Clinical Research Advances in Ulcerative Colitis

[Guest guest]

American College of Gastroenterology 66th Annual Scientific Meeting

Day 1 - October 22, 2001

Clinical Research Advances in Ulcerative Colitis

Bret A. Lashner, MD

Introduction

The 66th Annual Meeting of the American College of Gastroenterology offered

a forum for the exchange of ideas regarding the treatment and epidemiology

of ulcerative colitis.

Interesting insights were presented on the use of infliximab for an

unapproved indication, 5-aminosalicylic acid (5-ASA), experimental

therapies, ileal pouch-anal anastomosis concerns, and epidemiologic

associations. In all, there was much to learn about ulcerative colitis.

Infliximab for Ulcerative Colitis

Infliximab* has not been approved by the United States Food and Drug

Administration for use in ulcerative colitis, and therefore physicians have

been reluctant to use this medication off-label. National meetings offer

investigators an opportunity to present their experience, which hopefully

will entice the manufacturer to study it and expand the indication.

Su and colleagues[1] from the University of Pennsylvania presented their

collaborative experience with others from Atlanta, Georgia; New York, NY;

and Park Ridge, Illinois, using infliximab in 28 ulcerative colitis

patients. Nineteen (67%) patients responded and 13 (46%) went into remission

after a single infusion. Steroid reduction was seen in 90% of

steroid-dependent patients. Patients with steroid-refractory disease were

less likely to respond than other patients (33% vs 84%). The median

time-to-response was 4 days, and the median time-to-relapse was 8 weeks.

Chey and associates[2] treated 31 ulcerative colitis patients with

infliximab and found an excellent response in 27 (87%). Remissions lasted

from 3 to 30 months and 24 of 28 steroid-treated patients were successfully

weaned. Fleisher and colleagues[3] found that 13 of 17 (76%) patients

achieved remission by 8 weeks. Also, a patient in Rochester, New York, with

ulcerative colitis and consumptive coagulopathy (decreased platelets,

increased prothrombin time, and decreased D-dimers and fibrin degradation

products) was successfully treated with infliximab.[4] Response in

ulcerative colitis, however, does not appear to be related to serum tumor

necrosis factor (TNF) levels.[5] Investigators from Phoenix, Arizona, showed

that 3 of 4 ulcerative colitis patients responded to infliximab, but none

had increased serum TNF levels before therapy.

Certainly, there was promising experience presented at this meeting to

encourage a definitive randomized clinical trial.

Treatment Strategies With 5-Aminosalicylic Acid

After more than 50 years, we are still learning about the use of 5-ASA

agents in ulcerative colitis. Loftus and colleagues[6] from the Mayo Clinic

in Rochester, Minnesota, presented their experience with a population-based

cohort of 63 ulcerative colitis patients who received steroids as initial

therapy for their disease. Complete or partial short-term response was seen

in 38 of 42 (90%) patients who received 5-ASA therapy within 14 days of

steroid initiation compared with 15 of 21 (71%) patients who did not receive

5-ASA. More patients given 5-ASA therapy for at least 5 months had a

prolonged response (63%) than patients not given maintenance 5-ASA (32%).

Yang and coworkers[7] from the University of Pennsylvania found that

balsalazide could be used as " salvage " therapy for 5-ASA intolerance or

failure. Of 17 ulcerative colitis patients who did not respond (13 patients)

or were intolerant (4 patients) of other 5-ASA agents, 5 (29%) responded to

balsalazide 6.75 g/day within 7 days. There was no intolerance to

balsalazide.

Treatment Strategies With Investigational Therapies*

There is great interest among clinical investigators and pharmaceutical

companies to find new therapies that are effective and less toxic than

available agents.

APC-2059

Axys Pharmaceuticals (South San Francisco, California) is developing a

tryptase inhibitor (APC-2059) to decrease the proinflammatory effects of

tryptase, a serine protease, released from mast cells in ulcerative colitis

patients. Tremaine[8] from the Mayo Clinic, on behalf of a large consortium

of academic centers, presented the results of APC-2059 given as 20 mg

subcutaneously twice daily for 28 days to 56 ulcerative colitis patients.

Sixteen (29%) responded, including 5 of whom went into remission; an

additional 11 patients improved. The principal side effect was

injection-site-related.

