SURGERY
`Gynecology
`& Obstetrics
`
`810MfOJCA1 LIBRARY
`JAN14 1985
`
`UNIVI:.tl;)l 1 V OF ll/U.it-URNIA
`lOS ANGELES
`
`JanUalJl 1985 VOLUME lGO · NUMBER 1
`
`Cosmo Ex 2017-p. 1
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`I,
`ft
`
`DIFFERENCES IN PATHOGENESIS, INCIDENCE AND
`
`OUTCOME OF PERFORATION IN INFLAMMATORY
`
`BOWEL DISEASE
`
`A. J. Greenstein, M.D., F.R.c.s.(EDIN.)(ENG.), F.A.c.s., and
`A. H. Aufses, Jr., M.D., F.A.c.s., New York) New York
`
`PERFORATION is an uncommon but lethal com(cid:173)
`plication of inflammatory intestinal disease. It
`occurs more frequently in ulcerative colitis than
`in Crohn's disease irrespective of whether the
`latter originates in the small or large intestine.
`Despite early reports to the contrary (1), perfor(cid:173)
`ation in ulcerative colitis is usually preceeded by
`colonic dilation (2-6). In Crohn's disease,
`perforation without dilation of the small or large
`intestine is more common (7). The incidence and
`outcome of perforation with and without toxic
`megacolon in the two forms of' inflammatory in(cid:173)
`testinal disease are compared herein.
`
`MATERIAL AND METHODS
`The records of 1,623 patients with inflamma(cid:173)
`tory intestinal disease admitted to TJ:le Mount
`Sinai Hospital between 1960 and 1980 were re(cid:173)
`viewed retrospectively : there were 613 patients
`with ulcerative colitis (UC) and 1,010 with
`Crohn's disease (CD). Of the patients with CD,
`457 had ileocolitis (IC), 166 had Crohn's colitis
`(CC) and 387 regional enteritis (RE). Seventy(cid:173)
`five p a tients had colonic dilation, 61 with UC and
`14 with CD, and 29 patients with UC and 20 pa(cid:173)
`tients with CD had either a free or sealed off per(cid:173)
`foration.
`
`DEFINITIONS
`The diagnosis of granulomatous disease was
`based upon criteria published previously (8-10).
`The clinicopathologic diagnosis of ulcerative co(cid:173)
`litis was made on the basis of mucosal colitis ex(cid:173)
`tending proximally from the rectum in the ab(cid:173)
`sence of transmural disease, fissures, fistulas or
`skip areas. Free perforation was defined as spon(cid:173)
`taneous rupture of the small or large intestine
`
`the Depart~nt of Surgery, Mount Sinai School of
`From
`Medicine of the City University of New York and The Mount Sinai
`Hospital , New York.
`Reprint requests: Dr. Adrian J. Greenstein, tvlounl Sinai !Vledi(cid:173)
`cal Center, One Gu stave L. L evy Place, New York , New York
`10029.
`
`with spillage of intestinal contents into the gene(cid:173)
`ral peritoneal cavity and resulting peritonitis. A
`sealed perforation was occasionally recognized
`preoperatively as a tender palpable mass and es(cid:173)
`tablished at laparotomy as an area of localized
`perforation sealed by adherent mass of omentum
`or peritoneum. Toxic dilation was based upon
`criteria similar to that described in one study (4)
`and included one or more of these findings: ab(cid:173)
`dominal distension, signs of peritonitis, tempera(cid:173)
`ture of more than 101 degrees F., tachycardia of
`more than 120 per minute and a leukocyte count
`of more than 11,000 white blood cells per mil(cid:173)
`limeter cubed . The diagnosis of colonic dilation
`was accepted if the colon measured 6.0 centime(cid:173)
`ters or more in diameter on a roentgenogram or
`6.5 centimeters in diameter on barium enema.
`Mortality was defined as a death occurring dur(cid:173)
`ing the same hospital admission. Analysis of the
`ulcerative colitis and Crohn's disease data (Table
`I) was calculated using the programmed 2 XK chi
`square contingency table of a 9815A Hewlett(cid:173)
`Packa rd calculator.
`
`RESULTS
`P erforati on in ulcerative co litis. Twenty-nine
`of 613 patients with ulcerative colitis (4.7 per
`cent) sustained a perforation (Fig. 1). Twenty(cid:173)
`two of these occurred among 61 patients with
`toxic dilation (TCD) (36 per cent). Seven occur(cid:173)
`red among the remaining 552 patients without
`toxic dilation (1.3 per cent).
`Thirteen of 29 patients with UC died; nine of
`22 with TCD and four of seven without TCD.
