The presence of abnormal septal motion on echocardiography is a predictor of abnormal cardiac magnetic resonance in systemic sclerosis.

OBJECTIVES: We aimed to perform a comprehensive analysis of the ECG, two-dimensional echocardiography (2DE) and cardiac MRI (CMR) findings in patients with systemic sclerosis (SSc), and also to investigate correlations between CMR findings and some ECG and echocardiography (ECHO) results. METHODS: We retrospectively analysed data from patients with SSc who were regularly seen at our outpatient referral centre, all assessed with ECG, Doppler ECHO and CMR. RESULTS: Ninety-three patients were included; mean (s.d.) age of 48.5 (10.3) years, 86% female, 52% diffuse SSc. Eighty-four (90%) of the patients had sinus rhythm. The most common ECG finding was the left anterior fascicular block, recorded in 26 patients (28%). The abnormal septal motion (ASM) was found in 43 (46%) patients on ECHO. Myocardial involvement (inflammation or fibrosis), as assessed by multiparametric CMR, was present in >50% of our patients. The age- and sex-adjusted model showed that ASM on ECHO increased significantly the odds of increased extracellular volume [odds ratio (OR) 4.43, 95% CI 1.73, 11.38], increased T1 Relaxation time (OR 2.67, 95% CI 1.09, 6.54), increased T2 Relaxation time (OR 2.56, 95% CI 1.05, 6.22), increased signal intensity ratio in T2-weighted imaging (OR 2.56, 95% CI 1.05, 6.22), presence of late gadolinium enhancement (OR 3.85, 95% CI 1.52, 9.76) and mid-wall fibrosis (OR 3.64, 95% CI 1.48, 8.96). CONCLUSION: This study indicates that the presence of ASM on ECHO is a predictor of abnormal CMR in SSc patients, and a precise assessment of ASM may serve as an important point for selecting the patients that should be evaluated by CMR for early detection of myocardial involvement.

Translation and validation of the Persian version of the scleroderma health assessment questionnaire (SHAQ).

The present study aimed to translate and validate the Scleroderma Health Assessment Questionnaire (SHAQ) for Persian-speaking patients (SHAQ-P), using a cross-sectional study. This cross-sectional study included SSc patients with 2013 ACR/EULAR criteria. The SHAQ was translated using a "forward-backward" method. HAQ-DI and SSc-HAQ scores were calculated from the patient-answered questionnaires. Rheumatology experts assessed the face and content validities of the SHAQ-P. Psychometric properties of the SHAQ-P were then assessed: Structural validity was analyzed using principal component factor analysis. Discriminant and convergent validities were measured on subgroups of the initial patient population. Test-retest reliability was measured on patients who filled the SHAQ-P again after 1 month. The Scale-CVI-average (S-CVI/Ave) score for content validity was 88.7%. Face validity was measured to be 68.17% using the QQ10 questionnaire. Factor analysis revealed a two-factor structure with 20 out of 26 questions loading on the first factor (N = 285). One-way ANOVA showed that patients with a higher number of involved organs had higher average HAQ-DI and SSc-HAQ-scores (N = 60, P = 0.019 and 0.023, respectively). HAQ-DI and SSc-HAQ-scores were significantly correlated with the physical component score of SF36 (N = 31, correlation coefficient = - 0.65 and - 0.72, respectively). Reliability testing after one month demonstrated that HAQ-DI and SSc-HAQ-scores were significantly correlated with their initial (N = 40, correlation coefficient = 0.86 and 0.84, respectively), proving that the Persian SHAQ was a valid and reliable questionnaire to evaluate scleroderma patients' quality of life.

Efficacy and safety of the biosimilar denosumab candidate (Arylia) compared to the reference product (Prolia®) in postmenopausal osteoporosis: a phase III, randomized, two-armed, double-blind, parallel, active-controlled, and noninferiority clinical trial.

