Clinical prognosis, and a potential new treatment target

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Systemic sclerosis is a rare connective tissue disorder characterised by autoimmune features with vascular manifestations, causing fibrosis of the skin and internal organs. EULAR – The European Alliance of Associations for Rheumatology – is focused on systemic sclerosis as the rheumatic disease with the highest morbidity and mortality.1 New data presented at the EULAR 2026 Congress underscore key complications, and offer hope for a possible new therapeutic strategy.

Primary cardiac involvement (pCI) is a major contributor to morbidity and mortality in people with systemic sclerosis, and early cardiac manifestations may be under-recognised, particularly when there is no systematic screening in routine practice. At the EULAR 2026 Congress in London, Shirkhan Amikishiyev presented the baseline prevalence and clinical correlates of pCI in the SOLAR registry, summarising incident pCI during follow-up in 372 patients. At baseline, pCI was present in 6.5% – a small number that may partly reflect real-world reporting practices and the likelihood that subclinical disease is under-captured in a registry setting. Associated factors included older age, diffuse cutaneous subtype, myositis, pulmonary arterial hypertension, overlap syndrome, and hypertension – clustering with a higher-risk clinical profile. Among those who were pCI-negative at baseline, around 2% developed incident pCI. This emergence of new cases during follow-up suggests that a single baseline assessment may miss evolving cardiac involvement, supporting the need for structured and repeated cardiac evaluation in systemic sclerosis, especially in patients with multi-system disease.

A poster at the Congress also looked at ideas around progression and prognosis. Although the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) approach has improved early identification of systemic sclerosis in people with Raynaud’s phenomenon, current prognostic models rely on individual clinical or serological features – failing to capture complex, multidimensional interactions between demographics, immunological profiles, inflammatory burden, and early subclinical organ involvement. Vincenzo Venerito and colleagues used an unsupervised machine-learning technique to identify distinct clinical phenotypes among 238 VEDOSS patients – with the aim of evaluating differences in rate and timing of progression. The approach identified three distinct clusters. The first was younger patients with earlier Raynaud’s onset, minimal clinical and subclinical organ involvement, low inflammatory markers, and low prevalence of autoantibodies. This cluster had the lowest risk of progression to definite systemic sclerosis (21.4%) and the longest disease-free time period. Cluster 2 were a more intermediate age at Raynaud’s onset, with prominent vasculopathic and cutaneous features, and the highest prevalence of anti-centromere antibodies; this group had intermediate risk of progression (39.4%) and a relatively indolent disease course. Cluster 3 included older patients with later onset, higher inflammatory burden, early cardiopulmonary and gastrointestinal involvement, higher prevalence of anti-topoisomerase I antibodies, and evidence of subclinical organ dysfunction. This third cluster had the highest risk (58.0%) and a significantly shorter time to progression. Such phenotypic stratification could be useful to improve early prognostic accuracy, enabling personalised monitoring intensity, as well as risk-adapted therapeutic strategies in people with very early disease.

Systemic sclerosis is an immune-fibrotic disease. A key item on the research agenda in the 2023 EULAR recommendations is to expand the therapeutic portfolio to improve clinical outcomes for systemic sclerosis.1 Selective inhibition of PDE4B has recently been shown to be effective for progressive fibrosing interstitial lung disease,2,3 and it has been suggested that the fibro-immunomodulatory effects could be a promising strategy for systemic sclerosis. Until now, cell type–specific expression patterns across affected tissues in systemic sclerosis have not been systematically examined. But an oral abstract presentation on Friday 5th June has offered new insights. For the lung, two single cell RNA-sequencing datasets were integrated: one with samples from interstitial lung disease associated with systemic sclerosis (SSc-ILD), and one from idiopathic pulmonary fibrosis (IPF), plus lung samples from healthy controls. Single cell RNA-sequencing was also performed on peripheral blood mononuclear cells (PBMC) from patients with early, active disease and age-matched controls. Differential expression analysis showed an increase in PDE4B expression in several cell types, including both CD8⁺ and CD4⁺ T cells in SSc-ILD and IPF compared with controls – with additional upregulation in SSc-ILD relative to IPF. In PBMC, expression was significantly increased in B cells, CD8⁺ T cells, and monocytes of patients with systemic sclerosis. As another target organ in systemic sclerosis, skin single cell RNA-sequencing data were anaysed, revealing PDE4B upregulation in both myeloid and lymphoid populations in patients with systemic sclerosis. Immunohistochemistry confirmed increased expression of the PDE4B protein in skin.

Presenting the work, Astrid Hofman said “Overall, PDE4B expression emerges as a shared feature across tissues in systemic sclerosis, supporting its relevance as a potential therapeutic target.”

Source

Amikishiyev S, et al. Primary Cardiac Involvement in Early Systemic Sclerosis: Baseline Profile of the patients in the SOLAR Registry. Presented at EULAR 2026; OP0215. Ann Rheum Dis 2026; DOI: 10.1136/annrheumdis-2026-eular.B.2918.

Venerito V, et al. Multidimensional Approach to Predict disease Progression and prognosis in patients with Very Early Diagnosis Of Systemic Sclerosis (MAPPing VEDOSS). Presented at EULAR 2026; POS0325. Ann Rheum Dis 2026; DOI: 10.1136/annrheumdis-2026-eular.B.4080.

Hofman A, et al. Single-Cell Profiling Identifies PDE4B as a Disease-Relevant Target in Systemic Sclerosis Across Tissues and Cell Subsets. Presented at EULAR 2026; OP0309. Ann Rheum Dis 2026; DOI: 10.1136/annrheumdis-2026-eular.B.1248.

References

1. Del Galdo F, et al. EULAR recommendations for the treatment of systemic sclerosis: 2023 update. Ann Rheum Dis 2025;84(1):29–40. DOI: 10.1136/ard-2024-226430.

2. Maher TM, et al. Nerandomilast in Patients with Progressive Pulmonary Fibrosis. N Engl J Med 2025;392(22):2203–14. DOI: 10.1056/NEJMoa2503643.

3. Richeldi L, et al. Nerandomilast in Patients with Idiopathic Pulmonary Fibrosis. N Engl J Med 2025;392(22):2193–202. DOI: 10.1056/NEJMoa2414108.

About EULAR

EULAR is the European umbrella organisation representing scientific societies, health professional associations and organisations for people with rheumatic and musculoskeletal diseases (RMDs). EULAR aims to reduce the impact of RMDs on individuals and society, as well as improve RMD treatments, prevention, and rehabilitation. To this end, EULAR fosters excellence in rheumatology education and research, promotes the translation of research advances into daily care, and advocates for the recognition of the needs of those living with RMDs by EU institutions.

Contact

EULAR Communications, communications@eular.org