A phase I study assessing the safety, clinical response, and pharmacokinetics of an experimental infliximab formulation for subcutaneous or intramuscular administration in patients with rheumatoid arthritis

OBJECTIVE: To assess safety, clinical response, and pharmacokinetics of subcutaneous (SC) and intramuscular (IM) doses of an experimental formulation of infliximab [including experimental SC doses following administration of commercially-formulated intravenous (IV) infliximab] in patients with rheumatoid arthritis (RA) refractory to methotrexate. METHODS: In this randomized, open-label, 3-stage design, 43 subjects were enrolled in 7 dose groups. In Stage I, 15 subjects received single SC doses of 0.5, 1.5, or 3.0 mg/kg. In Stage II, 21 subjects received one of 3 regimens: 100 mg SC every 2 weeks (3 injections); 3 mg/kg commercially-formulated IV infliximab every 2 weeks (2 infusions) followed by 100 mg SC every 2 weeks (3 injections); or 100 mg IM every 2 weeks (3 injections). In Stage III, 7 subjects received 100 mg SC every 4 weeks (3 injections). RESULTS: No treatment-related serious adverse events were observed, and there were no serious injection site reactions. A low-titer infliximab antibody response was detected in 27% of subjects receiving single SC doses, 5% receiving multiple SC doses, and 43% receiving IM doses. SC administration yielded roughly dose-proportional increases in Cmax and AUC. American College of Rheumatology 20% response (ACR20) was achieved 2 weeks after the last injection by 86.7% of subjects receiving single SC doses, 85.7% receiving SC doses every 2 weeks, 85.7% receiving both IV and SC doses, 57.1% receiving multiple IM doses, and 80.0% receiving SC doses every 4 weeks. CONCLUSION: SC and IM treatment with this experimental infliximab formulation was well tolerated and was associated with a favorable ACR response.     

Double-blinded infliximab dose escalation in patients with rheumatoid arthritis

OBJECTIVE: To determine the efficacy, safety and pharmacokinetics of infliximab dose escalation in patients with rheumatoid arthritis (RA) who had an inadequate response to 3 mg/kg infliximab treatment or whose disease flared after initially responding. METHODS: Patients with active RA, despite receiving methotrexate, received infliximab 3 mg/kg at weeks 0, 2, 6 and 14 in one of the three arms of the START trial. Beginning at week 22, patients had their infliximab dose increased in a double-blind fashion in increments of 1.5 mg/kg if the total tender and swollen joint count did not improve by at least 20% from baseline (lack of response) or the improvement at week 22 or later worsened by 50% or more (criterion for flare). RESULTS: Of the 329 evaluable patients, 100 (30.4%) patients required dose escalation at or after week 22 because of flare or lack of response. The majority of patients (>80%) who received up to three dose escalations showed >/=20% improvement in the total tender and swollen joint count after their last dose escalation. Patients who required dose escalations generally had lower preinfusion serum infliximab concentrations than those who did not require them. The incidences of adverse events and serious adverse events for the patients who received dose escalation(s) were similar to those of patients who did not receive dose escalation. CONCLUSION: Fewer than one-third of patients required a dose escalation. The majority of patients showed improvement after receiving increased doses of infliximab, without an increased risk of adverse events.     

肿瘤坏死因子拮抗剂治疗风湿性疾病安全性的短期临床观察

目的 描述肿瘤坏死因子(TNF)-α拮抗剂治疗风湿性疾病发生的不良反应,评价临床应用的安全性和耐受性.方法 对2007年1月至2008年10月使用TNF-α拮抗剂的患者从临床症状、体征及实验室检查方面记录使用过程中发生的不良反应及程度和最终结局.结果 78例患者中35%(27/78)为类风湿关节炎(RA),41%(32/78)为强直性脊柱炎(AS),17%(13/78)为银屑病关节炎(PsA),6%(5/78)为未分化脊柱关节病(uSpA).59例患者使用依那西普,7例(12%)发生注射局部反应、上呼吸道感染及结核病等不良反应.19例患者使用英夫利西单抗,3例(16%)发生不良反应,1例(AS)为上呼吸道感染,1例(AS)前两次均在输注完24 h内出现伞身红色丘疹及心悸,1例(RA)输注4次后出现不明原因发热.部分不良反应可自行消失,其余经适当处理后痊愈.结论 证实依那西普和英夫利西单抗治疗风湿性疾病具有较好的安全性和耐受性,发生的不良反应是温和的,经适当处理可痊愈.     

