Diffuse Cutaneous Scleroderma Research Articles

Pulmonary and extra-pulmonary effects of lung transplantation in an Italian cohort of patients with systemic sclerosis

Abstract Objectives Lung transplantation (LuTx) is a life-saving intervention for Systemic Sclerosis (SSc) patients with end-stage lung disease. The aim of this study was to evaluate patients’ survival and LuTx outcomes on systemic disease manifestations. Methods A retrospective evaluation was conducted on SSc patients who underwent LuTx between 2010 and 2021. Outcomes assessed at baseline, 6, 12, and 24 months post-LuTx included skin involvement by modified Rodnan skin score (mRSS), global disease activity using a modified EUSTAR index (0–9 scale). Lung function rescue was evaluated by forced vital capacity (FVC). Patient survival was assessed by Kaplan-Meier analysis. Results 13 SSc patients were included, with a male/female ratio 9/4 and a median age of 48.7 years. Nine patients were affected by diffuse cutaneous scleroderma (dcSSc) and four by limited cutaneous scleroderma (lcSSc). FVC significantly increased from 56% of the predicted value at baseline to 78% at 2 years (p= 0.003). mRSS decreased from 7.4 ± 3.8–3.3 ± 2.5 in patients with dcSSc (p= 0.02). The modified EUSTAR index score decreased from 2.54 ± 1.8 at baseline to 0.49 ± 0.5 at 2 years (p= 0.02). Survival rate was 92.3% at 2 years, and 76.9% at 5 years. No unexpected adverse events were observed. Conclusions In SSc patients undergoing LuTx, an excellent 2-year survival was observed, without any disease-related adverse events. Our study supports LuTx as a viable option in SSc patients with end-stage lung disease. Apart from expected recovery of lung function, LuTx was associated with improvement of mRSS and global systemic disease activity.

Argumentaire « en faveur » de la greffe de cellules souches hématopoïétiques autologues dans la sclérodermie systémique

Autologous haematopoietic stem cell transplantation for systemic scleroderma, developed over more than 25 years, has shown in three randomised controlled clinical trials a significant impact not only in event-free survival, overall survival, cutaneous and pulmonary involvement, but also in the quality of life of patients living with recent severe diffuse cutaneous systemic scleroderma, compared with IV cyclophosphamid despite a transplant-related mortality between 2.4 and 10%. No immunosuppressants or biologics have shown such an impact on mortality in this disease. The risk of relapse is estimated between 9 and 24%, two years after transplant. On the basis of these results, French and international guidelines now position autologous haematopoietic stem cell transplantation as a level 1A evidence-based therapeutic alternative in severe early and rapidly progressive systemic scleroderma.

Purtscher-like retinopathy induced by diffuse cutaneous systemic scleroderma.

Abstract We report a rare case of Purtscher-like retinopathy related to systemic sclerosis, presented unprecedently an ultra-widefield optical coherence tomography angiography image for this combination, and showed not only retinal but also choroidal vascular nonperfusion.

Management of Uttana vatarakta (limited cutaneous systemic sclerosis): An experience through Ayurveda management strategies

Abstract Scleroderma (systemic sclerosis) is a group of rare diseases that involve the hardening and tightening of the skin and connective tissues. Diffuse cutaneous scleroderma and Limited Cutaneous Systemic Sclerosis (LcSSC) are the two major classifications of it. LcSSc usually affects the skin and further spreads to muscles and joints, but in about 10% cases, involvement of internal organs like gastrointestinal tract and manifestations like pulmonary hypertension is seen even after 10–15 years. The prevalence of the disease is 17.6/100,000 population. As far as the management of LcSSC in conventional medicine is concerned, other than symptomatic relief; immunosuppressive drugs are given, but long-term use of such medicines suppresses the immunity of the patient and hence the patient may get affected with opportunistic infections and causes severe complications. Hence, some alternatives in this direction are being explored from other systems of medicines for the betterment of patients. The direct description of the disease scleroderma is not available in Ayurvedic literature, but based on its presentation, it can be correlated with different stages of Vatarakta (~rheumatism due to blood tissue). A 20-year-old young male patient with presentation of limited scleroderma managed with Ayurveda therapy by Virechana (~therapeutic purgation) followed by Shamana (~palliative) therapy for one and half months and obtained encouraging results, inferring that Ayurveda therapeutic protocols can be successfully adopted in cases like LcSSC.

