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.

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.

"Your Skin Tells You" Campaign for Keratinocyte Cancers: When Individuals' Selection Makes the Difference.

BACKGROUND: Prevention campaigns for skin cancers have focused primarily on melanoma, and over time there has been increasing awareness of the need to select the population to be screened to maximize program effectiveness. OBJECTIVES: The objective of the study was to report the results of a free dermatological initiative, as part of an awareness campaign dedicated to keratinocyte cancers, targeting individuals pre-selected through a short questionnaire. METHODS: One day of dermatological consultations was held at 15 dermato-oncology referral centers during May 22-June 30, 2021. For selection, individuals answered a telephone interview consisting of 7 yes/no questions on risk factors. Demographics, clinical characteristics of suspicious tumors, and histopathologic diagnosis of excised lesions were collected. Suspicion rate, detection rate, and positive predictive values (PPVs) for any skin cancer, basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma were calculated. RESULTS: A total of 320 individuals (56.9% males; 43.1% females) with a median age of 69.6 (range 21-91) years qualified for the screening initiative. Overall, skin cancers and precancerous lesions were diagnosed in 65.9% of the patients. Suspicion rate was 28.7% for any skin cancer (92/320), 22.8% for BCC (73/320), 4.7% for cSCC (15/320), and 1.2% for melanoma (4/320). Detection rate was 23.4% for any skin cancer (PPV 93.7%), 18.1% for BCC (PPV 95.1%), 4.4% for cSCC (PPV 93.3%), and 0.9% for melanoma (PPV 75%). CONCLUSIONS: Selection of individuals at high risk is a cost-effective approach for early detection campaigns for keratinocyte cancers.

Bath-PUVA still represents a valuable treatment option for the subsets of psoriatic patients who are not eligible to or rejecting systemic treatments and are not responsive to NB-UVB phototherapy.

BACKGROUND: Photochemotherapy with bathwater delivery of psoralens plus UVA exposures (bath-PUVA) is mainly used for those psoriatic patients who are not responsive to narrowband (NB)-UVB phototherapy and oral-PUVA therapy and belong to two categories (1) patients with psoriasis without systemic comorbidities who do not need long-term continuous treatment and (2) patients who have contraindications to immunosuppressive drugs and oral-PUVA or refuse systemic drugs, including oral ingestion of psoralens, for personal reasons. However, it is not known how many patients belong to the second group and how much bath-PUVA is effective and safe for them. METHODS: We have reviewed the treatment results of a cohort of 120 patients with clinical indication to bath-PUVA for the above-mentioned reasons between 2010 and 2019. These patients were selected among 2640 patients with moderate and severe psoriasis who were treated in our department in the same time interval. RESULTS: Ninety-six patients completed at least one treatment cycle with bath-PUVA. A per-protocol analysis showed that average number of treatment sessions was 21.3 ± 9.0 and the cumulative UVA dose was 80.4 ± 60.0 J/cm2 . The average PASI scores decreased from 20.8 ± 7.9 to 5.1 ± 5.4 (p < .01). Sixty-seven (69.7%) patients achieved at least a 75% improvement (PASI75 ) and, of them, 38 (39.6%) had an improvement greater than 90% (PASI90 ). Adverse effects were mild and transitory. CONCLUSION: These findings demonstrate that bath-PUVA is still a valuable treatment option for a high number of patients who reject systemic treatments or have contraindications to systemic immune-modifying drugs and have had a limited or no improvement with NB-UVB phototherapy.

A Short Cycle of Narrow-Band UVB Phototherapy in the Early Phase of Dupilumab Therapy Can Provide a Quicker Improvement of Severe Atopic Dermatitis.

BACKGROUND: Since the best clinical response to dupilumab is achieved after 12-16 weeks, a combination therapy at the beginning of the treatment could be a helpful strategy to reach a faster response in patients with severe atopic dermatitis (AD). OBJECTIVES: To quantify the benefit of a combination of dupilumab treatment with a short course of narrow-band ultraviolet B (NB-UVB) phototherapy. METHODS: In the present pilot study adult patients suffering from severe AD were enrolled with a 2:1 ratio to receive treatment with dupilumab alone or dupilumab plus NB-UVB phototherapy, for 12 weeks. After the twelfth week, all patients received dupilumab only. A follow-up visit took place after 16 weeks. Both clinician-oriented and patient-oriented scores were assessed at baseline (T0) and after 4 (T1), 12 (T2) and 16 (T3) weeks. RESULTS: Forty-five adult patients were enrolled in the study. Both treatment regimens were well tolerated and very effective on all measured scores (EASI, SCORAD, BSA, NRS of itching, NRS of sleep loss, DLQI, POEM and HADS), but the combined regimen led to a more robust clinical improvement of lesions and relief of symptoms after 4 weeks. However, after 12 and 16 weeks, the additional therapeutic effect of phototherapy weakened. CONCLUSION: NB-UVB phototherapy can provide a faster remission of severe AD in the first few weeks of dupilumab therapy.

