P
`
`Inflammatory Bowel
`(cid:9) eases.
`
`Reivtiisoenc12 °
`
`FALKN000051 33
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
`
`

`
`Pu17,dish,er
`
`)R. FALK Pi--1/4-31VIA GmbH
` LptnemPeker,t• . 5
`- •
`Postiach 85.29
`• I 79041 Frea.)urg
` Germany
`
`( (cid:9)
`
`gwww.M • •
`
`0.2005 Dr. F-0 1.k Pharrn-a GmbH
`A cights reserved. (cid:9)
`
`6th revised editon 2005
`
`FALKN000051 34
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
`
`(cid:9)
`(cid:9)
`

`
`Contents
`
`Etiology and Pathogenesis
`Diagnostics: histological, radiological,. sonographical
`
`Clinical Overview
`Diagnostics/Follow-up in. the Doctors Practice
`D (cid:9) gnostics/Follow-up Gastroenterologist /Clinic
`Eictraintestinal Manifestations and Complications
`
`Therapy Concepts
`Drug Therapy of Crohn's Disease
`Drug Therapy of Ulcerative Colitis
`Surgery
`
`Pregnancy
`Children and Young Patients
`Nutrition
`Cancer Risk
`
`• . ...
`. .
`. (cid:9)
`
`.
`: (cid:9)
`..
`
`•
`
`Mesalazirie — Characterization of the Substance/Mechanism Of 4.VtiOn
`Salofate — Dosage Rirms/Dosage Recommendations
`Budesonide — Mechanism of Action
`Budenolaile3ing — Therapy Results/Dosage Recommendations:
`Azathioptine — Mechanism of Action/Therapy Results
`Azathioprine Dosa).:Ie Recominend.ations/Therapeutic:Schedule
`
`Information for Doctor and Patient
`.Patient OrganizatiOns
`Literature for the Doctor and Patients
`
`. (cid:9)
`
`..
`
`. : . ..
`. (cid:9)
`..
`. ..
`
`.
`.. (cid:9)
`.... ..
`... .
`
`. (cid:9)
`
`..
`
`..
`. (cid:9)
`..
`. (cid:9)
`..
`. (cid:9)
`. . ..
`
`.
`. . (cid:9)
`.. : . : ...
`
`.. : . : ...
`.. (cid:9) ..
`
`Basic Information on. Salofalle/Budenofall03mg
`References
`
`....
`
`: .....
`
`5.1.7. YAWN=
`,X424.iXeiMESBX83
`. •iir..owolv44:2:WOMMEE83
`SMV/28:0249:gRagge
`.r.>400.:>4?.:W.lagems3
`..M.4.040455%"i5Amisigai
`(or ..Y.WEIMMIEM
`f2;?•XWMX.:XiMSUS3XIMEI
`9...519..X.MWMMONN
`
`: (cid:9)
`
`: (cid:9)
`
`• •
`
`FALKN000051 35
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
`
`

`
`.-. -Productipreseritetidris:,:corc0;,>iign; and indicat ons as:,:roterencedtere•iii .
`- (cid:9)
`---- •
`,
`
`dfter:fron,, trp..)se in your cooltry. Tnererore.,
`ph ly (cid:9)
`iC
`(Gerrnan,„1; or the (-:). c.A.,31 Fat: carter
`Dr. Fa ::k (cid:9)
`
`
`
`•
`
`FALKN000051 36
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4
`
`

`
`Etiology and Pathogenesis
`
`Eticilogy and.
`Pathogenesis
`
`Inflammatory bowel diseases (1BD) are destructive
`inflammations of the intestinal tract which take an inter-
`mittent course. Crohn's disease and ulcerative colitis differ
`in their distribution pattern and in their macroscopic an.d
`histologic picture..
`
`Cretin's disease occurs. segmentally in all sections of the
`gastrointestinal tract and affects all layers of the wall.
`Ulcerative colitis, by contrast:begins in the rectum, can
`spread from here to all sections of the colon, and affects
`only the mucosa. Often only th.e chronic course of the
`illness produces the definitive diagnosis of IBD and
`differentiation between Crohn's disease and ulcerative
`colitis is not always possible.
`
`•
`
`The causal factors involved in th.e pathogenesis of I.BD
`are not yet known. Current genetic investigations confirm
`the results of gemellology. On the basis of genetic
`disposition., IBD only develops after contact with exogenic
`environmental factors.
`
`New immunological models designed to explain the patho-
`genesis have a number of- practical consequences for medi-
`cal procedure and also offer help in answering patients
`questions such as:
`
`"What actually causes my illness -.is it perhaps food
`or allergens?"
`- "What role is played by intestinal flora? Should I change
`my diet?"
`- "Why do I have to take cortisone again when it wakens
`my immune system? Would it not be better to try im-
`mune-stimulating therapy instead (alternative medicine)!
`and stop the cortisone?"
`
`FALKN000051 37
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 5
`
`

