Dupilumab treatment in paediatric atopic dermatitis (2 to 18 years): Spanish multicentre retrospective real-life study.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) can be difficult to manage in paediatric patients, with few licensed treatments in this age group. Dupilumab is approved for AD in children older than 6 months. OBJECTIVES: To assess the effectiveness and safety of dupilumab in a real-life cohort of paediatric AD patients in Spain. METHODS: A multicentre, retrospective real-life study on the effectiveness and safety of dupilumab in patients aged 2 to 18 years old with moderate-to-severe AD was conducted. Demographic and clinical characteristics were analysed, and effectiveness (EASI, IGA, DLQI, NRS itch), safety, and drug survival measures were assessed. A comparison of our results with other real-world outcomes and with clinical trials was made. RESULTS: Data from 243 patients from 19 centres was collected, with a mean follow-up of 85 weeks. Dupilumab exhibited significant effectiveness, with marked reductions in severity scores from week 4. By week 16, 79.4% of patients reached EASI75 and 40.5% reached EASI90. Mean percentage reduction in EASI was 79.7%. Increasing improvements were observed until week 52, with 85.8% and 49.6% achieving EASI75 and EASI90, respectively. Forty-three patients developed adverse events (AE) (43/243, 17.7%), being the most frequent ocular surface diseases (20/243, 8.2%), injection site reactions (8/243, 3.3%) and facial redness (7/243, 2.9%). Drug survival was high (96.9% and 93.1% after 1 and 2 years of follow-up, respectively), with only 19 (19/243, 7.8%) patients interrupting treatment: 7 (7/243, 2.9%) due to AE, 2 (2/243, 0.82%) due to secondary failure, 5 (5/243, 2.1%) were lost to follow-up and 5 (5/243, 2.1%) entered remission and stopped treatment. CONCLUSION: Real-life use of dupilumab in paediatric AD showcased sustained effectiveness, high drug survival, and acceptable safety profiles. Longer-term studies are crucial for AE surveillance and how to manage disease remission.

Periungual pyogenic granulomas after ravulizumab therapy in a child with acute myelomonocytic leukemia treated with hematopoietic stem cell transplant.

Development of periungual pyogenic granulomas (pPGs) has been associated with several systemic treatments, including retinoids, taxanes, epidermal growth factor receptor inhibitors, and vascular endothelial growth factor inhibitors. We present the case of an 8-year-old girl with a personal history of acute myelomonocytic leukemia treated with a haploidentical hematopoietic stem cell transplant who developed pPGs 2 months after starting ravulizumab. Ravulizumab is a monoclonal antibody directed against C5 protein. No previous reports of pPGs development have been described with ravulizumab.

Brentuximab vedotin in the treatment of cutaneous T-cell lymphomas: Data from the Spanish Primary Cutaneous Lymphoma Registry.

BACKGROUND: Brentuximab vedotin (BV) has been approved for CD30-expressing cutaneous T-cell lymphoma (CTCL) after at least one previous systemic treatment. However, real clinical practice is still limited. OBJECTIVES: To evaluate the response and tolerance of BV in a cohort of patients with CTCL. METHODS: We analysed CTCL patients treated with BV from the Spanish Primary Cutaneous Lymphoma Registry (RELCP). RESULTS: Sixty-seven patients were included. There were 26 females and the mean age at diagnosis was 59 years. Forty-eight were mycosis fungoides (MF), 7 Sézary syndrome (SS) and 12 CD30+ lymphoproliferative disorders (CD30 LPD). Mean follow-up was 18 months. Thirty patients (45%) showed at least 10% of CD30+ cells among the total lymphocytic infiltrate. The median number of BV infusions received was 7. The overall response rate (ORR) was 67% (63% in MF, 71% in SS and 84% in CD30 LPD). Ten of 14 patients with folliculotropic MF (FMF) achieved complete or partial response (ORR 71%). The median time to response was 2.8 months. During follow-up, 36 cases (54%) experienced cutaneous relapse or progression. The median progression free survival (PFS) was 10.3 months. The most frequent adverse event was peripheral neuropathy (PN) (57%), in most patients (85%), grades 1 or 2. CONCLUSIONS: These results confirm the efficacy and safety of BV in patients with advanced-stage MF, and CD30 LPD. In addition, patients with FMF and SS also showed a favourable response. Our data suggest that BV retreatment is effective in a proportion of cases.

Beyond plaque psoriasis - pathogenesis and treatment of other psoriasis phenotypes.

