Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

Background: This study was designed to assess the motivations of senior medical clinicians to teach medical students. This understanding could improve the recruitment and retention of important clinical teachers.

Granulomatous mastitis is a rare benign inflammatory breast disease that often clinically simulates carcinoma. Surgical resection of the entire lesion has been the main method of treatment but recurrence, infection, sinus formation and delayed wound healing can occur relatively commonly. Corticosteroids are also effective in recurrent or resistant cases but are associated with side-effects and relapse of disease after steroid withdrawal. A low weekly oral dose of methotrexate was used in five resistant cases after surgery plus corticosteroid. All cases achieved remission, withdrawal of corticosteroid without relapse and no methotrexate side-effect.

Objective. Although heparanase is recognized as a proangiogenic factor, the involvement of heparanase in rheumatoid arthritis (RA) is unclear. In this study, we assessed heparanase activity in synovial fluid (SF) and synovial tissue (ST) from patients with RA or osteoarthritis (OA), and analyzed the expression of angiogenic pathway-focused genes in ST from RA and OA patients.Methods. SF and ST were obtained from the knees of patients with either RA or OA and from asymptomatic donors with no documented history of degenerative or inflammatory joint diseases. Heparanase activity was determined by an enzymatic assay using a radiolabeled substrate, and the presence of heparanase in ST was demonstrated by Western blotting. The expression of angiogenesis genes, including heparanase, in ST was analyzed by real-time quantitative polymerase chain reaction.Results. Heparanase activity was dramatically higher (>100-fold) in SF and ST from RA patients than in SF and ST from OA patients and asymptomatic donors. Active heparanase enzyme was detected and heparanase messenger RNA was up-regulated in ST from RA patients. We also found that angiogenesis gene expression was significantly regulated in RA synovium, and was correlated with heparanase activity.Conclusion. These findings are novel and contribute to our understanding of joint destruction in RA, suggesting that heparanase may be a reliable prognostic factor for RA progression and an attractive target for the treatment of RA.

IntroductionPulmonary arterial hypertension is a major cause of mortality in systemic sclerosis. N-terminal pro-brain natriuretic peptide (NT-proBNP) has emerged as a candidate biomarker that may enable the early detection of systemic sclerosis-related pulmonary arterial hypertension (SSc-PAH). The objective of our study was to incorporate NT-proBNP into a screening algorithm for SSc-PAH that could potentially replace transthoracic echocardiography (TTE) as a more convenient and less costly "first tier" test.MethodsNT-proBNP levels were measured in patients from four clinical groups: a group with right heart catheter (RHC)-diagnosed SSc-PAH before commencement of therapy for PAH; a group at high risk of SSc-PAH based on TTE; a group with interstitial lung disease; and systemic sclerosis (SSc) controls with no cardiopulmonary complications. NT-proBNP levels were compared by using ANOVA and correlated with other clinical variables by using simple and multiple linear regression. ROC curve analyses were performed to determine the optimal cut point for NT-proBNP and other clinical variables in prediction of PAH.ResultsNT-proBNP was highest in the PAH group compared with other groups (P < 0.0001), and higher in the risk group compared with controls (P < 0.0001). NT-proBNP was positively correlated with systolic pulmonary artery pressure (PAP) on TTE (P < 0.0001), and mean PAP (P = 0.013), pulmonary vascular resistance (P = 0.005), and mean right atrial pressure (P = 0.006) on RHC. A composite model wherein patients screened positive if NT-proBNP was ≥ 209.8 pg/ml, and/or DLCOcorr was < 70.3% with FVC/DLCOcorr ≥ 1.82, had a sensitivity of 100% and specificity of 77.8% for SSc-PAH.ConclusionWe have proposed a screening algorithm for SSc-PAH, incorporating NT-proBNP level and PFTs. This model has high sensitivity and specificity for SSc-PAH and, if positive, should lead to TTE and confirmatory testing for PAH. This screening algorithm must be validated prospectively.

