Dietary Fiber Inulin Improves Murine Imiquimod-Induced Psoriasis-like Dermatitis.

Psoriasis is a chronic skin disease with interleukin (IL)-17-dominated inflammation and hyperproliferation of epidermis. Dietary fiber is fermented by the gut microbiome into short-chain fatty acids (SCFAs) that manifest anti-inflammatory effects. We examined if feeding with an inulin-enriched high-fiber diet (HFD) might improve topical imiquimod-induced psoriasis-like dermatitis in mice. HFD reduced thickening and total severity scores of imiquimod-induced dermatitis and reduced epidermal thickness, inflammatory infiltrates, including Ly6G+ neutrophils, and epidermal Ki67+ proliferating cells. HFD reduced mRNA levels of IL-17A, IL-17F, IL-22, IL-1ß, tumor necrosis factor (TNF)-α, CXCL1, CXCL2, and keratin 16 and increased those of transforming growth factor (TGF)-ß1 and cyclin-dependent kinase inhibitor 1A in imiquimod-induced dermatitis. In 16S rRNA sequencing of the gut microbiome, imiquimod increased relative abundance of phylum Firmicutes, while HFD increased that of phylum Bacteroidota and genus Bacteroides. HFD increased serum and fecal concentrations of SCFA propionate. Oral propionate reduced inflammatory infiltrates and epidermal Ki67+ cells and reduced mRNA levels of IL-17A, IL-17F, IL-17C, IL-22, IL-1ß, IL-6, TNF-α, CXCL1, CCL20 and increased those of TGF-ß1and IL-10 in imiquimod-indued dermatitis. Dietary inulin supplementation improves imiquimod-induced psoriasis-like dermatitis partially via propionate, and may be a promising adjunctive therapy for psoriasis.

O-GlcNAcylation of myocyte-specific enhancer factor 2D negatively regulates insulin secretion from pancreatic ß-cells.

Patients with type 2 diabetes often exhibit impairments in both glucose-induced insulin secretion (GIIS) and incretin-induced insulin secretion (IIIS). These phenotypes are associated with altered glucose metabolism in pancreatic ß-cells, although the molecular mechanisms remain unclear. Here, we used MIN6-K8 pancreatic ß-cell lines as a model to examine the effect of O-linked N-acetylglucosamine glycosylation (O-GlcNAcylation), a glucose-induced protein posttranslational modification, on insulin secretion. O-GlcNAcylation was enhanced in high-glucose-treated MIN6-K8 cells, and high levels of O-GlcNAcylation attenuated PKA-dependent phosphorylation, suggesting that the two protein modifications may compete with each other. Immunoprecipitation proteomic analysis identified six candidate proteins that were O-GlcNAcylated by high-glucose treatment, whereas the O-GlcNAcylations were removed by treatment with an incretin mimetic, exendin-4. Among these proteins, knockdown of myocyte enhancer factor 2D (Mef2d) enhanced insulin secretion, and high-glucose treatment increased the level of O-GlcNAcylation of Mef2d in MIN6-K8 cells. Furthermore, knockout of Mef2d promoted GIIS in MIN6-K8 cells, whereas adenovirus-mediated rescue of Mef2d decreased GIIS in the knockout cells. These results suggest that Mef2d negatively regulates insulin secretion through O-GlcNAcylation.

Dietary diversity and food choice motives during the COVID-19 pandemic among older Japanese: An Internet Panel Survey.

