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Infliximab for Induction and Maintenance

The new england journal of medicine

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Infliximab for Induction and Maintenance

Therapy for Ulcerative Colitis

Paul Rutgeerts, M.D., Ph.D., William J. Sandborn, M.D., Brian G. Feagan, M.D.,

Walter Reinisch, M.D., Allan Olson, M.D., Jewel Johanns, Ph.D.,

Suzanne Travers, M.D., Daniel Rachmilewitz, M.D., Stephen B. Hanauer, M.D.,

Gary R. Lichtenstein, M.D., Willem J.S. de Villiers, M.D., Ph.D.,

Daniel Present, M.D., Bruce E. Sands, M.D., and Jean Frédéric Colombel, M.D.

From the University H ospital Gasthuis-berg, Leuven, Belgium (P.R.); Mayo Clinic,Rochester, Minn. (W .J.S.); Robarts Research Institute, University of Western Ontario,London, Ont., Canada (B.G.F.); Univer-sit?tsklinik für Innere Medizin IV , Allge-meines Krankenhaus Wien, Vienna (W .R.);Centocor, Malvern, Pa. (A.O., J.J., S.T.);Shaare Zedak Medical Center, Jerusalem,Israel (D.R.); University of Chicago, Chica-go (S.B.H.); University of Pennsylvania,Philadelphia (G.R.L.); University of Ken-tucky, Lexington (W.J.S.V.); Mount Sinai Medical Center, New York (D.P.); Massa-chusetts General Hospital, Boston (B.E.S.);and H ?pital H uriez–Centre d’Investiga-tion Clinique INSERM Centre Hospitalier et Universitaire de Lille, Lille, France (J.F.C.).Address reprint requests for the Active Ul-cerative Colitis Trial 1 (ACT 1) to Dr. Rut-geerts at the Universitaire Ziekenhuizen Leuven, Inwendige Geneeskunde, UZ Gast-huisberg, H erestraat 49, B-3000 Leuven,Belgium, or at paul.rutgeerts@uz.kuleuven.ac.be. Address reprint requests for the Ac-tive Ulcerative Colitis Trial 2 (ACT 2) to Dr.Sandborn at the Mayo Clinic, 200 First St.SW, Rochester, MN 55905, or at sandborn.william@https://www.wendangku.net/doc/9112528924.html,.

Drs. Rutgeerts and Sandborn contributed equally to the article.

N Engl J Med 2005;353:2462-76.

background

Infliximab, a chimeric monoclonal antibody directed against tumor necrosis factor a ,is an established treatment for Crohn’s disease but not ulcerative colitis.

methods

Two randomized, double-blind, placebo-controlled studies — the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively) — evaluated the efficacy of inflix-imab for induction and maintenance therapy in adults with ulcerative colitis. In each study, 364 patients with moderate-to-severe active ulcerative colitis despite treatment with concurrent medications received placebo or infliximab (5 mg or 10 mg per kilo-gram of body weight) intravenously at weeks 0, 2, and 6 and then every eight weeks through week 46 (in ACT 1) or week 22 (in ACT 2). Patients were followed for 54 weeks in ACT 1 and 30 weeks in ACT 2.

results

In ACT 1, 69 percent of patients who received 5 mg of infliximab and 61 percent of those who received 10 mg had a clinical response at week 8, as compared with 37 percent of those who received placebo (P<0.001 for both comparisons with placebo). A response was defined as a decrease in the Mayo score of at least 3 points and at least 30 percent,with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute rectal-bleeding subscore of 0 or 1. In ACT 2, 64 percent of patients who re-ceived 5 mg of infliximab and 69 percent of those who received 10 mg had a clinical re-sponse at week 8, as compared with 29 percent of those who received placebo (P<0.001for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (P≤0.002 for all comparisons).In ACT 1, more patients who received 5 mg or 10 mg of infliximab had a clinical re-sponse at week 54 (45 percent and 44 percent, respectively) than did those who received placebo (20 percent, P<0.001 for both comparisons).

conclusions

Patients with moderate-to-severe active ulcerative colitis treated with infliximab at weeks 0, 2, and 6 and every eight weeks thereafter were more likely to have a clinical response at weeks 8, 30, and 54 than were those receiving placebo. (https://www.wendangku.net/doc/9112528924.html,

numbers, NCT00036439 and NCT00096655.)

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lcerativ e colitis is character- ized by mucosal ulceration, rectal bleed-ing, diarrhea, and abdominal pain. Phar-macologic management of ulcerative colitis has relied mainly on 5-aminosalicylates, corticosteroids,and immunosuppressants, including purine anti-metabolites and cyclosporine. 1,2 Corticosteroid de-pendence is a clinically important problem 3 ; fur-thermore, the probability of colectomy within the first five years after diagnosis ranges from 9 per-cent in patients with distal colitis to 35 percent in patients with total colitis, most commonly because of failed medical therapy. 4 The cumulative risk of recurrent inflammatory bowel disease in the form of pouchitis ranges from 15.5 percent 1 year after the procedure to 45.5 percent 10 years after the procedure. 5 Accordingly, new treatments for ulcer-ative colitis are needed.

