CLINICAL INSIGHTS 01

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1 P2 Borrowing a Treatment Paradigm From Rheumatoid Arthritis P4 Antidrug Antibody Monitoring in Practice P6 Proactive Drug Monitoring Informs Therapeutic Dose Adjustments P7 Keeping Patients in Remission CLINICAL INSIGHTS 01 A Treat-to-Target Strategy for Managing Inflammatory Bowel Disease APRIL 2016 FEATURED CLINICIAN Marla Dubinsky, MD Professor of Pediatrics and Medicine Chief, Pediatric Gastroenterology and Hepatology Co-Director, Susan and Leonard Feinstein IBD Center Icahn School of Medicine, Mount Sinai New York, New York Figure 21 Pathway leading to chronic intestinal inflammation in patients with IBD. 1 Genetic factors Environmental factors Inflammatory bowel diseases (IBDs), such as Crohn s disease and ulcerative colitis, are chronic relapsing gastrointestinal (GI) disorders that arise from a multifactorial and complex pathophysiology. In patients with IBD, genetic and environmental factors lead to impaired barrier function in the intestinal mucosa (Figure 1). 1 When barrier function is altered in IBD, bacteria and microbial products from the gut lumen translocate into the bowel wall, leading to activation of immune cells and subsequent production of proinflammatory cytokines. Anti-inflammatory mechanisms attempt to suppress the proinflammatory immune responses. However, when these mechanisms fail, acute mucosal inflammation does not resolve and chronic intestinal inflammation develops. 1 T Reg cell Microbial product Initiating triggers Impaired barrier function Immune cell activation Macrophage Bacteria Effector T cell Cytokine activity and the resulting chronic inflammation are responsible for the progressive tissue destruction and the complications fibrosis, stenosis, abscess, fistula, cancer, and extraintestinal manifestations that occur in patients with IBD. 1 IBD complications may be controlled with medication adjustments, but they can result in hospitalization and ultimately require surgery. 2 Chronic inflammation, tissue destruction, and complications Adapted with permission from Neurath. Monitoring of GI Inflammation vs GI Symptoms Crohn s disease is a progressive condition. Data from studies of patients with Crohn s disease suggest that early control of inflammation may prevent disease progression. As a result, effective intervention for patients with Crohn s disease should occur early in the course of the disease before irreversible bowel damage occurs. 3 Furthermore, in a study of patients with IBD who were in clinical remission, surveillance colonoscopies showed that a majority of the patients had mucosal inflammation even in the absence of clinical symptoms. 2 Therefore, instead of focusing solely on GI symptoms, a more effective approach to preventing long-term disease complications may involve: (1) setting treatment goals to control GI inflammation and (2) monitoring for objective evidence of inflammation by using endoscopy, cross-sectional imaging, or laboratory biomarkers. 4

2 Borrowing a Treatment Paradigm From Rheumatoid Arthritis Treat to target is a treatment paradigm used for the management of rheumatoid arthritis (RA), another progressive disease in which early control of inflammation prevents disease progression. 3-5 In 2010 an international task force, including rheumatologists with RA expertise and 1 patient with RA, published a statement describing the overarching principles along with 10 specific recommendations for a treatto-target model for RA (Table 1). These recommendations set clinical remission as the ideal treatment target, although low disease activity may be an acceptable goal for some patients. To reach and maintain target levels of disease control, the task force recommended that drug therapy be adjusted frequently and disease activity monitored regularly using validated measures to inform clinical decisions. In addition, patients should be well informed of treatment goals and the planned treatment approach. Ultimately, the goal of treat to target is to maximize long-term health-related quality of life for patients. 5 "You explain to the patient up front what your target is going to be, then explain how you are going to work with the patient to get there." Table 1 Treat-to-target recommendations. 5 Overarching principles (A) (B) (C) (D) The treatment of RA must be based on a shared decision between patient and rheumatologist The primary goal of treating the patient with RA is to maximize long-term health-related quality of life through control of symptoms, prevention of structural damage, normalization of function and social participation Abrogation of inflammation is the most important way to achieve these goals Treatment to target by measuring disease activity and adjusting therapy accordingly optimizes outcomes in RA 10 recommendations on treating RA to target based on both evidence and expert opinion (1) The primary target for treatment of RA should be a state of clinical remission (2) Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity (3) While remission should be a clear target based on available evidence, low disease activity may be an acceptable alternative therapeutic goal, particularly in established long-standing disease (4) Until the desired treatment target is reached, drug therapy should be adjusted at least every 3 months (5) Measures of disease activity must be obtained and documented regularly, as frequently as monthly for patients with high/moderate disease activity or less frequently (such as every 3 to 6 months) for patients in sustained low disease activity or remission (6) The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions (7) Structural changes and functional impairment should be considered when making clinical decisions, in addition to assessing composite measures of disease activity (8) The desired treatment target should be maintained throughout the remaining course of the disease (9) The choice of the (composite) measure of disease activity and the level of the target value may be influenced by consideration of comorbidities, patient factors, and drug-related risks (10) The patient has to be appropriately informed about the treatment target and the strategy planned to reach this target under the supervision of the rheumatologist Adapted with permission from Smolen. 2

