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Previously we showed that pressor and differential regional sympathoexcitatory responses (adrenal > renal ≥ lumbar) evoked by stimulation of A1 adenosine receptors located in the nucleus of the solitary tract (NTS) were attenuated/abolished by baroreceptor denervation or blockade of glutamatergic transmission in the NTS, suggesting A1 receptor-elicited inhibition of glutamatergic transmission in baroreflex pathways. Therefore we tested the hypothesis that stimulation of NTS A1 adenosine receptors differentially inhibits/resets baroreflex responses of preganglionic adrenal (pre-ASNA), renal (RSNA), and lumbar (LSNA) sympathetic nerve activity. In urethane-chloralose-anesthetized male Sprague-Dawley rats (n = 65) we compared baroreflex-response curves (iv nitroprusside and phenylephrine) evoked before and after bilateral microinjections into the NTS of A1 adenosine receptor agonist (N6-cyclopentyladenosine, CPA; 0.033-330 pmol/50 nl). CPA evoked typical dose-dependent pressor and differential sympathoexcitatory responses and similarly shifted baroreflex curves for pre-ASNA, RSNA, and LSNA toward higher mean arterial pressure (MAP) in a dose-dependent manner; the maximal shifts were 52.6 ± 2.8, 48.0 ± 3.6, and 56.8 ± 6.7 mmHg for pre-ASNA, RSNA, and LSNA, respectively. These shifts were not a result of simple baroreceptor resetting because they were two to three times greater than respective increases in baseline MAP evoked by CPA. Baroreflex curves for pre-ASNA were additionally shifted upward: the maximal increases of upper and lower plateaus were 41.8 ± 16.4% and 45.3 ± 8.7%, respectively. Maximal gain (%/mmHg) measured before vs. after CPA increased for pre-ASNA (3.0 ± 0.6 vs. 4.9 ± 1.3), decreased for RSNA (4.1 ± 0.6 vs. 2.3 ± 0.3), and remained unaltered for LSNA (2.1 ± 0.2 vs. 2.0 ± 0.1). Vehicle control did not alter the baroreflex curves. We conclude that the activation of NTS A1 adenosine receptors differentially inhibits/resets baroreflex control of regional sympathetic outputs. [ABSTRACT FROM AUTHOR]

Rituximab (RTX) has been reported to effectively maintain remission in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). In this multicenter study involving 57 patients who achieved remission after 24 weeks, we evaluated the effectiveness of RTX in maintaining remission in patients with AAV. Patients were divided into three groups based on RTX administration: continuous, induction phase-only, and maintenance phase-only groups. The continuous group had a remission maintenance rate after 48 weeks of treatment compared with the induction phase-only group (100% vs. 88.2%, p  = 0.29). More patients in the continuous group received three or more RTX doses during the induction period (82.4% vs. 52.9%, p  = 0.06), and this group had a lower incidence of infection (5.9% vs. 29.4%, p  = 0.08). Compared with the maintenance-only group, the continuous group had a numerically higher proportion of patients in remission after 48 weeks of treatment (100% vs. 83.3%, p  = 0.26) and a lower incidence of infection (5.9% vs. 50%, p  = 0.04); however, the N in the maintenance phase was small and suspected to have low power. Regardless of the method of RTX administration (induction phase-only or continuous), administering RTX during the induction phase may be crucial for achieving remission.

Objective: This systematic scoping review assess the effect of cyclophosphamide (CY) administration during childhood on ovarian function in patients with juvenile-onset connective tissue diseases., Methods: A MEDLINE database search was conducted using terms related to CY, juvenile-onset connective tissue diseases, and ovarian function. Studies were included if they met specific criteria., Results: The search, conducted on 28 November 2023, yielded 3328 references. After a two-stage screening process, six observational studies on systemic lupus erythematosus patients were included. All studies had a high risk of confounding bias, as none adjusted for confounding variables. Two studies assessing clinical ovarian dysfunction found no clear difference between CY and non-CY groups. However, statistical differences were observed in hormonal profiles. Decreased ovarian reserve was more frequent in CY-exposed patients. Two studies showed significantly higher follicle-stimulating hormone (FSH) levels in the CY group, while one showed a trend towards higher FSH levels without statistical significance., Conclusion: This review suggested that CY use in childhood may not conclusively have clinically significant effects on ovarian function. Further investigation needed on CY's effect on hormonal levels, fertility, and pregnancy outcomes., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Objective: To assess the prevalence and outcomes among regimens of glucocorticoid tapering for microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in real-world practice., Methods: We retrospectively examined the Japan Collaborative Registry of ANCA-associated Vasculitis (J-CANVAS) registry, and evaluated the prevalence of glucocorticoid tapering regimens in the PEXIVAS trial. In patients with newly diagnosed MPA and GPA, we compared outcomes among standard and reduced pace regimens. Relapse-free survival rates were compared after propensity score matching., Results: Of 364 eligible patients, 113 (31.0%) received standard tapering and 251 slower tapering. After matching, 87 pairs no significant difference was observed in relapse-free survival (p=0.506). Regarding the reduced regimen, there were so few patients (14/364, 3.8%) that statistical analysis was not performed., Conclusions: The glucocorticoid tapering for MPA and GPA in Japanese real-world practice was found to be generally slower than the standard regimen revealing a huge evidence-practice gap. Additionally, slower tapering did not improve relapse-free survival and might cause unnecessary glucocorticoid exposure., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Background: Pneumocystis jirovecii pneumonia (PCP) is an opportunistic infection in patients undergoing immunosuppressive therapy, such as glucocorticoid (GC) medication, for systemic autoimmune diseases like systemic lupus erythematosus (SLE). Despite the confirmed effectiveness of PCP prophylaxis, its clinical administration, especially in conjunction with GC dosage, remains unclear. We aimed to describe the clinical practice of PCP prophylaxis in association with SLE in Japan, evaluate the relationship between GC dosage and PCP prophylaxis, and explore the practice patterns associated with PCP prophylaxis., Methods: This cross-sectional study used data from the Lupus Registry of Nationwide Institutions in Japan from 2016 to 2021 and included patients diagnosed with SLE. Using descriptive statistics, multivariate analysis, and decision tree analysis, we examined the prevalence of PCP prophylaxis and its association with the GC dosage., Results: Out of 1,460 patients, 21% underwent PCP prophylaxis. The frequency of prophylaxis decreased with a decrease in GC dosage. After adjusting for confounders, logistic regression revealed the odds ratio of PCP prophylaxis increased with higher prednisolone (PSL) doses: 3.7 for 5 ≤ PSL < 7.5 mg, 5.2 for 7.5 ≤ PSL < 10 mg, 9.0 for 10 ≤ PSL < 20 mg, and 43.1 for PSL ≥ 20 mg, using PSL < 5 mg as the reference. Decision tree analysis indicated that a PSL dosage of < 11 mg/day and immunosuppressant use were key determinants of PCP prophylaxis., Conclusion: This study provides valuable insights into PCP prophylaxis practices in patients with SLE in Japan, underscoring the importance of GC dosage and concomitant immunosuppressant use., Competing Interests: Declarations Ethics approval and informed consent This study was conducted in accordance with the Declaration of Helsinki and Ethical Guidelines for Epidemiologic Research in Japan. The study protocol was approved by the Ethics Committee of Kakogawa Central City Hospital (authorization number: 2021–04). The patients provided written informed consent to participate in the and permission to publish their data. Consent for publication Not applicable. Competing interests KS received speaker fees from Glaxo Smith Kline and a research grant from Pfizer Inc. TY received speaker fees from Glaxo Smith Kline., (© 2024. The Author(s).)

