3 Clinical need and practice

The problem addressed

3.1 Although tumour necrosis factor (TNF)‑alpha inhibitors can help many people with Crohn's disease, there are some people whose disease does not respond to treatment. Also, many people whose disease first responds to treatment find that their disease stops responding over time (loss of response). This loss of response may be caused by:

  • changes in disease characteristics over time

  • inflammation unrelated to TNF‑alpha concentrations

  • antibodies to TNF‑alpha inhibitors

  • fluctuations in circulating drug levels.

3.2 The concentration of TNF‑alpha inhibitor in the blood immediately before the next dose of TNF‑alpha inhibitor is due (referred to as the 'trough level') can vary widely between people who have had the same previous dose. These variations can be caused by:

  • differences in drug pharmacokinetics between individuals

  • antibodies that bind to the TNF‑alpha inhibitor, neutralising its activity and leading to increased clearance

  • concomitant treatment with some immunosuppressive drugs, such as methotrexate.

3.3 Currently, treatment decisions for people with Crohn's disease are based on clinical judgement and 'trial and error', so adapting treatment to suit the person may be difficult. People whose disease responds well to a TNF‑alpha inhibitor may continue having the same level of treatment even when it may be possible to reduce the dose or withdraw the treatment without having any detrimental effect on clinical outcomes. This continued treatment may lead to people having side effects of the treatment unnecessarily. People whose disease loses response are typically treated with a higher dose of TNF‑alpha inhibitor to try to recover a clinical response. This approach can be successful for some people, but for others, the intensified treatment regimen is not effective because they continue to have an expensive drug that gives them no benefit and they may have unnecessary treatment side effects.

3.4 The symptoms of Crohn's disease can vary widely between people. The personal preferences of clinicians and patients also make it difficult to establish a standardised pathway for people with Crohn's disease. Measuring levels of TNF‑alpha inhibitors and antibodies against TNF‑alpha inhibitors in a person's blood could help clinicians to identify the best treatment strategy for a person with Crohn's disease.

3.5 The purpose of this assessment is to evaluate the clinical and cost effectiveness of using ELISA kits (LISA‑TRACKER, IDKmonitor and Promonitor) to test levels of TNF‑alpha inhibitors and antibodies to TNF‑alpha inhibitors in people with Crohn's disease:

  • whose disease responds to treatment with a TNF‑alpha inhibitor

  • whose disease loses response to maintenance treatment with a TNF‑alpha inhibitor.

The condition

3.6 Crohn's disease is a chronic inflammatory disease that affects the gastrointestinal tract, most commonly the large intestine or the last section of the small intestine. The prevalence of Crohn's disease in the UK is estimated to be 157 per 100,000 population (Steed et al. 2010). The condition can affect people of all ages, but most develop it between the ages of 16 and 30 years. Many also develop it between the ages of 60 and 80 years. Although the cause of Crohn's disease is unknown, it is likely that a genetic predisposition, smoking and intercurrent infection increase the risk of it developing.

3.7 The clinical course of Crohn's disease is marked by relapses (when the disease flares up) and remission (when there are few or no signs or symptoms). During relapses, people can have diarrhoea, abdominal pain, fatigue and weight loss.

3.8 There is no cure for Crohn's disease, so treatment is directed at symptom relief. The 2 main aims of treatment are inducing remission (active treatment of acute disease) and maintaining remission (preventing relapse). Complications of Crohn's disease include:

  • Intestinal stricture: inflammation may cause scar tissue to form, resulting in a narrowing of the affected area of the intestine. This can cause an obstruction leading to pain and vomiting.

  • Perforation: stricture can cause rupture of the bowel resulting in infection.

  • Fistula: inflammation may cause an ulcer to develop in the lining of the gastrointestinal tract, which can deepen over time and become a channel to another hollow organ or the skin, known as a fistula.

  • Cancer: Crohn's disease is associated with a small increase in the risk of developing colorectal cancer in later life.

  • Osteoporosis: weakening of the bones because of poor absorption of nutrients from food and the use of steroid medication.

  • Problems with growth and development in children with Crohn's disease, because their bodies are not absorbing enough nutrients.

The diagnostic and care pathways

3.9 Treatments for Crohn's disease aim to reduce symptoms and maintain or improve quality of life, while minimising toxicity related to drugs over both the short and long term. Managing Crohn's disease in adults, young people and children is covered in the NICE pathway on Crohn's disease. The following NICE guidance was used to create the pathway:

3.10 The World Congress of Gastroenterology on Biological Therapy for IBD with the European Crohn's and Colitis Organisation produced the London Position Statement (published in the American Journal of Gastroenterology); a paper that provides support to clinicians on when to start and stop therapy, which drug to choose, and how to predict response to biological therapy. The paper states:

  • A diminished or suboptimal response to infliximab can be managed by:

    • shortening the interval between dosing

    • increasing the dose to 10 mg/kg.

  • A diminished or suboptimal response to adalimumab can be managed by weekly dosing (shortened from every other week).

  • Patients who continue to have a diminished or loss of response after increasing the dose may benefit from switching to a different TNF‑alpha inhibitor.

  • When TNF‑alpha inhibitors fail, switching treatment to an agent with a different mechanism of action is logical.

3.11 Tests for the therapeutic monitoring of TNF‑alpha inhibitors and antibodies to TNF‑alpha inhibitors may be done in 2 ways:

  • Concurrent testing: tests for TNF‑alpha‑inhibitor drug levels and antibodies to TNF‑alpha inhibitors are done at the same time.

  • Reflex testing: the test for TNF‑alpha‑inhibitor drug levels is done first and the result used to guide follow‑up testing by the laboratory without a further request from the treating clinician. If the drug is undetectable, testing for antibodies to the TNF‑alpha inhibitor would be done. If TNF‑alpha inhibitor is present in the sample, then testing for antibodies would not be done.

  • National Institute for Health and Care Excellence (NICE)