TIlE EFFECT OF CC)RTISONE ON THE CLINICALCOLTRSE OF CHRo(NIC REGIONAL ENTERITIS

AND CHRONIC IDIOPATHIC IULCERATIVE COLITIS

1Y THONIAS E. MACHELLA, MI.D., and (by invitation)0. ROGER HOLLAN, -M.D."i

PI1ILA. PENNA.

The purpose of this report is to presenlt ol)servations madewheni Cortisonie was adminlisteredI to patients with clhronic regionalenteritis or clhronic ulcerative colitis. It was tlhoughlt that theconmpoutlnd mnight infltuence the course of the disease because ofthe occasionial associatioln of artlhritis aniiI of ervthllema nio(lostiimi.

S-UBJECTS

Three of the 6 patients (Cases 1, 2 anid 3 lhadl chroniicregional eniteritis, witlh or without involvement of the proxinmalcololl, wliile the remaining three had tv pical ulcerative colitis

TABLE IDESCRIPTION OF PATIENTS

Doir(l/ioni ini .lHontlsCase A ge/ Sex Extent ofPreseWthInvolvemientDisease Illfiess

I* 16/F 12 2 I)istal ileumn an(d transv. colon

2* 38/F 108 10 I)istal ileum -

3 18 M 20 4 Terminal ileuni an(1 proximal2/3 colon

4 28/F 54 3 Entire colon

5 34/-M 19 3 Rectum ancd sigIollid

6 38/ 9 9 Entire colon

*Relapse following resectioin of terminal ileum and cecum.

Froimi the (,astro-mlitestinal Section of tlle Me(lical Clinic, Hospital ofthe ixiversitv of Penisylvania, Philadelplhia, Peninisylvallia.

k\mnerican (;astroeniterological Associatioii Fellox- ill Gastroeinterology.

67

THOMLAS E. MACHELLAAND 0. ROGER IIOLLAN

(Table 1 ). Two of the latter had involxement of the entire colon(Cases 4 and(I 6) anid one, involvement of only the rectum andsigmoid (Case 5).

The dturatioln of the disease in the 6 lpatients ranged from 9 to108 monIithis alicl of the episo(le for which Cortisone was admllinis-tere(l, 2 to) 10 imontil>s.

Mfost of the l)atients lhadl a poor appetite, had lost weight, hadan ilncrease(l ervthrocvte sedimelntatioin rate ain(1 were passingitimerots liquid. 1lood-containincg stools (Table II). Fouir hada low-grade fever aindl an equtal number, varvilng degrees of anemia.

TABLE II

CLINICAL AND LABORATORY CHARACTERISTICS

Loss ofCase Appetite WVeight

(Lbs.)

291 t Poor (105-76)

422 Poor (130-88)

143t Poor (117-103)

214 Fair (142-121)

205 Poor (145-125)

196 I3oor (162 143)

oumberStools per24 Hrs.

3-8*

10-12

+ 47

0 61

33

32

3 + 73 42

12-15*

4-7*

15-20*

0 43 28

+ 100 30

+ 99 27

*Blood present in stools.tAlso had joint symptoms.

Two ( Cases I ani(l 3 had acuite artlhritic miianifestations. Onepatieint Case 1 ) xx'as having large hemiorrhages fromii the boweland was in ratlher (lesperate straits. She was the moiost critically ill

of the grotup at the onset of Cortisone therapylher blood pressure

cotild Inot b)e imleasuried.

Hb. Sed. rateF (%) (nnm. /hr.)

68

CORTISONE IN REGIONALI ENTERITIS AND ULCERATIVE COLITIS 69

The Cortisone* was inijecte(I sul)cutaneotsly acc()ordinlg to thefollowing schedule: 100 mng. (4 cc.) every 8 hours for three doses,then 200 mg. (S cc.) every 12l hours for 2 doses, and thereafter50 mlg. (2 cc.) every 12 lhours for 8 additional davs, the entireperiod of therapy lasting 10 days.

