Predictors of Non-response and Loss of Response in IBD Patients Treated With Anti-TNF.

Crohn's disease and ulcerative colitis are both chronic idiopathic inflammatory conditions of the gastrointestinal tract that result in a considerably decreased quality of life. Long term experience with standard therapies for inflammatory bowel disease patients up to the late 1990s demonstrated diverse limitations. Corticosteroids have good short term efficacy, but are not suitable for maintaining remission, while treatment with immunomodulators are associated with an important risk of side effects. The introduction of monoclonal antibody to tumor necrosis factor a (TNFa) therapy has offered new treatment options originally in patients with Crohn's disease and more recently in those with ulcerative colitis as well. Several clinicians based on the results of clinical trials, now advocate the early use of intensive therapy (immunosuppressants and/or biologics) to maintain a good quality of life from the first flare up and prevent any irreversible consequence of the disease.

In 1998 infliximab was the first anti-TNF therapy to be approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with moderately to severely active luminal and fistulizing CD who have an inadequate response to conventional therapies. In 2007 adalimumab was also approved for the treatment of adult patients with moderate to severe CD. More recently, infliximab has been approved for the treatment of ulcerative colitis patients. The current recommendation for infliximab dosing comprises induction with 5 mg/kg at 0, 2, and 6 weeks, followed by maintenance 5 mg/kg every 8 weeks. Adalimumab is administered at a dose of 160 mg initially followed by 80 mg 2 weeks later and then at a dose of 40 mg every other week.

Since the aim of administering anti-TNF therapy is achieving disease remission, it should be noted that in the clinical setting, remission is defined as the absence of any gut-related symptoms, with a normal C-reactive protein (CRP) or erythrocyte sedimentation ratio (ESR), hemoglobin, albumin, and platelet count. Clinical response is defined as the improvement of symptoms (reduced bowel frequency, reduced urgency, improved stool consistency, reduced abdominal pain, reduced rectal bleeding, improved general well-being, increased energy, and reduced lethargy) and improvement in blood test parameters (reduced CRP, ESR, and platelet count, and improved albumin and hemoglobin).

Despite the high response rate, some patients do not improve after initiation of anti-TNF therapy or worsen after initial response. In the ACCENT I trial, 42% of patients had a primary lack of response to infliximab induction therapy, while in the CHARM trial, 42% of patients had a primary non-response to open label adalimumab induction therapy. According to literature data, diminished or complete loss of initial response to anti-TNF therapy can occur at any time after treatment begins and can occur at 30-50% of the patients treated. Regaining response can be achieved by either reducing the frequency of infusions or by increasing the dose, whether sometimes an increase of the dose plus a reduction of the dose interval is required.

Primary non-response is defined as the lack of response or minimal, clinically insignificant response after initiation of a biological agent. To be defined as demonstrating primary non-response a patient should have objective evidence of active inflammation and symptoms related to IBD. There is currently no consensus on how long a biological drug should be continued before lack of response is declared, although 58% of patients who will demonstrate a response to infliximab do so within 2 weeks. A substantial proportion of patients, however, will demonstrate a response up to 12 weeks after commencing treatment. Most responders demonstrate a clinical response by week 14 (in the case of infliximab that usually includes three induction plus one further dose). With adalimumab induction therapy it may require up to 12 weeks to determine whether response has been achieved. Loss of response is defined as an initial response to a biological drug followed by a diminished or less durable response over time.