CrohnCrohn’’ss Disease:Disease:Challenges and new Challenges and new therapeutic optionstherapeutic options

Claudia MeyerClaudia MeyerJuly 2007July 2007

GreyGrey’’s Hospitals Hospital

Index patientIndex patient

29 year old gentleman, Mr. N.S.29 year old gentleman, Mr. N.S.Main complaintMain complaint: : Acute onset of severe, constant RIF pain, Acute onset of severe, constant RIF pain, since previous night, associated LOA, since previous night, associated LOA, no no n&v/diarrhoean&v/diarrhoea. . Four month history of severe, constant Four month history of severe, constant backpainbackpain, only partially relieved by , only partially relieved by analgesics. However, since the onset of analgesics. However, since the onset of abdominal pain, abdominal pain, backpainbackpain ceased.ceased.

History: continuedHistory: continued

PMH: CD was diagnosed in 1999 PMH: CD was diagnosed in 1999 →→initially managed with initially managed with sulfasalazinesulfasalazine. . In 2005 he was initiated on In 2005 he was initiated on AsacolAsacol and and prednisone 20mg prednisone 20mg dlydly. . A colonoscopy in June 2006: active A colonoscopy in June 2006: active CrohnCrohn’’ss ileitis, focal ileitis, focal ulceration in TC. ulceration in TC. AzathioprineAzathioprine added to added to his treatment.his treatment.

History: continuedHistory: continued

Unsuccessful at induction of remission Unsuccessful at induction of remission →→azathioprineazathioprine was gradually titrated was gradually titrated upwards from 75mg upwards from 75mg dlydly to 150mg to 150mg dlydly. . Patient became steroid dependentPatient became steroid dependentSince February 2007 Since February 2007 →→ lower back pain, lower back pain, spontaneous onset, nonspontaneous onset, non--progressive, progressive, radiating to R thigh, radiating to R thigh, o/eo/e normal alignment, normal alignment, tense tense paraspinalsparaspinals L > R, back nonL > R, back non--tender, tender, full ROM, hips FROM, full ROM, hips FROM, XrayXray spine: NADspine: NAD

History: continuedHistory: continuedPSH: incomplete bowel obstruction PSH: incomplete bowel obstruction →→ intestinal intestinal resection with endresection with end--toto--end end anastomosisanastomosis in 2000 in 2000 and 2002and 2002Medication: Medication: AzathioprineAzathioprine 150mg 150mg dlydly, Prednisone , Prednisone 12,5mg 12,5mg dlydly, , AsacolAsacol 800mg 800mg tdstds, Ca , Ca gluconategluconate 1 1 bdbd, Ferrous , Ferrous sulphatesulphate, Analgesics, AnalgesicsAllergies: nil knownAllergies: nil knownSocial: nonSocial: non--smoker, abstaining from alcohol, smoker, abstaining from alcohol, married, unable to maintain work due to his married, unable to maintain work due to his disease. disease. Family Family HxHx: nil of note: nil of note

ExaminationExaminationAcutely ill, drowsyAcutely ill, drowsyBP 59/36, HR 130BP 59/36, HR 130, RR 24, , RR 24, temp 39temp 39’’, mild deH2O, mild deH2ONo extraNo extra--intestinal features of intestinal features of CrohnCrohn’’ss diseasediseaseCVS: CVS: bounding pulses, warm peripheriesbounding pulses, warm peripheries, , regular, JVP regular, JVP →→, apex 5ICS, HS normal, no , apex 5ICS, HS normal, no murmurs, murmurs, septic shockseptic shockChest: not distressed, clear, Chest: not distressed, clear, bilatbilat br/sbr/sAbdomen: Abdomen: RIF tenderness, rebound & RIF tenderness, rebound & peritonismperitonism, no , no organomegalyorganomegaly, no , no perianalperianalcomplications, PR: no stool, no blood, no masscomplications, PR: no stool, no blood, no massNeuroNeuro: drowsy, no : drowsy, no meningismmeningism, no focal signs, no focal signs

Clinical assessmentClinical assessment

28 year old gentleman with chronic active 28 year old gentleman with chronic active CrohnCrohn’’ss disease, refractory to disease, refractory to azathioprineazathioprineas well as steroidas well as steroid--dependent, presenting dependent, presenting now with septic shock and localized now with septic shock and localized peritonitis in the right iliac peritonitis in the right iliac fossafossa. Possible . Possible cause: abscess formation or perforation.cause: abscess formation or perforation.