Objective: Late-onset systemic lupus erythematosus (LoSLE) is known to possess characteristics different from those of early-onset SLE (EoSLE), thereby making their diagnosis difficult. This study aimed to assess the characteristic features of LoSLE in Japan, a model country with a super-aged society., Methods: Data were obtained from the Lupus Registry of Nationwide Institutions, which includes a multicenter cohort of patients with SLE in Japan who satisfied the 1997 American College of Rheumatology revised classification criteria for SLE. Data were compared between patients with LoSLE (≥50 years old at onset) and EoSLE (<50 years old at onset). To identify factors associated with LoSLE, binary logistic regression was used for the multivariate analysis, and missing values were complemented by multiple imputations. We also conducted a sub-analysis for patients diagnosed within 5 years of onset., Results: Out of 929 enrolled patients, 34 were excluded owing to a lack of data regarding onset age. Among the 895 remaining patients, 100 had LoSLE, whereas 795 had EoSLE. The male-to-female ratio was significantly higher in the LoSLE group than in the EoSLE group (0.32 vs 0.11, p < 0.001). With respect to SLEDAI components at onset, patients with LoSLE exhibited a higher frequency of myositis (11.9% vs 3.75%, p = 0.031), lower frequency of skin rash (33.3% vs 67.7%, p < 0.001), and lower frequency of alopecia (7.32% vs 24.7%, p = 0.012). No significant differences in overall disease activity at onset were observed between the two groups. Regarding medical history, immunosuppressants were more commonly used in EoSLE. A multivariate analysis revealed that a higher male proportion and a lower proportion of new rash at onset were independent characteristic features of LoSLE. We also identified late onset as an independent risk factor for a high SDI score at enrollment and replicated the result in a sub-analysis for the population with a shorter time since onset., Conclusions: We clarified that LoSLE was characterized by a higher male proportion, a lower frequency of skin rash and a tendency to organ damage. Now that the world is faced with aging, our results may be helpful at diagnosis of LoSLE., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ken-ei Sada received a speaker’s fee from GlaxoSmithKline PLC and research grants from Pfizer Inc. Yohei Kirino received a speaker’s fee from Amgen and Novartis and research funding from Nippon Shinyaku. Ryusuke Yoshimi received a speaker’s fee from GlaxoSmithKline PLC, AstraZeneca PLC, and Sanofi S.A.

We aimed to clarify the long-term safety and efficacy of rituximab (RTX) as a remission induction therapy following severe relapse in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We retrospectively collected the data of patients with severely relapsed AAV from a Japanese multicentre cohort. The primary exposure was RTX use; the primary outcome was complete remission (CR) proportions at week 24. Baseline characteristics were compared between the RTX and non-RTX groups. We performed multivariate logistic regression analysis and one-to-one propensity score matching analysis as a sensitivity analysis. Totally, 100 patients were enrolled: 52 in the RTX group and 48 in the non-RTX group. Baseline characteristics were comparable between the two groups, except for age, AAV subtype and ANCA serotype. The median age was 71 vs. 75 years, and the PR3-ANCA positivity rate was 44.2% vs. 18.8% in the RTX and non-RTX groups, respectively. No significant difference was observed in CR proportions at week 24 between the two groups (79.2% vs. 68.1%, p = 0.321), with an adjusted odds ratio of 1.27 (95% confidence interval [CI] 0.47-3.51). At week 48, CR proportions were significantly higher in the RTX group (91.7% vs. 64.9%, p = 0.005), with an adjusted odds ratio of 2.95 (95% CI 0.97-9.91). Serious infection rates were lower in the RTX group than in the non-RTX group, with no statistically significant difference. RTX was not superior to conventional immunosuppressive therapies at week 24 but showed significantly favourable results at week 48 for severely relapsed AAV., (© 2024. The Author(s).)

Objective: Enhanced expression of transforming growth factor (TGF) β in the kidneys of patients with lupus nephritis (LN) can lead to progressive fibrosis, resulting in end-organ damage. ADAM9 activates TGFβ1 by cleaving the latency-associated peptide (LAP). We hypothesized that ADAM9 in the kidney may accelerate fibrogenesis by activating TGFβ1., Methods: We assessed the expression of ADAM9 in the kidneys of mice and humans who were lupus prone. In vitro experiments were conducted using tubular epithelial cells (TECs) isolated from mice and explored the mechanisms responsible for the up-regulation of ADAM9 and the subsequent activation of TGFβ1. To assess the role of ADAM9 in the development of tubular-intestinal fibrosis in individuals with LN, we generated MRL/lpr mice who were Adam9 deficient., Results: ADAM9 was highly expressed in tubules from MRL/lpr mice. The transcription factor hypoxia-inducible factor-1α was found to promote the transcription of ADAM9 in TECs. TECs from mice who were Adam9 deficient and exposed to the hypoxia mimetic agent dimethyloxalylglycine failed to cleave the LAP to produce bioactive TGFβ1 from latent TGFβ1. Coculture of TECs from mice who were Adam9 deficient with fibroblasts in the presence of dimethyloxalylglycine and latent TGFβ1 produced decreased amounts of type I collagen and α-smooth muscle actin (SMA) by fibroblasts. MRL/lpr mice who were Adam9 deficient showed reduced interstitial fibrosis. At the translational level, ADAM9 expression in tissues and urine of patients with LN was found to increase., Conclusion: Hypoxia promotes the expression of ADAM9 by TECs, which is responsible for the development of interstitial fibrosis in patients with LN by enhancing the TGFβ1 activation, which promotes fibroblasts to produce collagen and α-SMA., (© 2024 American College of Rheumatology.)

