A GP guide to Inflammatory A GP guide to Inflammatory Bowel DiseaseBowel Disease

Dr Azhar Ansari MRCP MD Dr Azhar Ansari MRCP MD Consultant Gastroenterologist Consultant Gastroenterologist

& Lead in IBD& Lead in IBDEast SurreyEast Surrey

Case report 1Case report 1HesterHester

Age 18: UC: steroid dependant Age 18: UC: steroid dependant

Age 26: AZA 2mg/kg: hepatotoxicity (1999)Age 26: AZA 2mg/kg: hepatotoxicity (1999)

Standard treatment: surgery: scheduledStandard treatment: surgery: scheduled

Interruption of medical studies: 1Interruption of medical studies: 1stst year clinical year clinical

Tx: ???Tx: ???

Case report 2Case report 2Daniel Age 19 yearsDaniel Age 19 years

Age 12: CD Age 12: CD

Neutropenia on high dose 6MP: NO responseNeutropenia on high dose 6MP: NO response

Age 14: Infliximab effective for 18 months, then Age 14: Infliximab effective for 18 months, then loss of response loss of response

Age 16: Ileostomy then reversalAge 16: Ileostomy then reversal

Steroid dependency: Avascular necrosis- Steroid dependency: Avascular necrosis- bilateral hip replacementsbilateral hip replacements

Age 18: Transferred to adult clinicAge 18: Transferred to adult clinic

Tx: ???Tx: ???

Case 3Case 3Maria DF 22Maria DF 22

Age 18: CD: Ileo-colonic and perianal. Severe Age 18: CD: Ileo-colonic and perianal. Severe eczemaeczema

Long steroid dependencyLong steroid dependency

Poor response to AZAPoor response to AZA

Loss of weight, social life, employment and self Loss of weight, social life, employment and self esteemesteem

Management: A blood test and colonoscopy.Management: A blood test and colonoscopy.

Tx: ???Tx: ???

Case 4Case 4Susan T 39Susan T 39

Age 22: CDAge 22: CD

Age 28: Ileal resection, stoma and reversal-Age 28: Ileal resection, stoma and reversal-complicated by a fistula. complicated by a fistula.

Age 37: AZA and steroids 10 years: Abdominal Age 37: AZA and steroids 10 years: Abdominal abscess and re-opening of entero-cutaneous abscess and re-opening of entero-cutaneous fistula 2010fistula 2010

Tx: ???Tx: ???

MRI Susan TMRI Susan T

20 surgeries over 12 years

Post treatment

Aims of treatment for IBDAims of treatment for IBD

Achieve remissionAchieve remission

Maintain remissionMaintain remission

Prevent complicationsPrevent complications

Improve quality of lifeImprove quality of life

Multi-disciplinary approach to treatment: Physician, Multi-disciplinary approach to treatment: Physician, Surgeon, IBD nurse Specialist, Dietician, Pharmacist and Surgeon, IBD nurse Specialist, Dietician, Pharmacist and Psychological support. Transition Clinic. MDM Psychological support. Transition Clinic. MDM discussionsdiscussions

UC in Childhood CRC 40%40 years

CD: Similar Findings

Natural History of UCNatural History of UC

UC acute attack Death 33%

Subsequent acute attack Death 12%

Edwards &Truelove 1963

Devroede 1971

UC Death 40%40 years

Weedon 1971

CD Inflammatory: 70% CD: Perforating Strictureing 70%

20 years

CD: Medical therapy: >90%AZA/6MP: 80%Monoclonals: 10-20%

Surgical therapy: 80%>1 Surgery 60%

20 years

UC5ASA: ChemopreventionSteroids Immunosupressives

UC: Failure of medical therapyRelapsing remitting course

20 years

UC: Medical therapy: 90% Surgical therapy: 20%20 years

Natural History past decade

Toxic ColonToxic Colon

Clinical Course of UCClinical Course of UC

Crohn’s Colon

Crohn’s ColonCrohn’s Fistula: Seton

Crohn’s SurgeryBy Permission from Mr CarapetiGuy’s and St Thomas’

Perianal Crohn'sPerianal Crohn'sMild Disease Mild Disease

Perianal Crohn'sPerianal Crohn'sModerate DiseaseModerate Disease

Perianal Crohn'sPerianal Crohn'sSevere DiseaseSevere Disease

Facts and FiguresFacts and Figures

IBD affects 1:400IBD affects 1:400

Doubling in CD over 30 years.Doubling in CD over 30 years.