`
`Etiology and Pathogenesis
`
`What is the principle behind these more recent ideas on the.
`pathogenesis. of inflammatory bowel diseases (IBD)?
`
`According to this immunologiCal concept, the pathogenic
`cascade of inflammation begins with the exposition of an
`antigen in the bowel. This unknown antigen may be a nutri-
`tional component o.r an infectious agent (bacteria/viruses?).
`
`in IBD, each patient seems to have his own individual
`pathogenic antigen pattern, while in the case of gluten-
`induced .sprue, for example, all patients react to the same
`antigen (gliadin) with the developMent of the same illness
`(:spree).
`
`This concept forms the basis for the individual exclusion
`diet, which is difficult to carry Out from a practical point of
`view but has produced excellent clinical results in English
`studies.
`
`The .pathogenic individual antigen is presented by the cells
`of the immunological detente Cells peculiar to the intestinal
`wall. This results in activation — via intermediate stages — of
`inflammatory messenger substances (cytokines) arid -- by
`triggering secondary inflammatory factors — destruction of
`the intestinal mucosa..
`
`intestinal lumen (cid:9)
`
`ntigen uptak,e •
`
`Antigen.processing
`in the .antigen- -
`resenting cells
`Tcell activation
`T-cell prc.):liferation
`Cytokine 3yntnesis
`
`"gut-associated lyrripiloid tissue (term for the immune system of the ts,rseveli
`Fig. 1: Induction Of an immune response in the bowel and possibilities of
`imrnu.nolboic intervention (modified from`!
`
`1
`
`I
`
`a
`
`FALKN000051 38
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 6
`
`

`
`•
`
`How does. this reaction differ in patients. with IBD compared
`to those with other bowel inflammations, e.g. self-limiting
`infectious bowel inflammation?
`
`In patients with .1BD there is primarily stimulation of the IgG-
`producing immune cells. In contrast to IgA-antibodies which
`are produced normally, IgG-antibodies trigger secondary
`inflammatory factorS vv.hic.h lead to the destruction of the
`intestinal wall.
`
`In addition to this, the balance between inflammatory and
`anti-inflammatory cytokines is clearly distOrbed. A dysregu-
`lation of the immune reaction causes excessive activation
`of inflammatory cytokines. Due to the pathologically pro-
`lOnged life-span of disease-sustaining T-Iymphocytes in
`patients with Crohn's disease, the illness progresses into
`a chronic. stage.
`
`It can thus be seen that there is no weakening of the im-
`mune system in IBD. On the-contrary, there is excessive and
`over-prolonged activation of the gut-associated immune
`system. One aim common to all immunomodulatory theta-
`pies is to restore the .bplance of this immune. system by
`means of suppression:
`
`These research findings explain the well-established thera-
`peutic. effects of drugs such as systemically and topically
`(budesonide) acting corticosteroids or azathioprine therapy
`and form the theoretic basis for new immunomodulatory
`therapies (interieukin-10 or monoclonal antibodies).
`
`The influence on the immune system is a rational explana-
`tiOn fair the effect-Of long-term situations of psychosocial or
`emotional stress on patients with IBD.
`
`111 (cid:9)
`
`11 (cid:9)
`
`•
`
`n
`
`
`
`S
`
`
`
`and
`-Pathogenesis
`
`FALKN000051 39
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 7
`
`

`
`Etiology and Pathogenesis
`
`Crohn's disease
`
`Localiz,ati on.
`
`Frequerloy of segmental, discontinuous Location of inflamMaton
`in individual bowel segments
`
`MONIMIAMen
`n###8##I#81N#8 ###8####8##
`.q@M•0801
`AM#A#4.Nal#0#68##
`EEEMSSWAMON8
`#5.8??MaiSrA#8 #02M.:#8##
`
`Esopha9us
`Stomach
`Duocienurn
`--5.%
`
`Smell
`intestine.
`end cOlon.
`40-55%
`
`Small Nestine
`only
`25-30%
`
`Colon only
`2.0-25%
`
`Invokiement
`of the rectum
`11.-25 %
`
`Anorectal di: eas,e
`Ian& fistulae, pria.i.fi5s:Lir6,=;s, p.eri-
`o.rootitic and -other dbeceases)
`30-4G%.
`
`End oscop y
`
`Fig. 2: Normal
`
`6
`
`Fig. 3: C.ithn's dis4ase
`Map•ahaped uldet with .raised red bdmier
`
`•
`
`!it
`a
`a
`
`I
`.•
`
`I
`
`a
`
`a
`
`a
`
`•
`
`I
`
`a
`
`a
`U
`•
`
`I
`
`I
`
`FALKN000051 40
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 8
`
`

`
`n
`U
`n
`
`a
`n
`a
`
`n
`
`........
`
`Etiology and.
`Paijidgeuusi5
`
`Ulcerative colitis
`
`Localization
`Frequency and extension of inflarnmation in the coon
`
`Entire colon 18 %
`
`Up to the left flexure 28%
`
`Rectosic.i-Inioid 54%
`
`Endoscopy
`
`F. 4: Normal
`StnOot.h, shiny mil:X-05a, cleari defined
`Veee els
`
`Fig, 5: UICeratiVe. colds
`Loss Of vascular pattern., granulation,
`velvety reddenilid
`
`FALKN000051 41
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 9
`
`

