Short-, mid- and long-term efficacy of dupilumab in moderate to severe atopic dermatitis: a real life multicenter Italian study on 2576 patients.

BACKGROUND: The efficacy and safety of dupilumab in atopic dermatitis (AD) have been defined in clinical trials but limited real-world evidence on long term treatment outcomes are currently available to inform clinical decisions. OBJECTIVES: to describe long-term effectiveness and safety of dupilumab up to 48 months in patients with moderate-to-severe AD. METHODS: a multicenter, retrospective, dynamic cohort study was conducted to assess long term effectiveness and safety of dupilumab in patients with moderate to severe AD in a real-world setting. Predictors of minimal disease activity (MDA) optimal treatment target criteria (defined as the simultaneous achievement of EASI90, itch NRS score ≤1, sleep NRS score ≤1 and DLQI ≤1) were investigated. RESULTS: 2576 patients were enrolled from June 2018 to July 2022. MDA optimal treatment target criteria were achieved by 506 (21.91%), 769 (40.63%), 628 (50.36%), 330 (55.37%) and 58 (54.72%) of those that reached 4, 12, 24, 36 and 48 months of follow-up, respectively. Logistic regression revealed a negative effect on MDA achievement for conjunctivitis and food allergy at all timepoints. Adverse events (AE) were mild and were observed in 373 (15.78%), 166 (7.02%), 83 (6.43%), 27 (4.50%) and 5 (4.55%) of those that reached 4, 12, 24, 36 and 48 months of follow-up. Conjunctivitis was the most frequently reported AE during the available follow-up. AE led to treatment discontinuation in <1% of patients during the evaluated time periods. CONCLUSION: High long-term effectiveness and safety of dupilumab were confirmed in this dynamic cohort of patients with moderate to severe AD, regardless of clinical phenotype and course at baseline. Further research will be needed to investigate the effect of Th2 comorbidities and disease duration on the response to dupilumab and other newer therapeutics for AD.

Factors Associated with Affective Symptoms and Quality of Life in Patients with Atopic Dermatitis.

The aim of this study was to detect demographic and clinical factors associated with affective symptoms and quality of life in patients with severe atopic dermatitis. First, one-way analyses of variance and correlations were performed to compare a large set of qualitative and quantitative clinical variables. Three final multivariable regression models were performed, with depression/anxiety subscales and Dermatology Life Quality Index scores as dependent variables, and the factors that were statistically significant on univariate analyses as independent ones. More severe anxiety symptoms and poorer quality of life (p < 0.01) were significantly associated with more severe depressive symptoms. Female sex and disturbed sleep (p = 0.03) were significantly associated with more severe anxiety. Finally, previous treatment with cyclosporine (p = 0.03) or methotrexate (p = 0.04), more severe depressive symptoms (p < 0.01), itch (p = 0.03), impaired sleep (p < 0.01) and perceived severity of dermatological illness (p < 0.01) were significant predictors of low quality of life. This study shows a complex interplay between the severity of atopic dermatitis, poor quality of life and presence of clinically relevant affective symptoms. These results will help dermatologists to identify patients who need psychiatric consultation within the framework of a multidisciplinary approach.

Effectiveness of dupilumab for the treatment of nummular eczema phenotype of atopic dermatitis in adults.

Nummular eczema (NE) is currently considered as one of the clinical phenotypes of atopic dermatitis (AD) of the adult. In this multicentre study, 30 adult patients (age ≥ 18 years) affected with nummular-like AD were treated with dupilumab, a monoclonal antibody against the receptor for interleukin(IL)-4 and IL-13. The evaluation of the results after 16 weeks of treatment showed a significant improvement of the disease, as demonstrated by reduction in Eczema Area Severity Score (EASI), visual analogue score (VAS) of pruritus, and Dermatology Life Quality Index (DLQI) scores. Conjunctivitis in one patient was the only side effect. In conclusion, dupilumab seems to be an effective and safe treatment in NE phenotype of AD of the adult.

Are there distinct clinical and pathological features distinguishing idiopathic from drug-induced subacute cutaneous lupus erythematosus? A European retrospective multicenter study.

