Systemic Sclerosis Patients Research Articles

Anti-Th/To Antibodies in Scleroderma: Good Prognosis or Serious Concern?

Systemic sclerosis (SSc) represents a rare and intricate autoimmune connective tissue disease, the pathophysiology of which has not been fully understood. Its key features include progressive fibrosis of the skin and internal organs, vasculopathy and aberrant immune activation. While various anti-nuclear antibodies can serve as biomarkers for the classification and prognosis of SSc, their direct role in organ dysfunction remains unclear. Anti-Th/To antibodies are present in approximately 5% of SSc patients, and are particularly prevalent among those with the limited subtype of the disease. Although the presence of these autoantibodies is associated with a mild course of the disease, there is a strong connection between them and severe clinical manifestations of SSc, including interstitial lung disease, pulmonary arterial hypertension and gastrointestinal involvement. Also, the additional clinical correlations, particularly with malignancies, need further research. Moreover, the disease's course seems to be influenced by antibodies, specific serum cytokines and TLR signaling pathways. Understanding the relationships between presence of anti-Th/To, its molecular aspects and response to treatment options is crucial for the development of novel, personalized therapeutic techniques and should undergo profound analysis in future studies.

Assessing the quality of forced vital capacity measurement in patients with systemic sclerosis

IntroductionForced vital capacity (FVC) is an important tool for monitoring lung functions in patients with systemic sclerosis (SSc). However, several disease manifestations may influence the quality of FVC test in SSc. We aimed to assess the quality of FVC measurements according to current guidelines in patients with SSc and determine the factors that may affect results. MethodIn this cross-sectional study, SSc patients and age/sex matched controls underwent spirometry. Quality of FVC measurements were graded according to updated American Thoracic Society (ATS) and European Respiratory Society (ERS) guidelines. Demographics, clinical features and parameters that may affect FVC test quality were compared between SSc patients with high and low quality FVC test. Results98 SSc patients (90 female) and 100 controls were included. The rate of high quality FVC measurement in SSc patients was significantly lower in SSc patients compared to controls. (80 % vs 60.2 % p = 0.002). Among SSc patients; diffuse disease, ILD, anti-topoisomerase 1 antibody positivity, immunosuppressive use, flexion contractures of hands, reduced mouth opening and decreased chest expansion were more frequent in patients with low quality FVC (p < 0.05 for all). Patients with muscle weakness and medium/high risk of malnutrition were also numerically higher in low quality FVC group. Presence of more than one condition that may affect FVC quality was significantly higher among patients with low quality FVC. ConclusionA significant percent of SSc patients had low quality FVC measurement. Physicians should be aware of this point while interpreting FVC test results especially in SSc patients with more than one condition that may affect the quality of the test.

Polypharmacy, drug-drug interactions, and adverse drug reactions among systemic sclerosis patients: A cross-sectional risk factor study.

ObjectivesPolypharmacy, drug-drug interactions (DDI) and related adverse drug reaction (ADR) are understudied in SSc. The aim of this work was to determine the prevalence and determinants of DDI and ADR in a real-life prospective cohort of SSc patients. MethodsWe performed a retrospective analysis of the drug prescriptions of SSc patients admitted to the daily scleroderma clinic between January 2020 and April 2022. DDI were identified using 2 prescription analysis applications, and adjudicated related ADRs occurring during a one-year follow-up were reported. Risk factors for DDI and ADR were identified using multivariate analysis. ResultsOne hundred and eight SSc patients were included. The median number of medications per patient was 6 [4–9]. Seventy-one (65.7 %) patients had 5 or more medications, and 23 (21.3 %) had 10 or more. Seventy-two (66.7 %) patients had DDIs on their prescriptions at inclusion. Patients with DDIs had more medications than patients without DDIs (7 [5–10] versus 3 [2–5], p < 0.0001). Six (8.3) patients experienced ADRs during the one-year follow-up. Patients with ADRs had more medications (14 [10–18] versus 7 [5–10] p < 0.001) and more DDIs (12 [7–32] versus 3 [1–6]; p < 0.001) than patients without ADRs. Multivariate analysis confirmed that the number of prescribed medications was independently positively associated with DDIs (OR: 2.25 [1.52–3.32], p < 0.0001) as well as with ADRs (OR: 1.68 [1.17–2.40], p < 0.01). ConclusionsSSc patients are significantly exposed to polypharmacy, DDIs and related ADRs, particularly in cases of severe illness, and especially if 5 or more medications are prescribed.

