Clinical features and natural history of Crohn's disease

GASTROENTEROLOGY

Clinical Features Crohn’s Disease

77:898-906,1979

and Natural History of

HAGOP S. MEKHJIAN, DONALD CLIFFORD S. MELNYK, GEORGE and RICHARD K. BROOKS

M. SWITZ, B. RANKIN,

Division of Gastrocnterology, Ohio State University Hospital, Columbus, Ohio; Division of Gastroenterology, Virginia Commonwealth University, Richmond, Virginia; Division of Gastrotmterology, University of Oregon School of Medicine, Portland, Oregon; and Department Gastroenterology. Cleveland Clinic Foundation, Cleveland, Ohio

Records of 1084 patients entered into the National Cooperative Crohn’s Disease Study were analyzed to gather information concerning the natural history and clinical features of Crohn’s disease. The age of onset reached a single peak between the second and fourth decade dnd was evenly distributed in both sexes. There was an average interval of 35 mo from onset of symptoms to diagnosis. Involvement of both colon and terminal ileum was the most frequent pattern and was present in 55% of patients. The disease was confined to the terminal ileum, other areas of the small intestine, or colon-only in 14%, 3%, and 15% of patients, respectively. Sigmoidoscopic abnormalities were seen in 34% of all patients and 51% of patients with Crohn’s colitis. Diarrhea, abdominal pain, weight loss, and fever were present in the majority of the patients. Lower GI bleeding, fever, and perianal complications characterized patients with colon-only involvement. The frequency of extraintestinal manifestations was similar in all groups. Among patients who were randomized to placebo, 32% achieved a spontaneous remission by the end of 17 wk, and 53~~ of these were still in remission at the end of 24 mo. Clinical remission was associated with an improvement in barium x-rays in 18% of the patients. The predicted factors associated with favorable outcome in placebo-treated patients were: previous surgical removal of all observable disease, absence of perianal disease, and Crohn’s Disease Activity Index value under 200.

Address requests for reprints to: National Cooperative Crohn’s Discase Study, Box B-158, 4200 E. 9th Avenue, Dcnvcr, Colorado 80262. 0 1979 by the American Gastroentcrological Association 0016.5085/79/100898-09$0200

of

Information about the natural history of Crohn’s disease is important for the interpretation of the results of treatment trials, for development of prognostic and management guidelines, and because little information is available concerning the course of disease affecting patients without prior surgical or medical treatment. The National Cooperative Crohn’s Disease Study (NCCDS) offered a large group of patients of diverse geographic origin from whom clinical data had been gathered in uniform fashion. These data have been analyzed in order to better characterize the natural history of the disease and to identify factors which might have predictive value in its clinical course. Specifically, the clinical course and characteristics of Crohn’s disease involving different segments of the gastrointestinal tract have been compared, the outcome of patients who had received no prior medical or surgical therapy has been determined and compared with that of previously treated patients, and the course of patients given only placebo treatment during z yr of follow-up has been characterized.

Patients

and Methods

Patients All patients the

14 study

Crohn’s

being

centers

disease

were

cases

were

referred

cians.

The

diagnosis

presence

of typical

ings as described At the time

followed

with

the

entered to the

histologic

in companion of entry

into

study

of Crohn’s

by the investigators established the study. from

disease and/or papers.’

to the study,

at

diagnosis In addition,

community was

of

physi-

based

on the

radiographic

find-

.’

each

patient

had

the

NATlJRAL

following data recorded on a standard form: date of onset of symptoms. date of diagnosis, date of most recent three operations for Crohn’s disease, sex, race, prior medical therapy for Crohn’s disease, location and maximal extent of bowel involvement with Crohn’s disease, and time of involvement of each segment. In addition prior records of hospitalization and surgery of randomized patients were obtained. Problems of inconsistencies or missing data were resolved insofar as possible by further record search. Five hundred sixty-nine patients were randomized, and an additional 515 patients entered the study but were excluded from randomization because of a variety of exclusion criteria. A detailed description of the randomization scheme. allocation of patients to treatment groups, and exclusion criteria is given in the companion paper on Conduct of Study.’ Three groups of patients were analyzed in special detail: The 178 patients randomized to placebo, the 60 patients with involvement of the colon-only, and the 68 previously untreated patients. Unless otherwise indicated mean f standard deviation is given for quantitative data in the sections that follow.

