Efficacy of combining oral Chinese herbal medicine and NB-UVB in treating psoriasis vulgaris: a systematic review and meta-analysis

Background The combination of a Chinese herbal medicine (CHM) bath and narrowband ultraviolet B (NB-UVB) improved the efficacy of NB-UVB treatment of psoriasis vulgaris, but bath therapy is inconvenient. Oral CHM plus NB-UVB has been tested in clinical practice. This study aims to evaluate whether adding oral CHM could be beneficial for NB-UVB therapy by a systematic review and meta-analysis. Methods Nine English and Chinese databases were searched from their inception to April 2014. Randomized controlled trials (RCTs) comparing the combination of orally administered CHM and NB-UVB with that of CHM placebo and NB-UVB or NB-UVB alone for treating psoriasis vulgaris and reporting Psoriasis Area Severity Index (PASI) outcomes were included. A systematic review, meta-analysis, risk of bias assessment and the GRADE assessment were conducted in accordance with Cochrane Collaboration methodology to assess the evidence for efficacy outcome. Data were analyzed in RevMan5.2. Results Eighteen eligible RCTs (n = 1416) were included for systematic review, and 17 (n = 1342) of them were included in meta-analysis. Risk of bias in terms of blinding was high and so was in publication bias. Quality of evidence was low according the GRADE assessment. PASI-60 or above [risk ratio (RR) = 1.35, 95 % confidence interval (CI) 1.26–1.45, I2 = 5 %, number needed to treat = 4.27] and PASI-90 or above (RR = 1.71, 95 % CI 1.45–2.01, I2 = 0 %, number needed to treat = 5.92) were higher in the intervention group. The combination treatment conferred a 24 % benefit of PASI-60 or above (83 vs 59 %, RR = 1.35, 95 % CI 1.26–1.45, P < 0.01). The incidence of NB-UVB-induced adverse events was lower in the intervention group (95/464 vs 123/428, RR = 0.66, 95 % CI 0.46–0.96, P < 0.01). Mild gastrointestinal reactions (2.87 %) and liver function impairments (0.68 %) were reported in the intervention group. No serious adverse events were reported. Conclusion The orally administrated CHM combined with NB-UVB in treating psoriasis vulgaris showed improved efficacy but quality of evidence was low. Electronic supplementary material The online version of this article (doi:10.1186/s13020-015-0060-y) contains supplementary material, which is available to authorized users.


Background
Psoriasis is a common, chronic and recurrent inflammatory skin disease with a global prevalence of 3-4 % [1]. The most common form, psoriasis vulgaris, affects 80-90 % of patients with psoriasis [2]. Ultraviolet-based therapies including psoralen plus ultraviolet A (PUVA), narrowband ultraviolet B (NB-UVB) and broad-band ultraviolet B (BB-UVB) are effective treatments for psoriasis vulgaris. There is an increased risk of developing skin cancer following PUVA therapy [3,4], although NB-UVB is more effective than BB-UVB and less effective than PUVA. Therefore, NB-UVB is preferred in the clinical management of psoriasis vulgaris [3,5]. Because the clearance rate of NB-UVB treatment was reported in 51-75 % [6], adjuvant treatments are used to improve the effectiveness. Chinese herbal medicine (CHM) has been used for treating psoriasis vulgaris in China. The combination of a CHM bath and NB-UVB was beneficial in psoriasis vulgaris patients [7], but this approach has limitations in practice because a 30-min bath was required prior to each NB-UVB session. Therefore, the combination of oral CHM and NB-UVB has been used in clinical practice for treating psoriasis vulgaris [8]. However, it is still unclear if oral CHM combined with NB-UVB is beneficial for psoriasis vulgaris treatment.
This study aims to evaluate whether oral CHM could provide an added beneficial effect on NB-UVB therapy by a systematic review and meta-analysis.

Search strategies
Nine English and Chinese electronic databases, namely, the PubMed, Embase, CINAHL, CENTRAL, AMED, China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature (CBM), Chinese Science Journals Full Text (CQVIP) and Wanfang databases, were searched from their inceptions to April 2014. Search terms were grouped in three categories: (1) condition (psoriasis); (2) intervention (CHM, acupuncture, moxibustion, and other traditional Chinese medicine therapies); and (3) study type (randomized controlled trials), adjusted for each database ( Table 1). The cited references of review articles were searched to identify additional studies.

