Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis.

BACKGROUND: The interleukin (IL)-1 receptor accessory protein (IL1RAP) is an essential coreceptor required for signalling through the IL-1, IL-33 and IL-36 receptors. Here, we investigate the antifibrotic potential of the combined inhibition of these cytokines by an anti-IL1RAP antibody to provide a scientific background for clinical development in systemic sclerosis (SSc). METHODS: The expression of IL1RAP-associated signalling molecules was determined by data mining of publicly available RNA sequencing (RNAseq) data as well as by imaging mass cytometry. The efficacy of therapeutic dosing of anti-IL1RAP antibodies was determined in three complementary mouse models: sclerodermatous chronic graft-versus-host disease (cGvHD), bleomycin-induced dermal fibrosis model and topoisomerase-I (topo)-induced fibrosis. RESULTS: SSc skin showed upregulation of IL1RAP and IL1RAP-related signalling molecules on mRNA and protein level compared with normal skin. IL-1, IL-33 and IL-36 all regulate distinct gene sets related to different pathophysiological processes in SSc. The responses of human fibroblasts and endothelial cells to IL-1, IL-33 and IL-36 were completely blocked by treatment with an anti-IL1RAP antibody in vitro. Moreover, anti-IL1RAP antibody treatment reduced dermal and pulmonary fibrosis in cGvHD-induced, bleomycin-induced and topoisomerase-induced fibrosis. Importantly, RNAseq analyses revealed effects of IL1RAP inhibition on multiple processes related to inflammation and fibrosis that are also deregulated in human SSc skin. CONCLUSION: This study provides the first evidence for the therapeutic benefits of targeting IL1RAP in SSc. Our findings have high translational potential as the anti-IL1RAP antibody CAN10 has recently entered a phase one clinical trial.

Induction of regulatory T cells and efficacy of low-dose interleukin-2 in systemic sclerosis: interventional open-label phase 1-phase 2a study.

BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune disease, with impaired immune response, increased fibrosis and endothelial dysfunction. Regulatory T cells (Tregs), which are essential to control inflammation, tissue repair and autoimmunity, have a decreased frequency and impaired function in SSc patients. Low-dose interleukin-2 (IL-2LD) can expand and activate Tregs and has, therefore, a therapeutic potential in SSc. OBJECTIVE: We aimed to assess the safety and biological efficacy of IL-2LD in patients with SSc. METHODS: As part of the TRANSREG open-label phase IIa basket trial in multiple autoimmune diseases, we studied nine patients with SSc without severe organ involvement. Patients received 1 million international units (MIU)/day of IL-2 for 5 days, followed by fortnightly injections for 6 months. Laboratory and clinical evaluations were performed between baseline and month 6. RESULTS: At day 8, the primary endpoint (Treg frequency) was reached with a 1.8±0.5-fold increase of Treg levels among CD4+ T lymphocytes (p=0.0015). There were no significant changes in effector T cells nor in B cells. IL-2LD was well tolerated, and no serious adverse events related to treatment occurred. There was a globally stable measurement in the modified Rodnan skin score and Valentini score at month 6. Disease activity and severity measures, the quality of life evaluated by EuroQL-5D-5L and pulmonary function test parameters remained stable during the study period. CONCLUSION: IL-2LD at a dosage of 1 MIU/day safely and selectively activates and expands Tregs. Clinical signs remain stable during the study period. This opens the door to properly powered phase II efficacy trials investigating IL-2LD therapeutic efficacy in SSc.

Prediction of progressive fibrosing interstitial lung disease in patients with systemic sclerosis: insight from the CRDC cohort study.

