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Although osteoarthritis (OA) is regarded as a disease of the articular cartilage, recent research has demonstrated alterations in periarticular muscles that surround the affected joint. Here, we investigated changes in periarticular muscle during the progression of OA, as well as the cause-and-effect relationship between muscle weakness and OA, in a mouse model of OA by destabilization of the medial meniscus (DMM). Pathological phenotypes in the periarticular muscles were assessed in the early and late stages of OA by DMM. OA pathology and pain behavior in the mice after DMM induction were examined in response to periarticular muscle weakness induced by multiple rounds of barium chloride (BaCl2) injections. The examinations were also performed in myostatin knockout mice with strengthened muscle phenotypes by muscle hypertrophy. Morphological alterations in the tibialis anterior (TA) and quadriceps muscles in DMM mice included variations in muscle-fiber size, aberrant extracellular matrix (ECM) deposition, inflammatory cell infiltration, and decreased muscle mass. Periarticular muscle fibers isolated from DMM mice showed reductions in the number of satellite cells and myogenic capacity of primary myoblast, as well as proliferation. DMM + muscle injury mice also showed exacerbated joint degeneration compared to the DMM vehicles. Myostatin knockout mice were characterized by attenuated OA and the complete abrogation of pain behavior after DMM. Our results suggest an association between muscle weakness and OA progression and pain. [ABSTRACT FROM AUTHOR]

Novel modalities, such as salivary ultrasonography (SGUS) and shear wave elastography (SWE), have previously been introduced to evaluate Sjögren's syndrome (SS). However, in secondary SS (sSS), the diagnostic performance of SGUS and its relationship with clinicopathological characteristics have not yet been clearly defined. In this study, we aimed to investigate sSS in RA patients using SGUS and SWE and sought to determine its pathological correlations. Thirty-one RA patients who presented with sicca symptoms were included to be evaluated on SS, and were compared with 18 primary SS (pSS) patients. All subjects were assessed through SGUS, SWE, and conventional diagnostic approaches for SS, including minor salivary gland biopsy (MSGB). In SGUS evaluation, two separate scoring systems, suggested by Hocevar and OMERACT, were used. Among 31 RA patients with sicca symptoms, 19 (61.2%) were diagnosed as sSS. Similar to pSS, SGUS showed good diagnostic performance (sensitivity 68.4% and 78.9%, and specificity 91.7% and 75.0% for Hocever and OMERACT, respectively) in differentiating sSS from RA patients with simple sicca symptoms. The sSS and pSS patients exhibited significantly higher lymphoid infiltration areas in MSGB than RA patients without SS. Focus score and lymphoid infiltration areas correlated well with sonographic severity. Severity of fibrosis in MSGB showed better positive correlation with SWE than with SGUS. Similar to pSS, SGUS shows good diagnostic performance for sSS in RA patients. SWE reflects histopathologic chronicity of MSGB well in both pSS and sSS. [ABSTRACT FROM AUTHOR]

Association between exposure to periodontal bacteria and development of autoantibodies related to rheumatoid arthritis (RA) has been widely accepted; however, direct causal relationship between periodontal bacteria and rheumatoid factor (RF) is currently not fully understood. We investigated whether periodontal bacteria could affect RF status. Patients with preclinical, new-onset, or chronic RA underwent periodontal examination, and investigation of subgingival microbiome via 16S rRNA sequencing. Degree of arthritis and RF induction was examined in collagen-induced arthritis (CIA) mice that were orally inoculated with different periodontal bacteria species. Subsequently, single-cell RNA sequencing analysis of the mouse spleen cells was performed. Patients with preclinical RA showed an increased abundance of the Porphyromonadacae family in the subgingival microbiome compared to those with new-onset or chronic RA, despite comparable periodontitis severity among them. Notably, a distinct subgingival microbial community was found between patients with high-positive RF and those with negative or low-positive RF (p=0.022). Oral infections with the periodontal pathogens P. gingivalis and Treponema denticola in CIA mice similarly enhanced arthritis score, but resulted in different levels of RF induction. Genes related to B cell receptor signaling, B cell proliferation, activation, and differentiation, and CD4+ T cell costimulation and cytokine production were involved in the differential induction of RF in mice exposed to different bacteria. In summary, periodontal microbiome might shape RF status by affecting the humoral immune response during RA pathogenesis. [ABSTRACT FROM AUTHOR]

