EDITORIAL Fecal Calprotectin–Guided Dosing of Mesalamine in Ulcerative Colitis: Concept Proved but More Data Needed ral mesalamine remains the preferred first line treatment for induction and maintenance of remission in patients with mild-to-moderately active ulcerative colitis (UC).1 UC is a mucosal disease, characterized by continuous inflammation, which is present exclusively in the colon. Different oral prodrugs and delayed- and sustained-release formulations of mesalamine have been developed to deliver mesalamine to the site of inflammation in the colon. Despite the differences in delivery systems, the different prodrugs and formulations are similarly effective.2,3 Initial clinical trials showed that delayed- or sustained-release formulations of mesalamine at doses ranging from 2.0 to 4.8 g/d were effective in patients with mild-to-moderately active UC, and that higher induction doses (range, 4.0–4.8 g/d) might be more effective than lower doses (range, 1.6–2.4 g/d).4–6 The subsequent randomized controlled trials Assessing the Safety and Clinical Efficacy of a New Dose (ASCEND) investigated the dose-dependent effect of delayedrelease mesalamine (Asacol; Procter and Gamble Pharmaceuticals, Mason, OH) 2.4 or 4.8 g/d for patients with mild-to-moderately active UC. The ASCEND I trial failed to show a difference between 2.4 g/d dosing compared with 4.8 g/d dosing for complete remission or response to therapy from baseline to week 6 (primary end point). Subgroup analysis including only patients with moderately active UC showed that 72% of patients (55 of 76) given delayed-release oral mesalamine 4.8 g/d and 57% of patients (53 of 93) given 2.4 g/d achieved the primary end point (P ¼ .0384).7 This influenced enrollment for the ASCEND II trial (ongoing at that time), to recruit primarily patients with moderately active UC.8 The primary efficacy population consisted of 268 patients with moderately active UC, of whom 72% (89 of 124) of patients receiving 4.8 g/d achieved complete remission or a clinical response to therapy from baseline at week 6, compared with 59% (77 of 130) of those who received 2.4 g/d (P ¼ .036).8 The ASCEND III trial, a 6-week noninferiority study, showed that 70% (273 of 389) of patients who received 4.8 g/d of mesalamine achieved treatment success at week 6, compared with 66% (251 of 383) of patients receiving 2.4 g/d, and thus that the primary objective of noninferiority was met. In addition, 43% of patients who received 4.8 g/d mesalamine achieved clinical remission at week 6 compared with 35% of patients who received 2.4 g/d (P ¼ .04).9 Furthermore, the Multi-Matrix System (MMX) mesalamine (Shire

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Pharmaceuticals Inc, Wayne, PA; in partnership with Giuliani SpA, Milan, Italy) randomized controlled trials failed to show an additional clinical and endoscopic benefit for 4.8 vs 2.4 g/d dosing.10,11 In patients with ulcerative colitis in endoscopic remission, there were no differences between delayed-release mesalamine (Asacol) 0.8 and 1.6 g/d, or between delayed-release mesalamine 1.6 g/d and MMX mesalamine 2.4 g/d for maintenance of endoscopic remission over 6 months.12,13 Thus, from a controlled trial perspective, there is little to no evidence of dose response on mesalamine greater than 1.6 to 2.4 g/d. Nevertheless, from an observational clinical practice perspective, some patients with moderately active UC or patients who do not respond to 2.4 g/d mesalamine appear to respond to a dose escalation to 4.0 to 4.8 g/d mesalamine (eg, those with previous mesalamine exposure).9–11 However, this strategy of mesalamine dose escalation in patients who fail to fully respond to mesalamine 2 g/d or less remains to be evaluated in a placebo-controlled trial. It also is important to note that all ASCEND and MMX mesalamine studies showed a similar safety profile both for 2.4 and 4.8 g/d mesalamine dosing.7–11 Calprotectin is a neutrophil-derived, 36-kilodalton, calcium- and zinc-binding protein that represents 60% of cytosolic proteins in granulocytes and can be detected in feces.14 The presence of fecal calprotectin (FC) in the stools of patients with inflammatory bowel disease (IBD) can be seen as directly proportional to the influx of neutrophils into the gastrointestinal tract and thus as a surrogate marker for inflammation. Because it remains stable in feces when stored at room temperature for up to 1 week, it is also a practical biomarker with which to work.15 Unfortunately, FC is not a specific biomarker because increased levels have been detected in patients with irritable bowel syndrome and colonic malignancy.16 The usefulness of FC as a biomarker for IBD-specific disease activity therefore boils down to the use of an endoscopic or clinically relevant cut-off level with good specificity and sensitivity. As a marker to predict relapse in patients with IBD, a recent meta-analysis including 6 prospective studies (354 Crohn’s disease and 318 UC patients) showed that the pooled positive likelihood ratio was 2.81, suggesting that relapse patients have an approximately 3-fold higher chance of a higher FC concentration compared with nonrelapse patients.17 As for the negative likelihood ratio, the value was 0.31, suggesting that a probability of relapse for the patient is 31% if the FC concentration was not greater than the cutoff value.17 Two prospective studies from the Belgian IBD Research and Development Group investigated the correlation between FC levels and endoscopic remission.18,19 At week 10 after starting infliximab treatment, a good correlation was found between endoscopic