BACKGROUND AND OBJECTIVES: We examined how food choice motives and dietary habits changed during the COVID-19 pandemic. METHODS AND STUDY DESIGN: Four hundred elderly Japanese completed an online questionnaire in early May in 2021. Participants were retrospectively asked about their intake of food groups and food choice motives before and during the COVID-19 pandemic. Dietary diversity was determined using the dietary variety score calculated from the food frequency questionnaire with 10 food groups. The importance of each of the nine food choice motives for elderly people was assessed. Each scores ranged from 1 to 5. Changes in food choice motives and dietary behaviors during the COVID-19 pandemic were assessed using the paired t-test and a general linear model. RESULTS: Among the food choice motives, scores for the importance of weight control, physical well-being and economical efficiency significantly increased in both sexes (all p<0.05). Dietary diversity score was lower during the COVID-19 pandemic than that before the pandemic in women (p=0.019), but there was no difference in men. In the multivariate adjustment model, physical well-being and economical efficiency were shown to have significant positive associations with the COVID-19 pandemic in women (p=0.034 and 0.009, respectively). In contrast, eating out was shown to have a significant inverse association with the COVID-19 pandemic in women (p=0.009). CONCLUSIONS: The findings suggest that the COVID-19 pandemic was associated with an increase in some food choice motives and a decrease in the frequency of eating out among elderly female Japanese.

Combining maintenance therapy with hydroxychloroquine increases LLDAS achievement rates in individuals with stable systemic lupus erythematosus.

BACKGROUND: Hydroxychloroquine (HCQ) has been positioned as an anchor drug for systemic lupus erythematosus (SLE). There is evidence supporting the benefits of HCQ; however, the effect of additional HCQ in maintenance therapy remains unclear. METHODS: Thirty patients with SLE who visited Juntendo University Hospital were receiving maintenance therapy before HCQ treatment and were able to complete more than 104 weeks of HCQ treatment were analyzed. Anti-DNA antibody titers, IgG and CH50 levels, the maintenance dose of corticosteroids, the SLE disease activity index (SLEDAI), and the achievement of the Lupus Low Disease Activity State (LLDAS) were evaluated at baseline and at 12, 24, 52, and 104 weeks after HCQ initiation. RESULTS: We observed improvements in the anti-DNA antibody titers, IgG and CH50 levels, maintenance dose of corticosteroids, and SLEDAI at week 104 relative to baseline. Moreover, the LLDAS achievement rate increased over time from 10% at baseline to 43% and 80% at week 52 and week 104, respectively. CONCLUSION: Two years of continuous HCQ treatment led to improvements in SLE disease activity and corticosteroid dose and an increase in LLDAS achievement, thereby demonstrating the significance of the maintenance dose of HCQ for the management of SLE.

Kidney function, blood pressure and proteinuria were associated with pregnancy outcomes of pregnant women with chronic kidney disease: a single-center, retrospective study in the Asian population.

BACKGROUND: Studies among pregnant Asian women with chronic kidney disease (CKD) have not been widely performed; therefore, clinical criteria for these patients have not been well established. METHODS: We conducted a retrospective study among pregnant women with CKD who received prenatal care at our institution for 8 consecutive years. Primary outcome was the development of severe adverse events (SAEs). We analyzed correlations between primary outcome and CKD parameters [age, body mass index (BMI), estimated glomerular filtration rate (eGFR), urinary protein-creatinine ratio (UP), systolic blood pressure (SBP), diastolic blood pressure (DBP), and not normal blood pressure (non-NBP)] at the time of referral. Secondary outcomes were low birth weight (LBW), preterm delivery (PreD), and small for gestational age (SGA). We divided into two categories, CKD stage G1, and G2 or higher according to eGFR, and proteinuria negative and proteinuria positive according to UP, respectively. RESULTS: We observed 89 pregnancies. SAE was observed in 28 pregnancies. In live birth cases, there were 28 PreD, 28 LBW and 13 SGA. Major SAEs included preeclampsia, superimposed preeclampsia, unscheduled cesarean section, neonatal intensive care unit admission, and fetal death. Stepwise logistic regression analysis selected eGFR (OR = 0.847, p = 0.026), SBP (OR = 1.897, p = 0.006) and proteinuria positive (OR = 2.96, p = 0.046) as the significant predictors of SAEs. There were no significant differences among the baseline characteristics stratified by SGA. CONCLUSIONS: This is the first study to report pregnancy outcomes among Japanese non-disease-oriented patients with CKD. In Asians, especially in the Japanese population, kidney function, blood pressure and proteinuria might affect pregnancy outcomes.

