Top Clinical Tips for Inflammatory Bowel Disease

Transcription

1 Job bag number: UK/AS/0165/07-13 Date of preparation: July 2013 Top Clinical Tips for Inflammatory Bowel Disease Dr Ayesha Akbar Consultant Gastroenterologist Honorary Senior Lecturer

2 Contents-focus on UC Case study Tests and history Background Treatment in relation to ECCO consensus Data from 5-ASA studies Summary

3 Case study 24 year old female Presents with 5 week history of bloody diarrhoea Mild weight loss What do you want to ask? What tests would you do? What is the differential diagnosis?

4 History Foreign travel Antibiotic usage Recurrent diarrhoea Extra-intestinal manifestations Family History Smoking history NSAIDs

5 Tests Bloods FBC/haematinics CRP LFTs and albumin U&Es Stool MC&S including CDT?Faecal calprotectin AXR if any tenderness or USS Flexible sigmoidoscopy

6 Differential diagnoses Post infective Ulcerative colitis (or Crohn s colitis) Ischaemic colitis Diverticulitis Cancer

7 The Spectrum of Inflammatory Bowel Disease (IBD) Crohn s disease Ulcerative colitis Stenoses Fistulae Deep abscesses Granuloma Extracolonic involvement ASCA Diarrhea Abdominal pain Relapsing course Anemia Extraintestinal manifestations Indeterminate colitis Bloody diarrhea Mucosal inflammation Continuous involvement panca Adapted from Satsangi J, et al. Inflammatory Bowel Diseases. Churchill Livingstone, 2003.

8 Pathophysiology of IBD Genetic Susceptibility Host (immune) Response Environment (microflora) UC IL-5, IL-10 Inflammation Crohn s IL-1, IL-12, TNFα, IFN-γ Shanahan F, et al. Gastroenterology. 2001;120:

9 Epidemiologic Risk Factors UC CD Appendectomy 1 Negative (protective) None Smoking 2 Negative Positive Oral contraceptive use 2 Questionable Positive Breast feeding/adverse perinatal events 2 High level of sanitation in childhood 2 Questionable Questionable Questionable Positive 1 Koutroubakis I, et al. Inflamm Bowel Dis. 2002;8: ; 2 Koutroubakis I, et al. Hepatogastroenterology. 1996;43:

10 Ulcerative Colitis Pathology Confluent disease, beginning above the anus Limited to mucosa Never involves small bowel (backwash ileitis) Rarely involves the anus

11 Ulcerative colitis

12 Ulcerative Colitis Symptoms Rectal bleeding Passage of mucus Diarrhoea frequency consistency Urgency incontinence Abdominal cramping / pain usually related to bowel opening

13 Ulcerative Colitis Anatomical Extent Substantial 10% Extensive 20% Proctitis 40% Left sided colitis 5% Procto-sigmoiditis 25% Extends from just above anus

14 Ulcerative Colitis Symptoms and Relationship to Extent Proctitis Rectal blood and mucus, urgency Extensive disease Loose motions, severe pain Extent may vary with time Extent defines treatment and cancer risk

15 Ulcerative Colitis Diagnosis Establish diagnosis sigmoidoscopy Determine severity sigmoidoscopy Determine extent rigid or flexy rigid or flexy colonoscopy if needed Caution with colonoscopy in very acute disease If need to decide extent with severe disease, use instant enema

16 Ulcerative Colitis Natural History Relapsing - remitting course (90%) always exclude infection: stool for CDT extent usually constant presentation usually similar Rarely severe colitis or toxic dilatation (10%) Colectomy rate greatest initially first year 10% first 10 years 25%

17 Extra-Intestinal Manifestations Are Common in IBD Patients Ocular inflammation 2% 13% Oral ulceration 20% 30% Ankylosing spondylitis 1% 6% Peripheral arthritis 10% 20% Erythema nodosum 6% 15% Pyoderma gangrenosum 0.5% 2% Satsangi J, et al. Inflammatory Bowel Diseases. Churchill Livingstone; 2003:

