Frequently Asked Questions in 5-Aminosalicylate Therapy for Inflammatory Bowel Disease

At an industry-sponsored symposium held in conjunction with the American College of Gastroenterology’s 2002 Annual Scientific Meeting, a panel of experts discussed frequently asked questions about the use of 5-aminosalicylate (5-ASA) therapy in inflammatory bowel disease (IBD). Topics included selection of the initial 5-ASA regimen for treating active ulcerative colitis, maintaining remission with 5-ASA therapy, management options for refractory proctitis, and potential effects of IBD pharmacotherapy on pregnancy and breast-feeding.

This program was jointly sponsored by the University of Chicago Pritzker School of Medicine, the Crohn’s and Colitis Foundation
of America, and SynerMed Communications. This program was supported by an unrestricted educational grant from Procter & Gamble Pharmaceuticals, Inc.

This material represents a compilation from a series of industry-sponsored educational symposia presented October 18–23, 2002 in conjunction with the Annual Meeting of the American College of Gastroenterology. This compilation is provided for information and critical scrutiny by physician readers, and is not intended to replace clinical judgment by the physician as to a specific patient.

The proceedings arise from industry-sponsored sessions, not from the official ACG program, and this synopsis/compilation of these sessions does not represent the official viewpoint of the American College of Gastroenterology.

Choosing the Appropriate Initial Therapy
I have a 25-year-old male patient withnewly diagnosed moderate left-sided UC. Should I choose 5-ASA for treatment?

The severity and anatomic extent of the disease affects the selection of an appropriate initial therapy for ulcerative colitis (UC), explained William J. Sandborn, MD, Professor of Medicine at the Mayo Medical School, and Head of the Inflammatory Bowel Disease Interest Group at the Mayo Clinic in Rochester, Minnesota. Location of disease is particularly relevant in the selection of 5-aminosalicylates (5-ASA), because they are available in oral and topical preparations. Diseased mucosa beyond the splenic flexure cannot be reached reliably with rectal therapy; therefore, extensive or pancolonic UC typically are treated with oral medications. Moreover, because approximately 50% to 60% of UC patients have UC involving the left side of the colon (Farmer RG, et al. Dig Dis Sci. 1993; 38:1137), agents used to treat them should be able to reach the site of the disease.

Other factors affecting drug selection include efficacy, dose response profile, systemic absorption, toxicity, patient adherence, and cost.

Oral 5-ASA Delivery Systems
All of the oral aminosalicylates deliver 5-ASA to the colon. Pentasa® (mesala-mine), a sustained release formulation, releases throughout the gastrointestinal tract, and Asacol® (mesalamine), a pH-dependent delayed release drug, begins to release at pHŽ7 at the terminal ileum (Sandborn WJ, et al. Aliment Pharmacol Ther. 2003;17:29). The site of activation of the three azo-bonded agents, Colazal™ (balsalazide disodium), Dipentum® (olsalazine sodium), and sulfasalazine is the colon.

Efficacy and Dose Response of Oral 5-ASA Agents
Oral 5-ASA drugs are effective in treating extensive, left-sided, and distal disease (Hanauer S, et al. Am J Gastroenterol. 1993;88: 1188), with no clear differences in efficacy in the treatment of pancolitis, left-sided disease, proctosigmoiditis, and proctitis (Stein RB, et al. Gastroenterol Clin North Am. 1999; 28:297). Important differences in dosing do exist among these agents. Sulfasalazine is effective at doses of 2 to 6 g/day, with improved efficacy at >3g/day (Stein RB, et al. Gastroenterol Clin North Am. 1999;28: 297), but dose-related toxicity limits higher dosing (Stein RB, et al. Gastroenterol Clin North Am. 1999;28:297). Mesalamine is effective at doses of 1.5 to 4.8 g/day, with improved responses at >2 g/day and no dose-related toxicity up to 4.8 g/day (Stein RB, et al. Gastro-enterol Clin North Am. 1999;28:297).

The dose-ranging response of mesalamine can vary per drug. Pentasa® 2g and 4g show significantly greater remission and improvement rates compared with the 1g dose,2 whereas Asacol® exhibits a clear dose-ranging response from 1.6 g (Schroeder KW, et al. N Engl J Med. 1987;317:1625) through 4.8 g (Sninsky CA, et al. Ann Intern Med. 1991;115:350).