Novel Noninvasive Index Combining Echocardiography and Computed Tomography for Screening for Pulmonary Hypertension in Patients With Systemic Sclerosis

BackgroundIn patients with systemic sclerosis (SSc), early detection of pulmonary hypertension (PH) improves survival. This study aimed to investigate whether a combination index (cPAT) of the tricuspid regurgitation jet peak gradient and the ratio of pulmonary artery (PA) diameter to aortic diameter measured by computed tomography (CT; PA ratio) can estimate the mean PA pressure (mPAP) and detect PH more accurately than conventional parameters in SSc patients. MethodsA total of 36 SSc patients who underwent PH screening were retrospectively analyzed. All patients were screened for PH between 2013 and 2017 by echocardiography, CT, and right heart catheterization. Patients with mPAP > 20 mm Hg by right heart catheterization were diagnosed as having PH. Additionally, patients with an mPAP > 20 mm Hg, pulmonary vascular resistance > 2 Wood units, and PA wedge pressure ≤ 15 mm Hg, for whom other causes were ruled out, including group 2-5, were defined as having pulmonary atrial hypertension. ResultsOf 36 patients, 29 patients were female (81%), and the average duration of SSc was 7.5 years. The mPAP was significantly correlated with the tricuspid regurgitation jet peak gradient (r = 0.734), the PA ratio (r = 0.584), and the cPAT (r = 0.848). In receiver operating characteristic analysis to identify PH, the cPAT showed the highest area under the curve, 0.906, among the 3 parameters. Additionally, in receiver operating characteristic analysis to identify pulmonary atrial hypertension, the cPAT also showed the highest area under the curve, 0.851, among the 3 parameters. ConclusionsThe cPAT is a new index combining echocardiogram and CT results that provides the most accurate noninvasive assessment of mPAP in SSc patients. The cPAT can also help detect PH early in SSc patients, thereby allowing for earlier treatment.

Rituximab retention rate in systemic sclerosis: a long term real-life multicenter study.

to report real-life data on rituximab retention-rate as indicator of safety and efficacy in a multicentric national cohort of systemic sclerosis patients. SSc patients treated with rituximab and followed for at least 36 months were included, clinically characterized, and longitudinally monitored. A competing risk analysis with sub-Hazard Ratio(sHR) definition was performed to explore the clinical variables linked to specific cause of rituximab discontinuation. One-hundred-fifty-two SSc-patients (mean age 47.3 ± 12.3 years; females 79.6%; diffuse disease 77.6%; anti-topoisomerase-I positivity 63.2%) were evaluated over a median(IQR) time of 3.3(1.7-5.0) years. The primary indication for rituximab were interstitial lung disease (ILD)(38.8%), worsening skin fibrosis(36.8%), and arthritis(13.8%); 138 patients(90.8%) received more than one rituximab course. The 5-years rituximab retention rate was 59.9%(44.6-64.7%). Clinical response was the most common reason for rituximab discontinuation[5.7(3.7-8.4) per 100 patient-year] and was associated with a shorter disease duration[sHR 0.8(0.7-0.9)], anti-topoisomerase-I negativity[sHR 0.4(0.2-0.9)], previous digital ulcers[sHR 2.6(1.1-6.2] and no history of arthritis[sHR 0.3 (0.1-0.8)]. Treatment failure was the second cause of rituximab discontinuation[3.7(2.2-6.0) per 100 patient-year] and was associated with anti-centromere antibody positivity[sHR 2.8(1.1-7.4)] and anti-topoisomerase-I negativity[sHR 0.2(0.1-0.6)]. Adverse events(AEs) were the less common cause of discontinuation[3.1(1.7-5.2) per 100 patient-year], associated with limited cutaneous subset[sHR 3.4(1.2-9.7)] and previous mycophenolate mofetil treatment[sHR 4.5(1.2-16.3)]. rituximab is a safe and effective treatment in SSc: clinical response emerged as the primary reason for rituximab discontinuation, and AEs had a limited impact on treatment persistence. The identification of specific disease features associated with a response to rituximab will be useful in the management of SSc-patients.

High Prevalence of the Lung Ultrasound Interstitial Syndrome in Systemic Sclerosis Patients with Normal HRCT and Lung Function-A Pilot Study.