Introduction: Chronic kidney disease (CKD) is a major risk factor for overall morbidity and mortality even in lupus nephritis (LN) patients. However, less attention has been paid to the development of CKD in patients with LN. The objective of this study was to identify predictors for CKD with 35-year experience depending on newly revised guidelines for patients with LN. Methods: We conducted a retrospective cohort study for 401 patients who visited Seoul St. Mary's Hospital between January 1985 and December 2019. We analyzed clinical and laboratory indices, treatment response, the final renal function, and biopsy findings. The timing and cumulative risk of developing CKD were identified by Kaplan–Meier methods. Independent risk factors for developing CKD were examined by Cox proportional hazard regression analyses. Results: The median follow-up time after the diagnosis of LN was 131 months. CKD occurred in 15.5% of patients within 10 years after the diagnosis of LN. The development of CKD was associated with delayed-onset LN, acute renal dysfunction at onset of LN, and failure to reach complete response (CR) at 6 or 12 months rather than histopathological findings or the severity of proteinuria at onset of LN. Cumulative incidence of progression to CKD was significantly higher in patients with the three predictors mentioned above. Conclusion: Ten-year cumulative incidence of CKD was about 15%. Our results showed that delayed-onset LN, acute renal dysfunction at the onset of LN, and inadequate treatment response assessed at 6 or 12 months after treatment were predictors for the development of CKD in LN. Key Points • CKD is a major risk factor for overall morbidity and mortality in LN patients. • Ten-year cumulative incidence of CKD was about 15% • Delayed-onset LN, acute renal dysfunction at the onset of LN, and inadequate treatment response assessed at 6 or 12 months after treatment were predictors for the development of CKD in LN. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the association between bone mineral status and spinal radiographic damage in patients with ankylosing spondylitis (AS) and determine whether bone mineral status can predict further spinal radiographic damage after 2 years. Methods: Bone mineral density (BMD) of the lumbar spine (anteroposterior and lateral projections), femoral neck, and total hip and trabecular bone score (TBS) of the lumbar spine were measured in AS patients (n = 54) who fulfilled the modified New York criteria. Spinal radiographic damage was scored on cervical and lumbar spine radiographs using modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) at baseline and after 2 years. Simple and multiple linear regression analyses were performed to examine predictors of spinal radiographic damage. Results: Patients with advanced AS exhibited low BMD on lumbar spine lateral projections, femoral neck, and total hip and low TBS. Low vertebral bone mass at baseline, assessed by BMD of the lateral projections or TBS, was independently associated with baseline mSASSS. After 2 years, mSASSS change from baseline was significantly associated with high baseline mSASSS, high baseline erythrocyte sedimentation rate and C-reactive protein (CRP) levels, and low baseline BMD of the lumbar spine lateral projections. The best predictive model for spinal radiographic progression consisted of baseline mSASSS, baseline CRP, and low BMD of lateral lumbar spine (area under curve = 0.826). Conclusions: BMD at vertebral lateral projections and TBS were inversely associated with baseline mSASSS in AS patients. Low BMD at vertebral lateral projections, as well as baseline mSASSS and inflammatory markers, might predict spinal radiographic damage in AS. Key Points • Vertebral bone mineral density of lateral projections and trabecular bone score are inversely associated with baseline mSASSS in patients with ankylosing spondylitis. • Baseline mSASSS, inflammatory markers, and low vertebral bone mineral density might predict spinal radiographic progression in patients with ankylosing spondylitis. [ABSTRACT FROM AUTHOR]

Microbial habitation in the human body begins immediately after birth, and adults are colonized by microbes outnumbering human cells by a factor of ten. Especially, intestinal track is a living space for diverse microbial species that have coevolved symbiotically. A principal function of the gut microbiota is to protect the host from harmful bacteria and to provide benefits for the host through several mechanisms, including direct competition for limited nutrients, training of host immune systems to recognize specifically foreign materials and conversion of otherwise indigestible food into energy and absorbable nutrients. Therefore, gut dysbiosis, a bacterial imbalance state, is related with the pathogenesis of various host diseases including autoimmune diseases. In the current review, we highlight the importance of gut microbiota in the normal health and autoimmune diseases. We also discuss regulation of gut dysbiosis and future direction for potential clinical applications, including treatment and diagnostics of autoimmune diseases. [ABSTRACT FROM AUTHOR]

