In the case of many rare diseases, researchers are still working to find a cure. This often includes identifying signaling pathways that drive disease progression then trying to figure out how to silence these pathogenic pathways. Unfortunately, a variety of pathways often contribute to the pathophysiology of a disease, and hence the quest to find a cure is rarely as simple as shutting down one problematic pathway. 

Indeed, one could argue that rare diseases remain difficult to treat because a number of strands in signaling pathways intertwine to produce the disease phenotype. Many scientists are still in pursuit of the “holy grail”—in this case, an on-and-off switch button that shuts down a disease completely—but in practical terms, the existence of a mechanism so simplistic is highly unlikely.

Perhaps the best way to get faster results is to invest research into understanding each pathogenic signaling pathway and how they can be safely switched off by one or a combination of drugs. But, even with the hype around so-called “precision therapies,” researchers urge a word of caution.


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“Multi-factorial [pharmacokinetic] interactions cannot necessarily be predicted based on the effect of each factor alone,” Bechtold and Clarke wrote in Expert Opinion on Drug Metabolism & Toxicology. “Thus, it is critical that the potential combined effects are accounted for and utilized in prediction models and clinical trials.” 

PAH as a Connective Tissue Disease 

In Pharmacology and Therapeutics, Zhao and colleagues took a slightly different approach when investigating treatment strategies for pulmonary arterial hypertension (PAH), starting with the idea that PAH is a connective tissue disease (CTD). The authors of the study quoted Chinese research that demonstrated PAH is predominantly associated with CTDs such as systemic lupus erythematosus (SLE), systemic sclerosis, or primary Sjögren’s syndrome. 

Read more about PAH etiology 

There are a few key features of PAH. First is inflammation. The dysregulation in the immune system can cause the release of immune cells that greatly drive PAH progression. Abnormal circulating levels of some cytokines and chemokines are associated with the pathogenesis of PAH. 

In addition, hypoxia and oxidative stress cause endothelial dysfunction, which results in the hyperproliferation of the extracellular matrix, one of the key features of PAH. 

As of now, the mainstay of PAH treatment involves immunosuppressive therapies (such as glucocorticoids). Secondary therapies for PAH have been largely unchanged over the years. However, viewing PAH as a form of CTD focuses the minds of researchers on other pathogenic pathways that may be worth exploring. 

“Extensive efforts have been made accordingly to develop novel effective strategies in CTD-PAH targeting pathogenic pathways, including [bone morphogenetic protein receptor type 2 (BMPR2)] signaling,” Zhao et al wrote. “A recent study of our group implied that deficiencies of BMPR2 signaling and proinflammatory factors together contribute to the development of PAH in SLE.” 

The hard pill to swallow is that despite decades of research, we are still at the stage of providing symptomatic improvements to patients with PAH, instead of reversing pulmonary vascular remodeling for good. PAH is still an incurable disease with a poor prognosis. Therefore, in addition to seeing PAH as a CTD and exploring treatment opportunities likewise, there is an urgent need to further identify underlying disease pathogenesis in order to develop therapies that target them. 

To this day, the main biomarkers of PAH that are under serious investigation are brain natriuretic peptide (BNP) and N-terminal prohormone of BNP. In Mayo Clinic Proceedings, Mandras and colleagues wrote, “Both markers correlate with myocardial dysfunction, provide prognostic information at diagnosis and during follow-up, and have been incorporated into risk scores.” 

Not Far Enough 

In my opinion, the treatment paradigm of PAH is still too much skewed towards symptomatic relief. For example, patients with PAH are often managed for comorbidities, such as sleep apnea and chronic obstructive pulmonary disease. In addition, supportive therapies, such as oxygen, diuretics, and the management of heart failure are also initiated. Oral anticoagulation is often given prophylactically. 

Although managing comorbidities of PAH can indeed do wonders, they still do not bring us an inch closer to finding a cure for the disease. Increasingly, targeted therapies are used in PAH, with lung transplantation being the measure of last resort. 

Read more about PAH treatment 

Let’s get to the heart of the matter before we wrap up this article: How much closer are we today from a cure of PAH compared to a decade ago? The answer is, predictably, complicated. Comorbidities that negatively affect vital signs require immediate attention, and that mostly consumes the time of attending physicians. If a PAH patient has deteriorated significantly, palliative care should be considered. 

In other words, there is simply not much that can be done in the hustle and bustle of ward life, and in this case we have no choice but to rely on our colleagues in the lab to carry out careful research that might one day lead to a breakthrough in the way we approach PAH. In good-faith partnership, we can only hope to see the end of PAH in our lifetime.

Reference

Bechtold B, Clarke J. Multi-factorial pharmacokinetic interactions: unraveling complexities in precision drug therapyExpert Opin Drug Metab Toxicol. 2021;17(4):397-412. doi:10.1080/17425255.2021.1867105

Mandras SA, Mehta HS, Vaidya A. Pulmonary hypertension: a brief guide for cliniciansMayo Clin Proc. 2020;95(9):1978-1988. doi:10.1016/j.mayocp.2020.04.039

Zhao J, Wang Q, Deng X, et al. The treatment strategy of connective tissue disease associated pulmonary arterial hypertension: evolving into the futurePharmacol Ther. 2022;108192. doi:10.1016/j.pharmthera.2022.108192