Certolizumab for the treatment of psoriasis and psoriatic arthritis: a real-world multicentre Italian study.

BACKGROUND: Certolizumab, a pegylated tumour necrosis factor-α inhibitor, reduced disease activity in randomized trials of patients with psoriasis and psoriatic arthritis. Real-life data are missing. OBJECTIVE: To confirm the effectiveness and safety of certolizumab in patients with psoriasis and psoriatic arthritis in routine clinical practice. METHODS: In this retrospective study involving 11 Italian sites, patients with psoriasis and psoriatic arthritis received subcutaneous certolizumab (400 mg loading dose at 0, 2 and 4 weeks, followed by 200 mg every 2 weeks) for up to 52 weeks. Primary outcomes included mean change from baseline in Psoriasis Area and Severity Index (PASI) and modified Nail Psoriasis Severity Index (mNAPSI) scores, and the proportion of patients achieving a 75%, 90% or 100% reduction in PASI score. Other endpoints included Disease Activity Score computed on 44 joints correlated with the erythrocyte sedimentation rate during the first hour (DAS44-ESR), Tender Joint Count (TJC), Swollen Joint Count (SJC), pain [visual analogue scale (VAS) score], inflammatory markers and quality of life (QOL). RESULTS: In the study were enrolled 153 patients (mean age: 55 years). Certolizumab reduced the mean PASI score from baseline by 4.45, 6.30 and 7.58 at weeks 12, 24 and 52, respectively (P < 0.001 for all). At weeks 24 and 52, 69.6% and 83.3% of patients had a PASI score ≤3. DAS44-ESR, TJC, SJC and mNAPSI scores, and pain VAS were also all significantly improved from baseline at each time point. C-reactive protein levels decreased during treatment, being significant at week 24. On multivariate analysis, psoriasis duration, baseline PASI, mNAPSI and pain VAS scores were found to be predictive of the improvement in PASI score at week 12. CONCLUSION: Certolizumab displayed also in the real-life encouraging results in both psoriasis and psoriatic arthritis patients.

Immunologic biomarkers for clinical and therapeutic management of psoriasis.

BACKGROUND: The therapeutic management of psoriasis includes conventional treatments as well as the new generation of highly effective TNF-α inhibitors. However, psoriasis has proven to be a complex therapeutic challenge and treatment failures are not uncommon. Thus, laboratory biomarkers of disease progression/therapeutic efficacy may greatly help in the clinical management of psoriasis. AIMS: To identify laboratory biomarkers for clinical management and therapeutic monitoring of psoriasis. METHODS: An observational study performed on 59 patients, presenting moderate to severe psoriasis, undergoing treatment with anti-TNF-α agents (etanercept, adalimumab, and infliximab). Soluble and cellular immune/inflammatory parameters were assessed at baseline and after 12 and 24 weeks of treatment. RESULTS: Clinical efficacy was achieved in 88% of the subjects at 12 weeks, reaching 90% after 24 weeks. IL-6 and IL-22, which were elevated at baseline, were significantly reduced, in association with a significant decrease of CLA+ T cells and an increase of Treg lymphocytes. T, B, and NK cell subsets and T cell response to recall antigens did not show any evidence of immune suppression. CONCLUSIONS: Immune/inflammatory parameters including IL-6 and IL-22, CLA+ T cells, and Treg lymphocytes may prove to be valuable laboratory tools for the clinical and therapeutic monitoring of psoriasis.

Progressive late-onset of cutaneous angiomatosis as possible sign of cerebral cavernous malformations.

