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Maintenance therapy for ulcerative colitis has no impact on changes in the extent of ulcerative colitis
Journal of Crohn’s and Colitis (2007) 1, 21–27
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
Maintenance therapy for ulcerative colitis has no impact on changes in the extent of ulcerative colitis N. Eleftheriadis a,⁎, G. Lambrecht b , G. D’Haens c , F. Baert d , M. Cabooter e , E. Louis f , G. Van Assche g , P. Schurmans h , P. Caenepeel i , M. Van Outryve j , P. Lammens k , A. Van Gossum l , M. De Vos a on behalf of the Belgian IBD Research Group a
Department of Gastroenterology, Ghent University Hospital (UZ Gent), De Pintelaan 185 9000 Gent, Belgium AZ Damiaan, Oostende, Belgium c Imelda Hospital Bonheiden, Belgium d Heilig Hart Ziekenhuis, Roeselaere, Belgium e A.Z.Sint-Jan AV, Brugge, Belgium f University Hospital of Liege, Belgium g University of Leuven, Belgium Gert h CAZ Hasselt, Belgium i ZOL Campus St. Jan, Genk, Belgium j Universitair Ziekenhuis Antwerpen, Edegem, Belgium k St. Jean Brussel, Belgium l Erasme Hospital, Brussels, Belgium b
Received 7 May 2007; accepted 1 June 2007
KEYWORDS Ulcerative colitis; Mesalamine; Corticosteroids; Immunosuppressives; Maintaining remission therapy; Extension of colitis
Abstract Background and aim: Although the efficacy of maintenance remission therapy in ulcerative colitis (UC) has been proved in many studies, little is known about its possible effect on the extent of the disease. The aim of the present multicenter Belgian study was to evaluate the potential role of UC maintenance therapy on the colonic extension of the disease. Materials and methods: A total of 98 patients, 56 males, 42 females, mean age 52 years, range 22–82 years, from 12 medical centers in Belgium, with an acute exacerbation of wellestablished, endoscopically and histologically proven left-sided UC, were included. The colonic extension was endoscopically determined at the time of the initial diagnosis and at the actual
⁎ Corresponding author. Perdika 13, Ptolemaida, PC 50200, Greece. Tel.: +302463022106; fax: +302463055546. On behalf of Prof. Dr. Martine DeVos, Gastroenterology Department, University Hospital Ghent (UZ Gent), De Pintelaan 185 9000, Gent, Belgium. Tel.: +32 9 2402371; fax: +32 9 2404984. E-mail addresses: [email protected], [email protected] (N. Eleftheriadis), [email protected] (G. Lambrecht), [email protected], [email protected] (G. D’Haens), [email protected] (F. Baert), [email protected] (M. Cabooter), [email protected] (E. Louis), [email protected] (G.V. Assche), [email protected] (P. Lammens), [email protected] (A.V. Gossum), [email protected] (M. De Vos). 1873-9946/$ - see front matter © 2007 European Crohn’s and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.crohns.2007.06.001
22
N. Eleftheriadis et al. flare-up. The mean duration of UC was 93 + 72 months, median was 84 months, and range was 3–372 months. Active smoking was reported in only 7% of patients, while the majority were nosmokers (63%) or ex-smokers (30%). The median colonic extension at the time of initial diagnosis was 25 cm, range 2–70 cm from the anal merge. Sixty-six percent of the patients had quiescent disease without flare-ups during last year. The χ2-test was used for statistical analysis. Results: 29/98 (29.6%) patients had not used any maintenance therapy in the last 3 months before the actual exacerbation. The most commonly used maintenance therapy was 5-ASA (43%), while combined therapy with 5-ASA, corticosteroids or immunosuppresives (mainly azathioprine) in all possible combinations was reported by 29.6% of patients. The extent of UC had not changed in 50.7% and 51.7% of patients, respectively, with and without maintaining therapy (NS, p = 0.99). Some degree of regression was observed in, respectively, 21.7% and 20.7% (NS, p = 0.99), and some degree of extension in, respectively, 27.5% and 27.6% (NS, p = 0.99). Furthermore, no relationship was found between changes in colonic extent and type of maintaining therapy, smoking habits or disease activity during the last year before the acute exacerbation. A tendency of beneficial effect of maintenance therapy on disease extent was observed in patients with continuous active disease of short duration. Conclusions: According to this multicenter study, maintenance remission therapy for left-sided UC was not found to have a statistically significant effect on colonic extension. Further longterm studies are necessary to confirm these results. © 2007 European Crohn’s and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
1. Introduction Despite the progress that has been made in the management of ulcerative colitis (UC) in the last decades, its natural history is still characterized by periods of remission interspersed with exacerbations, while the therapy is aimed to keep the general condition of the patient stable, maintaining remission whenever possible.1–3 The efficacy of long-term maintenance therapy for ulcerative colitis with aminosalicylates has been well established in many studies. Mesalazine is the drug of choice for maintaining remission in patients with ulcerative colitis.4–7 For more serious cases maintenance therapy with immunosuppressives, such as azathioprine, has been proven effective in patients with steroid-dependent or steroid-resistant ulcerative colitis.8–10 However, little is known about the potential efficacy of maintenance therapy in modifying or changing the natural history of ulcerative colitis and the extent of the chronic inflammation. The aim of the present multicenter study was to evaluate the role of long-term maintaining therapy for ulcerative colitis on the colonic extension during subsequent exacerbations.
