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Monday 20 May 2019
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Managing Crohn’s disease

Practical therapeutics

Daniel Greer, BPharm, Msc
Pharmacist Lecturer/Practitioner, University 
of Leeds/Leeds Teaching Hospitals, UK

Crohn's disease is one of the two major forms of inflammatory bowel disease – the other being ulcerative colitis. Both are chronic relapsing inflammatory conditions of the gut.

Crohn's disease is a disease of young people, with a peak incidence between the ages of 10 and 40 years. The incidence in westernised countries is between 5–10 per 100,000, with a prevalence of 50–100 per 100,000 population. There is some evidence that the incidence of Crohn's disease may be higher in northern Europe than southern Europe. The exact aetiology of Crohn's disease is unknown, but it is thought to occur in response to environmental triggers in genetically susceptible individuals.

The major clinical features of Crohn's disease are diarrhoea, abdominal pain and weight loss, though the predominant symptoms vary according to severity and location of the disease. Crohn's disease may occur anywhere along the gastrointestinal tract, but the most common location is ileocaecal. The pattern of disease may also vary, with inflammatory, stricturing or fistulising disease possible. Extra-intestinal manifestations of Crohn's can affect the eyes, joints, skin and liver.

Both medical and surgical therapies for Crohn's disease are available; however, surgery is not curative and there is a risk of recurrence. Half of patients with Crohn's disease will have surgery within 10 years of diagnosis, rising to 70–80% over a lifetime. Surgery is therefore conservative where possible.

The main aim of medical therapy is to induce and maintain remission. Choice of therapy will depend on severity, location and pattern of disease, and response to prior therapy.  

Traditionally, there has been a stepwise approach, moving from aminosalicylates, through immunosuppressants to biological therapy, using steroids to control acute flare-ups of the disease.  However, with the ability to predict at diagnosis those patients who are likely to have poor outcomes, there is an evolving paradigm in which immunosuppressants and biological therapy are considered at a much earlier stage in these patients – such as those presenting at a young age, with extensive disease, requiring initial treatment with steroids, or with perianal disease.1

Aminosalicylates
Aminosalicylates are available in a variety of formulations, with the aim of delivering mesalazine to the gut epithelial surface. Oral formulations include pH-dependant release (for example Asacol®, Mesren®, Salofalk®, Ipocol®), time-controlled release (Pentasa®), or delivery by carrier molecules with release of mesalazine after lysis by bacterial enzymes in the colon (for example olsalazine, sulphasalazine, balsalazide).

There is little clinical evidence that the choice of delivery system matters, but it is logical to choose a form that will release mesalazine at the known site of disease.

Although aminosalicylates are widely used in Crohn's disease, the evidence for their efficacy is weak. In active ileocolitis, although a meta-analysis of Pentasa showed a statistically significant benefit,2 the mean difference of 18 points in Crohn's disease activity index (CDAI) 
is of questionable clinical significance.  

Sulphasalazine is of some benefit 
in colonic disease and is suggested 
as option for mild colonic disease in European guidelines.1

For maintaining remission, a Cochrane review of mesalazine use after medically induced remission found no benefit over placebo.4 Another meta-analysis5 found that there was a benefit after surgically induced remission. European guidelines suggest a role for high doses of mesalazine (4g) after ileal resection.6

Mesalazine is generally well tolerated, with gastrointestinal side effects (nausea, diarrhoea) most commonly reported. Renal impairment is rare and although the summary of product characteristics for mesalazine preparations suggest regular renal function tests, this is probably only necessary for those with pre-existing renal impairment, concomitant use of nephrotoxic drugs or co-morbid disease Agranulocytosis may occur rarely and patients should be advised to report any unexplained bleeding, bruising, purpura, sore throat, fever or malaise during treatment. A blood count should be checked if there is any suspicion of blood dyscrasia.

Sulphasalazine is less well tolerated than mesalazine, principally because of the sulfapyridine carrier. Oligospermia (60%) is a common but reversible side effect in males. Patients should also be warned of discoloration of body fluids (orange), which may affect contact lenses.

