Abstract
Background
Indigo naturalis is effective against psoriasis. Indigo, indirubin and tryptanthrin, the main active components of indigo naturalis, have anti-inflammatory properties.
Objective
To evaluate the efficacy and safety of indigo naturalis and its active components in the treatment of psoriasis.
Methods
Seven databases were searched for studies of indigo naturalis and its active components for the treatment of psoriasis.
Results
The findings demonstrated a higher response rate in the Chinese herbal medicine (CHM) formula groups than in the control group for Psoriasis Area and Severity Index 60 (PASI60) (Rate difference [RD] = 0.22, p < .0001). Among all adverse events, only the incidence of gastrointestinal adverse reactions was higher in the CHM formula group than in the control group (RD = 0.09, p < .0001). In preclinical in vivo studies, indirubin showed better performance in improving the phenotype of psoriasis-like mice compared to that in controls, including the PASI score (mean difference [MD] = −3.58, p < .0001), epidermal thickness (MD = −29.13, p < .0001), interleukin-(IL) 17 A mRNA expression (MD = −2.27, p = .0066) and IL-23 mRNA (MD = −5.36, p = .01).
Conclusion
Indigo naturalis combined with conventional treatments is useful for treating psoriasis. Indigo naturalis display anti-proliferative, anti-inflammatory and anti-angiogenic effects by regulating the TAK1, JAK3/STAT3, Wnt/β-catenin, Akt/PKB, FAK and AP-1/c-Jun pathway.
Keywords: Psoriasis, indigo naturalis, efficacy, systematic review, cell, Strobilanthes cusia (nees) kuntze
KEY MESSAGES
Indigo naturalis, a Chinese herb and its main active components, indigo, indirubin and tryptanthrin are effective in treating psoriasis.
Indigo naturalis, indirubin, indigo and tryptanthrin have anti-proliferative, anti-inflammatory and anti-angiogenic effects via regulating the TAK1, JAK3/STAT3, Wnt/β-catenin, Akt/PKB, FAK and AP-1/c-Jun pathways.
1. Introduction
Psoriasis is a chronic inflammatory skin disease that affects approximately 3.6% of Caucasians [1]. In 2013, psoriasis treatment in the United States accounted for approximately $35.2 billion [2]. Currently, psoriasis is incurable with interleukin-17A (IL-17A) and IL-23 has been identified as a key driver of its progression [3]. Immune-targeted biological therapies can significantly improve the quality of life of patients with moderate-to-severe psoriasis [4]. However, these have side effects [5] and incur high economic costs. Therefore, effective alternative therapies need to be developed.
Strobilanthes cusia (Nees) Kuntze, a traditional Chinese medicinal plant, has been widely used for the past 1000 years as an antipyretic-alexipharmic drug. Indigo naturalis (IN, Qingdai) is a processed product of the leaves and stems. All the main active components of IN, including indigo, indirubin (IR) and tryptanthrin, have anti-inflammatory effects and regulate the genetic expression of inflammation-related cytokines [6–8].
Although IN is effective against psoriasis, no systematic reviews have been conducted on its therapeutic efficacy or safety. This study aimed to conduct a systematic review and meta-analysis of IN and its active components in the treatment of psoriasis and to summarize their mechanisms of action.
2. Methods and analyses
2.1. Search strategy
Databases such as PubMed, Embase, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, WanFang Database for Chinese Technical Periodicals, VIP Database and SinoMed were searched from 1 January 1970 (inception) to 5 July 2022, for literature on the use of IN and its active components in the treatment of psoriasis. In addition, an article by Nguyen et al. [9], although not available in the above databases, was manually searched for inclusion, owing to its high relevance to the current study and its scientific research methodology.
We combined the medical subject headings and free text words to retrieve all 49 relevant studies. The following keywords were used: ‘Psoriasis’, ‘Psoriases’, ‘Pustulosis of Palms and Soles’, ‘Pustulosis Palmaris et Plantaris’, ‘Palmoplantaris Pustulosis’, ‘Pustular Psoriasis of Palms and Soles’, ‘Indigo Naturalis’, ‘Qingdai compound’, ‘Qingdaisan’, ‘qing dai’, ‘Indigo Naturalis ointment’, ‘Indigo’, ‘Indigo Carmine’, ‘Carmine, Indigo’, ‘Soluble Indigo Blue’, ‘Indigo Blue, Soluble’, ‘Indigotindisulfonate Sodium’, ‘2-(1,3-Dihydro-3-oxo-5-sulpho-2H-indol-2-ylidene)-3- oxoindoline-5-sulphonic acid’, ‘Indigotindisulfonic Acid’, ‘Indigotindisulfonate’, ‘Indigo Disulfonate’, ‘FD and C Blue No. 2’, ‘D and C Blue NO. 6’, ‘Indigo Blue’, ‘Indigotin’, ‘(delta-2,2′-biindole)-3,3′-dione’, ‘indirubin’, ‘indigo red’, ‘tryptanthrine’, ‘indolo(2,1-b)quinazolin-6,12-dione’, ‘6,12-dihydro-6,12-dioxoindole(2,1-b)quinazoline’, ‘indolo (2, 1b) quinazoline-6, 12 dione’, and ‘tryptanthrin.’
2.2. Inclusion criteria
Clinical studies: (1) randomized clinical trials (RCTs), (2) the Psoriasis Area and Severity Index (PASI) score were used as outcome indicators and (3) patients with definite diagnostic standards of psoriasis were included.
Preclinical studies: psoriasis-like mouse models with control comparisons or psoriasis-like cell models with control comparisons.
The exclusion criteria were as follows: (1) case reports, reviews, conferences, repeat studies and scientific or technological achievements, (2) unreasonable setting of the control group.
2.3. Data extraction
Two authors (C-X W and P-P Y) independently screened the literature and extracted data.
Clinical studies: first author, year of publication, sample size, mean or median age of the participants, sex, duration of psoriasis, characteristics of intervention and control groups and information on efficacy and adverse events.
Preclinical studies: First author, year of publication, sample size, characteristics of the animals, including species, sex, weight, intervention characteristics and result indicators.
