Systemic Sclerosis Cases Research Articles

Potential role of the lectin pathway of complement in the pathogenesis and disease manifestations of systemic sclerosis: a case-control and cohort study.

IntroductionRepetitive episodes of ischemia and reperfusion (I/R) are a cardinal feature of the pathogenesis of systemic sclerosis (SSc), which precedes tissue fibrosis. The complement system is a key mediator of tissue damage after I/R, primarily by activation of the lectin pathway. This study investigated whether serum levels and polymorphisms of mannose-binding lectin (MBL) and ficolin-2 (FCN2), two pattern recognition receptors of the lectin pathway, are associated with the predisposition to and clinical features of SSc.MethodsA case-control study was undertaken involving 90 patients with SSc from a single SSc outpatient clinic and 90 age- and sex-matched blood donors. MBL and FCN2 levels and polymorphisms were measured in both groups, and in cases correlated with clinical data.ResultsMBL levels and genotypes were equally distributed in cases and controls while there were some significant differences in FCN2 polymorphisms. Median MBL levels were higher in SSc cases with diffuse disease compared with controls (2.6 versus 1.0 μg/ml, P <0.001).In cases, higher MBL levels were associated with the presence of clinical findings associated with vascular dysfunction and local tissue damage (digital ulcers, calcinosis and pitting). Moreover, MBL levels were associated with fibrotic disease manifestations as evidenced by the presence of diffuse disease (median 2.6 versus 0.8 μg/ml, P = 0.002), the modified Rodnan skin score (r = 0.39, P <0.001), and interstitial lung disease as measured by forced vital capacity (r = −0.33, P = 0.001). Importantly, MBL levels also correlated with the Scleroderma Health Assessment Questionnaire scores (r = 0.33, P = 0.002). The results for FCN2 levels were less striking. Phenotypic MBL results were largely confirmed by analysis of MBL polymorphisms. MBL levels were not associated with the presence of autoantibodies or hypocomplementaemia.ConclusionsOverall, predisposition to SSc was not influenced by the lectin pathway of complement in our matched case-control study. However, our preliminary data suggest that MBL, and to a lesser extent FCN2, may modulate disease manifestations of SSc, particularly in diffuse cutaneous disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0480-6) contains supplementary material, which is available to authorized users.

The Circulating Cell-free microRNA Profile in Systemic Sclerosis Is Distinct from Both Healthy Controls and Systemic Lupus Erythematosus

To evaluate the expression profile of cell-free circulating microRNA (miRNA) in systemic sclerosis (SSc), healthy controls (HC), and systemic lupus erythematosus (SLE). Total RNA was purified from plasma and 45 different, mature miRNA were measured using quantitative PCR assays after reverse transcription. Samples (n = 189) were from patients with SSc (n = 120), SLE (n = 29), and from HC (n = 40). Expression data were clustered by principal components analysis, and diagnostically specific miRNA profiles were developed by leave-one-out cross-validation. Diagnostic probability scores were derived from stepwise logistic regression. Thirty-seven miRNA specificities were consistently detected and 26 of these were unaffected by SSc sample age and present in more than two-thirds of SSc samples. SSc cases showed a distinct expression profile with 14/26 miRNA significantly decreased (false discovery rate < 0.05) and 5/26 increased compared with HC. A 21-miRNA classifier gave optimum accuracy (80%) for discriminating SSc from both HC and SLE. The discrimination between HC and SSc (95% accuracy) was strongly driven by miRNA of the 17 ∼ 92 cluster and by miR-16, -223, and -638, while SLE and SSc differed mainly in the expression of miR-142-3p, -150, -223, and -638. Except for a weak correlation between anti-Scl-70 and miR-638 (p = 0.048), there were no correlations with other patient variables. Circulating miRNA profiles are characteristic for SSc compared with both HC and SLE cases. Some of the predicted targets of the differentially regulated miRNA are of relevance for transforming growth factor-β signaling and fibrosis, but need to be validated in independent studies.