Questionnaire survey on the prescription of renal replacement therapy for acute phase patients on maintenance dialysis who developed cerebrovascular disease.

BACKGROUND: There is limited information about acute phase renal replacement therapy (RRT) for maintenance hemodialysis patients after the onset of cerebrovascular disease. This study aimed to investigate which modality of renal replacement therapy is currently selected in practice. METHODS: We conducted a mail-based survey in 317 dialysis facilities that were certified by three academic societies that focus on dialysis, neurology, and neurosurgery in Japan. RESULTS: We received responses from 103 facilities (32.5%). In cases of cerebral infarction (CI) and intracerebral hemorrhage (ICH), more than 80% of the facilities selected only intermittent RRT, and 22.3% (CI)/8.7% (ICH) of the facilities selected intermittent HD which is the same setting in normal conditions. Although continuous hemodiafiltration and peritoneal dialysis are recommended in the Japanese guidelines, these were selected in only a few facilities: 16.5% and 0% in CI, 16.5% and 1% in ICH, respectively. RRT on the day of onset tended to be avoided, irrespective of the duration following the last HD session. Furthermore, physicians preferred to modify anticoagulants and reduce dialysis performance in the acute phase. CONCLUSION: This questionnaire survey uncovered a gap between guidelines and actual practice, even in hospitals accredited as educational facility, which is a novel and important finding. Further studies with larger sample sizes are needed to determine the optimal modality of RRT for the acute phase of cerebrovascular disease.

Low-energy extracorporeal shock wave ameliorates ischemic acute kidney injury in rats.

BACKGROUND: Low-energy extracorporeal shock wave (SW) improves ventricular function in ischemic cardiomyopathy through the upregulation of vascular endothelial growth factor (VEGF). VEGF is known to play important roles in acute kidney injury (AKI), and the present study investigates the efficacy of SW for AKI by renal ischemia-reperfusion (I/R) injury. METHODS: Male 8-week-old Sprague-Dawley rats were divided into the following groups: SW-treated I/R group (I/R-SW), untreated I/R group (I/R), and Sham group. To induce I/R, the left renal pedicles were clamped for 45 min. The I/R-SW group was treated with SW to both kidneys on the immediate postoperative period (day 0), days 1, 2, 7, 8, 9, 14, 15, and 16. Rats were killed on day 2 and day 20 to determine histology, renal function, and Vegf family mRNA expression. RESULTS: Plasma creatinine on day 2 was significantly lower in the I/R-SW group than in the I/R group. Light microscopy revealed significantly lower tubular injury scores for the outer medulla in the I/R-SW group than in the I/R group. Podoplanin-positive lymphatic vessels were significantly increased in the left (affected side) outer medulla in the I/R-SW group on day 20. The expression levels of Vegf in the right (intact side) cortex were significantly higher in the I/R-SW group than in the I/R group on day 2. CONCLUSION: Shock wave ameliorated renal tubular injury and renal function in AKI model, through the stimulation of Vegf family expression and lymphangiogenesis. SW may be effective as a non-invasive treatment for ischemic AKI.

Efficacy of high-affinity liposomal astaxanthin on up-regulation of age-related markers induced by oxidative stress in human corneal epithelial cells.

Decreases in tear volume, unstable tear films and excessive tear evaporation are known to cause desiccation and hyperosmolar stress. These, in turn, induce oxidative stress that is thought to cause dry eye, which is also considered to be age-related disease. We hypothesized that oxidative stress induces up-regulation of age-related markers, and that the antioxidant astaxanthin prepared as a liposomal formulation may be a candidate for the treatment of dry eye. Herein, we examined age-related markers in an in vitro dry eye model, and evaluated the efficacy of high-affinity liposomes containing astaxanthin. The in vitro dry eye model showed desiccation time-dependent increases in reactive oxygen species. We confirmed the up-regulation of p53, p21 and p16 as a function of desiccation time. Pretreatment with both neutral and slightly-positively-charged astaxanthin liposomal formulations showed significant suppression of up-regulation of all markers, with the positively-charged liposomes exhibiting the greatest efficacy. Furthermore, positively-charged liposomes labeled with fluorescent dyes demonstrated much higher affinity to normal human corneal epithelial cells (HCECs) than neutral liposomes. Taken together, we confirmed the up-regulation of age-related markers, especially p16, in an in vitro dry eye model, and demonstrated the potential of high-affinity liposomal astaxanthin for the treatment of dry eye.

