Infliximab in the Treatment of Steroid-Dependent Ulcerative Colitis

European Review for Medical and Pharmacological Sciences 2004; 8: 231-233 Infliximab in the treatment of steroid-dependent ulcerative colitis

A. ARMUZZI, B. DE PASCALIS, A. LUPASCU, P. FEDELI, D. LEO, M.C. MENTELLA, F. VINCENTI, D. MELINA, G. GASBARRINI, P. POLA, A. GASBARRINI

Department of Internal Medicine, Gemelli Hospital, Catholic University of Rome (Italy)

Abstract. – Background and objectives: Introduction Infliximab has proven efficacious in the treatment of Crohn’s disease. Limited and contrast- Tumour necrosis factor alpha (TNF-α) is ing data are available on effectiveness of anti- recognized as a key cytokine involved in the TNF alpha therapy in ulcerative colitis. We eval- development and progression of several im- uated the efficacy of infliximab in the manage- mune mediated inflammatory disorders, in- ment of steroid-dependent ulcerative colitis. Methods: We report preliminary data from a cluding inflammatory bowel disease. The cy- randomized, open-label, methylprednisolone- tokine profiles of Crohn’s disease and ulcera- controlled trial of infliximab in the induction and tive colitis (UC) are usually different. The for- maintenance of remission of patients with mod- mer is associated with an overexpression of erate to severe steroid-dependent ulcerative col- Th1 related pro-inflammatory cytokines (e.g., itis. Twenty patients received either three infu- TNF-α), the latter, conversely, is associated sion of infliximab (5 mg/kg) at 0, 2 and 6 weeks and thereafter every 8 weeks (group A) or with an increased production of Th2 related in- methylprednisolone (0,7-1 mg/kg) daily for one flammatory molecules (e.g., interleukin 4 and week followed by a tapering regimen up to the 5)1. However, increased serum and colonic mu- minimal dose to maintain a symptom-free condi- cosa concentrations of TNF-α have been re- tion (group B). Clinical remission was defined as ported also in patient with UC2-5, suggesting a a DAI score less than 3. possible role in the pathogenesis of the disease. Results: Ten patients in group A (DAI: 8.9 ± Infliximab, a IgG1 chimeric monoclonal an- 1.4) achieved remission after the first infusion α (DAI: 1.6 ± 0,7; p = 0.005) and steroids were pro- tibody that effectively neutralizes TNF- , has gressively discontinued. At present (mean fol- been shown to have potent anti-inflammatory low-up: 9.8 ± 1.1 months), 9 out of 10 patients and disease modifying effects in an expanding maintain clinical remission, while one patient re- list of diseases, including rheumatoid arthritis, lapsed at 3 months. Ten patients in group B ankylosing spondylitis and Crohn’s disease6. (DAI: 8.7 ± 1.4) reached clinical remission at one There are limited and contrasting data on the week (DAI: 1.9 ± 0.3; p = 0.005). Eight out of 10 α patients were maintained at a minimal steroid role of antibodies to TNF- in the therapy of 7-14 dosage without any relapse at 9.7 ± 1.0 months ulcerative colitis (UC) . Steroid-dependency follow-up. Two patients relapsed at 6 and 8 may account for up to 20% of UC, usually ap- months, respectively. plying to patients who cannot taper or rapidly Conclusions: Infliximab seems to be as effec- flare (e.g., within 6 months) after steroid-with- tive as steroids in the management of moderate drawal15. The aim of the study was to evaluate to severe steroid-dependent ulcerative colitis. the effectiveness of infliximab in the manage- These preliminary data suggest the potential efficacy of repeated treatment with infliximab for ment of glucocorticoid-dependent UC. short-term maintenance of remission and steroid withdrawal in glucocorticoid-dependent ulcerative colitis. Key Words: Methods Steroid-dependent ulcerative colitis, Infliximab, Anti- TNF alpha monoclonal antibody. In a randomized, open-label, methylprednisolone controlled trial conducted in our

231 A. Armuzzi, B. De Pascalis, A. Lupascu, P. Fedeli, D. Leo, et al.

Table I. Demographic and disease characteristic of patients at week 0.

