M Peeters, H Nevens, F Baert, M Hiele, A M de Meyer, R Vlietinck, P Rutgeerts
Familial aggregation in Crohn's disease: increased age-adjusted risk and concordance in clinical characteristics.
Gastroenterology. 1996 Sep;111(3):597-603.
Abstract/Text
BACKGROUND & AIMS: Because the mode of Crohn's disease inheritance is unknown, age-adjusted risk estimates and knowledge of disease characteristics will aid genetic counseling and modeling. The aim of this study is to determine the prevalence of familial occurrence of inflammatory bowel disease in first-degree relatives of patients with Crohn's disease and estimate their age-adjusted risks. It also evaluates agreement in disease characteristics between generations within families with a history of Crohn's disease.
METHODS: Six hundred forty patients with Crohn's disease and 800 control subjects were questioned about the occurrence of inflammatory bowel disease in their first-degree relatives. Agreement for age at diagnosis, initial disease location, disease behavior, and number of bowel resections was determined in 68 families with two or more members affected and compared with data in 100 unrelated patients with Crohn's disease.
RESULTS: Probands with Crohn's disease had a more frequent positive family history than controls. The age at diagnosis between probands with and without a positive family history was insignificant. Crude and age-adjusted risk elements were higher in relatives of patients, especially daughters, compared with those of controls. The age at diagnosis was older for parents than offspring but similar between siblings. Initial disease location was especially striking between siblings.
CONCLUSIONS: This study confirms familial aggregation and a high degree of disease concordance in Crohn's disease. The age at diagnosis and initial disease location was especially strong within generations.
J Cosnes, L Beaugerie, F Carbonnel, J P Gendre
Smoking cessation and the course of Crohn's disease: an intervention study.
Gastroenterology. 2001 Apr;120(5):1093-9. doi: 10.1053/gast.2001.23231.
Abstract/Text
BACKGROUND AND AIMS: To evaluate the benefit of smoking cessation in individuals with Crohn's disease, we performed an intervention study in a large cohort of smokers with the disease.
METHODS: Repeated counseling to stop smoking, with easy access to a smoking cessation program, was given to 474 consecutive smokers with Crohn's disease. Patients who stopped smoking for more than 1 year (quitters) were included in a prospective follow-up study, which compared disease course and therapeutic needs with 2 control groups, continuing smokers and nonsmokers, paired for age, gender, disease location, and activity.
RESULTS: There were 59 quitters (12%). Predictors of quitting were the physician, previous intestinal surgery, high socioeconomic status, and in women, oral contraceptive use. During a median follow-up of 29 months (1-54 months), the risk of flare-up in quitters did not differ from that in nonsmokers and was less than in continuing smokers (P < 0.001). Need for steroids and for introduction or reinforcement of immunosuppressive therapy, respectively, were similar in quitters and nonsmokers and increased in continuing smokers. The risk of surgery was not significantly different in the 3 groups.
CONCLUSIONS: Patients with Crohn's disease who stop smoking for more than 1 year have a more benign disease course than if they had never smoked.
J Cosnes, F Carbonnel, F Carrat, L Beaugerie, S Cattan, J Gendre
Effects of current and former cigarette smoking on the clinical course of Crohn's disease.
Aliment Pharmacol Ther. 1999 Nov;13(11):1403-11.
Abstract/Text
BACKGROUND: Cigarette smoking is associated with a more severe course of Crohn's disease, but individual factors determining this effect are poorly known and it is not clear whether smoking cessation is associated with an improvement in the disease activity.
AIM: To assess the factors determining the harmful effect of smoking in individuals with Crohn's disease.
METHODS: A total of 622 consecutive patients with Crohn's disease and Crohn's disease activity index <200 were enrolled in a prospective 12-18 month cohort study. Patients were classified as current smokers, former smokers, or non-smokers. Alcohol consumption, oral contraceptive use, body mass index, and blood lipid levels were also recorded. The main outcome measure was the rate of flare-up.
RESULTS: A total of 139 current smokers (46%) developed a flare-up, vs. 79 non-smokers (30%) and 13 former smokers (23%). The relative risk of flare-up adjusted for confounding factors was 1.35 (1.03-1.76) in current smokers. This risk was increased in patients with previously inactive disease and in those who had no colonic lesions. It became significant above a threshold of 15 cigarettes per day. Former smokers behaved like non-smokers. Obesity, dyslipidaemia, and alcohol consumption had no significant effect.
CONCLUSIONS: Current smoking, particularly heavy smoking, markedly increases the risk of flare-up in Crohn's disease. Former smokers have a risk similar to that of non-smokers.
Laurent Beaugerie, Philippe Seksik, Isabelle Nion-Larmurier, Jean-Pierre Gendre, Jacques Cosnes
Predictors of Crohn's disease.
Gastroenterology. 2006 Mar;130(3):650-6. doi: 10.1053/j.gastro.2005.12.019.
Abstract/Text
BACKGROUND & AIMS: Early intensive therapy in Crohn's disease should be considered only in patients with disabling disease. The aim of our study was to identify at diagnosis factors predictive of a subsequent 5-year disabling course.
METHODS: Among the 1526 patients seen at our unit with Crohn's disease diagnosed between 1985 and 1998, we excluded patients operated on within the first month of the disease, patients with inadequate data, and patients with severe chronic nondigestive disease. In the 1188 remaining patients, Crohn's disease course within the first 5 years of the disease was categorized as disabling when at least 1 of the criteria of clinical severity, conventionally predefined, was present.
