Suanne Dougherty

Cyclosporin A in Severe, Treatment-Refractory Rheumatoid Arthritis: A Randomized Study

STUDY OBJECTIVE To assess the efficacy and toxicity of cyclosporin A in patients with severe, treatment-refractory rheumatoid arthritis. DESIGN Prospective randomized, double-blind 6-month trial. PATIENTS Thirty-one patients who had classic seropositive rheumatoid arthritis with active synovitis unresponsive to conventional therapy. INTERVENTIONS Patients were randomly assigned to high-dose (10 mg/kg body weight.d) or low-dose (1 mg/kg.d) cyclosporin A therapy. A reduction in the dose was permitted for adverse side effects. After 6 months of therapy, patients who showed clinically relevant improvement, defined as a 40% or greater reduction in their total joint activity score, were given the option to continue receiving the therapy for an additional 6 months. MEASUREMENTS AND MAIN RESULTS At 6 months, clinically relevant improvement occurred in 10 of 15 patients (95% CI, 38 to 88) receiving high-dose therapy and in 4 of 16 patients (CI, 7 to 52) receiving low-dose therapy (P = 0.02). Statistically significant improvements in individual measures were shown only in the high-dose group. Improvements were noted in the number of tender joints (-18.8; CI, -24.5 to -13.1) and swollen joints (-12.1; CI, -15.4 to -8.6), as well as in physicians global scores (-1.5; CI, -2.1 to -0.9) and patients global scores (-1.1; CI, -1.9 to -0.5). Improvement in disease activity was maintained through 12 months in the high-dose group. The clinical responses to cyclosporin A were most evident in patients with depressed in-vitro proliferative responses of peripheral blood mononuclear lymphocytes to soluble recall antigens. Toxicities, such as fatigue, gastrointestinal and neurologic complaints, and hypertrichosis were frequent but often reversible with a reduction in the dose. Nephrotoxicity, with a 20% increase in the serum creatinine level, was seen in 27 of 31 patients (CI, 71 to 97). CONCLUSIONS Cyclosporin A is an effective therapy for severe, treatment-refractory rheumatoid arthritis. Side effects, particularly nephrotoxicity, are common.

Prostaglandin e2 rather than lymphocyte-activating factor produced by activated human mononuclear cells stimulates increases in murine thymocyte camp.

Abstract Culture supernatants (SUPS) of endotoxin (LPS)-activated human mononuclear cells (MNL) stimulated greater production of cAMP by thymocytes than by spleen cells of C3H/HeJ or nude ( nu nu ) mice. Similarly, the addition of prostaglandin E 2 (PGE 2 ) stimulated higher levels of cAMP in thymocytes and progressively lower levels in spleen cells from C3H/HeJ mice and nu nu spleen cells, respectively. Partial purification on Bio-Gel P100 of the LPS-induced MNL SUPS yielded peaks of thymocyte proliferative activity characteristic of lymphocyte activation factor (LAF) but these fractions failed to stimulate cAMP levels in thymocytes. Moreover, MNL SUPS induced with LPS in the presence of indomethacin retained their LAF activity but no longer increased thymocyte cAMP levels. Radioimmunoassay of the SUPS for PGE 2 revealed significantly higher levels of PGE 2 in the media of those MNL cultures stimulated by LPS than when stimulated by phorbol myristic acetate, phytohemagglutin, or extracted cell wall fraction of Actinomyces viscosus . Thus, PGE 2 is produced by human MNL and may exert considerable immunoregulatory effects mediated by elevation of lymphocyte cAMP levels.