Association between maternal dupilumab exposure and pregnancy outcomes in patients with moderate-to-severe atopic dermatitis: A nationwide retrospective cohort study.

BACKGROUND: There is limited epidemiological evidence on outcomes associated with dupilumab exposure during pregnancy; monitoring pregnancy outcomes in large populations is required. OBJECTIVE: To investigate the potential association between exposure to dupilumab in pregnant women with atopic dermatitis and any adverse pregnancy, neonatal, congenital and post-partum outcomes. METHODS: We performed a multicentre retrospective cohort study across 19 Italian tertiary referral hospital. Childbearing women were eligible if aged 18-49 years and carried out the pregnancy between 1 October 2018 and 1 September 2022. RESULTS: We retrospectively screened records of 5062 patients receiving dupilumab regardless of age and gender, identifying 951 female atopic dermatitis patients of childbearing age, 29 of whom had been exposed to the drug during pregnancy (3%). The median duration of dupilumab treatment prior to conception was 22.5 weeks (range: 3-118). The median time of exposure to the drug during pregnancy was 6 weeks (range: 2-24). All the documented pregnancies were unplanned, and the drug was discontinued in all cases once pregnancy status was reported. The comparison of the study cohort and the control group found no significant drug-associated risk for adverse pregnancy, congenital, neonatal or post-partum outcomes. The absence of a statistically significant effect of exposure on the event was confirmed by bivariate analysis and multivariate analysis adjusted for other confounding factors. CONCLUSIONS: This cohort of pregnant patients exposed to dupilumab adds to the existing evidence concerning the safety of biologic agents in pregnancy. No safety issues were identified regarding the primary outcome assessed. In clinical practice, these data provide reassurance in case of dupilumab exposure during the first trimester. However, the continuous use of dupilumab throughout pregnancy warrants further research.

Therapeutic Impact and Management of Persistent Head and Neck Atopic Dermatitis in Dupilumab-Treated Patients.

BACKGROUND: Localization of atopic dermatitis (AD) in exposed areas such as the hands, head, and neck has been considered as a negative factor impacting on dupilumab response, although a comparison of exposed versus unexposed areas is not currently available. OBJECTIVES: The aim of this study is to evaluate the clinical response to dupilumab depending on the presence or persistency of AD skin manifestations in specific body areas. METHODS: The study retrospectively collected clinical and demographic data of adult patients affected by moderate to severe AD. Based on the anatomical sites involved, 5 subcohorts of patients were identified. RESULTS: A total of 41 patients were included in the study. Disease amelioration was detected during the study period, although baseline head/neck and hand localization was associated with a significantly lower likelihood of achieving an Eczema Area Severity Index (EASI) ≤1. In addition, patients with head/neck persistency showed a significantly lower response when compared to patients without persistency of head/neck AD in terms of both mean EASI and Dermatology Life Quality Index (DLQI) reduction. CONCLUSION: AD localization in exposed areas at the baseline and AD persistency at the head/neck may have a negative impact on certain treatment response parameters to dupilumab therapy.

Management of patients with atopic dermatitis undergoing systemic therapy during COVID-19 pandemic in Italy: Data from the DA-COVID-19 registry.