BACKGROUND: This study aims to establish a reliable prediction model of progressive fibrosing interstitial lung disease (PF-ILD) in patients with systemic sclerosis (SSc)-ILD, to achieve early risk stratification and to help better in preventing disease progression. METHODS: 304 SSc-ILD patients with no less than three pulmonary function tests within 6-24 months were included. We collected data at baseline and compared differences between SSc patients with and without PF-ILD. Least absolute shrinkage and selection operator regularisation regression and multivariable Cox regression were used to construct the prediction model, which were presented as nomogram and forest plot. RESULTS: Among the 304 patients with SSc-ILD included, 92.1% were women, with a baseline average age of 46.7 years. Based on the 28 variables preselected by comparison between SSc patients without PF-ILD group (n=150) and patients with SSc PF-ILD group (n=154), a 9-variable prediction model was constructed, including age≥50 years (HR 1.8221, p=0.001), hyperlipidemia (HR 4.0516, p<0.001), smoking history (HR 3.8130, p<0.001), diffused cutaneous SSc subtype (HR 1.9753, p<0.001), arthritis (HR 2.0008, p<0.001), shortness of breath (HR 2.0487, p=0.012), decreased serum immunoglobulin A level (HR 2.3900, p=0.002), positive anti-Scl-70 antibody (HR 1.9573, p=0.016) and usage of cyclophosphamide/mycophenolate mofetil (HR 0.4267, p<0.001). The concordance index after enhanced bootstrap resampling adjustment was 0.874, while the optimism-corrected Brier Score was 0.144 in internal validation. CONCLUSION: This study developed the first prediction model for PF-ILD in patients with SSc-ILD, and internal validation showed favourable accuracy and stability of the model.

Characterization of Vascular Niche in Systemic Sclerosis by Spatial Proteomics.

BACKGROUND: Systemic sclerosis (SSc) is a connective tissue disease that can serve as a model to study vascular changes in response to inflammation, autoimmunity, and fibrotic remodeling. Although microvascular changes are the earliest histopathologic manifestation of SSc, the vascular pathophysiology remains poorly understood. METHODS: We applied spatial proteomic approaches to deconvolute the heterogeneity of vascular cells at the single-cell level in situ and characterize cellular alterations of the vascular niches of patients with SSc. Skin biopsies of patients with SSc and control individuals were analyzed by imaging mass cytometry, yielding a total of 90 755 cells including 2987 endothelial cells and 4096 immune cells. RESULTS: We identified 7 different subpopulations of blood vascular endothelial cells (VECs), 2 subpopulations of lymphatic endothelial cells, and 3 subpopulations of pericytes. A novel population of CD34+;αSMA+ (α-smooth muscle actin);CD31+ VECs was more common in SSc, whereas endothelial precursor cells were decreased. Co-detection by indexing and tyramide signal amplification confirmed these findings. The microenvironment of CD34+;αSMA+;CD31+ VECs was enriched for immune cells and myofibroblasts, and CD34+;αSMA+;CD31+ VECs expressed markers of endothelial-to-mesenchymal transition. The density of CD34+;αSMA+;CD31+ VECs was associated with clinical progression of fibrosis in SSc. CONCLUSIONS: Using spatial proteomics, we unraveled the heterogeneity of vascular cells in control individuals and patients with SSc. We identified CD34+;αSMA+;CD31+ VECs as a novel endothelial cell population that is increased in patients with SSc, expresses markers for endothelial-to-mesenchymal transition, and is located in close proximity to immune cells and myofibroblasts. CD34+;αSMA+;CD31+ VEC counts were associated with clinical outcomes of progressive fibrotic remodeling, thus providing a novel cellular correlate for the crosstalk of vasculopathy and fibrosis.

Factors associated with satisfaction with social roles and activities among people with systemic sclerosis: a Scleroderma Patient-centered Intervention Network (SPIN) cohort cross-sectional study.

OBJECTIVE: The objectives were to (1) compare satisfaction with social roles and activities in a large multinational systemic sclerosis (SSc) cohort to general population normative data and (2) identify sociodemographic, lifestyle and SSc disease factors associated with satisfaction with social roles and activities. METHODS: Participants in the Scleroderma Patient-centered Intervention Network Cohort completed the Patient Reported Outcomes Information System Version 2 satisfaction with social roles and activities domain questionnaire. Multivariable regression was used to assess associations with sociodemographic, lifestyle and disease factors. RESULTS: Among 2385 participants, mean satisfaction with social roles and activities T-score (48.1, SD=9.9) was slightly lower than the US general population (mean=50, SD=10). Factors independently associated with satisfaction were years of education (0.54 per SD, 95% CI 0.14 to 0.93); non-White race or ethnicity (-1.13, 95% CI -2.18 to -0.08); living in Canada (-1.33, 95% CI -2.40 to -0.26 (reference USA)) or the UK (-2.49, 95% CI -3.92 to -1.06); body mass index (-1.08 per SD, 95% CI -1.47 to -0.69); gastrointestinal involvement (-3.16, 95% CI -4.27 to -2.05); digital ulcers (-1.90, 95% CI -3.05 to -0.76); moderate (-1.62, 95% CI -2.78 to -0.45) or severe (-2.26, 95% CI -3.99 to -0.52) small joint contractures; interstitial lung disease (-1.11, 95% CI -1.97 to -0.25); pulmonary arterial hypertension (-2.69, 95% CI -4.08 to -1.30); rheumatoid arthritis (-2.51, 95% CI -4.28 to -0.73); and Sjogren's syndrome (-2.42, 95% CI -3.96 to -0.88). CONCLUSION: Mean satisfaction with social roles and activities is slightly lower in SSc than the general population and associated with multiple sociodemographic and disease factors.

