Background:We investigated the prognostic potential of circulating biomarkers at baseline and the effects of nintedanib on changes in these biomarkers in subjects with progressive pulmonary fibrosis (PPF). Methods:In the INBUILD trial, subjects with PPF received nintedanib (n=332) or placebo (n=331). Associations between biomarker levels at baseline and the rate of forced vital capacity (FVC) decline (mL·year-1) over 52 weeks, time to interstitial lung disease (ILD) progression (absolute decline in FVC % predicted ≥10%) or death over 52 weeks, time to first acute exacerbation or death over the whole trial, and time to death over the whole trial were assessed in the placebo group. Changes in adjusted mean levels of biomarkers in the nintedanib and placebo groups were assessed using linear mixed models for repeated measures. Biomarker data were log2 transformed prior to analysis. Analyses were corrected for multiplicity. Results:Baseline level of s-ICAM was significantly associated with rate of FVC decline and time to ILD progression or death over 52 weeks in the placebo group. No biomarker was significantly associated with time to first acute exacerbation or death or time to death. Decreases in Krebs von den Lungen-6 (KL-6), surfactant protein D (SP-D), CA-125 and CA19-9 were observed in subjects who received nintedanib versus placebo over 52 weeks. The largest decrease was in CA-125. In a mediation analysis, 16.4% of the effect of nintedanib on change in FVC at week 52 was attributed to the treatment-related decrease in CA-125 at week 12. Conclusions:In subjects with PPF, nintedanib reduced circulating CA-125 and, to a lesser extent, other markers of epithelial dysfunction.

Autoantibodies against NOR-90 are rare and have been associated with systemic sclerosis (SSc). This study seeks to identify the characteristics of SSc participants with anti-NOR-90 autoantibodies. An international (Canada, Australia, USA, Mexico) cohort of 2143 SSc participants was included. Sera were tested using a line immunoassay (Euroimmun, Lübeck, Germany). Clinical associations with anti-NOR-90 autoantibodies were investigated. Single-specificity anti-NOR-90-positive was defined as anti-NOR-90-positivity without other SSc-related autoantibodies, except for anti-Ro52/TRIM21. 115 (5

OBJECTIVES:This study aimed to determine the prognostic significance of circulating proteins and the effects of nintedanib on these proteins in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in the safety and efficacy of nintedanib in systemic sclerosis study (SENSCIS) trial. METHODS:Patients had SSc with ≤7 years since their first non-Raynaud symptom. Candidate biomarkers of inflammation, epithelial dysfunction, extracellular matrix (ECM) synthesis, and ECM turnover were measured in serum/plasma. We assessed associations between baseline biomarker levels and decline in forced vital capacity (FVC) over 52 weeks and change in modified Rodnan Skin Score (mRSS) at week 52 in the placebo group, and changes in biomarker levels in nintedanib and placebo groups. RESULTS:Baseline Krebs von den Lungen-6 (KL-6) and citrullinated vimentin (VICM) degraded by MMP-2/8 levels were significantly associated with the rate of decline in FVC over 52 weeks in uncorrected analyses. A baseline KL-6 concentration of >1000 vs ≤1000 U/mL was associated with a greater rate of decline in FVC (mL) over 52 weeks (estimates: -132.5 [95% CI: -174.1, -91.0] vs -56.4 [-95.2, -17.6]; P = .009). Higher baseline N-terminal propeptide of type III collagen (Pro-C3), chemokine (C-C motif) ligand 2, and C-reactive protein levels were significantly associated with less improvement in mRSS at week 52 in analyses corrected for multiple comparisons. Decreases in cancer antigen (CA)-125 and N-terminal propeptide of type VI collagen (pro-C6) over 52 weeks were observed in patients who received nintedanib vs placebo. In mediation analysis, 48.0% of the effect of nintedanib on change in FVC at week 52 was attributed to the treatment-related decrease in CA-125 at week 24. CONCLUSIONS:Applying a dichotomised threshold for KL-6 can aid in identifying patients with SSc-ILD with more progressive ILD. Nintedanib reduced levels of the epithelial dysfunction marker, CA-125, and collagen synthesis epitope, pro-C6.

