Biologic

Therapy in Crohns Disease: The Tricky Tincture of Timing

Scott Tarver, Pharm.D.

PGY1 Pharmacy Resident
University Health System, San Antonio, TX
Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center
University of Texas Health Science Center at San Antonio

February 28, 2014






Learning Objectives

1.
2.
3.
4.

Describe the pathophysiology and traditional treatment approach for Crohns disease
Identify proposed alternative treatment strategies for Crohns disease
Discuss outcomes in Crohns disease patients treated with an early biologic strategy
Summarize a plan for the timing of biologic use in Crohns disease patients

CROHNS DISEASE OVERVIEW

I.

Definition and epidemiology

A. Crohns disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders primarily
of the gastrointestinal tract which are classified as inflammatory bowel disease (IBD)
B. Incidence and prevalence of CD worldwide have risen over the last several decades1

Table 1. Epidemiology of Crohns Disease
1,2

Incidence (per 100,000/year)

1-4
Prevalence (per 100,000)
4
Female : Male
2

Age of Onset
2

Ethnicity

0.03 15.5
3.6 214
0.82 : 1 (pediatrics)
1.18 : 1 (adults)
Most common between 10 30 or 60 80 years of
age, but can be any age
Jewish > Non-Jewish Caucasian > Black > Asian

II.

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Etiology and pathogenesis

A. Exact etiology is unknown, but is believed to arise from genetic, immunologic, and
environmental contributions
i. Genetics5
a. Familial aggregation 35% of monozygotic pairs but only 3% of dizygotic pairs
were concordant for IBD in a German nationwide study
b. Genome wide association studies link inflammatory extraintestinal symptoms and
associated autoimmune diseases with susceptibility loci
c. First-degree relatives of patients with IBD may have a 20-fold increase in risk2
ii. Immunobiology2,5 the immune theory hypothesizes an inappropriate response of the
immune system in CD
a. Autoimmune mechanisms
1. Abnormal adaptive immune response leads to chronic inflammation
2. Autoantibodies to abnormal structures on colon epithelial cells
b. Non-autoimmune mechanisms
1. Intestinal immune system reacts to external antigens but is usually tolerant
of the normal commensal microbiota (intestinal homeostasis)
a. Hypothesis inappropriate inflammation and changes in microbiome
(dysbiosis) develop due to a disruption of the intestinal homeostasis
2. The protective mucus biofilm may become insufficient in CD due to a
reduced expression of the mucin gene MUC1 in the terminal ileum
3. Changes in tight-junctions between intestinal epithelial cells may make the
intestine leaky, increasing access of intestinal antigens to immune cells
4. Dysregulation of cytokines an imbalance between helper T cells (Th) and
tolerance-inducing regulatory T cells (Treg) promotes the secretion of
interferon , tumor necrosis factor (TNF-) and interleukin 12, leading to
intestinal inflammation and damage
a. Th1 cell activity is upregulated in CD
b. Dendritic cell function of activating Treg cells may be impaired in CD
iii. Environmental factors5
a. Infections
1. Gastroenteritis CD has been shown to occur after gastric infections
a. Bacterial chemotactic factors can attract inflammatory immune cells
b. Some bacteria produce toxins that can cause direct mucosal damage

III.

2. Clostridium difficile infections can lead to more frequent relapses and an

increased severity of IBD
3. Increased numbers of intramucosal bacteria are present in CD patients
4. Animal studies have shown that viral infections can potentially convert a
genetic predisposition to IBD into a disease outbreak
b. Smoking2
1. Early exposure to tobacco smoke (first and second hand) has been shown to
increase the risk of developing CD
2. Patients who quit smoking have decreased disease severity
c. Other environmental factors associations noted but evidence is conflicting
1. Stress many patients endorse increased flares/severity with stress
2. Drugs NSAIDs may trigger flares; oral contraceptives
3. Diet Cows milk, refined sugar, dietary fat

Clinical and pathological characteristics
A. Common Features of CD2,6

Table 2. Common Features of Crohns Disease

Presenting symptoms
Location
Pattern of GI involvement
Rectal involvement
Ileal involvement
Strictures or fistulas
Depth of inflammation
Recurrence post-surgery

Abdominal pain, N/V/D, weight loss, rarely

obstructive or perforating symptoms
Can affect entire GI tract but often proximal
predominance with small bowel involvement
Often discontinuous/segmental but can be diffuse
Rare
Very common
Common
Transmural through all layers
Not cured

N/V/D=nausea/vomiting/diarrhea, GI=gastrointestinal

B.

C.

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Extraintestinal manifestations of CD2

i. Ocular (2% 29% occurrence) inflammation of the iris, uvea, episclera, and conjunctiva
ii. Oral (4% - 20% occurrence) aphthous stomatitis, pyostomatitis vegetans
iii. Hepatobiliary primary sclerosing cholangitis (PSC), cholelithiasis, hepatic steatosis
iv. Anemia (up to 74%) chronic blood loss, malnutrition, hemolysis, myelosuppression
v. Coagulopathies increased risk for venous thromboembolism (VTE)
vi. Osteoporosis/metabolic bone disease increased risk in IBD patients due to
corticosteroid use, chronic inflammation, and calcium & vitamin D deficiencies
vii. Joints typically asymmetric, large joints, and severity fluctuates with IBD activity
viii. Dermatologic Complications Erythema nodosum, pyoderma gangrenosum
Activity and course of disease1,2
i. Classifying activity of disease there is no classification system universally utilized for all
types of CD; the following classifications are most commonly used:
a. Crohns Disease Activity Index (CDAI) used for luminal, non-fistulizing CD to
determine response to therapy and onset of remission
b. Practice guidelines classify CD activity based on signs and symptoms, disease
activity and location, and phenotype (penetrating, stricturing, or inflammatory).
The following are general categories:

