Treatment options for DOCK8 deficiency‐related severe dermatitis

Ollech, Ayelet; Mashiah, Jacob; Lev, Atar; Simon, Amos J.; Somech, Raz; Adam, Etai; Barzilai, Aviv; Hagin, David; Greenberger, Shoshana

doi:10.1111/1346-8138.15955

Cited by 21 publications

(19 citation statements)

References 24 publications

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“…In a pooled analysis of clinical trials, the overall infection risk was not increased in patients under dupilumab compared to the placebo group 69 . Furthermore, in our study, a reduced infection risk had also been reported in two patients with HIES, which may be related to a restoration of balance between Th1 and Th2 immunity 25,30 . Based on the current literature, the use of dupilumab is generally safe in patients with genodermatosis.…”

Section: Discussionsupporting

confidence: 69%

Dupilumab in the treatment of genodermatosis: A systematic review

Dai

et al. 2023

J Deutsche Derma Gesell

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Summary Dupilumab interferes with the signaling pathways of IL‐4 and IL‐13 and is effective in treating atopic dermatitis. Specific genodermatoses, including Netherton syndrome, epidermolysis bullosa pruriginosa, and hyper‐IgE syndrome, are Th2 skewed diseases with activation of type 2 inflammation. We performed this systematic review to investigate the therapeutic role of dupilumab in the treatment of genodermatosis. A systematic search was conducted of the PubMed, Embase, Web of Science, and Cochrane databases from inception to December 13, 2021. The review included studies with relevant terms including “dupilumab,” “genodermatosis”, “Netherton syndrome”, “ichthyosis”, “epidermolysis bullosa” and “hyper‐IgE syndrome”. The initial search yielded 2,888 results, of which 28 studies and 37 patients with genodermatosis were enrolled. The assessed genodermatoses included Netherton syndrome, epidermolysis bullosa pruriginosa, hyper‐IgE syndrome, Hailey‐Hailey disease, and severe eczema associated with genetic disorders. Most of the reported cases showed significant clinical improvement after the initiation of dupilumab treatment without major adverse events. Decreased immunoglobulin E levels and cytokine normalization have also been documented. In conclusion, Dupilumab may have a potential therapeutic role in certain genodermatoses skewed towards T helper 2 (Th2) immunity, including Netherton syndrome, epidermolysis bullosa pruriginosa, hyper‐IgE syndrome, Hailey‐Hailey disease, and severe eczema associated with some genetic disorders.

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Section: Discussionsupporting

confidence: 69%

Dupilumab in the treatment of genodermatosis: A systematic review

Dai

et al. 2023

J Deutsche Derma Gesell

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“…240 It may also improve AD related to IL4/4R, IL13, DOCK8, CARD11, STAT3, SPINK5, ERBB2IP, and ZNF341 dysregulation. [241][242][243][244][245][246][247][248] Tralokinumab targets IL13 and is approved for moderate to severe AD in adults. 77 Topical ruxolitinib and oral upadacitinib, abrocitinib, and baricitinib (approved in Europe and Japan) are JAK inhibitors indicated for AD.…”

Section: Discussionmentioning

confidence: 99%

Genetic/Environmental Contributions and Immune Dysregulation in Children with Atopic Dermatitis

Chong¹,

Visitsunthorn²,

Ong³

2022

JAA

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Atopic dermatitis (AD) is one of the most common skin conditions in humans. AD affects up to 20% of children worldwide and results in morbidity for both patients and their caregivers. The basis of AD is an interplay between genetics and the environment characterized by immune dysregulation. A myriad of mutations that compromise the skin barrier and/or immune function have been linked to AD. Of these, filaggrin gene ( FLG ) mutations are the most evidenced. Many other mutations have been implicated in isolated studies that are often unreplicated, creating an archive of genes with potential but unconfirmed relevance to AD. Harnessing big data, polygenic risk scores (PRSs) and genome-wide association studies (GWAS) may provide a more practical strategy for identifying the genetic signatures of AD. Epigenetics may also play a role. Staphylococcus aureus is the most evidenced microbial contributor to AD. Cutaneous dysbiosis may result in over-colonization by pathogenic strains and aberrant skin immunity and inflammation. Aeroallergens, air pollution, and climate are other key environmental contributors to AD. The right climate and/or commensals may improve AD for some patients.

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“…Previous studies also support dupilumab treatment of atopic dermatitis in non- STAT3 -related-IEI, such as DOCK8 deficiency ( 40 ), CARD11-associated atopy with dominant interference of NF-kB signaling (CADINS) ( 41 ), Wiskott-Aldrich Syndrome ( 42 ), common variable immune deficiency (CVID) ( 43 ), TTC7A-associated combined immunodeficiency ( 44 ), and X-linked agammaglobulinemia ( 45 – 47 ). Thus, indications for dupilumab use in IEI are rapidly expanding, and it should be considered a main therapeutic modality in adult patients with AD-HIES along with standard topical care.…”

Section: Discussionmentioning

confidence: 77%

Dominant-negative signal transducer and activator of transcription (STAT)3 variants in adult patients: A single center experience

et al. 2022

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BackgroundAutosomal dominant hyper-IgE syndrome (AD-HIES) caused by dominant negative (DN) variants in the signal transducer and activator of transcription 3 gene (STAT3) is characterized by recurrent Staphylococcal abscesses, severe eczema, chronic mucocutaneous candidiasis (CMC), and non-immunological facial and skeletal features.ObjectivesTo describe our experience with the diagnosis and treatment of adult patients with AD-HIES induced by DN-STAT3 variants.MethodsThe medical records of adult patients (>18 years) treated at the Allergy and Clinical Immunology Clinic of Hadassah Medical Center, Jerusalem, Israel, were retrospectively analyzed. Immune and genetic workups were used to confirm diagnosis.ResultsThree adult patients (2 males; age 29-41 years) were diagnosed with DN-STAT3 variants. All patients had non-immunological features, including coarse faces and osteopenia. Serious bacterial infections were noted in all patients, including recurrent abscesses, recurrent pneumonia, and bronchiectasis. CMC and diffuse dermatophytosis were noted in two patients. Two patients had severe atopic dermatitis refractory to topical steroids and phototherapy. Immune workup revealed elevated IgE in three patients and eosinophilia in two patients. Whole exome sequencing revealed DN-STAT3 variants (c.1166C>T; p.Thr389Ile in two patients and c.1268G>A; p. Arg423Gln in one patient). Variants were located in DNA-binding domain (DBD) and did not hamper STAT3 phosphorylation Treatment included antimicrobial prophylaxis with trimethoprim/sulfamethoxazole (n=2) and amoxycillin-clavulanic acid (n=1), and anti-fungal treatment with fluconazole (n=2) and voriconazole (n=1). Two patients who had severe atopic dermatitis, were treated with dupilumab with complete resolution of their rash. No adverse responses were noted in the dupilumab-treated patients.DiscussionDupilumab can be used safely as a biotherapy for atopic dermatitis in these patients as it can effectively alleviate eczema-related symptoms. Immunologists and dermatologists treating AD-HIES adult patients should be aware of demodicosis as a possible manifestation. DN-STAT3 variants in DBD do not hamper STAT3 phosphorylation.

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Treatment options for DOCK8 deficiency‐related severe dermatitis

Cited by 21 publications

References 24 publications

Dupilumab in the treatment of genodermatosis: A systematic review

Dupilumab in the treatment of genodermatosis: A systematic review

Genetic/Environmental Contributions and Immune Dysregulation in Children with Atopic Dermatitis

Dominant-negative signal transducer and activator of transcription (STAT)3 variants in adult patients: A single center experience

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