Abstract
Introduction
The treatment of genital lichen sclerosus (GLS) remains challenging. Baricitinib has been introduced in the treatment of GLS, but there’s no imaging evaluation for GLS patients treated with it. No comparison of dermoscopy and reflectance confocal microscopy (RCM) assessments in GLS has been conducted. We performed this study to evaluate the efficacy and safety of baricitinib for GLS and to compare the value of dermoscopy and RCM assessments in GLS.
Methods
Participants were treated with baricitinib for 6 months and assessed at week 0, 2, 4, 6, 8, and every 4 weeks for the next 16 weeks. All patients were evaluated for clinical, dermoscopic, and RCM variables, with numeric scores assigned to each parameter.
Results
Twenty-six GLS patients were included in this study. All patients achieved Investigator’s Global Assessment score ≤ 1 (with ≥ 2-grade improvement) at week 20. The scores of pruritus and pain decreased since week 2 (both P < 0.05). The DLQI and VQLI scores significantly decreased since week 4 (both P < 0.0001). White structureless areas improved at week 2 and white shiny streaks and follicular plugs improved at week 4 under dermoscopic examination. Vessels (P < 0.001) and brown structureless areas (P = 0.003) increased at week 8. In RCM, inflammatory cells count significantly decreased at week 2 (100.03 ± 33.24, P < 0.0001), with substantial regression at week 8 (16.98 ± 5.54, P < 0.0001). Epidermal thickness increased at week 12 (157.44 ± 37.87 μm versus 134.13 ± 36.60 μm, P = 0.0284). Irregular papillae, spongiosis, and fiber structures improved at week 20, week 4, and week 6 (all P < 0.01). Transient hypercholesterolemia (11.54%), thrombocytosis (7.69%), and elevated alanine aminotransferase (7.69%) occurred during treatment.
Conclusion
Both dermoscopy and RCM can be useful and non-invasive adjuvant tools for the evaluation and therapeutic monitoring of GLS. We recommended white structureless areas under dermoscopy and inflammatory cells count under RCM as variables for dermatologic imaging evaluation for GLS. Baricitinib is effective and safe for GLS, while randomized controlled trials are warranted.
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Avoid common mistakes on your manuscript.
Why carry out this study? |
A systemic medication for genital lichen sclerosus (GLS) in treatment modalities besides topical corticosteroids is greatly lacking. |
No comparison of dermoscopy and reflectance confocal microscopy in GLS has been conducted. |
What was learned from the study? |
This study found that both dermoscopy and reflectance confocal microscopy examination showed usefulness in the evaluation and therapeutic monitoring of GLS. |
Baricitinib was effective and safe for the treatment of GLS, based on investigator evaluation, patients-reported outcomes, and dermatologic imaging evaluation. |
Baricitinib could induce fast regression of inflammation and symptoms of GLS with no severe adverse events. |
Introduction
Genital lichen sclerosus (GLS) is a chronic inflammatory skin disease that occurs in prepubertal and postmenopausal women, commonly in the anal and genital areas [1]. The true incidence of GLS is still unknown and the male-to-female ratio varies between 1:3 and 1:10 [2]. The main clinical manifestations are atrophic white papules and plaques, which can lead to urinary and sexual dysfunction and increased risk of squamous cell carcinoma [3]. The diagnosis of GLS is mainly based on typical clinical manifestations. When atypical features or diagnostic uncertainty is presented, dermatopathology and skin imaging can be used as additional diagnostic materials [4, 5]. Current research suggested GLS as an autoimmune disease with genetic and immunological factors, predominantly Th1 responses [4, 6]. But the etiology and pathogenesis are still poorly recognized. To date, the first-line treatment for GLS is topical corticosteroids, but the long-term curative effect of this treatment is unsatisfactory [7]. Thus, a more rapid-acting treatment with long-term efficacy is desirable to prevent the progress of GLS. In addition, both dermoscopy and reflectance confocal microscopy (RCM) had been separately applied for evaluation and therapeutic monitoring of GLS, but no comparison of both assessments in GLS had been conducted [8,9,10].