BACKGROUND: Cerebral cavernous malformations (CCM) comprise enlarged capillary cavities in the central nervous system, with possible retinal or cutaneous vascular malformations. This condition is associated with CCM1, CCM2, and CCM3 gene mutations. OBJECTIVE: Cutaneous clinical, histological and cerebral MRI findings, including CCM1, CCM2, and CCM3 gene sequencing, of two unrelated, neurological symptom-free patients who consulted for late-onset of deep multiple cutaneous angiomatoid lesions, are described. RESULTS: The diagnosis of multiple cutaneous angiomatosis was confirmed and related to CCM as detected by MRI in both cases. Analysis of our patients showed normal nucleotide sequences of the genes proposed. CONCLUSIONS: A progressive late-onset of multiple, deep cutaneous venous malformations may indicate the need to investigate a potential coexistence of CCM by MRI. Early diagnosis and prompt treatment is required in these patients. The absence of CCM1, CCM2, and CCM3 mutations might indicate that different genes could be involved in the pathogenesis of these late-onset patients. Careful questioning about family history of CCM is important; our first patient's daughter had a history of cerebral cavernoma.

Apremilast as a target therapy for nail psoriasis: a real-life observational study proving its efficacy in restoring the nail unit.

PURPOSE: Psoriasis, Psoriatic Arthritis and Nail psoriasis are chronic diseases that share a common underlying etiology of immunity dysregulation, enhanced activation of inflammatory pathways and remitting-relapsing course. Although nails represent a small percentage of the body surface involvement of this site can lead to impaired quality of life, severe discomfort and even result in permanent disability. Current therapeutic options for nail psoriasis include a variety of topical and systemic treatments although they are often reported as unsatisfactory from patients either due to their poor effectiveness or disturbing side effects. Recently small molecule drugs such as the PDE4 inhibitors were introduced in clinical practice and specifically apremilast has shown to be an effective new treatment option for psoriasis and psoriatic arthritis. Considering either the specific mechanism of action of apremilast, we performed a real-life observational study of 24 weeks assessing apremilast role in nail psoriasis. MATHERIALS AND METHODS: Patients received apremilast 30mg bid, orally. Safety and efficacy were assessed at weeks 0, 4, 8, 12 and 24 using Dermatologic Life Quality Index (DLQI) and Nail Area Psoriasis Severity Index (NAPSI). At T0 we took a nail sample to investigate the presence of onychomycosis. Culture tests were performed in all the patients to search for fungi. RESULTS: We recruited a total of 15 patients with nail psoriasis. The analysis of variance (one-way ANOVA) showed the following results: DLQI (F.15.7; p-value < .00001) and NAPSI (F.9.4; p-value < .00001). Three patients (20%) presented also onychomycoses at the beginning of the treatment. CONCLUSIONS: Apremilast showed fast and sustained improvement of nail psoriasis over time and a complete resolution of life quality impairment due to the disease.

Immunomodulatory agents as potential therapeutic or preventive strategies for COVID-19.

Currently, the COVID-19 pandemic, caused by the novel SARS-CoV-2 coronavirus, represents the greatest global health threat. Most people infected by the virus present mild to moderate respiratory symptoms and recover with supportive treatments. However, certain susceptible hosts develop an acute respiratory distress syndrome (ARDS), associated with an inflammatory "cytokine storm", leading to lung damage. Despite the current availability of different COVID-19 vaccines, the new emerging SARS-CoV-2 genetic variants represent a major concern worldwide, due to their increased transmissibility and rapid spread. Indeed, it seems that some mutations or combinations of mutations might confer selective advantages to the virus, such as the ability to evade the host immune responses elicited by COVID-19 vaccines. Several therapeutic approaches have been investigated but, to date, a unique and fully effective therapeutic protocol has not yet been achieved. In addition, steroid-based therapies, aimed to reduce inflammation in patients with severe COVID-19 disease, may increase the risk of opportunistic infections, increasing the hospitalization time and mortality rate of these patients. Hence, there is an unmet need to develop more effective therapeutic options. Here, we discuss the potential use of natural immunomodulators such as Thymosin α1 (Tα1), all-trans retinoic acid (ATRA), and lactoferrin (LF), as adjunctive or preventive treatment of severe COVID-19 disease. These agents are considered to be multifunctional molecules because of their ability to enhance antiviral host immunity and restore the immune balance, depending on the host immune status. Furthermore, they are able to exert a broad-spectrum antimicrobial activity by means of direct interactions with cellular or molecular targets of pathogens or indirectly by increasing the host immune response. Thus, due to the aforementioned properties, these agents might have a great potential in a clinical setting, not only to counteract SARS-CoV-2 infection, but also to prevent opportunistic infections in critically ill COVID-19 patients.

