Łuszczyca biała – Patofizjologia i mechanizm

Łuszczyca biała
Patofizjologia i mechanizm

Łuszczyca biała (lichen sclerosus) to przewlekła, zapalna choroba skóry o podłożu autoimmunologicznym, najczęściej zajmująca okolice anogenitalne. Patogeneza jest wieloczynnikowa i obejmuje dysregulację odpowiedzi immunologicznej typu Th1 z przewagą cytokin prozapalnych (IL-1, IL-7, IL-15, IFN-γ, TNF-α), obecność autoprzeciwciał IgG przeciwko ECM1 u 74% pacjentek, oraz zwiększoną ekspresję miR-155, która promuje autoimmunizację i włóknienie poprzez regulację proliferacji fibroblastów i supresję genów FOXO3 i CDKN1B. Procesy te prowadzą do nadmiernej syntezy kolagenu typu I i III, włóknienia, uszkodzenia naczyń i niedokrwienia tkanek. Stres oksydacyjny, manifestujący się m.in. wzrostem ekspresji p53 i obniżeniem p16INK4a oraz p27Kip1, odgrywa kluczową rolę w progresji choroby i ryzyku transformacji nowotworowej. Genetyczna predyspozycja wiąże się z antygenami HLA klasy II, zwłaszcza haplotypem DRB1*12/DQB1*0301/04/09/010. Czynniki środowiskowe, takie jak urazy, ekspozycja na mocz, zaburzenia hormonalne, infekcje i stres, mogą inicjować lub zaostrzać przebieg choroby. Dysbioza mikrobioty jelitowej i pochwy również może wpływać na patogenezę poprzez nasilenie stanu zapalnego i uszkodzenie bariery nabłonkowej.

Patogeneza Łuszczycy Białej

Łuszczyca biała (lichen sclerosus) jest przewlekłą, zapalną chorobą skóry o niejasnej etiologii, która najczęściej dotyka okolic anogenitalnych, choć może występować również w innych lokalizacjach. Pomimo intensywnych badań, dokładny mechanizm patogenetyczny tej choroby pozostaje w dużej mierze nieznany. Obecnie istnieją liczne dowody wskazujące na wieloczynnikową patogenezę, w której kluczową rolę odgrywają: predyspozycje genetyczne, zaburzenia immunologiczne, stres oksydacyjny oraz czynniki środowiskowe.¹²

Podłoże immunologiczne choroby

Łuszczyca biała jest obecnie uznawana za chorobę o charakterze autoimmunologicznym. Istnieje coraz więcej dowodów na to, że dysregulacja immunologiczna i przewlekły stan zapalny stanowią jeden z kluczowych mechanizmów patogenetycznych.¹²

W przebiegu choroby obserwuje się nieprawidłową aktywację odpowiedzi autoimmunologicznej typu Th1. Profil cytokinowy wskazuje na przewagę cytokin prozapalnych (IL-1, IL-7, IL-15, IFN-γ, TNF-α) nad przeciwzapalnymi (TNF-β), co potwierdza dominację limfocytów pomocniczych Th1 w patogenezie.¹² Infiltrat zapalny składa się głównie z aktywowanych limfocytów T, które uwalniają interleukiny (m.in. IL-4) oraz transformujący czynnik wzrostu (TGF-β).¹

Istotną rolę odgrywają również limfocyty T regulatorowe (Treg), których zmniejszona aktywność w tkankach dotkniętych chorobą może prowadzić do upośledzenia tolerancji immunologicznej wobec własnych antygenów i rozwoju autoimmunizacji.¹

Autoantygeny i przeciwciała

Badania wykazały obecność krążących autoprzeciwciał IgG skierowanych przeciwko białku macierzy pozakomórkowej 1 (ECM1) u 74% kobiet z łuszczycą białą okolic anogenitalnych w porównaniu z 7% w grupie kontrolnej.¹² Białko ECM1 znajduje się na granicy skórno-naskórkowej i jego dysfunkcja jest od dawna wiązana z patogenezą choroby.¹

Przeciwciała przeciwko ECM1 mogą aktywować metaloproteinazę macierzy 9 (MMP9), która z kolei aktywuje TGF-β, prowadząc do nadmiernej syntezy kolagenu i włóknienia.¹ Podkreśla się jednak, że autoprzeciwciała mogą być nie tyle przyczyną inicjującą chorobę, co raczej skutkiem uszkodzenia błony podstawnej, przyczyniającym się do progresji choroby.¹

Rola mikroRNA w patogenezie

Istotnym odkryciem ostatnich lat jest rola mikroRNA, szczególnie miR-155, w patogenezie łuszczycy białej. Wykazano zwiększoną ekspresję miR-155 w tkankach dotkniętych chorobą.¹²

miR-155 pełni podwójną rolę w patogenezie łuszczycy białej:

Uczestniczy w indukcji autoimmunizacji – jest wyrażany w aktywowanych komórkach immunologicznych (makrofagach, komórkach dendrytycznych, limfocytach B i T) i odgrywa istotną rolę regulacyjną w produkcji cytokin, chemokin i czynników transkrypcyjnych, promując różnicowanie limfocytów T w kierunku Th1¹
Przyczynia się do powstawania tkanki włóknistej – związany jest ze zmniejszoną ekspresją FOXO3 i CDKN1B, genów supresorowych nowotworów zaangażowanych odpowiednio w proliferację fibroblastów i supresję cyklu komórkowego¹²

Mechanizmy włóknistości i przebudowy tkanek

Drugim kluczowym mechanizmem patogenetycznym w łuszczycy białej jest promowanie wzrostu i aktywności fibroblastów oraz nieprawidłowa synteza kolagenu, prowadzące do postępującego tworzenia zhialinizowanej i stwardniałej tkanki skórnej.¹²

W przebiegu choroby dochodzi do istotnych zmian w macierzy pozakomórkowej. Cytokiny prozapalne i czynniki wzrostu, takie jak TGF-β i BMP2, indukują syntezę kolagenu typu I i III w fibroblastach.¹ Badania histopatologiczne wykazują nadmierne odkładanie zmienionego kolagenu, prowadzące do włóknienia.¹

Dodatkowo obserwuje się uszkodzenie naczyń, objawiające się zmniejszeniem liczby naczyń włosowatych oraz stwardnieniem istniejących naczyń, co przyczynia się do postępującego niedokrwienia tkanek.¹²

Stres oksydacyjny w patogenezie

Stres oksydacyjny (OS) odgrywa istotną rolę nie tylko w patogenezie łuszczycy białej, ale także w rozwoju i progresji choroby. Przewlekłe zapalenie indukuje produkcję reaktywnych form tlenu (ROS), które przyczyniają się do uszkodzenia tkanek.¹²

Stres oksydacyjny, powodując uszkodzenia DNA i peroksydację lipidów, przyczynia się bezpośrednio do możliwej transformacji nowotworowej, która jest znanym powikłaniem długotrwałej łuszczycy białej.¹ Wykazano, że u pacjentów z łuszczycą białą, podobnie jak w innych schorzeniach nabłonkowych, wzrost oksydacyjnego uszkodzenia DNA jest związany z obniżeniem ekspresji białek p16INK4a (kodowanego przez gen CDKN2A) i p27Kip1 (kodowanego przez gen CDKN1B).¹

