Proinflammatory action of the antiinflammatory drug infliximab in TNF-receptor associated periodic syndrome

Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK.
Arthritis & Rheumatology (Impact Factor: 7.76). 02/2009; 60(2):619-25. DOI: 10.1002/art.24294
Source: PubMed


Tumor necrosis factor receptor (TNFR)-associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory condition caused by mutations in the TNFRSF1A gene. Unlike other autoinflammatory diseases in which anti-TNF therapy is largely a successful treatment option, therapy with the anti-TNF drug infliximab is often ineffective in patients with TRAPS. Moreover, in certain cases, infliximab actually triggers severe episodes of inflammation. The aim of this study was to elucidate the mechanisms underlying such a reaction.
Peripheral blood mononuclear cells (PBMCs) were obtained from patients with TRAPS. Both caspase 3 activity and NF-kappaB subunit activity were determined by enzyme-linked immunosorbent assay. Cytokine secretion was assessed using a specific customized human multiplex bead immunoassay kit.
Unlike findings in controls, cells from a family of 9 patients, all of whom carried the T50M mutation in TNFRSF1A, failed to respond to infliximab through proapoptotic induction of caspase 3 activity. Instead, we observed enhanced antiapoptotic c-Rel subunit activity, accompanied by a significant increase in secretion of the proinflammatory cytokines interleukin- 1beta (IL-1beta), IL-1 receptor, IL-6, IL-8, and IL-12.
Altered extracellular conformation of TNFRI, resulting from the T50M mutation in TNFRSF1A, results in failure of PBMCs to induce an apoptotic response to infliximab. We hypothesize that failure to shed infliximab-bound TNF/TNFRI from the cell surface of cells from patients with the T50M mutation triggers c-Rel activation, and that this leads to a marked increase in cytokine secretion and an increased proinflammatory response. In light of these findings, we strongly advise caution when prescribing infliximab as anti-TNF therapy to patients with TRAPS.

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    • "Etanercept has been proven to induce a good disease control, although in some cases it gradually loses efficacy [45, 52–54]. Noteworthy, infliximab and adalimumab may paradoxically induce a typical acute inflammatory attack in TRAPS patients for reasons only partially understood [54, 55]. On the contrary, anti-IL-1 agents are reasonable treatment options in order to prevent disease relapses both in the short- and long-term [21, 22, 56]. "
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    • "In fact, etanercept has been proven to be useful in reducing the intensity and duration of acute attacks, although in some cases it gradually loses efficacy [78–81]. Infliximab and adalimumab, by contrast, for reasons only partially understood, may, paradoxically, evoke typical acute inflammatory attacks of the disease [81, 82]. "
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    • "In terms of the TNF-α neutralizing agents, both infliximab and adalimumab may cause paradoxical inflammatory attacks in TRAPS patients [81, 84]. Their paradoxical effect could be induced by (i) an increase in antiapoptotic activity and oversecretion of proinflammatory cytokines; (ii) more stable binding complexes with soluble TNF and their much higher binding avidity to transmembrane TNF of monoclonal antibodies than etanercept [85]; (iii) a reduced shedding infliximab-bound TNFα/TNF receptor from the cell surface, leading to a marked increase in cytokine secretion and increased proinflammatory response [84]. For these reasons, caution is strongly advised when prescribing infliximab and adalimumab in patients with TRAPS. "
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