BACKGROUND/OBJECTIVE: Osteoporosis is a global health concern with an increasing prevalence worldwide. Denosumab is an antiresoptive agent that has been demonstrated to be effective and safe in osteoporotic patients. This study aimed to compare the efficacy and safety of the biosimilar denosumab candidate (Arylia) to the originator product (Prolia®) in postmenopausal osteoporotic patients. METHODS: In this randomized, double-blind, active-controlled, noninferiority trial, postmenopausal osteoporotic patients received 60 mg of subcutaneous Arylia or Prolia® at months 0, 6, and 12 and were followed up for 18 months. The primary endpoint was the noninferiority of the biosimilar product to the reference product in the percentage change of bone mineral density (BMD) in 18 months at the lumbar spine (L1-L4), total hip, and femoral neck. The secondary endpoints were safety assessment, the incidence of new vertebral fractures, and the trend of bone turnover markers (BTMs). RESULTS: A total of 190 patients were randomized to receive either biosimilar (n = 95) or reference (n = 95) denosumab. In the per-protocol (PP) analysis, the lower limits of the 95% two-sided confidence intervals of the difference between Arylia and Prolia® in increasing BMD were greater than the predetermined noninferiority margin of - 1.78 at the lumbar spine, total hip, and femoral neck sites (mean differences [95% CIs] of 0.39 [- 1.34 to 2.11], 0.04 [- 1.61 to 1.69], and 0.41 [- 1.58 to 2.40], respectively). The two products were also comparable in terms of safety, new vertebral fractures, and trend of BTMs. CONCLUSION: The efficacy of the biosimilar denosumab was shown to be noninferior to that of the reference denosumab, with a comparable safety profile at 18 months. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03293108 ; Registration date: 2017-09-19.

A Phase IV Study of the Safety and Efficacy of CinnoPar® in Iranian Patients with Osteoporosis.

The safety of teriparatide has been studied in various phase III and phase IV trials. However, a postmarketing study of the biosimilar of teriparatide, CinnoPar®, has not been conducted on Iranian patients. This was a phase IV study conducted on osteoporotic patients who received an Iranian teriparatide biosimilar with a dose of 20 µg daily. The primary outcome of this study was to monitor for adverse events (AEs). Effectiveness as the secondary outcome was measured using the EQ-5D quality-of-life questionnaire and back pain Visual Analogue Scale (VAS) score. Among 193 analyzed patients between September 2015 and March 2019, the most common AEs were hypercalcemia (4%), nausea, and pain (3%). No deaths, serious AEs, or other significant AEs occurred in this study. The mean EQ-5D scores decreased after the course of the treatment from 2.3 ± 0.66 at the baseline to 2 ± 0.66. The mean back pain VAS scores also decreased from 4.9 ± 3.6 at baseline to 1.8 ± 2.1 at the end of the study. Both changes were statistically significant (p < 0.001). Consistent with the findings of previous studies and the drug monograph, no new safety concern was observed with this biosimilar teriparatide, and the drug was effective based on the VAS score and EQ-5D in osteoporotic patients.

Assessment of Treatment Safety and Quality of Life in Patients Receiving Etanercept Biosimilar for Autoimmune Arthritis (ASQA): A Multicenter Post-marketing Surveillance Study.

INTRODUCTION: Phase IV post-marketing surveillance studies are needed to evaluate the real-world safety and effectiveness of drug products. This study aimed to evaluate the safety and effectiveness of biosimilar etanercept (Altebrel, AryoGen Co., Iran) in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA). METHODS: In this open-label, multicenter, prospective, observational, post-marketing surveillance study, 583 patients received biosimilar etanercept 25 mg twice weekly or 50 mg once weekly and were followed up to 12 months. The primary objective was to evaluate the safety of biosimilar etanercept by documenting all the adverse events in the case report forms throughout the study period. The secondary objective was to evaluate the effectiveness of biosimilar etanercept in study patients, where longitudinal changes in health assessment questionnaire (HAQ), pain, and disease activity scores were assessed. RESULTS: A total of 583 patients (44.80 ± 13.09 years of age) were included and followed for an average of 8.12 ± 3.96 months. Among all patients, 172 (29.50%) experienced at least one adverse event, and injection site reaction, abdominal pain, and upper respiratory tract infection were the most common. HAQ scores decreased from 1.32 ± 0.77 at baseline to 0.81 ± 0.61 at 12 months in patients with RA/PsA (p < 0.01) and from 0.82 ± 0.58 at baseline to 0.66 ± 0.63 at 12 months in patients with AS (p = 0.18). Pain scores decreased from 6.49 ± 2.41 at baseline to 3.51 ± 2.39 at 12 months (p < 0.01). CONCLUSION: The results demonstrated the real-world safety and effectiveness of biosimilar etanercept in patients with RA, PsA, and AS. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04582084.