`
`Diagnostics:
`histological, radiologi
`: (cid:9)
`: (cid:9)
`: (cid:9)
`• (cid:9)
`
`(cid:9) sonographical
`: (cid:9)
`: (cid:9)
`:.::•:.:
`
`ihn's disease
`
`1 listology
`
`•
`
`•
`
`#M #M#8####8
`
`WO#08###
`Mi:MMSMS#####$###8##
`2Ve?•MMnM§
`Me
`8#,:1
`1I
`
`OMEM
`.1iip#8##
`
`Fig. 6: Trarismural inflammation
`AsyMenetrio;
`discontinuous,
`granulomas
`
`a3catg:7,IiRt*
`Fig. 7: Lymphocyte infiltratton, traosinural,
`distribution pattern discontinuous;
`focal lymphoid 11y,004'#.14f.-118;
`fibroshg of 0 layers of the wail;
`fissures; epitheloid.c.4911. gran idaireS (30-60
`in the submucosa; seldom crypt
`abscesses, goblet cella preserved (colon)
`
`Radiology
`
`Sonography
`
`8:- ITerriinal (cid:9)
`cobble-stone i'lliJOOSO
`
`stenosin.g,
`
`&ASS'
`Fig. 9: Poorly:echoing broadening of the well,
`typically eccentric
`
`FALKN000051 42
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 10
`
`

`
`Etiology and:
`Patilogtnesis
`
`Ulcerative colitis.
`
`Histo10,
`
`Fig., 10: tvluoasal inflammation
`Peopottioned,
`crypt abscesses,
`continuous
`
`Fig_ 11: comintio:us pdlymprphorluelear infiltra-
`titin, limited to the mt,fc.osa., crypt. abscesses,
`gpblet cell mass reduced
`
`U
`
`Zadiology.
`
`Sonography
`
`Fig, 12; Lcissciq haustretivn, "stiff pipe",
`pseLidOpplyps
`
`Fig: 13: Florid ulcerative Ceiiti8,. rpcderate. thick-
`ening of walls. The wall layers are preserved
`
`U
`
`FALKN000051 43
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 11
`
`

`
`Clinical Overview
`
`Crohn's
`disease
`
`indicating
`signs at first
`manifestation
`
`.• Segmental, discontinuOsiinflarnMation
`for thedistal segment Of the ilcrkin'i
`• Car*&SContinUously affect the WhOle „ s (cid:9)
`(mouth to rectUrn)
`Ogy transmUra inflarnmations (-> fistuia.e)
`
`:test oil tract
`
`testina
`I n
`
`• Abdominal pain (cid:9)
`Diarrhea
`• Bleeding
`Anal fistUlee*
`
`77%
`
`22
`
`Weight loss
`Fever
`Anemia
`Arthralgia
`Eye involvemf.3nt 1011;
`Erythema bodbsurn 8%
`
`Epidemiology
`
`• -An.nualincidence.2 4-cases/100 000 inhabitants
`• Prevalence 20-40 Casesil 00 000 irinabitants
`* Peak of illness20th 30th year of life
`
`Since asymmetric inflammation occurs transmurally throughout
`(cid:9) wall in Crohn's disease, the deeper layers of the
`all layers of
`bowel are often more severely affected. Accordingly, endo-
`scopy reveals only the tip of the iceberg in the urninal aspect
`of the bowels. As a result of this, clinical intensity does not
`necessarily correlate with endoscopic or histological findings
`or individual laboratory values. In an effort to solve.this prob-
`lem, indices were developed to determine disease activity
`and regulate therapy. The most widely known of these is the
`CDAI -(Crohn's. Disease Activity Index), *which is described in
`the following.
`
`Disease
`activity
`
`10
`
`FALKN000051 44
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 12
`
`

