1. Complementary and Alternative Therapies in IBD Hype or Hope?
Meenakshi Bewtra, MD, MPH, PhD
University of Pennsylvania
Division of Gastroenterology
Center for Clinical Epidemiology & Biostatistics
CCEB

2. Outline: Why CAM? Alternative therapies in IBD Conclusion
Acupuncture and moxibustion
Aloe Vera
Andrographis panniculata extract
Wormwood
Curcumin
Trichuris suis
Cannabis
Fish oil
Conclusion

3. Definition of Complementary and Alternative (CAM) Therapies
“…a group of diverse medical and health care systems, practices and products that are not presently considered part of conventional medicine.”
National Center for Complimentary and Alternative Medicine (NCCAM)
Complementary and Alternative are Different
Complementary: using non-mainstream approach together with conventional medicine
Alternative: using non-mainstream approach in place of conventional medicine

4. Use of CAM in N. America and Europe
Current use: %
Current and past use: %
Hilsden et al, IBD 2011:17,

5. Most common CAM therapies used in IBD
Hilsden et al, IBD 2011:17,

6. Issues in evaluating CAM in IBD
Lack of high-quality studies
Lack of studies in IBD population
Studies assessing CAM often suffer from inferior quality
small sample sizes
lack of adequate controls
inadequate study designs
weak results even when positive
poor reporting of results
no real follow-up studies

7. Why do IBD patients pursue CAM?
Existing therapies are not working
Fear of side effects of current available therapies
“they make sense”
Desire for greater control over their life and their IBD
Value of treating the “whole person”
Internet hype and misinformation
Improvement in concomitant IBS
Because we have not cured IBD yet!

8. Outline: Why CAM? Alternative therapies in IBD Conclusion
Acupuncture and moxibustion
Aloe Vera
Andrographis panniculata extract
Wormwood
Curcumin
Trichuris suis
Cannabis
Fish oil
Conclusion

9. Alternative Therapies in IBD (for today)
Acupuncture and moxibustion
Aloe Vera
Andrographis panniculata extract
Wormwood
Curcumin
Trichuris suis
Cannabis
Fish oil

10. Acupuncture and Moxibustion: UC Single-center single blind randomized controlled trial
15 patients
10 Acu/Mox sessions over 5 weeks
29 UC patients
mild-mod disease (CAI 4-10)
stable meds for ≥ 4 weeks
14 patients
10 Sham sessions over 5 weeks
Small differences in outcome (moxa/acupuncture vs sham acupuncture)
CAI: 8  4.2 vs 6.5  4.8 (p=0.048)
Both groups improved general well-being and quality of life (no difference between groups)
Both traditional and sham offer benefit
Joos et al Scand J of Gastro 2006; 41:

11. Acupuncture and Moxibustion: CD Single-center single blind randomized controlled trial
27 patients
10 Acu/Mox sessions over 4 weeks
51 CD patients
mild-mod disease (CDAI )
stable meds for ≥ 4 weeks
(no AZA/6-MP/MTX)
24 patients
10 Sham sessions over 4 weeks
Both groups improved general well-being and quality of life
Moxa/acupuncture group improved CDAI more
CDAI: 250  163 vs 220  181 (p=0.003)
Both traditional and sham offer benefit, but moxa/acupuncture more
Joos et al Digestion 2004, 69(3): 131-9

12. Aloe Vera Gel: UC Single-center single blind randomized controlled trial
30 patients
100 ml Aloe Vera Gel BID for 4 weeks
44 UC patients
mild-mod disease (SCCAI 4-10)
stable meds for ≥ 4 weeks
14 patients
100 ml Placebo BID for 4 weeks
Clinical response: 47% vs 14% (p<0.05)
Clinical remission: 30% vs 7% (p=0.09)
Sigmoidoscopy scores no different
Histological scores improved with aloe vera but not placebo (p=0.03)
Conclusion: mixed results but promising. Needs more study
Langmead et al Al Pharm Ther 2004; 19:

