Paediatric onset lymphomatoid papulosis: results of a multicentre retrospective cohort study, on behalf of the EORTC Cutaneous Lymphoma Tumours Group (CLTG).

BACKGROUND: Lymphomatoid Papulosis (LyP) is a rare cutaneous T-cell lymphoproliferative disorder. Comprehensive data on LyP in the paediatric population is scarce. OBJECTIVES: To characterize epidemiological, clinical, histopathological, and prognostic features of paediatric LyP. METHODS: This was a retrospective, multicentre international cohort study including 87 cases of children and adolescents with LyP diagnosed between 1998 and 2022. Patients aged ≤ 18 years old at disease onset were included. Diagnosis was made in each centre based on clinical-pathological correlation. RESULTS: Eighty-seven patients from 12 centres were included. The mean age at onset was 7.0 years (range 3 months-18 years) with a male to female ratio of 2:1. The mean time between onset of first cutaneous lesions and diagnosis was 1.3 years (range 0-14 years). Initial misdiagnosis concerned 26.4% of patients. Initially, LyP was most often misdiagnosed as Pityriasis lichenoides et varioliformis acuta (PLEVA), insect bites, or mollusca contagiosa. Erythematous papules or papulonodules were the most frequent clinical presentation. Pruritus was specifically mentioned for 20.7% of patients. The main histological subtype was type A in 55.1% of the cases. If analysed, monoclonal TCR rearrangement was found in 76.5% of the skin biopsies. The overall survival rate was 100% with follow up at 5 years available for 33 patients and at 15 years for 8 patients. A development of associated haematological malignancy (HM) occurred in 9.6% of the cases (7/73), including four mycosis fungoides (MF) cases, one primary cutaneous anaplastic large cell lymphoma (pc-ALCL), one systemic ALCL and one case of acute myeloid leukaemia. If we compare incidence rates of cancer with the world 0-19 years old population from 2001-2010, we estimate a significantly higher risk of associated malignancy in general, occurring before the age of 19 years old with incidence rate ratio of 87.49 (CI 86.01-88.99). CONCLUSIONS: We report epidemiological data from a large international cohort of children and adolescents with LyP. Overall the prognosis of the disease is good, with excellent survival rates for all patients. Due to increased risk of associated HM, a long-term follow-up should be recommended for LyP patients.

Real-world study on the use of pegylated interferon alpha-2a for treatment of mycosis fungoides/Sézary syndrome using Time to Next Treatment as a measure of clinical benefit: An EORTC CLTG study.

INTRODUCTION: Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon alpha (IFN-α, subtypes 2a and 2b) has been used for MF/SS since 1984, however its production was recently stopped and so the recombinant pegylated (PEG) form of IFN α-2a remains as single IFN alternative treatment, even though not approved for MF/SS. OBJECTIVE: To assess effectiveness and safety of PEG IFN α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in real world setting. METHODS: We conducted an international and multicenter retrospective study of patients with MF and SS at any stage, treated with PEG IFN α-2a, from July 2012 to February 2022. Patients were included across 11 centers in 10 countries. Primary endpoints were to determine TTNT of PEG IFN α-2a and the adverse events (AE) in MF/SS. RESULTS: In total 105 patients were included, mean age was 61 (22-86 years); 42 (40%) with disease stage IA-IIA, 63 (60%) with stage IIB-IVB. PEG IFN α-2a was combined with other therapies in 67 (64%) patients, usually with extracorporeal photopheresis (36%) and bexarotene (22%). Fifty-seven percent of stage I-IIA patients achieved ORR, whereas 51% of stage IIB-IVB. Combination therapy showed a TTNT of 10.4 months, while 7 months in monotherapy (p=0.0099). Overall, TTNT was 9.2 months, ORR was 53% (56/105), CR and PR were 13% and 40%, respectively.AE were described in 69% (72) of the patients. Flu-like symptoms (27%), lymphopenia (23%) and elevated liver function (10%) were the most frequently reported. Grade 3-4 adverse events were reported in 23 (21%) patients, which were mostly related to myelosuppression. LIMITATIONS: retrospective data analysis and unrestricted number of combination therapies. CONCLUSIONS: PEG IFN α-2a for MF/SS showed ORR of 53%, TTNT of 9.2 months, superiority of combination regimens in comparison to monotherapy and doses of 180 mcg/weekly related to higher ORR.

Dupilumab-associated head and neck dermatitis shows a pronounced type 22 immune signature mediated by oligoclonally expanded T cells.

