[Monoclonal antibodies for inflammatory, autoimmune and oncological skin diseases]. / Monoklonale Antikörper für entzündliche, autoimmune und onkologische Hauterkrankungen.

In 1997 rituximab, a genetically engineered chimeric monoclonal antibody (mAb) targeting CD20 expressed on B cells was approved for treatment of non-Hodgkin's lymphoma. Since then, pharmacological improvements combined with increased knowledge on the immunopathogenesis of diseases led to the development of specific mAb targeting different antigens (e.g., interleukins or transmembrane receptors). This approach reshaped the therapeutic methodology in many fields, including dermatology. Nowadays, the treatment of frequent and possibly impairing inflammatory disorders such as psoriasis, atopic dermatitis or hidradenitis suppurativa have different mAbs approved for both adult and pediatric patients. This class of drugs often shows a more favorable outcome and a better safety profile than routine immunosuppressants, such as steroids and steroid-sparing substances. For many years mAbs also represented a pillar of oncological treatment for severe diseases such as malignant melanoma or Merkel cell carcinoma. This review summarizes the current knowledge on already approved and promising new mAbs for the treatment of inflammatory and oncological skin diseases.

[Janus kinase inhibitors for skin disorders]. / Januskinaseinhibitoren für dermatologische Erkrankungen.

Immune factors such as interferon­É£ and interleukin 4 belong to the group of cytokines that are dependent on type I/II receptors for their signal transmission. Upon activation, these receptors transmit their signal to the cell nucleus and, thus, modulate gene transcription via a signaling cascade consisting of Janus kinases (JAK). This family of four kinases (JAK 1, JAK 2, JAK 3, and tyrosine kinase 2 (TYK2)) subsequently activate members of the signal transducer and activator of transcription (STAT). This finding turned the JAK/STAT signaling pathway into a pharmacological target for the treatment of inflammatory diseases in which cytokines using type I/II receptors play a pathogenic role. In 2018, the European Medicines Agency (EMA) approved tofacitinib for the treatment of psoriatic arthritis. This was the first approval of a JAK/STAT pathway inhibitor for patients treated by dermatologists and rheumatologists. Since then, several new JAK inhibitors have been approved for dermatologic diseases such as atopic dermatitis, alopecia areata, vitiligo, and plaque-type psoriasis. In addition, JAK inhibitors are being investigated for the treatment of many other skin diseases. Thus, systemic JAK inhibitors complete the spectrum of immunotherapeutics with a broader immunological approach compared to monoclonal antibodies. The low molecular weight of JAK inhibitors enables the preparation of these drugs for both systemic and topical administration. Their utilization could represent a valuable alternative to topical steroids. The safety profile of JAK inhibitors must be taken into account. Possible long-term effects may become apparent in the next few years. This article describes both approved JAK inhibitors and relevant new JAK inhibitors that are promising candidates for approval as therapeutics in dermatology.

Pathogenic relevance of antibodies against desmoglein 3 in patients with oral lichen planus.

BACKGROUND AND OBJECTIVES: Oral lichen planus (OLP) is a T cell driven disorder that significantly impairs patients' quality of life. Previous reports suggest that both cellular and humoral activities against desmoglein (dsg) 1 and 3 may be involved in OLP pathogenesis. Here, we aim to analyze the frequency of occurrence and pathological significance of anti-dsg antibodies in a large cohort of OLP patients. MATERIALS AND METHODS: OLP patients were screened for anti-dsg antibodies by enzyme-linked immunosorbent assay in three tertiary referral centers. OLP sera with anti-dsg antibodies were further analyzed by Western blot and dispase-based keratinocyte dissociation assay (DDA) to identify the targeted dsg ectodomains and to assess their pathogenicity. RESULTS: Of 151-screened individuals with OLP, only four patients (2.6%) with erosive OLP showed serum IgG against dsg1/3. Western blot analysis with recombinant dsg3 ectodomains revealed preferential recognition of the extracellular domain 5. By DDA with spontaneously immortalized human keratinocytes, none of the sera from these four patients induced acantholysis. CONCLUSIONS: Activation of humoral immunity occurs prevalently in patients with erosive OLP, probably due to epitope spreading. OLP serum antibodies are unable to induce loss of intercellular adhesion in vitro, strongly suggesting that they are not disease causing but rather an epiphenomenon.

TYK2 inhibition with deucravacitinib ameliorates erosive oral lichen planus.