Study selection criteria
Randomized controlled trials (RCT) that compared orally administered CHM plus NB-UVB with CHM placebo plus NB-UVB or NB-UVB alone for psoriasis vulgaris were selected. The Psoriasis Area Severity Index (PASI) was used in clinical trials for outcome measurement following psoriasis treatment. The PASI measures the redness, thickness and scaling of the lesions and the area of involvement, with a total score ranging from 0 to 72. Reduction of disease severity was assessed based on the percent change in PASI score. PASI-75, referring to a 75 % reduction in PASI, was considered effective in psoriasis treatment [6]. Only studies reporting PASI scores as an outcome were included. Studies were excluded if they met the following exclusion criteria: (1) participants had comorbidities; (2) CHM products included Western pharmaceuticals; and (3) there were co-interventions that used anti-psoriatic drugs or Chinese medicine treatments other than oral CHM.

Data extraction and quality assessment
Two authors (LY, CZ) independently extracted and crosschecked data using a pre-defined sheet including: study location, setting, participants, sample size, treatment duration, intervention details, dropouts, outcome measures and adverse events (AE). If data were incomplete or appeared incorrect, attempts were made to contact the authors to request additional information or clarifying data. LY and CZ conducted risk of bias assessments independently using the Cochrane Collaboration tool for assessing risk of bias [9]. The grades of recommendation, assessment, development and evaluation (GRADE) approach was used to assess the quality of the evidence for individual outcomes, considering risk of bias, heterogeneity, directness of evidence, precision of effect estimation, and risk of publication bias. Disagreements were resolved by discussion with the two other authors (XG, AZ).

Data analysis
Meta-analysis was performed in RevMan5.2. Risk ratios (RR) with 95 % confidence intervals (CI) for dichotomous data and mean differences (MD) with 95 % CIs for continuous data were reported. Data were pooled to estimate the effect size by the random-effects model [9]. Subgroup analysis was performed according to treatment duration, baseline severity, the CHM formulas and main formula ingredients. Sensitivity analysis was performed taking account of the risk of bias to assess the reliability of the pooled results. Dropouts or withdrawals were considered ineffective cases in an intention-to-treat (ITT) analysis to obtain a conservative estimation. Publication bias was assessed by funnel plots and Egger's linear regression test. An asymmetrical funnel plot or P < 0.05 in Egger's test indicated a publication bias.

Description of the included studies
The 18 included trials, involving 1416 participants with psoriasis vulgaris, were conducted in hospitals in China and published in Chinese from 2004 to 2014. Characteristics of the included studies are summarized in Table 2. All included studies evaluated oral CHM added to NB-UVB vs NB-UVB alone, and six [8,13,14,18,19,22,24] were three-arm trials that included a comparison with oral CHM alone (not analyzed in this study). A placebo was not used in any included study. Two studies used disease severity as one of the inclusion criteria. Fu et al. [11] recruited psoriasis vulgaris participants with an affected body surface area (BSA) >10 % and Sheng et al. [19] recruited psoriasis vulgaris participants with an affected BSA >10 % and PASI score ≥10. Ten studies reported mean PASI score at baseline. The mean PASI scores were <10 in two studies [10,17], >20 in one study [16], and ranged from 14.32 to 19.19 in the remaining seven studies [8,14,15,18,19,22,26]. Eight studies recruited psoriasis vulgaris participants targeting specific Chinese medicine patterns [8,10,15,16,21,22,25,26].

Interventions
All studies reported that NB-UVB phototherapy was consistently prescribed to intervention groups and control groups. However, there was variation across studies in terms of the initial dosage, dosage increment regimen, treatment frequency and total number of treatment sessions. Most of the studies applied phototherapy two to three times per week for 10-29 treatment sessions in total.

Treatment and follow-up durations
Sun et al. [20] only reported the total number of phototherapy treatment sessions. The treatment durations of the other 17 studies ranged from 4 to 12 weeks, and ten studies were of 8 weeks (2 months).

