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Efficacy and safety of infliximab induction therapy in Crohn's Disease in Central Europe - a Hungarian nationwide observational study

Efficacy and safety of infliximab induction therapy in Crohn's Disease in Central Europe - a... Background: Infliximab (IFX) has proven to be an effective addition to the therapeutic arsenal for refractory, fistulizing, and steroid dependent Crohn's disease (CD), with efficacy in the induction and maintenance of clinical remission of CD. Our objective in this study is to report the nationwide, multicenter experience with IFX induction therapy for CD in Hungary. Page 1 of 7 (page number not for citation purposes) BMC Gastroenterology 2009, 9:66 http://www.biomedcentral.com/1471-230X/9/66 Methods: During a 6-year-period, beginning in 2000, a total of 363 CD patients were treated with IFX as induction therapy (5 mg/kg IFX infusions given at week 0, 2 and 6) at eleven centers in Hungary in this observational study. Data analysis included patient demographics, important disease parameters and the outcome of IFX induction therapy. Results: Three hundred and sixty three patients (183 women and 180 men) were treated with IFX since 2000. Mean age was 33.5 ± 11.2 years and the mean duration of disease was 6.7 ± 6.1 years. The population included 114 patients (31.4%) with therapy-refractory CD, 195 patients (53.7%) with fistulas, 16 patients (4.4%) with both therapy-refractory CD and fistulas, and 26 patients (7.2%) with steroid dependent CD. Overall response rate was 86.2% (313/363). A higher response rate was observed in patients with shorter disease duration (p = 0.05, OR:0.54, 95%CI:0.29-0.99) and concomitant immunosuppressant therapy (p = 0.05, OR: 2.03, 95%CI:0.165-0.596). Concomitant steroid treatment did not enhance the efficacy of IFX induction therapy. Adverse events included 34 allergic reactions (9.4%), 17 delayed type hypersensitivity (4.7%), 16 infections (4.4%), and 3 malignancies (0.8%). Conclusion: IFX was safe and effective treatment in this cohort of Hungarian CD patients. Based on our experience co-administration of immunosuppressant therapy is suggested in patients receiving IFX induction therapy. However, concomitant steroid treatment did not enhanced the efficacy of IFX induction therapy. comitant medication, indication for biological therapy Background Infliximab (IFX) is a chimeric monoclonal antibody that and outcome of IFX induction therapy were registered ret- binds soluble and membrane bound tumor necrosis fac- rospectively. The study protocol was reviewed and tor-alpha (TNF-α). Previous studies have demonstrated its approved by the Semmelweis University Regional and efficacy in refractory, fistulizing, and steroid dependent Institutional Committee of Science and Research Ethics. Crohn's disease (CD) [1,2]. Furthermore, other studies have shown its efficacy as maintenance therapy for CD Patients with Crohn's Disease eligible for this observa- [3], moreover as induction and maintenance therapy for tional study had 1) single or multiple discharging abdom- ulcerative colitis [4]. inal and/or perianal fistulas of at least 3-6 months duration despite conventional immunosuppressant and In Hungary, IFX has been used in clinical studies since antibiotic therapy; 2) therapy refractory/steroid depend- 2000, and has served as an important component of the ent luminal disease. Minority of patients had active lumi- therapeutic arsenal for the treatment of CD since 2003. nal and fistulizing disease as well. Patients who are either Financial considerations limit the use of IFX treatment for unable to reduce corticosteroids below the equivalent of CD to eleven Hungarian Gastroenterological Centers prednisolone 10 mg/day within three months of starting which are licensed for its administration. Initially, IFX was corticosteroids without recurrent active disease, or who available only for induction therapy for patients suffering have a relapse within three months of stopping corticos- from fistulizing, therapy resistant, or steroid dependent teroids were defined as corticosteroid dependent patient. CD. However, as clinical evidence demonstrates the effi- Corticosteroid refractory disease was defined as active dis- cacy of IFX for maintenance therapy [3], currently IFX is ease despite prednisolone up to 0.75-1 mg/kg/day over a available for maintenance therapy as well. The objective period of four weeks defined as steroid refractory. Patients of this observational study is to report the nationwide, who not tolerate AZA in a dose at least 1.5 mg/kg body multicenter experience with IFX induction therapy for CD weight were considered as AZA intolerant. Failure of in Hungary. immunosupressants (AZA or else) therapy or AZA intoler- ance was an indication for IFX therapy also. Methods This observational study was initiated in 2004, therefore a As induction therapy five mg/kg body weight of inflixi- portion of the patient data (2000 through 2004) are retro- mab was administered in a 2 hour infusion at weeks 0, 2 spective. Patient data through six years from eleven Hun- and 6. In fistulizing disease response was defined as a garian Gastroenterological Centers are included in this decrease of 50% or more in the number of discharging fis- analysis. Microsoft Excel databases were used to compile tulas compared to baseline and remission was defined as and process patient data including demographic charac- absence of any discharging fistulas measured at week 12. teristics, localization and behaviour of the disease, con- In patients with therapy-refractory or steroid dependent Page 2 of 7 (page number not for citation purposes) BMC Gastroenterology 2009, 9:66 http://www.biomedcentral.com/1471-230X/9/66 luminal disease the response was defined as a ≥70 points apy. Detailed data on remission rates are shown in Table decrease in CDAI and a CDAI value below 150 was con- 2. sidered as clinical remission at week 12. The Crohn's Dis- ease Activity Index (CDAI) was calculated only in cases Among 304 (83.7%) patients treated simultaneously with with steroid dependent or therapy-refractory luminal dis- immunosuppressants, 268 responded (88.2%), and 36 ease. failed to respond (11.8%). Fifty nine (16.2%) patients did not receive any concomitant immunosuppressants and Infliximab 5 mg/kg body weight was given as mainte- the response rate was lower in these patients respect to nance therapy after week 6. Maintenance was given every those on concomitant immunosuppressive therapy (73% 8 weeks. The initiation of the maintenance therapy was vs 88.2%, p < 0.05). Among patients with concomitant based on the assessment of response following the induc- immunosuppressants, azathioprine (AZA) was used most tion regimen. However, financial restrictions prevented a frequently (78.9%). Other immunosuppressant therapies significant proportion of patients from receiving mainte- included methotrexate (5.9%), and only one patient nance therapy. Conventional induction therapy (1 mg/kg (0.3%) was treated with cyclosporine and another with body weight steroid therapy) was started in case of early mycophenolate mofetil (0.3%). Response rate to IFX disease relapse in patients with luminal CD. In case of late induction therapy was higher in patients receiving con- relapse (defined as relapse after at least 6 months of remis- comitant AZA or methotrexate (88.3% vs. 76.6%, p = sion) IFX re-induction regimen was administered. 