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Crohn ziekte / Crohn’s Disease

Also indexed as: Granulomatous Ileitis, Ileocolitis, Regional Enteritis
Crohn’s disease is a poorly understood inflammatory condition that usually affects the final part of the small intestine and the beginning section of the colon. It often causes bloody stools and malabsorption problems.

Rating Nutritional Supplements Herbs 
  • Fish oil (enteric-coated, free-fatty-acid form)***
  • Vitamin D
  • Multivitamin-mineral (for prevention or treatment of deficiency only)**
  • Saccharomyces boulardii
  • Zinc
  • Enzymes*
  • Folic acid
  • Lipase
  • Vitamin A
  • Vitamin B12 Agrimony
  • Aloe
  • Chamomile / Echte kamille
  • Cranesbill
  • Green tea / Groene thee
  • Licorice / Zoethout
  • Marshmallow / Heemst
  • Oak / Eik
  • Slippery elm
  • Witch hazel / Toverhazelaar
  • Yarrow / Duizendblad
What are the symptoms of Crohn’s disease? Chronic diarrhea with abdominal pain, fever, loss of appetite, weight loss, and a sense of fullness in the abdomen are the most common symptoms. About one-third of people with Crohn’s have a history of anal fissures (linear ulcers on the margin of the anus) or fistulas (abnormal tube-like passages from the rectum to the surface of the anus).

Conventional treatment options:
Diarrhea and cramps may be treated with anticholinergic drugs, such as loperamide (Imodium®), diphenoxylate (Lomotil®), or codeine. Anal irritation and loose stools may sometimes be improved by giving methylcellulose (e.g., Citrucel®) or psyllium preparations (e.g., Fiberall®, Konsyl®, Metamucil®, Perdiem®). Sulfasalazine (Azulfidine®) is used in patients with mild to moderate colitis. Corticosteroids may be used during acute exacerbations, although long-term corticosteroid therapy does more harm than good. Certain immunosuppressive drugs may also be effective, including azathioprine (Imuran®) and 6-mercaptopurine (6-MP, Purinethol®). Secondary infections are managed with antibiotics.

Dietary changes that may be helpful: 
A person with Crohn’s disease might consume more sugar than the average healthy person.1 A high-fiber, low-sugar diet led to a 79% reduction in hospitalizations compared with no dietary change in one group of people with Crohn’s disease.2 Another trial compared the effects of high- and low-sugar diets in people with Crohn’s disease.3 People with a more active disease were reported to fare better on the low-sugar diet than those eating more sugar. Several people on the high-sugar diet had to stop eating sugar because their disease grew worse. While details of how sugar injures the intestine are still being uncovered, doctors often suggest eliminating all sugar (including soft drinks and processed foods with added sugar) from the diets of those with Crohn’s disease.

A diet high in animal protein and fat (from foods other than fish) has been linked to Crohn’s disease in preliminary research.4 As with many other health conditions, it may be beneficial to eat less meat and dairy fat and more fruits and vegetables.

Some people with Crohn’s disease have food allergies and have been reported to do better when they avoid foods to which they are allergic. One study found that people with Crohn’s disease are most likely to react to cereals, dairy, and yeast.5 Increasingly, baker’s yeast (found in bread and other bakery goods) has been implicated as a possible trigger for Crohn’s disease.6 Yeast and some cheeses are high in histamine, which is involved in an allergenic response. People with Crohn’s disease lack the ability to break down histamine at a normal rate,7 so the link between yeast and dairy consumption and Crohn’s disease occurrence may not be coincidental. However, the allergy theory cannot account for all, or even most, cases of Crohn’s disease.

Elemental diets contain amino acids (rather than whole proteins, which can stimulate allergic reactions) and are therefore considered hypoallergenic. They have been used extensively as primary therapy in people with Crohn’s disease,8 9 10 with remission rates comparable to those of steroid drugs. Nevertheless, diets containing intact proteins derived from dairy and wheat have proven equally effective at controlling the symptoms of Crohn’s disease.11 12 13 Until more is known, it is premature to conclude that food allergy plays a significant role in the development of Crohn’s disease or that a hypoallergenic diet is any more likely to help than a diet whose protein is only partially broken down.

In one trial, people with Crohn’s disease were asked which foods aggravated their symptoms.14 Those without ileostomies found nuts, raw fruit, and tomatoes to be most problematic, though responses varied from person to person, and other reports have displayed different lists.15 (Ileostomies are surgical passages through the wall of the abdomen into the intestine that allow the intestinal contents to bypass the rectum and drain into a bag worn on the abdomen.) People with Crohn’s disease wishing to identify and avoid potential allergens should consult a doctor.

