Immune checkpoint inhibitor-induced arthralgia is tightly associated with improved overall survival in cancer patients.

OBJECTIVES: With the increased use of immune checkpoint inhibitors (ICIs) in cancer patients, arthralgia has been the most commonly reported musculoskeletal immune-related adverse event (irAE). We aimed to characterize arthralgia and its association with overall survival (OS). MATERIAL AND METHODS: Randomized controlled trials (RCTs) reporting on data for ICI-induced arthralgia from four online databases were comprehensively investigated. Odds ratios (ORs) with 95% CIs were calculated for arthralgia using a random-effects model meta-analysis. Individual patient data were reconstructed from RCTs assessing OS in patients with or without ICI-induced arthralgia. We also retrospectively collected data on the clinical features and outcomes of ICI-induced arthralgia in the Yokohama City University (YCU) registry. RESULTS: We analysed 14 377 patients from 24 RCTs. The OR of ICI-induced arthralgia was 1.37 (95% CI 1.20, 1.56). Of the 369 patients in the YCU registry, 50 (13.6%) developed ICI-induced arthralgia. Among them, 30 had other grade ≥2 irAEs, which was noticeably more frequent than in those without arthralgia (OR 1.92, 95% CI 1.04, 3.52). By irAE types, a significant difference was found for relative adrenal insufficiency (OR 3.88, 95% CI 1.80, 8.39). In the YCU registry, patients with (vs without) ICI-induced arthralgia had better OS (log-rank, P < 0.001). OS results were validated from RCT patients with matched cancer types, drugs, and time to arthralgia onset (hazard ratio 0.34, 95% CI 0.17, 0.65, P < 0.001). CONCLUSIONS: If arthralgia develops after ICIs, another irAE, such as relative adrenal insufficiency, may have developed. The incidence of arthralgia was associated with better OS, and the condition of patients with irAEs must be carefully evaluated to determine optimal management.

Pathogenic UBA1 variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis.

OBJECTIVES: To determine clinical and genetic features of individuals with relapsing polychondritis (RP) likely caused by pathogenic somatic variants in ubiquitin-like modifier activating enzyme 1 (UBA1). METHODS: Fourteen patients with RP who met the Damiani and Levine criteria were recruited (12 men, 2 women; median onset age (IQR) 72.1 years (67.1-78.0)). Sanger sequencing of UBA1 was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue. Droplet digital PCR (ddPCR) and peptide nucleic acid (PNA)-clamping PCR were used to detect low-prevalence somatic variants. Clinical features of the patients were investigated retrospectively. RESULTS: UBA1 was examined in 13 of the 14 patients; 73% (8/11) of the male patients had somatic UBA1 variants (c.121A>C, c.121A>G or c.122T>C resulting in p.Met41Leu, p.Met41Val or p.Met41Thr, respectively). All the variant-positive patients had systemic symptoms, including a significantly high prevalence of skin lesions. ddPCR detected low prevalence (0.14%) of somatic variant (c.121A>C) in one female patient, which was subsequently confirmed by PNA-clamping PCR. CONCLUSIONS: Genetic screening for pathogenic UBA1 variants should be considered in patients with RP, especially male patients with skin lesions. The somatic variant in UBA1 in the female patient is the first to be reported.

Elevated serum gasdermin D N-terminal implicates monocyte and macrophage pyroptosis in adult-onset Still's disease.