`
`: (cid:9)
`
`: (cid:9)
`
`: (cid:9)
`
`: (cid:9) .. (cid:9)
`
`. (cid:9)
`
`. (cid:9)
`
`; • (cid:9)
`
`. •
`
`•
`
`Ulcerative
`colitis
`
`•f•A!.tii
`
`.
`: (cid:9)
`• (cid:9)
`• (cid:9)
`.. (cid:9)
`Continuous inflammon : f the iti(idosa Of t colon,
`ati
`. (cid:9)
`.
`a (cid:9)lMoSt \Aiays beginning h the -ebtOn-1
`
`sprea ds to 'PrOx
`
`ao rbx. 50 O (cid:9)f cases
`•
`
`The terrOina1:11e0M is affected in rare cases (backwash ileitis)
`. (cid:9)
`. (cid:9)
`. (cid:9)
`.
`. (cid:9)
`. (cid:9)
`. (cid:9)
`.
`O :Lnterniit;tent acute episodes alterhatihglyvith, symptomless
`•
`
`
`i intervals,. (cid:9) 'rarely chrOric, Oontir (cid:9)a
`
`•
`No tra:nsmurarinflarnma iOn , : (cid:9) • (cid:9) •: (cid:9) • (cid:9) • (cid:9) •: (cid:9) • (cid:9) : (cid:9) • (cid:9) • (cid:9) •
`
`
`
`
`
`
`
`
`
`• Histology (cid:9)
`
`
`stage:, (cid:9)
`6lteinflammation with
`(3ran Ocy
`•inflar!ni
`.
`.
`i-ed.i6tien Of th.0.6(
`1t!clis
`Nor nal findi3OgSipOSSible; hp yeygr
`often ranfic6tibh of the crypt architect
`pseudopa. yOs
`i.solated. growth (cid:9)
`OYSPlasia possible
`OOOL4rrende of Oaf. dnOi-nas
`
`I r remission (cid:9)
`
`Chi
`
`intestinal
`
`Intestinal bleeding
`Diarrhea
`Abdominal,Ipal
`Anal fisS ires,.
`
`Anal fistulae
`
`ar.
`
`Initi a 1st
`80% 100
`5% %
`47% %
`
`0`%0
`
`Extraintestina I
`20
`Fever
`4, 0
`30-50
`Anemia
`'"
`o•
`30
`f, Aqhralgia
`30
`ilVeight loss
`0/
`symptoms 10
`irytherna nodosuil 8
`
`—9 cases/100 000 inhabitants
`Annual incidence
`Prevalencea00t-b*.
`40cases-100 000 inhabitants
`. (cid:9)
`. (cid:9)
`. (cid:9)
`. (cid:9)
`.
`- rOx. 20th year of life (cid:9)
`
`Peal' ._!Of disease. :JO
`
`. (cid:9) .. ... ..
`
`(cid:9) mu-
`Since there is continuous symmetric inflammation of
`cosa in the case of colitis, endoscopic and histological findings
`correlate with. the. clinical activity of the disease. Clinical and
`laboratory parameters enable graduation of the disease and
`regulation of therapy. Local therapy which is active from the
`bowel lumen (e.g. 5-ASA) is much more effective tha.n in
`Crohn's disease. Here, too, an index was developed (Rachmile-
`Witz Index) consisting of subjective and objective data on the
`development of disease activity.
`
`Indicating
`signs
`
`Epidemiology
`
`Disease
`activity
`
`11
`
`FALKN000051 45
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 13
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Crohn's Disease .Activity Index (CDAI) by Best
`
`The variables 1— 8 are entered according to the specifications made and
`multiplied by the importance factors. (cid:9)
`
`Importance factor (cid:9)
`
`Subtotal
`
`N'on her of unformed stools
`.in: the: lastW.eelc:
`
`Extent of ab1:10rninal pain:
`(surn:Over:One:•Wpelri: (cid:9)
`•
`
`•
`
`: (cid:9)
`
`•
`
`: (cid:9)
`
`: (cid:9)
`
`Gerieral state of halth (cid:9)
`(5:LOIEOVer: one Week)
`
`: (cid:9)
`
`• (cid:9)
`
`: (cid:9)
`
`• (cid:9)
`
`: (cid:9)
`
`• (cid:9)
`
`: : (cid:9)
`
`: : (cid:9)
`
`: (cid:9)
`
`: •• (cid:9)
`
`: (cid:9)
`
`• (cid:9)
`
`• (cid:9)
`
`h2 _
`
`
`X .
`
`: (cid:9)
`
`: (cid:9)
`
`.
`• . .
`
`: (cid:9)
`
`• (cid:9)
`: (cid:9)
`• : : . : : •
`
`: (cid:9)
`
`• (cid:9)
`
`: (cid:9)
`
`.
`
`In 5 disease•
`
`
`Othe - symptoms associated With
`(Please tick off Where p•pr.Olcable) (cid:9)
`:
`• : (cid:9)
`: (cid:9)
`ritiS (cid:9)
`1,Neitis (cid:9)
`•Lzryttie la (cid:9)
`nodOeum;
`Piocjerrn,
`g.-3r1grae
`10!::.311r1
`
`joint pan
`:Arti-trs
`Ani.--il fissur,e
`.final fistulae
`Ait..11<ebs;es,3es
`
`aPhthosa
`
`NinplOmatic
`diarrhea ,.reatrnent
`
`Other
`fistulae
`
`------- :
`
`Temperature
`abo.e37:5
`in the list (cid:9)
`wee (cid:9)
`
`
`
`
`kin !be- (:•,f
`poiijtt:3: ticked:
`Off.
`
`Z 2 )
`
`Resistance In he abdomen' 0 = no
`t.iestiorta
`= definite (cid:9)
`
`
`---- . --- - - ---- : --
`
`r1P T atc,crit
`
`A/eight (kg)
`
`Standard:
`weight (kg)
`
`42 rrfinds Het
`47-ThirjosH
`tl:e sign)
`
`iii (cid:9)
`
`We4ght
`Stanclardi**ght (cid:9)
`
`fnind
`
`the s
`gni
`
`Evaluation:
`s 150 = dormant illness
`'Sum (cid:9)
`Sum (cid:9)
`150 . active illness
`
`12
`
`00..00004001
`
`x
`
`Total
`CDAI Value
`
`FALKN000051 46
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 14
`
`(cid:9)
`

`
`Classification, of Ulcerative Colitis.
`
`Classification
`according
`to disease
`activity
`
`St00! frequency
`
`
`
`Bleed'
`
`4
`
`!slight
`
`moderate
`
`6
`
`pro use
`
`> 37.5
`
`< G.g/dI d
`
`one
`
`10
`
`Fever
`
`'emoglobil
`
`ESR
`
`
`Albumin
`
`mm
`.:< 30
`
`> 30 mm
`
`no.frna
`
`3-4 gid
`
`Endoscopic
`classification
`of disease
`
`emission
`
`Pale mucosa, torqued vesSels
`
`Grade 1
`
`(slight
`
`ctiVrt
`y)
`
`Erythema, slightly .grar warted s.artcce
`ibss o vascular
`
`Grad 2
`
`(moderate
`activity)
`
`Sing c ulcers, velvety mucosa,
`
`contact and Spontaneous bl ed ng
`
`(hid;
`3
`
`anti
`vity)11
`
`Pus,
`
`iargE
`
`spoptaneous
`r ulCeratbn
`
`bleed. ng
`
`Fig. 14: Grade 1
`
`15: Grade 2
`
`Fig. 16: Grade 3
`
`FALKN000051 47
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 15
`
`

