Postgrad Med J: first published as 10.1136/pgmj.44.515.696 on 1 September 1968. Downloaded from Postgrad. med. J. (September 1968) 44, 696-707.

The medical treatment of ulcerative colitis

GEOFFREY WATKINSON Consultant Physician to the York Hospitals

THE ADEQUATE treatment of any illness depends (i) To terminate the acute colitic attack or primarily upon a knowledge of its aetiology and relapse as quickly as possible. in a chronic relapsing illness, such as ulcerative (ii) To attempt by some form of maintenance colitis, an awareness of its natural history and therapy to prevent relapses or complications of complications. While the final cause of ulcerative the disease. colitis remains obscure, increasing knowledge of (iii) By a knowledge of factors known to possible causal factors and of the prognosis of influence the natural history and prognosis of the condition has markedly influenced its treat- colitis, to recognize that medical treatment has ment in recent years. failed to induce remission or to prevent relapses When colitis was thought to be of bacterial or complications and to refer the patient for origin specific sera were prepared but proved of urgent or elective surgery. no lasting value. Similarly, no effective agents to The physician has to accept, as Bargen (1961) Protected by copyright. inhibit mucinases have been evolved. Enthusiasts has emphasized that 'control' of colitis is far for the hypothesis that colitis is due to food more likely than 'cure' and that the patient must allergy have advocated the use of milk-free diets be supported through long weeks, months or in colitic patients with apparent benefit (Andre- years of chronic and often recurrent illness. This sen, 1942; Wright & Truelove, 1965a, b). Attempts is best done by a patient and persevering phys- to suppress supposed autoimmune reactions have ician who works in close association with a sur- been made with corticosteroids used orally, topic- geon interested and skilled in the difficult colonic ally or parenterally, by non-specific anti-inflam- surgery that colectomy in an acutely ill colitic matory agents, such as sulphasalazine or more patient may demand. Throughout a combined recently by immunosuppressive agents. Physicians medico-surgical approach should be adopted impressed by psychosomatic factors in the illness both in the day-to-day management of acute have advocated the use of psychotherapy, of attacks and through months and years of follow- sedatives and antidepressant drugs and even up of the chronic case at a colitis clinic run leucotomy to control the condition. jointly by a physician and surgeon. It has been http://pmj.bmj.com/ Assessment of the value of any therapeutic suggested that a psychiatrist should complete the measure proves difficult in a disease which varies team to cope with the frequent psychosomatic greatly in severity and extent, not only from problems which afflict these patients. While this is patient to patient but in the same individual from a debatable issue such a team obtained excellent attack to attack, making rigorous controlled results in the paediatric clinic of a Michigan trials of any measure necessary in large groups hospital (McDermott, John & Finch, 1964). of colitic patients before its values can be accep- ted. Treatment of the acute attack on September 28, 2021 by guest. Increasing knowledge of the nutritional and The measures used in treating severe initial biochemical problems encountered in these colitic attacks and relapses are summarized in patients, together with the introduction of more Table 1 below. potent drugs, such as sulphasalazine and cortico- steroids and the wider use of surgery, have mater- Rest ially improved the prognosis of ulcerative colitis Bed rest is recommended for any colitic re- in the last two decades. lapse and early hospitalization for patients with severe diarrhoea, copious bloody stools, fever Principles of medical treatment anaemia and weight loss. More adequate rest will The duties of a physician treating a patient be aided by the administration of sedative and with ulcerative colitis can simply be stated: tranquillizing drugs, such as phenobarbitone and Postgrad Med J: first published as 10.1136/pgmj.44.515.696 on 1 September 1968. Downloaded from Medical treatment of ulcerative colitis 697 amylobarbitone. In more anxious or obsessional given and if used in dosage sufficient to produce patients meprobamate, chlordiazepoxide or mild side-effects will often control both diarrhoea diazepam can be tried and where agitation is and cramping abdominal pains. They are con- complicated by nausea and vomiting, drugs traindicated in patients with glaucoma or previous such as promethazine hydrochloride or chlorpro- urinary retention and if given in excessive dosage mazine can be used. Adequate sleep is essential to severely ill patients may induce intestinal often making hypnotics, such as chloral hydrate, atony simulating a toxic megacolon. amylobarbitone, pentobarbitone or gluthemide, Belladonna given as the tincture or in a sus- necessary. tained release tablet (Belladenal retard or Donnatal) can be used or one of the numerous TABLE 1 synthetic anticholinergic drugs available, such as Medical treatment of ulcerative colitis propantheline bromide, poldine methylsulphate, methscopolamine bromide or penthionate brom- REST ide, exhibited. Bed rest-hospitalization For the control of copious diarrhoea the use Sedative and tranquillizing drugs Hypnotics of opiates is justified provided it is realized that these COLONIC REST drugs have addictive properties, may mask Parenteral feeding perforation or worsen ileus and, therefore, Fluid diet should only be prescribed for short periods and Low-residue, high-protein diet tapered off as soon as possible. Codein phosphate Antispasmodic and antidiarrhoeal drugs tablets, tincture of opium or tincture of chloro- MAINTENANCE OF NUTRITION AND OF FLUID AND form and morphia can be given. Lomotil is a ELECTROLYTE BALANCE