Young at risk: Teenagers/young adults second peak Young at risk: Teenagers/young adults second peak 50yrs50yrs

North Europe> S Europe. North UK > S UKNorth Europe> S Europe. North UK > S UK

““White collar” White collar”

£720 million/year. 14% of patients (hospitalisations & £720 million/year. 14% of patients (hospitalisations & surgeries) account for 50% of costsurgeries) account for 50% of cost

Cost per 6 months £1200 (UC) and £1600 (CD)Cost per 6 months £1200 (UC) and £1600 (CD)

Quiescent vs relapse = X3 ↑ costsQuiescent vs relapse = X3 ↑ costs

Hospitalisations = X20.Hospitalisations = X20.

Facts and FiguresFacts and FiguresSurgical Risk: CD 80% (most have >1 surgeries), UC 15-Surgical Risk: CD 80% (most have >1 surgeries), UC 15-40%40%

Chronic inflammation leads to the dysplasia Chronic inflammation leads to the dysplasia

Dysplasia = Severe: 40%, Mild 20% risk Synch. CRC. Dysplasia = Severe: 40%, Mild 20% risk Synch. CRC.

Extensive UC greatest risk of CRC: most significant after Extensive UC greatest risk of CRC: most significant after 10 yrs10 yrs– Risk 10-15%. 6-10x higher than normal populationRisk 10-15%. 6-10x higher than normal population

CD similar risk of CRC (surgeries may affect rate)CD similar risk of CRC (surgeries may affect rate)

Facts and FiguresFacts and Figures

Life time risk of steroids: 60-80% Life time risk of steroids: 60-80%

Osteoporosis: Steroids, inflammation and Osteoporosis: Steroids, inflammation and malnutrition assoc. malnutrition assoc.

Risk of fractures: 40% higher for IBD suffersRisk of fractures: 40% higher for IBD suffers

Osteoporosis: significant cost implicationsOsteoporosis: significant cost implications

IBD patients have shorter/”poorer” lives: 10ysIBD patients have shorter/”poorer” lives: 10ys

Incidence / prevalenceIncidence / prevalence

Incidence UCIncidence UC 10: 100,00010: 100,000

Incidence CDIncidence CD 6-7: 100,000 (increasing)6-7: 100,000 (increasing)

Prevalence about 150:100,000 for each Prevalence about 150:100,000 for each

IBD Cases in East Surrey Area = 1,000-IBD Cases in East Surrey Area = 1,000-1,500 1,500

CD

UC

Ulcerative colitis rates similar To Europe.Immigrant populations very high

Crohn’s disease rates lowerthan N Europe.Immigrant populations high.Significant increase in children

UK 13 300 new cases diagnosed each year150 000 IBD total andapproximately 2.2 million across Europe

Disease LocationDisease Location

UC: recto-sigmiod: 30-50% Left sided: 20-30% Pancolitis: 20-30%

CD: Colonic: 33% Ileocolonic: 33% Small bowel: 30%

Perianal: 23%Upper GI: 2-4%

Extra-intestinal ManifestationsExtra-intestinal Manifestations

Upto 36%Some ass with disease activity: Joint, skin, occular and oralUveitis/episcleritis: commonest 4-12%Arthropathies: Axial or peripheral (type I and II): 4-23%Erythema nodosum/PG: 2-34%Hepato-biliary: 5-15% PSC assoc with CRC and CholangioCa

CD: 50% higher than general popultion. Life expentancy 10 years lessDeaths: Cancers, VTE’sUC: slightly higher morality than general population. Risk of CRC falling

MortalityMortality

Uveitis

episcleritis

Erythema Nosdum

Peristomal Pyoderma gangrenosum

30 days full remission

UC: 31% 30 days partial remission

30 days NON RESPONSE

UC: 51%

UC: 18%

CD: 35%

CD: 40%

CD: 25%

The efficacy of corticosteroid therapy in inflammatory bowel disease: analysis of a 5-year UK inception cohort.