Objective Cardiac involvement significantly impacts prognosis in systemic sclerosis (SSc), highlighting the need for early risk stratification. Gastrointestinal (GI) symptoms are common and often manifest early. Emerging data suggest a link between GI and cardiac manifestations, possibly through shared mechanisms like dysautonomia. This study investigates the overall association between GI and cardiac involvement in early SSc and evaluates whether baseline GI symptoms predict future cardiac manifestations.Methods We analyzed 459 patients from the prospective Genetics versus Environment in Scleroderma Outcomes Study cohort. GI involvement at baseline was defined by one or more of the following: dysphagia, gastroesophageal reflux disease, peptic ulcer, bloating, diarrhea, malabsorption, constipation, or pseudo-obstruction. Cardiac manifestations included conduction defects and systolic dysfunction. Cox and multivariable logistic regression models assessed associations, adjusting for potential confounders.Results The cohort included 459 patients with SSc (82% female), with a median follow-up of 4.1 years (interquartile range 0.8-8.1). At baseline, 59% of patients had GI involvement. During follow-up, 26% of patients developed cardiac manifestations-mainly conduction defects (24%) and less commonly systolic dysfunction (5%). Baseline malabsorption and bloating were strong predictors of future cardiac involvement, with malabsorption showing the highest risk (hazard ratio 10.01 [95% confidence interval 3.7-26.9]). Interestingly, dysphagia and peptic ulcers were significantly associated with conduction defects, whereas malabsorption was significantly associated with systolic dysfunction, even after adjustment for potential confounders.Conclusion Upper GI dysfunction was associated specifically with conduction defects, suggesting that autonomic dysfunction contributes. In contrast, lower GI involvement, particularly malabsorption, was linked to systolic dysfunction in patients with SSc, potentially indicating a distinct biologic mechanism. These findings may support integrating early GI symptoms into cardiac risk stratification, and they provide a foundation for future translational studies.

OBJECTIVE:This study aims to identify factors associated with patient global assessment (PtGA) and physician global assessment (PhGA) and discordance between them in systemic sclerosis (SSc). METHODS:Data from adults with early SSc (<5 years) from the Collaborative National Quality and Efficacy Registry were included. PtGA and PhGA (0-10 scale), clinical evaluations, and patient-reported outcomes (PROs) were collected every six months. Multivariable mixed-effects linear regression identified factors associated with PtGA and PhGA using (1) clinical variables and (2) clinical variables plus PROs. Relative weight analysis (RWA) determined the relative importance of each variable. Discordance (≥2 points between PtGA and PhGA) was assessed using multinomial mixed-effects logistic regression. RESULTS:Among 956 patients (83% women, 33% limited disease), mean PtGA and PhGA at enrollment were 4.2 (SD 2.6) and 3.4 (SD 2.0), respectively (P < 0.001). RWA of clinical variables identified modified Rodnan skin score (mRSS) and New York Heart Association (NYHA) functional class as most influential for both global assessments. After including PROs, PtGA was most influenced by measures of pain, skin symptoms, and physical function. Discordance occurred in 53% of patients (35% PtGA worse, 18% PhGA worse). Worse PtGA was associated with higher overall pain and discomfort. Worse PhGA was associated with higher mRSS, worse NYHA class, higher pain interference, and lower diffusing capacity of the lung. CONCLUSION:Discordance between PtGA and PhGA occurs commonly, highlighting the need for comprehensive symptom management and measurement of disease burden in this complex disease. In SSc, differences in PtGA and PhGA reflect dissimilar weighting of data elements.

