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S.I. Artemyeva

Moscow Scientic and Practical Center of Dermatvenerology and Cosmetology

A.Y. Atabieva

Moscow Scientific and Practical Center of Dermatovenerology and Cosmetology

S.I. Bobko

Moscow Scientific and Practical Center of Dermatology, Venereology and Cosmetology of Moscow City Health Department

M.A. Smerdova

Moscow Scientific and Practical Center of Dermatovenerology and Cosmetology

Pruritus pathogenesis in dermatoses: prurigo, psoriasis, and squamous lichen planus

Authors:

S.I. Artemyeva, A.Y. Atabieva, S.I. Bobko, M.A. Smerdova

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To cite this article:

Artemyeva SI, Atabieva AY, Bobko SI, Smerdova MA. Pruritus pathogenesis in dermatoses: prurigo, psoriasis, and squamous lichen planus. Russian Journal of Clinical Dermatology and Venereology. 2022;21(3):350‑360. (In Russ., In Engl.)
https://doi.org/10.17116/klinderma202221031350

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Introduction

Pruritus is one of the most pressing issues in dermatological practice. Many patients with chronic dermatoses such as prurigo, squamous lichen planus (SLP) and psoriasis suffer from itching. However, a clear understanding of its pathogenesis has not been defined.

Prurigo

Prurigo is a chronic skin disease manifested by severe itching and excoriations persisting for a long time. Symmetrically arranged pruriginous papules, nodules, or plaques are typical for prurigo. According to the predominant type of rash, the subtype of chronic prurigo is classified as nodular (prurigo nodularis), papular, plaque, linear, or umbilicated prurigo. In addition to the clinical type, the clinical presentation also differs in the number and localization of the rash elements. The severity of the disease and itching can be identified by the presence of excoriations on the surface of the pruriginous elements. The vicious circle of itching and scratching significantly reduces the quality of life of these patients. Currently, dermatologists in Europe have no specific tools for objective assessment of pruriginous rashes, and there is no classification of chronic prurigo by severity based on clinical presentation. Treatment approaches are not fully established. Given the need to determine a pathogenesis-based approach to the treatment of prurigo, the study examined blood levels of biomarkers potentially associated with disease pathogenesis (calcitonin gene-regulated peptide — CGRP, vascular endothelial growth factor — VEGF-A, vasointestinal peptide — VIP). CGRP is known to be a marker of skin neuroinflammation, and several studies have noted an increase in its expression in skin nerve fibers of prurigo patients [1-3]. VEGF-A is known to be the main skin angiogenesis factor produced by some resident skin cells, including keratinocytes; its expression in the skin is increased and reflects the pathogenetic features of prurigo, correlating with the severity of the disease [4].

Lichen ruber planus

Lichen ruber planus (LRP) is one of the most common skin and oral mucosa (OM) diseases, but despite numerous studies, the pathogenesis of the disease is still largely unclear. LRP accounts for 0.16-1.2% of all skin diseases [5]. A typical feature of LRP is a tendency to clustered rashes on the skin and OM forming rings, garlands, and lines, accompanied by itching, which may be severe, causing anxiety and sleep disturbances in the patient. In most cases, the rash localizes symmetrically on the flexor surfaces of the limbs, torso, genitals, and OM. Rarely, palms, soles, and face are involved. During exacerbation of LRP, a positive Koebner phenomenon is observed: the appearance of new nodules at the site of skin trauma. LRP accounts for 35-70% diseases of OM [6]. The disease occurs more than twice as often in women than in men, mostly in perimenopause [7]. Depending on the form of OM LRP, the clinical presentation can range from asymptomatic reticular papules to painful erosive and ulcerative elements. The etiology of LRP is unknown. Several main theories of this disease are considered: autoimmune, genetic, viral, intoxication, neurogenic [8]. Initial symptoms and relapses can occur following psycho-emotional stress, which in turn can influence the severity of the disease [9]. Cytokines and other inflammatory mediators, including growth factors, angiogenesis factors, and neuropeptides, are involved in the development of inflammation in the skin and OM, as well as in the development of pruritus in patients with chronic inflammatory dermatoses [10].

