Disclosures New Paradigms, New None Management: Our Changing - - PDF document

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New Paradigms, New Management: Our Changing Understanding of Ulcerative Colitis and Diverticulitis

Jonathan P . Terdiman, MD

Professor of Clinical Medicine and Surgery Director, Gastroenterology Service

Disclosures

• None

2 Hospitalized UC Patient|

UC: History

• 20 year old woman, college student
• Developed bloody diarrhea during midterm
• examinations. 10+ BMs per day and night
• Roommate brings her to ED

– Pale – Tachycardic (> 120), BP 85/45, afebrile – Abdominal pain, Tender in LLQ, focal rebound – Bloody bowel movements in ED – WBC 16K, Hct 22%, crp 70 mg/L

• Admitted to Hospital

3 Hospitalized UC Patient|

In Hospital

• Dehydrated – IV fluids, VS normalize
• Diet: Clear liquids
• CT scan

– LB wall thickening and fat stranding, no dilation of the colon

• Stools collected for infectious agents
• for culture, E.coli 0157, O&P, C diff

4 Hospitalized UC Patient|

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>10 stools/day, continuous bleeding, toxicity, abdominal tenderness/distension, transfusion requirement, colonic dilation on x-ray <4 stools/day ± blood, normal ESR, no signs of toxicity >6 bloody stools/day + fever, tachycardia, anemia,

• r ­ ESR

≥4 stools/day, minimal signs of toxicity

Classification of UC Severity

Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105:501.

Mild Moderate Severe Fulminant

Predicators of Poor Response or Surgery

6 Hospitalized UC Patient|

• Stool frequency
• >8 or >5 after 3 days IV rx.
• Percentage bloody stools
• Body temperature > 37.5
• Heart rate >90 bpm
• CRP (>25, >45 mg/L)
• Transverse colon > 5 cm
• Low hemoglobin <10.5 g/dL
• Serum albumin
• ESR > 30 mm/h
• Bandemia
• Prolonged flare
• Active infection
• Hospitalization setting
• Disease duration

Lindgren SC et al. Eur J Gastroenterol Hepatol 1998;10(10):831-5. Gonzalez-Lama Y et al. Hepatogastroenterol 2008;55(86-87):1609-14. Suzuki Y et al Dig Dis Sci 2006;51(11):2031-8. Cacheux W. et al. A,m J Gastroenterol 2008;103(3):637-42. Ananthakrishnan AN et al. A, J Gastroenterol 2008;103(11):2789-98.

Flexible Sigmoidoscopy

7 Hospitalized UC Patient|

• Limited to rectosigmoid
• No prep
• Mucosa:
• Edema, Erythema
• Diffuse Ulceration
• Pattern

– Circumferential, continuous, no skip areas

Endoscopic Severity: UC

8 Hospitalized UC Patient|

Mild

• Granular mucosa
• Edematous
• Loss of normal

vascular pattern

Sutherland LR, et al. Gastroenterology. 1987;92:1894-1898.

• Coarsely granular
• Small ulcerations
• Friable

Moderate

• Frank ulcerations
• Spontaneous

hemorrhage

Severe

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Endoscopic Severity Predicts Colectomy

9 Hospitalized UC Patient|

Severe endoscopic colitis Moderate endoscopic colitis

Carbonnel F et al. Dig Dis Sci. 1994;39:1550.

100 Colectomy (%) Deep/ extensive ulcers 93% Mucosal detachment 30% Large mucosal abrasions 26% Well-like ulcers 17%

> 50% → colectomy

100 Superficial ulcers 77% Deep but nonextensive ulcers 8%

>20% → colectomy

Colectomy (%)

Infections in UC

10 Hospitalized UC Patient|

• No broad spectrum antibiotics
• C. difficile

– Oral vanco first line (40 v 10% colectomy rate) – 40% rule: 40% of UC flares, 40% no prior abx, 40% colectomy rate

• CMV

– IHC + up to 20-30% of severe UC – Bystander versus pathogen – Treat both, avoid CsA

Meanwhile, back in the hospital …

• No progression of exam, VS stable, no need for

further transfusion

• PPD placed, Hep serologies sent
• IV steroids started, solumedrol 1 mg/kg (40 mg)

daily

11 Hospitalized UC Patient|

IV Corticosteroids: Effective in Severe UC

12 Hospitalized UC Patient|

Outcomes: Severe UC by Day 15

78% 69% 65% 70% 93% 53%

0% 20% 40% 60% 80% 100% Dexa 100mg x3 HC 400mg M-pred 40mg M-pred 0.75-1..0 mg/kg HC 400 mg M-pred 64 mg

