The goal of treatment for inflammatory bowel disease is to improve and maintain patients’ general well-being.
Treat acute disease:
- Eliminate symptoms and minimize side effects and long-term adverse effects
- Reduce intestinal inflammation and if possible heal the mucosa
- Maintain corticosteroid-free remissions (decreasing the frequency and severity of recurrences and reliance on corticosteroids)
- Prevent complications, hospitalization, and surgery
- Maintain good nutritional status
Drugs in IBD management
Aminosalicylates — anti-inflammatory agents
This group includes:
- 5-aminosalicylic acid (5-ASA),
- mesalazine (U.S. Adopted Name mesalamine).
Useful both for treating colitis flare-ups and maintenance of remission.
Data on 5-ASA in CD remain limited
In patients with mild ileocecal or right-sided colonic CD who decline or cannot tolerate corticosteroids, or in whom corticosteroids are contraindicated, 5-ASA should be considered for a first presentation or a single inflammatory exacerbation in a 12-month period.
Do not offer 5-ASA for moderate to severe CD or exacerbations or for extensive small-bowel disease or disease with penetrating or fibrostenosing complications.
In CD, sulfasalazine and mesalazine/mesalamine are presumed to be mainly effective in disease affecting the colon. However, this has not been specifically studied.
Patients receiving sulfasalazine should take folic acid.
It is important to use adequate doses: 2.0–4.8 g/day for active disease, ≥ 2 g/day for maintenance. However, the evidence for a dose-response effect for 5-ASA beyond 2 g/day is weak.
These usually provide significant suppression of inflammation and rapid relief of symptoms.
Corticosteroids induce remission in patients with a first presentation or a single inflammatory exacerbation of CD within a 12-month period.
They have no role in the maintenance of remission.
Side effects limit (long-term) use.
Concurrent use of calcium and vitamin D is recommended, as well as monitoring of blood glucose and arterial blood pressure.
In patients with distal ileal, ileocecal, or right-sided CD who decline or cannot tolerate corticosteroids, or in whom they are contraindicated, budesonide should be considered for a first presentation or a single inflammatory exacerbation within a 12-month period.
Budesonide may have fewer side effects than conventional corticosteroids.
Do not offer budesonide for severe CD or exacerbations.
The route of administration depends on the location and severity of the disease:
- Intravenous (methylprednisolone, hydrocortisone).
- Oral (prednisone, prednisolone, budesonide, dexamethasone).
- Rectal (enema, foam preparations, suppository).
Immune modifiers — Thiopurines
Thiopurines are no more effective than placebo for inducing remission of CD or UC; they are effective for maintenance of remission induced by corticosteroids.
Do not offer azathioprine or mercaptopurine for CD or UC if thiopurine methyltransferase activity (TPMT) is deficient. Use at a lower dose if TPMT activity is below normal.
If TPMT measurement is not available, the thiopurine dose should be escalated from 50 mg to the full dose while monitoring the blood count. Asians appear to require lower doses of thiopurine to achieve efficacy, and the full dosage is usually limited by the development of cytopenia.
The addition of azathioprine or mercaptopurine to conventional corticosteroids or budesonide should be considered, in order to induce remission of CD if there are two or more inflammatory exacerbations within a 1-year period, or if the corticosteroid dose cannot be tapered and eliminated. It may also be considered if there are predictors of poor outcome even at the time of diagnosis (age < 40, corticosteroids for first flare, perianal disease, smoking, perforating phenotypes).
Thiopurines are associated with low rates of serious infection, but should be monitored more closely in the elderly.
Thiopurines increase the risk of lymphoma, although the extent of the increase is debated. Their use is also associated with an increased risk of non melanoma skin cancer.
Thiopurines in particular are associated with macrophage activation syndrome (MAS), most likely by promoting viral reactivation through inhibition of natural killer and cytotoxic T cells.
Patients should be monitored for neutropenia if they are taking azathioprine or mercaptopurine, even if TPMT enzyme levels are normal.
Azathioprine is used in resource-poor countries in patients with CD and UC because it is cheap, available, and appears to be safe. Patients often cannot afford 5-ASA and use corticosteroids, and present with severe complications; azathioprine is a better choice than corticosteroids.
Thiopurine metabolite tests are not available in many countries, but where available can help explain the lack of response.
Immune modifiers — calcineurin inhibitors
Cyclosporine A (CSA) or tacrolimus in UC and tacrolimus in CD.
The tacrolimus level should be measured and a trough of 10–15 ng/L should be aimed for.
Use of CSA is limited to acute (corticosteroid-refractory) severe colitis.
