Identification of MYH9 as a key regulator for synoviocyte migration and invasion through secretome profiling.

OBJECTIVES: 'Invasive pannus' is a pathological hallmark of rheumatoid arthritis (RA). This study aimed to investigate secretome profile of synovial fibroblasts of patients with RA (RA-FLSs), a major cell type comprising the invasive pannus. METHODS: Secreted proteins from RA-FLSs were first identified using liquid chromatography-tandem mass spectrometry analysis. Ultrasonography was performed for affected joints to define synovitis severity at the time of arthrocentesis. Expression levels of myosin heavy chain 9 (MYH9) in RA-FLSs and synovial tissues were determined by ELISA, western blot analysis and immunostaining. A humanised synovitis model was induced in immuno-deficient mice. RESULTS: We first identified 843 proteins secreted from RA-FLSs; 48.5% of the secretome was associated with pannus-driven pathologies. Parallel reaction monitoring analysis of the secretome facilitated discovery of 16 key proteins related to 'invasive pannus', including MYH9, in the synovial fluids, which represented synovial pathology based on ultrasonography and inflammatory activity in the joints. Particularly, MYH9, a key protein in actin-based cell motility, showed a strong correlation with fibroblastic activity in the transcriptome profile of RA synovia. Moreover, MYH9 expression was elevated in cultured RA-FLSs and RA synovium, and its secretion was induced by interleukin-1ß, tumour necrosis factor α, toll-like receptor ligation and endoplasmic reticulum stimuli. Functional experiments demonstrated that MYH9 promoted migration and invasion of RA-FLSs in vitro and in a humanised synovitis model, which was substantially inhibited by blebbistatin, a specific MYH9 inhibitor. CONCLUSIONS: This study provides a comprehensive resource of the RA-FLS-derived secretome and suggests that MYH9 represents a promising target for retarding abnormal migration and invasion of RA-FLSs.

Kynurenine pathway can be a potential biomarker of fatigue in primary Sjögren's syndrome.

OBJECTIVES: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease with low quality of life caused by various constitutional symptoms and glandular dysfunction. Although fatigue is one of the most frequent symptoms in pSS, its aetiology or biomarkers are poorly elucidated. We investigated potential relationship between severity of fatigue and the kynurenine pathway in pSS. METHODS: Clinical data and blood samples of 81 patients were obtained from a prospective cohort for pSS and compared with age- and sex-matched healthy controls (HC). Severity of fatigue was defined according to the fatigue domain scores in the ESSPRI. Potential biomarkers related to the kynurenine pathway were determined using ELISA. RESULTS: Of the total, 44 patients were defined as the "severe fatigue (ESSPRI fatigue ≥ 5)" group, whereas 37 as the "less fatigue (ESSPRI fatigue < 5)". Serum tryptophan levels in the severe fatigue group were significantly lower while those of kynurenine were higher. Serum interferon gamma, IDO1, and quinolinic acid levels were mostly higher in the less fatigue group. Kynurenine/tryptophan ratios were distinctly higher in the severe fatigue group than both HC and the less fatigue group (p < 0.001). This ratio showed a strong degree of positive correlation (r = 0.624, p < 0.001) with severity of fatigue in pSS while the other markers showed fair degrees of correlation. CONCLUSIONS: Serum markers related to the kynurenine pathway, especially the kynurenine/tryptophan ratio, may be associated with severity of fatigue in pSS. These results can provide guidance for further investigations on fatigue in pSS.

Hypergammaglobulinaemia predicts glandular and extra-glandular damage in primary Sjögren's syndrome: results from the KISS cohort study.