Neuropeptides are biologically active protein compounds synthesized and secreted by neurons of the central and peripheral nervous systems, regulating their functions. The contribution of neuropeptides to neurogenic inflammation is well-studied [11-13]. Sensory innervation neuropeptides not only contribute to inflammatory effects mediated by immune functions such as plasma extravasation, edema, the release of tissue cytokines, and leukocyte recruitment and proliferation [14-16] but also have trophic effects on healthy tissue and are involved in tissue damage repair [17-19]. The involvement of the nervous system in chronic inflammation has been studied in several diseases such as rheumatoid arthritis [20, 21], psoriasis [22, 23], etc. [24]. There are published studies that showed the increased level of regulatory neuropeptides (substance P, VIP, CGRP) in psoriatic plaques [10, 25]. CGRP, VIP, substance P are considered the most significant neuropeptides. CGRP is a natural 37 amino acid peptide that is formed through tissue-specific alternative processing of calcitonin mRNA and is widely distributed in the central and peripheral nervous systems. CGRP is localized predominantly in sensitive afferent and central neurons and mediates several biological actions, including vasodilation. CGRP stimulates keratinocyte proliferation, promotes mast cell degranulation, and migration of leukocytes and macrophages into the skin resulting in skin inflammation with erythema and edema. VIP is a neuropeptide consisting of 28 amino acids distributed throughout the central and peripheral nervous systems. It is found in postganglionic nerve fibers along with acetylcholine. In the skin, it is active in the basal membrane, keratinocytes, and Merkel cells and has immunomodulatory effects by inducing vasodilation, mast cell degranulation, and plasma extravasation [26]. Studies on the levels of the above neuropeptides in the tissues of the OM in LRP show a loss of nerve fibers in structurally damaged foci with extensive lymphocytic inflammation [27]. Similar local loss of innervation has been described in other inflamed tissues, especially in severe inflammation [28].

However, the significance of CGRP, VIP in the development of skin and OM LRP has not been fully elucidated.

An important role in the development of chronic inflammatory skin diseases is played by angiogenesis, which is the development of new blood vessels from the existing ones and is a determining factor in the formation of new tissues and their healing. This process is involved in physiological conditions such as embryonic development and wound healing, as well as in abnormal conditions such as cancer development and chronic inflammatory diseases (rheumatoid arthritis, psoriasis, etc.) [29].

The key regulator of angiogenesis is vascular endothelial growth factor (VEGF) [30]. It is a chimeric glycoprotein with a molecular weight of 34-45 kDa consisting of two subunits [31]. VEGF is produced by various cells such as endothelial cells, macrophages, fibroblasts and smooth muscle cells [32]. Various normal and abnormal conditions associated with hypoperfusion and/or hypoxia can cause VEGF activation. Elevated serum VEGF levels have been reported in patients with rheumatoid arthritis, poly- and dermatomyositis, and active systemic lupus erythematosus [33]. Scardina et al. reported that 64.2% of OM LRP tissue samples showed VEGF expression [34]. Tao et al. evaluated microvascular density and VEGF expression in patients with OM LRP and found that angiogenesis and VEGF expression were closely associated with different clinical types of lesions in OM LRP [35]. However, the significance of VEGF in the development of skin and OM LRP has not been fully elucidated.

Despite numerous studies of neuropeptide and vascular endothelial growth factor expression in tissues in LRP, little is known about their plasma levels in patients. Because it appears that neuropeptides (VIP, CGRP) and vascular endothelial growth factor (VEGF) may play an important role in cutaneous inflammation in skin and OM LRP, and this issue is understudied, we measured their plasma concentrations and compared them to those of healthy subjects.

