Advances in the Treatment of Crohn's Disease

[Guest guest]

American College of Gastroenterology 66th Annual Scientific Meeting

Day 1 - October 22, 2001

Advances in the Treatment of Crohn's Disease: Focus on the Biological

Approach

R. Lichtenstein, MD, and P. MacDermott, MD

General Introduction

Ulcerative colitis and Crohn's disease represent a group of disorders

characterized by chronic inflammation that affect the gastrointestinal tract

and have unknown etiology and typically a waxing and waning clinical course.

They are identified by well-defined clinical, endoscopic, radiographic, and

histologic characteristics.

This report summarizes some of the highlights of the 66th Annual Meeting of

the American College of Gastroenterology that help advance our understanding

of the pathogenesis and treatment of Crohn's disease.

Pathogenesis of Inflammatory Bowel Disease

As outlined in a state-of-the-art lecture given by MacDermott,

MD,[1] the factors involved in the development of Crohn's disease include

genetics, environmental parameters, and alterations in the immune system.

There is clear evidence for heightened activation of intestinal lymphocytes,

macrophages, and granulocytes, leading to an upregulated mucosal immune

response in inflammatory bowel disease (IBD).

Immune Factors

In IBD, the antigenic trigger is most likely the presence of common,

nonpathogenic microbial agents within the intestine, against which the

patient mounts an activated immune response. In healthy individuals, there

is a finely tuned, low-grade chronic inflammation in the intestinal lamina

propria caused by intestinal bacteria. Failure to suppress this inflammatory

response results in highly activated effector cells and, therefore, an

uncontrolled immune response within the intestine in IBD patients.

Tumor necrosis factor (TNF) serves as a pivotal inflammatory mediator, and

treatments based on downregulating and/or eliminating the effector cells

that produce TNF and other inflammatory cytokines have proven effective in

Crohn's disease. Downregulation of activated effector cells may be achieved

using suppressor cytokines or by stimulating suppressor-T-cell (T-helper 2)

function. Elimination of activated effector cells may be achieved by

inducing the cells to undergo apoptosis. TNF has numerous biologic

properties involving inflammation, proliferation, and differentiation. TNF

production leads to activation of macrophages, the priming of neutrophils,

and an increase in intestinal epithelial permeability.

TNF is primarily a product of activated macrophages, although it is also

produced by lymphocytes and natural killer cells. Immunologic-mediated

tissue injury results from the induction of proteases, prostaglandins,

leukotrienes, eicosanoids, and other products. However, some of these

products (such as prostaglandin E2) may also directly cause diarrhea by

prompting mucosal secretion of chloride and potassium.

Genetic and Environmental Factors

Over 15% of patients with IBD have first-degree relatives who also have the

disease. The lifetime risk of developing IBD in first-degree relatives of

individuals with IBD is 8.9% for offspring, 8.8% for siblings, and 3.5% for

parents. The incidence of IBD among first-degree relatives of IBD patients

is 30 to 100 times that of the general population. Dizygotic (nonidentical)

twins have the same rate of concordance for IBD that would be expected for

siblings, whereas monozygotic twins (identical) have higher rates of

concordance for both diseases (ie, ulcerative colitis and Crohn's disease).

The concordance rate for identical twins with Crohn's disease ranges from

29% to 67%, depending on the study. There is no reported case of monozygotic

twins in which one twin had Crohn's disease and the other had ulcerative

colitis. Also, there is no increased risk for IBD among spouses of

individuals with IBD.