`Among the patients with TCD, 13 sustained a
`free perforation with five deaths and nine a sealed
`perforation with four deaths. Thus, the mortality
`was similar for patients with and without toxic
`colonic dilation and was also similar irrespective
`of whether the perforation was free or sealed at
`the time of operation. All pati ents with free per(cid:173)
`foration except one were operated upon within
`
`Cosmo Ex 2017-p. 2
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`64 Surgery, Gynecology & Obstetrics
`
`TOTAL NO. OF CASES
`1623
`
`I
`J
`
`Crohn 's Dl.eau•
`1010
`
`t
`
`Coli lis
`161)
`
`+
`
`Enlcnlis
`387
`
`lleocolills
`~57
`
`Ulcerative CoHill
`613
`
`j
`
`Ulcer alive CoHiis
`613
`I
`
`J
`Toxic Oilalalion
`61
`
`n
`~
`
`Pcriorated
`22
`
`NonP.
`39
`
`~
`
`Dealhs
`1(26%)
`
`Doalhs
`9(41%)
`I
`
`Non-TO
`552
`
`+
`~
`
`p
`7
`
`~
`Deaths
`4(!j7%)
`I
`
`Morlalily 13129 P (45%)+
`
`623
`I
`
`Toxic D•lalal•on
`
`~
`·~
`n
`
`P.
`3
`
`Non P.
`11
`
`~
`
`~
`
`Deaths Deaths
`2(67%)
`0(0%)
`I
`
`Non TO
`609
`
`~
`
`P.
`IP
`
`Dcolhs
`0(0%)
`
`~
`t
`
`january 1985 · Volume 160
`consistent with disseminated intravascular coag(cid:173)
`ulation (DIC). Dy contrast, DIC developed in
`only two of nine patients with a perforated UC
`and toxic colonic dilation who later died. Per(cid:173)
`forati n in patients wi th toxic megacolon w as
`likely l be multiple and occured predominantly
`(52 per ent) in the transverse olon in luding the
`hepati and spl eni c flex ur s; 20 per cent oc urred
`in the sigm id colon.
`Perjo1·ation in C1·ohn 's disease. A free perfora(cid:173)
`tion develop d in twenty of 1,010 patients with
`rohn's disease (2 per cent) (Tabl e II a nd Fig. 1).
`Fourteen o _,cnn·ed a mong 623 pa tien s with co(cid:173)
`lonic involvement (CDC), four developed in 387
`patients with regional nt ,ritis (R E) and two pa(cid:173)
`tients had p rfora tions thro ugh at· as of rec trrent
`dis a
`( n in th e: ileum pt·oxima l t an ile stomy
`a nd n e in th e sigmoid colon) . rl. oxi dilation c(cid:173)
`C a nd c(cid:173)
`Ct.t rr d in 14 of 623 palicnls with
`lonic involvem nt (2.24 .per cent) ; five o urr din
`il eocoli tis (1.1 1 er cent.) and nine in granulom a(cid:173)
`tou s coli is (5.4 per cent) . Perfora tion occurred in
`three of 14 pa tients with
`and taxi dilation .
`One perforation was fre and Cwo wer
`sea l d.
`he two patients with se~ l ecl p rforations a nd
`toxic ·oloni dilation di d. I he ne pa tient w ith
`h
`fre-e pt!rfora tion su.t·vived.
`Among Lh 609 p atients with CDC, sponta(cid:173)
`n ou · f're 1 rforation with peritonitis occurred
`in an addi tio nal 'I 'I p ti en ts (nine in the colon
`alone, one irl Lh
`ileum al.on e and one synchro(cid:173)
`nously in th
`il · um and colon) without mOt'tality.
`Seven were sing! p •rforatious; one ha d four si(cid:173)
`multaneous synchronous perfora tions of ascen-
`
`P.
`4(SB)
`
`~
`
`Dcalhs
`0(0%)
`I
`
`Monahty 2'18 P (11%)t
`
`in ·idcn<:t:s of perforation a nd
`• JG. '1. omparison of lh
`mortality in 61 3 patients wilh ul crative coliti s a nd I ,010
`p a ticn LS with Crohn 's di sease. •, Two a dditiona l dcn ths in
`perfon1Lion in l'CCun·cnt ell seas · in ileocolitis, o ne in the
`small int cstin and one in the col on. 't. Ten coloni c (one with
`two ileal perforations), one small intestine. t, In perforated
`instances (excluding recurrent disease*).
`
`one to nine hours of the presumed perforation,
`whereas the patients with a sealed perforation
`had severe symptoms for an average of two days
`before operation.
`In UC without colonic dilation, massive bleed(cid:173)
`ing developed in four patients with perforation
`who later died. Three had a decreased platelet
`count and increased partial thromboplastin time
`
`TABLE I.-A CO MPARISON OF INCIDENCES OF TOXIC MEGACOLON , PERFORAT ION AND MORTALITY IN
`ULC ERATIVE C OLITIS AND CROHN 'S DISEASE
`U.C.
`Pe1· cent
`C. D.
`Percent* C. D.C. Percen tt
`
`P value
`
`X'
`
`Toxic megacolon
`UC versus CD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 1/ 613
`UCvcrsusCDC .. . .. .. .. .. .. . . ..... .. . . . .... . 61/613
`UC versus CC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 1/613
`UC versus IC. ........... .. ...... . . . . .. .. . .. . 61/613
`Perforati on
`All . . .. . . . ...... . . ... ... .. ... .... . . . . ... . .. .