The aim of this study was to compare anti-tumor necrosis factor-α (TNFα) treatment status in rheumatoid arthritis (RA) patients with the Korean National Health Insurance (KNHI) reimbursement eligibility criteria and with American College of Rheumatology (ACR) recommendations, Japan College of Rheumatology (JCR) guidelines and British Society for Rheumatology (BSR) guidelines. Between December 2011 and August 2012, outpatients from 17 South Korean general hospitals diagnosed with RA according to the 1987 ACR criteria were enrolled into a noninterventional, cross-sectional, observational study. Of 1700 patients (1414 female (83.2 %), mean age of 56.6 ± 12.0, mean disease duration 97.9 ± 91.8 months), 306 (18.0 %) had used anti-TNFα agents, and 224 (13.2 %) were currently using an anti-TNFα agent. Of 1394 anti-TNFα-naive patients, 32 (2.3 %) met KNHI reimbursement guidelines, 148 (10.6 %) met ACR recommendations, and 127 (9.1 %) and 126 (9.0 %) were considered eligible for anti-TNFα agents according to JCR and BSR guidelines, respectively. The main discrepancy was the higher active joint count required by the KNHI eligibility criteria. In the opinion of treating rheumatologists, the KNHI reimbursement criteria ineligibility accounted for 15.3 % ( n = 213) of the reasons for not initiating anti-TNFα agents in anti-TNFα-naive group. The anti-TNFα user group showed significantly higher disease activity than the anti-TNFα-naive group based on DAS28 score. In comparison with the ACR recommendations and JCR and BSR guidelines, fewer patients met KNHI reimbursement eligibility criteria for anti-TNFα agents. The current amendment of the KNHI criteria based on DAS28 score will improve an access to biologic agents including anti-TNFα treatment for South Korean patients with active RA. [ABSTRACT FROM AUTHOR]

The purpose of this study is to investigate the frequency of the subclinical synovitis in hand or wrist joints of the SLE patients using ultrasonography (US) and to correlate them with clinical parameters. Forty-eight systemic lupus erythematosus (SLE) patients without musculoskeletal (MS) involvement were enrolled and underwent clinical and laboratory examinations. Gray-scale and power Doppler (PD) US was performed for imaging the wrist, second and third metacarpophalangeal (MCP) joints, and flexor tendons on non-dominant sides of the individuals. US synovitis index (USSI) and PD index were calculated as sum of the synovitis and PD semiquantitative scores, respectively, obtained from each joint. Subclinical synovitis was found by US in 28 (58.3 %) out of 48 patients. US revealed synovitis of the wrist in 16 (33.3 %) patients, of the second MCP joint in 14 (29.2 %) and of the third MCP joint in 15 (31.3 %). PD signals in three (6.3 %) patients and tenosynovitis in two (4.2 %) were also detected. USSI scores showed significant positive correlation with erythrocyte sedimentation rate (ESR) levels ( r = 0.30, p < 0.05) or anti-dsDNA Ab titers ( r = 0.34, p < 0.05). Within 6 months after US examination, new MS symptoms were developed in 11 (22.9 %) patients. Older age at diagnosis (OR 1.283, 95 % CI 1.029-1.601, p = 0.027) or higher USSI scores (OR 12.93, 95 % CI 1.023-163.503, p = 0.048) were independently associated with development of new MS symptoms. Subclinical synovitis is common in SLE patients who do not suffer from MS symptoms. US is useful to detect joint abnormalities before symptoms appear in SLE patients. [ABSTRACT FROM AUTHOR]

The aim of this study is to clarify the association between serum leptin levels and the presence of syndesmophytes in male patients with ankylosing spondylitis (AS). Seventy-two male patients with AS and 20 age-matched healthy male controls were included. Patients were stratified by the presence of syndesmophytes. Serum leptin levels were measured and adjusted for body mass index (BMI). In addition, bone-specific alkaline phosphatase (BALP), osteocalcin, and telopeptide of type I collagen were determined. Patients with syndesmophytes were associated with older age ( p < 0.001), longer disease duration ( p = 0.003), and higher BMI ( p = 0.038). Serum leptin levels and leptin per BMI (leptin/BMI) ratio were not different between AS patients and healthy controls. However, serum leptin/BMI ratio was significantly higher in patients with syndesmophytes compared to those without ( p = 0.010). In multivariate analysis, higher serum leptin/BMI ratio remained significantly associated with the presence of syndesmophytes ( p = 0.029). Moreover, serum leptin/BMI ratio was positively correlated with serum BALP ( γ = 0.279, p = 0.039). However, there was no significant association between serum leptin/BMI ratio and bone mineral density. Serum leptin levels are elevated in male AS patients with syndesmophytes and were found to be correlated with bone formation marker, suggesting a potential role of leptin in new bone formation in AS. [ABSTRACT FROM AUTHOR]