Calcineurin inhibitors are reserved for special circumstances.
Use of CSA is limited almost exclusively to patients with acute severe colitis.
Use of tacrolimus in UC or CD in which other proven therapies have failed.
Calcineurin inhibitors should be discontinued within 6 months to limit nephrotoxicity, and alternative immunosuppressives such as azathioprine (AZA), 6-mercaptopurine (6-MP), or methotrexate (MTX) will therefore be required if CSA is being considered.
There is a high colectomy rate 12 months after the introduction of CSA.
After intravenous CSA, there should be a switch to oral therapy when a clinical response is achieved, and 6-MP, AZA, or MTX should be added.
Immune modifiers — methotrexate (MTX) in CD
Methotrexate is more effective than placebo for induction of remission of CD and for maintenance of remission induced by corticosteroids.
The addition of methotrexate to conventional corticosteroids or budesonide should be considered in order to induce remission of CD if patients cannot tolerate azathioprine or mercaptopurine, or in patients in whom TPMT activity is deficient if there are two or more inflammatory exacerbations within a 1-year period, or if the corticosteroid dose cannot be tapered.
Methotrexate should only be considered in order to maintain remission of CD in patients who needed methotrexate to induce remission, or who cannot tolerate or have contraindications to azathioprine or mercaptopurine — MTX should also be avoided in young women because of pregnancy issues.
Methotrexate is a good option if concomitant therapy with an anti-TNF agent is undertaken. It has been shown to not have any advantage over placebo in inducing and maintaining remission in persons with CD who have received high-dose corticosteroids and an induction and maintenance regimen with infliximab over 1 year. However, co-administration with methotrexate can reduce antibody formation to anti-TNF therapy, and this will likely increase the sustained response to the anti-TNF. It is considered that the likelihood of increasing the risk for lymphoma with methotrexate as a single or combination therapy is less than when thiopurines are used. This risk is considered to be small.
Co-administration of folic acid is recommended.
Hepatotoxicity with methotrexate treatment for IBD is typically mild and reversible on stopping the drug. Patients should be monitored for hepatotoxicity at initiation and during treatment with methotrexate.
Immune modifiers: uses
Can be used to reduce or eliminate corticosteroid dependence in patients with IBD.
Can be used in selected patients with IBD when 5-ASAs and corticosteroids are either ineffective or only partly effective.
Can be used to maintain remission in CD and in UC when 5-ASAs fail.
Can be used in for primary treatment of fistulas.
Are alternative treatments for CD relapses after corticosteroid therapy.
Can be used in for corticosteroid dependence, to maintain remission and allow withdrawal of corticosteroids.
Either thiopurines or methotrexate can be used concurrently with biologic therapy to enhance effectiveness and reduce the likelihood of antibody formation.
Anti-tumor necrosis factor (anti-TNF) agents
This may be the first-line therapy in patients who present with aggressive disease and in those with perianal CD.
Infliximab, adalimumab, and certolizumab have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of moderate to severe CD when there is an inadequate response to standard medications.
Infliximab and adalimumab show a better clinical response and better remission and mucosal healing than placebo, with no increase in adverse effects.
Infliximab, adalimumab, and certolizumab are effective in maintaining remission of CD induced by anti-TNF agents.
Infliximab (IFX) is used for rescue therapy in corticosteroid-refractory severe UC.
The effects of intravenous IFX treatment last for approximately 8 weeks; regular scheduled dosing leads to better remission rates than episodic therapy. When there is a suboptimal response, the dosage can be increased from 5 mg/kg to 10 mg/kg, or the interval can be reduced. Other dosage adjustments can be tailored to drug levels. Adalimumab and certolizumab are administered subcutaneously every 2 and 4 weeks, respectively. In the case of adalimumab, dosing can be increased to weekly if there is a suboptimal response.
Concomitant administration of immunomodulatory agents reduces the risk of infliximab antibody development and the risk of infusion reactions. It may be useful when administered with other anti-TNF agents, but this has not been formally tested — there is a concern, though, about the use of combined therapy (thiopurines + anti-TNF) in young male patients, because of the increased risk of hepatosplenic T cell lymphoma.
Infliximab is the only proven therapy in the treatment of fistulas, on the basis of adequately powered randomized controlled trials. Adalimumab is also useful for fistulas, but these data are only available from subgroups in larger CD studies not specifically designed to assess the fistula response.
Infliximab treatment reduces hospitalization and surgery rates in patients with IBD. This significantly reduces the costs associated with the disease.
There is only a small increase in malignancy in anti-TNF users.