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.     

Retrospective clinical study on the notable efficacy and related factors of infliximab therapy in a rheumatoid arthritis management group in Japan (RECONFIRM)

This study aims to reconfirm the clinical efficacy and related factors of infliximab therapy, the first biological agent introduced to Japanese patients with rheumatoid arthritis (RA). Data of 351 RA patients with infliximab were collected retrospectively from three major centers for management of rheumatic diseases in Japan. Infliximab was infused according to the approved method, and the clinical response was evaluated following 22 weeks of infliximab therapy in 258 patients using the European League Against Rheumatism (EULAR) response criteria. DAS28-CRP (Disease Activity Score including a 28-joint count/C-reactive protein) with a threshold of 4.1 or 2.7 for the high or low disease activity cut-off was also used. A total of 90.3% of patients exhibited high disease activity before infliximab therapy. After 22 weeks of infliximab therapy, the proportions of patients exhibiting high activity, moderate activity, low activity, or in clinical remission were 27.9%, 33.3%, 10.9%, or 27.9%, respectively, thereby indicating good overall efficacy of infliximab therapy. A good or moderate overall response to therapy was achieved in 84.5% of patients. Male sex, rheumatoid factor (RF) negativity, low CRP, lower swollen joint count and a low prednisolone dose were significantly related to the clinical response. Furthermore, male sex, older age, and a high tender joint count had a significant correlation with treatment discontinuation as a result of adverse reactions. In conclusion, we have reconfirmed the effectiveness of infliximab in Japanese patients with RA by using DAS28-CRP and EULAR response criteria. These data will facilitate more efficacious use of this expensive biological agent in the daily practice of rheumatology in Japan. An erratum to this article is available at .     

Dose escalation of infliximab in clinical practice: improvements seen may be explained by a regression-like effect

OBJECTIVE: To determine whether increased infliximab doses result in better clinical outcome in rheumatic diseases. METHODS: Subjects were 124 patients with rheumatoid arthritis treated with biological agents at a single institute. Index cases were 44 patients whose infliximab doses had been increased. Controls were patients treated with infliximab without dose increase (n = 44), and patients treated with etanercept (n = 36). Disease activity score (DAS28), ACR28 swollen joint counts, and numerical ACR responses were compared before and after dose increases. For the controls, the point at which the DAS28 value showed any increase (despite infliximab/etanercept treatment) was used as the reference time point. Comparisons were made between three sets of outcomes: best outcome achieved before the dose increase (cases) or before the reference time point (controls); outcomes at this point; and best outcomes after this point. RESULTS: Following dose increase, disease activity showed modest but statistically significant improvements. The improvement achieved after dosage escalation was equal to, but not better than, the best values before dose escalation. While this finding could be interpreted as "recapturing" the previous response, similar improvements were seen in both control groups. Thus the same pattern of worsening and subsequent improvement was seen with or without the infliximab dose increase. CONCLUSIONS: Clinical improvement with increased infliximab dose, and the impression that a previous response can be "recaptured" with higher doses, cannot be taken at face value, as similar improvements occurred in two control groups. The use of infliximab at doses higher than 3 mg/kg needs to be evaluated further.     

Clinical experience with infliximab for Crohn's disease: the first 100 patients in Edmonton, Alberta.

