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.

Talabostat, fibroblast activation protein inhibitor, attenuates inflammation and fibrosis in systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disorder characterized by excessive fibrosis, where activated fibroblasts play a pivotal role in disease progression. This study aimed to investigate the potential of Talabostat, a small molecule inhibitor of dipeptidyl peptidases, in alleviating fibrosis and inflammation associated with SSc pathogenesis. METHODS: Dermal fibroblasts were obtained from skin biopsies of ten diffuse cutaneous SSc patients and healthy controls. These fibroblasts were subjected to treatment with either TGF-ß alone or in combination with Talabostat. Immunofluorescence staining was conducted to evaluate FAPα and α-SMA protein levels. The expression of activated fibroblast markers (FAPα and ACAT2), pro-fibrotic (COL1A1 and COL1A2), anti-fibrotic (MMP1, MMP2, and MMP9), and inflammatory (IL-6 and TGFß1) related genes was measured by quantitative real-time PCR. Talabostat-treated fibroblasts were assessed for their migratory capacity using a scratch assay and for their viability through MTT assay and Annexin V staining. RESULTS: The basal expression of COL1A1 and TGFß1 was notably higher in healthy subjects, while MMP1 expression showed a significant increase in SSc patients. Furthermore, TGF-ß stimulation led to upregulation of activated fibroblast markers, pro-fibrotic, and inflammatory-related genes in SSc-derived fibroblasts, which were attenuated upon Talabostat treatment. Interestingly, Talabostat treatment resulted in an upregulation of MMP9 expression. Moreover, Talabostat exhibited a concentration-dependent inhibition of activated fibroblast viability in both healthy and SSc fibroblasts, and suppressed fibroblast migration specifically in SSc patients. CONCLUSION: In summary, Talabostat modulates fibrotic genes in SSc, thereby inhibiting myofibroblast differentiation, activation, and migration. These findings suggest promising therapeutic avenues for targeting fibrosis in SSc.

The effect of smoking on response to methotrexate in rheumatoid arthritis patients: A systematic review and meta-analysis.

OBJECTIVES: In the current study, we aimed to investigate the effect of smoking on inadequate response to methotrexate (MTX-IR) in rheumatoid arthritis (RA) patients. METHODS: We searched PubMed, Embase, and Web of Science until 6 June 2022. Observational or interventional studies investigating MTX-IR in RA patients based on smoking status were included. Two independent reviewers assessed the risk of bias and the certainty of the evidence using the Risk of Bias in Nonrandomized Studies-of Interventions and Grades of Recommendation, Assessment, Development, and Evaluation tools, respectively. RESULTS: We included 23 studies in the systematic review and 13 in the meta-analysis. Of the 13 included studies, 6 had a moderate risk, 3 had a serious risk, and 4 had a critical risk of bias. The overall random-effect meta-analysis suggested that smokers were 58% more likely to be MTX-IR when compared with nonsmokers [odds ratio (OR) 1.58, 95% confidence interval 1.21-2.06; P = .001; I2 = 69.3%]. The common-effect meta-analysis of the adjusted ORs demonstrated an overall OR of 2.69 (1.88-3.83; P < .001; I2 = 27.1%). CONCLUSIONS: The current study showed that smoking is a significant predictor of MTX-IR, especially in disease-modifying antirheumatic drug-naïve early RA patients, as most of the included studies in the meta-analysis consisted of this population.

Coronavirus disease 2019 (COVID-19) in patients with systemic autoimmune diseases or vasculitis: radiologic presentation.

Coronavirus disease 2019 (COVID-19) has transformed into a worldwide challenge, since its outbreak in December 2019. Generally, patients with underlying medical conditions are at a higher risk of complications and fatality of pneumonias. Whether patients with systemic autoimmune diseases or vasculitides, are at increased risk for serious complications associated with COVID-19, is not established yet. Computed tomography (CT) has been employed as a diagnostic tool in the evaluation of patients with clinical suspicion of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection with a reported sensitivity of higher than reverse transcription polymerase chain reaction (RT-PCR) test. Multifocal bilateral ground-glass opacities (GGOs) with peripheral and posterior distribution and subsequent superimposition of consolidations are considered the main imaging features of the disease in chest CT. However, chest CT images of underlying rheumatologic or autoimmune diseases or vasculitides, such as systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis, Behçet disease, and granulomatosis with polyangiitis, especially those with extensive lung involvement can overshadow or obliterate features of COVID-19. In addition, CT findings of such diseases may resemble manifestations of COVID-19 (such as ground glass opacities with or without superimposed consolidation), making the diagnosis of viral infections, more challenging on imaging. Comparing the imaging findings with prior studies (if available) for any interval change is the most helpful approach. Otherwise, the diagnosis of COVID-19 in such patients must be cautiously made according to the clinical context and laboratory results, considering a very high clinical index of suspicion on imaging.

