Department of Medicine, Division of Gastroenterology, Helsinki University Central Hospital, Helsinki, Finland;

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1 ORIGINAL ARTICLE Outcome After Discontinuation of TNFa-blocking Therapy in Patients with Inflammatory Bowel Disease in Deep Remission Pauliina Molander, MD,* Martti Färkkilä, MD, PhD,, Kimmo Salminen, MD, PhD, Helena Kemppainen, MD, PhD, Timo Blomster, MD, k Ritva Koskela, MD, PhD, k Airi Jussila, MD, Henna Rautiainen, MD, PhD,** Markku Nissinen, MD, PhD, Johanna Haapamäki, MD, PhD,, Perttu Arkkila, MD, PhD, Urpo Nieminen, MD, PhD, Juha Kuisma, MD, PhD, Jari Punkkinen, MD, PhD, Kaija-Leena Kolho, MD, PhD, kk Harri Mustonen, DSc, and Taina Sipponen, MD, PhD Background: Few data are available on the disease course in patients with inflammatory bowel disease (IBD) in deep remission after discontinuing tumor necrosis factor a (TNFa) blocking therapy. In this prospective multicenter study, we evaluated the relapse rate, predictive factors, and the response to retreatment after discontinuation of TNFa-blocking therapy in patients with IBD in deep remission. Methods: We recruited 52 patients (17 Crohn s disease, 30 ulcerative colitis, and 5 IBD unclassified) in clinical, endoscopic, and fecal calprotectin-based (,100 mg/g) remission after at least 1 year of TNFa-blocking therapy. Clinical and endoscopic remission and relapse were defined according to validated indices. After discontinuation of therapy, the patients were followed up with endoscopic assessment at 4 and 12 months. In the event of a clinical relapse with endoscopically active disease or minor clinical symptoms but severe endoscopic relapse, TNFa-blocking therapy was restarted. Results: After a median follow-up time of 13 (range, 12 15) months, 17/51 (33%) patients relapsed (5/17 Crohn s disease, 12/34 ulcerative colitis/ibd unclassified, 1 patient lost to follow-up at 6 mo). Ten experienced clinical and endoscopic relapse, 5 clinical relapse with mild endoscopic activity, and 2 severe endoscopic relapse. No specific predictive factors were associated with the relapse. Retreatment was effective in 94% of patients. Conclusions: After cessation of TNFa-blocking therapy in patients with IBD in deep remission, up to 67% remained in clinical remission during the 12-month follow-up. Importantly, 85% of these patients sustained endoscopic remission. The response to restart of TNFa antagonists was effective and well tolerated. (Inflamm Bowel Dis 2014;20: ) Key Words: Crohn s disease, ulcerative colitis, relapse, remission, TNFa-blocking therapy The tumor necrosis factor a (TNFa) antagonists, infliximab and adalimumab, induce and maintain remission in patients with moderate-to-severe Crohn s disease (CD) 1,2 and ulcerative colitis (UC). 3,4 The chronic nature of inflammatory bowel disease (IBD) and lack of recommendations for discontinuing the TNFa-blocking therapy may lead to long-term maintenance therapy with TNFa antagonists, raising questions on safety and economic issues. Acute infusion reactions, delayed hypersensitivity reactions, and infections Received for publication February 19, 2014; Accepted March 24, From the *Department of Medicine, Division of Gastroenterology, Maria Helsinki City Hospital and University of Helsinki, Helsinki, Finland; Department of Medicine, Division of Gastroenterology, Helsinki University Central Hospital, Helsinki, Finland; Division of Gastroenterology, Department of Medicine, Institute of Clinical Medicine, University of Helsinki, Helsinki, Finland; Department of Medicine, Division of Gastroenterology, Turku University Central Hospital, Turku, Finland; k Department of Medicine, Division of Gastroenterology, Oulu University Central Hospital, Oulu, Finland; Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland; **Department of Medicine, Division of Gastroenterology, Helsinki University Central Hospital, Jorvi Hospital, Espoo, Finland; Department of Medicine, Division of Gastroenterology, Helsinki University Central Hospital, Peijas Hospital, Vantaa, Finland; Department of Medicine, Hyvinkää Hospital, Hyvinkää, Finland; Department of Medicine, Porvoo Hospital, Porvoo, Finland; kk Children s Hospital, Helsinki University Central Hospital, Helsinki, Finland; and Department of Surgery, Helsinki University Central Hospital, Biomedicum Helsinki, Finland. P. Molander received lecture fees from