OBJECTIVE: To determine whether the clinical efficacy and safety of infliximab in diverse clinical referral practices was similar to that seen in the randomized, controlled clinical trials. METHODS: Data were gathered from a review of charts of 109 consecutive patients with inflammatory and/or fistulizing Crohn's disease who received infliximab infusions. Responses were recorded based on the physician's global clinical assessment and classified as complete, partial or nonresponse. RESULTS: One hundred nine patients were treated with one to nine infusions of infliximab at a dose of 5 mg/kg and followed up for a median of 24 weeks (range one to 40 weeks). Fifty-four patients were treated for inflammatory disease, 38 for fistulizing disease and 17 for both. Clinical response occurred in 73% (17% complete response, 55% partial response). The clinical response rate did not vary relative to patient demographics, disease distribution, indication for infliximab, or the concomitant use of corticosteroids or immune modifiers. For those taking concomitant immune modifiers, the response rate was 75%. The median time to response was two weeks (range one to six weeks). The median duration of response was 12 weeks (range six to 88 weeks). Reduction or cessation of steroids was possible in 17 of 32 patients. Adverse events related to infliximab occurred in 7% of patients. These events were characterized as mild and did not require stoppage of infliximab therapy, except in one patient who had a treatable anaphylactic-like infusion reaction. CONCLUSIONS: The patient group in the present study realized significant clinical benefit, with minimal adverse effects, following treatment with infliximab. Clinical response rates paralleled those previously described in placebo controlled trials and retrospective clinical practice reviews. Nevertheless, the complete response rate (ie, remission) in this patient group was lower than that previously described.     

Induction of autoantibodies during prolonged treatment with infliximab

OBJECTIVE: To determine the frequency and correlates of autoantibody formation in patients with rheumatic diseases treated with infliximab in a routine clinical setting. METHODS: All patients receiving at least 5 infusions of infliximab, and with anticipated continuation, were prospectively evaluated for the development of the following antibodies: antinuclear antibody (ANA), anti-DNA, anti-Sm, anti-RNP, anti-SSA and anti-SSB. Correlates with pharmacologic treatments, response to infliximab, and adverse events were assessed. RESULTS: Seventy-six percent of 42 patients receiving prolonged treatment with infliximab developed new autoantibodies, and these persisted in 57%. The most common new autoantibody was ANA in 45%, followed by anti-DNA in 33%, anti-Sm in 31%, and anti-RNP in 29%. New autoantibody formation was associated with both a greater number of infusions (p = 0.015) and a higher total dose of infliximab infused (p = 0.047). No other treatment, disease characteristic, or loss of efficacy to infliximab discriminated between those developing antibodies compared to those without new antibody formation. No patient developed clinical signs of a new connective tissue disease. CONCLUSION: Autoantibody formation is seen commonly in patients receiving prolonged treatment with infliximab. Concomitant immunosuppressive treatments did not preclude the formation of antibodies. The clinical significance of antibody formation remains to be determined.     

Titration of infliximab treatment in rheumatoid arthritis patients based on response patterns

OBJECTIVES: To observe the course of the disease activity in rheumatoid arthritis (RA) patients treated with the standard infliximab dosing regimen and to adjust treatment guided by the pattern of disease activity. METHODS: All RA patients starting infliximab treatment were included and observed for at least 37 weeks. At infusion 4 (week 14), European League Against Rheumatism response was assessed. In moderate responders the dose was unchanged and the disease activity was carefully observed. In case of stable disease activity, the dose was increased at infusion 5 (week 22). In case of a temporary response the interval was reduced. Paired t-testing was applied to the disease activity score with 28-joint counts (DAS28) at week 22 and study endpoint. RESULTS: A total of 76 patients were included. Response after 14 weeks: good 22 (29%) patients, moderate 26 (34%) patients, and non-response in 21 patients. Seven patients (9%) dropped out before week 14 due to adverse events (5) or patients' initiative (2). In patients with moderate response, the following disease course between infusion 4 and 5 was observed: improvement to good response 6, temporary response 6, stable disease activity 6, drop out 8. In moderate responders, interval reduction and dose increase resulted in a decrease in mean DAS28 from 5.1 to 3.6 [P = 0.005, mean interval 5.6 weeks, mean infliximab dose 4.8 mg/kg/8 week (endpoint)] and from 4.1 to 3.6 [P = 0.04, mean infliximab dose 7.3 mg/kg/8 week (endpoint)], respectively. CONCLUSION: Three different patterns of disease activity were observed in moderate responders after 14 weeks of infliximab treatment, i.e. further improvement, no change in disease activity or a temporary response. Both interval reduction and dose increase significantly reduced disease activity, however, with different mean infliximab dosages. In good responders the response was often sustained over follow-up, whereas non-responders showed modest or no improvement despite dose adjustments.     