0.014). Statistcal methods During induction therapy co-administration of pre-infu- Variables were tested for normality using Shapiro Wilk's sion corticosteroid therapy was applied in 165 patients. W test. T-test with separate variance estimates, ANOVA Response rates were similar for patients with or without 2 2 with post hoc Scheffe test, χ -test, and χ -test with Yates concomitant steroid treatment (88.5% vs. 85.8%, respec- correction were used to evaluate differences within sub- tively, p = NS). groups of IBD patients. The results are presented as means ± SD. Association between response, remission and clini- Patients who achieved remission or response after induc- cal variables (with variables with a p < 0.2 in univariate tion therapy were significantly younger than patients clas- analysis) was also tested by using logistic regression anal- sified as non-responders (26.8 ± 10.4 years vs. 33.2 ± 11.5 ysis. A p value of < 0.05 was considered as significant. For years of age, p < 0.01), furthermore the duration of CD the statistical analysis, SPSS15.0 (SPSS Inc, Chicago, IL) was shorter (5.9 ± 5.5 years vs. 7.2 ± 4.3 years, p < 0.001). was used. Abdominal surgery prior to IFX therapy was performed in 25.1% of CD patients. This subset of patients was older in Results During a 6-year-period 363 CD patients were treated with age (35 ± 10.9 years of age, p = 0.01), and the mean dura- IFX. The cohort comprised 183 females and 180 males; tion of disease was longer (8.5 ± 6.3 years, p < 0.0001) the mean age was 33.5 ± 11.2 years and the mean duration compared to the entire group of patients. Among patients of disease was 6.7 ± 6.1 years at the time of initiation of with previous surgical intervention 75% responded to IFX induction therapy. induction therapy. One hundred and ninety five (53.7%) fistulizing, 114 Out of 167 patients in remission 136 (81.4%) received (31.4%) therapy-refractory, and 26 (7.2%) steroid simultaneous immunosuppressive regimen. The majority dependent CD patients were treated. All patients were of patients in remission receiving concomitant immuno- naïve to TNFα-inhibitor therapy. Five (0.1%) patients suppressants were treated with AZA (132 patients, with metastatic CD and 7 (0.2%) patients with extra-intes- 97.0%), 4 patients (2.9%) received methotrexate, and tinal manifestations were also treated, but these patients mesalazine or sulphasalazine was used in 128 (93.4%) were not available for assessment of response. The details and 8 (5.9%) of them respectively. regarding the specific indications for IFX therapy are sum- marized in Table 1. A logistic regression analysis was performed to test the association between clinical variables, concomitant med- During the observation period 1,532 IFX infusions were ical therapy and remission and response to IFX induction administered. Complete induction regimen was per- treatment (Table 3.). Duration (p = 0.05, OR: 0.54, formed in 299 patients (82.3%). Overall response rate 95%CI: 0.29-0.99) and concomitant steroid therapy (p = was 86.2% thus 313 patients out of the 363 responded to 0.027, OR: 0.54, 95%CI: 0.31-0.93) were associated with the induction therapy. Details regarding the response rates remission at week 12 in the same logistic regression anal- are shown in Table 1. The overall remission rate was ysis. 46.0% (167 out of 363 patients) after IFX induction ther- Page 3 of 7 (page number not for citation purposes) BMC Gastroenterology 2009, 9:66 http://www.biomedcentral.com/1471-230X/9/66 Table 1: Indications and response rates of infliximab induction therapy Indication of IFX therapy Number and rate of disease type Response rate after induction Therapy-refractory CD 114 (31.4%) 83.3% By localization Ileum 10 (8.77%) Colon 29 (25.4%) 79.3% Ileo-colonic 46 (40.4%) 87.0% Ileo-colonic and small bowel 28 (24.6%) 78.6% Oesophagus 1 (0.9%) 1/1 Therapy-refractory and fistulizing 16 (4.4%) 93.8% Fistulizing 195 (53.7%) 85.6% By localization Perianal 148 (75.9%) 91.2% Enterocutaneous 24 (12.3%) 87.5% Enterovaginal 11 (5.6%) 9/11 Other 12 (6.2%) 7/12 Mixed 7 (3.6%) 5/7 Steroid dependent 26 (7.2%) 92.3% By localization Ileum 3 (11.5%) 3/3 Colon 4 (15.4%) 4/4 Ileo-colic 19 (73.1%) 17/19 Metastatic 5 (0.1%) Na. Other 7 (0.2%) Na. Na = not applicable Adverse events during induction treatment were observed (0.01%, 0.23/100 patient-years) such as two cases of in 78 patients (21.5%, 3.86/100 patient-years). Allergic tuberculosis, two intra-abdominal abscesses, and one reactions were detected in 34 patients (43.6% of all meningeal Listeriosis. The majority of infections (11/16, adverse events, 1.56/100 patient-years) including 4 events 68.8%) occurred in patients treated with concomitant progressing to anaphylactic shock - IFX therapy was immunosuppressants. No fatal infectious complications immediately discontinued in these cases. Patients suffer- were observed. ing from mild to moderate allergic reactions were able to finish the IFX therapy by pre-administering parenteral cor- In four cases symptoms of gut stenosis developed after IFX ticosteroids. Despite previous severe allergic reactions, in therapy (0.55%, 0.011/100 patient-years), two cases 2 patients successful desensitization was performed with required surgery. stepwise diluted IFX and they were subsequently re-chal- lenged with continuation of their IFX induction therapy. Three cases of malignant solid tumors were observed (0.82%, 0.137/100 patient-years). The first case was diag- nd Delayed type hypersensitivity reactions (DTHR), charac- nosed on the 2 week of therapy, and was considered terized by muscle pain, fever, joint pain and skin rashes unrelated to IFX treatment. In this case, an abdominal were observed in 17 patients (0.78/100 patient-years). In abscess was the initial diagnosis because of high fever and nd five of these cases the DTHR occurred after the 2 infu- diffuse, sharp abdominal pain. However, the diagnosis of sion of IFX induction regimen, and only one patient was colon malignancy was confirmed based on histological able continue IFX therapy after resolution of the DTHR. evaluation of a tissue sample. In the second case the malignancy was diagnosed in a patient 5 month after the Infections were observed in 16 patients (4.4%, 0.73/100 start of induction therapy. This patient had severe therapy- patient-years) including serious infections in 5 patients resistant and fistulizing CD with a 15-year disease dura- Page 4 of 7 (page number not for citation purposes) BMC Gastroenterology 2009, 9:66 http://www.biomedcentral.com/1471-230X/9/66 Table 2: Remission rate