Therapeutic Modulation of Dupilumab in Patients with Severe Atopic Dermatitis: Clinical Effectiveness in Real Life.

Background: De-escalation strategies have become increasingly used in the treatment of atopic dermatitis (AD) patients with dupilumab. Dose spacing (DS) refers to dose reduction by dosage elongation strategies from 2 to 8 weeks between dupilumab injections, in patients with stable response to treatment or affected by numerous adverse events. Objectives: Investigate safety and clinical effectiveness of DS strategy in AD patients treated with dupilumab. Methods: A retrospective cohort study was conducted on AD patients aged ≥18 years treated with dupilumab undergoing DS. Pre-post analyses were conducted on this cohort, termed cohort A, between effectiveness outcomes at baseline, at 16 weeks of treatment, at the index date identified as the mean follow-up time between dupilumab initiation and DS, and at subsequent two follow-up visits: T1 and T2. Based on the index date, a cohort B of AD patients on dupilumab treatment not experiencing DS was then compared with cohort A for the same outcomes at the same time points. Results: Seventy-three out of 452 patients treated with dupilumab underwent DS. The mean time since treatment initiation was 28.6 months. Mean Eczema Area Severity Index (EASI) from the index date remained stable until the second follow-up visit (T2) 0.2-0.8 with no significant pre-post differences (P > 0.05). Similar considerations can be made for mean number rating scale worst pruritus (NRSp), numerical rating scale disturbs of sleeping/sleeping disturb (NRSsd), mean Dermatology Life Quality Index (DLQI), and EASI Head and Neck. Attainment of relative outcomes remained stable for EASI75, 90, ≤ 7, DLQI ≤ 5, and NRSp ≤ 4. When compared with cohort B, no clinically significant differences were observed in mean reductions in all outcomes analyzed. Conclusions: DS in our study appears to be an effective and safe strategy in treating patients with severe AD after the initial therapeutic response.

Alcohol abuse and discretionary habits in psoriatic patients: impact on IL-17 and IL-23 inhibitor response.

BACKGROUND: Alcohol abuse is correlated with the onset and worsening of psoriasis, but its effects, as for smoking, on biological therapies are still poorly investigated. MATERIALS AND METHODS: This study aimed to determine the prevalence of alcohol abuse and other discretionary habits (such as smoking and sedentary lifestyle) in patients with psoriasis treated with topicals, conventional systemic and biologic therapies. The second objective is to investigate the impact of discretionary habits, focusing on alcohol abuse, on the response to biological therapy. To identify alcohol dependence, the CAGE questionnaire was distributed among patients of our clinic. RESULTS: 305 patients were included with 18% at high risk of alcohol abuse. Clinically, guttate psoriasis and psoriatic arthritis were more common in patients at higher risk of alcohol abuse. Furthermore, patients with an alcohol problem who started biological therapy reported a higher PASI than those who drank less. None of the considered variables seemed to correlate with discontinuation of medication or with lower achievement of the analyzed outcomes (PASI100, PASI90, and PASI≤3). There was a stronger association between alcohol dependence and patients receiving conventional therapy than with patients receiving biologics. CONCLUSIONS: The efficacy of biologicals did not seem to be impacted by alcohol consumption, smoking, or sedentary lifestyle.

Drug Survival, Safety, and Effectiveness of Secukinumab for up to 5 Years in Patients with Psoriasis and Psoriatic Arthritis: A Long-Term Real-Life Experience.

INTRODUCTION: the selective IL-17 inhibitor secukinumab has demonstrated efficacy and safety in the treatment of moderate-severe psoriasis in recent years. OBJECTIVE: evaluate effectiveness and drug survival (DS) of secukinumab in patients with psoriasis for up to 5 years. METHODS: This is a retrospective study on a monocentric cohort of patients with psoriasis on secukinumab evaluating the achievement of PASI100, PASI90, and PASI ≤ 3 and DS analysis up to 260 weeks. DS multivariate analysis was carried out considering sex, age, age of onset of the disease, obesity, cardiovascular comorbidities, diabetes, involvement of difficult-to-treat sites, psoriatic arthritis, treatment-naïve status, and mean baseline PASI. RESULTS: At baseline, we evaluated 255 patients on secukinumab. PASI100 was reached by 41.7% and 70.6% of patients at weeks 16 and 260, respectively. PASI90 showed a similar trend with 46.5% of patients achieving it at week 16 and 88.2% at week 260. Non-obese patients showed a faster response than patients with obesity in achieving PASI100, PASI90, and PASI ≤ 3, with significant differences at 28 weeks [55% vs. 40% (p = 0.033), 64% vs. 49% (p = 0.038), and 76% vs. 62% (p = 0.036), respectively]. The estimated DS for secukinumab was 84.3% at 12 and 48% at 60 months. Obesity and smoking habits were associated with a higher risk of discontinuation in multivariate models (HR 1.6 CI 1.05-2.45, p = 0.028; HR 1.48 CI 1.01-2.17, p = 0.043, respectively). CONCLUSIONS: Secukinumab showed effectiveness for up to 5 years of treatment, with a high DS and achievement of PASI100, PASI90, and PASI < 3 at these time points. Only obesity reduced the response and maintenance of DS.