The NOD2 gene family was initially identified as a class of plant

disease-resistant gene products that function as receptors within the cell

for bacterial lipopolysaccharide (LPS).[2] Subsequently, NOD2 was

characterized as being highly restricted to monocytes, with the ability to

induce nuclear factor kappaB (NF-kappaB) activation. NF-kappaB activation by

LPS should result in monocyte activation and a protective immune

response.[3] Using positional-cloning strategy, Hugot and colleagues[4]

identified 3 NOD2 gene mutations that confer susceptibility to Crohn's

disease by altering recognition of LPS and interfering with normal NF-kappaB

activation in monocytes. At the same time, in an independent study, Ogura

and associates[5] demonstrated a truncated NOD2 protein associated with

Crohn's disease. These investigators showed that the disease-associated NOD2

variant was functionally less active in conferring responsiveness to

bacterial LPS. The NOD2 gene mutations that have been described to date are

found in a subset of Crohn's disease patients. Therefore, Crohn's disease in

those patients with the NOD2 gene mutations may in fact be due to a

genetically determined inability to mount an appropriate immune response

against bacterial LPS.

Zhou and colleagues[6] performed allele and genotype analysis of the 3

genetic variants in 332 patients with Crohn's disease of Jewish descent. One

hundred eighteen patients had a family history of Crohn's disease and 214

were sporadic cases. The number of Crohn's disease patients who were

homozygous or compound heterozygotes for the NOD2 mutants was significantly

higher among the familial cases than the sporadic cases. The study authors

have thus suggested that NOD2 mutations may play a greater role in causing

Crohn's disease in multiplex families.

Their findings therefore support the notion that patients with familial

Crohn's disease are " genetically wired " to mount an intense immune response.

In the presence of the appropriate initiating event, this genetic

predisposing factor leads to nonspecific inflammation. Because of the

mutation in the NOD2 gene in patients with Crohn's disease and the inability

of monocytes to recognize LPS, the adaptive immune system responds with

chronic, uncontrolled intestinal inflammation and destruction. In the

future, additional genes that are involved in the altered recognition of

bacterial cell wall products will likely be implicated in the pathogenesis

of IBD as well.

Infliximab

Infliximab (Remicade; initially known as cA2) is a chimeric IgG1 monoclonal

antibody composed of 75% human and 25% murine sequences. This antibody has

been demonstrated to have a high specificity and affinity for TNF. In

October of 1998, infliximab was made available for the treatment of

moderate-to-severe Crohn's disease refractory to conventional therapy as

well as for fistulae in Crohn's disease. When given as a single intravenous

infusion of 5 mg/kg of body weight, infliximab has a half-life of about 10

days. Pharmacokinetic data have demonstrated that this agent does not

accumulate when given in 3 doses at 2- to 4-week intervals or when given in

repeated doses at 8-week intervals.

Initial Clinical Trials

In the initial multicenter study, Targan and colleagues[7] reported the

first phase of a randomized, double-blind, placebo-controlled efficacy

trial. This trial consisted of 2 phases: a dose-ranging portion and a

retreatment study. The dose-ranging portion of the study identified the most

effective dose (5 mg/kg given as a single dose) and the retreatment phase

reported the efficacy of repeat infusions at a dose of 10 mg/kg given every

8 weeks for maintenance of remission.

The primary end point of the first phase of this study was clinical response

at 4 weeks (defined as a decrease in the Crohn's Disease Activity Index

[CDAI] by > 70 points), and the secondary end point was remission (defined

as CDAI < 150) at 4 weeks. Sixty-one percent of infliximab-treated patients

had a clinical response by 2 weeks postinfusion compared with 17% of the

placebo patients (P < .001). Similarly, 27% of infliximab-treated patients

were in remission by 2 weeks postinfusion vs 4% of the placebo patients (P =

..06). Sixty-five percent of the infliximab-treated patients (combination of

all 3 doses: 5 mg/kg, 10 mg/kg, and 20 mg/kg) met the primary end point

(clinical response at 4 weeks) compared with 17% of the placebo patients (P

< .001). The 5-mg/kg dose of infliximab (when given by body weight)

consistently demonstrated the highest response and remission rates.

Forty-eight percent of the patients receiving infliximab (at 5 mg/kg) met

the secondary end point (clinical remission) at week 4.

