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Long-term oral plus topical mesalazine in frequently relapsing ulcerative colitis
Digestive and Liver Disease 37 (2005) 92–96
Alimentary Tract
Long-term oral plus topical mesalazine in frequently relapsing ulcerative colitis G. Frieria,∗ , M. Pimpoa , B. Gallettia , G. Palumboa , G. Corraob , G. Latellaa , M. Chiaramontea , R. Caprillic a
Gastroenterology, University of l’Aquila, L’Aquila, Italy Statistical Department, University of Milano–Bicocca, Italy Gastroenterology Unit, University ‘La Sapienza’, Rome, Italy
b c
Received 13 May 2004; accepted 26 September 2004 Available online 14 November 2004 See related Commentary on pages 82–84
Abstract Background. In cross-sectional studies, it was demonstrated that the therapeutic effect of mesalazine is closely related to its mucosal concentration. Aim. This study was carried out to verify in a longitudinal study if it was possible to improve the clinical course of ulcerative colitis at high risk of recurrence by increasing mucosal mesalazine concentration. Methods. Eighteen consecutive ulcerative colitis patients on continuous oral 5-ASA treatment (2.4–3.2 g/day) in clinical remission who had had at least four moderate to severe relapses in the preceding 2 years (referred period) were assigned to assume oral (3.2–4.8 g/day) and topical (4 g/day) mesalazine in order to increase mucosal drug concentration and were followed up for 2 years (study period). The localisation of disease was 12 pancolitis, six left colitis. The number and severity of recurrences, number of visits and endoscopies, courses of steroids and days of hospitalisation were compared with those of the previous 2 years. Rank signed test for paired data was used for statistical analysis. Results. The total number of recurrences was significantly lower during the study period in comparison with that of referred period (8 versus 80, respectively, p < 0.0001). No courses of steroids or hospitalisation were necessary during study period in comparison with those of referred period (0 versus 33, p < 0.0001; 0 versus 93, p = 0.03, respectively). A total number of 249 visits were done during the referred period and 116 during the study period (p < 0.0001) with a total of 87 endoscopies during referred period and 44 during study period (p < 0.0001). Conclusions. The continuous use of topical mesalazine associated with a high oral dosage significantly improves the clinical course of ulcerative colitis patients at high risk of relapse. © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: High risk of relapse; Mesalazine; Ulcerative colitis
1. Introduction Mesalazine is the most commonly used drug in ulcerative colitis (UC), first as an active moiety of Salazopyrine, then as a single molecule contained in slow or controlled release capsules [1,2]. In spite of the continuous use of the drug over the last 50 years, the therapeutic range of mesalazine remains ∗
Corresponding author. Tel.: +39 0862 368796; fax: +39 0862 322135. E-mail address: [email protected] (G. Frieri).
to be clearly established and thus, its optimal dosage and route of administration are still debated [3–5]. A cross-sectional study has demonstrated that the antiinflammatory effect of mesalazine is closely related to its mucosal concentration [6]. In other words, in a given colonic segment, the higher the mucosal concentration of mesalazine, the better the endoscopic and histological conditions of the mucosa. It is, therefore, reasonable to hypothesise that the optimal dose should be the one ensuring an adequate mucosal drug concentration in the affected sites [7]. However,
1590-8658/$30 © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2004.09.017
G. Frieri et al. / Digestive and Liver Disease 37 (2005) 92–96
mesalazine has a topical effect, which means that the drug may significantly concentrate into the intestinal mucosa only during its absorptive process. Thus, if it is absorbed by inflamed mucosa it may concentrate in the inflamed tissue, but if the drug is absorbed by normal mucosa it is almost completely lost for its therapeutic use. Thus, the goal of treatment is not only to achieve an optimal dosage, but especially to take the drug where it needs [8]. Pharmacokinetic studies have demonstrated that, when given per os, the active moiety of mesalazine is delivered mainly to the distal ileum and proximal large bowel thus ensuring a higher mucosal drug concentration in the right than in the left colon, with only negligible amounts of the drug reaching the rectal mucosa [9,10]. The increase in the oral dosage further increases the mucosal concentration in the proximal colonic segments, but does not significantly modify distal drug distribution [11]. Conversely, topical mesalazine administration assures a considerable drug availability in the recto-sigmoid sites and, to a lower extent, also in the descending colon [12,13]. Therefore, it appears that, if we would increase mucosal mesalazine concentration in UC patients along the entire length of their large bowel, beside an increase of oral dosage, a continuous topical treatment should be given. On the basis of these pharmacokinetic considerations, the present longitudinal study was aimed to verify whether an increasing of oral dosage of mesalazine, associated with its continuous topical administration, could increase mucosal drug concentration and modify the clinical course of a particular group of UC patients at high risk of relapse, with a not mild disease, that actually need repeated hospitalisations, courses of steroids and/or immunosuppressive drugs [14,15].
