Influences of advanced age in rheumatoid arthritis: A multicentre ultrasonography cohort study.

OBJECTIVES: We aimed to evaluate the effects of age on clinical characteristics and outcomes in biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD)-naïve patients with rheumatoid arthritis (RA). METHODS: We analysed the cases of 234 Japanese b/tsDMARD-naïve RA patients who underwent b/tsDMARD treatment in a multicentre ultrasound prospective observational cohort. We compared the clinical characteristics at baseline and outcomes at 12 months between those aged ≥60 years and those <60 years. RESULTS: Compared to the <60-year-old group (n = 78), the ≥60-year-old group (n = 156) had higher inflammatory marker values and ultrasound combined scores, especially wrist joints, at baseline. Age at baseline positively correlated significantly with the ultrasound scores at baseline; however, age was not a significant variable by the multiple regression analysis. The patients treated with different MOAs in the ≥60-year-old group had comparable outcomes and multiple regression analysis revealed that mechanism of action (MOA) was not a significant contributor to the Clinical Disease Activity Index at 12 months. CONCLUSIONS: RA patients with advanced age demonstrated distinctive clinical characteristics. The MOAs were not associated with clinical outcomes and ultrasound outcomes in RA patients with advanced age.

The impact of glucocorticoid use on the outcomes of rheumatoid arthritis in a multicenter ultrasound cohort study.

OBJECTIVE: Glucocorticoids are effective in treating rheumatoid arthritis (RA) when used appropriately considering the balance of the risks and benefits, especially at low doses. We aimed to evaluate the response of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients having already been treated with glucocorticoids. METHODS: We reviewed RA patients treated with b/tsDMARDs in a prospective multicenter ultrasound cohort study. We compared the differences in the clinical characteristics at baseline and outcomes at 12 months between the two groups having been treated with and without glucocorticoids at baseline. The differences in the clinical characteristics and the treatments were balanced by the inverse probability weighting (IPW) with the propensity score. RESULTS: Of 307 patients with RA, 160 patients were treated with glucocorticoids at baseline. The median dose of glucocorticoids was equivalent to 5.0 mg/day of prednisolone. Significant differences were in age and concomitant methotrexate use, composite measures for the disease activity, and the ultrasound grayscale score at baseline. Patients treated with glucocorticoids had less frequent remissions defined by composite measures and ultrasound findings than those treated without glucocorticoids. These significant differences in the achievement of remissions remained robust even after adjusting differences in the clinical characteristics and the treatments between the two groups by IPW. CONCLUSION: RA patients treated with glucocorticoids had a higher disease activity at baseline and a poorer response to treatments with b/tsDMARDs than those without glucocorticoids. The states of patients requiring glucocorticoids might be associated with the poor response to the b/tsDMARDs.

Evaluating the safety profile of calcineurin inhibitors: cancer risk in patients with systemic lupus erythematosus from the LUNA registry-a historical cohort study.

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.

The double shared epitope: Its impact on clinical features and ultrasound findings in rheumatoid arthritis.

OBJECTIVES: The link between the HLA-DRB1 locus and the risk of rheumatoid arthritis (RA) shown in genome-wide association studies strengthens the shared epitope (SE) hypothesis. We aimed to assess the impact of the double dose of the SE (double SE) on RA and explore its clinical associations, including the response to abatacept. METHODS: We evaluated RA patients treated with csDMARDs or abatacept for HLA-DRB1 typing, clinical characteristics at baseline, and disease activity and ultrasound findings over 12 months. RESULTS: Patients with the double SE (n = 12) had significantly higher anti-citrullinated protein antibody (ACPA) titers, higher total grayscale (GS) score, and power Doppler (PD) score at baseline than patients without the double SE. Patients with the double SE exhibited reduced rates of SDAI remission and pronounced improvements in multiple disease activity between baseline and 12 months, including SDAI, CDAI, total GS score, and total PD score. When focusing on abatacept-treated patients, the decreases in SDAI, CDAI, and total PD score between baseline and 12 months were significantly larger in patients with the double SE. CONCLUSIONS: Patients with the double SE exhibited distinct characteristics, increased disease activity, and improved response to abatacept treatment.

