Acute severe colitis- Do`s and Don`ts Dr.S Sebastian

Hendriksen C, Kreiner S, Binder V. Gut 1985;26:158-163. Disease Severity at Presentation 100 Severe Activity (9%) 80 60 Moderate Activity (71%) Patients with UC (%) 40 Slide 6 The prognosis of UC including survival, colectomy rate, activity of disease, and working capacity was estimated from a follow-up study of 783 patients with UC comprising all patients from the county of Copenhagen. The period of observation ranged from 1 to 18 years with a mean of 6.7 years. The following observations were made: The survival rate of woman did not differ from that of the general population. At diagnosis, men over age 40 had a slight excess mortality rate in the first 2 years after diagnosis. Colon cancer was seen in only 7 of 783 patients. Annual risk was 0.07%. The colectomy rate was 9.6% in first year of diagnosis. After 10 years, the colectomy rate was 23%. After 18 years, the colectomy rate was 31%. At 3 years after diagnosis, the capacity to work including those with colectomy was not different from that of the general population. The study also indicated that, at any given time, 50% of those with UC were without symptoms, 30% had low disease activity, and 20% had moderate to high disease activity. Within 10 years of diagnosis, 97% of patients experienced at least one relapse. References Hendriksen C, Kreiner S, Binder V. Long term prognosis in ulcerative colitis – based on results from a regional patient group from the county of Copenhagen. Gut 1985; 26:158-163. 20 Mild Activity (20%) Disease Activity Hendriksen C, Kreiner S, Binder V. Gut 1985;26:158-163.

The Walking (working) Wounded

Sick Unto Colectomy !!!

Actor With Refractory Pan-colitis Formerly in remission on AZA 15-20 BM/day Progressive weight loss

Key aspects …. Assessing and managing the disease daily Assessing and managing risks daily Joint care with colorectal surgery `Individualised care`

Aims of medical management… Achieve remission Avoid colectomy, if possible Avoid complications

Day 0- things to do Assessing severity of disease Clarifying extend of disease Ensuring no complications Identifying reasons for failure of OPD treatment Baseline tests Starting treatment

1. Clinical severity assessment Mild Less than 4 stools /day with or without blood No systemic disturbance Normal Plasma viscosity/ESR Moderate More than 4 stools/day Minimal/ no systemic disturbance Normal/ mild elevation in PV (<1.9) /ESR (<25) Severe More than 6 stools daily with blood Evidence of systemic disturbance- fever,anemia, tachycardia Plasma Viscosity >1.9 /ESR >30 Modified Truelove & Witts Criteria

CONSTRUCT TRIAL COmparison of iNfliximab and cyclosporin in STeroid Resistant Ulcerative Colitis: a Trial HTA funded- £1.6 milion Propoposal 2003 Started Sep 2010 First results expected in 2014

What tests to do FBC CRP BCP Mg AXR Stool culture Stool C Difficle

Infection and Flare up of UC Infections contribute in 14-16% of flare ups of UC Steadily increasing concern in IBD patients Retrospective studies- higher C Diff rates than other hospitalized patients Roderman et al Cli Gastro Hepatol 2007 Issa M et al Clin Gastro Hepatol 2007 Prevalence 39.4/1000 ? Selection bias

C Difficile in IBD May not have clear history of antibiotic use/hospitalization Community acquired C diff does not have a better prognosis Risk of toxic megacolon 2-3% No evidence @present for increase in hypervirulent strain in IBD cohort Predictors of higher risk Females Colonic involvement Winter and spring months Multiple immunomodulators

National survey (US) of C difficile Nguyen et al Am J Gastro 2008 Prevalence UC 37.3/1000 Crohns 10.9/1000 Non IBD 4.8/1000 Incidence doubled in 7yrs Greater Mortality in UC (OR 3.79, CI 2.84-5.06) but not in Crohn`s (OR 1.66, CI 0.75- 3.66) 45-65% increase in duration of stay and costs

Recommendation… All patients needing admission for flare up should have stool C difficile and Stool cultures in the work up algorithm If C diff negative may need to recheck again if lack of response to treatment

