Challenges to the Design, Execution, and Analysis of Randomized Controlled Trials for Inflammatory Bowel Disease
2012; Elsevier BV; Volume: 143; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2012.09.031
ISSN1528-0012
AutoresGeert R. DʼHaens, Brian G. Feagan, Jean–Frédéric Colombel, William J. Sandborn, Walter Reinisch, Paul Rutgeerts, F. Carbonnel, Jean‐Yves Mary, Silvio Danese, Richard N. Fedorak, Steven Hanauer, Marc Lémann,
Tópico(s)Eosinophilic Esophagitis
ResumoTreatment of inflammatory bowel disease has greatly improved with the development of targeted, monoclonal antibody–based therapies. Tumor necrosis factor antagonists are frequently used to treat patients with Crohn's disease or ulcerative colitis, but they have side effects and their efficacy often decreases with use. New, more effective drugs are therefore needed and in development. However, many agents that appeared to be promising in preclinical studies have failed to show efficacy in clinical trials. We discuss possible reasons for the failures of these reagents in trials, which include the high rate of response to placebo, an inadequate range of doses, inappropriate timing of end point measurements, the changing therapeutic environment, and the competitive trial system. We also review regulatory guidelines for end points and trial design and recommend ways to improve trials. Treatment of inflammatory bowel disease has greatly improved with the development of targeted, monoclonal antibody–based therapies. Tumor necrosis factor antagonists are frequently used to treat patients with Crohn's disease or ulcerative colitis, but they have side effects and their efficacy often decreases with use. New, more effective drugs are therefore needed and in development. However, many agents that appeared to be promising in preclinical studies have failed to show efficacy in clinical trials. We discuss possible reasons for the failures of these reagents in trials, which include the high rate of response to placebo, an inadequate range of doses, inappropriate timing of end point measurements, the changing therapeutic environment, and the competitive trial system. We also review regulatory guidelines for end points and trial design and recommend ways to improve trials. Designing clinical trials for complex disorders such as inflammatory bowel disease (IBD) is a challenge because symptoms do not always parallel signs of inflammation, different forms of the disease have different responses to treatment, and therapeutic approaches vary by location. Nonetheless, there is a continuous and intense search for new treatments for Crohn's disease (CD) and ulcerative colitis (UC) (Table 1). Disappointingly, many agents fail in early phases of clinical trials, often because of poor study design, lack of objective measurements, or insufficient sample sizes. Furthermore, regulators propose different approaches in different areas in the world. We attempt to offer guidance for this complicated area of clinical research.Table 1Molecules With Promising Efficacy Data From Early-Stage Studies (Incomplete List)NameTargetManufacturerPhaseRituximabCD20Roche1–2VisilizumabCD3PDL BioPharma1–2DaclizumabCD25PDL BioPharma/Roche1–2BasiliximabCD25Novartis1–2FontolizumabIFN-γPDL BioPharma1–2EtanerceptTNF receptorWyeth1–2OnerceptTNF receptorMerck Serono1–2AbataceptCD28Bristol-Myers Squibb3BriakinumabInterleukin-12/interleukin-23Abbott Laboratories3SargramostimGranulocyte-macrophage colony–stimulating factorBerlex3AlicaforsenIntercellular adhesion molecule 1Isis Pharmaceuticals3SomatotropinGrowth hormoneElli Lilly3 Open table in a new tab The strategies we propose are based on information from lectures presented at meetings of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) and the European Crohn's and Colitis Organisation (ECCO) in 2011, our own personal experience in designing investigator-initiated clinical studies of IBD, reports from industrial clinical trials, and our interactions with the US Food and Drug Administration and European Medicines Agency. We also received suggestions from authors who participated in the Clinical Trial Task Force of the IOIBD and the Clinical Committee of the ECCO. Until recently, most clinical trials for IBD investigated the ability of a reagent to induce or to maintain a response or remission. Usually, agents found to be effective at inducing a response or remission were then evaluated for maintenance. Patients were given open-label induction treatment with the new agent, and only responders were included in the maintenance phase of the study. A few trials have continued to blind patients to the test article throughout the induction and maintenance phases. However, the distinction between the induction and maintenance phases could gradually become less important as trial end points evolve beyond clinical assessments. Rather, investigators will begin to evaluate long-term benefits such as prevention of structural complications and surgery—outcomes that usually cannot be evaluated in short-term trials.1D'Haens G. Fedorak R. Lémann M. et al.Endpoints for clinical trials evaluating disease modification and structural damage in adults with Crohn's disease.Inflamm Bowel Dis. 2009; 15: 1599-1604Crossref PubMed Scopus (83) Google Scholar The short-term efficacy of a drug can be compared with either placebo or an active agent. However, it is often unethical to give untreated patients a placebo.2Guideline on the development of new medicinal products for the treatment of Crohn's disease.