A Familial Novel Putative-Pathogenic Mutation Identified in Plaque-Psoriasis by a Multigene Panel Analysis.

Psoriasis is a chronic multifactorial skin disorder with an immune basis. It is characterized by patches of skin that are usually red, flaky and crusty, and that often release silvery scales. The patches appear predominantly on the elbows, knees, scalp and lower back, although they may also appear on other body areas and severity may be variable. The majority of patients (about 90%) present small patches known as "plaque psoriasis". The roles of environmental triggers such as stress, mechanical trauma and streptococcal infections are well described in psoriasis onset, but much effort is still needed to unravel the genetic component. The principal aim of this study was to use a next-generation sequencing technologies-based approach together with a 96 customized multigene panel in the attempt to determine if there are germline alterations that can explain the onset of the disease, and thus to find associations between genotypes and phenotypes. To this aim, we analyzed a family in which the mother showed mild psoriasis, and her 31-year-old daughter had suffered from psoriasis for several years, whereas an unaffected sister served as a negative control. We found variants already associated directly to psoriasis in the TRAF3IP2 gene, and interestingly we found a missense variant in the NAT9 gene. The use of multigene panels in such a complex pathology such as psoriasis can be of great help in identifying new susceptibility genes, and in being able to make early diagnoses especially in families with affected subjects.

Guselkumab: an anti-IL-23 antibody for the treatment of moderate-to-severe plaque psoriasis.

Guselkumab, a subcutaneously administered fully human IgG1λ monoclonal antibody that selectively inhibits the p19 subunit of interleukin 23, is approved in both the USA and the EU for the treatment of adult patients with moderate-to-severe plaque psoriasis. The efficacy and safety of guselkumab were demonstrated in four randomized, double-blind, Phase III trials (VOYAGE 1 and 2, NAVIGATE, and ECLIPSE), which demonstrated high levels of clinical response over three years of continuous treatment, regardless of sex, age, body weight, and race, maintaining a favourable safety profile and long-term tolerability. Guselkumab was shown to be efficacious in patients with prior failure of other biologics, including adalimumab and ustekinumab, and was superior to both adalimumab and secukinumab in head-to-head trials. Guselkumab efficacy was also observed in the treatment of psoriasis localized in difficult-to-treat body regions including the scalp, palms and/or soles, and fingernails. Treatment with guselkumab improved health-related quality of life and patient-reported signs and symptoms. Guselkumab has a consistently favourable safety profile and is well tolerated over the long-term. Clinical development of guselkumab as a treatment is ongoing for other immune-mediated inflammatory diseases, including psoriatic arthritis, Crohn's disease, and ulcerative colitis. In the overall management of patients with plaque psoriasis, guselkumab is a robust treatment option with durable maintenance of response over time.

Psoriatic arthritis onset in psoriatic patients receiving UV phototherapy in Italy.

BACKGROUND: Psoriasis is a chronic, recurrent, and immune-mediated inflammatory disease that affects 2-3% of the world population. A substantial proportion of patients with psoriasis, approximately 40%, develop a form of inflammatory arthritis known as psoriatic arthritis (PsA), the arthritis follows the development of psoriasis, and it will develop simultaneously or possibly before the appearance of skin lesions. The presence of PsA indicates a need for more active intervention rather than purely topical therapies or UV-based therapies. The aim of this multicenter, retrospective, epidemiological study was to estimate the incidence of PsA in psoriatic patients receiving UV treatment as monotherapy. METHODS: A retrospective epidemiological study was performed in 8 dermatological reference center, located throughout Italy (2 from Northern, 3 from Center, 3 from Southern); a period of 1 year was considered. Data from the overall study population including 326 patients with a diagnosis of psoriasis were analyzed. Furthermore, data coming from follow-up visits, including screening for PsA onset through specific questionnaires were analyzed. RESULTS: PsA screening was positive in 27 patients (8.3%), whereas PsA diagnosis was confirmed by a rheumatologist in only 22/27 (81.5%) being therefore found in 22/326 (6.7%). Patients diagnosed with PsA had a statistically significantly higher abdominal circumference (96±15.3 vs. 88.9±18.3, P=0.048) and more commonly presented a positive past medical history for phototherapy (90.9% vs. 57.6% P=0.004). CONCLUSIONS: Our study showed that phototherapy is not able to prevent or slow down the risk of PsA development in psoriatic patients. PsA screening should be always carried out in those patients even if asymptomatic, especially in obese subjects which are at great risk to develop PsA due to their increased systemic inflammatory state.

Effectiveness and safety of secukinumab in Italian patients with psoriasis: an 84 week, multicenter, retrospective real-world study.