InvestigationsInvestigations

FBCFBC: WBC 7,1; : WBC 7,1; HB 8,2HB 8,2; PLT 260; MCV 83,5; PLT 260; MCV 83,5U&E:U&E: Na 141; K 4,1; Na 141; K 4,1; ClCl 110; Co2 26; 110; Co2 26;

urea 9,1; urea 9,1; creatcreat 9595LFTLFT: ALP 57; : ALP 57; BilBil 7; Prot 61; 7; Prot 61; alb 25alb 25; GGT 26; ; GGT 26;

ALT 11ALT 11CMPCMP:Corr:Corr Ca 2,36; Pho4 1,02; Mg 0,77Ca 2,36; Pho4 1,02; Mg 0,77Ultrasound:Ultrasound: Small collection on the right side Small collection on the right side of the pelvisof the pelvis

Initial managementInitial managementResuscitation with Resuscitation with voluvenvoluven, IV fluids, IV fluidsCiprofloxacin 400mg q8h IV, Ciprofloxacin 400mg q8h IV, MetronidazoleMetronidazole 500mg 500mg AzathioprineAzathioprine 150mg 150mg dlydly popoHydrocortisone 100mg Hydrocortisone 100mg qidqid IVIIVIUrgent surgical consultUrgent surgical consultCT abdomenCT abdomen: Right : Right paracolicparacolic abscess, defect in abscess, defect in wall at wall at anastomosisanastomosis between colon & terminal between colon & terminal ileumileumInterventionIntervention: : Pigtail drain insertedPigtail drain inserted under sonar under sonar guidance into RLQ collection, draining brown pus guidance into RLQ collection, draining brown pus & bowel contents. High& bowel contents. High--volume fistula suspected. volume fistula suspected. Irregular collection with multiple fistulous tracts.Irregular collection with multiple fistulous tracts.

CrohnCrohn’’ss Disease: Disease: Challenges and New Challenges and New Treatment strategiesTreatment strategies

Introduction Introduction Idiopathic inflammatory bowel disorder.Idiopathic inflammatory bowel disorder.Hypothesis: Hypothesis: CrohnCrohn’’ss disease occurs in a disease occurs in a genetically predisposed patient, when genetically predisposed patient, when various exogenous factors and hostvarious exogenous factors and host--factors factors cause cause dysregulationdysregulation of the mucosal immune of the mucosal immune function.function.

Pathogenesis Pathogenesis Genetic susceptibility:Genetic susceptibility:Polygenetic disease: 12 susceptibility regions Polygenetic disease: 12 susceptibility regions Exogenous factors:Exogenous factors:Smoking; Smoking; Hygiene hypothesisHygiene hypothesis

ImmunopathogenesisImmunopathogenesis: Initiating events: Initiating events1.1. Leaky epithelial barrierLeaky epithelial barrier2.2. Different pattern of tollDifferent pattern of toll--like receptor expressionlike receptor expression3.3. DendriticDendritic cells incorrectly recognize cells incorrectly recognize commensalcommensal

bacteria as pathogens bacteria as pathogens →→ initiate a Th1 immune initiate a Th1 immune response.response.

4.4. Epithelial cells activate Epithelial cells activate effectoreffector--T cellsT cells5.5. Activated T cells do not undergo apoptosisActivated T cells do not undergo apoptosis

Clinical presentationClinical presentationA .Clinical presentation depends on disease A .Clinical presentation depends on disease location: Intestinal manifestations:location: Intestinal manifestations:1. 1. ileocolitisileocolitis2. 2. jejunoileitisjejunoileitis3. colitis & 3. colitis & perianalperianal diseasedisease4. 4. gastroduodenalgastroduodenal diseasediseaseB. Complications: B. Complications: Intestinal obstruction, free perforation, intraIntestinal obstruction, free perforation, intra--abdominal abscess, fistula formation, massive abdominal abscess, fistula formation, massive hemorrhage, hemorrhage, malabsorptionmalabsorption, severe , severe perianalperianaldiseasediseaseC. C. ExtraintestinalExtraintestinal manifestationsmanifestations