Ponadto zaobserwowano wysoką immunoreaktywność p53 w keratynocytach podstawnych w zmianach łuszczycy białej, co sugeruje obecność stresu oksydacyjnego.¹ Akumulacja i wysoka ekspresja dzikiego typu p53 w zmianach chorobowych silnie wskazuje na obecność stresu oksydacyjnego w łuszczycy białej.¹

Predyspozycje genetyczne

Istnieją dowody na genetyczną predyspozycję do rozwoju łuszczycy białej. Wykazano rodzinne występowanie choroby oraz pozytywną korelację z antygenami HLA klasy II.¹²

Szczególnie istotne wydają się antygeny HLA-DQ7, -DQ8, -DQ9 i -DR12, a zwłaszcza haplotyp DRB1*12/DQB1*0301/04/09/010, które występują częściej u pacjentów z łuszczycą białą niż u osób zdrowych.¹² Antygeny HLA klasy II odgrywają kluczową rolę w regulacji odporności humoralnej, a ich pozytywna modulacja może znacząco zwiększać genetyczną podatność na łuszczycę białą.¹

Czynniki wyzwalające

Szereg czynników środowiskowych może wyzwalać lub zaostrzać przebieg łuszczycy białej, szczególnie u osób predysponowanych genetycznie:¹²

Miejscowe podrażnienie i urazy – opisywano liczne przypadki rozwoju choroby w następstwie urazów, zabiegów chirurgicznych oraz przewlekłego drażnienia skóry¹²
Ekspozycja na mocz – istnieje rosnąca liczba dowodów sugerujących, że przedłużone narażenie podatnych tkanek na drażniące działanie moczu może przyczyniać się do rozwoju łuszczycy białej; krople moczu, które pozostają po oddaniu moczu, mogą tworzyć środowisko okluzyjne, które nasila podrażnienie i stan zapalny¹²
Zaburzenia hormonalne – choroba częściej występuje u kobiet, szczególnie w okresie przed pokwitaniem i po menopauzie, co sugeruje potencjalny wpływ niedoboru estrogenów¹²
Czynniki infekcyjne – rozważano udział patogenów bakteryjnych i wirusowych, w tym Borrelia burgdorferi, wirusa Epsteina-Barr, ludzkiego wirusa brodawczaka (HPV), chociaż jednoznaczne potwierdzenie związku przyczynowego jest trudne¹²
Stres – podwyższony poziom stresu może negatywnie wpływać na układ odpornościowy poprzez uwalnianie kortyzolu i generowanie wysokiego poziomu markerów zapalnych we krwi, co może przyczyniać się do rozwoju i zaostrzenia choroby¹

Mikrobiom skórny i jelitowy

Coraz więcej badań wskazuje na potencjalną rolę dysbiosis (zaburzenia równowagi) mikrobioty skórnej i jelitowej w patogenezie łuszczycy białej.¹²

Badania wykazały, że dziewczęta z łuszczycą białą sromu mają wyższą względną obfitość bakterii Dialister spp. w jelitach, co jest zgodne z wynikami innych chorób zapalnych. Jednocześnie obserwowano niższą względną obfitość Roseburia faecis w porównaniu ze zdrowymi osobami z grupy kontrolnej.¹

Przewlekłe podrażnienie, stan zapalny i zaburzenie bariery nabłonkowej pośredniczone przez lokalny mikrobiom mogą przyczyniać się do patogenezy łuszczycy białej. Ponieważ dysbiosis mikrobioty pochwy może powodować przewlekłe podrażnienie, w tym nasilenie stanu zapalnego i uszkodzenie bariery nabłonkowej, istnieje hipoteza, że mikrobiom może wpływać na patogenezę choroby.¹

Modele patogenetyczne łuszczycy białej

Na podstawie dotychczasowych badań można zaproponować zintegrowany model patogenezy łuszczycy białej, w którym różnorodne, heterogeniczne czynniki środowiskowe działające na podatnym podłożu genetycznym wyzwalają autoimmunologiczną odpowiedź typu Th1, prowadzącą do przewlekłego stanu zapalnego.¹²

Ten stan zapalny powoduje zarówno uszkodzenie tkanek i mikronaczyń, jak i aktywację szlaków sygnałowych zaangażowanych w metabolizm fibroblastów i kolagenu. Sekwencja ta może wyjaśniać skuteczność leków przeciwzapalnych, zwłaszcza miejscowych kortykosteroidów lub miejscowych inhibitorów kalcyneuryny, w znaczącej poprawie zmian kolagenu skórnego.¹²

Zrozumienie złożonych mechanizmów patogenetycznych łuszczycy białej ma kluczowe znaczenie dla opracowania nowych, skuteczniejszych metod terapeutycznych. Pomimo dostępności licznych opcji terapeutycznych, wyniki leczenia mogą nie być w pełni zadowalające, a definitywne wyleczenie nie istnieje, co może wynikać z faktu, że dokładna etiopatogeneza choroby pozostaje nieznana.¹²

Implikacje kliniczne i terapeutyczne

Poznanie mechanizmów patogenetycznych łuszczycy białej ma bezpośrednie przełożenie na stosowane metody terapeutyczne:¹²

Miejscowe kortykosteroidy są leczeniem pierwszego wyboru ze względu na ich działanie przeciwzapalne, hamujące odpowiedź typu Th1¹
Inhibitory kalcyneuryny (takrolimus, pimekrolimus) mogą być alternatywą dla pacjentów nieodpowiadających na kortykosteroidy²
Badania nad nowymi terapiami celowanymi wskazują na potencjalną skuteczność inhibitorów JAK (Janus kinazy), takich jak baricitinib i abrocitinib, w leczeniu łuszczycy białej¹²
Inhibitory TNF-α, jak adalimumab, mogą stanowić obiecującą alternatywę w przypadkach opornych na leczenie, działając na kluczowe cytokiny prozapalne¹
Obiecujące wyniki w leczeniu łuszczycy białej wykazuje również osocze bogatopłytkowe (PRP), które może tłumić odpowiedź autoimmunologiczną poprzez szlak TGF-β/SMAD3¹

Podejście holistyczne do leczenia łuszczycy białej, obejmujące zarządzanie stresem i inne metodologie, może być pożądane z kilku powodów. Po pierwsze, może lepiej ukierunkować podstawową przyczynę schorzenia, aby zmniejszyć częstość występowania ciągłego rozwoju zmian. Ponadto podejścia holistyczne nie wiążą się z niepokojącymi skutkami ubocznymi, które mogą być problemem w przypadku leczenia miejscowymi steroidami.¹

Transformacja nowotworowa

Łuszczyca biała jest związana ze zwiększonym ryzykiem rozwoju raka płaskonabłonkowego w obrębie zmian chorobowych. Mechanizmy sprzyjające transformacji nowotworowej obejmują:¹²

