FormalPara Key Summary Points

Why carry out this study?

Erythrodermic psoriasis (EP) is a rare yet severe form of psoriasis that poses challenges in treatment.

Existing biologic drugs have limitations in certain EP populations, such as those with concurrent chronic hepatitis B (CHB).

This study evaluates the therapeutic effectiveness of oxymatrine in treating EP, particularly in cases with concurrent CHB.

What was learned from the study?

Oxymatrine shows efficacy and safety in treating EP, including EP with concurrent CHB.

Oxymatrine holds potential as an alternative treatment for EP, especially in cases with concurrent CHB.

Introduction

Erythrodermic psoriasis (EP) is the least common but a severe type of psoriasis [1]. EP is characterized by erythema and scaling that affects more than 75% of the body surface area (BSA) [2] and is difficult to cure; multiple failed treatment attempts are common [3, 4]. In 2010, the US National Psoriasis Foundation established guidelines for the management of EP. However, few high-quality studies have explored the optimal EP treatment [4]. A recent systematic review recommends biologics, such as infliximab or ustekinumab, as the first-line drugs to treat acute, severe cases of EP [5]. However, biologic drugs have limitations in treating EP in specific populations. For example, biologics may trigger reactivation of hepatitis B virus (HBV) infection in patients with EP comorbid with chronic hepatitis B (CHB) [6, 7]. Given the limitations of the existing biologic treatments, new therapies or innovative treatments are required to ultimately enhance medical care for patients with EP and concomitant CHB.

Oxymatrine is a natural alkaloid extracted from the root of Sophora flavescens, also commonly referred to as Kushen in traditional Chinese medicine [8]. Oxymatrine possesses a variety of health benefits through its biological effects, including antiviral antifibrosis, anticancer, anti-inflammatory, and immunoregulatory activity [9,10,11,12,13]. For instance, Lu et al. evaluated the efficacy and safety of oxymatrine in treating CHB in a randomized double-blind and placebo-controlled clinical trial [10]. The results indicated that oxymatrine markedly reduced levels of HBV DNA and liver transaminase in patients with CHB. Moreover, there was no statistically significant difference in the rates of adverse drug reactions between the oxymatrine and placebo groups, suggesting oxymatrine is an effective and safe treatment for chronic HBV [10]. In previous randomized controlled trials with larger sample sizes, mild adverse events mainly manifested as rash, bad taste, and symptoms of the upper alimentary tract, and no worsening of infections were reported in patients treated with oxymatrine [10, 14, 15]. The wide range of pharmacological effects and minimal toxicity make oxymatrine a candidate drug for the treatment of many complex diseases [16, 17]. Indeed, treatment with oxymatrine has been shown to effectively ameliorate plaque psoriasis, which is the most common form of psoriasis, and suppress relapses, with only minimal adverse events [18,19,20]. Moreover, we previously demonstrated that oxymatrine treatment alleviated severe plaque psoriasis, potentially through its inhibitory effects on epidermal cell proliferation and apoptosis in the skin lesions of patients [21]. The findings from our previous studies [21, 22], as well as other studies [10, 13], suggest that oxymatrine has the potential to treat EP, especially EP with certain comorbidities (e.g., CHB). However, the therapeutic potential of oxymatrine in EP, particularly in patients with concomitant CHB, has not been investigated.

The present clinical study was conducted to assess the efficacy and safety of oxymatrine in patients with EP, with attention to concomitant CHB.

