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% ABSTRACT ObjectivesTo determine the causes and predictors of mortality in systemic sclerosis (SSc). Methods Patients with SSc (n=5860) fulfi lling 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 fi brosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the nonSSc-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 modifi ed Rodnan skin score (HR 1.20 per 10 score points). Conclusion Disease-related causes, in particular pulmonary fi brosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.Systemic sclerosis (SSc) is a multisystem disease with vascular, infl ammatory and fi brotic components.
Objective. To assess the safety and efficacy of a novel Wnt pathway modulator, lorecivivint (SM04690), for treating pain and inhibiting structural progression in moderately to severely symptomatic knee osteoarthritis (OA). Methods. Subjects in this 52-week, phase IIa, multicenter, randomized, double-blind, placebo-controlled, doseranging trial received a single 2-ml intraarticular injection of lorecivivint (dose of 0.03 mg, 0.07 mg, or 0.23 mg) or placebo. Efficacy was assessed based on change from baseline on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score subscales for pain and function (scale 0-100 for each) and change from baseline in the radiographic medial joint space width (JSW). Baseline-adjusted analysis of covariance with multiple imputation was performed separately to evaluate efficacy. This proof-of-concept study evaluated the intent-to-treat population as well as a prespecified group of subjects with unilateral symptoms of knee OA (designated UNI) and an additional post hoc subgroup of subjects with unilateral symptoms but without widespread pain (designated UNI WP−). Results. In this trial, 455 subjects were randomized to a treatment group. The primary end point, significant improvement in the WOMAC pain score compared with placebo at week 13, was not met by any lorecivivint dose group (mean ± SD change from baseline, −23.3 ± 2.2 in the 0.03 mg group, −23.5 ± 2.1 in the 0.07 mg group, −21.3 ± 2.2 in the 0.23 mg group, and −22.1 ± 2.1 in the placebo group; each P > 0.05 versus placebo). All groups (including placebo) demonstrated clinically meaningful (≥20-point) improvements from baseline in the WOMAC pain score. The durability of response was evaluated through week 52. In the prespecified UNI group and post hoc UNI WP− group at week 52, treatment with 0.07 mg lorecivivint significantly improved the WOMAC pain score (between-group difference versus placebo, −8.73, 95% confidence interval [95% CI] −17.44, −0.03 [P = 0.049] and −11.21, 95% CI −20.99, −1.43 [P = 0.025], respectively) and WOMAC function score (between-group difference versus placebo, −10.26, 95% CI −19.82, −0.69 [P = 0.036] and −13.38, 95% CI −24.33, −2.43 [P = 0.017], respectively). Relative to baseline, the mean change in the medial JSW at week 52 was −0.04 mm in the 0.03 mg cohort, −0.09 mm in the 0.07 mg cohort, −0.16 mm in the 0.23 mg cohort, and −0.14 mm in the placebo cohort; no treatment group achieved a significant change in medial JSW compared with placebo at week 52. In both unilateral symptom subgroups, the 0.07 mg lorecivivint dose significantly increased medial JSW compared with placebo at week 52 (medial JSW 0.39 mm, 95% CI 0.06, 0.72 in the UNI group [P = 0.021] and 0.42 mm, 95% CI 0.04, 0.80 in the UNI WP− group [P = 0.032]). Changes observed in the 0.03 mg and 0.23 mg dose groups were not significantly different from those in the placebo group for any of these measures. Lorecivivint appeared safe and well tolerated. Conclusion. This phase IIa, proof-of-concept trial in patients with sym...
Behçet's disease (BD) is a systemic vasculitis with unclear etiology and pathogenesis. Although several viral and bacterial causes have been investigated in detail for several years, of late it is widely accepted that microorganisms may play a role as a trigger, or as a cross-reactive antigens that interfere with self-antigens, such as heat-shock proteins. Genes such as HLA-B51, MICA and TNF, considered to play a crucial role in the pathogenesis of BD, are located in the major histocompatibility complex (MHC). However, it has been accepted that, only HLA-B51 is directly related with pathogenesis of the disease, and others have strong linkage disequilibrium with HLA-B51. Some other genes such as IL1, Factor V and ICAM-1, KIR and eNOS assumed to take a part in the pathogenesis are settled out of the MHC region. In patients with BD, several abnormalities in innate and acquired immunity were detected. Mainly, the hypersensitivity of T lymphocytes to different types of antigens plays a critical role in the pathogenesis. However, it is not clear that whether defective signal transduction or antigen presenting cell (APC) dysfunction is responsible for T cell hypersensitivity. Cytokines and chemokines secreted from APCs and T cells are suggested to cause the neutrophil hyperactivation. Activated neutrophils secrete some cytokines, which prime themselves and also stimulate Th1 cells. These relationships among APCs, Th1 lymphocytes and neutrophils constitute the basis of immune responses in BD. In this review, we focus on the possible role of APC in the pathogenesis of BD with an attempt to take attention of researchers in this field to these cells at the crossroads of innate and adaptive immunity, and discuss other potential contributors including cells of the immune system and mediators.
Adult-onset Still's disease (AOSD) has often been regarded as the adult spectrum of systemic juvenile idiopathic arthritis (sJIA). The present study aims to compare the clinical and laboratory features, the disease course and the response to treatment in patients having AOSD with those having sJIA. Retrospective review of all available data that were filled out by adult and paediatric rheumatologists from six centers using a standard data extraction form was performed. A total of 95 patients with AOSD and 25 patients with sJIA were recruited for the study. The frequency of fever, rash, myalgia, weight loss and sore throat was higher in patients with AOSD. The pattern of joint involvement differed slightly. Laboratory findings were similar in both groups, except that liver dysfunction and neutrophilia were more common among adults. A multiphasic pattern dominated the childhood cases, whereas the most frequent course was a chronic one in adults. Corticosteroids and methotrexate were the most commonly employed therapy; however, chloroquine was another popular therapy in the adult group. We showed a difference in the rate of clinical and laboratory features between patients with AOSD and those with sJIA. AOSD and sJIA may still be the same disease, and children may simply be reacting differently as the result of the first encounter of the putative antigens with the immune system.
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