ExtraintestinalExtraintestinal manifestationsmanifestations

ExtraintestinalExtraintestinal manifestationsmanifestations

ExtraintestinalExtraintestinal manifestationsmanifestationsCardiacCardiac: : myocarditismyocarditisPulmonaryPulmonary: : pleuropericarditispleuropericarditis, ILD, ILDHebatobiliaryHebatobiliary: hepatic : hepatic steatosissteatosis, 1, 1’’ sclerosingsclerosingcholangitischolangitis, , cholelithiasischolelithiasis, , pancreatitispancreatitisRenalRenal: : nephrolithiasisnephrolithiasis, , hydronephrosishydronephrosis, fistulas, , fistulas, renal renal amyloidosisamyloidosisRheumatologicalRheumatological: migratory arthritis or : migratory arthritis or arthralgiaarthralgia, , ankylosingankylosing spondylitisspondylitis, , sacroiliitissacroiliitisDermatologicalDermatological: : erythemaerythema nodosumnodosum, , pyodermapyodermagangrenosumgangrenosum, , metastaticmetastatic crohncrohn’’ss, , aphthousaphthousstomatitisstomatitisOther:Other: Osteoporosis, Osteoporosis, thromboembolismsthromboembolisms

Disease activityDisease activityCrohnCrohn’’ss disease activity index used for disease activity index used for research purposesresearch purposesCombination of clinical assessment and Combination of clinical assessment and laboratory features used in practice: laboratory features used in practice: symptoms, weight, symptoms, weight, HbHb, albumin, ESR, , albumin, ESR, CRP, WBCCRP, WBC

DefinitionsDefinitionsRemissionRemission: Asymptomatic patients without : Asymptomatic patients without inflammatory inflammatory sequelaesequelae. . Chronic active CD Chronic active CD : Persisting/recurrent symptoms : Persisting/recurrent symptoms for > 6 months despite for > 6 months despite standardisedstandardised therapy. therapy. SteroidSteroid--dependent CD: dependent CD: Need for Need for c/sc/s to maintain the to maintain the pt in remission, after two unsuccessful attempts to pt in remission, after two unsuccessful attempts to withdraw withdraw c/sc/s within the last 6 months. within the last 6 months. SteroidSteroid--refractory CD: refractory CD: Persisting clinical activity Persisting clinical activity despite corticosteroids > 1mg/kg/daydespite corticosteroids > 1mg/kg/day..

ManagementManagement

1. 51. 5--Aminosalicylic acid Aminosalicylic acid compundscompunds2. Corticosteroids2. Corticosteroids3. Antibiotics3. Antibiotics4. Immunosuppressive agents4. Immunosuppressive agents5. Biological agents5. Biological agents6. Surgical management6. Surgical management

5 5 AminosalicylicAminosalicylic acid compoundsacid compounds

AzoAzo--BondBond: : SulfasalazineSulfasalazine sulfapyridinesulfapyridine--5ASA Colon5ASA ColonOlsalazineOlsalazine 55--ASAASA--55--ASA ColonASA ColonBalsalazideBalsalazide aminobenzoylaminobenzoyl-- ColonColon

alaninalanin--55--ASAASADelayedDelayedReleaseRelease: : AsacolAsacol EudragicEudragic (ph7) ileum(ph7) ileum--coloncolon

ClaversalClaversal EudragictEudragict (ph6) ileum(ph6) ileum--coloncolon

SustainedSustainedReleaseRelease: : PentasaPentasa ethylcelluloseethylcellulose stomach stomach -- coloncolon

microgranulesmicrogranules

5 5 AminosalicylicAminosalicylic acid compoundsacid compoundsSulfasalazineSulfasalazine effective in inducing remission effective in inducing remission in CD, in CD, espesp colitis, colitis, ileocollitisileocollitis ( ECCDS )( ECCDS )SulfasalzineSulfasalzine notnot effective for maintenance of effective for maintenance of remission ( NCCDS )remission ( NCCDS )AsacolAsacol significantly significantly ↓↓ relapse in pt in remission relapse in pt in remission Mechanism ( 5Mechanism ( 5--ASA )ASA )1. inhibition of NF1. inhibition of NF--κκB activityB activity2. inhibits 52. inhibits 5--lipoxygenase synthesis and lipoxygenase synthesis and

therefore inhibits synthesis of therefore inhibits synthesis of leukotrienesleukotrienes3. free radical scavenger3. free radical scavenger

CorticosteroidsCorticosteroidsPredinisonePredinisone: 17 wk course of prednisone (0,5: 17 wk course of prednisone (0,5--0,75mg/kg) induced remission in 60% pt ( NCCDS)0,75mg/kg) induced remission in 60% pt ( NCCDS)Maintenance therapy with low dose prednisone Maintenance therapy with low dose prednisone not not effective ( prednisone at 0,25mg/kg, NCCDS)effective ( prednisone at 0,25mg/kg, NCCDS)BudesonideBudesonide is effective at inducing remission is effective at inducing remission (NEJM 1994 ) and prolongs time to relapse. (NEJM 1994 ) and prolongs time to relapse. Extensive firstExtensive first--pass metabolism pass metabolism

