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Abstract Objective Patients with diffuse cutaneous systemic sclerosis (dcSSc) frequently show spontaneous improvement of skin fibrosis. Our aim was to examine whether an improvement in skin fibrosis predicts lower likelihood of visceral organ progression and better survival. Methods Patients from the European Scleroderma Trials and Research (EUSTAR) cohort with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, and valid mRSS at 12±3 months follow up were included. Regression/progression of skin fibrosis was defined as a decrease/increase in mRSS >5 points and ≥25% from baseline to follow up. The outcomes included progression of lung, renal, cardiac and gastrointestinal manifestations using consensus derived definitions and all-cause death. Regressive, stable and progressive patients were compared by univariate, Kaplan-Meier survival curve and Cox regression analysis. Results Of 1257 included patients, 883 (70.2%) were stable, 282 (22.4%) regressive, and 92 (7.3%) progressive. Regressive patients, adjusted for baseline mRSS, baseline immunosuppression, baseline FVC, and disease duration, showed a significantly lower probability of FVC decline ≥10% than progressive patients (p=0.00003), lower probability of all-cause mortality during follow up (p=0.035) compared to progressive patients. .Improvement of skin fibrosis was not associated with progression of other organ manifestations. Conclusion We found that regression of skin fibrosis is associated with a lower probability of lung progression and better survival at follow up. The link between the disease course of skin and lung fibrosis in SSc can help to better stratify patients in clinical practice and enrich for ILD progressive patients in clinical trials.

The clinical course, the outcomes of myocarditis, and the imaging progression of cardiac magnetic resonance imaging (MRI) in systemic sclerosis (SSc) are still unknown. We aimed at defining changes in cardiac MRI findings, the clinical course, and the outcomes of SSc patients previously defined as having myocarditis by cardiac MRI. Methods: This prospective cohort study included SSc patients, who had previously been diagnosed with myocarditis through cardiac MRI at the Scleroderma Clinic of Khon Kaen University, between 2018 and 2020 and had had annual follow-ups of cardiac MRI for at least 3 years. Data on demographics, clinical characteristics, cardiac MRI findings, treatment regimens, and outcomes were collected. Serial cardiac MRI on a yearly basis was analyzed to assess changes in myocardial involvement over the 3-year period. Ten SSc patients diagnosed with myocarditis via cardiac MRI were included. Most belonged to the diffuse cutaneous subset with a mean age of 58.3±8.6 years and were mildly symptomatic. Initial cardiac MRI findings showed myocardial edema and hyperemia in all patients and eight patients had had pre-existing myocardial scars, suggesting disease chronicity. Treatment for concomitant interstitial lung disease involved steroids with either cyclophosphamide or mycophenolate mofetil in 6 patients. Outcomes of myocarditis were stable, improving, and worsening in 4, 4, and 2 patients, respectively. There was no complete resolution of the cardiac MRI indices for myocarditis, and none had had major cardiac events. Although SSc myocarditis on cardiac MRI may improve or show stability, the changes remained persistent. Among patients with SSc and mildly symptomatic myocarditis, the efficacy of steroids and immunosuppressive therapy is inconclusive. Over a 3-year follow-up, the prognosis had been acceptably good with no cardiac events. [ABSTRACT FROM AUTHOR]

Abstract Anti-topoisomerase-I antibody (ATA) is associated with disease severity and internal organ involvement in patients with systemic sclerosis (SSc). The correlation between ATA levels and the clinical course of SSc is unclear. We aimed to determine the correlation between ATA level and survival time and the onset of internal organ fibrosis in SSc patients. This historical cohort study was conducted in adult SSc patients with quantitative tests of ATA between January 2019 and December 2022. Patients with overlap syndrome and no quantitative ATA test were excluded. According to the sample size calculation, and 10% compensated for missing data, a total of 153 patients were needed. The respective mean age on the study date and median ATA level was 59.9 ± 11.3 years and 370 U/mL (range 195–652). Most cases (107 cases; 69.9%) were the diffuse cutaneous SSc subset. According to a multivariable analysis, the ATA titer had a negative correlation with the onset of cardiac involvement (Rho − 0.47, p = 0.01), and had a positive correlation with skin thickness progression (Rho 0.39, p = 0.04). Eleven cases exhibited ATA levels

Abstract To examine clinical course of early systemic sclerosis (SSc) and identify factors for progression of acro-osteolysis by a retrospective cohort study. Dual time-point hand radiography was performed at median interval (range 3.0 ± 0.4 years) in 64 recruited patients. Progressive acro-osteolysis was defined as the worsening of severity of acro-osteolysis according to rating scale (normal, mild, moderate, and severe). Incidence of the progression was determined. Cox regression was analyzed for the predictors. A total of 193.6 per 100 person-years, 19/64 patients had progressive acro-osteolysis with incidence of 9.8 per 100-person-years (95% CI 6.3–15.4). The median time of progressive acro-osteolysis was 3.5 years. Rate of progression increased from 1st to 3rd years follow-up with the progression rate at 1-, 2- and 3-years were 0, 2.0 and 18.3%, respectively. Patients with positive anti-topoisomerase I tended to have more progressive acro-osteolysis but no significant predictors on Cox regression. 44%, 18%, and 33% of who had no, mild, and moderate acro-osteolysis previously developed progression and 10 turned to be severe acro-osteolysis. In conclusion, the incidence of progressive acro-osteolysis was uncommon in early SSc but the rate of progression was pronouncedly increasing after three years follow-up. A half of the patients progressed to severe acro-osteolysis.

Objective: To develop evidence-based recommendations for the non-pharmacological and pharmacological management of Raynaud's phenomenon (RP) and digital ulcers (DUs) in patients with systemic sclerosis and other immune-mediated connective tissue diseases (CTDs). Methods: A task force comprising 21 rheumatologists, 2 surgeons (vascular and plastic), 2 nurses, and 1 patient representative was established. Following a systematic literature review performed to inform the recommendations, statements were formulated and discussed during two meetings (one online and one in-person). Levels of evidence, grades of recommendation (GoR), and level of agreement (LoA) were determined. Results: Five overarching principles and 13 recommendations were developed. GoR ranged from A to D. The mean ± standard difference (SD) LoA with the overarching principles and recommendations ranged from 7.8±2.1 to 9.8±0.4. Briefly, the management of RP and DUs in patients with CTDs should be coordinated by a multidisciplinary team and based on shared decisions with patients. Nifedipine should be used as first-line therapy for RP and/or DUs. Sildenafil, tadalafil, and/or iloprost IV are second-line options for severe and/or refractory patients with RP and/or DUs. Sildenafil, tadalafil and/or Iloprost IV, should be prescribed for healing and prevention (also including bosentan) of DUs. In patients with RP and/or DUs, non-pharmacological interventions might be considered as add-ons, but there is limited quality and quantity of scientific evidence supporting their use. Conclusions: These recommendations will inform rheumatologists, specialist nurses, other healthcare professionals, and patients about a comprehensive and personalized management of RP and DUs. A research agenda was developed to address unmet needs, particularly for non-pharmacologic interventions. [ABSTRACT FROM AUTHOR]