OBJECTIVES: Elevation of serum IL-18 in adult-onset Still's disease (AOSD) and systemic JIA (sJIA) suggests the role of the inflammasome in these diseases. Gasdermin D is a pore-forming protein playing central roles in inflammasome-mediated inflammation, but its role in rheumatic disease is unknown. We aimed to elucidate the auto-inflammatory mechanisms in AOSD and sJIA. METHODS: Patients with AOSD, sJIA, hemophagocytic lymphohistiocytosis (HLH) and Behçet's disease followed at Yokohama City University (YCU), or US National Institutes of Health (NIH) were included in the study. Disease activity was evaluated by the modified Pouchot score. Ferritin and N-terminal gasdermin D levels in serum and culture supernatant were measured by ELISA. Primary monocytes (Mo) were stimulated with GM-CSF or M-CSF and differentiated into M1 macrophages (Mφ) or M2Mφ, respectively. The number of Mo/Mφ and their viability were monitored over time. RESULTS: Patients with active AOSD and sJIA had increased levels of serum gasdermin D N-terminal, which correlated with serum ferritin and IL-18 levels. Mo-derived Mφ from active AOSD patients showed reduced cell viability and increased cell death. The number of cultured Mφ cells on day nine was negatively correlated with the serum ferritin and gasdermin D levels. Higher ferritin and gasdermin D levels were observed in the M1Mφ culture supernatant of active AOSD patients. Gasdermin D inhibitors reduced the pyroptosis-mediated ferritin release in Mo. CONCLUSION: Elevation of serum gasdermin D N-terminal provides evidence for inflammasome activation triggering gasdermin D-mediated Mo and Mφ pyroptosis in AOSD and possibly sJIA.

Anti-TRIM21 antibody is associated with aberrant B-cell function and type I interferon production in systemic lupus erythematosus.

BACKGROUND: TRIM21 is a member of the tripartite motif family proteins and is one of the autoantigens which react with anti-SS-A antibody (Ab) present in sera of patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome. Previous studies have shown that TRIM21 dysfunction promotes aberrant B-cell differentiation and Ab production in SLE, and anti-TRIM21 Ab may be related to the TRIM21 dysfunction in human SLE pathogenesis. Here, we examined the relationship between anti-TRIM21 Ab and clinical and immunological characteristics in SLE patients. METHODS: Twenty-seven patients with SLE (23 women and four men) before immunosuppressive therapies, who fulfilled the revised 1997 American College of Rheumatology criteria for SLE, and four healthy controls (3 women and one man) were enrolled in the study. SLE patients were divided into two groups according to the seropositivity for anti-TRIM21 Ab. Serum anti-TRIM21 Ab levels were measured using enzyme-linked immunosorbent assays. The serum levels of cytokines and immunoglobulins were measured by cytometer beads arrays. The expression levels of TRIM21 protein in peripheral mononuclear cells (PBMCs) from SLE patients were evaluated by Western blotting. RESULTS: Sixteen and 9 patients showed seronegativity and seropositivity for anti-TRIM21 Ab, respectively. There were no significant differences in the background parameters, including female ratio, age, disease duration, SLE activity, and laboratory data between the two groups. The serum levels of interferon (IFN)-ß were significantly higher in patients with anti-TRIM21 Ab as compared with those without anti-TRIM21 Ab (P = .043). The levels of IgG1 and IgA were significantly higher in SLE patients with anti-TRIM21 Ab as compared with those without anti-TRIM21 Ab (P = .0022 and .032, respectively). The PBMCs of patients with anti-TRIM21 Ab showed a significantly lower expression of TRIM21 protein as compared with those of patients without anti-TRIM21 Ab (P = .014). CONCLUSIONS: Anti-TRIM21 Ab seropositivity was related to B-cell abnormalities and type I IFN overproduction in SLE patients. These findings suggest that anti-TRIM21 Ab may have an inhibitory effect on TRIM21 functions and be a novel biomarker for the level of dependence on type I IFN overproduction and B-cell abnormalities.

miR-1 is a novel biomarker for polymyositis/dermatomyositis-associated interstitial lung disease.

