1. Medicines Optimisation in IBD Can we base it on evidence?
Anja St.Clair Jones
Lead Pharmacist Digestive Diseases
Royal Sussex County Hospital
Brighton

2. Enable medicines optimisation in IBD
Aims and Objectives
Enable medicines optimisation in IBD
Understand Inflammatory Bowel Disease (IBD),
Describe drugs used in treatment of IBD
Develop strategies for medicines optimisation

3. Stomach
Duodenum
Splenic flexure
Hepatic flexure
Transverse colon
Descending colon
(Left sided/distal)
Ascending colon
(Right sided/ proximal)
Jejunum
Ileum
Caecum
Sigmoid colon
Terminal ileum
Rectum
Anus

4. Epidemiology Disease of YOUNG people (peak 10-25y, 50+y)
Up to 260’000 people affected in UK
UC: 10/100’000 per year
prevalence 146/100’000 (NICE 2013, CG 166)
Incidence stable
Difference in ethnic groups (Ashkenazi Jews)
50% have relapse in any year
25% acute sever colitis during lifetime (NICE 2013)
90% are able to FT work 1year after diagnosis
CD: 5-10/100’00 per year
prevalence 157/100’000 (NICE 2012, CG152)
Incidence increasing
75% able to work in year after diagnosis
15-20% disabled by disease within 5 years (NICE 2012)
50-80% require surgery for strictures (NICE 2012)

5. Anatomic distribution in Crohn’s

6. 80% left sided only

7. Pathogenesis Theories of inflammatory bowel disease etiology
-Toxic response to luminal contents -Specific microbial pathogen -Abnormal luminal constituents -Increased absorption of luminal macromolecules -Enhanced immunologic response to normal constituents -Autoimmune response -To epithelial cell or mucus glycoproteins -Molecular mimicry (cross-reactivity of intestinal microflora and epithelia) -To immune cells
Trigger – what?
Genetic involvement

8. Immune dysregulation in Crohn's disease
Immune dysregulation in Crohn's disease Immune dysregulation in Crohn's disease. Just as epidemiologic evidence points to a balance of environmental and genetic factors in the pathogenesis of Crohn's disease, etiologic models suggest that a balance of external stimuli and internal host responses determine the hyperreactivity of the gut immune system that is seen in Crohn's disease

9. CD or UC?

10. Ulcerative colitis
Crohn's disease
Site of disease
Colon only
Any part of gastrointestinal tract
Symptoms
Bleeding
+++ +
Diarrhea ++
Abdominal pain
Growth failure
Tenesmus
Perianal disease —
Endoscopic findings
Rectal involvement
Inflammation
Continuous
Discontinuous
Diffuse erythema
Patchy lesions
Ulceration in inflamed mucosa
Discrete ulcers in normal mucosa
Complications
Fistulas
Exceedingly uncommon
Frequent
(? Crohn's)
Strictures
Uncommon (? malignancy)
Common
Cancer risk (>10 years)
Increased

11. Fistulae in IBD

13. Diagnosis and investigations
History and examination
FBC, LFT, ESR or CRP
Microbiological testing (C. Diff., CMV)
Abdo imaging
Endoscopies +/- biopsies
Barium enema, small bowel studies
Colonoscopy
Assessment of disease extent

15. Figure 1a and 1b: endoscopic views of Crohn’s disease showing mucosal oedema, ulceration and exudates.

17. Crohn's Disease Activity Index
CDAI = 2x1 + 5x2 + 7x3 + 20x4 + 30x5 + 10x6 + 6x7 + (weight factor)8
1. Number of liquid or very soft stools in one week
2. Sum of seven daily abdominal pain ratings:     (0=none, 1=mild, 2=moderate, 3=severe)
3. Sum of seven daily ratings of general well-being:     (0=well, 1=slightly below par, 2=poor, 3=very poor, 4=terrible)
4. Symptoms or findings presumed related to Crohn's disease arthritis or arthralgia iritis or uveitis erythema nodosum, pyoderma gangrenosum, apththous stomatitis anal fissure, fistula or perirectal abscess other bowel-related fistula febrile (fever) episode over 100 degrees during past week
5. Taking Lomotil or opiates for diarrhea
6. Abnormal mass     0=none; 0.4=questionable; 1=present    
7. Hematocrit [ (Typical - Current) x 6 ]
x [(standard weight-actual body weight) / standard weight]

18. Harvey–Bradshaw Index for Crohn's disease
Number of liquid stools per day
Abdominal pain, sum of seven daily ratings: (0-none, 1-mild, 2-moderate, 3-severe)
Abdominal mass (0-none, 1-questionable, 2-definite, 3-definite & tender)
General well being (0-very well, 1-slightly below par, 2-poor, 3-very poor, 4-terrible)
Complications (score 1 point per item) Arthritis/arthalgia Skin/mouth lesions Iritis/uveitis Anal fissure, fistula/perianal abscess

