Ultrasonographic and radiographic results from a two-year controlled trial of immediate or one-year-delayed addition of infliximab to ongoing methotrexate therapy in patients with erosive early rheumatoid arthritis

OBJECTIVE: To compare the impact of immediate and delayed introduction of anti-tumor necrosis factor therapy on inflammation and structural damage in methotrexate (MTX)-treated patients with early rheumatoid arthritis (RA). METHODS: Twenty-four patients with erosive early RA (duration < 3 years) who were receiving MTX were randomized to receive infliximab 5 mg/kg or placebo infusions at weeks 0, 2, and 6, and then every 8 weeks through week 46. Beginning at week 54 and thereafter, all patients received infliximab 5 mg/kg. Metacarpophalangeal joints were scanned using high-frequency ultrasonography and power Doppler imaging. Radiographs were evaluated using the modified Sharp/van der Heijde scoring system. RESULTS: From baseline to week 54, total synovial thickness was significantly improved in the infliximab + MTX group compared with the placebo + MTX group (median reduction 95.8% versus 37.5%; P = 0.005), as was the total color Doppler area (CDA; vascularity assessment) (median reduction 100% and 47.1%, respectively; P = 0.025). From week 0 to week 110, no significant between-group difference was observed in the change from baseline for total synovial thickening or the total CDA. At week 54, greater progression in the Sharp/van der Heijde score was apparent in patients receiving placebo + MTX compared with those receiving infliximab + MTX. Although radiographic progression in the placebo + MTX group was greatly reduced in the second year (after initiation of infliximab therapy), marked differences were observed between the infliximab + MTX group (median change in the Sharp/van der Heijde score 4.0) and the placebo + MTX group (median change 14.5) from baseline to week 110 (P = 0.076). CONCLUSION: The results indicate that the efficacy of 2 years of combination therapy with infliximab + MTX for inhibiting cumulative structural damage was superior to that of 1 year of treatment with MTX alone followed by the addition of infliximab.     

IgG and IgM anticardiolipin antibodies following treatment with infliximab plus methotrexate in patients with early rheumatoid arthritis

OBJECTIVE: To assess the occurrence of anticardiolipin antibodies (aCL) in patients with early rheumatoid arthritis (RA) receiving treatment with infliximab plus methotrexate (MTX) versus MTX alone. METHODS: The first 299 patients enrolled in the randomized, Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) trial who had baseline (week 0) samples available for aCL testing were included in this study. Sera were collected at weeks 0, 30, and 54 from 110 patients taking infliximab 3 mg/kg plus MTX, 98 patients taking infliximab 6 mg/kg plus MTX, and 91 patients taking placebo plus MTX. IgG and IgM aCL were measured using an anticardiolipin assay. RESULTS: IgG and IgM aCL positivity at baseline was similar in all treatment groups. Most patients were negative for IgG aCL at baseline and remained so at the last followup evaluation. One percent (2 of 208) of patients who received infliximab plus MTX and were negative for IgG aCL at baseline were positive for IgG aCL at weeks 30 and 54. A slightly higher proportion of patients who received infliximab plus MTX and were negative for IgM aCL at baseline were positive for IgM aCL at weeks 30 and 54 (4.8% [10 of 208]) as compared with patients who received placebo plus MTX (1.1% [1 of 91]), but the difference was not significant. CONCLUSION: There was a low incidence of the development of aCL in patients with early RA who received infliximab in combination with MTX, and the difference was not significant compared with patients who received placebo plus MTX.     

Infliximab inhibits progression of radiographic damage in patients with active psoriatic arthritis through one year of treatment: Results from the induction and maintenance psoriatic arthritis clinical trial 2

OBJECTIVE: To evaluate the effect of infliximab on progression of structural damage over 1 year in patients with active psoriatic arthritis (PsA) enrolled in the Induction and Maintenance Psoriatic Arthritis Clinical Trial 2. METHODS: In this double-blind, placebo-controlled study, 200 patients with active PsA were randomly assigned (1:1 ratio) to receive infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, and 6, and every 8 weeks thereafter through week 54. At week 24, patients initially assigned to receive placebo crossed over to receive infliximab (5 mg/kg). Based on predefined criteria, patients randomized to receive placebo could enter early escape by receiving infliximab (5 mg/kg) starting at week 16, and patients randomized to receive infliximab could have the dose increased to 10 mg/kg starting at week 38. Patients were analyzed according to the treatment they were randomized to receive. Radiographs of hands and feet were obtained at baseline and at weeks 24 and 54. Two readers blinded to treatment assignment and radiograph sequence independently evaluated erosions and joint space narrowing using the Sharp/van der Heijde scoring method modified for PsA. RESULTS: At week 24, patients randomized to receive infliximab 5 mg/kg had significantly less radiographic progression compared with patients randomized to receive placebo, with mean +/- SD changes from baseline in the total Sharp/van der Heijde score of -0.70 +/- 2.53 and 0.82 +/- 2.62, respectively (P < 0.001). At week 54, mean +/- SD changes from baseline in the total Sharp/van der Heijde score were -0.94 +/- 3.40 in patients randomized to receive infliximab and 0.53 +/- 2.60 in those receiving placebo/infliximab (P = 0.001). CONCLUSION: Infliximab significantly inhibits radiographic progression in patients with PsA as early as 6 months after starting treatment, and the beneficial effect continues through 1 year of infliximab therapy.     

