Biologics and small molecules treatment for moderate-to-severe atopic dermatitis patients with comorbid conditions and special populations: an Italian perspective.

This comprehensive review offers a detailed look at atopic dermatitis (AD) treatment in Italy, focusing primarily on the use of biologics and small molecules. In response to advancing knowledge of AD's causes and treatments, there's a global need for updated guidelines to provide physicians with a more comprehensive clinical perspective, facilitating personalized treatment strategies. Dupilumab, a groundbreaking biologic, gained approval as a significant milestone. Clinical trials demonstrated its ability to significantly reduce AD severity scores, with an impressive 37% of patients achieving clear or nearly clear skin within just 16 weeks of treatment. Real-world studies further support its efficacy across various age groups, including the elderly, with a safety profile akin to that of younger adults. Tralokinumab, a more recent approval, shows promise in clinical trials, particularly among younger populations. However, its real-world application, especially in older individuals, lacks comprehensive data. Janus Kinases inhibitors like Upadacitinib, Baricitinib, and Abrocitinib hold substantial potential for AD treatment. Nevertheless, data remains limited for patients over 75, with older adults perceived to carry a higher risk profile. Integrated safety analyses revealed individuals aged 60 and above experiencing major adverse cardiovascular events and malignancies, underscoring the need for cautious consideration. While these therapies offer promise, especially among younger patients, further research is essential to determine their safety and efficacy in various populations, including pediatric, geriatric, and those with comorbidities. Biologics and small molecules are improving AD treatment, as shown in this review.

A Narrative Review of the State of the Art of CCR4-Based Therapies in Cutaneous T-Cell Lymphomas: Focus on Mogamulizumab and Future Treatments.

The CCR4 receptor is a pivotal target in cutaneous T-cell lymphoma (CTCL) therapy due to its role in impairing immune responses against malignant T-cells and expression profiles. Monoclonal antibodies like mogamulizumab effectively bind to CCR4, reducing tumour burden and enhancing patient outcomes by inhibiting the receptor's interaction with ligands, thereby hindering malignant T-cell migration and survival. Combining CCR4 antibodies with chemotherapy, radiation, and other drugs is being explored for synergistic effects. Additionally, small-molecular inhibitors, old pharmacological agents interacting with CCR4, and CAR-T therapies are under investigation. Challenges include drug resistance, off-target effects, and patient selection, addressed through ongoing trials refining protocols and identifying biomarkers. Despite advancements, real-life data for most of the emerging treatments are needed to temper expectations. In conclusion, CCR4-targeted therapies show promise for CTCL management, but challenges persist. Continued research aims to optimise treatments, enhance outcomes, and transform CTCL management. This review aims to elucidate the biological rationale and the several agents under various stages of development and clinical evaluation with the actual known data.

Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorders (SMPLPD), demographical, clinical, therapeutic and prognostic aspects: a retrospective monocentric analysis.

Primary Cutaneous CD4+ Small/Medium T-Cell Lymphoproliferative Disorders (SMPLPD), also known as PCS-TCLPD, represent a rare group of hematologic diseases primarily affecting the skin. In this retrospective single-centre case series study, we aimed to investigate the demographic, clinical, therapeutic, and prognostic aspects of SMPLPD. We collected data from cases diagnosed between 2010 and the present, employing histopathological and immunohistochemical methods following WHO criteria. We included 22 patients with a median age of 61.50 years and median time between clinical onset and diagnosis of 3.00 months. Surgical excision with conservative margins was the primary choice, showing clinical remission in 17 cases, while non-surgical treatments, including radiotherapy, high-potency steroid treatment and ablative laser, achieved clinical remission in four cases. Clinical presentations varied, but the most common one was a single violaceous nodule/papule on upper body parts. In conclusion, our single-centre case series provides valuable insights into SMPLPD, highlighting the effectiveness of surgical treatments and the potential of non-surgical ones. Even if controversial, the benign nature of SMPLPD emphasizes the importance of achieving tumour clearance with acceptable aesthetic outcomes.

The Role of Cytokines in Cutaneous T Cell Lymphoma: A Focus on the State of the Art and Possible Therapeutic Targets.