Objective: To perform a systematic literature review (SLR) aimed at evaluating the efficacy and safety of pharmacological and non-pharmacological treatments for Raynaud's phenomenon (RP) and digital ulcers (DU) in patients with systemic sclerosis (SSc) and other connective tissue diseases (CTD), in order to inform the Portuguese recommendations for managing RP and DU in these patients. Methods: A SLR was conducted until May 2022 to identify studies assessing the efficacy and safety of pharmacological and non-pharmacological interventions for RP and DU in SSc and other CTD. Eligible study designs included randomized controlled trials (RCTs), controlled clinical trials, and their extensions for assessing efficacy and safety of interventions. Observational studies with a comparator were included for evaluating the efficacy and safety of non-pharmacological interventions and safety of pharmacological interventions. The risk of bias of each study was assessed using standard tools. Results: Out of 71 publications meeting the inclusion criteria, 59 evaluated pharmacological and 12 nonpharmacological interventions. We found moderate quality evidence supporting the efficacy of calcium channel blockers, phosphodiesterase-5 inhibitors, and intravenous prostacyclin analogues in reducing RP frequency, severity, and duration. Intravenous iloprost had a small to moderate effect size in improving DU healing. Phosphodiesterase-5 inhibitors were effective in reducing total DU count, new DU occurrence, and enhancing DU healing. Bosentan effectively prevented new DU in SSc patients. No new safety concerns were associated with these treatments. The studies on non-pharmacological interventions were, in general, of low quality, and had a small sample size. Warming measures decreased frequency and duration of RP attacks; laser therapy improved RP-related outcomes; local oxygen-ozone therapy improved RP outcomes as an add-on therapy; bone marrow mononuclear cell implantation improved DU-associated pain; periarterial sympathectomy and vascular bypass reduced DU number and finger amputation risk. Conclusion: The available evidence supports the efficacy and safety of pharmacological interventions, namely nifedipine, sildenafil, iloprost, and bosentan in treating RP and DU in patients with SSc and other CTD. Scarce and low-quality evidence does support the use of some non-pharmacological interventions but with only a modest effect size. This SLR underscores the limited availability of high-quality evidence for determining the optimal treatment of RP and/or DUs, emphasising the need for further studies to evaluate efficacy and safety aspects. [ABSTRACT FROM AUTHOR]

To examine clinical course of early systemic sclerosis (SSc) and identify factors for progression of acro-osteolysis by a retrospective cohort study. Dual time-point hand radiography was performed at median interval (range 3.0 ± 0.4 years) in 64 recruited patients. Progressive acro-osteolysis was defined as the worsening of severity of acro-osteolysis according to rating scale (normal, mild, moderate, and severe). Incidence of the progression was determined. Cox regression was analyzed for the predictors. A total of 193.6 per 100 person-years, 19/64 patients had progressive acro-osteolysis with incidence of 9.8 per 100-person-years (95% CI 6.3–15.4). The median time of progressive acro-osteolysis was 3.5 years. Rate of progression increased from 1st to 3rd years follow-up with the progression rate at 1-, 2- and 3-years were 0, 2.0 and 18.3%, respectively. Patients with positive anti-topoisomerase I tended to have more progressive acro-osteolysis but no significant predictors on Cox regression. 44%, 18%, and 33% of who had no, mild, and moderate acro-osteolysis previously developed progression and 10 turned to be severe acro-osteolysis. In conclusion, the incidence of progressive acro-osteolysis was uncommon in early SSc but the rate of progression was pronouncedly increasing after three years follow-up. A half of the patients progressed to severe acro-osteolysis. [ABSTRACT FROM AUTHOR]

Objectives To explore prognostic and predictive markers of SSc-associated interstitial lung disease (SSc-ILD) outcomes in a phase 3 trial (focuSSced) and prognostic markers in a real-world cohort (SMART). Methods The focuSSced SSc-ILD subgroup included 68 of 106 placebo-treated and 68 of 104 tocilizumab-treated patients. The SMART cohort included 505 patients with SSc-ILD. Linear mixed-effect models were used to identify factors associated with change in forced vital capacity (FVC). Kaplan–Meier estimation and Cox regression were used for time-to-event analyses. Results In placebo-treated focuSSced patients, sex was a significant prognostic factor for FVC decline; males had increased risk for absolute decline ≥10% in percent-predicted FVC (ppFVC) and 0.22% faster weekly FVC decline than females (P   =  0.0001). FVC was 9.8% lower in patients with CRP >6 mg/ml vs those with CRP ≤6 mg/ml (P  = 0.0059). Tocilizumab reduced the risk for ≥10% decline in ppFVC in patients who were male, had earlier disease (<2 years duration), had IL-6 levels <10 pg/ml, or had anti-topoisomerase antibodies (ATA). In the SMART cohort, prognostic factors for ppFVC <70% were male sex, ATA, and low baseline FVC. Males had 3.3% lower FVC 1 year after disease onset (P  < 0.001) and 0.6% faster yearly decline (P  = 0.03) than females. Conclusion Prognostic markers in SSc-ILD were similar between focuSSced and SMART. Male sex and inflammatory markers were associated with lower FVC but IL-6 ≥10 pg/ml was not predictive of response to tocilizumab. Trial Registration ClinicalTrials.gov: NCT02453256. [ABSTRACT FROM AUTHOR]

Background: Systemic sclerosis (SSc) patients often become refractory to proton pump inhibitors (PPI)—a standard treatment for gastroesophageal reflux disease (GERD)—and intolerant to PPI in combination with domperidone. PPI with alginic acid is an alternative treatment option, but alginic acid is costly. Objectives: We compared the costs and effectiveness of alginic acid plus PPI versus standard treatments (PPI with/without antacids as needed and lifestyle modifications) for GERD in SSc patients unsuitable for, or intolerant to, domperidone. Methods: An economic evaluation using the Markov model was conducted among SSc patients aged between 40 and 65 years with GERD, having a partial or non‐response to 4 weeks of standard‐dose omeprazole (40 mg/day) and being unsuitable for or intolerant to domperidone. Using a societal perspective, we computed the incremental cost‐effectiveness ratios (ICERs) in terms of Thai baht (THB) per quality‐adjusted life‐year (QALY) between a combination of alginic acid plus PPI and standard treatment for GERD. The lifetime time horizon was used. Results: The ICER for alginic acid plus PPI versus standard treatments was 377 101 THB/QALY. According to the one‐way sensitivity analysis, the cost of alginic acid was the most impactful parameter. If the market prices of alginic acid plus PPI were reduced by 61%, this treatment option would become cost‐effective at the willingness‐to‐pay threshold of 160 000 THB/QALY (34.68 THB/USD data on 25 May 2023). Furthermore, if alginic acid were included in the public health insurance program, the national budget would be increased by 66 313 THB per patient, resulting in an overall budget increase of 5 106 101 to 8 885 942 THB compared with the standard treatment. Conclusions: Alginic acid plus PPI does not represent good value for money compared with the standard treatment among such SSc patients in Thailand unless its price is reduced significantly. [ABSTRACT FROM AUTHOR]