Objectives: Although intensive immunosuppressive treatment is necessary for the severe cases with polymyositis (PM)/dermatomyositis (DM), the prognostic factors or disease activity indices for PM/DM have not been established. Here we investigated the association between serum microRNA-1 (miR-1) level and clinical course of patients with PM/DM.Methods: We retrospectively reviewed baseline clinical and laboratory findings, treatment regimens and outcomes in patients with PM/DM. The serum samples were collected from PM/DM patients and healthy controls (HC). Serum miR-1 levels were determined by quantitative real-time PCR.Results: Twenty-two patients were recruited. The average serum miR-1 level was significantly higher in the PM/DM as compared to HC (p = .0085) and was decreased by treatment (p = .032). We divided the PM/DM-ILD patients into two groups, high and normal miR-1 groups. Although there were no significant differences in the clinical data and the initial prednisolone (PSL) dose between the two groups, PSL dose at 16 weeks, cumulative PSL dose until 16 weeks, and frequency of serious infections were significantly higher in the high miR-1 group as compared to the normal group (p = .025, .036, and .026, respectively).Conclusion: We propose serum miR-1 as a promising novel biomarker for predicting therapeutic response in PM/DM-ILD.

Dysfunction of TRIM21 in interferon signature of systemic lupus erythematosus.

OBJECTIVES: TRIM21 is an E3 ubiquitin ligase for interferon regulatory factors (IRFs) that are involved in innate and acquired immunity. Here, we evaluated the role of TRIM21 in the interferon (IFN) signature of systemic lupus erythematosus (SLE). METHODS: Twenty SLE patients and 24 healthy controls were enrolled in this study. We analyzed mRNA expression of TRIM21, type I IFN, and IFN-inducible genes in peripheral blood mononuclear cell (PBMC). The protein levels of IRFs were assessed by Western blotting in PBMCs cultured with or without MG-132. RESULTS: The expression of TRIM21 mRNA and protein was significantly higher in SLE PBMCs as compared to healthy controls. There was a correlation between TRIM21 mRNA expression and SLE activities. In contrast to a negative correlation between mRNA expression level of TRIM21 and those of type I IFNs in healthy controls, we found a positive correlation between them in anti-TRIM21 antibody-positive SLE patients. Neither positive nor negative correlation was observed in the autoantibody-negative SLE patients. Western-blotting analysis revealed impaired ubiquitin-dependent proteasomal degradation of IRFs in SLE PBMCs. CONCLUSION: Our study showed ubiquitin-dependent proteasomal degradation of IRFs was impaired in anti-TRIM21 antibody-dependent and -independent fashions, leading to amplification of IFN signature in SLE.

Musculoskeletal ultrasonography delineates ankle symptoms in rheumatoid arthritis.

OBJECTIVES: To clarify the use of musculoskeletal ultrasonography (US) of ankle joints in rheumatoid arthritis (RA). METHODS: Consecutive RA patients with or without ankle symptoms participated in the study. The US, clinical examination (CE), and patients' visual analog scale for pain (pVAS) for ankles were assessed. Prevalence of tibiotalar joint synovitis and tenosynovitis were assessed by grayscale (GS) and power Doppler (PD) US using a semi-quantitative grading (0-3). The positive US and CE findings were defined as GS score ≥2 and/or PD score ≥1, and joint swelling and/or tenderness, respectively. Multivariate analysis with the generalized linear mixed model was performed by assigning ankle pVAS as a dependent variable. RESULTS: Among a total of 120 ankles from 60 RA patients, positive ankle US findings were found in 21 (35.0%) patients. The concordance rate of CE and US was moderate (kappa 0.57). Of the 88 CE negative ankles, US detected positive findings in 9 (10.2%) joints. Multivariate analysis revealed that ankle US, clinical disease activity index, and foot Health Assessment Questionnaire, but not CE, was independently associated with ankle pVAS. CONCLUSION: US examination is useful to illustrate RA ankle involvement, especially for patients who complain ankle pain but lack CE findings.

On-demand ultrasonography assessment in the most symptomatic joint supports the 8-joint score system for management of rheumatoid arthritis patients.

