Lichen planus pemphigoides with predominant mucous membrane involvement: a series of 12 patients and a literature review.

Background: Lichen planus pemphigoides (LPP), an association between lichen planus and bullous pemphigoid lesions, is a rare subepithelial autoimmune bullous disease. Mucous membrane involvement has been reported previously; however, it has never been specifically studied. Methods: We report on 12 cases of LPP with predominant or exclusive mucous membrane involvement. The diagnosis of LPP was based on the presence of lichenoid infiltrates in histology and immune deposits in the basement membrane zone in direct immunofluorescence and/or immunoelectron microscopy. Our systematic review of the literature, performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, highlights the clinical and immunological characteristics of LPP, with or without mucous membrane involvement. Results: Corticosteroids are the most frequently used treatment, with better outcomes in LPP with skin involvement alone than in that with mucous membrane involvement. Our results suggest that immunomodulators represent an alternative first-line treatment for patients with predominant mucous membrane involvement.

PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens.

The peripheral T cell repertoire of healthy individuals contains self-reactive T cells1,2. Checkpoint receptors such as PD-1 are thought to enable the induction of peripheral tolerance by deletion or anergy of self-reactive CD8 T cells3-10. However, this model is challenged by the high frequency of immune-related adverse events in patients with cancer who have been treated with checkpoint inhibitors11. Here we developed a mouse model in which skin-specific expression of T cell antigens in the epidermis caused local infiltration of antigen-specific CD8 T cells with an effector gene-expression profile. In this setting, PD-1 enabled the maintenance of skin tolerance by preventing tissue-infiltrating antigen-specific effector CD8 T cells from (1) acquiring a fully functional, pathogenic differentiation state, (2) secreting significant amounts of effector molecules, and (3) gaining access to epidermal antigen-expressing cells. In the absence of PD-1, epidermal antigen-expressing cells were eliminated by antigen-specific CD8 T cells, resulting in local pathology. Transcriptomic analysis of skin biopsies from two patients with cutaneous lichenoid immune-related adverse events showed the presence of clonally expanded effector CD8 T cells in both lesional and non-lesional skin. Thus, our data support a model of peripheral T cell tolerance in which PD-1 allows antigen-specific effector CD8 T cells to co-exist with antigen-expressing cells in tissues without immunopathology.

The human microbiome in immunobullous disorders and lichen planus.

For several decades, there has been a significant growth in the incidence of autoimmune diseases. Studies indicate that genetic factors may not be the only trigger for disease development and that dysbiosis of the microbiome may be another mechanism involved in the pathogenesis of autoimmune diseases. The role of the microbiome in the development of common skin disorders such as psoriasis, atopic dermatitis, acne and rosacea is increasingly well understood. However, few studies have focused on lichen planus and the rare acquired immunobullous diseases, both mucocutaneous groups of disorders linked to skin, oral and gut microbiomes. This review provides an insight into the current understanding of how the microbiome may contribute to the development of autoimmunity and to the maintenance and exacerbation of acquired immunobullous and lichenoid diseases. These mechanisms may have implications for future preventive and therapeutic approaches.

Histopathological and immunohistochemical features of facial papules in frontal fibrosing alopecia.

BACKGROUND: Facial papules (FPs) are considered to be created by the inflammatory process, which involves facial vellus hairs, in frontal fibrosing alopecia. AIM: To demonstrate the histopathological features of FPs and the composition of the inflammatory infiltrate. METHODS: In total, 18 patients with FPs were enrolled in the study after histopathological confirmation of lichen planopilaris. Histopathological evaluation of the specimens was performed by two dermatopathologists. The samples were immunostained with CD4, CD8 and CD123 monoclonal antibodies, and the percentage and proportion of cells stained with these markers were investigated. RESULTS: A follicular lichenoid reaction and perifollicular fibrosis were present in all cases. Vellus hairs were detected in 83.3% of biopsy specimens (15 cases), all of which were involved by the inflammation. The majority of the follicles (72%) revealed follicular plugs. Reduction and destruction of elastic fibres were visible in the perifollicular (adventitial) and the papillary dermis (100% and 78% of specimens, respectively). Prominent sebaceous glands and dilated ducts were detected in 78% and 72% of samples, respectively. CD4-positive T cells formed 67.72% and CD8-positive T cells 32.28% of the infiltrate, and the mean CD4/CD8 ratio was 2.48. In 13 (72.2%) biopsy specimens < 10% of the infiltrate was positive for CD123 marker. CONCLUSIONS: Perifollicular inflammation, fibrosis and elastic-fibre destruction were constant histopathological features of FPs; furthermore, prominent sebaceous glands were present in the majority of samples. We also observed a CD4-positive predominance in the infiltrate.

