Real-world safety and efficacy of biologics in elderly patients with psoriasis: A multicenter observational study.

Clinical trials of biologics have frequently excluded elderly patients, resulting in inadequate data on their safety and efficacy. Additionally, evidence of their safety and efficacy remains limited, despite some real-world studies. To assess the safety and efficacy of biologics in elderly patients with psoriasis, we compared these outcomes in younger patients using data from the West Japan Psoriasis Registry (WJPR). The WJPR consists of approximately 30 facilities in Western Japan, including various healthcare settings. This study enrolled 1395 patients who participated in the 2022 follow-up survey of the WJPR and were either using or had used biologics during the survey. These included 456 patients in the elderly group (≥65 years) and 939 patients in the younger group (<65 years). Treatment-ending adverse events (TEAEs) occurred in 15.8% and 11.3% of elderly and younger patients, respectively. The incidence rate per 1000 patient-years (PY) for TEAEs was significantly higher in elderly patients than in younger patients (32.9 vs 23.2, p = 0.0234). Infectious diseases were more prevalent in the elderly group than the younger group; however, no significant difference in the frequency of infectious diseases was found between the two groups (p = 0.0807). Malignant neoplasms occurred significantly more frequently in the elderly group than in the younger group (p = 0.0169). Our results indicate a few concerns about infection when prescribing biologics to elderly patients. Biologics were effective for both elderly and younger patients. We found no significant differences in the proportion of patients with a body surface area score ≤3%, Physician's Global Assessment score 0/1, or Patient's Global Assessment score 0/1, as well as in the mean Dermatology Life Quality Index and the Itch Numerical Rating Scale between the younger and the elderly groups. Overall, our results confirm the appropriateness of using biologics in elderly patients with regard to safety and efficacy.

Survival rates of systemic interventions for psoriasis in the Western Japan Psoriasis Registry: A multicenter retrospective study.

Psoriasis affects approximately 0.3% of the Japanese population. Recently, various effective systemic drugs have become available, and the continuation of a given treatment has become critical because of the chronic nature of psoriasis. Factors affecting drug survival (the time until treatment discontinuation) in psoriasis treatment include efficacy, safety, ease of use, and patient preference. In the present study, the authors retrospectively surveyed a multifacility patient registry to determine the real-world evidence of the survival rate of systemic interventions for psoriasis treatment. Patients with psoriasis who visited 20 facilities in the Western Japan area between January 2019 and May 2020 and gave written consent were registered as study participants, and their medical history of systemic interventions for psoriasis (starting from 2010) was retrospectively collected and analyzed. The drugs investigated were adalimumab, infliximab, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, risankizumab, cyclosporine, and apremilast. When drugs were discontinued, the reasons were also recorded. A total of 1003 patients with psoriasis including 268 with psoriatic arthritis (PsA) were enrolled. In biologics, more recently released drugs such as interleukin 17 inhibitors showed a numerically higher survival rate in the overall (post-2010) analysis. However, in the subset of patients who began treatment after 2017, the difference in the survival rate among the drugs was smaller. The reasons for discontinuing drugs varied, but a loss of efficacy against dermatological or joint symptoms were relatively frequently seen with some biologics and cyclosporine. The stratification of drug survival rates based on patient characteristics such as bio-naive or experienced, normal weight or obese, and with or without PsA, revealed that bio-experienced, obese, and PsA groups had poorer survival rates for most drugs. No notable safety issues were identified in this study. Overall, the present study revealed that the biologics show differences in their tendency to develop a loss of efficacy, and the factors that negatively impact the survival rate of biologics include the previous use of biologics, obesity, and PsA.

Low-intensity ultrasound inhibits melanoma cell proliferation in vitro and tumor growth in vivo.