Replacement of fluid useful proprietary tablet combining a codein Mineral replacement salt, potassium, magnesium, calcium derivative diphenoxylate hydrochloride with Protected by copyright. Vitamin supplements atropine sulphate. Parenteral feeding Thickening of the stools with bulk-forming Anabolic agents laxatives seems to improve sphincter control while CORRECTION OF ANAEMIA Oral, parenteral, intravenous iron a few patients with proctocolitis may need mild Blood transfusion laxatives as they are in fact constipated. Hydro- DIET philic agents, such as psyllium seeds or methl- Low roughage, high-protein diet cellulose, are used with or without mild laxatives, Milk free diet on occasion such as milk of magnesia, liquid paraffin or stan- ANTIBIOTICS dardized senna. Used with caution, best given parenterally Penicillin and streptomycin Ampicillin, chloramphenicol Maintenance of nutrition and of fluid and electro- Neomycin lyte balance MORE SPECIFIC REMEDIES In acute fulminating attacks gross dehydration

Sulphasalazine and profound electrolytic and metabolic imbal- http://pmj.bmj.com/ Orally ances may develop making it vital that such cases Topically Coticosteroids be managed in hospital where adequate bio- Parenterally chemical facilities are available together with the Orally trained nursing and house officer staff to cope Topically with the intensive care which these cases may TREATMENTS UNDER EVALUATION require. Immunosuppressive agents In severe attacks gross dehydration with a

Rectal hypothermia on September 28, 2021 by guest. Leucotomy hyponatraemic, hypokalaemic acidosis may develop making it necessary to rapidly correct these deficiencies with intravenous 5% dextrose, Colonic rest 0-9% sodium chloride (150 mEq/l) or I M-lactate Colonic rest is achieved by dietary means and and adding potassium chloride 1-5 g (20 mEq) by various antispasmodic and antidiarrhoeal to each 500 ml of infusion fluid. Potassium deple- drugs. In the severely ill patient with continuous tion may be profound and up to 80 mEq daily diarrhoea complete withdrawal of oral fluid and may have to be given. Magnesium depletion may feedings is justified, the patient being maintained develop and is becoming more widely recognized by parenteral fluids. Later a fluid diet and finally as facilities for its estimation become more a low residue high protein diet are given. widely available. A wide variety of antispasmodic drugs can be Subsequently additional salt and potassium can Postgrad Med J: first published as 10.1136/pgmj.44.515.696 on 1 September 1968. Downloaded from 698 Geoffrey Watkinson be given orally as enteric coated tablets or as Diet effervescent tablets (1 g=6-5 mEq) of potassium. Rapid wasting occurs in both acute and chronic Reports that such tablets may cause intestinal attacks with hypoproteinaemia, vitamins and ulceration have led to the use of liquid prepara- nutritional deficiencies. It is therefore important tions of the chloride (6 5 mEq/g), the citrate that the patient eats as much of a high-protein (9-2 mEq/g) or the gluconate (20 mEq/ 15 ml). low-residue diet as his condition allows supplying Unfortunately, many of these preparations are 2500-3500 cal daily with 100-150 g of protein unpalatable and may cause diarrhoea in which presented as attractively as possible. This diet is case a slow release tablet incorporating 600 mg most widely used in ulcerative colitis. of potassium chloride (8 mEq) in a slow release The role of milk allergy in the pathogenesis of wax core is administered in a dosage of four to colitis was first suggested by Andresen (1942) eight tablets daily. and by Rowe (1942). Interest in the topic was Vitamin replacement is necessary in many re-awakened by Truelove (1961) who reported severely ill and debilitated patients. Supplements on a small group of patients who became of vitamins A and D (calciferol), B complex and symptom free on a milk-free diet and who re- C (parentrovite), cyanocobalamin and folic acid lapsed when milk was introduced into the diet. and vitamin K may have to be given intraven- Recently Wright & Truelove (1965a) have repor- ously or intramuscularly, particularly if complic- ted favourably on the results of a controlled ating liver disease is present. Subsequent adequate trial of a milk-free diet in twenty-six colitic oral replacement is given. patients who faired better on a milk-free diet Intravenous protein replacement may have to than twenty-four colitic patients receiving a be attempted in critically ill patients using whole normal or gluten-free diet. Twice as many blood, double strength plasma or protein hydro- patients on a milk-free diet remained symptom lysates (Amigen, Trophysan) supplying additional free and fewer patients suffered severe relapses,

calories with glucose or fat emulsions (Lipiphy- differences between the groups being only marg- Protected by copyright. san). Such infusions should be cautiously used as inally significant. Wright and Truelove estimate they may cause systemic reactions and phlebitis that approximately one in five patients with locally. Similarly, claims have been made that ulcerative colitis will benefit from milk restric- anabolic steroids, given intramuscularly, may tion, a proportion which may be greater in first accelerate weight gain and improve appetite in attacks of the disease. Regrettably, raised titres colitic patients (Kasisch, 1963). of circulating antibodies to milk provided no Correction of anaemia guide to the possible response of a colitic patient Anaemia may need to be corrected in both to a milk-free diet, making it impossible to select the acute and chronic phase of the disease. Blood patients who might benefit from withholding transfusion is often urgently required for massive milk. It will be of considerable interest to see blood loss or to correct the anaemia and hypo- if these results can be confirmed on a larger proteinaemia of the chronic case. Oral iron group of patients and the use of a milk-free diet