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.

Real-life effectiveness of tildrakizumab in chronic plaque psoriasis: A 52-week multicentre retrospective study-IL PSO (Italian landscape psoriasis).

BACKGROUND: Tildrakizumab is a humanized monoclonal antibody that binds selectively the p19 subunit of interleukin-23. It is approved for treatment of moderate-severe chronic plaque psoriasis. OBJECTIVES: We conducted a 52-week retrospective study to assess the effectiveness and safety of tildrakizumab in a real-life setting. METHODS: Our retrospective study included 237 consecutive adults with moderate-to-severe plaque psoriasis, enrolled in 10 different Italian centres, treated with tildrakizumab up to Week 52. Patient characteristics, comorbidities, previous treatments and the PASI (Psoriasis Area and Severity Index) score at each visit (baseline, Week 16, Week 28 and Week 52) were retrieved from the electronic medical records. The percentages of patients achieving 75%, 90% and 100% (PASI 75, PASI 90 and PASI 100) improvement in PASI with respect to baseline PASI were registered. RESULTS: At Week 52, 90.91%, 73.55% and 58.68% of patients achieved a PASI reduction ≥75% (PASI 75), PASI 90 and PASI 100, respectively. An absolute PASI ≤ 2 was reached by 85.95% at Week 52. Compared with Phase 3 clinical trials, we observed similar rates of PASI 75/90 responses and higher percentages of patients achieving PASI 100. Patients who had not responded to previous biologic treatments and patients with cardio-metabolic comorbidities were significantly more likely to achieve PASI 100 at Week 28 and PASI 90 at Week 52. The higher body mass index did not interfere with the odds of reaching PASI 75/90/100 at each time point. No significant safety findings were recorded throughout the study, and none of the patients had to interrupt the treatment because of adverse events. CONCLUSION: Our data suggest that the efficacy of tildrakizumab for plaque psoriasis in 'real-life' clinical practice is comparable with Phase 3 clinical trials with higher percentages of patients achieving complete skin clearance (PASI 100) at Weeks 16, 28 and 52.

Real-life effectiveness and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: A 104-week multicenter retrospective study - IL PSO (ITALIAN LANDSCAPE PSORIASIS).

BACKGROUND: Guselkumab is a fully human monoclonal antibody that binds selectively to the p19 subunit of interleukin-23, which has shown efficacy in patients with previous incomplete response to ustekinumab in the NAVIGATE clinical trial. [Correction added on [28-02-2023], after first online publication: 'humanized monoclonal antibody' has been changed to 'fully human monoclonal antibody' in the preceding sentence.] OBJECTIVES: We conducted a 104-week multicenter retrospective study to assess the effectiveness and safety of guselkumab in patients affected by plaque psoriasis with an inadequate response to ustekinumab in a real-life setting. METHODS: Our retrospective study included 233 adults affected by moderate-to-severe plaque psoriasis, enrolled in 14 different Italian centres, and treated with guselkumab after failing therapy with ustekinumab. Patient characteristics and PASI (Psoriasis Area and Severity Index) score at each visit (baseline, weeks 16, 52 and 104) were recorded. The percentages of patients achieving 75%, 90% and 100% (PASI 75, PASI 90 and PASI 100) improvement in PASI, compared with baseline, were registered. RESULTS: At week 52, PASI 75 was reached by 89.88% of patients, PASI 90 by 71.43%, PASI 100 by 58.83% and absolute PASI ≤2 by 90.48%. At week 104, similar effectiveness results were observed. Compared to the NAVIGATE trial, we observed higher rates of PASI 75/90/100. Patients with the involvement of difficult-to-treat areas were significantly less likely to achieve PASI90 and PASI100 at week 16. Obese patients had significantly lower rates of PASI75 and PASI ≤2 at week 52. At week 104, comparable responses were observed among all patients' subgroups, regardless of BMI status, involvement of difficult-to-treat areas, presence of cardiometabolic comorbidities and concomitant psoriatic arthritis. No significant safety findings were reported throughout the study. CONCLUSION: Our data suggest that the efficacy of guselkumab in patients with inadequate response to ustekinumab for plaque psoriasis in 'real-life' clinical practice is comparable with NAVIGATE study with higher percentages of patients achieving PASI90 and PASI100 at weeks 16, 52 and 104.

Real life long-term efficacy and safety of ixekizumab in moderate-to-severe psoriasis: A 192 weeks multicentric retrospective study-IL PSO (Italian landscape psoriasis).