`C olon .... . ... . ........ .. ... . .. . ... . ... .. . . · ..
`OfTM .. . . . . ... . . . . . ... . ...... . .... . . . .. .. .
`TnTMt .......... . . . . . .. . ........ . ... .. .. . .
`Mortality
`Perfora tion of colon ......... . ... . ... . ........ .
`Free perfora tion , no TM .. . . . . .... .. ... . ... ... .
`Free perfora tion§ , no TM ... . ..... . ...... . . . . . .
`Perfora tion in TM . .. : .... . .. . ... . . . . . . .. . ... .
`All primary perforation . .. . ... . .......... . .... .
`All pLrforations' . . . ... . ... . . . . . . . . . . . . . .
`UC; Ulcerative t'Oiitis, 613 pn1.ioms.
`·co, C rohn's disease, 1010 p3ticnts.
`tCOC, Crohn 's colili~ (CC), n<i ileocol itis (JC), 623 patients.
`t T M , Toxic megacolcm, 75 patienu-6 1 UC an d 14 CDC .
`§Free pc:rfonuion wit hout to:><! rnegacolnn in 20 pa ti ents.
`,'ln (~lud cs fwo mortnli1ics i l'\ it:C.u rrcnc Crohn's disease.
`"Fa iled lo rea ch stati stica l significance.
`
`13/613
`4/7
`4/7
`9/22
`13/29.
`13/29
`
`29/613
`29/613
`22/613
`22/61
`
`,,.l u(
`
`10
`10
`10
`10
`
`4.7
`4.7
`3.6
`36
`
`2
`57
`57
`41
`45
`45
`
`14/ 10 10
`
`1. 4
`
`20/1>010
`
`2.0
`
`0/15
`
`2/18
`4/20
`
`0
`
`11
`20
`
`14/623
`9/166
`5/457
`
`13/623
`3/623
`3/14
`
`3/623
`0/10
`
`2.2
`5.4
`1.1
`
`2.1
`0.5
`21
`
`0.5
`0
`
`2/3
`
`67
`
`0.001
`63.49
`0.001
`30.1
`3.28 NSt
`0.001
`35 .49
`
`. [
`
`9.9
`6.2
`14.4
`2.83
`
`6.3
`7.47
`10.47
`0.71
`5.81
`3.22
`
`0.005
`0.02
`0.005
`NS
`
`0.02
`0.01
`0.005
`NS
`0.02
`NSb
`
`I .
`
`Cosmo Ex 2017-p. 3
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`Greenstein and Aufses: PATHOGENESIS, INCIDENCE AND OUT COME Of PERFORATION 65
`
`ULCERATIVE
`COLITIS
`
`CROHN'S
`COLITIS
`
`I LEO-
`COLITIS
`
`ULCERATIVE
`COLITIS
`
`CROHN'S
`(ILEO)COLITIS
`
`w
`(_)
`z
`w 10
`0
`(_)
`z 8
`w
`<.9 6
`f=!
`z
`w 4
`0:: w 2
`
`o._
`
`(_)
`
`~ 10
`z
`w
`0
`u 8
`z
`w
`(.9
`<(
`
`6
`
`1-z
`w
`u
`0:: w
`0...
`
`4
`
`2
`
`I
`I
`!.
`I
`
`I
`I•
`I
`
`0
`To xi c
`megac olon
`61
`1
`Total cases 613
`(10%)
`
`9
`166
`(5.4%)
`
`5
`457
`(1.1%)
`
`. 3. Toxic megacolon is significantly more common in
`· t
`ulcerative colilis than in ilcocolitiR <md
`rohn's ·olitis thaJa
`in ilc coliLis. Although Lhc incidence is approximately twice
`as high in u l ccr~uiv olitis than in Cr hn's olitis, a sig(cid:173)
`nificant diiTcrcn .e could not be demonstrated.
`
`other two had suture and proximal colectomy and
`exteriorization with proximal colostomy, respec(cid:173)
`tively.
`A comparison of the incidence of toxic megaco(cid:173)
`lon in UC and CD. In this ~cries, the incidence of
`toxic megacol · n was signifi antly greater in UC
`c 01. rc (Fig. 3). In ad-
`Lhan in
`(Fig. 2),
`of tox ic megaco lon was
`diLion, Lhe
`inciden
`sigrufi antly gre< Ler for
`rohn'
`co li tis when
`compared with patients with ileocolitis (nin of
`166 versus five of 457,
`F = 1; X 2=10.38; p<
`0.001) (Fig. 3). How v ·r, wb n patients with
`d isease oniin d to the colon w r compared, al(cid:173)
`was almost twice as
`lhougb coloruc dilation in
`common as in CC (UC 10 versus CC 5.4 per
`cent) a significant difference in TCD could not be
`demonstrated (Fig. 3) (Table I).