Objective: High-resolution computed tomography (HRCT) may lack sensitivity for the early detection of interstitial lung disease associated with systemic sclerosis (SSc-ILD). Lung ultrasound is an emerging technique for the diagnosis of SSc-ILD. This cross-sectional study aimed to describe the prevalence of ultrasound interstitial syndrome in SSc patients with normal HRCT and pulmonary function tests (PFT). Methods: Thirty SSc patients with normal HRCT, FVC > 80% predicted and DLCO > 70% predicted were included. Echocardiography and PFT including impulse oscillometry and cardiopulmonary exercise testing were performed. Lung ultrasound was analyzed by two blinded operators. Patients were classified into two groups, according to the presence or absence of ultrasound interstitial syndrome, defined as the sum of B-lines in all thoracic areas ≥10 and/or pleural line thickness >3 mm on at least one thoracic area and/or a pleural line irregularity score >16%. Results: Ultrasound interstitial syndrome was present in 12 patients (40%). Inter-reader agreement for the diagnosis of ultrasound interstitial syndrome defined by the Kappa coefficient was 0.93 (95%CI 0.79-1.00). Patients with ultrasound interstitial syndrome were younger (37 years vs. 53 years, p = 0.009), more often had pitting scars (n = 7/12 vs. 3/18, p = 0.045) and had lower FVC (102 vs. 110% pred, p = 0.009), TLC (114 vs. 122% pred, p = 0.042) and low-frequency respiratory system reactance (Xrs5 Z-score 0.16 vs. 1.02, p = 0.018), while pulmonary gas exchange was similar. Conclusions: Ultrasound interstitial syndrome was detected in 12/30 SSc patients with normal HRCT and PFT. Patients with ultrasound interstitial syndrome had differences in lung function consistent with reduced respiratory compliance, suggesting minimal and/or early suspected SSc-ILD.

N-terminal pro-brain natriuretic peptide is associated with pulmonary hypertension or diastolic dysfunction in patients with systemic sclerosis: An Australian prospective cross-sectional study.

Pulmonary arterial hypertension and left ventricular diastolic dysfunction are associated with significant morbidity and mortality in systemic sclerosis. N-terminal pro-brain natriuretic peptide has been proposed as part of composite screening algorithms for pulmonary arterial hypertension. Our aim was to assess the prevalence of pulmonary hypertension and diastolic dysfunction, and evaluate their association with serum N-terminal pro-brain natriuretic peptide in systemic sclerosis patients. Patients with systemic sclerosis were prospectively enrolled to undergo N-terminal pro-brain natriuretic peptide testing and transthoracic echocardiography at a tertiary Australian centre from January to October 2022. We collected demographic and transthoracic echocardiography variables including pulmonary hypertension estimated by tricuspid regurgitant velocity and diastolic dysfunction assessed by the ASE/EACVI 2016 guidelines. Pearson's correlation coefficient was used to evaluate association between N-terminal pro-brain natriuretic peptide and echocardiographic parameters. Sixty-one patients were enrolled (median age = 62 years (interquartile range = 55-69 years); 84% female). Two-thirds of patients had limited systemic sclerosis (40/61). Five patients (8%) had high likelihood of pulmonary hypertension by transthoracic echocardiography. Seven patients (11%) had diastolic dysfunction; however, seven patients (11%) had indeterminate diastology. Six patients underwent right heart catheterisation, with five patients diagnosed with pulmonary hypertension. N-terminal pro-brain natriuretic peptide in patients with pulmonary hypertension or diastolic dysfunction was significantly higher (median = 207 and 226 pg/mL, respectively) compared to patients without either condition (median = 69 pg/mL, p = 0.01). N-terminal pro-brain natriuretic peptide showed a statistically significant although limited correlation with estimated pulmonary pressures measured by tricuspid regurgitant velocity (r = 0.44, p = 0.002) and left ventricular filling pressures (r = 0.27, p = 0.04). Pulmonary hypertension and diastolic dysfunction are both observed in systemic sclerosis. N-terminal pro-brain natriuretic peptide is associated with both conditions; however, it cannot distinguish between the two disease processes. Right heart catheterisation may be required to make this distinction.

Retinal Vascular Abnormalities and Clinical Parameters in Systemic Sclerosis.