Psoriasis is one of the commonest inflammatory skin diseases determining a very high impact on patients' quality of life and daily activities and relationships. Several biologic therapies have been approved through the years for the treatment of moderate-to-severe plaque psoriasis, and efficacy and safety profile have been analyzed in clinical trials. Ixekizumab is an immunoglobulin G subclass 4 monoclonal antibody that selectively targets and binds IL-17A with high specificity and affinity. Inhibiting IL-17A activity, ixekizumab reduces and turns down levels of inflammation, resulting in the clinical improvement of the disease. Long-term efficacy and safety profile of ixekizumab have been investigated and reported in the UNCOVER trials, but in literature there are only few studies based on real life experience. We present the efficacy and safety profile of ixekizumab in a cohort of 779 patients affected by moderate-to-severe plaque psoriasis and treated with ixekizumab in 11 Italian dermatology hospitals, with a follow-up of care until 192 weeks.

Real-world evidence of biologic treatments in moderate-severe psoriasis in Italy: Results of the CANOVA (EffeCtiveness of biologic treAtmeNts for plaque psOriasis in Italy: An obserVAtional longitudinal study of real-life clinical practice) study.

EffeCtiveness of biologic treAtmeNts for plaque psOriasis in Italy: An obserVAtional (CANOVA) study was aimed at providing real-world evidence of the effectiveness of biologics in Italian patients with moderate-severe psoriasis. It was an observational, retro-prospective cohort study conducted in 17 Italian dermatology clinics. Adult patients with moderate-severe plaque psoriasis, who started a biologic treatment between 24 weeks and 24 months before enrolment, were included. With a follow-up visit at 6 months after enrolment, each patient had at least 12 months of observation. The primary objective was to describe the clinical response rates (PASI 75) after 16/24/52 weeks from biologic treatment start. Secondary outcomes were sustained response, quality of life, and treatment satisfaction. Of the 669 eligible patients (64% males), 52% were naïve to biologics, though a mean duration of psoriasis since first diagnosis of 18.6 years (SD 13.2). The most frequently prescribed biologics were secukinumab (41%), ustekinumab (25%), TNF-inhibitors (22%) and ixekizumab (12%). PASI 75 was achieved by 86% of patients (95% CI: 82%-89%) at 16 weeks, 90% (87%-93%) at 24 weeks, and 91% (89%-94%) at 52 weeks. Patients achieving PASI 90 and PASI 100 at 52 weeks were 75% (71%-79%) and 53% (49%-57%), respectively. Sustained PASI 75 response after 1 year from treatment start was achieved by 78% (74%-82%) of patients. Mean DLQI total score was 2.3 (SD 3.9) at enrollment and decreased at the final visit to 1.8 (3.6). A high level of treatment satisfaction was expressed by patients over the study period. This large real-world study confirms in the clinical practice the good effectiveness and acceptability of biologics in psoriasis patients.

Incidence rates of hospitalization and death from COVID-19 in patients with psoriasis receiving biological treatment: A Northern Italy experience.

INTRODUCTION: Whether biologic therapies enhance the risk of coronavirus 2019 (COVID-19) or affect the disease outcome in patients with chronic plaque psoriasis remains to be ascertained. OBJECTIVE: We sought to investigate the incidence of hospitalization and death for COVID-19 in a large sample of patients with plaque psoriasis receiving biologic therapies compared with the general population. METHODS: This is a retrospective multicenter cohort study including patients with chronic plaque psoriasis (n = 6501) being treated with biologic therapy and regularly followed up at the divisions of dermatology of several main hospitals in the Northern Italian cities of Verona, Padua, Vicenza, Modena, Bologna, Piacenza, Turin, and Milan. Incidence rates of hospitalization and death per 10,000 person-months with exact mid-p 95% CIs and standardized incidence ratios were estimated in the patients with psoriasis and compared with those in the general population in the same geographic areas. RESULTS: The incidence rate of hospitalization for COVID-19 was 11.7 (95% CI, 7.2-18.1) per 10,000 person-months in patients with psoriasis and 14.4 (95% CI, 14.3-14.5) in the general population; the incidence rate of death from COVID-19 was 1.3 (95% CI, 0.2-4.3) and 4.7 (95% CI, 4.6-4.7) in patients with psoriasis and the general population, respectively. The standardized incidence ratio of hospitalization and death in patients with psoriasis compared with those in the general population was 0.94 (95% CI, 0.57-1.45; P = .82) and 0.42 (95% CI, 0.07-1.38; P = .19), respectively. CONCLUSIONS: Our data did not show any adverse impact of biologics on COVID-19 outcome in patients with psoriasis. We would not advise biologic discontinuation in patients on treatment since more than 6 months and not infected with severe acute respiratory syndrome coronavirus 2 to prevent hospitalization and death from COVID-19.

