Systemic Scleroderma Patients Research Articles

Skin Ultrasound Assessment of Patients with Systemic Scleroderma-An Observational Study.

This study aims to analyze the changes in dermal thickness in patients with systemic scleroderma (SSc) in comparison with normal skin and also compare clinical forms with diffuse and limited cutaneous involvement. The study group consisted of female patients diagnosed with SSc with a disease history not exceeding 5 years. The areas of interest for ultrasound examination included the proximal phalanx of the third finger, the second intermetacarpal space, and the extension surface of the lower third of the forearm. The study included 20 patients diagnosed with SSc and 14 controls. SSc patients were subdivided into two subgroups based on the clinical form. Compared to the control group, patients with SSc had higher mean measurements in all three skin areas, with statistically significant differences in the hand and forearm areas. Patients with diffuse SSc displayed, on average, higher skin thickness compared to limited SSc in all skin areas examined, with a statistically significant difference only in the forearm area. Based on disease manifestations, significant differences were observed only with regard to the presence of pulmonary hypertension in the diffuse SSc group. In conclusion, skin ultrasound is a useful and accessible imaging method for diagnosing and quantifying dermal fibrosis in systemic scleroderma.

ПРОГНОЗИРОВАНИЕ ПРОГРЕССИРОВАНИЯ ИНТЕРСТИЦИАЛЬНОГО ЗАБОЛЕВАНИЯ ЛЁГКИХ У ПАЦИЕНТОВ С СИСТЕМНОЙ СКЛЕРОДЕРМИЕЙ: АНАЛИЗ ДАННЫХ КОГОРТНОГО ИССЛЕДОВАНИЯ

Introduction. Systemic sclerosis (scleroderma) is an autoimmune disease that often causes inflammatory fibrosing lesions of the pulmonary interstitial tissue, referred to as interstitial lung disease. It is associated with a significant reduction in survival and is the leading immediate cause of the systemic scleroderma patients’ death. Progression rate of interstitial lung disease varies greatly. Since the specific immunosuppressive and antifibrotic treatment is only justified in case of progressive lesions, predicting the interstitial lung disease progression is of great practical importance. Aim: To develop approaches to predicting the progression of interstitial lung disease in systemic scleroderma patients. Materials and Methods. Our analysis included the data of patients observed in the Registry of Myositis, Systemic Scleroderma and Mixed Diseases (REMISSiZ). Inclusion criteria: Age 18+ years, the proven case of systemic scleroderma, eligibility for ACR/EULAR (2013), and the repeated high-resolution computed tomography of lungs with an interval of at least 1 year. All patients underwent 6-minute walking tests. Results and Discussion. The study included 44 patients (43 women) aged 62.9 ± 11.5 years in average. The average follow-up duration was 530 ± 231 days. Radiological progression was associated with younger age, p=0.03, severity of Raynaud’s phenomenon, p=0.032, shorter disease duration, p=0.038, and shorter distance covered in the 6-minute walk test, p=0.05. The progression of functional impairment, determined by the dynamics of the distance covered in the 6-minute walk test, was associated with a decrease in blood oxygen saturation at rest (p=0.003), the severity of breath shortness according to the Borg scale (p=0.006), the initial distance of the 6-minute walk test (p <0.001), the presence of topoisomerase I antibodies (anti-Scl-70, p=0.034), and complaints of breath shortness (p=0.043) and dysphagia (p=0.034). As a result of reverse stepwise selection of variables, three independent significant predictors were selected from the above indicators: Dysphagia, anti-Scl-70, and the initial walking distance in the 6-minute walk test. Based on these indicators, a regression formula is presented for predicting the progression of functional impairment in systemic scleroderma patients. Conclusions. X-ray-detected progression of interstitial lung disease in systemic sclerosis patients is associated with younger age and Raynaud’s phenomenon severity. To predict the decline in the systemic sclerosis patients’ functionality, it is advisable to consider the presence of dysphagia and topoisomerase I antibodies (anti-Scl-70).