The use of infliximab in academic rheumatology practice: an audit of early clinical experience

OBJECTIVE: To audit a first clinical experience of treating rheumatic disease patients with infliximab in the setting of an academic tertiary care rheumatology practice. METHODS: The infusion history of patients referred to the McGill University Health Centre during the first 18 month period of a special access program for treatment with infliximab, a tumor necrosis factor-a antibody, was audited for disease characteristics, dosing schedule for infliximab, concomitant treatments, response rate, and side effect profile. RESULTS: Forty-one patients received a total of 300 infusions of infliximab over a period of 9 +/- 5 months (mean +/- standard deviation). Rheumatic disease indications were rheumatoid arthritis in 30, spondyloarthropathy in 6, psoriatic arthritis in 2, juvenile onset polyarthritis in 2, and scleroderma in one. Disease duration was 17 +/- 11 years. Concomitant treatment with steroids and methotrexate was present in 68% and 54%, respectively. Infliximab treatment was continued beyond 5 infusions or 22 weeks in 63%. Of the 26 patients continuing treatment, adjustment to dosing and/or interval schedule of infusions was made in 58%. The clinical response rate was moderately to greatly improved in 96%. Severe side effects considered directly related to the treatment were observed in 6 (15%) patients; less severe side effects, which did not preclude continuation of treatment but frequently required medical intervention, were noted in 93%. CONCLUSION: Infliximab is a valuable treatment for patients with resistant rheumatic diseases in the short term. Both the serious, and the frequent, more benign complication rate observed in this group of patients should alert physicians to be vigilant in the routine care of patients treated with infliximab.     

Anti-infliximab antibodies in patients with rheumatoid arthritis who require higher doses of infliximab to achieve or maintain a clinical response

OBJECTIVE: To determine whether the need to use doses of infliximab greater than 3 mg/kg every 8 weeks to achieve or maintain clinical response in patients with rheumatoid arthritis (RA) is associated with differences in baseline clinical characteristics or anti-infliximab antibodies. METHODS: Baseline clinical characteristics and anti-infliximab levels were evaluated retrospectively in a cohort of 51 consecutive patients with RA treated with infliximab at a single center. Patients were divided into 2 groups for comparison: Group 1 patients achieved and maintained clinical responses with infliximab 3 mg/kg every 8 weeks; Group 2 patients required higher doses. RESULTS: Thirty-two (63%) patients required infliximab dose escalation (Group 2). There were no statistically significant differences in baseline or clinical characteristics between Group 1 and Group 2 patients. Anti-infliximab antibodies occurred in 47% of Group 2 versus 27% of Group 1 patients, with higher anti-infliximab antibody concentrations in Group 2 patients (mean +/- SD: 18.3 +/- 8.9 g/ml vs 7.5 +/- 4.8 g/ml; p = 0.02). Patients who developed anti-infliximab antibodies were younger and receiving less prednisone at the time of infliximab initiation than patients who did not. CONCLUSION: Finding higher anti-infliximab antibody concentrations in patients who needed dose escalation of infliximab to achieve or maintain clinical responses with lower serum trough levels of infliximab suggests that development of anti-infliximab antibodies may reduce clinical efficacy of infliximab in some patients with RA.     

Analysis of efficacy and safety of multiple intravenous infusion of anti-tumor necrosis factor-alpha monoclonal antibody (Remicade) combined with methotrexate compared with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis

The objective of the paper was compare the effects and tolerability of combined therapy of multiple intravenous infusions of anti-tumour necrosis factor-alfa (TNF-alfa) monoclonal antibody (Remicade) with methotrexate versus treatment with sodium aurothiomalate and intramuscular depot methylprednisolone in rheumatoid arthritis (RA). We investigate also the interval necessary to obtain the improvement in both treatment groups. 36 patients commencing intramuscular sodium aurothiomalate therapy with intramuscular depot methylprednisolone acetate at weeks 0, 4, 8 and 12 in addition to chrysotherapy were compared in retrospective analysis with 32 patients starting with multiple intravenous infusions of infliximab, anti-TNF-alfa monoclonal antibody (Remicade) and methotrexate at a stable dose. Patients were assessed by composite clinical score (DAS 28) and C-reactive protein during 22 weeks of therapy. At week 2 and 6 a significantly greater percentage of infliximab-treated than gold-treated RA patients achieved improvement in each clinical measurement of disease activity. At 22 week of treatment moderate and good response according to EULAR criteria was achieved in 91% of infliximab-treated patients and 58% gold treated patients (p < 0.001). Adverse events were more frequently observed in infliximab-treated patients, but only gold-treated patients discontinued treatment because adverse events (2 patients due to proteinuria, 2 patients due to mucocutaneous changes and one patient due to leucopenia). The higher percentage of adverse events in infliximab-treated patients was caused mainly by the occurrence of infusion reactions (23 reactions out of 160 infusions); most of them were mild (somnolentia and headache) and transient. Viral infections (including herpes simplex and zoster) were more common in patients treated with infliximab and methotrexate. Combination therapy of infliximab and methotrexate is more effective in reducing clinical and biochemical disease activity than gold with methylprednisolone treatment in RA patients during 22 weeks of treatment, especially in the first 6 weeks.     

