the course and prognosis ulcerative colitisshort-term prognosis in the initial attack, part ii the...

Gut, 1963, 4, 299

The course and prognosis of ulcerative colitisFELICITY C. EDWARDS AND S. C. TRUELOVE

From the Nuffield Department of Clinical Medicine,The Radcliffe Infirmary, Oxford

EDITORIAL SYNOPSIS The authors have produced a unique study of 624 patients with ulcerativecolitis for they have achieved a 1000% follow-up of all these patients admitted to the RadcliffeInfirmary or to the Churchill Hospital, Oxford, from 1938 to March 1962 inclusive or who attendedas out-patients during the same period. They are therefore able to present a most important analysisof the natural history of ulcerative colitis as it occurs in the general population. Part I concerns theshort-term prognosis in the initial attack, Part II the long-term prognosis; Part III discusses thecomplications of the disease, and Part IV the risk of carcinoma.

Ulcerative colitis continues to be a dangerousdisease without completely satisfactory treatment.Knowledge of its aetiology is so limited that medicaltreatment has evolved solely by trial and error, andit is uncertain whether recent innovations in therapyhave affected the long-term prognosis substantially.There is also controversy as to whether surgery,usually implying major procedures, should beemployed extensively. Of the many complications ofulcerative colitis, cancer of the colon is known to bean appreciable risk after some years of the disease,but it is still not known whether this risk is so greatthat preventive colectomy is indicated.Some of these issues were examined in a previous

study of the patients with this disease seen at theRadcliffe Infirmary and Churchill Hospital, Oxford,during the 11-year period 1938-48 inclusive (Rice-Oxley and Truelove, 1950a and b). The presentstudy, which extends the period of observationuntil 1962, can be regarded as a continuation of theearlier work.

DATA

The primary sources of data were the case notes of allthe patients with ulcerative colitis (includinghaemorrhagic proctitis) who were admitted to theRadcliffe Infirmary or to the Churchill Hospitalfrom 1938 to March 1962 inclusive or who attendedas out-patients during the same period. In theinterests of brevity, we shall refer to these twohospitals as the Radcliffe Infirmary; and this isreasonable because they are under the same manage-ment, have a single records system, and the seniormedical staff is common to both.

2

The diagnosis of ulcerative colitis was consideredacceptable for the present study if the symptomswere compatible, the illness was not apparentlycaused by pathogenic bacteria, and sigmoidoscopyor barium enema (usually both) supported thediagnosis; in a very few cases, the diagnosis wasmade at necropsy.A total of 624 patients fulfilled the diagnostic

criteria just mentioned. Of these, 238 were currentlyattending the hospital and 75 were known to bealready dead. A follow-up study has been made ofthe remaining 311 patients, using a variety ofapproaches, and it has proved possible to obtainadequate follow-up information about all of them.The follow-up enquiries took place during thefive-month period ending 31 March 1962; continu-ation data have since been obtained on the latestentrants to the study, so that there is a minimum of aone-year follow-up in every case. In brief, there isreliable and up-to-date information in respect of100% of the patients, the period of observationvarying from one to 24 years, according to whenthey first attended the hospital.

In order to determine as completely as possiblethe progress of the disease up to the end of the studyor until death, we have obtained reports from allother hospitals to which the patients were admitted,and from family doctors and specialists, to sup-plement the original questionnaire sent to everypatient not currently attending our own hospital. Inthe case of patients who have died we know thecertified cause of death in every instance; andwhenever a post-mortem examination was made, wehave obtained the pathologist's report.

It would have been impossible to obtain such a99

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Felicity C. Edwards and S. C. Truelove

complete picture of the course of this illness withoutthe active assistance of a large number of individualsand institutions, both lay and medical, and it is apleasure to acknowledge their help. We are alsograteful to the physicians and surgeons of theRadcliffe Infirmary for allowing us to include theirpatients in this study -so that it embraces the totalexperience of the hospital.

In order to analyse the extensive data at ourdisposal, we have transferred all the relevantclinical information obtained from the case historiesand the follow-up on to punched cards for mechanicalsorting. We shall now consider the results underfour main headings: 1 Short-term prognosis,2 long-term prognosis, 3 complications, and 4carcinoma of the colon.