Dupilumab, an IL4R-blocking antibody, has shown clinical efficacy for atopic dermatitis (AD) treatment. In addition to conjunctivitis/blepharitis, the de novo appearance of head/neck dermatitis is now recognized as a distinct side effect, occurring in up to 10% of patients. Histopathological features distinct from AD suggest a drug effect, but exact underlying mechanisms remain unknown. We profiled punch biopsies from dupilumab-associated head and neck dermatitis (DAHND) by using single-cell RNA sequencing and compared data with untreated AD and healthy control skin. We show that dupilumab treatment was accompanied by normalization of IL-4/IL-13 downstream activity markers such as CCL13, CCL17, CCL18 and CCL26. By contrast, we found strong increases in type 22-associated markers (IL22, AHR) especially in oligoclonally expanded T cells, accompanied by enhanced keratinocyte activation and IL-22 receptor upregulation. Taken together, we demonstrate that dupilumab effectively dampens conventional type 2 inflammation in DAHND lesions, with concomitant hyperactivation of IL22-associated responses.

Evaluation of mortality, prognostic parameters, and treatment efficacy in mycosis fungoides.

BACKGROUND AND OBJECTIVES: Mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, is characterized by a variable clinical course, presenting either as indolent disease or showing fatal progression due to extracutaneous involvement. Importantly, the lack of prognostic models and predominantly palliative therapy settings hamper patient care. Here, we aimed to define survival rates, disease prediction accuracy, and treatment impact in MF. PATIENTS AND METHODS: Hundred-forty MF patients were assessed retrospectively. Prognosis and disease progression/survival were analyzed using univariate Cox proportional hazards regression model and Kaplan-Meier estimates. RESULTS: Skin tumors were linked to shorter progression-free, overall survival and a 3.48 increased risk for disease progression when compared to erythroderma. The Cutaneous Lymphoma International Prognostic Index identified patients at risk in early-stage disease only. Moreover, expression of Ki-67 >20%, CD30 >10%, CD20+, and CD7- were associated with a significantly worse outcome independent of disease stage. Only single-agent interferon-α and phototherapy combined with interferon-α or retinoids/bexarotene achieved long-term disease control in MF. CONCLUSIONS: Our data support predictive validity of prognostic factors and models in MF and identified further potential parameters associated with poor survival. Prospective studies on prognostic indices across disease stages and treatment modalities are needed to predict and improve survival.

Regulation of the Immune Cell Repertoire in Psoriasis Patients Upon Blockade of IL-17A or TNFα.

INTRODUCTION: Targeting of the proinflammatory cytokine interleukin 17A (IL-17A) or tumor necrosis factor alpha (TNFα) with the monoclonal antibodies (mAbs) ixekizumab or adalimumab, respectively, is a successful therapy for chronic plaque psoriasis. The effects of these treatments on immune cell populations in the skin are largely unknown. METHODS: In this study, we compared the composition of cutaneous, lesional and non-lesional immune cells and blood immune cells in ixekizumab- or adalimumab-treated patients with psoriasis. RESULTS: Our data reveal that both treatments efficiently downregulate T cells, macrophages and different subsets of dendritic cells (DCs) in lesional skin towards levels of healthy skin. In contrast to lesional skin, non-lesional areas in patients harbor only few or no detectable DCs compared to the skin of healthy subjects. Treatment with neither ixekizumab nor adalimumab reversed this DC imbalance in non-lesional skin of psoriatic patients. CONCLUSION: Our study shows that anti-IL-17A and anti-TNFα therapy rebalances the immune cell repertoire of lesional skin in psoriatic patients but fails to restore the disturbed immune cell repertoire in non-lesional skin.

Evolution of characteristics and biologic treatment effectiveness in patients of the Austrian psoriasis registry from 2004-2022.

BACKGROUND AND OBJECTIVES: This study analyzed the extent to which the recent introduction of more effective treatments has led to an improvement in real-world psoriasis patients. PATIENTS AND METHODS: Patient characteristics and the first-year treatment effectiveness in biologic-naive patients have been analyzed since 2004 until now, irrespective of treatment switches. RESULTS: Data from 2,729 patients were eligible for this analysis. The proportion of female patients increased significantly over the years from 29.9% to 36.2% (p < 0.028), while the number of patients with psoriatic arthritis declined from 36.6% to 30.0% (p < 0.001). Moreover, the duration of psoriatic disease and PASI at the start of the treatment significantly decreased. Last observation carrief forward (LOCF) analysis indicated that PASI 90 response increased from 18.9 to 44.6% at 3 months and from 32.9 to 66.8% at 12 months after treatment started. Similary, the PASI ≤ 3 rates increased from 33.2% to 66.0% at 3 months and from 41.9% to 78.9% at 12 months after the treatment started. CONCLUSIONS: The continuous introduction of more efficient biologics has led to significant improvements in patient care and clinical outcomes. Though one out of three to five patients, depending on the endpoint selected, nowadays still does not achieve an entirely satisfactory treatment response (i.e., PASI 90 or PASI ≤ 3).

EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2023.

On behalf of the EORTC Cutaneous Lymphoma Tumours Group (EORTC-CLTG) and following up on earlier versions published in 2006 and 2017 this document provides an updated standard for the treatment of mycosis fungoides and Sézary syndrome (MF/SS). It considers recent relevant publications and treatment options introduced into clinical practice after 2017. Consensus was established among the authors through a series of consecutive consultations in writing and a round of discussion. Treatment options are assigned to each disease stage and, whenever possible and clinically useful, separated into first- and second line options annotated with levels of evidence. Major changes to the previous version include the incorporation of chlormethine, brentuximab vedotin, and mogamulizumab, recommendations on the use of pegylated interferon α (after withdrawal of recombinant unpegylated interferons), and the addition of paragraphs on supportive therapy and on the care of older patients. Still, skin-directed therapies are the most appropriate option for early-stage MF and most patients have a normal life expectancy but may suffer morbidity and impaired quality of life. In advanced disease treatment options have expanded recently. Most patients receive multiple consecutive therapies with treatments often having a relatively short duration of response. For those patients prognosis is still poor and only for a highly selected subset long term remission can be achieved with allogeneic stem cell transplantation. Understanding of the disease, its epidemiology and clinical course, and its most appropriate management are gradually advancing, and there is well-founded hope that this will lead to further improvements in the care of patients with MF/SS.

No impact of disease duration on response to tildrakizumab treatment among patients with moderate-to-severe plaque psoriasis: Post hoc analyses from two phase 3 (reSURFACE 1 and reSURFACE 2) and one phase 4 (TRIBUTE) studies.

In the literature there is no consensus on the correlation between early systemic intervention and better treatment response in psoriasis. Here we present data on the impact of disease duration (<5 years, 5-<10 years, and ≥10 years) on response to tildrakizumab treatment among patients with moderate-to-severe plaque psoriasis from the reSURFACE 1 and reSURFACE 2 phase 3 trials and the TRIBUTE phase 4 study. Overall, there was no significant effect of disease duration on the Psoriasis Area and Severity Index ≤1, ≤3, and ≤5, or the Dermatology Life Quality Index 0-1 response rates. Tildrakizumab was highly effective regardless of the psoriasis disease duration.

Single-cell RNA sequencing defines disease-specific differences between chronic nodular prurigo and atopic dermatitis.

BACKGROUND: Chronic nodular prurigo (CNPG) is an inflammatory skin disease that is maintained by a chronic itch-scratch cycle likely rooted in neuroimmunological dysregulation. This condition may be associated with atopy in some patients, and there are now promising therapeutic results from blocking type 2 cytokines such as IL-4, IL-13, and IL-31. OBJECTIVES: This study aimed to improve the understanding of pathomechanisms underlying CNPG as well as molecular relationships between CNPG and atopic dermatitis (AD). METHODS: We profiled skin lesions from patients with CNPG in comparison with AD and healthy control individuals using single-cell RNA sequencing combined with T-cell receptor sequencing. RESULTS: We found type 2 immune skewing in both CNPG and AD, as evidenced by CD4+ helper T cells expressing IL13. However, only AD harbored an additional, oligoclonally expanded CD8A+IL9R+IL13+ cytotoxic T-cell population, and immune activation pathways were highly upregulated in AD, but less so in CNPG. Conversely, CNPG showed signatures of extracellular matrix organization, collagen synthesis, and fibrosis, including a unique population of CXCL14-IL24+ secretory papillary fibroblasts. Besides known itch mediators such as IL31 and oncostatin M, we also detected increased levels of neuromedin B in fibroblasts of CNPG lesions compared with AD and HC, with neuromedin B receptors detectable on some nerve endings. CONCLUSIONS: These data show that CNPG does not harbor the strong disease-specific immune activation pathways that are typically found in AD but is rather characterized by upregulated stromal remodeling mechanisms that might have a direct impact on itch fibers.

Single-cell RNA sequencing analysis of a COVID-19-associated maculopapular rash in a patient with psoriasis treated with ustekinumab.