RESULTS: Among the 1123 patients with follow-up data allowing full 5-year course classification, the rate of disabling disease was 85.2%. Independent factors present at diagnosis and significantly associated with subsequent 5-year disabling were the initial requirement for steroid use (OR 3.1 [95% CI: 2.2-4.4]), an age below 40 years (OR 2.1 [95% CI: 1.3-3.6]), and the presence of perianal disease (OR 1.8 [95% CI: 1.2-2.8]). The positive predictive value of disabling disease in patients with 2 and 3 predictive factors of disabling disease was 0.91 and 0.93, respectively. These values were 0.84 and 0.91, respectively, when tested prospectively in an independent group of 302 consecutive patients seen at our institution from 1998.
CONCLUSIONS: At diagnosis of Crohn's disease in a referral center, factors predictive of subsequent 5-year disabling course are an age below 40 years, the presence of perianal disease, and the initial requirement for steroids.
F L Wolters, M G V M Russel, R W Stockbrügger
Systematic review: has disease outcome in Crohn's disease changed during the last four decades?
Aliment Pharmacol Ther. 2004 Sep 1;20(5):483-96. doi: 10.1111/j.1365-2036.2004.02123.x.
Abstract/Text
BACKGROUND: Disease outcome in Crohn's disease might have changed during the last four decades. Disease outcome measurement in Crohn's disease has methodological difficulties because of patient selection and lack of proper definition of diagnostic and outcome measurement criteria.
AIM: To assess possible changes in disease outcome in Crohn's disease during the last four decades.
METHODS: A systematic literature search was performed using the MEDLINE search engine and major international conference libraries. Articles and abstracts were selected according to stringent inclusion criteria.
RESULTS: Forty articles and nine abstracts complied with the inclusion criteria. Seven studies with a median follow-up time between 11.1 and 17 years showed standard mortality ratios in Crohn's disease ranging between 2.16 and 0.72 with a tendency of decline during the last four decades. One study with 11.4 years mean follow-up time showed a statistically significant increased relative risk for colorectal cancer that was not confirmed by three others. Sixteen publications applied in the disease recurrence category. Probability of first resective surgery ranged between 38 and 96% during the first 15 years after diagnosis. The overall recurrence and surgical recurrence rates after first resective surgery ranged between 50 and 60, and 28 and 45% respectively during the following 15 years without an apparent time trend.
CONCLUSION: This structured literature review provides no hard evidence for change in disease outcome in Crohn's disease during the last four decades.
Copyright 2004 Blackwell Publishing Ltd
F Casellas, J López-Vivancos, X Badia, J Vilaseca, J R Malagelada
Impact of surgery for Crohn's disease on health-related quality of life.
Am J Gastroenterol. 2000 Jan;95(1):177-82. doi: 10.1111/j.1572-0241.2000.01681.x.
Abstract/Text
OBJECTIVE: When patients with Crohn's disease (CD) express concerns about their disease, they emphasize worries about surgery. However, most studies about the impact of surgery in CD on health-related quality of life (HRQOL) have compared postsurgical changes on HRQOL relative to HRQOL before surgery, not taking into account the influence of CD activity on HRQOL. Our aim was to assess whether surgical treatment of CD modifies HRQOL, compared with inactive CD, active CD, or healthy controls.
METHODS: Outcomes of 29 CD patients in remission with a previous bowel resection were compared with those from 42 clinically active CD patients and 48 patients with medically induced remission. A reference control group of 63 healthy individuals was also studied. HRQOL was measured by the Inflammatory Bowel Disease Questionnaire (IBDQ), the Psychological General Well Being Index (PGWBI), and the EuroQol.
RESULTS: Active CD patients scored the lowest on the IBDQ. Both operated and nonoperated inactive CD patients had lower HRQOL scores than controls in overall IBDQ and in all five domains. However, neither global score, digestive, systemic, emotional, social, or functional dimensions differed significantly between operated and nonoperated inactive CD patients. PGWBI and the visual analog scale of the EuroQol were also similar in both groups of inactive CD patients (103 [range, 94-107] vs. 103 [97-106] and 90 [73-87] vs. 82 [76-84]), but significantly higher than in active CD.
CONCLUSIONS: HRQOL is impaired in active CD, and improves during remission irrespective of whether it had been achieved medically or surgically. Our results suggest that to improve HRQOL it is more important to achieve remission than the approach, drugs or surgery, chosen.
D C Broering, C F Eisenberger, A Koch, C Bloechle, W T Knoefel, J R Izbicki
Quality of life after surgical therapy of small bowel stenosis in Crohn's disease.
Dig Surg. 2001;18(2):124-30. doi: 50112.
Abstract/Text
BACKGROUND: Improvement in quality of life is one of the important determinants in the treatment of Crohn's disease. Since there is no cure with radical resection of inflamed bowel, strictureplasty has become a useful surgical technique in the treatment of small bowel obstruction. The scope of this study was to define the results of strictureplasty and resection in terms of quality of life, surgical recurrence and postoperative complications.
METHODS: The charts of 67 patients with Crohn's disease of the small bowel were analyzed retrospectively. Patients were treated either by strictureplasty (group A) or resection (group B). Quality of life was evaluated in follow-up examinations using the Inflammatory Bowel Disease Questionnaire (IBDQ).
