Autoimmune blistering diseases are characterized by autoantibodies against structural adhesion proteins of the skin and mucous membranes. Extensive characterization of their autoantibody targets has ...improved understanding of pathogenesis and laid the basis for the study of antigens/epitopes diversification, a process termed epitope spreading (ES). In this review, we have reported and discussed ES phenomena in autoimmune bullous diseases and underlined their functional role in disease pathogenesis. A functional ES has been proposed: (1) in bullous pemphigoid patients and correlates with the initial phase of the disease, (2) in pemphigus vulgaris patients with mucosal involvement during the clinical transition to a mucocutaneous form, (3) in endemic pemphigus foliaceus, underlining its role in disease pathogenesis, and (4) in numerous cases of disease transition associated with an intermolecular diversification of immune response. All these findings could give useful information to better understand autoimmune disease pathogenesis and to design antigen/epitope specific therapeutic approaches.
Pemphigus encompasses a heterogeneous group of autoimmune blistering diseases, which affect both mucous membranes and the skin. The disease usually runs a chronic-relapsing course, with a potentially ...devastating impact on the patients' quality of life. Pemphigus pathogenesis is related to IgG autoantibodies targeting various adhesion molecules in the epidermis, including desmoglein (Dsg) 1 and 3, major components of desmosomes. The pathogenic relevance of such autoantibodies has been largely demonstrated experimentally. IgG autoantibody binding to Dsg results in loss of epidermal keratinocyte adhesion, a phenomenon referred to as acantholysis. This in turn causes intra-epidermal blistering and the clinical appearance of flaccid blisters and erosions at involved sites. Since the advent of glucocorticoids, the overall prognosis of pemphigus has largely improved. However, mortality persists elevated, since long-term use of high dose corticosteroids and adjuvant steroid-sparing immunosuppressants portend a high risk of serious adverse events, especially infections. Recently, rituximab, a chimeric anti CD20 monoclonal antibody which induces B-cell depletion, has been shown to improve patients' survival, as early rituximab use results in higher disease remission rates, long term clinical response and faster prednisone tapering compared to conventional immunosuppressive therapies, leading to its approval as a first line therapy in pemphigus. Other anti B-cell therapies targeting B-cell receptor or downstream molecules are currently tried in clinical studies. More intriguingly, a preliminary study in a preclinical mouse model of pemphigus has shown promise regarding future therapeutic application of Chimeric Autoantibody Receptor T-cells engineered using Dsg domains to selectively target autoreactive B-cells. Conversely, previous studies from our group have demonstrated that B-cell depletion in pemphigus resulted in secondary impairment of T-cell function; this may account for the observed long-term remission following B-cell recovery in rituximab treated patients. Likewise, our data support the critical role of Dsg-specific T-cell clones in orchestrating the inflammatory response and B-cell activation in pemphigus. Monitoring autoreactive T-cells in patients may indeed provide further information on the role of these cells, and would be the starting point for designating therapies aimed at restoring the lost immune tolerance against Dsg. The present review focuses on current advances, unmet challenges and future perspectives of pemphigus management.
Etanercept therapy for toxic epidermal necrolysis Paradisi, Andrea, MD; Abeni, Damiano, MD; Bergamo, Fabio, MD ...
Journal of the American Academy of Dermatology,
08/2014, Letnik:
71, Številka:
2
Journal Article
Recenzirano
Background Toxic epidermal necrolysis (TEN) is a severe and potentially lethal drug reaction for which no standard treatment is available. Objective To describe a case series of patients with TEN ...treated with a single dose of etanercept. Methods We observed 10 consecutive patients with TEN. For each patient, we recorded the presence of comorbidities and all the drugs recently started (ie, in the last month). In all cases, 50 mg of etanercept was administered in a single subcutaneous injection. The clinical severity of disease was computed using the SCORe of Toxic Epidermal Necrosis (SCORTEN) scale. Using the probabilities of death linked to each level of SCORTEN score, we calculated the expected probability of death in our patients. Healing was defined as complete reepithelialization, and a time to healing curve was then obtained using the Kaplan–Meier method. Results All patients promptly responded to treatment, reaching complete reepithelialization without complications or side effects. The median time to healing was 8.5 days. Limitations This is a small, uncontrolled case series. Conclusion These preliminary results suggest the possibility that tumor necrosis factor–alfa may be an effective target for control of TEN, a dangerous skin condition for which no effective cure has yet been found.