Background: Systemic sclerosis is a complex autoimmune disease characterized by vasculopathy, fibrosis, and immune dysregulation. Ocular manifestations in these patients are increasingly recognized, suggesting potential correlations between systemic vascular abnormalities and ocular microvascular changes. Advancements in molecular immunology and imaging technology using ocular coherence tomography (OCT) have unveiled intricate pathways underlying possible disease pathogenesis. Understanding the interplay between retinal vascular abnormalities and molecular immunology parameters could provide insights into disease mechanisms and potential biomarkers. Purpose: The aim of this study was to investigate vascular abnormalities, detected with optical coherence tomography angiography (OCT-A), in systemic sclerosis patients and to find correlations between the severity of the disease detected with molecular immunology findings and OCT-A parameters. Methods: A group of 32 systemic sclerosis patients were compared with 9 healthy controls. Ganglion cell complex thickness (GCC), retina thickness of the fovea and parafovea, nerve fiber layer thickness (RNFL) and cup/disc area ratio were investigated using OCT. Vessel density (VD) of the superficial (SCP) and deep capillary plexus (DCP) of the whole macular area and ETDRS grid, size of the foveal avascular zone (FAZ) and vessel density of the radial peripapillary capillary plexus (RPCP) were evaluated using OCT-A. Modified Rodnan skin score (mRSS), capillaroscopy and disease duration were used to stage disease severity. Results: There was a statistically significant reduction in retina thickness of the fovea and parafovea, VD of the whole DCP, VD of the SCP and DCP in ETDRS grid in the patient group compared to controls (p < 0.001). The patients presented a significant enlargement of the FAZ (p 0.005). No significant correlation between OCT and OCT-A parameters and disease severity scores was found. Conclusions: OCT-A could represent a non-invasive tool to detect retinal microvascular damage in systemic sclerosis.

Levels of anti-topoisomerase I antibody correlated with short onset of cardiopulmonary involvement in Thai systemic sclerosis patients

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 < 7 U/mL and outlier ATA levels were excluded, 142 cases were included in the sensitivity analysis, and multivariable analysis showed the correlation between early onset of ILD and cardiac involvement (Rho − 0.43, p = 0.03 and Rho − 0.51, p = 0.01, respectively). The ATA level was correlated with neither the survival time nor the onset of renal crisis in both analyses. High ATA levels were correlated with a short onset of ILD and cardiac involvement and the presence of extensive skin tightness. Quantitative tests of ATA could serve as an effective tool for identifying patients at risk of an unfavorable prognosis.

Causes and predictors of death among Finnish patients with systemic sclerosis

Objective The aim of this study was to assess causes and predictors of death among Finnish patients with systemic sclerosis (SSc). Method Medical records of patients registered with the ICD-10 code M34 from 1996 to 2018 in two university hospitals were reviewed retrospectively. Clinical data were collected until the end of 2020. Death certificates were obtained from Statistics Finland up to August 2021. Using death certificates and patient records, the cause of death for each patient was determined. The mean age at death, median time from SSc diagnosis, and factors predicting death were analysed. Results Among 313 SSc patients, 91 deaths occurred between April 2000 and September 2020. Overall 5 and 10 year survival rates were 88.4% and 80.2%, respectively. SSc was the most common primary cause of death (n = 35) and interstitial lung disease (ILD) was the most common SSc-related cause of death (n = 13). Moreover, 52% of the patients with diffuse SSc and 33% of those with limited cutaneous SSc died as a result of SSc itself. Patients who died because of SSc were significantly younger [mean ± sd age 65.6 ± 12.7 years, 95% confidence interval (CI) 61.2–70.1] than those who died from other causes (74.2 ± 9.6 years, 95% CI 71.5–76.9) (p = 0.0006). ILD, pulmonary arterial hypertension, gastrointestinal involvement, male gender, and older age at disease onset predicted death. Conclusion The disease itself was the major cause of death among Finnish SSc patients, in both diffuse and limited forms of SSc.

Overlap syndrome of systemic sclerosis with antineutrophil cytoplasmic antibody-associated vasculitis according to 2022 ACR/EULAR criteria.

This study applied the 2022 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) criteria for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) to patients with systemic sclerosis (SSc) and investigated the frequency of overlap syndrome of SSc and AAV (SSc-AAV-OS). Among the 232 patients diagnosed with SSc, 105 with signs suggestive of small- or medium-vessel vasculitis, which were defined as the present of interstitial lung disease (ILD), peripheral neuropathy, or suspected renal vasculitis, were included in this study and analyzed. Among the 105 SSc patients, the detection rate of ANCA was 19.0%. When the 2022 ACR/EULAR criteria were applied, the frequency of SSc-AAV-OS was 20.0%, which was much higher than 1.7% reported with previous criteria for AAV. ANCA positivity contributed to the reclassification of SSc-AAV-OS more than ANCA negativity in SSc patients with signs suggestive of small- or medium-vessel vasculitis. The frequency of SSc-AAV-OS in SSc patients with signs suggestive of small- or medium-vessel vasculitis at diagnosis was 20.0%. Therefore, we suggest that physicians should perform ANCA tests in SSc patients exhibiting signs suggestive of small- or medium-vessel vasculitis and apply the new criteria for AAV.

