PDE4B Emerges as Shared Therapeutic Target Across Tissues in Systemic Sclerosis
核心洞察
Single-cell RNA sequencing reveals PDE4B (搜索) upregulation across lung, skin, and blood in systemic sclerosis (搜索) patients, supporting its relevance as a therapeutic target.
PDE4B (搜索) expression was significantly increased in CD8⁺ and CD4⁺ T cells in SSc-ILD (搜索) compared to both healthy controls and idiopathic pulmonary fibrosis (搜索) samples.
Machine-learning analysis of VEDOSS patients identifies three distinct phenotypic clusters with progression risks ranging from 21.4% to 58.0%, enabling risk-adapted therapeutic strategies.
Systemic sclerosis (搜索), a rare connective tissue disorder with the highest morbidity and mortality among rheumatic diseases, was a major focus at the EULAR (搜索) 2026 Congress in London, where new findings highlighted both emerging therapeutic targets and critical gaps in clinical monitoring. Among the most notable presentations was the discovery that phosphodiesterase 4B (PDE4B (搜索)) is consistently upregulated across multiple affected tissues, positioning it as a promising shared therapeutic target for this immune-fibrotic disease.
PDE4B (搜索): A Cross-Tissue Therapeutic Target
Selective inhibition of PDE4B (搜索) has recently demonstrated efficacy in progressive fibrosing interstitial lung disease, and its fibro-immunomodulatory effects have been proposed as a potential strategy for systemic sclerosis (搜索). Until now, however, cell type-specific expression patterns across affected tissues had not been systematically examined.
An oral abstract presentation on Friday 5th June offered new insights by integrating two single-cell RNA-sequencing datasets: one from interstitial lung disease associated with systemic sclerosis (搜索) (SSc-ILD (搜索)) and one from idiopathic pulmonary fibrosis (搜索) (IPF), alongside 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 (搜索) expression in several cell types, including both CD8⁺ and CD4⁺ T cells in SSc-ILD (搜索) 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 (搜索). Analysis of skin single-cell RNA-sequencing data further revealed PDE4B upregulation in both myeloid and lymphoid populations in systemic sclerosis patients, with immunohistochemistry confirming increased expression of the PDE4B protein in skin.
Presenting the work, Astrid Hofman said: "Overall, PDE4B (搜索) expression emerges as a shared feature across tissues in systemic sclerosis (搜索), supporting its relevance as a potential therapeutic target."
Machine Learning Stratifies Early Disease Progression Risk
In a separate presentation, Vincenzo Venerito and colleagues applied unsupervised machine-learning techniques to identify distinct clinical phenotypes among 238 patients enrolled through the Very Early Diagnosis of Systemic Sclerosis (搜索) (VEDOSS) approach. Current prognostic models rely on individual clinical or serological features, failing to capture complex multidimensional interactions.
The analysis identified three distinct clusters. Cluster 1 comprised younger patients with earlier Raynaud's onset, minimal clinical and subclinical organ involvement, low inflammatory markers, and low prevalence of autoantibodies — this group had the lowest risk of progression to definite systemic sclerosis (搜索) (21.4%) and the longest disease-free time period. Cluster 2 featured intermediate age at Raynaud's onset, prominent vasculopathic and cutaneous features, and the highest prevalence of anti-centromere antibodies, with an intermediate progression risk of 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 group had the highest progression risk at 58.0% and a significantly shorter time to progression.
Such phenotypic stratification could improve early prognostic accuracy, enabling personalised monitoring intensity and risk-adapted therapeutic strategies in people with very early disease.
Cardiac Involvement: Under-Recognised and Evolving
Primary cardiac involvement (pCI) is a major contributor to morbidity and mortality in systemic sclerosis (搜索), yet early cardiac manifestations may be under-recognised without systematic screening. Shirkhan Amikishiyev presented baseline prevalence and clinical correlates of pCI from the SOLAR registry, summarising data from 372 patients.
At baseline, pCI was present in 6.5% of patients — a figure 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, approximately 2% developed incident pCI during follow-up.
This emergence of new cases suggests that a single baseline assessment may miss evolving cardiac involvement, supporting the need for structured and repeated cardiac evaluation in systemic sclerosis (搜索), especially in patients with multi-system disease. The finding aligns with broader data on cardiovascular risk in systemic autoimmune diseases, where a systematic review and meta-analysis of 40 studies representing over 210,000 patients and more than 800,000 controls found systemic sclerosis and rheumatoid arthritis had the strongest associations with atrial fibrillation, ventricular arrhythmias, and atrioventricular block.