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Background: Cardiac involvement in systemic sclerosis (SSc) is more prevalent than previously thought. In this study, the frequency and severity of cardiovascular involvement were assessed in SSc patients referred to Firouzgar Hospital. Methods: Fifty-eight patients with SSc, selected from the data bank of SSc patients, were reviewed for the frequency and severity of 8 organ involvements in this case series. The preliminary severity scale, published by international SSc study groups, was employed for the determination of the severity grade in the cardiovascular system. In the cardiac scoring scale, grade 0 represents normal heart (no cardiac involvement), grade 1 denotes mild involvement [electrocardiography (ECG) conduction defect and a left ventricular ejection fraction (LVEF) of 45-49%)], grade 2 signifies moderate involvement (arrhythmia, LVEF = 40-44%), grade 3 indicates severe involvement (LVEF <40%)], and grade 4 stands for end stage (congestive heart failure and arrhythmia requiring treatment). Results: In this study, 24 (41.4%) patients were in the diffuse cutaneous (dcSSc) subset. The female to male ratio was 10.5:1, and the mean duration from symptom onset to diagnosis was 7.35 years for the dcSSc subset and 8.41 years for the limited cutaneous (lcSSc) subset of disease, there being no significant difference. Cardiac involvement in this series was seen in 13 (22.4%) cases, and there was no significant difference in terms of frequency and severity between the two disease subgroups (p value = 0.96 and p value = 0.46 respectively). Conclusion: Our findings showed that the cardiac involvement in this series was infrequent and that there was no significant difference in the severity of cardiovascular involvement between the two subtypes of SSc in the late stage of the disease. [ABSTRACT FROM AUTHOR]

What is known and objective Calcinosis cutis (or cutaneous calcification) is a type of calcinosis wherein calcium deposits form in the skin and frequently encountered in limited cutaneous subtype of disease. So far, no treatment has shown an explicit beneficial effect. Medical therapy for calcinosis cutis with rituximab is limited and of variable benefit. Case summary Our patient was 54-year-old lady, a case of limited cutaneous scleroderma with widespread progressive calcinosis cutis unresponsive to current therapy. She went under treatment with rituximab with no successful outcome. What is new and conclusion Results of therapy with rituximab on regression/improvement of systemic sclerosis-related calcinosis are limited and non-conclusive. [ABSTRACT FROM AUTHOR]