Outcome measures
Seventeen of the 18 studies reported the numbers of participants who achieved PASI-95 or PASI-90, and PASI-60 (at least 95, 90, 60 % reduction in PASI), with reference to the Consensus of Diagnosis and Treatment of Psoriasis Vulgaris with Integrative Medicine [27]. One study reported PASI-95 and PASI-70 [16]. As PASI-50 was taken as the minimum clinically meaningful improvement [6,28], PASI-60 and PASI-70 were conservatively pooled as PASI-60 to analyze the effect of the combination of oral CHM and NB-UVB. Four studies reported the relapse rates at the end of the follow-up [10,11,18,23], but the definitions of relapse were not stated.

Dropouts and withdrawals
Liu and Sheng [13] reported that one participant in the treatment group and two in the control group were excluded after randomization because of comorbidities, and there were five dropouts in the treatment group and four dropouts in the control group for low compliance. Yan et al. [24] reported one withdrawal in the NB-UVB group owing to AEs, but a phototoxicity reaction was not observed. No dropout was reported in the other 16 studies.

Overall efficacy
One study was not included in the meta-analysis, because the outcome measures were PASI-25 and PASI-10 [25]. This study reported that the effect rate was much higher in the combination group than in the NB-UVB group in terms of PASI-25 (78.4 vs 8.1 %). The results of the remaining 17 studies were pooled to estimate the efficacy of the combination treatment.

PASI-60 and above
The mean percentage of participants who achieved PASI-60 at the end of treatment was 83 % in the combination group and 59 % in the NB-UVB group. PASI-60 was significantly higher in the combination group than in the NB-UVB group [ Fig. 2    T: Nausea, loose stools at the beginning of treatment (12) All studies provided NB-UVB for all participants in both treatment group and control group T treatment group, C control group, NS not-stated, CM Chinese medicine, NS not-stated, BH blood heat, BS blood stasis, BD blood dryness, WH wind heat, g gram, NB-UVB narrow-band ultraviolet B, MED minimal erythema dose, qod every 2 days, ALT alanine aminotransferase, AST anti-aspartate aminotransferase 1.26-1.45, P < 0.01, I 2 = 5 %; number needed to treat (NNT) = 4.27]. The most common treatment duration of the included studies was 2 months. Subgroup analysis showed that the pooled results were consistent between studies with 4-6 weeks treatment (five studies, RR = 1.38, 95 % CI 1.22-1.55, P < 0.01, I 2 = 0 %) and studies with 8-12 weeks treatment (12 studies, RR = 1.34, 95 % CI 1.23-1.47, P < 0.01, I 2 = 16 %). For the seven studies that included participants with moderate to severe psoriasis, the result for PASI-60 was similar to that for the total pool (RR 1.35, 95 % CI 1.17-1.56, P < 0.01, I 2 = 45 %).
The most common herb combination used was R. glutinosa, A. sinensis and S. glabra. When the studies using this herb combination were pooled, the result was consistent with the result of the total pool (Table 3), but with moderate heterogeneity (six studies, RR = 1.31, 95 % CI 1.16-1.54, P < 0.01, I 2 = 22 %). Of these six studies, one study [8] prescribed three different formulas targeting three different Chinese medicine patterns, and the above three-herb combination was only included in one of the formulas. However, PASI-60 was not reported separately according to the different formulas. Therefore, the data reported did not represent the outcome of the particular formula which contained the three common herbs. When this study was excluded, the result showed a superior effect for the combination treatment without heterogeneity (RR = 1.37, 95 % CI 1.22-1.54, P < 0.01, For the five studies judged low risk on sequence generation, the result (RR = 1.39, 95 % CI 1.23-1.58, P < 0.01, I 2 = 0 %) was consistent with that for the total pool.

Post-follow-up relapse rate
The mean relapse rate of the three studies that followed participants who achieved PASI-90 was 11 % in the combination group and 60 % in the NB-UVB group 3 months-1 year after treatment. Because the definition of relapse was unclear and there were different follow up durations, meta-analysis of these studies was not performed.