BACKGROUND: Few and small studies have described the management of immunomodulant/immunosuppressive therapies or phototherapy in atopic dermatitis (AD) patients during coronavirus disease 2019 (COVID-19) pandemic. METHODS: A national registry, named DA-COVID-19 and involving 35 Italian dermatology units, was established in order to evaluate the impact of COVID-19 pandemic on the management of adult AD patients treated with systemic immunomodulant/immunosuppressive medications or phototherapy. Demographic and clinical data were obtained at different timepoints by teledermatology during COVID-19 pandemic, when regular visits were not allowed due to sanitary restrictions. Disease severity was assessed by both physician- and patient-reported assessment scores evaluating itch intensity, sleep disturbances, and AD severity. RESULTS: A total of 1831 patients were included, with 1580/1831 (86.3%) continuing therapy during pandemic. Most patients were treated with dupilumab (86.1%, 1576/1831) that was interrupted in only 9.9% (156/1576) of cases, while systemic immunosuppressive compounds were more frequently withdrawn. Treatment interruption was due to decision of the patient, general practitioner, or dermatologist in 39.9% (114/286), 5.6% (16/286), and 30.1% (86/286) of cases, respectively. Fear of increased susceptibility to SARS-CoV-2 infection (24.8%, 71/286) was one of the main causes of interruption. Sixteen patients (0.9%) resulted positive to SARS-CoV-2 infection; 3 of them (0.2%) were hospitalized but no cases of COVID-related death occurred. CONCLUSIONS: Most AD patients continued systemic treatments during COVID pandemic and lockdown period, without high impact on disease control, particularly dupilumab-treated patients.

Successful Combination of Systemic Agents for the Treatment of Atopic Dermatitis Resistant to Dupilumab Therapy.

BACKGROUND: Dupilumab, a monoclonal antibody inhibiting the signaling pathway of IL-4/IL-13, was shown to be safe and effective in the treatment of moderate/severe atopic dermatitis (AD) in several clinical trials and real-life experiences, with only a small percentage of patients showing to be resistant or to lose disease control. OBJECTIVES: In this study, we investigated the effectiveness and safety in combining dupilumab with systemic agents or phototherapy in patients experiencing an inadequate response to dupilumab. METHODS: This retrospective, monocentric, observational study consecutively included patients aged >18 years, with moderate-severe AD, under treatment with dupilumab. In this cohort of patients, we analyzed data of subjects who experienced an inadequate response to dupilumab, even when combined with topical corticosteroids, and for whom an additional systemic treatment or phototherapy was combined to dupilumab. RESULTS: In this study, we included a total population of 69 patients treated with dupilumab. In 12/69 patients (17.4%) showing an inadequate response to dupilumab, a combined treatment consisting of dupilumab plus methylprednisolone (n = 5), cyclosporine (n = 4), methotrexate (n = 2), or narrow band-UVB (n = 1) was administered. Overall, after 8 weeks of combined therapy, the majority of patients (11 of 12) obtained an improvement of signs and symptoms of AD. Patients treated with combined therapy did not experience any adverse events, neither did they withdraw treatment because of the occurrence of adverse events. CONCLUSIONS: This study suggests that the combination of dupilumab with a conventional drug or phototherapy may represent a valid therapeutic choice, maintaining a good safety profile in AD patients recalcitrant to dupilumab monotherapy.

Dupilumab improves clinical manifestations, symptoms, and quality of life in adult patients with chronic nodular prurigo.

BACKGROUND: Chronic nodular prurigo (CNPG) is a multifactorial skin disease characterized by itchy papules and nodules, usually resistant to standard treatment and associated with markedly impaired quality of life. OBJECTIVE: To describe dupilumab effectiveness and tolerability in treating adult patients with CNPG refractory to both topical and systemic therapies. METHODS: Retrospective, multicenter study including adult patients affected by CNPG, who were treated with dupilumab for at least 16 weeks. RESULTS: Twenty-seven CNPG patients showed clinical improvement in terms of skin lesions, itch, sleeplessness, and quality of life. A consistent proportion of patients (24/27; 88.9%) had at least 16-week continuous treatment and achieved Investigator Global Assessment score 1 (11/24; 45.8%). An increased number of patients achieved at least a 2-grade reduction in Investigator Global Assessment score (19/24; 79.2%). Numeric rating scale values for itch and sleeplessness decreased from 8.9 to 2.7 and from 8.2 to 1.7, respectively (P < .001) after 16-week therapy. Ten patients achieved 36 weeks of continuous treatment while maintaining clinical efficacy. LIMITATIONS: Major limitations included lack of validated assessment tools at the initial data collection, a limited cohort of treated patients, and a short-term observation period. CONCLUSION: Dupilumab was proven effective in reducing itch and improving CNPG skin lesions.

