Clinicopathological definition, management and prognostic value of mogamulizumab-associated rash and other cutaneous events: A systematic review.

Mogamulizumab is a first-in-class IgG1k monoclonal antibody that selectively targets the chemokine receptor type 4. The drug has received Food and Drug administration authorisation for mycosis fungoides and Sézary syndrome following failure of at least one previous course of systemic therapy and now is available in Europe. One of the most common treatment-related side effects observed has been the mogamulizumab-associated rash (MAR), which affects up to a quarter of patients and is the most frequent adverse event leading to drug discontinuation. The aim of this study is to perform a systematic review of the literature on patients diagnosed with MAR and other mogamulizumab-related cutaneous events to describe the clinical and histological characteristics, the management in clinical practice and to assess whether these events have prognostic implications. In total, 2073 records were initially identified through a literature search, 843 of which were duplicates. After screening for eligibility and inclusion criteria, 49 articles reporting mogamulizumab-associated cutaneous events were included. Totally, 1516 patients were retrieved, with a slight male prevalence as for the available data (639 males and 570 females, i.e. 52.9% vs. 47.1%). Regarding the reported clinicopathological findings of the cutaneous reactions, the five most common patterns were spongiotic/psoriasiform dermatitis (22%), eruptions characterized by the presence of papules and/or plaques (16.1%), cutaneous granulomatosis (11.4%), morbilliform or erythrodermic dermatitis (9.4%) and photodermatitis (7.1%). Our results highlight how the majority of the reported cutaneous adverse events on mogamulizumab are of mild-to-moderate entity and generally manageable in clinical practice, though prompt recognition is essential and case-by-case assessment should be recommended. Future research will need to focus on the MAR prognostic implications and to identify genomic and molecular markers for a more rapid and accurate diagnosis.

Current treatment goals are achieved by the majority of patients with atopic dermatitis treated with tralokinumab: results from a multicentric, multinational, retrospective, cohort study.

BACKGROUND: Tralokinumab is a human monoclonal antibody targeting interleukin-13 that is approved for the treatment of moderate-severe atopic dermatitis. Studies analyzing the efficacy and safety of tralokinumab in a real-world setting are scarce. RESEARCH DESIGN AND METHODS: A European, multicentric, real-world, retrospective cohort study was defined to assess the effectiveness and safeness profile of tralokinumab, investigating the achievement of pre-specified treatment goals; and to detect potential differences in terms of effectiveness and safeness across some selected patient subcohorts. RESULTS: A total of 194 adult patients were included in this study. A significant improvement in physician-assessed disease severity was detected at each follow-up visit as compared with baseline and similar trend was observed for patient-reported outcomes and quality of life. No meaningful difference in effectiveness was found when considering patient age (<65 versus ≥65 years), neither dissecting patient cohort in dupilumab-naive vs dupilumab-treated subjects. Among tralokinumab-treated patients, 88% achieved at least one currently identified real-world therapeutic goal at week 16. CONCLUSIONS: This retrospective multicenter study confirmed the effectiveness and safeness of tralokinumab throughout 32 weeks of observation, showing the achievement of therapeutic goals identified in both trial and real-world settings in a large proportion of tralokinumab-treated patients.

Topical ruxolitinib: A new treatment for vitiligo.

Vitiligo is a chronic autoimmune skin disorder whose diagnosis is often psychologically upsetting. The efficacy of the available therapies, including topical corticosteroids and topical calcineurin inhibitors, has historically been limited and the management of vitiligo is still challenging. As vitiligo is a chronic disease limited to the skin, topical rather than systemic therapies may be preferable (especially among patients with localised lesions) to avoid the long-term side-effects of the latter. A topical formulation of ruxolitinib, a selective JAK1/2 inhibitor, has recently been approved in the United States for the treatment of non-segmental vitiligo in patients aged >12 years based on data from the phase III TRuE-V1 and TRuE-V2 clinical trials. The aim of this review is to describe the current evidence concerning the efficacy and safety of topical ruxolitinib in the treatment of vitiligo, and discuss issues regarding its use in younger children and pregnant or breastfeeding women, as well as the duration and durability of treatment. The promising results obtained so far suggest that 1.5% ruxolitinib cream is an effective means of treating vitiligo.