Predisposition to conjunctivitis and male sex reduces drug survival of dupilumab in adults and adolescents.

BACKGROUND: There are currently limited data on dupilumab drug survival (DS), especially on factors possibly associated with drug discontinuation. MATERIALS AND METHODS: The primary endpoint of this study is to evaluate the parameters that may determine drug discontinuation and the predictive factors associated with dupilumab DS. We considered as independent associated factors: childhood onset of disease, gender, age of onset of AD, age of initiation of dupilumab, previous use of cyclosporine, initial mean EASI, atopic family history, and predisposition to allergic conjunctivitis. RESULTS: On 413 patients DS was 94.5% at 1 year, 89.5% at 2 years, and 83.7% at 3 years, and after a mean follow-up of 40.5 months (±1.6) 53 patients had discontinued the drug permanently (12.8%). Univariate analysis showed that the only factor associated with a reduction in drug survival was a predisposition to allergic conjunctivitis (p 0.009). At multivariate Cox regression, male sex (HR, 2.34; 95% CI, 1.14-4.78; p 0.02) and predisposition to allergic conjunctivitis (HR, 2.61; 95% CI, 1.37-5.00; p 0.004) were associated with lower DS of dupilumab. CONCLUSION: Male gender and predisposition to allergic conjunctivitis are negative predictors for maintenance of response to treatment with dupilumab and consequently associated with lower DS rates.

Clinical characteristics and response to biological therapies for inverse psoriasis: a real-life comparison between the therapeutic effects of anti-IL-23 and anti-IL-17 agents.

BACKGROUND: Inverse psoriasis (IP) is a variant of plaque psoriasis involving flexor surfaces. A clear definition of IP is still lacking. Therapy is based on topical and systemic treatments, including classic systemic drugs and biologic agents, but a well-defined therapeutic strategy is absent. MATERIALS AND METHODS: This retrospective study investigated the general characteristics of patients with IP or vulgar psoriasis and compared the effectiveness of anti-interleukin-17 or anti-interleukin-23 agents in the same groups. Second, treatment effectiveness and the demographic characteristics of IP patients treated with IL-23 and IL-17 inhibitors were also compared. IP patients were included if they had specific psoriatic involvement of the axillary, inguinal, or submammary lines, breast folds, antecubital and popliteal pits, intergluteal fold, and perianal area. Patients with vulgar plaque psoriasis and concomitant intertriginous involvement were included in the vulgar psoriasis cohort. RESULTS: Patients with IP were prevalently female and treated with IL-17 inhibitors compared to those with vulgar psoriasis. They also had a greater risk of drug discontinuation and subsequent therapeutical switch (32.1% vs. 18.1%, P = 0.002). At later time points, those with IP showed progressively slower achievement of PASI100 and 90 compared to the cohort with vulgar psoriasis. In the IP cohort, there was greater joint involvement in patients treated with an anti-IL-17 agent (P = 0.011), who also had a lower median age of onset (P = 0.011) compared to patients treated with an anti-IL-23 agent. Patients with IP treated with an anti-IL-23 agent initiated with a lower mean PASI and showed a slower response than patients on an anti-IL-17 agent. At later time points, progressively greater effectiveness of IL-23 inhibitors was observed compared to IL-17 inhibitors. CONCLUSIONS: Patients with IP responded less to biologic agents than those with vulgar psoriasis. In the IP cohort, IL-17 inhibitors had a faster onset than IL-23 inhibitors, but long-term anti-IL-23 agents seem to be associated with better outcomes.

Drug survival, effectiveness, and safety of brodalumab for moderate-to-severe psoriasis up to 3 years.