`
`Diagnostics/Follow-up in the Doctors Practice
`
`Initial (cid:9)
`diagnosis (cid:9)
`
`The period from the appearance. of the first symptoms to
`diagnosis in inflammatory bowel diseases (Crohn's disease,
`ulcerative colitis) is often very long (too long) in the case of
`many patients.
`Diagnosis can be complicated by the fact that the main indi-
`cating sign from a. clinical point of view - "diarrhea" - is
`often concealed by primarily more intense extraintestinal
`manifestations, so that the intestinal symptoms make only
`a secondary impression.
`
`Basic diagnostics
`
`History] (cid:9)
`
`Clinic (cid:9)
`
`Laboraivy (cid:9)
`
`LLD in the family
`Stay abroad
`
`
`
`Number of stools/day
`Blood deposits
`Abdominal pain (cid:9)
`
`flam.priation parameters
`ESR (cid:9)
`- CRP (cid:9)
`Anen-lia
`Thrombooytosis
`
`• :
`
`
`
`•
`
`.
`
`Stool inspection
`with suspected infection
`
`.
`Serology (cid:9)
`with suspected Salmonellae,
`Yerainiae,
`Campylobacter jejuni/coli
`
`14
`
`n
`
`FALKN000051 48
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 16
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Abdomen
`sonogram
`
`q(bric-graphjQ 0,dict,aTjng
`Thi0 ening: .of t0e intestina!
`dile to ii-111i-bititciry or fuh-brous
`
`Further
`inV.esqigationS
`
`S
`
`suspected
`With
`0
`Lactose it teleranco
`actoSe-H, breath test
`Nalabsorptian:.:
`XVoSe--abso(,p,ion test
`:•:.
`Diverliculesis 01verticflitis
`ColOnoScOpy,
`'don contrast enema
`Celiac disease:::
`against alia
`kik-antibodies
`
`S
`
`IRefer 'a[ to
`
`gastrOeilte01Pgist/Clinic,
`
`With
`
`pected',
`
`Acute attack::
`Toxic megadOlon
`(ulcerative co4is)
`Chronic refrac,tbry
`
`course
`
`.1. (cid:9)
`
`: (cid:9)
`
`• IOVV-UOS
`:
`
`Li.iboi-atc?ry
`
`J'ITI
`
`Kno./Y11 ilIheSS
`
`Activ ty
`
`Ces:
`
`15
`
`FALKN000051 49
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 17
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Diagnostics/Follow-up Gastroenterologist/Clinic
`
`Outpatient.
`clarification
`
`• Rectoscopy
`s Sigmoidoscopy
`* Complete ileocolonoscopy
`* Esophagogastroduodenosoopy-(EGD)
`• X-ray of small.intestine according to.Sellink (cid:9)
`•• Contrast etyma-
`
`CrOhn's disease With signs pointing to Cro:hn's disease, complete diagnostic
`procedures (EGD, X-ray/Sellink, ileocolonoscopy) should be
`carried out before start of therapy so as to incorporate all the.
`affected sections- of the bowel in a segments involvement
`pattern. This is also important for therapy planning (topical
`versus systemic).
`
`Ulcerative (cid:9)
`colitis (cid:9)
`
`Follow-up (cid:9)
`
`!,n patient
`treatment (cid:9)
`
`16
`
`If indications point to ulcerative colitis, complete ileocolo-
`noscopy should be carried out before start of therapy in
`order to obtain macroscopic and histological evidence of
`the exact extent of involvement (seldom discontinuous).
`
`Primarily clinic, laboratory parameters, endoscopy where
`necessary
`
`• Toxic colitis (with or vvithout megacolon)
`
`• Suspebted Sepsis
`• 'Suspected concealed or open perforation
`* Subileusilleus
`
`n
`
`FALKN000051 50
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 18
`
`(cid:9)
`(cid:9)
`

`
`n
`
`By making full use of all diagnostic options it is generally pos-
`sible to differentiate between Crohn's disease and Ulcerative
`colitis. Several points of reference present a useful guideline
`here:
`
`Findings
`
`J.ICeratiVe
`colitiS11
`
`Crone's (cid:9)
`disease
`
`%V.OMM.r.,MWAMYOZI/41,WM2,%•00**
`
`d
`
`1Ct ice • (cid:9)
`
`Bloody stools
`Abdominal pain
`Involver erf:of
`
`C t
`
`curative
`
`cers
`blvErn.)
`
`of -€ terrni
`
`Perianal lesions
`Fistulae
`Toxic driatatioi
`Re,currence after
`urgery
`Endoscopy
`Apl Atha
`Longitudinal
`Continuous
`nvolvemenl
`i eurn
`Epithe oickicei
`
`comMori
`rare
`always
`-t;
`ra re
`
`rare
`
`
`no
`
`n0
`
`.1 0 11
`
`.1 (cid:9)
`
`lar
`
`rl
`
`r o !!
`
`rate
`corn in o
`rare (20
`common
`common
`rare
`
`common
`
`common
`cornrnon
`rare
`com1T10
`—60
`%)
`(40
`present
`(40 % )
`: (cid:9)
`: (cid:9)
`• (cid:9)
`•
`
`FALKN000051 51
`
`g-anj mas
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 19
`
`(cid:9)
`

