Ami A. Shah

SUMMARY: Background: Systemic sclerosis (SSc) and dermatomyositis (DM) are autoimmune diseases that have been proposed as models of cancer immunoediting. Autoantibody-defined subsets show divergent cancer risks, yet malignancy often remains clinically occult. We tested whether circulating tumor DNA (ctDNA) can reveal subclinical cancer in new-onset SSc and DM. Methods: We prospectively recruited adults with recent SSc or DM onset. Plasma ctDNA was assessed using a targeted next-generation sequencing panel covering commonly mutated cancer genes. Patients were followed for 18–24 months on average. ctDNA positivity was correlated with subsequent cancer diagnoses. Findings: Among 134 patients (69 SSc, 65 DM), cancer was diagnosed in six (4·5%; three SSc, three DM). ctDNA was detected in four of these six patients (67%) a median of 13 months (range 1·4–17) before clinical diagnosis; in three of four patients, mutations detected in plasma matched those subsequently identified in the same patients’ primary tumors. ctDNA was also detected in 16 of 128 patients without a cancer diagnosis. ctDNA positivity conferred an 11·4-fold higher risk of malignancy relative to ctDNA negativity and yielded a negative predictive value of 98% and a positive predictive value of 20% for cancer within the observation window. Interpretation: ctDNA testing identified most cancers that emerged within 18 months in new-onset SSc and DM and stratified near-term cancer risk. These findings support larger, interventional trials to determine whether ctDNA-guided surveillance improves timeliness of cancer detection, optimizes imaging and biopsy strategies, and enhances outcomes in patients with SSc and DM. Funding: NIH, Scleroderma Research Foundation, Stabler Foundation, Chresanthe Staurulakis Memorial Fund, Sara and Alex Othon Research Fund, Bechtle Precision Medicine Fund for Scleroderma, Zhang Discovery Fund, Dr. Peter Buck Fund, Jerome L. Greene Foundation, Lustgarten Foundation for Pancreatic Cancer Research, Sol Goldman Sequencing Facility, Virginia and D.K. Ludwig Fund for Cancer Research. RESEARCH IN CONTEXT: 1. Evidence before this study: Patients with new onset systemic sclerosis (SSc) and dermatomyositis (DM) have an increased risk of contemporaneous cancer in distinct autoantibody subgroups, and mechanistic studies suggest that these patients may have cancer-induced autoimmunity. The optimal approach to cancer detection, and whether subclinical malignancy may be present in patients with new onset rheumatic disease, remains unknown. 2. Added value of this study: We show that circulating tumor DNA (ctDNA) is present in ∼15% of patients with new onset SSc and DM. Patients with ctDNA have a higher risk of subsequent malignancy, with data suggesting that it can detect cancer earlier than conventional methods in this patient population. 3. Implications of all the available evidence: These findings suggest that subclinical malignancy may be present in a subset of patients with new onset SSc and DM and that ctDNA may be a valuable tool to risk stratify patients for cancer.

Objectives: Cardiovascular events (CVEs) and malignancy are important non-disease-related causes of mortality in SSc. We evaluated secondary care utilisation and impact of deprivation on comorbidity patterns in SSc in England. Methods: We analysed secondary care service utilisation in SSc using Hospital Episode Statistics for England for 2024. Cases were linked to Index of Multiple Deprivation deciles. Myocardial infarction (MI), lung cancer, breast cancer, melanoma rates and short-term all-cause mortality were explored, alongside comparisons with SLE and RA. Results: In 2024, ≈6000 people with SSc (84.6% female, 70.8% between 51 and 80 years of age, 73.3% White ethnicity) accessed secondary healthcare in England. Older SSc patients were overrepresented in less-deprived postcodes (P < 0.001). MI, lung cancer, breast cancer and melanoma were more common in SSc compared with unmatched estimates in the general population. Lung cancer was more frequent among less-deprived patients (P < 0.001). The all-cause mortality attrition rate was ≈3% in SSc over 3 months (30.8% with lung cancer and >60% with melanoma). Rates of breast cancer were higher in SSc compared with SLE (P = 0.014) and RA (P = 0.012). There was a higher rate of lung cancer in SSc compared with SLE (P < 0.001). Melanoma rates were similar across diseases (≈0.2%). Conclusion: Secondary care utilisation in SSc suggests less deprived SSc patients are older. All-cause mortality is higher in SSc patients receiving cancer care. Cancer occurrence is higher in SSc compared with SLE and RA. Our findings might support healthcare services planning and cancer screening for SSc in England.