1. Mild-Moderate (CDAI 150 220) ambulatory patients with no

dehydration, weight loss, abdominal tenderness, mass, or obstruction
2. Moderate-Severe (CDAI 220 450) fever, weight loss, dehydration,
abdominal tenderness, N/V, obstruction, anemia; includes mild-moderate
presentations that fail to respond to initial treatment
3. Severe-Fulminant (CDAI > 450) persistent symptoms or toxicity despite
steroid or biologic treatment or intractable symptoms plus cachexia,
rebound tenderness, obstruction, or abscess
ii. Disease course
a. Periods of disease exacerbation alternating with periods of remission
b. A large percentage of patients will have a favorable course with only
approximately 50% requiring initiation of corticosteroid therapy7
c. Depending on severity, presentations can range from intractable symptoms to
those with longer periods of remission

IV. Diagnosis of IBD
A. Based on a combination of clinical presentation, imaging, and laboratory findings
B. Intestinal imaging5,6
i. Endoscopy is the gold standard for all patients with suspected IBD cannot detect IBD
located only in the small intestines
a. Ileocolonoscopy identifies disease in the terminal ileum and colon; CD lesions
appear thickened, fatty, edematous with cobblestone or fried egg appearance
b. Esophagogastroduodenoscopy (EGD) can identify more proximal lesions in CD in
the esophagus, stomach, and the first part of the duodenum
c. Biopsies are taken and examined for mucosal inflammation and damage
ii. Small bowel follow through
a. Used to identify small bowel disease if EGD and ileocolonoscopy are negative
b. Barium contrast is ingested and X-rays are taken to visualize small intestines
C. Laboratory findings5,6
i. No laboratory tests can specifically establish a diagnosis of IBD
ii. Biomarkers are used as indicators of inflammation but are nonspecific
a. Erythrocyte Sedimentation Rate (ESR)
b. C-Reactive Protein (CRP)
c. Fecal granulocyte proteins lactoferrin and calprotectin

V. Non-pharmacologic treatments2,6
A. Nutritional support
i. Patients are often malnourished due to impaired absorption of nutrients, impaired
digestion, and anorexia secondary to nausea and pain
ii. Exclusion diets to eliminate certain foods thought to exacerbate disease are not routinely
recommended; may result in unnecessarily excluding nutritious foods
iii. Enteral nutrition can aid in reducing intestinal inflammation and cytokine production
which promotes healing and induction of remission
B. Surgery
i. May be necessary due to severe inflammation, when medical management is
unsuccessful, or with complications including perforation, stricturing, uncontrolled
hemorrhaging, and toxic megacolon
ii. Recurrence after surgical resection is common

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VI. Pharmacologic therapies by class

A. Aminosalicylates (AS) commonly used but no longer recommended by CD guidelines6
Several dosage formulations of 4 drugs with different brand names:
Sulfasalazine (Azulfidine) [sulfonamide antibiotic + mesalamine]
Mesalamine (Canasa, Rowasa, Pantasa, Lialda, Asacol, Asacol HD)
Balsalazide (Colazal)
Olsalazine (Dipentum, Apriso)
MOA: acts topically in the gut; mechanism not fully understood but has anti-inflammatory
effects related to inhibition of cyclooxygenase and lipoxygenase enzymes (decreases
prostaglandin and leukotriene production), interference with TNF-, and suppression
of IL-1 production
B. Antibiotics some evidence for inducing remission and decreasing relapses in CD2; often used
for treating secondary complications (e.g. abscesses or fistulas)
Metronidazole, Ciprofloxacin, Rifamycin derivatives
MOA: unknown, but have anti-inflammatory and immunosuppressive properties
Adverse Effects: antibiotic resistance and increased risk of C. difficile, especially with long-
term use
C. Corticosteroids (CS) induction treatment in IBD (70% 80% response)6
Prednisone, prednisolone, methylprednisolone, budesonide, hydrocortisone
MOA: exact mechanism unknown but corticosteroids suppress the immune system and
inhibit cytokines and prostaglandins
i. Do not work for maintenance of remission and systemic use has significant long-term
side effects and complications (e.g. increased risk of infection)
ii. Budesonide enteric-coated reduced toxicity due to high first pass effect; useful for
distal ileal involvement in CD or right-sided colon disease
iii. Hydrocortisone rectal suspension useful in proctitis, proctosigmoiditis, and left-sided
colon disease
Adverse Effects: adrenal suppression, glucose intolerance, hypertension, sodium/water
retention, osteoporosis, cataracts, impaired wound healing
D. Immunomodulators used to maintain remission and reduce steroid use
Azathioprine, mercaptopurine, methotrexate, cyclosporine, tacrolimus
MOA: Suppression of the immune system by different mechanisms
i. Traditionally reserved for patients that fail aminosalicylate therapy, are refractory to
steroids, or have become steroid-dependent
ii. May induce remission but are not preferred due to their slow onset of action (weeks to
months) must be used with another agent with faster onset
iii. Cyclosporine and tacrolimus are reserved for severe or refractory cases
Adverse Effects
i. Azathioprine and Mercaptopurine: pancreatitis, bone marrow suppression, nausea,
diarrhea, rash, hepatotoxicity; Risk of hepatosplenic T-cell lymphoma (especially in
young male patients) with increased risk if combined with anti-TNF biologics
ii. Methotrexate: bone marrow suppression, nausea, diarrhea, rash, pneumonitis,
pulmonary fibrosis, hepatotoxicity, neurotoxicity

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E.