History of pre-eclampsia does not appear to be a risk factor for vascular phenotype in women with systemic sclerosis.

BACKGROUND: Vascular phenotype is associated with a poor prognosis in systemic sclerosis (SSc). The identification of its risk factors could facilitate its early detection. OBJECTIVES: To explore risk factors for a vascular phenotype of SSc, among them a history of pre-eclampsia. METHODS: This observational multicentre case-control study enrolled adult women fulfilling European Alliance of Associations for Rheumatology 2013 diagnosis criteria for SSc and having a pregnancy history≥6 months before SSc diagnosis in 14 French hospital-based recruiting centres from July 2020 to July 2022. Cases had specific vascular complications of SSc defined as history of digital ischaemic ulcers, pulmonary arterial hypertension, specific cardiac involvement or renal crisis. Women with SSc were included during their annual follow-up visit and filled in a self-administered questionnaire about pregnancy. A case report form was completed by their physician, reporting data on medical history, physical examination, clinical investigations and current medication. The main outcome was the presence/absence of a personal history of pre-eclampsia before SSc diagnosis, according to the validated pre-eclampsia questionnaire. RESULTS: 378 women were included: 129 cases with a vascular phenotype and 249 matched controls. A history of pre-eclampsia was reported in 5 (3.9%) cases and 12 (4.8%) controls and was not associated with a vascular phenotype (OR=0.96, 95% CI 0.28 to 3.34, p=0.9). Besides, Rodnan skin score and disease duration≥5 years were risk factors for vascular phenotype. CONCLUSIONS: In women with SSc and a pregnancy history≥6 months before SSc, a history of pre-eclampsia is not associated with a vascular phenotype.

Characteristics and disease course of untreated patients with interstitial lung disease associated with systemic sclerosis in a real-life two-centre cohort.

BACKGROUND: Interstitial lung disease (ILD) is the leading cause of death in systemic sclerosis (SSc). According to expert statements, not all SSc-ILD patients require pharmacological therapy. OBJECTIVES: To describe disease characteristics and disease course in untreated SSc-ILD patients in two well characterised SSc-ILD cohorts. METHODS: Patients were classified as treated if they had received a potential ILD-modifying drug. ILD progression in untreated patients was defined as (1) decline in forced vital capacity (FVC) from baseline of ≥10% or (2) decline in FVC of 5%-9% associated with a decline in diffusing capacity for carbon monoxide (DLCO)≥15% over 12±3 months or (3) start of any ILD-modifying treatment or (4) increase in the ILD extent during follow-up. Multivariable logistic regression was performed to identify factors associated with non-prescription of ILD-modifying treatment at baseline. Prognostic factors for progression in untreated patients were tested by multivariate Cox regression. RESULTS: Of 386 SSc-ILD included patients, 287 (74%) were untreated at baseline. Anticentromere antibodies (OR: 6.75 (2.16-21.14), p=0.001), limited extent of ILD (OR: 2.39 (1.19-4.82), p=0.015), longer disease duration (OR: 1.04 (1.00-1.08), p=0.038) and a higher DLCO (OR: 1.02 (1.01-1.04), p=0.005) were independently associated with no ILD-modifying treatment at baseline. Among 234 untreated patients, the 3 year cumulative incidence of progression was 39.9% (32.9-46.2). Diffuse cutaneous SSc and extensive lung fibrosis independently predicted ILD progression in untreated patients. CONCLUSION: As about 40% of untreated patients show ILD progression after 3 years and effective and safe therapies for SSc-ILD are available, our results support a change in clinical practice in selecting patients for treatment.

Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases by cohort-wide immunophenotyping.

OBJECTIVE: Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases (AIRDs) is essential towards personalised medicine. METHODS: We conducted large-scale and cohort-wide immunophenotyping of 46 peripheral immune cells using Human Immunology Protocol of comprehensive 8-colour flow cytometric analysis. Dataset consisted of >1000 Japanese patients of 11 AIRDs with deep clinical information registered at the FLOW study, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In-depth clinical and immunological characterisation was conducted for the identified RA patient clusters, including associations of inborn human genetics represented by Polygenic Risk Score (PRS). RESULTS: Multimodal clustering of immunophenotypes deciphered underlying disease-cell type network in immune cell, disease and patient cluster resolutions. This provided immune cell type specificity shared or distinct across AIRDs, such as close immunological network between mixed connective tissue disease and SLE. Individual patient-level clustering dissected patients with AIRD into several clusters with different immunological features. Of these, RA-like or SLE-like clusters were exclusively dominant, showing immunological differentiation between RA and SLE across AIRDs. In-depth clinical analysis of RA revealed that such patient clusters differentially defined clinical heterogeneity in disease activity and treatment responses, such as treatment resistance in patients with RA with SLE-like immunophenotypes. PRS based on RA case-control and within-case stratified genome-wide association studies were associated with clinical and immunological characteristics. This pointed immune cell type implicated in disease biology such as dendritic cells for RA-interstitial lung disease. CONCLUSION: Cohort-wide and cross-disease immunophenotyping elucidate clinically heterogeneous patient subtypes existing within single disease in immune cell type-specific manner.

Connective tissue disease-associated interstitial lung disease / Doença pulmonar intersticial associada a doença do tecido conjuntivo

ABSTRACT Connective tissue disease-associated interstitial lung disease (CTD-ILD) represents a group of systemic autoimmune disorders characterized by immune-mediated organ dysfunction. Systemic sclerosis, rheumatoid arthritis, idiopathic inflammatory myositis, and Sjögren's syndrome are the most common CTDs that present with pulmonary involvement, as well as with interstitial pneumonia with autoimmune features. The frequency of CTD-ILD varies according to the type of CTD, but the overall incidence is 15%, causing an important impact on morbidity and mortality. The decision of which CTD patient should be investigated for ILD is unclear for many CTDs. Besides that, the clinical spectrum can range from asymptomatic findings on imaging to respiratory failure and death. A significant proportion of patients will present with a more severe and progressive disease, and, for those, immunosuppression with corticosteroids and cytotoxic medications are the mainstay of pharmacological treatment. In this review, we summarized the approach to diagnosis and treatment of CTD-ILD, highlighting recent advances in therapeutics for the various forms of CTD.

RESUMO Doença pulmonar intersticial associada à doença do tecido conjuntivo (DPI-DTC) representa um grupo de distúrbios autoimunes sistêmicos caracterizados por disfunção de órgãos imunomediada. Esclerose sistêmica, artrite reumatoide, miosite inflamatória idiopática e síndrome de Sjögren são as DTC mais comuns que apresentam acometimento pulmonar, bem como pneumonia intersticial com achados autoimunes. A frequência de DPI-DTC varia de acordo com o tipo de DTC, mas a incidência total é de 15%, causando um impacto importante na morbidade e mortalidade. A decisão sobre qual paciente com DTC deve ser investigado para DPI não é clara para muitas DTC. Além disso, o espectro clínico pode variar desde achados assintomáticos em exames de imagem até insuficiência respiratória e morte. Parte significativa dos pacientes apresentará doença mais grave e progressiva, e, para esses pacientes, imunossupressão com corticosteroides e medicamentos citotóxicos são a base do tratamento farmacológico. Nesta revisão, resumimos a abordagem do diagnóstico e tratamento de DPI-DTC, destacando os recentes avanços na terapêutica para as diversas formas de DTC.

Risk of kidney failure in patients with systemic sclerosis: a nationwide population-based study.