Oral 5-ASA Agents Have Comparable Systemic Absorption Profiles
An overview of multi-dose and pharmacokinetic studies involving healthy volunteers and patients with UC found that the rates of 24-hour urinary excretion of the free drug and its major metabolites were comparable for sulfasalazine (8%-37%), Asacol® (mesala-mine; 11%-40%), Pentasa® (mesalamine; 23%-36%), Colazal™ (balsalazide disodium; 12%-35%), and Dipentum® (olsalazine sodium; 5%-31%) (Sandborn W, et al. Aliment Pharmacol Ther. 2002. In press). Therefore, Dr. Sandborn concluded that the selection of an oral 5-ASA agent may be based on factors such as efficacy, dose response, toxicity of parent compound and its metabolites, adherence issues related to dosing, and cost.

Are Topical Therapies Effective in Treating Left-sided UC?
Topical therapies are more effective than placebo and may not exhibit a dose response, Dr. Sandborn observed, but data comparing topical and oral regimens are limited. He reported that he initially recommends oral therapy for most patients and prescribes rectal therapy if the patients do not respond. Alternatively, combinations of oral and rectal therapies, which provide a higher overall dose of 5-ASA, may be used for initial treatment.

Inducing and Maintaining Remission
In the previous case, the patient did not improve on mesalamine 2.4 g/day, so the dose was
escalated to 4.8 g/day, resulting in remission. How do you maintain remission in this patient?

The 5-aminosalicylate (5-ASA) agents exhibit dose-ranging responses in patients with ulcerative colitis (UC), reported Asher Kornbluth, MD, Associate Clinical Professor of Medicine at Mount Sinai Medical Center and School of Medicine in New York City. Dr. Kornbluth would recommend resuming the 4.8 g/day regimen in this patient to maintain remission.

The different 5-ASA agents show similar efficacy in inducing and maintaining remission in UC. A comprehensive meta-analysis of studies comparing sulfasalazine with Dipentum®, Asacol®, and Pentasa® in patients with UC demonstrated that these drugs were equally effective in maintaining remission at 6 months to 1 year (Figure 1) (Sutherland L, et al. Ann Intern Med. 1993;118:540).

The goals of maintenance therapy should include sustaining the patient’s quality of life. Dr. Kornbluth pointed out that, although the efficacy of the newer 5-ASA compounds is not superior to that of sulfasalazine, some physicians choose the newer drugs because these are perceived as having more favorable tolerability profiles. Further, maintenance therapy should involve prevention of complications related to disease and the treatment. Dr. Kornbluth cautioned against attempting to achieve remission with steroids, which can adversely affect the patient’s quality of life.

Management of Refractory Colitis

A thorough history and examination are critical for accurate diagnosis and treatment of patients with inflammatory bowel disease (IBD), noted Daniel H. Present, MD, Clinical Professor of Medicine at Mount Sinai School of Medicine and Attending Physician at the Mount Sinai Hospital in New York City. In patients with proctitis who do not respond to combination therapies, other disorders (eg, sexually transmitted diseases), should be ruled out first. For example, Dr. Present noted that the induction and maintenance of remission in IBD requires adequate drug delivery, with optimal dosing of
appropriate duration. Although the
5-aminosalicylate (5-ASA) compounds are comparable in efficacy, two studies have reported on differences in their dosing and potential toxicity (Schroeder KW, et al. N Engl J Med. 1987;317:1625; Sninsky CA, et al. Ann Intern Med. 1991;115:350).

Management Options for Refractory Colitis: Distal Ulcerative Colitis
Rectal mesalamine is effective in patients with distal ulcerative colitis (UC). High-dose mesalamine (4.8 g/day or higher) may be used for non-responding patients. Azathioprine and 6-mercaptopurine are effective in achieving and maintaining remission in steroid-dependent or steroid-refractory patients.

Colectomy, while unusual, should be considered only after all medical therapies have been exhausted, because “colectomy and ileoanal anastomoses in patients with distal proctitis have been reported to restore the patient’s quality of life,” Dr Present reported. Importantly, indications for colectomy do not depend on the extent of the disease.

Cigarette smoking in former smokers can induce remission in patients, but nicotine patches are not effective. Cyclosporine has been proposed as a management option, but Dr. Present advises against such an aggressive therapy for refractory proctitis unless all other measures have failed.

Best Approach to TreatingRefractory Proctitis
Dr. Present recommends the use of high-dose oral mesalamine (eg, 4.8 g/day) in combination with a topical 5-ASA agent. Non-responding patients should receive topical corticosteroids (2-3 times/day for 1 week), followed by immunomodulators. Finally, proctocolectomy, while rare, should be considered depending on the extent to which the patient’s quality of life has been adversely affected and the perceived prospect for a marked improvement by the surgery (Figure 1).

Anecdotal evidence indicates that lidocaine, heparin, and short-chain fatty acids may be effective in treating UC, but these findings have not been confirmed conclusively in placebo-controlled trials. Likewise, diverting ileostomy, initially proposed as a suitable alternative to colectomy, and cyclosporine enemas have not been convincingly demonstrated to be effective in treating refractory colitis.

