The medical treatment of ulcerative colitis · therapy to prevent relapses or complications of the...

Postgrad. med. J. (September 1968) 44, 696-707.

The medical treatment of ulcerative colitis

GEOFFREY WATKINSONConsultant Physician to the York Hospitals

THE ADEQUATE treatment of any illness dependsprimarily upon a knowledge of its aetiology andin a chronic relapsing illness, such as ulcerativecolitis, an awareness of its natural history andcomplications. While the final cause of ulcerativecolitis remains obscure, increasing knowledge ofpossible causal factors and of the prognosis ofthe condition has markedly influenced its treat-ment in recent years.When colitis was thought to be of bacterial

origin specific sera were prepared but proved ofno lasting value. Similarly, no effective agents toinhibit mucinases have been evolved. Enthusiastsfor the hypothesis that colitis is due to foodallergy have advocated the use of milk-free dietsin colitic patients with apparent benefit (Andre-sen, 1942; Wright & Truelove, 1965a, b). Attemptsto suppress supposed autoimmune reactions havebeen made with corticosteroids used orally, topic-ally or parenterally, by non-specific anti-inflam-matory agents, such as sulphasalazine or morerecently by immunosuppressive agents. Physiciansimpressed by psychosomatic factors in the illnesshave advocated the use of psychotherapy, ofsedatives and antidepressant drugs and evenleucotomy to control the condition.Assessment of the value of any therapeutic

measure proves difficult in a disease which variesgreatly in severity and extent, not only frompatient to patient but in the same individual fromattack to attack, making rigorous controlledtrials of any measure necessary in large groupsof colitic patients before its values can be accep-ted.

Increasing knowledge of the nutritional andbiochemical problems encountered in thesepatients, together with the introduction of morepotent drugs, such as sulphasalazine and cortico-steroids and the wider use of surgery, have mater-ially improved the prognosis of ulcerative colitisin the last two decades.

Principles of medical treatmentThe duties of a physician treating a patient

with ulcerative colitis can simply be stated:

(i) To terminate the acute colitic attack orrelapse as quickly as possible.

(ii) To attempt by some form of maintenancetherapy to prevent relapses or complications ofthe disease.

(iii) By a knowledge of factors known toinfluence the natural history and prognosis ofcolitis, to recognize that medical treatment hasfailed to induce remission or to prevent relapsesor complications and to refer the patient forurgent or elective surgery.The physician has to accept, as Bargen (1961)

has emphasized that 'control' of colitis is farmore likely than 'cure' and that the patient mustbe supported through long weeks, months oryears of chronic and often recurrent illness. Thisis best done by a patient and persevering phys-ician who works in close association with a sur-geon interested and skilled in the difficult colonicsurgery that colectomy in an acutely ill coliticpatient may demand. Throughout a combinedmedico-surgical approach should be adoptedboth in the day-to-day management of acuteattacks and through months and years of follow-up of the chronic case at a colitis clinic runjointly by a physician and surgeon. It has beensuggested that a psychiatrist should complete theteam to cope with the frequent psychosomaticproblems which afflict these patients. While this isa debatable issue such a team obtained excellentresults in the paediatric clinic of a Michiganhospital (McDermott, John & Finch, 1964).

Treatment of the acute attackThe measures used in treating severe initial

colitic attacks and relapses are summarized inTable 1 below.

RestBed rest is recommended for any colitic re-

lapse and early hospitalization for patients withsevere diarrhoea, copious bloody stools, feveranaemia and weight loss. More adequate rest willbe aided by the administration of sedative andtranquillizing drugs, such as phenobarbitone and

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Medical treatment of ulcerative colitis

amylobarbitone. In more anxious or obsessionalpatients meprobamate, chlordiazepoxide ordiazepam can be tried and where agitation iscomplicated by nausea and vomiting, drugssuch as promethazine hydrochloride or chlorpro-mazine can be used. Adequate sleep is essentialoften making hypnotics, such as chloral hydrate,amylobarbitone, pentobarbitone or gluthemide,necessary.

TABLE 1


RESTBed rest-hospitalizationSedative and tranquillizing drugsHypnotics

COLONIC RESTParenteral feedingFluid dietLow-residue, high-protein dietAntispasmodic and antidiarrhoeal drugs

MAINTENANCE OF NUTRITION AND OF FLUID ANDELECTROLYTE BALANCE

Replacement of fluidMineral replacement salt, potassium, magnesium, calciumVitamin supplementsParenteral feedingAnabolic agents

CORRECTION OF ANAEMIAOral, parenteral, intravenous ironBlood transfusion

DIETLow roughage, high-protein dietMilk free diet on occasion

ANTIBIOTICSUsed with caution, best given parenterallyPenicillin and streptomycinAmpicillin, chloramphenicolNeomycin

MORE SPECIFIC REMEDIESSulphasalazine

OrallyTopically

CoticosteroidsParenterallyOrallyTopically

TREATMENTS UNDER EVALUATIONImmunosuppressive agentsRectal hypothermiaLeucotomy

Colonic restColonic rest is achieved by dietary means and

by various antispasmodic and antidiarrhoealdrugs. In the severely ill patient with continuousdiarrhoea complete withdrawal of oral fluid andfeedings is justified, the patient being maintainedby parenteral fluids. Later a fluid diet and finallya low residue high protein diet are given.A wide variety of antispasmodic drugs can be

given and if used in dosage sufficient to producemild side-effects will often control both diarrhoeaand cramping abdominal pains. They are con-traindicated in patients with glaucoma or previousurinary retention and if given in excessive dosageto severely ill patients may induce intestinalatony simulating a toxic megacolon.