Psoriasis

Psoriasis is a common, chronic, inflammatory disease with immune dysregulation as the primary pathogenetic mechanism [36]. On average, 2-7% of the human population worldwide has psoriasis [37].Psoriasis has a pronounced negative impact on various aspects of patients' lives.For a long time, psoriasis was thought to be a non-itching dermatosis, but clinical evidence suggests otherwise, and patients often complain of itching. According to foreign studies, psoriasis is associated with pruritus in 60-80% of cases [38-40]. According to the results of the study for 2020-2021 conducted in the Moscow Research Center for Dermatovenerology and Cosmetology, a high rate of itching was shown: 58% in 403 patients with psoriasis. Thus, the high rate of itching in psoriasis confirms the relevance of studying the issue of pruritus and its mechanisms to select an adequate treatment. Itching in psoriasis can be intermittent or continuous, often intensifying at night and disrupting the patient's sleep. Most patients with psoriasis consider itching the most aggravating symptom of their disease. Therefore, the study of itching pathogenesis in psoriasis is relevant, which will make it possible to determine effective therapies for alleviating this symptom. We analyzed domestic and foreign literature on pruritus pathogenesis in psoriasis. The literature data warrant further study of pruritus pathogenesis to select appropriate, effective, and safe treatment considering the absence of specific antipruritic therapy in psoriasis. According to the literature, it is relevant to study the correlation of serum markers with the severity of itching in psoriasis. It is currently believed that cytokines and other inflammatory mediators, including neuropeptides and growth factors, are involved in the development of skin inflammation and pruritus in patients with chronic inflammatory dermatoses [41].

Markers from the group of neuropeptides and antimicrobial peptides were selected to study the itching pathogenesis in psoriasis. Neuropeptides include neuropeptide Y (NPY), which is produced in the skin by the endings of sensitive nerve c-fibers. A decrease in plasma NPY levels was shown, with a persistent reduction correlated with itching severity [38]. This neuropeptide is involved in the development of itching, which is caused by the effect of itching mediators on the ends of pruritoceptive nerve fibers. Another marker, VAP-1, is a dimeric membrane protein that consists of an N-terminal cytoplasmic tail, a transmembrane domain, and a large extracellular domain. VAP-1 promotes the rolling, adhesion and transmigration of lymphocytes and polymorphonuclear leukocytes through the vascular endothelial layer. Some studies reported increased levels of soluble vascular adhesive protein-1 (sVAP-1) in patients with "itchy" psoriasis, which requires further investigation. Serum VAP-1 measurement can provide valuable information for disease activity diagnosis and contribute to prognosis assessment [41, 42].

Several studies also show the effect of antimicrobial peptides on the development of itching. Antimicrobial peptides include lipocalin-2 (LCN2) and beta-defensin 2 (DEFb2/hBD-2).

LCN2 is a protein of the family of low molecular weight polypeptides, lipocalins. Their function is related to the immune response, cell growth, apoptosis, etc. Thus, LCN-2, also known as neutrophil gelatinase associated lipocalin (NGAL), is involved in defense responses against bacteria. It is thought to kill bacterial cells by eliminating iron ions needed for life. This is evidenced by its ability to bind to bacterial siderophores, iron ion trapping molecules. Iron cations (Fe3+) are known to be essential for critical cellular functions such as respiration and DNA synthesis. The fact of persistent elevation of this peptide in patients with "itchy" psoriasis is interesting [43]. Another antimicrobial peptide is beta-defensin 2 (DEFb2/hBD-2). Current data show a persistent elevation of this marker in the blood of patients with psoriasis, which was also observed in patients with pruritus.

Since we can affect the production levels of neuropeptides and growth factors in the skin, the data on the involvement of the above biomarkers of inflammation and itching will allow further development of therapeutic approaches for patients with “itchy” dermatoses based on the severity of the disease and itching.

Aim: to study the role of blood biomarkers in pathogenesis of pruritus in chronic skin and mucous membrane diseases.

The following objectives are set:

1) To determine serum levels of CGRP, VIP and VEGF-A biomarkers in prurigo patients;

2) To determine serum levels of CGRP, VIP and VEGF-A biomarkers in patients with various types of LRP;

3) To determine serum levels of biomarkers DEFb2/hBD-2, LCN2, sVAP-1, NPY in psoriasis patients.

Materials and methods

Study object: patients diagnosed with prurigo, LRP, psoriasis, healthy volunteers (control group).

Materials and methods for the Objective 1.

Thirty patients with prurigo were examined at the Moscow Research Center for Dermatovenerology and Cosmetology.

Patients were divided into the following groups:

1) Prurigo patients (n=30);

2) Control group consisting of healthy volunteers without skin lesions (n=17).