Use of brodalumab for the treatment of chronic plaque psoriasis: a one-year real-life study in the Lazio region, Italy.

Background: Information is limited from real-life studies evaluating the efficacy and safety of brodalumab.Research design and methods: In this real-life study, we retrospectively examined a database of 90 patients with moderate-to-severe psoriasis treated with brodalumab (210 mg, s.c.) and followed for 1 year. Disease severity and treatment response were assessed by the Psoriasis Area and Severity Index (PASI) at baseline and after 4, 12, 24, 36, and 48 weeks. Predictors of a PASI response were evaluated by logistic regression.Results: After 48 weeks, 92.2% of patients (mean age 50.2 ± 15 years) treated with brodalumab achieved a PASI score of <3. PASI score decreased from 17.4 ± 10.3 at baseline to 1.7 ± 3.9 and 1.4 ± 3.7 at 12 and 24 weeks, and PASI 75, 90, and 100 response was achieved in 87.3%, 81.8%, and 72.7% of patients, respectively, at 48 weeks.Univariate regression revealed that previous exposure to anti-IL17A treatment was associated with poorer PASI response between 36 and 48 weeks. In difficult-to-treat cases previously having failed with other biologics, brodalumab significantly improved outcome, leading to complete remission.Conclusion: Brodalumab was observed to be effective and safe in patients with moderate-to-severe chronic psoriasis in a real-world setting.

Melanoma-associated markers expression in blood: MUC-18 is associated with advanced stages in melanoma patients.

BACKGROUND: Multimarker reverse transcriptase-polymerase chain reaction (RT-PCR) was originally reported to reveal melanoma-associated mRNAs (MAMs) in melanoma cells but not in the peripheral blood of healthy individuals. OBJECTIVES: To evaluate the expression of MAMs in the peripheral blood of melanoma patients at different American Joint Committee on Cancer (AJCC) stages, and to correlate their presence with early and/or advanced stages of the disease. MATERIALS AND METHODS: One hundred blood samples of melanoma patients (AJCC I-IV) were analysed using multimarker RT-PCR to assess the co-expression of Tyr-OH, MART-1, MAGE-3, MUC-18/MCAM and p97. Patients were stratified into two disease categories: early and advanced stages. The former includes in situ and melanoma stages AJCC I-II, the latter AJCC III-IV. chi(2) and Fisher's exact tests were used to statistically evaluate the association between each MAM and disease categories. The recognized significant associations were subsequently resubmitted to univariate logistic regression. Furthermore, sensitivity and specificity were established. RESULTS: At least one MAM could be detected in 24% of our series. Tyr-OH was the most common marker (14%), followed by MUC-18 (12%), MART-1 (5%), MAGE-3 (4%) and p97 (3%). No significant association among Tyr-OH, MART-1, MAGE-3, p97 and disease stages were evidenced. Only MUC-18 was statistically associated (P < 0.009) with advanced stages alone or co-expressed with other MAMs. According to logistic regression univariate analysis, MUC-18 increases the probability (odds ratio: 33) being in advanced stages and the incidence of recurrences (95% CI 2.9-374). CONCLUSIONS: MUC-18 RT-PCR assay could be proposed as an adjunctive molecular method in the management of melanoma patients and is useful in the monitoring of study protocols.

Dermoscopic Analysis of 72 "Atypical" Seborrheic Keratoses. / Análisis dermatoscópico de 72 queratosis seborreicas «atípicas¼.