Belladonna given as the tincture or in a sus-tained release tablet (Belladenal retard orDonnatal) can be used or one of the numeroussynthetic anticholinergic drugs available, such aspropantheline bromide, poldine methylsulphate,methscopolamine bromide or penthionate brom-ide, exhibited.For the control of copious diarrhoea the use

of opiates is justified provided it is realized thatthese drugs have addictive properties, may maskperforation or worsen ileus and, therefore,should only be prescribed for short periods andtapered off as soon as possible. Codein phosphatetablets, tincture of opium or tincture of chloro-form and morphia can be given. Lomotil is auseful proprietary tablet combining a codeinderivative diphenoxylate hydrochloride withatropine sulphate.

Thickening of the stools with bulk-forminglaxatives seems to improve sphincter control whilea few patients with proctocolitis may need mildlaxatives as they are in fact constipated. Hydro-philic agents, such as psyllium seeds or methl-cellulose, are used with or without mild laxatives,such as milk of magnesia, liquid paraffin or stan-dardized senna.

Maintenance of nutrition and of fluid and electro-lyte balance

In acute fulminating attacks gross dehydrationand profound electrolytic and metabolic imbal-ances may develop making it vital that such casesbe managed in hospital where adequate bio-chemical facilities are available together with thetrained nursing and house officer staff to copewith the intensive care which these cases mayrequire.

In severe attacks gross dehydration with ahyponatraemic, hypokalaemic acidosis maydevelop making it necessary to rapidly correctthese deficiencies with intravenous 5% dextrose,0-9% sodium chloride (150 mEq/l) or I M-lactateand adding potassium chloride 1-5 g (20 mEq)to each 500 ml of infusion fluid. Potassium deple-tion may be profound and up to 80 mEq dailymay have to be given. Magnesium depletion maydevelop and is becoming more widely recognizedas facilities for its estimation become morewidely available.

Subsequently additional salt and potassium can

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be given orally as enteric coated tablets or aseffervescent tablets (1 g=6-5 mEq) of potassium.Reports that such tablets may cause intestinalulceration have led to the use of liquid prepara-tions of the chloride (6 5 mEq/g), the citrate(9-2 mEq/g) or the gluconate (20 mEq/ 15 ml).Unfortunately, many of these preparations areunpalatable and may cause diarrhoea in whichcase a slow release tablet incorporating 600 mgof potassium chloride (8 mEq) in a slow releasewax core is administered in a dosage of four toeight tablets daily.

Vitamin replacement is necessary in manyseverely ill and debilitated patients. Supplementsof vitamins A and D (calciferol), B complex andC (parentrovite), cyanocobalamin and folic acidand vitamin K may have to be given intraven-ously or intramuscularly, particularly if complic-ating liver disease is present. Subsequent adequateoral replacement is given.

Intravenous protein replacement may have tobe attempted in critically ill patients using wholeblood, double strength plasma or protein hydro-lysates (Amigen, Trophysan) supplying additionalcalories with glucose or fat emulsions (Lipiphy-san). Such infusions should be cautiously used asthey may cause systemic reactions and phlebitislocally. Similarly, claims have been made thatanabolic steroids, given intramuscularly, mayaccelerate weight gain and improve appetite incolitic patients (Kasisch, 1963).

Correction of anaemiaAnaemia may need to be corrected in both

the acute and chronic phase of the disease. Bloodtransfusion is often urgently required for massiveblood loss or to correct the anaemia and hypo-proteinaemia of the chronic case. Oral irontherapy may be poorly tolerated by the coliticpatient, making it necessary to use a liquid prep-aration, an enteric coated or sustained releasetablet or to give iron intramuscularly or intrav-enously.

AntibioticsAntibiotics should be used with caution in

ulcerative colitis as their oral administrationmay worsen diarrhoea and predispose to secon-dary infection with monilial organisms. Useddiscriminately and given parenterally to theacutely ill febrile patient they may dramaticallyimprove the patient's condition. A combinationof penicillin and streptomycin is best triedinitially. Alternatively, intramuscular tetracycline,chloramphenicol or ampicillin can be given.Neomycin or succinylsulphathiazole, given orally,will often produce improvement and are usefulpre-operatively.