RESULTS: Postoperative morbidity was 14.8% after strictureplasty and 17% after resection (p = 0.8). 50% of the patients treated by strictureplasty and 37% treated by resection developed recurrent disease (p = 0.40). Quality-of-life measurement revealed no significant difference between patients treated by strictureplasty or resection.
CONCLUSION: Results after strictureplasty are comparable to those after resection in terms of complications, recurrence and quality of life in the treatment of small bowel strictures in Crohn's disease. In the long run there might be an advantage for strictureplasty because it prevents complications caused by resectional therapy such as short bowel syndrome.
Copyright 2001 S. Karger AG, Basel
Jean Frédéric Colombel, William J Sandborn, Walter Reinisch, Gerassimos J Mantzaris, Asher Kornbluth, Daniel Rachmilewitz, Simon Lichtiger, Geert D'Haens, Robert H Diamond, Delma L Broussard, Kezhen L Tang, C Janneke van der Woude, Paul Rutgeerts, SONIC Study Group
Infliximab, azathioprine, or combination therapy for Crohn's disease.
N Engl J Med. 2010 Apr 15;362(15):1383-95. doi: 10.1056/NEJMoa0904492.
Abstract/Text
BACKGROUND: The comparative efficacy and safety of infliximab and azathioprine therapy alone or in combination for Crohn's disease are unknown.
METHODS: In this randomized, double-blind trial, we evaluated the efficacy of infliximab monotherapy, azathioprine monotherapy, and the two drugs combined in 508 adults with moderate-to-severe Crohn's disease who had not undergone previous immunosuppressive or biologic therapy. Patients were randomly assigned to receive an intravenous infusion of 5 mg of infliximab per kilogram of body weight at weeks 0, 2, and 6 and then every 8 weeks plus daily oral placebo capsules; 2.5 mg of oral azathioprine per kilogram daily plus a placebo infusion on the standard schedule; or combination therapy with the two drugs. Patients received study medication through week 30 and could continue in a blinded study extension through week 50.
RESULTS: Of the 169 patients receiving combination therapy, 96 (56.8%) were in corticosteroid-free clinical remission at week 26 (the primary end point), as compared with 75 of 169 patients (44.4%) receiving infliximab alone (P=0.02) and 51 of 170 patients (30.0%) receiving azathioprine alone (P<0.001 for the comparison with combination therapy and P=0.006 for the comparison with infliximab). Similar numerical trends were found at week 50. At week 26, mucosal healing had occurred in 47 of 107 patients (43.9%) receiving combination therapy, as compared with 28 of 93 patients (30.1%) receiving infliximab (P=0.06) and 18 of 109 patients (16.5%) receiving azathioprine (P<0.001 for the comparison with combination therapy and P=0.02 for the comparison with infliximab). Serious infections developed in 3.9% of patients in the combination-therapy group, 4.9% of those in the infliximab group, and 5.6% of those in the azathioprine group.
CONCLUSIONS: Patients with moderate-to-severe Crohn's disease who were treated with infliximab plus azathioprine or infliximab monotherapy were more likely to have a corticosteroid-free clinical remission than those receiving azathioprine monotherapy. (ClinicalTrials.gov number, NCT00094458.)
2010 Massachusetts Medical Society
Brian G Feagan, William J Sandborn, Christopher Gasink, Douglas Jacobstein, Yinghua Lang, Joshua R Friedman, Marion A Blank, Jewel Johanns, Long-Long Gao, Ye Miao, Omoniyi J Adedokun, Bruce E Sands, Stephen B Hanauer, Severine Vermeire, Stephan Targan, Subrata Ghosh, Willem J de Villiers, Jean-Frédéric Colombel, Zsolt Tulassay, Ursula Seidler, Bruce A Salzberg, Pierre Desreumaux, Scott D Lee, Edward V Loftus, Levinus A Dieleman, Seymour Katz, Paul Rutgeerts, UNITI–IM-UNITI Study Group
Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease.
N Engl J Med. 2016 Nov 17;375(20):1946-1960. doi: 10.1056/NEJMoa1602773.
Abstract/Text
BACKGROUND: Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy.
METHODS: We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150).
RESULTS: The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups.
CONCLUSIONS: Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).
Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, Lukas M, Fedorak RN, Lee S, Bressler B, Fox I, Rosario M, Sankoh S, Xu J, Stephens K, Milch C, Parikh A. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. Massachussetts Medical Society; 2013;369(8):711–721.
Geert D'Haens, Remo Panaccione, Filip Baert, Peter Bossuyt, Jean-Frederic Colombel, Silvio Danese, Marla Dubinsky, Brian G Feagan, Tadakazu Hisamatsu, Allen Lim, James O Lindsay, Edward V Loftus, Julian Panés, Laurent Peyrin-Biroulet, Zhihua Ran, David T Rubin, William J Sandborn, Stefan Schreiber, Ezequiel Neimark, Alexandra Song, Kristina Kligys, Yinuo Pang, Valerie Pivorunas, Sofie Berg, W Rachel Duan, Bidan Huang, Jasmina Kalabic, Xiaomei Liao, Anne Robinson, Kori Wallace, Marc Ferrante
Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials.
Lancet. 2022 May 28;399(10340):2015-2030. doi: 10.1016/S0140-6736(22)00467-6.
Abstract/Text
BACKGROUND: Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease.
METHODS: ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete.
FINDINGS: Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14-30; 146/336) with risankizumab 600 mg and 41% (19%, 11-27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6-24; 66/191) with risankizumab 600 mg and 40% (20%, 12-29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug.