Uszkodzenie oksydacyjne DNA – stanowiąc przewlekły, ciągły bodziec do regeneracji komórek i tkanek, znacząco przyczynia się do złośliwej transformacji choroby¹
Peroksydację lipidów – przyczyniającą się do uszkodzenia błon komórkowych¹
Zaburzenia epigenetyczne – w tym modyfikacje genów supresorowych nowotworów¹
Przewlekły stan zapalny – związany z łuszczycą białą może prowadzić do nieprawidłowości molekularnych, które z kolei mogą ułatwiać proliferację nowotworową¹

Dowodem na znaczenie oksydacyjnego uszkodzenia DNA jako czynnika sprzyjającego progresji choroby i transformacji w raka jest fakt, że stężenie tkankowe specyficznego biomarkera oksydacyjnego uszkodzenia DNA wzrasta od jednego stanu patologicznego do drugiego w następującej kolejności: łuszczyca biała; nieinwazyjny rak sromu; inwazyjny rak sromu.¹

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Materiały źródłowe

#1 Vulvar Lichen Sclerosus from Pathophysiology to Therapeutic Approaches: Evidence and Prospects
https://pmc.ncbi.nlm.nih.gov/articles/PMC8394941/
Vulvar lichen sclerosus (VLS) is a chronic, distressing, inflammatory disease with an enormous impact on quality of life. […] Despite the availability of numerous therapeutic options, treatment outcome may not be entirely satisfactory and a definitive cure does not exist. This may be due to the fact that the exact VLS etiopathogenesis remains unknown. […] Based on current knowledge, it is conceivable that various, heterogeneous environmental factors acting on a genetic background trigger an autoimmune, Th-1 response, which leads to a chronic inflammatory state. […] This pathogenetic sequence may explain the effectiveness of anti-inflammatory treatments, mostly topical corticosteroids, in improving VLS clinical-pathological changes. […] The available evidence indicates the role of two main pathomechanisms, which act on a susceptible genetic background. Suspected triggering factors complete this pathogenetic scenario.
#1 Lichen Sclerosus: An autoimmunopathogenic and genomic enigma with emerging genetic and immune targets
https://www.ijbs.com/v15p1429.htm
Collectively, these emerging targets serve not only as inherently potential therapeutic targets for treatment, but may also provide further insight into this debilitating and cryptic disease. […] However, there are emerging molecular targets that may provide better insight into the progression of LS and the onset of morphological features that lead to the diseased state. […] Despite the strong association with autoimmune disease, the etiology of LS remains a large mystery. […] However, potential therapeutic targets in recent years have been implicated in LS pathology and these emerging targets are discussed below and may be further categorized based on their functional roles in LS pathogenesis and progression via their involvement in (1) activating autoimmunogenic mechanisms, (2) inducing sclerotic tissue formation, or (3) triggering oxidative stress.
#1 Lichen Sclerosus: An autoimmunopathogenic and genomic enigma with emerging genetic and immune targets
https://www.ijbs.com/v15p1429.htm
Given the familial occurrence of LS and the close, positive association between HLA class II antigens and autoimmune disease, many researchers speculated LS pathogenesis may progress along an immunogenetic route towards humoral autoimmunity as the development of autoantibodies to an unknown autoantigen may account for the histological changes seen as extensive extracellular remodeling. […] Dysfunction of extracellular matrix protein 1 (ECM1), found at the dermal-epidermis junction, has long been implicated in the pathogenesis of LS. […] Gene expression profiles of LS have further suggested LS as an immunogenic disease, given increased expression in genes responsible for immune response. […] In particular, more pro-inflammatory cytokines were upregulated in LS (IL-1, IL-7, IL-15, IFN-, TNF-) than anti-inflammatory cytokines (TNF-), suggesting LS is specifically mediated by a T-helper type 1 (Th1) course of action.
#1 Lichen Sclerosus – StatPearls – NCBI Bookshelf
https://www.ncbi.nlm.nih.gov/books/NBK538246/
Lichen sclerosus is an uncommon autoimmune condition characterized by skin atrophy and hypopigmentation. […] Review the role of T cells, autoantibodies and cytokines in the pathophysiology of lichen sclerosus. […] LS is considered to be an autoimmune condition; however, its etiology remains unclear. […] The underlying pathogenesis of LS includes an infiltrate of activated T cells releasing interleukin 4 (IL 4) and transforming growth factor (TGF ). So, these cytokines activate fibroblasts producing significantly altered collagen leading to fibrosis. Besides, the pathogenesis includes vascular damage by the decrease in the number of capillaries. […] Interleukin 1 (IL 1) and interleukin one receptor antagonist (IL 1ra) may also be included in the pathogenesis of lichen sclerosus as well as increased number of monoclonal T lymphocyte CD4 +, lymphocyte T dendritic CD1a + cells, macrophages, mast cells, and decreased number of T lymphocyte CD3 +. […] Another hypothesis has been suggested such as an increased number of circulating IgG autoantibodies targeting extracellular matrix 1 (ECM 1) protein leading to widespread deposition of hyaline material in the dermis.
#1 Advances in Understanding Vulva Lichen Sclerosus: Pathogenesis and Treatment
https://www.gavinpublishers.com/article/view/advances-in-understanding-vulva-lichen-sclerosus-pathogenesis-and-treatment
In females, VLS is considered to be an autoimmune disease. It exhibits characteristics consistent with other autoimmune diseases, including a higher prevalence in females and positive correlations with other female autoimmune conditions. […] Gene expression profiling supports VLS as an inflammatory disease mediated by upregulation of T helper type 1 (Th1) cytokines. A well-established link exists between Th1 responses and autoimmune diseases. […] Furthermore, research indicates that the pathogenesis of vulva lichen sclerosus may be related to Th1 cytokines such as IFN- and epithelial-derived IgG, rather than Th2 or Th17 cytokines and HD-5. […] Studies also suggest that reduced activity of regulatory T cells (Tregs) may be present in VLS tissues. Tregs play a crucial role in maintaining immune tolerance. Consequently, decreased Treg function may lead to impaired self-antigen immune tolerance and autoimmune dysfunction.
#1
https://link.springer.com/article/10.1007/s40257-012-0006-4
Lichen sclerosus (LS) is a chronic, inflammatory, mucocutaneous disorder of genital and extragenital skin. […] Many findings obtained in recent years point more and more towards an autoimmune-induced disease in genetically predisposed patients and further away from an important impact of hormonal factors. […] The etiology of LS has not yet been adequately explained, but there is increasing evidence that autoimmune mechanisms play a pathogenetic role. […] There appears to be a genetic susceptibility to LS. […] In common with many autoimmune diseases, LS is more prevalent in female patients. […] Circulating IgG autoantibodies targeting extracellular matrix 1 (ECM1) protein have been demonstrated in the sera of 74 % of women with anogenital LS compared with 7 % in controls. […] The authors propose that chronic irritation of the genital epithelium may lead to previously sequestered site-specific skin epitopes being revealed and that those patients with an autoimmune diathesis would subsequently be more likely to develop antibodies.
#1 Frontiers | Lichen sclerosus: The 2023 update
https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1106318/full