2. Patients and Methods In the present multicenter, cross-sectional study from 12 medical centers in Belgium, patients with actual exacerbation of well established, endoscopically and histologically proven left-sided UC were included. The same clinical questionnaire was used for all patients and included date of birth, sex, disease duration, smoking habits and date of initial diagnosis and actual and previous flare-ups. The extension of UC was endoscopically determined at the time of the initial diagnosis and at the actual flare up. Colonic extension was classified in two groups: Left-sided colitis including (a) rectum, (b) sigmoid and (c) descending colon, and pancolitis including (d) colitis up to the trans-
versum and (e) pancolitis. Disease was determined as inactive if no flare up was recorded in previous year. Furthermore, a detailed history and chart review were retrospectively taken from all patients regarding their initial management and intake of maintenance therapy at the time of actual flare-up, as well as during 3 and 6 months before the actual UC exacerbation. According to UC maintenance remission therapy, all patients were classified in seven groups: (1) no therapy; (2) 5-aminosalicylate (5ASA) only; (3) corticosteroids only; (4) immunosuppressive only; (5) 5-ASA and corticosteroids; (6) corticosteroids and immunosuppressives and (7) 5-ASA, corticosteroids and immunosuppressives. Finally, the change in colonic involvement (regression or extension) between the actual UC exacerbation and the initial localization was defined as: (a) minimal if the
Table 1
Demographic and disease characteristics
Baseline characteristics Sex n (%) Male Female Age Median (range) Smoking Non-smoker Active smoker Ex-smoker Disease activity No flare-up in the previous year One or more flare-up in the previous year Duration of ulcerative colitis (UC) Mean + SD Median (range)
Left-side colitis (n = 98) 56 (57%) 42 (43%) 47 years (22–82) 63% 7% 30% 66.3% 33.7%
93 + 72 months 84 months (3–372)
Maintaning therapy and extension of UC
23 Table 3 Changes in UC extension in relation to maintenance remission therapy the last 3 months before the actual flare-up Change in UC extension No change Regression Total population (n = 98) With maintenance therapy (n = 69) Without maintenance therapy (n = 29)
Figure 1 Initial UC localization in relation to maintenance remission therapy.
change in colonic extension involved one colonic segment according to the above-mentioned five-scale classification; (b) moderate (regression or extension) if involving two colonic segments; (c) important if involving three colonic segments and (d) very important if involving four colonic segments.
2.1. Statistics Continuous data are reported as mean ± SD or median and ranges if the data were not normally distributed. For comparison of categorical data the χ2-test was used. All calculations were performed with SPSS version 10.1 software (SPSS, Chicago, IL).
3. Results Finally, a total of 98 randomly recruited patients, 56 males and 42 females, with mean age of 52 years and age range of 22–82 years, with actual exacerbation of well established, endoscopically and histologically proven left-sided UC were included. The baseline demographic and disease history characteristics of all patients are reported in Table 1. The median time interval between initial diagnosis and actual flare up was 84 months (range 3–372 months). At the time of initial diagnosis, the majority of patients with left-sided colitis had rectosigmoid disease (78%), while a
50 (51%)
35 (50.7%) 15 (21.7%) 15 (51.7%)
Extension
21 (21.4%) ⁎ 27 (27.6%) ⁎
6 (20.7%)
19 (27.5%) 8 (27.6%)
⁎ p b 0.005 (extension or regression vs. no change in total population).
minority had colitis up to the descending colon (22%). Mean colonic extension was 27 + 16 cm, range 2–70 cm from the anal merge. The initial UC localization, with and without maintenance therapy during the last three months before the actual exacerbation, is shown in Fig. 1. Maintenance therapy, during the period of 3 and 6 months before the actual exacerbation, was taken by, respectively, 70% and 74% of patients (Table 2). Monotherapy with 5-ASA was the commonest therapy used by 43% of patients as monotherapy and in 21% of patients in combination with corticosteroids (12%), immunosuppressives (3%) or both (6%). Corticosteroids or immunosuppressives during the 6 months before the actual exacerbation alone or in combination with other drugs were used in, respectively, 22% and 14% of patients. Topical therapy with 5-ASA alone or in combination with corticosteroids was reported by 19% of patients, oral therapy by 29% and combined oral and local therapy by 22%, 3 months before the actual flare-up. In the total population no changes in colonic extension between the actual flare up and the initial localization were found in 51% of patients, while significantly less patients experienced some form of extension (27.6% of patients; p = 0.0033) or regression (21.4%; p = 0.00037) irrespective of use of maintenance therapy (Table 3). In 69 patients on maintenance therapy, the extent remained unchanged in 50.7%, regressed in 21.7% and extended in 27.5% of patients.
Table 2 Medical treatment of left-sided UC at the time of initial diagnosis, actual flare-up, as well as during 3 and 6 months before the actual exacerbation Therapy
5-ASA only Corticosteroids only Immunosuppressive only 5-ASA and corticosteroids 5-ASA and immunosuppressive Corticosteroids and immunosuppressive 5-ASA and corticosteroids and immunosuppressive No
Initial diagnosis
Actual flare-up
3 months before actual flare-up
6 months before actual flare-up
% (cumulative)
% (cumulative)
% (cumulative)
% (cumulative)
62% (62%) 6% (68%) 0% (68%) 28% (96%) 0% (96%) 1% (97%) 1% (98%) 2% (100%)
43% (43%) 3% (46%) 3% (49%) 11% (60%) 2% (62%) 3% (65%) 4% (69%) 31% (100%)
43% (43%) 2% (45%) 2% (47%) 12% (59%) 3% (62%) 2% (64%) 6% (70%) 30% (100%)
47% 2% 3% 11% 2% 1% 8% 26%
(47%) (49%) (52%) (63%) (65%) (66%) (74%) (100%)
24
N. Eleftheriadis et al.
Table 4
Change in UC extension in relation to initial colonic localization Change in UC extension No change
Initial UC localization
Rectum
22 62.9% 21 51.2% 7 31.8% 50 51.0%
Sigmoid Descendens Total
Total
Regression
Extension
9 22.0% 12 54.6% ⁎ 21 21.4%
13 37.1% 11 26.8% 3 13.6% ⁎ 27 27.6%
35 100.0% 41 100.0% 22 100% 98 100.0%
⁎ p b 0.05 (extension vs. regression).
