Drug Survival of Dupilumab, Methotrexate, and Cyclosporine A in Children With Atopic Dermatitis.

Importance: Dupilumab, methotrexate (MTX), and cyclosporine A (CsA) are valuable treatment options for pediatric patients with refractory moderate to severe atopic dermatitis (AD). Yet, comparative data on these treatments in pediatric patients are scarce. Objective: To evaluate drug survival of dupilumab, MTX, and CsA, and identify associated predictors in a multicenter daily practice cohort study of pediatric patients with AD. Design, Setting, and Participants: This multicenter daily practice cohort study included patients with AD aged 2 to 17 years treated with dupilumab, MTX, and/or CsA in 5 tertiary centers in the Netherlands between 2013 and 2023. Data were extracted from the prospective BioDay and TREAT Netherlands registries and electronic medical records. Exposures: Dupilumab, MTX, CsA. Main Outcomes and Measures: Drug survival was analyzed using Cox proportional hazard regression models. Univariable and multivariable Cox regression analyses were conducted to identify variables associated with drug discontinuation. Results: A total of 502 treatment episodes in 362 unique patients were included, comprising 192 dupilumab episodes, 94 MTX episodes, and 216 CsA episodes. Overall, the mean (SD) age at treatment initiation was 12.9 (3.8) years, and 272 treatment episodes (54.2%) in female patients. The 1-year, 2-year, and 3-year overall drug survival rates, respectively, were 84.1%, 72.3%, and 62.0% for dupilumab; 60.7%, 39.3%, and 25.3% for MTX; and 43.9%, 21.5%, and 10.4% for CsA. Ineffectiveness was the most frequent reason for drug discontinuation, accounting for 178 episodes (35.5%), mostly in patients treated with CsA, followed by adverse effects in 94 patients (18.7%). Treatment with MTX and treatment with CsA were independently associated with a higher risk for drug discontinuation due to ineffectiveness (hazard ratio [HR], 4.45 [95% CI, 2.38-8.34] and HR, 10.88 [95% CI, 6.23-19.02], respectively) and adverse effects (HR, 4.39 [95% CI, 2.05-9.39] and HR, 3.83 [95% CI, 1.85-7.92], respectively) compared to treatment with dupilumab. Patients aged 12 to 17 years starting systemic treatment were independently associated with a higher risk for drug discontinuation due to ineffectiveness (HR, 1.55 [95% CI, 1.10-2.20]) and adverse effects (HR, 2.39 [95% CI, 1.33-4.30]). Conclusions and Relevance: This multicenter daily practice cohort study demonstrated a superior 1-year, 2-year, and 3-year overall drug survival for dupilumab, followed by MTX, with the lowest rates observed for CsA in pediatric patients with AD. This study also identified characteristics associated with discontinuation. These results provide insight into drug survival resulting from the effectiveness, safety, and tolerability of these systemic treatments in pediatric patients with AD and contribute to the optimization of patient outcomes.

International consensus on methotrexate dosing for patients with atopic dermatitis: An eDelphi study.

BACKGROUND: Despite the widespread off-label use of methotrexate (MTX) for the treatment of atopic dermatitis (AD), there is limited high-quality evidence on dosing regimens and existing guidelines do not provide clear recommendations regarding dosing strategies. OBJECTIVE: The aim of this study was to achieve international consensus among AD experts to standardize the dosing regimen for MTX treatment in adults and children with AD. METHODS: An electronic Delphi (eDelphi) study was conducted from October 2021 to September 2022. Recruitment was conducted through dermatology societies and AD interest groups. Participation was open to dermatologists and dermatology residents experienced in treating AD patients with MTX. The study consisted of three online rounds. The first round was informed by a systematic review of relevant literature, and subsequent rounds were adjusted based on the results of the previous round. Participants voted on 19 proposals using a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree). Consensus was achieved when at least 70% of participants agreed, and less than 15% disagreed. Proposals that did not reach consensus in the first three rounds were discussed in a consensus meeting, where consensus was defined as less than 30% disagreement. RESULTS: In total, 152 participants completed Round 1, 104 (68%) completed all survey rounds, and 43 (28%) joined the consensus meeting. Consensus was achieved on 7 proposals in Round 1, 4 in Round 2 and 6 in Round 3. The final 2 proposals reached consensus during the consensus meeting. Consensus topics include test dose, start dose, maximum dose, administration route, dosing schedule, management of stopping treatment, treatment duration and folic acid supplementation. CONCLUSIONS: This eDelphi study achieved consensus on 19 proposals related to MTX dosing for adults and children with AD. These results aim to guide prescribing decisions and encourage a standardized global approach to MTX use in AD.

The wide variety of methotrexate dosing regimens for the treatment of atopic dermatitis: a systematic review.

