Invariant NKT cells limit activation of autoreactive CD1d-positive B cells

Faulty activation of autoreactive B cells is a hallmark of autoimmune diseases like systemic lupus erythematosus (SLE). An important feature restricting activation of autoreactive B cells is efficient removal of apoptotic material. Mounting evidence also connects a primary defect in invariant natural killer T (iNKT) cells to autoimmune disease development. However, exactly how this unconventional T cell subset is involved remains to be defined. Here, we identify a suppressive role for iNKT cells in a model where autoantibody production is triggered by an increased load of circulating apoptotic cells, resembling the situation in SLE patients. Absence or reduction of iNKT cells as well as absence of CD1d-expression on B cells, needed for direct iNKT–B cell interaction, leads to increased autoreactive B cell activation and symptoms of disease. The suppression mediated by the iNKT cells is observed before B cell entry into germinal centers and can be rescued by transferring iNKT cells to deficient mice. This links iNKT cells to handling of dying cells and identifies a novel peripheral tolerance checkpoint relevant for autoimmune disease. Thus, these observations connect two clinical observations in SLE patients previously considered to be unrelated and define a new target for immunotherapy

An open-label pilot study of the efficacy and safety of anakinra in patients with psoriatic arthritis refractory to or intolerant of methotrexate (MTX)

Only limited data have been published about the therapeutic use of anakinra in patients with psoriatic arthritis. We undertook this study to evaluate the efficacy and safety of anakinra in patients with active psoriatic arthritis. In a prospective open-label single-center study, 20 patients were treated with 100 mg anakinra everyday either alone or in combination with ongoing methotrexate over 6 months. Safety and efficacy was evaluated using Psoriasis Arthritis Response Criteria (PsARC), Disease Activity Score (DAS) 28, American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), Psoriasis Area and Severity Index Score, Dactylitis Score and Health Assessment Questionnaire (HAQ), and the C-reactive protein, and erythrocyte sedimentation rate. Of the 20 patients enrolled, six completed 24 weeks, 18 completed 12 weeks, and 19 completed 4 weeks of treatment. Early-treatment termination was mainly due to inefficacy (13 patients) and only one drop-out occurred because of an unrelated adverse event. Six patients fulfilled continuously the PsARC until week 24. A moderate EULAR response was achieved by four patients and a good EULAR response by three patients in week 24. Five patients reached ACR 20, four patients ACR 50, and two patients ACR 70 in week 24. HAQ improved slightly throughout the study (n = 19, mean (SD); baseline, 1.127 (0.671); week 24, 1.055 (0.812)) just as DAS 28 (n = 16; baseline, 4.7(1.5); week 24, 4.0(2.0)). Only nine patients showed skin manifestations affecting > 3% of their body surface area which improved in two, worsened in four, stabilized in two patients, and newly evolved in one patient. Adverse events were mainly mild (95%). Fifteen (75%) patients showed injection site reactions. No serious infections occurred. Anakinra was well tolerated with no occurrence of serious drug-associated adverse events and lead to improvement of signs and symptoms in nine out of 19 patients, therefore providing a potential therapeutic option in patients with active psoriatic arthritis

First clinical trials of a new heteropolymer technology agent in normal healthy volunteers and patients with systemic lupus erythematosus: safety and proof of principle of the antigen-heteropolymer ETI-104

Background: The heteropolymer technology was developed to remove pathogens from the circulation. Objectives: To evaluate the safety and tolerability of a single administration and to establish proof of principle for ETI-104 in normal healthy volunteers (NHV) and patients with systemic lupus erythematosus (SLE) Methods: The drug was given intravenously to 11 NHV and six patients with SLE. Over 28 days, vital signs were noted, a haematological and chemical analysis of blood and urine was carried out, and adverse events were recorded. CR1 receptor numbers, the ability of antigen based heteropolymers to bind to red blood cells (RBCs), and the clearance of high avidity and total anti-dsDNA antibodies were measured by Farr assays and FACS analysis. Results: No safety measure differed significantly from normal in both groups; no drug related serious adverse events occurred. ETI-104 rapidly bound to RBCs in NHV and patients with SLE. Binding of the drug to RBCs of patients with SLE also caused a rapid reduction of circulating anti-dsDNA antibodies in the plasma 15 minutes after administration, with a maximum reduction of 55% (range 43–62). At 28 days statistically significant decreases were maintained in three patients, while in the other three the values had returned to baseline levels. Conclusion: These clinical trials established the safety and the proof of principle of the new immunoconjugate ETI-104. This provides the basis for further development of this technology for numerous indications—for example, therapeutic options for autoimmune diseases or viral and bacterial infections