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.

     

The good initial response to therapy with a combination of traditional disease‐modifying antirheumatic drugs is sustained over time: The eleven‐year results of the Finnish rheumatoid arthritis combination therapy trial

Objective

To evaluate the evolution of functional and clinical outcomes over 11 years in patients with early rheumatoid arthritis (RA) initially treated with a combination of 3 disease‐modifying antirheumatic drugs (DMARDs) or with a single DMARD.

Methods

A cohort of 199 patients with early active RA were initially randomized to receive treatment with a combination of methotrexate, sulfasalazine, and hydroxychloroquine with prednisolone or treatment with a single DMARD (initially, sulfasalazine) with or without prednisolone. After 2 years, the drug treatment strategy became unrestricted, but still targeted remission. At 11 years, function was assessed with the Health Assessment Questionnaire (HAQ), and clinical outcomes were assessed with the modified Minimal Disease Activity (MDA) measure and the American College of Rheumatology (ACR) criteria for remission.

Results

At 11 years, 138 patients were assessed (68 in the combination‐DMARD group and 70 in the single‐DMARD group). The mean ± SD HAQ scores were 0.34 ± 0.54 in the combination‐DMARD group and 0.38 ± 0.58 in the single‐DMARD group (P = 0.88). Modified MDA was achieved by 63% (95% confidence interval [95% CI] 51, 77) and by 43% (95% CI 32, 55) (P = 0.016) of the combination‐DMARD group and the single‐DMARD group, respectively, and ACR remission by 37% (95% CI 26, 49) and by 19% (95% CI 11, 29) (P = 0.017), respectively.

Conclusion

Initial therapy with a combination of DMARDs in early RA results in higher rates of patients achieving modified MDA and strict ACR remission even over the long term than initial single‐DMARD therapy. Targeting remission with tight clinical controls results in good functional and clinical outcomes in most RA patients.

     

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

Objective

To evaluate the long‐term frequency of disease remissions and the progression of joint damage in patients with early rheumatoid arthritis (RA) who were initially randomized to 2 years of treatment with either a combination of 3 disease‐modifying antirheumatic drugs (DMARDs) or a single DMARD.

Methods

In this multicenter prospective followup study, a cohort of 195 patients with early, clinically active RA was randomly assigned to treatment with a combination of methotrexate, sulfasalazine, hydroxychloroquine, and prednisolone or with a single DMARD (initially, sulfasalazine) with or without prednisolone. After 2 years, the DMARD and prednisolone treatments became unrestricted, but were still targeted toward remission. The long‐term effectiveness was assessed by recording the frequency of remissions and the extent of joint damage seen on radiographs of the hands and feet obtained annually up to 5 years. Radiographs were assessed by the Larsen score.

Results

A total of 160 patients (78 in the combination group and 82 in the single group) completed the 5‐year extension study. At 2 years, 40% of the patients in the combination‐DMARD group and 18% in the single‐DMARD group had achieved remission (P < 0.009). At 5 years, the corresponding percentages were 28% and 22% (P not significant). The median Larsen radiologic damage scores at baseline, 2 years, and 5 years in the combination‐DMARD and single‐DMARD groups were 0 and 2 (P = 0.50), 4 and 12 (P = 0.005), and 11 and 24 (P = 0.001), respectively.

Conclusion

Aggressive initial treatment of early RA with the combination of 3 DMARDs for the first 2 years limits the peripheral joint damage for at least 5 years. Our results confirm the earlier concept that triple therapy with combinations of DMARDs contributes to an improved long‐term radiologic outcome in patients with early and clinically active RA.

     

Impact of initial aggressive drug treatment with a combination of disease‐modifying antirheumatic drugs on the development of work disability in early rheumatoid arthritis: A five‐year randomized followup trial

Objective

To compare the efficacy of therapy with a combination of disease‐modifying antirheumatic drugs (DMARDs) versus therapy with a single DMARD in the prevention of work disability in patients with early rheumatoid arthritis (RA).

Methods

In the Finnish Rheumatoid Arthritis Combination Therapy trial, 195 patients with recent‐onset RA were randomly assigned to receive either combination therapy with DMARDs (sulfasalazine, methotrexate, hydroxychloroquine) plus prednisolone or single therapy with a DMARD with or without prednisolone. After 2 years, the drug treatment strategy was no longer restricted. At baseline, 162 patients (80 in the combination‐treatment group and 82 in the single‐treatment group) were still working or at least available for work. After 5 years of followup, data on all sick leave and retirement were obtained from social insurance registers or case records. The main outcome for each patient was the cumulative duration of all sick leaves and RA‐related disability pensions, divided by the observation period during which the patient was not retired because of another disease or because of age.