18 Inflammatory Bowel Disease Extra-intestinal Manifestations - Skin Pyoderma gangrenosum

19 Inflammatory Bowel Disease Extra-intestinal Manifestations - Skin - Erythema nodosum

20 Inflammatory Bowel Disease Extra-intestinal Manifestations - Joints Large joint inflammation usually only one joint disease activity related Polyarthropathy peripheral joints independent of disease activity Sacroiliitis and ankylosing spondylitis stiff back independent of disease activity

21 Inflammatory Bowel Disease Extra-intestinal Manifestations - Eyes Anterior uveitis, episcleritis, conjunctivitis independent of disease activity all cause painful, gritty red eye

22 Inflammatory Bowel Disease Extra-intestinal Manifestations - Liver Minor abnormalities of LFTs in 50% Fatty liver in severe relapses Chronic autoimmune hepatitis in 2.5% Gallstones in 30% Primary sclerosing cholangitis in 2.5% Progressive inflammatory disorder of biliary system Cholangiocarcinoma in 0.1%

23 Inflammatory Bowel Disease Extra-intestinal Manifestations - Other Thrombo-embolic disease especially in smokers, bed-bound, septic need maximal prophylactic anticoagulation Amyloidosis rare terminal event Osteoporosis...

24 Osteoporosis in IBD Disease activity leads to loss of bone density DEXA scanning osteopaenia T score (healthy controls) >1 s.d. below mean Osteoporosis T score >2.5 s.d. below mean

25 Osteoporosis in IBD Contributory factors disease activity steroid treatment impaired Vitamin D and calcium absorption (especially Asians) smoking (especially women) sex hormone deficiency malnutrition genetic factors

26 Osteoporosis in IBD At-risk Patients History of fractures Recurrent courses of steroid Postmenopausal with > 1 course steroid per year T score below -1

27 Osteoporosis in IBD Treatment Exclude osteomalacia (blood tests) Check Calcium and Vit D levels if low, best is Calcium and Vit D supplements if normal, best is a bisphosphonate HRT of little value Check bone density every 2 years Prevention

28 Prognosis Ulcerative Colitis 75% relapsing-remitting 10% only one episode 20% chronic active 5% fulminant

29 Ulcerative Colitis Cancer Risk Population risk 1 in 30 for colorectal cancer Site of disease Distal X 1.5 Left-sided X 4 Risk vs general population Total X 19 All patients X1.5

30 Ulcerative Colitis Cancer Risk Risk greatest if disease more than 8 years disease greater than left-sided coexisting sclerosing cholangitis coexisting bowel polyps family history of colorectal cancer Surveillance after 8 years if extensive disease or any of the above with less disease if find high-grade dysplasia, consider colectomy

31 Surveillance BSG: UC-pancolitis after 8 years; left sided After 10 years Annual if high risk e.g. PSC 3 years moderate risk 5 years in low risk

32 Corticosteroids have serious side effects (long-term) Osteoporosis Cataracts/glaucoma Higher risk of infections Growth retardation Oedema/Cushing syndrome Behavioral changes Striae Diabetes

33 Mild to moderate UC Treat with 5-ASA-in flare escalate dose Rule out infection-stool MC&S Consider topical therapy Lack of response at 14 days, consider steroids-use reducing regime. 30mg/day for 1 week; reduce by 5mg/day to zero Concomitant Calcichew D3 (calcium carbonate, colecalciferol) with steroids

34 Benefits of St Mark s hospital Diagnosis Patient education Patient support-3 excellent IBD nurses at St Mark s Fast access if flare Complex cases-weekly IBD MDM Clinical trials-refractory patients Multi disciplinary teamnutrition/surgeons

35 Weekly IBD MDM

36 Patient pathway Established diagnosis Mild to moderate flare Treat in community with increased 5-ASA dose (IBD nurse support) Resolution of symptoms Failure of resolution after days or worsening symptoms Hospital review

37 Management of moderately active ulcerative colitis (UC) Prescribing information can be found at the end of this presentation. Job Job Number: Number: UK/AS/0192/ UK/AS/0027/ Date Date of preparation: of preparation: January February

38 What do patients need from their UC treatment? Fast symptom relief, among other attributes, is important to patients. Evidence shows that patients consider fast relief, relief from rectal bleeding, constant relief and prevention of flare to be among the most important attributes of treatment. In the most recent ECCO 1 guidelines, it states that: days is a suitable time-point at which to assess improvement in rectal bleeding, in line with one of the key treatment goals for patients. If rectal bleeding persists beyond days, then the response can be said to be slow and therapy augmented. 1. Dignass A et al. J Crohn's Colitis 2012, Job Number: UK/AS/0027/ Date of preparation: February 2013.

