Identification and management of interstitial lung disease associated with systemic sclerosis (SSc-ILD), rheumatoid arthritis (RA-ILD), and polymyositis/dermatomyositis (PM/DM-ILD): development of expert consensus-based clinical algorithms.

BACKGROUND: Clinical guidance on the identification and management of connective tissue disease-associated interstitial lung disease (CTD-ILD) is needed for optimal clinical practice. We aimed to develop clinical algorithms for identifying and managing three common CTD-ILDs: those associated with systemic sclerosis (SSc-ILD), rheumatoid arthritis (RA-ILD), and polymyositis/dermatomyositis (PM/DM-ILD). RESEARCH DESIGN AND METHODS: Meetings were held October - November 2023 to create consensus-based algorithms for identifying and managing SSc-ILD, RA-ILD, and PM/DM-ILD in clinical practice, based on expert consensus statements for identification and management of CTD-ILD previously derived from a Delphi process. RESULTS: We developed clinical algorithms for SSc-ILD, RA-ILD, and PM/DM-ILD that highlight both commonalities and differences in the identification and management of these CTD-ILDs. Importantly, ILD should be suspected in patients with SSc, RA, or PM/DM who have respiratory symptoms. Chest high-resolution computed tomography has utility for screening, diagnosis and assessment of severity. Furthermore, regular follow-up and multidisciplinary management are important. Disease-specific considerations include unique risk factors such as anti-topoisomerase I antibodies in SSc-ILD, high-titer cyclic citrullinated peptide antibodies in RA, anti-aminoacyl tRNA synthetase antibodies in PM/DM, and anti-melanoma differentiation-associated gene 5 antibody in DM. CONCLUSIONS: These algorithms may help physicians to identify and manage patients with SSc-ILD, RA-ILD, or PM/DM-ILD.

IQGAP1 Regulates Actin Polymerization and Contributes to Bleomycin-Induced Lung Fibrosis.

We previously found IQ motif containing GTPase activating protein (IQGAP1) to be consistently elevated in lung fibroblasts (LF) isolated from patients with scleroderma (systemic sclerosis, SSc)-associated interstitial lung disease (ILD) and reported that IQGAP1 contributed to SSc by regulating expression and organization of α-smooth muscle actin (SMA) in LF. The aim of this study was to compare the development of ILD in the presence and absence of IQGAP1. Pulmonary fibrosis was induced in IQGAP1 knockout (KO) and wild-type (WT) mice by a single-intratracheal instillation of bleomycin. Two and three weeks later, mice were euthanized and investigated. We observed that the IQGAP1 KO mouse was characterized by a reduced rate of actin polymerization with reduced accumulation of actin in the lung compared to the WT mouse. After exposure to bleomycin, the IQGAP1 KO mouse demonstrated decreased contractile activity of LF, reduced expression of SMA, TGFß, and collagen, and lowered overall fibrosis scores compared to the WT mouse. The numbers of inflammatory cells and expression of pro-inflammatory cytokines in lung tissue were not significantly different between IQGAP1 KO and WT mice. We conclude that IQGAP1 plays an important role in the development of lung fibrosis induced by bleomycin, and the absence of IQGAP1 reduces the contractile activity of lung fibroblast and bleomycin-induced pulmonary fibrosis. Thus, IQGAP1 may be a potential target for novel anti-fibrotic therapies for lung fibrosis.

Single-cell transcriptomes and chromatin accessibility of endothelial cells unravel transcription factors associated with dysregulated angiogenesis in systemic sclerosis.

OBJECTIVES: Vasculopathy emerges early in systemic sclerosis (SSc) and links to endothelial cell (EC) injury and angiogenesis. Understanding EC transcriptomes and epigenomes is crucial for unravelling the mechanisms involved. METHODS: Transcriptomes and chromatin accessibility were assessed by single-cell RNA sequencing and single-nucleus transposase-accessible chromatin sequencing. Immunofluorescent staining of skin and proteomics assay were employed to confirm the altered SSc EC phenotypes. Gain-of-function assay was used to evaluate the effects of ETS transcription factors on human dermal ECs (hDECs). RESULTS: Both control and SSc ECs shared transcriptomic signatures of vascular linages (arterial, capillary and venous ECs) and lymphatic ECs. Arterial ECs in SSc showed reduced number and increased expression of genes associated with apoptosis. Two distinct EC subpopulations, tip and proliferating ECs, were markedly upregulated in SSc, indicating enhanced proangiogenic and proliferative activities. Molecular features of aberrant SSc-ECs were associated with disease pathogenesis and clinical traits of SSc, such as skin fibrosis and digital ulcers. Ligand-receptor analysis demonstrated altered intercellular networks of SSc EC subpopulations with perivascular and immune cells. Furthermore, the integration of open chromatin profiles with transcriptomic analysis suggested an increased accessibility of regulatory elements for ETS family transcription factors in SSc ECs. Overexpression of ETS genes in hDECs suggested ELK4, ERF and ETS1 may orchestrate arterial apoptosis and dysregulated angiogenesis in SSc. CONCLUSIONS: This study unveils transcriptional and chromatin alterations in driving endovascular dysregulation in SSc, proposing ELK4, ERF and ETS1 as novel targets in ECs for addressing vascular complications in the condition.

