Efficacy and safety of curcumin in psoriasis: preclinical and clinical evidence and possible mechanisms

Background: Psoriasis is a chronic and immune-mediated inflammatory skin disease. Many studies have shown that curcumin (CUR) has strong anti-inflammatory effects and can improve psoriasis; however, its efficacy and safety have not been confirmed, and the specific mechanism remains to be elucidated. Objective: To evaluate the efficacy, safety, and possible mechanisms of CUR in the treatment of psoriasis. Methods: The Cochrane Library, Embase, PubMed, Web of Science, China National Knowledge Infrastructure, Wanfang, and VIP (China Science and Technology Journal Database) were systematically searched for clinical trials and preclinical studies on the use of CUR in psoriasis treatment. All databases were searched from inception to January 2022. The meta-analysis was performed using RevMan 5.3 software. Results: Our meta-analysis included 26 studies, comprising seven clinical randomized controlled trials and 19 preclinical studies. A meta-analysis of clinical trials showed that both CUR monotherapy and combination therapy improved Psoriasis Area and Severity Index (PASI) scores in patients compared to controls (standard mean difference [std.MD]: −0.83%; 95% confidence interval [CI]: −1.53 to 0.14; p = 0.02). In preclinical studies, CUR showed better performance in improving the phenotype of psoriatic dermatitis mice compared to controls, including total PASI score (std.MD: 6.50%; 95% CI: 10.10 to −2.90; p = 0.0004); ear thickness (p = 0.01); and the expression of inflammatory cytokines such as interleukin (IL)-17, tumor necrosis factor (TNF)-α, IL-17F, and IL-22 (p < 0.05). In cell studies, CUR inhibited cell proliferation (p = 0.04) and the cell cycle (p = 0.03) and downregulated the inflammatory cytokines IL-6 and IL-8 (p < 0.05). Conclusions: CUR has excellent efficacy and broad potential to treat psoriasis in multiple ways. Its use also plays a crucial role in improving the psoriasis phenotype and reducing the inflammatory microenvironment. In conclusion, our findings suggest that CUR alone or in combination with other conventional treatments can effectively treat psoriasis.


Introduction
Psoriasis is an immune-mediated chronic inflammatory skin disease that affects 2%-3% of all individuals worldwide (Kopp et al., 2015). It typically presents as well-circumscribed, erythematous, and itchy plaques covered with silvery scales that can coalesce and cover large skin areas. Common sites affected by psoriasis include the trunk, extensor surfaces of the extremities, and scalp (Boehncke and Schön, 2015). The pathogenesis of psoriasis involves many factors, including immune abnormalities (Lowes et al., 2014), inflammatory activation (Rendon and Schäkel, 2019), cell proliferation and apoptosis (Shi et al., 2019), and neural mediators (Harvima and Nilsson, 2012). But its pathogenesis remains to be fully elucidated.
Psoriasis is characterized by epidermal keratinocyte (KC) hyperproliferation, abnormal differentiation and dermal inflammatory cell infiltration. IL-23/IL-17 axis is a key link in the pathogenesis of psoriasis. Triggering factors act on keratinocytes, causing activation of macrophage and dendritic cells that stimulate T H 17 to produce pro-inflammatory cytokines, exacerbating the inflammatory response in psoriasis (Rivas Bejarano and Valdecantos, 2013;Fan et al., 2015;Griffiths et al., 2021). The current treatments for psoriasis include immunosuppressants (cyclosporine A and tacrolimus), vitamin D analogs, topical corticosteroids, retinoids, oral methotrexate, and cyclosporine, all of which have limitations in terms of treatment response and adverse effects (Deng et al., 2016). Biological drugs include secukinumab, which targets interleukin (IL)-17A; ustekinumab, which targets IL-12/IL-23; and infliximab, which antagonizes tumor necrosis factor (TNF)α. Biologics are costly and may lose potency with prolonged use (Egeberg et al., 2018;Armstrong and Read, 2020). Therefore, complementary and alternative treatments for psoriasis need to be studied.
However, the efficacy and mechanism of CUR in the treatment of psoriasis have not been fully elucidated. Therefore, we aimed to systematically review all published reports related to preclinical studies and clinical trials on the use of CUR in psoriasis treatment, as well as to quantitatively analyze its therapeutic effects and possible therapeutic targets from a mechanistic perspective.

Data sources and searches
The following electronic databases were searched: Cochrane Library, Embase, PubMed, Web of Science, China National Knowledge Infrastructure, Wanfang, and VIP (China Science and Technology Journal Database). Studies published in English and Chinese were searched in the databases. All databases were searched from inception to January 2022. The following MeSH (Medical Subject Headings) terms were used as search keywords to find studies that examined the effects of turmeric (Curcuma longa) or CUR on psoriasis: "curcumin," "curcuma," "turmeric," "Curcuma domestica," "Curcuma longa," "psoriasis," and "psoriases."