Biological agents monoclonal antibodies effective for induction and maintenance

Table 3. Biologic Agents Used in Crohns Disease
Class
Medication

Tumor Necrosis Factor Inhibitors

Infliximab
Adalimumab
Certolizumab
(Remicade)
(Humira)
(Cimzia)
Approved
1998
2007
2008
FDA Approved
CD
CD
CD
Indications*
UC
UC
Antibody Type Chimeric (Mouse)
Human 100%
Peg-Humanized
75% Human
95% Human
Mechanism of Binds TNF-, inhibiting its effects:
Action
Normal TNF- Functions Inhibited Effect of Inhibition
- Induces inflammatory cytokines Inflammation
- Increases VEGF Angiogenesis
- Increases adhesion molecules Immune cell
infiltration

Administration
IV infusion
Subcutaneous
Subcutaneous
Dosing
I: 5 mg/kg on
I: 160 mg on
I: 400 mg on
weeks 0, 2, 6
week 0, 80 mg weeks 0, 2, 4
M: Every 8 weeks on week 2
M: 400 mg
M: 40 mg every
every 4 weeks
other week

Black Box
Infection: risk of serious and opportunistic bacterial,
Warnings
viral, and fungal infections
Cancer: in children/teenagers; hepatosplenic T-cell
lymphoma in young males taking AZA or 6-MP
Tuberculosis: reactivation of latent disease

4 Integrin Inhibitor
Natalizumab
(Tysabri)
2008
CD
Humanized
95% Human
Blocks integrin binding
to vascular receptors
inhibiting the adhesion
and transmigration of
leukocytes into tissues
(not specific for gut
tissue)
IV infusion
I: 300 mg on week 0
M: 300 mg every
4 weeks

Progressive Multifocal
Leukoencephalopathy:
opportunistic infection
cause by JC virus;
screening required

*All are approved for moderately to severely active forms of the corresponding disease with inadequate response to
conventional therapy (a full and adequate course of CS and/or immunomodulator therapy)

6-MP=mercaptopurine, AZA=azathioprine, CD=Crohns disease, I=Induction, M=maintenance, TNF-=tumor necrosis factor alpha,
UC=ulcerative colitis, VEGF=vascular endothelial growth factor

Adverse effects
i. Infusion reactions (infliximab & natalizumab): hypotension, fever, chills, urticaria,
pruritus; can pretreat with acetaminophen and diphenhydramine
ii. Delayed hypersensitivity: fever, rash, myalgia, headache, or sore throat 3 10 days after
administration
iii. Exacerbation of heart failure: relatively contraindicated in New York Heart Association
class III/IV
iv. Antibody induction: up to 50% of patients can develop antinuclear antibodies
v. Bone marrow suppression (pancytopenia)
vi. Hepatitis: can cause reactivation of hepatitis B virus; autoimmune hepatitis
vii. Vasculitis with CNS involvement

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TREATMENT STRATEGIES AND GUIDELINES

I.

Traditional treatment approach (step-up strategy)

A. Less toxic (but often less effective) medications are used initially and those with higher risk
profiles are added as disease severity progresses
i. Aminosalicylates first-line for mild disease
ii. Corticosteroids first-line for moderate to severe disease
iii. Immunomodulators added when patient becomes CS dependent or resistant
iv. Biologics added when immunomodulators and CS are no longer effective
B. Problems with the traditional strategy
i. Focuses on treatment of acute flares and maintenance of clinical remission instead of
prevention of disease progression
ii. CS use is effective short-term but a large percentage of patients become refractory or
dependent and the side effects become a major problem with prolonged use
iii. Reserving biologics until the disease progresses has not been shown to reduce
complications or the need for surgery in retrospective studies8

II.

Proposed alternative treatment strategies

A. Accelerated step-care starting treatment in early CD with an immunomodulator plus a CS
then adding a biologic upon disease progression
B. Top-down strategies use biologics early in hopes of preventing disease progression
i. Start an immunomodulator plus a biologic as combination therapy initially
ii. Start biologic monotherapy early for induction and maintenance

III.

DEFINING THE CLINICAL QUESTION

I.

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Guidance from clinical practice guidelines

A. American College of Gastroenterology1,9
i. A large percentage of patients will have a mild disease course and can be controlled with
occasional treatment using CS, metronidazole, or ciprofloxacin
ii. Moderate Severe CD
a. Anti-TNF biologics have been shown to be effective for induction and maintenance
and are generally recommended for use in patients that have not responded to
aminosalicylates, antibiotics, CS, or immunomodulators
B. European Crohns and Colitis Organization10
i. Moderate severe localized CD
a. Anti-TNF biologics should generally be reserved for CS refractory or dependent
patients while CS and immunomodulators are first line treatments
b. Early use of anti-TNF biologics is not directly recommended but is noted as an
approach to minimize CS use
ii. Extensive small bowel CD
a. Early anti-TNF biologic use can be considered in extensive (> 100 cm) disease for
patients with clinical indicators of poor prognosis

Preventing disease progression

A. Focus on therapies that will prevent complications and the need for surgery
B. Comparisons with rheumatoid arthritis (RA)
i. Earlier use of disease-modifying antirheumatic drugs (immunomodulators and biologics)
has been successful in preventing clinical and radiologic progression of RA
ii. This early use of immunomodulators or biologics has also been shown to prevent
erosions and joint-space narrowing in patients who do not have these complications yet

II.