Infliximab treatment maintains employability in patients with early rheumatoid arthritis

OBJECTIVE: To evaluate the impact of infliximab therapy on the employment status of patients with early rheumatoid arthritis (RA). METHODS: Methotrexate (MTX)-naive patients with active early RA were randomly allocated to receive MTX plus placebo or MTX plus infliximab (3 mg/kg or 6 mg/kg) at weeks 0, 2, and 6 and then every 8 weeks through week 46. Data for patients younger than age 65 years were included in the analyses. A patient was categorized as employable if he or she was employed or felt well enough to work if a job were available. RESULTS: The change in actual employment was not significantly different between patients receiving MTX plus infliximab and those receiving MTX plus placebo (0.5% versus 1.3%; P > 0.5). However, the proportion of patients whose status changed from employable at baseline to unemployable at week 54 was smaller in the group receiving MTX plus infliximab compared with that in the group receiving MTX alone (8% versus 14%; P = 0.05). Patients who were treated with infliximab plus MTX had a significantly greater likelihood of improvement rather than deterioration in employability (odds ratio 2.4; P < 0.001); this likelihood was not significantly greater in patients receiving MTX alone. The proportion of employed patients who lost workdays during the trial was smaller in the MTX plus infliximab group than in the MTX-alone group (P = 0.010). CONCLUSION: The actual employment rates among patients in the 2 treatment groups were not different. However, patients with early RA who were treated with MTX plus infliximab had a higher probability of maintaining their employability compared with those who were treated with MTX alone.     

英夫利西单抗对类风湿关节炎患者外周血单核细胞CD147表达的影响

目的 探讨抗肿瘤坏死因子-α人鼠嵌合单克隆抗体英夫利西单抗(infliximab)治疗前后类风湿关节炎(RA)患者外周血单核细胞CD147表达的变化.方法 30例经甲氨蝶呤(MTX)治疗至少3个月病情仍处于活动期的RA患者按3:1:1比例由计算机程序产生随机分配方案分为A、B、C 3组,A组接受为期14周的英夫利西单抗(3 mg/kg)治疗;B组接受为期6周的英夫利两单抗(3 mg/kg)治疗;C组接受为期14周的安慰剂治疗.治疗期间继续口服原剂量的MTX.流式细胞术检测RA患者外周血CD14+单核细胞CD147平均荧光强度水平(MFI)变化,并观察其与临床相关指标的关系.数据采用SPSS 13.0软件进行单因素方差分析、Spearman相关分析和Kruskal-Wallis秩和检验.结果 ①治疗前RA患者外周血CD14+单核细胞CD147 MFI为(101±25),健康志愿者为(78±18),差异有统计学意义(P=0.019).RA患者外周血CD147 MFI与病情活动指标DAS28(r=0.471,P=0.000)、红细胞沉降率(ESR)(r=0.371,P=0.000)、C反应蛋IQ(CRP)(r=0.249.P=0.010)、晨僵持续时间(r=279,P=0.010)呈正相关.②3组患者治疗后外周血CD14+单核细胞CD147 MFI均有下降,第18周与基线相比,A组平均改变差值(-26.9±21.7)、B组平均改变差值(-35.4±15.5)与C组平均改变差值(-10.0±6.0)相比,差异有统计学意义(P<0.05).结论 活动期RA患者外周血CD14+单核细胞CD147表达增高;与单用MTX相比,英夫利西单抗联合MTX治疗CD147 MFI表达下降更明显.     