INTERPRETATION: Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease.
FUNDING: AbbVie.
Copyright © 2022 Elsevier Ltd. All rights reserved.
Marc Ferrante, Remo Panaccione, Filip Baert, Peter Bossuyt, Jean-Frederic Colombel, Silvio Danese, Marla Dubinsky, Brian G Feagan, Tadakazu Hisamatsu, Allen Lim, James O Lindsay, Edward V Loftus, Julián Panés, Laurent Peyrin-Biroulet, Zhihua Ran, David T Rubin, William J Sandborn, Stefan Schreiber, Ezequiel Neimark, Alexandra Song, Kristina Kligys, Yinuo Pang, Valerie Pivorunas, Sofie Berg, W Rachel Duan, Bidan Huang, Jasmina Kalabic, Xiaomei Liao, Anne Robinson, Kori Wallace, Geert D'Haens
Risankizumab as maintenance therapy for moderately to severely active Crohn's disease: results from the multicentre, randomised, double-blind, placebo-controlled, withdrawal phase 3 FORTIFY maintenance trial.
Lancet. 2022 May 28;399(10340):2031-2046. doi: 10.1016/S0140-6736(22)00466-4.
Abstract/Text
BACKGROUND: There is a great unmet need for new therapeutics with novel mechanisms of action for patients with Crohn's disease. The ADVANCE and MOTIVATE studies showed that intravenous risankizumab, a selective p19 anti-interleukin (IL)-23 antibody, was efficacious and well tolerated as induction therapy. Here, we report the efficacy and safety of subcutaneous risankizumab as maintenance therapy.
METHODS: FORTIFY is a phase 3, multicentre, randomised, double-blind, placebo-controlled, maintenance withdrawal study across 273 clinical centres in 44 countries across North and South America, Europe, Oceania, Africa, and the Asia-Pacific region that enrolled participants with clinical response to risankizumab in the ADVANCE or MOTIVATE induction studies. Patients in ADVANCE or MOTIVATE were aged 16-80 years with moderately to severely active Crohn's disease. Patients in the FORTIFY substudy 1 were randomly assigned again (1:1:1) to receive either subcutaneous risankizumab 180 mg, subcutaneous risankizumab 360 mg, or withdrawal from risankizumab to receive subcutaneous placebo (herein referred to as withdrawal [subcutaneous placebo]). Treatment was given every 8 weeks. Patients were stratified by induction dose, post-induction endoscopic response, and clinical remission status. Patients, investigators, and study personnel were masked to treatment assignments. Week 52 co-primary endpoints were clinical remission (Crohn's disease activity index [CDAI] in the US protocol, or stool frequency and abdominal pain score in the non-US protocol) and endoscopic response in patients who received at least one dose of study drug during the 52-week maintenance period. Safety was assessed in patients receiving at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03105102.
FINDINGS: 712 patients were initially assessed and, between April 9, 2018, and April 24, 2020, 542 patients were randomly assigned to either the risankizumab 180 mg group (n=179), the risankizumab 360 mg group (n=179), or the placebo group (n=184). Greater clinical remission and endoscopic response rates were reached with 360 mg risankizumab versus placebo (CDAI clinical remission was reached in 74 (52%) of 141 patients vs 67 (41%) of 164 patients, adjusted difference 15% [95% CI 5-24]; stool frequency and abdominal pain score clinical remission was reached in 73 (52%) of 141 vs 65 (40%) of 164, adjusted difference 15% [5-25]; endoscopic response 66 (47%) of 141 patients vs 36 (22%) of 164 patients, adjusted difference 28% [19-37]). Higher rates of CDAI clinical remission and endoscopic response (but not stool frequency and abdominal pain score clinical remission [p=0·124]) were also reached with risankizumab 180 mg versus withdrawal (subcutaneous placebo; CDAI clinical remission reached in 87 [55%] of 157 patients, adjusted difference 15% [95% CI 5-24]; endoscopic response 74 [47%] of 157, adjusted difference 26% [17-35]). Results for more stringent endoscopic and composite endpoints and inflammatory biomarkers were consistent with a dose-response relationship. Maintenance treatment was well tolerated. Adverse event rates were similar among groups, and the most frequently reported adverse events in all treatment groups were worsening Crohn's disease, arthralgia, and headache.
INTERPRETATION: Subcutaneous risankizumab is a safe and efficacious treatment for maintenance of remission in patients with moderately to severely active Crohn's disease and offers a new therapeutic option for a broad range of patients by meeting endpoints that might change the future course of disease.
FUNDING: AbbVie.
Copyright © 2022 Elsevier Ltd. All rights reserved.
Jessica Coelho, Laurent Beaugerie, Jean Frédéric Colombel, Xavier Hébuterne, Eric Lerebours, Marc Lémann, Philippe Baumer, Jacques Cosnes, Arnaud Bourreille, Jean Pierre Gendre, Philippe Seksik, Antoine Blain, Etienne H Metman, Andrée Nisard, Guillaume Cadiot, Michel Veyrac, Benoît Coffin, Xavier Dray, Fabrice Carrat, Philippe Marteau, CESAME Pregnancy Study Group (France)
Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME Study.
Gut. 2011 Feb;60(2):198-203. doi: 10.1136/gut.2010.222893. Epub 2010 Nov 29.