The patients wvere permitted access to unlimited amounts oflow--residue foods; no special therapeutic measures wrere employedduring the period of Cortisonie therapy with the exception of atrainsfusion of a plint of 1)lood( to Case I whlio vas having massivebowel hemorrlhage at the time Cortisone administration was begun.It was felt unwise to withhold 1)1ood in view of her shock-like state.

REsUtLTS

a) Sutbjective C/ln ygesFollowing institution of Cortisone therapy, a sense of well

being was experienced l)1 5 of the 6 patients, the exception beingCase 6. In two of tlhenm (Cases 1 and 2) this sense of well beingamouinte(l to eulhoria. A\ppetites which had l)een poor l)ecameexcellent; in fact, voracious in Cases 1 and 2. Joint pain andstiffness, present in two patients (Cases 1 an(l 3 ), dlisappearedwithini 2 days after 1)eginning the admiiinistration of Cortisone.

1)) Objective C/lia yes1. Total nuimiiiber- of cosiniop/lils. Following the institution of

Cortisone therapy, a decrease in the total number of eosinophilsoccurred in each patient ( Table III ).

2. Fever. A low-grade fever present in 4 of the 6 patients(Cases 1, 3, 4 and( 6) prior to therapy (Table IV) disapl)earedduring the period of Cortisone administration. It recurred in 2of them (Cases 5 and 6) after Cortisone was discontinued.

In one patienit (Case 4 ) fevter, absent prior to therapy, de-veloped dutring the first three (lay's of treatmiient. It then disap-

*Salinie suspei)sioni of Cortoioe Acetate, NMerck a1)(I Co., Inic.

TIIONIAS E. MACHELLA AND 0. ROGER HOLLAN

TABLE III

TOTAL , NIBER OF EOSINOPH I LS (per mInm. 3)BEFORE, DURING AND AFTER CORTISONE TREATMIENT

Case

2

3

4

Before

70

69

237

225

5 275

6 1312*

Duiring

2

38

19

81

46

After(Da v)

175 (50)

63 (29)

113 (7)

156 (28)

118 (50)

38

*Repeat; 1060.

peared ai(l reimiainied alb)sentthe lhospital.

during the rest of her I 7-day stay in

TABLE IN'

EFFECT OF CORTISONE THERAPY ON FEVER

C(ase

3

4

5

6

Before

0

+0

+

Ist 1/2

0

0

+

0

_-

Du2ring

2nd 1 '2After

0

0

0

0

0

0

0

0

3. Dilr)oca. \ chanige in clharacter an(l numlber of the stoolsoccturredi in 5 of the 6 p)atients wlho manifested improvemnent duringthe period of Cortisone therapy Table V ). This clhanige consistedof a decrease in the number of stools. in tlheir l)ecoming forme(dandl in the (lisappearanice of gross l)ldo(l when suiclh was present.

70

CORTISONE IN REGIONAL ENTERITIS AND ULCERATIVE COLITIS 71

TABLE \

EFFECT OF CORTISONE ON NUMBER AND CHARACTEROF STOOLS

Before

3-8 L

10-12 L

3 S

12-15 L

4-7 L

15-20 L

Number of stools per 24 houirs

Duirinig At end

0-4 F 1-3 F

1-5 F 0-3 F

3 F 3 F

3-9 S 0-2 F

3 F 2 F

6-18 L 8-12 L

L, liquid. S, soft. F, foriimed.

In the refractorv patient ( Case 6) little or n1o change occurred inthe iumbher anid character of stools.

4. body woif/lit. Five of the 6 p)atienits gaiile(l weight dntiringthe periodI of Cortisone therapy (Tahle VI). Tlis weight gainranlged from 3i2 to 18 lbs. Signs of fluid acctiimutilation in the

TABLE VICOU'RSE OF BODY W;\EIGHT (LBS.)

Bodv weight in rel(ation to Cortisonte treatmentAt en(d

Ga inl

18

7

14

0 127

3-112 129

7 145**

*Obvious fluid retentioni in tissues.**1 week.