A Critical Reappraisal of Off-Label Use of Photodynamic Therapy for the Treatment of Non-Neoplastic Skin Conditions.

BACKGROUND: In the past 30 years, topical photodynamic therapy (PDT) has been investigated for the treatment of a broad spectrum of cosmetic, inflammatory, and infectious skin conditions with variable, and often contrasting, results. However, the non-expert clinician may be in difficulty evaluating these results because different sensitizers, concentrations, formulations, light sources, and irradiation protocols have been used. In addition, many of these studies have poor quality design being case reports and uncontrolled studies of few cases. SUMMARY: With the aim to clarify the potential usefulness of PDT for the treatment of infectious and inflammatory skin diseases as well as selected cosmetic indications, we searched for randomized controlled clinical trials, non-randomized comparative studies, retrospective studies, and case series studies with a number of at least 10 patients, published since 1990. Later, we reappraised the results in order to give a simple critical overview. Key Messages: Evidence from the literature seems to strongly support the use of ALA- and MAL-PDT for the treatment of common skin diseases such as acne, warts, condylomata, and Leishmania skin infection and for photorejuvenation, i.e., the correction of selected cosmetic changes of aging and photoaging. For other disorders, the level of evidence and strength of recommendation are lower, and controlled randomized studies with prolonged follow-ups are necessary in order to assess the clinical usefulness and other potential advantages over current treatment options.

A Multidisciplinary Approach Is Beneficial in Atopic Dermatitis.

Atopic dermatitis (AD) is a highly heterogeneous chronic inflammatory skin disorder that is frequently associated with a plethora of comorbidities. AD is, therefore, considered a systemic disease impacted by a considerable burden and leading to poor quality of life, especially in patients with moderate-to-severe disease. Since atopic and non-atopic comorbidities can further worsen the disease course, accurate establishment of the patient's individual intrinsic risk profile and needs is crucial and may help in guiding the selection of the best treatment option. Better quality of care for patients with AD can be delivered through a multidisciplinary team led by a dermatologist, for comprehensive patient management. The implementation of a multidisciplinary approach for AD could enhance the delivery of optimised and safe treatments, improve the standard of care and patient outcomes in the short and long term, and prevent or delay the lifelong impact of uncontrolled AD. Understanding the unmet needs, assessing correctly the patient risk profile and enhancing the shared patient-physician decision-making process can lead to disease control and quality-of-life improvement, especially in the context of the introduction of newer treatment for AD. This narrative review is a call for more data to establish standardised patient profiles and multidisciplinary strategies in AD management. In view on the fast-evolving treatments for AD, this review aims at highlighting the importance of a multidisciplinary approach to a comprehensive assessment and holistic care in patients with moderate-to-severe AD.

Drug Survival of Upadacitinib and Predicting Factors of Discontinuation in Adult Patients Affected by Moderate-to-Severe Atopic Dermatitis: An Italian Multicenter Analysis.

Background: Limited real-world data are available on upadacitinib drug survival in patients with atopic dermatitis (AD). Objectives: To investigate upadacitinib drug survival, and the reasons and predictors of drug discontinuation in AD patients. Methods: All consecutive patients aged 18-75 years, affected by moderate-to-severe AD, and treated with upadacitinib for more than 1 month at dermatological clinics were included during November 2020-August 2023. Upadacitinib survival was investigated through Kaplan-Meier survival analysis and the predictors through multivariable logistic regression analysis. Results: Overall, 325 adult AD patients (mean (SD) age, 38.6(15.6) years) had a 1-year and 1.5-year upadacitinib drug survival of 91.5% and 80.2%, respectively. The main reasons for drug discontinuation (25/325, 7.7%) were adverse events (4.9%), including cutaneous or infectious diseases (1.5%), such as acne and herpes zoster; blood test changes (1.2%), including hypercholesterolemia, creatine phosphokinase or liver enzyme elevation, and lymphopenia; urinary or respiratory infections (0.9%); deep venous thrombosis (0.3%); malignancies (0.3%); loss of consciousness (0.3%); and arthralgias (0.3%); followed by ineffectiveness (0.6%). No specific characteristic was significantly associated with an increased risk of upadacitinib discontinuation. Conclusions: Our findings show that upadacitinib was effective in moderate-to-severe AD after more than 1 year of continuous treatment but point to the need for clinical and laboratory monitoring of patients.