Subepithelial autoimmune blistering dermatoses: Clinical features and diagnosis.

Subepithelial autoimmune blistering dermatoses are a group of rare skin disorders that are characterized by the disruption of the dermal-epidermal junction through the action of autoantibodies. The third article in this continuing medical education series explores the background, epidemiology, clinical features, and diagnostic criteria of each of the major subepithelial autoimmune blistering dermatoses, including bullous pemphigoid, pemphigoid gestationis, lichen planus pemphigoides, mucous membrane pemphigoid, linear IgA bullous dermatosis, and dermatitis herpetiformis.

Annular atrophic lichen planus induced by anti-HER2 antibodies.

Pertuzumab and trastuzumab are monoclonal antibody inhibitors targeting human epidermal growth factor receptor 2 (HER-2) and are increasingly being utilised in the management of HER2-positive breast cancer, having been demonstrated to improve progression-free survival in conjunction with docetaxel. We present a rare presentation of a lichenoid drug eruption, in an annular atrophic variant, in a 35-year-old woman after initiation of HER2-inhibitor (pertuzumab and trastuzumab) therapy for metastatic breast cancer.

The attentive focus on T cell-mediated autoimmune pathogenesis of psoriasis, lichen planus and vitiligo.

T cell-mediated autoimmune skin diseases develop as a result of the aberrant immune response to the skin cells with T cells playing a central role. These chronic inflammatory skin diseases encompass various types including psoriasis, lichen planus and vitiligo. These diseases show similarities in their immune-pathophysiology. In the last decade, immunomodulating agents have been very successful in the management of these diseases thanks to a better understanding of the pathophysiology. In this review, we will discuss the immunopathogenic mechanisms and highlight the role of T lymphocytes in psoriasis, lichen planus and vitiligo. This study could provide new insights into a better understanding of targeted therapeutic pathways and biological therapies.

The inflammation in cutaneous lichen planus is dominated by IFN-ϒ and IL-21-A basis for therapeutic JAK1 inhibition.

Cutaneous lichen planus (CLP) and psoriasis (PSO) are both common chronic inflammatory skin diseases for which development of new treatments requires the identification of key targets. While PSO is a typical Th17/IL-17-disorder, there is some evidence that Th1/IFN-É£ dominate the inflammatory process in CLP. Nonetheless, the immunopathogenesis of CLP is not fully explained and key immunological factors still have to be recognized. In this study, we compared the immune signature of CLP lesions with the well-characterized inflammation present in PSO skin. First, we analysed the histological and immunohistological characteristics of CLP and PSO. Second, we assessed the cytokine expression (IL1A, IL1B, IL4, IL6, IL8, IL10, IL17A, IL19, IL21, IL22, IL23A, IL13, IFNG, TNF, IL12A, IL12B and IL36G) of lesional skin of CLP with PSO by qPCR. Histology revealed a similar epidermal thickness in CLP and PSO. Immunohistochemically, both diseases presented with an inflammatory infiltrate mainly composed by CD3+ CD4+ T cells rather than CD3+ CD8+ . Importantly, mRNA analysis showed a distinct cytokine signature: while levels of IL12B, IL1A, IL6 and IL23 were similar between the two groups, the characteristic PSO-associated cytokines IL8, IL17A, IL22, IL19 and IL36G were expressed at very low levels in CLP. In contrast, CLP lesional skin was dominated by the expression of IFNG, IL21, IL4, IL12A and TNF. Immunohistochemistry confirmed the dominance of IL-21, IFN-É£ and also pSTAT1 in the dermal infiltrate of CLP, while IL-17A was more present in PSO. Collectively, this study improves our understanding of the immunological factors dominating CLP. The dominating cytokines and signalling proteins identified suggest that anti-cytokine therapeutics like JAK inhibitors may be beneficial in CLP.

