Current and Evolving Therapy of Crohn’s Disease (CD)

Orooj khan MBBS Ali Minhas MBBS Maya Srivastava MD PhD

Introduction

• Crohn's disease (CD) is a chronic inflammatory disorder of the digestive tract with a wide spectrum of clinical presentations and an unpredictable disease course.

• The estimated annual prevalence is 50 per 100,000 • The estimated annual incidence of CD is five per 100,000 • CD is more prevalent in Western countries • Affects all age groups, but is more commonly diagnosed in adults during the second and third decades of life.

Introduction

• Patients are faced with a lifetime of recurrent

disease flare-ups and remission

•

CD remains incurable medically

(despite

and surgically

advancements understanding its etiology and pathogenesis) in • Management towards strategies must

lifelong management

be targeted (both short- and long-term aspects of the disease).

Changing Standards…

• The ultimate goal is

Inducing and Maintaining

clinical remission • The current standard approach by using first-line agents (aminosalicylates [5-ASA], corticosteroids, and antibiotics), then immunomodulators and then biological therapy.

medical practice-

‘Step-up'

–sequential • This approach does successfully treat the acute disease, and maintains remission, but

does not alter the long-term course of CD

.

• The question- “ by an early introduction of therapies currently reserved for the 'top' (i.e.

Is it possible to alter the natural history of 'top-down' approach

).

CD?”

• We aim to present the rationale for the use of 'top-down' versus 'step-up' therapy for the treatment of CD.

Natural history of CD

• Intermittent exacerbation of alternating with periods of quiescence symptoms • A cohort study from Scandinavia by Munkholm

et al.

demonstrated: -13% of patients will achieve complete remission -20% of patients will experience annual relapse -67% will have a combination of relapse and remission within the first 8 years after initial diagnosis.

• In a population-based cohort study, Silverstein et al found that a CD patient spends: -24% of the time in medical remission without medications -41% of the time in postsurgical remission without medications -7% of the time in medical treatment with 5-ASA derivatives -7% of the time having disease activity mandating treatment with corticosteroids or immunomodulators.

Disabling course….

• A population-based study from Olmsted County, MN, USA by Schwartz et al. demonstrated: • Risk for the development of fistulas was 33% at 10 years

and 50% after 20 years

• The majority (83%) of fistulae required a surgical approach • Recurrence rate of perianal fistulae has been reported to be as high as 59-71% • presence of perianal disease, younger age of disease onset, need for corticosteroids predict a disabling course (85% of patients developed a disabling course within 5 years of diagnosis). (Beaugerie et al.)

Current Available Therapies

•

The First-Line therapies

: 1) 5-ASA (not FDA approved) -exert their therapeutic effect topically within the intestinal lumen.

-include the slow-release formulations -A

Cochrane

systematic review ( 6 randomized placebo controlled trials with 12-month follow-up) demonstrated

no superiority of 5-ASA placebo in maintaining remission of CD over

First Line Therapies

2) Antibiotics (not FDA approved): -Metronidazole and ciprofloxacin are the most widely used -Can be used alone or in combination . -In a Scandinavian Trial Metronidazole was found to be equally efficacious to sulfasalazine -Data are limited on the efficacy of antibiotics as maintenance therapy . -Potentially serious side effects (peripheral neuropathy and tendinitis or tendon rupture)

3) Budesonide (oral)- controlled-release • high topical activity and low-systemic bioavailability • used in patients with mild-to-moderately active CD involving the ileum and/or right colon.

• No evidence for the use of budesonide in fistulizing disease. • Not recommended as a maintenance treatment for CD.

Second-line therapy (Systemic corticosteroids)

• Highly effective in achieving clinical remission.

• A population-based cohort study observed that 84% of patients had either complete or partial response.

•

But

, within 1-year ,

28% of patients with CD became corticosteroid-dependent

•

38% of CD patients underwent surgery

• Increased risk of significant side effects, so

use is not recommended long-term

Third-line therapy ( immunomodulators & methotrexate)

• AZA and 6-MP • Effective in maintaining clinical remission with steroid sparing effect •

Slow onset of action

as inductive agents of 3-6 months precludes their use •

Serious side effects

associated with the prolonged use of these medications- non-Hodgkin lymphoma and hepatosplenic T-cell lymphoma • .

