When patients with Crohn’s disease experience recurrent or persistent symptoms despite taking anti–tumor necrosis factor therapy, clinicians should not automatically assume that the treatment has failed, Dr. David H. Bruining and Dr. William J. Sandborn said in a commentary published in the May issue of Clinical Gastroenterology and Hepatology.

Instead, it is crucial to systematically reassess the patient before making any changes in the treatment regimen, said Dr. Bruining of the Mayo Clinic in Rochester, Minn., and Dr. Sandborn of the University of California, San Diego.

First, make sure the symptoms actually result from Crohn’s disease rather than some other cause, because several studies have shown that symptoms correlate poorly with objective measures of inflammatory disease in the lumen.

Clinical symptoms as measured by the CDAI (Crohn’s Disease Activity Index) have been shown not to correlate with colonoscopic evidence of mucosal ulceration and inflammation as measured by the CDEIS (Crohn’s Disease Endoscopic Index of Severity) or the SES-CD (Simple Endoscopic Score for Crohn’s Disease). Symptoms also do not correlate with measures of C-reactive protein, fecal calprotectin, and fecal lactoferrin. In addition, the latter two measurements cannot detect the presence of structural damage or disease complications, both of which can cause symptoms that overlap with those of active Crohn’s disease.

"CT or MR enterography, and in some selected cases, capsule endoscopy, should be performed prior to altering treatment," with the caveat that capsule endoscopy could potentially precipitate small-bowel obstruction requiring surgery, they wrote (Clin Gastroenterol Hepatol 2011 [doi:10.1016/j.cgh.2011.01.019]).

"Further experience with use of the patency capsule prior to capsule endoscopy may obviate this caveat."

CT or MR assessments are important because they can differentiate the many other comorbid conditions that can produce symptoms that overlap with those of Crohn’s disease. Fibrosis with formation of stricture, as well as transmural penetration of ulcers with the formation of fistulas and abscesses, are two possibilities. Surgery to address ileal involvement can lead to bile acid–induced diarrhea, steatorrhea, and bacterial overgrowth in the small bowel.

Enteric infections (either bacterial or viral) can simulate Crohn’s exacerbations. Clostridium difficile infections have increased dramatically and have become a major concern in patients with Crohn’s disease. Cytomegalovirus (CMV) is less common but can also mislead clinicians into thinking that anti-TNF therapy has failed.

"Both C. difficile and CMV infections should be considered in all symptomatic patients on anti-TNF therapy," Dr. Bruining and Dr. Sandborn noted.

Concomitant irritable bowel syndrome also can present as an exacerbation of Crohn’s symptoms. One study using the Rome II diagnostic criteria for IBS found that nearly 8% of patients had IBS rather than a flare-up of Crohn’s, and another study using the Manning criteria for diagnosing IBS found a rate of 9%.

Major depression also can account for some symptoms – including fatigue – that might be attributed to Crohn’s. One study of 24 patients with Crohn’s disease identified major depression in all 24 of them.

Notably, patients with concurrent depression showed lower response rates to the anti-TNF agent infliximab, compared with patients who were not depressed.

In general, "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 alternative] etiology should be sought and treated," the authors wrote.

If the problem turns out to be actual failure of anti-TNF therapy, determine if it is only a partial failure that merely requires some adjustment. Perhaps the current agent "can be manipulated or maximized to improve efficacy" before it is assumed that all anti-TNF agents will be ineffective, they said.

Patients who have mild intolerance, for example, can be managed with conservative support measures. Others who may be intolerant of one specific drug rather than the entire class of anti-TNF agents can be switched to a different anti-TNF drug. One study showed that among 95 patients who were intolerant of infliximab, 22% remitted and more than half responded within 4 weeks to a switch to adalimumab.

In another study involving 198 patients who were intolerant of infliximab because of hypersensitivity reactions, a switch to certolizumab led to a 63% response rate at 6 weeks.

Finally, infliximab is unique in that there is a commercial laboratory test – a measurement of HACA (human antichimeric antibody) levels – to determine whether therapeutic concentrations of the drug have been attained. In one study of 153 patients who were showing loss of response, HACA testing demonstrated that only one-third of the group had achieved therapeutic concentrations of the drug in the circulation. Simple dose escalation improved the rate of clinical response to 86%.

Dr. Bruining reported receiving support in the past from Centocor Ortho Biotech. Dr. Sandborn is a consultant for and has received research grants from Centocor Ortho Biotech, Abbott Laboratories, UCB Pharma, Schering Plough, and Given Imaging.

Recurrent Symptoms Do Not Necessarily Reflect Treatment Failure in Crohn's