Abbvie and MSD and consulting fees from Abbvie and Tillotts Pharma. M. Färkkilä received consulting fees from MSD, Abbvie, Janssen, Orion Pharma, Medivir, and Roche, and lecture fees from MSD, Abbvie, Bayer, Janssen, and Tillots Pharma. R. Koskela received consulting fees from MSD and lecture fees from Orion Pharma and Tillotts Pharma. T. Blomster received lecture fees from Abbvie and Tillotts Pharma and consulting fees from Abbvie. A. Jussila received lecture fees from Abbvie, MSD, and Tillotts Pharma and consulting fees from Abbvie and MSD. P. Arkkila received lecture fees from Abbvie, MSD, GSK, and Roche. J. Haapamäki received lecture fees from MSD and consulting fees from Tillotts Pharma. H. Rautiainen received lecture fees from MSD, Roche, and Tillotts Pharma. J. M. Punkkinen received consulting fees from Almirall and Shire. K-L. Kolho received consulting fees from MSD, Abbvie, and Tillotts Pharma. The remaining authors have no conflicts of interest to disclose. Supported by grants from the Helsinki University Central Hospital Research Fund (EVO grant), the Finnish Cultural Foundation, Mary and George C. Ehrnrooth Foundation and Finnish Foundation for Gastroenterological Research. Reprints: Pauliina Molander, MD, Department of Medicine, Division of Gastroenterology, Maria Helsinki City Hospital, 6501, Helsinki FIN-00099, Finland ( pauliina.molander@welho.com). Copyright 2014 Crohn s & Colitis Foundation of America, Inc. DOI /MIB Published online 2 May Inflamm Bowel Dis Volume 20, Number 6, June

2 Molander et al Inflamm Bowel Dis Volume 20, Number 6, June 2014 are the most common side effects. 5 The slightly increased risk of lymphomas in patients with IBD treated with TNFa-blocking agents 6,7 and safety issues during pregnancy are still to some extend unclear. 8 Although decision analysis models have established that TNFa-blocking agents are cost-effective, 9,10 it is by no means certain that these agents are cost-effective in the long run. Disappointingly, a recent systematic survey and meta-analysis on TNFa-blocking agents demonstrated no reduction in the need for surgery. 11 Thus, the debate on optimal treatment strategies is ongoing. In clinical practice, the decision on whether to continue or discontinue treatment in patients in deep remission is still very much based on assessment of the patient s individual risks and benefits. Existing guidelines have concluded that because of limited evidence, no recommendations can be made on when and in whom to discontinue TNFa-blocking therapy after having obtained clinical remission However, evaluation of the risks and benefits of continuing the therapy after 1 year of treatment is recommended. 14 Several studies are available that have identified candidates for TNFa-blocking agent withdrawal, mainly in patients with CD. These studies have shown that up to half of the patients with IBD in stable remission relapsed within 2 years after discontinuing the TNFa-blocking therapy. Importantly, these studies have demonstrated that higher risk of relapse is associated with risk factors, such as short duration of remission, previous surgical operations, endoscopically active disease, high markers of inflammation, and high infliximab trough level. Reassuringly, retreatment with infliximab is effective and well tolerated The aim of this study was to assess the relapse rate and predictive factors of relapse after cessation of maintenance therapy with TNFa-blocking agents in patients with IBD in deep remission, defined as no clinical symptoms, concomitant endoscopic remission, and normal fecal calprotectin (FC) concentration (,100 mg/g). 19 In addition, we evaluated the response to retreatment with TNFa-blocking agents in the event of relapse. MATERIALS AND METHODS Patients This prospective multicenter study was carried out at 9 gastroenterological units in Finland between February 2010 and June All patients were at least 18 years of age and had an established IBD diagnosis, based on endoscopic and histological criteria. Patients with CD, UC, and IBD unclassified (IBDU) were recruited. Eligible patients had received TNFa-blocking maintenance therapy for a minimum of 1 year. All patients were in clinical and endoscopic remission and had normal FC levels (,100 mg/g) at the time of the ileocolonoscopy and were also in corticosteroidfree remission over the 6 months previous to the inclusion. The exclusion