英利昔单抗联合甲氨蝶呤治疗类风湿关节炎的随机双盲临床研究

目的评价英利昔单抗与甲氨蝶呤(MTX)联合使用与单独使用MTX,在治疗类风湿关节炎(RA)中的疗效与安全性。方法本研究为随机、双盲、平行对照的临床试验。49例接受过至少3个月稳定剂量MTX治疗的活动性RA患者随机分为试验组(24例)和对照组(25例)。两组受试者在第0、2、6、14周分别接受3mg/kg的英利昔单抗或安慰剂静脉滴注,同时每周按固定剂量继续服MTX。并于试验的第0、2、6、14、18周随访,评价疗效和不良反应。以美国风湿病学会(ACR)疗效评价指标ACR20为主要疗效指标,ACR50、ACR70、晨僵时间、关节肿胀数、关节肿胀指数、关节压痛数、关节压痛指数；次要疗效指标为疼痛目视模拟测量表(VAS)评分、疲乏VAS评分、疾病总体状况的医生评价VAS评分、疾病总体状况的病人评价VAS评分、健康评价问卷(HAQ)评分。结果治疗后第2周时,英利昔单抗联合MTX组ACR20有效率为62．5%,对照组仅为8．0%(P=0．002)；晨僵时间、关节压痛数、关节压痛指数、关节肿胀数、关节肿胀指数、疼痛VAS、疲乏VAS、医生总体评价VAS、病人总体评价VAS、HAQ和血沉等较对照组也均有显著的改善(P＜0．05或P＜0．01)。第18周时,英利昔单抗联合MTX组ACR20有效率为79．2%,对照组只有48．0%(P=0．024)。两组之间不良事件发生率差异无统计学意义。结论英利昔单抗联合MTX治疗RA的疗效明显优于单用MTX的疗效,能迅速改善与RA有关的各项症状、体征和实验室炎性活动指标,具有良好的安全性。     

Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial

OBJECTIVE: To identify disease characteristics leading to progression of joint damage in patients with early rheumatoid arthritis (RA) treated with methotrexate (MTX) versus those treated with infliximab plus MTX. METHODS: Patients who had not previously been treated with MTX with active RA were randomly assigned to receive escalating doses of MTX up to 20 mg/week plus placebo or infliximab at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Radiographic joint damage was assessed using the modified Sharp/van der Heijde score (SHS). The relationship between disease activity measures at baseline and week 14, as well as those averaged over time, were examined in relation to the change in SHS from baseline through week 54. RESULTS: C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint count were associated with greater joint damage progression in the MTX-only group, while none of these parameters was associated with progression in the infliximab plus MTX group. Mean changes in SHS among patients in the highest CRP (> or = 3 mg/dl) and ESR (> or = 52 mm/hour) tertiles in the MTX-only group were 5.62 and 5.89, respectively, compared with 0.73 and 1.12 in the infliximab plus MTX group (P < 0.001). Patients with greater joint damage at baseline (SHS > or = 10.5) showed less progression with infliximab plus MTX compared with MTX alone (-0.39 versus 4.11; P < 0.001). Patients receiving MTX alone who had persistently active disease at week 14 showed greater radiographic progression of joint damage than those taking MTX plus infliximab. CONCLUSION: High CRP level, high ESR, or persistent disease activity was associated with greater radiographic progression in the group taking MTX alone, while little radiographic progression was seen in patients receiving both MTX and infliximab, regardless of the abnormal levels of these traditional predictors.     

Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study

OBJECTIVE: To assess the relationship between inflammation and joint destruction in rheumatoid arthritis (RA) patients who have not responded clinically to treatment. METHODS: Changes from baseline to week 54 in clinical variables and measures of radiographic progression were compared between patients who received infliximab (3 mg/kg or 10 mg/kg every 4 or 8 weeks) plus methotrexate (MTX) and those who received MTX plus placebo in the Anti-Tumor Necrosis Factor Trial in RA with Concomitant Therapy trial. RESULTS: At week 54, patients who did not show 20% improvement by American College of Rheumatology criteria (ACR20 nonresponders) while receiving infliximab plus MTX exhibited mild but statistically significant improvement in clinical variables, including the 28-joint Disease Activity Score (DAS28) (P < 0.001), tender joint count (P = 0.014), swollen joint count (P < 0.001), and C-reactive protein (CRP) level (P < 0.001). Whereas the clinical and CRP changes among ACR20 nonresponders to infliximab plus MTX were small and much lower than among ACR20 responders to this treatment, radiographic progression among ACR20 nonresponders to infliximab plus MTX was significantly inhibited (P < 0.001) compared with ACR20 nonresponders to MTX plus placebo. Radiographic progression was much greater in patients receiving MTX plus placebo than in patients receiving infliximab plus MTX, irrespective of ACR response status (mean change in modified Sharp/van der Heijde score 6.0 in ACR20 responders and 7.2 in ACR20 nonresponders in the MTX plus placebo-treated group, versus 0.1 in ACR20 responders and 1.2 in ACR20 nonresponders in the infliximab plus MTX-treated group). Furthermore, among patients who were ACR20 nonresponders through week 54, patients who were DAS nonresponders at weeks 30 and 54, and patients without any improvement in individual clinical variables, those receiving infliximab plus MTX still demonstrated inhibition of structural damage that was statistically significant compared with inhibition in patients who received MTX plus placebo (P < 0.05 to P < 0.001). CONCLUSION: Even in patients without clinical improvement, treatment with infliximab plus MTX provided significant benefit with regard to the destructive process, suggesting that in such patients these 2 measures of disease are dissociated.     

Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial

OBJECTIVE: To compare the benefits of initiating treatment with methotrexate (MTX) and infliximab (anti-tumor necrosis factor alpha [anti-TNFalpha] monoclonal antibody) with those of MTX treatment alone in patients with rheumatoid arthritis (RA) of < or =3 years' duration. METHODS: RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor. One thousand forty-nine patients were randomly assigned in a 4:5:5 ratio to 3 treatment groups: MTX-placebo, MTX-3 mg/kg infliximab, and MTX-6 mg/kg infliximab. MTX dosages were rapidly escalated to 20 mg/week, and infliximab or placebo infusions were given at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. RESULTS: At week 54, the median percentage of American College of Rheumatology improvement (ACR-N) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the MTX-placebo group (38.9% and 46.7% versus 26.4%, respectively; P < 0.001 for both comparisons). Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone (mean +/- SD changes in van der Heijde modification of the total Sharp score at week 54: 0.4 +/- 5.8 and 0.5 +/- 5.6 versus 3.7 +/- 9.6, respectively; P < 0.001 for each comparison). In addition, physical function improved significantly more in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group. Infliximab therapy was associated with a significantly higher incidence of serious infections, especially pneumonia. CONCLUSION: For patients with active RA in its early stages, combination therapy with MTX and infliximab provides greater clinical, radiographic, and functional benefits than treatment with MTX alone.     

The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various comorbidities: a large, randomized, placebo-controlled trial

OBJECTIVE: To assess the risk of serious infections following 22 weeks of infliximab therapy, and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis (RA) with various comorbidities. METHODS: Patients with active RA despite receiving methotrexate (MTX) were randomly assigned to receive infusions of placebo (group 1, n=363), 3 mg/kg infliximab (group 2, n=360), or 10 mg/kg infliximab (group 3, n=361) at weeks 0, 2, 6, and 14. At week 22, patients in placebo group 1 began receiving 3 mg/kg infliximab, and patients in group 3 continued to receive an infliximab dose of 10 mg/kg. Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg. RESULTS: At week 22, the relative risk of developing serious infections in groups 2 and 3, compared with group 1, was 1.0 (95% confidence interval [95% CI] 0.3-3.1, P=0.995) and 3.1 (95% CI 1.2-7.9, P=0.013), respectively. The incidence of serious adverse events was 7.8% in groups 2 and 3 compared with 7.5% in group 1. From week 22 to week 54, 11.8%, 9.9%, and 10.3% of patients in groups 1, 2, and 3, respectively, reported occurrences of serious adverse events. Through week 54, 1 patient in group 1, 2 patients in group 2, and 4 patients in group 3 developed active tuberculosis. CONCLUSION: The risk of serious infections in patients receiving the approved infliximab dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone. Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22.     

Chimeric anti-tumor necrosis factor-alpha monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy

