Distinctive clinical traits of lupus-related myocarditis: a multicentre retrospective study.

OBJECTIVES: Cardiovascular involvement in systemic lupus erythematosus (SLE) is frequent but little is known about possible distinctive traits of SLE-related myocarditis (myoSLE) in comparison to patients with SLE (onlySLE) or myocarditis alone (onlyMyo). METHODS: A retrospective analysis was performed comparing patients with myoSLE (n = 25) from three centres with consecutive patients with onlySLE (n = 279) and onlyMyo (n = 88). SLE patients were dichotomised by disease duration ≤1 vs >1 year into recent onlySLE/early myoSLE vs longstanding onlySLE/late myoSLE. Further stratification into disease duration of 1-5, 5-10 and >10 years was also performed. SLE disease activity index 2000 (SLEDAI-2K) was used to estimate disease activity. Myocarditis was diagnosed through biopsy or magnetic resonance. RESULTS: Women were significantly more frequent among myoSLE than among onlyMyo (72% vs 43%; p= 0.013). Compared with onlyMyo, myoSLE patients had a higher frequency of conduction abnormalities (22% vs 5%; p= 0.046) and presented with numerically higher frequencies of left ventricular function compromise (48% vs 30%), along with higher pro-brain natriuretic peptide levels. Inflammation markers were higher in myoSLE compared with onlyMyo and to patients with onlySLE with >10 years of disease duration. SLEDAI-2K was significantly higher in late myoSLE than in longstanding onlySLE. Antiphospholipid syndrome was more frequent in myoSLE than in onlySLE. Multivariate analysis showed an association among myoSLE, anti-beta-2-glycoprotein I antibodies (aB2GPI, p= 0.014) and a higher number of involved British Isles Lupus Assessment Group domains in patient history (p= 0.003). CONCLUSION: myoSLE has unique clinical traits compared with other forms of myocarditis and is associated with aB2GPI and a more severe SLE course.

Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

Anti-U11/U12 Antibodies as a Rare but Important Biomarker in Patients with Systemic Sclerosis: A Narrative Review.

Anti-nuclear (ANA) are present in approximately 90% of systemic sclerosis (SSc) patients and are key biomarkers in supporting the diagnosis and determining the prognosis of this disease. In addition to the classification criteria autoantibodies for SSc [i.e., anti-centromere, anti-topoisomerase I (Scl-70), anti-RNA polymerase III], other autoantibodies have been associated with important SSc phenotypes. Among them, anti-U11/U12 ribonucleoprotein (RNP) antibodies, also known as anti-RNPC-3, were first reported in a patient with SSc, but very little is known about their association and clinical utility. The U11/U12 RNP macromolecular complex consists of several proteins involved in alternative mRNA splicing. More recent studies demonstrated associations of anti-anti-U11/U12 antibodies with SSc and severe pulmonary fibrosis as well as with moderate to severe gastrointestinal dysmotility. Lastly, anti-U11/U12 autoantibodies have been strongly associated with malignancy in SSc patients. Here, we aimed to summarize the knowledge of anti-U11/U12/RNPC-3 antibodies in SSc, including their seroclinical associations in a narrative literature review.

Defining the Role of Monocytes in Sjögren's Syndrome.

Sjögren's syndrome is one of the most prevalent autoimmune diseases after rheumatoid arthritis, with a preference for middle age, and is characterised by exocrine glandular involvement leading to xerostomia and xerophthalmia. It can have systemic implications with vascular, neurological, renal, and pulmonary involvement, and in some cases, it may evolve to non-Hodgkin's lymphoma. For a long time, B- and T-lymphocytes have been the focus of research and have been considered key players in Sjögren's syndrome pathogenesis and evolution. With the development of new technologies, including omics, more insights have been found on the different signalling pathways that lead to inflammation and activation of the immune system. New evidence indicates that a third actor linking innate and adaptive immunity plays a leading role in the Sjögren's syndrome play: the monocyte. This review summarises the recent insights from transcriptomic, proteomic, and epigenetic studies that help us to understand more about the Sjögren's syndrome pathophysiology and redefine the involvement of monocytes in this disease.