The utility of layering systemic therapies in connective tissue diseases

AbstractBackgroundCutaneous manifestations in connective tissue diseases (CTDs) are often chronic and difficult to control.ObjectivesThis study aims to review the use of combination systemic medications in CTDs and assess disease response.MethodsAn IRB‐approved, retrospective chart review was conducted at a single large academic institution in New Orleans, Louisiana. Inclusion criteria were adult patients with CTDs on two or more systemic therapies.ResultsOut of 101 patients, 37.62% were taking combination systemic agents. Of these patients, 44% were diagnosed with lupus, 18% with dermatomyositis (DM), 8% with systemic scleroderma (SSc), 10% with morphea/limited scleroderma (M), 12% with mixed connective tissue disease (MCTD), and 8% with rheumatoid arthritis (RA). The most common regimen for lupus, MCTD, and SSc patients was hydroxychloroquine (HCQ) + prednisone (PRED) + mycophenolate mofetil (MMF). DM patients were most commonly taking combinations of the above regimen with intravenous immunoglobulin (IVIG). Morphea and RA patients were on multiple combinations of steroid and nonsteroidal agents including MMF, IVIG, azathioprine, methotrexate, HCQ, sulfasalazine, upadacitinib, apremilast, and tofacitinib.ConclusionsThis study aims to assess the efficacy of combination systemic medications and disease response in CTDs. Lupus was the most common CTD in our study, with patients taking 2–4 combination medications. HCQ, MMF, and PRED were the most common medications used within a combination regimen with minimal adverse effects. Though our study has several limitations including its retrospective nature and small sample size, it shows that CTDs can be resistant to monotherapy and that combination therapy might be required. More research in layering systemic agents is needed since this topic is currently limited to minimal case series and clinical trials.

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.

The basal and stimulated secretion of TNF by cultured monocytes from the blood of systemic scleroderma patients

The basal and stimulated secretion of TNF by cultured monocytes from the blood of systemic scleroderma patients

Assessment of the skin with 2D-shear wave elastography in the systemic scleroderma and its correlation with pulmonary involvement.

The purpose of this study was to assess the skin involvement in systemic scleroderma patients (SSc) with 2D-Shear Wave Elastography (2D-SWE) and to review the corelation between skin elasticity and pulmonary involvement. Thirty SSc patients and 30 controls were examined using 2D-SWE. The demographics matched both groups. B-mode ultrasound (US) and 2D-SWE assessed skin thickness and elastography from the ventral side of the right forearm in each subjective. ROC analysis determined optimal group separation cut-off values. A rheumatologist applied mRSS for SSc patients. US, mRSS, and pulmonary involvement correlations were reviewed. US parameter values (skin thickness, median kPa, median m/s) were higher in the SSc patient group (1.78 ± 0.36 mm, 22.15 ± 16.26, 2.60 ± 0.82, respectively) compared to the control group (1.55 ± 0.2 mm, 7.45 ± 1.84, 1.56 ± 0.2, respectively, p < 0.05). When the optimal cut-off SWE values for separating groups was determined as 10.5 kPa and 1.87 m/s, the sensitivity was 93% and the specificity was 97%. Pearson's correlation analysis showed a strong positive correlation between mRSS and median SWE values (kPa, r = 0.626, p = 0.001; m/s, r = 0.638, p < 0.001). There was no correlation between pulmonary involvement of SSc patients with mRSS and US parameters. 2D-SWE is a promising non-invasive method to evaluate skin involvement in SSc patient group. For pulmonary involvement we need more data with bigger patient groups.

Comprehensive description of the prevalence, serological and clinical characteristics, and visceral involvement of systemic sclerosis (scleroderma) in a large cohort from the United Arab Emirates Systemic Sclerosis Registry.

Systemic sclerosis is an autoimmune condition characterized by a wide range of clinical presentations. Registries may serve to expand understanding about systemic sclerosis and aid in patient care and follow-up. The objective of this study was to analyze the prevalence of systemic sclerosis in a large cohort from the United Arab Emirates Systemic Sclerosis Registry and find the significant similarities and differences between the different subsets. All scleroderma patients in the United Arab Emirates were included in this multicenter national retrospective analysis. Data on demographics, comorbidities, serological characteristics, clinical aspects, and treatment were collected and analyzed, highlighting the most common traits identified. A total of 167 systemic scleroderma patients from diverse ethnic backgrounds were enrolled. Overall, 54.5% (91/167) of the patients were diagnosed with diffuse cutaneous systemic sclerosis, and 45.5% (76/167) with limited cutaneous systemic sclerosis. The prevalence of systemic sclerosis was 1.66 per 100,000 for the total registry and 7.78 per 100,000 for United Arab Emirates patients. Almost all patients in the diffuse cutaneous systemic sclerosis and limited cutaneous systemic sclerosis groups tested positive for the immunofluorescence antinuclear antibody. Antibodies against Scl-70 were significantly more associated with diffuse cutaneous systemic sclerosis, whereas anticentromere antibodies were significantly more associated with the limited cutaneous systemic sclerosis group (p < 0.001). Sclerodactyly, shortness of breath, and digital ulcers were more common in diffuse cutaneous systemic sclerosis patients compared with the limited cutaneous systemic sclerosis subtype in terms of clinical symptoms and organ involvement. Telangiectasia was much more common in the limited cutaneous systemic sclerosis group. Furthermore, diffuse cutaneous systemic sclerosis patients had more lung fibrosis (interstitial lung disease) than limited cutaneous systemic sclerosis patients (70.5% vs 45.7%), and pulmonary arterial hypertension was twice as common in limited cutaneous systemic sclerosis patients as it was in diffuse cutaneous systemic sclerosis patients. Local registries are paramount to understanding the clinical/serological characteristics of scleroderma. This study emphasizes the importance of raising disease awareness and distinguishing between the various systemic sclerosis subsets to implement patient-tailored strategies for early detection, better management, and higher quality of care.

