Publications by authors named "Yoshiya Tanaka"

817 Publications

Consensus statement on blocking interleukin-6 receptor and interleukin-6 in inflammatory conditions: an update.

Ann Rheum Dis 2022 Aug 11. Epub 2022 Aug 11.

Scienze Cliniche e Biologiche, Università degli Studi di Torino, Torino, Italy.

Background: Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway.

Methods: A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document.

Results: The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring.

Conclusions: The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers.
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http://dx.doi.org/10.1136/ard-2022-222784DOI Listing
August 2022

Long-Term Safety and Efficacy of Filgotinib Treatment for Rheumatoid Arthritis in Japanese Patients Naïve to MTX Treatment (FINCH 3).

Mod Rheumatol 2022 Aug 3. Epub 2022 Aug 3.

Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Objectives: To evaluate long-term safety and efficacy of filgotinib for Japanese patients with rheumatoid arthritis (RA) and limited/no prior methotrexate (MTX) exposure. We present a Japanese population subanalysis of a global randomised-controlled trial at Week 52 and interim long-term extension (LTE) to Week 48 through June 2020.

Methods: Patients were randomised to filgotinib 200 mg plus MTX, filgotinib 100 mg plus MTX, filgotinib 200 mg, or MTX for 52 weeks. At completion, eligible patients could enrol in the LTE. Those receiving filgotinib continued; those receiving MTX were rerandomised (blinded) to filgotinib 200 or 100 mg upon discontinuation of MTX. After a 4-week washout period, MTX could be re-added.

Results: Adverse event rates at Week 52 and in the LTE to Week 48 were comparable across treatment groups. Week 52 American College of Rheumatology 20% improvement (ACR20) rates were 83% (19/23), 82% (9/11), 75% (9/12), and 76% (19/25) for filgotinib 200 mg plus MTX, filgotinib 100 mg plus MTX, filgotinib 200 mg, and MTX, respectively. Through LTE Week 48, ACR20 rates were maintained.

Conclusions: In the 56 Japanese patients treated with filgotinib, efficacy was maintained through Week 52 and beyond, with no increases in the incidence of adverse events.
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http://dx.doi.org/10.1093/mr/roac083DOI Listing
August 2022

Safety and Efficacy of Filgotinib for Japanese Patients with RA and Inadequate Response to MTX: FINCH 1 52-Week Results and FINCH 4 48-Week Results.

Mod Rheumatol 2022 Aug 3. Epub 2022 Aug 3.

Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, and Saitama Medical University, Iruma, Saitama, Japan.

Objective: To present safety and efficacy of the JAK1 preferential inhibitor filgotinib in Japanese patients with prior inadequate response (IR) to methotrexate (MTX) from a 52-week randomised controlled parent study (PS) and long-term extension (LTE) through June 2020.

Methods: The PS (NCT02889796) randomised MTX-IR patients to filgotinib 200 (FIL200) or 100 mg (FIL100), adalimumab (ADA) 40 mg, or placebo; all took stable background MTX. At week (W) 24, placebo patients were rerandomised to FIL200 or FIL100. The primary endpoint was W12 American College of Rheumatology 20% improvement (ACR20); safety was assessed by adverse event (AE) reporting. For the LTE (NCT03025308), eligible filgotinib patients continued FIL200/FIL100; ADA patients were rerandomised (blinded) to FIL200 or FIL100; all continued MTX.

Results: 114/147 Japanese patients completed the PS; 115 enrolled in LTE; 103 remained on study in June 2020. In the PS, AEs were consistent with the overall population, and W24 efficacy was maintained or improved through W52, comparable with the overall population. LTE AE incidences were similar between doses; filgotinib efficacy was consistent from baseline to W48 and similar between PS ADA and filgotinib patients.

Conclusion: Among MTX-IR Japanese patients, filgotinib maintained efficacy over 1 year; LTE safety was consistent with the PS.
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http://dx.doi.org/10.1093/mr/roac084DOI Listing
August 2022

Management of non-renal manifestations of systemic lupus erythematosus: A systematic literature review for the APLAR consensus statements.

Int J Rheum Dis 2022 Aug 2. Epub 2022 Aug 2.

Division of Rheumatology, Department of Medicine, Tuen Mun Hospital, Hong Kong SAR, China.

The prevalence of systemic lupus erythematosus (SLE) is higher in Asians than Caucasians, with higher frequency of renal and other major organ manifestations that carry a poorer prognosis. The outcome of SLE is still unsatisfactory in many parts of the Asia Pacific region due to limited access to healthcare systems, poor treatment adherence and adverse reactions to therapies. The Asia Pacific League of Associations for Rheumatology (APLAR) SLE special interest group has recently published a set of consensus recommendation statements for the management of SLE in the Asia Pacific region. The current article is a supplement of systematic literature search (SLR) to the prevalence and treatment of non-renal manifestations of SLE in Asian patients.
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http://dx.doi.org/10.1111/1756-185X.14413DOI Listing
August 2022

Use of platelet inhibitors for digital ulcers related to systemic sclerosis: EUSTAR study on derivation and validation of the DU-VASC model.

Rheumatology (Oxford) 2022 Jul 29. Epub 2022 Jul 29.

Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Objective: To develop and validate the prognostic prediction model DU-VASC to assist the clinicians in decision-making regarding the use of platelet inhibitors (PIs) for the management of digital ulcers in patients with systemic sclerosis. Secondly, to assess the incremental value of PIs as predictor.

Methods: We analysed patient data from the European Scleroderma Trials and Research group registry (one time point assessed). Three sets of derivation/validation cohorts were obtained from the original cohort. Using logistic regression, we developed a model for prediction of DUs. C-statistics and calibration plots were calculated to evaluate the prediction performance. Variable importance plots and the decrease in C-statistics were used to address the importance of the predictors.

Results: Of 3710 patients in the original cohort, 487 had DUs and 90 were exposed to PIs. For the DU-VASC model, which includes 27 predictors, we observed good calibration and discrimination in all cohorts (C-statistics = 81.1% [95%CI: 78.9%-83.4%] for the derivation and 82.3% [95%CI: 779.3%-85.3%] for the independent temporal validation cohort). Exposure to PIs was associated with absence of DUs and was the most important therapeutic predictor. Further important factors associated with absence of DUs were: lower mRSS, anti-Scl-70 negativity and normal CRP. Conversely, the exposure to PDE-5i, prostacyclin analogues or ERAs seemed to be associated with the occurrence of DUs. Nonetheless, previous DUs remains the most impactful predictor of DUs.