Methods

Patients

In this open-label, investigator-initiated, clinical trial, constitutive patients diagnosed with EP were enrolled from the General Hospital of Ningxia Medical University (Yinchuan, Ningxia, China) between March 2018 and October 2019. The diagnosis of EP was made according to clinical or histological examinations as described previously [2]. During patient enrollment, the following inclusion criteria were used: (1) EP with the BSA score ≥ 75%; (2) disease course of EP ≥ 6 months; and (3) a history of at least one failed attempt of systemic treatment for EP. Patients with the following conditions were excluded from this study: (1) allergy to the study drug oxymatrine; (2) severe liver and kidney damage or other serious organic disease, mental illness, or hematopoietic dysfunction; (3) treatment with immunosuppressants, high doses of glucocorticoids or retinoid within the past 8 weeks, or with topical drugs within the 4 weeks; and (4) pregnancy or lactation. In addition, age- and gender-matched healthy volunteers were recruited from those who underwent plastic surgery procedures at General Hospital of Ningxia Medical University during the study period.

This study was approved by the Ethics Committee of General Hospital of Ningxia Medical University (Approval No. 2018-352). Each patient and volunteer provided written informed consent. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. This study was registered at the Chinese Clinical Trial Registry (www.chictr.org.cn; Registration number ChiCTR-TRC-14004301).

Treatment and Follow-up

Patients were treated with 0.6 g/100 mL of oxymatrine (Tianqingfuxin®, Zhengdatianqing Company Ltd., Jiangsu, China) intravenously once daily for 8 weeks without the use of any other topical or systemic medications. Each patient was followed up for at least 24 weeks, and the decision on whether to receive treatment with oxymatrine again or other appropriate treatments thereafter depended on the patient’s condition.

Measurement of Efficacy and Safety

The primary efficacy outcome was at least 75% improvement from the baseline in the psoriasis area and severity index (PASI 75) at week 32 (i.e., with 8-week treatment and 24-week follow-up) [23]. Secondary efficacy outcomes included at least 90% improvement from the baseline in PASI (PASI 90) and 100% improvement with complete skin clearance (PASI 100), reduction in BSA [24], and improvement in the dermatology life quality index (DLQI) [25]. Histological examination of affected skin was conducted to assess the histological changes before and after the treatment. Laboratory tests such as complete blood count, serum electrolytes, liver and kidney function markers, HBV load, blood lipids, and instrumental examinations such as electrocardiogram and abdominal color Doppler ultrasound were performed, and adverse events were observed to evaluate the safety.

Examination of Cytokines in Skin Tissue and Serum

The specimens of full-thickness skin lesions before and after treatment were obtained from the patients with EP under local anesthesia, and normal skin specimens were obtained from four age- and gender-matched healthy volunteers during their plastic surgery procedures in the Department of Plastic Surgery, General Hospital of Ningxia Medical University. The sections of skin specimens were stained with antibodies specific for tumor necrosis factor alpha (TNFα), interleukin (IL)-12, IL-23, IL-17A, and IL-36γ. Three visual fields/regions of the epidermis were quantified in each case at a magnification of ×200. Quantitative comparison of immunohistochemical staining was measured by digital image analysis of the immunohistochemistry (IHC) Profiler plugin in Image J software (Image J bundled with 64-bit Java 8, National Institutes of Health) after color deconvolution. The fraction of TNFα, IL-12, IL-23, IL-17A, and IL-36γ immunoreactive cell area relative to the total investigated area was determined.

Serum samples from patients were collected before and after the treatment, and TNFα, IL-12, IL-23, IL-17A, and IL-36γ were detected via enzyme-linked immunosorbent assay (ELISA). Normal serum samples were also obtained from four age- and gender-matched healthy volunteers during their plastic surgery procedures in the Department of Plastic Surgery, General Hospital of Ningxia Medical University. The kits for human TNFα, IL-12, IL-17A, and IL-23 assay were purchased from Neobioscience (Shenzhen, China); the kit for human IL-36γ assay was purchased from Abcam (Cambridge, UK).