Pulmonary hypertension in connective tissue diseases: epidemiology, pathogenesis, and treatment.

Pulmonary hypertension (PH) is a clinical condition characterized by increased pulmonary arterial pressure arising from a heterogeneous range of diseases that has a deteriorating effect on the quality of life and may cause early mortality if left untreated. Connective tissue disorders (CTD)-associated PH is the second most common cause of pulmonary arterial hypertension (PAH), after the idiopathic form, categorized as group I. Systemic scleroderma (SSc) accounts for 75% of CTD-associated PH cases. Although SSc ranks first place for CTD-associated PH, SSc is followed by systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), having a lesser frequency of PH occurrence, while it occurs as a rare complication in cases with rheumatoid arthritis (RA) and inflammatory myositis. PH may also occur during non-SSc CTDs and even other rheumatic diseases, including Behcet's disease and adult-onset Still's disease, albeit to a lesser extent. The prognosis of CTD-associated PH is worse than the other forms of PH. Although, as in idiopathic pulmonary arterial hypertension (IPAH), the mechanism of CTD-related PH is associated with an increase in vasoconstrictors like endothelin-1 and a decrease in vasodilators like prostacyclin and nitric oxide production, inflammation, and autoimmune mechanisms also play a role in the development and progression of PH. This may lead to the involvement of more than one mechanism in CTD-associated PH. Knowing which mechanism is dominant is very important in determining the treatment option. This review will primarily focus on the epidemiology, risk factors, and prognosis of PH that develops during rheumatic diseases; the pathogenesis and treatment will be briefly mentioned in light of the newly published guidelines. Key Points • Pulmonary arterial hypertension (PAH) associated with connective tissue disease (CTD) in Western countries is the second most common type of PAH after idiopathic PAH (IPAH). • CTD-PH can be seen most often in systemic scleroderma (SSc), less in systemic lupus erythematosus (SLE), mixed CTD (MCTD), and rarely in other CTDs. • While current guidelines recommend annual transthoracic echocardiography as a screening test for asymptomatic SSc patients, screening for PH is not advised in the absence of symptoms suggestive of PH in other CTDs. • CTD-PH treatment can be divided into specific vasodilator PH treatments and immunosuppressive therapy. Current treatment guidelines recommend the same treatment algorithm for patients with CTD-associated PH as for patients with IPAH. Several case series have shown the beneficial effect of immunosuppressive agents in patients with SLE-PH and MCTD-PH.

Effect of crosstalk between Th17 and Th9 cells on the activation of dermal vascular smooth muscle cells in systemic scleroderma and regulation of tanshinone IIA

BackgroundTo evaluate the effect of T-helper 17 (Th17) cells and Th9 cells on the activation of dermal vascular smooth muscle cells (DVSMCs) in systemic scleroderma (SSc) and regulation of tanshinone IIA. MethodsThe expression of interleukin 17 receptor (IL-17R) and interleukin 9 receptor (IL-9R) in the skin of SSc patients was assessed by immunofluorescence. The expression of IL-9 and IL-9R mRNA in peripheral blood mononuclear cells (PBMCs) of SSc patients were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The proportion of Th9 cells in PBMCs of SSc patients was sorted by flow cytometry. The effect of IL-9 on the differentiation of Th17 and IL-17 on that of Th9 was detected by flow cytometry. The proportion of Th9 and Th17 cells in SSc patients was detected by flow cytometry. The level of collagen I, III, α-SMA, IL-9R, IL-17R, JNK, P38, and ERK were analyzed using western blot (WB). ResultsTh9 cells were highly expressed in SSc. IL-9 stimulated the differentiation of immature T cells into Th17 cells. IL-17 induced the differentiation of immature T cells into Th9 cells. Tanshinone IIA inhibited the differentiation of immature T lymphocytes into Th17 and Th9. WB showed that the combined action of IL-17 and IL-9 upregulated the inflammation and proliferation of DVSMCs. Anti-IL17, anti-IL9, and tanshinone IIA inhibited the functional activation of DVSMCs. Study limitationsFor Th17, Th9 and vascular smooth muscle cells, the study on the signal pathway of their interaction is not thorough enough. More detailed studies are needed to explore the mechanism of cell-cell interaction. ConclusionsThe current results suggested that Th17 and Th9 cells induced the activation of DVSMCs in SSc through crosstalk in vitro, and tanshinone IIA inhibited the process.

