Abstract
Vitiligo, an autoimmune disease, is a depigmentation skin disorder characterized by hypopigmentation spots and patches that are difficult to treat. The purpose of this study is to analyze the clinical efficacy of simvastatin in the treatment of vitiligo. From December 2016 to October 2019, five vitiligo patients from Peking Union Medical College Hospital were treated with simvastatin and tacrolimus. For simvastatin, the first three patients (patient 1, patient 2, and patient 3) began to take 40 mg/day, and the latter two patients began to take 20 mg/day. From week 5, patients 1 and 2 received 20 mg simvastatin once a day. And the 0.1% tacrolimus ointment was used topically. The response was measured using the Vitiligo European Task Force (VETF) scoring system at baseline and at the fourth and eighth weeks of treatment. The results of the VETF score showed that three of the patients achieved significant clinical efficacy. There was no significant improvement in the other two cases. No serious acute or chronic side effects were observed. In conclusion, our results suggest that conventional oral simvastatin is safe, although it may not be effective in the treatment of vitiligo.
Key messages
What is already known about this subject?
Vitiligo is a depigmentation skin disorder characterized by hypopigmentation spots and patches caused by the loss of melanocytes from the epidermis. Although there are many methods to treat vitiligo at present, the curative effect is often poor, and many of them lack evidence-based medicine.
What are the new findings?
Conventional oral simvastatin is safe, but may not be effective in the treatment of vitiligo.
How might these results change the focus of research or clinical practice?
Efficacy of oral simvastatin in the treatment of patients with vitiligo in individual cases is good and could guide future research.
Introduction
Vitiligo is a depigmentation skin disorder characterized by hypopigmentation spots and patches caused by loss of melanocytes from the epidermis. According to Alikhan et al,1 the estimated prevalence of vitiligo is 0.5%–1% of the total population. Its damage to the patient’s face seriously affects the patient’s self-esteem and quality of life. Generally speaking, vitiligo is caused by the interaction of genetic factors and environmental factors, which causes the skin melanocytes to be attacked and damaged by the autoimmune system. Although there are many methods to treat vitiligo at present, the curative effect is often poor, and many of them lack evidence-based medicine.
Recent studies have shown that increased infiltration of autoreactive, melanocyte-specific CD8+ T cells and enhanced interferon-γ (IFN-γ) signaling are associated with the pathogenesis of vitiligo.2–6 In vitro experiments showed that statins can inhibit signal transducer and activator of transcription 1 (STAT1) activation, which is involved in IFN-γ signaling.7 Statins inhibit STAT1-α mRNA and protein levels in a dose-, time-, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-dependent manner. They also inhibit the phosphorylation of STAT1-α and its recruitment to the promoter of CD40, a member of the tumor necrosis factor receptor superfamily, which is critical for the activation of immune responses.8
Simvastatin is an HMG-CoA reductase inhibitor approved by the Food and Drug Administration (FDA) for the treatment of hypercholesterolemia.7 Research using a vitiligo mouse model revealed that simvastatin both prevents and reverses depigmentation.9 The activity of simvastatin to reduce the proliferation and IFN-γ production of premelanosome protein-specific T-cell receptor (TCR)-transgenic CD8+ T cells via the HMG-CoA reductase pathway contributes to its therapeutic effects against depigmentation.9 It is widely used in the treatment of dyslipidemia and cardiovascular disease. In addition to its lipid-lowering effect, simvastatin can also regulate the inflammatory process, immune response, and oxidative stress. A recent study has shown that simvastatin can protect melanocytes from oxidative stress through its antioxidant effect and elucidates that simvastatin can activate the MAPK (mitogen-activated protein kinases) pathway and upregulate p62 expression in the way of mevalonate rather than cholesterol, and the interaction between them can jointly activate Nrf2–ARE (nuclear factor erythroid 2-related factor 2–antioxidant responsive element) signaling pathway to play its antioxidant protection on melanocytes under oxidative stress.9 10 These findings support simvastatin as a potential therapeutic agent for vitiligo.
Although simvastatin has shown promising results in the treatment of vitiligo in some studies, the results are inconsistent. The purpose of this study is to explore the clinical efficacy and tolerance of oral simvastatin in the treatment of vitiligo through a clinical trial.