BACKGROUND: Clinical and pathologic criteria to distinguish drug-induced subacute lupus erythematosus (DI-SCLE) from idiopathic (I-SCLE) are controversial. OBJECTIVE: The aim of the survey was a retrospective analysis of a consistent number of iatrogenous and idiopathic SCLE cases, by means of clinical and histopathologic investigation. METHODS: Eleven European university dermatology units collected all diagnosed cases from January 2000 to December 2016. Board-certified dermatopathologists reviewed the histopathologic specimens. Statistical analysis included Student t test, exact test of goodness-of-fit, Fisher's exact test, and the Cochran-Mantel-Haenszel test for repeated measures. RESULTS: Out of 232 patients, 67 (29%) belonged to the DI-SCLE group. Patients with DI-SCLE were significantly older and reported more systemic symptoms than those with I-SCLE. No statistical differences were found for presentation pattern or serology, while histopathology showed a significant association of mucin deposition (P = .000083), direct immunofluorescence positivity for granular immunoglobulin M, and C3 deposits on the basement membrane zone (P = .0041) for I-SCLE and of leukocytoclastic vasculitis (P = .0018) for DI-SCLE. LIMITATIONS: This is a retrospective study. CONCLUSION: An integrated clinical and immunopathologic evaluation is useful to differentiate I-SCLE from DI-SCLE. Older age at onset and more frequent systemic symptoms characterize DI-SCLE. Mucin deposition and immunofluorescence findings are found in I-SCLE, and leukocytoclastic vasculitis is found in DI-SCLE.

Pyoderma gangrenosum-like ulcerations in granulomatosis with polyangiitis: two cases and literature review.

Granulomatosis with polyangiitis (GPA) is a systemic necrotizing small vessel vasculitis associated with circulating anti-neutrophil cytoplasmic antibodies (ANCAs). Skin manifestations, mostly represented by palpable purpura, papulonodular lesions and livedo reticularis, are present in up to 50% of the cases. Ulcerations with undermined, raised erythematous-violaceous border resembling pyoderma gangrenosum (PG) have rarely been reported as skin involvement in GPA. The presence of circulating ANCAs with a cytoplasmic labelling pattern, the involvement of internal organs, particularly of the lung, and the absence on histology of a mainly neutrophilic infiltrate in early phases of the cutaneous lesions may be regarded as clues to rule out true PG and confirm the diagnosis of GPA skin ulcerations simulating PG. Herein, we describe two paradigmatic cases of such a unique presentation of GPA and a literature review focusing on clinicopathological features of GPA presenting with PG-like ulcerations in the skin has been provided. Moreover, referring to the scenario observed in these two cases, an easy-to-use working approach for the differential diagnosis between the two conditions has also been proposed.

Assessment of Patient-Reported Outcomes at 48 Months of Treatment with Dupilumab for Severe Atopic Dermatitis: A Single-Center Real-Life Experience with 126 Patients.

BACKGROUND: The main objective was to analyze patient-reported outcomes (PRO) trends over a four-year period in severe atopic dermatitis (AD) patients treated with dupilumab. METHODS: data from 126 severe patients receiving dupilumab for at least 48 months were collected. The clinical scores assessed included the Eczema Area and Severity Index (EASI), Pruritus Numerical Rating Scale (NRS), Sleep NRS, Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), and Atopic Dermatitis Control Tool (ADCT). RESULTS: the study compellingly demonstrates dupilumab's effectiveness in reducing EASI and improving PROs, with sustained enhancements observed beyond the initial twelve months of treatment. Univariate and multivariate regression analyses show that baseline factors do not significantly increase the risk of adverse outcomes related to Pruritus NRS, POEM, or ADCT at T48. The robust correlation between ADCT and other PROs suggests closely aligned changes. CONCLUSION: Dupilumab's benefits endure beyond the first year, emphasizing its long-term efficacy, and consistently improves AD outcomes regardless of individual characteristics or clinical variables. ADCT appears to be a practical and versatile tool for the streamlined assessment of AD treatment outcomes.