The five major autoimmune diseases increase the risk of cancer: epidemiological data from a large-scale cohort study in China.

BackgroundCancer incidence and mortality have received critical attention during the long‐term management of morbidities in patients with autoimmune diseases (AIDs). This study aimed to investigate and compare the risk of cancer associated with five major AIDs in a large‐scale Chinese cohort.MethodsA total of 8,120 AID patients consecutively admitted to a national tertiary referral center in China were included and followed‐up for 38,726.55 patient‐years, including those with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS), systemic scleroderma (SSc), and idiopathic inflammatory myositis (IIM). Demographic data, cancer incidence, predilecting sites and cancer onset time were recorded and compared among the five AIDs.ResultsFour hundred and thirty (5.3%) patients developed cancer. Their median age was 57.5 years and AID duration was 79.8 months. The estimated total standardized incidence ratio (SIR) of cancer in AIDs patients was 3.37, with the highest SIR observed in IIM (4.31), followed by RA (3.99), SSc (3.77), SS (2.88) and SLE (2.58). The increased SIR of cancers in AID patients showed a female predominance (female vs. male: 3.59 vs. 2.77) and younger patient involvement (age <50 vs. ≥50 years: 4.88 vs. 3.04). Patients with SLE had increased SIRs for developing hematologic malignancies and solid tumors located in the urinary bladder, corpus uteri and cervix uteri. Patients with SS had a significantly high SIR for developing non‐Hodgkin's lymphoma. Within 3 years of IIM diagnosis, 74.6% of the patients developed cancer and they had a high risk of ovarian cancer. RA was associated with a wide distribution of scancers, including non‐Hodgkin's lymphoma, gynecologic, urinary tract, thyroid gland and lung cancers. SSc patients had increased SIRs for developing cervical uterine, lung, and breast cancers.ConclusionPatients with five major AIDs in China had an increased risk of developing cancer, with a predominance in women and younger patients, although cancer incidence, predilection sites and cancer onset time may vary greatly in each AID entity.

Collagen triple helix repeat containing-1 exerts antifibrotic effects on human skin fibroblast and bleomycin-induced dermal fibrosis models

BackgroundSystemic scleroderma (SSc) is an acquired disorder characterized by excessive deposition of extracellular matrix in the skin and internal organs. So far, the molecular mechanisms underpinning the pathogenesis of SSc have remained unknown. Collagen triple helix repeat containing-1 (CTHRC1) has been indicated to be a cell type-specific inhibitor of transforming growth factor-β (TGF-β), which could have the potential for extensive clinical application owing to its ability to reduce collagen deposition. Our previous studies showed that CTHRC1 inhibited TGF-β1-induced collagen type I synthesis in keloid fibroblasts. In our present research, we attempted to probe the role of CTHRC1 in dermal fibrosis in bleomycin (BLM)-treated mice.MethodsCTHRC1 and TGF-β1 expression was detected in dermal tissues from patients with SSc and BLM-treated mice by immunohistochemistry. A 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay was used to assess TGF-β1-induced proliferation of human dermal fibroblasts. Collagen expression and fibroblast synthesis were evaluated by quantitative real-time polymerase chain reaction and the 3H-proline incorporation. Masson’s trichrome staining and western blotting were carried out to analyze the deposits and protein levels of type I collagen, respectively.ResultsCompared with those in normal tissues, the levels of CTHRC1 and TGF-β1 were elevated in dermal tissues from patients with SSc and in skin tissues from BLM-treated mice, respectively. Furthermore, recombinant CTHRC1 was found to inhibit TGF-β1-stimulated collagen deposition by fibroblasts. Finally, the in vivo experiments showed that CTHRC1 alleviated BLM-induced dermal fibrotic changes.ConclusionsCTHRC1 can inhibit human dermal fibroblast collagen deposition and can also exert protective effects against BLM-induced dermal fibrosis in mice. This research provides an indication that CTHRC1 may be a promising treatment choice for dermal fibrosis in SSc patients.