Clinical question: Is earlier use of biologics in moderate severe CD better?

A. Definition of earlier use
i. There is no single definition used uniformly in the literature, but there are two that are
seen in several studies:
a. Early in disease course: time since diagnosis
b. Early in treatment course: nave to immunomodulators/biologics or using them
earlier than would be done in the conventional step-up treatment approach
B. Measuring the benefit (defining what is better)
i. Short-term outcome measures
a. Response and remission rates
b. Corticosteroid use
c. Relapse rates
ii. Long-term outcome measures
a. Complications
b. Need for surgery
c. Hospitalizations
iii. Mucosal healing (MH)
a. Important treatment goal increasingly studied in clinical trials
b. Interpretation of studies is difficult due to lack of a standard definition and timing
of endoscopic evaluation11
c. Definition of MH used as an outcome measure in several clinical trials: complete
absence of all inflammatory and ulcerative lesions12
d. Anti-TNF biologics can induce rapid and sustained MH11
1. MH as a primary outcome measure in the EXTEND trial13
a. After the first 12 weeks, MH was seen in 27.4% of adalimumab patients
and 13.1% of placebo patients (p = 0.056)
b. At 52 weeks in 129 patients, MH was seen in 24.2% adalimumab
patients and 0% of placebo patients (P < 0.001)
e. Complete MH (as compared to no or incomplete healing) in early CD two years
after initiation of therapy was associated with significantly higher rates of CS-free
clinical remission during years three and four14

III.

Safety concerns of immunosuppressive therapy

A. Infection
i. Overall risk of infection may be increased by immunomodulators and biologics
ii. A meta-analysis of placebo-controlled trials enrolling 5,356 patients concluded that the
use of TNF antagonists did not increase the risk of serious infections or death15
iii. Observational case-control study of opportunistic infections from the Mayo Clinic16
a. CS, AZA, and infliximab use were each independently associated with a
significantly increased risk of opportunistic infection
b. Combined treatment with two or three of these medications resulted in an OR of
14.5 (95% CI, 4.9 to 43)
c. Patients > 50 years old had three times more risk of serious opportunistic infection
iv. TREAT registry study of the long-term safety of infliximab and other treatments17
a. Infliximab use was associated with an increased risk of serious infection
b. Prednisone was the only immunosuppressant associated with increased mortality
B. Cancer
i. Patients with colonic CD have an increased risk of colon cancer18

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ii. AZA and 6-MP are associated with an increased risk of non-Hodgkins lymphoma19
iii. In all cases of hepatosplenic T-cell lymphoma reported in IBD, patients have had at least
2 years of exposure to thiopurine therapy alone or in combination with TNF antagonists19
iv. TREAT registry18
a. No overall increase in cancer incidence observed in patients receiving infliximab
b. No significant increase in the incidence of lymphoma, non-melanoma skin cancer,
or solid tumors was seen relative to the general population

EARLY BIOLOGIC THERAPY FOR CD IN THE LITERATURE

Table 4. PRECiSE 2 Post hoc Schreiber S, Colombel JF, Bloomfield R, et al.
Increased response and remission rates in short-duration CD with subcutaneous certolizumab pegol: an
20
analysis of PRECiSE 2 randomized maintenance trial data. Am J Gastroenterol. 2010;105(7):1574-1582.
Purpose
To analyze the efficacy and safety of certolizumab pegol based on duration of CD at baseline
Design


Population

Methods


Results

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Post hoc analysis of data from the PRECiSE 2 trial

A 6 week open-label certolizumab pegol lead-in identified patients with a clinical response
These patients were randomized to the double-blind, placebo-controlled phase which
continued through week 26
Ages: Adults 18 years old with CD diagnosis for > 3 months
Duration of CD*
Activity, mean SD (Baseline CDAI)** Prior Treatment History
< 1 year (n = 54)
291.1 48.7
All types of previous
1 to < 2 years (n = 42)
295.4 57.0
treatment histories were
2 to < 5 years (n = 100)
303.9 66.3
allowed
5 years (n = 229)
307.6 61.6
* Stratified by time since diagnosis at baseline
** All patients had moderate severe CD based on CDAI between 220 and 450
Induction with certolizumab pegol 400 mg SC was given at weeks 0, 2, & 4
Patients with a clinical response at week 6 (reduction in CDAI of 100 points, CR100)
continued into the randomized maintenance phase
Maintenance was certolizumab pegol or placebo given every 4 weeks from weeks 8 to 24
Response defined as CR100; Remission defined as CDAI 150
Independent predictors of week 26 response to certolizumab pegol
o Shorter duration of CD, < 2 years (p < 0.006)
o No prior resection, no prior infliximab use, and no corticosteroid use on entry
Induction of response & remission by open-label treatment at week 6
o No trends identified across disease duration
o Duration subgroup rates were similar to the rates in the overall population


Response Rates at Week 6 (%) Remission Rates at Week 6 (%)
Overall Population
62.5
43.3
< 1 year
61.7
45.7
1 to < 2 years
58.0
37.7
2 to < 5 years
65.4
49.0
5 years
62.3
41.5

