State of the Art Management of Crohn’s Disease Talal Al-Taweel Haya Al-Habeeb Gastroenterology Center Mubarak Al-Kabeer Hospital March 2015

Disclosures Travel/accommodation/meeting expenses: Janssen; AbbVie; Novartis

Introduction

Definition Crohn's disease is a condition of chronic inflammation potentially involving any location of the alimentary tract from mouth to anus, but with a propensity for the distal small bowel and proximal large bowel. Inflammation is discontinuous along the longitudinal axis of the intestine and can involve all layers from mucosa to serosa

History Intestinal inflammation characteristic of Crohn's disease first described by Morgagni in 1761 In 1932, the landmark publication of Crohn, Ginzburg, and Oppenheimer called attention to “terminal ileitis” as a distinct entity and chronic disease Underwent many naming changes due to discovery of multiple GI tract sites “Crohn’s disease” has been adopted to encompass the many clinical presentations of this pathologic entity

General Approach

Step Up or Top Down? Step up: Begin treatment with drugs that have a relatively long track record and safety profile progressing to more potent (and potentially more toxic) treatments in patients with severe or refractory disease Top down: Aggressive treatment with more potent treatments (such as infliximab or other immunomodulators) relatively early in the course of disease, before patients become corticosteroid dependent and possibly even before they receive corticosteroids

D’Haens et al. Lancet 2008 open-label RCT Combo = IFX + IMM Conventional = Steroids => IMM => IFX D’Haens et al. Lancet 2008

Weighing down the Value of Top-Down Therapy Pros Cons Early promotion of mucosal healing to prevent complications Evidence of immunomodulators and biologics to promote mucosal healing Serious side effects Development of antibodies (biologics) Cost Majority of patients do not require more potent treatments initially

So why not go all guns a blazing? Not every patient needs “top-down” or “early intensive therapy” We need to determine Who has high risk versus low risk disease How patients may respond to specific medications If patients agree with our plan

Not everyone develops complications of CD quickly Cosnes et al. Inflamm Bowel Dis 2002

Who is going to have “bad” Crohn’s? Clinical Risk Factor P value Age of onset < 40 years 0.0004 Perianal lesion at diagnosis 0.01 Required steroids for first flare 0.0001 Smokers 0.09 Beaugerie et al. Gastroenterology 2006

How about “good” Crohn’s? Cosnes et al. Gut 2012

Drugs

Sulfasalazine 5-ASA linked to sulfapyridine by an azo bond Salicylazosulfapyridine (sulfasalazine) was originally proposed as a treatment for rheumatoid arthritis Subsequently discovered that sulfasalazine was also efficacious in treating IBD.

Sulfasalazine Large controlled clinical trials completed in the 1970s and the 1980s demonstrated benefits of sulfasalazine 3-6g/day over placebo for induction of remission with mild to moderate active ileocolonic and colonic CD Not effective for patients with active disease limited to the small intestine No consistent maintenance benefits after medical inductive therapy Use largely limited by side effect profile Rash, anemia, reversible infertility in males

5-ASA Salicylazosulfapyridine (sulfasalazine) was originally proposed as a treatment for rheumatoid arthritis Subsequently discovered that sulfasalazine was also efficacious in treating IBD. 5-aminosalicylic acid (5-ASA) medications were developed because many patients were intolerant of or allergic to sulfasalazine

5-ASA Conflicting older data of efficacy in CD, with variable definitions of remission and response Meta-analysis of three large trials with mesalamine, 4 g daily, demonstrated a statistically significant (P = 0.04) but a non-clinically relevant difference (CDAI benefit of 18 points) compared with placebo Two more recent meta-analyses in 2010 and 2011 showed mesalamine not to be superior to placebo in induction or maintenance of remission CDAI: remission < 150, response 70 drop Hanauer et al. Clin Gastroenterol Hepatol 2004 Ford et al Am J Gastroenterol 2011

Geary Inflamm Bowel Dis 2007

Antibiotics Sutherland et al. Gut 1991 Widely used but no consistent evidence for luminal disease Metronidazole Not more effective than placebo for inducing remission in mild to moderate disease Post hoc subgroup analysis indicated that metronidazole might be effective in patients with colonic involvement The well-documented risk of peripheral neuropathy necessitates monitoring for symptoms or signs of paresthesias Ciprofloxacin, rifaximin and anti-TB drugs - inconsistent evidence of efficacy in luminal disease Sutherland et al. Gut 1991

Antibiotics Perianal disease Use well established in fistulizing peri-anal disease Abscesses require surgical drainage Non-suppurative perianal complications of CD typically respond to metronidazole alone or in combination with ciprofloxacin No placebo-controlled maintenance trials, but it appears that continuous therapy is necessary to prevent recurrent drainage

Steroids 2 large major published RCTs show that corticosteroids are effective agents for induction of remission in patients with CD. The National Cooperative Crohn’s Disease Study (NCCDS) Prednisone 0.5– 0.75 mg/kg daily with tapering over 17 weeks 60% clinical remission rates compared with 30% in the placebo group

Steroids European Cooperative Crohn’s Disease Study (ECCDS) Prednisolone 1 mg/kg with tapering over 18 weeks 83% clinical remission vs. 38% receiving placebo Preponderance of evidence that low-dose conventional steroids are ineffective for maintaining remissions in CD and therefore should not be used as long-term agents to prevent relapse of CD