Results

The cumulative duration of work disability per patient‐observation year was significantly lower in those randomized to combination therapy than in those randomized to single therapy: median 12.4 days (interquartile range [IQR] 0–54) versus 32.2 days (IQR 6–293) (P = 0.008, sex‐ and age‐adjusted P = 0.009). This was mainly due to the difference in sick leaves (i.e., work disability periods ≤300 days): median 11.7 days (IQR 0–44) per patient‐observation year in those treated with combination therapy and 30.0 days (IQR 6–68) in those treated with single therapy (P = 0.002). No statistically significant difference was seen in RA‐related disability pensions.

Conclusion

Aggressive initial treatment of RA with a combination of DMARDs improves 5‐year outcome in terms of lost productivity in patients with RA of recent onset.

     

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.

     

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.

     

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.

     

Delay to institution of therapy and induction of remission using single‐drug or combination–disease‐modifying antirheumatic drug therapy in early rheumatoid arthritis

Objective

To study the impacts of 1) the delay from the onset of symptoms to the institution of disease‐modifying antirheumatic drug (DMARD) therapy, 2) two treatment strategies (treatment with a combination of DMARDs or with a single drug), and 3) the presence of HLA–DRB1 alleles (shared epitope) on the prediction of disease remission after 2 years in patients with early rheumatoid arthritis (RA).

Methods

In the FIN‐RACo (FINnish Rheumatoid Arthritis Combination therapy) trial, 195 patients with recent‐onset RA (median duration 6 months) were randomly assigned to receive either 1) a combination of DMARDs (sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone) or 2) a single DMARD with or without prednisolone. The presence of a shared epitope was tested for in 165 of the 178 patients completing the study. The additional variables of age, sex, presence of rheumatoid factor, number of fulfilled American College of Rheumatology criteria for the classification of RA, and length of delay from onset of symptoms to institution of therapy were entered into a logistic regression model to determine the significant predictors for remission at 2 years.

Results

The delay to therapy (cut point of 4 months) was the only significant predictor for remission in patients treated using the single‐DMARD strategy, while no variable was a significant predictor for remission in those treated using the combination‐DMARD strategy. The frequency of achieving remission in the combination‐DMARD group after 2 years was similar in patients with short (0–4 months) and long (>4 months) delay periods (11 of 26 patients and 22 of 53 patients, respectively [∼42% in each group]), while the corresponding frequencies in the single‐DMARD group were 8 of 23 patients (35%) and 7 of 63 patients (11%) (P = 0.021). The presence of a shared epitope was not related to the induction of remission.

Conclusion

The delay of a few months from the onset of symptoms to institution of therapy decreases the ability of the traditional single‐drug strategy to induce remission in early RA.

     

The effectiveness of anti–tumor necrosis factor therapy in preventing progressive radiographic joint damage in rheumatoid arthritis: A population‐based study

Objective

To compare the effectiveness of 3 therapeutic strategies in preventing progressive joint damage, in a population‐based cohort. The 3 strategies were infliximab with concomitant disease‐modifying antirheumatic drugs (DMARDs), etanercept with concomitant DMARDs, and etanercept alone.

Methods

We used sequential radiographs to assess all patients who were treated with infliximab or etanercept for >10 months. The rates of erosion progression and joint space narrowing (JSN) were analyzed using multivariate regression models for longitudinal data, with adjustment for potential confounders.

Results

A total of 372 patients treated with anti–tumor necrosis factor (TNF) therapies met the inclusion criteria. The baseline characteristics of the patients assigned to the 3 strategies were not significantly different, except that, as expected, more patients were receiving combination therapy with infliximab. The combination of infliximab plus DMARDs was significantly more effective than etanercept alone for controlling erosion progression (P < 0.001), but the effectiveness of the 2 combination‐treatment strategies was similar (P = 0.07). The combination of infliximab plus DMARDs was also more effective at controlling progressive JSN compared with etanercept alone (P = 0.04) or etanercept plus DMARDs (P = 0.02). Treatment with anti‐TNF agents (infliximab or etanercept) plus concomitant DMARDs was more effective than treatment with etanercept alone for controlling erosion progression (P = 0.045).