criteria in this study included escalation of TNFa-blocking agents during the previous 6 months, perianal disease with no other effective medication available, history of relapse after TNFablocking agent withdrawal, severe arthritis as an concomitant indication for TNFa-blocking therapy, and pregnancy. Study Design At baseline, all patients underwent an ileocolonoscopy, and clinical and demographic data were collected. After cessation of TNFa-blocking therapy, the patients were followed up for at least 12 months or, in the event of relapse, up to 12 months after the retreatment. Follow-up contacts with clinical activity assessment were performed every 4 weeks up to 6 months and later every 2 months up to 12 months. The median duration of infliximab treatment before cessation of therapy was 13 (n ¼ 46; range, 11 77) months and the median duration of adalimumab therapy was 27 (n ¼ 5; range, 16 36) months. No changes were made to the immunosuppressive medication after cessation of TNFa-blocking therapy. Endoscopic assessment of disease activity was performed at 4 and 12 months after drug withdrawal. The blood samples for hemoglobin, white blood cell count, platelet count, and C-reactive protein (CRP) levels were drawn at baseline and 2, 4, 8, and 12 months after withdrawal. In the event of clinical relapse, ileocolonoscopy was performed, except in patients who had undergone an ileocolonoscopy less than 2 months before relapse and in whom the endoscopic disease activity had been at least moderate (Simple endoscopic score for Crohn s disease [SES-CD].7 or Mayo endoscopic score $2) without clinical relapse. In the event of clinically and endoscopically active disease or severe endoscopic relapse (SES-CD, 7 15 or Mayo endoscopic score of 3), the TNFa-blocking therapy was restarted. The patients were retreated with infliximab or adalimumab at the same dose and frequency as before withdrawal. Blood and stool samples were taken, and a clinical activity index was scored at the time of relapse and 1, 3, and 12 months after the restart. The ileocolonoscopy was performed at 12 months after restart of TNFa-blocking therapy. Clinical Criteria of Remission and Relapse Clinical disease activity was assessed with the Harvey Bradshaw Index (HBI) 20 in CD and with the Mayo score 21 in UC and IBDU every 4 weeks up to 6 months and later every 2 months up to 12 months. Clinical remission was defined as HBI,4, mildly active disease as HBI of 4 7, moderately active disease as HBI of 8 16, and severely active disease as HBI $17. Clinical relapse was defined as HBI $8 or an increase of.3 points in HBI to at least an HBI of 5 points. 22 For partial Mayo score (without endoscopic subscore), 3 different clinical variables were graded: frequency of evacuation (0 3), amount of blood in the stool (0 3), and overall well-being (0 3). A partial Mayo score of 0 was defined as remission, and clinical relapse was defined as a partial Mayo score $3. 21 Endoscopic Criteria of Remission and Relapse During all endoscopies performed, experienced gastroenterologists scored the endoscopic findings according to the SES-CD 23 in CD and according to the Mayo endoscopic subscore

3 Inflamm Bowel Dis Volume 20, Number 6, June 2014 TNFa-blocking Therapy in Patients with IBD in UC and IBDU. 21 An SES-CD of 0 2 was defined as remission, 3 6 as mildly active disease, 7 15 as moderately active disease, and $16 as severely active disease. 24 For the Mayo endoscopic subscore, the findings were graded as normal (0), mild (1), moderate (2), or severe (3); a subscore of 0 1 was defined as remission, and a subscore of $2 as active disease. 25 Stool Samples for FC Assays At baseline, all patients showed FC concentrations,100 mg/g, the value quoted as normal in our laboratory. 