Tumor necrosis factor a (TNF- a ) is a key proin-flammatory cytokine in patients with Crohn’s dis-ease but is also found in increased concentrations in the blood, colonic tissue, and stools of patients with ulcerative colitis. 6-8 However, the role of TNF - a in the pathogenesis of ulcerative colitis has been debated. 9-13

Infliximab, a chimeric IgG1 monoclonal anti-body, binds with high affinity to TNF- a , neutraliz-ing its biologic activity. 14 Infliximab therapy is ef-fective for the induction and maintenance of clinical remission; closure of enterocutaneous, perianal,and rectovaginal fistulas; maintenance of fistula closure; and corticosteroid sparing in patients with Crohn’s disease. 15-18 However, the few small stud-ies of infliximab in patients with active ulcerative colitis have yielded conflicting results. 19-23 We therefore conducted 54-week and 30-week studies of infliximab in patients with moderate-to-severe ulcerative colitis: the Active Ulcerative Colitis Trials

These multicenter, randomized, double-blind, pla-cebo-controlled studies were conducted globally between March 2002 and March 2005 among 364patients at 62 sites in the ACT 1 trial and 364 pa-tients at 55 sites in the ACT 2 trial. The institutional review board or ethics committee at each site ap-proved the protocols. All patients gave written in-formed consent.

All eligible patients had an established diagno-

sis of ulcerative colitis. Patients with positive tu-berculin skin tests with the use of purified pro-tein derivative were ineligible. Also, standard chest radiographs were obtained during screening. En-doscopy (flexible sigmoidoscopy unless surveillance colonoscopy was clinically indicated) with biopsy was performed during screening to confirm the di-agnosis of ulcerative colitis by both the physician performing the endoscopy and the pathologist re-viewing the biopsy specimen. Patients who received a diagnosis of indeterminate colitis, Crohn’s dis-ease, or clinical findings suggestive of Crohn’s dis-ease (i.e., fistula or granulomas on biopsy) were ex-cluded. Eligible patients had active ulcerative colitis with a Mayo score 24

of 6 to 12 points (scores can range from 0 to 12, with higher scores indicating more severe disease activity) (Table 1) and moder-ate-to-severe active disease on sigmoidoscopy (Mayo endoscopic subscore of at least 2) despite concur-rent treatment with corticosteroids alone or in com-bination with azathioprine or mercaptopurine in

*The Mayo score ranges from 0 to 12, with higher scores indicating more se-vere disease. Data are from Schroeder et al. 24

?Each patient serves as his or her own control to establish the degree of abnor-mality of the stool frequency.

?The daily bleeding score represents the most severe bleeding of the day.

§The physician’s global assessment acknowledges the three other criteria, the patient’s daily recollection of abdominal discomfort and general sense of well-being, and other observations, such as physical findings and the patient’s per- formance status.

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ACT 1 or despite concurrent treatment with corti-costeroids alone or in combination with azathio-prine or mercaptopurine and medications contain-ing 5-aminosalicylates in ACT 2. Concurrent therapy was not required at enrollment for patients in ACT 1and ACT 2 who had had no response to corticoste-roids within the preceding 18 months or who could not tolerate corticosteroids, patients in either study who had had no response to azathioprine or mer-captopurine within the preceding 5 years or who could not tolerate these drugs, and patients in ACT 2 who had had no response to medications con-taining 5-aminosalicylates within the preceding 18 months or who could not tolerate such drugs.Rectally administered corticosteroids or medica-tions containing 5-aminosalicylates were not per-mitted within two weeks before screening. Patients previously exposed to infliximab or any other anti-TNF agent were excluded.

study design

Eligible patients were randomly assigned in a 1:1:1ratio to receive intravenous infusions of infliximab (Remicade, Centocor) at a dose of 5 mg or 10 mg per kilogram of body weight or placebo at weeks 0,2, and 6 and then every eight weeks through week 22 in ACT 2 or week 46 in ACT 1. Patients were fol-lowed through week 30 in ACT 2 and week 54 in ACT 1.

Each study used central randomization with a dynamic treatment allocation stratified according to the investigational site and whether patients had ulcerative colitis that was refractory to corticoste-roid therapy. Patients were considered to have ul-cerative colitis that was refractory to corticoste-roids if their symptoms of ulcerative colitis had not improved after they received the equivalent of at least 40 mg of prednisone daily, administered oral-ly for at least two weeks or intravenously for at least one week.

Doses of concomitant medications remained constant except for corticosteroids, which were ta-pered by 5 mg weekly after week 8 until a dose of 20 mg per day was reached. Thereafter, the dose was reduced by 2.5 mg weekly until discontinuation.

follow-up and safety and efficacy evaluations

Patients in both studies were evaluated at weeks 0,2, 6, 8, 14, 22, and 30. Patients in ACT 1 were also evaluated at weeks 38, 46, and 54. The Mayo score (Table 1) was determined at weeks 0, 8, and 30 for

patients in both studies and at week 54 for patients in ACT 1. A partial Mayo score (Mayo score without endoscopy) was determined at all visits.

Clinical response was defined as a decrease from baseline in the total Mayo score of at least 3 points and at least 30 percent, with an accompanying de-crease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1. Clinical remission was defined as a total Mayo score of 2 points or lower, with no individu-al subscore exceeding 1 point. Mucosal healing was defined as an absolute subscore for endosco-py of 0 or 1.

Clinical response, clinical remission, and mu-cosal healing were assessed at weeks 8 and 30 in both studies and at week 54 in ACT 1. Patients who had a clinical response or who were in clinical re-mission at each time were considered to have a sus-tained clinical response or to be in sustained clini-cal remission, respectively.

In both studies, adverse events and concomi-tant medications were recorded at each visit. Se-rum specimens for the identification of antibodies against infliximab and antinuclear antibodies were collected at weeks 0 and 30 in both studies and at week 54 in ACT 1, with the use of previously de-scribed methods. 25 Samples positive for antinucle-ar antibodies were tested for antibodies against double-stranded DNA.

statistical analysis

The primary end point was a clinical response at week 8. Secondary end points were a clinical re-sponse or clinical remission with discontinuation of corticosteroids at week 30 in both studies and at week 54 in ACT 1, a clinical remission and mucosal healing at weeks 8 and 30 in both studies and at week 54 in ACT 1, and a clinical response at week 8 in patients with a history of disease refractory to corticosteroids. Patients who took prohibited medi-cation because of lack of efficacy or loss of response to the study medication, who discontinued the study medication because of lack of efficacy, or who un-derwent a colectomy or ostomy were not consid-ered to have had a clinical response, to be in clinical remission, or to have had mucosal healing from the time of the event onward, regardless of their Mayo score. In addition, patients with insufficient data for the assessment of a response were not con-sidered to have had a clinical response, to be in clinical remission, or to have had mucosal heal-ing at that visit.