Evaluation of the association between KIR polymorphisms and systemic sclerosis: a meta-analysis.

BACKGROUND: The results of investigations on the association between killer cell immunoglobulin-like receptor (KIR) gene polymorphisms and the risk of systemic sclerosis (SSc) are inconsistent. To comprehensively evaluate the influence of KIR polymorphisms on the risk of SSc, this meta-analysis was performed. METHODS: A systematic literature search was performed in electronic databases including Scopus and PubMed/MEDLINE to find all available studies involving KIR gene family polymorphisms and SSc risk prior to July 2019. Pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were measured to detect associations between KIR gene family polymorphisms and SSc risk. RESULTS: Five articles, comprising 571 patients and 796 healthy participants, evaluating the KIR gene family polymorphisms were included in the final meta-analysis according to the inclusion and exclusion criteria, and 16 KIR genes were assessed. None of the KIR genes were significantly associated with the risk of SSc. CONCLUSIONS: The current meta-analysis provides evidence that KIR genes might not be potential risk factors for SSc risk.

Cervical cancer screening and Pap test non-adherence risk factors in systemic sclerosis patients.

Systemic sclerosis is a rare autoimmune disorder that potentially affects nearly every organ of the body. Malignancies are one of the most common non-systemic sclerosis related cause of mortality. There are controversial findings regarding the cervical cancer rate among these patients, but prolonged immunosuppressive medication makes them more susceptible to cervical cancer. In the present study, we have aimed to investigate the cervical cancer screening result and the Pap test non-adherence risk factors among systemic sclerosis patients. This cross-sectional study was conducted on 100 systemic sclerosis patients. The clinicodemographic variables in addition to cervical cancer risk factors were obtained from the patients. Pap test performed using the liquid-based method. The non-adherence risk factors were determined by univariate and multivariate logistic regression analysis. Benign inflammatory and atrophic changes were reported in 26 and 5%, respectively. None of the cases had abnormal cytological finding. Twenty-two percent of the participants were a routine Pap test performer. According to the multivariate model, higher age was associated with Pap test non-adherence [odds ratio (95% confidence interval): 1.058 (1.010-1.108) and P-value: 0.018]. In the present study, we have shown that compliance with Pap test performing is extremely low among Iranian systemic sclerosis patients. In addition, we have demonstrated that older age is a risk factor for non-adherence. These findings highlighted the crucial role of the physicians in motivating the patients toward cancer screening.

microRNAs are potentially regulating the survivin gene in PBMCs from systemic sclerosis patients.

Background: Survivin is an important anti-apoptotic protein and is involved in increasing auto-reactivity during the autoimmune diseases like systemic sclerosis (SSc).Aims: In the current study, we investigate the expression level of total survivin (survivin-TS) and its three important variants alongside with evaluation of the expression level of important microRNAs (miRNAs) that are involved in survivin expression regulation.Methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 50 healthy controls, 25 diffuse cutaneous SSc (DcSSc), and 25 limited cutaneous SSc (LcSSc) patients. RNA was extracted and single-strand cDNA was synthesized. Quantitative real-time PCR was used to evaluate the expression level of survivin-TS and its variants as well the miRNAs.Results: Overexpression of survivin-2B and downregulation of survivin wild-type (survivin-WT) were found in total-SSc patients; however, expression level of survivin-TS had no significant difference. The expression levels of miR-335-5p, miR-485-5p, miR-16-5p, miR-150-5p, miR-34a-5p, miR-218-5p and miR-708-5p were higher in total-SSc patients. Significantly negative correlations were found between transcript levels of miR-150-5p, miR-16-5p, and miR-485-5p with survivin-TS mRNA expression.Conclusion: Survivin variants had altered expression in total-SSc patients. In addition, miRNAs might potentially and negatively regulate the survivin-TS expression. Altered expression of survivin, regulated by miRNAs, may result in apoptosis resistance and auto-reactivity in lymphocytes from patients and have important roles in SSc pathogenicity.