Inflammatory tissue priming: novel insights and therapeutic opportunities for inflammatory rheumatic diseases.

Due to optimised treatment strategies and the availability of new therapies during the last decades, formerly devastating chronic inflammatory diseases such as rheumatoid arthritis or systemic sclerosis (SSc) have become less menacing. However, in many patients, even state-of-the-art treatment cannot induce remission. Moreover, the risk for flares strongly increases once anti-inflammatory therapy is tapered or withdrawn, suggesting that underlying pathological processes remain active even in the absence of overt inflammation. It has become evident that tissues have the ability to remember past encounters with pathogens, wounds and other irritants, and to react more strongly and/or persistently to the next occurrence. This priming of the tissue bears a paramount role in defence from microbes, but on the other hand drives inflammatory pathologies (the Dr Jekyll and Mr Hyde aspect of tissue adaptation). Emerging evidence suggests that long-lived tissue-resident cells, such as fibroblasts, macrophages, long-lived plasma cells and tissue-resident memory T cells, determine inflammatory tissue priming in an interplay with infiltrating immune cells of lymphoid and myeloid origin, and with systemically acting factors such as cytokines, extracellular vesicles and antibodies. Here, we review the current state of science on inflammatory tissue priming, focusing on tissue-resident and tissue-occupying cells in arthritis and SSc, and reflect on the most promising treatment options targeting the maladapted tissue response during these diseases.

Identification and validation of anti-protein arginine methyltransferase 5 (PRMT5) antibody as a novel biomarker for systemic sclerosis (SSc).

OBJECTIVES: In the complex panorama of autoimmune diseases, the characterisation of pivotal contributing autoantibodies that are involved in disease progression remains challenging. This study aimed to employ a global antibody profiling strategy to identify novel antibodies and investigate their association with systemic sclerosis (SSc). METHODS: We implemented this strategy by conducting immunoprecipitation (IP) following on-bead digestion with the sera of patients with SSc or healthy donors, using antigen pools derived from cell lysates. The enriched antigen-antibody complex was proceeded with mass spectrometry (MS)-based quantitative proteomics and over-represented by bioinformatics analysis. The candidate antibodies were then orthogonally validated in two independent groups of patients with SSc. Mice were immunised with the target antigen, which was subsequently evaluated by histological examination and RNA sequencing. RESULTS: The IP-MS analysis, followed by validation in patients with SSc, revealed a significant elevation in anti-PRMT5 antibodies among patients with SSc. These antibodies exhibited robust diagnostic accuracy in distinguishing SSc from healthy controls and other autoimmune conditions, including systemic lupus erythematosus and Sjögren's syndrome, with an area under the curve ranging from 0.900 to 0.988. The elevation of anti-PRMT5 antibodies was verified in a subsequent independent group with SSc using an additional method, microarray. Notably, 31.11% of patients with SSc exhibited seropositivity for anti-PRMT5 antibodies. Furthermore, the titres of anti-PRMT5 antibodies demonstrated a correlation with the progression or regression trajectory in SSc. PRMT5 immunisation displayed significant inflammation and fibrosis in both the skin and lungs of mice. This was concomitant with the upregulation of multiple proinflammatory and profibrotic pathways, thereby underscoring a potentially pivotal role of anti-PRMT5 antibodies in SSc. CONCLUSIONS: This study has identified anti-PRMT5 antibodies as a novel biomarker for SSc.

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.

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.

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.

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.

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.

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.

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.

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.

Quality of sleep in individuals with systemic sclerosis and its correlation with functional disability and quality of life: a cross-sectional study

SUMMARY OBJECTIVE: This study aimed to evaluate the quality of sleep in individuals with systemic sclerosis and its correlation with the quality of life and disability. METHODS: This is a cross-sectional study, carried out in a tertiary service of a university hospital. Inclusion criteria were diagnosis of systemic sclerosis according to the criteria of the American College of Rheumatology/European League Against Rheumatism 2013 or the preliminary criteria of the American College of Rheumatology 1980, age ≥ 18 years; regularly monitored at the outpatient clinic of rheumatology. Clinical and demographic data of the patients were obtained through a structured interview and evaluation of the medical records. Sleep quality was assessed using the Pittsburgh Sleep Quality Index questionnaire, daytime sleepiness using the Epworth Sleepiness Scale, quality of life using 12-item short-form health survey, and disability using the scleroderma health assessment questionnaire. RESULTS: A total of 50 patients with systemic sclerosis were included, with 92% female, mean age 48.9 years, mean disease duration 8.9 years, and 60% limited cutaneous form. Most systemic sclerosis patients (84%) have poor sleep quality and 20% have excessive daytime sleepiness. There was a significant negative correlation between Pittsburgh Sleep Quality Index and the physical and mental components of the 12-item short-form health survey (r=-0.42, p=0.003 and r=-0.43, p=0.002, respectively) and a positive correlation with the scleroderma health assessment questionnaire (r=0.52, p=<0.001). CONCLUSION: This study showed that poor sleep quality is a very common finding among systemic sclerosis patients, and it negatively affects both the quality of life and the degree of disability.

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.

[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.

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.

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.