Summary

of Study

Design

Each patient was followed periodically with protocol-specified clinical and laboratory procedures.’ The study consisted of two parts: part I, which assessed the therapeuiic effect of prednisone, sulfasalazine, or azathioprint compared to placebo in patients with active disease, and part II which evaluated the effect of each drug in comparison to placeho in patients with quiescent disease. If disease worsened, patients were withdrawn from study hy predetermined criteria. Nine percent were withdrawn for noncompliance: with the protocol, and 4% withdrew for reasons unrelated to Crohn’s disease or therapy; these patients were evenly distrihuted among the four treatment groups. ’

Evaluation

of Outcome

The Crohn’s Disease Activity Index (CDIA)” was used as a uniform measure of severity of disease in all patients at randomization. This is a numerical expression for the patient’s degree of illness, composed of eight items each shown to correlate with physicians’ global estimate of patient illness. The Index is scaled in such a way that values below 150 occur with quiescent disease or remission, values between 150 and 300 indicate moderate severity, and values ahovc 300 indicate severe illness. The Wilcoxon Rank Sum test was the primary method of statistical comparison of the outcome of treatment in different groups of patients.’ A secondary method for evaluating outcome used life tables constructed by the method of Kaplan and Meier.” The Cox method’ was used to compare lift tables of outcome. Barium radiographs of the entire gut. taken at randomization and completion of the study on every patient, were evaluated under code by the study Radiology Panel to assess change in severity of involvement and length of bowel involved.,’

Predictors

HISTORY

OF CROiiN’S

DISEASE

899

of Outcome

The evaluation of the importanc,e of possible prognostic factors was done hy stepwise multiple linear rcgression.“’ The percentile rank outcome was taken as the “rcvariable, Y. Twenty-seven sponse” or “dependent” candiate prognostic factors (Tahlr A) w(‘rc the “regressor” or “independent” variables: X,, X_,, , X,.. Y was expressed as the “best fitting” (least squares) linear function of thr: Xs: Y = h,, + h,X, + b,X, + + h,,X,,. That variable, the deletion of which would least diminish the goodness of overall prediction, was deleted at each stage. A P-value was then calculated for each remaining coefficient reflecting the likelihood that ;I coefficient of absolute magnitude at least as large> as observed might hc: seen hy chance alone in the face of a zero coefficient in the population. When all remaining such f’-values were equal or less than 0.05, the process was terminated. The remaining variables were the factors considered to have prognostic significance. One must realizrt. however, that when thcrt: is a high intercorrelation hratwcrln prcdictnr variahles, some may be deleted which in the absence of the would have’ bran rc>lativc:ly good pretlic:other variables tnrs. Stlldent’s t-test” was used to compare> the sex ratios and ago distributions of the randnmizc!d and excluded patients.

Results Clinical

Features at Entry

Demographic data. A(:E. The age of patients to the placebo group in parts I and I1 of the study was 33.7 f 11.7 and 31.6 + 11.7 yr, respectively. The age distribution of patients with ileocolitis, small-bowel-only involvement, and colon-only involvement was similar. There was no secondary peak of incidence among older patients with disease limited to the colon. The age distributions of randomized and excluded patients were virtually idcntical (mean age: 31.5 ?Z 11.4 vs. 32.3 f 13.3 yr). SEX. 52% of randomized patients and 46% of excluded patients were male. RACE. 94% of patients wore of Caucasian race in both the randomized and excluded groups. Duration of symptoms before diagnosis ond randomization. The mean interval between onset of symptoms and randomization was 76.9 f 77 and 72 -+ 71 mo for patients in parts I and II, respectively. The mean interval from definite diagnosis to randomization was 42.6 + 58 mo and 39.2 + 56 mo for parts I and II, respectively. Thus there was an average interval of about 35 mo from onset of symptoms to the time of diagnosis of Crohn’s disease. The duration of symptoms before randomization was shorter for patients with Crohn’s colitis than for those with small bowel disease (58.9 f 56.5 and 69.3 -+ 67.1 mo, respectively). As might be expected, unrandomized

900

Table

MEKHJIAN

1.

ET AL.

