Disease-modifying anti-rheumatic drug selection in Japanese patients with rheumatoid arthritis treated with biologics or JAK inhibitors without methotrexate: A retrospective hospital-based administrative claims database study.

OBJECTIVES: We evaluated the medication selection and clinical characteristics of rheumatoid arthritis (RA) patients who started treatment with/without methotrexate (using biologic disease-modifying antirheumatic drugs or Janus kinase inhibitors [JAKi] instead) in Japan. METHODS: Using a Japanese hospital-based administrative claims database, RA patients who received treatment (abatacept, interleukin-6 receptor inhibitor [IL-6Ri], tumor necrosis factor inhibitor, or JAKi) between 1/January/2015 and 31/December/2019 were enrolled. RESULTS: In total 19,301 patients were included (10,530 receiving methotrexate; 8,771 not receiving methotrexate within 60 days of the first treatment). Mean ages at diagnosis were 60.7 and 65.9 years in the methotrexate and non-methotrexate groups (p <0.0001). The non-methotrexate group had higher proportions of patients with Charlson Comorbidity Index ≥1 (p <0.0001), and higher comorbidity rates. Abatacept was the most frequently used drug among patients with infectious/parasitic, circulatory, and respiratory diseases at baseline. IL-6Ri had the highest use rate among patients with neoplasms; blood, gastrointestinal, and genitourinary diseases; and abnormal clinical/laboratory findings. Abatacept had the highest persistence probability from 6 months onward. CONCLUSIONS: Methotrexate is used less frequently among older Japanese RA patients or those with comorbidities. Abatacept is the most frequently used drug, followed by IL-6Ri, in patients not using methotrexate at the treatment start.

Treatment patterns of systemic drug use in Japanese patients with plaque psoriasis: A retrospective chart review.

Plaque psoriasis (PsO) is a chronic immune-mediated inflammatory disease with skin lesions accompanied by an inflammation-related comorbidity risk. The development of various oral drugs and biologics for PsO has provided increasing systemic treatment options for patients with PsO, and the guidance regarding the use of biologics and PsO treatment schemes are widespread in Japan. However, no comprehensive guidelines regarding systemic drug use are available, and the current treatment patterns of systemic drugs for PsO in Japan remain unclear. We conducted a retrospective chart review to clarify the current treatment patterns of systemic drugs for PsO. We enrolled 114 patients who started systemic drugs for PsO between January 2017 and December 2020 at four institutes, with a mean follow-up of 37.2 months. The mean disease duration was 7.8 (standard deviation 9.5) years at the systemic drug initiation. Of all the patients, 78.1% started with oral drugs (phosphodiesterase [PDE] 4 inhibitors 56.1%. calcineurin inhibitors 14.0%. vitamin A derivatives 7.9%), whereas 21.9% started with biologics (interleukin [IL]-17 inhibitors 9.6%. tumor necrosis factor inhibitors 7.0%. IL-23 inhibitors 3.5%. IL-12/23 inhibitors 1.8%). Oral drugs had shorter drug persistence than biologics: the 12-month persistence of the oral drugs vitamin A derivative, calcineurin inhibitor, and PDE4 inhibitor, was 35.5%, 25.8%, and 60.1%, respectively, compared with that of the biologics IL-23 and IL-17 inhibitors, which was 85.6% and 84.7%, respectively. During the study period, the incidence of treatment changes was 59.1/100 patient-years. Lack of efficacy was the most common reason for treatment changes from monotherapy (34.1%). This retrospective medical chart review allowed us to understand the real-world, long-term treatment patterns of systemic drugs for PsO and the relationships between the reasons for treatment changes and subsequent treatment selection, indicating that there is still room for improvement in the appropriate use of systemic drugs for PsO in Japan.

Treatment patterns, healthcare resource utilization, and costs in patients with moderate-to-severe psoriasis treated with systemic therapy in Japan: A retrospective claims database study.