`
`Extraintestinal Manifestations and. Complications
`
`Extraintestinal (cid:9)
`manifestations (cid:9)
`
`Extraintestinal symptoms occur in approx. 60 % of patients
`with 1B.D..They can play a key role in determining the clinical
`course of the primary disease. Extraintestinal symptoms are
`principally divided into two groups: extraintestinal manifes-
`tations and extraintestinal complications. These differ from
`each other in that the.pathogenesis of the manifestations,
`as of the: primary disease, remains .unclarified, while the
`pathogenesis: of the complications in most cases is known.
`
`For the most part, extraintestinal manifestations affect
`joints, skin., eyes and the perianal region. Other organs are.
`more rarely affected. The symptoms can occur.as initial
`symptoms., especially the joint complaints and the.
`erythema nodosum. Occasionally, diagnosis of priMary
`sclerosing cholangitis (PSC) in chronic liver disease leads to
`the diagnosis of ulcerative colitis.
`
`There is rare (< 1 %) incidence of pancreatitis, vasculitis,.
`pericarditis, myocarditis, autoimmune .hemolytic anemia and
`thrombotic diseases.
`
`Extra intestinal manifestations
`
`Sklrt (cid:9)
`
`EyeS
`hg.:
`Heap;
`1.31o0c1:
`
`Tissue:
`
`Erythema nodosOrn
`Pyodernie gangraenosurr.)
`Polyarthritis, monarthntis,
`
`cc ro
`
`Alveolitis, lung fibrosis
`Perirriyocarditis
`
`Thrornboernbolic uliar ges (cid:9)
`Autoirnmune hernplytic anernia (cid:9)
`ArnyloidosiS:
`
`18
`
`I
`
`FALKN000051 52
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 20
`
`

`
`,Extrainte..tiOal
`complidatierns
`
`EgraaMtZAWN,O.;:::',FSNME.#
`
`1811181111111111111,
`klmipomem§1
`
`Extraintestinai complications are essentially caused by a (cid:9)
`lack or (rarely) an excess of exogenous and endogenous (cid:9)
`substances in the body as resu t of the disturbed bowel
`function. Of decisive importance here are Vitamins, trace:-
`elements, protein, bile acids, Ok8.1.id acid and water.
`Deficiencies can lead to the following symptoms: anemia,
`osteomalacia, sensory disturbances (zinc deficiency,
`vitamin B deficiency). Changes in absorption can cause gall-
`stones (impaired bile acid absorption) and kidney stories:
`
`As'far as eye and joint changes are concerned, target-spe-
`cific ophthalmological and rheumatological diagriostics are
`indicated. Liver changes, gallstones. and kidney stones can
`often be demonstrated sonographically: primary.scleresing
`cholangitis (PSC)is only diagnosed. by means of endoscopic
`retrograde cholangiopancreaticography (ERCP). In order to
`detect deficienties before symptoms occur, annual follow-
`ups of the parameters Fe, Ca, Mg, Zr, ferritin, folic avid,
`vitamin A, Bit, D, E, K are recor-nrnended.. The Schilling Test
`permits early clarification of the need for permanent
`'vitamin B12 substitution.
`
`Side effects of the drugs and drug interactions are to
`be taken into consideration like impaired absorption of
`ca cium (glucocorticoids) or folic acid (sulfasalazi*.
`
`aU
`
`
`a
`
`U
`
`a
`U
`n
`n
`
`U
`
`a
`
`•
`
`19
`
`FALKN000051 53
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 21
`
`

`
`Extraintestin.al Manifestations and Complications
`
`Etraib: §Linal
`
`eticien
`
`r7. Ki osteornalacla,
`D, (cid:9)
`1 (cid:9)
`atrbpky, ntght; biindness ,.sens/.-3ty
`rr (cid:9)
`diStLIrbdhabs, t.-liperkeratoses. ariernli
`h) MinPra tiet uorry.calpiun rilognt--)iur
`anemia,:osteonialacla, dsturbarce (cid:9)
`gro\At
`
`r) Pn'Tte:n defiriericy edemas
`
`chanries
`
`V3SS kidr e‘,ones
`
`b) B:ie acid.deficiency (cid:9)
`
`stones
`
`20
`
`I
`
`FALKNO00051 54
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 22
`
`

`
`C ityic Ark]
`Practice
`
`•
`
`Eye involvement
`Episcleritis,
`Uveitis,
`Conjunctivitis
`
`Heart involvement
`Pleuropericarditis,
`Myocarditis
`
`Kidney involvement
`Oxalate stones,
`.Kidney tubular damage
`
`Skin involvement
`Pyoderma gangraenosum,
`Erythema nodosum
`
`U
`
`•
`
`n
`
`n
`
`Vascular involvement
`Vasculitis,
`Thromboembolisms
`
`Liver involvement
`Fatty liver,
`Chronic active hepatiti
`Primary sclerosing
`cholangitis
`
`Joint involvement
`Peripheral. arthropathy,
`Sacroileitis,
`Spondylits
`
`Fig. 17: Extraintestinal rhanifdstations and coriViitatiotis in Crohh's diteas
`
`21
`
`FALKN00005155
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 23
`
`(cid:9)
`

