Dupilumab is highly effective for moderate-to-severe atopic dermatitis (AD). Increasing reports of cutaneous T-cell lymphoma (CTCL) diagnosed during or after dupilumab therapy have raised concern, although a causal relationship remains unproven. Interpretation of the available evidence is limited by its retrospective, observational nature, diagnostic overlap between AD and early CTCL, and detection and surveillance bias. These clinical consensus recommendations, developed through expert consensus among European CTCL specialists, primarily address dupilumab receipt in patients initially diagnosed with AD in whom CTCL is suspected, while briefly considering selective IL-13 inhibitors for which evidence remains limited. Clinical, epidemiologic, and mechanistic evidence is synthesized to develop practice-oriented recommendations. Dupilumab remains an appropriate treatment for moderate-to-severe AD but should be avoided if mycosis fungoides or Sézary syndrome is suspected or confirmed. In atypical or treatment-refractory disease, particularly adult-onset AD without atopic history, clinicians should maintain a high index of suspicion for CTCL, with a low threshold for skin biopsy, clinicopathologic correlation, and T-cell clonality assessment. Lack of response, disease worsening, or emerging atypical features during therapy should prompt reassessment. These recommendations reflect expert consensus that is based on available evidence and highlight the need for prospective studies to better define risk profiles and guide patient selection.

In this multicentre observational retrospective study, bimekizumab demonstrated high effectiveness, together with a good safety profile, over a period of 78 weeks. The presence of psoriatic arthritis, obesity and longer disease duration seemed to influence response to treatment negatively in the mid term (24 weeks), while previous biologic exposure affected clinical outcomes in the long term (52 weeks).

BACKGROUND:In advanced-stage cutaneous T-cell lymphoma (CTCL), current therapeutic options rarely provide long-lasting responses. We aimed to evaluate the efficacy and safety of a histone deacetylase inhibitor, resminostat, as maintenance therapy in patients with advanced-stage mycosis fungoides or Sézary syndrome, in whom disease control had been previously met. METHODS:We conducted a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial (RESMAIN) at 55 medical centres in Austria, Belgium, France, Germany, Greece, Italy, the Netherlands, Poland, Spain, Switzerland, the UK, and Japan. Adult patients (aged ≥18 years) with histologically confirmed, stage IIB-IVB mycosis fungoides or Sézary syndrome; an Eastern Cooperative Oncology Group performance status score of 0-2; and disease control after at least one previous systemic therapy or total skin electron beam were eligible for inclusion. Patients were randomly assigned to receive either oral resminostat (600 mg) or matching oral placebo once daily for 5 days, followed by a treatment-free period of 9 days, within a 14-day treatment cycle. Randomisation was stratified by disease stage (IIB-IVA1 vs IVA2-IVB) and remission status following previous therapy (complete or partial response vs stable disease) by use of a dynamic block allocation process (block size 100 patients). Participants, investigators, site staff, and study personnel involved in outcome assessment and data analysis were masked to group assignment. Patients with disease progression during masked treatment were unmasked; patients on placebo were offered open-label resminostat. Treatment was continued until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, defined as the time from randomisation to disease progression or death from any cause (whichever occurred first), analysed by intention to treat. This trial is registered with ClincalTrials.gov (NCT02953301) and has been completed. FINDINGS:Between Jan 9, 2017, and May 11, 2022, 234 patients were screened for eligibility, of whom 201 (86%) patients were randomly assigned: 100 (50%) to resminostat and 101 (50%) to placebo. 123 (61%) participants were men and 78 (39%) were women, with a median age of 64 years (range 30-87). Most participants (173 [86%]) were White, 19 (9%) were Asian (mainly Japanese), two (1%) were Black, and seven (3%) were either another race or ethnicity, or did not disclose these data. Median progression-free survival was 8·3 months (95% CI 4·2-15·7) in the resminostat group and 4·2 months (2·8-6·4) in the placebo group (HR 0·62 [95% CI 0·42-0·92]; p=0·015). Median follow-up time for progression-free survival was 11·2 months (95% CI 5·6-19·6) in the resminostat group and 17·0 months (13·9-30·5) in the placebo group. Adverse events were reported in 96 (96%) patients receiving resminostat and in 81 (80%) patients receiving placebo. Serious adverse events occurred in 19 (19%) patients in the resminostat group, 11 (11%) of which were considered related to treatment, and in 12 (12%) in the placebo group, of which one (1%) was considered to be treatment-related. Adverse events of grade 3 or above occurred in 38 (38%) patients in the resminostat group and in 15 (15%) patients in the placebo group. The most common treatment-related adverse events were nausea (68 [68%] in the resminostat group vs six [6%] in the placebo group), diarrhoea (44 [44%] vs nine [9%]), vomiting (32 [32%] vs one [1%]), and fatigue (29 [29%] vs 14 [14%]). There were no treatment-related deaths. INTERPRETATION:These findings support the beneficial effect of resminostat maintenance therapy in patients with advanced CTCL. The overall safety profile of resminostat was acceptable, with gastrointestinal side-effects occurring most frequently. Anti-emetic prophylaxis should be considered in the future to manage side-effects and to improve tolerability and adherence to maintenance therapy. FUNDING:4SC AG.