2.4. Risk of bias assessment
The Cochrane Collaboration tool was used to assess the risk of bias in clinical trials. The Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) was used to assess the risk of bias in preclinical trials. Three reviewers (N-X L, S-H W and Y-T Y) independently assessed the quality of clinical and preclinical studies. If a disagreement presented in the evaluation, the researcher (LL) participated in the discussion to reach a consensus.
2.5. Statistical analyses
R-4.1.3 was used for data analyses. Q-text and I2 statistics were used to test heterogeneity of the data, and the random-effects model was used if I2 > 50%. Rate differences (RD) with 95% confidence intervals (CI) were calculated for dichotomous data and mean differences (MD) with 95% CI were calculated for continuous variables.
3. Results
3.1. Selection of studies
A total of 490 articles were initially retrieved by searching subject headings and free words. Of these, 293 duplicates and irrelevant studies were removed, while 50 case reports, letters, conference papers, commentaries, and reviews were excluded after reading the abstracts and full text. Seventy-five articles were excluded because they were not RCTs, did not include an appropriate outcome, or lacked appropriate comparisons. Five articles had incomplete data. Eighteen articles had no full texts. Finally, 49 articles were included in our meta-analyses, including 26 RCTs and 23 preclinical studies (Supplementary Figure S1).
3.2. Characteristics of included studies
The 26 clinical trials comprised of six interventions in form of decoctions containing IN and Chinese herbal medicine (CHM) formulas with IN as the major herb (IND), topical CHM formulas, such as ointments and oils containing IN (INT), other oral drugs (OOD) including diyin tablets, acitretin, compound aminopeptide tablets, methotrexate and compound glycyrrhizin capsule, light therapy (LT), and other topical therapies (OTT) such as calcipotriol ointment, tacrolimus ointment and placebo (PBO). We selected PASI60 as the primary efficacy outcome. Three studies [10–12] were used to compare the efficacies of IND and OOD. Five studies [13–17] were used to compare the combined use of IND and OOD against OOD alone. Four studies [18–21] compared the combined use of IND and LT against LT alone. Five studies [22–26] compared the combined use of IND, OOD and OTT with that of OOD and OTT alone. One study [27] compared the combined use of INT and OOD with that of OOD alone. One study [28] compared use of INT against placebo. A study [29] was used to compare the efficacy of INT to that of OTT (Supplementary Table S1). Of the total preclinical studies used, seven were in vivo [30–36] and 15 were in vitro studies [6,30,34,36–47]. Five studies [31,33–36] used BALB/c mice, one [30] used IKK2 knockout mice, while another [32] used Hartley guinea pigs. The routes of administration included subcutaneous injection [35,36], gastric filling [33,34] and topical use [30–32]. The dosage forms of IN for external use included oil [32], ointment [30] and micro emulsification (ME) gel [31]. Five studies used an imiquimod-induced (IMQ-induced) psoriasis-like mouse model [31,33–36], while one employed a model of psoriatic lesions induced by propranolol hydrochloride [32]. One study used male mice bearing a tamoxifen-induced (TMF-induced) IKK2 deletion in the epidermis [30].
Five cells lines employed in the systematic review of the vitro experiments included human keratinocytes [30,40,43,44], human immortal keratinocyte (HaCaT) cells [34,36,42,45,47], γδ T cells [34], CD4+ T cells [6,41] and human umbilical vein endothelial cells [37–39]. We prepared a checklist of IN and its main components as well as in vivo and in vitro studies that included access, route of administration, experimental concentration, dose and preparation method (Supplementary Table S2).
3.3. Risk of bias
3.3.1. Clinical studies
Supplementary Figures S2 and S3 show the risks of bias in the 26 studies that were included. Of these, six studies [13,17,21,22,25,48] used the random number table method, while 20 studies [10–12,14–16,18–20,23,24,26–29,49–53] used the random method. Allocation concealment was employed by only one study [48]. Six studies [10,12,15,19,27,29] failed to mention blinding. All studies reported complete results.
3.3.2. Preclinical studies
The SYRCLE tool was used to evaluate the risk of bias in the eight preclinical animal experiments. One study [36] used the random number table method, and three studies [32,34] used the random method. Three studies [32,34,36] provided the baseline data. None of the studies used employed allocation concealment or blinding, suggesting a high risk of bias. One study [36] mentioned a standard diet while another [34] mentioned single-cage feeding. None of the studies mentioned whether blind method was used for animal selection and outcome evaluation. However, all the studies reported bias in the data such as, incomplete outcome data, selective outcome reporting and other sources of bias. Above mentioned factors thus led to the overall quality of the included studies to be relatively low (Supplementary Figure S4).
3.4. Primary outcomes of the clinical studies
3.4.1. PASI60
PASI 60 refers to a 60% reduction in the PASI score of patients and is considered an indicator of the effectiveness of psoriasis treatment. A meta-analyses of 20 clinical trials [10–29] evaluated PASI60 in patients and divided them into seven subgroups. Combined with IN can increase the efficacy of psoriasis treatment (RD = 0.22, 95% CI [0.16; 0.28], p < .0001), IND + OOD and OOD (RD = 0.25, 95% CI [0.16; 0.34], p < .0001, I2 = 0%), IND+LT and LT (RD = 0.16, 95% CI [0.07; 0.25], p < .0005, I2 = 0%), IND+OOD+OTT and OOD+OTT (RD = 0.19, 95% CI [0.11; 0.27], p < .0001, I2 = 0%), INT+OOD and OOD (RD = 0.23, 95% CI [0.07; 0.39], p < .0001), INT and PBO (RD = 0.58, 95% CI [0.42; 0.74], p < .0001). However, the statistical differences between IND and OOD (p = .1556) and INT and OTT (p = .0651) were insignificant, indicating that IN monotherapy, whether systemic or topical, had no difference as compared to that in the control groups. The details have been presented in Table 1.
Table 1.