North East 25%, Yorkshire and Humber 45% IBD audit-Stool Culture & CDT UK Median 45% North East 25%, Yorkshire and Humber 45% 17

VTE in IBD Complication in IBD 0.7 to 7.7 % Extensive, unusual sites Increased mortality and morbidity

VTE Time trend analysis Age adjusted VTE per1000 admissions

Cumulative risk of VTE

Recommendation…. All IBD patients admitted to hospital should have VTE prophylaxis

North East 55%, Yorkshire and Humber 75% % Prophylactic heparin - UC UK Median 60% North East 55%, Yorkshire and Humber 75% 22

Clarifying extend… Why important How to clarify Safety of endoscopy

Ensure no complications… Examine look for distension, peritonism Abd X-ray

Identifying reasons for failure Natural course of disease Non compliance Infection Proximal constipation Suboptimal mucosal drug concentration Co-existent IBS Inaccurate diagnosis

What treatment to start IV steroids DVT prophylaxis K replacement Mg replacement Nutritional management Individualised management Based on factors identified for failure Patient preferences

Drugs to avoid Anti diarrhoeals Codeine Tramadol NSAIDs Anti-cholinergics

What to look for every day Stool chart Abdominal pain, tenderness, distention Temp Bloods- CRP,FBC, Mg+, K+ See results !!! Decide repeat AXR needed Look @ drug card !

Acute abdominal pain in a colitic Examine !! Look for peritonism Abdo x-ray Avoid bowel paralytics Analgesia-pethidine Seek help

Case …. 47 yr old with known pancolitis on oral mesalazine Admitted via AAU for uncontrolled flare up despite oral steroids Stools > 10/day, Blood+++, abdominal pain CP 113, WCC 16,Platelets 497, Alb 27, K 2.9 Started on IV steroids

Case …ctd 24hrs later- Diarrhoea settled but increasing pain Review by SHO- Tramadol IM Review by gastro Repeat AXR

What is toxic megacolon? Non obstructive colonic dilatation in the presence of toxic colitis Jalan Criteria Radiographic evidence of colonic dilatation ( Transverse >6cm) 3 of 4: Fever, tachycardia, anaemia, leucocytosis 1 of : hypotension, altered mentation, electrolyte imbalance Not exclusive to UC but can occur with infective, ischemic or radiation colitis Jalan KN. Gastroenterology. 1969; 57: 68.

Toxic megacolon in IBD Lifetime risk in UC- 1-2.5% 2-5% of severe attacks of UC needing admission develop megacolon. Risk factors Extensive active disease Abrupt discontinuation of steroids/5-ASA Use of loperamide, anticholinergics, opiates Hypokalemia particularly after steroids

Toxic megacolon in IBD…. Perforation leads to mortality up to 20% Signs of peritonism may be masked by steroids Suspect micro perforation of increasing pain Serial x-rays Liaise with/ transfer care to gastroenterology and surgery

Drug therapy in acute severe colitis

Steroids-old dog still the `best` Overall response 67% (95%CI 65-69) Colectomy rate 29% (95% CI 28-31) Mortality 1% (95 % CI 0.7-1.7) How to improve response without compromising safety? Turner D et al 2007

Rescue therapies in 2009 Infliximab Cyclosporine/tacrolimus Adacolumn Vizilizumab Choice will depend on center expertise with drug choices and availability of expert surgical support Greatly tempered by pt preference Averaged preferences support the use of medical interventions, 1/3 of individuals may benefit most from proceeding directly to colectomy