Морфологическая оценка кожи больных системной склеродермией до и после трансплантации гемопоэтических стволовых клеток костного мозга

Some promising clinical results of hematopoietic stem cell transplantation (HSCT) are reported in severe autoimmune diseases. When treating the patients with systemic scleroderma (SSD), histological evaluation of skin fibrosis includes scoring of myofibroblasts that are associated with excessive deposition of extracellular matrix components. The aim of our study was to evaluate morphological condition of skin in SSD patients before and after transplantation of autologous hematopoietic bone marrow stem cells. Patients and methods Twenty-eight patients were observed at the National Research Medical Center (Nur-Sultan), at the age of 45+11 years old (2 males, 26 females) with verified diagnosis of SSD according to ACR/EULAR (2013). Duration of the disease was 12+5.4 years old. Control group (12 persons) received conventional basic therapy Treatment protocol for the main group included autologous HSCT. Resistance to immunosuppressive therapy was a pre-requisite for HSCT. Bone marrow aspiration was performed from the iliac crest, the autologous mononuclear cells were isolated in Percoll density gradient and incubated for 72 hours at 37°С. Autologous HSCT was performed at a mean dose of 88×106 cells in 200 mL of physiological saline i/v over 3 hours. Clinical effect was evaluated by the recognized criteria (European Scleroderma Trials and Research Group, skin score by Rodnan). For morphological studies, the punch biopsies of tibial skin were taken in 15 patients before therapy, and in 9 three months after the treatment. The cellular therapy was accompanied by improved skin condition. The paraffin sections were stained with hematoxilin and eosin, as well as by Masson-trichrome technique. For electron microscopy, the skin biopsies were processed by conventional method, then being Epon-embedded. Semi-thin slices were stained with Methylene Blue, Azur II and basic fuchsine. For EM, the ultrathin sections were contrasted with uranyl acetate and lead citrate. Results Skin of SSD patients before treatment was characterized by induration and dystrophy and epithelial destruction, sclerosis and hyalinosis of dermal connective tissue, pathology of microcirculatory vessels. Ultrastructure of myofibroblasts in the sclerotized derma was characterized by functional overload. The active participants of fibrillogenesis were located in perivascular area, being represented by lymphocytes and fibroblasts of a specific SSD-specific population producing higher amounts of collagen and interstitial matrix. However, three months after HSCT, the main group of the patients exhibited a pronounced clinical effect with sufficient decrease of skin induration, reduced dysphagia, mitigation of muscle contractures, couping vasospasm attacks (Raynaud syndrome). Skin density was significantly decreased, with Rodnan scores changed from 12.9 to 8.7 (only 1-point decrease in the controls). HSCT promoted biodegradation of skin fibrotic tissue in SSD patients. The myofibroblasts were subjected to destruction, multiple and prolonged capillaries were observed, the cell composition of perivascular infiltrate shifted to normal state. Numerous phagocytic and secretory macrophages appeared, thus suggesting angiogenesis induction, tissue remodeling, regulation of fibroclast population, suppression of T- and B-lymphocytes playing an important role on SSD pathogenesis. Extensive telocyte connections presumed their participation in neoangiogenesis and transmission of regeneration signaling. Conclusion Transplantation of cultured autologous hematopoietic marrow stem cells in SSD patients promoted biodegradation of sclerotized dermal layer, as well as angiogenesis stimulation, restoration of epithelium and skin appendages 3 months after HSCT, thus corresponding to improvement of clinical symptoms.

Sleep Disturbance in Scleroderma.

Sleep quality may be impaired in systemic scleroderma (SSc) patients and contribute to loss of life quality. The aims of this study were to study the prevalence of sleep disturbance in SSc patients and its possible association with epidemiological, clinical and laboratory data, treatment used, and depression, and to verify the association of sleep disturbance and quality of life in this group of patients. This is a cross-sectional study including 60 SSc patients. Epidemiological, clinical, laboratory, and treatment data were extracted from the medical records. To evaluate sleep quality, the PSQI (Pittsburgh Sleep Quality Index) was used; to evaluate depression, the CES-D (Center for Epidemiological Scale-Depression) was used; and to evaluate quality of life, SF-12 (12-Item Short-Form Health Survey) was used. Disease severity was evaluated by the Medsger index and the degree of cutaneous involvement by the modified Rodnan index. The prevalence of patients with sleep disturbance was 73.3%. Sleep disturbance was associated with esophageal involvement (p = 0.03), Medsger index with higher disease severity (p = 0.01), and more depressive mood (p = 0.002). Patients with poor quality of sleep had worse quality of life by the SF-12 in mental (p = 0.001) and physical domains (p = 0.0008). No associations were found with epidemiological, serological, and treatment variables (all P's = nonsignificant). There is a high prevalence of sleep disturbance in patients with SSc that is associated with esophageal involvement, severity of disease, depression, and worse quality of life.