Xeroderma Pigmentosum: General Aspects and Management.

Xeroderma Pigmentosum (XP) is a rare genetic syndrome with a defective DNA nucleotide excision repair. It is characterized by (i) an extreme sensitivity to ultraviolet (UV)-induced damages in the skin and eyes; (ii) high risk to develop multiple skin tumours; and (iii) neurologic alterations in the most severe form. To date, the management of XP patients consists of (i) early diagnosis; (ii) a long-life protection from ultraviolet radiation, including avoidance of unnecessary UV exposure, wearing UV blocking clothing, and use of topical sunscreens; and (iii) surgical resections of skin cancers. No curative treatment is available at present. Thus, in the last decade, in order to prevent or delay the progression of the clinical signs of XP, numerous strategies have been proposed and tested, in some cases, with adverse effects. The present review provides an overview of the molecular mechanisms featuring the development of XP and highlights both advantages and disadvantages of the clinical approaches developed throughout the years. The intention of the authors is to sensitize scientists to the crucial aspects of the pathology that could be differently targeted. In this context, the exploration of the process underlining the conception of liposomal nanocarriers is reported to focus the attention on the potentialities of liposomal technology to optimize the administration of chemoprotective agents in XP patients.

Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients.

OBJECTIVES: The analysis of annotated transcripts from genome-wide expression studies may help to understand the pathogenesis of complex diseases, such as systemic sclerosis (SSc). We performed a whole blood (WB) transcriptome analysis on RNA collected in the context of the European PRECISESADS project, aiming at characterising the pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations. METHODS: Samples from 162 patients and 252 controls were collected in RNA stabilisers. Cases and controls were divided into a discovery (n=79+163; Southern Europe) and validation cohort (n=83+89; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the Functional Analysis of Individual Microarray Expression (FAIME) algorithm. In parallel, immunophenotyping of 28 circulating cell populations was performed. We tested the presence of differentially expressed genes/pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated. RESULTS: Overall, 15 224 genes and 1277 functional pathways were available; of these, 99 and 225 were significant in both sets. Among replicated pathways, we found a deregulation in type-I interferon, Toll-like receptor cascade, tumour suppressor p53 protein function, platelet degranulation and activation. RNA transcripts or FAIME scores were jointly correlated with cell subtypes with strong geographical differences; neutrophils were the major determinant of gene expression in SSc-WB samples. CONCLUSIONS: We discovered a set of differentially expressed genes/pathways validated in two independent sets of patients with SSc, highlighting a number of deregulated processes that have relevance for the pathogenesis of autoimmunity and SSc.

CXCL4 triggers monocytes and macrophages to produce PDGF-BB, culminating in fibroblast activation: Implications for systemic sclerosis.

OBJECTIVE: To analyze how monocyte and macrophage exposure to CXCL4 induces inflammatory and fibrotic processes observed in Systemic sclerosis (SSc) patients. METHODS: In six independent experiments, monocytes of healthy controls (HC) and SSc patients were stimulated with CXCL4, TLR-ligands, IFNɑ or TGFß and the secretion of cytokines in the supernatant was assessed by multiplex immunoassays. PDGF-BB production by monocyte-derived macrophages was quantified using immunoassays. The number of monocytes and PDGF-BB in circulation was quantified in HC and SSc patients with the Sysmex XT-1800i haematology counter and immunoassays. Intracellular PDGF-BB was quantified in monocytes by Western blot. PDGF-receptor inhibition was achieved using siRNA-mediated knockdown or treatment with Crenolanib. The production of inflammatory mediators and extracellular matrix (ECM) components by dermal fibroblasts was analyzed by qPCR, ELISA and ECM deposition assays. RESULTS: SSc and HC monocytes released PDGF-BB upon stimulation with CXCL4. Conversely, TLR ligands, IFNɑ or TGFß did not induce PDGF-bb release. PDGF-BB plasma levels were significantly (P = 0.009) higher in diffuse SSc patients (n = 19), compared with HC (n = 21). In healthy dermal fibroblasts, PDGF-BB enhanced TNFɑ-induced expression of inflammatory cytokines and increased ECM production. Comparable results were observed in fibroblasts cultured in supernatant taken from macrophages stimulated with CXCL4. This effect was almost completely abrogated by inhibition of the PDGF-receptor using Crenolanib. CONCLUSION: Our findings demonstrate that CXCL4 can drive fibroblast activation indirectly via PDGF-BB production by myeloid cells. Hence, targeting PDGF-BB or CXCL4-induced PDGF-BB release could be clinically beneficial for patients with SSc.