Subgroup analysis of PASI60 in clinical studies.
| Study | Comparison | Experimental group |
Control group |
Risk difference | p Value | ||
|---|---|---|---|---|---|---|---|
| Events | Total | Events | Total | [95% CI] | |||
| 1. PASI60 | |||||||
| 1.1 IND VS. OOD | |||||||
| Chen et al. [10] | IND VS. OOD | 33 | 61 | 32 | 55 | −0.04 [−0.22; 0.14] | – |
| Liang et al. [11] | IND VS. OOD | 23 | 30 | 15 | 30 | 0.27 [ 0.03; 0.50] | – |
| Wang et al. [12] | IND VS. OOD | 24 | 30 | 16 | 30 | 0.27 [ 0.04; 0.50] | – |
| Subtotal (95% CI) I2 = 67% | 0.15 [−0.06; 0.36] | .1556 | |||||
| 1.2 IND + OOD VS. OOD | |||||||
| Xue et al. [16] | IND + OOD VS. OOD | 28 | 34 | 19 | 34 | 0.26 [ 0.05; 0.48] | – |
| Cai et al. [13] | IND + OOD VS. OOD | 22 | 33 | 10 | 33 | 0.36 0.14; 0.59] | – |
| Wu et al. [15] | IND + OOD VS. OOD | 45 | 60 | 21 | 50 | 0.33 [ 0.15; 0.51] | – |
| Zhang et al. [17] | IND + OOD VS. OOD | 46 | 60 | 38 | 60 | 0.13 [−0.03; 0.30] | – |
| Pang et al. [14] | IND + OOD VS. OOD | 35 | 45 | 25 | 45 | 0.22 [ 0.03; 0.41] | – |
| Subtotal (95% CI) I2 = 0% | 0.25 [ 0.16; 0.34] | <.0001 | |||||
| 1.3 IND + LT VS. LT | |||||||
| Xie et al. [20] | IND + LT VS. LT | 31 | 49 | 24 | 48 | 0.13 [−0.06; 0.33] | – |
| Yang et al. [21] | IND + LT VS. LT | 37 | 58 | 28 | 58 | 0.16 [−0.02; 0.33] | – |
| Ji [18] | IND + LT VS. LT | 35 | 52 | 25 | 52 | 0.19 [ 0.01; 0.38] | – |
| Wang [19] | IND + LT VS. LT | 37 | 44 | 29 | 43 | 0.17 [−0.01; 0.34] | – |
| Subtotal (95% CI) I2 = 0% | 0.16 [ 0.07; 0.25] | .0005 | |||||
| 1.4 IND + OOD + OTT VS. OOD + OTT | |||||||
| Han et al. [22] | IND + OOD + OTT VS. OOD + OTT | 41 | 51 | 30 | 50 | 0.2 [ 0.03; 0.38] | – |
| Yang et al. [21] | IND + OOD + OTT VS. OOD + OTT | 25 | 41 | 20 | 41 | 0.12 [-0.09; 0.34] | – |
| Lin [25] | IND + OOD + OTT VS. OOD + OTT | 45 | 50 | 34 | 50 | 0.22 [ 0.07; 0.37] | – |
| Lin et al. [24] | IND + OOD + OTT VS. OOD + OTT | 29 | 31 | 23 | 31 | 0.19 [ 0.02; 0.37] | – |
| Han et al. [23] | IND + OOD + OTT VS. OOD + OTT | 42 | 48 | 33 | 48 | 0.19 [ 0.03; 0.35] | – |
| Subtotal (95% CI) I2 = 0% | 0.19 [ 0.11; 0.27] | <.0001 | |||||
| 1.5 INT + OOD VS. OOD | |||||||
| Chen [29] | INT + OOD VS. OOD | 50 | 60 | 34 | 56 | 0.23 [ 0.07; 0.39] | – |
| Subtotal (95% CI) | 0.23 [ 0.07; 0.39] | .0053 | |||||
| 1.6 INT VS. PBO | |||||||
| Lin et al. [28] | INT VS. PBO | 36 | 48 | 8 | 48 | 0.58 [ 0.42; 0.74] | – |
| Subtotal (95% CI) | 0.58 [ 0.42; 0.74] | <.0001 | |||||
| 1.7 INT VS. OTT | |||||||
| Chen et al. [29] | INT VS. OTT | 17 | 20 | 12 | 20 | 0.25 [−0.02; 0.52] | – |
| Subtotal (95% CI) | 0.25 [−0.02; 0.52] | .0651 | |||||
| Total (95% CI) I2 =46% | 0.22 [0.16; 0.28] | <.0001 | |||||
Note: PASI60: Psoriasis Area and Severity Index 60.
3.5. Secondary outcomes of clinical studies
3.5.1. PASI
The PASI score, a quantitative tool for evaluating the severity and extent of psoriasis, is calculated by erythema, induration and desquamation and then multiplied by the area affected. We evaluated the PASI scores of patients with psoriasis from 13 studies [11,12,14,17–19,21,23,24,27,28,49,52,53] and concluded that the efficacy of IND was better than that of OOD (mean difference [MD] = −2.31, 95%CI [−3.79; −0.83], p = .0022, I2 = 0%), the effect of IND combined with OOD was better than that of OOD alone (MD = −2.78, 95%CI [−3.65; −1.91], p < .0001, I2 = 0%), that of IND + LT was better than LT alone (MD = −3.54, 95%CI [−3.70; −3.37], p < .0001, I2 = 50%), IND + OOD + OTT was better than OOD + OTT (MD = −2.41, 95%CI [−3.22; −1.60], p < .0001, I2 = 0%) and of INT + OOD was better than OOD alone (MD = −4.38, 95%CI [−6.40; −2.36], p < .0001). In addition, IND and INT were more effective than placebo (p < .0001). However, one study [53] compared INT with betamethasone and concluded a lower clinical response of the prior in comparison with topical betamethasone (MD = 2.99, 95%CI [1.35; 4.62], p = .0003, I2 = 0%) (Table 2).
Table 2.