The association between air pollution and the severity at diagnosis and progression of systemic sclerosis-associated interstitial lung disease: results from the retrospective ScleroPol study

ObjectiveTo investigate the association of air pollution exposure with the severity of interstitial lung disease (ILD) at diagnosis and ILD progression among patients with systemic sclerosis (SSc)-associated ILD.MethodsWe conducted a retrospective two-center study of patients with SSc-associated ILD diagnosed between 2006 and 2019. Exposure to the air pollutants particulate matter of up to 10 and 2.5 µm in diameter (PM10, PM2.5), nitrogen dioxide (NO2), and ozone (O3) was assessed at the geolocalization coordinates of the patients’ residential address. Logistic regression models were used to evaluate the association between air pollution and severity at diagnosis according to the Goh staging algorithm, and progression at 12 and 24 months.ResultsWe included 181 patients, 80% of whom were women; 44% had diffuse cutaneous scleroderma, and 56% had anti-topoisomerase I antibodies. ILD was extensive, according to the Goh staging algorithm, in 29% of patients. O3 exposure was associated with the presence of extensive ILD at diagnosis (adjusted OR: 1.12, 95% CI 1.05–1.21; p value = 0.002). At 12 and 24 months, progression was noted in 27/105 (26%) and 48/113 (43%) patients, respectively. O3 exposure was associated with progression at 24 months (adjusted OR: 1.10, 95% CI 1.02–1.19; p value = 0.02). We found no association between exposure to other air pollutants and severity at diagnosis and progression.ConclusionOur findings suggest that high levels of O3 exposure are associated with more severe SSc-associated ILD at diagnosis, and progression at 24 months.

P150 The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis

Abstract Background/Aims Scleroderma (systemic sclerosis, SSc) is an autoimmune inflammatory-fibrosis syndrome that damages the skin and internal organs and is considered a prototypic complex fibrotic disease. In SSc, persistently activated myofibroblasts are maintained by an excessive, autocrine mechanotranductive/pro-adhesive signaling loop. Drugs targeting this pathway are therefore of likely therapeutic benefit in SSc. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid plant-derivative celastrol has recently been identified as a YAP inhibitor; however, if celastrol can alleviate SSc fibrosis, and its underlying mechanism of action, is as yet unclear. Methods We cultured age-, sex-, and site-matched human dermal fibroblasts sampled from healthy individuals and patients with early onset (<18 month after first diagnosis) diffuse cutaneous scleroderma (systemic sclerosis, dcSSc) and treated with or without transforming growth factor β1 (TGFβ1, 4ng/ml) in the presence or absence of celastrol (500nM). We also subjected C57BL6J mice to the inflammatory-driven bleomycin-induced model of skin SSc, in the presence or absence of celastrol (28days, every day, 0.1U bleomycin, 1mg/kg celastrol). RNA expression was assessed using RNAseq and real-time polymerase chain reaction analysis. Protein expression was determined using Western blot and enzyme-linked immunosorbent assay. Fibrosis was monitored by hematoxylin and eosin and trichrome staining of tissue sections, and by using indirect immunofluorescence analysis with anti-alpha-smooth muscle actin (SMA) antibodies to detect myofibroblasts. Results In dermal fibroblasts, celastrol impaired the ability of TGFβ1 to induce an SSc-like pattern of gene expression, including the induction of cellular communication network factor 2 (CCN2), collagen I and TGFβ1 protein (N = 6, all p < 0.01). Celastrol also alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients, including the overproduction of CCN2 and collagen (N = 3, p < 0.05). Finally, in the bleomycin-induced model of SSc dermatopathology, celastrol inhibited skin thickness/collagen deposition in vivo and blocked nuclear localization of YAP in SMA-positive myofibroblasts (all N = 6, p < 0.01). Conclusion Our data are consistent with the hypothesis that compounds, such as celastrol, that antagonize the YAP pathway warrant further consideration as potential treatments for SSc skin fibrosis. Disclosure A. Leask: Grants/research support; CIHR, NSERC, Arthritis Society of Canada. R.J. Stratton: None. S. Xu: None. P. Chitturi: None.