Granulocyte Apheresis

Naganuma and colleagues[9] compared intravenous cyclosporine A with

granulocyte apheresis in 35 steroid-resistant or steroid-dependant

ulcerative colitis patients. In the cyclosporine group, there was a 44%

remission rate, a 56% response rate, and 43% had adverse effects as compared

with 35% remission, 53% response, and no adverse effects in the granulocyte

apheresis group. Kanke and coworkers[10] treated 23 ulcerative colitis

patients with 5 sessions of apheresis. Nine of 15 (60%) patients with

severely active disease improved and steroids were tapered in 2

steroid-dependant patients. Although there were no remissions reported, this

therapy is worth considering.

sPLA2

Lilly Research Laboratories (Indianapolis, Indiana) presented their study

using a secreted phospholipase A2 (sPLA2) inhibitor for treatment of

ulcerative colitis.[11] (sPLA2 is inhibited by steroids.) In this

placebo-controlled randomized clinical trial, the drug was given orally for

8 weeks to 44 patients. The study was terminated after only 22 patients

completed the course because no therapeutic effect was seen. Adverse effects

were similar among the 2 patient groups.

Rebamipide

Rebamipide (also known as OPC-12759), is currently under development by

Otsuka America Pharmaceuticals (Rockville, land). Rebamipide is a

quinolone derivative with the ability to protect the gastrointestinal tract

from the harmful effects of reactive oxygen species. Farhadi and

colleagues[12] from Rush University in Chicago, Illinois, showed that

neutrophils from ulcerative colitis patients have a decreased inhibition of

fMLP (formyl-leucyl-methionyl-phenylalanine)-induced respiratory bursts and

that this effect is reduced with rebamipide. In theory then, rebamipide

could be effective in ulcerative colitis as an oral or topical agent.

Ileal Pouches

Patients with ulcerative colitis who do not respond to medical therapy or

who develop colorectal cancer or dysplasia often are offered total

proctocolectomy with ileal pouch-anal anastomosis (TPC-IPAA).

Mahadavan and colleagues[13] from the Mayo Clinic examined the rate of

postsurgical complications related to immunosuppressive therapy.

Complications were found in 26% (12/46) of patients treated preoperatively

with azathioprine or 6-mercaptopurine, 33% (4/12) of patients treated with

cyclosporine, and 32% (49/151) of patients not given immunosuppression. A

high complication rate was seen with steroid treatment and increased

severity of ulcerative colitis. Azathioprine, 6-mercaptopurine, or

cyclosporine does not appear to increase the postsurgical complication rate.

As reported by Quinn and Fazio[14] from the Cleveland Clinic in

Cleveland, Ohio, the quality of life, regardless of scoring system used, is

good following TPC-IPAA and better in men and younger patients. High

self-esteem is the most important independent determinant of a good quality

of life.

The diarrhea that occurs in some patients following TPC-IPAA may not be due

to an inflammation of the pouch. Shen and colleagues,[15] also from

Cleveland Clinic, found that only 52% of 50 consecutive patients presenting

with diarrhea had pouchitis. The remainder of the patients had inflammation

of the cuff (cuffitis; seen in 8%) and a normal-appearing pouch, labeled by

these investigators as the irritable pouch syndrome (seen in 40%).

Approximately 45% of patients with the irritable pouch syndrome respond to

anticholinergic, antidiarrheal, and/or antidepressants -- a response rate

that is similar to that found in patients with irritable bowel syndrome.

Therefore, when a patient with TPC-IPAA presents with diarrhea, should that

patient be treated with antibiotics, and, if he/she does not respond, be

endoscoped to confirm the diagnosis? Or should the patient be endoscoped

initially and treated according to the endoscopic and histologic findings?

Shen and colleagues[16] performed a decision analysis to see which of these

strategies was most cost-effective. Interesting to note was that the cost

per correct diagnosis was similar for the 2 approaches. The test-then-treat

strategy was recommended because it reduces the diagnostic delay and

therefore avoids unnecessary antibiotics in some patients.

In order to determine whether TPC-IPAA patients were at risk for developing

cancer or dysplasia, Gorfine and associates[17] from Mount Sinai Medical

School in New York biopsied 118 patients who were more than 1 year

postsurgery. None of the patients developed cancer or dysplasia, but 1 had

indefinite dysplasia in 2 locations. Dysplasia and cancer do not appear to

present an important risk in TPC-IPAA patients.