Part 1 Short-term prognosis

We shall consider here the immediate outcome of theattack of ulcerative colitis which first brought thepatient to the Radcliffe Infirmary. When dealingwith a disease which can pursue either an inter-mittent or continuous course over many years,which may never recur after the original attack, orwhich may terminate fatally in that attack, bias maybe introduced for several reasons if all such cases areconsidered together, and much valuable informationwill remain hidden. We have therefore made aninitial separation of the patients into two groups:those who were referred in their first attack ofulcerative colitis ('first attack group') and those whowere referred because of a relapse of establisheddisease ('relapse group'). For the purpose of thisstudy, any patientwho had had continuous symptomsfor more than 12 months from the onset of thedisease up to the time of referral was included in therelapse group. For the most part, the results of theanalysis are presented separately for these two maingroups.

RESULTS

Table I shows the composition of the series. Itshows that there were approximately 50% morewomen than men, and this applies equally to the

TABLE ICOMPOSITION OF SERIES BY SEX,

AND BY WHETHER PATIENTS FIRST ATTENDED THERADCLIFFE INFIRMARY IN FIRST ATTACK OR IN A

RELAPSE OF ESTABLISHED DISEASEMen Women Total

First attacks

Relapses

Total

94 156 250

157 217 374

251 373 624

first attack cases and to the cases first seen in arelapse of established disease. About 40% of theseries consisted of patients seen in their first attackof the disease and this was true for both men andwomen.

AGE OF ONSET Table II shows a detailed breakdownof the whole series, separately by sex, for the age ofonset. It shows that there were relatively few casesbeginning in childhood, but from the age of 15years upwards the cases became numerous andexactly 75% of the series began their illness between15 and 49 years of age. A substantial number of thepatients (108, or 17%) were over the age of 50when they first developed symptoms, and there were12 patients (2 %) in whom the illness developed whenthey were over 70 years of age.

Age at First AttackOnset (yr.)

Men

No. %

TABLE IICOMPOSITION OF THE SERIES BY AGE AT ONSET OF THE DISEASE

*s Relapses Whole Series

Women Total Men Women Total Men

No. % No. % No. % No. % No. % No. %/

144812391552512

l

3-812-832-924-314-76-73-203

1-3

93068624713183

1

3-611-927.124-718 85.27-11-204

741989752392662S

1-911-026-326-013-910-57.01.60.51.3

167116615999.524493S

2-611-426-625 515-98-3701-40.50-8

374 100-0 251 100-0 373 100-0 624 100-0

300

0-910-1920-2930-3940-4950-5960-6970-7980-84UnknownTOTAL

914262071421

94

1*19-614927-621-37.4

14-92-11-1

100-0

14294224201862

156

0-69018-626-915412-811-53.91-3

100-0

223436844273283

250

Women Total

No. % No. %080-89-217-227-217-610-81283-21-2

100-0

82154362764

157

5113-434.422-917-23-82-60-6

100-0

627695528198

5217

2-812431 825312-98-83.7

2-3100-0



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The course andprognosis of ulcerative colitis

TABLE II (condensed)Age at Onset Whole Series Statistical(yr.) - Significance of

Men Women Total the Differences

< 1515 - 49SO +

Total

2419235

1927678

43468113

x2 = 85n = 2

p <005

251 373 624

The age of onset shows interesting variationsaccording to sex. Below the age of 15 there was noappreciable difference between the number of malesand females, there actually being a small surplus ofboys, but from 15 onwards there is a consistentsurplus of women which becomes more pronouncedafter the menopause. These relationships are shownin the condensed version of Table II and the differ-ences in the age distribution by sex is statisticallysignificant.

DURATION OF DISEASE BEFORE REFERRAL Table IIIshows the duration of the disease before referral tothe Radcliffe Infirmary. As far as first attacks areconcerned, the majority were referred during thefirst six months. When the relapse group is considered,there was wide variation in the length of history,with many longstanding cases of more than 10years' duration.

TABLE IIIDURATION OF DISEASE AT TIME OF

REFERRAL TO THE RADCLIFFE INFIRMARYFirst Attacks Relapses

Months No. of % Years No. of %Patients Patients

< 1 49 19-6 < 1 391-2 98

1 - 2 78 31-2 3 - 4 573 - 5 68 27-2 5 - 9 68

10- 19 746- 12 55 22-0 20 + 34

U.K. 4Total 250 100-0 374

10-426-215218-219-89-11-1

100-0

INCREASING NUMBER OF REFERRALS Figure 1 showsthe number of patients with ulcerative colitisreferred to the Radcliffe Infirmary since 1938 byseparate five-year periods. It shows a progressiveincrease in the numbers with the most marked riseduring the final period. One cannot conclude fromthis figure that the incidence of the disease isincreasing because many patients with ulcerativecolitis are referred from outside the normal catch-ment area of the hospital, especially recently. Forthe purpose of the present study, it is important tonote that the proportion of first attacks remainedremarkably constant throughout, being approxi-mately 40% of the total cases.