Disease Severity Is Associated with Alexithymia in Patients with Atopic Dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder that is associated with higher rates of psychological disorders, but limited evidence supported the association with alexithymia, a psychoaffective dysfunction. OBJECTIVES: This study was aimed to investigate the occurrence of alexithymia in AD patients, compared to healthy subjects. METHODS: This cross-sectional study assessed AD severity by the Eczema Area and Severity Index (EASI) score, sleeplessness and itch by a numeric rating scale (NRS), and alexithymia by the 20-item Toronto Alexithymia Scale (TAS-20) score. The association between disease characteristics and alexithymia was evaluated through several logistic regression models. RESULTS: 202 AD patients and 240 healthy subjects were included in this study. The alexithymic personality trait (TAS-20 ≥51) was more frequently observed among AD patients compared to the control group (62.4% [126/202] vs. 29.2% [70/240], p < 0.0001). In particular, alexithymia (TAS-20 score ≥61) was detected in a significantly higher number of AD patients than in the controls (27.7% [56/202] vs. 7.5% [18/240]; p < 0.0001), whereas borderline alexithymia was detected in 34.6% (70/202) of AD patients compared to 21.7% of healthy controls. Alexithymia was more common among severe AD patients (43.6%) compared to mild AD patients (15.6%) and correlated with itch intensity and sleep disturbances. Among clinical variables, ordered logistic regression analyses revealed disease severity as predictor of alexithymia. Indeed, univariate analysis showed EASI score, sleep NRS, and itch NRS being significantly associated with alexithymia, while a multivariate model identified increased EASI score values as predicting factor. CONCLUSION: This study described alexithymia in AD patients correlating its occurrence with clinical AD severity markers (EASI score, itch, and sleeplessness) and identifying the increase in EASI score as predicting factor.

Successful Use of Dupilumab in the Treatment of Acquired Perforating Dermatosis Associated with Atopic Dermatitis.

Acquired reactive perforating collagenosis is a rare cutaneous disorder characterised by the extrusion of abnormal connective tissue trough epidermidis and/or follicular units. Reactive perforating collagenosis is often associated with systemic diseases in which pruritus is a common symptom (e.g., diabetes and chronic kidney disease). Less commonly, it has been associated with chronic inflammatory dermatoses, including atopic dermatitis, as in this case. In this report, we describe the exceptional case of a 35-year-old man affected by acquired reactive perforating collagenosis associated with atopic dermatitis who was resistant to conventional topical and systemic treatment and experienced complete resolution of clinical signs and symptoms after 12 weeks of treatment with dupilumab. In our patient, the severe pruritus induced by atopic dermatitis likely contributed to the development of acquired perforating collagenosis lesions, which are thought to be a reactive response to chronic scratching and repetitive injury to the skin. Chronic pruritus in atopic dermatitis is known to be driven by type 2 cytokines, including IL-4 and IL-13, and dupilumab, a monoclonal antibody inhibiting IL-4 and IL-13 signalling, has been shown to be effective in the treatment of moderate to severe atopic dermatitis as well as other type 2-driven pruritic dermatological conditions. This case supports the potential use of dupilumab for the treatment of reactive perforating dermatosis.

Therapeutic Potential of IL-1 Antagonism in Hidradenitis Suppurativa.

The immunopathogenesis of HS is partially understood and exhibits features of an autoinflammatory disease; it is associated with the potential involvement of B cells and the contribution of Th1 or Th17 cell subsets. Recently, the pathogenic role of both innate immunity and IL-1 family cytokines in HS has been deeply investigated. Several agents targeting the IL-1 family pathway at different levels are currently available and under investigation for the treatment of HS. HS is still characterized by unmet clinical needs and represents an expanding field in the current scientific research. The aim of this narrative review is to describe the pathological dysregulation of IL-1 family members in HS and to provide an update on therapeutic strategies targeting IL-1 family cytokine signaling. Further clinical and preclinical data may likely lead to the enrichment of the therapeutic armamentarium of HS with IL-1 family cytokine antagonists.