Corticosteroids
The role for steroids is to treat active disease, with the choice of steroids depending on severity and disease location. Two major trials support the 
use of systemic corticosteroids with a number needed to treat (NNT) of 2–3 
for inducing remission.7,8

An alternative is enteric-coated budesonide, a corticosteroid with limited bioavailability and extensive first-pass metabolism. Release is targeted to the terminal ileum and proximal colon. It is better tolerated than prednisolone, but it is less effective.9

The principal role for budesonide is therefore for mild ileocaecal disease, with more severe disease requiring systemic steroids by the oral or intravenous route. Steroid regimes are tapered to reduce the risk of relapse and to prevent adrenal insufficiency. Tapering regimes vary, but UK guidelines advise a course of eight weeks.3 There is no evidence to support 
the use of steroids to maintain remission and neither UK nor European guidelines support such use.1,3

Side effects of steroids are divided into early and late effects. Acute effects include acne, oedema, skin striae (Cushing's syndrome), sleep and mood disturbance, dyspepsia and glucose intolerance. Hydrocortisone also has significant mineralocorticoid side effects resulting in sodium and water retention and potassium loss.

Effects associated with longer-term use (>12 weeks) include osteoporosis, osteonecrosis of the femoral head, 
muscle wasting and susceptibility to infection. Patients should be informed 
to reduce doses gradually and to report signs of infection promptly. Repeated course of steroids indicate the need to step up treatment.

As patients with Crohn's are inherently at greater risk of osteoporosis, UK guidelines suggest co-prescription of calcium and vitamin D while on steroids, with a bisphosphonate for those aged over 65. It is recommended that patients younger than 65 receiving steroids for more than three months receive a DEXA scan, with consideration of bisphophonates if the T-score is less than -1.5.10

Thiopurines
Azathioprine (2–2.5mg/kg) and mercaptopurine (1–1.5mg/kg) are considered equivalent for Crohn's disease, as azathioprine is metabolised to mercaptopurine, though the majority of evidence is for azathioprine. Both are unlicensed in inflammatory bowel disease. The onset of action of thiopurines is 2–3 months, making them unsuitable for sole use in acute disease. For maintenance, a Cochrane review11 found a NNT of six for maintaining remission and an NNT of three for a steroid-sparing effect.

Traditionally, the role of thiopurines has been viewed as steroid-sparing, with UK guidelines suggesting that thiopurines should be considered for patients who:

  • Have  a severe relapse or frequently relapsing disease
  • Require two or more corticosteroid courses per year
  • Whose disease relapses as steroids 
are reduced or recently stopped.3

However, in view of the poor 
evidence for mesalazine in maintaining remission, there is an increasing tendency to start azathioprine earlier 
in the course of the disease. 

Side effects of azathioprine are common, with 10–20% of patients unable to tolerate it. Patients who do not tolerate azathioprine may be able to tolerate mercaptopurine. Early side effects include nausea and flu-like effects (headache, myalgia, diarrhoea).

Idiosyncratic side effects include myelosupression, pancreatitis, and hepatotoxicity, hence regular monitoring of full blood count and liver function tests are recommended. Some centres measure thiopurine methyl transferase (TPMT), an enzyme that metabolises azathioprine, for which there is genetic variation, though there is no clear evidence that this predicts the likelihood of myelosuppresssion. 

Patients should be warned to report signs of infection promptly and signs of liver/pancreatic disease such as abdominal pain, dark urine, or yellowing of the skin.

There may be an increased risk of lymphoma and skin cancer, though a definitive answer is lacking because the risk is, at best, small and much of the literature comes from other disease states with multiple-agent immunosuppression. Patients should be advised to use sunblock, and minimise sun exposure in line with advice for preventing skin cancer in the general population.

Methotrexate
Methotrexate is an alternative immunosuppressant for Crohn's disease, principally in those intolerant or refractory to thiopurines. There is less evidence than for thiopurines, with a single successful randomised controlled trial of 25mg once weekly intramuscular methotrexate for active disease (39% remission vs 19% placebo after 16 weeks) followed by a randomised controlled trial of 15mg once weekly by the same route in patients who achieved remission with 25mg (65% remission versus 39% placebo at 40 weeks).12,13

Oral and subcutaneous routes are more commonly used, though variability in absorption in patients with Crohn's, and lack of evidence for the oral route, means that careful monitoring of clinical response is needed if the oral route is chosen.

Side effects of methotrexate include gastrointestinal side effects, and the administration of folic acid 5mg on non-methotrexate days may reduce 
this. Important long-term side effects include myelosuppression, hepatotoxicity and pneumonitis.

As with thiopurines, regular monitoring of full blood counts and liver function tests is advised, as well as warning patients to report signs of infection or liver disease promptly. A baseline chest X-ray is recommended and patients should be advised to report any signs of progressive breathlessness.

Anti-TNF agents
Infliximab and adalimumab are licensed for severe Crohn's disease where treatment with corticosteroids and/or immunomodulators has failed or where there is intolerance or contraindications to these agents. Infliximab is also licensed for fistulising Crohn's disease where standard therapy has failed.