Abstract Background/Aims Nerandomilast is a preferential inhibitor of phosphodiesterase 4B with antifibrotic and immunomodulatory properties. The Phase III FIBRONEER-ILD trial in patients with progressive pulmonary fibrosis (PPF) showed that nerandomilast significantly reduced the decline in forced vital capacity (FVC) and had an acceptable safety profile. We explored the efficacy and safety of nerandomilast in the subgroup of patients with autoimmune disease-related interstitial lung diseases (ILDs) (autoimmune ILDs) in the FIBRONEER-ILD trial. Methods Patients with PPF (excluding idiopathic pulmonary fibrosis) were randomized 1:1:1 to receive nerandomilast 9 mg bid, nerandomilast 18 mg bid, or placebo. PPF was defined using the same criteria as in the INBUILD trial. Patients taking nintedanib (at a stable dose for ≥12 weeks) or not taking nintedanib (for ≥8 weeks) were eligible to participate. Cyclophosphamide, tocilizumab, mycophenolate, or rituximab were not permitted at enrolment but could be initiated after 6 months to manage worsening systemic disease. Prednisone >15 mg/day (or equivalent) was not permitted at enrolment but could be prescribed during the trial for acute exacerbation of ILD or after 6 months to manage worsening systemic disease. In the subgroup with autoimmune ILDs, we evaluated absolute change from baseline in FVC (mL) at week 52 and adverse events up to week 52. Analyses were pre-specified. Results Among 1176 treated patients, 325 (27.6%) had autoimmune ILDs (100 placebo, 112 nerandomilast 9 mg bid, 113 nerandomilast 18 mg bid). At baseline, among patients with autoimmune ILDs, 212 (65.2%) were female, mean (SD) age was 63.4 (11.2) years, FVC was 71.5 (15.0) % predicted, diffusing capacity for carbon monoxide (DLco) was 51.5 (16.8) % predicted; 111 (34.2%) patients were taking nintedanib. The most frequent autoimmune disease diagnoses were rheumatoid arthritis (118 patients [36.3%]), systemic sclerosis (75 [23.1%]), and mixed connective tissue disease (47 [14.5%]). Among patients with autoimmune ILDs, adjusted mean changes in FVC (mL) at week 52 were -107.1 (95% CI: -156.1, -58.0) in the placebo group, -61.2 (-106.9, -15.5) in the nerandomilast 9 mg bid group (difference vs placebo: 45.9 [95% CI: -20.8, 112.6]), and -64.9 (-111.0, -18.7) in the nerandomilast 18 mg bid group (difference vs placebo: 42.2 [-24.9, 109.3]). The most frequent adverse event was diarrhea. Adverse events leading to treatment discontinuation were similar across treatment groups. Conclusion In the FIBRONEER-ILD trial, the efficacy of nerandomilast on slowing decline in FVC in patients with autoimmune ILDs was consistent with that observed in the overall trial population. Nerandomilast had an acceptable safety and tolerability profile. Disclosure A. Hoffman-Vold: Consultancies; Boehringer Ingelheim, AbbVie, Avalyn, Bristol Myers Squibb, Calluna Pharma, Genentech, Janssen, Medscape, Merck Sharp & Dohme, Pliant Therapeutics, Roche, Werfen. Honoraria; Boehringer Ingelheim, Janssen, Medscape, Merck Sharp & Dohme, Novartis, Roche. Grants/research support; Boehringer Ingelheim, Janssen. S. Assassi: Consultancies; Boehringer Ingelheim, AbbVie, AstraZeneca, aTyr, CSL Behring, Mitsubishi Tanabe, Merck Sharp & Dohme, Takeda, TeneoFour. Grants/research support; aTyr, Boehringer Ingelheim, Janssen. V. Cottin: Consultancies; AbbVie, AstraZeneca, Avalyn, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, CSL Vifor, Ferrer/United Therapeutics, Gossamer, GlaxoSmithKline, Liquidia, Pliant, PureTech, Roche, Roivant, Sanofi, Shionogi. Honoraria; Boehringer Ingelheim, Ferrer/United Therapeutics, Roche, Sanofi. Other; GlaxoSmithKline, Molecure, FibroGen. M. Kreuter: Corporate appointments; Deutsche Gesellschaft für Pneumologiex, European Respiratory Society. Consultancies; AstraZeneca, Avalyn, Boehringer Ingelheim, Bristol Myers Squibb, GlaxoSmithKline, Pliant, Roche. Honoraria; Boehringer Ingelheim, Roche. Grants/research support; Boehringer Ingelheim, Roche. C. Valenzuela: Consultancies; Boehringer Ingelheim, Bristol Myers Squibb, Ferrer, Pliant, Roche. Other; Boehringer Ingelheim, Pliant, Roche, Ferrer. M.S. Wijsenbeek: Corporate appointments; Dutch Lung Fibrosis and Sarcoidosis Patient Associatiations. Consultancies; AstraZeneca, Avalyn, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Galapagos, Galecto, GlaxoSmithKline, Hoffman-La Roche, Horizon Therapeutics, Kinevant Sciences, Molecure, NeRRe Therapeutics, Novartis, PureTech Health, Trevi, Vicore. Honoraria; Avalyn, Boehringer Ingelheim, CSL Behring, Novartis, Sanofi. Grants/research support; AstraZeneca/Daiichi Sankyo, Boehringer Ingelheim, Hoffman-La Roche, Sarcoidosis.nl, The Dutch Lung Foundation, The Dutch Pulmonary Fibrosis Patients Association, The Netherlands Organization for Health Research and Development, The Thorax Foundation. Other; European Respiratory Society, Boehringer Ingelheim, GlaxoSmithKline, Hoffman-La Roche. H. Gu: Corporate appointments; Boehringer Ingelheim. I. Ritter: Corporate appointments; Boehringer Ingelheim. S. Stowasser: Corporate appointments; Boehringer Ingelheim. G. Weimann: Corporate appointments; Boehringer Ingelheim. T. Maher: Consultancies; AbbVie, Amgen, AstraZeneca, Bayer, Biogen, Blade Therapeutics, Bristol Myers Squibb, Boehringer Ingelheim, Endeavour BioMedicines, Galapagos, Galecto, GlaxoSmithKline, Gossamer Bio, Merck, Pfizer, Pliant, Roche, Redx Pharma, Trevi Pharma, Three Lakes Partners, UCB, United Therapeutics, Vicore Pharma. Honoraria; Boehringer Ingelheim, Roche. Grants/research support; AstraZeneca, GlaxoSmithKline, UCB.