19 FC was measured by a quantitative enzyme immunoassay (the CALPRO calprotectin enzyme-linked immunosorbent assay test [ALP; Calpro AB, Lysaker, Norway]). Stool samples for FC were collected every month up to 6 months and every 2 months up to 12 months and stored at 2208C until for later analyses. Assessment of Quality of Life The patients were asked to fill out questionnaires on the quality of life (Inflammatory Bowel Disease Questionnaire [IBDQ] and 15D) at baseline, at the time of possible relapse, and at the time of the ileocolonoscopies. Inflammatory Bowel Disease Questionnaire The disease-specific health-related quality of life was assessed with the IBDQ, a standardized 32-item questionnaire in which the responses are graded on a 7-point Likert scale. A total IBDQ score, ranging from 32 to 224, is calculated by summing 4 different aspects of life (digestive symptoms, social function, emotional status, and systemic symptoms) with a higher score indicating better quality of life. 26,27 The IBDQ was used under license from McMaster University, Hamilton, Ontario, Canada. The 15D The single-index score (15D) is a generic, standardized, and self-administered measure of health-related quality of life among adults. The 15D includes the following 15 dimensions: breathing, mental function, speech (communication), vision, mobility, usual activities, vitality, hearing, eating, elimination, sleeping, distress, discomfort and symptoms, sexual activity, and depression. The 15D score varies from 0 (decreased) to 1 (no problems in any dimension). A difference of $0.03 in the 15D score is considered clinically important in the sense that a person can, on an average, feel the difference. 28 Statistics For data analyses, we used the Statistical Package for the Social Sciences (SPSS version 17.0 and PASW 18) for Windows software (SPSS, Chicago, IL). The results were given as percentages, as median and range or as mean and SDs. Normality of the continuous variables was tested with the Kolmogorov Smirnov test. The t test was used to test for differences between groups in continuous normally distributed variables and the Mann Whitney U test for differences between groups in non-normally distributed variables and in variables with ordered categories. Fisher s exact test was used to determine differences in binary variables. The significance was set at P, 0.05, and two-tailed tests were used. Kaplan Meier survival analysis served for estimation of relapse-free survival rates, and the log-rank test was used to determine the differences between the groups. The Cox regression of proportional hazards was used to calculate univariate hazard ratios for categorical and continuous variables. Ethical Statement The study protocol and all documents were approved by the ethics committees at Helsinki University Central Hospital and at each participating University Central Hospital. All patients gave their informed written consent for participation in this study. Research study permission number, 195/2009, was received from the Department of Medicine, Helsinki University Central Hospital in December RESULTS The baseline characteristics (and concomitant medications) of the 52 patients included are described in Table 1. Because of its small size, the subgroup IBDU with 5 patients was combined with the UC group. One patient with UC was dropped out at 6 months while in clinical remission. Of the remaining 51 patients, 5/17 patients with CD (29%) and 12/34 patients with UC/IBDU (35%) relapsed after a median follow-up time of 13 months (range, 12 15) (Fig. 1). Relapses occurred at a median of 6 months (range, ) after cessation of TNFa-blocking therapy. Importantly, at a median of 13 months after cessation of therapy, 67% of patients remained in clinical remission, and of these patients, 85% (29/34) were also in endoscopic remission. The timeto-relapse curve of patients with IBD is shown in Figure 2 and with CD or UC/IBDU in Figure 3. No significant difference was found in the relapse rate between CD and UC/IBDU, P ¼ Relapse Rate Of 52 patients, 10 patients (19%) (3 CD, 7 UC) experienced both clinical and endoscopic relapse and 2 patients with CD (4%) experienced a nonsymptomatic severe endoscopic relapse. Five patients with UC (10%) experienced clinical relapse with mild endoscopic activity (Mayo score 1) not fulfilling the predefined criteria for endoscopic relapse (endoscopic Mayo score $2) but were considered as relapsers (severe symptoms + mild activity). No clinical relapse without any signs of endoscopic activity occurred (Table 2). At the time of relapse, 14 patients (82%) were on immunosuppressive therapy and 3 patients received mesalamine as a monotherapy. Risk Factors for Relapse Based on univariate analysis (Cox model), no specific factors such as gender, age at diagnosis, disease duration, localization or behavior of the disease, smoking, previous surgery, the TNFa-blocking therapy used, duration of the TNFa-blocking