Antibiotics Antibiotics MetronidazoleMetronidazole : : perianalperianal and fistulous CD, abscessand fistulous CD, abscessCiprofloxacineCiprofloxacine ( 500mg ( 500mg bdbd) : ) : perianalperianal, fistulous CD, fistulous CD

Immunosuppressive agentsImmunosuppressive agents

Indications:Indications:Chronic active diseaseChronic active diseaseSteroidSteroid--dependent diseasedependent diseaseLongLong--term maintenance following a term maintenance following a biological agentbiological agentPrevention of Prevention of immunogenicityimmunogenicity to to biological agentsbiological agentsPrevention of postPrevention of post--operative recurrenceoperative recurrence

AzathioprineAzathioprineNot ideal induction agent Not ideal induction agent d/td/t slow onset of actionslow onset of actionEffective maintenance of remission; Dose: 2 Effective maintenance of remission; Dose: 2 –– 2,5mg/kg2,5mg/kgSideSide--effects:effects:

-- bone marrow depression, bone marrow depression, espesp leukopenialeukopenia ( ( ↑↑ risk: TPMT risk: TPMT deficiency, codeficiency, co--drugs: drugs: allopurinolallopurinol, , sulfasalazinesulfasalazine ))

-- pancreatitispancreatitis, hepatitis, infection, lymphoma, hepatitis, infection, lymphoma-- if lacking the if lacking the thiopurinethiopurine methyltransferasemethyltransferase →→ acc acc

thioguaninethioguanine metabolitesmetabolites

MethotrexateMethotrexateAction:Action: inhibits inhibits dihydrofolatedihydrofolate reductasereductaseresulting in impaired DNA synthesis & resulting in impaired DNA synthesis & decreased production of IL 1decreased production of IL 1

MethotrexateMethotrexate: Trials: TrialsMethotrexateMethotrexate for induction: for induction: MTXMTX 25mg IMI25mg IMIweekly. weekly. Improvement in Improvement in SxSx in 6 weeks. in 6 weeks. 17% of pt in 17% of pt in methotrexatemethotrexate group had group had adverse event ( adverse event ( aSxaSx ↑↑ALT, nausea, skin ALT, nausea, skin rash, P, optic neuritisrash, P, optic neuritis). ). MethotrexateMethotrexate for maintenance: for maintenance: MTX MTX 15mg IMI weekly, effective as 15mg IMI weekly, effective as maintenacemaintenace, , no severe adverse events reported in no severe adverse events reported in RCT. RCT.

MethotrexateMethotrexateSideSide--effects:effects:

-- leukopenialeukopenia, BM suppression, BM suppression-- infectioninfection-- hepatic fibrosis, hepatic fibrosis, ↑↑ ALT, ALT, hypersensitivity Phypersensitivity P-- teratogenicteratogenic, , mucositismucositis, rash, rashBone marrow toxicityBone marrow toxicity : a late complication of Rx. Median : a late complication of Rx. Median delay to delay to neutropenianeutropenia 16.9 months VERSUS onset within 16.9 months VERSUS onset within days to weeksdays to weeks↑↑ RiskRisk: Drugs: : Drugs: C/SC/S, NSAIDS, , NSAIDS, omeprazoleomeprazole, , penicillinpenicillin, , CoCo--trimoxazoletrimoxazole. Larger dose, . Larger dose, ↓↓ renal renal FxFx, , ascitesascites/ / oedemaoedema/effusion. /effusion. IV contrast can precipitate toxicityIV contrast can precipitate toxicityTreatmentTreatment: 1. stop MTX 2. Give : 1. stop MTX 2. Give folinicfolinic acid/acid/leucovorinleucovorin3. Granulocyte CSF 4. Abs3. Granulocyte CSF 4. Abs

Biotechnology agentsBiotechnology agents

InfliximabInfliximab:: chimericchimeric IgG1 monoclonal antibody IgG1 monoclonal antibody induction: 5 or 10 mg/kg IVI and week 0, 2, 6. induction: 5 or 10 mg/kg IVI and week 0, 2, 6. maintenance: 5 or 10mg/kg IVI every 8 weeks.maintenance: 5 or 10mg/kg IVI every 8 weeks.Action:Action: neutralize TNF neutralize TNF αα, induce apoptosis in T , induce apoptosis in T lymphocytes, mediate ABlymphocytes, mediate AB--dependent cellular dependent cellular cytotoxicitycytotoxicity and Cand C’’ fixationfixationAdalimumabAdalimumab:: human IgG1 human IgG1 mAbmAb (100% human (100% human protprot))