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003214.pdfGoogle Scholar The European Medicines Agency has stated that the test reagent should be compared with and be “at least as effective and safe as the standard of care, which currently in the majority of cases includes corticosteroids,” but this comparison is rarely put into practice. The test reagent should be safe and effective. However, corticosteroids are only effective for a short time, have many side effects, increase mortality, and offer no durable benefit.3Sandborn W.J. Löfberg R. Feagan B.G. et al.Budesonide for maintenance of remission in patients with Crohn's disease in medically induced remission: a predetermined pooled analysis of four randomized, double-blind, placebo-controlled trials.Am J Gastroenterol. 2005; 100: 1780-1787Crossref PubMed Scopus (106) Google Scholar Thus, it might not be appropriate for test reagents to be compared with corticosteroids. In contrast, aminosalicylates are safe and effective short-term and long-term therapeutics for patients with UC. It would be reasonable for trials of first-line treatments for mild to moderate UC to compare the test reagent with aminosalicylates.4Travis S.P. Stange E.F. Lémann M. et al.European Crohn's and Colitis OrganisationEuropean evidence-based Consensus on the management of ulcerative colitis: current management.J Crohns Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (516) Google Scholar However, these drugs have not been sufficiently effective in trials for CD to be used as the standard of care.5Ford A.C. Kane S.V. Khan K.J. et al.Efficacy of 5-aminosalicylates in Crohn's disease: systematic review and meta-analysis.Am J Gastroenterol. 2011; 106: 617-629Crossref PubMed Scopus (169) Google Scholar In induction trials for CD, placebo is a better standard than aminosalicylate or corticosteroid therapy. In trials of “second-line” agents (for patients who did not respond to their initial therapy), it is acceptable and even recommended that the test article be compared with placebo. However, combining the investigational agent with treatments such as immunosuppressive agents could increase the risk of adverse events. Thus, in specific situations, it might be appropriate for study participants to discontinue their previous medications. Most randomized controlled trials designed to assess the superiority of an agent over placebo have been powered to detect a minimum, clinically important difference in rate of response or remission (15%–20%), which requires each study group to include approximately 100 to 150 patients.6Sandborn W.J. Feagan B.G. Hanauer S.B. et al.A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease.Gastroenterology. 2002; 122: 512-530Abstract Full Text Full Text PDF PubMed Scopus (558) Google Scholar The goal of noninferiority trials is to show that the investigational agent is no worse than the standard therapy. Any observed difference in clinical response must be insignificant (based on a one-sided analysis, with a 95% confidence interval) if the test reagent is to be considered noninferior. Regulatory authorities have proposed that a noninferiority margin as low as 4% should be used to compare 2 different 5-aminosalicylic acid drugs for maintenance of remission in patients with UC. A noninferiority trial with a margin of 7.5% would require randomly assigning more than 1200 patients to 2 groups. In our opinion, a trial of this size is hardly feasible.7Wiens B.L. Choosing an equivalence limit for noninferiority or equivalence studies.Control Clin Trials. 2002; 23: 2-14Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar Recent noninferiority trials of patients with UC have taken more than 2 years to recruit the required number of participants.8D'Haens G. Sandborn W.J. Barrett K. et al.Once-daily MMX® mesalamine for endoscopic maintenance of remission of ulcerative colitis.Am J Gastroenterol. 2012; 107: 1064-1077Crossref PubMed Scopus (39) Google Scholar, 9Sandborn W.J. Korzenik J. Lashner B. et al.Once-daily dosing of delayed-release oral mesalamine (400-mg tablet) is as effective as twice-daily dosing for maintenance of remission of ulcerative colitis.Gastroenterology. 