Statistical Analysis

The Shapiro–Wilk test was used to test the normality and lognormality of the measurement data. Normally distributed data are expressed as mean ± standard deviation, and those with abnormal distribution are shown as median (interquartile range) for statistical description. The quantification data with normal distribution were analyzed with the paired t test for the pre- and posttreatment comparison, or unpaired t test for the comparison between the normal control and patients’ post treatment. Wilcoxon matched-pairs signed rank test (paired) nonparametric test, or the Mann–Whitney test (unpaired), where appropriate, was used for the comparison of abnormally distributed data between the two groups. GraphPad Prism 9 (GraphPad Software Inc., San Diego, CA, USA) was used for statistical analyses. All the tests were two-tailed, and the difference was considered statistically significant at P < 0.05.

Results

Patient Characteristics

A total of five patients were diagnosed with EP during the study period; one was excluded as he refused to receive oxymatrine treatment, and thus four constitutive patients (A–D) were enrolled in this study (Table S1 in Supplementary Material).

Patient A was a 54-year-old woman [body mass index (BMI) 25.3] with fever, dry and painful skin, chronic HBV infection (without HCV infection), HBV-associated liver cirrhosis (Child Pugh class A), hypokalemia, and hyperuricemia (Fig. 1; Table S1 and Figs. S1, S2 in Supplementary Material). She was referred to our outpatient department in July 2019 when psoriasis progressively worsened for 5 weeks after cessation of topical and systemic treatment. The patient had a 30-year history of moderate-to-severe plaque psoriasis that was previously alleviated by the treatment with topical and systemic medications (e.g., compound glycyrrhizin tablets, Chinese patent medicine, topical glucocorticoid ointment, and calcipotriol cream). The patient was diagnosed with EP on the basis of medical history, physical examination, and laboratory tests (PASI score 70.8, BSA involving 98.4%, DLQI 30).

Fig. 1
figure 1

Clinical index scores and statistical analysis from 0 to 8 weeks for four patients. The effectiveness of oxymatrine for the treatment of EP was measured by the percentage of improvement in the psoriasis area and severity index (PASI; left scale, illustrated as red line), decrease in body surface area (BSA) involvement (left scale, illustrated as yellow line), and reduction in the dermatology life quality index (DLQI; right scale, illustrated as green line). The four main panels show the clinical index scores of patient A, B, C, and D, respectively. There was significant improvement in the PASI score (small right panel from the top, P < 0.001 for all patients), but not BSA (small middle panel) and DLQI score (small bottom panel). The paired t test was used for the comparison of PASI score, BSA, and DLQI score at weeks 2, 4, 6, and 8 vs. the baseline

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Patient B was a 28-year-old woman (BMI 19.5) presenting with widespread erythema, desquamation, painful skin, and chronic HBV infection (without HCV infection and no signs of cirrhosis) (Table S1 in Supplementary Material, Figs. 1, 2). She was referred to our outpatient department in May 2019. The patient was infected with HBV through mother-to-baby perinatal transmission and developed a chronic HBV infection with high viral load. She was diagnosed with plaque psoriasis at the age of 12 when she was treated with corticosteroids intravenously for 1 month at the initial tolerance stage of HBV infection, and rapid withdrawal from systemic corticosteroids was considered to trigger psoriasis. Then, she received dexamethasone and traditional Chinese medicine with a progressively reduced dose, but she had recurrent flares. The diagnosis of EP was made according to her medical history, physical examination, and laboratory tests (PASI score 64.8, BSA involving 93%).

Fig. 2
figure 2

Representative photographs of skin lesions before and after 8-week treatment, and during follow-up in patient B

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Patient C was a 73-year-old man (BMI 22.2) presenting with extensive erythema and desquamation (without HBV and HCV infection) (Fig. 1; Table S1 and Fig. S3 in Supplementary Material). He was hospitalized with pustular psoriasis. As a result of continuous deterioration of his condition, the patient was hospitalized three times in the second half of 2017, during which he experienced recurrent flares and developed pustules. He had been previously treated with topical and systemic drugs (e.g., acitretin, compound glycyrrhizin, traditional Chinese medicine, and narrow band ultraviolet B phototherapy), with only partial and transitory improvement. He was diagnosed with EP on the basis of his medical history, physical examination, and laboratory tests (PASI score 67.2, BSA 93%, DLQI 30) with malaise and hyperuricemia.

