GASTROENTEROLOG\ I :-s rER:\.-\ I 10'.\.\L Cop� 1 i�ht f 199� h� hn..::1 national L 1\1\ c1 ,it� P1cv,

WORKING TEAM REPORT

Proposed Classification of Patient Subgroups in

Crohn's Disease

D.B. SACHAR' (Chairman), H.A. ANDREWS\ R.G. FARMER\ F. PALLONE4, A.S. PENN,

C. PRANTERA6 AND P. RUTGEERTS7

1Depl. <>fMedi ·ine, The Mount Sinai Medi al Center, New York City, New York, USA; 2The General Hospital, Birmingham, UK; 3The Cleveland Clinic, Cle1 eland. Ohio, USA; 4Dept of Experimental Medicine, University

of R. Calabria, Caran-aro, Italy; 5Gastroe11rerofo 'Y Unit, Free University, Amsterdam, The Netherlands; 6

Regina Margherita Hospital, Rome, Italy; and 7Dept. of Medicine, University of Leuven, Leuven, Belgium

Clinical studies of Crohn's disease must rely upon homogeneity of patient subgroups. We do not believe that merely "lumping" all cases into the Procrustean bed of a numerical index accomplishes this purpose. We therefore propose that all cases be described primarily by anatomical location ( e.g. gastroduodenitis, jejunitis, ileitis, colitis, perianal disease, etc.) and anatomical extent (localised or diffuse), with modifiers for disease behaviour (primarily fibrostenotic, primarily inflammatory, or primarily fistulising) and operative history (primary or recurrent).

INDEX TERMS: Crohn's Disease: immunological markers; biochemical markers; life style influences; pathology; symptoms; surgery; prognosis; therapy.

PART 1. THE WORKING TEAM REPORT

1.1. The Team's goal

Crohn's disease is not a single homogeneous clinical entity. The various forms in which it appears are so fundamentally diverse in their course, prognosis, and responses to standard therapies that it is virtually meaning­less to identify a case as "Crohn's disease" in the absence of additional, more detailed descriptors. We therefore propose a simple classification of Crohn' s disease that distinguishes its principal varieties on the basis of essen­tial differences in their clinical behaviours and outcomes. This classification seeks to meet Feinstein's challenge to the medical profession at large to develop "a specific taxonomy to standardise the names and to categorise the severity of disorders, based on a scientific classification system of functional severity" (1). With more specific reference to Crohn' s disease, we are following the guide­lines of Walvoort and Pena: "A major contemporary challenge with regard to Crohn's disease is to design a scientifically reliable classification presentation, which ispertinent to effective patient care" (2).

1.2. The background

Our efforts toward a classification of subgroups of patients with Crohn's disease must begin with a confession of

Address correspondence ro: Dr D.B. Sachar, Gmrroenterology

Division, Box 1069, The Mount Sinai Medical Ce111er. One

Gustave L. Levy Plc1ce, Neu· York, NY, 10029-6574, USA.

ignorance: we do not know the cause(s) of this disease. We are not even certain that what we call Crohn' s disease is, as Crohn, Ginzburg and Oppenheimer described it in their classic 1932 paper, "a pathologic and clinical entity" (3). A large number of aetiologies have been proposed, vary­ing from extrinsic infectious, dietary, and chemical agents to intrinsic physiological and immunological defects, but very few survive today as likely causative agents. The apparent impossibility to establish a satisfactory aetiology for Crohn's disease, after more than a half-century of research, surely supports the hypothesis that Crohn' s dis­ease may not be a single disease entity. It is a syndrome of functional and morphological lesions which reflects a basic response pattern of the gastrointestinal tract. This Crohn' s response is elicited by several non-specific agents in individuals genetically predisposed to display this reac­tion pattern. Any of these agents is presumably very relevant to the disease and to the treatment of the patients in which it is found, but as such it provides no explanation for the whole spectrum of the Crohn syndrome. However, in spite of the theoretical considerations suggesting a classification based on aetiological agents, our know ledge today does not allow us to identify subgroups of patients based on this principle. Therefore, successful patient management is currently more in need of a scientifically sound classification system according to disease severity and location than of the speculative search for a unifying aetiology.

1.3. The available evidence

The futility of seeking an aetiopathogenic classification system for Crohn' s disease in our current state of know I-

-.J.2

SACHAR ET AL. G.�Sl ROENl E�OLOGY [NTERNATIONAL

edge ha b ·en ninpl demonstrated in a r'cen1 revit''vv article(_), and for ur purposes need nly bi.:: summarised in pp,mclixA. Effor1stoc nstructacla :ilkatior,scheme ba. e I up n immuno ·hemical and bi chemical markers nre reviewed in App •1ulix B. It is clear that no such syst m L currently adequat f r the functional cla. it'icaiion of the g neral populati n · f rohn'. dis ase patient.. or have epidemiologi al ·tudie identified any I mographic features that reliably di ·tinguish amoug I henotypi · ·at­egorie. of rohn's di. ea ·e patient . even,, h n they r cus on familial a ·e· or on su 11 potentially inl'luential en i­ronmernal factor. a. ral contraceptive . ·m king. and diet (Appendix J .. If we are to oncentrate 11 "functi nal ·everity · that i · ··pertinem 10 effective patient car ". wemighr imagine that gr is. pathological and endo · opiappearance. fc!is a ewouldbe u.efulcriteriaf rcla .. i­fication. The e f ature me r· viewed in ppe11dix D.Except f r Lhe nppearan f early post-operati le. i n.in the prc-anustomolic ne t rminal ileum. howev r.endo copi pattern appear to be of little pracl'ical u e inthe cla sification f rohn· di. ea. e. Finally, the reviewf ch available evidence ha. h wn that in any functional

cla · i fication of patient ·ub!!roup in Crobn s di ea e, the 111 st useful (and , idely rec gni ed) tarting point i. t ·p· cify anatomical I • Lion of di:ea · · (4.5). Thiaddr . ed in Appendix£.

1.4. The proposed classification

Thecon eptofdi tingui. hingrh clinicalpatt rnofCrohn's disea ·e n the basis of a11ato111ical location was pioneered by Farmer and others 4,5). The Working Team ha r a ·hed a unanim us con en Lt. that at least three other m difier. co anatomkal locations will be u eful in a ciemific cla. ·ification y. tem of functional severity that

i pertinent to effective patient care. The fir. t m difier i · anatomical extent - i.e. whed1er the di. ea e i diffuse or Localised. AILhou0h the preci e di. tin Li n between "dif­fu, e' and• localised" disease is bound t be arbitrary, the underlying principl holds that the anatomical extent of di ease ha. implications for phy. iological con equenc (e.g. rnalab orption in small inte tine. p rotein loss in olon) and for feas.ibility of resection. Initial appro ima�

tion for the b undari.e. between diff

u e and locali ed di ea e might b in the range ofonc metre but at thi tage in ur thinking it is Lhe general concept that is mor important than th exact calibration. The ·ec nd prop . ed m di fier to location after extent, is

what we might call "disease behaviour'' - viz. primarily fibros1e110tic (i.e. cicatri ing), primarily inflc11111natory, or primarily penetrc,ting (i.e. Fi llllising). The WorkingTeam i not oblivi u to the fa l that many ca. e may have combined r verlapping feature . Indeed. on form may proore.. wilh time 10 one of the other . nerheles., we mainta.in thatin mo.t ca e·.acagiven poinlin time. ne of these fearure tend t dominate the clinical picture in uch a way a, to dictate management decisions. For example, primarily innammat ry disea. e sugge. I:! medi al rather than ·urgical treatment: primarily fibro tenotic di ea. e call. I' r a surn.ical rather than medical approach; while fistulising disease might b managed either way d pend-

ing uµ 11 the naltll' r the pr b'f m and its c mplicarion quail i111pona11t. th se categ ries of "di ·ease behav­

iour" may pr et have ind pendent influence. on post­operative progno ·i . ln the year since the M unt inai group 't1gg ted that there mi0hl' be contra. Ling· ind lent" ancJ··aggres ive"form:or rohn'. disca.e(6.7) a number or other . cudi · ha e c nfirmed the ob ervati n that cer­tain Ii ea e pattern. have a predicti e valu for . urg ry (8 .anc! that pre- perative dis a·e patternsand indicati n als have a preclicti e alu r r po t-operative outcome· (9-13). ome r the therapeuti implications f the. e anatomical ·rnd behavioral di. < . e categories are brielly re ic\J ed in App ,,ulix F. Finally. the third 111 difier i. operative hi ·101)' - viz.

whether the di ea.s · i · pri111c11:\· (i ... unop ·rated) or r 'Cur­rem (i.e. po ·c-op rati e). There are. f course, ample data L . how that the natural hi t ry and medi al respon i ve­n · . of Crohn'. disease are altered by n or more resec-

ns (14-18).