after infliximab induction therapy Indication of IFX therapy Number and rate of remission Overall 167 (46%) Therapy-refractory CD 45 (39.47%) by localization Ileum 3/10 (30%) Colon 7/29 (24.13%) Ileo-colonic 29/46 (63.04%) Ileo-colonic and other small bowel 5/28 (17.85%) Oesophagus 1/1 Therapy-refractory and fistulizing 6 (37.5%) Fistulizing 95 (48.71%) Perianal 72/148 (48.64%) Enterocutaneous 7/24 (29.16%) Enterovaginal 3/11 Other 4/12 Mixed 6/7 Steroid dependent 15 (57.69%) Ileum 3/3 Colon 3/4 Ileo-colic 9/19 (47.36%) Metastatic 5 Na. Other 1 Na. Na = not applicable Table 3: Logistic regression: Predictive factors for response to IFX induction therapy at week 12 in Crohn's disease Factor Coefficient P value OR 95% CI Gender 0,070 0.828 - - Longer disease duration -1.161 < 0.001 0.349 0.165-0.596 (≤ 10 years vs. > 10 years) Disease behavior -0,312 0.349 - - Concomitant AZA/methotrexate use 0.710 0.05 2.03 1.001-4.168 Steroid use -0,438 0.184 - - The coefficient is equivalent to the natural log of the OR; p value: level of significance; OR: odds ratio; 95% CI: 95% confidence interval. Page 5 of 7 (page number not for citation purposes) BMC Gastroenterology 2009, 9:66 http://www.biomedcentral.com/1471-230X/9/66 tion, and was diagnosed with rectal carcinoma resulting in Based on the further data collection a single induction IFX multiple mesenterial adenocarcinoma metastases. The therapy may maintain the remission in a relatively high patient died a few months after the diagnosis. The third proportion of patients with luminal disease [13]. malignant solid tumor observed in this cohort was a lung cancer. The patient was diagnosed 4 months after the start The most common adverse events were allergic reactions. of induction therapy, although chest X-rays obtained prior In our Gastroenterology Centers, steroid pre-medication to the start of IFX induction therapy did not show any evi- was not routinely administered at the initiation of induc- dence of solid tumor. Initially, the patient was observed tion therapy. However, in case of allergic reactions re- for fever, a bad cough and swelling of lower extremities. treatment was attempted applying parenteral corticoster- Computer tomography of the chest revealed the tumor, oid administration and slower infusion rate of IFX accord- which was diagnosed histologically as a squamous cell ing to recommendations of Sandborn et al. [14]. Farrel et carcinoma. The overall mortality rate was 0.82% (0.137/ al. [15] found lower anti-infliximab antibody (ATI) for- 100 patients-years). mation after intravenous hydrocortisone pre-medication. Based on these findings and our experience, regular ster- Discussion oid pre-medication remains questionable when regular The results of this observational study of CD patients immunosuppressant therapy is administered in parallel. treated at eleven Gastroenterology Centers in Hungary confirm the efficacy of IFX induction therapy reported in Two patients despite severe allergic reaction were further previous investigations [5,6]. Data collection was partially treated with IFX based on the instructions of Duburgue et retrospective which was one of the limitations of the al [16]. Applying this method we were able to continue study. Although, all centers had to have collect some data maintenance therapy in one patient, however in the sec- regarding their patients because of financial requirement. ond patient, the second dilution series lead to an allergic These kinds of data were collected in the retrospective and reaction. prospective phase also. The diagnosis of delayed type hypersensitivity reaction Overall response and remission rates observed in this must be considered in case of fever, muscle or joint pain study were 86% and 46%, respectively. Notably, the and rash appear several weeks after IFX therapy [17]. response rate was higher among younger patients, and in Increasing the dose of immunosuppressant and introduc- patients with a shorter duration of CD. Among patients ing corticosteroid pre-medication was effective and safe in with perianal and enterovaginal fistulas a high response one of our patients experiencing a delayed hypersensitiv- rate were observed after IFX therapy, which is in concord- ity reaction [18]. ance with previously reported data [7,8]. Five patients experienced serious infection and all were Higher response and remission rates after induction IFX treated with broad spectrum antibiotics. One of these therapy were observed in patients receiving concomitant patients with meningitis caused by Listeria monocytogenes therapy with immunosuppressants. In Hungary AZA is the had to be further treated in intensive care unit. most commonly used immunosuppressant. Given that there are little data on co-administration of other immu- In two patients tuberculosis was diagnosed (0.55%, 0.09/ nosuppressants would improve the therapeutic benefits of 100-patient years). Based on our experience the observed IFX in CD [9], we conclude that AZA would be an appro- tuberculosis incidence is higher among patients treated priate first choice [10]. In the present study early response with IFX and other immuosupressive co-medication than was higher in patients with concomitant AZA, while the reported average 0.02% tuberculosis incidence in remission rates at week 12 were higher in patients receiv- Hungary in 2005 [19]. Tuberculin skin tests were applied ing steroids. The combined effect of the two drugs was not in all patients before initiating IFX therapy. Results of the investigated. In addition shorter disease duration was tests were hardly interpretable because the immunization associated with a higher response and remission rate in a of a newborn is obligatory in Hungary. It was important logistic regression analysis. Recent results in SONIC study to take into consideration the social circumstances and confirms our experiences, but only in AZA naïve patients family history of the patients in this situation. [11]. In contrast, disease location or behavior were not independent predictors for early response or remission. General incidence of infections was also reported to be higher in IFX treated patients [20], but IFX treatment itself Based on our experience IFX therapy was effective therapy did not predispose to infections [21]. We conclude that for patients with metastatic CD or intractable skin mani- performing a tuberculin test and chest x-ray should be festations. In some cases we achieved significant improve- mandatory in all situations before anti-TNF therapy. Fur- ment of the symptoms, in accordance with results thermore, regular x-ray examination is suggested for IFX- observed by others [12]. treated patients in geographic areas with high prevalence Page 6 of 7 (page number not for citation purposes) BMC Gastroenterology 2009, 9:66 http://www.biomedcentral.com/1471-230X/9/66 8. Orlando A, Colombo E, Kohn A, Biancone L, Rizzello F, Viscido A, of tuberculosis. Overall mortality rate was similar to that Sostegni R, Benazzato L, Castiglione F, Papi C, Meucci G, Riegler G, calculated from the database of the TREAT registry [20]. Mocciaro F, Cassinotti A, Cosintino R, Geremia A, Morselli C, Ange- lucci E, Lavagna A, Rispo A, Bossa F, Scimeca D, Cottone M: Inflixi- mab in the treatment of Crohn's disease: predictors of Conclusion response in an Italian multicentric open study. Dig Liver Dis IFX was safe and effective as induction therapy in this 2005, 37(8):577-583. 