Objective: The outcome of patients with COVID-19 improved over the pandemic, including patients with systemic rheumatic diseases. However, data on patients with systemic sclerosis (SSc) are lacking. This study aimed to assess the outcome of patients with both SSc and COVID-19 over several waves., Methods: Patients with both SSc and COVID-19 who were registered in the European Scleroderma Trials and Research group (EUSTAR) were collected between April 2020 and April 2021. Patients were assigned to waves 1, 2, or 3 depending on the date of their COVID-19 diagnosis. Primary endpoints were death, intensive care unit stay, or ventilatory support (severe outcome). Subgroup analyses of patients who were hospitalized or died were conducted. General and SSc-specific characteristics and treatment were compared over the waves. Descriptive statistics and multivariate logistic regression were applied., Results: A total of 333 patients were included; 57 patients (17%) had a severe outcome, and 30 patients (9%) died. Compared to wave 1, significantly fewer patients with SSc suffered from severe COVID-19 in waves 2 and 3 (28.2% vs 9.8% and 12.7%; P < 0.001), fewer patients required hospitalization (46.7% vs 19.6% and 25.5%; P < 0.001) or ventilatory support (24.0% vs 8.7% and 10.9%; P = 0.001), and fewer patients died (15.7% vs 5.0% and 7.5%; P = 0.011). Patients were significantly younger, more often men, had less frequent arterial hypertension, and less SSc cardiac involvement over waves 1 to 3. Patients received significantly less medium to high doses of corticosteroids as they did SSc treatment., Conclusion: The outcome of patients with both SSc and COVID-19 improved significantly over time because of intrinsic and extrinsic factors., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: The aim of the study was to evaluate the association between the tricuspid annular plane systolic excursion (TAPSE)/systolic pulmonary artery pressure (sPAP) ratio and estimated glomerular filtration rate (eGFR) and their association with mortality in the European Scleroderma Trials and Research (EUSTAR) cohort., Methods: Patients with systemic sclerosis (SSc) from the EUSTAR database with TAPSE, sPAP, and parameters required to calculate eGFR were included. Logistic regression and Cox regression analysis were performed to evaluate TAPSE/sPAP as a risk factor for chronic kidney disease (CKD) and overall survival., Results: A total of 2,370 patients with SSc were included; 284 (12%) patients had CKD stage 3a-5. TAPSE/sPAP (odds ratio [OR] 0.479; 95% CI 0.310-0.743; P < 0.001), arterial hypertension (OR 3.118; 95% CI 2.173-4.475; P < 0.001), diastolic dysfunction (OR 1.670; 95% CI 1.148-2.428; P < 0.01), and N-terminal pro-B-type natriuretic peptide (OR 1.165; 95% CI 1.041-1.304; P < 0.01) were associated with CKD stage 3a-5. TAPSE/sPAP ≤0.32 mm/mm Hg (hazard ratio [HR] 3.589; 95% CI 2.236-5.761; P < 0.001), eGFR <60 mL/min per 1.73 m 2 (HR 2.818; 95% CI 1.777-4.468; P < 0.001), and age (HR 1.782; 95% CI 1.348-2.356; P < 0.001) were the most significant predictive factors for all-cause mortality. A total of 276 patients with SSc had pulmonary hypertension (PH) confirmed by right heart catheterization, with 69 (25%) having CKD stage 3a-5. No difference was found in eGFR between patients with PH with reduced or normal cardiac index., Conclusion: Reduced TAPSE/sPAP ratio is independently associated with CKD. TAPSE/sPAP ratio ≤0.32 mm/mm Hg and eGFR <60 mL/min per 1.73 m 2 are prognostic factors for all-cause mortality. In patients with SSc with PH, eGFR is independent by reduced cardiac output., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Our knowledge of the COVID-19 infection impact on systemic sclerosis (SSc) is scarce. This study aimed to assess the prevalence of COVID-19 infection and to determine the predictive factors of worse outcomes and death in SSc patients., Methods: In this cohort study all patients who attended our clinic between 20 th February 2020 and 20th May 2021 were followed, and those with a history of COVID-19 infection completed the questionnaire. Results of para-clinical tests were extracted from the SSc database. The outcomes were classified as: alive vs. deceased and, mild vs. worse outcomes. Descriptive statistics and binary logistic regression models were applied., Results: Of the total 192 SSc patients studied, COVID-19 affected 12.5%; 6% experienced mild disease, 7% were hospitalized and 3% died. The worse outcome was associated with: older age [95%CI: 1.00-1.08], smoking [95%CI: 2.632-33.094], diabetes [95%CI: 1.462-29.654], digital pitting scars (DPS) [95%CI: 1.589-21.409], diffusing capacity of the lungs for carbon monoxide [DLCO<70 [95%CI: 1.078-11.496], left ventricular ejection fraction (LVEF)<50% [95%CI: 1.080-38.651], systolic pulmonary artery pressure (sPAP)>40 mmHg [95%CI: 1.332-17.434], pericardial effusion (PE) [95%CI: 1.778-39.206], and tendon friction rub [95%CI: 1.091-9.387]. Death was associated with male gender [95%CI: 1.54-88.04], hypertension [95%CI: 1.093-2.155], digital ulcers (DU) [95%CI: 0.976-18.34], low forced vital capacity (FVC) [95%CI: 0.03-0.81], and joint flexion contracture (JFC) [95%CI: 1.226-84.402]., Conclusion: Risk factors for the worse outcome in COVID-19 infected SSc patients included, older age, smoking, diabetes, DPS, DLCO<70, LVEF<50%, sPAP>40 mmHg, PE, and TFR. Death was associated with the male gender, hypertension, DU, low FVC, and JFC., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Mediterranean Journal of Rheumatology (MJR).)