200RELAPSES

TOTAL CASES* FIRST ATTACKS

150 -

a 100 *

so

0

z

1938- 1943- 1948- 1953- 1958-62

FIG. 1. The number ofpatients referred to the RadcliffeInfirmary in five-year periods.

DEATH IN THE FIRST REFERRED ATTACK

Table IV shows the proportion of patients in whomthe attack of the disease for which the patient wasfirst referred to the Radcliffe Infirmary terminatedfatally. During the first decade covered by the study,firstattacks were decidedly more dangerous thanrelapses, but since 1948 this difference has dis-appeared. It can also be seen that there has been aprogressive diminution in the proportion of fatalcases, the most marked change occurring in 1953,since when the fatality rate has been approximatelysteady. Such an improvement in short-term prog-nosis could be the result of various factors, the twomost obvious possibilities being changes in treatmentand changes in the severity of the disease at the timethe patient reached hospital.

SEVERITY OF THE ATTACK The clinical severity of theattack has a profound influence upon short-termprognosis. We have classified each first referredattack into three grades of severity, employing thesame criteria as were used in a large-scale thera-peutic trial (Truelove and Witts, 1955), namely:

Severe Severe diarrhoea (six or more motions a

TABLE IVPERCENTAGE OF PATIENTS DYING IN FIRST REFERRED

ATTACK, ACCORDING TO PERIOD OF REFERRALFirst Attacks Relapses All Cases

1938-421943-471948-521953-571958-March 1962

21 722-212-11*6

12-29-611-96-0

17-214-812-14-1

6f3 3-8 4-8

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TABLE VRELATIONSHIP BETWEEN CLINICAL SEVERITY OF FIRST REFERRED ATTACK AND DEATH IN

THAT ATTACK SHOWN SEPARATELY FOR FIRST ATTACKS AND RELAPSESty First Attacks Relapses All Cases

No. of % No. of % No. of %Patients Died Patients Died Patients Diec

136 0767 9047 38-3250 10-0

'Excluding three patients in complete remission on referral, and two for whom classification was not possible.

day) with macroscopic blood in stools; fever (meanevening temperature more than 99.50 F. (37.50 C.), ora temperature of 100° F. (37.80 C.) or more on atleast two days out of four; tachycardia (mean pulserate more than 90 per minute); anaemia (haemo-globin 75% or less, allowance being made for recenttransfusion); E.S.R. much raised (more than 30 mm.in one hour).Mild Mild diarrhoea (four or less motions a day)

with no more than small amounts of macroscopicblood in stools. No fever. No tachycardia. Anaemianot severe. E.S.R. not raised above 30 mm. in onehour.

Moderately severe Intermediate between severeand mild.

Table V and Fig. 2 demonstrate the close relation-ship between clinical severity at the time the patientreaches hospital and the risk of dying in that attack.For the whole series, mild attacks carried a very lowrisk of death, whereas severe attacks carried a graveshort-term prognosis with nearly one-third dying.

Table VI shows that severe attacks have become asmaller proportion of the total referrals throughoutthe period of study, being counterbalanced by aprogressive increase in the proportion of mild

0/030-

z

io

0

MILD MODERATE SEVERECLINICAL SEVERITY

FIG. 2. Percentage fatality rate in the first referredattack in relation to the clinical severity of that attack.

TABLE VIRELATIVE FREQUENCY OF SEVERE, MODERATE, ANDMILD ATTACKS ON REFERRAL TO THE RADCLIFFE

INFIRMARY'Period of No. of Severe Moderate MildReferral Patients ('%) (%) (0%)

1938.421943-471948-521953-571958-62

6488116146205

20-330-724-113-010-7

35.921-620-724-722-9

43-847.755262-366-4

CONDENSED VERSION OF THE ABOVE

1938-521953-62

268 25.4 24-6 50 0351 11*7 23-6 64-7

'Whole series, but excluding the same five patients as in Table V.

attacks, while moderately severe attacks haveremained a fairly steady proportion. It is evidentfrom what has already been shown of the relation-ship between clinical severity of the attack and theshort-term fatality rate that this shift in itself wouldbe expected to improve the overall short-termprognosis in the second major period of the study.In order to see whether it can entirely account for theimproved prognosis, the data must be analysed totake account simultaneously of severity of attackand time-period. This is done in Table VII and Fig. 3,which show a striking fall in the fatality rate ofattacks of moderate severity, the change beinghighly significant statistically. Mild attacks carried avery low immediate risk of death in the earliertime-periods so no very great improvement couldoccur in terms of fatality. At the other end of theclinical scale, severe attacks have remained highlydangerous; a small improvement occurred in thesecond major time period, but it is not significantstatistically.

