An open label, single dose study to evaluate the safety, efficacy, and effects on CD25 expression of ciclosporin in patients with active rheumatoid arthritis despite treatment with methotrexate and infliximab.

OBJECTIVE: To explore the safety, efficacy, and lymphocyte activation of a triple therapeutic regimen with infliximab, methotrexate (MTX), and ciclosporin A (CsA) by an open label, pilot study. PATIENTS AND METHODS: 19 patients (mean age 52.9 years) with active rheumatoid arthritis (mean DAS28 7.3) after a mean of 16.8 infliximab infusions and dose adjustments of both infliximab and MTX were enrolled. CsA was added to a stable therapeutic regimen. Disease activity was evaluated by the DAS28. Lymphocyte activation was evaluated by assessing CD25 expression on peripheral blood mononuclear cells (PBMCs). Primary end points were safety and efficacy according to the EULAR response criteria at 24 weeks. RESULTS: Eight patients (42%) discontinued treatment: adverse events (3), inefficacy (2) or non-compliance (2). One patient had a stroke and died. 5/11 (45%) patients who completed 24 weeks' treatment were moderate responders. CD25 expression, both on unstimulated and phytohaemagglutinin stimulated PBMCs in five patients assessed, was reduced (mean (SD) values from 37 (34)% to 15 (10)% and from 50 (15)% to 29 (20)%, respectively). CONCLUSION: In this group of patients with refractory, highly active disease, addition of CsA reduced lymphocyte activation, and resulted in a modest response and a high rate of discontinuation. In such patients, other new approaches need to be explored.

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.

Infliximab treatment for rheumatoid arthritis, with dose titration based on the Disease Activity Score: dose adjustments are common but not always sufficient to assure sustained benefit.

BACKGROUND: Randomised controlled trials have shown that treatment with anti-tumour necrosis factor (anti-TNF) agents is effective in refractory rheumatoid arthritis (RA). OBJECTIVE: To determine the effectiveness of anti-TNF in a general unselected group of patients with refractory RA. METHODS: 68 patients with active RA despite treatment with disease modifying antirheumatic drugs were studied during 12 infliximab infusions. Infliximab (3 mg/kg/infusion) was given every 8 or 6 weeks. Clinical efficacy was assessed by the Disease Activity Score (DAS) index (44 joints). Dose adjustments were based on residual disease activity (DAS score >2.4). The primary end points were the percentage of patients achieving good or moderate response by the EULAR response criteria and the proportion of patients requiring dose adjustment. RESULTS: 20 (29%) patients discontinued treatment owing to side effects, early inefficacy, or other considerations. Among the patients who continued treatment, 27 (56%) and 32 (67%) were responders on the 6th and 12th infliximab infusion, respectively. In the same patients, disease activity gradually improved without modifications in the initial dosing in 10 (21%), whereas in 38 (79%) the dose of infliximab and/or methotrexate was increased. Intensification of treatment led to a significant decrease in the mean DAS score in this group (from 5.27 just before dose modification to 4.54 before the 12th infusion, p<0.002). The EULAR response category improved in only 10/38 (26%), however. CONCLUSIONS: In this initial observational study of patients with RA treated with recommended doses of infliximab, adjustments in treatment were common but not always sufficient to maintain adequate disease control. Longitudinal controlled trials are needed to define the optimal dose escalation in patients with suboptimal response.