Objectives: To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA)., Methods: We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomized into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day and IVMP 1.0 g/day. The primary outcome was all-cause mortality, and the secondary outcomes were composite all-cause mortality and kidney failure, severe relapse and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine-Gray subdistribution hazard model were used., Results: In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (3%) died, 4 (2.0%) had kidney failure, 11 (5.5%) had severe relapse, and 40 (19.9%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause mortality 0.46 (95% CI: 0.07, 2.81) and 0.07 (95% CI: 0.01, 0.41), respectively; all-cause mortality/kidney failure 1.18 (95% CI: 0.26, 5.31) and 0.59 (95% CI: 0.08, 4.52), respectively; subdistribution HRs for severe relapse were 1.26 (95% CI: 0.12, 13.70) and 3.36 (95% CI: 0.49, 23.29), respectively; and for serious infection 1.88 (95% CI: 0.76, 4.65) and 0.94 (95% CI: 0.28, 3.13), respectively., Conclusion: IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study investigated the clinically relevant factors for headaches in patients with systemic lupus erythematosus (SLE) using a registry from a Japanese multicenter cohort., Methods: This cross-sectional study analysed the clinical information of patients with SLE who experienced headache episodes using the Migraine Disability Assessment (MIDAS) questionnaire. Significant findings in the comparisons between patients with headache (HA patients) and those without headache (non-HA patients) and in the comparisons depending on the grades of headache-induced disability in daily life based on the MIDAS scores were evaluated. Multivariate logistic regression analyses were performed to identify the relevant factors for headache., Results: We analyzed 369 patients (median age, 45 years; female, 90.8%), including 113 HA patients who were significantly younger than non-HA patients ( p < .005). HA patients had significantly higher frequencies of photosensitivity, rashes, and mucosal ulcers than non-HA patients ( p < .05). Age and photosensitivity were significantly associated with headache (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.95-0.99; OR 2.11, 95% CI 1.29-3.49, respectively). In the HA patients, hypocomplementemia was significantly associated with a disability of more than mild grade (OR 2.89, 95% CI 1.14-7.74), while rash was significantly observed in those presenting with moderate and severe disability., Conclusion: This study suggests that photosensitivity is a relevant manifestation of headache in patients with SLE. Persistent hypocomplementemia can contribute to headache-induced disability in daily life, whereas a rash may be a dominant manifestation in patients presenting with moderate/severe headache-induced disability., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: To identify the optimal dose of intravenous cyclophosphamide (IVCY) for induction therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis., Methods: We retrospectively assessed patients with antibody-associated vasculitis who received IVCY every 2-3 weeks during the remission induction phase. The associations of the IVCY dose with infection-free survival and relapse-free survival were analysed using a Cox regression model. We compared patients in three categories: very low-dose (VLD), low-dose (LD), and conventional dose (CD) (<7.5 mg/kg, 7.5-12.5 mg/kg, and >12.5 mg/kg, respectively). The non-linear association between IVCY dose and the outcomes was also evaluated., Results: Of the 80 patients (median age 72 years), 12, 42, and 26 underwent the VLD, LD, and CD regimens, respectively, of whom 4, 3, and 7 developed infection or died. The adjusted hazard ratios for infection or death were 4.3 (95% confidence interval (CI) 0.94-19.8) for VLD and 5.1 (95% CI 1.21-21.3) for CD, compared with LD. We found the hazard ratio for infection or death increased when the initial IVCY dose exceeded 9 mg/kg. Relapse-free survival did not differ clearly., Conclusion: Low-dose IVCY (7.5-12.5 mg/kg) may result in fewer infections and similar relapse rates compared with the conventional regimen (>12.5 mg/kg)., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Objectives: The predictive validity of disease-specific quality of life (QOL) remains unknown in patients with systemic lupus erythematosus (SLE), although disease-specific measures are equally or more responsive to changes than generic QOL. We aimed to examine the predictive validity of the Lupus patient-reported outcome (PRO) for damage accrual., Methods: Patients with SLE and ≥2 measurements over time were included in Japanese nationwide multicentre registry (LUNA). The Lupus PRO questionnaire contains both health-related (HR) and non-HR-QOL measures. Damage accrual was evaluated using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). We examined the association between the Lupus-PRO score at baseline and longitudinal SDI scores using mixed-effects models adjusted for prognostic factors., Results: Among 1295 patients, those with higher HR-QOL of Lupus PRO at baseline demonstrated a significantly lower increase in SDI (-0.005/year, 95% confidence interval [CI]: -0.007 to - 0.004, p < 0.001). According to the categorisation of HR-QOL based on tertile, a similar dose-dependent effect of HR-QOL on longitudinal SDI was identified (second vs first tertile category: -0.101/year, 95% CI: -0.172 to - 0.030; third tertile category: -0.211/year, 95% CI: -0.281 to - 0.142). Non-HR-QOL was not significantly associated with the SDI scores. Among the HR-QOL domains, cognition, procreation, and physical health were significantly associated with the total SDI scores over time. HR-QOL was associated with corticosteroid-dependent and -independent SDI scores., Conclusion: A higher HR-QOL of Lupus PRO was associated with a lower increase in SDI scores. Our findings imply the importance of disease-specific HR-QOL measurements in assessing prognosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The increasing prevalence of dermatophyte resistance to terbinafine, a key drug in the treatment of dermatophytosis, represents a significant obstacle to treatment. Trichophyton rubrum is the most commonly isolated fungus in dermatophytosis. In T. rubrum , we identified TERG&#95;07844, a gene encoding a previously uncharacterized putative protein kinase, as an ortholog of budding yeast Saccharomyces cerevisiae polyamine transport kinase 2 (Ptk2), and found that T. rubrum Ptk2 (TrPtk2) is involved in terbinafine tolerance. In both T. rubrum and S. cerevisiae , Ptk2 knockout strains were more sensitive to terbinafine compared with the wild types, suggesting that promotion of terbinafine tolerance is a conserved function of fungal Ptk2. Pma1 is activated through phosphorylation by Ptk2 in S. cerevisiae . Overexpression of T. rubrum Pma1 (TrPma1) in T. rubrum Ptk2 knockout strain (ΔTrPtk2) suppressed terbinafine sensitivity, suggesting that the induction of terbinafine tolerance by TrPtk2 is mediated by TrPma1. Furthermore, omeprazole, an inhibitor of plasma membrane proton pump Pma1, increased the terbinafine sensitivity of clinically isolated terbinafine-resistant strains. These findings suggest that, in dermatophytes, the TrPtk2-TrPma1 pathway plays a key role in promoting intrinsic terbinafine tolerance and may serve as a potential target for combinational antifungal therapy against terbinafine-resistant dermatophytes., Competing Interests: The authors declare no conflict of interest.

Lupus nephritis (LN) is a severe complication of systemic lupus erythematosus, with high mortality rates despite medical advancements. The complexity of its pathogenesis, including the pivotal role of podocytes - kidney-localized cells - remains a challenge, lacking effective treatments and biomarkers. Recent studies highlight the significant contribution of these cells to LN's development, particularly through their immune-related functions and interaction with other kidney cells. This new understanding opens possibilities for targeted therapies aimed at these cellular mechanisms. This review aims to summarize these recent developments, shedding light on the intricate involvement of podocytes in LN and potential avenues for innovative treatments., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024. Published by Elsevier Inc.)

Background: Previous studies have shown conflicting evidence regarding the incidence of cancer in patients with systemic lupus erythematosus (SLE) compared with that in healthy individuals. Calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus have been widely used to treat SLE; however, their effects on cancer risk remain unclear. We aimed to investigate the incidence of cancer in patients with SLE and determine the potential association between CNI use and cancer risk., Methods: The standardized incidence ratio (SIR) of cancer among patients with lupus in the Lupus Registry of Nationwide Institutions (LUNA) was calculated based on the age-standardized incidence rate of cancer reported by Japan's Ministry of Health, Labour and Welfare. We also examined the association between CNI exposure and cancer risk, while considering potential confounding factors. The analysis accounted for confounding variables such as age, sex, smoking history, maximum glucocorticoid dose, treatment history with cyclophosphamide, ongoing hydroxychloroquine, Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index (SDI) value (excluding cancer occurrence), comorbidity of diabetes mellitus, and smoking history., Results: The study included 704 patients with SLE (625 females; 88.8%) with a median age of 44 years [interquartile range (IQR) = 34-55] years. The median past maximum glucocorticoid dose was 40 mg/day [IQR = 30-60 mg/day], and the SDI at registration was 1 [IQR = 0-2]. Among the patients, 246 (35.1%) had smoking histories, and 38 (5.4%) experienced cancer complications. Gynecological malignancies accounted for 63.2% of all cancers. The SIR of cancer in the LUNA cohort was 1.08 (95% confidence interval [CI] = 0.74-1.43). No statistically significant risks of cancer were found in relation to CNI treatment history; the odds ratio using multiple logistic regression was 1.12 (95% CI = 0.42-3.00), the risk ratio using standardization was 1.18 (95% CI = 0.47-2.16), and the risk ratio using inverse probability weighting was 1.8 (95% CI = 0.41-4.66)., Conclusions: The incidence of cancer in patients with SLE in the LUNA cohort did not significantly differ from that in the general population. These findings suggest that CNI treatment in this cohort did not pose a risk factor for cancer development., (© 2024. The Author(s).)