Nevus counts in the divergent pathway model of melanoma development have been studied mainly in patients in Australia. Our aim was to compare nevus counts and the melanoma subtype for melanomas arising on chronically sun-exposed body versus non-chronically sun-exposed body locations in Southern European patients. This was a retrospective study of prospectively collected data from 2013 to 2023 at a melanoma referral center in Athens, Greece, in patients diagnosed with invasive melanoma of the superficial spreading melanoma (SSM) or nodular melanoma subtype. Multivariate multinomial logistic regression analysis was performed. In 1252 patients with SSM or nodular melanoma, the median age (interquartile range) was 57 (46, 67) years old and 51% were males. Regarding nevus counts, 57.9% of patients had 0-25 nevi (low), while the remaining 42.1% had greater than 25 nevi (high). In multivariate analysis, those with greater than 25 nevi (versus ≤25) were significantly less likely to have melanoma developing on the head/neck (chronically sun exposed body site) [odds ratio (OR): 0.60, 95% confidence interval (CI): 0.38-0.93] or on the lower extremity (OR: 0.63, 95% CI: 0.44--0.87), compared with having melanoma on the trunk (non-chronically sun exposed). Regarding the melanoma subtype, those with SSM versus nodular melanoma subtype were 53% less likely to have melanoma developing on the head/neck (OR: 0.47, 95% CI: 0.30-0.75), compared with the trunk. The melanoma subtype (SSM or nodular melanoma) did not significantly differ across upper extremity (OR: 0.94, 95% CI: 0.59-1.51) or lower extremity (OR: 1.03, 95% CI: 0.66-1.62) locations of melanoma development compared with the trunk. In conclusion, the association of higher nevus counts with melanomas developing on the trunk supports the divergent pathways of melanoma development in Southern European patients. Melanomas on the head/neck were significantly associated with lower numbers of nevi and were more likely to be nodular melanoma subtype.