Percentages were similar in patients without any form of maintenance treatment during the last 3 months (Table 3). In patients with initial colonic localization up to the descendens, significantly greater degree of regression (55%) than extension (14%) (p b 0.05) was observed, while patients with initial rectal disease showed either no change (63%) or extension (37%) of colonic extent. Half of the patients (51%) with initial sigmoidal disease showed no change in extent of colitis, while, respectively, 22% showed regression and 27% extension of colitis, irrespective to maintenance therapy (Table 4). The degree of regression was always mild to moderate in all patients with reduction in colonic extent, while extension of disease was mild to moderate in 20/27 (74%) patients and large to very large in 7/27 (26%), irrespective to maintenance therapy. In all groups, 66 to 77% of patients were on maintenance therapy. Type of maintenance therapy (local or oral) had also no influence on extension of disease (Table 5), while no beneficial effect on the extent of colonic disease was observed by the use of combined drug categories (Fig. 2). In the total population we found no correlation between changes in colonic extension and disease activity: no changes were found in 54% and 45% of patients with quiescent vs. active disease, regression of colonic extension in, respectively, 18% and 27% and progression in 28% and 27%. However, in the subgroup without maintenance therapy a trend to greater regression was observed in patients with quiescent Table 5 Change in colonic extension in relation to the type of maintenance remission UC maintenance therapy the last 3 months before the actual flare-up Without therapy Oral only therapy Local only therapy Oral and local therapy Total
Change in UC extension N (%) No change
Total
Regression Extension
15 (52 %) 12 (43%) 11 (58%)
6 (21%) 7 (25%) 3 (16%)
8 (28%) 9 (32%) 5 (26%)
29 28 19
12 (55%)
5 (23%)
5 (23%)
22
50 (51%)
21 (21%)
27 (28%)
98
p N 0.5 NS, in all groups studied.
than with active disease. A tendency to opposite relationship was found in patients with therapy (15% vs. 31%, p = 0.5) (Table 6). Active smoking was reported in only 7% of patients, while the majority of patients were no-smokers (63%) or exsmokers (30%). The relation between smoking habit and change in UC extension is shown in Table 7. A tendency to regression was observed in active smokers (45%) vs. nosmokers or ex-smokers (19%), although differences were not significant (p N 0.5). Finally, the relationship between mean UC duration in months and changes in colonic extension is presented in Fig. 3. The duration of the UC was more than 1 year in the majority of patients (92%). In patients with shorter disease duration (less than 1 year) either no change (63%) or regression (38%) of colonic involvement was observed, while in patients with more than 1 year disease duration, no change was observed in 50%, regression in 20% and extension in 30% of patients.
4. Discussion Ulcerative colitis is a chronic relapsing disease with frequent remissions and exacerbations. This intermittent course of UC represents the most significant inherent characteristic of its natural history.1,2 Up to 90% of patients with UC have been reported to experience a chronic intermittent course, while according to the available literature, relapses of UC are still unpredictable, despite the progress that has been done the last decades in its management.11,12 The efficacy of chronic maintenance therapy, mainly with aminosalicylates, on clinical symptoms and endoscopic healing has been shown in many studies, with follow-up periods ranging between 6 and 12 months.1–4 Particularly, long-term maintenance therapy with aminosalicylates was found to be superior to placebo in maintaining remission (71% vs. 24% with sulfasalazine and placebo).4,13–17 Furthermore, although great progress has been made the last decades concerning the understanding of the pathogenesis, genetic and environmental factors as well as the management of acute flare-ups, little is known about a possible modification of the extent of UC with long-term maintenance therapy. Especially, the role, if any, of chronic maintaining remission therapy for UC on the extent of colonic disease is unknown.11,12,18
Maintaning therapy and extension of UC
Figure 2
25
Change in UC extension in relation to number of drug categories used as maintenance therapy.
In a population-based study from Copenhagen, it is reported that the extent of UC is a dynamic process with changes with time in approximately half of the patients. They reported 25% cumulative probability of extension of colitis within 5 years in patients with proctosigmoiditis at initial diagnosis and 9% to 20% progression in patients with substantial colitis after 10 years of disease duration. The cumulative probability for regression in the above-mentioned study was 45% for substantial colitis and 58% for pancolitis after five years (Langholz et al.11). Furthermore, Moum et al.13 reported 16–24% progression and 23–25% regression rates in extent of colitis in patients with initial rectosigmoidal or left-sided disease, during a 1-year follow-up period using colonoscopy. Similar figures are also reported in the present study. Table 6 Change in UC extension in relation to last year’s disease activity and maintenance therapy Maintenance therapy at 3 months
Last year’s disease activity No flare-up
Without therapy
No change Regression Extension Total
With therapy
No change Regression Extension Total
12 48% 6 24% 7 28% 25 100% 23 58% 6 15% 11 28% 40 100%
p N 0.5 NS, in all subgroups studied.