OBJECTIVES: To investigate whether temporal changes in immunoglobulin (Ig) levels and persistent hypergammaglobulinaemia cause glandular and extra-glandular damage in patients with primary Sjögren's syndrome (pSS). METHODS: Cumulative demographics and clinical and serological data from pSS patients in the Korean Initiative pSS cohort were evaluated. Persistent hypergammaglobulinaemia was defined as mean IgG levels of ≥1600 mg/dL over 3 years. Salivary gland damage was assessed by measuring salivary flow impairment, and lacrimal gland damage was assessed by examining ocular structural abnormalities. Solid organ damage included neurological and pleuropulmonary damage, renal impairment and lymphoproliferative disease. Independent predictors of glandular and extra-glandular damage in the third year were identified by logistic regression. RESULTS: Of 256 patients with pSS (median age, 55 years; 98% female), 47% had hypergammaglobulinaemia at baseline. IgG levels fell during the first 2 years in patients with hypergammaglobulinaemia at baseline, but not in those with normal IgG levels. Changes in IgG levels were associated with hydroxychloroquine and glucocorticoids. In the third year of follow-up, salivary flow impairment and solid organ damage were present in 71% and 9% of patients, respectively. After adjusting for age and medication use, persistent hypergammaglobulinaemia was associated with salivary flow impairment and solid organ damage in the third year. Patients in whom IgG fell by more than 80 mg/dL from baseline over 2 years showed less solid organ damage. CONCLUSIONS: Persistent hypergammaglobulinaemia was associated with salivary gland and solid organ damage. Decreased IgG may attenuate progression to solid organ dysfunction.

Effectiveness and safety of biologic and targeted synthetic disease-modifying anti-rheumatic drugs in elderly patients with rheumatoid arthritis: real-world data from the KOBIO Registry.

OBJECTIVES: We aimed to evaluate the clinical outcomes and safety of biologic and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs) and to identify predictors of treatment responses to b/tsDMARDs in elderly patients with rheumatoid arthritis (RA). METHODS: Data from the nationwide cohort of elderly (≥ 65 years) patients enrolled in the KOBIO Registry were analysed. Clinical outcomes were assessed, including changes in the Simplified Disease Activity Index, after treatment. Adverse events and reasons for drug discontinuation were assessed. Multivariable logistic regression analyses were performed to determine which baseline variables affected treatment responses and adverse events (AE). RESULTS: Elderly patients treated with b/tsDMARDs (n=355) or conventional synthetic DMARDs (csDMARDs) (n=104) were included. The median age was 70 years and 77% were female. After 1 year, 63% of patients in the b/tsDMARD group and 68% in the csDMARD group achieved remission or low disease activity (LDA). Overall, 27% of patients in the b/tsDMARDs group and 24% in the csDMARDs group experienced AE. A total of 43.4% of patients on b/tsDMARDs discontinued therapy due to lack of effectiveness (27%), AE (34%), or other reasons (35%). The estimated median retention of b/tsDMARDs was 2.5 years. Male sex and non-exposure to tobacco at baseline were independent factors associated with achieving remission or LDA after 1 year. Interstitial lung disease (ILD) was the most prominent comorbidity associated with AE. CONCLUSIONS: Treatment with b/tsDMARDs is effective and well tolerated in elderly patients with RA; nonetheless, ILD is a key comorbidity that should be monitored carefully.

Positive histopathologic assessment in salivary glands shows little impact on clinical features of established primary Sjögren's syndrome in a Korean population.

OBJECTIVES: The presence and severity of focal lymphocytic sialadenitis in minor salivary glands is a pathognomonic feature in primary Sjögren's syndrome (pSS). However, it has not been determined whether performing minor salivary gland biopsy (MSGB) in a setting of serologically and clinically established pSS provides additional clinical value. Therefore, we aimed to investigate the necessity of MSGB in established pSS patients with anti-Ro/SSA antibodies. METHODS: We extracted 185 patients with anti-Ro/SSA antibody-positive pSS from the Korean Initiative of pSS study, a prospective cohort study. We assigned them into two groups, 161 patients with focus scores ≥1 and another 24 with focus scores <1. The two groups were compared in various clinical aspects, including the severity of glandular dysfunction, systemic disease activity, extra- glandular manifestations, and other clinical indices and laboratory values. We also evaluated the relationship between focus scores and clinically important variables in pSS. RESULTS: Between the two groups, there were no significant differences in the severity of secretory dysfunction, the frequency of extra-glandular manifestations, systemic disease activity represented by various clinical indices, and laboratory findings possibly predicting the risk for lymphoma. Rather, theSjögren's syndrome disease damage index was higher in the group with focusscores <1. Among all variables, only serum immunoglobulin G levels were correlated with focus scores. CONCLUSIONS: Given the little influence on clinical phenotypes, routine MSGB could be omitted for serologically and clinically established pSS patients, especially in low-risk areas for lymphoproliferative diseases.

