Subtherapeutic hydroxychloroquine concentration is associated with increased disease activity and greater organ damage in lupus.

OBJECTIVE: To investigate the effects of the serum HCQ concentration on clinical manifestations, disease activity and organ damage in a longitudinal cohort of SLE patients. METHODS: The 338 SLE patients were assessed with respect to their demographic data, clinical and laboratory findings, Physician's Global Assessment (PGA), adjusted mean SLEDAI-2000 (AMS) and SLICC Damage Index (SDI) annually for 5 consecutive years. Patients were divided into two groups according to their serum HCQ concentration at baseline: subtherapeutic (<500 ng/ml) and therapeutic (≥500 ng/ml) groups. The impact of the HCQ concentration on the clinical outcomes was evaluated in a longitudinal analysis using a generalized estimating equation (GEE). RESULTS: Of the 338 patients, 287 (84.9%) were in the subtherapeutic group at baseline. This group had a higher incidence of newly developed LN (P = 0.036) and had been prescribed higher mean and cumulative doses of prednisolone (P = 0.003 and P = 0.013, respectively) than the therapeutic group. In multivariable analyses based on GEE, the subtherapeutic group had a higher AMS score (ß = 1.398, 95% CI 0.607, 2.189; P < 0.001), higher PGA score (ß = 0.328, 95% CI 0.215, 0.441; P < 0.001) and higher SDI score (ß = 0.366, 95% CI 0.061, 0.671; P = 0.019) across all 5 years. CONCLUSION: The subtherapeutic HCQ concentration was associated with the development of new-onset LN, and had significant associations with disease activity and cumulative organ damage in SLE patients over time.

Ramosetron as an add-on therapy for refractory fibromyalgia: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: This study aimed to assess the efficacy and safety of intravenous ramosetron for pain relief in patients with fibromyalgia (FM) unresponsive to conventional treatments. METHODS: In this prospective, double-blind, placebo-controlled trial, 80 FM patients were randomly allocated to receive either placebo (n = 40) or ramosetron (n = 40) at a dosage of 0.3 mg/day intravenously for five consecutive days. The primary outcome was the reduction in pain intensity at the end of the treatment period, evaluated using a visual analogue scale (VAS). Secondary outcome measures included the FM Impact Questionnaire, Beck Depression Inventory (BDI), Multi-Dimensional Health Assessment Questionnaire (MDHAQ), EQ-5D and State-Trait Anxiety Inventory on days 5 (end of treatment), 7, 10 and 28. Safety was continuously monitored throughout the study. RESULTS: At the end of the treatment phase, the ramosetron group demonstrated a significantly greater reduction in VAS pain scores compared with the placebo group (1.18 ± 1.60 vs 0.54 ± 1.59, P < 0.05). Additionally, the ramosetron group exhibited significant improvements in BDI (4.42 ± 5.18 vs 1.33 ± 4.87, P < 0.05) and MDHAQ pain scale (0.37 ± 0.74 vs 0.04 ± 0.52, P < 0.05) scores. However, these improvements in pain VAS and BDI scores were not sustained through day 28. The safety profile of ramosetron was favorable, with gastrointestinal symptoms, particularly constipation, being the most commonly reported adverse events. CONCLUSIONS: Intravenous administration of ramosetron provided safe and effective short-term relief of pain intensity in FM patients with inadequate response to standard treatments.

Folate deficiency is associated with increased radiographic severity of osteoarthritis in knee joints but not in hand joints.

OBJECTIVES: No previous studies have explored the effect of folate deficiency on the severity of osteoarthritis (OA). Therefore, we investigated the relationship between folate level and features on knee and hand radiographs in a large, population-based OA cohort. METHODS: Among 9,260 subjects enrolled in the Dong-gu study, 2,489 who had knee and hand joint radiographs were included. Of these, subjects with a history of amputation or total knee replacement were excluded. Serum folate levels were measured using blood samples collected at the time of enrolment and stored. A semi-quantitative system was used to grade the severity of hand and knee x-ray changes. Linear regression was performed to assess relationships between serum folate levels and knee and hand radiographic scores after adjusting for age, sex, body mass index, smoking, alcohol consumption, education, physical activity, occupation, vitamin D, and ferritin. RESULTS: A total of 2,322 subjects were recruited. After adjusting for confounders, participants with folate deficiency (<4 ng/mL) had higher total (p<0.001), osteophyte (p<0.001), joint space narrowing (p=0.002), tibial attrition (p<0.001), and sclerosis (p=0.005) scores for knee joint radiographs compared to participants with a normal folate level. After adjusting for confounders, the radiographic scores for hand joints did not differ between the groups. CONCLUSIONS: Folate deficiency is associated with increased radiographic severity of OA in knee joints, but not in hand joints. Further studies are needed to explore the differential effects of folate on the severity of knee and hand OA.

Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study.

OBJECTIVE: Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. METHODS: We built gene expression predictive models in blood B cells, CD4+ and CD8+ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. RESULTS: TWAS identified 171 genes for SLE (p<1.0×10-5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10-8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10-9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. CONCLUSIONS: Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

Korean LupusPRO: Cross-Cultural validation study for systemic lupus erythematosus.

OBJECTIVE: To establish the reliability and validity of the Korean version of LupusPRO version 1.7 (v1.7) for systemic lupus erythematosus (SLE) patients. METHODS: LupusPRO v1.7 was translated into Korean, followed by pretesting among five native Korean speakers. We administered the LupusPRO v1.7 survey to five SLE patients and made minor changes to clarify the language. Then, 133 SLE patients participated in the validation procedure. In each domain, the internal consistency reliability (ICR) and test-retest reliability (TRR) were assessed using Cronbach's alpha and the intra-class correlation coefficient (ICC), respectively. Criterion validity was evaluated using Spearman's correlation coefficient with the other measures such as SF-36, EQ-5D VAS, and SELENA-SLEDAI PGA. Construct validity was assessed by confirmatory factor analysis (CFA) using the unweighted least square estimation method. RESULTS: The mean age of the 133 patients was 36.14 years, and 97% of them were women. Analysis of 130 returned questionnaires revealed that most ICRs of the Korean LupusPRO v1.7 domains were acceptable, with Cronbach's alphas in the range of 0.579-0.949, and most TRRs were good with ICCs from 0.582 to 0.851. Criterion validities presented significant correlations between the LupusPRO v1.7 and other measures validated. In the analysis of the CFA model, the goodness of fit indices demonstrated an acceptable fit. Factor loadings for most individual items were between 0.548 and 0.985. The average variance extracted (AVE) and composite reliability (CR) of most domains were greater than 0.5 and 0.7, respectively, demonstrating acceptable convergent and discriminant validities. CONCLUSIONS: The Korean version of LupusPRO v.17 had acceptable reliability and validity.

Non-adherence to methotrexate was associated with high disease activity and poor health-related outcomes during a 4-year follow-up of rheumatoid arthritis patients.

OBJECTIVES: Although methotrexate (MTX) is the first-line drug for management of rheumatoid arthritis (RA), non-adherence to MTX is highly prevalent and under-recognised. Here, we investigated adherence to MTX and its impact on clinical outcomes during follow-up in patients with RA. METHODS: In total, 367 RA patients were included in this study, with patient visits conducted annually for 4 consecutive years. Adherence was defined by the medication possession ratio during the follow-up period. We divided the patients into two groups; patients who took ≥80% of their prescribed MTX doses and those who did not. In a prospective cohort, the generalised estimating equations were used to identify longitudinal associations between drug adherence and clinical outcomes including disease activity, physical function, and quality of life. RESULTS: Of the 367 RA patients, 8.7% were found to have taken MTX <80% during the period of follow up. After adjustment for confounders, non-adherence to MTX was significantly associated with higher DAS28-ESR during the follow-up period (coefficient ß=0.989, 95%; CI: 0.603-1.375; p<0.001). In addition, non-adherence to MTX was a significant predictor of RAPID3 (coefficient ß=1.847; 95% CI: 0.221-3.472; p=0.026) and EQ-5D (coefficient ß= -0.051; 95% CI: -0.090-0.012; p=0.010) after adjustment for confounding factors. CONCLUSIONS: Non-adherence to MTX was significantly associated with worse clinical outcomes, as evidenced by higher disease activity, poorer physical function, and lower health-related quality of life during a 4-year follow-up of RA patients.

Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians.

