Appeal type: Medical necessity
Decision: Overturned

Diagnosis: Ulcerative Colitis. 
Treatment: Remicade 10mg/kg. 

The insurer denied Remicade 10mg/kg as not medically necessary. 
The health plan's determination is overturned. 

This patient has severe ulcerative colitis and has previously failed steroids. The patient was started on Remicade at standard dosing during a hospitalization for severe colitis associated with elevated inflammatory markers and severe colitis on flexible sigmoidoscopy. The patient did not achieve remission on standard dosing. Therapeutic drug monitoring revealed low infliximab levels. Therefore, the attending physician escalated the dose of Remicade to 10 milligrams per kilogram (mg/kg) every 8 weeks to treat this patient's severe ulcerative colitis. 

Dose escalation is the standard of care when using biological agents to treat inflammatory bowel disease and can be done either by shortening the interval between infusions or increasing the dose of the drug or sometimes both shortening the interval and dose increase. 

The continued use of Remicade is medically necessary to treat this patient's severe ulcerative colitis. Testing for tuberculosis (TB) at initiation of anti-tumor necrosis factor (TNF) or other biological therapy is considered the standard of care. Sometimes when an anti TNF agent is started emergently as in this case, the TB and hepatitis B screening may be overlooked. TB testing and screening for hepatitis B was not included in the documentation provided for review and should be done (if not done already) in accordance with the standard of care. The only reason to stop Remicade or any other anti TNF agent used for treatment of ulcerative colitis is an adverse reaction or a contraindication or loss of response to the medication. 

Remicade was the first anti-tumor necrosis factor (TNF) agent Food and Drug Administration (FDA) approved for the treatment of moderate to severe ulcerative colitis since 2005. The use of anti-tumor necrosis factor agents are standard of care in moderate to severe Ulcerative Colitis. Anti-TNF therapy should be initiated in patients with acute severe (refractory to corticosteroids) ulcerative colitis and in patients with moderate-to-severe ulcerative colitis who are not responsive to conventional treatment with aminosalicylates, corticosteroids and immune modulators. The only reason to stop Remicade or any other anti TNF agent used for treatment of ulcerative colitis is an adverse reaction or a contraindication or loss of response to the medication. Up to now, no prospective head-to-head comparison has been performed in ulcerative colitis (UC) between infliximab, adalimumab, and golimumab, although most clinical experience has been gained with infliximab. 

Infliximab leads to higher remission rates and mucosal healing, at least in the short term. Remicade has been available for a longer duration than anti TNF agents and there are more safety data on Remicade than there are for any other biologic therapy used in the treatment of ulcerative colitis. A study by Dumitrescu G and colleagues showed that Infliximab dose doubling led to short- and long-term event-free survival in UC patients, who had a loss of response to infliximab, in greater than 50% (percent) of the cases. The benefits of such a strategy were significantly improved by adding a concomitant immunomodulator. Another study by Taxonera C and colleagues showed that UC patients who lost response to infliximab during maintenance, infliximab dose escalation enabled recovery of short-term response in nearly 70% of patients. In the long term, 58% of patients maintained sustained clinical benefit, and 9 of 10 avoided colectomy. Short-term response was associated with an 86% reduction in the relative risk of colectomy. Govani and colleagues showed that in a retrospective review, 69.7% of those failing to respond to single-dose infliximab were able to avoid colectomy with an accelerated rescue induction strategy without worsening postoperative outcomes. Current data suggests that there is a significant association between serum levels of anti-tumor necrosis factor agents and level of mucosal healing. Serum levels of 6-10 g/mL (micrograms per milliliter) for infliximab and 8-12 g/mL for adalimumab are required to achieve mucosal healing in 80%-90% of patients with inflammatory bowel disease (IBD), and that this could be considered as a "therapeutic window." Exceeding these levels produces only a negligible gain in proportion of patients with mucosal healing.

Research has documented a higher incidence of tuberculosis after anti-TNF therapy. All patients being considered for biologic anti-TNF therapy should receive a tuberculin skin test, or a Quantiferon Gold test even if the patient has previously received the BCG (Bacillus Calmette Guerin) vaccination. Test results, in addition to patient risk for TB and other tests, should be used to assess the patient's risk for latent TB infection. This is a patient safety measure and is considered the standard of care. Additionally, the use of anti-TNF agents, including Remicade, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. Therefore, patients should be tested for HBV infection before initiating anti-TNF therapy, including Remicade.