Monique Hinchcliff

Systemic sclerosis (SSc) is a rare autoimmune disease characterized by vasculopathy and fibrosis of the skin and internal organs. Individuals with SSc often suffer from chronic acid reflux and dysphagia due to loss of esophageal motility. To determine whether distinct changes in esophageal epithelial cells contribute to esophageal involvement in SSc, we investigated the stratified squamous esophageal epithelium from proximal and distal biopsies using single-cell RNA sequencing in individuals with SSc compared with those with gastroesophageal reflux disease (GERD) and healthy controls. Cellular and molecular changes in SSc were highly correlated with those seen in GERD, indicating they were secondary to reflux; however, their magnitudes were more pronounced in the proximal esophagus, suggesting that esophageal dysmotility leads to greater proximal acid exposure, which may contribute to aspiration. SSc-specific gene dysregulation implicated immunoregulatory pathways likely pertinent to pathogenic mechanisms. Ligand-receptor interaction analysis revealed enhanced profibrotic signaling between fibroblasts and epithelial cells in SSc. Cell type localization and SSc-specific changes were confirmed by spatial molecular imaging. By offering a comprehensive view of transcriptional dysregulation at single-cell resolution in human esophageal epithelial cells in SSc compared with GERD and healthy tissue, this work clarifies the state of epithelial cells in SSc-induced esophageal dysfunction.

Objectives: Calcinosis cutis (CC) is disabling for SSc patients, and quantitative outcomes and treatments are needed. We performed computer-assisted mapping of CC lesions on CT exams and quantified CC during sodium thiosulphate (STS) treatment. Methods: In a pilot study, SSc-CC patients underwent CT imaging of a painful lesion followed by 6–12 month 25% STS, intradermal monthly injections or twice daily cream, treatment. Post-treatment CT exams were obtained, and three assessors used open-source software (BioImageSuite/BIS Web) to map and quantify CC volume, termed scleroderma calcinosis cutis score (SC2S). Results were compared with the Scleroderma Clinical Trials Consortium Radiologic Scoring System for Hand Calcinosis as appropriate. Results: Five women with SSc-CC involving the arm, ischial tuberosities, hands (two patients) and patellae, received topical (n = 2) or intradermal (n = 3) STS. Lesion mapping with BIS Web showed high inter-rater agreement between independent assessors (intraclass correlation coefficient = 0.93). SC2S revealed 75% and 10% reductions in left and right buttock, respectively; 28% reduction in arm; 18% increase in left forefinger; 27% increase in right hand and 12% reduction in left, and 4% increase in right, patellae, respectively. CC volume differences on repeated measures 1-week apart were ≤3%. Mapping time ranged from 4 h for finger/hand and patellae. Conclusion: SC2S may be a highly reproducible, broadly applicable, quantitative outcome that is sensitive to CC change. SC2S highlights the variable response of SSc-CC to STS treatment. Future work to automate CC mapping will reduce lesion mapping time.

Objectives: Cardiovascular death is the second leading cause in systemic sclerosis (SSc), with coronary microvascular dysfunction (CMVD) playing a key role. PET-derived myocardial blood flow (MBF) and flow reserve (MFR) offer a validated, non-invasive way to assess CMVD. We studied the prevalence of impaired MFR in SSc and its association with vasodilator or immunomodulatory therapy. Methods: SSc patients who underwent dynamic 82-Rubidium PET myocardial perfusion imaging (MPI) at Yale New Haven Hospital (July 2016 to April 2025) were studied. Patients were matched 3:1 with controls without autoimmune rheumatologic disease based on age, sex, BMI and cardiovascular comorbidities. Abnormal MFR was defined as <2.0. Results: The cohort included 67 SSc patients (87% female, age: 61 ± 11 years, 21% diffuse cutaneous SSc, SSc duration: 12 ± 10 years) and 201 controls. Rest MBF was higher in SSc (1.14 [IQR 0.91–1.39] ml/g/min) vs controls (1.00 [IQR 0.78–1.25]; P = 0.01), while MFR was lower (2.17 [IQR 1.84–2.57] vs 2.44 [IQR 1.96–2.96]; P = 0.01). Stress MBF was similar (2.47 [IQR 1.99–2.82] vs 2.43 [IQR 1.91–3.04]; P = 0.85). Multivariable analysis showed MMF use linked to lower odds of abnormal MFR (OR 0.09 [95% CI 0.01–0.56]; P = 0.017), while calcium channel blockers (OR 7.77 [1.93–42.53]; P = 0.008) and statins (OR 7.14 [1.86–36.87]; P = 0.008) increased odds. Conclusions: PET MPI reveals reduced MFR in SSc. Treatment associations, including MMF, should be interpreted cautiously given the retrospective design. PET-derived MFR may serve as a non-invasive marker of vascular involvement, warranting prospective validation.