Development and validation of Hebrew version of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument 2.0.

The aim of this study was to test the reliability of the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA SCTC GIT) 2.0 questionnaire in Hebrew. UCLA SCTC GIT 2.0 was translated into Hebrew using the translation-retranslation method. The Hebrew version of the UCLA SCTC GIT 2.0 and the Hebrew version of the Short Form 36 (SF-36) were administered to 19 Hebrew-speaking patients with systemic sclerosis. Internal reliability was assessed using Cronbach's alpha. The Hebrew questionnaire was then tested for external validity using Spearman's correlation coefficient. Correlations (rho) ⩽ 0.29 were considered small, 0.30 to 0.49 were moderate, and those ⩾0.50 were considered large. Differences were considered statistically significant at p < 0.05. A group of 19 patients treated at Sheba Medical Center meeting the ACR/EULAR classification system for systemic sclerosis were included in the study. The mean age of the participants was 60.4 ± 12 years with a female predominance (84%). Diffuse cutaneous scleroderma accounted for 10 of the participants (54%), 7 had limited cutaneous scleroderma (36%) with 2 having an overlap syndrome (10%). The Cronbach's alpha value for the UCLA SCTC GIT 2.0 scale was 0.908 showing reliability. In addition, the UCLA SCTC GIT 2.0 showed correlation to the SF-36. The translation of the Hebrew UCLA SCTC GIT 2.0 scale was reliable and valid with a total Cronbach's alpha score among the participants of 0.908. Cronbach's alpha was particularly reliable in reflux, bloating, social function, and emotional well-being. Our results suggest that our Hebrew version of the UCLA SCTC GIT 2.0 scale can be used as a tool in future studies with Hebrew-speaking patients. In the abstract conclusion, it states that "Cronbach's alpha was particularly reliable in reflux, bloating, social function, and emotional well-being." The related data should be listed in the results section and then an interpretation of the results should be listed in the conclusions section. Please revise.

A cell-based assay for detection of anti-fibrillarin autoantibodies with performance equivalent to immunoprecipitation.

Anti-fibrillarin autoantibodies are useful for the diagnosis and prognosis of systemic sclerosis (SSc). Anti-fibrillarin produces a clumpy nucleolar pattern in indirect immunofluorescence assay on HEp-2 cells (HEp-2 IFA). Here we develop and validate a reliable cell-based anti-fibrillarin assay (Fibrillarin/CBA) for use in clinical diagnostic laboratories. A TransMembrane Signal was fused to the human fibrillarin gene (TMS-fibrillarin). HEp-2 cells overexpressing transgenic TMS-fibrillarin at the cytoplasmic membrane were used as IFA substrate in the Fibrillarin/CBA. Sixty-two serum samples with nucleolar pattern in the HEp-2 IFA (41 clumpy; 21 homogeneous/punctate) were tested for anti-fibrillarin using Fibrillarin/CBA, immunoprecipitation (IP), line-blot and ELISA. In addition, samples from 106 SSc-patients were evaluated with Fibrillarin/CBA and the results were correlated with disease phenotypes. Thirty-eight of 41 samples with the clumpy nucleolar pattern (92.7%) were positive in the Fibrillarin/CBA, while all 21 samples with other nucleolar patterns were negative. Fibrillarin/CBA results agreed 100% with IP results. Among the 38 Fibrillarin/CBA-positive samples, only 15 (39.5%) and 11 (29%) were positive for anti-fibrillarin in line-blot and ELISA, respectively. Higher frequency of diffuse cutaneous SSc (dcSSc) phenotype (72.7% vs 36.8%; p=0.022), cardiac involvement (36.4% vs 6.5%; p=0.001) and scleroderma renal crisis (18.2% vs 3.3% p = 0.028) was observed in SSc patients with positive compared to negative Fibrillarin/CBA result. Performance of Fibrillarin/CBA in the detection of anti-fibrillarin autoantibodies was comparable to the gold standard IP. Positive Fibrillarin/CBA results correlated with disease phenotypes known to be associated with anti-fibrillarin autoantibodies, underscoring the clinical validation of this novel assay.

