Induction of clinical response and remission of inflammatory bowel disease by use of herbal medicines: A meta-analysis

Table 1 Characteristics of studies included in the meta-analysis

Study	Scientific name of plant(s)	Study design	Method of randomization	Blindness	Withdrawal	Jadad score	Inclusion criteria	Exclusion criteria	Interventions	Concomitant medications	Duration	Outcomes
Sandborn et al[17]	Andrographis paniculata	Randomized, placebo-controlled, double-blind	Block randomization schedule	Double-blind	32 patients in Andrographis group and 11 in placebo group	4	Patients with at least 18 yr of age and confirmed diagnosis of mildly to moderately active UC (Mayo Score of 4-10 points and endoscopic subscore of at least 1) while receiving either oral mesalamine (or equivalent medications sulfasalazine, balsalazide, and olsalazine) for at least 4 wk or no medical therapy	Patients with CD or indeterminate colitis, severe UC (Mayo Score of 11 or 12 points, toxic mega-colon, toxic colitis), previous colonic surgery or probable requirement for intestinal surgery within 12 wk, enteric infection within 2 wk, a history of tuberculosis, a positive chest X-ray or tuberculin protein-purified derivative skin test, active infection with hepatitis B or any infection with hepatitis C, infection with human immunodeficiency virus, cancer within 5 yr, inadequate bone marrow, hepatic, or renal function, a history of alcohol or drug abuse that would interfere with the study, significant concurrent medical diseases, allergy to plants in the Acanthacea family, women who were pregnant or breastfeeding , receiving oral or rectal steroids within 1 mo, rectal mesalamine within 1 wk, antibiotics within 2 wk, or azathioprine, 6-mercaptopurine, anti-tumor necrosis factor agents, or immunosuppressive therapy within 6 wk	Group 1: Capsules containing 1200 or 1800 mg Andrographis paniculata ethanol extract. [n = 149 (male/female: 81/68)]. 1 cap tds	Mesalazine	8 wk	(1) Clinical response (a decrease from baseline in the total Mayo Score by at least 3 points and at least 30% with an accompanying decrease in rectal bleeding subscore of at least 1 point or a absolute rectal bleeding subscore of 0 or 1 point ); (2) Clinical remission (a total Mayo Score of 2 points or lower, with no individual subscore exceeding 1 point); (3) Mucosal healing (a decrease from baseline in the endoscopy subscore by at least 1 point and an absolute endoscopy subscore of 0 or 1 point)
									Group 2: The same capsules without herbal extract. [n = 75 (male/female: 41/34)]. 1 cap tds
Holtmeier et al[20]	Boswellia serrata	Randomized, placebo-controlled, double-blind	A computer generated randomization scheme: In blocks of four	Double-blind	9 patients in Boswellia group and 7 in control group	4	Outpatients between 18 and 75 yr with a history of CD currently in remission with at least two documented relapses during the last 4 yr, one within the last 18 mo, or a recent resection (fibrotic strictures without inflammation were not considered a relapse); CDAI < 150 and no symptoms suspicious of activity for the previous 28 d	CDAI of > 150 at screening and at baseline visit (≥ 28 d apart); severe fistulizing CD; abscesses; symptomatic stenoses; any condition that places the patient at an undue risk; surgical bowel resections within 3 mo, short bowel syndrome; total proctocolectomy; serious infections, nutritionally compromised patients requiring enteral or parenteral therapy; severe hypertension, chronic liver disorder; impaired renal function; myocardial infarction < 3 mo, cerebral blood flow disturbances or cerebral infarction < 6 mo; any history of malignancy within the past 5 yr (except for squamous or basal cell carcinoma of the skin); subjects with severe psychiatric illnesses, inability to give informed consent; and history of severe alcoholism and drug abuse; taken monoclonal antibody therapy (e.g., infliximab) within 12 mo, immunosuppressives (azathioprine/6-mercaptopurine, cyclosporine, methotrexate) within 4 mo, or corticosteroids, mesalamine/sulfasalazine, or Boswellia serrata within 6 wk prior to randomization	Group 1: Capsules containing 400 mg 8% ethanol extract of Boswellia serrata resin. [n = 42 (male/female: 13/29)]. 2 caps tds	ND	52 wk	(1) Maintenance of remission (maintenance of CDAI < 150 throughout study); (2) Relapse (relapse was defined as both a CDAI score > 150 points and an increase in the CDAI score of ≥ 70 points)
									Group 2: The same capsules without herbal extract. [n = 40 (male/female: 15/25)]. 2 caps tds
Krebs et al[18]	Artemisia absinthium	Randomized, open label	ND	Unblinded	Not any	2	Patients between 18 and 80 yr with CDAI ≥ 200 at least for 3 mo receiving CD treatments with 5-aminosalicylates stable dose for at least 4 wk, azathioprine stable dose for 8 wk, methotrexate stable dose for 6 wk or steroids with stable dose in the range of 20-30 mg (equivalent to dexamethasone)	Treatment with TNF-α inhibitors such as infliximab; Patients with serious pathological findings in ECG, liver, kidney and heart functions, or coexisting organic diseases such as a history of cancer, asthma or other autoimmune disease, or pregnancy; any condition that in the investigators opinion placed the patient at undue risk by participating in the study; parasites in the patient’s stools, positive Clostridium difficile toxin test and active fungal or viral infection	Group 1: Capsules containing 250 mg leave and stem powder of Artemisia bsinthium. [n = 10 (male/female: 6/4)]. 3 caps tds	Azathioprine, mesalazine	6 wk	Response: a decrease in the CDAI score of at least 70 points from the qualifying score, or a decrease in 30% of CDAI score from the baseline score
									Group 2: No medication. [n = 10 (male/female: 3/7)]