Hyperhomocysteinemia has been shown to increase the incidence of osteoporosis and osteoporotic fractures. Endoplasmic reticulum (ER) stress was recently shown to be associated with apoptosis in several types of cells. In this study, we determined the effect of homocysteine (Hcy) on the apoptosis of osteoblastic cells and investigated whether ER stress participates in Hcy-induced osteoblast apoptosis. Human osteoblastic cells were incubated with Hcy. Hcy dose-dependently decreased cell viability and increased apoptosis in osteoblastic cells. Osteoblastic cells are more susceptible to Hcy-mediated cell death than other cell types. Expression of cleaved caspase-3 was significantly increased by Hcy, and pretreatment with caspase-3 inhibitor rescued the cell viability by Hcy. Hcy treatment led to an increase in release of mitochondrial cytochrome c. It also triggered ER stress by increased expression of glucose-regulated protein 78, inositol-requiring transmembrane kinase and endonuclease 1α (IRE-1α), spliced X-box binding protein, activating transcription factor 4, and C/EBP homologous protein. Silencing IRE-1α expression by small interfering RNA effectively suppressed Hcy-induced apoptosis of osteoblastic cells. Our results suggest that hyperhomocysteinemia induces apoptotic cell death in osteoblasts via ER stress. [ABSTRACT FROM AUTHOR]

The purpose of this study is to compare the efficacy of tramadol 37.5 mg/acetaminophen 325 mg combination tablets (tramadol/APAP) with that of nonsteroidal anti-inflammatory drugs (NSAIDs) as maintenance therapy following tramadol/APAP and NSAID combination therapy in knee osteoarthritis (OA) pain which was inadequately controlled by NSAIDs. Subjects with knee OA for over 1 year and moderate pain (numerical rating scale [NRS] ≥5) despite at least 4 weeks' NSAID therapy (meloxicam 7.5 mg or 15 mg qd or aceclofenac 100 mg bid) received tramadol/APAP add-on (combination with NSAID) for 4 weeks. Thereafter, subjects with significant pain improvement (NRS <4) were randomized to receive either tramadol/APAP or NSAID for 8 weeks. On days 29 and 57, Western Ontario and McMaster Universities (WOMAC) OA index score was measured. Secondary measures included pain intensity (NRS), pain relief score, and subjects' and investigators' overall medication assessments. Of 143 subjects enrolled, 112 completed the 4-week tramadol/APAP and NSAID combination phase and 97 (67.8%) experienced significant pain improvement. Of the 97 subjects randomized, 36 in tramadol/APAP group and 47 in NSAID group completed the 8-week comparator study. On days 29 and 57, WOMAC scores and pain intensities did not increase in both groups compared to measurements immediately after the combination therapy. At these two time points, there were no significant differences in WOMAC scores, pain intensities, and other secondary measures between the two groups. Overall adverse event rates were similar in both groups. Tramadol/APAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs. In those subjects who showed favorable response to tramadol/APAP and NSAID combination therapy, both tramadol/APAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadol/APAP and NSAIDs. [ABSTRACT FROM AUTHOR]

Extensive angiogenesis in the synoviums is a characteristic pathology of rheumatoid arthritis (RA). We have demonstrated that anti-flt-1 hexapeptide, GNQWFI, specifically inhibits the interaction of VEGF or PlGF with its receptor flt-1 (Yoo et al. []). In this study, we investigate the feasibility of the synthetic D-form of anti-flt-1 hexapeptide conjugated with 8-amino-3,6-dioxaoctanoic acid (mini-PEG) for treatment of RA. We first modified the structure of anti-flt-1 peptide from the L-form (GNQWFI) to all D-form (gnqwfi; allD) and then conjugated allD with mini-PEG to enhance its stability. The result showed that the allD anti-flt-1 peptide showed an increased stability in the sera without major loss of inhibitory activity. The allD and its mini-PEGylated derivative similarly suppressed wounding migration, chemotaxis, and tube formation of endothelial cells in vitro. However, in the Matrigels assay, the in vivo anti-angiogenic activity of mini-PEGylated allD was stronger than that of native allD or L-form. Moreover, oral and subcutaneous administration of mini-PEGylated allD, but not oral feeding of original L-form, successfully suppressed severity of collagen-induced arthritis. After a single subcutaneous injection, the Cy5-labeled mini-PEGylated allD was found to be distributed systemically and accumulated in arthritic joints of mice, particularly in joints with a severe clinical score. In conclusion, our data suggests that mini-PEGylated allD is more beneficial in the treatment of RA than unmodified anti-flt-1 peptides, since it has increased stability and the possibility of oral delivery, and could be applied to treat angiogenesis-dependent human diseases, including RA. [ABSTRACT FROM AUTHOR]