Dupilumab therapy of atopic dermatitis of the elderly: a multicentre, real-life study.

BACKGROUND: Treatment of moderate-to-severe atopic dermatitis (AD) in the elderly may be challenging, due to side-effects of traditional anti-inflammatory drugs and to comorbidities often found in this age group. Furthermore, efficacy and safety of innovative drugs such as dupilumab are not yet well known. OBJECTIVES: A multicentre retrospective, observational, real-life study on the efficacy and safety of dupilumab was conducted in a group of patients aged ≥65 years and affected by severe AD. Their main clinical features were also examined. METHODS: Data of elderly patients with severe (EASI ≥24) AD treated with dupilumab at label dosage for 16 weeks were retrospectively collected. Treatment outcome was assessed by comparing objective (EASI) and subjective (P-NRS, S-NRS and DLQI) scores at baseline and after 16 weeks of treatment. RESULTS: Two hundred and seventy-six patients were enrolled in the study. They represented 11.37% of all patients with severe AD. Flexural eczema was the most frequent clinical phenotype, followed by prurigo nodularis. The coexistence of more than one phenotype was found in 63/276 (22.82%) subjects. Data on the 16-week treatment with dupilumab were available for 253 (91.67%) patients. Efficacy of dupilumab was demonstrated by a significant reduction of all the scores. No statistically significant difference regarding efficacy was found in elderly patients when compared to the group of our AD patients aged 18-64 years, treated with dupilumab over the same period. Furthermore, only 18 (6.52%) patients discontinued the drug due to inefficacy. Sixty-one (22.51%) patients reported adverse events, conjunctivitis and flushing being the most frequent. One (0.36%) patient only discontinued dupilumab due to an adverse event. CONCLUSIONS: Therapy with dupilumab led to a significant improvement of AD over a 16-week treatment period, with a good safety profile. Therefore, dupilumab could be considered as an efficacious and safe treatment for AD also in the elderly.

Response to IL-17A inhibitors secukinumab and ixekizumab cannot be explained by genetic variation in the protein-coding and untranslated regions of the IL-17A gene: results from a multicentre study of four European psoriasis cohorts.

BACKGROUND: Genetic predictors for treatment response could optimize allocation of biological treatment in patients with psoriasis. There is minimal knowledge about pharmacogenetics of anti-IL-17 agents. OBJECTIVES: To assess whether genetic variants in the protein-coding region or untranslated regions of the IL-17A gene are associated with response to IL-17A inhibitors in patients with psoriasis. METHODS: This was a multicenter European cohort study investigating pharmacogenetics of IL-17A inhibitors in patients with psoriasis. Patients with plaque psoriasis treated with secukinumab or ixekizumab in daily practice were included. For all participants, the protein-coding region and untranslated regions of the IL-17A gene were analysed using Sanger sequencing. Identified genetic variants were tested for association with response to secukinumab/ixekizumab, measured as ∆PASI, after 12 weeks (primary outcome) and after 24 weeks (secondary outcome). Association was tested using a linear regression model with correction for baseline PASI as a fixed covariate and for biological naivety and body mass index as additional covariates. RESULTS: In total, 134 patients treated with secukinumab or ixekizumab were included. Genotyping of the cohort identified genetic variants present in untranslated regions and intronic DNA, but not in the protein-coding region of the IL-17A gene. Five genetic variants in non-coding DNA with a known or suspected functional effect on IL-17A expression were selected for association analyses: rs2275913, rs8193037, rs3819025, rs7747909 and rs3748067. After 12 weeks, 62% of patients achieved PASI75 and 39% achieved PASI90. At week 24, PASI75 and PASI90 response rates were 72% and 62%, respectively. No associations were found between the five genetic variants and ∆PASI, PASI75 or PASI90 after 12 and 24 weeks of anti-IL-17A treatment. CONCLUSIONS: Response to IL-17A inhibitors secukinumab and ixekizumab cannot be explained by genetic variation in the protein-coding and untranslated regions of the IL-17A gene. Pharmacogenetics of IL-17A inhibitors in the treatment of psoriasis requires further exploration.