Ho GT 2006 AP&T

Steroids 30 day responseSteroids 30 day response

1 yr prolonged response

UC: 17% 1 yr steroid dependence

1 yr surgery

UC: 55%

UC: 21%

CD: 24%

CD: 38%

CD: 35%

The efficacy of corticosteroid therapy in inflammatory bowel disease: analysis of a 5-year UK inception cohort.

Ho GT 2006 AP&T

Although corticosteroids are effective, dependence/resistance remains common. Patients with extensive ulcerative colitis and fistulizing/stricturing Crohn's are most at risk of failing corticosteroid therapy.

Need for steroids within 5 yrs: CD: 75%, UC: 63%

Steroids 1 year responseSteroids 1 year response

High risk (RR>2)

Modifiable• Low weight (BMI <20 – 25 or <40 kg)• Weight loss > 10%• Physical inactivity• Steriods• Use of anticonvulsants

Non-modifiable• Age > 70 years• Prior osteoporotic fracture

Moderate risk (RR 1-2)

Modifiable• Smoking• Low calcium intake

Non-modifiable• Female• Untreated early menopause (<45)• Late menarche (>15)• Short fertile period (<30 years)• Family history of osteoporotic fracture

BSG Guidelines IBD/Coeliac Lewis, BB Scott 2007

• Exercise + nutritious diet• Ca: 1g/day (1.2g for PM women) Adcal (600mg) and Sandocal-400 (400mg)• Treat vit. D deficiency. • Stop smoking• Avoid alcohol excess

Achieve/maintain remission= Steroid avoidance

• Azathioprine/mercaptopurine• budesonide • elemental or polymeric diet • biologic/surgery if steroid-free remission not achieved

For those on steroids

• >65: consider bisphosphonate at commencement of steroids • <65 at high risk and requiring steroids >3 months: DEXA and consider bisphosphonate if T-score<-1.5

• Vitamin D and calcium whilst on steroids: Adcal D3 Calcichew D3 Forte I bd

General BONE advice

Classification of ulcerative colitisAdapted Kornbluth and Sachar 2004.

Mild Moderate Severe Fulminant

<4 stools +/- blood No systemic signs of toxicity Normal ESR

>4 stools Minimal signs of toxicity

>6 bloody stools Evidence of toxicity: fever, tachycardia, anemia, elevated ESR

>10 movements bleeding Abdominal tenderness distension Blood transfusion requirement Colonic dilatation

DefinitionsDefinitions

Severe colitisSevere colitis (Truelove and Witts Br Med J 1955)(Truelove and Witts Br Med J 1955)

6 or more bloody stools per day6 or more bloody stools per day

Temp > 37.5Temp > 37.5

tachycardia > 90tachycardia > 90

Hb < 10.5Hb < 10.5

ESR >30ESR >30

Toxic / ‘fulminant’Toxic / ‘fulminant’

fever, abrupt onset, abdo tenderness, colicky pain, anorexia. Considered toxic if ‘severe’ fever, abrupt onset, abdo tenderness, colicky pain, anorexia. Considered toxic if ‘severe’ colitis + 2 or more of fever >38.6, tachy >100, WCC >10.5 and low albumincolitis + 2 or more of fever >38.6, tachy >100, WCC >10.5 and low albumin

Toxic megacolonToxic megacolon

First recognised in 1950 First recognised in 1950 (Marshak (Marshak et al.,et al., Gastroenterology 1950;16768) Gastroenterology 1950;16768)

‘‘Segmental or total colonic distension of > 6cm in the presence of acute colitis and signs of Segmental or total colonic distension of > 6cm in the presence of acute colitis and signs of toxicity’toxicity’