DietRapid wasting occurs in both acute and chronic

attacks with hypoproteinaemia, vitamins andnutritional deficiencies. It is therefore importantthat the patient eats as much of a high-proteinlow-residue diet as his condition allows supplying2500-3500 cal daily with 100-150 g of proteinpresented as attractively as possible. This diet ismost widely used in ulcerative colitis.The role of milk allergy in the pathogenesis of

colitis was first suggested by Andresen (1942)and by Rowe (1942). Interest in the topic wasre-awakened by Truelove (1961) who reportedon a small group of patients who becamesymptom free on a milk-free diet and who re-lapsed when milk was introduced into the diet.Recently Wright & Truelove (1965a) have repor-ted favourably on the results of a controlledtrial of a milk-free diet in twenty-six coliticpatients who faired better on a milk-free dietthan twenty-four colitic patients receiving anormal or gluten-free diet. Twice as manypatients on a milk-free diet remained symptomfree and fewer patients suffered severe relapses,differences between the groups being only marg-inally significant. Wright and Truelove estimatethat approximately one in five patients withulcerative colitis will benefit from milk restric-tion, a proportion which may be greater in firstattacks of the disease. Regrettably, raised titresof circulating antibodies to milk provided noguide to the possible response of a colitic patientto a milk-free diet, making it impossible to selectpatients who might benefit from withholdingmilk. It will be of considerable interest to seeif these results can be confirmed on a largergroup of patients and the use of a milk-free dietcannot at present be routinely advocated.

PsychotherapyOne of the most controversial aspects of the

treatment of ulcerative colitis is the role ofpsychotherapy. First advocated by Murray in1930, psychotherapy has found many enthusiasticsupporters through the years (Paulley, 1950;Grace & Wolff, 1951; Grace & Graham, 1952;Groen, 1961). These authors advocate thata constructive patient-physician relationshipshould be established where the patient is en-couraged to discuss their symptoms and theirpersonal and environmental difficulties with aphysician who gives the patient 'time, kindness,tangible signs of understanding and support' andwho is 'available at all times by phone', 'as oftenas daily' if the patient's condition demands it.Such a relationship makes exacting, exhaustingand prolonged demands on the physician who

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is only able to treat a limited number of coliticpatients at one time or even in his working life.

Other physicians have had less fortunate ex-periences with formal psychotherapy in ulcera-tive colitis. Crohn & Yarnis (1951), reporting thatonly one of twelve patients so treated obtainedbenefit while two colonic perforations occurredduring active psychotherapy.

It follows that if psychotherapy is to be prac-tised it must be used by or in close associationwith a physician skilled in the management ofcolitic patients who is capable of recognizing thedangerous and potentially lethal complications ofthe condition. In these circumstances in chronicrelapsing cases psychotherapy is often rewardingbut there is certainly no place for expertpsychotherapy in isolation.

SulphasalazineSulphasalazine (salazopyrin or azulfidine) is a

diazo compound of salicylic acid and sulphapy-ridine and has been used successfully in the treat-ment of ulcerative colitis since its developmentin Sweden in 1941 by Svartz and is capable ofinducing remissions in a significant proportionof patients treated (Svartz, 1956, 1961 ; Moertal &Bargen, 1959; Watkinson, 1961a, b, 1962; True-love, Watkinson & Draper, 1962; Morrison 1963).The drug's mode of action is unknown; ithas an affinity for connective tissue through-out the body and reaches high concentrationsin serous fluids, liver and intestinal wall. It hasno effect on the intestinal flora and seems toexert its beneficial effect by a non-specific anti-inflammatory action in the colonic wall andlumen.Dosage can be varied with the severity of the

attack; plain tablets containing 0-5 g are giveninitially reserving the enteric-coated tablets forpatients exhibiting gastro-intestinal intolerance tothe plain tablets. Usually two to four tablets fourto six times daily are used, depending on thetolerance of the patient. Unfortunately, in about20% of patients receiving sulphasalazine unplea-sant side effects will develop. Nausea, vomitingand headache are most common and are usuallycontrolled by substituting the enteric-coatedtablet in the same dosage. Rarely drug fever,skin rashes, muscular pains, leucopenia, acutehaemolytic anaemia or even agranulocytosis maydevelop and call for an immediate cessation oftherapy, though in a proportion it may be poss-ible to cautiously re-introduce the drug later. Itfollows that therapy should be monitored initiallyby frequent blood counts during the period ofintensive therapy.

Results obtained by various workers in treat-

ing acute attacks of the disease are summarizedin Table 2 below. In the 861 patients reviewed,remission or improvement occurred in between47% and 78% of those treated while side effectsdeveloped in between 16% and 45%. Mucosal im-provement on sigmoidoscopy has been reportedin 43% of fifty-eight patients treated (Trueloveet al., 1962). Salazopyrin, therefore, emerges as auseful drug in the treatment of all types of colitiswith better than even chances of success. Sideeffects somewhat limit the value of the drug,many of which can be overcome by the useof enteric-coated tablets, which, incidentally,have still to be shown as effective as the plaintablets by further clinical trials.A chemical analogue of sulphasalazine, salicy-

lazosulphadimethyl-pyrimidine (azudimidine) wassubmitted to limited trials with conflicting resultsby several workers, most finding the drug to beless effective and more toxic than sulphasalazine(Braders & Bargen, 1960; Baron et al., 1962a;Watkinson, unpublished data 1967). For thisreason the manufacturers have withdrawn thiscompound.