Evaluation of the association between KIR polymorphisms and systemic sclerosis: a meta-analysis

Abstract Background: The results of investigations on the association between killer cell immunoglobulin-like receptor (KIR) gene polymorphisms and the risk of systemic sclerosis (SSc) are inconsistent. To comprehensively evaluate the influence of KIR polymorphisms on the risk of SSc, this meta-analysis was performed. Methods: A systematic literature search was performed in electronic databases including Scopus and PubMed/ MEDLINE to find all available studies involving KIR gene family polymorphisms and SSc risk prior to July 2019. Pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were measured to detect associations between KIR gene family polymorphisms and SSc risk. Results: Five articles, comprising 571 patients and 796 healthy participants, evaluating the KIR gene family polymorphisms were included in the final meta-analysis according to the inclusion and exclusion criteria, and 16 KIR genes were assessed. None of the KIR genes were significantly associated with the risk of SSc. Conclusions: The current meta-analysis provides evidence that KIR genes might not be potential risk factors for SSc risk.(AU)

Analysis of gene expression profiles and protein-protein interaction networks in multiple tissues of systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc), a multi-organ disorder, is characterized by vascular abnormalities, dysregulation of the immune system, and fibrosis. The mechanisms underlying tissue pathology in SSc have not been entirely understood. This study intended to investigate the common and tissue-specific pathways involved in different tissues of SSc patients. METHODS: An integrative gene expression analysis of ten independent microarray datasets of three tissues was conducted to identify differentially expressed genes (DEGs). DEGs were mapped to the search tool for retrieval of interacting genes (STRING) to acquire protein-protein interaction (PPI) networks. Then, functional clusters in PPI networks were determined. Enrichr, a gene list enrichment analysis tool, was utilized for the functional enrichment of clusters. RESULTS: A total of 12, 2, and 4 functional clusters from 619, 52, and 119 DEGs were determined in the lung, peripheral blood mononuclear cell (PBMC), and skin tissues, respectively. Analysis revealed that the tumor necrosis factor (TNF) signaling pathway was enriched significantly in the three investigated tissues as a common pathway. In addition, clusters associated with inflammation and immunity were common in the three investigated tissues. However, clusters related to the fibrosis process were common in lung and skin tissues. CONCLUSIONS: Analysis indicated that there were common pathological clusters that contributed to the pathogenesis of SSc in different tissues. Moreover, it seems that the common pathways in distinct tissues stem from a diverse set of genes.

Bundle Branch Blocks and Fragmented QRS Complex in Iranian Patients with Systemic Sclerosis.

Background: Cardiac involvement, as one of the life-threatening manifestations of systemic sclerosis (SSc), is chiefly caused by collagen fiber deposition in the myocardium, which subsequently leads to conduction abnormalities. In the present study, we aimed to investigate the prevalence and clinical significance of bundle branch blocks (BBBs) and the fragmented QRS complex (fQRS) in Iranian patients with SSc. Methods: Forty-one patients with SSc were enrolled from the outpatient SSc clinic of Shariati Hospital, Tehran University of Medical Sciences, between October 2016 and February 2017. Twelve-lead ECG was obtained and interpreted for BBBs and the fQRS. To adjust for the confounding effects of non-SSc-related cardiovascular risk factors, we calculated the Framingham risk score to estimate the risk of cardiovascular diseases. The associations between the studied conduction abnormalities and SSc cutaneous subtypes; disease duration; and the Medsger SSc severity scale of cutaneous, pulmonary, and vascular involvements were also analyzed. Results: The study population consisted of 41 Iranian patients with SSc at a mean age of 47.48±11.57 years (82.9% female). The prevalence of BBBs and the fQRS was 26.8% and 36.6%, respectively. The fQRS was associated with the limited cutaneous SSc subtype (OR: 0.100, 95%CI: 0.018-0.553, and P=0.028). BBBs and the fQRS were not associated with either the Framingham risk score or the rest of the clinicodemographic variables. Conclusion: BBBs and the fQRS were more prevalent in our patients with SSc, without any association with the involvement of the other organs. These findings may suggest the independent pathophysiology of cardiac involvement in SSc.

MicroRNA-21 and microRNA-29a modulate the expression of collagen in dermal fibroblasts of patients with systemic sclerosis.