Cardiopulmonary exercise testing in a combined screening approach to individuate pulmonary arterial hypertension in systemic sclerosis.

OBJECTIVES: The DETECT algorithm has been developed to identify SSc patients at risk for pulmonary arterial hypertension (PAH) yielding high sensitivity but low specificity, and positive predictive value. We tested whether cardiopulmonary exercise testing (CPET) could improve the performance of the DETECT screening strategy. METHODS: Consecutive SSc patients over a 30-month period were screened with the DETECT algorithm and positive subjects were referred for CPET before the execution of right-heart catheterization. The predictive performance of CPET on top of DETECT was evaluated and internally validated via bootstrap replicates. RESULTS: Out of 314 patients, 96 satisfied the DETECT application criteria and 54 were positive. PAH was ascertained in 17 (31.5%) and pre-capillary pulmonary hypertension in 23 (42.6%) patients. Within CPET variables, the slope of the minute ventilation to carbon dioxide production relationship (VE/VCO2 slope) had the best performance to predict PAH at right-heart catheterization [median (interquartile range) of specificity 0.778 (0.714-0.846), positive predictive value 0.636 (0.556-0.750)]; exploratory analysis on pre-capillary yielded a specificity of 0.714 (0.636-0.8) and positive predictive value of 0.714 (0.636-0.8). CONCLUSION: In association with the DETECT algorithm, CPET may be considered as a useful tool in the workup of SSc-related pulmonary hypertension. The sequential determination of the VE/VCO2 slope in DETECT-positive subjects may reduce the number of unnecessary invasive procedures without any loss in the capability to capture PAH. This strategy had also a remarkable performance in highlighting the presence of pre-capillary pulmonary hypertension.

Abatacept to treat chronic intestinal pseudo-obstruction in five systemic sclerosis patients with a description of the index case.

Chronic intestinal pseudo-obstruction is a severe complication of systemic sclerosis. Inflammatory neuropathy and immunological alterations have a prominent role in the development of systemic sclerosis-related chronic intestinal pseudo-obstruction and immunomodulation might be beneficial in this context. An accidental observation of a patient with juvenile arthritis and a biopsy-proven diagnosis of autoimmune ganglionitis led us to experiment with a new approach to treat systemic sclerosis-related chronic intestinal pseudo-obstruction. In our arthritis patient, the severity and frequency of recurrent episodes of chronic intestinal pseudo-obstruction and aspiration pneumonia were reduced whenever steroids were used to treat arthritic flares, which dramatically improved with abatacept therapy. A systemic sclerosis patient presented typical chronic intestinal pseudo-obstruction features that were neither controlled by dietary interventions nor by prokinetics and were often complicated by acute episodes (5-year) requiring hospitalization. Increased food tolerance was observed whenever parenteral steroids were used during hospitalization. An adequate long-term control of symptoms was then obtained with the use of intramuscular methylprednisolone 20 mg/day; however, symptoms promptly recurred after tapering. Following this motivating example, immunomodulation with abatacept was started. Symptoms were then well controlled and steroids could be weaned off without further acute episodes of sub-occlusion. We postulate that inflammatory neuropathy resembling myenteric ganglionitis may be suspected in selected systemic sclerosis patients with chronic intestinal pseudo-obstruction features. Immunomodulation with drugs that act on T function and restore the regulatory/effector T cell balance may be beneficial in these subjects. The outcomes of four additional systemic sclerosis patients with severe and refractory symptoms of intestinal pseudo-obstruction successfully treated with abatacept are also presented.