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Demographic and baseline characteristics were compared with the use of the chi-square test or Fisher’s exact test for categorical variables and with the use of analysis of variance for van der Waerden normal scores for continuous variables. A two-sid-ed Cochran–Mantel–Haenszel chi-square test, at a significance level of 0.05, stratified according to corticosteroid-refractory status and the location of the study center, was used to compare dichotomous end points (i.e., clinical response, clinical remis-sion, mucosal healing, and clinical remission with discontinuation of corticosteroids) among treat-ment groups. All efficacy analyses used intention-to-treat methods. Safety comparisons were per-formed with the use of Fisher’s exact test and were based on the combination of the two groups receiv-ing infliximab as compared with the placebo group.Assuming a response rate of 30 percent in the pla-

*Plus–minus values are means ±SD.

?P values for all categorical variables except race and smoking status are based on a two-sided chi-square test. P values for race and smoking status are based on Fisher’s exact test. P values for continuous variables are based on analysis of variance for the van der Waerden normal scores. Race was assigned by the local investigator.

?The Mayo scores range from 0 to 12, with higher scores indicating more severe disease. §Elevated baseline C-reactive protein values were those of 0.6 mg per deciliter or more.

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cebo group and a two-sided probability of 0.05, we estimated that 120 patients would be needed in each group to give the study a statistical power of 95 percent to detect an improvement in the re-sponse rate to 50 percent.

These studies were designed and conducted by the steering committees for ACT 1 and ACT 2 and by Centocor. The members of the steering commit-tee and Centocor jointly analyzed and interpreted the data and contributed to the manuscript. The ac-ademic authors had full access to the data and vouch for the veracity and completeness of the data

In ACT 1, 364 patients underwent randomization:121 were assigned to receive placebo, 121 to receive 5 mg of infliximab, and 122 to receive 10 mg of in-fliximab. The baseline characteristics of the patients were similar (Table 2), although the mean duration of disease among patients who received 10 mg of infliximab was longer than among those who re-ceived 5 mg or placebo. Treatment was discontin-ued prematurely by 74 patients in the placebo group (61.2 percent), 45 patients in the group receiving 5 mg of infliximab (37.2 percent), and 49 patients in the group receiving 10 mg of infliximab (40.2 per-cent) (Fig. 1).

In ACT 2, 364 patients underwent randomiza-tion: 123 were assigned to receive placebo, 121 to receive 5 mg of infliximab, and 120 to receive 10 mg of infliximab. The baseline characteristics of the patients were similar (Table 2). More than twice as many patients in the placebo group as in the other two groups prematurely discontinued the study in-fusions (Fig. 1).

efficacy

In ACT 1 at week 8, 69.4 percent of patients in the group receiving 5 mg of infliximab (84 of 121) and 61.5 percent of patients in the group receiving 10mg of infliximab (75 of 122) had had a clinical re-sponse, as compared with 37.2 percent of patients in the placebo group (45 of 121, P<0.001 for both comparisons) (Fig. 2A). In ACT 2 at week 8, 64.5percent of patients in the group receiving 5 mg of infliximab (78 of 121) and 69.2 percent of patients in the group receiving 10 mg of infliximab (83 of

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120) had had a clinical response, as compared with 29.3 percent of patients in the placebo group (36of 123, P<0.001 for both comparisons) (Fig. 2A).In both studies, the proportions of patients who had a clinical response or remission at weeks 8 and 30, and at week 54 in the ACT 1 trial, were higher by a factor of 1.7 to more than 2 in the infliximab groups than in the placebo groups (Fig. 2A and 2B).The rates of clinical response were similar between the subpopulations of patients who were cortico-steroid-refractory and those who were not corti-costeroid-refractory (Table 3).

The proportions of patients with a sustained

clinical response or remission were significantly higher in the infliximab groups than in the placebo groups (Fig. 3). The partial Mayo scores in both stud-ies provide evidence of clinical improvement as ear-ly as week 2 (Table 3).

Mucosal healing at weeks 8 and 30 in each study and at week 54 in ACT 1 occurred in significantly more patients in the infliximab groups than in the placebo groups (P≤0.009 for all comparisons) (Ta-ble 3 and Fig. 2C).

At baseline, 61.0 percent of patients (222 of 364)were receiving corticosteroids in ACT 1, as were 51.1 percent in ACT 2 (186 of 364). The baseline

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median daily corticosteroid dose was 20 mg per day in both studies. The proportions of patients who were in clinical remission and had discontinued cor-ticosteroids at week 30 in both studies and at week 54 in ACT 1 were higher in the infliximab groups than in the placebo groups. Similarly, the decreases in the median daily corticosteroid doses were great-er among patients in the infliximab groups than among those in the placebo group (Table 3).

antibodies against infliximab

At week 54, among 229 patients in ACT 1 who had serum samples available for the assessment of an-tibodies against infliximab, 14 (6.1 percent) had positive tests for antibodies at some point after the first infusion of infliximab (Table 4), 36 (15.7 per-cent) had negative tests (undetectable serum inflix-imab concentrations), and 179 (78.2 percent) had inconclusive tests (negative for antibodies in the presence of detectable serum infliximab concen-trations). Among 188 patients in ACT 2 who had serum samples available for the assessment of an-tibodies against infliximab, 12 (6.4 percent) had positive tests for antibodies, 34 (18.1 percent)had negative tests, and 142 (75.5 percent) had in-conclusive tests.