OBJECTIVE: Data from a decade ago have shown that patients with systemic sclerosis (SSc) have a higher risk of kidney failure than the general population. However, as the incidence of kidney failure due to SSc has been declining, the comparative risk of kidney failure between patients with SSc and the general population could have changed over time. We investigated the risk of kidney failure in patients with SSc compared with the general population, up to more recent years. METHODS: This was a nationwide population-based study using the Korean National Health Insurance Service database. Patients with claims data for SSc between 2010 and 2017 (n=2591) and 1:5 age-matched and sex-matched controls (n=12 955) were selected. The index date was the earliest date of claim for SSc between 2010 and 2017. The follow-up duration was from the index date to 2019. The adjusted HRs (aHRs) and 95% CI for kidney failure were estimated using multivariable Cox proportional hazard models. RESULTS: Over 5.2±2.6 years, the incidence rates of kidney failure in patients with SSc and controls were 2.88 and 0.35 per 1000 person-years, respectively. Patients with SSc had a significantly higher risk of kidney failure than controls (aHR=7.244, 95% CI=4.256 to 12.329). The effect size was larger in patients diagnosed with SSc between 2014 and 2017 (aHR=9.754, 95% CI=3.254 to 29.235) than in those diagnosed before 2010 (aHR=6.568, 95% CI=2.711 to 15.571) or between 2010 and 2013 (aHR=6.553, 95% CI=2.721 to 15.781). CONCLUSION: The risk of kidney failure remains higher in patients with SSc than in the general population.

[Characteristics of patients with systemic sclerosis who develop interstitial lung disease]. / Características de los pacientes con esclerosis sistémica que desarrollan enfermedad pulmonar intersticial.

Background: Systemic sclerosis associated-interstitial lung disease (SSc-ILD) show a high mortality. The factors associated SSc-ILD have shown variability in different populations. There are few studies in Mexican mestizos. Objective: To analyze the epidemiological, clinical and paraclinical factors associated with SSc-ILD. Material and methods: Cross-sectional study, where patients > 18 years of age with a diagnosis of SSc according to EULAR/ACR 2013 criteria and diagnosis of ILD by forced vital capacity (FVC) < 70% and > 5% of affected lung area on tomography were included. The strength of association of the factors for ILD was measured by odds ratio (OR) with 95% confidence intervals (95% CI). The significant variables were analyzed by multiple logistic regression with adjustment. Results: Of the 80 patients with SSc, 38 (47.5%) had ILD. Risk factors such as smoking, higher activity index, lower FVC, anti-topoisomerase I antibodies, and protective factors such as a limited SSc, early capillaroscopic pattern, and anti-centromere antibodies (ACA) were associated with ILD. In the multivariate analysis, a higher activity index with OR 4.17, (95% CI 2.01-8.65) persisted as a risk factor, while ACA with OR 0.17, (95% CI 0.03-0.85) persisted as a protective factor associated with SSc-ILD. Conclusions: A higher index of activity and ACA persisted as factors associated with SSc-ILD.

Introducción: la enfermedad pulmonar intersticial (EPI) está relacionada a una mayor mortalidad en esclerosis sistémica (ES). Los factores asociados a su presentación han mostrado variabilidad en diferentes poblaciones. Pocos estudios se han realizado en mestizos mexicanos. Objetivo: analizar los factores clínicos y paraclínicos asociados a EPI en pacientes con ES. Material y métodos: estudio retrospectivo de casos y controles en el que se incluyeron pacientes > 18 años con diagnóstico de ES, según criterios EULAR/ACR 2013 y EPI por capacidad vital forzada (CVF) < 70% y > 5% de área pulmonar efectada en tomografía. La fuerza de asociación de los factores para EPI se midió por razón de momios (RM) con intervalos de confianza del 95% (IC95%). Las variables significativas se analizaron por regresión logística múltiple con ajuste. Resultados: de los 80 pacientes con ES, 38 (47.5%) tenían EPI. Factores de riesgo como tabaquismo, mayor índice de actividad, menor CVF, anticuerpos antitopoisomerasa I y factores protectores como variedad limitada de ES, patrón capilaroscópico temprano y anticuerpos anticentrómero estuvieron asociados a EPI. En el análisis multivariado un mayor índice de actividad con RM 4.17, (IC95%: 2.01-8.65) persistió como un factor de riesgo; en cambio, los anticuerpos anticentrómero con RM 0.17, (IC95%: 0.03-0.85) persistieron como un factor protector asociado a EPI. Conclusiones: un mayor índice de actividad y la presencia anticuerpos anticentrómero persistieron como factores asociados a la presencia de EPI en ES.