TGF-Î² and BMP2 induce the synthesis of collagen I and III in fibroblasts. […] Along with inflammation, the vessel sclerosis contributes to the oxidative stress in LS, leading to downregulation of tumor suppressors genes and overexpression of p53 in the skin, factors related with the development of skin carcinomas. The precise sequence of events and their interactions are only incompletely understood.
#1
https://link.springer.com/article/10.1007/s40257-012-0006-4
The detection of autoantibodies to ECM1 and to BMZ components suggests that autoimmunity to these components might contribute to the pathogenesis of LS. […] However, those antibodies rather than being causative and involved in the initiation, might be a result of damage to the BMZ, and contribute to the progression of the disease. […] An infectious etiology has been proposed, but could never be definitively confirmed. […] Hormonal influences do not seem to play a major role.
#1 Frontiers | Lichen sclerosus: The 2023 update
https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2023.1106318/full
There is also a particular expression of tissue remodeling associated genes and an exacerbated oxidative stress that may lead to scarring and malignancy. […] The established diagnosis of LS based on the clinical features is usually sufficient, and a skin biopsy should only be performed in case of clinical doubts, differential diagnosis or suspected malignancy. […] A summary of the pathogenesis and histological changes in LS is depicted in Figure 1. […] The inflammatory early stage of LS is unspecific and shows a dermoepidermal interface band of mostly T-cells. […] miR-155 is overexpressed in LS, stimulates the Th1 profile and the dermal sclerosis. […] Th1 cytokines implicated in the pathogenesis of LS. […] The autoantibodies against EMC1 may activate MMP9, which subsequently activates TGF-Î².
#1 Lichen Sclerosus: An autoimmunopathogenic and genomic enigma with emerging genetic and immune targets
https://www.ijbs.com/v15p1429.htm
An aberrant level of microRNA expression is therefore implicated in LS pathogenesis. […] miR-155 has been shown to be expressed in activated immune cells (i.e. macrophages, dendritic cells, B cells, and T cells) and plays a significant regulatory role in the production of cytokine, chemokine, and transcription factors towards promoting Th1 T-cell differentiation. […] Thus, miR-155 may serve as a critical regulator triggering the loss of normal Treg suppressive function and loss of CD4+ self-tolerance in this proposed autoimmunogenic mechanism for LS pathogenesis. […] In addition to its possible role for inducing autoimmunity, miR-155 is also associated with sclerotic tissue formation. […] Specifically, Ren et al. found increased expression levels of miR-155 in LS tissues along with an associated decrease in FOXO3 and CDKN1B, two tumor suppressor genes involved in fibroblast cell proliferation and cell cycle suppression, respectively.
#1 Vulvar Lichen Sclerosus from Pathophysiology to Therapeutic Approaches: Evidence and Prospects
https://pmc.ncbi.nlm.nih.gov/articles/PMC8394941/
Immunological dysreactivity and chronic inflammation represent one of the two aforesaid key pathomechanisms. On the other hand, promoting fibroblast growth and activity as well as abnormal collagen synthesis, which leads to a progressive formation of hyalinised and sclerotic dermal tissue is the other crucial event in VLS pathogenesis. […] However, the link between these two events and their exact sequence, as well as the role of potential triggers, have not yet been clarified. […] A significant positive association with genes regulating HLA class II antigens further strengthens the view that there is a genetic susceptibility to VLS. […] In particular, HLA-DQ7, -DQ8, -DQ9 and -DR12, mostly haplotype DRB1*12/DQB1*0301/04/09/010, are shown to appear more frequently in LS patients than in controls.
#1 Vulvar Lichen Sclerosus from Pathophysiology to Therapeutic Approaches: Evidence and Prospects
https://pmc.ncbi.nlm.nih.gov/articles/PMC8394941/
A higher percentage of VLS patients, when compared with controls, have one or more autoimmune-related disease or a family history of autoimmune disease or autoimmune antibodies. […] An abnormal activation of a Th1 autoimmune response has been found in affected tissue. […] This supports the likelihood that a Th1 reactivity may promote the development of VLS. […] Chronic inflammation also induces the production of reactive oxygen species (ROS), which are deemed responsible for contributing to tissue damage. […] Promoting fibroblast growth and activity, as well as abnormal collagen synthesis, is another crucial event in VLS pathogenesis and progressive formation of hyalinised and sclerotic dermal tissue. […] The current evidence on physiopathology of VLS points towards a complex, multifactorial process.
#1 Lichen sclerosus: the role of oxidative stress in the pathogenesis of | RRU
https://www.dovepress.com/lichen-sclerosus-the-role-of-oxidative-stress-in-the-pathogenesis-of-t-peer-reviewed-fulltext-article-RRU
Lichen sclerosus (LS) is an autoimmune chronic inflammatory disease usually involving the anogenital skin of both sexes; more rarely LS exclusively involves extragenital areas. […] Oxidative stress (OS) has been proven to play a role not only in the pathogenesis of LS, but also in the development and progression of the disease. OS, by causing DNA damage and lipid peroxidation, contributes directly to the possible malignant transformation of LS. […] It has been proven, furthermore, that in patients with LS, as in other both cancerous and non-cancerous epithelial diseases, the increase in oxidative DNA damage is associated with downregulation of the expression of p16IINK4 (a protein encoded by gene CDKN2A/cyclin-dependent kinase inhibitor 2A) and p27Kip1 (a protein encoded by gene CDKN1B/cyclin-dependent kinase inhibitor 1B).
#1 Lichen Sclerosus: An autoimmunopathogenic and genomic enigma with emerging genetic and immune targets
https://www.ijbs.com/v15p1429.htm
High p53 immunoreactivity in immunostaining, interpreted as p53 overexpression, was found in basal keratinocytes in LS. […] Such findings collectively suggest an intricately complex and interwoven relationship between autoimmunity and oxidative stress in LS. […] Given these collective findings, the accumulation and high expression of wild-type p53 in LS lesions strongly suggest the presence of oxidative stress in LS. […] In general, both protein products inhibit aberrant cell growth through different mechanisms: p16INK4a activates the Rb protein family to block G1 to S-phase progression, whereas p14ARF rescues p53 from MDM2 ubiquitin protein degradation. […] With the absence of p53 and CDKN2A mutations in LS, investigators considered the role of epigenetic modifications in LS, particularly for its potential to induce malignant transformation.
#1 Lichen Sclerosus: Background, Pathophysiology, Etiology
https://emedicine.medscape.com/article/1123316-overview
In LS, inflammation and altered fibroblast function in the papillary dermis lead to fibrosis of the upper dermis. […] It has been hypothesized that oral manifestations are underdiagnosed or misdiagnosed as oral lichen planus, or that environmental effects play a large role in disease expression. […] The etiology and pathogenesis of LS have not been defined but may include genetic, infectious, environmental, and hormonal factors. […] However, the sequence of events that leads to the altered fibroblast function, microvascular changes, and hyaluronic acid accumulation in the upper dermis remains a subject of research. […] Oral contraceptives in premenopausal women have been shown to give rise to a relative risk of 2.5, which suggests an altered hormonal axis as a possible contributory factor. […] A genetic predisposition, based on family clustering, has been described. […] Local irritation or trauma seems to play a role in some cases of LS, especially in genetically predisposed individuals.
