Background and review of literature
Ulcerative colitis (UC) is a chronic, idiopathic, inflammatory disease of the colon. Current understanding of the pathogenesis suggests that a dysregulated immune response to environmental and microbial stimuli leads to UC in a genetically susceptible host. Studies estimated that 4.1–14.8% of patients with UC undergo colectomy during their disease course.1,2 For years, management primarily included the use of 5-aminosalicylates, corticosteroids, azathioprine, and surgery. The introduction of biologic-based therapies for UC has revolutionized the management of this disease.
Treat to target strategy in treatment of IBD involves looking beyond clinical or symptomatic remission. The drive to achieve mucosal healing (MH) with its apparent benefits is the true goal of successful therapy but the “target†of the “treat to target†strategy is still not very clear. Most studies targeted for deep remission (clinical remission + mucosal healing). Although a standardized definition of MH has not been established, a practical accepted definition is the complete resolution of the visible alterations or lesions, irrespective of their severity and/or type at baseline colonoscopy.
Although a great number of scoring systems have been developed (Baron score, Mayo score, Sutherland, Powell-Tuck and Rachmilewitz indices) none of them have been prospectively validated. The Mayo Clinic endoscopy subscore is most commonly used in recent clinical trials, defining mucosal healing as a score of ≤ 1 (normal mucosa or loss of vascular pattern, but no mucosal friability).
As early as in 1966, Wright et al reported a higher relapse rate in patients who did not achieve MH after oral and rectal steroids when compared with patients who did achieve MH (40% vs 18%). In ACT1/ACT 2 trial ,patients treated with infliximab who exhibited MH at week 8 showed a higher rate of clinical remission at week 30 than patients without MH (48.3% vs 9.5%).4
In a post-hoc analysis of the ACT1/ACT2 trials conducted by Colombel et al reported a lower probability of colectomy in patients who achieved mucosal healing.5 Another observational study in 513 UC patients, also showed the colectomy rate is lower in patients with MH.6 An Italian cohort study indicated a lower CRC risk at 17 years of follow-up in azathioprine (AZA)-treated UC patients with mucosal healing.7
Recently in CALM study by Colombel et al. have done a RCT to evaluate the efficacy of treat to target strategy in 244 Crohn’s Disease patients found a greater rate of deep remission, endoscopic remission and biologic remission in patients of treat to target group. They evaluated serum CRP and fecal calprotectin as the biochemical markers of inflammation.
Calprotectin is a calcium binding protein constitute a major portion of neutrophilic cytosolic protein. During intestinal inflammation as neutrophil transferred to intestinal lumen and injured mucosa disrupts neutrophil, calprotectin is released in the lumen. Fecal calprotectin has been evaluated as a markers of intestinal inflammation in several studies. Calprotectin appears to be distributed homogeneously in feces and is stable up to 7 days at room temperature.8 In a study of 228 patients it was found fecal calprotectin (r = 0.821) more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger Index, C-reactive protein (r = 0,556), platelets, hemoglobin, and blood leukocytes.9
Recently, appealing data have indicated a possible prognostic role for histologic remission in terms of reductions of flares, surgery/hospitalization and CRC incidence. But at present, more evidence is needed before considering histological remission as a possible goal of treatment in UC patients.
This study will evaluate the outcome of treatment targeting mucosal healing in patients of Ulcerative colitis and how different it is compared to conventional symptom based treatment approach.
 
Aims and Objective -
To evaluate the efficacy and safety of treatment to target strategy in active ulcerative colitis patients compared to conventional treatment.
METHODS
Setting:
The study will be conducted at AIIMS, a tertiary care academic center.
Study design:
It will be a Randomized Controlled trial.
Study duration:
The study will begin from February 2018 and end in June 2019.
Study population:
All patients of ulcerative colitis hospitalized or coming to OPD in the department of Gastroenterology in AIIMS, New Delhi will be screened for the study.
Sample size:
Sample size calculated from one similar studies in past. 10 % dropouts also added. Total sample size will be 124 with 62 in each group.