13. Andrographis panniculata extract
Study: Sandborn, 5 countries USA/Europe, 2013
Population: Active UC
Patients: 224
CAM: 1800 mg daily
Comparator: placebo
Duration: 8 weeks
Remission/Response:
38% (CAM) vs 25% (PBO), p=0.1
60% (CAM) vs 40% (PBO), p=0.02
Phase III clinical trial currently enrolling patients with UC on mesalamine

14. Wormwood: CD Multi-centre double blind randomized placebo controlled trial
20 patients
Wormwood capsules 500mg TID
40 CD patients
CDAI > 170
Excluded IFX-treated patients
20 patients
Wormwood capsules 500mg TID
Omer et al Phytomedicine 2007; 14: 87-95

15. Wormwood: CD Multi-centre double blind randomized placebo controlled trial
400
(n=20)
CDAI
300
(n=20)
200
P=0.01*
100
*proportion with 70 pt dec. in CDAI
Week
Baseline
Double blind treatment
Follow up observation period
Omer et al Phytomedicine 2007; 14: 87-95

16. No steroids/AZA/6MP/CsA
Curcumin Multi-center double blind randomized maintenance trial in quiescent UC
45 patients
Curcumin 1g po BID + 5-ASA
89 UC patients
CAI ≤ 4
No steroids/AZA/6MP/CsA
44patients
Placebo 1g po BID + 5-ASA
2 patients relapsed
8 patients relapsed
Curcumin
Placebo NS
X2=0.049
Treatment Period
Follow up Period
3 months months months months 50
100
Patients in Remission (%)
Hanai et al Clin Gastro Hep 2006; 4:

17. Stable AZA/6MP; no IFX, steroids
Curcumin Multi-center double blind randomized controlled trial in active UC
26 patients
Curcumin 3g po qd + 5-ASA
50 UC patients
CAI 5-12
Stable AZA/6MP; no IFX, steroids
24 patients
Placebo 3g po qd + 5-ASA
Lang et al Clin Gastro Hep 2015; Aug;13(8):

18. Parasites: The question or the answer?
The Environmental Illness Resource webpage (accessed 8/2015)

19. Trichuris suis ova (worm eggs)
Safety and Tolerability of Trichuris ova in CD1
Trichuris suis therapy for active UC2
Study:
RCT of 54 pts (12 wk Tx)
Results:
Study:
36 patients (2 to 6 mo F/U)
Results:
GI symptoms: 7( 25.9%) in ova vs 3 (33.3%) in placebo group.
No dose dependent relationship.
No clinically meaningful changes in GI signs and symptoms.
Clinical Outcomes
TSO
(n=30)
Placebo (n=24)
P-value
Clinical response
(↓UCDAI ≥ 4)
43% (13/30)
16.7% (4/24)
0.04
Cochrane: “Insufficient evidence…regarding efficacy and safety of helminth therapy…further RCT needed”3
1. Sandborn W et al. Aliment Pharmacol Ther. 2013;38(3): ; 2. Summers RW et al. Gastroenterology 2005;128(4)825-32; 3. Gark SK et al Cochrane 2014

20. Trichuris suis ova (worm eggs)
Schölmerich J, et al., (2014), Efficacy and safety of Trichuris suis ova for treatment of mildly-to-moderately active Crohn's disease: A randomized, double-blind, placebo-controlled, phase II study, UEG Journal, 2(1S):A123 (OP392)
Phase II clinical trial of 252 CD pts treated with T. suis eggs
Study did not meet its primary endpoint of improving response nor the key secondary endpoint of remission
Ongoing study: Phase II – RCT of Suis Ova Treatment in left-sided UC and its effects on Mucosal Immune State and Microbiota (NCT )
Treatment arms:
7500 Trichuris suis ova every 2 weeks for 10 weeks versus placebo

21. Cannabis and IBD: patients’ perspective
18% of patients of surveyed patients reported current or past use
Heard cannabis would help  46%
Frustrated with their disease  41%
Wanted to try a different approach  38%
Medications prescribed haven’t worked  27%
39% of patients discussed cannabis use with their physicians
82% of patients reported physicians were indifferent or not supportive of cannabis use for IBD treatment
82% plan to continue using cannabis for as part of their IBD treatment
88% would recommend cannabis to other IBD patients
Storr et al. Inflamm Bowel Dis 2014;20:

22. Cannabis and IBD: patients’ perspective
91% of cannabis users indicated it helped with their IBD symptoms
Cannabis users:
More severe disease activity
More abdominal pain
More hospitalizations for IBD
More flares within the past year
More surgeries for IBD
More analgesic use, including narcotics
More complementary and alternative medicine use
Storr et al. Inflamm Bowel Dis 2014;20:

23. Mechanism of Cannabinoid Derivatives in IBD
Unknown
Appetite stimulant
Bowel relaxant/anticholinergic
No evidence that it is anti-inflammatory
Very little clinical evidence demonstrating efficacy

24. Controlled Trial of THC in CD
Inclusion: IBD patients with CDAI>200 refractory to steroids, IMMs or anti-TNFs.
RCT of Δ9-tetrahydrocannabinol (THC)
Cigarettes with 115mg THC vs no THC
Primary endpoint complete remission
Clinical Outcomes
THC
(n=11)
Placebo (n=10)
P-value
Clinical remission
45% (5/11)
10% (1/10)
0.43
Clinical response (CDAI↓ >100)
90% (10/11)
40% (4/10)
0.028
Naftali T et al. Clin Gastroenterol Hepatol 2013;11:

25. Controlled Trial of THC in CD: Objective data
Naftali T et al. Clin Gastroenterol Hepatol 2013;11:

26. Controlled Trial of THC in CD: Objective data
No endoscopic data / objective evidence of improvement in inflammation
No difference in objective parameters of disease activity
No difference in CRP change
3 cannabis patients had a decrease in CRP > 0.5mg/dL
2 placebo patients had a decrease in CRP > 0.5mg/dL
19/21 patients were able to tell which group they were in
Essentially not blinded
More studies needed if convincing data desired!
Naftali T et al. Clin Gastroenterol Hepatol 2013;11:

27. Fish oil in CD
Two multinational multi-center randomized double-blind placebo-controlled studies (EPIC-1, EPIC-2)
Patients with CD (CDAI <150) assigned 4g/d FFA or PBO for 58 weeks
Feagan B et al 2008 JAMA

28. Outline: Why CAM? Alternative therapies in IBD Conclusion
Acupuncture and moxibustion
Aloe Vera
Andrographis panniculata extract
Wormwood
Curcumin
Trichuris suis
Cannabis
Fish oil
Conclusion

29. Conclusion: summary of IBD CAM therapies (from today)
Compound
Conclusion
Moxibustion/Acup
Small superiority in UC activity index
Superior in CD activity index
Aloe Vera
Superior in UC activity index but no endoscopic change
Andrographis panniculata
Promising, RCT ongoing, perhaps first herbal backed by real clinical trial data
Wormwood
No clear statistical comparisons, looked promising (but would you trust CAM from study with no stats)
Curcumin
Improvement at 6 months for UC maintenance
Superior for UC induction for those failing 2 weeks 5ASA, reasonable data
Trichuris suis
Neg CD study, Study ongoing in UC
Cannabis
Improves symptoms, not inflammation
Fish oil
Not effective in maintaining remission in Crohn’s

30. Conclusion: how to integrate CAM
First, do no harm:
Ensure no opportunity cost (ie, do not delay treating a serious illness for which there is known effective therapy);
If the CAM therapy carries little risk of harm, then consider its use and follow the patient closely;
If the CAM therapy carries serious risk of harm, advise the patient accordingly and follow the patient closely;
Where possible, it is recommended to try to follow an evidence-based rationale for therapy
Where the evidence is lacking, try to maintain an open mind and a balanced approach.
Consider the patient’s reason for pursuing CAM…

31. Why do IBD patients pursue CAM?
Existing therapies are not working
Optimize therapy; refer if necessary
Fear of side effects of current available therapies
Appropriate education about therapies and risks
Internet hype and misinformation
You’re doing it now!
Improvement in concomitant IBS
If little harm, and improving IBS, consider continuing CAM therapy
Desire for greater control over their life and their IBD
Improve shared-decision making
Refer to resources
Value of treating the “whole person”
Ask about quality of life and depression; consider appropriate referrals
Because we have not cured IBD yet!
Crohn’s and Colitis Foundation of America

32. Thank you