PURPOSE OF REVIEW: Psoriasis vulgaris is the commonest presentation of psoriatic disease, but morphologic variants such as pustular psoriasis (PP) and a closely related disease, pityriasis rubra pilaris (PRP), have been known for a long time, have been associated with rheumatologic manifestations indistinguishable from psoriatic arthritis (PsA) that may go unrecognized, and often represent a therapeutic conundrum. There is recent evidence that underlying genetic and pathogenetic differences may provide the basis for newer therapeutic approaches. RECENT FINDINGS: This narrative review highlights the clinical, genetic and pathogenetic characteristics of PP and PRP, their association with PsA and recent developments in their treatment, especially with biologic agents targeting IL-36 and other cytokines of pathogenic relevance. SUMMARY: The clinical manifestations of PP and PRP are less well known to rheumatologists than those of psoriasis, and recent advances in our insight on their pathogenesis may eventually overcome the therapeutic difficulties faced by dermatologists and rheumatologists in the management of these diseases and their rheumatologic manifestations.

Clinical and molecular response to dasatinib in an adult patient with Penttinen syndrome.

Penttinen type of premature aging syndrome is an autosomal-dominant disorder that can be caused by the c.1994T>A pVal665Ala pathogenic variant in platelet-derived growth factor receptor-B (PDGFRB). Imatinib, a receptor tyrosine kinase (RTK) inhibitor, has been used in Penttinen syndrome (PS) patients with good results. A 21-year-old male presented shortly after birth with a prematurely aged appearance with distinctive facial features and cutaneous atrophy with hypertrophic scar-like lesions. Generalized brachydactyly with acro-osteolysis was observed. Flexion contractures limited his daily activities. Cognitive impairment was not present. Genetic testing found a heterozygous variant c.1994T>A pVal665Ala in exon 14 of PDGFRB. A diagnosis of PS was made and imatinib treatment was started with partial response. After lack of further improvement, in vitro molecular studies with imatinib and dasatinib showed that the Val665Ala variant had greater sensitivity to dasatinib than imatinib. This was seen examining levels of P-PDGFRB directly and on downstream ligands P-AKT and P-STAT. Improved clinical response was observed after treatment with dasatinib. We report a new case of PS with clinical and molecular response to dasatinib after incomplete response to imatinib. Our work provides further molecular and clinical evidence of RTK inhibitors' efficacy in this rare disorder.

IL-1 Family Cytokines in Inflammatory Dermatoses: Pathogenetic Role and Potential Therapeutic Implications.

The interleukin-1 (IL-1) family is involved in the correct functioning and regulation of the innate immune system, linking innate and adaptative immune responses. This complex family is composed by several cytokines, receptors, and co-receptors, all working in a balanced way to maintain homeostasis. Dysregulation of these processes results in tissue inflammation and is involved in the pathogenesis of common inflammatory dermatoses such as psoriasis, hidradenitis suppurativa, and atopic dermatitis. Therefore, therapeutic targeting of IL-1 pathways has been studied, and several monoclonal antibodies are currently being assessed in clinical trials. So far, promising results have been obtained with anti-IL-36R spesolimab and imsidolimab in pustular psoriasis, and their efficacy is being tested in other conditions.

Net-like superficial lymphatic malformation.

The net-like superficial lymphatic malformation (LM) is a newly described entity with distinctive clinical, dermoscopic, and histologic characteristics. Clinical picture consists of red to purplish macules with a finely reticulated pattern of vascular structures. Dermoscopy shows arborizing telangiectatic vessels. Histology is characterized by a vascular proliferation composed of thin-walled vessels, located in the upper dermis, that stains positive with podoplanin (D2-40). We report a new case of LM with an additional clinical feature, hypopigmented areas.

Exploring the Role of IL-36 Cytokines as a New Target in Psoriatic Disease.

Unmet needs in the treatment of psoriasis call for novel therapeutic strategies. Pustular psoriasis and psoriatic arthritis often represent a therapeutic challenge. Focus on IL-36 cytokines offers an interesting approach, as the IL-36 axis has been appointed a critical driver of the autoinflammatory responses involved in pustular psoriasis. Two IL-36R blocking antibodies, imsidolimab and spesolimab, are currently undergoing phase II and III clinical trials, with promising results.

Propranolol-resistant infantile hemangioma successfully treated with sirolimus.

Infantile hemangiomas are the most common benign vascular tumors in childhood. Propranolol is the first-line treatment for infantile hemangiomas, but failures may occur. Sirolimus, an mTOR inhibitor, is a promising drug for the treatment of vascular malformations and vascular tumors. We present the case of a child with multiple infantile hemangiomasthat was successfully treated with sirolimus and propranolol after failure of combined propranolol and prednisolone treatment.