OBJECTIVES:A loss-of-function variant in deoxyribonuclease 1-like 3 (DNASE1L3), encoding Arg to Cys substitution at amino acid 206 (R206C), was previously identified as a heritable susceptibility factor for systemic sclerosis (SSc). We analysed mortality and pulmonary outcomes in patients with SSc with or without the DNASE1L3 R206C variant. METHODS:Mortality, pulmonary hypertension (PH), and interstitial lung disease (ILD) were ascertained in the UTHealth Houston, Royal Free Hospital, and Johns Hopkins University cohorts. Mortality risk and precapillary PH time-to-event from SSc onset were estimated using Cox proportional hazards models. Meta-analyses were performed to generate overall risk estimates. RESULTS:In the mortality analysis (n = 2366 patients, 46.6% of whom were deceased), after adjustment for age of SSc onset and sex, DNASE1L3 R206C was associated with significantly greater mortality (hazard ratio [HR]: 1.16, 95% CI: 1.02-1.32). In the precapillary PH analysis (n = 1170 patients, 20.3% of whom had precapillary PH), after adjustment for age of SSc onset, sex, and the presence of ILD, DNASE1L3 R206C was associated with significantly greater precapillary PH risk (HR: 1.69, 95% CI: 1.31-2.19). The majority of patients with precapillary PH did not have ILD, indicating that they had WHO Group I, ie pulmonary arterial hypertension (PAH). CONCLUSIONS:We report a previously unknown impact of DNASE1L3 polymorphism on PAH susceptibility in SSc. The association between loss-of-function of an immunoregulatory gene (DNASE1L3) and PAH susceptibility supports further exploration of downstream sequelae of DNASE1L3 dysfunction in SSc pathogenesis and the mechanisms underlying the well-recognised but poorly understood susceptibility of patients with SSc to PAH.