PURPOSE: To determine the effect of low-intensity ultrasound on cancer cell proliferation in vitro and tumor growth in vivo. METHODS: In vitro, several cancer cell lines were exposed to low-intensity ultrasound at 0.11 W/cm2 for 2 min. Of the cell lines screened, melanoma C32 is one of the cell lines that showed sensitivity to growth inhibition by ultrasound and was therefore used in succeeding experiments. In vivo, under the same ultrasound conditions used in vitro, C32 tumors in mice were exposed to ultrasound daily for 2 weeks, and the tumor volumes were monitored weekly using sonography. RESULTS: In vitro, C32 cell growth was inhibited, attaining 43.2% inhibition on the 3rd day. In vivo, tumor growth was significantly inhibited, with the treated tumors exhibiting 2.7-fold slowed tumor growth vs. untreated tumors at week 2. Such inhibition was not associated with increased cell death. Several genes related to the cell cycle and proliferation were among those significantly regulated. CONCLUSION: These findings highlight the potential of low-intensity ultrasound to inhibit tumor growth in a noninvasive, safe, and easy-to-administer way. In addition, this may suggest that the mechanical stress induced by ultrasound on C32 cells may have affected the intrinsic biomolecular mechanism related to the cell growth of this particular cell line. Further research is needed to identify which of the regulated genes played key roles in growth inhibition.

Ethylene treatment of "Maekawa-Jiro" persimmon affects peel characteristics and consequently, enables boil-peeling.

In a previous study, we reported that ethylene treatment facilitated boil-peeling in persimmons and in several other fruits; however, the mechanism underlying the facilitating effect of ethylene was not examined in detail. Thus, in this study, we investigated the effect of ethylene treatment on the peel characteristics of persimmons, that facilitated boil-peeling, using chemical, genomic, and histochemistry analyses. The results of the study showed that the ethylene-related genes, DK-ACS1 and DK-ACO2, and the pectinase-active gene DKPG were not expressed, even though a minor increase in ethylene generation was observed after ethylene treatment. Conversely, significant accumulation of toluidine blue O and ruthenium red dyes were observed in the sarcocarp and exocarp of the fruits, indicating an increase in the quantity of polysaccharides, including pectic substances, at the site. The results also indicate that the increased cellulase activity observed in the pericarp of the fruits may be due to the aging of the fruits, and not necessarily as a result of ethylene treatment. Furthermore, ethylene treatment increased the quantity of polysaccharides, including pectic substances, directly below the pericarp, which caused the dissolution of the site, resulting in peeling. This study provides new insights on the effect of ethylene on boil-peeling in persimmons and provides a foundation for future research studying the effect of heat treatment in the peeling of fruits or tomato.

Mycobacterium tuberculosis infection in psoriatic patients treated with biologics: Real-world data from 18 Japanese facilities.

Although rare, tuberculosis has been reported with biologic treatment against psoriasis in Japan, a tuberculosis medium-burden country. Mycobacterial infection often develops after a long incubation period and might not have been adequately identified in clinical trials or post-marketing surveillance. To determine the real-world incidence of tuberculosis in psoriatic patients treated with biologics, we conducted a retrospective, multicenter, observational study in 18 facilities in Western Japan. Psoriatic patients who visited a participating facility between 2010 and March 2017 and received biologic reagents were enrolled. Information on sex, age at first biologic treatment, results of interferon-γ release assay (IGRA) for Mycobacterium tuberculosis, treatment history with isoniazid, and onset of active and/or latent tuberculosis was collected. A total of 1117 patients (830 men and 287 women) were enrolled. The mean duration of biologic treatment was 3.54 years. Sixty-five patients (5.8%) showed positive IGRA results at screening. Active tuberculosis developed in two patients after the administration of tumor necrosis factor inhibitors (both involved miliary tuberculosis). Latent tuberculosis was observed in two patients treated with anti-interleukin-12/23p40 antibody. The incidence rate of tuberculosis, including latent tuberculosis, in this survey was 0.36%. Although the incidence rate of tuberculosis was low considering the observation period of biologic treatment, active tuberculosis was found in both the screening-negative group and a screening-positive subject after isoniazid prophylaxis (both miliary tuberculosis), concluding that negative screening or isoniazid treatment does not always assure that an individual has no tuberculosis. Hence, dermatologists still need to pay careful attention to tuberculosis at every patient visit.

Ethylene facilitates boil-peeling in fruits.