Association of denosumab with serum cytokines, chemokines, and bone-related factors in patients with rheumatoid arthritis: A post hoc analysis of a multicentre, open-label, randomised, parallel-group study.

OBJECTIVES: To clarify changes in serum cytokines, chemokines, and bone-related factors during denosumab treatment in rheumatoid arthritis (RA) patients. METHODS: This was a post hoc analysis of a multicentre, open-label, randomised, parallel-group study. Patients were randomly assigned to continue treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) plus receive treatment with denosumab (csDMARDs plus denosumab group) or to continue treatment with csDMARD therapy alone for 12 months. Serum biomarker levels were measured at baseline and 6 and 12 months. RESULTS: Baseline and 6-month data from the csDMARDs plus denosumab (n = 22) and csDMARD therapy alone (n = 22) groups were analysed. Statistically significant changes from baseline were seen: dickkopf-related protein 1 decreased at 6 and 12 months (both groups); osteopontin decreased at 6 months in the csDMARDs plus denosumab group; osteopontin and soluble CD40 ligand increased at 6 and 12 months in the csDMARD therapy alone group; osteocalcin decreased at 6 and 12 months, epidermal growth factor decreased at 12 months, and macrophage-derived chemokine decreased at 6 months in the csDMARDs plus denosumab group; and interferon gamma-induced protein-10 increased at 12 months in the csDMARD therapy alone group. CONCLUSIONS: Denosumab may inhibit bone destruction by suppressing bone-related factors/chemokines.

Anti-melanoma Differentiation-associated Gene 5 Antibody-positive Dermatomyositis Presenting as Refractory Gingivitis at the First Clinical Manifestation.

We herein report a case of melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis that developed in a patient with refractory gingivitis. The diagnosis of anti-MDA5 antibody-positive dermatomyositis was made based on a characteristic skin rash, weakness of proximal muscles, interstitial pneumonia, and positivity for anti-MDA5 antibody. The patient was started on triple therapy with high-dose prednisolone, tacrolimus, and intravenous cyclophosphamide. After treatment, the refractory gingivitis disappeared, and the other skin rash and interstitial lung disease also improved. In the diagnosis and treatment of anti-MDA5 antibody-positive dermatomyositis, it is necessary to pay attention to the intraoral findings, including the gingiva.

The Evaluation of Lipoma Arborescens with Intermittent Knee Joint Effusion Based on an Analysis of Serum Cytokine Levels and an Immunohistological Examination: A Case Report.

We herein report a 27-year-old woman who presented with recurrent knee pain. Laboratory findings revealed minimal inflammation. Arthrography revealed structures resembling adipose tissues. Magnetic resonance imaging showed a high signal intensity of these structures, leading to the diagnosis of lipoma arborescens (LA). Synovectomy was performed. Pathology revealed adipocyte proliferation and B-cell clusters but no T-cell infiltration. A serum cytokine analysis revealed low levels of interleukin-6 and tumor necrosis factor-α compared with patients with rheumatoid arthritis. The pathogenesis of LA remains unclear, but immunostaining and serum cytokine levels may provide valuable data for future investigations.

Impact of SARS-CoV-2 mRNA vaccine on arthritis condition in rheumatoid arthritis.