MicroRNAs (miRNAs) are well-known candidates for modulating the dysregulated signaling pathways during fibrosis. In this study, we investigated the expression pattern of 16 miRNAs, which have previously been confirmed or predicted to target genes involved in extracellular matrix (ECM) homeostasis. Primary culture of dermal fibroblasts was obtained from skin biopsies of diffused cutaneous SSc (dcSSc) patients and healthy controls. Expression of let-7a, miR-1, miR-15a, miR-17, miR-19a, miR-20a, miR-21, miR-27b, miR-26a, miR-29a, miR-29b, miR29c, miR-141, miR-125a-5p, miR-193a-3p, and miR-200a were quantified by Real-time PCR. Functional analysis of microRNAs was performed using synthetic oligonucleotides. To further confirm the pro- or anti-fibrotic effects of miRNAs, normal fibroblasts were treated with 10 ng/mL of transforming growth factor (TGF)-ß to generate an in vitro model of dermal fibrosis. miR-21 and miR-29a were upregulated and downregulated, respectively, in both dcSSc and TGF-ß-treated fibroblasts. We observed that restoration of miR-29a expression or blockade of miR-21 function negatively affected collagen production. COL1A1 expression in SSc fibroblasts is more sensitive to changes of miR-29a and miR-21 expression in compare to normal fibroblasts. miR-29a alone was effective to decrease TGF-ß-induced collagen production in dermal fibroblasts. miR-21 and TGF-ß had synergistic effects on induction of collagen production. However, neither miR-21 nor miR-29a affected alpha smooth muscle actin (α-SMA) expression in the presence or absence of TGF-ß in dermal fibroblasts. miR-21 and miR-29a as pro- and anti-fibrotic miRNAs modulate collagen production in an opposing manner. Focusing on miR-21 and miR-29s as therapeutic targets would be effective in patients with SSc or other fibrotic diseases which show aberrant expression of collagen expression.

Downregulation of miR-542-3p Contributes to Apoptosis Resistance in Dermal Fibroblasts from Systemic Sclerosis Patients via Survivin Overexpression.

Systemic sclerosis (SSc) is characterized by excessive production of collagens by fibroblasts that leads to vast fibrosis. Resistance to apoptosis is one of the possible underlying mechanisms of fibrosis in these patients. Survivinis involved in inhibition of apoptosis and aberrantly functions in SSc. Since dysregulation of survivin-targeting microRNAs (miRNAs) has frequently been observed in cancer and some autoimmune disorders, this study aimed to investigate their expression status in dermal fibroblasts from SSc patients. DiffuseSSc patients were selected according to American College of Rheumatology criteria. Isolated fibroblasts from 10 SSc and 10 healthy skin biopsies were cultured. After examining purity of the cells, mRNA and miRNAs extraction was performed followed by complementary DNA (cDNA) synthesis. Relative expressions ofsurvivin mRNA, miR-16-5p, miR-320a, miR-218-5p, miR-708-5p and miR-542-3p were analyzed using real time PCR. Survivin mRNA expression was significantly 1.85-fold upregulated in fibroblasts from SSc patients compared with healthy controls (p=0.046). Among the studied miRNAs, miR-542-3p expression was significantly decreased (p=0.033), while enhanced expression of miR-708-5p was observed in SSc fibroblasts (p=0.05) in comparison to healthy subjects. Downregulation of miR-542-3p significantly correlated with survivin overexpression (r=-0.45, p=0.049). Downregulation of miR-542-3p that is correlated with higher surviving expression levels might be a possible cause of apoptosis resistance in SSc fibroblasts, hence providing a new understanding of the disease pathogenesis.

Overexpression of apoptosis-related protein, survivin, in fibroblasts from patients with systemic sclerosis.

BACKGROUND/OBJECTIVES: Recent studies suggest that, in addition to activation and hypersecretion of matrix components, fibroblasts from patients with systemic sclerosis (SSc) are resistant to apoptosis. Previous studies have shown that survivin, a member of inhibition of apoptosis (IAP) family, plays an important role in apoptosis resistance. Accordingly, we decided to study the expression of the most important members of IAP family in SSc fibroblasts, which can block apoptosis either by binding and inhibiting caspases or through caspase-independent mechanisms. METHOD: Skin biopsy samples were obtained from 19 patients with diffuse cutaneous SSc (DcSSc) and 16 healthy controls. Dermal fibroblasts were cultured and the total RNA was isolated from cells followed by cDNA synthesis. Real-time PCR was performed using SYBR Green PCR master mix and specific primers for cIAP1, cIAP2, XIAP, and Survivin mRNA quantification. RESULTS: A significantly increased expression level of Survivin was observed in fibroblasts from SSc patients compared to controls (2.26-fold, P = 0.04). However, mRNA expression of cIAP1, cIAP2, and XIAP did not change significantly between cases and controls. CONCLUSIONS: Our results showed that survivin is upregulated in SSc skin fibroblast which may lead to resistance to apoptosis. Further studies should be performed to reveal the role of survivin in apoptosis pathway of SSc fibroblasts.

