The evaluation and treatment of patients with Crohn s

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9:395 399 PERSPECTIVE Do Not Assume Symptoms Indicate Failure of Anti Tumor Necrosis Factor Therapy in Crohn s Disease DAVID H. BRUINING* and WILLIAM J. SANDBORN *Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota; and Division of Gastroenterology, University of California San Diego, La Jolla, California Podcast interview: www.gastro.org/cghpodcast. It is a challenge to monitor patients with Crohn s disease who remain symptomatic despite anti tumor necrosis factor therapy. Clinicians must use a systematic approach for each patient and obtain objective evidence about disease activity and response to therapy. Alternate etiologies for symptoms should be sought and treated, if found. Active Crohn s disease despite therapy requires reassessment and adjustments to management plans. Keywords: Anti-TNF Therapy; Crohn s Disease; Treatment Failure. The evaluation and treatment of patients with Crohn s disease remains a clinical challenge. In addition to addressing the patient s symptoms, physicians are seeking evidence-based management strategies to modify the natural history of the disease by healing mucosal and transmural lesions in the short term and reducing steroid dependency, surgery, and disability in the long term. In that context, anti tumor necrosis factor alpha (anti-tnf) agents have emerged as a potential disease-modifying therapy. These agents, infliximab, adalimumab, and certolizumab pegol, have been shown to heal mucosal lesions, reduce hospitalizations, decrease the need for surgery, and diminish postoperative recurrence. 1 5 Findings from the recently published SONIC trial demonstrated an incremental benefit of infliximab therapy as compared with azathioprine. 6 These findings have led to a shift toward earlier use of anti-tnf agents in Crohn s disease. One consequence of this paradigm shift is that physicians are increasingly faced with the clinical scenario of persistent or recurrent symptoms despite the use of anti-tnf therapy. Need for Reassessment of Disease Activity It is important to systematically reassess the disease activity of patients with Crohn s disease who are receiving anti-tnf therapy and have persistent or recurrent symptoms that suggest ongoing intestinal inflammation. The stakes are high for these patients because they face the possibility of adding or changing anti-tnf agents, immunomodulator drugs, steroids, natalizumab, and surgery, each of which has inherent risks and ultimately might not be of benefit if the patient s symptoms are from causes other than active Crohn s disease. 7 Misdiagnoses can lead to inappropriate or premature discontinuation of an effective therapy or surgical interventions that could otherwise be avoided. Conversely, patients with active disease despite anti-tnf therapy should be identified and their treatment strategy should be altered, because uncontrolled inflammation is believed to be the root cause of disease progression to the complications of stricture, fistula, and abscess formation. For these reasons, it is important to reevaluate disease activity and establish the presence or absence of other comorbid conditions before instituting major changes in therapy. Symptoms Are Not Enough A key concept in the modern management of patients with Crohn s disease is the idea that symptoms correlate poorly with objective measures of inflammatory disease in the lumen. Modigliani et al 8 reported no significant correlation between clinical symptoms as measured by the Crohn s Disease Activity Index (CDAI) and objective evidence of mucosal ulceration and inflammation seen at ileocolonoscopy and measured with the Crohn s Disease Endoscopic Index of Severity. Other investigators have similarly shown a lack of significant correlation between the CDAI and a variety of objective measures of inflammation including C-reactive protein, fecal calprotectin and lactoferrin, and findings at ileocolonoscopy as measured by the Simple Endoscopic Severity for Crohn s Disease. 9 In the ACCENT I study of anti-tnf therapy with infliximab for moderate to severe inflammatory luminal Crohn s disease (CDAI, 220 450), 99 of the 573 recruited patients with ileocolonic disease participated in an endoscopic substudy and underwent ileocolonoscopy at baseline. 2,10 Among these 99 patients, 17 (18%) had no evidence of endoscopic inflammation (no mucosal ulceration). Similarly, in the recent SONIC trial, 93 of 508 patients (18%) had no evidence of ulcers at baseline ileocolonoscopy. 6 Not surprisingly, there were no differences in the treat- Abbreviations used in this paper: anti-tnf, anti tumor necrosis factor; CDAI, Crohn s Disease Activity Index; CMV, cytomegalovirus; CTE, computed tomography enterography; HACA, human anti-chimeric antibody; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; MRE, magnetic resonance enterography; UC, ulcerative colitis. 2011 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2011.01.019