It is plain that the improvement in the overallshort-term fatality rate is partly due to a biggerproportion of patients being seen with mild attacksof the disease and partly due to a sharp decline in thefatality associated with attacks of moderate severity.This second factor can reasonably be attributed toimproved methods of management. The medical

Clinical Severi

MildModerateSevereTotal

2258262

369

0911-025-87.3

!d

361149109

6191

0-810-131-28-4

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The course and prognosis of ulcerative colitis

TABLE VIIPERCENTAGE OF PATIENTS DYING IN FIRST REFERRED ATTACK ACCORDING TO THE

CLINICAL SEVERITY OF THAT ATTACK'Severe

Total No. %No. of Died DiedPatients

Moderate


Mild


1938-521953-62

Statistical significance of thedifferences

6841

23 33-8 66 13 19-7 1341 1 26-8 83 2 2-4 227

x2= 0.58 n = 1 p > 0-05Not significant

x'= 12-1 n= 1 p<001Highly significant

'Whole series, but excluding the same five patients as in Table V.

management of an attack of ulcerative colitisconsists of general medical measures and certainspecific measures. The general medical measuresconsist essentially of steps designed to counteract theharmful effects of the disease, such as blood trans-fusion to replace blood lost through the bowel,parenteral therapy to overcome dehydration andelectrolyte deficiencies, and a high-calorie, high-protein diet with added vitamins to preserve thestate of nutrition. These general measures have notaltered in principle during the period under study buttechnical advances have facilitated their application;for example, the development of flame photometryhas improved control of electrolyte therapy and the

E 1938-52 * 1953-62

40

20

0

40

20

0

40

20

0

FIRST ATTACKS

introduction of the National Blood TransfusionService has made blood transfusion an easy andsafe form of treatment. The major change inspecific medical treatment has been the introductionof corticosteroid therapy, which began to be used inthis hospital in 1952. In effect, when we deal withour two major time-periods, 1938-52 and 1953-62,we are concerned with the pre-cortisone eras.

Since 1952, corticosteroids have been increasinglyused, but the exact type of treatment has varied.Apart from cortisone itself, A.C.T.H. was used for atime but has now been almost completely supersededby the modern synthetic analogues of cortisone,such as prednisolone. The systemic use of cortico-steroids has been supplemented by local cortico-steroid therapy applied by rectal drip since 1955,although initially only a few patients were sotreated. Although a series of controlled therapeutictrials has shown these measures to be beneficial inshort-term treatment, their introduction into theroutine clinical practice of the hospital inevitablylagged behind the formal studies and became theusual form of specific treatment only from about1958. Any beneficial effects of corticosteroid treat-ment are therefore only partially shown in thepresent study.The other specific therapy, sulphasalazine (Salazo-

pyrin or Asulfidine) only became available in thiscountry in 1955, although used in Sweden from 1940onwards (Svartz, 1942). Sulphasalazine has not beenused in a major way as specific therapy for ulcerativecolitis in Oxford and has usually been employed incombination with corticosteroids. Its use is atpresent increasing.

In brief, although this type of retrospective studyis obviously inferior to a controlled therapeutictrial for assessing the value of specific forms oftreatment, it is nevertheless of interest that, since1953, among the patients who died in their firstreferred attack of the disease about half had had nospecific form of medical treatment (Table VIII).

Surgery has been employed in only a small

Time Period

2 151 04

Obviously not significant

SEVERITY OF DISEASEFIG. 3. Percentage fatality rate in the first referredattack, separately for first attacks and relapses, inrelation to (a) severity of the disease, (b) treatment period.

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TABLE VIIIPERCENTAGE OF PATIENTS DYING IN FIRST REFERREDATTACK IN RELATION TO USE OF SPECIFIC MEDICAL

TREATMENT FOR THAT ATTACK"Specific MedicalTreatment (A.C.T.H.,Corticosteroids, Total Number of Number (%)Salazopyrin) Patients? Died Died

WithWithout

AGE GROUPS<30 30-59 EJ60+

OljIs -

102 7 6-922 6 27-3

'Applies only to patients referred since 1953."Excluding mild attacks.

proportion of patients in their first referred attackthroughout the entire period covered by the study(Table IX). Any improvement in short-termprognosis cannot be attributed to the more extensiveuse of surgery. Among those patients treatedsurgically, the fatality rate has fallen during theperiod covered by this study, a change which mustpartly reflect improved surgical technique.