3 Borrowing a Treatment Paradigm From Rheumatoid Arthritis (continued) This treat-to-target approach can be adapted for Crohn s disease. For example, the gastroenterologist could discuss a treatment strategy with the patient to attain the clinical target: absence of endoscopic ulceration (ie, mucosal healing). Then, regular monitoring of clinical symptoms and objective measures of inflammation could be performed to inform clinical decisions until ulceration ceases. Initiation of highly effective disease-modifying therapy would be recommended early in the disease course for high-risk patients, and treatment would continue to be monitored and adjusted using a predefined objective target to avoid long-term bowel damage and disability (Figure 2). 3 "The first part of treat to target is identifying the high-risk patient. You want to identify which patients are likely to experience disease progression and complications, including bowel wall damage." The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative assembled a global committee of 33 specialists with expertise in treating IBD to determine an appropriate evidencebased treat-to-target regimen for patients with IBD. After a thorough review of the literature, they identified mucosal healing as a therapeutic goal for patients Figure 2 Baseline assessment High Risk of progression Low Target Predefined time frame Therapy according to risk and target Unreached target Reprinted with permission from Bouguen. Overview of the treat-to-target concept. 3 with Crohn s disease or ulcerative colitis and defined remission as the resolution of both clinical symptoms and inflammation. (Clinical symptoms include abdominal pain for patients with Crohn s disease, rectal bleeding for those with ulcerative colitis, and normalization of bowel habit in both Crohn s disease and ulcerative colitis.) In this treat-to-target regimen, the committee recommended that physicians regularly assess patient outcomes at a frequency dependent on the patient s symptoms. This monitoring should be no less than every 3 months while symptoms are present. Once symptoms resolve, assessment should continue but can slow to every 6 to 12 months. 6 Mucosal healing, which is defined as the absence of ulceration and erosions, has been associated with decreased need for corticosteroids, decreased hospitalization rates, sustained clinical remission, decreased colectomy and bowel resection, and decreased risk of colorectal cancer. 7 Because it Assessment Target Assessment Continue therapy target surveillance Control of intestinal inflammation Avoidance of long-term bowel damage and subsequent disability has been associated with better outcomes in patients with IBD in both cohort studies and randomized controlled trials, mucosal healing was recommended as a key therapeutic goal. 6 However, assessment of mucosal healing requires colonoscopy, which is costly in terms of time and resources and presents a risk of perforation, bleeding, or sedation. 7 The availability of noninvasive, less costly biomarkers may help to overcome these limitations. 7 Validation of biomarkers of mucosal healing is needed to aid clinicians in measuring disease activity and in gaining information that may be useful in guiding therapeutic decisions. 4 The following articles in this newsletter review recent studies that evaluate treat-to-target strategies. In addition, the clinical advantages of therapeutic drug monitoring for IBD patients receiving biologic therapy are discussed. 3

4 Antidrug Antibody Monitoring in Practice Minimum Infliximab Levels Are Required to Maintain Clinical Response to Treatment In patients with Crohn s disease, low drug levels of infliximab (IFX) are associated with worse clinical outcomes. One of the reasons for low IFX levels may be that patients treated with IFX often develop antibodies to infliximab (ATI), and the presence of these antibodies is associated with a greater risk of loss of clinical response. 8 Using a homogenous mobility shift assay (HMSA), investigators measured IFX levels to determine trough concentrations of IFX required to maintain clinical remission. Remission was defined by C-reactive protein (CRP) concentrations of 5 mg/l or less. Analysis of serum samples from 483 patients receiving treatment with IFX demonstrated that trough IFX concentrations greater than 2.79 µg/ml were associated with increased rates of remission. The investigators also performed HMSA to assess the influence of ATI on disease activity. They found that the presence of ATI also increased the risk of relapse ATI concentrations less than 3.15 U/mL were associated with remission. Therapeutic drug monitoring (TDM) has been recommended to guide clinical decision making for patients who lose response to treatment with IFX. The establishment of thresholds for IFX and ATI levels that are predictive of remission increases the utility of TDM to assist in clinical decision making. 8 Infliximab Levels at Week 14 Are Predictive of Disease Activity at Week 54 A prospective, observational study measured trough IFX levels in pediatric patients with Crohn s disease or ulcerative colitis at week 14 after the initiation of IFX treatment. The investigators found that week-14 IFX levels positively correlated with IFX levels at week 54, and higher IFX levels at week 14 were associated with persistent remission at week 54. The median IFX level was 4.7 µg/ml at week 14 for patients in persistent remission at week 54 compared with 2.6 µg/ml at week 14 for those who were not in persistent remission at week 54. These data suggest that early dose optimization is crucial to improve long-term therapeutic outcomes for patients treated with anti tumor necrosis factor (TNF)α agents. 9 Elevated ATI Levels During Induction Lead to Increased Rate of IFX Clearance Approximately one-third of patients with ulcerative colitis have limited or no response to induction therapy with IFX, a phenomenon known as primary nonresponse. Because loss of response to IFX during maintenance therapy is associated with ATI development in some patients, ATI production during induction may also be responsible for some cases of primary nonresponse. Until recently, this possibility has been difficult to study as most commercial and research assays are not able to detect antidrug antibodies in the presence of drug. However, HMSA has been shown to be both highly sensitive and highly specific and, importantly, is able to accurately determine ATI levels in the presence of IFX. 10 4

