Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome.

BACKGROUND: Disabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder, characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and squamous-cell carcinoma. The cause is unknown, and mortality is high. METHODS: We evaluated four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM. Genomic sequencing independently identified three heterozygous variants in a specific region of the gene that encodes signal transducer and activator of transcription 4 (STAT4). Primary skin fibroblast and cell-line assays were used to define the functional nature of the genetic defect. We also assayed gene expression using single-cell RNA sequencing of peripheral-blood mononuclear cells to identify inflammatory pathways that may be affected in DPM and that may respond to therapy. RESULTS: Genome sequencing revealed three novel heterozygous missense gain-of-function variants in STAT4. In vitro, primary skin fibroblasts showed enhanced interleukin-6 secretion, with impaired wound healing, contraction of the collagen matrix, and matrix secretion. Inhibition of Janus kinase (JAK)-STAT signaling with ruxolitinib led to improvement in the hyperinflammatory fibroblast phenotype in vitro and resolution of inflammatory markers and clinical symptoms in treated patients, without adverse effects. Single-cell RNA sequencing revealed expression patterns consistent with an immunodysregulatory phenotype that were appropriately modified through JAK inhibition. CONCLUSIONS: Gain-of-function variants in STAT4 caused DPM in the families that we studied. The JAK inhibitor ruxolitinib attenuated the dermatologic and inflammatory phenotype in vitro and in the affected family members. (Funded by the American Academy of Allergy, Asthma, and Immunology Foundation and others.).

Interferon-Gamma-Inducible Protein-10 (IP-10) and Tumor Necrosis Factor-α (TNF-α) as Serological Predictors of Active Disease Status in Localized Scleroderma.

We investigated the ability of a panel of immune-related cytokines and chemokines to predict the disease activity state in localized scleroderma (LS) subjects followed longitudinally. A total of 194 sera samples were obtained from 45 LS subjects with diverse types of LS (40% linear, 20% mixed, 16% craniofacial, 13% generalized, and 11% circumscribed) in our cohort. Cytokines/chemokines that were significantly elevated at the baseline active disease visit compared to the inactive disease state at follow-up were Interferon-Gamma-Inducible Protein (IP)-10 (p < 0.021) and Tumor Necrosis Factor (TNF)-α (p < 0.033). Mixed effect logit modeling identified IP-10 (Odds Ratio (OR) [95% confidence interval] = 2.1 [1.4, 3.2], p < 0.001), TNF-α (OR = 1.8 [1.1, 3.0], p = 0.016), and Monocyte Chemoattractant Protein (MCP)-1 (OR = 2.0 [1.1, 3.9], p = 0.034) as significant predictors of active disease status. These findings support earlier correlations between IP-10 and TNF-α with disease activity parameters in a cross-sectional Luminex™ serological study and may enhance clinical decision-making when disease activity is challenging to assess by clinical examination alone.

Characterization of Endothelial Cell Subclusters in Localized Scleroderma Skin with Single-Cell RNA Sequencing Identifies NOTCH Signaling Pathway.

Localized scleroderma (LS) is an autoimmune disease characterized by inflammation and fibrosis, leading to severe cutaneous manifestations such as skin hardening, tightness, discoloration, and other textural changes that may result in disability. While LS shares similar histopathologic features and immune-fibroblast interactions with systemic sclerosis (SSc), its molecular mechanisms remain understudied. Endothelial cells (EC) are known to play a crucial role in SSc but have not been investigated in LS. Single-cell RNA sequencing (scRNA-seq) now allows for detailed examination of this cell type in the primary organ of interest for scleroderma, the skin. In this study, we analyzed skin-isolated cells from 27 LS patients (pediatric and adult) and 17 healthy controls using scRNA-seq. Given the known role of EC damage as an initial event in SSc and the histologic and clinical skin similarities to LS, we focused primarily on endothelial cells. Our analysis identified eight endothelial subclusters within the dataset, encompassing both disease and healthy samples. Interaction analysis revealed that signaling from diseased endothelial cells was predicted to promote fibrosis through SELE interaction with FGFBP1 and other target genes. We also observed high levels of JAG in arterial endothelial cells and NOTCH in capillary endothelial cells, indicating the activation of a signaling pathway potentially responsible for epidermal abnormalities and contributing to LS pathogenesis. In summary, our scRNA-seq analysis identified potential disease-propagating endothelial cell clusters with upregulated pathways in LS skin, highlighting their importance in disease progression.

