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.

Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus.

LL37 exerts a dual pathogenic role in psoriasis. Bound to self-DNA/RNA, LL37 licenses autoreactivity by stimulating plasmacytoid dendritic cells-(pDCs)-Type I interferon (IFN-I) and acts as autoantigen for pathogenic Th17-cells. In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is target of pathogenic autoantibodies. However, whether LL37 activates T-cells in SLE and how the latter differ from psoriasis LL37-specific T-cells is unknown. Here we found that 45% SLE patients had circulating T-cells strongly responding to LL37, which correlate with anti-LL37 antibodies/disease activity. In contrast to psoriatic Th17-cells, these LL37-specific SLE T-cells displayed a T-follicular helper-(TFH)-like phenotype, with CXCR5/Bcl-6 and IL-21 expression, implicating a role in stimulation of pathogenic autoantibodies. Accordingly, SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro. Importantly, we identified abundant citrullinated LL37 (cit-LL37) in SLE tissues (skin and kidney) and observed very pronounced reactivity of LL37-specific SLE T-cells to cit-LL37, compared to native-LL37, which was much more occasional in psoriasis. Thus, in SLE, we identified LL37-specific T-cells with a distinct functional specialization and antigenic specificity. This suggests that autoantigenic specificity is independent from the nature of the autoantigen, but rather relies on the disease-specific milieu driving T-cell subset polarization and autoantigen modifications.

Sox2 is not required for melanomagenesis, melanoma growth and melanoma metastasis in vivo.

Melanoma is a dangerous form of skin cancer derived from the malignant transformation of melanocytes. The transcription factor SOX2 is not expressed in melanocytes, however, it has been shown to be differentially expressed between benign nevi and malignant melanomas and to be essential for melanoma stem cell maintenance and expansion in vitro and in xenograft models. By using a mouse model in which BRafV600E mutation cooperates with Pten loss to induce the development of metastatic melanoma, we investigated if Sox2 is required during the process of melanomagenesis, melanoma growth and metastasis and in the acquisition of resistance to BRAF inhibitors (BRAFi) treatments. We found that deletion of Sox2 specifically in Pten null and BRafV600E-expressing melanocytes did not prevent tumor formation and did not modify the temporal kinetics of melanoma occurrence compared to Sox2 wt mice. In addition, tumor growth was similar between Sox2 wt and Sox2 deleted (del) melanomas. By querying publicly available databases, we did not find statistically significant differences in SOX2 expression levels between benign nevi and melanomas, and analysis on two melanoma patient cohorts confirmed that Sox2 levels did not significantly change between primary and metastatic melanomas. Melanoma cell lines derived from both Sox2 genotypes showed a similar sensitivity to vemurafenib treatment and the same ability to develop vemurafenib resistance in long-term cultures. Development of vemurafenib resistance was not dependent on SOX2 expression also in human melanoma cell lines in vitro. Our findings exclude an oncogenic function for Sox2 during melanoma development and do not support a role for this transcription factor in the acquisition of resistance to BRAFi treatments.

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.

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.

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.

Long-term treatment of plaque psoriasis with efalizumab: an Italian experience.

Biologic agents are an important new class of drugs, offering targeted treatment for chronic skin diseases such as psoriasis. The biologic therapy efalizumab is an anti-CD11a monoclonal antibody, which was approved by the European regulatory agency in 2004 for the treatment of moderate-to-severe plaque psoriasis. Here we describe our 2-year experience in treating over 100 patients with moderate-to-severe psoriasis with efalizumab at two dermatology centres in Italy. Overall, we found efalizumab is efficacious for a large subset of patients, regardless of previous therapies received, and has an easily manageable safety profile. We believe one important quality of efalizumab is the stability and maintenance of clinical response over time. We found that most patients who respond to treatment experience a long-term clearing of psoriasis with only mild recurrence events. Our experience with individual cases provides specific insights into efalizumab re-treatment, the use of efalizumab in patients with a history of heart failure, and the management of patients who become pregnant or conceive while receiving efalizumab therapy. In summary, our off-trial experience in over 100 patients confirms the efficacy and safety of efalizumab in the treatment of moderate-to-severe plaque psoriasis.

[Principles of the clinical evaluation of the vulvar region]. / Principi di valutazione clinica della regione vulvare.