Patient D was a 32-year-old man (BMI 23.1) presenting with diffuse dry erythema, desquamation, and skin pain throughout the body (without HBV and HCV infection) (Fig. 1; Table S1 and Fig. S4 in Supplementary Material). He was referred to our outpatient department in January 2019. He had a 10-year history of EP that required several cycles of systemic drugs and topical drugs (intermittent intramuscular injection of glucocorticoid, external application of glucocorticoid, and traditional Chinese medicine), with only partial and transitory improvement. At administration, he had not used any medications for 2 months with the PASI score 72, BSA 100%, and DLQI 30, associated with hyperuricemia.

Efficacy of Oxymatrine in Treatment of Patients with EP

All four patients completed the 8-week treatment with oxymatrine (Fig. 1). Upon completion, the four patients had significant decreases in PASI scores relative to the baseline (P < 0.05). Three of the four (75.0%) patients (A–C) achieved PASI 75. Specifically, the percentages of the improvement in PASI were 83.8%, 86.4%, 85.7%, and 33.3% for patients A, B, C, and D, respectively (Fig. 1). Histological examinations showed that the affected skin was nearly normalized after oxymatrine treatment in patients A–C (Fig. 3). In addition to the high therapeutic effectiveness of oxymatrine for the skin lesions, in patients A and B with comorbid CHB, the viral load decreased modestly after treatment (Table S1 in Supplementary Material). For patient D, PASI 75 was not reached after 8 weeks of treatment with oxymatrine, and there was only slight improvement in erythema and lesions of the skin, and unchanged BSA (99%) and DLQI (29; Fig. 1).

Fig. 3
figure 3

Representative images of hematoxylin and eosin staining (H.E.) of the skin lesion and immunohistochemistry for tumor necrosis factor alpha (TNFα), interleukin (IL)-12, IL-17A, IL-23, and IL-36γ in skin lesions. Top panel, before treatment; middle panel, after 8-week treatment; bottom panel, normal skin specimen from a health volunteer

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All four patients were followed up after the completion of the 8-week treatment. Three patients (A–C) were followed up for 37, 57, and 105 weeks, respectively, and all achieved PASI 75 at week 32; patient D discontinued after follow-up for 19 weeks, and thus it was not possible to analyze the primary efficacy outcome. As shown in Fig. 4, the PASI score, BSA, and DLQI decreased significantly after the treatment and during the follow-up period (all P < 0.05). PASI 75 was maintained in all these three patients (A–C) at the initial 24-week follow-up. At week 32 (24 weeks after the completion of the treatment), patient A showed 77.4% improvement in PASI (PASI score of 16), BSA 51.1%, and DLQI 8; patient B had 97.2% improvement in PASI (PASI score 1.8), BSA 1%, and DLQI 0; and patient C achieved complete skin clearance with 100% improvement in PASI (PASI score 0), BSA 0%, and DLQI 0 (Figs. 1, 2; Figs. S1 and S3 in Supplementary Material). The PASI score, BSA, and DLQI of the three patients were significantly lower than the corresponding parameters before treatment (all P < 0.05; Fig. 4). At week 37 (29 weeks after the completion of the treatment), patient A was treated with oxymatrine again for 8 weeks in order to consolidate the therapeutic effect of oxymatrine and the lesions improved further, with PASI 8.7 and BSA 3.8% (Fig. 1; Fig. S1 in Supplementary Material). It is worth noting that the residual skin lesions continued to subside even after the completion of the treatment, and that skin conditions remained stable without recurrence for all these three patients (Figs. 1, 2, 4; Figs. S1 and S3 in Supplementary Material).

