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.

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.

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.

Pharmacotherapeutic management of psoriasis in adolescents and children.

Introduction: Psoriasis is a relatively common condition, with a lot of discordance in studies about the peak of onset. In a large German study, an almost linear prevalence increase was reported during childhood, ranging from 0.12% at 1 year to 1-2% at 18 years. According to recent studies, plaque psoriasis is the most common variant in childhood disease. Areas covered: This article focuses on topical, systemic and biologic therapies used in childhood psoriasis. The authors performed a full literature PubMed research, while incorporating case reports and experience. Topical agents are considered the first step, but they always have little efficacy in the extensive form of the disease. In this case, systemic and particularly biological therapy must be evaluated. The most studied treatment in the pediatric population is etanercept, but adalimumab and ustekinumab are also approved in pediatric and adolescent populations. Expert opinion: Larger studies are needed to further investigate the use of new compounds in childhood psoriasis. Recent evidence suggests that practitioners should consider interceding in the early immunologic psoriatic process to halt this march and stunt immunological scar development. An early investment would provide lasting effects and serious impact in long-term disease modification.

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).

Antifungal properties of silver coating on tumour endoprostheses: an in vitro study.

OBJECTIVE: We tested and quantified the in vitro effect of silver coating on preventing development of fungal biofilm over titanium, as found in some megaprosthesis used for musculoskeletal oncological reconstruction, to evaluate the antiseptic effect of this additional feature on this class of pathogens. MATERIALS AND METHODS: Different strains and species of Candida (C. albicans, C. tropicalis, C. parapsilosis) were cultured over 6 silver-coated and 6 non silver-coated titanium (Ti-6Al-4V) samples following a standardized procedure. Then spectrophotometrical analysis and viability assay were conducted after 5 days of incubation to quantify the different extension of biofilm produced by pathogens RESULTS: Significant differences between groups (p<0.05) were found in terms of biofilm extension and pathogens viability over the different materials for any single experiment reported, with silver-coating group showing substantially lower values in terms of fungal development in all conducted assays. CONCLUSIONS: The results suggest that silver coating is a reliable and effective implementation for antifungal purpose, in addition to its widely known and demonstrated antibacterial potential. Therefore, the use of silver-coated implants may be an even wiser choice in an oncological surgical procedure where patients are particularly at risk for this infective complication due to immunosuppression caused by pharmacological treatments, although the relevant antifungal potential here shown needs to be confirmed in vivo.

A clinical case of severe disease burden: an erythrodermic psoriatic patient treated with secukinumab.

Erythrodermic psoriasis is a severe variant of psoriasis characterized by prominent erythema, affecting the entire body surface. Management of erythrodermic psoriasis is difficult, not standardized, and often ineffective. As clinical studies are lacking, reporting of clinical experience with secukinumab may help to gather insight in this field. Here, we describe the case of a 55-year-old man, with a 10-year history of moderate-to-severe plaque psoriasis. He presents a flare of erythroderma involving approximately 90% of his body surface area and a Psoriasis Area and Severity Index score of 42, with an important impact on his quality of life (DLQI score was 20.0; Skindex-29 score was 67.2). The patient presented also alexithymic features. Due to severity of clinical features and poor quality of life, the patient started secukinumab treatment; we observed a striking and rapid response to therapy with an excellent safety profile and a satisfactory compliance. Furthermore, therapy with secukinumab considerably enhanced patient's quality of life. Although further studies are needed to better understand the role of the IL-23/Th17 pathway, secukinumab can be an effective therapeutic option for patients affected by erythrodermic psoriasis.

A safety evaluation of guselkumab for the treatment of psoriasis.

INTRODUCTION: Guselkumab is a fully human monoclonal IgG1λ antibody for the treatment of plaque psoriasis that inhibits interleukin (IL)-23p19 subunit, reducing the proliferation of type 17 helper T (Th-17) cells and thus production of Th-17-derived pro-inflammatory cytokines, especially IL-17 and IL-22. Areas covered: In the following article, the mechanism of action and mainly the efficacy and safety profile of guselkumab available from results of trials will be discussed. We summarized these data after a literature review including PubMed search, relating proceedings and abstracts from relevant international conferences, assessment reports from European and United States regulatory agencies and treatment guidelines up to April 2018. Expert opinion: The central role of IL-23 in psoriasis pathogenesis is supported by genetic links of IL-23 and IL-23R alleles to psoriasis susceptibility; early clinical trials have demonstrated that sufficient inhibition of IL-23p19 results in rapid resolution of the disease. Targeting IL-23, may be responsible for the high efficacy and durable responses of guselkumab, avoiding some adverse effects of IL-17A blockade, like mucocutaneous candida infections or triggering/worsening of inflammatory bowel disease, experienced with agents acting selectively against this molecule and that seem to be class related.