OTHER FACTORS INFLUENCING THE CHANCE OF DYINGIN THE FIRST REFERRED ATTACK A number of fac-tors can be shown to have a bearing on the short-term prognosis as far as death is concerned.Sex of the patient Analysis of the data revealed

no significant effect of sex on the short-term fatalityrate (results not shown).Age of the patient The age of the patient has a

pronounced effect on the short-term fatality rate,which increases sharply in the older age groups,namely, at 60 years and over. This effect is con-sistent in first attacks and in relapses, and isstatistically significant (Table X and Fig. 4). It is notdue to older patients being more likely to present in asevere attack (Fig. 5).There has been no appreciable proportionate

increase of patients over the age of 60 in their first

I-

I.-

I-

10

S

0FIRST

RELAPSESALL

ATTACKS REASS CASES

FIG. 4. The effect of age on the risk of dying in the firstreferred attack.

referred attack, and the improvement in fatalityrate that occurred in the second main period of thestudy applied as much to them as to youngerpatients, the proportionate fall being almostidentical (results not shown).

Type ofonset The type of onset, whether acute orgradual, has little bearing on the short-termfatality rate (Table XI). We have confined ourselvesto considering patients suffering from their firstattack of ulcerative colitis, and we have excluded 29patients in whom the information was not suffi-ciently precise to allow of classification.Length of history As far as first attacks are

TABLE IXPERCENTAGE OF PATIENTS TREATED BY ILEOSTOMY WITH OR WITHOUT COLECTOMY

IN FIRST REFERRED ATTACKFirst Attacks Relapses

No. of Patients No. Treated Surgically % No. of Patients No. Treated Surgically %

First period (1938-52) 108 7 6-5 160 14 8-8Second period (1953-62) 142 9 6-3 214 13 6.1

TABLE XEFFECT OF AGE ON DEATH IN THE FIRST REFERRED ATTACK

Age (yr.) First Attacks Relapses Whole Series

No. ofPatients % Died No. of Patients % Died No. of Patients % Died

<30 68 5-9 102 6-9 170 6 530-5960+

13943

10.116-3

24230

7-016-7

38173

8-116-4

Comparing the over-sixties with the remainder x? =6-3 n = 1 p <0-02

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TABLE XIIDEATH IN FIRST ATTACK OF THE DISEASE ACCORDING

TO LENGTH OF HISTORY BEFORE ADMISSION TOHOSPITAL

Duration(months)

< 11 - 56 - 12

01 L 'II W ~ -1w-1wzi

1938-52 1953-62

FIG. 5. Percentage ofpatients with a severe first referredattack, separately for three main age groups and for twotreatment periods.

No. ofPatients No. Died

4914655

9133

% Died

18-48-95.5

Comparing less than one month's duration with remainder: xl = 4.74,n = 1, P = < 005 significant.

right-sided or segmental colitis and 100 patients forwhom the data were inadequate. It will be notedthat first attacks of the disease are more dangerousthan relapses even when the extent of the disease istaken into consideration. When patients areclassified according to extent of the disease, as inTable XIII, it has been found that there has beenlittle change in the proportions of the variouscategories during the period studied (results notshown).

concerned, the shorter the history before referral tohospital, the worse the immediate prognosis(Table XII). This is probably no more than areflection of the likelihood that early referral tohospital implies a severe attack of the disease.

Extent ofthe disease The extent of the disease, asjudged by sigmoidoscopy, barium enema and, when

TABLE XIDEATH IN FIRST ATTACK OF THE DISEASE,

ACCORDING TO TYPE OF ONSET, ACUTE OR GRADUALNo. of Difference

Onset Patients No. Died % Died and S.E.

Acute 80 9 11-3 3.5 ± 4-2not

Gradual 141 11 7-8 significant

relevant, the findings at surgery or necropsy, has animpressive effect upon the short-term fatality rateand this effect is consistent for first attacks andrelapses (Table XIII). The results are based upon 502patients for whom the information was precise and itexcludes 22 patients because they suffered from

Extent of Disease

RELATIONSHIP BETWEEN CLINICAL SEVERITY ANDEXTENT OF THE DISEASE In view of the fact that theclinical severity of the first referred attack has amajor influence on the short-term prognosis andthat the extent of the disease likewise has a pro-nounced effect, we have examined the extent to whichthese factors are correlated. A considerable measureof correlation exists but the distribution is heavilyskewed. A clinically severe attack almost alwaysimplies substantial or entire involvement of thecolon; by contrast, involvement of the entire colonmay be present when the attack of the disease isclinically mild, this being the case in about 20% ofall the mild cases.