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.

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.

Nailfold videocapillaroscopy changes in Takayasu arteritis and their association with disease activity and subclavian artery involvement.

INTRODUCTION: Takayasu arteritis (TA) is a large vessel vasculitis characterized by the involvement of the aorta and its branches. In the present study, the nailfold videocapillaroscopy (NVC) findings of the TA patients were evaluated and compared to healthy individuals. Additionally, the association of NVC abnormalities with disease activity and subclavian artery involvement was also investigated. METHOD: In the present study, NVC changes of 15 TA patients and 15 age- and sex-matched healthy controls were compared. The frequency of hypertension, dyslipidemia, and smoking status was not different between the case and control group. Capillary density, avascular area, tortuosity, micro-hemorrhages, and ramification were investigated. Among capillaries' diameters; capillary length and width, arterial and venous limbs diameters were also compared between two groups. RESULTS: The capillary length and venous limb diameter were lower in TA patients compared to control cases (P-value: 0.026 and 0.049, respectively). Moreover, TA patients have more tortuous capillaries (P-value: 0.035). Among TA patients; capillary length, width, arterial and venous limbs diameter was lower in hands with subclavian involvement (P-value: 0.014, 0.034, 0.009 and 0.022, respectively). Furthermore, the arterial and venous limbs diameter were lower in TA patients with active disease compared to patients with inactive disease (P-value: 0.018 and 0.049, respectively). CONCLUSION: In the present study, we have shown that the hands with subclavian artery involvement have short, thin and tortuous capillaries which could be secondary to hypoperfusion. To the best of our knowledge, this is the first report describing NVC changes in TA.

Behcet's disease in Iran: Analysis of 7641 cases.

Objective: To analyze Behcet's Disease (BD) in Iran, from 1975 to 2018, and compare to 35 large/small reports from other countries.Methods: Patients from all over Iran, when suspected, were sent to the BD Unit. The diagnosis was done by expert opinion. All data were recorded in the BD registry (updated in each follow-up). The data are given in percentage with 95% confidence Intervals.Results: The mean age at onset was 25.6 years. Standard deviation (SD) was 9.8. The mean disease duration was 11.7 years (SD: 8.9). Males were 55.8% (54.7-56.9), Females 44.2% (43.1-45.3), Oral Aphthosis (OA) 97.5% (97.1-97.9), genital aphthosis (GA) 64.4% (63.3-65.5), skin lesions 62.2% (61.1-63.3), ocular lesions 55.6% (54.5-56.7), Joint Manifestations 38.1% (37.0-39.2), Gastrointestinal 6.8% (6.2-7.4), Vascular 8.9% (8.3-9.5), neurological (central-peripheral) 3.9% (3.5-4.3), epididymitis 4.6% (4.1-5.1). Lab tests were positive pathergy test 50.4% (49.3-51.5), elevated ESR 51.1% (50.0-52.2), abnormal urinalysis 13.4% (12.6-14.2). The International Study Group (ISG, 1990) criteria and the International Criteria for Behcet's Disease (ICBD, 2014) had respectively a sensitivity of 76.2% (75.2-77.2) and 96.6% (96.2-97.0). The specificity was 99.3% (99.1-99.5) and 97.3% (96.9-97.7). The accuracy was 86.4% (85.8-87.0) and 96.9% (96.6-97.2).Conclusion: The most frequent manifestations were OA, GA, skin manifestations, and ocular manifestations.

HBV reactivation in rheumatic diseases patients under therapy: A meta-analysis.

