D. M. Carruthers

Dysregulated intracellular Ca2+ stores and Ca2+ signaling in synovial fluid T lymphocytes from patients with chronic inflammatory arthritis.

OBJECTIVE Peripheral blood (PB) T cells from rheumatoid arthritis (RA) patients proliferate poorly to mitogen, a change that is related to decreased intracellular Ca2+ ([Ca2+]i) signaling after T cell receptor (TCR) stimulation. We hypothesized that this was, in part, due to the effect of mediators of inflammation and predicted that greater changes in [Ca2+]i signaling would be seen in synovial fluid (SF) T cells. We also examined the mechanisms underlying the altered [Ca2+]i signals. METHODS Paired PB and SF T cells from patients with chronic inflammatory arthritis were stimulated with mitogen to assess the magnitude of the [Ca2+]i signal in cell populations by fluorometry, the pattern of the [Ca2+]i signal in individual cells in a single-cell ion-imaging system, and the spatial distribution of Ca2+ within intracellular organelles. RESULTS There was a significantly smaller [Ca2+]i signal after phytohemagglutinin protein stimulation of SF T cells (peak rise in [Ca2+]i signal PB versus SF 200 nM versus 180 nM; P < 0.05). In single SF T cells, a change in the pattern of the [Ca2+]i signal and a reduction in the number of responding cells was seen. These changes were a magnification of those seen in RA PB compared with control PB T cells. The contribution of Ca2+ release from intracellular stores to the final [Ca2+]i signal in PB and SF T cells was equal, but there was a significant increase in the Ca2+ remaining in the endoplasmic reticulum (ER) in SF T cells after TCR activation (PB versus SF 6 nM versus 19 nM; P < 0.05). Non-ER Ca2+ stores were not similarly affected. CONCLUSION We found abnormalities in the magnitude, pattern, and spatial distribution of [Ca2+]i signaling in T cells from SF of patients with chronic inflammatory arthritis. A reduction in the number of responding SF T cells may partly explain some of our observations. However, we propose that the observed redistribution of SF Ca2+ stores may underlie the altered [Ca2+]i signaling, thus making these cells hyporesponsive to mitogen. The inflammatory environment of the joint and the late stage of differentiation of SF T cells are both likely to contribute to these changes in [Ca2+]i signaling, resulting in aberrant T cell function and promotion of disease chronicity.

Evidence-based management of ANCA vasculitis

The vasculitides associated with antineutrophil cytoplasmic antibodies (ANCAs) present to and are managed by a wide spectrum of physicians, reflecting the multi-organ nature of the conditions. Treatment strategies for these primary inflammatory vascular diseases have varied based on the outcomes of different clinical trials and practice reviews. The individual drugs used and their route of administration, dose, and duration of therapy have varied and have been the source of much debate. Advances in our understanding of disease immunopathogenesis, clinical assessment and outcome have formed the basis for several recent good-quality clinical trials. Now, with the results of these large-scale multicentre collaborative studies, there is a firmer evidence base to guide management decisions for individual patients. This evidence base, reviewed here, has led to the publication of treatment guidelines which importantly encompass many of the broader aspects of disease management.

Localized bowel vasculitis: Postoperative cyclophosphamide or not?

We describe 2 patients with necrotizing vasculitis localized to the bowel, who were treated by excision of the involved tissue. Postoperatively, there was no evidence of active vasculitis, and both patients remain in remission on followup, without the use of immunosuppressive treatment. Evidence that an abnormal local microenvironment is necessary to sustain chronic inflammation may explain why surgical excision can be an important tool in the treatment of vasculitis.

Combination therapy in autoimmune disease: vasculitis

ConclusionTherapy is becoming more effective as it is increasingly tailored to both the degree of activity, or disease extent, and the specific syndrome. As acute mortality has decreased, the need to look beyond the immediate flare has supported the use of staged regimes using combinations of drugs which can diminish toxicity. However, the residual mortality, morbidity and high relapse rate suggest there is a continuing need to improve these regimes.