1.5. Conclusion

In conclusion, the Workirg Team recogni ·e lhal clinical studies ofCrohn's diseasemu t rely upon homogeneity of patient subgroups. We do rot beli ve that merely' lump­ing" all cases into the Procnitean bed ofa numerical index accomplishes this purpose. We therefore propose (Table I) that all cases be described primarily by anatomicallocation (e.g. gastroduodenitis, jejunitis, ileitis, colitis,perianal disease, etc.) and anatomical extent (localised ordiffuse), with modifiers for disease behaviour (primarilyfibrostenotic, primarily inflammatory, or primarilyfistulising) and operative history (primary or recurrent).

TABLE I

Modifier

A. Location *

B. Extent

C. Behaviour

D. Operative history

1 'moW1'atWDuodenum 2. Jejunum3. Ileum4. Colon5. Rectum6. Anal - Perianal

I. Localised2. Diffuse

1. Primarily inflammatory2. Primarily fistulising3. Primarily fibrostenotic

1. Primary2. Recurrent

* "Location" refers to site(s) primarily involved, not to thosewhich might be "innocent" recipients of fistulae fromelsewhere. In case of multiple locations, indicate all sites (e.g.ileocolon= 3-4) as well as the sites predominantly involved(e.g. ileocolon, predominantly ileum).

Vol. 5. �o. 3. 1992 CROHN'S DISEASE 143

e offer this pr po al only t ntnti ely. sine it has n t been in any way tested, mu h less vcritied: but . ff· r it n n thete a a fir. I .. tep toward bringing funher )rd r into th chao of Crohn' di ·ease. We think the next step mu:! be LO ubject the prop ed clnssificalion l trial f inter-ob erver ariati n. Validaring tbe clinical and prog­nostic value of thi cla ificati n may be a long way f

f

, but let u · ee if we can at lea t g t people who deal with groups of Crohn'. di. ea patiem to tart peaking the ·amc language!

REFERENCES- PART 1

I. Feinstein AR. The intellectual crisis in clinical science: medaledmodels and muddled mertle. Perspect Biol Med 1987; 30:215-230.

2.Walvoort HC, Pena AS. Crohn's disease: Entity andaetiopathogenic concepts. J Clin Nutr Gastroenterol 1987: 2: I 94-200.

3. Crohn BB, Ginzburg L, Oppenheimer GD. Regional ileitis. Apathologic and clinic entity. J Am Med Assoc 1932; 99: 1323-1329.

4. Farmer RG, Hawk WA, Turnbull RB. Clinical patterns in Crohn'sdisease. A statistical study of 615 cases. Gastroenterology 1975;70:369-370.

5. Farmer RG, Whelan G, Fazio YW. Long term follow up of patientswith Crohn's disease: relationship between the clinical patternand prognosis. Gastroenterology 1985; 88: 1818- J 825.

6. Sachar DB, Wolfson DM, Greenstein AJ, Golberg J, Janowitz HD.Risk factors for postoperative recurrence of Crohn' s disease.Gastroenterology 1983; 85:917-921.

7. Greenstein AJ, Lachman P, Sachar DB, Springhorn J, Heimann T,Janowitz HD, Aufses AH Jr. Perforating and non perforatingindications for repeated operations in Crohn's disease: Evidencefor two clinical forms. Gut 1988; 29:588-592.

8. Prantera C, Levenstein S, Capocaccia R, Mariotti S, Luzi C,Cosentino R, Simi M. Prediction of surgery for obstructionin Crohn's ileitis. Dig Dis Sci 1987; 32:1363-1369.

9. Pallone F, Boirivant M, Stazi MA, Cosentino R, Prantera C, Torsoli A. Analysis of the clinical course of postoperative recurrence in Crohn's disease. Dig Dis Sci 1992 (in press).

10. Griffiths SM, Wesson DE, Shandling B, Corey M, Sherman PM.Factors influencing postoperative recurrence of-Crohn' s diseasein childhood. Gut 1991, 32:491-495.

11. Levine E, Schwartz 1, Bayless T. Distal ilea! Crohn's disease; thetime course of fixed bowel obstruction. Gastroenterology 1987;92: 1504 (abstract).

12. Rutgeerts P, Geobes K, Yantrappen G, Beyls J, Kerremans R, HieleM. Predictability of postoperative course of Crohn's disease.Gastroenterology 1990; 99:956-963.

13. Francois Y, Gaujuox F, Descos L, Vigna! J. Crohn Perforant -Crohnnon Perforant: mythe ou realite9 Lyon Chir 1990; 86:386-389.

14. Lock MB, Fazio VW, Farmer RG. et al. Proximal recurrence andthe fate of the rectum following excisional surgery for Crohn'sdisease of the large bowel. Ann Surg 1981; 194:754-760.

15. Greenstein AJ., Sachar DB, Pasternack BS, et al. Reoperation andrecurrences in Crohn's disease and ileocolitis: Crude and cumu­lative rates. N Engl J Med 1975; 293:685-690.

16. Lennard-Jones JE, Stalder GA. Prognosis after resection ofchronic regional ileitis. Gut 1967; 8:332-336.

17. Trnka YM, Glotzer DJ, Kasdon EJ, et al. The long term outcomeof restorative operation in Crohn 's disease: Influence of location,prognostic factors and surgical guidelines. Ann Surg 1982;196:345-354.

18. Summers RW, Switz DM. Sessions JT, et al. National Coopera­tive Crohn's Disease Study:Results of drug treatment. Gastroen­terology 1979; 77:847-869.

