Characterization of a Musculoskeletal Syndrome of Enthesitis and Arthritis in Patients With Atopic Dermatitis Treated With Dupilumab, an Interleukin-4/13 Inhibitor.

OBJECTIVE: To characterize the presentation and outcomes of patients with atopic dermatitis (AD) who developed musculoskeletal symptoms after treatment with dupilumab, a human IgG4 monoclonal antibody that blocks the functions of interleukin-4 (IL-4) and IL-13, key pathologic pathways in AD. METHODS: This article reports an observational cohort of patients receiving dupilumab who developed new-onset musculoskeletal symptoms after dupilumab therapy at our center. All patients had a comprehensive rheumatologic history and examination, with imaging by ultrasonography (US) or magnetic resonance imaging (MRI) in most patients. RESULTS: Between October 2018 and February 2021, we recorded 470 patients with AD commencing dupilumab treatment from routine clinical care records. Of 36 patients referred for rheumatologic assessment, we identified 26 patients (14 male, 12 female) with a musculoskeletal syndrome of inflammatory enthesitis, arthritis, and/or tenosynovitis. Clinical findings were confirmed by US and MRI. All patients had very good response to dupilumab treatment, and no specific predictors of musculoskeletal syndrome were noted. Symptoms were mild in 16 patients, moderate in 6 patients, and severe in 4 patients. Receipt of nonsteroidal antiinflammatory drugs or cyclooxygenase 2 inhibitors, reduction of dupilumab dose/frequency, and cessation of dupilumab therapy led to improvement, but moderate or severe symptoms persisted for many months. CONCLUSION: We report a new musculoskeletal syndrome of inflammatory enthesitis/arthritis/tenosynovitis in some patients receiving the IL-4 receptor antagonist dupilumab. This response to a cytokine-targeting therapy provides key insights into the pathogenesis of enthesitis.

The clinical relevance of dupilumab serum concentration in patients with atopic dermatitis: a two-center prospective cohort study.

BACKGROUND: Dupilumab is prescribed in one dosage across adult atopic dermatitis patients. Differences in drug exposure may explain variation in treatment response. OBJECTIVE: Investigating the clinical relevance of dupilumab serum concentration in atopic dermatitis in real-world practice. METHODS: In two centers (Netherlands, UK), adults treated with dupilumab for atopic dermatitis were evaluated for effectiveness and safety pretreatment and at 2, 12, 24, and 48 weeks; trough serum samples were analyzed for dupilumab concentration at corresponding time points. RESULTS: In 149 patients, median dupilumab levels during follow-up ranged from 57.4 to 72.4 µg/mL. Levels showed high inter-patient and low intra-patient variability. No correlation was found between levels and ΔEASI. At 2 weeks, levels of ≥64.1 µg/mL predict EASI ≤7 at 24 weeks (specificity:100%, sensitivity:60%; p = .022). At 12 weeks, ≤32.7 µg/mL predicts EASI >7 at 24 weeks (sensitivity:95%, specificity:26%; p = .011). Inverse correlations were found between baseline EASI and levels at 2, 12, and 24 weeks (r = -0.25 to 0.36; p ≤ .023). Low levels were particularly observed in patients with adverse events, treatment interval deviation, and discontinuation. CONCLUSION: At the on-label dosage, the measured range of dupilumab levels does not seem to yield differences in treatment effectiveness. However, disease activity does seem to influence dupilumab levels - higher baseline disease activity results in lower levels at follow-up.

Comparison of real-world treatment outcomes of systemic immunomodulating therapy in atopic dermatitis patients with dark and light skin types.

Background: Few data exist on differences in treatment effectiveness and safety in atopic dermatitis patients of different skin types. Objective: To investigate treatment outcomes of dupilumab, methotrexate, and ciclosporin, and morphological phenotypes in atopic dermatitis patients, stratified by Fitzpatrick skin type. Methods: In an observational prospective cohort study, pooling data from the Dutch TREAT (TREatment of ATopic eczema) NL (treatregister.nl) and UK-Irish A-STAR (Atopic eczema Systemic TherApy Register; astar-register.org) registries, data on morphological phenotypes and treatment outcomes were investigated. Results: A total of 235 patients were included (light skin types [LST]: Fitzpatrick skin type 1-3, n = 156 [Ethnicity, White: 94.2%]; dark skin types [DST]: skin type 4-6, n = 68 [Black African/Afro-Caribbean: 25%, South-Asian: 26.5%, and Hispanics: 0%]). DST were younger (19.5 vs 29.0 years; P < .001), more often had follicular eczema (22.1% vs 2.6%; P < .001), higher baseline Eczema Area and Severity Index (EASI) scores (20.1 vs 14.9; P = .009), less allergic contact dermatitis (30.9% vs 47.4%; P = .03), and less previous phototherapy use (39.7% vs 59.0%; P = .008). When comparing DST and LST corrected for covariates including baseline EASI, DST showed greater mean EASI reduction between baseline and 6 months with only dupilumab (16.7 vs 9.7; adjusted P = .032). No differences were found for adverse events for any treatments (P > .05). Limitations: Unblinded, non-randomized. Conclusion: Atopic dermatitis differs in several characteristics between LST and DST. Skin type may influence treatment effectiveness of dupilumab.

An innate-like Vδ1+ γδ T cell compartment in the human breast is associated with remission in triple-negative breast cancer.

Innate-like tissue-resident γδ T cell compartments capable of protecting against carcinogenesis are well established in mice. Conversely, the degree to which they exist in humans, their potential properties, and their contributions to host benefit are mostly unresolved. Here, we demonstrate that healthy human breast harbors a distinct γδ T cell compartment, primarily expressing T cell receptor (TCR) Vδ1 chains, by comparison to Vδ2 chains that predominate in peripheral blood. Breast-resident Vδ1+ cells were functionally skewed toward cytolysis and IFN-γ production, but not IL-17, which has been linked with inflammatory pathologies. Breast-resident Vδ1+ cells could be activated innately via the NKG2D receptor, whereas neighboring CD8+ αß T cells required TCR signaling. A comparable population of Vδ1+ cells was found in human breast tumors, and when paired tumor and nonmalignant samples from 11 patients with triple-negative breast cancer were analyzed, progression-free and overall survival correlated with Vδ1+ cell representation, but not with either total γδ T cells or Vδ2+ T cells. As expected, progression-free survival also correlated with αß TCRs. However, whereas in most cases TCRαß repertoires focused, typical of antigen-specific responses, this was not observed for Vδ1+ cells, consistent with their innate-like responsiveness. Thus, maximal patient benefit may accrue from the collaboration of innate-like responses mounted by tissue-resident Vδ1+ compartments and adaptive responses mounted by αß T cells.

How genetic variation affects patient response and outcome to therapy for psoriasis.

Psoriasis is a prevalent chronic inflammatory condition that affects the skin. There are many treatments available for psoriasis but they are not universally effective and some have associated toxicities. Pharmacogenetics and pharmacogenomics explore the relationship between individual genetic variation and drug effect to allow targeted 'personalized' therapy for patients. There has been very limited pharmacogenetic research regarding psoriasis, with most limited to small retrospective case-control studies looking at single-nucleotide polymorphisms in candidate genes involved in drug pharmacokinetics. We review the pharmacogenetic investigation of treatments for psoriasis to date, including emerging pharmacogenomic studies. In addition, we discuss how such genetic data could be incorporated into routine clinical practice and future areas for development in this field.