Drug Treatment

for Crohn’s

Disease

Taken

at Any

Time Before Randomization

All randomized patients (n = 569) Drug

Number

Sulfasalazinc Antibiotics or other Azathioprinc Systemic Steroid Rectal Steroid I’These

60 colon-only

379 139

sulfa

19

patients

Vol. 77, No. 4, Part 2

GASTROENTEROLOGY

are included

W)

All excluded patients (n = 515) Number 376

(67)

27

(3)

(65)

53

(9)

46

(9)

treated patients had a short interval from onset (35 mo) and diagnosis (5.6 mo) to randomization. History of prior medical therapy. The history of prior drug therapy in the randomized, excluded and colon-only patients is given in Table 1. The three groups were very similar in this respect. Location and extent of disease. Table 2 shows that the sites of involvement in randomized and excluded patients were very similar. The small intestine was involved in 89% of randomized patients and the colon in 69%. Isolated involvement of the small bowel was present in 31% of randomized patients, with only terminal ileum being involved in half of these. The colon alone was involved in 11% of randomized patients, and the combination of colon and small bowel involvement was most common, occurring in 58% of randomized patients. Severity of disease at randomization. Figure 1 illustrates the distribution of CDAI values at randomization in all randomized patients and in the colon-only and untreated subgroups. At the time of randomization the mean CDAI for colon-only patients, untreated patients and all patients was 174 f 105, 196 + 92, and 170 & 58.4, respectively. No CDAI was calculated for excluded patients. Thus no major differences existed in the severity of Crohn’s disease among these three groups. Surgical status at’ randomization. The surgical history of randomized and excluded patients was similar. The surgical history of the combined group of randomized (n = 596) and excluded (n = 515) patients is related to their age in Figure 2. Among the randomized patients, 252 or 44% had never been operated for Crohn’s disease at the time of randomization; 421 (74%) had never had a second operation for Crohn’s disease; 67 patients (12%) had had three or more operations. Table 3 lists the type of surgical procedure as well as the frequency of each procedure in randomized and excluded patients. The only notable difference between patients in parts I and those in II is that 18% of the part II patients had had extirpative surgery within a year of randomization without recurrence. This difference is an artifact of

(67)

13

(22)

2

(5)

334

the 569 randomized

40

(26)

(59)

(‘X,)

Number

(73)

134

(24)

Colon-only patients” (n = 60)

(W

335

among

or Exclusion

(3)

38

(63) (23)

14

patients

the study design because any patient who had had surgery within the year before randomization and had a recurrence of active disease (i.e., CDAI > 150) would have been included in part I of the study. Clinical manifestations at randomization. Some important clinical manifestations of the randomized patients and of the colon-only and previously untreated subgroups are listed on Table 4. The low incidence of liver disease did not result from the fact that liver disease was an exclusion criterion from the study as only 12 of 1084 patients were excluded for this reason. In the entire group of

Table

2.

Patterns Crohn’s Patients

of Involvement of the Bowel with Disease in Randomized and Excluded

Pattern of bowel involvement” Small-bowel-only Only terminal ileum Only proximal to terminal ileum Both proximal and terminal ileum Colon-only Sparing rectum Rectum and proximal colon Rectum only” Colon and small bowel Colon + rectum + terminal ileum Colon k rectum + proximal small bowel Colon f rectum + both terminal ileum + proximal small bowel Rectum + small bowel

Randomized patients n = 569

Excluded patients n = 515

Total n = 1084

177 (31) 79 (14)

152 (29) 70 (14)

329 (30) 149 (14)

15 (3)

17 (3)

32 (3)

A3 (15) 60 (11)

148 (14) 156 (15)

27 (5)

65 (13) 96 (19) 36 (7)

33 (6) 0 332 (58)

50(10) 10 (2) 267 (52)

63 (6) 10 (1) 599 (55)

152 (27)

117 (23)

269 (25)

16 (3)

29 (6)

47 (4)

127 (22)

101 (20)

226 (21)

35 (6)

16 (3)

51 (5)

63 (6)

I’Figures in parenthesis give percentages of total number tients in the group. ” Patients with involvement confined rectum were excluded from the study as a requirement protocol.

of pato the of the

!I01

NATIJRAL HISTORY OF (:ROHN‘S DISEASE

placebo-treated patients had achieved a CDAI below 150 on at least one occasion before 17 wk. Patients who received placebo in phase 1 of part I showed an average decrease of 3.2 cm in length of small bowel involved with disease. Although this change was statistically “significant,” it may rcpresent chance occurrence of a difference this large when multiple comparisons w:crt: made. Eighteen percent of patients treated with placebo were judged to have had improvement in their barium x-rays.

