THERAPY OF ULCERATIVE COLITIS AND CROHN'S DISEASE

THERAPY OF ULCERATIVE COLITIS AND CROHN'S DISEASE

• Although traditional drugs such as steroids, sulfasalazine, and 5-ASA compounds are the mainstays of the medical management of IBD, many other modalities and drugs are used, including the immunomodulator drugs (azathioprine and 6-mercaptopurine), immunosuppressives (cyclosporine and methotrexate), and the latest cytokine therapy.
  

Sulfasalazine and 5-Aminosalicylic Acid

• Sulfasalazine is composed of sulfapyridine linked to 5-ASA.
• It is poorly absorbed in the upper gastrointestinal tract and is degraded into its two components—sulfapyridine and 5-ASA—by colonic bacteria.
• 5-ASA is the active anti-inflammatory compound of sulfasalazine, whereas sulfapyridine acts only as the carrier for 5-ASA.
• It is the sulfapyridine moiety to which some patients have side effects and allergic reactions.
• Because of this, various 5-ASA compounds have been developed (mesalamine [Asacol, Rowasa]) that have been shown to be as effective as sulfasalazine but with reduced side effects.
• Both sulfasalzine and the various 5-ASA compounds inhibit the various products of the metabolism of arachidonic acid (prostaglandin G2, leukotriene B4, and thromboxane A2)—all known to play a major role in the inflammatory process in the intestinal mucosa.
• They also decrease the synthesis of other inflammatory cytokines (IL-1 and TNF-β) and inhibit the action of interferon.
• Sulfasalazine and 5-ASA enemas may be of benefit in limited colonic distal disease and proctitis.
• Foam preparations and suppositories are more effective than the liquid preparations due to the enhanced retention and absorption, but both can be used for distal disease.
• Mesalamine in the form of suppositories or enemas is the most effective agent in the treatment of distal UC, but its efficacy has not been proved in anorectal CD.
  

Sulfasalazine

• Sulfasalazine is the oldest and the least expensive 5-ASA compound in use.
• In a low dosage (1 to 2 g/day), it is used to maintain remission in patients with UC, whereas in a higher dosage (4 to 6 g/day), it can be used to treat active UC.
• In CD, the efficacy of sulfasalazine is less clear and depends on the site of the disease.
• Because sulfasalazine is cleaved into its active compounds in the colon, its use is limited to CD with ileocolonic or colonic involvement.
• It is of little known benefit in isolated small bowel disease.
• Side effects of sulfasalazine are common and include nausea, headaches, malaise, and vomiting.
• These side effects can be minimized or prevented by initiation of therapy with a relatively low dose and gradual increase in the dosage.
• Hypersensitivity reaction to sulfasalazine can cause rash, fever, hemolytic anemia, hepatic toxicity, and sperm abnormality.
• Should these side effects or hypersensitivity reactions occur, administration of the drug should be discontinued immediately.
  

Olsalazine

• Olsalazine (Dipentum) delivers intact 5-ASA to the terminal ileum, which is then cleaved by the colonic bacteria.
• Olsalazine has been shown to be of benefit in patients with active UC, but no therapeutic benefit has been shown in patients with mild to moderate attacks of CD.
  

Mesalamine

• Pentasa is one brand of mesalamine in which the 5-ASA is coated with ethyl cellulose that is gradually released from the small bowel to the colon.
• Mesalamine at dosages between 3 and 4 g/day has been shown to cause clinical improvement or remission in the mild to moderately active form of CD.
• At a dosage of 2.4 to 4.6 g/day, mesalamine has been beneficial in patients with UC and was found to be as effective as sulfasalazine in maintaining remission in patients with UC.
• In a comparison of medically with postoperatively induced remission in patients with CD, mesalamine has been shown to be more effective in preventing clinical relapse after surgical resection than after medically induced remission.
• In patients with mild to moderate UC, improvement can be achieved with 2 to 4 g/day of a 5-ASA compound.
• Once improvement has been achieved, mesalamine can be continued at the same dose to maintain remission.
• Mesalamine enemas at dosages of 1 to 4 g/day are effective in treating patients with distal UC, whereas patients with limited ulcerative proctitis can benefit from mesalamine suppositories at a dosage of 500 mg twice a day.
  