Objectives SSc is an autoimmune disease characterized by excessive fibrosis in multiple organs, including the gastrointestinal (GI) tract. GI symptoms of SSc such as intestinal pseudo-obstruction (IPO) are often refractory to conventional intervention and can result in longer in-hospital stay or even increased mortality. We aimed to summarize the insights to date regarding the efficacy of IVIG against GI symptoms of SSc to unveil what we should focus on in future studies. Methods Herein we report the response of GI symptoms in three cases with SSc-myositis overlap who received IVIG administration. We also conducted a systematic literature review to summarize previous reports regarding the efficacy of IVIG upon the GI manifestations of SSc, according to the PRISMA 2020 guideline. Results The case series demonstrated remarkable and rapid improvement of GI symptoms, including IPO, after IVIG administration. The literature review revealed that previous reports also support the efficacy and safety of IVIG against GI manifestations of SSc. However, they were all retrospective studies and lacking description of the short-term outcome after IVIG administration with objective and quantitative metrics. Conclusion IVIG seems to be a promising therapeutic option for the management of GI symptoms in SSc, including IPO. Investigators should focus more on short-term outcomes to properly assess the therapeutic benefit of IVIG, ideally using reliable quantitative measures in a multicentre randomized placebo-controlled setting. [ABSTRACT FROM AUTHOR]

Kookwan Sawadpanich,1 Palinee Promasen,1 Pisaln Mairiang,1 Wattana Sukeepaisarnjareon,1 Apichat Sangchan,1 Tanita Suttichaimongkol,1 Kawin Tangvoraphonkchai,1 Chingching Foocharoen2 1Division of Gastroenterology and Hepatology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand; 2Division of Rheumatology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, ThailandCorrespondence: Chingching Foocharoen, Division of Rheumatology, Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand, Tel +66-43-363-746 ; +66-43-363-664, Email fching@kku.ac.thBackground: Abnormal liver function tests (LFTs) can indicate cirrhosis or liver cancer leading to mortality among systemic sclerosis (SSc) patients. No recent studies have investigated the clinical predictors of an abnormal LFT in SSc. We aimed to determine the incidence of abnormal LFT (including from hepatitis and cholestasis) and to identify its clinical predictors in SSc patients.Methods: An historical cohort was conducted on 674 adult SSc patients who attended the Scleroderma Clinic, Khon Kaen University, between January 2012 and November 2019 and who underwent routine screening for LFT. A Cox regression was used to analyze the clinical predictors of abnormal LFT.Results: Four hundred and thirty cases, representing 4190 person-years, had abnormal LFTs (viz, from hepatitis, cholestasis, and cholestatic hepatitis) for an incidence rate of 10.2 per 100 person-years. The respective incidence of hepatitis, cholestasis, and cholestatic hepatitis was 20.5, 12.9, and 20.4 per 100 person-years. The respective median first-time detection of hepatitis, cholestasis, and cholestatic hepatitis was 3.0, 5.9, and 2.8 years, and none had signs or symptoms suggestive of liver disease. According to the Cox regression analysis, the predictors of an abnormal LFT in SSc were elderly onset of SSc (hazard ratio (HR) 1.02), alcoholic drinking (HR 1.74), high modified Rodnan Skin Score (mRSS) (HR 1.03), edematous skin (HR 2.94), Raynaud’s phenomenon (HR 1.39), hyperCKaemia (HR 1.88), and methotrexate use (HR 1.55). In contrast, current sildenafil treatment (HR 0.63) and high serum albumin (HR 0.70) were protective factors.Conclusion: Occult hepatitis, cholestasis, and cholestatic hepatitis can be detected in SSc patients using LFT screening, especially in cases of early disease onset. The long-term outcome is uncertain, and more longitudinal research is required.Keywords: systemic sclerosis, scleroderma, scleroderma and related disorders, hepatitis, cholestasis, cholestatic hepatitis, abnormal liver function test, liver, cohort study

Scleroderma is a rare, potentially fatal, clinically heterogeneous, systemic autoimmune connective tissue disorder that is characterized by progressive fibrosis of the skin and visceral organs, vasculopathy and immune dysregulation. The more severe form of the disease, diffuse cutaneous scleroderma (dcSSc), has no cure and limited treatment options. Haematopoietic stem cell transplantation has emerged as a potentially disease-modifying treatment but faces challenges such as toxicity associated with fully myeloablative conditioning and recurrence of autoimmunity. Novel cell therapies—such as mesenchymal stem cells, chimeric antigen receptor-based therapy, tolerogenic dendritic cells and facilitating cells—that may restore self-tolerance with more favourable safety and tolerability profiles are being explored for the treatment of dcSSc and other autoimmune diseases. This narrative review examines these evolving cell therapies. [ABSTRACT FROM AUTHOR]

Abstract Background The gold standard for skin thickness assessment in systemic sclerosis (SSc) is the modified Rodnan skin score (mRSS); however, inter- and intra-rater variation can arise due to subjective methods and inexperience. The study aimed to determine the inter- and intra-rater variability of mRSS assessment using a skin model. Methods A comparative study was conducted between January and December 2020 at Srinagarind Hospital, Khon Kaen University, Thailand. Thirty-six skin sites of 8 SSc patients underwent mRSS assessment: 4 times the first day and 1 time over the next 4 weeks by the same 10 raters. No skin model for mRSS assessment was used for the first two assessments, while one was used for the remaining three rounds of assessments. The Latin square design and Kappa statistic were used to determine inter- and intra-rater variability. Results The kappa agreement for inter-rater variability improved when the skin model was used (from 0.4 to 0.5; 25%). The improvement in inter-rater variability was seen in the non-expert group, for which the kappa agreement rose from 0.3 to 0.5 (a change of 66.7%). Intra-rater variability did not change (kappa remained at 0.9), and the long-term effect of using a skin model slightly decreased by week 4 (Δkappa 0.9–0.7). Conclusions Using a skin model could be used to improve inter-rater variation in mRSS assessment, especially in the non-expert group. The model should be considered a reference for mRSS assessment in clinical practice and health education.