Case

1

2

3

4

5

Caise

2

3

4

5

6

Before

76

88

103

121

125

143

2 weeks after

84

92

115

94*

95

117

121

128-1 2

150

THOMAS E. MACHELLA AND 0. ROGER IIOLLAN

70-~~~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ E

4 O0 RAT E

60-

50-\.40

94 - , ~~~~~~~~~~BODYWGT.89- *+ (LRS.)8 4-

7 90 C '

0 STOOLS

04 R S

~~~~I

38 42 46 50O 54 58 6 2 66 70 74 78 82- D A Y S

FWU;RE 1. Thle eftect of Cortisone admlinlistration on1 the clinical courseof a l)atienlt ( Ca-se 1 ) critically ill with regional enteritis. During 46 days ofhosp)itali7altionl Irior to thle adminlistrationl of Cortisone, shle became pro-gressively x or.se. Shle ran a loxx gradle fever-, w\as anorexic, lost xxeight, haddiarrheca, arthlritic manifesta1tionls anld xxas greatly dleprcsscd. On thle 4oth(lay thle secon(l of a1 series of m-tssive bowefl hlemorrhlages occurred. At thetim. Cortisonle xxa.s be'gun her bgloodl pressure coul(l nlot hc measure(l. Folloxx-ling thle inlstitutionI of Corti.sonle thlerapy ( 48th (lay of hlospitalizationl ) shlepromlptly became more alert, euphloric, (leveb()pe(l a voracious appetite, jointpainls vanishled, diarrhlea ceasedl, 1)100(1 disapplearedl from thle stools, theerytblrocvte sedimlenatationl rate decreased andl a gradlual inacrease in hemoglobinlpercenitage ocetirred. .\ tranisfusionl of 1 pinlt o)f xx ole bloodl xvas admtinisteredat l)oinit (1'I) inidicaited by arroxv. Shle gainled 18 lbsx. inl weighlt, somle of xx hichxxas unldoubtedly duelc to) retenitionl of fluidl as. folloxx ing cessationl of Cortisonleadmlinilstration, los.s of xxei,ght ocetirredl simiultanIeoulysi xx ith a dituresis. A&relap)se in thec dliarrheca occu1rred1 4 da1ys after stolpl)inig Cortisonec, thle inicreaseinl nulmber of stools last'-] 4 (laXs. Thec i icreasedl apopetite colltinlue(l. D)uringatb"n initerval of imlpro'emlet, s'xter4o badl emiotiontal .situatio)ns xvere cor-recte(l thlese includled the finineilg of a nlex hlomie for hecr illeXgitim-iate child,reassignmIlent of the+> patienit to anlothler fo)ster hlomie sxxhere she xxould niot b)esubhjected( to thle advsances of hler p)uardianl, an(cl thle p)romiise of resumptionl ofschool by the patienit xx ith the beginninIg of thle schlool te'rml. Shle has conItinluedto do wvell and has not relapsed during the past 9 months.

72

CORTISONE IN REGIONAL ENTERITIS AND ULCERATIVE COLITIS 73

TABLE VII

SEDIMENTATION RATE* BEFORE, I)DURING AND AFTERCORTISONE THERAPY

Case Before During After cessationi of Rx.

(Dav 1 da 1wIeek 2 weeks

1 33 28 (2) 19 13 36

2 32 13 (9) 10 24 38

3 42 19 (5) 22 25 28

4 28 31 (6) 28 30

5 30 25 (6) 30 23 24

6 27 36 (7) 36 34

*WXintrobe method.

tisstues o f the retrosacral region were detecte(I in the patient inwhonm the greatest weig-ht gain (1 8 lbs.) occurred (Case 1). Inher, a diniresis associated witlh loss of weight ( Fig. 1 ) occurredfollowing cessation of Cortisonie atimiinistrationi.

5. Sedim1eltatio i-ate. (Table VII). A (lecrease in the rate ofsedimentation of ervthro)cvtes (WVintrobe imietlhod) occturred intlhree patieints ( Cases 1 2 an(l 3 ). TIhese three patients manifestedthe greatest degree of all-arotunld iml)rovement. The remiiaining 3Ipatients revealed n1o consistenit tren(l or miiarked changes in se(limen-

tation rate.

6. HIemio(/loNl)il. Thlle changes in henmoglobi-in were in(co(nsistent.In tlhree ilnstances ( Cases 1 2 andI 4 ) henmolobin increased; in two'Cases 5 aind 6) it decreased, and in one ( Case 3) it remiiaine(lessentiallv tunchanged.

/7. Sif]1noidoscop( cpi-tiet!t'. Eriee of the patients (Cases 4, 5an(l 6) had changes tvpical of uilcerative colitis visualized by meansof the signoildoscope. In two of tlheml (Cases 4 and 5) improve-mlenit in tl1e appearance of the bowel was reported at the end of the

THOMAS E. MACHELLA AND 0. ROGER HOLLAN

10-day period of Cortisone therapy. This improvement consistedof less hyperemiiia and edema, and less tendency of the mucosa tobleed when traumatized. Regressioin was observed 2 weeks later.The third patient (Case 6), who did not respond to Cortisone, wasnot subjected to sigmoidoscopy.

8. Roenitgeni appearanice of involvzed areas. No significantchange in the roentgen appearance of the involved sections ofdiseased bowel was (letected during the period of clinical improve-ment while on Cortisone.

c) Couirse Followeinig Cor-tisonie Tlierapy,A relapse occurredl in each of the five patients who improved

while Cortisone was being administered; the relapses occurred in5 to 73 days following cessation of the treatment.

In one of the fivTe (Case 1), the milost critically ill of thegroup, the relapse was transient (Fig. 1). It occurred 5 days aftercessation of Cortisone and lasted 4 days. The improvement in herclinical course which followe(d the institution of Cortisone therapywas prompt and dramatic, and it seemnied that Cortisone was respon-sible for sav;ing her life. She remainls well after 9 months. Theabsence of a relapse dturing this period is attributed to the factthat the emlotional factors important in the pathogenesis of herdisease were successfully handled (see Fig. 1 ).

The remaining four relapsed in from 13 to 73 days after cessa-tion of Cortisone therapy. Their emotionial problems have not beensuccessftully handled. Three of them (Cases 2, 3 and 4) have beensubjected to surgery and the fourth (Case 5) probably will be. Thepatient (Case 6), who was refractory to Cortisone, also has beenoperated on.

DIscUSSION

Moderate-to-miiarked remission of symptoms occurred in 5 of 6cases of regional enteritis and/or colitis while on Cortisone therapy.Little or no improvement occurred in the sixth. In three of the

74

CORTISONE IN REGIONAL ENTERITIS AND ULCERATIVE COLITIS 75

90 TT T80 HB

70

6 0

5 0

40 130

125