Total eosinophil count as a biomarker for therapeutic effects of upadacitinib in atopic dermatitis over 48 weeks.

Background: Atopic dermatitis (AD) is a chronic skin disease characterized by type 2-skewed immune responses, and significantly influenced by cytokines dependent on Janus kinases (JAKs). Upadacitinib, a JAK1 inhibitor, is effective for moderate-to-severe AD. This study aims to identify biomarkers that reflect long-term therapeutic effects of upadacitinib 15 mg or 30 mg. Methods: A retrospective study from August 2021 to July 2023 included 213 AD patients treated with upadacitinib 15 mg and 70 AD patients with 30 mg. We analyzed eczema area and severity index (EASI), peak pruritus-numerical rating scale (PP-NRS), serum immunoglobulin E (IgE), thymus and activation-regulated chemokine (TARC), lactate dehydrogenase (LDH), and total eosinophil count (TEC) at weeks 0, 4, 12, 24, 36, and 48 of treatment. Results: Both treatments with upadacitinib 15 mg and 30 mg significantly reduced EASI and PP-NRS scores over week 4 to 48 compared to baseline. Upadacitinib 15 mg or 30 mg treatment significantly decreased TEC compared to baseline through week 4 to 36 or week 4 to 48, respectively. The percent reduction of TEC correlated with those of EASI and PP-NRS through week 4 to 48 of treatment with upadacitinib 15 mg, or through week 12 to 48 with 30 mg, respectively. After adjusting for % reductions of other laboratory markers, the significance of correlations was preserved at weeks 36 and 48 of 15 mg treatment, while at weeks 4 and 36 of 30 mg treatment. Conclusion: The % reduction of TEC correlated with those of EASI and PP-NRS during upadacitinib treatment, indicating its potential as a biomarker reflecting treatment responses to upadacitinib in AD patients. However, the variability of significant correlation during treatment indicates that further inspection is needed for its usefulness in monitoring responses to upadacitinib treatment for AD.

Sustained Effectiveness of Upadacitinib in Moderate-to-Severe Atopic Dermatitis: A 48-Week Real-World Study.

Clinical trials and real-world studies have shown the effectiveness of upadacitinib for treating rash and pruritus in patients with atopic dermatitis (AD). This study aimed to determine whether the early reduction in rash or pruritus at week 12 of upadacitinib treatment could be maintained at later treatment stages. This retrospective study involved 227 and 73 patients with moderate-to-severe AD treated with 15 and 30 mg upadacitinib daily, respectively. The eczema area and severity index (EASI) scores, peak pruritus numerical rating scale (PP-NRS), and investigator's global assessment (IGA) were analyzed. At week 12, patients were divided into achievers and non-achievers of EASI 75, 90, 100, absolute EASI ≤ 2, IGA0/1, PP-NRS4, or absolute PP-NRS ≤ 1. Achievement rates for each endpoint were assessed at later time points (weeks 24, 36, and 48) in both groups. Week 12 achievers largely maintained their endpoint achievements until week 48, regardless of dosage (15 mg or 30 mg). Week 12 non-achievers saw an increasing achievement rate of EASI 75 until week 48. The initial reduction in rash and pruritus at week 12 persisted until week 48 with upadacitinib treatment, suggesting potential benefits for patients requiring prolonged treatment despite not achieving EASI 75 at week 12.

Changes in higher-level functional capacity during the COVID-19 pandemic among older adults living in Japan.