Total
Active disease 9 75%
1 25% 4 100% 12 41% 9 31% 8 28% 29 100%
15 52% 6 21% 8 28% 29 100% 35 51% 15 22% 19 28% 69 100%
However, in the above-mentioned studies, the changes in UC extension were not correlated to chronic maintenance remission therapy, while in the study by Langholz et al.11 the extent of UC was determined using sigmoidoscopy and double-contrast barium enema in contrast to the present study, in which the extent of UC was accurately determined using colonoscopy. In the present multicenter study the extent of UC seemed not influenced by the intake of maintenance therapy. Half of the patients had no change in extent whereas the other half of patients showed either regression (21%) or extension (28%) irrespective of use of maintenance therapy. The observed degree of extension or regression of colonic involvement was almost always minimal and only in 1–5% of patients more pronounced. The results of this study were not influenced by the type of medication (drug category, oral vs. local administration) nor by combination of different drugs. In fact, a small although insignificant trend to progression of anatomic involvement of disease was observed by the use of combined drug categories possibly reflecting the more aggressive form of disease. The most commonly used maintenance therapy was 5-ASA (47% of patients), while only a small number of patients (3%) was on immunosuppressive only therapy, making the interpretation of the results more difficult. Use of aminosalicylates was accompanied with an extension of disease in 24% and regression in 26% of patients. Furthermore, if we take into account that the mean time between previous and actual UC exacerbations in the current Table 7
Effect of smoking habit in UC extension Smoking habit
Change in UC extension
No change Regression Extension
p N 0.5 in all subgroups studied.
No- and ex-smokers
Active
53% 19.0% 28.0%
36% 45.0% 18.0%
26
N. Eleftheriadis et al. activity, may lead to a conclusion of a potential positive effect of maintenance therapy on colonic extent in patients with active disease. However the small number of patients precludes definite conclusions. In conclusion, although in our study chronic maintenance remission therapy for ulcerative colitis was not found effective in reducing the colitis extension during subsequent ulcerative colitis exacerbation, further long-term studies, as well as use of new drug categories,21 are necessary to determine the role of chronic maintenance remission therapy for ulcerative colitis in the natural history of disease.
Figure 3 Change in UC extension in relation to disease duration (months).
References
study was 29 months, while the mean duration of UC was 93 months, the common follow-up period of 6 months to 1 year used in the majority of prospective studies concerning the role of maintenance therapy in UC, is not sufficient and further studies with longer follow-up are necessary to determine the efficacy of chronic maintenance therapy in modifying the extent of UC. As far as smoking habit is concerned, the majority of patients in this study were non-smokers or ex-smokers. Patients with active smoking showed the greatest degree of regression in colonic extension in comparison to non-smokers or ex-smokers, irrespective to maintenance therapy, however, without statistically significant differences. This finding is another indirect argument for the potential protective effect of smoking in UC, which is in accordance to other studies.19,20 An interesting finding of this study was that in patients with short disease duration (less than 1 year) either no change (63%) or regression (38%) of colonic involvement was observed, in contrast to previous studies reporting the highest extension rate of ulcerative colitis during the first year of disease.11 Use of maintenance therapy was even associated with larger regression (60%). However, the small number of patients precludes definite conclusions. Moreover, the mean disease duration was greater in patients with extension of ulcerative colitis (115 months) than in patients who showed no change (87 months) or regression (79 months) of ulcerative colitis extent (Fig. 3). Although the small number of patients made definite conclusions difficult, we could assume that ulcerative colitis patients during the first year after initial diagnosis may benefit from chronic maintenance therapy with regard to colitis extent. Finally, in the total population, patients with continuously active disease during the last year before actual flare-up, tended to show more frequently regression in colonic extent (27%) than patients with quiescent disease (18%) (p = 0.8, NS), in contrast to other studies, which reported that the occurrence of continuous active disease was related to extension of colitis.11,13 Moreover, patients with active disease showed a trend to greater regression rate with maintenance therapy than patients with quiescent disease, although not significant, while in the group of patients without maintenance therapy, greater regression was observed in patients with quiescent disease. This inverse correlation of regression rates with and without maintenance therapy, in relation to disease
1. Robinson M. Optimizing therapy for inflammatory bowel disease. Am J Gastroenterol 1997;92:12S–7S. 2. Sachar DB. Maintenance therapy in ulcerative colitis and Crohn’s disease. J Clin Gastroenterol 1995;20:117–22. 3. Ardizzone S, Porro GB. A practical guide to the management of distal ulcerative colitis. Drugs 1998;55:519–42. 4. Schroeder KW. Role of mesalazine in acute and long-term treatment of ulcerative colitis and its complications. Scand J Gastroenterol 2002:42–7 [Suppl]. 5. An oral preparation of mesalamine as long-term maintenance therapy for ulcerative colitis. A randomized, placebo-controlled trial. The Mesalamine Study Group. Ann Intern Med 1996;124:204–11. 6. Miner P, Hanauer S, Robinson M, Schwartz J, Arora S. Safety and efficacy of controlled-release mesalamine for maintenance of remission in ulcerative colitis. Pentasa UC Maintenance Study Group. Dig Dis Sci 1995;40:296–304. 7. Mulder CJ, Tytgat GN, Weterman IT, Dekker W, Blok P, Schrijver M, et al. Double-blind comparison of slow-release 5-aminosalicylate and sulfasalazine in remission maintenance in ulcerative colitis. Gastroenterology 1988;95:1449–53. 8. Paoluzi OA, Pica R, Marcheggiano A, Crispino P, Iacopini F, Iannoni C, et al. Azathioprine or methotrexate in the treatment of patients with steroid-dependent or steroid-resistant ulcerative colitis: results of an open-label study on efficacy and tolerability in inducing and maintaining remission. Aliment Pharmacol Ther 1902;16:1751–9. 9. Fraser AG, Morton D, McGovern D, Travis S, Jewel DP. The efficacy of methotrexate for maintaining remission in inflammatory bowel disease. Aliment Pharmacol Ther 2002;16: 693–7. 10. Fernandez-Banares F, Bertran X, Esteve-Comas M, Cabre E, Menacho M, Humbert P, et al. Azathioprine is useful in maintaining long-term remission induced by intravenous cyclosporine in steroid-refractory severe ulcerative colitis. Am J Gastroenterol 1996;91:2498–9. 11. Langholz E, Munkholm P, Davidsen M, Nielsen OH, Binder V. Changes in extent of ulcerative colitis: a study on the course and prognostic factors. Scand J Gastroenterol 1996;31:260–6. 12. Langholz E, Munkholm P, Davidsen M, Binder V. Course of ulcerative colitis: analysis of changes in disease activity over years. Gastroenterology 1994;107:3–11. 13. Moum B, Ekbom A, Vatn MH, Elgjo K. Change in the extent of colonoscopic and histological involvement in ulcerative colitis over time. Am J Gastroenterol 1999;94:1564–9. 14. Misiewicz JJ, Lennard-Jones JE, Connell AM, et al. Controlled trial of sulfasalazine in maintenance therapy for ulcerative colitis. Lancet 1965;1:185–8. 15. Riley SA, Mani V, Goodman MJ, Herd ME, Dutt S, Turnberg LA. Comparison of delayed-release 5-aminosalicylic acid (mesalazine) and sulfasalazine as maintenance treatment for patients with ulcerative colitis. Gastroenterology 1988;94: 1383–9.