therapy may be poorly tolerated by the colitic cannot at present be routinely advocated. patient, making it necessary to use a liquid prep- Psychotherapy aration, an enteric coated or sustained release http://pmj.bmj.com/ tablet or to give iron intramuscularly or intrav- One of the most controversial aspects of the enously. treatment of ulcerative colitis is the role of psychotherapy. First advocated by Murray in Antibiotics 1930, psychotherapy has found many enthusiastic Antibiotics should be used with caution in supporters through the years (Paulley, 1950; ulcerative colitis as their oral administration Grace & Wolff, 1951; Grace & Graham, 1952; may worsen diarrhoea and predispose to secon- Groen, 1961). These authors advocate that dary infection with monilial organisms. Used a constructive patient-physician relationship discriminately and given parenterally to the should be established where the patient is en- on September 28, 2021 by guest. acutely ill febrile patient they may dramatically couraged to discuss their symptoms and their improve the patient's condition. A combination personal and environmental difficulties with a of penicillin and streptomycin is best tried physician who gives the patient 'time, kindness, initially. Alternatively, intramuscular tetracycline, tangible signs of understanding and support' and chloramphenicol or ampicillin can be given. who is 'available at all times by phone', 'as often Neomycin or succinylsulphathiazole, given orally, as daily' if the patient's condition demands it. will often produce improvement and are useful Such a relationship makes exacting, exhausting pre-operatively. and prolonged demands on the physician who Postgrad Med J: first published as 10.1136/pgmj.44.515.696 on 1 September 1968. Downloaded from Medical treatment of ulcerative colitis 699 is only able to treat a limited number of colitic ing acute attacks of the disease are summarized patients at one time or even in his working life. in Table 2 below. In the 861 patients reviewed, Other physicians have had less fortunate ex- remission or improvement occurred in between periences with formal psychotherapy in ulcera- 47% and 78% of those treated while side effects tive colitis. Crohn & Yarnis (1951), reporting that developed in between 16% and 45%. Mucosal im- only one of twelve patients so treated obtained provement on sigmoidoscopy has been reported benefit while two colonic perforations occurred in 43% of fifty-eight patients treated (Truelove during active psychotherapy. et al., 1962). Salazopyrin, therefore, emerges as a It follows that if psychotherapy is to be prac- useful drug in the treatment of all types of colitis tised it must be used by or in close association with better than even chances of success. Side with a physician skilled in the management of effects somewhat limit the value of the drug, colitic patients who is capable of recognizing the many of which can be overcome by the use dangerous and potentially lethal complications of of enteric-coated tablets, which, incidentally, the condition. In these circumstances in chronic have still to be shown as effective as the plain relapsing cases psychotherapy is often rewarding tablets by further clinical trials. but there is certainly no place for expert A chemical analogue of sulphasalazine, salicy- psychotherapy in isolation. lazosulphadimethyl-pyrimidine (azudimidine) was submitted to limited trials with conflicting results Sulphasalazine by several workers, most finding the drug to be Sulphasalazine (salazopyrin or azulfidine) is a less effective and more toxic than sulphasalazine diazo compound of salicylic acid and sulphapy- (Braders & Bargen, 1960; Baron et al., 1962a; ridine and has been used successfully in the treat- Watkinson, unpublished data 1967). For this ment of ulcerative colitis since its development reason the manufacturers have withdrawn this in Sweden in 1941 by Svartz and is capable of compound. Protected by copyright. inducing remissions in a significant proportion Sulphasalazine incorporated into a suppository of patients treated (Svartz, 1956, 1961 ; Moertal & containing 1 g of the drug has recently been Bargen, 1959; Watkinson, 1961a, b, 1962; True- shown by controlled trials to exert a beneficial love, Watkinson & Draper, 1962; Morrison 1963). topical action if inserted nightly in patients with The drug's mode of action is unknown; it distal proctocolitis, fifteen of eighteen patients has an affinity for connective tissue through- receiving potent suppositories going into clinical out the body and reaches high concentrations remission as compared with five of eighteen in serous fluids, liver and intestinal wall. It has treated by insert suppositories. No side effects no effect on the intestinal flora and seems to were observed (Watkinson, unpublished data exert its beneficial effect by a non-specific anti- 1967). inflammatory action in the colonic wall and TABLE 2 lumen. Immediate results of treatment with sulphasalazine of acute Dosage can be varied with the severity of the colitic episodes in 861 patients treated in Sweden, America