Subgroup analysis of PASI, PSI and shNAPSI in clinical studies.
| Study | Comparison | Outcomes (mean ± SD) |
Mean difference | p Value | |
|---|---|---|---|---|---|
| Experiment | Control | [95%CI] | |||
| 2. 1 PASI | |||||
| 2.1.1 IND VS. OOD | |||||
| Liang et al. [11] | IND VS. OOD | 3.14 ± 3.57 | 5.45 ± 4.53 | −2.31 [−4.37; −0.25] | – |
| Wang et al. [12] | IND VS. OOD | 3.15 ± 3.67 | 5.46 ± 4.63 | −2.31 [−4.42; −0.20] | – |
| Subtotal (95% CI) I2 = 0% | −2.31 [−3.79; −0.83] | .0022 | |||
| 2.1.2 IND + OOD VS. OOD | |||||
| Zhang et al. [17] | IND + OOD VS. OOD | 16.58 ± 4.90 | 19.47 ± 4.85 | −2.89 [−4.63; −1.15] | – |
| Pang et al. [14] | IND + OOD VS. OOD | 3.81 ± 2.42 | 6.55 ± 2.43 | −2.74 [–3.74; −1.74] | – |
| Subtotal (95% CI) I2 = 0% | −2.78 [–3.65; −1.91] | <.0001 | |||
| 2.1.3 IND + LT VS. LT | |||||
| Yang et al. [21] | IND + LT VS. LT | 3.11 ± 0.52 | 6.78 ± 1.01 | −3.67 [–3.96; −3.38] | – |
| Ji [18] | IND + LT VS. LT | 5.20 ± 0.50 | 8.70 ± 0.60 | −3.50 [−3.71; −3.29] | – |
| Wang [19] | IND + LT VS. LT | 4.45 ± 2.83 | 6.98 ± 2.51 | −2.53 [−3.65; −1.41] | – |
| Subtotal (95% CI) I2 = 50% | −3.54 [−3.70; −3.37] | <.0001 | |||
| 2.1.4 IND + OOD + OTT VS. OOD + OTT | |||||
| Lin et al. [24] | IND + OOD + OTT VS. OOD + OTT | 3.03 ± 1.97 | 5.57 ± 1.93 | −2.54 [−3.51; −1.57] | – |
| Han et al. [23] | IND + OOD + OTT VS. OOD + OTT | 3.14 ± 2.15 | 5.25 ± 4.79 | −2.11 [−3.60; −0.62] | – |
| Subtotal (95% CI) I2 = 0% | −2.41 [−3.22; −1.60] | <.0001 | |||
| 2.1.5 INT VS. OTT | |||||
| Yazdanpanah et al. [53] | INT VS. OTT | 5.80 ± 3.13 | 3.09 ± 2.23 | 2.71 [0.33; 5.09] | – |
| Yazdanpanah et al. [53] | INT VS. OTT | 6.32 ± 2.85 | 3.09 ± 2.23 | 3.23 [0.99; 5.47] | – |
| Subtotal (95% CI) I2 = 0% | 2.99 [1.35; 4.62] | .0003 | |||
| 2.1.6 IND VS. PBO | |||||
| Wang [52] | IND VS. PBO | 2.12 ± 0.07 | 9.64 ± 2.46 | −7.52 [−8.45; −6.59] | – |
| Subtotal (95% CI) | −7.52 [−8.45; −6.59] | <.0001 | |||
| 2.1.7 INT VS. PBO | |||||
| Cheng et al. [49] | INT VS. PBO | 2.64 ± 1.50 | 8.30 ± 4.00 | −5.66 [−8.53; −2.79] | – |
| Subtotal (95% CI) | −5.66 [−8.53; −2.79] | .0001 | |||
| 2.1.8 INT + OOD VS. OOD | |||||
| Chen [27] | INT + OOD VS. OOD | 16.18 ± 4.62 | 20.56 ± 6.28 | −4.38 [−6.40; −2.36] | – |
| Subtotal (95% CI) | −4.38 [−6.40; −2.36] | <.0001 | |||
| Total (95% CI) I2 = 91.4% | −2.66 [−4.05; −1.26] | .0002 | |||
| 2.2 PSI | |||||
| Lin et al. [28] | INT VS. PBO | 2.27 ± 2.68 | 5.98 ± 2.58 | −3.71 [−4.76, −2.66] | – |
| Lin et al. [50] | INT VS. PBO | 6.43 ± 1.35 | 12.85 ± 1.41 | −6.42 [−7.08, −5.76] | – |
| Total (95% CI) I2 = 95% | −5.10 [−7.75, −2.44] | .0002 | |||
| 2.3 shNAPSI | |||||
| Lin et al. [48] | INT VS. PBO | 10.70 ± 6.20 | 15.50 ± 6.20 | −4.80 [−7.94, −1.66] | – |
| Lin et al. [51] | INT VS. OTT | 14.40 ± 8.90 | 20.40 ± 8.50 | −6.00 [−10.20, −1.80] | – |
| Total (95% CI) I2 = 0% | −5.23 [−7.74, −2.72] | <.0001 | |||
Note: PASI: Psoriasis Area and Severity Index; PSI: psoriasis severity index; shNAPSI: single hand nail psoriasis severity index.
3.5.2. PSI
The Psoriasis Severity Index (PSI) score is a sum of the grading for erythema, induration and scaling on a five-point scale (0 = absent, 1 = slight, 2 = moderate; 3 = severe and 4 = very severe), with the maximum score being 12. Meta-analyses of two studies [28,50] evaluated PSI in patients with recalcitrant plaque-type psoriasis, who topically applied either IN or vehicle ointments. The results showed a significant reduction in the PSI scores (MD = −5.10, 95%CI [−7.75, −2.44], p = .0002, I2 = 95%), the details for which have been presented in Table 2.
3.5.3. shNAPSI
The Nail Psoriasis Severity Index (NAPSI), the only validated clinical scale, is a simple and objective tool for the clinical assessment of nail psoriasis. The efficacy of INT was superior to that of placebo or OTT (MD = −5.23, 95% CI [−7.74, −2.72], p < .001, I2 = 0%) (Table 2).
