Identifying “super-responders” could significantly enhance outcomes in patients with systemic sclerosis-associated pulmonary arterial hypertension, researchers say | Cleveland Clinic Journal of Medicine
Presenter: Sumbal Wajid, MBBS, Albany Medical Center, Albany, NY
Tailoring therapies based on individual responses and genetic profiles could promote sustained treatment benefits, improved symptoms, and longer survival in patients with systemic sclerosis-associated pulmonary arterial hypertension, according to authors of a recent literature review on the topic.
Improved recognition of “super-responders” to treatment could lead to substantial improvements in treatment outcomes among patients with systemic sclerosis-associated pulmonary arterial hypertension, according to authors of a recent literature review.
Better identification of these super-responders, or patients who experience better-than-average improvements following treatment, may yield advances in precision medicine and continued survival benefits, the authors reported in a poster presentation of the review at CHEST 2024.
Improving outcomes in this disease population is critical, as despite recent treatment advances, pulmonary arterial hypertension remains a leading cause of death in systemic sclerosis, said author Sumbal Wajid, MBBS, of Albany Medical Center, in Albany, NY.
Notably, patient responses to different therapies vary significantly, Dr. Wajid said in an interview.
“Recognizing the variability in treatment response among patients with systemic sclerosis-associated pulmonary arterial hypertension is crucial,” said Dr. Wajid. “Tailoring therapies based on individual responses and genetic profiles could significantly enhance patient outcomes.”
In their recent review, Dr. Wajid and co-authors highlight current literature on super-responders, and propose further studies to elucidate their characteristics, which they say could offer a “meaningful avenue” for advancing treatment of systemic sclerosis-associated pulmonary arterial hypertension.
They conducted a search of published literature through 2024 to identify review articles, observational studies, and clinical trials using keywords such as “pulmonary arterial hypertension,” “super-responders,” “scleroderma,” and “systemic sclerosis.” In total, 12 relevant publications were identified.
In those publications, super-responders were typically defined as those who experience greater clinical improvements than the population mean following treatment in specific hemodynamic measures, functional status indicators, or survival metrics.
Specifically, those criteria with substantial between-patient variability have included pulmonary artery pressure, pulmonary vascular resistance, right atrial pressure, cardiac index, 6-minute walking distance, New York Heart Association and World Health Organization functional class, and long-term survival.
According to the review authors, the variability was first observed in patients with pulmonary arterial hypertension who had reductions in pulmonary artery pressure during acute vasodilator response testing with calcium channel blockers. Heterogeneity of responses has also been observed for endothelin-receptor antagonists, as shown by decreases in pulmonary vascular resistance and increases in cardiac index. In addition, variations in response by sex have been observed among patients receiving phosphodiesterase-5 inhibitors.
A patient’s genetic profile may help predict super-response to both calcium channel blockers and endothelin-receptor antagonists, as recent studies have identified genomic links with response to these drugs. However, according to the authors, to date there are no molecular markers to identify super-responders to phosphodiesterase-5 inhibitors.
The concept of super-responders to prostacyclin therapy has not yet been recognized, according to the authors. However, variable responses have been observed in clinical trials of prostacyclin. Specifically, some patients have experienced near-normalization of hemodynamics, long-term survival, and in some cases, patients have been transitioned from intravenous prostacyclin to oral therapies.
While phosphodiesterase-5 inhibitors and endothelin-receptor antagonists improve pulmonary hemodynamics, only prostacyclin therapy has been proven to enhance survival in randomized clinical trials, including those enrolling patients with connective tissue disease and systemic sclerosis-associated pulmonary arterial hypertension, the authors note in their discussion of super-responders.
Future research should focus on exploring the genetic and molecular mechanisms underlying the super-responder phenomenon, which could lead to targeted therapies and improved patient stratification, Dr. Wajid said in the interview.
Specifically, the role of epithelial progenitor cells as potential surrogate markers to measure response to prostacyclin therapy needs to be studied.
Some recent studies suggest that prostacyclin therapy may influence the vascular remodeling process through mechanisms that include recruitment of epithelial progenitor cells into the pulmonary vasculature, according to Dr. Wajid and co-authors.
Defective epithelial progenitor cells have also been implicated in the pathogenesis of systemic sclerosis, which may explain survival benefits seen with prostacyclins in systemic sclerosis-associated pulmonary arterial hypertension, they added.
“Identifying super-responders in systemic sclerosis-associated pulmonary arterial hypertension could not only yield sustained benefits but also improve symptoms and survival rates,” Dr. Wajid said.
Disclosures:
Dr. Wajid and co-authors reported no relationships relevant to this work.
Suggested Reading:
Halliday SJ, Hemnes AR. Identifying "super responders" in pulmonary arterial hypertension. Pulm Circ 2017; 7(2):300–311. doi: 10.1177/2045893217697708.