CAUSES OF DEATH IN THE FIRSTREFERRED ATTACK

Death occurred in the first referred attack from a

variety of causes (Table XIV). In some patientssevere but uncomplicated ulcerative colitis proceededto a fatal termination under medical treatment. Some

TABLE XIIIEFFECT OF EXTENT OF THE DISEASE ON DEATH IN FIRST REFERRED ATTACK

First Attacks Relapses

No. ofPatients

% Died No. ofPatients

%/ Died

Distal type:Rectum and rectosigmoid

Substantial involvement:Sigmoid ±

Descending +

TransverseEntire colon

55

96

00

7.3

61

121

00

1.7

51 255

40

W.)

a

on

5-

30'

20

10'

305

1 18 17-8



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patients with severe uncomplicated ulcerativecolitis died after emergency surgery. In otherpatients, particular complications of the diseasewere judged to be the immediate cause of death. Intwo patients death occurred from unrelated illnesses.

There has been a sharp reduction in the number ofdeaths from uncomplicated ulcerative colitis andthis probably reflects improved medical treatment.It has already been shown (Table IX) that there wasa small decline in the proportion of patients dealtwith by emergency surgery. In effect, virtually thesame number of patients was operated on in theirfirst referred attack in each of the two main periods,although the total number of patients seen was muchgreater in the second period.Deaths attributed to complications other than

carcinoma of the colon also became less frequent.The complications of ulcerative colitis are diverse,but those chiefly liable to cause death in an attack ofthe disease are perforation of the colon and massivehaemorrhage.

OUTCOME OF THE FIRSTREFERRED ATTACK

If the patients did not die in the first referredattack, they usually became symptom-free in duecourse, although the period of time that elapsedbefore complete remission occurred was veryvariable.The outcome of the first referred attack is given in

Table XV. This deals with the entire series, with theexception of eight patients in whom the immediatecourse after they left hospital could not be ascer-

tained, although the final outcome was discoveredduring the course of follow-up.

It is interesting to note that, since 1953, whencorticosteroids began to be used, there has been anincrease in the proportion of patients who go intocomplete remission (Table XVI). Of course, thistable gives no information about the time taken toreach complete freedom from symptoms and it isknown from controlled therapeutic trials thatspecific treatment with combined systemic and localcorticosteroid therapy greatly increases the chance ofrapid remission (Truelove, 1960; Truelove, Watkin-son, and Draper, 1962). In other words, Table XVIalmost certainly underestimates the reduction inmorbidity which has occurred since 1953.

DISCUSSION

The present study has shown that ulcerative colitis

TABLE XVIIMMEDIATE OUTCOME OF FIRST REFERRED

ATTACK ACCORDING TO THE TWO MAIN TIME PERIODS

Outcome

DiedCompleteremissionImprovedUnchangedColectomyTotal'

1938-52

No. of %Patients

38 14.5

201 76-719 7*33 111 04

262 100.0

1953-62

No. of %Patients

16 4.5

304 85929 822 063 08

354 100.0

'Excluding the eight patients in Table XV for whom the immediateoutcome was unknown.

TABLE XIVCAUSES OF DEATH IN FIRST REFERRED ATTACK

Uncomplicated Ulcerative Complications of Carcinoma Emergency SurgeryColitis Ulcerative Colitis Other Coli

than Carcinoma

Time Period

1938-52(268 patients) 14 10 4 101953-62(356 patients) 3 5 1 5 2

TABLE XVIMMEDIATE OUTCOME OF FIRST REFERRED ATTACK OF ULCERATIVE COLITIS

(WHOLE PERIOD 1938-62)Outcome First Attacks Relapses Whole Series

No. ofPatients % No. ofPatients % No. ofPatients %

DiedComplete remissionImprovedUnchangedColectomyUnknownTotal

252091222

250

10-08364 80808

1000

2929636328

374

78792960805

2.1100-0

54505485

48

624

8.78097.708061.3

100-0

OtherDisease

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remains a formidable disease even in the shortterm and ignoring the dangers which arise fromits being a chronic disorder. Appreciable numbersof patients still die in the attack for which theyare referred to hospital. The main factors whichlead to a high risk of dying in this attack are a severeclinical picture at the time of referral, extensivedisease especially when the whole colon is involved,and the development of a dangerous complication ofwhich perforation of the colon is the chief example;the risk is considerably accentuated if the patient isover the age of 60 years.

In the previous study from this hospital, firstattacks were found to be much more dangerous thanrelapses. In the present study there is not much tochoose between them, but it must be emphasizedthat the earlier study took into consideration allrelapses treated in the hospital whereas here we havebeen concerned only with the first referred attack. Ifwe had included all relapses treated in hospital, weshould again find a much lower fatality rate forrelapses.