A stretchable hardness sensor for the assessment of skin disease in systemic sclerosis.

OBJECTIVE: To determine the validity of a hardness sensor to objectively assess skin induration in patients with systemic sclerosis, and to compare the hardness sensor with the modified Rodnan skin score (MRSS) and a durometer. METHODS: The skin induration was measured in two assessments: a Latin square experiment to examine the hardness sensor's intraobserver and interobserver reliability; and a longitudinal cohort to evaluate the distribution of hardness sensor measurements, the correlation between hardness sensor, durometer and MRSS, and the sensitivity to change in skin hardness. Other outcome data collected included the health assessment questionnaire (HAQ) disability index and Keitel function test (KTF) score. RESULTS: The reliability of the hardness sensor was excellent, with high intraobserver and interobserver intraclass correlation coefficients (0.97; 0.96), which was higher than MRSS (0.86; 0.74). Interobserver reproducibility of hardness sensor was only poor in abdomen (0.38), yet for durometer it was poor in face (0.11) and abdomen (0.33). The hardness sensor score provided a greater dynamic evaluation range than MRSS. Total hardness sensor score correlated well with MRSS (r=0.90, p<0.001), total durometer score (r=0.95, p<0.001), HAQ disability index (r=0.70, p<0.001) and KTF score (r=0.66, p<0.001). Change in hardness sensor score also correlated with change in MRSS (r=0.78, p<0.001), total durometer score (r=0.85, p<0.001), HAQ disability index (r=0.76, p<0.001) and KTF score (r=0.67, p<0.001). CONCLUSION: The hardness sensor showed greater reproducibility and accuracy than MRSS, and more application sites than durometer; it can also reflect patients' self-assessments and function test outcomes.

Anti-SMN autoantibodies in mixed connective tissue disease are associated with a severe systemic sclerosis phenotype.

OBJECTIVES: The survival of motor neuron (SMN) complex has an essential role in the assembly of small nuclear ribonucleoproteins (RNP). Recent reports have described autoantibodies (aAbs) to the SMN complex as novel biomarkers in anti-U1RNP+ myositis patients. The aim of this study was to compare phenotypic features of anti-U1RNP+ mixed connective tissue disease (MCTD) patients with and without anti-SMN aAbs. METHODS: A retrospective MCTD cohort was studied. Addressable laser bead immunoassay was used to detect specific anti-SMN aAbs with <300 mean fluorescence intensity (MFI) as normal reference range, 300-999 MFI as low-titre and ≥1000 MFI as high-titre positivity. Comparison of clinical features between anti-SMN+ and anti-SMN- subgroups used two-tailed Fisher's exact test, and logistic regression analyses. RESULTS: Sixty-six patients were included. Median age at MCTD diagnosis was 40.6 years, and duration of follow-up was 12 years. Based on the highest available titre, 39 (59%) were anti-SMN+: 10 (26%) had low titre and 29 (74%) had high titre. Anti-SMN+ patients had a higher frequency of fingertip pitting scars (anti-SMN+ 23% vs anti-SMN- 4%, p=0.04), lower gastrointestinal (GI) involvement (26% vs 4%, p=0.04), and myocarditis (16% vs 0%, p=0.04). The combined outcome of pitting scars and/or lower GI involvement and/or myositis and/or myocarditis was highest among high-titre anti-SMN+ patients: adjusted OR 7.79 (2.33 to 30.45, p=0.002). CONCLUSIONS: Anti-SMN aAbs were present in 59% of our MCTD cohort. Their presence, especially at high-titres, was associated with a severe systemic sclerosis (scleroderma) phenotype including myositis, myocarditis and lower GI involvement.

Autoantibody status according to multiparametric assay accurately estimates connective tissue disease classification and identifies clinically relevant disease clusters.

