Frequently Asked Questions in Inflammatory Bowel Disease: First-Line Therapy—The Continuum of Care

At a symposium moderated by Daniel H. Present, MD, and held in conjunction with the American College of Gastroenterology’s 2003 Annual Meeting, five specialists in gastroenterology presented one virtual patient case, followed over time from 20 to 60 years old, to address frequently asked questions about inflammatory bowel disease. Topics included first-line treatment of ulcerative colitis, risk factors and surveillance for colorectal cancer, and considerations around pregnancy and aging.

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 10–15, 2003 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.

Differential Diagnosis and First-Line Therapy for Ulcerative Colitis

To ensure an accurate diagnosis of inflammatory bowel disease (IBD), an understanding of the differences between ulcerative colitis (UC) and Crohn’s disease in pathophysiology as well as in clinical and endoscopic presentation is essential, said Asher Kornbluth, MD, Associate Professor of Medicine, Mount Sinai Medical Center and School of Medicine, New York. Dr. Kornbluth provided an overview of the key considerations for differential diagnosis in the virtual case of Karen, a college student who initially presented with a 6-week history of intermittent bloody diarrhea and rectal urgency (Case Study, Part 1).

Differential Diagnosis
“The differential diagnosis is challenging in IBD, with 10% to 20% of cases remaining indeterminate colitis. In Karen’s case, it is also important to rule out infectious and non-infectious conditions that mimic IBD—especially since she has just returned from Morocco,” said Dr. Kornbluth (ACG Ulcerative Colitis Practice Guidelines. Am J Gastroenterol. In Press, 2004). Infectious conditions may include bacterial (food-borne or Clostridium difficile), parasitic (amebiasis or Giardia), or viral (cytomegalovirus) infections, while non-infectious conditions may be inflammatory or medication related (NSAIDs, contraceptives) (ACG Ulcerative Colitis Practice Guidelines. Am J Gastroenterol. In Press, 2004). An accurate diagnosis requires consideration of patient history, and clinical, endoscopic, and serologic findings.

In Karen’s case, the findings point to the likelihood of either UC, Crohn’s disease, or infectious colitis. According to Dr. Kornbluth, a key feature in Karen’s diagnosis is the endoscopic finding, noting inflammation from the anal verge with an abrupt transition after 13 cm to normal mucosa. Ultimately, all stool tests were negative, and biopsy was consistent with UC. Thus, the diagnosis for Karen is mild ulcerative colitis (proctitis).

First-Line Treatment of Ulcerative Colitis (Proctitis)
“The decision regarding which first-line therapy Karen will receive for ulcerative colitis [proctitis] will, in large part, determine the natural course of her disease and how it will affect the rest of her life,” said James F. Marion, MD, Assistant Clinical Professor of Medicine, Mount Sinai School of Medicine, and Assistant Attending Physician, Mount Sinai Hospital, New York.

According to Dr. Marion, “The 5-aminosalicylate [5-ASA] agents remain the standard for first-line therapy for mild to moderate UC, with all agents having good safety profiles and comparable efficacy.” When choosing a
5-ASA agent, the anatomic geography of drug delivery is an important consideration. Agents, such as sulfasalazine, are released primarily in the colon. Mesalamine (Asacol) is released in the distal ileum and mesalamine (Pentasa) in the stomach, both with good delivery throughout the colon.

Oral 5-ASA agents are considered to have good safety profiles and efficacy for extensive, left-sided, and distal disease (Hanauer et al. Am J Gastroenterol 1993;88:1188-19). However, dose-related toxicity can limit higher dosing with agents such as sulfasalazine, Dr. Marion noted. “The dose-toxicity response of mesalamine appears not to be an issue up to 4.8 g/d2,” the speaker explained (Stein et al. Gastroenterol Clin North Am 1999;28:297-323). In cases in which dose-related toxicity becomes a barrier, Dr. Marion recommended the use of lower doses of a combination of 5-ASA agents.

“To treat Karen, I would consider induction therapy with a combination of oral and topical 5-ASA agents,” Dr. Marion said. Oral 5-ASAs are effective in proximal and distal colitis, while topical mesalamine is effective in distal colitis (Hanauer et al. In: Kirsner, ed, Inflammatory Bowel Disease, Philadelphia, 2000). Dr. Marion added that while corticosteroids can also be useful in more severe cases of UC, clinicians should not start steroids without a quick and safe tapering strategy.

It is important to prescribe doses sufficient to induce remission, Dr. Marion noted. “With 5-ASA agents, the level of induction therapy dictates the maintenance therapy dose. The optimal mesalamine maintenance dose is the same as the induction dose,” he explained (Kefalides et al. Hospital Physician 2002:53-63. Hanauer et al, In: Kirsner, ed, Inflammatory Bowel Disease, Philadelphia, 2000). In addition, in proctitis and distal colitis, oral and rectal mesalamine combined is more effective than oral therapy alone (DAlbasio et al. Am J Gastroenterol 1998;93:799-803). According to Dr. Marion, corticosteroids should never be used as a maintenance therapy for UC.