Sulphasalazine incorporated into a suppositorycontaining 1 g of the drug has recently beenshown by controlled trials to exert a beneficialtopical action if inserted nightly in patients withdistal proctocolitis, fifteen of eighteen patientsreceiving potent suppositories going into clinicalremission as compared with five of eighteentreated by insert suppositories. No side effectswere observed (Watkinson, unpublished data1967).

TABLE 2Immediate results of treatment with sulphasalazine of acutecolitic episodes in 861 patients treated in Sweden, Americaand England, together with the frequency of drug intolerance

% recovered % showingPatients or much drugtreated improved intolerance

Svartz (1956, 1961) 439 77 'Few'Morrison (1963) 60 70 21Moertal & Bargen (1959) 133 64 17Watkinson (1961a) 69 47 16Truelove, Watkinson & 58 50 22

Draper (1962)Dick et al. (1964) 32 78 45Lennard-Jones et al. 20 65 40

(1960)

CorticosteroidsThe value of corticosteroids in ulcerative colitis

remained in doubt for some years, but in thelast 15 years a number of carefully controlledtrials have demonstrated that steroids, whetherused systemically or topically, are capable of

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inducing remissions in a significant proportionof patients treated. They have emerged as avaluable adjuvant in therapy capable, on occas-ion, of producing remarkable remissions butregrettably often failing unpredictably to controlacute attacks of colitis or to prevent relapse orthe development of complications. Whether theirbeneficial effects are due to a reduction of thevascular and tissue responses to inflammation ora damping down of autoimmune or hypersensit-ivity reactions in the bowel wall is not known.The indications for systemic treatment with

steroids have been reviewed elsewhere (Watkin-son, 1966). They should be used in any severecolitic attack or relapse which is not controlledby simple measures particularly when associatedwith systemic colitic complications, such as arth-ritis, skin or eye lesions known to be improvedby steroids. They should be used with cautionin patients with established electrolyte disturban-ces, malnutrition, marked abdominal distensionor rectal bleeding or if coincident disease knownto be worsened by steroids is present, such asdiabetes, tuberculosis or peptic ulcer. The drugsare contra-indicated if perforation or peritonitisare suspected, if a toxic megacolon has developedor if severe perianal disease is present.The dosage and method of administration

will vary with the severity of the attack. Infulminating disease ACTH will produce moreremissions than cortisone particularly if adminis-tered intravenously initially and followed by theintramuscular injection of 40-80 units of ACTHgel twice daily. As the patient improves dosage isgradually tailed off and oral steroids substituted.Hydrocortisone 50 mg intravenously and 50-100 mg intramuscularly 8-hourly producescomparable results and has a more rapid onsetof action. In cases of moderate severity cortisoneacetate 150-300 mg is given orally and producesrather fewer remissions than does ACTH, poss-ibly because of poor intestinal absorption. For

milder attacks in ambulatory patients prednisone20-60 mg daily is used initially with a reductionto 10-15 mg as improvement occurs.The results to be expected from systemic steroid

therapy are summarized in Table 3 below. Incontrolled trials conducted between 1950 and1959 (Truelove & Witts, 1955, 1959) it was shownthat the 40% remission rate induced in 109 colitispatients receiving 100mg daily of cortisone wassignificantly better than the 16% remission rateinduced in 101 patients receiving inert tablets.First attacks, at all grades of severity, faredbetter than chronic relapsing cases where remis-sion rates were 42 and 26%, respectively. In asecond trial it was shown that no better resultswere achieved by doubling the dose of cortisoneto 200 mg daily, where again two out of everyfive patients treated went into remission. How-ever, a significantly higher remission rate wasobtained in eighty-four patients treated by 80units of ACTH daily where 61 % went into remis-sion, relapsing cases faring better than firstattacks, remission rates being 71 and 50%, res-pectively. Similar results have been achieved bymany workers throughout the world, for example,the Chicago group had treated 340 patients withsteroids up to 1962 and report an immediatelyfavourable response in 20% of those treated and asustained improvement in 73 % (Spencer et al.,1962). Where it was shown in the trials of True-love & Witts (1955, 1959) that steroids bothhalved the mortality and recourse to surgery inthose treated many limitations of therapyemerged} Perianal suppurative conditions occur-red three times more commonly in the steroid-treated group making it desirable to combinesteroids with either suphasalazine or a parenter-ally administered antibiotic.While some authorities (Brooke, 1956) have

claimed that steroids may actually induce colonicperforation and certainly mask its presence, inthe controlled trial reported by Truelove &

TABLE 3Results of steroid treatment in ulcerative colitis

Remission rates (°)Daily dose No. patients

All cases First attacks Relapses

Cortisone* 100 mg 109 41 42 26Inert - 101 16 13 17Cortisone* 200 mg 85 39 42 37ACTH 80 units 84 61 50 71Cortisone and ACTHt 200-300 mg 340 68 - -

or 120 units

*Truelove & Witts (1955, 1959).tSpencer et al. (1962).