• Methotrexate • MTX was three-times more efficacious than placebo in maintaining remission of CD (

Cochrane

database meta-analysis randomized placebo-controlled trials) of (3 • • Potential adverse events liver fibrosis, pneumonitis and bone marrow suppression

Therefore the optimal duration maintenance therapy remains unknown of

The fourth-line therapy: anti-TNF (infliximab, adalimumab & certolizumab pegol)

• Designed to block or neutralize proinflammatory cytokines • • • • • • • • 1) Infliximab (FDA approved) For

induction and maintenance therapy

in patients with moderate-to severe CD refractory to conventional therapies (ACCENT I trial) Effective in

reducing the number of draining fistulae

fistula closure and maintaining Maintenance therapy was associated with: higher clinical response and remission rates significant reduction in hospitalizations and surgical procedures prolonged mucosal healing, faster steroid weaning, better quality of life.

2) Adalimumab- monoclonal anti-TNF antibody of fully human origin (Approved by the FDA in 2007) • As an induction agent (CLASSIC I trial) • A maintenance agent (CLASSIC II and CHARM trials) in adult patients unresponsive to conventional therapy • Patients intolerant to or lost response to infliximab • Patients with fistulizing CD treated with adalimumab had a significantly decreased number of draining fistulae per day (CHARM trial)

3) Certolizumab pegol (FDA approved 2008) • High binding affinity for TNF-alpha.

• Effective in inducing clinical response (PRECISE I trial) • Maintaining Remission (PRECISE II trial) • Not more efficacious on fistula closure (either of the mentioned trials).

Medical therapy for the nonresponders: selective adhesion molecule inhibitors (natalizumab)

• Natalizumab - new class of biologic agents (approved by the FDA in 2008 • Targeted against the [alpha]4 subunit of integrin molecules • Treatment to induce clinical response ENCORE trial • Maintain Remission ENACT 2 trial • Only in patients

conventional agents

.

who had inadequate response or intolerance to

CD therapies,

including the anti-TNF-[alpha]

• Approved for use only as a monotherapy owing to an underlying risk of PML.

So which one is better? Step-up versus top-down

• Step-up therapy • Refers to a sequential treatment strategy • Begins with a less effective, potentially less toxic treatment strategy, ( aminosalicylates, antibiotics or budesonide) • Escalation to the highly effective but potentially more toxic treatment (prednisone, immunomodulators and biological therapy) • In this strategy-avoid overtreating and unnecessary exposure to the risk of developing adverse events.

• For the reason of toxicity, physicians are often reluctant to advance therapy (may result in inadequate treatment and prolonged inflammation).

• Top-down therapy • Many studies have shown that most patients treated with the conventional step-up therapy go on to develop stricturing or penetrating disease .

• UK Study- looked at the influence of (infliximab) on resources in CD and found: • There were fewer bed days and number of abdominal operations was halved (Jewell et al)

• ACCENT I trial- demonstrated significant mucosal healing in 73% of patients treated early imunosuppression.

• There was a greater proportion of patients who achieved early clinical remission at week 14 (p = 0.0001) and week 26 (60 vs 36%; p = 0.0062) • A significant difference- number of patients in remission without corticosteroids and without surgery at weeks 26 and 52.

• Safety issues remain a major concern in the top-down approach. • Increased risk of TB, opportunistic infections and malignancy. • The risks of lymphoma and hepatosplenic T-cell lymphoma have been found to be associated with long-term immunomodulator use.

• The cost for initiating treatment may be higher in patients receiving early combination therapy • But take account indirect costs- as cost of lost productivity, quality of life, hospitalization and surgery rate,

• 1-year data from the recent SONIC trial have shown that monotherapy with infliximab or combination therapy consisting of infliximab and AZA are more likely to

maintain long-term corticosteroid-free remission than monotherapy with AZA

Whom & when to treat?

• There are no simple answers • Our ability to risk stratify patients remains rudimentary • Identify clinical factors associated with a disabling course and certain genetic and serologic profiles that may require a more aggressive therapy • The real challenge- development of an improved classification system (identify subgroups to maximize the treatment benefit-risk profile).

The Future…..

• Need to improve our ability to assess prognosis at the time of diagnosis, personalize treatment and target the patients will develop complicated disease • we hope to invert the treatment pyramid in selected target populations • Goals of disease modification, mucosal healing, reduced pharmacoeconomics, • Improved quality-of-life