A TNFSF13B functional variant is not involved in systemic sclerosis and giant cell arteritis susceptibility.

BACKGROUND: The TNFSF13B (TNF superfamily member 13b) gene encodes BAFF, a cytokine with a crucial role in the differentiation and activation of B cells. An insertion-deletion variant (GCTGT→A) of this gene, leading to increased levels of BAFF, has been recently implicated in the genetic predisposition to several autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Based on the elevated levels of this cytokine found in patients with giant cell arteritis (GCA) and systemic sclerosis (SSc), we aimed to assess whether this functional variant also represents a novel genetic risk factor for these two disorders. METHODS: A total of 1,728 biopsy-proven GCA patients from 4 European cohorts, 4,584 SSc patients from 3 European cohorts and 5,160 ethnically-matched healthy controls were included in the study. The single nucleotide polymorphism (SNP) rs374039502, which colocalizes with the genetic variant previously implicated in autoimmunity, was genotyped using a custom TaqMan assay. First, association analysis was conducted in each independent cohort using χ2 test in Plink (v1.9). Subsequently, different case/control sets were meta-analyzed by the inverse variance method. RESULTS: No statistically significant differences were found when allele distributions were compared between cases and controls for any of the analyzed cohorts. Similarly, combined analysis of the different sets evidenced a lack of association of the rs374039502 variant with GCA (P = 0.421; OR (95% CI) = 0.92 (0.75-1.13)) and SSc (P = 0.500; OR (95% CI) = 1.05 (0.91-1.22)). The stratified analysis considering the main clinical subphenotypes of these diseases yielded similar negative results. CONCLUSION: Our data suggest that the TNFSF13B functional variant does not contribute to the genetic network underlying GCA and SSc.

Moving towards a molecular taxonomy of autoimmune rheumatic diseases.

Autoimmune rheumatic diseases pose many problems that have, in general, already been solved in the field of cancer. The heterogeneity of each disease, the clinical similarities and differences between different autoimmune rheumatic diseases and the large number of patients that remain without a diagnosis underline the need to reclassify these diseases via new approaches. Knowledge about the molecular basis of systemic autoimmune diseases, along with the availability of bioinformatics tools capable of handling and integrating large volumes of various types of molecular data at once, offer the possibility of reclassifying these diseases. A new taxonomy could lead to the discovery of new biomarkers for patient stratification and prognosis. Most importantly, this taxonomy might enable important changes in clinical trial design to reach the expected outcomes or the design of molecularly targeted therapies. In this Review, we discuss the basis for a new molecular taxonomy for autoimmune rheumatic diseases. We highlight the evidence surrounding the idea that these diseases share molecular features related to their pathogenesis and development and discuss previous attempts to classify these diseases. We evaluate the tools available to analyse and combine different types of molecular data. Finally, we introduce PRECISESADS, a project aimed at reclassifying the systemic autoimmune diseases.

Idiopathic inflammatory myopathies: state of the art on clinical practice guidelines [corrected].