The pathogenesis of idiopathic pulmonary fibrosis (IPF) is quite similar to that of cancer pathogenesis, and several pathways appear to be involved in both disorders. The mammalian target of the rapamycin (mTOR) pathway harbors several established oncogenes and tumor suppressors. The same signaling molecules and growth factors, such as vascular endothelial growth factor (VEGF), contributing to cancer development and progression play a part in fibroblast proliferation, myofibroblast differentiation, and the production of extracellular matrix in IPF development as well. The expression of candidate genes acting upstream and downstream of mTORC1, as well as Vegf and low-density lipoprotein receptor related protein 1(Lrp1), was assessed using specific primers and quantitative polymerase chain reaction (qPCR) within the lung tissues of bleomycin (BLM)-induced IPF mouse models. Lung fibrosis was evaluated by histological examinations and hydroxyproline colorimetric assay. BLM-exposed mice developed lung injuries characterized by inflammatory manifestations and fibrotic features, along with higher levels of collagen and hydroxyproline. Gene expression analyses indicated a significant elevation of regulatory associated protein of mTOR (Raptor), Ras homolog enriched in brain (Rheb), S6 kinase 1, and Eukaryotic translation initiation factor 4E-binding protein 1 (4Ebp1), as well as a significant reduction of Vegfa, Tuberous sclerosis complex (Tsc2), and Lrp1; no changes were observed in the Tsc1 mRNA level. Our findings support the elevation of S6K1 and 4EBP1 in response to the TSC/RHEB/mTORC1 axis, which profoundly encourages the development and establishment of IPF and cancer. In addition, this study suggests a possible preventive role for VEGF-A and LRP1 in the development of IPF.

Background: MicroRNAs are short nucleotide sequences that contribute to the regulation of various biological functions and therefore their roles have been investigated in many pathologic conditions such as epithelial to mesenchymal transition in cancer and fibrosis; among them, miR-138 has been mostly studied in cancer biology and is well-known for its suppressing effect on cancer progression. Being able to suppress major pathways involved in EMT, miR-138 could be a good candidate to be investigated in fibrotic responses too. Based on our previous studies, and the capability of miR-138 to target and regulate several components of the EMT pathway; we hypothesized a role for miR-138 in systemic sclerosis. Accordingly, the gene expression of miR-138 was assessed to find any alterations in the whole blood of the SSc patients., Methods: Blood was collected from 70 patients with systemic sclerosis (equally divided between 2 groups of limited and diffuse categories) and 30 healthy individuals as controls. RNA was immediately isolated from the fresh whole blood; afterward, the resulting RNA was reverse transcribed into cDNA and then the relative expression of miR-138 was compared between the patients and the controls by the means of qPCR, and specific TaqMan primer and probes., Results: The relative expression of miR-138 was significantly lower in patients with systemic sclerosis compared to the controls. No significant difference was observed between the limited and diffuse patient groups. ROC curve analysis showed an appropriate diagnostic value of miR-138 in effectively differentiating SSc patients from the healthy controls., Conclusion: miR-138 is likely involved in the pathogenesis of SSc and with further evaluations may be utilized as a diagnostic biomarker in SSc. Also, targeting miR-138 in future studies could be promising for finding a novel treatment option for patients with SSc., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s) 2022.)

Systemic sclerosis (SSc) or scleroderma is a multiorgan rheumatoid disease characterized by skin tightening or organ dysfunction due to fibrosis, vascular damage, and autoimmunity. No specific cause has been discovered for this illness, and hence no effective treatment exists for it. On the other hand, due to the lack of diagnostic biomarkers capable of effectively and specifically differentiating the patients, early diagnosis has not been possible. Due to their potent regulatory roles in molecular pathways, microRNAs are among the novel candidates for the diagnosis and treatment of diseases like SSc. MiR-27a is a microRNA known for its role in the pathogenesis of fibrosis and cancer, both of which employ similar signaling pathways; hence we hypothesized that Mir-27a could be dysregulated in the blood of individuals affected by SSc and it might be useful in the diagnosis or treatment of this disease. Blood was collected from 60 SSc patients (30 limited and 30 diffuse) diagnosed by a rheumatologist according to ACR/AULAR criteria; following RNA isolation and cDNA synthesis; real-time qPCR was performed on the samples using Taq-Man probes and data were analyzed by the ΔΔCT method. Also, potential targets of miR-27a were evaluated using bioinformatics. It was revealed that miR-27a was significantly down-regulated in SSc patients in comparison to healthy individuals, but there was no difference in miR-27 expression between limited and diffused SSc patients. Besides, miR-27a was found to target several contributing factors to SSc. It seems that miR-27a has a protective role in SSc, and its downregulation could result in the disease's onset. Based on bioinformatics analyses, it is speculated that miR-27a likely targets factors contributing to the pathogenesis of SSc, which are elevated upon the downregulation of miR-27a; hence, miR-27a mimics could be considered as potential therapeutic agents for the treatment of SSc in future studies. Since no difference was observed between limited and diffuse patient groups, it is unlikely that this microRNA has a role in disease progression. According to ROC analysis of qPCR data, miR-27a could be employed as a valuable diagnostic biomarker for SSc., (© 2022. The Author(s).)