Objectives Symptoms of people who have SSc are heterogeneous and difficult to address clinically. Because diverse symptoms often co-occur and may share common underlying mechanisms, identifying symptoms that cluster together may better target treatment approaches. We sought to identify and characterize patient subgroups based on symptom experience. Methods An exploratory hierarchical agglomerative cluster analysis was conducted to identify subgroups from a large SSc cohort from a single US academic medical centre. Patient-reported symptoms of pain interference, fatigue, sleep disturbance, dyspnoea, depression and anxiety were used for clustering. A multivariate analysis of variance (MANOVA) was used to examine the relative contribution of each variable across subgroups. Analyses of variance were performed to determine participant characteristics based on subgroup assignment. Presence of symptom clusters were tallied within subgroup. Results Participants (n  = 587; 84% female, 41% diffuse cutaneous subtype, 59% early disease) divided into three subgroups via cluster analysis based on symptom severity: (i) no/minimal, (ii) mild, and (iii) moderate. Participants in mild and moderate symptoms subgroups had similar disease severity, but different symptom presentation. In the mild symptoms subgroup, pain, fatigue and sleep disturbance was the main symptom cluster. Participants in the moderate symptoms subgroup were characterized by co-occurring pain, fatigue, sleep disturbance, depression and anxiety. Conclusion Identification of distinct symptom clusters, particularly among SSc patients who experience mild and moderate symptoms, suggests potential differences in treatment approach and in mechanisms underlying symptom experience that require further study. [ABSTRACT FROM AUTHOR]

Objectives Autologous haematopoietic stem cell transplantation (AHSCT) is a disease-modifying treatment for patients with severe SSc. Here, we aimed at assessing cardiopulmonary function outcomes of SSc patients after AHSCT. Methods Twenty-seven SSc adult patients treated with AHSCT were included in this retrospective study. Most had the diffuse cutaneous subset (93%) and pulmonary involvement (85%). Before and 12 months after AHSCT, patients underwent cardiopulmonary exercise testing, transthoracic echocardiography, pulmonary function test with diffusing capacity for carbon monoxide (DLCO), 6-min walk test (6MWT) and quality of life evaluations. Results After AHSCT, the peak VO2 increased from 954 to 1029 ml/min (P  = 0.02), the percentage of predicted peak VO2 increased from 48.9 to 53.5 m (P  = 0.01), and the distance measured by the 6MWT increased from 445 to 502 m (P  = 0.01), compared with baseline. Improvements in peak VO2 correlated positively with improvements in 6MWT distance, and negatively with a decrease in resting heart rate. At baseline, patients with DLCO >70% had higher peak VO2 values than those with DLCO <70% (P  = 0.04), but after AHSCT all patients showed improved VO2 values, regardless of baseline DLCO levels. Increases in VO2 levels after AHSCT positively correlated with increases in the physical component scores of the Short Form-36 quality of life questionnaire (r  = 0.70; P  = 0.0003). Conclusion AHSCT improves the aerobic capacity of SSc patients probably reflecting combined increments in lungs, skeletal muscle and cardiac function. [ABSTRACT FROM AUTHOR]

Background: Skin tightness is a hallmark of systemic sclerosis (SSc), and the fingers are an affected body part, so much so that fingerprints can be significantly affected among those with extensive skin tightness of the finger. Objective: We aimed to compare the difference between the current and past (pre-disease onset) fingerprints of SSc patients. Methods: We conducted a cross-sectional study among adult SSc patients who attended the Scleroderma Clinic, Khon Kaen University, between October 2019, and September 2020. All eligible patients consented to obtaining their current and previous prints from the Central Registration Bureau, Department of Provincial Administration, Ministry of the Interior. The current prints were obtained using the Crossmatch (Lite UE) live scan from the Central Institute of Forensic Science of Thailand. We investigated the concordance between the prints before disease onset and the current (enroll date) via the Printquest AFIS system with officers from the Central Institute of Forensic Science, Thailand. Results: One hundred SSc patients, according to the sample size calculation, were enrolled (mean age 59.4 ± 9.6 years; 66% female). Most (70%) had the diffuse cutaneous SSc subset. A respective 59%, 55%, and 6% presented acro-osteolysis, hand deformities, and digital ulcers. Some challenges were experienced in obtaining prints from patients with loss of the fingertip fat pad, finger joint contracture, and/or acro-osteolysis; notwithstanding, all fingerprints were usable and without individualized changes. Conclusion: Fingerprints were affected by fingertip lesions and finger joint contractures; notwithstanding, the prints remained usable for personal identification. Key Points • Skin involvement in systemic sclerosis (SSc) affects the prints, particularly at the fingertip. • Despite disease onset, the fingerprints of SSc patients do not change significantly. • Fingerprints are inadequate for personal identification among SSc patients with hand deformities due to poor quality or difficulty acquiring them. [ABSTRACT FROM AUTHOR]

Abstract Background Autologous hematopoietic stem cell transplantation (AHSCT) treats patients with severe and progressive systemic sclerosis (SSc). However, basic mechanisms associated with the therapeutic efficacy of the procedure are not entirely understood. We aimed to evaluate how AHSCT affects skin fibrosis in SSc patients. Methods Clinical data, serum, and skin samples from 39 SSc patients who underwent AHSCT were retrospectively evaluated. Skin biopsies were analyzed by immunohistochemistry with anti-MMP-1, -MMP-2, -MMP-3, -MMP-9, -TIMP-1, -α-SMA, -TGF-β, and -NF-κB p65 antibodies, and stained with hematoxylin and eosin and picrosirius red to assess skin thickness and collagen density, respectively. Serum samples were evaluated by Multiplex Assay for COL1A1, COL4A1, FGF-1, MMP-1, MMP-3, MMP-12, MMP-13, PDGF-AA, PDGF-BB, S100A9, and TIMP-1 levels and compared to healthy controls. Results After AHSCT, SSc patients showed clinical improvement in skin involvement, assessed by modified Rodnan’s skin score (mRSS). Histologically, collagen density and skin thickness decreased after AHSCT. Immunohistochemical analyses showed increased expression of MMP-2, MMP-3, MMP-9, and TIMP-1 after AHSCT, whereas expression of NF-κB p65 decreased. At baseline, serum levels of COL4A1 and S100A9 were higher than in healthy controls. Serum levels of S100A9 normalized after AHCST in SSc patients compared to controls. Serum levels of PDGF-AA, PDGF-BB, TIMP-1, and MMP-1 decreased, while COL1A1 increased after AHSCT in SSc patients. No changes were detected in MMP-3, MMP-12, MMP-13, and FGF-1 serum levels after AHSCT. Conclusions Our results suggest that the therapeutic effects of AHSCT on skin fibrosis are related to changes in molecules associated with connective tissue maintenance and inflammation in SSc.