2. Patients and methods This study was designed to compare the clinical course of UC patients recorded during the 2 years prior to the study (referred period RP) with that seen in the subsequent 2 years, when the same patients were assigned to the treatment under investigation (study period SP). This was a “before-after” comparison study in which each patient was compared with him/herself, thus representing his/her own control. The clinical, endoscopic and histological characteristics of all consecutive UC patients prospectively recorded through a standardised follow-up procedure in our Gastroenterology Department between June and December 1998, were retrospectively evaluated for number, frequency and severity of recurrences. All patients without significant hepatic, renal or cardiovascular diseases as well as non-pregnant women who had four or more clinical relapses (at least three of them moderate to severe), in the preceding 2 years, were invited to be included in the present investigation. All, but two, patients accepted to be included. Of these, one was operated within 2 months, the second was lost to follow-up.
93
The accuracy of this kind of evaluation was guaranteed by the standardised follow-up procedure used by our IBD study group since 1990. The procedure consists of prospectively filling in three multiple-choice questionnaires (for clinical, endoscopic and histological assessment), either at a fixed time interval during remission (every 4 months for clinical assessment; every year for endoscopic and histological evaluation) or at the time of relapse occurrence. The questionnaires simply collect all data useful for calculating the scores of the disease. The same clinical questionnaire is also self-filled by patients during remission and is used as a personal diary early after hospitalisation, during tapering of steroids or when a strict clinical monitoring is necessary at home. Finally, information on drug assumption and complications is also recorded in the same sheet. The same follow-up procedure was used also for the SP of the present investigation. As far as the clinical assessment of the disease, the Truelove and Witts score was used [16]. The endoscopic score ranges from 0 (normal appearance with visible vessels) to 3 (ulcers and/or vasting denudations and/or spontaneous bleeding) according to Baron criteria [17]. For the histological assessment of colitis, a score ranging from 0 to 5 according to Flor´en criteria is used [18]. Informed consent was obtained from all 18 patients enrolled in the present investigation. The general characteristics of patients are shown in Table 1. The maintenance treatment of patients during the RP consisted of continuous oral mesalazine (2.4–3.2 g/day), and immunosuppressive drugs for two patients. Upon relapse, topical mesalazine and/or oral (prednisone: 0.5–1 mg/(kg die)) or intravenous steroids (hydrocortisone: 400 mg/die) were used depending on general clinical conditions, severity of the relapse and response to treatment. Two patients were treated with immunosuppressive drugs (Cyclosporine: 300 mg/day for 5 months and Azathioprine: 150 mg/day for 15 and 10 months, respectively). At enrolment, all patients had been in clinical remission for at least 1 month and were able to retain enemas for at least 6 h. All patients were given a treatment consisting of oral plus topical mesalazine (Asacol Giuliani-Bracco, Italy). Oral dosage was tailored for each patient in order to increase the preceding dosage by about 50%. In this way, the oral dosages of mesalazine ranged from 3.6 to 4.8 g daily. Topical treatment consisted of 4 g/day of mesalazine for the first 6 months. Afterwards, the frequency of enema administration was reduced to three times a week, to favour the long-term compliance. Any other maintenance therapy was discontinued during SP. In the case of moderate or severe relapses occurring during SP, steroids and immunosuppressive drugs Table 1 General characteristics of patients Age (years) M/F Time from last relapse (months) Localisation of disease Duration of disease (years)
22–80 11/7 1–3 12 pancolitis, 6 left colitis 3–8
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G. Frieri et al. / Digestive and Liver Disease 37 (2005) 92–96
were used with the same criteria during RP. If mild, relapses were treated either by ‘wait and watch’ or by restoring the daily frequency of enemas if the recurrence occurred after the sixth month of treatment. In each patient, the number and clinical severity of recurrences, the courses of steroids, the days of hospitalisation, the number of visits and endoscopies were evaluated in the SP and compared with those of the RP. Endoscopic and histological features were also calculated but were not submitted to statistical analysis for the different time table of assessments during RP and SP. In fact, in our follow-up procedure, the timing of endoscopic and histological assessments, even if planned by a fixed time-table, depend on clinical needs. Thus, data between RP and SP are not comparable and will be given only as observational data. During the SP, patients were requested to report on a diary any clinical variations in their physical condition and any incorrect use of the drugs. The diaries were checked at each follow-up. As far as compliance concerns, we considered as non-compliant, patients missing more than 50% of oral therapy for 7 consecutive days, or more than 50% of topical therapy for 2 weeks. Mucosal mesalazine concentration was measured both at the enrolment (the start of SD) and at 1 year of follow-up. During the endoscopies, rectal biopsies were taken and frozen to −80 ◦ C. In a later section, the biopsies were gently thawed, sonicated and finally analysed by HPLC method according to previously described method [19] Rank signed test for paired data was used for statistical analysis.
