Oral Chinese herbal medicine combined with pharmacotherapy for psoriasis vulgaris: a systematic review

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1 Review Oral Chinese herbal medicine combined with pharmacotherapy for psoriasis vulgaris: a systematic review Claire Shuiqing Zhang 1, PhD, Jason Jingjie Yu 1,2, MMED, Shefton Parker 1, BAPPSC, Anthony Lin Zhang 1, PhD, Brian May 1, PhD, Chuanjian Lu 1,2, PhD, and Charlie Changli Xue 2,3, PhD 1 Traditional & Complementary Medicine Research Program, Health Innovations Research Institute, School of Health Sciences, RMIT University, Bundoora Campus, Vic., Australia, 2 Guangdong Provincial Academy of Chinese Medical Sciences & Guangdong Provincial Hospital of Chinese Medicine, Guangzhou,, and 3 Health Innovations Research Institute, School of Health Sciences, RMIT University, Bundoora Campus, Vic., Australia Correspondence Prof Charlie Changli Xue, PhD School of Health Sciences, College of Science Engineering and Health Traditional & Complementary Medicine Program, RMIT Health Innovations Research Institute (HIRi) RMIT University PO Box 71 Bundoora Vic Australia charlie.xue@rmit.edu.au Abstract Clinically, oral Chinese herbal medicine (CHM) is widely used in the treatment of psoriasis. This review evaluates the effects of oral CHM in combination with pharmacotherapy for psoriasis vulgaris. The Cochrane Library, PubMed, Embase, CINAHL, CNKI, and CQVIP were searched from their inceptions to November Randomized controlled trials (RCTs) investigating CHM plus pharmacotherapy compared to pharmacotherapy were included. Data were analyzed using Review Manager Seventeen RCTs were included, conducted in, and employed a diversity of both herbal medicines and pharmacotherapies. When the meta-analyses were restricted to studies that used a wellknown pharmacotherapy as the comparator with 60% or greater clinical improvement in psoriasis as the outcome, five studies used oral acitretin, one used topical calcipotriol, and one used topical clobetasol propionate as control interventions. At the end of treatment, there was a benefit for the pooled result of the five studies that compared CHM plus acitretin with acitretin alone and no serious adverse events were reported. However, none of these studies was blind, so there is considerable risk of bias in this result. In addition, there was inadequate reporting of longer-term results, so it remains unclear whether the reported effect could be maintained or whether the prolonged use of the CHM in conjunction with acitretin would be safe. The main plants used in these studies, Rehmannia glutinosa root, Salvia miltiorrhiza root, and Lithospermum erythrorhizon root, have shown anti-inflammatory and/or antiproliferative effects in experimental studies. These actions may at least partially explain the observed results. Conflicts of interest: None. Background Psoriasis is a recurring skin condition that varies in severity from minor localized patches to large lesions covering multiple body surface areas. The condition is thought to be caused by an immune system dysfunction, with increased infiltration of immune cells such as lymphocytes (T cells) and hyperproliferation of skin cells. 1 The global average prevalence of psoriasis was estimated as 3 4%. 2 Among all seven types of psoriasis, vulgaris (plaque) is the most common, presenting in 90% of people with psoriasis. 3 Although psoriasis is not life threatening, research links it to an increased risk of cardiovascular disease, diabetes, and cancer among other morbidities. 3 Additionally, the impact on quality of life for people with psoriasis is substantial and may precipitate them to develop psychological and emotional disorders. 4,5 Evidence also reveals that a significant economic burden arises from the direct and indirect costs of the disease. 6 8 Current pharmacotherapies are effective for psoriasis symptoms but usually do not cure the disease and may cause unwanted side effects with long-term use. 3,7 CHM has a long history of treating dermatological conditions and has been reported to be effective and safe for psoriasis. 9,10 This review analyzes the results from randomized controlled trials (RCTs) to investigate the efficacy and safety of oral CHM combined with various forms of pharmacotherapy for psoriasis vulgaris ª 2014 The International Society of Dermatology International Journal of Dermatology 2014, 53,

2 1306 Review Chinese herbal medicine for psoriasis Zhang et al. Methods Search strategy The Cochrane Library, PubMed, Embase, CINAHL, CNKI, and CQVIP were searched from their inceptions to November Three groups of search terms were used as follows: condition (psoriasis vulgaris and synonyms); intervention type (oral CHM and synonyms); and study type (RCT and synonyms). These groups of terms were combined and the results downloaded to a dedicated file. Full lists of terms are available upon request. References listed in review articles were searched for additional studies. Study selection and data extraction Included studies were RCTs published in English or Chinese that compared oral CHM plus pharmacotherapy with the pharmacotherapy. Participants were limited to people with psoriasis vulgaris, but no limits were placed on stage or severity of disease and participants age or gender. Journal articles, conference proceedings, and theses were considered. If the RCT consisted of more than two arms, only the data for the CHM plus pharmacotherapy arm and the pharmacotherapy arm were included. Studies that used non-oral CHM or phototherapy, or treated other types of psoriasis were excluded. One reviewer (JJY) screened the Chinese titles and abstracts, and another (SP) screened the English search results. Full-text articles were obtained for further assessment of eligibility. Any uncertainty was resolved through discussion with a third author (CSZ). Reasons for exclusion were recorded. Data were extracted from the remaining RCTs to a predefined Excel table and cross-checked by two reviewers (JJY and CSZ). When