Different preparations of mesalamine for UC therapy

Delayed release Slow release Prodrugs Prodrugs Topicals Sulfasalazine

Formulation Asacol Pentasa Olsalazine Balsalazide Mesalamine enema

CostCheapest per gram if SSZ and salofalk excluded

Preparation Enteric coated 400 mgCapsule 250 mg or 500 mg1 gram sachets

Capsule 250 mg Capsule 750 mg4 g/60 ml rectal suspension 1 g rectal suppository

Solubility pH > or equal 7 Continuous release pH independent pH independent

Location of delivery Terminal ileium Small bowel, colon Colon Colon Rectum Small bowel, colon

Maintenance of remission

2–4 g/day 2–4 g/day 1 g/day 2.25 g TID 4 g/day 2 g/day

Mild to moderate 2.4 to 4.8 g/daily 2–4 g/daily 2–3 g/daily 6.75 g/day 4 g/per rectum 3–4 g/day

Active disease proctitis

TID dosingTDS dosingOnce dailyRectal therapy

BID dosing TID dosing

BID 1g/BID Active disease: 1 g BID (suppository) or 4 g enema qd or BID Maintenance:1 g supp. Daily or prn symptoms

BD-QID dosing

How to improve 5ASA How to improve 5ASA ResponseResponse

Ascend II

Marteau2004

Safdi 97

1. Use higher dose of 5ASA2. Use rectal therapy in extensive UC3. Use rectal therapy in left sided UC4. Rectal therapy can help: use for at least 2 weeks

ImmunosuppressivesImmunosuppressives

CD: 70-80% start AZA/6MPCD: 70-80% start AZA/6MP

UC: 40% start AZA/6MPUC: 40% start AZA/6MP

Side effects-30-40%, poor response in 20-Side effects-30-40%, poor response in 20-30% of those who tolerate treatment30% of those who tolerate treatment

Can we improve on this?Can we improve on this?

ImmunosuppressivesImmunosuppressives

Low dose AZA/6MP* + allopurinol **Low dose AZA/6MP* + allopurinol **

Few side effects. Monitored exactly as full Few side effects. Monitored exactly as full dose AZA/6MPdose AZA/6MP

Attains response in poor responders: 70%Attains response in poor responders: 70%

By passes ADRs: GI disturbance, flu like By passes ADRs: GI disturbance, flu like symptoms and hepatotoxicitysymptoms and hepatotoxicity

Patients: Reduced surgeries, hospitalisations Patients: Reduced surgeries, hospitalisations and high cost drug expenditure.and high cost drug expenditure.

• * 1/4-1/3 TPMT adjusted dose• ** 50-100mg

Alternative Immunosuppressive/ Alternative Immunosuppressive/ treatmentstreatments

MethotrexateMethotrexate

T(h)ioguanineT(h)ioguanine

MychophenolateMychophenolate

CyclophosphamideCyclophosphamide

Ant-Mycobacterial therapy/ThalidomideAnt-Mycobacterial therapy/Thalidomide

Autologous Stem Cell TransplantationAutologous Stem Cell Transplantation

Monoclonals: Infliximab & AdalimumabMonoclonals: Infliximab & Adalimumab

Shared care and protocolsShared care and protocols

Available for:Available for:

6MP/AZA6MP/AZA

MTXMTX

CiclosporinCiclosporin

Thioguanine- soon to be submitted to D&TThioguanine- soon to be submitted to D&T

Infliximab/AdalimumabInfliximab/Adalimumab

Heterocyclic bases and Heterocyclic bases and analogues of nucleosidesanalogues of nucleosides

Hitchings and ElionHitchings and Elion

DiaminopurineDiaminopurine

6-Thioguanine6-Thioguanine

6 Mercaptopurine 6 Mercaptopurine

AzathioprineAzathioprine

AllopurinolAllopurinol

PyrimethaminePyrimethamine

TrimethoprimTrimethoprim

PiritreximPiritrexim

AcyclovirAcyclovir

Zidovudine (AZT) (Barry 1986)Zidovudine (AZT) (Barry 1986)