Erosive oral lichen planus (OLP) is a challenging disease. This T cell driven disorder frequently shows a treatment unresponsive course and strongly limits patients' quality of life. The disease lacks FDA or EMA approved drugs for its treatment and the efficacy of the commonly administered treatments (i.e. topical and systemic steroids, steroid sparing agents) is often only partial. Although the etiopathogenesis of the disease still needs to be fully elucidated, recent advances helped to identify interferon-É£ (IFN-É£) as a pivotal cytokine in OLP pathogenesis, thus making the interference with its signalling a therapeutic target. Janus kinase (JAK) inhibitors therefore gained relevance for their inhibitory effect on IFN-É£ signalling. While some drugs such as abrocitinib, upadacitinib, tofacitinib directly interfere with IFN-É£ signalling through blockade of JAK1 and/or JAK2, deucravacitinib, a selective TYK-2 inhibitor indirectly interferes on IFN-É£ activation through interference with interleukin (IL)-12, a potent promotor for Th1/IFN-É£ responses. This mechanism of action makes deucravacitinib a candidate drug for the treatment of OLP. Here we provide initial evidence that deucravacitinib 6 mg daily has a beneficial effect in three patients with oral OLP.

Alterations of circulating free fatty acids in patients with pemphigus vulgaris.

Free fatty acids (FFA) have gained research interest owing to their functions in both local and systemic immune regulation. Changes in the serum levels of anti-inflammatory short chain fatty acids (SCFA), primarily derived from the gut microbiota, and pro-inflammatory medium (MCFA) and long (LCFA) chain fatty acids, derived from either the gut microbiota or the diet, have been associated with autoimmunity. Circulating FFA were retrospectively analysed by a gas chromatography-mass spectrometry method in the serum of 18 patients with pemphigus vulgaris (PV) at the baseline and 6 months (n = 10) after immunosuppressive treatments, and 18 healthy controls (HC). Circulating FFA were correlated with the Pemphigus Disease Area Index (PDAI) and serum concentrations of interferon-gamma (IFN-γ), Interleukin (IL)-17A, IL-5, IL-10 and IL-21. Principal Component analysis computed on FFA abundances revealed significant differences in the profile of SCFA (p = 0,012), MCFA (p = 0.00015) and LCFA (p = 0,035) between PV patients and HC, which were not significantly changed by immunosuppressive treatments. PV patients showed a significantly lower serum concentration of propionic (p < 0.0005) and butyric (p < 0.0005) acids, SCFA with anti-inflammatory functions, while hexanoic (p < 0.0005) and hexadecanoic (p = 0.0006) acids, pro-inflammatory MCFA and LCFA respectively, were over-represented. Treatments induced a significant decrease of hexanoic (p = 0.035) and a further increase of hexadecanoic (p = 0.046) acids. Positive correlations emerged between IFN-γ and acetic acid (Rho = 0.60), IFN-γ and hexanoic acid (Rho = 0.46), IL-5 and both hexadecanoic acid (Rho = 0.50) and octadecanoic acid (Rho = 0.53), butyric acid and PDAI (Rho = 0.53). PV was associated with a remarked imbalance of circulating FFA compared to HC. The serum alterations of SCFA, MCFA, and LCFA may contribute to promoting inflammation in PV. Deeper insights into the immunomodulatory functions of these molecules may pave the way for personalized dietary interventions in PV patients.

Non-biologic immunosuppressive drugs for inflammatory and autoimmune skin diseases.

Non-biologic immunosuppressive drugs, such as azathioprine, dapsone or methotrexate are fundamental treatment options for a wide range of autoimmune and chronic inflammatory skin diseases. Some of these drugs were initially used for malignancies (e.g., azathioprine or methotrexate) or infectious diseases (e.g., hydroxychloroquine or dapsone) but are nowadays mostly used for their immunosuppressive/immunomodulating action. Although dermatologists have years of clinical experience with these drugs, some of the mechanisms of action are not fully understood and are the subject of research. Although these drugs are commonly used, lack of experience or knowledge regarding their safety profiles and management leads to skepticism among physicians. Here, we summarize the mechanism of action and detailed management of adverse effects of the most commonly used immunosuppressive drugs for skin diseases. Furthermore, we discuss the management of these drugs during pregnancy and breastfeeding, as well as their interaction and handling during vaccination.

Type 2 T-Cell Responses against Distinct Epitopes of the Desmoglein 3 Ectodomain in Pemphigus Vulgaris.

Pemphigus vulgaris (PV) is an autoimmune blistering disorder of the skin and/or mucous membranes caused by IgG autoantibodies that predominantly target two transmembrane desmosomal cadherins: desmoglein (DSG)1 and DSG3. DSG-specific T cells play a central role in PV pathogenesis because they provide help to autoreactive B cells for autoantibody production. In this study, we characterized DSG3-specific peripheral T cells in a cohort of 52 patients with PV and 41 healthy controls with regard to cytokine profile and epitope specificity. By ELISpot analysis, type 2 T cells reactive with the DSG3 ectodomain were significantly increased in patients with PV compared with those in healthy controls. By dextramer analysis, CD4+ T cells specific for an epitope within the extracellular domain of DSG3, DSG3(206-220), were found at significantly higher frequencies in patients with PV than in HLA-matched healthy controls. T-cell recognition of two distinct DSG3 epitopes, that is, DSG3(206-220) and DSG3(378-392), correlated significantly, suggesting a synergistic effect in B-cell help. Immunization of HLA-DRB1∗04:02-transgenic mice with PV with the same set of DSG3 peptides induced pathogenic DSG3-specific IgG antibodies, which induced loss of keratinocyte adhesion in vitro. Thus, DSG3 peptide-specific T cells are of particular interest as surrogate markers of disease activity and potential therapeutic targets in PV.