Maintenance of response & remission at week 26
o Response and remission rates were inversely related to disease duration
o Response rate for the < 1 year subgroup (89.5%) was statistically higher than the
response rate for the > 5 year subgroup (57.3%); p < 0.05

o Remission rates showed similar trend as response rates but did not achieve significance

Response Rates at Week 26 (%) Remission Rates at Week 26 (%)

Certolizumab
Placebo
Certolizumab
Placebo
c
c
All Patients
62.8
36.2
47.9
28.6
b
a
< 1 year
89.5
37.1
68.4
37.1
1 to < 2 years
75.0
50.0
55.0
36.4
a
2 to < 5 years
62.2
36.4
46.7
29.1
c
c
5 years
57.3
32.7
44.3
23.5
a
b
c
p<0.05, p<0.01, p<0.001

Authors

Conclusions

Strengths

Weaknesses

Take Home
Points

Safety
o Overall incidence of any adverse event was not affected by disease duration at baseline
o A trend toward more serious events in longer CD duration was noted
o The incidence of serious AEs was lower in certolizumab patients than placebo patients
o There were no serious AEs in certolizumab treated patients with CD duration < 2 years
The efficacy and safety of certolizumab pegol for the treatment of CD over 26 weeks is
independent of disease duration
Treatment outcomes with certolizumab pegol may be better in CD of shorter duration
Included all types of prior treatment history and allowed concomitant non-biologic
treatments of CD to be continued
Open-label 6 week lead-in helped identify responders and exclude primary non-responders
Post hoc analysis
Relatively short 26 week study does not provide long-term outcome data
CD duration may be an independent predictor of response to certolizumab pegol
Patients with early CD (< 1 year) may have higher rates of maintaining response with
certolizumab pegol maintenance treatment than those with longer duration ( 5 years)

AE=adverse effects, CD=Crohns disease, CDAI=Crohns disease activity index, CR100=reduction in CDAI of 100 points,
SC=subcutaneous, SD=standard deviation

Table 5. CHARM/ADHERE Post hoc Schreiber S, Reinisch W, Colombel JF, et al.

Subgroup analysis of the placebo-controlled CHARM trial: increased remission rates through 3 years for
21
adalimumab treated patients with early Crohn's disease. J Crohns Colitis. 2013;7(3):213-221.
Purpose
Assess the relationship between CD duration and remission rates in moderately to severely

active CD patients treated with adalimumab
Design
Post hoc analysis of data from the CHARM trial and the follow-on ADHERE trial

CHARM trial a 56 week, randomized, double-blind, placebo-controlled trial of adalimumab

treatment for induction and maintenance
ADHERE trial patients from the CHARM study could continue in this open-label study of
continued adalimumab maintenance for a total of 3 years (from the beginning of CHARM)
Population Ages: Adults 18 to 75 years old with CD diagnosis for > 4 months

Duration of CD*
Activity (Mean Baseline CDAI)** Prior Treatment History

< 2 year (n = 93)
298.8
All types of previous
2 to < 5 years (n = 148)
302.9
treatment histories were
allowed
5 years (n = 536)
315.5
* Stratified by time since diagnosis at baseline
** All patients had moderate severe CD based on CDAI between 220 and 450

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10

Methods

Results

Induction with adalimumab 80 mg SC week 0 and 40 mg SC week 2 was given to all patients
On week 4 patients were randomized to 3 groups: adalimumab 40 mg SC every other week,
adalimumab 40 mg SC weekly, and placebo for 52 weeks (total study period = 56 weeks)
For patients that continued in the ADHERE follow-on study, those still on blinded treatment
were changed to adalimumab 40 mg every other week (with the option to increase to weekly
if required) and those already on open-label adalimumab continued their current dose
For the analysis of remission for patients continuing in ADHERE, only patients randomized to
adalimumab in CHARM were included (total of 3 years adalimumab maintenance treatment)
Response defined as CR100; Remission defined as CDAI 150
Predictors of remission at week 56 with adalimumab maintenance treatment
o Baseline CD duration (p = 0.046) and aminosalicylate use (p = 0.033) not significant
predictors at 26 weeks
o Baseline CRP and CDAI, prior anti-TNF use all were also significant at week 26
Maintenance of remission at weeks 26 and 56
o Remission rates at 56 weeks were significantly greater in adalimumab treated patients
than placebo treated patients in all CD duration subgroups
o At both weeks 26 and 56, the CD duration < 2 years subgroup had numerically higher
remission rates than the other CD duration subgroups

All Patients
< 2 years
2 to < 5 years
5 years

Remission Rates at Week 26 (%)

Remission Rates at Week 56 (%)
Adalimumab Placebo P Value Adalimumab Placebo P Value
33
14
< 0.001
30
10
< 0.001
46
19
0.008
43
19
0.024
28
23
0.56
30
13
0.028
32
10
< 0.001
28
8
< 0.001

Results for response were similar to those for remission

Long-term remission rates by CD duration subgroup (3 years of adalimumab therapy)
o The < 2 years CD duration subgroup had consistently higher remission rates

Authors

Conclusions

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Safety
o Overall rate of any adverse event was highest in the 5 years subgroup
o Placebo patients tended to have more serious AEs and discontinuations due to AEs
o The incidence of serious infections was low in all groups regardless of treatment
o No serious infections seen in adalimumab treated patients with CD duration < 2 years
Significantly higher remission and response rates were obtained with adalimumab vs. placebo
at weeks 26 and 56 in almost all CD duration subgroups (excluding only the week 26, 2 to < 5
years subgroup)
Shorter CD duration was associated with a higher likelihood of maintaining clinical remission
with adalimumab through 3 years of maintenance treatments