There is preliminary evidence that people who eat fast foods at least two times per week more than triple their risk of developing Crohn’s disease.16

Lifestyle changes that may be helpful: 
People with Crohn’s disease are more likely to smoke, and there is evidence that continuing to smoke increases the rate of disease relapse.17

Nutritional supplements that may be helpful: 
Vitamin D malabsorption is common in Crohn’s18 and can lead to a deficiency of the vitamin.19 Successful treatment with vitamin D for osteomalacia (bone brittleness caused by vitamin D deficiency) triggered by Crohn’s disease has been reported.20 Another study found 1,000 IU per day of vitamin D prevented bone loss in people with Crohn’s, while an unsupplemented group experienced significant bone loss.21 A doctor should evaluate vitamin D status and suggest the right level of vitamin D supplements.

Inflammation within the gut occurs in people suffering from Crohn’s disease. EPA and DHA, the omega-3 fatty acids found in fish oil, have anti-inflammatory activity. A two-year trial compared the effects of having people with Crohn’s disease eat 3.5 to 7 ounces of fish high in EPA and DHA per day or having them eat a diet low in fish.22 In that trial, the fish-eating group had a 20% relapse rate compared with 58% among those not eating fish. Salmon, herring, mackerel, albacore tuna, and sardines are all high in EPA and DHA.
In a double-blind trial, people with Crohn’s disease who took supplements providing 2.7 g of EPA/DHA per day had a recurrence rate of 26% after one year, compared to a 59% recurrence rate among those taking placebo. 23 Participants in this study used a special enteric-coated, “free-fatty-acid” form of EPA/DHA taken from fish oil. Other blinded trials using other fish oil supplements that were neither enteric-coated nor in the free-fatty-acid form have reported no clinical improvement.24 25 These disparate outcomes suggest that the enteric-coated, free-fatty-acid form may have important advantages, including the reported elimination of gastrointestinal symptoms that often result from taking regular fish oil supplements.26 Unfortunately, enteric-coated “free-fatty-acid” fish oil is not commercially available at this time.

In double-blind research, diarrhea caused by Crohn’s disease has partially responded to supplementation with the beneficial bacterium Saccharomyces boulardii.27 Although the amount used in this trial, 250 mg taken three times per day, was helpful, as much as 500 mg taken four times per day has been administered in research successfully using Saccharomyces boulardii as a supplement with people suffering from other forms of diarrhea.28

Crohn’s disease often leads to malabsorption. As a result, deficiencies of many nutrients are common. For this reason, it makes sense for people with Crohn’s disease to take a high potency multivitamin-mineral supplement. In particular, deficiencies in zinc, folic acid, vitamin B12, vitamin D, and iron have been reported.29 30 31 Zinc, folic acid, and vitamin B12 are all needed to repair intestinal cells damaged by Crohn’s disease. Some doctors recommend 25 to 50 mg of zinc (balanced with 2 to 4 mg of copper), 800 mcg of folic acid, and 800 mcg of vitamin B12. Iron status should be evaluated by a doctor before considering supplementation.

Vitamin A is needed for the growth and repair of cells that line both the small and large intestine.32 At least two case reports describe people with Crohn’s disease who have responded to vitamin A supplementation.33 34 However, in one trial, vitamin A supplementation failed to maintain remission of the disease.35 Therefore, although some doctors recommend 50,000 IU per day for adults with Crohn’s disease, this approach remains unproven. An amount this high should never be taken without qualified guidance, nor should it be given to a woman who is or could become pregnant.

People with Crohn’s disease may be deficient in pancreatic enzymes, including lipase.36 In theory, supplementing with enzymes might improve the nutrient malabsorption that is often associated with Crohn’s disease. However, people with Crohn’s disease considering supplementation with enzymes should consult a doctor.

Herbs that may be helpful: 
Doctors sometimes use a combination of herbs to soothe inflammation throughout the digestive tract. One formula contains marshmallow, slippery elm, cranesbill, and several other herbs.37 Marshmallow and slippery elm are mucilaginous plants that help soothe inflamed tissues. Cranesbill is an astringent. Clinical trials using this combination have not been conducted.

A variety of anti-inflammatory herbs historically have been recommended by doctors for people with Crohn’s disease. These include yarrow, chamomile, licorice, and aloe juice. Cathartic preparations of aloe should be avoided. No research has been conducted to validate the use of these herbs for Crohn’s disease.

Tannin-containing herbs may be helpful to decrease diarrhea during acute flare-ups and have been used for this purpose in traditional medicine. A preliminary trial using isolated tannins in the course of usual drug therapy for Crohn’s disease found them to be more effective for reducing diarrhea than was no additional treatment.38 Tannin-containing herbs of potential benefit include agrimony (Agrimonia spp.), green tea, oak, witch hazel, and cranesbill. Use of such herbs should be discontinued before the diarrhea is completely resolved; otherwise the disease may be aggravated.

