March 18, 2016
The introduction of biologics, especially anti-tumor necrosis factor (anti-TNF) agents, significantly changed the management of inflammatory bowel disease (IBD). Therapeutic targets now include both symptom control and sustained control of intestinal inflammation. Yet a majority of patients never achieve those goals.
More than one-third of patients with IBD fail induction therapy and up to 60 percent of primary responders lose response over time. Only about one-fifth of patients are in remission a year after diagnosis. Despite the clear effect of anti-TNFs on the course of IBD, many patients continue to struggle and management of their disease remains challenging.
One problem is that disease flares are not always indicative of treatment resistance. Edward V. Loftus Jr., M.D., director of the IBD clinic at Mayo Clinic's campus in Rochester, Minnesota, says a common mistake is to assume that worsening symptoms in a patient with established IBD are due to the underlying disease. Instead, disease exacerbation can result from unrelated conditions, including concomitant enteric infections, especially Clostridium difficile and cytomegalovirus infections, celiac disease, irritable bowel syndrome, bile acid malabsorption, or small intestine bacterial overgrowth.
A small percentage of patients develop a hypersensitivity to sulfasalazine and mesalamine derivatives, leading to a paradoxical worsening of colitis symptoms. A more substantial number develop intestinal fibrosis, which can lead to stricture formation in the small intestine — a frequent cause of poor response to medical therapy. Although biologics such as infliximab are effective for inflammatory stenosis, they are ineffective in the setting of fibrosis, and this subset of patients often requires surgery or endoscopic dilatation to treat fibrotic strictures.
When patients are genuinely refractive to medical management, a failed response is often due to inadequate serum concentrations of the prescribed drug(s), a high inflammatory burden or the formation of anti-drug antibodies.
In a study published in The American Journal of Gastroenterology, members of the inflammatory bowel disease interest group at Mayo Clinic's campus in Minnesota examined the records of 155 patients with IBD whose human anti-chimeric antibody (HACA) and infliximab concentrations had been measured. The main indications for testing were partial response to the drug, loss of response and possible hypersensitivity reactions. Of those patients, 35 (23 percent) had antibodies and just 51 (33 percent) had therapeutic concentrations of infliximab — results that affected treatment decisions in nearly three-fourths of cases.
In 92 percent of HACA-positive patients, changing to another anti-TNF agent led to a partial or complete response, whereas a dose increase was associated with a response in only 17 percent. In patients with subtherapeutic infliximab concentrations, increasing the infliximab dose resulted in a complete or partial clinical response in 86 percent of patients; changing to another anti-TNF agent led to a response in 33 percent.
Dr. Loftus says the study points to many of the issues involved in managing refractory disease. "If a patient isn't responding to a biologic, you have to check for anti-drug antibodies; all biologics are potentially immunogenic, and antibodies can reduce their efficacy and cause other problems. For a significant proportion of these patients, improvement in clinical response is achieved after switching to another anti-TNF."
For patients who are not antibody positive but fail or lose response to an anti-TNF blockade, treatment should first be optimized by increasing the dose, shortening treatment intervals or switching from monotherapy to combination therapy.
"We don't like to switch biologics until all options are exhausted; switching too soon increases the risk of immunogenicity," Dr. Loftus says. "It's a tough dynamic; we don't want to give up on a drug too early, but if doubling the dose or adding an immunomodulator such as azathioprine or methotrexate doesn't work, we try a different biologic.
Dr. Loftus stresses that any treatment change requires reassessment with an objective test such as C-reactive protein, cross-sectional imaging or fecal calprotectin, usually within four to six months. "We routinely treat to target, so every time we make a change we have to follow it up. The exact timing depends on the severity of symptoms; it might be three months or six months, but we can't rely on symptoms alone to determine whether or not we're making headway," he says.
For patients who remain resistant, the next option may be an off-label drug such as ustekinumab, a human interleukin-12 (IL-12) and IL-23 antagonist. Currently approved for use in psoriasis and active psoriatic arthritis, it is expected to receive Food and Drug Administration approval for Crohn's disease (CD) in late 2016. The anti-rejection drug tacrolimus also has some effect on medically refractive CD and ulcerative colitis (UC), but requires careful monitoring of kidney function.
Surgical resection: Last resort?
Up to 30 percent of patients with UC eventually require surgery. Depending on the severity and duration of disease, the quality of life for many patients may be better after surgery than before. Crohn's disease is another matter.
"We perform surgery when we have to if the patient has developed an obstructive stricture or abscess. Otherwise, we are very careful about recommending surgery in CD. In a study involving a cohort of IBD surgical patients in Olmsted County, the five-year risk of recurrence was 50 percent and many had multiple resections," Dr. Loftus says. "A small percentage of those patients developed short bowel syndrome and ended up on total parenteral nutrition. This is where the art of medicine comes in. You have to really understand each patient because you can't predict who will do well with surgery and who won't. These are tough patients to treat."
More options for management of refractory disease are likely to develop as microbiome research continues at an accelerated pace. Results of one large trial of fecal microbiota transplantation for UC will be presented at Digestive Disease Week 2016 in San Diego.
For more information
Affif W, et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. The American Journal of Gastroenterology. 2010;105:1133.
Peyrin-Biroulet L, et al. Surgery in a population-based cohort of Crohn's disease from Olmsted County, Minnesota (1970-2004). The American Journal of Gastroenterology. 2012;107:1693.