Sparing effect of hemiplegia on skin fibrosis and microvascular involvement: Reports of two cases of systemic sclerosis and review of the literature

ObjectivesThe sparing effect of hemiplegia in rheumatic diseases has been described, but reports on systemic sclerosis (SSc)-spectrum disorders are unusual. SSc-spectrum disorders are complex diseases of unknown origin characterized by multisystem involvement, skin and organ fibrosis, microvascular alterations, and immunologic abnormalities. We describe two cases of patients with hemiplegia who developed Raynaud׳s phenomenon and skin fibrosis of the non-paretic limb. MethodsClinical, laboratory, and investigation findings of two cases with hemiplegia who developed scleroderma spectrum disorders of the non-paretic limb are presented. A review of the medical literature was performed in PubMed for all articles in English. ResultsA total of 46 reports from 1935 to 2012 were identified, especially on osteoarthritis and rheumatoid arthritis. Only two case reports on patients with SSc describe asymmetric SSc skin involvement and unilateral acro-osteolysis on x-ray images of the non-paretic limb. By contrast, we report the first description of capillaroscopic microvascular changes in patients with hemiplegia and asymmetric SSc skin involvement. ConclusionsOur cases point out the potential role of a “cross-talk” between the nervous system and the skin in SSc-spectrum disorders and suggest future directions for research in studies of pathogenesis.

Informatics can identify systemic sclerosis (SSc) patients at risk for scleroderma renal crisis

BackgroundElectronic medical records (EMR) provide an ideal opportunity for the detection, diagnosis, and management of systemic sclerosis (SSc) patients within the Veterans Health Administration (VHA). The objective of this project was to use informatics to identify potential SSc patients in the VHA that were on prednisone, in order to inform an outreach project to prevent scleroderma renal crisis (SRC). MethodsThe electronic medical data for this study came from Veterans Informatics and Computing Infrastructure (VINCI). For natural language processing (NLP) analysis, a set of retrieval criteria was developed for documents expected to have a high correlation to SSc. The two annotators reviewed the ratings to assemble a single adjudicated set of ratings, from which a support vector machine (SVM) based document classifier was trained. Any patient having at least one document positively classified for SSc was considered positive for SSc and the use of prednisone≥10mg in the clinical document was reviewed to determine whether it was an active medication on the prescription list. ResultsIn the VHA, there were 4272 patients that have a diagnosis of SSc determined by the presence of an ICD-9 code. From these patients, 1118 patients (21%) had the use of prednisone≥10mg. Of these patients, 26 had a concurrent diagnosis of hypertension, thus these patients should not be on prednisone. By the use of natural language processing (NLP) an additional 16,522 patients were identified as possible SSc, highlighting that cases of SSc in the VHA may exist that are unidentified by ICD-9. A 10-fold cross validation of the classifier resulted in a precision (positive predictive value) of 0.814, recall (sensitivity) of 0.973, and f-measure of 0.873. ConclusionsOur study demonstrated that current clinical practice in the VHA includes the potentially dangerous use of prednisone for veterans with SSc. This present study also suggests there may be many undetected cases of SSc and NLP can successfully identify these patients.

AB1017 What Are the Distinct Capillaroscopic Features in Connective Tissue Disease as Compared with Diseases of Social Importance – Arterial Hypertension and Diabetes Mellitus?

BackgroundThe diseases of social importance such as arterial hypertension (AH) and diabetes mellitus (DM) are frequent concomitant pathology in patients with rheumatic diseases. At present, the capillaroscopic findings in these...

Systematic Review of the Role of Microparticles in Systemic Sclerosis.

Microparticles (MPs) are small, membrane-coated vesicles released in response to injury, cell activation or apoptosis. Growing evidence suggests associations between MPs and disease manifestations in systemic sclerosis (SSc). The aim of this study is to systematically review published articles and abstracts that discuss the role of MPs in SSc. The Web of Science(®), PubMed(®) and Google Scholar databases were searched for all articles and abstracts that discussed MPs in the context of SSc. The literature search was conducted on 18 July 2013 and restricted to English-language articles and abstracts. From a total of 150 distinct articles and 10 abstracts, only 14 articles and 4 abstracts met the criteria for an attempt of quantitative synthesis. Twenty articles were accepted for a review of reviews. Conference proceedings and journals not cataloged in either Web of Science(®) or PubMed(®) or searchable by Google Scholar would have been undetected. There is a risk of valid studies with negative results going unpublished. Few studies have been conducted on MPs in patients with SSc so it was possible to thoroughly consider each. While there is low quality evidence from studies that plasma concentrations of circulating endothelial and platelet MPs are elevated in SSc patients and that plasma concentrations of circulating endothelial MPs are higher in SSc cases with either pulmonary hypertension or interstitial lung disease than those SSc cases without, definitive conclusions are not possible due to heterogeneity of the studies with respect to inclusion criteria, populations studied, laboratory analysis methods, and choice of outcome statistics.

