Background: In heterogeneous conditions with insufficient predictable disease course, like systemic sclerosis (SSc), appropriate measurement of disease activity, as well as predictors of disease progression are necessary for optimizing individual outcome. Systemic sclerosis is associated, despite emerging new therapies with a variable unpredictable course of disease with a high morbidity and mortality. Notably, innate lymphoid cells (ILCs), specifically ILC2, are gaining recognition as significant contributors to cytokines-driven fibrotic tissue remodelling. Elevated levels of ILC2s have been observed in both skin sections and the circulation of SSc patients commpared to healthy controls.

Objectives: The study aims to assess the predictive value of type 2 ILCs over a period of 5-year follow-up in patients with systemic sclerosis.

Methods: Fifty-two consecutive patients meeting the 2013 ACR/EULAR classification criteria for SSc were included in the study. Clinical parameters were assessed according to EUSTAR recommendations by experienced rheumatologists. Blood samples were analysed using flow cytometry. Annual pulmonary function test (PFT), echocardiography and EKG were conducted. High-resolution computed tomography (HRCT) scans of the lungs were evaluated by experienced radiologists, who were blinded with regard to the clinical data and the study question and some patients underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP, ⁶⁸Ga-FAP inhibitor (FAPI)-04). Disease worsening was defined as decrease in pulmonary function tests (FVC or DLCOcSB decline ≥ 10%), progression of fibrotic lesions in HRCT, switch or new begin of immunosuppressive or anti-fibrotic therapy, increase in mRSS defined as increase in mRSS >5 points and ≥25% from baseline, or death.

Results: The baseline cohort comprised 52 patients with SSc, including 12 patients with diffuse (23.07%) cutaneous SSc (dcSSc) and 11 (21.15%) male. Mean ± SD disease duration was 7.5 ± 6.9 years. Among the 52 patients, three (5.76%) patients were lost to follow-up and eight (15.38%) died. Circulating ILC2 were significantly increased in patients with a fibrotic subtype of disease (including important skin fibrosis and lung fibrosis, adapted from DeSScipher observational studies), followed by the vascular subtype (represented by marked digital ulcers and pulmonary arterial hypertention), while musculo-skeletal (arthritis or muscular disease as leading symptoms) and normal-like subtype had similar low levels (mean ILC2 4.18 vs. 1.80 vs. 1.28 vs. 1.01/µl respectively, p<0.001). Baseline ILC2 number correlated with lung disease progression, worsening of mRSS and mortality. Patients requiring intensive immunosuppressive or anti-fibrotic therapy during the follow-up time had significantly higher ILC2 counts at baseline (3.73/µl vs 1.25/µl, p<0.001). The ILC2 cutoff value of 1.57/µl demonstrated high sensitivity (>90%) and specificity (>70%) in identifying stable patients (area under the curve 0.879, p<0.0001). Patients with ILC2 count above 1.57/µl experienced a more rapid decline in pulmonary function test, increased mRSS scores and a higher mortality. Multivariate analysis revealed that an increased ILC2 number at baseline was a significant predictor of lung disease progression (≥10% decline in FVC, ≥10% decline in DLCO, progression of lung fibrosis in HRCT scans) and death. Furthermore, high ILC2 counts correlated with increase SUVmax and SUVmean in FAPI PET-CT imaging, indicating heightened activity in these patients.

Conclusion: The baseline number of ILC2s correlated with disease progression and serves as a prognostic marker even in patients with longstanding disease, providing evidence for profibrotic role of ILC2 in SSc.

REFERENCES: NIL.

Acknowledgements: Supported by the German Research Foundation (grant SO 1735/2-1), Novartis Pharma GmbH

Disclosure of Interests: Alina M Ramming: None declared, Christian Schmidkonz: None declared, Armin Atzinger: None declared, Maria Gabriella Raimondo: None declared, Simon Rauber: None declared, Jörg Distler: None declared, Georg Schett: None declared, Andreas Ramming Novartis Pharma GmbH, Novartis Pharma GmbH.