OBJECTIVE:Cardiac involvement significantly impacts prognosis in systemic sclerosis (SSc), highlighting the need for early risk stratification. Gastrointestinal (GI) symptoms are common and often manifest early. Emerging data suggest a link between GI and cardiac manifestations, possibly through shared mechanisms like dysautonomia. This study investigates the overall association between GI and cardiac involvement in early SSc and evaluates whether baseline GI symptoms predict future cardiac manifestations. METHODS:We analyzed 459 patients from the prospective Genetics versus Environment in Scleroderma Outcomes Study cohort. GI involvement at baseline was defined by one or more of the following: dysphagia, gastroesophageal reflux disease, peptic ulcer, bloating, diarrhea, malabsorption, constipation, or pseudo-obstruction. Cardiac manifestations included conduction defects and systolic dysfunction. Cox and multivariable logistic regression models assessed associations, adjusting for potential confounders. RESULTS:The cohort included 459 patients with SSc (82% female), with a median follow-up of 4.1 years (interquartile range 0.8-8.1). At baseline, 59% of patients had GI involvement. During follow-up, 26% of patients developed cardiac manifestations-mainly conduction defects (24%) and less commonly systolic dysfunction (5%). Baseline malabsorption and bloating were strong predictors of future cardiac involvement, with malabsorption showing the highest risk (hazard ratio 10.01 [95% confidence interval 3.7-26.9]). Interestingly, dysphagia and peptic ulcers were significantly associated with conduction defects, whereas malabsorption was significantly associated with systolic dysfunction, even after adjustment for potential confounders. CONCLUSION:Upper GI dysfunction was associated specifically with conduction defects, suggesting that autonomic dysfunction contributes. In contrast, lower GI involvement, particularly malabsorption, was linked to systolic dysfunction in patients with SSc, potentially indicating a distinct biologic mechanism. These findings may support integrating early GI symptoms into cardiac risk stratification, and they provide a foundation for future translational studies.

Objective: Systemic sclerosis (SSc), or scleroderma, is an autoimmune disorder marked by increased mortality due to excessive collagen accumulation in the body. The modified Rodnan Skin Score (mRSS) is the standard for assessing dermal thickening in SSc but shows high observer variability. Optical coherence elastography (OCE) is a promising alternative for evaluating skin involvement in SSc, though comprehensive comparative studies with histological and clinical assessment are lacking. Methods: We evaluated OCE's face (SSc versus healthy skin), construct (correlation to mRSS), and criterion (correlation with histology) validities in 20 control and 55 SSc patients, with assessments on the finger, hand, and forearm. Assessors were blinded to results in the other domains, and OCE was performed completely contact free at ∼500 Hz, 1 kHz, 5 kHz, and 10 kHz stimulation. Results: There was a significant difference in OCE measurements between control and SSc skin at all examined locations (face validity). However, there was a weak to moderate correlation between OCE and mRSS at certain frequencies (construct validity). Additionally, OCE exhibited weak to moderate correlations with histological parameters. Conclusion: Although OCE demonstrated strong face validity, its construct and criterion validity were moderate at best, highlighting the need for further development. Significance: This research is the most exhaustive comparison of OCE against clinical and histological markers of skin involvement in SSc. The results strongly support OCE's face validity, but the weak to moderate construct and criterion validity underline the need for further development. Nevertheless, these results show critical progress towards developing an objective skin assessment tool for SSc.

