Management of Crohn’s disease

Discuss Medical management of Crohn’s disease?

  • The severity of CD is more difficult to assess than UC. The general principles are to consider the site (ileal, ileocolic, colonic, other), pattern (inflammatory, stricturing, fistulating) and activity of the disease before treatment decisions are made in conjunction with the patient.
  • An alternative explanation for symptoms other than active disease should be considered (such as bacterial overgrowth, bile salt malabsorption, fibrotic strictures, dysmotility, gall stones) and disease activity confirmed (usually by CRP or ESR) before initiating.
  • Individuals with CD have many investigations over their lifetime and imaging (colonoscopy, small bowel radiology) should not be repeated unless it will alter management or a surgical decision depends on the result.

Discuss the management of active ileal/ileocolonic/colonic disease?

  • ASA
    • High dose mesalazine (4 g/daily) may be sufficient initial therapy. Sulphasalazine 4 g daily is effective for active colonic disease, but is not recommended as first line therapy in view of a high incidence of side effects. It may be appropriate in selected patients with joint symptoms. Sulphasalazine is not effective for small bowel disease.
    • Topical mesalazine is effective in left sided colonic CD.
    • Although some studies suggest that, for the treatment of acute CD, different 5-ASA formulations may be chosen, depending on the location of the disease, more research is needed to clarify this topic.
    • Response to ASA is seen within 4 weeks.
  • Steroids
    • For patients that have failed to respond to oral mesalazine, oral prednisolone 40 mg daily is appropriate. Up to 80 percent of patients respond within 10 to 14 days. The steroids are gradually tapered by 5 mg every week till they are discontinued.  More rapid reduction is associated with early relapse.
    • Budesonide 9 mg daily is appropriate for patients with isolated ileo-caecal disease. It is marginally less effective than prednisolone. (the authors use 9mg OD for 3 weeks, 6mg OD for 3 weeks and then 3 mg OD for 3 weeks)
    • Intravenous steroids (hydrocortisone 400 mg/day or methylprednisolone 60 mg/day) are appropriate for patients with severe disease. Concomitant IV metronidazole is often advised, because it may be difficult to distinguish between active disease and a septic complication.
  • Symptomatic treatment
    • In those patients not completely responding to first line therapy, symptomatic treatment with antidiarrheal agents should be considered.
    • Loperamide is the initial drug of choice because of its efficacy and safety.
    • Cholestyramine may also be considered in patients with ileal disease or a previous ileal resections for bile salt diarrhea. The initial dose of 4 g/day is increased as needed to 12 g/day in three divided doses.
    • For patients intolerant of cholestyramine because of dyspepsia, colestipol, a similar binding resin, is often a suitable alternative.
  • Other treatments
    • Nutrition therapy (see the relevant section)
    • Metronidazole (10–20 mg/kg/day) – is effective for CD. However, it is not recommended as first line therapy in view of the potential for side effects. It has a role in selected patients with colonic or treatment resistant disease.
    • Immunomodulators

Discuss the role of immunomodulators?

Immunomodulators are used to maintain remission. The immunomodulators used are the thiopurines – Azathioprine (AZA) or 6- mercaptopurine (6-MP)

When to consider the use of immunomodulators?
Thiopurines should be considered for patients:

  • Who require two or more corticosteroid courses within a calendar year;
  • those whose disease relapses as the dose of steroid is reduced below 15 mg;
  • relapse within 6 weeks of stopping steroid steroids; or
  • Post-operative prophylaxis of complex (fistulating or extensive) CD.

Discuss the effectiveness of immunomodulators?

About 40% to 50% of adults treated with high-dose AZA are able to sustain steroid-induced remissions. A similar story can be told for methotrexate (MTX).

How long to continue thiopurines?

In a prospective trial, 83 patients with CD who had been in remission for 3.5 years on AZA were randomised to continue AZA or placebo and followed for 18 months. Relapse rates were 21% and 8% in placebo and AZA groups respectively (p=0.0195). Practical advice for patients with either CD or UC who are started on AZA is to continue treatment for 3–4 years and then stop, except in those with evidence of continuing disease activity. For the 20% who relapse, AZA can be restarted and continued.

Which thiopurine (azathiopurine or mercaptopurine) is preferred?

No direct comparisons of the efficacy of AZA and MP in IBD exist. However, some patients who are intolerant of AZA (especially GI side effects) may tolerate MP.

Discuss the doses for thiopurines?

  • Aim for a maintenance dose of AZA of 2–2.5 mg/kg/day and 6-MP of 1–1.5 mg/kg/day in both UC and CD. The ‘‘maximum’’ dose will differ between individuals and effectively means that level at which leucopenia develops. The main role for thiopurines is steroid sparing (NNT=3)
  • 30% of patients started on steroids will have surgical resection in a year.  The need for steroid therapy identifies a group of patients who have more severe disease and who, because of the transient efficacy of corticosteroid therapy, go on to continued fibrosis and the need for surgical resection.
  • When patients are started on steroids, about 80% improve and go into remission over the first 4 weeks or so of steroid therapy. However, once the steroids are tapered, approximately 75% of patients either relapse or become steroid-dependent.
  • Once a patient is started on steroids, consideration should be given as to what to do next, as only about 20% to 25% of patients will be able to tolerate a short course of steroids and stay in a prolonged remission.

