About 80% of scleroderma patients develop either PAH or interstitial lung disease.
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CHICAGO—Scleroderma patients with pulmonary arterial hypertension (PAH) might benefit from more aggressive therapy, an expert in the field said in a session on lung involvement in rheumatic diseases at the American College of Rheumatology’s 2015 State-of-the-Art Clinical Symposium in May.
Newer trials—the SERAPHIN trial on macitentan, GRIPHON on selexipag, and AMBITION on an ambrisentan/tadalafil combination—show potential benefits, said Hap Farber, MD, director of the Pulmonary Hypertension Center at the Boston University School of Medicine.1
PAH is considerably more serious when it’s tied to scleroderma than when it’s not—with these patients four times more likely to die from their disease, compared with idiopathic PAH, Dr. Farber said.
Studies using registry data have shown that the hemodynamics of connective tissue-related PAH are better than in the idiopathic forms, but hospitalizations and survival rates are worse in connective tissue forms.
The hemodynamic profile might lead clinicians not to pursue more aggressive treatments early on, Dr. Farber said. And he suggested that might be a mistake.
Early, Aggressive Therapy
The AMBITION combination therapy trial data “show that more aggressive up-front therapy tends to be better.
“You have fewer events farther down the road, and that may be what’s really necessary in people with scleroderma,” Dr. Farber said. “So even though we think that their hemodynamics are better, we know that their outcome is worse. So it may be that treating them with more aggressive—maybe multidrug—therapy up front, and/or prostacyclins, earlier on, is much more important. It might lead to better outcomes.”
More understanding is needed in scleroderma-associated PAH mechanisms, Dr. Farber said. It has been an understudied disease. Trials on rituximab are underway, and data from Dr. Farber’s own project, called PIONEER, on using pharmacogenomics and genomics to determine, up front, how a patient will respond to a drug should be published in the next few months.
Interstitial Lung Disease
Aryeh Fischer, MD, associate professor of medicine at the University of Colorado School of Medicine, tackled the vagaries of diagnosis in another serious consequence of connective tissue disease: interstitial lung disease (ILD). He said that all the possibilities should be considered before determining that ILD is actually connective tissue related—including infection and drug toxicity, among other causes.
Dr. Fischer
“We don’t want to jump to the conclusion that it’s CTD associated until we’ve done a thorough evaluation to exclude other etiologies,” Dr. Fischer said.
A proper assessment for CTD is crucial because the type of ILD affects both treatment and diagnosis—those with CTD-related ILD tend to do better than those with idiopathic forms.2 Plus, identifying new CTD in patients who present with ILD is fairly common—a 2009 study of 114 consecutive ILD patients found that 30% had well-defined CTD, and, for 17% of patients, the CTD diagnosis was new.3
Those whose ILD might seem “idiopathic” because of a lack of classic symptoms, could, upon a closer look, have systemic sclerosis sine scleroderma—identified by nucleolar ANA antibodies Scl-70 or Th/To antibodies, as well as subtle features of systemic sclerosis, as reported in a study he led in 2006, Dr. Fischer said.
“We tried to highlight to the pulmonary community, ‘When you all are seeing idiopathic NSIP (non-specific interstitial pneumonia), when you’re seeing idiopathic UIP (usual interstitial pneumonia), and you see those subtle features—the nucleolar ANA, the palmar telangiectasia, the puffy hands—even without skin thickening, don’t forget about the scleroderma spectrum,” he said.
Anti-synthetase syndrome can be tricky as well—it can often be a non-Jo and ANA-negative form and present as “idiopathic,” he said. In a study published in 2009, Dr. Fischer and his colleagues identified nine such non-Jo-1 patients, who were identified with different antibodies, such as PL-7 and PL-12.
As for management, Dr. Fischer said that for now, connective tissue disease-related ILD management is not evidence based, but experience based. He said mycophenolate mofetil is a common steroid-sparing option and warrants prospective study. But he emphasized that treatment with immunosuppression is only indicated in those with clinically significant, progressive interstitial lung disease.
“Remember, this is a scenario [in which] patients are dying,” Dr. Fischer said. “And we don’t do a lot of good in terms of improving their lung function. … But we are looking at stabilizing disease.”
The need for better therapies and clinical trials, Dr. Fischer said, is “desperate.”
Drug Toxicity
Kristin Highland, MD, MSCR, who has dual appointments at Cleveland Clinic’s Respiratory Institute and Orthopedics and Rheumatology Institute, said clinicians need to stay vigilant about drug-related lung toxicities, because most medications have at least some potential to be toxic to the lung.
The website, Pneumotox, should be “your friend,” because it ranks the risk of lung toxicity for each drug based on all the reports of toxicity incidence in the literature.
Ranked highest are methotrexate and TNF-alpha inhibitors—at five stars. They’re followed by rituximab at four; azathioprine, cyclophosphamide, D-penicillamine, gold, leflunomide and sulfasalazine at three; cyclosporine, hydroxychloroquine, mycophenolate and tofacitinib at two; and anakinra with one star. Abatacept is not yet listed in the database and may be the least toxic option based on what’s known now, Dr. Highland said.
Despite methotrexate’s potential for toxicity, there is no evidence that patients with preexisting pulmonary disease are at increased risk for further deterioration of lung function, Dr. Highland said.
Dr. Highland
“I believe that, if methotrexate is working to treat the joint disease, having interstitial lung disease is not a contraindication to continuing therapy,” Dr. Highland said.
As for TNF-alpha inhibitors, the other class with the worst rank, whether or not they remain a risk factor for ILD remains debatable, she said.
An important consideration when determining whether a drug has become toxic to the lung is ruling out a possible infection. Shortness of breath, unproductive cough and fever are all signs of both drug toxicity and infection.
Also, prophylaxis treatment for pneumocystis jiroveci pneumonia—the first line treatment is Bactrim—should be considered, Dr. Highland said.
“There is no such thing as a free lunch, and we have to really [weigh] the risks and benefits of these therapies in our patients,” she said. She also added a word of caution: “I think you can expect that with time we’ll start to see even more drug toxicities with some of the drugs that maybe aren’t on the radar screen yet.”
Thomas R. Collins is a freelance medical writer based in Florida.
References
- Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013 Aug 29;369(9):809–818.
- Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: Idiopathic versus collagen vascular disease-related subtypes. Am J Respir Crit Care Med. 2007 Apr 1;175(7):705–711.
- Beyeler C, Jordi B, Gerber NJ, et al. Pulmonary function in rheumatoid arthritis treated with low-dose methotrexate: A longitudinal study. Br J Rheumatol. 1996 May;35(5):446–452.