In the second phase of the trial (in an effort to assess maintenance of

remission), Rutgeerts and coworkers[8] reported on a randomized,

double-blind, multicenter, placebo-controlled efficacy study of repeated

infusions of infliximab for patients with Crohn's disease. The study

enrolled 73 patients and treated them with 4 repeated infusions of either

infliximab (n = 37) at a dose of 10 mg/kg or placebo (n = 36) every 8 weeks

(weeks 12, 20, 28, and 36). Corticosteroid tapering was permitted, but an

increase in corticosteroid dose was not permitted. The primary end points

were clinical response and remission, as assessed by the CDAI. Maintenance

was achieved in those patients receiving repeated infusions of infliximab.

Fewer patients in the retreatment group described lack of efficacy as a

reason for discontinuing the study protocol -- 10.8% vs 33% of placebo

patients. Clinical remission increased from 37.8% at 12 weeks to 52.9% at 44

weeks in the retreatment arm, whereas in the placebo arm clinical remission

decreased from 44.4% at 12 weeks to 20% at 44 weeks. Additionally, the

median time to loss of clinical response was greater in the retreatment arm

(over 47 weeks vs 37 weeks in the placebo arm; P = .057). Also, the number

of patients in remission was higher in the retreatment arm at the end of the

trial (44 weeks) as compared with the number of patients in remission at the

beginning of the trial (12 weeks).

ACCENT I Trial

A pivotal trial studying retreatment and remission maintenance in patients

with Crohn's disease was presented at these meeting proceedings by Rutgeerts

and colleagues.[9] This trial is ACCENT I (A Crohn's Disease Clinical Trial

Evaluating Infliximab in a New Long-term Treatment Regimen). ACCENT I is a

multicenter, randomized, double-blind international trial evaluating the

safety and efficacy of infliximab maintenance therapy in 573 patients with

moderately to severely active Crohn's disease. The duration of the trial was

54 weeks with similar follow-up. The objectives of this trial were to: (1)

evaluate maintenance therapy (infliximab given every 8 weeks) compared with

single-dose therapy (infliximab administered as a single dose) while

assessing time to loss of response, response, remission, and quality of

life; (2) evaluate the steroid-sparing effect of infliximab; (3) evaluate

the effectiveness of infliximab treatment on mucosal healing at week 10; (4)

evaluate the safety of long-term retreatment therapy with infliximab.

The primary end point (at 54 weeks) and interim 30-week end-point data from

this study were presented. Of a total of 573 patients, 335 (58.5%)

demonstrated a clinical response to infliximab at 2 weeks. At week 10, 53%

of patients in the single-dose group compared with 65% of patients in the

maintenance group had a clinical response (CDAI decrease >/= 70 and 25%

decrease from baseline). On 10-week follow-up of the patients who had

responded at 2 weeks, the portion of those patients demonstrating mucosal

healing was zero in the single-dose group and 31% in the infliximab 5 mg/kg

every 8 weeks group, combined with the infliximab 10 mg/kg every 8 weeks

group.

Three-dose induction regimen. As a subanalysis in the ACCENT I study, the

comparative effect of single vs 3-dose (given at weeks 0, 2, and 6)

induction regimens of infliximab was assessed.[10] At week 10, the 3-dose

induction regimen resulted in a statistically significant difference (P <

..001) in both the response and remission rates. At week 10, 62% of

individuals who received a single infusion had a clinical response compared

with 71% (P = .035) in the 3-dose induction group. At week 10, these

investigators found that 40% of patients receiving the 3-dose induction

regimen were in remission and 67% had a decrease in CDAI by more than 70

points. In contrast, 28% of patients receiving a single dose were in

remission (P = .006) and 56% had a decrease in CDAI by more than 70 points

(P = .001). Patients' quality of life was also assessed during this clinical

trial.[11] At 6 and 10 weeks, the 3-dose regimen resulted in a greater

increase in total IBD quality of life (IBDQ) than the single-dose regimen.

At week 10, the increase in IBDQ was significantly different (P < .05).

Feagan and associates therefore concluded that infliximab given in a 3-dose

induction regimen can provide a rapid and substantial improvement in the

quality of life of Crohn's disease patients.

