Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease.
OBJECTIVE
We investigated if inhibition of mitogen-activated protein kinases (MAPKs) was beneficial in Crohn's disease.


METHODS
Inhibition of JNK and p38 MAPK activation with CNI-1493, a guanylhydrazone, was tested in vitro. Twelve patients with severe Crohn's disease (mean baseline, CDAI 380) were randomly assigned to receive either 8 or 25 mg/m(2) CNI-1493 daily for 12 days. Clinical endpoints included safety, Crohn's Disease Activity Index (CDAI), Inflammatory Bowel Disease Questionnaire, and the Crohn's Disease Endoscopic Index of Severity.


RESULTS
Colonic biopsies displayed enhanced JNK and p38 MAPK activation. CNI-1493 inhibition of both JNK and p38 phosphorylation was observed in vitro. Treatment resulted in diminished JNK phosphorylation and tumor necrosis factor production as well as significant clinical benefit and rapid endoscopic ulcer healing. No serious adverse events were noted. A CDAI decrease of 120 at week 4 (P = 0.005) and 146.5 at week 8 (P = 0.005) was observed. A clinical response was seen in 67% of patients at 4 weeks and 58% at 8 weeks. Clinical remission was observed in 25% of patients at week 4 and 42% at week 8. Endoscopic improvement occurred in all but 1 patient. Response was seen in 3 of 6 infliximab failures, 2 of whom showed remission. Fistulae healing occurred in 4 of 5 patients, and steroids were tapered in 89% of patients.


CONCLUSIONS
Inflammatory MAPKs are critically involved in the pathogenesis of Crohn's disease and their inhibition provides a novel therapeutic strategy.
Hommes
Daan
D
Department of Gastroenterology and Hepatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. d.w.hommes@amc.uva.nl
van den Blink
Bernt
B
Plasse
Terry
T
Bartelsman
Joep
J
Xu
Cuiping
C
Macpherson
Bret
B
Tytgat
Guido
G
Peppelenbosch
Mailkel
M
Van Deventer
Sander
S
D000293:Adolescent; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage* / Q000009:adverse effects; D001706:Biopsy; D003424:Crohn Disease / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010450:Endopeptidases / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000008:administration & dosage* / Q000009:adverse effects; D066298:In Vitro Techniques; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D012720:Severity of Illness Index; D048051:p38 Mitogen-Activated Protein Kinases; D000813:Anilides; D006146:Guanidines
D000894:Anti-Inflammatory Agents, Non-Steroidal; D010450:Endopeptidases; D004791:Enzyme Inhibitors; D006835:Hydrazones; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C097256:semapimod; D000813:Anilides; D006146:Guanidines; C099844:TNF-R releasing enzyme