Article evaluation and selection
Two independent reviewers (SZ and JW) screened the articles. In the first screening, related articles were identified from the titles and abstracts, and relevant articles were retrieved in full text and validated for inclusion in the systematic review. A third reviewer (LL) independently validated the selected articles.

Eligibility criteria for studies included in this review
All eligible clinical and preclinical studies were included in this systematic review. Randomized controlled trials that used CUR or CUR-related preparations, CUR-treated psoriasis-like mouse models with control comparisons, or psoriasis-like cell models with CUR interventions and control comparisons were included in this review. The exclusion criteria were articles lacking primary data, review articles, and studies published only in abstract form. Duplicate studies, cohort studies, metaanalyses, and conference abstracts were also excluded. A flowchart of the article selection process is shown in Figure 1.

Data collection and quality assessment
Basic information about the study was extracted from each article, comprising article title, year of publication, study design, sample size, mean or median age of the participants, sex, intervention of the experimental group and the control group, and study outcome. The Cochrane Collaboration tool for assessing risk of bias was used for the assessment of the risk of bias in clinical trials. The SYRCLE (Systematic Review Centre for Laboratory Animal Experimentation) risk-of-bias tool, which is based on the Cochrane Collaboration risk-of-bias tool, was used to judge the quality of animal studies (low, high, or unclear risk of bias) (Hooijmans et al., 2014;Liu et al., 2021).

Statistical methods
Statistical analysis was performed using RevMan (version 5.3; The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark). Standard mean differences (std.MDs) with 95% confidence intervals (CIs) were calculated for continuous variables, and odds ratios (ORs) with 95% CIs were calculated for binary variables. Heterogeneity was assessed Frontiers in Pharmacology frontiersin.org 03 using I 2 statistics. To analyze the possible reasons for heterogeneity, we conducted a subgroup analysis. When I 2 >50%, we used the random-effects model to evaluate the overall effect; otherwise, the fixed-effects model was used (Qu, 2018).

Results
3.1 Literature search and study characteristics 3.1.1 Literature search A total of 398 relevant articles were identified by searching for subject headings and free words. After the removal of duplicates, 312 articles remained. 316 irrelevant articles were excluded by reading titles and abstracts. After the full-text assessment, 47 articles were excluded because they were not randomized controlled trials, did not include an appropriate comparator, or lacked usable data. Finally, 26 studies (seven clinical studies and 19 preclinical studies) were included in our systematic review and meta-analysis.

.1 Psoriasis area and severity index of CUR alone and CUR combination therapy for psoriasis
The PASI score, a gold standard indicator of psoriasis severity, was the primary outcome measure in the included clinical studies. Calculation of the PASI score mainly involves the evaluation of erythema, infiltration, and scaling. A meta-analysis of four studies (Bnys et al., 2015;Carrion-Gutierrez et al., 2015;Bahraini et al., 2018;Bilia et al., 2018) that evaluated the PASI score in patients treated with CUR alone or CUR combination therapy for psoriasis showed that CUR alone resulted in a statistically significant improvement in the PASI score compared to placebo (std.MD: −1.26%; 95% CI: −2.39 to −0.12; p = 0.03). When CUR was used alone, the result was not significantly different from that of the positive control; that is, the effect of CUR alone was not better than that of conventional treatment (std.MD: 0.22%; 95% CI: −0.29 to 0.72; p = 0.40). However, the combined effects of CUR and conventional therapy improved the PASI scores in patients compared with conventional therapy alone (std.MD: −0.91%; 95% CI: −1.34 to −0.48; p < 0.0001). The details are listed in Table 1. 3.2.2 PASI50, PASI75, and PASI90 of CUR for psoriasis PASI50 refers to a 50% reduction in PASI. According to the Disease of Traditional Chinese Medicine Syndrome Diagnosis Curative Standard, a treatment that reduces skin lesions by ≥50% is considered effective. A PASI score of >50 is considered an indicator of the effectiveness of psoriasis treatment. A meta-analysis of two studies (Antiga et al., 2015;Bilia et al., 2018) described in Table 2 showed that CUR in combination with an active control drug was more effective than the active control drug alone in improving PASI50 (OR: 3.94%; 95% CI: 1.56-9.92; p = 0.004) and PASI75 in the 12th week (OR: 4.31%; 95% CI: 1.49-12.43; p = 0.007); however, no difference was observed for PASI90 in the 12th week (OR: 4.16%; 95% CI: 1.01-17.08; p = 0.05).