Pharmacokinetic drug evaluation of dalbavancin for the treatment of skin infections.

INTRODUCTION: Acute bacterial skin and skin structure infections (ABSSIs), defined as a bacterial infection of the skin with a lesion size area of at least 75 cm, are a leading cause of hospital admission and ambulatory care visits worldwide. Dalbavancin is a lipoglycopeptide antibiotic recently approved by the United States Food and Drug Administration (FDA) and by European Medicines Agency (EMA) for ABSSSIs. The authors review and provide updates of efficacy and safety by several studies on dalbavancin. Areas covered: A PubMed search was performed for relevant literature. We especially focused our attention on pharmacokinetics. Expert opinion: Dalbavancin provides an important new therapy for management of ABSSI, maintaining a spectrum of activity similar to vancomycin against gram-positive organisms. Use of dalbavancin, with its 1-week-shot treatment, consist in a reduction of the length of hospital stay or in a reduction of hospital admissions, with important cost savings.

Soft tissue adhesion patterns over Trevira tube on modular endoprosthesis for malignant bone tumours: an in vitro study.

A reliable and effective technique in case of limb salvage surgery after resection of extensive bone tumors is represented by the implant of modular or custom-made megaprosthesis. Fixation of the residual surrounding soft tissue on the implant represent a challenge for the surgeon and the use of a polyethylene terephthalate (PET) tube over it, also known as Trevira, is currently a common choice for reattachment with good clinical outcomes. We compared fibroblastic cell culture potential over simple titanium coating vs titanium surrounded by Trevira and evaluated cell viability and replication at 24, 48 and 72 h using MTT cell growth assay and scanning electron microscopy to determine if there was any difference in the potential of cell growth associated to the material used. No significant difference was found at different timings in terms of total cell count for cultures over the two materials, but the absolute cell count was slightly higher in the Trevira group in the early time points, reversing the trend at 72 h of incubation. Ninety-four % of the cells analyzed were vital, regardless of the materials involved in the experiment, confirming the biocompatibility of titanium and PET. According to the results shown, we are able to confirm the in vitro safety and efficacy, in terms of newly formed cells extension and adhesion pattern, of using an attachment tube made from Trevira fibers surrounding an oncological megaprosthesis in order to achieve the most anatomical reinsertion of remaining soft tissue following resection.

Pharmacokinetic drug evaluation of brodalumab for the treatment of psoriasis.

INTRODUCTION: Psoriasis is now understood to also be under the driving influence of the IL-17/IL-23 axis, and the medical breakthrough of novel IL-17 inhibitor medications signals a paradigm shift in the way psoriatic patients are managed medically. Brodalumab, a fully human Chinese hamster ovary cell-derived immunoglobulin G2 (IgG2) anti-IL-17RA monoclonal antibody, is currently the most-developed treatment that binds to the IL-17RA. The authors review and provide updates of efficacy and safety by several studies on brodalumab. Areas covered: A PubMed search was performed for relevant literature. Among the trials of brodalumab, the most common adverse events included nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. Suicidal ideation and completed suicides had been observed in the brodalumab programme, although evidence to date was quoted as not suggesting a causal association. Expert opinion: Brodalumab provides an important new therapy for management of psoriasis, because there remains a significant unmet patient need for new agents that can provide novel mechanisms of action, rapid onset of effect, improved, and sustained total skin clearance, greater compliance, and minimization of drug-specific safety concerns.

Brodalumab for the treatment of psoriasis.

INTRODUCTION: Psoriasis is a complex disease in which the alteration of the IL-23/Th17 axis appears to be crucial for its pathogenic mechanisms, and anti-IL17 agents are rapidly becoming important therapeutic tools. Brodalumab, a fully human Chinese hamster ovary cell-derived immunoglobulin G2 (IgG2) anti-IL-17RA monoclonal antibody, is currently the most-developed treatment that binds to the IL-17RA. The authors review and provide updates of efficacy and safety by several studies on brodalumab. Areas covered: A PubMed search was performed for relevant literature. Among the trials of brodalumab, the most common adverse events included nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. Suicidal ideation and completed suicides had been observed in the brodalumab programme, although evidence to date was quoted as not suggesting a causal association. Expert commentary: By blocking the IL-17 receptor A, brodalumab antagonizes signaling from IL-17A, IL-17F, IL-17A/F and IL-25, and this probably contributes to the high efficacy observed in clinical trials. Considering the different therapeutic target and the potential biological implications that blocking IL-17RA instead of IL-17A might have, brodalumab may not necessarily belong to the same class that includes secukinumab and ixekizumab, but it may be classified in a distinct group.