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Witts (1955) the frequency of perforation wasgreater in the group not treated by steroids. Thiscontention was supported by Goldgraber andothers in 1957 and later by our own study of thefrequency of perforation in 165 patients studiedover a 10-year period which showed the fre-quency of perforation to be identical in groupsof patients receiving and not receiving steroidswith frequencies of 4-3 and 4-1 %, respectively(de Dombal et al., 1965a). There is littleevidence therefore, to suggest that steroids pre-dispose either to perforation or to massivecolonic haemorrhage, while the frequency ofpostoperative complications and collapse wasgreater in groups of patients treated preoper-atively with steroids than in those not receivingthem. Differences were not satisfactorily signifi-cant and the data difficult to appraise becauseof the greater perforation of seriously ill patientsin the steroid group (Watts et al., 1966a, b;Lennard-Jones & Vivian, 1960).

Topical treatment of colitis with corticosteroidsSteroids were first used topically in colitis by

Truelove in 1956 and their value in distal diseaseconfirmed by a series of controlled trials (True-love, 1958; Watkinson, 1958, 1961a, b; Matts,1960, 1962; Matts & Gaskell, 1961; Spencer &Kirsner, 1962; Patterson et al. 1965). The majorattractions of this method of treatment are thatminimal or no side-effects develop, and it ispossible to obtain much higher concentrations ofsteroid locally than could be achieved by sys-temic therapy.

Its disadvantages are that the method mayprove cumbersome and distasteful to manypatients while those with profuse diarrhoea maybe unable to retain the enemata adequately.

The dosage, relative potencies, method ofadministration, limitations and advantages to-gether with the results of various types of topicalsteroid therapy are shown in Table 4 below.

Freshly prepared hydrocortisone hemisuccin-ate sodium can be administered by rectal drip,may penetrate to the right colon and have abeneficial effect in 52-69% of the patients treated(Truelove, 1958; Patterson et al., 1965; Watkin-son, 1961a). The stability of prednisolone 21-phosphate enabled it to be administered fromdisposable enema bags as a retention enema andremission rates of 75-88% were claimed inpatients with distal disease (Matts & Gaskell,1961; Patterson et al., 1965; Spencer & Kirsner,1962). While betamethazone, a steroid fifty timesmore potent than cortisone, given in doses of5-10 mg as a retention enema produced remis-sions in four-fifths of patients treated, side-effectswere frequent and severe and led to the with-drawal of this type of enema by the manufac-turers (Matts, 1962). It is possible that the newsteroid betamethasone-1 7-valerate (betnovate)which has enhanced topical and reduced systemiceffects now under evaluation given in tablet formor as a retention enema may prove as effectiveas preliminary trials have suggested (Gill et al.,1965).

Steroids can be most conveniently administeredtopically as suppositories containing prednisoloneor betnovate and have been proved by controlledtrials to improve patients with distal proctocolitis(Truelove, 1959; Patterson et al., 1965; Lennard-Jones et al., 1962).

Topical steroid treatment therefore emerges asa most useful form of therapy, most applicableto mild cases of colitis with distal disease orproctocolitis.

BLE 4

Topical use of steroids in ulcerative colitis

Type of steroids Dosage Method of Advantages Disadvantages Remission(mg) administration No. %

Hydrocortisone, ( x 1) 100 Saline rectal drip Best penetration, no Cumbersome, unstable 58 69*side effects 73 52t

Prednisolone 21-phosphate 20 Plastic enema bag Convenient, stable, Distasteful to some 20 75*( x 5) minimal side effects patients 100 88t

Betamethazone ( x 50) 5-10 Plastic enema bag Convenient, stable Consistent, severe 48 82$side effects

Betnovate ( x 1/50) 2-5 Plastic enema bag Convenient Insoluble, incidence of Under evaluationor tablet side effects unknown

Oral prednisone 20 Enema and Convenient Side effects from oral 56 65tTopical hydrocortisone 100 tablets steroid

Figures in parentheses refer to relative potencies of steroids (hydrocortisone= 1)*Truelove (1958, 1959, 1960a, b). tWatkinson (1958, 1961a, b, 1962).tMatts (1960), Matts & Gaskell (1961) and Matts (1962).

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Combined topical and systemic steroidsA combination of topical and systemic steroid

therapy was first advocated by Truelove (1960a)and it was later shown by a controlled trial thata combination of hydrocortisone retentionenemata and prednisone by mouth would inducesymptomatic remissions in 65% of a group offifty-eight patients so treated, with mucosal im-provement in 79% (Truelove et al., 1962).

Treatments under evaluation

Immunosuppressive agentsThe temporary improvements induced in auto-

immune diseases such as disseminated lupuserythematosus by the use of immunosuppressiveagents made it not unreasonable to use these inthe treatment of ulcerative colitis, as was firstadvocated by Bean in Australia in 1962. Whilethese drugs can suppress immune reactions theycan also unpredictably produce marrow depres-sion with resulting anaemia, leucopenia andthrombocytopenia which do not aid the physicianin treating a condition with well-established infec-tive and haemorrhagic features.Two groups of Australian workers (Bean,