InfliximabInfliximab: side: side--effects effects Infections, Infections, espesp TB, TB, histoplasmosishistoplasmosis→→ Odds ratio 2.0 for serious Odds ratio 2.0 for serious infinf; ; NNH: 59, within a Rx period of NNH: 59, within a Rx period of 2 2 –– 12 months12 monthsLymphoma: nonLymphoma: non--HodgkinHodgkin’’s, Skin cancers: s, Skin cancers: squamoussquamous & basal cell CA& basal cell CA →→ odds ratio 3.3; odds ratio 3.3; NNH was 154 for 1 additional malignancy within a NNH was 154 for 1 additional malignancy within a Rx period of 6 Rx period of 6 –– 12 months12 monthsMultiple sclerosis, optic neuritisMultiple sclerosis, optic neuritisAcute infusion reactions, delayed Acute infusion reactions, delayed hypershypers reactionsreactionsFormation of autoFormation of auto--antibodiesantibodies, , egeg ANFANF

Other biotechnology agentsOther biotechnology agentsNatalixumabNatalixumab:: humanized IgG4 monoclonal humanized IgG4 monoclonal antibody against antibody against αα4 4 integrinintegrin (95%human). (95%human). Action: Action: neutralizes neutralizes αα4 4 integrinintegrinCertolizumabCertolizumab pegolpegol: : pegylatedpegylated humanized humanized monoclonal antibody F AB fragment.monoclonal antibody F AB fragment.

Mild CD: InductionMild CD: InductionFirst lineFirst line: : budesonidebudesonide or or sulfasalazinesulfasalazineSecond lineSecond line: Oral : Oral prednisoloneprednisolone 40 40 –– 60mg 60mg dlydlyThird lineThird line: : MethotrexateMethotrexate 25mg weekly IMI25mg weekly IMI

-- AzathioprineAzathioprine not ideal not ideal d/td/t slow onset of actionslow onset of action-- InfliximabInfliximab 5mg/kg at weeks 0, 2, 6 or 5mg/kg at weeks 0, 2, 6 or AdalimumabAdalimumab

FulminantFulminant or refractory CDor refractory CDFirst lineFirst line: IV corticosteroids 1mg/kg/day: IV corticosteroids 1mg/kg/daySecond lineSecond line: IV : IV infliximabinfliximab or or adalimumabadalimumabSurgery if obstructive complication or not able to Surgery if obstructive complication or not able to tolerate medical therapytolerate medical therapy

FistulisingFistulising CrohnCrohn’’ss diseasediseaseFirst lineFirst line: : CiprofloxacineCiprofloxacine 500mg 500mg bdbd , , metronidazolemetronidazole 1000mg 1000mg –– 1500mg 1500mg dlydlySecond line:Second line: AzathioprineAzathioprine 2,5mg/kg/day2,5mg/kg/dayThird lineThird line: : InfliximabInfliximabFourth lineFourth line: : FistulotomyFistulotomy

SurgerySurgeryFibroticFibrotic strictures strictures →→ bowel obstructionbowel obstructionInternal fistulas complicated by abdominal Internal fistulas complicated by abdominal abscessabscessEnterovesicalEnterovesical fistulasfistulasEnterocutaneousEnterocutaneous fistulasfistulas

PatientPatient’’s Progresss Progress

Week 2/day 10Week 2/day 10: Pt developed a high: Pt developed a high--output output enterocutaneousenterocutaneous fistula. fistula. MxMx: TPN, IV AB: TPN, IV ABWeek 5/day 32:Week 5/day 32: Necrotizing Necrotizing fasciitisfasciitis, abscesses , abscesses ant & posterior to right ant & posterior to right iliailia crest crest →→ MxMx: : debridementdebridement, TPN, , TPN, PiperacillinPiperacillin--TazobactamTazobactam, , metronidazolemetronidazole, Ciprofloxacin, CiprofloxacinWeek 7/ Day 47Week 7/ Day 47: Massive GIT bleed. : Massive GIT bleed. HbHb 9,7 9,7 →→6,5; 6,5; GastroscopyGastroscopy: no ulcer, : no ulcer, oesoes candidiasiscandidiasis, , MxMx: : IV PPI, transfusion, IV PPI, transfusion, fluconazolefluconazole