Soluble siglec-5 is a novel salivary biomarker for primary Sjogren's syndrome.

Despite advances in the understanding of the pathogenesis, disease-specific biomarkers have not been included in the classification criteria for Primary Sjogren's syndrome (pSS). Based on a microarray of peripheral blood mononuclear cells (PBMCs) from patients with primary Sjogren's syndrome (pSS), we aimed to investigate whether soluble sialic acid-binding immunoglobulin-like lectin (siglec)-5 in saliva might be a biomarker for pSS. The concentration of siglec-5 in saliva and sera was determined by ELISA. Clinical parameters related with pSS were obtained from pSS registry and correlation with salivary siglec-5 level was evaluated. Receiver operating curve (ROC) analysis was performed to determine cut off value. A separate validation cohort consisted of subjects with suspicious pSS was evaluated to determine the performance. The level of salivary siglec-5 was significantly higher in pSS patients (n = 170) compared with HCs (n = 25), non SS sicca patients (n = 78) or patients with systemic lupus erythematosus (SLE) (n = 43) (1346.8 [202.8-4280.0] pg/mL, 6.08 [0-134.0] pg/mL, 195 [0-947.5] pg/mL, and 0 [0-238.7] pg/mL, median [interquartile range], P < 0.001). Salivary siglec-5 level negatively correlated with salivary flow rate (spearman's rho: -0.420, P < 0.001), and positively correlated with ocular surface score (rho: 0.331, P < 0.001) and serum immunoglobulin G level (rho = 0.202, P = 0.008). In ROC analysis, area under the curve was 0.774[0.724-0.826]. With a cut off value of 400 pg/mL, sensitivity and specificity was 0.69 and 0.70 respectively. In validation cohort (45 pSS patients and 45 non SS sicca patients), sensitivity and specificity of siglec-5 was 64.4% and 77.8%, respectively. In conclusion, the level of soluble siglec-5 is significantly higher in the saliva from pSS patients, which reflects the severity of hyposalivation and ocular surface damage. This novel salivary biomarker may provide benefits for pSS diagnosis.

Distinct clinical characteristics of anti-Ro/SSA-negative primary Sjögren's syndrome: data from a nationwide cohort for Sjögren's syndrome in Korea.

OBJECTIVES: To investigate clinical characteristics of patients with primary Sjögren's syndrome (SS) who were negative for anti-Ro/SSA antibody but positive for minor salivary gland biopsy (MSGB) compared to patients who presented positivity for anti-Ro/SSA antibody. METHODS: The data of 355 patients from the Korean Initiative of primary Sjögren's Syndrome (KISS), a nationwide prospective cohort for primary SS in Korea, were analysed. All patients fulfilled the 2016 American College of Rheumatology/European League Against Rheumatism (EULAR) classification criteria. Of these patients, 326 were positive for anti-Ro/SSA antibody and 29 were antibody-negative, although they had positive findings in MSGB. Various clinical features including all kinds of tests for evaluating secretory function, disease-related clinical indices and serological values available in the cohort were compared between the two groups. RESULTS: The anti-Ro/SSA-negative group showed less rheumatoid factor positivity (p<0.001), leucopenia (p=0.003), hyper-gammaglobulinaemia (p<0.001), lower serum ß2-microglobulin level (p=0.034), more anti-centromere antibody positivity (p<0.001), higher score in dryness domain of EULAR SS patient-reported index (p=0.048) and more positivity for peripheral nervous system domain in EULAR SS disease activity index and loss of teeth in SS disease damage index (p=0.021 and 0.041, respectively) than patients who were positive for anti-Ro/ SSA antibody. CONCLUSIONS: Primary SS patients who are negative for anti-Ro/SSA antibody have different clinical characteristics compared to patients who are positive for such antibody in Korea. Therefore, clinicians should consider MSGB in patients with suspicious symptoms who are anti-Ro/SSA-negative.