Pemphigus and pemphigoids: Clinical presentation, diagnosis and therapy.

Pemphigus and pemphigoid are two potentially life-threatening groups of autoimmune diseases, characterized by autoantibodies targeting structural components of desmosomes or hemidesmosomes, respectively. Affected patients typically show itchy/painful plaques or blistering skin lesions and/or impairing mucosal blistering and erosions, which may strongly impact their quality of life. Since the milestone work of Walter Lever in 1953, who differentiated these two groups of diseases by histopathological analysis of the level of antibody-mediated skin cleavage, enormous progresses occurred. Achievements made in laboratory diagnostics now allow to identify antigen specific structural proteins of the skin that are targeted by pathogenic autoantibodies. These progresses were accompanied by an increased understanding of the pathogenesis of these diseases thanks to the establishment of animal models reproducing disease and on studies on skin and blood of affected individuals, which have been leading to novel and disease-specific treatments. Yet, given their phenotypical overlap with more common dermatological diseases, correct diagnosis and appropriate treatment are often delayed, in some cases leading to irreversible sequelae, including organ dysfunction (i.e., loss of vision in mucous membrane pemphigoid). Here, we provide a concise overview of the clinical appearance, diagnosis and therapeutic management of pemphigus and pemphigoid diseases.

Dermatomyositis: a comprehensive review of clinical manifestations, serological features, and therapeutic approaches.

Dermatomyositis (DM) is an autoimmune disorder, which belongs to a group of rare autoimmune dermatoses characterized by different skin features and variable muscle involvement. We recognize four main variants of DM: classic DM, clinically amyopathic DM, paraneoplastic DM, and juvenile DM. Clinically, patients show several skin features, but heliotrope rash, and violaceous papules located at the interphalangeal or metacarpophalangeal joints (Gottron's papules) are the most frequently observed. Together with skin features, patients show muscle involvement, most commonly with symmetrical weakness of the proximal muscles. DM belongs to the facultative paraneoplastic dermatoses and a wide range of solid or hematologic malignancies can be detected in DM patients. Serologically, a wide range of autoantibodies can be detected in patients with DM. Indeed, distinct serotypes can be related to specific phenotypes with specific clinical features, carrying a different risk for systemic involvement and for malignancies. Systemic corticosteroids are still considered the first-line approach, but several steroid-sparing agents, such as methotrexate, azathioprine or mycophenolate mofetil, have been reported as effective in treating DM. Furthermore, new class of drugs, such as monoclonal antibodies, purified immunoglobulins or Janus kinase inhibitors are becoming more relevant in the clinical practice or are currently under investigation. In this work, we aim to offer a clinical overview of the diagnostic workout, the characteristics of DM variants, the role of autoantibodies in DM, and the management of this life-threatening systemic disorder.

Enzymatic Debridement in Geriatric Burn Patients-A Reliable Option for Selective Eschar Removal.

The treatment of geriatric burn patients represents a major challenge in burn care. The objective of this study was to evaluate the efficacy of enzymatic debridement (ED) in geriatric burn patients. Adult patients who received ED for treatment of mixed pattern and full thickness burns (August 2017-October 2022) were included in this study and grouped in the younger (18-65 years) and geriatric (≥65 years) groups. Primary outcome was a necessity of surgery subsequent to ED. Both groups (patient characteristics, surgical and non-surgical treatment) were compared. Multiple logistic and linear regression models were used to identify the effect of age on the outcomes. A total of 169 patients were included (younger group: 135 patients, geriatric group: 34 patients). The burn size as indicated by %TBSA (24.2 ± 20.4% vs. 26.8 ± 17.1%, p = 0.499) was similar in both groups. The ASA (2.5 ± 1.1 vs. 3.4 ± 1.1, p < 0.001) and ABSI scores (6.1 ± 2.8 vs. 8.6 ± 2.3, p < 0.001) were significantly higher in the geriatric group. The %TBSA treated with ED (5.4 ± 5.0% vs. 4.4 ± 4.3%, p = 0.245) were similar in both groups. The necessity of additional surgical interventions (63.0 % vs. 58.8 %, p = 0.763) and the wound size debrided and grafted (2.9 ± 3.5% vs. 2.2 ± 2.1%; p = 0.301) were similar in both groups. Regression models yielded that age did not have an effect on efficacy of ED. We showed that ED is reliable and safe to use in geriatric patients. Age did not have a significant influence on the surgical outcomes of ED. In both groups, the size of the grafted area was reduced and, in many patients, surgery was avoided completely.