OBJECTIVES: To investigate whether on-demand ultrasonography (US) assessment alongside a routine examination is useful in the management of rheumatoid arthritis (RA). METHODS: US was performed in eight (bilateral MCP 2, 3, wrist and knee) joints as the routine in a cumulative total of 406 RA patients. The most symptomatic joint other than the routine joints was additionally scanned. Power Doppler (PD) and gray-scale images were scored semiquantitatively. Eight-joint scores were calculated as the sum of individual scores for the routine joints. RESULTS: The most symptomatic joint was found among the routine joints in 209 patients (Group A) and in other joints in 148 (Group B). The PD scores of the most symptomatic joint correlated well with the 8-joint scores in Group A (rs = 0.66), but not in Group B (rs = 0.33). The sensitivity and specificity of assessment of the most symptomatic joint for routine assessment positivity were high (84.0% and 100%, respectively) in Group A, but low (50.0% and 61.8%, respectively) in Group B. Additional examination detected synovitis in 38% of Group B with negative results in the routine. CONCLUSIONS: On-demand US assessment in the most symptomatic joint, combined with the routine assessment, is useful for detecting RA synovitis.

(18)F-FDG and (18)F-NaF PET/CT demonstrate coupling of inflammation and accelerated bone turnover in rheumatoid arthritis.

OBJECTIVE: To compare the findings in rheumatoid arthritis (RA)-affected joints between (18)F-fluorodeoxyglucose (FDG) and (18)F-fluoride (NaF) positron emission tomography (PET)/computed tomography (CT). METHODS: We enrolled twelve RA patients who started a new biologic agent (naïve 9 and switch 3). At entry, both hands were examined by (18)F-FDG PET/CT, (18)F-NaF PET/CT, and X-ray. Intensity of PET signals was determined by standardized uptake value max (SUVmax) in metacarpophalangeal (MCP), proximal interphalangeal (PIP), and ulnar, medial, and radial regions of the wrists. Hand X-rays were evaluated according to the Genant-modified Sharp score at baseline and 6 months. RESULTS: Both (18)F-FDG and (18)F-NaF accumulated in RA-affected joints. The SUVmax of (18)F-FDG correlated with that of (18)F-NaF in individual joints (r = 0.65), though detail distribution was different between two tracers. (18)F-NaF and (18)F-FDG signals were mainly located in the bone and the surrounding soft tissues, respectively. The sum of SUVmax of (18)F-NaF correlated with disease activity score in 28 joint (DAS28), modified health assessment questionnaire (MHAQ), and radiographic progression. (18)F-FDG and (18)F-NaF signals were associated with the presence of erosions, particularly progressive ones. CONCLUSION: Our data show that both (18)F-FDG and (18)F-NaF PET signals were associated with RA-affected joints, especially those with ongoing erosive changes.

A novel 8-joint ultrasound score is useful in daily practice for rheumatoid arthritis.

OBJECTIVES: To investigate the optimal number and combination of joints to be assessed by power Doppler ultrasonography (PDUS) in daily practice for rheumatoid arthritis (RA). METHODS: PDUS were performed in 24 joints, including all proximal interphalangeal, metacarpophalangeal (MCP), and bilateral wrist and knee joints in 234 patients with RA. PD signals were scored semiquantitatively from 0 to 3 in each joint, and total PD score-24 was calculated by summing them up as comprehensive assessment. RESULTS: Positive PD signals were more frequently found in bilateral wrist, knee, and the second and third MCP joints than the other joints. The individual PD scores of these 8 joints also showed higher correlation coefficients with total PD score-24 (rs ≥ 0.4). Among the sum PD scores of various selected joint combinations, the score of the combination of 8 joints (total PD score-8), including bilateral second and third MCP, wrist, and knee joints, showed the highest sensitivity and negative predictive value (98.1% and 96.2%, respectively). Total PD score-8 showed high correlation with the total PD score-24 (rs = 0.97, p < 0.01). CONCLUSIONS: Total PD score-8 is simple and efficient enough for monitoring disease activity and judging imaging remission of RA in daily practice.

Predicting joint destruction in rheumatoid arthritis with power Doppler, anti-citrullinated peptide antibody, and joint swelling.