Inclusion criteria:
1. Patients of active ulcerative colitis presenting within 1 year of disease onset.
2. Patients with left sided or pancolitis.
3. Patients who have not received any dose of steroid, immune-modulators or biologics.
4. Patient giving written informed consent.
Exclusion criteria:
1. Age < 18 years, >75 years.
2. Patients with only rectal involvement (E1 disease).
3. Patients presenting with acute severe ulcerative colitis.
4. Patients with indeterminate form of colitis.
5. Patients infected with HBV, HCV or HIV.
6. Pregnancy
7. Patient with concomitant gastrointestinal infection.
6. Other major co-morbid conditions like acute myocardial infarction, chronic kidney disease or chronic liver disease.
Diagnostic criteria (Definitions):
Ulcerative colitis -
The diagnosis of UC will be considered in patients with -
1. Typical clinical features.
2. Colonoscopic findings suggestive of UC.
3. Histopathology confirming diagnosis of UC.
Active UC – UC patients with either clinically active disease (partial mayo score > 1) or active mucosal disease (Mayo endoscopic subscore 2/3)
Severity assessment –
Clinical severity: Clinical severity will be assessed using SCCAI and partial mayo score index.
• Partial mayo score index
1. Stool Frequency (based on the past 3 days)
Normal number of stools = 0
1â€2 stools more than normal = 1
3â€4 stools more than normal = 2
5 or more stools more than normal = 3
2. Rectal Bleeding (based on the past 3 days)
No blood seen = 0
Streaks of blood with stool less than half the time = 1
Obvious blood with stool most of the time = 2
Blood alone passed = 3
3. Physician’s Global Assessment
Normal = 0
Mild disease = 1
Moderate disease = 2
Severe disease = 3
o Remission = 0â€1
o Mild Disease = 2â€4
o Moderate Disease = 5â€6
o Severe Disease = 7â€9
o Response to treatment = 3 or more score reduction
Mucosal disease severity: Mucosal disease activity will be assessed as per Mayo endoscopic score.
Mayo endoscopic score
0 - Inactive disease and normal mucosa.
1- Erythema and mild friability.
2- Marked erythema, absent vascular pattern, friability, erosions.
3- Spontaneous bleeding and diffuse ulceration.
o - Mucosal healing.
o 2 - Moderate disease.
o 3- Severe disease.
Mucosal disease activity will also be assessed by biochemical parameter fecal calprotectin level.
• Target fecal calprotectin level for predicting mucosal healing - <50 microgm/gm.
Disease extent: Disease extent will be evaluated as per Montreal classification.
• E1 (ulcerative proctitis): involvement limited to the rectum (proximal extent of inflammation is distal to the rectosigmoid junction).
• E2 (left-sided UC): involvement limited to a portion of the colorectum distal to the splenic flexure.
• E3 (extensive UC): involvement extends proximal to the splenic flexure.
Targets -
 Clinical remission –Mayo partial score index (0-1).
 Partial response – Mayo partial score reduction of 3 or more but not in remission.
 Mucosal Healing – Mayo endoscopic subscore- (0-1) or fecal calprotectin level < 50 microgm/ gm.
 Deep remission – (clinical remission + mucosal healing)
 Biological remission – (clinical remission + normal fecal calprotectin level)
 Complete remission – (clinical remission + endoscopic remission + histological remission)
Evaluation of patients: Patients’ data will be collected as per protocol on demographics (age, gender, occupation), clinical manifestations, laboratory investigations, colonoscopic examination and other relevant information.
Laboratory investigations:
Routine lab investigations will be done in all subjects, complete blood counts, liver function test, renal function test, serum electrolytes, chest X-RAY, viral serology.
Fecal- calprotectin will be assessed every 3 months for evaluation of mucosal inflammation in the intervention group.
Colonoscopy will be done at the baseline and at the end of the study for all, and at every 6 months in the intervention group.
Colonoscopic biopsy will be taken at the end of 1 and ½ years of all the patients to look for histological remission.
Treatment Of ulcerative colitis –
• There will be 2 groups, Control group will be treated conventionally with aim of symptomatic remission.
• The intervention group will be started on steroid course of 12 weeks + 5-ASA and followed up with periodic evaluation of biochemical markers of mucosal inflammation (fecal calprotectin) every 3 months and sigmoidoscopic evaluation for mucosal healing every 6 months.
• Patients who will achieve deep remission at 12 weeks (subgroup A) will be continued on 5- ASA with dose adjustment and topical therapy as needed and be followed up for 18 months.