In ACT 1, a clinical response at week 54 occurred in 3 of 14 patients with positive tests for antibodies (21.4 percent), as compared with 3 of 36 patients with negative tests (8.3 percent) and 103 of 179 pa-tients with inconclusive tests (57.5 percent). In ACT 2, a clinical response at week 30 occurred in 11 of 19 patients with positive tests for antibodies (57.9 percent), as compared with 45 of 79 patients with negative tests (57.0 percent) and 71 of 92 pa-tients with inconclusive tests (77.2 percent).

safety

In the 54-week ACT 1, patients were treated for a mean of 24.2 weeks in the placebo group, 34.8

*Dashes denote not applicable.

?Mayo scores range from 0 to 12, with higher scores indicating more severe disease. A partial Mayo score is the Mayo score without the endo- scopic subscore.

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weeks in the group receiving 5 mg of infliximab,and 33.3 weeks in the group receiving 10 mg of in-fliximab. In the 30-week ACT 2, patients received treatment for 14.4 weeks in the placebo group,19.3 weeks in the group receiving 5 mg of inflix-imab, and 18.6 weeks in the group receiving 10 mg of infliximab (Table 4).

In both studies, the proportions of patients with adverse events were similar in the placebo group and the two infliximab groups (Table 4). In ACT 1,serious adverse events occurred in 25.6 percent of patients in the placebo group, 21.5 percent of pa-tients receiving 5 mg of infliximab, and 23.8 per-cent of patients receiving 10 mg of infliximab. In ACT 2, the respective rates of serious adverse events

were 19.5 percent, 10.7 percent, and 9.2 percent.In both studies, serious adverse events were most commonly related to the gastrointestinal system.In ACT 1, similar numbers of patients in each group discontinued treatment because of an ad-verse event; in ACT 2, more patients in the placebo group than in the two infliximab groups discon-tinued treatment because of an adverse event (Ta-ble 4). Among adverse events in ACT 1, prostatic adenocarcinoma developed in one patient with a two-year history of an elevated prostate-specific an-tigen concentration, and colonic dysplasia devel-oped in one patient; both had received 5 mg of in-fliximab. Basal-cell carcinoma developed in one patient treated with 10 mg of infliximab. In ACT 2,

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basal-cell carcinoma developed in one patient who received placebo, and rectal adenocarcinoma developed in one patient treated with 5 mg of in-fliximab.

Only three neurologic events occurred, all in pa-tients treated with infliximab. In ACT 1, optic neu-ritis developed in one patient who received 5 mg of infliximab. After the completion of ACT 2, a multi-focal motor neuropathy with conduction block syn-drome developed in one patient who received 10 mg of infliximab and optic neuritis developed in one patient who received 5 mg of infliximab.

In both studies, the development of antinuclear antibodies and anti–double-stranded DNA antibod-ies was more common among patients in the in-fliximab groups than among those in the placebo group (Table 4). Only one patient had a lupus-like reaction. This patient was enrolled in ACT 2 and re-ceived 5 mg of infliximab.

The incidence of infections was similar among the groups in both studies (Table 4). In ACT 1, seri-ous infections occurred in five patients (4.1 per-cent) in the placebo group, three patients (2.5 per-cent) in the group receiving 5 mg of infliximab, and eight patients (6.6 percent) in the group receiving 10 mg of infliximab. In ACT 2, serious infections occurred in one patient (0.8 percent) in the placebo group, two patients (1.7 percent) in the group re-ceiving 5 mg of infliximab, and three patients (2.5percent) in the group receiving 10 mg of inflix-imab. In ACT 1, tuberculosis developed in one pa-tient treated with 10 mg of infliximab. Histoplas-ma pneumonia developed in one patient in the group receiving 5 mg of infliximab during the ACT 2 extension, a study phase in which patients who completed the 30-week, double-blind phase —and in the opinion of the investigators would bene-fit from continued treatment — were enrolled and continued to receive the study medication to which they had been randomly assigned. The disease pro-gressed to acute respiratory distress syndrome, re-sulting in the patient’s death.

In ACT 1, infusion reactions occurred in 13 pa-tients (10.7 percent) in the placebo group, 12 pa-tients (9.9 percent) in the group receiving 5 mg of infliximab, and 15 patients (12.3 percent) in the group receiving 10 mg of infliximab (Table 4). A possible delayed hypersensitivity reaction devel-oped in two patients (1.7 percent) in the placebo group and two patients (1.7 percent) in the group receiving 5 mg of infliximab. In ACT 2, infusion re-actions occurred in 10 patients (8.1 percent) in the

placebo group, 14 patients (11.6 percent) in the group receiving 5 mg of infliximab, and 14 patients (11.7 percent) in the group receiving 10 mg of in-fliximab. A possible delayed hypersensitivity reac-tion occurred in one patient (0.8 percent) in the group receiving 10 mg of infliximab.

