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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/m 2 /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.

Previous studies demonstrated limited efficacy of immune checkpoint inhibitors in unresectable acral melanoma (AM); it remains unclear how this translates to the adjuvant setting. This study investigates clinical outcomes of acral compared to cutaneous melanoma (CM) patients treated with adjuvant anti-PD-1 after complete resection. All stages III-IV AM and CM patients receiving adjuvant anti-PD-1 after complete resection between 2018 and 2022 were included from the prospective nationwide Dutch Melanoma Treatment Registry. We analyzed recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). A multivariable Cox regression analysis of RFS was performed to adjust for potential confounders. We included 1958 (86 AM and 1872 CM) patients. At baseline, AM patients more frequently had KIT mutations, higher disease stages, and Eastern Cooperative Oncology Group Performance Status, and fewer BRAF and NRAS mutations. Median RFS was 14.8 months (95% confidence interval [CI]: 11.5-29.3) in AM and 37.4 months (95% CI: 34.6 to not reached) in CM (p = .002). After correcting for potential confounders, AM remained associated with a higher risk of recurrence (HR adj 1.53; 95% CI: 1.07-2.17; p = .019). Two-year DMFS tended to be worse for AM than for CM: 64.5% versus 79.7% (p = .050). Two-year OS was significantly lower in AM (71.5% vs. 84.3%; p = .027). The results of this study suggest a poorer outcome of adjuvant-treated AM compared to CM. Studies assessing the added value of adjuvant treatment in AM are needed. Future research should investigate alternative treatment strategies to improve outcomes of high-risk AM., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Importance: Long-term survival data from clinical trials show that survival curves of patients with advanced melanoma treated with immune checkpoint inhibitors (ICIs) gradually reach a plateau, suggesting that patients have a chance of achieving long-term survival., Objective: To investigate long-term survival in patients with advanced melanoma treated with ICIs outside clinical trials., Design, Setting, and Participants: Cohort study using prospectively collected data from the nationwide Dutch Melanoma Treatment Registry, including patients in the Netherlands with advanced melanoma treated with first-line ICIs from 2012 to 2019. Data were analyzed from January to September 2023., Exposures: Patients were treated with first-line ipilimumab-nivolumab, antibodies that target programmed cell death (anti-PD-1), or ipilimumab., Main Outcomes and Measures: Progression-free survival (PFS) and melanoma-specific survival were analyzed, and a Cox proportional hazards model was used to investigate factors associated with PFS after reaching partial response (PR) or complete response (CR)., Results: A total of 2490 patients treated with first-line ICIs were included (median [IQR] age, 65.0 [55.3-73.0] years; 1561 male patients [62.7%]). Most patients had an Eastern Cooperative Oncology Group Performance Status of 1 or lower (2202 patients [88.5%]) and normal lactate dehydrogenase levels (1715 patients [68.9%]). PFS for all patients was 23.4% (95% CI, 21.7%-25.2%) after 3 years and 19.7% (95% CI, 18.0%-21.4%) after 5 years. Overall survival for all patients was 44.0% (95% CI, 42.1%-46.1%) after 3 years and 35.9% (95% CI, 33.9%-38.0%) after 5 years. Patients with metastases in 3 or more organ sites had a significantly higher hazard of progression after reaching PR or CR (adjusted hazard ratio, 1.37; 95% CI, 1.11-1.69)., Conclusions and Relevance: This cohort study of patients with advanced melanoma treated with ICIs in clinical practice showed that their survival reached a plateau, comparable with patients participating in clinical trials. These findings can be used in daily clinical practice to guide long-term surveillance strategies and inform both physicians and patients regarding long-term treatment outcomes.