Human leukocyte antigen (HLA) is a key genetic factor conferring risk of systemic lupus erythematosus (SLE), but precise independent localization of HLA effects is extremely challenging. As a result, the contribution of specific HLA alleles and amino-acid residues to the overall risk of SLE and to risk of specific autoantibodies are far from completely understood. Here, we dissected (a) overall SLE association signals across HLA, (b) HLA-peptide interaction, and (c) residue-autoantibody association. Classical alleles, SNPs, and amino-acid residues of eight HLA genes were imputed across 4,915 SLE cases and 13,513 controls from Eastern Asia. We performed association followed by conditional analysis across HLA, assessing both overall SLE risk and risk of autoantibody production. DR15 alleles HLA-DRB1*15:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB1*06:02 (P = 7.4x10-23, OR = 1.55) formed the most significant haplotype (OR = 2.33). Conditioned protein-residue signals were stronger than allele signals and mapped predominantly to HLA-DRB1 residue 13 (P = 2.2x10-75) and its proxy position 11 (P = 1.1x10-67), followed by HLA-DRB1-37 (P = 4.5x10-24). After conditioning on HLA-DRB1, novel associations at HLA-A-70 (P = 1.4x10-8), HLA-DPB1-35 (P = 9.0x10-16), HLA-DQB1-37 (P = 2.7x10-14), and HLA-B-9 (P = 6.5x10-15) emerged. Together, these seven residues increased the proportion of explained heritability due to HLA to 2.6%. Risk residues for both overall disease and hallmark autoantibodies (i.e., nRNP: DRB1-11, P = 2.0x10-14; DRB1-13, P = 2.9x10-13; DRB1-30, P = 3.9x10-14) localized to the peptide-binding groove of HLA-DRB1. Enrichment for specific amino-acid characteristics in the peptide-binding groove correlated with overall SLE risk and with autoantibody presence. Risk residues were in primarily negatively charged side-chains, in contrast with rheumatoid arthritis. We identified novel SLE signals in HLA Class I loci (HLA-A, HLA-B), and localized primary Class II signals to five residues in HLA-DRB1, HLA-DPB1, and HLA-DQB1. These findings provide insights about the mechanisms by which the risk residues interact with each other to produce autoantibodies and are involved in SLE pathophysiology.

Clinical Characteristics of Patients With Psoriatic Spondylitis Versus Those With Ankylosing Spondylitis: Features at Baseline Before Biologic Therapy.

BACKGROUND: Clinical characteristics and manifestations of psoriatic arthritis (PsA) have been extensively studied in western countries, yet data of Korean patients with PsA are very limited. We aimed to investigate the clinical traits of patients with PsA and dissect the characteristics of those with axial involvement. METHODS: In this observational study, we analyzed clinical data of 109 patients with PsA who were enrolled in the Korean College of Rheumatology Biologics and Targeted Therapy registry between December 2012 and March 2022 at the time point of initiating or switching to a biologic agent. Data from 2,221 patients with ankylosing spondylitis (AS) registered during the same period were also analyzed. We divided patients with PsA into patients with or without axial involvement and then added AS patients with psoriasis (total three subgroups) for comparative analyses. RESULTS: Asymmetric oligoarthritis was the most common clinical manifestation in patients with PsA, followed by symmetric polyarthritis and spondylitis. Our analysis indicated that methotrexate and sulfasalazine were the two most prescribed disease-modifying antirheumatic drugs for patients with PsA before starting biologic therapy. The patients with psoriatic spondylitis had more peripheral joint involvement (P = 0.016), less prior uveitis (P < 0.001), and lower human leukocyte antigen B27 (HLA-B27) positivity (P < 0.001) than the AS patients with psoriasis. Furthermore, syndesmophytes and radiographic sacroiliitis were prevalent among patients with PsA and AS patients with psoriasis who had the HLA-B27 gene. CONCLUSION: Our study shows that the degree of peripheral arthritis is less severe in Korean patients with PsA who require biologics and reestablishes that psoriatic spondylitis is a common and important clinical pattern in Korean patients with PsA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01965132.

Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations. METHODS: We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations. RESULTS: We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10-8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=-0.242) and non-albumin protein (rg=0.238). CONCLUSION: This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

Comparison of three different definitions of low disease activity in patients with systemic lupus erythematosus and their prognostic utilities.

