The skin is one of the most common extraintestinal organ system affected in patients with inflammatory bowel disease (IBD), including both Crohn's disease and ulcerative colitis. The skin manifestations associated with IBD are polymorphic and can be classified into 4 categories according to their pathophysiology: (1) specific, (2) reactive, (3) associated, and (4) induced by IBD treatment. Cutaneous manifestations are regarded as specific if they share with IBD the same granulomatous histopathological pattern: perianal or metastatic Crohn's disease (commonly presenting with abscesses, fistulas or hidradenitis suppurativa-like features) is the prototype of this setting. Reactive cutaneous manifestations are different from IBD in the histopathology but have close physiopathological links: pyoderma gangrenosum, a neutrophil-mediated autoinflammatory skin disease typically manifesting as painful ulcers, is the paradigm of this group. Among the cutaneous diseases associated with IBD, the most commonly seen are erythema nodosum, a form of panniculitis most commonly involving bilateral pretibial areas, and psoriasis, a T helper 1/T helper 17-mediated erythematous squamous inflammatory disease. Finally, the number of cutaneous adverse reactions because of IBD therapies is progressively increasing. The most frequent drug-induced cutaneous manifestations are psoriasis-like, eczema-like, and lichenoid eruptions, as well as cutaneous lupus erythematosus for biologics, and nonmelanoma skin cancer, mainly basal cell and squamous cell carcinomas for thiopurines.

Selective in vivo and in vitro activation of the contact system in susceptible Lewis rats suggests that this pathway is one determinant of genetic susceptibility to granulomatous enterocolitis and systemic complications.

Bradykinin is a mediator of inflammation, responsible for pain, vasodilation, and capillary permeability. Bradykinin receptor 1 (B1R) and bradykinin receptor 2 (B2R) are G protein-coupled receptors that mediate kinin effects. The latter is constitutive and rapidly desensitized; the former is induced by inflammatory cytokines and resistant to densensitization. The distribution of bradykinin receptors in human intestinal tissue was studied in patients with inflammatory bowel disease (IBD), namely ulcerative colitis (UC) and Crohn's disease (CD). Both B2R and B1R proteins are expressed in the epithelial cells of normal and IBD intestines. B1R protein is visualized in macrophages at the center of granulomas in CD. B2R protein is normally present in the apexes of enterocytes in the basal area and intracellularly in inflammatory tissue. In contrast, B1R protein is found in the basal area of enterocytes in normal intestine but in the apical portion of enterocytes in inflamed tissue. B1R protein is significantly increased in both active UC and CD intestines compared with controls. In patients with active UC, B1R mRNA is significantly higher than B2R mRNA. However, in inactive UC patients, the B1R and B2R mRNA did not differ significantly. Thus bradykinin receptors in IBD may reflect intestinal inflammation. Increased B1R gene and protein expression in active IBD provides a structural basis of the important role of bradykinin in chronic inflammation.

Ezetimibe is the first agent used in hypercholesterolemia treatment known to lower intestinal cholesterol uptake that is able to inhibit NPC1L1 transport proteins in the brush boarder of enterocytes and macrophages. Furthermore, it demonstrates anti-inflammatory and immunomodulatory properties and influences the expression of certain antigens. The drug is rapidly absorbed from the gastrointestinal tract and is then glucuronidated to form the active metabolite. It also undergoes extensive enterohepatic circulation. Various genetic polymorphisms seem to influence the pharmacokinetics of ezetimibe with different effects. The drug also presents a complex impact on cytochrome P450 enzymes, as it is a metabolism-dependent inhibitor of CYP3A4. Ezetimibe does not demonstrate any clinically significant interactions with statins, fibrates, mipomersen sodium, levothyroxine or lopinavir. However, its effect in conjunction with cyclosporine is not neutral. The use of this cholesterol absorption inhibitor has been shown to be safe and effective among patients after cardiac, renal and liver transplants, as well as in HIV patients.

A specific plasma kallikrein inhibitor, Bz-Pro-Phe-boroArg (P8720), was used to define the relationship between the kallikrein-kinin (K-K) system and acute intestinal inflammation induced by bacterial peptidoglycan-polysaccharide (PG-APS) in Lewis rats. Group I received human serum albumin (HSA) intramurally in the intestine and was treated with HSA. Group II received PG-APS and was treated with P8720. Group III received PG-APS and was treated with HSA. P8720 attenuated the decrease of high-molecular-weight kininogen and factor XI activity (group II vs group III, P < 0.01). P8720 therapy significantly but modestly decreased acute intestinal inflammation measured by gross gut score (P < 0.01) and more dramatically reduced the tissue myeloperoxidase activity (P < 0.05), a measure of granulocyte recruitment, in group II compared with group III. We conclude that the K-K system is directly involved in the pathogenesis of the acute phase of experimental acute inflammation. A specific inhibitor may modulate inflammatory bowel disease.