Systemic sclerosis with sarcoidosis: Case report and review of the published work

Sarcoidosis and systemic sclerosis (SSc) rarely coexist. Here, we report a Japanese female SSc patient who developed systemic sarcoidosis. Her SSc was a limited type negative for anti-Scl-70 antibody and positive for anticentromere antibody (ACA). Moreover, we performed a review of the English-language published work that described cases of concurrent SSc and sarcoidosis. Then, we found that most SSc and sarcoidosis concurrent patients positive for anti-Scl-70 antibody were male (77.8%). On the other hand, most patients positive for ACA were female (87.5%). These results suggest some relationships between autoantibody profiles and sex in SSc and sarcoidosis concurrence.

Pulmonary Arterial Hypertension and Systemic Sclerosis Relation: A Single Centre Experience

In systemic sclerosis (SSc), this single-centre study aimed to define the frequency and association of pulmonary arterial hypertension (PAH), occurring either alone in SSc-PAH or together with interstitial lung disease (ILD-PH). SSc cases between the years 1990-2011 were reviewed, retrospectively. Patients' clinical, laboratory findings, Modified Rodnan Skin Score and Medsger score, 6-minute walk distance (6MWD), carbon monoxide diffusion test (DLCO), echocardiography, thorax HRCT, and right heart catheterisation findings were recorded. One hundred and forty-one cases (F/M:124/17, diffuse cutaneous SSc (DcSSc)/limited cutaneous SSc (LcSSc): 84/57) were included in the study with the mean age of 52.70±15.17 years and disease duration of 107.07±99.44 months. PaO₂, FEV1 and FVC were lower in DcSSc (p<0.05) as compared to LcSSc, but DLCO and 6MWD did not differ significantly, between the two forms. Ground glass opacity (64.7%) and interlobular septal thickening (58.8%) were the most frequent findings on HRCT of such subjects. PAH was detected in 34 subjects (24.1%). Seven of them had SSc associated PAH (SSc-PAH) and 27 ILD-PH. Both frequencies were similar between DcSSc and LcSSc. Mean sPAP was higher in SSc-PAH. PAH was observed in approximately one fourth of patients; therefore advanced cardio-pulmonary investigation should be routinely performed in the SSc patients' management.

Leri’s pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassingGDF6andSDC2and provides insight into systemic sclerosis pathogenesis

Leri's pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis. Whole-genome single-nucleotide polymorphism genotyping in two families with LP defined microduplications of chromosome 8q22.1 as the cause of this condition. Expression analysis of dermal fibroblasts from affected individuals showed overexpression of two genes, GDF6 and SDC2, within the duplicated region, leading to dysregulation of genes that encode proteins of the extracellular matrix and downstream players in the transforming growth factor (TGF)-β pathway. Western blot analysis revealed markedly decreased inhibitory SMAD6 levels in patients with LP. Furthermore, in a cohort of 330 systemic sclerosis cases, we show that the minor allele of a missense SDC2 variant, p.Ser71Thr, could confer protection against disease (p<1×10(-5)). Our work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-β/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing 'TGF-β-pathies' group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill-Marchesani syndromes and stiff skin syndrome. Identification of a systemic sclerosis-protective SDC2 variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future.

Immunochip Analysis Identifies Multiple Susceptibility Loci for Systemic Sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci.

