Management of patients with the atrophic variant of vulvar lichen sclerosus

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Abstract

Aim.The objective is to optimize the diagnosis and management of the atrophic variant of the vulvar lichen sclerosus (LS).

Materials and methods. We examined 58 female patients from 20 to 70 years old with the atrophic variant of the vulvar LS. The control group included 30 deemed healthy females 20–70 years old. The atrophic variant of LS was diagnosed based on symptoms (dryness and discomfort in the vulva, superficial vulvodynia and dyspareunia, mild itching) and signs (marked atrophy of the external genitalia tissue up to aplasia of the labia minora and clitoris, vaginal stenosis, minimal hypopigmentation, absence of sclerosis). In addition, the following cytokines were measured in the peripheral blood of patients: interleukin (IL)-20, 23, 10, tumor necrosis factor-α, and interferon-γ. The measurements were performed before and after immunotherapy with sodium deoxyribonucleate.

Results. In all patients, there was a rapid shrinkage of the labia minora and clitoris, thinning and easy traumatization of the dermis and epidermis, contributing to secondary infection and synechiae formation up to complete vaginal occlusion. An increase in IL-23 (19.01 [18.0; 38.5] vs. 16.6 [12.98; 20.71] in the control group), 2.7-fold (p<0.03) decrease in tumor necrosis factor-α, interferon-γ and IL-20 are common for the atrophic variant of LS. The immunomodulatory and clinical efficacy of sodium deoxyribonucleate was demonstrated. Severe vulvodynia before treatment was noted in 29 (50%) patients and no patient (0%) after therapy; 44 (75.8%) patients reported complete reversal of superficial vulvodynia after treatment, and there were no patients without vulvodynia before treatment (0%). Mild itching before treatment was noted by 20 (40%) patients and 2 (3.4%) patients after treatment. Considering the cytokine levels, topical glucocorticoids in atrophic LS are inappropriate and can lead to atrophy and immunosuppression aggravation, contributing to the secondary infection.

Conclusion. The observed differences in cytokine levels in patients with atrophic vulvar LS confirm the relevance of LS clinical classification by variants, support their use for LS diagnosis and immunotherapy efficacy control, and also suggest a differentiated approach to the treatment of different LS variants considering the effect of the drugs used on cytokine status.

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Sclerotic lichen (SL) is a chronic inflammatory progressive skin disease that more often affects the anogenital region [1]. SL can occur at any age and in both sexes, but it is most common in women. In recent years, there has been a significant increase in the incidence of vulvar cancer all over the world, as well as its "rejuvenation" [2]. On average, the prevalence of vulvar CP ranges from 0.1% in prepubertal to 3% in postmenopausal periods [3;4]. However, it is necessary to take into account the underestimation of this pathology, associated with both errors in diagnosis and low access of women with vulvar cancer to specialists, especially in the early stages of the disease. At the same time, vulvar cancer significantly reduces the quality of life of patients, starting with sexual dysfunction and ending with the development of anxiety and depressive disorders [5]. In addition, the pathology can transform into squamous cell cancer of the vulva (the estimated risk is up to 5%) [6].Immune (autoimmune) and genetic hypotheses are currently leading among the main pathogenetic hypotheses of the development of SL, and the possible role of infectious, endocrine, neurogenic and other factors is also being considered [7;8;9]. The presence of immune dysfunction in patients with CF [10.;11;12] indicates the prospect of using immunocorrection in the treatment of vulvar CF. However, there is still no consensus among scientists and specialists around the world about the pathogenesis of SL, its diagnosis and treatment [13]. Meanwhile, in our opinion, the main problem of insufficient effectiveness of vulvar CP therapy is the lack of a unified clinical classification of vulvar CP, taking into account the peculiarities of the course and clinical picture of the disease, which served as the basis for the development of a clinical classification of various variants of the course of vulvar CP, based on the identification of objective and subjective clinical criteria (atrophy, sclerosis, depigmentation, stenosis of the vestibule of the vagina, itching, vulvodynia, dyspareunia, etc.), and depending on the characteristics and predominance of certain criteria, 3 clinical variants of the course of the vulva were identified: sclerosing, scleroatrophic and atrophic [14;15]. Accordingly, when choosing CP therapy, it is necessary to take into account which variant of the course takes place in a particular patient. In particular, this article describes and analyzes the features of the management of patients with an atrophic variant of the course of the vulva.