Maintaning therapy and extension of UC 16. Rijk MC, van Lier HJ, van Tongeren JH. Relapse-preventing effect and safety of sulfasalazine and olsalazine in patients with ulcerative colitis in remission: a prospective, double-blind, randomized multicenter study. The Ulcerative Colitis Multicenter Study Group. Am J Gastroenterol 1992;87:438–42. 17. Marshall JK, Irvine EJ. Putting rectal 5-aminosalicylic acid in its place: the role in distal ulcerative colitis. Am J Gastroenterol 2000;95:1628–36. 18. Sinclair TS, Brunt PW, Mowat NA. Nonspecific proctocolitis in northeastern Scotland: a community study. Gastroenterology 1983;85:1–11.
27 19. Rubin DT, Hanauer SB. Smoking and inflammatory bowel disease. Eur J Gastroenterol Hepatol 2000;12:855–62. 20. Russel MG, Stockbrugger RW. Epidemiological developments and insights in chronic inflammatory bowel diseases. Ned Tijdschr Geneeskd 2001;145:1448–52. 21. Fooks LJ, Gibson GR. Probiotics as modulators of the gut flora. Br J Nutr 2002;88(Suppl 1):S39–49.
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
Maintenance therapy for ulcerative colitis has no impact on changes in the extent of ulcerative colitis N. Eleftheriadis a,⁎, G. Lambrecht b , G. D’Haens c , F. Baert d , M. Cabooter e , E. Louis f , G. Van Assche g , P. Schurmans h , P. Caenepeel i , M. Van Outryve j , P. Lammens k , A. Van Gossum l , M. De Vos a on behalf of the Belgian IBD Research Group a
Department of Gastroenterology, Ghent University Hospital (UZ Gent), De Pintelaan 185 9000 Gent, Belgium AZ Damiaan, Oostende, Belgium c Imelda Hospital Bonheiden, Belgium d Heilig Hart Ziekenhuis, Roeselaere, Belgium e A.Z.Sint-Jan AV, Brugge, Belgium f University Hospital of Liege, Belgium g University of Leuven, Belgium Gert h CAZ Hasselt, Belgium i ZOL Campus St. Jan, Genk, Belgium j Universitair Ziekenhuis Antwerpen, Edegem, Belgium k St. Jean Brussel, Belgium l Erasme Hospital, Brussels, Belgium b
Received 7 May 2007; accepted 1 June 2007
KEYWORDS Ulcerative colitis; Mesalamine; Corticosteroids; Immunosuppressives; Maintaining remission therapy; Extension of colitis
Abstract Background and aim: Although the efficacy of maintenance remission therapy in ulcerative colitis (UC) has been proved in many studies, little is known about its possible effect on the extent of the disease. The aim of the present multicenter Belgian study was to evaluate the potential role of UC maintenance therapy on the colonic extension of the disease. Materials and methods: A total of 98 patients, 56 males, 42 females, mean age 52 years, range 22–82 years, from 12 medical centers in Belgium, with an acute exacerbation of wellestablished, endoscopically and histologically proven left-sided UC, were included. The colonic extension was endoscopically determined at the time of the initial diagnosis and at the actual
⁎ Corresponding author. Perdika 13, Ptolemaida, PC 50200, Greece. Tel.: +302463022106; fax: +302463055546. On behalf of Prof. Dr. Martine DeVos, Gastroenterology Department, University Hospital Ghent (UZ Gent), De Pintelaan 185 9000, Gent, Belgium. Tel.: +32 9 2402371; fax: +32 9 2404984. E-mail addresses: [email protected], [email protected] (N. Eleftheriadis), [email protected] (G. Lambrecht), [email protected], [email protected] (G. D’Haens), [email protected] (F. Baert), [email protected] (M. Cabooter), [email protected] (E. Louis), [email protected] (G.V. Assche), [email protected] (P. Lammens), [email protected] (A.V. Gossum), [email protected] (M. De Vos). 1873-9946/$ - see front matter © 2007 European Crohn’s and Colitis Organisation. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.crohns.2007.06.001
22
N. Eleftheriadis et al. flare-up. The mean duration of UC was 93 + 72 months, median was 84 months, and range was 3–372 months. Active smoking was reported in only 7% of patients, while the majority were nosmokers (63%) or ex-smokers (30%). The median colonic extension at the time of initial diagnosis was 25 cm, range 2–70 cm from the anal merge. Sixty-six percent of the patients had quiescent disease without flare-ups during last year. The χ2-test was used for statistical analysis. Results: 29/98 (29.6%) patients had not used any maintenance therapy in the last 3 months before the actual exacerbation. The most commonly used maintenance therapy was 5-ASA (43%), while combined therapy with 5-ASA, corticosteroids or immunosuppresives (mainly azathioprine) in all possible combinations was reported by 29.6% of patients. The extent of UC had not changed in 50.7% and 51.7% of patients, respectively, with and without maintaining therapy (NS, p = 0.99). Some degree of regression was observed in, respectively, 21.7% and 20.7% (NS, p = 0.99), and some degree of extension in, respectively, 27.5% and 27.6% (NS, p = 0.99). Furthermore, no relationship was found between changes in colonic extent and type of maintaining therapy, smoking habits or disease activity during the last year before the acute exacerbation. A tendency of beneficial effect of maintenance therapy on disease extent was observed in patients with continuous active disease of short duration. Conclusions: According to this multicenter study, maintenance remission therapy for left-sided UC was not found to have a statistically significant effect on colonic extension. Further longterm studies are necessary to confirm these results. © 2007 European Crohn’s and Colitis Organisation. Published by Elsevier B.V. All rights reserved.