Madisch et al[21]	Boswellia serrata	Randomized, placebo-controlled, double-blind	Groups of four patients according to a central computer-generated randomization list	Double-blind	5 patients in Boswellia group	5	Patients, aged between 18 and 80 yr were eligible for the study if they had at least five liquid or soft stools per day on average per week, a complete colonoscopy performed within the last 4 wk before randomization, and a histologically confirmed diagnosis of collagenous colitis	Treatment with budesonide, salicylates, steroids, prokinetics, antibiotics, ketoconazole, or non-steroidal anti-inflammatory drugs within 4 wk before randomization, other endoscopically or histologically verified causes for diarrhea, infectious diarrhea, pregnancy or lactation, previous colonic surgery, and known intolerance to Boswellia extract	Group 1: 400 mg capsules containing boswellia serrata extract standardized to 80% boswellic acids, 1 capsule tid	Loperamide was allowed for the first 3 wk but was not allowed for the last 3 wk of the study. Patients were allowed to use butylscopolamine in case of abdominal pain	6 wk	Clinical remission (stool frequency equal to or less than three soft or solid stools per day on average during the last week of treatment)
									Group 2: Identical placebo capsules, 1 capsule tid
Omer et al[19]	Artemisia absinthium	Double-blind, placebo-controlled	ND	Double-blind	ND	2	Patients between 18 and 80 yr with CDAI ≥ 200 at least for 3 mo receiving CD treatments with 5-aminosalicylates stable dose for at least 4 wk, azathioprine stable dose for 8 wk, methotrexate stable dose for 6 wk or corticosteroids (prednisolone, prednisone or budesonide) at the equivalent of 40 mg/d of prednisone or Less stable dose for 3 wk	Treatment with infliximab; patients with serious pathological findings in ECG, liver, kidney and heart functions, or coexisting organic diseases such as a history of cancer, asthma or other autoimmune disease, or pregnancy; any condition that in the investigators opinion placed the patient at undue risk by participating in the study; parasites in the patient’s stools, positive Clostridium difficile toxin test and active fungal or viral infection	Group 1: Capsules containing 250 mg leave and stem powder of Artemisia bsinthium. [n = 20 (male/female: 12/8)]. 3 caps bid	Glucocorticoids, 5-aminosalicylates, azathioprines, methotrexate	10 wk	A decrease in the CDAI score of at least 70 points from the qualifying score, or a decrease in 30% of CDAI score from the baseline score
									Group 2: The same capsules without Artemisia absinthium. [n = 20 (male/female: 11/9)]. 3 caps bid
Langmead et al[16]	Aloe vera	Randomized, double-blind, placebo-controlled	Computer-generated, block-design, in 2:1 ratio	Double-blind	6 patients in aloe group and 3 in the placebo group	4	Age of 18-80 yr, mildly to moderately active UC (as defined by a modified SCCAI ≥ 3) and no recent changes in conventional prophylactic therapy	Acute severe UC requiring hospital admission (SCCAI > 12); inactive disease (SCCAI < 3); positive stool examination for pathogens; CD or indeterminate colitis; use of antibiotics, warfarin, cholestyramine, sucralfate, anti-diarrhoeal drugs (loperamide, codeine phosphate, diphenoxylate), non-steroidal anti-inflammatory drugs, aspirin > 75 mg/d, aloe vera or other herbal remedies; alcohol or drug abuse; pregnancy or breast feeding; female of child-bearing age not taking adequate contraception; participation in another drug trial in the previous 3 mo; and serious liver, renal, cardiac, respiratory, endocrine, neurological or psychiatric illness, alteration in their dosage of aminosalicylates in the previous 4 wk, had taken > 10 mg/d or had altered oral prednisolone dosage in the previous 4 wk, changed their dose of azathioprine or 6-mercaptopurine in the previous 3 mo, or had used more than five corticosteroid or aminosalicylate enemas in the previous 2 wk	Group 1: Aloe vera gel. [n = 30 (male/female: 16/14)]. 100 mL bid	5-ASA, prednisolone, azathioprine, topical 5-ASA, topical steroid	4 wk	(1) Clinical remission (SCCAI ≤2); (2) Sigmoidoscopic remission [Baron score of zero (normal-looking mucosa) or one (mucosal oedema as indicated by loss of the normal vascular pattern)]; (3) Histological remission (Savery-muttu score of ≤ 1, i.e., no loss of colonocytes, absence of crypt inflammation, and normal lamina propria content of mononuclear cells and neutrophils); (4) Clinical improvement (a reduction in SCCAI of ≥ 3 points); (5) Clinical response (remission or improvement); (6) Sigmoidoscopic improvement (decrease in Baron score of ≥ 2 points; and (7) Histological improvement (decrease in Savery-muttu score of ≥ 3 points)
									Group 2: The same lipqiud product without Aloe vera gel. [n = 14 (male/female: 6/8)]
Ben-Arye et al[22]	Triticum aestivum	Randomized, double-blind, placebo-controlled	ND	Double blind; both the true juice and the placebo were packaged in coded, identical, sealed, opaque containers. A driver, blinded to the allocation scheme and given only the addresses for each package, then distributed all the packages	2 patients in triticum group and 1 in the placebo group	4	Age > 18 yr; sigmoidoscopic finding of active UC that involves the left colon; clinical activity comparable with UC; no change in drug treatment (type and dosage) in the month prior to entry; lack of serious systemic involvement–fever > 38 °C, erythema nodosum, arthritis; blood hemoglobin > 11 g%; negative stool culture and test for ova and parasites	ND	Group 1: 100 mL of Triticum aestivum seed juice. [n = 11 (male/female: 6/5)]	-	1 mo	Improvement (larger than 0.4 in an analog scale where -3 designates the lowest score of aggravation, 0 no change, and +3 highest score of improvement)
									Group 2: 100 mL of matching placebo. [n = 12 (male/female: 9/3)]