Boil-peeling is a common method of cooking or processing some horticultural crops. While boil-peeling is possible in some horticultural crops, a comprehensive list of crops for which boil-peeling is possible does not exist. According to a previous study, ethylene facilitates boil-peeling of kiwifruits. Thus, we studied the effect of ethylene treatment on boil-peeling in the kiwifruit variety "Rainbow red." We found that with increasing ethylene concentration in the fruits, boil-peeling success of kiwifruits increased. In the no-ethylene treatment, flesh firmness of the fruits decreased and boil-peeling could not be carried out successfully. Thus, it was clear that ethylene facilitates boil-peeling in kiwifruit. Furthermore, boil-peeling was possible after ethylene treatment in persimmon and Japanese pear, which had proved to be impossible so far. Kiwifruits, persimmon, and Japanese pear were classified as climacteric fruits that react with high ethylene sensitivity. Thus, ethylene may facilitate boil-peeling in climacteric fruits. This finding can possibly suggest new application for ethylene during fruit processing or in processed fruits.

Cross-sectional multicenter observational study of psoriatic arthritis in Japanese patients: Relationship between skin and joint symptoms and results of treatment with tumor necrosis factor-α inhibitors.

Psoriatic arthritis (PsA) is an inflammatory arthritis with as yet unclear pathophysiology. This retrospective, multicenter, cross-sectional study was conducted in 19 facilities in western Japan and aimed to identify patients' characteristics and factors that affect the results of treatment with biologic agents. Of 2116 patients with psoriasis, 285 (13.5%) had PsA. Skin manifestations preceded joint manifestations in 69.8%, the onset was simultaneous in 17.2%, whereas PsA preceded skin manifestations in 2.5%. Peripheral arthritis was most common, occurring in 73.7%, compared with axial disease in 21.8%, enthesitis in 23.5% and dactylitis in 35.4%. Patients with severe skin manifestations were significantly younger at onset (P = 0.02) and more frequently had axial disease (P < 0.01). Biologic agents were used in 206 patients (72.3%), anti-tumor necrosis factor (TNF)-α antibodies being prescribed first to 157 of them. Anti-TNF-α antibodies were continued by 105 participants and discontinued by 47, the remaining five patients being lost to follow up. Patients who discontinued anti-TNF-α antibodies were significantly older than those who continued (55 vs 51 years, P = 0.04) and significantly older at onset of joint manifestations (50 vs 44 years, P = 0.01). Multivariate analysis revealed that patients over 50 years significantly more frequently terminated anti-TNF-α antibodies (P < 0.01). In conclusion, patients with PsA and severe skin manifestations have earlier onset and axial disease, which seriously impacts on quality of life. Anti-TNF-α antibodies were generally effective enough to continue but less so in patients aged over 50 years. Further detailed research is needed.

Ultrasound-mediated interferon ß gene transfection inhibits growth of malignant melanoma.

We investigated the effects of ultrasound-mediated transfection (sonotransfection) of interferon ß (IFN-ß) gene on melanoma (C32) both in vitro and in vivo. C32 cells were sonotransfected with IFN-ß in vitro. Subcutaneous C32 tumors in mice were sonicated weekly immediately after intra-tumor injection with IFN-ß genes mixed with microbubbles. Successful sonotransfection with IFN-ß gene in vitro was confirmed by ELISA, which resulted in C32 growth inhibition. In vivo, the growth ratio of tumors transfected with IFN-ß gene was significantly lower than the other experimental groups. These results may lead to a new method of treatment against melanoma and other hard-to-treat cancers.

Synergistic inhibition of malignant melanoma proliferation by melphalan combined with ultrasound and microbubbles.

The cavitational effects of ultrasound (US) exposure induce transient pores on the cell membrane (sonoporation). Sonoporation have been applied in the field of cancer therapy by promoting delivery of extracellular molecules such as drugs and genes into cytoplasm. In addition, it is known that using US together with microbubbles (MB) elevates permeability of these agents. In this study, by applying the US-MB strategy for melanoma chemotherapy, we evaluated the antitumor effect of melphalan combined with US-MB on a melanoma cell line (C32) in vitro and in vivo. The in vitro cytotoxic effect of the melphalan with US-MB was greater than that of melphalan alone or melphalan in combination with US. In vivo experiments using xenografts, intratumoral injection of melphalan and MB with US exposure led to a greater degree of tumor regression than did the intratumoral injection of the melphalan alone or melphalan in combination with US. These results suggest that US-MB promotes the antitumor effect of melphalan by increasing delivery of molecules into cells and that this strategy may become an effective method of adjuvant therapy against malignant melanoma.

