MANCHESTER, England — A new analysis presented at the British Society for Rheumatology (BSR) 2025 Annual Meeting suggests that while early immunosuppression does not prevent the onset of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc), it may improve survival in those who do develop the condition.

Study Background and Key Investigators

Dr. Christopher Denton, professor of experimental rheumatology at UCL Medical School and head of the Centre for Rheumatology at the Royal Free Hospital, noted that PAH in SSc is typically considered non-inflammatory. However, preliminary data indicated a potential protective effect of hydroxychloroquine in reducing PAH risk—an unexpected finding given the drug’s reputation as relatively mild in immunosuppressive action.

“Hydroxychloroquine stood out. Patients on this drug seemed less likely to develop PAH,” Dr. Denton said, suggesting immunomodulation may still play a role in disease progression.

PAH: A Severe SSc Complication

Dr. Stefano Rodolfi, who presented the findings, emphasized that PAH remains one of the most devastating complications of SSc, affecting roughly 8–13% of patients. The 3-year survival rate remains poor, hovering around 50%.

He described PAH’s pathogenesis as beginning with pulmonary vascular injury, leading to a fibroproliferative response, vascular remodeling, and, ultimately, right heart failure. Despite its vascular basis, Rodolfi highlighted mounting evidence pointing to immune dysregulation, including autoantibodies, inflammatory cytokines, and activated immune cells in affected patients.

Study Design: Who Was Studied?

The retrospective analysis included 629 patients with well-documented SSc. After exclusions based on significant interstitial lung disease (ILD) or low lung function, 607 patients were analyzed. Of these, 320 had received immunosuppressive therapy at some point, while 287 had not.

Patients were grouped based on the timing of treatment:

• Early immunosuppression (within 5 years of diagnosis) – n = 206
• Late immunosuppression (after 5 years) – n = 144
• No immunosuppression – n = 287

Immunosuppression was defined as the sustained use of glucocorticoids, conventional DMARDs, or biologic agents.

Findings: PAH Risk and Survival Outcomes

Over a 21-year median follow-up, 77 patients developed PAH. Incidence by the group was:

• Early immunosuppression: 5.3%
• Late immunosuppression: 14.6%
• No immunosuppression: 15.7%

At first glance, early treatment may reduce PAH risk. However, after adjusting for confounders (such as gender, autoantibody profile, renal involvement, and diffuse cutaneous SSc), the time to PAH onset was statistically similar across all groups (P = .581).

Interestingly, when individual drugs were analyzed, mycophenolate mofetil (MMF) showed significantly lower odds of PAH (OR 0.12; P = .048).

Other risk factors included:

• ILD (OR 3.01; P = .006)
• Scleroderma renal crisis (OR 6.54; P = .035)
• Anticentromere antibodies (OR 2.94; P = .026)

Conversely, the anti–scl–70 antibody appeared protective (OR 0.15; P = .009).

Survival Benefits Of Immunosuppression

In a separate analysis focusing on 72 SSc-PAH patients, researchers compared those who had ever received immunosuppressants (n = 30) to those who had not (n = 42). Though baseline characteristics varied (e.g., more diffuse disease and ILD in the immunosuppressed group), the results showed:

• Median survival from PAH diagnosis was 7 years (treated) vs 4 years (untreated)
• Immunosuppression reduced mortality risk (OR 0.41; P = .045)

Most striking was the impact of hydroxychloroquine. Of 9 patients on the drug, only 2 died, and both more than 17 years post-PAH diagnosis (HR 0.04; P = .004).

Rodolfi noted that preclinical studies support these findings, with hydroxychloroquine demonstrating vascular protective effects and anti-remodeling properties in animal models.

Clinical Implications and the Road Ahead

Commenting on the findings, Dr. Carmel Stober from Cambridge University Hospitals said the study may change clinical thinking, particularly regarding hydroxychloroquine use in patients with limited cutaneous SSc, where immunosuppression is not routine.

“If there’s even modest benefit and low risk, clinicians may start rethinking hydroxychloroquine’s role,” she said.

Still, experts agree that randomized controlled trials are needed. A UK multicenter RCT is already underway, investigating whether MMF plus standard care can slow SSc progression compared to standard care alone.

Conclusion

While early immunosuppression does not appear to prevent PAH onset in systemic sclerosis, specific agents—particularly MMF and hydroxychloroquine—may offer survival benefits and delay disease progression. These findings support a more nuanced, drug-specific approach and signal the need for further prospective studies.