Background: Immune checkpoint inhibitor (ICI)-related inflammatory arthritis occurs in approximately 6% of ICI-treated patients, and is often long-lasting. The clinical presentation is heterogeneous, and often loosely resembles either rheumatoid arthritis (ICI-IA) with peripheral presentation, or polymyalgia rheumatica (ICI-PMR) with predominant bilateral shoulder and hip pain and stiffness. Our objective was to compare clinical features, immunosuppressive treatment, and cancer outcomes between ICI-IA and ICI-PMR. Methods: Data were extracted from the Rheumatology Adverse Events Due to Immunotherapy Observational Study multicenter prospective registry, regarding patients with rheumatologist-diagnosed ICI-IA or ICI-PMR and no preexisting primary IA/PMR. Clinical features were collected at the first visit in the registry. Multivariable logistic regression was used to compare second-line immunosuppressive drug utilization between groups. Kaplan-Meier curves were constructed to compare time of prednisone tapering to a dose of (1) 10 mg and (2) 5 mg from the baseline registry visit. Cox proportional hazard models were used to compare progression-free survival (PFS). Date of first cancer progression from arthritis onset was extracted based on documentation of imaging and/or pathology in the medical record. Patients with ICI-PMR were also compared with an independent cohort of patients with primary PMR. Results: We analyzed 490 patients: 418 with ICI-IA and 72 with ICI-PMR. Compared with patients with ICI-IA, patients with ICI-PMR were older (70 vs 63 years old, p<0.001), more likely to be male (p=0.034), had shorter onset after ICI initiation (87 vs 125 days, p=0.011) and had less peripheral synovitis (15% vs 72%, p<0.001). Time to a prednisone dose of 10 and 5 mg/day was comparable between groups. Patients with ICI-IA were more likely to receive a second-line immunosuppressive drug (OR 3.51 (95% CI 1.50 to 8.21, p=0.004)). PFS was comparable between groups. Compared with primary PMR (n=189), the sex ratio was inversed in ICI-PMR, but there was a similar proportion with peripheral arthritis (15%). Conclusions: Patients with ICI-IA were more likely to require a second-line immunosuppressive drug than patients with ICI-PMR, but PFS was the same. Future therapeutic clinical trials in ICI-IA/PMR should stratify patients according to phenotype.

Background: Scleroderma (systemic sclerosis; SSc) is a chronic autoimmune disease known for wide heterogeneity in patients' disease progression in multiple organ systems. Our goal is to guide clinical care by real‐time classification of patients into clinically interpretable subpopulations based on their baseline characteristics and the temporal patterns of their disease progression. Methods: A Bayesian multivariate growth mixture model was fit to identify subgroups of patients from the Johns Hopkins Scleroderma Center Research Registry who share similar lung function trajectories. We jointly modeled forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) as pulmonary outcomes for 289 patients with SSc and anti‐topoisomerase 1 antibodies and developed a framework to sequentially update class membership probabilities for any given patient based on her accumulating data. Results: We identified a “stable” group of 150 patients for whom both biomarkers changed little from the date of disease onset over the next 10 years, and a “progressor” group of 139 patients that, on average, experienced a clinically significant decline in both measures starting soon after disease onset. For any given patient at any given time, our algorithm calculates the probability of belonging to the progressor group using both baseline characteristics and the patient's longitudinal FVC and DLCO observations. Conclusions: Our method calculates the probability of being a fast progressor at baseline when no FVC and DLCO are observed, then sequentially updates it as more information becomes available. This sequential integration of patient data and classification of her disease trajectory has the potential to improve clinical decisions and ultimately patient outcomes.

Novel autoantibodies target hotspots on the XIST ribonucleoprotein complex in female-biased autoimmune diseases.

