Patients with rheumatic disease who take anti-tumor necrosis factor drugs are four times more likely to develop mycobacterial diseases than patients not taking the drugs, and up to 14 times more likely to die from those diseases.
Anti-TNF drugs were associated with significantly increased risks for tuberculosis and nontuberculous mycobacterial disease, Dr. Kevin Winthrop and colleagues reported in the April 20 online edition of the Annals of the Rheumatic Diseases (Ann. Rheum. Dis. 2012 April 20 [doi:10.1136/annrheumdis-2011-200690]). Because most of the deaths in their retrospective study occurred in patients with nontubercular mycobacterial (NTM) disease, physicians should consider anti-TNF agents carefully in such patients, they said.
"It is currently unclear if patients with active NTM disease can safely receive anti-TNF therapy," wrote Dr. Winthrop of the Oregon Health and Science University, Portland, and his coauthors. "These cases [in this study] and the reports of others, suggest patients with NTM disease should discontinue anti-TNF therapy."
The investigators extracted their data from a large health care database, identifying 8,418 patients who took anti-TNF medications from 2000-2008. Most of these subjects had a diagnosis of rheumatoid arthritis (61%); 64% were female and 61% white.
There were 16 cases of tuberculosis and 18 cases of NTM that developed after the initiation of therapy. Among the TB cases, 69% (11) were pulmonary and 25% (4) extrapulmonary. Disease location was unknown in one patient. Rheumatoid arthritis was the most common diagnosis in this group (75%; 12 patients); one patient had Crohn’s disease, one had ulcerative colitis, and three had psoriasis. Their median age was 57 years.
Tuberculosis developed a median of 670 days after beginning the drug, but the time of onset varied widely (1-3,181 days). At the time of diagnosis, nine (44%) were taking prednisone and four (25%) were taking methotrexate; most (63%) were taking anti-TNF drugs.
Three patients (19%) died during the study period, with a median time of 74 days between disease onset and death.
Of the NTM cases, 67% (12) were pulmonary and four (22%) extrapulmonary; disease location was unknown in two patients. All of the patents had rheumatoid arthritis. Three (15%) also had psoriasis and two (11%) ankylosing spondylitis. Their median age was 68 years.
The median onset of disease was 1,027 days after beginning therapy (range 77-2,832). At the time of diagnosis nine (50%) were taking prednisone and two (11%) were taking methotrexate; most (83%) were also taking anti-TNF drugs.
Seven of this group (39%) died during the study period, with a median time of 569 days (range 21-2,127 days) between disease onset and death.
Both tuberculosis and NTM were more common in anti-TNF exposed patients than in the general population. In exposed patients, the investigators calculated a rate of 105 NTM cases and 56 tuberculosis cases per 100,000 persons per year, compared to 3 and 4 per 100,000 respectively in the general population. Incidence of both diseases was highest among those taking monoclonal antibodies (123 tuberculosis and 168 NTM cases per 100,000). Etanercept was associated with the lowest incidence – 17 tuberculosis and 35 NTM cases per 100,000.
Compared to non-infected anti-TNF users, those with tuberculosis were less likely to be white and significantly more likely to have diabetes or chronic renal disease. Those with NTM were significantly older, and more likely to be white, have gastroesophageal reflux disease, or chronic lung disease.
All of those with NTM had a diagnosis of rheumatoid arthritis, compared to 60% of uninfected anti-TNF users. NTM patients were four times more likely to have used infliximab than the uninfected group (67% vs. 33%; odds ratio, 4.0).
The investigators also stratified findings by age. In an analysis of patients 50 years and older, they found a significant association between NTM and a rheumatoid arthritis diagnosis. "All seven of the observed NTM case deaths were in this group," they noted. "NTM disease rates were substantially higher in this ... subset."
The finding of more NTM than tuberculosis cases is "not surprising," the authors wrote, "Given the low prevalence of tuberculosis in the U.S. and given that tuberculosis screening guidelines have been well-publicized in the last 5 years, making it likely that tuberculosis cases were averted in our study population."
Nevertheless, the study highlights the importance of identifying risk factors for both diseases in patients taking anti-TNF medications.
"These include chronic renal disease and diabetes mellitus for tuberculosis and chronic lung disease for NTM. These associations are important for physicians to recognize when considering anti-TNF therapy use."
The study was funded by a grant from UCB Pharmaceuticals. Dr. Winthrop has received grant money from the company as advisory board remuneration from Amgen, Genentech, and Oxford Immunotec. Coauthors also reported a number of disclosures, including links to UCB.