BACKGROUND:In the FIBRONEER-ILD trial in patients with progressive pulmonary fibrosis (PPF), nerandomilast 9 mg twice daily and 18 mg twice daily (hereafter nerandomilast 9 mg and 18 mg, respectively) reduced the decline in forced vital capacity at week 52 compared with placebo (primary end-point). We assessed the effects of nerandomilast up to the final database lock. METHODS:Time to first acute exacerbation of interstitial lung disease, hospitalisation for respiratory cause or death (key secondary end-point) and other time-to-event end-points were assessed. RESULTS:1176 patients, of whom 512 were taking background nintedanib, received nerandomilast or placebo. At the final database lock, the mean±sd exposure to trial medication was 15.1±5.7 months and the mean±sd observation period was 17.0±4.1 months. Compared with placebo, the hazard ratio for the key secondary end-point was 0.78 (95% CI 0.61-1.00) for nerandomilast 9 mg and 0.77 (95% CI 0.60-0.99) for nerandomilast 18 mg; hazard ratios were lower among patients not taking nintedanib (0.69 (95% CI 0.49-0.97) and 0.65 (95% CI 0.46-0.92), respectively) than among those taking background nintedanib (0.90 (95% CI 0.63-1.30) and 0.93 (95% CI 0.65-1.34), respectively). For death, the hazard ratio versus placebo was 0.51 (95% CI 0.34-0.78) for both nerandomilast doses. Adverse events led to discontinuation of trial medication in 12.5%, 12.0% and 12.3% of the placebo, nerandomilast 9 mg and nerandomilast 18 mg groups, respectively. CONCLUSIONS:In the FIBRONEER-ILD trial in patients with PPF, nerandomilast reduced the risk of clinically important outcomes, including death, over the whole trial. Nerandomilast had a favourable safety and tolerability profile.

Objective Anti-RNA-polymerase-III (ARA) and anti-topoisomerase-I (ATA) autoantibodies are associated with diffuse cutaneous SSc (dcSSc). ARA is associated with rapidly progressive skin thickening, scleroderma renal crisis (SRC), and gastric antral vascular ectasia, while ATA is associated with severe interstitial lung disease (ILD). However, these associations were derived from heterogenous SSc cohorts. As SSc is now often diagnosed earlier, we aimed to ascertain whether these relationships hold true in early dcSSc and to examine autoantibody associations with organ involvement in early dcSSc. Methods The Prospective Registry of Early Systemic Sclerosis (PRESS) includes adults with dcSSc ≤2 years from the first non-Raynaud’s phenomenon symptom who met 2013 ACR/EULAR classification criteria for SSc. Participants were enrolled at 12 U.S. academic centers and evaluated every 6 months. Those with dual-positivity were excluded. Differences across autoantibody groups were assessed using appropriate parametric and nonparametric tests. Results Of 303 enrolled, 233 participants were included (108 ARA+, 68 ATA+, 57 double-negative). Mean age was 51 years; 68% were female. Mean disease duration was 1.2 years. ATA+ participants had lower baseline FVC% predicted (76.0% vs 86.0% ARA+, p=0.0011) and higher prevalence of ILD (69.6% vs 44.3% ARA+, p=0.0029). ARA+ participants had higher baseline mRSS (25.0 vs 17.9 ATA+, p<0.0001) and higher prevalence of SRC (14.4% vs 0.0% ATA+, p=0.0024). Only the double-negative group had improvement in FVC% predicted over time (+1.39% per year, p=0.03). Conclusions Autoantibody-specific differences in organ involvement were evident early. The double-negative group uniquely showed improvement in lung function over time.

[This corrects the article DOI: 10.1117/1.JBO.30.3.036007.].