3. Results During SP no severe or moderate recurrences were recorded and only six patients showed mild signs of relapse. A total number of 80 episodes of relapses were observed during RP and 8 during the SP (p < 0.0001). Mild relapses were 25 during RP and 8 during SP (p < 0.0001), moderate relapses were 36 during RP and none during SP (p < 0.0001) and severe relapses occurred in 19 instances during RP but in none during SP (p < 0.0001) (Table 2). All relapses occurred when the frequency of topical treatment was reduced to three enemas a week and all were successfully treated by restoring the daily enema administration. Relapses were characterised by a slight bowel habit modification (up to three evacuation per day, reduction of stool consistency) and, in three cases, mild amount of mucus in the faeces. Table 2 Number of relapses during the RP and the SP Relapses
RP
p
SP
Total Mild Moderate Severe
80 25 36 19
<0.0001 <0.0001 <0.0001 <0.0001
8 8 0 0
Table 3 Courses of steroid, days of hospitalisation, number of visits and endoscopies during the RP and the SP
Courses of steroid Days of hospitalisation Number of visits Number of endoscopies
RP
p
SP
33 93 249 87
<0.0001 <0.03 <0.0001 <0.0001
0 0 116 44
Six out of eight relapses observed during SP showed mild endoscopic lesions (score 1) while normal endoscopic findings were observed in the remaining two cases. In all instances, mild histological inflammation was present (score 2). No courses of steroids were necessary during SP while they were employed 33 times during RP (p < 0.0001). Days of hospitalisation amounted to a total of 93 during the RP and 0 during SP (p = 0.03). A total of 249 visits was done during the RP and 116 during the SP (p < 0.0001) with a total of 87 endoscopies during RP and 44 during SP (p < 0.0001) (Table 3). As far as the activity scores of colitis were concerned, clinical scores ranged from remission to severe during RP and from remission to mild during SP; endoscopic scores ranged from 0 to 3 during RP and from 0 to 1 during SP; histological scores ranged from 1 to 5 during RP and from 1 to 2 during SP. Patient compliance was generally good. Less than 15% of the study, medications were not taken during the SP, and at the end of the study, only three patients agreed to discontinue the treatment. Finally, no side effects due to therapy were recorded during the study and neither clinical signs nor haematological alterations were observed during the followup. The mesalazine concentration detected in the rectal mucosa after 1 year of continuous high dosage double treatment, was significantly higher in comparison with that obtained at the enrolment during the standard oral mesalazine therapy (median values: 259.81 ng/ml, range: 151.2–595.97 ng/ml versus 3.065 ng/mg, range: 0.62–5.3 ng/mg, respectively; p < 0.001).
4. Discussion Previous cross-sectional studies have demonstrated that the efficacy of mesalazine is related to its mucosal concentration and that to increase large bowel drug availability, the oral dosage should be increased and a topical treatment should be continuously associated [6,13,20]. In the present investigation, we adopted this therapeutic strategy in a longitudinal study to establish whether or not it could change the clinical course of a particular group of UC patients with a moderate to severe disease at high risk of recurrence, i.e. patients that in the 2 years before the study had four or more recurrences with at least one of which was of severe form. We have chosen
G. Frieri et al. / Digestive and Liver Disease 37 (2005) 92–96
this particular group of patients because, even if they represent a small rate of UC population (less than 20%), they often represent a critical challenge in a gastroenterology unit and absorb a large amount of public health costs for the disease [14,15]. We did not include patients with less severe disease because they showed long-lasting remission periods, showed a quick response to acute treatment and were already largely studied [21,22]. The use of the treatment under investigation has resulted in a marked improvement in the clinical course of patients studied with a significant reduction of recurrences, need for medical visits, endoscopies and, at least in the present series, the abolition of steroids and hospitalisation. To our knowledge, this represents the first demonstration that the increase of oral treatment and the continuous topical therapy can improve the clinical course of UC even in patients with frequently relapsing severe disease over a 2 years of follow-up. Results of the present study suggest that it is possible to increase the clinical efficacy of mesalazine in UC patients by adopting a therapeutic strategy aimed at increasing mucosal drug concentration of the large bowel. In other words, it is possible that, in a given clinical circumstance, such as the frequently recurring patients, the difficulty in maintaining remission, besides the severity of the disease, might be due to dosage and/or mode of administration not allowing the drug to reach the mucosal concentration necessary to treat that particular condition [23–26]. In the present series, the combined, high dosage treatment resulted in a surprisingly high concentration of the drug in the rectal mucosa. These values represent the highest rectal mesalazine concentrations ever reported in the literature [10,11,13]. Analogous values were only recorded in the caecum and right colon, sites where the majority of oral pharmaceutical preparation of mesalazine releases the active moiety of the drug. We are not sure whether such a concentration was really