Infliximab treatment in combination with cyclosporin A in patients with severe refractory rheumatoid arthritis

OBJECTIVE: To investigate whether infliximab can be used in combination with cyclosporin A (CsA) in patients with refractory rheumatoid arthritis (RA) who cannot tolerate methotrexate (MTX). MATERIALS AND METHODS: Eighteen patients with refractory RA receiving low dose CsA (2 mg/kg/day) and prednisone (5 mg/day) were treated with intravenous infliximab. The patients were given infliximab (3 mg/kg weight) at 0, two, six, and every eight weeks thereafter for a total period of 12 months. Clinical improvement was evaluated according to the American College of Rheumatology (ACR) 20% response criteria. RESULTS: Eighty per cent of patients receiving the combination treatment with CsA and infliximab achieved the 20% ACR criteria for response to treatment, whereas 39% satisfied the 50% response criteria. In addition, a 76% reduction in swollen and tender joint count was found. Finally, a reduction in C reactive protein and erythrocyte sedimentation rate was maintained throughout the study. In general, treatment was well tolerated, with minimal adverse drug reactions. Two patients dropped out; one because of an immediate hypersensitivity reaction and the other because of the development of pulmonary tuberculosis. CONCLUSION: Multiple infusions of infliximab and low doses of CsA improve patients with refractory RA. It seems that CsA may be an alternative disease modifying drug to be used in combination with infliximab in patients with refractory RA who cannot tolerate MTX.     

A dose adjustment in patients with rheumatoid arthritis not optimally responding to a standard dose of infliximab of 3 mg/kg every 8 weeks can be effective: a Belgian prospective study

OBJECTIVES: To analyse the effect of a dose increase in patients with severe rheumatoid arthritis (RA) with insufficient clinical response to 3 mg/kg infliximab every 8 weeks. METHODS: Patients suffering from active refractory RA despite methotrexate, were treated with i.v. infusions of infliximab (3 mg/kg) on week 0, 2, 6 and every 8 weeks thereafter. Based on the clinical judgement at week 22, patients received a dose increase of 100 mg from week 30 on. The American College of Rheumatology (ACR) core set for disease activity measures was regularly assessed. RESULTS: Five hundred and eleven RA patients were included. At week 22, 61.4, 34 and 14.1% of all patients met ACR 20, ACR 50 and ACR 70 criteria, respectively, and 6.1% of patients were in remission. A low swollen joint count at baseline was correlated with improvement at week 22 for ACR 20 (P < 0.06), ACR 50 (P < 0.06) and ACR 70 (P < 0.005). The change in HAQ score between weeks 0 and 22 was predictive for response at week 54 (P < 0.01). The dose of infliximab was increased by 100 mg in 22% of the patients. Most baseline values of patients requiring dose increase were higher (P < or = 0.001) than the baseline values of the remaining patients. Increasing the dose of infliximab by one vial from week 30 on could circumvent the partial loss of response in these patients. CONCLUSION: Infliximab use in this large out-patient cohort resulted in a significant clinical improvement. A subgroup that partially lost response during the first 22 weeks could regain response by adding 100 mg of infliximab to the subsequent doses. Due to the current study design, however, a regression to the mean like effect could not be ruled out.     