PART 2. THE SUPPORTING APPENDICES

Appendix A. The case against an aetiopathogenic clas­sification of Crohn's disease

fter m re than five decade f intensiv linical and ba. ic research, n . ingle aetiol gy for rohn'. disea: ha� emerged. Propo ed a tiological fact r appear to apply to a ·mall pr portion of Crohn' patient nty. Moreov r. clinical and path logi at scruri11y during the e y ars ha e reveal d that the functional morph logi al le ion f 1he di ea e are by n mean specific. but rather repre ent a pectrum of phenotypic manife. tation . the diagn i. or a

fair pr p rtion of which remaining equivocal. These con iderati 11 pr mpt u to ·tep back and seriou ·ly c n­template the po. ibility that Cr hn' di ea. e might not b adi ea e entity(l-4). lfCrohn'·di ea.e werenoradi ea.e entity with regard to a tiology, but a heterogeneou di or­der. thi would imply that more than one a tiologicat mechani m uld lead 10 the cUnico-pathological syn­drome which we all Crohn disca e (5,6). Thi iew would have much impact on th rapy. a one group f patiem, then might need a different therapeutic approach from an ther group, according to the relevant aetiological factor involved in each on . An amazinoly wide variety f extri.n ic an I intrin i aetiol gi al factors ha been pro­po. ed, which in Jude phy ical. chemical (oral contracep­tive ). dietary (proce ed f, t. ). biotic (flora), g neti , immunopathological, p ychogenic and behavioural agent Of the everal aetiopathogenetic hypo1J1e es and the many putative aeLiological agent., only a few urvive a likely one, today (7-9). 01 only could the cau ative a ociali n of mo t of the ·e agent with Crohn's disea e not be confirmed in other ludie., but many of the propo ed aetiological factor were found in a di appointingly lim­ited proportion of the Crohn pa.tient, . For example, a proposed complement dy funcii n wa. identified in only eight of 21 rohn patien ( I 0), and a strain of like! causati e mycobacteria in only three of 14 patient (11 . Furth nnore. allh ugh in rea ed inte tinal permeability a. an aetiological fa tor wa. · learly . upponcd by a tati. -tically significant incren e in the mean permeability ofCrohn patient. ver us control., at lea. t five of the 11 rohnpatient· tudied had a permeability value welt within thec ntrol range 12. Thi d e n tjustify the opinion thatany ne of these lement, con titute the principaJ cause ofthe dj ea e. It i. likely that rohn'. di ea ha a complexaetiology and for the di ease Lo d elop, a on erted actionof extrin . .ic environmental and intrin ic hereditary factor·appear 10 be nece ary. Even if ome of the orig:inallyeliciUng factors wer known management of a patientwould primarily dep nd on typ grade and tage of theparticular disea. e pattern. Thi require. a cla. ·ifica1ion. y. tern bas d on progno i · rather than on aetiology. ln anexcell nt es ay. Feinstein ( 13) argue. that "functionalc n ·equenccs in the . everit of di. ease, rather than itspathol gic essence, are u ·ually the rea ns why mo lpati nt. arc treated or h pi tali ed ·, but that prognosis hasbeen given relatively liule scien1ific attention. Our cur­rent, aeti logy-ba ·ed, conceptual motlel yield. diagnosewhi h reflect a ·ingle and tali aspect of the patient. and

C

I (

·r

I! ci

I(

1(

d

Vol. 5. No. 3, I 992 CROHN'S DISEASE 145

tory parameters of inflammation, eight possible patterns emerge into which each patient may fall ( once or in several instances) during the course of his/her life-long disease (Table B2.I) (20). A retrospective analysis of the preva­lence of the eight patterns indicated that in approximately one-fifth of the attendances, patients present with no or minimal clinical symptoms but have abnormal laboratory findings (20). This analysis also showed that approxi­mately 50% of patients with macroscopic disease in clini­cal remission have positive indices of inflammation. Pos­sible implications of these findings are: (a) patients in remission with positive laboratory tests may have not achieved a "stable" remission and are therefore more likely to relapse early; (b) if so, these patients may benefit from active treatment even if asymptomatic; (c) a labora­tory remission should be the optimal goal of medical treatment.

These issues have been addressed in more recent studies showing that: (a) asymptomatic patients undergoing an early relapse tend to have abnormal laboratory indices of inflammation (22); (b) the one-year likelihood of clinical relapse in asymptomatic patients is significantly higher in those with high serum CRP (23); (c) in patients in clinical remission for one year the likelihood of clinical relapse in the second follow-up year i higher in those with high serum CRPduring rhe first years (23); (d) in asymptomatic Crohn's di ea e patients, relapses can be predicted with a relatively good accuracy on the basis of positive test of inflammation (22); (e) it is not yet clear whether active treatment with steroids or salicylates is effective in asymp­tomatic patients with positive laboratory tests in terms of prevention of clinical relapse, although a trend for a

TABLE B2.I. Clinical patterns according to macroscopic

disease, clinical symptoms and laboratory parameters in 476

consecutive attendances (adapted from ref. 20 to Appendix B).

Macroscopic* Clinical** Laboratory*** %

Pattern I No No No 20 Pattern 2 No No Yes I

Pattern 3 Yes No No 20 Pattern 4 Yes No Yes 20 Pattern 5 No Yes No 0.4 Pattern 6 No Yes Yes 0.6 Pattern 7 Yes Yes No 10 Pattern 8 Yes Yes Yes 28

* Yes= X-ray and/or endoscopic evidence of macroscopic

disease

No = No X-ray and/or endoscopic evidence of

macroscopic disease

** Yes=CDAI> 150 orSl>4

No = CDAI < 150 or SI< 4 (34-35)

*** Yes = Abnormal values of at least two of the following:

ESR, C-reactive protein. seromucoids, serum albumin,

serum iron

No = all the above within the normal range

beneficial effect has been shown for steroids (24) and mesalazine; (f) patients in clinical remission with persist­ently abnormal laboratory findings after a course of ster­oids have active macroscopic disease as shown by endoscopy (25).

Measurements of alpha-1-antitrypsin faecal excretion are believed to reflect the "lesional" activity of CD (26-27). It has also been shown that these measurements (either the clearance or the faecal concentration) are sen­sitive and specific markers of asymptomatic post-opera­tive recurrence (28). Post-heparin plasma diaminoxidase (DAO) is an indirect indicator of enterocytic mass and is significantly decreased in patients with Crohn' s disease (29). The decrease in the DAO levels is more pronounced in patients with active disease and it appears to be related to disease extent. No evidence has been provided to show that either of these markers may help in distinguishing subgroups of Crohn's disease patients.

REFERENCES - APPENDIX B

I. Pallone F, Montano S, Fais S, Borivant M, Signore A, Pozzillli P.Studies or pheripheral blood lymphocytes in Crohn's disease.Circulating activatedTcells. ScandJGastroenterol 1983; 18:1003-1008.

2. Raedler A, Fraenkel S, Klose G, Seyfarth Thiele HG. Involvementof the immune system in the pathogenesis of Crohn's disease.Gastroenterology 1985; 88:978-983.

3. Pallone F, Fais S, Squarcia 0, Biancone L, Pozzilli P, Boirivant M.Activation of peripheral blood and intestinal lamina proprialymphocytes in Crohn' s disease. In vivo state of activation and invitro response to stimulation as defined by the expression of earlyactivation antigens. Gut 1987; 28:745-753.

4. Raedlcr A. Fnicnkel S. Klose G. Thiele HG. lcvated number fperipheral T cell. in inllammatory bO\ el di ·ease displaying T9 antigen and Fe receptors. Clin Exp lmmunol 1985: 60:518-524.

5. chreiber S. Mac Dermo!! RP. Raedler A. Pinnau R. Bertovich MJ,ash GS. Increased activation ofisol11ted inte tinal lamina propria

mononuclear cells in inflammatory bowel di�en e. Gasu enrcr l­ogy 1991; 101:1020-1030.

6. Boirivant M, Quintieri F, Pugliese 0, Famularo G, Fais S, PalloneF. A limiting-dilution analysis of activated circulating B cells inCrohn's disease. J Clin Immunol 1990; 10; 128-134.

7.Mucller h.KnollacliP.Zielinski C.T-cellactivatl n in r hn'sdisease - Increased Je,•el of ·oluble interleukin- recepror in·crum and in supcrnarn111s of sti mulatecl peri1 hernl bl odm n nuclear cell.. Gastr nterology 1990: 98:639-64 .

8. Fais . Capobianchi MR. Pnllo11e F. Di Ma.re P. B irivnnt M.Dian1.ani F. Tor. Ji A. pontaneousrclcn.c flntcrfcron-gammaby intes1innl lamina propria lymphocytes in Crohn·s di case.Kinetic· of in vi1.ro respon c to interferon gamma inducers. Gut19 I . 32. 403-407.