References:
1. Mayberry JF, Rhodes J. Epidemiological aspects of Crohn’s disease: a review of the literature. Gut 1984;886–99.
2. Heaton KW, Thornton JR, Emmett PM. Treatment of Crohn’s disease with an unrefined-carbohydrate, fibre-rich diet. BMJ 1979;2(6193):764–6.
3. Brandes JW, Lorenz-Meyer H. Sugar free diet: a new perspective in the treatment of Crohn disease? Randomized, control study. Z Gastroneterol 1981;19:1–12.
4. Shoda R, Masueda K, Yamato S, Umeda N. Epidemiologic analysis of Crohn’s disease in Japan: increased dietary intake of n-6 polyunsaturated fatty acids and animal protein relates to the increased incidence of Crohn’s disease in Japan. Am J Clin Nutr 1996;63:741–5.
5. Riordan AM, Hunter JO, Cowan RE, et al. Treatment of active Crohn’s disease by exclusion diet: East Anglian Multicentre Controlled Trial. Lancet 1993;342:1131–4.
6. Alic M. Baker’s yeast in Crohn’s disease—can it kill you? Am J Gastroenterol 1999;94:1711 [letter/review].
7. Wantke F, Gotz M, Jarisch R. Dietary treatment of Crohn’s disease. Lancet 1994;343:113 [letter].
8. O’Morain C, Segal AW, Levi AJ. Elemental diet as primary treatment of acute Crohn’s disease: a controlled trial. Br Med J (Clin Res Ed) 1984;288:1859–62.
9. Gorard DA, Hunt JB, Payne-James JJ, et al. Initial response and subsequent course of Crohn’s disease treated with elemental diet or prednisolone. Gut 1993;34:1198–202.
10. Teahon K, Pearson M, Levi AJ, Bjarnason I. Practical aspects of enteral nutrition in the management of Crohn’s disease. JPEN J Parenter Enteral Nutr 1995;19:365–8.
11. Raouf AH, Hildrey V, Daniel J, et al. Enteral feeding as sole treatment for Crohn’s disease: controlled trial of whole protein v amino acid based feed and a case study of dietary challenge. Gut 1991;32:702–7.
12. Rigaud D, Cosnes J, Le Quintrec Y, et al. Controlled trial comparing two types of enteral nutrition in treatment of active Crohn’s disease: elemental versus polymeric diet. Gut 1991;32:1492–7.
13. Park RH, Galloway A, Danesh BJ, et al. Double-blind controlled trial comparing elemental and polymeric diets as primary therapy in active Crohn’s disease. Eur J Gastroenterol Hepatol 1991;32:1492–7.
14. McDonald PJ, Fazio VW. What can Crohn’s patients eat? Eur J Clin Nutr 1988;42:703–8.
15. Gaby AR. Commentary. Nutr Healing 1998;January:1,10–1 [review].
16. Persson PG, Ahlbom A, Hellers G. Diet and inflammatory bowel disease: a case-control study. Epidemiology 1992;3:47–52.
17. Cottone M, Rosselli M, Orlando A, et al. Smoking habits and recurrence in Crohn’s disease. Gastroenterol 1994;106:643–8.
18. Leichtmann GA, Bengoa JM, Bolt MJG, Sitrin MD. Intestinal absorption of cholecalciferol and 25-hydrocycholecalciferol in patients with both Crohn’s disease and intestinal resection. Am J Clin Nutr 1991;54:548–52.
19. Harris AD, Brown R, Heatley RV, et al. Vitamin D status in Crohn’s disease: association with nutrition and disease activity. Gut 1985;26:1197–203.
20. Driscoll RH, Meredith SC, Sitrin M, Rosenberg IH. Vitamin D deficiency and bone disease in patients with Crohn’s disease. Gastroenterol 1982;83:1252–8.
21. Vogelsang H, Ferenci P, Resch H, et al. Prevention of bone mineral loss in patients with Crohn’s disease by long-term oral vitamin D supplementation. Eur J Gastroenterol Hepatol 1995;7:609–14.
22. Mate J, Castanos R, Garcia-Samaniego J, Pajares JM. Does dietary fish oil maintain the remission of Crohn’s disease: a case control study. Gastroenterology 1991;100:A228 [abstract].
23. Belluzzi A, Brignola C, Campieri M, et al. Effect of an enteric-coated fish-oil preparation on relapses in Crohn’s disease. N Engl J Med 1996;334:1557–60.
24. Lorenz R, Weber PC, Szimnau P, et al. Supplementation with n-3 fatty acids from fish oil in chronic inflammatory bowel disease—a randomized, placebo-controlled, double-blind cross-over trial. J Intern Med Suppl 1989;225:225–32.
25. Lorenz-Meyer H, Bauer P Nicolay C, et al. Omega-3 fatty acids and low carbohydrate diet for maintenance of remission in Crohn’s disease. A randomized controlled multicenter trial. Study Group Members (German Crohn’s Disease Study Group). Scand J Gastroenterol 1996;31:778–85.
26. Belluzzi A, Brignola C, Campieri M, et al. Effects of new fish oil derivative on fatty acid phospholipid-membrane pattern in a group of Crohn’s disease patients. Dig Dis Sci 1994;39:2589–94.
27. Plein K, Hotz J. Therapeutic effects of Saccharomyces boulardii on mild residual symptoms in a stable phase of Crohn’s disease with special respect to chronic diarrhea—a pilot study. Z Gastroenterol 1993;31:129–34.
28. Bleichner G, Blehaut H, Mentec H, Moyse D. Saccharomyces boulardii prevents diarrhea in critically ill tube-fed patients. A muticenter, randomized, double-blind placebo-controlled trial. Intensive Care Med 1997;23:517–23.
29. Imes S, Plinchbeck BR, Dinwoodie A, et al. Iron, folate, vitamin B-12, zinc, and copper status in out-patients with Crohn’s disease: effect of diet counseling. J Am Dietet Assoc 1987;87:928–30.
30. Sandstead HH. Zinc deficiency in Crohn’s disease. Nutr Rev 1982;40:109–12.
31. Driscoll RH Jr, Meredith SC, Sitrin M, et al. Vitamin D deficiency and bone disease in patients with Crohn’s disease. Gastroenterology 1982;83:1252–8.
32. Dvorak AM. Vitamin A in Crohn’s disease. Lancet 1980;i:1303–4.
33. Skogh M, Sundquist T, Tagesson C. Vitamin A in Crohn’s disease. Lancet 1980; i:766 [letter].
34. Dvorak AM. Vitamin A in Crohn’s Disease. Lancet 1980;i:1303–4 [letter].
35. Wright JP, Mee AS, Parfitt A, et al. Vitamin A therapy inpatients with Crohn’s disease. Gastroenterology 1985;88:512–4.
36. Hegnhoj J, Hansen CP, Rannem T, et al. Pancreatic function in Crohn’s disease. Gut 1990;31:1076–9.
37. Pizzorno JE, Murray MT. Textbook of Natural Medicine. London: Churchill Livingstone, 1999, 1335–49.
38. Plein K, Burkard G, Hotz J. Treatment of chronic diarrhea in Crohn disease. A pilot study of the clinical effect of tannin albuminate and ethacridine lactate. Fortschr Med 1993;111:114–8 [in German].


