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Asthma is a chronic inflammatory disease that constitutes one of the leading causes of chronic obstructive pulmonary disease(1). Most patients with moderate or severe disease are treated with inhaled corticosteroids, but many patients have refractory disease(2). Treatment options for these refractory patients are limited; there are emerging data on the effectiveness of tumor necrosis factor alpha (TNF)α inhibitors(3–5), but there are no long-term studies.
In this report, we studied a large prospective RA cohort, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), to identify a case series of patients with both RA and asthma, who were treated with TNFα inhibitors. We aimed to determine whether asthma symptoms correlated with TNFα inhibitor therapy.
The study population consisted of patients with RA treated at the Brigham and Women’s Hospital in Boston, MA, who were enrolled in BRASS, a longitudinal cohort with 933 patients enrolled by October of 2006. The diagnosis of RA was made by the treating physician based upon the revised American College of Rheumatology criteria(6). Each patient was evaluated by a physician at baseline and every 12 months; in addition, every six months, participants completed questionnaires that included items regarding functional status, comorbid conditions, RA medicine use, non-RA medicine use, and review of symptoms, including wheezing. Eligible patients included those who reported wheezing and who also started or stopped a TNFα inhibitor after baseline, during 18 months of follow-up. Switching TNFα inhibitors was not considered stopping. The decision to use TNFα inhibitors was made by the attending rheumatologist, if the patient had active disease despite treatment with one or more conventional disease-modifying anti-rheumatic drugs. In this study, patient-reported wheezing was taken as a proxy for asthma, without external validation; we excluded patients with self-reported or physician-diagnosed interstitial lung disease or emphysema. The IRB that approved of the BRASS study also approved all aspects of the current study.
There were 933 patients in the BRASS cohort; 123 (13%) reported wheezing. Among these patients, 19 (15.4%) initiated or discontinued TNFα inhibitor therapy during the first 18 months of the study. Two of these 19 were enrolled in a double-blinded study involving abatacept, two had interstitial lung disease, one had emphysema, and data were incomplete on two. These seven patients were excluded from the study, leaving 12. Of these 12, 9 (75%) were female. Their median age at enrollment was 58 years, and the median disease duration was 12 years. Seven (58%) were RF-positive. Six reported prior history of smoking, but only one patient (# 2) reported smoking at baseline. This patient’s smoking status did not change during the study.
Data on use of inhaled corticosteriods and reports of wheezing, as well as use of TNFα inhibitor therapy and corticosteroids for all 12 patients are shown in Figure 1. Etanercept was used by patients 1, 2, 9, 11, and 12, infliximab by patients 3, 4, and 10, and adalimumab by patients 5, 6, 7, and 8. Nine RA patients began use of a TNFα inhibitor during the study period and continued to use them at the end of the study period (Figure 1a). Eight of them (1 – 7, 9) reported wheezing during the six month period before or coincident with starting the TNFα inhibitor, while the other developed wheezing during the six months after initiation of TNFα inhibitor therapy; none of the nine reported wheezing at the end of the study period. Three patients discontinued a TNFα inhibitor during the study period (Figure 1b), all of whom reported wheezing following discontinuation. The TNFα inhibitor was restarted in patient 11, whose wheezing subsequently resolved.
Data on use of oral corticosteroids are also shown in Figure 1; these were prescribed by the rheumatologist to treat the patient’s RA. Among the five patients who started TNFα inhibitors and also used corticosteroids (Figure 1a), the steroid dose was decreased after initiation of the TNFα inhibitor, yet wheezing improved in all of them, suggesting that the improvement in wheezing was not due to concomitant oral corticosteroid therapy. In contrast, among the three who discontinued TNFα inhibitors (Figure 1b), one had an increase in the corticosteroid dose, another had a decrease, and a third never used.
We reviewed the records of 12 patients with RA who either started or discontinued TNFα inhibitor therapy and who also reported a history of wheezing; all of them were followed prospectively for 18 months. We found that all nine of the patients who began TNFα inhibitors and reported wheezing during the 18-month study period demonstrated resolution by the end of the follow-up period. In contrast, of the three patients who discontinued TNFα inhibitor therapy and reported wheezing during the study period, the wheezing developed in all three cases after discontinuing the medicine.
This study has important limitations. The most important is its non-randomized, observational design, and the small number of patients studied, which precludes statistical analysis or evaluation of potential confounding factors. In addition, we were unable to confirm that the etiology of the wheezing was due to asthma; however, self-reported wheezing has greater than 90% specificity for asthma (7, 8). Further, most other causes of wheezing, such as chronic infections and congestive heart failure, serve as contraindications to TNFα therapy and might be expected to worsen as a result of such therapy. Finally, pulmonary function tests were not performed in any of these patients, so we were not able to confirm improvements in wheezing. Despite these limitations, this study does have several strengths including the long duration of follow-up, detailed information on medicine use and respiratory symptoms, patient and provider lack of awareness of our hypothesis regarding TNFα inhibitors and asthma, and the consistency of our findings.
Thus, this case series adds to the growing body of literature on the potential role of TNFα inhibition in patients with asthma. Large randomized controlled studies are needed to confirm these findings.
Sources of support:
Dr. Solomon receives salary support from the NIH, the Arthritis Foundation, and the Engalitcheff Arthritis Outcomes Initiative. He has also received research grants in the last three years from Merck, Pfizer, Procter & Gamble, and Savient.
JF Simard is supported by the Arthritis Foundation, Doctoral Dissertation Award.
Dr. Karlson is supported by NIH grants R01 AR49880, and K24 AR0524-01.
Dr. Weinblatt receives grant support from Amgen and Abbott and consultancy fees from Amgen, Abbott, Centocor, UCB, and Wyeth.
Dr Shadick receives salary support from the NIH, and the Centers for Disease Control. She has also received research grants in the last three years from GlaxoSmithKline, Millennium Pharmaceuticals, Biogen Idec, Dow Chemical Corp, Amgen and the Bristol Myers Squibb Foundation.
We would like to thank the study participants in the BRASS cohort and their rheumatologists who have donated their efforts to this work.