~~~~~~BODY W GT.

- + *+t_s- ~~~~~~~~~~~~(LBS.)- 120

1 5 -115

I0

-

CCORTI SONE

0 2 4 6 8 10 14 1 8 22 26 30D A Y S

FITURitE 2. Illustrates the course of Case 4 in xxlhorin improvement occurrcdlduring Cortisonie tleralpy but in xwh1oml it was niot certaini tllat siilllar im-p)rovemelnt wvould have occturred w ithout Cortisolne. Tlle reasonl for ulni-certainity is that the patielnt had heen ohserved to imaprove ii a similar manniierdurinig previous hospitali7ations xxwhen Cortisonie lia(i niot l)eei employe(l.

5 improvedl p)atients (Cases 1, 2 and 3) the improvement seeme(ito he definitelv relatedI to the Cortisone; in the remaining two(Cases 4 and 5), it may well have b)een, but the evidence is lessclear than in the otlher tlhree. In onie of these cases (Case 4), theclinical cotirse ( Fig. 2) wvas qtite similar to that observed dturingprevious adimiissions to the hosl)ital whein no specific treatmenit wasadministere(d; she did, however, maui fest aIn increasedI sense of wellbeing and(I increase(i appetite asi soonI as Cortisonie a(lmlinistrationwas l)egtln.