OBJECTIVES: Three definitions of low-level disease activity in patients with SLE have been proposed by different groups. These include minimal disease activity (MDA), low disease activity (LDA) and the lupus low disease activity state (LLDAS). We investigated the performance of these definitions in SLE patients. METHODS: We recruited 299 SLE patients who were followed up annually for 4 consecutive years. We compared the three definitions of low disease activity via longitudinal analysis; we used a generalized, linear-mixed effects model and generalized estimating equations. RESULTS: The LLDAS was significantly associated with a lower SLICC/ACR damage index (ß coefficient=-0.064, 95% CI: -0.129, -0.002, P=0.050), reduced flare (odds ratio = 0.090, 95% CI: 0.034, 0.239, P<0.001), an improved SF-36 physical component score (ß coefficient=0.782, 95% CI: 0.046, 1.519, P=0.037), and an improved SF-36 mental component score (ß coefficient=1.522, 95% CI: 0.496, 2.547, P=0.004). Neither the MDA nor the LDA were associated with these variables. CONCLUSION: The LLDAS definition performs better than the MDA and LDA definitions, showing that LLDAS is associated with less organ damage and flare, and a better quality of life, during follow-up.

A clinical comparison of an endothelin receptor antagonist and phosphodiesterase type 5 inhibitors for treating digital ulcers of systemic sclerosis.

OBJECTIVES: To assess the efficacy of an endothelin receptor antagonist (ERA) and phosphodiesterase type5 inhibitors (PDE5is) for treating SSc-related digital ulcers (DUs). METHODS: This prospective, multicentre, observational cohort study recruited patients with active SSc-related DUs from 13 medical centres in South Korea. The primary outcome was time to cardinal ulcer (CU) healing. A secondary outcome was time to new DU occurrence. Patients were followed up 4, 8, 12 and 24 weeks after treatment initiation. RESULTS: Sixty-three patients were analysed. Their mean age was 49.9 years (s.d. 11.4) and 49 were female. Twenty-eight had limited SSc. Forty-nine patients received ERA, 11 received a PDE5i (9 sildenafil, 1 udenafil and 1 tadalafil) and 3 received other medication. The hazard ratio (HR) for time to CU healing in the ERA group vs the PDE5i group was 0.75 (95% CI 0.35, 1.64; P = 0.47) in an unadjusted model and 0.80 (95% CI 0.36, 1.78; P = 0.59) in a model adjusted for age, sex, use of calcium channel blockers (CCBs), total DU number and initial CU area. The HR for new DU development in the ERA group vs the PDE5i group was 0.39 (95% CI 0.16, 0.93; P = 0.03) in an unadjusted model and 0.32 (95% CI 0.13, 0.81; P = 0.02) in an adjusted model. No patients receiving CCBs developed new DUs at 24 weeks. CONCLUSION: Time to CU healing is comparable for ERA and PDE5i. ERAs are more effective in reducing new DU occurrence than PDE5is. CCBs may be effective as a background medication.

Uric acid as a risk factor for progression to chronic kidney disease in patients with lupus nephritis: results from the KORNET registry.

OBJECTIVES: Little is known regarding the effect of hyperuricaemia on the progression of kidney function in patients with lupus nephritis (LN). Thus, we investigated the effect of uric acid (UA) on the long-term outcome of patients with biopsy-proven LN. METHODS: Data were obtained from KORNET, a prospective longitudinal systemic lupus erythematosus registry in the Republic of Korea. All 137 patients with LN included in this study had undergone a kidney biopsy and were subsequently treated with immunosuppressants. The patients were divided into two groups: UA ≤7 mg/dL and >7 mg/dL; their sociodemographic, clinical, treatment-related data, and outcomes were compared. Cox-proportional regression analyses were performed to identify independent predictors of renal outcome in patients with LN. RESULTS: Among the 137 patients, 37 (27.0%) had UA >7 mg/dL. This higher UA group included fewer women, but more patients with hypertension, proliferative type LN, and a chronicity index >12. The 24-h urinary protein excretion and the creatinine level were higher in this group; haemoglobin, platelet, and albumin levels were lower. During 85.0 months of follow-up, complete remission at 1 year was less frequent in the higher UA group, whereas chronic kidney disease (CKD) and end-stage renal disease were more prevalent. In the Cox proportional hazards regression analysis, UA >7 mg/dL was a signi cant predictor of progression to CKD in patients with LN (hazard ratio=2.437; p=0.020). CONCLUSIONS: Our findings suggest that hyperuricaemia at LN onset is an independent risk factor that predicts the development of CKD in patients with LN.