Overall, the short-term fatality rate has shown aconsiderable improvement during the last decade ofthe study. This is partly because of the lowerproportion of patients severely ill at the time theyreach hospital; it is not due to a lower proportion ofpatients with disease involving the whole colon,which is the same as previously; nor is it due to anydecrease in the proportion of patients over 60 yearsof age at the time of the first referred attack.However, when allowance is made for the changein proportion of severe attacks, there is still evidenceof considerable improvement since the introductionof cortisone treatment in 1952, but on analysis this isfound to be almost entirely due to a markedimprovement in the outcome of patients moderatelyill on arrival at hospital. Those severely ill on arrivalhave shown only a small improvement and theyremain as a challenge to the physician.

It must be appreciated that the results of a studysuch as this, which deals with the total experience ofa hospital, are likely to lag behind the changesoccurring in specialized units. For example, whencortisone began to be used in this hospital in 1952, itwas employed only in the patients admitted to aformal therapeutic trial and even then only half thepatients received the drug. It was not until 1954 thatthis trial was concluded and cortisone or A.C.T.H.began to be used more generally in the treatment ofthis disease. Local corticosteroid treatment began tobe used in 1955 but was at first confined to selectedmild or moderate cases (Truelove, 1956, 1957).When subsequent controlled trials had shown it to bebeneficial in such cases (Truelove, 1958; Watkinson,1958) it began to be used more extensively but its use

in severe attacks of the disease did not begin until1957. Subsequently the combined use of systemicand local corticosteroid treatment was found to. beadvantageous (Truelove, 1960) and as a result thiscombined corticosteroid treatment has begun toenter general hospital practice. It is therefore plainthat the results obtained for the period 1953-62 canbe expected to show only a partial reflection of thebenefits possible from corticosteroid therapy and afurther study will be necessary to evaluate the fulleffect of this in the general hospital population ofulcerative colitis cases.The question nevertheless arises whether a severe

attack of the disease is not an indication for emer-gency colectomy. There are few physicians whowould contemplate such a step as an immediateprocedure in every patient admitted to hospitalseverely ill with ulcerative colitis. Some surgeonshave advocated emergency colectomy in suchpatients if they do not show swift improvement witha full medical regime, but opinion is divided on howlong to wait before resorting to colectomy. Forexample, Brooke (1956) considered that persistencewith corticosteroid therapy in the absence ofdefinite clinical improvement might lead to friabilityof the entire colon and so prejudice the results ofemergency surgery. He concluded that 'steroidtherapy should cease in any patient showing noresponse after one or two weeks', the implicationbeing that they would then be treated by surgery.Lennard-Jones and Vivian (1960) discussed theexperience of St. Mark's Hospital and the CentralMiddlesex Hospital in the management of fulmi-nating ulcerative colitis, by which was implied avery severe attack; unfortunately they did not use aprecise definition of a 'fulminating' attack but fromtheir description of the cases, they appear tocorrespond roughly with our own 'severe' category.Among the 32 patients reviewed, 26 were brought tosurgery, with eight deaths (30.8 %). The authorscontrast this high operative fatality rate with the lowrate after elective surgery in St. Mark's Hospitalduring the same period. Similarly Goligher (1961)has reported a low fatality rate for elective surgerybut a high figure for emergency surgery. The closecorrespondence between these two surgical series canbe seen when the operative fatality rates aretabulated:-

ElectiveSurgery

Lennard-Jones and Vivian(1960) 4.4°/

Goligher (1961) 2.9'

EmergencySurgery

30-8%29.3%

The authors of both of these series conclude that,if corticosteroid treatment is employed in these

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308 Felicity C. Edwards and S. C. Truelove

severe attacks, its use should not be continuedbeyond a specified time limit if there is no sign of amajor clinical improvement. Their view of the timelimit differs, Lennard-Jones and Vivian taking fourdays as the period of medical trial, whereas Golighertakes 10 days. Their assumption is that emergencysurgery would be less hazardous if performedearlier in the course of the illness than was usual intheir cases. This view is strongly pressed byGallagher, Goulston, Wyndham, and Morrow (1962)who claim that their overall results for severeulcerative colitis have improved since they adoptedthe policy of early operation after a short period ofintensive treatment usually lasting one to threeweeks; among 22 patients so treated, there were onlytwo deaths (91 %).

