Non tuberculosis mycrobacteria- risk using anti tnf

Tumor necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine that is integral to host defense against granulomatous mycobacterial and fungal infections.36-38 Medications that target the TNF pathway are the cornerstone of treatment for autoimmune inflammatory conditions including rheumatoid arthritis, psoriasis, and Crohn's Disease. Five TNF-alpha inhibitors are currently approved: infliximab, adalimumab, golimumab, and certolizumab are anti-TNF alpha monoclonal antibodies, and etanercept is a soluble receptor fusion protein.39 In a U.S. study in new users of inflixamab, etanercept, or adalimumab anti-TNF therapy, the overall rates of NTM disease were five to tenfold higher than disease rates seen in the unexposed background RA and general populations and more common than TB.15 The drug-specific incidence rates per 100,000 patient-years and 95% confidence intervals were 35 (1-69) for etanercept, 116 (30-203) for infliximab, and 122 (3-241) for adalimumab. In South Korea a higher incidence of NTM disease of 230 per 100,000 patients was reported in two separate hospital-based reviews of 509 and 1165 patients treated with TNF antagonists.40,41 In a review of U.S. Food and Drug Administration MedWatch reports, just over half (55%) of NTM cases were pulmonary.25 In the U.S. and South Korea, 70% to 100% of NTM infections were in patients with rheumatoid arthritis who frequently have associated underlying lung disease including bronchiectasis and interstitial lung disease.15,25,41,42

Other biologic agents used in this setting include rituximab (anti-CD20 monoclonal antibody), abatacept (T-cell costimulator modulator), tocilizumab (anti-IL-6 monoclonal antibody), and ustekinumab (anti-IL-12 monoclonal antibody). There is a theoretical increased risk of NTM infection with these agents, but very little safety data exists and further study is required.39 At the present time, the evidence of NTM risk is limited to small case series of NTM disease in patients treated with rituximab (2 cases) and tocilizumab (4 cases, 3 were also taking prednisolone +/− tacrolimus and 2 had prior NTM infection).43,44 It should be noted that rituximab has been used as an adjunct to successfully treat otherwise recalcitrant chronic NTM infections in patients with auto-antibody states involving IFN-


Diagnosis, Prevention, and Treatment
Prospective screening is not recommended for any of immunosuppressed groups, unlike tuberculosis where there are clear benefits to screening for latent infection prior to the initiation of biologics and immunosuppressive therapy.23 However, some groups should be considered for further clinical work-up prior to initiation of biologic therapy. Patients with chronic cough that cannot be explained by usual causes should be considered for further workup for pulmonary NTM, including CT imaging and respiratory sampling.

Treatment is described in Table 3, and is species specific requiring antimicrobial susceptibility for all except MAC, unless macrolide-resistant MAC is suspected.23 When possible, decreasing or dropping immunosuppressive medications likely improves the likelihood of successful treatment.38 Non-biologics such as methotrexate should be considered, or second-line therapies such as abatacept or tocilizumab which are currently considered lower risk.15 Outcomes of treatment for pulmonary disease are variable. Case fatality rates range from <10% to 15% in U.S. studies with short term follow up. Winthrop et al. reported a higher case fatality rate of 39% with a median of 569 days (range 21-2127) between diagnosis and death. Evidence from a small Japanese case series suggests that pulmonary NTM disease in rheumatoid arthritis patients who stop biologics have generally positive outcomes with NTM treatment, or stable NTM disease with no treatment, and deaths were related to underlying lung disease including pulmonary aspergillosis and intersitial lung disease.43,47

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The drug-specific incidence rates per 100,000 patient-years and 95% confidence intervals were 35 (1-69) for etanercept, 116 (30-203) for infliximab, and 122 (3-241) for adalimumab.

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The calculation of events per patient-year(s) is the number of incident cases divided by the amount of person-time at risk. The calculation can be accomplished by adding the number of patients in the group and multiplying that number times the years that patients are in a study in order to calculate the patient-years (denominator). Then divide the number of events (numerator) by the denominator.

Example: 100 patients are followed for 2 years. In this case, there are 200 patient-years of follow-up.
If there were 8 myocardial infarctions in the group, the rate would be 8 MIs per 200 patient years or 4 MIs per 100 patient-years.
The rate can be expressed in various ways, e.g., per 100, 1,000, 100,000, or 1 million patient-years. In some cases, authors report the average follow-up period as the mean and others use the median, which may result in some variation in results between studies.

Another example: Assume we have a study reporting one event at 1 year and one event at 4 years, but no events at year 2 and 3. This same information can be expressed as 2 events/10 (1+2+3+4=10) years or an event rate of 0.2 per person-year.

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