Cyclosporin A First drug proven in steroid failures Response rate of CsA- 70-80% Rapid response Short half life Check cholesterol and magnesium 2mg/Kg sufficient Before treatment with IV CSA was initiated all patients were treated with IV glucocorticosteroids (minimum, 40 mg methylprednisolone/day). Patients were considered for CSA if their clinical condition did not improve after 5–7 days of IV steroid treatment or when there was a subjective or objective deterioration in their condition. Patients received CSA at a dose of 4 mg/kg/day or 2 mg/kg/day as a continuous IV infusion for a total of 7 days. The conditions of all patients were assessed daily by the treating physician and the consulting surgeon and when patients failed to improve after 7–10 days or when their medical condition worsened, they were scheduled for immediate colectomy. During IV treatment, CSA blood levels were kept between 250 and 450 ng/mL (4 mg/kg) or between 150 and 250 ng/mL (2 mg/kg). Patients who had a response were switched to oral treatment with Neoral (Novartis, Basel, Switzerland) at an initial dose of 8 mg/kg/day and the dose was adjusted to blood levels between 150 and 250 ng/mL. Intravenous glucocorticosteroids were continued at stable doses during IV CSA treatment. Those patients who achieved a response to IV CSA were switched to a tapering dose of oral glucocorticosteroids. CSA was continued in responders for a total of 3 months. Patients who already were taking azathioprine or 6-mercaptopurine were continued at their current levels. Those patients not taking azathioprine or 6- mercaptopurine were started at a dose of 2.5 mg/kg and 1.5 mg/kg, respectively, at the time of response to CSA during their hospitalization, if they had no known intolerance. Lightiger NEJM 2004 Van Assche G. Gastro 2003. 125(4);1025-1031

CsA Long Term Results Oxford; 76 pt retrospective series All severe UC, got steroids or CsA 56 (74%) initial remission At 12 months 65% of CsA remitters had 1+ flare At 84 months, 58% had colectomy AZA did not effect rates in subgroup analysis. Several European tertiary center series 68-88% colectomy rates within 7 years Moskowitz 2006; Campbell 2003, 2005

IV Cyclosporine: Major Toxicity Hypertension 25% Renal insufficiency 23% Infection 20% Seizures 3% Deaths 2% Anaphylaxis 1% 4

ACT1 Patient Population Subjects with: Moderately to severely active ulcerative colitis (UC): Mayo score  6 points (on 12 point scale) Endoscopy subscore  2 points Subjects must meet at least 1 of the following criteria: Current treatment with ≥ 1 of the following: Oral corticosteroids, 6‑mercaptopurine (6- MP), or azathioprine (AZA) Have failed to successfully taper, tolerate, or respond to corticosteroids within the past 18 months Have failed to tolerate or respond to 6-MP or AZA within the previous 5 years The inclusion criteria included: 1. Evidence of moderate-to-severe disease, indicated by a Mayo score of 6 to 12 points, with an endoscopic subscore of at least 2. The Mayo score is an assessment of ulcerative colitis activity, the total Mayo score ranging from 0 to 12 points, higher scores indicating more severe disease. The Mayo score is a composite of four measurements including stool frequency, rectal bleeding, findings of flexible proctosigmoidoscopy, and physician's global assessment . 2. AND either concurrent treatment with corticosteroids, azathioprine and/or 6-MP OR failure to tolerate or respond to at least one of the aforementioned therapies.

ACT 1 vs Real Life Clinical series 20-75% have colectomy within 3 months Elective surgery in INF patients safe but what about emergency surgery? Scottish survey 2/23 died, 3 have fungal sepsis Possibly better response in moderate and less severe scenario ACT, Jarnerot et al More worrying- patients having steroids, then cyclosporine then infliximab and then death! Cannot recommend combination therapy to avoid colectomy

IFX RISK FOR SUBSEQUENT COLECTOMY? Mayo Clinic report IFX patients had more postop. complication after tac/ipaa than non-INFX However, more AZT and high-dose steroids in INFX group MGH review All IBD (413/156UC) patients with surgery 2003-2007 assessed IFX exposure within 3 months; compared postop outcomes No sig. diff in death, leak, infection no diff in infection controlling for UC/CD, steroids, preop infection. OR for IFX =2.5, p0.14. Selvasekar 2007; Kunitake 2008

IFX RISK FOR SUBSEQUENT COLECTOMY? Cleveland Clinic (n=523) IFX-treated/matched controls who underwent proctocolectomy 2000-2006 Postoperative complications and rate of three- stage procedures compared adjusted OR of early complication for the IFX group was 3.54 OR of sepsis was 13.8 for the IFX group OR for late complication was 2.19 for the IFX group OR for three-stage procedures was 2.07 in the IFX group Mor 2008