Janus kinase (JAK) inhibitors (JAKi) could inhibit the activity of one or more of the JAK enzymes (JAK1, JAK2, JAK3, and tyrosine kinase 2), which are associated with the signal transduction of various cytokine receptors [11]. Baricitinib is an oral selective inhibitor of JAK1 and JAK2, approved for the treatment of rheumatoid arthritis, atopic dermatitis, vitiligo, and alopecia areata [12, 13]. Off-label use of baricitinib has shown promising results for some inflammatory and immune diseases, including extragenital lichen sclerosus, dermatomyositis, polyarteritis nodosa, hypereosinophilic syndrome, and chronic actinic dermatitis et al. [11, 14,15,16,17,18,19].
In this study, we attempted to compare dermoscopy and RCM in the evaluation and therapeutic monitoring of GLS. In addition, we aimed to assess the efficacy and safety of baricitinib for the treatment of GLS based on investigator evaluation, patient-reported outcomes, and dermatologic imaging evaluation.
Methods
Participants
From March 2021 to October 2022, GLS patients eligible to participate in the study were enrolled at dermatology outpatient clinic in the First Affiliated Hospital of Fujian Medical University. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. The study was approved by the Medical Technology Clinical Application Ethics Committee of the First Affiliated Hospital of Fujian (No. [2021]95). Written informed consent was obtained from each patient. GLS patients who were histopathologically diagnosed were included, aged 18–65 years. Exclusion criteria were previous history of JAKi treatment, agranulosis (absolute neutrophil count < 1.0 × 109/L), lymphopenia (absolute lymphocyte count < 0.5 × 109/L), anemia (hemoglobin < 80 g/L), history of venous thromboembolism (including deep vein thrombosis and pulmonary embolism), active hepatitis B virus infection or tuberculosis, severe bacterial or fungal infection, pregnancy or breast-feed, internal organ dysfunction (including liver, kidney, and heart), and existing cancer.
Treatment
After discontinuation of topical ultrapotent corticosteroids or calcineurin inhibitors for 4 weeks, patients were treated with baricitinib 4 mg once daily as monotherapy which was discontinued after 6 months of treatment.
Evaluations and Follow-up
Patients were assessed at week 0, 2, 4, 6, 8, and every 4 weeks for the next 4 months. The efficacy was evaluated by objective clinical appearances, Investigator’s Global Assessment (IGA, see in Supplementary Table 1), symptoms, Dermatology Life Quality Index (DLQI, scale 0–30, see in Supplementary Table 2), Vulvar Quality of Life Index (VQLI, scale 0–45, modified for both genders, see in Supplementary Table 3), dermoscopy, and RCM. Two independent dermatologists, blinded to the time of treatment, evaluated all clinical, dermoscopic, and RCM variables.
The clinical pictures were captured with the same camera at the same location. IGA evaluation included erythema/whitening, infiltration, lichenification, and excoriation. The symptoms included pruritus, pain, erectile tightness (for males), dysuria, and dyspareunia. Dermoscopic images were captured by a digital dermoscopy system (handheld, CH-DS50, Guangzhou Chuanghong Medical Technology Co., Ltd.) in polarized light mode at 20-fold or 40-fold magnification. All patients were examined using the RCM system, the VivaScope 1500 (Lucid Inc., USA). All images were obtained by the same dermatologist to avoid diversification. More than one image was collected to acquire the different appearances of the lesions for each patient. Two independent dermatologists assessed dermoscopic variables, including vessels, white structureless areas, white shiny streaks, follicular plugs, and brown structureless areas. The variables of RCM were epidermal thickness, spongiosis, inflammatory cells count, irregular papillae, and prominent fiber structures. IGA, symptoms, and most variables of dermatological imaging evaluation were quantified on a six-point scale: 0 = absent, 1 = minimal, 2 = mild, 3 = moderate, 4 = marked, and 5 = severe. Epidermal thickness was the thickness from the stratum corneum to the stratum basale. Inflammatory cells in the superficial dermis in a field of 2.5 × 2.5 mm were counted.
The laboratory tests include complete blood count, biochemical tests, coagulation function tests, and inflammatory markers. In addition, we also evaluated the adverse effects of baricitinib through a questionnaire.