9. MacDonald TT, Choy MY, Hutchings PA. Cooke A. Local produc­tion oftumornecrosis factor alpha in inflammatory bowel disease.Clin Exp Immunol 1990: 81 :351-356

10. Hodgson HJF. Potter BJ, Jewell DP. Immune-complexes inulcerative colitis and Crohn's disease. Clin Exp Immunol 1977:29:187-193.

11. Pall ne F. Montano . Ricci R, Lnvic Ii M. Di Mario . ewevidence f circulnting immune complexes in rohn's diseaseusing two sensitive method . J Clin Lab immunol 1981: 5:23-26.

12. Pallone F. M,11ricardi PM. quurciaO. ·ais •. Le Moli . Boirivan1M. Pnoluzi P. D' Amelio R. Rai. cd �erum levels of lgM-Rhcuma­toid factor and anti-F(abJ2 autoantibodics in patient. with act ivlnllamnwtory bowel lisea.�c. J lin Lab lmmunol 19 : 19:175-

Vol. 5. No. 3. I 992 CROHN'S DISEASE 147

further research into the long-term effects of feeding with human milk.

Diverse other dietary factors have been assessed. The diet of high-risk Ashkenazi Jews in Tel Aviv includes more meat, mild and eggs than the low-risk non-Ashkenazi population (22). The Israeli diet contains more carbohy­drate and fibre and less fat and meat than that of the American population who e inciden e rate are higher. Break fa ·t cereal ha e been i1�ve, ligated by everal au­thor· wiLh c nfli ting re. ult (23-25). In 1976, a German study (26-27) reported that b fore de eloping r hn's disea e, the paLienis had eaten more refined ugar than matched control . A carefully comrolled Ludy (28) con­finned che e result in 1979 and later tudie agre that refined ugar i an aetiological factor (2 - I) but i inde­pendent of moking habits (32). Both smoking and ugar could operate or trigger a common mechani m. In con­tra ·t, a recem tudy from Sweden (19) showed that sugar c nsumpti n increased with longstanding disease and sugge ted that it was a secondary phenomenon with no aetiologi.cal importance.

REFERENCES - APPENDIX C

l. Rhodes JM, Cocke] R, Allan RN, Hawker PC. Dawson J, Elias E.Colonic Crohn's disease and use of oral contraceptive. Br Med J1984; 288:595-596.

2. Royal College of General Practitioners. Oral contraceptives and health: An interim report from the oral contraceptive study of theRCGP. New York: Pitman, 1974.

3. Logan RFA, Kay CR, Scott L. Oral contraception, smoking andinflammatory bowel disease. Findings in the RCGP oral contra­ceptive study. Int J Epidemiol 1989; l 8: l 95-107.

-1. Ramcharan S. The Walnut reek contraceptive drug study.A prospective study of the side cffe I of oral contraceptive.. ol.III. Wa hinglon DC: Government Printing Oflice. 19 I.

5. Vessey M. Jewell D. mith A. Yeates D. McPher on K. Chronicinflammatory bowel disease. cigarette smoking and oral contra­ceptive use: finding in a large cohort study of women ofhilclbeuring age. Br Med J I 86: 292: 1101-1103.

6. Lashner BA, Kane SY, Hanauer SB. Lack of association betweenoral contraceptive use and Crohn's disease: A community basedmatched case control study. Gastroenterology l 989; 97: 1442-1447.

7. Heatley RV, Thomas P, Prokipchuk EG, Gauldie J, SieniewiczDJ, Bienstock J. Pulmonary function abnormalities in patientswith inflammatory bowel disease. Quart J Med 1982: 203:241-250.

8. Harries A. Baird A, Rhodes J. Non-smoking: a feature of ulcera­tive colitis. Br Med J 1982; 284:706.

9. Logan RFA, Edmond M, Somerville KW, Langman MJS. Smok­ing and ulcerative colitis. Br Med J 1984; 288:751-753.

I 0. Jick H. Walker AM. Cigarette smoking and ulcerative colitis. N Engl J Med 1983; 308:261-263.

11. omcrville KW, Logan RFA, Edmond A. Langman MJ . Smok­ing and Crohn' · clise:ise. Br Med J 1984: 289:954-956.

12. Holdstock G. Savage D, Harman M, Wright R. Should patient.1 ithinflammatoryboweldi·ca.e m kc?BrMcdJ 1984:288:362.

13.l lannue:rSB.Sill•erstein 111).E an. A.KirsnerJB. Acasecontrolstudy of smoking and inll:m1mawry bowel disease compared to the irrirnblc bowel syndrome. Clin Re. 19 4: 32:223A.

14. alkin R. Lilien field A. Mendcloff A. Garland F. mokingfactor. in ulcerative colitis nnd Crohn' disea c in Baltimore.

mer J pidemi I 1984: 120:498.

15. Tobin MY. Logan RF. Langman MJS. McConnell RB. GilmoreIT. Cigarette smoking and inflammatory bowel disease. Gastro­enterology 1987: 93:316-321.

16. Lindberg E. Tysk C. Anderson K. J�rnerot G. Smoking andinflammatory bowel disease. A case control study. Gut 1988:29:352-357.

17. Silverstein MD, LashnerBA. Hanauer SB. Ev and AA. Kirsner JB.Cigarette smoking in Crohn's disease. Amer J Gastroenterol1989; 84:31-33.

18. Koletzko S, Sherman P, Corey M. Griffiths A. Smith C. Role ofinfant feeding practices in development of Crohn · s disease in childhood. Br Med J 1989; 298:617-618.

19. Bergstrand 0, Hellers G. Breast feeding during infancy in p a -tients who develop Crohn's disease. Scand J Gastroenterol 1983;18:903-906.

20. Whorwell PJ, Hodstock G, Whorwell GM, Wright R. Bottlefeeding, early gastroenteritis and inflammatory bowel disease. BrMed J 1979; I :382.

21. Davis MK, Savitz DA, Grubara BI. Infant feeding and childhoodcancer. Lancet 1988; 2:365-368.

22. Rozen P, Zonis J, Yekutiel P, Gilat T. Crohn's disease in theJewish population of Tel-Aviv. Gastroenterology 1979; 76:25-30.

23. James AH. Breakfast and Crohn · s disease. Br Med J 1977; I :943-945.

24. Archer LNJ, Harvey RF. Breakfast and Crohn' s disease. Br MedJ 1978; 2:540.

25. Rawcliffe PM, Truelove SC. Breakfast and Crohn's disease I. BrMed J 1978; 2:539-540.

26. Martini GA, Brandes JN. Increased consumption of refinedcarbohydrates in patients with Crohn' s disease. Klin Wochenschr1976: 54:367-371.

27. Kaspar H, Sommer H. Dietary fibre and nutrient intake in Crohn' sdisease. Amer J Clin Nutr 1979; 32:898-901.

_g_ Thornt n JR. Emmet PM. Heaton K . Diet and Cr hn· di ea c char:ictcri. tics of the prc-illnc. s diet. Br Med J 1979; ii:762-764.

29. Muyberry JF. Rhodes J. ewe mbe RG. Increased .ugnrc nsump1ion in Crohn' di ea.e . .Dige 1ion 1980: 20: 23-326.

30. Silkoff K. Hallnk A. Yegena L. Cl al. Con umption of re med carbohydrate by patients with Crohn'. di ca e in Tel-Avi1•. YafoPo. tgrad Med J 1980: 56:842- 46.

31. Mayberry JF, Rhodes J, Allan RN, et al. Diet in Crohn's disease.Two studies of current and previous habits in newly diagnosedpatients. Dig Dis Sci 1981; 26:444-448.