BACKGROUND: Hepatitis B is one of the most common infectious diseases worldwide. In patients undergoing immunosuppressive therapy such as rheumatic diseases, reactivation of hepatitis B virus (HBV) is considered clinically important. This systematic review and meta-analysis were performed to determine the prevalence rate of HBV reactivation in rheumatic patients from different parts of the world. METHODS: The authors performed a systematic literature review from several reliable databases including Scopus, ISI Web of Science and PubMed. Furthermore, the keywords of this research were "Hepatitis B virus", "Rheumatic diseases", "HBV reactivation", "Anti-TNF", "DMARDs" and "Biologic agents". RESULTS: The authors selected 30 studies out of 983 for the present review. The overall estimation of the prevalence of HBV reactivation was 1.4 (95% confidence interval (CI): 1.3-1.6). Also, the heterogeneity in estimating the pooled prevalence among the studies was shown; Cochran Q test, P < 0.001, I2 = 99.9%. It should be noted that max and min reactivation rate of HBV were in Italy and France respectively. CONCLUSIONS: Rheumatic disease patients with resolved hepatitis B should be tightly monitored for possible HBV reactivation by elevation of liver enzymes and HBV DNA levels.

Evaluation of ITGB2 (CD18) and SELL (CD62L) genes expression and methylation of ITGB2 promoter region in patients with systemic sclerosis.

Systemic sclerosis (SSc), an autoimmune disease of connective tissue, is characterized by inflammation, fibrosis, and vessel endothelial damage. Products of Integrin subunit beta 2 (ITGB2) and selectin L (SELL) genes participate in several functional pathways of immune system. The aim of this investigation was to survey the transcript level of ITGB2 and SELL genes as well as methylation status of CpG sites in promoter region of differently expressed gene in PBMCs of SSc patients. PBMCs were isolated from whole blood of 50 SSc patients and 30 healthy controls. Total RNA and DNA contents of PBMCs were extracted. Gene expression was analyzed by real-time PCR using the SYBR Green PCR Master Mix. To investigate the methylation status of CpG sites, DNA samples were treated by bisulfite, amplified through nested PCR, and sequenced through Sanger difficult sequencing method. ITGB2 gene in PBMCs of SSc patients was overexpressed significantly in comparison to healthy controls. However, no altered SELL expression was observed. Three CpG sites of 12, 13 and 14 were significantly hypomethylated in patients group, despite overall methylation status of ITGB2 gene promoter revealed no significant difference between study groups. There was no statistically significant correlation between methylation status of ITGB2 promoter and the gene expression in patients. Regarding to lack of correlation of increased expression of ITGB2 with its promoter hypomethylation in SSc patients, our study suggests that upregulation of ITGB2 in PBMCs from SSc patients is probably due to another mechanism other than methylation alteration.

New-onset ANCA-associated vasculitis presenting with neuropathy after COVID-19 infection: A case report and literature review.

Coronavirus Disease 2019 (COVID-19) is a viral infection caused by SARS-CoV-2, which can trigger autoimmune diseases such as antineutrophilic cytoplasmic antibody (ANCA) associated vasculitis (AAV) that affect small and medium-sized blood vessels in multiple organs. This study discusses a case with neuropathy and positive ANCA after COVID-19 infection and reviews the literature on AAV following COVID-19 infection. A 59-year-old man is presented that was referred to Shariati Hospital for evaluation of neurologic problems after a COVID-19 infection. Initially, he had flu-like symptoms. A few days later, he developed right distal upper and lower limb paresthesia. His electromyography (EMG) and nerve conduction velocity (NCV) results were consistent with polyneuropathy. Lumbar puncture (LP) was normal except for positive COVID-19 polymerase chain reaction (PCR). The patient's paresthesia worsened. Laboratory data showed leukocytosis, anemia, thrombocytosis, high erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Perinuclear anti-neutrophil cytoplasmic antibody (MPO-ANCA) was positive. According to the results, vasculitis was the main differential diagnosis. The sural nerve biopsy was performed, and the result was consistent with small to medium-sized vessel vasculitis. The patient was diagnosed with COVID-induced AAV. He was prescribed methylprednisolone and cyclophosphamide and was discharged with prednisolone and cotrimoxazole. In this study, a unique case of AAV induced by COVID-19 infection confirmed by nerve biopsy is presented. A review of the literature found 48 cases of new-onset AAV in adults and pediatrics after COVID-19 infection. Further research is needed to completely understand the relationship between COVID-19.

Sleep disorders and other medical and socio-demographic factors in systemic scleroderma.