POS0872 CLINICAL FEATURES AND OUTCOME OF 1054 PATIENTS WITH SYSTEMIC SCLEROSIS: AN ANALYSIS OF THE PORTUGUESE REUMA.PT REGISTRY FOR SCLERODERMA (REUMA.PT/SSC)

Background:Systemic sclerosis (SSc) may present distinctive manifestations and survival in different ethnic and geographic groups.Objectives:To describe the clinical features, treatments, and survival of adult SSc patients registered in Reuma.pt/SSc.Methods:Demographic features, SSc subsets, fulfilment of classification criteria, clinical and immunologic characteristics, comorbidities, medication and deaths were reviewed. Survival was calculated for patients included in the registry within the first 2 years of diagnosis.Results:In total, 1054 patients were included, 87.5% female, mean age at diagnosis 52.7 ± 14.8 years. The most common subset was limited cutaneous (lc)SSc (56.3%), followed by diffuse cutaneous (dc)SSc (17.5%), preclinical SSc (13%), overlap syndrome (9.8%) and SSc sine scleroderma (3.3%). Raynaud’s phenomenon (93.4%) and skin thickening (76.9%) were the most observed manifestations. Gastrointestinal (62.8% vs 47.8%), pulmonary (59.5% vs 23%) and cardiac (12.8% vs 6.9%) involvement were significantly more prevalent in dcSSc compared to lcSSc (Table 1). 52.5% of patients were ACA positive and 21% anti-topoisomerase positive, with significant differences between lcSSc and dcSSc. One third of patients was treated with immunomodulators, 53.6% with vasodilators, 23% received glucocorticoids and 2.3% biologics.During the median follow-up 12.4 years, 83 deaths (7.9%) were verified. The overall 1, 2 and 5 years survival was 98.0%, 96.8% and 92.6% respectively, without significant differences between lcSSc and dcSSc (Figure 1).Conclusion:Reuma.pt/SSc register is useful in routine patient monitoring and contributes to improve knowledge about this rare and complex disease. Clinical features of Portuguese SSc patients are similar to what has been described in other populations although the overall 5-year survival in recently diagnosed patients appears to be higher than previously reported.Table 1.Cumulative clinical and immunologic characteristics of Portuguese SSc patientsClinical and immunologic featuresTotalN=1054Limited cutaneous SScN= 576 (56.3%)Diffuse cutaneous SScN=180 (17.5%)P valueSkin involvement – N(%) N=987688 (90.6)525 (90.7)180 (100)&lt;0.01Skin thickening * – N (%) N= 962680 (76.9)512 (88.9)180 (100)&lt;0.01Digital ulcers – N (%) N=970325(33.5)186 (34.7)4 (51.5)&lt;0.01Raynaud’s Phenomenon – N (%) N=1010943 (93.4)539 (95.7)157 (92.4)0.06Musculoskeletal involvement – N(%) N=972346 (45.6)247 (42.7)99 (55)&lt;0.01Cardiac involvement –N(%) – N=92471 (7.7)36 (6.9)19 (12.8)0.02Renal involvement –N(%) – N= 91717 (1.9)8!1.5)6 (4.1)0.07Gastrointestinal involvement - N(%) N=933508 (48.2)277 (47.8)113 (62.8)&lt;0.01Pulmonary involvement – N(%) N=915261 (28.5)119 (23)88 (59.5)&lt;0.01PAH – N(%) N= 87114 (1.6)10 (2)1 (0.7)0.23Intersticial lung disease – N(%) N=765218 (28.5)100 (22.7)75 (57.7)&lt;0.01Antinuclear antibodies - N(%) N=1040934 (89.8)522 (90.2)154 (88.5)0.57Anti-centromere – N(%) N= 1027540 (52.6)383 (67.1)16 (9.5)&lt;0.01Anti-Scl70 – N(%) N=1020214 (21)12 (3.3)104 (60.1)&lt;0.01Anti-RNA polymerase III – N(%) N=71025 (3.5)12 (3.3)7 (5.6)0.38ComorbiditiesHypertension – N(%) N=431117 (27.1)76 (29.7)67 (20.7)0.1Hyperlipidemia – N(%) N=43171 (13.4)72 (12.2)24 (15.9)0.08Neoplasia – N(%) N=105429 (2.8)12 (2.1)7 (3.9)0.14PDE-5 (phosdiasterase-5); PPIs (proton pump inhibitors); PAH-Pulmonary arterial hypertension confirmed by right heart catheterization. Immunomodulators includes Metothrexate, Leflunomide, Hydroxycloroquine; Azathioprine, Mycophenolate Mofetil and Cyclophosphamide; * Does not include sclerodactyly.Figure 1.Panel A - Survival in years from diagnosis of patients with SSc included in Reuma.pt in the first 2 years of disease (N=472). Panel B - survival according to SSc subset (lcSSc and dcSSC).Disclosure of Interests:None declared

