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

Outline: Why CAM? Alternative therapies in IBD Conclusion 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 Conclusion 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: 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; 41:1056-1063

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 150-350) 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

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: 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: 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

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 -2 2 6 10 16 20 Baseline Double blind treatment Follow up observation period Omer et al Phytomedicine 2007; 14: 87-95

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 6 months 9 months 12 months 50 100 Patients in Remission (%) Hanai et al Clin Gastro Hep 2006; 4:1502-1506

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):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: 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):255-63.; 2. Summers RW et al. Gastroenterology 2005;128(4)825-32; 3. Gark SK et al Cochrane 2014

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 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;20:472-480

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 Conclusion 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 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

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 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

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