Psoriasis Area and Severity Index response in moderate-severe psoriatic patients switched to adalimumab: results from the OPPSA study.

BACKGROUND: Few studies have compared the efficacy of switching to adalimumab in the real-life setting in plaque psoriasis patients. OBJECTIVE: To evaluate the effect of adalimumab in psoriasis patients previously treated with other biologics. METHODS: In this multicentre study, psoriasis patients (N = 262) treated with an anti-TNF-alpha agent, ustekinumab or naïve to biologics then switched to adalimumab were included. Disease severity was assessed by the Psoriasis Area and Severity Index (PASI) at baseline and after 3, 6, 12, 24 and 36 months. The association between clinical risk factors and achievement of PASI response was evaluated by logistic regression. RESULTS: Adalimumab treatment resulted in a decrease in PASI (15.1 ± 6.2 at baseline vs. 2.7 ± 4.8 at 6 months, P < 0.0001), regardless of previous biologic treatment. Furthermore, adalimumab allowed 92.5%, 79% and 56% of patients to achieve PASI response (PASI 50, 75 and 90, respectively) and complete remission (PASI 100 response) in 48.4% of patients, by 6 months and maintained over 3 years, independent of prior biologic treatment. The absence of metabolic syndrome, dyslipidemia, hypertension and lower PASI and lower age at baseline was associated with achievement of PASI response at 3, 6 and 12 months, whereas at later time points (24 and 36 months), PASI 90 and PASI 100 response was associated with diagnosis of psoriasis/psoriatic arthritis. CONCLUSION: Adalimumab was effective at reducing PASI score over 3 years, irrespective of whether patients were biologic naïve or previously treated with a TNF-alpha or IL-12/23 inhibitor.

Role of the HLA-C*06 allele in clinical response to ustekinumab: evidence from real life in a large cohort of European patients.

BACKGROUND: Little is known about the role of the HLA-C*06 allele in the response to psoriasis treatments. OBJECTIVES: To confirm the role of HLA-C*06 as a pharmacogenetic marker of response to ustekinumab in a new, large cohort of patients involving four European centres. METHODS: In this retrospective multicentre study we reviewed data of 255 patients with psoriasis genotyped for HLA-C*06 who started ustekinumab treatment between January 2014 and March 2015. The severity of psoriasis and response to treatment were evaluated using the Psoriasis Area and Severity Index (PASI) score at baseline and then at follow-up visits on weeks 4, 12, 28, 40 and 52. The primary end point was the proportion of patients achieving ≥ 50% reduction in PASI score (PASI 50) at week 4. A ≥ 75% reduction in PASI score (PASI 75) and a ≥ 90% reduction in the PASI score (PASI 90) after 12 weeks were secondary end points. RESULTS: At week 4, PASI 50 was seen in 71·7% of HLA-C*06-positive (C*06POS) and 35·2% of HLA-C*06-negative (C*06NEG) patients. At week 12, PASI 75 was reached by 69.1% of C*06POS patients and 40·5% of C*06NEG patients. After 52 weeks, PASI 75 was reached by 83.7% of C*06POS patients and 58.8% of C*06NEG patients. CONCLUSIONS: The results from our new, large cohort of European patients treated with ustekinumab in daily clinical practice confirm the role of HLA-C*06 as a potential predictor of response to ustekinumab.

Italian guidelines on the systemic treatments of moderate-to-severe plaque psoriasis.

Psoriasis is a common disease, which has a considerable impact on the healthcare system. Therefore, appropriate use of therapeutic resources is very important. Management of psoriasis in daily clinical practice is highly variable because many issues are still debated and not definitely addressed by the evidence-based medicine. Moreover, the different availability and reimbursability of drugs in each country justifies national guidelines. Expert consensus can provide helpful guidelines for optimizing patient care. A total of 20 dermatologists from different areas of Italy and with large experience in the treatment of psoriasis agreed to participate in the guidelines expert panel who aimed to reach consensus on the factors influencing psoriasis severity, the indications for systemic treatments, the parameters to be considered in the choice of treatment, and the factors to be considered in the choice of biological treatment. The recommendations for the use, screening and monitoring of systemic therapies were based on the 2015 S3 European Dermatology Forum/European Academy of Dermatology and Venereology psoriasis guidelines. Recommendations on the treatment of psoriasis in special patient populations were also agreed. The final document was discussed in a meeting moderated by a facilitator with participation of the entire group and adopting a nominal group technique to reach consensus. A statement was regarded as consented when agreement was achieved by at least 75% of the voting experts according to the Delphi procedure.