necessary or exceeded the patients’ actual needs. Certainly, this therapeutic approach was able to guarantee 2 years of complete remission in the majority of our patients, but was unable to eliminate even mild recurrence in others. This means that differences in disease severity and/or differences in host immuno-inflammatory response might require tailoring of the drug in different patients. Thus, the notion of an optimal dosage of mesalazine should be substituted by the concept of the need of personalised dosage for any individual patient. Differences in pharmacogenetic and pharmacogenomic characteristics should be also taken into account [27,28]. The main problem in the therapeutic strategy adopted in this study may be the compliance to adhere to the daily enema program [29]. In our series, the abolition of hospitalisation and needs of steroids increased the patients’ well being so much that they were been willing to strictly comply with even the complex schedule treatment. However, it is out of doubt that compliance represents the main problem in this kind of drug administration. If in the future we can obtain higher recto-colonic mesalazine concentration us-
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ing drugs with pharmacokinetic characteristics allowing a simpler schedule treatment, a new therapeutic chance can be given to patients with a moderate to severe disease at high risk of recurrence. The present study was designed to investigate the variations in the clinical course of an individual patient by modifying maintenance treatment. In this kind of study, the control group is not represented by placebo, but each patient is compared with him/herself and thus each patient represents his own control. The main weakness of this methodology is that blindness is not required and that a spontaneous regression of the disease during SP cannot be excluded. To overcome any possible bias, we have strictly applied the same followup procedure of RP to SP and studied hard points such as hospitalisation and needs of steroids in which a blind evaluation may not be necessary. A randomised control study may resolve the above potential bias and should be the next step to confirm this study’s results. As far as a possible spontaneous regression of the disease, we have considered a long enough follow-up period to allow for at least one recurrence to be expected in patients that during the same time period had had more than four flare ups of the disease. Therefore, even if a spontaneous remission of the disease during SP cannot be excluded, this hypothesis does not appear the most likely. In conclusion, the present investigation has demonstrated that it is possible to improve the clinical course of UC patients at high risk of relapse by adopting a therapeutic strategy aimed at increasing rectal mucosa mesalazine concentration. These modifications in patients’ lifetime might be considered as a therapeutic gain. Conflict of interest statement None declared.
References [1] Khan A, Piris J, Truelove SC. An experiment to determine the active therapeutic moiety of sulphasalazine. Lancet 1977;2:892–905. [2] Hanauer SB. Inflammatory bowel disease. N Engl J Med 1996;334:841–8. [3] Riley SA. What dose of 5-aminosalicylic acid (mesalazine) in ulcerative colitis? Gut 1998;42:761–3. [4] Mulder CJJ, van de Hazel SJ. Drug therapy: dose–response relationship of oral mesalazine in inflammatory bowel disease. Med Inflamm 1998;7:135–6. [5] Quasim A, Seery J, O’Morian CA. 5-Aminosalicylates in inflammatory bowel disease: choosing the right dose. Dig Liver Dis 2001;33:393–8. [6] Frieri G, Giacomelli R, Pimpo M, Palumbo G, Passacantando A, Pantaleoni G, et al. Mucosal 5-aminosalicylic acid concentration inversely correlates with severity of colonic inflammation in patients with ulcerative colitis. Gut 2000;47:410–4. [7] Clemett D, Markham A. Prolonged-release mesalamine. A review of its therapeutic potential in ulcerative colitis and Crohn’s disease. Drugs 2000;59:929–56. [8] Sandborn WJ, Hanauer SB. The pharmacokinetic profiles of oral mesalazine formulations and mesalazine pro-drugs used in
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G. Frieri et al. / Digestive and Liver Disease 37 (2005) 92–96 the management of ulcerative colitis. Aliment Phamacol Ther 2003;17:29–36. Hebden JM, Blackshaw PE, Perkins AC, Wilson CG, Spiller RC. Limited exposure of the healthy distal colon to orally-dosed formulation is further exaggerated in active left-sided ulcerative colitis. Aliment Pharmacol Ther 2000;14:155–61. DeVos M, Verdievel H, Shoonjans R, Praet M, Bogaert M, Barbier F. Concentrations of mesalazine and Ac-mesalazine in human ileocolonic biopsy homogenates after oral mesalazine preparations. Gut 1992;33:1338–42. Hussain F, Ajjan R, Rilay SA. Dose loading with delayed release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters. Br J Clin Pharmacol 2000;49:323–30. Campieri M, Corbelli C, Gionchetti P, Brignola C, Belluzzi A, Di Febo G, et al. Spread and distribution of mesalazine colonic foam and mesalazine enema in patients with ulcerative colitis. Dig Dis Sci 1992;12:1890–7. Frieri G, Pimpo MT, Palumbo GC, Onori L, Viscido A, Latella G, et al. Rectal and colonic mesalazine concentration in ulcerative colitis: oral vs. oral plus topical treatment. Aliment Pharmacol Ther 1999;13:1413–7. Longobardi T, Jacobs P, Wu L, Bernstein CN. Work losses related to inflammatory bowel disease in Canada: results from a National Population Health Survey. Am J Gastroenterol 2003;98:722–3. Ward FM, Bodger K, Daly MJ, Heatley RV. Clinical economics review: medical management of inflammatory bowel disease. Aliment Pharamcol Ther 1999;13:15–25. Truelove SC, Witts LJ. Cortisone in ulcerative colitis: final report on a therapeutic trial. Br Med J 1955;2:1041–8. Baron JH, Connell AM, Lennard-Jones JE. Variations between observers in describing mucosal appearances in proctocolitis. Br Med J 1964;1:89–92. Flor´en C, Benoni C, Willen R. Histological and colonoscopic assessment of disease extension in ulcerative colitis. Scand J Gastroenterol 1987;22:459–62. Palumbo GC, Carlucci G, Mazzeo P, Frieri G, Pimpo MT, Fanini D. Simultaneous determination of 5-aminosalycilic acid, acetyl-5aminosalicylic acid and 2,5-dihydroxybenzoic acid in endoscopic intestinal biopsy samples in humans by high-performance liquid