Idiopathic pulmonary fibrosis (IPF) is among the illnesses with a high mortality rate, yet no specific cause has been identified; as a result, successful treatment has not been achieved. Among the novel approaches for treating such hard-to-cure diseases are induced pluripotent stem cells (IPSCs). Some studies have shown these cells' potential in treating IPF. Therefore, we aimed to investigate the impact of IPSCs on insulin-like growth factor (Igf) signaling as a major contributor to IPF pathogenesis.  C57BL/6 mice were intratracheally instilled with Bleomycin (BLM) or phosphate-buffered saline; the next day, half of the bleomycin group received IPSCs through tail vein injection. Hydroxyproline assay and histologic examinations have been performed to assess lung fibrosis. The gene expression was evaluated using specific primers for Igf-1, Igf-2, and insulin receptor substrate 1 (Irs-1) genes and SYBR green qPCR master mix. The data have been analyzed using the 2-ΔΔCT method. The mice that received Bleomycin showed histological characteristics of the fibrotic lung injury, which was significantly ameliorated after treatment with IPSCs comparable to the control group. Furthermore, gene expression analyses revealed that in the BLM group, Igf1, Igf2, and Irs1 genes were significantly upregulated, which were returned to near-normal levels after treatment with IPSCs. IPSCs could modulate the bleomycin-induced upregulation of Igf1, Igf2, and Irs1 genes. This finding reveals a new aspect of the therapeutic impact of the IPSCs on IPF, which could be translated into other fibrotic disorders.

Background: Systemic sclerosis is a chronic disease of connective tissue accompanied by fibrosis of the skin and inner organs and an increased risk of foot ulcers. Biomechanical indices such as soft-tissue thickness and compressibility may correlate with the risk of this phenomenon., Objective: The aim of this study was to assess heel pad and first metatarsal head (MTH) soft-tissue thickness and compressibility index (CI) in scleroderma patients compared to matched healthy individuals. Not all patients had foot ulcers., Methods: Heel pad thickness in standing (loaded) and lying (unloaded) positions were measured in 40 scleroderma patients by means of a lateral foot radiograph. CI was measured as the ratio of loaded to unloaded thickness. The Soft-tissue thickness of the first MTH was measured by ultrasound. Results were compared with 40 healthy controls of matched age and body mass index. All patients' diagnoses were made based on the American College of Rheumatology classification criteria., Results: Forty scleroderma patients (36 females, 4 males) with the following demographics were studied; mean age (SD) 45(12), mean body mass index 25.5 (4), and mean disease duration=10(9.6) years; only 8 (20%) had digital ulcers. Patients' heel pad thickness and CI in the dominant side and MTH soft-tissue thickness on both sides were significantly different compared to the control group. Comparison of results in patients with and without foot ulcers also showed a significant difference in soft-tissue thickness. Thickness was negatively associated with disease duration, but the CI did not change over time., Conclusion: Soft-tissue thickness of the foot decreases in scleroderma patients and is associated with foot ulcers and digital ulcers in the hands., (© 2022 The Mediterranean Journal of Rheumatology (MJR).)

Background: Gender-related factors have explained the higher prevalence of autoimmune diseases in women. Sex hormones play a key role in the immune system and parenchymal cells function; therefore, these hormones can be important in the pathogenesis of autoimmune diseases as a risk or beneficial factor. Lung fibrosis is the main cause of mortality in systemic sclerosis, a female predominant autoimmune disease. The objective of this study was to examine the effect of progesterone on lung fibrosis in a mouse model of systemic sclerosis., Methods: Mice with bleomycin-induced lung fibrosis treated with progesterone subcutaneously for 21 and 28 days. Blood was collected for hormone and cytokine measurement at the end of treatment then, skin and lung tissues were harvested for histological assessment, gene expression, cytokine, hydroxyproline, and gelatinase measurement., Results: Trichrome staining and hydroxyproline measurements showed that progesterone treatment increased the content of collagen in fibrotic and normal lung tissues. Progesterone increased α-SMA (P < 0.01), TGF- β (P < 0.05) and decreased MMP9 (P < 0.05) in fibrotic lung tissues. Also progesterone treatment decreased the gene expression of Col1a2 (P <0.05), Ctgf (P <01), End1 (0.001) in bleomycin- injured lung tissues. The serum level of TNF-α was decreased, but the serum level of cortisol was increased by progesterone treatment in fibrotic mice (P< 0.05)., Conclusion: Our results showed that progesterone aggravates lung fibrosis in a mouse model of systemic sclerosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Vafashoar, Mousavizadeh, Poormoghim, Haghighi, Pashangzadeh and Mojtabavi.)