Cutaneous T cell lymphomas (CTCLs), encompassing mycosis fungoides (MF) and Sézary syndrome (SS), present a complex landscape influenced by cytokines and cellular responses. In this work, the intricate relationship between these inflammatory proteins and disease pathogenesis is examined, focusing on what is known at the clinical and therapeutic levels regarding the most well-known inflammatory mediators. An in-depth look is given to their possible alterations caused by novel immunomodulatory drugs and how they may alter disease progression. From this narrative review of the actual scientific landscape, Interferon-gamma (IFN-γ) emerges as a central player, demonstrating a dual role in both promoting and inhibiting cancer immunity, but the work navigates through all the major interleukins known in inflammatory environments. Immunotherapeutic perspectives are elucidated, highlighting the crucial role of the cutaneous microenvironment in shaping dysfunctional cell trafficking, antitumor immunity, and angiogenesis in MF, showcasing advancements in understanding and targeting the immune phenotype in CTCL. In summary, this manuscript aims to comprehensively explore the multifaceted aspects of CTCL, from the immunopathogenesis and cytokine dynamics centred around TNF-α and IFN-γ to evolving therapeutic modalities. Including all the major known and studied cytokines in this analysis broadens our understanding of the intricate interplay influencing CTCL, paving the way for improved management of this complex lymphoma.

New insights into the oncological risk in heart transplant recipients: could skin tumors represent a marker of increased risk for solid neoplasm?

BACKGROUND: Solid organ transplant recipients are at increased risk for skin cancers due to immune-suppressive therapies. However, little is known about the risk and the characteristics of neoplasms in heart transplant recipients (HTRs). The aim of this study is to delineate the incidence of different skin tumors in HTRs and to correlate it with the incidence of other malignancies, including solid tumors and hematological neoplasms. METHODS: Patients who underwent to HTRs between January 1991 and November 2021 were retrieved. Clinical data on immunosuppressive therapies, skin tumors, solid and hematological neoplasms were obtained. HTRs with skin tumors were included in group A, while patients with no evidence of skin tumors during the follow-up were included in group B. RESULTS: One hundred and eight patients were retrieved. A significant increase in solid tumors was observed in group A, while no significant difference in hematological neoplasms was detected between the two groups. CONCLUSIONS: HTRs with skin tumors showed a significantly higher incidence of solid neoplasms. In most of the cases the skin tumor preceded the onset of the solid neoplasm, suggesting that the skin tumor could represent a 'marker' of immunosuppression eventually leading to the development of an internal malignancy.

PD-1 and PD-L1 expression in mycosis fungoides and Sézary Syndrome.

BACKGROUND: The mechanisms involved in mycosis fungoides, and Sezary Syndrome progression are largely unknown. Over the last decade the interest in immune system contrast of neoplasm has grown owing to the introduction of immunotherapy. PD-1 and its ligand (PD-L1) are the target of several immunotherapy treatment. In the literature reports on the expression of PD-1 and PD-L1 have provided contrasting results. METHODS: In our analysis we investigated PD-1 expression in neoplastic cells and in tumor infiltrating lymphocytes (TILs) as well as PD-L1 expression in tumor cells and in tumor associated macrophages (TAMs). PD-L1 and PD-1 positive cells were counted in 5 high-power fields (HPF) and scored as the average number of positive neoplastic cells/TILs/TAMs per HPF. RESULTS: From databases of two institutions (Bologna and Florence) thirty-five patients corresponding to 43 biopsies were retrieved. In seven instances sequential biopsies were present. No statistically significant expression was observed comparing early to advanced stages by analysing PD-1 by tumor cells and TILs and of PD-L1 by tumor cells and TAMs. CONCLUSIONS: Our results corroborate that PD-1 and PD-L1 expression is not stage-dependent in mycosis fungoides and Sezary syndrome. However, PD-1 and PD-L1 expression in affected patients provides a rationale to schedule anti PD-1/PD-L1 drugs.

Erythroderma: psoriasis or lymphoma? A diagnostic challenge and therapeutic pitfall.

BACKGROUND: Psoriasis and lymphoma risk is widely debated, but few is known about misdiagnosis risk between erythrodermic psoriasis and lymphoma. In fact, erythroderma might represent a clinical presentation of psoriasis, cutaneous T-cell lymphomas and skin dissemination of systemic lymphomas. METHODS: All patients referred to psoriasis outpatient service with a diagnosis of erythrodermic psoriasis were re-examined. Among them, all the patients with a subsequent lymphoma diagnosis were included. For each patient data concerning age, gender, age at erythroderma onset, age at lymphoma diagnosis, immune-suppressive therapy, type of lymphoma and relative stage, lymphoma treatment and outcome were obtained. RESULTS: Twenty-five patients (15 females and 10 males) with a diagnosis of erythrodermic psoriasis were retrieved. Among them, 9 patients (5 males and 4 females) were affected by erythrodermic lymphoma, including 4 patients with Sèzary Syndrome, 3 with mycosis fungoides, and 2 with peripheral T-cell lymphoma not otherwise specified. Prior to lymphoma diagnosis all the patients (9/9) received cyclosporine, two (2/9) of them methotrexate, one (1/9) azatioprine, and two (2/9) systemic corticosteroids. The prognosis of our patients was poor, due to immune-suppressive drugs administration in patients with undiagnosed lymphoma. The only exception was one (1/9) patient with Sèzary Syndrome still alive with disease after 120 months of follow-up. CONCLUSIONS: In case of patients with erythroderma, multiple skin biopsies and specific peripheral blood studies like flow cytometry and T-cell receptor gene rearrangement analysis are required in order to avoid misdiagnosis risk between psoriasis and lymphoma.