OBJECTIVE: Assessment of circulating autoantibodies represents one of the earliest diagnostic procedures in patients with suspected connective tissue disease (CTD), providing important information for disease diagnosis, identification and prediction of potential clinical manifestations. The purpose of this study was to evaluate the ability of multiparametric assay to correctly classify patients with multiple CTDs and healthy controls (HC), independent of clinical features, and to evaluate whether serological status could identify clusters of patients with similar clinical features. METHODS: Patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjogren's syndrome (SjS), undifferentiated connective tissue disease (UCTD), idiopathic inflammatory myopathies (IIM) and HC were enrolled. Serum was tested for 29 autoantibodies. An XGBoost model, exclusively based on autoantibody titres was built and classification accuracy was evaluated. A hierarchical clustering model was subsequently developed and clinical/laboratory features compared among clusters. RESULTS: 908 subjects were enrolled. The classification model showed a mean accuracy of 60.84±4.05% and a mean area under the receiver operator characteristic curve of 88.99±2.50%, with significant discrepancies among groups. Cluster analysis identified four clusters (CL). CL1 included patients with typical features of SLE. CL2 included most patients with SjS, along with some SLE and UCTD patients with SjS-like features. CL4 included anti-Jo1 patients only. CL3 was the largest and most heterogeneous, including all the remaining subjects, overall characterised by low titre or lower-prevalence autoantibodies. CONCLUSION: Extended multiparametric autoantibody assay allowed an accurate classification of CTD patients, independently of clinical features. Clustering according to autoantibody titres is able to identify clusters of CTD subjects with similar clinical features, independently of their final diagnosis.

Sub-oclusión intestinal y desnutrición severa en esclerosis sistémica sin esclerodermia

La esclerosis sistémica sin escleroderma es una forma no común de compromiso sistémico de esta enfermedad, con ausencia de manifestaciones cutáneas. Presentamos el caso de una mujer de 71 años con índice de masa corporal (IMC) en 16,9 kg/m2, con historia de hipotiroidismo y estreñimiento crónico, quien acude a emergencia por dolor y distensión abdominal, asociado a náuseas. Se realizó una tomografía abdomino-pélvica encontrándose cámara gástrica colapsada, asas intestinales con algunos segmentos distendidos, con signos de fecalización de asa delgada. La colonoscopía describió dolicocolon severo. Se observaron placas induradas en codo derecho y en ambos glúteos. Los exámenes auxiliares: ANA 1/640 patrón centromérico, anticuerpos anticentrómero = 227 U/mL (valor normal - VN: 0-25), Anti SCL-70 = 1,9 U/mL (VN 0-25) y anti RNP = 0,1 U/mL (VN 0-25). La capilaroscopía de borde ungueal a 200x mostró megacapilares. El diagnóstico clínico fue esclerosis sistémica sin esclerodermia. Se inició tratamiento con dieta rica en fibra y nutrición parenteral por 1 semana. La evolución de la paciente fue favorable.

Systemic sclerosis sine Scleroderma is an uncommon form of systemic compromise of this disease, in the abscense of cutaneous manifestations. We present the case of a 71 years-old woman, body mass index (BMI) in 16.9 kg/m2, with history of hypothyroidism and chronic constipation, who goes to the emergency with pain, abdominal bloating, and nausea. An abdominopelvic tomography was made, reporting a collapse of the gastric chamber, some segments of intestinal loops distended with signs of fecalization in the small intestine. A colonoscopy described severe dolicocolon. We observed indurated plaques in left elbow and in both buttocks. Lab tests: ANA 1/640 with anticentromeric pattern, anticentromere antibodies = 227 U/mL (0-25), Anti-SCL-70 = 1.9 U/mL (0-25), anti-RNP = 0.1 U/mL (0-25). Peri-ungueal cappilaroscopy 200x showed mega capillaries. Clinical diagnosis was systemic sclerosis sine scleroderma. We initiated treatment with a high-fiber diet and parenteral nutrition for a week. The patient evolution was favorable.

Single-cell analysis reveals key differences between early-stage and late-stage systemic sclerosis skin across autoantibody subgroups.