CDAI

The Cfinicul Course of Patients Plucebo in Part II

-25

0

100

50

150

200

250

300

350

400

+

CDAI

All

H,in
0

50

100

150

200

250

outcome of placebo patients in part II is in Figure 4. At the end of 1 yr 28% of pasuffered a relapse and 41% had relapsed of 2 yr.

Surgery Treated

Pat,?“,\

$!! -25

The illustrated tients had by the end

300

350

400

+

CDAI

for Crohn’s

Disease

in Plucebo-

Patients

In the course of their participation NCCDS 19 of the 178 patients (11%) in the group underwent abdominal operations for disease. The indications for surgery and the procedures performed in these patients are Table 6.

F‘igrlrc 1. ‘The distribution of CDAI values at randomization for al1 randomizcxl patients and for patients with diwasc confint~d to the c:olon and those: not previously trtratcd.

randomized patients, the sigmoidoscopy was abnormal in 34% and was characteristic of Crohn’s disease in 16% (Table 5). When only the colon was involved, diagnostic sigmoidoscopic and biopsy findings were seen in 28%) and 22% of the patients, respectively. Stool tests for occult blood were positive in 40% of colon-only patients and in 27% of the entire group. The presence of a definite abdominal mass was noted on initial physical examination in 14% of patients in part 1 and 6% of patients in part II.

Toking

Factors Taking

Predictive Plucebo

of the Outcome

in the placebo Crohn’s surgical listed in

of Patients

Several characteristics of patients randomized to placebo treatment in part I proved useful in predicting their subsequent course. The 23 patients who entered with recurrent disease after complete resection ranked significantly better in outcome than the 54 patients who entered with no prior history of

Number 360

390

of 150

Peteenls 107

77

1084

100 Operations Crohn’s

7’he Clinical Course Placebo in Port I

of Patients

for Dosease 0

Taking

1 2

The outcome of patients randomized to placebo (n = 77) in part I, phase 1 is illustrated in Figure 3 (curve A) as a life-table plot of the cumulative incidence of CDAI of less than 150 for the first time. Also illustrated (curve B) is the cumulative incidence of improvement (CDAI < 150) which persisted throughout the remainder of 17 wk. By 17 weeks, 30% of placebo patients had achieved and maintained a CDAI less than 150. Forty-nine percent of

3 or more

IS-24

‘%

3s-44

45-54

55 +

TOtal

Age Figure

2.

Surgical history rolatod tu agv for all patients r:ntcrc:d in tho study. Operations for Crohn‘s distrast~ include pwanal surgery.

902

Table

MEKHlIAN

3.

ET AL.

Surgical

GASTROENTEROLOGY

Status of Randomized

and Excluded

No abdominal surgery for Crohn’s disease Number Part I (n = 295) Part II (n = 274) Total parts I and II (n = 569)

192 147 339

Excluded

271

patients

(n = 515)

(“/) (65) (54) (60) (53)

Vol. 77, No. 4, Part 2

Patients

Complete resection with recurrence Number

Partial resection with persistence (W)

Number

Bypass with persistence (“/)

Number

83 61 144

(28) (22) (25)

15 11 26

(5) (4) (5)

1;

176

(34)

28

(5)

12

surgery or after incomplete resection (P < 0.03). Patients with perianal disease and those with initial CDAI value greater than 200 ranked significantly poorer in outcome than patients without these characteristics at randomization (P = 0.002 and P < 0.001, respectively). The course of patients who were and those who were not taking systemic steroids at the time of randomization is shown in Table 7. Twenty percent of patients withdrawn from systemic steroids at randomization achieved a subsequent remission while 41% of placebo-group patients who had not been taking steroids achieved remission. Comparison of the outcome rank of patients in these two groups reveals that the prior-steroid group ranked worse, but the difference was not statistically significant (P = 0.2). The fate of previously untreated patients randomized to placebo was of particular interest. The number of such patients in part I, only 13, was too small to permit construction of meaningful life-table plots. However, by 17 wk, 33% of such patients had achieved and maintained a CDAI below 150, and 50% were still on-study. This result is very similar to that of all patients receiving placebo (Figure 3, curve B), suggesting that the short-term course of untreated patients was similar to that of previously treated patients when randomized to placebo. None of the other prognostic factors (Table 8) examined showed any significant predictive value in patients who received placebo. There was no correlation between outcome and age of the patient, presence or absence of anergy, or presence or absence of any extraintestinal manifestation of Crohn’s disease.

