Does Immunosuppression Prevent PAH in Systemic Sclerosis?

Medscape

06-05-2025

MANCHESTER, England — Use of immunosuppressive drugs within 5 years of the onset of systemic sclerosis (SSc) did not lower patients' risk for developing pulmonary arterial hypertension (PAH) but was associated with a significantly lower likelihood of death in patients with the complication, researchers reported at the British Society for Rheumatology (BSR) 2025 Annual Meeting.
Senior author for the study, Christopher Denton, MD, PhD, professor of experimental rheumatology at UCL Medical School and head of the Centre for Rheumatology at the Royal Free Hospital, London, England, told Medscape Medical News , 'Pulmonary hypertension is one of the complications of scleroderma that has been thought traditionally not to be so inflammatory or immunologically driven. But we got an interesting signal, which was that patients who were on hydroxychloroquine seem to have a lower frequency of developing pulmonary hypertension' than those who were not using immunosuppressants.
Christopher Denton, MD, PhD
Denton noted that, generally speaking, hydroxychloroquine was thought to be 'quite a benign drug,' so the result begs the question as to whether it could be beneficial to give to people with SSc who may be at risk for developing PAH.
'It does suggest that maybe immunomodulation could be helpful, although hydroxychloroquine does lots of other things as well as immunomodulation,' and this was a small study, Denton cautioned.
A 'Dreadful Complication'
Stefano Rodolfi, MD, who presented the study's findings and works as a clinical research fellow at the Royal Free Hospital, said that PAH was 'one of the most dreadful complications' of SSc that affects an estimated 8%-13% of patients during the disease course. The 3-year survival rate is around 50%, he said.
Stefano Rodolfi, MD
It is 'a complication whose proposed pathophysiological mechanism is thought to start with an initial vascular injury to the pulmonary vasculature, leading to an aberrant fibroproliferatory repair process, progressive obliterative pulmonary vasculopathy, ultimately resulting in an increase in the mean pulmonary arterial pressures, increasing pulmonary vascular resistances, and right ventricular dysfunction,' Rodolfi explained.
'However, we have evidence for a role of immune dysfunction in the pathogenesis and pathophysiology,' he said. There are data showing that various autoantibodies are present, such as antibodies against the endothelin-1 receptor, angiotensin II receptor, and fibroblasts. There are also data suggesting a proinflammatory cytokine profile and the presence of activated monocytes in patients with SSc-PAH.
'Furthermore, we have indirect evidence on the role of immunosuppression in this complication,' Rodolfi added. Thus, one might expect that immunosuppression would be part of the management approach for SSc-PAH, but its 'treatment mirrors the same approach of the idiopathic counterpart of PAH, being based on a combination of vasodilatory and antiproliferative agents.'
Study Overview
Rodolfi explained that a retrospective analysis of 629 'well-characterized' patients with SSc was performed to answer two key questions: First, can early immune suppression prevent the development of PAH? Second, does immunosuppression alter survival in SSc-PAH?
PAH was defined using the Venice definition of precapillary pulmonary hypertension: Mean pulmonary artery pressure ≥ 25 mm Hg, pulmonary vascular resistance > 3 Wood units, and a pulmonary wedge pressure ≤ 15 mm Hg. Rodolfi noted that this was a prior definition.
After excluding patients with interstitial lung disease (ILD) that extended ≥ 20% on a high-resolution CT scan or who had a forced vital capacity < 70%, there were 607 patients available for analysis. Of these, 320 had received immunosuppression through their disease course, and 287 had not.
Early Immunosuppression and Development of SSc-PAH
For the first part of the analysis, patients were divided into three groups: Those who had received immunosuppression 'early,' ie, within the first 5 years of their SSc diagnosis (n = 206); those who had received immunosuppression 'late,' receiving it after 5 years of their SSc diagnosis (n = 144); and those who received no immunosuppression (n = 287).
Immunosuppression was defined as treatment with glucocorticoids (prednisone equivalent ≥ 10 mg/d for ≥ 6 months) or conventional synthetic or biologic disease-modifying antirheumatic drugs.
Over a median follow-up of 21 years, 77 patients developed PAH: 11 (5.3%) in the early immunosuppression group, 21 (14.6%) in the late suppression group, and 45 (15.7%) in the no suppression group. The difference between those with early immunosuppression and those without any use of immunosuppression was significant ( P < .001).