1. Introduction Despite the progress that has been made in the management of ulcerative colitis (UC) in the last decades, its natural history is still characterized by periods of remission interspersed with exacerbations, while the therapy is aimed to keep the general condition of the patient stable, maintaining remission whenever possible.1–3 The efficacy of long-term maintenance therapy for ulcerative colitis with aminosalicylates has been well established in many studies. Mesalazine is the drug of choice for maintaining remission in patients with ulcerative colitis.4–7 For more serious cases maintenance therapy with immunosuppressives, such as azathioprine, has been proven effective in patients with steroid-dependent or steroid-resistant ulcerative colitis.8–10 However, little is known about the potential efficacy of maintenance therapy in modifying or changing the natural history of ulcerative colitis and the extent of the chronic inflammation. The aim of the present multicenter study was to evaluate the role of long-term maintaining therapy for ulcerative colitis on the colonic extension during subsequent exacerbations.
2. Patients and Methods In the present multicenter, cross-sectional study from 12 medical centers in Belgium, patients with actual exacerbation of well established, endoscopically and histologically proven left-sided UC were included. The same clinical questionnaire was used for all patients and included date of birth, sex, disease duration, smoking habits and date of initial diagnosis and actual and previous flare-ups. The extension of UC was endoscopically determined at the time of the initial diagnosis and at the actual flare up. Colonic extension was classified in two groups: Left-sided colitis including (a) rectum, (b) sigmoid and (c) descending colon, and pancolitis including (d) colitis up to the trans-
versum and (e) pancolitis. Disease was determined as inactive if no flare up was recorded in previous year. Furthermore, a detailed history and chart review were retrospectively taken from all patients regarding their initial management and intake of maintenance therapy at the time of actual flare-up, as well as during 3 and 6 months before the actual UC exacerbation. According to UC maintenance remission therapy, all patients were classified in seven groups: (1) no therapy; (2) 5-aminosalicylate (5ASA) only; (3) corticosteroids only; (4) immunosuppressive only; (5) 5-ASA and corticosteroids; (6) corticosteroids and immunosuppressives and (7) 5-ASA, corticosteroids and immunosuppressives. Finally, the change in colonic involvement (regression or extension) between the actual UC exacerbation and the initial localization was defined as: (a) minimal if the
Table 1
Demographic and disease characteristics
Baseline characteristics Sex n (%) Male Female Age Median (range) Smoking Non-smoker Active smoker Ex-smoker Disease activity No flare-up in the previous year One or more flare-up in the previous year Duration of ulcerative colitis (UC) Mean + SD Median (range)
Left-side colitis (n = 98) 56 (57%) 42 (43%) 47 years (22–82) 63% 7% 30% 66.3% 33.7%
93 + 72 months 84 months (3–372)
Maintaning therapy and extension of UC
23 Table 3 Changes in UC extension in relation to maintenance remission therapy the last 3 months before the actual flare-up Change in UC extension No change Regression Total population (n = 98) With maintenance therapy (n = 69) Without maintenance therapy (n = 29)
Figure 1 Initial UC localization in relation to maintenance remission therapy.
change in colonic extension involved one colonic segment according to the above-mentioned five-scale classification; (b) moderate (regression or extension) if involving two colonic segments; (c) important if involving three colonic segments and (d) very important if involving four colonic segments.
2.1. Statistics Continuous data are reported as mean ± SD or median and ranges if the data were not normally distributed. For comparison of categorical data the χ2-test was used. All calculations were performed with SPSS version 10.1 software (SPSS, Chicago, IL).
3. Results Finally, a total of 98 randomly recruited patients, 56 males and 42 females, with mean age of 52 years and age range of 22–82 years, with actual exacerbation of well established, endoscopically and histologically proven left-sided UC were included. The baseline demographic and disease history characteristics of all patients are reported in Table 1. The median time interval between initial diagnosis and actual flare up was 84 months (range 3–372 months). At the time of initial diagnosis, the majority of patients with left-sided colitis had rectosigmoid disease (78%), while a
50 (51%)
35 (50.7%) 15 (21.7%) 15 (51.7%)
Extension
21 (21.4%) ⁎ 27 (27.6%) ⁎
6 (20.7%)
19 (27.5%) 8 (27.6%)
⁎ p b 0.005 (extension or regression vs. no change in total population).
minority had colitis up to the descending colon (22%). Mean colonic extension was 27 + 16 cm, range 2–70 cm from the anal merge. The initial UC localization, with and without maintenance therapy during the last three months before the actual exacerbation, is shown in Fig. 1. Maintenance therapy, during the period of 3 and 6 months before the actual exacerbation, was taken by, respectively, 70% and 74% of patients (Table 2). Monotherapy with 5-ASA was the commonest therapy used by 43% of patients as monotherapy and in 21% of patients in combination with corticosteroids (12%), immunosuppressives (3%) or both (6%). Corticosteroids or immunosuppressives during the 6 months before the actual exacerbation alone or in combination with other drugs were used in, respectively, 22% and 14% of patients. Topical therapy with 5-ASA alone or in combination with corticosteroids was reported by 19% of patients, oral therapy by 29% and combined oral and local therapy by 22%, 3 months before the actual flare-up. In the total population no changes in colonic extension between the actual flare up and the initial localization were found in 51% of patients, while significantly less patients experienced some form of extension (27.6% of patients; p = 0.0033) or regression (21.4%; p = 0.00037) irrespective of use of maintenance therapy (Table 3). In 69 patients on maintenance therapy, the extent remained unchanged in 50.7%, regressed in 21.7% and extended in 27.5% of patients.