396 BRUINING AND SANDBORN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 5 Table 1. Alternate Etiologies of Symptoms in Crohn s Disease Patients Alternate etiologies Disease complications Stricture Fistula Abscess Development of disease in new location Malignancy Complications of surgical resection Bile acid malabsorption Short gut (manifested as steatorrhea) Small bowel bacterial overgrowth Enteric infections Clostridium difficle CMV Celiac disease IBS Depression ment groups (no therapeutic benefit) if the baseline C-reactive protein concentration was 8 mg/l or if the baseline colonoscopy did not demonstrate ulcers. 6 In an analogous observation, Hanauer et al 11 reported in a placebo-controlled trial of mesalamine and 6-mercaptopurine for prevention of postoperative recurrence that clinical relapse-free survival rates were lower than the endoscopic and radiologic relapse-free survival rates, indicating that a significant number of patients had recurrent symptoms but no objective evidence of recurrent inflammation as assessed by endoscopic and radiographic evaluation. All of these observations highlight the need for objective measures of disease activity. In patients with a history of ileal involvement and a negative ileocolonoscopy, computed tomography enterography (CTE) or magnetic resonance enterography (MRE) and, in some selected cases, capsule endoscopy should be performed before altering treatment in patients with persistent or recurrent symptoms despite anti-tnf therapy. The caveat regarding capsule endoscopy is related to the potential for precipitating small bowel obstruction requiring operation in patients with known Crohn s disease. 12 Further experience with use of the patency capsule before capsule endoscopy might obviate this caveat. 13 Fecal calprotectin and lactoferrin could serve as alternatives to these imaging studies. However, although these laboratory tests can detect persistent or recurrent inflammation, they cannot detect the presence of structural damage and/or disease complications, which might also cause symptoms that overlap with active Crohn s disease. If Not Active Crohn s Disease, Then What? A large number of comorbid conditions can result in symptoms that overlap with active Crohn s disease (Table 1). The natural history of Crohn s disease that is not sufficiently suppressed with medical therapy is a progression from luminal and transmural inflammation to complications such as fibrosis with formation of stricture(s) and transmural penetration of ulcers with the formation of fistula(s) and abscess(es). A retrospective review of 357 patients with Crohn s disease who underwent a clinically indicated CTE reported penetrating disease in 74 patients (21%), of which 43 (58%) represented a new finding. 14 In addition, after 20 years of Crohn s disease, 60% 80% of individuals with ileal involvement will require surgery. 15,16 These patients might develop bile acid induced diarrhea, steatorrhea, and/or small bowel bacterial overgrowth. Cosnes et al 17 examined the effect of surgical resection on bowel function, correlating fecal weight and fat with a postoperative handicap index score. A linear relationship became exponential as the handicap index scores increased to higher levels. Small bowel bacterial overgrowth, as determined by breath testing, has been reported in up to 33% of Crohn s disease patients with a history of surgery and 29% with stricturing disease. 18 Concomitant enteric infections with bacteria and viruses including Clostridium difficile and cytomegalovirus (CMV) have become an important concern in patients with Crohn s disease. Both of these infections can result in clinical findings that are similar to and overlap with active Crohn s disease and in some instances can explain why a patient receiving anti-tnf therapy relapses or fails to achieve remission. The temporal trends for C difficile infections in patients with Crohn s disease have increased dramatically. Issa et al 17 reported that 4% of hospitalized patients with a diagnosis of C difficile in 2003 also had a diagnosis of inflammatory bowel disease (IBD), compared with an increased rate of 16% just 2 years later in 2005. 19 CMV is less common than C difficile infections, and most reported cases have occurred in ulcerative colitis (UC) rather than Crohn s disease. Kim et al 20 recently demonstrated positive CMV immunostains in 12 of 122 (10%) UC patients with acute disease exacerbations. Both C difficile and CMV infections should be considered in symptomatic patients on anti-tnf therapy. Concomitant irritable bowel syndrome (IBS) and/or depression can be the driving force behind symptoms in patients with Crohn s disease. Minderhoud et al 21 explored the overlap between IBS and IBD in patients with IBD in remission (no steroids within 3 months and normal inflammatory markers). With the ROME II diagnostic criteria for IBS, 7.6% of control patients had IBS, compared with 41.7% of patients with Crohn s disease and 31.5% with UC. With the Manning diagnostic criteria for IBS, 9.1% of control patients had IBS, compared with 23.5% and 34.2% of patients with Crohn s disease and UC, respectively. It should be noted that the patients in these studies were not systematically evaluated for inflammation and disease complications by using colonoscopy and CTE or MRE, and they did not undergo evaluation for small bowel bacterial overgrowth, bile salt diarrhea, and steatorrhea. Thus, some patients who were judged to have IBD might have had other etiologies for their symptoms. Further studies on this topic with state-of-the-art investigations to exclude diagnoses other Figure 1. Diagnostic approach to Crohn s disease patients who remain symptomatic on anti-tnf therapy.