Abstract The PROspective Cutaneous Lymphoma International Prognostic Index Study ‘PROCLIPI’ (ClinicalTrials.Gov ID: NCT02848274) opened in 2015 at > 50 international expert centres for mycosis fungoides (MF) and Sézary syndrome (SS). The aim of the study was to determine a prognostic index to better stratify patients for survival. A prognostic index for advanced MF and SS has recently been published that stratifies patients with advanced MF/SS into risk groups with significantly different 5-year overall survival. A CLIPI for early-stage MF is urgently needed to allow dermatologists to identify patients at risk of progression to advanced stage and subsequently select treatments for improved survival, as PROCLIPI shows that 5-year overall survival varies between 72.4% and 95.4% in early-stage MF and SS. Prospectively collected predefined datasets were analysed, including clinical, pathological, genotypic, treatment and quality-of-life data, in patients with newly diagnosed MF or SS. In total, 2004 patients with early-stage disease (IA, n = 921; IB, n = 853; IIA, n = 154) were recruited across 52 sites, presenting at a median age of 57 years (interquartile range 43–68). In multivariate analysis, the presence of cutaneous plaques (P < 0.001), nodal enlargement (Nx–N2) (P < 0.001), age > 60 years (P = 0.02) and large cell transformation in skin (P < 0.001) were significant factors for progression and overall survival. Notably, plaques have a high correlation with disease progression and poor overall survival (83.2% 5-year survival) compared with patients with patch-only disease (94.9% 5-year survival). Early-stage MF is typically reported as a low-grade lymphoma, but data from PROCLIPI have found low 5-year survival rates coupled with a median age of diagnosis of 57 years. Thus there is a marked reduction in life expectancy for some patients. However, 5-year survival rates for patients with patch-only disease are comparable with those of the average 57-year-old individual in Europe. In addition to plaques, PROCLIPI has identified other significant factors associated with poor survival, enabling the identification of at-risk patients using markers such as nodal enlargement and large cell transformation in the skin. The data highlight the need for better stratification of patients with early-stage MF and SS to allow improved management.

Mycosis fungoides, a cutaneous T-cell lymphoma, is characterized by clonal proliferation of aberrant CD4+ T cells and an evolving tumor microenvironment. Immunological heterogeneity across lesion stages and its role in disease severity remain poorly defined. We investigated lesion-specific aberrant T cells and immune cells in mycosis fungoides skin lesions using mass cytometry, cross-validated with public single-cell RNA-sequencing data, and assessed their associations with clinical outcome. Aberrant CD4+CD7-CD26-CCR4hi T cells expressing high levels of PD-1, PD-L1, and OX-40 were enriched in tumor lesions but absent in patches. Aberrant PD-L1+ T cells exhibited central memory/effector memory phenotype, whereas aberrant PD-1+ T cells demonstrated a terminal effector phenotype. Tumor microenvironment analysis revealed increased frequencies of PD-L1+IgD- memory B cells, PD-L1+ regulatory T cells, PD-L1+NCR- type 3 innate lymphoid cells, and PD-1+CD4+/CD8+ T cells in tumors. Patches lacked innate lymphoid cells, memory B cells and naïve/central memory CD8+ T cells. Large cell transformation was associated with elevated frequencies of naïve B cells, PD-1+ monocytes, and PD-1+CD8+ central memory/effector memory T cells. High frequencies of PD-L1+ memory B cells, PD-1+ dendritic cell, and PD-1+ naïve CD4+ T cells correlated with shorter progression-free survival, whereas normal levels of PD-1+ transitional monocytes were associated with longer overall survival. Lesion-specific aberrant T cells and tumor microenvironment remodeling may drive mycosis fungoides severity and contribute to future immunotherapy.

Psoriasis and psoriatic arthritis (PsA) are chronic inflammatory diseases, affecting patients' quality of life, particularly when involving difficult-to-treat areas. While randomized controlled trials have shown that ixekizumab is effective for psoriatic disease, real-world evidence is essential for assessing its broader applicability. This retrospective, single-centre study evaluated the effectiveness and safety of ixekizumab in 37 Greek patients with psoriasis and/or PsA, including involvement of difficult-to-treat areas, over 52 weeks of treatment. Ixekizumab led to significant and sustained improvements in skin disease up to week 52. Joint manifestations and difficult-to-treat sites showed marked improvement, as did patient-reported quality of life. Biologic-naïve patients and those with early-onset disease showed better responses. No serious adverse events were reported, and cardiovascular parameters remained stable. These findings support ixekizumab's strong efficacy and safety in routine clinical use, including in patients with prior biologic exposure and complex disease, reinforcing its role as a cornerstone therapy.