Report of terbinafine resistant Trichophyton spp. in Italy: Clinical presentations, molecular identification, antifungal susceptibility testing and mutations in the squalene epoxidase gene.

BACKGROUND: Numerous reports of resistance to terbinafine in Trichophyton spp. from all over the world are arousing justified attention and concern. Point mutations in the gene that encodes the squalene epoxidase (SQLE) enzyme are responsible for these therapeutic resistances. OBJECTIVES: Primary objective of the study was to describe first isolates of Trichophyton spp. resistant to terbinafine among the patients treated between September 2019 and June 2022 at the Dermatology Units of Ospedale Maggiore Policlinico and San Bortolo Hospital. Secondary objective was to study the resistance mechanism. METHODS: Patients with confirmed Trichophyton spp. infection has been treated with systemic and topical terbinafine. Patients were then re-evaluated 12 weeks after the therapy. Patients with incomplete or absent response to terbinafine underwent a new skin scraping for direct mycological examination, new identification of dermatophyte species from culture and MALDI-TOF, molecular species identification, antifungal susceptibility testing and molecular analysis of SQLE gene. RESULTS: We identified five patients without clinical response to treatment with terbinafine. The DNA sequencing of the ITS region identified one Trichophyton rubrum and four Trichophyton indotineae. The T. rubrum strain showed minimum inhibitory concentration (MIC) (90% growth inhibition) of 4 mg/L for terbinafine. The four T. indotineae strains showed a MICs range of 0.25-4 mg/L for terbinafine. The analysis of the SQLE gene in the T. rubrum strain showed a nucleotide substitution generating a missense mutation (L393F). The SQLE gene sequencing in the T. indotineae strains showed a nucleotide substitution generating a missense mutation (F397L) in two strains, a nucleotide substitution L393S in one strain and a nucleotide substitution F415C in another strain. CONCLUSIONS: We report the first cases of terbinafine-resistant Trichophyton isolates in the Italian population. Solid antifungal management programs will be needed to promote more responsible use of antimycotics and preserve their therapeutic efficacy to control antifungal resistance.

Updated S2 K guidelines for the management of bullous pemphigoid initiated by the European Academy of Dermatology and Venereology (EADV).

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or, most frequently, generalized bullous lesions. A subset of patients only develops excoriations, prurigo-like lesions, and eczematous and/or urticarial erythematous lesions. The disease, which is significantly associated with neurological disorders, has high morbidity and severely impacts the quality of life. OBJECTIVES AND METHODOLOGY: The Autoimmune blistering diseases Task Force of the European Academy of Dermatology and Venereology sought to update the guidelines for the management of BP based on new clinical information, and new evidence on diagnostic tools and interventions. The recommendations are either evidence-based or rely on expert opinion. The degree of consent among all task force members was included. RESULTS: Treatment depends on the severity of BP and patients' comorbidities. High-potency topical corticosteroids are recommended as the mainstay of treatment whenever possible. Oral prednisone at a dose of 0.5 mg/kg/day is a recommended alternative. In case of contraindications or resistance to corticosteroids, immunosuppressive therapies, such as methotrexate, azathioprine, mycophenolate mofetil or mycophenolate acid, may be recommended. The use of doxycycline and dapsone is controversial. They may be recommended, in particular, in patients with contraindications to oral corticosteroids. B-cell-depleting therapy and intravenous immunoglobulins may be considered in treatment-resistant cases. Omalizumab and dupilumab have recently shown promising results. The final version of the guideline was consented to by several patient organizations. CONCLUSIONS: The guidelines for the management of BP were updated. They summarize evidence- and expert-based recommendations useful in clinical practice.

Topical tacrolimus during systemic therapy for severe atopic dermatitis in the clinical practice.