32. Katschinski B. Logan RIA, Edmond M, Langman MJS. Smoking and sugar intake are separate but interactive risk factors in Crohn's disease. Gut 1988; 29:1202-1206.

Appendix D. Gross pathological and endoscopic classi­fication of Crohn's disease

In the laLe 1970s and early I 980 , studi published on ndo copy in innammaLory b wel di ea (IBD were

mostly de criptive. The rnaj r aim f endo opy at that time was to differ miate between rohn' coliti and u lcerari ve coli tis and other peci fi c Ii t id by the macro­. copic and hi ·to logical appearan e f the inflammatory le ions. In the la t five year . endo ·copy with bi p ·y ha been u ed more a a re. earch ro l for the tudy of the naLUral hi t ry f Lhe di ca e, the pauern of healing under therapy. etc. Devel pment and validation of rohn dis­ease endo. copic indices will probably further stimulate advances in endo copic research in IBD (I).

When end sc pie appearance of the disease is consid­ered as a basis for behavioural classification of the disease, the following four considerations need to be taken into

148 SACHAR ET AL. GASTROENTEROLOGY INTERNATIONAL

account.

First. ic ha I ng been ob er ed by 0

a tr enterologists that in contrast r.o ul erativ c litis, there is a poor corre­lation betw en •ndo opic. verity and lini al activity of Crohn·. di'ea.e. Thi linical impre.sion ha been sub­stantiated by the y temati end scopi studies of Modigliani and the G �T JD grou1 (2). Aphthae are the acute Crohn's lesion ond are aL· frequent! found at a distance from more ever le. ion. in "chr nic" disease. Cobblestones and strictures are only found in "chronic" disease. Fistulae are not well appreciated at endoscopy.

Second, the specific feature in endoscopic biopsies for the diagnosis of Crohn' s disease, namely the presence of granulomas, differs according to disease location. In the oesophagus, endoscopic biopsies (limited data) yield the presence of granulomas in nearly 100% of cases. Also, in the stomach Crohn's lesions are characteri ed by a high incidence of granulomas in endoscopic biop. i . (>60o/c ). In the ileum, granulomas are rarely found in endo. copic biopsies ( < 5-10% ), whereas in the col011 and recLUm th incidence is higher (15-30%). Some of these differences, of course, are determined simply by differing criteria required to establish the diagnosis of Crohn' s disease in different locations.

Third the pattern of healing of endo pie l.e ions under cortico. teroid therapy i very different d pending on the I cati n of the le ions. For example, o sophag al le ions di appear complete I under c rlico' Ler id therapy while ga tric Crohn' Le ion do not change under therapy even if there i ·ymptomatic relief. The same i true for ilea! lesions. Glucocorticoid treatment can achieve relief of ymptom. but endo. copically and radiologically no heal­

ing of le ions i. b erved (3). Colonic le·ion heal lowly although remi sion i al read achieved much earlier. Only 29% f parient in clini al rem.i ion al o achieve endoscopic remission of colonic Crohn' s disease, but healing may continue even after corticosteroids are ta­pered and discontinued (4).

Finally, the natural history of Crohn' s ileitis (5) is re­flected by recurrence of Crohn' s disease in the neoterminal ileum after curative ileal resection. The first recurrent lesions unequivocally observed are aphthae, which are found already within a few months of surgery. These recurrent lesions are nearly always located in the neoterminal ileum, whereas the post-anastomotic colon is spared. The severity of these recurrent lesions determine subsequent clinical evolution. It seems that these lesions are "new" and do not originate from microendoscopic lesions left behind at surgery. Moreover they seem faecal stream dependent (6).

REFERENCES - APPENDIX D

I. Mary JY, et al. Development and validation of a Crohn's diseaseendoscopic index: a prospective multicentre study. Gut 1989;30:983-989.

2. Modigliani R, et al. Clinical, biological and endoscopic pictureof attacks of Crohn's disease. Gastroenterology 1990; 98:811-

818.

3. Olaison B, et al. GI ucocorticoid treatment in ilea! Crohn 's disease:

relief of symptoms but not of endoscopically viewed inflamma­

tion. Gut 1990; 31 :325-328.

4. Modigliani R, et al. Acute attacks of colonic and ileocolonic

Crohn's disease (CICD): Is colonscopic follow-up useful toadjust steroid treatment duration? Gastroenterology 1990:98:Al93.

5. Rutgeerts P, et al. Predicability of the postoperative course of

Crohn's disease. Gastroenterology 1990; 99:956-963.

6. Rutgeerts P, et al. Effect of faecal stream diversion on recurrenceof Crohn's disease in the neoterminal ileum. Lancet 1991; 338:

771-774.

Appendix E. Classification based on anatomical location

El. Clinical patterns

Although Crohn's disease is known to have a variety of anatomical locations throughout the gastrointestinal tract, the comparative importance of this phenomenon was not recognised for many years, despite the fact that certain varieties had been described; e.g. regional enteritis, termi­nal ileitis, Crohn' s disease of the colon. Since it is usually possible to identify a specific anatomical location of disease, the classification by initial anatomical localisa­tion is both reasonable and logical, but must be verified as an indicator for prognostic purposes. In the mid-1960s at the Cleveland· Clinic, a registry of 615 consecutive pa­tients newly diagnosed with Crohn's disease was devel­oped. After follow-up of these patients for 10 years, the thesis was proposed that the initial anatomical involve­ment in Crohn's disease was a major determinant in prognosis (1). Approx.imately 96% of Lhe.e patient. were then followed for an additional IO year (2). Analy i · of the cases revealed the occmTence of clinical paltern of the disease process that were dependent on initial I cation of disease. Clinical patterns were established for the follow­ing anatomical locations of disease: ileocolic (involve­ment of right colon and distal ileum), 252 paLient (41 %); mall inte tine (without colon involvement) 176 patient

(28.6%); colon (without small intestine involvement), 166 patient (27%); and anorectal (without other demon Lrable involvement initially), 21 patients (3.4%). A small number of patients had gastroduodenal involvement.

E2. Symptoms

Statistically significant associations between symptoms and locations (p< 0.001) were rectal bleeding with colon involvement and rectal fistulae with ileocolic or colon involvement. Among statistically significant associations between complications and locations (p<0.001) were perianal fistulae, internal fistulae and intestinal obstruc­tion with ileocolic pattern; perianal fistulae, toxic megacolon and arthritis with the colon pattern; and intes­tinal obstruction with the small intestine pattern. Surgery was required for 73% of patients with the ileocolic clinical pattern and for 51 % of patients with each of the small intestine and colon patterns. Subsequently, others adapted a similar approach and Table E2.I illustrates the results of this type of study from five institutions (3-6).

Vol. 5. No. 3. l 992

TABLE E2.l. Crohn's disease initial location of disease.

Series Ileocolic

Cleveland

Clinic 41%

NCCDS 55%

Stockholm 41%

Oxford 42%

European 49%

TABLE E3.I. Indications for surgery in Crohn' s disease.

1/eocolic Pattern

Intestinal obstruction

Internal fistula and abscess

Perianal disease, severe

Small Bowel Pattern

Intestinal obstruction

Internal fistula and abscess

Colonic Pattern

Toxic megacolon

Internal fistula

Stricture with obstruction

Perianal disease, severe

Poor response to medical therapy and chronic disability;

malnutrition

Anorecta/ Pattern

Severe perianal disease

Other

Hydronephrosis (ilea!)

Pyoderma (colon), severe

Arthritis (colon), severe

Eye manifestations (colon), severe

Growth retardation (colon)

Massive haemorrhage (rare)

CROHN'S DISEASE 149

Small

intestine

29%

30%

41%

30%

30?

Colon Other

27% 3'7c

14% I o/c

17% 1%

26% 2%

21% 0%

TABLE E3.II. Statistical differences in indications for surgery in

Crohn's disease.