AYURVEDIC MANAGEMENT OF SYSTEMIC SCLEROSIS - A SINGLE CASE STUDY

Systemic sclerosis (SSc) is a multisystem autoimmune disorder caused by unknown factors. Which results in fibrosis of the skin, blood vessels, and visceral organs, including the gastrointestinal tract, lungs, heart, and kidneys. One among subset is referred to as diffuse cutaneous scleroderma and characterized by the rapid development of symmetric skin thickening of proximal and distal extremity, face, and trunk. When it affects on musculoskeletal system, the synovium in patients with arthritis is similar to that seen in early rheumatoid arthritis and shows edema with infiltration of lymphocytes and plasma cells. A 35-year-old house wife with this diagnosis came to OPD, which is managed by the principle of Amavata (diseases of connective tissue in Ayurveda) line of treatment. Vaitarana basti and Valuka sweda has done for 7 days with oral medication Vaishwanara churna ½ teaspoon with first morsal of food for 3 times. The QOL (quality of life) has been improved with in 7 days of treatment.

Scleroderma renal crisis: observations from the South Australian Scleroderma Register.

Scleroderma renal crisis (SRC) is a rare but feared complication with high morbidity and mortality. Its aetiopathogenesis is unclear. To investigate epidemiological, serologic and clinical features of all patients with SRC listed on the population-based South Australian Scleroderma Register and to examine possible factors in aetiopathogenesis. A case note review was performed on all SRC patients with relevant data extracted to determine incidence, clinical phenotype, presence of autoantibodies and survival. Possible precipitating and aetiopathogenic factors were also examined. Data from the South Australian Scleroderma Register and Australia Bureau of Statistics was sourced for comparative purposes. Over the 34-year period (1985-2018), 30 patients (21 females, 9 males) presented with SRC giving a South Australian mean annual incidence of 0.58/million/year (95% CI 0.39-0.89). Twenty-eight of these patients had diffuse cutaneous scleroderma and two with limited cutaneous scleroderma. The mean age at first symptom of scleroderma was 51.2 ± 15.9 (mean ± SD) years with SRC occurring 4.6 years later (median = 3.0 years, range 0.1-20 years). Possible precipitating factors for SRC included high dose steroids in five patients. Twelve patients were anti- RNA polymerase3 (RNAPol3) positive and two were anti-topoisomerase 1 (Topo1) positive. Renal outcome was poor with 13 patients requiring renal replacement therapy and two proceeding to renal transplantation. The mean age at death was 61.2 ± 11.6 years with SRC patient survival being significantly shorter than patients with diffuse scleroderma without renal involvement (P = 0.002). There was no significant difference in survival between the 1985-2002 and the 2003-2018 SRC cohorts (P = 0.2). Nailfold capillaroscopy performed in 10 patients revealed extensive microvascular damage with prominent capillary drop out. SRC is a rare occurrence with an incidence of 0.58/million/year in South Australia. This frequency has not changed over time. It continues to have a severe adverse outcome with frequent requirement for renal replacement therapy and poor survival. Nailfold capillaroscopy revealed evidence of extensive capillary damage. No improvement in survival was observed over the 34-year study period.

Diffuse Cutaneous Systemic Scleroderma with Secondary Infection: A Case Report

Diffuse Cutaneous Systemic Scleroderma with Secondary Infection: A Case Report

Genetic Susceptibility to Systemic Sclerosis in the Greek-Cypriot Population: A Pilot Study.