At week 54 in ACT 1, 35.7 percent of patients with positive tests for antibodies against infliximab (5 of 14) had infusion reactions, as compared with 9.8 percent of patients with negative or inconclu-sive tests (21 of 215). In ACT 2, at week 30, 50.0percent of patients with positive tests for antibod-ies against infliximab (6 of 12) had infusion reac-tions, as compared with 9.7 percent of patients with negative or inconclusive tests (17 of 176). No pa-tient in either study who had a positive test for anti-bodies had a serious infusion reaction or an ana-phylactic reaction. Only one patient in the group receiving 5 mg of infliximab in ACT 1 who had a positive test for antibodies had a serious delayed

clinical remission and minimizing the use of corti-costeroids are unmet goals in the treatment of pa-tients with ulcerative colitis, particularly those who have not had a response to corticosteroids, aza-thioprine, or mercaptopurine. 26 Our results show that infliximab is effective in patients who have mod-erate-to-severe disease despite the use of conven-tional therapy, in terms of a clinical response and remission. As compared with patients who received placebo, patients who received infliximab were sig-nificantly more likely to have a clinical response and be in clinical remission at weeks 8 and 30 in both trials and in week 54 in ACT 1. Similarly, patients who received infliximab were significantly more likely to have mucosal healing at weeks 8 and 30 in both trials and in week 54 in ACT 1. These findings are of particular importance in light of the recent suggestion that mucosal healing is the strongest predictor of a reduced risk of cancer among pa-tients with ulcerative colitis. 27,28

It is noteworthy that these studies were con-ducted in patients who had active disease despite treatment with conventional therapy. At baseline,among all 728 patients, 72 percent were receiving 5-aminosalicylates, 56 percent were receiving cor-ticosteroids, and 46 percent were receiving immu-nosuppressants. Of the patients who were receiv-Downloaded from https://www.wendangku.net/doc/9112528924.html, on May 25, 2006 . Copyright ? 2005 Massachusetts Medical Society. All rights reserved.

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*N D d e n o t e s n o t d o n e , a n d d a s h e s n o t a p p l i c a b l e .?P v a l u e s a r e b a s e d o n F i s h e r ’s e x a c t t e s t f o r t h e c o m p a r i s o n o f t h e c o m b i n e d i n f l i x i m a b g r o u p s w i t h t h e p l a c e b o g r o u p .?D e n o m i n a t o r s r e p r e s e n t p a t i e n t s w i t h n e g a t i v e f i n d i n g s a t b a s e l i n e . T e s t r e s u l t s f o r a n t i n u c l e a r a n t i b o d i e s w e r e c o n s i d e r e d p o s i t i v e i f t h e t i t e r w a s a t l e a s t 1:40. S a m p l e s p o s i t i v e f o r a n -t i n u c l e a r a n t i b o d i e s w e r e t e s t e d f o r a n t i b o d i e s a g a i n s t d o u b l e -s t r a n d e d D N A . T e s t r e s u l t s f o r a n t i –d o u b l e -s t r a n d e d D N A w e r e p o s i t i v e i f t h e t i t e r w a s a t l e a s t 1:10 (a c c o r d i n g t o a c r i t h i d i a a s s a y ) a n d a t l e a s t 5.4 I U (a c c o r d i n g t o F a r r r a d i o i m m u n o a s s a y ).§D e n o m i n a t o r s r e p r e s e n t p a t i e n t s w i t h a p p r o p r i a t e s e r u m s a m p l e s (i .e ., p a t i e n t s w i t h e i t h e r a n t i b o d i e s a g a i n s t i n f l i x i m a b a t s o m e t i m e a f t e r t h e i r f i r s t i n f u s i o n o r a t l e a s t o n e s a m p l e o b -t a i n e d a f t e r t h e i r l a s t i n f u s i o n ).

?I m m u n o s u p p r e s s a n t s i n c l u d e m e r c a p t o p u r i n e a n d a z a t h i o p r i n e .

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2474 ing corticosteroids at baseline, approximately 22percent of patients treated with infliximab had dis-continued corticosteroids by week 30 among 269patients in both studies or by week 54 among 143patients in ACT 1 while maintaining clinical remis-sion. Since corticosteroid therapy is associated with considerable morbidity, 29 this corticosteroid-sparing effect is likely to be clinically meaningful.Our data do not show any major differences in efficacy between the two doses of infliximab that were studied. Thus, the preferred initial dose of in-fliximab in patients with ulcerative colitis is 5 mg per kilogram on the basis of a combination of safe-ty, efficacy, and pharmacoeconomic issues.

In both studies, the proportions of patients re-porting any adverse event were similar among the three groups. The numbers of serious infections,lupus-like reactions, and neurologic diseases were slightly higher among patients treated with inflix-imab than among patients who received placebo.The case of tuberculosis and the fatal case of histo-plasmosis in patients receiving infliximab under-score the need for physicians and patients to re-main vigilant for signs and symptoms of infection.Studies such as ACT 1 and ACT 2 were designed to evaluate efficacy and lack sufficient statistical pow-er to detect differences among treatment groups in the occurrence of rare side effects. The safety find-ings in these studies were similar to the data re-ported in clinical studies of infliximab in patients with Crohn’s disease, 15,16,30-32 in cohort stud-ies, 33,34 and in post-marketing surveillance. 35

The risks of infliximab use must be weighed against the risks of colectomy with the creation of an ileoanal pouch, which include pouchitis in ap-proximately 50 percent of patients, 5 pouch failure in approximately 10 percent of patients, 36 an 80percent reduction in female fecundity, 37 and the in-convenience of nocturnal fecal incontinence in ap-proximately 24 percent of patients. 38

The rate of development of antibodies against infliximab after the three-dose induction regimen and after the maintenance dose every eight weeks in the patients with ulcerative colitis in our studies is similar to that reported for patients with Crohn’s disease. 15,16,25,31 As was true of patients with Crohn’s disease who were treated with infliximab,patients with ulcerative colitis who had positive

tests for antibodies were more likely than those without antibodies to have infusion reactions; how-ever, most of these infusion reactions were mild.In contrast to previous experience, patients with positive or inconclusive tests for antibodies were more likely to have a clinical response at week 30or 54 25 than were patients with negative antibody tests. Patients with negative tests had a lower rate of clinical response at those times, perhaps owing to undetectable serum infliximab concentrations. This effect was most prominent at week 54. Concomi-tant use of mercaptopurine or azathioprine may have protected against the development of anti-bodies against infliximab; however, these findings should be interpreted with caution because of the small number of patients with positive tests for antibodies.