Statistical Analysis
Data normality was tested using the Shapiro–Wilk normality test. Normal data were shown as mean ± standard deviation and tested in paired t-test. Non-normal data were shown as the median (first quartile (Q1), third quartile (Q3)) [minimum, maximum] and tested in the Wilcoxon rank sum test. Statistical analysis was performed by SPSS software (Version 25.0, SPSS Inc., Chicago, IL, USA). The Friedman test was used to compare differences in clinical variables, RCM variables, dermoscopic variables, and subjective symptoms among baseline, 4 weeks post-treatment, and 12 weeks post-treatment. A P value < 0.05 was considered statistically significant.
Results
Clinical Characteristics
From March 2021 to October 2022, a total of 26 patients in the First Affiliated Hospital of Fujian Medical University were enrolled in this study. There were 20 females (20/76.92%) and 6 males (6/23.08%) with a mean age of 34.8 years (ranging from 19 to 55 years). Baseline characteristics are presented in Table 1 (see more details in Supplementary Table 4). The mean duration after diagnosis and symptoms of GLS were 34.34 months and 42.26 months, respectively. The most common location was the vulva in women and the foreskin in men.
The baseline scores were as follows: IGA score, pruritus score, pain score, DLQI score, and VQLI score were: 3 (2.25, 3) [2, 4], 3 (1.25, 3) [0, 5], 1 (0, 2) [0, 4], 12.50 ± 5.15, and 18.46 ± 5.22, respectively. Five uncircumcised male patients reported erectile tightness with scores of 3, 1, 3, 1, and 1, respectively. No dysuria or dyspareunia were recorded. Table 2 shows the changes in clinical variables, subjective symptoms, and dermoscopic and RCM variables with baricitinib treatment.
Disease control was defined as IGA score ≤ 1 (with ≥ 2-grade improvement). All patients achieved disease control at week 20, and the texture of the skin lesion became soft at week 4. The scores of pruritus and pain gradually decreased with the treatment. Patients reported a significant amelioration of pruritus at week 2 (P < 0.0001) and substantial resolution at week 12 (P < 0.0001). Additionally, significant pain relief happened at week 2 (P < 0.05), and the pain score decreased to 0 at week 6 (P < 0.001). The erectile tightness score decreased to 0 at week 4 (P = 0.042). The DLQI and VQLI scores significantly decreased since week 4 (both P < 0.0001). IGA, pruritus, pain, DLQI, and VQLI scores were 1 (0, 1) [0, 1], 0, 0, 0.35 ± 0.49, and 0.85 ± 0.92 at 6 months, respectively. Figure 1 shows the changes in clinical variables, subjective symptoms, and clinical lesions with baricitinib treatment.
Dermoscopic Assessment
The white structureless areas improved at week 2, which is earlier than other dermoscopic variables (Fig. 2a). The scores of white shiny streaks and follicular plugs decreased significantly at week 4. The scores of vessels (P < 0.001) and brown structureless areas (P = 0.0003) began to increase significantly at week 8 (Fig. 2b). Figure 2c–f showed representative images of dermoscopic variables.
Scores of dermoscopic variables. a Changes of white structureless areas, white shiny streaks, follicular plugs, b vessels and brown structureless areas with baricitinib treatment. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Representative dermoscopic changes before (c, e) and after (d, f) baricitinib treatment: c, d improvements of white structureless areas (black circle), white shiny streaks (black arrow), and increase of vessels (red arrow); e, f improvements of follicular plugs (yellow arrow) and increase of brown structureless areas (red circle) (magnification × 20)
RCM Assessment
The rapid and significant decrease of inflammatory cells count under RCM was observed at week 2 (mean count 100.03 ± 33.24, P < 0.0001) in all patients, with substantial regression at week 8 (mean count 16.98 ± 5.54, P < 0.0001) (Fig. 3a). The epidermal thickness, spongiosis, irregular papillae, and fiber structures improved gradually, while there was no significant increase in epidermal thickness until week 12. Substantial resolution of spongiosis was observed at week 4, fiber structures at week 6, and irregular papillae at week 20. Figure 3a and b showed the changes in RCM variables. Figures 3c–f and 4 showed representative RCM images.