Abstract/Text
BACKGROUND AND AIMS: Few studies have been conducted addressing the safety of thiopurine treatment in pregnant women with inflammatory bowel disease (IBD). The aim of this study was to evaluate the pregnancy outcome of women with IBD who have been exposed to thiopurines.
METHODS: 215 pregnancies in 204 women were registered and documented in the CESAME cohort between May 2004 and October 2007. Physicians documented the following information from the women: last menstrual date, delivery term, details of pregnancy outcome, prematurity, birth weight and height, congenital abnormalities, medication history during each trimester, smoking history and alcohol ingestion. Data were compared between three groups: women exposed to thiopurines (group A), women receiving a drug other than thiopurines (group B) and women not receiving any medication (group C).
RESULTS: Mean age at pregnancy was 28.3 years. 75.7% of the women had Crohn's disease and 21.8% had ulcerative colitis, with a mean disease duration of 6.8 years at inclusion. Of the 215 pregnancies, there were 138 births (142 newborns), and the mean birth weight was 3135 g. There were 86 pregnancies in group A, 84 in group B and 45 in group C. Interrupted pregnancies occurred in 36% of patients enrolled in group A, 33% of patients enrolled in group B, and 40% of patients enrolled in group C; congenital abnormalities arose in 3.6% of group A cases and 7.1% of group B cases. No significant differences were found between the three groups in overall pregnancy outcome.
CONCLUSIONS: The results obtained from this cohort indicate that thiopurine use during pregnancy is not associated with increased risks, including congenital abnormalities.
Fabian Schnitzler, Herma Fidder, Marc Ferrante, Vera Ballet, Maja Noman, Gert Van Assche, Bernard Spitz, Ilse Hoffman, Kristel Van Steen, Séverine Vermeire, Paul Rutgeerts
Outcome of pregnancy in women with inflammatory bowel disease treated with antitumor necrosis factor therapy.
Inflamm Bowel Dis. 2011 Sep;17(9):1846-54. doi: 10.1002/ibd.21583. Epub 2011 Jan 6.
Abstract/Text
BACKGROUND: Infliximab (IFX) and adalimumab (ADA) are attractive treatment options in patients with inflammatory bowel disease (IBD) also during pregnancy but there is still limited data on the benefit/risk profile of IFX and ADA during pregnancy.
METHODS: This observational study assessed pregnancy outcomes in 212 women with IBD under antitumor necrosis factor alpha (TNF) treatment at our IBD unit. Pregnancy outcomes in 42 pregnancies with direct exposure to anti-TNF treatment (35 IFX, 7 ADA) were compared with that in 23 pregnancies prior to IBD diagnosis, 78 pregnancies before start of IFX, 53 pregnancies with indirect exposure to IFX, and 56 matched pregnancies in healthy women.
RESULTS: Thirty-two of the 42 pregnancies ended in live births with a median gestational age of 38 weeks (interquartile range [IQR] 37-39). There were seven premature deliveries, six children had low birth weight, and there was one stillbirth. One boy weighed 1640 g delivered at week 33, died at age of 13 days because of necrotizing enterocolitis. A total of eight abortions (one patient wish) occurred in seven women. Trisomy 18 was diagnosed in one fetus of a mother with CD at age 37 under ADA treatment (40 mg weekly) and pregnancy was terminated. Pregnancy outcomes after direct exposure to anti-TNF treatment were not different from those in pregnancies before anti-TNF treatment or with indirect exposure to anti-TNF treatment but outcomes were worse than in pregnancies before IBD diagnosis.
CONCLUSIONS: Direct exposure to anti-TNF treatment during pregnancy was not related to a higher incidence of adverse pregnancy outcomes than IBD overall.
Copyright © 2011 Crohn's & Colitis Foundation of America, Inc.
Stephen B Hanauer, Brian G Feagan, Gary R Lichtenstein, Lloyd F Mayer, S Schreiber, Jean Frederic Colombel, Daniel Rachmilewitz, Douglas C Wolf, Allan Olson, Weihang Bao, Paul Rutgeerts, ACCENT I Study Group
Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.
Lancet. 2002 May 4;359(9317):1541-9. doi: 10.1016/S0140-6736(02)08512-4.
Abstract/Text
BACKGROUND: We did a randomised controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn's disease who respond to a single infusion of infliximab.
METHODS: 573 patients with a score of at least 220 on the Crohn's disease activity index (CDAI) received a 5 mg/kg intravenous infusion of infliximab at week 0. After assessment of response at week 2, patients were randomly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 (group I), repeat infusions of 5 mg/kg infliximab at the same timepoints (group II), or 5 mg/kg infliximab at weeks 2 and 6 followed by 10 mg/kg (group III). The prespecified co-primary endpoints were the proportion of patients who responded at week 2 and were in remission (CDAI <150) at week 30 and the time to loss of response up to week 54 in patients who responded. Analyses of the co-primary endpoints were by intention to treat.
FINDINGS: 335 (58%) patients responded to a single infusion of infliximab within 2 weeks. At week 30, 23 of 110 (21%) group I patients were in remission, compared with 44 of 113 (39%) group II (p=0.003) and 50 of 112 (45%) group III (p=0.0002) patients. Thus, patients in groups II and III combined were more likely to sustain clinical remission than patients in group I (odds ratio 2.7, 95% CI 1.6-4.6). Throughout the 54-week trial, the median time to loss of response was 38 weeks (IQR 15 to >54) and more than 54 weeks (21 to >54) for groups II and III, respectively, compared with 19 weeks (10-45) for group I (p=0.002 and p=0.0002, respectively). Infliximab safety was consistent with that seen in other trials of infliximab in Crohn's disease and rheumatoid arthritis. In particular, the incidence of serious infections was similar across treatment groups.