#1 Advances in Understanding Vulva Lichen Sclerosus: Pathogenesis and Treatment
https://www.gavinpublishers.com/article/view/advances-in-understanding-vulva-lichen-sclerosus-pathogenesis-and-treatment
While the exact etiology of VLS remains unclear, there is evidence to suggest that the disease is an autoimmune disorder with genetic associations. […] Human leukocyte antigen class II (HLA-II) antigens play a crucial role in humoral immunity regulation. Studies have shown that genetic susceptibility to VLS can be significantly enhanced through positive modulation of HLA-II antigen genes. […] In recent years, increasing evidence has indicated that disturbances in endogenous hormone levels play an important role in vulvar white lesions. […] The unique anatomical location of the vulva makes it susceptible to irritants such as urine, menstrual fluid, and vaginal secretions. […] In some patients with vulvar white lesions, vaginal infections can be present, including Candida species, Treponema pallidum, and Escherichia coli.
#1 Lichen sclerosus: Role of occlusion of the genital skin in the pathogenesis – Indian Journal of Dermatology, Venereology and Leprology
https://ijdvl.com/lichen-sclerosus-role-of-occlusion-of-the-genital-skin-in-the-pathogenesis/
Lichen sclerosus (LS) is a chronic inflammatory skin disease, which most commonly involves the anogenital region. […] The etiology of LS is obscure, but genetic susceptibility, autoimmune mechanisms, infective agents like human papillomavirus and spirochaetes, and Koebner phenomenon has been postulated as causative factors. […] This observation of involvement of the genital mucosa restricted to the opposing surfaces of the glans and the vulva suggests the role of occlusion in the development of genital LS. […] There are several possible mechanisms that may either alone or collectively, explain the effect of occlusion of the genital skin in the pathogenesis of LS. […] This pilot observation suggests that occlusion of the genital skin may be playing a greater role in the causation of LS than is currently thought.
#1 Lichen sclerosus – Wikipedia
https://en.wikipedia.org/wiki/Lichen_sclerosus
Lichen sclerosus is a chronic, inflammatory skin disease, of unknown cause, which can affect any body part of any person, but has a strong preference for the genitals (penis, vulva), and is also known as balanitis xerotica obliterans when it affects the penis. […] Although it is not clear what causes LS, several theories have been postulated. Lichen sclerosus is not contagious and cannot be caught from another person. […] Several risk factors have been proposed, including exposure to the irritant effects of urine, autoimmune diseases, infections and genetic predisposition. […] There is a growing body of evidence suggesting that prolonged exposure of susceptible tissues to the irritant effects of urine may contribute to the development of lichen sclerosus. […] Urine droplets that leak after urination can become trapped in the external genitalia (e.g., beneath the foreskin), creating an occluded environment that exacerbates irritation and inflammation.
#1
https://link.springer.com/article/10.1007/s11033-024-09318-7
The association between HLA DR, DQ antigens, and vulval lichen sclerosus in the UK: HLA DRB112 and its associated DRB112/DQB10301/04/09/010 haplotype confers susceptibility to vulval lichen sclerosus. […] Lichen Sclerosus premenarche: autoimmunity and immunogenetics. […] Genomic profiling of Vulvar Lichen Sclerosus patients shows possible pathogenetic disease mechanisms. […] Differentially regulated miRNAs and their related molecular pathways in lichen sclerosus. […] The possible role of human papillomavirus infection in the development of lichen sclerosus. […] Possible role of Borrelia burgdorferi sensu lato infection in lichen sclerosus. […] The possible role of Epstein-Barr virus and human papillomavirus infection in vulvar lichen sclerosus.
#1 Can Lichen Sclerosus be Caused by Stress
https://coyleinstitute.com/lichen-sclerosus-and-stress/
Lichen sclerosus (LS) is a concerning skin condition characterized by itchy and sometimes painful patches of skin around the female genitalia. […] The precise cause of LS is unknown. However, established research has uncovered hormonal, genetic, environmental, and even immune-system-response-related risk factors. […] According to a study published in 2019 in the Open Access Journal of Urology, oxidative stress (OS) plays a role in the development, pathogenesis, and progression of LS. Researchers state that DNA damage and peroxidation of the lipids caused by OS may directly contribute to the development of LS skin lesions. […] High levels of stress take a toll on the immune system over time. The stress-induced release of cortisol generates high levels of inflammatory markers in the blood. These inflammatory markers can, in turn, have a negative impact on many body systems, including the skin. Therefore, stress could very well be an underlying factor in the development of LS.
#1 Potential role of the skin and gut microbiota in premenarchal vulvar lichen sclerosus: A pilot case-control study | PLOS One
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245243
The etiology of vulvar lichen sclerosus (LS) remains unclear; however, alterations in cutaneous and gut microbiota may be contributing to the pathogenesis of this inflammatory condition. […] Genetic, immunologic, and hormonal factors have been implicated in the pathogenesis of LS, however, the exact etiology of LS remains unclear. […] Given the inflammatory nature of LS, we hypothesized that alterations in the skin or gut microbiotas may be contributing to the pathogenesis of LS. […] We demonstrated that girls with LS have a higher relative abundance of Dialister spp. in the gut, which is consistent with findings from other inflammatory diseases. […] Conversely, girls with LS had a lower relative abundance of Roseburia faecis in the gut compared to healthy controls and girls with nonspecific vulvovaginitis.
#1 The relationship between the vaginal and vulvar microbiomes and lichen sclerosus symptoms in post-menopausal women | Scientific Reports
https://www.nature.com/articles/s41598-024-78372-9
Lichen sclerosus is a chronic inflammatory condition of unknown etiology that affects the genital and extragenital skin, which can lead to sexual dysfunction and has been associated with vulvar cancer. […] Understanding the role of these bacteria in lichen sclerosus pathogenesis will be an essential future investigation. […] Chronic irritation, inflammation, and epithelial barrier disruption mediated by the local microbiome may contribute to the pathogenesis of LS. […] As dysbiosis of the vaginal microbiome can cause chronic irritation, including increased inflammation and epithelial barrier damage, we hypothesized the microbiome may influence the pathogenesis of LS. […] This suggests that a shift in the microbiome may lead to irritation or inflammation that could contribute to LS.
#1 Vulvar Lichen Sclerosus from Pathophysiology to Therapeutic Approaches: Evidence and Prospects
https://pmc.ncbi.nlm.nih.gov/articles/PMC8394941/
It is conceivable that environmental factors acting on a genetic background trigger autoimmune processes, with subsequent inflammation which, in turn, leads to tissue and microvascular injury as well as to activation of signalling pathways involved in fibroblast and collagen metabolism. […] This sequence would explain the efficacy of anti-inflammatory treatments, especially topical corticosteroids or topical calcineurin inhibitors, in significantly improving dermal collagen changes.
#1 Advances in Understanding Vulva Lichen Sclerosus: Pathogenesis and Treatment
https://www.gavinpublishers.com/article/view/advances-in-understanding-vulva-lichen-sclerosus-pathogenesis-and-treatment