Objectives: Physician's evaluation of interstitial lung disease (ILD) extension with high-resolution computed tomography (HRCT) has limitations such as lack of objectivity and reproducibility. This study aimed to investigate the utility of computer-based deep-learning analysis using QZIP-ILD® software (DL-QZIP) compared with conventional approaches in connective tissue disease (CTD) -related ILD., Methods: Patients with CTD-ILD visiting our Rheumatology Centre between December 2020 and April 2024 were recruited. Quantitative scores, including the percentage of lung involvement in ground-glass opacity (QGG), total fibrotic lesion (QFIB), and overall ILD extension encompassing both QGG and QFIB (QILD), calculated by DL-QZIP, were compared with semiquantitative visual method, employing intraclass correlation coefficients (ICC). We compared the capability of QILD scores to distinguish patients with forced vital capacity (FVC) % <70 in both methods determined by the area under the curve (AUC) by the receiver-operating characteristic curve analysis and DeLong's test., Results: Eighty patients (median age, 66 years; 14 men) were included. Median QGG, QFIB, and QILD scores were 3.45%, 2.19%, and 5.35% using DL-QZIP, and 3.25%, 4.06%, and 8.48% using visual method, respectively. Correlations between DL-QZIP and visual method were 0.75 for QGG, 0.61 for QFIB, and 0.75 for QILD. The AUC of QILD scores for FVC% <70 was significantly higher with DL-QZIP (0.833) compared with visual method (0.660) (p < 0.01)., Conclusion: QZIP-ILD® demonstrates superior capability in distinguishing patients with a radiological scenario correlated to severe physiological impairment, while showing relatively good correlations in quantifying the extent on HRCT compared with conventional method in CTD-ILD., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective Systemic sclerosis (SSc) is a rare, chronic disease characterized by fibrosis, vascular alterations and digital ulcerations. Few drugs have shown efficacy to enhance wound healing of existing SSc-related ulcers. Local delivery of treprostinil, a prostacyclin analogue, may improve wound healing. The present work aimed first at developing a mouse model of SSc-related ulcerations and second at assessing the effect of iontophoresis of treprostinil on wound healing. Methods We used two murine models of SSc: chemically induced with HOCl, and urokinase-type plasminogen activator receptor (uPAR)-deficient. Excisional wounding was performed on the dorsal midline with a biopsy punch. Animals were randomized into three groups: treated with electrostimulation alone, with treprostinil iontophoresis or untreated. We assessed wound healing over time, as well as skin microvascular reactivity, inflammation, microvessel density and collagen distribution, before wounding and after re-epithelialization. Results uPAR–/– mice, but not HOCl-treated mice, showed impaired wound healing and decreased microvascular reactivity compared with their controls. Treprostinil iontophoresis improved wound healing and microvascular density and decreased inflammation in uPAR–/– mice, while electro-stimulation did not. However, treprostinil had no effect on microvascular reactivity and collagen distribution. Conclusion This study suggests that excisional wounds in uPAR–/– mice are a relevant model of SSc-related ulcers. In addition, treprostinil iontophoresis enhances wound healing in this model. Further work in now needed to show whether this effect translates in humans. [ABSTRACT FROM AUTHOR]

Introduction: Vasculopathy is a crucial feature of systemic sclerosis (SSc). It occurs in almost every patient with SSc, with Raynaud's phenomenon (RP) and digital ulcers (DU) having a great impact on the quality of patients' lives. Intravenous (IV) iloprost, a synthetic analogue of prostacyclin, is broadly used to treat RP and DU secondary to SSc. Currently, there is no standard protocol defined for the iloprost treatment of SSc-associated RP and DU, and, consequently, the management of this treatment is largely based on each centre's experience. Objective: The objective of this study is to evaluate the safety profile of a particular scheme of IV iloprost used in our centre as the standard treatment of SSc-related vascular complications. Methods: We retrospectively evaluated the clinical records of SSc patients, classified according to the 2013 European Alliance of Associations for Rheumatology (EULAR) criteria (31) with SSc-related DU and/or severe RP not responsive to calcium channel blockers (CCB), receiving or who have received IV iloprost infusions from January 1st 2011 to March 31st 2021 Results: Within this time frame, 60 patients (n=44 for DU; n=16 for severe RP) were treated with a monthly 10-hour IV iloprost perfusion with a dosing regimen adapted to individual tolerance. Forty-nine of these 60 patients (81.7%) were on iloprost for more than one year. Within 12 months of therapy, 40 patients have healed the DUs (90.9%), with only 4 patients maintaining active DUs. A significant clinical improvement in RP at 12 months was observed in 87.5% (n=14/16) of SSc patients with severe RP. Eleven AE implying treatment dose/frequency adjustments or suspension were recorded (18.3% of patients): severe headache (n=5), hypotension (n=3), tachycardia (n=1), flushing (n=1) and generalised erythroderma (n=1). In all patients, the perfusion rate was reduced in the following treatment sessions with good tolerance, with the exception of the patient with the generalised erythroderma reaction, who suspended the perfusion and was later switched to bosentan. After a mean follow-up time of 6.9 (+/-) 4.0 years of treatment (range 0.06-22), 24 patients (40%) stopped the therapy, 14 (58.3%) of whom due to clinical improvement. The overall 5-, and 10-year survival rates of IV iloprost were 68.2% and 55.6%, respectively. Conclusion: SSc patients who received this flexible IV iloprost regimen achieved clinical improvement, reflected in the high persistence rate of the drug, with a good tolerability profile. In addition, most side effects were mild and easily managed. [ABSTRACT FROM AUTHOR]

Objective: Autologous hematopoietic stem cell transplantation (AHSCT) is a therapeutic option for patients with severe and progressive systemic sclerosis (SSc). Here, we aimed to investigate how AHSCT affects the vasculopathy of SSc patients. Methods: Twenty-seven SSc patients were retrospectively assessed, before and after AHSCT, for vessel morphology (nailfold capillaroscopy), skin expression of endothelial markers and serum levels of markers of inflammation, angiogenesis and endothelial activation. Skin biopsies were analyzed by immunohistochemistry (IHC) for expression of CD31, VE-cadherin, E-selectin, angiopoietin-1 (Ang1), angiopoietin-2 (Ang2), Tie-2, vascular endothelial growth factor A (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2), and endothelin-1 before and 12 months post-AHSCT. Serum samples from SSc patients were assessed before and up to 36 months after AHSCT for IL-6, von Willebrand factor (vWF), CXC Motif Chemokine Ligand 8 (CXCL8), Endothelin-1, epidermal growth factor (EGF), VEGFA, Pentraxin-3, Intercellular Adhesion Molecule 1 (ICAM-1), E-selectin, P-selectin, Thrombomodulin and IL-18 levels, and compared to healthy control samples. Results: On nailfold capillaroscopy, the number of capillaries increased at 1 year, while giant capillaries decreased at 6 months and 1 year after AHSCT. In the skin biopsies, expression of E-selectin notably decreased and Ang1 increased after AHSCT. At baseline, all vascular markers evaluated in the serum were significantly higher in SSc patients when compared to healthy controls, except for ICAM-1. When compared at different time points after AHSCT, Thrombomodulin, Pentraxin-3, vWF, and IL-18 levels remained generally stable at high levels until 36 months after AHSCT. Conclusion: Our results suggest that AHSCT contributes to improvements of the vessel morphology and dermal microvasculopathy, but does not normalize elevated levels of serum vascular markers in SSc patients. Additional vascular therapeutic approaches might contribute to more effectively treat the endothelial injury. [ABSTRACT FROM AUTHOR]