OBJECTIVE: To evaluate the safety and efficacy of single and multiple doses of a chimeric anti-TNF-alpha monoclonal antibody (infliximab) in patients with rheumatoid arthritis (RA) who had active disease despite therapy with methotrexate (MTX). METHODS: Twenty-eight patients with active RA despite receiving therapy with 10 mg/week of MTX were randomized to receive a single, blinded infusion of either placebo or 5, 10, or 20 mg/kg infliximab. Twenty-three patients who completed the blinded study entered an open, multiple dose extension study in which they received up to 3 additional infusions of 10 mg/kg infliximab at Weeks 12, 20, and 28. Safety, efficacy, and pharmacokinetics were evaluated during the blinded and open trial. RESULTS: There were no serious infusion related reactions. In the blinded phase, 17 (81.0%) of 21 patients receiving infliximab achieved an American College of Rheumatology (ACR) 20% response at some point during the 12 weeks of followup compared to one (14.3%) of 7 patients receiving placebo (p = 0.003). Clinical improvement was evident by the first week and was sustained through Week 12. For the 19 patients who received infliximab during the blinded part of the trial and continued into the open label trial, 53% maintained an ACR 20% response with multiple infusions of 10 mg/kg infliximab through Week 40. Three patients withdrew from the trial during the open continuation phase because of adverse events: cellulitis, infusion related dizziness and headache, and vasculitic rash. Infliximab in doses of 5 to 20 mg/kg had a mean terminal half-life ranging from 9 to 12 days and was detectable in sera from most patients 8 to 12 weeks after dosing. CONCLUSION: Infliximab is generally well tolerated during 40 weeks of therapy. A single infusion of 5 to 20 mg/kg infliximab significantly decreases the signs and symptoms of RA compared to placebo in patients with active disease receiving MTX. Multiple doses of infliximab produce sustained clinical benefit for up to 40 weeks.     

Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate

OBJECTIVE: To evaluate the efficacy and safety of repeated administration of infliximab plus methotrexate (MTX) over a 2-year period in patients with rheumatoid arthritis (RA) who previously experienced an incomplete response to MTX. METHODS: Four hundred twenty-eight patients were randomly assigned to receive MTX plus placebo or infliximab at a dose of 3 or 10 mg/kg plus MTX for 54 weeks, with an additional year of followup. The protocol was later amended to allow for continued treatment during the second year. Of 259 patients who entered the second year of treatment, 216 continued to receive infliximab plus MTX for 102 weeks. Ninety-four of these 259 patients experienced a gap in therapy of >8 weeks before continuing therapy. Infusions were administered at weeks 0, 2, and 6, followed by treatment every 4 weeks or every 8 weeks (alternating with placebo infusions in the interim 4-week visits) at a dose of 3 or 10 mg/kg for a total of 102 weeks (including the gap in therapy). For safety and efficacy assessments, data on the patients who were randomized to receive treatment, irrespective of whether treatment was administered for 102 weeks, were evaluated using all actual observations available. The efficacy measures included the Health Assessment Questionnaire (HAQ) (physical function), Short Form 36 health survey (SF-36) (health-related quality of life), total radiographic scores (structural damage), and the American College of Rheumatology 20% improvement criteria (ACR20) (signs and symptoms). RESULTS: The infliximab plus MTX regimens resulted in significantly greater improvement in HAQ scores (P < or = 0.006) and SF-36 physical component summary scores (P < or = 0.011) compared with the MTX-only group. There also was stability in the SF-36 mental component summary score among patients who received the infliximab plus MTX regimens. Median changes from baseline to week 102 in the total radiographic score were 4.25 for patients who received the MTX-only regimen and 0.50 for patients who received the infliximab plus MTX regimen. The proportion of patients achieving an ACR20 response at week 102 varied from 40% to 48% for the infliximab plus MTX groups compared with 16% for the MTX-only group. CONCLUSION: Throughout 102 weeks of therapy, infliximab plus MTX provided significant, clinically relevant improvement in physical function and quality of life, accompanied by inhibition of progressive joint damage and sustained improvement in the signs and symptoms of RA among patients who previously had an incomplete response to MTX alone.     

The safety of infliximab,combined with background treatments,among patients with rheumatoid arthritis and various comorbidities: A large,randomized, placebo‐controlled trial

Objective

To assess the risk of serious infections following 22 weeks of infliximab therapy, and to further characterize the safety profile of infliximab in combination with background treatments during 1 year in patients with rheumatoid arthritis (RA) with various comorbidities.

Methods

Patients with active RA despite receiving methotrexate (MTX) were randomly assigned to receive infusions of placebo (group 1, n = 363), 3 mg/kg infliximab (group 2, n = 360), or 10 mg/kg infliximab (group 3, n = 361) at weeks 0, 2, 6, and 14. At week 22, patients in placebo group 1 began receiving 3 mg/kg infliximab, and patients in group 3 continued to receive an infliximab dose of 10 mg/kg. Patients in group 2 who failed to meet predefined response criteria received increasing doses of infliximab in increments of 1.5 mg/kg.