attack; plain tablets containing 0-5 g are given and England, together with the frequency of drug intolerance http://pmj.bmj.com/ initially reserving the enteric-coated tablets for patients exhibiting gastro-intestinal intolerance to % recovered % showing Patients or much drug the plain tablets. Usually two to four tablets four treated improved intolerance to six times daily are used, depending on the tolerance of the patient. Unfortunately, in about Svartz (1956, 1961) 439 77 'Few' 20% of patients receiving sulphasalazine unplea- Morrison (1963) 60 70 21 Moertal & Bargen (1959) 133 64 17 sant side effects will develop. Nausea, vomiting Watkinson (1961a) 69 47 16 and headache are most common and are usually Truelove, Watkinson & 58 50 22 on September 28, 2021 by guest. controlled by substituting the enteric-coated Draper (1962) tablet in the same dosage. Rarely drug fever, Dick et al. (1964) 32 78 45 Lennard-Jones et al. 20 65 40 skin rashes, muscular pains, leucopenia, acute (1960) haemolytic anaemia or even agranulocytosis may develop and call for an immediate cessation of therapy, though in a proportion it may be poss- Corticosteroids ible to cautiously re-introduce the drug later. It The value of corticosteroids in ulcerative colitis follows that therapy should be monitored initially remained in doubt for some years, but in the by frequent blood counts during the period of last 15 years a number of carefully controlled intensive therapy. trials have demonstrated that steroids, whether Results obtained by various workers in treat- used systemically or topically, are capable of Postgrad Med J: first published as 10.1136/pgmj.44.515.696 on 1 September 1968. Downloaded from 700 Geoffrey Watkinson inducing remissions in a significant proportion milder attacks in ambulatory patients prednisone of patients treated. They have emerged as a 20-60 mg daily is used initially with a reduction valuable adjuvant in therapy capable, on occas- to 10-15 mg as improvement occurs. ion, of producing remarkable remissions but The results to be expected from systemic steroid regrettably often failing unpredictably to control therapy are summarized in Table 3 below. In acute attacks of colitis or to prevent relapse or controlled trials conducted between 1950 and the development of complications. Whether their 1959 (Truelove & Witts, 1955, 1959) it was shown beneficial effects are due to a reduction of the that the 40% remission rate induced in 109 colitis vascular and tissue responses to inflammation or patients receiving 100mg daily of cortisone was a damping down of autoimmune or hypersensit- significantly better than the 16% remission rate ivity reactions in the bowel wall is not known. induced in 101 patients receiving inert tablets. The indications for systemic treatment with First attacks, at all grades of severity, fared steroids have been reviewed elsewhere (Watkin- better than chronic relapsing cases where remis- son, 1966). They should be used in any severe sion rates were 42 and 26%, respectively. In a colitic attack or relapse which is not controlled second trial it was shown that no better results by simple measures particularly when associated were achieved by doubling the dose of cortisone with systemic colitic complications, such as arth- to 200 mg daily, where again two out of every ritis, skin or eye lesions known to be improved five patients treated went into remission. How- by steroids. They should be used with caution ever, a significantly higher remission rate was in patients with established electrolyte disturban- obtained in eighty-four patients treated by 80 ces, malnutrition, marked abdominal distension units of ACTH daily where 61 % went into remis- or rectal bleeding or if coincident disease known sion, relapsing cases faring better than first to be worsened by steroids is present, such as attacks, remission rates being 71 and 50%, res- diabetes, tuberculosis or peptic ulcer. The drugs pectively. Similar results have been achieved byProtected by copyright. are contra-indicated if perforation or peritonitis many workers throughout the world, for example, are suspected, if a toxic megacolon has developed the Chicago group had treated 340 patients with or if severe perianal disease is present. steroids up to 1962 and report an immediately The dosage and method of administration favourable response in 20% of those treated and a will vary with the severity of the attack. In sustained improvement in 73 % (Spencer et al., fulminating disease ACTH will produce more 1962). Where it was shown in the trials of True- remissions than cortisone particularly if adminis- love & Witts (1955, 1959) that steroids both tered intravenously initially and followed by the halved the mortality and recourse to surgery in intramuscular injection of 40-80 units of ACTH those treated many limitations of therapy gel twice daily. As the patient improves dosage is emerged} Perianal suppurative conditions occur- gradually tailed off and oral steroids substituted. red three times more commonly in the steroid- Hydrocortisone 50 mg intravenously and 50- treated group making it desirable to combine 100 mg intramuscularly 8-hourly produces steroids with either suphasalazine or a parenter- comparable results and has a more rapid onset ally administered antibiotic. http://pmj.bmj.com/ of action. In cases of moderate severity cortisone While some authorities (Brooke, 1956) have acetate 150-300 mg is given orally and produces claimed that steroids may actually induce colonic rather fewer remissions than does ACTH, poss- perforation and certainly mask its presence, in ibly because of poor intestinal absorption. For the controlled trial reported by Truelove & TABLE 3 Results of steroid treatment in ulcerative colitis on September 28, 2021 by guest. Remission rates (°) Daily dose No. patients All cases First attacks Relapses Cortisone* 100 mg 109 41 42 26 Inert - 101 16 13 17 Cortisone* 200 mg 85 39 42 37 ACTH 80 units 84 61 50 71 Cortisone and ACTHt 200-300 mg 340 68 - - or 120 units *Truelove & Witts (1955, 1959). tSpencer et al. (1962). Postgrad Med J: first published as 10.1136/pgmj.44.515.696 on 1 September 1968. Downloaded from Medical treatment of ulcerative colitis 701