Adverse events
All studies reported AEs (Table 2). Zhong et al. [26] only reported AEs in the combination group, and three studies [18,21,24] reported skin reactions but did not mention which group these occurred in. One participant withdrew because of a phototherapy AE [24]; the other withdrawals were not associated with AEs. All AEs reported in the NB-UVB groups were skin reactions, with a mean rate of 31.58 % (8-80 %). AEs reported in the combination groups were skin reactions, gastrointestinal reactions and elevated liver enzymes. The total AE rate (24.42 %) in the combination groups was a little lower than that in NB-UVB groups. In addition, combination treatment lowered the incidence rate of skin reactions including pruritus, skin dryness, erythema, blistering and hyperpigmentation  distension and stool change, were reported in the combination groups (21/732, 2.87 %) [12-14, 16, 17, 26]. Five cases of elevated liver enzymes were reported (5/732, 0.68 %). One case returned to normal within 1 month without additional treatment [12], three returned to normal by reducing the dosage of the CHMs [17], and the outcome was not reported for one [14]. The relationships between the AEs and the interventions were not further discussed in any study. No severe AE was reported.

Risk of bias assessment
Risk of bias assessments are presented in Fig. 4. Attempts were made to contact the original authors to obtain further information on 13 studies but the authors of 12 studies could not be reached and the author of one study refused to provide the further information we requested; therefore, risk of bias assessments were based on the published texts. For "sequence generation", five studies that used random number tables (a table of random numbers is available in statistics textbooks or generated by computer) [14,16,17] and drawing lots (including cointossing, dice-throwing, or card-shuffling) [13,19] were assessed as "low risk", and the others were assessed as "unclear". All studies were assessed as "unclear" for "allocation concealment" owing to the lack of information. All studies were assessed as "high risk" for "blinding of participants and research personnel", because all studies used an add-on therapy and a placebo was not used for the CHM in any study. The blinding of outcome assessors was judged "unclear" because information was not provided.
One study [24] had one withdrawal in the NB-UVB group, and it was assessed as "low risk" for "incomplete outcome data", because the proportion of missing data was not enough to have an impact on the effect estimate. The amount of missing outcome data in one study [13] was 12.5 % and ITT analysis was not performed, so this study was assessed as "high risk" for "incomplete outcome data". The others were assessed as "unclear". All studies were "low risk" for "selective reporting" because all studies reported the outcomes pre-specified in the methods. All studies were assessed as "low risk" for "other bias", which refers to the inappropriate influence of funders.

Publication bias
Asymmetrical funnel plots and significant Egger's test (t = 3.88, P < 0.01) indicated potential publication bias in favor of more positive results for the smaller studies (Fig. 5).

Quality of evidence
Owing to defects in study design and the risk of publication bias, the quality of evidence was downgraded to low according to the GRADE system (Table 4).

Efficacy
The combination of oral CHM and NB-UVB was more effective than NB-UVB alone in achieving PASI-60

Adverse events
Skin reactions such as pruritus and erythema were the most commonly reported AEs following combination treatment with oral CHM plus NB-UVB, and were the same as for NB-UVB phototherapy [8]. The combination treatment might lower incidence rates of NB-UVB-associated AEs after 8-12 weeks of treatment. Occasional mild gastrointestinal reactions (2.87 %) and rare liver function impairment (0.68 %) were reported in the combination group. All gastrointestinal reactions associated with oral CHM administration were transient and required no additional treatment. Liver function impairment presented as elevated liver enzymes. The studies did not discuss whether the impairment was caused by oral CHM administration, but three of the five participants returned to normal following a reduction in the dosage of CHMs, which suggested that the liver function impairment might be associated with the oral CHMs.
Overdose might be a factor leading to AEs. The dosages of ten herbs, Polygonum multiflorum (he shou wu), R. glutinosa, S. miltiorrhiza, Dictamnus dasycarpus (bai xian pi), Curcuma zedoaria (e zhu), Sophora japonica (huai hua), Scolopendra (wu gong), Bombyx batryticatus   [29]. The latest information bulletin on drug adverse reactions published by the China Food and Drug Administration reported that P. multiflorum and products containing this plant might be associated with liver function impairment [30], and that overdose and long-term usage could increase the risk of adverse reactions.