Results

At week 22, the relative risk of developing serious infections in groups 2 and 3, compared with group 1, was 1.0 (95% confidence interval [95% CI] 0.3–3.1, P = 0.995) and 3.1 (95% CI 1.2–7.9, P = 0.013), respectively. The incidence of serious adverse events was 7.8% in groups 2 and 3 compared with 7.5% in group 1. From week 22 to week 54, 11.8%, 9.9%, and 10.3% of patients in groups 1, 2, and 3, respectively, reported occurrences of serious adverse events. Through week 54, 1 patient in group 1, 2 patients in group 2, and 4 patients in group 3 developed active tuberculosis.

Conclusion

The risk of serious infections in patients receiving the approved infliximab dose of 3 mg/kg plus MTX was similar to that in patients receiving MTX alone. Patients receiving the unapproved induction regimen of 10 mg/kg infliximab plus MTX followed by a 10 mg/kg maintenance regimen had an increased risk of serious infections through week 22.

     

Rapid improvement in rheumatoid arthritis patients on combination of methotrexate and infliximab: clinical and magnetic resonance imaging evaluation

The objectives of this study was to assess, using clinical and magnetic resonance imaging (MRI) criteria, the efficacy of combination infliximab therapy in patients with active rheumatoid arthritis (RA) refractory to methotrexate (MTX) treatment and to ascertain whether the changes in MRI parameters correlate with the clinical response. Four infusions of infliximab (3 mg/kg) at weeks 0, 2, 6, and 14 were added to a stable background dose of MTX in 19 patients with active disease. Clinical parameters were assessed before each infusion and at week 14. Dynamic contrast-enhanced MRI examination of the most severely affected wrist was performed at baseline and week 14. Synovitis severity, volume of synovitis, and synovial perfusion indices were evaluated. Significant improvement in all clinical disease activity parameters was seen at week 14 with reduction in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and DAS28. Sixty-eight percent of patients achieved ACR20. MRI disease activity parameters also significantly decreased after treatment with reduction in grading of synovitis, volume of active synovitis, and perfusion enhancement slope. Significant positive correlations were seen between the baseline volume of synovitis and the pain score (r=0.65), patient global score (r=0.68), and health assessment questionnaire (HAQ) score (r=0.46). In conclusion, addition of infliximab to methotrexate rapidly reduces inflammation in longstanding patients with RA. Assessment of enhancing synovial volume and perfusion indices on serial MRI examination was helpful in documenting the effect of treatment over this short period.     

Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone

OBJECTIVE: To compare the effects of methotrexate (MTX), alone or in combination with intravenous (IV) methylprednisolone (MP) or infliximab, on magnetic resonance imaging (MRI)-detected synovitis, bone edema, and erosive changes in patients with early rheumatoid arthritis (RA). METHODS: Forty-four patients with early RA were randomized to receive MTX alone (MTX group), MTX plus IV MP (IV MP group), or MTX plus infliximab (infliximab group), infused on day 0 and weeks 2, 6, 14, 22, 30, 38, and 46. Gadolinium-enhanced MRI scans of the metacarpophalangeal joints, wrists, and metatarsophalangeal joints were performed at baseline, week 18, and week 52. RESULTS: Scores for MRI-detected synovitis and bone edema improved over time in the 3 groups, with significantly lower synovitis scores in the infliximab group compared with the MTX group and significantly lower bone edema scores in the infliximab group compared with the MTX and the IV MP groups. Scores for MRI-detected erosion significantly increased over time in all groups. There were no differences in erosion scores between the MTX group and the other groups. It is of note that patients treated with IV MP showed more significant progression in MRI-detected erosions compared with patients treated with infliximab. At week 22, response rates according to the American College of Rheumatology 20% improvement criteria (ACR20), the ACR50, and the ACR70 were significantly higher in both the IV MP group and the infliximab group compared with the MTX group. At week 52, remission was achieved in 40% of patients in the MTX group and in 70% of patients in the IV MP and infliximab groups. Health Assessment Questionnaire scores improved significantly over time in all groups, with patients receiving IV MP experiencing significantly more improvement compared with patients treated with MTX alone. No severe side effects were observed, except 1 case of MTX-related pneumonitis. CONCLUSION: The combination of MTX and infliximab is superior to MTX alone for reducing MRI-detected signs of synovitis and bone edema in patients with early RA. Progression of MRI-detected erosion was greater in patients treated with MTX plus IV MP compared with that in patients who received MTX plus infliximab.     