Pharmacogenetics of psoriasis: HLA-Cw6 but not LCE3B/3C deletion nor TNFAIP3 polymorphism predisposes to clinical response to interleukin 12/23 blocker ustekinumab.

BACKGROUND: Our understanding of the genetic basis of predisposition to psoriasis is increasing exponentially due to the progress of genetic studies. However, so far little is known about genetic predisposition in relation to the response to psoriasis treatments. Recent data identified genetic predictors for the clinical outcome of conventional treatments such as methotrexate, acitretin and vitamin D derivatives, but few studies are available on genetic predictors of response to biologics. We hypothesized that genetic variations associated with increased risk of developing psoriasis may also act as predictors for the outcome of biologic therapy. OBJECTIVES: The aim of our study was to analyse the presence of three different psoriasis susceptibility genetic variations (HLA-Cw6; TNFAIP3 rs610604 polymorphism; LCE3B/3C gene deletions) in a cohort of patients affected by moderate to severe psoriasis under ustekinumab treatment. Our primary endpoint was to evaluate the association between Psoriasis Area and Severity Index (PASI) 75 response at week 12 and HLA-Cw6 status. METHODS: Fifty-one patients were genotyped by standard methods and psoriasis severity (PASI score) was evaluated at day 0 and after 4, 12, 24 and 40 weeks of treatment. RESULTS: We observed increased response to ustekinumab in Cw6-positive (Cw6POS) patients [PASI 75 at week 12: 96·4% in Cw6POS vs. 65·2% in Cw6-negative (Cw6NEG) patients; P = 0·008]. In addition, we show that HLA-Cw6POS patients responded faster to ustekinumab, 89·3% of them reaching PASI 50 at week 4, after a single injection (vs. 60·9% of HLA-Cw6NEG patients). The superior response of HLA-Cw6POS patients was maintained throughout the study period, reaching the highest statistical significance for PASI 75 at week 28 (96·35% Cw6POS vs. 72·7% Cw6NEG; odds ratio 9·8). Analysis of TNFAIP3 rs610604 polymorphism and LCE3B/3C gene deletions did not show any significant association with response to ustekinumab. CONCLUSIONS: Our observations underline the role of HLA-Cw6 not only as a psoriasis susceptibility gene, but also as a pharmacogenetic marker of response to ustekinumab in psoriasis.

Laparoscopic ischemic conditioning of the stomach prior to esophagectomy.

Several complications after esophagectomy with gastric pull-up are associated with ischemia within the gastric conduit. The aim of this study is to assess the feasibility of laparoscopic ischemic preconditioning of the stomach prior to thoracotomy, esophagectomy, and gastric pull-up with an intrathoracic anastomosis. A retrospective review of 24 consecutive patients between October 2008 and July 2011 with esophageal adenocarcinoma (stage I-III) undergoing laparoscopic gastric ischemic conditioning prior to esophagectomy was conducted. Conditioning included laparoscopic ligation of the left and short gastric arteries, celiac node dissection, and jejunostomy tube placement. Formal resection and reconstruction was then performed 4-10 days later. Of the 24 patients, 88% received neoadjuvant chemotherapy/radiation therapy. Twenty-three of the 24 patients underwent successful laparoscopic ischemic conditioning and subsequent esophagectomy. Total mean number of lymph nodes harvested was 21.8 (±8.0), and a mean of 5.3 (±2.4) celiac lymph nodes identified. There were no conversions to an open procedure. Length of stay was 3.8 (±4.8) days with a median length of stay of 2 (1-24) days. Three patients experienced anastomotic leak, six patients experience delayed gastric emptying, and two patients developed anastomotic stricture. There were no surgical site infections. R0 resection was achieved in all patients who underwent laparoscopic ischemic conditioning followed by esophagectomy. Laparoscopic ischemic conditioning of the gastric conduit has been shown to be feasible and safe.

