Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept

OBJECTIVE: Two tumor necrosis factor alpha (TNFalpha) antagonists were recently licensed in the US. Infliximab was licensed in 1998 for the treatment of Crohn's disease (CD), and since 1999, it has been licensed in combination with methotrexate for treatment of rheumatoid arthritis (RA). Etanercept was licensed in 1998 for treatment of RA and, more recently, for juvenile RA and psoriatic arthritis. Because of potential immunosuppression related to use of anti-TNFalpha agents, we sought to identify postlicensure cases of opportunistic infection, including histoplasmosis, in patients treated with these products. METHODS: The US Food and Drug Administration's (FDA) passive surveillance database for monitoring postlicensure adverse events was reviewed to identify all reports received through July 2001 of histoplasmosis in patients treated with either infliximab or etanercept. RESULTS: Ten cases of Histoplasma capsulatum (HC) infection were reported: 9 associated with infliximab and 1 associated with etanercept. In patients treated with infliximab, manifestations of histoplasmosis occurred within 1 week to 6 months after the first dose and typically included fever, malaise, cough, dyspnea, and interstitial pneumonitis. Of the 10 patients with histoplasmosis, 9 required treatment in an intensive care unit, and 1 died. All patients had received concomitant immunosuppressive medications in addition to infliximab or etanercept, and all resided in HC-endemic regions. CONCLUSION: Postlicensure surveillance suggests that acute life-threatening histoplasmosis may complicate immunotherapy with TNFalpha antagonists, particularly infliximab. Histoplasmosis should be considered early in the evaluation of patients who reside in HC-endemic areas in whom infectious complications develop during treatment with infliximab or etanercept.     

Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor α antagonists

Objective

To describe a group of patients who were treated with tumor necrosis factor α (TNFα) antagonists and who developed coccidioidomycosis, and to test the hypothesis that patients with inflammatory arthritis receiving TNFα antagonist therapy are at higher risk for developing symptomatic coccidioidomycosis.

Methods

Cases of coccidioidomycosis were identified and reviewed from among patients receiving TNFα antagonist therapy from May 1998 through February 2003 in 5 practices within the areas endemic for coccidioidomycosis (Arizona, California, and Nevada). In addition, the relative risk of developing symptomatic coccidioidomycosis was calculated in patients with inflammatory arthritis who were receiving treatment with infliximab, in comparison with patients with inflammatory arthritis who were not receiving infliximab, from January 2000 to February 2003 in a single medical center.

Results

Thirteen cases of documented coccidioidomycosis were associated with TNFα antagonist therapy. Twelve cases were associated with the use of infliximab and 1 case with etanercept. Among the cohort of patients from a single medical center, 7 of the 247 patients receiving infliximab and 4 of the 738 patients receiving other therapies developed symptomatic coccidioidomycosis (relative risk 5.23, 95% confidence interval 1.54–17.71; P < 0.01).

Conclusion

Patients with inflammatory arthritis who are undergoing treatment with infliximab appear to be at higher risk for developing symptomatic coccidioidomycosis as compared with those not receiving infliximab.

     

Interleukin‐6 receptor shedding is enhanced by interleukin‐1β and tumor necrosis factor α and is partially mediated by tumor necrosis factor α–converting enzyme in osteoblast‐like cells

Objective

Interleukin‐6 (IL‐6) and soluble IL‐6 receptor (sIL‐6R) activation of gp130 represents an alternative pathway for osteoclast development in inflammatory conditions. The goal of the present study was to investigate changes in sIL‐6R levels in response to the inflammatory cytokines IL‐1β and tumor necrosis factor α (TNFα) and to determine the role of TNFα‐converting enzyme (TACE) in this process.

Methods

Levels of sIL‐6R in the culture media of MG63 and SAOS‐2 osteoblast‐like cell lines after exposure to various agents were determined by immunoassay. TACE protein levels were measured by Western immunoblotting. Cells were transfected with small interfering RNA (siRNA) or with an expression plasmid for IL‐6R and TACE to determine the potential involvement of TACE in IL‐6R shedding.