Table 2 Medical treatment of left-sided UC at the time of initial diagnosis, actual flare-up, as well as during 3 and 6 months before the actual exacerbation Therapy
5-ASA only Corticosteroids only Immunosuppressive only 5-ASA and corticosteroids 5-ASA and immunosuppressive Corticosteroids and immunosuppressive 5-ASA and corticosteroids and immunosuppressive No
Initial diagnosis
Actual flare-up
3 months before actual flare-up
6 months before actual flare-up
% (cumulative)
% (cumulative)
% (cumulative)
% (cumulative)
62% (62%) 6% (68%) 0% (68%) 28% (96%) 0% (96%) 1% (97%) 1% (98%) 2% (100%)
43% (43%) 3% (46%) 3% (49%) 11% (60%) 2% (62%) 3% (65%) 4% (69%) 31% (100%)
43% (43%) 2% (45%) 2% (47%) 12% (59%) 3% (62%) 2% (64%) 6% (70%) 30% (100%)
47% 2% 3% 11% 2% 1% 8% 26%
(47%) (49%) (52%) (63%) (65%) (66%) (74%) (100%)
24
N. Eleftheriadis et al.
Table 4
Change in UC extension in relation to initial colonic localization Change in UC extension No change
Initial UC localization
Rectum
22 62.9% 21 51.2% 7 31.8% 50 51.0%
Sigmoid Descendens Total
Total
Regression
Extension
9 22.0% 12 54.6% ⁎ 21 21.4%
13 37.1% 11 26.8% 3 13.6% ⁎ 27 27.6%
35 100.0% 41 100.0% 22 100% 98 100.0%
⁎ p b 0.05 (extension vs. regression).
Percentages were similar in patients without any form of maintenance treatment during the last 3 months (Table 3). In patients with initial colonic localization up to the descendens, significantly greater degree of regression (55%) than extension (14%) (p b 0.05) was observed, while patients with initial rectal disease showed either no change (63%) or extension (37%) of colonic extent. Half of the patients (51%) with initial sigmoidal disease showed no change in extent of colitis, while, respectively, 22% showed regression and 27% extension of colitis, irrespective to maintenance therapy (Table 4). The degree of regression was always mild to moderate in all patients with reduction in colonic extent, while extension of disease was mild to moderate in 20/27 (74%) patients and large to very large in 7/27 (26%), irrespective to maintenance therapy. In all groups, 66 to 77% of patients were on maintenance therapy. Type of maintenance therapy (local or oral) had also no influence on extension of disease (Table 5), while no beneficial effect on the extent of colonic disease was observed by the use of combined drug categories (Fig. 2). In the total population we found no correlation between changes in colonic extension and disease activity: no changes were found in 54% and 45% of patients with quiescent vs. active disease, regression of colonic extension in, respectively, 18% and 27% and progression in 28% and 27%. However, in the subgroup without maintenance therapy a trend to greater regression was observed in patients with quiescent Table 5 Change in colonic extension in relation to the type of maintenance remission UC maintenance therapy the last 3 months before the actual flare-up Without therapy Oral only therapy Local only therapy Oral and local therapy Total
Change in UC extension N (%) No change
Total
Regression Extension
15 (52 %) 12 (43%) 11 (58%)
6 (21%) 7 (25%) 3 (16%)
8 (28%) 9 (32%) 5 (26%)
29 28 19
12 (55%)
5 (23%)
5 (23%)
22
50 (51%)
21 (21%)
27 (28%)
98
p N 0.5 NS, in all groups studied.
than with active disease. A tendency to opposite relationship was found in patients with therapy (15% vs. 31%, p = 0.5) (Table 6). Active smoking was reported in only 7% of patients, while the majority of patients were no-smokers (63%) or exsmokers (30%). The relation between smoking habit and change in UC extension is shown in Table 7. A tendency to regression was observed in active smokers (45%) vs. nosmokers or ex-smokers (19%), although differences were not significant (p N 0.5). Finally, the relationship between mean UC duration in months and changes in colonic extension is presented in Fig. 3. The duration of the UC was more than 1 year in the majority of patients (92%). In patients with shorter disease duration (less than 1 year) either no change (63%) or regression (38%) of colonic involvement was observed, while in patients with more than 1 year disease duration, no change was observed in 50%, regression in 20% and extension in 30% of patients.
4. Discussion Ulcerative colitis is a chronic relapsing disease with frequent remissions and exacerbations. This intermittent course of UC represents the most significant inherent characteristic of its natural history.1,2 Up to 90% of patients with UC have been reported to experience a chronic intermittent course, while according to the available literature, relapses of UC are still unpredictable, despite the progress that has been done the last decades in its management.11,12 The efficacy of chronic maintenance therapy, mainly with aminosalicylates, on clinical symptoms and endoscopic healing has been shown in many studies, with follow-up periods ranging between 6 and 12 months.1–4 Particularly, long-term maintenance therapy with aminosalicylates was found to be superior to placebo in maintaining remission (71% vs. 24% with sulfasalazine and placebo).4,13–17 Furthermore, although great progress has been made the last decades concerning the understanding of the pathogenesis, genetic and environmental factors as well as the management of acute flare-ups, little is known about a possible modification of the extent of UC with long-term maintenance therapy. Especially, the role, if any, of chronic maintaining remission therapy for UC on the extent of colonic disease is unknown.11,12,18
Maintaning therapy and extension of UC
Figure 2
25
Change in UC extension in relation to number of drug categories used as maintenance therapy.