We aimed to investigate sleep disorders in patients with systemic scleroderma (SSc) and its relationship with socio-demographic and medical factors and to provide a suitable solution to better control the disease and improve the quality of life in these patients. This cross-sectional study evaluated SSc patients seen at a rheumatology clinic from September 1, 2022, through April 1, 2023.The patients were examined by the main investigator of the project and entered the study after taking the medical history and meeting the criteria of ACR 2013 Classification Criteria. Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS) and STOP-Bang Questionnaire were employed to investigate sleep disorders. A total of 103 patients were included in the study. The average age of the patients was 48.42 ± 12.4 years. PSQI showed lower quality of sleep scores among SSc (68% of patients), which was significantly related to the degree of skin stiffness in patients, telangiectasia, interstitial lung disease (ILD) in computed tomography (CT) scan, patient age, duration of the disease, and pulmonary artery pressure (PAP). STOP-Bang Questionnaire revealed that obstructive sleep apnea (OSA) was significantly associated with telangiectasia, ILD, patient age, disease onset age, disease duration, body mass index and PAP. Insomnia had a statistically significant relationship with telangiectasia, ILD and patient age. Drowsiness during daily activities was not significantly related to any of the individual variables and disease-related variables. Sleep disorders are common in patients with systemic scleroderma. Telangiectasia, ILD and patient age were related to all sleep quality disorders and respiratory apnea and insomnia. Furthermore, the amount of skin involvement significantly causes disturbances in the quality of sleep of patients, where in the group with diffuse skin stiffness, 80% of patients exhibited disturbances in the quality of sleep. Therefore, paying attention to sleep health can be an effective factor in improving the quality of life of patients with SSc.

Interferon-γ Induces Interleukin-6 Production and Alpha-smooth Muscle Actin Expression in Systemic Sclerosis Fibroblasts.

Systemic sclerosis (SSc) is an autoimmune systemic disease that is characterized by immune dysregulation, inflammation, vasculopathy, and fibrosis. Tissue fibrosis plays an important role in SSc and can affect several organs such as the dermis, lungs, and heart. Dysregulation of interferon (IFN) signaling contributes to the SSc pathogenesis and interferon regulatory factor 1 (IRF1) has been indicated as the main regulator of type I IFN. This study aimed to clarify the effect of IFN-gamma (-γ) and dexamethasone (DEX) on the IRF1, extracellular signal-regulated kinase 1/2 (ERK1/2), and the expression of alpha-smooth muscle actin (α-SMA) in myofibroblasts and genes involved in the inflammation and fibrosis processes in early diffuse cutaneous systemic sclerosis (dcSSc). A total of 10 early dcSSc patients (diffuse cutaneous form) and 10 unaffected control dermis biopsies were obtained to determine IFNγ and DEX effects on inflammation and fibrosis. Fibroblasts were treated with IFNγ and DEX at optimum time and dose. The expression level of genes and proteins involved in the fibrosis and inflammation processes have been quantified by quantitative real-time PCR (RT-qPCR) and western blot, respectively. IFNγ could up-regulate some of the inflammation-related genes (Interleukin-6; IL6) and down-regulate some of the fibrosis-related genes (COL1A1) in cultured fibroblasts of patients with early dcSSc compared to the untreated group. Besides, it has been revealed that IFNγ can induce fibroblast differentiation to the myofibroblast that expresses α-SMA. Concerning the inhibitory effect of IFNγ on some fibrotic genes and its positive effect on the inflammatory genes and myofibroblast differentiation, it seems that IFNγ may play a dual role in SSc.

Glomerulonephritis associated with systemic sclerosis: a case report.