Clinical Pattern

Small

Indications for Surgery Ileocolic Intestine Colon

Perianal disease + 0 +

Intestinal obstruction + + 0

Internal fistula and abscess + + 0

Toxic megacolon 0 0 +

Poor response to medical therapy 0 0 +

E3. Indications for surgery

Among our 615 patients, 316 had primary operations performed at the Cleveland Clinic between 1966 and 1969. In addition, in 1972 and 1973 there were 184 patients for whom the primary decision for surgery was made at the Cleveland Clinic, and the operation then performed. Thus, in the 6-year period (] 966 to 1969 and 1972 to 1973) there were 500 patients who had indications for surgery (7). The indications for surgery for these patients, in tabular form, are described in Table E3.I. Of the 225 patients with the ileocolic pattern, 91 % had spe­cific surgical indications as follows: internal fistula and abscess, 44%; intestinal obstruction, 35%; and perianal disease, 12 % . Among the 130 patients with the small intestine pattern, two indications made up 87% of the surgical indications: intestinal obstruction, 55%; and in­ternal fistula with abscess, 32%. Of the 127 patients with the colon pattern, a greater variety of surgical indications were observed. These included poor response to medical therapy (26%), internal fistula and abscess (23%), toxic

150 SACHAR ET AL. GASTROENTEROLOGY J NTERNATIONAL

megacolon (20% ), perianal disease ( 19%) and intestinal obstruction ( 12% ). For the patients with the anorectal patterns in whom colonic disease developed, indications for surgery were either the perianal disease itself or poor response to therapy. Comparison was made of the three major patterns and the statistical significance of each surgical indication was defined. There were highly sig­nificant statistical differences in indications for surgery based on anatomical location of Crohn' s disease (Table E3.II).

E4. Recurrence and re-operation

In a study of recurrences and reoperation for patients with Crohn' s disease, it was found that recurrence after surgery in Crohn's disease could be correlated with the original location of disease (8). In this study, 361 patients were followed for a mean of 11.5 years following the first operation for Crohn' s disease. Among these patients, 40% had ileocolic location of disease, 30% small intestine disease and 30% large intestine disease. There were 123 patients (34%) who had a recurrence requiring operation. The incidence of recurrence was lowest in patient with disease of the large bowel (24%) or small bowel (28.5%); the recurrence rate was highest for patients with ileocolic disease ( 44% ). These data showed that for the first eight years there was a 3.9% per year risk of recurrence requir­ing resection and after eight years the risk declined to about 1.4% per year. Thus, the cumulative risk was about 42% at 15 years, with 85% of all recurrences having occurred within the first eight years following the initial operation. Further analysis of the data revealed that the initial surgical indication of intestinal fistula with abscess, particularly when associated with ileocolic location of disease, was associated with the highest risk of recurrence requiring further operation (9).

ES. Long-term prognosis

As the mean follow-up of the original Cleveland Clinic's cohort of patients approached 15 years, it became quite apparent that the majority of patients had required an

TABLE ES.I. Crohn's disease study from the Cleveland Clinic.

Clinical Original diagnosis

pattern 1966-1969

Ileocolic 252 (41.0%)

Small intestine 176 (28.6%)

Colon/ Anorectal 187 (30.4%)

TOTAL 615 (100%)

operation (Table ES.I) (2). Evaluation was made of quality of life as assessed by 502 patients with a mean 15-year follow-up (2). Questions directed to the patients related to their ability to function generally in comparison with their peers socially and economically; to the fre­quency and type of symptoms; to the frequency and type of medication used; and to the need for hospitalisation. Quality of life was considered good if the patient had normal or nearly normal function, in comparison to peer group, and had few, if any, symptoms and no regular use of medications; the patient was rated as fair if there was suboptimal overall functioning with symptoms or use of medications, or both, on a sporadic basis; and the patient was considered poor if there was impaired function with need for hospitalisation or regular use of medications, or both (Table ES.II).

Many patients were noted to function on a suboptimal basis. Patients who fared best were those who had under­gone one operation and who had no recurrence and those who had not required surgery. There was also a relation­ship between disease localisation and prognosis; patients who had the most favourable prognosis, with both fewer complications and better quality of life, were those with localised ileal disease or segmental colonic involvement. Among 50 patients with segmental colonic disease, 33 (66%) described their quality of life as good, whether or not they had undergone an operation. Of the 123 patients with ilea] disease location, 57 ( 46%) described their qual­ity of life as good, regardless of whether or not a resection had been necessary (2).

In the most recent study at the Cleveland Clinic, the long- term outcome of Crohn's disease was reviewed in 139 patients who were treated and followed for a minimum of 15 years with a mean of 23 years (Table ES. III) ( 10). At the time of diagnosis, 27%, 28%, and 45% of patients had small bowel, large bowel and ileocolic disease, respec­tively. A total of 122 patients (88%) underwent at least one definitive operation for the disease. As can be noted, the long-term complications included both renal and biliary calculi as well as short bowel syndrome, usually associ­ated with multiple operations.

Follow-up*

246 (97.6%)

165 (93.8%)

181 (96.8%)

592 (96.3%)

Patients with

operations

225 (91.5%)

108 (65.5%)

105 (58.0%)

438 (74.0%)

* Mean duration exceeds 13 years; minumum 7 years (adapted from Farmer RG, Whelan G, Fazio VW. Gastroenterology 1985;

88: 1818).

Vol. 5. No. 3. 1992 CROHN'S DISEASE 151

TABLE ES.II. Quality of life for patients with Crohn �isease.

Status Operated

Qualiry of life*

Good 149 (40%)

Fair 185 (50%)

Poor 37 (10%)

TOTAL 371 (100%)

Non-operated

69 (53%)

57 (44%)

5( 3'7c)

131 (100%)

*Good= normal or nearly normal functioning, with comparison to peer group: (I) few if any symptoms and (2) no regular use ofmedications.

Fair= suboptimal overall functioning with symptoms or use of medications, or both, on a sporadic basis.

Poor= impaired functioning, with need for hospitalisation or regular use of medications, or both.

TABLE ES.III. Crohn's disease long-term complications.

Small bowel disease

N= 38

Complications* N (%)

Ureteric calculi 8 (21)

Gallstones 6 (16)

Short bowel syndrome 4 (11)

Death 6 (16)

* Mean follow-up, 23 years

E6. Prognostic indicators

Despite continued efforts to find predictive factors indi­cating prognostic variability in Crohn' s disease, many aspects of the "natural course" of the disease remain unpredictable, although some generalisations can be made. Using the anatomical classification as the primary clinical characteristic of Crohn' s disease, a temporal relationship can be established, as well as a disease behavioural char­acteristic. The complications of Lhe di ea. e u ually are associated with a clinical event,. uch a. need for operation. Table E6. I attempts to illustrate the e event n a temp ral basis, also correlated with disease behaviour and di ea,e location. Disease which is diffuse has more of a "sys­temic" effect than does disease which is localised. In the experience at the Cleveland Clinic ( 1,2, 7-9 ), the indicators of a poor progno · is include sepsis, malnutrition, megacolon and absce ·; the indicators of a good prognosis include lo ali ed di. ea e particularly to the ileum or the colon.