Steroid group Infliximab group

Age (y) 36.3 (24-53) 36.2 (24-50) Extensive UC 4 5 Left sided UC 3 2 Distal UC 3 3 Duration of UC (y) 5.5 (2-10) 4.8 (2-8) Prednisolone equivalent (gm/day) 15.5 (10-25) 16.0 (10-25) DAI (mean ± SD) 8.7 ± 1.4 8.9 ± 1.4

IBD unit, we evaluated the role of infliximab (0,7-1 mg/kg body weight) daily for one week in the treatment of patients with moderate to followed by a tapering regimen up to the severe glucocorticoid-dependent UC. minimal dose to maintain a symptom-free Patients were included in the study if they condition. had (1) an established diagnosis of UC (en- Disease activity was assessed at recruit- doscopy plus histological confirmation), (2) ment, within two weeks after the first inflix- moderate to severe disease according to a imab infusion and every 8 weeks thereafter. disease activity index (DAI) score16 more Clinical remission was defined as a DAI than 6, (3) minimum of one year of continu- score less than 3. ous steroid-dependent UC, (4) negative stool microscopy and colture, (5) negative immunohistochemistry for CMV on bowel biop- sies, (6) absence of known serious infection in Results the previous three months, (7) no need of ur- gent colectomy. Twenty patients were studied (10 in each Consecutive patients who met the inclusion group). Population demographics and disease criteria were 1:1 randomised to receive either characteristics are summarised in Table I. All infusion of infliximab (5 mg/kg body weight) patients in group A (DAI: 8.9 ± 1.4) achieved at 0, 2 and 6 weeks and thereafter every 8 remission after the first infusion (DAI: 1.6 ± weeks (Group A) or methylprednisolone 0,7; p = 0.005) and steroids were progressively DAI

Time (wk)

Figure 1. Disease Activity Index scores of infliximab group.

232 Infliximab in the treatment of steroid-dependent ulcerative colitis discontinued. At present (mean follow-up: 9.8 5) REINECKER HC, STEFFEN M, WITTHOETT T, et al. ± 1.1 months), 9 out of 10 patients maintain Enhanced secretion of tumor necrosis factor alpha, IL-6, and IL-1 beta by isolated lamina pro- clinical remission (Figure 1). One patient re- pria mononuclear cells from patients with ulcera- lapsed after 3 and 7 months requiring shorter tive colitis and Crohn’s disease. Clin Exp intervals between infliximab infusions in the Immunol 1993; 94: 174-181. first and steroids in the last occasion to achieve 6) SANDS BE. Crohn’s disease: not all anti-TNFs are remission. Finally, the patient underwent elec- the same! Inflamm Bowel Dis 2002; 8: 232-235. tive colectomy after relapsing again after 11 7) SANDS BE, TREMAINE WJ, SANDBORN WJ, et al. months. Infusions with infliximab produced no Infliximab in the treatment of severe, steroid-re- significant adverse events. All patients in group fractory ulcerative colitis: a pilot study. Inflamm B (DAI: 8.7 ± 1.4) reached clinical remission Bowel Dis 2001; 7: 83-88. (DAI: 1.9 ± 0.3; p = 0.005). Eight out of 10 pa- 8) CHEY WY, HUSSAIN A, RYAN C, POTTER GD, SHAH A. tients were maintained at a minimal steroid Infliximab for refractory ulcerative colitis. Am J dosage (residual dose of steroids – pred- Gastroenterol 2001; 96: 2373-2381. nisolone equivalent: 16.25 ± 5.2 mg/day) with- 9) KASER A, MAIRINGER T, VOGEL W, TILG H. Infliximab in out any relapse at 9.7 ± 1.0 months follow-up. severe steroid-refractory ulcerative colitis: a pilot study. Wien Klin Wochenschr 2001; 113: 930-933. Two patients relapsed at 6 and 8 months, respectively. They were then offered infliximab 10) KOHN A, PRANTERA C, PERA A, et al. Anti-tumour necrosis factor alpha (infliximab) in the treatment treatment: one patients, although with marked of severe ulcerative colitis: result of an open study evidence of clinical improvement, refused con- on 13 patients. Dig Liver Dis 2002; 34: 626-630. trol colonoscopy and was lost to follow-up. The 11) ACTIS GC, BRUNO M, PINNA-PINTOR M, ROSSINI FP, second patients achieved clinical remission, but RIZZETTO M. Infliximab for treatment of steroid re- relapsed after 10 months requiring again fractory ulcerative colitis. Dig Liver Dis 2002; 34: steroid treatment to obtain remission. 631-634. 12) SU C, SALZBERG B, LEWIS JD, et al. Efficacy of anti- tumor necrosis factor therapy in patients with ulcerative colitis. Am J Gastroenterol 2002; 97: 2577-2584

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