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Abstract 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

Abstract 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.

Abstract 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.

Abstract 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

Abstract Objective To identify potential biomarkers to distinguish familial Mediterranean fever (FMF) from sepsis. Method We recruited 28 patients diagnosed with typical FMF (according to the Tel Hashomer criteria), 22 patients with sepsis, and 118 age-matched controls. Serum levels of 40 cytokines were analyzed using multi-suspension cytokine array. We performed a cluster analysis of each cytokine in the FMF and sepsis groups in order to identify specific molecular networks. Multivariate classification (random forest analysis) and logistic regression analysis were used to rank the cytokines by importance and determine specific biomarkers for distinguishing FMF from sepsis. Results Fifteen of the 40 cytokines were found to be suitable for further analysis. Levels of serum granulocyte-macrophage colony-stimulating factor (GM-CSF), fibroblast growth factor 2, vascular endothelial growth factor, macrophage inflammatory protein-1b, and interleukin-17 were significantly elevated, whereas tumor necrosis factor-α (TNF-α) was significantly lower in patients with FMF compared with those with sepsis. Cytokine clustering patterns differed between the two groups. Multivariate classification followed by logistic regression analysis revealed that measurement of both GM-CSF and TNF-α could distinguish FMF from sepsis with high accuracy (cut-off values for GM-CSF = 8.3 pg/mL; TNF-α = 16.3 pg/mL; sensitivity, 92.9%; specificity, 94.4%; accuracy, 93.4%). Conclusion Determination of GM-CSF and TNF-α levels in combination may represent a biomarker for the differential diagnosis of FMF from sepsis, based on measurement of multiple cytokines.

Abstract Objective To compare the efficacy and safety of tofacitinib and baricitinib in patients with RA in a real-world setting. Methods A total of 242 patients with RA who were treated with tofacitinib (n = 161) or baricitinib (n = 81) were enrolled. We evaluated efficacy and safety between tofacitinib and baricitinib using multivariable analyses to avoid confounding. Their clinical disease activity and AEs were evaluated for 24 weeks. Results The mean (SD) DAS28-ESR change from baseline to 24 weeks was 1.57 (1.55) (tofacitinib) and 1.46 (1.36) (baricitinib). There was no significant difference in the clinical response between the two groups (adjusted mean difference, 0.04; 95% CI, −0.35 to 0.28). The efficacy was not significantly changed in the patients without concomitant MTX use in both groups, but the concomitant MTX use showed better clinical efficacy in the cases of baricitinib treatment. In both groups, the most common AE was herpes zoster infection, and the AE rates were similar between the two groups. However, the predictive factors contributing to clinical response as revealed by a multivariable logistic analysis differed. The concomitant oral steroid use was independently associated with the achievement of DAS-low disease activity in the tofacitinib group, whereas in the baricitinib group, the number of biological and/or targeted synthetic DMARDs previously used was associated. Conclusions Our findings indicate that tofacitinib and baricitinib had comparable continuing efficacies and safety profiles. However, there is a possibility that the influence of clinical characteristics on the treatment response differs. The comparison provides useful information to the optimal use of JAK inhibitors in real-world settings.

Abstract Background To evaluate the effect of treatment on serum bone biomarkers and explore whether serum bone biomarkers are associated with therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept. Methods We enrolled 59 RA patients treated with abatacept from a multicenter, exploratory, short-term, prospective and observational ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) therapy. We evaluated the patients’ clinical disease activity and musculoskeletal ultrasound (MSUS) scores. The serum concentrations of five bone biomarkers were evaluated (dickkopf-1 [Dkk-1], sclerostin [SOST], osteocalcin [OC], osteopontin [OPN], and osteoprotegerin [OPG]) by multiplex bead assays at baseline, 3, and 6 months: the change over 6 months was defined as the Δ value. ‘Power Doppler (PD) responder’ was defined as a patient whose Δtotal PD score over 6 months was greater than the median change. Results Abatacept significantly improved the clinical disease activity and MSUS score over 6 months. Serum OPG was significantly elevated at 6 months after the abatacept introduction (p = 0.016). The ΔSOST and ΔOPG were significantly greater in the PD responders versus the non-PD responders (p = 0.0041 and 0.0073, respectively). The serum Dkk-1 at baseline was significantly lower in the PD responders (n = 30) vs. the non-PD responders (n = 29) (p = 0.026). A multivariate logistic regression analysis showed that the serum Dkk-1 at baseline (odds ratio 0.50, 95% confidence interval [CI] 0.23–0.91, p = 0.043) was an independent predictor of PD responder status. Conclusion Serum levels of bone biomarkers may be useful for predicting RA patients’ therapeutic responses to abatacept. Trial registration Name of the registry: Assessment of therapeutic responsiveness by imaging of the joints in patients with rheumatoid arthritis; A observational cohort study Trial registration number: UMIN000012524 Date of registration: 12/9/2013 URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000014657