Background:Methotrexate is an off-label therapy for atopic dermatitis. A lack of consensus on dosing regimens poses a risk of underdosing and ineffective treatment or overdosing and increased risk of side effects. This systematic review summarizes the available evidence on dosing regimens.Materials and methods:A literature search was conducted, screening all randomized controlled trials (RCTs) and guidelines published up to 6 July 2023, in the MEDLINE, Embase, and Cochrane Library databases.Results:Five RCTs and 21 guidelines were included. RCTs compared methotrexate with other treatments rather than different methotrexate dosing regimens. The start and maintenance doses in RCTs varied between 7.5-15 mg/week and 14.5-25 mg/week, respectively. Despite varied dosing, all RCTs demonstrated efficacy in improving atopic dermatitis signs and symptoms. Guidelines exhibited substantial heterogeneity but predominantly proposed starting doses of 5-15 mg/week for adults and 10-15 mg/m2/week for children. Maintenance doses suggested were 7.5-25 mg/week for adults and 0.2-0.7 mg/kg/week for children. One guideline suggested a test dose and nearly half advised folic acid supplementation.Conclusion:This systematic review highlights the lack of methotrexate dosing guidelines for atopic dermatitis. It identifies commonly recommended and utilized dosing regimens, serving as a valuable resource for clinicians prescribing methotrexate off-label and providing input for an upcoming consensus study.

Effects of sustained hyperprolactinemia in late gestation on the mammary parenchymal tissue transcriptome of gilts.

BACKGROUND: Gilts experiencing sustained hyperprolactinemia from d 90 to 109 of gestation showed an early onset of lactogenesis coupled with premature mammary involution. To better understand the molecular mechanisms underlying the premature mammary involution observed in these gilts, a transcriptomic analysis was undertaken. Therefore, this study aimed to explore the effect of hyperprolactinemia on the global transcriptome in the mammary tissue of late gestating gilts and identify the molecular pathways involved in triggering premature mammary involution. METHODS: On d 90 of gestation, gilts received daily injections of (1) canola oil until d 109 ± 1 of gestation (CTL, n = 18); (2) domperidone (to induce hyperprolactinemia) until d 96 ± 1 of gestation (T7, n = 17) or; (3) domperidone (until d 109 ± 1 of gestation (T20, n = 17). Mammary tissue was collected on d 110 of gestation and total RNA was isolated from six CTL and six T20 gilts for microarray analysis. The GeneChip® Porcine Gene 1.0 ST Array was used for hybridization. Functional enrichment analyses were performed to explore the biological significance of differentially expressed genes, using the DAVID bioinformatics resource. RESULTS: The expression of 335 genes was up-regulated and that of 505 genes down-regulated in the mammary tissue of T20 vs CTL gilts. Biological process GO terms and KEGG pathways enriched in T20 vs CTL gilts reflected the concurrent premature lactogenesis and mammary involution. When looking at individual genes, it appears that mammary cells from T20 gilts can simultaneously upregulate the transcription of milk proteins such as WAP, CSN1S2 and LALBA, and genes triggering mammary involution such as STAT3, OSMR and IL6R. The down-regulation of PRLR expression and up-regulation of genes known to inactivate the JAK-STAT5 pathway (CISH, PTPN6) suggest the presence of a negative feedback loop trying to counteract the effects of hyperprolactinemia. CONCLUSIONS: Genes and pathways identified in this study suggest that sustained hyperprolactinemia during late-pregnancy, in the absence of suckling piglets, sends conflicting pro-survival and cell death signals to mammary epithelial cells. Reception of these signals results in a mammary gland that can simultaneously synthesize milk proteins and initiate mammary involution.

Methotrexate dosing regimen for plaque-type psoriasis: an update of a systematic review.

BACKGROUND: Methotrexate (MTX) is a systemic treatment for plaque-type psoriasis. At the time of approval, no dose-ranging studies were performed. Nowadays, a uniform dosing regimen is lacking. This might contribute to suboptimal treatment with the drug. OBJECTIVE: To summarize the literature involving the MTX dosing regimens in psoriasis patients. METHODS: In this SR, RCTs and documents with aggregated evidence (AgEv) on the MTX dosing regimen in psoriasis were summarized. All randomized controlled trials (RCTs) in which oral, subcutaneous or intramuscular MTX was used in patients with psoriasis and AgEv, were included. The MEDLINE, EMBASE and CENTRAL databases were searched up to June 20, 2022. This SR was registered in PROSPERO. RESULTS: Thirty-nine RCTs had a high risk of bias. Test dosages were given in only 3 RCTs. In the RCTs, MTX was usually prescribed in a start dose of 7.5 mg/week (n = 13). MTX was mostly given in a start dose of 15 mg/week, in the AgEv (n = 5). One guideline recommended a test dose, in other aggregated evidence a test dose was not mentioned or even discouraged. CONCLUSIONS: There is a lack of high-quality evidence and available data for dosing MTX in psoriasis is heterogeneous.