Which Factors Are Associated with Persistence of Depressive and Anxiety Symptoms in Patients Affected by Atopic Dermatitis despite 2-Year Treatment with Dupilumab?

Background: Atopic Dermatitis (AD) is a prevalent inflammatory skin disease whose course is often complicated by the presence of concomitant anxiety and depressive disorders. Dupilumab has been demonstrated to be largely effective in AD. The aims of the present study were to (1) to verify the effectiveness of 2-year dupilumab treatment on the depressive and anxiety symptoms of patients affected by AD and (2) to identify predictors of the persistence of psychiatric symptoms despite maintenance treatment with dupilumab. Methods: A total of 331 patients with severe AD were assessed at baseline and at different times over 2 years by a large set of rating scales, including the Eczema Area and Severity Index (EASI), the Hospital Anxiety and Depression Scale (HADS), and the Dermatology Life Quality Index (DLQI). Paired sample t-tests were performed to verify the effectiveness of dupilumab on the severity of AD and mental health items. Two binary logistic regression models were then used to identify the predictors of the persistence of clinically significant depression and anxiety, defined by a score ≥ 8 on each sub-scale of the HADS. Results: After 2 years of treatment with dupilumab, the patients benefited, showing a significant improvement in both the dermatological disease and comorbid depression/anxiety (p < 0.001 for all scales). Overall, 17.5% and 13% of patients, respectively, reported residual depressive and anxiety symptoms after the 2-year treatment with dupilumab. The baseline predictors of the persistence of clinically significant depressive symptoms after the 2-year treatment with dupilumab were found to be a higher body mass index (BMI) (p = 0.012), a lower impact of dermatological disease on quality of life (p = 0.015), and more severe depressive symptoms (p < 0.01), while for anxiety, the only predictor was found to be female gender (p = 0.03). Conclusions: Using a multidisciplinary approach, at baseline, dermatologists should more closely monitor patients who are at a greater risk of maintaining residual psychiatric symptoms despite therapy, such as those with more severe depressive symptoms and those who are overweight.

Mental health in patients affected by atopic dermatitis: which effects of treatment with dupilumab?

Atopic dermatitis (AD) is an inflammatory skin disease. Patients with AD are prone to develop anxiety and mood disorders. Aim of this study is to investigate if treatment with dupilumab may improve mental health status of patients affected by AD. A total of 66 patients with severe AD were included: 24 subjects were candidate or have just started (one month) treatment with dupilumab, and 42 have been in treatment for one year. 25.8%, 30.3%, and 45.5% of the total sample showed, respectively, clinically significant anxiety, depression, and symptoms of Internet addiction. Patients with anxiety symptoms resulted to have more severe AD, more sleep problems ( P  = 0.028), less quality of life ( P  = 0.001), more severe depressive symptoms ( P  < 0.001), to be more frequently women ( P  = 0.016), to be less frequently treated with dupilumab for one year ( P  = 0.025). Similarly, patients with clinically significant depressive symptoms resulted to have more severe AD, more sleep problems ( P  = 0.003), less quality of life ( P  < 0.001), more severe anxiety symptoms ( P  < 0.001), to be less frequently treated with dupilumab for one year ( P  = 0.008). Patients with AD treated for one year with dupilumab showed a better mental health profile in terms of less severe anxiety and depression with respect to their counterparts.

Five-year real-world drug survival of dupilumab in severe atopic dermatitis and associate predictors.