Good response to pulsed dye laser in patients with capillary malformation-arteriovenous malformation syndrome (CM-AVM).

Capillary malformation-arteriovenous malformation syndrome (CM-AVM) is an autosomal dominant disorder caused by heterozygous mutations in RASA1 and EPHB4. Capillary stains in CM-AVM are compatible with Schöbinger's phase I AVMs. Vascular laser has been classically contraindicated for the treatment of AVMs, as there is a fear of accelerating their progression. In this study, we have treated capillary stains in five CM-AVM patients with pulsed dye laser, with improvement and without worsening or recurrence of the lesions after 1 year of clinical and ultrasound follow-up.

Lentigo maligna: a comprehensive review on diagnosis and treatment.

Lentigo maligna (LM), a form of melanoma in situ, and LM melanoma (LMM), its invasive counterpart, exhibit distinctive epidemiology, risk factors, and clinical features compared to other melanoma subtypes. Notably, LM occurs on chronically sun-damaged skin presenting as a slow-growing, ill-defined patch which makes it difficult to diagnose and to treat. Additionally, while LM generally presents a favourable prognosis, it can also lead to dermal invasion and behave similarly to other melanomas with the same Breslow thickness. Hence, surgery continues to be the cornerstone treatment. Wide excisions are often necessary, but challenges arise when these lesions manifest in cosmetically sensitive regions, limiting the feasibility and desirability of large excisions. Specialized approaches, including margin-controlled surgery and image-guided treatment with reflectance confocal microscopy, have been developed to address these issues. Other non-surgical treatments such as cryosurgery, imiquimod, radiotherapy, or photodynamic therapy, may also be used but commonly present with recurrent/persistent disease. Herein we comprehensively review the existing literature on the management of LM/LMM, and discus the potential new advances on managing this challenging skin cancer.

Efficacy and Safety of JAK1 Inhibitor Abrocitinib in Atopic Dermatitis.

Abrocitinib is a JAK1 selective inhibitor recently approved for the treatment of moderate-to-severe atopic dermatitis in adults. It has demonstrated efficacy and safety in several clinical trials, both in children and adults, in monotherapy, and compared with dupilumab. The expected EASI-75 response rate estimates at week 12 are 62.9% (95% CrI 42.5-79.9%) for abrocitinib 200 mg and 43.0% (95% CrI 24.8-64.0%) for abrocitinib 100 mg. Abrocitinib has shown a faster effect than dupilumab as regards early alleviation of itch. Because of the incomplete target selectivity of JAK inhibitors, when abrocitinib treatment is considered, laboratory screening is necessary, latent tuberculosis must be screened for, active infections are a contraindication, and special caution must be exerted in treating elderly patients and those predisposed to thromboembolic events. Even though recent meta-analyses of clinical trials have not shown that atopic dermatitis, or its treatment with JAK inhibitors or dupilumab, modify the risk of deep venous thrombosis or pulmonary embolism, long-term follow-up studies will better define the safety profile of abrocitinib.

Sclerotic Bone Lesions as a Clue in the Diagnosis of Three Generations of Tuberous Sclerosis Complex: Case Report and Review of Literature.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that can involve multiple organ systems. Diagnosis is based on independent clinical diagnostic criteria and genetic diagnostic criteria (pathogenic variants on TSC1 and TSC2 genes). To make a definitive diagnosis can be especially difficult in oligosymptomatic or asymptomatic patients and in those patients with genetic variants of uncertain significance (VUS). Early diagnosis and lifelong surveillance are paramount to avoid morbidity and potentially life-threatening complications. To increase diagnostic sensibility, less known manifestations of TSC can be helpful. Herein we show a case in which SBLs were used as a diagnostic clue to help diagnose three generations of oligosymptomatic TSC carrying a VUS in TSC1. SBLs are commonly detected in imaging studies of patients with TSC and have been recently included as a minor clinical diagnostic criterion. Clinicians and radiologists should be aware of their significance as they can be mistaken with osteoblastic metastases.

Dual inhibition of IL-17A and IL-17F in psoriatic disease.

Psoriasis and psoriatic arthritis are chronic immune-mediated disorders with involvement of interleukin (IL)-17 cytokines in their pathogenesis. IL-17A has been considered to be the most biologically active, but IL-17F is also over-expressed in skin and synovial tissues of patients with these diseases. Many therapeutic advances have been made in the past years, but some needs remain unmet. Dual inhibitor and bispecific antibodies simultaneously targeting IL-17A and IL-17F could provide better disease control. Herein we review current evidence on bimekizumab and sonelokimab. The antigen-binding site of bimekizumab neutralizes both IL-17A and IL-17F; phase I, II, and III studies have demonstrated its efficacy and safety in psoriasis and psoriatic arthritis. Sonelokimab is a trivalent nanobody targeting IL-17A and IL-17F; phase I and II studies with this molecule have yielded promising results in psoriasis.