Background: Systemic Sclerosis (SSc), also known as scleroderma, is an autoimmune rheumatic disease, which is clinically subdivided into two major subgroups; limited (lcSSc) and diffuse cutaneous scleroderma (dcSSc). Even though the SSc etiologies remains unclear, some HLA and non-HLA genetic variants have been associated with the disease.Aim: This study was designed to evaluate the associations between several HLA-related genetic variants and SSc in the Greek-Cypriot population.Methods: Forty-one SSc patients and 164 controls were genotyped at 18 selected single nucleotide polymorphisms (SNPs) using restriction fragment length polymorphism analyses, Sanger sequencing, and a multiplex SNaPshot minisequencing assay. Logistic regression analysis under the log-additive model was used to evaluate all possible associations between these SNPs and SSc; nominal statistical significance was assumed at p < 0.05.Results: Associations of SSc with SNPs rs3117230, rs3128930, and rs3128965 within the HLA-DPB1 and HLA-DPB2 regions were observed in the Greek-Cypriot population at the level of p < 0.05. However, none of these associations survived a Bonferroni correction. The direction of the effect is consistent with the direction reported in previous studies. In addition, allele frequencies of the majority of the selected SNPs in the Greek-Cypriot population are similar to those reported in the European population.Conclusion: This study initiates the genetic investigation of SSc in the Greek-Cypriot population, a relatively small newly investigated population. Further investigation with a larger sample size and/or additional SSc susceptibility loci may confirm the association of some of these variants with SSc in the Greek-Cypriot population that could potentially be used for predictive testing.

Clinical and serological profile of systemic sclerosis in Tunisia: A retrospective observational study

The Prevalence of systemic sclerosis (SSc) and different clinical subsets varies across the world. Few data have been published on SSc patients in North Africa. Our objective was to describe a SSc cohort in south of Tunisia and to compare clinical findings, disease subsets and antibodies with other international SSc populations. In this retrospective observational study, Folders of patients with SSc seen in the internal medicine section of the Hedi Chaker Hospital between 2000 and 2013 were retrospectively analyzed. The diagnosis of SSc was retained according to ACR/EULAR 2013 criteria. Patients were classified into diffuse cutaneous SSc and limited cutaneous SSc subsets. Comparison with other cohorts was made based on published information. A higher female: male ratio (8:1) and a higher diffuse subset prevalence (82%) was found in this Tunisian cohort comparing with others. We also found a lower prevalence of calcinosis and anticentromere antibodies. Within each subset, diffuse cutaneous and limited cutaneous scleroderma clinical findings were similar with other systemic sclerosis populations except for a very low prevalence in renal crisis and pulmonary hypertension. Our results indicate overlap syndrome defined as scleroderma associated with others connective tissue disorder's is a relatively common condition. With slight variations, perhaps due to genetic, environmental or referral factors, SSc in this cohort appears to be similar to that described in other part of the world.

Severe Pericardial Effusion Heralding Scleroderma Renal Crisis: A Case Report and the Literature Review

Introduction: Both scleroderma renal crisis and severe pericardial effusion are rare and life-threatening complications of systemic sclerosis. This article describes a case of scleroderma renal crisis heralded by severe pericardial effusion. Case Presentation: The patient was a 39-year-old woman with a history of 8 years diffuse cutaneous scleroderma and extensive skin involvement who referred to Imam Khomeini Hospital Complex, Tehran, Iran, with worsening dyspnea and pleuritic chest pain. Echocardiography revealed severe pericardial effusion, which was drained by the pericardial window. Thereafter, the patient became gradually anuric and her blood pressure was uncontrolled despite maximum doses of antihypertensive agents, including captopril. The serum creatinine level was increased progressively; thus, hemodialysis started. Concomitantly, microangiopathic hemolytic anemia complicated the course of the disease, which responded to plasma exchange. Kidney biopsy revealed pieces of evidence indicating thrombotic microangiopathy. Conclusions: This case report denotes to a probable association between scleroderma the renal crisis and severe pericardial effusion. Therefore, physicians should be vigilant about the renal crisis in patients with systemic sclerosis and pericardial effusion.