Our results also provide insight into the patho-genesis of ulcerative colitis. Ulcerative colitis is believed to result from an immune response of type 2 helper T cells in the colonic mucosa, where-as Crohn’s disease is considered an immune dis-ease of type 1 helper T cells, which would suggest that TNF- a is not an important mediator in ulcer-ative colitis. Our findings show that TNF- a plays a role in the disease process and that targeting this cytokine is an effective therapy for ulcerative coli-tis. Whether the mechanism of action of infliximab in ulcerative colitis also includes the induction of apoptosis of inflammatory cells expressing mem-brane-bound TNF- a , as in Crohn’s disease, 39 re-quires further investigation.

In conclusion, an induction regimen of three doses of infliximab followed by maintenance infu-sions every eight weeks in patients with moderate-to-severe active ulcerative colitis was superior to pla-cebo in achieving clinical response and remission,mucosal healing, and corticosteroid-sparing effects during 30 to 54 weeks of therapy.

Supported by a research grant from Centocor, Malvern, Pa., and Schering Plough, Kenilworth, N.J.

Drs. Rutgeerts, Sandborn, Feagan, Hanauer, Lichtenstein, and Colombel report having served as consultants for Centocor. Drs.Rutgeerts, Sandborn, Feagan, Hanauer, and Lichtenstein report having participated in continuing medical education events sup-ported by unrestricted educational grants from Centocor. Drs. Ol-son, Johanns, and Travers are employees of Centocor.

We are indebted to Mr. James Barrett at Centocor for editorial

support.

The following principal investigators, listed alphabetically, participated in ACT 1 and ACT 2: L. Abreu, Clinica Puerta de Hierro, Madrid; F.Anderson, Liver and Intestinal Research Centre, Vancouver, B.C., Canada; J.P. Baker, St. Michael’s Hospital, Toronto; P. Bampton, Flinders Medical Centre, Bedford Park, S.A., Australia; M. Barclay, Christchurch Hospital, Christchurch, New Zealand; C. Barish, Wake Research