Adverse events
Three studies reported adverse events. One of the studies (Antiga et al., 2015) reported diarrhea in one patient in the experimental group, but nausea in one patient and another one complained of a papular eruption on the face occurring in the control group. The other study (Bilia et al., 2018) reported nausea and vomiting in one patient, peeling of the palms in one patient, and mild cheilitis in six patients in the experimental group. One study (Bahraini et al., 2018) reported dry skin lesions in two individuals in the control group. The other included articles did not report any adverse reactions.

Summary of evidence
To our knowledge, this is the first systematic review of the clinical efficacy, safety, and potential mechanisms of CUR and its active ingredients in the treatment of psoriasis. We conclude that CUR has anti-inflammatory properties and improves psoriasis by inhibiting KC proliferation and the release of inflammatory factors. Thus, it acts as a key link in the immune inflammatory response in the pathogenesis of psoriasis. However, the conventional treatment for psoriasis is un satisfactory. First-line drugs, such as methotrexate, often cause side effects such as bone marrow suppression and hepatotoxicity. Numerous studies have confirmed the safety and efficacy of CUR for treating psoriasis. Our study once again confirmed that CUR can effectively alleviate psoriatic skin lesions alone or incombination with other drugs. Thus, CUR can be a complementary alternative therapy for psoriasis to reduce the side effects of its conventional treatments.

Limitations
Our study had some limitations. First, the sample size of the included clinical trials was small, the methodological quality of some of the included studies was not high, and there was high heterogeneity among some outcome indicators. Second, a doctoral thesis (not a standard peer-reviewed journal article) was included in the literature that we analyzed. Finally, most of the included studies investigated a single mechanism, which makes it difficult to identify the key targets of CUR in the treatment of psoriasis. Thus, further research is required to illustrate how and to what extent CUR or its derivatives can be used safely and efficiently as an adjuvant or main therapy for psoriasis.

Implications
Curcuma longa L is a natural herb, and CUR is the main active ingredient extracted from Curcuma longa L. CUR has been proposed as a treatment for various skin diseases, such as scleroderma, psoriasis, eczema, and skin cancer, by scientists and clinicians worldwide (Vaughn et al., 2016).
In clinical studies, we analyzed the efficacy of CUR according to the severity of skin lesions as assessed using the PASI score, PASI50, PASI75, and PASI90 in patients with psoriasis. CUR is considered a prominent anti-psoriatic compound owing to its potent antioxidant and anti-inflammatory properties . In one clinical study (Sarafian et al., 2015), 34 patients applied a turmeric microemulsion to plaques on the right arm and a control placebo to symmetrical plaques on the left arm. The results showed a statistically significant reduction in erythema, desquamation, and plaque thickness after CUR treatment. Kurd et al. (2008) conducted a phase II, open-label, Simon's two-stage trial of 4.5 g/d oral CUR C3 complex in patients with plaque psoriasis. Oral CUR was well tolerated and safe in patients with psoriasis. All adverse events were mild and limited to gastrointestinal discomfort, heat intolerance, or hot flashes. Only two of the 12 participants achieved a PASI score of 75. This low response rate may be due to the low bioavailability of oral CUR.
Multiple human clinical trials have shown that CUR is safe and effective. The reported toxic side effects of oral CUR on the human body are minimal. Even at higher doses, there are no obvious toxic and side effects. However, CUR is less absorbed when taken orally, and there is a first-pass effect (Pan and Wang,  Frontiers in Pharmacology frontiersin.org 09 2012). The low bioavailability in vivo limits the promotion and use of CUR (Liu et al., 2016). To improve its efficacy and bioavailability, CUR dosage forms have been modified; for example, CUR formulated as nanoparticles showed higher solubility and favorable safety profile (Bilia et al., 2018). Meriva, a novel bioavailable lecithin-based delivery form of CUR, increased the plasma curcuminoid concentrations after its oral administration (Antiga et al., 2015). CUR esterified with mycophenolic acid showed enhanced oral bioavailability (Yuyun et al., 2021). As for the treatment of skin diseases, topical drugs can be directly applied to the affected area of the skin. CUR has been formulated into a variety of topical dosage forms and products to increase the effect of CUR transdermal absorption (Mohanty and Sahoo, 2017;Sun et al., 2017;Zhang et al., 2019;Jin et al., 2020). The use of skin-permeating nanoparticles (NPs) can facilitate delivery of CUR to the deeper layers of the skin (Mao et al., 2017). Topical CUR avoids the liver first-pass effect and can be directly applied to the affected area of the skin to improve the therapeutic effect of psoriasis.
Immune system abnormalities are an important mechanism in the pathogenesis of psoriasis; activated T cells and dendritic cells are critical in maintaining the psoriatic phenotype; the IL-23 and type 17 T cell axis is the central link in development; and keratinocyte (KC) changes are secondary to abnormal cellular immunity (Luo et al., 2021). Our research found that CUR affects many upstream and downstream links in the psoriatic inflammatory cascade.
For preclinical studies, we performed a meta-analysis of relevant assays in animal and cellular models of psoriasis following the CUR intervention. CUR inhibits the expression of inflammatory cytokines (TNF-α and IL-6) and decreases the levels of the key inflammatory factor IL-17 A in the skin of psoriatic mice (Mao et al., 2017;Jin et al., 2020). CUR also exerts anti-inflammatory effects that improve psoriasis by inhibiting the signaling pathways of mitogen-activated protein kinase (MAPK) proteins P38, ERK, and JNK (Yuyun et al., 2021). Specifically, CUR inhibited the MAPK (P38, JNK, ERK) signaling pathways and downregulated the expression of IL-1β, IL-6, TNF-α, and