Objective: Cardiac involvement in systemic sclerosis (SSc) is a leading cause of death. We sought to investigate predictors of incident left ventricular systolic dysfunction (LVSD) and cardiac recovery in SSc. Methods: In total, 2,303 patients in the Johns Hopkins Scleroderma Center Research Registry and 13,209 echocardiograms were analyzed. We identified predictors associated with incident LVSD defined by transitions in left ventricular ejection fraction (EF) states (EF ≥50% declining to 35% dropping to ≤35% [severe LVSD]) by fitting multivariate logistic regression models with time‐varying and invariant variables. Variables associated with cardiac recovery were identified by fitting multivariate logistic regression models using important variables identified from random forest analysis. Results: Male sex, Black race, diffuse skin disease, higher modified Rodnan skin score (mRSS), echocardiographic evidence of pulmonary hypertension (PH), kidney disease, and atrial fibrillation (AFib) were associated with increased odds of incident LVSD (EF < 50%), whereas anticentromere and anti–topoisomerase‐1 were protective. Male sex, higher mRSS, PH, skeletal myopathy, kidney disease, AFib, and anti‐Ku antibodies were associated with higher odds of incident severe LVSD (EF ≤ 35%). For previous EF 35%. Conclusion: Distinct demographic SSc‐specific and cardiac characteristics are associated with increased risk of incident LVSD in SSc, with skeletal myopathy and anti‐Ku antibodies being important risk factors for severe disease. Some patients improved, which was more likely in anti–RNAP III positive patients.

Objective: Interstitial lung disease (ILD) is a significant cause of morbidity and mortality in systemic sclerosis (SSc), particularly among Black patients. Pulmonary function tests (PFTs) are critical to screen for and monitor SSc‐ILD. We examined whether race‐specific and race‐neutral PFT reference equations impact classification of restrictive lung disease (RLD) severity in Black and White patients with SSc. Methods: Baseline percent predicted forced vital capacity (ppFVC) was calculated for self‐identified Black (n = 641) and White (n = 2,909) patients in the Johns Hopkins Scleroderma Center Research Registry using race‐specific (Global Lung Function Initiative 2012 [GLI 2012] and National Health and Nutrition Examination Survey III) and race‐neutral (GLI Global) equations. The percentage of Black and White individuals who switched RLD severity categories (normal [ppFVC ≥ 80%], mild [70% ≤ ppFVC < 80%], moderate [60% ≤ ppFVC < 70%], severe [50% ≤ ppFVC < 60%], or very severe [ppFVC < 50%]) with the use of race‐neutral versus race‐specific equations was calculated. The percentages of patients who would meet typical ppFVC thresholds for immunosuppression, clinical trial eligibility, and lung transplant referral were compared. Results: Black individuals had lower absolute FVC values than White individuals. Forty‐seven percent (n = 303) of Black individuals were reclassified as having more severe RLD, and 17% (n = 487) of White individuals were reclassified as having less severe RLD when using the GLI Global versus GLI 2012 equations. Statistically greater proportions of Black individuals met ppFVC thresholds for immunosuppression, clinical trial eligibility, and lung transplant referral with race‐neutral versus race‐specific equations. Conclusion: The use of race‐specific PFT reference equations may result in systematic misclassification of ILD severity with potential impact on health care delivery and clinical trial eligibility.

Objective: In complex diseases, it is challenging to assess a patient's disease state, trajectory, treatment exposures, and risk of multiple outcomes simultaneously, efficiently, and at the point of care. Methods: We developed an interactive patient‐level data visualization and analysis tool (VAT) that automates illustration of the trajectory of a patient with scleroderma across multiple organs and illustrates this relative to a reference population, including patient subgroups who share risk factors with the index patient, to improve estimation of disease state. We conducted VAT usability testing with patients and clinicians. We then embedded results from internally cross‐validated, Bayesian multivariate mixed models that calculate an individual's risk of critical events, using baseline risk factors, patient‐level information in past trajectories in multiple dimensions, and known outcomes from the entire population and relevant subgroups. Results: The web‐based application aggregates complex, longitudinal data to illustrate patient‐, subgroup‐, and population‐level health trajectories across multiple organ systems. Patients (n = 7) exposed to the VAT reported increased knowledge about their disease and confidence in medical decision‐making. Rheumatologists (n = 4) were able to access 8.6 times more data in 81.5% of the time using two‐thirds fewer clicks using the VAT compared with an electronic medical record system. Statistical modeling was successfully embedded in the VAT, enabling real‐time estimation of a patient's risks of multiple complications. Conclusion: Systematic analysis and visualization of individual‐ and population‐level data in a complex disease has potential to improve medical decision‐making and warrants further study. Individualized risk estimation disseminated at the point of care may enable targeted screening and early intervention in high‐risk patients.