11

Strengths

Weaknesses

Take Home
Points

Included all types of prior treatment history and allowed concomitant non-biologic
treatments of CD to be continued
Provides response and remission data for an extended period of time (3 years)
Post hoc analysis
Did not exclude primary non-responders to adalimumab induction therapy
CD duration may be an independent predictor of response to adalimumab
Patients with early CD (< 2 years) may have higher rates of maintaining remission & response
with adalimumab maintenance treatment than those with longer duration ( 5 years)
Long-term maintenance treatment with adalimumab (3 years) showed that the shorter CD
duration subgroup (< 2 years) maintained higher rates of remission than the longer CD
duration subgroups

AE=adverse effects, CD=Crohns disease, CDAI=Crohns disease activity index, CR100=reduction in CDAI of 100 points,
SC=subcutaneous

Table 6. Step-up vs. Top-down Trial D'Haens G, Baert F, van Assche G, et al.
Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's
22
disease: an open randomised trial. Lancet. 2008;371(9613):660-667.
Purpose
Compare the effectiveness of early combined immunosuppression (infliximab + AZA or MTX)

with conventional step-up therapy in newly diagnosed CD patients nave to CS,
immunomodulators, and TNF inhibitors
Design
Prospective, open-label, multi-center, randomized trial

Early combined immunosuppression vs. conventional management with a follow-up of 2 years
Population Ages: 16 to 75 years old

Prior Treatment: All patients had never received CS, immunomodulators, or TNF inhibitors

Activity, mean SD
Treatment Group
Weeks from diagnosis, median (IQR)
(Baseline CDAI)*
Early Combined (n = 65)
330 92
2.0 (1.0 5.0)
Conventional (n = 64)
306 80
2.5 (1.0 11.0)
* All patients had active CD defined as a CDAI > 200 for a minimum of 2 weeks
No significant differences between any baseline characteristics
Methods
Response or Worsening Defined by CDAI

Initial CDAI of 200 250: response = 50 point reduction

Initial CDAI of 250 350: response = 75 point reduction
Initial CDAI > 350: response = 100 point reduction
Worsening defined as CDAI increase of 50 to give a score > 200
Early Combined Immunosuppression
Three infusions of infliximab 5 mg/kg given at weeks 0, 2, and 6 in combination with AZA 2.0
2.5 mg/kg daily starting from day 0
o If patient responded and tolerated this regimen, AZA was continued for the entire trial
o Patients who did not tolerate AZA were given MTX 25 mg weekly x 12 weeks then 15
mg weekly thereafter
If a patient worsened, additional infliximab infusions were given
If symptoms persisted, methylprednisolone was started and AZA or MTX was continued
Conventional Management
Induction treatment of methylprednisolone or budesonide was given (if patient responded,
the dose was tapered, for a total CS treatment of 10 weeks for either medication)
o If symptoms worsened during tapering, the CS was increased back to the initial dose
and the CS induction was repeated
o If symptoms continued to worsen after the second CS attempt, AZA or MTX was added

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Results

Patients who relapsed after a successful CS induction were advanced to CS + AZA or MTX
Any patient who remained symptomatic after 16 weeks of AZA were advanced to infliximab
induction course + AZA or MTX
Patients who were intolerant to both AZA and MTX were given infliximab monotherapy
(induction course + repeat infusions for symptom relapse) if symptoms persisted after
infliximab infusion, CS course was started
Remission defined as CDAI 150
Primary Outcome = remission + no CS treatment + no intestinal resection at weeks 26 and 52

Week 26
Early
Combined

Conventional

60.0%

35.9%

Week 52
P Value
(95% CI of difference)
0.0062
(7.3 40.8)

Early
Combined

Conventional

61.5%

42.2%

P Value
(95% CI of difference)
0.0278
(2.4 36.3)

Authors

Conclusions

Strengths

Weaknesses

Take Home
Points

Secondary Outcomes
Median time to relapse after successful induction at week 14, p = 0.031
o Early Combined: 329.0 days, IQR 91.0 not reached
o Conventional: 174.5 days, IQR 78.5 274.0
th
Daily methylprednisolone dose (95 percentiles)
o Early Combined: 0 mg
o Conventional: 35 mg
Mucosal healing (proportion without ulcers at 104 weeks) - subgroup analysis, p = 0.0028
o Early Combined: 19/26 (73.1%)
o Conventional: 7/23 (30.4%)
Safety
o No significant differences in any adverse events was found between groups
Combined immunosuppression with infliximab and AZA or MTX initiated early after CD
diagnosis in patients nave to CS, antimetabolites, and TNF inhibitors was more effective than
conventional management for inducing remission
Starting more intensive treatment regimens earlier in the course of CD may lead to better
outcomes
Compared an early combined immunosuppression (top-down) strategy directly to
conventional management (step-up strategy)
Assessed subjective measures (CDAI) in addition to objective measures (ulcers on endoscopy)
Unblinded study
Infliximab maintenance therapy every 8 weeks was not used; may provide more benefit
Early combined immunosuppression with infliximab + AZA or MTX resulted in higher remission
rates than conventional management in newly diagnosed CD patients
The early combined strategy resulted in less CS use than conventional management, lower
rates of relapse, and a higher rate of patients without ulcers at 2 years

AZA=azathioprine, CD=Crohns disease, CDAI=Crohns disease activity index, CS=corticosteroids, IQR=inter-quartile range,
MTX=methotrexate, SD=standard deviation

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Table 7. SONIC Trial Colombel JF, Sandborn WJ, Reinisch W, et al.