OBJECTIVE: To evaluate change in higher-level functional capacity of older Japanese individuals during the COVID-19 pandemic. METHODS: Four hundred older Japanese individuals completed an online questionnaire in early May 2021. Participants were asked retrospectively about their higher-level functional capacity and lifestyle before and during the COVID-19 pandemic. Higher-level functional capacity was determined as total score on the Tokyo Metropolitan Institute of Gerontology Index of Competence (TMIG-IC). Total TMIG-IC score ranges from 0 to 13. A decline in higher-level functional capacity was defined as a decrease in TMIG-IC score of more than 2 points during the COVID-19 pandemic. Changes in higher-level functional capacity during the COVID-19 pandemic were assessed by paired t-test and a general linear model. RESULTS: Decreased TMIG-IC scores were found in 43 (21.5%) men and 61 (30.5%) women. Among those with higher-level functional capacity, scores for total TMIG-IC and Social Role decreased significantly in both sexes (all p<0.005). CONCLUSION: The findings suggest an association of the COVID-19 pandemic with a decrease in higher-level functional capacity, especially in Social Role, among older adults living in Japan. J. Med. Invest. 71 : 66-74, February, 2024.

Early itch relief with upadacitinib predicts later skin clearance in Atopic dermatitis.

BACKGROUND: Though Janus kinase inhibitors such as upadacitinib rapidly relieve itch in atopic dermatitis (AD) patients, how early itch relief impacts later skin clearance is not examined. OBJECTIVES: This study aims to determine if early itch relief by upadacitinib could predict complete skin clearance in later phases. METHODS: This retrospective study involved 105 patients with moderate-to-severe AD treated with upadacitinib 15 mg/day. Eczema area and severity index (EASI), atopic dermatitis control tool, and achievement rate of EASI 100 were evaluated at weeks 4, 12, and 24. The threshold of early peak pruritus-numerical rating scale (PP-NRS) predicting later skin clearance was assessed by area under the receiver-operating characteristic curve, and predictors for EASI 100 achievement were determined by logistic regression analysis. RESULTS: The rate of achieving EASI 100 at week 24 was extremely higher in patients who achieved week 2 PP-NRS ≤ 1 (42.9%) than in non-achievers (1.4%). The logistic regression analysis showed that the achievement of week 2 PP-NRS ≤ 1 and low body mass index were associated with achievement of EASI 100 at weeks 12 and 24. CONCLUSIONS: The achievement of week 2 PP-NRS ≤ 1 may predict later skin clearance in upadacitinib treatment.

Predictive factors for responders to upadacitinib treatment in patients with atopic dermatitis.

BACKGROUND: Janus kinase 1 inhibitor upadacitinib is therapeutically effective for atopic dermatitis (AD). However, predictive factors for high responders to upadacitinib have not been established in real-world clinical practice. OBJECTIVES: To identify predictive factors for responders to upadacitinib 15 mg or 30 mg, defined as achievers of investigator's global assessment (IGA) 0/1 with ≥ 2-point improvement from basal IGA. METHODS: A retrospective study was conducted from August 2021 to July 2023 on 159 AD patients treated with upadacitinib 15 mg and 52 patients with 30 mg. Patients in each group were categorized into responders (achievers of IGA 0/1 at week 12) and non-responders (non-achievers). We compared baseline values of clinical and laboratory parameters between responders and non-responders. Logistic regression analysis was used to detect variables predicting responders. Receiver-operating characteristic curves were used for evaluating prediction capabilities of the variables. RESULTS: In logistic regression analysis, responders to 15 mg upadacitinib were associated with lower total EASI and higher age whereas responders to 30 mg were associated with lower LDH and lower IgE. CONCLUSIONS: Lower total EASI and higher age may predict responders to upadacitinib 15 mg while lower IgE and lower LDH may predict responders to 30 mg.

Effectiveness of Dose Increase in Upadacitinib from 15 mg to 30 mg for Patients with Moderate-to-Severe Atopic Dermatitis: A Real-World Clinical Practice in Japan.