The reasoni why somile of the patients seenie(l to respon(l toCortisone anI( others didl so less ohvioumsly or not at all, is not

THOMIAS E. MACHELLA AND 0. ROGER HOLLAN

apparent at this timle. The following dlifferences betweein the twogroups existed.

1) 1'vPC of dise(ase. Those whlo iml)roved most (dramlaticallywhen Cortisone therapy was instituted (Cases 1, 2 and 3) had-egional enteritis Nvith involvement of ileulm witlh or without in-volvement of the proximal colon; those in whom improvementoccurred, l)ut in whliom it might have occuirredl if Cortisone had notlbeen aclministered (Cases 4 and 5), had involvement of the colononly. The inv-olxeenieiit in Case 6, whlo wvas refractory, was alsolimited to the colon. In this coninectioln it is of interest that theone goodI responise out of 4 replorted by Dearing and Brown' oc-curred in a patient with segmiiental colitis. Their remaining 3patients, in wlhomi a satisfactory response was not obtained, hadinvolvement of the enitire colon. ()n the other hand, Gray and hisassociates) observed a very gratifying response following admini-stration of ACTH in a patienit with extensive involvement of theentire colon.

2) Lezvel of imitial tot(al cosiM op/lil cout. The best responseswere olbtainied in the two patienits (Cases I and 2) who had thelowest initial total eosinophil couints ( Table III). The patient(Case 6) who hadl the highest eosinoplil couint experienced noimprovement. The eosinophil cotunts in the two patiei-ts who im-proved but in wholml the improvemient max' have b)een unlrelatedIto Cortisone therapy, fell inito ani interme(liate range.

3) SvCZrity of illecss. Two (Cases 1 and 2) of the threepatients (Cases 1. 2 anl(I 3) who respondle(d micost dranmatically werethe two imiost critically ill of the groul). These two patients alsohadl the lowest initial total eosilnophil counIlts. Dutoit3 who treated2 case. of chronic ulcerative colitis wvith adrenocorticotropichlorimionie also oblserved lproil)t improvement in the mlore acutelyand severely ill of his two patients, while there was sonme (tluestionas to whetlher or- niot the less critically ill patient was at all benefited.That the severity of the illlness a)ppears to be. at least at present, oneof the factors wh-lich1 (leterminleies when a good response will beobtained is also su--ested bw the metabolic sttudies of Posev aldI

76

CORTISONE IN REGIONAL ENTERITIS AND ULCERATIVE COLITIS 77

Bargen.4 Tllese authors sllrve-edl 44 patients witll chronic ulcera-tive colitis anlle found( wi(lesprea(l metal)olic (listuribances wlhiclh be-ca-me progressively more severe with increasing gravitv of thedisease. Urinary excretion of 1 7-ketosteroids was (dimllinished,alb'normal urinary excretions of corticosteroilds vere noted anda(lrenal reserve ftunictioln was iilipaire(l.

Cortisone therapy isI)eing use(l in a fur-ther series of patientsin or(ler to dletermiine wlhetlher or not any one or combination of theal)ove three (liffereinces are of any significance in the selection ofcases in which improvemeint might le expected fromii such therapy.

CONCLUSIONS

A) A trial of Cortisonie therapy would appear to be worthwhile in certaini cases of regional enteritis or ulcerative colitis,lparticuilarlv in criticallv ill patients when the situationi is (lesperateanlid a temporary l)eriod of improvemnient is desired in order topermit suifficient tinme for the effective use of otlher therapetuticmeastures.

2') The use of the compoun(l (loes nlot promise to cure the(lisease as a relapse may wsell occur followxinig cessation of its ad-imstration.

R,F}EFERENCES

1. DE) \RI N, \W. 1. anlld 1Rw(P. \\.: xperiences with Cortisonie anidACTH in clhronic tilcerative colitis. Proc. Staff Meet. Mayo Cliniic, 25:486, 195'9.

2. GRAYx, S. J., Si'nRO, H. M. and REIFFEN STEIN, R. WV.: ACTH and1I gastro-initestinal ennzmes. Bull. of New Fn-. MIed. Ceniter, 12: 169, 1950.

