Transcript Inflammatory Bowel Disease

A GP guide to Inflammatory
Bowel Disease
Dr Azhar Ansari MRCP MD
Consultant Gastroenterologist
& Lead in IBD
East Surrey
Case report 1
Hester
Age 18: UC: steroid dependant
Age 26: AZA 2mg/kg: hepatotoxicity (1999)
Standard treatment: surgery: scheduled
Interruption of medical studies: 1st year clinical
Tx: ???
Case report 2
Daniel Age 19 years
Age 12: CD
Neutropenia on high dose 6MP: NO response
Age 14: Infliximab effective for 18 months, then
loss of response
Age 16: Ileostomy then reversal
Steroid dependency: Avascular necrosisbilateral hip replacements
Age 18: Transferred to adult clinic
Tx: ???
Case 3
Maria DF 22
Age 18: CD: Ileo-colonic and perianal. Severe
eczema
Long steroid dependency
Poor response to AZA
Loss of weight, social life, employment and self
esteem
Management: A blood test and colonoscopy.
Tx: ???
Case 4
Susan T 39
Age 22: CD
Age 28: Ileal resection, stoma and reversalcomplicated by a fistula.
Age 37: AZA and steroids 10 years: Abdominal
abscess and re-opening of entero-cutaneous
fistula 2010
Tx: ???
MRI Susan T
20 surgeries
over 12 years
Post treatment
Aims of treatment for IBD
Achieve remission
Maintain remission
Prevent complications
Improve quality of life
Multi-disciplinary approach to treatment: Physician,
Surgeon, IBD nurse Specialist, Dietician, Pharmacist and
Psychological support. Transition Clinic. MDM
discussions
Natural History of UC
UC acute attack
Death 33%
Subsequent acute attack
Death 12%
Death 40%
Edwards &
Truelove 1963
CRC 40%
Devroede 1971
40 years
UC
40 years
UC in Childhood
CD: Similar Findings
Weedon 1971
Natural History past decade
20 years
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
UC
5ASA: Chemoprevention
Steroids
Immunosupressives
UC: Failure of medical therapy
Relapsing remitting course
20 years
UC: Medical therapy: 90%
Surgical therapy: 20%
Toxic Colon
Clinical Course of UC
Crohn’s Colon
Crohn’s Surgery
By Permission from Mr Carapeti
Guy’s and St Thomas’
Crohn’s Fistula: Seton
Crohn’s Colon
Perianal Crohn's
Mild Disease
Perianal Crohn's
Moderate Disease
Perianal Crohn's
Severe Disease
Facts and Figures
IBD affects 1:400
Doubling in CD over 30 years.
Young at risk: Teenagers/young adults second peak
50yrs
North Europe> S Europe. North UK > S UK
“White collar”
£720 million/year. 14% of patients (hospitalisations &
surgeries) account for 50% of cost
Cost per 6 months £1200 (UC) and £1600 (CD)
Quiescent vs relapse = X3 ↑ costs
Hospitalisations = X20.
Facts and Figures
Surgical Risk: CD 80% (most have >1 surgeries), UC 1540%
Chronic inflammation leads to the dysplasia
Dysplasia = Severe: 40%, Mild 20% risk Synch. CRC.
Extensive UC greatest risk of CRC: most significant after
10 yrs
– Risk 10-15%. 6-10x higher than normal population
CD similar risk of CRC (surgeries may affect rate)
Facts and Figures
Life time risk of steroids: 60-80%
Osteoporosis: Steroids, inflammation and
malnutrition assoc.
Risk of fractures: 40% higher for IBD suffers
Osteoporosis: significant cost implications
IBD patients have shorter/”poorer” lives: 10ys
Incidence / prevalence
Incidence UC
10: 100,000
Incidence CD
6-7: 100,000 (increasing)
Prevalence about 150:100,000 for each
IBD Cases in East Surrey Area = 1,0001,500
CD
UK 13 300 new cases diagnosed each year
150 000 IBD total and
approximately 2.2 million across Europe
Crohn’s disease rates lower
than N Europe.
Immigrant populations high.
Significant increase in children
UC
Ulcerative colitis rates similar
To Europe.