`A comparison of pe1jorations of large or smaLl
`intestine. In UC, the incidence of perforation was
`
`TABLE !I.-PERFORATION IN CROHN'S DISEASE ALL
`CROHN'S DISEASE 20 OF 1,010
`
`_COLITIS AND ILEOCOLITIS-
`N=16 of 623
`
`O L..-.--.....IU£o~--____._.~ _ __,
`Tox ic
`megacolon
`Total cases
`
`14
`61
`613
`623
`(10%)
`(2 .2 %)
`FIG. 2. A sign ificant grea te'r incidence of toxic megacolon
`in u lcerative coli tis than in Crohn 's disease involving the
`col on is shown (C roh n's disease and ileoco litis).
`
`ding, transverse, descending and sigmoid colon,
`and one had metachronous perforations each in
`the descending colon.
`Four of 383 pati nts with regional enteritis
`(1.04 per cent) sustained a spontaneous fre - per(cid:173)
`foration. r wo 0 curred in the jejunum in j juno(cid:173)
`ileitis and two in th
`ileum in 1·egiona l ileitis. All
`four pat ients had evid nee of dilation with stric(cid:173)
`ture distal to the site of perforation. Three had a
`segmental small intestine or ileocolic resection
`and one resection with ileostomy and distal mu(cid:173)
`latter underwent subs q uent
`cous fistu la. Th
`su ce sful reanastomosis. The f ur patients sur(cid:173)
`vived, as did the patient with synchronous ileal
`and colon ic perforations. 'I hus, the 15 patients
`with spontaneous free perfora.ti n w ith perito(cid:173)
`njtis without toxk coloni dilation in CD all SUI' (cid:173)
`vived; this compares favorably with two deaths
`among
`three patients with
`toxic dilation in
`Crohn's disease and nine deaths among 22 pa(cid:173)
`tients with toxic colonic dilation in UC.
`Management of patients with perforation. Nine
`of 11 patients with colitis or ileocolitis in Crohn's
`disease had resection with a proximal diverting
`ileostomy in eight and a colostomy in one. The
`
`_REGIONAL ENTERITIS_
`N=4 or 387
`
`No .
`2
`2
`
`S ite
`Ileum
`Jejunum
`
`No.
`Site
`1
`Ileum
`10
`Colon*
`3
`Colon with TM (2t)
`2
`Recurrent disease (2:f:)
`... One with two concomitant ileal perforations.
`tlviortalitics: 2 of three in toxic megacolon-sealed perforations.
`tOoth with recurrcnl disease-rrec perfonuions (one ileum and one colon).
`TM, Toxic megacolon.
`
`Cosmo Ex 2017-p. 4
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`',
`
`\'
`I
`q ,.
`
`t'
`
`I.
`
`1
`1 1 '
`'i
`
`'I
`I
`
`66 Surgery, Gynecology & Obstetrics · January 1985 · Volume 160
`
`PERFORATIONS
`TOTAL
`WITH
`COLON
`TOXIC MEGACOLON
`PERFORATIONS
`~ Ulcerative colitis
`
`w
`u
`z
`w
`0
`u z
`w
`(9
`~
`~ 2
`u
`a::
`w
`a_
`
`w
`u
`z 40
`w
`0
`u
`z 30
`w
`(.9
`~ 20
`z
`w
`~ 10
`w
`()_
`
`ULCERATIVE
`COLITIS
`
`CROHN 1S
`( ILEO)C.OLITIS
`
`NS
`
`o ~--~~~----~~~~--~
`Perfora tions
`29
`13
`22
`3
`Total cases
`613 623
`613 623
`(4.7%) ( 2.1%)
`(3.6%)(0.5%)
`FIG. 4
`
`0 '--...LL.tti.~--___J,;_,:,:,;:..!..!..I..-_ _}
`Perforations
`3
`22
`14
`61
`(21%)
`(36%)
`F IG. 5
`
`Toxic megacolon
`
`F1o. 4. A signflcantly greater incidence of total colonic perforation and perforation with toxic
`megacolon in ulcerative colitis compared with Grahn's disease involving the colon is ·shown (colitis
`and ileocolitis) when considered as a proportion of the total series.
`Fm. 5. Perforation in toxic megacolon is not significantly different in ulcerative colitis and
`Crohn's colitis involving the colon when it is considered as a proportion of all patients with
`megacolon.
`
`28 times as frequent in patients with TCD than
`in those without; compared with ten times the
`frequency in patients with CD and TCD (Table
`I). Within the context of the total series, colonic
`perforation in patients with disease confined to
`the colon and patients with perforation in toxic
`megacolon were both significantly greater in pa(cid:173)
`t~ent~ with UC (Fig. 4). The increase in perfora(cid:173)
`tiOn m UC was due to the higher incidence and
`proportion of toxic megacolon in UC and prob(cid:173)
`ably also to the higher proportion of perforation
`in patients with UC and TCD (36 versus 21 per
`cent) (Fig. 5). However, if one examines only the
`7 5 patients with toxic megacolon with UC and
`CD, although the proportion of patients who had
`perforations was almost twice as great in the
`~orme:, the difference was not statistically signif(cid:173)
`Ica~t m this series (Fig. 5). The incidence of co(cid:173)
`lome perforation in the absence of toxic megaco-.