Surgical intervention in Crohn' s disease may not be

Large bowel Ileocolic Total disease disease N= 39 N=62 N = 139

N (%) N (%) N (%)

3 (8) 12 (19) 23 (17)

3 (8) 10 ( 16) 19 (14)

2

(3) 2 ( 3) 5 ( 5)

(5) 2 ( 3) 10 ( 7)

preventable but may be predictable, which may help the physician communicate to the patient a realistic view of prognosis. Certainly, the mere presence of disease is not in itself an indication for sugery. Likewise, when surgical resection is indicated, extensive resection is usually not advisable because of recurrence (2,4,5,9). A recurrence study by Greenstein et al. ( 11 ), indicated that one could correlate disease activity based on "perforating and non­perforating indications" for operation, and that this classi­fication could be correlated with aggressive or indolent disease but appeared to be independent of anatomical distribution. However, in agreement with Cleveland Clinic studies, the indications for second operation were closely dependent on the indication for primary resection, thus emphasising the value of disease classification. This concept has been expressed recently by Sachar (12), not­ing that Crohn' s disease may follow at least two different patterns: "aggressive" disease characterised primarily by fistulae and abscesses, early requirement for surgery, and

152 SACHAR ET AL. GASTROENTEROLOGY INTERNATIONAL

TABLE E6.I. Crohn's disease complications.

Disease location Temporal relationship Disease activity --------------------

Early (less than 2 years)

Perianal disease

Early to mid course (0-5 years) ("aggressive'')

Fistula/abscess

Megacolon

Extra-intestinal

Late in course (more than 5 years) ("indolent'')

Obstruction

Renal and gallstones

"Chronic illness"

Cancer

relatively rapid fistulising-type recurrence; versus "indo­lent" disease characterised mostly by fibrotic stenosis and strictures, late requirement for surgery, and relatively slower obstructive type recurrence. However, as has been emphasised (13), prevention of death and significant mor­bidity remain the primary concern of the clini ian dealing with a patient who ha Crohn di ea e over a long period of time. This has been confirmed in a recent tudy by Andrews et al. (14 , who correlated mortality in rohn's disease with anatomical location and other factors, the most common causes of death being sepsis, digestive disease, cancer, pulmonary embolism, metabolic disor­ders; these occurred particularly after emergency surgical treatment.

E7. Comment

Based on the long-term studies at the Cleveland Clinic (1,2), the following observations can be made: the ana­tomical location of disease (clinical pattern) is a major determinant of clinical course, complications and reasons for operation in patients with Crohn's disease; although long-term mortality is similar among the three clinical patterns, morbidity is greater with ileocolic location of disease, particularly in terms of need for operation. Crohn' s disease is associated with site-specific complications, par­ticularly obstruction associated with small intestine loca­tion, fistula/abscess with ileocolic location, and megacolon with colonic location of disease. The most frequent complication overall is perianal disease, which is an early manifestation and is associated more with colonic and ileocolic patterns than with small intestine location of disease. The most favourable long-term prognosis is for patients with segmental colonic or localised ilea! disease.

There has been a considerable amount of attention to classification of Crohn' s disease, with anatomical location being a primary feature, along with disease activity and temporal factors. Holdstock et al. emphasised the differ­ences between Crohn's disease of the colon and of the small intestine (17), and Beaujerie et al. emphasised the disease activity/temporal relationship (16). The classifi-

cation of Crohn's disease along anatomical lines is in­tended to be a clinical one, to facilitate assessment of the clinical picture associated with the anatomical involve­ment, complications, indications for surgery, recurrences, and prognosis. As Lennard-Jones has recently stated, "anatomical classifications do not necessarily imply dif­ferences in aetiology" ( 17), but co1Telation of the anatomi­cal location of disease with clinical characteristics of Crohn's disease has proved to be a valuable form of clinical classification.

REFERENCES - APPENDIX E

I. Farmer RG, Hawk WA, Turnbull RB. Clinical patterns in Crohn'sdisease. A statistical study of 615 cases. Gastroenterology 1975;70:369-370.

2. Farmer RG. Whelan G, Fazio VW. Long term follow up of patientswith Crohn' s disease: relationship between the clinical pattern andprognosis. Gastroenterology 1985; 88: 1818-1825.

3. Mekhjian HS, et al. Clinical features and natural history ofCrohn's disease. Gastroenterology 1979; 77:898-906.

4. Hellers G. Crohn's disease in Stockholm County, 1955-1974. Astudy of epidemiology, results of surgical treatment and long termprognosis. Acta Chir Scand (S) 1979; 490: 1-84.

5. Truelove SC, Pena AS. Course and prognosis of Crohn's disease.Gut 1976; 17:192-201.

6. Steinhard HJ, Loeschke K, Kasper H, et al. European cooperativeCrohn's disease study (ECCDS): clinical features and naturalhistory. Digestion 1985; 31 :97-108.

7. Farmer RG, Hawk WA, Turnbull RB. Indications for surgery inCrohn's disease. An analysis of 500 cases. Gastroenterology1976; 7 I :245-250.

8. Lock MR, Farmer RG, Fazio VW, et al. recurrence and reoperationfor Crohn's disease: the role of disease location in prognosis. NEngl J Med 1981; 304: 1585-1588.

9. Whelan G, Farmer RG, Fazio VW, Goormastic M. Recurrenceafter surgery in Crohn's disease - relationship to location of disease (clinical pattern) and surgical indication. Gastroenterol­ogy 1985; 88:1286-1833.

10. Harper PH, Fazio VW, Lavery IC, et al. The long term outcomein Crohn's disease. Dis Colon Rectum 1987; 30:174-179.

11. Greenstein AJ, Lachman P, Sachar DB, et al. Perforating and non­perforating indications for repeated operations in Crohn' s disease:evidence for two clinical forms. Gut 1988; 29:588-592.

12. Sachar DB. The problem of postoperative recurrence of Crohn'sdisease. Med Clin N Amer 1990; 74: 183-188.

13. Sachar DB. Crohn's disease in Cleveland: a matter of life anddeath. Gastroenterology 1985; 88:1996-1997.

14. Andrews HA, Lewis P, AJlan RN. Mortality in Crohn's disease -a clinical analysis. Quart J Med 1989; 71 :399-405.

15. Holdstock G, Savage D, Harman M, Wright R. An investigationinto the validity of the present classification of inflammatorybowel disease. Quart J Med 1985; 54:183-190.

16. Beaugerie L, LeQuintrec Y, Paris JC, et al. Testing for coursepatterns in Crohn's disease using clustering analysis. Gastr ClinBiol 1989; 13: I 036-1041.

17. Lennard-Jones JE. Classification of inflammatory bowel disease.Scand J Gastroenterol 24 1989; 170:2-6.

Appendix F. Proposed classifications of Crohn's dis­ease: therapeutic implications

Fl. Diet

Total parenteral nutnt10n (TPN) is effective in acute diffuse Crohn' s colitis ( 1) but is less effective in treatment of disease activity. It may allow bowel rest to promote

Vol. 5, No. 3, I 992 CROHN'S DISEASE 153

healing in more localised aggressive disease with fistula formation or in diffuse small bowel disease. Elemental diet improves nutritional status and alleviates disease activity (2,3) and in some cases the remission is main­tained ( 4) but it is not effective in localised distal colonic or perianal disease (5).

F2. Drug treatment

Steroids are better than placebo in the active phase of both small bowel and colonic disease (6,7) but are of no value where there is long-standing stricture formation. Topical steroids are effective in the rectum and sigmoid. Anti­inflammatory agents such as 5-aminosalicylic acid (sulphasalazine, mesalazine, olsalazine) are effective in maintaining remission in colonic Crohn's disease and are marginally better than placebo in diffuse jejunoileitis, but have little value in the acute phase. Metronidazole is also helpful in colonic Crohn's disease and where there is bacterial overgrowth due to stasis, e.g. blind loop or dilatation between multiple strictures (8). It is most valuable in perianal sepsis (9) and may be of value in containing intra-abdominal sepsis while the patient awaits definitive surgery. Immunosuppressives (6-mercaptopurine, azathioprine, methotrexate and cyclosporine) have all been shown to be useful in main­taining remission in colonic Crohn's disease and where there are perianal fistulae (10). Except for cyclosporine, they require a mean of three months to be effective and their side-effects sometimes limit widespread long-term use.