OBJECTIVE: To evaluate the role of tacrolimus ointment in the management of patients on dupilumab therapy for severe atopic dermatitis, in a real-life setting. PATIENTS AND METHODS: Consecutive patients with severe AD treated with dupilumab were enrolled. Topical treatment was associated according to the clinical practice. Eczema Area and Severity Index (EASI), itching and sleep Numerical Rating Scale (NRS) and Dermatologic quality of Life (DLQI) were recorded at baseline and after 4, 16 and 52 weeks of treatment with dupilumab. RESULTS: Overall, 342 patients were enrolled, and 307 were evaluable. Tacrolimus was used by 6.5% (n=20) of patients at baseline, 11%, 13.5%, and 11.3% after 1, 4 and 12 months, respectively; the mean time to introduce tacrolimus after initiation of dupilumab was 8.3 ± 0.3 months. Low EASI score (<7; mild disease) after 1 month of systemic therapy was more frequent in patients who applied tacrolimus at baseline than in patients who did not (72.2% vs. 55.8%, p=0.027). Female sex, low DLQI scores, low age at dupilumab initiation, and non-generalized AD were correlated with an increased probability to start tacrolimus at any time during the study. CONCLUSIONS: Data suggested that early treatment of localized areas with tacrolimus improves systemic treatment efficacy.

New insights on ocular surface disease in patients with atopic dermatitis treated with dupilumab.

Our study sought to describe ocular surface alterations at baseline and after 4 months of dupilumab treatment in patients with severe AD. Our findings highlight that all 25 patients showed ocular surface alterations prior to dupilumab treatment. Dupilumab may cause the worsening of clinical or subclinical pre-existing ocular alterations belonging to the spectrum of AKC.

Clinical and serological predictors of relapse in pemphigus: a study of 143 patients.

BACKGROUND: Pemphigus is an autoimmune bullous disease mediated by autoantibodies targeting epithelial cell-cell adhesion molecules. Predictors of relapse have not yet been clearly identified. AIMS: To identify factors at diagnosis and during follow-up that could be predictors of relapse. METHODS: Clinical and immunopathological data at diagnosis, clinical remission and first relapse from patients with pemphigus vulgaris or foliaceus and at least a 36-month follow-up were collected retrospectively. Based on the autoantibody profile at diagnosis, three serological patient subsets were devised: (i) anti-desmoglein (Dsg)1-positive and anti-Dsg3-negative; (iii) anti-Dsg1-negative and anti-Dsg3-positive; and (iii) anti-Dsg1-positive and anti-Dsg3-positive. RESULTS: Data from 143 patients were collected. No significant differences were found between relapsers (n = 90) and nonrelapsers (n = 53) for time to remission or for anti-Dsg1 and anti-Dsg3 titres at diagnosis and remission. In the analysis of all patients, a higher risk of relapse was found for a body surface area (BSA) score of 3 compared with BSA < 3 (OR = 3.30, 95% CI 1.17-9.28; P = 0.02) and for a positive titre of either anti-Dsg1 or anti-Dsg3 autoantibodies at remission compared with both being negative (OR = 2.42, 95% CI 1.21-4.85, P = 0.01). In patients who were anti-Dsg3-positive and anti-Dsg1-negative at diagnosis, failure to achieve anti-Dsg3 negativity at clinical remission was a significant predictor of relapse (OR = 7.89, 95% CI 2.06-30.21; P < 0.01). Similarly, failure to achieve anti-Dsg1 negativity at clinical remission was a significant predictor of relapse in patients with both anti-Dsg1 and anti-Dsg3 positivity at diagnosis (OR = 5.74, 95% CI 1.15-28.61; P = 0.03), but not in those who were anti-Dsg1-positive/anti-Dsg3-negative at diagnosis (OR = 1.08, 95% CI 0.27-4.30; P = 0.91). CONCLUSION: Regardless of pemphigus subtype, autoantibody titre negativity at clinical remission in patients classified based on their anti-Dsg1 and anti-Dsg3 profile at diagnosis and BSA were useful tools in predicting relapse.

European guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part I.