Background: Long term data on the real-life use of secukinumab are scant. The aim of this study was to investigate the real-life effectiveness, safety and treatment persistence of secukinumab in patients with moderate-to-severe psoriasis. Research design and methods: This 84-week, multicenter (n = 7) retrospective study analyzed data from patients who initiated and received at least 6 months of secukinumab treatment between June 2016 and June 2018 in the Campania region of Italy. Patient demographic and treatment characteristics, duration of treatment and reasons for discontinuation as well as Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA), and Dermatology Life Quality Index (DLQI) scores were assessed. Results: 324 patients (63% male, mean age 50.2 years) were enrolled and received a mean 11.7 months of secukinumab treatment. Overall, 9.5% discontinued secukinumab, including 5.2% who discontinued due to secondary inefficacy and 1.8% due to adverse events. PASI, BSA and DLQI scores were significantly improved from baseline at every follow-up visit (p < 0.001) and mean PASI decreased from 15.3 ± 6.3 at baseline to 0.5 ± 1.0 at week 84. Secukinumab had comparable effectiveness in biologic naïve and non-naïve patients. Conclusions: This study confirmed the effectiveness and safety of secukinumab in real-world patients with psoriasis.

Psoriasis Features in Patients with Inflammatory Bowel Disease.

BACKGROUND: Psoriasis and inflammatory bowel diseases (IBD) share common pathways based on immune dysregulation with an important role of tumour necrosis factor-α and Th17 cells, as well as the genetic background. Several studies showed an increased prevalence of psoriasis in IBD patients. However, data regarding psoriasis features in IBD patients are still lacking. AIM: We aimed to conduct an observational study to assess psoriasis clinical features and its severity in a group of patients with IBD. METHODS: Dermatological assessment was performed consecutively in 200 IBD patients (123 with CD and 77 with UC) attending the IBD Care Centre of Gastroenterology at the University of Naples Federico II from 2015 to 2016. RESULTS: A group of 32 from 200 IBD patients (16%) had a familiar history positive for psoriasis, whereas, medical history and dermatologic examination revealed that 18 (9%) IBD patients were affected by psoriasis: 11 out of these 18 subjects (61.2%) had CD, and 7 had UC (38.2%); no significant differences were found between CD and UC groups. Concerning psoriasis severity, the mean psoriasis area severity index score was 3.7. CONCLUSION: This one-year retrospective study showed that psoriasis and IBD both require the use of immunosuppressive drugs so; we can count on a better treatment outcome for both diseases.

Intralesional Methotrexate for the Treatment of Keratoacanthoma: The Neapolitan Experience.

INTRODUCTION: Keratoacanthomas are cutaneous neoplasms known for their rapid growth and spontaneous regression over a long time period. Their treatment can be difficult because of the potentially large field size and number of lesions. Intralesional methotrexate constitutes an effective, nonsurgical treatment of keratoacanthomas, as proven by our experience. METHODS: We treated 11 elderly patients affected by keratoacanthoma with intralesional methotrexate. The injections were performed weekly, followed by 10 mg of folic acid to be taken 24 h later. RESULTS: All our patients underwent complete resolution of the lesions after 4-8 injections, without side effects. CONCLUSION: Intralesional methotrexate seems to be an effective and safe nonoperative treatment modality for keratoacanthoma, especially when it arises in anatomic areas difficult to treat with surgery, in elderly debilitated patients, and in those refusing surgery.

A case of erythrodermic psoriasis successfully treated with ixekizumab.

Erythrodermic psoriasis (EP) is the most severe form of psoriasis, resulting in significant morbidity and mortality. International guidelines on EP treatment are lacking, with most of the biologic drugs being used basing on case reports or small case series. Ixekizumab, a fully human anti-interleukin (IL)-17A monoclonal antibody, is approved for moderate to severe plaque psoriasis while its use in EP is off label. However, two studies conducted on eight Japanese EP patients have showed ixekizumab as an efficacious and well tolerated therapy up to 24 and 52 weeks, respectively. To date, no case reports on Caucasian patients have been described. We report the case of a 66-year-old Caucasian female with EP successfully treated with ixekizumab, reaching PASI 100 after only 6 weeks of therapy and still maintaining this response at week 24. Our case report suggests ixekizumab as a highly efficacious treatment in EP, presenting also a very rapid action which leads to complete resolution of the disease after 6 weeks. Further studies are warrant to confirm our data, with controlled trials specifically dedicated to EP being strictly needed in order to verify the role and efficacy of the new biologics in EP.

Paraoxonases and psoriasis: negative imbalance of antioxidant endogenous mechanisms.