Conclusion: The DU-VASC model, with good calibration and discrimination ability, revealed that PIs treatment was the most important therapy-related predictor associated with reduced DUs occurrence.
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http://dx.doi.org/10.1093/rheumatology/keac405DOI Listing
July 2022

Light chain proximal tubulopathy after improvement of tubulointerstitial nephritis in Sjögren's syndrome.

Pathol Int 2022 Jul 25. Epub 2022 Jul 25.

Department of Pathology and Oncology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

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http://dx.doi.org/10.1111/pin.13263DOI Listing
July 2022

Association between time in range and postprandial glucose contribution rate in non-insulin-treated type 2 diabetic patients: Inverse correlation of time in range with postprandial glucose contribution rate.

Diabetes Technol Ther 2022 Jul 18. Epub 2022 Jul 18.

Sangyo Ika Daigaku, 13137, First Department of Internal Medicine, Kitakyushu, Japan;

Background: Whether time in range (TIR), a parameter derived from continuous glucose monitoring (CGM), is a marker of postprandial hyperglycemia remains to be determined. Here we examined the association between TIR and postprandial glucose in non-insulin-treated type 2 diabetic patients.

Methods: Our cross-sectional study included 729 non-insulin-treated patients with type 2 diabetes who underwent CGM without any changes in drug therapy on admission. The 24-hr CGM record was analyzed for average glucose, standard deviation, percentage coefficient of variation, time above range, TIR, time below range, area under the curve (AUC) of basal glucose, AUC of postprandial glucose, and postprandial glucose contribution rate (%). The primary endpoint was the association between TIR and the postprandial glucose contribution rate.

Results: We made TIR groups divided into 10% increments for a 7-group and compared with <40% to > 90%. The basal and postprandial glucose AUCs correlated negatively with TIR. The postprandial glucose contribution rate correlated with TIR. The cutoff value for TIR, where postprandial glucose contribution rate was lower than the basal glucose contribution rate, was 66.3%.

Conclusions: In non-insulin-treated type 2 diabetic patients, postprandial glucose AUC was higher in the high TIR group, while the basal glucose AUC was higher in the low TIR group. Good glycemic control can be achieved with therapeutic interventions that target postprandial glucose and basal glucose in patients with TIR ≥66.3% and <66.3%, respectively.
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http://dx.doi.org/10.1089/dia.2022.0194DOI Listing
July 2022

Phase 3, multicentre, randomised, placebo-controlled study evaluating the efficacy and safety of ustekinumab in patients with systemic lupus erythematosus.

Ann Rheum Dis 2022 Jul 7. Epub 2022 Jul 7.

Clinical Development Immunology, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA.

Objective: Evaluate the efficacy and safety of ustekinumab, an anti-interleukin-12/23 p40 antibody, in a phase 3, randomised, placebo-controlled study of patients with active systemic lupus erythematosus (SLE) despite receiving standard-of-care.

Methods: Active SLE patients (SLE Disease Activity Index 2000 (SLEDAI-2K) ≥6 during screening and SLEDAI-2K ≥4 for clinical features at week 0) despite receiving oral glucocorticoids, antimalarials, or immunomodulatory drugs were randomised (3:2) to receive ustekinumab (intravenous infusion ~6 mg/kg at week 0, followed by subcutaneous injections of ustekinumab 90 mg at week 8 and every 8 weeks) or placebo through week 48. The primary endpoint was SLE Responder Index (SRI)-4 at week 52, and major secondary endpoints included time to flare through week 52 and SRI-4 at week 24.

Results: At baseline, 516 patients were randomised to placebo (n=208) or ustekinumab (n=308). Following the planned interim analysis, the sponsor discontinued the study due to lack of efficacy but no safety concerns. Efficacy analyses included 289 patients (placebo, n=116; ustekinumab, n=173) who completed or would have had a week 52 visit at study discontinuation. At week 52, 44% of ustekinumab patients and 56% of placebo patients had an SRI-4 response; there were no appreciable differences between the treatment groups in the major secondary endpoints. Through week 52, 28% of ustekinumab patients and 32% of placebo patients had a British Isles Lupus Assessment Group flare, with a mean time to first flare of 204.7 and 200.4 days, respectively. Through week 52, 70% of ustekinumab patients and 74% of placebo patients had ≥1 adverse event.

Conclusions: Ustekinumab did not demonstrate superiority over placebo in this population of adults with active SLE; adverse events were consistent with the known safety profile of ustekinumab.

Trial Registration Number: NCT03517722.
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http://dx.doi.org/10.1136/ard-2022-222858DOI Listing
July 2022

Effect of bimekizumab on symptoms and impact of disease in patients with psoriatic arthritis over 3 years: results from BE ACTIVE.

Rheumatology (Oxford) 2022 Jul 5. Epub 2022 Jul 5.

Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France.

Objectives: Evaluate effects of long-term bimekizumab treatment on patient-reported outcome (PRO) measures, symptoms and the impact of psoriatic arthritis (PsA) on patients.

Methods: Patients with active PsA were enrolled into BE ACTIVE, a 48-week randomised controlled trial (NCT02969525). After week 48, patients could enter a 104-week open-label extension (NCT03347110), receiving bimekizumab 160 mg every four weeks. PRO measures assessed included arthritis pain visual analogue scale (VAS), Psoriatic Arthritis Impact of Disease (PsAID)-9, 36-Item Short Form Survey (SF-36), and Health Assessment Questionnaire-Disability Index (HAQ-DI). Results were analysed as mean (standard error [SE]) changes from baseline (CfB) from week 0 to the end of the open-label extension (3 years) and as percentage of patients reaching patient-acceptable symptom state (PASS) for global impact (PsAID-9 total score ≤4) and normal function (HAQ-DI total score <0.5). Non-responder imputation was applied to missing binary outcomes.

Results: In 206 patients (mean age 49.3 years, 51.0% male), completion rate was high; 161 (78.2%) patients completed week 152. Bimekizumab treatment was associated with long-term sustained improvements in pain (arthritis pain VAS CfB; week 48: -29.9 [1.9]; week 152: -32.0 [1.9]) and fatigue (PsAID-9 fatigue CfB; -2.4 [0.2]; -2.7 [0.2]). High percentages of patients achieved acceptable symptom state (PsAID-9 PASS: 75.2%; 65.0%) and normalised function (HAQ-DI <0.5: 49.0%; 46.1%). Improvements in patient global assessment and SF-36 Physical Component Summary were also sustained.

Conclusions: Bimekizumab treatment was associated with long-term sustained improvements in pain and fatigue, reducing overall impact of PsA on patients. Physical function and quality of life improved up to 3 years.

Trial Registration: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02969525, NCT03347110.
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http://dx.doi.org/10.1093/rheumatology/keac353DOI Listing
July 2022

Safety and effectiveness of mepolizumab therapy in remission induction therapy for eosinophilic granulomatosis with polyangiitis: a retrospective study.