9. Caprilli R, Angelucci E, Cocco A, Viscido A, Annese V, Ardizzone S, cohort of Hungarian CD patients. Based on our experi- Biancone L, Castiglione F, Cottone M, Meucci G, Paoluzi P, Papi C, ence in 11 Gastroenterology Centers in Hungary, co- Sturniolo GC, Vecchi M: Appropriateness of immunosuppres- administration of immunosuppressant therapy and sive drugs in inflammatory bowel diseases assessed by RAND method: Italian Group for IBD (IG-IBD) position shorter disease duration was associated with significantly statement. Dig Liver Dis 2005, 37(6):407-417. improved response/remission rates suggested in patients 10. Feagan BGMJ, Ponich T: A randomized trial of methotrexate in receiving IFX induction therapy. combination with infliximab for the treatment of Crohn's disease. Gastroenterology 2008, 135(1):294-295. 11. Colombel JFRP, Reinisch W, Mantzaris GJ, Rachmilewitz D, Lichtiger Competing interests S, D'Haens G, Woude CJ van der, Diamond RH, Broussard D, Hegedus R, Sandborn WJ: SONIC: A randomized, double-blind, The authors declare that they have no competing interests. controlled trial comparing infliximab plus azathioprine to azathioprine in patients with Crohn's disease naive to immu- Authors' contributions nomodulators and biologic therapy. Gut 2008, 57(Suppl II):. OP001(abstract) This study represents a nationwide experience concerning 12. Rispo A, Lembo G, Insabato L, Cozzolino A, Pesce G, Castiglione F: infliximab induction therapy in Crohn's disease. All of the Successful treatment of therapy-resistant metastatic Crohn's disease with infliximab. Br J Dermatol 2004, authors work tertiary reference centers which are able to 150(5):1045-1046. administer infliximab in Hungary. PM, PLL, GM, TM, TS, 13. Molnár TFK, Miheller P, Nyári T, Szepes Z, Herszényi L, Müzes Gy, ZC, ÁS, JC, GR, KP, MP, ZJ, AS, AG, LL, ZB, CB, IR, MZ, ZD, Nagy F, Tulassay Zs, Wittmann T: Is the efficacy of successful inf- liximab induction therapy maintained for one year lasting IA, BH, LS, JP, FN, JL, LÚ, GM, LH, ZT collected data without retreatment in different behavior types of Crohn's regarding their infliximab treated patients and partici- disease. Journal of Crohn's and Colitis 2008, 2(4):322-326. pated in data processing as well and manuscript prepara- 14. Sandborn WJ, Hanauer SB: Infliximab in the treatment of Crohn's disease: a user's guide for clinicians. Am J Gastroenterol tion. PM, TM, GH, PK, ZT and PLL were actively 2002, 97(12):2962-2972. participating in the design of the trial and database con- 15. Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P: Intravenous hydrocortisone premedication reduces anti- struction. Statistical analysis was performed by PLL and bodies to infliximab in Crohn's disease: a randomized con- PM. All authors've read and approved the final manu- trolled trial. Gastroenterology 2003, 124(4):917-924. script. 16. Duburque C, Lelong J, Iacob R, Seddik M, Desreumaux P, Fournier C, Wallaert B, Cortot A, Colombel JF: Successful induction of toler- ance to infliximab in patients with Crohn's disease and prior Acknowledgements severe infusion reactions. Aliment Pharmacol Ther 2006, There was not any support for this observational research. 24(5):851-858. 17. Hanauer SRP, Targan S, Kam L, Present D, Mayer L, Wagner C, LaSorda J, Sands B, Livingston R: Delayed hypersensitivity to inf- References liximab (Remicade) re-infusion after a 2-4 year interval with- 1. Farrell RJ, Shah SA, Lodhavia PJ, Alsahli M, Falchuk KR, Michetti P, out treatment (abstract). Gastroenterology 1999, 116:. Peppercorn MA: Clinical experience with infliximab therapy in A731(abstract) 100 patients with Crohn's disease. Am J Gastroenterol 2000, 18. Miheller P, Muzes G, Lakatos G, Mihaly E, Tulassay Z: Repeated inf- 95(12):3490-3497. liximab therapy after serum sickness-like reaction in Crohn's 2. Hommes DW, Heisteeg BH van de, Spek M van der, Bartelsman JF, disease. J Emerg Med 2007, 32(2):209-210. van Deventer SJ: Infliximab treatment for Crohn's disease: 19. Jonas JBF, Kiss P, Peterfine TM: Incidence and prevalence of one-year experience in a Dutch academic hospital. Inflamm tuberculosis in Hungary in 2005. [http://www.koranyi.hu/ Bowel Dis 2002, 8(2):81-86. evkonyv05/incidencia.htm]. 3. Lichtenstein GR, Yan S, Bala M, Blank M, Sands BE: Infliximab main- 20. Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, tenance treatment reduces hospitalizations, surgeries, and Chen DM, Pritchard ML, Sandborn WJ: Serious infections and procedures in fistulizing Crohn's disease. Gastroenterology 2005, mortality in association with therapies for Crohn's disease: 128(4):862-869. TREAT registry. Clin Gastroenterol Hepatol 2006, 4(5):621-630. 4. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns 21. JF Colombel GDH, Rutgeerts P, Panes J, Fleig WE, Prantera C, Boke- J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers meyer B, Barai U, Wiekowski M: No new safety signals identified WJ, Present D, Sands BE, Colombel JF: Infliximab for induction in Crohn's disease patients treated with infliximab in an and maintenance therapy for ulcerative colitis. N Engl J Med interim review of the ENCORE registry. Journal of Crohn's and 2005, 353(23):2462-2476. Colitis 2009, 2(1):. P013(abstract) 5. Cohen RD: Efficacy and safety of repeated infliximab infusions for Crohn's disease: 1-year clinical experience. Inflamm Bowel Pre-publication history Dis 2001, 7(Suppl 1):S17-22. 6. Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, G VANA, Hoff- The pre-publication history for this paper can be accessed man I, Van Steen K, Vermeire S, Rutgeerts PJ: Long-term outcome here: of treatment with infliximab in 614 Crohn's disease patients: results from a single centre cohort. Gut 2009, 58(4):492-500. 7. Vermeire S, Louis E, Carbonez A, Van Assche G, Noman M, Belaiche http://www.biomedcentral.com/1471-230X/9/66/pre J, De Vos M, Van Gossum A, Pescatore P, Fiasse R, Pelckmans P, Rey- pub naert H, D'Haens G, Rutgeerts P: Demographic and clinical parameters influencing the short-term outcome of anti- tumor necrosis factor (infliximab) treatment in Crohn's dis- ease. Am J Gastroenterol 2002, 97(9):2357-2363. Page 7 of 7 (page number not for citation purposes) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Gastroenterology Springer Journals

Efficacy and safety of infliximab induction therapy in Crohn's Disease in Central Europe - a Hungarian nationwide observational study

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Springer Journals
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Copyright © 2009 by Miheller et al; licensee BioMed Central Ltd.
