Treating the Outpatient with Severe IBD: Case Discussions William Tremaine, MD Corey A. Siegel, MD.

Treating the Outpatient with Severe IBD:

Case Discussions

William Tremaine, MDCorey A. Siegel, MD

Tremaine Case 1

• 36 year old man, college custodian

• Onset 6 months ago of diarrhea, some stools mixed with blood, urgency, abdominal cramps.

• Evaluated 5 months ago:• Negative stool studies for infection• Flexible sigmoidoscopy: moderately active colitis as

far as examined• Biopsies: Chronic colitis, no granulomas

Tremaine Case 1 continued

• Started: Prednisone 40 mg/d, tapered over 6wkMesalamine 1.2 g BID

• Improved, but worsened 1 week off prednisone

• Restarted Prednisone, tapered over 6 wk• Started Azathioprine 2.4 mg/kg/d

• Improved, but worsened 1 week off prednisone


• Check stools for infection again…negative

• Colonoscopy with biopsies…left sided UC, biopsies showed chronic colitis, stains negative for CMV

• MR enterography?... not done


• Infliximab added• Continued symptoms after 4 weeks

• Restarted Prednisone 40 mg/day, improved


• Stopped mesalamine

• Tapered and discontinued prednisone

• No symptoms on Azathioprine and Infliximab

Exacerbation of UC with Mesalamine

• 2 case reports• Both got worse on mesalamine• Both improved on prednisone

• One of the patients • In remission off meds• Flex sig showed quiet disease• Challenged with two 4gm mesalamine enemas • Repeat flex sig after 24 hours

• Marked worsening• Biopsies showed eosinophils and neutrophils

Sturgeon JB et al. Gastroenterology 1995; 108: 1889-93

Tremaine Case 2

• 53 year old nephrologist

• Ulcerative proctitis for 35 years

• Extends 12 cm above the dentate

• Intermittent symptoms

• Poorly controlled with:• Mesalamine oral and rectal• Steroids oral and rectal• Azathioprine 2.5 mg/kg for 4 month trial


• Stool studies: no infection

• Colonoscopy• Moderate proctitis• Normal above the rectum to the cecum

• Biopsies• Chronic colitis• No granulomas, inclusions, dysplasia

• Current Symptoms• Fecal urgency, stools or mucus >10 day, including 2-

3 nocturnal stools


What to do?

1. Proctocolectomy with J pouch

2. Anti-TNFα therapy

3. Methotrexate

4. Tacrolimus

5. Diverting sigmoid colostomy


• Tacrolimus suppositories• 1 mg compounded in local pharmacy

• Tacrolimus blood level 12 hours post suppository• 3.4 ng/ml

• Suppositories gradually decreased to once each 2-3 nights, as needed

Tacrolimus Suppositories for Ulcerative Proctitis

• Netherlands, multi-center

• Suppository composition• Tacrolimus capsules• adeps solidus

• Whole blood trough levels

• 10/12 pt (83%) improved

2hr 4hr 6hr 24hr0

1

2

3

4

5

6

μg/L

Tacrolimus Blood level

Van Dieren JM et al. Inflamm Bowel Dis 2009; 15:193-198

Tremaine Case 3

• 40 year old hair stylist

• Previous smoker, stopped 7 years ago

• Ulcerative colitis, hepatic flexure distally, for 5 years• Treated with mesalamine 1.2 g BID• Remission for 3 years• Then recurrent symptoms

• Controlled with prednisone• On Prednisone > 6 months in the past year

• Hates prednisone, feels jittery


• Weight gain of 25 kg • Increased ALT, Alkaline Phos.• Ultrasound: steatosis• Lost weight with dieting, liver tests normalized

• One year ago, left eye pain and loss of vision• Diagnosis, optic neuritis, treated with i.v. steroids• resolved over 14 days, no subsequent neurologic

symptoms


• Current symptoms• 4-6 stools daily, some with blood, urgency• Abdominal cramping pain 3-4 /10 severity

• Stopped mesalamine for a 5 days, worsened, restarted

• Declines further steroids

• Stools negative for infection

• Liver enzymes, TPMT normal

• Azathioprine: fever after 3 days to 102°F, resolved after 2 days off azathioprine


Treatment options?

1. Proctocolectomy with J pouch

2. Anti-TNFα therapy

3. 6-mercaptopurine

4. Methotrexate

5. Cyclosporine A

6. Oral mesalamine plus mesalamine enemas

Methotrexate in UC: Veterans Study

• National VA database

• 2001-2011

• 91 pt with UC met criteria• Methotrexate• Prednisone• > 15 mo follow-up

• Methotrexate• Oral: 68 pt 14mg/wk• I.M., S.Q. 23 pt

25mg/wk

• Prednisone Initial average Dose• Oral MTX group: 12 mg/d• I.M., S.Q MTX group: 25 mg/d

Off Prednisone0

5

10

15

20

25

30

35

40

45

50

MTX Oral

MTX I.M., S.Q.