39 Patients (%) What do patients want from their UC treatment? Patient preference survey: treatment-related attributes rated by importance* (n=100) % 94% 93% 89% Provides relief of rectal bleeding Provides consistent relief Prevents a flare of UC Provides fast relief Patient preference survey attribute Overall, efficacy and safety-related attributes were more important to patients than those related to dosing regimen, cost and formulary coverage Gray et al. Aliment Pharmacol Ther 2009; 29: Data on file. Job Number: UK/AS/0027/ Date of preparation: February *Percentage of patients rating attributes of 4 or 5 out of 5 on a scale of importance, with 5 being most important

40 The ASCEND trials evaluated Asacol (mesalazine) in patients with moderately active UC The ASCEND clinical trials (ASCEND I, II and III) are the only trials that have specifically evaluated Asacol (mesalazine) in patients with moderately active UC 1-3 Other studies investigating the treatment of mesalazine have combined mild and moderate UC populations 4,5 1. Hanaeur SB et al. Can J Gastroenterol 2007; 21: Hanaeur SB et al. Am J Gastroenterol 2005; 100: Sandborn WJ et al. Gastroenterol 2009; 137: e Marteau P et al. Gut 2005; 54: Sandborn WJ et al. Aliment Pharmacol Ther 2007; 26: Job Number: UK/AS/0027/ Date of preparation: February 2013.

41 Symptom improvement Time at which 50% of patients (median time) achieve symptom improvement* with Asacol 800 mg MR tablets at 4.8 g/day Improvement of rectal bleeding n=161 4 Improvement of stool frequency n=160 4 Both n= Median time to symptom improvement (days) *Symptom improvement: a decrease of at least 1 point for rectal bleeding and stool frequency symptom score from baseline Adapted from Orchard TR et al. Alim Pharmacol Ther 2011: 33(9); Job Number: UK/AS/0027/ Date of preparation: February 2013.

42 Symptom resolution Time at which 50% of patients (median time) achieve symptom resolution* with Asacol 800 mg MR tablets at 4.8 g/day Absence of rectal bleeding n=161 9 Normalisation of stool frequency n= Both n= Median time to symptom resolution (days) *Symptom resolution: cessation of rectal bleeding and normalisation of stool frequency Adapted from Orchard TR et al. Alim Pharmacol Ther 2011: 33(9); Job Number: UK/AS/0027/ Date of preparation: February 2013.

43 Proportion of patients (%) In the PINCE trial, 37% of patients responded to oral treatment alone within 2 weeks P= g/day oral Pentasa (mesalazine) sachets plus placebo enema (n=53) P= % 33% 37% 63% 4 g/day oral Pentasa (mesalazine) sachets plus 1 g mesalazine enema (n=63) Remission = UC-DAI score of < 2 Improvement = a decrease in UC-DAI of 2 points from baseline 0 Remission Improvement UC-DAI, ulcerative colitis disease activity index Data from a post hoc analysis of efficacy at 2 weeks of the PINCE trial; patients with extensive mild to moderately active UC, N=127. The Intent to Treat (ITT) population consisted of 116 patients, who received at least one dose of study drug and had at least one efficacy evaluation after baseline. 1,2 Remission included patients who had some UC symptoms (UC-DAI scores <2) 2 1. Marteau P et al. ECCO, Feb 2010, Prague 2010; Abstract P Marteau P et al. Gut 2005; 54 : Job Number: UK/AS/0027/ Date of preparation: February 2013.