Recent UK guidance from NICE supports the use of these agents, stating that both are clinically and cost-effective for Crohn's disease, though the guidance recommends review after one year with consideration of withdrawal if patients are in full remission.14 Although no head-to-head studies have been conducted, they are considered to be broadly similar in effectiveness.

Choice is based on indication, availability, patient preference, cost and national guidance. If patients are intolerant or lose response to infliximab, adalimumab may be effective, although the response and remission rates to a second anti-TNF agent are lower. A third anti-TNF agent certolizumab is only licensed in Switzerland, the European Medicines Agency having rejected the application for Europe-wide use.

Initially, these agents tended to be used after failure of immunosuppressants or in patients with acute severe disease who failed to respond to steroids and whose disease activity meant it was inappropriate to wait for the delayed effect of thiopurines. However, the recently published SONIC study15 found that in immunosuppressant-naïve patients infliximab is more effective 
than azathioprine (44% versus 30% remission at 26 weeks), with the result that biological therapy is beginning to 
be considered earlier in patients with severe disease.

The principal risk with anti-TNF agents is infection. Prior to starting therapy, active or latent tuberculosis should be excluded. There have also been reports of re-activation of viral hepatitis, hence viral serology is also recommended prior to commencing therapy. Active sepsis is a contraindication for therapy, hence patients should be told to report any signs of infection.

Allergic reactions can occur, ranging from mild infusion reactions or injection site reactions to anaphylaxis. Other adverse reactions reported include nervous system effects (headache, vertigo, dizziness, demyelination), gastrointestinal effects (diarrhoea, abdominal pain, nausea), skin rashes, increased hepatic enzymes and development of auto-antibodies.

There may be an increased risk of lymphoma, but, as with thiopurines, the difficulty is differentiating the risk from concomitant immunosuppressants and disease severity. There have been reports of hepatosplenic T-cell lymphoma, mainly in combination with azathioprine. 

In light of this, there is some debate as to whether immunosuppressants should be continued when anti-TNF agents are started. In immunosuppressant-naïve patients in the SONIC study, the combination of azathioprine and infliximab was more effective than infliximab alone (57% versus 44% remission at 26 weeks); however, in those patients who are already receiving immunosuppressants the benefit is less clear. Concomitant use may reduce development of antibodies against infliximab and result in improved efficacy, but this data is derived from studies using episodic as opposed to regular maintenance therapy that is most commonly used.

Other agents
Patients with active disease are at increased risk of thromboembolism and should receive heparin thromboprophylaxis while hospitalised. Antibiotics such as ciprofloxacin and metronidazole are mainly used in septic complications and in perianal disease.

A range of other immunosuppressants including mycophenolate, thalidomide, tacrolimus and ciclosporin have been used in Crohn's disease, though data from randomised controlled trials to support these agents is lacking. They are sometimes considered on an individual patient basis when standard therapy has failed and further surgery is considered unsuitable.

Conclusion
There is a range of therapeutic agents 
for treating Crohn's disease, and choice 
is influenced by the balance between efficacy and side effects, as well as disease activity and location. It is important that patients are involved in this choice and pharmacists can play a valuable role in discussing the benefits and risks of pharmacotherapy as well as ensuring the safe ongoing use of these medicines.

References

  1. Dignass A et al. Journal of Crohn's and Colitis 2010;4:28-62.
  2. Hanauer S et al. Clin Gastroenterol Hepatol 2004;2:379-88.
  3. Mowat C et al. Gut 2011;60:571-607
  4. Akobeng A et al. Cochrane Database of Systematic Reviews 2005, Issue 1.
  5. Camma C et al. Gastroenterology 1997;113:1465-73.
  6. Van Assche G et al. Journal of Crohn's and Colitis 2010;4:63-101.
  7. Summers R et al. Gastroenterology 1979;77:847-69.
  8. Malchow H et al. Gastroenterology 1984;86:249-66.
  9. Seow CH et al. Cochrane Database of Systematic Reviews 2008, Issue 3.
  10. Lewis N et al. British Society of 
Gastroenterology 2007
  11. Prefontaine E et al. Cochrane Database of Systematic Reviews 2009, Issue 1.
  12. Feagan B et al. N Engl J Med 1995;332:292-97.
  13. Feagan B et al. N Engl J Med 2000;342:1627-32.
  14. NICE, 2010. www.nice.org
  15. Colombel J et al. N Engl J Med 2010;362:1383-95.

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