`Ion was similar in the twu series (seven of 552 for
`UC, 1.2 per cent versus 11 of 607 with, CDC, 1.8
`per cent).
`C:omparison of mortality'. The over-all mor(cid:173)
`tahty for perforations of the colon as a proportion
`of the total series was four times greater in UC
`
`than in CDC (2 versus 0.5 per cent) and the dif(cid:173)
`ference was statistically significant (Table I). If
`one examines all 47 primary spontaneous per(cid:173)
`forations, omitting the two deaths which occurred
`with recurrent disease, there is a significant dif(cid:173)
`ference in mortality between UC and CD (Fig.
`6). With the addition of the two perforations in
`recurrent Crohn's disease, the results of the chi
`square te t fail lo reach statistical signifi anc .
`Mortality was signi(icantly grea Ci' in pati nts
`with perforation in U
`than
`in
`those with
`!'ohn'. dis a. e in both the ver-all series and in
`the absenc~ of toxic megacolon, but not in toxic
`mega olon if extlmined separately. A comparison
`of fre p rforation in, lh absen e of taxi dilation
`revealed a highly significan difr renee between
`the two gmups (Fig. 7). More than ne-1 alf of
`th patients with UC di d-
`four of sev n pa(cid:173)
`tients, 57 per c nt.
`h_is inci.de-n
`is comparable
`wilh the 41 per cent morta lity for perforation in
`\.vith toxic rn gac Ion. All 15 patients with
`Crohn's dis asc (including. all
`n patients wiLh
`fre coloni perforation and fiv with free small
`intestin a l perforflticm) (Table II) survived (Fig.
`7.) MMtality was no differ nt in Loxic m gacolon
`
`I
`(
`
`Cosmo Ex 2017-p. 5
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`Greenstein and Aufses: PATHOGEN ESIS, INCIDENCE AND OUTCOME OF PERFORATION
`
`67
`
`ULCERATIVE
`COLITIS
`
`CROHN'S
`DISEASE
`
`w ~50
`u
`z
`w
`0 40
`u
`z
`w 30
`<.9
`~
`z
`20
`w
`u
`0::
`w
`0..
`
`10
`
`WITHOUT
`WITH
`TOXIC MEGACOLON TOXIC MEGACOLON
`~ Ulcerative ~olitis
`' [2] Crahn's (ileo)colitis
`
`0
`0
`v
`Q..
`
`100
`
`LLl
`
`u z
`w
`0 u
`z
`w
`<..!)
`~ z
`w
`u
`0:::
`w
`0...
`
`0
`2
`9
`Deaths
`3
`No. of perforation s 22
`(4 1%) (67%)
`
`0
`4
`10
`7
`(57%) (0%)
`
`0 L--_,__...4A-__-~ ............... L . . - - -1
`2
`Deaths
`13
`18
`Perforations
`2 9
`(45'%)
`(II%)
`
`F rt;. 7. The morta li1y of 42 palients with colon ic pc l'fora(cid:173)
`tions is sig ni fica ntly greater in pr·ima ry perfora tion of the in(cid:173)
`testine wi thout toxi c megacolon in ulr.crativc colitis tl a n in
`rohn 's disease in volving the colon . In toxic megacolon, the
`mo rta lity was equally hig h, a llhoug h there were on ly ~hrce
`such 1 a ticm s
`in
`the gr oup of pa ti ents wilh
`.rolm'
`di sease.
`
`F10 . 6. Mortality was significa ntly greater in primary per(cid:173)
`forations of the intestine in ulcerative colitis than in Crohn's
`disease when 29 patients with ulcerative colitis are compared
`with 18 patients with Crohn' s disease.
`
`in the patients with UC compared with those
`with Crohn's disease or in patients with UC with
`free perforation compared with those with sealed
`perforations. We have no explanation for the
`remarkable cl iff r nee in . urviva l in fr e perfora(cid:173)
`tion in the ab n ~e or Loxic megacolon in UC and
`CD, but it ma y b du e lo differing immunologic
`states or pathogeneti · mecha nisms.
`
`DISCUSSIO N
`was r cogniz d
`P erf ra tion of the olon in
`in 187 5 (11). The associa tion of p rf ra tion with
`tox ic megacolon w as no din 1955 (1 2) and sin e
`that time t.h r ha v
`I een m a ny repons of this
`association.
`Although it h as been suggested that Morgagni,
`in 1769, gave us the first description of Crohn's
`disease with free perforation (13), others are
`skeptical of the actual nature of the original in(cid:173)
`stance which Morgagni described . Janowitz be(cid:173)
`li eves Crohn's disease to be a disease of recent
`onset (14). The first perforated abscess
`in
`Crohn's disease was described from this institu(cid:173)
`tion in 1935 (15). Free perforation of the colon in
`
`Crohn's disease was described in 1965 (16). Since
`then an additional 15 instances have been repor(cid:173)
`ted (17).
`In one study, 32 publications which reported
`upon 604 patients with toxic colonic dilation in
`UC were reviewed (18) . One hundred and four(cid:173)
`teen patients or 19 per cent had perforations with
`a mortality in surgically treated patients of 41.2
`per cent compared with 8.8 per cent associated
`with patients without perforations (18).