INTERPRETATION: Patients with Crohn's disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids, and to maintain their response for a longer period of time, if infliximab treatment is maintained every 8 weeks.
A H Steinhart, K Ewe, A M Griffiths, R Modigliani, O O Thomsen
Corticosteroids for maintenance of remission in Crohn's disease.
Cochrane Database Syst Rev. 2003;(4):CD000301. doi: 10.1002/14651858.CD000301.
Abstract/Text
BACKGROUND: The efficacy of corticosteroids in the setting of maintenance therapy for Crohn's disease has never been clearly demonstrated. It would be important to determine, based upon the currently available data from controlled trials, if the use of chronic corticosteroid therapy is of benefit in patients with quiescent Crohn's disease or if there is an identifiable subgroup of Crohn's disease patients, such as those in whom therapy cannot be successfully tapered, who might benefit from such treatment.
OBJECTIVES: To evaluate the effectiveness and safety of conventional systemic corticosteroid therapy in maintaining clinical remission in Crohn's disease.
SEARCH STRATEGY: A computer-assisted search of the on-line bibliographic database MEDLINE of studies published in English, French, Spanish, Italian and German between 1966 and July, 2003. Manual searches of the reference lists from the potentially relevant studies were performed in order to identify additional studies that may have been missed using the computer-assisted search strategy. Proceedings from major gastrointestinal meetings were also manually searched from 1985 to 2003 in order to identify unpublished studies. The Cochrane Central Register of Controlled Trials and the Inflammatory Bowel Disease Review Group Specialized Trials Register were also searched.
SELECTION CRITERIA: Randomized double-blind placebo-controlled trials involving patients of any age with Crohn's disease in clinical remission as defined by a CDAI < 150 or by the presence of no symptoms or only mild symptoms at the time of entry into the trial. The experimental treatment consisted of oral conventional corticosteroid therapy (excluding budesonide, fluticasone, etc). Clinical disease relapse was used as the outcome measure of interest.
DATA COLLECTION AND ANALYSIS: Eligible studies were selected by 4 reviewers and data were extracted onto standardized data extraction forms. Disagreements in eligibility or data extraction were resolved by consensus. Data were converted into individual 2x2 tables for each study. The presence of significant heterogeneity among studies was tested using the chi-square test. The 2x2 tables were synthesized into a summary test statistic using the pooled odds ratio and 95% confidence intervals as described by Cochran and Mantel and Haenszel (the 'odds ratio' in MetaView). A fixed effects model was used for the pooling of data.
MAIN RESULTS: Four studies were initially judged as being eligible for inclusion. After obtaining additional information on one of the studies it was excluded because it was not double-blind. The total number of subjects included in the analysis at the time points of 6, 12 and 24 months were 142, 131 and 95 for the corticosteroid group and 161, 138 and 87 for the control group. The odds ratios for relapse on active treatment and the corresponding 95% confidence intervals were 0.71 (0.39, 1.31), 0.82 (0.47, 1.43) and 0.72 (0.38, 1.35) at 6, 12 and 24 months.
REVIEWER'S CONCLUSIONS: The use of conventional systemic corticosteroids in patients with clinically quiescent Crohn's disease does not appear to reduce the risk of relapse over a 24 month period of follow-up. This review updates the existing review of corticosteroids for maintaining remission of Crohn's disease which was published in the Cochrane Library (Issue 2, 2003).
Bruce E Sands, Frank H Anderson, Charles N Bernstein, William Y Chey, Brian G Feagan, Richard N Fedorak, Michael A Kamm, Joshua R Korzenik, Bret A Lashner, Jane E Onken, Daniel Rachmilewitz, Paul Rutgeerts, Gary Wild, Douglas C Wolf, Paul A Marsters, Suzanne B Travers, Marion A Blank, Sander J van Deventer
Infliximab maintenance therapy for fistulizing Crohn's disease.
N Engl J Med. 2004 Feb 26;350(9):876-85. doi: 10.1056/NEJMoa030815.
Abstract/Text
BACKGROUND: Infliximab, a monoclonal antibody against tumor necrosis factor, is an effective maintenance therapy for patients with Crohn's disease without fistulas. It is not known whether infliximab is an effective maintenance therapy for patients with fistulas.
METHODS: We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn's disease and one or more draining abdominal or perianal fistulas of at least three months' duration. Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0, 2, and 6. A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then randomly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54. The primary analysis was the time to the loss of response among patients who had a response at week 14 and underwent randomization.
RESULTS: The time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance (more than 40 weeks vs. 14 weeks, P<0.001). At week 54, 19 percent of patients in the placebo maintenance group had a complete absence of draining fistulas, as compared with 36 percent of patients in the infliximab maintenance group (P=0.009).
CONCLUSIONS: Patients with fistulizing Crohn's disease who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks.
Copyright 2004 Massachusetts Medical Society
William J Sandborn, Paul Rutgeerts, Robert Enns, Stephen B Hanauer, Jean-Frédéric Colombel, Remo Panaccione, Geert D'Haens, Ju Li, Marie R Rosenfeld, Jeffrey D Kent, Paul F Pollack
Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial.
Ann Intern Med. 2007 Jun 19;146(12):829-38. Epub 2007 Apr 30.