Study methods

The following methods were used to measure serum biomarker levels: Human VEGF-A — immunoassay kit for the quantitative determination of human vascular endothelial growth factor A, ELISA (manufactured by ThermoFisher scientific, guidance provided by ZAO BioChemMack); Vasointestinal peptide (no extraction) — immunoassay kit for the quantitative determination of vasointestinal peptide (VIP) in blood plasma, (BCM Diagnostics, guidance provided by ZAO BioChemMack); Peptide related to calcitonin gene; ELISA test kit (Cloud-Clone Co., official distributor in Russia).

Statistical analysis was performed using SPSS Statistics 27 software (IBM). Distribution quartiles were used to describe the data due to small samples and large data variations. The nonparametric Mann-Whitney test was used to compare groups. The critical level of significance was p<0.05.

Materials and methods for the Objective 2.

Fourty-one patients with LRP and combined skin and OM involvement and isolated OM LRP (exudative-hyperemic and erosive-ulcerative types) were examined in the Moscow Research Center for Dermatovenerology and Cosmetology.

Patients were divided into the following groups:

1) Patients with LRP with combined skin and OM involvement (n=21);

2) Patients with isolated OM LRP (exudative-hyperemic and erosive-ulcerative types) (n=20);

3) Control group consisting of healthy volunteers without skin lesions (n=17).

Study methods

1. The following methods were used to measure serum biomarker levels: Human VEGF-A — immunoassay kit for the quantitative determination of human vascular endothelial growth factor A, ELISA (manufactured by ThermoFisher scientific, guidance provided by ZAO BioChemMack); Vasointestinal peptide (no extraction) — immunoassay kit for the quantitative determination of vasointestinal peptide (VIP) in blood plasma, (BCM Diagnostics, guidance provided by ZAO BioChemMack); Peptide related to calcitonin gene; ELISA test kit (Cloud-Clone Co., official distributor in Russia).

2. Statistical analysis was performed using Jamovi 1.6.23 solid software. The significance of the difference between the samples was calculated using the nonparametric Mann-Whitney test. The p<0.05 was considered statistically significant.

Materials and methods for the Objective 3.

Eighty-eight patients with psoriasis were examined at the Moscow Research Center for Dermatovenerology and Cosmetology.

Patients were divided into the following groups:

1) Patients with extremely severe psoriasis (n=30);

2) Patients with comorbidities and "itchy" psoriasis (n=30);

3) Comparison group (non-itchy psoriasis), patients with moderate severity receiving standard therapies (n=28).

Study methods

1. The following methods were used to measure serum biomarker levels: ELISA (DEFb2/hBD-2, LCN2, sVAP-1 and NPY), immunoassay kits for quantitative determination of biomarkers in blood serum (Cloud-Clone Co., official distributor in Russia).

2. Statistical analysis was performed using Jamovi 1.6.23 solid software. The significance of the difference between the samples was calculated using the nonparametric Mann-Whitney test. The p<0.05 was considered statistically significant.

Inclusion criteria: age over 18, confirmed diagnosis (diagnostic criteria: medical history, physical examination — typical clinical presentation), and availability of informed voluntary consent. Exclusion criteria: presence of severe psychiatric disorder complicating the examination; concomitant dermatological and somatic diseases causing itching; pregnancy.

Results and discussion

The serum levels of biomarkers were measured by ELISA in accordance with the manufacturer's guidance. The serum levels of biomarkers (VEGF-A, VIP, CGRP) were determined in 30 patients with prurigo (11 males aged 41-89 years, mean age 62.8 years, and 19 females aged 20-88 years, mean age 58.4 years).