`In 1960, 16 instances of colonic dilation in UC
`were reported; in retrospect, two patients clearly
`had Crohn's disease (19) . There have since been
`r ep ort of tox:i · mega olon in
`rohn's disease
`(20- 22) , wi th a n inciden e of T M as high as 20
`p er enl (23). Colonic p erforation in U C in th
`a bsence of toxi c dilation is t·e!ativ ly !'a re (2-6) .
`P el'for a tion w ithout dilation of the la rge or· small
`intestine is more frequent in C r ohn's disease a nd
`
`TABLE Ili.- PERFORATION WITH AND WITHOUT
`TOXIC MEGACOLON IN ULCERATINE COLITIS
`__ Toxic megacolon_
`Yes
`No
`Total
`
`Lumb and co-workers (12), 1955 ... .• .
`Edwards an d T r uelove ( 1 ), 1964 . . . . . .
`Goligher and co-workers (27), 1970 . . . .
`Block and associates ( 6 ), 1977. . . . . . . . .
`Albrechtson and co-worke rs (5) , 198 1 . .
`Presen t series, 1983 . . . . . . . . . . . . . . . . .
`
`1
`2
`38
`4
`61
`
`19
`6
`1
`0
`7
`
`20
`8
`39
`4
`68
`
`Cosmo Ex 2017-p. 6
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`l(f,
`
`I
`i
`
`68 Surgery, Gynecology & Obstetrics · January 7985 · Volume 760
`may occur in both the large and small intestines
`48 hours after admission to the hospital. At-
`(7, 17, 24, 25).
`hough nono erative management remains the
`first therapeutic modality fo1· toxi ' colonic dila(cid:173)
`The relationship of perforation to TCD is ex(cid:173)
`amined in Table III. In 1964 (1), 624 patients
`tion, the pati nt must b · t.:arfully monitored by
`I oth the gastroent rologist and urgeon. If mor(cid:173)
`with UC were reported upon. 1 he incicl nc of
`fr e perforation was 3.2 p r c n and the inci(cid:173)
`tality is to be avoid · d, then surgi al treatment
`denc, of toxic mega~olon wa • 1.6 per cent. Nin -
`must be carried out early if there is n
`immediate
`teen of 20 patients had perforation develop with(cid:173)
`response to primary therapy.
`out vid nc of colonic dilation and 75 per cent of
`oloni · perforation remains a highly letha l
`the. patients died (Table III). Ten were diag(cid:173)
`complication of inflamma tory intestinal disease,
`nos d at autopsy. Thu , it is possible that thes
`particularly in th pr· s nee of toxic colonic dila(cid:173)
`p·Hj .nt may well have had coloni c dilation and
`tion. Excellent survival is possibl
`in
`.rohn's dis(cid:173)
`perforation of a dilat d intestine prior to their
`ease without TCD. The remarkable difference in
`death. However, three of nine pati nts with toxic
`urvival in patients with fr
`perforation and )JCJ'(cid:173)
`megacolon died. An aut< p ·y was perf rmed upon
`itonJtls 111 D ompared with C is difficult to
`understand. It may reflect differing immunologi
`two, find th ·re was no evid nc · of p rl'oration in
`slates. It may a lso indi at diffel'ing 1 athogeneti
`any of the patients. In 1965, 465 patients with
`i Lh
`UC w r studied (26) and a so ·iatcd toxic dila(cid:173)
`l1 anisms. Perforation in
`nd result
`m
`tion in five r 13 patients who had 20 ::;ep r t
`of slowly progressive fissure formation culminat(cid:173)
`is b -
`pe1'f rations wa · found (26) . However, i
`ing in rupture, whF-reas in UC deep ulceration
`licv d that perforations without toxic dilation are
`and extensive tissue necrosis may occur rapidly
`uncommon (4) and the r'su lts of r ·cent studies
`prior to rupture and result in systemic liberation
`of toxic tissue substances.
`support this i01p1· ssion (5, 6). ln one study (6),
`nly one instanc of p rforation without toxic di (cid:173)
`lation (T D) was found among 39 patients with
`UC whq und rwent emerg ncy su1·gical treat(cid:173)
`ment (Table III). In another study, no instances
`of perforation among 87 patients with UC and
`without TCD who were operated upon were
`found, and only four of 45 instances of TCD were
`found, whi h was allributed to a policy of early
`colectomy. W have similarly found that perfor(cid:173)
`ation in U
`is usua lly associated with TCD. In
`our series, TCD developed in 61 of 613 patients
`with UC, 10.0 per cent, but in only 14 of 623 pa(cid:173)
`tients with CDC, 2.24 per cent (2). The correla(cid:173)
`(2) is due
`tion of perforation with TCD in
`mainly to tb high incidence of t xic megacolon
`(10 p r cent) in UC. n
`l'ohn's disease, 20 of
`1,010 pa·Li nts had p rforations, but only thre
`ccurr d among 14 patients with TC compared
`with 22 among 61 with toxi mega ·olon in UC.