Discussion This study provides clinical information on a large number of patients with documented Crohn’s disease. The demographic characteristics of this group of patients, drawn from 14 cities across the

Complete resection within 1 yr before randomization without evidence of recurrence

5

(“/)

(‘Yn)

Number

(2) (3) (2) (2)

48 48 28

(18) (6) (5)

United States, are in general agreement with previous data.‘“-” The patients randomized were closely similar in all respects analyzed to those excluded. Thus the randomized patients are representative of the Crohn’s population at the 14 study centers, and it is reasonable to suppose may also be representative of such patients in the United States as a whole. The clinical history of Crohn’s disease in this group of patients was consistent with previous reports.‘,‘.‘4 The age distribution of our patients shows a peak between the second and fourth decade. We did not observe a secondary peak of incidence above 50 yr of age among those patients with disease involving only the colon: it has been suggested that such a peak in some studies may be secondary to the inclusion of cases of ischemic colitis misdiagnosed as Crohn’s colitis.‘“,“’ The interval of 35 mo from the onset of symptoms to the diagnosis of Crohn’s dis-

Table

4.

Clinical Manifestations Observed at Randomization or by History in Patients Randomized

Diarrhea Abdominal pain Lower G.I. bleeding Weight loss (> 5 lb.) Fever Anal fissure, abscess, or fistula Other internal fistula Enterocutaneous fistula Arthritis or spondylitis Iritis Hepatitis. pericholangitis Erythema nodosum/ pyoderma gangrenosum

to the NCCDS Total

Colon-

patient group (n = 569)

only patients (n = 60)

(“/)

(%)

92 95 41 R5 56 36

92 93 62 f36 72 47

93 94 32 82 36 12

16 5 19 4 4 5

8 3 22 7 5 8

6 0 18 3 0 3

Untreated patients (n = 68) _~..__

(C)

oc.lohc~r

Table

NATIJRAL

1979

Sigmoidoscopic and Histologic Findings in all Randomized the Colon and those not Previously Treated

5.

Patients

RANDOMIZED Typical

Normal Number

(1%)

Number

Crohn’s ____ (‘a)

HISTORY

OF (:ROHN’S

with Disease

and in Patients

PATIENTS

9t13

DISEASE

Limited

(n = 569)

Abnormal,

atypical

(Inknown”

Number

(‘%)

Number

(‘X,)

Sig appcaranw

353

(62)

91

(16)

100

(18)

25

(4)

Hislology

324

(57)

54

(

152

(27)

39

(7)

nppcaranw

9)

COLON-ONLY 24 25

Sig appt:,~ranc:c: Histology ;~ppc:arancc

(40) (42)

(n = 60)

17

(28)

14

(23)

5

(8)

13

(W

17

WI)

5

Ku

IJNTREATED

PATIENTS

(n = 66)

Sig appcxanw

37

(54)

16

(24)

13

(19)

2

(3)

Histology

31

(46)

13

(19)

2.2

(32)

2

(3)

appcarancc

I’Sigmoidoscopy study, patient

or rectal biopsy refusal, etc.

was not obtained

on these

patients

ease highlights the difficulties involved in its diagnosis. The somewhat shorter interval in the patients with Crohn’s colitis suggests that the clinical manifestations of colitis are more readily recognized. The pattern of bowel involvement in our randomized patients is also similar to that of other American seriesi While the small intestine was involved in 89% of cases, disease limited to the small intestine

‘0

r

60 t

5

0

10

15

Weeks

A

*77

B

77 *No

Figure

60

:j.