The real-world treatment landscape for patients with moderate-to-severe psoriasis receiving systemic therapies in Japan is not well understood. This study describes the demographic and clinical characteristics, treatment patterns, healthcare resource utilization, and psoriasis-associated costs in these patients. This retrospective observational study used data from the Japan Medical Data Center database between January 2016 and December 2020. Eligible patients had a confirmed diagnosis of psoriasis, ≥1 claim for a systemic treatment of interest, medical history for ≥6 months, and follow-up data for ≥12 months. Systemic therapies comprised biologics (tumor necrosis factor and interleukin inhibitors) and oral treatments (a phosphodiesterase-4 inhibitor, immunosuppressants, and vitamin A). Patient demographics and clinical characteristics, treatment patterns, healthcare resource utilization, and costs were evaluated. The study identified 1770 patients satisfying all inclusion criteria. The mean age was 49.0 years, with 68% of patients aged 20-54 years. Overall, 90.6% and 9.4% of patients received oral medications and biologics as index treatment, respectively. Treatment patterns, healthcare resource utilization, and costs were assessed for treatments received by ≥20 patients (n = 1730). During the 12-month follow-up period, 1102/1730 patients (63.7%) discontinued index treatment, of whom 9.9% switched to alternative systemic treatments. The persistence rate was ≥70% for most biologics and <50% for oral systemic treatments. All 1730 patients had ≥1 all-cause outpatient visit (2.0 visits per person per month) and hospitalization frequency was ≤0.01 per person per month. Persistent patients incurred inflation-adjusted costs of Japanese Yen (JPY) 88 667 per person per month. Treatment switching was associated with an increase in total cost: JPY 128 039 per person per month after switching versus JPY 117 504 before switching. This study of Japanese patients with moderate-to-severe psoriasis demonstrated low persistence, high discontinuation, and low rates of treatment switching with systemic therapies. Switching was associated with increased total cost. These results indicate unmet needs for new treatments.

The importance of specific citrullinated clusterin and vimentin found in a multi-coloured bead-based citrulline-peptide array system in rheumatoid arthritis.

OBJECTIVES: The importance of citrullination in rheumatoid arthritis (RA) has been reported, but the degree to which individual citrullinated proteins affect the onset and progression of RA is still unclear. We aimed to identify citrullinated proteins that may play an important role in the onset and progression of RA using an individualised anti-citrullinated protein antibody (ACPA) evaluation system with citrullinated peptides as probes. METHODS: Serum samples from 50 normal donors and 51 RA patients were evaluated using a custom MagPlexTM bead array with 13 types of citrullinated peptide. The presence/absence of ACPAs that react to each citrullinated peptide in each subject was determined using the Z-score, which was calculated based on the fluorescence intensity distribution of a sample from a normal donor. Whether the fluorescence intensity was inhibited when free citrullinated peptides were added to a system was also evaluated. RESULTS: Median fluorescence intensities obtained from beads coupled with the 13 types of citrullinated peptide were all significantly higher in RA patients versus normal donors. With a Z-score ≥2 as the cut-off value for the presence of ACPAs, ACPAs that recognised five types of citrullinated peptides derived from fibrinogen A, fillagrin, clusterin, and vimentin were widely detected in RA patients. In addition, inhibition experiments showed that citrullinated vimentin, clusterin, and enolase 1A peptides inhibited coupling of ACPAs to other citrullinated peptides. CONCLUSIONS: ACPAs to many citrullinated proteins exhibited cross-reactivity to citrullinated clusterin and vimentin, suggesting the importance of citrullinated clusterin and vimentin in the early stages of RA pathogenesis.

Long-term safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis: 3-year follow-up of a postmarketing surveillance.

OBJECTIVES: To analyse the long-term safety and effectiveness of abatacept for rheumatoid arthritis using real-world, Japanese, postmarketing surveillance data, focusing on serious infections and malignancies as priority events. METHODS: This 3-year, multicentre surveillance registered patients undergoing abatacept treatment by intravenous infusion between July 2011 and October 2012. RESULTS: The safety and effectiveness analysis sets included 647 and 596 patients, respectively. The total observation period for the safety analysis was 1280 patient-years. Over the 3-year follow-up, the incidence rates of adverse drug reactions (ADRs) and serious ADRs were 19.92 per 100 patient-years (22.87% of patients) and 4.06 per 100 patient-years (6.65% of patients), respectively. Infections and infestations were the most common ADRs (14.68%), followed by respiratory, thoracic, and mediastinal disorders (3.09%). Incidence rates of serious infections as ADRs and malignancy as adverse events were 1.95 and 1.02 per 100 patient-years, respectively. Retention rates at 1 and 3 years were 67.4% and 43.9%, respectively. Significant decreases from baseline were observed in Disease Activity Score (DAS) 28-erythrocyte sedimentation rate and DAS28-C-reactive protein, as well as Health Assessment Questionnaire-Disability Index (HAQ-DI) and modified HAQ scores. CONCLUSIONS: No new safety signals were detected during the 3-year observation period and effectiveness was maintained over time.

Gene expression analysis in the lung of the rasH2 transgenic mouse at week 4 prior to induction of malignant tumor formation by urethane and N-methylolacrylamide.

