CHICAGO -- Rheumatologists need to be alert for pulmonary hypertension (PH) in their patients and have some understanding of its proper management, a researcher said here, because the condition is seen in a wide variety of inflammatory diseases.
Among them: scleroderma, lupus, rheumatoid arthritis, dermatomyositis, polymyositis, and Sjogren's syndrome, said Stephen Mathai, MD, of Johns Hopkins University in Baltimore, speaking at the American College of Rheumatology's 2018 State of the Art Symposium.
Although most cases of PH in the general population are in patients with cardiac and pulmonary disease -- most commonly heart failure with preserved ejection fraction, accounting for an estimated 83% of all cases -- Mathai cited data indicating that the prevalence of pulmonary arterial hypertension (PAH), a subset of PF overall, ranges from about 1% in rheumatoid arthritis patients to as much as 60% in mixed connective tissue disease.
In practice, that means that most rheumatologists will have at least several patients in their current caseloads.
The importance of recognizing the condition was illustrated in a , Mathai said, that showed markedly improved long-term survival among systemic sclerosis patients screened routinely for PAH compared with those managed under usual care (as defined at the time).
An helps considerably in screening for PH in connective tissue disease, he said. Central to DETECT, in turn, is measurement of diffusing capacity of the lung for carbon monoxide (DLCO), with a cutoff of <60% as the main flag for PH. The DETECT algorithm, which also involves several other parameters such as telangiectasis history and serum urate and NT-proBNP, outperforms guidelines issued by two European medical societies in 2009, Mathai said.
Echocardiography alone cannot diagnose PH, he emphasized. "It can only be diagnosed with right heart catheterization," he said. Screening should take place years, particularly for patients with systemic sclerosis (SSc) or mixed connective tissue disease with SSC features. Screenings can include echocardiography but must also check DLCO percentage, NT-proBNP, and include pulmonary function tests. Positive results must then be confirmed with catheterization.
PH can have a number of triggers, he noted. Mathai outlined five categories: thrombotic, left heart disease, respiratory disease, inflammatory/multifactorial, and PAH. Of those, only two -- thrombotic PH and PAH -- have approved treatments.
In PAH, these take the form of drugs targeting the endothelin, nitric oxide, and prostacyclin pathways. A dozen agents in total are available. These include endothelin antagonists such as ambrisentan (Letairis), PDE5 inhibitors such as sildenafil (Revatio). Drugs modulating prostacyclin (a member of the prostaglandin family) are the most varied, Mathai noted, with delivery via infusion, injection, inhalation, and oral administration as options.
Drug combinations are possible in PAH, and appear to make a significant dent in the otherwise poor prognosis for SSc patients with PAH. One study, published in , showed that a combination of ambrisentan and tadalafil outperformed monotherapy with either drug in reducing serious disease events (death, hospitalization for worsening PAH, disease progression, or lack of long-term clinical improvement) by approximately 15%-20%.
found benefit for the same combination in a range of biomarkers, most notably pulmonary vascular resistance, which was halved in patients with PAH associated with scleroderma. This was accompanied by a mean 11% improvement in right ventricular function, Mathai said.
For the future, he said, other treatments for SSc-related PAH might someday include the B-cell depleting agent rituximab (Rituxan); bardoxolone, an Nrf2 pathway activator; and ifetroban, a thromboxane receptor antagonist that may inhibit fibrosis.
For a number of issues related to PH in rheumatologic conditions, though, Mathai said there is no firm guidance available. For example, it's unclear whether to increase screening frequency in patients with positive initial results but negative findings on right heart catheterization. Also, there remains controversy over whether patients showing multiple signs of PH but whose DLCO does not fall below 60% should be considered to have a positive screen.
Similarly, with respect to treatment, there is no consensus on the best treatment for PAH in patients with non-SSc disease such as lupus, nor for patients with PH in functional class II (early stage). Definitions of response to therapy also remain a matter of debate, Mathai said.
Finally, Mathai urged the audience to be cautious about prescribing PAH medications. Annual costs for the currently approved drugs start at $75,000 and go up from there, reaching $250,000 for intravenous treprostinil (Remodulin), and he noted that the Choosing Wisely campaign has included PAH drug therapy in its lists of treatments that are overprescribed.
Disclosures
Mathai reported relationships with Actelion and United Therapeutics.