44 Job Job Number: Number: UK/AS/0192/ UK/AS/0027/ Date Date of preparation: of preparation: January February Mucosal healing

45 UC therapy should restore/maintain the bowel mucosa integrity as well as control symptoms 1 Published peer-reviewed papers recommend incorporating mucosal healing (along with symptom resolution) into the primary endpoints of therapeutic studies in mild to moderately active UC 2,3 The UC-DAI and the Mayo Score of Endoscopic Disease include clinical measures of UC as well as endoscopic measures 3 Score UC-DAI endoscopy score 4 Mayo Score of Endoscopic Disease 5 0 Normal Normal or inactive disease 1 Mild disease 2 Moderate disease 3 Severe disease Mild friability Moderate friability Spontaneous bleeding and exudation Erythema, decreased vascular pattern, mild friability Marked erythema, absent vascular pattern, friability and erosions Spontaneous bleeding, ulceration UC-DAI, ulcerative colitis disease activity index 1. Lichtenstein GR et al. Aliment Pharmacol Ther 2011; 33: D Haens G et al. Gastroenterol 2007; 132: Lichtenstein GR et al. Inflamm Bowel Dis 2010; 16: Sutherland LR et al. Gastroenterol 1987; 92: Schroeder KW et al. N Eng J Med 1987; 317: Job Number: UK/AS/0027/ Date of preparation: February 2013.

46 Proportion of patients (%) In ASCEND I and II, Asacol demonstrated mucosal healing in 80% of patients by week g/day Asacol 800 mg MR tablet % Mucosal healing 32% Complete mucosal healing Defined by the Mayo Score of Endoscopic Disease: Mucosal healing = endoscopy score of 0 or 1 Complete mucosal healing = endoscopy score of 0 Data from a post hoc analysis of combined ASCEND I and II data in patients with moderately active UC receiving 4.8 g/day Asacol 800 mg MR tablets, N=213. This n=156 analysis included patients with an endoscopy subscore of 2 at baseline (N=182). Mucosal healing was apparent across all disease extents (proctitis, proctosigmoiditis, left-sided colitis and pancolitis; 73 86%) 1. Lichtenstein GR et al. Aliment Pharmacol Ther 2011; 33: Job Number: UK/AS/0027/ Date of preparation: February 2013.

47 Mucosal healing demonstrated across all disease extent Proctitis Proctosigmoiditis Left-sided colitis Pancolitis 79% (n=24) 73% (n=37) 82% (n=57) 86% (n=35) Mucosal healing is becoming an objective marker for stable disease response 1 1. Lichtenstein GR et al. Aliment Pharmacol Ther 2011; 33: Job Number: UK/AS/0027/ Date of preparation: February 2013.

48 Proportion of patients (%) Proportion of patients (%) Mezavant XL (mesalazine) treatment for up to 8 weeks led to complete mucosal healing in 32% of patients % Endoscopic remission (all patients; n=85) 36% Clinical & Endoscopic remission (patients with moderately active disease; n=50) 4.8 g/day Mezavant XL 1.2 g tablet Endoscopic Remission = Modified UC-DAI sigmoidoscopy score of 1 (with a 1-point decrease from baseline) and no mucosal friability UC-DAI, ulcerative colitis disease activity index % Complete Mucosal Healing 4.8 g/day Mezavant XL 1.2 g tablet Complete mucosal healing = Modified UC-DAI sigmoidoscopy score of 0 UC-DAI, ulcerative colitis disease activity index Data from an 8-week randomised, double-blind, placebo-controlled trial of Mezavant XL in mild to moderately active UC, N=85 1 Data from a post hoc analysis of two 8-week randomised, double-blind, placebo-controlled trials of Mezavant XL in mild to moderately active UC, N=174 2 Patients with ulcerative proctitis (extent of inflammation 15 cm or less from the anus) were excluded from these studies 2 1. Kamm MA et al. Gastroenterol 2007; 132: Sandborn WJ et al. Aliment Pharmacol Ther 2007; 26: Job Number: UK/AS/0027/ Date of preparation: February 2013.