Objective: Racial and ethnic differences in presentation and outcomes have been reported in systemic sclerosis (SSc) and SSc-interstitial lung disease (ILD). However, prior studies have limited diversity. We aim to evaluate if there are racial/ethnic differences associated with ILD, time intervals between SSc and ILD and with emergency department (ED) visit or hospitalization rates., Methods: Clinical and sociodemographic variables were extracted for 756 patients with SSc from longitudinal health records in an integrated health-system. Logistic regression models analyzed the association of covariates with ILD and age at SSc-ILD. Healthcare outcomes were analyzed with complementary log-log regression models., Results: Overall, 33.7% of patients in the cohort had an ILD code, with increased odds for Asian (odds ratio [OR], 2.60; 95% confidence interval [CI], 1.29-5.28; p=0.008) compared with White patients. The predicted age in years of SSc-ILD was younger for Hispanic (estimate, -6.5; 95% CI, -13--0.21; p = 0.04) and Black/African American patients (-10; 95% CI -16--4.9; p < 0.001) compared with White patients. Black/African American patients were more likely to have an ILD code before an SSc code (59% compared with 20.6% of White patients), and the shortest interval from SSc to ILD (3 months). Black/African American (HR, 2.59; 95% CI 1.47-4.49; p = 0.001) and Hispanic patients (HR 2.29; 95% CI 1.37- 3.82; p = 0.002) had higher rates of an ED visit., Conclusion: We found that odds of SSc-ILD differed by racial/ethnic group, minoritized patients had earlier age of presentation, and greater rates of an ED visit., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

This article discusses the condition of calcinosis in systemic sclerosis (SSc), which is characterized by the deposition of insoluble calcium salts in tissues. The exact cause of calcinosis is unknown, and there are currently no effective medical treatments for this condition. Imaging, particularly X-rays, plays a crucial role in detecting and tracking the progression of calcinosis. The article presents a case study of a 74-year-old Caucasian woman with SSc who exhibited cutaneous calcinosis and other symptoms. The authors emphasize the importance of detailed physical examination for diagnosing SSc at a late stage of the disease. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Objective SSc reduces upper extremity function and performance of everyday activities; however, there are few evidence-based rehabilitation interventions. This study examined short and longer-term effects of two occupational therapy interventions on hand disability. Methods Participants with diffuse cutaneous SSc were randomized to one of two 18-week interventions: Intensive group, receiving eight weekly in-person occupational therapy sessions with App-delivered home exercises, or App Alone group. The primary outcome was QuickDASH hand disability; secondary outcomes were physical function (PROMIS scale), and total active hand motion. Linear mixed models were used to examine treatment effects. Results Most participants were female (72%); the mean age was 52 years (13.4) (n  = 32). There were no significant between-group effects on QuickDASH (P = 1.0; mean change −6.4 on 0–100 scale in both groups at 18 weeks). Left lateral pinch, an exploratory outcome, improved in App Alone compared with Intensive from baseline to 18 weeks. Within groups, the Intensive group had the largest improvements after 8 weeks (−8.5 on QuickDASH; P = 0.03), but then lost gains from 8 to 18 weeks while the App Alone group had modest improvements from baseline to 8 weeks, but then continued to improve. Of completers, 50% had clinically meaningful improvement on QuickDASH in the Intensive group and 64% had improvement in App Alone. Conclusion Both interventions showed beneficial effects on hand disability. Participants in the App Alone group improved equally to the Intensive group at 18 weeks. Our findings provide support for further study into telehealth rehabilitation approaches. Trial registration NCT03482219 [ABSTRACT FROM AUTHOR]

ObjectiveDyspnoea is a common, multifactorial source of functional impairment among patients with dcSSc. Our objective was to assess the reliability, construct validity and responsiveness to change of the Saint George's Respiratory Questionnaire (SGRQ) in patients with early dcSSc participating in a multicentre prospective study.MethodsAt enrolment and 1 year, patients completed the SGRQ (a multi-item instrument with four scales: symptoms, activity, impact and total), a visual analogue scale (VAS) for breathing and the HAQ Disability Index (HAQ-DI) and underwent 6 min walk distance and pulmonary function tests, physician and patient global health assessments and high-resolution CT (HRCT). We assessed internal consistency reliability using Cronbach's α. For validity we examined the ability of the SGRQ to differentiate the presence vs absence of interstitial lung disease (ILD) on HRCT or restrictive lung disease and evaluated the 1 year responsiveness to change using pulmonary function tests and patient- and physician-reported anchors. Correlation coefficients of 0.24-0.36 were considered moderate and >0.37 was considered large.ResultsA total of 177 patients were evaluated. Reliability was satisfactory for all SGRQ scales (0.70-0.93). All scales showed large correlations with the VAS for breathing and diffusing capacity of the lung for carbon monoxide in the overall cohort and in the subgroup with ILD. Three of the four scales in the overall cohort and the total scale in the ILD subgroup showed moderate to large correlation with the HAQ-DI and the predicted forced vital capacity (r = 0.33-0.44). Each scale discriminated between the presence and absence of ILD and restrictive lung disease (P ≤ 0.0001-0.03). At follow-up, all scales were responsive to change using different anchors.ConclusionThe SGRQ has acceptable reliability, construct validity and responsiveness to change for use in a dcSSc population and differentiates between patients with and without ILD.

