Case Discussions - Advances in Inflammatory Bowel Diseases

Report
Treating the Outpatient with Severe IBD:
Case Discussions
William Tremaine, MD
Corey 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 6wk
Mesalamine 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
Tremaine Case 1 continued
• Check stools for infection again…negative
• Colonoscopy with biopsies…left sided UC, biopsies
showed chronic colitis, stains negative for CMV
• MR enterography?... not done
Tremaine Case 1 continued
• Infliximab added
• Continued symptoms after 4 weeks
• Restarted Prednisone 40 mg/day, improved
Tremaine Case 1 continued
• 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
Tremaine Case 2 continued
• 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 23 nocturnal stools
Tremaine Case 2 continued
What to do?
1. Proctocolectomy with J pouch
2. Anti-TNFα therapy
3. Methotrexate
4. Tacrolimus
5. Diverting sigmoid colostomy
Tremaine Case 2 continued
• 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
μg/L
6
• Suppository composition
• Tacrolimus capsules
• adeps solidus
5
• Whole blood trough levels
2
• 10/12 pt (83%) improved
1
Tacrolimus Blood level
4
3
0
2hr
4hr
6hr 24hr
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
Tremaine Case 3 continued
• 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
Tremaine Case 3 continued
• 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
Tremaine Case 3 continued
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
• I.M., S.Q. 23 pt
14mg/wk
25mg/wk
• Prednisone Initial average Dose
• Oral MTX group: 12 mg/d
• I.M., S.Q MTX group: 25 mg/d
%
50
45
40
35
30
25
20
15
10
5
0
12 Month Follow-up
MTX Oral
MTX I.M.,
S.Q.
Off Prednisone
Khan N et al. Inflam Bowel Dis 2013; 19: 1379-83
Tremaine Case 3 continued
• 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
Tremaine Case 4 continued
• Stool studies negative for
infection
• Colonoscopy
• Biopsies: moderate activity
• Treatment options
• Proctocolectomy with
J pouch
• Calcineurin inhibitor
• Methotrexate
• Anti-diarrheals, antispasmodics
Oral Tacrolimus Maintenance Rx for
Refractory UC
50
%
• 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
6 Month Outcome
45
40
Remission
35
Adverse
Effects
30
25
20
15
10
5
0
Landy J et al J Crohn’s & Colitis 2013; 7: e516-21
Tremaine Case 4 continued
• 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
Siegel Case 1 continued
• Ileoscopy showed 5cm of mildly active inflammation in
most distal neo-terminal ileum (active chronic nonspecific enteritis), mild diversion colitis
• Topical tacrolimus for pyoderma, budesonide for small
bowel inflammation – no improvement in skin (worse)
Siegel Case 1 continued
Treatment options and rate of success
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%
Poritz LS, et al. J Am Coll Surg 2008;206:311
Siegel Case 1 continued
• 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
Siegel Case 2 continued
• 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
Siegel Case 2 continued
• Start ustekinumab
• 90mg SQ at week 0 and 2,
then every 8 weeks
Sandborn WJ, et al. N Engl J Med 2012;367:1519-28
Siegel Case 2 continued
• Did very well for 1 year, then symptoms
returned, endoscopically active disease
(small bowel and colon), losing weight
• Next steps?
40.8%
33.7%
• After ruling out infection and immune
deficiency syndrome, starting tofacitinib
38.8%
28.1%
• Oral JAK inhibitor (UC and Crohn’s)
• At 15mg, dose dependent increase in
LDL
• Treating with 10mg PO bid
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
Siegel Case 3 continued
• 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
8 days after an
infiximab dose,
drug level = 1.8
Dose 1
5mg/kg
9/24/12
Dose 2
5mg/kg
10/10/12
Dose 3
5mg/kg
11/12/12
Dose 4
10mg/kg
12/26/12
Data courtesy of Dr. Randall Pellish, UMASS Medical Center
Slide created by Kimberly Thompson, Dartmouth-Hitchcock Medical Center
16+ weeks!
Dose 5
5mg/kg
4/19/13

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