56

52

46 69

72 at

49

67

44

43 64

42

41

40

62 60 59 58 57

risk

Ltftr-tablr plot of the cumulative incidence among placxhr, patients of CDAI less than 150 for the first time (A), and of CDAI less than 150 and staying below 150 to

I hc

vnd

of 17 wk (B).

for a variety

to

of reasons,

e.g., severe

pcrianal

discasc:,

recent

barium

was present in only 31%. Only the colon was inand the combination of the volved in 11% of patients colon and terminal ileal involvement (i.e., ileocolitis) was the most frequent presentation, occurring in 58% of patients. This distribution of patterns of involvement differs strikingly from that reported in Great Britain and Australia where recent series find with disease confined to the coover 50% of patients lon.‘,‘“’ The pattern of bowel involvement is important since the site of involvement has prognostic implications, ileocolitis being associated with the highest recurrence rate after surgery.“’ The major clinical manifestations of diarrhea, abdominal pain, and weight loss were seen in a high percentage of patients. Colon-only patients more frequently had lower GI bleeding and perianal disease. Sigmoidoscopic abnormalities and occult blood in the stools were also most frequent in the colon-only group compared to the rest of the randomized patients, a finding consistent with the significantly higher incidence of abnormalities on biopsy in our patients with colon disease.-’ IJnlike the series reported by Greenstein et al.,-“’ the incidence of extraintestinal manifestations was similar in colon-only patients and the entire group. The incidence of diagnostic sigmoidoscopic abnormalities has been a subject of some debate in the literature. Some authors have reported a high incidcnce of abnormalities in the rectum when the colonic mucosa is examined by sensitive techniques such as measuring the transmucosal potential difference.” Similarly, it has been stated that if serial sections are obtained from biopsies of normal appearing colonic mucosa even more diagnostic abnormalities are noted.” 24The 16% incidence of diagnostic abnormalities observed in our studies is

904

MEKHJIAN

ET AL.

Of 6

Figure

4. Percentage

GASTROENTEROLOGY

12

I8

of patients remaining in remission cebo after entering with quiescent disease.

24

on pla-

probably representative of the practice and the findings of clinical gastroenterologists and pathologists who do not employ such specialized techniques. The outcome of patients taking placebo was significantly worse than that of patients taking either prednisone or sulfasalazine in part I, phase 1.” However, after 4 mo 30% of placebo patients had undergone a spontaneous remission, and among those who had not been taking systemic steroids at randomization the remission rate reached 41% (Table 7). This confirms that spontaneous remission does occur in patients with Crohn’s disease and emphasizes that evaluation of drug therapy requires a conin the current placebo group.25 The improvement barium x-rays of 18% of patients randomized to placebo may have resulted either from spontaneous remission or may simply indicate the variability of the radiographic appearance during a period of careful follow-up. Moss et al.” have recently reported radiographic improvement in 57% of patients with Crohn’s disease who were treated with broad spectrum antibiotics in an uncontrolled study. Our findings raise the possibility that some of the improvement noted by Moss et al. might have been unrelated to the antibiotic therapy. Several factors appeared to correlate with prognosis on placebo treatment in part I, i.e., predict the short-term course of untreated Crohn’s disease. Patients taking systemic steroids immediately before randomization to placebo had outcomes generally worse than those who had not been taking steroids before randomization. Only 20% of patients in the former group were in remission at 4 mo compared with 41% of the latter group, and at the end of 2 yr 4% and 23%, respectively, remained in remission

Vol. 77, No. 4, Part 2

(Table 7). A likely explanation for this finding is that patients with more severe clinical illness had been placed on steroids before entry to the study with resultant partial improvement. When the steroids were withdrawn, their more severe illness was again manifest. Other predictive factors individually associated with a favorable outcome for placebo-treated patients in part I were: previous removal of all observable disease, absence of history or findings of perianal disease, and CDAI under ZOO. The only surprise among these predictive factors was the finding that patients with active recurrent disease had a significantly better outcome while taking placebo treatment than those with disease which had been bypassed or never operated. Patients with recurrent disease may indeed have a milder short-term course than those with unoperated disease of long standing. One factor was of particular interest as showing no correlation with outcome of placebo treatment. Age of onset of Crohn’s disease has been thought to influence the course, with disease beginning at a young age having worse prognosis than that starting later in life,“.““” The lack of significant correlation between age of onset and outcome on placebo or any drug in either part I or part II of the NCCDS speaks against this contention. The fate of previously untreated patients randomized to placebo was particularly revealing of the natural history of Crohn’s disease. Two factors may have been responsible for the similarity of the course of these patients to that of patients previously treated with either surgery or the study medications. Since patients with a history of prior surgery had better outcome than those without prior surgery (see above), that factor would tend to favor the previously treated patients. On the other hand,