BACKGROUND: Atopic dermatitis (AD) profoundly impacts patients' lives, necessitating long-term systemic treatments. METHODS: This retrospective study involved 709 severe AD patients receiving dupilumab. Drug survival (DS) was analyzed using Kaplan-Meier curves, evaluating reasons for discontinuation. The log-rank test and Cox regression analysis were applied to assess differences in drug survival across baseline clinical characteristic groups. RESULTS: Dupilumab showcased remarkable overall drug survival, reaching 74.1% at 65 months. Survival rates remained robust even when considering discontinuation solely due to primary or secondary inefficacy (86.4% at 65 months). For overall DS, the log-rank test did not reveal a statistically significant difference among the groups. Cox regression analysis showed that patients with nummular eczema-like as a phenotype have an increased risk of discontinuing dupilumab due to the development of psoriasis (p < .001, hazard ratio = 26.15, confidence interval [CI] 6.903-99.016). The multivariate logistic regression analysis confirmed these results (p < .001, OD = 18.956, CI 4.205-85.458), even when considering other clinical and epidemiological characteristics. CONCLUSION: This investigation establishes dupilumab's enduring efficacy and safety in severe AD, emphasizing its potential as a sustained therapeutic option over 5+ years. Baseline characteristics did not seem to influence DS, with the exception of the nummular eczema-like phenotype, which emerged as a significant predictor of psoriasis occurrence.

Emerging Systemic Treatments for Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic or chronically relapsing inflammatory skin disease which results from a complex, multifaceted interaction between environmental factors in genetically predisposed patients. Epidermal barrier impairment, alteration of the cutaneous microbiota, effect of external antigens, neurosensory dysfunction, and inflammatory and immune dysregulation all play a pivotal role in inducing and maintaining AD lesions. AD significantly impacts the patient's quality of life and general well-being and is often associated with anxiety and/or depressive symptoms. Classical treatment options include topical corticosteroids and calcineurin inhibitors, phototherapy, and systemic immunosuppression with oral corticosteroids, cyclosporine, methotrexate, and azathioprine in more severe cases. A turning point in facing AD was accomplished when the efficacy and safety of dupilumab, a monoclonal antibody targeting the interleukin (IL)-4 receptor α subunit, led to its approval for the treatment of moderate-to-severe or severe AD in children, adolescents, and adults. Subsequently, a more extensive understanding of AD etiology and pathogenesis has allowed the development of several topical and systemic novel therapy options. Most of these drugs are monoclonal antibodies which interfere with the type 2 inflammatory cascade, especially its key cytokines IL-4 and IL-13, or its downstream Janus kinase signaling pathway. However, considering the relevance of other subtypes of T helper (Th) cells, such as Th1 and Th22, and the important role of specific cytokines (IL-31) in generating pruritus, the horizon of potential therapeutic targets has widened extremely. In this review, we aim to present the most promising systemic agents currently under investigation and illustrate the most significant aspects of their efficacy, safety, and tolerability.

Predictive Factors of Early Response to Dupilumab in Patients with Moderate-to-Severe Atopic Dermatitis.

Efforts have been made to identify factors influencing clinical response in patients with atopic dermatitis (AD) treated with dupilumab. A retrospective single-center observational study was carried out by analyzing data from 492 patients aged 12 years and older with moderate-to-severe AD. The study aimed to identify baseline demographic and clinical factors that could predict the achievement of a mild level of disease, i.e., an Eczema Area and Severity Index (EASI) ≤ 7, within 4 weeks from dupilumab initiation. Classic, generalized lichenoid and inflammatory phenotypes compared with a nummular eczema phenotype (OR = 6.9, 95% CI 2.04-23.48 and OR = 4.22, 95% CI 1.22-14.66, respectively) and a baseline EASI ≤ 24 and between 24-29, compared with a baseline EASI ≥ 29 (OR = 3.1, 95% CI 1.81-5.41 and OR = 1.8, 95% CI 1.05-3.07, respectively), were found to be predictive factors of early response to dupilumab, highlighting the importance of early biological treatment of AD.

Asthma improvement in patients treated with dupilumab for severe atopic dermatitis.