Objective: We hypothesized that glucocorticoids would induce remission in very early Systemic Sclerosis patients by inhibition of inflammation driving the disease. We examined the efficacy and safety of methylprednisolone in very early Systemic Sclerosis., Methods: In this trial adults with puffy fingers for less than three years, specific auto-antibodies and meeting the Very Early Diagnosis of Systemic Sclerosis criteria were randomly assigned (2:1) to methylprednisolone 1000 mg intravenously or placebo for 3 consecutive days 3 times with monthly intervals. The primary end point was nailfold capillary density at week 12. Capillary density at 52 weeks, number of megacapillaries, and patient-reported outcomes were secondary outcomes. In addition, we assessed disease progression and lung function decline over 52 weeks. We used linear regression analyses adjusted for baseline values and stratification variables to estimate differences between groups., Results: Between February 2017 and February 2021, 87 patients were screened, of whom 30 (70% female, median (IQR) age 52·9 (40·8-60·8) years, median (IQR) disease duration 11.4 (4.6-18.6) months) were randomly assigned to methylprednisolone (n = 21) or placebo (n = 9). We found no difference in nailfold capillary density at 12 weeks: -0.5 (95% CI 1.1, 0.2) nor in any of the secondary outcomes. Eleven (37%) patients showed disease progression during 1 year follow up, 7 (23%) patients had a relevant pulmonary function decline. No serious adverse events were reported., Conclusions: No clinically relevant effect of short-term methylprednisolone in patients with very early Systemic Sclerosis was observed. A substantial proportion of patients showed disease progression., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective Interstitial lung disease (ILD) is a leading cause of mortality in SSc. Little is known about the benefits of immunosuppressive drugs in mild ILD. Our aim was to determine whether use of CYC or MMF was associated with an improved ILD course in patients with normal or mildly impaired lung function. Methods A retrospective cohort of SSc subjects with ILD, disease duration below seven years and no exposure to CYC or MMF prior to the baseline visit was constructed from the Canadian Scleroderma Research Group registry. Subjects were categorized as having mild ILD if baseline forced vital capacity (FVC % predicted) was >85%. The primary exposure was any use of CYC or MMF at the baseline visit. FVC at one year was compared between exposed and unexposed subjects, using multivariate linear regression. Results Out of 294 eligible SSc-ILD subjects, 116 met criteria for mild ILD. In this subgroup, mean (s. d.) disease duration was 3.7 (2.0) years. Thirteen (11.2%) subjects were exposed to CYC or MMF at baseline. The one-year FVC was higher in exposed subjects compared with unexposed subjects, by a difference of 8.49% (95% CI: 0.01–16.98%). None of the exposed subjects experienced clinically meaningful progression over two years, whereas 24.6% of unexposed subjects did. Conclusion In this real-world setting, CYC/MMF exposure at baseline was associated with higher FVC values and a lower risk of progression among subjects with mild ILD. These data suggest a window of opportunity to preserve lung function in SSc-ILD. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the impact of digital ulcers (DUs) in daily life of systemic sclerosis (SSc) Spanish patients. We developed a multicenter observational study to compare functional disability in SSc patients with active DUs vs. those without DUs. An additional correlation between perception of patients and physicians on disability due to DUs was performed. A total of 199 patients were enrolled, 70 (35%) with DUs. Patients with DUs were younger (48 vs. 58 years; p < 0.001) and had more frequently the diffuse subtype of SSc (45 vs. 24%; p = 0.004) than patients without DUs. Patients with DUs showed significantly higher scores in the Cochin Hand Function Scale overall (p < 0.002) and for each of its five dimensions. They also showed higher scores in the Systemic Sclerosis Health Assessment Questionnaire items related to hand function such as, dress and self-care (p < 0.013), eat (p < 0.013) and grip (p < 0.03), and higher Visual Analogic Scale scores for pain (p < 0.013), trouble related with Raynaud's Phenomenon (p < 0.001) and sense of severity (p < 0.004). Impact on daily activities was significantly higher in patients with DUs (p = 0.002), with a non-significant trend to experience higher impact on work productivity (p = 0.07). A high correlation was found between DUs patients and physicians opinion on the impact of DUs (daily life: Pearson R = 0.86; work productivity: Pearson R = 0.87). Study findings show an impaired hand function and increased disability for daily life activities and work productivity in SSc patients with DUs compared with patients without DUs in Spanish population. [ABSTRACT FROM AUTHOR]

Objective. The DETECT algorithm was developed for screening patients with SSc at high risk of pulmonary arterial hypertension (PAH). We evaluated the impact of this algorithm in a SSc population. Methods. Patients from the unselected, prospective Oslo University Hospital SSc study were divided into the Early and DETECT cohorts, respectively, depending on whether an incident right heart catheterization (RHC) was performed before (2009-13) or after (2014-17) the DETECT algorithm was instituted. A PAH diagnosis and patient risk stratification (low, intermediate and high risk) were performed according to 2015 European Society of Cardiology guidelines. Results. At the time of the incident RHC, PAH frequency was similar between the DETECT (15/84 with PAH; 18%) and Early (16/77; 21%) cohorts, but more patients had borderline pulmonary hypertension (PH) in the DETECT (31%) than in the Early (17%) cohort. PAH risk levels were distributed differently. In the DETECT cohort, 27% and 27% were at low and high risk, respectively, at the time of PAH diagnosis. In the Early cohort, 19 and 44% were at low and high risk, respectively. A follow-up RHC, performed after [mean (SD)] 2.4 (1.8) years, showed that 39% of patients with borderline PH in the Early cohort had developed PAH. Conclusion. The DETECT algorithm did not alter PAH incidence in this unselected SSc population. However, it appeared to affect the risk distribution at the time of PAH diagnosis and increased the frequency of borderline PH cases. These findings may translate into novel opportunities for earlier PAH treatment and, possibly, prevention. [ABSTRACT FROM AUTHOR]

Objective. The early, simple and reliable detection of pulmonary arterial hypertension (PAH) in SSc (DETECT) study described a new algorithm for early detection of PAH in patients with SSc. The aim of this retrospective, single-centre, cross-sectional study was to apply a modified DETECT calculator in patients with SSc in the East Bohemian region, Czech Republic, to assess the risk of PAH and to compare these results with PAH screening based on the European Society of Cardiology/European Respiratory Society (ESC/ERS) 2009 guidelines. Methods. Sixty patients were recruited with a diagnosis of SSc (according to ACR criteria), aged 2778 years. A modified DETECT algorithm using the modified parameter of (1.4right ventricle diameter)² in place of right atrium area was applied to all patients. Right heart catheterization (RHC) was performed in all patients with an estimated (by echocardiography) increased systolic pulmonary artery pressure 550mm Hg in accordance with the ESC/ERS guidelines; however, RHC was not performed in patients solely recommended for RHC using the modified DETECT algorithm. Results. Using the modified DETECT calculator, 24/58 (41.4%) patients were recommended for RHC, compared with 14/58 (24.1%) when applying the ESC/ERS 2009 guidelines. PAH was diagnosed in 7/58 (12.1%) patients. During follow-up, PAH was diagnosed in six patients. Of these, four were modified DETECT scorepositive for 2 years and all for 1 year before PAH diagnosis. Conclusion. The modified DETECT algorithm detects all patients with PAH diagnosed according to ECS/ ERS 2009 guidelines and RHC. Data of the 2-year follow-up indicate a possible positive predictive role for the modified DETECT calculator. [ABSTRACT FROM AUTHOR]