Fig. 4
figure 4

Clinical indexes of three patients (A–C) who achieved the efficacy outcomes. There was significant improvement in the average the psoriasis area and severity index (PASI) score (left panel), body surface area (BSA, middle panel), and the dermatology life quality index (DLQI) score (right panel). The paired t test was used for the comparison of PASI score, BSA, and DLQI score at weeks 8, 12, 16, 20, 24, 28, and 32 with the baseline score at week 0

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Patient D, who was followed up for only 19 weeks, showed slight improvement in skin lesions, with 33.3% improvement in PASI upon the completion of the treatment and the skin lesions remained stable during the 19-week follow-up (Fig. 1; Fig. S4 in Supplementary Material).

Upon the completion of the initial 24-week follow-up, the three patients were continuously followed up for various periods to receive continuous care (patient A, 5 weeks; patient B, 33 weeks; patient C, 81 weeks), during which their skin conditions remained stable with no clinical signs of relapse (Figs. 1, 2; Figs. S1 and S3 in Supplementary Material).

Adverse Events

Laboratory test and instrumental examinations, including blood cell counts, serum electrolytes, liver and kidney function parameters, HBV load, blood lipids, electrocardiogram, and abdominal color Doppler ultrasound, did not show any significant changes during the treatment and follow-up (Tables S1 and S2, Fig. S2 in Supplementary Material). Neither infusion-related reactions nor oxymatrine-associated short- or long-term adverse events were observed (Table S1 and S2 in Supplementary Material).

Tissue and Serum Levels of Psoriasis-Associated Inflammatory Cytokines

Immunohistochemical staining revealed that levels of psoriasis-associated inflammatory cytokines, including TNFα, IL-12, IL-17A, IL-23, and IL-36γ, were significantly greater in skin biopsy samples in patients with EP than in the volunteers’ normal skin samples (all P < 0.001; Figs. 3, 5). It was noteworthy that after treatment, the levels of these inflammatory cytokines in the skin samples from patients with EP were significantly decreased (all P < 0.001; Fig. 5). Changes in serum IL-12 and TNFα levels were consistent with those in the skin biopsies in patients with EP (Fig. S5 in Supplementary Material).

Fig. 5
figure 5

Levels of tumor necrosis factor alpha (TNFα), interleukin (IL)-12, IL-17A, IL-23, and IL-36γ in the skin tissue samples from patents with erythrodermic psoriasis (EP, n = 4) before and after 8-week treatment with oxymatrine and healthy volunteers (n = 4). Three samples were taken from each subject, and tests were done in triplicate for each sample). Paired t test was used for comparing TNFα, IL-12, IL-17A, IL-23, and IL-36γ levels between before and after treatment. Unpaired t test was used for comparing IL-12, IL-17A, IL-23, and IL-36γ levels and Mann–Whitney test was used for comparing TNFα level between the control and post-treatment groups

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Discussion

The present clinical study demonstrated that the disease responded favorably to oxymatrine treatment in three of four patients with EP, with rapid achievement of PASI 75 after 8-week treatment, and significant reduction in BSA and DLQI. The skin lesions in the three responding patients continued to improve throughout follow-up period (range 29–105 weeks). The HBV load decreased modestly after 8 weeks of treatment in the two patients with comorbid CHB. Oxymatrine treatment significantly decreased levels of the psoriasis-associated inflammatory cytokines in the patients’ skin samples. In addition, there was no evident toxicity or adverse events associated with oxymatrine use. These findings suggest that oxymatrine may be a new efficacious and safe natural drug that can provide optimal care for patients with EP. To our best knowledge, this small-sized clinical trial of a rare disease is the first study to show oxymatrine administered intravenously for 8 weeks is a potentially promising treatment for EP.

Zhou et al. [18] reported that treatment with oxymatrine ameliorated severe plaque psoriasis. Our study provides further evidence that oxymatrine treatment is efficacious in most patients with EP. Specifically, patients A–C achieved the efficacy outcome, PASI 75. After treatment completion, the percentages of the improvement in PASI were 83.8%, 86.4%, and 85.7% for patient A, B, and C, respectively. Moreover, at week 32 (i.e., at the 24-week follow-up), patients A and B showed 77.4% and 97.2% improvement in PASI, and patient C even achieved complete skin clearance with 100% improvement in PASI. After the initial 24-week follow-up, the three patients continued to be followed up for an additional 5 to 81 weeks, during which their skin conditions remained stable with no clinical signs of recurrence.

