The Mirage of Individualized Therapy in the United States: Barriers in Pulmonary Hypertension Due to Sickle Cell Disease and Sarcoidosis

Pulmonary hypertension (PH) is a highly morbid condition caused by a wide variety of etiologies, and its incidence and prevalence appear to be increasing. These etiologies are systematically classified in the World Symposium on Pulmonary Hypertension (WSPH) group framework, which has been serially revised and codified in international consensus guidelines (1, 2). The field of PH has recently been a hotbed of intense research, with the introduction of numerous therapeutic options efficacious in certain groups of the disease, primarily pulmonary arterial hypertension (WSPH group 1) and chronic thromboembolic PH (WSPH group 4).

Despite these advances in treatment, many etiologies of PH are intrinsic complications of rare diseases with few or no large-scale clinical studies to guide their management. This is most pronounced within WSPH group 5, “pulmonary hypertension with unclear and/or multifactorial mechanisms,” which includes sickle cell disease (SCD) and sarcoidosis. These are orphan diseases in which associated PH is heterogeneous and unpredictable, creating significant challenges in running large placebo-controlled trials. Lacking robust clinical data to guide treatment, societal recommendations emphasize judicious individualized therapy managed by a multidisciplinary team with PH expertise. The official American Thoracic Society guidelines for PH in SCD “suggest targeted [pulmonary arterial hypertension] therapy with either a prostacyclin agonist or an endothelin receptor antagonist” in “carefully selected” patients with precapillary PH (3). The World Association of Sarcoidosis and Other Granulomatous Disease statement on PH in sarcoidosis features an algorithm for precapillary disease suggesting consideration of various pulmonary vasodilators on a case-by-case basis (4).

However, in the United States, the prospects of pursuing such individualized therapy in these types of PH are bleak. Because of the lack of robust evidence to guide the use of pulmonary vasodilators in these two diseases, and indirectly their classification within group 5, rejected authorizations for these expensive PH therapies are routine. These rejections are based on the lack of U.S. Food and Drug Administration approval for these drugs for SCD or sarcoidosis, even when they have shown favorable safety data and are often prescribed off label in patients with precapillary disease (5). Paying for most of these medications without insurance coverage would be unrealistic even for the wealthy.

Under this system, approval for medication for any PH classified under the umbrella of WSPH group 1 disease is comparatively ensured, regardless of subtype, whereas use in group 5 is consistently rejected. This administrative nuance results in an inability to provide the individualized, multidisciplinary care that is used more regularly in other countries. A study of a cohort of French patients with SCD and PH described a variety of therapies in use, including 53% of patients’ receiving pulmonary vasodilators as off-label therapy, in addition to red-cell exchange and interventions for chronic thromboembolic disease (6). Similar access to therapy for sarcoidosis-associated PH (SAPH) was represented in a study of 126 patients with SAPH from the French Pulmonary Hypertension Registry (7). In the United States, as neither etiology carries the group 1 designation needed for realistic insurance approval, medication access issues consistently prevail over clinician expertise and societal guidelines, and rates of pulmonary vasodilator use in both groups are assuredly lower.

This situation has resulted in unintended inequities in care for patients with PH in the United States. SCD overwhelmingly affects African Americans, who are statistically more likely than non–African Americans to develop PH as a result (8). SCD is strongly linked to high degrees of socioeconomic vulnerability, with two-thirds of births with SCD occurring in areas of high social vulnerability (9). In the United States, sarcoidosis has a strong predilection for African Americans, especially young women, with the interplay among genetic, socioeconomic, environmental factors suggested as a factor to explain this finding (10). PH in either group has a profound impact on survival. The presence of PH confirmed by right heart catheterization or suggested by echocardiography significantly raised mortality in an SCD cohort, and patients with SCD and PH also appear to be at a higher risk of early death of PH with relatively modest elevations in pulmonary pressures (11, 12). The presence of SAPH is an independent predictor of mortality compared with patients with sarcoidosis who do not have PH (13). As complex as the pathways for underlying PH may be in either etiology, this is clearly a population wanting for therapeutic options.

There is no doubt that high-quality prospective data regarding the use of pulmonary vasodilators in these two diseases are still sorely needed. Data from registry cohorts such as those described above are limited in their ability to illustrate the highly individual needs of these often profoundly complex patients. Indiscriminate use of these medications in unproven settings without right heart catheterization should not be encouraged, and safety should be prioritized. The use of pulmonary vasodilators may have unforeseen pitfalls, as observed in the Walk-PHaSST (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) trial, in which the rate of hospitalization for pain increased with sildenafil, albeit at final doses higher than those in typical contemporary use. Myalgias and back pain are now better understood as a class effect of phosphodiesterase 5 inhibitors, and no significant increases in acute chest syndrome or laboratory derangements were observed in the trial (14). Subsequent use of the soluble guanylate cyclase stimulator riociguat showed no such adverse effects in patients with SCD (15). Despite these and other available data, the appearance of large, robust trials in PH due to sarcoidosis or SCD may be many years away. In the meantime, individualized therapy for precapillary PH in the United States remains a mirage given the inability to prescribe these medications for off-label use.

We assert strongly that under the banner of individualized therapy, patients with these group 5 diseases who have evidence of precapillary PH and elevated pulmonary vascular resistance should have access to group 1 and group 4 pharmacotherapy. Presently, the chance to one day use these medications for these conditions comes down to a waiting game between the appearance of the right data and an substantial drop in drug costs. Pending either one, it is our most vulnerable and disenfranchised patients who are caught in the middle.