Inflammatory Bowel Disease: Medical Management

Eric J. Dozois, MD
Assistant Professor of Surgery
Division of Colon and Rectal Surgery
Mayo Clinic College of Medicine
Rochester, Minnesota

Treating patients with inflammatory bowel disease (IBD) often requires both medical and surgical management.  Although most patients with IBD will be managed medically by gastroenterologists and other medical specialists, surgeons need to keep updated on current medical modalities and understand the rationale and potential side effects of these drugs.  A wide variety of therapy exists and new drugs are constantly being developed and evaluated in clinical trials.  Medical therapies include anti-inflammatory drugs, antibiotics, corticosteroids, immunosuppressives, and biotechnology medications. 

 Anti-Inflammatory Medications (5-Aminosalicylates)

Drugs that deliver 5-aminosalicylate (5-ASA) to the colon include; sulfasalazine, oral mesalamine (Pentasa, Asacol), rectal mesalamine (Rowasa), olsalazine, and balsalazide (Table 1).  Sulfasalazine, the first drug developed in this class, was designed to combine the anti-inflammatory properties of 5-ASA with the antibacterial property sulfapyridine for the treatment of rheumatoid arthritis. It was later found to be effective for UC and that it served as a pro-drug for the active ingredient 5-aminosalicylate.  In placebo controlled trials sulfasalazine was shown to be effective for inducing and maintaining remission in patients with mild to moderately active ulcerative colitis (1).  For patients with mild to moderately active CD, controlled trials of sulfasalazine have demonstrated only modest efficacy for inducing remission.  Drug associated toxicity occurs in up to 30% of patients treated with sulfasalazine and includes headache, epigastric pain, nausea, vomiting, and skin rash.  Sulfasalazine may be use during pregnancy and while breastfeeding.

Other 5-ASA drugs used to treat UC and CD include mesalamine, olsalazine and balsalazide.  These different preparations vary in formulation, dose, and site of delivery and are utilized based on clinical presentation (extent of disease and active versus maintenance therapy) (Table 1).  This group of drugs are better tolerated than sulfasalazine (2).  Olsalazine, balsalazide, and mesalamine may be used during pregnancy and while breast feeding.

Antibiotics

Antibiotics including vancomycin, metronidazole, ciprofloxacin, and tobramycin have been evaluated in controlled trials but have not demonstrated efficacy in patients with UC or active CD (3).  Controlled trials which utilized metronidazole for 3 months after ileal resection, demonstrated that the occurrence of severe endoscopic lesions could be delayed for up to one year in patients undergoing operation for Crohn’s disease (4).     

For fistulizing CD, uncontrolled studies have reported that metronidazole and ciprofloxacin may be effective, particularly in patients with perianal fistulas (5).  Antibiotic therapy is widely utilized for this treatment indication and is considered to be first line therapy.  Moreover, metronidazole 750-1500 mg daily and ciprofloxacin 1000mg daily are effective for inducing remission in patients with acute pouchitis following colectomy and ileal pouch –anal anastomosis for UC (6).  Ciprofloxacin appears to be better tolerated than metronidazole and may have better efficacy (7).  

Adverse reactions observed with metronidazole include paresthesias, peripheral neuropathy, a metallic taste, and intolerance to alcohol.  Adverse events observed with ciprofloxacin include photosensitivity, nausea, rash.  These drugs should not be used during pregnancy.    

Corticosteroids have been used to treat patients with active IBD for many years.  Several studies have been published that show its efficacy in both UC and CD (8, 9).  Pharmacologic studies have been conducted with corticosteroids in patients with IBD which can be used to guide route of administration and dosing.  Dose-response studies in patients with active ulcerative colitis demonstrated that prednisone at doses of 40 or 60 mg per day is more effective than prednisone 20 mg per day.  Patients with severely active UC and CD who fail to respond to oral corticosteroids require intravenous therapy to ensure adequate bioavailability.  Despite significant initial response rates, some patients will become steroid dependent to keep disease activity under control and a number will fail and go on to require surgical intervention.  A recent retrospective study reported steroid dependancy in 28% and 22% of CD and UC patients respectively, and steroid resistance in 16% (10).  In this population-based study, the 1-year operation rate was 38% in CD patients and 29% in UC patients.   

Budesonide is a newer corticosteroid with 90% first pass metabolism in the liver. It can be administered orally as a controlled ileal release (CIR) formulation (release is pH dependent) or rectally as an enema.  A placebo controlled trial demonstrated that CIR budesonide is effective for inducing remission in patients with mild to moderately active Crohn's disease (11).  Comparative studies have demonstrated that oral CIR budesonide is more effective than mesalamine and equivalent to traditional oral corticosteroids for introducing remission in patients with active Crohn's disease (12).   