`
`Therapy Concepts
`
`•
`As the etiology of inflammatory bowel disease has not yet
`been clarified; no actual causal approaches exist.
`
`Conseouently, first line therapy concepts consist of drug
`therapy, which is aimed at combating the symptoms of
`the acute attack and maintaining remission, and operative
`interventions, whiCh are designed to avoid life-threatening.
`situations.
`
`The principal classes of drug used in both ulcerative colitis
`and Crohn's disease are: preparations which release
`.(mesalazine) or split off (sulfasalazine) 5-aminOsalicylic acid;
`topically.active (budesonide) and systemically active cortico-
`steroids; immun:osuppressives. Despite incomplete patho-
`physiological understanding, empiric tests have shown that
`there. are therapeutic approaches which enable approx. 3/4
`of .all patients suffering an acute attack of 113D to be treated
`successfully with drugs. Therapy-refractory and chronically
`active cases still present a therapeutic problem. The side-
`effect rate of the drugs must always be borne in mind.
`
`All three of the above drug groups are employed in the
`differential-therapeutic treatment of Crohn's disease end
`ulcerative. colitis. For this reason the two diseases are dealt
`with separately..
`
`Moreover, the German Society for Digestive Diseases
`(:DGVS) has recently published therapeutic guidelines:for
`ulcerative. colitis (2001) and Crohn's disease (2003).
`
`FALKN000051 56
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 24
`
`

`
`WOAVJZZ. (cid:9)
`
`• 4,,Ak
`
`• : (cid:9)
`
`• (cid:9)
`
`: (cid:9)
`
`: (cid:9)
`
`: (cid:9)
`
`• (cid:9)
`
`: (cid:9)
`
`• (cid:9)
`
`: (cid:9)
`
`: : (cid:9)
`
`: (cid:9)
`
`. (cid:9)
`
`• (cid:9) ::::: (cid:9)
`: (cid:9)
`
`: (cid:9)
`
`: (cid:9)
`
`.
`
`Crohnis disease — Therapy concepts
`
`•
`
`• (cid:9)
`
`- (cid:9)
`
`: (cid:9)
`• (cid:9)
`
`- • (cid:9)
`
`- (cid:9)
`
`• (cid:9)
`
`• (cid:9)
`
`• (cid:9)
`
`.
`: (cid:9)
`
`• (cid:9)
`
`• (cid:9)
`
`: (cid:9)
`
`• (cid:9)
`
`• (cid:9)
`
`: (cid:9)
`
`• • (cid:9)
`
`: (cid:9)
`
`•
`
`Acute attack
`•
`Cc ticpsteroios
`To,pically:Adtive
`budesbnide
`Systernically active
`:
`prednisbl'one
`• !Mesa lazine o sUlfaSala
`•
`It necessarv,,m m
`Ji10
`SupPreaSiVeS
`(66, atothibp-ine,
`•
`Elementary cliet
`
`ine
`
`!Maintenance of remission
`•
`IVesalazi e
`Fibre-rich diet
`defidits
`Compensation o
`zinc),
`(e.gvitamin B1 ,),
`with: (cid:9)
`®' Cholestyrarnine
`chologetliC ciar
`rhea
`• AntidiarrheticS
`
`
`•
`
`Chronic active dipeae,
`teroid-dependency and fistula
`
`Azath€oprine
`Non-response to Ilrrn no
`l_iriOrOssor'ts
`•'!Anii-TNE-11:-ari 7) di0,s
`
`Icerative colitis -Therapy concepts.
`
`Mild attack:
`* Mesalazin:e or ulfasc. la • i e
`
`Moderate attack
`
`Cqrticosteroids
`® iViesalaz:
`
`Severe attack..
`
`• „Ort.iCO:tit4rOiCiS
`
`sulfasala
`*1\ileSala2.16
`* Parente al
`or!lonte a!
`SubStituit .or
`nutrition or
`
`Maintenance of remission
`
`
`.6, Mesalazine
`•:Fibre-ridi diet
`
`e
`
`!(;if intol-rant of le a az' le)
`
`Chronic active diseesei
`steroid-dependency and m ain
`tenance of remission after
`cyclosporine or tacrolirnus
`induced remission
`• Azathioprine
`
`A
`
`::: (cid:9)
`
`....
`
`• • (cid:9)
`
`.. (cid:9)
`
`.. (cid:9)
`
`• • (cid:9)
`
`,
`
`23
`
`FALKN00005157
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 25
`
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Drug Therapy of Crohn s Disease
`
`Acute attack
`
`The most effective drugs at present are the corticosteroids.
`Besides the conventional systemic corticosteroids (predni-
`Sone, brednisolone, 6imethylpred.nisolone) there is &so
`budesonide,. a non-systemic (topical) glucocorticOid. Bude-
`sonide exhibits a high first pass effect in the liver. After
`absorption in the bowel, over 90 % of the substance is in-
`activated in the liver. Budesonide is thus characterized by its
`excellent efficacy at the site of inflammation and its lower
`rate of steroid side effects.
`The following. scheme shows a dosage plan for conventio-
`nal corticosteroids in current use. For patients with highly
`active C:rohn's disease, conventional systemic corticostemid
`therapy is recommended; in the case Of moderately active
`attacks, budesonide can be. employed with a view to reduc
`ing the glucocorticoid side effects.
`
`:TheraOY Scheme
`
`With
`
`.
`: (cid:9)
`: (cid:9)
`• (cid:9)
`• (cid:9)
`. (cid:9)
`8'!disease
`steroids active erchn
`•
`•
`• (cid:9)
`• (cid:9)
`•
`• (cid:9)
`• (cid:9)
`
`• (cid:9)
`
`, (cid:9)
`
`•• (cid:9)
`
`•
`
`ide
`
`P, ecini,9o1bi
`
`e
`
`6-Methylpreclnis01ihe
`
`60 mg
`
`f the
`a y (cid:9)
`star
`weekly
`reduction
`of!
`
`rng
`
`49 ra
`
`8 rng.
`
`30 rng
`
`rn
`
`week.
`
`24 m
`
`1 -ng
`
`-ng
`
`8th wee,
`
`9 rug
`
`•
`
`FALKN000051 58
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 26
`
`