3.5.4. Cytokines and cells
Six clinical studies have described changes in cytokines and immune cells in the serum of patients with psoriasis after IND treatment. The number of CD4+ T cells increased (MD = 4.84, 95% CI [3.6143; 6.07], p < .0001) while that of CD8+ T cells decreased (MD = −4.11, 95% CI [−5.07; −3.15], p < .0001) in the serum of patients compared to serum from control participants, thus increasing the CD4+ T cell/CD8+ T cell ratio (MD = 0.41, 95% CI [−0.30; 0.52], p < .0001). Compared to the control group, patients treated with IND had increased serum IL-4 levels (MD = 5.39, 95% CI [4.55; 6.23], p < .0001, I2 = 0%) and decreased serum IL-8 levels (MD = −4.88, 95% CI [−7.34; −2.41], p = .0001, I2 = 0%). Additionally, IND treatment decreased TNF-α levels (MD = −12.83, 95% CI [−16.76; −8.90], p < .0001, I2 = 0%) and IL-17 (MD = −14.28, 95% CI [−18.30; −10.26], p < .0001, I2 = 41%) in the serum of patients compared to untreated control serum samples; however, no statistically significant change in IL-23 levels was observed compared to the control group (MD = −44.18, 95% CI [−89.23; 0.87], p = .0546, I2 = 98%). Details are presented in Table 3.
Table 3.
Analysis of cells and cytokines in clinical studies.
| Study | Comparison | Outcomes (mean ± SD) |
Mean difference | p Value | |
|---|---|---|---|---|---|
| Experiment | Control | [95%CI] | |||
| 3.1 CD4+ T cell | |||||
| Zhang et al. [17] | IND + OOD VS. OOD | 41.92 ± 3.46 | 37.08 ± 3.39 | 4.84 [3.6143; 6.07] | <.0001 |
| 3.2 CD8+ T cell | |||||
| Zhang et al. [17] | IND + OOD VS. OOD | 24.40 ± 2.65 | 28.51 ± 2.72 | −4.11 [−5.07; −3.15] | <.0001 |
| 3.3 CD4 T + cell /CD8+ T cell | |||||
| Zhang et al. [10] | IND + OOD VS. OOD | 1.72 ± 0.33 | 1.31 ± 0.30 | 0.41 [0.30; 0.52] | <.0001 |
| 3.4 IL-4 | |||||
| Pang et al. [14] | IND + OOD VS. OOD | 22.89 ± 3.15 | 17.22 ± 2.83 | 5.67 [4.43; 6.91] | |
| Lin [25] | IND + OOD + OTT VS. OOD + OTT | 23.01 ± 3.16 | 17.86 ± 2.65 | 5.15 [4.01; 6.29] | |
| Total (95% CI) I2 = 0% | 5.39 [4.55; 6.23] | <.0001 | |||
| 3.5 IL-8 | |||||
| Pang et al. [14] | IND + OOD VS. OOD | 45.81 ± 9.63 | 50.33 ± 9.41 | −4.52 [−8.45; −0.59] | |
| Lin [25] | IND + OOD + OTT VS. OOD + OTT | 46.14 ± 7.92 | 51.25 ± 8.23 | −5.11 [−8.28; −1.94] | |
| Total (95% CI) I2 = 0% | −4.88 [−7.34; −2.41] | .0001 | |||
| 3.6 TNF-α | |||||
| Cai et al. [13] | IND + OOD VS. OOD | 95.20 ± 17.10 | 109.20 ± 16.20 | −14.00 [−22.04; −5.96] | |
| Yang et al. [21] | IND + LT VS. LT | 93.26 ± 11.79 | 105.43 ± 13.97 | −12.17 [−17.77; −6.57] | |
| Xie et al. [20] | IND + LT VS. LT | 94.20 ± 17.40 | 107.20 ± 17.60 | −13.00 [−20.58; −5.42] | |
| Total (95% CI) I2 = 0% | −12.83 [−16.76; −8.90] | <.0001 | |||
| 3.7 IL-17 | |||||
| Cai et al. [13] | IND + OOD VS. OOD | 161.20 ± 17.10 | 182.20 ± 17.80 | −21.00 [−29.42; −12.58] | |
| Yang et al. [21] | IND + LT VS. LT | 95.23 ± 10.14 | 106.72 ± 15.48 | −11.49 [−17.15; −5.83] | |
| Xie et al. [20] | IND + LT VS. LT | 166.80 ± 17.80 | 180.60 ± 18.10 | −13.80 [−21.57; −6.03] | |
| Total (95% CI) I2 = 41% | −14.28 [−18.30; −10.26] | <.0001 | |||
| 3.8 IL-23 | |||||
| Cai et al. [13] | IND + OOD VS. OOD | 203.20 ± 15.80 | 293.60 ± 28.90 | −90.40 [−101.64; −79.16] | |
| Yang et al. [21] | IND + LT VS. LT | 187.25 ± 13.49 | 209.78 ± 16.42 | −22.53 [ −29.03; −16.03] | |
| Xie et al. [20] | IND + LT VS. LT | 192.50 ± 22.70 | 212.50 ± 24.60 | −20.00 [ −30.25; −9.75] | |
| Total (95% CI) I2 = 98% | −44.18 [−89.23; 0.87] | .0546 | |||
3.5.5. Adverse events
Eighteen articles reported adverse events associated with psoriasis treatment, with the most common being gastrointestinal reactions, skin dryness, itching, dry mouth and erythema. These articles were divided into two groups: the external drug group (Supplementary Figure S5) and the systematic drug group (Supplementary Figure S6). Increased gastrointestinal reactions were reported in the systemic drug group compared to the control group (RD = 0.09, 95% CI [0.05; 0.13], p < .0001). However, other side effects in the systematic drug group and all side effects in the external drug group showed no statistically significant differences compared with the control group (Supplementary Figure S5 and S6).
3.6. Primary outcomes of preclinical in vivo studies
3.6.1. Psoriasis area and severity index of IR for psoriasis
One study [34] assessed the total scores in an IR-treated psoriasis mouse model on day 7, IR significantly reduced the total scores compared to those of the controls (MD = −3.58, p < .0001, 95% CI [−4.11; −3.05]). At the same time, the scale (MD = −1.08, p < .0001, 95% CI [−1.26; −0.91]), thickness (MD = −1.19, p < .0001, 95% CI [−1.30; −1.07]) and erythema (MD = −1.31, p < .0001, 95% CI [−1.54; −1.08]) scores displayed improvement compared with those of the controls (Table 4).
Table 4.
