The mesalazine chamaeleon Ailsa Hart Lead IBD Unit, St Marks - PowerPoint PPT Presentation

Oxford Inflammatory Bowel Disease MasterClass The mesalazine chamaeleon Ailsa Hart Lead IBD Unit, St Mark’s Hospital Senior Clinical lecturer Imperial College, London

Oxford Inflammatory Bowel Disease MasterClass Disclosure I have received honoraria for speaking, or acting in an advisory capacity for the following companies MSD, AbbVie, Warner Chilcott, Ferring, Shire, Falk Parma, Atlantic

Outline :mesalazine chamaeleon  Role in ulcerative colitis  Induction of remission  Maintenance of remission  Mucosal healing  Role in Crohn’s disease  Role in chemoprevention  Side effect profile  Tomorrow’s World – what’s round the corner

Oxford Inflammatory Bowel Disease MasterClass Do we know exactly what we are giving our patients?

foam enemas Liquid enemas

Dose & delivery systems of 5ASA formulations Drug Dose/ tablet Formulation Delivery site mg Sulphasalazine/ 500 5ASA ↔ colon salazopyrin sulfapyridine azo bond Balsalazide/colazal 750 5ASA ↔ 4ABA colon azo bond Olsalazine/ dipentum 250 5ASA dimer colon Mesalazine/ salofalk 250 Eudragit L Mid/distal ileum; colon Mesalazine/ pentasa 500,1000,2000 Ethylcellulose Duodenum to microgranules rectum Mesalamine/ asacol 400, 800 Eudragit S TI, colon Mesalamine/ mezavant 1200 Eudragit S TI, colon multi-matrx system

Oxford Inflammatory Bowel Disease MasterClass 5ASA in ulcerative colitis

5ASA for induction and maintenance of remission in UC

Oral 5ASA for induction of remission in UC Summary of findings  5ASA superior to placebo & no more effective than sulphasalazine  5ASA dosed once daily as effective & safe as conventionally dosed 5ASA  “do not appear to be any differences in efficacy or safety among the various 5ASA formulations”  Daily 2.4g appears to be effective and safe induction for mild to moderate UC  Patients with moderate disease may benefit from initial dose of 4.8g/day

Oral 5ASA for maintenance of remission in UC Summary of findings  5ASA superior to placebo for maintenance therapy  5ASA inferior to sulphasalazine* for maintenance  5ASA dosed once daily as effective and safe as conventionally dosed 5ASA for maintenance  “do not appear to be any differences in efficacy or safety among the various 5ASA formulations”  Patients with extensive UC/ frequent relapses may benefit from higher maintenance doses * Role in enteropathic arthropathy, particularly peripheral involvement / early disease; Side effects: allergic reactions and intolerance (up to 20%) – sulphapyridine

Mucosal healing in UC

How to optimise 5-ASA Maximise Combine oral and dose 1 rectal 5-ASA 2 5-ASA 4.8 g/d is better 5-ASA combined oral and Optimise than 2.4 g/d at inducing rectal therapy is better clinical response or than oral therapy alone 5-ASA complete remission 60% of patients achieved Extended duration remission after a further of treatment 3 8 weeks of 5-ASA therapy 1. Hanauer SB et al. Am J Gastroenterol 2005;100:2478 – 85; 2. Marteau P et al. Gut 2005;54:960; 3. Kamm MA et al. Inflamm Bowel Dis 2009;15:1-8.

How to optimise 5-ASA Maximise Combine oral and dose 1 rectal 5-ASA 2 Adherence Extended duration of treatment 3 1. Hanauer SB et al. Am J Gastroenterol 2005;100:2478 – 85; 2. Marteau P et al. Gut 2005;54:960; 3. Kamm MA et al. Inflamm Bowel Dis 2009;15:1-8.

Adherence to 5-ASA therapy in UC 100 Average adherence rate (%) 80% 80 40 – 60% 60 Rate particularly low 40 (40%) in patients in symptomatic remission 20 0 Clinical trials Community based trials Kane SV. Aliment Pharmacol Ther 2006;23:577 – 585.

Once a day vs conventional dosing UC maintenance Study not designed to measure efficacy 100 100 Asacol 2.4 g/day 90 78* 75 Once a day 80 Compliance (% patients) 70 BD or TDS 70 60 50 40 30 20 10 n=12 n=10 n=12 n=10 0 * p <0.05 BD/TDS vs QD 3 months 6 months Kane S et al. Clin Gastro Hepatol 2003;1:170 – 3

Predictors of non-adherence in chronic diseases 70% of non-compliance is intentional 1 Strong evidence 2 Weak evidence  Gender  Beliefs about illness (cause, timeline)  Income  Necessity (perceived need) for treatment  Age  Perceived effect of drug  Race  Concerns about treatment (fear of side effects)  Personality 1. Harris Interactive and the Boston Consulting Group (BCG) survey on reasons for patient non-adherence 2002. 2.McHorney CA, Spain CV. Health Expert. 2011;14:307-20

Optimising adherence

Optimising adherence

Oxford Inflammatory Bowel Disease MasterClass 5ASA in Crohn’s disease

Oral 5ASA for induction of remission in CD 310 patients. CDAI = 151-400 Randomised to Pentasa 1g, 2g, 4g /day or placebo Δ CDAI Δ CDAI Ileal disease Remisssion (%)  Pentasa 4g/day – meta-analysis of 3 studies 2 :pentasa superior to placebo ? How relevant reduction in CDAI (63) 2 Hanauer Clin Gastroenterol Hepatol 2004: 379 – 388 1 Singleton Gastroenterology 1993;104:1293 – 1301.