Deregulation of long noncoding RNAs ANCR, TINCR, HOTTIP and SPRY4-IT1 in plasma of systemic sclerosis patients: SPRY4-IT1 as a novel biomarker of scleroderma and its subtypes

Systemic sclerosis or systemic scleroderma (SSc) is an inflammatory autoimmune disease whose pathogenesis remains ambiguous; however, epigenetics, including long noncoding RNAs (lncRNAs) is an emerging paradigm. To date, the expression, role and clinical significance of most lncRNAs in SSc remain unelucidated. Herein, we investigated the plasma expression profiles of lncRNAs; ANCR, TINCR, HOTTIP, and SPRY4-IT1, which were linked to skin biology, in SSc patients and its subtypes, their potential as diagnostic tools and their correlations with autoantibodies and disease manifestations. Sixty-three SSc patients and thirty-five healthy volunteers were recruited. Autoantibody profile (anti-Scl-70, anti-centromere, anti-RNA polymeraseIII, anti-ribonucleoprotein, antinuclear, and anti-phospholipid antibodies) was determined. lncRNAs analysis was conducted using RT-qPCR. Plasma TINCR, HOTTIP, and SPRY4-IT1 upregulation and ANCR downregulation were observed in SSc patients compared with controls. SPRY4-IT1 was superior in SSc diagnosis in ROC analysis and predicted its risk in multivariate logistic analysis. Plasma SPRT4-IT1 was higher in diffuse than limited SSc. SPRY4-IT1 and HOTTIP were positively correlated with modified Rodnan skin score while ANCR showed a negative correlation only in limited SSc. ANCR and TINCR were positively correlated with disease duration and ESR, respectively. ANCR and SPRY4-IT1 were positively correlated with pulmonary hypertension. HOTTIP was positively correlated with antinuclear antibody. SPRY4-IT1 was positively correlated with HOTTIP in the whole group, and with TINCR only in diffuse SSc. We introduce plasma SPRY4-IT1, HOTTIP, ANCR and TINCR as novel candidate biomarkers for SSc, with SPRY4-IT1 could predict SSc diagnosis and discriminate its subtypes. Our findings widen the epigenetic landscape of SSc and provide surrogates for future predictive studies.

A circulating population of CD4+ cutaneous resident memory T cells is diminished in humans with fibrotic disease

Abstract Tissue-resident memory T cells (TRM) persist mainly in non-lymphoid tissues where they promote immune recall responses to recurrent insults. We previously defined a population of CD4+CD103+ TRM cells from human skin that become CD69neg and re-enter the circulation, but maintain expression of the skin-associated marker cutaneous lymphocyte antigen (CLA) and the capacity to return to the skin. Comparing blood- and skin-derived CLA+ memory populations, we found that the recirculating fraction of CD103+ TRM are clonally, transcriptionally, and phenotypically most similar to skin-resident CD103+ T cells. We now report that the circulating CD4+CLA+CD103+ T cells are functionally distinct from classically-defined CD4+ T helper lineages, highlighted by the co-production of IL-22 and IL-13. As these cytokines can promote tissue repair macrophage- and epithelial cell-mediated fibrosis and wound healing, we assessed the circulating skin TRM pool during systemic scleroderma (SSc), an autoimmune disorder highlighted by fibrosis of the skin and the underlying organs. Compared to healthy donors, SSc patients had a reduced frequency of circulating CD4+CLA+CD103+ T cells with diminished per-cell IL-13 production, both of which correlated with late-onset disease. Our ongoing work aims to understand how changes in the circulating TRM fraction might be a litmus for the onset or progression of SSc and similar skin diseases. Therefore, circulating CD4+CLA+CD103+ T cells represent a broadly available pool from which the isolation and study of skin TRM cell responses is possible both in health and disease.

Uncovering the Regulation of Fibrotic Signaling in Scleroderma by the Ubiquitin E3 Ligase KLHL42

Systemic scleroderma (SSc) is an autoimmune disease of unknown cause that affects over 2.5 million people globally. SSc results in dysfunctional connective tissues with excessive pro‐fibrotic signaling, affecting skin, cardiovascular, and particularly lung tissue. Over three‐quarters of SSc patients develop pulmonary fibrosis within five years; excessive scarring in SSc lung fibrosis is the main driver of mortality. There are no approved medicines to treat lung SSc. Recent research suggests that TGFb signaling is directly tied to SSc disease, through its pro‐fibrotic transcription factor signaling. Previous studies have shown ubiquitin e3 ligases potently control TGFb signaling through the targeted degradation of key regulator proteins, however their role in SSc‐TGFb signaling remains unclear. We utilized primary SSc patient lung cells for High Throughput Screening of modulators of TGFb signaling through High Content Imaging of the fibrotic transcription factor SMAD2/3 nuclear translocation. We screened an RNAi library targeting Ubiquitin E3 ligases and observed that the knockdown of the E3 ligase KLHL42 impaired TGFb‐dependent fibrotic signaling. KLHL42 knockdown reduced the production of fibrotic material and decreased TGFb‐mediated SMAD activation. We utilized unbiased ubiquitin proteomics to identify the phosphatase PP2A regulator PPP2R5e to be a KLHL42 substrate. Mechanistic studies validated the ubiquitin‐mediated control of PPP2R5e stability through KLHL42. Knockdown of PPP2R5e exacerbated TGFb‐mediated fibrotic signaling, demonstrating a role for PPP2R5e in the regulation of fibrotic signaling in SSc. Finally, we observed KLHL42 affected overall PP2A phosphatase activity through its targeted degradation of the subunit PPP2R5e. Here we report the characterization of the KLHL42‐PPP2R5e axis regulating fibrotic signaling in SSc lung fibroblasts. Future studies will investigate the potential for chemical inhibition of KLHL42 to ameliorate fibrotic signaling in SSc.Support or Funding Information5F31HL143843, 1R01DK119627, 5P50AR060780‐08, 1K08HL144820, 5R01HL142777, 5R35HL139860, and 5R01HL133184.