`In inflammatory intestinal diseas , per:foration
`may be diffi ult to re ognize clinically (1), par(cid:173)
`ticularly in patients taking high dosage st raids.
`'1 hercfore, it l1as b en sugge ted that early surgi(cid:173)
`cal treatment should be carried out upon patients
`·with a sus1 ect d perforation, signs of peritonitis
`or recognized tox1c 'megacolon. In one study, a
`r du tion in perforatiC'rt rates was found in UC
`tr ated by arly operat.ion- 32.5 to 11.1 per c nt
`(27). A per~ ration rate of only 3.0 per cent and.
`mortality .of 5.3 per c nt was found (5) when
`sutgical trc. tment was ar~·ied out within 24 to 48
`hours o th onset. of indications for operation and
`
`SUMMARY
`We have studied the patient records of 49 or
`1,623 patients in whom perforation occurred
`during the course of inflammatory intestinal
`disease. Perforation occurred most commonly
`with toxic megacolon in UC, but without toxic
`megacolon in Crohn's disease of the colon.
`The incidence of perforation was significantly
`greater in UC than in Crohn's disease involving
`the colon. This was due primarily to the higher
`incidence of perforations with toxic megacolon in
`the former. The incidence of toxic meg;1colon was
`significantly greater in ulcerative colitis than in
`Crohn's disease involving the colon (CC and IC)
`and in UC than in ileocolitis. Although almost
`twice as frequent in UC Lltan in Crohn's colitis
`alone, a significant difference could not be dem(cid:173)
`onstrated in this series for patients with UC
`compared with CC. In UC, the incidence of per(cid:173)
`foration was 28 times as frequent if toxic colonic
`dilation occurred, compared with ten times the
`frequency of TCD in Crohn's disease involving
`the colon. There was a significantly higher inci(cid:173)
`dence 'of perforation in patients with UC with
`toxic megacolon. The incidence of colonic per(cid:173)
`foration in the absence of toxic megacolon was
`similar in the two series (7 of 552 for UC, 1.2 per
`cent, versus '11 of 607 for CDC, 1.8 per cent).
`Mortality was no different in toxic megacolon
`in patients with UC compared with those with
`Crohn's disease or in patients with UC with free
`
`Cosmo Ex 2017-p. 7
`Mylan v Cosmo
`IPR2017-01035
`
`

`

`Greenstein and Aufses: PATHOGENESIS, INCIDEN CE AND OUTCOME OF PERFORATION 69
`
`perforation compared with those with scaled
`perforation. Mortality was significantly greater
`in patients with perforation in UC than in those
`with Crohn's disease in· the absenc'e of toxic
`megacolon. All 15 patients with spontaneousfree
`perforation in Crohn's disease treated by resec(cid:173)
`tion or exteriorization with diversion survived
`compared with four of seven deaths of free per(cid:173)
`foration in UC. We have no explanation for the
`remarkable difference in survival of free perfora(cid:173)
`tion in the absence of toxic megacolon in UC and
`CD, but it may be due to differing immunologic
`states or pathogenetic mechanisms.
`
`REFERENCES
`1. EnwARDS, F. C., and TRUELOVE, S. C. The course and
`prognosis of ulcerative colitis-
`III, complications. Gut,
`1964, 5: 1-22.
`2. GREENSTEIN, A. J., SACHAR, D. B., GmAS, A., and
`others. Outcome of toxic dilation in uk~r'ltive and
`rohn 's coliti s. Unpubl ished data.
`3. G1u:EN::;·n •:1N, A. J., l>AHTII, J. A., and AuFSES, A . H.,
`.J n. I· r ·c c;o lo nic perfora tion without dilation in ulcera(cid:173)
`tive coli ti s. In pr ·s.
`4. j,\L.AN, 1<. N., Strtcus, W ., CA lm, W. J. , a nd oth.(:t'S. An
`cxp Tience of ulcerative lco lit is- 1, toxi · clila tion in 55
`cases. Gast roe ntero log y, I ?69, 57: 69-82.
`5. A I .UIH::c:u Ts N, D ., Bt.mG J~N, A ., NvCAJ\l!D, K., a nd
`others. UrgcnL s urgery for u lcc r<Hivc t:ulitis; cady ol·c(cid:173)
`LOmy in 132 p<tticnt·. WorldJ . Surg., 198 1,5:607-615.
`6. B• .. ~1<,
`·. E., N!oossA, A. R., SrMONOWtT7., D. a nd
`1-lAJ>.'i,,N, S. z. :.mcrgcn<.:y colectomy for· in(lammatory
`bowe l di sease. Sur-gery, 1977, 82: 53 1-536.
`7. GRL\ I.>NSTE.tN, A . J., IV!ANN, 0., a nd 1\ uFsHs, !\.H ., jR.
`vrcc 1 erfonllion of the smal l a nd l;u·gc bowel in
`rC)hn's
`d i scasc. In prcp;u ·!ll ion .
`8. Loc KHART-MUMMERY, H .' E., and MoRSON , n. c .