OBJECTIVE: To determine combined evaluation of musculoskeletal ultrasonography (MSUS) and power Doppler (PD) signals, anti-citrullinated peptide antibody (ACPA), and other clinical findings improve the prediction of joint destruction in rheumatoid arthritis (RA). METHODS: We performed a retrospective study of 331 RA patients (female n = 280 and male n = 51, mean age: 57.9 ± 13.2 years) who underwent MSUS from 2002 to 2012. Correlations with progression of joint destructions in 1,308 2nd and 3rd metacarpophalangeal (MCP) joints and various factors including PD signals of the same joints, clinical findings, age, disease duration at the study entry, gender, observation period, radiographic bone scores according to modified Sharp-van der Heijde methods, ACPA, and rheumatoid factor (RF) were analyzed in patient- and joint-based fashions, using univariate and multivariate logistic regression analyses and generalized linear mixed model. RESULTS: Patients' characteristics were as follows: mean disease duration: 5.7 ± 7.5 years, observation period: 4.6 ± 2.6 years, RF positivity: 79.9%, and ACPA positivity: 77.5%. PD-positive 2nd and 3rd joints showed higher rate of joint destruction, especially in ACPA-positive patients. Moreover, PD-positive joints in ACPA-positive patients showed joint destruction even in joints without swelling. Multivariate analysis determined PD, swollen joint (SJ), observation period, basal radiographic bone scores, and ACPA as independent risks for joint destruction. CONCLUSION: PD, SJ, basal radiographic bone scores, and ACPA are independent predictors for the joint destruction of 2nd and 3rd MCPs in RA; thus, considering these factors would be useful in daily practice.

Efficacy and safety of abatacept in patients with rheumatoid arthritis with previous malignancy.

Background: Abatacept (ABT) is known to lower infection risk than other biologics and is effective and safe in elderly patients with rheumatoid arthritis (RA). However, there were inconsistent reports on the impact of ABT on malignancies which are more common in the elderly and strongly related to prognosis. Objectives: This study aimed to evaluate the efficacy and safety of ABT in patients with RA with previous malignancy in clinical practice. Design: A multicenter, retrospective study. Methods: Patients who received ABT for RA in two hospitals in Yokohama until May 2022 were included in this study. The patients were divided into two groups according to the presence or absence of a history of malignancy (no previous malignancy: NP group, previous malignancy: PM group). The collected parameters were compared between the groups using propensity score matching. Results: In this study, 312 patients were included, of whom 73 had previous malignancies when starting ABT. The age at ABT initiation was significantly higher in the PM group, the rate of methotrexate use was significantly lower in the PM group, and the Steinbrocker stage was significantly higher in the PM group. After matching these 3 factors, 68 patients were selected from each group. No significant differences in the ABT continuation rate, and malignancy incidence were observed between the two groups after ABT initiation. In addition to these factors, when matched for smoking history, interstitial lung disease, disease duration, sex, and inflammatory status, which are known risk factors for malignancy in RA, 40 patients were selected from each group. No significant differences in the ABT continuation rate, and malignancy incidence were observed between the two groups after ABT initiation. Conclusion: In our clinical practice, ABT was as effective and safe in patients with a history of malignancy as in those without.

Clinical and genetic features of Japanese cases of MDS associated with VEXAS syndrome.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a new disease entity with autoinflammatory disorders (AID) driven by somatic variants in UBA1 that frequently co-exists with myelodysplastic syndromes (MDS). Clinicopathological and molecular features of Japanese cases with VEXAS-associated MDS remain elusive. We previously reported high prevalence of UBA1 variants in Japanese patients with relapsing polychondritis, in which 5 cases co-occurred with MDS. Here, we report clinicopathological and variant profiles of these 5 cases and 2 additional cases of MDS associated with VEXAS syndrome. Clinical characteristics of these cases included high prevalence of macrocytic anemia with marked cytoplasmic vacuoles in myeloid/erythroid precursors and low bone marrow (BM) blast percentages. All cases were classified as low or very low risk by the revised international prognostic scoring system (IPSS-R). Notably, 4 out of 7 cases showed significant improvement of anemia by treatment with prednisolone (PSL) or cyclosporin A (CsA), suggesting that an underlying inflammatory milieu induced by VEXAS syndrome may aggravate macrocytic anemia in VEXAS-associated MDS. Targeted deep sequencing of blood samples suggested that MDS associated with VEXAS syndrome tends to involve a smaller number of genes and lower risk genetic lesions than classical MDS.