Arthritis Res Ther 2022 06 29;24(1):159. Epub 2022 Jun 29.

The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Kitakyushu, 807-8555, Japan.

Objectives: To investigate the safety and effectiveness of mepolizumab (MPZ), an anti-interleukin-5 antibody, as remission induction therapy for severe eosinophilic granulomatosis with polyangiitis (EGPA).

Methods: The clinical courses of patients with severe EGPA over 6 months were retrospectively investigated and compared between patients treated with high-dose corticosteroid (CS) plus MPZ therapy (MPZ group, n = 7) and those treated with high-dose CS plus intravenous cyclophosphamide (IVCY) pulse therapy (IVCY group, n = 13). The primary endpoints were the MPZ retention rate and the IVCY completion rate. The secondary endpoints were adverse events and changes in the Birmingham Vasculitis Activity Score (BVAS), Vascular Damage Index (VDI), eosinophil counts, and concomitant CS doses, and the extent and rates of these changes were compared between the MPZ and IVCY groups.

Results: Regarding the primary endpoints, the MPZ retention rate was 100%, and the IVCY completion rate was 61.5%. Regarding the secondary endpoints, adverse events were detected in 2/7 patients (28.6%) in the MPZ group and 7/13 patients (53.8%) in the IVCY group. BVAS and eosinophil counts significantly decreased in both groups at and after month 1, but there was no significant difference in the magnitude of changes between the two groups. VDI scores did not significantly increase in either group, and the degree of changes did not significantly differ between the two groups. Although concomitant CS doses significantly decreased at and after month 1 in both groups, the rates of decrease in CS doses at and after month 3 were significantly higher in the MPZ group.

Conclusions: This study suggested that the use of MPZ as remission induction therapy for severe EGPA might be safe and effective for controlling disease activity and reducing CS doses.
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http://dx.doi.org/10.1186/s13075-022-02845-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9241238PMC
June 2022

Multi-trait and cross-population genome-wide association studies across autoimmune and allergic diseases identify shared and distinct genetic component.

Ann Rheum Dis 2022 Jun 26. Epub 2022 Jun 26.

Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan

Objectives: Autoimmune and allergic diseases are outcomes of the dysregulation of the immune system. Our study aimed to elucidate differences or shared components in genetic backgrounds between autoimmune and allergic diseases.

Methods: We estimated genetic correlation and performed multi-trait and cross-population genome-wide association study (GWAS) meta-analysis of six immune-related diseases: rheumatoid arthritis, Graves' disease, type 1 diabetes for autoimmune diseases and asthma, atopic dermatitis and pollinosis for allergic diseases. By integrating large-scale biobank resources (Biobank Japan and UK biobank), our study included 105 721 cases and 433 663 controls. Newly identified variants were evaluated in 21 778 cases and 712 767 controls for two additional autoimmune diseases: psoriasis and systemic lupus erythematosus. We performed enrichment analyses of cell types and biological pathways to highlight shared and distinct perspectives.

Results: Autoimmune and allergic diseases were not only mutually classified based on genetic backgrounds but also they had multiple positive genetic correlations beyond the classifications. Multi-trait GWAS meta-analysis newly identified six allergic disease-associated loci. We identified four loci shared between the six autoimmune and allergic diseases (rs10803431 at , OR=1.07, p=2.3×10, rs2053062 at , OR=0.90, p=2.9×10, rs2210366 at , OR=1.07, p=2.5×10 in Japanese and rs4529910 at , OR=0.96, p=1.9×10 across ancestries). Associations of rs10803431 and rs4529910 were confirmed at the two additional autoimmune diseases. Enrichment analysis demonstrated link to T cells, natural killer cells and various cytokine signals, including innate immune pathways.

Conclusion: Our multi-trait and cross-population study should elucidate complex pathogenesis shared components across autoimmune and allergic diseases.
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http://dx.doi.org/10.1136/annrheumdis-2022-222460DOI Listing
June 2022

Phase II/III results of the anti-TNF multivalent NANOBODY® compound 'ozoralizumab' in patient with rheumatoid arthritis (OHZORA trial).

Arthritis Rheumatol 2022 Jun 21. Epub 2022 Jun 21.

University of Occupational and Environmental Health Japan, Kitakyushu, Japan.

Objective: This study aimed to assess the efficacy and safety of subcutaneous administration of ozoralizumab 30 mg or 80 mg + methotrexate (MTX) in patients with active rheumatoid arthritis (RA), despite MTX therapy.

Methods: In this multicenter, double-blind, parallel-group, placebo-controlled phase II/III trial, 381 patients were randomized to placebo, ozoralizumab 30 mg or ozoralizumab 80 mg, and subcutaneously injected every 4 weeks with MTX for 24 weeks. The primary endpoints were a 20% improvement rate in the American College of Rheumatology criteria (ACR20 response rate) at Week 16 and change in the baseline modified total Sharp score (ΔmTSS) at Week 24.

Results: The proportion of patients with an ACR20 response at Week 16 was significantly higher (p < 0.001) in both ozoralizumab groups (30 mg, 79.6%; 80 mg, 75.3%), compared with placebo (37.3%); these improvements were observed from the first week of treatment. The proportion of the patients with structural nonprogression (ΔmTSS ≤ 0) was significantly higher in both ozoralizumab groups than in the placebo group. In some secondary endpoints, significantly greater improvements were observed starting from as early as Day 3. Serious adverse events occurred in four patients in the 30 mg and five patients in the 80 mg ozoralizumab groups.

Conclusions: In patients with active RA who receive MTX therapy, ozoralizumab significantly reduced the signs and symptoms of RA, compared with placebo. Ozoralizumab showed acceptable tolerability with no new safety signals, when compared with other antibodies against tumour necrosis factor alpha.
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http://dx.doi.org/10.1002/art.42273DOI Listing
June 2022

Pentacyclic triterpenoid ursolic acid induces apoptosis with mitochondrial dysfunction in adult T-cell leukemia MT-4 cells to promote surrounding cell growth.

Med Oncol 2022 Jun 8;39(8):118. Epub 2022 Jun 8.

Department of Immunology and Parasitology, School of Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.