Steroids

• The benefit of corticosteroid therapy for UC was first reported by Truelove and Witts, and they are the most commonly used agents in the treatment of moderate to severe forms of IBD.
• Their mechanism of action is thought to be via prevention of the liberation of arachidonic acid from the membranes.
• Steroids also decrease neutrophilic phagocytosis and diminish adherence and chemotaxis of neutrophils, eosinophils, and monocytes.
• They inhibit the release of other inflammatory cytokines—mainly IL-1 and IL-2.
• The initial treatment in patients with moderate to severe UC is prednisone at 40 to 60 mg/day.
• In severely ill, hospitalized patients, initial therapy is 100 mg intravenous hydrocortisone three times daily.
• Steroids are also effective in the treatment of moderate to severe CD.
• Prednisone administered at dosages of 0.25 to 0.75 mg/kg/day to 85 patients with active CD resulted in remission in 60% of patients compared with a rate of only 30% in a placebo group.
• The systemic side effects of the traditional steroids in use have led to the development of more potent steroid formulations, which are more rapidly metabolized and offer the promise of being as effective as the traditional steroids with fewer systemic side effects.
• Similar to 5-ASA preparations, different packaging of these agents is available, which offers the possibility of drug delivery to the small bowel and the colon with minimum side effects.
• Budesonide is the most notable of these new steroids used in IBD, and favorable results were demonstrated in distal UC and in active CD.
• Steroids applied topically may be of benefit in patients with either limited distal disease or with rectal involvement along with more proximal disease.
• Steroid enemas or foams can be used for the treatment of active disease, but no role in maintenance therapy has been proved.
  

Antibiotics

• The results of clinical and experimental trials suggest that bacteria may play a role in the pathogenesis of Crohn's disease due to an unusual response of the mucosa to the intestinal flora, a breakdown in the normal mucosal barrier that allows micro-organisms to invade the intestinal mucosa, or even a specific bacteria such as Mycobacterium.
• Metronidazole is the most studied and used of the antibiotics.
• This drug is effective in patients with CD, particularly in those with perianal disease.
• However, when treatment with metronidazole is discontinued, relapse is common.
• Another antibiotic that has also been effective in CD is ciprofloxacin.
• Its maximum benefit is reached within 1 month and continues for at least an additional 5 months.
• Ciprofloxacin can be combined with metronidazole.
• Such combination therapy of metronidazole and ciprofloxacin in fistulous CD produced fistula healing in 3 of 14 patients and improvement in 9 of 14 patients after 3 months of therapy.
• When therapy was discontinued, most patients experienced a relapse, so continuous treatment may be necessary.
• Clarithromycin is another broad-spectrum antibiotic that may be effective in the eradication of micro-organisms at the center of the granulomas in CD.
• A trial with clarithromycin in patients with active CD, of whom many had been resistant to other forms of therapy, demonstrated impressive results.
  

Immunomodulators and Immunosuppressives

• Immunosuppressive agents are of routine use in the treatment of patients with refractory IBD.
• Their use is widely accepted in patients who are not candidates for surgery and in patients in whom steroid treatment has already caused significant adverse reactions.
• These drugs act by blocking the proliferation and activation of the T-helper lymphocytes, which play a major role in the inflammatory cascade through the production of various cytokines, of which the most important in IBD are IL-1, IL-2, IL-6, IL-8, TNF-β, and interferon-γ.
• In the case of Imuran, the therapeutic effects are not seen until after 3 to 4 months of treatment, a period that can sometimes be shortened by initial intravenous loading of the drug.
  

