Proinflammatory action of the antiinflammatory drug infliximab in tumor necrosis factor receptor-associated periodic syndrome.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Nedjai
Belinda
B
Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK.
Hitman
Graham A
GA
Quillinan
Niamh
N
Coughlan
Robert J
RJ
Church
Leigh
L
McDermott
Michael F
MF
Turner
Mark D
MD
D000893:Anti-Inflammatory Agents / Q000009:adverse effects*; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D017209:Apoptosis / Q000235:genetics; D053148:Caspase 3 / Q000097:blood; D000075202:Contraindications; D010505:Familial Mediterranean Fever / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000069285:Infliximab; D007378:Interleukins / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000097:blood / Q000235:genetics; D017211:Treatment Failure
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D007378:Interleukins; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human; D000069285:Infliximab; D053148:Caspase 3