Response to pneumococcal vaccine in patients with early rheumatoid arthritis receiving infliximab plus methotrexate or methotrexate alone

OBJECTIVE: We assessed whether the addition of anti-tumor necrosis factor (TNF) agent to methotrexate (MTX) therapy might alter the response of patients with rheumatoid arthritis (RA) to pneumococcal vaccination. METHODS: Seventy patients with early RA (n = 20, 36, and 14 in the infliximab 3 mg/kg plus MTX, infliximab 6 mg/kg plus MTX, and placebo plus MTX groups, respectively) were included in an analysis of patients enrolled in an ASPIRE substudy. Patients received 0.5 ml pneumococcal vaccine (Pneumovax) 34 weeks after initiation of study treatment; patient sera were collected 4 weeks later (week 38). Antibody responses were tested using enzyme immunoassay methods for reactivity to a panel of 12 serotypes of the pneumococcal vaccine. RESULTS: No significant difference in response to Pneumovax was observed between the infliximab plus MTX and placebo plus MTX groups. Roughly 80%-85% of patients responded to at least one serotype; however, only 20%-25% of patients in the different treatment groups responded to at least 6 different serotypes. Comparable proportions of patients in the 3 treatment groups responded to an increasing number (> or = 1 to > or = 6) of different serotypes. Patients < 45 years of age and those receiving oral corticosteroids generally appeared to respond better than those age 45 to 65 years and those not receiving oral corticosteroids. CONCLUSION: All treatment groups in this study had lower responses to vaccine than would be expected in the normal population. However, the addition of the anti-TNF agent infliximab to MTX therapy did not appear to affect the response of patients with RA to pneumococcal vaccination.     

Maintenance of infliximab treatment in ankylosing spondylitis: results of a one-year randomized controlled trial comparing systematic versus on-demand treatment

OBJECTIVE: Continuous treatment with the anti-tumor necrosis factor alpha (anti-TNFalpha) antibody infliximab is efficacious in ankylosing spondylitis (AS), whereas treatment discontinuation results in disease relapse, with variable delay. This study was undertaken to compare the efficacy of continuous treatment with infliximab with that of a treatment regimen adapted to symptom recurrence. Methotrexate (MTX) in combination with infliximab was also tested. METHODS: Patients with active AS were randomly assigned at week 0 to receive infliximab every 6 weeks (continuous treatment) or upon symptom recurrence (on-demand treatment), following infusions at weeks 4, 6, and 10. Patients in the on-demand group were randomly assigned to receive either MTX in combination with infliximab or infliximab alone. Patients were monitored for 1 year. The primary end point was the proportion of patients who met the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at week 58. RESULTS: Of 247 patients, 124 were assigned to receive infliximab every 6 weeks and 123 to receive on-demand treatment. Among the latter, 62 received MTX, and 61 received infliximab alone. A greater proportion of patients receiving infliximab every 6 weeks fulfilled ASAS20 response criteria at week 58 than did patients receiving on-demand treatment (75% versus 46%; P<0.0001). Patients in the continuous treatment group received more infliximab infusions after week 10 than did those in the on-demand group (mean+/-SD 5.8+/-2.2 versus 3.5+/-2; P<0.0001). Addition of MTX did not significantly affect the proportion of patients with an ASAS20 response at week 58, nor the number of infliximab infusions administered. CONCLUSION: These findings indicate that continuous treatment of AS with infliximab is more efficacious than on-demand treatment, and that the addition of MTX to infliximab provides no significant benefit.     

Dose escalation of parenteral methotrexate in active rheumatoid arthritis that has been unresponsive to conventional doses of methotrexate: a randomized, controlled trial