We investigated the antitumor effects of oleanolic acid (OA) and ursolic acid (UA) on adult T-cell leukemia cells. OA and UA dose-dependently inhibited the proliferation of adult T-cell leukemia cells. UA-treated cells showed caspase 3/7 and caspase 9 activation. PARP cleavage was detected in UA-treated MT-4 cells. Activation of mTOR and PDK-1 was inhibited by UA. Autophagosomes were detected in MT-4 cells after UA treatment using electron microscopy. Consistently, mitophagy was observed in OA- and UA-treated MT-4 cells by confocal microscopy. The mitochondrial membrane potential in MT-4 cells considerably decreased, and mitochondrial respiration and aerobic glycolysis were significantly reduced following UA treatment. Furthermore, MT-1 and MT-4 cells were sorted into two regions based on their mitochondrial membrane potential. UA-treated MT-4 cells from both regions showed high activation of caspase 3/7, which were inhibited by Z-vad. Interestingly, MT-4 cells cocultured with sorted UA-treated cells showed enhanced proliferation. Finally, UA induced cell death and ex vivo PARP cleavage in peripheral blood mononuclear cells from patients with adult T-cell leukemia. Therefore, UA-treated MT-4 cells show caspase activation following mitochondrial dysfunction and may produce survival signals to the surrounding cells.
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http://dx.doi.org/10.1007/s12032-022-01707-xDOI Listing
June 2022

Effect of active vitamin D treatment on development of type 2 diabetes: DPVD randomised controlled trial in Japanese population.

BMJ 2022 05 25;377:e066222. Epub 2022 May 25.

University of Occupational and Environmental Health, Kitakyushu, Japan.

Objective: To assess whether eldecalcitol, an active vitamin D analogue, can reduce the development of type 2 diabetes among adults with impaired glucose tolerance.

Design: Double blinded, multicentre, randomised, placebo controlled trial.

Setting: Three hospitals in Japan, between June 2013 and August 2019.

Participants: People aged 30 years and older who had impaired glucose tolerance defined by using a 75 g oral glucose tolerance test and glycated haemoglobin level.

Interventions: Participants were randomised to receive active vitamin D (eldecalcitol 0.75 μg per day; n=630) or matching placebo (n=626) for three years.

Main Outcomes: The primary endpoint was incidence of diabetes. Prespecified secondary endpoints were regression to normoglycaemia and incidence of type 2 diabetes after adjustment for confounding factors at baseline. In addition, bone densities and bone and glucose metabolism markers were assessed.

Results: Of the 1256 participants, 571 (45.5%) were women and 742 (59.1%) had a family history of type 2 diabetes. The mean age of participants was 61.3 years. The mean serum 25-hydroxyvitamin D concentration at baseline was 20.9 ng/mL (52.2 nmol/L); 548 (43.6%) participants had concentrations below 20 ng/mL (50 nmol/L). During a median follow-up of 2.9 years, 79 (12.5%) of 630 participants in the eldecalcitol group and 89 (14.2%) of 626 in the placebo group developed type 2 diabetes (hazard ratio 0.87, 95% confidence interval 0.67 to 1.17; P=0.39). Regression to normoglycaemia was achieved in 145 (23.0%) of 630 participants in the eldecalcitol group and 126 (20.1%) of 626 in the placebo group (hazard ratio 1.15, 0.93 to 1.41; P=0.21). After adjustment for confounding factors by multivariable fractional polynomial Cox regression analysis, eldecalcitol significantly lowered the development of diabetes (hazard ratio 0.69, 0.51 to 0.95; P=0.020). In addition, eldecalcitol showed its beneficial effect among the participants with the lower level of basal insulin secretion (hazard ratio 0.41, 0.23 to 0.71; P=0.001). During follow-up, bone mineral densities of the lumbar spine and femoral neck and serum osteocalcin concentrations significantly increased with eldecalcitol compared with placebo (all P<0.001). No significant difference in serious adverse events was observed.

Conclusions: Although treatment with eldecalcitol did not significantly reduce the incidence of diabetes among people with pre-diabetes, the results suggested the potential for a beneficial effect of eldecalcitol on people with insufficient insulin secretion.

Trial Registration: UMIN Clinical Trials Registry UMIN000010758.
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http://dx.doi.org/10.1136/bmj-2021-066222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9131780PMC
May 2022

Mechanism of action of baricitinib and identification of biomarkers and key immune pathways in patients with active systemic lupus erythematosus.

Ann Rheum Dis 2022 May 24. Epub 2022 May 24.

Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland, USA.

Objectives: To elucidate the mechanism of action of baricitinib, a Janus kinase (JAK) 1/2 inhibitor, and describe immunological pathways related to disease activity in adults with systemic lupus erythematosus (SLE) receiving standard background therapy in a phase II trial.

Methods: Patients with SLE were treated with baricitinib 2 mg or 4 mg in a phase II randomised, placebo-controlled study. Sera from 239 patients (baricitinib 2 mg: n=88; baricitinib 4 mg: n=82; placebo: n=69) and 49 healthy controls (HCs) were collected at baseline and week 12 and analysed using a proximity extension assay (Target 96 Inflammation Panel (Olink)). Interferon (IFN) scores were determined using an mRNA panel. Analytes were compared in patients with SLE versus HCs and in changes from baseline at week 12 between baricitinib 2 mg, 4 mg and placebo groups using a restricted maximum likelihood-based mixed models for repeated measures. Spearman correlations were computed for analytes and clinical measurements.

Results: At baseline, SLE sera had strong cytokine dysregulation relative to HC sera. C-C motif chemokine ligand (CCL) 19, C-X-C motif chemokine ligand (CXCL) 10, tumour necrosis factor alpha (TNF-α), TNF receptor superfamily member (TNFRSF)9/CD137, PD-L1, IL-6 and IL-12β were significantly reduced in patients treated with baricitinib 4 mg versus placebo at week 12. Inflammatory biomarkers indicated correlations/associations with type I IFN (CCL19, CXCL10, TNF-α and PD-L1), anti-double stranded DNA (dsDNA) (TNF-α, CXCL10) and Systemic Lupus Erythematosus Disease Activity Index-2000, tender and swollen joint count and worst joint pain (CCL19, IL-6 and TNFRSF9/CD137).

Conclusion: These results suggest that baricitinib 4 mg downregulated key cytokines that are upregulated in patients with SLE and may play a role in a multitargeted mechanism beyond the IFN signature although clinical relevance remains to be further delineated.

Trial Registration Number: NCT02708095.
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http://dx.doi.org/10.1136/annrheumdis-2022-222335DOI Listing
May 2022

Concordance and discordance in SLE clinical trial outcome measures: analysis of three anifrolumab phase 2/3 trials.

Ann Rheum Dis 2022 07 17;81(7):962-969. Epub 2022 May 17.

BioPharmaceuticals R&D, AstraZeneca US, Gaithersburg, Maryland, USA

Objectives: In the anifrolumab systemic lupus erythematosus (SLE) trial programme, there was one trial (TULIP-1) in which BILAG-based Composite Lupus Assessment (BICLA) responses favoured anifrolumab over placebo, but the SLE Responder Index (SRI(4)) treatment difference was not significant. We investigated the degree of concordance between BICLA and SRI(4) across anifrolumab trials in order to better understand drivers of discrepant SLE trial results.