Materials and methods
Research object
Five patients in this study were diagnosed with vitiligo and were treated with oral simvastatin from December 2016 to October 2019 at the Department of Dermatology, Peking Union Medical College Hospital, Beijing, China. Among them, there were three men and two women. The average age of diagnosis was 56.2 years (48–65 years), and the median age was 56 years. All five patients were given tacrolimus before and during simvastatin treatment. A retrospective review of these patients’ medical records was performed after patient consent. For each case, the following data were collected: demographics (date of birth, gender, age range at diagnosis, and disease duration before diagnosis), general medical history, photographs of the lesions under Wood’s lamp at each visit, treatment to date, and Vitiligo European Task Force (VETF) scores at baseline and at the fourth and eighth weeks of treatment. Regarding simvastatin, the dose, duration of treatment, side effects, disease response, and reason for stopping the medication were documented. Patients who were administered other systemic therapies during oral simvastatin treatment did not attend a follow-up appointment and were referred elsewhere for their follow-up were excluded. All these patients were diagnosed and treated by a single observer.
Inclusion and exclusion criteria
Inclusion criteria were as follows: (1) patients with typical skin lesions and clinical diagnosis of vitiligo; (2) patients without autoimmune disease history; (3) patients without pregnancy or lactation; and (4) segmental vitiligo or non-segmental vitiligo. Exclusion criteria were as follows: (1) received systemic and topical treatment of corticosteroids, immunosuppressants, ultraviolet rays, and photosensitive drugs within 4 weeks before admission; (2) allergic to the test drugs; (3) accompanied with heart, liver, kidney, and blood system diseases; and (4) pregnant and lactating patients.
Observation index
The “staging” and “spreading” VETF items of vitiligo were assessed as recommended following natural light and Wood’s lamp examination.11 This evaluation individually assesses five body regions (head and neck, trunk, upper extremities, lower extremities, hands, and feet) for (1) extent of the disease (percentage affected body surface, scored 0%–100%); (2) stage of disease (staging: normal pigmentation, incomplete depigmentation, complete depigmentation, complete depigmentation plus partial leukotrichia, complete depigmentation plus complete leukotrichia, scored 0–4, respectively); and (3) disease progression (spreading: regressive, stable, progressive, scored −1 to +1, respectively). The total score for the staging and spreading items ranges, respectively, from 0 to 16 for staging and from −5 to +5 for spreading.
Results
Demographic, vitiligo characteristics, and clinical response of subjects
Patients who received other systemic treatment during simvastatin oral therapy, who did not participate in follow-up appointments, or referred to other places for follow-up were not included in the final analysis. In the end, five patients with vitiligo met the therapeutic effect analysis standard of simvastatin. At the time of the medical record review, two patients stopped taking simvastatin orally and three patients were receiving simvastatin orally. For simvastatin, the first three patients (patient 1, patient 2, and patient 3) began to take 40 mg/day, and the latter two patients began to take 20 mg/day. From week 5, patients 1 and 2 received 20 mg simvastatin once a day. And the 0.1% tacrolimus ointment was used topically. The average treatment time of simvastatin was 23.2 weeks (1–98 weeks). Patient 2 stopped taking simvastatin at the end of week 8 due to no improvement. Patient 3 stopped taking simvastatin at the end of the first week and used other non-statins to control blood lipid better without consulting his dermatologist. The demographic characteristics and clinical reactions of five patients with vitiligo are shown in table 1.
Safety evaluation
All five patients tolerated treatment well with no severe adverse effects. Patient 3 experienced mild diarrhea, which resolved spontaneously on withdrawal of oral simvastatin, and the patient was not rechallenged with oral simvastatin.
VRTF scores of subjects at baseline and at the end of the fourth and eighth weeks of simvastatin treatment
Patient 1 received significant clinical efficacy after taking simvastatin at the end of the eighth week. Patients 2 and 3 failed at least 1 week after treatment due to the progression of depigmentation and evidence of ongoing disease activity. Both patients took alternative drugs. Patients 4 and 5 were in the treatment, less than 8 weeks, but according to their VETF scores in the fourth week, all obtained significant clinical efficacy. The VETF scores for all patients at baseline, week 4, and week 8 (except for patient 3) are shown in table 2.