Abstract Background While survival of systemic lupus erythematosus (SLE) patients has improved substantially, problems remain in the management of their emotional health. Medium to high-dose glucocorticoid doses are known to worsen emotional health; the effect is unclear among patients receiving relatively low-dose glucocorticoids. This study aims to investigate the association between low glucocorticoid doses and emotional health in lupus low disease activity state (LLDAS). Methods This cross-sectional study drew on data from SLE patients in 10 Japanese institutions. The participants were adult patients with SLE duration of ≥ 1 year who met LLDAS criteria at the study visit from April 2018 through September 2019. The exposure was the daily glucocorticoid dose (mg oral prednisolone). The outcome was the emotional health score of the lupus patient-reported outcome scale (range: 0 to 100). Multiple linear regression analysis was performed with adjustment for confounders including disease-related damage, activity, and psychotropic drug use. Results Of 192 patients enrolled, 175 were included in the analysis. Their characteristics were as follows: female, 89.7%; median age, 47 years (interquartile range (IQR): 37.0, 61.0). Median glucocorticoid dose was 4.0 mg (IQR 2.0, 5.0), and median emotional health score 79.2 (IQR 58.3, 91.7). Multiple linear regression analysis showed daily glucocorticoid doses to be associated with worse emotional health (β coefficient = − 2.54 [95% confidence interval − 4.48 to − 0.60], P = 0.01). Conclusions Daily glucocorticoid doses were inversely associated with emotional health among SLE patients in LLDAS. Further studies are needed to determine whether glucocorticoid tapering leads to clinically significant improvements in emotional health.

Abstract Background Liver cirrhosis is the irreversible fibrosis of the liver and causes refractory ascites and hepatic encephalopathy, which might not respond to treatment. Living donor liver transplantation (LDLT) is an effective treatment for patients with cirrhosis. However, post-LDLT patients are prone to muscle atrophy and sarcopenia. Therefore, physiotherapy of post-LDLT patients is essential for preventing the progression of sarcopenia. Recently, rehabilitation using neuromuscular electrical stimulation (NMES) has been reported to be useful for preventing the progression of sarcopenia. Similarly, nutrition therapy is essential for post-LDLT patients because these patients frequently experience malnutrition. However, the effects of combined NMES and nutrition therapy on post-LDLT patients remain unknown. Methods/design This open-label, randomized, parallel-group study will compare the effects of combined therapy with NMES and branched-chain amino acids (BCAA) with those of NMES alone in patients with decompensated cirrhosis after LDLT. After LDLT, 50 patients with decompensated cirrhosis will be randomly assigned to receive NMES with BCAA or NMES without BCAA. The duration of the intervention will be 3 months. To analyze the change in skeletal muscle mass, InBody 770 body composition and body water analysis and ultrasonography will be performed before LDLT and 4 weeks and 12 weeks post-LDLT. The primary endpoint is changes in the skeletal muscle mass from baseline to 3 months. Important secondary endpoints are the changes in the skeletal muscle mass from baseline to 1 month and changes in the quadriceps strength from baseline to 1 month. Discussion The results of this study are expected to provide evidence regarding the effect of NMES combined with BCAA therapy on the skeletal muscle of post-LDLT patients. Trial registration Japan Registry of Clinical Research jRCTs071190051 . Registered on February 26, 2020.