Anti-psoriatic actions of NB-UVB
Suppression of epidermal hyperproliferation by inhibition of keratinocyte nuclear DNA synthesis is an important mechanism of action of UVB in the treatment of psoriasis [31]. UVB also has anti-inflammatory effects, with inhibition of T cell activation, induction of T cell apoptosis and reduction of the release of a variety of proinflammatory cytokines [6].

Anti-psoriatic actions of herbal medicines
Extracts, compounds or both, of all of the five herbs commonly used in multiple studies, exhibited antiinflammatory effects [32]. In a guinea pig ear model of a psoriasis-like lesion induced by propranolol, parakeratosis pathological changes were significantly alleviated and epidermal proliferation was inhibited by catapol treatment (a major compound of R. glutinosa) [33], but an extract of R. glutinosa did not show an anti-proliferative effect on human epidermal keratinocytes (HaCaT cells) in vitro [34]. S. miltiorrhiza showed effects on inflammation, proliferation and angiogenesis [35]. In psoriasis-like lesions in guinea pig ears induced by topical propranolol, injection of angelica polysaccharide (a compound in A. sinensis) increased keratinocyte apoptosis [36] and decreased the expression level of proliferating cell nuclear antigen [37]. S. glabra exhibited anti-inflammatory effects and antitumor effects, and inhibited cellular immunity [38]. Anti-proliferative effects of S. glabra were observed in an in vivo study using a mouse vaginal epithelium model and a mouse tail model [39], but there was a negative result observed in an in vitro study using the HaCaT cell line [34]. Glycyrrhetinic acid (a compound in G. uralensis) had a dose-dependent anti-proliferative effect [40].

Synergetic interaction between NB-UVB and herbal medicine
Psoralen in combination with NB-UVB was more effective than NB-UVB alone [41]. Herbs with a high content of psoralen such as Psoralea corylifolia (bu gu zhi) [42] were not used in the included studies. Saposhnikovia divaricata (fang feng), which was used in three studies, contains psoralens such as 5-methoxypsoralen [43]. A. sinensis, which is used in 11 studies, and other Angelica species contain coumarins with photosensitising effects [44]. However, studies are required to examine the effects of combining coumarin-containing herbs and NB-UVB. The combination treatment reduced the incidence of NB-UVB-induced AEs. Several herbal medicines showed protective effects against UVB-induced skin damage and can relieve pruritus. Survival of normal HaCaT cells pretreated with a water extract of S. miltiorrhiza prior to UVB exposure was significantly higher than that of cells without pre-treatment [45]. In addition, S. miltiorrhiza showed anti-inflammatory effects by reducing secretion of TNF-α and IL-1β. Similar results were found in research on Scutellaria baicalensis (huang qin) and Ligusticum chuanxiong (chuan xiong) [46]. Licoflavone and glycyrrhizin (compounds from G. uralensis), exhibited photo-protective effects on HaCaT cells irradiated by UVB radiation [47], and UV protective effects for glycyrrhizin and extracts of S. baicalensis and S. divaricata were reported [48]. In a guinea pig foot pruritus model induced by histamine phosphate treatment, catapol (a compound in R. glutinosa) significantly relieved pruritus [33].

Strengths and limitations of this meta-analysis
The 17 studies included in the meta-analysis were comparable in that they assessed a CHM combined with NB-UVB compared with NB-UVB treatment alone, with the difference in PASI score as an outcome. Although the meta-analysis results for the subgroups and sensitivity analyses tended to be consistent with those for the total pool, in terms of the quality of the evidence, a number of issues led to this being downgraded to low. Because none of the studies used a placebo for the CHM in the control arm, blinding of participants could not be achieved. Consequently, any placebo effect could not be distinguished from a genuine add-on biological therapeutic effect. Sequence generation was unclear in 13 studies; we are not sure whether these studies were truly randomized. The asymmetrical funnel plot showed that the smaller studies reported more positive results, suggesting that there might be a publication bias.
Other issues that may impact upon the interpretability of the results were variability in the severity of psoriasis in the participants, the duration and dosage of the NB-UVB and CHM treatments, and variability in the composition and quality of the CHMs. It was not feasible to explore all of these issues owing to limitations in the available data, but the sub-group analyses that were undertaken were consistent with the PASI-60 results for the total pool. Additionally, all included studies were conducted in China and the samples were restricted to