Inflammatory Basis of Pulmonary Arterial Hypertension

Implications for Perioperative and Critical Care Medicine

Neil M. Goldenberg, M.D., Ph.D.; Marlene Rabinovitch, M.D.; Benjamin E. Steinberg, M.D., Ph.D.


Anesthesiology. 2019;131(4):898-907. 

In This Article

Pulmonary Arterial Hypertension Clinical Trials Targeting the Immune System

Given the lack of meaningful long-term improvement seen with vasodilator therapy, clinicians and scientists are attempting to test new management paradigms clinically. To that end, the predominance of clinical and preclinical evidence pointing to the importance of the immune system in pulmonary arterial hypertension has spawned a host of clinical trials. The guiding principles for such trials are outlined above with both cellular and soluble immune targets now informing clinical inquiry.

To investigate the current clinical interest in immunotherapy for pulmonary arterial hypertension, we conducted a search of active clinical trials in pulmonary arterial hypertension using the United States National Library of Medicine's clinical trials registry (Figure 2; see legend for search details). From January 1, 2015, to the present, 70 active trials met our inclusion criteria from a total of 170. Of the included trials, the largest group continues to investigate the use of vasodilator therapy (54%), which is in line with the current role of these drugs in standard of care. Notably, therapies targeting metabolism and nutrition (21%) represented the next largest group, followed closely by immunotherapies (20%). Of course, many of the tested therapies cross between these overall categories: metabolic treatments may have antiinflammatory roles, as do several traditional vasodilators. However, entirely immunologic therapeutics, such as inhibition of neutrophil elastase by elafin, the use of stem and progenitor cells, interleukin-1β antagonism with anakinra, and nuclear factor kappa-light-chain-enhancer of activated B cells inhibition by bardoxolone, are the subject of large-scale human trials.

Figure 2.

The immune system is being investigated as a potential therapeutic target in pulmonary arterial hypertension (PAH). (A) Current clinical trials investigating PAH therapies. A search was performed on for "pulmonary hypertension" from January 1, 2015, to the January 1, 2019. Limits were set to "interventional study," and adult patients only. Trial status classifications included were not yet recruiting, recruiting, enrolling by invitation, active not recruiting, and unknown status. A total of 170 studies were identified, and inclusion and exclusion categories are depicted in the flow chart. Of the 70 interventional trials included, half (54%) are investigating vasodilator therapy, 20% focus on immunological targets, and 21% are targeting metabolism and nutrition. (B) Specific examples of immune targets and therapies currently under clinical study in PAH. NCT refers to the registered Clinical Trial number, with study information available at

One patient group of particular interest is systemic sclerosis–associated pulmonary arterial hypertension, which is one of the deadliest forms of the disease.[1] Etiologically, systemic sclerosis–associated pulmonary arterial hypertension has a strong autoimmune component, driven in part by B lymphocytes. As such, a prospective, double-blind, placebo-controlled trial is currently underway testing B cell depletion with the anti-CD20 monoclonal antibody, rituximab (NCT01086540), in patients with systemic sclerosis–associated pulmonary arterial hypertension.

Soluble mediators are also being targeted. In the recently reported Canakinumab Antiinflammatory Thrombosis Outcome Study trial[55] of 10,061 patients with previous myocardial infarction and elevated C-reactive protein and on optimal medical therapy, interleukin-1β inhibition with the monoclonal antibody canakinumab reduced the incidence of repetitive atherothrombotic events, albeit with a small effect size. This study provides evidence that an antiinflammatory therapy can modify an inflammatory vascular disease in humans. Moreover, in a case report, interleukin-1β antagonism with the interleukin-1 receptor inhibitor, anakinra, was found to reverse pulmonary arterial hypertension in a single patient with Still's disease.[56] A clinical trial of anakinra is currently underway to assess exercise tolerance and safety in adults with pulmonary arterial hypertension (NCT03057028). These data will provide important insights into the potential feasibility of immunomodulation as a treatment paradigm in pulmonary arterial hypertension.

Similarly, there are case reports of pulmonary arterial hypertension improvement in patients with pulmonary hypertension secondary to inflammatory conditions treated with the interleukin-6 receptor antagonist tocilizumab.[57] A small Phase 2 trial of tocilizumab in pulmonary arterial hypertension has since been completed (NCT02676947).[58] Although the full data have not yet been reported, the drug was administered to 23 patients with a good safety profile. A larger, therapeutic study is expected.

Many of the inflammatory and immune pathways discussed in this review are under the control of the transcription factor nuclear factor κB. Nuclear factor κB activation results in the upregulation of genes encoding interleukin-6, interleukin-1β, tumor necrosis factor, and other important immunologic signals.[59] These pathways promote the recruitment and activation of immune cells in target tissues, including the lung. Multiple lines of evidence from rodent models have shown that nuclear factor κB blockade can prevent the development of pulmonary hypertension.[60] Furthermore, patients with idiopathic pulmonary arterial hypertension have activated nuclear factor κB in their lung tissue,[61] indicating a potential role for this pathway in human disease. It is therefore no surprise that neutralization of nuclear factor κB signaling is an active field of clinical investigation in pulmonary arterial hypertension. A trial is currently assessing the drug bardoxolone for the treatment of connective tissue disease–associated pulmonary arterial hypertension (NCT02657356). Bardoxolone blocks nuclear factor κB by stimulating the regulatory transcription factor nuclear factor (erythroid-derived 2)–like 2.[62] This trial will assess the effect of bardoxolone on 6-minute walk test distance in patients with connective tissue disease–associated pulmonary arterial hypertension. Another trial is currently completing a long-term follow-up in connective tissue disease–associated pulmonary arterial hypertension patients who received bardoxolone previously (NCT03068130). These studies will assess the safety profile of nuclear factor κB manipulation in pulmonary arterial hypertension and will likely stimulate further trials looking at transcription regulators in inflammation.

A final area of current clinical therapeutic inquiry involving inflammation and pulmonary arterial hypertension centers on the inhibition of neutrophil elastase. Elastase, which can also be secreted by pulmonary vascular smooth muscle cells, plays a fundamental role in the adverse remodeling of the lung vasculature in pulmonary arterial hypertension. Although the clinical use of elastase inhibitors has been limited by hepatotoxicity, the endogenous elastase inhibitor, elafin, remains a promising therapeutic possibility. Elafin, in addition to blocking the action of elastase, enhances bone morphogenic protein receptor–mediated signaling, inhibits nuclear factor κB, and dampens the innate immune system.[63] Administration of elafin in animal models reverses pulmonary arterial hypertension.[64] As such, clinical exploration of elafin as a pulmonary arterial hypertension therapy is underway, beginning with a safety and tolerance trial in healthy volunteers (NCT03522935). The position of elafin at the crossroads of so many disease-relevant pathways makes this line of investigation particularly exciting.