information was found to be unclear, attempts were made to contact the authors. In the event there was no reply, a judgment was made through discussion between CSZ, JJY, and SP. Risk of bias assessment Risk of bias was assessed by two reviewers (JJY and CSZ) using the Cochrane Collaboration tool 11 for the following items: sequence generation, allocation concealment, blinding of participants and practitioner, blinding of outcome assessors, incomplete outcome data, selective outcome reporting, and other bias (defined as funding resource). Meta-analysis Meta-analysis used Review Manager (The Cochrane Collaboration) 5.1. Studies were grouped according to the pharmacotherapy used and the outcome measure. Dichotomous data were expressed as risk ratio (RR), and continuous data were presented as mean difference (MD), both with 95% confidence intervals (CI). A fixed-effect or randomeffect model was used according to heterogeneity. Any dropouts were included in the meta-analysis as ineffective following an intention-to-treat (ITT) approach. Results In total, 1883 records were obtained through database searches, and 198 potentially relevant articles were identified after screening titles and abstracts. Among them, 17 RCTs met the inclusion criteria and were included in the review. Five studies were included in the meta-analysis (Fig. 1). Description of studies All RCTs were conducted in hospitals in and published in Chinese within the last 10 years. A placebo CHM control was not used in any of the 17 studies. Three studies had a third arm for CHM alone, but data from the third arm were not included in the review (Table 1). Participants The total number of participants included in the two arms of the 17 RCTs was 1542, with 839 in the CHM plus pharmacotherapy groups and 703 in the pharmacotherapy groups. In two studies, there were inconsistencies in the number of participants reported in the text and in the results tables. 12,13 Attempts were made to contact the authors but these were unsuccessful, so the numbers of participants in the results tables were used. Participants ages ranged from 13 to 70 years. Two studies 12,15 did not provide information on participants gender, and this information in Wan was unclear so it was excluded. 13 The remaining 14 RCTs included 728 males and 551 females. All RCTs recruited people with psoriasis vulgaris, with durations since initial onset varying from two weeks 16 to 30 years. 17 Four studies reported a baseline psoriasis area severity index (PASI score) (all >10) Other studies did not provide information on baseline disease severity, although baseline balance was reported in all studies. One study 22 mentioned that only patients with the stationary stage of psoriasis vulgaris were included, while four RCTs 14,16,20,23 recruited patients known to be in progressive or stationary stages. The remaining 12 did not provide this information. Interventions All studies investigated multi-ingredient CHM formulas. Of these, 15 studies used decoctions, 13 15,17 28 and two used granulated powders. 12,16 Each study employed a different formula. The names of the formulas are listed in Table 1. Ten studies applied a standardized CHM formula, 12,13,15,17,18,21,23,24,26,28 whereas the other seven studies modified the CHM according to the stage of psoriasis vulgaris, 16 the Chinese medicine syndrome, 25 or individual symptoms. 14,19,20,22,25,27 A total of 70 different herbs were included in the 17 studies. The most frequently used herbs were Rehmannia glutinosa root (Sheng International Journal of Dermatology 2014, 53, ª 2014 The International Society of Dermatology

3 Zhang et al. Chinese herbal medicine for psoriasis Review 1307 Figure 1 Flow chart of study selection according to PRISMA guidelines. CHM, Chinese herbal medicine; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta- Analyses; PT, pharmacotherapy; RCT, randomized controlled trial Di) (in 15 studies), Angelica sinensis root (Dang Gui) (12), Smilax glabra root (Tu Fu Ling) (11), Paeonia veitchii root (Chi Shao) (nine), Salvia miltiorrhiza root (Dan Shen) (nine), and Lithospermum erythrorhizon root (Zi Cao) (nine). Ten studies used a single pharmacotherapy as comparator, 12 14,17,18,21 24,28 five studies used two, 16,20,25 27 and two studies combined three drugs. 15,19 In total, 10 different drugs were used, including the following topical medications: the vitamin D3 analogues, calcipotriol, 15,18 and tacalcitol, 27 as ointments in three studies, and the corticosteroid clobetasol propionate ointment in one study. 26 The oral retinoid acitretin was used in eight studies. 12,14 16,20,21,23,24 In addition, the following pharmacotherapies, which are used in for psoriasis management, were employed. Oral Diyin tablets were used in seven studies. 13,16,17,22,25,26,28 Diyin anti-psoriasis tablets contain multiple amino acids and peptides, aminophylline, and chlorpheniramine maleate and aim to regulate immune response, improve microcirculation, benefit metabolism, provide microelements, and reduce the proliferation of psoriasis. 29,30 Compound glycyrrhizin solution via IV drip was used in two studies. 15,27 It contains glycyrrhizin, cysteine hydrochloride, and glycine, and is said to produce an effect similar to a glucocorticoid, including reduce inflammation. 31 An IV drip containing 10% calcium gluconate solution was used in two studies. 19,25 It aims to reduce itch in various dermatological conditions. 32 However, these pharmacotherapies are not included in international guidelines. ª 2014 The International Society of Dermatology International Journal of Dermatology 2014, 53,