Methods: TULIP-1, TULIP-2 (both phase 3) and MUSE (phase 2b) were randomised, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks, 48 weeks; TULIP-1/TULIP-2: n=180; MUSE: n=99) or placebo (TULIP-1: n=184, TULIP-2: n=182; MUSE: n=102). Week 52 BICLA and SRI(4) outcomes were assessed for each patient.

Results: Most patients (78%-85%) had concordant BICLA and SRI(4) outcomes (Cohen's Kappa 0.6-0.7, nominal p<0.001). Dual BICLA/SRI(4) response rates favoured anifrolumab over placebo in TULIP-1, TULIP-2 and MUSE (all nominal p≤0.004). A discordant TULIP-1 BICLA non-responder/SRI(4) responder subgroup was identified (40/364, 11% of TULIP-1 population), comprising more patients receiving placebo (n=28) than anifrolumab (n=12). In this subgroup, placebo-treated patients had lower baseline disease activity, joint counts and glucocorticoid tapering rates, and more placebo-treated patients had arthritis response than anifrolumab-treated patients.

Conclusions: Across trials, most patients had concordant BICLA/SRI(4) outcomes and dual BICLA/SRI(4) responses favoured anifrolumab. A BICLA non-responder/SRI(4) responder subgroup was identified where imbalances of key factors driving the BICLA/SRI(4) discordance (disease activity, glucocorticoid taper) disproportionately favoured the TULIP-1 placebo group. Careful attention to baseline disease activity and monitoring glucocorticoid taper variation will be essential in future SLE trials.

Trial Registration Numbers: NCT02446912 and NCT02446899.
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http://dx.doi.org/10.1136/annrheumdis-2021-221847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213793PMC
July 2022

Impact of serum interleukin-22 as a biomarker for the differential use of molecular targeted drugs in psoriatic arthritis: a retrospective study.

Arthritis Res Ther 2022 04 15;24(1):86. Epub 2022 Apr 15.

The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka, Yahata-nishi, 807-8555, Kitakyushu, Japan.

Background: We explored whether serum cytokines could be used as biomarkers for optimal use of tumor necrosis factor inhibitors (TNF-i) and interleukin (IL)-17 inhibitors (IL-17-i) in patients with psoriatic arthritis (PsA).

Methods: In cohort 1 (47 patients treated with IL-17-i [n=23] or TNF-i [n=24] for ≥1 year), we identified serum cytokines that predicted the achievement of Disease Activity in Psoriatic Arthritis-remission (DAPSA-REM), Psoriasis Area and Severity Index (PASI) 90, and Minimal Disease Activity after 1 year of TNF-i or IL-17-i therapy. Subsequently, we developed treatment strategies based on the identified cytokines; initiation of IL-17-i therapy in patients with low IL-22 concentrations (IL-22 <0.61376 pg/ml) and TNF-i therapy in patients with high IL-22 concentrations (0.61376< IL-22 pg/ml). In cohort 2 (34 patients), treatment responses were compared between the strategic treatment group (n=17), which was treated based on the treatment strategies, and the mismatched treatment group (n=17) to verify the validity of the treatment strategies developed using serum cytokines as biomarkers.

Results: In cohort 1, serum IL-22 concentration was identified as a predictor of DAPSA-remission after 1 year of IL-17-i therapy. Regarding treatment strategies, we selected TNF-i for patients with high IL-22 concentrations and IL-17-i for those with low IL-22 concentrations. There were no significant differences in the baseline characteristics between the strategic and mismatched treatment groups. Regarding treatment effects, activity significantly improved at 1 year in both groups. Upon comparison of the treatment effects, the rate of achieving DAPSA-REM and Minimal Disease Activity at month 12 was significantly higher in the strategic treatment group.

Conclusions: The results of this pilot study suggest that IL-22 may be a biomarker of treatment response to TNF-i and IL-17-i in patients with PsA. Further large-scale studies in independent, prospectively collected datasets are required to verify that IL-22 is indeed a biomarker of treatment response in these patients.
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http://dx.doi.org/10.1186/s13075-022-02771-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9011943PMC
April 2022

Dawn of Precision Medicine in Psoriatic Arthritis.

Front Med (Lausanne) 2022 18;9:851892. Epub 2022 Mar 18.

The First Department of Internal Medicine, University of Occupational and Environmental Health Japan, Kitakyushu, Japan.

The establishment of precision medicine is considered particularly important in heterogeneous autoimmune diseases (e.g., psoriatic arthritis, systemic lupus erythematosus), which reveal clinical and molecular heterogeneity. The selection of optimal treatment strategies for individual patients may be more important and complex in autoimmune diseases than in other diseases. Two factors are important in precision medicine: patient stratification and use of targeted. When both factors work, patients are likely to have good outcomes. However, research into precision medicine and its practice in systemic autoimmune diseases is lacking. In contrast, the usefulness of peripheral immune cell phenotyping in the evaluation of immunological characteristics and stratification into subgroups of individual patients with systemic autoimmune diseases such as immunoglobulin 4-related disease, systemic lupus erythematosus, and anti-neutrophil cytoplasmic antibody-related vasculitis was reported. Furthermore, the potential of precision medicine using biological disease-modifying antirheumatic drugs based on peripheral immune cell phenotyping was recently demonstrated for psoriatic arthritis in the clinical setting. Precision medicine has not yet been sufficiently investigated in real world clinical settings. However, a dawn of precision medicine has emerged. We should shed further light on precision medicine in PsA and other autoimmune diseases. Here, we first review the usefulness of peripheral immune cell phenotyping in systemic autoimmune diseases and the potential of precision medicine in PsA based on this method.
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http://dx.doi.org/10.3389/fmed.2022.851892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8973395PMC
March 2022

A patient with eosinophilic granulomatosis with polyangiitis successfully weaned from corticosteroids through remission induction therapy with mepolizumab.

Mod Rheumatol Case Rep 2022 06;6(2):243-247

The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.