BACKGROUND: Seborrheic keratoses (SK) are easily recognizable by clinical and dermoscopic approach, nevertheless, some lesions act as a simulator of different skin conditions lacking typical clinical and dermoscopic criteria. OBJECTIVE: The aim of our study was to find specific dermoscopic features or a global pattern to improve diagnostic skills for challenging SK. MATERIALS AND METHODS: We examined 72 atypical SK excised from September 2014 up to September 2017 by using the 2-step algorithm modified by Malvehy (2002) and Argenziano (2003). RESULTS: In our study population, an average of 4.04 out of 15 dermoscopic specific criteria for SK was found (for example, multiple milia-like cysts). Additional criteria not included in 2-step algorithm were blue-whitish veil (found in 3 SK; 4.2%), polymorphous vessels (18 SK; 25%), blotch/globules (6 SK; 8.3%), shiny white streaks (3 lesions; 4.2%). The most represented global patterns were reticular (27 SK; 37.5%) and not specific (15 SK; 20.8%). All lesions exhibited peculiar findings of SK, furthermore elements suggestive for melanocytic lesion were found in 79.2% of all lesions. Comparing the literature and our results, we found 3 significant differences: a) the less prevalence of SK specific criteria in our study population; b) the description of findings usually not related to SK, among which blue-whitish veil, polymorphous vessels, blotch/globules and shiny white streaks, and c) 2 patterns not previously defined represented by "not specific pattern" (20.9% of all lesions examined) and "vascular pattern" (12.5% of all lesions examined) were also described. No specific feature or global pattern, statistically significant for dermoscopic diagnosis of difficult-to-diagnose SK have been found. CONCLUSION: Nevertheless the useful findings, no specific feature or global pattern statistically significant for dermoscopic diagnosis of challenging SK have been found. According to the 2-step algorithm and the dermatoscopic scoring system for melanocytic and not melanocytic lesion, SK with one or more dermatoscopic findings typical of melanocytic lesion should be removed surgically to exclude classic melanoma or melanoma mimicking SK.

Antimicrobial properties of the medicinal plant Cardiospermum halicacabum L: new evidence and future perspectives.

The emergence and rapid spread of multidrug-resistance in human pathogenic microorganisms urgently require the development of novel therapeutic strategies for the treatment of infectious diseases. From this perspective, the antimicrobial properties of the natural plant-derived products may represent an important alternative therapeutic option to synthetic drugs. Among medicinal plants, the Cardiospermum halicacabum L. (C. halicacabum), belonging to Sapindaceae family, could be a very promising candidate for its antimicrobial activity against a wide range of microorganisms, including both Gram-positive and Gram-negative bacteria, as well as fungal pathogens. Although the antimicrobial properties of C. halicacabum have been intensively studied, the mechanism/s by which it exerts the inhibitory activity towards the pathogenic microbes have not yet been completely understood. This review focuses on the main antimicrobial activities displayed in vitro by the plant extract, with particular attention on our recent advances. We demonstrated that C. halicacabum is able to exert in vitro a dose-dependent fungistatic effect against Trychophyton rubrum (T. rubrum) through molecular interaction with the fungal heat shock protein (Hsp)-90 chaperone. These findings are supported by a growing body of research indicating the crucial role played by the Hsp90 in the virulence of the pathogenic microorganisms, including fungal pathogens. The possible future use of C. halicacabum for treating a wide range of infectious diseases is also discussed.

Whole exome sequencing approach to childhood onset familial erythrodermic psoriasis unravels a novel mutation of CARD14 requiring unusual high doses of ustekinumab.