CD: Crohn’s disease; CDAI: Crohn’s disease activity index; ND: Not determined; SCCAI: Simple clinical colitis activity index; UC: Ulcerative colitis; ASA: Aminosalicylic acid. ECG: Electrocardiography; TNF: Tumor necrosis factor.

Table 2 Results for outcomes investigated for each included studies

Herbal product	IBD type	Study	Patients reported AE		Clinical efficacy		Endoscopic efficacy		Histological efficacy		Recurrence relapse
			Any AE	Serious AE	Clinical remission	Clinical response	Endoscopic remission	Endoscopic response	Histological remission	Histological response
Aloe vera	UC	16	H: 6/30	-	H: 9/ 30	H: 14/30	H: 7/26	H: 12/26	H: 6/21	H: 14/21	-
			C: 4/14		C: 1/14	C: 2/14	C: 2/11	C: 3/11	C: 4/9	C: 7/9
Andrographis paniculata	UC	17	H: 84/149	H: 4/149	H: 53/148	H: 78/148	H: 65/148	-	-	-	-
			C: 45/75	C: 2/75	C: 19/75	C: 30/75	C: 25/75
Artemisia absinthium	CD	18	-	H: 0/10	-	H: 8/10	-	-	-	-	-
				C: 0/10		C: 2/10
Artemisia absinthium	CD	19	-	-	H: 13/20	H: 18/20	-	-	-	-	-
					C: 0/20	C: 0/20
Boswellia serrata	CD	20	H: 29/42	H: 4/42	-	-	-	-	-	-	H: 14/42
			C: 34/40	C: 4/40							C: 14/40
Boswellia serrata	Collagenous colitis	21	H: 2/16	H: 0/16	H: 10/16	-	-	-	-	-	-
			C: 1/15	C: 0/15	C: 4/15
Triticum aestivum	UC	22	-	-	-	H: 10/11	-	-	-	-	-
						C: 5/12

AE: Adverse event; C: Control; CD: Crohn’s disease; H: Herbal product; UC: Ulcerative colitis; IBD: Inflammatory bowel disease.

Table 3 Results obtained from sub-analyses based on plant type

Plant	IBD type	Study	Patients reported AE		Clinical efficacy		Endoscopic efficacy		Histological efficacy		Recurrence relapse
			Any AE	Serious AE	Clinical remission	Clinical response	Endoscopic remission	Endoscopic response	Histological remission	Histological response
Aloe vera	UC	16	0.70 (0.25-2.08)	-	4.20 (0.84-24.84)	3.27 (1.06-12.13)	1.48 (0.44-5.84)	1.69 (0.69-5.04)	0.64 (0.25-1.81)	0.86 (0.55-1.55)	-
Andrographis paniculata	UC	17	0.94 (0.75-1.20)	1.01 (0.22-4.65)	1.41 (0.92-2.23)	1.32 (0.98-1.84)	1.32 (0.93-1.93)	-	-	-	-
Artemisia absinthium	CD	18	-	1.00 (0.06-16.69)	-	9.61 (0.73-126.15), P = 0.09	-	-	-	-	-
	CD	19	-	-	27.00 (3.23-260.81)		-	-	-	-	-
Boswellia serrata	CD	20	0.82 (0.66-1.04), P = 0.11	0.95 (0.27-3.31), P = 0.94	-	-	-	-	-	-	0.95 (0.52-1.73)
	Collagenous colitis	21			2.34 (1.02-6.07)	-	-	-	-	-	-
Triticum aestivum	UC	22	-	-	-	2.18 (1.19-4.78)	-	-	-	-	-

Results are expressed as relative risk (95%CI). AE: Adverse event; CD: Crohn’s disease; UC: Ulcerative colitis; IBD: Inflammatory bowel disease.