Serum CCL11 level is associated with radiographic spinal damage in patients with ankylosing spondylitis.

The clinical significance of C-C motif chemokine11 (CCL11) in bone metabolism in ankylosing spondylitis (AS) is not clearly elucidated. Thus, this cross-sectional study aimed to compare serum levels of CCL11 between patients with AS and healthy controls and to investigate the relationship between serum levels of CCL11 and radiographic spinal damage in patients with AS. We consecutively recruited 55 male patients with AS and 26 age- and sex-matched healthy controls. Serum levels of CCL11, tumor necrosis factor-α (TNF-α), interleukin-17, and Dickkopf-1 (DKK-1) were measured with commercially available enzyme-linked immunosorbent assay kits. Radiographs were scored according to the modified Stoke ankylosing spondylitis spine score (mSASSS), and syndesmophytes were defined as mSASSS ≥ 2. The serum levels of CCL11 in AS patients with syndesmophytes were significantly higher than those in AS patients without syndesmophytes (p = 0.007) and healthy controls (p = 0.006). In AS patients, the serum levels of CCL11 were significantly and positively correlated with mSASSS (p = 0.006), number of syndesmophytes (p = 0.029). After adjusting for confounding factors, elevated serum levels of CCL11 were associated with increased mSASSS (ß = 0.007, p = 0.03) and higher risk for the presence of syndesmophytes (OR 2.34 per 50 pg/ml increase, p = 0.012) in AS patients. We found that the serum level of CCL11 was associated with structural damage in patients with AS, suggesting that CCL11 may serve as a promising biomarker for new bone formation in AS.

Performance of the 2016 ACR-EULAR classification criteria for primary Sjogren's syndrome in a Korean cohort.

This study compared the performance of the newly proposed 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria to the 2002 American-European Consensus Group (AECG) and 2012 ACR classification criteria for primary Sjogren's syndrome (pSS) in well-characterized Korean patients. Patients with pSS from 12 university-affiliated hospitals in Korea were enrolled from October 2013 to January 2017. Clinical and laboratory data were reviewed. For the validation set, patients who underwent evaluation tests to rule out pSS at Seoul St. Mary's hospital from November 2016 to December 2017 were analyzed. Baseline registry data were available in 458 patients, and 328 patients had sufficient data to determine the fulfillment of each criteria set. All three sets of criteria were met by 307 patients (93.6%). The newly proposed 2016 ACR/EULAR criteria were met by 325 patients (99.1%). The 2002 AECG and 2012 ACR criteria were met by 325 (99.1%) and 310 patients (94.5%), respectively. In a validation cohort consisting of 161 patients with pSS-related symptoms/signs, the sensitivity and specificity of the 2016 ACR/EULAR criteria were 100% [95% confidence interval (CI), 96.11-100.00] and 81.8% [95% CI, 76.15-94.26], respectively. Agreement between the 2016 criteria and 2012 or 2002 criteria was high (Cohen's kappa 0.736 and 0.769, respectively). The newly proposed 2016 ACR/EULAR criteria were met by most patients diagnosed with pSS according to previous criteria and showed higher sensitivity and lower specificity compared with both previous criteria sets.

Sleep Quality Independently Affects Health-related Quality of Life and Cognitive Function in Korean Female Patients with Rheumatoid Arthritis: a Case-control Study.