Eosinophilic granulomatous polyangiitis is a systemic vasculitis associated with bronchial asthma and eosinophilic sinusitis. Here, we describe an unusual presentation of eosinophilic granulomatous polyangiitis that initially manifested as swelling of the oral cavity floor and cervical soft tissue. A 58 year-old Japanese man was diagnosed with bronchial asthma during childhood but did not receive regular medication. Prior to this presentation, he had a persistent cough for over 1 month, and a local physician diagnosed him with bronchial asthma. However, 6 months later, his cough worsened, and a blood test revealed elevated eosinophil levels. Immediately afterward, swelling of the floor of the oral cavity and cervical soft tissue developed. Cellulitis was suspected and antimicrobial treatment was initiated; however, the symptoms persisted and abdominal pain developed. An endoscopic examination revealed duodenitis and a duodenal ulcer. The patient was diagnosed with eosinophilic granulomatous polyangiitis based on three items of the 2022 American College of Rheumatology/European College of Rheumatology classification criteria: obstructive airway disease, blood eosinophil count ≥1 × 109 cells/L, and extravascular eosinophilic infiltration with a score of 10. Oral prednisolone (70 mg/day), intravenous cyclophosphamide (500 mg/m2), and subcutaneous mepolizumab (300 mg every 4 weeks) were administered. The patient's symptoms improved after these treatments, and the eosinophil count and inflammatory marker levels declined. When swelling of the oral cavity floor and cervical soft tissue following an increase in eosinophilia and allergic symptoms occurs, it is crucial to consider the likelihood of eosinophilic granulomatous polyangiitis and collaborate with otolaryngologists and dentists to ensure its prompt identification., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: To investigate the association between decreased serum IgG levels caused by remission-induction immunosuppressive therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the development of severe infections., Methods: We conducted a retrospective cohort study of patients with new-onset or severe relapsing AAV enrolled in the J-CANVAS registry, which was established at 24 referral sites in Japan. The minimum serum IgG levels up to 24 weeks and the incidence of severe infection up to 48 weeks after treatment initiation were evaluated. After multiple imputations for all explanatory variables, we performed the multivariate analysis using a Fine-Gray model to assess the association between low IgG (the minimum IgG levels <500 mg/dl) and severe infections. In addition, the association was expressed as a restricted cubic spline (RCS) and analysed by treatment subgroups., Results: Of 657 included patients (microscopic polyangiitis, 392; granulomatosis with polyangiitis, 139; eosinophilic granulomatosis with polyangiitis, 126), 111 (16.9%) developed severe infections. The minimum serum IgG levels were measured in 510 patients, of whom 77 (15.1%) had low IgG. After multiple imputations, the confounder-adjusted hazard ratio of low IgG for the incidence of severe infections was 1.75 (95% confidence interval: 1.03-3.00). The RCS revealed a U-shaped association between serum IgG levels and the incidence of severe infection with serum IgG 946 mg/dl as the lowest point. Subgroup analysis showed no obvious heterogeneity between treatment regimens., Conclusion: Regardless of treatment regimens, low IgG after remission-induction treatment was associated with the development of severe infections up to 48 weeks after treatment initiation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To determine the molecular differences between iMCD-thrombocytopenia, anasarca, fevers, reticulin myelofibrosis, organomegaly (TAFRO), and iMCD-not otherwise specified (NOS)., Methods: CD4-positive T cells were isolated from two iMCD-TAFRO and two iMCD-NOS patients for RNA sequencing comparison. Serum proteins of two iMCD-TAFRO and four iMCD-NOS patients were comprehensively analyzed to identify pathogenesis-associated proteins. IGFBP-1 protein, extracted from serum analysis, was compared to healthy controls, iMCD, systemic lupus erythematosus, and rheumatoid arthritis patients., Results: RNA sequencing of CD4-positive T cells revealed enhanced mTOR-related signaling in iMCD-TAFRO compared to iMCD-NOS. Comprehensive serum analysis found IGFBP-1 linked to iMCD pathogenesis, significantly higher in iMCD-TAFRO. This protein may be elevated in patients with iMCD caused by an enhanced mTOR pathway., Conclusion: The mTOR pathway is suggested to be activated in iMCD-TAFRO compared to iMCD-NOS, which may elevate the protein IGFBP-1. This protein may be a biomarker to distinguish iMCD-TAFRO from iMCD-NOS., Competing Interests: Declaration of Competing Interest The authors have declared no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: Infection is a leading cause of death in patients with systemic lupus erythematosus (SLE). Alt hough hydroxychloroquine (HCQ) has been reported to inhibit infection, evidence from Asian populations remains insufficient. We investigated this effect in Japanese SLE patients., Methods: Data from the Lupus Registry of Nationwide Institutions were used in this study. The patients were ≥20 years old and met the American College of Rheumatology (ACR) classification criteria revised in 1997. We defined "severe infections" as those requiring hospitalization. We analyzed the HCQ's effect on infection suppression using a generalized estimating equation (GEE) logistic regression model as the primary endpoint and performed a survival analysis for the duration until the first severe infection., Results: Data from 925 patients were used (median age, 45 [interquartile range 35-57] years; female, 88.1%). GEE analysis revealed that severe infections were significantly associated with glucocorticoid dose (odds ratio [OR] 1.968 [95% confidence interval, 1.379-2.810], p <0.001), immunosuppressants (OR 1.561 [1.025-2.380], p =0.038), and baseline age (OR 1.043 [1.027-1.060], p <0.001). HCQ tended to suppress severe infections, although not significantly (OR 0.590 [0.329-1.058], p =0.077). Survival time analysis revealed a lower incidence of severe infections in the HCQ group than in the non-HCQ group ( p <0.001). In a Cox proportional hazards model, baseline age (hazard ratio [HR] 1.029 [1.009-1.050], p =0.005) and HCQ (HR 0.322 [0.142-0.728], p =0.006) were significantly related to incidence., Conclusion: HCQ may help extend the time until the occurrence of infection complications and tends to decrease infection rates., Competing Interests: KS received a speaker’s fee from GlaxoSmithKline PLC and research grants from Pfizer Inc. YKi received a speaker’s fee from Amgen and Novartis and research funding from Nippon Shinyaku. RY received a speaker’s fee from GlaxoSmithKline PLC, AstraZeneca PLC, and Sanofi S.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hidekawa, Yoshimi, Saigusa, Tamura, Kojitani, Suzuki, Sakurai, Yoshioka, Sugiyama-Kawahara, Kunishita, Kishimoto, Higashitani, Sato, Komiya, Nagai, Hamada, Maeda, Tsuchida, Hirahara, Soejima, Takase-Minegishi, Kirino, Yajima, Sada, Miyawaki, Ichinose, Ohno, Kajiyama, Sato, Shimojima, Fujiwara and Nakajima.)

Objective: To clarify seasonal and other environmental effects on the onset of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)., Methods: We enrolled patients with new-onset eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA), and granulomatosis with polyangiitis (GPA) registered in the database of a Japanese multicenter cohort study. We investigated the relationship between environmental factors and clinical characteristics. Seasons were divided into 4 (spring, summer, autumn, and winter), and the seasonal differences in AAV onset were analyzed using Pearson chi-square test, with an expected probability of 25% for each season., Results: A total of 454 patients were enrolled, with a mean age of 70.9 years and a female proportion of 55.5%. Overall, 74, 291, and 89 patients were classified as having EGPA, MPA, and GPA, respectively. Positivity for myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA was observed in 355 and 46 patients, respectively. Overall, the seasonality of AAV onset significantly deviated from the expected 25% for each season ( P = 0.001), and its onset was less frequently observed in autumn. In ANCA serotypes, seasonality was significant in patients with MPO-ANCA ( P < 0.001), but not in those with PR3-ANCA ( P = 0.97). Additionally, rural residency of patients with AAV was associated with PR3-ANCA positivity and biopsy-proven pulmonary vasculitis., Conclusion: The onset of AAV was influenced by seasonal variations and was less frequently observed in autumn. In contrast, the occurrence of PR3-ANCA was triggered, not by season, but by rural residency., (Copyright © 2023 by the Journal of Rheumatology.)

Objectives: To investigate the appropriate timing, useful findings and combination of magnetic resonance imaging (MRI) and ultrasound (US) for predicting the radiographic progression in early rheumatoid arthritis (RA)., Methods: Forty-four active RA patients, who examined by both of MRI and US in the symptomatic wrist and finger joints, were recruited in Nagasaki University Hospital from 2010 to 2017 and treated by the treat-to-target therapeutic strategy for 1 year. MRI was evaluated by RA MRI scoring and US by Outcomes Measures in Rheumatology Clinical Trial, respectively. Plain radiographs were assessed by the Genant-modified Sharp score for the symptomatic side in the same manner as MRI and US. Radiographic progression was defined as an annual increase ≥0.75 at 1 year. Factors associated with radiographic progression were analysed. Also, the optimal combination of MRI and US at each timepoint was considered., Results: Logistic regression model revealed that MRI-proven bone marrow oedema at baseline and 6 months and joint counts of power-Doppler grade ≥2 articular synovitis at 3 or 6 months were significantly associated with radiographic progression at 1 year., Conclusion: This study may suggest the favourable timing and combination of MRI and US at each point to predict radiographic progression in patients with early-stage RA., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We encountered a 78-year-old Japanese man with IgG4-related sialoadenitis complicated with marked eosinophilia. We diagnosed him with IgG4-RD (related disease) with a submandibular gland tumor, serum IgG4 elevation, IgG4-positive plasma cell infiltration, and storiform fibrosis. During follow-up after total incision of the submandibular gland, the peripheral eosinophil count was markedly elevated to 29,480/μL. The differential diagnosis of severe eosinophilia without IgG4-RD was excluded. The patient exhibited a prompt response to corticosteroid therapy. His peripheral blood eosinophil count was the highest ever reported among similar cases. We also review previous cases of IgG4-RD with severe eosinophilia.