Objective: Systemic sclerosis (SSc) is characterized by dysregulated immunity, microvascular damage, and progressive fibrosis. SSc‐related interstitial lung disease (SSc‐ILD) is the leading disease‐specific cause of death; it is therefore important to identify biomarkers associated with SSc‐ILD. We hypothesized that the skin transcriptome would provide mechanistic clues that could further our understanding of lung impairment in SSc‐ILD. Methods: We conducted a multistage analysis of SSc transcriptomes using weighted gene correlation analysis, gene set enrichment analysis, and single‐cell RNA sequencing. Results: We identified seven modules correlated with skin and lung function involvement. Unsupervised clustering of these genes classified patients into two groups, one of which showed severe multiorgan involvement characterized by increased skin fibrosis and decreased lung function ( P < 0.05). The KRAS pathway was enriched in the severe cluster. Deconvolution of the severe cutaneous signature in SSc skin and lungs showed increased expression in stromal cells and monocytes, whereas the KRAS pathway was enriched in stromal cells only. Profiling KRAS and downstream signaling in lungs from individuals with SSc‐ILD demonstrated activation of these pathways ( P < 0.05). Conclusion: We found a severe cutaneous transcriptomic signature of SSc associated with multiorgan involvement. By deconvoluting the severe cutaneous signature, we have identified pathways enriched in specific cell types, including KRAS in stromal cells and a combination of stromal and immune cells in the severe signature. The severe SSc signature can provide a framework for understanding shared mechanisms in skin and lung fibrosis and may help identify additional molecular pathways.

Objectives: The assessment of systemic sclerosis–associated Raynaud phenomenon (ASRAP) questionnaire was recently developed. We tested the convergent validity of the ASRAP instrument with patient demographics and capillary morphology on nailfold capillaroscopy (NFC). Methods: Participants completed the ASRAP (range 20–80; higher scores unfavourable) and underwent NFC using Dinolite™. We collected demographic and relevant clinical data. Two blinded assessors classified NFC images as ‘scleroderma pattern’ present or absent and recorded specific abnormalities. We assigned the NFC semi-quantitative score (range 0–3) based on the frequency of these abnormalities. Descriptive statistics were generated, and regression and correlation analyses were used to evaluate associations between ASRAP, NFC and clinical factors. Results: Seventy-five patients [87% women, 78% white, 77% with limited cutaneous SSc] with a mean (SD) age of 58 (14) were recruited from scleroderma clinics. ASRAP scores were 11.2 points higher in women compared with men with other significant variables held constant. The NFC semi-quantitative score weakly correlated with ASRAP (Spearman’s σ = 0.23, P = 0.05), with moderate correlation in winter (Spearman’s σ = 0.36, P = 0.04). Holding other variables constant, patients with dilated capillaries and capillary dropout had higher ASRAP scores by 6.1 and 6.8 points, respectively. Conclusion: In SSc patients, females reported higher ASRAP scores. Greater proportion of ‘scleroderma pattern’ NFC abnormalities as well as specific abnormalities like dilated capillaries and capillary dropout were associated with higher ASRAP providing mechanistic insight and supporting the construct validity of ASRAP for assessing SSc-RP.