49 Maintenance of Remission Job Job Number: Number: UK/AS/0192/ UK/AS/0027/ Date Date of preparation: of preparation: January February

50 Proportion (%) of patients The majority of patients with quiescent UC remain in remission at 12 months with Asacol 800 mg MR tablets at 2.4 g/day in divided doses 1,2 100% Maintenance of remission at 1 year (per protocol population) p= % 60% 40% 20% 0% 80% 63/79 Once daily 64% 46/72 Three times daily 1. Hawthorne AB et al. Inflamm Bowel Dis 2012; 18: Hawthorne AB et al. Poster presented at the British Society of Gastroenterology, Glasgow, UK. June 2013 (PTU-058) Job Number: UK/AS/0027/ Date of preparation: February 2013.

51 Summary The majority of UC patients experience moderate to highly active disease within the first year of diagnosis. 1 Moderate disease should be distinguished from mild disease. 2 ECCO suggests that escalation of therapy should be considered for patients in whom rectal bleeding persists beyond days of treatment initiation. 3 In patients with moderately active disease, high-dose Asacol (4.8 g/day) provides: Symptom improvement at 2 weeks in 73% of cases 4 Mucosal healing at 6 weeks in 80% of cases overall, across all disease extents (proctitis to pancolitis) 5 ECCO, European Crohn's and Colitis Organis a tion 1. Langholz E et al. Scand J Gastroenterol 1991; 26: Stange EF et al. J Crohn s Colitis 2008; 2: Travis SPL et al. J Crohn s Colitis 2008; 2: Orchard TR et al. Aliment Pharmacol Ther 2011; 33: Lichtenstein GR et al. Aliment Pharmacol Ther 2011; 33: Job Number: UK/AS/0027/ Date of preparation: February 2013.

52 Summary Complex patients- surgical/medical discussion; IBD MDM Always involve patient Nutrition Job Number: UK/AS/0027/ Date of preparation: February 2013.