It must be appreciated that these are all uncon-trolled studies and the evidence in favour of earlyemergency colectomy is far from achieving theweight of scientific proof. The medical treatmentof a severe attack of ulcerative colitis is attended by aconsiderable fatality rate, but emergency colectomyis also dangerous in a patient who is alreadyseriously ill. There thus appears to be an incontro-vertible case for a fully controlled therapeutic trialto compare, on the one hand, early emergencycolectomy with, on the other hand, a full medicalregime in which emergency colectomy is onlypractised when medical treatment is plainly failingor when there is some complication requiring urgentsurgery, such as perforation of the colon.

SUMMARY OF PART I

A study has been made of the clinical course andprognosis in 624 patients treated for ulcerativecolitis at the Radcliffe Infirmary between 1938 and1962 and completely followed-up. In this part of thestudy we have confined ourselves almost entirely toconsidering death in the first referred attack.The chief factors affecting the fatality rate in the

first referred attack of the disease were as follows:

SEVERITY OF THE ILLNESS AT TIME OF REFERRAL TOHOSPITAL Patients severely ill had a high chance ofdying, patients moderately ill had a much lower butstill appreciable risk, whereas patients only mildly illhad a negligible risk.

EXTENT OF THE DISEASE Universal colitis carried thehighest risk, involvement of a substantial part of thecolon a lower risk, whereas the distal type confined tothe rectum and rectosigmoid carried virtually norisk to life.

AGE OF THE PATIENT Patients over the age of 60 hada much greater chance of dying than younger

patients. This was not because they were more liableto suffer from severe attacks of the disease butbecause they did not survive such attacks as readilyas the younger patients.There has been a pronounced decline in the overall

fatality rate since the introduction of corticosteroidtherapy in 1952. This decline is not due to an increasein the employment of radical surgery in the acuteattack, although there is evidence of a certainmeasure of improvement in the operative fatalityrate. Part of the decline is due to a lower proportionof the patients being severely ill when reachinghospital in their first attack. When allowance ismade for this fact, a substantial improvement canstill be shown for the overall results. However, moredetailed analysis shows that this improvement comesalmost entirely from a sharp improvement in theoutcome of the illness in patients moderately ill onarrival at hospital, while patients severely ill onarrival have shown only a small decline in fatalityrate.From the point of view of the short-term course,

the finding that severe attacks of the disease continueto carry a considerable fatality rate brings out themain unanswered question of therapy at the presenttime. This is whether or not an emergency colectomyshould be performed with minimal delay in patientswho present with such severe attacks. The availablepublished evidence bearing on this issue is brieflydiscussed and it is concluded that only a fullycontrolled therapeutic trial would permit of a properanswer.

REFERENCES

Brooke, B. N. (1956). Cortisone and ulcerative colitis: an adverseeffect. Lancet, 2, 1175-1177.

Gallagher, N. D., Goulston, S. J. M., Wyndham, N., and Morrow, W.(1962). The management of fulminant ulcerative colitis. Gut, 3,306-311.

Goligher, J. C. (1961). Surgical treatment of ulcerative colitis. Brit.med. J., 1, 151-154.

Lennard-Jones, J. E., and Vivian, A. B. (1960). Fulminating ulcerativecolitis: recent experience in management. Ibid., 2, 96-102.

Rice-Oxley, J. M., and Truelove, S. (1950a). Complications ofulcerative colitis. Lancet, 1, 607-611.

- , -(1950b). Ulcerative colitis: course and prognosis. Ibid., 1,663-666.

Svartz, N. (1942). Salazopyrin, a new sulfanilamide preparation.Acta med. scand., 110, 577-598.

Truelove, S. C. (1956). Treatment of ulcerative colitis with localhydrocortisone. Brit. med. J., 2, 1267-1272.

(1957). Treatment of ulcerative colitis with local hydrocortisonehemisuccinate sodium. Ibid., 1, 1437-1443.

(1958). Treatment of ulcerative colitis with local hydrocortisonehemisuccinate sodium: a report on a controlled therapeutictrial. Ibid., 2, 1072-1077.

(1960). Systemic and local corticosteroid therapy in ulcerativecolitis. Ibid., 1, 464-467.Watkinson, G., and Draper, G. (1962). Comparison of cortico-steroids and sulphasalazine therapy in ulcerative colitis. Ibid.,2, 1708-1711.and Witts, L. J. (1955). Cortisone in ulcerative colitis: finalreport on a therapeutic trial. Ibid., 2, 1041-1048.

Watkinson, G. (1958). Treatment of ulcerative colitis with topicalhydrocortisone hemisuccinate sodium: a controlled trialemploying restricted sequential analysis. Ibid., 2, 1077-1082.



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