneously every other week plus oral MTX, adalimumab 40 mg subcutaneously every other week, or weekly oral MTX. Co‐primary end points at year 1 were American College of Rheumatology 50% improvement (ACR50) and mean change from baseline in the modified total Sharp score.

Results

Combination therapy was superior to both MTX and adalimumab monotherapy in all outcomes measured. At year 1, more patients receiving combination therapy exhibited an ACR50 response (62%) than did patients who received MTX or adalimumab monotherapy (46% and 41%, respectively; both P < 0.001). Similar superiority of combination therapy was seen in ACR20, ACR70, and ACR90 response rates at 1 and 2 years. There was significantly less radiographic progression (P ≤ 0.002) among patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units) or the adalimumab arm (3.0 and 5.5 Sharp units). After 2 years of treatment, 49% of patients receiving combination therapy exhibited disease remission (28‐joint Disease Activity Score <2.6), and 49% exhibited a major clinical response (ACR70 response for at least 6 continuous months), rates approximately twice those found among patients receiving either monotherapy. The adverse event profiles were comparable in all 3 groups.

Conclusion

In this population of patients with early, aggressive RA, combination therapy with adalimumab plus MTX was significantly superior to either MTX alone or adalimumab alone in improving signs and symptoms of disease, inhibiting radiographic progression, and effecting clinical remission.

     

A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent‐onset rheumatoid arthritis

Objective

To develop a clinical pharmacogenetic model to predict the efficacy of methotrexate (MTX) in rheumatoid arthritis (RA).

Methods

Two hundred five patients with newly diagnosed RA and active disease were treated with MTX (initiated at a dosage of 7.5 mg/week and increased to 15 mg/week after 4 weeks) and folic acid (1 mg/day). If the Disease Activity Score (DAS) was >2.4 at 3 months, the dosage of MTX was increased up to 25 mg/week. Twenty‐four baseline variables possibly influencing disease state and drug response were selected. In addition, 17 polymorphisms in 13 genes related to the MTX mechanism of action, purine and pyrimidine synthesis, were determined. Factors were compared between responders (defined as patients with a DAS ≤2.4 at 6 months) and nonresponders. In case of differences, a stepwise selection procedure identified the predictors for response. A clinical score was designed by simplifying regression coefficients of the independent variables. Cutoff levels were chosen based on the clinical score, and positive and negative response rates were calculated. An evaluation of the model was performed in a second group of patients.

Results

The model for MTX efficacy consisted of sex, rheumatoid factor and smoking status, the DAS, and 4 polymorphisms in the AMPD1, ATIC, ITPA, and MTHFD1 genes. This prediction model was transformed into a scoring system ranging from 0 to 11.5. Scores of ≤3.5 had a true positive response rate of 95%. Scores of ≥6 had a true negative response rate of 86%. Sixty percent of the patients were categorized as either responders or nonresponders, whereas 32% of the patients were categorized using a nongenetic model. Evaluation of the model in 38 additional patients with RA supported the results.

Conclusion

This study established a model for predicting the efficacy of MTX in patients with RA. This pharmacogenetic model may lead to better‐tailored initial treatment decisions in patients with RA.

     

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

Objective

To determine the efficacy and safety of treatment with rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to anti–tumor necrosis factor (anti‐TNF) therapies and to explore the pharmacokinetics and pharmacodynamics of rituximab in this population.

Methods

We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the Randomized Evaluation of Long‐Term Efficacy of Rituximab in RA (REFLEX) Trial, a 2‐year, multicenter, randomized, double‐blind, placebo‐controlled, phase III study of rituximab therapy. Patients with active RA and an inadequate response to 1 or more anti‐TNF agents were randomized to receive intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each) or placebo, both with background MTX. The primary efficacy end point was a response on the American College of Rheumatology 20% improvement criteria (ACR20) at 24 weeks. Secondary end points were responses on the ACR50 and ACR70 improvement criteria, the Disease Activity Score in 28 joints, and the European League against Rheumatism (EULAR) response criteria at 24 weeks. Additional end points included scores on the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT‐F), Health Assessment Questionnaire (HAQ) Disability Index (DI), and Short Form 36 (SF‐36) instruments, as well as Genant‐modified Sharp radiographic scores at 24 weeks.

Results

Patients assigned to placebo (n = 209) and rituximab (n = 311) had active, longstanding RA. At week 24, significantly more (P < 0.0001) rituximab‐treated patients than placebo‐treated patients demonstrated ACR20 (51% versus 18%), ACR50 (27% versus 5%), and ACR70 (12% versus 1%) responses and moderate‐to‐good EULAR responses (65% versus 22%). All ACR response parameters were significantly improved in rituximab‐treated patients, who also had clinically meaningful improvements in fatigue, disability, and health‐related quality of life (demonstrated by FACIT‐F, HAQ DI, and SF‐36 scores, respectively) and showed a trend toward less progression in radiographic end points. Rituximab depleted peripheral CD20+ B cells, but the mean immunoglobulin levels (IgG, IgM, and IgA) remained within normal ranges. Most adverse events occurred with the first rituximab infusion and were of mild‐to‐moderate severity. The rate of serious infections was 5.2 per 100 patient‐years in the rituximab group and 3.7 per 100 patient‐years in the placebo group.

Conclusion

At 24 weeks, a single course of rituximab with concomitant MTX therapy provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more anti‐TNF therapies.

     

Double‐blind randomized controlled clinical trial of the interleukin‐6 receptor antagonist,tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate

Objective

To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti–interleukin‐6 (IL‐6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA).

Methods

The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo.

Results

A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose‐related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C‐reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high‐density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX.

Conclusion

These results indicate that targeted blockade of IL‐6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.

     

Brief Report: Long‐term outcome of a randomized clinical trial comparing methotrexate to cyclophosphamide for remission induction in early systemic antineutrophil cytoplasmic antibody–associated vasculitis

Objective

The NORAM (Nonrenal Wegener's Granulomatosis Treated Alternatively with Methotrexate [MTX]) trial demonstrated that MTX can replace cyclophosphamide (CYC) as remission‐inducing treatment for patients with newly diagnosed early systemic antineutrophil cytoplasmic antibody–associated vasculitis. Duration of relapse‐free survival was longer among CYC‐treated patients than among MTX‐treated patients during short‐term followup. The aim of the present study was to describe the long‐term outcome in patients enrolled in the randomized clinical trial.

Methods

Outcome questionnaires were sent to investigators who had recruited patients for the NORAM trial. Patients treated with MTX for induction of remission (n = 49) were compared to CYC‐treated patients (n = 46) with respect to immunosuppressive therapy during followup, relapse‐free survival, mortality, and occurrence of other clinical events.

Results

The median duration of followup was 6 years (range 0.1–10.8 years). One patient developed end‐stage renal disease, and 11 died. The number of patients affected by serious infection, malignancy, or severe organ failure did not differ between treatment groups, and no difference in survival rate was observed. The duration of corticosteroid therapy was longer in the MTX group during the 18 months of the trial (P = 0.005). During subsequent followup, patients who were in the MTX group in the NORAM trial received corticosteroids, CYC, and other immunosuppressive agents (azathioprine, MTX, and/or mycophenolate mofetil) for longer periods than those who were in the CYC group (P = 0.004, P = 0.037, and P = 0.031, respectively). The cumulative relapse‐free survival tended to be lower in the MTX group (P = 0.056).

Conclusion

In the NORAM cohort, no difference in occurrence of major adverse events was observed between treatment groups during long‐term followup. However, first‐line treatment with MTX was associated with less effective disease control than CYC‐based induction therapy.