PatientPatient’’s Progresss ProgressWeek 8/ day 49: Week 8/ day 49: Initiated on Initiated on methotrexatemethotrexate 25mg 25mg IMI weekly plus folic acid, longIMI weekly plus folic acid, long--term ciprofloxacin to term ciprofloxacin to induce fistula closureinduce fistula closureWeek 9/ day 62:Week 9/ day 62: Febrile Febrile neutropenianeutropenia, temp 39,5, temp 39,5’’, , HR 135, lungs clear, CXR: NAD, uHR 135, lungs clear, CXR: NAD, u--dipstick : NAD. dipstick : NAD. MxMx: : PiperacillinPiperacillin-- TazobactamTazobactam, , MetronidazoleMetronidazole, , Ciprofloxacin, stop MTX, stop Ciprofloxacin, stop MTX, stop azathioprineazathioprineWeek 10/ day 65:Week 10/ day 65: Poor response to AB, rePoor response to AB, re--exploration of groin wound: clean, no pus exploration of groin wound: clean, no pus collection, collection, HbHb: 8,7; WBC 0,4; : 8,7; WBC 0,4; neutroneutro 0,1; PLT 90. 0,1; PLT 90. Blood & uBlood & u--MCS: no growth x4. MCS: no growth x4. MxMx: : NeupogenNeupogen, , LeucovorinLeucovorin, , PiperacillinPiperacillin--TazobactamTazobactam, , MetronidazoleMetronidazole, , AmikacinAmikacin addedadded

PatientPatient’’s Progresss ProgressWeek 10/ day 68Week 10/ day 68: : PiperacillinPiperacillin--TazobactamTazobactamsubstituted with substituted with meropenemmeropenem, IV , IV FluconazoleFluconazoleWeek 10/ day 69Week 10/ day 69: Fever & tachycardia resolved, : Fever & tachycardia resolved, minimal minimal petechiaepetechiae right knee. right knee. PancytopeniaPancytopeniapersisted, WBC 0,4; persisted, WBC 0,4; NeutroNeutro 0,3;HB 7,3; PLT 36, 0,3;HB 7,3; PLT 36, MPV 10,7; RPI 0,7%. Smear: NCNC, no MPV 10,7; RPI 0,7%. Smear: NCNC, no fragments, no PLT clumping; INR 1,22; APTT 24,6. fragments, no PLT clumping; INR 1,22; APTT 24,6. Blood culture: repeatedly no growth, urea& Blood culture: repeatedly no growth, urea& creatcreat: : WNL. WNL. MxMx IV AB, packed cells, K replacementIV AB, packed cells, K replacement

PerspectivePerspective28yr old pt with 28yr old pt with CrohnCrohn’’ss disease, previously disease, previously treated with treated with azathioprineazathioprine for one year, weekly for one year, weekly MTX was initiated 20 days ago. Pt received daily MTX was initiated 20 days ago. Pt received daily folatefolate as well as INH prophylaxis.as well as INH prophylaxis.Febrile Febrile neutropenianeutropenia and and pancytopeniapancytopenia, not , not responding to responding to leucovorinleucovorin and and neupogenneupogen..Differentials:Differentials:-- MethotrexateMethotrexate induced induced myelosuppressionmyelosuppression-- AzathioprineAzathioprine induced induced myelosuppressionmyelosuppression-- Opportunistic infection Opportunistic infection egeg TB, TB, HistoplasmosisHistoplasmosis

PatientPatient’’s Progresss ProgressWeek 11/ day 70: Week 11/ day 70: Sudden depressed LOC. Pinpoint pupils Sudden depressed LOC. Pinpoint pupils bilaterally, no bilaterally, no meningismmeningism, globally depressed , globally depressed tone, left tone, left hemiparesishemiparesis, , plantarsplantars equivocal equivocal bilaterally;bilaterally;→→ no response to no response to naloxonenaloxone, , →→ required required intubationintubation for airway protection for airway protection →→ IV fluids, Platelets, FDP, urgent CT brainIV fluids, Platelets, FDP, urgent CT brain

PatientPatient’’s Progresss ProgressLarge R Large R parietoparieto--occipital ICH occipital ICH with smaller ICH on the L with smaller ICH on the L occipital lobe with occipital lobe with oedemaoedemaMass effect & midline shift to Mass effect & midline shift to leftleftInfarct left external capsule Infarct left external capsule ( ( subcutesubcute ))→→ CD pt with extensive CD pt with extensive bilateral bilateral ICHsICHs, as well as an , as well as an infarctinfarct

NeurologicNeurologic manifestations of IBDmanifestations of IBD

CVD CVD d/td/t thrombosis and thrombosis and thromboembolismthromboembolismCerebral Cerebral vasculitisvasculitis, necrotizing , necrotizing angiitisangiitisImmune mediated neuropathy and Immune mediated neuropathy and cerebral cerebral demyelinationdemyelination

Question arisesQuestion arises: Could this patient have : Could this patient have had cerebral had cerebral vasculitisvasculitis/necrotizing /necrotizing angiitisangiitiswhich resulted in which resulted in ICHsICHs in the presence of in the presence of significant significant thrombocytopaeniathrombocytopaenia??