The risk of lymphoma is very low, but this remains a concern. Other cancers may be increased, especially nonmelanoma skin cancers and possibly melanoma.
Treatment of IBD with infliximab, adalimumab, certolizumab, and golimumab significantly increases the risk of opportunistic infections in comparison with placebo.
The risk of minor and serious infections is of concern. Anti-TNF agents are associated with low rates of serious infection, but they are associated with opportunistic infections, including Mycobacterium tuberculosis, histoplasmosis, coccidiomycosis, and listeriosis. There is an increased risk of reactivation of latent TB and of hepatitis B, which is endemic in many parts of the developing world.
If treatments fail or the patients become intolerant of one anti-TNF agent, a second anti-TNF agent can be effective.
In patients treated with infliximab, infliximab antibodies lead to a 2–6-fold increase in the risk of infusion reactions.
Therapeutic drug monitoring (which includes both measurement of circulating drug levels and also measurement of antibodies to the drug) is more widely available for infliximab than any other anti-TNF. It can help determine the cause of a secondary loss of response and may be adopted in dose reduction strategies.
Adhesion molecule antagonists
Vedolizumab (an antibody to alpha 4-beta 7) has recently been approved for the treatment of UC and CD and is effective at both inducing and maintaining remission. It has few side effects and no known risk for malignancy.
Metronidazole and ciprofloxacin are the most commonly used antibiotics in CD. Antibiotics are used to treat CD complications (perianal disease, fistulas, inflammatory mass, bacterial overgrowth in the setting of strictures).
There has never been an adequately sized randomized controlled trial proving the efficacy of metronidazole and/or ciprofloxacin in perineal fistulas, but these are typically first-line therapies. There is an increased risk for C. difficile–associated disease (CDAD), and patients presenting with a flare of diarrheal disease should be checked for C. difficile and other fecal pathogens.
There are no data showing that any antibiotics are effective in UC, but they are used in the setting of fulminant colitis.
IBD may be caused or aggravated by alterations in the gut flora.
While many patients may use probiotics, there is no evidence that they are effective in either UC or CD. VSL#3, which is a combination of eight probiotics, induces and maintains remission of UC, and may be as effective as 5-ASA.
However, no such benefit has been demonstrated for CD.
Symptomatic therapy and supplements
Antidiarrheals such as loperamide (Imodium) if colitis is not fulminant; cholestyramine if the patient has previously undergone ileal resection.
Analgesics such as acetaminophen, or even codeine if acetaminophen is insufficient. However, narcotic use should be avoided, as it is associated with increased mortality in patients with IBD.
Nutritional supplementation for those with malnutrition, or during periods of reduced oral intake.
Vitamin B12 replenishment for those with deficiency.
Vitamin D supplementation if the local area does not allow sun exposure for much of the year— and for patients on thiopurines who are using sunscreens.
Routine vitamin D and calcium supplementation for corticosteroid users.
Routine multivitamin supplementation for all.
For chronic iron-deficiency anemia, parenteral iron should be administered (either as weekly intramuscular shots or dosing with intravenous iron) if oral iron is not tolerated.
Surgery in CD
70–75% of CD patients require surgery at some point to relieve symptoms if drug treatment fails, or to correct complications although the incidence of surgery in CD is falling.
Surgery should be considered as an alternative to medical treatment early in the disease course for short-segment CD limited to the distal ileum.
Surgery is rarely curative in CD; the condition recurs frequently after surgery. However, surgery can lead to long-lasting remission in some patients with CD. After surgery, azathioprine and metronidazole should be considered for at least 3 months, as this has been shown to reduce recurrence.
Laparoscopic ileocecal resection has perioperative morbidity rates similar to or better than those with open surgery for treatment of CD. Convalescence is shorter with the laparoscopic approach, although the operating time is longer.
Balloon dilation may be useful in patients with a single stricture that is short, straight, and accessible by colonoscopy. It should be ensured that abdominal surgery is available to manage complications or failure of balloon dilation.
Surgical options are:
- Drainage of abscesses
- Segmental resection
- Bowel-sparing stricturoplasty
- Ileorectal or ileocolonic anastomosis
- Ileocolic resection
- Temporary diverting ileostomy/colostomy in severe perianal fistula
- Laparoscopic ileocecal resection
Surgery in UC
25–30% of UC patients may require surgery if medical treatment is not completely successful, or in the presence of dysplasia.
Surgical options are:
- Total proctocolectomy plus permanent ileostomy.
- Ileal pouch–anal anastomosis (IPAA).
- Segmental resection can be considered for localized neoplasms in the elderly, or in patients with extensive co morbidity.