Witts (1955) the frequency of perforation was The dosage, relative potencies, method of greater in the group not treated by steroids. This administration, limitations and advantages to- contention was supported by Goldgraber and gether with the results of various types of topical others in 1957 and later by our own study of the steroid therapy are shown in Table 4 below. frequency of perforation in 165 patients studied Freshly prepared hydrocortisone hemisuccin- over a 10-year period which showed the fre- ate sodium can be administered by rectal drip, quency of perforation to be identical in groups may penetrate to the right colon and have a of patients receiving and not receiving steroids beneficial effect in 52-69% of the patients treated with frequencies of 4-3 and 4-1 %, respectively (Truelove, 1958; Patterson et al., 1965; Watkin- (de Dombal et al., 1965a). There is little son, 1961a). The stability of prednisolone 21- evidence therefore, to suggest that steroids pre- phosphate enabled it to be administered from dispose either to perforation or to massive disposable enema bags as a retention enema and colonic haemorrhage, while the frequency of remission rates of 75-88 % were claimed in postoperative complications and collapse was patients with distal disease (Matts & Gaskell, greater in groups of patients treated preoper- 1961; Patterson et al., 1965; Spencer & Kirsner, atively with steroids than in those not receiving 1962). While betamethazone, a steroid fifty times them. Differences were not satisfactorily signifi- more potent than cortisone, given in doses of cant and the data difficult to appraise because 5-10 mg as a retention enema produced remis- of the greater perforation of seriously ill patients sions in four-fifths of patients treated, side-effects in the steroid group (Watts et al., 1966a, b; were frequent and severe and led to the with- Lennard-Jones & Vivian, 1960). drawal of this type of enema by the manufac- turers (Matts, 1962). It is possible that the new Topical treatment of colitis with corticosteroids steroid betamethasone-1 7-valerate (betnovate) Steroids were first used topically in colitis by which has enhanced topical and reduced systemic Protected by copyright. Truelove in 1956 and their value in distal disease effects now under evaluation given in tablet form confirmed by a series of controlled trials (True- or as a retention enema may prove as effective love, 1958; Watkinson, 1958, 1961a, b; Matts, as preliminary trials have suggested (Gill et al., 1960, 1962; Matts & Gaskell, 1961; Spencer & 1965). Kirsner, 1962; Patterson et al. 1965). The major Steroids can be most conveniently administered attractions of this method of treatment are that topically as suppositories containing prednisolone minimal or no side-effects develop, and it is or betnovate and have been proved by controlled possible to obtain much higher concentrations of trials to improve patients with distal proctocolitis steroid locally than could be achieved by sys- (Truelove, 1959; Patterson et al., 1965; Lennard- temic therapy. Jones et al., 1962). Its disadvantages are that the method may Topical steroid treatment therefore emerges as prove cumbersome and distasteful to many a most useful form of therapy, most applicable patients while those with profuse diarrhoea may to mild cases of colitis with distal disease or be unable to retain the enemata adequately. proctocolitis. http://pmj.bmj.com/

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 on September 28, 2021 by guest. 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 evaluation or tablet side effects unknown Oral prednisone 20 Enema and Convenient Side effects from oral 56 65t Topical 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). Postgrad Med J: first published as 10.1136/pgmj.44.515.696 on 1 September 1968. Downloaded from 702 Geoffrey Watkinson Combined topical and systemic steroids periods of 3-18 months (Mandache et al., 1965). A combination of topical and systemic steroid This trial was uncontrolled and the method therapy was first advocated by Truelove (1960a) requires investigation. It might have a place in and it was later shown by a controlled trial that controlling massive rectal bleeding in the few a combination of hydrocortisone retention colitic patients in which it occurs. enemata and prednisone by mouth would induce symptomatic remissions in 65% of a group of Leucotomy fifty-eight patients so treated, with mucosal im- Leucotomy or selective pre-frontal electrocoag- provement in 79% (Truelove et al., 1962). ulation has been advocated and successfully practiced in a Swiss clinic in colitic patients Treatments under evaluation (Wissmer, 1959). Again critical assessment and prolonged follow up would be required before Immunosuppressive agents this drastic and irreversible form of therapy The temporary improvements induced in auto- could be advocated. The same criticisms can be immune diseases such as disseminated lupus made about the value of electric shock therapy erythematosus by the use of immunosuppressive or prolonged narcosis also advised in ulcerative agents made it not unreasonable to use these in colitis. the treatment of ulcerative colitis, as was first advocated by Bean in Australia in 1962. While Maintenance treatment these drugs can suppress immune reactions they Having controlled acute attacks of colitis the can also unpredictably produce marrow depres- physician next tries by some form of maintenance sion with resulting anaemia, leucopenia and treatment to prevent relapses or complications of thrombocytopenia which do not aid the physician the disease. This may be attempted either by in treating a condition with well-established infec- giving small doses of sulphasalazine or small orProtected by copyright. tive and haemorrhagic features. large doses of steroids on a long term basis. Two groups of Australian workers (Bean, 1966; MacKay, Wall & Goldstein, 1966) have Sulphasalazine used such drugs as 6-mercaptopurine, busulphan Sulphasalazine given in doses of four tablets or azothioprine (Imuran) to treat fourteen colitic daily has been claimed to keep between one- patients, twelve of whom showed immediate and half and three-quarters of large groups of patients eleven sustained improvement and in whom in remission for periods of 1-5 years with infre- serious marrow depression was rare. While eight quent side effects (Svartz, 1956; Moertal & out of ten patients, treated with azothioprine Bargen, 1959; Watkinson, 1962). Such trials were in Professor Kirsner's clinic in Chicago, showed however uncontrolled and the ability of small