Results

IL‐1β and TNFα increased the levels of sIL‐6R in the culture media of MG63 osteoblast‐like cells. This effect was not influenced by cycloheximide or 5,6‐dichlorobenzimidazole riboside but was markedly inhibited by the calcium chelator EGTA and by the TACE and matrix metalloproteinase inhibitor hydroxamate (Ru36156). IL‐1β and TNFα had no influence on the alternatively spliced form of IL‐6R RNA. Levels of sIL‐6R were reduced when MG63 cells were transiently transfected with TACE siRNA. Transfection of SAOS‐2 cells with expression plasmids for IL‐6R and TACE produced a dose‐dependent increase in sIL‐6R levels.

Conclusion

IL‐1β‐ and TNFα‐mediated induction of IL‐6R shedding in osteoblast‐like cells is at least partly dependent on TACE activation.

     

Detection of tumor necrosis factor α but not tumor necrosis factor β in rheumatoid arthritis synovial fluid and serum

Synovial fluids from 6 of 12 patients with rheumatoid arthritis (RA) and from 3 of 11 patients with reactive arthritis contained measurable levels of tumor necrosis factor α (TNFα). Seven of 12 sera from RA patients contained TNFα, while only 1 of those from reactive arthritis patients was positive. Gamma-inter-feron was detected in the synovial fluids and sera of only the RA patients. Tumor necrosis factor β was not detected in any sera or synovial fluids. RA patients with detectable TNFα had higher erythrocyte sedimentation rates and synovial fluid leukocyte counts.     

Successful tumor necrosis factor α blockade treatment in therapy‐resistant sarcoidosis

Sarcoidosis is a multisystemic disorder histologically characterized by a noncaseating granulomatous inflammatory process. The etiology remains unclear, but tumor necrosis factor α seems to play a crucial role. Herein we describe a patient with severe sarcoidosis involving the lung and liver. Various treatment regimens with azathioprine, methotrexate, cyclophosphamide, and pentoxifylline failed to control the disease. Therefore, salvage therapy with infliximab was commenced. Arthritis and pulmonary and liver involvement improved. We were then able to taper the corticosteroid treatment to a lower‐dose regimen with no need for additional immunosuppressive treatment. To our knowledge, this is the first reported case of successful treatment of multiorgan sarcoidosis that was previously resistant to conventional therapy.     

Interleukin‐1 and tumor necrosis factor α blockade treatment of experimental polymyositis in mice

Objective

Histologic studies of the muscles suggest that cytokines are involved in inflammatory myopathy. The therapeutic effects of cytokine blockade are controversial, with anecdotal reports of clinical efficacy. The aim of this study was to discern the significance of interleukin‐1 (IL‐1) and tumor necrosis factor α (TNFα) as therapeutic targets in polymyositis (PM) by studying their involvement and the effects of their blockade in C protein–induced myositis (CIM), a murine model of PM.

Methods

C57BL/6 mice were immunized with recombinant skeletal C protein fragments to induce CIM. The expression of IL‐1 and TNFα in the muscles of mice with CIM was detected using immunohistochemical and real‐time polymerase chain reaction analyses. After the onset of myositis, the mice with CIM were treated with recombinant IL‐1 receptor antagonist (IL‐1Ra), anti–IL‐1R monoclonal antibody, recombinant TNF receptor (p75)–fusion protein (TNFR‐Fc), or anti‐TNFα monoclonal antibody. The muscles were examined histologically for the severity of myositis.

Results

IL‐1α– and TNFα‐positive macrophages were observed in the muscle tissue of mice with CIM as early as 7 days after immunization. IL‐1α, IL‐1β, and TNFα expression in the muscles increased as the severity of myositis peaked, at both the messenger RNA and protein levels. Continuous subcutaneous delivery of IL‐1Ra resulted in suppression of established CIM. Intermittent delivery (1‐day intervals) of anti–IL‐1R monoclonal antibody suppressed myositis, while intermittent delivery of IL‐1Ra did not suppress myositis. Treatment with anti‐TNFα monoclonal antibody and with TNFR‐Fc also reduced the severity of CIM.

Conclusion

IL‐1 and TNF blockade ameliorated CIM after disease onset and should potentially be a new strategy for the treatment of inflammatory myopathy. As IL‐1 blockade, treatment with anti–IL‐1R monoclonal antibody appeared more feasible than the other approaches.