BACKGROUND: This study aimed to address sleep quality in patients with rheumatoid arthritis (RA) and to determine how it affects health-related quality of life (HRQoL) and cognitive function. METHODS: One hundred and twenty-three patients with RA and 76 healthy controls were enrolled in this study. Sleep quality was assessed using the Korean version of the Pittsburgh Sleep Quality Index (PSQI). Cognitive function and HRQoL was evaluated by a Korean-Montreal Cognitive Assessment (MoCA-K) and 36-item Short-Form Health Survey (SF-36), respectively. Other clinical, demographic, and laboratory data were obtained from retrospective medical chart review. RESULTS: More patients in the RA group reported poor sleep quality (PSQI > 5) than in the control group (61% [75/123] vs. 39.5% [30/76]; P = 0.003). Total PSQI was also significantly higher in the RA group (median [interquartile range], 7 [5-11] vs. 5 [3-6.75]; P = 0.001). Total PSQI score negatively correlated with MoCA-K score (Spearman's rho (r) = -0.223; P = 0.003) with a physical component summary (PCS) of SF-36 (r = -0.221; P = 0.003) and a mental component summary (MCS) of SF-36 (r = -0.341; P < 0.001), which means that poor sleep quality was associated with poor cognitive function and low HRQoL. CONCLUSION: The findings of this study suggest that poor sleep quality is an independent risk factor for low HRQoL and cognitive dysfunction. Efforts to improve the sleep quality of RA patients seem to be an important aspect of integrative treatment for RA.

The EULAR Sjögren's Syndrome Patient-Reported Index is an independent determinant of health-related utility values of Korean patients with primary Sjögren's syndrome.

OBJECTIVES: This study was undertaken to evaluate the health-related quality of life (HRQoL) in patients with primary Sjögren's syndrome (pSS) and to identify its predictors among various clinical parameters. METHODS: The EuroQoL-5 dimension (EQ-5D) was used to measure the patients' HRQoL. The utility values of 178 patients with pSS enrolled in a prospective pSS cohort in Korea were analysed and compared with the Korean normative data. The associations among the clinical parameters and utility values were evaluated. RESULTS: The mean utility value of the pSS patients was significantly lower than that of the Korean general population (0.773±0.138 vs. 0.944±0.095, p<0.001). The proportion of patients with problems in the 4 dimensions was significantly higher in the pSS patients than in the general population (anxiety/depression 70.2 vs. 24.2%, pain 78.7 vs. 28.8%, usual activities 37.6 vs. 9.8%, and mobility 40.4 vs. 12.5%, p<0.001). Bivariate correlation analyses revealed that the degree of pain, fatigue, and patient global assessment of the disease was positively correlated with the utility value. The xerostomia inventory score, ocular surface disease index, and the EULAR Sjögren's syndrome patient-reported index (ESSPRI) also correlated with the utility value. On multiple regression analysis, only the ESSPRI remained in the model after stepwise selection adjusted for age and sex (coefficient ß =-0.053, p<0.001). CONCLUSIONS: The HRQoL of pSS patients is significantly lower than that of the general population, and the ESSPRI is an independent predictor of the HRQoL in pSS patients.

Translation and Validation of a Korean Version of the Xerostomia Inventory in Patients with Primary Sjögren's Syndrome.