Interactions of HLA-DR and Topoisomerase I Epitope Modulated Genetic Risk for Systemic Sclerosis

The association of systemic sclerosis with anti-Topoisomerase 1 antibody (ATASSc) with specific alleles of human leukocyte antigen (HLA)-DR has been observed among various ethnics. The anti-Topoisomerase 1 antibody is a common autoantibody in SSc with diffuse cutaneous scleroderma, which is one of the clinical subtypes of SSc. On the other hand, an immunodominant peptide of topoisomerase 1 (Top1) self-protein (residues 349–368) was reported to have strong association with ATASSc. In this study, molecular dynamics simulation was performed on the complexes of Top1 peptide with various HLA-DR subtypes divided into ATASSc-associated alleles (HLA-DRB1*08:02, HLA-DRB1*11:01 and HLA-DRB1*11:04), suspected allele (HLA-DRB5*01:02), and non-associated allele (HLA-DRB1*01:01). The unique interaction for each system was compared to the others in terms of dynamical behaviors, binding free energies and solvation effects. Our results showed that three HLA-DR/Top1 complexes of ATASSc association mostly exhibited high protein stability and increased binding efficiency without solvent interruption, in contrast to non-association. The suspected case (HLA-DRB5*01:02) binds Top1 as strongly as the ATASSc association case, which implied a highly possible risk for ATASSc development. This finding might support ATASSc development mechanism leading to a guideline for the treatment and avoidance of pathogens like Top1 self-peptide risk for ATASSc.

Mesenchymal Stromal Cells Based Therapy in Systemic Sclerosis: Rational and Challenges.

Systemic Sclerosis (SSc) is a rare chronic disease, related to autoimmune connective tissue diseases such as Systemic Lupus Erythematosus and Sjögren's Syndrome. Although its clinical heterogeneity, main features of the disease are: extensive tissue fibrosis with increase matrix deposition in skin and internal organ, microvascular alterations and activation of the immune system with autoantibodies against various cellular antigens. In the diffuse cutaneous scleroderma subtype, the disease is rapidly progressive with a poor prognosis, leading to failure of almost any internal organ, especially lung which is the leading cause of death. Primary trigger is unknown but may involve an immune process against mesenchymal cells in a genetically receptive host. Pathophysiology reveals a pivotal role of fibrosis and inflammation alterations implicating different cell subtypes, cytokines and growth factors, autoantibodies and reactive oxygen species. Despite improvement, the overall survival of SSc patients is still lower than that of other inflammatory diseases. Recommended drugs are agents capable of modulating fibrotic and inflammatory pathways. Cellular therapy has recently emerged as a credible option. Besides autologous hematopoietic stem cell transplantation which demonstrated remarkable improvement, mesenchymal stromal cells (MSCs) represent promising therapeutic candidates. Indeed, these cells possess anti-inflammatory, antiproliferative, antifibrotic, and immunomodulary properties especially by secreting a large panel of bioactive molecules, addressing the most important key points of the SSc. In addition, these cells are very sensitive to their environment and are able to modulate their activity according to the pathophysiological context in which they are located. Autologous or allogeneic MSCs from various sources have been tested in many trials in different auto-immune diseases such as multiple sclerosis, Crohn's disease or systemic lupus erythematosus. They are characterized by a broad availability and no or low acute toxicity. However, few randomized prospective clinical trials were published and their production under ATMP regulatory procedures is complex and time-consuming. Many aspects have still to be addressed to ascertain their potential as well as the potential of their derived products in the management of SSc, probably in association with other therapies.

Scleroderma and Related Disorders

Scleroderma spectrum diseases are a heterogeneous group of disorders that are distinguished by abnormalities of the connective tissue in the skin and, in some cases, other organs. Each disorder may be characterized by the extent of cutaneous and internal involvement, as well as histopathologic features of skin biopsy. Scleroderma spectrum diseases include systemic scleroderma, localized scleroderma, and eosinophilic fasciitis. This chapter reviews the classification, epidemiology, etiology, pathophysiology and pathogenesis, diagnosis, differential diagnosis, treatment, outcome measures, management, and clinical course of scleroderma as well as the definition and classification, etiology/genetics, differential diagnosis, and treatment of localized scleroderma. Also discussed are the definition and classification, epidemiology, etiology/genetics/pathogenesis, diagnosis, differential diagnosis, and treatment of eosinophilic fasciitis. Tables review the classification of—and antinuclear antibodies in—scleroderma as well as the key assessments and interventions in scleroderma management. Figures illustrate the disease's presentation and clinical manifestations, including several images of scleroderma of the hands; face, palmar, and buccal telangiectasias in a patient with scleroderma; a radiograph demonstrating calcinosis of the elbow; Raynaud’s phenomenon; high-resolution computed tomographic images of diffuse cutaneous scleroderma, scleroderma and severe pulmonary hypertension, and limited cutaneous scleroderma; plus an esophagram demonstrating hypomotility. This review contains 11 highly rendered figures, 3 tables, and 72 references.

