Paradoxical response with increased tumor necrosis factor-α levels to anti-tuberculosis treatment in a patient with disseminated tuberculosis

Abstract

It has been reported that tuberculosis (TB) worsens after cessation of tumor necrosis factor-α inhibitors and starting anti-TB treatment. Little is known about the immunological pathogenesis of this paradoxical response (PR). We report the first case of a TB patient in whom PR occurred concurrently with elevation of circulating tumor necrosis factor-α (TNFα) levels. A 75-year-old woman, who had been treated with adalimumab for SAPHO syndrome, developed disseminated TB. Soon after administration of anti-TB treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol), and after discontinuation of adalimumab, a PR occurred. Serial testing of serum cytokine levels revealed a marked increase in TNFα, and a decline in interferon-γ levels. Despite intensive treatment with antibiotics, prednisolone, noradrenaline, and mechanical ventilation, acute respiratory distress syndrome developed and she died. Thus, overproduction of TNFα after cessation of TNFα inhibitors may partially account for the pathogenesis of a PR. This supports preventative or therapeutic reinitiation of TNFα inhibitors when PR occurs. Serial monitoring of circulating inflammatory cytokine levels could lead to earlier identification of a PR.

Treatment with Tumor Necrosis Factor-α Inhibitors, History of Allergy, and Hypercalcemia Are Risk Factors of Immune Reconstitution Inflammatory Syndrome in HIV-Negative Pulmonary Tuberculosis Patients

“…Although it has been known that HIV infection is involved with the onset of IRIS, Brown et al reported that immunosuppressive condition decreased the odds ratio of IRIS onset in HIV-negative cases [12]. In recent years, case reports on TB-IRIS upon treatment with anti-TNF-α antibodies have been increased in HIV-negative cases [10,[17][18][19]. In the analysis of patients using anti-TNF-α antibodies against underlying diseases such as rheumatoid arthritis (RA) or Crohn's disease, disseminated TB, past TB infection, and corticosteroid use at the time of diagnosis have been reported as the risk factors of IRIS development [9].…”

Immune reconstitution inflammatory syndrome in non‐HIV immunosuppressed patients

“…56 A lethal case of disseminated tuberculosis after discontinuation of adalimumab because of invalidation in a patient with synovitis, acne, pustulosis, hyperostosis and osteitis syndrome has been reported, in whom paradoxical events occurred concurrently with the elevation of circulating TNF-a and a decline in IFN-c levels. 57 If tuberculosis is found during anti-TNF-a therapy, then the anti-TNF-a agent should not be withdrawn because it may lead to severe tuberculosis. TNF-a inhibitors also induce psoriasiform rashes as an adverse event in patients with Crohn's disease and RA.…”

“…Because a mild case of IRIS responds to specific treatment for the underlying pathogens, anti‐inflammatory therapies are not generally required. TNF‐α inhibitors and anti‐IL‐6 antibodies can be treatment options for patients with non‐HIV IRIS. Recently, statins have attracted attention as immunomodulators and anti‐inflammatory agents in the management of GVHD.…”

Immune reconstitution inflammatory syndrome associated with disseminated histoplasmosis and TNF-alpha inhibition

“…Treatment of IRIS can at times requires the administration of steroids. However, this approach is not always successful and there have been reports of patients who present with a severe inflammatory response during the treatment of TB or fungal infections that appear to be steroid-refractory and require other treatment options [2], [3], [4].…”