BACKGROUND: Systemic sclerosis is a multiorgan autoimmune disease that can overlap with other rheumatologic disorders; however, co-occurrence with antineutrophil cytoplasmic antibody-associated vasculitis is rare. CASE PRESENTATION: A 39-year-old Persian female patient with systemic sclerosis according to American College of Rheumatology/European League Against Rheumatism 2013 criteria with a disease duration of 6 years was admitted to the hospital due to a rise in creatinine level in July 2021. She had complaints of nasal speech and feeling of nasal perforation. The first symptoms of antineutrophil cytoplasmic antibody-associated vasculitis had started 5 years earlier with palpable purpura in the lower limbs, hemoptysis, and positive perinuclear (p)-antibody-associated vasculitis level (> 300 AU/mL). Still, the diagnosis was not achieved due to the patient's reluctance to undergo a biopsy. She was treated with azathioprine (150 mg/day) and prednisolone (10 mg/day) during the 5-year follow-up. Her renal biopsy results showed cortical renal tissue with a cellular crescent in more than 50% of the specimen, rupture of the Bowman capsule and the glomerular basement membrane, peri-glomerular inflammation, and mild tubular atrophy in microscopic examinations. The immunofluorescence study resulted in a granular pattern of immune deposits along the glomerular basement membrane, mesangial tissue, and tubular basement membranes. CONCLUSION: We reported a rare case of comorbid systemic sclerosis and antineutrophil cytoplasmic antibody-associated vasculitis with nasal perforation. Her renal biopsy showed immune deposits along the glomerular basement membrane, mesangial tissue, and tubular basement membranes. Overlapping with other collagen vascular diseases can occur in rheumatology patients with uncommon manifestations. In systemic sclerosis, renal involvement in the form of glomerulonephritis is infrequent, and comorbid systemic lupus erythematosus or antineutrophil cytoplasmic antibody-associated vasculitis should be considered.

Association of anti-Ro52 autoantibody with interstitial lung disease in autoimmune diseases: a systematic review and meta-analysis.

OBJECTIVES: Interstitial lung disease (ILD) is an important manifestation of autoimmune diseases that can lead to morbidity and mortality. Although several autoantibodies have been linked with ILD presentation and adverse outcomes, the association of anti-Ro52 antibody with ILD is less studied. Hence, we investigated this association in various autoimmune diseases in the current study. DESIGN: We designed a systematic review and meta-analysis and did a comprehensive search from inception until 2 January 2023. DATA SOURCES: A systematic search was conducted in four electronic databases: PubMed, Web of Science, Scopus and Embase. ELIGIBILITY CRITERIA: Observational studies that reported ILD diagnosis (outcome) and anti-Ro antibody (exposure) status in any autoimmune conditions (population) were included. The association between rapidly progressive ILD (RP-ILD) and anti-Ro52 was studied in idiopathic inflammatory myopathies (IIM). DATA EXTRACTION AND SYNTHESIS: Collected data included study characteristics and ORs with 95% CIs. Quality assessment was performed using a modified version of the Newcastle-Ottawa Scale for cross-sectional studies. Random effects meta-analysis was used to pool the effect estimates. RESULTS: A total of 2353 studies were identified, from which 59 articles met the eligibility criteria. Anti-Ro52/SSA positivity was associated with ILD in all autoimmune disease subgroups: IIM (OR=3.08; 95% CI: 2.18 to 4.35; p value<0.001; I2=49%), systemic lupus (OR=2.43; 95% CI: 1.02 to 5.79; p=0.046; I2=71%), Sjogren (OR=1.77; 95% CI: 1.09 to 2.87; p=0.021; I2=73%), systemic sclerosis (OR=1.71; 95% CI: 1.04 to 2.83; p=0.036; I2=43%), mixed connective tissue disease (OR=3.34; 95% CI: 1.82 to 6.13; p<0.001; I2=0%). Additionally, anti-Ro52-positive myopathy patients were more likely to have simultaneous RP-ILD (OR=2.69; 95% CI:1.50 to 4.83; p<0.001; I2=71%). CONCLUSION: Anti-Ro52/SSA positivity is associated with a higher frequency of ILD diagnosis in various autoimmune diseases. Anti-Ro52/SSA is also linked with a more severe lung involvement (RP-ILD). Future studies can investigate the benefits of screening for anti-Ro52 and its association with ILD development. PROSPERO REGISTRATION NUMBER: CRD42022381447.

Association of Killer Cell Immunoglobulin-like Receptor (KIR) Genes and their HLA Ligands with Susceptibility to Takayasu Arteritis in the Iranian Population.