BACKGROUND: Numerous reports have shown that psoriasis patients are more exposed to lipoprotein peroxidation and to a decrease in the activity of paraoxonase (PON)1, an antioxidant and anti-inflammatory enzyme. Thus, it has been suggested that malfunction of the antioxidant system and an increased production of reactive oxygen species drive immune inflammatory events, that result in progressive skin cell damage in patients with psoriasis. The PON protein family, including PON1, PON2 and PON3, is one of the most important endogenous defense mechanisms against oxidative stress. In the present study, we investigated PON gene expression in psoriasis and in cutaneous oxidative stress. METHODS: The study population included 10 patients affected by moderate-to-severe plaque psoriasis and 15 healthy donors who have undergone to plastic surgery, were used as control. Skin punch biopsies of lesional and non lesional psoriatic skin were performed for analysis of PON2 and PON3 gene expression. In addition, oxidation assays in ex vivo full-thickness healthy skin organ cultures were performed. RESULTS: No significant differences were observed between PON2 and PON3 gene expression in psoriatic lesional and non lesional skin compared with healthy controls. H2O2 treatment induced a significant decrease of PON2 and PON3 expression in ex vivo full-thickness healthy skin organ cultures; conversely the pretreatment of samples with the antioxidant reagent N-acetyl-L-cysteine (NAC) induced a significant increase. Interestingly, no significant alterations were reported for PON2 and PON3 expression in ex vivo full-thickness healthy skin organ cultures stimulated with IL-17. CONCLUSIONS: Taken together our findings have revealed that a strong pro-oxidative activity is not effectively countered by antioxidant endogenous mechanisms both in psoriatic skin and in ex vivo experimental model.

A multicenter retrospective case-control study on Suspension of TNF-inhibitors and Outcomes in Psoriatic patients (STOP study).

BACKGROUND: There is limited information on patients undergoing withdrawal after long-term treatment with anti-TNF alpha drugs and their clinical evolution during the post-interruption period in real-life settings. The purpose of the present retrospective case-control study was to provide a clearer insight into the clinical management of psoriatic patients with adequate response to long-term adalimumab, etanercept and infliximab treatment once these biologic agents are interrupted. METHODS: A total of 270 patients undergoing anti-TNF alpha agents discontinuation and 253 controls treated with a continuous regimen were enrolled. The primary endpoint was the change in disease activity in each study group over six months (or until treatment of psoriatic recurrence) as measured by the PASI score every month. Then, we evaluated the rate of and time to relapse, the rate of clinical worsening (PASI≥5) and the clinical variables influencing the loss of response. RESULTS: Our study showed that about 50% of patients achieving a long-term and optimal response to the aforementioned anti-TNF alpha agents did not experience any relapse over a 6-month follow-up period after withdrawal. We also observed that subjects displaying a complete remission (PASI=0) at anti-TNF alpha therapy withdrawal experienced less frequently disease worsening and/or relapse compared to subjects having a PASI>0. CONCLUSIONS: Our findings confirmed that all three anti-TNF alpha agents tend to retain their effectiveness upon re-administration in case of recurrence, even if they have been previously used for long time.

The anti-inflammatory and antioxidant properties of 1,2-decanediol and willow bark extract in lipopolysaccharide-stimulated keratinocytes.

BACKGROUND: 1,2-Decanediol (S-Mal) is an organic compound belonging to the 1,2-alkanediol family, with two hydroxyl groups located on the first and second carbon of the alkane chain, probably responsible for the enhanced anti-bacterial efficacy. The willow bark total extract (W-Mal) has been used since thousands of years as an herbal remedy for its antipyretic, analgesic, anti-inflammatory and anti-microbial activities. S-Mal is used in cosmetic preparations, whether W-Mal can be topically or systemically administered. Aim of our study was to evaluate in vitro the anti-inflammatory and antioxidant properties of S-Mal and W-Mal, singularly or in combination, in LPS-stimulated keratinocytes. METHODS: The possible toxic effect of S-Mal and W-Mal was assessed through analysis of cell viability 24 hours after treatment. The anti-inflammatory and antioxidant activities were evaluated by measuring IL-8, TNF-α and IL-1ß production as well as cellular antioxidants (GSH and NADPH) consumption, 24 and 48 hours, respectively, after LPS stimulation. RESULTS: Both substances resulted able to: 1) increase cell viability (P<0.05); 2) decrease the release of inflammatory mediators (IL-8, TNF-α and IL-1ß) (P<0.05 - P<0.001); and 3) limit the depletion of cellular antioxidants (GSH and NADPH) (P<0.001). CONCLUSIONS: S-Mal and W-Mal have shown a potential cytoprotective activity when used together, and good anti-inflammatory and antioxidant effects when used either singularly or in combination. In light of our results, S-Mal and W-Mal could represent effective and safe options in the management of bacterial-induced or aggravated skin conditions.

Treatment of Atopic Dermatitis with Biologic Drugs.