Impaired LAIR-1-mediated immune control due to collagen degradation in fibrosis

Tissue repair is disturbed in fibrotic diseases like systemic sclerosis (SSc), where the deposition of large amounts of extracellular matrix components such as collagen interferes with organ function. LAIR-1 is an inhibitory collagen receptor highly expressed on tissue immune cells. We questioned whether in SSc, impaired LAIR-1-collagen interaction is contributing to the ongoing inflammation and fibrosis.We found that SSc patients do not have an intrinsic defect in LAIR-1 expression or function. Instead, fibroblasts from healthy controls and SSc patients stimulated by soluble factors that drive inflammation and fibrosis in SSc deposit disorganized collagen products in vitro, which are dysfunctional LAIR-1 ligands. This is dependent of matrix metalloproteinases and platelet-derived growth factor receptor signaling.In support of a non-redundant role of LAIR-1 in the control of fibrosis, we found that LAIR-1-deficient mice have increased skin fibrosis in response to repeated injury and in the bleomycin mouse model for SSc. Thus, LAIR-1 represents an essential control mechanism for tissue repair. In fibrotic disease, excessive collagen degradation may lead to a disturbed feedback loop. The presence of functional LAIR-1 in patients provides a therapeutic opportunity to reactivate this intrinsic negative feedback mechanism in fibrotic diseases.

Cardiovascular disease in patients with systemic autoimmune diseases: The relationship between self-perceived risk and actual risk

IntroductionAutoimmune diseases are known to be associated with an elevated risk of cardiovascular diseases; however, there exists a lack of awareness regarding this increased risk among patients. ObjectiveThis study aimed to assess the prevalence of cardiovascular risk factors and events in various systemic autoimmune diseases, including Systemic Sclerosis (SSc), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Sjögren's syndrome (SS), matched by age, sex, and disease duration. Additionally, the study aimed to evaluate the perceived and actual risks of cardiovascular disease among patients. MethodsA cross-sectional self-reported survey on the patient's perspective of cardiovascular risk was conducted between January and June 2023. Sociodemographic and clinical data, including disease activity, were collected through medical records and questionnaires. Traditional cardiovascular risk factors and events were assessed, alongside the perceived cardiovascular risk. The SCORE calculation and Charlson Comorbidity Index (CCI) were employed for cardiovascular risk assessment. ResultsSurvey responses from 180 patients (45 patients each with SSc, SLE, RA, and SS) with systemic autoimmune diseases revealed that 20% perceived a low risk, 23% perceived neither lower nor higher, and 56% perceived a higher risk of developing cardiovascular diseases in the next ten years. Only 45% agreed that their autoimmune disease could increase the risk of a heart attack, even in the absence of other risk factors, and 46.7% were unaware that NSAIDs pose a cardiovascular risk. An association between cardiovascular risk measured by SCORE, comorbidities, and risk perception was observed in RA, SSc, and SS patients, with no association found in SLE patients (p=0.27). Except for SS patients (p=0.02), no association between CCI and disease activity level was found. Regarding the influence of age, working status, and education in CVD risk perception, an association between CVD risk perception and age was observed (p=0.01), with patients over 40 years exhibiting a higher perception of CVD risk. No differences were found regarding working status (p=0.19) nor education level (p=0.06). ConclusionsPatients with SS, RA, and SSc displayed a heightened perception of cardiovascular risk, correlating with their actual risk and preexisting comorbidities. However, patients exhibited unawareness of certain cardiovascular risk behaviors. This underscores the need for tailored education programs on cardiovascular risk for autoimmune disease patients, to be implemented at the time of diagnosis and during follow-up in outpatient clinics.

Untangling the relationship between smoking and systemic sclerosis: an analysis of the EUSTAR cohort

ObjectivesTo untangle the association between smoking and systemic sclerosis (SSc).MethodsIn the European Scleroderma Trials and Research cohort, the autoantibody status was compared between ever-smokers and never-smokers. Time until disease progression...

Sildenafil Versus Placebo for Early Pulmonary Vascular Disease in Scleroderma (SEPVADIS): protocol for a randomized controlled trial

BackgroundPulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21–24 mmHg).MethodsThe SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks.DiscussionThe SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP.Trial registrationClinicalTrials.gov Identifier NCT04797286.

