Use of Biologics in IBD
When?
- Moderately to severely active Crohn’s disease that is refractory to conventional therapy.
- Fistulising Crohn’s disease that is refractory to conventional therapy
Clinical trials have demonstrated significant utility of infliximab for induction of remission in moderately active, steroid refractory Crohn’s disease, improvement in quality of life, and maintenance of remission in these patients for up to 54 weeks after initial infusion.
How?
2 strategies
- Scheduled maintenance- Dose 5mg/kg. Induction doses at 0,2 and 6 weeks and then retreatment of patients who respond to initial therapy every four- to eight-week interval at 5 mg/kg depending upon how quickly relapse of the Crohn’s disease symptoms occurs.
- Episodic use- on demand retreatment with 5 mg/kg after a single inductive infusion of infliximab. Inductive infusion is at 0, 2 and 6 weeks for fistulising Crohn’s disease and then on demand retreatment.
Discuss episodic treatment?
- Safety and cost are important aspects of all drug usage. Toxicity is not substantially enhanced and infusion reactions are not decreased by regularly scheduled infusions.
- Drug costs tend to decrease with time and competition and thus should not be used as a major reason for opting for an episodic regime. Further considering the costs of surgery and hospitalisations, a maintenance regime of infliximab is cost effective.
- In ACCENT I study, the authors stress the clinical superiority of the scheduled maintenance treatment groups over the episodic strategy, with significant advantages in remission and response rates, quality of life, mucosal healing, Crohn’s disease related hospitalizations, and intra-abdominal surgery. However, regularly scheduled administration of the FDA-approved dose of 5 mg/kg infliximab was significantly better than episodic infusion in only 2 parameters (hospitalization, 23% vs. 38%; P =0.047; intra-abdominal surgeries, 3% vs. 7%; P =0.04).
- Remission and response are the most widely accepted outcome measurements for Crohn’s disease clinical trials. ACCENT I- only a minority of patients (44%) in the 5-mg/kg regularly scheduled group completed the study as designed; 26% discontinued treatment without crossover and 30% were crossed over to 10 mg/kg “rescue” therapy. Therefore, an alternative interpretation of these results is that on-demand retreatment with 5 mg/kg after a single inductive infusion of infliximab is comparable to the more expensive strategy of 3 inductive infusions followed by scheduled treatments every 8 weeks.
- Certainly, a patient with luminal Crohn’s disease who requires infliximab treatment and who is not yet on immunosuppressant drugs can be induced with a single infliximab infusion after beginning maintenance 6MP, azathioprine, or methotrexate, thereby reserving regularly scheduled infliximab infusions for those patients failing optimal immunosuppressant maintenance treatment.
Discuss management strategy of patients who initially respond but then lose their response?
Antibodies to infliximab reduce infliximab blood levels and causes loss of response. This can be overcome by 4 different strategies;
- decrease the intervals between re infusions to 7, 6, 5, or 4 week intervals
- increase the infliximab dose to 10 mg/kg
- Both
- Switch to adalimumab
Discuss efficacy of infliximab treatment?
| Luminal Crohn’s disease (ACCENT I data) | Fistulising Crohn’s (ACCENT II data) |
|---|---|
| 65% of the patients had a clinical response, including 40 percent who achieved remission. | All patients initially received an initial series of infliximab (5 mg/kg) given at weeks 0, 2 and 6. Response was defined as at least a 50 percent reduction in the number of draining fistulas.
64% responded by week 14. |
| In patients who initially had a clinical remission, maintenance of remission (at 54 weeks) occurred in only 14 percent of patients in the single dose group compared to 28 percent of patients maintained on infliximab 5 mg/kg every eight weeks and 38 percent of patients on infliximab 10 mg/kg every eight weeks | At week 54, significantly more patients assigned to maintenance therapy had complete absence of draining fistulas (36 versus 19 percent). |
Discuss the tests before initiating infliximab/biologics?
Most physicians tend to do a CXR and montoux test or T spot- test.
Problems with tuberculin sensitivity tests (montoux test)- Issues with administering & interpreting test, Previous BCG vaccination and a return visit from the patient is required in order to assess the result.
What is T Test-?
- In vitro T cell based assay
- Principle- T cells of individuals previously sensitized with TB antigens will produce ?-IFN when they reencounter TB antigens.
- Thus, a high level of interferon-gamma production is presumed to be indicative of TB infection.
- Two methods for detecting the IFN-gamma released by the T cell- ELISA and an enzyme-linked immunospot assay (ELISPOT, eg, T SPOT-TB assay).
Adalimumab
Discuss dosing?
The approved induction dosing of adalimumab in Crohn’s disease is 160 mg given subcutaneously initially at week zero, 80 mg at week two, followed by a maintenance dose of 40 mg every other week beginning at week four. The drug is available in a single-use prefilled pen (HUMIRA Pen)
Discuss the efficacy?
Patients generally respond within the first week. Responses were maximal by three doses in the CLASSIC and CHARM studies. Patients who do not respond within this interval should not continue adalimumab.
Efficacy similar to Infliximab
Discuss the indications?
- Same as Infliximab
- Adalimumab can be used in patients who had lost response to or are intolerant of infliximab. Used as such in GAIN study, adalimumab was more effective than placebo at achieving clinical remission (21 versus 7 percent) and response (38 versus 25 percent)
NICE (2010) recommendations for use of biologics
When to use?