This guideline on mucous membrane pemphigoid (MMP) has been elaborated by the Task Force for Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology (EADV) with a contribution of physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline encompassing a systematic review of the literature until June 2019 in the MEDLINE and EMBASE databases. This first part covers methodology, the clinical definition of MMP, epidemiology, MMP subtypes, immunopathological characteristics, disease assessment and outcome scores. MMP describes a group of autoimmune skin and mucous membrane blistering diseases, characterized by a chronic course and by predominant involvement of the mucous membranes, such as the oral, ocular, nasal, nasopharyngeal, anogenital, laryngeal and oesophageal mucosa. MMP patients may present with mono- or multisite involvement. Patients' autoantibodies have been shown to be predominantly directed against BP180 (also called BPAG2, type XVII collagen), BP230, laminin 332 and type VII collagen, components of junctional adhesion complexes promoting epithelial stromal attachment in stratified epithelia. Various disease assessment scores are available, including the Mucous Membrane Pemphigoid Disease Area Index (MMPDAI), the Autoimmune Bullous Skin disorder Intensity Score (ABSIS), the 'Cicatrising Conjunctivitis Assessment Tool' and the Oral Disease Severity Score (ODSS). Patient-reported outcome measurements (PROMs), including DLQI, ABQOL and TABQOL, can be used for assessment of quality of life to evaluate the effectiveness of therapeutic interventions and monitor disease course.

European Guidelines (S3) on diagnosis and management of mucous membrane pemphigoid, initiated by the European Academy of Dermatology and Venereology - Part II.

This guideline has been initiated by the task force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology, including physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline that systematically reviewed the literature on mucous membrane pemphigoid (MMP) in the MEDLINE and EMBASE databases until June 2019, with no limitations on language. While the first part of this guideline addressed methodology, as well as epidemiology, terminology, aetiology, clinical presentation and outcome measures in MMP, the second part presents the diagnostics and management of MMP. MMP should be suspected in cases with predominant mucosal lesions. Direct immunofluorescence microscopy to detect tissue-bound IgG, IgA and/or complement C3, combined with serological testing for circulating autoantibodies are recommended. In most patients, serum autoantibodies are present only in low levels and in variable proportions, depending on the clinical sites involved. Circulating autoantibodies are determined by indirect IF assays using tissue substrates, or ELISA using different recombinant forms of the target antigens or immunoblotting using different substrates. The major target antigen in MMP is type XVII collagen (BP180), although in 10-25% of patients laminin 332 is recognized. In 25-30% of MMP patients with anti-laminin 332 reactivity, malignancies have been associated. As first-line treatment of mild/moderate MMP, dapsone, methotrexate or tetracyclines and/or topical corticosteroids are recommended. For severe MMP, dapsone and oral or intravenous cyclophosphamide and/or oral corticosteroids are recommended as first-line regimens. Additional recommendations are given, tailored to treatment of single-site MMP such as oral, ocular, laryngeal, oesophageal and genital MMP, as well as the diagnosis of ocular MMP. Treatment recommendations are limited by the complete lack of high-quality randomized controlled trials.

S2k guidelines (consensus statement) for diagnosis and therapy of dermatitis herpetiformis initiated by the European Academy of Dermatology and Venereology (EADV).

INTRODUCTION: Dermatitis herpetiformis (DH) is a chronic, pruritic, gluten-induced skin disorder characterized by subepidermal granular IgA deposition and a variable degree of enteropathy identical to that seen in coeliac disease. So far, there has been no European consensus about the management of DH. METHODS: The guidelines were created by small subgroups of a guideline committee consisting of 26 specialists from various medical fields and one patients' representative. The members of the committee then discussed the guidelines and voted for the final version at two consensus meetings. The guidelines were developed under the support of the European Academy of Dermatology and Venereology (EADV) and in collaboration with the European Dermatology Forum (EDF). RESULTS: The guidelines summarize evidence-based and expert-based recommendations (S2 level) for the management of DH (see Appendix). CONCLUSION: These guidelines will improve the quality of management of DH and support dermatologists in their diagnostic and therapeutic decisions.