Figure 1.
One approach to managing refractory colitis involves using a combination of oral high-dose mesalamine (eg, 4.8 g/day) and topical 5-ASA. Non-responders may require topical corticosteroids, followed by immunomodulators. Cigarette smoking, but not nicotine patches, also is effective in former smokers, and proctocolectomy may be considered after all medical options have been considered and if the patient’s quality of life remains severely compromised.

Best Approach to Refractory Proctitis
• Maximize combinations of oral (to 4.8 g/d) and topical 5–ASAs
• In non-responders
   – Add topical corticosteroids
   – Add immunomodulator
   – Nicotine patches (smoking)
• Consider proctocolectomy but ONLY for patients with poor quality of life despite medical therapy

Management of IBD in Pregnancy
A 26-year-old woman has a history of steroid-dependent Crohn’s disease (ileocolitis) but has now been in clinical remission for 6 months on azathioprine alone. She now wants to conceive. How do you counsel her?

Approximately 75% of women with inactive Crohn’s disease (CD) at the time of conception remain in remission during their pregnancy (Miller J. J R Soc Med. 1986;79:221), reported Sunanda V. Kane, MD, MSPH, Assistant Professor of Medicine at the University of Chicago Pritzker School of Medicine in Chicago, Illinois. This patient would not be at increased risk for disease activity compared with a non-pregnant woman, Dr. Kane explained. However, there is some evidence that patients with active CD are at increased risk for spontaneous abortion, still birth, or premature delivery. Approximately one third will experience worsened disease activity, while one third will continue with the same level of activity, and one third will have decreased activity (Miller J. J R Soc Med. 1986; 79:221).

What Is the Effect of Crohn’s Disease on Pregnancy?
Jarnero reported that rates of spontaneous abortion, congenital abnormalities, and stillbirth were not higher in women with inflammatory bowel disease (IBD) than in the general population (Jarnerot G. Scand J Gastroenterol. 1982;17:1). Recently, Dominitz et al have shown statistically significant increased odds ratios for preterm delivery, low birth weight (<2,500 g), small gestational age, cesarean section delivery, and congenital malformation among babies born to mothers with CD (Dominitz J, et al. Am J Gastroenterol. 2002;97:641). This study underscores the need for close obstetric monitoring of IBD patients during pregnancy. However, as Dr. Kane explained, the data must be interpreted as “broad strokes,” because this study did not consider potential risk factors: important historic information, such as the mother’s pharmacotherapy or disease activity at delivery, were not reported.

What About the Use of Azathioprine in Pregnancy? Should She Stop Her Medications?
Azathioprine is a category D drug (Briggs G, et al. Drugs in Pregnancy and Lacta-tion. 5th ed. Philadelphia:Lippincott Williams & Wilkins. 1998) and has been associated with thymic hypoplasia, lymphopenia, and chromatid breaks (Davison J, Lindheimer M. Semin Nephrol. 1984;4:240). However, the rate of congenital abnormalities among azathioprine users mirrors that of the normal population (~4%) and large transplant studies with appropriate controls have reported successful pregnancies (Davison J, Lindheimer M. Semin Nephrol. 1984;4:240).

Studying the effects of azathioprine and 6-mercaptopurine on pregnancy, Francella et al found that, although the prematurity rates were higher among women using these drugs, incidences of congenital abnormalities and neonatal infections did not increase (Francella A, et al. Gastroenterology. 1996;110: A909). Thus, the use of these agents appears to confer no markedly increased risk for adverse outcomes when taken by the appropriate patients, concluded Dr. Kane.

What About the Effects of Pharmacotherapy on Breast-feeding?
Limited data exist regarding the safety of azathioprine, 6-mercaptopurine, and infliximab in breast-feeding mothers. Methotrexate and cyclosporine commonly are contraindicated for use during breast-feeding, whereas oral and topical mesalamine, sulfasalazine, and corticosteroids may be safe to use when warranted. Studies are underway in patients with IBD to examine whether breast-feeding is associated with increased disease activity, as has been shown to occur in patients with rheumatoid arthritis (Barrett J, et al. Arthritis Rheum. 2000; 43:1010).

Treatment Options
For women who have achieved remission with azathioprine therapy, Dr. Kane recommends that they continue the treatment during pregnancy. Alternatively, patients could switch to a high-dose 5-aminosalicylate regimen and be treated acutely with corticosteroids if flares occur. Also, patients may choose to discontinue azathioprine therapy and undergo close monitoring of their disease activity by their gastroenterologist (eg, telephone call every month to treat disease symptoms and aggressively induce remission if the CD flares).

All contents Copyright © 1999 - 2003 Medical Association Communications