Adverse reactions occur frequently in patients treated with corticosteroids.  Short-term toxicities include moon face, acne, hypertension, hirsutism, striae, and psychosis.  Long-term toxicities include diabetes, increased risk of infection, osteonecrosis, osteoporosis, myopathy, cataracts, and glaucoma.  Corticosteroids may be used during pregnancy.  

Azathioprine is a pro-drug that is rapidly converted to 6-mercaptopurine (6MP) after administration.  Placebo controlled trials have demonstrated that azathioprine and 6MP are effective for inducing and maintaining remission in patients with CD and UC (13).  Though effective for steroid sparing in IBD, onset of action of azathioprine is delayed (up to 6 months) and will not ameliorate symptoms in the acute setting.  Placebo controlled trials and retrospective reviews have also demonstrated that azathioprine and 6MP are effective for inducing remission and closing fistulas in patients with active Crohn's disease (14, 15).  Most studies show a high recurrence rate of fistulae unless drug therapy is maintained continuously.   Toxic side effects frequently limit the use of azathioprine and 6MP.  

Adverse events that have been associated with azathioprine and 6MP include pancreatitis, bone marrow suppression, and drug hepatitis.  A causal link between azathioprine or 6MP, inflammatory bowel disease, and lymphoma has not been clearly established, but lymphoma may be a rare complication.  Azathioprine and 6-mercaptopurine can be administered in pregnancy in selected cases.  

When patients with IBD don’t respond to azathioprine or 6MP, or if these drugs are contraindicated, methotrexate may be used as an alternative.  Placebo controlled trials of methotrexate have shown effectiveness for inducing remission in patients with steroid dependent and steroid refractory UC and CD (16).  Trials have also demonstrated that methotrexate is effective for maintenance of remission and is steroid sparing in patients with Crohn's disease.  Although methotrexate is general well tolerated in low doses, serious toxicity limits its use.   

The adverse events include rash, mucositis, diarrhea, bone marrow suppression, hypersensitivity pneumonitis, and hepatic fibrosis or cirrhosis.   Methotrexate is contraindicated in pregnant patients.  

Cyclosporine, thought to work by blocking lymphocytes, can be effective in the treatment of patients with severe UC who are hospitalized and otherwise in need of urgent proctocolectomy.  Cyclosporine is usually added to a patient’s medical regimen after they have failed to improve on high dose steroids for 7 – 10 days. Controlled trials of intravenous cyclosporine administered as a continuous infusion demonstrated efficacy for inducing remission in patients with severely active, steroid refractory ulcerative colitis (17).  Tacrolimus, a related compound has demonstrated efficacy for fistulizing Crohn’s disease (18).  

Adverse reactions related to cyclosporine and tacrolimus include tremor, paresthesias, seizures, hypertrichosis, gingival hyperplasia, renal insufficiency, hepatotoxicity.  Although not absolutely contraindicated, cyclosporine and tacrolimus should generally be avoided in pregnant patients.  

Infliximab is a chimeric monoclonal antibody directed toward tumor necrosis factor alpha.  Its mechanism of action is incompletely understood but its effectiveness suggests that TNF may play a pivotal role among regulatory peptides associated with IBD (19).  Controlled trials have demonstrated that infliximab administered 1-3 times over six weeks as an intravenous infusion is effective for inducing remission and closing fistulas in patients with active Crohn's disease (20).  For patients who have a response to induction therapy with infliximab, re-treatment every 8 weeks is effective for maintenance of remission in Crohn’s disease and is steroid sparing.  

Treatment of ulcerative colitis with infliximab has been recently evaluated.  Two randomized, double-blind, placebo controlled studies have been published in which patients with moderate-to-severe active UC were treated with infliximab.  In these studies, patients receiving infliximab were significantly more likely to have a clinical response and be in clinical remission at 8, 30, and 54 weeks than those treated with placebo (21).  Several criticisms of this study have been noted including; a high number of patients receiving placebo had an improved clinical response, and that a number of serious infections, lupus-like reactions, and neurologic complications were seen in patients receiving infliximab.  

Several important questions remain to be addressed as to the most appropriate use of infliximab in treating patients with IBD.  It is a costly drug, it requires maintenance therapy to be effective, it has a high rate of anti-body formation, patients appear to have a dose-dependant increased risk of malignancy, and adverse events can be significant, including tuberculosis, histoplasmosis and sepsis which leads to death in some patients (19).  

The adverse events that may occur with infliximab therapy include formation of human anti-chimeric antibodies, infusion reactions, delayed hypersensitivity reactions, auto-antibody formation, drug-induced lupus, infection (particular tuberculosis and fungal infections such as histoplasmosis), and possibly non-Hodgkin's lymphoma.    