Protective effect of hydroxychloroquine on infections in patients with systemic lupus erythematosus: an observational study using the LUNA registry.

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.

Case Report: Tocilizumab Treatment for VEXAS Syndrome With Relapsing Polychondritis: A Single-Center, 1-Year Longitudinal Observational Study In Japan.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an autoinflammatory disease caused by somatic variants in the UBA1 gene that lead to severe systemic inflammation and myelodysplastic syndrome. Although no standard therapy has been established yet, azacitidine and bone marrow transplantation have been reported to be promising possibilities; however, the indications for these treatments are problematic and not necessarily applicable to all patients. We previously reported the results of short-term treatment with tocilizumab (TCZ) and glucocorticoids in three patients with VEXAS syndrome. In this paper, we report that the combination of TCZ and glucocorticoids allowed the patients to continue treatment for at least one year without significant disease progression. Glucocorticoids were able to be reduced from the start of TCZ. Adverse events were herpes zoster, skin ulceration after cellulitis, and decreased blood counts. The results suggest the significance of this treatment as a bridge therapy for the development of future therapies.

Initial hydroxychloroquine monotherapy in systemic lupus erythematosus: report of three cases.

Glucocorticoids (GCs) use is associated with increased organ damage in systemic lupus erythematosus (SLE), and the treatment goal is to stop their use. Treatment with hydroxychloroquine (HCQ) without daily GCs may benefit patients by minimising the cumulative dose of GCs, but clinical experience with HCQ monotherapy is limited. To accumulate evidence for initial HCQ monotherapy in SLE, we retrospectively analysed three new SLE patients who visited Yokohama City University Hospital in 2015. The patients were all Japanese females with a mean age of 26.0 ± 5.3 years, high anti-dsDNA antibody titres, no major organ damage, and a mean pre-treatment Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 9.3 ± 3.1. During the mean observation period of 3.8 ± 0.8 years, none of them received daily GCs or immunosuppressants, but one of the three patients were treated with short-term oral GCs and NSAIDs for a skin rash or arthralgia flairs. SLEDAI-2K was reduced to 3.3 ± 1.2. No other new SLE symptoms emerged, and the Systemic Lupus International Collaborating Clinics Damage Index (SDI) of them were maintained at 0. None of the patients developed HCQ-related retinal toxicity. Current experience with initial HCQ monotherapy suggests that such a therapeutic strategy may be useful in managing disease activity and preserving cumulative GCs in SLE patients without organ involvements.

TRIM21 Dysfunction Enhances Aberrant B-Cell Differentiation in Autoimmune Pathogenesis.

TRIM21 is one of the autoantigens that reacts with an anti-SS-A antibody (Ab) present in patients with systemic lupus erythematosus (SLE) and Sjögren's syndrome. TRIM21 is thought to play a role in B-cell proliferation and apoptosis, among other activities. Here we examined a pathological role of TRIM21 in SLE. Trim21-deficient MRL/lpr mice were generated by backcrossing Trim21-deficient C57BL/6 mice to MRL/lpr mice. The levels of serum anti-dsDNA Ab and urine protein at 28 weeks of age were significantly higher in Trim21-deficient MRL/lpr mice as compared to wild-type MRL/lpr mice (p = 0.029 and 0.003, respectively). Resting B cells from Trim21-deficient mice showed significantly higher abilities to differentiate into plasmablasts and to produce Ab as compared with control mice. Due to the reduction of TRIM21-mediated ubiquitylation, IRF5 protein expression was increased in Trim21-deficient MRL/lpr mice (p = 0.021), which correlated with increased plasmablast generation and immunoglobulin production. B cells from SLE patients with anti-TRIM21 Ab seropositivity also showed a significantly higher ability to differentiate into plasmablasts as compared with those without anti-TRIM21 Ab or healthy controls. These results suggest that TRIM21 dysfunction contributes to SLE pathogenesis by promoting B-cell differentiation, for which anti-TRIM21 Ab may be partly responsible.