Abstract Objectives The preferential phosphodiesterase 4B (PDE4B) inhibitor nerandomilast was recently approved for treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis. Its proposed immunomodulatory, anti-fibrotic, and endothelial-stabilising actions target all three cardinal features of SSc, yet PDE4B expression has not been systematically characterised in SSc tissue. We aimed to define PDE4B expression across fibrotic organs and cellular compartments in SSc. Methods PDE4B expression was profiled in SSc lung, peripheral blood mononuclear cells (PBMCs) and skin on the transcript level using single-cell RNA sequencing data and on the protein level using immunohistochemistry, immunofluorescence and multiplexed immunofluorescent stainings. Results PDE4B was consistently dysregulated in immune cells across SSc tissue and PBMCs, with compartment-specific direction and distribution. In SSc-ILD lung, expression was increased in CD8⁺ and CD4⁺ memory T-cells. In PBMCs, expression was increased in B cells, monocytes, and CD8⁺ T-cells, and stratified patients into three endotypes (PDE4B ˡᵒ / ᵐᵉᵈ / hi ) not distinguishable by clinical variables. In skin, bulk RNA-seq showed a significant global increase, which localized to myeloid cells in scRNA-seq data. Approximately 90% of FAP⁺ activated fibroblasts co-expressed PDE4B at the protein level in SSc skin, identifying the activated fibroblast compartment as a candidate target for PDE4B inhibition. No PDE4B dysregulation was detected in vascular cell types. Conclusions This first cell-type-resolved characterisation of PDE4B in SSc demonstrates consistent immune-cell dysregulation across tissues and protein-level enrichment in activated fibroblasts. This provides a human-tissue rationale for the immunomodulatory and anti-fibrotic effects of PDE4B inhibition and supporting PDE4B as a disease-relevant therapeutic target in SSc. Key messages What is already known on this topic Nerandomilast (BI 1015550), a PDE4B-preferential inhibitor, was approved for idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. Pre-clinical studies indicate that PDE4B inhibition may act on all cardinal features of SSc. What this study adds First cell-type-resolved characterization of PDE4B expression across SSc-affected lung, PBMCs, and skin. PBMC PDE4B expression is heterogeneous, stratifying patients into PDE4Bˡᵒ/ᵐᵉᵈ/ʰⁱ endotypes independent of standard clinical variables. scRNA-seq shows increased myeloid PDE4B expression in SSc skin, while ∼90% of FAP⁺ activated fibroblasts in SSc skin express PDE4B protein. How this study might affect research, practice or policy The study strengthens the human-level evidence underpinning the target rationale for PDE4B inhibition in SSc.

OBJECTIVES:Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of mortality in systemic sclerosis (SSc), yet its genetic architecture remains incompletely understood. Therefore, given the key role of the major histocompatibility complex (MHC) in SSc, we aimed to perform a comprehensive MHC-wide association study in the largest SSc-ILD cohort to date. METHODS:We analysed 2412 patients with SSc-ILD⁺, 3550 patients with SSc-ILD⁻, and 15,076 controls of European ancestry from 10 international cohorts. After quality control, the MHC region was imputed, and inverse variance weighted meta-analysis was performed. Subsequently, conditional stepwise analyses, adjustment for antitopoisomerase autoantibody (ATA) status, and functional annotation of significant single-nucleotide polymorphisms were performed. Finally, we constructed a composite score combining genetic, clinical, and demographic variables to predict SSc-ILD. RESULTS:After conditional analysis, we detected 12 significant associations within class I and class II human leukocyte antigen (HLA) genes. ATA adjustment reduced the significance of class II HLA variants, whereas class I HLA variants remained unaffected. Finally, the built composite score had an area under the curve of 0.754, significantly outperforming the models including any of the variables alone. CONCLUSIONS:In this study, we identify genetic mechanisms underlying SSc-ILD that support the potential implication of CD8+ T cells and ATAs in its pathogenesis. Moreover, we also demonstrate the enhanced efficacy of integrating genetic information into predictive models to detect patients at high risk of SSc-ILD. These findings provide new insights into disease pathogenesis and suggest potential biomarkers and therapeutic targets for improved patient management.