4 Molander et al Inflamm Bowel Dis Volume 20, Number 6, June 2014 TABLE 1. Patient Characteristics at Baseline Characteristics CD (n¼ 17) UC/IBDU (n¼ 35) Age at onset, median (range) 22 (13 42) 26 (8 45) Age at induction, median (range) 32 (15 52) 32 (13 58) Gender (female/male) 9/8 15/20 Active smoker, n (%) 4 (24) 4 (13) Disease duration, median (range) 10 (3 26) 6 (1 35) Disease behavior (Mb Crohn), n (%) Inflammatory (B1) 11 (65) Stricturing (B2) 4 (23) Penetrating (B3) 1 (6) B1 6 perianal disease 0 B2 6 perianal disease 1 (6) B3 6 perianal disease 0 Disease location Ileum (L1) 1 Proctitis 0 Colon (L2) 4 Left colon 15 Ileocolon (L3) 12 Extensive colitis 20 Previous surgical resection, n (%) 8 (47) TNFa-blocking therapy, n (%) Infliximab 12 (71) 35 (100) Adalimumab 5 (29) Duration of TNFa-blocking therapy before cessation of therapy (mo) Infliximab, median (range) 32 (11 72) 14 (11 78) Adalimumab, median (range) 26 (16 36) Concomitant medications, n (%) No concomitant medications 1 (6) 1 (3) Mesalamine 3 (18) 4 (12) Azathioprine/6-MP 7 (41) 12 (34) Azathioprine/6-MP + mesalamine 5 (29) 18 (51) Methotrexate + mesalamine 1 (6) Biologic variables, median (range) Hemoglobin level (g/l) 136 ( ) 141 ( ) Leukocyte count (10 9/L) 4.9 ( ) 4.7 ( ) Platelet count (10 9/L) 265 ( ) 250 ( ) CRP (mg/l),3 (,3 16),3 (,3 15) Fecal calprotectin (mg/g) 55 (7 99) 34 (3 97) 6-MP, 6-Mercaptopurine. therapy, concomitant medications, quality of life, or hemoglobin or CRP levels at the time of discontinuation were associated with the relapse (Table 3). Restart of TNFa-blocking Therapy The median time of follow-up after retreatment with TNFablocking agents was 12 months (range, 9 14). No serious adverse events or infusion reactions were reported in the retreated patients during the follow-up. One patient with UC with relapse was treated with corticosteroid instead of TNFa-blocking agents and was withdrawn from the restart follow-up study and another patient with UC without response to restart of infliximab underwent colectomy less than 2 months after the restart of TNFa-blocking therapy. At 3 months, 14 of 15 patients (93%) were in clinical remission. At 12 months, follow-up data were available for 14 patients (4 CD, 10 UC). All 4 patients with CD and 9 (90%) patients with UC were in clinical remission at 12 months. Three patients with CD and 9 patients with UC underwent a 12-month follow-up ileocolonoscopy, showing mild activity in all 3 patients with CD but endoscopic remission in all patients with UC. There was no tendency toward increase in clinical or endoscopic activity indices or decrease in IBDQ or 15D scores before actual relapse

5 Inflamm Bowel Dis Volume 20, Number 6, June 2014 TNFa-blocking Therapy in Patients with IBD FIGURE 1. Trial profile. occurred (data not shown). As expected, the IBDQ score (193 [ ] versus 142 [ ], P, 0.001) and 15D score (0.955 [ ] versus [ ], P, 0.001) were significantly lower at relapse, but the difference was no longer found at 12 months after the restart of TNFa-blocking therapy (P ¼ and P ¼ 1.0, respectively). DISCUSSION To our knowledge, this is the first prospective study to demonstrate the duration of remission after discontinuation of TNFa-blocking therapy in patients with IBD in clinical, endoscopic, and FC-based remission (i.e., deep remission) including both patients with UC and CD. This study demonstrates that up to 67% of patients FIGURE 2. Duration of remission after discontinuation of TNFa-blocking agents in patients with IBD, n ¼ 17/51. FIGURE 3. Duration of remission after discontinuation of TNFa-blocking agents in patients with Crohn s disease (CD), n ¼ 5/17 or ulcerative colitis (UC)/inflammatory bowel disease unclassified (IBDU), n ¼ 12/

6 Molander et al Inflamm Bowel Dis Volume 20, Number 6, June 2014 TABLE 2. Relapse Rate CD (%) UC (%) Clinical relapse (with mild endoscopic activity) 5/12 (42) Endoscopic relapse 2/5 (40) Clinical and endoscopic relapse 3/5 (60) 7/12 (58) with IBD in deep remission at the time of cessation of TNFa-blocking therapy remained in clinical remission during the 12-month followup. The majority of patients (85%) in clinical remission also remained in endoscopic remission. Furthermore, the response to restart of TNFa antagonists seemed to be effective and well tolerated. Several studies, mainly with patients with CD, have been published on the duration of remission after discontinuation of TNFa-blocking therapy, and none of these studies has assessed endoscopic activity during the follow-up. In the observational prospective STORI trial, patients with CD in clinical remission were included, and a baseline endoscopy with scoring of the CD endoscopic index of severity was performed, but endoscopic remission was not an inclusion criterion. 