Daily Dose

% Remission or Substantial Response Sood, A et al. J Clin Gastroenterol 2002;35(4):328-31. Panes, J et al. Gastroenterology 2000;119:903-8. Mantzaris, GJ et al. Scand J Gastroenterol 2001;36:971-4. Mantzaris, GJ et al. Am J Gastroenterol 1994;89:43-6. D’Haens G et al. Gastroenterology 2001;120:1323-9. Chapman et al. Gut 1986;27:1210-2

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Hospital Day 3

• Patient with minimal response
• Still multiple poorly –formed, bloody bowel movements,

cramps (> 10)

• Hgb < 7, 2 units of blood given, CRP > 50, xray with T colon

at 4 cm

• Options?

1) Wait longer on IV steroids 2) Start cyclosporin or tacrolimus 3) Start infliximab 4) Operation

13 Hospitalized UC Patient|

Steroid Failure: Day 3 assessment

IV Cyclosporin: Highly Effective

15 Hospitalized UC Patient|

Outcomes: Severe UC by Day 15

82% 69% 79% 56% 91% 86% 64% 0% 20% 40% 60% 80% 100%

4mg/kg 4mg/kg 5mg/kg 4mg/kg 4mg/kg 4mg/kg 4mg/kg

Daily Dose % Response

Lichtiger et al. N Engl J Med 1994;330:1841-5. Stack WA et al. Aliment Pharmacol Ther 1998;12:973-8. Van Gossum A et al. Acta Gastroenterol Belg 1997;60:197-200. Cohen RD et al. Am J Gastroenterol 1999;94:1587-92. Wenzl HH et al. Z Gastroenterol 1998;36:287-93. D’Haens G et al. Gastroenterology 2001;120:1323-9 Hyde GM et al. Eur J Gastroenterol Hepatol 1998;10:411-3.

CSA: Colectomy Avoidance with AZA

16 Hospitalized UC Patient| Actis GC et al. BMC Gastro 2007;7:13-19

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17 Hospitalized UC Patient| Jarnerot G, et al. Gastroenterol. 2005;128(7):1805-1811. 80% 70% 60% 40% 10% 0% 29% 67% Infliximab Placebo 20% 30% 50% 1.0 0.8 0.6 0.4 0.2 0.0 30 60 90 P=0.0038 (log rank – test) Time in Days Probability Not Operated Infliximab Placebo

• No. of Patients at Risk

Infliximab 24 17 17 17 Placebo 21 7 7 7

Colectomy

Infliximab: IV steroid-refractory UC

18 Hospitalized UC Patient|

• 23 GETAID and 6 ECCO centres
• 111 pts failing 5 days IV steroids: : Lichtiger score>10
• Patients randomized to either i.v.:
• Cys 2mg/kg/d x 1 week, then oral CSA x 91 days
• IFX 5mg/kg at weeks 0-2-6
• All patients started on azathioprine 2.5 mg/kg/d
• Steroids tapered
• Failure:
• No response day 7
• Absence Remission Day 98
• Relapse Day 7 – 98
• Severe AE or Death
• Colectomy

CSA vs. IFX: Severe IV Steroid-Refractory UC CSA vs. IFX: Severe IV Steroid-Refractory UC

19 Hospitalized UC Patient|

p=0.97

Response: Lichtiger score < 10 and decrease ≥ 3 points as compared to baseline

85.4% 85.7% 0% 20% 40% 60% 80% 100% Cys (n=55) IFX (n=56)

Response: Day 7

p=0.49 60% 54% 0% 20% 40% 60% 80% 100% Cys (n=55) IFX (n=56)

Treatment Failure *

Laharie et al. 2011 * Failure:

• No response day 7
• Absence Remission Day 98
• Relapse Day 7 – 98
• Severe AE or Death
• Colectomy

IFX vs CsA (Narula, et al. Am J Gastroenterol 2016; 111:477–491)

Colectomy rates at 12 months

20 Hospitalized UC Patient|

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IFX vs CsA (Narula, et al. Am J Gastroenterol 2016; 111:477–491)

• Drug adverse events

21 Hospitalized UC Patient| 22 Hospitalized UC Patient|

• Never together. Too much risk (20-30% SAE)
• Some Exceptions:

1. Cyclosporin: effective, but then has allergic reaction to azathioprine / 6-MP. (wash out for 48-72 hours) 2. Cyclosporin: intolerable side-effect (wash out for 48- 72 hours) 3. Infliximab: Once given NO CsA

BOTH Cyclosporin and Infliximab?