November 2014

remission and clinical Mayo score in 53 UC patients, as reflected by an area under the curve of the receiver operator characteristic analyses of 0.94 and with FC measurements (area under the curve, 0.91): all patients with FC levels less than 50 mg/kg and a normal clinical Mayo score (score, 0) were in endoscopic remission.18 In a prospective 12-month follow-up study including 113 UC patients in clinical remission on infliximab maintenance therapy, FC levels were measured every 4 weeks and showed that patients with sustained deep remission had median FC levels less than 40 mg/kg at all time points.19 Patients who experienced a disease flare had significantly higher FC levels (median, >300 mg/kg) 3 months before the flare, and 2 consecutive FC measurements of greater than 300 mg/kg with an interval of 1 month were identified as the best predictor of flare (sensitivity, 61.5%; specificity, 100%). In contrast, in a placebo-controlled trial of tofacitinib, the agreement between FC-defined remission and either endoscopic remission or clinical remission was less than 50%.20 Based on these data, it is still unclear whether FC can be used as a surrogate biomarker of endoscopic or clinical disease activity on which treatment decisions can be based. In the study by Osterman et al,21 the authors randomized 52 UC patients in clinical remission despite having FC concentrations of 50 mg/kg or greater, treated with oral MMX mesalamine 3 g/d or less, to either continue their current mesalamine dose or increase their dose by 2.4 g/d for 6 weeks. The primary end point at 6 weeks after randomization was defined as continued clinical remission with a FC concentration less than 50 mg/kg. Significantly more patients who were doseescalated achieved a FC concentration less than 50 mg/kg (26.9%; 7 of 26 patients) compared with those who were kept on their original dosing regimen (3.8%; 1 of 26 patients) (P ¼ .0496), although the patient numbers were small. Furthermore, it is unclear what the clinical relevance is of achieving a FC concentration less than 50 mg/kg and to use this cut-off level to stratify patients who are likely to benefit from mesalamine dose escalation. Indeed, the authors did not show a significant difference in time to clinical relapse through week 48 for the comparison of patients who were randomized to dose escalation vs those who were kept on their original dosing regimen and for patients who had a FC concentration less than 50 mg/kg vs those who had a FC concentration of 50 mg/kg or greater at baseline. The authors attributed this to either low statistical power or that the protocol allowed for dose escalation to 4.8 g/d at week 6 if indicated by persistently increased FC. Nevertheless, the authors observed that patients who were in clinical remission after the optimization phase and had a FC concentration of 200 mg/kg or greater were more likely to relapse compared with patients with FC concentrations less than 200 mg/kg, which potentially seems to be a more clinically relevant cut-off level.19 However, these results are post hoc and thus hypothesis-generating, rather than