BACKGROUND: Brodalumab is a monoclonal antibody and IL-17 RA inhibitor that is approved for the treatment of moderate-to-severe psoriasis. The present study aims to estimate the drug survival (DS), effectiveness, and safety of brodalumab over a period of 156 weeks. METHODS: The primary objectives were: (i) to determine the treatment response rate at Weeks 16, 28, 52, 78, 104, and 156 as defined by PASI100, PASI90, and an absolute PASI ≤ 3 and (ii) long-term DS. Secondary objectives included the evaluation of possible predictive factors associated with the achievement of response outcomes, and possible predictive factors associated with lower DS. RESULTS: The treatment response was rapid, with 80.3% of patients achieving PASI ≤ 3, 66% PASI90, and 54.3% the complete clearance of disease at Week 16. The response improved at Week 28, when a plateau was achieved with mild loss of response at later time points, in particular for PASI100 and PASI90 in 55.2 and 65.5% of patients, respectively, at Week 156. After 156 weeks of treatment, 66.22% of patients were still on therapy, and the previous use of IL-17 inhibitors appeared to be associated with an increased risk of treatment discontinuation (HR: 2.51, CI: 1.06-5.98, P = 0.037), and achievement of PASI ≤ 3 until Week 16 with less risk (HR: 0.27 CI: 0.14-0.51, P < 0.001). Bio-naïve status was favorably associated with treatment response, while high BMI negatively affected the achievement of outcomes. CONCLUSION: Our study confirms the good effectiveness and favorable safety profile of brodalumab in a real-world setting for up to 3 years of treatment.

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.

Multi-failure psoriasis patients: characterization of the patients and response to biological therapy in a multicenter Italian cohort.

INTRODUCTION: Patients with psoriasis who have failed multiple biologic drugs have been defined as "multi-failure," although there are no clear data on the characteristics, comorbidities, and best treatment strategies for this population. Nowadays, given the next generation and the number of biologics available, patients are considered multi-failure when ≥4 biologics fail to achieve a good response. METHODS: Demographic characteristics and efficacy of anti-interleukin drugs in multi-failure patients were compared to a cohort of general psoriatic patients treated with IL-23 or IL-17 inhibitors. RESULTS: In total 97 multi-failure patients (≥4 lines of biologics) were compared with 1,057 patients in the general cohort. The current drugs in the multi-failure group were risankizumab (34), ixekizumab (23), guselkumab (21), brodalumab (7), tildrakizumab (5), ustekinumab (4), secukinumab (2), and certolizumab pegol (1). A significant difference was found in the multi-failure cohort for age of psoriasis onset (mean 29.7 vs. 35.1, P < 0.001), concurrent psoriatic arthritis (45.4 vs. 26.9%, P < 0.001), diabetes mellitus (30.9 vs. 10.9%, P < 0.001), and cardiovascular comorbidity (54.6 vs. 39.8%, P = 0.005). In multi-failure patients, current biological therapy showed a good initial response (PASI 90 and 100 of 41.24 and 27.84%, respectively, at 16 weeks); the response tended to decline after 40 weeks. Anti-IL-17 agents showed clinical superiority over IL-23 agents in terms of achieving PASI90 at 28 weeks (P < 0.001) and 40 weeks (P = 0.007), after which they reached a plateau. In contrast, IL-23 agents showed a slower but progressive improvement that was maintained for up to 52 weeks. A similar trend was also seen for PASI100 (28 weeks P = 0.032; 40 weeks P = 0.121). CONCLUSIONS: The multi-failure patient is characterized by many comorbidities and longstanding inflammatory disease that frequently precedes the introduction of systemic biologic therapy. Further studies are needed to identify more specific criteria that could be applied as a guideline by clinicians.

Drug survival and clinical effectiveness of secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, tildrakizumab for psoriasis treatment.

BACKGROUND: Biologics targeting IL-23 and IL-17 show efficacy and safety in the treatment of moderate-to-severe psoriasis. OBJECTIVE: To investigate drug survival in patients with psoriasis treated with biologics. PATIENTS AND METHODS: We performed a comparative evaluation of the achievement of PASI 90 and PASI ≤ 3 at 16, 28, and 52 weeks along with a DS (drug survival) analysis with IL-17 and IL-23 inhibitors brodalumab, ixekizumab, secukinumab, risankizumab, tildrakizumab, and guselkumab on 1,057 patients. RESULTS: IL-17 inhibitors showed a faster achievement of PASI 90 and PASI ≤ 3 with significant superiority over IL-23 inhibitors at week 16 (p < 0.001; 56% vs. 42% and 70% vs. 59%, respectively). A difference was shown in favor of IL-23 inhibitors regarding DS (p < 0.001), which was 88% at 24 months vs. 75% for IL-17 inhibitors. In multivariate analysis, IL-23 inhibitors (HR 0.54 CI 0.37-0.78, p = 0.001), and male sex (HR 0.57 CI 0.42-0.76, p < 0.001) were all associated with a lower probability of drug interruption. Risankizumab (HR 0.42 CI 0.26-0.69, p = 0.001), guselkumab (HR 0.49 CI 0.24-0.99, p = 0.046), and male sex (HR 0.57 CI 0.43-0.77, p < 0.001) were associated with a lower probability of drug interruption than secukinumab. CONCLUSIONS: IL-23 inhibitors showed the best performance on DS. Overall, the most effective class was IL-17 inhibitors considering the short-term effectiveness, but long-term effectiveness is in favor of anti-IL-23.