Increased Serum Level and High Tissue Immunoexpression of Interleukin 17 in Cutaneous Lichen Planus: A Novel Therapeutic Target for Recalcitrant Cases?

BACKGROUND: Interleukin-17 is supposed to play an important role in the pathogenesis of oral lichen planus (OLP). However, there is scarce data in the literature on its significance in the cutaneous variant of the disease. OBJECTIVES: To determine the serum level and tissue immunoexpression of IL-17 in cutaneous lichen planus (CLP). METHODS: Fifty-two adult patients with CLP, without any significant autoimmune or inflammatory conditions, were included in the first part of the study. The control group consisted of 27 age- and sex-matched healthy volunteers. Serum concentration of IL-17 was quantified using enzyme-linked immunosorbent assay (ELISA) kit. In the second part of the study, the tissue expression of IL-17 was assessed in archival paraffin-embedded biopsy specimens from CLP (n = 14) against normal control tissues (n = 11) using immunohistochemical assays. The expression was evaluated using Zeiss Axio Imager A2 light microscope. Positively stained cells were counted in 10 fields of view for biopsy specimen at 200x magnification, and the mean value was calculated. RESULTS: The serum level of IL-17 was significantly elevated in patients with CLP, compared with healthy volunteers (0.218 ± 0.221 ng/ml versus 0.126 ± 0.058 ng/ml, respectively; p = 0.025). No correlation was found between the serum concentration of IL-17 and patient age, gender, disease duration, extent of skin involvement, the presence or intensity of pruritus, and coexistence of mucosal lesions. In tissue samples from CLP lesions, significantly higher numbers of cells expressing IL-17 were found when compared to a healthy skin (p < 0.001). CONCLUSION: Elevated serum concentration of IL-17 and high expression in a lesional skin support the hypothesis that IL-17 is implicated in the immunopathogenesis of CLP. These findings may constitute a premise for the future use of anti-IL-17 monoclonal antibodies in the treatment of severe and recalcitrant forms of CLP.

No evidence for association between cutaneous lichen planus and hepatitis B and C virus infection in south Poland - a case-control study.

BACKGROUND: The incidence of hepatitis C virus (HCV) infection among patients with lichen planus (LP) varies considerably. Currently, there is more evidence for the association between hepatitic C and oral LP (OLP) than cutaneous LP (CLP). There is also lack of data on the Polish population. The study aimed at assessing the prevalence of HCV infection and liver test abnormalities among patients with CLP in south Poland. METHODS: Eighty-four patients with CLP and 130 patients with other dermatoses (controls) were included in this retrospective case-control study. Medical records were reviewed for the presence of anti-HCV antibodies and hepatitis B surface antigen (HBsAg) and serum levels of liver function tests: aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glumatyltranspeptidase (GGT). RESULTS: Anti-HCV antibodies were not found in any of the patients in the study or control group. HBsAg was detected in one (1.19%) patient with CLP and none of the controls. Considering the prevalence of abnormal liver function parameters, there were no statistically significant differences in the frequencies of AST (P = 0.87), ALT (P = 0.9), and GGT (P = 0.81) above the upper limit between patients with CLP and patients with other dermatoses. CONCLUSIONS: Currently, there is no evidence confirming the relationship between HCV infection and CLP in southern Poland. There is also no increased incidence of liver function abnormalities compared to patients with other dermatoses. However, there is a need for further research on larger groups of patients.

Isolated nail lichen planus: An expert consensus on treatment of the classical form.

