T cell subsets and their role in the pathogenesis of rheumatic disease.

PURPOSE OF REVIEW: T lymphocytes are critical to the pathogenesis of systemic rheumatic diseases. Understanding of the roles of T cells in disease has been enriched by the description of highly distinct effector subsets of CD4 T lymphocytes. The purpose of this review is to describe selected advances in the biology of T lymphocytes that are pertinent to the pathogenesis or treatment of rheumatic diseases. RECENT FINDINGS: Knowledge is expanding about not only pathogenic effector T cell subsets, such as the TH17 cells, but also of regulatory T cells (Treg), the functions of which are defective, but correctable, in several rheumatic diseases. Although the initial agent that demonstrated a role for T cells in rheumatoid arthritis was CTLA4-Ig (abatacept), use of this biologic is now expanding to other rheumatic diseases. Moreover, effects of other biologics are now understood to in part be mediated by effects on T cell subsets. Experimental model systems in rodents continue to be valuable testing grounds for future approaches to treatment of human disease. Meanwhile, the roles of effector T cell subsets are becoming clearer in conditions such as Sjogren's syndrome and scleroderma. Finally, rheumatic diseases, including rheumatoid arthritis and spondyloarthropathies, have been critical for identification of new innate-like T cell subsets. SUMMARY: Imbalances in the numbers and functions of specific T cell subsets are key pathogenic derangements in systemic rheumatic diseases, and these insights are leading to changes in clinical practice.

N-α-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide, a protein arginine deiminase inhibitor, reduces the severity of murine collagen-induced arthritis.

Rheumatoid arthritis is associated with the development of autoantibodies to citrullinated self-proteins. Citrullinated synovial proteins, which are generated via the actions of the protein arginine deiminases (PADs), are known to develop in the murine collagen-induced arthritis (CIA) model of inflammatory arthritis. Given these findings, we evaluated whether N-α-benzoyl-N5-(2-chloro-1-iminoethyl)-L-ornithine amide (Cl-amidine), a recently described pan-PAD inhibitor, could affect the development of arthritis and autoimmunity by treating mice in the CIA model with Cl-amidine on days 0-35. Cl-amidine treatment reduced total synovial and serum citrullination, decreased clinical disease activity by ∼50%, and significantly decreased IgG2a anti-mouse type II collagen Abs. Additionally, histopathology scores and total complement C3 deposition were significantly lower in Cl-amidine-treated mice compared with vehicle controls. Synovial microarray analyses demonstrated decreased IgG reactivity to several native and citrullinated epitopes compared with vehicle controls. Cl-amidine treatment had no ameliorative effect on collagen Ab-induced arthritis, suggesting its primary protective mechanism was not mediated through effector pathways. Reduced levels of citrullinated synovial proteins observed in mice treated with Cl-amidine are consistent with the notion that Cl-amidine derives its efficacy from its ability to inhibit the deiminating activity of PADs. In total, these results suggested that PADs are necessary participants in the autoimmune and subsequent inflammatory processes in CIA. Cl-amidine may represent a novel class of disease-modifying agents that modulate aberrant citrullination, and perhaps other immune processes, necessary for the development of inflammatory arthritis.

A Primer on Rheumatologic Laboratory Tests: What They Mean and When to Order Them.

Rheumatologic laboratory tests are frequently ordered by primary care physicians in patients who complain of joint pain. Clinicians should keep in mind the pretest probability of a rheumatologic disorder before ordering any test because laboratory tests in rheumatology are not diagnostic of any particular disease. Any rheumatologic laboratory test result should only be used to further refine the diagnosis, and it should not replace a thorough history and physical examination. In this article, the authors discuss the diagnostic utility of the commonly ordered rheumatologic laboratory tests based on their sensitivity, specificity, and likelihood ratios.

Pharmacotherapy: concepts of pathogenesis and emerging treatments. Co-stimulation and T cells as therapeutic targets.

Full activation and differentiation of resting T cells into effector T cells requires at least two signals, the first through engagement of the T cell antigen receptor (TCR) by the antigen-major histocompatibility complex (MHC) on antigen-presenting cells (APCs), and the second by engagement of co-stimulatory molecules such as CD28, on T cells by ligands such as CD80/86 on APCs. Effector T cell differentiation is associated with proliferation, secretion of cytokines and expression of additional surface molecules. These inducible structures may have stimulatory (ICOS, OX40 and 4-1BB) or inhibitory (cytotoxic T-lymphocyte antigen (CTLA)-4) potential. To the extent that T cells have a role in particular immune-mediated diseases, interruption of T cell co-stimulation is a potentially worthwhile approach to the treatment of those conditions. This article summarises the experience in treating rheumatological disease by perturbation of T cell co-stimulation, and also describes structures that could be future targets for this type of therapeutic approach.

Rheumatoid arthritis (RA)-specific autoantibodies in patients with interstitial lung disease and absence of clinically apparent articular RA.

The purpose of this study was to identify rheumatoid arthritis (RA)-related autoantibodies in subjects with interstitial lung disease (ILD) and no articular findings of RA, supporting the hypothesis that RA-related autoimmunity may be generated in non-articular sites, such as the lung. This was a retrospective chart review utilizing clinic databases of patients with ILD to identify cases with lung disease, RA-related autoantibody positivity, and no clinical evidence of articular RA. Four patients with ILD, RF, and anti-CCP positivity and no articular findings of RA were identified. All four patients were male with a mean age at time of diagnosis of ILD of 70 years old. All had a history of smoking. Three patients died within 2 years of diagnosis of ILD and never developed articular symptoms consistent with RA; the final case met full criteria for articular RA several months after stopping immunosuppressive treatment for ILD. RF and anti-CCP can be present in smokers with ILD without clinical evidence of articular RA and in one case symptomatic ILD and autoantibody positivity preceded the development of articular RA. These findings suggest that RA-specific autoimmunity may be generated due to immunologic interactions in the lung and may be related to environmental factors such as smoking.