Spatial Transcriptomics Identifies Cellular and Molecular Characteristics of Scleroderma Skin Lesions: Pilot Study in Juvenile Scleroderma.

Juvenile localized and systemic scleroderma are rare autoimmune diseases which cause significant disability and morbidity in children. The mechanisms driving juvenile scleroderma remain unclear, necessitating further cellular and molecular level studies. The Visium CytAssist spatial transcriptomics (ST) platform, which preserves the spatial location of cells and simultaneously sequences the whole transcriptome, was employed to profile the histopathological slides from skin lesions of juvenile scleroderma patients. (1) Spatial domains were identified from ST data and exhibited strong concordance with the pathologist's annotations of anatomical structures. (2) The integration of paired ST data and single-cell RNA sequencing (scRNA-seq) from the same patients validated the comparable accuracy of the two platforms and facilitated the estimation of cell type composition in ST data. (3) The pathologist-annotated immune infiltrates, such as perivascular immune infiltrates, were clearly delineated by the ST analysis, underscoring the biological relevance of the findings. This is the first study utilizing spatial transcriptomics to investigate skin lesions in juvenile scleroderma patients. The validity of the ST data was corroborated by gene expression analyses and the pathologist's assessments. Integration with scRNA-seq data facilitated the cell type-level analysis and validation. Analyses of immune infiltrates through combined ST data and pathological review enhances our understanding of the pathogenesis of juvenile scleroderma.

Single-Cell Transcriptome Analysis Identifies Subclusters with Inflammatory Fibroblast Responses in Localized Scleroderma.

Localized scleroderma (LS) is an autoimmune disease with both inflammatory and fibrotic components causing an abnormal deposition of collagen in the skin and underlying tissue, often leading to disfigurement and disability. Much of its pathophysiology is extrapolated from systemic sclerosis (SSc) since the histopathology findings in the skin are nearly identical. However, LS is critically understudied. Single-cell RNA sequencing (scRNA seq) technology provides a novel way to obtain detailed information at the individual cellular level, overcoming this barrier. Here, we analyzed the affected skin of 14 patients with LS (pediatric and adult) and 14 healthy controls. Fibroblast populations were the focus, since they are the main drivers of fibrosis in SSc. We identified 12 fibroblast subclusters in LS, which overall had an inflammatory gene expression (IFN and HLA-associated genes). A myofibroblast-like cluster (SFRP4/PRSS23) was more prevalent in LS subjects and shared many upregulated genes expressed in SSc-associated myofibroblasts, though it also had strong expression of CXCL9/10/11, known CXCR3 ligands. A CXCL2/IRF1 cluster identified was unique to LS, with a robust inflammatory gene signature, including IL-6, and according to cell communication analysis are influenced by macrophages. In summary, potential disease-propagating fibroblasts and associated gene signatures were identified in LS skin via scRNA seq.

Synthetic Nucleic Acid Antigens in Localized Scleroderma.

We investigated the impact of synthetic nucleic acid antigens on the autoantibody profiles in patients with localized scleroderma, an autoimmune skin disease. Anti-DNA antibodies, including double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA), are common among autoimmune diseases, such as systemic lupus erythematosus and localized scleroderma. Based on recent studies, we hypothesized that the sequence of nucleic acid antigens has an impact on the autoimmune reactions in localized scleroderma. To test our hypothesis, we synthesized a panel of DNA and RNA antigens and used them for autoantibody profiling of 70 children with localized scleroderma compared with the healthy controls and patients with pediatric systemic lupus erythematosus (as a disease control). Among the tested antigens, dsD4, which contains the sequence of the human oncogene BRAF, showed a particularly strong presence in localized scleroderma but not systemic lupus erythematosus. Disease activity in patients was significantly associated with dsD4 autoantibody levels. We confirmed this result in vivo by using a bleomycin-induced mouse model of localized scleroderma. When administered intraperitoneally, dsD4 promoted an active polyclonal response in the mouse model. Our study highlights sequence specificity for nucleic acid antigens in localized scleroderma that could potentially lead to developing novel early-stage diagnostic tools.

DNA methylation patterns in juvenile systemic sclerosis and localized scleroderma.

