Efalizumab

Introduction: Conventional systemic therapies for psoriasis are associated with serious toxicities that can limit long-term use. In recent years, biological therapies have offered the possibility of long-term therapy with improved safety and efficacy for the treatment of psoriasis. Biological therapies can be classified into three categories: the T-cell modulating agents (alefacept and efalizumab), the inhibitors of TNF-alpha (adalimumab, etanercept, infliximab) and the inhibitors of IL-12 and -23 (ustekinumab). Efalizumab is a humanized recombinant monoclonal IgG1 antibody. It targets multiple stages in the immunopathogenesis of psoriasis: initial T-cell activation, migration of T-cells into dermal and epidermal tissues, and T-cell reactivation. On 19 February 2009, the Committee for Medicinal Products for Human Use (CHMP) recommended the suspension of the marketing authorisation for efalizumab.Areas covered: Numerous clinical trials have demonstrated the efficacy, safety and health-related quality of life benefits of efalizumab in patients with moderate-to-severe chronic plaque psoriasis. Efalizumab was approved by the FDA in November 2003 and by the European Medicines Evaluation Agency in September 2004 for the treatment of adult patients with moderate-to-severe chronic plaque psoriasis. Recently, three cases of progressive multifocal leukoencephalopathy were described in patients on long-term (> 3 years) efalizumab therapy, leading to its withdrawal from the market.Expert opinion: Although initially favorable, the safety profile of efalizumab revealed the appearance of severe adverse events in long-term treated patients. Therefore, post-marketing surveillance is essential for correct evaluation of drug potential

Methods and advanced Equipment for Simulation and Treatment in Radiation Oncology: programa MAESTRO

n/

Allelic Variants of HLA-C Upstream Region, PSORS1C3, MICA, TNFA and Genes Involved in Epidermal Homeostasis and Barrier Function Influence the Clinical Response to Anti-IL-12/IL-23 Treatment of Patients with Psoriasis

Several biologic therapies have been developed to treat moderate-to-severe psoriasis, with patients exhibiting different clinical benefits, possibly due to the heterogeneity of pathogenic processes underlying their conditions. Ustekinumab targets the IL-12/IL-23-p40 subunit and inhibits type-1 and type-17 T-cell responses. Although ustekinumab is effective as both short- and long-term treatment, therapeutic response varies considerably among patients. Ustekinumab biosimilars will be commercialized in the very next future, likely broadening the use of this drug in the treatment of psoriasis patients. Our pharmacogenomic study evaluated the influence of 417 single-nucleotide polymorphisms (SNPs) in psoriasis-risk alleles on the clinical response to ustekinumab in a cohort of 152 patients affected by moderate-to-severe plaque-type psoriasis. Differences in SNP pattern characterizing HLA-Cw6(+) or HLA-Cw6(-) patients, showing high or low responses to ustekinumab, were also analysed. We identified twelve SNPs in HLA-C upstream region (rs12189871, rs4406273, rs9348862 and rs9368670), PSORS1C3 (rs1265181), MICA (rs2523497), LCE3A-B intergenic region (rs12030223, rs6701730), CDSN (rs1042127, rs4713436), CCHCR1 (rs2073719) and in TNFA (rs1800610) genes associated with excellent response to ustekinumab. We also found that HLA-Cw6(+) and HLA-Cw6(-) patients carried out distinct patterns of SNPs associated with different clinical responses. The assessment of HLA-C alleles, together with other genetic variants, could be helpful for defining patients who better benefit from anti-IL-12/IL-23 therapy

Novel transglutaminase 1 mutations in patients affected by lamellar ichthyosis

Lamellar Ichthyosis (LI) is a form of congenital ichthyosis that is caused by mutations in the TGM1 gene that encodes for the transglutaminase 1 (TG1) enzyme. Functional inactivation of TG1 could be due to mutations, deletion or insertions. In this study, we have screened 16 patients affected by LI and found six new mutations: two transition/transversion (R37G, V112A), two nonsense mutations and two putative splice site both leading to a premature stop codon. The mutations are localized in exons 2 (N-terminal domain), 5, 11 (central catalytic domain), and none is located in the two beta-barrel C-terminal domains. In conclusion, this study expands the current knowledge on TGM1 mutation spectrum, increasing the characterization of mutations would provide more accurate prenatal genetic counselling for parents at-risk individuals

Tildrakizumab in moderate-to-severe plaque psoriasis: A multicenter, retrospective, real-life study