Artemisia absinthium / Absintalsem
De flavonoïden in absintalsem hebben een ontstekingsremmende werking. In in-vitro- en in-vivo-onderzoek is aangetoond dat p7F (tetramethoxyhydroxyflavon) uit absintalsem een antioxidatieve en ontstekingsremmende werking heeft en COX-2 (cyclooxygenase-2), iNOS (inducible nitric oxide synthase) en NFB-activering remt. Op basis hiervan zijn de onderzoekers van mening dat p7F geschikt is voor de behandeling van ontstekingziekten. 

Absintalsem in plaats van corticosteroïden
De studie naar het effect van alsemkruid bij de ziekte van Crohn duurde twintig weken. In aanvulling op de gebruikelijke medicatie (5-aminosalicylaten en/of azathioprine of methotrexaat) gebruikten veertig proefpersonen drie maal 500 mg gestandaardiseerd absintalsempoeder (met 0,2 - 0,38 % absinthine en 0,25 - 1,52 % essentiële olie) of een placebo gedurende tien weken. Bij aanvang van de studie gebruikten ze nog corticosteroïden: een dosis equivalent aan 40 mg prednison of minder welke na de tweede week van de studie afgebouwd werd.

Aan het eind van de negende week gebruikte niemand meer corticosteroïden. Na tien weken mochten de deelnemers weer corticosteroïden innemen als dat nodig was. Het effect van alsemkruid werd vastgesteld aan de hand van de Crohn's disease activity index (CDAI), de Inflammatory bowel disease questionnaire (IBDQ), de Hamilton depression scale (HAMD) en een visuele analoge schaal waarmee het algemene welbevinden werd aangegeven. 

