The Clinical and Molecular Spectrum of GM1 Gangliosidosis.

OBJECTIVE: To evaluate the clinical presentation of patients with GM1 gangliosidosis and to determine whether specific clinical or biochemical signs could lead to a prompt diagnosis. STUDY DESIGN: We retrospectively analyzed clinical, biochemical, and genetic data of 22 patients with GM1 gangliosidosis from 5 metabolic centers in Germany and Austria. RESULTS: Eight patients were classified as infantile, 11 as late-infantile, and 3 as juvenile form. Delay of diagnosis was 6 ± 2.6 months in the infantile, 2.6 ± 3.79 years in the late-infantile, and 14 ± 3.48 years in the juvenile form. Coarse facial features, cherry red spots, and visceromegaly occurred only in patients with the infantile form. Patients with the late-infantile and juvenile forms presented with variable neurologic symptoms. Seventeen patients presented with dystonia and 14 with dysphagia. Laboratory analysis revealed an increased ASAT concentration (13/20), chitotriosidase activity (12/15), and pathologic urinary oligosaccharides (10/19). Genotype analyses revealed 23 causative or likely causative mutations in 19 patients, 7 of them being novel variants. In the majority, a clear genotype-phenotype correlation was found. CONCLUSIONS: Diagnosis of GM1 gangliosidosis often is delayed, especially in patients with milder forms of the disease. GM1 gangliosidosis should be considered in patients with progressive neurodegeneration and spastic-dystonic movement disorders, even in the absence of visceral symptoms or cherry red spots. ASAT serum concentrations and chitotriosidase activity may be of value in screening for GM1 gangliosidosis.

Management of dupilumab-associated conjunctivitis in atopic dermatitis.

Since September 2017, the monoclonal antibody dupilumab (Dupixent® ) has been approved in the EU for the treatment of moderate-to-severe atopic dermatitis. By blocking IL-4 and IL-13 signaling pathways, dupilumab improves both objective signs and subjective symptoms of the disease. Blocking of the IL-4aRα subunit leads to improvement of the skin's barrier function and reduction in Th2-mediated inflammation. While the rate of adverse events on dupilumab is generally low, mild-to-moderate conjunctivitis associated with redness as well as a burning and foreign body sensation has been reported in up to 28 % of patients. Treatment options include topical corticosteroids and topical calcineurin inhibitors. The present review highlights the clinical presentation of dupilumab-associated conjunctivitis and addresses pharmacological and non-pharmacological options available for the treatment of this clinically highly relevant condition.

Tumor lysis syndrome induced by tebentafusp.

Tebentafusp, a bispecific T-cell receptor fusion protein directed against gp100 and CD3, can improve survival in patients with metastatic uveal melanoma and was recently approved for the treatment of HLA-A*02:01-positive uveal melanoma patients. Since tebentafusp often induces cytokine-release syndrome, doses must be escalated and patients monitored as inpatients after the first infusions. The occurrence of tumor lysis syndrome, a potentially life-threatening condition, after administration of a single dose of tebentafusp, is reported here. With adequate therapy, including the application of rasburicase, the patient made a full recovery. It is important to raise awareness of the adverse event profile of this new therapeutic approach among healthcare professionals to promptly recognize and treat side effects.

Tebentafusp is a new treatment for a type of eye cancer called uveal melanoma. It helps the body's defense system fight against cancer cells and has shown promise in helping patients live longer. However, not all patients with uveal melanoma can use this treatment. Only those who have a specific gene marker called HLA-A*02:01-positive can benefit from it. Like any new treatment, tebentafusp may have some side effects. One of them is called cytokine-release syndrome, which can cause symptoms like rash, fever and flu-like feelings. Usually, this side effect is not serious and can be treated well. There was a rare but serious case where one patient had a bad reaction after getting only one dose of tebentafusp. This reaction is called tumor lysis syndrome, which happens when cancer cells break down quickly and release harmful substances into the blood. This can be life-threatening. Thankfully, the patient received the right treatment and got better. This information is shared here with doctors and patients, so they know about possible side effects and can use tebentafusp safely.

Tebentafusp in Patients with Metastatic Uveal Melanoma: A Real-Life Retrospective Multicenter Study.