Antisense oligonucleotide (ASO) is a major tool used for silencing pathogenic genes. For stroke in the hyperacute stage, however, the ability of ASO to regulate genes is limited by its poor delivery to the ischemic brain owing to sudden occlusion of the supplying artery. Here we show that, in a mouse model of permanent ischemic stroke, lipid-ligand conjugated DNA/RNA heteroduplex oligonucleotide (lipid-HDO) was unexpectedly delivered 9.6 times more efficiently to the ischemic area of the brain than to the contralateral non-ischemic brain and achieved robust gene knockdown and change of stroke phenotype, despite a 90% decrease in cerebral blood flow in the 3 h after occlusion. This delivery to neurons was mediated via receptor-mediated transcytosis by lipoprotein receptors in brain endothelial cells, the expression of which was significantly upregulated after ischemia. This study provides proof-of-concept that lipid-HDO is a promising gene-silencing technology for stroke treatment in the hyperacute stage., Competing Interests: Declaration of interests T.Y. collaborates with Daiichi Sankyo Company, Ltd.; Rena Therapeutics Inc.; Takeda Pharmaceutical Company, Ltd.; and Toray Industries, Inc., in addition to serving as an academic adviser for Rena Therapeutics Inc. and Braizon Therapeutics Inc. All other authors declare no competing interests., (Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: Fatigue is one of the most common complaints and is a potentially modifiable issue in systemic lupus erythematosus (SLE). Studies suggest that alcohol consumption has a protective effect against the development of SLE; however, an association between alcohol consumption and fatigue in patients with SLE has not been studied. Here, we assessed whether alcohol consumption was associated with fatigue using lupus patient-reported outcomes (LupusPRO)., Methods: This cross-sectional study, conducted between 2018 and 2019, included 534 patients (median age, 45 years; 87.3% female) from 10 institutions in Japan. The main exposure was alcohol consumption, which was defined as the frequency of drinking [<1 day/month (none group), ≤1 day/week (moderate group), and ≥2 days/week (frequent group)]. The outcome measure was the Pain Vitality domain score in LupusPRO. Multiple regression analysis was performed as the primary analysis after adjusting for confounding factors, such as age, sex, and damage. Subsequently, the same analysis was performed as a sensitivity analysis after multiple imputations (MIs) for missing data ( n = 580)., Results: In total, 326 (61.0%) patients were categorized into the none group, 121 (22.7%) into the moderate group, and 87 (16.3%) into the frequent group. The frequent group was independently associated with less fatigue compared with none group [β = 5.98 (95% CI 0.19-11.76), p = 0.04], and the results did not substantially deviate after MI., Conclusions: Frequent drinking was associated with less fatigue, which highlights the need for further longitudinal studies focusing on drinking habits in patients with SLE.

Introduction: Patients with systemic lupus erythematosus (SLE) frequently change attending physicians. The number of changes in attending physicians is related to the accumulated organ damage in patients with diabetes mellitus and inflammatory bowel disease, although similar results are not known for patients with SLE. This study investigated whether the number of attending physicians after the onset of SLE is associated with organ damage., Methods: Patients with SLE were enrolled in a multicenter registry of 14 institutions (the Lupus Registry of Nationwide Institutions). Patients with a disease duration of 6 months to 10 years were included. Exposure was defined as the number of attending physicians. The primary outcome was the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI). The secondary outcomes were corticosteroid- and non-corticosteroid-related damage. Multiple logistic regression analysis was used to estimate the association between the number of attending physicians and SDI, adjusting for potential confounders, including age, sex, disease duration, number of hospitalizations due to SLE, disease activity at diagnosis, and emotional health., Results: Of the 702 patients, 86.5% were women (median age 46 years, interquartile range 35-58). The disease duration was 7.3 years (4.3-11.3), the number of hospitalizations due to SLE was 1 (1-3), the number of attending physicians was 3 (2-4), and SDI was 0 points (0-1). The number of attending physicians was significantly associated with SDI [odds ratio (OR) 1.14, 95% confidence interval (CI) 1.03-1.26]. In the secondary outcome, the number of attending physicians was significantly associated with corticosteroid-related damage (OR 1.22, 95% CI 1.09-1.38). The number of attending physicians was not significantly associated with non-corticosteroid-related damage (OR 1.08, 95% CI 0.99-1.19)., Conclusions: This study showed that SDI could increase as the number of attending physicians increases. The impact of changing attending physicians warrants greater attention for SLE and other diseases., (© 2023. The Author(s).)

Background: In patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, prediction of renal survival should guide the choice of therapy, but a prediction of the histological classification has inconsistencies., Objectives: To evaluate the usefulness of renal risk score (RRS) for Japanese patients with ANCA-associated glomerulonephritis (AAGN) and compare the prediction for end-stage renal disease (ESRD) between RRS and the histological classification., Methods: We retrospectively analyzed 96 patients with AAGN who underwent a renal biopsy. Renal survival was categorized by RRS, and the histological classification was assessed separately. We compared the predictive values for RRS and the histological classification., Results: The median observational period was 37.5 (interquartile range [IQR] 21.5-77.0) months. The median RRS point at the time of renal biopsy was 2 (IQR 0-7.8), and the patients were categorized into low- (n = 29), medium- (n = 43), and high-risk groups (n = 24) using RRS. As expected, the renal prognosis was the worst in the "high-risk" group and the best in the "low-risk" group. In the histological classification, the survival deteriorated progressively from "focal" (best) to "mixed," "crescentic," and "sclerotic" (worst) classes, different from the order in the original proposal for this system. Multivariable Cox regression analysis revealed that RRS was independently associated with ESRD. The difference in prediction for renal survival between RRS and the histological classification was not significant using area under receiver-operating-characteristic curves., Conclusion: We evaluated the usefulness of RRS in Japanese patients with AAGN and found it a stable predictor of renal survival in such patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Uchida, Ichinose, Yamashita, Muta, Kitamura, Sato, Iwamoto, Nishino and Kawakami.)

