Susceptibility to Crohn’s disease and psoriasis have also been reported to be associated with polymorphisms in the IL23R gene.6,7 This shared association suggests that there may be a common mechanism in the pathogenesis of seronegative spondyloarthropathies that lends itself to treatment. IL-23 shares the p40 protein subunit with IL-12 and plays a critical role in the generation of effector memory T cells and IL-17-producing T cells. These IL-17-producing T cells are critical in sustaining organ specific inflammation in several different mouse models of autoimmune disease. Targeting IL23R would theoretically also reduce IL-17 production. Therapeutic trials assessing the efficacy of IL12/23 inhibitors in Crohn’s disease are underway.8,9 The genetic link between AS and Crohn’s disease implies that clinical success using the IL12/23 inhibitors in Crohn’s disease may translate therapeutically to AS by targeting a common mechanism.
- Chang SC, Momburg F, Bhutani N, Goldberg AG. The ER aminopeptidase, ERAP1, trims precursors to lengths of MHC class I peptides by a “molecular ruler” mechanism. Proc Natl Acad Sci USA. 2005;102:17107-17112.
- Saveanu L, Carroll O, Lindo V, et al. Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum. Nat Immunol. 2005;6:689-697.
- Cui X, Rouhani FN, Hawari F, Levine SJ. Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding. J Immunol. 2003;171:6814-6819.
- Cui X, Rouhani FN, Hawari F, Levine SJ. An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding. J Biol Chem. 2003;278:28677-28685.
- Cui X, Hawari F, Alsaaty S, et al. Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding. J Clin Invest. 2002;110:515-526.
- Duerr RH, Taylor KD, Brant SR, et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science. 2006;314:1461-1463.
- Cargill M, Schrodi SJ, Chang M, et al. A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet. 2007;80:273-290.
- Billich, A. Drug evaluation: Apilimod, an oral IL-12/IL-23 inhibitor for the treatment of autoimmune diseases and common variable immunodeficiency. IDrugs. 2007;10:53-59.
- Burakoff R, Barish CF, Riff D, et al. A phase 1/2A trial of STA 5326, an oral interleukin-12/23 inhibitor, in patients with active moderate to severe Crohn’s disease. Inflamm Bowel Dis. 2006;12:558-565.
New Tool for Predicting Hip Fracture Risk
By Daniel Hal Solomon, MD, MPH