AtopyReg®, the Prospective Italian Patient Registry for Moderate-to-Severe Atopic Dermatitis in Adults: Baseline Demographics, Disease Characteristics, Comorbidities, and Treatment History.

BACKGROUND AND OBJECTIVE: AtopyReg® is a multicenter, prospective, observational, non-profit cohort study on moderate-to-severe atopic dermatitis in adults promoted in 2018 by the Italian Society of Dermatology and Venereology (SIDeMaST). We aimed to describe baseline demographics, disease characteristics, comorbidities, and therapeutic data of adult patients affected by moderate-to-severe atopic dermatitis. METHODS: Patients were selected based on the following inclusion criteria: age ≥ 18 years; Eczema Area and Severity Index score ≥ 16 or localization in visible or sensitive areas (face, neck, hands, or genitalia), or a Numeric Rating Scale itch score ≥ 7 or a Numeric Rating Scale sleep loss score ≥ 7, or a Dermatology Life Quality Index score ≥ 10. Demographic and clinical data at baseline were recorded and analyzed. RESULTS: A total of 1170 patients (male 51.1%; mean age: 44.7 years; range 18-90 years) were enrolled by 12 Italian Dermatology Units between January 2019 and November 2022. Skin lesions were eczematous in 83.2% of patients, the most involved site were the flexures (53.9%), face (50.9%), and neck (48.0%). Mean Eczema Area and Severity Index score was 22.3, mean Dermatology Life Quality Index value was 17.6, mean Patient Oriented Eczema Measure score was 13.1, and mean Numeric Rating Scale itch and sleep loss scores were 7.6 and 5.9, respectively. Previous systemic therapies were corticosteroids in 77.7% of patients, antihistamines in 50.3% of patients, and cyclosporine A in 42.6% of patients. CONCLUSIONS: This baseline data analysis deriving from AtopyReg® provides real-life evidence on patients with moderate-to-severe atopic dermatitis in Italy confirming the high burden of atopic dermatitis with a significant impact on patients' quality of life.

Italian S3-Guideline on the treatment of Atopic Eczema - Part 1: Systemic therapy, adapted from EuroGuiDerm by the Italian Society of Dermatology and STD (SIDEMAST), the Italian Association of Hospital Dermatologists (ADOI) and the Italian Society of Allergological and Environmental Dermatology (SIDAPA).

SIDeMaST (Società Italiana di Dermatologia Medica, Chirurgica, Estetica e delle Malattie Sessualmente Trasmesse) contributed to the development of the present guideline on the systemic treatment of chronic plaque psoriasis. With the permission of EuroGuiDerm, SIDeMaST adapted the guideline to the Italian healthcare context to supply a reliable and affordable tool to Italian physicians who take care of patients affected by atopic dermatitis. The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This first part of the guideline includes general information on its scope and purpose, the health questions covered, target users and a methods section. It also provides guidance on which patients should be treated with systemic therapies, as well as recommendations and detailed information on each systemic drug. The systemic treatment options discussed in the guideline comprise conventional immunosuppressive drugs (azathioprine, ciclosporin, glucocorticosteroids, methotrexate and mycophenolate mofetil), biologics (dupilumab, lebrikizumab, nemolizumab, omalizumab and tralokinumab) and janus kinase inhibitors (abrocitinib, baricitinib and upadacitinib). Part two of the guideline will address avoidance of provocation factors, dietary interventions, immunotherapy, complementary medicine, educational interventions, occupational and psychodermatological aspects, patient perspective and considerations for pediatric, adolescent, pregnant and breastfeeding patients.

Italian S3-Guideline on the treatment of Atopic Eczema - First Update, adapted from EuroGuiDerm by the Italian Society of Dermatology and STD (SIDEMAST), the Italian Association of Hospital Dermatologists (ADOI) and the Italian Society of Allergological and Occupational Dermatology (SIDAPA).