This study was conducted to generate and validate a cross-culturally adapted Korean version of the xerostomia inventory (XI), an 11-item questionnaire designed to measure the severity of xerostomia. The original English version of the XI was translated into Korean according to the guidelines for cross-cultural adaptation of health-related quality-of-life measures. Among a prospective cohort of primary Sjögren's syndrome (pSS) in Korea, 194 patients were analyzed. Internal consistency was evaluated by using Cronbach's alpha, and test-retest reliability was obtained by using an intraclass correlation coefficient (ICC) analysis. Construct validity was investigated by performing a correlation analysis between XI total score and salivary flow rate (SFR). Cronbach's alpha for internal consistency was 0.868, and the ICC for test-retest reliability ranged from 0.48 to 0.827, with a median value of 0.72. Moderate negative correlations between XI score and stimulated SFR, unstimulated SFR, and differential (stimulated minus unstimulated) SFR were observed (Spearman's rho, ρ = -0.515, -0.447, and -0.482, respectively; P < 0.001). The correlation analysis between the visual analogue scale (VAS) score of overall dryness and SFR indicated a smaller ρ value (-0.235 [P = 0.006], -0.243 [P = 0.002], and -0.252 [P = 0.003], respectively), which supports that XI more accurately reflects the degree of xerostomia in the pSS patients. In conclusion, the Korean version of the XI is a reliable tool to estimate the severity of xerostomia in patients with pSS.

The risk of osteoporotic fractures according to the FRAX model in Korean patients with rheumatoid arthritis.

The aim of the current study is to identify patients without osteoporosis who met the criteria of the fracture risk assessment tool (FRAX) of the National Osteoporosis Foundation (NOF) only. The incidence of fractures was investigated in patients who met only the FRAX criteria of the NOF and patients who presented osteoporosis. Five hundred and forty five patients with rheumatoid arthritis who visited a single center were recruited in Korea. In the follow-up period of median 30 months, the new onset of fractures was investigated. Of 223 patients who have no osteoporosis, 39 (17.4%) satisfied the FRAX criteria for pharmacological intervention. During the follow-up period, 2 new onset fractures occurred in patients who met only the FRAX criteria and 22 new onset fractures did in patients with osteoporosis by bone mineral density. The incidence rate for new onset fractures of patients who met only the FRAX criteria was with 295.93 per 10,000 person-years higher than in the general population with 114.99 per 10,000 person-years. Patients who met the FRAX criteria of the NOF only need pharmacological intervention because their numbers of incidence for new onset fractures are similar to those of patients with osteoporosis by BMD.

Serum and urine lipidomic profiles identify biomarkers diagnostic for seropositive and seronegative rheumatoid arthritis.

Objective: Seronegative rheumatoid arthritis (RA) is defined as RA without circulating autoantibodies such as rheumatoid factor and anti-citrullinated protein antibodies; thus, early diagnosis of seronegative RA can be challenging. Here, we aimed to identify diagnostic biomarkers for seronegative RA by performing lipidomic analyses of sera and urine samples from patients with RA. Methods: We performed untargeted lipidomic analysis of sera and urine samples from 111 RA patients, 45 osteoarthritis (OA) patients, and 25 healthy controls (HC). These samples were divided into a discovery cohort (n = 97) and a validation cohort (n = 84). Serum samples from 20 patients with systemic lupus erythematosus (SLE) were also used for validation. Results: The serum lipidome profile of RA was distinguishable from that of OA and HC. We identified a panel of ten serum lipids and three urine lipids in the discovery cohort that showed the most significant differences. These were deemed potential lipid biomarker candidates for RA. The serum lipid panel was tested using a validation cohort; the results revealed an accuracy of 79%, a sensitivity of 71%, and a specificity of 86%. Both seropositive and seronegative RA patients were differentiated from patients with OA, SLE, and HC. Three urinary lipids showing differential expression between RA from HC were identified with an accuracy of 84%, but they failed to differentiate RA from OA. There were five lipid pathways that differed between seronegative and seropositive RA. Conclusion: Here, we identified a panel of ten serum lipids as potential biomarkers that can differentiate RA from OA and SLE, regardless of seropositivity. In addition, three urinary lipids had diagnostic utility for differentiating RA from HC.

Serum amyloid A expression in liver promotes synovial macrophage activation and chronic arthritis via NFAT5.