12 Month Follow-up

Khan N et al. Inflam Bowel Dis 2013; 19: 1379-83

%


• Treated with

• MTX 25 mg S.Q. weekly

• Folic acid 2 mg p.o. daily

• Continued oral mesalamine 1.2 g BID

• Symptoms largely resolved after 2 months

Tremaine Case 4

• 34 year old attorney

• UC with pan-colonic involvement for 12 years

• Continued symptoms despite: • mesalamine• prednisone• azathioprine, nausea• Mercaptopurine• Anti-TNFα biologics, 2 agents

• Currently: 2-3 stools a day with blood mixed Urgency, cramps


• Stool studies negative for infection

• Colonoscopy

• Biopsies: moderate activity

• Treatment options• Proctocolectomy with

J pouch• Calcineurin inhibitor• Methotrexate• Anti-diarrheals, anti-

spasmodics

Oral Tacrolimus Maintenance Rx for Refractory UC

• London, retrospective

• 25 pt with UC

• Failed steroids• 23 failed thiopurines• 5 failed anti TNFα

• Tacrolimus 0.1 mg/kg/day• 12 hour dosing

• Trough levels 5-10ng/ml

Series10

5

10

15

20

25

30

35

40

45

50

RemissionAdverse Ef-fects

6 Month Outcome%

Landy J et al J Crohn’s & Colitis 2013; 7: e516-21


• Treatment• Tacrolimus 2 mg Q12 hours

• Dose adjusted upwards to trough level 8-10 ng/ml• Prednisone 40 mg/day

• Tapered and stopped after 4 weeks• Methotrexate 25 mg S.Q. weekly• Folic acid 2 mg /day• TMP/SMZ DS twice weekly while on prednisone• Calcium, Vitamin D

• Tacrolimus and MTX continued for 6 mo, then Tacrolimus was stopped

Siegel Case 1

• 36 year old woman, attorney – NH public defender

• Diagnosed with Crohn’s disease at age 15

• Colonic and perianal disease

• Prior use of 6MP, infliximab (secondary non-responder), adalimumab (horrible psoriasis)

• Colectomy with ileostomy and Hartmann’s pouch 2011

• Fine OFF all meds until 2013…

Siegel Case 1 continued

• Presumed peristomal pyoderma


• Ileoscopy showed 5cm of mildly active inflammation in most distal neo-terminal ileum (active chronic non-specific enteritis), mild diversion colitis

• Topical tacrolimus for pyoderma, budesonide for small bowel inflammation – no improvement in skin (worse)


Treatment Receiving Rx Rx Successful % success

Steroid injection 4 1 25%

Topical antibiotics 5 1 20%

Systemic steroids 8 1 12%

Systemic antibiotics 6 1 17%

Systemic cyclosporine 7 2 29%

Infliximab 6 2 33%

Stoma closure 5 5 100%

Treatment options and rate of success

Poritz LS, et al. J Am Coll Surg 2008;206:311


• No response to intralesional steroid injection, antibiotics, prednisone 40mg, oral antibiotics

• Sulfa allergy prevented use of dapsone

• Ustekinumab (anti-IL23) ?

• Responding very nicely after 1st 2 doses of ustekinumab!

Guenova E, et al. Arch Dermatol 2011;147:1203. Am J Gastroenterol 2012; 107:794.

Siegel Case 2

• 26 year old woman, works part-time for a coffee roaster

• Diagnosed with Crohn’s disease at age 15

• Perianal and colonic disease, s/p subtotal colectomy with ileosigmoid anastomosis at age 19

• 6MP with GREAT drug levels, but…

• Recurrent colonic disease and NEW diffuse small bowel disease

• Suicidal on prednisone (police intervention!)

• Infusion reaction to to infliximab, short duration response to adalimumab, no response to certolizumab


• Prochymal (mesenchymal stem cell) trial – no response

• Natalizumab for 3 months, no benefit (and scared)

• Next treatment options? Methotrexate TPN Antibiotics and budesonide Another clinical trial Off label use of something


• Start ustekinumab• 90mg SQ at week 0 and 2,

then every 8 weeks

Email from patient -

Dear Dr. Siegel,

Ustekinumab is the

drug for me! I am

feeling great.

Thank you,

XXXXX

Sandborn WJ, et al. N Engl J Med 2012;367:1519-28


• Did very well for 1 year, then symptoms returned, endoscopically active disease (small bowel and colon), losing weight

• Next steps?

• After ruling out infection and immune deficiency syndrome, starting tofacitinib

• Oral JAK inhibitor (UC and Crohn’s)

• At 15mg, dose dependent increase in LDL

• Treating with 10mg PO bid

28.1%

33.7%38.8%

40.8%

Sandborn WJ, Ghosh S, Panes, J, et al. Gastroenterology 2011;140:S124

Siegel Case 3

• 20 year old woman, college student majoring in sociology

• Diagnosed at age 16 with ileal and esophageal disease

• Pancreatitis to 6MP, serious delayed hypersensitivity reaction to infliximab

• Secondary loss of response to adalimumab

• Certolizumab + methotrexate with good ileal response, but persistent esophageal disease


• Management of esophageal Crohn’s PPIs Topical agents Systemic agents

Siegel Case 4

• 22 year old gentleman, college student

• 3 year history of ulcerative colitis, transverse colon to rectum

• Failing 5-ASAs and oral steroids

• Brief response with 1st infliximab dose, but persistent symptoms

20 year old male with UC: varying clearance of infliximab over the course of a flare

Data courtesy of Dr. Randall Pellish, UMASS Medical Center Slide created by Kimberly Thompson, Dartmouth-Hitchcock Medical Center

Dose 15mg/kg9/24/12

Dose 25mg/kg10/10/12

Dose 35mg/kg 11/12/12

Dose 410mg/kg 12/26/12

16+ weeks! Dose 55mg/kg 4/19/13

8 days after an infiximab dose, drug level = 1.8

Treating the Outpatient with Severe IBD: Case Discussions William Tremaine, MD Corey A. Siegel, MD.

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Transcript of Treating the Outpatient with Severe IBD: Case Discussions William Tremaine, MD Corey A. Siegel, MD.