The aim of the study is to optimize approaches to the diagnosis and management tactics of women with an atrophic variant of the course of the vulva.

Materials and methods. The study involved 58 patients with an atrophic variant of the course of the vulva. All patients underwent such studies as a survey, anamnesis collection, general clinical and gynecological examination, vulvoscopy, vulva biopsy with morphological examination of the biopsy. The atrophic variant of the course of SL was established on the basis of subjective (pronounced dryness and discomfort in the vulva, superficial vulvodynia and dyspareunia, mild itching, or its absence) and objective symptoms (pronounced atrophy of the tissues of the external genitalia (NGO), including dermis and subcutaneous fat against the background of aplasia of the labia minora and clitoris, stenosis the vestibule of the vagina of the I-III degree, minimal manifestations of hypopigmentation, absence of sclerosis and thickening of the vulva skin). In addition, the content of cytokines IL-20, IL-23, IL-10, TNFa, and IFNy in the blood plasma of patients was evaluated before and after immunotherapy using a nucleic acid preparation (sodium deoxyribonucleate). The use of immunocorrection on the 1st tap of vulvar CP therapy is justified by a large amount of data available in the scientific literature on the role of immunological factors in the pathogenesis of CP [16;17;18]. In addition, the use of immunomodulators for vulvar cancer is recommended by the American Association of Pediatric and Adolescent Gynecologists in the absence of an effect and/or when patients refuse drugs containing glucocorticoids [19]. As an immunomodulatory therapy, we selected a drug based on eukaryotic DNA: sodium deoxyribonucleate, Derinat, manufactured by Technomedservice CJSC FP, Russia. The choice of this domestic immunomodulator is due to the fact that it, being an agonist of pathogen-recognizing receptors (TLR9) of innate immunity cells [20], has immunoregulatory ability, as well as reparative properties [21], which is especially important in the atrophic variant of the course of the vulva. In addition, the undoubted advantage of Derinate, which distinguishes it from many other immunomodulatory drugs, is the absence of contraindications for its use in cases of signs of an autoimmune process (according to the official instructions for use). Inclusion criteria: age 20-70 years, atrophic variant of the course of the vulva, lack of treatment with immunotropic drugs during the last year. Exclusion criteria: viral infections (HPV, HSV-1,2); sexually transmitted infections; acute infectious process (including vulvitis and vaginitis); presence of oncological process; pregnancy; unwillingness of the patient to participate in the study. The control group included 30 conditionally healthy women without vulvar pathology aged 20 to 70 years. All clinical trials were conducted after receiving the informed consent of the patients. The assessment of subjective symptoms (complaints) before and after treatment was carried out using the Numerical rating scale for pain, which is a digital version of the visual-analog scale (VAS) [22], where 0 is "no pain", 5 is "moderate pain" and 10 — "the greatest pain imaginable."The study of the content of IL-20, IL-23, TNFa, IFNy and IL-10 in the peripheral blood of patients was carried out by an enzyme immunoassay using a Multiscan FC photometer (Finland) and test systems manufactured by R&D Systems (USA), Bender Medsystems (Austria)) before and 1 month after immunotherapy. Derinat was applied 1 amp. (15 mg / ml) intramuscularly 1 time a day, with an interval of 48 hours, a course of 10 injections, combined with local (before bedtime on the vulva area,) applications of vegetable (linseed) oil as an emollient. Statistical processing of the obtained data was performed using the statistical program "GraphPad Prism 6.0" with an assessment of the nonparametric Mann-Whitney U—test without an assessment of the normality of the distribution. Differences at p≤0.05 were considered statistically significant.

Results and discussion. When analyzing the age of the onset of the disease in patients with an atrophic variant of the course of vulvar CP, it was found that the onset of CP occurs not only in elderly postmenopausal women, as was previously believed. Most often, the onset of the disease occurred in the period before menopause (54.5 ± 4.9%), most often at the age of 35-55 years.An important feature was that almost all patients with an atrophic variant of the vulva noted a rapid progressive decrease in the labia minora and clitoris until their complete disappearance.

Fig. 1 shows an atrophic variant of vulva SL in patients of different ages. In Fig. 1a shows an image of the vulva of a 29-year-old patient with an atrophic variant of SL. The disease occurred at a fairly young age – 25 years.