Effective Oral Psoralen Plus Ultraviolet A Therapy for Digital Ulcers with Revascularization in Systemic Sclerosis

Systemic sclerosis (SSc) is a heterogeneous disorder characterized by excessive fibrosis and microvascular damage to the skin and various internal organs, including the lungs, kidneys, oesophagus and heart. Raynaud’s phenomenon is an almost universal symptom of SSc; 95% of patients are affected. Digital ulcers are observed frequently, especially in intractable cases with severe Raynaud’s phenomenon, and there is considerable morbidity, with gangrene and amputations (1). To date, there is no promising treatment for severe cases of SSc that are complicated by digital ulcers. Apart from immunosuppressive drugs, administration of oral psoralen plus ultraviolet A (PUVA) therapy has been used in patients with SSc with progressive skin sclerosis complications, with some improvement (2). We report here the first case of successful oral PUVA therapy in a patient with SSc complicated by progressive skin sclerosis and digital ulcers.

2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative

ObjectiveThe 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of...

2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative

ObjectiveThe 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc.MethodsUsing consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma‐like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc.ResultsIt was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc‐related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus‐based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc.ConclusionThe ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

Abnormal cardiac enzymes in systemic sclerosis: a report of four patients and review of the literature

Cardiac involvement in systemic sclerosis (SSc) is heterogeneous and can include primary involvement of the myocardium, pericardium and coronary arteries or be secondary to cardiac complications of pulmonary and renal disease. Primary cardiac involvement in SSc is uncommon but can result in ventricular dysfunction, organ failure, arrhythmias and death. It can remain clinically silent and the prevalence is likely to be under-reported. We report four cases of SSc associated with a raised serum troponin T (TnT), in a proportion of whom cardiac MRI myocardial abnormalities were detected. These cases highlight the heterogeneity of cardiac involvement in SSc, the role of cardiac MRI and promising biochemical responses to immunosuppression. Cardiac biomarkers such as TnT may be useful screening tools to identify subclinical cardiac disease and assess response to therapeutic intervention.

Influence of Interstitial Lung Disease on Outcome in Systemic Sclerosis

Interstitial lung disease (ILD) is a frequent complication of systemic sclerosis (SSc) and a major cause of SSc-related deaths. This study aimed to determine the influence of ILD on SSc in a population-based historical cohort study. The hypothesis was that patients with SSc who develop ILD have increased morbidity and mortality when compared with patients with SSc without ILD. Using the record linkage system of the Rochester Epidemiology Project in Olmsted County, Minnesota, this study identified the incidence of SSc between 1980 and 2010 and point prevalence on December 31, 2010 and determined the progression of organ involvement and its influence on outcome. During the 30-year interval, we identified 64 incident cases of SSc: 57 women and seven men, median age 49.1 years (interquartile range [IQR], 39.8-67.6 years). There were 43 prevalent cases. ILD occurred in 19 cases, usually after the diagnosis of SSc (median, 2 years; IQR, 0-10 years), with only three cases occurring 6 to 24 months beforehand. Pulmonary arterial hypertension (PAH) was diagnosed in 14 cases, heart failure in 27 cases, and chronic kidney disease (CKD) in 21 cases. Seventeen patients died during the study period, with a median survival time after diagnosis of 22.9 years. ILD, PAH, and CKD were associated with an increased risk of death. The incidence of ILD associated with SSc was relatively low in this population-based cohort. ILD appeared to be a contributing factor to mortality. Other factors, including age, PAH, and CKD, were also associated with poor outcome.

AB0840 Scleroderma classification criteria: Disease-specific methods for valid case comparisons

BackgroundClassification criteria for systemic sclerosis (SSc) are being developed. Twenty-three candidate criteria have been identified and validated. Standardized cases need to be developed for criteria reduction and possible weighting.ObjectivesTo develop...

OP0033 Classification Criteria for Systemic Sclerosis: Preliminary Results

BackgroundThe existing 1980 classification criteria for systemic sclerosis (SSc) are suboptimal for patients with early SSc and some patients with limited cutaneous SSc (lcSSc) where an important subset do not...