Immigrant populations very high
Disease 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 Manifestations
Upto 36%
Some ass with disease activity: Joint, skin, occular and oral
Uveitis/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
Mortality
CD: 50% higher than general popultion. Life expentancy 10 years less
Deaths: Cancers, VTE’s
UC: slightly higher morality than general population. Risk of CRC falling
Uveitis
episcleritis
Erythema Nosdum
Peristomal Pyoderma gangrenosum
Steroids 30 day response
CD: 40%
UC: 51%
30 days full remission
CD: 35%
UC: 31%
30 days partial remission
CD: 25%
UC: 18%
30 days NON RESPONSE
The efficacy of corticosteroid therapy in inflammatory bowel disease: analysis of a 5-year UK inception cohort.
Ho GT 2006 AP&T
Steroids 1 year response
CD: 38%
UC: 55%
1 yr prolonged response
CD: 24%
UC: 17%
1 yr steroid dependence
CD: 35%
UC: 21%
1 yr surgery
Need for steroids within 5 yrs: CD: 75%, UC: 63%
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.
The efficacy of corticosteroid therapy in inflammatory bowel disease: analysis of a 5-year UK inception cohort.
Ho GT 2006 AP&T
BSG Guidelines IBD/Coeliac
Lewis, BB Scott 2007
High risk (RR>2)
Moderate risk (RR 1-2)
Modifiable
• Low weight (BMI <20 – 25 or <40 kg)
• Weight loss > 10%
• Physical inactivity
• Steriods
• Use of anticonvulsants
Modifiable
• Smoking
• Low calcium intake
Non-modifiable
• Age > 70 years
• Prior osteoporotic fracture
Non-modifiable
• Female
• Untreated early menopause (<45)
• Late menarche (>15)
• Short fertile period (<30 years)
• Family history of osteoporotic
fracture
General BONE advice
• 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
Classification of ulcerative colitis
Adapted Kornbluth and Sachar 2004.
Mild
Moderate
Severe
Fulminant
>10 movements
<4 stools
>6 bloody stools
bleeding
+/- blood
>4 stools
Evidence of toxicity: Abdominal tenderness
No systemic signs of Minimal signs fever, tachycardia, distension
toxicity
of toxicity
anemia, elevated
Blood transfusion
Normal ESR
ESR
requirement
Colonic dilatation
Definitions
Severe colitis
(Truelove and Witts Br Med J 1955)
6 or more bloody stools per day
Temp > 37.5
tachycardia > 90
Hb < 10.5
ESR >30
Toxic / ‘fulminant’
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 albumin
Toxic megacolon
First recognised in 1950 (Marshak et al., Gastroenterology
1950;16768)
‘Segmental or total colonic distension of > 6cm in the presence
of acute colitis and signs of toxicity’
Different preparations of mesalamine for UC
therapy
Formulation
Delayed release
Slow release
Prodrugs
Prodrugs
Topicals
Asacol
Pentasa
Olsalazine
Balsalazide
Mesalamine enema
4 g/60 ml rectal
suspension
1 g rectal suppository
Sulfasalazine
Cheapest per gram if
SSZ and salofalk
excluded
Cost
Preparation
Capsule 250 mg or
Enteric coated 400 mg 500 mg
1 gram sachets
Capsule 250 mg
Capsule 750 mg
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
TID dosing
BID 1g/BID Active
disease: 1 g BID
(suppository) or 4 g
BD-QID dosing
enema qd or BID
Maintenance:1 g supp.
Daily or prn symptoms
Active disease
proctitis
TID dosing
TDS dosing
Once daily
Rectal therapy
BID dosing
How to improve 5ASA
Response
1. Use higher dose of 5ASA
2. Use rectal therapy in extensive UC
3. Use rectal therapy in left sided UC
4. Rectal therapy can help: use for at
least 2 weeks
Marteau
2004
Ascend II
Safdi 97
Immunosuppressives
CD: 70-80% start AZA/6MP
UC: 40% start AZA/6MP
Side effects-30-40%, poor response in 2030% of those who tolerate treatment
Can we improve on this?
Immunosuppressives
Low dose AZA/6MP* + allopurinol **
Few side effects. Monitored exactly as full
dose AZA/6MP
Attains response in poor responders: 70%
By passes ADRs: GI disturbance, flu like
symptoms and hepatotoxicity
Patients: Reduced surgeries, hospitalisations
and high cost drug expenditure.