A plethora of dimeric natural products exist with diverse chemical structures and biological activities. A major strategy for dimerization is aryl coupling catalyzed by cytochrome P450 or laccase. Actinorhodin (ACT) from Streptomyces coelicolor A3(2) has a dimeric pyranonaphthoquinone structure connected by a C-C bond. In this study, we identified an NmrA-family dimerizing enzyme, ActVA-ORF4, and a cofactor-independent oxidase, ActVA-ORF3, both involved in the last step of ACT biosynthesis. ActVA-ORF4 is a unique NAD(P)H-dependent enzyme that catalyzes the intermolecular C-C bond formation using 8-hydroxydihydrokalafungin (DHK-OH) as the sole substrate. On the other hand, ActVA-ORF3 was found to be a quinone-forming enzyme that produces the coupling substrate, DHK-OH and the final product, ACT. Consequently, the functional assignment of all essential enzymes in the biosynthesis of ACT, one of the best-known model natural products, has been completed., (© 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular endothelial dysfunction and skin fibrosis. Recently, the presence and pathogenic role of immune complexes (ICs) of SSc patients were reported. However, the identities of antigens in these ICs are unknown. Therefore, we examined ICs in the serum of SSc patients to elucidate SSc pathogenesis. In this study, IC concentrations in serum samples from SSc and systemic lupus erythematosus (SLE) patients were measured by C1q enzyme-linked immunosorbent assays; immune complex analysis was used for comprehensive identification and comparison of antigens incorporated into ICs (IC-antigens). The expression patterns of SSc-specific IC-antigens in skin sections were investigated by immunohistochemistry. Compared with SLE patients who developed disease because of IC deposition, SSc patients had a greater number of IC-antigens and a smaller difference in IC concentrations, suggesting that SSc pathogenesis is affected by the proteins present in ICs. In contrast, the IC concentration and number of IC-antigens did not significantly differ according to the clinical phenotype of SSc. We identified 478 IC-antigens in SSc patients, including multiple RNAP II-associated proteins that were targeted by antibodies previously associated with SSc pathogenesis. The most frequently detected RNAP II-associated protein, RNA polymerase II transcription subunit 30 (MED30), was strongly expressed at lesion sites and reportedly regulates endothelial differentiation. Therefore, increased expression of MED30 in lesions may have an antigenic effect, and MED30 function may be impaired or inhibited by IC formation. RNAP II-associated proteins may SSc pathogenesis through mechanisms such as the MED30 pathway., Competing Interests: Declarations of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Low concentrations of nitric oxide (NO) produced by constitutive NO synthase (cNOS) has been shown to suppress apoptosis in pancreatic β-cells. In the present study, the influence of asymmetric dimethylarginine (ADMA), the major endogenous inhibitor of NOS, on the apoptosis-suppressive effect of NO was investigated. The expression of dimethylarginine dimethylaminohydrolase 2 (DDAH2), an ADMA-metabolizing enzyme, in INS-1 β-cells and in mouse pancreatic islets was drastically reduced by in vitro exposure to high-concentration glucose (20 mM) and by in vivo treatment of mice with the insulin receptor blocker S661, which resulted in hyperglycemia, respectively. In line with this, a higher ADMA level was observed in INS-1 cells exposed to 20 mM glucose. The treatment of INS-1 cells with ADMA, similarly to with the NOS inhibitor N G -nitro-L-arginine methyl ester, significantly facilitated 20 mM glucose-induced increase in cleaved caspase-3 protein expression. Furthermore, increased protein expression of cleaved caspase-3 and CHOP was observed in INS-1 cells with knockdown of DDAH2. These results suggest that ADMA accumulation through a decrease in DDAH2 expression in β-cells, which is induced under hyperglycemic conditions, facilitates β-cell apoptosis through suppression of cNOS-mediated NO production., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Rationale: Eosinophilic granulomatosis with polyangiitis (EGPA) is belongs to the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) subgroups. EGPA, unlike other subgroups of AAV, including microscopic polyangiitis (MPA) and granulomatosis with polyangiitis, has the unique feature that both ANCA and eosinophilic inflammation are involved in its pathogenesis. Although AAV often relapses, there are currently no reports of EGPA developing during other subgroups of AAV. Herein, we document a case of EGPA that developed during the clinical course of MPA., Patient Concerns: A 61-year-old Japanese woman was diagnosed with MPA based on interstitial lung disease and myeloperoxidase-ANCA positivity. After starting immunosuppression therapy, including prednisolone and tacrolimus, she was expected to achieve clinical remission. Nonetheless, she occasionally experienced MPA relapse, which required an increased prednisolone dose, rituximab, intravenous cyclophosphamide, and plasma exchange. Three years after MPA onset, she developed renal amyloidosis; thus, subcutaneous tocilizumab was added to her regimen. Following clinical remission, the administration interval of her subcutaneous tocilizumab therapy was extended and immunosuppressants were discontinued. She then developed bronchial asthma and mild eosinophilia (eosinophilic count: ~1000/μL). Further, a year later, she underwent total hip replacement using a titanium implant. Subsequently, she developed abnormal sensation in both hands, numbness, and muscle weakness, as well as palpable purpura and massive eosinophilia (eosinophilic count: ~8500/μL)., Diagnosis: We diagnosed the patient with EGPA based on 5 items (asthma, multiple mononeuropathies, sinus abnormality, and extravascular eosinophils) of the 1990 American College of Rheumatology classification criteria., Interventions: We administered 400 mg/kg intravenous immunoglobulin for 5 consecutive days, 300 mg mepolizumab subcutaneously every 4 weeks, and 40 mg/day prednisolone following pulsed methylprednisolone therapy (1000 mg/day for 3 consecutive days)., Outcomes: After these treatments, the patient's symptoms improved, and eosinophilic count and inflammatory markers declined., Lessons: The present case suggests that EGPA can be induced by the development of eosinophilic inflammation in other subgroups of AAV., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE), a rheumatic disease affecting the elderly, responds well to corticosteroids; however, our RS3PE patients' corticosteroid therapy is longer than expected. Elderly-onset rheumatoid arthritis (EORA) patients are reported to be at a significantly increased risk for steroid-related side effects including cardiovascular diseases (CVDs). To clarify the complications during a 1-year follow-up in corticosteroid-treated RS3PE patients compared to EORA patients. We retrospectively analyzed the records of 47 RS3PE patients (28 men, 19 women, age 78.4 ± 7.5 years) and 46 EORA patients (10 men, 36 women; 77.0 ± 6.8 yrs) to compare the complications over a 1-year follow-up. The RS3PE and EORA groups' average initial PSL doses were 16.5 ± 7.2 mg/day and 7.3 ± 4.6 mg/day, respectively. During the 1-year follow-up after treatment, there was no significant increase in CVDs in both groups. However, infections occurred in nine RS3PE patients, which is a significantly higher incidence compared to the EORA patients with infections ( n  = 3). The initial PSL dose was the independent variable associated with the incidence of infection. Infections were significantly increased during elderly RS3PE patients' steroid therapy. The initial corticosteroid dose was an infection-risk factor.Key messagesInfections are increased during steroid therapy in elderly patients with RS3PE syndrome.The initial dose of corticosteroids was one of the risk factors for infections.

Objective: It is still unclear how glucocorticoids (GCs) affect the long-term clinical course of patients with SLE. The objective of this study is to explore the factors associated with GC-free treatment status., Methods: Using data from the lupus registry of nationwide institutions, GC dose at registration was compared between short, middle and long disease durations of <5, 5-20 and ≥20 years, respectively. After excluding patients who never used GC, we evaluated the relationship between GC-free status and chronic damage using Systemic Lupus International Collaborating Clinics Damage Index., Results: GC doses at enrolment of the 1019 patients were as follows: GC-free in 101 (10%); 0

Background: This study investigated the characteristics of hypertrophic pachymeningitis (HP) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), using information from a multicenter study in Japan., Methods: We analyzed the clinical information of 663 Asian patients with AAV (total AAV), including 558 patients with newly diagnosed AAV and 105 with relapsed AAV. Clinical findings were compared between patients with and without HP. To elucidate the relevant manifestations for HP development, multivariable logistic regression analyses were additionally performed., Results: Of the patients with AAV (mean age, 70.2 ± 13.5 years), HP was noted in 30 (4.52%), including 20 (3.58%) with newly diagnosed AAV and 10 (9.52%) with relapsed AAV. Granulomatosis with polyangiitis (GPA) was classified in 50% of patients with HP. A higher prevalence of GPA was significantly observed in patients with HP than in those without HP in total AAV and newly diagnosed AAV (p < 0.001). In newly diagnosed AAV, serum proteinase 3 (PR3)-ANCA positivity was significantly higher in patients with HP than in those without HP (p = 0.030). Patients with HP significantly had ear, nose, and throat (ENT) (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.03-2.14, p = 0.033) and mucous membrane/eye manifestations (OR 5.99, 95% CI 2.59-13.86, p < 0.0001) in total AAV. Moreover, they significantly had conductive hearing loss (OR 11.6, 95% CI 4.51-29.57, p < 0.0001) and sudden visual loss (OR 20.9, 95% CI 5.24-85.03, p < 0.0001)., Conclusion: GPA was predominantly observed in patients with HP. Furthermore, in newly diagnosed AAV, patients with HP showed significantly higher PR3-ANCA positivity than those without HP. The ear and eye manifestations may be implicated in HP development., (© 2022. The Author(s).)