Immunological features in anti-U1-ribonucleoprotein antibody positive patients with systemic scleroderma

In anti-U1-ribonucleoprotein (anti-U1-RNP) antibody positive patients with systemic scleroderma (SSD), the clinical picture and course of the disease have specific features: there is a preponderance of its limited form; inflammatory damage to the joints and muscles comes to the fore; and cutaneous manifestations are mild. Moreover, a high frequency (68%) of interstitial lung disease is found. At the same time, the autoimmune profile in this group has been little studied.Objective:to investigate the level of major autoantibodies (autoAbs) in anti-U1RNP antibody positive patients with SSD and to compare the frequency of the autoAbs in this group and in the groups of patients with SSD phenotypes associated with anti-centromere antibodies (ACA) and anti-topoisomerase I (anti-Scl70) antibodies.Patients and methods. The investigation enrolled a total of 144 patients meeting the 2013 ACR/EULAR SSD classification criteria. Forty-four anti-U1RNP antibody positive patients were found to have autoAbs, rheumatoid factor (RF), anti-cyclic citrullinated peptide (ACCP), anti-Ro, anti-La, anti-double-stranded DNA (anti-dsDNA), anti-Smith (anti-Sm), anti-cardiolipin (aCL), anti-histidyl tRNA synthetase (anti-Jo1), anti-Scl70, and anti-RNA polymerase III (anti-RNAP-III) antibodies, and ACA in two points. The study group (anti-U1RNP antibody positive patients with SSD) and the comparison groups (anti-Scl70 and ACA positive patients) were comparatively analyzed.Results and discussion. Anti-U1RNP antibody positive patients with SSD were commonly observed to have overlaps (34%) with rheumatoid arthritis and systemic lupus erythematosus, as well as concurrence with Sjögren’s syndrome (SS) (32.5%). The study group was found to have frequently RF (27%), anti-Ro (41%), anti-dsDNA (50%) antibodies, rarely anti-Sm (9%), ACCP (9%), anti-La (7%), ACA (11%), anti-Scl70 (9%), and aCL (2%) antibodies. Anti-Jo1 and anti-RNAP-III antibodies were not detected in any patient. SSD patients who were highly positive for anti-U1RNP antibodies (more than 2 upper limits of the reference range) significantly more frequently exhibited RF, anti-Ro and anti-dsDNA antibodies (p&lt;0.01). Over time, anti-U1RNP antibodies detected at the onset of the disease persisted in 75% of patients. autoAbs were observed to disappear in patients with a low baseline titer of anti-U1RNP antibodies. Re-examination demonstrated that the detection rate of other autoAbs remained high in the group of patients who were highly positive for anti-U1RNP antibodies. Comparison of the three groups showed that the specific feature of the study group was the more frequent presence of other autoAbs, among which anti-Ro antibodies were most important. Their presence was associated with SS.Conclusion. In addition to clinical features, patients with SSD and anti-U1RNP antibody overproduction differ from those with major SSD phenotypes by the more frequent presence of other autoAbs. Persons who are highly positive for anti-U1RNP show the steady-state elevated levels of RF, anti-Ro and anti-dsDNA antibodies and the rare detection of SSD-specific autoAbs (ACA, anti-Scl70 and anti-RNAP-III).

Juvenile Scleroderma: A Referral Center Experience.