Oral lichen planus (OLP) is an inflammatory disease of the oral mucosa. Clinically, two main subsets are described, namely non-erosive and erosive OLP. While non-erosive OLP is usually responsive to ...local therapies, erosive OLP is often refractory also to systemic therapies and extremely reduces the quality of life of the patients. Furthermore, in some erosive OLP cases different autoantibodies have been detected, including anti-desmoglein 1 and 3 autoantibodies, and anti-bullous pemphigoid 180 and 230 autoantibodies. However, their potential role is still not clear. In this paper, we reviewed the literature about the detection of autoantibodies against desmoglein 1 and 3, the main target antigens of pemphigus vulgaris, in patient with OLP, summarizing the more recent insights on this topic.
Skin manifestations of systemic disease and malignancy are extremely polymorphous. Clinicians should be familiarized with paraneoplastic dermatoses in order to perform an early diagnosis of the ...underlying neoplasm. Lack of familiarity with cutaneous clues of internal malignancy may delay diagnosis and treatment of cancer. In this review, we described several paraneoplastic dermatoses and discussed extensively two paradigmatic ones, namely paraneoplastic pemphigus and paraneoplastic dermatomyositis.
Paraneoplastic pemphigus is a rare autoimmune skin disease that is always associated with a neoplasm. Usually, oral, skin, and mucosal lesions are the earliest manifestations shown by paraneoplastic ...pemphigus patients. The pathogenesis of paraneoplastic pemphigus is not yet completely understood, although some immunological aspects have been recently clarified. Because of its rarity, several diagnostic criteria have been proposed. Besides, several diagnostic procedures have been used for the diagnosis, including indirect immunofluorescence, direct immunofluorescence, and ELISA. We reviewed the most recent literature, searching on PubMed "paraneoplastic pemphigus". We included also papers in French, German, and Spanish. We found 613 papers for "paraneoplastic pemphigus". Among them, 169 were review papers. Because of its varying clinical features, paraneoplastic pemphigus still represents a challenge for clinicians. Furthermore, diagnosis and management of paraneoplastic pemphigus requires close collaboration between physicians, including dermatologist, oncologist, and otorhinolaryngologist.
Cutaneous squamous cell carcinoma (cSCC), a non-melanoma skin cancer, is a keratinocyte carcinoma representing one of the most common cancers with an increasing incidence. cSCC could be in situ ...(e.g., Bowen's disease) or an invasive form. A significant cSCC risk factor is advanced age, together with cumulative sun exposure, fair skin, prolonged immunosuppression, and previous skin cancer diagnoses. Although most cSCCs can be treated by surgery, a fraction of them recur and metastasize, leading to death. cSCC could arise de novo or be the result of a progression of the actinic keratosis, an in situ carcinoma. The multistage process of cSCC development and progression is characterized by mutations in the genes involved in epidermal homeostasis and by several alterations, such as epigenetic modifications, viral infections, or microenvironmental changes. Thus, cSCC development is a gradual process with several histological- and pathological-defined stages. Dermoscopy and reflectance confocal microscopy enhanced the diagnostic accuracy of cSCC. Surgical excision is the first-line treatment for invasive cSCC. Moreover, radiotherapy may be considered as a primary treatment in patients not candidates for surgery. Extensive studies of cSCC pathogenic mechanisms identified several pharmaceutical targets and allowed the development of new systemic therapies, including immunotherapy with immune checkpoint inhibitors, such as Cemiplimab, and epidermal growth factor receptor inhibitors for metastatic and locally advanced cSCC. Furthermore, the implementation of prevention measures has been useful in patient management.