P135 Association of Serum Anti-Muscarinic 3 Antibodies with Gastrointestinal Disease in Systemic Sclerosis

Abstract Background/Aims Gastrointestinal (GI) complications of systemic sclerosis (SSc) are frequent and debilitating with symptoms ranging from reflux to faecal soilage. The pathogenesis of GI disease in SSc is poorly understood. Circulating antibodies against Muscarinic type 3 Receptors (anti-M3R) have been implicated in GI smooth muscle dysfunction and neural activation impairment. We examine whether anti-M3R antibodies associate with objective measures of gastrointestinal symptoms. Methods Sera were collected from SSc patients fulfilling the American College of Rheumatology (ACR) classification criteria for SSc. Healthy control (HC) sera were obtained from age-matched volunteers. SSc patients completed the UCLA GIT 2.0 (UCLA GIT) questionnaire. Serum anti-M3R antibodies were measured using specific enzyme-linked immunosorbent assay (ELISA)(CellTrend GmbH, Germany). SSc sera had elevated anti-M3R antibodies if the concentration exceeded two standard deviations above the mean of HC sera. Statistical comparisons were made using Fisher’s exact test and two sample t-test. Results Sera from 40 SSc patients and five HC were assayed for anti-M3R antibodies. Anti-M3R antibody was higher in SSc patients in comparison to HC (1547 vs 1183U/ml, p = 0.33). Anti-M3R antibody levels were significantly elevated in nine (23%) SSc patients. Cohort characteristics were compared based on anti-M3R antibody levels for SSc patients (Table 1). Group demographics were similar in gender, age and disease duration. There was a trend for higher anti-M3R antibodies in limited compared with diffuse cutaneous SSc subset (66.7 vs 32.2, p = 0.12). Although there was no significant association between Anti-M3R antibody level and GIT score (r = 0.014 p = 0.51), SSc patients with elevated anti-M3R antibody did report numerically more severe reflux symptoms (1.24 vs 0.8, p = 0.23) and fewer lower GI domains of severe soilage (0.56 vs 0.87, p = 0.37) and constipation (0.28 vs 0.52, p = 0.2). Conclusion These results show that there is a subset of SSc patients with elevated anti-M3R antibodies which could be pathogenic by perturbing cholinergic neurotransmission in the GI tract. The trend observed of elevated anti-M3R antibodies with more severe GI symptoms warrants further exploration in a larger cohort of SSc. If confirmed, our findings provide mechanistic rationale for reported benefit from intravenous immunoglobulin on symptom severity in SSc GI disease. Disclosure E. Roblin: None. C. Beesley: None. R. Maclean: None. F. Ahmed: None. C. Murray: None. V.H. Ong: None. C. Denton: Consultancies; C.P.D. has received consulting fees from Arxx Therapeutics, Roche, Janssen, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Boehringer Ingelheim, CSL Behring and Acceleron. Honoraria; C.P.D. has received honoraria from Janssen, Boehringer Ingelheim, and Corbus. Grants/research support; C.P.D. has received research grants to the institution from Servier, Horizon, Arxx Therapeutics and GlaxoSmithKline.

OA26 Paired bulk and single cell analysis of transitional B cells in systemic sclerosis highlights defective peripheral tolerance

Abstract Background/Aims Transitional B cells comprise a distinct population of B cells that have recently migrated to the periphery from the bone marrow. In systemic sclerosis (SSc), there are differences in the number and function of transitional B cells compared with healthy controls (HCs). In addition, we have previously shown that transitional B cells evade peripheral tolerance from SSc patients who are seropositive for anti-topoisomerase I autoantibodies (ATA). To investigate mechanisms that underpin this defect, we performed a paired bulk and single-cell RNA sequencing study of transitional B cell subsets in treatment-naïve ATA-positive patients with diffuse cutaneous SSc (dcSSc) and HCs. Methods CD19+CD24hiCD38hi transitional B cells (5000) were sorted from four HCs and four treatment-naïve ATA-positive dcSSc patients. Single-cell RNA-sequencing was performed on the sorted B cells and the data was analysed using Seurat in RStudio. Paired bulk RNA-sequencing of the sorted transitional T1 (CD19+CD24hiCD38hi CD27-IgMhiIgDmed) and T2 (CD19+CD24hiCD38hiCD27-IgMhiIgDhi) subsets was undertaken in a subset of this cohort. Results From the sorted CD19+CD24hiCD38hi lymphocytes single cell transcriptomics identified six B cell clusters in SSc patients and HCs with differential expression of key genes such as CD19 and TCL1A. This included a cluster of marginal zone precursor cells expressing PLD4 and MZB1 which is expanded in SSc. We also identified an interesting memory-like B cell cluster which was diminished in the SSc group and expresses genes such as TNFRSF13B (BAFF), AICDA (AID) and S100A10. In the HCs, this cluster also expresses genes such as CD27 and IGHA1 which are absent in SSc indicating that B cell development is impaired in the disease. Subsequent pathway analyses provided evidence for the molecular bases of defective tolerance in SSc patients. This appears to be related to dysregulated NF-κB signalling and aberrant extrafollicular B cell development as evidenced through pseudotime trajectory analysis. Differential gene expression analyses using bulk RNA-sequencing of sorted T1 and T2 transitional B cells further identified five candidate gene signatures such as MYC-targets and DNA repair which are significantly enriched in the T2 subset. This latter finding is in congruence with the single cell data and provides further evidence to support the existence of a peripheral tolerance/selection checkpoint at the transitional B cell stage. Conclusion We have identified four transitional B cell subsets and have characterised their transcriptomic profile in SSc. Additionally, we provide new evidence for a potential breach in peripheral tolerance of SSc patients. Further studies are underway to identify key pathways that underpin B cell dysregulation in SSc and explore the relevance of such findings for better targeted therapies. Disclosure C. Beesley: Grants/research support; C.B. is supported through Versus Arthritis (grant number 558800). N. Goldman: None. D. Abraham: None. C. Denton: None. R. Mageed: None. V.H. Ong: None.