5 Antidrug Antibody Monitoring in Practice (continued) Elevated ATI Levels During Induction Lead to Increased Rate of IFX Clearance (continued) A recent study used HMSA to measure ATI levels in 19 patients with moderate to severe ulcerative colitis who initiated treatment with IFX. The patients were followed for 8 weeks, and all patients were endoscopically assessed before treatment and at the 8-week time point. The investigators found that 11 of the 19 patients showed an endoscopic response to IFX induction at 8 weeks; of the 8 endoscopic nonresponders, 6 patients had detectable ATI. In total, ATI were detected in 7 patients; the 7th patient who had shown an endoscopic response at week 8 experienced an acute infusion reaction after the study was completed. It is important to note that ATI could be detected as early as day 18 (4 days after the second IFX infusion), as demonstrated in 2 exemplary patients (Figure 3). Patients who were ATI positive had a significantly increased rate of IFX clearance and lower serum IFX levels at week 6 compared with ATI-negative patients. Furthermore, 5 of the 7 patients with detectable ATI had elevated CRP levels (>50 mg/ml) at baseline, suggesting high inflammatory burden may be predictive of immunogenicity. Thus, patients with high inflammatory burden are more likely to experience increased IFX clearance and effectively lower drug exposure. These patients may benefit from an intensified IFX induction schedule. 10 Serum IFX Concentration, µg/ml Serum IFX Concentration, µg/ml Figure Patient A Weeks Patient B Weeks Serum IFX concentration ATI titer Adapted with permission from Brandse. Serum IFX concentrations and ATI titers of 2 patients who developed ATI by day 18, 4 days after receiving a second IFX infusion ATI Titer, AU/mL ATI Titer, AU/mL "Once you get patients to target, you need to keep them there. The way to keep them there is to optimize their therapies and make sure optimal drug levels are maintained." 5

6 Proactive Drug Monitoring Informs Therapeutic Dose Adjustments Drug Concentration Based Dose Adjustments May Reduce Risk of Relapse When optimizing IFX dosing for patients with IBD, clinicians have 2 options: they can adjust the dose based on clinical symptoms or on drug concentrations. A randomized controlled trial, Trough Concentration Adapted Infliximab Treatment (TAXIT), evaluated these 2 dosing strategies. While investigators did not see a significant difference in rates of clinical and biochemical remission between the 2 groups after 1 year, patients in the concentration-based IFX dosing group experienced fewer relapses (7%) compared with those in the symptombased dosing group (17%). Targeting IFX trough concentrations in the range of 3 to 7 µg/ml resulted in a higher proportion of patients in remission, while reducing costs and potential adverse events associated with supraoptimal dosing. These findings confirm that appropriate drug exposure results in improved drug efficacy. 11 Concentration-Based IFX Dose Titration Supports Long-term Maintenance of IFX Response An observational pilot study demonstrated the long-term benefit of continued concentration-based IFX dose titration in patients with IBD. Although no differences in drug continuation were apparent at 1 year, patients who had proactive TDM were more likely to stay on IFX in the long run (Figure 4). Specifically, 86% of patients who had proactive TDM remained on IFX therapy at 5 years compared with 52% in the group that did not have TDM. None of the 48 patients in the proactive TDM group discontinued IFX due to recurrent symptoms of IBD, whereas 15 of the 78 patients who did not have proactive TDM stopped treatment as a result of recurrent symptoms. As patients in clinical remission frequently experience low or undetectable IFX levels, TDM and subsequent dose escalation are effective strategies to keep IFX at therapeutically effective concentrations. 12 Figure 4 Duration of IFX treatment in patients who had proactive TDM vs those who did not Patients on IFX, % TDM No TDM Adapted with permission from Vaughn. Week 6