BACKGROUND: Atopic dermatitis is characterized by persistent eczema and pruritus. Janus kinase inhibitors, including upadacitinib, are effective treatments for moderate-to-severe atopic dermatitis. If patients do not respond well to a certain dose of a Janus kinase inhibitor, increasing the dose may improve their treatment responsiveness. OBJECTIVES: We assessed the outcomes of a dose increase in upadacitinib from 15 mg to 30 mg for Japanese patients with moderate-to-severe atopic dermatitis. METHODS: In 23 patients who showed insufficient responses to upadacitinib 15-mg treatment, the dose of upadacitinib was increased to 30 mg. We evaluated total Eczema Area and Severity Index (EASI), EASI on the head and neck, trunk, upper, or lower limbs, EASI of erythema, edema/papulation, excoriation, or lichenification, and Peak Pruritus Numerical-Rating Scale at baseline (onset of upadactinib 15 mg), week 0 (time of increase), and weeks 4 and 12 after the increase. RESULTS: Total EASI, EASI on each anatomical site, EASI of each clinical sign, and Peak Pruritus Numerical-Rating Scale were markedly reduced at weeks 4 or 12 compared with week 0. After the dose increase, the achievement rates of EASI 75 and EASI 90 significantly improved; EASI 75 4.3%, 68.2%, and 66.7%; EASI 90 0%, 18.2%, and 38.1% at weeks 0, 4, and 12, respectively. CONCLUSIONS: These results suggest that upadacitinib 30 mg can ameliorate rash and pruritus insufficiently improved by upadacitinib 15 mg, and that the dose increase to 30 mg may be considered as a treatment option for patients with atopic dermatitis with a limited response to upadacitinib 15 mg.

Therapeutic effectiveness of upadacitinib on individual types of rash in Japanese patients with moderate-to-severe atopic dermatitis.

Atopic dermatitis (AD) is a chronic eczematous disease with various types of rash, erythema, edema/papulation, excoriation, or lichenification. Janus kinase 1 inhibitor upadacitinib is effective for moderate-to-severe AD. We aimed to investigate the therapeutic effects of upadacitinib on each rash type in AD patients in real-world clinical practice. Seventy-two Japanese patients with moderate-to-severe AD were treated with oral upadacitinib 15 mg/day plus topical corticosteroids. The Eczema Area and Severity Index (EASI) scores for erythema, edema/papulation, excoriation, or lichenification on the whole body or on head and neck, upper limbs, lower limbs, or trunk were assessed at weeks 0, 4, and 12 of treatment. The proportions of patients who achieved resolution or at least 75% reduction of EASI from baseline (EASI 75) for individual rash types were calculated at weeks 4 and 12 on the whole body or each anatomical site. The resolution rates for excoriation, erythema, edema/papulation, or lichenification on the whole body were 38.3%, 23.7%, 21.7%, and 8.3% at week 4 and 18.3%, 18.6%, 11.6%, and 13.3% at week 12, respectively. The EASI scores for all rash types significantly decreased at weeks 4 and 12 compared to week 0. The achievement rates of EASI 75 for excoriation, erythema, edema/papulation, or lichenification on the whole body were 67.2%, 66.7%, 49.2%, and 37.7% at week 4 and 57.3%, 65%, 41%, and 41% at week 12, respectively. The achievement rate of EASI 75 for erythema on head and neck at week 4 (45.3%) was lower than that on upper limbs (71%) and on lower limbs (70.8%), and that on head and neck at week 12 (42.2%) was lower than that on lower limbs (69.2%). These results indicate that upadacitinib is effective for all AD rash types, especially for excoriation and erythema, while head-and-neck erythema might be less responsive to upadacitinib.

Effectiveness and Safety of Upadacitinib in Combination with Topical Corticosteroids in Adolescent Patients with Moderate-to-Severe Atopic Dermatitis.

