Andrew R. Baldassare

Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I/II randomized, blinded, placebo-controlled, dose-ranging study†

OBJECTIVE Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was studied in a first-in-human trial in rheumatoid arthritis (RA) patients receiving concomitant methotrexate (MTX). METHODS The ACTION trial was a combined phase I/II study of placebo plus MTX versus ocrelizumab plus MTX in 237 RA patients (intent-to-treat population). During phase I, 45 patients were treated with 1 of 5 escalating doses of study drug (infusions on days 1 and 15, 10-1,000 mg per each infusion). An additional 192 patients were randomized during phase II. Eligible patients had active disease, an inadequate response to treatment with at least MTX, rheumatoid factor positivity, and elevated levels of acute-phase reactants. The total study duration was 72 weeks. B cell pharmacodynamics over time was investigated. RESULTS Baseline demographics were similar among the treatment groups. Based on the entire 72-week data set, the incidence of serious adverse events in the ocrelizumab-treated patients was 17.9%, as compared with 14.6% in placebo-treated patients. The incidence of serious infections was 2.0% in all ocrelizumab-treated patients and 4.9% in placebo-treated patients. Infusion-associated adverse events were mostly grade 1 or grade 2 and were more frequent around the time of the first infusion. No serious infusion-associated adverse events were reported in the ocrelizumab group. Evidence of clinical activity was observed at all doses evaluated. Peripheral B cell depletion after infusion was rapid at all doses, with earlier repletion of B cells at doses of 10 mg and 50 mg. Human anti-human antibodies were detected in 19% and 10%, respectively, of those receiving 10 mg and 50 mg of ocrelizumab, compared with 0-5% of those receiving 200, 500, and 1,000 mg. CONCLUSION Ocrelizumab therapy in combination with MTX was well tolerated. Doses of 200 mg (2 infusions) and higher showed better clinical responses, better reduction of C-reactive protein levels, and very low immunogenicity.

The Prosorba column for treatment of refractory rheumatoid arthritis: A randomized, double-blind, sham-controlled trial

OBJECTIVE To evaluate the efficacy and safety of the Prosorba column as a treatment for rheumatoid arthritis (RA) in patients with active and treatment-resistant (refractory) disease. METHODS A sham-controlled, randomized, double-blind, multicenter trial of Prosorba versus sham apheresis was performed in patients with RA who had failed to respond to treatment with methotrexate or at least 2 other second-line drugs. Patients received 12 weekly treatments with Prosorba or sham apheresis, with efficacy evaluated 7-8 weeks after treatment ended. Patients were characterized as responders if they experienced improvement according to the American College of Rheumatology (ACR) response criteria at the efficacy time point. A data safety monitoring board (DSMB) evaluated interim analyses for the possibility of early completion of the trial. RESULTS Patients in the trial had RA for an average of 15.5 years (range 1.7-50.6) and had failed an average of 4.2 second-line drug treatments prior to entry. After the completion of treatment of 91 randomized patients, the DSMB stopped the trial early due to successful outcomes. Of the 47 patients in the Prosorba arm, 31.9% experienced ACR-defined improvement versus 11.4% of the 44 patients in the sham-treated arm (P = 0.019 after adjustment for interim analysis). When results from 8 additional patients, who had completed blinded treatments at the time of DSMB action, were added to the analysis (n = 99), results were unchanged. The most common adverse events were a short-term flare in joint pain and swelling following treatment, a side effect that occurred in most subjects at least once in both treatment arms. Other side effects, although common, occurred equally as frequently in both treatment groups. CONCLUSION Apheresis with the Prosorba column is an efficacious treatment for RA in patients with active disease who have failed other treatments.

Skin lesions in viral hepatitis: Histologic and immunofluorescent findings

A variety of skin rashes are knowned to occur as a part of the serum sickness-like prodrome of acute viral hepatitis which is thought to be due to immune complex deposition. We report the histologic and immunofluorescent findings in the skin and the seroloigc abnormalities in a patient with both erythematous maculopapular and purpuric rashes. We found circulating hepatitis B surface antigen (HBsAg), hypocomplementemia and cultaneous vasculitis associated with deposition of immunoglobulin and complement in the skin. We could not demonstrate intradermal deposition of HBsAg, but the findings are consistent with the immune complex hypothesis.

Hidden 19S IgM rheumatoid factor in juvenile rheumatoid arthritis.

Summary: One-hundred twenty-five serum samples from 82 patients with juvenile rheumatoid arthritis (JRA) were studied for the presence of hidden rheumatoid factor (RF) in an effort to find a better serologic marker to define JRA. Hidden 19S IgM RF was detected by means of a hemolytic assay utilizing the IgM-containing fraction of serum. The IgM fraction was obtained after acid separation of serum on a Sephadex G-200 column. Hidden 19S IgM RF was present in 68% of patients with seronegative JRA with a mean titer of 1:63. The mean titer for the polyarticular JRA group was 1:83, for the pauciarticular JRA group, it was 1:32, and for the systemic type-onset JRA patients, it was 1:32. When disease was active, the mean titer for all JRA patients was 1:108, for the active polyarticular JRA group it was 1:119, for the active pauciarticular JRA, it was 1:97, and for the active systemic JRA patients, it was 1:64. All values were significant at the P ≤ 0.001 when compared to disease and normal controls.The hemolytic assay for RF on the IgM-containing fraction of serum thus enhances the serologic capabilities of defining JRA.Speculation: These studies showing the correlation of disease activity and the presence of hidden rheumatoid factor will aid in evaluating and following disease activity in juvenile rheumatoid arthritis.