Role of TNF in the pathogenesis of UC Although UC, like Crohn’s disease, is a chronic inflammatory disorder of unknown origin, some elements in the cascade driving the inflammatory reaction and the tissue damage in the colonic mucosa and submucosa have been elucidated. In contrast to Crohn’s disease, which is characterized by a predominant T-helper-1 cytokine profile with secretion of cytokines such as interleukin-2 (IL-2) and interferon-gamma (IFN-gamma), the uncontrolled tissue damage in the mucosa and submucosa of UC patients appears to be fostered by humoral immunity with antibody-secreting plasma, T lymphocytes with a T-helper- 2 cytokine profile, and neutrophils. Plasma cells isolated from the gut wall of UC patients produce copious amounts of immunoglobulin G (IgG) and complement-activating IgG1 antibodies are preferentially secreted (Halstensen et al. 1993). Also, autoantibodies directed against endogenous proteins such as tropomyosins are secreted in the serum of UC patients, corroborating the role of humoral, B-cell-mediated immunity in UC (Das et al. 1993). Despite these apparent differences in lymphocyte subtypes driving the inflammatory reaction in Crohn’s disease and UC, the effector phase of the immune response in both types of IBD is characterized by the secretion of similar inflammatory cytokines such as TNF and IL-1-beta. Indeed, several lines of evidence support the development of anti-TNF agents to treat patients with active UC. In inflamed mucosa, in the serum, and in the stools of both Crohn’s disease and UC patients the proinflammatory cytokines IL-1, IL-6, and TNF predominate. More specifically, TNF immunoreactive cells are increased in the lamina propria of UC and Crohn’s disease patients (Murch et al. 1993). This phenomenon is found in both adults and children with IBD, although in children the TNF increase is particularly elevated in Crohn’s disease (Murch et al. 1993; Breese et al. 1994). Intraluminal TNF levels obtained by colonic lavage are increased in active but not in endoscopically quiescent UC (Casellas et al. 1994). Serum TNF levels are markedly elevated in patients with UC, and patients with active disease have a 1.7-fold higher level than patients with inactive disease (Komatsu et al. 2001). Furthermore, an imbalance in the secretion of TNF and neutralizing soluble TNF receptors favoring the secretion of TNF has been observed in culture supernatants of colonic biopsies from patients with active colitis (Noguchi et al. 1998). Moreover, the TNF-alfa converting enzyme (TACE), which serves to activate and release TNF from the cell membrane, is specifically increased in colonic biopsies of UC patients as compared to biopsies from patients with Crohn’s disease or healthy individuals (Brynskov et al. 2002). Indeed, in the cotton-top tamarin animal model of UC, humanized anti-TNF antibodies ameliorate the spontaneous colitis (Watkins et al. 1997). In Crohn’s disease a clear defect in apoptosis of lamina propria and circulating T cells has been reported (Ina et al. 1999); also, in UC, deficiencies in T-cell apoptosis have been observed (Boirivant et al. 1999). Anti-TNF agents may act in IBD through the induction of T-cell apoptosis or through restoration of defective apoptosis rather than through simple neutralization of soluble or membrane-bound TNF. In Crohn’s disease, ex-vivo and recently also in-vivo evidence points to this hypothesis (Lügering et al. Core Evidence 2007;2(3) Infliximab | place in therapy review 2001; Van den Brande et al. 2003; Shen et al. 2007). In UC the relative role of apoptosis induction relative to TNF neutralization for the efficacy of anti-TNF antibodies needs further study. Antimetabolite immunosuppressives such as azathioprine and 6-mercaptopurine also may act by inducing T-cell apoptosis or by inhibiting T-cell proliferation in patients with UC. Although the data on the role of TNF in the pathogenesis of UC have not been unequivocal, taken together they suggest that TNF contributes to the mucosal damage and chronic inflammation responsible for signs and symptoms of active UC (Table 2). Table 2 | Preclinical evidence supporting use of infliximab in ulcerative colitis patients Evidence Increase in mucosal TNF immunoreactive cells Increased TNF levels in mucosa, serum, and stools Stool TNF levels specifically increased in endoscopically active UC Imbalance favoring TNF over neutralizing soluble TNF receptors Specific increase in TNF-activating enzyme TNF, tumor necrosis factor; UC, ulcerative colitis. Reference Murch et al. 1993 Murch et al. 1993; Casellas et al. 1994; Komatsu et al. 2001 Casellas et al. 1994 Noguchi et al. 1998 Brynskow et al. 2002 Current therapy options The medical management of UC should be tailored to the disease severity in every individual patient. Mild UC can usually be managed with oral 5-aminosalicylates (mesalamine or sulfasalazine). Since recent evidence suggests that 5-aminosalicylates have a dose-dependent effect in UC above a daily dose of 2 g, higher doses of these compounds are generally used because they are well tolerated. For patients with moderate disease (interfering with activities of daily life) refractory to medical therapy, oral systemic steroids (at an initial dose of 40 mg of prednisolone equivalent) have been proven to induce clinical improvement and remission. However, systemic steroids have a high burden of side effects when used long term and are only used in courses of 3 to 4 months. Steroid-dependent patients (those not being able to taper steroid therapy or needing several courses of systemic steroids within 1 year) are therefore a key target for drug development in UC. Patients who have achieved a steroid-induced remission can return to 5-aminosalicylate maintenance or start antimetabolite therapy (e.g. methotrexate). Patients who have not responded to a 2- to 4-week course of oral systemic steroids (at an initial dose of 40 mg prednisolone equivalent or higher) are usually considered to fail oral steroids (steroid-refractory) and need other treatment options. Rectal therapy Rectal therapy with 5-aminosalicylates offers clinical benefit for fast relief of symptoms and increases disease remission and 153