PatientPatient’’s Progress: Differentialss Progress: DifferentialsClinically:Clinically: frothy sputum, frothy sputum, bibasalbibasal crepitationscrepitations, PO2 , PO2 16.19 16.19 kPakPa on Ton T--piece piece NeurogenicNeurogenic pulmpulmoedemaoedemaLRTI: LRTI: PneumocystisPneumocystis, TB, , TB, aspiration aspiration ILD: related to MTX or ILD: related to MTX or CrohnCrohn’’ss DDAlveolar Alveolar haemorrhagehaemorrhage, , ALIALI

PatientPatient’’s Progresss Progress

Week 11/ day 71: Week 11/ day 71: Not for neurosurgical Not for neurosurgical intervention due to extensive intervention due to extensive haemorrhageshaemorrhages and and thrombocytopenia. Supportive management with thrombocytopenia. Supportive management with mannitolmannitol, , dexamethasonedexamethasone, IV antibiotics., IV antibiotics.Week 11/ day 72:Week 11/ day 72: Patient rested in peace Patient rested in peace surrounded by his family & friendssurrounded by his family & friends..

ReferencesReferencesBaumgartBaumgart DC. Inflammatory bowel disease: cause and DC. Inflammatory bowel disease: cause and immunobiologyimmunobiology. Lancet 2007:369:1627. Lancet 2007:369:1627--4040BaumgartBaumgart DC. Inflammatory bowel DC. Inflammatory bowel disease:clinicaldisease:clinicalaspects and established and evolving therapies. Lancet aspects and established and evolving therapies. Lancet 2007;369:16412007;369:1641--5757Shanahan F. Shanahan F. CrohnCrohn’’ss Disease. Lancet 2002; 359:62Disease. Lancet 2002; 359:62--6969HarrisonHarrison’’s Principles of Internal Medicine, 16s Principles of Internal Medicine, 16thth editioneditionKumar and ClarkKumar and ClarkSatsangiSatsangi J. The Montreal classification of IBD: J. The Montreal classification of IBD: controversies, consensus, and implications. Gut 2006; controversies, consensus, and implications. Gut 2006; 55: 74955: 749--753753

ReferencesReferencesSytemicSytemic review: the potential influence of review: the potential influence of mesalazinemesalazine formulation on maintenance of formulation on maintenance of remission in remission in CrohnCrohn’’ss disease. Aliment disease. Aliment PharmacolPharmacol TherTher. 2007;25:1389. 2007;25:1389--9999Oral Oral budesonidebudesonide for active for active CrohnCrohn’’ss. NEJM . NEJM 1994;331:8361994;331:836BueningBuening C. Conventional therapy for C. Conventional therapy for CrohnCrohn’’ssdisease. World J disease. World J GastroenterolGastroenterol 2006; 12: 47942006; 12: 4794--48064806FeaganFeagan BG. A Comparison of BG. A Comparison of MethotrexateMethotrexate with with placebo for the maintenance of remission in placebo for the maintenance of remission in CrohnCrohn’’ss Disease. NEJM 2000;342:1627Disease. NEJM 2000;342:1627--3232

ReferencesReferencesBongartzBongartz T. AntiT. Anti--TNF Antibody therapy in TNF Antibody therapy in Rheumatoid arthritis and the Risk of Serious Rheumatoid arthritis and the Risk of Serious Infections and Malignancies. JAMA 2006;295: Infections and Malignancies. JAMA 2006;295: 22752275--22852285ScheidScheid R. R. NeurologicNeurologic manifestations of manifestations of ulcerative colitis. European J of Neurology 2007; ulcerative colitis. European J of Neurology 2007; 14:48314:483--493493Johns DR. Johns DR. CerebrovascularCerebrovascular complications of complications of inflammatory bowel disease. Am J inflammatory bowel disease. Am J GastroenterolGastroenterol1991;86:3671991;86:367--7070

Thank youThank you

Disease activity cont.Disease activity cont.MildMild--moderatemoderate: ambulatory pts tolerating oral : ambulatory pts tolerating oral meals without dehydration or >10% weight lossmeals without dehydration or >10% weight loss