Editorial 1895

results that can be accepted and applied to clinical practice. In short, the authors have shown that dose escalation of mesalamine in patients with UC in clinical remission who have an increased FC concentration less than 50 mg/kg can result in a reduction in FC concentrations from baseline. However, the clinical consequences and importance of reducing FC was not shown. Additional studies will be required to further explore the clinical utility of dose escalation among patients with UC and an increased FC, and to explore whether higher FC concentration thresholds might result in larger-magnitude clinical effects. In the meantime, the current data are not sufficient to warrant the use of mesalamine dose escalation in patients with UC in clinical remission who have an increased FC concentration greater than 50 mg/kg. NIELS VANDE CASTEELE, PharmD, PhD Division of Gastroenterology University of California San Diego La Jolla, California Department of Pharmaceutical and Pharmacological Sciences KU Leuven - University of Leuven Leuven, Belgium Robarts Clinical Trials Western University London, Ontario, Canada WILLIAM J. SANDBORN, MD Division of Gastroenterology University of California San Diego La Jolla, California Robarts Clinical Trials Western University London, Ontario, Canada

References 1. Ordas I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet 2012;380:1606–1619. 2. Feagan BG, Macdonald JK. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2012;10:CD000543. 3. Feagan BG, Macdonald JK. Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev 2012;10:CD000544. 4. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317: 1625–1629. 5. Sninsky CA, Cort DH, Shanahan F, et al. Oral mesalamine (Asacol) for mildly to moderately active ulcerative colitis. A multicenter study. Ann Intern Med 1991;115:350–355. 6. Hanauer S, Schwartz J, Robinson M, et al. Mesalamine capsules for treatment of active ulcerative colitis: results of a controlled

1896 Vande Casteele and Sandborn trial. Pentasa Study Group. Am J Gastroenterol 1993;88: 1188–1197. 7. Hanauer SB, Sandborn WJ, Dallaire C, et al. Delayed-release oral mesalamine 4.8 g/day (800 mg tablets) compared to 2.4 g/day (400 mg tablets) for the treatment of mildly to moderately active ulcerative colitis: The ASCEND I trial. Can J Gastroenterol 2007;21:827–834. 8. Hanauer SB, Sandborn WJ, Kornbluth A, et al. Delayed-release oral mesalamine at 4.8 g/day (800 mg tablet) for the treatment of moderately active ulcerative colitis: the ASCEND II trial. Am J Gastroenterol 2005;100:2478–2485. 9. Sandborn WJ, Regula J, Feagan BG, et al. Delayed-release oral mesalamine 4.8 g/day (800-mg tablet) is effective for patients with moderately active ulcerative colitis. Gastroenterology 2009; 137:1934–1943.e1–3. 10. Lichtenstein GR, Kamm MA, Boddu P, et al. Effect of once- or twice-daily MMX mesalamine (SPD476) for the induction of remission of mild to moderately active ulcerative colitis. Clin Gastroenterol Hepatol 2007;5:95–102. 11. Kamm MA, Sandborn WJ, Gassull M, et al. Once-daily, highconcentration MMX mesalamine in active ulcerative colitis. Gastroenterology 2007;132:66–75; quiz 432–433. 12. Hanauer SB, Sninsky CA, Robinson M, et al. An oral preparation of mesalamine as long-term maintenance therapy for ulcerative colitis. A randomized, placebo-controlled trial. Ann Intern Med 1996;124:204–211. 13. D’Haens G, Sandborn WJ, Barrett K, et al. Once-daily MMX(®) mesalamine for endoscopic maintenance of remission of ulcerative colitis. Am J Gastroenterol 2012;107:1064–1077. 14. Vermeire S, Van Assche G, Rutgeerts P. Laboratory markers in IBD: useful, magic, or unnecessary toys? Gut 2006;55:426–431. 15. Roseth AG, Fagerhol MK, Aadland E, et al. Assessment of the neutrophil dominating protein calprotectin in feces. A methodologic study. Scand J Gastroenterol 1992;27:793–798. 16. Tibble J, Teahon K, Thjodleifsson B, et al. A simple method for assessing intestinal inflammation in Crohn’s disease. Gut 2000; 47:506–513. 17. Mao R, Xiao YL, Gao X, et al. Fecal calprotectin in predicting relapse of inflammatory bowel diseases: a meta-analysis of prospective studies. Inflamm Bowel Dis 2012;18:1894–1899. 18. De Vos M, Dewit O, D’Haens G, et al. Fast and sharp decrease in calprotectin predicts remission by infliximab in anti-TNF naive patients with ulcerative colitis. J Crohns Colitis 2012;6: 557–562.