Evaluation of clinical and ultrasonographic parameters in psoriatic arthritis patients treated with adalimumab: a retrospective study.

OBJECTIVES: The aim of this study was to evaluate clinical and US-PD parameters in PsA during adalimumab treatment. METHODS: A retrospective study has been conducted in forty patients affected by moderate-to-severe peripheral PsA. Clinical, laboratory, and US-PD evaluations were performed at baseline, after 4, 12, and 24 weeks of treatment. They included erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), visual analogue scale (VAS), Health Assessment Questionnaire (HAQ) modified for Spondyloarthritis, Psoriasis Area Severity Index (PASI) score, the 28-joint Disease Activity Score (DAS 28), and US-PD assessment. US-PD findings were scored according to a semiquantitative scale (ranging 0-3) for synovial proliferation (SP), joint effusion (SE), bone erosions (BE), and PD. RESULTS: Data obtained for clinical, laboratory findings and US-PD evaluation showed statistical significant improvement in all the measures performed except for BE. A significant parallel decrease in SE, SP, and PD values were demonstrated. CONCLUSION: This study demonstrated that US-PD is a valid technique in monitoring the response to adalimumab in moderate-to-severe PsA.

Patients with moderate to severe plaque psoriasis: one year after the European Medicines Agency recommendation of efalizumab suspension.

BACKGROUND: In February 19, 2009, the European Medicines Agency (EMA) had recommended the suspension of the marketing authorization for efalizumab after the occurrence of cases of progressive multifocal leukoencephalopathy. OBJECTIVE: To explore the efficacy of alternative therapies for psoriasis and the health status of patients who discontinued efalizumab. METHODS: An observational study was performed on 101 patients. After the EMA communication, efalizumab was discontinued in the following 2-3 months. In agreement with the patients, we decided to either prescribe other treatments or none at all. RESULTS: After 1 year, 11 patients are still not treated, 63 patients are treated with biologics, and 9 patients are treated with systemic conventional therapies. CONCLUSION: In order to prevent rebound or relapse, various approaches are available, including cyclosporine, methotrexate and biologic therapies. Interestingly, in 11 out of 31 patients who did not receive any systemic drug, psoriasis is still under control, suggesting a long-term effect of efalizumab.

The effects of bevacizumab on postoperative complications in patients undergoing colorectal and pancreatic cancer resection.

Bevacizumab (Avastin™; rhuMab VEGF), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has seen increased use in the perioperative treatment of colorectal and pancreatic cancer. Little is known, however, regarding its impact on surgical outcomes in patients undergoing resection. The objective of this review was to examine if the addition of bevacizumab to existing neoadjuvant regimens increases morbidity after cancer resection.

Continuous treatment of plaque-type psoriasis with etanercept: an observational long-term experience.

To assess the long-term efficacy and safety profile and the patient-reported outcomes (PRO) in patients with moderate-to-severe plaque-type psoriasis receiving continuous etanercept treatment. An open-label study was conducted to evaluate etanercept as long-term treatment for moderate-to-severe plaque psoriasis. Continuous therapy was administered at a dose of 50 mg subcutaneously twice weekly for 12 weeks followed by a continuous treatment with 50 mg subcutaneously once weekly or 25 mg twice weekly throughout a 96-week study. The primary measure of efficacy was the proportion of patients with PASI 75 at week 24, 48 and 96. Patient-reported outcomes (PRO) were also assessed during the study, at week 24, 48 and 96, including the Dermatology Life Quality Index (DLQI) and the Psoriasis Disability Index (PDI). At baseline, mean PASI score, DLQI and PDI for patients eligible to initiate treatment with etanercept showed significant disease severity, quality-of-life impairment and psoriasis-related disability. At week 96, patients showed statistically significant and meaningful improvements. The continuous etanercept regimen provided a consistent improvement in both clinical disease parameters and PRO measures.