Idiopathic inflammatory myopathies (IIMs) encompass a heterogeneous group of rare autoimmune diseases characterised by muscle weakness and inflammation, but in antisynthetase syndrome arthritis and interstitial lung disease are more frequent and often inaugurate the disease. Clinical practice guidelines (CPGs) have been proposed for IIMs, but they are sparse and heterogeneous. This work aimed at identifying: i) current available CPGs for IIMs, ii) patients ' and clinicians' unmet needs not covered by CPGs. It has been performed in the framework of the European Reference Network on rare and complex connective tissue and musculoskeletal diseases (ReCONNET), a network of centre of expertise and patients funded by the European Union's Health Programme. Fourteen original CPGs were identified, notably recommending that: i) extra-muscular involvements should be assessed; ii) corticosteroids and methotrexate or azathioprine are first-line therapies of IIMs. ii) IVIG is a treatment of resistant-DM that may be also used in other resistant-IIMs; iii) physical therapy and sun protection (in DM patients) are part of the treatment; v) tumour screening for patients with DM include imaging of chest, abdomen, pelvis and breast (in woman) along with colonoscopy (in patients over 50 years); vi) disease activity and damages should be monitor using standardised and validated tools. Yet, only half of these CPGs were evidence-based. Crucial unmet needs were identified both by patients and clinicians. In particular, there was a lack of large multidisciplinary working group and of patients ' preferences. The following fields were not or inappropriately targeted: diagnosis; management of extra-muscular involvements other than skin; co-morbidities and severe manifestations.

Earliest Phase of Systemic Sclerosis Typified by Increased Levels of Inflammatory Proteins in the Serum.

OBJECTIVE: Patients with definite systemic sclerosis (SSc) who lack fibrotic features can be stratified into an intermediate stage of disease severity between preclinical/early SSc (EaSSc) and fibrotic subsets (limited cutaneous SSc [lcSSc] and diffuse cutaneous SSc [dcSSc]). The aim of the present study was to molecularly characterize nonfibrotic SSc and EaSSc on the basis of a broad panel of serum markers of inflammation and tissue damage, in order to increase the knowledge of the pathophysiologic mechanisms underlying SSc progression before the development of fibrosis. METHODS: An 88-plex immunoassay was performed in serum samples from a discovery cohort composed of 21 patients with EaSSc (meeting the LeRoy and Medsger criteria), 15 with nonfibrotic SSc (meeting the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria, without skin or lung fibrosis), and 11 healthy controls. Analyte concentrations that were consistently significantly different at the exploratory P value threshold of 0.1 were selected for replication analysis in a larger group composed of 47 patients with EaSSc, 48 with nonfibrotic SSc, and 43 healthy controls, as well as 51 patients with lcSSc and 35 with dcSSc. The value of the replicated molecules in predicting SSc progression (at a family-wise error rate of 0.05) was tested. RESULTS: Based on the results of the explorative analysis, 16 molecules were selected for testing in the replication set. The results showed that CXCL10, CXCL11, tumor necrosis factor receptor type II (TNFRII), and chitinase 3-like protein 1 levels were significantly increased in patients with EaSSc and those with nonfibrotic SSc as compared to healthy controls. The disease in patients with high concentrations of CXCL10 and TNFRII was also characterized by a faster rate of progression from EaSSc and from nonfibrotic SSc to worse disease stages. CONCLUSION: SSc patients with preclinical/early SSc and those with established, yet nonfibrotic, disease exhibit clear molecular alterations that are associated with faster rates of disease evolution. These data open novel avenues for disease interception in SSc.

Serum levels of vascular dysfunction markers reflect disease severity and stage in systemic sclerosis patients.

OBJECTIVE: To improve knowledge of vasculopathy in SSc through the assessment of serum levels of circulating angiogenetic and endothelial dysfunction markers in patients at different stages of the disease. METHODS: Sera from 224 subjects were obtained and concentrations of angiopoietin-2, chemokine (C-X-C motif) ligand (CXCL)-16 (CXCL16), E-selectin, soluble intercellular adhesion molecule-1, IL-8 (CXCL8), soluble vascular adhesion molecule-1 and VEGF were determined by a Luminex assay. Subjects included 43 healthy controls, 47 early SSc patients according to LeRoy and Medsger without other signs and symptoms of evolutive disease, 48 definitive SSc (defSSc) patients according to the 2013 ACR/EULAR criteria without skin or lung fibrosis, 51 lcSSc subjects and 35 dcSSc subjects. RESULTS: The four groups of patients showed well-distinct clinical and laboratory characteristics, with a linear decreasing trend in forced vital capacity and diffusing capacity for carbon monoxide % predicted values from early SSc to defSSc to lcSSc and to dcSSc, and a linear increasing trend in ESR, and in the prevalence of abnormal CRP, serum gamma globulins and lung fibrosis (all P < 0.0001). Highly significant linear trends pointing to an increase in angiopoietin-2 (P < 0.0001), CXCL16 (P < 0.0001), E-selectin (P = 0.001) and soluble intercellular adhesion molecule-1 (P = 0.002) in relation to the different disease subsets were observed. CONCLUSION: Markers characterizing vascular activation are found to be increased in SSc patients from the earliest stages of disease when clinical and laboratory findings of advanced disease cannot yet be detected. These abnormalities progress with the appraisal of the first sclerodermatous manifestation in defSSc and further increase with the onset of fibrotic manifestations.