Lichen planus is a benign inflammatory disorder of unknown etiology that may affect the skin, mucosae, scalp, and nails. When the nails are affected, it may lead to permanent destruction with severe functional and psychosocial consequences. Therefore, prompt diagnosis and early treatment are essential, even in mild cases. There are currently no guidelines for the management of nail lichen planus and the published literature on treatment is limited. The aim of this review is to provide practical management recommendations for the classical form of nail lichen planus, especially when restricted to the nails. Topical treatment has poor short-term efficacy and may cause long-term side effects. Instead, intralesional and intramuscular triamcinolone acetonide should be considered first-line therapies. Oral retinoids are second-line choices, and immunosuppressive agents may also be considered.

Successful treatment of psoriatic arthritis and comorbid annular atrophic lichen planus with etanercept.

Psoriasis vulgaris and lichen planus are distinct T-cell-driven inflammatory skin diseases. Both present in a variety of clinical subtypes. Mucosal or nail involvement may be present. Here, we report the rare concomitant clinical presentation of psoriatic arthritis and annular atrophic lichen planus on the trunk of a 52-year-old male patient. Treatment with sulfasalazine failed to control inflammatory activity; methotrexate and leflunomide were ceased due to side-effects. After confirmation of both diagnoses, we initiated a tumor necrosis factor (TNF)-α-directed therapy with the fusion protein etanercept resulting in significant improvement of both conditions. This case report aims to highlight the rare colocalization of psoriasis and lichen planus, the rare entity of annular atrophic lichen planus, and to discuss a possible beneficial impact of certain TNF-α inhibitors on subtypes of lichen planus.

Immunostimulatory Endogenous Nucleic Acids Perpetuate Interface Dermatitis-Translation of Pathogenic Fundamentals Into an In Vitro Model.

Interface dermatitis is a histopathological pattern mirroring a distinct cytotoxic immune response shared by a number of clinically diverse inflammatory skin diseases amongst which lichen planus and cutaneous lupus erythematosus are considered prototypic. Interface dermatitis is characterized by pronounced cytotoxic immune cell infiltration and necroptotic keratinocytes at the dermoepidermal junction. The initial inflammatory reaction is established by cytotoxic immune cells that express CXC chemokine receptor 3 and lesional keratinocytes that produce corresponding ligands, CXC motif ligands 9/10/11, recruiting the effector cells to the site of inflammation. During the resulting anti-epithelial attack, endogenous immune complexes and nucleic acids are released from perishing keratinocytes, which are then perceived by the innate immune system as danger signals. Keratinocytes express a distinct signature of pattern recognition receptors and binding of endogenous nucleic acid motifs to these receptors results in interferon-mediated immune responses and further enhancement of CXC chemokine receptor 3 ligand production. In this perspective article, we will discuss the role of innate nucleic acid sensing as a common mechanism in the perpetuation of clinically heterogeneous diseases featuring interface dermatitis based on own data and a review of the literature. Furthermore, we will introduce a keratinocyte-specific in vitro model of interface dermatitis as follows: Stimulation of human keratinocytes with endogenous nucleic acids alone and in combination with interferon gamma leads to pronounced production of distinct cytokines, which are essential in the pathogenesis of interface dermatitis. This experimental approach bears the capability to investigate potential therapeutics in this group of diseases with unmet medical need.

Increased regulatory T cells and eosinophils characterize atopic dermatitis-like graft-versus-host disease compared with lichen planus-like graft-versus-host disease.

BACKGROUND: Graft-versus-host disease (GVHD) has various cutaneous manifestations. Little is known about the mechanisms of cutaneous GVHD with different clinical features. OBJECTIVE: To characterize the immunologic features and skin barrier functions of cutaneous GVHD. METHODS: The study included 19 patients with atopic dermatitis (AD)-like GVHD, 8 with lichen planus (LP)-like GVHD, 24 with AD, and 15 healthy controls. The subpopulation of T cells in peripheral blood and skin lesions was measured by flow cytometry and immunofluorescence, respectively. Filaggrin expression in skin lesions was measured by Western blot and immunohistochemistry. Transepidermal water loss was also measured using Tewameter TM 300 (Courage & Khazaka Electronic GmbH, Köln, Germany). RESULTS: The number of peripheral blood eosinophils in AD-like GVHD was significantly higher than that in LP-like GVHD. Type 2 helper T cells in peripheral blood and skin lesions were increased in AD-like GVHD and LP-like GVHD. Regulatory T cells in peripheral blood and skin lesions were increased in AD-like GVHD. Filaggrin expression and transepidermal water loss were increased in skin lesions of AD-like GVHD and LP-like GVHD. LIMITATIONS: The number of patients is limited. CONCLUSION: Although AD-like GVHD and LP-like GVHD both had elevated type 2 helper T cells and impaired skin barrier, increased eosinophils and regulatory T cells were found only in AD-like GVHD.