De ziektesymptomen namen in de loop van de studie geleidelijk in ernst af bij 18 van de 20 patiënten (90 %) die alsemkruid innamen, ondanks het afbouwen van de dosis corticosteroïden. Opmerkelijk was dat bij 13 van de 20 (65 %) deelnemers na acht weken vrijwel totale remissie van de ziekte was opgetreden. In de placebogroep bleef iedereen echter klachten houden. De remissie bij (voormalige) gebruikers van absintalsem bleef bestaan tot het einde van de observatieperiode (week 20) en aanvullend gebruik van corticosteroïden was niet nodig. In de placebogroep trad tijdens het afbouwen van de dosis corticosteroïden verslechtering op: 16 van de 20 proefpersonen (80 %) moesten na de tiende week weer corticosteroïden gaan gebruiken. De resultaten suggereren dat het gebruik van absintalsem naast de standaardmedicatie de behoefte aan corticosteroïden significant vermindert en een gunstig effect heeft op het ziektebeeld. Absintalsem zorgt voor significante verbetering van de stemming en de kwaliteit van leven vergeleken met placebo.

Omer B, Krebs S, Omer H, Noor TO. Steroid-sparing effect of wormwood (Artemisia absinthium) in Crohn's disease: A double-blind placebo-controlled study. Phytomedicine. 2007;14(2-3):87-95.



Complementary and alternative medicine (CAM), particularly herbal therapy, is widely used by patients with inflammatory bowel disease (IBD) but controlled data are limited.

Aim To systematically review the literature on the efficacy of herbal therapy in the treatment of ulcerative colitis (UC) and Crohn's disease (CD).
Methods Publications in English and non-English literatures (MEDLINE, EMBASE, EBM Reviews, AMED, Global Health) were searched from 1947 to 2013 for controlled clinical studies of herbal therapy in IBD. Outcome measures included response and remission rates.
Results Twenty-one randomised controlled trials (14 UC; 7 CD) including a total of 1484 subjects (mean age 41, 50% female) were analysed. In UC, aloe vera gel, Triticum aestivum (wheat grass juice), Andrographis paniculata extract (HMPL-004) and topical Xilei-san were superior to placebo in inducing remission or response, and curcumin was superior to placebo in maintaining remission; Boswellia serrata gum resin and Plantago ovata seeds were as effective as mesalazine, whereas Oenothera biennis (evening primrose oil) had similar relapse rates as omega-3 fatty acids in the treatment of UC. In CD,Artemisia absinthium (wormwood) and Tripterygium wilfordii were superior to placebo in inducing remission, and preventing clinical recurrence of post-operative CD respectively.
Conclusions Randomised controlled trials of herbal therapy for the treatment of IBD show encouraging results but studies remain limited and heterogenous. Larger controlled studies with stricter endpoints and better-defined patient groups are required to obtain more conclusive results on the use of CAM therapies in IBD.

Treatment of Ulcerative Colitis

Eleven randomised studies assessed the use of herbal therapy in the induction of remission for UC,[21–28] and three studies assessed their use in the maintenance of remission in UC.[29–32] Six studies have compared herbal therapy with placebo, five studies have compared herbal therapy with mesalazine/sulphasalazine/steroid enema, and three studies have evaluated the efficacy of herbal therapy in addition to conventional therapy. The number of subjects included in the studies ranged from 14 to 224. In the inductions studies, treatment duration ranged from 4 to 12 weeks, and in the maintenance studies treatment duration ranged from 6 to 12 months. Most herbal therapies were not associated with any major adverse effects. Minor adverse effects reported were nausea, constipation and flatulence.

Induction of Remission in Ulcerative Colitis. A randomised double-blind controlled trial from the United Kingdom showed that aloe vera gel, administered for 4 weeks, to patients with moderately active UC, was superior to placebo. Clinical remission, improvement and response were reported in 9, 11 and 14 patients on aloe vera, respectively, compared with one, one and two patients on placebo.[21] In a randomised, double-blind, placebo-controlled study from Israel, 23 patients with active distal UC were randomised to wheat grass juice (Triticum aestivum), or placebo, daily for 4 weeks. Ten of 11 patients (91%) on active treatment responded compared with 5 of 12 on placebo (42%). Seven of nine (78%) patients on active treatment had sigmoidoscopic improvement compared with three of ten (30%) patients on placebo. Rectal bleeding, abdominal pain and physician global assessment score significantly reduced in the active treatment arm. The most common adverse effect in patients on wheat grass juice was nausea.[22] A recent large randomised, double-blind, placebo-controlled trial compared Andrographis paniculata extract (HMPL-004) to placebo in 224 adults with mild-to-moderate UC. Treatment with HMPL-004 at a higher dose (1800 mg daily) was associated with greater clinical response than placebo (60% vs. 40%; P = 0.018), but remission rates at 8 weeks were not different between both groups (38% vs. 34%; P = 0.101).[33]