OBJECTIVE: To examine whether dose escalation of intramuscular (IM) methotrexate (MTX) up to 45 mg/week improves disease control in patients who have active rheumatoid arthritis (RA) despite receiving conventional doses (15 mg/week) of IM MTX, and to obtain preliminary data on patient tolerability and adverse effects of higher doses of IM MTX. METHODS: Patients >18 years of age who had active RA, defined as a European League Against Rheumatism (EULAR) Disease Activity Score in 28 joints (DAS28) of >3.2, and who had received 15-20 mg/week of oral MTX for at least 2 months were switched (week 0) to 15 mg/week of IM MTX for 6 weeks. Patients whose DAS28 remained >3.2 at both week 4 and week 6 were randomized, in a double-blind manner, either to continue to receive 15 mg/week IM MTX with monthly placebo escalation or to receive escalating doses of IM MTX monthly up to 45 mg/week. The dose of MTX or placebo was escalated every 4 weeks if the DAS28 was >2.5. Safety assessments and determination of the DAS28 were performed every 2 weeks and monthly, respectively. Disease activity parameters from the American College of Rheumatology (ACR) core disease activity set and health status as recorded on the Medical Outcomes Study Short-Form 12 were determined at baseline (week 0) and final assessment (week 22). The primary outcome was the percentage of patients in each group achieving a target DAS28 of <3.2. Secondary outcomes comprised the percentage of patients whose DAS28 improved by >1.2, the percentage of patients achieving a 20% improvement in the ACR core disease activity measures (ACR20), and the percentage of patients achieving a good response, a moderate response, or no response in accordance with the EULAR response criteria. RESULTS: Sixty-four patients were eligible for entry and were switched from oral MTX to 15 mg/week IM MTX. At baseline, the mean +/- SD DAS28 was 5.6 +/- 0.88; after 6 weeks of IM MTX, the DAS28 had improved by a mean of 0.42 (95% confidence interval [95% CI] 0.15-0.69). At 6 weeks, 54 patients still had a DAS28 of >3.2 and were therefore eligible for randomization. By 22 weeks, 1 patient (3.7%) in each group achieved the primary outcome of a DAS28 <3.2 (95% CI for the difference between the groups -15% to +15%). Five patients (18.5%) in each group showed an improvement of >1.2 in the DAS28 (95% CI for the difference between the groups -18% to +18%). One patient (3.7%) in each group achieved an ACR20 response, but none achieved a good response as defined by the EULAR response criteria. One patient in each group had a serious adverse reaction; minor adverse reactions were more frequently reported in the dose escalation group. CONCLUSION: Switching from oral to parenteral MTX 15 mg/week results in a minor improvement in disease control. For patients with active RA receiving 15 mg/week IM MTX, increasing the dose up to 45 mg/week does not improve disease control. Higher doses of IM MTX were generally well tolerated and not associated with an increase in serious adverse reactions to the drug.     

Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study

OBJECTIVE: To assess the efficacy, safety, and pharmacology of subcutaneous administration of golimumab in patients with active rheumatoid arthritis (RA) despite treatment with methotrexate (MTX). METHODS: Patients were randomly assigned in a double-blinded manner to receive injections of placebo plus MTX or 50 mg or 100 mg golimumab every 2 or 4 weeks plus MTX through week 48. Patients originally assigned to receive injections every 2 weeks had the interval increased to every 4 weeks starting at week 20. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 16. The study was powered to detect a difference in the primary end point when the combined golimumab groups and at least 1 of the individual dose groups were compared with placebo. RESULTS: The primary end point was attained. Sixty-one percent of patients in the combined golimumab plus MTX dose groups achieved an ACR20 response at week 16 compared with 37% of patients in the placebo plus MTX group (P=0.010). In addition, 79% of patients in the group receiving 100 mg golimumab every 2 weeks achieved an ACR20 response (P<0.001 versus placebo). Through week 20 (after which patients receiving placebo were switched to active infliximab therapy), serious adverse events were reported in 9% of patients in the combined golimumab groups and in 6% of patients in the placebo group. CONCLUSION: Golimumab plus MTX effectively reduces the signs and symptoms of RA and is generally well tolerated in patients with an inadequate response to MTX.     

Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial

OBJECTIVES: To evaluate further in a phase III, double blind trial the efficacy of infliximab in patients with active psoriatic arthritis (PsA), as observed in the smaller IMPACT trial. METHODS: 200 patients with active PsA unresponsive to previous treatment were randomised to infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22. Patients with inadequate response entered early escape at week 16. The primary measure of clinical response was ACR20. Other measures included Psoriatic Arthritis Response Criteria (PsARC), Psoriasis Area and Severity Index (PASI), and dactylitis and enthesopathy assessments. RESULTS: At week 14, 58% of patients receiving infliximab and 11% of those receiving placebo achieved an ACR20 response and 77% of infliximab patients and 27% of placebo patients achieved PsARC (both p<0.001). Among the 85% of patients with at least 3% body surface area psoriasis involvement at baseline, 53/83 (64%) patients receiving infliximab had at least 75% improvement in PASI compared with 2/87 (2%) patients receiving placebo at week 14 (p<0.001). These therapeutic effects were maintained through the last evaluation (week 24). Fewer infliximab patients than placebo patients had dactylitis at week 14 (18% v 30%; p = 0.025) and week 24 (12% v 34%; p<0.001). Fewer infliximab patients (22%) than placebo patients (34%) had active enthesopathy at week 14 (p = 0.016); corresponding figures at week 24 were 20% and 37% (p = 0.002). Infliximab was generally well tolerated, with a similar incidence of adverse events in each group. CONCLUSIONS: Infliximab 5 mg/kg through 24 weeks significantly improved active PsA, including dactylitis and enthesopathy, and associated psoriasis.