Introduction: Atopic dermatitis (AD) is considered a systemic type 2 immune driven disease, and it is associated to many atopic comorbidities including asthma. The aim of our study was to prospectively evaluate the respiratory outcomes in patients with persistent allergic asthma treated with dupilumab due to severe AD (sAD). Methods: We enrolled eligible patients with sAD for dupilumab treatment from September 2018 to December 2020. We then selected the subgroup of patients sensitized to perennial allergens. Dupilumab's efficacy and safety on AD and comorbid asthma were assessed at baseline, one month, four months, and then every 4 months up to one year. Results: A total of 437 patients with sAD were enrolled for dupilumab treatment due to sAD, and 273 reached 48 weeks of therapy. Respiratory outcomes were evaluated in the 85 asthmatic patients with positivity only to perennial allergens. Our patients showed statistically and clinically significant improvement in asthma control (Asthma Control Test and Asthma Control Questionnaire) and airway obstruction parameters (FEV1), in addition to the expected AD-related skin outcomes. Specifically, a significant improvement was achieved at the fourth month of dupilumab therapy, and this trend was maintained up to twelve months, regardless of asthma severity. Conclusions: Our results showed the overall improvement of the clinical picture that dupilumab offers for patients with severe AD and persistent allergic asthma of any severity, highlighting the importance of a global multidisciplinary approach of type 2 driven disease.

Tomesa balneophototherapy in mild to severe psoriasis: a retrospective clinical trial in 174 patients.

Psoriasis is a chronic inflammatory skin disease with a high social and psychological impact on the quality of life of patients. Tomesa balneophototherapy is based on bathing in a magnesium-rich salt solution combined with exposure to narrowband ultraviolet B phototherapy. We conducted a retrospective clinical trial on 174 patients affected by mild to severe psoriasis undergoing Tomesa balneophototherapy. The basal course consisted of three to five sessions per week for a total of 30 sessions. Subsequently, patients could continue with a maintenance course of one session per week for a total of 30 sessions. We recorded a significant reduction of the mean Psoriasis Area and Severity Index (PASI) index with an achievement of at least PASI 75 in 52.1% of the 119 patients who completed the basal course and an improvement of the 'quality of life' of patients. The good efficacy obtained by this treatment, and the psychological impact on the quality of life of patients, demonstrated that Tomesa balneophototherapy could be a good option for the treatment of a chronic disease associated with psychological distress, like psoriasis.

Acral subcutaneous steatocystoma multiplex: a distinct subtype of the disease?

Steatocystoma multiplex (SM) is a hamartomatous malformation of the pilosebaceous duct consisting of dermal cysts filled with a sebum-like material. SM lesions are typically located in areas with sebaceous follicles, although atypical presentations involving sites lacking sebaceous follicles have exceptionally been described. We reviewed retrospectively a series of 32 histologically diagnosed SM observed in our department in the period 2006-2010, evaluating the kinds of lesions and their locations, and family history of SM and associated disorders, to focus on the clinical features of the acral subcutaneous variety of SM and to estimate its prevalence. We found five patients (four women and one man) with asymptomatic deep, skin-colored nodules on the flexor surfaces of distal upper extremities with a mean age at diagnosis and at disease onset of 32.5 and 26 years, respectively. The prevalence was 15%. All five cases were sporadic. The male patient had eruptive syringomas as an associated condition, together with a family history of this tumour. Acral subcutaneous SM may represent a distinct disease variety by virtue of its distinctive clinical features. Dermatologists should be aware of this form, which has to be included in the wide panel of diseases involving subcutaneous tissue.

Remission of Alopecia Universalis after 1 Year of Treatment with Dupilumab in a Patient with Severe Atopic Dermatitis.

Alopecia areata (AA), an autoimmune disease with a relapsing-remitting course, represents the second cause of non-scarring alopecia worldwide and is associated with several comorbidities, notably atopic dermatitis (AD). In particular, AD is related to its more severe forms alopecia totalis (AT) and alopecia universalis (AU) [Nat Rev Dis Primers. 2017;3:17011]. Considering that AA has been classified as T helper 1-driven disease, whereas AD is the prototypical T helper 2 (Th2)-driven skin disorder, recent studies suggest that these forms may underlie a different chemokine expression resulting in a Th2 skewing as a key pathomechanism that could explain this association [JAMA Dermatol. 2015 May;151(5):522-8]. Several reports showed that dupilumab, a fully human monoclonal antibody targeting the interleukin 4α receptor and thus downregulating Th2 response, led to an improvement of AA associated with AD; most of these patients were females with AT or AU, early-onset AD, and atopic comorbidities [Exp Dermatol. 2020 Aug;29(8):726-32]. We report here a case to further support this hypothesis.