The interferon type I signature is present in systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis.

BACKGROUND: Interferon (IFN) signature has been reported in definite systemic sclerosis (SSc) but it has not been characterised in early SSc (EaSSc). We aim at characterising IFN type I signature in SSc before overt skin fibrosis develops. METHODS: The expression of 11 IFN type I inducible genes was tested in whole-blood samples from 30 healthy controls (HCs), 12 subjects with primary Raynaud's phenomenon (RP), 19 patients with EaSSc, 7 patients with definite SSc without cutaneous fibrosis, 21 limited cutaneous SSc and 10 diffuse cutaneous SSc subjects. The correlation between IFN activity in monocytes, B cell activating factor (BAFF) mRNA expression and type III procollagen N-terminal propeptide (PIIINP) serum levels was tested. RESULTS: In all the SSc groups, higher IFN scores were observed compared with HC. An IFN score ≥7.09 discriminated HCs from patients with SSc (sensitivity=0.7, specificity=0.88, area under receiving operating characteristic (AUROC)=0.82); the prevalence of an elevated IFN score was: HC=3.3%; RP=33.3%, EaSSc=78.9%, definite SSc=100%, limited cutaneous SSc=42.9%, diffuse cutaneous SSc=70.0%. In monocytes an IFN score ≥4.12 distinguished HCs from patients with fibrotic SSc (sensitivity=0.62, specificity=0.85, AUROC=0.76). Compared with IFN-negative subjects, IFN-positive subjects had higher monocyte BAFF mRNA levels (19.7±5.2 vs 15.20±4.0, p=2.1×10(-5)) and serum PIIINP levels (median=6.0 (IQR 5.4-8.9) vs median=3.9 (IQR 3.3-4.7), p=0.0004). CONCLUSIONS: An IFN type I signature is observed in patients with SSc from the earliest phases of the disease, even before overt skin fibrosis. The presence of IFN type I signature in monocytes is correlated with BAFF mRNA expression and serum PIIINP levels, supporting a contribution in the pathogenesis and progression of SSc.

Validation of a novel radiographic scoring system for calcinosis affecting the hands of patients with systemic sclerosis.

OBJECTIVE: There are currently no validated outcome measures to assess calcinosis severity in systemic sclerosis (SSc; scleroderma). We sought to develop and validate a novel radiographic scoring system for calcinosis affecting the hands of SSc patients for potential use in future clinical trials. METHODS: Following a 1-hour teleconference training session, 12 investigators (8 rheumatologists, 1 dermatologist, and 3 radiologists) scored 12 hand radiographs in random order using 2 scoring systems (termed "simple" and "complex") and re-scored 2 randomly assigned radiographs after a minimum of 24 hours. Interrater and intrarater reliability were assessed using a weighted kappa coefficient for the simple system (κ), and an intraclass correlation coefficient (ICC) for the complex system (ICC <0.4 for poor, 0.4­0.7 for moderate, and >0.7 for excellent). RESULTS: Mean time to complete the complex scoring system was significantly longer than the simple scoring system (4.0 versus 0.4 minutes; P < 0.0001). Overall interrater reliability for the simple scoring system was poor (κ = 0.39, 95% confidence interval [95% CI] 0.1­0.52) but improved if dichotomized as mild/moderate versus severe (κ = 0.51, 95% CI 0.26­0.7). Interrater reliability was excellent for the complex scoring system (ICC 0.89, 95% CI 0.86­0.92). Intrarater reliability was moderate for the simple scoring system (κ = 0.67, 95% CI 0.37­0.96) but almost perfect for the complex scoring system (ICC 0.93, 95% CI 0.89­0.97). CONCLUSION: We developed a novel radiographic scoring system that accounts for the area coverage, density, and anatomic location of calcinosis affecting the hands in patients with SSc. This scoring system is feasible with excellent reliability and should undergo further validation testing for use in clinical trials.