Dose down-titration of biological disease-modifying antirheumatic drugs in daily clinical practice: Shared decision-making and patient treatment preferences in Japanese patients with rheumatoid arthritis.

AIM: To determine characteristics of rheumatoid arthritis (RA) patients in Japan who received the same biological disease-modifying antirheumatic drugs (bDMARDs) for at least 6 months and to identify factors associated with successful down-titration of bDMARDs dependent on shared decision-making. METHODS: We included consecutive RA patients who received the same bDMARD with low disease activity or remission for at least 6 months in our two university hospitals. Patients treated with the bDMARD standard dose were defined as SD, while those treated with bDMARD down-titration were defined as DT. We retrospectively reviewed clinical charts and compared data between the two groups. RESULTS: Of 288 patients with RA, 204 (70.8%) and 84 (29.2%) continued standard dose treatment and underwent down-titration treatment, respectively. Sixty-six of 84 (78.6%) down-titration-treated patients continued to show low disease activity or remission, whereas 18 (21.4%) relapsed 18.9 ± 24.4 months after bDMARD down-titration was started. Univariate predictor analysis showed that the probable factors of down-titration were no history of bDMARD treatment (P = .001) and low initial Disease Activity Assessment of 28 joint score (P = .048). Other clinical characteristics had no significant relationship with successful down-titration. CONCLUSIONS: Thus, bDMARD-naïve patients and those with low initial disease activity are more likely to agree to attempt down-titration. However, the timing and method of down-titration should be made in shared decision-making between patients and rheumatologists.

Dysregulated heme oxygenase-1low M2-like macrophages augment lupus nephritis via Bach1 induced by type I interferons.

BACKGROUND: Innate immunity including macrophages (Mϕ) in lupus nephritis (LN) has been gaining attention, but roles of Mϕ in LN remain uncertain. METHODS: Immunohistochemical staining was performed to determine CD68, CD163, heme oxygenase (HO)-1 (a stress-inducible heme-degrading enzyme with anti-inflammatory property), pSTAT1, and CMAF-expressing Mϕ in the glomeruli of patients with LN. Effects of type I interferons on the expression levels of CD163, HO-1, BTB and CNC homology 1 (Bach1; a transcriptional HO-1 repressor), interleukin (IL)-6, and IL-10 by human M2-like Mϕ, which were differentiated in vitro from peripheral monocytes with macrophage colony-stimulating factor, were assessed by RT-PCR and immunocytostaining. Clinical manifestations, anti-double-stranded DNA (anti-dsDNA), and local HO-1 expression were compared in Bach1-deficient and wild-type MRL/lpr mice. RESULTS: The number of glomerular M2-like Mϕ correlated with the amounts of proteinuria in patients with LN. Unlike monocyte-derived M2-like Mϕ, HO-1 expression was defective in the majority of glomerular M2-like Mϕ of patients with LN. Stimulation of human M2-like Mϕ with type I interferons led to reduced HO-1 expression and increased Bach1 and IL-6 expression. Bach1-deficient MRL/lpr mice exhibited increased HO-1 expression in kidneys, prolonged survival, reduced urine proteins, and serum blood urea nitrogen levels, but serum anti-dsDNA antibody levels were comparable. Increased expression of CD163 and HO-1 was found in peritoneal Mϕ from Bach1-deficient MRL/lpr mice. CONCLUSIONS: Our data suggest that dysregulated M2-like Mϕ play a proinflammatory role in LN. Bach1 is a potential therapeutic target that could restore the anti-inflammatory property of M2 Mϕ.