Complaints of dryness in the vulva, rapid reduction and then complete disappearance of the labia minora. The patient noted vulvar itching as insignificant (1 point on a scale from 0 to 10). Tissue depigmentation is practically absent. When examining the external genitalia with a cotton swab, soreness is noted when touching the skin of the vulva and mucous membrane in the area of the vestibule of the vagina (superficial vulvodynia – 6 points on a scale from 0 to 10), with a vaginal examination (with one finger), deep pain was not noted. Examination in mirrors was difficult due to the presence of stenosis of the vestibule of the vagina of the II degree.

Fig. 1 Atrophic variant of vulva SL: 1a) the patient is 29 years old, the duration of the process is 4 years; 1b) the patient is 36 years old, the duration of the process is 5 years; 1b) the patient is 40 years old, the duration of the process is 10 years

In Fig. 1b a 36-year-old patient had similar complaints and tissue changes as the patient in Fig. 1a, but the itching did not bother (0 points). The duration of the disease is 5 years. The skin is dry, smoother and shinier in the “parchment” type against the background of unexpressed depigmentation. In the area of the vestibule of the vagina, the vascular network shines through the thinned epithelium. There are no thickening of the skin and changes in the type of tissue sclerosis. When examining the external genitalia with a cotton swab, moderate superficial vulvodynia was also detected (5 points), there was no pain during vaginal examination. Examination in mirrors was possible only when using a small gynecological mirror (S).Fig. 1b shows changes in vulva tissues that occurred within 10 years from the onset of the disease (the onset of the disease - at 30 years). Complaints only about a slight dryness of the skin. The patient's mother was also diagnosed with vulval SL. Taking into account the experience of the mother, the patient from the very beginning of the disease carried out prevention and therapeutic measures to prevent exacerbations and progression of vulvar cancer, and therefore, even after 10 years, she had minimal subjective and objective signs, mainly manifested by aplasia of the clitoris and labia minora. The itching of the vulva did not bother the patient, there was no vulvodynia and dyspareunia.  An important feature of the atrophic variant of the course of the vulva is the rapidly occurring atrophy of the vulva tissues with thinning of the dermis and epidermis, with their slight traumatization, which often leads to the addition of secondary infection, inflammation and the formation of synechiae. Figure 2 shows patients with an atrophic variant of the course of the vulva, complicated by an inflammatory process.

Fig. 2 Atrophic variant of vulva SL with an inflammatory process in the vulva and the entrance to the vagina: 2a) the patient is 55 years old, the duration of the process is 2 years; 2b) the patient is 28 years old, the duration of the process is 3 years, in both cases there is complete atrophy of the clitoris and labia minora, dryness in the area of the external genitalia, a feeling of skin tightening, burning, periodic pain and pain when urinating.

In both cases, there is complete atrophy of the clitoris and labia minora, dryness in the area of the external genitalia, a feeling of skin tightening, burning, periodic pains and pain when urinating. Against the background of a thinned epidermis, especially in the area of the vestibule of the vagina, foci of inflammation (hyperemia) due to secondary infection are noted.Recurrent inflammatory processes against the background of vulvar atrophy in the absence of timely treatment lead to serious and, often, irreversible complications, such as vaginal stenosis of varying degrees up to its complete overgrowth. In Fig. 3 presents an image of an NGO of a 69-year-old patient with a complication of the atrophic variant of SL in the form of stenosis of the vestibule of the vagina of the III degree. Urine enters the vagina through a small hole, where it accumulates and then slowly flows out through a small hole 2 mm in diameter. This complication is associated precisely with the long course of the atrophic variant of SL (23 years), accompanied by frequent episodes of inflammatory processes in the vulva and vagina. Thinned tissues stuck together against the background of the inflammatory process, and then fused. For 23 years, the patient was bothered by minor itching, dry skin, then pain when urinating joined.Fig. 3 Atrophic variant of the course of CP in a 69-year-old patient, complicated by grade III vaginal stenosis (duration of the process is 23 years).In the image, we see skin changes of the “parchment” type, the complete disappearance of the labia minora and the fusion of the labia majora against the background of a moderate violation of skin pigmentation. The patient successfully underwent median resection of the vulva with plastic reconstruction of the vestibule of the vagina.As a result of the conducted immunological study, a significant significant decrease in the level of proinflammatory cytokines was revealed in patients with an atrophic variant of the course of the vulva: TNFa – 2.7 times (p<0.03), IFNy - 2 times (p<0.03) compared with the control group. There was also a tendency to decrease the concentration of IL levels in the blood-20 (4,91[3, 54;8, 11]) compared with its level in the control group (7.66 [1.71;20.6]). The concentration of anti-inflammatory IL-10 corresponded to the age norm, while the content of IL-23 significantly increased (19.01 [18.0;38.5]) relative to the control group (16.6 [12.98;20.71]). Thus, for the atrophic variant of SL, the most characteristic is the combination of an increase in IL-23 with a decrease in TNFa, as well as a decrease in the level of most proinflammatory cytokines. At the same time, it is known that IL-23 is able to enhance the secretion of IL-17 and IL-22 - active participants in autoimmunity [23], and TNF-α, in addition to proinflammatory activity, is able to initiate the fibrotic process [24]. Perhaps it is precisely because of the low concentration of TNF-α in patients with an atrophic variant of SL that there are no phenomena of fibrosis and tissue sclerosis characteristic of other variants of the course of SL.

