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 medically and surgically incurable (despite advancements in understanding its etiology and pathogenesis)

• Management strategies must be targeted towards lifelong management (both short- and long-term aspects of the disease).

Changing Standards…• The ultimate goal is Inducing and Maintaining clinical remission

• The current standard medical practice-‘Step-up'–sequential approach by using first-line agents (aminosalicylates [5-ASA], corticosteroids, and antibiotics), then immunomodulators and then biological therapy.

• This approach does successfully treat the acute disease, and maintains remission, but does not alter the long-term course of CD.

• The question- “Is it possible to alter the natural history of CD?” by an early introduction of therapies currently reserved for the 'top' (i.e.'top-down' approach).

• 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 symptoms alternating with periods of quiescence

• 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 over

placebo in maintaining remission of CD

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 long-term use is not recommended

Third-line therapy (immunomodulators & methotrexate) • AZA and 6-MP

• Effective in maintaining clinical remission with steroid sparing effect

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

• 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 of (3 randomized placebo-controlled trials)

• Potential adverse events- liver fibrosis, pneumonitis and bone marrow suppression

• Therefore the optimal duration of maintenance therapy remains unknown

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 and maintaining fistula closure

• 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 who had inadequate response or intolerance to conventional CD therapies, including the anti-TNF-[alpha] agents.

• 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