Coronavirus disease 2019 (COVID-19) primarily affects the respiratory system but extrapulmonary manifestations, including the skin, have been well documented. However, transcriptomic profiles of skin lesions have not been performed thus far. Here, we present a single-cell RNA sequencing analysis in a patient with COVID-19 infection with a maculopapular skin rash while on treatment with the interleukin (IL)-12/IL-23 blocker ustekinumab for his underlying psoriasis. Results were compared with healthy controls and untreated psoriasis lesions. We found the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral entry receptors ACE2 and TMPRSS2 in keratinocytes of the patient with COVID-19, while ACE2 expression was low to undetectable in psoriasis lesions and healthy skin. Among all cell types, ACE2+ keratinocyte clusters showed the highest levels of transcriptomic dysregulation in COVID-19, expressing type 1-associated immune markers such as CXCL9 and CXCL10. In line with a generally type 1-skewed immune microenvironment, cytotoxic lymphocytes showed increased expression of the IFNG gene and other T-cell effector genes, while type 2, type 17, or type 22 T-cell activation was largely absent. Conversely, downregulation of several anti-inflammatory mediators was observed. This first transcriptomic description of a COVID-19-associated rash identifies ACE2+ keratinocytes displaying profound transcriptional changes, and inflammatory immune cells that might help to improve the understanding of SARS-CoV-2-associated skin conditions.

Characteristics and outcomes of patients with psoriasis treated with apremilast in the real-world in Austria - results the APPRECIATE study.

Background: Apremilast, an oral phosphodiesterase 4 inhibitor, is approved in the European Union for the treatment of moderate-to-severe chronic plaque psoriasis in adult patients refractory or contraindicated to or intolerant of other systemic therapies. Objectives: The APPRECIATE study assessed apremilast use in real-world practice and its clinical value to physicians and patients. APPRECIATE was a multinational, observational, retrospective, cross-sectional study. Methods: Apremilast effectiveness at 6 (±1) months was assessed on the basis of psoriasis severity and health-related quality-of-life scores and treatment satisfaction using physician/patient-reported outcomes, respectively. We report the Austrian cohort of 72 patients. Results: At 6 (±1) months, three-quarters of patients remained on apremilast, while physicians and patients reported treatment benefits across all psoriasis symptoms and manifestations. Of patients, the majority were satisfied with their treatment and achieved treatment goals considered most relevant. Patients' and physicians' perceptions of treatment effectiveness were aligned, and health-related quality-of-life scores indicated an improvement in the majority of patients. Apremilast tolerability was consistent with the known safety profile. Conclusions: Among psoriasis patients receiving apremilast in Austria, improvement in clinical outcomes were observed and satisfaction with apremilast treatment among patients and physicians was high. Registration: ClinicalTrials.gov NCT02740218.

Chlormethin-Gel zur Behandlung der Mycosis fungoides: Ein Expertenkonsens aus Deutschland, Österreich und der Schweiz (DACH-Region) zum Therapiemanagement.

HINTERGRUND: Chlormethin-Gel ist in Europa zur Therapie von Patienten mit Mycosis fungoides in allen Krankheitsstadien zugelassen. Die optimalen Behandlungsregime hinsichtlich Frequenz, Dosierung, Kombinations- oder Erhaltungstherapien sind noch nicht vollständig etabliert. METHODIK: Zehn in der Erforschung und Behandlung kutaner T-Zell-Lymphome erfahrene Experten aus Deutschland, Österreich und der Schweiz (DACH-Region) wurden schriftlich zu Indikation, Anwendungsfrequenz, Beurteilung des Therapieerfolgs, Begleittherapie, Nebenwirkungen, Kombinationstherapien in späteren Krankheitsstadien, Erhaltungstherapie und Adhärenz im Rahmen der Therapie der Mycosis fungoides mit Chlormethin-Gel befragt. Die strukturiert aufbereiteten Ergebnisse der Umfrage wurden in einer Konsensuskonferenz diskutiert und Empfehlungen zum Management der Therapie mit Chlormethin-Gel entwickelt. ERGEBNISSE: Wesentlich für die Therapie mit Chlormethin-Gel ist ein individuelles, symptomorientiertes Therapiemanagement. Systemische Nebenwirkungen des Wirkstoffs sind wegen der fehlenden systemischen Verfügbarkeit bei topischer Anwendung unwahrscheinlich. Die häufig auftretende allergische oder irritativ-toxische Kontaktdermatitis kann durch eine Anpassung des Therapieregimes, Therapiepausen sowie nebenwirkungsspezifische und unterstützende Maßnahmen häufig beherrscht werden. Ein einschleichender Therapiebeginn mit Anwendung von Chlormethin-Gel jeden zweiten Tag kann die Tolerabilität wesentlich verbessern, insbesondere wenn die Therapie alternierend mit topischen Kortikosteroiden erfolgt. SCHLUSSFOLGERUNGEN: Die Anwendung von Chlormethin-Gel bei Mycosis fungoides wird durch die begleitende Kontaktdermatitis häufig eingeschränkt. Mit einem geeigneten Therapie- und Nebenwirkungsmanagement können vermeidbare Therapieabbrüche verhindert werden und mehr Patienten von der Therapie profitieren.