4 1308 Review Chinese herbal medicine for psoriasis Zhang et al. Table 1 Characteristics of included RCTs Author, year, setting, country Sample size (T/ C); mean, (range) (T/C) CHM interventions Chen 2010, 200 (150/50); T: 42.3, C: 43 CHM decoction (Ke Yin Yi Hao), b.i.d., no Chen 2004, Huang 2010, Mild AEs in both groups: dry mouth, dry lips, dry skin, scaly skin, due to Acitretin. No SAE Jin 2009, 56 (30/26); T: 32.4 (16 65); C: 33.2 (17 63) 70 (40/30); NS 60 (30/30); T: , C: CHM decoction (no formula name), b.i.d., no Xiaoyin formula granulated powder: 3.5 g t.i.d., no individual modification CHM decoction (no formula name), b.i.d., no Kong 2007, Liu 2005, Mild AEs: dry mouth, dry skin, scaly skin, skin itchiness, T < C; No SAE 86 (45/41); T: , C: (40/20); T: 33.63, C: 32.7 CHM decoction (no formula name), b.i.d., no CHM decoction (Jian Pi yi Shen Tang), b.i.d., according to symptoms Pharmaceutical interventions Treatment/ follow-up duration Outcome measures Reported results, ES Oral acitretin: 30 mg t.i.d., then 20 mg t.i.d. Oral Diyin tablets: 5 tablets, b.i.d. Oral acitretin capsules: 20 mg q.d. 60 days; 6 weeks; TER based on lesion reduction (three levels, scoring NS); change in serum IL-6, IL-8 level TER based on % lesion reduction (100, 90, 60, 30, 0); liver & kidney function Reported T > C for TER, no definition of effectiveness, ES analysis not possible ES for 60% lesion reduction: RR 1.14 (0.86, 1.51) No information TER based on % lesion reduction (100, 60, 30, 0) Topical calcipotriol b.i.d. 12 weeks; Oral Diyin tablets: 3 4 tablets b.i.d., IV 10% gluconate calcium, 40 ml q.d. 6 weeks; (90, 60, 20, 0), PASI score TER based on lesion reduction (three levels, scoring NS) Reported T > C for TER & PASI score; ES for PASI 60: RR 1.27 (1.01, 1.61); ES for PASI score: MD 1.63, (0.58, 2.68) Reported T > C for TER. ES analysis not possible Oral Diyin tablets: 5 tablets, b.i.d. No information (95, 70, 30, 0) Adverse Events (AE/ SAE) NS Mild AEs: dry mouth, dry lips, dry skin, scaly skin, skin itchiness. T < C; No SAE Reported T > C for TER; ES analysis not possible due to errors in data reporting Five participants from two groups reported mild skin redness, due to Calcipotriol NS Reported T > C for TER; ES for PASI 70: RR 1.93 (1.02, 3.64) International Journal of Dermatology 2014, 53, ª 2014 The International Society of Dermatology

5 Zhang et al. Chinese herbal medicine for psoriasis Review 1309 Table 1 Continued Author, year, setting, country Luo 2010, Mao 2007, Shen 2005, Tan 2010, Tian 2011, Wan 2012, Wu 2009, Xie 2006, Yu 2007, Sample size (T/ C); mean, (range) (T/C) CHM interventions 174 (74/100); T: , C: (31/31); T: 45.48, C: (30/30); total average 37 CHM decoction (no formula name), b.i.d., no CHM decoction (no name), b.i.d., individual modification according to psoriasis vulgaris stage CHM decoction (Xiao Yin Fang), b.i.d, no 90 (50/40); Total: (30/30); T: , C: CHM decoction (Liang Xue Xiao Yin Tang), b.i.d., individual modification according to symptoms CHM decoction (Qing Fei Liang Xue Tang), b.i.d., according to symptoms 64 (32/32); T: 13 66, C: (79/79); T: , C: CHM decoction (Er Dong Huo Xue Tang) b.i.d., no CHM decoction (Yin Xie Kang), q.d., individual modification according to symptoms 52 (32/20); T: 32.5, C: (30/28); Total: CHM decoction (Tui Yin Tang), b.i.d., individual modification according to symptoms CHM decoction (Qing Re Huo Xue Tang), b.i.d., according to symptoms Pharmaceutical interventions Oral acitretin capsules: 0.5 mg/kg per day; IV complex glycyrrhizin, 30 ml q.d.; topical calcipotriol, b.i.d. Oral acitretin capsules, 10 mg b.i.d.; oral Diyin tablets, five tablets b.i.d. Oral Diyin tablets: 5 tablets b.i.d.; topical clobetasol propionate ointment IV complex glycyrrhizin, 40 ml q.d.; topically Tacalcitol, b.i.d. Oral antihistamine, vitamin C, B6, IV gluconate calcium Oral Diyin tablets: 5 tablets, b.i.d. Oral acitretin capsules: 0.5 mg/kg per day; boric acid ointment, b.i.d. Oral acitretin capsules: 10 mg t.i.d. for 30 days, then 10 mg b.i.d. for 60 days Oral Diyin tablets: 5 tablets, b.i.d. Treatment/ follow-up duration Outcome measures Reported results, ES 6 weeks; (95, 60, 30, 0) ES for PASI 60: RR 1.71 (1.30, 2.24) 8 weeks; 3 months 8 weeks; (90, 60, 30, 0); recurrence rate; liver & kidney function (90, 60, 30, 0) ES for PASI 60: RR 1.09 (0.81, 1.46) ES for PASI 60: RR 1.38 (0.92, 2.05) 8 weeks; (90, 60, 20, 0); liver & kidney function ES analysis not possible 60 days; 1 month; 3 months 12 weeks, 3 months; 2 months; (90, 60, 20, 0); PASI score TER based on % lesion reduction (95, 75, 30, 0). recurrence rate (90, 60, 30, 0); PASI score; liver & kidney function TER based on lesion reduction (95, 50, 0) TER based on score of PASI & DLQI (4 levels) Reported T > C for TER & PASI score; ES for PASI 60: RR 2.27, (1.38, 3.74); ES for PASI score: MD 5.48, ( 6.98, 3.98) ES analysis not possible due to errors in data reporting Reported T > C for TER & PASI score; ES for PASI 60: RR 1.32 (1.11, 1.57); ES for PASI score: MD 4.03, ( 4.97, 3.09) ES for 50% lesion reduction: RR: 1.24 (0.62, 2.49) ES analysis not possible Adverse Events (AE/ SAE) Mild AEs in C group only, caused by pharmacotherapies; No SAE Mild AEs of skin dryness, pruritus, T/C: (1/3); No SAE Mild AEs in both groups: dry month, scaly skin, T < C; No SAE Three mild AEs, skin irritation due to pharmacotherapy; No SAE NS No AE Mild AEs in both groups, dry & scaly skin, due to pharmacotherapy; T < C; No SAE Mild AEs: dry mouth, dry skin, scaly skin, skin itchiness, in C group only; no SAE NS ª 2014 The International Society of Dermatology International Journal of Dermatology 2014, 53,