53 Combined Abbreviated Prescribing Information Please refer to the SPC before prescribing, particularly in relation to side effects, precautions and contraindications Combined Abbreviated Prescribing Information: Asacol 400mg MR Tablet, Asacol 800mg MR Tablet, Asacol 250mg and 500mg Suppositories and Asacol Foam Enema Presentation: Asacol 400mg MR Tablets, PL 10947/0011; each modified release tablet contains 400mg mesalazine (5-aminosalicylic acid). Bottles of 120, Bottles of 90, Asacol 800mg MR Tablets, PL 10947/0012; each modified release tablet contains 800mg mesalazine (5- aminosalicylic acid). Bottles of 180, Asacol 250mg Suppositories, PL 10947/0013, each containing 250mg mesalazine. Packs of 20, Asacol 500mg Suppositories, PL 10947/0014, each containing 500mg mesalazine. Packs of 10, Asacol Foam Enema, PL 10947/0015, 1g mesalazine per metered dose. Carton containing can of 14 metered doses, 14 disposable applicators and 14 disposable plastic bags, Indications: Ulcerative colitis: Treatment of mild to moderate acute exacerbations. Maintenance of remission. Suppositories particularly appropriate for distal disease, Foam Enema for distal colon disease only. 400mg Tablets, 800mg Tablets, Suppositories: Maintenance of remission. 400mg Tablets and 800mg Tablets only: Crohn's ileo-colitis: Maintenance of remission. Dosage and administration: ADULTS: 400mg Tablets: Acute disease: 6 tablets a day, in divided doses, with concomitant corticosteroid therapy where clinically indicated. Maintenance therapy: 3 to 6 tablets a day, in divided doses. 800mg Tablets: Mild acute exacerbations of ulcerative colitis: 3 tablets a day in divided doses. Moderate acute exacerbations of ulcerative colitis: 6 tablets a day in divided doses. Maintenance of remission of ulcerative colitis: Up to 3 tablets a day, once daily or in divided doses. Maintenance of remission of Crohn s ileocolitis: Up to 3 tablets a day in divided doses. Suppositories: 250mg: 3 to 6 a day, in divided doses, with the last dose at bedtime. 500mg: A maximum of 3 a day, in divided doses, with the last dose at bedtime. Foam Enema: 1 (disease of rectosigmoid region) or 2 (disease of descending colon) metered doses as single daily dose for 4-6 weeks. ELDERLY: The normal adult dosage may be used unless renal function is impaired. CHILDREN: 800mg Tablets: Not recommended. 400mg Tablets, Suppositories, Foam Enema: No dosage recommendation. Contra-indications: A history of sensitivity to salicylates or renal sensitivity to sulfasalazine. Confirmed severe renal impairment (GFR <20ml/min). 400mg Tablets, Suppositories and Foam Enema only: Children under 2 years of age. 800mg Tablets only: Hypersensitivity to any of the ingredients. Severe hepatic impairment. Gastric or duodenal ulcer, haemorrhagic tendency. Precautions: Use in the elderly should be cautious and subject to patients having a normal renal function. Asacol should be used with extreme caution in patients with confirmed mild to moderate renal impairment. Renal function should be monitored (with serum creatinine levels measured) prior to start of treatment, and periodically during treatment, taking into account individual history & risk factors. Mesalazine should be discontinued if renal function deteriorates. If dehydration develops, normal fluid & electrolyte balance should be restored as soon as possible. Serious blood dyscrasias (some with fatal outcome) have been very rarely reported with mesalazine. Haematological investigations including a complete blood count may be performed prior to therapy initiation, during therapy, and are required immediately if the patient develops unexplained bleeding, bruising, purpura, anaemia, fever or sore throat. Stop treatment if suspicion or evidence of blood dyscrasia. Concurrent use of other known nephrotoxic agents, e.g. NSAIDs & azathioprine, may increase risk of renal reactions. 400mg Tablets and 800mg Tablets: Lactulose or similar preparations which lower stool ph should not be concomitantly administered. 400mg tablets, Suppositories, Foam Enema: Only use during pregnancy if benefits outweigh the risk. Avoid during lactation unless essential. 800mg Tablets only: Mesalazine should be used with caution during pregnancy and lactation when the potential benefit outweighs the possible hazards in the opinion of the physician. If neonate develops suspected adverse reactions consideration should be given to discontinuation of breast-feeding or discontinuation of treatment of the mother. Discontinue treatment immediately if acute symptoms of intolerance occur including vomiting, abdominal pain or rash. Patients with the rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine because of the presence of lactose monohydrate. Standard haematological indices (including the white cell count) should be monitored repeatedly in patients taking azathioprine, especially at the beginning of such combination therapy, whether or not mesalazine is prescribed. Undesirable Effects: Common: Nausea, diarrhoea, abdominal pain, headache. Rare reports of leucopenia, neutropenia, agranulocytosis, aplastic anaemia, thrombocytopenia, peripheral neuropathy, pancreatitis, abnormalities of hepatic function and hepatitis, myocarditis, pericarditis, alopecia, lupus erythematosus-like reactions and rash (inc. urticaria), drug fever, interstitial nephritis and nephrotic syndrome with oral mesalazine treatment, usually reversible on withdrawal. Renal failure has been reported. Suspect nephrotoxicity in patients developing renal dysfunction. Very rarely, mesalazine may be associated with exacerbation of the symptoms of colitis, Stevens Johnson syndrome & erythema multiforme. 400mg Tablets, Suppositories, Foam Enema: Rare reports of allergic and fibrotic lung reactions. 800mg Tablets only: Common: vomiting, arthralgia / myalgia. Rare reports of vertigo, bronchospasm, eosinophilic pneumonia, bullous skin reactions. Very rarely, interstitial pneumonitis. Suppositories, Foam Enema: Rarely, local irritation may occur after use of rectal dosage forms of mesalazine. Legal category: POM. Marketing Authorisation Holder: Warner Chilcott UK Ltd, Old Belfast Road, Millbrook, Larne, County Antrim, BT40 2SH, UK. Asacol is a trademark. Refer to Summary of Product Characteristics before prescribing. Date of preparation April 2013 Job Bag Number: UK/AS/0095/04-13 Adverse events should be reported Reporting forms and information can be found at Adverse events should also be reported to Warner Chilcott UK Ltd on Job Number: UK/AS/0027/ Date of preparation: February 2013.