IV vs. PO steroids? Parenteral steroids are used for severe or fulminant CD unresponsive to PO steroids No studies directly addressing issue, but overwhelming anecdotal evidence supports its use Methylprednisolone (60mg/day) preferred over hydrocortisone due to its decreased mineralocorticoid effects

Budesonide Budesonide is a corticosteroid with a high hepatic first pass metabolism Predominantly topical glucocorticoid activity resulting in fewer systemic side effects compared with conventional steroids Best combination of short-term efficacy and safety in a series of well-controlled randomized trials. Greenberg NEJM 1994

Budesonide Controlled-release oral budesonide formulations at a dose of 9mg/day have been demonstrated to be more effective than mesalamine 4g/day and similar efficacy to steroids for the treatment of disease in patients with mild–moderately active CD involving the distal ileum and/or right colon Reduces the time to relapse in ileal and/or right colonic disease, but does not provide significant maintenance benefits after 6 months Seow Expert Opinion on Drug Metabolism and Toxicology 2009 Tromm Gastroenterology 2011

Thiopurines Thiopurines should be considered for patients who require two or more corticosteroid courses within a calendar year steroid dependent steroid refractory postoperative prophylaxis of complex (fistulizing or extensive) CD Slow onset of action, with a response usually seen within 3-6 months.

Thiopurines – induction Rx 13 RCT Chande et al. Cochrane Database Syst Rev 2013

Thiopurines - maintenance Rx 8 RCT, forrest plot Prefontaine et al. Cochrane Database Syst Rev 2009

Thiopurines Dosage AZA 2-2.5 mg/kg/day 6MP 1-1.5 mg/kg/day Safety/tolerance issues nausea/malaise (switch agents) lymphoma risk (4/10,000) opportunistic infections (vaccinate) pancreatitis (idiosyncratic) Myelosuppression (minimized if TPMT and metabolites checked)

Methotrexate Alternative for the patient who does not tolerate or is unresponsive to azathioprine or 6-MP May be used in preference to azathioprine or 6-MP in patients with troublesome CD-related arthropathy. The drug should be initiated IM at a dose of 25 mg per week and a response anticipated within 3 months

Methotrexate Toxicity Remission rates reported up to 65% for MTX vs. 39% for placebo at 40 weeks Long-term open-label survival analysis has shown parenteral (but not oral) methotrexate to be effective in maintenance of a methotrexate-induced remission in 47% of patients with CD at 48 months Safety issues hepatic fibrosis interstitial pneumonitis teratogenicity nausea Toxicity early - nausea, vomiting, diarrhoea, and stomatitis) and this may be limited by co-prescription of folic acid 5 mg two or three days apart from the MTX. Late: hepatic-toxicity and pneumonitis Treatment is discontinued in 10–18% of patients because of side effects. PO and 15mg not effective

Biologics

Anti-TNF Engineered Antibodies Chimeric monoclonal antibody Human recombinant antibody Humanized Fab’ fragment VL VH No Fc CH1 Mouse Human PEG IgG1 IgG1 PEG Infliximab Adalimumab Certolizumab pegol PEG = polyethylene glycol

N Engl J Med 1997;337:1029-35

Lancet 2002; 359: 1541–49

3 groups: Placebo, 5mg/kg and 10mg/kg Clinical response=reduction in CDAI to 70 points and 25% from baseline. Clinical remission=CDAI <150 points

NEJM 2004;350:876-85

NEJM 2010;362: 1383-95

Adalimumab – induction Rx CLASSIC-I Hanauer et al. CLASSIC-I, Gastroenterology 2006

Adalimumab – maintenance Rx Colombel et al. CHARM, Gastroenterology 2007

Adalimumab – LOR to infliximab Uncontrolled, 12 week open label trial for non-responders to IFX N=24 Sandborn et al. GAIN, Am J Gastroenterol 2004

Can I combo adalimumab? No published studies specifically addressing issue of combination therapy of adalimumab with immunomodulator Sub-group analyses of major trials showed a trend towards a beneficial effect of combo vs. monotherapy Generally felt to be a class effect among all anti-TNF agents, although some experts would only use combination therapy with infliximab

18 trials

limited: heterogeneity, only 1 trial looked directly at the prespecified outcome, rest all SGA

Vedolizumab Monoclonal antibody that binds to integrin α4β7 (LPAM-1, lymphocyte Peyer's patch adhesion molecule 1) Blocking the α4β7 integrin results in gut-selective anti- inflammatory activity by way of interfering with lymphocyte trafficking IV administration q8 weeks after induction dosing Recently FDA and EMA approved for both CD and UC

Induction Maintenance Sandborn et al. NEJM 2013

Ustekinumab Human monoclonal antibody directed against interleukin 12 and interleukin 23 FDA approved for plaque psoriasis and psoriatic arthropathy Off-label use for refractory CD who are unresponsive or lost response to anti-TNF

Sandborn et al. CERTIFI, NEJM 2012

Ustekinumab – McGill experience Kopylov, Al-Taweel et al. J Crohns Colitis 2014

CD Treatment Pyramid Predicted disease activity Get it right the Very aggressive/ Refractory to Rx Surgery Ustekinumab Get it right the first time! Start the correct treatment at dx! Vedolizumab IMM + TNF antagonist Moderately aggressive/More difficult to treat AZA/6-MP/MTX Systemic corticosteroids TNF antagonists ( early intervention?) Budesonide Systemic corticosteroids Uncomplicated/ easily treated SSZ (colonic dx) ? No Rx AZA, azathioprine; 6-MP, 6-mercaptopurine; MTX, methotrexate