In a population-based study from Copenhagen, it is reported that the extent of UC is a dynamic process with changes with time in approximately half of the patients. They reported 25% cumulative probability of extension of colitis within 5 years in patients with proctosigmoiditis at initial diagnosis and 9% to 20% progression in patients with substantial colitis after 10 years of disease duration. The cumulative probability for regression in the above-mentioned study was 45% for substantial colitis and 58% for pancolitis after five years (Langholz et al.11). Furthermore, Moum et al.13 reported 16–24% progression and 23–25% regression rates in extent of colitis in patients with initial rectosigmoidal or left-sided disease, during a 1-year follow-up period using colonoscopy. Similar figures are also reported in the present study. Table 6 Change in UC extension in relation to last year’s disease activity and maintenance therapy Maintenance therapy at 3 months
Last year’s disease activity No flare-up
Without therapy
No change Regression Extension Total
With therapy
No change Regression Extension Total
12 48% 6 24% 7 28% 25 100% 23 58% 6 15% 11 28% 40 100%
p N 0.5 NS, in all subgroups studied.
Total
Active disease 9 75%
1 25% 4 100% 12 41% 9 31% 8 28% 29 100%
15 52% 6 21% 8 28% 29 100% 35 51% 15 22% 19 28% 69 100%
However, in the above-mentioned studies, the changes in UC extension were not correlated to chronic maintenance remission therapy, while in the study by Langholz et al.11 the extent of UC was determined using sigmoidoscopy and double-contrast barium enema in contrast to the present study, in which the extent of UC was accurately determined using colonoscopy. In the present multicenter study the extent of UC seemed not influenced by the intake of maintenance therapy. Half of the patients had no change in extent whereas the other half of patients showed either regression (21%) or extension (28%) irrespective of use of maintenance therapy. The observed degree of extension or regression of colonic involvement was almost always minimal and only in 1–5% of patients more pronounced. The results of this study were not influenced by the type of medication (drug category, oral vs. local administration) nor by combination of different drugs. In fact, a small although insignificant trend to progression of anatomic involvement of disease was observed by the use of combined drug categories possibly reflecting the more aggressive form of disease. The most commonly used maintenance therapy was 5-ASA (47% of patients), while only a small number of patients (3%) was on immunosuppressive only therapy, making the interpretation of the results more difficult. Use of aminosalicylates was accompanied with an extension of disease in 24% and regression in 26% of patients. Furthermore, if we take into account that the mean time between previous and actual UC exacerbations in the current Table 7
Effect of smoking habit in UC extension Smoking habit
Change in UC extension
No change Regression Extension
p N 0.5 in all subgroups studied.
No- and ex-smokers
Active
53% 19.0% 28.0%
36% 45.0% 18.0%
26
N. Eleftheriadis et al. activity, may lead to a conclusion of a potential positive effect of maintenance therapy on colonic extent in patients with active disease. However the small number of patients precludes definite conclusions. In conclusion, although in our study chronic maintenance remission therapy for ulcerative colitis was not found effective in reducing the colitis extension during subsequent ulcerative colitis exacerbation, further long-term studies, as well as use of new drug categories,21 are necessary to determine the role of chronic maintenance remission therapy for ulcerative colitis in the natural history of disease.
Figure 3 Change in UC extension in relation to disease duration (months).
References
study was 29 months, while the mean duration of UC was 93 months, the common follow-up period of 6 months to 1 year used in the majority of prospective studies concerning the role of maintenance therapy in UC, is not sufficient and further studies with longer follow-up are necessary to determine the efficacy of chronic maintenance therapy in modifying the extent of UC. As far as smoking habit is concerned, the majority of patients in this study were non-smokers or ex-smokers. Patients with active smoking showed the greatest degree of regression in colonic extension in comparison to non-smokers or ex-smokers, irrespective to maintenance therapy, however, without statistically significant differences. This finding is another indirect argument for the potential protective effect of smoking in UC, which is in accordance to other studies.19,20 An interesting finding of this study was that in patients with short disease duration (less than 1 year) either no change (63%) or regression (38%) of colonic involvement was observed, in contrast to previous studies reporting the highest extension rate of ulcerative colitis during the first year of disease.11 Use of maintenance therapy was even associated with larger regression (60%). However, the small number of patients precludes definite conclusions. Moreover, the mean disease duration was greater in patients with extension of ulcerative colitis (115 months) than in patients who showed no change (87 months) or regression (79 months) of ulcerative colitis extent (Fig. 3). Although the small number of patients made definite conclusions difficult, we could assume that ulcerative colitis patients during the first year after initial diagnosis may benefit from chronic maintenance therapy with regard to colitis extent. Finally, in the total population, patients with continuously active disease during the last year before actual flare-up, tended to show more frequently regression in colonic extent (27%) than patients with quiescent disease (18%) (p = 0.8, NS), in contrast to other studies, which reported that the occurrence of continuous active disease was related to extension of colitis.11,13 Moreover, patients with active disease showed a trend to greater regression rate with maintenance therapy than patients with quiescent disease, although not significant, while in the group of patients without maintenance therapy, greater regression was observed in patients with quiescent disease. This inverse correlation of regression rates with and without maintenance therapy, in relation to disease
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