Purpose: To investigate the therapeutic effectiveness and safety of Janus kinase 1 inhibitor upadacitinib in adolescent patients with atopic dermatitis (AD). Patients and Methods: This study examined therapeutic effectiveness and safety of upadacitinib for 39 Japanese adolescent patients (aged 12-17 years) diagnosed with moderate-to-severe AD from August 2021 to January 2023. The patients were treated with upadacitinib 15 mg/day plus twice daily topical corticosteroids. Total eczema area and severity index (EASI) or EASI on head and neck, upper limbs, lower limbs, and trunk or for erythema, edema/papulation, excoriation, or lichenification, atopic dermatitis control tool (ADCT), peak pruritus-numerical rating scale (PP-NRS), and laboratory indexes were assessed at weeks 0, 4, and 12 of treatment. Treatment-emergent adverse events were recorded. Results: Total EASI or EASI on 4 anatomical sites or for 4 rash types, ADCT, and PP-NRS were significantly reduced at week 4 and 12 compared to week 0. The achievement rates at weeks 4 or 12 were 64.1% or 62.5% for EASI 75, 93.5% or 73.1% for ADCT <7-point, and 80.6% or 60% for PP-NRS ≥4-point improvement, respectively, indicating their peak at week 4 and slight decrease at week 12. The percent reduction of EASI for excoriation was higher than that for lichenification or edema/papulation at week 4 or week 12, respectively. The percent reductions of EASI for erythema and edema/papulation on head and neck were lower than those on lower limbs at week 12. Total eosinophil counts (TEC) and IgE reduced at week 4 compared to week 0 while TARC, IgE, TEC, and LDH increased at week 12 compared to week 4. Conclusion: These results suggest therapeutic effectiveness and tolerability of upadacitinib and support its therapeutic usefulness for adolescent AD patients.

Effectiveness of switching from baricitinib 4 mg to upadacitinib 30 mg in patients with moderate-to-severe atopic dermatitis: a real-world clinical practice in Japan.

BACKGROUND: Atopic dermatitis (AD) is a chronic eczematous disease with severe pruritus. Janus kinase (JAK) inhibitors, upadacitinib, baricitinib, and abrocitinib, are systemic treatments for AD. The outcomes of switching from one JAK inhibitor to another have not been examined. OBJECTIVES: We assessed the outcomes of switching from baricitinib 4 mg to upadacitinib 30 mg in Japanese patients with moderate-to-severe AD. METHODS: Twenty patients treated with baricitinib 4 mg, showing insufficient response or adverse events, were switched to treatment with upadacitinib 30 mg. We evaluated total eczema area and severity index (EASI), EASI at head and neck, trunk, upper, or lower limbs, EASI of erythema, edema/papulation, excoriation, or lichenification, and peak pruritus numerical-rating scale (PP-NRS) at baseline (start of baricitinib), weeks 0 (time of switching), and 4 and 12 after switching. RESULTS: Total EASI, EASI at each anatomical site, EASI of each clinical sign, and PP-NRS were markedly reduced at weeks 4 or 12 compared to week 0. Achievement rates of more than 75% or 90% reduction of EASI from baseline significantly improved after switching. CONCLUSIONS: Switching from baricitinib 4 mg to upadacitinib 30 mg effectively improved rash and pruritus.

Cadmium induces chondroitin sulfate synthase 1 via protein kinase Cα and elongates chondroitin/dermatan sulfate chains in cultured vascular endothelial cells.

Cadmium is an environmental pollutant and a risk factor for atherosclerosis. In the atherosclerotic intima, dermatan sulfate chains accelerate accumulation and oxidation of LDL cholesterol. The major type of dermatan sulfate proteoglycan that is synthesized by vascular endothelial cells is biglycan. In the present study, we analyzed the effect of cadmium on the biglycan synthesis using cultured bovine aortic endothelial cells. Cadmium did not induce biglycan mRNA and core protein expression; however, it elongated the chondroitin/dermatan sulfate chains of biglycan. Among elongation enzymes of the chondroitin/dermatan sulfate chain, chondroitin sulfate synthase 1 (CHSY1) mRNA and protein expression were dose- and time-dependently upregulated by cadmium depending on protein kinase Cα. This finding suggests that CHSY1-dependent elongation of chondroitin/dermatan sulfate chains of biglycan may exacerbate cadmium-induced atherosclerosis.