Can intermittent, time-restricted circadian fasting modulate cutaneous severity of dermatological disorders? Insights from a multicenter, observational, prospective study.

The impact of intermittent circadian fasting (ICF) on skin disorders is far to be plenty deciphered. However, the circadian rhythm seems to exert a modulation on dermatoses severity, drug-response, and drug-related side effects. We aimed to evaluate ICF effect in the daily management of dermatological diseases. In this multicenter, prospective observational study we enrolled patients willing to undergo the 2018 ICF (from May 16 to June 14). Dermatoses severity were evaluated at the beginning of ICF (T0) and at the end of ICF (T1) by two independent board-certified dermatologists. Seventy-two patients suffering from different dermatoses volunteered to take part into the study. They displayed a mean age of 40.38 ± 12.46 years (median 41.0 years), 25 subjects were males (34.7% of the entire sample). The median weight change was 0 kg. The overall ICF effect size was -0.58 ([95% CI -0.83 to -0.33], P < .0001, medium effect size). Since in the present investigation no weight loss occurred, we could speculate that the impact of fasting in terms of improvements in the clinical symptoms could be rather due to the perturbation of the human biological clock. Despite our data remain preliminary, a chronobiological approach should be incorporated in the dermatological armamentarium.

Real-life Effectiveness and Safety of Risankizumab in Moderate-to-severe Plaque Psoriasis: A 40-week Multicentric Retrospective Study.

Risankizumab is a humanized monoclonal antibody that binds the p19 subunit of interleukin-23. It is approved for treatment of moderate-severe chronic plaque psoriasis. This retrospective study included 66 consecutive adults with moderate-to-severe psoriasis vulgaris treated with risankizumab in monotherapy up to week 40 in a "real-life" setting. At week 40, 98.7%, 85.7% and 62.3% of patients achieved a Psoriasis Area and Severity Index (PASI) reduction ≥ 75% (PASI 75), PASI 90 and PASI 100, respectively. Patients who had not responded to 2 or more previous biologic treatments were significantly less likely to achieve PASI 75/90 at week 16 and PASI 90/100 at week 40 compared with those who had been previously treated with only 1 biologic, and compared with those treated with risankizumab as a first-line biologic. Increasing body mass index decreased the chances of reaching PASI 90 at week 40. No significant safety findings were recorded throughout the study, and none of the patients had to interrupt the treatment. These data suggest that the efficacy of risankizumab for plaque psoriasis in "real-life" clinical practice could differ from pivotal clinical trials data.

A real-world economic analysis of biologic therapies for moderate-to-severe plaque psoriasis in Italy: results of the CANOVA observational longitudinal study.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease which can also involve joints. It is often associated with burdensome comorbidities which negatively impact prognosis and quality of life (QoL). Biologic agents have been shown to be effective in controlling disease progression, but their use is associated with higher costs compared with traditional systemic treatments. The economic analysis of the CANOVA (EffeCtiveness of biologic treAtmeNts for plaque psOriasis in Italy: an obserVAtional longitudinal study of real-life clinical practice) study aims to assess the costs and cost-effectiveness of biologics in a real-world context in Italy. METHODS: The annualised overall direct costs of moderate-to-severe plaque psoriasis management, the annualised cost of biologic drugs and the cost per responder in the Italian National Health System perspective were assessed. More specifically, the cost per response and cost per sustained response of the most prescribed biologic therapies for the treatment of moderate-to-severe plaque psoriasis within the CANOVA study were assessed using the Psoriasis Area Severity Index (PASI) at several score levels (75, 90 and 100%). RESULTS: The most frequently used biologic therapies for plaque psoriasis were secukinumab, ustekinumab, adalimumab originator, and ixekizumab. Cost of biologics was the driver of expenditure, accounting for about 98% of total costs. Adalimumab originator was the biologic with the lowest cost per responder ratio (range: €7848 - €31,378), followed by secukinumab (range: €9015 - €33,419). Ustekinumab (range: €11,689 - €39,280) and ixekizumab (range: €11,092 - €34,289) ranked respectively third and fourth, in terms of cost-effectiveness ratio. As concerns the cost per sustained response analysis, secukinumab showed the lowest value observed (€21,375) over the other options, because of its high response rate (86% vs. 60-80%), which was achieved early in time. CONCLUSION: Biologic therapy is a valuable asset for the treatment of moderate-to-severe plaque psoriasis. Concomitant assessment of treatment costs against the expected therapeutic response over time can provide physicians and payers additional insights which can complement the traditional risk-benefit profile assessment and drive treatment decisions.