Infliximab: Not always successful

23 Hospitalized UC Patient|

39% 30% 26% 30% 0% 10% 20% 30% 40% 50% UCCS <3 Baron = 0

Week 6 Results

Infliximab Placebo

P= 0.76 P= 0.96

Probert CSJ et al. Gut 2003;52:998-1002.

• No difference in IBDQ or EuroQol Scores
• Randomized Placebo-Controlled Trial
• Infliximab 5mg/kg @ weeks 0, 2
• Placebo

Infliximab failure….Why?

24 Hospitalized UC Patient|

Results

• IFX: Detected in all pts stool.
• Highest in the first days post

infusion.

• Nonresponders, had much

high amounts of drug lost in stool.

Brandse JF, et al. Presented at DDW; May ,2013. Abstract 157.

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Higher Trough Levels: Better Outcomes

25 Hospitalized UC Patient| Murthy S, et al. 2012 Steroid-free Remission by IFX/ATI Status

100 60 20 Patients in Remission (%) 80 40 IFX+ ATI- 70.0 16.6 28.5 13.0 IFX+ ATI+ IFX- ATI- IFX- ATI+ P=0.84 P=0.073 P<0.001 Serum IFX ≤ 2µg/ml Serum IFX > 2µg/ml

Steroid-free Remission by IFX Trough Status

100 60 20 Patients in Remission (%) 80 40 17.5 69.4 P<0.001

Colectomy by IFX Trough Status

100 60 20 Colectomy (%) 80 40 Serum IFX ≤ 2µg/ml 55.5 17.7 Serum IFX > 2µg/ml P<0.001

• 125 Steroid-Refractory UC pts
• IFX “Infliximab”; ATI “Antibody to

Infliximab”

• Trough Infliximab >2 µg/ml
• Remission: OR 10 (3,35)
• Colectomy: 0.18 (0.07, 0.44)

Accelerated Infliximab Dosing: Success ?

26 Hospitalized UC Patient|

6.7% 40% 0% 20% 40% 60% 80% 100% Colectomy During Induction

Accelerated Normal

• Retrospective
• 50 hospitalized UC pts
• Corticosteroid refractory
• Standard dose infliximab: 5mg/kg Weeks 0,2,6,

then q8 w

• Accelerated dose: 3 doses within median 24 days

Gibson DJ et al. Clin Gastroenterol Hepatol 2014

Colectomy for severe UC

• Colectomy

– Surgical consult by day 3 for refractory patients – Toxic megacolon, perforation, refractory bleeding – Failure of medical therapy at 7-10 days

• Total abdominal colectomy with Hartmann

– Mortality < 1% – Laparoscopic or robotic – J pouch in 3 stages if eligible, but NOT during acute illness

27 Hospitalized UC Patient|

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Colonic Diverticulitis: History

• 57 year old man with sudden onset of LLQ

pain, constipation and fever

• T is 38.2, LLQ tender to palpation with

palpable mass, but no rebound

• WBC is 16K
• CT

Diverticulitis

• IV abx
• IR places drainage catheter, Cx + E. coli
• Within 48 hours pain and fever and elevated

WBC resolve

• Management?
• 1. Sigmoid colectomy prior to discharge
• 2. Sigmoid colectomy after 2-4 weeks of abx and

drainage

• 3. Abx for 2 weeks, drain removal after abscess

resolves, observation

Department

• f Medicine

Burden of Disease

• Prevalence of diverticulosis increased with age, affected 70%
• f individuals 80+ years old
• It is the most common finding reported on

colonoscopy

3 Everhart et al, Gastroenterology 2009

Taxonomy

Symptomatic uncomplicated diverticular disease (SUDD) Segmental colitis associated with diverticulosis (SCAD)

Strate et al, Am J Gastroenterol 2012

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Department

• f Medicine

Risk of diverticulitis

• The cumulative diverticulitis probability over 130 months was

4.3 % . For every additional decade of life, there was a 24 % lower risk of diverticulitis.

Strate et al, Am J Gastroenterol 2012 Department

• f Medicine

vAge

• Decreased risk with increased age of dx

vMedications

• NSAIDs, steroids, opiates increase risk for

diverticulitis

• Calcium channel blockers, statins may be protective

vGenetics

• Twin studies Sweden and Denmark
• OR 3x higher in monozygotic vs. dizygotic twins
• 40-50% of liability attributable to genetic factors

Templeton and Strate Curr Gastroenterol 2012

Risk factors for diverticulitis

Department

• f Medicine

Fiber Helps!