P137 A multinational survey to identify the clinicians perspectives concerning proton pump inhibitors in patients with systemic sclerosis

Abstract Background/Aims Proton Pump Inhibitors (PPIs) are widely used in Systemic Sclerosis (SSc) for the treatment of gastroesophageal reflux disease (GERD). However, there is scarce evidence to support their use while long-term safety has been questioned. The aim of our study was to identify healthcare providers’ perspectives and experience regarding PPIs therapy in SSc patients. Methods An online survey in English language targeting clinicians involved in the care of SSc patients, was developed and distributed through social media and international physician networks. The survey was launched on 27th November 2022 and kept open for three weeks. Results Responses from 227 clinicians from 36 countries were recorded: most of them (86%) were between 30-70 years and gender was equally represented (F: 52%; M: 48%). The majority ‘agreed’ (41%) or ‘strongly agreed’ (45%) that GERD is a major cause of morbidity in SSc. Lifestyle modifications and non-pharmacological approaches alone were seldom (16%) considered effective. Only half of respondents ‘agreed’ (43%) or ‘strongly agreed’ (11%) there is solid evidence supporting PPIs efficacy in SSc. A range of PPIs was prescribed by clinicians, most frequently pantoprazole (74%), esomeprazole (72%), omeprazole (72%), and lansoprazole (68%). The most common reasons for PPIs prescription (Table 1) were symptomatic GERD unresponsive to lifestyle modification (95%), objective evidence of GERD (82%), and hoarseness or respiratory symptoms (71%). Multiple concerns were raised about PPI long-term safety. The three highest (mean, 10 being very concerned) reasons were: small intestinal bacterial overgrowth (5.5), osteoporosis (5.4), and drug interactions (5.2). There were significant differences in attitudes towards surgery for refractory GERD: ‘strongly disagreed’ (14%), ‘disagreed’ (26%) ‘neutral’ (52%), ‘agreed’ (13%), ‘strongly agreed’ (3%). Furthermore, half of respondents had concerns about potential complications (i.e., worsening of dysphagia): ‘disagreed’ (26%) or ‘strongly disagreed’ (6%), ‘neutral (52%), ‘agreed’ (13%), ‘strongly agreed’ (3%). Conclusion Our survey confirms that PPIs are frequently prescribed for GERD in SSc patients, despite the absence of randomized clinical trials demonstrating their efficacy and safety. Clinicians are concerned about side effects, especially regarding long-term use. There is significant heterogeneity in attitudes towards surgery for refractory GERD. Future research and practical treatment recommendation are urgently needed. Disclosure G. Bandini: None. A. Alunno: None. F. Oliveira Pinheiro: None. C. Campochiaro: None. I. Galetti: None. P. Matucci Cerinic: None. B. Ruaro: None. A. Moggi Pignone: None. L. Dagna: None. M. Matucci Cerinic: None. Z. McMahan: None. M. Hughes: None.

E060 A multinational survey investigating the unmet needs and patient perspectives concerning proton pump inhibitors in systemic sclerosis