F3. Surgery

Most patients with Crohn' s disease will undergo at least one operation during their lifetime. This observation is supported by studies from centres all over the world ( 11-14 ). Surgery is undertaken for the complications of Crohn's disease. These include obstruction, perforation, bleeding and non-response to intensive medical therapy. The likelihood of a patient undergoing surgery largely depends on the location and clinical behaviour of the disease (13-15). Symptomatic gastro-duodenal disease results from strictures in the second or third part of the duodenum. Surgical treatment (by-pass with gastrojejunostomy or strictureplasty) is reserved for se­vere persistent symptoms. Diffuse small bowel disease (jejuno-ileitis) will usually respond to corticosteroid ± immunosuppressive treatment but healing with fibrous stricture may be the long-term result and obstructive symptoms may supervene and require surgical interven­tion. Minimal resection or strictureplasty is the treatment of choice and careful examination of the whole small bowel is necessary at laparotomy to exclude other stric­tures (16). Many patients with terminal ilea] disease will have fibrous strictures at presentation and minimal resec­tion for localised disease or strictureplasty for widespread strictures is the treatment of choice (16, 17), giving good symptomatic relief. More aggressive disease will result in perforation of the gut wall with local abscess or fistula formation. An abscess needs to be drained and resection

of the associated diseased bowel undertaken ( 17). Macro­scopic disease associated with persistent enterocutaneous fistula is an indication for surgical treatment but entero­enteric fistula may persist harmlessly for years unless the associated stenotic disease itself requires excision (18). Ileovesical fistula may cause distressing cystitis and re­quire early operative intervention, although medical therapy is also possible (19). Some workers have shown (20, 21) that re-operation on these patients with aggressive perfo­rating complications occurs earlier and for the same com­plication.

Ileocolonic disease with involvement of the caecum and ascending colon is managed in the same way as ileocaecal disease alone. Fibrous strictures are usually the cause of symptoms. This is a common site in the elderly and usually runs a benign course but occasionally may neces­sitate urgent surgery for colonic perforation occurring either at presentation or during follow-up (26). Surgery may be delayed because it is not definitive treatment and recurrence can develop. Most recurrences are confined to the short segment of gut around the anastomosis and are easily dealt with. Nevertheless, recurrence is the ex­pected outcome and the rate will vary with the anatomical site of disease and the type of operation originally per­formed (27). Recurrence should not be a deterrent to surgery since it offers most patients many years of good quality life.

REFERENCES - APPENDIX F

J. Matuchanisky C. Parenteral nutrition in inflammatory bowel disease.Gut 1986; 27:81-84.

2. Rocchio MA, Mocha CJ, Haas KF. Use of chemically defined dietsin the management of patients with acute inflammatory boweldisease. Am J Surg 1973; 127:469-475.

3. Voitik AJ, Echave B, Feller JH. Experience of elemental diets inthe treatment of inflammatory bowel disease. Is this primarytherapy? Archives Surgery 1973; J 07:329-333.

4. Le Quintrec Y, Cosnes J, LeQuintrec M, et al. Alirnentationenterale elementaire exclusive dans Jes formes corticorestantes etcorticodependatens de la malaide de Crohn. Gastroenterol UniBiol 1987; 11:477-482.

5. Sanderson lR, Udeen S, Davies PSW, et al. Remission induced byelemental diet in small bowel Crohn's disease. Arch Dis Child1987; 61:123-127.

6. Malchow H, Ewe K, Brandes JW et al. European co-operativeCrohn's disease study: Results of treatment. Gastroenterology1984; 86:249.

7. Summers RW, Switz DH, Sessions JT, et al. National co­operative Crohn's disease study: Results of drug treatment. Gas­troenterology 1979; 77:847.

8. Rosen A, Ursing B, Alm T, et al. A comparative study ofmetronidazole and sulfasalazine for active Crohn's disease. Theco-operative Crohn's disease study in Sweden. I. design andmethodologic considerations. Gastroenterology 1982; 83:541-549.

9. Bernstein LH, Frank MH, Brandt LJ, et al. Healing of perinea]Crohn's disease with metronidazole. Gastroenterology 1980;79:357-365.

10. Nyman M, Hansson I, Eriksson S. Long term immunosuppressive treatment in Crohn 's disease. Scand J Gastroenterol 1985; 20: 1197-1203.

11. Greenstein AJ. The surgery ofCrohn's disease. Surg Clin North Am 1987; 67:573-592.

12. Greenstein AJ, Meyers S, Sher L, et al. Surgery and its sequelae

154 SACHAR ET AL. 0ASTROENTEROLOGY INTERNATIONAL

in Crohn's colitis and ileocolitis. Arch Surg 1981; 116:285-288. 13. Mekhjian HS. Switz EM, Watts HD. National co-operative

Crohn 's disease study. Factors determining recurrence of Crohn · sdisease after surgery. Gastroenterology 1979: 77:907-913.

14. Cooke WT, Mallas E, Prior P, et al. Crohn's disease. Course.treatment and long-term prognosis. QJM I 986: 49:363-384.

15. Farmer RO. Hawk WA. Turnbull RB. Indications for surgery inCrohn · s disease. Analysis of 500 cases. Gastroenterology 1976:71 :245-250.

16. Alexander Williams J, Haynes IO. Up to date management of small bowel Crohn's disease. Adv Surg 1987; 20:245-264.

17. Higgens CS, Allan RN. Crohn's disease of the distal ielum. Gut1980: 21 :933.

18. Give! JC, HawkerP. Allan R, Keighley MRB, Alexander Willams J.Entero-enteric fistula complicating Crohn's disease. J ClinGastroenterol l 983: 5:321-323.

19. Greenstein AJ, Sachar DB, Tzakis A. et al. Course of enterovesical

fistulas in Crohn's disease. Am J Surgery 1984; 147:788-792.20. Greenstein AJ, Lachman P, Sachar DB, et al. Perforating and

non-perforating indications for repeated operations in Crohn'sdisease incidence for two clinical forms. Gut 1988; 29:588-592.

21. Whelan G, Farmer RG, Fazio VW, Goormastic M. Recurrenceafter surgery in Crohn's disease. Gastroenterology 1985; 88: I 826-1833.

22. Andrews HA, Lewis P, Allan RN. Prognosis after surgery forcolonic Crohn 's disease. Br J Surg 1989; 76: 1184-1190.

23. Goligher JC. Surgical treatment of Crohn's disease affectingmainly or entirely the large bowel. World J Surg 1988; 12: 186-

190.

24. Scammell B. Ambrose NS, Alexander-Williams J, et al. Recur­

rent small bowel disease is more frequent after subtotal colectomyand ileorectal anastomosis than after proctocolectomy. Dis ColonRectum 1985: 28:770-771.

25. Longo WE, Ballantyre GI, Calhow CE. Treatment of Crohn'scolitis. Segmental or total colectomy? Arch Surg 1988; 123:588-

590.26. Fabricius PJ, Gyde SN, Shouler P, Keighley MRB, et al. Crohn's

disease in the elderly. Gut 1985: 26:461.27. Sachar DB. The problem of post-operative recurrence in Crohn's

disease. Med Clin N Amer 1990; 74: 183-188.

CONCLUSION

In conclusion, the response of patients with Crohn' s dis­ease to the various modes of medical and surgical treat­ment supports a new classification of Crohn's disease which takes in account the anatomical site, the disease behaviour, and the operative history in the individual patient. Such a classification may pave the way for a more unified approach to management.

ACKNOWLEDGMENT

This study was supported in part by an educational grant provided by BRACCO S.p.A., Milano, Italy.