In the present study, patients A and B with comorbid CHB experienced a reduction in the viral load after the 8-week treatment. Apparently, oxymatrine alone not only improved the skin lesions and DLQI but also reduced the HBV load. Previously, it was reported that in a multicenter, longitudinal, disease-based registry of patients with psoriasis receiving or eligible to receive conventional systemic or biologic therapy, a higher hazard of serious infections was associated with some biologic drugs when compared with non-biologic systemic therapies [26]. The reactivation of HBV and/or hepatitis C virus (HCV) infection in response to biological drugs has been suspected, especially with TNF inhibitors [6]. The efficacy of biologic agents in patients with psoriasis with concomitant viral hepatitis is not well defined [7], while long-term use of biological agents is needed for EP to maintain efficacy [27]. For patients with EP with HBV/HCV infection, we need to control the viral load before using biological agents [7]. Oxymatrine has been demonstrated to possess anti-HBV and anti-hepatic fibrotic activities [10, 11, 28], indicating its therapeutic effects for CHB. The present study, for the first time, provides evidence supporting such therapeutic effects in patients with EP.

Previous studies have shown that treatment with oxymatrine is associated with only minor adverse events in patients with severe plaque psoriasis, and no obvious toxic effect in patients with HBV infection or solid tumor [9,10,11, 16,17,18]. Compared with acitretin, cyclosporin, and methotrexate that have been associated with clinically apparent liver injury and nephrotoxicity, oxymatrine has minimal or even no hepatotoxicity [29]. Consistent with these previous findings, no evident toxicity or adverse events were observed after the use of oxymatrine in the present study.

The mechanism by which oxymatrine exerts its therapeutic effect for psoriasis has been investigated, but it remains unclear [19, 20, 30]. Psoriasis is often triggered by infections and other various factors, resulting in metabolic abnormality and an imbalance in immune modulation [31, 32]. Inflammatory cell infiltration is among the important pathological features [33, 34]. Psoriasis is indeed a cytokine-driven inflammatory skin disease in which interferon (IFN)-γ, TNFα, IL-17, and IL-22 cytokines have a pathogenic action [35,36,37,38]. Oxymatrine not only changes the STAT pathway (i.e., IL-17 pathway) in the pathogenesis of psoriasis, but also affects the inflammatory, infection, and metabolic pathways, and consequently achieves multiple therapeutic effects [19, 20]. In the present study, TNFa, IL-12, IL-23, IL-17A, and IL-36γ levels were significantly elevated in the patients with EP, compared with that of the healthy volunteers, and the abnormally high levels declined with oxymatrine treatment. The reduced inflammatory cytokine levels after treatment with oxymatrine may be attributable to the anti-inflammatory and immunoregulatory effects of oxymatrine as reported previously [39, 40]. We postulate that oxymatrine may inhibit the key nodes in the cytokine network, thereby leading to its therapeutic effect in EP.

This pilot study is limited by the small number of patients; the rarity of EP precludes a large sample. Although the National Psoriasis Foundation has developed EP management guidelines [4], it has reported that there are few high-quality studies to permit reliable comparisons of EP treatment options. In the absence of such studies, pilot clinical trials, such as ours, are a useful contribution.

Conclusion

Oxymatrine appears to be efficacious and safe in the treatment of EP, including for patients with concomitant CHB, and thus may hold promise as an alternative treatment for EP, especially when concomitant with CHB. This drug has advantages over immunomodulator drugs and biologic agents in the treatment of the disease in that it may exert multiple therapeutic effects. However, its use as first-line treatment for EP should be further evaluated in well-designed, well-powered randomized clinical trials.