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-tosevere 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