The pathogenesis of vulvar lichen sclerosus (VLS) is associated with multiple factors, including immune factors, genetic factors, and infectious factors. Currently, there is a lack of treatment options that provide stable efficacy and prevent recurrence. […] In recent years, topical glucocorticoids have been preferred as the first-line treatment, showing good effectiveness in controlling disease progression.
#1 Lichen sclerosis â GPnotebook
https://gpnotebook.com/en-GB/pages/gynaecology/lichen-sclerosis
Lichen sclerosus (LS) is a chronic lymphocyte mediated inflammation of the skin which most commonly affects the ano-genital epithelium in women. Although the aetiology of lichen sclerosus is unknown, there is evidence of an autoimmune mechanism in the pathogenesis. […] Lichen sclerosus may represent an autoimmune disorder. […] There is evidence of the beneficial effects of Janus kinase (JAK) inhibitors in treating genital lichen sclerosus.
#1
https://journals.lww.com/10.1097/LGT.0000000000000862
This case series aims to evaluate the demographic features, disease characteristics, and treatment outcomes of 8 patients receiving subcutaneous (SC) adalimumab for severe, refractory vulval lichen sclerosus (VLS) and/or vulval lichen planus (VLP). […] Adalimumab, a TNF- inhibitor, may offer a promising alternative by targeting the inflammatory cytokine implicated in the pathogenesis of both conditions. […] The observed clinical benefits suggest that adalimumab targets key inflammatory pathways in these conditions.
#1 JCPM2025.02.11 | Do This Next (with your business) | Lichen Sclerosus, Mechanism of PRP’s Effect | – Cellular Medicine Association
https://cellularmedicineassociation.org/jcpm2025-02-11-do-this-next-with-your-business-lichen-sclerosus-mechanism-of-prps-effect/
We still dont have a complete understanding of what causes lichen sclerosus. […] When youre treating lichen sclerosus, you must block the autoimmune response thats thought to be causing the sclerotic and ulcerative skin breakdown. […] We know PRP attenuates the autoimmune response, and this is, I dont even know how many papers we now have on wound healing and treating infection. […] This one talks about both people and mice and gives a detailed explanation of how platelet-rich plasma or platelet-rich fibrin might be working to help with lichen sclerosus. […] Sun et al., Platelet-Rich Fibrin Attenuates Inflammation and Fibrosis in Vulvar Lichen Sclerosus via the TGF-/SMAD3 Pathway. […] Behnia-Willison et al., Use of Platelet-Rich Plasma for Vulvovaginal Autoimmune Conditions Like Lichen Sclerosus.
#1 Can Lichen Sclerosus be Caused by Stress
https://coyleinstitute.com/lichen-sclerosus-and-stress/
Taking a more holistic approach to LS treatment through stress management and other methodologies can be desirable for a few reasons. For one, you may better target the conditions underlying cause to lower the incidence of ongoing lesion development. Further, holistic approaches do not come along with concerning side effects, which can be an issue with topical steroid treatment.
#1 Lichen Sclerosus and Squamous Cell Carcinoma | Actas Dermo-SifiliogrÃ¡ficas
https://www.actasdermo.org/en-lichen-sclerosus-squamous-cell-carcinoma-articulo-S1578219012000479
Lichen sclerosus is a chronic inflammatory disease that can progress to malignancy. The literature indicates an association with anogenital squamous cell carcinoma and verrucous carcinoma. […] Two pathogenic pathways, differentiated vulvar and penile intraepithelial neoplasias, which have recently been described in relation to squamous cell carcinoma, are both highly associated with genital lichen sclerosus independently of human papilloma virus (HPV) infection. Furthermore, tumor-promoting molecular changes unrelated to HPV infection have been demonstrated and may explain the malignant potential of lichen sclerosus. […] Overall though, the evidence suggests that lichen sclerosus is an HPV-independent carcinogenic factor. This corroborates its potential for malignant transformation and the need for long-term follow-up in these patients.
#1 Lichen sclerosus: the role of oxidative stress in the pathogenesis of | RRU
https://www.dovepress.com/lichen-sclerosus-the-role-of-oxidative-stress-in-the-pathogenesis-of-t-peer-reviewed-fulltext-article-RRU
It appears evident, as in other chronic inflammation processes, that OS plays an important role not only in the pathogenesis, but also in the development, maintenance, and progression of LS. Furthermore, OS, by causing DNA damage, contributes directly to malignant transformation of the disease. […] The crucial points in which OS can decisively contribute to carcinogenesis arising from LS lesions are the following: oxidative DNA damage, lipid peroxidation, and epidermal atrophy. […] Oxidative DNA damage, by causing a persistent, continuous stimulus to cell and tissue regeneration, heavily contributes to malignant transformation of the disease. […] Vulvar LS, being a chronic fibrotic inflammatory disease with an evident phenotype of keratinocyte proliferation, has therefore been considered a starter condition favoring the development of SCC, since due to the strong oxidation state DNA damage is constantly present.
#1 Lichen Sclerosus and Squamous Cell Carcinoma | Actas Dermo-SifiliogrÃ¡ficas
https://www.actasdermo.org/en-lichen-sclerosus-squamous-cell-carcinoma-articulo-S1578219012000479
Although the exact carcinogenic mechanism of lichen sclerosus is still under debate, several HPV-independent hypotheses have been put forward. […] The authors therefore concluded that they were dealing with another carcinogenic mechanism, independent of HPV, for the development of anogenital SCC. […] It seems that chronic inflammation associated with lichen sclerosus could lead to molecular abnormalities that in turn could facilitate neoplastic proliferation. […] HPV-independent oncogenic molecular changes have been shown that could explain the malignant potential of lichen sclerosus in its own right. […] Lichen sclerosus is an HPV-independent etiopathogenic factor in some types of usual and verrucous penile SCC, with differentiated PIN and squamous cell hyperplasia being the histological variants associated with and implicated in carcinogenesis. […] The exact mechanisms responsible for the association of lichen sclerosus and verrucous carcinoma are not clear, but factors such as HPV infection, mutations in the p53 gene, chronic inflammation, and oxidative stress could all play a part.
#1 Lichen sclerosus: the role of oxidative stress in the pathogenesis of | RRU
https://www.dovepress.com/lichen-sclerosus-the-role-of-oxidative-stress-in-the-pathogenesis-of-t-peer-reviewed-fulltext-article-RRU
Proof of how important oxidative DNA damage is as a condition favoring disease progression and transformation into carcinoma lies in the fact that the tissue concentrations of the specific biomarker of oxidative DNA damage have been shown to increase from one pathological condition to the other, in the following order: LS; non-invasive vulvar carcinoma; invasive vulvar carcinoma.
#2 Advances in Understanding Vulva Lichen Sclerosus: Pathogenesis and Treatment
https://www.gavinpublishers.com/article/view/advances-in-understanding-vulva-lichen-sclerosus-pathogenesis-and-treatment
Vulva lichen sclerosus (VLS) is a chronic, painful, inflammatory disease that has a significant impact on quality of life. […] Currently, there have been numerous reported treatment approaches for this disease, but the outcomes are not satisfactory, and there is no definitive cure. This may be due to the fact that the exact pathogenesis of VLS remains unknown. Possible mechanisms of VLS development include immune factors, genetic factors, hormonal factors, local environmental factors, and infectious factors. […] To date, the etiology and pathogenesis of VLS remain unclear. Existing evidence suggests that immune dysregulation and chronic inflammation, operating against a genetic background, play a role in the development of this condition triggered by certain factors. Additionally, the promotion of fibroblast growth and activity, as well as collagen synthesis, leading to the progressive formation of transparent and sclerotic dermal tissue, represents another key factor in the pathogenesis of VLS.