Background: The SARS-CoV-2 mRNA vaccine has been reported to cause various adverse reactions, including the development or exacerbation of autoimmune diseases, but the adverse reactions and the effects of the vaccines on disease activity in patients with rheumatoid arthritis (RA) remain unknown. We therefore investigated the arthritis condition in RA patients after SARS-CoV-2 vaccination. Methods: RA patients who visited our hospital from January to April 2022 completed a questionnaire regarding adverse reactions to the SARS-CoV-2 vaccine. We compared the frequency and duration of post-vaccination arthralgia between RA patients and health care workers in our hospital. For the RA patients who reported post-vaccination arthralgia, we collected medical records for the 6 months after vaccination. Results: Of the 1198 vaccinated RA patients, 256 (21.4%) had systemic inflammatory symptoms, 18 (1.5%) had allergies including urticaria and asthma, and 37 (3.1%) had arthralgia. A few patients had extra-articular manifestations such as acute exacerbation of interstitial lung disease. Compared with health care workers, RA patients more frequently developed arthralgia, and the arthralgia was longer lasting than that in controls: only 9 (0.8%) of the 1117 health care workers reported arthralgia, and all cases resolved within 3 days. Data from 31 of the 37 RA patients with post-vaccination arthralgia were further analyzed; in these patients, disease activity was highest after 2 months, and 10 patients required additional DMARDs within 6 months. The proportion of concomitant use of PSL at vaccination was higher in these patients. No patients on biological DMARDs or targeted synthetic DMARDs prior to vaccination needed additional DMARDs or a change of regimen. Conclusion: RA patients had more frequent and longer-lasting arthralgia after vaccination than healthy subjects, and one-third of patients with post-vaccination arthralgia required additional DMARDs. Although the SARS-CoV-2 mRNA vaccine was administered safely in most RA patients, in some patients RA symptoms may worsen after vaccination.

Denosumab improves bone mineral density and microarchitecture in rheumatoid arthritis: randomized controlled trial by HR-pQCT.

INTRODUCTION: This pre-specified exploratory analysis investigated the effect of denosumab on bone mineral density (BMD) and bone microarchitecture in patients with rheumatoid arthritis (RA) treated with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). MATERIALS AND METHODS: In this open-label, parallel-group study, patients were randomly assigned (1:1) to continuous treatment with csDMARDs plus denosumab or continuous treatment with csDMARD therapy alone for 12 months. BMD and bone microarchitecture were measured by dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT). RESULTS: Of 46 patients enrolled in the primary study, 43 were included in the full analysis set. The mean age was 65.3 years, 88.4% were female, and 60.5% had osteoporosis. Areal BMD of the lumbar spine increased from baseline to 6 and 12 months in both groups, but the increase was higher in the csDMARDs plus denosumab group. Areal BMD of the total hip and femoral neck increased from baseline to 6 and 12 months only in the csDMARDs plus denosumab group. Cortical volumetric BMD and cortical thickness of the distal tibia increased in the csDMARDs plus denosumab group at 6 and 12 months but decreased in the csDMARD therapy alone group. Trabecular bone parameters of the distal tibia improved only in the csDMARDs plus denosumab group at 12 months. CONCLUSION: Denosumab may be recommended for patients with RA treated with csDMARDs to increase BMD and improve bone microarchitecture.

Impact of stereopure chimeric backbone chemistries on the potency and durability of gene silencing by RNA interference.

Herein, we report the systematic investigation of stereopure phosphorothioate (PS) and phosphoryl guanidine (PN) linkages on siRNA-mediated silencing. The incorporation of appropriately positioned and configured stereopure PS and PN linkages to N-acetylgalactosamine (GalNAc)-conjugated siRNAs based on multiple targets (Ttr and HSD17B13) increased potency and durability of mRNA silencing in mouse hepatocytes in vivo compared with reference molecules based on clinically proven formats. The observation that the same modification pattern had beneficial effects on unrelated transcripts suggests that it may be generalizable. The effect of stereopure PN modification on silencing is modulated by 2'-ribose modifications in the vicinity, particularly on the nucleoside 3' to the linkage. These benefits corresponded with both an increase in thermal instability at the 5'-end of the antisense strand and improved Argonaute 2 (Ago2) loading. Application of one of our most effective designs to generate a GalNAc-siRNA targeting human HSD17B13 led to ∼80% silencing that persisted for at least 14 weeks after administration of a single 3 mg/kg subcutaneous dose in transgenic mice. The judicious use of stereopure PN linkages improved the silencing profile of GalNAc-siRNAs without disrupting endogenous RNA interference pathways and without elevating serum biomarkers for liver dysfunction, suggesting they may be suitable for therapeutic application.

Evaluation of a renal risk score for Japanese patients with ANCA-associated glomerulonephritis in a multi-center cohort study.

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.

Comparison of risks of cancer, infection, and MACEs associated with JAK inhibitor and TNF inhibitor treatment: a multicentre cohort study.