Regional implantation of autologous adipose tissue-derived cells induces a prompt healing of long-lasting indolent digital ulcers in patients with systemic sclerosis.

Digital ulcers (DUs) are a rather frequent and invalidating complication in systemic sclerosis (SSc), often showing a very slow or null tendency to heal, in spite of the commonly used systemic and local therapeutic procedures. Recently, stem cell therapy has emerged as a new approach to accelerate wound healing. In the present study, we have tentatively treated long-lasting and poorly responsive to traditional therapy SSc-related DUs by implantation of autologous adipose tissue-derived cell (ATDC) fractions. Fifteen patients with SSc having a long-lasting DU in only one fingertip who were unresponsive to intensive systemic and local treatment were enrolled in the study. The grafting procedure consisted of the injection, at the basis of the corresponding finger, of 0.5-1 ml of autologous ATDC fractions, separated by centrifugation of adipose tissue collected through liposuction from subcutaneous abdominal fat. Time to heal after the procedure was the primary end point of the study, while reduction of pain intensity and of analgesic consumption represented a secondary end point. Furthermore, the posttherapy variation of the number of capillaries, observed in the nailfold video capillaroscopy (NVC) exam and of the resistivity in the digit arteries, measured by high-resolution echocolor-Doppler, were also taken into account. A rather fast healing of the DUs was reached in all of the enrolled patients (mean time to healing 4.23 weeks; range 2-7 weeks). A significant reduction of pain intensity was observed after a few weeks (p < 0.001), while the number of capillaries was significantly increased at 3- and 6-month NVC assessment (p < 0.0001 in both cases). Finally, a significant after-treatment reduction of digit artery resistivity was also recorded (p < 0.0001). Even with the limitations related to the small number of patients included and to the open-label design of the study, the observed strongly favorable outcome suggests that local grafting with ATDCs could represent a promising option for the treatment of SSc-related DUs unresponsive to more consolidated therapies.

A candidate gene approach identifies an IL33 genetic variant as a novel genetic risk factor for GCA.

INTRODUCTION: Increased expression of IL-33 and its receptor ST2, encoded by the IL1RL1 gene, has been detected in the inflamed arteries of giant cell arteritis (GCA) patients. The aim of the present study was to investigate for the first time the potential influence of the IL33 and IL1RL1 loci on GCA predisposition. METHODS: A total of 1,363 biopsy-proven GCA patients and 3,908 healthy controls from four European cohorts (Spain, Italy, Germany and Norway) were combined in a meta-analysis. Six genetic variants: rs3939286, rs7025417 and rs7044343, within the IL33 gene, and rs2058660, rs2310173 and rs13015714, within the IL1RL1 gene, previously associated with immune-related diseases, were genotyped using predesigned TaqMan assays. RESULTS: A consistent association between the rs7025417 polymorphism and GCA was evident in the overall meta-analysis, under both allele (P(MH) = 0.041, OR = 0.88, CI 95% 0.78-0.99) and recessive (P(MH) = 3.40E-03, OR = 0.53, CI 95% 0.35-0.80) models. No statistically significant differences between allele or genotype frequencies for the other IL33 and IL1RL1 genetic variants were detected in this pooled analysis. CONCLUSIONS: Our results clearly evidenced the implication of the IL33 rs7025417 polymorphism in the genetic network underlying GCA.

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.