Results of reflectance confocal microscopy (RCM) variables. a Changes in inflammatory cells count, epidermal thickness, b fibrous structure, spongiosis, and irregular papillae with baricitinib treatment. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Representative changes of RCM before (c, e) and after (d, f) baricitinib treatment: c, d improvement of fibrous structure (blue circle). e, f improvement of irregular papillae (red arrow)
Safety Evaluation
Two patients (7.69%) reported upper respiratory tract infection, and one (3.84%) reported coronavirus disease 2019 during the treatment. The laboratory results reported hypercholesterolemia (11.53%), thrombocytosis (11.53%), and alanine aminotransferase elevation (7.69%) during treatment, which were proved transient after follow-up without discontinuation of baricitinib. Transient hypercholesterolemia (11.54%), thrombocytosis (7.69%), and elevated alanine aminotransferase (7.69%) occurred during treatment but were absent with continued baricitinib in later follow-up (Table 3) (Supplementary Table 5 showed the laboratory test results at baseline and week 24).
Discussion
GLS is a chronic inflammatory skin disease mediated by lymphocytes. White atrophic plaques and erythema with depigmentation (hyperkeratosis or sclerosis) on the vulva or penis could be signs of GLS [20]. The ultrapotent or potent topical corticosteroids were recommended as first-line treatment [7]. Many treatments are less effective, so there is a need to investigate effective and safe treatment for GLS. The anti-inflammatory effect makes JAK inhibitors a potentially powerful treatment for GLS. There’s a limitation in efficacy evaluation for this new therapy of GLS [21,22,23,24,25]. In this study, we first performed multi-sample prospective research about baricitinib for GLS, which revealed a rapid efficacy and safety assessed by investigator evaluation, patient-reported outcomes, and dermatologic imaging evaluation.
The improvement of dermatological imaging results could reflect pathological change. Pathologically, GLS is characterized by the increase and homogenization of collagen in the superficial dermis and inflammatory cells infiltration. Our study showed that baricitinib could ameliorate the change in collagen. Under RCM, the fibrous structure is a clue to fibrosis and the disease severity of GLS. Under dermoscopy, white structureless areas and white shiny streaks are other signs of a fibrous process, and the assessment of vessels could be enhanced by the decrease of homogenized collagen in the superficial dermis [8]. These variables mentioned above displayed an improving trend in our study, along with the softening of lesional palpation, implying the ameliorative effect on fibrosis of baricitinib [8]. Our study revealed that baricitinib could induce rapid regression of inflammation, according to the significant decrease of inflammatory cells count under RCM at week 2. Under RCM, the irregularity of the papillae, indicating basal hydropic degeneration, and spongiosis result from inflammatory cells infiltration [26]. Under dermoscopy, the brown structureless areas may correspond to the post-inflammatory hyperpigmentation of GLS that preferred Asian patients in the previous study [27, 28]. The decrease of irregular papillae and spongiosis under RCM and the increase of brown structureless areas under dermoscopy observed in our study also supported the regression of inflammation, which is consistent with known studies [24].
Follicular plugs under dermoscopy are histopathologically related to keratotic plugs caused by follicular hyperkeratosis [29]. The decreased score of follicular plugs after treatment suggested that baricitinib may regulate keratinization in GLS. It is supported by a previous study that revealed that overexpression of JAK1 in autoimmune inflammatory diseases can lead to hyperkeratinization [30]. As GLS progressed, the inflammation can be more severe. Therefore, follicular plugs may be an indicator for the evaluation of disease severity. Epidermal thickness increased at month 2, although there was no significant difference. As epidermis atrophy may induce skin barrier dysfunction, emollients should be applied clinically as a barrier preparation for GLS patients [7]. Whether the combination of baricitinib and emollients can accelerate epidermal thickness recovery remains to be studied.
In this study, we observed that all dermoscopic features significantly improved at week 8, and all RCM features significantly improved at week 16. Dermoscopic images can be easily acquired by handheld dermoscopy. RCM is less convenient than dermoscopy, but it can get more information at the level of cells, including measurement of epidermal thickness and inflammatory cells count [31]. As both white structureless areas under dermoscopy and inflammatory cells count under RCM improved at week 2, our study suggests that both dermoscopy and RCM can be non-invasive tools for evaluation and therapeutic monitoring of GLS, among which white structureless areas under dermoscopy and inflammatory cells count under RCM were improved earlier than other variables [32].