The evidence- and consensus-based guideline on atopic eczema, published in JEADV on 18 August 2022 (part 1) and 3 September 2022 (part 2) was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. To reflect the most recent evidence on novel systemic medications, an update was published in October 2022. According to the purpose of the Italian Society of Dermatology and STD (SIDEMAST), the Italian Association of Hospital Dermatologists (ADOI) and the Italian Society of Allergological and Environmental Dermatology (SIDAPA) to adapt the EuroGuiDerm guideline on the treatment of atopic eczema into the Italian Healthcare setting, the original update has been supplemented by inserting notes, well highlighted by the original text, to emphasize the laws, rules, procedures and suggestions of the Italian Ministry of Health and regional Health authorities.

Italian S3-Guideline on the treatment of Atopic Eczema - Part 2: non-systemic treatments and treatment recommendations for special AE patient populations, adapted from EuroGuiDerm by the Italian Society of Dermatology and STD (SIDEMAST), the Italian Association of Hospital Dermatologists (ADOI) and the Italian Society of Allergological and Occupational Dermatology (SIDAPA).

SIDeMaST (Società Italiana di Dermatologia Medica, Chirurgica, Estetica e delle Malattie Sessualmente Trasmesse) contributed to the development of the present guideline on the systemic treatment of chronic plaque psoriasis. With the permission of EuroGuiDerm, SIDeMaST adapted the guideline to the Italian healthcare context to supply a reliable and affordable tool to Italian physicians who take care of patients affected by atopic dermatitis. The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This second part of the guideline includes recommendations and detailed information on basic therapy with emollients and moisturizers, topical anti-inflammatory treatment, antimicrobial and antipruritic treatment and UV phototherapy. Furthermore, this part of the guideline covers techniques for avoiding provocation factors, as well as dietary interventions, immunotherapy, complementary medicine and educational interventions for patients with atopic eczema and deals with occupational and psychodermatological aspects of the disease. It also contains guidance on treatment for pediatric and adolescent patients and pregnant or breastfeeding women, as well as considerations for patients who want to have a child. A chapter on the patient perspective is also provided. The first part of the guideline, published separately, contains recommendations and guidance on systemic treatment with conventional immunosuppressive drugs, biologics and janus kinase (JAK) inhibitors, as well as information on the scope and purpose of the guideline, and a section on guideline methodology.

The realistic positioning of UVA1 phototherapy after 25 years of clinical experience and the availability of new biologics and small molecules: a retrospective clinical study.

Background: Since the early 1990s, Ultraviolet (UV) A1 phototherapy has been described as an effective and safe treatment of a multitude of skin disorders. However, after 30 years, its use has remained limited to few dermatological centers. Objective: To analyze the changes over the years and the current position of UVA1 phototherapy through a Real-World Evidence (RWE) study at a single tertiary referral center. Methods: We reviewed the medical files of 740 patients treated between 1998 and 2022. Treatment results were collected, efficacy was assessed by a grading scale and acute adverse effects were registered. Results: We treated patients with 26 different diseases. We registered marked improvement (MI) or complete remission (CR) in 42.8% of patients with morphea, 50% with Urticaria Pigmentosa, 40.7% with Granuloma annulare and 85.7% with skin sarcoidosis. Good results were obtained also in the treatment of chronic Graft Versus Host Disease (GVHD), Eosinophilic Fasciitis, Sclero-atrophic Lichen, skin manifestations of systemic lupus erythematosus and psoriasis of HIV+ patients. Systemic Sclerosis, Romberg's Syndrome, Bushke's Scleredema, Nephrogenic Fibrosing Dermopathy, REM Syndrome, Follicular Mucinosis, Pretibial Myxedema, Scleromyxedema, pemphigus foliaceus, chronic cutaneous lupus erythematosus, erythroderma of Netherton Syndrome and Necrobiosis Lipoidica were no or poorly responsive. In clinical indications where UVA1 was used as a second line phototherapy after narrow-band (NB)-UVB, we saw good MI or CR rates in Mycosis Fungoides (57% of patients), Atopic Dermatitis (33.9%), Pitiryasis Lichenoides chronica (50%), Pityriasis Lichenoides et varioliformis acute (75%) and Lymphomatod Papulosis (62.5%). Short-term adverse events were uncommon and mild. Conclusion: Over the past decade, the annual number of treated patients has progressively declined for several reasons. Firstly, UVA1 phototherapy has taken a backseat to the cheaper and more practical NB-UVB phototherapy, which has proven effective for common indications. Secondly, the emergence of new, safe, and effective drugs for conditions such as atopic dermatitis, GVHD, and connective tissue disorders. Finally, our research has shown that UVA1 therapy is often ineffective or minimally effective for some rare diseases, contrary to previous case reports and small case series. Nonetheless, UVA1 continues to be a valuable treatment option for patients with specific skin disorders.