• British study of cohort of 700,000

women with no known diverticular disease, 6- year follow-up.

• 17,000 admitted to hospital with

diverticular disease.

• Higher intake of dietary fiber is

associated with reduced risk of diverticular disease.

29 Crowe et al, Gut 2014

• The Health Professionals Follow-up Study,cohort of

men prospectively followed 1986-2004.

• 47,000 men, age 40-75 years, baseline were free of

diverticulosis and returned a food-frequency questionnaire.

• Outcome was incident diverticulitis and diverticular

bleeding.

Nuts, corn, popcorn to blame?

Strate et al, JAMA 2008

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Department

• f Medicine

No increased risk!

Strate et al, JAMA 2008

Antibiotics for acute diverticulitis?

• Multicenter randomized controlled trial in Sweden and Iceland
• f 623 patients with uncomplicated left-sided diverticulitis

(confirmed on CT), excluded if abscess, fistula, free air, high fever, peritonitis, or sepsis

• Randomized to broad-spectrum antibiotics of IV fluids alone
• Also no difference in mean hospital stay, complications, or

recurrent diverticulitis necessitating re-admission over 1 year

• Authors concluded that antibiotics should be used only in cases
• f complicated diverticulitis

Chabok et al, Br J Surg 2012

Antibiotics for acute diverticulitis?

• Retrospective cohort of 246 patients admitted

with diverticulitis in 2011 to Vastmanland Hospital, Sweden

• All cases confirmed by CT, 195 with AUD
• 178 (91.3%)were not given antibiotics
• 6 pts readmitted, 2 had abscess
• Only 25 patients(12.8%) presented with

recurrence at 1 year

Wille-Jorgensen Coch Syst Rev 2012

When to operate?

• Emergency
• Free Perforation
• Diffuse Peritonitis
• Complete Colonic Obstruction
• Relative emergency
• Fail medical therapy, 72-96 hours
• Recurrence in the same admission
• Partial colonic obstruction
• Immunocompromised patients
• Unable to r/o carcinoma

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What happens after an episode of diverticulitis?

Recurrence free survival N=2366

3165 patients 12 Kaiser hospitals in Southern California Emergent colectomy 20% Non op management 80% Of those 13% had recurrence 7% had colectomy Mean follow up 9 years

0.00 0.25 0.50 0.75 1.00 Time to Recurrence (months) 20 40 60 80 100 0.00 0.25 0.50 0.75 1.00 Time to Recurrence (months) 20 40 60 80 100

Free from recurrence Free from recurrence w complication

Hazard Ratio 95% CI Retroperitoneal Abscess 4.5 1.1-18.4 Family history of diverticulitis 2.2 1.4-3.2 Segment > 5 cm 1.7 1.3-2.3 Right colonic disease 0.27 0.09-0.86

Risk of Recurrence per # of prior episodes

Number Patients Follow-Up Recurrence 2052 9 years 5% 1 222 9 years 11% 2 65 10 years 21% 3 18 9 years 33% 4 5 7 years 57%

Do Multiple Recurrences Predict a Less Favorable Outcome?

• Prior episodes

1-2 >2

• # of patients

122 35

• Perforation

17% 0%

• Stoma

37% 3%

Chapman et al, Ann Surg 2006

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Surgery after percutaneous drainage

Lamb and Kaiser Dis Colon Rect 2104 Li D, et al. Ann Surgery 2014

Department

• f Medicine
• Retrospective chart review of 1100 cases diverticulitis at

UCLA Veteran’s Administration Hospital + matched controls

• Cases were 4.7 fold (CI 1.6-14; p = 0.006) more likely to be

diagnosed with IBS (CI 1.6-14)

• 2.4 fold (CI 1.6-3.6; p = < 0.001) more likely to be diagnosed

with a functional bowel disorder

Post-diverticulitis IBS

Incidence of new IBS diagnosis

Cohen et al, Clin Gastroenterol Hepatol 2013

Incidence of new functional bowel disorder

Department

• f Medicine

IBS and diverticulosis

23

Jung et al, Am J Gastroenterol 2010

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• Case series demonstrate chronic inflammation in

biopsy specimens taken from within and around diverticula of patients without overt diverticulitis or colitis.

– Abnormal pathology in random biopsies taken from 16 of 17 patients with diverticulosis, with most demonstrating a lymphocytic infiltrate without overt colitis – There was evidence of chronic inflammation in and around diverticula in three quarters of resected specimens from 930 patients undergoing surgery for symptomatic uncomplicated diverticular disease but not overt diverticulitis

Floch et al, J Clin Gastroenterol 2006; Horgan et al, Dis Colon Rectum 2001

Inflammation

Department

• f Medicine

Visceral hypersensitivity

• Study of 10 patients with asymptomatic diverticulosis (ADD),11

SUDD patients, 9 controls.