Previous studies revealed that the imbalance between pro-inflammatory cytokines and anti-inflammatory cytokines was observed in the GLS lesions [33]. It is suggested that cytokine expression in GLS may fit a Th 1 immunity based on increased pro-inflammatory cytokines (IFN-γ, IL-1, IL-2, IL-7, IL-15, TNF-α, CXCR3, CXCL10, CXCL11, CCR5, CCL4, and CCL5) and decreased anti-inflammatory cytokines (TGF-β2) [4, 34, 35]. The intracellular signal transformation of IFN-γ and IL-2 was mainly mediated by JAK, mainly JAK1 and JAK2 [11]. Increased CXCL10-CXCR3 interaction could result in the recruitment of CXCR3+ CD8+ cytotoxic T cells [4, 35,36,37]. Baricitinib may inhibit IFN-γ and CXCL10 via JAK1 inhibition and further decrease cytotoxic T cell infiltration. In addition, the transforming growth factor-β (TGF-β) signal pathway plays a key role in fibroblast proliferation and collagen deposition [38,39,40]. JAK are downstream of the TGF-β mediated profibrotic signal, and the activation of the JAK/STAT pathway has been shown to lead to fibrosis [39]. Baricitinib has demonstrated effects on inhibiting the TGF-β mediated fibrosis in morphea mouse model and patients [41]. These evidence might explain the potential mechanism of baricitinib for GLS.
The results reported herein should be viewed in the sight of some limitations. Our work was a single-arm study with a small sample size of Chinese people, which limited the generalization of this result. In addition, IGA, one of our evaluation tools, has not been fully validated for the evaluation of GLS patients. Thus, we applied multiple assessment methods to prove the effectiveness of baricitinib.
Conclusions
In summary, our study indicated that both dermoscopy and RCM can visualize the characteristics of GLS and represent valid options for therapeutic monitoring. Baricitinib could be an efficient and safe treatment option for GLS, although the underlying mechanism requires further investigation. However, as US Food and Drug Administrator has announced a black box warning for certain JAK inhibitors about serious side effects, randomized controlled trials with larger sample size and longer follow-up duration are necessary to confirm our findings.
Data Availability
The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
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Funding
This work was supported by grants from the Fujian Provincial Health Technology Project (No.2020CXA034), the Joint Funds for the Innovation of Science and Technology, Fujian Province (No.2021Y9120), and the National Natural Science Foundation of China (No.82271194). The authors would pay the rapid service fee for this work.
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Conceptualization: Chao Ji, Methodology: Ting Gong, Yan Zhao; Data acquisition: Chengbei Bao, Renwei Luo, Zequn Tong, Zheyu Zhuang; Formal analysis and investigation: Chengbei Bao, Qiuyun Xu, Wenjia Dai, Bohan Gu; Writing—original draft preparation: Chengbei Bao, Qiuyun Xu; Writing—review and editing: Ting Gong, Bo Cheng; Resources: Chao Ji; Supervision: Chao Ji.
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All authors, including Chengbei Bao, Yan Zhao, Renwei Luo, Qiuyun Xu, Zequn Tong, Zhixun Xiao, Zheyu Zhuang, Wenjia Dai, Bohan Gu, Ting Gong, Bo Cheng, and Chao Ji, have nothing about conflicts of interest to disclose.
Ethical Approval
This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. The study was approved by the Medical Technology Clinical Application Ethics Committee of the First Affiliated Hospital of Fujian (No. [2021]95). The patients in this manuscript have given written informed consent to the publication of their case details.
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Bao, C., Zhao, Y., Luo, R. et al. Application and Comparison of Dermoscopy and Reflectance Confocal Microscopy in the Target Treatment of Genital Lichen Sclerosus: A Single-Arm Prospective Study. Dermatol Ther (Heidelb) 13, 3071–3084 (2023). https://doi.org/10.1007/s13555-023-01039-2
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DOI: https://doi.org/10.1007/s13555-023-01039-2