BACKGROUND: Autosomal dominant gain of function mutations in caspase recruitment domain family member 14 (CARD14) is a rare condition associated with plaque-type psoriasis, generalized pustular psoriasis, palmoplantar pustular psoriasis and pityriasis rubra pilaris. Recently, a new CARD14 -associated phenotype defined as CAPE (CARD14-associated papulosquamous eruption) with clinical features of both psoriasis and pityriasis rubra pilaris was reported. We describe a family carrying a novel heterozygous mutation in CARD14 gene, with childhood-onset erythrodermic psoriasis requiring an unusual extremely high dose (up to 2 mg/kg every 8 weeks) of ustekinumab to achieve disease remission. CASE PRESENTATION: We describe a large family with three pairs of twins presenting a clinical phenotype characterized by childhood-onset erythrodermic psoriasis; in some family members is also reported psoriatic arthritis. The two probands presented poor clinical response to topic and systemic therapy with antihistamine, steroid, retinoids, cyclosporine and etanercept. After exclusion of the most common genes associated to autoinflammatory diseases (IL36RN, IL1RN, MVK, TNFRSF1A, NLRP3, NLRP12, MEFV, NOD2, PSMB8, PSTPIP1, LPIN2) we approached a new gene search by subjecting to Whole Exome Sequencing (WES) analysis five members of the family. A novel heterozygous mutation (c.446 T > G, leading to the missense amino acid substitution p.L149R) in the exon 4 of the CARD14 gene was identified in all affected members. Increasing dosages (up to 2 mg/kg every 8 weeks) of ustekinumab, a human monoclonal antibody targeting interleukin-12 (IL-12) and interleukin-23 (IL-23), allowed the complete control of the clinical manifestations, with an evident reduction of circulating Th17 and Th22 CD4+ T cell subsets. CONCLUSIONS: We describe the association of mutations of the CARD14 gene with an erythrodermic psoriasis pedigree, underlying the necessity to investigate CARD14 mutations in childhood-onset psoriasis cases and confirming the presence of CARD14 causative mutations also in erythrodermic psoriasis form, as recently reported. Also in pediatric age, ustekinumab represents a powerful therapeutic option for this rare condition, that is usually refractory to other treatments. In young children, high and frequent dosages allowed a complete control of the clinical manifestations without any severe side effects, with a long-term follow-up.

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.

The use of high-dose immunoglobulin in the treatment of pyoderma gangrenosum.

BACKGROUND: Immunosuppressive medications such as corticosteroids and cyclosporin are the most commonly employed therapies in pyoderma gangrenosum. We describe a patient with multiple ulcers of pyoderma gangrenosum on the lower extremities in whom immunosuppressive therapy caused serious side effects and had to be discontinued but who was subsequently treated successfully with high dose intravenous immunoglobulin (IVIG). METHODS: IVIG was given intravenously at a dose of 400 mg/kg per day for 5 consecutive days. After 1 week there was an arrest in the progression of the ulcers and a marked reduction in pain. Two weeks later clinical improvement of the ulcers was observed. Subsequently, IVIG was given at a dose of 1 g/kg per day for 2 consecutive days. RESULTS: The treatment induced a dramatic clinical improvement of one ulcer and healing of the others. Side effects were minimal and well tolerated, and consisted of chills and a slight fever, which resolved with the administration of acetaminophen. CONCLUSION: We feel that IVIG can be used in patients with pyoderma gangrenosum in whom conventional therapies are ineffective or produce serious side effects.

[New functions and applications of vitamin D in internal medicine]. / Nuove funzioni e applicazioni della Vitamina D in Medicina Interna.

The role of vitamin D (Vit. D) in bone metabolism is well known. It has recently been described that Vit. D exerts immunoregulatory activity, anti-proliferative and pro-differentiation mediated by intracellular receptors of the vitamin (VDR), so it seems to prevent the onset of some cancers (colon, prostate, etc.) and finally has a role in the evolution of some skin dermatoses such as psoriasis and atopic dermatitis. It well known that the presence of low blood levels of Vit. D, associated with the polymorphism of the VDR gene, may correlate with some inflammatory diseases such as also indicated by some authors, according to which the metabolites of Vit. D would be the clinical markers of certain diseases chronic and autoimmune diseases.