This manuscript provides expert recommendations on the role of allogeneic hematopoietic cell transplantation (allo-HCT) for cutaneous T-cell lymphoma (CTCL), specifically Mycosis Fungoides (MF) and Sezary Syndrome (SS). Critical aspects such as patient selection, timing, and bridging therapy are addressed, as well as donor source, conditioning regimens and post-transplant management. These consensus guidelines are based on a thorough literature review and discussions among leading dermatologists and hematologists. These recommendations aim to harmonise clinical practice towards improving patient outcomes in these rare but aggressive lymphomas. It is of critical importance to consider allo-HCT early in the management of eligible patients with high-risk disease. Advanced stage, large-cell transformation, relapsed or refractory disease following systemic treatment, and N3-stage lymph node involvement are indicators that should trigger consultation with a transplant hematologist in parallel with a donor search. Early interaction between dermatologists and transplant hematologists is vital to avoiding delays, which can significantly impact post-transplant outcomes and survival.

Hidradenitis suppurativa (HS) is associated with a cumulative life course impairment and patients commonly present with signs of depression and anxiety. This study aimed to investigate the association between systemic inflammation, measured by laboratory markers, and psychological burden, evaluated using specific psychometric scores, in patients with HS. The study also evaluated the impact of treatment initiation on inflammatory biomarkers and psychometric scores. A prospective, observational, monocentric study was conducted on adult patients with HS of Hurley stage I, II and III, who were eligible for treatment initiation. Disease severity was assessed using the Hurley stage, and disease activity through the IHS4 scoring system. Laboratory evaluation of systemic inflammation included measurement of White Blood Cell count, Erythrocyte Sedimentation Rate (ESR) and C-reactive protein levels, at the study onset, right before treatment initiation, at 12 weeks and at 24 weeks following treatment onset. The impact of the disease on psychological status and overall quality of life was evaluated through psychometric scores. Our results indicate that systemic inflammation, reflected by laboratory inflammatory markers such as ESR, is associated with a higher probability of depression, loneliness and reduced quality of life independently of Hurley stage, severity score, and clinical characteristics such as gender and smoking status. Psychometric evaluation, including the presence of depression and loneliness in HS patients, independent of Hurley stage is advisable, especially in cases where serum inflammatory markers, such as ESR, are high.

In recent classifications several cutaneous lymphomas were reclassified as lymphoproliferative disorder (LPDs). These include primary cutaneous CD4+ small/medium T-cell LPD (PCSM-TCLPD), primary cutaneous acral CD8+ T-cell LPD (acral CD8+ TCLPD) and primary cutaneous marginal zone lymphoma/LPD (PCMZL/LPD). The latter is still classified as primary cutaneous marginal zone lymphoma (PCMZL) in the 5th edition of the World Health Organization classification. A survey was previously carried out among 30 cutaneous lymphoma centres on the effects of this new terminology on clinical management. The results revealed considerable heterogeneity and emphasized the need to develop uniform recommendations for management and treatment of these disorders. Our objective was to develop consensus recommendations for staging, treatment and follow-up in PCSM-TCLPD, acral CD8+ TCLPD and PCMZL/LPD. Two surveys with questions regarding staging, treatment and follow-up of cutaneous LPDs were distributed among 30 cutaneous lymphoma expert centres collaborating within the EORTC-CLTG, USCLC and ISCL. Consensus recommendations were formulated based on these surveys, an extensive literature search, two rounds of feedback and a final consensus meeting. Important changes compared with current practice and literature are as follows. (i) Staging examinations, other than thorough clinical examination of skin and peripheral lymph nodes, are not required in typical cases of PCSM-TCLPD and acral CD8+ TCLPD. (ii) Low-dose radiotherapy (4-8 Gy) can be used rather than dose ≥ 20 Gy for PCSM-TCLPD and acral CD8+ TCLPD, and 4 Gy can be used for PCMZL/LPD. The dose can be escalated to 20-24 Gy in the case of local failure. (iii) Intralesional corticosteroids are also recommended as initial treatment in all three LPDs. (iv) A limited follow-up period (2 years) is acceptable in PCSM-TCLPD and acral CD8+ TCLPD LPD. These EORTC/USCLC/ISCL consensus recommendations reflect the state-of-the-art management and treatment as agreed upon by major cutaneous lymphoma centres. They may contribute to uniform staging, treatment and follow-up policy in patients with cutaneous LPDs.