In closing, Dr. Marion noted that “convenience, frequency of administration, pill size, and palatability can also be significant factors in whether patients take their medications—and ultimately whether their disease is treated effectively.”

Treatment for Ulcerative Colitis: Considerations for Pregnancy

Many women with inflammatory bowel disease (IBD) express concern about whether they will be able to have children. “When treating patients with ulcerative colitis [UC], it is important to discuss issues of fertility, potential impact of pregnancy on a patient’s disease and of the disease and its treatment on a pregnancy,” said Sunanda V. Kane, MD, MSPH, Assistant Professor of Medicine, University of Chicago Pritzker School of Medicine, Chicago. In the virtual case of Karen, the patient is now a 31-year-old with an 11-year history of UC (proctitis) who wishes to become pregnant (Case Study, Part 2).

Fertility Issues
“The fertility rate of women with UC overall is the same as that of those without UC,” Dr. Kane noted (Alstead et al. Gut 2003;52:159-61). Women with UC who have undergone surgery and have pouches are at increased risk for infertility. However, these women ovulate normally, making in vitro fertilization an option. For men, the agent sulfasalazine is associated with sperm abnormalities in 60% of those receiving this agent, regardless of its dose. This effect, however, is reversible (Alstead et al. Gut 2003;52:159-61).

Impact of Pregnancy on Disease
Current data indicate that remission at the time of conception is the best protective factor against relapse during pregnancy. “Of those who have inactive disease at conception, the chance of relapse is comparable to that of non-pregnant women: about 30%,” Dr. Kane said. In contrast, for those who have active disease at conception, approximately one third will have exacerbation of disease, one third will have improvement of disease, and one third will maintain the same level of disease (Miller. J R Soc Med 1986;79:221-5).

Impact of Disease on Pregnancy
According to Kornfeld and colleagues, in women with IBD who become pregnant, the risk is increased for needing a cesarian section, and for having babies born prematurely and at lower birth weight than the general population. However, research also shows these children function within normal limits, reaching developmental milestones at the appropriate ages (Kornfeld et al. Am J Obstet Gynecol 1997;177:942-6). “One study also showed an increased incidence of congenital malformation in the babies of women with IBD; however, this study did not note the disease activity of these women,” Dr. Kane pointed out (Dominitz et al. Am J Gastro 2002;97:641-8). Newer data indicate no difference in congenital abnormality incidence between babies born to women with UC and a control group (Norgard et al. Am J Gastroenterol 2003;98:2006-10).

During pregnancy, most agents used to treat UC are safe for use. Sulfasalazine crosses the placenta, but has not been associated with any increase in fetal malformation and is present only minimally in breast milk (Miller. J R Soc Med 1986;79:221-5). “The caveat about sulfasalazine is that women taking this drug also need to take increased doses of folic acid,” Dr. Kane pointed out (Czeizel et al. N Engl J Med 1992;327:1832-5). In a recent study examining mesalamine use during pregnancy, Norgard and colleagues found a statistically significant 6.7% versus 3.7% incidence of fetal malformation in those taking mesalamine or normal control group, respectively (Norgard et al. Gut 2003;52:243-7). However, Dr. Kane noted, “The clinical relevance of these data is questionable, given the study design.” In addition, a prospective controlled study by Diav-Citrin and colleagues showed no teratogenic risk with mesalamine use (Diav-Citrin et al. Gastroenterology 1998;114: 23-8). The data on topical 5-ASA agents show no increase in fetal abnormalities, with minimal excretion in breast milk (Bell & Habal. Am J Gastroenterol 1997;92:2201-2). Corticosteroids are associated with only rare teratogenicity in humans, and thus can be used during pregnancy and tapered at the time of delivery (Briggs et al. Drugs Preg Lact, Philadelphia, 1998).

In closing, Dr. Kane emphasized that active disease clearly poses greater risk to the fetus than use of appropriate medical therapies for UC (Briggs et al. Drugs Preg Lact, Philadelphia, 1998).

Ulcerative Colitis and Risk for Colorectal Cancer

“Inflammatory bowel disease [IBD] is a risk factor for colorectal cancer. Understanding an individual’s combined risk factors is key to understanding risk for colorectal cancer in IBD,” said David T. Rubin, MD, Assistant Professor of Medicine and Director of Clinical Education for Gastroenterology, University of Chicago. Evaluation of the current virtual patient case, Karen, now age 40, involves understanding her risk factors, performing surveillance colonoscopy with biopsy, and effectively managing any dysplasia that may be found (Case Study, Part 3).

Colorectal Cancer: Risk Factors
Among the risk factors for colorectal cancer related to IBD are: extensive colonic involvement, primary sclerosing cholangitis, long duration of IBD, young age of IBD onset, stricture, and family history of colorectal cancer, independent of a family history of IBD (Eaden et al. Am J Gastroenterol 2000;95:2710-9. Askling et al. Gastroenterology 2001; 120: 1356-62). Since patients with UC are at increased risk for colorectal cancer, risk reduction becomes an important consid- eration. “Our approach to cancer prevention in IBD has historically been through surveillance, but we are now shifting our efforts to include the primary prevention of dysplasia via chemoprevention,” said Dr. Rubin.