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chromatography with electrochemical detection. J Pharmacol Biomed Anal 1995;14:175–80. Frieri G, Pimpo MT, Andreoli A, Annese V, Comberlato M, Corrao G, et al. Prevention of postoperative recurrence of Crohn’s disease requires adequate mucosal concentration of mesalazine. Aliment Pharmacol Ther 1999;13:577–82. D’Albasio G, Pacini F, Camarri E, Messori A, Pharm D, Trallori G, et al. Combined therapy with 5-aminosalicylic acid tablets and enemas for maintaining remission in ulcerative colitis: a randomised double-blind study. Am J Gastroenterol 1997;92:1143–7. Paoluzi P, D’Albasio G, Pera A, Bianchi Porro G, Paoluzzi OA, Pica R, et al. Oral and topical 5-aminosalicilyc acid (mesalazine) in inducine and maintaining remission in mild-moderate relapse of ulcerative colitis: one year randomised multicentre trial. Dig Liver Dis 2002;34:787–93. Riley SA, Mani V, Goodman MJ, Lucas S. Why do patients with ulcerative colitis relapse? Gut 1990;31:179–83. Stew´enius J, Adnerhill I, Ekelund GR, Floren C-H, Fork F-T, Janzon L. Risk of relapse in new cases of ulcerative colitis and indeterminate colitis. Dis Colon Rectum 1996;39:1019–25. Bitton A, Peppeccorn MA, Antonioli DC, Niles JL, Shah S, Bousvaros A, et al. Clinical, biological, and histologic parameters as predictors of relapse in ulcerative colitis. Gastroenterology 2001;120:13–20. 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. Hein DW, Doll MA, Fretland AJ, Leff MA, Webb SJ, Xiao GH, et al. Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Biomarkers Prev 2000;9:29–42. Ricart E, Taylor WR, Loftus EV, O’Kane D, Weinshilboum RM, Tremain WJ, et al. N-Acetyltransferase 1 and 2 genotypes do not predict response or toxicity to treatment with mesalazine and sulfasalazine in patients with ulcerative colitis. Am J Gastroenterol 2002;97:1763–8. Kane S, Huo D, Aikens J, Hanauer S. Medication nonadherence and the outcomes of patients with quiescent ulcerative colitis. Am J Med 2003;114:39–43.
Alimentary Tract
Long-term oral plus topical mesalazine in frequently relapsing ulcerative colitis G. Frieria,∗ , M. Pimpoa , B. Gallettia , G. Palumboa , G. Corraob , G. Latellaa , M. Chiaramontea , R. Caprillic a
Gastroenterology, University of l’Aquila, L’Aquila, Italy Statistical Department, University of Milano–Bicocca, Italy Gastroenterology Unit, University ‘La Sapienza’, Rome, Italy
b c
Received 13 May 2004; accepted 26 September 2004 Available online 14 November 2004 See related Commentary on pages 82–84
Abstract Background. In cross-sectional studies, it was demonstrated that the therapeutic effect of mesalazine is closely related to its mucosal concentration. Aim. This study was carried out to verify in a longitudinal study if it was possible to improve the clinical course of ulcerative colitis at high risk of recurrence by increasing mucosal mesalazine concentration. Methods. Eighteen consecutive ulcerative colitis patients on continuous oral 5-ASA treatment (2.4–3.2 g/day) in clinical remission who had had at least four moderate to severe relapses in the preceding 2 years (referred period) were assigned to assume oral (3.2–4.8 g/day) and topical (4 g/day) mesalazine in order to increase mucosal drug concentration and were followed up for 2 years (study period). The localisation of disease was 12 pancolitis, six left colitis. The number and severity of recurrences, number of visits and endoscopies, courses of steroids and days of hospitalisation were compared with those of the previous 2 years. Rank signed test for paired data was used for statistical analysis. Results. The total number of recurrences was significantly lower during the study period in comparison with that of referred period (8 versus 80, respectively, p < 0.0001). No courses of steroids or hospitalisation were necessary during study period in comparison with those of referred period (0 versus 33, p < 0.0001; 0 versus 93, p = 0.03, respectively). A total number of 249 visits were done during the referred period and 116 during the study period (p < 0.0001) with a total of 87 endoscopies during referred period and 44 during study period (p < 0.0001). Conclusions. The continuous use of topical mesalazine associated with a high oral dosage significantly improves the clinical course of ulcerative colitis patients at high risk of relapse. © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: High risk of relapse; Mesalazine; Ulcerative colitis
1. Introduction Mesalazine is the most commonly used drug in ulcerative colitis (UC), first as an active moiety of Salazopyrine, then as a single molecule contained in slow or controlled release capsules [1,2]. In spite of the continuous use of the drug over the last 50 years, the therapeutic range of mesalazine remains ∗
Corresponding author. Tel.: +39 0862 368796; fax: +39 0862 322135. E-mail address: [email protected] (G. Frieri).