Scleroderma refers to a group of chronic fibrotic immune-mediated diseases of unknown etiology. Characterizing epigenetic changes in childhood-onset scleroderma, systemic sclerosis or localized scleroderma, has not been previously performed. The aim of this study was to assess DNA methylation differences and similarities between juvenile systemic sclerosis (jSSc) and juvenile localized scleroderma (jLS) compared to matched healthy controls. Genome-wide DNA methylation changes in peripheral blood mononuclear cell samples were assessed using the MethylationEPIC array followed by bioinformatic analysis and limited functional assessment. We identified a total of 105 and 144 differentially methylated sites compared to healthy controls in jSSc and jLS, respectively. The majority of differentially methylated sites and genes represented were unique to either jSSc or jLS suggesting a different underlying epigenetic pattern in both diseases. Among shared differentially methylated genes, methylation levels in a CpG site in FGFR2 can distinguish between LS and healthy PBMCs with a high accuracy. Canonical pathway analysis revealed that inflammatory pathways were enriched in genes differentially methylated in jSSc, including STAT3, NF-κB, and IL-15 pathways. In contrast, the HIPPO signaling pathway was enriched in jLS. Our data also suggest a potential role for NOTCH3 in both jSSc and jLS, and revealed a number of transcription factors unique to each of the two diseases. In summary, our data revealed important insights into jSSc and jLS and suggest a potentially novel epigenetic diagnostic biomarker for LS.

Preliminary evidence on abatacept safety and efficacy in refractory juvenile localized scleroderma.

OBJECTIVE: To evaluate the safety and efficacy of abatacept treatment for refractory juvenile localized scleroderma (jLS) in a retrospective study. METHODS: A multicentre cohort study was performed to evaluate jLS subjects treated with abatacept with follow-up for 12 months to maximum of 24 months. Assessments at 6-month intervals included skin activity measures and physician global assessment of activity (PGA-A). Descriptive statistical analysis was performed. RESULTS: Eighteen subjects were studied with median age of 13.4 years, the majority had linear scleroderma subtype, and musculoskeletal involvement. All had previously failed MTX and/or mycophenolate mofetil treatment and glucocorticoids. Abatacept was added to the subject's maintenance DMARD treatment; 13 also received glucocorticoids at start of abatacept. No serious adverse events occurred. Skin activity and PGA-A scores declined in nearly all by 6 months and continued to improve from 6 to 12 months. At 12 months, 15 (83%) subjects were considered responders, two (11%) treatment failures, and one dropped out for adverse event. Response was sustained for 11 (61%) subjects to 18 months and eight (44%) to 24 months. Overall, four (22%) subjects were treatment failures and three (16.7%) discontinued abatacept for adverse event. Active musculoskeletal problems improved in most affected subjects. Ten subjects were able to discontinue initial glucocorticoid and six concomitant DMARD treatment. CONCLUSION: Abatacept was found to be safe and effective for jLS subjects refractory to standard of care treatment. Subjects experienced improvement in both skin and musculoskeletal activity. Prospective studies should be performed to more fully evaluate abatacept's efficacy.

Extracutaneous involvement is common and associated with prolonged disease activity and greater impact in juvenile localized scleroderma.

OBJECTIVE: The aim of this study was to evaluate factors associated with extracutaneous involvement (ECI) in juvenile localized scleroderma (jLS). METHODS: A prospective, multicentre, 6-month observational study was performed. The data collected included disease features, global assessments, and subject symptoms. Bivariate and linear multilevel regression analyses were performed. RESULTS: A total of 86 jLS subjects (80% female, 80% Caucasian), median age of disease onset 7.7 years, were evaluated. Most had linear scleroderma or mixed morphea. Of the 86 subjects, 49 (57%) had 125 extracutaneous problems {median 2 [interquartile range (IQR) 1, 3] per subject} from nine organ systems. Most of these subjects had multiple musculoskeletal problems. ECI was associated with more extensive cutaneous involvement, higher number of symptoms, family history of autoimmunity, and ANA and RF positivity. Subjects with ECI had higher scores for physician global assessment of damage (PGA-D), and parental global assessment of disease impact, but not baseline physician global assessment of disease activity (PGA-A). Although subjects with ECI received more MTX and glucocorticoid treatment, they had a slower reduction in PGA-A scores and symptoms over time, suggesting a poorer response to treatment. In logistic regression modelling, female sex had the largest effect on parental impact scores. CONCLUSION: ECI occurred in the majority of subjects with jLS, and was associated with more medication use, longer treatment duration, higher PGA-D scores, and higher parental assessment of disease impact. Our findings suggest that jLS subjects with ECI have greater overall disease burden, both cutaneous and extracutaneous, and poorer response to treatment. More study of the treatment needs of this population is warranted.

The importance of development standards for anchoring vignettes: an illustrative example from pediatric localized scleroderma quality of life.