23

Infliximab, azathioprine, or combination therapy for Crohn's disease. N Engl J Med. 2010;362(15):1383-1395.
Purpose
Compare the efficacy of infliximab, AZA, and the two drugs combined for inducing and

maintaining CS-free remission in biologic and immunomodulator nave patients with active CD
Design
Prospective, double-blind, placebo-controlled, multi-center, randomized trial

30-week trial with a 20-week extension in which blinding was continued
Population Ages: 21 years old and diagnosed with CD for 6 weeks

Prior Treatment: All patients had never taken AZA, 6-MP, MTX, or an anti-TNF biologic agent and

met one of the following criteria:
o CS-dependent (having a CDAI of 220 after reducing the CS dose)
o Being considered for a second course of CS within 12 months
o No response to 4 weeks of either mesalamine or budesonide treatment
Median disease
Activity, mean SD
Treatment Group
(Baseline CDAI)*
Duration (years)
All Patients (n = 508)
287.3 56.7
2.3
Combination (n = 169)
289.9 55.0
2.2
Infliximab (n = 169)
284.8 62.1
2.2
AZA (n = 170)
287.2 52.9
2.4
* All patients had moderate severe CD based on CDAI between 220 and 450
No significant differences between any baseline characteristics
Methods
Patients were randomized to one of three groups:

o Infliximab 5 mg/kg at weeks 0, 2, and 6 then every 8 weeks + AZA 2.5 mg/kg daily

o Infliximab 5 mg/kg at weeks 0, 2, and 6 then every 8 weeks + placebo capsules daily
o AZA 2.5 mg/kg daily + placebo infusions at weeks 0, 2, and 6 then every 8 weeks
At week 30, patients were given the option of continuing blinded therapy for 20 more weeks
For patients taking mesalamine at baseline, it was continued at the same dose
Systemic CS could be continued or initiated for the first 14 weeks; after week 14 the dose was
tapered by at least 5 mg/week
Budesonide could be maintained or dose reduced up to week 14 after which it was reduced
by 3 mg every 2 weeks to a dose 6 mg/day
Ileocolonoscopy was performed at baseline; the procedure was repeated at week 26 in
patients found to have mucosal ulcers at baseline
Results
Corticosteroid-free clinical remission defined as CDAI < 150 and no budesonide at a dose > 6
mg daily or any systemic CS for 3 weeks
Primary Outcome = rate of CS-free clinical remission at week 26

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Secondary Outcomes
Mucosal Healing at week 26 (absence of ulcers in patients with ulcerations at baseline)

Authors

Conclusions
Strengths

Weaknesses

Take Home
Points

Rate of CS-free remission at week 50
(patients not continuing in extension trial were assumed to not be in remission)
Treatment Group
CS-free Remission, No. (%)
P Values
Combination (n = 169)
78 (46.2)
Combination vs. Infliximab
0.04
Infliximab (n = 169)
59 (34.9)
Combination vs. AZA
< 0.001
AZA (n = 170)
41 (24.1)
Infliximab vs. AZA
0.03
In patients with normal CRP (< 0.8 mg/dL) or with no baseline ulcerations, there were no
differences in rates of CS-free remission between the three groups, however, combination
therapy and infliximab monotherapy did have significantly higher rates than AZA
monotherapy in patients with elevated CRP or mucosal ulcerations at baseline
Safety
o The incidence of adverse events was similar between the three groups
o There was a numerically higher incidence of infusion reactions in the infliximab group
Treatment with infliximab monotherapy and combination infliximab and AZA compared to
AZA monotherapy in patients nave to immunomodulators and biologics with active moderate
severe CD resulted in significantly higher rates of CS-free clinical remission
Prospective, randomized, double-blind, placebo-controlled
Included data on mucosal healing
Subgroup analyses provide information regarding which patient subpopulations might benefit
Mucosal healing analysis was performed for only a subset of the population
Does not provide any long-term data (only 1 year in length)
This study is essentially comparing one group treated with the conventional step-up method
(AZA monotherapy) to two different types of accelerated top-down strategies (infliximab
monotherapy and combination infliximab + AZA)
The combination of infliximab + AZA resulted in significantly higher rates of CS-free remission
than either infliximab or AZA monotherapy in patients nave to immunomodulators and
biologics; infliximab monotherapy was also better than AZA monotherapy
Mucosal healing of baseline ulcerations occurred at a significantly higher rate in the
combination and the infliximab monotherapy groups as compared to the AZA group

6-MP=Mercaptopurine, AZA=azathioprine, CD=Crohns disease, CDAI=Crohns disease activity index, CRP=C reactive protein,
CS=corticosteroids, MTX=methotrexate, SD=standard deviation

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RISKS AND BENEFITS OF EARLY BIOLOGIC THERAPY IN CD

I.

II.

III.