After immunotherapy (after 1 month), the immunomodulatory efficacy of the eukaryotic DNA preparation was established in patients with atrophic variant of SL in the form of the occurrence of most indicators within the normal limits, which confirms the expediency of its use in this category of patients, and also confirms the possibility of using cytokine indicators as criteria for the effectiveness of immunotherapy (table).

Table. Deviations in the cytokine status and immunotropic effects of the eukaryotic DNA preparation in the treatment of patients with an atrophic variant of the course of SL (Me [Q1;Q3])

Indicator

Group 2 (control)

n=30

Group 1 (atrophic variant of SL)

n=58

Before treatment

After treatment

IL-20,

pkg\ml

7,66

[1, 71;20, 6]

4,91

[3, 54;8, 11]

 

7,05 [5, 95;7, 98]

 

IL-23,

pkg\ml

16,6

[12, 98;20, 71]

19,01

[18, 0;38, 5]

p<0,012*

16,31

[12, 03;21, 51]

p<0,012**

TNFα,

pkg\ml

1,830

[1, 61; 1, 95]

0,66

[0, 583; 0, 94]

p<0,03*

1,85

[1, 613; 1, 940]

IFNγ,

pkg\ml

18,17

[17, 71; 19, 00]

8,83

[8, 258; 9, 3]

p<0,03*

18,09

[14, 87; 19, 74]

p<0,03**

IL-10,

pkg\ml

3,41

[3, 03; 3, 65]

3,4

[3, 1; 3, 4]

3,6

[3, 35; 3, 72]

Note. * — statistical significance of the differences compared to the control, ** — compared to the baseline level.In addition to normalization of immunological parameters, 1 month after the course of treatment, a significant part of the patients showed clinical improvement in relation to the main subjective criteria, first of all, the most frequent and pronounced symptom - superficial vulvodynia. With a score assessment of the severity of superficial vulvodynia in patients with atrophic variant of the course of the vulva before treatment, pronounced vulvodynia (from 8 to 10 points) was noted by 29 patients out of 58 (50%), while a month after therapy, none of the patients noted the presence of pronounced superficial vulvodynia from 8 to 10 points (0%). Only 6 patients (10%) after treatment estimated the severity of vulvodynia from 4 to 7 points, whereas before treatment there were 19 such patients (32.7%). At the same time, 44 patients (75.8%) noted the complete absence of superficial vulvodynia after treatment, despite the fact that there were no patients without complaints of vulvodynia before treatment (0%). The clinical efficacy of immunotherapy with respect to superficial vulvodynia in patients with atrophic variant of the course of the vulva is shown in Fig. 4. As for itching of the vulva, it is a less characteristic symptom for this variant of the course of the vulva, and before treatment it manifested itself only in the form of mild itching in 20 (40%) patients. After treatment, complaints of minor itching remained only in 2 (3.4%) patients. The data obtained confirm not only the immunological, but also the clinical efficacy of the eukaryotic DNA drug in patients with an atrophic variant of the course of the vulva.