Maintenance and tolerability of infliximab in a cohort of 152 patients with rheumatoid arthritis

OBJECTIVE: To determine the maintenance, tolerability and safety of infliximab in an unselected cohort of patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: One hundred and fifty-two RA patients receiving at least one course of infliximab between 2000 and 2003 were included in this study. Response to treatment and safety were assessed through recording adverse events, physical examinations and standard laboratory tests. The dosage of infliximab was patient specifically modified, when therapeutic response was judged inadequate by the assessment of a physician. RESULTS: The mean duration of follow-up was 401 days (85-1221). One hundred and twenty-two patients (78%) continued to receive infliximab after one year. 40 patients (26.3%) stopped infliximab therapy: 14 (9.2%) for inefficacy, 21 (13.8%) for adverse events. Fifty nine patients (38.8%) required an increase of the dosage (n=23, 15%) or a shortening of the interval between the infusions (n=20, 13.2%), or both (n=16, 10.5%) for symptomatic control. Infliximab discontinuation tended to be more frequent in smokers (p=0.055). Ninety-four patients (62%) reported at least one adverse event during the study: 64 infections (43%), 35 infusion reaction events (23%) which led to a discontinuation for 10 patients. Infusion reactions were more frequent in patients with a history of allergy. Three cases of tuberculosis and 1 breast carcinoma were reported during the study. CONCLUSIONS: Adjustments in the treatment of RA patients treated with recommended doses of infliximab were common (38.8% of the treated patients). Furthermore, the observed rate of infections (43%), including three cases of tuberculosis, should alert physicians to be vigilant in the routine care of patients treated with infliximab.     

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.     

Low dose of infliximab is inadequate in most patients with spondylarthropathies

OBJECTIVES: The recommended starting dose for infliximab for ankylosing spondylitis 5mg/kg is higher than that for rheumatoid arthritis. Because of the high expense of the drug lower doses may be considered. We report our experience with lower initial doses. METHODS: Thirty patients with active SpA (16 psoriatic arthritis, 12 ankylosing spondylitis and 2 undifferentiated) received 6 infliximab infusions. Patients had substantial axial disease (mean BASDAI at baseline 5.5). Concomitant therapy (methotrexate or prednisolone) remained stable throughout treatment period. The mean initial dose of infliximab was 3.5 mg/kg/infusion. Clinical efficacy was assessed by BASDAI. The criterion for dose adjustment was a BASDAI improvement of less than 50%. The primary end-points were the proportion of patients requiring a dose adjustment and the percentage of patients achieving 50% improvement in BASDAI after 6 infusions. RESULTS: In this cohort, 2 patients discontinued therapy, 1 for pulmonary infection and 1 for allergic reaction. Twelve patients (40%) showed 50% improvement in BASDAI between baseline and prior to the 7th infusion, while 15 patients (50%) had an improvement > 2 points. To achieve clinical response the frequency and/or the dose of infliximab infusions were increased in 63% of patients. The mean infliximab dose increased from 3.5 mg/kg at the first infusion to 4.3 mg/kg (p < 0.001) at the 7th infusion, resulting in a cumulative dose at the end of the study period comparable to the recommended one. CONCLUSIONS: In the majority of our SpA patients low starting doses of infliximab required subsequent adjustment. In these patients infliximab should be administered at the recommended dose of 5mg/kg/infusion.     

Open-label, pilot protocol of patients with rheumatoid arthritis who switch to infliximab after an incomplete response to etanercept: the opposite study

OBJECTIVE: To incorporate a new trial design to examine clinical response, cytokine expression and joint imaging in patients with rheumatoid arthritis (RA) switching from etanercept to infliximab treatment. METHODS: A randomised, open-label, clinical trial of 28 patients with an inadequate response to etanercept was conducted. Eligible patients received background methotrexate and were randomised 1:1 to discontinue etanercept and receive infliximab 3 mg/kg at weeks 0, 2, 6, 14 and 22, or to continue etanercept 25 mg twice weekly. Data were analysed for clinical response, serum biomarker levels, radiographic progression, MRI and adverse events. RESULTS: At week 16, 62% of infliximab-treated patients achieved American College of Rheumatology 20% criteria for improvement in RA (ACR20) responses compared with 29% of etanercept-treated patients. A 30.8% decrease from baseline in Disease Activity Score 28 was observed in patients receiving infliximab, compared with a 16.0% decrease in patients receiving etanercept. ACR20 and American College of Rheumatology 50% criteria for improvement in RA responses correlated at least minimally with intracellular adhesion molecule-1 and interleukin 8 in patients receiving infliximab. 38% of patients who were switched to infliximab showed reductions in Health Assessment Questionnaire scores (>0.4), compared with 0% of patients receiving etanercept. MRI analyses were inconclusive. Both drugs were well tolerated; 54% of infliximab-treated patients and 50% of etanercept-treated patients reported adverse events. CONCLUSIONS: In this exploratory, open-label trial (with single-blind evaluator), patients were randomised to continue with etanercept or switch to infliximab. The small sample size of this hypothesis-generating study was underpowered to show statistical differences between groups. There was a numerical trend favouring patients who switched to infliximab, therefore warranting further study with a more rigorous design.     