Response rates over 30 weeks. At 30 weeks, a clinical response was seen in

27% of patients in the single-dose group compared with 51% in the infliximab

5 mg/kg every 8 weeks group and 59% in the infliximab 10 mg/kg every 8 weeks

group. Of the 473 (83%) patients in the study who ultimately responded, 325

(69%) responded by week 2, and another 127 (27%) responded by week 10. Among

the 248 patients not responding at week 2, 147 (60%) responded later on.[12]

In addition, at 30 weeks a clinical remission was seen in 21% of patients in

the single-dose group as compared with 39% in the infliximab 5 mg/kg every 8

weeks group and 45% of patients in the infliximab 10 mg/kg every 8 weeks

group. Furthermore, at 30 weeks, a clinical remission and successful

tapering off steroids was seen in 11% of patients in the single-dose group

as compared with 31% in the infliximab 5 mg/kg every 8 weeks group and 37%

of patients in the infliximab 10 mg/kg every 8 weeks group. Finally, at 30

weeks the median steroid dose was 10 mg of prednisone in patients in the

single-dose group as compared with 0 mg in the infliximab 5 mg/kg every 8

weeks group and 0 mg of prednisone in patients in the infliximab 10 mg/kg

every 8 weeks group.

Extraintestinal manifestations and response to therapy. Hanauer and

colleagues[13] reported on the incidence and response to therapy of patients

with extraintestinal manifestations of Crohn's disease. Maintenance therapy

with infliximab was found to be superior to a single dose in resolving the

most prevalent extraintestinal manifestation of Crohn's disease:

arthritis/arthralgia. Other extraintestinal manifestations assessed in the

trial, including iritis/uveitis, pyoderma gangrenosum, and fever, also

improved with infliximab maintenance therapy. The presence of aphthous

stomatitis was not affected by infliximab treatment.

Data at 54 weeks. At 54 weeks, a clinical response was seen in 17% of

patients in the single-dose group compared with 43% in the infliximab 5

mg/kg every 8 weeks group and 53% in the infliximab 10 mg/kg every 8 weeks

group. At 54 weeks, the median duration of response was 19 weeks in patients

in the single-dose group compared with 38 weeks in the infliximab 5 mg/kg

every 8 weeks group and greater than 54 weeks in the infliximab 10 mg/kg

every 8 weeks group. In addition, at 54 weeks, a clinical remission was seen

in 14% of patients in the single-dose group compared with 28% in the

infliximab 5 mg/kg every 8 weeks group and 38% in the infliximab 10 mg/kg

every 8 weeks group.

Furthermore, at 54 weeks, a clinical remission and successful tapering off

steroids was seen in 9% of patients in the single-dose group compared with

28% in the infliximab 5 mg/kg every 8 weeks group and 32% in the infliximab

10 mg/kg every 8 weeks group. Important to note is that 52.2% of the week-2

responders were receiving corticosteroids at baseline. The median dose was

20 mg daily. By week 30, the median corticosteroid dose for placebo

maintenance patients was 10 mg daily and 0 mg daily in both the 5 and 10

mg/kg maintenance groups. Additionally, 10.7% of placebo maintenance

patients, 31.0% of 5-mg/kg maintenance patients (P = .008), and 36.8% of

10-mg/kg maintenance patients (P = .001) had discontinued corticosteroids

and were in clinical remission with a CDAI < 150. A consistent benefit was

appreciated among patients who were on corticosteroids for 1 year or less

prior to study entry or for more than 1 year prior to enrollment in the

study.[14]

At 54 weeks, the median improvement in the IBDQ Index in patients in the

single-dose group was 3 points vs 21 points in the infliximab 5 mg/kg every

8 weeks group and 28 points in the infliximab 10 mg/kg every 8 weeks group.

At 54 weeks, the proportion of patients on immunomodulators and in remission

in the single-dose group was 23% compared with 11% in the single-dose group

without immunomodulators. In contrast, at 54 weeks, the proportion of

patients on immunomodulators and in remission in the infliximab 5 mg/kg

every 8 weeks group, combined with the infliximab 10 mg/kg every 8 weeks

group, was 50% vs 41% in the single-dose group without immunomodulators.