2010; 138: 1286-1296Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar For inclusion in induction trials, patients should have a definitive diagnosis of IBD based on accepted criteria,10Van Assche G. Dignass A. Panes J. et al.European Crohn's and Colitis OrganisationThe second European evidence-based Consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis.J Crohns Colitis. 2010; 4: 7-27Abstract Full Text Full Text PDF PubMed Scopus (882) Google Scholar with disease duration of at least 3 months, objective evidence of active inflammation, and the possibility for improvement from treatment with the test product. Patients with pure fibrostenotic CD without associated inflammation are therefore not good candidates for trials of anti-inflammatory therapy. The symptom scores that have been developed and validated for CD are not reliably associated with the presence of active inflammatory lesions,11Mary J.Y. Modigliani R. Development and validation of an endoscopic index of the severity for Crohn's disease: a prospective multicentre study.Gut. 1989; 30: 983-989Crossref PubMed Google Scholar so it has become common practice to document the presence of active inflammation using markers in serum (C-reactive protein [CRP]) or stool samples (calprotectin) or by direct endoscopic assessment. In some current trials, video-recorded ileocolonoscopies are reviewed by experts to ascertain the presence of active ulceration, a process that has been facilitated by improved technology. Magnetic resonance enterography, a noninvasive, highly accurate diagnostic imaging technology, could eventually replace endoscopy.12Rimola J. Rodriguez S. García-Bosch O. et al.Magnetic resonance for assessment of disease activity and severity in ileocolonic Crohn's disease.Gut. 2009; 58: 1113-1120Crossref PubMed Scopus (510) Google Scholar We believe that objective assessment of disease activity improves trial efficiency by reducing rates of response to placebo.13Feagan BJ, Sandborn WJ, D'Haens G, et al. The value of a central image management system (CIMS) in the conduct of randomized controlled trials of therapy for ulcerative colitis (UC) (abstr). Presented at: ACG 2012 Annual Scientific Meeting; October 19–24, 2012; Las Vegas, NV.Google Scholar Medications that patients take along with the test agent can affect trial results, so potential drug interactions must be considered. Participants in a trial of the Janus kinase inhibitor tofacitinib had to stop taking thiopurines, because each drug can cause leukopenia.14Sandborn W.J. Ghosh S. Panes J. et al.Phase 2 study of tofacitinib (CP-690,550), an oral Janus kinase inhibitor, in active Crohn's disease.Gastroenterology. 2011; 140: 745Google Scholar Similarly, it has been proposed that combination therapy with immunosuppressive and anti-integrin agents can increase the risk of progressive multifocal leukoencephalopathy.15Yousry T.A. Major E.O. Ryschkewitsch C. et al.Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy.N Engl J Med. 2006; 354: 924-933Crossref PubMed Scopus (699) Google Scholar Although it is necessary to restrict concomitant medications in some situations, this limits our ability to apply findings to the overall population. A recent analysis showed that most patients do not meet the inclusion and exclusion criteria for phase 3 trials of agents for IBD.16Ha C. Ullman T.A. Siegel C.A. et al.Patients enrolled in randomized controlled trials do not represent the inflammatory bowel disease patient population.Clin Gastroenterol Hepatol. 2012; 10: 1002-1007Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar Some trials have restrictive inclusion criteria based on parameters other than disease activity. For example, studies of changes in progression of CD might require patients with a relatively short history of disease (early-stage CD).1D'Haens G. Fedorak R. Lémann M. et al.Endpoints for clinical trials evaluating disease modification and structural damage in adults with Crohn's disease.Inflamm Bowel Dis. 2009; 15: 1599-1604Crossref PubMed Scopus (83) Google Scholar Trials of topically delivered agents require patients with disease localized to a specific area.17Greenberg G.R. Feagan B.G. Martin F. et al.Oral budesonide for active Crohn's disease Canadian Inflammatory Bowel Disease Study Group.N Engl J Med. 1994; 331: 836-841Crossref PubMed Scopus (523) Google Scholar, 18Marshall J.K. Thabane M. Steinhart A.H. et al.Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis.Cochrane Database Syst Rev. 2010; 1 (CD004115)Google Scholar Trials investigating fistula healing or prevention of postoperative recurrence require subjects with draining fistulas or recent ileocolonic resection, respectively.19Sands B.E. Anderson F.H. Bernstein C.N. et al.Infliximab maintenance therapy for fistulizing Crohn's disease.N Engl J Med. 2004; 350: 876-885Crossref PubMed Scopus (1840) Google Scholar, 20Hanauer S.B. Korelitz B.I. Rutgeerts P. et al.Postoperative maintenance of Crohn's disease remission with 6-mercaptopurine, mesalamine, or placebo: a 2-year trial.Gastroenterology. 