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Medicine & Public Health; Gastroenterology; Internal Medicine; Hepatology
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Abstract

Background: Infliximab (IFX) has proven to be an effective addition to the therapeutic arsenal for refractory, fistulizing, and steroid dependent Crohn's disease (CD), with efficacy in the induction and maintenance of clinical remission of CD. Our objective in this study is to report the nationwide, multicenter experience with IFX induction therapy for CD in Hungary. Page 1 of 7 (page number not for citation purposes) BMC Gastroenterology 2009, 9:66 http://www.biomedcentral.com/1471-230X/9/66 Methods: During a 6-year-period, beginning in 2000, a total of 363 CD patients were treated with IFX as induction therapy (5 mg/kg IFX infusions given at week 0, 2 and 6) at eleven centers in Hungary in this observational study. Data analysis included patient demographics, important disease parameters and the outcome of IFX induction therapy. Results: Three hundred and sixty three patients (183 women and 180 men) were treated with IFX since 2000. Mean age was 33.5 ± 11.2 years and the mean duration of disease was 6.7 ± 6.1 years. The population included 114 patients (31.4%) with therapy-refractory CD, 195 patients (53.7%) with fistulas, 16 patients (4.4%) with both therapy-refractory CD and fistulas, and 26 patients (7.2%) with steroid dependent CD. Overall response rate was 86.2% (313/363). A higher response rate was observed in patients with shorter disease duration (p = 0.05, OR:0.54, 95%CI:0.29-0.99) and concomitant immunosuppressant therapy (p = 0.05, OR: 2.03, 95%CI:0.165-0.596). Concomitant steroid treatment did not enhance the efficacy of IFX induction therapy. Adverse events included 34 allergic reactions (9.4%), 17 delayed type hypersensitivity (4.7%), 16 infections (4.4%), and 3 malignancies (0.8%). Conclusion: IFX was safe and effective treatment in this cohort of Hungarian CD patients. Based on our experience co-administration of immunosuppressant therapy is suggested in patients receiving IFX induction therapy. However, concomitant steroid treatment did not enhanced the efficacy of IFX induction therapy. comitant medication, indication for biological therapy Background Infliximab (IFX) is a chimeric monoclonal antibody that and outcome of IFX induction therapy were registered ret- binds soluble and membrane bound tumor necrosis fac- rospectively. The study protocol was reviewed and tor-alpha (TNF-α). Previous studies have demonstrated its approved by the Semmelweis University Regional and efficacy in refractory, fistulizing, and steroid dependent Institutional Committee of Science and Research Ethics. Crohn's disease (CD) [1,2]. Furthermore, other studies have shown its efficacy as maintenance therapy for CD Patients with Crohn's Disease eligible for this observa- [3], moreover as induction and maintenance therapy for tional study had 1) single or multiple discharging abdom- ulcerative colitis [4]. inal and/or perianal fistulas of at least 3-6 months duration despite conventional immunosuppressant and In Hungary, IFX has been used in clinical studies since antibiotic therapy; 2) therapy refractory/steroid depend- 2000, and has served as an important component of the ent luminal disease. Minority of patients had active lumi- therapeutic arsenal for the treatment of CD since 2003. nal and fistulizing disease as well. Patients who are either Financial considerations limit the use of IFX treatment for unable to reduce corticosteroids below the equivalent of CD to eleven Hungarian Gastroenterological Centers prednisolone 10 mg/day within three months of starting which are licensed for its administration. Initially, IFX was corticosteroids without recurrent active disease, or who available only for induction therapy for patients suffering have a relapse within three months of stopping corticos- from fistulizing, therapy resistant, or steroid dependent teroids were defined as corticosteroid dependent patient. CD. However, as clinical evidence demonstrates the effi- Corticosteroid refractory disease was defined as active dis- cacy of IFX for maintenance therapy [3], currently IFX is ease despite prednisolone up to 0.75-1 mg/kg/day over a available for maintenance therapy as well. The objective period of four weeks defined as steroid refractory. Patients of this observational study is to report the nationwide, who not tolerate AZA in a dose at least 1.5 mg/kg body multicenter experience with IFX induction therapy for CD weight were considered as AZA intolerant. Failure of in Hungary. immunosupressants (AZA or else) therapy or AZA intoler- ance was an indication for IFX therapy also. Methods This observational study was initiated in 2004, therefore a As induction therapy five mg/kg body weight of inflixi- portion of the patient data (2000 through 2004) are retro- mab was administered in a 2 hour infusion at weeks 0, 2 spective. Patient data through six years from eleven Hun- and 6. In fistulizing disease response was defined as a garian Gastroenterological Centers are included in this decrease of 50% or more in the number of discharging fis- analysis. Microsoft Excel databases were used to compile tulas compared to baseline and remission was defined as and process patient data including demographic charac- absence of any discharging fistulas measured at week 12. teristics, localization and behaviour of the disease, con- In patients with therapy-refractory or steroid dependent Page 2 of 7 (page number not for citation purposes) BMC Gastroenterology 2009, 9:66 http://www.biomedcentral.com/1471-230X/9/66 luminal disease the response was defined as a ≥70 points apy. Detailed data on remission rates are shown in Table decrease in CDAI and a CDAI value below 150 was con- 2. sidered as clinical remission at week 12. The Crohn's Dis- ease Activity Index (CDAI) was calculated only in cases Among 304 (83.7%) patients treated simultaneously with with steroid dependent or therapy-refractory luminal dis- immunosuppressants, 268 responded (88.2%), and 36 ease. failed to respond (11.8%). Fifty nine (16.2%) patients did not receive any concomitant immunosuppressants and Infliximab 5 mg/kg body weight was given as mainte- the response rate was lower in these patients respect to nance therapy after week 6. Maintenance was given every those on concomitant immunosuppressive therapy (73% 8 weeks. The initiation of the maintenance therapy was vs 88.2%, p < 0.05). Among patients with concomitant based on the assessment of response following the induc- immunosuppressants, azathioprine (AZA) was used most tion regimen. However, financial restrictions prevented a frequently (78.9%). Other immunosuppressant therapies significant proportion of patients from receiving mainte- included methotrexate (5.9%), and only one patient nance therapy. Conventional induction therapy (1 mg/kg (0.3%) was treated with cyclosporine and another with body weight steroid therapy) was started in case of early mycophenolate mofetil (0.3%). Response rate to IFX disease relapse in patients with luminal CD. In case of late induction therapy was higher in patients receiving con- relapse (defined as relapse after at least 6 months of remis- comitant AZA or methotrexate (88.3% vs. 76.6%, p = sion) IFX re-induction regimen was administered. 