Jennifer G. Walker

Autoantibodies in systemic sclerosis.

Autoantibodies directed against a variety of nuclear, cytoplasmic and extracellular autoantigens are a serological hallmark of systemic sclerosis. This review provides an overview of the history and clinical association of many of the autoantibodies identified in SSc sera to date. Some of these autoantibodies predate the clinical diagnosis of SSc, some are pathogenic while others have no apparent role in pathogenesis. It was once thought that the autoantibody spectrum of individual SSc sera were less complex than other systemic autoimmune rheumatic diseases with respect to heterogeneous B cell responses reflected in circulating autoantibodies. However, with the advent of array technologies, there is now an unprecedented capability to detect multiple autoantibodies in an individual serum and this long held tenet of clinical diagnostic immunology is being reexamined.

Isolated pulmonary hypertension in scleroderma

Background: Isolated pulmonary hypertension (PHT) is now the most frequent cause of disease‐related death in limited cutaneous scleroderma, the commonest disease variant of this disabling connective tissue disorder. Endothelin‐1 receptor antagonists provide symptomatic benefit but to date have not been shown to prolong survival.

Update on autoantibodies in systemic sclerosis

Purpose of reviewThis is a review of autoantibodies described in systemic sclerosis with an emphasis on recently published studies. In the past, most, if not all of the discussion on this topic focused on antinuclear antibodies, but it is now appreciated that autoantibodies to cytoplasmic, cell surface, intercellular and plasma components are also important in the context of systemic sclerosis. Recent findingsA number of recent studies have highlighted the disease associations of autoantibodies and the potential pathogenic role of the more traditional autoantibodies, such as antitopoisomerase I and anticentromere antibodies. The recent identification of autoantibodies directed to the platelet-derived growth factor receptor is of particular interest because of its possible association with the pathogenesis of systemic sclerosis. SummaryAutoantibodies in systemic sclerosis are associated with demographic, diagnostic, pathological, and prognostic features of the disease. Emerging research on the pathogenic roles of newer autoantibodies provides valuable insights into disease pathogenesis and potential therapeutic targets.

Scleroderma renal crisis: poor outcome despite aggressive antihypertensive treatment

Background:  Scleroderma renal crisis (SRC) is a rare but feared complication of scleroderma. Angiotensin‐converting enzyme (ACE) inhibition has significantly improved survival, but it is unknown whether prophylactic ACE inhibitors will prevent this complication.

Characterisation of a dendritic cell subset in synovial tissue which strongly expresses Jak/STAT transcription factors from patients with rheumatoid arthritis

Objectives: To characterise the phenotype of the putative dendritic cells strongly expressing Jak3 and STAT4, which have been previously identified in the synovial tissue of patients with active rheumatoid arthritis (RA). Methods: Synovial biopsy specimens were obtained at arthroscopy from 30 patients with active RA (42 synovial biopsies). Immunohistological analysis was performed using monoclonal antibodies to detect dendritic cell subsets, including activation markers and cytokines relevant to dendritic cell function. Co-localisation of cell surface markers and cytokines was assessed primarily using sequential sections, with results confirmed by dual immunohistochemistry and immunofluorescence with confocal microscopy. Results: The dendritic cells identified in RA synovial tissue that strongly express Jak3 also strongly express STAT4 and STAT 6 and are correlated with the presence of serum rheumatoid factor. These cells are not confined to a single dendritic cell subset, with cells having phenotypes consistent with both myeloid- and plasmacytoid-type dendritic cells. The activation status of these dendritic cells suggests that they are maturing or mature dendritic cells. These dendritic cells produce IL12 as well as interferon α and γ. Conclusions: The close correlation of these dendritic cells with the presence of serum rheumatoid factor, a prognostic factor for worse disease outcome, and the strong expression by these cells of components of the Jak/STAT transcription factor pathway suggest a potential therapeutic target for the treatment of RA.

Changes in synovial tissue Jak-STAT expression in rheumatoid arthritis in response to successful DMARD treatment.