1966; MacKay, Wall & Goldstein, 1966) haveused such drugs as 6-mercaptopurine, busulphanor azothioprine (Imuran) to treat fourteen coliticpatients, twelve of whom showed immediate andeleven sustained improvement and in whomserious marrow depression was rare. While eightout of ten patients, treated with azothioprinein Professor Kirsner's clinic in Chicago, showedinitial improvement this was only sustained inone patient and difficulties with marrow depres-sion have led this group to no longer advocatethis form of therapy (Bowen et al., 1966; Kirsner,personal communication 1967). The rapid deathof a young colitic patient from agranulocytosisfollowing treatment with azothioprine led Jonesand others (1966) to emphasize the potentialdangers of this form of treatment.The results, therefore, in twenty-five patients

treated to date have been far from impressive andthe routine use of these particularly dangerousdrugs cannot be recommended at present inulcerative colitis until further careful prolongedassessments have been made in research centresused to handling colitic patients.Rectal hypothermiaThe control of haemorrhage from the stom-

ach and from the prostatic bed by local freezingled a group of Rumanian workers to freeze therectal mucosa in nine patients with 'ulcerativeand haemorrhagic proctocolitis' with immediateimprovement in all cases which was sustained for

periods of 3-18 months (Mandache et al., 1965).This trial was uncontrolled and the methodrequires investigation. It might have a place incontrolling massive rectal bleeding in the fewcolitic patients in which it occurs.

LeucotomyLeucotomy or selective pre-frontal electrocoag-

ulation has been advocated and successfullypracticed in a Swiss clinic in colitic patients(Wissmer, 1959). Again critical assessment andprolonged follow up would be required beforethis drastic and irreversible form of therapycould be advocated. The same criticisms can bemade about the value of electric shock therapyor prolonged narcosis also advised in ulcerativecolitis.

Maintenance treatmentHaving controlled acute attacks of colitis the

physician next tries by some form of maintenancetreatment to prevent relapses or complications ofthe disease. This may be attempted either bygiving small doses of sulphasalazine or small orlarge doses of steroids on a long term basis.

SulphasalazineSulphasalazine given in doses of four tablets

daily has been claimed to keep between one-half and three-quarters of large groups of patientsin remission for periods of 1-5 years with infre-quent side effects (Svartz, 1956; Moertal &Bargen, 1959; Watkinson, 1962). Such trials werehowever uncontrolled and the ability of smallmaintenance doses of sulphasalazine to preventcolitic relapses has only recently been proved bya controlled trial (Misiewicz et al., 1965). In thistrial two groups of similar colitic patientsreceived either sulphasalazine 0-5g four timesdaily or identical dummy tablets over a 12-month follow up period. Remissions were main-tained in two-thirds of these receiving sulphasala-zine and in less than one-quarter of those receiv-ing inert therapy representing a significant advan-tage for the drug. No side effects were observed.Sulphasalazine emerges as a drug capable inmoderate maintenance dosage of preventingcolitic relapses in a significant proportion of thosetreated.

CorticosteroidsIn attempting to prevent colitic relapse with

steroids the physician may either give large dosesof steroids in sufficient amounts to suppress thedisease accepting high incidence of inducedside-effects (Spencer et al., 1962). Alternatively anattempt may be made by small maintenancedoses of steroids to control the disease accepting

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an appreciable relapse rate and recourse to sur-gery but avoiding steroid complications (Watkin-son, 1966).While large maintenance doses of cortisone or

ACTH given by the Chicago workers kept two-thirds of their 340 colitic patients in remissionor good health for long periods with a lowmortality and recourse to surgery, side effectsdeveloped in 85% of those treated. These in-cluded psychological upset (16%) diabetes orglycosuria (12%) serious electrolyte upsets (12%)osteoporosis (4%) melaena or peptic ulcer (4%)while nine deaths could be directly attributedto steroid therapy. The authors felt that goodcontrol of the disease was adequate compensa-tion for the side-effects encountered and remainkeen advocates of long term large dosage steroidtreatment.

Unfortunately, there is no evidence to suggestthat small doses of steroids prevent colitic re-lapses. One controlled trial (Truelove & Witts,1959) failed to show any difference in relapserates in two groups of colitic patients followedfor a year receiving either cortisone or identicaldummy tablets. A second controlled trial(Lennard-Jones et al., 1965) treated two compar-able groups of colitic patients with either 15 mgof prednisone daily or with identical inert tablets.Even though larger doses of steroids were used,inducing side-effects in one quarter of the patientstreated, by the end of 6 months identical relapserates occurred in both groups, namely in eighteenof thirty-two patients receiving prednisone and inseventeen of thirty controls.

Regrettably, therefore, there is no fully con-trolled evidence that prolonged treatment withsmall or large doses of steroids influence thenatural history of ulcerative colitis, though inindividual cases both patient and physician mayconsider them of value.

Modifications of treatment in relation to severity,extent, clinical pattern and complications ofcolitis

Medical treatment has had to be modified withincreasing knowledge of the factors affecting theprognosis of ulcerative colitis, namely, the sever-ity of the attack, the extent of the disease, theage of the patient and the presence of associatedcolonic and systemic complications.