Two studies had compared the efficacy of herbal therapy to mesalazine. In the first study, 30 patients with chronic active UC were randomised to gum resin of Boswellia serrata (900 mg daily in three doses; n = 20) or sulphasalazine (3 g daily in three doses; n = 10) for 6 weeks. Fourteen of 20 patients treated with Boswellia gum resin and 4 of 10 treated with sulphasalazine achieved remission. Eighteen of 20 patients treated with Boswellia gum resin and 6 of 10 patients on sulphasalazine showed an improvement in one of more of the parameters including stool properties, histopathology and scanning electron microscopy.[24] The second study was a randomised double-blind multicentre 8-week parallel-group study which showed that HMPL-004 was as effective as mesalazine (response 76% vs. 82%; remission 21% vs. 16%) in the treatment of mild-to-moderate UC but there was no difference in endoscopic remission rates at 8 weeks between the two groups (28% vs. 24%).[25]

In a randomised controlled trial, 153 patients with UC were randomly assigned to three groups. Group I: Jian Pi Ling (JPL) tablet with retention-enema of Radix Sophorae Flavescentis and Flos Sophora decoction; group II: sulphasalazine and retention-enema of dexamethasone; group III: placebo and retention-enema of decoction as that in group I. Remission rates at 3 months in group 1 were significantly higher (53%) than those in the other two groups (28% and 19% respectively). However, the very low efficacy rate of conventional therapy makes this study hard to interpret.[26]

In another randomised controlled trial from China, 118 patients with active UC were treated with a traditional Chinese remedy, Kui jie qing (KJQ) enemas four times daily (n = 95) whereas 11 patients treated with sulphasalazine, oral prednisolone and prednisolone enemas served as controls. Effective 'cure' was shown in 72% of KJQ-treated patients but only in 9% of controls although the definition of 'cure' or 'improvement' in this study was not clear.[27]

One study has assessed the use of herbal therapy in addition to conventional treatment. 118 patients with active UC were treated with oral Yukui tang tablets ('decoction for ulcer healing') and herbal decoction enemas, in addition to oral prednisolone 15 mg daily, neomycin and vitamin B for 40 days. Eighty-six control patients who received only low dose prednisolone, neomycin and vitamin B were used for comparison. The remission rates and response rates were 33% and 51%, respectively, in the active group, compared with 17% and 43%, in the control group.[28]

Three studies assessed the use of herbal enemas in the treatment of ulcerative proctitis. Fourteen patients with mild-to-moderate active UC were treated with bovine colostrum enemas or placebo containing albumin solution twice daily for 4 weeks in addition to mesalazine. The colostrum, but not the placebo group, showed a mean reduction in symptom score, and an improvement in histological score.[23] In an 8-week double-blind randomised study, Xilei-san, a traditional Chinese herbal medicine with anti-inflammatory properties, was compared with dexamethasone enemas in 35 subjects with mild-to-moderate active ulcerative proctitis. Subjects were followed up for 12 weeks. Both treatments showed significant improvement in clinical, endoscopic and histological score compared with baseline.[34] In a separate randomised controlled trial, 30 subjects with intractable ulcerative proctitis despite 4 weeks of topical mesalazine or corticosteroid were randomised to xilei-san suppositories or placebo suppositories for 2 weeks. The number of patients who achieved remission (clinical activity index ≤4) was significantly higher in the Xilei-san group compared with placebo (P < 0.04). Endoscopic and histological improvements were also significantly higher and relapse rate at 180 days was significantly lower in the active treatment arm compared with placebo.[35] Rectal Xilei-san appeared to be well tolerated in both studies. Table 1 shows studies of herbal therapy used for the induction of remission in UC.

Maintenance of Remission in Ulcerative Colitis

Curcumin, a biologically active phytochemical substance found in turmeric, has been shown to have anti-inflammatory and antioxidant properties in cell culture and animal studies. A randomised, double-blind, multicentre Japanese study assessed the efficacy of curcumin as maintenance therapy in patients with quiescent UC. Eighty-nine patients were randomised to curcumin (1 g twice daily), or placebo, in addition to sulphasalazine or mesalazine, for 6 months. Relapse rate was significantly lower in the curcumin than placebo group (4.7% vs. 20.5%; P = 0.04).[29]

Colonic fermentation of Plantago ovata seeds (dietary fibre) produces butyrate, and butyrate enemas may be effective in the treatment of UC. In an open label, parallel-group, multicentre, randomised clinical trial, 105 patients with UC in remission were randomised into groups to receive Plantago ovata seeds (10 g twice daily), mesalazine (500 mg three times daily), and Plantago ovata seeds plus mesalazine at the same doses. Relapse rate at 12 months were similar in the three groups (40% vs. 35% vs. 30%). Mild side effects included constipation and/or flatulence.[30]

In a placebo-controlled study, 43 patients with stable UC were randomised to receive either MaxEPA (Oenothera biennis) (n = 16), super evening primrose oil (n = 19), or olive oil as placebo (n = 8) for 6 months, in addition to their normal treatment. Compared with MaxEPA and placebo, evening primrose oil significantly improved stool consistency and the difference was maintained even after treatment was discontinued. There was, however, no difference in stool frequency, rectal bleeding, disease relapse, sigmoidoscopic appearance or histology in the three treatment groups.[31] Table 2 summarises studies of herbal therapy used for the maintenance of remission in UC.