The impact of methodological approaches for presenting long-term clinical data on estimates of efficacy in psoriasis illustrated by three-year treatment data on infliximab.

BACKGROUND: Psoriasis affects about 2-3% of the Caucasian population. Biologics such as infliximab, etanercept, adalimumab and ustekinumab are efficacious treatments of plaque-type psoriasis. Critical to monitoring drug efficacy and safety is availability of long-term data. Despite the chronic nature of psoriasis, to date limited long-term clinical data have been available, as challenges are inherent in conducting a long-term analysis. With increasing time, it is more likely that the number of patients discontinuing treatment will also increase, due to loss of efficacy, adverse events or loss to follow-up. Interpretation of these data becomes confounded when one must consider missing data. Several approaches to analysing long-term data exist, and each accounts for missing data differently. OBJECTIVE: To demonstrate that the choice of a particular analysis method to account for missing data has great impact on the assessed response rate. METHODS: We used data from an open-label study over 3 years of continuous treatment with infliximab in patients with plaque-type psoriasis. These data were analysed by three methods--last observation carried forward, observed values and non-responder imputation--to account for missing data. RESULTS: The 3-year PASI 75 responses varied from 41 to 75%, depending on the method of analysis; this shows that the response rate can almost double when a more liberal analytical approach is used. CONCLUSIONS: While it is clear that the need for long-term data on biologics in psoriasis is great, considering the analysis undertaken is important when designing long-term studies and interpreting the resulting data. When analysis methods such as observed values only or last observation carried forward are used, the results of the more conservative non-responder imputation should also be presented to give a fair overview of the long-term efficacy of a treatment for plaque-type psoriasis.

Ustekinumab treatment for moderate-to-severe plaque psoriasis: eight-year real-life experience.

Background: Limited information is available from real-life studies evaluating the long-term efficacy and drug retention of ustekinumab.Research design and methods: Data from 378 patients with moderate-severe psoriasis were retrospectively analyzed. Over 8 years, disease severity and treatment response were evaluated using the PASI score. Predictors of PASI response were evaluated by logistic regression. Ustekinumab retention rate was calculated by the Kaplan-Meier method.Results: Over the 8 years, >80% of patients achieved a PASI score of <3 and PASI 75, 90 and 100 response was achieved in 76.2%, 61.9% and 57.1% of patients, respectively. Predictor variables for improved PASI response (after 2 years) were HLA-C*06-POS patients, female gender and BMI <30 Kg/M2. The 2-year retention rate was 81% and 59% after 8 years with mean retention rate of 5.4 years. Improved retention rate was observed in patients positive for the HLA-C*06 allele (3.7 vs. 2.5 years, p = 0.005) and female gender (3.7 vs. 3.3 years, p = 0.06), with no significant difference observed in other patient groups. Ustekinumab was generally well tolerated without evidence of cumulative toxicity or organ toxicity.Conclusion: The long-term use of ustekinumab was observed to be effective and safe in patients with moderate-severe chronic psoriasis in a real world-setting.

Clinical and histopathological characterization of eczematous eruptions occurring in course of anti IL-17 treatment: a case series and review of the literature.

Background: Real-life data often highlight the side effects of certain drugs not previously reported in randomized controlled trials (RCTs).Objective: To describe cutaneous inflammatory eruptions in psoriatic patients treated with an anti IL-17A agent (secukinumab or ixekizumab).Methods: Retrospective analysis of a cohort of patients with chronic plaque psoriasis who started an anti IL-17A agent between September 2016-February 2019 and who developed cutaneous inflammatory eruptions during treatment. A systematic review of similar events reported in the literature was performed.Results: Data of 468 patients were reviewed and 27 cutaneous inflammatory eruptions of 27 (5.8%) patients were collected. The eruptions appeared after a mean of 16.9 ± 17.0 weeks of therapy showing a classical acute eczema in 11 patients (40.7%), an atopic dermatitis-like rash in 11 patients (40.7%) and a psoriasiform eruption in 5 patients (18.5%). Histopathology of 12/27 cases showed epidermal spongiosis in all these variants.Conclusion: We described the clinic-pathologic features of some eczematous eruptions occurring in psoriatic patients, 3-4 months after treatment initiation with an anti IL-17A agent. Further investigations are needed to explain this phenomenon, that might be defined a paradoxical adverse event, based upon the role of IL17 in eczema pathogenesis.