Elevation of peripheral blood eosinophils during dupilumab treatment for atopic dermatitis is associated with baseline comorbidities and development of facial redness dermatitis and ocular surface disease.

INTRODUCTION: Transient eosinophilia is not uncommon in patients with moderate-to-severe atopic dermatitis (AD) treated with dupilumab. METHODS: A retrospective, single center, observational study was conducted to assess the difference in terms of absolute eosinophil count (AEC) change at 4 months and at 12 months, relative to the baseline, in predefined subgroups of patients affected by moderate-to-severe AD treated with dupilumab. RESULTS: Complete data for 373, 289 and 210 patients were available at the baseline, 4 months and 12 months, respectively. Patients with a history of conjunctivitis (n = 152) had greater increases in AEC at 4 months as compared with those (n = 137) who did not (+16%vs0%,p = 0.01). Patients with food allergies (n = 46) showed similar increases (+39%vs + 5%, p = 0.01). Patients experiencing facial redness dermatitis on dupilumab (n = 46) had greater increases in AEC at 4 months than those (n = 243) who did not (+40%vs + 5%, p = 0.03). Patients that had dupilumab-induced ocular surface disease (n = 44) had greater increases in AEC at 4 months than those (n = 245) who did not (+43%vs + 5%, p = 0.01). CONCLUSIONS: Atopic comorbidities are associated with a paradoxical increase in AEC at 4 months in AD patients treated with dupilumab. Patients experiencing dupilumab-related ocular surface disease or facial redness dermatitis also have remarkable increases in AEC at 4 months.

Cutaneous T-cell/histiocyte-rich B-cell lymphoma: a case report and review of the literature.

BACKGROUND: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) primarily presenting on the skin is an extremely rare entity with only sporadic cases reported in the literature. METHODS: We here report an extraordinary case of primary cutaneous THRLBCL with self-healing and 24 months of follow-up. RESULTS: The lesion was a dermohypodermal/subcutaneous circumscribed ulcerated nodosity. Histological examination with immunohistochemical, molecular analysis and comparative genomic hybridization were performed. A complete staging was negative for secondary involvement. CONCLUSION: Our case is remarkable because it is the second well-documented primary cutaneous THRLBCL in which we observed a complete self-regression of skin lesions without recurrences or dissemination of the disease. According to the literature, we highlight that the tumoral microenvironment, in our case, could play a relevant role in stopping lymphoma growth. Furthermore, this case supports the observation that THRLBCL primarily presenting on the skin shows an overall good prognosis.

Skin barrier status during dupilumab treatment in patients with severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common chronic-relapsing inflammatory skin disease hallmarked by epidermal barrier dysfunction, increased transepidermal water loss (TEWL) and decreased skin hydration. Recent findings on the T helper 2 (Th2)-driven pathogenesis of AD have led to the development of dupilumab, a monoclonal antibody directed against interleukin-4 and interleukin-13 that has been demonstrated to be effective in the treatment of moderate-to-severe AD. The effect of dupilumab on skin barrier dysfunction, however, has not yet been adequately investigated. OBJECTIVES: The primary endpoint of this study was to assess the status of the skin barrier in nonlesional skin of patients with severe AD treated with dupilumab, by evaluating the association between the relative variation of TEWL and the achievement of a 75% reduction of EASI (EASI75) over time. METHODS: TEWL was measured below the antecubital fossae by means of the Vapometer® at baseline, at week 4 (T4), at week 16 (T16) and at week 32 after dupilumab starting. EASI and NRS-itch were measured at the same time points. RESULTS: Seventy-eight patients with severe AD treated with dupilumab were enrolled. Median TEWL relative variation respect to baseline was significantly higher in patients who achieved EASI75 as compared with those who did not achieve EASI75 at T16 and at T32, but not at T4. CONCLUSION: During dupilumab treatment, TEWL on nonlesional skin tends to significantly improve 4 months after treatment initiation and could be a good tool for monitoring response to therapy.