Objective. To evaluate barriers that prevent rheumatoid arthritis (RA) patients from achieving Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) scores within the current recommended levels for low disease activity (LDA) or clinical remission (DAS28-ESR score <3.2). Methods. Using an electronic medical record program, clinical data for RA patients treated in Optimising Patient Outcomes in Australian Rheumatology clinics, with a recorded DAS28-ESR score, were collected at one point in time. The data included demographics, medications, disease measures, and the rheumatologist's opinion of the main barriers preventing improvement to the recommended DAS28 score. Results. Of the 4,037 patients with a recorded DAS28-ESR score, 304 patients (7.5%) had high disease activity (HDA) and 1,211 patients (30%) had moderate disease activity (MDA). For 584 HDA or MDA patients, the barriers to disease control (BTCs) were recorded by the rheumatologist when there was no adjustment to disease-modifying antirheumatic drug (DMARD) therapy. The recorded BTCs were irreversible joint damage (19.7%), patient-driven preference (14.7%), noninflammatory musculoskeletal pain (9.2%), insufficient time to assess the effect of recently initiated DMARDs (9.2%), safety concerns (7.5%), comorbidities (6.5%), resistant disease (6.3%), and other less common reasons. These patients received DMARDs (97.4%), including biologic agents (34.1%), methotrexate (74.8%), and oral corticosteroids (41.8%). Conclusion. This study identified clinical situations in which rheumatologists elected to continue RA patients with MDA or HDA on DMARD therapy without adjustment to achieve clinical remission or an LDA target of a DAS28-ESR score <3.2.

IntroductionThe aim of the study was to interrogate the genetic architecture and autoimmune pleiotropy of scleroderma susceptibility in the Australian population.MethodsWe genotyped individuals from a well-characterized cohort of Australian scleroderma patients with the Immunochip, a custom array enriched for single nucleotide polymorphisms (SNPs) at immune loci. Controls were taken from the 1958 British Birth Cohort. After data cleaning and adjusting for population stratification the final dataset consisted of 486 cases, 4,458 controls and 146,525 SNPs. Association analyses were conducted using logistic regression in PLINK. A replication study was performed using 833 cases and 1,938 controls.ResultsA total of eight loci with suggestive association (P <10-4.5) were identified, of which five showed significant association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNP03-IRF5 and VCAM1). The most notable findings were at the DNASE1L3 locus, previously associated with systemic lupus erythematosus, and VCAM1, a locus not previously associated with human disease. This study identified a likely functional variant influencing scleroderma susceptibility at the DNASE1L3 locus; a missense polymorphism rs35677470 in DNASE1L3, with an odds ratio of 2.35 (P = 2.3 × 10−10) in anti-centromere antibody (ACA) positive cases.ConclusionsThis pilot study has confirmed previously reported scleroderma associations, revealed further genetic overlap between scleroderma and systemic lupus erythematosus, and identified a putative novel scleroderma susceptibility locus.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0438-8) contains supplementary material, which is available to authorized users.

ObjectiveNonadherence to disease‐modifying antirheumatic drugs (DMARDS) in rheumatoid arthritis (RA) and spondyloarthritis (SpA) results in increased disease activity and symptoms and poorer quality of life. We aimed to describe patients’ attitudes and experiences of DMARDs in RA and SpA to inform strategies to improve medication adherence.MethodsDatabases (MEDLINE, Embase, PsycINFO, and CINAHL) were searched to January 2016. Thematic synthesis was used to analyze the findings.ResultsFrom 56 studies involving 1,383 adult patients (RA [n = 1,149], SpA [n = 191], not specified [n = 43]), we identified 6 themes (with subthemes): intensifying disease identity (severity of sudden pharmacotherapy, signifying deteriorating health, daunting lifelong therapy), distressing uncertainties and consequences (poisoning the body, doubting efficacy, conflicting and confusing advice, prognostic uncertainty with changing treatment regimens), powerful social influences (swayed by others’ experiences, partnering with physicians, maintaining roles, confidence in comprehensive and ongoing care, valuing peer support), privilege and right of access to biologic agents (expensive medications must be better, right to receive a biologic agent, fearing dispossession), maintaining control (complete ownership of decision, taking extreme risks, minimizing lifestyle intrusion), and negotiating treatment expectations (miraculous recovery, mediocre benefit, reaching the end of the line).ConclusionPatients perceive DMARDs as strong medications with alarming side effects that intensify their disease identity. Trust and confidence in medical care, positive experiences with DMARDS among other patients, and an expectation that medications will help maintain participation in life can motivate patients to use DMARDs. Creating a supportive environment for patients to voice their concerns may improve treatment satisfaction, adherence, and health outcomes.