0.014). Statistcal methods During induction therapy co-administration of pre-infu- Variables were tested for normality using Shapiro Wilk's sion corticosteroid therapy was applied in 165 patients. W test. T-test with separate variance estimates, ANOVA Response rates were similar for patients with or without 2 2 with post hoc Scheffe test, χ -test, and χ -test with Yates concomitant steroid treatment (88.5% vs. 85.8%, respec- correction were used to evaluate differences within sub- tively, p = NS). groups of IBD patients. The results are presented as means ± SD. Association between response, remission and clini- Patients who achieved remission or response after induc- cal variables (with variables with a p < 0.2 in univariate tion therapy were significantly younger than patients clas- analysis) was also tested by using logistic regression anal- sified as non-responders (26.8 ± 10.4 years vs. 33.2 ± 11.5 ysis. A p value of < 0.05 was considered as significant. For years of age, p < 0.01), furthermore the duration of CD the statistical analysis, SPSS15.0 (SPSS Inc, Chicago, IL) was shorter (5.9 ± 5.5 years vs. 7.2 ± 4.3 years, p < 0.001). was used. Abdominal surgery prior to IFX therapy was performed in 25.1% of CD patients. This subset of patients was older in Results During a 6-year-period 363 CD patients were treated with age (35 ± 10.9 years of age, p = 0.01), and the mean dura- IFX. The cohort comprised 183 females and 180 males; tion of disease was longer (8.5 ± 6.3 years, p < 0.0001) the mean age was 33.5 ± 11.2 years and the mean duration compared to the entire group of patients. Among patients of disease was 6.7 ± 6.1 years at the time of initiation of with previous surgical intervention 75% responded to IFX induction therapy. induction therapy. One hundred and ninety five (53.7%) fistulizing, 114 Out of 167 patients in remission 136 (81.4%) received (31.4%) therapy-refractory, and 26 (7.2%) steroid simultaneous immunosuppressive regimen. The majority dependent CD patients were treated. All patients were of patients in remission receiving concomitant immuno- naïve to TNFα-inhibitor therapy. Five (0.1%) patients suppressants were treated with AZA (132 patients, with metastatic CD and 7 (0.2%) patients with extra-intes- 97.0%), 4 patients (2.9%) received methotrexate, and tinal manifestations were also treated, but these patients mesalazine or sulphasalazine was used in 128 (93.4%) were not available for assessment of response. The details and 8 (5.9%) of them respectively. regarding the specific indications for IFX therapy are sum- marized in Table 1. A logistic regression analysis was performed to test the association between clinical variables, concomitant med- During the observation period 1,532 IFX infusions were ical therapy and remission and response to IFX induction administered. Complete induction regimen was per- treatment (Table 3.). Duration (p = 0.05, OR: 0.54, formed in 299 patients (82.3%). Overall response rate 95%CI: 0.29-0.99) and concomitant steroid therapy (p = was 86.2% thus 313 patients out of the 363 responded to 0.027, OR: 0.54, 95%CI: 0.31-0.93) were associated with the induction therapy. Details regarding the response rates remission at week 12 in the same logistic regression anal- are shown in Table 1. The overall remission rate was ysis. 46.0% (167 out of 363 patients) after IFX induction ther- Page 3 of 7 (page number not for citation purposes) BMC Gastroenterology 2009, 9:66 http://www.biomedcentral.com/1471-230X/9/66 Table 1: Indications and response rates of infliximab induction therapy Indication of IFX therapy Number and rate of disease type Response rate after induction Therapy-refractory CD 114 (31.4%) 83.3% By localization Ileum 10 (8.77%) Colon 29 (25.4%) 79.3% Ileo-colonic 46 (40.4%) 87.0% Ileo-colonic and small bowel 28 (24.6%) 78.6% Oesophagus 1 (0.9%) 1/1 Therapy-refractory and fistulizing 16 (4.4%) 93.8% Fistulizing 195 (53.7%) 85.6% By localization Perianal 148 (75.9%) 91.2% Enterocutaneous 24 (12.3%) 87.5% Enterovaginal 11 (5.6%) 9/11 Other 12 (6.2%) 7/12 Mixed 7 (3.6%) 5/7 Steroid dependent 26 (7.2%) 92.3% By localization Ileum 3 (11.5%) 3/3 Colon 4 (15.4%) 4/4 Ileo-colic 19 (73.1%) 17/19 Metastatic 5 (0.1%) Na. Other 7 (0.2%) Na. Na = not applicable Adverse events during induction treatment were observed (0.01%, 0.23/100 patient-years) such as two cases of in 78 patients (21.5%, 3.86/100 patient-years). Allergic tuberculosis, two intra-abdominal abscesses, and one reactions were detected in 34 patients (43.6% of all meningeal Listeriosis. The majority of infections (11/16, adverse events, 1.56/100 patient-years) including 4 events 68.8%) occurred in patients treated with concomitant progressing to anaphylactic shock - IFX therapy was immunosuppressants. No fatal infectious complications immediately discontinued in these cases. Patients suffer- were observed. ing from mild to moderate allergic reactions were able to finish the IFX therapy by pre-administering parenteral cor- In four cases symptoms of gut stenosis developed after IFX ticosteroids. Despite previous severe allergic reactions, in therapy (0.55%, 0.011/100 patient-years), two cases 2 patients successful desensitization was performed with required surgery. stepwise diluted IFX and they were subsequently re-chal- lenged with continuation of their IFX induction therapy. Three cases of malignant solid tumors were observed (0.82%, 0.137/100 patient-years). The first case was diag- nd Delayed type hypersensitivity reactions (DTHR), charac- nosed on the 2 week of therapy, and was considered terized by muscle pain, fever, joint pain and skin rashes unrelated to IFX treatment. In this case, an abdominal were observed in 17 patients (0.78/100 patient-years). In abscess was the initial diagnosis because of high fever and nd five of these cases the DTHR occurred after the 2 infu- diffuse, sharp abdominal pain. However, the diagnosis of sion of IFX induction regimen, and only one patient was colon malignancy was confirmed based on histological able continue IFX therapy after resolution of the DTHR. evaluation of a tissue sample. In the second case the malignancy was diagnosed in a patient 5 month after the Infections were observed in 16 patients (4.4%, 0.73/100 start of induction therapy. This patient had severe therapy- patient-years) including serious infections in 5 patients resistant and fistulizing CD with a 15-year disease dura- Page 4 of 7 (page number not for citation purposes) BMC Gastroenterology 