Nuclear factor of activated T-cells 5 (NFAT5), an osmo-sensitive transcription factor, can be activated by isotonic stimuli, such as infection. It remains unclear, however, whether NFAT5 is required for damage-associated molecular pattern-triggered (DAMP-triggered) inflammation and immunity. Here, we found that several DAMPs increased NFAT5 expression in macrophages. In particular, serum amyloid A (SAA), primarily generated by the liver, substantially upregulated NFAT5 expression and activity through TLR2/4-JNK signalling pathway. Moreover, the SAA-TLR2/4-NFAT5 axis promoted migration and chemotaxis of macrophages in an IL-6- and chemokine ligand 2-dependent (CCL2-dependent) manner in vitro. Intraarticular injection of SAA markedly accelerated macrophage infiltration and arthritis progression in mice. By contrast, genetic ablation of NFAT5 or TLR2/4 rescued the pathology induced by SAA, confirming the SAA-TLR2/4-NFAT5 axis in vivo. Myeloid-specific depletion of NFAT5 also attenuated SAA-accelerated arthritis. Of note, inflammatory arthritis in mice strikingly induced SAA overexpression in the liver. Conversely, forced overexpression of the SAA gene in the liver accelerated joint damage, indicating that the liver contributes to bolstering chronic inflammation at remote sites by secreting SAA. Collectively, this study underscores the importance of the SAA-TLR2/4-NFAT5 axis in innate immunity, suggesting that acute phase reactant SAA mediates mutual interactions between liver and joints and ultimately aggravates chronic arthritis by enhancing macrophage activation.

Changes in the cholesterol profile of patients with rheumatoid arthritis treated with biologics or Janus kinase inhibitors.

Objective: To assess the effects of biological and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) on lipid profiles in patients with moderate-to-severe rheumatoid arthritis (RA). Methods: This retrospective single-center observational study included patients with RA taking a tumor necrosis factor-α inhibitor (TNFi), abatacept, tocilizumab, or a Janus kinase inhibitor (JAKi) for at least 6 months. Changes in lipid profile were assessed at 6 months after the start of treatment, and associations between changes in lipid profiles and clinical efficacy, concomitant medications, and comorbidities were evaluated. Results: This study included 114 patients treated with TNFi, 81 with abatacept, 103 with tocilizumab, and 89 with JAKi. The mean percentage change (from baseline to 6 months) in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and non-HDL-C levels was higher in those taking tocilizumab and JAKi than in those taking TNFi and abatacept. A significant change in non-HDL-C was associated with JAKi (versus TNFi odds ratio [OR], 3.228; 95% confidence interval [CI], 1.536~6.785), tocilizumab (versus TNFi OR, 2.203; 95% CI, 1.035~4.689), and statins (OR, 0.487; 95% CI, 0.231~1.024). However, changes in disease activity in 28 joints were not associated with a significant change in non-HDL-C. Conclusion: Tocilizumab- and JAKi-associated increases in serum non-HDL-C levels were observed regardless of changes in disease activity. Statins are recommended for RA patients showing a significant increase in cholesterol levels after initiating biological and targeted synthetic DMARDs.

Factors associated with the composition of the gut microbiome in patients with established rheumatoid arthritis and its value for predicting treatment responses.

BACKGROUND: We aimed to investigate the gut microbiota of patients with established rheumatoid arthritis (RA) who have been managed with disease-modifying anti-rheumatic drugs (DMARDs) for a long time. We focused on factors that might affect composition of the gut microbiota. Furthermore, we investigated whether gut microbiota composition predicts future clinical responses to conventional synthetic DMARDs (csDMARDs) in patients with an insufficient response to initial therapy. METHODS: We recruited 94 patients with RA and 30 healthy participants. Fecal gut microbiome was analyzed by 16S rRNA amplificon sequencing; the resulting raw reads were processed based on QIIME2. Calypso online software was used for data visualization and to compare microbial composition between groups. For RA patients with moderate-to-high disease activity, treatment was changed after stool collection, and responses were observed 6 months later. RESULTS: The composition of the gut microbiota in patients with established RA was different from that of healthy participants. Young RA patients (< 45 years) had reduced richness, evenness, and distinct gut microbial compositions when compared with older RA patients and healthy individuals. Disease activity and rheumatoid factor levels were not associated with microbiome composition. Overall, biological DMARDs and csDMARDs, except sulfasalazine and TNF inhibitors, respectively, were not associated with the gut microbial composition in patients with established RA. However, the combination of Subdoligranulum and Fusicatenibacter genera was associated with a future good response to second-line csDMARDs in patients who showed an insufficient response to first-line csDMARDs. CONCLUSION: Gut microbial composition in patients with established RA is different from that in healthy individuals. Thus, the gut microbiome has the potential to predict responses of some RA patients to csDMARDs.

