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Outcomes Have Improved for PAH in Connective Tissue Disease

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Survival rates for patients with pulmonary arterial hypertension associated with connective tissue diseases have improved significantly in recent years, and there is growing evidence that treatments for idiopathic pulmonary arterial hypertension can also benefit this group.

In an article published online Feb. 3, 2021, in Arthritis & Rheumatology, researchers report the outcomes of a meta-analysis to explore the effect of more modern pulmonary arterial hypertension treatments on patients with conditions such as systemic sclerosis.



Outcomes Have Improved for PAH in Connective Tissue Disease 2

Dr Dinesh Khanna

First author Dinesh Khanna, MBBS, MSc, of the division of rheumatology at the University of Michigan, Ann Arbor, said in an interview that connective tissue disease–associated pulmonary arterial hypertension (CTD-PAH) was a leading cause of death, but earlier clinical trials had found poor outcomes in patients with CTD, compared with those with idiopathic PAH.

“Recent clinical trial data show that aggressive, up-front PAH treatments have better outcomes in those with CTD-PAH, and we wanted to explore these observations carefully in a systematic review and meta-analysis,” Khanna said.

The analysis included 11 randomized, controlled trials, involving 4,329 patients with PAH (1,267 with CTD), and 19 registries with a total of 9,739 patients with PAH, including 4,008 with CTD. Trials were required to report long-term clinical outcomes with a median enrollment time of greater than 6 months, and outcomes measured between 3-6 months after the patients started treatment.

Patients with CTDs had an older mean age and a lower 6-minute walk distance than did those with idiopathic PAH.

Five randomized, controlled trials – involving 3,172 patients, 941 of whom had a CTD – found that additional PAH treatment was associated with a 36% reduction in the risk of morbidity or mortality events, compared with controls both in the overall PAH group and in those with CTD.

Additional therapy was also associated with a 34.6-meter increase in 6-minute walk distance in the general PAH population, and a 20.4-meter increase in those with CTD.

The authors commented that the smaller improvement in 6-minute walk distance among patients with CTD may be influenced by comorbidities such as musculoskeletal involvement that would be independent of their cardiopulmonary function.

Differential Patient Survival Among PAH Etiologies

“Our meta-analysis of RCTs demonstrated that patients with CTD-PAH derive a clinically significant benefit from currently available PAH therapies which, in many patients, comprised the addition of a drug targeting a second or third pathway involved in the pathophysiology of PAH,” the authors wrote.

When researchers analyzed data from nine registries that included a wide range of PAH etiologies, they found the overall survival rates were lower among patients with CTD, compared with the overall population. The analysis also suggested that patients with systemic sclerosis and PAH had lower survival rates than did those with systemic lupus erythematosus.

Khanna said this may relate to different pathophysiology of PAH in patients with CTDs, but could also be a reflection of other differences, such as older age and the involvement of other comorbidities, including lung fibrosis and heart involvement.

Data across all 19 registries also showed that survival rates among those with CTD were higher in registries where more than 50% of the registry study period was during or after 2010, compared with registries where 50% or more of the study period was before 2010.

The authors suggested the differences in survival rates may relate to increased screening for PAH, particularly among people with CTDs. They noted that increased screening leads to earlier diagnosis, which could introduce a lead-time bias such that later registries would have younger participants with less severe disease. However, their analysis found that the later registries had older patients but also with less severe disease, and they suggested that it wasn’t possible to determine if lead-time bias was playing a role in their results.

Improvements in treatment options could also account for differences in survival over time, although the authors commented that only six registries in the study included patients from 2015 or later, when currently available treatments came into use and early combination therapy was used more.

“These data also support the 2018 World Symposium on Pulmonary Hypertension recommendations to initiate up-front combination pulmonary arterial hypertension therapy in majority of cases with CTD-PAH,” Khanna said.

“Still Have to Be Aggressive at Identifying the High-Risk Patients”

Commenting on the findings, Virginia Steen, MD, of the division of rheumatology at Georgetown University, Washington, said clinicians were finally seeing some significant changes over time in scleroderma-associated PAH.

“Although some of it may be just early diagnosis, I think that the combination of early diagnosis and more aggressive treatment with combination medication is definitely making a difference,” Steen said in an interview. “The bottom line is that we as rheumatologists still have to be aggressive at identifying the high-risk patients, making an early diagnosis, and working with our pulmonary hypertension colleagues and aggressively treating these patients so we can make a long-term difference.”

The authors of an accompanying editorial said the meta-analysis’ findings showed the positive impact of early combination therapy and early diagnosis through proactive screening.

“It is notable because the present analysis again confirms that outcomes are worse in CTD-PAH than in idiopathic or familial forms of PAH, the impact of treatments should no longer be regarded as insignificant,” the editorial’s authors wrote. “This is a practice changing observation, especially now that many of the drugs are available in generic formulations and so the cost of modern PAH treatment has fallen at the same time as its true value is convincingly demonstrated.”

They also argued there was strong evidence for the value of combination therapies, both for PAH-targeted drugs used in combination and concurrent use of immunosuppression and drugs specifically for PAH in some patients with CTD-PAH.

However, they pointed out that not all treatments for idiopathic PAH were suitable for patients with CTDs, highlighting the example of anticoagulation that can improve survival in the first but worsen it in the second.

The study was funded by Actelion. Six authors declared funding and grants from the pharmaceutical sector, including the study sponsor, and three authors were employees of Actelion.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

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