Abstract/Text
BACKGROUND: Adalimumab, a fully human tumor necrosis factor (TNF) antagonist, is an effective treatment for patients with Crohn disease who are naive to the chimeric TNF antagonist, infliximab. No anti-TNF agent has been evaluated prospectively in patients with Crohn disease who had responded to another anti-TNF agent and then lost that response or were intolerant of the agent.
OBJECTIVE: To determine whether adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who have symptoms despite infliximab therapy or who cannot take infliximab because of adverse events.
DESIGN: 4-week, randomized, double-blind, placebo-controlled trial (November 2004 to December 2005).
SETTING: 52 sites in the United States, Canada, and Europe.
PATIENTS: 325 adults 18 to 75 years of age who had a history of Crohn disease for 4 months or more that was moderate to severe at baseline (Crohn's Disease Activity Index [CDAI] score, 220 to 450 points).
INTERVENTION: Patients were randomly assigned to receive induction doses of adalimumab, 160 mg and 80 mg, at weeks 0 and 2, respectively, or placebo at the same time points.
MEASUREMENTS: The primary end point was induction of remission at week 4. Decreases in CDAI score by 70 or more and 100 or more points (secondary end points) were also measured.
RESULTS: A total of 301 patients completed the trial. Twenty-one percent (34 of 159) of patients in the adalimumab group versus 7% (12 of 166) of those in the placebo group achieved remission at week 4 (P < 0.001). The absolute difference in clinical remission rates was 14.2 percentage points (95% CI, 6.7 to 21.6 percentage points). A 70-point response occurred at week 4 in 52% (82 of 159) of patients in the adalimumab group versus 34% (56 of 166) of patients in the placebo group (P = 0.001). The absolute difference in 70-point response rates was 17.8 percentage points (CI, 7.3 to 28.4 percentage points). Two of 159 patients in the adalimumab group and 4 of 166 patients in the placebo group discontinued treatment because of adverse events. No patients in the adalimumab group and 4 of 166 patients in the placebo group had a serious infection.
LIMITATIONS: The trial did not directly compare alternative active treatments and did not evaluate maintenance of response or long-term immunogenicity of adalimumab.
CONCLUSION: Adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who cannot tolerate infliximab or have symptoms despite receiving infliximab therapy. For more information on adalimumab in Crohn disease, click here. ClinicalTrials.gov registration number: NCT00105300.
田中郁子，大島久三：ステロイド性骨粗鬆症の診断と治療に関する縦断研究．診断・治療指針への予備的検討．Osteoporosis Jpn 2003;11:11-14.
難治性の肝・胆道疾患に関する調査研究班、肝硬変を含めたウイルス性肝疾患の治療の標準化に関する研究班編：免疫抑制・化学療法により発症するB型肝炎対策ガイドライン（改訂版）、2011年.
Kakuta Y, Naito T, Onodera M, Kuroha M, Kimura T, Shiga H, Endo K, Negoro K, Kinouchi Y, Shimosegawa T. NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD. Pharmacogenomics J. Nature Publishing Group; 2016 Jun 1;16(3):280–285.
C Canavan, K R Abrams, J Mayberry
Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn's disease.
Aliment Pharmacol Ther. 2006 Apr 15;23(8):1097-104. doi: 10.1111/j.1365-2036.2006.02854.x.
Abstract/Text
BACKGROUND: Crohn's disease is associated with small bowel cancer whilst risk of colorectal cancer is less clear.
AIM: To ascertain the combined estimates of relative risk of these cancers in Crohn's disease.
METHODS: MEDLINE was searched to identify relevant papers. Exploding references identified additional publications. When two papers reviewed the same cohort, the later study was used.
RESULTS: Meta-analysis showed overall colorectal cancer relative risk in Crohn's disease as 2.5 (1.3-4.7), 4.5 (1.3-14.9) for patients with colonic disease and 1.1 (0.8-1.5) in ileal disease. Meta-regression showed reduction in relative risk over the past 30 years. Subgroup analysis showed Scandinavia had significantly lower colorectal cancer relative risk than the UK and North America. Cumulative risk analysis showed 10 years following diagnosis of Crohn's disease relative risk of colorectal cancer is 2.9% (1.5%-5.3%). Meta-analysis showed small bowel cancer relative risk in Crohn's disease is 33.2 (15.9-60.9). Small bowel cancer relative risk has not significantly reduced over the last 30 years.
CONCLUSION: Relative risk of colorectal and small bowel cancers are significantly raised in Crohn's disease. Cumulative risk of colorectal cancer of 2.9% at 10 years suggests a potential benefit from routine screening. However, the value of screening requires rigorous appraisal.
Toshihiro Inokuchi, Jun Kato, Sakiko Hiraoka, Shiho Takashima, Asuka Nakarai, Daisuke Takei, Yuusaku Sugihara, Masahiro Takahara, Seiji Kawano, Keita Harada, Hiroyuki Okada
Fecal Immunochemical Test Versus Fecal Calprotectin for Prediction of Mucosal Healing in Crohn's Disease.
Inflamm Bowel Dis. 2016 May;22(5):1078-85. doi: 10.1097/MIB.0000000000000728.
Abstract/Text
BACKGROUND: Mucosal healing (MH) has been proposed as a treatment goal of inflammatory bowel disease patients. We reported recently that not only fecal calprotectin (Fcal) but also the fecal immunochemical test (FIT) can predict MH in ulcerative colitis. However, the predictive power of the fecal markers for MH in Crohn's disease (CD), particularly with small bowel lesions, has not been reported in detail. The aim of this study was to evaluate the predictability of FIT versus Fcal for MH in CD.