Biologics increase the risk of SARS-CoV-2 infection and hospitalization, but not ICU admission and death: Real-life data from a large cohort during red-zone declaration.

During COVID-19 outbreak there are discordant opinions toward the impact of biologics in psoriatic (PsO) patients. Thus we performed a single-center case-control study in Lombardia, the Italian region with the higher number of COVID-19 confirmed cases. We enrolled 1193 PsO patients treated with biologics and small molecules and we used the entire Lombardia population as controls. Notably, 17 PsO patients COVID-19 confirmed were quarantined at home and five hospitalized, no PsO patients were admitted to intensive care unit (ICU) or died. With respect to the general population of Lombardy, patients on biologics were at higher risk to test positive for COVID-19 (odds ratio [OR] 3.43 [95% confidence interval (CI) 2.25-5.73], P < .0001), to be self-quarantined at home (OR 9.05 [95% CI 5.61-14.61], P < .0001) and hospitalized (OR 3.59 [95% CI 1.49-8.63], P = .0044), however, not increased risk of ICU admission or death were found. PsO patients on biologics should be carefully monitored with telemedicine during COVID-19 outbreak and early treated at home to limit hospital overwhelm.

COVID-19 knowledge prevents biologics discontinuation: Data from an Italian multicenter survey during RED-ZONE declaration.

SARS-CoV-2 become pandemics and there is still a dearth of data about its the potentially among dermatological patients under biologics. We aimed to assess health literacy, disease knowledge, treatment dissatisfaction and biologics attitudes toward COVID-19. We performed a cross-sectional, questionnaire-based survey on 98/105 consecutive dermatological patients treated with biologics-51 suffering from plaque psoriasis, 22 from atopic dermatitis, and 25 from hidradenitis suppurativa. An ad hoc, validated questionnaire has 44 items investigating the following domains: knowledge of COVID-19 related to (a) epidemiology, (b) pathogenesis, (c) clinical symptoms, (d) preventive measures, and (e) attitudes. Patients data and questionnaires were collected. Despite only 8.1% thought that biologics may increase the risk of COVID-19, 18.4% and 21.4% of the patients were evaluating the possibility to discontinue or modify the dosage of the current biologic therapy, respectively. Globally, male patients (P = .001) with higher scholarity level (P = .005) displayed higher knowledge of COVID-19. Patients with lower DLQI (P = .006), longer disease duration (P = .051) and lower scholarity (P = .007) have thought to discontinue/modify autonomously their biologic therapy. At the multivariate logistic regression, only the knowledge of epidemiology and preventive measures resulted independent predictors of continuation vs discontinuation and modification vs no modification, respectively. Dermatologists should promote COVID-19 knowledge to prevent biologics disruption.

Predicting Secukinumab Fast-Responder Profile in Psoriatic Patients: Advanced Application of Artificial-Neural-Networks (ANNs).

BACKGROUND: Drug resistance to biologics in psoriasis therapy can occur – it may be acquired during a treatment or else present itself from the beginning. To date, no biomarkers are known that may reliably guide clinicians in predicting responsiveness to biologics. Biologics may pose a substantial economic burden. Secukinumab efficiently targets IL-17 in the treatment of psoriasis. OBJECTIVE: To assess the “fast responder” patient profile, predicting it from the preliminary complete blood count (CBC) and clinical examination. MATERIALS AND METHODS: From November 2016 to May 2017 we performed a multicenter prospective open label pilot study in three Italian reference centers enrolling bio-naive plaque psoriasis patients, undergoing the initiation phase secukinumab treatment (300mg subcutaneous at week 0,1,2,3,4). We define fast responders as patients having achieved at least PASI 75 at the end of secukinumab induction phase. Clinical and CBC data at week 0 and at week 4 were analyzed with linear statistics, principal component analysis, and artificial neural networks (ANNs), also known as deep learning. Two different ANNs were employed: Auto Contractive Map (Auto-CM), an unsupervised ANNs, to study how this variables cluster and a supervised ANNs, Training with Input Selection and Testing (TWIST), to build the predictive model. RESULTS: We enrolled 23 plaque psoriasis patients: 19 patients were responders and 4 were non-responders. 30 attributes were examined by Auto-CM, creating a semantic map for three main profiles: responders, non-responders and an intermediate profile. The algorithm yielded 5 of the 30 attributes to describe the 3 profiles. This allowed us to set up the predictive model. It displayed after training testing protocol an overall accuracy of 91.88% (90% for responders and 93,75% for non-responders). CONCLUSIONS: The present study is possibly the first approach employing ANNs to predict drug efficacy in dermatology; a wider use of ANNs may be conducive to useful both theoretical and clinical insight. J Drugs Dermatol. 2020;19(12) doi:10.36849/JDD.2020.5006.