Conclusion

When combined with traditional DMARDs, both etanercept and infliximab appear to offer similar protection against progressive structural joint damage, and combination therapy with either of these agents appears to be more effective than treatment with etanercept alone.

     

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.

     

Disease remission state in patients treated with the combination of tumor necrosis factor blockade and methotrexate or with disease‐modifying antirheumatic drugs: A clinical and imaging comparative study

Objective

For patients with rheumatoid arthritis (RA) in remission who are receiving disease‐modifying antirheumatic drugs (DMARDs), radiographic progression correlates with imaging‐detected synovitis as measured by power Doppler activity. In contrast, patients with disease in remission who are receiving the combination of tumor necrosis factor (TNF) blockade with methotrexate (MTX) (combination treatment) have reduced radiographic damage for the equivalent clinical state. We undertook this study to determine whether the difference in radiographic outcome is a result of more complete suppression of imaging‐detected synovitis.

Methods

One hundred patients with RA in remission (Disease Activity Score in 28 joints [DAS28] <2.6) for at least 6 months while receiving either combination treatment (n = 50) or DMARDs (n = 50) were matched for clinical variables. Ultrasound of metacarpophalangeal joints 1–5 and the wrist joints was performed. Remission according to imaging results was defined as a score of 0 for both grey scale synovitis and power Doppler activity.

Results

In patients receiving combination treatment or DMARDs (median DAS28 1.65 versus 1.78, median disease duration 120 months versus 90 months, and median duration of remission 13 months versus 18 months), the proportion with remission according to imaging results was not significantly different (10% versus 16%, respectively). The combination treatment group had more grey scale synovitis (P < 0.001) but similar power Doppler activity (48% versus 60%, respectively; P = 0.229) in any joint as compared with the DMARD group. Results were not affected by stratification for duration of disease or remission.

Conclusion

In RA patients with disease in remission, imaging‐detected synovitis persists, with power Doppler activity seen in ≥48% of the patients regardless of therapy. These results suggest that superior radiographic outcomes in patients treated with the combination of TNF blockade and MTX may not be due to complete suppression of imaging‐detected synovitis.

     

Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease‐modifying antirheumatic drugs: A one‐year randomized,placebo‐controlled study

Objective

To assess the safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis (RA) who had been receiving ≥1 traditional nonbiologic and/or biologic disease‐modifying antirheumatic drugs (DMARDs) approved for the treatment of RA for at least 3 months prior to entry into the study.

Methods

This was a 1‐year, multicenter, randomized, double‐blind, placebo‐controlled trial. Patients were randomized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range, or placebo.

Results

The abatacept and placebo groups exhibited similar frequencies of adverse events (90% and 87%, respectively), serious adverse events (13% and 12%, respectively), and discontinuations due to adverse events (5% and 4%, respectively). Five patients (0.5%) in the abatacept group and 4 patients (0.8%) in the placebo group died during the study. Serious infections were more frequent in the abatacept group than in the placebo group (2.9% versus 1.9%). Fewer than 4% of patients in either group experienced a severe or very severe infection. The incidence of neoplasms was 3.5% in both groups. When evaluated according to background therapy, serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent (22.3%) than in the other subgroups (11.7–12.5%).

Conclusion

Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician‐ and patient‐reported disease outcomes. However, abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events. Therefore, abatacept is not recommended for use in combination with biologic therapy.

     

Timing and Impact of Decisions to Adjust Disease‐Modifying Antirheumatic Drug Therapy for Rheumatoid Arthritis Patients With Active Disease

Objective

Guidelines recommend that rheumatoid arthritis (RA) patients with moderate‐to‐high disease activity (MHDAS) adjust disease‐modifying antirheumatic drug (DMARD) therapy at least every 3 months until reaching low disease activity or remission (LDAS). We examined how quickly RA patients with MHDAS adjust DMARD therapy in clinical practice, and whether those who adjust DMARDs within 90 days in response to MHDAS reach LDAS sooner.

Methods

We identified RA patients with MHDAS in the University of Pittsburgh Rheumatoid Arthritis Comparative Effectiveness Research registry, and conducted a competing risks regression on time to DMARD therapy adjustment and a Cox regression on time to LDAS.