IntroductionIn Cutaneous T-cell Lymphoma (CTCL), T cells can be activated either by cytokines produced by malignant T cells or through immunological synapses, such as the interaction between OX-40 and OX-40L on dendritic cells. Both are co-expressed in tumor cells in Mycosis fungoides/Sézary syndrome and correlate with disease severity markers. Using a model of spontaneous metastasis in chick embryos, the present study aimed to determine the functional role of OX-40 in CTCL and assess its potential as a therapeutic target.MethodsOX-40 knockout MyLa and SeAx CTCL cells using CRISPR-Cas9 were engrafted onto the chorioallantoic membrane of chick embryos. We assessed tumor growth, dissemination, and TME modulation in the presence or absence of macrophages. Transwell-based transendothelial migration assays and co-culture experiments were performed to further explore the interactions between CTCL cells and macrophages. Angiogenesis and lymphangiogenesis have also been investigated.ResultsOX-40 expression promoted intravasation, metastasis, and cytokine secretion, and increased M2 macrophages. Additionally, it restores transendothelial migration and dissemination in the presence of M2 macrophages, possibly through ERK activation. Co-culture experiments revealed that OX-40 promoted a Th2 cytokine profile in CTCL, correlating with M2 macrophages in xenografts. Although OX-40 did not affect angiogenesis in this model, it promoted lymphangiogenesis via VEGF-C expression.DiscussionUsing the CTCL spontaneous metastasis model in chick embryos, we demonstrated that OX-40 regulates the TME to promote M2 increase, lymphangiogenesis, CAM intravasation, and metastasis. Therefore, the in vivo chick embryo metastasis model may serve as a valuable preclinical tool for identifying novel anti-tumor targets in CTCL. The OX-40 axis was identified as a key driver of CTCL progression, promoting tumor growth and metastasis through ERK activation while validating the chick embryo model as a preclinical tool for therapeutic testing.

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL). The diagnosis of early-stage MF can be very challenging due to shared clinical and histopathological features with benign inflammatory dermatoses. Moreover, a lack of understanding of the aetiopathology is having a negative impact on efficient diagnosis and therapy. State-of-the-art bioinformatics tools were used to identify differentially expressed miRNAs that are potentially involved in the molecular pathogenesis of MF, with further investigation of their potential role as diagnostic biomarkers or therapeutic targets. The expression of miRNAs (miR-26a, miR-92a, miR-106b, miR-142, miR-146a, miR-155, miR-181a, miR-222, and miR-494) was evaluated in the serum of early-stage MF patients using RT-PCR as well as skin biopsies and CTCL cell lines (MyLa and SeAx). Our data showed that these miRNAs were significantly upregulated in plasma and biopsies of early-stage MF patients and CTCL cell lines compared to controls (p<0.05). Downregulation of miR-142, miR-146a, and miR-155 in CTCL cell lines using specific antagomirs significantly decreased cell proliferation and increased apoptosis of malignant cells. Overall, detailed bioinformatics analysis, followed by experimental validation in CTCL plasma, tissues, and cell lines, indicated that detection of miR-142, miR-146a, and miR-155 upregulation by liquid biopsy may represent a potential non-invasive diagnostic technique as well as a new therapeutic targeting approach for early-stage MF.