Therefore, at week 54, 10 mg/kg every 8 weeks maintenance therapy with

infliximab was superior to 5 mg/kg every 8 weeks as well as to a single-dose

of infliximab at 5 mg/kg, with respect to clinical response and remission

rates. In addition, infliximab maintenance therapy was steroid-sparing, and

patients maintained on immunomodulatory therapy were more likely to be in

clinical remission. Finally, the analysis at 54 weeks demonstrates that

retreatment with infliximab 10 mg/kg every 8 weeks is the optimal approach

to prolonging the duration of remission in patients with moderate-to-severe

Crohn's disease.

Can Infliximab Be Used as Initial First-line Therapy?

The inclusion criteria for the ACCENT I trial were that patients had to be

refractory or intolerant to standard medical therapy. In order to begin to

address the question of whether infliximab can be used as initial first-line

therapy, Fleisher and colleagues[15] evaluated 30 patients who had not been

previously treated with steroids or surgery but who were refractory to

mesalamine and antibiotics. Of the 30 patients treated, 15 received

prednisone 40 mg orally daily and 15 received infliximab 5 mg/kg at 0, 2,

and 6 weeks. Analysis of remission (CDAI < 150) was performed at weeks 4, 8,

and 12. Based on the findings, the study authors suggest that infliximab

therapy resulted in higher remission rates than did steroid therapy. It

should be noted that long-term follow-up and statistical analysis were not

provided in this study. Nevertheless, this study demonstrates the need for

future double-blind, placebo-controlled trials to evaluate the use of

infliximab as first-line therapy for Crohn's disease.

Adverse Events and Tolerability

In the ACCENT I trial, infliximab was well tolerated with few adverse events

occurring. The most common adverse effects were headache, upper respiratory

tract infection, abdominal pain, and nausea, which occurred in 20% to 30% of

patients studied. There was no difference in occurrence between treatment

groups.

Infusion reactions. Infusion reactions occurred in 5.2% of infliximab

infusions vs 2.7% of placebo infusions. Overall, 1.0% of patients had

serious infusion reactions and 2.4% of patients developed delayed

hypersensitivity-like reactions. Cheifetz and associates[16] reported on

infusion reactions in 165 consecutive patients receiving 479 infliximab

infusions. They observed an overall incidence of infusion reactions to

infliximab in 5.8% of all infusions, of which 89.3% were acute. The severity

of the acute infusion reactions was mild in 2.9% of infusions, moderate in

1.3% of infusions, and severe in 1.0% of infusions. Using appropriate

treatment protocols that included diphenhydramine, acetaminophen, and

corticosteroids, the acute infusion reactions were effectively treated and

subsequently prevented upon retreatment in nearly all patients.

In a similar study, Lichtenstein and colleagues[17] evaluated 861 patients

from 125 centers (13 academic and 112 community practices). Minor reactions

were observed in 11.0% of all infusions. The most frequent reaction was

headache (3.6%) followed by nausea (2.2%). Ninety-five percent of infliximab

infusions were completed without interruptions; 4% were interrupted and then

completed; 1% were not completed. Of the infusions not completed (n = 6), 4

patients received a subsequent infusion that was completed without

interruption. Only 2 out of 861 patients did not receive additional

infusions.

Tuberculosis and other infections. The increased number of patients

developing tuberculosis deserves special comment, even though no new data

were presented during this meeting. Ongoing infections are an absolute

contraindication to the use of infliximab. Patients who are suspected of

having an abscess should undergo evaluation and appropriate drainage prior

to treatment. Infliximab should be discontinued in patients who develop a

serious infection, including sepsis. In the controlled trials to date,

serious infections were observed in approximately 5% of patients treated

with infliximab for all indications and in 4% of those treated for Crohn's

disease, a result similar to that observed in patients treated with placebo

(8% in all studies and 4% in studies of Crohn's disease only). Serious

infections have included pneumonia, cellulitis, sepsis, skin ulceration,

urinary tract infection, and abscess. Fatal infections, including sepsis and

disseminated tuberculosis, have been reported in patients receiving

infliximab as well as TNF-blocking agents in general.