`
`•
`
`sulfasaia.zim is clearly less effective. Mesalazine at a
`dosage of 2 gidayis also inferior to the steroid-. Better
`results were achieved with a dosage of z. 4 giday.
`Use: of mesalazine is recommended when corticoids are.
`not suitable for treatment.
`
`if long-term glucocorticoid treetrrent fails to Lead to remis- (cid:9)
`.sion, the. employment of immunosuppressants has to be (cid:9)
`considered. Azathioprine is the drug of choice and is given
`in. addition to the gluoocorticoid due to the slow onset of
`.activity after 2-6 months. Side effects YVith .pOssible Severe
`complications (especially complete blood count, Liver;= pan-
`creas) have to by taken into account, The optimal daily dose
`of azathiopdne seems to be. 2-3 mg/kg body weight (see
`also page 66/6.7).
`The aim of the treatment has to be reduction of corticoste-
`mid. dosage besides the induction of clinical remission.
`
`Detection of surgically removable causes of symptoms.
`(stenoses, fistuia.e) car lead to improvement after the
`appropriate surgery:
`
`Patients with .CrOhn's disease :suffer from a. high recurrence (cid:9)
`rate. For this reason, when steroid-induced remission has (cid:9)
`been achieved, steroid treatment is phased out gradually
`over a to 6- Months: Studies an recurrence.prpphylaxis'with
`rnesalazine show a Positive .effett on maintenance Of re-
`mis.sio n A daily dose of.3_d/day is. favourable.
`
`Chronic
`active form
`
`Moihrerpnep
`of remiS$I00:
`
`•
`
`MI (cid:9)
`
`U
`
`FALKN000051 59
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 27
`
`

`
`Drug Therapy of Crohn's Disease
`
`Treatment (cid:9)
`of fistulae (cid:9)
`
`Fistulae can be treated using metronidazole. Studies show
`that in Up to 50 % of cases, closure of the fistula is achieved
`over a period of about 3 months ('). It must be noted, how-
`ever, that according to the terms of its registration, metro-
`nidazole should not be given for longer than 10 days. This
`means that careful. monitoring ofside effects is necessary
`when patients are treated over longer periods With metro-
`nidazole in the event of peripheral neuropathies with
`tingling paresthesia in the legs, metronidazole must be dis-
`continued imme:diately in order to bring about reversal of
`the symptoms. Mere reduction of the dose is not sufficient,
`
`In azathioprine-treatment of fistula a significantly higher
`healing rate of 31 % in the azathioprine group versus 6 % in
`the placebo group has been shown in different studies.'
`
`Crohn's disease patients suffering from fistula without re-
`sponse to conventional treatment are indicated for therapy
`with. a nti-TNF-ct-a ntibodies..
`
`26
`
`U
`
`FALKN000051 60
`
`Dr. Falk Ex. 2008
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 28
`
`

`
`Therapy
`E verview
`Crohn's
`disease
`
`Drug: therapy of the acute inflammatory attack
`and sqns• and CI;! ica li!;(i•ngs 'abc,'ratcr
`:
`: (cid:9)
`: (cid:9)
`• (cid:9)
`. (cid:9)
`. (cid:9)
`89st'S Eictivi.tyinde:(CIDA1) > 150
`
`. (cid:9)
`
`.
`
`Mild to tooderate.attack:
`.
`MeSalazina (5-13S,,"1)
`4.5 .d d.y oral
`
`y me:lo•,,herapy vt-ith
`attack):
`
`(p (cid:9)
`
`and/or.
`Budesonide 9 m g gaily oral
`ilecoeca localczatic:n a, ..
`- (cid:9)
`F.isoendens
`exyaIntesinal symptoms jr.'
`nan testatiors
`
`'11;th involvement the rectum
`and •:he Ci%St 3i ccIc is
`Locai Eh:erlapi: Wi'd•‘• mesaiazi„e
`S
`f.'LJ(06sitdrii?,s or -eriOn,9
`Scel'o!d tb,•31-0 ce.1.-enerias
`ene):1- 1c.
`• : (cid:9)
`•
`
`Medium-severe to severe
`attack:
`l'tecinisone or prednisone
`etpkiValentwaily
`necessary
`1Si week
`yveek
`
`<IV t
`5