PURPOSE: Anchoring vignettes (AVs) are a promising measurement technique to reduce bias in patient-reported outcome (PRO) measures by helping researchers understand differences in how individuals and groups interpret response options. However, little attention has been paid to ensure quality development of AVs, and their performance has not been well assessed in pediatric populations. In this study, we explore the application of a rigorous development process for AVs based upon current standards for PROs, as well as feasibility of AVs when administered to children and adolescents. METHODS: We developed AVs using a rigorous, patient-centered mixed methods process including three phases: (1) development, (2) a pilot study, and (3) a field test. Our proposed process included the generation of a conceptual framework based on the PRO, the Localized Scleroderma Quality of Life Instrument, and numerous vignette-specific considerations. We qualitatively explored readability and comprehension of the AVs (pilot study) and then analyzed ranking patterns within vignette sets (field test). RESULTS: Four sets of four vignettes were developed. Revisions were suggested at each phase of development. The pilot study demonstrated that children ≥ 10 years had no trouble indicating understanding of the AVs. In the field test, although appropriate rankings of vignettes were generally demonstrated by participants, the percentage of tied rankings was higher than expected in this pediatric group. CONCLUSIONS: This work supports the need for rigorous developmental standards for AVs, as each stage of development suggested revisions. Additionally, AVs showed initial promise for use with pediatric populations; general feasibility and understanding were supported.

Use of C-Reactive Protein and Ferritin Biomarkers in Daily Pediatric Practice.

Recent pediatric clinical research has begun to focus on risk stratification tools using multibiomarker models. C-reactive protein (CRP) and ferriti biomarkers are widely available and used to varying degrees in daily practice, but there is no single source examining the evidence behind their use.We set out to summarize the evidence behind the use of CRP and ferritin biomarkers in pediatric practice and to begin development of a consensus for their future use for pediatricians.All the literature involving CRP and ferritin in pediatrics available on PubMed was surveyed. Research applicable to daily pediatric practice was summarized in the body of the article. Pediatric clinicians of various subspecialties contributed to the summary of the use of CRP and ferritin biomarkers in clinical practice in various disease processes. A clinical decision pathway is described, and evidence is summarized.CRP and ferritin biomarkers have diverse uses with various cutoff values in the literature, making their use in daily practice difficult. Elevation of these markers coincides with their significant elevation in uncontrolled inflammation.CRP and ferritin biomarkers are widely used in pediatrics. This review provides a resource summarizing evidence into a single source. There is sufficient evidence to indicate that these biomarkers of inflammation can be useful in guiding clinical decision making in specific clinical scenarios; however, further work is needed to improve their use in clinical practice.

Development of minimum standards of care for juvenile localized scleroderma.

Juvenile localized scleroderma (jLS), also known as morphea, is an orphan disease. Pediatric guidelines regarding diagnosis, assessment, and management are lacking.Our objective was to develop minimum standards of care for diagnosis, assessment, and management of jLS. A systematic review was undertaken to establish the pediatric evidence for assessment and monitoring of jLS. An expert panel, including members of the Pediatric Rheumatology European Society (PRES) Scleroderma Working Group, were invited to a consensus meeting where recommendations were developed based on evidence graded by the systematic review and, where evidence was lacking, consensus opinion. A nominal technique was used where 75% consensus was taken as agreement. Recommendations for diagnosis, assessment, and management were developed. Due to a lack of pediatric evidence, these were primarily consensus driven. Careful assessment for extra-cutaneous manifestations including synovitis, brain involvement, and uveitis were key features together with joint assessments between Dermatology and Rheumatology to improve and standardize care. CONCLUSION: Management of jLS is varied. These recommendations should help provide standardization of assessment and care for those with this rare and potentially debilitating condition. What is Known: • Children with juvenile localized scleroderma (jLS) are managed by a number of specialties including pediatric rheumatologists and dermatologists, sometimes in shared clinics. Studies have shown that management varies considerably and that there are notable differences between specialties [1]. • There is very little published guidance on management of jLS. What is new: • These recommendations aim to standardize diagnosis, assessment, and management through review of pediatric evidence and consensus agreement. • Joint review of patients by both pediatric rheumatologists and dermatologists is recommended.

Challenges and complications in juvenile localized scleroderma: A practical approach.