Analysis of PASI scores and epidermal thickness in vivo preclinical studies.
| Study | Outcomes (mean ± SD) |
Mean difference | p Value | |
|---|---|---|---|---|
| Experiment | Control | [95%CI] | ||
| 4.1 Total PASI sore | ||||
| Xie et al. [33] − 1 | 2.84 ± 0.60 | 6.59 ± 0.86 | −3.75 [−4.59; −2.91] | – |
| Xie et al. [33] − 2 | 2.99 ± 0.68 | 6.59 ± 0.86 | −3.60 [−4.48; −2.72] | – |
| Xie et al. [33] − 3 | 3.34 ± 1.07 | 6.59 ± 0.86 | −3.25 [−4.35; −2.15] | – |
| Total (95% CI) I2 = 0% | −3.58 [−4.11; −3.05] | <.0001 | ||
| 4.2 Scales | ||||
| Xie et al. [33] − 1 | 0.92 ± 0.24 | 2.06 ± 6.00 | −1.14 [−1.43; −0.85] | – |
| Xie et al. [33] − 2 | 1.02 ± 0.20 | 2.06 ± 6.00 | −1.04 [−1.31; −0.77] | – |
| Xie et al. [33] − 3 | 0.99 ± 0.42 | 2.06 ± 6.00 | −1.07 [−1.47; −0.67] | – |
| Total (95% CI) I2 = 0% | −1.08 [−1.26; −0.91] | <.0001 | ||
| 4.3 Thickness | ||||
| Xie et al. [33] − 1 | 1.08 ± 0.14 | 2.32 ± 0.21 | −1.24 [−1.44; −1.04] | – |
| Xie et al. [33] − 2 | 1.08 ± 0.08 | 2.32 ± 0.21 | −1.24 [−1.42; −1.06] | – |
| Xie et al. [33] − 3 | 1.29 ± 0.20 | 2.32 ± 0.21 | −1.03 [−1.26; −0.80] | – |
| Total (95% CI) I2 = 15% | −1.19 [−1.30; −1.07] | <.0001 | ||
| 4.4 Erythema | ||||
| Xie et al. [33] − 1 | 0.83 ± 0.78 | 2.25 ± 0.34 | −1.42 [−2.10; −0.73] | – |
| Xie et al. [33] − 2 | 0.89 ± 0.19 | 2.25 ± 0.34 | −1.36 [−1.67; −1.05] | – |
| Xie et al. [33] − 3 | 1.06 ± 0.39 | 2.25 ± 0.34 | −1.19 [−1.60; −0.78] | – |
| Total (95% CI) I2 = 0% | −1.31 [−1.54; −1.08] | <.0001 | ||
| 4.5 Epidermal thickness | ||||
| Xie et al. [33] − 1 | 36.10 ± 7.32 | 70.52 ± 5.69 | −34.42 [−41.84; −27.01] | – |
| Xie et al. [33] − 2 | 41.65 ± 4.88 | 70.52 ± 5.69 | −28.87 [−34.87; −22.87] | – |
| Xie et al. [33] − 3 | 45.58 ± 5.69 | 70.52 ± 5.69 | −24.94 [−31.38; −18.50] | – |
| Total (95% CI) I2 = 44% | −29.13 [−34.18; −24.08] | <.0001 | ||
Note: PASI: Psoriasis Area and Severity Index.
3.6.2. Epidermal thickness
Compared to that of the controls, epidermal thickness in psoriasis-like mice was significantly reduced seven days after the IR treatment (MD = −29.13, p < .0001, 95% CI [−34.18; −24.08]) (Table 4).
In a similar comparison, another meta-analyses from a study [9] clarified that IL-22-induced mouse ear thickness was reduced by topical IR treatment (MD = −0.05, p < .0001, 95% CI [−0.07; −0.03]) (Supplementary Table S4).
3.6.3. Cytokine gene expression
Effects of the inflammatory mediators, post the IR treatment, in psoriasis-like mice were assessed by two studies [34,36]. IR significantly reduced the mRNA expression of IL-17A (MD = −2.27, p = .0066, 95% CI [−3.92; −0.63]) and IL-23 (MD = −5.36 [−13.74; 3.03], p = .01, 95% CI [−13.74; 3.03]) in psoriasis-like mice compared to those of the controls. However, no such effects were observed in IL-22 mRNA expression (MD = −18.74, p = .0513, 95% CI [−37.60; 0.11]) (Table 5).
Table 5.
Analysis of cytokines and cytokine genes expression and cells cycle in vivo preclinical studies.
