End points in IBD treatmentMucosal healing Vs Symptom relief

Jose FrancisLakeshore Hospital

Kochi

Introduction

• No cure for IBD

No end points available!!

Treatment goals

* Maintenance of remission

* Maintenance of QOL

* SYMPTOM RELIEF

Additional goals!!

* Disease modification

* Mucosal healing

* Pharmacoeconomics

* Disease prevention!

* MUCOSAL HEALING

New therapeutic goals in IBD

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

Definition - mucosal healing

• 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)

Key question

• Does healing of mucosa

* Improves the outcome?

• Unfortunately treatments that heal

* Do not cure

• When one stops Rx, the disease will recur

Not uncommon situation

• 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’’

Clinical endpoints- Assessment

• 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

Surrogates for Mucosal Healing

• ESR• CRP• Calprotectin• Lactoferrin• Imaging (MRE, CT,USG)• Endoscopy – MAYO, CDEI• HistopathologyDifficulty 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

Mucosal healing as a surrogate for longer term outcomes

• Associated with

* Better quality of life

* Fewer hospitalizations

* Fewer surgeries

* Longer time to clinical relapse

* Reduction in dysplasia/cancer

Why is mucosal healing animportant treatment endpoint?

• 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

To attain mucosal healing

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

Escalating dose

• 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;100:2478-2485Aliment Pharmacol Ther. 2005;21:133-140.

Can J Gastroenterol. 2007;21:827-834.Clin Gastroenterol Hepatol. 2007;5:95-102Aliment Pharmacol Ther. 2011;33:672-678

Infliximab Dose

• 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%

Adequate dose

• ASA• Steroids• Azathiopurine• Biologic agents

Maintenance dose

5-ASA switching

• 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

Infliximab - switching

• 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;92:1867-1871Am J Gastroenterol. 1997;92:1143-1147

Infliximab/Azathioprine combination

Mesalamine for postsurgicalmaintenance 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 postsurgicalmaintenance 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

Trough levels

THIOPURINES - 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.

Managing adherence

• 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

Infliximab - Antibodies• 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;359:1541-1549N 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

Step Up Vs Top Down Results

Step Up Vs Top DownComplete 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

Safety issues

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

• 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?

Benefits Disadvantages

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

Mucosal healing

• Existing evidence

• Achieve mucosal healing in about 44%

Colombel JF et al N Engl J Med 2010: 362: 1383 - 1395

SUMMARY

• 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!!

Thank You