20. UC activity scores

24. Therapeutic aim Remission Avoid surgery CRC (5x) Also:
Smoking cessation
VTE prophylaxis (always!!)
Pain control (no NSAIDs)
Osteoporosis prophylaxis
Opportunistic infections

25. Treatments

26. How to optimise treatment?
Correct dose
Co-prescribing
TDM
Exit strategies
Rescue strategies

27. Steroids Indication: CD and UC
Moderate to severe relapse
Maximise local effect and limit systemic effect
No role in maintenance
40mg OD Prednisolone reduced slowly by 5mg/week
≤ 15mg ineffective in active disease
Budesonide not as effective as Pred but alternative in ileo-ascending colonic disease
Less systemic effect
Osteoporosis

28. Rectal steroids Only for patient not responding to rectal mesalazine
Hydrocortisone (Colifoam) 1 od-bd
High plasma levels after administration
Prednisolone NaPhos (Predsol) 1 bd
Rectal mucosa only
Prednisolone metosulphbenzoate (Predenema 1 od)
Poorly absorbed
Increased spread (reached ascending colon in some patient)
Prednisolone metosulphbenzoate (Predfoam 1od-bd)
Retained in rectum and sigmoid colon

29. Rectal steroids Rectal steroid Peak plasma nmols/L Peak tissue ng/g
Prednisolone phosphate 20mg
365 (2hrs) 44
Predenema
Prednisolone meta-
sulphbenzoate 20mg
45 (2hrs)
257
Predfoam
320 (4hrs)
4874
Colifoam
Hydrocortisone Acetate 125mg
510(4hrs)
Not recorded

30. Optimisation Correct dose Correct formulation Prevent osteoporosis
Start at 40mg and slow reduction
Correct formulation
Know where the disease is located
Prevent osteoporosis
Consider infection risk

31. Rectal reparations: site of action and indication
Formulation
Site of action
Disease extent
Suppository
Rectum
Proctitis
Foam
Sigmoid Colon
Procto-sigmoiditis
Enema
Descending colon to splenic flexure and in some cases even distal part of transverse colon.
Left sided ( distal)colitis

32. 5-ASA Dose: Crohn’s: UC: Rectal preparations (PINCE)
higher doses ≥ 4g no evidence (post op only)
UC:
Induction of remissions ≥ 4g/day
Maintenance of remission ≥ 2g/day
Rectal preparations (PINCE)
15% past splenic flexure:2g bd oral + 1g OD rectal (64% remission at week 8 vs 43% oral)
Compliance at week 8
(PODIUM: OD vs BD:71% vs 59% remission)

33. pH-dep. delayed release (>6) and matrix
Drug
Formulation
Optimal drug release pH
Site of drug release
Mesalazine
Asacol MR
400mg: Enteric coated with Eudragit S
800mg: Enteric coated with layer of Eudragit S followed by Eudragit S+L
pH-dep. delayed release (>7)
Terminal ileum & large bowel (colon & rectum)
Ipocol
Enteric coated with Eudragit S
>7
Terminal ileum & colon
Mesren MR
Octasa MR
Mezavant XL
Film coated with methacrylate copolymers Type A, Type B
Gastroresistant coating with Lipophylic and hydrophilic matrix
(>7)
Colon
Pentasa
Ethylcellulose coated microgranules to allow slow continuous release
Diffusion through semi-permeable membrane (Enteral pH)
Duodenum to rectum
Salofalk
Tablets: Enteric coated with Eudragit L
Granules: Eudragit L and matrix granule structure (slow continuous release)
pH-dep. delayed release (>6) and matrix
Azo-bonded preparations
Salazopyrin (Sulfasalazine)
Colazide (Balsalazide)
Dipentum (Olsalazide)
5-ASA +SA
Prodrug
Dimer
Cleavage by intestinal bacteria
Azoreductase

34. Adherence and switching
39% adherence in maintenance
Robinson; APT 2013
61% chance of relapse vs 11%
Increased risk of CRC 31% vs 3%
75% risk reduction in adherers
Cost :14% admission = 49% of cost
Kane 2006, Bassi 2004, Hawthorne 2008
Switch patients had 3.5-fold risk of relapse
Endoscopic healing rate is not equivalent

35. Optimisation Top and tail in sever flares Consider switching carefully
Support Adherence
Tailor formulation to patient
Reinforce message of CRC prevention
Consider switch of preparation carefully
Consider impact on endoscopic healing