• In the rectum, the SUDD group had increased perception

scores compared with the control group (p = 0.010) and the ADD group (p = 0.030). In the sigmoid colon, in the pre- and postprandial periods, the SUDD group had increased perception scores compared with the control group (p = 0.018)

21 Clemens et al, Gut 2004 Department

• f Medicine

Colonic Motility

• 12 patients with SUDD underwent 24-hour colonic

manometric recordings and compared to 20 healthy controls

• Patients with SUDD displayed increased duration of

rhythmic, low frequency, contractile activity, particularly in the segments bearing diverticular – a pattern described as “spastic colon”.

• Patients with diverticulosis have significantly reduced

density of interstitial cells of Cajal – the so- called “pacemaker cells” of the intestine.

25 Bassotti et al, Dig Dis 2012; Bassotti Eur J Gastroenterol Hepatol 2004

• Hypothesis - Shifts in intestinal microbiota lead to

chronic inflammation. Fecal stasis may lead to chronic dysbiosis in turn promote formation of abnormal metabolites.

• Study of 90 patients with history of diverticulitis, 60%

had small bowel bacterial overgrowth

• Use of probiotics and rifaximin help symptoms?

Intestinal Microbiota?

27 Tursi et al, W orld J Gastroenterol 2005

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Department

• f Medicine

New Paradigm of chronic illness?

Strate et al, Am J Gastroenterol 2012

Department

• f Medicine
• Multicenter, double-blind, placebo-controlled trial of 120 patients in Germany
• Randomized to mesalazine 1g PO TID vs. placebo
• 6 week trial, primary end point = change in abdominal pain after 4 weeks
• A daily dose of 3.0 g mesalazine may relieve pain of uncomplicated

diverticular disease.

Mesalamine

Difference of daily pain intensity score Median time to complete pain relief % patients with complete pain relief

Kruis et al, Ailment Pharmacol Ther 2013 Department

• f Medicine

Mesalamine

• Multicenter, double-blinded, placebo-controlled study. 210

SUDD patients randomized to mesalazine (1.6g/day) + probiotic placebo, probiotic + mesalazine placebo, probiotic + mesalazine, placebo only) for 10 days/ mo x 12 months

• Both cyclic mesalazine and Lactobacillus casei subsp.,

particularly when given in combination, appear to be better than placebo for maintaining remission of symptomatic uncomplicated diverticular disease

placebo

Tursi et al, Al Pharm Ther, 2013

Mesalazine + lactobacillus lactobacillus mesalazine

Department

• f Medicine

Rifaximin for SUDD

• In symptomatic uncomplicated diverticular disease, treatment

with rifaximin plus fibre supplementation is effective in obtaining symptom relief and preventing complications at 1 year

• NNT = 3 for symptom relief; NNT = 59 for complications

Bianchi et al, Aliment Pharmacol Ther 2011

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Department

• f Medicine

Combination Rx for SUDD

• 218 patients with recurrent

diverticulitis

• Randomized to rifaximin 400mg

po bid + mesalazine 2.4g/day x 7 days each month vs. rifaximin alone

• Severity of symptoms

improved significantly in dual therapy group and more likely to prevent recurrence

Tursi et al, Dig Liver Dis 2002 Gastroenterology 2014 147, 793-802DOI: (10.1053/j.gastro.2014.07.004)

Mesalamine Did Not Prevent Recurrent Acute Diverticulitis in Phase 3 Controlled Trials (N = 590, 592)

Raskin JP Gastroenterology 2014

Department

• f Medicine

Rifaximin for Acute Recurrent Diverticulitis

• Multicenter, randomized, open controlled study in 165

patients with recent episode of diverticulitis

• Rifaximin 400mg BID + fiber vs. fiber alone for 1 week/

month x 12 months

• OR 3.2 (95% CI 1.16-8.82, p=0.025)
• Cyclic rifaximin treatment reduces the risk of recurrences
• f diverticulitis.

Lanas et al, Dig Liver Dis 2013

Take Home Points

• IV abx may not be needed for acute

uncomplicated diverticulitis.

• Operative therapy is rarely needed for

recurrent uncomplicated diverticulitis or complicated diverticulitis.

• Diverticular disease is complex disorder

(motility, heightened visceral sensation, bacterial overgrowth, immune) and novel therapies may be effective.