OBJECTIVES: The objective of this study was to compare the incidence rates (IRs) of infectious diseases, major adverse cardiovascular events (MACEs), and malignancies in RA patients treated with tofacitinib, baricitinib or a TNF inhibitor. METHODS: We retrospectively analysed the cases of 499 RA patients treated with tofacitinib (n = 192), baricitinib (n = 104), or a TNF inhibitor (n = 203). We determined the IRs of infectious diseases and the standardized incidence ratio (SIR) of malignancies and investigated factors related to infectious diseases. After adjusting the clinical characteristic imbalance by propensity score weighting, we compared the incidence of adverse events between the Janus kinase (JAK)-inhibitor and TNF-inhibitor groups. RESULTS: The observational period was 959.7 patient-years (PY), and the median observational period was 1.3 years. The IRs within the JAK-inhibitor treatment group were: serious infectious diseases other than herpes zoster (HZ), 8.36/100 PY; HZ, 13.00/100 PY. Multivariable Cox regression analyses revealed independent risk factors: the glucocorticoid dose in serious infectious diseases other than HZ, and older age in HZ. Two MACEs and 11 malignancies were identified in JAK-inhibitor-treated patients. The overall malignancy SIR was (non-significantly) higher than that of the general population (1.61/100 PY, 95% CI: 0.80, 2.88). The IR of HZ in the JAK-inhibitor-treated group was significantly higher than the TNF-inhibitor-treated group, but there were no significant differences in the IRs of other adverse events between the JAK-inhibitor-treated group and the TNF-inhibitor-treated group, or between the treatment groups of the two JAK inhibitors. CONCLUSIONS: The infectious disease IR in RA was comparable between tofacitinib and baricitinib, but the IR for HZ in these treatment groups was high compared with that in the TNF inhibitor treatment group. The malignancy rate in the JAK-inhibitor-treated group was high but not significantly different from that of the general population or that of the TNF-inhibitor-treated group.

Immune complexome analysis of a rich variety of serum immune complexes identifies disease-characteristic immune complex antigens in systemic sclerosis.

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.

Prediction of radiographic progression during a treat-to-target strategy by the sequential application of MRI-proven bone marrow oedema and power-Doppler grade ≥2 articular synovitis in rheumatoid arthritis: Retrospective observational study.

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.

Inhibition of calcium/calmodulin-dependent protein kinase IV in arthritis: dual effect on Th17 cell activation and osteoclastogenesis.

OBJECTIVE: To investigate the role of calcium/calmodulin-dependent protein kinase IV (CaMK4) in the development of joint injury in a mouse model of arthritis and patients with RA. METHODS: Camk4-deficient, Camk4flox/floxLck-Cre, and mice treated with CaMK4 inhibitor KN-93 or KN-93 encapsulated in nanoparticles tagged with CD4 or CD8 antibodies were subjected to collagen-induced arthritis (CIA). Inflammatory cytokine levels, humoral immune response, synovitis, and T-cell activation were recorded. CAMK4 gene expression was measured in CD4+ T cells from healthy participants and patients with active RA. Micro-CT and histology were used to assess joint pathology. CD4+ and CD14+ cells in patients with RA were subjected to Th17 or osteoclast differentiation, respectively. RESULTS: CaMK4-deficient mice subjected to CIA displayed improved clinical scores and decreased numbers of Th17 cells. KN-93 treatment significantly reduced joint destruction by decreasing the production of inflammatory cytokines. Furthermore, Camk4flox/floxLck-Cre mice and mice treated with KN93-loaded CD4 antibody-tagged nanoparticles developed fewer Th17 cells and less severe arthritis. CaMK4 inhibition mitigated IL-17 production by CD4+ cells in patients with RA. The number of in vitro differentiated osteoclasts from CD14+ cells in patients with RA was significantly decreased with CaMK4 inhibitors. CONCLUSION: Using global and CD4-cell-targeted pharmacologic approaches and conditionally deficient mice, we demonstrate that CaMK4 is important in the development of arthritis. Using ex vivo cell cultures from patients with RA, CaMK4 is important for both Th17 generation and osteoclastogenesis. We propose that CaMK4 inhibition represents a new approach to control the development of arthritis.