Table

6. Indications for Surgery and the Surgical Procedure Performed in the 178 Patients Randomized to Placebo

Number of Patients 10

Intestinal

4

Abscess

3

Increase in symptoms attributable to Crohn’s disease Free performation of ileum Enteric fistula

1 1 TOTAL

19

Procedure

Indication Obstruction

Intestinal Resection anastomosis Drainage and/or Bypass (3) Rescction (1) Resection

Resection Resection

and

NATlJRAL

oc:tl,t,r~r 1!17Y

T&e

Outcome

7. Clinicnl

~ Oft study during phase: Nllrnhc>r

I3

1 (%) (27)

of Phcebo

Patients

PATIENTS ~~._ Off study at and of phase 1 Number 9

(‘X1)

IO

(34)

10

(34)

WITH

NO PRIOR

(XI)

19

(25)

STEROID

In remission t:nd of phase Num her 15 WITH

PRIOR 5

COMBINED .___~~~~.__~.._ 23

OF (:ROkIN‘!i

DISIIASF.

905

Part 1 (n = 77)

(19) PATIENTS

HISTORY

20)

I” (‘X1)

THERAPY (n = 46) ___~ Off study during phase 11”

STEROID

GROUP (32)

Numht~r

(8)

I(

(23)

4

(14)

1

(4)

8

(10)

Y

(15)

4 THERAPY

(20)

(‘WI)

(1%)

Number

(41)

In rc,mission r.ntl of phase II

(n = 29)

(n = 77)

ratt: is calculated hy dividing tht: numhr!r of ” El~von p;ltir,nts c:;rmc’ off study during phase I and 3 patients during phasr II. ‘Tho remission paticants in remission hy the total number of patients in the group minus those coming off study for nonCrohn’s rtrlatod causes. ” Four patlcnts cam,: off study during phase I for noncrohn‘s discas,: rclatcd canscs. No patient came off during phase I1 for nonCrohn’s tlis-

abscnc:e of prior steroid treatment would bc a favorable factor for thr! untreated patients. The net result of theso two factors may explain the similarity of (;ourscs of the two groups in part I, phase I. In part II, since none of the drugs showed any beneficial effect, it is not surprising that patients without prior medical treatment demonstrated a course similar to that of previously treated patients. ‘I’clblr: 8. Variables

Used in Step-Wise Multiple Linear Regression Progrom for Predictors of Percentile Rank of Outcome

Complotc rc:st:c:tion with rocurrcnce Partial rt’sctction with pcrsistcnce Bypass with pcrsistcnco Arthritis or spondylitis Iritis ilcpatitis. pcricholangitis Erythrma nodosum or pyodcrma gangrenosum Internal fistrlla (othu than pcrianal) Entc:roc:llt;lnc:o~ls fistula Pcrianal disoasc~ Abdominal pain During of discasc since! onset Duration of discaso since diagnosis Agr, at c1nsc:t Taking steroids at entry Taking sulfasalazinc: ‘It entry FIistory of small howcl involvcmcnt Chnr;ic:tc:ristic:s dctormmtrd at entry Maximal c*xtcnt of small bowel involvement Maximal c,xtcnt of colon involvement Maximal t:xtcnt of total involvcmcnt Skin tr*st rcactivlty CDAI cIt c%ntry ticmatocrit at entry (pcrccnt hclow normal) f+rr:c!nt undcrwcight at entry Randomization to sulfasalazint* Randomization to prodnisonc Randomization to azathioprint*

In the course of their participation in the NCCDS, 19 of the 178 placebo-trcatcd patients underwent abdominal operations for Crohn’s discasc. The indications and surgical procedures in this group of patients (Table 6) wore similar to the surgical experience of the entire group of NCCDS patients,“’ and no different than that of any group rccciving active drug treatment. Thus, it is apparent that drug thcrapy was neither superior to placebo in long-term management,” nor did it reduce the nrlmbcr of operations performed.

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