Takayasu arteritis (TA) is a chronic inflammatory disorder characterized by vascular damage and fibrosis in the intima that commonly occurs in the aorta. In many damaged sites in TA patients, natural killer (NK) cells have been shown to be hyperactivated and produce inflammatory cytokines and toxic components. Killer cell immunoglobulin-like receptors (KIRs) are found on NK cells and interact with human leukocyte antigen (HLA) class I ligands to activate or suppress NK cells. The present study assessed the possible role of KIR and their HLA ligand genes in susceptibility to TA in Iranian patients. This case-control study included 50 TA patients and 50 healthy subjects. DNA was extracted from whole peripheral blood samples, and polymerase chain reaction with sequence-specific primers (PCR-SSP) was performed to recognize the presence or absence of polymorphism in 17 KIR genes and 5 HLA class I ligands in each participant. Among the KIR and HLA genes, a significant decrease was detected in the frequency of 2DS4 (full allele) in TA patients (38%) compared with healthy controls (82%) (OR=0.13, 95% CI=0.05-0.34). However, none of the KIR and HLA genotypes or the interactions between these genes were associated with susceptibility to TA. The KIR2DS4 gene might be involved in the regulation of activation as well as the production of cytotoxic mediators of NK cells in patients with TA.

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.

The phenotype of mixed connective tissue disease patients having associated interstitial lung disease.

OBJECTIVE: We aimed to compare two matched populations of patients with MTCD with and without associated ILD and to identify predictive factors for ILD progression and severity. METHODS: This international multicenter retrospective study (14 tertiary hospitals), included MCTD patients who fulfilled at least one historical MCTD classification criteria. ILD was defined by the presence of typical chest high-resolution computed tomography (HRCT) abnormalities. Factors associated with ILD were assessed at baseline. Long-term progressive ILD was assessed in MCTD-ILD patients with multiple forced vital capacity (FVC) measurements. RESULTS: 300 patients with MCTD were included. Mean age at diagnosis was 39.7 ± 15.4 years and 191 (63.7%) were women. Mean follow-up was 7.8 ± 5.5 years. At baseline, we identified several factors associated with ILD presence: older age (p = 0.01), skin thickening (p = 0.03), upper gastro-intestinal (GI) symptoms (p<0.001), FVC <80% (p<0.0001), diffusing capacity for carbon monoxide <80% (p<0.0001), anti-topoisomerase antibodies (p = 0.01), SSA/Ro antibodies (p = 0.02), cryoglobulinemia (p = 0.04) and elevated C-reactive protein (p<0.001). Patients with MTCD-ILD were more likely to be treated with synthetic immunosuppressant agents (p<0.001) in particular mycophenolate mofetil (p = 0.03). Digital ulcers (DU) were identified as a risk factor for FVC decline >10%. During follow-up mortality was higher in the MTCD-ILD group (p<0.001). CONCLUSION: In this large international cohort of patients with MTCD, we identified different factors associated with ILD. Our findings also provide evidence that MCTD-ILD patients have increased mortality and that DU are associated with progressive lung disease.

The role of endothelin and RAS/ERK signaling in immunopathogenesis-related fibrosis in patients with systemic sclerosis: an updated review with therapeutic implications.

Systemic sclerosis (SSc) is a disease of connective tissue with high rate of morbidity and mortality highlighted by extreme fibrosis affecting various organs such as the dermis, lungs, and heart. Until now, there is no specific cure for the fibrosis occurred in SSc disease. The SSc pathogenesis is yet unknown, but transforming growth factor beta (TGF-ß), endothelin-1 (ET-1), and Ras-ERK1/2 cascade are the main factors contributing to the tissue fibrosis through extracellular matrix (ECM) accumulation. Several studies have hallmarked the association of ET-1 with or without TGF-ß and Ras-ERK1/2 signaling in the development of SSc disease, vasculopathy, and fibrosis of the dermis, lungs, and several organs. Accordingly, different clinical and experimental studies have indicated the potential therapeutic role of ET-1 and Ras antagonists in these situations in SSc. In addition, ET-1 and connective tissue growth factor (CTGF) as a cofactor of the TGF-ß cascade play a substantial initiative role in inducing fibrosis. Once initiated, TGF-ß alone or in combination with ET-1 and CTGF can activate several kinase proteins such as the Ras-ERK1/2 pathway that serve as the fundamental factor for developing fibrosis. Furthermore, Salirasib is a synthetic small molecule that is able to inhibit all Ras forms. Therefore, it can be used as a potent therapeutic factor for fibrotic disorders. So, this review discusses the role of TGF-ß/ET-1/Ras signaling and their involvement in SSc pathogenesis, particularly in its fibrotic situation.