15 Of 115 patients with CD, 56% remained in clinical remission 1 year after discontinuation of infliximab. In their study, 23% of baseline CD endoscopic index of severity values were above a score of 3% and 34% of patients had ulcers remaining, indicating ongoing inflammatory activity at the time of cessation of the therapy that differed from that in our study. In the STORI trial, 74% of patients had a baseline FC measurement that was elevated in some patients. Furthermore, their trial identified the male individuals, the absence of previous surgical resection, steroid treatment in the previous 6 12 months, an endoscopic activity score.0, hemoglobin 145 g/l, white blood count /L, a CRP level 5.0 mg/l, FC 300 mg/g, and high drug trough level as predictors of relapse after the discontinuation of infliximab. Interestingly, simplified model that did not include infliximab trough level, steroid use, or CD endoscopic index of severity score indicated that the presence of 2 or fewer of the remaining 6 risk factors was associated with a 15% risk of relapse. Relapse results comparable with those in the STORI trial were recently published by Molnar et al 29 for patients with CD in clinical TABLE 3. Demographic, Clinical, and Laboratory Variables and the Relapse in the Study Population Variables Relapse (n ¼ 17) Remission (n ¼ 34) Hazard Ratio 95% CI P Male sex (%) 9 (53) 19 (56) Positive family history 2 (12) 8 (24) Age at diagnosis, median (range), yr 22 (8 44) 26 (16 45) Age at induction of the TNFa-blocking therapy, median (range), yr 32 (13 52) 32 (17 58) Duration of the disease, median (range), yr 8 (2 26) 7 (1 35) Duration of the TNFa-blocking therapy, median (range), mo 26 (10 71) 22 (10 77) Localization of CU Proctosigmoiditis 5 (45%) 10 (45%) 1.00 Extensive colitis 6 (55%) 12 (55%) Localization of CD Ileum 1 (16%) Ileocolon 4 (66%) 9 (75%) Colon 1 (17%) 3 (25%) Disease behavior (Mb Crohn) Inflammatory (B1) 5 (83%) 7 (58%) Stricturing (B2) 1 (17%) 3 (25%) Penetrating (B3) 1 (8%) B2 + perianal 1 (8%) Previous surgery 1 (6%) 7 (21%) Smoker or previous smoker 4 (24%) 16 (47%) TNFa-blocking therapy used Infliximab 16 (94%) 30 (88%) 1.00 Adalimumab 1 (6%) 4 (12%) Concomitant immunosuppressive therapy 14 (82%) 29 (85%) CRP at discontinuation mean (range) 2.6 (1 3) 3.8 (1 16) Hemoglobin at discontinuation 142 ( ) 138 ( ) IBDQ at discontinuation, mean (range) 193 ( ) 197 ( ) D at discontinuation, mean (range) 0.96 ( ) 0.95 ( )

7 Inflamm Bowel Dis Volume 20, Number 6, June 2014 TNFa-blocking Therapy in Patients with IBD remission after 1 year of TNFa antagonist treatment. In their study, dose intensification, previous biological therapy, smoking and steroid therapy at the time of induction, CRP.10 mg/l at the beginning and end of therapy, and male individuals were identified as predictors of the need for restarting biological therapy. Nonetheless, many of the risk factors shown in previous studies were associated with incomplete remission with ongoing inflammatory disease activity at the time of discontinuation, which may explain the lower remission rate than in our study, which included only patients in deep IBD remission. In our study, because of tight inclusion and exclusion criteria, no patients with moderate or severe perianal CD or with severe arthritis were included. These tight criteria could, in theory, explain the high remission rate in our study. However, we consider this unlikely, because our exclusion criteria are comparable with those used in STORI trial, 15 where patients with predominantly fistulizing perianal disease without significant luminal disease, with active fistulizing disease, and with severe extraintestinal manifestations were excluded. In a study of patients with CD with a longer follow-up after discontinuation of therapy, 35% of patients with CD remained in sustained clinical remission for nearly 7 years. 