Attenuation of aquaporin-3 and epidermal growth factor receptor expression and activation in systemic sclerosis dermal fibroblasts.

OBJECTIVES: Impaired wound healing and skin dehydration are the mainstay of systemic sclerosis (SSc) cutaneous manifestations. Aquaporin-3 (AQP3) has a pivotal role in skin hydration and wound healing. Epidermal growth factor receptor (EGFR) activation is impaired in SSc fibroblasts. It is unclear whether AQP3 downregulation or epidermal growth factor (EGF) signaling are the primary points of dysregulation in SSc patients. METHODS: Skin punch biopsies were obtained from 10 SSc patients and 10 healthy subjects. The mRNA and/or protein expression levels of AQP3, EGFR/p-EGFR, matrix metalloproteinase-1/2/9 (MMP-1/2/9), and tissue inhibitors of metalloproteinase-1 (TIMP1) at baseline and after EGF and transforming growth factor-ß1 (TGF-ß1) treatment was evaluated in extracted fibroblasts using real-time polymerase chain reaction and western blot analysis. RESULTS: SSc fibroblasts expressed lower AQP3 and EGFR, compared with normal fibroblasts. Normal fibroblasts increased AQP3 expression in response to EGF whereas AQP3 expression had no change in EGF-treated-SSc fibroblasts. Likewise, EGFR was activated in response to EGF in the normal group but not SSc group. Baseline expression of MMP-1/2/9 and TIMP1 was not different between SSc and controls. EGF treatment did not result in alteration of any MMPs expression in either of the groups. Combination treatment resulted in a significant upregulation of MMP-1 in normal fibroblasts compared with SSc fibroblasts, while in SSc fibroblasts MMP-9 expression was upregulated in response to treatment with TGF-ß1 only. CONCLUSION: Downregulation of AQP3 expression in SSc fibroblasts may be related to reduced EGFR expression and activation. TGF-ß1 (alone or in combination with EGF) only can upregulate AQP3 expression in SSc fibroblasts so, TGF-ß1 affect MMP-1 and MMP-9 just in SSc fibroblasts.

Analysis of the genetic component of systemic sclerosis in Iranian and Turkish populations through a genome-wide association study.

Objectives: SSc is an autoimmune disease characterized by alteration of the immune response, vasculopathy and fibrosis. Most genetic studies on SSc have been performed in European-ancestry populations. The aim of this study was to analyse the genetic component of SSc in Middle Eastern patients from Iran and Turkey through a genome-wide association study. Methods: This study analysed data from a total of 834 patients diagnosed with SSc and 1455 healthy controls from Iran and Turkey. DNA was genotyped using high-throughput genotyping platforms. The data generated were imputed using the Michigan Imputation Server, and the Haplotype Reference Consortium as a reference panel. A meta-analysis combining both case-control sets was conducted by the inverse variance method. Results: The highest peak of association belonged to the HLA region in both the Iranian and Turkish populations. Strong and independent associations between the classical alleles HLA-DRB1*11: 04 [P = 2.10 × 10-24, odds ratio (OR) = 3.14] and DPB1*13: 01 (P = 5.37 × 10-14, OR = 5.75) and SSc were observed in the Iranian population. HLA-DRB1*11: 04 (P = 4.90 × 10-11, OR = 2.93) was the only independent signal associated in the Turkish cohort. An omnibus test yielded HLA-DRB1 58 and HLA-DPB1 76 as relevant amino acid positions for this disease. Concerning the meta-analysis, we also identified two associations close to the genome-wide significance level outside the HLA region, corresponding to IRF5-TNPO3 rs17424921-C (P = 1.34 × 10-7, OR = 1.68) and NFKB1 rs4648133-C (P = 3.11 × 10-7, OR = 1.47). Conclusion: We identified significant associations in the HLA region and suggestive associations in IRF5-TNPO3 and NFKB1 loci in Iranian and Turkish patients affected by SSc through a genome-wide association study and an extensive HLA analysis.

