Mathematical modeling of the cause of tuberculosis during tumor necrosis factor blockade

Abstract

Objective. Tumor necrosis factor (TNF) blockade increases the risk of tuberculosis (TB). The purpose of this study was to use Markov modeling to examine the contributions of reactivation of latent tuberculous infection (LTBI) and the progression of new infection withMycobacterium tuberculosis to active TB due to TNF blockade. These 2 pathogenic mechanisms cannot otherwise be readily distinguished.Methods. Monte Carlo simulation was used to represent the range of reported values for the incidence of TB associated with infliximab (TNF monoclonal antibody) and etanercept (soluble TNF receptor) therapy. Iterative methods were then used to identify for each pair of incidence rates the Markov model parameters that most accurately represented the distribution of time to onset of TB as reported to the Food and Drug Administration.Results. Modeling revealed an apparent median monthly rate of reactivation of LTBI by infliximab treatment of 20.8%, which was 12.1 times that with etanercept treatment (P < 0.001). In contrast, both drugs appeared to pose a high risk of progression of new M tuberculosis infection to active TB. Progression of new infection appeared to cause nearly half of the etanercept-associated cases; it became the predominant cause of infliximab-associated cases only after the first year.Conclusion. Despite sharing a common therapeutic target, infliximab and etanercept differ markedly in the rates at which they reactivate LTBI. Confirmation of these findings will require the application of molecular epidemiologic tools to studies of TB in future biologics registries. Hidden Markov modeling and Monte Carlo simulation are powerful tools for revealing otherwise hidden aspects of the pathogenesis of TB.

Life-threatening disseminated tuberculosis as a complication of TNF-α blockade in an adolescent

“…Despite appropriate LTBI screening, patients receiving TNF blockers are at risk for active tuberculosis due to rapid progression of a newly acquired TB infection [30]. In contrast to adults, this pathway may be predominant in children, as LTBI prevalence is supposedly lower in children than in adults.…”

“…In adults, reactivation of latent TB infection (LTBI) seems to account for the majority of cases with a median time to onset of TB of 12-21 weeks after initiation of anti-TNF treatment [30]. There is good evidence that routine testing (and INH Fig.…”

Advancing host-directed therapy for tuberculosis

“…One trial of adjunctive etanercept (a soluble TNF receptor), in which patients with tuberculosis were given 25 mg twice weekly for 1 month, found etanercept to be safe and well tolerated, and there was a small benefit on sputum culture conversion and a trend towards improved chest radiography 68 . It is now recognized that etanercept is ineffective for other chronic granulomatous inflammatory conditions, such as Crohn disease and sarcoidosis 69,70 , and that it is also inefficient at reactivating LTBI (doing so at a rate estimated at 1.7% per month) 71 . These observations make it unlikely that a clinically significant benefit of etanercept would occur in larger tuberculosis trials.…”

Infectious Complications Associated with Monoclonal Antibodies and Related Small Molecules

“…Time to developing TB was likewise shorter with infliximab than with etanercept (1:1.7 to 1:4.6). Using Markov and Monte Carlo simulation computer models, Wallis (187) attempted to determine the respective contributions of the reactivation of latent TB versus new TB infection. He found that while both infliximab and etanercept presented high risks for new TB infection, the rate of reactivation of latent TB was 12 times higher for infliximab than for etanercept.…”