Telangiectasis in CREST syndrome and systemic sclerosis: correlation of clinical and pathological features with response to pulsed dye laser treatment

Telangiectasia are cardinal features of systemic sclerosis (SS) and calcinosis, Raynaud's syndrome, esophageal motility, sclerodactyly, telangiectasias (CREST) syndrome. The etiology of telangiectasia in these syndromes is unknown, but vascular dysfunction has been proposed. However, the telangiectasia of CREST have anecdotally been considered relatively resistant to pulse dye laser (PDL), the treatment of choice for classic telangiectasia. The study was designed to test whether SS/CREST telangiectasia require more treatments than sporadic telangiectasia and to identify clinical and histological features that could explain such an effect. Nineteen skin biopsies from patients with SS or CREST and 10 control biopsies were examined and compared for features that may predict a differential response to PDL. Sixteen cases of SS or CREST treated with PDL between 1997 and 2007 were evaluated and response to treatment was compared with 20 patients with sporadic telangiectasis. Relative to normal skin, CREST/scleroderma telangiectasia exhibited thickened vessels in 17 out of 19 sections and thickened collagen fibers in the reticular or deep dermis in all sections. The number of treatments required to clear SS/CREST telangiectasia was approximately twofold higher. SS/CREST telangiectasia are more resistant to PDL but can be effectively cleared with more treatments.

Connective tissue diseases in primary biliary cirrhosis: A population-based cohort study

To establish the frequency and clinical features of connective tissue diseases (CTDs) in a cohort of Chinese patients with primary biliary cirrhosis (PBC). Three-hundred and twenty-two Chinese PBC patients were screened for the presence of CTD, and the systemic involvement was assessed. The differences in clinical features and laboratory findings between PBC patients with and without CTD were documented. The diversity of incidence of CTDs in PBC of different countries and areas was discussed. For the comparison of normally distributed data, Student's t test was used, while non-parametric test (Wilcoxon test) for the non-normally distributed data and 2 × 2 χ(2) or Fisher's exact tests for the ratio. One-hundred and fifty (46.6%) PBC patients had one or more CTDs. The most common CTD was Sjögren's syndrome (SS, 121 cases, 36.2%). There were nine cases of systemic sclerosis (SSc, 2.8%), 12 of systemic lupus erythematosus (SLE, 3.7%), nine of rheumatoid arthritis (RA, 2.8%), and 10 of polymyositis (PM, 3.1%) in this cohort. Compared to patients with PBC only, the PBC + SS patients were more likely to have fever and elevated erythrocyte sedimentation rate (ESR), higher serum immunoglobulin G (IgG) levels and more frequent rheumatoid factor (RF) and interstitial lung disease (ILD) incidences; PBC + SSc patients had higher frequency of ILD; PBC + SLE patients had lower white blood cell (WBC) count, hemoglobin (Hb), platelet count, γ-glutamyl transpeptidase and immunoglobulin M levels, but higher frequency of renal involvement; PBC + RA patients had lower Hb, higher serum IgG, alkaline phosphatase, faster ESR and a higher ratio of RF positivity; PBC + PM patients had higher WBC count and a tendency towards myocardial involvement. Besides the common liver manifestation of PBC, systemic involvement and overlaps with other CTDs are not infrequent in Chinese patients. When overlapping with other CTDs, PBC patients manifested some special clinical and laboratory features which may have effect on the prognosis.

Estimating the Prevalence of Systemic Sclerosis in the Lorraine Region, France, by the Capture–recapture Method

To assess the prevalence of systemic sclerosis (SSc) in the Lorraine region, France. Data from three sources - general practitioners and community and hospital specialists, medical records departments, and regional and national laboratories-and a capture-recapture method with log-linear models were used to estimate SSc prevalence in the region. Double recording was checked, and reported cases were validated after a review of medical records. We identified 560 records of suspected SSc cases corresponding to 327 unique suspected SSc cases existing on June 30, 2006, in Lorraine. On the basis of the 193 validated cases (22 [11.4%] with diffuse disease, 136 [70.5%] with limited disease, 31 [16.1%] with limited involvement and 4 unknown), the observed overall crude prevalence of SSc was 105.4 cases per million adult inhabitants (95% confidence interval [CI]: 91.0; 121.4). With the capture-recapture method, the estimated number of SSc cases was 233 (95% CI: 217.3; 260.0), so an estimated 40 cases were not identified by the three sources. The estimated overall prevalence was 132.2 cases per million adult inhabitants (95% CI: 115.8; 154.0). Our study provides the first estimate of SSc prevalence in the Lorraine region. The capture-recapture method allowed us to estimate an additional 21% of unobserved cases and is a good alternative to the community-based study design for estimating the prevalence of rare diseases.