Infliximab versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a preliminary study from China

Aim: To report the efficacy and safety of infliximab in the treatment of active rheumatoid arthritis (RA) in Chinese patients. Methods: This is a multicentre double‐blind placebo controlled study. Patients with active RA despite being on a stable dose of methotrexate were randomly assigned to receive either infliximab 3 mg/kg body weight or placebo infusion at weeks 0, 2, 6 and 14. All patients continued their stable dose of methotrexate throughout the study. Patients were assessed at weeks 0, 2, 6, 14 and 18 for the American College of Rheumatology (ACR) 20%, 50% and 70% response (ACR20, 50 and 70, respectively). Health assessment questionnaire (HAQ), erythrocyte sedimentation rate (ESR), c‐reactive protein (CRP), duration of morning stiffness and adverse effects were monitored. Results: Infliximab was effective in improving the disease activity of RA with significant ACR20 response observed at week 2 (infliximab vs. placebo 52.87%vs. 13.95%, P < 0.05). Significant differences in the ACR20 and ACR50 response rates between the two treatment groups were also observed at week 18 (75.86% and 43.68% of patients receiving infliximab vs. 48.84% and 25.58% and 13.95% of patients on placebo, P = 0.0003 and P = 0.011, respectively). Infliximab was generally well tolerated. The rate of adverse events and withdrawal due to adverse events were similar between the two groups. Most adverse reactions were transient. One patient in the infliximab group developed tuberculosis during the study. One patient in the placebo group developed antinuclear antibodies without obvious signs of systemic lupus erythematosus. Conclusion: In this preliminary study, infliximab infusions, at a dose of 3 mg/kg body weight given at various intervals over 14 weeks, were effective in controlling the signs and symptoms of active RA in Chinese. Infliximab also appeared to be well tolerated. Further studies involving a larger number of patients over a more prolonged period will further evaluate the long‐term efficacy and safety of infliximab in this group of patients.     

Infliximab treatment in patients with rheumatoid arthritis and spondyloarthropathies in clinical practice: adverse events and other reasons for discontinuation of treatment

OBJECTIVE: To determine from single-centre data the treatment continuation, discontinuation, and reasons for discontinuation among the patients with active rheumatoid arthritis (RA) or spondyloarthropathies (SpA) who were treated with infliximab as their first biological anti-rheumatic drug. METHODS: All (n = 104) RA and SpA patients who were treated with infliximab as their first biological treatment according to the national guidelines in the Centre for Rheumatic Diseases, Tampere University Hospital during 1999-2005 were analysed at baseline and after 6 months of treatment. The treatment was regarded as ineffective if the response was lower than American College of Rheumatology (ACR) response criteria ACR50 in RA or the reduction of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was lower than 50% or 2 cm in SpA. RESULTS: After 6 months, 71% of the patients continued infliximab treatment and the prednisolone dose was diminished by 40%. Infliximab was discontinued in 30 patients and seven of them discontinued due to remission. Eight patients were regarded as poor responders. Thirteen patients discontinued because of adverse events, mainly infections and hypersensitivity reactions. One patient discontinued the treatment because of drug-related leucopaenia and one because of elevated aminotransferases. CONCLUSION: In this study, infliximab treatment was started in patients who had active disease despite ongoing treatment with combinations of disease-modifying anti-rheumatic drugs (DMARDs). Seventy-eight per cent achieved at least 50% response when infliximab was added to their DMARD treatment. Adverse events, mainly infections and hypersensitivity reactions, were in line with previous reports. Two rare adverse events were reported, one patient with leucopaenia and one with elevated aminotransferases.