Comparison of the clinical phenotype of systemic sclerosis patients in Iran and France in two university centers.

Objectives: Systemic sclerosis is a severe and rare chronic auto-immune multisystem disorder characterized by vasculopathy and skin stiffness. Ethnic and geographical origin can influence the outcomes. In this study, we compared the phenotypic characteristics of Iranian and French patients. Methods: This cross-sectional study was performed on 200 Iranian and 268 French systemic sclerosis patients. Iranian patients collected from the Iranian systemic sclerosis cohort of the Rheumatology Research Center, Shariati hospital, Tehran University of Medical Sciences. The French population was monocentric, and it was constituted by the patients included locally in the EUSTAR database in December 2016. Results: The mean age at onset was significantly lower in Iranian patients (35.58 ± 11.68 vs 47.06 ± 13.54, p-value < 0.001). The female-to-male ratio was approximately 5.2:1 and was not different in the two populations. The prevalence of diffuse cutaneous systemic sclerosis was significantly higher in Iranian patients (60.2% vs 42.85%, p-value < 0.001). Calcinosis cutis and joint synovitis were more prevalent in French patients (p-value = 0.013, <0.001). The positivity of anti-topoisomerase antibody was higher in Iranian patients, whereas the anti-centromere antibody predominated in French cases (p-value < 0.001). Restrictive pattern of pulmonary function test was more common in Iranian patients (p-value < 0.001), while estimated pulmonary arterial pressure by echocardiography was higher in French patients (p-value < 0.001). Conclusion: It seems that systemic sclerosis occurred in younger ages among Iranian female with the predominance of diffuse cutaneous subtype. In addition, lung interstitial disease appeared to be more prevalent and severe in Iranians than French patients.

Genetic implications in the pathogenesis of systemic sclerosis.

Systemic sclerosis (SSc) is a chronic autoimmune disease of the connective tissues of unknown etiology, characterized mainly by fibrosis of the skin, vascular abnormalities, and systemic involvement of other organs, such as gastrointestinal tract, kidneys, lungs, and heart. SSc has been associated with a complex etiology with the involvement of both environmental and genetic factors in the onset and outcome of the disease. Although several major histocompatibility complex (MHC) and non-MHC genes have been associated with the disease risk, there are several questions to answer. This article's purpose was to provide an extensive overview of the identified genetic factors in the etiopathogenesis of SSc.

A phase I/II randomized, controlled, clinical trial for assessment of the efficacy and safety of ß-D-mannuronic acid in rheumatoid arthritis patients.

BACKGROUND: Following the potent efficacy of ß-D-mannuronic acid (M2000) in phase I/II trial in ankylosing spondylitis patients, the present clinical trial was conducted to evaluate the efficacy, safety, and tolerability of this novel drug in rheumatoid arthritis (RA) patients who had inadequate response to conventional therapy. METHOD: The study was a 12-week randomized, controlled, phase I/II clinical trial with two treatment arms: M2000 and conventional treatment. Patients who had RA according to the modified American College of Rheumatology (ACR) criteria, with active disease at baseline also inadequate response to conventional therapy, were enrolled in this study. M2000 was administrated at a dose of two capsules (500 mg) per day orally during a period of 12 weeks. The primary endpoint was the proportion of patients fulfilling the ACR 20% improvement criteria after 12 weeks of M2000 therapy. Moreover, the patients were also followed up for safety. RESULTS: There were no statistically significant differences between treatment and conventional groups at baseline characteristics. The ACR20 response rate was significantly higher among M2000-treated patients than conventional-treated control, so that 74% of patients in treatment group showed an ACR20 response after 12 weeks of M2000 therapy (74 versus 16%; P = 0.011). 10% of M2000-treated patients and 57.1% of conventional-treated patient's adverse events occurred during this study. CONCLUSION: Treatment with M2000 in combination with conventional therapy showed a significantly superior efficacy along with a high safety profile compared to conventional-treated patients. Thereby, M2000 might be suggested as a suitable option in the treatment of RA.