From randomized clinical trials to real life data. An Italian clinical experience with ixekizumab and its management.

Interleukin(IL)-17 inhibitors display higher efficacy than both TNFi and IL-12/23i, which increased the goal psoriasis area severity index (PASI) from 75 to PASI 90 or even PASI 100. Ixekizumab, a recombinant, humanized IgG4 monoclonal antibody targeting IL-17A displayed a high efficacy and safety in RCTs, namely UNCOVER-2 and UNCOVER-3. However, few studies examined real-life data for these medications, and those which exist highlight discrepancies in efficacy and safety between RCTs and real-life data, likely due to the heterogeneity of patients treated outside of trials. Thus, we performed a single center large prospective observational study (RLSD) that enrolled 47 psoriatic patients followed for 20 weeks and we compared the obtained data with the UNCOVER studies. At week 20 in RLSD versus UNCOVER-3 both PASI-90 and PASI-100 results were similar, whilst at week 12, the RLSD cohort obtained higher PASI 90 (76 vs 69,3%) and PASI-100 (55 vs 39%) than UNCOVER cohorts. Interestingly we also reported higher injection-site related pain that disappeared after week 12. In conclusion, real-life data together with RCTs contribute to enrich the information background available to dermatologists in daily practice.

When IL-17 inhibitors fail: Real-life evidence to switch from secukinumab to adalimumab or ustekinumab.

Psoriasis is a chronic, systemic inflammatory disease that in the moderate to severe forms may benefit of biologics, namely TNF and IL-12/23 and IL-17 inhibitors. Loss of response, lack of response, or discontinuation due to adverse events represent a concrete therapeutic challenge for dermatologists that have to switch patients to other treatments. Although some evidences already exist toward the switch from IL-12/23 and TNF inhibitors to IL-17 inhibitors, conversely nothing is present toward the switch from IL-17 inhibitors to IL-12/23 and TNF inhibitors. We performed a real-life study enrolling 50 patients randomly switched to adalimuamb, a TNF inhibitor, or ustekinumab, an IL-12/23 inhibitor. Our observational study suggests that switching from IL-17i to TNFi and IL-12/23i is a safe and effective therapeutic strategy.

Switching from Secukinumab to Ustekinumab in Psoriasis Patients: Results from a Multicenter Experience.

BACKGROUND: Switching between biologics is commonly performed for the management of plaque psoriasis. However, no evidence about switching from secukinumab to ustekinumab has been reported. METHODS: This retrospective observational multicenter study aimed to describe efficacy and safety of ustekinumab in secukinumab nonresponder patients. RESULTS: A total of 21 patients unresponsive to secukinumab were treated with ustekinumab for a mean period of 53.3 weeks. Ustekinumab was effective in reducing disease severity, with significant improvements of both psoriasis area severity index (PASI) and dermatology quality of life index (DLQI) scores. PASI score improvements of 31.8, 44, 77.8, 80.3, 80.5, and 89.6%, at week 4, 12, 24, 36, 48, and above 60 weeks, respectively, were detected (p < 0.05), achieving PASI 50, 75, and > 90 responses in 93.8, 87.5, and 50% of patients at week 48. Four patients withdrew from ustekinumab treatment because of inefficacy, and failure of multiple biologic agents (> 2) seemed to affect ustekinumab drug survival. No serious adverse events (AEs) were reported while 38.1% of patients experienced mild AEs. CONCLUSION: Ustekinumab was safe and effective in treating patients unresponsive to secukinumab.

IL12B (p40) Gene Polymorphisms Contribute to Ustekinumab Response Prediction in Psoriasis.

BACKGROUND: Psoriasis is characterized by multiple genetic variations. Some of these variations, such as the presence of HLA-Cw6 or TNFAIP3 single-nucleotide polymorphisms (SNPs), have been correlated to the response to biologic treatments. OBJECTIVE: The aim of our study was to evaluate the effects of IL12B and IL6 SNPs on the response to ustekinumab. METHODS: We retrospectively analyzed the genotypes of 64 patients who had been treated with ustekinumab for up to 1 year. Efficacy data were evaluated using 'intention to treat-last observation carried forward' analysis. RESULTS: We confirmed the positive role of HLA-Cw6 as a predictor of the response to ustekinumab and discovered that presence of the GG genotype on the IL12B rs6887695 SNP and absence of the AA genotype on the IL12B rs3212227 SNP significantly increase the probability of therapeutic success in HLA-Cw6 positive patients. CONCLUSIONS: The availability of pharmacogenetic data will influence therapeutic decisions in the clinical management of psoriatic patients.