17 In their study, no extrinsic factor was associated with the duration of CD remission. So far, only 1 retrospective report evaluated TNFa antagonist discontinuation in patients with UC. Steenholdt et al 18 reported a relapse rate of 68% in CD and 36% in UC 1 year after discontinuation of infliximab. The relapse rate in UC was similar to that in our study, although at the time of discontinuation, some patients with UC had mild inflammation assessed by endoscopy, and the biological assessment of remission was set only by normal CRP (,10 mg/ml) and white blood count ( /L). Moreover, no variables were significantly associated with relapse or prolonged remission in UC. This may be because the previously defined risk factors such as hemoglobin, CRP, and white blood count were largely within the normal range. These findings are in line with our study. Clear recommendations for discontinuing TNFa-blocking therapy are needed. A multidisciplinary European expert panel (European Panel on the Appropriateness of Crohn s Disease Treatment II, EPACT-II) evaluated when and under what circumstances withdrawal of TNFa-blocking therapy could be appropriate in CD. 30 They considered discontinuing TNFa-blocking therapy to be appropriate after 4 years but also after 2 years if the patient were in deep remission. Our results suggested that, withdrawal of TNFa-blocking therapy could already be possible after 1 year of therapy while patients were in deep remission, especially in UC. When restarting medication after drug-free interval, the risk of immunization resulting in hypersensitivity reactions, and loss of effect should be considered. 31 In our study, retreatment with TNFablocking therapy was well tolerated and effective. No hypersensitivity reactions occurred. All but 1 patient with relapse achieved clinical remission or response, and 75% of patients (9/12) achieved endoscopic remission at the median follow-up time of 12 months. Similar findings were also reported in the STORI trial. 15 Our study has some limitations. The patient group was limited and heterogeneous with both CD and UC patients included, regardless of localization, behavior, or duration of disease, and the number of patients in the subgroups remained fairly low. Moreover, although the SES-CD is a validated score for assessment of endoscopic activity in CD, no validated cutoffs for endoscopic remission or relapse are available. For remission, we used an SES-CD score of 0 2 that was published as an abstract. 24 In patients with UC, an endoscopic Mayo score of 0 1 was defined as a remission, making it possible that some patients with UC had very mild endoscopic activity at baseline. However, we consider that inclusion of a low baseline FC value as another criterion of remission ruled out patients with notable inflammatory activity. 32 Furthermore, both clinical and endoscopic scoring were performed by several experienced gastroenterologists, making some interobserver variability in the scoring system possible. However, the strength of this study is that the disease activity surveillance also included ileocolonoscopies that were not performed in previous studies. An endoscopic relapse, despite clinical remission necessitating the restart of TNFa-blocking therapy, was detected in 12% of the patients with CD but none of the patients with UC. In conclusion, up to 67% of patients with IBD in deep remission at the time of cessation of TNFa-blocking therapy remained in clinical remission during the 12-month follow-up. The majority of these patients (85%) also remained in endoscopic remission. In relapsers, the response to restart of TNFa antagonists seems to be effective and well tolerated. ACKNOWLEDGMENTS The authors thank study nurses Pirkko Tuukkala, Paula Karlsson, Virpi Pelkonen, and Annen Nikkonen for their excellent assistance. The authors also thank Heimo Nurmi, MD, Perttu Sahlman, MD, Hanni Salin, MD, and Ulla Turunen, MD for their help in recruiting the patients. Author contributions: Study design: P. Molander, M. Färkkilä, T. Sipponen; data collection: P. Molander, M. Färkkilä, K. Salminen, H. Kemppainen, R. Koskela, T. Blomster, A. Jussila, H. Rautiainen, M.Nissinen,J.Haapamäki,P.Arkkila,U.Nieminen,J.Kuisma, J. M. Punkkinen, K-L. Kolho, T. Sipponen; statistical analysis: P. Molander, H. Mustonen; drafting the manuscript: P. Molander, M. Färkkilä, T. Sipponen; final reading and approval of the manuscript: all authors. REFERENCES 1. Hanauer S, Feagan B, Lichtenstein G, et al. Maintenance infliximab for Crohn s disease: the ACCENT I randomised trial. 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