to be clearly established and thus, its optimal dosage and route of administration are still debated [3–5]. A cross-sectional study has demonstrated that the antiinflammatory effect of mesalazine is closely related to its mucosal concentration [6]. In other words, in a given colonic segment, the higher the mucosal concentration of mesalazine, the better the endoscopic and histological conditions of the mucosa. It is, therefore, reasonable to hypothesise that the optimal dose should be the one ensuring an adequate mucosal drug concentration in the affected sites [7]. However,
1590-8658/$30 © 2004 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2004.09.017
G. Frieri et al. / Digestive and Liver Disease 37 (2005) 92–96
mesalazine has a topical effect, which means that the drug may significantly concentrate into the intestinal mucosa only during its absorptive process. Thus, if it is absorbed by inflamed mucosa it may concentrate in the inflamed tissue, but if the drug is absorbed by normal mucosa it is almost completely lost for its therapeutic use. Thus, the goal of treatment is not only to achieve an optimal dosage, but especially to take the drug where it needs [8]. Pharmacokinetic studies have demonstrated that, when given per os, the active moiety of mesalazine is delivered mainly to the distal ileum and proximal large bowel thus ensuring a higher mucosal drug concentration in the right than in the left colon, with only negligible amounts of the drug reaching the rectal mucosa [9,10]. The increase in the oral dosage further increases the mucosal concentration in the proximal colonic segments, but does not significantly modify distal drug distribution [11]. Conversely, topical mesalazine administration assures a considerable drug availability in the recto-sigmoid sites and, to a lower extent, also in the descending colon [12,13]. Therefore, it appears that, if we would increase mucosal mesalazine concentration in UC patients along the entire length of their large bowel, beside an increase of oral dosage, a continuous topical treatment should be given. On the basis of these pharmacokinetic considerations, the present longitudinal study was aimed to verify whether an increasing of oral dosage of mesalazine, associated with its continuous topical administration, could increase mucosal drug concentration and modify the clinical course of a particular group of UC patients at high risk of relapse, with a not mild disease, that actually need repeated hospitalisations, courses of steroids and/or immunosuppressive drugs [14,15].
2. Patients and methods This study was designed to compare the clinical course of UC patients recorded during the 2 years prior to the study (referred period RP) with that seen in the subsequent 2 years, when the same patients were assigned to the treatment under investigation (study period SP). This was a “before-after” comparison study in which each patient was compared with him/herself, thus representing his/her own control. The clinical, endoscopic and histological characteristics of all consecutive UC patients prospectively recorded through a standardised follow-up procedure in our Gastroenterology Department between June and December 1998, were retrospectively evaluated for number, frequency and severity of recurrences. All patients without significant hepatic, renal or cardiovascular diseases as well as non-pregnant women who had four or more clinical relapses (at least three of them moderate to severe), in the preceding 2 years, were invited to be included in the present investigation. All, but two, patients accepted to be included. Of these, one was operated within 2 months, the second was lost to follow-up.