Severity

Acute fulminating colitisFulminating colitis is a serious medical emer-

gency with a high mortality and frequentlyrequires surgical intervention. Depressing mortal-

ities have been reported: between 28 and 50%by Lennard-Jones & Vivian (1960) and by Gouls-ton et al. (1960) and there is evidence to suggestthat modern treatment has not much reduced themortality in that type of case (Edwards & True-love, 1964).The management of this type of case is, there-

fore, one of extreme urgency. Frequently lament-able delay in diagnosis occurs, the patient havingbeen investigated at home or in an infectiousdiseases hospital as a possible case of a dysen-teric illness. While it is vital by stool culture toexclude this possibility, in cases where these provenegative early sigmoidoscopy together with a plainabdominal X-ray will make the true state ofaffairs apparent and the patient should beurgently transferred to a general medical wardwhere he can be reviewed daily by both physicianand surgeon. Strict bed rest and sedation areenforced, colonic rest promoted by either with-holding fluids by mouth or giving a fluid diet,parenteral fluids are administered liberally, thereplacement of potassium being particularly im-portant, and liberal blood transfusions are almostalways necessary. Adequate vitamin replacementsand parenteral feeding are often required. Thepatient should be given sulphasalazine by mouth,1-2 g four times daily, and large doses of steroidsparenterally. In this type of case ACTH orcortisone should be given intravenously initiallysupplemented by intramuscular doses later. At-tempts should also be made to administersteroids topically in the form of a rectal drip ofhydrocortisone or retention enemata of prednesolwhich if retained adequately will speed recovery(Truelove, 1960b). Fulminating cases are oftenmarkedly improved by a short course of an anti-biotic, such as penicillin and streptomycin,ampicillin or erythromycin given parenterally.In addition to this intensive nursing and medicalcare, levels of haemoglobin, haematocrit andelectrolytes should be estimated daily in order toplan the parenteral therapy given. Daily assess-ments jointly by physician and surgeon are con-tinued and attempts were formerly made to allowthis medical treatment to have its full effect over10-14 day period. However, when this principlewas applied to 124 patients with severe coliticattacks in Leeds between 1952 and 1963, only52% went into remission, 5% died under medicaltreatment and 32% required emergency surgery,the overall mortality remaining depressingly highat 11-3% (Goligher et al., 1967).

Accordingly, it was decided, for a trial period,to invoke surgical aid at a much earlier stagein these severe attacks unless there was evidenceof a rapid and unequivocal improvement on max-

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imal medical treatment. Indications for urgentsurgery can be briefly summarized as continuingmassive haemorrhage, perforation, sudden deter-ioration in the general condition of the patient,and after 2 or 3 days of conservative manage-ment in elderly subjects and within 4-5 days ofinitiation of therapy in younger patients. Theresults of this policy in eighty-one patients withsevere attacks treated in Leeds between 1964 and1966 were quite dramatic.Remissions occurred with similar frequency,

namely in 47%, and no deaths occurred undermedical treatment. Urgent surgery was under-taken in half these patients and the overallmortality was reduced to 1-3%. While this wasnot in any way a controlled trial, this experienceand that of others (Gallagher et al., 1962), wouldsuggest that surgery has an increasing role toplay in fulminating attacks of ulcerative colitisuntil some improved type of medical treatmentcan be devised.

Chronic ulcerative colitisHere the physician has adequate time to apply

the full therapeutic programme previously des-cribed, remembering however, that at any timefurther fulminating attacks may occur, that thedisease tends to extend and that as the yearspass on an increasing number of complicationsmay develop. There seems to be little tendencyfor the disease to burn itself out so that surgerywill often be required for the invalidism in-duced by recurring attacks of the disease or thedevelopment of colonic or systemic complications.

Extent of colonic involvementThe management of ulcerative colitis is mater-

ially affected by the extent of colonic involve-ment.

ProctocolitisThese patients are mainly troubled by rectal

bleeding and by constipation and by a blood-stained rectal discharge. They seldom becomeacutely ill save from the effects of anaemia.Bulk-forming laxatives, senokot or milk ofmagnesia should be given in sufficient amounts topromote a bulky soft daily bowel action. If rectalbleeding continues suppositories of either sulpha-salazine or prednisolone should be inserted onwaking and retiring. For more intractable casestopical treatment with retention enemata ofprednisolone should be tried and rarely shortcourses of sulphasalazine and prednisone have tobe given orally.

Iron therapy is often required to correct theanaemia present.

Distal proctocolitisPatients with involvement of the pelvic and

descending colon can get colitic attacks of allgrades of severity but carry a rather better prog-nosis than those with total involvement and arerelatively free from the risk of malignant change.Medical trerLtment by dietary means, by sulpha-salazine and by steroids topically and systemic-ally, can therefore be safely persisted in for longperiods. Regrettably the disease in many casestends to spread proximally making the need forelective surgery to be kept constantly under re-view.

Colitis with total colonic involvementWhile many of these patients can be kept well

through the years on maintenance treatment andmany have spontaneous remissions of symptoms,studies of the natural history of the conditionhave shown that these are the patients most likelyto develop relapses and complications of thecolitis itself and as the years pass to be increas-ingly prone to the risk of malignant change inthe colon. Furthermore, the disease is unlikelyto become less extensive under the influence ofmedical treatment. In these circumstances thephysician should not persist with medical treat-ment indefinitely and when total colonic involve-ment has been demonstrated unequivocally radio-logically should explain the risks at stake to thepatient and elective proctocolectomy should beadvised. Patients are usually, understandably,reluctant to accept this advice while they aresymptom-free. They should be warned that surgeryis desirable and pressure put upon them to acceptsurgery when a relapse occurs.