Fluid-Dependent Single-Frequency Bioelectrical Impedance Fat Mass Estimates Compared to Digital Imaging and Dual X-ray Absorptiometry.

The need for a practical method for routine determination of body fat has progressed from body mass index (BMI) to bioelectrical impedance analysis (BIA) and smartphone two-dimensional imaging. We determined agreement in fat mass (FM) estimated with 50 kHz BIA and smartphone single lateral standing digital image (SLSDI) compared to dual X-ray absorptiometry (DXA) in 188 healthy adults (69 females and 119 males). BIA underestimated (p < 0.0001) FM, whereas SLSDI FM estimates were not different from DXA values. Based on limited observations that BIA overestimated fat-free mass (FFM) in obese adults, we tested the hypothesis that expansion of the extracellular water (ECW), expressed as ECW to intracellular water (ECW/ICW), results in underestimation of BIA-dependent FM. Using a general criterion of BMI > 25 kg/m2, 54 male rugby players, compared to 40 male non-rugby players, had greater (p < 0.001) BMI and FFM but less (p < 0.001) FM and ECW/ICW. BIA underestimated (p < 0.001) FM in the non-rugby men, but SLSDI and DXA FM estimates were not different in both groups. This finding is consistent with the expansion of ECW in individuals with excess body fat due to increased adipose tissue mass and its water content. Unlike SLSDI, 50 kHz BIA predictions of FM are affected by an increased ECW/ICW associated with greater adipose tissue. These findings demonstrate the validity, practicality, and convenience of smartphone SLSDI to estimate FM, seemingly not influenced by variable hydration states, for healthcare providers in clinical and field settings.

Identification of clinical predictors for dupilumab dose spacing in adults with atopic dermatitis: a real-world study.

BACKGROUND: Dupilumab is a monoclonal antibody against the IL-4/IL-13 receptor-subunit approved for the treatment of moderate-severe atopic dermatitis (AD). Some attempts to increase dose interval have been described in both trial and real-world settings. OBJECTIVE: This study aimed to identify predictive clinical and demographic factors affecting patient selection for dose spacing or treatment withdrawal due to satisfactory response. MATERIALS AND METHODS: This retrospective study included adult patients with moderate-to-severe AD treated with dupilumab for at least 16 weeks. Descriptive statistics were performed to analyze demographic and clinical variables. Logistic regression models were used to identify predictor variables. RESULTS: A total of 818 adult patients with moderate-to-severe AD was included in the study and 12% (97/818) of them performed dose spacing to 3-4 weeks or treatment withdrawal (8%, 67/818). The presence of non-cutaneous atopic manifestations (OR = 1.59, 95%CI = 1.06-2.38, p = 0.024), prurigo nodularis phenotype (OR = 4.5, 95%CI = 1.87-10.9, p = 0.001) and the age at treatment initiation (OR = 1.82, 95%CI = 1.12-2.94, p = 0.015) were confirmed as the strongest predictors of dose spacing or treatment withdrawal while maintaining dupilumab effectiveness. CONCLUSION: Our findings contribute to define the patient profile that could maintain the therapeutic response after dose spacing or treatment withdrawal.

Predicting factors identified patients with dupilumab who could benefit of dose spacing or treatment withdrawal.

Low grade of satisfaction related to the use of current systemic therapies among pustular psoriasis patients: a therapeutic unmet need to be fulfilled.