Infliximab and adalimumab are recommended as treatment options for adults with severe active Crohn’s disease or active fistulising Crohn’s disease, whose disease has not responded to conventional therapy (including antibiotics, drainage, immunosuppressive and/or corticosteroid treatments), or who are intolerant of or have contraindications to conventional therapy.
How long to use?
Infliximab or adalimumab should be given as a planned course of treatment until treatment failure (including the need for surgery), or until 12 months after the start of treatment, whichever is shorter.
Should treatment be stopped at 12 months?
People should then have their disease reassessed to determine whether ongoing treatment is still clinically appropriate. Treatment with infliximab or adalimumab should only be continued if there is clear evidence of ongoing active disease as determined by clinical symptoms, biological markers and investigation, including endoscopy if necessary.
People who continue treatment with infliximab or adalimumab should have their disease reassessed at least every 12 months to determine whether ongoing treatment is still clinically appropriate. People whose disease relapses after treatment is stopped should have the option to start treatment again.
Which biologic to use: infliximab or adalimumab?
Treatment should normally be started with the less expensive drug (taking into account drug administration costs, required dose and product price per dose). The costs will vary depending on local arrangement
Discuss the treatment regime?
| Infliximab | Adalimumab |
|---|---|
| Severe Active Crohn’s disease
5-mg/kg intravenous infusion followed by another 5-mg/kg infusion 2 weeks after the first. If a person’s disease does not respond after two doses, no additional treatment with infliximab should be given. In people whose disease responds-maintenance treatment (another 5-mg/kg infusion at 6 weeks after the initial dose, followed by infusions every 8 weeks). In adults, dose escalation is an option for people whose disease has stopped responding. Continued therapy should be carefully reconsidered in patients who show no evidence of therapeutic benefit after dose adjustment. |
Severe Crohn’s disease (both luminal and fistulising)
80 mg via subcutaneous injection, followed by 40 mg 2 weeks later. If there is a need for a more rapid response to therapy, a dose of 160 mg followed by 80 mg 2 weeks later can be used, though the risk of adverse events with this higher dose is greater during induction. (Higher dose in increasingly used in clinical practice) After induction treatment the recommended dose is 40 mg every other week. This can be increased to 40 mg every week in people whose disease shows a decrease in response to treatment. Continued therapy should be carefully reconsidered in patients whose disease does not respond within 12 weeks of initiating treatment. |
| Fistulising disease
5-mg/kg infusion followed by additional 5-mg/kg infusions at 2 and 6 weeks after the first. If a person’s disease does not respond after three doses, no further treatment with infliximab should be given. In people whose disease responds, infliximab can be given as maintenance treatment (5-mg/kg infusions every 8 weeks) or as re-administration treatment (5-mg/kg when signs and symptoms recur, followed by infusions of 5-mg/kg every 8 weeks). In adults, dose escalation is an option for people whose disease has stopped responding. |
Define severe disease as discussed in NICE guidance?
- Severe active Crohn’s disease is defined as very poor general health and one or more symptoms such as weight loss, fever, severe abdominal pain and usually frequent (3–4 or more) diarrhoeal stools daily.
- People with severe active Crohn’s disease may or may not develop new fistulae or have extra-intestinal manifestations of the disease.
- This clinical definition normally, but not exclusively, corresponds to a Crohn’s Disease Activity Index (CDAI) score of 300 or more, or a Harvey-Bradshaw score of 8 to 9 or above.
- The CDAI is frequently used to assess disease severity. It is a composite of overall activity of Crohn’s disease as assessed by clinicians, and has eight variables weighted according to their ability to predict disease activity. It gives a score ranging from 0 to over 600, based on a diary of symptoms kept by the patient for 1–7 days, and other measurements such as the patient’s weight and haematocrit. A CDAI score of less than 150 is considered to be remission, a score greater than 220 is considered to define moderate to severe disease, and a score greater than 300 is considered to be severe disease. The paediatric CDAI (PCDAI) is an instrument similar to the CDAI but with less emphasis on subjectively reported symptoms and more emphasis on laboratory parameters of intestinal inflammation. Calculate CDAI score here
- The Harvey-Bradshaw Index is another commonly used tool, which correlates well with CDAI. It is based on assessments of general wellbeing, abdominal pain, number of diarrhoeal stools per day, and the presence of abdominal mass and associated complications. Patients with a score of 8 to 9 or higher are considered to have severe disease. Calculate Harvey- Bradshaw Index here
Discuss paediatric use of biologics?
Infliximab, within its licensed indication, is recommended for the treatment of people aged 6–17 years with severe active Crohn’s disease whose disease has not responded to conventional therapy (including corticosteroids, immunomodulators and primary nutrition therapy), or who are intolerant of or have contraindications to conventional therapy. The need to continue treatment should be reviewed at least every 12 months.
Fistulising Crohn’s disease: For people aged 6–17 years, infliximab is given as a 5-mg/kg intravenous infusion followed by additional 5-mg/kg doses at 2 and 6 weeks after the first dose, then every 8 weeks thereafter.
NICE guidance: TA187 Crohn’s disease – infliximab (review) and adalimumab (review of TA40)