OBJECTIVES: The severity of skin involvement in diffuse cutaneous systemic sclerosis (dcSSc) depends on stage of disease and differs between anti-RNA-polymerase III (ARA) and anti-topoisomerase antibody (ATA) subsets. We have investigated cellular differences in well-characterised dcSSc patients compared with healthy controls (HCs). METHODS: We performed single-cell RNA sequencing on 4 mm skin biopsy samples from 12 patients with dcSSc and HCs (n=3) using droplet-based sequencing (10× genomics). Patients were well characterised by stage (>5 or <5 years disease duration) and autoantibody (ATA+ or ARA+). Analysis of whole skin cell subsets and fibroblast subpopulations across stage and ANA subgroup were used to interpret potential cellular differences anchored by these subgroups. RESULTS: Fifteen forearm skin biopsies were analysed. There was a clear separation of SSc samples, by disease, stage and antibody, for all cells and fibroblast subclusters. Further analysis revealed differing cell cluster gene expression profiles between ATA+ and ARA+ patients. Cell-to-cell interaction suggest differing interactions between early and late stages of disease and autoantibody. TGFß response was mainly seen in fibroblasts and smooth muscle cells in early ATA+dcSSc skin samples, whereas in early ARA+dcSSc patient skin samples, the responding cells were endothelial, reflect broader differences between clinical phenotypes and distinct skin score trajectories across autoantibody subgroups of dcSSc. CONCLUSIONS: We have identified cellular differences between the two main autoantibody subsets in dcSSc (ARA+ and ATA+). These differences reinforce the importance of considering autoantibody and stage of disease in management and trial design in SSc.

Screening tool development for hand surgery referrals in systemic sclerosis.

BACKGROUND: Systemic Sclerosis (SSc) patients may need hand surgery. OBJECTIVE: To develop a screening tool for rheumatologists to identify potential candidates with systemic sclerosis for hand surgery, optimizing referrals. METHODS: A pilot cross-sectional study from January 2015 to December 2016. SAMPLE SIZE: 51 participants. INCLUSION CRITERIA: ≥ 18 years old, meeting the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc and hand impairment. DATA COLLECTED: age, sex, race, disease duration, SSc subtypes, vasodilator use, skin thickness, finger stiffness, presence of Digital Ulcers (DU) and/or calcinosis, presence of Raynaud's Phenomenon (RP) attacks, health status and disability, disease status, pain intensity and functional status of the hands. Data were analyzed by a multivariate logistic regression model. RESULTS: Fulfillment of surgical criteria: 68.8%. The surgical group had higher scores on the HAQ-DI (1.39 vs. 0.96, p = 0.032) and CHFS (25.0 vs. 12.0, p = 0.005) questionnaires, and a higher frequency of DU (91.43% vs. 18.75%, p < 0.0010), calcinosis (60.0% vs. 0.0%, p < 0.001), use of vasodilators (100.0% vs. 75.0%, p = 0.007) and digital stiffness (28.57% vs. 0.0%, p = 0.017). The presence of DU increased the chance of surgical indication by 46.2 times (ORIC 95% = 8.23 to 259.49). The statistical model showed good accuracy (86.3%, p < 0.001), sensitivity (91.4%), and specificity (81.2%). CONCLUSION: The presence of DU in SSc could be used as a screening feature for early identification and referral of potential candidates for hand surgery.

Systematic literature review informing the EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus and systemic sclerosis.

Through this systematic literature review, we assembled evidence to inform the EULAR recommendations for the non-pharmacological management of systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). We screened articles published between January 2000 and June 2021. Studies selected for data extraction (118 for SLE and 92 for SSc) were thematically categorised by the character of their intervention. Of 208 articles included, 51 were classified as robust in critical appraisal. Physical activity was the most studied management strategy and was found to be efficacious in both diseases. Patient education and self-management also constituted widely studied topics. Many studies on SLE found psychological interventions to improve quality of life. Studies on SSc found phototherapy and laser treatment to improve cutaneous disease manifestations. In summary, non-pharmacological management of SLE and SSc encompasses a wide range of interventions, which can be combined and provided either with or without adjunct pharmacological treatment but should not aim to substitute the latter when this is deemed required. While some management strategies i.e., physical exercise and patient education, are already established in current clinical practice in several centres, others e.g., phototherapy and laser treatment, show both feasibility and efficacy, yet require testing in more rigorous trials than those hitherto conducted.