Introduction: Pustular psoriasis is considered a separate entity from plaque psoriasis and can be categorized as generalized pustular psoriasis (GPP), acrodermatitis continua of Hallopeau, or palmoplantar pustulosis (PPP). Current guidelines mostly include treatment options that have not been specifically developed for the treatment of pustular psoriasis. The majority of them does not have indication for the treatment of pustular psoriasis. Their effectiveness and safeness have been described in small cohort-based studies or case series with a low level of evidence. Previous studies evaluated treatment response through physician-based assessment but none reported patient satisfaction to treatment, quality of life and patient perception of disease severity during systemic therapies, particularly with biologics commonly used in plaque psoriasis. This study aimed to investigate patient satisfaction to treatment and patients' quality of life during treatment, correlating patient-reported outcomes with residual disease severity. Methods: A cross-sectional, cohort-based, single center study included patients affected by pustular psoriasis undergoing treatment with systemic agents. Demographic, clinical characteristics were collected. Treatment satisfaction as well as disease severity were assessed through dedicated assessment scores. Results: A total of 31 patients affected by GPP or PPP were included. Despite biologic treatment, 80.6% of patients continued to experience mild-to-severe disease activity, with discrepancies between patient and physician assessments. Patients reported a substantial impairment in their quality of life, with notable limitations in physical activity and emotional distress. Mental health conditions, such as depression and anxiety disorders, were common. Treatment satisfaction varied, with moderate scores for effectiveness and convenience. Only a small proportion of patients (41.9%) reported complete or high overall treatment satisfaction. GPP and PPP subcohorts exhibited similar quality of life and treatment satisfaction levels. Discussion: This study highlights the suboptimal control of PP despite biologic therapies, resulting in a significant impact on patients' quality of life and treatment satisfaction. The findings highlight the need for specific therapies and standardized guidelines for managing PP. New targeted therapies, such as spesolimab, hold promise for optimizing treatment satisfaction and improving patients' quality of life in this challenging condition. Future research should focus on refining treatment strategies to address the unmet needs of PP patients comprehensively.

Analysis of predictive factors influencing dupilumab continuation rate in adult patients with atopic dermatitis: results from an Italian multicenter study.

OBJECTIVES: The purpose of this study was to analyze the drug survival rate of dupilumab up to 2 years in a large real-world cohort of adult patients affected by moderate/severe atopic dermatitis (AD), and to investigate the clinical, demographic and predictive factors influencing the patients' treatment persistence. MATERIAL AND METHODS: This study included adult patients affected by moderate-to-severe AD treated with dupilumab for at least 16 weeks who visited 7 dermatologic outpatient clinics in Lazio, Italy, from January 2019 until August 2021. RESULTS: A total of 659 adult patients (345 male [52.3%], mean age: 42.8 years) with an average treatment duration of 23.3 months were enrolled in the study. Overall, 88.6% and 76.1% of patients were still on treatment after 12 and 24 months, respectively. The drug survival rate for discontinuation due to AEs and dupilumab ineffectiveness was 95.0% at 12 months and 90.0% at 24 months. The main reasons for drug discontinuation included inefficacy (29.6%), failed compliance (17.4%), persistent efficacy (20.4%) and adverse events (7.8%). Adult AD onset (≥18 years) and EASI score severity measured at the last follow-up visit were the only factors significantly associated with lower drug survival. CONCLUSION: This study revealed an increased cumulative probability of dupilumab survival at 2 years, reflected by a sustained effectiveness and a favorable safety profile of the drug.

Long-term Effectiveness and Safety of Upadacitinib for Atopic Dermatitis in a Real-world Setting: An Interim Analysis Through 48 Weeks of Observation.