2009, 9:66 http://www.biomedcentral.com/1471-230X/9/66 Table 2: Remission rate after infliximab induction therapy Indication of IFX therapy Number and rate of remission Overall 167 (46%) Therapy-refractory CD 45 (39.47%) by localization Ileum 3/10 (30%) Colon 7/29 (24.13%) Ileo-colonic 29/46 (63.04%) Ileo-colonic and other small bowel 5/28 (17.85%) Oesophagus 1/1 Therapy-refractory and fistulizing 6 (37.5%) Fistulizing 95 (48.71%) Perianal 72/148 (48.64%) Enterocutaneous 7/24 (29.16%) Enterovaginal 3/11 Other 4/12 Mixed 6/7 Steroid dependent 15 (57.69%) Ileum 3/3 Colon 3/4 Ileo-colic 9/19 (47.36%) Metastatic 5 Na. Other 1 Na. Na = not applicable Table 3: Logistic regression: Predictive factors for response to IFX induction therapy at week 12 in Crohn's disease Factor Coefficient P value OR 95% CI Gender 0,070 0.828 - - Longer disease duration -1.161 < 0.001 0.349 0.165-0.596 (≤ 10 years vs. > 10 years) Disease behavior -0,312 0.349 - - Concomitant AZA/methotrexate use 0.710 0.05 2.03 1.001-4.168 Steroid use -0,438 0.184 - - The coefficient is equivalent to the natural log of the OR; p value: level of significance; OR: odds ratio; 95% CI: 95% confidence interval. Page 5 of 7 (page number not for citation purposes) BMC Gastroenterology 2009, 9:66 http://www.biomedcentral.com/1471-230X/9/66 tion, and was diagnosed with rectal carcinoma resulting in Based on the further data collection a single induction IFX multiple mesenterial adenocarcinoma metastases. The therapy may maintain the remission in a relatively high patient died a few months after the diagnosis. The third proportion of patients with luminal disease [13]. malignant solid tumor observed in this cohort was a lung cancer. The patient was diagnosed 4 months after the start The most common adverse events were allergic reactions. of induction therapy, although chest X-rays obtained prior In our Gastroenterology Centers, steroid pre-medication to the start of IFX induction therapy did not show any evi- was not routinely administered at the initiation of induc- dence of solid tumor. Initially, the patient was observed tion therapy. However, in case of allergic reactions re- for fever, a bad cough and swelling of lower extremities. treatment was attempted applying parenteral corticoster- Computer tomography of the chest revealed the tumor, oid administration and slower infusion rate of IFX accord- which was diagnosed histologically as a squamous cell ing to recommendations of Sandborn et al. [14]. Farrel et carcinoma. The overall mortality rate was 0.82% (0.137/ al. [15] found lower anti-infliximab antibody (ATI) for- 100 patients-years). mation after intravenous hydrocortisone pre-medication. Based on these findings and our experience, regular ster- Discussion oid pre-medication remains questionable when regular The results of this observational study of CD patients immunosuppressant therapy is administered in parallel. treated at eleven Gastroenterology Centers in Hungary confirm the efficacy of IFX induction therapy reported in Two patients despite severe allergic reaction were further previous investigations [5,6]. Data collection was partially treated with IFX based on the instructions of Duburgue et retrospective which was one of the limitations of the al [16]. Applying this method we were able to continue study. Although, all centers had to have collect some data maintenance therapy in one patient, however in the sec- regarding their patients because of financial requirement. ond patient, the second dilution series lead to an allergic These kinds of data were collected in the retrospective and reaction. prospective phase also. The diagnosis of delayed type hypersensitivity reaction Overall response and remission rates observed in this must be considered in case of fever, muscle or joint pain study were 86% and 46%, respectively. Notably, the and rash appear several weeks after IFX therapy [17]. response rate was higher among younger patients, and in Increasing the dose of immunosuppressant and introduc- patients with a shorter duration of CD. Among patients ing corticosteroid pre-medication was effective and safe in with perianal and enterovaginal fistulas a high response one of our patients experiencing a delayed hypersensitiv- rate were observed after IFX therapy, which is in concord- ity reaction [18]. ance with previously reported data [7,8]. Five patients experienced serious infection and all were Higher response and remission rates after induction IFX treated with broad spectrum antibiotics. One of these therapy were observed in patients receiving concomitant patients with meningitis caused by Listeria monocytogenes therapy with immunosuppressants. In Hungary AZA is the had to be further treated in intensive care unit. most commonly used immunosuppressant. Given that there are little data on co-administration of other immu- In two patients tuberculosis was diagnosed (0.55%, 0.09/ nosuppressants would improve the therapeutic benefits of 100-patient years). Based on our experience the observed IFX in CD [9], we conclude that AZA would be an appro- tuberculosis incidence is higher among patients treated priate first choice [10]. In the present study early response with IFX and other immuosupressive co-medication than was higher in patients with concomitant AZA, while the reported average 0.02% tuberculosis incidence in remission rates at week 12 were higher in patients receiv- Hungary in 2005 [19]. Tuberculin skin tests were applied ing steroids. The combined effect of the two drugs was not in all patients before initiating IFX therapy. Results of the investigated. In addition shorter disease duration was tests were hardly interpretable because the immunization associated with a higher response and remission rate in a of a newborn is obligatory in Hungary. It was important logistic regression analysis. Recent results in SONIC study to take into consideration the social circumstances and confirms our experiences, but only in AZA naïve patients family history of the patients in this situation. [11]. In contrast, disease location or behavior were not independent predictors for early response or remission. General incidence of infections was also reported to be higher in IFX treated patients [20], but IFX treatment itself Based on our experience IFX therapy was effective therapy did not predispose to infections [21]. We conclude that for patients with metastatic CD or intractable skin mani- performing a tuberculin test and chest x-ray should be festations. In some cases we achieved significant improve- mandatory in all situations before anti-TNF therapy. Fur- ment of the symptoms, in accordance with results thermore, regular x-ray examination is suggested for IFX- observed by others [12]. treated patients in geographic areas with high prevalence Page 6 of 7 (page number not for citation purposes) BMC Gastroenterology 2009, 9:66 http://www.biomedcentral.com/1471-230X/9/66 8. Orlando A, Colombo E, Kohn A, Biancone L, Rizzello F, Viscido A, of tuberculosis. Overall mortality rate was similar to that Sostegni R, Benazzato L, Castiglione F, Papi C, Meucci G, Riegler G, calculated from the database of the TREAT registry [20]. Mocciaro F, Cassinotti A, Cosintino R, Geremia A, Morselli C, Ange- lucci E, Lavagna A, Rispo A, Bossa F, Scimeca D, Cottone M: Inflixi- mab in the treatment of Crohn's disease: predictors of Conclusion response in an Italian multicentric open study. Dig Liver Dis IFX was safe and effective as induction therapy in this 2005, 37(8):577-583. 