6 1310 Review Chinese herbal medicine for psoriasis Zhang et al. Table 1 Continued Adverse Events (AE/ SAE) Treatment/ follow-up duration Outcome measures Reported results, ES Pharmaceutical interventions Sample size (T/ C); mean, (range) (T/C) CHM interventions Author, year, setting, country NS ES for 75% lesion reduction: RR 1.64, (1.23, 2.19) TER based on lesions reduction (95, 75, 30, 0) 4 weeks; Oral acitretin capsules: 10 mg t.i.d. CHM decoction (Qing Ying Tang), t.i.d., no 112 (56/56); Total: Zhang 2012, Mild AEs in both groups: gastrointestinal reactions in both groups; leukocyte decrease in C group only; No SAE Reported T > C for TER & PASI score; ES for PASI 60: RR 2.00, (1.21, 3.32); ES for PASI score: MD 2.45, ( 3.60, 1.30) (95, 60, 30, 0); PASI score 8 weeks; Oral acitretin capsules: started at 20 mg/day, then increased to mg/day, then decreased to mg/day CHM decoction (Xiao Yin Ke Bi Tang), b.i.d., no 120 (60/60); T: , C: Zheng 2011, AE, adverse events; b.i.d., twice a day; C, control; CHM, Chinese herbal medicine; DLQI, dermatological life quality index; ES, effect size; IV, intravenous drip; MD, mean difference; PASI, psoriasis area and severity index; q.d., once a day; RR, risk ratio; SAE, severe adverse events; T>C, treatment group is significantly greater to control group; T, treatment; t.i.d., three times a day; TER, total effective rate. Treatment duration and follow-up The shortest treatment was for one month 13,23 while the longest was three months. 14 The most common treatment duration was eight weeks. 16,21,26,27 All studies applied CHM and pharmacotherapy for equal durations. One study had a follow-up at three months, 16 and one was at six months. 13 Outcome measures All studies employed total effective rate (TER) as the primary outcome measure. This was calculated based on PASI score reduction in nine studies, 15,16,18 22,26,27 lesion score reduction in five studies, 12 14,17,23 and a combination of PASI and the Dermatological Life Quality Index scores in one study. 28 However, Yu and Pan 28 did not provide information on the method of score calculation. Furthermore, two studies did not specify the scoring method used. 24,25 The TERs were categorized as cured, remarkably effective, effective, and ineffective. However, the definition of these categories varied among the studies. For example, in three studies PASI score reductions of 90, 60, and 30% (PASI 90, 60, 30) were used, 16,20,26 whereas one study used 95, 70, and 30% (PASI 95, 70, 30) as the criteria, 22 while another study employed lesion score reductions of 95, 75, and 30%. 23 Furthermore, the symptom scoring methods used in six studies had not been validated ,17,23,28 PASI 60 or a lesion score reduction of 60% was the most common criterion for remarkably effective. The actual PASI score was reported in four studies, and one study reported serum interleukin (IL)-6 and IL-8 levels. 24 Adverse events (AEs) were monitored by all studies with 10 studies examining full blood count, urine tests, and blood tests for renal and liver function. 12,14 20,26,27 Dropouts Fifteen studies reported no dropouts or were judged as having no dropouts, as they reported equal numbers of participants randomized and completed. One study did not provide information on dropouts or number completed. 27 One study reported eight dropouts (three from the treatment group and five from the control group), due to minor AEs or loss of contact during follow-up. 20 Although this study mentioned treating dropouts as ineffective in the data analysis, the dropouts were not included in the data table, so the numbers were adjusted for meta-analysis. Use of Chinese medicine syndrome differentiation for psoriasis vulgaris According to Evidence-based Guidelines for Clinical Practice in Chinese Medicine, 33 the most common syndrome in the progressive stage of psoriasis vulgaris is blood heat syndrome, while blood stasis syndrome is common in the International Journal of Dermatology 2014, 53, ª 2014 The International Society of Dermatology

7 Zhang et al. Chinese herbal medicine for psoriasis Review 1311 stationary stage. The guidelines indicate that the CHM prescription should be modified according to the syndrome to maximize the efficacy of treatment. Among the 17 studies, one study 16 employed two different CHM formulas for the two stages of psoriasis vulgaris, one study 25 used four formulas to treat four syndromes, six studies 14,19,20,22,25,27 used according to patients symptoms, and all other studies used one standardized formula (Table 1). Risk of bias assessment One study was assessed as low risk for sequence generation as it used a randomization number table, 19 while the other 16 studies were assessed as unclear due to lack of information. Allocation concealment was not reported by any study so all were assessed as unclear; all studies received high-risk assessments for blinding of participants and practitioner as none reported a blinding method or used a placebo for the CHM; all studies were judged as unclear for blinding of outcome assessors as no details were reported. For incomplete outcome data, 13 studies were assessed as low risk because there was no dropout while Wu et al. 20 was judged as low risk because the dropout numbers were low and balanced across the two groups (X 2 = 0.476, d.f. = 1, P = 0.49). Tan and Li 27 did not report on dropouts and was assessed as unclear, while two studies 12,13 were assessed as high risk as the numbers of participants reported in the post-treatment section did not match the number of participants being randomized with no explanations provided for the differences. All studies were assessed as low risk for selective reporting; however, none of the studies had published trial protocols. For other bias, no conflict of interest from funding sources was detected in any of the studies. Wan was excluded from analysis due to inconsistency in the results tables and consequent high risk of bias in the results. 13 Efficacy All RCTs reported superior efficacy for the combination of CHM and pharmacotherapy in terms of the TER at the end of treatment, and four studies reported that the combination was more effective for the PASI score However, some studies used the PASI score as a basis for TER calculation while others used lesion score based on Chinese guidelines, and the definition of effectiveness differed across studies. Clinical guidelines suggest the criterion for treatment success should be a PASI score reduction of 75% (PASI 75) or greater, and treatment failure is a PASI score reduction of 50% (PASI 50) or less. 7 In, PASI 60 is considered by Consensus of Diagnosis and Treatment of Psoriasis Vulgaris in Integrative Medicine 34 as the cut-off level to measure effectiveness of treatment. Ten studies reported the number of participants who achieved a 60% reduction in PASI or symptom scores, and three studies reported 70 or 75% reductions, so 60% reduction or more in PASI or symptom score was selected as the criterion for meta-analysis of TER. The pharmacotherapies used in six studies were not recommended by international guidelines for the treatment of psoriasis. 