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.