Moderate to severeModerate to severe: failure to respond to : failure to respond to treatment for mild disease, fever, weight loss, treatment for mild disease, fever, weight loss, abdabdpain /tenderness, intermittent N&V without pain /tenderness, intermittent N&V without obstruction, significant obstruction, significant anaemiaanaemia

Severe to Severe to fulminantfulminant: persisting : persisting sxsx on on c/sc/s, high , high fevers, persistent vomiting, intestinal obstruction, fevers, persistent vomiting, intestinal obstruction, rebound tenderness, rebound tenderness, cachexiacachexia, abscess, abscess

AzathioprineAzathioprineDoseDose: 2 : 2 –– 2,5mg/kg2,5mg/kgActionAction: : azathioprineazathioprine →→ 66-- mercaptopurinemercaptopurine →→thioinosinicthioinosinic acid acid →→ inhibitor of inhibitor of purinepurineribonucleotideribonucleotide synthesis & cell proliferation, synthesis & cell proliferation, inhibits immune responseinhibits immune responseNot ideal induction agent Not ideal induction agent d/td/t slow onset of actionslow onset of actionEffective maintenance of remissionEffective maintenance of remissionPossibly effective in fistula closurePossibly effective in fistula closure

MethotrexateMethotrexateMethotrexateMethotrexate for maintenance: for maintenance: MTX 15mg IMI MTX 15mg IMI weekly. At week 40, 65% pt in remission in MTX weekly. At week 40, 65% pt in remission in MTX group versus 39% in placebo group. P 0,04. No group versus 39% in placebo group. P 0,04. No severe adverse eventssevere adverse events..SideSide--effects:effects:-- leukopenialeukopenia, bone marrow suppression, bone marrow suppression-- hepatic fibrosis, raised hepatic fibrosis, raised transaminasestransaminases-- hypersensitivity hypersensitivity pneumonitispneumonitis-- teratogenicteratogenic-- mucositismucositis, rash, nausea, , rash, nausea, diarrhoeadiarrhoea-- infectioninfection

““ TopTop--down down ““ TherapyTherapy

Use of AntiUse of Anti--TNF agents early in the course TNF agents early in the course of CD. Larger studies needed to asses of CD. Larger studies needed to asses safety and efficacy.safety and efficacy.

MethotrexateMethotrexateAction:Action: inhibits inhibits dihydrofolatedihydrofolate reductasereductaseresulting in impaired DNA synthesis & resulting in impaired DNA synthesis & decreased production of IL 1decreased production of IL 1MethotrexateMethotrexate for induction: for induction: MTXMTX 25mg IMI 25mg IMI weekly.weekly. After 16 weeks: 39% in MTX After 16 weeks: 39% in MTX vsvs 19,1% in 19,1% in placebo group in remission. P 0,025. placebo group in remission. P 0,025. 17% of pt in 17% of pt in methotrexatemethotrexate group had adverse group had adverse event ( event ( aSxaSx ↑↑ALT, nausea, skin rash, ALT, nausea, skin rash, pneumonia, optic neuritispneumonia, optic neuritis). ). Improvement in Improvement in SxSx in 6 weeks in in 6 weeks in methotrexatemethotrexategroupgroup

Biotechnology agentsBiotechnology agents

Mechanism of action:Mechanism of action:InfliximabInfliximab, , adalimumabadalimumab, , certolizumabcertolizumabpegolpegol: neutralize TNF : neutralize TNF ααInfliximabInfliximab and and adalimumabadalimumab also induce also induce apoptosis in T lymphocytes in vitro and apoptosis in T lymphocytes in vitro and mediate antibodymediate antibody--dependent cellular dependent cellular cytotoxicitycytotoxicity and complement fixationand complement fixationNatalixumabNatalixumab neutralizes neutralizes αα4 4 integrinintegrin

MethotrexateMethotrexate: bone marrow : bone marrow suppressionsuppression

Bone marrow toxicity with MTX a late Bone marrow toxicity with MTX a late complication of Rx. Median delay to complication of Rx. Median delay to neutropenianeutropenia16.9 months16.9 monthsDrugs that can cause BM suppression if Drugs that can cause BM suppression if combine with MTX: combine with MTX: corticosteoridscorticosteorids, NSAIDS, , NSAIDS, omeprazoleomeprazole, penicillin, Co, penicillin, Co--trimoxazoletrimoxazole..Treatment:Treatment: stop MTX stop MTX

-- Give Give folinicfolinic acidacid-- Granulocyte colony stimulating factor if poor Granulocyte colony stimulating factor if poor

response or pt severely illresponse or pt severely ill-- ABsABs according to local guidelines.according to local guidelines.