| Study | Outcomes (mean ± SD) |
Mean difference | p Value | |
|---|---|---|---|---|
| Experiment | Control | [95%CI] | ||
| 5.1 IL-17A mRNA | ||||
| Xie et al. [33] | 1.39 ± 0.44 | 2.12 ± 0.16 | −3.18 [−4.13; −2.23] | – |
| Xue [36] | 4.57 ± 0.86 | 3.62 ± 0.27 | −1.50 [−1.72; −1.28] | – |
| Total (95% CI) I2 = 91% | −2.27 [−3.92; −0.63] | .0066 | ||
| 5.2 IL-23 mRNA | ||||
| Xie et al. [33] | 0.89 ± 0.35 | 1.98 ± 0.67 | −1.09 [ −1.83; −0.35] | – |
| Xue [36] | 7.46 ± 1.26 | 17.10 ± 0.94 | −9.65 [−10.74; −8.56] | – |
| Total (95% CI) I2 = 99% | −5.36 [−13.74; 3.03] | .01 | ||
| 5.3 IL-22 mRNA | ||||
| Xie et al. [33] | 8.54 ± 5.24 | 17.32 ± 5.12 | −8.78 [−15.96; −1.60] | – |
| Xue [36] | 23.84 ± 0.92 | 51.87 ± 1.38 | −28.03 [−29.18; −26.88] | – |
| Total (95% CI) I2 = 96% | −18.74 [−37.60; 0.11] | .0513 | ||
| 5.4 G0/G1 phase | ||||
| Liu et al. [45] − 1 | 44.39 ± 1.16 | 33.29 ± 0.92 | 11.10 [9.42; 12.77] | – |
| Liu et al. [45] − 2 | 53.64 ± 1.39 | 33.29 ± 0.92 | 20.35 [18.46; 22.23] | – |
| Liu et al. [45] − 3 | 63.82 ± 1.85 | 33.29 ± 0.92 | 30.52 [28.18; 32.86] | – |
| Total (95% CI) I2 = 99% | 20.63 [9.65; 31.62] | .0002 | ||
| 5.5 S phase | ||||
| Liu et al. [45] − 1 | 42.54 ± 1.16 | 41.85 ± 0.69 | 0.69 [ −0.83; 2.22] | – |
| Liu et al. [45] − 2 | 31.45 ± 0.69 | 41.85 ± 0.69 | −10.40 [−11.51; −9.29] | – |
| Liu et al. [45] − 3 | 24.51 ± 1.39 | 41.85 ± 0.69 | −17.34 [−19.10; −15.59] | – |
| Total (95% CI) I2 = 99% | −9.01 [−19.29; 1.27] | .0858 | ||
| 5.6 TNF-α | ||||
| Li et al. [42]-1 | 1.30 ± 0.10 | 1.55 ± 0.09 | −0.25 [−0.40; −0.10] | – |
| Li et al. [42]-2 | 1.06 ± 0.08 | 1.55 ± 0.09 | −0.49 [−0.63; −0.35] | – |
| Li et al. [42]-3 | 0.90 ± 0.18 | 1.55 ± 0.09 | −0.65 [−0.88; −0.42] | – |
| Nguyen et al. [9] | 14.75 ± 0.64 | 17.08 ± 0.85 | −2.33 [−3.53; −1.13] | – |
| Total (95% CI) I2 = 84% | −0.55 [−0.83; −0.26] | .0002 | ||
| 5.7 IL-6 | ||||
| Li et al. [42]-1 | 1.35 ± 0.21 | 1.68 ± 0.05 | −0.33 [ −0.57; −0.09] | – |
| Li et al. [42]-2 | 0.50 ± 0.16 | 1.68 ± 0.05 | −1.18 [−1.37; −0.99] | – |
| Li et al. [42]-3 | 0.42 ± 0.19 | 1.68 ± 0.05 | −1.26 [−1.48; −1.04] | – |
| Nguyen et al. [9] | 34.74 ± 5.68 | 53.05 ± 5.47 | −18.31 [−27.23; −9.39] | – |
| Total (95% CI) I2 = 94% | −1.01 [−1.65; −0.38] | .002 | ||
3.7. Primary outcome of preclinical studies in vitro
3.7.1. Cell cycle
IR can arrest HaCaT cells in the G0/G1 phase (MD = −20.63, p = .0002, 95% CI [9.65; 31.62]); there was however no evidence to indicate any effect of IR on the S phase of the HaCaT cell cycle (MD = −9.01, p = .0858, 95% CI [−19.29; 1.27]) (Table 5).
3.7.2. Cytokine
IR could significantly decrease the production of TNF-α (MD = −0.55, p = .0002, 95% CI [−0.83; −0.26]) and IL-6 (MD = −1.01, p = .002, 95% CI [−1.65; −0.38]) in IL-22-treated or non-IL-22-treated HaCaT cells (Table 5).
4. Discussion
4.1. Summary of evidence
Our systematic review included 49 studies: 26 clinical trials and 23 preclinical trials. Evidence from 26 clinical trials, involving 1952 participants, showed that decoctions used for psoriasis treatment, containing IN and CHM formulas with IN as the major herb can reduce PASI, PSI and shNAPSI scores. Preclinical studies comprising eight animal experiments on 279 mice and 16 cell experiments involving five cell lines demonstrated that IN, IR, indigo and tryptanthrin had anti-proliferative, anti-inflammatory and anti-angiogenic effects in animal models of psoriasis.
4.2. Limitations
Though clinical research has identified the efficacy of CHM formulations, it has not been substantiated enough by the toxicological and pharmacological studies, quality control of each component, product information of the formulas and authentication methods. Owing to the complex composition of CHM formulations, it is difficult to identify therapeutic and harmful ingredients therein. The follow-up periods of these research were relatively short and rarely focused on disease recurrence or long-term adverse effects, rendering the quality of the clinical trials included in these meta-analyses to be low. Moreover, a comparison between the use of IN alone and the standard treatment for psoriasis is lacking. Finally, most of the included cell experiments reported single and incomplete signaling pathways, which made it difficult to confirm the key targets of the mechanisms of psoriatic IN treatment.
4.3. Implications
A combination with IN can improve the curative effects of conventional treatments used to alleviate psoriasis. These convention treatment strategies involve the use of methotrexate, amino peptide tablets, calcipotriol cream, mometasone furoate and acitretin. However, the curative effect of a single drug is weaker than that of hormones. These adverse effects make IN a complementary treatment option for psoriasis.
The pathogenesis of psoriasis involves multiple processes. Keratinocytes play an important role in the regulation of skin inflammation through the release of proinflammatory cytokines, chemokines and antimicrobials. Two studies have shown that IN, IR and tryptanthrin can reduce the expression of anti-microbial S100A9 peptide, chemokine (C–C motif) ligand 20 (CCL20), IL1β, IL6, IL8, IL23A and tumor necrosis factor-α (TNF-α) cytokines in activated keratinocytes [30,42]. Similarly, Xie et al. reported that IR inhibited the expression of IL1, IL6, IL22, IL23 and IL17A in IMQ-induced psoriasis-like skin lesions [33]. Cheng et al. [30] showed that IN and tryptanthrin differentially reduced the expression of CCL20 chemokine, independent of NF-κB-p65-activation [30]. However, this contradicts the conclusions of Zhao et al. [47], who reported that IR strongly inhibits CCL20 expression and secretion in IL-17A-stimulated HaCaT cells by modulating the mitogen-activated protein kinase kinase kinase 7 (TAK1) signaling pathway, including NF-κB-p65 [47].
The inflammatory cytokine IL-17 plays a critical role in psoriasis pathogenesis. IL-17-secreting cells include T helper 17 cells (Th 17) and γδ T cells. Recent evidence has suggested that innate dermal γδ T cells are the primary cells that produce IL-17 [54–56]. IR can reduce the expression and secretion of IL-17 in IL-1β- and IL-23-induced-γδ T cells via the JAK3/STAT3 pathway [33].