Objective. SSc causes intractable ischaemic ulcers. To avoid major amputation, we examined the safety and efficacy of therapeutic vascular angiogenesis for digital ulcers due to SSc. Methods. A single-centre, open-label pilot study was conducted in patients with an ischaemic digital ulcer [n = 40, mean age 65 years (S.D. 8), Rutherford class III-5 or III-6) due to lcSSc (n = 11) or arteriosclerosis obliterans (ASO; n = 29). Bone marrow mononuclear cells (0.4–5.1 × 1010 cells in total) were administered into the ischaemic limbs. We evaluated short-term safety and efficacy by means of a pain scale, 99mTc-tetrofosmin scintigraphy and transcutaneous oxygen tension (TcPO2) before and 4 weeks after treatment. Also, the 2-year outcome was compared. Results. There was a case of amputation in each group within 4 weeks after therapy. The pain scale significantly decreased in both groups [lcSSc 93 mm (S.D. 9) to 11 (S.D. 16), P < 0.01; ASO 77 mm (S.D. 22) to 16 (S.D. 13), P < 0.01] and TcPO2 significantly improved [lcSSc 9.0 mmHg (s.d. 9) to 35 (S.D. 14), P < 0.01; ASO 18 mmHg (S.D. 10) to 29 (S.D. 21), P < 0.05). At the 2-year follow-up, the limb amputation rate was 9.1% in lcSSc and 20.7% in ASO (P = 0.36), while the recurrence rate was 18.2% in lcSSc and 17.2% in ASO (P = 0.95). All-cause mortality was 27.3% in lcSSc and 17.2% in ASO (P = 0.65). Conclusion. In patients with lcSSc, bone marrow mononuclear cell implantation provides clinical benefit and is safe, without major adverse reactions, and may become an effective strategy. [ABSTRACT FROM AUTHOR]

Objectives. To compare the SSc-line immunoassay (LIA) with conventional techniques of antibody detection, to evaluate its diagnostic utility and to describe clinical associations of antibodies in Asian SSc patients.Methods. Stored sera from patients with SSc (n = 68), SLE (n = 49), OA (n = 41) and normal controls (NCs, n = 32) were evaluated. Cohen's κ and Bland–Altman plots were used to evaluate agreement.Results. There was good agreement between LIA and ELISA for anti-Scl-70 (κ = 0.97), anti-CENPA (κ = 0.83), anti-CENPB (κ = 0.96) and anti-PmScl100 (κ = 1.00) (5.48–8.22% of values outside the 95% limits of agreement using Bland–Altman plots), and between LIA and IIF for anti-CENPA (κ = 0.81) and anti-CENPB (κ = 0.77) (P < 0.001). Using LIA, of 32 (32/68, 47%) SSc patients negative for anti-Scl-70 and anti-CENPA/B, 5 (5/32, 15%) were positive for anti-Ku, -Nor90, -fibrillarin and -RP155. Specificity of each antibody for SSc was at least 97% (vs OA/NC) and 94% (vs SLE), except for anti-Ro52 (63%). Anti-CENPB was associated with joint pain [odds ratio (OR) 0.17], interstitial lung disease (OR 0.24) and telangiectasia (OR 4.00) (P < 0.05). Anti-Ro60 was associated with pulmonary arterial hypertension (OR 3.89, P = 0.041).Conclusion. The SSc-LIA has good agreement with conventional techniques for selected antibodies and has good diagnostic utility. [ABSTRACT FROM AUTHOR]

Objectives. To describe pathways of care and referral to paediatric rheumatology from onset of first symptom (noticed by the patient or their family) to diagnosis for children and young people diagnosed with localized scleroderma (LS) or juvenile SSc (jSSc).Methods. Retrospective case note audit of patients under paediatric rheumatology care who presented during January 2005–January 2010. Data included disease subtype, sex, age at key points in the referral pathway and health care professional (HCP) contact. All patient and HCP data were pseudo-anonymized in accordance with good clinical practice.Results. Data were from eight UK centres that saw 89 cases: 62 females, 26 males; 73 LS, 16 jSSc. Median time from first symptom to first HCP review was 4 (range 0–72) months (LS) and 1 (range 0–50) month (jSSc). Median time from first symptom to paediatric rheumatology review was 15 (range 1–103) months (LS) and 7 (range 0–50) months (jSSc). Median time from first HCP review to first paediatric rheumatology review was 11 (range 0–103) months (LS) and 2 (range 0–10) months. First HCP seen (74%) was usually a general practitioner. The referring HCP to paediatric rheumatology was usually a dermatologist (56%) for LS. Median time from first symptom to diagnosis was 13 (range 1–102) months (LS) and 8 (range 1–50) months (jSSc).Conclusion. A prolonged interval occurs from first symptom to definitive diagnosis, which may adversely affect outcome. There is a need to raise awareness of this rare diagnosis and facilitate earlier recognition. [ABSTRACT FROM PUBLISHER]

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.)

Objective: SSc causes intractable ischaemic ulcers. To avoid major amputation, we examined the safety and efficacy of therapeutic vascular angiogenesis for digital ulcers due to SSc., Methods: A single-centre, open-label pilot study was conducted in patients with an ischaemic digital ulcer [n = 40, mean age 65 years (s.d. 8), Rutherford class III-5 or III-6) due to lcSSc (n = 11) or arteriosclerosis obliterans (ASO; n = 29). Bone marrow mononuclear cells (0.4-5.1 × 10(10) cells in total) were administered into the ischaemic limbs. We evaluated short-term safety and efficacy by means of a pain scale, (99m)Tc-tetrofosmin scintigraphy and transcutaneous oxygen tension (TcPO2) before and 4 weeks after treatment. Also, the 2-year outcome was compared., Results: There was a case of amputation in each group within 4 weeks after therapy. The pain scale significantly decreased in both groups [lcSSc 93 mm (s.d. 9) to 11 (s.d. 16), P < 0.01; ASO 77 mm (s.d. 22) to 16 (s.d. 13), P < 0.01] and TcPO2 significantly improved [lcSSc 9.0 mmHg (s.d. 9) to 35 (s.d. 14), P < 0.01; ASO 18 mmHg (s.d. 10) to 29 (s.d. 21), P < 0.05). At the 2-year follow-up, the limb amputation rate was 9.1% in lcSSc and 20.7% in ASO (P = 0.36), while the recurrence rate was 18.2% in lcSSc and 17.2% in ASO (P = 0.95). All-cause mortality was 27.3% in lcSSc and 17.2% in ASO (P = 0.65)., Conclusion: In patients with lcSSc, bone marrow mononuclear cell implantation provides clinical benefit and is safe, without major adverse reactions, and may become an effective strategy., Trial Registration: UMIN-CTR, http://www.umin.ac.jp/ctr/index-j.htm, no. UMIN000004112.