DiscoveriesDiscoveriesITPA gene characterisedITPA gene characterisedITPA predicts side effects: patented and NHS awardITPA predicts side effects: patented and NHS awardTPMT predicts responseTPMT predicts responseTGN do not predict responseTGN do not predict responseTPMT heterozygotes high risk of ADRTPMT heterozygotes high risk of ADRIntroduced deliberate use of allopurinol to improve Introduced deliberate use of allopurinol to improve hepatotoxicity and side effect and response to AZAhepatotoxicity and side effect and response to AZARole of Xanthine oxidase in CD patients exposed to AZARole of Xanthine oxidase in CD patients exposed to AZAMDRP predicts resistance to AZAMDRP predicts resistance to AZAAldehyde dehydrogenase predicts response to AZAAldehyde dehydrogenase predicts response to AZA6TG can b used safely in IBD6TG can b used safely in IBDMTHFR polymprphisms protect from Side effectsMTHFR polymprphisms protect from Side effectsVNTR do not modify TPMT activityVNTR do not modify TPMT activityTPMT activity is not induced by AZA/6MPTPMT activity is not induced by AZA/6MP

Prospective evaluation of the pharmacogenetics of azathioprine in the treatment of inflammatory bowel disease.Ansari A, Arenas M, Greenfield SM, Morris D, Lindsay J, Gilshenan K, Smith M, Lewis C, Marinaki A, Duley J, Sanderson J.Aliment Pharmacol Ther. 2008 Oct 15;28(8):973-83.

Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel diseaseA. ANSARI1, T. ELLIOTT1, B. BABURAJAN1, P. MAYHEAD1, J. O’DONOHUE2, P. CHOCAIR3, J. SANDERSON1, J. DULEY4

Alimentary Pharmacology & TherapeuticsVolume 28, Issue 6, pages 734–741, September 2008

Low-dose azathioprine or mercaptopurine in combination withallopurinol can bypass many adverse drug reactions in patientswith inflammatory bowel diseaseA. ANSARI * ,, N. PATEL, J. SANDERSON, J. O’DONOHUE§, J. A. DULEY– & T. H. J. FLORIN**Alimentary Pharmacology & Therapeutics

Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease.Ansari A, Hassan C, Duley J, Marinaki A, Shobowale-Bakre EM, Seed P, Meenan J, Yim A, Sanderson J.Aliment Pharmacol Ther. 2002 Oct;16(10):1743-50.

Novel pharmacogenetic markers for treatment outcome in azathioprine-treated inflammatory bowel disease M.A. Smith; A.M. Marinaki; M. Arenas; M. Shobowale-Bakre; C. M. Lewis; A. Ansari; J. Duley; J.D.  Sanderson

Further experience with the use of 6-thioguanine in patients with Crohn's disease.Ansari A, Elliott T, Fong F, Arenas-Hernandez M, Rottenberg G, Portmann B, Lucas S, Marinaki A, Sanderson J. Inflamm Bowel Dis. 2008 Oct;14(10):1399-405.

Influence of xanthine oxidase on thiopurine metabolism in Crohn's disease.Ansari A, Aslam Z, De Sica A, Smith M, Gilshenan K, Fairbanks L, Marinaki A, Sanderson J, Duley J. Aliment Pharmacol Ther. 2008 Sep 15;28(6):749-57.

Mutation in the ITPA gene predicts intolerance to azathioprineMarinaki, AM, Duley, JA, Arenas, M, Ansari, A, Sumi, S, Lewis, CM, Shobowale-Bakre, M, Fairbanks, LD and Sanderson, J (2004) Mutation in the ITPA gene predicts intolerance to azathioprine. Nucleosides Nucleotides & Nucleic Acids, 23 8-9: 1393-1397

Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase) Marinaki Anthony M, Ansari Azhar, Duley John A, Arenas Monica, Sumi Satoshi, Lewis Cathryn M, Shobowale-Bakre El-Monsor, Escuredo Emilia, Fairbanks Lynette D, Sanderson Jeremy D

Pharmacogenetics (2004).