93
The accuracy of this kind of evaluation was guaranteed by the standardised follow-up procedure used by our IBD study group since 1990. The procedure consists of prospectively filling in three multiple-choice questionnaires (for clinical, endoscopic and histological assessment), either at a fixed time interval during remission (every 4 months for clinical assessment; every year for endoscopic and histological evaluation) or at the time of relapse occurrence. The questionnaires simply collect all data useful for calculating the scores of the disease. The same clinical questionnaire is also self-filled by patients during remission and is used as a personal diary early after hospitalisation, during tapering of steroids or when a strict clinical monitoring is necessary at home. Finally, information on drug assumption and complications is also recorded in the same sheet. The same follow-up procedure was used also for the SP of the present investigation. As far as the clinical assessment of the disease, the Truelove and Witts score was used [16]. The endoscopic score ranges from 0 (normal appearance with visible vessels) to 3 (ulcers and/or vasting denudations and/or spontaneous bleeding) according to Baron criteria [17]. For the histological assessment of colitis, a score ranging from 0 to 5 according to Flor´en criteria is used [18]. Informed consent was obtained from all 18 patients enrolled in the present investigation. The general characteristics of patients are shown in Table 1. The maintenance treatment of patients during the RP consisted of continuous oral mesalazine (2.4–3.2 g/day), and immunosuppressive drugs for two patients. Upon relapse, topical mesalazine and/or oral (prednisone: 0.5–1 mg/(kg die)) or intravenous steroids (hydrocortisone: 400 mg/die) were used depending on general clinical conditions, severity of the relapse and response to treatment. Two patients were treated with immunosuppressive drugs (Cyclosporine: 300 mg/day for 5 months and Azathioprine: 150 mg/day for 15 and 10 months, respectively). At enrolment, all patients had been in clinical remission for at least 1 month and were able to retain enemas for at least 6 h. All patients were given a treatment consisting of oral plus topical mesalazine (Asacol Giuliani-Bracco, Italy). Oral dosage was tailored for each patient in order to increase the preceding dosage by about 50%. In this way, the oral dosages of mesalazine ranged from 3.6 to 4.8 g daily. Topical treatment consisted of 4 g/day of mesalazine for the first 6 months. Afterwards, the frequency of enema administration was reduced to three times a week, to favour the long-term compliance. Any other maintenance therapy was discontinued during SP. In the case of moderate or severe relapses occurring during SP, steroids and immunosuppressive drugs Table 1 General characteristics of patients Age (years) M/F Time from last relapse (months) Localisation of disease Duration of disease (years)
22–80 11/7 1–3 12 pancolitis, 6 left colitis 3–8
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G. Frieri et al. / Digestive and Liver Disease 37 (2005) 92–96
were used with the same criteria during RP. If mild, relapses were treated either by ‘wait and watch’ or by restoring the daily frequency of enemas if the recurrence occurred after the sixth month of treatment. In each patient, the number and clinical severity of recurrences, the courses of steroids, the days of hospitalisation, the number of visits and endoscopies were evaluated in the SP and compared with those of the RP. Endoscopic and histological features were also calculated but were not submitted to statistical analysis for the different time table of assessments during RP and SP. In fact, in our follow-up procedure, the timing of endoscopic and histological assessments, even if planned by a fixed time-table, depend on clinical needs. Thus, data between RP and SP are not comparable and will be given only as observational data. During the SP, patients were requested to report on a diary any clinical variations in their physical condition and any incorrect use of the drugs. The diaries were checked at each follow-up. As far as compliance concerns, we considered as non-compliant, patients missing more than 50% of oral therapy for 7 consecutive days, or more than 50% of topical therapy for 2 weeks. Mucosal mesalazine concentration was measured both at the enrolment (the start of SD) and at 1 year of follow-up. During the endoscopies, rectal biopsies were taken and frozen to −80 ◦ C. In a later section, the biopsies were gently thawed, sonicated and finally analysed by HPLC method according to previously described method [19] Rank signed test for paired data was used for statistical analysis.
3. Results During SP no severe or moderate recurrences were recorded and only six patients showed mild signs of relapse. A total number of 80 episodes of relapses were observed during RP and 8 during the SP (p < 0.0001). Mild relapses were 25 during RP and 8 during SP (p < 0.0001), moderate relapses were 36 during RP and none during SP (p < 0.0001) and severe relapses occurred in 19 instances during RP but in none during SP (p < 0.0001) (Table 2). All relapses occurred when the frequency of topical treatment was reduced to three enemas a week and all were successfully treated by restoring the daily enema administration. Relapses were characterised by a slight bowel habit modification (up to three evacuation per day, reduction of stool consistency) and, in three cases, mild amount of mucus in the faeces. Table 2 Number of relapses during the RP and the SP Relapses
RP
p
SP
Total Mild Moderate Severe
80 25 36 19
<0.0001 <0.0001 <0.0001 <0.0001
8 8 0 0
Table 3 Courses of steroid, days of hospitalisation, number of visits and endoscopies during the RP and the SP
Courses of steroid Days of hospitalisation Number of visits Number of endoscopies
RP
p
SP
33 93 249 87
<0.0001 <0.03 <0.0001 <0.0001
0 0 116 44
Six out of eight relapses observed during SP showed mild endoscopic lesions (score 1) while normal endoscopic findings were observed in the remaining two cases. In all instances, mild histological inflammation was present (score 2). No courses of steroids were necessary during SP while they were employed 33 times during RP (p < 0.0001). Days of hospitalisation amounted to a total of 93 during the RP and 0 during SP (p = 0.03). A total of 249 visits was done during the RP and 116 during the SP (p < 0.0001) with a total of 87 endoscopies during RP and 44 during SP (p < 0.0001) (Table 3). As far as the activity scores of colitis were concerned, clinical scores ranged from remission to severe during RP and from remission to mild during SP; endoscopic scores ranged from 0 to 3 during RP and from 0 to 1 during SP; histological scores ranged from 1 to 5 during RP and from 1 to 2 during SP. Patient compliance was generally good. Less than 15% of the study, medications were not taken during the SP, and at the end of the study, only three patients agreed to discontinue the treatment. Finally, no side effects due to therapy were recorded during the study and neither clinical signs nor haematological alterations were observed during the followup. The mesalazine concentration detected in the rectal mucosa after 1 year of continuous high dosage double treatment, was significantly higher in comparison with that obtained at the enrolment during the standard oral mesalazine therapy (median values: 259.81 ng/ml, range: 151.2–595.97 ng/ml versus 3.065 ng/mg, range: 0.62–5.3 ng/mg, respectively; p < 0.001).