Immunoglobulin G4-related Disease with Marked Eosinophilia: A Case Report and Literature Review.

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.

Inhibition of bone erosion, determined by high-resolution peripheral quantitative computed tomography (HR-pQCT), in rheumatoid arthritis patients receiving a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) plus denosumab vs csDMARD therapy alone: an open-label, randomized, parallel-group study.

BACKGROUND: This exploratory study compared the inhibition of bone erosion progression in rheumatoid arthritis (RA) patients treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) plus denosumab versus csDMARD therapy alone and investigated the effects of denosumab on bone micro-architecture and other bone-related parameters using high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: In this open-label, randomized, parallel-group study, patients with RA undergoing treatment with a csDMARD were randomly assigned (1:1) to continue csDMARD therapy alone or to continue csDMARDs with denosumab (60-mg subcutaneous injection once every 6 months) for 12 months. The primary endpoint was the change from baseline in the depth of bone erosion, measured by HR-pQCT, in the second and third metacarpal heads at 6 months after starting treatment. Exploratory endpoints were also evaluated, and adverse events (AEs) were monitored for safety. RESULTS: In total, 46 patients were enrolled, and 43 were included in the full analysis set (csDMARDs plus denosumab, N = 21; csDMARD therapy alone, N = 22). Most patients were female (88.4%), and the mean age was 65.3 years. The adjusted mean (95% confidence interval) change from baseline in the depth of bone erosion, measured by HR-pQCT, in the 2-3 metacarpal heads at 6 months was - 0.57 mm (- 1.52, 0.39 mm) in the csDMARDs plus denosumab group vs - 0.22 mm (- 0.97, 0.53 mm) in the csDMARD therapy alone group (between-group difference: - 0.35 mm [- 1.00, 0.31]; P = 0.2716). Similar results were shown for the adjusted mean between-group difference in the width and volume of bone erosion of the 2-3 metacarpal heads. Significant improvements in bone micro-architecture parameters were shown. The incidence of AEs and serious AEs was similar between the csDMARDs plus denosumab and the csDMARD therapy alone groups (AEs: 52.2% vs 56.5%; serious AEs: 4.3% vs 8.7%). CONCLUSIONS: Although the addition of denosumab to csDMARDs did not find statistically significant improvements in bone erosion after 6 months of treatment, numerical improvements in these parameters suggest that the addition of denosumab to csDMARDs may be effective in inhibiting the progression of bone erosion and improving bone micro-architecture. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, UMIN000030575. Japan Registry for Clinical Trials, jRCTs071180018.

The monocyte-to-osteoclast transition in rheumatoid arthritis: Recent findings.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation leading to joint destruction and deformity. The crucial role of osteoclasts in the bone erosion in RA has been demonstrated. Deregulated osteoclastogenesis which is affected by environmental factors including the inflammatory state, as well as genetic and epigenetic factors, is one of hallmarks of RA pathogenesis. An enhanced-monocyte-to-osteoclast transition plays an important role in osteoclast upregulation in RA because under specific stimuli, circulating monocytes might migrate to a specific location in the bones and fuse with each other to become mature multinucleated osteoclasts. To understand the mechanism of bone damage in RA and to develop novel treatments targeting osteoclast upregulation, it is important to clarify our understanding of the monocyte-to-osteoclast transition in RA. Several potential targets which inhibit both inflammation and osteoclastogenesis, as well as regulators that affect the monocyte-to-osteoclast transition have been revealed by recent studies. Here, we review the factors affecting osteoclastogenesis in RA, summarize the anti-osteoclastogenic effects of current RA treatments, and identify promising therapeutic targets relating to both inflammation and osteoclastogenesis.

The Association of Increase of Human T-Cell Leukemia Virus Type-1 (HTLV-1) Proviral Load (PVL) With Infection in HTLV-1-Positive Patients With Rheumatoid Arthritis: A Longitudinal Analysis of Changes in HTLV-1 PVLs in a Single Center Cohort Study.

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.