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Associates, Raleigh, N.C.; C. Beglinger, Kantonsspital Basel, Basel, Switzerland; C.N. Bernstein, Health Sciences Centre, Winnipeg, Man.,Canada; M.A. Bigard, H?pital Brabois Adulte, Vandoeuvre les Nancy, France; D. Binion, Medical College of Wisconsin, Milwaukee; W . Bray,Digestive Health Specialists, Winston-Salem, N.C.; A. Brzezinski, Cleveland Clinic Foundation, Cleveland; J.R. Cangemi, Mayo Clinic–Jack-sonville, Jacksonville, Fla.; R.M. Chasen, Maryland Digestive Disease Research, Laurel; W . Chey, Rochester Institute for Digestive Diseases & Sciences, Rochester, N.Y.; A. Cohen, Jewish General Hospital, Montreal; J. Collins, Oregon Health Sciences University, Portland; F. Com-inelli, University of Virginia, Charlottesville; M. Cottone, Ospedaliera V . Cervello, Palermo, Italy; J.F. Dahlerup, Aarhus University Hospital,Aarhus Kommunehospital, Aarhus, Denmark; G. D’Haens, Imelda Ziekenhuis, Bonheiden, Belgium; A. DiMarino, Thomas Jefferson Uni-versity, Philadelphia; I. Dotan, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; R. Duchmann, Universit?tsklinik Benjamin Franklin, Ber-lin; B. Duclos, H?pital Hautepierre, Strasbourg, France; A. Ertan, Baylor College of Medicine, Houston; J. Fallingborg, Aalborg Hospital South, Aalborg, Denmark; R. Farrell, Beth Israel Deaconess Medical Center, Boston; R. Fedorak, University of Alberta, Edmonton, Alta.,Canada; T. Florin, Mater Adult Hospital, South Brisbane, Qld., Australia; P. Frankish, North Shore Hospital, Takapuna, Auckland, New Zealand; S. Friedman, Brigham & Women’s Hospital, Boston; M. Gaspari, Carolina Digestive Health Associates, Charlotte, N.C.; S. Ghosh,Hammersmith Hospital, London; P. Gibson, Box Hill Hospital, Box Hill, Vic., Australia; B. G?ke, Klinikum der Universit?t München, Mu-nich, Germany; M. Grimm, St. George Clinical School, Kogarah, N.S.W ., Australia; W . Harlan, Asheville Gastroenterology, Asheville, N.C.;A.B. Hawthorne, University Hospital of Wales, Cardiff, Wales; D. Helper, Indiana University Medical Center, Indianapolis; R. Inglese, Valley Gastroenterology Associates, Beaver Falls, Pa.; K. Isaacs, University of North Carolina Hospitals, Chapel Hill; D. James, Green Country Di-agnostics Center, Tulsa, Okla.; M. Kamm, St. Marks Hospital, London; J.A. Katz, University Hospitals of Cleveland, Cleveland; S. Katz,Long Island Clinical Research, Great Neck, N.Y.; B.P. Kaufmann, AGA Clinical Research Associates, Egg Harbor Township, N.J.; J.W . Kon-turek, Elbe Klinikum Stade, Stade, Germany; G. Koval, West Hills Gastroenterology–Portland Digestive Diseases Research Center, Port-land, Oreg.; S. Krumholz, Waterside Clinical Research Services, West Palm Beach, Fla.; G.A. Kullak-Ublick, University Hospital Zürich,Zurich, Switzerland; M. Lane, Auckland Hospital, Grafton, Auckland, New Zealand; M. Lawson, Permanente Medical Group, Sacramento,Calif.; P. Lebovitz, Allegheny Center for Digestive Health, Pittsburgh; J. Leighton, Mayo Clinic Scottsdale, Scottsdale, Ariz.; M. Lemann,H?pital Saint Louis, Paris; H. Lochs, Charite Campus Mitte, Berlin; F . Macrae, the Royal Melbourne Hospital, Department of Gastroenter-ology, Melbourne, Vic., Australia; E. Melzer, Kaplan Medical Center, Rehovot, Israel; P. Miner, Oklahoma Foundation for Digestive Re-search, Oklahoma City; B. Mitchell, Launceston General Hospital, Gastroenterology Unit, Launceston, Tas., Australia; J. Moreau, H?pital Rangueil, Toulouse, France; A.J. Morris, Glasgow Royal Infirmary, Glasgow, Scotland; P.L. Moses, University of Vermont College of Medi-cine, South Burlington; C. Mowat, Ninewells Hospital, Dundee, Scotland; P. Munkholm, Hvidorvre Hospital, University of Copenhagen,Hvidorvre, Denmark; A.H.J. Naber, UMC St. Radboud, Nijmegen, the Netherlands; T. Naftali, Meir Hospital–Sapir Medical Center, Kfar Sa-va, Israel; J. Onken, Duke University Medical Center, Durham, N.C.; R. Panaccione, University of Calgary, Gastrointestinal Research Depart-ment of Community Health Sciences, Calgary, Alta., Canada; P. Paré, CHAUQ–H?pital du St-Sacrement, Quebec, Que., Canada; D. Patter-son, Virginia Mason Medical Center, Seattle; P. Pavli, the Canberra Hospital, Woden, A.C.T., Australia; J.M. Pique, Hospital Clinic de Barcelona, Barcelona; G.B. Porro, University Luigi Sacco, Milan; G. Radford-Smith, Royal Brisbane Hospital, Herston, Qld., Australia; M.Regueiro, University of Pittsburgh Medical Center, Pittsburgh; J. Rhodes, University of Liverpool, Liverpool, United Kingdom; D. Riff, Ad-vanced Clinical Research Institute, Anaheim, Calif.; D. Rubio, Hospital Clinico San Carlos, Madrid; J.S. Sabel, South Denver Gastroenterol-ogy, Englewood, Colo.; M. Safdi, Consultants for Clinical Research, Cincinnati; F. Saibil, Sunnybrook and Women’s College Health Scienc-es Center, Toronto; A. Sambueli, Hospital de Gastroenterologia, Capital Federal, Argentina; E.J. Scherl, New York Presbyterian Hospital,New York; H. Schwartz, Miami Research Associates, Miami; F. Seibold, Inselspital Bern, Bern, Switzerland; J. Shaffer, Hope Hospital,Manchester, United Kingdom; S. Shah, Gastroenterology Associates, Providence, R.I.; D.R. Silvers, Drug Research Services, Metairie, La.;D.B. Stanton, Community Clinical Trials, Orange, Calif.; H. Steinhart, Mt. Sinai Hospital, Toronto; C.D. Stone, Washington University School of Medicine, St. Louis; A. Stronkhorst, Catharina Ziekenhuis, EJ Eindhoven, the Netherlands; J.P . Terdiman, University of California at San Francisco, San Francisco; J. van der Woude, University Hospital Rotterdam, GD Rotterdam, the Netherlands; A. van Gossum, Free University Hospital Erasme, Brussels; P.A.M. van Hees, Sint Antonius Ziekenhuis, CM Nieuwegein, the Netherlands; G. Varilek, Gastroen-terology Specialties, Lincoln, Nebr.; W . Vogel, University Hospital Innsbruck, Innsbruck, Austria; P. Vyhnalek, Hospital Pardubice, Pardu-bice, Czech Republic; I. Wallace, Shakespeare Specialist Group, Milford, Auckland, New Zealand; D.I. Weinberg, Minnesota Gastroenter-ology, Plymouth; L. Wruble, Summit Research Solutions, Memphis, Tenn.; Z.H. Younes, Gastroenterology Center of the MidSouth,Memphis, Tenn.; Z. Zadorova, University Hospital Kralovske Vinohrady, Praha, Czech Republic; M. Zimmerman, Royal Perth Hospital,Perth, W

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New England Journal of Medicine

CORRECTION

In?iximab for Induction and Maintenance Therapy for

Ulcerative Colitis

In?iximab for Induction and Maintenance Therapy for Ulcerative Col-

itis.On page2473in Table4,the percentage of patients in Active

Ulcerative Colitis Trial(ACT)2receiving10mg of in?iximab who had

antibodies against double-stranded DNA should have read6.0,rather

than60.0,as printed.We regret the error.