Cyclosporin A

• Cyclosporin A is a potent immunosuppressive drug that is used in organ transplantation as well as in patients with IBD, especially those with more severe or refractory disease.
• It acts via inhibition of the T-helper lymphocytes, thus inhibiting the production and liberation of the above-mentioned cytokines.
• Intravenous cyclosporin A has been shown to be effective in the short term in patients with severe cases of UC as well as CD.
• The major problem with the drug is that although short-term improvement may be achieved, long-term maintenance with the oral form of the drug produces excessive side effects.
• Side effects and toxicity of treatment with cyclosporin A include seizures, nephrotoxicity, hypertension, tremors, and headaches, which can occur in up to 60% of patients treated.[
  

Azathioprine and 6-Mercaptopurine

• Azathioprine (Imuran) and 6-mercaptopurine are purine analogue compounds used in the management of steroid-dependent IBD.
• They act either via inhibition of purine RNA synthesis and cell proliferation or via inhibition of natural killer cells and suppression of cytotoxic T-cell functions.
• These mechanisms of action likely explain the 3- to 4-month delay in the onset of their clinical effectiveness.
• Azathioprine and 6-mercaptopurine are both used in the management of patients with active CD and UC who have not responded to systemic steroids.
• In addition, both drugs have been successfully used as steroid-sparing agents in patients with IBD who are unable to be weaned from steroid therapy.
• Furthermore, as maintenance therapy, both drugs have been shown to be effective in UC as well as in CD.
  
• Among the side effects of azathioprine and 6-mercaptopurine are pancreatitis, which occurs in 3 to 5% of patients, usually presents within the first 6 weeks of therapy, and resolves promptly when the drug is withdrawn.
  

Methotrexate

• Methotrexate acts via impairment of DNA synthesis and reduction in IL-1.
• A multicenter, placebo-controlled trial with 141 patients with active CD confirmed that methotrexate at a dosage of 25 mg administered intramuscularly or subcutaneously once a week, over 16 weeks, allowed steroid tapering and maintenance of remission in 39% of patients treated compared with 19% in those receiving placebo.
• Potential side effects of methotrexate include
• leukopenia and
• hepatic fibrosis, necessitating routine monitoring of blood count and liver function.
  

Cytokine Therapy
In the discussion of the cause and pathogenesis of IBD, the role of cytokines was mentioned. Based on these findings, a rationale for treatment with cytokines was defined, and the number of trials in which the efficacy of cytokine therapy is investigated is rapidly increasing. The effect of cytokine therapy is achieved either through the administration of anti-inflammatory cytokines (IL-4, IL-10, or TGF-β) or through the inhibition of proinflammatory cytokines (IL-1 and TNF).

• Patients with steroid refractory UC who were treated with IL-10 enemas showed clinical improvement.
• When rats with experimental colitis received an expression vector carrying the TGFp cDNA, the colitis was alleviated, suggesting that this therapy for IBD patients merits further investigation.
• IL-1, one of the anti-inflammatory cytokines, may be inhibited in one of three ways:
• with an IL-1 receptor antagonist,
• with soluble IL-1 receptors, or
• with IL-1-specific monoclonal antibodies.
• However, most of the studies were performed on mice, and beneficial effects were not demonstrated.
  

As early as 1995, Van Dullemen et al. showed that the use of anti-TNF antibodies (infliximab [Remicade]) decreased the Crohn's Disease Activity Index score while producing an improvement in the colonoscopic findings in patients with CD.

• A similar randomized, placebo-controlled trial in another population of CD patients showed that a single infusion of infliximab induced a clinical response in 81% of patients and clinical remission in 48%.
• Retreatment of those patients with infliximab every 8 weeks maintained a clinical benefit in nearly all patients throughout the treatment period and 8 weeks after the last infusion.
• In another study of patients with active CD who were treated with infliximab, a response rate was achieved in 82% and closure of fistulas occurred in 68%.
• The consistent benefit of infliximab treatment in patients with moderate to severe active CD and in patients with fistulas was further shown in other studies.
• The treatment with infliximab in another placebo-controlled trial of patients with fistulous CD showed a reduction by more than 50% from baseline in the number of draining fistulas.
• The second stated end point was the closure of all fistulas, and 55% of the patients receiving infliximab had closure of all fistulas.
  

Another cytokine used in the treatment of IBD is interferon.

• Interferon-α has been used in several trials of CD and UC patients.
• Clinical results were impressive in patients with UC but only moderate in patients with CD.

Although the newer agents seem to have great potential, many questions must be answered before cytokines can be considered standard treatment for IBD. Their longer-term efficacy as well as the complications produced must be further assessed.