.3. DLTOIT, C. H.. The treatmiienit of clhronic idiopathic ulcerative colitis withadre-:oc()rtic(\tr( )pc l:ormo:ie. Ahst., Pro-ram of 42nd(l Ann. Meet.,

\Nmer. Soc. for Clii. Invest., I)ag-e 19, May 1, 1950.

4. POsEY, E. L. and BARGEN, J. A.: Metaholic derangemienlts in chlrollic uil-cerative colitis. Gastroenterology, 16: 39, 1950.

78 THOMAS E. MACHELLA AND 0. ROGER IIOLLAN

DIl SCUSSION(

DR. RANx FLETC HER FARQUIIARSON [o()ronto, Onitario, Canlada] \VNehlave treated tlhree of tonr patientP \who hiad rep-in)al ent' ritis and(I have lhadindihierenit resnlits, although they all claimnid conisiderable cliical improve-mlenit. In oie l)atient, hoxxever, the resuilt was imost gratifying.

This patient la(l hiad (lisease for a lonig tiime; four siniuses ere draininigfecal nmiacterial through tIme ahd(lomiinial wall, and(I lhe xX-as in a state of greatuniderniutritio xxwhen cortisonie wax a(lminlistered. On1 cortisonie tlherapy, thesiniuses ceased to (1isclharge anlle it became possible to have tlle p)atient operatedoni, ani(1 hie has imiadle a good teml)orary iniprovement.

Atnotlher patient, xxwho improved considerahly oni cortisonie, suffered frominitestinial ohsbtruction at the end(I of the course an(l hlad ani operation. At tllattime, onie cotul(d see the actix-e lesions. The sur-geon felt it xas Inot xise to takea hiopsy, bhut it xas ovbvious that the lesioni lha(l inot heen controlled.

I shIoLuld like to ask L)r. Machella xhether any of hiis p)atielnts lhad hadsteatorrlhoea.

\VNe liad a p)atient wxithi markedI idiolpathic steatorrhioea, nio regionial eni-teritis or colitis, but xerrv miarke(d steatorrlmoeca, wIo xas failimig rapidly; shelost in xweight to about 62 I)oun(l; oni a diet containing 20 gramis of fat, shieexcreted 17 gramis in hier stool. Whlieni given cortisonie, there xxas a mostremarkable iniprovemient: lher stools becamie forim ed and, xwhereas shie baclformierly hiad 18 to 20 per (lay, the numiber of stools fell to 1 to 2 per (lay; shiegainied 20 or 30) pounds and(I becamie xery xwel. After the adnministration of thecortisoi e, shie was able to absorb 80 ioer cenit of a m11UchI larger amount of fatin lher (liet.

I wxxonder if I)r. Mlachiella hias lia(l anv experience if that kind(l.DR. CIIES'IlFR 'M. JONxS [Bostoni, Mass.1: We have liad thiree cases of

sprie recently, txxo of thiemII treated x ithi .\CTH and(I onie with cortisonie.Tllere xasano clinical imnproveiment in eithier (f the patients treated xx itliACTH. Careful balaice studclies shoe dl nio chianige inm stool fats or ally evi-denice of improved absorption. Onie patient treatedl xxith cortisonle showx ed a(mite clitferenit resl)on se. Slhe becamile euphomric and(I somewhhat cyanotic unitila somewx hat reluced (lose xxas given and tloemo showx ed very strikinig cliinicalimprovemient in lher sprue s miltomis. The number of stools xx as markedllydimiinishied, anid the fat conitemit dropiped very appreciably, xxith correspondinglgaimi in wx eight anid strenigthi. The contrast w as very definite wx hen coimpare(dwith the results of pirevious imotensixe anid contitioed treatimienit by imioreortlhodox imietlho(ds.

\Ve have also treate(I paticents wxith regional euiteritis amud ulcerativecolitis bioth xw ith .W\T''H anid x itho cortisone. ['he r-esults hlavec been similarto those (1-scrihie(d hy I)r. Mlacliella.

78