FIGURE 2
Diagram of the mechanism of curcumin (CUR) in in vitro preclinical studies. Mechanism of CUR in psoriatic dermatitis. The cytokines IL-12 and IL-23 released by DCs stimulate Th1 cells to produce TNF-α and INF-γ, and stimulate Th17 cells to produce IL-22 and other cytokines. IL-17 and TNFα induced KCs to produce pro-inflammatory factors, such as IL-6 and IL-8, causing massive accumulation of neutrophils and activation of the NF-κB signaling pathway. IL-22 secreted by Th17 cells activates the JAK-STAT3 and MAPK signaling pathway. CUR inhibited IL-22 induced phosphorylation of STAT3, and reduces vascular proliferation by inhibiting VEGF. CUR reduced the secretion of inflammatory factors by inhibiting KCs and further blocks the activation of the NF-κB, JAK-STAT3 and MAPK signaling pathway. DCs, dendritic cells; KCs, keratinocytes; VEGF, vascular endothelial growth factor; Th17, T helper 17; IL, interleukin; NF-κB, nuclear factor-κB; JAK-STAT3, (Janus tyrosine Kinase)-(Signal Transducer and Activator of Transcription).

Frontiers in Pharmacology
frontiersin.org 10 other pro-inflammatory cytokines in psoriasis. Psoriasis activates several signaling pathways that increase cell proliferation, which can be mediated through the activation of the transcription factor NF-ĸB. NF-ĸB activation requires the removal of its inhibitory protein, IĸB, by phosphorylation of its kinase, which prevents NF-κB activation by inhibiting IĸBα phosphorylation and degradation (Liczbiński et al., 2020). Cho et al. (2007) found that CUR dramatically inhibited the TNF-α-induced activation of p65 NF-κB induced by TNF-α-treated HaCaT cells. As analyzed by in vitro studies, CUR inhibited HaCaT cell proliferation and exerted anti-inflammatory effects. Cyclin D1 is a positive regulator of the cell cycle, promoting cell cycle progression from the G0/G1 phase to the S phase, mitosis, and cell proliferation. CUR can arrest KCs in the G0/ G1 phase and inhibit cyclin D1 in KCs and Bcl-2 protein expression. The therapeutic effect of CUR may be related to the downregulation of cyclin D1 and Bcl-2 expression, and the arrest of cells in the G0/G1 phase (Wang et al., 2019a). The mechanism of CUR in the treatment of psoriasis is shown in Figure 2.
In summary, we evaluated the efficacy and safety of CUR in the treatment of psoriasis through a meta-analysis of clinical studies and elucidated its specific mechanisms based on preclinical studies that used a psoriasis-like mouse model and a psoriasis cell model. Large-scale, highquality, multi-center studies are needed to confirm our conclusion, so as to increase market development efforts and to provide more methods and strategies for the treatment of psoriasis.

Conclusion
CUR can improve psoriatic skin lesions effectively with few adverse effects. CUR exerts ameliorating effects on psoriasis by reducing the release of inflammatory factors, thus inhibiting cell proliferation and cell cycle through multiple signaling pathways. Therefore, the findings of this study support CUR as a promising complementary and alternative therapy for managing psoriasis.

Data availability statement
The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding authors.

Author contributions
XL and XM conceived the study. SZ and JW designed the review. LL and XC performed the article searches. XS and YZ performed data extraction. SC and YL assessed the quality of the trials described in the selected articles. MH and GY analyzed the data. SZ and JW wrote the original draft of the manuscript. SZ, JW, LL, XS, YZ, XL, and XM. contributed to the revision of the manuscript. All authors have read and approved the final manuscript.