Relationship Between Ventricular Arrhythmias, Conduction Disorders, and Myocardial Fibrosis in Patients With Systemic Sclerosis.

Delayed-enhancement magnetic resonance imaging (DE-MRI) is a noninvasive diagnostic tool able to identify myocardial fibrosis. In patients with scleroderma, its relationship with arrhythmias and conduction disorders has not been fully explored. The aim of this study was to evaluate the possible correlations between ventricular arrhythmias, conduction disorders, and myocardial fibrosis in patients with systemic sclerosis. Thirty-six patients with diffuse or limited cutaneous scleroderma underwent 12-lead electrocardiogram (ECG), 24-hour Holter ECG monitoring, transthoracic echocardiography, and cardiac DE-MRI, with gadolinium administration in 33 patients. High-quality DE-MRI scans were obtained in 30 patients. Myocardial fibrosis was detected in 25 patients (83.3%). Eighteen patients (60%) had ventricular arrhythmias or conduction disorders. There was no significant difference in ventricular arrhythmia burden (the total number of premature ventricular contractions [PVCs]/24 hours) (48 ± 304 vs. 69 ± 236, P = 0.97), ventricular arrhythmia severity (couplets, triplets, runs) on Holter ECG, or in the presence of conduction disorders (36% vs. 40%, P = 0.86) between patients with and without myocardial fibrosis. In univariate analysis, diffuse fibrosis was weakly associated with the number of PVCs/24 hours (R = 0.157, P = 0.03). A number of at least 597 PVCs/24 hours had a sensitivity of 60% and a specificity of 92% in predicting the presence of diffuse fibrosis on DE-MRI (area under the curve = 0.640). Delayed-enhancement magnetic resonance imaging can identify myocardial fibrosis in a high percentage of scleroderma patients. Its presence does not seem to influence the ventricular arrhythmia burden and severity or the presence of conduction disorders, with the exception of diffuse myocardial fibrosis, which modestly influences the total number of PVCs/24 hours.

Juvenile Systemic Sclerosis: Review of 17 Portuguese Patients

Introduction Juvenile systemic sclerosis (jSSc) represents about 10% of all systemic sclerosis patients. We aim to describe the clinical characteristics and disease progression of children with jSSc followed in Portuguese pediatric rheumatology centers. Methods Clinical and laboratory features as well as medication and outcomes of jSSc children were reviewed. Results Seventeen patients were included in the analysis, 5 of whom had overlap syndromes. Thirteen girls, with a mean age at diagnosis of 10.6 ± 3.9 years and mean disease duration of 10.5 ± 3.9 years, of these 12 had diffuse cutaneous scleroderma. In 94% cases, the first symptom was Raynaud's phenomenon (RP), followed by arthritis and/or puffy hands (59%). Pulmonary involvement was documented in 7 patients at disease diagnosis, despite the paucity of respiratory complaints. Thirteen patients presented periungual capillaropathy. During follow-up, RP and skin thickening were the most frequent clinical manifestations (100%), followed by arthralgia (94%) and arthritis (76%). Pulmonary, as well as gastrointestinal involvement was documented in eight patients. Sixteen children were antinuclear (ANA) positive, eight tested positive for anti-Scl70, and one for anti-fibrillarin antibodies. Immunosuppressants (94%), proton pump inhibitors (76%) and glucocorticoids (65%) were the most common therapeutic options. One child needed autologous bone marrow transplant due to severe refractory disease. An improvement of skin thickening and stabilization of pulmonary involvement was documented in most cases. No deaths were registered in this cohort. Conclusions Raynaud's phenomenon as well as capillaroscopic abnormalities were almost universal at disease presentation. Internal organ involvement was common and occurred early during disease course, although asymptomatic in several cases.