The clinical presentation included localized or generalized rashes on the skin of the trunk and extremities in the form of spots, excoriated papules or nodes, plaques, point and linear excoriations accompanied by itching and other sensations, including burning, tingling, prickly sensations localized in-depth (pain); the rash elements resolve in atrophic scars and hyperpigmented spots. A third of the patients had grade I of severity (practically intact skin), 1 to 5 pruriginous elements after the therapy (systemic steroids, phototherapy, topical glucocorticosteroid therapy); a third of patients had grade II of prurigo severity (mild), from 6 to 19 pruriginous elements was observed; about a third of patients had grade III of severity (moderate), from 20 to 100 pruriginous elements; none of the examined patients had grade IV of severity (severe), more than 100 pruriginous elements. However, in 1 patient, the objectively severe disease was observed with less than 100 elements, which corresponded to the grade III of severity (moderate). For comparison, a control group was enrolled, represented by subjects without skin disorders (2 males aged 55 to 72 years, mean age 63.5 years, and 17 females aged 34 to 64 years, mean age 43.17 years).

The median value of VEGF-A blood level in patients in the study group was 43.15 pg/ml (1st and 3rd quartiles 24.2 and 82.01, respectively) vs. 86.39 pg/ml (48.28 and 117.04) in the control group. Thus, the study group had a lower VEGF-A blood levels. This difference was statistically significant (p=0.015, non-parametric Mann-Whitney U-test).

CGRP blood levels in patients in the study group were 48.46 pg/ml (1st and 3rd quartiles 14.48 and 78.05) vs. 83.34 pg/ml (49.98 and 92.6) in the control group. The observed difference between the study and control groups was also statistically significant (p=0.003).Sex and age had no effect on CGRP (p>0.05) (Fig. 1).

Fig. 1. Biomarker levels (CGRP and VEGF-A) in serum of prurigo patients and controls, pg/ml.

The median VIP blood level in patients in the study group was 0.855 ng/ml (1st and 3rd quartiles 0.366 and 1.207), vs. 0.81 ng/ml (0.732 and 0.978) in the control group. This difference was statistically non-significant (p=0.924, non-parametric Mann-Whitney U-test) (Fig. 2).

Fig. 2. Biomarker level (vasoactive intestinal peptide — VIP) in serum of prurigo patients and controls, ng/ml.

Recent studies are helping to better understand the pathophysiology of chronic prurigo. It was shown that in prurigo, for unknown reasons, several types of cells lead to inflammation, acanthosis, fibrosis, hypervascularization, and neuroplasticity, including keratinocytes, nerve fibers, vessels, mast cells, and “inflammatory” cells (T-lymphocytes, eosinophils) [44]. Pro-inflammatory Th2 cytokines play the most significant role in pruritus pathophysiology in chronic prurigo [45]. In prurigo, the expression of T-cell interleukin 31 and its receptor in the skin was shown to be increased [46]. Substance P, which highly specifically binds to the type 1 neurokinin receptor, plays a role in the pro-inflammatory signal transmission in chronic prurigo and the release of neurotrophins. Dermal nerves in the affected skin containing substance P are also involved in the disease pathogenesis [47]. It has also been shown that nerve fibers in pruriginous lesions express CGRP, affecting neurogenic inflammation by involving inflammatory cells [2]. Immunohistological studies have shown dermal neuronal hyperplasia in prurigo [48], which is consistent with an increased level of nerve growth factor and its tyrosine kinase A receptor in the dermis of pruriginous lesions [49]. In the excoriated epidermis, the density of nerve fibers is reduced due to axotomy [50, 51]. The density of intraepidermal nerve fibers normalizes after healing of pruriginous lesions [51]. Despite the neuromorphological changes observed in prurigo, functional damage to peripheral nerves was not detected using quantitative sensory tests [52]. Prurigo excoriations have been shown to disrupt the epidermal barrier and stimulate the release of pro-inflammatory mediators. It results in the itching increase through the activation of signaling pathways; this phenomenon is called the itching and scratching cycle [53].

In our study, the levels of vascular endothelial growth factor and calcitonin-regulated peptide in patients with prurigo were lower than in the control group (subjects without skin disorders). On the one hand, it can be explained by the test systems' features and their low analytical sensitivity. On the other hand, according to the literature, the expression of these markers is increased in skin biopsy specimens of prurigo patients but not in blood serum. In addition, in biopsy specimens, a decrease in the density of nerve fibers is observed due to the pathogenetic features of the disease course and neuropathy caused by excoriations. Thus, it is reasonable to assume decreased release of neurotransmitters and pathogenesis-associated molecules (e.g., CGRP and VEGF-A) and their intake into the blood. However, these assumptions have their limitations associated with a relatively small sample of patients with prurigo (30 subjects in the main group). Additional studies are required to further assumptions and conclusions.

