Immunomodulatory effects of etanercept (TNFR:Fc) and its use in a patient with Crohn's disease.
Designer drug etanercept (TNFR:Fc) is an inhibitor of TNF-alpha that binds with greater affinity than membrane receptors. Its full immunomodulatory effects are unknown. Approved for rheumatoid arthritis, its therapeutic potential in Crohn's disease has yet to be explored. We describe the course of a steroid-dependent patient with Crohn's disease given etanercept, and its effects on cytokine protein and mRNA expression and transcription factor activity in human leukocytes. Etanercept 25 mg s.c., was given twice weekly for 1 month. Weekly ESR, disease activity index, prednisone requirement, and serum cytokines were determined. In vitro, effects of physiologic concentrations of etanercept on cytokine protein and mRNA, and NFKB and GR transcription factor activity, were determined using MOT and U937 cell lines and peripheral blood mononuclear cells. Rapid clinical, biochemical, and immunologic improvement occurred, but obstruction due to stricture developed after 4 weeks. In vitro, constitutive and stimulated production of TNF-beta, IL-1beta, MIP-1beta, and IL-8 by normal mononuclear cells declined with etanercept, detectable TNF-alpha increased. MOT TNF-alpha expression tripled, mRNA for IL-12 p40 doubled, GR activity declined in U937 cells, NFKB was unaffected. Etanercept has complex immunomodulatory effects, and may be useful in Crohn's disease, but acutely decreased inflammation could worsen stricture.
Srivastava
M D
MD
Department of Pediatrics, MetroHealth Medical Center, Cleveland, Ohio 44109, USA.
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D003424:Crohn Disease / Q000188:drug therapy*; D016207:Cytokines / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D011241:Prednisone / Q000627:therapeutic use; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019914:Taq Polymerase; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D003907:Dexamethasone; D019914:Taq Polymerase; D000068800:Etanercept; D011241:Prednisone