Ocular Surface Disease in Patients With Atopic Dermatitis Treated With Dupilumab: A Prospective Case-Control Study.

PURPOSE: The aim of this study was to evaluate the variation of dry eye disease (DED) prevalence in patients with atopic dermatitis (AD) treated with dupilumab. METHODS: This prospective case-control study included consecutive patients with moderate-to-severe AD scheduled for dupilumab between May and December 2021 and healthy subjects. DED prevalence, the Ocular Surface Disease Index, tear film breakup time test, osmolarity, Oxford staining score, and Schirmer test results were collected at baseline, 1 month, and 6 months after dupilumab therapy. The Eczema Area and Severity Index was assessed at baseline. Ocular side effects and discontinuation of dupilumab were also recorded. RESULTS: Seventy-two eyes from 36 patients with AD treated with dupilumab and 36 healthy controls were included. Prevalence of DED increased from 16.7% at baseline to 33.3% at 6 months in the dupilumab group ( P = 0.001), whereas it remained unchanged in the control group ( P = 0.110). At 6 months, the Ocular Surface Disease Index and Oxford score increased (from 8.5 ± 9.8 to 11.0 ± 13.0, P = 0.068, and from 0.1 ± 0.5 to 0.3 ± 0.6, P = 0.050, respectively), the tear film breakup time test and Schirmer test results decreased (from 7.8 ± 2.6 s to 7.1 ± 2.7 s, P < 0.001, and from 15.4 ± 9.6 mm to 13.2 ± 7.9 mm, P = 0.036, respectively) in the dupilumab group, whereas they remained stable in the control group ( P > 0.05). Osmolarity was unchanged (dupilumab P = 0.987 and controls P = 0.073). At 6 months after dupilumab therapy, 42% of patients had conjunctivitis, 36% blepharitis, and 2.8% keratitis. No severe side effects were reported, and none of the patients discontinued dupilumab. No association between Eczema Area and Severity Index and DED prevalence was shown. CONCLUSIONS: DED prevalence increased in patients with AD treated with dupilumab at 6 months. However, no severe ocular side effects were found and no patient discontinued therapy.

Synchronous occurrence of primary cutaneous B-cell lymphoma and cutaneous Rosai-Dorfman disease in distinct lesions: A unique association.

Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy (SHML), is a rare subtype of reactive histiocytosis which is seldom associated with Hodgkin's and non-Hodgkin's lymphomas. To date, the coexistence in the same patient of extra nodal SHML and primary cutaneous B-cell lymphoma (PCBCL) has been reported in the literature, as metachronous diagnosis in the anatomical area of the original PCBCL or synchronous occurrence in the same lesions. However, no data have been published as for synchronous occurrence of the two pathological entities in distinct anatomical sites. Herein, we report the first ever described synchronous occurrence of PCBCL and SHML, detected in distinct lesions, affecting the same patient. The complete resolution of the patient's PCBCL after rituximab treatment and the concomitant regression of SHML suggest that this clinically benign reactive histiocytic proliferation, potentially triggered by the lymphoma microenvironment itself, may take place not only in the site of the PCBCL lesion, but also in other distant areas not directly affected by the primary cutaneous lymphoma.

Aging Impact in Response to Different Classes of Biological Treatment in Psoriatic Patients: A Real-Life Observational Study.

Over the last decade, the treatment landscape for moderate to severe psoriasis has undergone transformative changes with the advent of biotechnological drugs. Monoclonal antibodies targeting the IL-17 and IL-23 pathways have displayed remarkable clinical efficacy and safety, even among patients with complex comorbidities. These innovations have extended across various age groups within the psoriatic population. However, a scarcity of age-specific data remains regarding the efficacy and safety of these medications. Our study tries to bridge this gap by systematically presenting data obtained from the analysis of 1055 patients treated for psoriasis with anti-IL17 and anti-IL23 drugs during a 1-year period. The effectiveness and safety of anti-IL-17 and anti-IL23 drugs for moderate to severe psoriasis were assessed across four different age groups ranging from patients less than 26 years old to patients older than 65 years, divided in four year ranges. In the studied population, baseline PASI score was significantly higher in the age group of individuals over 65 years compared to those under 26 years old. Patients over 65 years also exhibited a slower rate of improvement in PASI-90 and PASI < 3 at the 16-week mark compared to other age groups. However, no clinically significant differences in treatment response were found when comparing overall responses among different age groups. In age groups older than 26 years, anti-IL17 drugs seems faster in the achievement of PASI-100 when compared to anti-IL23 drugs. This trend became more pronounced with increasing age. The investigation provides insights into treatment responses and patient characteristics, highlighting the influence of age as a significant variable in patient management.