In the ACCENT I trial, the frequency of infections requiring antibiotic

treatment was 32%, whereas 3.8% of patients developed serious infections.

Although the percentage of infections was similar among all treatment

groups, 1 patient developed tuberculosis subsequent to the fourth infusion.

Recently, Keane and colleagues[18] published their analysis of all reports

of tuberculosis after infliximab therapy that had been received as of May

29, 2001, through the Med/Watch spontaneous reporting system. There were 70

reported cases of tuberculosis after treatment with infliximab for a median

of 12 weeks. The infliximab had been given for Crohn's disease in 18

patients and for rheumatoid arthritis in 47 patients. The ages of the

patients involved ranged from 18 to 83 years, with a median age of 57 years.

Fifty-six percent of these patients had extrapulmonary disease and

approximately 25% had disseminated disease. Twelve deaths, most likely due

to tuberculosis, occurred. Important to note is that 55 (79%) of the

patients had also received other immunosuppressive therapies. Based on these

published data, it is now recommended that patients about to receive

infliximab be appropriately screened for the possibility of having active

tuberculosis or an untreated past history of tuberculosis (latent

tuberculosis), using tuberculin PPD (tuberculin purified protein derivative)

skin testing and chest x-ray. The patient should be treated prior to

infusion of infliximab if evidence of past or present tuberculosis is found.

An advisory has been issued by the manufacturer (Centocor) regarding cases

of tuberculosis reported to them as of June 30, 2001, which included 84

patients (3 from Centocor-sponsored clinical trials and 81 from

postmarketing surveillance), with 14 deaths, of which 10 were attributable

to tuberculosis. The majority of the cases of tuberculosis were pulmonary,

with one third of cases being disseminated. Important to note is that the

advisory issued by the manufacturer regarding tuberculosis was based on

extensive worldwide clinical experience with infliximab, which has been

given to over 170,000 patients. It should also be noted that these

observations are explainable on a scientific basis, because infliximab

causes monocytes and T cells to undergo apoptosis, and therefore the

potential for opportunistic organisms to evade innate immune system

detection is high, particularly when patients are also on other

immunomodulators.

In addition to tuberculosis, other infections have been noted in association

with infliximab use. Keane and colleagues indicated that 12 patients have

been reported with listeriosis, 9 with Pneumocystis carinii pneumonia, 7

with histoplasmosis, 6 with aspergillosis, and 7 with severe Candida

infections. It should be emphasized, however, that neither concurrent use of

immunosuppressants in these infected patients nor population rates of

infection were reported in this paper. During the current meeting

proceedings, a patient with cutaneous nocardiosis was reported. This patient

had been enrolled in the ACCENT II trial, which is evaluating the ability to

induce and maintain remission of fistula closure in patients with

fistulizing Crohn's disease. [19]

Conclusion

Since the initial description of Crohn's disease in 1932 (which has been

credited to Drs. Crohn, Ginzburg, and Oppenheimer), great advances have been

made in our understanding of the role of genetics, the mucosal immune

system, and intestinal bacteria in its underlying etiopathogenesis.

Laboratory-based investigations have paved the way to a clearer

understanding of the cause of Crohn's disease. The laboratory has also

helped us better understand the role of cytokines in the perpetuation and

augmentation of inflammation.

In the future, better understanding of genomics will allow us to more

effectively predict which patients will benefit from defined biologic

therapies.

References

MacDermott RP. J. Berk Distinguished Lecture -- Immunology and

Therapy of IBD. Program and abstracts of the American College of

Gastroenterology 66th Annual Scientific Meeting; October 22-24, 2001; Las

Vegas, Nevada.

Inohara N, Ogura Y, Chen FF, Muto A, Nunez G. Human NOD1 confers

responsiveness to bacterial lipopolysaccharides. J Biol Chem.

2001;276:2551-2554.

Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G. Family member

that is Restricted to monocytes and activates NF-kappaB. J Biol Chem.