IFX RISK FOR SUBSEQUENT COLECTOMY? Cedars-Sinai Chart review of pts undergoing IPAA or colectomy for refractory UC 2000-2005 17 patients failed IFX, 134 patients never treated with IFX IPAA performed in 112 patients (74%) and subtotal colectomy in 39 patients (36%) There were no deaths. Postoperative complications in 43 patients (28%) no statistically significant difference between IFX-treated (37%) and IFX-untreated patients (27%) 61 patients (40%) treated with preoperative CsA 5 patients also had IFX w/ 80%complication rate 29% in CsA only Schluender 2007

Cyclosporin Vs Infliximab Long experience Trail and experience data Short half life Rapid onset High short term toxicity No increased risk post colectomy Relatively short experience Paucity of trial data Longer half life Rapid onset Lower short term toxicity Suggestion of increased risk post colectomy Individualize patients Consult with an IBD Physician

My take on infliximab data in severe acute colitis Short term benefit in avoiding/delaying colectomy but with unknown but potential risks in those proceeding to surgery NICE – For acute severe colitis as rescue therapy to avoid colectomy as an alternative to cyclosporine

Timing of colectomy in severe UC The most taxing clinical judgement in UC As therapeutic options increase do do the opportunity for medical indecision making One death from complications of operating too late will negateball benefits of medical therapy How to identify @ early stage those who need colectomy?

Predictive Factors of colectomy Radiological Colonic dilatation >5.5 cms – 75% Mucosal islands on plain film – 75 % 3 or more small bowel loops of gas - 50% stool frequency >12 on day 2 – 55% Frequency >8 /day on day 3 – 85% frequency >8 /day & CRP >45 mg/ on day 3 -85% Frequency >4 and CRP >25 on day 3 – 75% Albumin <30 before day 4 -55% Genetic profile

What I Use? Travis Index On Day 3 after intensive treatment Stool frequency >8/day or Stool frequency 3-8/day CRP >45 mg/L 85% chance of colectomy within 6 months

No change in 50yrs !!! 116 patients Colectomy 33 (28%) Howthorne, Travis Gut 2002 116 patients Colectomy 33 (28%) Response 47 (41%) Partial response 36 (28%) 1955 results (Trulove & Witts) Remission 41% Improved 27% Worse 32%

Decision on Colectomy Decision is a triangular decision between patient, gastroenterologist and surgeon Daily review by an IBD physician, surgeon facilitates early decision making Close liason with stoma therapist Do not delay decision

Tenuous Balancing Act

A Century of Problems with Drugs “If the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be all the better for mankind, and all the worse for the fishes.” Oliver Wendell Holmes Medical Essays, “Comments and Counter” Currents in Medical Science

Take home Avoid the temptation to go on and on and on and ……..on medical treatment Use objective indices to predict colectomy preferably by day 3 Joint decision by IBD specialist and IBD surgeon

Problem with decisions/indecision

Refractory UC and CMV: Culprit or Companion? Detection of CMV genome is higher in IBD in general Current systemic steroids related to CMV infection (p = 0.03); p=NS for severity, past Rx Colectomy specimens (n=85) 20% stained positive 27% (15/55) of steroid-refractory 9% (6/68) positive PRE-op biopsies NO post-op CMV in any of 85 (pouch bx) High false negative retes on preop biopsies 1) Dimitroulia E et al IBD 2006. 12(9):879-84 Greek two center study 85 pts with IBD, 42 controls. 58 UC, 27 CD Controls: Immunostain: None PCR +12% in blood, 2% in tissue; UC Immunostain: + PCR associated with shorter duration of IBD 2) Maconi G et al Dig Liver Dis 2005. 37(6):418-23 Italian surgical series 77 consecutive resections for UC 55 steroid refractory 6 megacolon, 7 dysplasia/ cancer, 9 dysfunction

Final Points There is no “one size fits all” to IBD therapy Therapy and decision making are tailored to the individual Algorithms are based upon available evidence Evidence is in constant flux Success of algorithms depends upon optimization of each step of therapy and considerable judgment about each outcome Skillful application of medical therapy makes all the difference in outcomes

Sick Unto Colectomy