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State of the Art Management of Crohn’s Disease

Talal Al-TaweelHaya Al-Habeeb Gastroenterology Center

Mubarak Al-Kabeer HospitalMarch 2015

Disclosures

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

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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

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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

Weighing down the Value of Top-Down Therapy

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

Pros Cons

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?

Beaugerie et al. Gastroenterology 2006

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

How about “good” Crohn’s?

Cosnes et al. Gut 2012

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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

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

Hanauer et al. Clin Gastroenterol Hepatol 2004Ford et al Am J Gastroenterol 2011

Geary Inflamm Bowel Dis 2007

Antibiotics

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

Chande et al. Cochrane Database Syst Rev 2013

Prefontaine et al. Cochrane Database Syst Rev 2009

Thiopurines - maintenance Rx

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

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

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Biologics

Anti-TNF Engineered Antibodies

Chimeric monoclonal

antibody

Human recombinant

antibody

Humanized Fab’

fragment

Infliximab Adalimumab Certolizumabpegol

PEG = polyethylene glycol

PEG

PEG

VHVL

CH1No Fc

IgG1 IgG1

Mouse

Human

N Engl J Med 1997;337:1029-35

Lancet 2002; 359: 1541–49

NEJM 2004;350:876-85

NEJM 2010;362: 1383-95

Adalimumab – induction Rx

Hanauer et al. CLASSIC-I, Gastroenterology 2006

Adalimumab – maintenance Rx

Colombel et al. CHARM, Gastroenterology 2007

Adalimumab – LOR to infliximab

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

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

AZA/6-MP/MTX

Systemic corticosteroids

SSZ (colonic dx)

Budesonide

SurgeryUstekinumab

IMM + TNF antagonist

Vedolizumab

TNF antagonists ( early intervention?)

AZA, azathioprine; 6-MP, 6-mercaptopurine; MTX, methotrexate

CD Treatment Pyramid

Moderately

aggressive/More difficult to treat

Very aggressive/

Refractory to Rx

Uncomplicated/easily treated

Predicted disease activity

Get it right the first time!

Start the correct treatment at dx!

? No Rx

Systemic corticosteroids