2004; 127: 723-729Abstract Full Text Full Text PDF PubMed Scopus (409) Google Scholar Symptoms of UC, compared with CD, are more frequently associated with mucosal inflammation. Subjects in trials for UC should receive a baseline endoscopy examination and be reevaluated within 6 to 10 weeks, because mucosal healing (restitution of epithelial integrity) improves prognosis.21Frøslie K.F. Jahnsen J. Moum B.A. et al.Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort.Gastroenterology. 2007; 133: 412-422Abstract Full Text Full Text PDF PubMed Scopus (919) Google Scholar In general, sigmoidoscopy has been considered sufficient for assessment of mucosal healing, although this procedure might not yield complete information about the proximal extent and inflammatory burden of UC. In terms of severity, participants in most trials of agents for active UC should have, at a minimum, documented friability on endoscopy.22D'Haens G. Sandborn W.J. Feagan B.G. et al.A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis.Gastroenterology. 2007; 132: 763-786Abstract Full Text Full Text PDF PubMed Scopus (795) Google Scholar Some studies have specific entry criteria. The Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease (SONIC) enrolled patients with active CD who had not received any immunosuppressive or biologic therapies, had not responded to corticosteroid therapy (or been considered for a second course of corticosteroids within 12 months), or had not responded to budesonide or aminosalicylates.23Colombel J.F. Sandborn W.J. Reinisch W. et al.Infliximab, azathioprine, or combination therapy for Crohn's disease.N Engl J Med. 2010; 362: 1383-1395Crossref PubMed Scopus (2413) Google Scholar The study was designed to identify patients who had not responded to first-line therapies but did respond to immunomodulators. The UC SUCCESS trial (Efficacy and Safety of Infliximab, as Monotherapy or in Combination with Azathioprine, versus Azathioprine Monotherapy in Moderate to Severe Ulcerative Colitis) enrolled patients who had not responded to treatment with aminosalicylates but not received tumor necrosis factor (TNF) antagonists.24Panaccione R. Ghosh S. Middleton S. et al.Infliximab, azathioprine, or infliximab + azathioprine for treatment of moderate to severe ulcerative colitis: The UC SUCCESS trial.J Crohns Colitis. 2012; 6 (abstract)Google Scholar In SONIC and UC SUCCESS, patients were randomly assigned to groups treated with infliximab, azathioprine, or a combination of both. Trials to test combinations of reagents should be performed after the efficacy of each individual agent has been established. As management strategies become more complex, there will be a greater need to evaluate treatment algorithms. Cluster randomization trials, in which the unit of randomization is a practice or a hospital, are well suited for these types of analyses.25Donner A. Birkett N. Buck C. Randomization by cluster Sample size requirements and analysis.Am J Epidemiol. 1981; 114: 906-914Crossref PubMed Scopus (525) Google Scholar Most randomized controlled trials of agents for IBD have a primary, several secondary, and then exploratory end points. Historically, symptom-based end points have been used to assess efficacy, particularly for CD. However, times are changing. For example, in the EXTEND (Extend the Safety and Efficacy of Adalimumab through Endoscopic Healing) trial of adalimumab for CD,26Rutgeerts P. D'Haens G. Van Assche G. et al.Adalimumab induces and maintains mucosal healing in patients with moderate to severe ileocolonic Crohn's disease-first results of the EXTEND trial.Gastroenterology. 2012; 142: 1102-1111Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar results of endoscopic analysis were used as the primary end point. The Crohn's Disease Activity Index (CDAI) is used to measure clinical disease activity in almost all trials for CD, although it is does not always identify patients with inflammation.27Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn's Disease Activity Index.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (3002) Google Scholar Clinically meaningful improvement has been defined as a reduction in the CDAI by 70 to 100 points, whereas remission is defined as a CDAI less than 150. Thia et al analyzed CDAI data in placebo-controlled induction studies and showed that differences in treatment effects were maximized if the primary end point was defined as a reduction in CDAI of 100 points or a reduction by 70 points at 2 consecutive visits.28Thia K.T. Sandborn W.J. Lewis J.D. et al.Defining the optimal response criteria for the Crohn's disease activity index for induction studies in patients with mildly to moderately active Crohn's disease.Am J Gastroenterol. 2008; 103: 3123-3131Crossref PubMed Scopus (32) Google Scholar Several recent trials have used the single-day Harvey–Bradshaw Index29Harvey R.F. Bradshaw J.M. A simple index of Crohn's-disease activity.Lancet. 