May 2011 ANTI-TNF THERAPY 397 than Crohn s disease in remission and IBS are needed. In addition, Persoons et al 22 have described major depression diagnosed by a patient health questionnaire in 24 of 100 consecutive patients (24%) with Crohn s disease who were beginning biological therapy with infliximab. In this study, patients without depression had greater rates of response to infliximab. All of these findings highlight the fact that a multitude of other comorbid conditions can cause symptoms similar to or overlap with those of active Crohn s disease. To accurately treat the root cause of the patient s symptoms, a disciplined diagnostic and treatment algorithm should be used in patients who fail to respond to anti-tnf therapy or when they lose response (Figure 1). In those patients with symptoms in whom active disease is not demonstrated or the degree of inflammation is out of proportion to the symptoms, an alternate etiology should be sought and treated. Active Crohn s Disease Despite Anti Tumor Necrosis Factor Therapy: Now What? Several challenging clinical scenarios exist for patients with active luminal or fistulizing Crohn s disease despite anti- TNF therapy. Many of these patients are not absolute anti-tnf failures but rather partial failures (or alternatively, partial successes) who require adjustments to maximize efficacy of anti- TNF therapy. Primary Nonresponse to Anti Tumor Necrosis Factor Therapy Management of primary nonresponders to anti-tnf therapy remains a topic of great debate among clinicians. This is largely driven by limited data to support evidence-based practice guidelines. Published studies have examined the efficacy and safety of a second or third anti-tnf agent, but this is in patients with a secondary loss of response or drug intolerance. 23 25 We typically discuss this paucity of data with our patients and consider a non anti-tnf based regime. Anti Tumor Necrosis Factor Intolerance Patients might be failing an anti-tnf agent because of medication intolerance. Intolerance can be more commonly a result of a specific anti-tnf drug (for instance, an immediate or delayed allergic response) or less commonly if the entire anti- TNF drug class (for example, demyelinating disease or congestive heart failure). Mild intolerance might be managed in some patients with conservative supportive measures. In the setting of severe intolerance to a specific drug, a switch to another anti-tnf agent is appropriate. In a trial of adalimumab induction therapy in 325 patients with moderate to severe Crohn s disease and secondary infliximab failure, 95 patients were intolerant to infliximab. 24 Clinical remission (CDAI, 150 points) was achieved at 4 weeks in 22% of patients and clinical response in more than 50% of patients. 24 A similar study was performed with certolizumab pegol in patients with moderate to severe Crohn s disease and secondary failure to infliximab. Of the 539 patients enrolled in the 26-week trial, 198 had been intolerant to infliximab because of hypersensitivity reactions. After openlabel induction with subcutaneous certolizumab pegol 400 mg at weeks 0, 2, and 4, clinical response at 6 weeks (reduction from baseline in CDAI score of at least 100 points) was observed in 63% of infliximab-intolerant patients. 23 Secondary Loss of Response Another clinical scenario of anti-tnf failure is one of secondary loss or attenuated response. It is important to distinguish these patients from primary nonresponders. By definition, secondary loss implies a previous clinical response to anti-tnf therapy. The preferred initial approach with secondary failure is to determine whether the current agent can be manipulated or maximized to improve efficacy before changing to an alternate agent. Unique to infliximab is the commercial availability of laboratory tests to measure infliximab and human antichimeric antibody (HACA) concentrations. This is beginning to replace the previous practice of empiric dose escalation. Infliximab levels 12 g/ml at 4 weeks after infusion or a detectable concentration ( 1.4 g/ml) at trough are considered therapeutic. 26,27 Afif et al 28 examined the clinical utility of measuring infliximab and HACA concentrations in 153 patients with IBD, most of whom were experiencing loss or attenuation of response to inflixmab. Only 51 patients (33%) in this selected patient cohort had therapeutic infliximab concentrations. Dosing escalation (either increased dose or frequency) in those patients with subtherapeutic infliximab concentrations led to higher rates of clinical response compared with switching to an alternate anti-tnf agent (86% vs 33%, P.016). In contrast, among 35 patients who had evidence of immunogenicity to infliximab (HACA-positive), switching to another anti-tnf agent resulted in a complete or partial response in 92% of patients. These data support the use of infliximab concentration and HACA testing in patients with secondary loss of response to infliximab to help guide management. Managing secondary loss of response with empiric dosing adjustments (in the absence of ability to measure the therapeutic antibody or antidrug antibody) has also been explored with open-label studies in patients receiving treatment with adalimumab or certolizumab pegol. Colombel et al 29,30 reported findings from the CHARM trial that compared various adalimumab dosing strategies for the long-term treatment of moderate to severe Crohn s disease. Of the 260 patients randomized to adalimumab 40 mg every other week, 71 (26%) required escalation to open-labeled weekly therapy by week 56. Results from the PRECiSE 4 study examined reinduction with certolizumab pegol in patients with relapsed Crohn s disease. 