However, after adjusting for potential confounding factors, such as male sex, diffuse cutaneous onset of SSc, ILD, scleroderma renal crisis, severe cardiac involvement, and presence of specific autoantibodies, there was no difference between the groups in terms of the time to developing PAH.
Time to PAH was 'superimposable' across the three groups (10.5 vs 11 vs 11 years, respectively; P = .581), 'so we can conclude that early immune suppression did not significantly impact on the development of PAH,' Rodolfi reported.
However, when analyzing the potential effects of individual immunosuppressive agents, treatment with mycophenolate mofetil (MMF) was associated with significantly reduced odds (odds ratio [OR], 0.12; P = .048) of developing PAH vs not using MMF.
Other notable findings were that the presence of ILD, even if 'mild,' was associated with the development of PAH (OR, 3.01; P = .006). Other factors associated with increased risk for SSc-PAH were scleroderma renal crisis (OR, 6.54; P = .035) and the presence of anticentromere antibodies (OR, 2.94; P = .026). Conversely, the presence of anti–Scl-70 was associated with reduced odds of developing PAH (OR, 0.15; P = .009).
The fact that MMF was associated with a reduced odds of developing SSc-PAH fits with other data, Rodolfi said. The drug has been shown to alleviate thickening of pulmonary arterial walls and inhibit abnormal vascular remodeling in a mouse model of PAH, and its efficacy has been reported in cases of PAH associated with other connective tissue diseases other than SSc.
Mortality Impact
For the second part of the analysis that examined the possible effect of immunosuppression on mortality in SSc-PAH, two groups of 'ever' (n = 30) or 'never' (n = 42) users of immunosuppression were formed.
Rodolfi reported that more patients in the 'ever' than 'never' group had diffuse cutaneous SSc (20% vs 0%) and ILD (60% vs 14.6%), but fewer had anticentromere antibodies (55.2% vs 86.1%).
Over a median follow-up of 7 years, 22 patients (73%) died in the 'ever' group and 30 died (71%) in the 'never' group. The median duration of survival from the time of PAH diagnosis was 7 years and 4 years, respectively, in the two groups (OR, 0.41; P = .045).
'When analyzing the impact of single agents, hydroxychloroquine was associated with reduced mortality risk,' Rodolfi said. Of the nine patients who had been treated with hydroxychloroquine, two died 17 years after their PAH diagnosis (hazard ratio, 0.04; P = .004).
'Once again, this is corroborated by preclinical evidence,' Rodolfi said, adding that it's not the first time either that hydroxychloroquine has been shown to have a possible beneficial clinical effect. Although a different endpoint was used, prior data have shown that treatment with hydroxychloroquine given in the first 18 months of SSc onset may reduce the risk for developing PAH.
It is 'not quite the same finding as we had. Our signal was towards a benefit in survival, but still, something to corroborate the role of hydroxychloroquine in this setting.'
Are There Any Practice Implications?
But are the findings enough to have an impact on practice as it stands today? Consultant rheumatologist Carmel Stober, MD, PhD, who works for Cambridge University Hospitals NHS Trust, Cambridge, England, told Medscape Medical News that the results could potentially have an impact on how some patients with systemic sclerosis were treated.
'For example, if someone has got limited cutaneous systemic sclerosis, you would not necessarily get them on immunosuppression,' but you might give hydroxychloroquine if it has an effect on risk for PAH and there is a risk-benefit advantage for it, she said.
The hypothesis is that PAH is modifiable by immunosuppression, Stober said, noting that the second part of the study looked at people who were already receiving immunosuppression and whether that decreased their risk for PAH. But the answer as to whether immunosuppression truly has that effect lies perhaps in a randomized controlled trial.
Rodolfi noted that an ongoing multicenter, open-label, randomized trial of about 120 patients with limited cutaneous SSc in the United Kingdom is aiming to determine if MMF plus standard of care can slow down disease progression vs standard of care alone.
The study's findings have been previously presented as a poster at the American College of Rheumatology (ACR) 2024 Annual Meeting.
The study was independently supported. Rodolfi and Stober had no financial conflicts of interest to report. Denton reported receiving no financial relationships on the abstract but has in the past received speaker or advisory fees, research support, or clinical trial funding from various pharmaceutical companies, including Actelion, Pfizer, GlaxoSmithKline, Sanofi-Aventis, and Novartis.