INVESTIGATIONAL AGENTS

            Advances in the understanding of the pathophysiology of IBD have led to a great interest in the evaluation of new therapeutic agents with novel actions (such as probiotic mixtures and fish oil).  In the near future we will likely be hearing more about the cytokine network, the central role of macrophage-produced interleukin-12 and strategies to block recruitment of leukocytes to the site of mucosal inflammation.    

Induction of Remission

Sulfasalazine, oral mesalamine, olsalazine, and balsalazide are effective for inducing remission in patients with active extensive or pan colonic ulcerative colitis.  Patients with active ulcerative colitis, ulcerative proctosigmoiditis, or left sided ulcerative colitis maybe treated with rectal mesalamine enemas or suppositories, or corticosteroid enemas, or with the oral therapies outlined above for extensive and pan colonic ulcerative colitis, or in combination of oral and rectal therapy.  For patients who have disease that is moderate to severe and in patients who have failed sulfasalazine, oral rectal mesalamine, olsalazine, or balsalazide, the next step is second line therapy with prednisone.  Patients with moderately active disease can receive oral prednisone as an outpatient.  Patients with persistent symptoms may require Azathioprine, or 6-mercaptopurine, but both are of limited utility as induction agents in patients with significantly active UC because of their slow onset of action.  Methotrexate is not effective for ulcerative colitis and infliximab remains under investigation.   

Maintenance of Remission

Sulfasalazine, oral mesalamine, olsalazine, and balsalazide are effective for maintaining remission in patients with extensive colonic disease.  Patients with ulcerative proctitis, ulcerative proctosigmoiditis, or left sided ulcerative colitis can receive maintenance treatment with rectal mesalamine enemas or suppositories, or with the oral therapies outlined above for extensive and pan colonic disease.  Azathioprine and 6 mercaptopurine are effective for maintenance of remission, particularly steroid induced remission, and for steroid sparing.     

TREATMENT STRATEGIES FOR CROHN’S DISEASE

Induction of Remission

Sulfasalazine is modestly effective for inducing remission in patients with active Crohn’s disease, with the benefit confined largely to patients with Crohn’s colitis and ileocolitis.  Mesalamine and metronidazole are not consistently effective for inducing remission.  Budesonide is more effective than mesalamine and similarly effective but safer than prednisone. Thus, budesonide is the first line treatment of choice for inducing remission in patients with mild to moderately active Crohn’s disease involving the terminal ileum or right colon, whereas sulfasalazine is the optimal first line therapy in patients with Crohn’s colitis.   

For patients who have disease that is moderate to severe, and in patients who have failed budesonide or sulfasalazine, the next step is second line therapy with prednisone.  Patients with moderately active disease can receive oral prednisone as an outpatient, whereas patients who are more severely ill should be hospitalized for intravenous corticosteroid therapy.  Azathioprine, 6-mercaptopurine, and methotrexate are of limited utility as induction agents in patients with significantly active Crohn’s disease because of their slow onset of action.  Infliximab is effective for the treatment of active Crohn’s disease in patients who are refractory to other therapies.  Concomitant immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate is required to suppress the formation of human anti-chimeric antibodies against infliximab. 

Maintenance of Remission:

Azathioprine, 6-mercaptopurine, and methotrexate are effective for maintenance of remission, particularly steroid induced remission.  Infliximab is effective for maintenance of remission in patients who are refractory to other therapies.     

Postoperative Maintenance of Remission:

Metronidazole 20 mg/kg for 3 months reduces recurrence of severe endoscopic lesions at 3 months but does not alter clinical recurrence at one year, and side effects are common.  Azathioprine and 6-mercaptopurine may be effective but there is limited clinical data.  In the absence of definitive data, these agents are currently the treatment of choice in patients who are deemed to be at “high risk” for recurrence.     

Closure of Fistulas and Maintenance of Fistula Closure:

Antibiotics may be effective for fistula closure, but a placebo-controlled trial has never been performed.  Similarly, azathioprine and 6-mercaptopurine may be effective for this treatment indication, but no controlled trials where fistula closure is the primary endpoint have been conducted.  A placebo- controlled trial of tacrolimus did demonstrate effectiveness for fistula closure in patients with refractory fistulizing Crohn’s disease.  Infliximab is effective for both inducing fistula closure and maintaining fistula closure.  Infliximab is the best evidence based therapy for fistulas at the present time. 

Table 1.  5-Aminosalicylate preparations

With permission by William J. Sandborn

Table 2.  Ulcerative colitis: indications for treatment  

  With permission by William J. Sandborn


Table 3.  Crohn’s disease: indications for treatment  

With permission by William J. Sandborn

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