`Crohn's disease of the large intestine. Gut, I 964, 5: 493-
`509.
`9. CooK, M.D., and DrxoN, M. F. An analysis of the rc(cid:173)
`liabili ty of detection and diagnostic value of various
`pathological features in Crohn's cli seil,se and ulcerative
`colitis. Gut, 1973, 14: 155-262.
`10. GRimNSTEIN, A . J., GELLER, S . A., DREIJ.JNG, D. A., and
`AuFSES, A. H ., jR. Crohn's disease of the colon-IV.
`Arn . J. G as t•-oenterol., 1975,64: 191-199 .
`I i. WrLKS, S., and MoxoN, W. Lectures on pathological
`a natomy. London: Churchill Livingstone Ltd ., 1875.
`
`12. LuMD, G., PROTHERO£, R. H. B., and RAMSAY, G. S.
`Ulcerative colitis with toxic dilatation of the colon. Hr. ·
`J. Surg., 1955 , 43: 182-188,
`13 . M oncAON I, J. 13. De sedibu s cl ausis morba rum . T he
`scats and auscs c1f discas s investigated by ana tomy, in
`5 books co nl aining a g r eat variety of dissection and
`rem arks. Translated by Bc11ja min AJcxa ndc.r. Edited b~­
`A. Mil l r· and T.
`'ade ll. Pp. 64; 1,769. N ew York:
`H afner Publishing
`'o., Inc., 1960.
`14 . jANOwrrz, H . D .
`rohn's di sease; 50 years la te•·
`(Edi~nrial). N. Engl. J. Mcd ., 1981, 304: 1600- 1602 .
`15. ARNII ~tM , E. E . R egion a l ileitis with perfora ti on, ab(cid:173)
`scess and peritonit is. J. Mr . Sin a i Hosp., 1935,2:6 1 63.
`16. RtsCIIMAN, D. 1 1. , a nd GRuzowov, J. Ileocolitis d ·
`rohn con pcrfontcion li br . Pre nsa IVIed. Argent.,
`1965,52:2 116-2 11 9.
`17 . 0RDA, R ., ·Got.DWASER, B. , and WIZNITZ ER, T . Free
`perforation of the colon in Crohn's disease. Report of a
`case and review of the literature. Dis. Colon Rectum,
`1982, 25: 145-147.
`18. STnAuss, R. J.,
`. W. , PLATT, N., and others.
`'l .. tNT,
`Th · surgical 1mH1agc:menL of toxic dilatation of the co(cid:173)
`lon; a report of 281 cases an d a r•cv icw of the literature.
`1\nn. Surg., 1976, 184: 682-688.
`19. lV[AlUilt!\K, R. H., K J~C:UT7., B . l., Kt.BJN, S. H., a nt!
`others. Toxic dila ta tion of the colon in the ours of ul(cid:173)
`ccnnivc coli Li s. GastroentCJ'()logy, 1960, 48: 165-180.
`20. 13 uzzARD, A. J., B,\t<lm , W. N . W., Nk:tm uAM , P . R . G.,
`and WAIHlt::N, R . E. Acute toxic dil, ta tion of th
`o lon
`in Crohn 's <.:o1iti -.
`·u L, 1974, 15: 4 16-4 '19.
`21. jAVt::"I"J", S. L., a nd tl!t KE, B. N. Acute dil atati on of
`the colon in Croh n's disease. Lan<:ct, 1970, 2: 12 6-1 2 8.
`n t::ENsTmN, /\. J., KMu<, A. E ., and Dn. ' H.INo,
`. A.
`rohn's disease of the colon- HI, wx.i c d ilata tion of th ·
`rohn's disease. Am . J.
`astro'nl mi. , 1975,
`colon in
`63: I 17- 128.
`23 . HAWK , W. A ., and TuRNBULl., R . B . Primary ulcerative
`disease of the colon. G as troenterology, 1966, 51: 802-
`805 .
`24. NASR, K ., MoROWITZ, D. A., ANDERSON, J. G ., and
`KmsNER , J. B. Free perforation in regional enteritis.
`Gut, 1969, 10: 206-208.
`25. STEINBERG, D . M ., CooKE, W. T., and ALEXANDER(cid:173)
`Wru.IAMS, J. Free perforation in Crohn's disease . Gut,
`1973,14: 187-190.
`26. DEDOMBAL, F . T ., WATTS, J. M. , WATKINSON, G., and
`Gol.IGHE,R, J. C. Intraperitoneal perforation of the co(cid:173)
`lon in ulcerative colitis. Proc. Roy. Soc. Ivied ., 1965, 58:
`713-715.
`27. GouGnER, J. C., 1-IoFI'MI\N, I . C., and DEDOMBAr.,
`F. T. Surgical trc<\lment of scvcrr, nttncl<s of ulcerative
`colitis, with special rcfercnc:c• to th e advantages of early
`operations. J3r. Med. J., 1970, 4: 7 0 3-706.
`
`22.
`
`Cosmo Ex 2017-p. 8
`Mylan v Cosmo
`IPR2017-01035
`
`