Is there clinical, epidemiological and molecular evidence for two forms of Crohn's disease?

Crohn's disease is an idiopathic chronic panenteric intestinal inflammatory disease. Data concerning the pathogenesis of, and the immune responses occurring in, Crohn's disease are often conflicting. Current therapy is empirical and either non-specifically immunosuppressive or surgically ablative in nature. Although controversial, Crohn's disease may be thought of as having two different presentations, an aggressive fistulizing form and an indolent obstructive form. This is analogous to the tuberculoid and lepromatous manifestations of leprosy. If correct, this subclassification may provide key insights into the pathogenesis and differing host immune responses in Crohn's disease and also allow the development of more rational therapies.

Molecular evidence for two forms of Crohn disease.

Recent epidemiological evidence suggests that there are two forms of Crohn disease (CD): perforating and nonperforating. We hypothesized that, just as with tuberculoid and lepromatous leprosy, differences in the two forms of CD would be both identified and determined by differences in the host immune response. Resected intestinal tissue from control patients as well as perforating and nonperforating CD patients was evaluated for mRNA levels. We employed 32P PCR amplification with published or custom-designed primers of a housekeeping gene (beta-actin); a human T-cell marker (CD3-delta); and the cytokines tumor necrosis factor alpha, transforming growth factor beta, granulocyte/macrophage colony-stimulating factor, interleukin (IL) 1 beta, IL-1ra, and IL-6. Differences were identified with IL-1 beta (control = 162 +/- 57 vs. perforating = 464 +/- 154 vs. nonperforating = 12,582 +/- 4733; P < or = 0.02) and IL-1ra (control = 1337 +/- 622 vs. perforating = 2194 +/- 775 vs. nonperforating = 9715 +/- 2988; P < or = 0.02). These data corroborate the epidemiological observation that there are two forms of CD. Nonperforating CD, the more benign form, is associated with increased IL-1 beta and IL-1ra mRNA expression. We conclude that it is the host immune response that determines which form of CD becomes manifest in any given individual and discuss the investigative, diagnostic, and therapeutic implications of these observations.