Risks of early biologic use
A. General concerns
i. Infection possible increased risk of:
a. Opportunistic infections
b. Serious Infections
ii. Corticosteroids are the only immunosuppressant associated with increased mortality17
iii. Cancer risk appears to be similar to the general population in CD patients treated with a
biologic18
B. Safety findings20-23
i. Trend toward higher rate of AEs or more serious AEs with longer CD duration
ii. More serious AEs seen in placebo treated patients compared to biologic treated patients
iii. No serious AEs were reported in biologic treated patients with CD duration < 2 years

Benefits of early biologic use
A. Short-term outcome measures
i. Response and remission rates
a. Higher rates observed in early CD (< 1 to 2 years) than in late CD ( 5 years)20,21
b. In newly diagnosed patients, combination therapy (biologic + immunomodulator)
achieved higher remission rates than conventional step-up treatment22
c. In patients nave to immunomodulators and biologics, CS-free remission rates
from highest to lowest were, Combination Therapy (biologic + immunomodulator)
> Biologic Monotherapy > Immunomodulator Monotherapy23
ii. Corticosteroid use & relapse rates
a. Combination therapy (biologic + immunomodulator) resulted in less CS use and
lower rates of relapse than conventional management22
B. Long-term outcome measures the impact of early biologic treatment strategies on CD
complications, hospitalizations, or the need for surgery has not been reported due to the
relatively short duration of follow-up in the studies
C. Mucosal healing
i. Biologics used in combination and monotherapy strategies in early CD have been
associated with higher rates of MH compared to conventional treatment22,23
ii. In a post hoc analysis of the SONIC trial, MH rates were higher in patients with CD
duration 2 years compared to those with duration > 2 years24

Cost of biologic therapy
A. Specific costs for biologic agents are highly dependent on the health care system but the cost
is significantly higher than that of corticosteroids or immunomodulators
B. A cost-effectiveness analysis based on a United Kingdom cohort found that early use of
adalimumab or infliximab was cost-effective for a treatment period of up to 4 years compared
to conventional treatment; use of these biologics past four years was not cost-effective25

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ANSWERING THE CLINICAL QUESTION

I.

II.

Is earlier use of biologics in moderate severe CD better?
A. Yes, but only in the right patients
B. Factors to consider for selection of patients for early biologic therapy
i. Approximately half of patients presenting with CD will have a non-progressing course
a. Indiscriminant use of biologics in these patients would unnecessarily expose many
patients to the associated AE and cost burden
ii. Patients with elevated CRP ( 0.8 mg/dL) and/or ulcers prior to initiation of therapy have
been shown to have higher rates of CS-free clinical remission with early biologic
treatment strategies compared to conventional treatment23
iii. Predictors of disease progression and disability (poor prognostic factors)
a. Disease of the terminal ileum is associated with an increased risk of stricturing,
penetration, and need for surgery19
b. Presentation at diagnosis of young age (< 40 years old), initial need for CS therapy,
perianal disease, stricturing behavior, and loss of > 5 kg were found to be
independent risk factors for a severe disease course26,27
c. Severity of ulceration presence of deep ulcers was significantly associated with
an increased risk of bowel resection28
d. The presence of genetic markers and serologic immune responses may help
identify patients at risk of disease progression in the future19

Recommendations
A. Determining risk of severe disease course
i. Create three risk categories based on:
a. Guideline classification of CD activity at diagnosis
b. Presence of poor prognostic factors

Table 8. Poor Prognostic Factors at Diagnosis

Disease of the terminal ileum
Perianal disease
Stricturing
Weight loss > 5 kg
Deep ulcers

B.

ii. Classify as low, moderate, or high risk

iii. Risk category should be established at diagnosis and used to help determine the initial
treatment strategy
Stratifying the strategies
i. Based on CD risk class at diagnosis (Figure 1, pg. 18)

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CD Activity
Poor Prognostic
Risk of Severe
Initial Treatment

Classification
Factors
Disease Course
Strategy


Conventional

None
Low Risk

Step-Care
Mild -

Moderate

1



Moderate
Accelerated

Risk
Step-Care

None

Moderate -


Severe

1

Top-Down


High Risk
Biologic

Severe
-


Strategy
Fulminant



Figure 1. Initial treatment strategy for CD based on the risk of having a severe disease course

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REFERENCES

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2.
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17.
18.
19.
20.

21.
22.
23.
24.
25.
26.
27.
28.
29.

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Peyrin-Biroulet L, Deltenre P, de Suray N, Branche J, Sandborn WJ, Colombel JF. Efficacy and safety of tumor necrosis factor
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Toruner M, Loftus EV, Harmsen WS, et al. Risk factors for opportunistic infections in patients with inflammatory bowel
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19

APPENDIX

Appendix A: Crohns Disease Activity Index6

Variable
No. of liquid stools
Abdominal pain
General well-being
Extraintestinal
complications
Antidiarrheal drugs
Abdominal mass
Hematocrit
Body weight

Description
Sum of 7 days
Sum of 7 days
Sum of 7 days
Number of listed
complications
Use in the
previous 7 days

Expected minus
observed level
From within the
previous 7 days

Score

Multiplier

0 = none, 1 = mild, 2 = moderate, 3 = severe
0 = generally well, 1 = slightly under par, 2 = poor, 3 = very poor, 4 = terrible
Arthritis, arthralgia, iritis, erythema nodosum, pyodermagangrenosum,
o
o
uveitis, apthous stomatitis, anal fissure/fistula, abscess, fever > 37.8 C (100 F)
0 = no, 1 = yes

2
5
7
20

0 = no, 2 = questionable, 5 = definite

Male: 47% - observed; Female: 42% - observed

10
6

1 (ideal observed) x 100

30

1 (not if < 10)

Remission=CDAI < 150, Response: decrease in CDAI of > 70 or > 100 (depending on the trial), Moderate to Severe Crohns disease=
CDAI of 220 450, Severe Crohns disease = CDAI > 450

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