4. Discussion Previous cross-sectional studies have demonstrated that the efficacy of mesalazine is related to its mucosal concentration and that to increase large bowel drug availability, the oral dosage should be increased and a topical treatment should be continuously associated [6,13,20]. In the present investigation, we adopted this therapeutic strategy in a longitudinal study to establish whether or not it could change the clinical course of a particular group of UC patients with a moderate to severe disease at high risk of recurrence, i.e. patients that in the 2 years before the study had four or more recurrences with at least one of which was of severe form. We have chosen
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this particular group of patients because, even if they represent a small rate of UC population (less than 20%), they often represent a critical challenge in a gastroenterology unit and absorb a large amount of public health costs for the disease [14,15]. We did not include patients with less severe disease because they showed long-lasting remission periods, showed a quick response to acute treatment and were already largely studied [21,22]. The use of the treatment under investigation has resulted in a marked improvement in the clinical course of patients studied with a significant reduction of recurrences, need for medical visits, endoscopies and, at least in the present series, the abolition of steroids and hospitalisation. To our knowledge, this represents the first demonstration that the increase of oral treatment and the continuous topical therapy can improve the clinical course of UC even in patients with frequently relapsing severe disease over a 2 years of follow-up. Results of the present study suggest that it is possible to increase the clinical efficacy of mesalazine in UC patients by adopting a therapeutic strategy aimed at increasing mucosal drug concentration of the large bowel. In other words, it is possible that, in a given clinical circumstance, such as the frequently recurring patients, the difficulty in maintaining remission, besides the severity of the disease, might be due to dosage and/or mode of administration not allowing the drug to reach the mucosal concentration necessary to treat that particular condition [23–26]. In the present series, the combined, high dosage treatment resulted in a surprisingly high concentration of the drug in the rectal mucosa. These values represent the highest rectal mesalazine concentrations ever reported in the literature [10,11,13]. Analogous values were only recorded in the caecum and right colon, sites where the majority of oral pharmaceutical preparation of mesalazine releases the active moiety of the drug. We are not sure whether such a concentration was really necessary or exceeded the patients’ actual needs. Certainly, this therapeutic approach was able to guarantee 2 years of complete remission in the majority of our patients, but was unable to eliminate even mild recurrence in others. This means that differences in disease severity and/or differences in host immuno-inflammatory response might require tailoring of the drug in different patients. Thus, the notion of an optimal dosage of mesalazine should be substituted by the concept of the need of personalised dosage for any individual patient. Differences in pharmacogenetic and pharmacogenomic characteristics should be also taken into account [27,28]. The main problem in the therapeutic strategy adopted in this study may be the compliance to adhere to the daily enema program [29]. In our series, the abolition of hospitalisation and needs of steroids increased the patients’ well being so much that they were been willing to strictly comply with even the complex schedule treatment. However, it is out of doubt that compliance represents the main problem in this kind of drug administration. If in the future we can obtain higher recto-colonic mesalazine concentration us-
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ing drugs with pharmacokinetic characteristics allowing a simpler schedule treatment, a new therapeutic chance can be given to patients with a moderate to severe disease at high risk of recurrence. The present study was designed to investigate the variations in the clinical course of an individual patient by modifying maintenance treatment. In this kind of study, the control group is not represented by placebo, but each patient is compared with him/herself and thus each patient represents his own control. The main weakness of this methodology is that blindness is not required and that a spontaneous regression of the disease during SP cannot be excluded. To overcome any possible bias, we have strictly applied the same followup procedure of RP to SP and studied hard points such as hospitalisation and needs of steroids in which a blind evaluation may not be necessary. A randomised control study may resolve the above potential bias and should be the next step to confirm this study’s results. As far as a possible spontaneous regression of the disease, we have considered a long enough follow-up period to allow for at least one recurrence to be expected in patients that during the same time period had had more than four flare ups of the disease. Therefore, even if a spontaneous remission of the disease during SP cannot be excluded, this hypothesis does not appear the most likely. In conclusion, the present investigation has demonstrated that it is possible to improve the clinical course of UC patients at high risk of relapse by adopting a therapeutic strategy aimed at increasing rectal mucosa mesalazine concentration. These modifications in patients’ lifetime might be considered as a therapeutic gain. Conflict of interest statement None declared.
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