13,17,19,22,25 As these drugs could not be considered reliable comparators, only studies that employed well-recognized pharmacotherapies were included in meta-analyses. Of the wellrecognized pharmacotherapies, oral acitretin was used in eight studies, 12,14 16,20,21,23,24 and four studies used other well-recognized topical drugs. 15,18,26,27 Of the eight studies that used acitretin as comparator, Huang 12 had errors in the results, Chen 24 did not provide information on the criteria for effectiveness, and Xie 14 used 50% rather than 60% lesion score reduction as a criterion, so these three studies were excluded from the meta-analysis pool. Therefore, five studies of acitretin provided TER data suitable for pooling. The actual PASI score was reported in two of these five studies. 20,21 These five studies were pooled in five groups, and the results were as follows (Fig. 2): Group 1.1 used acitretin alone as the pharmacotherapy with PASI 60 as the criterion and found CHM plus acitretin to be superior to acitretin alone (RR 2.00, [1.21, 3.32]). 21 Group 1.2 used acitretin alone as the pharmacotherapy with a 75% symptom reduction as the criterion found CHM plus acitretin to be superior to acitretin alone (RR 1.64, [1.23, 2.19]). 23 The pooled effect for these two studies was RR 1.77, (1.36, 2.29), I 2 = 0%. Group 1.3 included three studies that used acitretin plus other drugs as pharmacotherapy. 15,16,20 The pool showed a superior effect of the combination of CHM plus pharmacotherapy (RR 1.40, [1.22, 1.60], I 2 = 62%). Among these three studies, two studies found that adding CHM was more effective than the pharmacotherapy alone, 15,16 but one study showed no benefit. 20 However, sensitivity analysis found the heterogeneity in this group was due to Luo. 15 Once Luo was removed, the heterogeneity was reduced to 17% (RR 1.25, [1.08, 1.46]). The overall effect for these five studies showed superiority for the combined groups (RR 1.50, [1.33, 1.70]) with moderate heterogeneity (I 2 = 56%; Fig. 2). Sensitivity analysis showed that the removal of Mao and Mao 16 and Wu et al. 20 reduced the heterogeneity to zero (RR 1.74, [1.44, 2.10]). These studies used different co-interventions in addition to acitritin, Mao and Mao 16 used Diyin tablets, and Wu et al. 20 used topical boric acid ointment, which may have contributed to the heterogeneity. Two studies that reported PASI score were included in the meta-analysis (Fig. 3). Group 2.1 used acitretin only ª 2014 The International Society of Dermatology International Journal of Dermatology 2014, 53,

8 1312 Review Chinese herbal medicine for psoriasis Zhang et al. Figure 2 Forest plot (CHM + acitretin vs acitretin: TER). CHM, Chinese herbal medicine; PASI, psoriasis area and severity index; TER, total effective rate; M-H, Mantel-Haenszel as pharmacotherapy and showed superiority for the CHM plus acitretin group (MD 2.45, [ 3.85, 1.05]). 21 Group 2.2 used acitretin combined with boric acid ointment as pharmacotherapy and found the combination therapy to be more effective in terms of PASI score (MD 4.03, [ 4.97, 3.09]). 20 The pooled effect for these two studies showed CHM plus acitretin was more effective than acitretin alone (MD 3.54, [ 4.32, 2.76]) but the heterogeneity was high (I 2 = 70%). Only single studies were available for other standard pharmacotherapies. Jin et al. used topical calcipotriol and showed a benefit for the combined therapy group based on PASI 60 (RR 1.27 [1.01, 1.61]) but an opposite effect for PASI score (MD 1.63, [0.58, 2.68]). 18 Shen and Zhao used topical clobetasol propionate combined with oral Diyin tablets and showed benefits for the combined therapy group for PASI 60 (RR 2.27, [1.38, 3.74]) and for PASI score (MD 5.48, [ 6.98, 3.98]). 26 Recurrence of psoriasis vulgaris was reported at three months follow-up in one study as 0% in the combined therapy group versus 12.9% in the acitretin control, 16 but it was not explained how the recurrence rate was determined. Safety One study 13 reported no AE during the treatment period, while four studies 19,24,25,28 did not report information on AEs. The other 12 studies reported AEs, including: dry mouth, skin dryness/scale/itchiness, 12,14 17,20,22,26 skin irritation, 18,27 15, 20 an increase of blood cholesterol level, mild gastrointestinal reactions, 21 and decreased blood leukocyte count. 21 Among these 12 studies, seven studies reported either that AEs only occurred in the pharmacotherapy group, 14,15,21 or the occurrence in the pharmacotherapy group was significantly higher than that in the CHM plus pharmacotherapy group. 17,20,22,26 Five studies 12,15,18,20,27 concluded that all the AEs were caused by the pharmacotherapies used in the trials. No serious AE was reported in any study. Discussion Methodological quality of included studies The risk of bias assessments identified deficiencies in sequence generation and allocation concealment, and there was no blinding in any of the studies, which meant that at least part of the identified effects was likely to International Journal of Dermatology 2014, 53, ª 2014 The International Society of Dermatology