Hypotonia-induced cell swelling enhances ultrasound-induced mechanical damage to cancer cells.

INTRODUCTION: It has been shown that killing of suspended cells by low-intensity ultrasound (0.08-0.11 W/cm(2)) can be enhanced by a mild non-lethal hypotonic (146 mOsm) medium. PURPOSE: In this study we wished to determine whether hypotonia-induced cell swelling of suspension cells was directly related to enhancement of ultrasound-mediated cell killing, and to verify whether similar effects could be observed on circulating and attached cells. METHODS: U937 cells under mild hypotonia were exposed to ultrasound for different times with real-time monitoring of cell size using a particle-size-distribution analyzer. To study the effect on attached cells, HeLa cells were exposed to ultrasound while under hypotonia in an in vivo-simulated set-up. RESULTS: The result showed that the enhanced cell killing (up to more than twice) was directly proportional to hypotonia-induced cell swelling. Similar membrane damage based on PI staining could be observed on HeLa cells treated with hypotonia. An in vivo-simulated circulating system also showed similar findings for hypotonia-enhanced ultrasound cell killing. CONCLUSION: These findings showed that mild hypotonia can be used to augment the effect of ultrasound in the treatment of cancers, particularly leukemia. The results showing that such enhancement is related to cell swelling could guide us toward proper timing of sonication while under hypotonic treatment.

Growth inhibition of neurofibroma by ultrasound-mediated interferon γ transfection.

PURPOSE: We have previously shown that ultrasound-mediated transfection (sonotransfection) can be optimized using a concept based on the ultrasound-induced apoptosis produced in our in vitro experiments. At optimized conditions, we have shown, using five cancer cell lines, that sonotransfection is superior to other conventional nonviral methods. Interferon gamma (IFN-γ) transfection using lipofection has been found to markedly inhibit the proliferation of neurofibroma cell lines. In this study, we investigated whether sonotransfection of IFN-γ to neurofibroma cell lines can suppress cell proliferation. METHODS: The ultrasound device used was the SonoPore KTAC-4000, which is capable of various acoustic settings. Ultrasound transducers at an oscillation frequency of 1.011 MHz were used; the potential ideal conditions were an intensity of 0.17 W/cm(2) at a burst frequency of 0.5 Hz, 25% duty factor, and 30-s sonication duration. Cells were assayed at 3 and 5 days after sonication. RESULTS: The transfection efficiency was found to be 12%. The ultrasound-treated cells were successfully transfected with IFN-γ genes as detected by enzyme-linked immunosorbent assay, and the cell growth ratio in the IFN-γ sonotransfection group tended to be lower than that in the other experimental groups. CONCLUSION: These results suggested that IFN-γ sonotransfection could potentially become a nonsurgical method for treating skin lesions such as neurofibromas.

Therapeutic potential of low-intensity ultrasound (part 1): thermal and sonomechanical effects.

In this first part of the review, we will focus on and discuss various aspects of low-intensity ultrasound (US), with emphasis on mild thermal effects, apoptosis induction, and sonomechanical effects. Mild thermal effects of US have been commonly applied to physical therapy. Though US has clear beneficial effects, the advantage of using US over other heating modalities remains unclear. US has also been used in vivo and clinically in the treatment of wounds and fractures, with promising results. On the biomolecular level, studies have shown that US can induce apoptosis and that certain conditions can provide optimal apoptosis induction. As to potential therapeutic applications, in addition to the thermal and other physical effects, apoptosis induction by US may offer direct and rapid treatment of tumors or cancer tissues. Technological advances and rapidly accelerating research in this field are providing an ever-increasing array of therapeutic options for lowintensity US.