Efficacy of efalizumab in psoriasis patients previously treated with tumour necrosis factor blockers.

BACKGROUND: Biological therapy for moderate to severe psoriasis includes tumour necrosis factor (TNF) blockers (infliximab, etanercept and adalimumab) and T-cell-targeting agents (efalizumab, alefacept) that act in different steps of a common pathogenic pathway. Large amounts of data coming from clinical trials indicate each of these drugs as highly effective and safe. However, little is known about the efficacy of a second biological therapy after the failure of the first. OBJECTIVE: To evaluate whether the response to efalizumab in psoriasis patients was influenced by previous treatment with other biological agents. PATIENTS AND METHODS: We have retrospectively analyzed a group of 155 psoriasis patients treated with efalizumab during the last 5 years and determined its efficacy in patients previously treated with anti-TNF drugs comparing it with the efficacy and safety observed in patients previously treated with traditional systemic drugs instead. RESULTS: Efalizumab was shown to be as efficacious and safe in patients previously treated with biological agents as in those previously treated with traditional systemic drugs. Although not statistically significant, we observed a higher rate of response to efalizumab in patients previously treated with anti-TNF-alpha. PASI 75 was achieved at week 24 in 76.2% of the patients previously treated with biological agents versus 54.4% in patients previously treated with traditional drugs (OR = 2.9). CONCLUSIONS: These data suggest that efalizumab can be successfully used in psoriasis patients when TNF blockers cannot efficiently control the disease due to lack or loss of response, or when they have to be interrupted for intolerance or adverse events.

The safety of anti-interleukins monoclonal antibodies for the treatment of psoriasis.

Introduction: Psoriasis is a chronic inflammatory disease and affects about 10% of the world's population. Psoriasis is associated with a number of comorbidities. Biologic therapies for the treatment of moderate-severe plaque psoriasis include tumor necrosis factor α inhibitors (TNFi), and newer molecules targeting IL-12 and 23, blocking p40 subunit, or targeting subunit p19 of IL-23 and other molecules blocking IL-17A, or directed against the IL-17 receptor. Areas covered: Anti-interleukin drugs show great improvement in disease control and on the other hand are not affected by important adverse reactions of older compounds. Approach to chronic disease affected patients, in particular, and to patients with multiple comorbidities is revolutionized by novel molecules that are safer and more manageable. Expert opinion: A recent work suggests that pro-fibrogenic cytokines, IL-17, might be important player of liver damage and even in regulation of obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD) pathogenesis. Choosing to interfere with IL-23/Il-17 axis, definitely, is like acting against psoriatic march and in a parallel way against its comorbidities.

Spotlight on brodalumab in the treatment of plaque psoriasis: the evidence to date.

The IL-17/IL-23 axis is now understood to influence psoriasis, and the development of novel IL-17 inhibitor medications marks a sea change in the treatment of psoriasis. Brodalumab is a recombinant, fully human immunoglobulin IgG2 monoclonal antibody specifically targeted against IL-17RA. This article discusses the mechanism of action and the efficacy and safety profile of brodalumab presented in the literature. Brodalumab, the latest approved anti-IL-17-class medication, is the only one that exerts its effects on IL-17C as well as on IL-17A and IL-17F, blocking the shared IL-17 receptor A. In this sense, considering the recent evidence, brodalumab could have beneficial effects not only on psoriasis, but also on atopic dermatitis. It could also serve as a therapeutic alternative in patients who develop paradoxical eczematous reactions or atopic-like dermatitis during treatment with other anti-IL-17A (secukinumab, ixekizumab).