HistoryHistorystool frequency/consistency/blood or mucusstool frequency/consistency/blood or mucusWeight lossWeight lossdietdietUrgency / pain / bloating / nocturnal diarrhoeaUrgency / pain / bloating / nocturnal diarrhoeaAssociated symptoms (fatigue, joint/eye/skin Associated symptoms (fatigue, joint/eye/skin problems,mouth ulcers)problems,mouth ulcers)duration diseaseduration diseasemedication (Abx/NSAIDs)medication (Abx/NSAIDs)TravelTravelFamily historyFamily historySmoking / alcoholSmoking / alcohol

ExaminationExamination

fever, tachycardia, abdo findings fever, tachycardia, abdo findings (tender/peritonitic)(tender/peritonitic)

EIM’sEIM’s

Weight / BMIWeight / BMI

InvestigationInvestigation

FBC, CRP, ESR, U&E, LFTs, anti TTG, glucose, TFTstool cultures

Differential diagnosesDifferential diagnoses

InfectiveInfective– Bacterial: salmonella, shigella, Bacterial: salmonella, shigella,

campylobacter, E coli (O157), Gonococcal campylobacter, E coli (O157), Gonococcal proctitis, C difficileproctitis, C difficile

– Viral: HS (or chlamydial) proctitis, CMVViral: HS (or chlamydial) proctitis, CMV

– Protozoal: amoebiasisProtozoal: amoebiasis

Differential diagnosesDifferential diagnoses

Non-infectiveNon-infectiveVascular: ischaemic colitisVascular: ischaemic colitisIdiopathic: microscopic colitisIdiopathic: microscopic colitisDrugs (eg) NSAIDsDrugs (eg) NSAIDsNeoplasiaNeoplasiaRadiationRadiationBehcet’sBehcet’sDiverticulitisDiverticulitis

Investigation of IBDInvestigation of IBD

BloodsBloods

Stool MCSStool MCS

EndoscopyEndoscopy

CTCT

MRI small bowel: Crohn’s disease evaluationMRI small bowel: Crohn’s disease evaluation

Faecal calpotectin/ Small bowel permeabilityFaecal calpotectin/ Small bowel permeability

(Barium imaging: Becoming out-dated)(Barium imaging: Becoming out-dated)

Known UC when to worry / referKnown UC when to worry / refer

‘‘Flare’ suggested by increased stool Flare’ suggested by increased stool frequency, pain, urgency, blood, mucus, frequency, pain, urgency, blood, mucus, weight loss, constitutional symptomsweight loss, constitutional symptoms

Fever, tachycardiaFever, tachycardia

What is current Rx?What is current Rx?

How were previous flares managed?How were previous flares managed?

Algorithm for managing ulcerative Algorithm for managing ulcerative colitiscolitis

MILD MODERATE SEVERE

5 ASA / steroid(topical:supp/enema)

PROCTITIS

LEFT SIDED

PANCOLITIS

5 ASA / steroid(topical:enema

+ Oral)

5 ASA(Oral+/-topical)

5 ASA / steroid(topical:supp/enema)

+/-Oral steroids

+/-Immunomodulator

(azathioprine/6MP/ thioguanineMTX,Mycophenolate)

+/-surgery

ParenteralSteroids +/-Ciclosporin +/-surgery

Crohn’s disease diagnosis

surgery

steroidsElemental diet

Antituberculous chemotherapy

worms

Thiopurines (TP): AZA/6MP

methotrexate

Anti-TNF α strategies

antibiotics

natalizumab

Leucocytophoresis

Stop smoking

infliximab

adalimumab

Thalidomide?

5 ASAs

Tacrolimus

Stem cell Tx

Low dose TP + Allopurinol

Thioguanine

TPN

MiscellaneousMiscellaneous

Give Ca / vit D with prednisoloneGive Ca / vit D with prednisolone

Long term steroids are not an answerLong term steroids are not an answer

Get smokers with CD to stopGet smokers with CD to stop

Where are bloods monitored?Where are bloods monitored?

IBD nurse specialistIBD nurse specialist

How to referHow to refer

IBD clinics: Monday & Thursday East SurreyIBD clinics: Monday & Thursday East Surrey

Wednesday CrawleyWednesday Crawley

Flares – open accessFlares – open access

On call registrar/GI RegistrarOn call registrar/GI Registrar

IBD nurse specialist: Helen McSorelyIBD nurse specialist: Helen McSorely

Email: Email: Helen.McSorley@sash.nhs.uk ext 2815 ext 2815

The EndThe End