Background: Infection is a major cause of mortality in patients with systemic lupus erythematosus (SLE). Therefore, minimizing the risk of infection is an important clinical goal to improve the long-term prognosis of SLE patients. Treatment with ≥7.5 mg prednisolone (PSL) or equivalent has been reported to increase the risk of infections. However, it remains unclear whether <7.5 mg PSL or equivalent dose affects the risk of infection in SLE patients. This study evaluated the association between the occurrence of infection in patients with SLE and low-dose glucocorticoid (GC) usage, especially <7.5 mg PSL or equivalent, to explore the GC dose that could reduce infection occurrence., Methods: This prospective cohort study included patients from the Japanese multicenter registry of patients with SLE (defined as ≥4 American College of Rheumatology 1997 revised criteria) over 20 years of age. The PSL dose was categorized as PSL 0-2.5, 2.6-5.0, 5.1-7.5, and 7.6-15.0 mg. The primary outcome was infection requiring hospitalization. We conducted a multivariable analysis using time-dependent Cox regression analysis to assess the hazard ratio of infection occurrence compared with a dose of 0-2.5 mg PSL or equivalent in the other three PSL dose groups. Based on previous reports and clinical importance, the covariates selected were age, sex, and concurrent use of immunosuppressants with GC. In addition, two sensitivity analyses were conducted., Results: The mean age of the 509 SLE patients was 46.7 years; 89.0% were female, and 77.2% used multiple immunosuppressants concomitantly. During the observation period, 52 infections requiring hospitalization occurred. The incidence of infection with a PSL dose of 5.0-7.5 mg was significantly higher than that in the PSL 0-2.5 mg group (adjusted hazard ratio: 6.80, 95% confidence interval: 2.17-21.27). The results of the two sensitivity analyses were similar., Conclusions: Our results suggested that the use of 5.0-7.5 mg PSL or equivalent could pose an infection risk in SLE patients. This finding indicates that PSL dose should be reduced to as low as possible in SLE patients to avoid infection., (© 2022. The Author(s).)

Objective: This study investigated the effectiveness of treatment with Janus kinase (JAK) inhibitors in rheumatoid arthritis (RA) assessed by ultrasonography (US) activity, and the influence of patient characteristics and previous treatments., Method: This prospective study assessed 60 treatment initiations among 53 Japanese patients diagnosed with RA who underwent treatment with JAK inhibitors during June 2013 to February 2020. Of the 53 patients, seven patients were enrolled in duplicate because they were treated with two different JAK inhibitors at different periods. For each case, the improvement rate on the power Doppler (PD) score was assessed at 6 month follow-up. Median improvement rate of PD score was used to classify cases as either US responders or non-responders, and patient characteristics were compared between the two groups., Results: All indicators of clinical disease activity and US activity showed a significant improvement at 3 months compared with baseline. Although the JAK inhibitor-cycler group and the interleukin-6 (IL-6) inhibitor inadequate response (IR) group tended to show a later improvement for US activity, all indicators of clinical disease activity and US activity showed a significant improvement at 6 months compared with baseline for both groups. Multivariate analysis showed that concomitant methotrexate use and an IR to the previous biologic or targeted-synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) treatment were independently and significantly associated with US responders., Conclusion: Use of a JAK inhibitor in combination with methotrexate and an absence of IR to any previous b/tsDMARDs demonstrated superior effectiveness for patients with RA.

Background: Although vitamin D concentration is reportedly associated with the pathogenesis and pathology of systemic lupus erythematosus (SLE), benefits of vitamin D supplementation in SLE patients have not been elucidated, to our knowledge. We investigated the clinical impacts of vitamin D supplementation in SLE., Methods: A cross-sectional analysis was performed using data from a lupus registry of nationwide institutions. We evaluated vitamin D supplementation status associated with disease-related Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) as a parameter of long-term disease activity control., Results: Of the enrolled 870 patients (mean age: 45 years, mean disease duration: 153 months), 426 (49%) received vitamin D supplementation. Patients with vitamin D supplementation were younger (43.2 vs 47.5 years, P < 0.0001), received higher doses of prednisolone (7.6 vs 6.8 mg/day, P = 0.002), and showed higher estimated glomerular filtration rates (79.3 vs 75.3 mL/min/1.73m2, P = 0.02) than those without supplementation. Disease-related SDI (0.73 ± 1.12 vs 0.73 ± 1.10, P = 0.75), total SDI, and SLE Disease Activity Index (SLEDAI) did not significantly differ between patients receiving and not receiving vitamin D supplementation. Even after excluding 136 patients who were highly recommended vitamin D supplementation (with age ≥ 75 years, history of bone fracture or avascular necrosis, denosumab use, and end-stage renal failure), disease-related SDI, total SDI, and SLEDAI did not significantly differ between the two groups., Conclusions: Even with a possible Vitamin D deficiency and a high risk of bone fractures in SLE patients, only half of our cohort received its supplementation. The effect of vitamin D supplementation for disease activity control was not observed., Competing Interests: The authors have declared that no competing interests exist.

Actinorhodin (ACT) is a benzoisochromanequinone antibiotic produced by Streptomyces coelicolor A3(2), which has served as a favored model organism for comprehensive studies of antibiotic biosynthesis and its regulation. (S)-DNPA undergoes various modifications as an intermediate in the ACT biosynthetic pathway, including enoyl reduction to DDHK. It has been suggested that actVI-ORF2 encodes an enoyl reductase (ER). However, its function has not been characterized in vitro. In this study, biochemical analysis of recombinant ActVI-ORF2 revealed that (S)-DNPA is converted to DDHK in a stereospecific manner with NADPH acting as a cofactor. (R)-DNPA was also reduced to 3-epi-DDHK with the comparable efficacy as (S)-DNPA, suggesting that the stereospecificity of ActVI-ORF2 was not affected by the stereochemistry at the C-3 of DNPA. ActVI-ORF2 is a new example of a discrete ER, which is distantly related to known ERs according to phylogenetic analysis., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: We evaluated changes of HTLV-1 proviral loads (PVLs) during treatment for rheumatoid arthritis (RA) and investigated whether these changes affect the clinical course in HTLV-1-positive RA patients., Methods: A total of 41 HTLV-1-positive RA patients were analyzed. Their clinical picture including disease activity [Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR), DAS28-CRP, simplified disease activity index (SDAI), and clinical disease activity index (CDAI)] and comorbidity were evaluated over a 2-year period. PVLs from peripheral blood mononuclear cells were investigated by real-time polymerase chain reaction (PCR). We investigated whether HTLV-1 PVLs is altered, or which clinical characteristics affect changes of HTLV1-PVLs during 2-year treatment., Results: Clinical disease activity was not changed during the 2-year observational period. The mean HTLV-1 PVL value change from baseline to 2 years was -1.2 copies/1000 PBMCs, which was not statistically significant. No baseline clinical characteristics influenced changes in HTLV-1 PVL. However, a numerical change of HTLV-1 PVLs was increased in 4 patients initiating the new biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) at 2-10 months after starting the new b/ts DMARDs (numerical increase was 24.87 copies/1000 PBMCs). Infection occurred in 4 patients, and 3 of those patients showed an increased HTLV-1 PVL. Univariate analysis revealed an association between increase of HTLV-1 PVL and incidence of infection., Conclusions: Over 2 years, HTLV-1 PVL did not significantly change in our HTLV-1-positive RA patients. Individual changes in HTLV-1 PVL were correlated with incidence of infection but not disease activity which indicate that we may take precaution toward infection at the uptick of HTLV-1 PVL in HTLV-1-positive RA patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Iwamoto, Araki, Umetsu, Takatani, Aramaki, Ichinose, Terada, Hirakata, Ueki, Kawakami and Eguchi.)

A 49-year-old Japanese man with a 2-month history of a fever, headache, and bilateral conjunctival hyperemia was admitted. His condition fulfilled the giant cell arteritis classification criteria (new headache, temporal artery tenderness, elevated ESR) and atypical Cogan's syndrome (CS) with scleritis and sensorineural hearing loss (SNHL). The interleukin (IL)-6 serum level was extremely high. Two weeks after his insufficient response of SNHL and scleritis to oral prednisolone, we administered tocilizumab (TCZ); rapid improvements in scleritis and SNHL occurred. Early IL-6 target therapy can help prevent irreversible CS-induced sensory organ damage.