2001;276:4812-4818.

Hugot JP, Chamalliard M, Zouall H, et al. Association of NOD2 leucine-rich

repeat variants with susceptibility to Crohn's disease. Nature.

2001;411:599-603.

Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2

associated with susceptibility to Crohn's disease. Nature. 2001; 411:603-

606.

Zhou Z, Lin X, Akolkar P, et al. Variations in the NOD-2 locus in familial

and sporadic cases of Crohn's disease in the Ashkenazi Jewish population. Am

J Gastroenterol. 2001;96:A54.

Targan SR, Hanauer SB, van Deventer SJH, et al. A short-term study of

chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's

disease. N Engl J Med. 1997;337:1029-1035.

Rutgeerts P, D'Haens G, Targan S, et al. Efficacy and safety of retreatment

with anti-tumor necrosis factor antibody (infliximab) to maintain remission

in Crohn's disease. Gastroenterology. 1999;117:761-769.

Rutgeerts P, Colombel JF, Schreiber S, et al. Treatment of Crohn's disease

(CD): Response to Remicade® (infliximab) in the ACCENT I trial through week

54. Am J Gastroenterol. 2001;96:A7.

Mayer L, Hanauer S, Han C, et al. Three dose induction regimen of infliximab

(Remicade) is superior to a single dose in patients with Crohn's disease.

Program and abstracts of the American College of Gastroenterology 66th

Annual Scientific Meeting; October 22-24, 2001; Las Vegas, Nevada. [P257]

Feagan BM, Yan S, Han C, Bala M, Olson A. Infliximab (Remicade) treatment

results in rapid improvement in quality of life in patients with Crohn's

disease. Program and abstracts of the American College of Gastroenterology

66th Annual Scientific Meeting; October 22-24, 2001; Las Vegas, Nevada.

[P256]

Hanauer SB, Schreiber S, Bao W, et al. ACCENT I Trial: Infliximab response

rates over 30 weeks. Program and abstracts of the American College of

Gastroenterology 66th Annual Scientific Meeting; October 22-24, 2001; Las

Vegas, Nevada. [P252]

Hanauer SB, Lichtenstein GR, Mayer L, Keenan G, Rutgeerts PJ.

Extraintestinal manifestations of Crohn's disease: Response to infliximab

(Remicade) in the ACCENT I trial through 30 weeks. Am J Gastroenterol.

2001;96:A26.

Lichtenstein GR, Rutgeerts PJ, Bao W, Keenan G, Bala M, Hanauer SB.

Infliximab (Remicade) treatment allows Crohn's disease patients to reduce or

discontinue concomitant corticosteroid use. Am J Gastroenterol 2001. Program

and abstracts of the American College of Gastroenterology 66th Annual

Scientific Meeting; October 22-24, 2001; Las Vegas, Nevada. [P253]

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

Crohn's disease: Is it a steroid-sparing agent or a steroid-replacing agent

? Program and abstracts of the American College of Gastroenterology 66th

Annual Scientific Meeting; October 22-24, 2001; Las Vegas, Nevada. [P243]

Cheifetz A, Mayer L, Plevy S. The incidence and management of infusion

reactions to infliximab: A large center experience. Program and abstracts of

the American College of Gastroenterology 66th Annual Scientific Meeting;

October 22-24, 2001; Las Vegas, Nevada. [P239]

Lichtenstein GR, Keenan G, Vreeland MG, Chen DM. Infliximab tolerability in

Crohn's disease patients. Am J Gastroenterol. 2001;96:A25.

Keane J, Gershon S, Wise R, et al. Tuberculosis associated with infliximab,

a tumor necrosis factor alpha-neutralizing agent. N Engl J Med.

2001;345:1098-1104.

Singh S, Rau N, H, et al. Cutaneous nocardiosis complicating Crohn's

disease management with infliximab. Program and abstracts of the American

College of Gastroenterology 66th Annual Scientific Meeting; October 22-24,

2001; Las Vegas, Nevada. [P254]