9 Zhang et al. Chinese herbal medicine for psoriasis Review 1313 Figure 3 Forest plot (CHM + acitretin vs acitretin: PASI 60 CHM, Chinese herbal medicine; PASI, psoriasis area and severity index; IV, Inverse variance have been due to the addition of an extra intervention. Although a few studies used PASI as an outcome, none reported PASI 75, which makes it difficult to compare directly the results achieved with those reported in international studies. Only one study mentioned a quality of life assessment, but no separate scores were provided. 28 Participant flow diagrams were not provided by any study, none of the studies covered all items listed in the CONSORT statement, 35 and ITT was not employed in data analysis. These aspects compromise the reliability of the results and future trials need to address these issues. Safety of oral Chinese herbal medicine combined with pharmacotherapy All of the mild AEs were reported as they are probably due to the pharmacotherapies but there were no clear justifications for these judgments. Four studies 17,20,22,26 concluded that the AEs in the CHM plus pharmacotherapy groups were significantly fewer than in the pharmacotherapy groups, suggesting that adding oral CHM may have reduced the occurrence of AEs due to the pharmacotherapy. These included skin dryness, skin itchiness, dry mouth/lips, which occurred in studies using Diyin tablets, 17,22,26 as well as dry/scaly skin, which occurred when taking acitretin. 20 However, the approaches used for collecting AE data were not clearly described, and the lack of blinding increased the risk of bias in AE data reporting and collection. No serious AE was reported, but only 12 studies reported on AEs, and only four studies monitored liver and kidney function. Among the five studies included in the meta-analysis of acitretin, Zhang did not report on AEs 23 while the other four reported only mild AEs, as did Xie, 14 which also used acitretin. Two of these studies monitored liver and kidney function. Therefore, the combination of CHM plus acitretin did not appear to result in additional AEs, at least with short-term use. Efficacy of oral Chinese herbal medicine combined with pharmacotherapy for psoriasis vulgaris Although all the studies in this review concluded that the combination of oral CHM and pharmacotherapy was superior to pharmacotherapy alone at the end of the treatment phase, this was not necessarily confirmed by the effect size analyses. Six studies did not provide data suitable for the calculation of the effect size. 12,13,24,25,27,28 Of the remaining 11 studies, seven showed significant differences in TER in favor of the combined therapy groups 15,18 23 and four showed no difference. 14,16,17,26 Of the four studies that provided PASI scores, three showed a benefit for the combination therapy group 19,20,23 while one showed a benefit for the control. 18 One reason for the difference between the reported results and those found in this meta-analysis is the adoption of an ITT approach, and another reason is the different approach taken to statistical analysis. Using risk ratio with a criterion of a 60% improvement or higher, removed any cases for which there was a small improvement. In one study of oral CHM plus calcipotriol, there was a contradiction between the result for TER and that for PASI score. The TER showed a benefit for the combination group at weeks 8 and 12 of treatment, while the mean PASI score showed the opposite result at the same time points, but no explanation was provided. 18 Considering the diversity of pharmacotherapies used in all the studies and the differences in outcome measures, it was not feasible to pool all studies in a meta-analysis. To ensure the meaningfulness of the results, data were only pooled for five of the studies that used oral acitretin as ª 2014 The International Society of Dermatology International Journal of Dermatology 2014, 53,

10 1314 Review Chinese herbal medicine for psoriasis Zhang et al. comparator. Four of these studies found that the combination of CHM and acitretin was more effective than acitretin alone, but this was only at the end of the treatment period. Only one of these studies provided a recurrence rate at three months. This favored the combination group, but there was no definition of how this recurrence was determined, so an effect size calculation was not possible. Consequently, none of these studies can provide an indication of any longer-term benefit for combining the CHMs with acitretin. How might Chinese herbal medicine alleviate psoriasis vulgaris symptoms? Although different herbal formulae were used in the studies, certain plants appeared in multiple formulas. The herbs used by the five studies included in meta-analysis are listed in Table 2. In these five studies, three constituents appear repeatedly: R. glutinosa root (Sheng Di) (five), S. miltiorrhiza root (Dan Shen) (four), and L. erythrorhizon root (Zi Cao) (four). Each of these plants has received recent research attention for activities of relevance to psoriasis therapy. Rehmannia glutinosa root A recent study reported that an aqueous extract of R. glutinosa root had anti-inflammatory effects via inhibiting inducible nitric oxide synthase (inos), cyclooxygenase-2 and IL-6 36 while another study reported the high free radical scavenging activity of a water extract as due to suppressing the expression of proinflammatory genes, including tumor necrosis factor (TNF)-a, monocyte chemotactic protein-1, interferon inducible protein-10, cyclooxygenase-2, and inos. 37 Catalpol, a major constituent of R. glutinosa root, has been found to suppress inflammation by reducing the expression of proinflammatory mediators, including monocyte chemotactic protein-1, TNF-a, inos, and the receptor for advanced glycation end-products, as well as reducing the transcriptional activation of nuclear factor-jb. 38,39 An in vitro study reported that an aqueous extract of fresh R. glutinosa root inhibited the release of histamine and the production of TNF-a in mast cells. 40 In addition, an extract from steamed R. glutinosa root inhibited IL-1 and TNF-a secretion from mouse astrocytes. 41 Although these experiments were not focused on psoriasis, they indicate that extracts of this plant and its constituent catalpol have anti-inflammatory effects. Salvia miltiorrhiza root This plant and its multiple active constituents have received considerable research attention with regard to anti-inflammatory, antioxidant, antiproliferative effects as well as its protective effects on the liver and cardiovascular system. 