Treatment of Crohn's Disease (CD)

Four studies have evaluated the use of herbal therapy to induce remission in active CD,[36–38] one study to maintain remission in CD,[39] and two placebo-controlled trials assess the use in the prevention of disease recurrence after surgery for CD.[40, 41]

In a German double-blind study, 40 patients with CD on a stable daily dose of steroids were randomised to receive the herbal blend containing wormwood herb (Artemisia absinthium) or placebo for 10 weeks. Clinical remission was seen in 13 of 20 (65%) patients on woodworm compared to none on placebo at 8 weeks.[36] In a separate controlled trial, 20 patients with active CD were given in addition to their existing CD therapy either dried powdered wormwood or placebo. At 6 weeks, 8 of 10 (80%) on wormwood and two of 10 patients (20%) on placebo achieved clinical remission defined as a Crohn's disease activity index (CDAI) below 170 or a reduction in CDAI by 70 points. Six of ten, and none of ten patients, on woodworm and placebo had a clinical response.[37]

In a randomised, double-blind, non-inferiority, parallel-group study, 102 patients with active CD were randomised to Boswellia serrata extract (H15) or mesalazine. The mean reduction in CDAI was 90 for H15 and 53 for mesalazine.[38] A separate double-blind, placebo-controlled, randomised, parallel study from 22 centres in Germany evaluated the long-term efficacy and safety of Boswellia serrata extract (Boswelan, PS0201Bo) in maintaining remission in 108 patients with CD. At 52 weeks, there was no significant difference in the proportion of patients in clinical remission between the actively treated and the placebo group (59.9% vs. 55.3%). The mean time to relapse was also not different between the two groups (171 vs. 185 days).[39] The traditional Chinese medicine, Tripterygium wilfordii Hook F (TWHF), has both immunomodulatory and anti-inflammatory activities. Twenty adult patients with active CD were treated with T2 pills for 12 weeks. CDAI scores dropped during the first 8 weeks and endoscopic improvements were observed at week 12. Furthermore, a significant decrease in serum levels of C reactive protein and pro-inflammatory cytokines was reported.[42]

Two placebo-controlled studies assessed the role of Tripterygium wilfordii (GTW) in preventing post-operative recurrence of CD. Forty-five patients with CD were randomly assigned to receive GTW or mesalazine after their operation. No clinical recurrence occurred in both groups at 3 months. There were no significant differences in clinical relapse at 6 months (18% vs. 22%) or 12 months (32% vs. 39%) between the GTW and mesalazine groups. Endoscopic recurrence at 12 months was also similar in the two groups (46% vs. 61%).[40] The second study randomised 39 CD patients to GTW (n = 21) or sulphasalazine (n = 18) 2 weeks after resection for CD. Clinical recurrence was reported in 6% on GTW and 25% on sulphasalazine, and endoscopic recurrence was reported in 22% on GTW and 56% on sulphasalazine. GTW appeared to be as effective, if not more effective, than mesalazine in preventing recurrence of post-operative CD.[41] Table 3 shows studies of herbal therapy in the treatment and prevention of post-operative recurrence in CD.

Discussion

At least 50 percent of patients with IBD have used some form of CAM during their disease course. This appeal is enhanced by the common belief that CAM therapies are safer and less toxic than conventional treatment.[43] In many surveys, vitamin supplements[44] and herbal therapies are the most commonly used form of CAM in IBD patients accounting for up to 65% and 58% of the proportion of CAM users respectively.[14, 45, 46] Other forms of CAM used in IBD include homeopathy, traditional Chinese medicine, acupuncture or probiotics.[5] The frequency of use for individual therapy varies greatly and likely reflects local patterns of CAM use.

We have focused on herbal therapies as others have extensively reviewed the evidence for other forms of CAM. In two systematic reviews, omega-3 fatty acids appear not effective for the maintenance of remission in CD[18, 19] In contrast, a meta-analysis showed that acupuncture and moxibustion are superior to western medicine in the treatment of UC with good safety profile.[20] In this systematic review, several studies have reported superiority of herbal therapy or at least equivalent efficacy, whereas others have shown that herbal therapies are less efficacious than conventional therapies. For example, curcumin a natural remedy used to cook curry was reported to be more effective than placebo for maintaining remission in patients with quiescent UC. Herbs such as Aloe vera and Boswellia serrata have also demonstrated efficacy in UC based on their anti-oxidant properties. Wheat grass juice appeared effective and safe as a single or adjuvant treatment of active distal UC. HMPL-004 showed better clinical response than placebo, and comparable efficacy as mesalazine in patients with active mild-moderate-UC whereas Plantago ovata seeds might be as effective as mesalazine in preventing relapse of UC. In patients who are intolerant to mesalazine, these therapeutic options may serve as attractive alternatives. Most subjects with UC had found greater benefit from herbal therapy than those with CD.[47]