Objective: To evaluate clinical associations of anti-PM/Scl antibodies in patients with SSc in a multicentre international cohort, with particular focus on unresolved issues, including scleroderma renal crisis (RC), malignancies, and functional outcome of interstitial lung disease (ILD)., Methods: (1) Analysis of SSc patients from the EUSTAR database: 144 anti-PM/Scl+ without SSc-specific autoantibodies were compared with 7202 anti-PM/Scl-, and then to 155 anti-Pm/Scl+ with SSc-specific antibodies. (2) Case-control study: additional data were collected for 165 anti-PM/Scl+ SSc patients (85 from the EUSTAR registry) and compared with 257 anti-PM/Scl- SSc controls, matched for sex, cutaneous subset, disease duration and age at SSc onset., Results: Patients with isolated anti-PM/Scl+, as compared with anti-Pm/Scl-, had higher frequency of muscle involvement, ILD, calcinosis and cutaneous signs of DM, but similar frequency of SRC and malignancies (either synchronous with SSc onset or not). The presence of muscle involvement was associated with a more severe disease phenotype. Although very frequent, ILD had a better functional outcome in cases than in controls. In patients with both anti-PM/Scl and SSc-specific antibodies, a higher frequency of typical SSc features than in those with isolated anti-PM/Scl was observed., Conclusion: The analysis of the largest series of anti-PM/Scl+ SSc patients so far reported helps to delineate a specific clinical subset with muscle involvement, cutaneous DM, calcinosis and ILD characterized by a good functional outcome. SRC and malignancies do not seem to be part of this syndrome., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Aim: Systemic sclerosis (SSc) is a chronic connective tissue disease with the clinical hallmark of skin thickening and tethering. Correlation of musculoskeletal features with other parameters should be considered in SSc patients., Methods: We reviewed the records of all patients who had more than one visit and standard anteroposterior radiography of hand. We used univariate analysis, and factors with p<0.05 were included in logistic regression to find out dependent factors., Results: Overall, 180 SSc patients were enrolled in our study, 161 (89.4%) of whom were women. Median age (IQR) was 47.0 years (16), and 52% had diffuse subtype of the disease. In multivariate analysis, tendon friction rubs (TFRs) was associated with the presence of calcinosis, muscle tenderness, and flexion contracture (FC) on physical examination (p<0.05). Arthritis showed no differences in the two subtypes of the disease (p=0.98), and in multivariate analysis, there were no correlations between radiographic arthritis and serological and clinical features. The radiographic results indicated that disease duration correlated with joint erosion, acro-osteolysis, resorption of distal ulna, calcinosis and radiologic FC (p< 0.05). Acro-osteolysis was more frequent in the dcSSc subtype, TFRs, and anti-TOPO I antibody. Radiologic FC showed association with skin score, calcinosis and haematocrit <30% (p<0.05). Joint flexion on radiography was associated with disease duration, modified Rodnan skin score, calcinosis, and low haematocrit (P<0.01)., Conclusion: Disease duration was a main dependent factor for developing joint erosion, acro-osteolysis, bone resorption, calcinosis, and flexion contracture on hand radiography. Acro-osteolysis presented in the severe form of the disease. Acro-osteolysis was the only dependent variable associated with bone demineralization., (© 2020 The Mediterranean Journal of Rheumatology (MJR).)

Systemic sclerosis is a fibrotic autoimmune disease in which aberrant remodeling of the extracellular matrix in organs disturbs their functionalities. The aim of this study was to investigate the expression of gelatinases on systemic sclerosis. Consequently, a mouse model of systemic sclerosis was employed and the gelatinolytic activity of gelatinases was evaluated on the fibrotic tissues of this model. Two groups of ten mice were considered in this work: a group of systemic sclerosis model and control group. For the generation of systemic sclerosis model, mice received bleomycin, while the control group was subjected to phosphate buffered saline (PBS) reception. Mice were tested for fibrosis by using trichrome staining, hydroxyproline measurement and α-SMA detection in tissue sections. Additionally, the gelatinolytic activity of matrix metalloproteinase 2 and matrix metalloproteinase 9 were measured using gelatin zymography in lungs and skin tissue homogenates. The obtained results indicated that subcutaneous injection of bleomycin-induced fibrosis in skin and lung tissues of mice. Pro and active forms of matrix methaloproteinase 9 were increased in fibrotic lung tissues (p<0.05 and p<0.01, respectively), while, the gelatinolytic activity of MMP2 was unaffected in these tissues. Additionally, in skin tissues of bleomycin-treated animals, both pro and active forms of MMP9 and MMP2 were increased (p<0.05). Pro and active forms of gelatinases increase differently in skin and lung tissues of bleomycin-induced scleroderma.

