Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease

doi:10.1053/gast.2002.30770

Gastroenterology

Volume 122, Issue 1, January 2002, Pages 7-14

https://doi.org/10.1053/gast.2002.30770 Get rights and content

Abstract

Background & Aims: 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/m² 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.

GASTROENTEROLOGY 2002;122:7-14

Section snippets

Effect of CNI-1493 on JNK and p38 MAPK activation in vitro

Peripheral blood mononuclear cells (PBMCs) obtained from healthy volunteers were stimulated with LPS for 15 minutes in the presence of increasing concentrations of CNI-1493 or diluent. Analysis of MAPK phosphorylation was performed using Western blotting and phosphospecific antibodies (Cell Signalling, Beverly, MA).

Patients

Twelve patients were enrolled in a doubled-blinded fashion to receive either 8 or 25 mg/m² of CNI-1493 intravenously once daily for 12 consecutive days. Patients were required to

JNK and p38 MAPK are activated in active CD

Although MAPKs have been implicated in regulation of inflammatory responses, actual involvement of MAPKs in chronic inflammatory disease has not yet been demonstrated. Recently, Waetzig et al.²⁰ reported increased activity of stress-activated MAPKs in CD. In colonic biopsies taken from patients with active CD, we show that activation of JNK and p38 MAPK is markedly present (Figure 1A and D).

. Involvement of MAPKs in CD. Patients received 12 days of intravenous infusions with CNI-1493 (8 or 25 mg/m

Discussion

We tested CNI-1493, a synthetic guanylhydrazone known to inhibit both JNK and p38 MAPK, in patients with moderate to severe CD. Although it is now generally recognized that inflammation involves the activation of stress-activated MAPKs, the actual importance of these kinases in human pathology is poorly understood. CNI-1493 has been shown to be protective in several experimental models involving inflammatory cytokine excess; however, clinical experience with CNI-1493 is limited. In a phase I

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^*: Address requests for reprints to: Daan W. Hommes, M. D., Department of Gastroenterology and Hepatology, Academic Medical Center, C2-116, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands. e-mail: [email protected]; fax: (31) 20 566 9285.

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Rapid CommunicationsInhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease*

Abstract

Section snippets

Effect of CNI-1493 on JNK and p38 MAPK activation in vitro

Patients

JNK and p38 MAPK are activated in active CD

Discussion

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

J Biol Chem

Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease

Nature

A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease

Nature

Review article: targeting TNF alpha as a key cytokine in the inflammatory processes of Crohn's disease–the mechanisms of action of infliximab

Aliment Pharmacol Ther

A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease

N Engl J Med

Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation

Physiol Rev

Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function

J Pharmacol Exp Ther

Rapid Communications
Inhibition of stress-activated MAP kinases induces clinical improvement in moderate to severe Crohn's disease*