Discuss role of immunomodulators in induction of remission?

Immunomodulators can be used for induction of remission. However, its slow onset of action precludes its use as a sole therapy (grade A). A response to these medications will usually be seen within three to six months. During this period patients often require concomitant steroid therapy with a gradual reduction in the steroid dose after one to two months of treatment with azathioprine or 6-MP. The response rate to these medications is 60 to 70 percent in both small bowel and colonic disease.

Discuss the role of methotrexate?
Methotrexate (MTX) is effective for inducing remission or preventing relapse in CD.

  • Remission induction- Methotrexate is an alternative for remission induction for the patient who does not tolerate or is unresponsive to azathioprine or 6-MP. To guarantee bioavailability, the drug should be initiated intramuscularly at a dose of 25 mg per week and a response anticipated within three months. For those patients on steroid therapy, the drug should be continued during this period with a gradual lowering of the prednisone dose. Once a response to intramuscular methotrexate is achieved, the patient can be switched to oral methotrexate with an attempt to lower the dose gradually over several months.
  • Remission maintenance- Methotrexate (15–25 mg IM weekly) is effective for patients whose active disease has responded to IM methotrexate. It is appropriate for those intolerant of, or who have failed, azathioprine/mercaptopurine therapy once potential toxicity and other options, including surgery, have been discussed with the patient. Folic acid 5 mg once a week, taken 3 days after methotrexate, may reduce side effects. Subcutaneous or oral therapy may be effective.
    At present, the role of MTX is in the treatment of active or relapsing CD in those refractory to or intolerant of AZA or MP. Unlike rheumatoid arthritis, doses of <15 mg/week are ineffective for CD and 25 mg/week is standard. For practical reasons relating to the reconstitution of parenteral cytotoxic drugs, oral dosing is most convenient, although parenteral administration may be more effective. Subcutaneous administration may be reserved for patients with small intestinal CD who do not absorb oral MTX. Duration of therapy is debated. The 3 year remission rate for methotrexate in one series was 51%, which compares with data on azathioprine from the same centre (69% 3 year remission rate for azathioprine).

Discuss other options to maintain remission?

  • Smoking cessation is probably the most important factor in maintaining remission.
  • Mesalazine has limited benefit and is ineffective at doses less than 2 g/day, or for those who have needed steroids to induce remission. NNT of 21 i.e. to prevent one recurrence 21 patients need to be treated. A pharmacoeconomic assessment indicates that the cost of preventing each relapse can be $4000-10,000, which compares favourably with the average cost of treating a relapse.

Discuss postoperative recurrence?

  • Following resection and anastomosis, endoscopic signs of recurrence (Aphthous and serpiginous ulcers) may be present in 50-80% of patients within 1-3 years of surgery.
  • The post op recurrence rate is much lower in patients with Crohn’s colitis who undergo a total colectomy and ileostomy. Such patients have only a 10 percent recurrence rate in the small intestine at 10 years usually in the bowel immediately above the stoma.
  • Whether the endoscopic findings correlate with clinical course is uncertain. While some studies have found that endoscopic findings predicted symptomatic recurrence others have shown poor correlation between endoscopic and clinical recurrence.
  • Repeat surgery within 10 years is needed in almost 50% of patients after ileocolonic resection and anastomosis.
  • Risk factors for recurrence- smoking, fistulising disease, widespread disease.

Discuss prevention of postoperative recurrence?

  • For patients who smoke, cessation significantly reduces postoperative relapse.
  • Additional medical therapy should be considered after surgery, especially if disease has frequently relapsed prior to surgery, or after surgery for fistulating disease, or after a second operation.
  • Azathioprine or mercaptopurine should be considered in patients at high risk of recurrence. These include patients with jejuna or extensive ileo-colonic disease, patients whose initial Crohn’s presentation required surgery, fistulising disease, second resection and smokers
  • Mesalazine (>2 g/day) should be considered in patients with low risk of relapse. It lowers postoperative recurrence in small bowel disease but is ineffective after colonic resection. This regimen should be continued indefinitely. The risk of clinical recurrence may be significantly reduced by 5-ASA maintenance treatment in patients with surgically induced remission. However, the magnitude of the overall effect is small (reduces risk by 13% and NNT is 10). This combined with the excellent safety profile makes it a reasonable choice in low risk patients.

Discuss the options in difficult/refractory disease?

  • Chronic low dose steroids- Some pts can achieve a relative degree of remission only with low-dose prednisone. Such patients can be maintained on the lowest dose that is necessary for maintenance of decreased symptoms; alternate-day therapy can be tried for maintenance to minimize toxicity.
  • TPN or enteral feeding with an elemental or polymeric diet- There are, however, potential problems with bowel rest in addition to relapse when regular feedings are resumed. Many patients will not tolerate enteral feedings and long-term TPN is associated with side effects. Nevertheless, these nutritional approaches should be considered in refractory patients and can be lifesaving in those with short bowel syndrome.

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