Neuropsychiatric systemic lupus erythematosus (NPSLE) varies in presentation and is one of the leading causes of morbidity and mortality among patients with SLE. This study determined the most critical serum biomarkers for the development of NPSLE as they may have clinical utility prior to the onset of neuropsychiatric symptoms. We retrospectively analyzed 35 NPSLE patients, 34 SLE patients, 20 viral meningitis (VM) patients, and 16 relapsing-remitting multiple sclerosis (MS) patients. We measured anti-suprabasin antibodies concentrations in serum by using Luciferase immunoprecipitation system (LIPS) assay. The serum concentrations of cytokines/chemokines were measured by using multiplex bead-based assay. We found serum FGF-2 level was significantly higher in the NPSLE group compared to the SLE group and the healthy control group. The anti-suprabasin antibody relative concentration (SRC) has high positive predictive values for the development of NPSLE. The most essential biomarkers are VEGF, anti-suprabasin antibodies, sCD40L, IL-10, GRO, MDC, IL-8, IL-9, TNF-α, MIP-1α., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Nuclear factor-kappa B (NF-κB) signaling is an intracellular signaling pathway involved in inflammatory responses and the pathogenesis of various cancers, including ependymoma, which is a rare and chemotherapy-resistant glioma. Several isoforms of fusion proteins that consist of a nuclear protein, zinc finger translocation associated (ZFTA), and RELA (ZFTA-RELA), an NF-κB-signaling effector transcription factor, cause excessive activation of the NF-κB signaling pathway and result in supratentorial ependymomas (ST-EPN-RELA). As inhibitors of NF-κB activity induced by ZFTA-RELA are expected to be therapeutic agents for ST-EPN-RELA, we established an NF-κB responsive luciferase reporter cell line that expresses the most common isoform of ZFTA-RELA in a doxycycline-dependent manner. Using this reporter cell line, we screened fungus extracts for compounds that inhibit the NF-κB activity induced by ZFTA-RELA expression and identified aszonalenin, an alkaloid from Aspergillus novofumigatus. We also purified analogs of aszonalenin, namely acetylaszonalenin and epi-aszonalenin B and C. In a luciferase assay using cells constitutively expressing luciferase (counter assay), acetylaszonalenin and epi-aszonalenin C showed non-specific inhibition of the luciferase activity. Aszonalenin and epi-aszonalenin B inhibited the NF-κB responsive luciferase activity by expressing ZFTA-RELA more strongly than the luciferase activity in the counter assay. The upregulation of endogenous NF-κB responsive genes, such as CCND1, ICAM1, and L1CAM, by ZFTA-RELA expression was inhibited by epi-aszonalenin B, but not by aszonalenin. This study suggests that epi-aszonalenin B may be a lead compound for the therapeutic development of ST-EPN-RELA., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Hot flashes, a symptom of menopause, can decrease women's quality of life. Sympathetic nervous system activation has been identified as an important factor in the occurrence of hot flashes. Given that somatosensory stimulation of the oral cavity can affect autonomic nervous activity, we aimed to investigate the possibility that somatosensory stimulation of the gums ( i.e. , gum massage) could improve hot flashes., Materials and Methods: Nineteen women experiencing at least one hot flash per day were instructed to perform a gum massage on themselves before undertaking mental workload, using arithmetic task, and the frequency of hot flashes experienced during this task was measured. Changes in autonomic nervous activity were assessed based on heart rate variability., Results: Massage conditions promoted a significantly lower arithmetic task-induced hot flash frequency compared with nonmassage conditions ( p  < 0.05). During gum massage, the ratio between low and high frequency (LF/HF) values decreased significantly under massage conditions compared with nonmassage conditions ( p  < 0.01). During the arithmetic task, the gum massage-induced reduction in LF/HF, which changed from baseline, was significantly correlated with the gum massage-induced reduction in hot flash frequency., Conclusions: The results of this study indicate that gum massage can reduce the subjective frequency of hot flashes over a certain period under mental workload. Our study also indicates that gum massage can potentially decrease sympathetic nerve activity, which is known to be involved in the occurrence of hot flashes., Clinical Trial Registration number 328 (the institutional review board of Lion Corporation)., Competing Interests: K.I., R.M., A.M., S.M., T.I., and Y.Y. are employees of Lion Corporation (Tokyo, Japan). Recruitment of participants was performed by PLUG, Inc. (Tokyo, Japan) under consignment from Lion Corporation., (© Kanako Ichinose et al., 2022; Published by Mary Ann Liebert, Inc.)

Autonomic disorders are common in patients with systemic lupus erythematosus (SLE), but the therapeutic strategy and methods for evaluating the effects of therapy have not been established. We describe the three cases of SLE patients who developed severe autonomic disorders as demonstrated by the head-up tilt table test (HUT). All three patients were treated by intensive immunosuppressive treatments including intravenous cyclophosphamide (IVCY); their HUT results all became negative. Our cases suggest that IVCY treatment can be a good therapeutic option for severe autonomic disorders in SLE patients. The HUT is a useful objective method for the diagnosis of and the evaluation of longitudinal therapeutic effects on autonomic disorders in SLE patients with orthostatic intolerance., (© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects almost any organ. Multiple immunological abnormalities involving every domain of the immune system contribute to the expression of the disease. It is now recognized that elements of the immune system instigate processes in tissue resident cells which execute organ damage. Although correction of ongoing immune aberrations is important in the control of disease activity, targeting tissue specific injurious processes may prove desirable in limiting organ damage., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives : Using multicentre ultrasound (US) cohort data among patients with rheumatoid arthritis (RA), we aimed to identify baseline factors that permit differentiation between two patient cohorts achieving US remission and clinical remission, and to determine the factors contributing to the discrepancy. Method : We reviewed 248 Japanese patients diagnosed with RA who underwent treatment with biological disease-modifying anti-rheumatic drugs at 13 centres. We performed US assessments of the synovia of 22 joints. We assessed the percentages of patients with clinical remission and US remission, defined as total power Doppler scores of 0 at 12 months. Results : The 87 patients who achieved US remission were divided into a group that achieved both clinical and US remission (n = 53) and a group that achieved US remission only (n = 34). Baseline factors that were significantly and independently associated with clinical remission at 12 months among patients who also achieved US remission included short disease duration, the presence of concomitant methotrexate use, and low patient global assessment score (p < 0.05, p < 0.05, and p < 0.005, respectively). Conclusions : RA patients with baseline high patient global assessment scores and long disease duration at baseline were unlikely to achieve clinical remission even after achieving US remission. Objective joint assessments using US provide additional information of potential importance for the management of RA.

Objectives: To investigate the utility of 18F-FDG PET/CT in the diagnostic procedure of IgG4-related disease (IgG4-RD), we analysed the association between quantitative method of 18F-FDG PET/CT and histological findings., Methods: Twenty-one patients with IgG4-RD in whom 18F-FDG PET/CT was performed at the time of diagnosis were enrolled. Tissue biopsy was performed at 24 sites in 21 patients. To perform quantitative analysis of 18F-FDG PET/CT imaging, the highest standardised uptake value (SUV) of the pixels (SUVmax) and the average SUV (SUVmean) within the biopsied lesion were measured. The SUVmean of the liver was also measured as a reference., Results: The mean age at diagnosis was 64.6±11.9 years, and the median serum IgG4 level was 650 mg/dl. Histological findings were consistent with IgG4-RD (histopathology-positive) at 19 out of 24 sites. Although there was no significant difference in the values of SUVmax between histopathology-positive and histopathology-negative tissues, the values of SUVmean were significantly higher in the histopathology-positive tissue (4.98 and 3.54, respectively p<0.05). The values of SUVmean/liver were also higher in the histopathology-positive tissue (2.17 and 1.52, respectively p<0.05). To establish a cut-off value of SUVmean to determine which of multiple lesions should be biopsied, a ROC curve was constructed. ROC curve analysis indicated SUVmean=4.07 or SUVmean/liver=1.66 as a cut-off value., Conclusions: Our present study suggested that quantitative analysis of 18F-FDG-PET/CT imaging might be useful for selecting the biopsy site in IgG4-RD. The calculation of SUVmean, not of SUVmax, is important for evaluating IgG4-RD-related lesions in 18F-FDG PET/CT imaging.