Mucosal healing Vs Symptom relief
Jose Francis
Lakeshore Hospital
Kochi

• No cure for IBD

* SYMPTOM RELIEF
* Maintenance of remission
* Maintenance of QOL

* Disease modification
* Mucosal healing
* Pharmacoeconomics
* Disease prevention!

Clinical
Induction & maintenance of remission off steroids
Closure of fistulas
Bowel
Mucosal & maintenance of healing
Healing of fistula tracks
Long term
Avoidance of complications, hospitalizations, surgeries & mortality

• Clinician will say “I know it when I see it”
* Intact bowel mucosa
• Clinical trials - secondary endpoint
• Remember!!
Normal mucosa when biopsied
* Granulomas (ileum/colon)
* Focal enhancing gastritis (antrum)
* Lymphocytic infiltration (rectum)

• Does healing of mucosa
* Improves the outcome?
• Unfortunately treatments that heal
* Do not cure
• When one stops Rx, the disease will recur

• Patient feels fine
– Physicians say “you’re better now, let’s just keep doing what we’re doing”
• Colonoscopy – activity
• Physicians do not say
“The fact that you are better now and we’ve achieved this level of mucosal healing through therapy escalation likely means that you’ll be in better shape in 10 years’’

• CDAI ( Remission <150)
• CAI
• Difficulty in evaluation
- Assess symptom relief only
- Non specific & non sensitive
- Inconsistencies in the way symptoms are reported, collected and understood, and symptom-based indices are limited when it comes to predicting how patients will fare
• (CDAI)
- Disease-focused, but not disease specific
- Symptom-based index has little to no prognostic value

• ESR
• CRP
• Calprotectin
• Lactoferrin
• Imaging (MRE, CT,USG)
• Endoscopy – MAYO, CDEI
• Histopathology
Difficulty in evaluation
- Invasive tests
- the incidence of procedures & cost
- Compliance (when pt. is feeling fine)
- No standardization

What’s Wrong with Using Clinical
Endpoints Rather Than Mucosal Healing?
• Crohn’s disease
* No correlation with endoscopic findings
* Patients treated to clinical endpoints
- Have progression of disease
• Ulcerative colitis
* Complete clinical remission & mucosal healing (score of 0) - good prognosis
* No escalation for mild residual symptoms

• Associated with
* Better quality of life
* Fewer hospitalizations
* Fewer surgeries
* Longer time to clinical relapse
* Reduction in dysplasia/cancer

• Mucosal healing
- Measure of the underlying inflammation
• Clinical symptoms
- Secondary surrogate
• Clinical symptoms are important, but treating the underlying inflammatory condition is likely the more critical factor

• Escalating dose
• Adequate & Maintenance dose
• Switching over
• Combination
• Efficacy of anti-TNF drug are trough levels
• Adherence to treatment

• 3 weeks, mucosal healing
– 65% with moderately active UC (4.8 g/d)
– 58% of patients 2.4 g/d ( P =.219)
• After 6 weeks, mucosal healing
– 80% compared with 68%( P =.012)
Am J Gastroenterol. 2005;100:2478-2485
Aliment Pharmacol Ther. 2005;21:133-140.
Can J Gastroenterol. 2007;21:827-834.
Clin Gastroenterol Hepatol. 2007;5:95-102
Aliment Pharmacol Ther. 2011;33:672-678

• Dose escalation
- Decrease of the interval between infusions
- Dose increase to 10 mg/kg
• ACCENT I study
- 90% who lose response can be rescued
• ACCENT II study
- Fistulizing disease
- Successful in 60%

• ASA
• Steroids
• Azathiopurine
• Biologic agents

• Few studies
• Granulated mesalamine 1.5 g once daily or placebo
• Maintained remission after 6 months of treatment
78% vs 59%; P<.001
• Relapse-free at 6 months
(77% vs 50%; P <.001).
Am J Gastroenterol. 2008;103(Suppl 1):A429-A430

• Switching to another biologic agent
• Adalimumab
• Certolizumab

ASA - Oral/rectal combination therapy
• Decrease in CAI scores
• Decrease in no. of relapses
Am J Gastroenterol. 1997;92:1867-1871
Am J Gastroenterol. 1997;92:1143-1147

Infliximab/Azathioprine combination

Mesalamine for postsurgical maintenance in Crohn’s disease?
• Preventing relapse
(OR, 0.68; 95% CI 0.52 to 0.90)
Gastroenterology. 2000;118:264-273.
Cochrane Database Syst Rev. 2011:CD008414

Infliximab for postsurgical maintenance in Crohn’s disease?
• 5 mg/kg within 4 weeks of surgery
• Maintenance for 1 year
• Endoscopic recurrence from 85% to 9%
Gastroenterology 2009; 136: 441 –50e1

Trough levels

• Active metabolites
6-thioguanine (6-TGN)
6-methylmercaptopurine nucleotide (6-MMPN)
• Meta-analysis of 12 studies
6-TGN levels higher among patients in remission
- 62% with 6-TGN levels above 230 –260 pmol/8 x108 RBC
- 36% below this value( P <.001)
• Gastroenterology. 2006;130:1047-1053 .

• 89% remain in remission over the long term
• 39% of those who are nonadherent
• Pill burden
• Educational intervention
Am J Med. 2003;114:39-43.
Am J Gastroenterol. 2002;97:1853

• Human antichimeric antibodies (HACAs)
- Episodic dosing 37% to 61%
- Scheduled infliximab 6% and 16%
• Similar in adalimumab & certolizumab
• Detectable trough concentrations had
- Higher rates of clinical remission
- Lower CRP
- Higher rate of endoscopic improvement
Lancet . 2002;359:1541-1549
N Engl J Med . 2003;348:601-608
Clin Gastroenterol Hepatol . 2006;4:1248-1254

Early Aggressive Biologic Therapy Vs
Conventional management of Crohn’s Disease

D'Haens G, et al. Lancet 2008;371:660-667

Complete Remission at 2 Years

Actuarial analysis of symptomatic recurrence in patients stratified according to severity of endoscopic lesions
Rutgeerts P, et al. Gastroenterology. 1990;99:956-963

 Infections
 Reactivation of latent TB
 Possible lymphoma risk
 Hepatosplenic T-cell lymphoma in young patients on infliximab plus concomittant azathioprine (n = 8)

Weighing the Value of Top-Down Therapy
Benefits Disadvantages
• Maintenance of remission
• Improved function and
QOL
• Early promotion of mucosal healing to prevent complications
• Side effects
• Cost
• Majority of patients may not require more potent treatments initially
• Under-treatment of most severe patients with episodic strategy?
Lichtenstein GR, et al. Inflamm Bowel Dis . 2004;10:S2 –S10.
Caprilli R, et al. Digestive Liver Dis . 2005;37:973 –979.

Predictors of More Severe Disease
Crohn’s disease
• Young age of onset
(<40 years)
• Ileal or ileocolonic extent
• Fistulizing disease at diagnosis
• Early need for steroids
• ASCA / other serologies?
• Genetics?
Ulcerative Colitis
• Extensive colitis
• Male gender
• Early need for steroids
• Early hospitalization

• Existing evidence
• Achieve mucosal healing in about 44%
Colombel JF et al N Engl J Med 2010: 362: 1383 - 1395

• There is no “one size fits all” to IBD therapy
– Tailored to the individual
• Current Rx guidelines for CD / UC
- Step-up treatment
• There is insufficient data to universally adopt top-down therapy into clinical practice at the present time

Symptom relief Vs Mucosal healing
Long way to go!!