7 Keeping Patients in Remission "Tight control means you keep patients in a very tight state of remission. To do that, you need to monitor other factors, including fecal calprotectin, which is a marker of remission it provides a way of tracking patients that are falling in and out of remission." Fecal Calprotectin Levels Can Predict Pharmacokinetics of Anti-TNFα Therapy A study examined fecal calprotectin (FC) levels in IBD patients in deep remission who were no longer being treated with an anti-tnfα agent. To prevent relapse in this population, it is important to predict which patients are at risk for relapse and could benefit from reinitiation of treatment. A quantitative enzyme immunoassay was used to measure FC concentrations in stool samples collected at baseline and every 4 weeks for 6 months and every 2 months thereafter from 52 patients with IBD. Patients who had relapsed based on either clinical or endoscopic criteria during the 12-month followup period had significantly higher median FC concentrations before relapse relative to baseline compared with those who did not relapse. Elevations in FC were detected 2, 4, and 6 months prior to relapse and remained elevated until the time of relapse (Figure 5). These findings Figure 5 FC Level, μg/g FC levels in patients in sustained remission compared with patients who relapsed during the 12-month follow-up. 13,a Patients in remission Patients with relapse P=.258 P=.156 P=.597 P=.250 P=.240 P=.827 P=.037 P=.010 P= Month a Boxes indicate interquartile ranges (IQR). Median values are indicated by horizontal lines and whiskers indicate the upper and lower limits of the IQR. Outliers are represented by circles (>1.5 IQR) and stars (>3 IQR). Reprinted with permission from Molander. support the effectiveness of FC as a surrogate marker for predicting relapse in patients with IBD. Thus, measurement of FC can be used in clinical practice to identify patients who may require close follow-up due to elevated risk of relapse. 13 Recent advances in the monitoring of both drug and antidrug antibody levels, combined with disease activity monitoring, are poised to provide clinicians with the information they need to optimize treatment for their patients with IBD. As an approach, treat to target has the potential to improve patient outcomes. The future development of highly sensitive, noninvasive biomarkers for mucosal healing will lead the way to making a treat-to-target approach more viable. "Clinicians are constantly looking, fixing, adjusting, realigning, and recasting depending on the patient s state of affairs." 7

8 References: 1. Neurath MF. Cytokines in inflammatory bowel disease. Nat Rev Immunol. 2014;14(5): Baars JE, Nuij VJ, Oldenburg B, Kuipers EJ, van der Woude CJ. Majority of patients with inflammatory bowel disease in clinical remission have mucosal inflammation. Inflamm Bowel Dis. 2012;18(9): Bouguen G, Levesque BG, Feagan BG, et al. Treat to target: a proposed new paradigm for the management of Crohn s disease. Clin Gastroenterol Hepatol. 2015;13(6): Sandborn WJ, Hanauer S, Van Assche G, et al. Treating beyond symptoms with a view to improving patient outcomes in inflammatory bowel diseases. J Crohns Colitis. 2014;8(9): Smolen JS, Aletaha D, Bijlsma JW, et al; T2T Expert Committee. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis. 2010;69(4): Peyrin-Biroulet L, Sandborn W, Sands BE, et al. Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): determining therapeutic goals for treat-to-target. Am J Gastroenterol. 2015;110(9): Walsh A, Palmer R, Travis S. Mucosal healing as a target of therapy for colonic inflammatory bowel disease and methods to score disease activity. Gastrointest Endosc Clin N Am. 2014;24(3): Vande Casteele N, Khanna R, Levesque BG, et al. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn s disease. Gut. 2015;64(10): Singh N, Rosenthal CJ, Melmed GY, et al. Early infliximab trough levels are associated with persistent remission in pediatric patients with inflammatory bowel disease. Inflamm Bowel Dis. 2014;20(10): Brandse JF, Mathôt RA, van der Kleij D, et al. Pharmacokinetic features and presence of antidrug antibodies associate with response to infliximab induction therapy in patients with moderate to severe ulcerative colitis. Clin Gastroenterol Hepatol. 2016;14(2): Vande Casteele N, Ferrante M, Van Assche G. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015;148(7): Vaughn BP, Martinez-Vazquez M, Patwardhan VR, Moss AC, Sandborn WJ, Cheifetz AS. Proactive therapeutic concentration monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease: results from a pilot observational study. Inflamm Bowel Dis. 2014;20(11): Molander P, Färkkilä M, Ristimäki A, et al. Does fecal calprotectin predict short-term relapse after stopping TNFα-blocking agents in inflammatory bowel disease patients in deep remission? Crohns Colitis. 2015;9(1):33-40.