Fig.4. Dynamics of clinical symptoms in patients with atrophic variant of the course of the vulva before and after treatment with eukaryotic DNA (subjective assessment of the severity of superficial vulvodynia in points)

As for the standard therapy of vulvar CP, the obtained results of the cytokine level in the atrophic variant of the course of CP not only confirm the expediency of dividing this pathology into different variants of the clinical course, but also justify a differentiated approach to the therapy of patients with CP, depending on the variant of its course. So it is known that the use of local glucocorticoids (GC) belongs to the first-line therapy for CP [25].  At the same time, there are contradictory data in the literature on the effectiveness of topical GC in the treatment of vulvar CP, indicating both positive [26] and negative (thinning of the skin, rebound reactions, scarring of tissues, reactivation of fungal and papillomavirus infection) results [27].  In our opinion, such opposite results of treatment of SL with the help of GC can be explained by the lack of consideration of clinical variants of the course of SL. In particular, in the presence of low levels of proinflammatory cytokines in patients with an atrophic variant of the course of SL, the use of GC with immunosuppressive effect [28, 29] can only worsen the course of SL, as well as increase vulvar atrophy and cause an even greater decrease in the concentration of cytokines in the lesion, which will only increase the risks of secondary infection. This can explain the results of many clinical studies using topical GC in patients with vulvar CF, in which, on average, 30% of patients either had no clinical effect or had negative consequences of such therapy. It is possible that these 30% of patients had an atrophic variant of the course of SL, which explains the ineffectiveness of the therapy used.

Thus, in the treatment of an atrophic variant of the course of the vulva, first of all, it is necessary to exclude, or identify and treat the concomitant infectious process in the vulva and vagina. In addition, the use of first-line therapy in the form of topical GC in this category of patients is not only inappropriate, but can also lead to an aggravation of pathological processes in the vulva, even greater atrophy and local immunosuppression, contributing to the development of secondary bacterial, fungal and viral infections. In the period of exacerbation of the atrophic variant of the vulva, the most rational use of immunocorrecting therapy (Derinat), local anti-inflammatory therapy (according to indications), as well as permanent (lifelong) use of emmolents. As for topical preparations of female sex hormones, their local use in the atrophic variant of SL is justified only if the woman is in the period of peri- or postmenopause.

Conclusion.
The revealed differences in the content of cytokines in patients with atrophic variant of the course of the vulva confirm the rationality of our proposed clinical classification of the vulva according to its course variants, substantiate the expediency of assessing their content at the stage of diagnosis of the vulva and in order to control the effectiveness of immunomodulatory therapy, as well as a differentiated approach to the treatment of various variants of the course of the vulva, taking into account the influence of the drugs used on the cytokine status.

 

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About the authors

Ekaterina V. Kolesnikova

Kuban State Medical University

Author for correspondence.
Email: jokagyno@rambler.ru
ORCID iD: 0000-0002-6537-2572

Cand. Sci. (Med.)

Russian Federation, Krasnodar

Alexander V. Zharov

Kuban State Medical University; Regional Clinical Hospital №2

Email: zharov.1966@yandex.ru
ORCID iD: 0000-0002-5460-5959

D. Sci. (Med.)

Russian Federation, Krasnodar; Krasnodar

Grigory A. Penzhoyan

Kuban State Medical University

Email: pga05@mail.ru
ORCID iD: 0000-0002-8600-0532

D. Sci. (Med.), Prof.

Russian Federation, Krasnodar

Natalia V. Mingaleva

Kuban State Medical University

Email: mingalevan008@yandex.ru
ORCID iD: 0000-0001-5440-3145

D. Sci. (Med.)

Russian Federation, Krasnodar

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Supplementary files

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2. Fig. 1. Atrophic variant of vulvar lichen sclerosus (LS): a – 29-year-old patient, the disease duration is 4 years; b – 36-year-old patient, the disease duration is 5 years; c – 40-year-old patient, the disease duration is 10 years.

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3. Fig. 2. Atrophic variant of vulvar LS with inflammation of the vulva and vaginal opening: a – 55-year-old patient, the disease duration is 2 years; b – 28-year-old patient, the disease duration is 3 years.

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4. Fig. 3. Atrophic variant of LS in a 69-year-old female patient complicated by grade 3 vaginal stenosis (the disease duration is 23 years).

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5. Fig. 4. Change over time of signs and symptoms in patients with the atrophic vulvar LS before and after the treatment with eukaryotic DNA (self-assessment of the superficial vulvodynia severity in points).

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