The patient was a 74-year-old man who was admitted to our hospital for fever, purpura, abdominal pain, and bilateral numbness. Although the patient tested negative for anti-neutrophil cytoplasmic antibody (ANCA), he presented with an elevated peripheral eosinophil count, increased inflammatory responses, duodenitis, cholecystitis, lung lesions, renal disorder, and peripheral neuropathy. The skin biopsy findings revealed vasculitis. Thus, the patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA). Given the advanced age of the patient, in addition to the poor general condition and hepatic and renal dysfunction, administration of immunosuppressants was considered to pose a high risk. After obtaining informed consent, remission induction therapy was initiated with mepolizumab (MPZ; 300 mg/M) in combination with high-dose corticosteroid therapy (equivalent to 70 mg/day of prednisolone). After treatment initiation, eosinophil counts and inflammatory responses decreased. Moreover, the abdominal pain and purpura resolved, and renal/hepatic dysfunction and peripheral neuropathy also improved. While the corticosteroid dose was subsequently reduced, no relapse was observed. Approximately 2 years later, the corticosteroid was discontinued. After the discontinuation of the corticosteroid, the patient continued treatment with MPZ alone and has remained in remission for approximately 6 months. Therefore, MPZ may be useful as a remission induction therapy in ANCA-negative EGPA resistant to steroids.
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http://dx.doi.org/10.1093/mrcr/rxac017DOI Listing
June 2022

Integrated Safety Analysis of Filgotinib Treatment for Rheumatoid Arthritis in Patients from Japan Over a Median of 1.5 Years.

Mod Rheumatol 2022 Apr 2. Epub 2022 Apr 2.

Keio University School of Medicine, Tokyo, Japan.

Objective: Characterize safety of the Janus kinase-1 preferential inhibitor filgotinib in Japanese patients with moderately to severely active rheumatoid arthritis.

Methods: Data from three Phase 3 trials (NCT02889796, NCT02873936, NCT02886728) and a long-term extension (NCT03025308) through September 2019 were integrated; patients received ≥1 dose of filgotinib 200 (FIL200) or 100 mg (FIL100) daily, or placebo (PBO). We calculated exposure-adjusted incidence rates (EAIRs) per 100 patient-years filgotinib exposure (100PYE) for treatment-emergent adverse events (TEAEs) and adverse events of special interest.

Results: Among 3691 total patients and 6080.7 PYE, 229 Japanese patients received filgotinib for 311.4 PYE (median 1.5, maximum 2.5 years). During the 12-week PBO-controlled period, serious TEAEs and TEAEs leading to study drug disruption were comparable between filgotinib and PBO. Serious infection rates were 1.9%, 0%, and 2% for FIL200, FIL100, and PBO during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.8 and 2.1/100PYE. No herpes zoster or major adverse cardiovascular events (MACE) occurred during the PBO-controlled period; long-term FIL200 and FIL100 EAIRs were 3.0 and 2.1/100PYE (herpes zoster) and 0.6 and 0/100PYE (MACE).

Conclusion: Long-term filgotinib treatment (median 1.5, maximum 2.5 years exposure) was well tolerated at 100- and 200-mg doses in Japanese patients with rheumatoid arthritis.
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http://dx.doi.org/10.1093/mr/roac020DOI Listing
April 2022

Allogeneic stem cell transplantation for trisomy 8-positive myelodysplastic syndrome or myelodysplastic/myeloproliferative disease with refractory Behçet's disease: Case report and the review of literature.

Mod Rheumatol Case Rep 2022 06;6(2):273-277

Department of Hematology, Kokura Memor ial Hospital, Kitakyushu, Japan.

We had two cases of trisomy 8-positive myelodysplastic syndrome (MDS) with incomplete Behçet's disease (BD) in which the remissions of both diseases were maintained by allogeneic stem cell transplantation (allo-SCT). Among MDS with BD patients, sometimes it is difficult to control the symptoms of BD with standard therapies such as corticosteroids and tumor necrosis factor (TNF) inhibitors. Although there should be careful consideration regarding indications for transplantation, our two cases, in which refractory BD was completely controlled by allo-SCT, suggest that allo-SCT can be one of the treatment options for higher-risk MDS with BD patients.
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http://dx.doi.org/10.1093/mrcr/rxac032DOI Listing
June 2022

Down-Regulated Th17 Cells in a Patient With Familial Mediterranean Fever Associated with AA Amyloidosis in the Treatment of Canakinumab.

Mod Rheumatol Case Rep 2022 Mar 29. Epub 2022 Mar 29.

Section of Rheumatology, Sakurajyuji Hospital, Kumamoto, Japan.

Autoinflammatory diseases are innate immune-mediated inflammatory disorders, unlike autoimmune diseases, which are characterised by abnormalities in adoptive immunity, although autoimmune and autoinflammatory diseases have certain similar clinical features. Familial Mediterranean fever (FMF), the most common monogenic autoinflammatory disease, is associated with mutations in the MEFV gene that encodes pyrin, which results in inflammasome activation and uncontrolled production of interleukin (IL)-1β. Regular use of colchicine, the primary drug for FMF treatment, prevents febrile attacks and reduces long-term risk of subsequent complications of amyloid A (AA) amyloidosis. However, a minority of FMF patients develop colchicine resistance, and anti-IL-1β treatment with canakinumab (CNK), which is a genetically modified human IgG1 monoclonal antibody specific for human IL-1β, was beneficial in inhibiting inflammation in such patients. Here, we present a patient with FMF associated with AA amyloidosis, who was treated with CNK and demonstrated down-regulated Th17 cells and activated Th17 cells (from 21.4% to 12.8%, and from 1.45% to 0.83%, respectively) in peripheral blood, as shown by immunophenotyping via multicolor flow cytometry and by disease activity and improved laboratory inflammatory surrogate markers; C-reactive protein (CRP) and serum amyloid A protein (SAA). CRP had values within normal limits, but SAA did not (Spearman's rank correlation coefficient; ρ=0.133). We report that SAA and IL-1β may differentiate Th17 cells from CD4-naïve T cells, and we discuss interactions between autoinflammation and autoimmunity as a model based on this case, through modes of action with IL-1β and SAA. This report is the first demonstrating that an IL-1β antagonist may reduce Th17 cells in FMF as a therapeutic option.
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http://dx.doi.org/10.1093/mrcr/rxac031DOI Listing
March 2022

Anifrolumab efficacy and safety by type I interferon gene signature and clinical subgroups in patients with SLE: post hoc analysis of pooled data from two phase III trials.

Ann Rheum Dis 2022 07 25;81(7):951-961. Epub 2022 Mar 25.

BioPharmaceuticals R&D, AstraZeneca US, Gaithersburg, Maryland, USA

Objectives: To characterise the efficacy and safety of anifrolumab in patients with systemic lupus erythematosus (SLE) according to interferon gene signature (IFNGS), demographic and clinical subgroups.

Methods: We performed post hoc analyses of pooled data from the 52-week phase III TULIP-1/TULIP-2 placebo-controlled trials of intravenous anifrolumab in moderate-to-severe SLE. Outcomes were assessed in predefined subgroups: IFNGS (high/low), age, sex, body mass index, race, geographic region, age of onset, glucocorticoid use, disease activity and serological markers.