Epidemiology

Many diverse epidemiologic studies of ulcerative colitis patients were

presented during these annual meeting proceedings.

Adherence to Medical Therapy

Kane[18] from the University of Chicago examined adherence rates to medical

therapy for ulcerative colitis from a national (prescription-based) database

of 27,328 prescriptions of 5-ASA drugs. Adherence, defined as possession of

at least 75% of the prescribed drug over a 1-year period, ranged from 71% to

77%, depending on the drug formulation. Rectal formulation was associated

with low adherence rates and acquisition via mail-order prescription

service; female sex and younger age were associated with higher adherence

rates. Certainly adherence to medical therapy for ulcerative colitis

patients is lower than suspected.

Surveillance Colonoscopy

Cancer surveillance colonoscopy for detection of dysplasia has become the

standard of care for ulcerative colitis patients. Sprung and Lundberg[19]

questioned this standard. Among 319 ulcerative colitis patients in their

practice, the only individual who developed cancer had no dysplasia found on

a surveillance colonoscopy 1 year earlier. None of the 20 patients who

developed low-grade dysplasia went on to develop cancer (only 2 had surgery)

and no patient was detected with high-grade dysplasia. Furthermore, all

follow-up colonoscopies of patients with low-grade dysplasia had no

dysplasia detected.

Is dysplasia actually reversible? Was follow-up long enough in these

patients with low-grade dysplasia? Was the pathology confirmed to be true

low-grade dysplasia? These provocative questions need to be addressed before

the standard of care is altered.

hMLH1 Mismatch Repair Gene Mutation

Bagnoli and colleagues[20] studied a specific mutation on exon 8 of the

hMLH1 mismatch repair gene on chromosome 3p. Of interest, the mutation was

present in 40% of ulcerative colitis patients whose disease was either

refractory to steroids or steroid-dependent. Only 13.4% of other ulcerative

colitis patients and 9.8% of controls were positive for the mutation. This

provocative finding may be used in the future to predict or understand the

natural history of disease.

Selective Cyclooxygenase-2 Inhibitors

Controversy exists about the use of selective cyclooxygenase-2 inhibitors in

the setting of inflammatory bowel disease (IBD). In a series by Mahadevan

and colleagues[21] from the Mayo Clinic, only 2 of 27 IBD patients who used

these drugs had exacerbation of their disease. Therefore, these drugs appear

to be safe.

Bone Mineral Density and Hypercoagulation

Toth and coworkers[22] determined that dual-energy x-ray absorptiometry

(DEXA) was very sensitive in detecting osteopenia and osteoporosis among

ulcerative colitis patients who had been treated with steroid therapy.

Alternatively, quantitative ultrasound was not sufficiently sensitive to

detect differences in bone mineral density between ulcerative colitis

patients who had taken steroids and those who had never taken steroids.

Shah and associates[23] showed that hypercoagulability was common among 11

IBD patients; 7 had IgM anticardiolipin antibodies and 1 had a lupus

anticoagulant. Furthermore, hypercoagulability, and not cumulative steroid

dose, was associated with osteonecrosis seen on magnetic resonance imaging.

Conclusion

A wide range of topical issues related to ulcerative colitis was addressed

during these scientific sessions. Clinical investigators and pharmaceutical

companies each perceive this meeting as being an important vehicle for the

dissemination of timely information to the clinical gastroenterology

community.

Indeed, our understanding of the natural history and treatment of ulcerative

colitis has been advanced following these proceedings, and future meetings

are likely to build on this new information.

* The United States Food and Drug Administration has not approved this

medication for this use.

References

Su CG, Salzberg B, J, et al. Efficacy of anti-tumor necrosis factor

therapy in patients with ulcerative colitis. Am J Gastroenterol.

2001;96:S310.

Chey WY, Kunze GY, Shah AN. Observations on therapeutic effect of infliximab

on ulcerative colitis. Am J Gastroenterol. 2001;96:S288.

Fleisher MR, Rubin SD, Levine AE, et al. Infliximab in the treatment of

steroid-naive ulcerative colitis. Am J Gastroenterol. 2001;96:S291-292.