英语作文关于共享单车的篇精编

(一) 假定你是红星中学初三学生李华。你的美国朋友Jim在给你的邮件中提到他对中国新近出现的一种共享单车“mobike”很感兴趣，并请你做个简要介绍。请你给Jim回信，内容包括： 1. 这种单车的使用方法(如：APP查看车辆、扫码开锁等); 2. 这种单车的优势; 3. 你对这种单车的看法。注意：1. 词数不少于80; 2. 开头和结尾已给出，不计入总词数。提示词：智能手机smartphone, 二维码the QR code 参考范文 Dear Jim, I’m writing to tell you more about the new form of sharing bike mobike mentioned in your latest letter. It’s very convenient to use if you have a smartphone. What you do is find a nearest mobikethrough the APP, scan the QR code on the bike, and enjoy your trip. Compared to other forms of sharing bike, the greatest advantage of mobike is that you can easily find one and never worry about where to park it. It is becoming a new trend as a means of transportation, which relieves the traffic pressure and does good to the environment as well. Hope to ride a mobike with you in China. Yours, Li Hua (二) 最近很多大城市都投放了共享单车(shared bikes)，比如摩拜单车(Mobike)、Ofo共享单车等。由于它们方便停放，骑车也能起到锻炼身体的作用，作为代步工具很受大家欢迎。但是，各地也出现了很多毁车现象，比如刮掉车上的二维码(QR code)、上私锁等。你对这种现象怎么看?你对共享单车公司有什么建议吗?写一篇符合逻辑的英语短文，80词左右。参考词汇：bike-sharing companies 共享单车公司，Mobike 和Ofo 是两家共享单车公司，convenience 方便，register登记参考范文 The shared bikes like Mobike and Ofo bring great convenience to people. You needn’t lock them by simply using your smart phone. They can take you where the subway and bus don’t go. And they can be left anywhere in public for the next user. However, bad things happen. Some people damage the QR code on the bike, or use their own lock, which causes trouble to other users. In my opinion, it’s difficult to turn these people’s ideas in a short time. Therefore, bike-sharing companies like Mobike and Ofo need to do something. For example, those who damage the bike should pay for their actions. Also, because people use their real name toregister as a user, it’s a good way to connect to one’s personal credit. In the end, what I want to say is to take good care of public services. (三) 共享单车(bicycle sharing)已成为时下最热的话题之一，请你就这一话题写一篇短文。内容须包括三方面：1. 共享单车蓬勃发展，成为社会热潮;2. 共享单车带来便利，但也存在问题;3. 我对解决问题的建议。参考范文 Bicycle Sharing With the development of technology, bicycle sharing comes into people's lives. It becomes more and more popular and much news reported it. At the same time, we should see that there are some problems caused by bicycle sharing. On one side, bicycle sharing makes it very convenient of people traveling. You can find a bicycle anywhere at any time when you want to go out for a cycling, and the price of one trip is very low. It can save time for people. On the other side, its management is not perfect. Even kids can open the lock and ride the bicycle, there is no doubt that such behavior is very dangerous.

脐带干细胞综述

脐带间充质干细胞的研究进展间充质干细胞（mesenchymal stem cells,MSC S ）是来源于发育早期中胚层的一类多能干细胞[1-5]，MSC S 由于它的自我更新和多项分化潜能，而具有巨大的治疗价值 ,日益受到关注。MSC S 有以下特点：(1)多向分化潜能，在适当的诱导条件下可分化为肌细胞[2]、成骨细胞[3、4]、脂肪细胞、神经细胞[9]、肝细胞[6]、心肌细胞[10]和表皮细胞[11, 12]；(2)通过分泌可溶性因子和转分化促进创面愈合；(3) 免疫调控功能，骨髓源（bone marrow ）MSC S 表达MHC-I类分子，不表达MHC-II 类分子，不表达CD80、CD86、CD40等协同刺激分子，体外抑制混合淋巴细胞反应，体内诱导免疫耐受[11, 15]，在预防和治疗移植物抗宿主病、诱导器官移植免疫耐受等领域有较好的应用前景；(4)连续传代培养和冷冻保存后仍具有多向分化潜能，可作为理想的种子细胞用于组织工程和细胞替代治疗。1974年Friedenstein [16] 首先证明了骨髓中存在MSC S ，以后的研究证明MSC S 不仅存在于骨髓中，也存在于其他一些组织与器官的间质中：如外周血[17]，脐血[5]，松质骨[1, 18]，脂肪组织[1]，滑膜[18]和脐带。在所有这些来源中，脐血(umbilical cord blood)和脐带(umbilical cord)是MSC S 最理想的来源，因为它们可以通过非侵入性手段容易获得，并且病毒污染的风险低，还可冷冻保存后行自体移植。然而，脐血MSC的培养成功率不高[19, 23-24]，Shetty 的研究认为只有6%，而脐带MSC的培养成功率可达100%[25]。另外从脐血中分离MSC S ，就浪费了其中的造血干/祖细胞(hematopoietic stem cells/hematopoietic progenitor cells,HSCs/HPCs) [26, 27]，因此，脐带MSC S (umbilical cord mesenchymal stem cells, UC-MSC S )就成为重要来源。一．概述人脐带约40 g, 它的长度约60–65 cm, 足月脐带的平均直径约1.5 cm[28, 29]。脐带被覆着鳞状上皮，叫脐带上皮，是单层或复层结构，这层上皮由羊膜延续过来[30, 31]。脐带的内部是两根动脉和一根静脉，血管之间是粘液样的结缔组织，叫做沃顿胶质，充当血管外膜的功能。脐带中无毛细血管和淋巴系统。沃顿胶质的网状系统是糖蛋白微纤维和胶原纤维。沃顿胶质中最多的葡萄糖胺聚糖是透明质酸，它是包绕在成纤维样细胞和胶原纤维周围的并维持脐带形状的水合凝胶，使脐带免受挤压。沃顿胶质的基质细胞是成纤维样细胞[32]，这种中间丝蛋白表达于间充质来源的细胞如成纤维细胞的，而不表达于平滑肌细胞。共表达波形蛋白和索蛋白提示这些细胞本质上肌纤维母细胞。脐带基质细胞也是一种具有多能干细胞特点的细胞，具有多项分化潜能，其形态和生物学特点与骨髓源性MSC S 相似[5, 20, 21, 38, 46]，但脐带MSC S 更原始，是介于成体干细胞和胚胎干细胞之间的一种干细胞，表达Oct-4, Sox-2和Nanog等多

介绍北京的英语作文(2)

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