Juvenile localized scleroderma is characterised by inflammation which drives fibrosis in skin and soft tissues. The more severe subtypes of localized scleroderma such as linear and craniofacial are more common in children. Additionally, extracutaneous involvement is seen in half of all children and is associated with poorer treatment outcomes and health-related quality of life. Evidence for the management of craniofacial and extracutaneous involvement is lacking and therefore poses a challenge to clinicians. This review aims to provide a practical approach to management of these most challenging features of juvenile localized scleroderma through case studies where we present the available evidence, current recommendations and considerations for management.

Endpoints and outcomes for localized scleroderma/morphea: a scoping literature review.

BACKGROUND: Current treatment for localized scleroderma (LS) has been shown to halt disease activity, but little is still known about patient experiences with these treatments, nor is there consensus about optimal measurement strategies for future clinical trials. OBJECTIVE: Conduct a scoping review of the literature for the types of outcomes and measures (i.e. clinician-, patient-, and caregiver-reported) utilized in published treatment studies of LS. METHODS: Online databases were searched for articles related to the evaluation of treatment efficacy in LS with a special focus on pediatrics. RESULTS: Of the 168 studies, the most common outcomes used were cutaneous disease activity and damage measured via clinician-reported assessments. The most frequently cited measure was the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT). Few patient-reported outcome measures (PROMs) were used. LIMITATIONS: Some studies only vaguely reported the measures utilized, and the review yielded a low number of clinical trials. CONCLUSION: In addition to evaluating disease activity with clinician-reported measures, the field could obtain critical knowledge on the patient experience by including high-quality PROMs of symptoms and functioning. More clinical trials using a variety of outcomes and measures are necessary to determine the most suitable course of treatment for LS patients.

Capturing the Range of Disease Involvement in Localized Scleroderma: The Localized Scleroderma Total Severity Scale.

OBJECTIVE: Juvenile localized scleroderma (jLS) is a chronic autoimmune disease commonly associated with poor outcomes, including contractures, hemiatrophy, uveitis, and seizures. Despite improvements in treatment, >25% of patients with jLS have functional impairment. To improve patient evaluation, our workgroup developed the Localized scleroderma Total Severity Scale (LoTSS), an overall disease severity measure. METHODS: LoTSS was developed as a weighted measure by a consensus process involving literature review, surveys, case vignettes, and multicriteria decision analysis. Feasibility was assessed in larger Childhood Arthritis and Rheumatology Research Alliance groups. Construct validity with physician assessment and inter-rater reliability was assessed using case vignettes. Additional evaluation was performed in a prospective patient cohort initiating treatment. RESULTS: LoTSS severity items were organized into modules that reflect jLS disease patterns, with modules for skin, extracutaneous, and craniofacial manifestations. Construct validity of LoTSS was supported by a strong positive correlation with the Physician Global Assessment (PGA) of severity and damage and weak positive correlation with PGA-Activity, as expected. LoTSS was responsive, with a small effect size identified. Moderate-to-excellent inter-rater reliability was demonstrated. LoTSS was able to discriminate between patient subsets, with higher scores identified in those with greater disease burden and functional limitation. CONCLUSION: We developed a new LS measure for assessing cutaneous and extracutaneous severity and have shown it to be reliable, valid, and responsive. LoTSS is the first measure that assesses and scores all the major extracutaneous manifestations in LS. Our findings suggest LoTSS could aid assessment and management of patients and facilitate outcome evaluation in treatment studies.

Best clinical practice in the treatment of juvenile systemic sclerosis: expert panel guidance - the result of the International Hamburg Consensus Meeting December 2022.

INTRODUCTION: Juvenile systemic sclerosis (jSSc) is an orphan disease with a prevalence of 3 in 1,000,000 children. Currently there is only one consensus treatment guideline concerning skin, pulmonary and vascular involvement for jSSc, the jSSc SHARE (Single Hub and Access point for pediatric Rheumatology in Europe) initiative, which was based on data procured up to 2014. Therefore, an update of these guidelines, with a more recent literature and expert experience, and extension of the guidance to more aspects of the disease is needed. AREAS COVERED: Treatment options were reviewed, and opinions were provided for most facets of jSSc including general management, some of which differs from adult systemic sclerosis, such as the use of corticosteroids, and specific organ involvement, such as skin, musculoskeletal, pulmonary, and gastroenterology. EXPERT OPINION: We are suggesting the treat to target strategy to treat early to prevent cumulative disease damage in jSSc. Conclusions are derived from both expert opinion and available literature, which is mostly based on adult systemic sclerosis (aSSc), given shared pathophysiology, extrapolation of results from aSSc studies was judged reasonable.