Discussion
The research shows that vitiligo is a disease in which oxidative stress and autoimmunity act on melanocytes to lead to the loss of epidermal pigment under a specific genetic background, and the key link of vitiligo is the immune imbalance caused by oxidative stress. In 1989, the FDA approved simvastatin as a specific drug for the treatment of hypercholesterolemia. However, in recent years, it has been found that simvastatin not only has the classic lipid-lowering effect but also has the multiple effects of immune regulation, anti-inflammatory, antitumor, and antioxidation, and its antioxidation effect has been confirmed in many diseases.
In 2004, Noël et al 12 first reported a 55-year-old male vitiligo patient whose vitiligo lesions were relieved after the administration of 80 mg simvastatin at bedtime for 5 months to lower elevated blood cholesterol levels. However, except the case reported by Noël et al,12 studies using statins in patients with vitiligo showed no significant improvement in experimental groups compared with control groups. Vanderweil et al 13 conducted a randomized, double-blind, placebo-controlled, phase II clinical trial in which the treatment group was administered 40 mg simvastatin daily for the first month and 80 mg for the following 5 months, whereas the control group was given placebo. Iraji et al 14 reported that patients with vitiligo were randomized to either 0.1% betamethasone valerate cream for external use two times per day alone or in combination with 80 mg oral simvastatin daily. Nguyen et al 15 conducted a randomized clinical trial evaluating the effectiveness of a combination of 40 mg oral atorvastatin daily for 1 month followed by 80 mg oral atorvastatin daily for 5 months and narrow-band ultraviolet B (NB-UVB) phototherapy twice per week for 6 months versus NB-UVB phototherapy alone twice per week for 6 months in patients with active vitiligo. No significant difference in the change in the mean Vitiligo Area Scoring Index or VETF Vitiligo Extent Score was detected in these studies. In our case series, patients 1, 4, and 5 achieved a significant response with oral simvastatin, while patients 2 and 3 failed the treatment. Our outcome was consistent with the clinical trials of these people, which also failed to improve overall response. However, Agarwal et al 9 found that the effectiveness of 0.8 mg simvastatin (up to 40 mg/kg) intraperitoneal injection thrice weekly in the treatment of a vitiligo mouse model induced with premelanosome protein-specific TCR-transgenic CD8+ T cells in sublethally irradiated (500 rad) Krt14-Kitl* mice. After 4 to 6 weeks of treatment, a significant increase in pigmentation was observed.9
The disparate findings between the studies in patients and mouse models can be attributed to differences in dose. FDA approved the safe and effective dose of simvastatin for the human body to be 40 mg/day, and the maximum dose is 80 mg/day. However, in a previous study,9 in vivo studies in mice (up to 40 mg/kg/day) are much higher than what is used in humans (up to 80 mg/day). Studies have shown that oral high doses of simvastatin can cause serious side effects, such as myopathy and rhabdomyolysis,16 thus limiting its application in the treatment of patients with vitiligo. Therefore, the research and development of simvastatin ointment and related clinical trials are imminent. Otuki et al 17 reported the anti-inflammatory effects of topical simvastatin in a mouse skin inflammation model, suggesting that topical statin preparations may represent an alternative option in treating vitiligo. A randomized, double-blinded, placebo-controlled pilot study using topical statins in the treatment of patients with vitiligo is underway.18 In addition, more specific investigations are required to target and use the exact mechanisms of statins involved in the treatment of vitiligo.
Conclusion
In conclusion, the results of this study suggest that conventional oral simvastatin is safe, but may not be effective in the treatment of vitiligo, which is consistent with previous studies. However, this study included a small number of samples and is not a randomized controlled study. Although the efficacy of individual cases is good, more case studies and the mechanism of statins in the treatment of vitiligo still need to be studied in the future.
Footnotes
Contributors SZ and TW contributed to the conception and design of the study. All authors participated in the clinical practice, including diagnosis, treatment, consultation, and follow-up of patients. YL and HJ contributed to the acquisition of data. HJ and TW contributed to the analysis of data. SZ wrote the manuscript. TPZ revised the manuscript. All authors approved the final version of the manuscript.
Funding This work was supported by grants from the Fundamental Research Funds for the Central Universities (3332018025), National Scientific Data Sharing Platform for Population and Health Clinical Center (NCMI-ABD02-201709), and Beijing Dongcheng District Excellent Talent Support Training project (2019JGM-5).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The institutional review board of Peking Union Medical College Hospital approved this study. Informed consents for participation were obtained from the patients.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.