Clinicopathologic and immunophenotypic characterization of lichen planopilaris and central centrifugal cicatricial alopecia: A comparative study of 51 cases.

BACKGROUND: The purpose of the study was to compare the histopathologic and immunophenotypic features of central centrifugal cicatricial alopecia (CCCA) and lichen planopilaris (LPP) to better characterize and differentiate these two clinical entities. CCCA remains an ill-defined and still-unsettled histologic entity and many hair loss experts regard CCCA to be histologically indistinguishable from LPP. Given the overlapping histologic features of these two lymphocyte-predominant cicatricial alopecias, and the lack of consensus regarding the significance of proposed distinctions, dermatopathologists face difficulty in providing clinicians and patients certainty with a definitive diagnosis of CCCA vs LPP. METHODS: We performed a retrospective review of 51 scalp biopsies of patients with either the clinical diagnosis of CCCA (27 cases) or LPP (24 cases). Clinical information, histologic features of hematoxylin-eosin-stained sections, and a panel of immunohistochemical markers were evaluated on scalp biopsies. Tested parameters were quantified, and statistical analysis was performed. RESULTS: Our study found no differences on either histologic assessment or immunophenotypic characterization between cases of classic LPP and CCCA. CONCLUSION: The conclusion of this study is that the inflammatory infiltrates in CCCA and LPP are not only histologically similar but also immunophenotypically indistinguishable.

Diffuse variants of scalp lichen planopilaris: Clinical, trichoscopic, and histopathologic features of 40 patients.

BACKGROUND: Fibrosing alopecia in a pattern distribution and cicatricial pattern hair loss are poorly recognized diffuse variants of lichen planopilaris (LPP). OBJECTIVES: The medical features of 40 patients affected by a diffuse hair thinning associated with a long-lasting history of pruritus and erythema of the scalp and a histopathologic diagnosis of LPP were reviewed. METHODS: Clinical data, results of trichoscopy and histopathology, response to treatment, and follow-up were analyzed. RESULTS: There were 18 patients diagnosed with fibrosing alopecia in pattern distribution and 2 patients with cicatricial pattern hair loss. A new variant of diffuse LPP, named "lichen planopilaris diffuse pattern," was described in 20 individuals. LIMITATIONS: Low number of cases due to rarity of the diseases. CONCLUSION: In patients complaining of a long-lasting history of scalp erythema, itching/dysesthesia, and diffuse hair thinning, it is advisable to consider diffuse variants of LPP.

IFN-γ enhances cell-mediated cytotoxicity against keratinocytes via JAK2/STAT1 in lichen planus.

Lichen planus (LP) is a chronic debilitating inflammatory disease of unknown etiology affecting the skin, nails, and mucosa with no current FDA-approved treatments. It is histologically characterized by dense infiltration of T cells and epidermal keratinocyte apoptosis. Using global transcriptomic profiling of patient skin samples, we demonstrate that LP is characterized by a type II interferon (IFN) inflammatory response. The type II IFN, IFN-γ, is demonstrated to prime keratinocytes and increase their susceptibility to CD8+ T cell-mediated cytotoxic responses through MHC class I induction in a coculture model. We show that this process is dependent on Janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1), but not JAK1 or STAT2 signaling. Last, using drug prediction algorithms, we identify JAK inhibitors as promising therapeutic agents in LP and demonstrate that the JAK1/2 inhibitor baricitinib fully protects keratinocytes against cell-mediated cytotoxic responses in vitro. In summary, this work elucidates the role and mechanisms of IFN-γ in LP pathogenesis and provides evidence for the therapeutic use of JAK inhibitors to limit cell-mediated cytotoxicity in patients with LP.