However, not all studies have shown consistent and promising result of herbal therapy in IBD. The reasons for the discrepancies from studies could be related to the different study designs, small sample size, lack of adequate controls, overlapping treatment effects, variety of drug formulations and doses used and poor reporting of results, which have led to results that are, in some instances, difficult to interpret.[48, 49] The major problem in interpreting these results is the generally low quality of the randomised controlled trials. Publication bias is also likely to be a significant problem whereby positive results are being preferentially published.[50] Most herbal medicines should undergo a similar level of rigorous testing as pharmaceutical drugs. With the increasing demand from the public, the manufacture, marketing, and prescription of herbal medicines is expected to continue to grow.

Most of the published herbal therapies used in IBD have been associated with minimal adverse effects. At least in short-term studies, the overall incidence of adverse events reported in patients treated with herbal therapy has been similar to those receiving placebo or mesalazine. This treatment will therefore be attractive to many patients, particularly those with a preference for 'natural remedies,' those who have had surgery, and those who have experienced side effects from conventional drugs. The cost is also likely to be less than that of high doses of mesalazine, the most widely used agents for relapse prevention. Cost-effectiveness analysis of CAM is warranted.

Most herbal therapies have been reported to have anti-inflammatory properties and plausible mechanisms of action in IBD. Bovine colostrum consists of immunoglobulins and growth factors and may be efficacious in UC. Preparations from the gum resin of Boswellia serrata have been used as a traditional remedy in Ayurvedic medicine in India for the treatment of inflammatory diseases. In vitro studies have reported the suppression of tumour necrosis factor-α (TNF-α) and pro-inflammatory interleukins by wormwood (Artemisia absinthium) extracts. Boswellic acids inhibit the leukotriene biosynthesis in neutrophilic granulocytes via noncompetitive inhibition of 5-lipoxygenase, resulting in a significant dropped in the mean serum TNF-alpha level; this effect was not observed in the placebo group.[37] Andrographis paniculata has in vitro inhibitory activity against TNF-α, IL-1β and NF-κB.[33]

This study has several limitations. First, we were not able to pool data for analysis due to differences in outcomes and methodology among the included studies. The studies were clinically heterogeneous. Publication bias is likely to be present, but the assessment of bias cannot be performed with very limited number of included trials in each herbal therapy category. Although many of these herbal therapies seem to be effective in the management of UC based on clinical experiences, their long-term efficacies and safety profile need further investigation. Second, selection bias may be present as we have limited our review to herbal remedies that have been tested in human IBD. Other promising herb, for example Bromelain, that has been shown to have anti-inflammatory activities in vitro but has yet been investigated in patients with the disease, was not included. Third, although herbal therapy such as curcumin has promising benefit in IBD, our review is based on only one study and these results need to be reproduced in other populations and larger longitudinal studies are required to prove the efficacy and safety. If such studies continue to demonstrate a favourable safety profile, then it may be possible to combine these herbal therapies with conventional drugs of known efficacy such as corticosteroids, thiopurine and anti-TNF agents, with the aim of achieving synergistic efficacy without incurring synergistic toxicity. Pharmacokinetic and drug interactions studies will be important. Pending results of these studies, the popularity of CAM among IBD patients challenges the physicians who need to enhance their awareness and knowledge about this common practice to better advice or counsel their patients, especially the young women and those with severe disease and those requiring hospitalisation and those who are at increased risk of using CAM.[10] One study from Germany showed that only 48% of all IBD patients regarded a scientific foundation for CAM treatment as being important[14] and 65% will continue to use CAM even if scientific reports showed that the therapy was not effective. Lastly, whether CAM is applicable to all IBD patients has not been fully elucidated. Individual CAM may serve as an alternative treatment in patients who are failing mesalazine. At present, the majority of studies have been conducted in patients with UC and more studies of CD with different disease phenotypes and behaviour are needed. Nevertheless, taken together, all these studies suggest the effectiveness of these new therapeutic approaches, not only when conventional treatment fails or is not tolerated, but also, in some instances, as potential first-line treatment.

In conclusion, clinical studies of herbal therapy in IBD have shown promising efficacy data and acceptable safety profile but studies remain limited and heterogenous. Conducting high-quality clinical trials with appropriate blinding and large number of patients is necessary to obtain more conclusive results on the risk–benefit ratio of herbal therapy in IBD.

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