Comparison of remission criteria in patients with rheumatoid arthritis treated with biologic or targeted synthetic disease-modifying anti-rheumatic drugs: results from a nationwide registry.

Background: Biologic or targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARD) are widely used for treatment of rheumatoid arthritis (RA), enabling patients to better achieve remission. Objective: The objective of the study was to investigate and compare remission rates in RA patients treated with different b/tsDMARDs during the period 2013-2019. Design: A longitudinal observational analysis was performed on data from a nationwide RA registry. Methods: Remission rates in the KOBIO-RA registry were defined by a disease activity score in 28 joints (DAS28), clinical disease activity index (CDAI), simplified disease activity index (SDAI), and Boolean-based assessment. After initiating treatment with b/tsDMARDs, yearly remission rates in response to b/tsDMARDs, either all or as subgroups (tumor necrosis factor-α inhibitors, tocilizumab, abatacept, and Janus kinase inhibitors), were investigated for 5 years. Sustained remission was defined as remission maintained for two consecutive years. Results: Patients (N = 1805) who completed at least one follow-up visit were analyzed (mean age = 55 years; 83.2% female). At month 12, 56.0% of patients achieved remission based on DAS28-C-reactive protein (CRP), 36.2% on DAS28-erythrocyte sedimentation rate (ESR), 10.4% on CDAI, 12.7% on SDAI, and 12.9% on Boolean criteria. Sustained remission rates were 62%, 40%, 13%, 11%, and 8% for the DAS28-CRP, DAS28-ESR, Boolean, SDAI, and CDAI remission criteria, respectively. Remission rates using the DAS28 definition varied most among the b/tsDMARD subgroups. Conclusion: Assessment of sustained remission using the CDAI, SDAI, or Boolean criteria is more stringent, yet congruous with the DAS28-based criteria in RA patients treated with b/tsDMARDs.

Dysbiotic but nonpathogenic shift in the fecal mycobiota of patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is closely associated with the oral and gut microbiomes. Fungal cell wall components initiate inflammatory arthritis in mouse models. However, little is known regarding the role of the fungal community in the pathogenesis of RA. To evaluate the association between RA and the gut microbiome, investigations of bacterial and fungal communities in patients with RA are necessary. Therefore, we investigated the compositions and associations of fecal bacterial and fungal communities in 30 healthy controls and 99 patients with RA. The relative abundances of Bifidobacterium and Blautia decreased, whereas the relative abundance of Streptococcus increased, in patients with RA. The relative abundance of Candida in the fecal fungal community was higher in patients with RA than in healthy controls, while the relative abundance of Aspergillus was higher in healthy controls than in patients with RA. Candida species-specific gene amplification showed that C. albicans was the most abundant species of Candida. Ordination analysis and random forest classification models supported the findings of structural changes in bacterial and fungal communities. Aspergillus was the core fecal fungal genus in healthy controls, although Saccharomyces spp. are typically predominant in Western cohorts. In addition, bacterial-fungal association analyses showed that the hub node had shifted from fungi to bacteria in patients with RA. The finding of fungal dysbiosis in patients with RA suggests that fungi play critical roles in the fecal microbial communities and pathogenesis of RA.