Abstract Background Most patients with systemic lupus erythematosus (SLE) progress to lupus nephritis (LN) within 5 years of their SLE diagnosis, although it is not uncommon for LN to develop at later time points. Here we evaluated the clinical features of early- and late-onset LN. Patients and methods We retrospectively analyzed the cases of 184 of the 201 patients who underwent a renal biopsy at Nagasaki University Hospital and associated community hospitals between 1990 and 2016 and were diagnosed as having LN. Early onset was defined as the development of LN within the first 5 years after the patient’s SLE diagnosis, and late onset was defined as LN development > 5 years post-diagnosis. We analyzed the complete renal response (CR) at 6 and 12 months after induction therapy, the classification of renal pathology, and the mortality of the early- and late-onset LN groups. Results The mean follow-up duration after the renal biopsy was 123 ± 85 months. There were 113 (61.4%) early-onset patients and 71 (38.6%) late-onset patients. A multivariate analysis revealed that the following factors were predictive of CR: at 6 months: female sex (odds ratio [OR] 3.93, 95% confidence interval [CI] 1.31–11.77, p = 0.010), proteinuria (OR 0.83, 95% CI 0.71–0.97, p = 0.009), index of activity (0–24) (OR 0.83, 95% CI 0.70–0.99, p = 0.030), and early-onset LN (OR 2.39, 95% CI 1.15–4.98, p = 0.018); at 12 months: female sex (OR 3.60, 95% CI 1.32–9.83, p = 0.013), mixed LN (OR 0.18, 95% CI 0.04–0.80, p = 0.024), index of activity (0–24) (OR 0.80, 95% CI 0.68–0.94, p = 0.007), and early-onset LN (OR 2.10, 95% CI 1.05–4.23, p = 0.035). In a Cox proportional hazards and Fine-Gray regression model, the early-onset LN group had a significantly better mortality rate than the late-onset LN group (p = 0.038 and p = 0.043, respectively). Conclusions In our cohort, early-onset LN was a better predictor of CR at 6 and 12 months than late-onset LN. Our results suggest that early-onset LN patients had lower mortality than late-onset LN patients.

Abstract Objective To identify potential biomarkers to distinguish adult-onset Still’s disease (AOSD) from sepsis. Method We recruited 70 patients diagnosed with AOSD according to the Yamaguchi criteria, 22 patients with sepsis, and 118 age-matched controls. Serum levels of 40 cytokines were analyzed using multi-suspension cytokine array. We performed a cluster analysis of each cytokine in the AOSD and sepsis groups in order to identify specific molecular networks. Further, multivariate classification (random forest analysis) and logistic regression analysis were used to rank the cytokines by their importance and determine specific biomarkers for distinguishing AOSD from sepsis. Results Seventeen of the 40 cytokines were found to be suitable for further analyses. The serum levels of eleven were significantly higher in patients with AOSD than healthy controls. Levels of serum fibroblast growth factor 2 (FGF-2), vascular endothelial growth factor (VEGF), granulocyte colony-stimulating factor (G-CSF), and interleukin (IL)-18 were significantly elevated in patients with AOSD compared with those with sepsis, and cytokine clustering patterns differed between these two groups. Multivariate classification followed by logistic regression analysis revealed that measurement of both FGF-2 and IL-18 could distinguish AOSD from sepsis with high accuracy (cutoff value for FGF-2 = 36 pg/mL; IL-18 = 543 pg/mL, sensitivity 100%, specificity 72.2%, accuracy 93.8%). Conclusion Determination of FGF-2 and IL-18 levels in combination may represent a biomarker for the differential diagnosis of AOSD from sepsis, based on the measurement of multiple cytokines.

Abstract Background Patients with systemic sclerosis (SSc) complicated by gastrointestinal dysmotility are difficult to treat and have high mortality. To clarify the pathogenesis of gastrointestinal manifestations, we aimed to demonstrate the association among the clinical features of SSc, the serological markers, the autoantibodies against nicotinic acetylcholine receptor at autonomic ganglia (gAChR). Methods Fifty patients were enrolled and divided into two groups according to the presence or absence of gastrointestinal manifestations, and the characteristics were analyzed between these two groups. We measured biomarkers and the autoantibodies against two gAChRα3 and β4 subunits to test sera samples. Furthermore, patients were classified based on the presence or absence of anti-gAChR autoantibodies, and their clinical features were compared. Results In patients with SSc and gastrointestinal manifestations, digital ulcers were more frequent (p = 0.050) and VEGF expression was significantly higher (p = 0.038). Seven subjects with SSc were seropositive for α3 subunit, whereas one patient was seropositive for β4 subunit. The mean level of anti-gAChRα3 autoantibodies in SSc patients with gastrointestinal manifestations was significantly higher than that in SSc patients without gastrointestinal manifestations (p = 0.001). The group of patients with SSc and gAChR autoantibodies had significantly higher endostatin levels (p = 0.046). Conclusions This study is the first to demonstrate that clinical characteristics of SSc patients with seropositivity for gAChR autoantibodies. Patients with SSc have circulating autoantibodies against gAChR, which may contribute to gastrointestinal manifestations associated with this disease, suggesting that gAChR-mediated autonomic neurotransmission may provide a pathomechanism for gastrointestinal dysmotility in SSc.