Colorectal Cancer: Surveillance and Chemoprevention
The current management of patients with long-standing UC includes surveillance colonoscopy with biopsy to detect malignancy or premalignancy. “Our group and others have advised three to four biopsies per 10 cm of involved mucosa, in addition to biopsies of nodules, masses, and strictures,” Dr. Rubin noted. If dysplasia is found, a colectomy is warranted given the risk for progression to adenocarcinoma or concurrent adenocarcinoma. (Rubin & Hanauer. Semin Colon Rectal Surg 2000;11:34-40).

In addition, chemoprevention can be considered to help reduce the risk of dysplasia. Agents that show promise include folic acid, calcium, and 5-ASA agents. In a recent Mayo Clinic study, patients with UC and PSC taking delayed-release mesalamine had decreased incidence of dysplasia and colorectal cancer compared to controls (Pardi et al. Gastroenterology 2003;124:889-93.) University of Chicago researchers have found in a retrospective case control study that 5-ASA throughout the course of disease was associated with a 72% risk reduction for dysplasia and colorectal cancer (Rubin et al. Abstract: Digestive Disease Week, May 2003, Orlando). In addition, researchers at Mount Sinai in New York found that 5-ASA therapy in patients with low- or indefinite-grade dysplasia was associated with a dose-related reduction in risk for progression to higher grade of neoplasm (Croog et al. Poster: Digestive Disease Week, May 2003, Orlando).

“Our patient, Karen, has a number of risk factors, but her biopsies have been negative and she has no family history of colorectal cancer. I would advise surveillance colonoscopy every 2 to 3 years, and encourage adherence to her maintenance therapy both for ongoing control of disease as well as for probable chemopreventive effects,” Dr. Rubin concluded.

Ulcerative Colitis Treatment and Risk for Osteoporosis

A number of factors, including female gender and advanced age, place individuals at increased risk for osteopenia and osteoporosis. “Women with ulcerative colitis [UC] are at even greater risk than those in the general population for osteopenia, osteoporosis, and thus fracture,” said Terrence A. Barrett, MD, Associate Professor of Medicine, Division of Gastroenterology, Northwestern University Medical School, Chicago. The virtual case study of Karen demonstrates several risk factors and ultimately osteoporosis, and warrants aggressive management of disease (Case Study, Part 4).

Osteopenia and Osteoporosis: Risk Factors
According to the World Health Organization, osteopenia is defined as –1 to – 2.5 SD and osteoporosis is greater than – 2.5 SD below mean bone density. “The risk of fracture approximately doubles for each SD below bone peak mass,” Dr. Barrett said (Cummings et al. Lancet 1993;341:72-5). In addition to the risk factors for osteoporosis that healthy women face, those with UC may also have additional risk factors of low weight or body mass index, physical inactivity, exposure to inflammatory cytokines, and corticosteroid therapy (Valentine et al. Am J Gastroenterol 1999;94:878-83. Guimbaud et al. Am J Gastroenterol 1998;93:2397-2404. Bjarnason et al. Gut 1997;40:228-33).

In patients with UC, studies indicate an increased risk for fracture of the spine, hip, wrist/forearm, and rib (Bernstein et al. Ann Intern Med 2000;133:795-9). “Women with IBD are at high risk for osteoporosis-related fracture, with the use of oral corticosteroids being a significant contributor to this risk,” Dr. Barrett said (Van Staa et al. J Bone Min Res 2000;15:993-1000). Studies have shown that bone loss is dependent on corticosteroid dose and duration, although the most rapid bone loss occurs in the first weeks of therapy (NIH Consensus Statement. 2000;17:1-36. Valentine et al. Am J Gastroenterol 1999;94:878-83). “In addition, the majority of fractures are clinically silent and typically go undetected,” Dr. Barrett said (Klaus et al. Gut 2002;51:654-8).

Evaluation and Treatment
According to Dr. Barrett, all women who have IBD and are older than 60 years need to be evaluated for osteoporosis. Those with other risk factors, particularly corticosteroid use for greater than 3 months or on a recurrent basis, also require evaluation (American College of Gastroenterology, 2002. Valentine et al. Am J Gastroenterol 1999;94:878-83).

“Treatment for individuals with IBD and osteopenia/osteoporosis, may include calcium and vitamin D supplementation, although these are not effective in patients taking corticosteroids,” Dr. Barrett noted. Hormone replacement therapy or selective estrogen receptor modulator therapy may also be appropriate in some patients. “Importantly, bisphosphonate therapy represents an effective treatment option for patients with osteopenia or osteoporosis—especially those taking corticosteroids,” Dr. Barrett said. Recent studies have demonstrated efficacy with risedronate not only in reversing but also in preventing corticosteroid-related osteoporosis (Cohen et al. Arthritis Rheum 1999;41:2309-18. Reid et al. J Bone Min Res 2000;15:1006-13).

In closing, Dr. Barrett noted that patients with IBD and osteoporosis, such as Karen, require prompt therapy with calcium carbonate, vitamin D, and bisphosphonate therapy.

All contents Copyright © 1999 - 2004 Medical Association Communications