Results

We identified 538 eligible subjects with 943.5 patient‐years of followup. Sixty percent of patients with persistent MHDAS adjusted DMARDs within 90 days. Among all subjects, median times to DMARD adjustment and LDAS were 154 (interquartile range [IQR] 1–706) days and 301 (IQR 140–706) days, respectively. Being elderly (subdistribution hazard ratio [SHR] 0.61, P = 0.02), lower baseline disease activity (SHR 0.72, P < 0.01), longer duration of RA (SHR 0.98, P < 0.01), and biologic use (SHR 0.71, P < 0.01) were significantly associated with longer times to therapy adjustment. African American race (hazard ratio [HR] 0.63, P = 0.01), higher baseline disease activity (HR 0.75, P < 0.01), and not adjusting DMARD therapy within 90 days (HR 0.76, P = 0.01) were associated with longer times to LDAS.

Conclusion

Adjusting DMARDs within 90 days was associated with shorter times to LDAS, but many patients with persistent MHDAS waited >90 days to adjust DMARDs. Interventions are needed to address the timeliness of DMARD adjustments for RA patients with MHDAS.

     

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.

     

Very early treatment with infliximab in addition to methotrexate in early,poor‐prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage,with sustained benefit after infliximab withdrawal: Results from a twelve‐month randomized,double‐blind,placebo‐controlled trial

Objective

Anti–tumor necrosis factor α agents are among the most effective therapies for rheumatoid arthritis (RA). However, their optimal use is yet to be determined. This 12‐month double‐blind study attempted remission induction using standard therapy with or without infliximab in patients with early, poor‐prognosis RA. The primary end point was synovitis (measured by magnetic resonance imaging [MRI]). Clinical observations continued to 24 months.

Methods

All patients had fewer than 12 months of symptoms. Assessments included full metrologic evaluation, laboratory tests, radiographs, functional evaluation using the Health Assessment Questionnaire (HAQ), and quality of life measurement using the RA Quality of Life (RAQoL) questionnaire. MRI was performed at 0, 4, 14, and 54 weeks; MR images were scored blindly. Patients received methotrexate (MTX) and were randomized to receive either infliximab or placebo for 12 months.

Results

Twenty patients were recruited (mean age 52 years, mean symptom duration 6 months, mean C‐reactive protein level 42 mg/liter, and 65% rheumatoid factor positive). At 1 year, all MRI scores were significantly better, with no new erosions in the infliximab plus MTX group; a greater percentage of infliximab plus MTX–treated patients fulfilled the American College of Rheumatology (ACR) 50% and 70% improvement criteria (78% versus 40% in the placebo plus MTX group and 67% versus 30%, respectively) and had a greater functional benefit (P < 0.05 for all comparisons). Importantly, at 1 year after stopping induction therapy, response was sustained in 70% of the patients in the infliximab plus MTX group, with a median Disease Activity Score in 28 joints (DAS28) of 2.05 (remission range). At 2 years, there were no significant between‐group differences in the DAS28, ACR response, or radiographic scores, but differences in the HAQ and RAQoL scores were maintained (P < 0.05).

Conclusion

Remission induction with infliximab plus MTX provided a significant reduction in MRI evidence of synovitis and erosions at 1 year. At 2 years, functional and quality of life benefits were sustained, despite withdrawal of infliximab therapy. These data may have significant implications for the optimal use of expensive biologic therapies.

     

Comparison of etanercept and methotrexate,alone and combined,in the treatment of rheumatoid arthritis: Two‐year clinical and radiographic results from the TEMPO study,a double‐blind,randomized trial

Objective

To evaluate the efficacy, including radiographic changes, and safety of etanercept and methotrexate (MTX), used in combination and alone, in patients with rheumatoid arthritis (RA) in whom previous treatment with a disease‐modifying antirheumatic drug other than MTX had failed.

Methods

Patients with RA were treated with etanercept (25 mg subcutaneously twice weekly), oral MTX (up to 20 mg weekly), or combination therapy with etanercept plus MTX through a second year, in a double‐blinded manner. Clinical response was assessed using American College of Rheumatology (ACR) criteria and the Disease Activity Score (DAS), in a modified intent‐to‐treat analysis with the last observation carried forward (LOCF) and in a population of completers. Radiographs of the hands, wrists, and forefeet were scored for erosions and joint space narrowing at annual intervals.