9. Caprilli R, Angelucci E, Cocco A, Viscido A, Annese V, Ardizzone S, cohort of Hungarian CD patients. Based on our experi- Biancone L, Castiglione F, Cottone M, Meucci G, Paoluzi P, Papi C, ence in 11 Gastroenterology Centers in Hungary, co- Sturniolo GC, Vecchi M: Appropriateness of immunosuppres- administration of immunosuppressant therapy and sive drugs in inflammatory bowel diseases assessed by RAND method: Italian Group for IBD (IG-IBD) position shorter disease duration was associated with significantly statement. Dig Liver Dis 2005, 37(6):407-417. improved response/remission rates suggested in patients 10. Feagan BGMJ, Ponich T: A randomized trial of methotrexate in receiving IFX induction therapy. combination with infliximab for the treatment of Crohn's disease. Gastroenterology 2008, 135(1):294-295. 11. Colombel JFRP, Reinisch W, Mantzaris GJ, Rachmilewitz D, Lichtiger Competing interests S, D'Haens G, Woude CJ van der, Diamond RH, Broussard D, Hegedus R, Sandborn WJ: SONIC: A randomized, double-blind, The authors declare that they have no competing interests. controlled trial comparing infliximab plus azathioprine to azathioprine in patients with Crohn's disease naive to immu- Authors' contributions nomodulators and biologic therapy. Gut 2008, 57(Suppl II):. OP001(abstract) This study represents a nationwide experience concerning 12. Rispo A, Lembo G, Insabato L, Cozzolino A, Pesce G, Castiglione F: infliximab induction therapy in Crohn's disease. All of the Successful treatment of therapy-resistant metastatic Crohn's disease with infliximab. Br J Dermatol 2004, authors work tertiary reference centers which are able to 150(5):1045-1046. administer infliximab in Hungary. PM, PLL, GM, TM, TS, 13. Molnár TFK, Miheller P, Nyári T, Szepes Z, Herszényi L, Müzes Gy, ZC, ÁS, JC, GR, KP, MP, ZJ, AS, AG, LL, ZB, CB, IR, MZ, ZD, Nagy F, Tulassay Zs, Wittmann T: Is the efficacy of successful inf- liximab induction therapy maintained for one year lasting IA, BH, LS, JP, FN, JL, LÚ, GM, LH, ZT collected data without retreatment in different behavior types of Crohn's regarding their infliximab treated patients and partici- disease. Journal of Crohn's and Colitis 2008, 2(4):322-326. pated in data processing as well and manuscript prepara- 14. Sandborn WJ, Hanauer SB: Infliximab in the treatment of Crohn's disease: a user's guide for clinicians. Am J Gastroenterol tion. PM, TM, GH, PK, ZT and PLL were actively 2002, 97(12):2962-2972. participating in the design of the trial and database con- 15. Farrell RJ, Alsahli M, Jeen YT, Falchuk KR, Peppercorn MA, Michetti P: Intravenous hydrocortisone premedication reduces anti- struction. Statistical analysis was performed by PLL and bodies to infliximab in Crohn's disease: a randomized con- PM. All authors've read and approved the final manu- trolled trial. Gastroenterology 2003, 124(4):917-924. script. 16. Duburque C, Lelong J, Iacob R, Seddik M, Desreumaux P, Fournier C, Wallaert B, Cortot A, Colombel JF: Successful induction of toler- ance to infliximab in patients with Crohn's disease and prior Acknowledgements severe infusion reactions. Aliment Pharmacol Ther 2006, There was not any support for this observational research. 24(5):851-858. 17. Hanauer SRP, Targan S, Kam L, Present D, Mayer L, Wagner C, LaSorda J, Sands B, Livingston R: Delayed hypersensitivity to inf- References liximab (Remicade) re-infusion after a 2-4 year interval with- 1. Farrell RJ, Shah SA, Lodhavia PJ, Alsahli M, Falchuk KR, Michetti P, out treatment (abstract). Gastroenterology 1999, 116:. Peppercorn MA: Clinical experience with infliximab therapy in A731(abstract) 100 patients with Crohn's disease. Am J Gastroenterol 2000, 18. Miheller P, Muzes G, Lakatos G, Mihaly E, Tulassay Z: Repeated inf- 95(12):3490-3497. liximab therapy after serum sickness-like reaction in Crohn's 2. Hommes DW, Heisteeg BH van de, Spek M van der, Bartelsman JF, disease. J Emerg Med 2007, 32(2):209-210. van Deventer SJ: Infliximab treatment for Crohn's disease: 19. Jonas JBF, Kiss P, Peterfine TM: Incidence and prevalence of one-year experience in a Dutch academic hospital. Inflamm tuberculosis in Hungary in 2005. [http://www.koranyi.hu/ Bowel Dis 2002, 8(2):81-86. evkonyv05/incidencia.htm]. 3. Lichtenstein GR, Yan S, Bala M, Blank M, Sands BE: Infliximab main- 20. Lichtenstein GR, Feagan BG, Cohen RD, Salzberg BA, Diamond RH, tenance treatment reduces hospitalizations, surgeries, and Chen DM, Pritchard ML, Sandborn WJ: Serious infections and procedures in fistulizing Crohn's disease. Gastroenterology 2005, mortality in association with therapies for Crohn's disease: 128(4):862-869. TREAT registry. Clin Gastroenterol Hepatol 2006, 4(5):621-630. 4. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns 21. JF Colombel GDH, Rutgeerts P, Panes J, Fleig WE, Prantera C, Boke- J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers meyer B, Barai U, Wiekowski M: No new safety signals identified WJ, Present D, Sands BE, Colombel JF: Infliximab for induction in Crohn's disease patients treated with infliximab in an and maintenance therapy for ulcerative colitis. N Engl J Med interim review of the ENCORE registry. Journal of Crohn's and 2005, 353(23):2462-2476. Colitis 2009, 2(1):. P013(abstract) 5. Cohen RD: Efficacy and safety of repeated infliximab infusions for Crohn's disease: 1-year clinical experience. Inflamm Bowel Pre-publication history Dis 2001, 7(Suppl 1):S17-22. 6. Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, G VANA, Hoff- The pre-publication history for this paper can be accessed man I, Van Steen K, Vermeire S, Rutgeerts PJ: Long-term outcome here: of treatment with infliximab in 614 Crohn's disease patients: results from a single centre cohort. Gut 2009, 58(4):492-500. 7. Vermeire S, Louis E, Carbonez A, Van Assche G, Noman M, Belaiche http://www.biomedcentral.com/1471-230X/9/66/pre J, De Vos M, Van Gossum A, Pescatore P, Fiasse R, Pelckmans P, Rey- pub naert H, D'Haens G, Rutgeerts P: Demographic and clinical parameters influencing the short-term outcome of anti- tumor necrosis factor (infliximab) treatment in Crohn's dis- ease. Am J Gastroenterol 2002, 97(9):2357-2363. Page 7 of 7 (page number not for citation purposes)

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Published: Sep 10, 2009

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