• * 1/4-1/3 TPMT adjusted dose
• ** 50-100mg
Alternative Immunosuppressive/
treatments
Methotrexate
T(h)ioguanine
Mychophenolate
Cyclophosphamide
Ant-Mycobacterial therapy/Thalidomide
Autologous Stem Cell Transplantation
Monoclonals: Infliximab & Adalimumab
Shared care and protocols
Available for:
6MP/AZA
MTX
Ciclosporin
Thioguanine- soon to be submitted to D&T
Infliximab/Adalimumab
Heterocyclic bases and
analogues of nucleosides
Hitchings and Elion
Diaminopurine
6-Thioguanine
6 Mercaptopurine
Azathioprine
Allopurinol
Pyrimethamine
Trimethoprim
Piritrexim
Acyclovir
Zidovudine (AZT) (Barry 1986)
Discoveries
ITPA gene characterised
ITPA predicts side effects: patented and NHS award
TPMT predicts response
TGN do not predict response
TPMT heterozygotes high risk of ADR
Introduced deliberate use of allopurinol to improve
hepatotoxicity and side effect and response to AZA
Role of Xanthine oxidase in CD patients exposed to AZA
MDRP predicts resistance to AZA
Aldehyde dehydrogenase predicts response to AZA
6TG can b used safely in IBD
MTHFR polymprphisms protect from Side effects
VNTR do not modify TPMT activity
TPMT 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 disease
A. ANSARI1, T. ELLIOTT1, B. BABURAJAN1, P. MAYHEAD1, J. O’DONOHUE2, P. CHOCAIR3, J. SANDERSON1, J. DULEY4
Alimentary Pharmacology & Therapeutics
Volume 28, Issue 6, pages 734–741, September 2008
Low-dose azathioprine or mercaptopurine in combination with
allopurinol can bypass many adverse drug reactions in patients
with inflammatory bowel disease
A. 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 azathioprine
Marinaki, 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).
History
stool frequency/consistency/blood or mucus
Weight loss
diet
Urgency / pain / bloating / nocturnal diarrhoea
Associated symptoms (fatigue, joint/eye/skin
problems,mouth ulcers)
duration disease
medication (Abx/NSAIDs)
Travel
Family history
Smoking / alcohol
Examination
fever, tachycardia, abdo findings
(tender/peritonitic)
EIM’s
Weight / BMI
Investigation
FBC, CRP, ESR, U&E, LFTs, anti TTG, glucose,
TFT
stool cultures
Differential diagnoses
Infective
– Bacterial: salmonella, shigella,
campylobacter, E coli (O157), Gonococcal
proctitis, C difficile
– Viral: HS (or chlamydial) proctitis, CMV
– Protozoal: amoebiasis
Differential diagnoses
Non-infective
Vascular: ischaemic colitis
Idiopathic: microscopic colitis
Drugs (eg) NSAIDs
Neoplasia
Radiation
Behcet’s
Diverticulitis
Investigation of IBD
Bloods
Stool MCS
Endoscopy
CT
MRI small bowel: Crohn’s disease evaluation
Faecal calpotectin/ Small bowel permeability
(Barium imaging: Becoming out-dated)
Known UC when to worry / refer
‘Flare’ suggested by increased stool
frequency, pain, urgency, blood, mucus,
weight loss, constitutional symptoms
Fever, tachycardia
What is current Rx?
How were previous flares managed?
Algorithm for managing ulcerative
colitis
MODERATE
MILD
PROCTITIS
SEVERE
5 ASA / steroid
(topical:supp/enema)
LEFT SIDED
5 ASA / steroid
(topical:enema
+ Oral)
PANCOLITIS
5 ASA
(Oral+/-topical)
5 ASA / steroid
(topical:supp/enema)
+/Oral steroids
+/Immunomodulator
(azathioprine/6MP/ thioguanine
MTX,Mycophenolate)
+/surgery
Parenteral
Steroids
+/Ciclosporin
+/surgery
Crohn’s disease diagnosis
5 ASAs
Stop smoking
steroids
Elemental diet
antibiotics
Thiopurines (TP): AZA/6MP
Antituberculous chemotherapy
Low dose TP + Allopurinol
Thioguanine
methotrexate
Anti-TNF α strategies
Tacrolimus
natalizumab
Stem cell Tx
adalimumab
Thalidomide?
Leucocytophoresis
worms
infliximab
TPN
surgery
Miscellaneous
Give Ca / vit D with prednisolone
Long term steroids are not an answer
Get smokers with CD to stop
Where are bloods monitored?
IBD nurse specialist
How to refer
IBD clinics: Monday & Thursday East Surrey
Wednesday Crawley
Flares – open access
On call registrar/GI Registrar
IBD nurse specialist: Helen McSorely
Email: [email protected] ext 2815
The End