Systemic sclerosis is a female predominant, a fibrotic autoimmune disease in which disturbance in tissue homeostasis and cell turnover including cell apoptosis are central events in pathogenesis. Sex hormones are known as the important players in sexual dimorphism of autoimmune diseases and in tissue homeostasis. Progesterone influences autoimmune disease via its immunomodulatory effect or by its direct action on parenchymal cell function. On the other hand, this hormone impacts tissue homeostasis by acting on cell apoptosis in a different situation. The objective of this study was to examine the effect of progesterone on cellular apoptosis of skin and lung tissues in a mouse model of scleroderma. Four group of mice were involved in this study with 10 mice in each. The fibrotic model was induced by daily subcutaneous injection of bleomycin for 28 days. One week after initiation of fibrosis induction, mice received subcutaneous progesterone alone or with bleomycin for 21 days. Control group received only Phosphate buffered saline PBS. After 28 days, under lethal anesthesia skin and lung tissues were harvested for histological assessment and hydroxyproline measurement. Apoptosis in tissue sections was detected by TUNEL assay technique. Bleomycin administration induced fibrosis in skin and lung tissues. Severe apoptosis was seen in skin and lung tissues of the bleomycin-treated group (p<0.001 in the skin and p<0.05 in the lung). Progesterone injection either in the skin (p>0.05) or in the lung (p>0.05) did not alter apoptosis in bleomycin-treated animals. Our data confirm the role of apoptosis in the pathogenesis of fibrosis in this model; however, progesterone does not affect cellular apoptosis in skin and lung tissues of bleomycin-injured animals.

Gender medicine is a new era of science which focuses on the impact of sex hormones and gender on normal physiology, pathobiology and clinical features of diseases. In this study we investigated the impact of pregnancy doses of progesterone hormone on the expression of a couple of matrix metalloproteinase (MMPs), which are known to be involved in tissue remodeling of lungs in health and disease, namely MMP7 and 13. Pregnancy maintenance dose of progesterone was administered to female BALB/c mice for 21 and 28 days, the control group received PBS for the same days. After removal of the lungs and RNA extraction, quantitative real-time PCR was done using specific primers for MMP7 and MMP13. We found that progesterone can slightly (not significantly) decrease the expression of MMP13 but had no effect on MMP7. Our results shows that progesterone has minimal effect on the expression of matrix metalloproteinase7 and matrix metalloproteinase 13, but it may still have an effect on corresponding tissue inhibitor of matrix metalloproteinases (TIMPs) or other components of the Extracellular matrix  which remains to be elucidated. Also, the effect of progesterone on these MMPs can be further studied in a fibrosis model.

The aims of the study were to determine prognostic factors for survival and causes of death in a cohort of patients with systemic sclerosis (SSc). This was a cohort study of SSc patients in single rheumatologic center from January 1998 to August 2012. They fulfilled the American College of Rheumatology classification criteria for SSc or had calcinosis Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia or sine sclerosis. Causes of death were classified as SSc related and non-SSc related. Kaplan-Meier and Cox proportional hazard regression models were used in univariate and multivariate analysis to analyse survival in subgroups and determine prognostic factors of survival. The study includes 220 patients (192 female, 28 male). Out of thirty-two (14.5 %) who died, seventeen (53.1 %) deaths were SSc related and in nine (28.1 %) non-SSc-related causes, and in six (18.8 %) of patients causes of death were not defined. Overall survival rate was 92.6 % (95 % CI 87.5-95.7 %) after 5 years and 82.3 % (95 % CI 73.4-88.4 %) after 10 years. Pulmonary involvement was a major SSc-related cause of death, occurred in seven (41.1 %) patients. Cardiovascular events were leading cause of in overall death (11) 34.3 % and 6 in non-SSc-related death. Independent risk factors for mortality were age >50 at diagnosis (HR 5.10) advance pulmonary fibrosis (HR 11.5), tendon friction rub at entry (HR 6.39), arthritis (HR 3.56). In this first Middle Eastern series of SSc registry, pulmonary and cardiac involvements were the leading cause of SSc-related death.