1980; 1: 514Abstract PubMed Scopus (2112) Google Scholar to measure clinical response; results from the index correlate with the CDAI.30Vermeire S. Schreiber S. Sandborn W.J. et al.Correlation between the Crohn's disease activity and Harvey-Bradshaw indices in assessing Crohn's disease severity.Clin Gastroenterol Hepatol. 2010; 8: 357-363Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar However, it is not clear if the Harvey–Bradshaw Index is acceptable to regulatory authorities. For induction trials that use the CDAI as a primary end point, assessments are best made at study weeks 4 to 6 if the CDAI is only determined once or at study weeks 8 or 12 if the index is determined twice. Both of these strategies have been successful in limiting the numbers of patients that appear to respond to placebo. In maintenance trials, tapering and withdrawal of corticosteroids can be used as an end point and should be described as corticosteroid-free remission. It is important that corticosteroid tapering regimens are standardized in designing maintenance trials. Although corticosteroid-free remission is an important end point for patients and clinicians, it has not been used or required as a primary end point in registration trials. Reagents are usually tested at predetermined doses. However, the protocol can allow dose adjustments if a dose-response effect is observed without classifying patients with dose adjustments as nonresponders. Better understanding of the relationship between serum drug concentration and clinical efficacy will allow more extensive studies for optimizing drug efficacy.31Afif W. Loftus Jr, E.V. Faubion W.A. et al.Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease.Am J Gastroenterol. 2010; 105: 1133-1139Crossref PubMed Scopus (427) Google Scholar Results from endoscopy analysis are not usually used as secondary end points in induction trials for CD. However, in the EXTEND trial, mucosal healing was observed by study week 12.26Rutgeerts P. D'Haens G. Van Assche G. et al.Adalimumab induces and maintains mucosal healing in patients with moderate to severe ileocolonic Crohn's disease-first results of the EXTEND trial.Gastroenterology. 2012; 142: 1102-1111Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar Other induction trials have included endoscopic analyses of subsets of patients.32Rutgeerts P. Diamond R.H. Bala M. et al.Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease.Gastroenterology. 2004; 126: 402-413Abstract Full Text Full Text PDF PubMed Scopus (861) Google Scholar It might not be necessary for all patients in a trial to undergo endoscopy, as long as the characteristics of the endoscopy subgroup are comparable to those of the overall study population. Studies with endoscopic end points could considerably reduce sample size requirements. It is therefore important to validate endoscopic features as surrogate markers for clinical efficacy. Actuarial analyses are interesting to include in trials for IBD. Time to response or time to remission could be an important analytical approach to evaluate the rapidity of an effect, which could have clinical relevance. Methods to analyze these times are complicated and not well developed. The Turnbull method should be used instead of Kaplan–Meier estimates.33Turnbull B. The empirical distribution function with arbitrarily grouped, censored and truncated data.J R Stat Soc B. 1976; 38: 290-295Google Scholar Many more tools have been developed to evaluate UC than CD, but few have been validated.22D'Haens G. Sandborn W.J. Feagan B.G. et al.A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis.Gastroenterology. 2007; 132: 763-786Abstract Full Text Full Text PDF PubMed Scopus (795) Google Scholar The most frequently used tools are indices that combine clinical and endoscopic parameters. In trials of various biologic agents for UC, the Mayo Clinic score has been used consistently. It is a 12-point system that produces 4 subscores (based on stool frequency, rectal bleeding, physician global assessment, and endoscopic findings), each with a range of 0 to 3 points.34Schroeder K.W. Tremaine W.J. Ilstrup D.M. Coated oral aminosalicylic acid therapy for mildly to moderately active ulcerative colitis.N Engl J Med. 1987; 317: 1625-1629Crossref PubMed Scopus (2050) Google Scholar Response is defined as a decrease from baseline in the total Mayo score of ≥3 points or ≥30% and a decrease in the rectal bleeding subscore ≥1 point or an absolute rectal bleeding subscore of 0 or 1 point; remission is defined as a total Mayo score ≤2 points with no subscore >1 point. The ideal time to assess the primary end point in UC induction trials is usually 6 to 8 weeks, although an earlier time point (for instance, 7–14 days) might be required for trials that evaluate hospitalized patients with severe UC. Studies of hospitalized patients with severe UC that is refractory to oral treatment (usually corticosteroids) often use clinical improvement or rate of colectomy, rather than remission, as an end point. Trials that have studied this population have often used the Lichtiger score, a derivative of the original modified Truelove and Witts severity classification scheme.35Lichtiger S. Present D.H. Kornbluth A. et al.Cyclosporine in severe ulcerative colitis refractory to steroid therapy.N Engl J Med. 1994; 330: 1841-1845Crossref PubMed Scopus (1502) Google Scholar, 36D'Haens G. Lemmens L. Geboes K. et al.Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis: a double-blind controlled randomised trial.Gastroenterology. 2001; 120: 1323-1329Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar However, neither the score itself nor the proposed cutoffs have been validated. The score ranges from 0 to 21 and has only patient-reported items and one physician-reported parameter (abdominal tenderness). Recent studies have indicated that short-term clinical improvement based on the Lichtiger score does not parallel clinically meaningful outcomes, such as mucosal healing, clinical remission, corticosteroid withdrawal, and colectomy.37Laharie D. Bourreille A. Branche J. et al.Cyclosporin versus infliximab in severe acute ulcerative colitis refractory to intravenous steroids: a randomized trial.Lancet. 2012 October 9; ([Epub ahead of print])Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, 38Sandborn W.J. Colombel J.F. Frankel M. et al.Anti-CD3 antibody visilizumab is not effective in patients with intravenous corticosteroid-refractory ulcerative colitis.Gut. 2010; 59: 1485-1492Crossref PubMed Scopus (73) Google Scholar, 39Baumgart D.C. Targan S.R. Dignass A.U. et al.Prospective randomized open-label multicenter phase I/II dose escalation trial of visilizumab (HuM291) in severe steroid-refractory ulcerative colitis.Inflamm Bowel Dis. 2010; 16: 620-629Crossref PubMed Scopus (49) Google Scholar We therefore do not believe that the Lichtiger score is an ideal instrument of disease activity in patients with UC. Biomarkers are also used as secondary end points in clinical trials. The most widely used biomarker is serum level of CRP. Although the concentration of CRP is normal in up to 20% of patients with active CD and 50% of patients with active UC,40Langhorst J. Elsenbruch S. Koelzer J. et al.Noninvasive markers in the assessment of intestinal inflammation in inflammatory bowel diseases: performance of fecal lactoferrin, calprotectin, and PMN-elastase, CRP, and clinical indices.Am J Gastroenterol. 2008; 103: 162-169Crossref PubMed Scopus (481) Google Scholar reductions in CRP usually correlate with clinical response in patients who have increased levels of CRP at baseline. A post hoc analysis of data from SONIC revealed a better separation between treatment groups of patients that had increased concentrations of CRP at baseline than among those with normal levels of CRP.23Colombel J.F. Sandborn W.J. Reinisch W. et al.Infliximab, azathioprine, or combination therapy for Crohn's disease.N Engl J Med. 2010; 362: 1383-1395Crossref PubMed Scopus (2413) Google Scholar It is therefore important to determine the presence of active inflammation using objective measures. Other blood biomarkers of inflammation include platelet or leukocyte counts, serum levels of albumin, and erythrocyte sedimentation rate. Fecal biomarkers include calprotectin and lactoferrin. Levels of these markers correlate with clinical symptoms and the presence of mucosal lesions in patients with CD or UC; the magnitude of change usually corresponds with the degree of clinical improvement.41Sipponen T. Savilahti E. Kolho K.L. et al.Crohn's disease activity assessed by fecal calprotectin and lactoferrin: correlation with Crohn's disease activity index and endoscopic findings.Inflamm Bowel Dis. 2008; 14: 40-46Crossref PubMed Scopus (390) Google Scholar Fecal biomarkers are, however, nonspecific, because infections, use of nonsteroidal anti-inflammatory medications, and many other medical conditions can increase levels of calprotectin.42van Rheenen P.F. Van de Vijver E. Fidler V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis.BMJ. 2010; 341: c3369Crossref PubMed Scopus (489) Google Scholar When used as a surrogate biomarker for endoscopic severity, levels of fecal calprotectin greater than 250 μg/g could identify patients with CD who had large ulcers or significant amounts of inflammation (Mayo score of 2–3) in UC.43D'Haens G. Ferrante M. Vermeire S. et al.Faecal calprotectin is a surrogate marker for endoscopic lesions in inflammatory bowel diseases.Inflamm Bowel Dis. 2012 Feb 16; ([Epub ahead of print])Crossref Scopus (574) Google Scholar Tests of fecal biomarkers can be performed rapidly and repeatedly, even at the bedside (a point of care test). Although mucosal healing must be evaluated to assess therapies for UC, it is a relatively
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