31 Of the 124 patients who experienced disease relapse after induction with certolizumab pegol 400 mg at weeks 0, 2, and 4, 49 had received continuous maintenance therapy with certolizumab 400 mg every 4 weeks. Patients who relapsed on continuous maintenance therapy with certolizumab pegol received a single extra 400-mg dose of certolizumab pegol (400 mg every 2 weeks for 3 doses) and had a week 6 response rate of 63%. Similarly, results from the WELCOME study of certolizumab pegol in patients with secondary loss of response to infliximab suggest that in patients who initially responded to induction therapy with certolizumab pegol but relapsed during maintenance therapy, dosage adjustment from 400 mg every 4 weeks to 400 mg every 2 weeks resulted in regaining response in more than 70% of patients. 23 These data suggest that similar to infliximab, dosing adjustments can be an effective strategy in some adalimumab and certolizumab patients who experience a secondary loss of response.

398 BRUINING AND SANDBORN CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 5 A second strategy in managing loss of response to anti-tnf therapy is switching within the class to an alternate anti-tnf agent. This might be less preferable than dosing adjustments of the original agent, to prevent rapidly exposing the patient to all of the agents in the class (which might result in immunization to all agents and limit future therapeutic options) and possibly because of reduced efficacy with switching. Previous exposure to an anti-tnf drug might be associated with a reduced clinical response to a second anti-tnf agent. 28 At times, however, a change might represent a reasonable alternative to continuing therapy with the same agent. For example, in patients receiving infliximab who are HACA positive, changing to an alternate anti-tnf drug was associated with a partial or complete response in 92%, compared with a response of 17% with infliximab dose escalation. 28 In patients with a secondary loss of response to infliximab (not because of intolerance), adalimumab induction therapy achieved clinical remission (CDAI, 150) at week 4 in 20% of patients and clinical response in more than 50%. 24 The presence of HACA is associated with lower serum drug concentrations, reduced response rates, and an increased risk of adverse drug reactions. Nevertheless, some patients with HACA can be successfully managed with continued therapy with infliximab. 32 Certolizumab pegol use in 272 patients who had lost response to infliximab without evidence of intolerance resulted in a clinical response at week 6 (CDAI at least 100 points reduced from baseline) in 64% of patients. 23 Recently, Allez et al 25 examined the efficacy of a third anti-tnf monoclonal antibody after secondary failures and/or intolerance of 2 anti-tnf antibodies in 68 patients who were receiving adalimumab or certolizumab pegol. Clinical responses were 61% and 51% at weeks 6 and 20, respectively. Conclusions The initial approach with symptomatic patients on anti-tnf therapy should not be to assume treatment failure but rather to systematically reassess the patient. Colonoscopy and/or CTE/MRE should be performed to evaluate for the presence or absence of objective evidence of ongoing intestinal inflammation, to determine whether the disease extent and severity of disease are proportionate to the patient s symptoms, and to exclude the presence of disease complications (Figure 1). Capsule endoscopy might have a role in select patients in whom there is not a suspicion of stricturing disease. Alternate etiologies for patient symptoms should be identified and treated when present. If active Crohn s disease is identified, the physician must determine whether treatment failure is due to primary nonresponse, intolerance, or a secondary loss of response (Figure 2). The use of an alternative anti-tnf therapy in primary nonresponders is poorly studied. Consideration can be given to offering a non anti-tnf based management regime. Patients who are intolerant can be switched within the class to an alternate anti-tnf agent. Dosing adjustment should be considered in patients with a secondary loss of response. Infliximab and HACA testing should be considered in patients on infliximab with attenuated response to help guide management. Figure 2. Management approach to active Crohn s disease despite anti-tnf therapy. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at doi:10.1016/ j.cgh.2011.01.019. References 1. Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn s disease. Gastroenterology 2004;126:402 413. 2. Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn s disease. Gastrointest Endosc 2006;63:433 442. 3. Hara AK, Alam S, Heigh RI, et al. 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