initial improvement this was only sustained in maintenance doses of sulphasalazine to prevent one patient and difficulties with marrow depres- colitic relapses has only recently been proved by sion have led this group to no longer advocate a controlled trial (Misiewicz et al., 1965). In this this form of therapy (Bowen et al., 1966; Kirsner, trial two groups of similar colitic patients personal communication 1967). The rapid death received either sulphasalazine 0-5g four times http://pmj.bmj.com/ of a young colitic patient from agranulocytosis daily or identical dummy tablets over a 12- following treatment with azothioprine led Jones month follow up period. Remissions were main- and others (1966) to emphasize the potential tained in two-thirds of these receiving sulphasala- dangers of this form of treatment. zine and in less than one-quarter of those receiv- The results, therefore, in twenty-five patients ing inert therapy representing a significant advan- treated to date have been far from impressive and tage for the drug. No side effects were observed. the routine use of these particularly dangerous Sulphasalazine emerges as a drug capable in drugs cannot be recommended at present in moderate maintenance dosage of preventing on September 28, 2021 by guest. ulcerative colitis until further careful prolonged colitic relapses in a significant proportion of those assessments have been made in research centres treated. used to handling colitic patients. Corticosteroids Rectal hypothermia In attempting to prevent colitic relapse with The control of haemorrhage from the stom- steroids the physician may either give large doses ach and from the prostatic bed by local freezing of steroids in sufficient amounts to suppress the led a group of Rumanian workers to freeze the disease accepting high incidence of induced rectal mucosa in nine patients with 'ulcerative side-effects (Spencer et al., 1962). Alternatively an and haemorrhagic proctocolitis' with immediate attempt may be made by small maintenance improvement in all cases which was sustained for doses of steroids to control the disease accepting Postgrad Med J: first published as 10.1136/pgmj.44.515.696 on 1 September 1968. Downloaded from Medical treatment of ulcerative colitis 703 an appreciable relapse rate and recourse to sur- ities have been reported: between 28 and 50% gery but avoiding steroid complications (Watkin- by Lennard-Jones & Vivian (1960) and by Gouls- son, 1966). ton et al. (1960) and there is evidence to suggest While large maintenance doses of cortisone or that modern treatment has not much reduced the ACTH given by the Chicago workers kept two- mortality in that type of case (Edwards & True- thirds of their 340 colitic patients in remission love, 1964). or good health for long periods with a low The management of this type of case is, there- mortality and recourse to surgery, side effects fore, one of extreme urgency. Frequently lament- developed in 85% of those treated. These in- able delay in diagnosis occurs, the patient having cluded psychological upset (16%) diabetes or been investigated at home or in an infectious glycosuria (12%) serious electrolyte upsets (12%) diseases hospital as a possible case of a dysen- osteoporosis (4%) melaena or peptic ulcer (4%) teric illness. While it is vital by stool culture to while nine deaths could be directly attributed exclude this possibility, in cases where these prove to steroid therapy. The authors felt that good negative early sigmoidoscopy together with a plain control of the disease was adequate compensa- abdominal X-ray will make the true state of tion for the side-effects encountered and remain affairs apparent and the patient should be keen advocates of long term large dosage steroid urgently transferred to a general medical ward treatment. where he can be reviewed daily by both physician Unfortunately, there is no evidence to suggest and surgeon. Strict bed rest and sedation are that small doses of steroids prevent colitic re- enforced, colonic rest promoted by either with- lapses. One controlled trial (Truelove & Witts, holding fluids by mouth or giving a fluid diet, 1959) failed to show any difference in relapse parenteral fluids are administered liberally, the rates in two groups of colitic patients followed replacement of potassium being particularly im- for a year receiving either cortisone or identical portant, and liberal blood transfusions are almost Protected by copyright. dummy tablets. A second controlled trial always necessary. Adequate vitamin replacements (Lennard-Jones et al., 1965) treated two compar- and parenteral feeding are often required. The able groups of colitic patients with either 15 mg patient should be given sulphasalazine by mouth, of prednisone daily or with identical inert tablets. 1-2 g four times daily, and large doses of steroids Even though larger doses of steroids were used, parenterally. In this type of case ACTH or inducing side-effects in one quarter of the patients cortisone should be given intravenously initially treated, by the end of 6 months identical relapse supplemented by intramuscular doses later. At- rates occurred in both groups, namely in eighteen tempts should also be made to administer of thirty-two patients receiving prednisone and in steroids topically in the form of a rectal drip of seventeen of thirty controls. hydrocortisone or retention enemata of prednesol Regrettably, therefore, there is no fully con- which if retained adequately will speed recovery trolled evidence that prolonged treatment with (Truelove, 1960b). Fulminating cases are often small or large doses of steroids influence the markedly improved by a short course of an anti- natural history of ulcerative colitis, though in biotic, such as penicillin and streptomycin, http://pmj.bmj.com/ individual cases both patient and physician may ampicillin or erythromycin given parenterally. consider them of value. In addition to this intensive nursing and medical care, levels of haemoglobin, haematocrit and Modifications of treatment in relation to severity, electrolytes should be estimated daily in order to extent, clinical pattern and complications of plan the parenteral therapy given. Daily assess- colitis ments jointly by physician and surgeon are con- with tinued and attempts were formerly made to allow Medical treatment has had to be modified on September 28, 2021 by guest. increasing knowledge of the factors affecting the this medical treatment to have its full effect over prognosis of ulcerative colitis, namely, the sever- 10-14 day period. However, when this principle ity of the attack, the extent of the disease, the was applied to 124 patients with severe colitic age of the patient and the presence of associated attacks in Leeds between 1952 and 1963, only colonic and systemic complications. 