Atopic dermatitis (AD) is a chronic, pruritic, inflammatory skin disease which predominately affects children and usually clears up during infancy or childhood. However, AD may persist with a chronic relapsing course until adulthood or develop at a later age. AD treatment can often be complicated. Treating moderate-to-severe AD can be challenging: only a few therapeutic options are available, with cyclosporine being the only approved and labeled systemic drug. In the last few years, advances in the knowledge of AD pathogenesis have been made that can provide the basis for developing new topical and systemic drugs. Among them, biologic drugs targeting specific cytokines involved in the development of the disease will probably revolutionize AD therapy. Currently, dupilumab, a monoclonal antibody that binds to the shared alpha chain subunit of the receptors for IL-4 and IL-13, is the only biologic drug licensed for the treatment of AD in adults. However, other biologic drugs that selectively target some key cytokines in AD pathogenesis (IL-13, IL-31, and IL-22) are also being studied. In this review, we discuss all of the biologic drugs that have been studied for AD treatment.

Psoriasis, Cardiovascular Events, and Biologics: Lights and Shadows.

Nowadays, it is well established a link between psoriasis and cardiovascular (CV) diseases. A series of different overlapping mechanisms including inflammation, homeostasis dysregulation, and genetic susceptibility are thought to underlie this association. Advances in understanding the molecular patterns involved in the complex scenario of psoriasis have highlighted a tight correlation with atherosclerosis. Indeed, common profiles are shared in term of inflammatory cytokines and cell types. In the last decade, the management of psoriasis patients has been revolutionized with the introduction of biological therapies, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-12/23, and IL-17 inhibitors. In clinical setting, the effectiveness of these therapies as well as the incidence of CV events is related to the type of biologics. In particular, anti-TNF-α agents seem to reduce these events in psoriasis patients whereas anti-IL-12/23 agents related CV events reduction still remain to clarify. It has to be taken into account that IL-12/23 inhibitors have a shorter post-marketing surveillance period. An even more restricted observational time is available for anti-IL-17 agents. IL-17 is associated with psoriasis, vascular disease, and inflammation. However, IL-17 role in atherosclerosis is still debated, exerting both pro-atherogenic and anti-atherogenic effects depending on the specific context. In this review, we will discuss the differences between the onset of CV events in psoriasis patients, referred to specific biological therapy and the underlying immunological mechanism. Given the development of new therapeutic strategies, the investigation of these inhibitors impact on heart failure outcome is extremely important.

Multicenter clinical trial on a permanent hair dye containing paratoluenediamine.

BACKGROUND: Adverse reactions to hair dyes are frequent and usually caused by sensitization to paraphenylenediamine (PPD). The aim of the study was to evaluate the tolerability of a PPD-free permanent hair dye (Shine On, BioNike, Milan, Italy) containing paratoluenediamine (PTD) in a group of subjects sensitized to PPD. METHODS: The trial, which carried out at four dermatology centers, included subjects sensitized to PPD that turned out negative to patch testing to PTD. The subjects underwent to an open test consisting in the application of two hair dye colors of the product under examination. Finally, subjects who were negative upon the open test were offered to undergo the usage test with the dye, with dermatological evaluations carried out 48 and 96 hours after product application. RESULTS: Sixty subjects were enrolled. They underwent the open test with two shades of dyes: "color 1 - black," the dye color with the highest concentration of color intermediates, and "color 7.3 - golden blonde," the dye color with the highest number of chemically different color intermediates. No reactions occurred with "color 7.3 - golden blonde," while 3 cases (3 out of 60) showed erythema and edema reactions to color 1. The hair dye usage test was negative for all the 21 subjects that were enrolled. CONCLUSIONS: The hair dye evaluated in this study (Shine On, BioNike) can be a valid alternative for subjects sensitized to PPD.

Guselkumab for the treatment of psoriasis.

INTRODUCTION: Psoriasis is a chronic immune mediated disease in which the interplay of T cells and keratinocytes seems to play a key role. In this context, the interleukin (IL)-23/IL-17 axis is currently considered to be crucial in the pathogenesis of psoriasis and the selective inhibition of IL-23 may be viewed as an improvement of treatments blocking both IL-23 and IL-12, since its upstream actions. Areas covered: The authors performed a thorough and updated review on guselkumab, a fully human IgG1λ monoclonal antibody that blocks the p19 subunit of IL-23, analyzing efficacy and safety data from phase I, II and III trials. Expert opinion: Guselkumab represents a very promising therapy, providing an alternative mechanism of action with high efficacy and safety profiles, sustained total skin clearance, and rapid onset of effect also to psoriasis patients who previously failed or experienced an inadequate response to anti-TNF-α or anti-IL12/23. Guselkumab will definitively shift therapeutic goals of psoriasis management from PASI 75 to PASI 90 and 100 due to its exciting trials results, also favored by its increased treatment adherence due to its administering regimen (100 mg injection at week 0, 4 and then every 8 weeks).