Segmental colitis and entero-colitisThe difficulties in distinguishing ulcerative

colitis and Crohn's disease of the colon and smallintestine have been emphasized elsewhere. Ifsymptoms and signs of a malabsorption state arepresent or if severe unusual perianal diseaseoccurs and the rectum looks normal on sigmoid-oscopy, Crohn's disease should be suspected andmedical treatment persisted in for as long aspossible. Here dietary measures, particularly therestriction of fat and the long-term usage ofsulphasalazine and steroids are advocated butstill have to be shown to modify the long-termcourse of the condition. In many cases the devel-opment of obstruction or internal fistula forma-tion or the development of perianal disease willmake surgery inevitable.

If true segmental ulcerative colitis is suspectedand the rectum appears normal on sigmoido-scopy, early surgery should be advised and thediseased segment resected followed by ileo-colic

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or colo-colic anastomosis. If medical treatmentis persisted in there is a tendency for the diseaseto spread distally, eventually to involve therectum, making the less acceptable operation oftotal proctocolectomy and ileostomy necessary.

Clinical pattern of colitis

Age of the patientAdditional problems in the management of

ulcerative colitis occur at the extremes of life inchildren and in the elderly; the particular prob-lem in children is that colitis in the first decadeis a cause of infantilism with physical retardationof growth and a delayed onset of puberty. Oncetotal colonic involvement has occurred thesechildren are just as susceptible to relapses andcomplications and to malignant change as areadults and because of the early onset of symp-toms develop them at a very tender age (Rosen-qvist et al., 1959).

While medical treatment follows a similar pat-tern to that for adults, particular attention to theprotein and calorie needs of the patient is neces-sary and the correction of anaemia is vital if thechance of physical retardation is to be reduced.Emotional conflicts seem more common in coliticchildren who often have aging, ambitious andover-attentive parents who often make excessiveacademic demands on children of average ability.Treatment of the whole family by explanationand common sense psychotherapy is often neces-sary. Tragically physical retardation, togetherwith extensive and long-standing disease, oftenmake proctocolectomy and ileostomy inevitable.The operation is usually well tolerated by the childand surprising degrees of growth and weight gainwill often follow operation.The serious prognosis of acute colitic attacks

in elderly patients is emphasized elswhere makingit necessary to consider emergency colectomy ata much earlier stage than in younger patients(Goligher et al., 1967). While many lives canundoubtedly be saved in these elderly patientsthe effects of an ileostomy life in this age grouphas not yet been studied in detail.

Ulcerative colitis and pregnancyThe effect of pregnancy on the natural history

of colitis together with the effect of colitis onthe mother and foetus is described elsewhere,(de Dombal et al., 1965b), where it was shownthat pregnancy had little effect on the relapse rateof colitis compared to a control population andthe relapse occurred most commonly during thefirst trimester or during the immediate post-par-tum period. The incidence of abortion and foetalD

abnormality was below that which might havebeen expected suggesting that neither the colitisnor its treatment with sulphasalazine or steroidshad affected the foetus.

Statistically, therefore, there are few groundsfor advising termination in pregnancy. However,each case has to be assessed individually and thedesire for the child assessed against the effect ofthe colitic attack on the mother. If the child iswanted improvement usually occurs, particularlyin the second and third trimesters. There is acase for increasing full supportive treatment withsulphasalazine and steroids during the first 3months of pregnancy and for 2 or 3 months afterdelivery. If the child is unwelcome relapse islikely and if the mother's health deterioratesrapidly in the first trimester, termination of preg-nancy may have to be advised often with dram-atic cessation of symptoms. The ability of coliticpatients to conceive and be delivered of normalchildren after colectomy and ileostomy isemphasized by the authors.

Effects of complications of the colitis on medicaltreatmentThe serious colonic complications of colitis

such as perforation, toxic megacolon and massiverectal haemorrhages are indications for urgentcolectomy, continuing medical treatment beingboth unwise and dangerous. Similarly extensivestricture formation and gross pseudopolyposiswith total colonic involvement make it extremelyunlikely that any form of medical treatment willbe successful and in these circumstances electiveproctocolectomy and ileostomy are advised.Similarly severe perianal disease may beworsened by medical treatment particularly bysteroids and will sway the physician again to-wards advising surgery.Of the systemic complications skin conditions

and recurrent attacks of colitic arthritis mayprove extemely refractory to medical treatmentbut are usually cured by colectomy. Iritis, liverdisease and sacro-ileitis however are unlikely tobe improved by colectomy and in these casesintensive treatment of the colitis by dietary means,steroids and sulphasalazine should be persistedin (Watkinson, 1968).

ConclusionsIn this paper the medical treatment of ulcera-

tive colitis has been reviewed and its ability toterminate acute attacks, prevent relapse andcomplications assessed. The fact that medicaltreatment fails sometimes to achieve all theseobjectives makes it vital that the cases be man-aged jointly by physician and surgeon both in the

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acute attack and in long-term management thepossibility of operation being kept constantlyunder review.

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