42 More specifically, an in vitro study of mouse keratinocytes Table 2 Chinese herbal medicine ingredients used in the five studies included in meta-analysis Author, year Chinese herbal medicine ingredients: Botanical name, part (Chinese name in pin yin) amount Luo, 2010 Angelica sinensis root (Dang Gui) 12 g, Rehmannia glutinosa root (Sheng Di) 30 g, Scrophularia ningpoensis root (Xuan Shen) 15 g, Lithospermum erythrorhizon root (Zi Cao) 9 g, Paeonia veitchii root (Chi Shao) 6 g, Paeonia suffruticosa root bark (Mu Dan Pi) 9 g, Prunus persica seed (Tao Ren) 10 g, Salvia miltiorrhiza root (Dan Shen) 30 g, Isatis indigotica leaf (Da Qing Ye) 15 g, Phellodendron amurense bark (Huang Bai) 15 g, Cyptotympana atrata slough (Chan Tui) 10 g, Saposhnikovia divaricata root (Fang Feng) 10 g, Sophora flavescens root (Ku Shen) 10 g, Glycyrrhiza uralensis root (Gan Cao) 10 g Mao, 2007 For progressive stage: Rehmannia glutinosa root (Sheng Di) 30 g, Smilax glabra root (Tu Fu Ling) 30 g, Sophora japonica flower (Huai Hua) 15 g, Imperata cylindrica root (Bai Mao Gen) 30 g, Lithospermum erythrorhizon root (Zi Cao) 15 g, Paeonia veitchii root (Chi Shao) 15 g, Salvia miltiorrhiza root (Dan Shen) 15 g, Gentiana scabra root (Long Dan Cao) 10 g, Scutellaria baicalensis root (Huang Qin) 10 g, Glycyrrhiza uralensis root (Gan Cao) 10 g For stationary stage: Rehmannia glutinosa root (Sheng Di) 30 g, Smilax glabra root (Tu Fu Ling) 30 g, Angelica sinensis root (Dang Gui) 10 g, Ligusticum wallichii root (Chuan Xiong) 10 g, Sparganium stoloniferum rhizome (San Leng) 10 g, Curcuma phaeocaulis rhizome (Er Zhu) 10 g, Prunus persica seed (Tao Ren) 10 g, Citrus aurantium fruit (Zhi Ke) 10 g, Artemisia capillaris aerial parts (Yin Chen) 20 g, Glycyrrhiza uralensis root (Gan Cao) 10 g Wu, 2009 Astragalus membranaceus root (Huang Qi), Rehmannia glutinosa root (Sheng Di), Lithospermum erythrorhizon root (Zi Cao), Salvia miltiorrhiza root (Dan Shen), Angelica sinensis root (Dang Gui), Asparagus cochinchinensis tuber (Tian Dong), Ophiopogon japonicus rhizome (Mai dong), Smilax glabra root (Tu Fu Ling), Hedyotis diffusa aerial parts (Bai Hua She She Cao), no dosage information Zhang, 2012 Zheng, 2011 Bubalus bubalis horn (Shui Niu Jiao) 30 g, Rehmannia glutinosa root (Sheng Di) 15 g, Scrophularia ningpoensis root (Xuan Shen) 9 g, Lophatherum gracile young leaf (Zhu Ye Xin) 3 g, Ophiopogon japonicus rhizome (Mai dong) 9 g, Salvia miltiorrhiza root (Dan Shen) 6g,Coptis chinensis Rhizome (Huang Lian) 5 g, Lonicera japonica flower (Jin Yin Hua) 9 g, Forsythia suspensa fruit (Lian Qiao) 6 g Bubalus bubalis horn (Shui Niu Jiao) 20 g, Rehmannia glutinosa root (Sheng Di) 10 g, Paeonia suffruticosa root bark (Mu Dan Pi) 10 g, Paeonia veitchii root (Chi Shao) 15 g, Saposhnikovia divaricate root (Fang Feng) 30 g, Sophora flavescens root (Ku Shen)12 g, Dictamnus dasycarpus root bark (Bai Xian Pi) 12 g, Kochia scoparia fruit (Di Fu Zi) 12 g, Lithospermum erythrorhizon root (Zi Cao) 15 g, Cyptotympana atrata slough (Chan Tui) 10 g, Scutellaria baicalensis root (Huang Qin) 12 g, Saposhnikovia divaricata root (Fang Feng) 10 g, Imperata cylindrica root (Bai Mao Gen) 30 g, Atractylodes lancea root (Cang Zhu) 10 g International Journal of Dermatology 2014, 53, ª 2014 The International Society of Dermatology

11 Zhang et al. Chinese herbal medicine for psoriasis Review 1315 indicated that tanshinone IIA, a constituent of S. miltiorrhiza root, inhibited keratinocyte proliferation in a dose- and time-dependent manner by inducing apoptosis via the caspase pathway. 43 Another possible mechanism of action for tanshinone IIA in keratinocytes is via inhibiting the dimerization of the activator protein 1 transcription factor resulting in reduced interferon sensitivity, which in turn could lead to a reduced inflammatory response. 44 Lithospermum erythrorhizon root Shikonin, a bioactive L. erythrorhizon root, has shown an inhibitory effect on angiogenesis 45 and has been investigated for its antiproliferative effects on a number of cell lines, including liver cancer HepG2 cells 46 and lung cancer A549 cells. 47 An in vitro study reported inhibitory effects of L. erythrorhizon extracts on lipopolysaccharide-stimulated production of inflammatory cytokines. 48 In rats, L. erythrorhizon extract inhibited release of histamine induced by compound 48/80 and inhibited activation of nuclear factor-kappa B and I kappa B-alpha degradation. 49 In an atopic dermatitis model in mice, oral L. erythrorhizon extract reduced scratching behavior, serum IgE, and epidermal hyperproliferation. 50 Although these experiments were in cell lines or animal models, they suggest that each of these frequently used plants contains active constituents that could have antiinflammatory and/or antiproliferative effects in humans, and this may account for the benefits in addition to those of acitretin that were reported in the clinical trials included in this review. Future studies should focus on these plants to investigate further their potential as adjunctive therapies in psoriasis vulgaris. Conclusion This systematic review of 17 RCTs on the administration of an oral CHM in addition to a form of pharmacotherapy found a considerable diversity in both the herbal medicines and pharmacotherapies used. When the meta-analyses were restricted to studies that used a well-known pharmacotherapy as the comparator with 60% or greater clinical improvement in psoriasis as the outcome, five studies used oral acitretin, one used topical calcipotriol, and one used topical clobetasol propionate as control interventions. At the end of treatment, there was a benefit for the pooled result of the five studies that compared a combination of CHM plus acitretin versus acitretin alone, and there were no serious AEs reported; however, none of these studies was blind so there is considerable risk of bias in this result. In addition, there was inadequate reporting of longer-term results, so it remains unclear whether the reported effect could be