Complementary and Alternative Therapies in IBD Hype or Hope? Meenakshi Bewtra, MD, MPH, PhD University of Pennsylvania Division of Gastroenterology Center.

Complementary and Alternative Therapies in IBDHype or Hope?

Meenakshi Bewtra, MD, MPH, PhDUniversity of Pennsylvania

Division of GastroenterologyCenter for Clinical Epidemiology &

Biostatistics

CCEB

Outline:• Why CAM?• Alternative therapies in IBD

– Acupuncture and moxibustion– Aloe Vera– Andrographis panniculata extract– Wormwood – Curcumin– Trichuris suis– Cannabis– Fish oil

• Conclusion

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

Use of CAM in N. America and Europe

• Current use: 11-34%• Current and past use: 21-60%

Hilsden et al, IBD 2011:17,2 665-662

Most common CAM therapies used in IBD

Hilsden et al, IBD 2011:17,2 665-662

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

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!

Outline:• Why CAM?• Alternative therapies in IBD

– Acupuncture and moxibustion– Aloe Vera– Andrographis panniculata extract– Wormwood – Curcumin– Trichuris suis– Cannabis– Fish oil

• Conclusion

Alternative Therapies in IBD(for today)

• Acupuncture and moxibustion• Aloe Vera• Andrographis panniculata extract• Wormwood • Curcumin• Trichuris suis• Cannabis• Fish oil

Acupuncture and Moxibustion: UCSingle-center single blind randomized controlled trial

• 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

29 UC patientsmild-mod disease (CAI 4-10)

stable meds for ≥ 4 weeks

15 patients10 Acu/Mox sessions over 5 weeks

14 patients10 Sham sessions over 5 weeks

Joos et al Scand J of Gastro 2006; 41:1056-1063

Acupuncture and Moxibustion: CDSingle-center single blind randomized controlled trial

• 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

51 CD patientsmild-mod disease (CDAI 150-350)

stable meds for ≥ 4 weeks(no AZA/6-MP/MTX)

27 patients10 Acu/Mox sessions over 4 weeks

24 patients10 Sham sessions over 4 weeks

Joos et al Digestion 2004, 69(3): 131-9

Aloe Vera Gel: UCSingle-center single blind randomized controlled trial

• 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

44 UC patientsmild-mod disease (SCCAI 4-10)

stable meds for ≥ 4 weeks

30 patients100 ml Aloe Vera Gel BID for 4 weeks

14 patients100 ml Placebo BID for 4 weeks

Langmead et al Al Pharm Ther 2004; 19: 739-747

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

Wormwood: CDMulti-centre double blind randomized placebo controlled trial

40 CD patientsCDAI > 170

Excluded IFX-treated patients

20 patientsWormwood capsules 500mg TID

20 patientsWormwood capsules 500mg TID

Omer et al Phytomedicine 2007; 14: 87-95

Omer et al Phytomedicine 2007; 14: 87-95

Wormwood: CDMulti-centre double blind randomized placebo controlled trial

100

200

300

400

Week -2 2 6 10 16 20

(n=20)

(n=20)

Placebo Wormwood

P=0.01*

Baseline Double blind treatment Follow up observation period

CD

AI

*proportion with 70 pt dec. in CDAI

CurcuminMulti-center double blind randomized maintenance trial in quiescent UC

Hanai et al Clin Gastro Hep 2006; 4:1502-1506

89 UC patientsCAI ≤ 4

No steroids/AZA/6MP/CsA

45 patientsCurcumin 1g po BID + 5-ASA

44patientsPlacebo 1g po BID + 5-ASA

2 patients relapsed

8 patients relapsed

8 patients relapsed

8 patients relapsed

Curcumin

PlaceboNS

X2=0.049

Treatment Period Follow up Period

3 months 6 months 9 months 12 months0

50

100

Pat

ient

s in

Rem

issi

on (

%)

CurcuminMulti-center double blind randomized controlled trial in active UC

50 UC patientsCAI 5-12

Stable AZA/6MP; no IFX, steroids

26 patientsCurcumin 3g po qd + 5-ASA

24 patientsPlacebo 3g po qd + 5-ASA

Lang et al Clin Gastro Hep 2015; Aug;13(8):1444-1449

Parasites: The question or the answer?

The Environmental Illness Resource webpage (accessed 8/2015)

Trichuris suis ova (worm eggs)Safety and Tolerability of

Trichuris ova in CD1

Trichuris suis therapy for active UC2

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.

Study: • RCT of 54 pts (12 wk Tx)

Results:Clinical Outcomes

TSO(n=30)

Placebo (n=24)

P-value

Clinical response(↓UCDAI ≥ 4)

43% (13/30)

16.7% (4/24)

0.04

1. Sandborn W et al. Aliment Pharmacol Ther. 2013;38(3):255-63.; 2. Summers RW et al. Gastroenterology 2005;128(4)825-32; 3. Gark SK et al Cochrane 2014

Cochrane: “Insufficient evidence…regarding efficacy and safety of helminth therapy…further RCT needed”3

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 (NCT01953354)– Treatment arms:

• 7500 Trichuris suis ova every 2 weeks for 10 weeks versus placebo

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;20:472-480

Cannabis and IBD: patients’ perspective

Storr et al. Inflamm Bowel Dis 2014;20:472-480

91% of cannabis users indicated it helped with their IBD symptoms

abdominal pain

abdominal cramps

joint pain

diarrhea

0% 20% 40% 60% 80% 100%

84%

77%

48%

29%

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

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

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;11:1276-1280.

Controlled Trial of THC in CD: Objective data

Naftali T et al. Clin Gastroenterol Hepatol 2013;11:1276-1280.

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;11:1276-1280.

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

Outline:• Why CAM?• Alternative therapies in IBD

– Acupuncture and moxibustion– Aloe Vera– Andrographis panniculata extract– Wormwood – Curcumin– Trichuris suis– Cannabis– Fish oil

• Conclusion

Conclusion: summary of IBD CAM therapies(from today)

Compound Conclusion

Moxibustion/Acup Small superiority in UC activity indexSuperior 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 maintenanceSuperior 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

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…

Why do IBD patients pursue CAM?Existing therapies are not working Optimize therapy; refer if necessaryFear 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 therapyDesire for greater control over their life and their IBD

Improve shared-decision makingRefer 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

Thank you