The rasH2 transgenic (Tg) mice are susceptible to genotoxic and some non-genotoxic carcinogens. In carcinogenicity studies carried out using rasH2 Tg mice, the carcinogenic potential of chemicals are evaluated over a 26-week experimental period. In the present study, we examined the comprehensive gene expressions in the lungs of Tg and non-Tg mice prior to the induction of malignant tumors. Urethane (UR), a mutagenic carcinogen, was administered for 4 weeks, and thereafter withdrawn for 22 weeks. N-methylolacrylamide (NMA), a non-mutagenic carcinogen, was administered for 26 weeks. At week 4, gene expression analysis of non-neoplastic part of the lungs demonstrated changes in the expressions of the cell-cycle and inflammation related genes following UR and NMA treatment, respectively, in both the Tg and non-Tg mice. The gene expressions of epireguline, aurora kinase B, and cyclin B1 increased in the UR-treated Tg mice. We also found an increase in the plasma carcinoembryonic antigen level in the UR-treated Tg mice. Although UR treatment induced the formation of adenomas or adenocarcinomas in the lungs in all mice, earlier induction was apparent in the Tg mice. NMA treatment was found to induce the formation of adenomas and adenocarcinomas at week 26 in the Tg mice, but not in the non-Tg mice, and no expressions of specific genes were apparent in either genotype of mice. Our results indicate that analysis of cancer-related gene expressions in the lungs and plasma biomarkers at week 4 in rasH2 Tg mice could be a screening tool for carcinogenicity, especially of mutagenic carcinogens.

Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.

By analyzing 1,780,295 5'-end sequences of human full-length cDNAs derived from 164 kinds of oligo-cap cDNA libraries, we identified 269,774 independent positions of transcriptional start sites (TSSs) for 14,628 human RefSeq genes. These TSSs were clustered into 30,964 clusters that were separated from each other by more than 500 bp and thus are very likely to constitute mutually distinct alternative promoters. To our surprise, at least 7674 (52%) human RefSeq genes were subject to regulation by putative alternative promoters (PAPs). On average, there were 3.1 PAPs per gene, with the composition of one CpG-island-containing promoter per 2.6 CpG-less promoters. In 17% of the PAP-containing loci, tissue-specific use of the PAPs was observed. The richest tissue sources of the tissue-specific PAPs were testis and brain. It was also intriguing that the PAP-containing promoters were enriched in the genes encoding signal transduction-related proteins and were rarer in the genes encoding extracellular proteins, possibly reflecting the varied functional requirement for and the restricted expression of those categories of genes, respectively. The patterns of the first exons were highly diverse as well. On average, there were 7.7 different splicing types of first exons per locus partly produced by the PAPs, suggesting that a wide variety of transcripts can be achieved by this mechanism. Our findings suggest that use of alternate promoters and consequent alternative use of first exons should play a pivotal role in generating the complexity required for the highly elaborated molecular systems in humans.

Molecular characterization of mammalian dicarbonyl/L-xylulose reductase and its localization in kidney.

In this report, we first cloned a cDNA for a protein that is highly expressed in mouse kidney and then isolated its counterparts in human, rat hamster, and guinea pig by polymerase chain reaction-based cloning. The cDNAs of the five species encoded polypeptides of 244 amino acids, which shared more than 85% identity with each other and showed high identity with a human sperm 34-kDa protein, P34H, as well as a murine lung-specific carbonyl reductase of the short-chain dehydrogenase/reductase superfamily. In particular, the human protein is identical to P34H, except for one amino acid substitution. The purified recombinant proteins of the five species were about 100-kDa homotetramers with NADPH-linked reductase activity for alpha-dicarbonyl compounds, catalyzed the oxidoreduction between xylitol and l-xylulose, and were inhibited competitively by n-butyric acid. Therefore, the proteins are designated as dicarbonyl/l-xylulose reductases (DCXRs). The substrate specificity and kinetic constants of DCXRs for dicarbonyl compounds and sugars are similar to those of mammalian diacetyl reductase and l-xylulose reductase, respectively, and the identity of the DCXRs with these two enzymes was demonstrated by their co-purification from hamster and guinea pig livers and by protein sequencing of the hepatic enzymes. Both DCXR and its mRNA are highly expressed in kidney and liver of human and rodent tissues, and the protein was localized primarily to the inner membranes of the proximal renal tubules in murine kidneys. The results imply that P34H and diacetyl reductase (EC ) are identical to l-xylulose reductase (EC ), which is involved in the uronate cycle of glucose metabolism, and the unique localization of the enzyme in kidney suggests that it has a role other than in general carbohydrate metabolism.