In the study of biomarker blood levels in patients with LRP, the following samples were used: 41 blood samples obtained from patients with LRP (35 females, 6 males, mean age 60.6±12.2 years); 21 blood samples obtained from patients with a combined skin and OM LRP involvement (Group 1); 20 blood samples obtained from patients with isolated OM LRP (exudative-hyperemic and erosive-ulcerative types, Group 2) and 17 blood samples obtained from healthy volunteers (control group). VEGF-A blood levels (M±σ) in patients of Group 1 (70.4±69.0 pg/ml) and Group 2 (53.8±34.6 pg/ml) were lower compared to control group (111.7±109.4 pg/ml), and in Group 2, the difference was statistically significant (p<0.05) in contrast to that in Group 1 (p<0.2) (Fig. 3).

Fig. 3. VEGF-A blood levels in SLP patients of groups 1, 2 and controls.

CGRP blood levels (M±σ) in the patients of Group 1 (52.5±43.4 pg/ml) and Group 2 (44.6±38.8 pg/ml) was also lower compared to the control group (81.4±32.3 pg/ml); Group 1 — p<0.07, Group 2 — p<0.01 (statistically significant difference) (Fig. 4).

Fig. 4. CGRP blood levels in SLP patients of groups 1, 2 and controls.

VIP blood levels (M±σ) in patients of Group 1 (1.46±.38 pg/ml) and Group 2 (1.28±0.93 pg/ml) was also lower compared to the control group (0.93±0.48 pg/ml); Group 1 — p<0.1, Group 2 — p<0.2 (Fig. 5).

Fig. 5. VIP blood levels in SLP patients of groups 1, 2 and controls.

Thus, the study showed statistically significant lower blood levels of VEGF-A and CGRP in patients with LRP and the isolated involvement of OM (Group 2) compared to the control group. This observation indicates the involvement of biomarkers in the pathogenesis of OM LRP and may be due to systemic impairment of angiogenesis and neurotransmitter metabolism, which modulates and maintains a cascade of immunological events that ultimately lead to chronic inflammation of the OM. The parameters in patients with skin and OM involvement (Group 1) did not differ significantly from those in the control group, which could be due to the small sample size.

The biomaterial was sampled from 88 patients with psoriasis to determine the serum levels of biomarkers and accomplish Objective 3. Patients were divided into 3 groups according to the severity of the skin involvement, therapy, and presence of itching: Group 1 included patients with extremely severe psoriasis (n=30), Group 2 included patients with comorbidities and “itchy” psoriasis (n=30), Group 3 included comparison group (non-itchy psoriasis), patients with disease of moderate severity, receiving standard therapies (n=28). In all patients with psoriasis, ELISA was used according to the manufacturer's guidance to measure DEFb2/hBD-2, LCN2, sVAP-1, and NPY.

The blood levels of DEFb2/hBD-2 in patients of Group 1 (3982±663 pg/ml) and Group 2 (5578±449 pg/ml) were higher compared to the control group (1245±803 pg/ml) by 2737 pg/ml (p<0.001) and 4333 pg/ml (p<0.001), respectively. Thus, the highest level of DEFb2/hBD-2 was noted in Group 2 (itchy psoriasis), followed by patents with severe psoriasis and non-itchy psoriasis (comparison group) (Fig. 6).

Fig. 6. Beta-defensin-2 levels in psoriasis patients.

The blood levels of LCN2 in patients of Group 1 (8.51±1.17 pg/ml) and Group 2 (15.5±7.17 pg/ml) exceeds those in the comparison group (5.19±1.11 pg/ml) by 3.32 pg/ml (p=0.011) and 10.36 pg/ml (p<0.001), respectively. The difference in the mean values between the Group 1 and Group 2 is 7.03 pg/ml (p<0.001). Thus, the highest level of LCN2 was noted in Group 2 (itchy psoriasis), followed by patents with severe psoriasis and non-itchy psoriasis (comparison group) (Fig. 7).