maintained or whether the prolonged use of the CHM in conjunction with acitretin would be safe. Acknowledgments We acknowledge the funding support form Guangdong Provincial Academy of Chinese Medical Sciences, and the International Science & Technology Cooperation Program of. This funding is to support JJY and SPs study in RMIT University. Questions (see answers after references) 1 How many RCTs are included in this review? a25 b20 c17 d15 e10 2 What is the risk of bias assessment results for the included RCTs? a All RCTs were judged as low risk for sequence generation b All RCTs were judged as low risk for allocation concealment c All RCTs were judged as low risk for blinding d All RCTs were judged as low risk for incomplete outcome data e None of above is correct 3 Did any of the RCT use placebo control? a No, none of the included RCTs used a placebo control b Yes, one RCT used a placebo control c Yes, two RCTs used a placebo control d Yes, three RCTs used a placebo control e Yes, four RCTs used a placebo control 4 How many participants were involved in the two arms of the included RCTs? a 1894 b 936 c 2012 d 1542 e How many herbs are used in the included RCTs? a 80 herbs b 70 herbs c 60 herbs d 50 herbs e 40 herbs 6 How many pharmacotherapeutic agents are used in the included RCTs? a15 b12 c10 d8 e6 ª 2014 The International Society of Dermatology International Journal of Dermatology 2014, 53,

12 1316 Review Chinese herbal medicine for psoriasis Zhang et al. 7 How many studies are included in meta-analysis? a 10 studies b 9 studies c 8 studies d 7 studies e 6 studies 8 What are the meta-analysis results? a CHM combined with acitretin appears more effective than acitretin alone using PASI 60 as the outcome measure b CHM combined with acitretin appears more effective than acitretin alone using PASI 75 as the outcome measure c CHM appears more effective than acitretin alone using PASI 60 as the outcome measure d CHM combined with methotrexate appears more effective than methotrexate alone using PASI 60 as the outcome measure e CHM appears more effective than clobetasol alone using PASI 60 as the outcome measure 9 Which of the following plants has shown antiproliferative effects in experimental studies? a Rehmannia glutinosa only b Salvia miltiorrhiza only c Lithospermum erythrorhizon only d Rehmannia glutinosa and Lithospermum erythrorhizon e Lithospermum erythrorhizon and Salvia miltiorrhiza 10 Is adding herbal medicine to conventional pharmacotherapy beneficial for psoriasis vulgaris treatment? a It appears that adding herbal medicine to some conventional pharmacotherapies may be beneficial in the short term for psoriasis vulgaris treatment b Adding herbal medicine to some conventional pharmacotherapies appears beneficial in both the short and long term for psoriasis vulgaris treatment c Adding herbal medicine to conventional pharmacotherapy shows no evidence of benefit for psoriasis vulgaris treatment d Adding herbal medicine to some conventional pharmacotherapies appears beneficial in the long-term treatment for psoriasis vulgaris treatment e Herbal medicine appears superior to conventional pharmacotherapy in the treatment of psoriasis vulgaris treatment in the short term References 1 Raut AS, Prabhu RH, Patravale VB. Psoriasis clinical implications and treatment: a review. Crit Rev Ther Drug Carrier Syst 2013; 30: Cimmino MA. Epidemiology of psoriasis and psoriatic arthritis. Reumatismo 2007; 59(Suppl. 1): Menter A, Gottlieb A, Feldman SR, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. JAm Acad Dermatol 2008; 58: Basavaraj KH, Navya MA, Rashmi R. Stress and quality of life in psoriasis: an update. Int J Dermatol 2011; 50: Sampogna F, Tabolli S, Abeni D. Living with psoriasis: prevalence of shame, anger, worry, and problems in daily activities and social life. Acta Derm Venereol 2012; 92: Levy AR, Davie AM, Brazier NC, et al. Economic burden of moderate to severe plaque psoriasis in Canada. Int J Dermatol 2012; 51: Nast A, Boehncke WH, Mrowietz U, et al. S3 Guidelines on the treatment of psoriasis vulgaris (English version) Update. J Dtsch Dermatol Ges 2012; 10(Suppl. 2): S1 S95. 8 Tang MM, Chang CC, Chan LC, et al. Quality of life and cost of illness in patients with psoriasis in Malaysia: a multicenter study. Int J Dermatol 2013; 52: May BH, Zhang AL, Zhou W, et al. Oral herbal medicines for psoriasis: a review of clinical studies. Chin J Integr Med 2012; 18: Wang G, Liu Y. Traditional Chinese medicine is effective and safe in the treatment of psoriasis. Int J Dermatol 2004; 43: Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions, Version [updated March 2011]. The Cochrane Collaboration, Available from handbook.org Huang JM. Clinical observation of integration of traditional and Western medicine for psoriasis. J Tradit Chin Med 2010: (in Chinese). 13 Wan HL. Clinical observation of integration of Chinese medicine and Western medicine treatment for psoriasis. Guide Med 2012; 10: (in Chinese). 14 Xie Y. Clinical effect of Tuiyin decoction combined with acitretin capsules for psoriasis vulgaris. J Pract Tradit Chin Med 2006; 22: (in Chinese). 15 Luo XF. The observe of clinical therapeutic effect on the treatment of psoriasis with acitretin capsules combined with Chinese herbal compound. Master thesis, Hubei University of Chinese Medicine, 2010 (in Chinese). 16 Mao H, Mao YH. Clinical observation of integration of Chinese medicine and western medicine treatment for psoriasis vulgaris. Healthc Innov 2007; 19: 64. (in Chinese). 17 Chen BY, Tan XL. Diyin tablets combined with Kang Yinxie Fang for the treatment of psoriasis vulgaris. Guangdong Med J 2004; 25: (in Chinese). 18 Jin L, Ma YB, Jiang YS, et al. Topical calcipotriol ointment therapy combination with oral Chinese medicine treatment in plaque psoriasis vulgaris. Chin J Dermatovenereol Integr Tradit West Med 2009; 4: (in Chinese). International Journal of Dermatology 2014, 53, ª 2014 The International Society of Dermatology

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