The Microenvironment's Role in Mycosis Fungoides and Sézary Syndrome: From Progression to Therapeutic Implications.

BACKGROUND: Mycosis fungoides (MF) and Sezary Syndrome (SS) are the most common cutaneous T-cell lymphomas. It has been hypothesized that the interaction between the immune system, cutaneous cells, and neoplastic elements may play a role in MF/SS pathogenesis and progression. METHODS: This paper aims to revise in a narrative way our current knowledge of the microenvironment's role in MF/SS. RESULTS AND CONCLUSIONS: Literature data support a possible implication of microenvironment cells in MF/SS pathogenesis and progression, opening up new therapeutic avenues.

Immune Check Point Inhibitors in Primary Cutaneous T-Cell Lymphomas: Biologic Rationale, Clinical Results and Future Perspectives.

Primary cutaneous T-cell lymphomas (PCTCL) are the most common types of cutaneous lymphomas, with Mycosis fungoides as the most frequent subtype. Besides early stages which usually have a good prognosis, advanced stages remain a great therapeutic challenge with low survival rates. To date, none of the currently available therapeutic options have significantly improved the outcomes of advanced cutaneous lymphomas. Recent studies have demonstrated that immune-checkpoint molecules, such as PD-1 and CTLA-4, play part in the proliferation pathways of neoplastic T-cells, as well as in other tumors. Hence, the potential role of immune-checkpoint-inhibitors in treating cutaneous lymphomas has been investigated in the last years. Herein, we outline the current knowledge regarding the role of immune-checkpoint molecules in PCTCL, their signaling pathways, microenvironment and therapeutic inhibition rationale. Moreover, we review the published data on immunotherapies in PCTCL and summarize the currently ongoing clinical trials in this field.

PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis.

Germline PTEN pathogenic variants cause a spectrum of disorders collectively labeled PTEN Hamartoma Tumor Syndrome (PHTS) and featured by hamartomas, developmental anomalies and increased cancer risk. Studies on experimental models provided evidence that PTEN is a "haploinsufficient" tumor-suppressor gene, however, mechanisms involved in the pathogenesis of clinical manifestations in PHTS patients remain elusive. Beyond analyzing clinical and molecular features of a series of 20 Italian PHTS patients, we performed molecular investigations to explore the mechanisms involved in the pathogenesis of PTEN-associated manifestations, with special focus on mucocutaneous manifestations. Typical mucocutaneous features were present in all patients assessed, confirming that these are the most important clue to the diagnosis. The most frequent were papules located in the trunk or extremities (73.7%), oral mucosa papules (68.4%), acral/palmoplantar keratosis and facial papules (both 57.9%), according with literature data. Molecular analyses on one trichilemmoma suggested that the wild-type PTEN allele was retained and expressed, reinforcing the evidence that PTEN does not require a second somatic hit to initiate pathogenic processes. Unexpectedly, one patient also displayed a cutaneous phenotype consistent with atypical mole/melanoma syndrome; no variants were detected in known melanoma genes, but Whole Exome Sequencing showed the rare truncating variant c.495G>A in the CDH13 gene that might have cooperated with PTEN-haploinsufficiency to generate such phenotype. Our findings confirm the reproducibility of known PHTS manifestations in real-world practice, highlighting the role of mucocutaneous manifestations in facilitating prompt diagnosis of the syndrome, and provide some insights into the pathogenic process induced by PTEN alterations, which may contribute to its understanding.

Clinical and trichoscopic features in 18 cases of Folliculotropic Mycosis Fungoides with scalp involvement.