New biologic agents targeting interleukin (IL)23/T-helper17 axis, such as tildrakizumab, have been developed for the treatment of plaque psoriasis. To analyze the efficacy and safety of tildrakizumab in a real life setting of patients affected by moderate-to-severe psoriasis over a 28-week treatment period. A multicentric retrospective study was conducted in patients who initiated tildrakizumab between February 2020 and March 2021. Psoriasis Area and Severity Index-PASI was measured at baseline and after 4, 16 and 28 weeks. The percentage change in PASI value from baseline to the considered time-points, proportion of patients with absolute PASI <3 at week 28 and the percentages of achieving a PASI75 or PASI90 response were assessed. Data about potential safety issues and adverse events (AEs) were collected. Statistical analysis were performed for establish clinical efficacy and for variables predicting clinical response. Fifty nine patients with psoriasis were included. Overall mean PASI percentage reduction was of 88% from baseline to week 28 and 47 out of 59 patients (79.7%) at week 28 had an absolute PASI <3. PASI75 and PASI90 responses at week 28 were achieved by 48 (81.40%) patients and 38 (64.4.0%) patients, respectively. No substantial associations between gender, body mass index - BMI, PASI at baseline and prior exposition to biological therapies and the efficacy endpoints were retrieved. No serious safety issues or discontinuations related to adverse events were reported. In our real-life study, tildrakizumab showed high efficacy and a favorable safety profile, regardless of patient- and disease-related factors

Erythrodermic psoriasis treated with ustekinumab: An Italian multicenter retrospective analysis

Erythrodermic psoriasis (EP) is one of the most severe cutaneous conditions which may lead to serious morbidity and even mortality. This condition is often difficult to manage and, due to its rarity (estimated prevalence 1–2.25% of psoriatic patients) there is a lack of high-quality medical literature examining treatment options [1]

Proton imaging apparatus for protontherapy application

Radiotherapy with protons, due to the physical properties of these particles, offers several advantages for cancer therapy as compared to the traditional radiotherapy with photons. In the clinical use of proton beams, a pCT (proton Computed Tomography) apparatus can contribute to improve the accuracy of the patient positioning and dose distribution calculation. In this paper a pCT apparatus built by the PRIMA (PRoton IMAging) Italian Collaboration will be presented and the preliminary results will be discussed

Data acquisition system for a proton imaging apparatus

New developments in the proton-therapy field for cancer treatments, leaded Italian physics researchers to realize a proton imaging apparatus consisting of a silicon microstrip tracker to reconstruct the proton trajectories and a calorimeter to measure their residual energy. For clinical requirements, the detectors used and the data acquisition system should be able to sustain about 1 MHz proton rate. The tracker read-out, using an ASICs developed by the collaboration, acquires the signals detector and sends data in parallel to an FPGA. The YAG:Ce calorimeter generates also the global trigger. The data acquisition system and the results obtained in the calibration phase are presented and discussed

Dose ratio proton radiography using the proximal side of the Bragg peak

Purpose: In recent years there has been a movement towards single-detector proton radiography, due to its potential ease of implementation within the clinical environment. One such single-detector technique is the dose ratio method, in which the dose maps from two pristine Bragg peaks are recorded beyond the patient. To date, this has only been investigated on the distal side of the lower energy Bragg peak, due to the sharp fall-off. We investigate the limits and applicability of the dose ratio method on the proximal side of the lower energy Bragg peak, which has the potential to allow a much wider range of water-equivalent thicknesses (WET) to be imaged. Comparisons are made with the use of the distal side of the Bragg peak. Methods: Using the analytical approximation for the Bragg peak we generated theoretical dose ratio curves for a range of energy pairs, and then determined how an uncertainty in the dose ratio would translate to a spread in the WET estimate. By defining this spread as the accuracy one could achieve in the WET estimate, we were able to generate look-up graphs of the range on the proximal side of the Bragg peak that one could reliably use. These were dependent on the energy pair, noise level in the dose ratio image and the required accuracy in the WET. Using these look-up graphs we investigated the applicability of the technique for a range of patient treatment sites. We validated the theoretical approach with experimental measurements using a complementary metal oxide semiconductor active pixel sensor (CMOS APS), by imaging a small sapphire sphere in a high energy proton beam. Results: Provided the noise level in the dose ratio image was 1% or less, a larger spread of WETs could be imaged using the proximal side of the Bragg peak (max 5.31 cm) compared to the distal side (max 2.42 cm). In simulation it was found that, for a pediatric brain, it is possible to use the technique to image a region with a square field equivalent size of 7.6 cm2, for a required accuracy in the WET of 3 mm and a 1% noise level in the dose ratio image. The technique showed limited applicability for other patient sites. The CMOS APS demonstrated a good accuracy, with a root-mean-square-error of 1.6 mm WET. The noise in the measured images was found to be σ =1.2% (standard deviation) and theoretical predictions with a 1.96σ noise level showed good agreement with the measured errors. Conclusions: After validating the theoretical approach with measurements, we have shown that the use of the proximal side of the Bragg peak when performing dose ratio imaging is feasible, and allows for a wider dynamic range than when using the distal side. The dynamic range available increases as the demand on the accuracy of the WET decreases. The technique can only be applied to clinical sites with small maximum WETs such as for pediatric brains