This study aims to evaluate the demographic and clinical features, laboratory data, treatment modalities, and outcomes of juvenile systemic sclerosis (JSS) and juvenile localized scleroderma (JLS) patients at a referral pediatric rheumatology center in Turkey. Medical records of a total of 57 patients, including 29 with JSS (1 male, 28 females; mean age 18.3±3.2 years; range 14 to 27 years) and 28 with JLS (6 males, 22 females; mean age 14.4±4.8 years; range 6 to 23 years), diagnosed betweenJanuary 2006 and Mart 2015 and followed-up for at least six months were evaluated in this retrospective longitudinal study. All medical records were retrospectively analyzed for demographic, clinical, and laboratory findings. Mean age at disease onset was 9.9±4.2 years and 7.7±3.9 years for JSS and JLS, respectively. Mean ages at diagnosis and at the time of study were lower in JLS: 9.1±3.5 years vs. 11.7±3.7 years and 14.4±4.8 years vs. 18.3±3.2 years, respectively. Mean disease duration was 7.8±5.2 years and 8.0±4.3 years for JSS and JLS, respectively. Among JSS patients, interstitial lung disease was seen in eight (27%), pulmonary hypertension in three (10%), and arrhythmia in one (3%). One JSS patient (3%) died as a consequence of cardiac sclerosis. Corticosteroids with methotrexate were used in 29 JSS patients (100%) and in 21 JLS patients (75%). Patients with vasculopathy were treated with nifedipine (n=18, 62%) and bosentan (n=12, 41%). Internal organ involvement was treated with high-dose cyclophosphamide (n=10, 34%) or biological agent (n=3, 10%). Close monitoring of internal organ involvement is of great importance in preventing disease-related complications in JSS and JLS. Although rare, vital organ involvement has a devastating effect on prognosis. Biological agents represent an option for patients resistant to standard immunosuppressive treatment.

Sklerodermalı Hastalarımızın Klinik ve Laboratuvar Sonuçları ve Prognozu: Tek Merkez Deneyimi

Systemic scleroderma (SSc) is a rare connective tissue disease accompanied by progressive fibrosis. Especially pulmonary, cardiac and renal involvement is a major cause of morbidity and mortality in the disease while skin involvement and Raynaud's phenomenon (RP) can also decrease the quality of life by increasing morbidity. In this study, our aim was to determine the demographics, organ involvement and prognosis of our SSc patients followed up in Rheumatology department and compare the data with the literature. For this purpose, the data of 79 patients who were followed up in our department were evaluated retrospectively. 74 (93.7%) of the 79 patients were female, the mean age of the patients was 54.3 ± 12.7 (22-76) years and the mean duration of disease was 7.29 ± 7.02 years. 71 (89.8%) had limited cutaneous SSc (lcSSc), 6 (7.6%) had diffuse cutaneous SSc (dcSSc) and 2 (2.5%) had sine scleroderma. When the cumulative organ involvement of the patients was evaluated, it was seen that 73 (92.4%) had RP, 63 (79.7%) sclerodactyly, 14 (17.7%) digital ulcer and 22 (27.8%) telangiectasia. Eight (10.1%) patients had articular complaints. Antinuclear antibody (ANA) was (+) in 49 (62%) of the patients and anti-Scl-70 was (+) in 31 (39.2%). 74 patients (93.7%) were still alive and 5 (6.3%) died. No disease-related factor was found to be effective on mortality (p> 0.05). Malignancy was developed in 4 (5.1%) patients. Only high resolution computed chest tomography (HRCT) shot count were found to be an effective factor for cancer development (OR 1.74, p = 0.023 (CI 1.081-2.829). In conclusion, causes of mortality and malignancy were similar with the literature in patients we followed up with SSc. We found a correlation between the incidence of chest CT and the malignancy development unlike the literature. This result should be supported by studies involving larger patient numbers.

Novel classification for global gene signature model for predicting severity of systemic sclerosis.

Progression of systemic scleroderma (SSc), a chronic connective tissue disease that causes a fibrotic phenotype, is highly heterogeneous amongst patients and difficult to accurately diagnose. To meet this clinical need, we developed a novel three-layer classification model, which analyses gene expression profiles from SSc skin biopsies to diagnose SSc severity. Two SSc skin biopsy microarray datasets were obtained from Gene Expression Omnibus. The skin scores obtained from the original papers were used to further categorize the data into subgroups of low (<18) and high (≥18) severity. Data was pre-processed for normalization, background correction, centering and scaling. A two-layered cross-validation scheme was employed to objectively evaluate the performance of classification models of unobserved data. Three classification models were used: support vector machine, random forest, and naive Bayes in combination with feature selection methods to improve performance accuracy. For both input datasets, random forest classifier combined with correlation-based feature selection (CFS) method and naive Bayes combined with CFS or support vector machine based recursive feature elimination method yielded the best results. Additionally, we performed a principal component analysis to show that low and high severity groups are readily separable by gene expression signatures. Ultimately, we found that our novel classification prediction model produced global gene signatures that significantly correlated with skin scores. This study represents the first report comparing the performance of various classification prediction models for gene signatures from SSc patients, using current clinical diagnostic factors. In summary, our three-classification model system is a powerful tool for elucidating gene signatures from SSc skin biopsies and can also be used to develop a prognostic gene signature for SSc and other fibrotic disorders.