Clinical Gastroenterology and Hepatology Vol. 12, No. 11 19. De Vos M, Louis EJ, Jahnsen J, et al. Consecutive fecal calprotectin measurements to predict relapse in patients with ulcerative colitis receiving infliximab maintenance therapy. Inflamm Bowel Dis 2013;19:2111–2117. 20. Sandborn W, Panes J, Zhang H, et al. Tu1109 evaluation of the relationship between fecal calprotectin concentrations and clinical and endoscopic outcome measures in a phase 2 study of tofacitinib, an oral janus kinase inhibitor, in active ulcerative colitis. Gastroenterology 2013;144:S-764. 21. Osterman MT, Aberra FN, Cross R, et al. Mesalamine dose escalation reduces fecal calprotectin in patients with quiescent ulcerative colitis. Clin Gastroenterol Hepatol 2014;12: 1887–1893.

Conflicts of interest This author discloses the following: William Sandborn has received consulting fees from ActoGeniX NV, AGI Therapeutics, Inc, Alba Therapeutics Corporation, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas Pharma, Athersys, Inc, Atlantic Healthcare Limited, Axcan Pharma (now Aptalis), BioBalance Corporation, Boehringer-Ingelheim, Inc, Bristol Meyers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai Medical Research, Inc, Elan Pharmaceuticals, EnGene, Inc, Eli Lilly, Enteromedics, Exagen Diagnostics, Inc, Ferring Pharmaceuticals, Flexion Therapeutics, Inc, Funxional Therapeutics Limited, Genzyme Corporation, Genentech (now Roche), Gilead Sciences, Given Imaging, Glaxo Smith Kline, Human Genome Sciences, Ironwood Pharmaceuticals (previously Microbia, Inc), Janssen (previously Centocor), KaloBios Pharmaceuticals, Inc, Lexicon Pharmaceuticals, Lycera Corporation, Meda Pharmaceuticals (previously Alaven Pharmaceuticals), Merck Research Laboratories, MerckSerono, Millennium Pharmaceuticals (subsequently merged with Takeda), Nisshin Kyorin Pharmaceuticals Co, Ltd, Novo Nordisk A/S, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, Inc, PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb Limited, Purgenesis Technologies, Inc, Receptos, Relypsa, Inc, Salient Pharmaceuticals, Salix Pharmaceuticals, Inc, Santarus, Schering Plough Corporation (acquired by Merck), Shire Pharmaceuticals, Sigmoid Pharma Limited, Sirtris Pharmaceuticals, Inc (a GSK company), S.L.A. Pharma (UK) Limited, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG (acquired by Zeria Pharmaceutical Co, Ltd), TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics Limited, Warner Chilcott UK Limited, Wyeth (now Pfizer); has received lecture fees from Bristol Meyers Squibb, and Janssen (previously Centocor); and has received research support from Bristol Meyers Squibb, Genentech, GlaxoSmithKline, Janssen (previously Centocor), Millennium Pharmaceuticals (now Takeda), Novartis, Pfizer, Procter and Gamble Pharmaceuticals, Shire Pharmaceuticals, and UCB Pharma. The remaining author discloses no conflicts. Funding Niels Vande Casteele is a Postdoctoral Fellow of the Research Foundation– Flanders (Belgium). http://dx.doi.org/10.1016/j.cgh.2014.06.011

Fecal calprotectin-guided dosing of mesalamine in ulcerative colitis: concept proved but more data needed.

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