Abstract Background The aim of this study was to identify fibrosis-related serological surrogate outcome measures in patients with immunoglobulin G4-related disease (IgG4-RD). Methods This was a clinical observational study of 72 patients with untreated IgG4-RD from four institutions in Japan. The serum concentrations of growth differentiation factor 15 (GDF-15), CCL2, hyaluronic acid (HA), amino-terminal propeptide of type III procollagen (PIIINP), and tissue inhibitor of metalloproteinases 1 (TIMP-1) were measured by enzyme-linked immunosorbent assays. The enhanced liver fibrosis (ELF) score was calculated from the TIMP-1, PIIINP, and HA values. We evaluated associations between the values of these biomarkers and laboratory data, the IgG4-RD responder index (IgG4-RD RI) score, and organ involvements. Results Compared with the 44 healthy controls, the patients with IgG4-RD showed significantly elevated serum concentrations of GDF-15, MCP-1, HA, PIIINP, and TIMP-1 and ELF scores. The patients’ serum concentrations of GDF-15, CCL2, HA, and TIMP-1 (but not PIIINP) were positively correlated with each other. Among them, serum GDF-15 most efficiently distinguished patients with IgG4-RD from healthy controls. Serum GDF-15 was not associated with the IgG4-RD RI score or the number of organ involvements but was independently associated with the presence of retroperitoneal fibrosis and with parotid gland involvement. Conclusions We observed increased serological surrogate outcome measures of fibrosis in IgG4-RD. GDF-15 may precisely reflect the fibrotic degree in patients with IgG4-RD.

Abstract Background We showed previously that Japanese individuals with familial Mediterranean fever (FMF) have a more atypical phenotype compared to endemic areas. The clinical differences between young-onset FMF (YOFMF), adult-onset FMF (AOFMF), and late-onset FMF (LOFMF) in Japan are unclear. Methods We enrolled 395 consecutive patients. We defined YOFMF, AOFMF, and LOFMF as the onset of FMF at

Abstract Background Fibroblast-like synovial cells (FLS) have multilineage differentiation potential including osteoblasts. We aimed to investigate the role of microRNAs during the osteogenic differentiation of rheumatoid arthritis (RA)-FLS. Methods RA-FLS were differentiated in osteogenic medium for 21 days. Osteogenic differentiation was evaluated by alkaline phosphatase (ALP) staining and Alizarin Red staining. MicroRNA (miRNA) array analysis was performed to investigate the differentially expressed miRNAs during osteogenic differentiation. Expression of miR-218-5p (miR-218) during the osteogenic differentiation was determined by quantitative real-time PCR. Transfections with an miR-218 precursor and inhibitor were used to confirm the targets of miR-218 and to analyze the ability of miR-218 to induce osteogenic differentiation. Secreted Dickkopf-1 (DKK1) from FLS transfected with miR-218 precursor/inhibitor or roundabout 1 (ROBO1) knockdown FLS established using ROBO1-small interfering RNA (siRNA) were measured by ELISA. Results The miRNA array revealed that 12 miRNAs were upregulated and 24 miRNAs were downregulated after osteogenic differentiation. We observed that the level of miR-218 rose in the early phase of osteogenic differentiation and then decreased. Pro-inflammatory cytokines modified the expression of miR-218. The induction of miR-218 in RA-FLS decreased ROBO1 expression, and promoted osteogenic differentiation. Both the overexpression of miR-218 and the knockdown of ROBO1 in RA-FLS decreased DKK1 secretion. Conclusion We identified miR-218 as a crucial inducer of the osteogenic differentiation of RA-FLS. MiR-218 modulates the osteogenic differentiation of RA-FLS through the ROBO1/DKK-1 axis. The induction of the osteogenic differentiation of proliferating RA-FLS through the provision of miR-218 into RA-FLS or by boosting the cellular reservoir of miR-218 might thus become a therapeutic strategy for RA.

Abstract Background In the present study, we explored the risk factors for relapse after discontinuation of biologic disease-modifying antirheumatic drug (bDMARD) therapy in patients with rheumatoid arthritis (RA) whose ultrasound power Doppler (PD) synovitis activity and clinical disease activity were well controlled. Methods In this observational study in clinical practice, the inclusion criteria were based on ultrasound disease activity and clinical disease activity, set as low or remission (Disease Activity Score in 28 joints based on erythrocyte sedimentation rate