Background: Effectivity of BRAF(/MEK) inhibitor rechallenge has been described in prior studies. However, structured data are largely lacking., Methods: Data from all advanced melanoma patients treated with BRAFi(/MEKi) rechallenge were retrieved from the Dutch Melanoma Treatment Registry. The authors analyzed objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) for both first treatment and rechallenge. They performed a multivariable logistic regression and a multivariable Cox proportional hazards model to assess factors associated with response and survival., Results: The authors included 468 patients in the largest cohort to date who underwent at least two treatment episodes of BRAFi(/MEKi). Following rechallenge, ORR was 43%, median PFS was 4.6 months (95% confidence interval [CI], 4.1-5.2), and median OS was 8.2 months (95% CI, 7.2-9.4). Median PFS after rechallenge for patients who discontinued first BRAFi(/MEKi) treatment due to progression was 3.1 months (95% CI, 2.7-4.0) versus 5.2 months (95% CI, 4.5-5.9) for patients who discontinued treatment for other reasons. Discontinuing first treatment due to progression and lactate dehydrogenase (LDH) levels greater than two times the upper limit of normal were associated with lower odds of response and worse PFS and OS. Symptomatic brain metastases were associated with worse survival, whereas a longer treatment interval between first treatment and rechallenge was associated with better survival. Responding to the first BRAFi(/MEKi) treatment was not associated with response or survival., Conclusions: This study confirms that patients benefit from rechallenge. Elevated LDH levels, symptomatic brain metastases, and discontinuing first BRAFi(/MEKi) treatment due to progression are associated with less benefit from rechallenge. A prolonged treatment interval is associated with more benefit from rechallenge., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: The prognosis of advanced melanoma patients has significantly improved over the years. We aimed to evaluate the survival per year of diagnosis., Methods: All systemically treated patients diagnosed with advanced melanoma from 2013 to 2021 were included from the Dutch Melanoma Treatment Registry. Baseline characteristics and overall survival (OS) were compared between the different years of diagnosis. A multivariable Cox proportional hazards model was used to estimate the association between year of diagnosis and OS., Findings: For this cohort study, we included 6260 systemically treated advanced melanoma patients. At baseline, there was an increase over the years in age, the percentage of patients with an ECOG PS ≥ 2, with brain metastases, and a synchronous diagnosis of primary and unresectable melanoma. Median OS increased from 11.2 months (95% CI 10.0-12.4) for patients diagnosed in 2013 to 32.0 months (95% CI 26.6-36.7) for patients diagnosed in 2019. Median OS was remarkably lower for patients diagnosed in 2020 (26.6 months; 95% CI 23.9-35.1) and 2021 (24.0 months; 95% CI 20.4-NR). Patients diagnosed in 2020 and 2021 had a higher hazard of death compared to patients diagnosed in 2019, although this was not significant. The multivariable Cox regression showed a lower hazard of death for the years of diagnosis after 2013. In contrast, patients diagnosed in 2020 and 2021 had a higher hazard of death compared to patients diagnosed in 2019., Interpretation: After a continuous survival improvement for advanced melanoma patients between 2013 and 2019, outcomes of patients diagnosed in 2020 and 2021 seem poorer. This trend of decreased survival remained after correcting for known prognostic factors and previous neoadjuvant or adjuvant treatment, suggesting that it is explained by unmeasured factors, which-considering the timing-could be COVID-19-related., Funding: For the Dutch Melanoma Treatment Registry (DMTR), the Dutch Institute for Clinical Auditing foundation received a start-up grant from governmental organization The Netherlands Organization for Health Research and Development (ZonMW, project number 836002002). The DMTR is structurally funded by Bristol-Myers Squibb, Merck Sharpe & Dohme, Novartis, and Roche Pharma. Roche Pharma stopped funding in 2019, and Pierre Fabre started funding the DMTR in 2019. For this work, no funding was granted., Competing Interests: AvdE has advisory relationships with Amgen, Bristol Myers Squibb, Roche, Novartis, MSD, Pierre Fabre, Sanofi, Pfizer, Ipsen, Merck and has received research study grants not related to this paper from Sanofi, Bristol Myers Squibb, Idera and TEVA and has received travel expenses from MSD Oncology, Roche, Pfizer, Pierre Fabre, and Sanofi. JH has advisory relationships with AstraZeneca, Achilles Therapeutics, BioNTech, BMS, CureVac, Iovance Bio, Eisai, Instil Bio, Imcyse, MSD, Neogene Therapeutics, Novartis, Roche, Sanofi, Sastra Cell Therapy, TRV, and T-Knife. And has received research grants not related to this paper from Asher Bio, Amgen, Bristol Myers Squibb, BioNTech, Novartis, and Sastra Cell Therapy. All grants were paid to the institutions. MA has advisory board/consultancy honoraria from Amgen, Bristol Myers Squibb, Novartis, MSD-Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Astellas, Bayer. She received travel expenses from Astella, BMS, Janssen, Pfizer, and Sanofi and a research grant from Merck-Pfizer. Not related to current work and paid to institute. GH consultancy/advisory relationships with Amgen, Bristol Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi, Pierre Fabre and has received research grants not related to this paper from Bristol Myers Squibb and Seerave. All payments were paid to the institution. RI has no declarations of interest for this research, but is employed at MSD since January 2022. DP has advisory relationships/consultancy honororia with Pierre Fabre and Novartis and received travel expenses from Pierre Fabre. AvdV has consultancy relationships with Bristol Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Pfizer, Sanofi, Ipsen, Eisai all paid to the institute. KS has consulting/advisory relationship with Abbvie, Pierre Fabre, and Sairopa. She received honoraria received from Novartis, Roche, Merck Sharp and Dome and research funding not related to this paper from Genmab, TigaTx, Bristol Myers Squibb, and Philips. All paid to institution. All remaining authors have declared no conflicts of interest., (© 2024 The Author(s).)

The efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma that develop brain metastases (BM) remains unpredictable. In this study, we aimed to identify prognostic factors in patients with melanoma BM who are treated with ICIs. Data from advanced melanoma patients with BM treated with ICIs in any line between 2013 and 2020 were obtained from the Dutch Melanoma Treatment Registry. Patients were included from the time of the treatment of BM with ICIs. Survival tree analysis was performed with clinicopathological parameters as potential classifiers and overall survival (OS) as the response variable. In total, 1278 patients were included. Most patients were treated with ipilimumab-nivolumab combination therapy (45%). The survival tree analysis resulted in 31 subgroups. The median OS ranged from 2.7 months to 35.7 months. The strongest clinical parameter associated with survival in advanced melanoma patients with BM was the serum lactate dehydrogenase (LDH) level. Patients with elevated LDH levels and symptomatic BM had the worst prognosis. The clinicopathological classifiers identified in this study can contribute to optimizing clinical studies and can aid doctors in giving an indication of the patients' survival based on their baseline and disease characteristics.

Background: The TREatment of ATopic eczema (TREAT) Registry Taskforce is a collaborative international network of registries collecting data of atopic eczema (AE) patients receiving systemic and phototherapy with the common goal to provide long-term real-world data on the effectiveness, safety and cost-effectiveness of therapies. A core dataset, consisting of domains and domain items with corresponding measurement instruments, has been developed to harmonize data collection., Objectives: We aimed to give an overview of the status and characteristics of the eight established TREAT registries, and to perform a mapping exercise to examine the degree of overlap and pooling ability between the national registry datasets. This will allow us to determine which research questions can be answered in the future by pooling data., Methods: All eight registries were asked to share their dataset and information on the current status and characteristics. The overlap between the core dataset and each registry dataset was identified (according to the domains, domain items and measurement instruments of the TREAT core dataset)., Results and Conclusions: A total of 4702 participants have been recruited in the eight registries as of 1st of May 2022. Of the 69 core dataset domain items, data pooling was possible for 69 domain item outcomes in TREAT NL (the Netherlands), 61 items in A-STAR (UK and Ireland), 38 items in TREATgermany (Germany), 36 items in FIRST (France), 33 items in AtopyReg (Italy), 29 items in Biobadatop (Spain), 28 items in SCRATCH (Denmark) and 20 items in SwedAD (Sweden). Pooled analyses across all registries can be performed on multiple important domain items, covering the main aims of analysing data on the (cost-)effectiveness and safety of AE therapies. These results will facilitate future comparative or joint analyses., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

High-quality dermatology patient registries often require considerable time to develop and produce meaningful data. Development time is influenced by registry complexity and regulatory hurdles that vary significantly nationally and institutionally. The rapid emergence of the coronavirus disease 2019 (COVID-19) global pandemic has challenged health services in an unprecedented manner. Mobilization of the dermatology community in response has included rapid development and deployment of multiple, partially harmonized, international patient registries, reinventing established patient registry timelines. Partnership with patient organizations has demonstrated the critical nature of inclusive patient involvement. This global effort has demonstrated the value, capacity, and necessity for the dermatology community to adopt a more cohesive approach to patient registry development and data sharing that can lead to myriad benefits. These include improved utilization of limited resources, increased data interoperability, improved ability to rapidly collect meaningful data, and shortened response times to generate real-world evidence. We call on the global dermatology community to support the development of an international federation of patient registries to consolidate and operationalize the lessons learned during this pandemic. This will provide an enduring means of applying this knowledge to the maintenance and development of sustainable, coherent, and impactful patient registries of benefit now and in the future., Competing Interests: Conflict of interest C.F. is Chief Investigator of the UK-Irish Atopic eczema Systemic TherApy Register (A-STAR). C.F., A.I., and P.S. co-lead the SECURE-AD register, which studies the impact of COVID-19 infection episodes on atopic dermatitis. D.W. and R.S. co-lead and are members of the Steering Committee, along with L.B., N.M., D.J.T., and K.Y., of the SECURE-Alopecia registry, which studies the impact of COVID-19 infection on patients with all forms of hair loss. R.S., D.W., N.M., K.Y., and L.B. are leading the development of Global Registry of Alopecia areata disease Severity and treatment Safety (GRASS). C.F., P.S., and C.A. are members of the international TREatment of Atopic eczema Taskforce (TREAT) Executive Committee. C.E.M.G. is Chief Investigator of the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) and an Executive Member of the PsoProtect and Psoprotectme Registries. C.H.S. is Research Chair of BADBIR, and joint Principle Investigator (PI) of PsoProtect and PsoProtectMe Registries. S.K.M. is joint Principle Investigator of PsoProtect and PsoProtectMe Registries. I.L.C. is part of the Pediatric Dermatology Research Alliance COVID-19 Response Task Force, a collaboration between the Society for Pediatric Dermatology (SPD) and the Pediatric Dermatology Research Alliance (PeDRA). B.W.M.A. is a patient representative for the SECURE-AD patient register, and the Dutch TREAT NL and BioDAY registers. P.S. is member of the PsoProtect International Scientific Advisory Board. H.B.N is a board member of the Hidradenitis Suppurativa Foundation. R.A., J.R.I., and H.B.N. are members of the Steering Committee of the Global Hidradenitis Suppurativa COVID-19 Registry., (Copyright © 2021. Published by Elsevier Inc.)