The interleukin-1 family cytokines in psoriasis: pathogenetic role and therapeutic perspectives.

Introduction: IL-1 family cytokines play an important role in the innate immune system and their uncontrolled activation and expression can initiate a pathologic inflammatory response. Their role in psoriasis, pustular psoriasis, and psoriatic arthritis has been studied, and they offer potential interest as therapeutic targets.Areas covered: This review focuses on the role that interleukin (IL)-1 family cytokines play in psoriasis pathogenesis, with a special focus on pustular psoriasis, and how these cytokines can be used as therapeutic targets. Using PubMed, we review the literature for articles related to IL-1 family cytokines and psoriasis, focusing on pustular psoriasis, and including pathogenesis, genetics and therapeutic targets.Expert opinion: IL-1 and IL-36 cytokines act as critical drivers of the autoinflammatory responses involved in pustular psoriasis. Studies on the specific role of each IL-1 cytokine are needed, as well as of their regulatory pathways. Targeting of IL-1 family cytokines has been used in pustular psoriasis, with IL-1 and IL-36 R blockade showing promising results.

Excellent response to secukinumab in an infant with severe generalized pustular psoriasis.

Generalized pustular psoriasis (GPP) represents the rarest form of psoriasis, which may be potentially fatal. In the last decade, (likely) pathogenic variants in the IL36RN, CARD14 and AP1S3 genes have been associated with monogenic GPP forms. Despite these advances, the genetic basis of most patients with GPP remains unidentified. Treatment of GPP patients is often difficult, with no consensus about the best available options to date. We report herein an infant with severe GPP in whom the disease started at the age of 2 months. Genetic investigations identified a heterozygous pathogenic variant in the IL36RN gene associated with a heterozygous variant of uncertain significance in the CARD14 gene. After previous treatment failures with acitretin, cyclosporin and anakinra, treatment with the interleukin-17 antagonist secukinumab resulted in a dramatic and prompt positive response that persisted at 12-month follow up. According to our experience, we believe secukinumab can be an effective and safe treatment for pediatric patients with GPP even before 1 year of age.

The safety of brodalumab for the treatment of psoriasis.

Introduction: Brodalumab is a newly developed targeted biologic agent for the treatment of psoriasis that blocks IL-17 receptor A.Areas covered: This review sought to provide a detailed overview on safety of brodalumab for the treatment of psoriasis. A PubMed search was conducted for relevant literature. Here we review the efficacy and safety data from key phase II, phase III and open-label extension clinical trials, as well as systematic reviews and meta-analyses.Expert opinion: The unique mechanism of action of brodalumab offers advantages on efficacy over other targeted treatments, with a quick onset of action and long-term maintenance of treatment response. Brodalumab has a favorable safety profile, similar to other IL-17 inhibitors. Infections, especially mucocutaneous candidiasis, must be monitored. Suicidal ideation was detected in brodalumab trials, although a causal relationship has not been revealed. Brodalumab is a highly efficacious and comparably safe therapeutic choice in patients with moderate to severe psoriasis, especially when rapid control of the disease is desired.

Lentigo Maligna: Clinical Presentation and Appropriate Management.

Lentigo maligna (LM) is a type of melanoma in situ that has distinctive characteristics regarding epidemiology, risk factors and clinical features. In addition, LM has a potential to progress to an invasive tumor with potentially aggressive behavior: lentigo maligna melanoma (LMM). Overall, LM has a very good prognosis, whereas LMM has the same prognosis as other invasive melanomas with similar Breslow thickness. LM/LMM represents a challenging entity not only regarding the diagnosis but also regarding the management. Diagnostic criteria are not well established, and there is an overlap of clinical, dermoscopic and pathological features with other benign pigmented skin lesions such as lentigines, pigmented actinic keratoses or macular seborrheic keratoses. LM/LMM's common appearance within photodamaged skin makes lesion border identification difficult. Wide excisions are often required, but since LM/LMM typically appears on cosmetically sensitive areas such as the face, sometimes large excisions are not possible nor desirable. In this sense, specialized approaches have been developed such as margin-controlled surgery or image-guided treatment using reflectance confocal microscopy. Other treatments for LM such as cryosurgery, imiquimod, radiotherapy or photodynamic therapy have been proposed, although recurrence/persistence is common. The current manuscript reviews extensively the published data regarding the diagnosis, treatment and management of both complex entities LM and LMM.