• Partial responders at 12 weeks (Subgroup B) will be started on azathioprine in addition. These patients will be evaluated at 24 weeks for deep remission. Patients who will achieve deep remission will be followed up for 18 months with periodic biochemical and endoscopic evaluation.
• Patients who will not achieve deep remission at 24 weeks and patient with steroid refractory disease will be out of the study.
Study Intervention: Patients will be randomized into two groups.
 
Follow up: All the patients will be followed up clinically at (1- 3) months interval depending on disease severity for 1 and 1/2 year. And any adverse effect of drugs or symptom exacerbation will be assessed immediately.
• Fecal calprotectin will be done in the intervention group every 12 weeks.
• Sigmoidoscopy will be done every 24 weeks in the intervention group to look for mucosal healing.
Randomization:
Randomization will be done by a computer generated random number table.
Blinding:
It will be an open level study.
Assessment of adverse events:
The adverse events of study medication will be assessed in detail in both the groups. Any new symptom or sign after giving study medication will be noted. Any change in hematological or biochemical parameters will also be documented. Any adverse events will be attributed to study medication based on biological plausibility and available literature.
CONSORT guideline:
The study will follow CONSORT guideline for a randomized controlled trial.
Outcome measures:
Primary outcome-
a) Proportion of patients in deep remission at the end of 24 weeks and 18 months in both the group.
b) Proportion of patients in biological remission at the end of 18 months in both the group.
c) Proportion of patients having complete remission at the end of 18 months in both the group.
Secondary outcome-
a) Clinical relapse rate in both the group.
b) Number of patients who have episode of acute severe ulcerative colitis or require surgery (colectomy) during this period in both the group.
c). Number of hospitalization in both the group.
d). Treatment related adverse events in both the group.
Trial registration:
The trial will be registered at www.ctri.nic.in
Ethical consideration:
The study will be started after obtaining ethical approval and patients will be included after an informed written consent.
Statstical analysis:
Student’s t test will be used for comparing continuous variables between the groups. Chi squqre test will be used for comparing qualitative data. A p-value of 0.05 will be considered significant.
References:
1. Targownik L., Singh H., Nugent Z. and Bernstein C. The epidemiology of colectomy in ulcerative colitis: results from a population-based cohort. Am J Gastroenterol. 2012(107):1228–35.
2. Solberg I., Lygren I., Jahnsen J., Aadland E., Hoie O., Cvancarova M. et al. Clinical course during the first 10 years of ulcerative colitis: results from a population-based inception cohort. Scand J Gastroenterol. 2009;(44):431–40.
3. Wright R, Truelove SR. Serial rectal biopsy in ulcerative colitis during the course of a controlled therapeutic trial of various diets. Am J Dig Dis 1966; 11: 847-57.
4. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, Travers S, Rachmilewitz D, Hanauer SB, Lichtenstein GR, de Villiers WJ, Present D, Sands BE, Colombel JF. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353: 2462-76.
5. Colombel JF, Rutgeerts P, Reinisch W, Esser D, Wang Y, Lang Y, Marano CW, Strauss R, Oddens BJ, Feagan BG, Hanauer SB, Lichtenstein GR, Present D, Sands BE, Sandborn WJ. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Gastroenterology. 2011; 141:1194-201.
6. Frøslie KF, Jahnsen J, Moum BA, Vatn MH. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology 2007;133:412-22.
7. Actis GC, Pellicano R, David E, Sapino A. Azathioprine, mucosal healing in ulcerative colitis, and the chemoprevention of colitic cancer: a clinical-practice-based forecast. Inflamm Allergy Drug Targets. 2010;9:6-9.
8. Lasson A, Stotzer PO, Öhman L, Isaksson S, Sapnara M, Strid H. The intra-individual variability of faecal calprotectin: a prospective study in patients with active ulcerative colitis. J Crohns Colitis. 2015;9:26–32.
9. Schoepfer AM, Beglinger C, Strauman A, et al. Fecal calprotectin more accurately reflects endoscopic activity of ulcerative colitis than the Lichtiger Index, C-reactive protein, platelets, hemoglobin and blood leukocytes. Inflamm Bowel Dis. 2013;19:332–41.