The clinical examination of the vulva, using an articulated method, should form part of the routine gynecological examination thus enabling both the correct diagnosis and treatment of numerous alterations and the prevention and early diagnosis of VIN and invasive neoplasias. A correct evaluation should include basic anamnestic data, a list of symptoms localised in the vulva region, a careful inspection and palpation. The successive aim is to identify the main clinical aspects of the lesion which can be summarized as changes of colour, presence of swellings on surface and loss of substance. The critical evaluation of lesions should allow critical evaluation of lesions should allow the gynecologist to formulate a diagnosis to propose to the pathologist. In this way the collaboration between clinician and pathologist can contribute to progress in the diagnosis and treatment of vulvar diseases.

[Possible relationship between childhood malaise and psychiatric disorders in adulthood. Preliminary study on an in-patient sample from the psychiatric unit of the general hospital in Pavia]. / Possibili rapporti tra disagio infantile e patologia psichiatrica adulta. Studio preliminare su un campione di utenti del SPDC di Pavia.

The authors report the preliminary data of a study which aims to identify the variables (socio-demographic, clinical and nosographic) which may be used to predict the evolution of psychiatric disorders. A retrospective follow-back study was carried out using the medical records and any other documentation available from medical and psychological centers in order to identify the evolutionary stages of disease and possible pre-disease antecedents. The sample group examined was selected from users attending the Diagnosis and Treatment Psychiatric Unit at Pavia Hospital who were found to have undergone infantile neuropsychiatric outpatient or hospital treatment during childhood. The preliminary phase of the study reports the results of the first 42 cases. The predictive value of the diagnosis made during childhood emerges from an analysis of the results and consequently emphasises the need to orient Infantile Neuropsychiatric structure not only towards diagnosis and care but also, towards a more strictly therapeutic action.

Neoadjuvant chemotherapy or chemotherapy and endocrine therapy in locally advanced breast carcinoma. A prospective, randomized study.

Forty-nine patients with locally advanced breast carcinoma were prospectively randomized to be treated with either CMF or CMF plus T for four courses, both before and after mastectomy. The overall clinical objective remission rate for induction treatment was similar (71% with CMF and 64% with CMF + T). The time to progression or recurrence of the disease was also not significantly different between the two groups. Overall survival was shorter after CMF + T treatment (median value of 41.5 months) than after CMF treatment alone (median value of 79.7 months; p = 0.05). Even after progression or recurrence, survival was shorter for patients receiving CMF + T than those receiving CMF (median values of 7.5 and 17.3 months, respectively; p = 0.09). These results show that the addition of T to CMF in the treatment of locally advanced breast carcinoma, before and after mastectomy, offers no advantage for improving the overall response rate. Moreover, this addition may have an adverse impact on survival in this disease setting.

Problems in evaluating response of primary breast cancer to systemic therapy.

The evaluation of the response of primary breast cancer to systemic therapy is difficult. Evaluable primary lesions may be assessed both by physical and by mammographic examination. In this study, response to therapy was evaluated after 4 cycles of CMF or CMF plus tamoxifen in 49 patients with locally advanced breast cancer entering a prospective randomized trial. In 35 patients response was evaluated by both physical examination and mammography. In some cases there was disagreement between physical examination and mammography in quantifying the magnitude of response. In 8 of 35 (22.9%), the overall response was overestimated by physical examination versus mammography, while in 3 of 35 (8.6%) the reverse was true. Taking into consideration different criteria in attributing the overall response, i.e. selecting physical examination only, mammography only, or the most favorable or the least favorable response between the two methods of assessment, the objective remission rates were 65.7%, 54.3%, 71.4% and 45.7%, respectively. The data suggest that both physical examination and mammography should be used in evaluating the response of primary breast cancer to a systemic treatment. Should these two methods yield contrasting results, the data obtained with each method should be reported. The best observed response may be employed in determining the overall response.

Home vs hospital care of children with behavior disorders. A controlled investigation.

A controlled investigation was conducted to assess and compare the treatment outcomes of community and hospital care for children with behavior disorders. Findings showed that (1) community care was effective with regard to behavioral control, and (2) both treatments were comparable concerning educational achievement, parent role function, family adjustment, and parent satisfaction with treatment. It was noted that many severely disturbed children who are in dire socioeconomic predicaments can be maintained in the community with special care and intervention.

Experience with a new vascular prosthetic device (Sparks mandril) for periodic haemodialysis.

In eighteen months, eleven Sparks mandrils have been implanted in ten patients who presented serious vascular access problems. So far nine mandrils have been anastomosed and six are functioning. In one patient the apparatus, inserted in the right leg, clotted after 108 dialyses and was reinserted in the left arm; after a further forty dialyses the patient died from causes not connected with dialysis. Another patient's Sparks mandril thrombosed from infection on the fourth post-operative day. Using a single needle apparatus, 693 dialyses have been carried out with particular problems either for the patients or the grafts.