Silver-Coated Hip Megaprosthesis in Oncological Limb Savage Surgery.

Silver coating has demonstrated good antimicrobial activity and low toxicity. Silver-coated megaprostheses have been introduced in oncological musculoskeletal surgery considering the high rate of infection. We conducted a retrospective analysis on 68 cases of primary or metastatic bone tumors, affecting the proximal femur, treated between 2005 and 2016 with wide margins resection and tumor implants reconstruction. All patients were treated by the same surgeon, with antibiotic prophylaxis according to a standard protocol. In 55.9% of patients silver-coated hip hemiarthroplasty was implanted; in the remaining 44.1% uncoated megaprostheses were implanted. Patients were reevaluated recording the complications and focusing the analysis on infective complications. The average follow-up was 46.5 months. No patient has shown any sign of local or general silver toxicity. A SEM analysis was conducted on the 3-silver-coated hip hemiarthroplasty explanted confirming a severe degradation with a small amount of residual silver on the coating surface. Silver-coated hip prostheses have a lower rate of early infection than traditional implants but showed a reduction of antimicrobial activity for silver coating wear. We recommend using silver-coated prosthesis as primary implants for limb salvage surgery, in primary or metastatic bone tumors affecting the proximal femur, considering the absence of signs of toxicity and the lower rate of early infection.

Tofacitinib for the treatment of psoriasis.

INTRODUCTION: The identification of a number of psoriasis-susceptibility genes and a better understanding of the pathogenesis of the intracellular metabolic pathways, have generated new perspectives on psoriasis treatment, in particular new compounds that inhibit certain intracellular proteins involved in the immune response. In contrast to biologic agents, these compounds block intracellular targets such as transcriptional factors or enzymes. AREAS COVERED: Tofacitinib is a small molecule that acts as a reversible, competitive inhibitor of ATP in the ATP binding site of JAK proteins, determining their inactivation, thus prevents the downstream activation of the STAT proteins, which are then unable to up-regulate the pro-inflammatory genes implicated in psoriasis. The authors present an overview of Phases I - III clinical trials of tofacitinib for psoriasis based on peer-reviewed literature. EXPERT OPINION: In clinical practice, it is important to assess the response of psoriasis to tofacitinib and identify possible clinical, genetic, and immune biomarkers to predict the response. Comorbidities associated with psoriasis, in particular metabolic syndrome and obesity, are also an important aspect of using tofacitinib in clinical practice. There are some evidences that a drug such as tofacitinib could be used to improve not only psoriasis, but also some of its important comorbidities.

Endothelial dysfunction and tendinopathy: how far have we come?

Symptomatic tendon tears are one of the most important causes of pain and joint dysfunction. Among the intrinsic causes, vascularization recently gained a major role. Endothelial function is indeed a key factor, as well as vascular tone and thrombotic factors, in the regulation of vascular homeostasis and the composition of vascular wall. In this review, we studied systematically whether there is a relationship between endothelial dysfunction and tendinopathy. A literature search was performed using the isolated or combined keywords endothelial dysfunction and tendon,' 'nitric oxide (NO) and tendinopathy,' and 'endothelial dysfunction in tendon healing.' We identified 21 published studies. Of the selected studies, 9 were in vivo studies, 2 focusing on animals and 7 on humans, while 12 reported about in vitro evaluations, where 7 were carried out on humans and 5 on animals. The evidence about a direct relationship between tendinopathy and endothelial dysfunction is still poor. As recent studies have shown, there is no significant improvement in clinical and functional assessments after treatment with NO in patients suffering from tendinopathy in different locations. No significant differences were identified in the outcomes reported for experiment group when compared with controls treated with conventional surgical procedures or rehabilitation programs. Nitric oxide could be a marker to quantify the response of the endothelium to mechanical stress or hypoxia indicating the final balance between vasodilatating and vasoconstricting factors and their effects, but more ad stronger evidence is still needed to fully support this practice.