Abstract Background/Aims The gastrointestinal (GI) tract is largely (&amp;gt;95%) affected in systemic sclerosis (SSc) and its involvement is associated with significant morbidity, mortality and huge impact on the quality of life. Upper GI tract dysfunction, often presenting with gastroesophageal reflux disease (GERD) is one of the principal complaints. Proton pump inhibitors (PPIs) are widely used to treat GERD in SSc. However, not all patients respond to this therapy, and many remain on long-term treatment. Significant concerns about PPI long-term safety have been raised. Our aim was to identify perspectives and unmet needs of SSc patients on PPIs. Methods An online English survey, targeting SSc patients on PPIs was developed and distributed through social media and international patient associations. The survey was launched on 4th November 2022 and kept open for 4 weeks. Results 301 respondents from 14 countries completed the survey (UK 19.3% and US 70.4%). Most respondents were between 30-70 years and the majority were female (95%). The most frequently reported symptoms were acid reflux (97%), dysphagia (60%), and trouble swallowing or food got stuck in the chest (32%). Multiple PPIs use (two: 30% and three: 21%; in series) was common and the majority (89%) reported improvement in GI symptoms with PPIs. Even though only 19% experienced side effects on PPIs, most respondents (79%) were concerned (Table 1). Half (47%) experienced a flare of symptoms after initial improvement with PPIs and 58% received lifestyle information, while most (85%) searched online for information about PPIs. A minority (12%) reported that a surgical approach was discussed, and 46% indicated that they would be willing to undergo surgery, despite having significant concerns. Conclusion Our survey highlights the importance of upper GI symptoms in SSc patients and the frequent use of PPIs. There is significant heterogeneity in use, and treatment is often not fully effective. Patients have concerns about side effects related to long-term PPI use. There is a clear unmet need regarding patients’ education about PPIs. A surgical approach is rarely discussed, although patients would potentially consider this approach. Further research is needed to optimize the therapeutic strategy concerning PPIs in SSc. Disclosure G. Bandini: None. A. Alunno: None. F. Oliveira Pinheiro: None. C. Campochiaro: None. I. Galetti: None. P. Matucci Cerinic: None. B. Ruaro: None. K. El Aoufy: None. M. Melis: None. A. Moggi Pignone: None. L. Dagna: None. M. Matucci Cerinic: None. Z. McMahan: None. M. Hughes: None.

P134 Developing a potential composite pharmacodynamic serum marker of skin severity in systemic sclerosis

Abstract Background/Aims Previously, through multilevel and high dimensional analysis, we derived a composite biomarker for modified Rodnan Skin Score (mRSS) in systemic sclerosis (SSc) patients using a derivation cohort (BIOPSY). This identified 4 blood proteins (COMP, COL4A1, TNC and SPON1) that independently correlated with mRSS and also with skin gene and dermal blister expression at a separate 12-month timepoint. These proteins likely reflect overlapping aspects of SSc skin pathobiology that are not overly influenced by other disease compartments. In the present study, we undertake technical and biological validation of this novel composite marker in well characterised SSc patients. Methods COMP (DCMP0, R&amp;D Systems), COL4A1 (CSB-EL005741HU, Cusabio), TNC (ab213831, Abcam) and SPON1 (CSB-EL022599HU, Cusabio) were examined in serum samples from diffuse cutaneous SSc (dcSSc) cases in two independent cohorts of patients, BIOPSY (n = 33) and MODERNISE (n = 37). The BIOPSY cohort was previously used to derive the composite marker and MODERNISE was a novel validation cohort. Later, early dcSSc patients from both cohorts were combined into a third analysis group (n = 36). Multiple regression analysis derived a formula for a composite biomarker score which predicted mRSS based on serum ELISA results. Results Serum concentration positively correlated with mRSS for COMP and TNC, particularly in early dcSSc patients (COMP, r = 0.10, p = 0.05; TNC, r = 0.13, p = 0.03). No significant correlation was observed for COL4A1 (r = 0.03, p = 0.34). Interpretable data could not be obtained for SPON1 due to technical limitations of the ELISA. Confirming previous results multiple regression analysis derived a formula for the prediction of mRSS using the three remaining serum proteins (r = 0.15, p = 0.009). mRSS = 9.896 + 0.01719(COMP) - 0.006481(COL4A1) - 0.002318(TNC). Patients receiving mycophenolate mofetil showed numerically lower serum concentrations of COMP (p = 0.16), COL4A1 (p = 0.32), TNC (p = 0.15) and a lower composite biomarker score (p = 0.22) with increasing treatment duration in early dcSSc cases (Table 1). Conclusion Our results confirm this novel three-protein composite serum marker predicts skin severity in SSc better than each individual analyte. After further validation, this blood-based approach may help evaluate treatment response to standard immunosuppression. Further work will establish utility of this composite measure as a predictive or prognostic biomarker. Disclosure E. Roblin: None. K.E.N. Clark: None. C. Beesley: None. V.H. Ong: None. C.P. Denton: Consultancies; C.P.D. has received consulting fees from Arxx Therapeutics, Roche, Janssen, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Boehringer Ingelheim, CSL Behring and Acceleron. Honoraria; C.P.D. has received honoraria from Janssen, Boehringer Ingelheim, and Corbus. Grants/research support; C.P.D. has received research grants to the institution from Servier, Horizon, Arxx Therapeutics and GlaxoSmithKline.