Results: In pooled data, patients received anifrolumab 300 mg (360/726) or placebo (366/726); 82.6% were IFNGS-high. IFNGS-high patients had greater baseline disease activity and were more likely to have abnormal serological markers versus IFNGS-low patients. In the total population, a greater proportion of patients treated with anifrolumab versus placebo achieved British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response at week 52 (difference 16.6%; nominal p<0.001). BICLA response treatment differences with anifrolumab versus placebo were comparable to the total population across most predefined subgroups, including subgroups for baseline glucocorticoid dosage (<10/≥10 mg/day prednisone/equivalent) and for clinical disease activity (SLE Disease Activity Index 2000 score <10/≥10). Subgroups with larger treatment differences included IFNGS-high patients (18.2%), patients with abnormal baseline serological markers (23.1%) and Asian patients (29.2%). The safety profile of anifrolumab was similar across subgroups.

Conclusions: Overall, this study supports the consistent efficacy and safety of anifrolumab across a range of patients with moderate-to-severe SLE. In a few subgroups, small sample sizes limited conclusions from being drawn regarding the treatment benefit with anifrolumab.

Trial Registration Number: NCT02446912, NCT02446899.
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http://dx.doi.org/10.1136/annrheumdis-2021-221425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9213795PMC
July 2022

Associations between continuous glucose monitoring-derived metrics and HbA1c in patients with type 2 diabetes mellitus.

Diabetes Res Clin Pract 2022 Apr 18;186:109836. Epub 2022 Mar 18.

Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, 2-1-1 Bunkyo-ku, Tokyo, Japan.

Aims: The aim of this study was to define the relationship between time in range (TIR) and hemoglobin A1c (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM).

Methods: The glycemic profile of 999 Japanese patients was analyzed with FreeStyle Libre Pro Continuous Glucose Monitoring (FLP-CGM) while they continued their prescribed glucose-lowering medications. FLP-CGM data recorded over 8 consecutive days were analyzed.

Results: The regression model for HbA1c on TIR was HbA1c = 9.4966-0.0309 × TIR. The predicted HbA1c level for TIR of 70% was 7.33% and is higher than reports subjecting mostly T1DM. The TIR corresponding to HbA1c 7.0% was 80.64%. The patients with low TIR tended to have long duration of diabetes, used high dose of daily insulin, high body mass index, high HbA1c, liver dysfunction and high triglyceride. Relatively higher percentages of patients of this group used sulfonylureas, glucagon like peptide-1 receptor agonists and insulin.

Conclusions: Our data showed predicted HbA1c corresponding to TIR is largely depends on study population, thus is not uniform. Our results provide new insights on the management of T2DM. However, caution should be exercised in extending the HbA1C-TIR relationship using FLP-CGM to any other sensors since there could be a risk of hypoglycemia in doing so.
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http://dx.doi.org/10.1016/j.diabres.2022.109836DOI Listing
April 2022

Short-Term Prognostic Factors in Hospitalized Herpes Zoster Patients and Its Associated Cerebro-Cardiovascular Events: A Nationwide Retrospective Cohort in Japan.

Front Med (Lausanne) 2022 4;9:843809. Epub 2022 Mar 4.

The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan.

Background: Short-term mortality and incidence of cerebrovascular and cardiovascular events (C-CVE) during hospitalization of patients with severe herpes zoster (HZ) have not been sufficiently investigated. We aimed to investigate short-term prognosis and incidence of C-CVE associated with HZ in hospitalized patients.

Methods: This retrospective cohort study from April 2016 to March 2018 included HZ inpatient cases selected from the Diagnosis Procedure Combination database-a Japanese nationwide inpatient database. HZ and C-CVE were diagnosed based on the 10 revision of the International Classification of Diseases and Injuries codes. The definition of primary exposure was that treatments were initiated within 7 days of admission, and antivirals were administered for ≥7 days. Main Outcomes were in-hospital deaths and C-CVE onset after hospitalization.

Results: Among 16,811,501 in-hospital cases registered from 1,208 hospitals, 29,054 cases with HZ were enrolled. The median age was 71.0 years, 15,202 cases (52.3%) were female, and the HZ types were the central nervous system (n=9,034), disseminated (n=3,051), and ophthalmicus (n=1,069) types. There were 301 (1.0%) in-hospital deaths and 385 (1.3%) post-hospitalization onset of C-CVE. The 30-day in-hospital survival rates with or without underlying disease were 96.8% and 98.5%, respectively. Age ≥75 years (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.55-3.05), liver cirrhosis or hepatic failure (HR, 5.93; 95% CI, 2.16-16.27), chronic kidney disease (HR, 1.82; 95% CI, 1.24-2.68), heart failure (HR, 1.65; 95% CI, 1.22-2.24), and old cerebrovascular events (HR, 1.92; 95% CI, 1.10-3.34) were associated with poor short-term prognosis. Age ≥75 years (odds ratio [OR], 1.70; 95% CI, 1.29-2.24), diabetes (OR, 1.50; 95% CI, 1.19-1.89), dyslipidemia (OR, 1.95; 95% CI, 1.51-2.51), hyperuricemia (OR, 1.63; 95% CI, 1.18-2.27), hypertension (OR, 1.76; 95% CI, 1.40-2.20), heart failure (OR, 1.84; 95% CI, 1.32-2.55), and glucocorticoid administration (OR, 1.59; 95% CI, 1.25-2.01) were associated with increased risks for in-hospital C-CVE onset.

Conclusions: The underlying diseases that could influence the short-term mortality of severe HZ were identified. Glucocorticoid is a possible risk factor for the in-hospital onset of C-CVE after severe HZ development.
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http://dx.doi.org/10.3389/fmed.2022.843809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931312PMC
March 2022

'Not at target': prevalence and consequences of inadequate disease control in systemic lupus erythematosus-a multinational observational cohort study.

Arthritis Res Ther 2022 03 14;24(1):70. Epub 2022 Mar 14.

University of Occupational and Environmental Health, Kitakyushu, Japan.

Background: The unmet need in systemic lupus erythematosus (SLE) with the current standard of care is widely recognised, but few studies have quantified this. The recent definition of treat-to-target endpoints and other thresholds of uncontrolled disease activity provide an opportunity to formally define unmet need in SLE. In this study, we enumerated the prevalence of these states and examined their association with adverse outcomes.

Methods: Data were collected prospectively in a 13-country longitudinal SLE cohort between 2013 and 2019. Unmet need was defined as never attaining lupus low disease activity state (LLDAS), a time-adjusted mean SLEDAI-2K (AMS) > 4, or ever experiencing high disease activity status (HDAS; SLEDAI-2K ≥10). Health-related quality of life (HRQoL) was assessed using SF36 (v2) and damage accrual using the SLICC-ACR SLE Damage Index (SDI).