Qutob TS, Mantry P, Decross A, Shah A. Consumptive coagulopathy in an

ulcerative colitis: a case that responded to treatment with infliximab. Am J

Gastroenterol. 2001;96:S306.

J, Shernoff NJ, FC. The role of serum TNF in predicting

response to infliximab therapy in patients with active IBD. Am J

Gastroenterol. 2001;96:S289.

Loftus EV, Faubion WA, Sandborn WJ. Outcome of combination therapy with

sulfasalazine or 5-aminosalicylates and corticosteroids in a

population-based cohort of patients with inflammatory bowel disease. Am J

Gastroenterol. 2001;96:S299.

Yang Y-X, Su CG, Deren J, et al. Balsalazide as salvage therapy for

mesalamine failure/intolerance in patients with ulcerative colitis. Am J

Gastroenterol. 2001;96:S313-S314.

Tremaine WJ, Brzezinski A, Katz JA, et al. Treatment of mildly to moderately

active ulcerative colitis with a tryptase inhibitor (APC2059): an open-label

pilot study. Am J Gastroenterol. 2001;96:S311-S312.

Naganuma M, Hibi T, Iwao Y, et al. Treatment options of intravenous

cyclosporine A and granulocytapheresis for ulcerative colitis. Am J

Gastroenterol. 2001;96:S301-S302.

Kanke K, Hiraishi H, Nakano M, et al. Treatment of ulcerative colitis by

granulocyte apheresis. Am J Gastroenterol. 2001;96:S295.

Lashner BA, Korzenik J, Dmitrienko A, et al. Safety and efficacy of an sPLA2

inhibitor in treating ulcerative colitis. Am J Gastroenterol. 2001;96:S297.

Farhadi A, Keshavarzian A, Fitzpatrick LR, et al. The modulatory effects of

plasma and colonic milieu of patients with ulcerative colitis on OPC

antioxidant. Am J Gastroenterol. 2001;96:S290.

Mahadevan U, Loftus EV, Tremaine WJ, et al. Preoperative

azathioprine/6-mercaptopurine use is not associated with increased

complications following proctocolectomy and ileal pouch anal anastomosis for

ulcerative colitis. Am J Gastroenterol. 2001;96:S300.

Quinn MT, Fazio VW, Quality of life of patients with mucosal

ulcerative colitis following ileal pouch-anal anastomosis. Am J

Gastroenterol. 2001;96:S293.

Shen B, Lashner BA, Achkar J-P, et al. Irritable pouch syndrome is a common

diagnosis in symptomatic patients with ileal pouch-anal anastomosis. Am J

Gastroenterol. 2001;96:S308.

Shen B, Lashner BA, Achkar J-P, et al. Diagnostic strategies in symptomatic

patients with ileal pouch-anal anastomosis: a cost-effectiveness analysis.

Am J Gastroenterol. 2001;96:S307-S308.

Gorfine SR, Bauer JJ, Nilubol N, et al. In search of ileal mucosal

dysplasia: a prospective study of 138 pelvic pouch patients recalled one or

more years following restorative proctocolectomy. Am J Gastroenterol.

2001;96:S292.

Kane SV. National adherence rates with IBD therapy: PO vs PR. Am J

Gastroenterol. 2001;96:S296.

Sprung DJ, Lundberg K. Do surveillance colonic biopsies in patients with

ulcerative colitis prevent cancer in a community setting? Am J

Gastroenterol. 2001;96:S309.

Bagnoli S, Ortolani C, Papi L, et al. Refractory ulcerative colitis is

associated with the hMLH1 mismatch repair gene. Am J Gastroenterol.

2001;96:S286-S287.

Mahadevan U, Loftus EV, Tremaine WJ, et al. Safety of selective

cyclooxygenase-2 inhibitors in IBD. Am J Gastroenterol. 2001;96:S300-S301.

Toth M, Miheller P, Zagoni T, et al. Bone mineral density measured by DEXA

and quantitative ultrasonography in patients with ulcerative colitis. Am J

Gastroenterol. 2001;96:S311.

Shah SA, Nugent A, Patel S, et al. Hypercoagulability and osteonecrosis of

the femoral head in patients with inflammatory bowel disease. Am J

Gastroenterol. 2001;96:S307.