#2 Vulvar Lichen Sclerosus from Pathophysiology to Therapeutic Approaches: Evidence and Prospects
https://pmc.ncbi.nlm.nih.gov/articles/PMC8394941/
A higher percentage of VLS patients, when compared with controls, have one or more autoimmune-related disease or a family history of autoimmune disease or autoimmune antibodies. […] An abnormal activation of a Th1 autoimmune response has been found in affected tissue. […] This supports the likelihood that a Th1 reactivity may promote the development of VLS. […] Chronic inflammation also induces the production of reactive oxygen species (ROS), which are deemed responsible for contributing to tissue damage. […] Promoting fibroblast growth and activity, as well as abnormal collagen synthesis, is another crucial event in VLS pathogenesis and progressive formation of hyalinised and sclerotic dermal tissue. […] The current evidence on physiopathology of VLS points towards a complex, multifactorial process.
#2 Advances in Understanding Vulva Lichen Sclerosus: Pathogenesis and Treatment
https://www.gavinpublishers.com/article/view/advances-in-understanding-vulva-lichen-sclerosus-pathogenesis-and-treatment
In females, VLS is considered to be an autoimmune disease. It exhibits characteristics consistent with other autoimmune diseases, including a higher prevalence in females and positive correlations with other female autoimmune conditions. […] Gene expression profiling supports VLS as an inflammatory disease mediated by upregulation of T helper type 1 (Th1) cytokines. A well-established link exists between Th1 responses and autoimmune diseases. […] Furthermore, research indicates that the pathogenesis of vulva lichen sclerosus may be related to Th1 cytokines such as IFN- and epithelial-derived IgG, rather than Th2 or Th17 cytokines and HD-5. […] Studies also suggest that reduced activity of regulatory T cells (Tregs) may be present in VLS tissues. Tregs play a crucial role in maintaining immune tolerance. Consequently, decreased Treg function may lead to impaired self-antigen immune tolerance and autoimmune dysfunction.
#2 Lichen Sclerosus: An autoimmunopathogenic and genomic enigma with emerging genetic and immune targets
https://www.ijbs.com/v15p1429.htm
Given the familial occurrence of LS and the close, positive association between HLA class II antigens and autoimmune disease, many researchers speculated LS pathogenesis may progress along an immunogenetic route towards humoral autoimmunity as the development of autoantibodies to an unknown autoantigen may account for the histological changes seen as extensive extracellular remodeling. […] Dysfunction of extracellular matrix protein 1 (ECM1), found at the dermal-epidermis junction, has long been implicated in the pathogenesis of LS. […] Gene expression profiles of LS have further suggested LS as an immunogenic disease, given increased expression in genes responsible for immune response. […] In particular, more pro-inflammatory cytokines were upregulated in LS (IL-1, IL-7, IL-15, IFN-, TNF-) than anti-inflammatory cytokines (TNF-), suggesting LS is specifically mediated by a T-helper type 1 (Th1) course of action.
#2 Lichen Sclerosus: An autoimmunopathogenic and genomic enigma with emerging genetic and immune targets
https://www.ijbs.com/v15p1429.htm
An aberrant level of microRNA expression is therefore implicated in LS pathogenesis. […] miR-155 has been shown to be expressed in activated immune cells (i.e. macrophages, dendritic cells, B cells, and T cells) and plays a significant regulatory role in the production of cytokine, chemokine, and transcription factors towards promoting Th1 T-cell differentiation. […] Thus, miR-155 may serve as a critical regulator triggering the loss of normal Treg suppressive function and loss of CD4+ self-tolerance in this proposed autoimmunogenic mechanism for LS pathogenesis. […] In addition to its possible role for inducing autoimmunity, miR-155 is also associated with sclerotic tissue formation. […] Specifically, Ren et al. found increased expression levels of miR-155 in LS tissues along with an associated decrease in FOXO3 and CDKN1B, two tumor suppressor genes involved in fibroblast cell proliferation and cell cycle suppression, respectively.
#2
https://link.springer.com/article/10.1007/s11033-024-09318-7
Oxidative stress is implicated in the pathogenesis of lichen sclerosus. […] The role of oxidative stress in the pathogenesis of the disease and its possible transformation into carcinoma. […] The Importance of Immunological Disorders in the Pathogenesis of Lichen Sclerosus in Pediatric Patients: A Systematic Review. […] An autoimmune phenotype in vulvar lichen sclerosus and lichen planus: a Th1 response and high levels of microRNA-155. […] Transcriptome Profiling and Network Analysis Provide Insights into the pathogenesis of Vulvar Lichen Sclerosus. […] MiR-155-5p promotes fibroblast cell proliferation and inhibits FOXO signaling pathway in vulvar lichen sclerosis by targeting FOXO3 and CDKN1B. […] Study of Langerhans cells and T lymphocytes in vulvar lichen sclerosus lesions. […] Characterization of IgG autoantibodies to extracellular matrix protein 1 in lichen sclerosus.
#2 Vulvar Lichen Sclerosus from Pathophysiology to Therapeutic Approaches: Evidence and Prospects
https://www.mdpi.com/resolver?pii=biomedicines9080950
The available evidence indicates the role of two main pathomechanisms, which act on a susceptible genetic background. Suspected triggering factors complete this pathogenetic scenario. […] More in detail, immunological dysreactivity and chronic inflammation represent one of the two aforesaid key pathomechanisms. On the other hand, promoting fibroblast growth and activityâas well as abnormal collagen synthesis, which leads to a progressive formation of hyalinised and sclerotic dermal tissueâis the other crucial event in VLS pathogenesis. […] Several lines of evidence suggest a pivotal role of autoimmunity in VLS pathogenesis. […] An abnormal activation of a Th1 autoimmune response has been found in affected tissue. […] This immune imbalance perpetuates an up-regulation of pro-inflammatory cytokines and, in turn, leads to a cell-mediated attack against self-antigens.
#2 Clinical and histopathological spectrum of genital lichen sclerosus in 133 cases: Focus on the diagnosis of pre-sclerotic disease – Indian Journal of Dermatology, Venereology and Leprology
https://ijdvl.com/clinical-and-histopathological-spectrum-of-genital-lichen-sclerosus-in-133-cases-focus-on-the-diagnosis-of-pre-sclerotic-disease/
The pathogenesis of lichen sclerosus probably involves an immune reaction to the basement membrane at the epidermal interface and around the adnexa. The initial band of inflammation shifts gradually downwards from the epidermal interface into the dermis destroying the vascular channels and appendages, resulting in excessive deposition of altered extracellular matrix. Basilar infiltration of lymphocytes along with a grossly vacuolated or thickened basement membrane is proposed as the characteristic diagnostic feature of the pre-sclerotic stage. […] Unlike other interface dermatitides, the band of inflammation in lichen sclerosus slowly recedes from the epidermal interface along with the deposition of hyaluronic acid in the papillary dermis. Altered distribution of tenascin, fibrinogen and fibronectin has been reported indicating a significant disorganisation of the extracellular matrix.