Oral 5ASA for maintenance of remission in CD  6 trials 12/12  ASA 362/663  Placebo 370/676  1 trial 24/12  ASA 54/80  Placebo 55/81 Akobeng Cochrane Database Syst Rev . 2005 (1):CD003715

Oral 5ASA in prevention in post-operative CD Relapse rates were reported after 1 to 3 years. All trials used 3 g sulfasalazine per day. Relapse occurred in Sulfasalazine 125/225 (55.6%) receiving sulfasalazine 133/223 (59.6%) on placebo / no therapy. RR of relapse with sulfasalazine: 0.97 (95%CI=0.72 – 1.31) Relapse rates were reported after 48 weeks to 3 years. One trial used 2.4g of mesalamine , 5 trials used ≥3g/day or more. Relapse occurred in 152/415 (36.6%) receiving mesalamine Mesalazine 191/419 (45.6%) on placebo or no therapy. RR of relapse with mesalazine: 0.80 (95%CI=0.70 – 0.92) NNT to prevent relapse in one patient was 10 (95%CI=6 – 25). RR=0.86 (95%CI=0.74 – 0.99) Combined NNT=13 (95%CI=7 – 50) Ford Am J Gastroenterol 2010

Summary – 5ASA in CD  Induction  While sulphasalazine may be (slightly) effective at inducing remission in (colonic) CD, less evidence for 5ASA and different disease locations  Maintenance  Little evidence to support 5ASA in maintenance of (medically induced) remission  Post-operative prevention  5ASA is mildly effective at preventing post-operative recurrence - NNT > 10

Oxford Inflammatory Bowel Disease MasterClass 5ASA in chemoprevention of IBD

IBD as risk for colorectal cancer Eaden et al . Gut 2001 Apr; 48 (4): 526-35 Jess et al . Gastroenterology 2012;143:375 – 381

5-ASA as chemoprevention for CRC  Velayos et al, Gastroenterology , 2005  Meta-analysis  9 studies containing 334 cases of CRC/140 dysplasia within total population of 1,932  Significant reduction in CRC risk (OR = 0.51; 95% CI; 0.37-0.69)

St Mark’s IBD -Cancer Surveillance Group Dr Siwan Thomas- Mr J Warusavitarne Dr Ailsa Hart Prof Brian Saunders Gibson (Consultant (Consultant IBD (Inflammatory Bowel (Chief of Wolfson Unit of Endoscopist,St. Mark’s) Surgeon, St. Mark’s) Disease Lead, St. Mark’s) Endoscopy, St. Mark’s) Prof Sir Nick Wright Dr Trevor Graham Dr Matt Rutter Dr Ryan Choi (Histopathologist, Lead (Lab lead, Cancer (Director of BCSP, (IBD Research Fellow, Centre for Tumour evolution laboratory, University hospital of St. Mark’s) Biology, QMUL) QMUL) North Tees)

St Mark’s IBD -Cancer Surveillance Group  Update St Mark’s IBD surveillance database  Biology of inflammation → cancer pathway

Oxford Inflammatory Bowel Disease MasterClass Side effect profile of 5ASA in IBD Generally well tolerated nephrotoxicity blood disorders (aplastic anaemia, leucopaenia, neutropaenia, thrombocytopaenia) skin reactions (lupus erythematous-like syndrome, Stevens-Johnson) pancreatitis, hepatitis worsening of IBD symptoms

5-ASA induced nephrotoxicity  Incidence:  Clinical trials: mean annual risk 0.26% 1  BSG/RA 2002 study: 1/4000 patient yrs 2  Immune-mediated interstitial nephritis  Clinical recommendations:  Blood monitoring recommended  Failure to detect 5-aminosalicylate nephrotoxicity is a cause of medical litigation 1. Gisbert IBD 2007 2. Muller APT 2005

GWAS & serious drug reactions Nat Genet. 2009

SAE Consortium Dr Rinse Dr Jonas Weersma Halfvarsson Professor Epameinondas Tsianos Dr Annese Vito Dr D'Incà Renata Prof Mark Silverberg Joanne Stempak Prof Graham Radford-Smith Prof Ian Lawrance So et al . DDW 2013

5ASA nephrotoxicity - Results  151 patients with 5ASA nephrotoxicity (M>F)  118 (78.7%) presented due to routine monitoring  Median time from starting 5ASA to first abnormal creatinine - 914 days (range 5 – 12,924 days)  Median oral dose 5ASA 2.25g daily (range 400mg – 8g), 1 patient received only rectal 5-ASA  42 patients (28%) demonstrated full recovery of renal function  14 (9.3%) patients had renal replacement therapy So et al . DDW 2013

Oxford Inflammatory Bowel Disease MasterClass