METHODS: Consecutive CD patients underwent colonoscopy or balloon-assisted enteroscopy according to the disease location. FIT and Fcal were examined using stool samples collected the day before endoscopy.
RESULTS: Seventy-one CD patients were analyzed, of whom 42 (59%) underwent balloon-assisted enteroscopy because of the presence of affected lesions in the small intestine. Both the Fcal and the FIT results were significantly correlated with endoscopic activity (r = 0.67 and 0.54, respectively). However, the FIT results did not correlate with the activity in patients with small bowel lesions alone, whereas Fcal did (r = 0.42 versus 0.78). Fcal predicted MH in CD with 87% sensitivity and 71% specificity, whereas the values for FIT were 96% and 48%, respectively. The specificity for MH among patients with small bowel lesions alone was low for FIT (40%) compared with Fcal (80%).
CONCLUSIONS: Both FIT and Fcal were correlated with the mucosal status of CD. However, the specificity of FIT was not satisfactory, particularly for small bowel lesions.
Shinichiro Shinzaki, Katsuyoshi Matsuoka, Hiroki Tanaka, Fuminao Takeshima, Shingo Kato, Takehiro Torisu, Yuki Ohta, Kenji Watanabe, Shiro Nakamura, Naoki Yoshimura, Taku Kobayashi, Akiko Shiotani, Fumihito Hirai, Sakiko Hiraoka, Mamoru Watanabe, Minoru Matsuura, Shohei Nishimoto, Shinta Mizuno, Hideki Iijima, Tetsuo Takehara, Tetsuji Naka, Takanori Kanai, Takayuki Matsumoto
Leucine-rich alpha-2 glycoprotein is a potential biomarker to monitor disease activity in inflammatory bowel disease receiving adalimumab: PLANET study.
J Gastroenterol. 2021 Jun;56(6):560-569. doi: 10.1007/s00535-021-01793-0. Epub 2021 May 3.
Abstract/Text
BACKGROUND: This multicenter prospective study (UMIN000019958) aimed to evaluate the usefulness of serum leucin-rich alpha-2 glycoprotein (LRG) levels in monitoring disease activity in inflammatory bowel disease (IBD).
METHODS: Patients with moderate-to-severe IBD initiated on adalimumab therapy were enrolled herein. Serum LRG, C-reactive protein (CRP), and fecal calprotectin (fCal) levels were measured at week 0, 12, 24, and 52. Colonoscopy was performed at week 0, 12, and 52 for ulcerative colitis (UC), and at week 0, 24, and 52 for Crohn's disease (CD). Endoscopic activity was assessed using the Simple Endoscopic Score for Crohn's Disease (SES-CD) for CD and the Mayo endoscopic subscore (MES) for UC.
RESULTS: A total of 81 patients was enrolled. Serum LRG levels decreased along with improvements in clinical and endoscopic outcomes upon adalimumab treatment (27.4 ± 12.6 μg/ml at week 0, 15.5 ± 7.7 μg/ml at week 12, 15.7 ± 9.6 μg/ml at week 24, and 14.5 ± 6.8 μg/ml at week 52), being correlated with endoscopic activity at each time point (SES-CD: r = 0.391 at week 0, r = 0.563 at week 24, r = 0.697 at week 52; MES: r = 0.534 at week 0, r = 0.429 at week 12, r = 0.335 at week 52). Endoscopic activity better correlated with LRG compared to CRP and fCal on pooled analysis at all time points (SES-CD: LRG: r = 0.636, CRP: r = 0.402, fCal: r = 0.435; MES: LRG: r = 0.568, CRP: 0.389, fCal: r = 0.426).
CONCLUSIONS: Serum LRG is a useful biomarker of endoscopic activity both in CD and UC during the adalimumab treatment.
A M Griffiths, A Ohlsson, P M Sherman, L R Sutherland
Meta-analysis of enteral nutrition as a primary treatment of active Crohn's disease.
Gastroenterology. 1995 Apr;108(4):1056-67.
Abstract/Text
BACKGROUND/AIMS: The efficacy of enteral nutrition as primary therapy of active Crohn's disease is controversial. The aim of the study was to compare by meta-analysis the likelihood of clinical response to liquid diet therapy vs. corticosteroids and to assess the importance of formula composition to efficacy.
METHODS: Randomized controlled trials comparing exclusive enteral nutrition with corticosteroids and elemental with nonelemental formulas were identified through a combination of computerized and hand-searching techniques. Rates of clinical remission of active Crohn's disease, based on the intention-to-treat principle, were extracted from the studies by two independent reviewers. Odds ratios for likelihood of clinical response were calculated.
RESULTS: In eight trials comprising 413 patients, enteral nutrition was inferior to corticosteroids (pooled odds ratio, 0.35; 95% confidence interval, 0.23-0.53). In five trials comprising 134 patients, there was no difference in the efficacy of elemental versus nonelemental formulas (pooled odds ratio, 0.87; 95% confidence interval, 0.41-1.83).
CONCLUSIONS: Corticosteroids are more effective than enteral nutrition in the treatment of active Crohn's disease. Limited sample size precludes definitive conclusions about the importance of formula composition in the efficacy of enteral nutrition; however, data analyzed in this study do not support an advantage to elemental feedings compared with a polymeric formulation.