The Localized Scleroderma Cutaneous Assessment Tool: responsiveness to change in a pediatric clinical population.

BACKGROUND: Lack of agreement on how to accurately capture disease outcomes in localized scleroderma (LS) has hindered the development of efficacious treatment protocols. The LS Cutaneous Assessment Tool (LoSCAT), consisting of the modified LS Skin Severity Index (mLoSSI) and the LS Damage Index, has potential for use in clinical trials. OBJECTIVE: The goal of this article is to further evaluate the clinical responsiveness of the LoSCAT. Based on the modifiable nature of disease activity versus damage, we expected the mLoSSI to be responsive to change. METHODS: At 2 study visits, a physician completed the LoSCAT and Physician Global Assessment (PGA) of Disease Activity and of Disease Damage for 29 patients with LS. Spearman correlations were used to examine the relationships between the change in the LoSCAT and the PGA scores. To evaluate contrasted group validity, patients were grouped according to disease activity classification and change scores of groups were compared. Minimal clinically important differences were calculated and compared with the standard error of measurement. RESULTS: Change in the mLoSSI score correlated strongly with change in the PGA of Disease Activity score, whereas change in the LS Damage Index score correlated weakly with change in the PGA of Disease Damage score. The mLoSSI and PGA of Disease Activity exhibited contrasted group validity. Minimal clinically important differences for the activity measures were greater than the respective standard errors of measurement. LIMITATIONS: Only 2 study visits were included in analysis. CONCLUSION: This study gives further evidence that the LoSCAT, specifically the mLoSSI, is a responsive, valid measure of activity in LS and should be used in future treatment studies.

Pulmonary Nodules in Juvenile Systemic Sclerosis: A Case-Series from the National Registry for Childhood Onset Scleroderma (NRCOS).

BACKGROUND: Juvenile systemic sclerosis (jSSc) is a systemic inflammatory and fibrotic autoimmune disease. Adult guidelines recommend obtaining a screening high-resolution computed tomography scan (CT) at diagnosis. As these recommendations are adopted as standard of care for jSSc, increased screening with CT may lead to increased detection of nodules. The implications of nodules identified in jSSc are unclear and unreported. METHODS: A retrospective chart review was performed on the prospectively enrolled National Registry for Childhood-Onset Scleroderma (NRCOS) cohort over an enrollment period of 20 years. Clinical associations with presence of nodules and nodule characteristics were investigated. RESULTS: In this jSSc cohort, the prevalence of pulmonary nodules was 31% (n = 17 of 54). Nodule characteristics were heterogeneous, and most displayed stability over time. More participants with nodules had structural esophageal abnormalities, restriction, and reduced diffusing capacity on lung function tests, and follow-up imaging. Most participants had multiple nodules, and although most nodules were <5 mm, most participants had at least one nodule >5 mm. CONCLUSIONS: Pulmonary nodules are seen in children with jSSc and may be related to more severe disease and/or esophageal dysfunction. More work is needed to provide guidance on radiologic follow-up and clinical management of pulmonary nodules in jSSc.

Clinical Characteristics Associated with Musculoskeletal Extracutaneous Manifestations in Pediatric and Adult Morphea: A Prospective, Cohort Study.

Morphea is an autoimmune condition of the skin associated with functional sequelae resulting from musculoskeletal involvement. Systematic investigation of risk for musculoskeletal involvement is limited, particularly in adults. This knowledge gap impairs patient care because practitioners are unable to risk stratify patients. To address this gap, we determined the frequency, distribution, and type of musculoskeletal (MSK) extracutaneous manifestations affecting joint and bone with overlying morphea lesions using cross-sectional analysis of 1,058 participants enrolled in two prospective cohort registries (Morphea in Children and Adults Cohort [n = 750] and National Registry for Childhood Onset Scleroderma [n = 308]). Additional analysis included the identification of clinical features associated with MSK extracutaneous manifestations. MSK extracutaneous manifestations occurred in 274 of 1,058 participants (26% overall, 32% pediatric, and 21% adults). Children had a limited range of motion of larger joints (i.e., knees/hips/shoulders), whereas the involvement of smaller joints (i.e., toes/temporomandibular joint) was more common in adults. Multivariable logistic regression showed that deep tissue involvement had the strongest association with musculoskeletal features, with a lack of deep tissue involvement having a negative predictive value of 90% for MSK extracutaneous manifestations. Our results underscore the need to evaluate MSK involvement in adult and pediatric patients and the utility of using depth of involvement in addition to anatomic distribution to risk stratify patients.