Introduction
Immunotherapy has changed the management of patients with various types of malignancies (melanoma, renal, lung, and bladder cancers) but immune checkpoint inhibitors may be associated ...with several adverse events. Up to 20% of patients treated with immune checkpoint inhibitors may develop dermatological immune-related adverse events, mostly rashes and pruritus but rarely even bullous pemphigoid.
Case report
We report a case of an elderly patient with advanced non-small cell lung cancer in therapy with pembrolizumab, 200 mg/body every three weeks. After 26 cycles of therapy, the patient developed widespread itching and then after 28 cycles she developed strained blisters filled with serous fluids on predominantly erythematous skin with suspicious of bullous pemphigoid.
Management and outcome: Skin biopsy confirms bullous pemphigoid, so we decided to permanently discontinue therapy with pembrolizumab and the patient is currently on therapy with doxycycline, nicotinamide, and clobetasol propionate with good regression of symptoms and cutaneous lesions.
Discussion
In the literature, the first case of bullous pemphigoid induced by pembrolizumab has been described in 2015. On Pubmed, from 2015 to date, we have found 19 cases of bullous pemphigoid during pembrolizumab therapy but only three of them are related to non-small cell lung cancer, adding our patient we reach a total of 20 cases. It could be interesting to investigate if there is a specific relationship between the appearance of itching and the development of bullous pemphigoid.
Pemphigus is a potentially lethal autoimmune bullous skin disorder, which is associated with IgG autoantibodies against desmoglein (DSG) 3 and DSG1. Notably, a subset of patients with pemphigus ...presents with a similar clinical phenotype in the absence of anti-DSG IgG, suggesting the presence of serum IgG reactive with desmosomal components other than DSG1 or DSG3. We and others have previously shown that such patients have serum IgG autoantibodies against desmocollin 3 (DSC3), a component of desmosomes, which induce loss of keratinocyte adhesion ex vivo. Moreover, DSC3 hypomorphic mice show a severe blistering phenotype of the mucous membrane, which is highly characteristic of pemphigus. These findings prompted us to study the induction and regulation of anti-human DSC3 IgG in humanized mice transgenic for HLA-DRB1∗04:02, which is a highly prevalent haplotype in pemphigus. We show that IgG from sera of immunized mice induces acantholysis in a dispase-based keratinocyte dissociation assay through the activation of p38 MAPKs and EGFR. Passive IgG transfer from mice immunized with recombinant human DSC3 into neonates did not induce intraepidermal loss of adhesion presumably owing to the lack of homology between human and mouse DSC3. Ex vivo stimulation of splenocytes from DSC3-immunized mice with human DSC3 leads to a significant proliferative IFN-γ and IL-4 T-cell response, which is restricted by HLA-DR/HLA-DQ. These findings suggest that the induction of pathogenic anti-DSC3 IgG is associated with DSC3-specific T cells that recognize DSC3 in association with HLA-DRB1∗04:02.
Oral lichen planus (OLP) is a chronic inflammatory disease of the oral mucosa. Several clinical subtypes of OLP have been reported, including the reticular and erosive one. On the one hand, reticular ...OLP is usually asymptomatic and is characterized by white streaks surrounded by well-defined erythematous borders. On the other hand, erosive OLP shows ulcerations and erosions surrounded by erythematous mucosa. While reticular OLP is relatively easy to control, erosive OLP is extremely painful and refractory to therapies, limiting the quality of life of the patients. In addition, treating erosive OLP is extremely tricky, and a gold standard treatment has not yet been established. However, several therapeutic approaches have been reported as effective, including systemic corticosteroids, systemic retinoids, and anti-interleukin (IL)-17/anti-IL-23 drugs. Indeed, our group and other several authors reported the effectiveness of anti-IL17, anti-IL12/23, and anti-IL23 agents in refractory OLP, highlighting the urgency of clinical studies on the use of anti-IL agents in OLP patients. In this paper, we reviewed the English- and German-language literature about therapeutic strategies for treating OLP, focusing on new systemic therapies for erosive OLP.
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