Results: A total of 3384 SLE patients were followed over 30,313 visits (median [IQR] follow-up 2.4 [0.4, 4.3] years). Eight hundred thirteen patients (24%) never achieved LLDAS. Median AMS was 3.0 [1.4, 4.9]; 34% of patients had AMS > 4. Twenty-five per cent of patients had episodes of HDAS. Each of LLDAS-never, AMS>4, and HDAS-ever was strongly associated with damage accrual, higher glucocorticoid use, and worse HRQoL. Mortality was significantly increased in LLDAS-never (adjusted HR [95% CI] = 4.98 [2.07, 12.0], p<0.001) and HDAS-ever (adjusted hazard ratio (HR) [95% CI] = 5.45 [2.75, 10.8], p<0.001) patients.

Conclusion: Failure to achieve LLDAS, high average disease activity, and episodes of HDAS were prevalent in SLE and were significantly associated with poor outcomes including organ damage, glucocorticoid exposure, poor quality of life, and mortality.
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http://dx.doi.org/10.1186/s13075-022-02756-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8919535PMC
March 2022

Usefulness of Ultrasound as a Predictor of Elderly-Onset Rheumatoid Arthritis with Polymyalgia Rheumatica-Like Onset.

Mod Rheumatol 2022 Mar 14. Epub 2022 Mar 14.

The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

Objectives: Differentiation between polymyalgia rheumatica (PMR) and elderly onset rheumatoid arthritis (EORA), especially in elderly patients, is often difficult due to similarities in symptoms and serological kinetics. In this study, we aimed to analyze the predictors of EORA with PMR-like onset.

Methods: Seventy-two patients diagnosed with PMR, who attended our hospital for routine care and underwent musculoskeletal ultrasonography (MSUS) at that time were evaluated. Synovitis was evaluated semi-quantitatively (0-3) by gray scale (GS) and power doppler (PD) in 24 joints (both hands [wrist, metacarpophalageal, and proximal interphalangeal joints] and both shoulder joints).

Results: Overall, 18 patients had RA (25.0%); the mean age was 75.0 years, and 34.7% and 65.3% were male and female, respectively. In PMR and PMR/EORA groups, multivariate logistic analysis showed that rheumatoid factor (RF) positivity, GS ≥2 of hand joints, and PD ≥1 of hand joints were independent factors with significant differences. At least 1 of the 3 factors had a sensitivity of 88.9% and specificity of 92.6%.

Conclusions: Presence of at least one of the criteria: RF positivity, GS ≥ 2, and PD ≥ 1 of hand joints, suggested the possibility of developing EORA within 1 year of PMR diagnosis.
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http://dx.doi.org/10.1093/mr/roac024DOI Listing
March 2022

Nailfold microvascular abnormalities are associated with a higher prevalence of pulmonary arterial hypertension in patients with MCTD.

Rheumatology (Oxford) 2022 Mar 14. Epub 2022 Mar 14.

First Department of Internal Medicine, University of Occupational and Environmental Health, Japan.

Objective: Mixed connective tissue disease (MCTD) manifests with microvasculopathy and overlapping clinical features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and idiopathic inflammatory myopathies (IIM). The aim of this study was to investigate the clinical significance of microvasculopathy in patients with MCTD using nailfold videocapillaroscopy (NVC).

Methods: Fifty patients with newly diagnosed and untreated MCTD were enrolled in this multicentre, prospective, and observational study. Clinical features and NVC findings were assessed at baseline and after 1-year post-intervention, along with disease controls [SLE (n = 40), SSc (n = 70), and IIM (n = 50)].

Results: All MCTD patients presented Raynaud's phenomenon and were positive for anti-U1 ribonucleoprotein antibodies, and 22.0% (11/50) had pulmonary arterial hypertension (PAH). The prevalence of NVC scleroderma patterns in MCTD was 38.0%, which was lower than SSc (88.6%) but higher than SLE (10.0%). In addition, when we divided MCTD patients into two groups by presence or absence of NVC scleroderma patterns, we found that a higher prevalence of PAH in patients with NVC scleroderma patterns. Namely, NVC scleroderma patterns were observed in all MCTD patients with PAH, and in 21.0% of those without PAH. After intensive immunosuppressive therapy, NVC scleroderma patterns disappeared in half of the MCTD patients but were not changed in SSc patients.

Conclusions: MCTD differed from SLE, SSc and IIM in terms of the prevalence and responsiveness of NVC scleroderma patterns to immunosuppressive therapy. Detection of nailfold microvascular abnormalities in MCTD could contribute to predicting PAH and help us to understand further aspects of the pathogenesis of MCTD.
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http://dx.doi.org/10.1093/rheumatology/keac165DOI Listing
March 2022

Association of Viral Infection With the Development and Pathogenesis of Systemic Lupus Erythematosus.

Front Med (Lausanne) 2022 25;9:849120. Epub 2022 Feb 25.

First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage in women of childbearing age and has a relapsing-remitting course. SLE is caused by the interaction between genetic and environmental factors, however, its underlying triggers remain unknown. Among the environmental factors, the involvement of infections as a trigger for SLE, especially those of viral etiology, has been widely reported. Human endogenous retroviruses (HERVs) may put patients at a genetic predisposition to SLE, while the Epstein-Barr virus (EBV) may play a role as an environmental factor that triggers the development of SLE. It has been suggested that EBV-infected B-cells may become resistant to apoptosis, resulting in the activation, proliferation, and antibody production of autoreactive B-cells, which cause tissue damage in SLE. However, the interaction between the virus and immune cells, as well as the impact of the virus on the differentiation and dysfunction of immune cells, remain unclear. In this review, we focus on the relationship between the development and pathogenesis of SLE and viral infections, as well as the mechanism of SLE exacerbation via activation of immune cells, such as B-cells, based on the latest findings.
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http://dx.doi.org/10.3389/fmed.2022.849120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8914279PMC
February 2022

A case of mixed connective tissue disease complicated by pulmonary hypertension and ascites after addition of pulmonary vasodilators.

Mod Rheumatol Case Rep 2022 06;6(2):203-208

The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.

We present the case of a 54-year-old woman with a long history of pulmonary hypertension associated with mixed connective tissue disease. She was being treated with pulmonary vasodilators, including epoprostenol and bosetan, but her mean pulmonary arterial pressure (mPAP) gradually worsened. Although her mPAP began to improve with adding sildenafil, ascites occurred. Discontinuing newly initiated drugs and starting diuretics improved her ascites. This suggested that an intensification of the treatment with vasodilators might have led to ascites (on a background of a probable arteriovenous shunt formation) in this patient with a long history of pulmonary hypertension.
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http://dx.doi.org/10.1093/mrcr/rxac019DOI Listing
June 2022
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