In addition, infiltration of inflammatory cells also plays a crucial role in the pathogenesis of psoriasis. The migration of inflammatory cells from the circulatory system to skin is mediated by cell adhesion molecules. Vascular cell adhesion molecule-1 (VCAM-1) in the endothelium is important for the initial trafficking of memory T cells in psoriatic lesions [57]. IN can inhibit TNF-α-induced VCAM-1 expression, but not of the intercellular adhesion molecule-1 (ICAM-1), in human umbilical vein endothelial cells via inhibition of the AP-1/c-Jun pathway [38]. Another pathological mechanism in the development of psoriasis is the disturbance in epidermal barrier function [58]. IN ameliorates psoriatic plaques by increasing claudin-1 expression and re-establishes the function of tight junctions in human primary keratinocytes [43].
Keratinocyte hyperproliferation plays a pivotal role in the pathogenesis of psoriasis. IN and its main components, IR, indigo and tryptanthrin, exhibit anti-proliferative effects by causing G2/M or G0/G1 cell cycle arrest in epidermal keratinocytes or vascular endothelial cells, targeting proliferating cell nuclear antigen (PCNA), cyclin-dependent kinases (CDKs) and cyclins via multiple signaling pathways. IN and IR, in epidermal keratinocytes, can differentially suppress the expression of cell division cycle 25 B (CDC25B) at both, the mRNA and protein levels [40]. Tryptanthrin arrests the cell cycle at the G2/M phase and inhibits the expression of cyclin A, cyclin B and CDK 1 and 2, by blocking the Akt and focal adhesion kinase (FAK) pathways in human vascular endothelial cells [37]. Another critical cell cycle regulatory protein is PCNA, which traverses the cell cycle from the G1 to S phase. Lin et al. found that PCNA expression was substantially decreased in both IN-treated lesions and cultured keratinocytes in vitro. The major components, IR and indigo, can cause cell cycle arrest at the G0/G1 phase in a dose-dependent manner [44]. Similar results were observed in HaCaT cells treated with IR. IR exerts an anti-proliferative effect by promoting demethylation of Wnt inhibitory factor 1 (wif-1) and suppressing the Wnt/β-catenin signaling pathway, leading to cell cycle arrest at the G0/G1 phase [45].
Moreover, IR can also moderate keratinocyte differentiation. Liu et al. [45] demonstrated that IR could downregulate the mRNA expression levels of involucrin and the transcriptional activation of transglutaminase 1 (TGase 1) and keratin 17 to improve the differentiation of HaCaT cells [45].
Finally, anti-angiogenesis is an important strategy for the treatment of psoriasis. IN and tryptanthrin exert anti-angiogenic effects by inhibiting the migration and tube formation of vascular endothelial cells by blocking the Akt/PKB, FAK [37], or apelin pathways [39] (Figure 1).
Figure 1.
Diagram of the mechanism of indigo naturalis (IN) and its active components in psoriasis treatment using preclinical in vitro analysis. Diagram of the mechanisms of indigo naturalis (IN) and its active components in psoriasis treatment Indirubin (IR) inhibits the hyperproliferation and differentiation of keratinocytes (KCs) and expression of pro-inflammatory mediators. Moreover, IR suppressed the expression of IL-17 in γδ T-cells. IN and tryptanthrin have anti-proliferative and anti-angiogenic effects on vascular endothelial cells. The efficacy of indigo naturalis and its components may be attributed to the regulation of the mitogen-activated protein kinase kinase kinase 7 (TAK1), JAK3/STAT3, Wnt/β-catenin, Akt/PKB, focal adhesion kinase (FAK) and AP-1/c-Jun pathways.
5. Conclusion
Conventional treatment complemented with the use of IN enhances the therapeutic effects of psoriasis. As a single drug, indigo also has good therapeutic effect and few side effects. Multiple cell experiments have identified that IN, IR, indigo and tryptanthrin have anti-proliferative, anti-inflammatory and anti-angiogenic effects, via the regulation of the TAK1, JAK3/STAT3, Wnt/β-catenin, Akt/PKB, FAK and AP-1/c-Jun pathways.
Supplementary Material
Funding Statement
This work was sponsored by the National Natural Science Foundation of China (No. 81874470), Xinglin Scholar, Shanghai University of Traditional Chinese Medicine (No. RY411.14.12), National Natural Science Foundation of China (No. 82074427), Traditional Chinese Medicine Research Program of Hebei Provincial Administration of Traditional Chinese Medicine – the clinical research of Indigo Naturalis ointment in the treatment of blood-fever psoriasis (No. 2020329), Key Discipline Construction Project of Shanghai’s Three Year Action Plan for Strengthening the Construction of Public Health System (No. GWVI-11.1-24), High-level Chinese Medicine Key Discipline Construction Project (Integrative Chinese and Western Medicine Clinic) of National Administration of T CM (No. zyyzdxk-2023065), Shanghai 2021 "Science and Technology Innovation Action Plan" Medical Innovation Research Special Project (No. 21Y21920102), Project "Aurora Program" (No. 22SG41).
Author contributions
Chunxiao Wang contributed to data curation, methodology, writing the original draft and revision of the paper for important intellectual content.
Panpan Yang contributed to data curation, methodology, writing the original draft and revision of the paper for important intellectual content.
Jiao Wang contributed to data curation and revision of the paper for important intellectual content.
Liu Liu contributed to data curation and revision of the paper for important intellectual content.
Jiale Chen contributed to analysis and interpretation of data for the work.
Xiaoce Cai contributed to validation and revision of the paper for important intellectual content.
Miao Zhang contributed to data analysis and revision of the paper for important intellectual content.
Naixuan Lin contributed to article quality assessment and revision of the paper for important intellectual content.
Sihan Wang contributed to article quality assessment, visualization and revision of the paper for important intellectual content.
Yuanting Yu contributed to article quality assessment and revision of the paper for important intellectual content.
Linge Li contributed to the conception and design of the study and the final approval of the version to be published.
Xin Li contributed to the design of the study, conceptualization, methodology, funding support and final approval of the version to be published.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
The authors confirm that the data supporting the findings of this study are available within the article.
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