Flare during drug withdrawal as a method to support efficacy in rheumatoid arthritis: amiprilose hydrochloride as an example in a double blind, randomized study.

OBJECTIVE: To evaluate the use of a randomized, double blind, drug withdrawal design as a means to test the efficacy of longterm therapy with antirheumatic drugs. METHODS: We evaluated 286 patients with rheumatoid arthritis (RA) treated with amiprilose hydrochloride for 1-3 years, with response, with or without other antirheumatic therapy, in a double blind, 12 week withdrawal study that compared patients randomized to continue amiprilose therapy vs patients randomized to placebo. The primary efficacy variable was preventing a predefined degree of clinical reactivation, or flare; the statistical tests of success were a difference in the proportion of flares and in the mean time to flare. RESULTS: Thirty percent of patients taking amiprilose and 43% of placebo patients experienced flare (p = 0.026). Patients taking amiprilose had a longer flare-free interval compared to placebo patients (p = 0.027), with the time to reactivation or flare becoming statistically different 73 days after withdrawal. CONCLUSION: Placebo controlled withdrawal designs are useful as evidence to support the longterm effectiveness of therapy in a proportion of patients with RA.

Cyclosporine treatment of steroid resistant interstitial pneumonitis associated with dermatomyositis/polymyositis.

We report the successful treatment with cyclosporine of a patient with steroid resistant interstitial pneumonitis associated with polymyositis and review the literature regarding the use of cyclosporine in the treatment of interstitial lung disease.

Comparative study of reticuloendothelial system pools of the normal and immunologically activated rabbit synovium with radiocolloids.

A quantitative study of the uptake of radiocolloids by the joint synovium relative to other reticuloendothelial system organs was performed in the rabbit model. The radiocolloids of 198Au and 99mTc-sulfide colloid were administered intravenously and distribution in synovial pad, liver, spleen, bone marrow, blood, lung, and other tissues was determined in a gamma counter. The uptake of radiocolloids by both normal and immunologically activated synovial pad was very small in comparison with the reticuloendothelial cells in liver, spleen, and bone marrow.

Studies of serum immunoglobulin binding to synovial fibroblast cell cultures from patients with rheumatoid arthritis.

Using a sensitive 125I-protein A (PrA) binding assay to detect cell surface IgG, we have studied seven different synovial fibroblast cell cultures from patients with rheumatoid arthritis (RA). When these cultures were incubated in the presence of serum from 18 autologous and allogeneic RA patients (all seropositive), we were unable to detect significant IgG binding. Since IgM rheumatoid factor (RF) can block PrA binding, sera were absorbed with aggregated IgG to remove RF without affecting the results. Similar studies on three cell lines with seven rheumatoid sera were performed by antibody-dependent cell-mediated cytotoxicity. No significant cytotoxicity was observed. Since antibodies to collagen are present in rheumatoid sera, several cultures were incubated with ascorbic acid (12.5 microgram/ml) to optimize synthesis of cell surface collagen. These culture conditions did not affect serum immunoglobulin binding by the 125I-PrA assay. Thus, we can find no evidence for a direct humoral immune mediation of synovial proliferation in rheumatoid arthritis. These data do not support the hypothesis that the inflammatory process within the synovium of RA patients is an immunologic response to a fibroblast-associated antigen in the synovial membrane.

Measurement of immunoglobulin binding to synovial fibroblast monolayers: comparison of staphylococcal protein A binding to cytotoxic assay methods.

We have studied the binding of rabbit antibody to cultured synovial fibroblasts by 3 methods: complement mediated cell lysis, 125I-labeled staphylococcal protein A ([125I]PrA) and antibody dependent cell mediated cytotoxicity (ADCC). The relative sensitivities of these 3 methods is 1 : 33 : 3300 respectively. The [125I]PrA binding method is shown to quantitatively detect cell bound IgG with a molar stoichiometry of approximately 1 : 1, protein A (PrA) to IgG if PrA is present in excess.