BACKGROUND: Tebentafusp has recently been approved for the treatment of metastatic uveal melanoma (mUM) after proving to have survival benefits in a first-line setting. PATIENTS AND METHODS: This retrospective, multicenter study analyzed the outcomes and safety of tebentafusp therapy in 78 patients with mUM. RESULTS: Patients treated with tebentafusp had a median PFS of 3 months (95% CI 2.7 to 3.3) and a median OS of 22 months (95% CI 10.6 to 33.4). In contrast to a published Phase 3 study, our cohort had a higher rate of patients with elevated LDH (65.4% vs. 35.7%) and included patients with prior systemic and local ablative therapies. In patients treated with tebentafusp following ICI, there was a trend for a longer median OS (28 months, 95% CI 26.9 to 29.1) compared to the inverse treatment sequence (24 months, 95% CI 13.0 to 35.0, p = 0.257). The most common treatment-related adverse events were cytokine release syndrome in 71.2% and skin toxicity in 53.8% of patients. Tumor lysis syndrome occurred in one patient. CONCLUSIONS: Data from this real-life cohort showed a median PFS/OS similar to published Phase 3 trial data. Treatment with ICI followed by tebentafusp may result in longer PFS/OS compared to the inverse treatment sequence.

Dupilumab for the treatment of adolescents with atopic dermatitis.

INTRODUCTION: Dupilumab is a treatment option newly licensed for adolescents with moderate to severe atopic dermatitis (AD). It reduces type 2 inflammation by blocking the shared receptor subunit for IL-4/-13. Dupilumab affects three disease mechanisms in atopic dermatitis: the skin barrier, the Th2-cell differentiation and the class switch to IgE. This report is based on a systematic literature search of the PubMed Database. AREAS COVERED: Dupilumab showed promising results in improving AD signs, symptoms and quality of life in adolescents with moderate to severe AD. The safety profile of dupilumab in adolescents with moderate to severe AD closely resembled the known safety profile of dupilumab in adults with moderate to severe AD. Injection-site reactions and conjunctivitis were the relevant side-effects. Skin infections were less frequently observed compared to placebo. EXPERT COMMENTARY: Dupilumab was approved by the Food and Drug Administration in March 2019 and by the European Medicines Agency in August 2019 for the treatment of adolescents with moderate to severe atopic dermatitis whose disease is not adequately controlled with topical therapies or when those therapies are not advisable. Since it is the first licensed drug it will likely become the reference drug for adolescents with moderate to severe AD.

Food-Related Contact Dermatitis, Contact Urticaria, and Atopy Patch Test with Food.

A wide variety of foods may cause or aggravate skin diseases such as contact dermatitis, contact urticaria, or atopic dermatitis (AD), both in occupational and private settings. The mechanism of action underlying allergic disease to food, food additives, and spices may be immunologic and non-immunologic. The classification and understanding of these reactions is a complex field, and knowledge of the possible reaction patterns and appropriate diagnostic test methods is essential. In addition, certain foods may cause worsening of atopic dermatitis lesions in children. The atopy patch test (APT) is a well-established, clinically useful tool for assessing delayed type reactions to protein allergens in patients and may be useful to detect protein allergens relevant for certain skin diseases. The APT may even detect sensitization against allergens in intrinsic atopic dermatitis patients, who show negative skin prick test and negative in vitro IgE test results against these allergens. Native foods, SPT solutions on filter paper, and purified allergens in petrolatum have been used for APT. The European Task Force on Atopic Dermatitis (ETFAD) has worked on standardizing this test in the context of AD patients, who are allergic to aeroallergens and food. This recommended, standardized technique involves test application at the upper back of children and adults; use of large, 12-mm Finn chambers; avoidance of any pre-treatment such as tape stripping or delipidation; standardized amounts of purified allergens in petrolatum; and use of the standardized ETFAD reading key. The APT may not be the best working or best standardized of all possible skin tests, but it is the best test that we currently have available in this niche.

Dupilumab for treatment of atopic dermatitis.

INTRODUCTION: Dupilumab is a new treatment option for patients with moderate-to-severe atopic dermatitis. It blocks IL-4/IL13-signaling and thereby inhibits receptor signaling downstream the JAK-STAT-pathway. Three of the main disease mechanisms of atopic dermatitis are affected by blocking this pathway; the decrease of skin barrier function, the class switch to IgE and the TH2-differentiation. Areas Covered: Dupilumab showed promising results in clinical trials of phase I-III. Clinical outcome parameters such as SCORAD, EASI, IGA and BSA improved with dupilumab. A positive effect on patient-reported outcomes like DLQI or pruritus-rating-scales was also demonstrated. The safety profile of dupilumab is superior to conventional immunosuppressive drugs, such as cyclosporine or methotrexate. Injection-site reactions and conjunctivitis were the most relevant side-effects. Skin infections were less frequently observed compared to placebo. Data on the use of dupilumab during pregnancy or in children are not published to date. Expert Commentary: Dupilumab was approved by the FDA in April 2017 for the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.