Fig. 7. Lipocalin-2 levels in patients with psoriasis.

The blood levels of sVAP-1 in patients of Group 1 (434±66.4 pg/ml) and Group 2 (689±205 pg/ml) exceeds those in the control group (214±38.3 pg/ml) by 220 pg/ml (p=0.011) and 475 pg/ml (p<0.001), respectively. The difference in the mean values between the Group 1 and Group 2 is 255 pg/ml (p<0.001). Thus, the highest level of sVAP-1 was noted in Group 2 (itchy psoriasis), followed by patents with severe psoriasis and non-itchy psoriasis (comparison group) (Fig. 8).

Fig. 8. Soluble vascular adhesive protein-1 levels in psoriasis patients.

The blood levels of NPY in patients of Group 1 (141±35.3 pg/ml) and Group 2 (59.3±14.7 pg/ml) exceeds those in the control group (573±837 pg/ml) by 433 pg/ml (p=0.002) and 514 pg/ml (p<0.001), respectively. Thus, in patients with itchy psoriasis, the NPY level is lower compared to other groups (Fig. 9).

Fig. 9. Neuropeptide Y levels in psoriasis patients.

The study of DEFb2/hBD-2, LCN2, and sVAP-1 biomarkers showed their unidirectional changes: the highest levels of biomarkers were found in the blood of patients with "itchy" psoriasis compared with patients with severe psoriasis and non-itching psoriasis. At the same time, the levels of these biomarkers in the groups of severe and "itchy" psoriasis were significantly higher than reference values. On the contrary, the blood levels of NPY in patients with "itchy" psoriasis, compared with patients with severe psoriasis and non-itchy psoriasis, were significantly lower. NPY levels were significantly below the reference range in patients with severe and "itchy" psoriasis. These significant changes in the studied biomarkers indicate that the biomolecules selected for the study are definitely involved in the pathogenesis of pruritus in psoriasis and probably may be potential therapeutic targets for leveling the pruritus in psoriasis.

Conclusion

Based on the results of the study, the following conclusions were drawn:

— significantly lower blood levels of CGRP and VEGF-A in patients with prurigo compared to the control group (subjects without skin disorders) were observed, which may indicate the role of these biomarkers in the pathogenesis of the disease;

— statistically significant lower blood levels of VEGF-A and CGRP in patients with LRP and the isolated involvement of OM compared to the control group were observed. This observation indicates the involvement of biomarkers in the pathogenesis of OM LRP and may be due to systemic impairment of angiogenesis and neurotransmitter metabolism, which modulates and maintains a cascade of immunological events that ultimately lead to chronic inflammation of the OM.

— unidirectional changes in biomarkers DEFb2/hBD-2, LCN2, and sVAP-1 in patients with psoriasis were observed: the highest blood levels of these markers were found in patients with "itchy" psoriasis compared with patients with severe psoriasis and non-itchy psoriasis; on the contrary, blood levels of NPY in patients with "itchy" psoriasis were significantly lower compared with patients with severe psoriasis and non-itchy psoriasis; these significant changes in the studied biomarkers indicate that the biomolecules selected for the study are involved in the pathogenesis of pruritus in psoriasis and probably may be potential therapeutic targets for leveling the pruritus in psoriasis.

Authors’ contributions:

The concept and design of the study — S.I. Artemyeva, A.Ya. Atabieva, S.I. Bobko

Collecting and interpreting the data — S.I. Artemyeva, A.Ya. Atabieva, S.I. Bobko, M.A. Smerdova

Statistical analysis — S.I. Artemyeva, A.Ya. Atabieva, S.I. Bobko

Drafting the manuscript — S.I. Artemyeva, A.Ya. Atabieva, S.I. Bobko

Revising the manuscript — S.I. Artemyeva, A.Ya. Atabieva, S.I. Bobko

The authors declare no conflict of interest.


*The study is carried out as part of the research project “Diagnosis, treatment, and management tactics of patients with skin and subcutaneous tissue diseases, and skin neoplasms. Implementation of the results in Moscow health care” (stage 2, interim). A program of the Moscow Healthcare Department. “Scientific support for Moscow healthcare system”, 2020—2022.

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