The aim of this study was to evaluate efficacy of azathioprine (AZA) and cyclophosphamide (CYC) as a therapeutic regimen for interstitial lung disease associated with systemic sclerosis (SSc). Thirty-six selected patients included in this retrospective cohort and received one of the two drugs; the first group consists of 15 patients who were treated with AZA (1.5-2 mg/kg/day) and the second group with 21 patients received oral CYC (up to 2 mg/kg/day). Both groups received additional low dose of prednisolone (≤10 mg) for 6 months. Forced vital capacity (FVC), diffusion lung capacity for carbon monoxide (DLCO) and skin score were assessed as outcome measures. Modified Rodnan skin score (mRSS), pulmonary function test and DLCO were evaluated at entry and at the end of study after 12 months. The mean (SD) FVC percentages obtained at baseline and post-treatment in AZA-treated patients were 62.8 ± 9.8 and 71.1 ± 20.9 with mean difference of FVC% +7.6 ± 13.1, p = 0.05, and in CYC-treated patients 59.5 ± 10.7, 63.1 ± 16.2 and +2.9 ± 11.5, respectively, p = 0.19. Baseline and post-treatment DLCO% in AZA-treated patients were 61.4 ± 25.8 and 76.7 ± 24.0 with mean difference of +15.0 ± 14.5, respectively, p = 0.01. In CYC-treated patients, those measures were 67.7 ± 27.5 and 60.0 ± 22.9 with mean difference of -8.0 ± 23.7 (p = 0.12). Following 12 months of treatment in AZA-treated patients, mean difference of changes in mRSS was -2.9 ± 3.7 and -1.4 ± 4.5 in CYC-treated patients. Our results indicated that AZA can be effective in ameliorating or stabilizing lung function in selected SSc patient groups.

To evaluate demographic, clinical and laboratory features associated with scleroderma-specific auto-antibodies. Sera of 100 patients with systemic sclerosis (SSc) were analyzed by an indirect immunofluorescence technique with HEp-2 cells as a substrate. Specific ANA such as anti-centromere antibodies (ACA), anti-topoisomerase (TOPO), anti-RNA polymerase III (Pol 3), anti-U3-RNP (U3-RNP), anti-Th/To (Th/To) and anti-PM/Scl (PM/Scl) were detected by line immunoassay and anti-U1-RNP (U1-RNP) by ELISA. Frequency of clinical features associated with a specific antibody group was reported cumulatively over the follow-up period. Frequency of specific clinical features was compared across the two disease subtype including limited cutaneous (lcSSc) or diffuse cutaneous (dcSSc) as well as the auto-antibody groups. Ninety-four percent of patients were ANA positive with significant higher skin score, Raynauds and digital ulcer/gangrene. Anti-TOPO was detected in 71% of all patients, in 90.5% of dcSSC and in 65.8% of lcSSc. Anti-TOPO was significantly associated with dcSSc, higher skin score, digital ulcer/gangrene, pulmonary fibrosis, DLCO <70%. U1-RNP antibody was associated with lower fibrosis in lung. ACA was positive in 7% of patients and exclusively in those with lcSSc. We did not find association between gender and presence of auto-antibodies. Anti-TOPO antibody had a high prevalence in contrast to low prevalence of ACA antibody. There were no differences in clinical subtypes of the disease in patients with positive anti-TOPO and positive ACA. Differences in prevalence of auto-antibodies are suggestive of further genetic study.

To assess the effectiveness of cyclophosphamide in the management of scleroderma-related interstitial lung disease (ILD). In this systematic review study, the primary outcome measures were change in forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (D(L)CO) of the patients after 6 and 12 months. To assess the effect of cyclophosphamide on early stage of ILD, alveolitis, in SSc patients, we selected the studies that used the BAL findings or HRCT or recent deterioration of PFT with minimal chest X-ray finding in early stage of disease as diagnosis of alveolitis. A sensitive systematic search strategy was used to find all relevant studies. Finally, 17 trials were included in the analysis that was performed using STATA. (Version 8) and Review Manager (version 4.1; MetaView version 4.1) softwares. Results from 10 studies were pooled for the outcome variable of FVC after 12 months. The summary WMD (random effects) was 2.45 (95% CI, 0.760-4.149 P = 0.005), which means that cyclophosphamide was able to prevent deterioration of FVC after 12 months. In pooled data of 13 studies, about DLCO after 12 months WMD (random effects) was 2.003 2.96 (95% CI, -0.228 to 6.159 P = 0.069), which means that cyclophosphamide was not able to prevent deterioration of D(L)CO after 12 months. If we considered clinically sensible improvement as absolute value ≥10% in DLCO and VC, then result of treatment with cyclophosphamide treatment in scleroderma patients with ILD was not significant.

