Addition of cyclosporine-A (Neoral^®) in patients on anti-TNF and methotrexate therapy improves disease activity: an open-label, pilot study

Background

Combining anticytokine treatment with a T-cell directed agent such as cyclosporine A (CsA) may rescue patients refractory to anti-TNF treatment. We performed an open label, pilot study to explore the safety and initial efficacy of a triple therapeutic regimen with anti-TNF, methotrexate (MTX) and CsA.

Methods

Nineteen patients with treatment-resistant RA have been enrolled. Patients had considerable residual disease activity (mean DAS-28 6.8, 4.5–8.6), although they had received a mean of 16.8 infliximab infusions (range 6–23) and adequate dose adjustments of both infliximab (mean dose 4.2 mg/kg q6w) and MTX (mean dose 17.1 mg/week). CsA (mean dose of 2.7 mg/kg per day, range 1.6–3.2) was added to a stable therapeutic regimen. Clinical evaluation of disease activity and treatment side effects was performed before each infliximab infusion. Disease activity was evaluated according to DAS-28 index. Primary end-points were treatment safety profile and efficacy according to the EULAR response criteria. Peripheral blood monocytes (PBMCs) were collected from five patients at baseline and after 12 weeks, and were assessed for markers of activation (CD25 expression) by FACS analysis, with or without activation with PHA.

Results

Sixteen patients completed 12 weeks of triple therapy. Three patients discontinued treatment because of adverse events: one for pneumonia, one for lymph node tuberculosis and one for gastrointestinal discomfort. Seven out of 16 patients (43.7%) achieved moderate response according to the EULAR response criteria. Statistically significant improvements in the mean values of tender joints (from 18.5 to 13.1; P = 0.04), swollen joints (from 18.6 to 12.1; P = 0.004), HAQ (from 1.2 to 0.7; P = 0.01), patients' global assessment (from 67 to 46; P = 0.02) and pain (from 64 to 42; P = 0.04) were identified in those 16 patients. CD25 expression both in unstimulated and in PHA stimulated PBMCs was reduced (37 ± 34% to 15 ± 10%, and 50 ± 15% to 29 ± 20%, respectively).

Conclusion

In this preliminary report, addition of CsA to a maximum combination therapy of anti-TNF and MTX was well tolerated. Infectious complications that occurred underscore the importance of close follow up of patients on combined immunosuppressive therapy. Longer follow up is required to investigate further the safety and initial efficacy of this regimen.