state of the art management of crohn ’ s disease talal al-taweel haya al-habeeb gastroenterology...
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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