Results

A total of 503 of 686 patients continued into year 2 of the study. During the 2 years, significantly fewer patients receiving combination therapy withdrew from the study (29% of the combination therapy group, 39% of the etanercept group, and 48% of the MTX group). Both the LOCF and the completer analyses yielded similar results. The ACR 20% improvement (ACR20), ACR50, and ACR70 responses and the remission rates (based on a DAS of <1.6) were significantly higher with combination therapy than with either monotherapy (P < 0.01). Similarly, improvement in disability (based on the Health Assessment Questionnaire) was greater with combination therapy (P < 0.01). The combination therapy group showed significantly less radiographic progression than did either group receiving monotherapy (P < 0.05); moreover, radiographic progression was significantly lower in the etanercept group compared with the MTX group (P < 0.05). For the second consecutive year, overall disease progression in the combination therapy group was negative, with the 95% confidence interval less than zero. Adverse events were similar in the 3 treatment groups.

Conclusion

Etanercept in combination with MTX reduced disease activity, slowed radiographic progression, and improved function more effectively than did either monotherapy over a 2‐year period. No increase in toxicity was associated with combination treatment with etanercept plus MTX.

     

Long‐term impact of early treatment on radiographic progression in rheumatoid arthritis: A meta‐analysis

Objective

Although early initiation of disease‐modifying antirheumatic drugs (DMARDs) is effective in controlling short‐term joint damage in individuals with rheumatoid arthritis (RA), the long‐term benefit in disease progression is still controversial. We examined the long‐term benefit of early DMARD initiation on radiographic progression in early RA.

Methods

We identified published and unpublished clinical trials and observational studies from 1966 to September 2004 examining the association between delay to treatment initiation and progressive radiographic joint damage. We included studies of persons with RA disease duration <2 years and DMARD therapy of similar efficacy during followup. The differences in annual rates of radiographic progression between early and delayed therapy were pooled as standardized mean differences (SMDs).

Results

A total of 12 studies met the inclusion criteria. The pooled estimate of effects from these studies demonstrated a significant reduction of radiographic progression in patients treated early (?0.19 SMD, 95% confidence interval [95% CI] ?0.34, ?0.04), which corresponded to a ?33% reduction (95% CI ?50, ?16) in long‐term progression rates compared with patients treated later. Patients with more aggressive disease seemed to benefit most from early DMARD initiation (P = 0.04).

Conclusion

These results support the existence of a critical period to initiate antirheumatic therapy, a therapeutic window of opportunity early in the course of RA associated with sustained benefit in radiographic progression for up to 5 years. Prompt initiation of antirheumatic therapy in persons with RA may alter the long‐term course of the disease.

     

Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: Twelve‐month results of a phase iib,double‐blind,randomized, placebo‐controlled trial

Objective

To determine the clinical efficacy, safety, and immunogenicity of abatacept (CTLA‐4Ig), a selective costimulation modulator, in patients with rheumatoid arthritis (RA) that has remained active despite methotrexate (MTX) therapy.

Methods

This was a 12‐month, multicenter, randomized, double‐blind, placebo‐controlled study. A total of 339 patients with active RA despite MTX therapy were randomly assigned to receive 10 mg/kg abatacept (n = 115), 2 mg/kg abatacept (n = 105), or placebo (n = 119). This report focuses on the results observed at month 12 of a phase IIb trial.

Results

A significantly greater percentage of patients treated with 10 mg/kg abatacept met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at 1 year compared with patients who received placebo (62.6% versus 36.1%; P < 0.001). Greater percentages of patients treated with 10 mg/kg abatacept also achieved ACR50 responses (41.7% versus 20.2%; P < 0.001) and ACR70 responses (20.9% versus 7.6%; P = 0.003) compared with patients who received placebo. For patients treated with 10 mg/kg abatacept, there were also statistically significant and clinically important improvements in modified Health Assessment Questionnaire scores compared with patients who received placebo (49.6% versus 27.7%; P < 0.001). Abatacept at a dosage of 10 mg/kg elicited an increase in rates of remission (Disease Activity Score in 28 joints of <2.6) compared with placebo at 1 year (34.8% versus 10.1%; P < 0.001). The incidence of adverse events was comparable between the groups, and no significant formation of neutralizing antibodies was noted.

Conclusion

Abatacept was associated with significant reductions in disease activity and improvements in physical function that were maintained over the course of 12 months in patients with RA that had remained active despite MTX treatment. Abatacept was found to be well tolerated and safe over the course of 1 year. Abatacept in combination with MTX has the potential to play an important role in future RA therapy.