Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database.

OBJECTIVES: To determine the causes and predictors of mortality in systemic sclerosis (SSc). METHODS: Patients with SSc (n=5860) fulfilling the American College of Rheumatology criteria and prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. EUSTAR centres completed a structured questionnaire on cause of death and comorbidities. Kaplan-Meier and Cox proportional hazards models were used to analyse survival in SSc subgroups and to identify predictors of mortality. RESULTS: Questionnaires were obtained on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes; in 4% the cause of death was not assigned. Of the SSc-related deaths, 35% were attributed to pulmonary fibrosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the non-SSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Of the non-SSc-related fatalities, 25% died of causes in which SSc-related complications may have participated (pneumonia, sepsis and gastrointestinal haemorrhage). Independent risk factors for mortality and their HR were: proteinuria (HR 3.34), the presence of PAH based on echocardiography (HR 2.02), pulmonary restriction (forced vital capacity below 80% of normal, HR 1.64), dyspnoea above New York Heart Association class II (HR 1.61), diffusing capacity of the lung (HR 1.20 per 10% decrease), patient age at onset of Raynaud's phenomenon (HR 1.30 per 10 years) and the modified Rodnan skin score (HR 1.20 per 10 score points). CONCLUSION: Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.

Activation of the interferon-gamma signaling pathway in systemic lupus erythematosus peripheral blood mononuclear cells.

OBJECTIVE: To investigate interferon-gamma (IFNgamma) signaling in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) by analyzing IFNgamma receptor (IFNgammaR) expression, STAT-1 expression and phosphorylation, and the regulation of IFNgamma-inducible genes. METHODS: Fluorocytometry was used to investigate expression of STAT-1, pSTAT-1, CD95, HLA-DR, class I major histocompatibility complex (MHC), IFNgamma-inducible 10-kd protein (IP-10), monokine induced by IFNgamma (Mig), and IFNgammaR in PBMCs from SLE patients and healthy individuals. STAT-1 phosphorylation was determined by fluorocytometry and Western blotting after stimulation with IFNalpha or IFNgamma. Quantitative polymerase chain reaction was used to assess messenger RNA (mRNA) expression of the IFNgamma-inducible genes IP-10 and Mig shortly after preparation or after stimulation with IFNgamma in monocytes. RESULTS: STAT-1 expression was increased in PBMCs from SLE patients and correlated significantly with disease activity and with the IFN-inducible expression of CD95 and HLA-DR. STAT-1 expression also showed a trend toward association with class I MHC expression. In addition, the expression of other IFNgamma-inducible genes, such as IP-10 or Mig, was increased in SLE monocytes. While STAT-1 phosphorylation in SLE PBMCs and PBMCs from healthy individuals was similar after IFNalpha stimulation, incubation with IFNgamma induced STAT-1 phosphorylation only in SLE lymphocytes. Moreover, SLE monocytes showed a considerably higher increase in pSTAT-1 expression upon IFNgamma stimulation than monocytes from healthy individuals. Increased responsiveness of SLE monocytes to IFNgamma was also confirmed on the mRNA level, where expression of the IFN-inducible, STAT-1-dependent genes IP-10 and Mig was more efficiently increased in SLE cells. However, IFNgammaR was similarly expressed on SLE lymphocytes and monocytes and those from healthy individuals. CONCLUSION: In addition to supporting the role of IFNs in SLE immunopathogenesis in general, the findings of the present study support a role of IFNgamma in this disease.

Concepts important to persons with systemic lupus erythematosus and their coverage by standard measures of disease activity and health status.

OBJECTIVE: To explore the array of concepts important to patients with chronic systemic lupus erythematosus (SLE) and to compare these with instruments assessing disease activity, damage, and health status. METHODS: We conducted a qualitative focus-group study of patients with SLE concerning their problems in daily functioning. The group sessions were tape recorded, transcribed, and divided into meaning units. The concepts contained in these meaning units were extracted and linked to the International Classification of Functioning, Disability and Health (ICF). We then compared the concepts from the focus groups with those concepts covered by SLE activity scores, the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), and the Short Form 36 Health Survey (SF-36). RESULTS: A total of 92 concepts emerged from 5 focus groups; of these, 28 related to body functions and structures, 24 to activities and participation, and 25 to environmental factors. Two concepts were linked to the health condition itself and 6 to personal factors. Seven were not covered by the ICF. Of the 28 concepts regarding body functions and structures, 24 (86%) were covered by the combination of activity scores and the SDI. The SF-36 also addressed 3 of these concepts and contained 9 (38%) of 24 concepts in activities and participation. CONCLUSION: Although the combination of SLE activity scores, SDI, and SF-36, as suggested for SLE studies, well covers body functions and structures and includes a significant portion of problems regarding activities and participation, neither environmental nor personal factors are covered at all.

Engulfed cell remnants, and not cells undergoing apoptosis, constitute the LE-cell phenomenon.

The LE cell has been one of the first immunological signs of active systemic lupus erythematosus, included into the ACR criteria. LE cells consist of a phagocyte engulfing material of disputed origin, which was interpreted as either cellular remnants from necrotic cells or as early apoptotic cells. It is well established that LE cell formation is dependent on autoantibodies against the linker histone H1. In view of this fact, we investigated whether anti-histone H1 antibodies and LE cell positive sera bound to cells where apoptosis had been induced by gliotoxin or actinomycin D or which were necrotic after heating. Necrotic cell remnants, but not (early) apoptotic cells were bound by anti-histone H1 antibodies and LE cell positive sera, establishing that the process of LE cell formation, which is dependent on anti-H1 binding, leads to engulfment of necrotic (or late apoptotic) material, but not of early apoptotic cells.