52% went into remission, 5% died under medical treatment and 32% required emergency surgery, Severity the overall mortality remaining depressingly high at 11-3% (Goligher et al., 1967). Acute fulminating colitis Accordingly, it was decided, for a trial period, Fulminating colitis is a serious medical emer- to invoke surgical aid at a much earlier stage gency with a high mortality and frequently in these severe attacks unless there was evidence requires surgical intervention. Depressing mortal- of a rapid and unequivocal improvement on max- Postgrad Med J: first published as 10.1136/pgmj.44.515.696 on 1 September 1968. Downloaded from 704 Geoffrey Watkinson imal medical treatment. Indications for urgent Distal proctocolitis surgery can be briefly summarized as continuing Patients with involvement of the pelvic and massive haemorrhage, perforation, sudden deter- descending colon can get colitic attacks of all ioration in the general condition of the patient, grades of severity but carry a rather better prog- and after 2 or 3 days of conservative manage- nosis than those with total involvement and are ment in elderly subjects and within 4-5 days of relatively free from the risk of malignant change. initiation of therapy in younger patients. The Medical trerLtment by dietary means, by sulpha- results of this policy in eighty-one patients with salazine and by steroids topically and systemic- severe attacks treated in Leeds between 1964 and ally, can therefore be safely persisted in for long 1966 were quite dramatic. periods. Regrettably the disease in many cases Remissions occurred with similar frequency, tends to spread proximally making the need for namely in 47%, and no deaths occurred under elective surgery to be kept constantly under re- medical treatment. Urgent surgery was under- view. taken in half these patients and the overall Colitis with total colonic involvement mortality was reduced to 1-3%. While this was While many of these patients can be kept well not in any way a controlled trial, this experience through the years on maintenance treatment and and that of others (Gallagher et al., 1962), would many have spontaneous remissions of symptoms, suggest that surgery has an increasing role to studies of the natural history of the condition play in fulminating attacks of ulcerative colitis have shown that these are the patients most likely until some improved type of medical treatment to develop relapses and complications of the can be devised. colitis itself and as the years pass to be increas- Chronic ulcerative colitis ingly prone to the risk of malignant change in

Here the physician has adequate time to apply the colon. Furthermore, the disease is unlikelyProtected by copyright. the full therapeutic programme previously des- to become less extensive under the influence of cribed, remembering however, that at any time medical treatment. In these circumstances the further fulminating attacks may occur, that the physician should not persist with medical treat- disease tends to extend and that as the years ment indefinitely and when total colonic involve- pass on an increasing number of complications ment has been demonstrated unequivocally radio- may develop. There seems to be little tendency logically should explain the risks at stake to the for the disease to burn itself out so that surgery patient and elective proctocolectomy should be will often be required for the invalidism in- advised. Patients are usually, understandably, duced by recurring attacks of the disease or the reluctant to accept this advice while they are development of colonic or systemic complications. symptom-free. They should be warned that surgery is desirable and pressure put upon them to accept surgery when a relapse occurs. Extent of colonic involvement The management of ulcerative colitis is mater- Segmental colitis and entero-colitis ially affected by the extent of colonic involve- The difficulties in distinguishing ulcerative http://pmj.bmj.com/ ment. colitis and Crohn's disease of the colon and small intestine have been emphasized elsewhere. If Proctocolitis symptoms and signs of a malabsorption state are These patients are mainly troubled by rectal present or if severe unusual perianal disease bleeding and by constipation and by a blood- occurs and the rectum looks normal on sigmoid- stained rectal discharge. They seldom become oscopy, Crohn's disease should be suspected and acutely ill save from the effects of anaemia. medical treatment persisted in for as long as Bulk-forming laxatives, senokot or milk of possible. Here dietary measures, particularly the on September 28, 2021 by guest. magnesia should be given in sufficient amounts to restriction of fat and the long-term usage of promote a bulky soft daily bowel action. If rectal sulphasalazine and steroids are advocated but bleeding continues suppositories of either sulpha- still have to be shown to modify the long-term salazine or prednisolone should be inserted on course of the condition. In many cases the devel- waking and retiring. For more intractable cases opment of obstruction or internal fistula forma- topical treatment