Folliculotropic Mycosis Fungoides (FMF) is a rare variant of Mycosis Fungoides involving the scalp leading to alopecia. The clinical and trichoscopic features in 18 patients were analyzed and compared with the reports in the literature. Gender, age, disease stage, site of onset were taken into consideration. Clinical and trichoscopic analyses were performed on each patient. From a clinical point of view, Folliculotropic Mycosis Fungoides lesions involving the scalp presented as generalized alopecia (27.8%) or patchy-plaque alopecia (72.2%). Trichoscopic analysis revealed six most frequent features: single hair (83.3%), dotted dilated vessels (77.8%), broken-dystrophic hairs (66.7%), vellus hairs (61.1%), spermatozoa-like pattern vessels (55.6%), and yellow dots (55.6%). Additional identified trichoscopic patterns were dilation of follicular openings, scales-crusts, purpuric dots, short hair with split-end, pigtail hairs, perifollicular hyperkeratosis, milky-white globules, black dots, white dots/lines and absence of follicular dots. These trichoscopic features were further correlated to clinical presentations and stage of the disease. The rarity of the disease is a limitation. The relatively high number of patients allowed to identify several clinical and trichoscopic patterns that could be featured as specific or highly suspicious for FMF in order to consider trichoscopy as a complementary diagnostic approach and improve the differential diagnoses between FMF and other scalp disorders.

Second neoplasm in cutaneous T-cell lymphoma patients: a marker of worse prognosis?

BACKGROUND: Epidemiologic studies have shown that cutaneous T-cell lymphoma (CTCL) patients have an increased risk of the development of a second neoplasm (SN). The aim of our study was to evaluate the risk of SN and to correlate any possible change in CTCL course after the diagnosis of a subsequent neoplasm. METHODS: A ten-year retrospective study was carried out in two centers (Bologna and Florence) all the patients who developed a SN six months at least after a CTCL were included. Two groups were selected: group 1 featuring patients who developed a SN and group 2 characterized by patients affected by MF age and sex-matched with group 1 (control group). Data concerning any stage change after SN, time between MF and SN onset, modified Severity Weighted Assessment Tool (mSWAT) score before and after SN, concerning Group 1 and after a median time of 36 months in Group 2 were analyzed. RESULTS: Thirteen patients were detected. Before SN onset, early MF patients were mainly present, while SN cases in advanced stage (ten patients) were observed. SN type predominant was lung cancer, along with prostate and pancreatic cancer, while isolated cases presenting with vulvar, colon, mammalian, prostate cancer along with Hodgkin's Lymphoma. Mean mSWAT at MF diagnosis and after SN showed a significant difference (P value = 0.0037). After SN diagnosis, nine patients experienced an MF stage progression and ten patients died at follow-up. CONCLUSIONS: In all the instances, statistical analysis showed that mean mSWAT score before/after SN diagnosis had a significantly difference (P=0.0037) suggesting that patients with a SN may have a worse clinical outcome. By secreting immunosuppressive cytokines or recruiting immunosuppressive cells, a sort of mutual help between the two neoplasms may be prompted. Our data suggested that SN development in MF patients may be regarded as a worse prognostic marker.

Phenotypical Markers, Molecular Mutations, and Immune Microenvironment as Targets for New Treatments in Patients with Mycosis Fungoides and/or Sézary Syndrome.

Primary cutaneous lymphomas encompass a wide spectrum of rare lymphoproliferative disorders originating in the skin, among which, mycosis fungoides (MF) is the most common subtype. The treatment of this disease is based on skin-directed therapies eventually in association with biologic response modifiers in the early phases, whereas in patients with the advanced stages, several therapeutic strategies can be used including mono and/or polychemotherapy and bone marrow transplantation. In recent years, the identification of specific markers (phenotypical, immunological, and molecular) has led to the development of several studies (including two randomized phase III trials). The results of these studies are modifying our therapeutic strategy toward a personalized treatment approach in which the clinical characteristics of the patients and tumor-node-metastasis-blood stage are considered together with the expression of specific markers (i.e., a CD30-positive expression for the use of brentuximab vedotin). This review will provide a comprehensive scenario of the main phenotypical, molecular, and immunological markers related to MF pathogenesis and disease evolution, which could represent the target for the development of innovative effective treatments in this disease.

Cutaneous adverse-events in patients treated with Ibrutinib.

Ibrutinib is a Burton tyrosine kinase inhibitor (BTKi) approved for the treatment of several hematologic malignancies. Analyze skin adverse events (SAE). All the patients treated with Ibrutinib featuring cutaneous adverse events were selected. Twenty five patients were retrieved with a median interval between Ibrutinib start and SAE time of onset of 120 days. Most common SAE observed involved hairs and nails. Eczematous reaction and leucocytoclastic vasculitis were also detected. One patient had a long-history Ibrutinib treatment and experienced numerous cutaneous adverse events. Infective disease such as superficial mycosis and impetigo were rarely present in our series. Despite the development of cutaneous SAE, all the patients continued their concomitant drugs without the onset of any further SAE. Our data suggest Ibrutinib-associated rash should be distinguished in early and late events and a careful dermatologic management of patients should be scheduled.