#2 Vulvar Lichen Sclerosus from Pathophysiology to Therapeutic Approaches: Evidence and Prospects
https://www.mdpi.com/resolver?pii=biomedicines9080950
Chronic inflammation also induces the production of reactive oxygen species (ROS), which are deemed responsible for contributing to tissue damage. […] Promoting fibroblast growth and activity, as well as abnormal collagen synthesis, is another crucial event in VLS pathogenesis and progressive formation of hyalinised and sclerotic dermal tissue. […] Several pathways seem to be involved in disrupting fibroblast and collagen homeostasis. […] The current evidence on physiopathology of VLS points towards a complex, multifactorial process. […] It is conceivable that environmental factors acting on a genetic background trigger autoimmune processes, with subsequent inflammation which, in turn, leads to tissue and microvascular injury as well as to activation of signalling pathways involved in fibroblast and collagen metabolism. […] This sequence would explain the efficacy of anti-inflammatory treatments, especially topical corticosteroids or topical calcineurin inhibitors, in significantly improving dermal collagen changes.
#2 Lichen sclerosus – Wikipedia
https://en.wikipedia.org/wiki/Lichen_sclerosus
Lichen sclerosus may have a genetic component. A high correlation of lichen sclerosus has been reported between twins and between family members. […] Autoimmunity is a process in which the body fails to recognize itself and therefore attacks its own cells and tissue. Specific antibodies have been found in LS sufferers. […] Both bacterial and viral pathogens have been implicated in the etiology of LS. […] Since LS in females is primarily found in women with a low estrogen state (prepubertal and postmenopausal women), hormonal influences have been postulated. […] Some findings suggest that LS can be initiated through scarring or radiation, although those findings were sporadic and very uncommon.
#2
https://link.springer.com/article/10.1007/s11033-024-09318-7
The association between HLA DR, DQ antigens, and vulval lichen sclerosus in the UK: HLA DRB112 and its associated DRB112/DQB10301/04/09/010 haplotype confers susceptibility to vulval lichen sclerosus. […] Lichen Sclerosus premenarche: autoimmunity and immunogenetics. […] Genomic profiling of Vulvar Lichen Sclerosus patients shows possible pathogenetic disease mechanisms. […] Differentially regulated miRNAs and their related molecular pathways in lichen sclerosus. […] The possible role of human papillomavirus infection in the development of lichen sclerosus. […] Possible role of Borrelia burgdorferi sensu lato infection in lichen sclerosus. […] The possible role of Epstein-Barr virus and human papillomavirus infection in vulvar lichen sclerosus.
#2 Anogenital Lichen Sclerosus: Clinical Considerations and Management – Journal of the Turkish Academy of Dermatology
https://www.jtad.org/articles/anogenital-lichen-sclerosus-clinical-considerations-and-management/doi/jtad.galenos.2022.64936
Lichen sclerosus (LS) is a chronic inflammatory disease of unknown etiology that commonly involves anogenital region. […] Several factors including genetic factors, autoimmunity, hormonal factors, infections and drugs have been suspected, which are beyond the scope of this review. However, as they are important from clinical point of view, chronic irritation and trauma (Koebnerization) will be briefly discussed. The chronic contact with urine has been implicated in the development of LS. […] Thus, it is likely that the moist and occlusive environment under the prepuce contributes to the pathogenesis of LS. […] Genital LS may also occur following trauma, such as surgery, instrumentation and at sites of genital jewelries, and recurs in circumcision scars and grafts.
#2 The relationship between the vaginal and vulvar microbiomes and lichen sclerosus symptoms in post-menopausal women | Scientific Reports
https://www.nature.com/articles/s41598-024-78372-9
Lichen sclerosus is a chronic inflammatory condition of unknown etiology that affects the genital and extragenital skin, which can lead to sexual dysfunction and has been associated with vulvar cancer. […] Understanding the role of these bacteria in lichen sclerosus pathogenesis will be an essential future investigation. […] Chronic irritation, inflammation, and epithelial barrier disruption mediated by the local microbiome may contribute to the pathogenesis of LS. […] As dysbiosis of the vaginal microbiome can cause chronic irritation, including increased inflammation and epithelial barrier damage, we hypothesized the microbiome may influence the pathogenesis of LS. […] This suggests that a shift in the microbiome may lead to irritation or inflammation that could contribute to LS.
#2 Vulvar Lichen Sclerosus from Pathophysiology to Therapeutic Approaches: Evidence and Prospects
https://www.mdpi.com/resolver?pii=biomedicines9080950
Vulvar lichen sclerosus (VLS) is a chronic, distressing, inflammatory disease with an enormous impact on quality of life. […] Despite the availability of numerous therapeutic options, treatment outcome may not be entirely satisfactory and a definitive cure does not exist. This may be due to the fact that the exact VLS etiopathogenesis remains unknown. […] Based on current knowledge, it is conceivable that various, heterogeneous environmental factors acting on a genetic background trigger an autoimmune, Th-1 response, which leads to a chronic inflammatory state. This, in turn, can determine both tissue and micro-vascular injury and activation of signaling pathways involved in fibroblast and collagen metabolism. […] The etiopathogenetic framework of this disease may be the perspective from which to consider the current therapeutic options and, ideally, address new ones.
#2 Advances in Understanding Vulva Lichen Sclerosus: Pathogenesis and Treatment
https://www.gavinpublishers.com/article/view/advances-in-understanding-vulva-lichen-sclerosus-pathogenesis-and-treatment
The pathogenesis of vulvar lichen sclerosus (VLS) is associated with multiple factors, including immune factors, genetic factors, and infectious factors. Currently, there is a lack of treatment options that provide stable efficacy and prevent recurrence. […] In recent years, topical glucocorticoids have been preferred as the first-line treatment, showing good effectiveness in controlling disease progression.
#2 Drug Website, Directory & Medical Information | MIMS Malaysia
https://www.mims.com/malaysia
Baricitinib, abrocitinib show promise in treatment of lichen sclerosus.
#2 Lichen sclerosus: the role of oxidative stress in the pathogenesis of | RRU
https://www.dovepress.com/lichen-sclerosus-the-role-of-oxidative-stress-in-the-pathogenesis-of-t-peer-reviewed-fulltext-article-RRU
It appears evident, as in other chronic inflammation processes, that OS plays an important role not only in the pathogenesis, but also in the development, maintenance, and progression of LS. Furthermore, OS, by causing DNA damage, contributes directly to malignant transformation of the disease. […] The crucial points in which OS can decisively contribute to carcinogenesis arising from LS lesions are the following: oxidative DNA damage, lipid peroxidation, and epidermal atrophy. […] Oxidative DNA damage, by causing a persistent, continuous stimulus to cell and tissue regeneration, heavily contributes to malignant transformation of the disease. […] Vulvar LS, being a chronic fibrotic inflammatory disease with an evident phenotype of keratinocyte proliferation, has therefore been considered a starter condition favoring the development of SCC, since due to the strong oxidation state DNA damage is constantly present.