BACKGROUND: Janus kinase (JAK) inhibitors, including upadacitinib, have been recently approved for the treatment of moderate-severe atopic dermatitis (AD) and real-world data on upadacitinib effectiveness and safety are limited. This interim analysis aimed to assess effectiveness and safety of upadacitinib throughout 48 weeks of observation in a real-world adult AD population. METHODS: This prospective study collected data on adult patients affected by moderate-to-severe AD and treated with upadacitinib at the dosage of either 15 mg or 30 mg daily based on the physician decision. Upadacitinib was prescribed in the context of a national compassionate use programme. In this interim analysis, within patient comparisons of continuous scores of different scales (namely Eczema Area and Severity Index [EASI], body surface area [BSA], Dermatology Life Quality Index [DLQI], Patient Oriented Eczema Measure [POEM], Numeric Rating Scale [NRS] subtests) were performed. The percentage of patients achieving EASI 75, EASI 90 and EASI 100 at Week 16, 32 and 48 was also evaluated. RESULTS: One hundred and forty-six patients were included in the analysis. Upadacitinib 15 mg or 30 mg daily was prescribed as monotherapy in most cases (127/146, 87.0%). Upadacitinib was initially prescribed at the dosage of 30 mg daily in 118 of 146 (80.8%) patients and 15 mg daily in 28/146 (19.2%) patients. A significant improvement in the clinical signs and symptoms of AD was detected by Week 16 and throughout the study period. EASI 75, EASI 90 and EASI 100 responses were achieved by 87.6%, 69.1% and 44.3% at Week 48, associated with a sustained reduction in the mean values of all physician-reported (EASI and BSA) and patient-reported (Itch- Sleep- and Pain-NRS, DLQI, and POEM) disease severity outcomes, up to 48 weeks of treatment. Treatment response observed in 15 mg upadacitinib-treated patients was comparable with that detected in 30 mg upadacitinib-treated patients, revealing no statistical difference between the two patient sub-cohorts. Through the observation period, dose reduction or escalation was observed in 38/146 (26%) of treated cases. Overall, 26 of 146 (17.8%) patients experienced at least one adverse event (AE) during the treatment period. In total, 29 AEs were recorded and most of them were evaluated as mild to moderate, while in 4 cases the occurrence of AE led to drug discontinuation, for a total of 7/146 (4.8%) dropouts. CONCLUSION: This study provides strong evidence of a sustained response obtained by upadacitinib in AD patients, who had failed to respond to conventional or biological systemic agents, through 48 weeks of observation. Upadacitinib was also demonstrated to be advantageous in terms of flexibility in dose reduction or escalation as upadacitinib dose was shaped on clinical needs that, in a real-world setting, might frequently change.

Head injury assessment in Italian Rugby Union: a two-seasons prospective analysis.

BACKGROUND: In Italy, to the best of our knowledge, there is no literature relating to injury and concussion epidemiology in rugby union. Therefore, the primary aim of this study is to describe the incidence of sport-related concussion in Italian rugby union and the associated management of Head Injury Assessment (HIA). METHODS: This is an observational prospective study, analyzing the Italian elite rugby championship (Top 12 and Coppa Italia) for two seasons (2018/2019 and 2019/2020). Twelve male teams of the Italian elite rugby championship were included. The diagnosis of traumatic brain injury was provided by a team doctor with HIA, while no match day doctor or video analysis was available. A concussion expert of Italian Rugby Federation reviewed all the HIAs. The outcome of interest were: incidence, playing situation and mechanism responsible for traumatic brain injury. RESULTS: In the study period, 47 HIAs were performed during matches (45.3/1000 player-match-hours) and 7 concussions were diagnosed by team doctors (6.75/1000 player-match-hours). After the concussion expert HIAs' review, the thirty-three percent of 16 diagnoses were made later, during follow-up, or based on clinical suspicion. Most symptoms complained about by players were neck pain and headache, in 14.6% and 13.4% of HIA, respectively. Concussions were predominately the result of tackling (46.5%) for the tackler (90.9%). CONCLUSIONS: The incidence of concussion in Italian Rugby appears to be low compared to that of rugby outside Italy, which is likely due to the learning curve of HIA and the absence of video analysis and match day doctors during competitions. The implementation of educational projects may be fundamental to promoting HIA process.