with retention enemata of tion or the development of perianal disease will prednisolone should be tried and rarely short make surgery inevitable. courses of sulphasalazine and prednisone have to If true segmental ulcerative colitis is suspected be given orally. and the rectum appears normal on sigmoido- Iron therapy is often required to correct the scopy, early surgery should be advised and the anaemia present. diseased segment resected followed by ileo-colic Postgrad Med J: first published as 10.1136/pgmj.44.515.696 on 1 September 1968. Downloaded from Medical treatment of ulcerative colitis 705 or colo-colic anastomosis. If medical treatment abnormality was below that which might have is persisted in there is a tendency for the disease been expected suggesting that neither the colitis to spread distally, eventually to involve the nor its treatment with sulphasalazine or steroids rectum, making the less acceptable operation of had affected the foetus. total proctocolectomy and ileostomy necessary. Statistically, therefore, there are few grounds for advising termination in pregnancy. However, Clinical pattern of colitis each case has to be assessed individually and the desire for the child assessed against the effect of Age of the patient the colitic attack on the mother. If the child is Additional problems in the management of wanted improvement usually occurs, particularly ulcerative colitis occur at the extremes of life in in the second and third trimesters. There is a children and in the elderly; the particular prob- case for increasing full supportive treatment with lem in children is that colitis in the first decade sulphasalazine and steroids during the first 3 is a cause of infantilism with physical retardation months of pregnancy and for 2 or 3 months after of growth and a delayed onset of puberty. Once delivery. If the child is unwelcome relapse is total colonic involvement has occurred these likely and if the mother's health deteriorates children are just as susceptible to relapses and rapidly in the first trimester, termination of preg- complications and to malignant change as are nancy may have to be advised often with dram- adults and because of the early onset of symp- atic cessation of symptoms. The ability of colitic toms develop them at a very tender age (Rosen- patients to conceive and be delivered of normal qvist et al., 1959). children after colectomy and ileostomy is While medical treatment follows a similar pat- emphasized by the authors. tern to that for adults, particular attention to the protein and calorie needs of the patient is neces- Effects of complications of the colitis on medical Protected by copyright. sary and the correction of anaemia is vital if the treatment chance of physical retardation is to be reduced. The serious colonic complications of colitis Emotional conflicts seem more common in colitic such as perforation, toxic megacolon and massive children who often have aging, ambitious and rectal haemorrhages are indications for urgent over-attentive parents who often make excessive colectomy, continuing medical treatment being academic demands on children of average ability. both unwise and dangerous. Similarly extensive Treatment of the whole family by explanation stricture formation and gross pseudopolyposis and common sense psychotherapy is often neces- with total colonic involvement make it extremely sary. Tragically physical retardation, together unlikely that any form of medical treatment will with extensive and long-standing disease, often be successful and in these circumstances elective make proctocolectomy and ileostomy inevitable. proctocolectomy and ileostomy are advised. The operation is usually well tolerated by the child Similarly severe perianal disease may be and surprising degrees of growth and weight gain worsened by medical treatment particularly by

will often follow operation. steroids and will sway the physician again to- http://pmj.bmj.com/ The serious prognosis of acute colitic attacks wards advising surgery. in elderly patients is emphasized elswhere making Of the systemic complications skin conditions it necessary to consider emergency colectomy at and recurrent attacks of colitic arthritis may a much earlier stage than in younger patients prove extemely refractory to medical treatment (Goligher et al., 1967). While many lives can but are usually cured by colectomy. Iritis, liver undoubtedly be saved in these elderly patients disease and sacro-ileitis however are unlikely to the effects of an ileostomy life in this age group be improved by colectomy and in these cases has not yet been studied in detail. intensive treatment of the colitis by dietary means, on September 28, 2021 by guest. steroids and sulphasalazine should be persisted Ulcerative colitis and pregnancy in (Watkinson, 1968). The effect of pregnancy on the natural history of colitis together with the effect of colitis on Conclusions the mother and foetus is described elsewhere, In this paper the medical treatment of ulcera- (de Dombal et al., 1965b), where it was shown tive colitis has been reviewed and its ability to that pregnancy had little effect on the relapse rate terminate acute attacks, prevent relapse and of colitis compared to a control population and complications assessed. The fact that medical the relapse occurred most commonly during the treatment fails sometimes to achieve all these first trimester or during the immediate post-par- objectives makes it vital that the cases be man- tum period. The incidence of abortion and foetal aged jointly by physician and surgeon both in the D Postgrad Med J: first published as 10.1136/pgmj.44.515.696 on 1 September 1968. Downloaded from 706 Geoffrey Watkinson acute attack and in long-term management the GROEN, J.J. 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cotrophin in ulcerative colitis. Brit. med. J. i, 387. Gastroenterol. Philadelphia. Protected by copyright. http://pmj.bmj.com/ on September 28, 2021 by guest.