Background: Modulation of Jak-STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis (IA). Objective: To examine the effect of successful disease-modifying antirheumatic drug (DMARD) treatment on the expression of Jak-STAT in a cohort of patients with active rheumatoid arthritis. Methods: Synovial tissue biopsy specimens from 16 patients with active rheumatoid arthritis, taken before and after initiation of DMARD treatment, were examined for the presence of janus kinase (Jak)3, signal transducer and activator of transcription (STAT)1, STAT4 and STAT6 expression using immunohistochemistry. Results: Successful treatment with DMARDs results in reduction in STAT1 expression in the lining, and STAT1 and STAT6 in the sublining of rheumatoid arthritis synovial tissue. Although the overall expression of STAT4 and Jak3 was not significantly altered by DMARD treatment, there was a significant reduction in the expression of the STAT4 and Jak3 bright cells, thought to be an activated dendritic cell subpopulation. Conclusion: Results show that Jak3, STAT1, STAT4 expression and STAT6 sublining expression decrease in response to successful treatment of rheumatoid arthritis with standard DMARDs. Therefore, altering the expression of these pathways may represent an alternative treatment option, either through promoting up-regulation of inhibitory pathways, or suppressing inflammatory paths.

The development of systemic sclerosis classification criteria

Systemic sclerosis (SSc) is a rare connective tissue disorder whose aetiology remains obscure, although environmental and genetic influences are likely to play a role. Disease registries have contributed to enhancing our understanding of this debilitating illness, but without sensitive, specific, and extensively validated classification criteria, accurate comparison between registries and the identification of patients suitable for clinical trials can be problematic. The American College of Rheumatology (ACR) criteria, published in 1980, have become outdated as our understanding of disease specific autoantibodies and nailfold capillaroscopy has improved. In addition, the sensitivity of the ACR criteria is low with respect to limited SSc. Although subsequent classification systems have been proposed, none has gained universal approval. The two- versus three-subset disease model remains a point of debate. Newly derived criteria are likely to draw upon the older classification systems as well as incorporating up-to-date diagnostic techniques and biomarkers. Validation will be critical before their use becomes widespread.

Survival in scleroderma: results from the population‐based South Australian Register

Aim:  To ascertain the mortality risk and investigate clinical and serological factors influencing survival of patients listed on the South Australian Scleroderma Register (SASR).

Apoptosis in the rheumatoid arthritis synovial membrane: modulation by disease-modifying anti-rheumatic drug treatment

OBJECTIVES RA is characterized at the synovial tissue level by synovial lining hyperplasia, angiogenesis and mononuclear cell infiltrates. A failure of apoptotic pathways may explain these pathological changes in RA synovial tissue. This study aims to demonstrate the presence of initiators and inhibitors of apoptosis in RA synovial tissue and the effect of treatment with DMARDs on apoptotic pathways in RA. METHODS Synovial biopsy specimens were obtained at arthroscopy from 16 RA patients before and at 3- or 6-month intervals after commencing treatment with a DMARD. Apoptosis (by the terminal deoxynucleotidyl transferase mediated dUTP nick end labelling method and polyADP-ribose polymerase staining), proteins regulating apoptosis [Fas, FADD-like IL1b converting enzyme inhibitory protein (FLIP), Bcl-2, Survivin and X-linked inhibitor of apoptosis protein (XIAP)] and the presence of activated caspases (caspases 3 and 8) were detected by immunohistochemistry and quantified using image analysis and semiquantitative techniques. RESULTS Fifteen patients responded to treatment, with an ACR response of > or =20%, 13 achieving an ACR response of > or =50% and 3 achieving an ACR remission. There was a significant reduction in SM macrophages and memory T cells, with an increase in fibroblast-like synovial lining cells following DMARD treatment. Apoptosis was not detected in the inflamed synovial tissue of RA patients before starting treatment, despite evidence of caspase activation, but was detectable after successful treatment with DMARDs. Inhibitors of activated caspases (FLIP, Survivin and XIAP) were detected in RA synovial tissue and were down-modulated with successful DMARD treatment. CONCLUSIONS Apoptotic pathways are defective in RA synovial tissue from patients with active disease, despite the presence of activated caspases, possibly due to the abundant expression of inhibitors of the caspase pathway in RA synovial tissue. DMARD treatment can modulate apoptosis in the RA SM, which may lead to restoration of the SM architecture towards that of normal synovial tissue.

Scleroderma in South Australia: further epidemiological observations supporting a stochastic explanation

Background: The aim of this study was to determine the incidence, prevalence, survival and selective demographic characteristics of scleroderma occurring in South Australia over the 10‐year period 1993–2002.