Pachydermoperiostosis PDP (idiopathic or primary hypertrophic osteoarthropathy) is a rare congenital disease that inherited in an autosomal fashion. The disease is more common in males and develops gradually from adulthood. The disease is characterized by coarse facial features, clubbing of the fingers and radiographic periostitis of the distal long bones. The patient was a 37-year-old man with acroosteolysis and digital clubbing of hands and feet fingers and lion facies.

In systemic sclerosis (SSc), major determinant of morbidity and mortality is pulmonary complication including pulmonary interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH). In this study, the natural course of pulmonary involvement in SSc patients was investigated. This was a historical cohort study of SSc patients at a referral center for SSc in Iran between February 1998 and December 2007. Patients had a standardized initial evaluation, and interstitial pulmonary involvement was established by high-resolution CT scan (HRCT). Pulmonary hypertension was assessed by tricuspid gradient on echocardiography. Development of abnormal FVC or DLCO was considered as secondary outcome. Analysis of pulmonary survival was performed for primary and secondary outcomes. Ninety-one SSc patients were included in the study with the mean age of 44.1 (14.8). Among these, 65 (71.4%) patients were classified as limited subtype (lcSSc) and 84 (93.3%) were women. PAH was investigated in 8 (8.2%) patients, 1 (6.7%) in dcSSc and 7 (15.9%) in lcSSc subtype of disease. ILD had developed after a median of 107 (SE = 24.4) months after the first symptom of SSc, and 29 patients (31.9%) developed pulmonary fibrosis. Alveolitis and fibrosis had developed after a median of 129.0 (22.9) and 259.0 (74.2) months, respectively. There was a significant difference in Alveolitis-free pulmonary survival between two subgroups of the disease, which showed pulmonary alveolitis developed later in limited SSc (P = 0.03). The difference was not significant in two subtypes when Cox regression model was used to identify the effect of other prognostic factors on pulmonary survival in patients. In the present study, clinical manifestations of two subtypes of disease were divergent at first; however they became convergent in late stages, and this was the same as results in previous studies. Echocardiography for evaluation of pulmonary hypertension and pulmonary function tests for early detection of ILD and PAH is recommended for SSc patients to detect early stages of pulmonary involvement before significant vascular and fibrotic changes occur.

Background: The HLA class I molecules serve as ligands for both T cell receptors and killer cell immunoglobulin-like receptors (KIRs)., Objective: We investigated the HLA-C and HLA-Bw4 alleles as well as KIRs expression on CD56 positive lymphocytes to evaluate whether these genes and molecules could influence Ankylosing Spondylitis (AS) susceptibility, alone or in combination., Methods: We typed 40 AS patients and 40 normal controls for HLA-C asn⁸⁰ (group 1) and HLA-C lys⁸⁰ (group 2), HLA-B Bw4(thero), HLA-B Bw4(iso) and HLA-A Bw4 alleles by PCR-SSP method. We also assessed the expression of KIR2DL1/2DS1, KIR2DL2/2DL3, KIR3DL1 and KIR2DS4 by flow cytometry. The Pearson chi-square or Fisher exact test was performed for statistical analysis., Results: The frequency of HLA-B Bw4(iso) but not HLA-B Bw4(thero) and HLA-A Bw4, ligand for the inhibitory KIR3DL1, was significantly reduced in AS patients as compared with controls (p<0.01). No significant differences were observed in gene carrier frequencies of HLA-C group 1 and 2 between AS and controls. Although no differences were found in the expression of KIR receptors between AS and normal subjects, we found that expression of KIR3DL1 in the presence of HLA Bw4-B(iso) gene was reduced in patients with AS compared to healthy controls (p<0.009)., Conclusion: We conclude that HLA-B Bw4(iso), the ligand of inhibitory KIR3DL1, with and without the expression of KIR3DL1 might be involved in protection against AS. Our results suggest that besides the HLA and KIR genotype, expression levels of KIRs may be involved in the pathogenesis of AS disease.