The optimal use of chlormethine gel for mycosis fungoides: An expert consensus from Germany, Austria and Switzerland (DACH region).

BACKGROUND: In Europe chlormethine gel is licensed for the management of patients with mycosis fungoides of all stages. However, the optimal regimen regarding frequency and dosing as well as combination and maintenance therapy is not well established. METHODS: Ten experts experienced in research and management of cutaneous T-cell lymphomas from Germany, Austria, and Switzerland (DACH region) were asked in written form to report on indication for chlormethine gel, frequency of use, monitoring, concomitant therapies, adverse effects, combination therapies in later stages of the disease, maintenance therapy, and adherence to this therapy for mycosis fungoides. The structured answers were discussed in a consensus conference and recommendations were developed. RESULTS: Essential for therapy with chlormethine gel is an individualized and symptom-oriented management. Because of the lack of systemic resorption of topically administered chlormethine gel, systemic adverse events are unlikely. An allergic or irritative-toxic contact dermatitis is common but manageable with adaptation of the regimen, interruption of administration, and symptom-specific supportive measurements. A step-up initial approach with application of chlormethine gel every other day is associated with a better tolerability, especially if it is alternated with topical corticosteroids. CONCLUSIONS: The use of chlormethine gel in the management of mycosis fungoides is often limited by a concomitant contact dermatitis. An adequate therapeutic regimen and the management of adverse effects can preclude an unnecessary withdrawal of therapy so that more patients can benefit from this treatment option.

Single-cell RNA sequencing reveals markers of disease progression in primary cutaneous T-cell lymphoma.

BACKGROUND: In early-stage mycosis fungoides (MF), the most common primary cutaneous T-cell lymphoma, limited skin involvement with patches and plaques is associated with a favorable prognosis. Nevertheless, approximately 20-30% of cases progress to tumors or erythroderma, resulting in poor outcome. At present, factors contributing to this switch from indolent to aggressive disease are only insufficiently understood. METHODS: In patients with advanced-stage MF, we compared patches with longstanding history to newly developed plaques and tumors by using single-cell RNA sequencing, and compared results with early-stage MF as well as nonlesional MF and healthy control skin. RESULTS: Despite considerable inter-individual variability, lesion progression was uniformly associated with downregulation of the tissue residency markers CXCR4 and CD69, the heat shock protein HSPA1A, the tumor suppressors and immunoregulatory mediators ZFP36 and TXNIP, and the interleukin 7 receptor (IL7R) within the malignant clone, but not in benign T cells. This phenomenon was not only found in conventional TCR-αß MF, but also in a case of TCR-γδ MF, suggesting a common mechanism across MF subtypes. Conversely, malignant cells in clinically unaffected skin from MF patients showed upregulation of these markers. CONCLUSIONS: Our data reveal a specific panel of biomarkers that might be used for monitoring MF disease progression. Altered expression of these genes may underlie the switch in clinical phenotype observed in advanced-stage MF.

Mycosis fungoides and Sézary syndrome.

Mycosis fungoides (MF) and Sézary syndrome (SS) are primary cutaneous T-cell lymphomas (CTCL) with not yet fully understood etiology and pathogenesis. Conceptually, MF and SS are classified as distinct entities arising from different T helper cell subsets. MF is the most common CTCL entity, while SS is very rare. MF presents clinically with patch, plaque and/or tumor stages, but can also evolve as erythroderma, which in turn is pathognomonic for SS. SS is characterized by a detectable tumor-cell burden (Sézary cells) in the peripheral blood consistent with advanced-stage disease and a poor prognosis. In early-stage disease of MF, which is the predominant form, the prognosis is generally favorable. However, in up to 30 % of patients, there is progression of skin lesions, which can ultimately lead to visceral involvement. The histological manifestation of MF can be subtle in early-stage disease and therefore a careful clinicopathological correlation is paramount. The treatment of MF/SS is dependent on the disease stage. Therapeutic options include both skin-directed and systemic regimens. Apart from allogeneic stem cell transplantation (alloSCT), there is as yet no curative therapy for MF/SS. Accordingly, the treatment approach is symptom oriented and aims to reduce the tumor burden and improve health-related quality of life. However, the therapeutic landscape for CTCL is constantly being expanded by the discovery of novel therapeutic targets.