COVID-19 Vaccination in Patients with Autoimmune Inflammatory Rheumatic Diseases: Clinical Guidance of the Korean College of Rheumatology.

The coronavirus disease 2019 (COVID-19) pandemic has caused more than 100 million infections and 2 million deaths worldwide. In up to 20% of cases, COVID-19 infection can take a severe, life-threatening course. Therefore, preventive measures such as mask-wearing, hand hygiene, and social distancing are important. COVID-19 vaccines that use novel vaccine technology can prevent up to 95% of infections. However, the uncertainty regarding the efficacy and safety of vaccination in patients with autoimmune inflammatory rheumatic disease (AIIRD), who are immunocompromised due to underlying immune dysfunction and concomitant immunosuppressive treatment, warrants clear guidance. A task force of the Korean College of Rheumatology formulated a set of vaccination guidance based on the currently available data and expert consensus. The currently available COVID-19 vaccines are considered to be safe and effective. Every patient with AIIRD should receive one of the available COVID-19 vaccines unless contraindicated for medical reasons such as prior allergy/anaphylaxis to the COVID-19 vaccine or its components. Patients should continue immunosuppressive treatment for their underlying AIIRD, including biological and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). Corticosteroids should be reduced to the lowest dose possible without aggravating the AIIRD. To improve the vaccine response, methotrexate can be withheld for 1-2 weeks after each vaccination, and the timing of rituximab and abatacept infusion should be adjusted if clinically acceptable. Rheumatologists should play a leading role in educating and vaccinating patients with AIIRD.

Erratum: Correction of Authors' Name Spelling in the Article "COVID-19 Vaccination in Patients with Autoimmune Inflammatory Rheumatic Diseases: Clinical Guidance of the Korean College of Rheumatology".

This corrects the article on p. e95 in vol. 36, PMID: 33783147.

Patient Perspectives and Preferences Regarding Gout and Gout Management: Impact on Adherence.

BACKGROUND: Patient-centered management is becoming increasingly important in gout, but there are limited studies exploring patients' perspectives and preferences. We aimed to investigate patients' perspectives and preferences regarding gout and gout management, and their impacts on adherence to urate lowering therapy (ULT). METHODS: A paper-based survey was performed in patients with gout seen at the rheumatology outpatient clinics of 16 tertiary hospitals. The survey included questions regarding demographics, comorbidities, gout attacks, current treatment and adherence, and patients' perspectives and preferences regarding gout and gout management. Multivariate regression analysis was performed to determine the factors associated with ULT adherence. RESULTS: Of 809 surveyed patients with gout, 755 (94.5%) were using ULT. Among those using ULT, 89.1% had ≥ 80% adherence to ULT. Majority of the patients knew management strategies to some extent (94.8%), perceived gout as a life-long disease (91.2%), and were making efforts toward practicing at least one lifestyle modification (89.2%). Most patients (71.9%) obtained information about gout management during their clinic visits. Approximately half of the patients (53.6%) preferred managing their disease with both ULT and lifestyle modification, 28.4% preferred ULT only, and 17.4% preferred lifestyle modification only. Adherence was better in patients with older age (odds ratio [OR], 1.03), those with better knowledge of gout management strategies (OR, 3.56), and those who had preference for ULT (OR, 2.07). CONCLUSION: Patients' perspectives and management preferences had high impacts on adherence to ULT in gout. Consideration of patients' perspectives and preferences is important for achieving the desired clinical outcome in gout.

Genome-wide association study in a Korean population identifies six novel susceptibility loci for rheumatoid arthritis.

OBJECTIVE: Genome-wide association studies (GWAS) in rheumatoid arthritis (RA) have discovered over 100 RA loci, explaining patient-relevant RA pathogenesis but showing a large fraction of missing heritability. As a continuous effort, we conducted GWAS in a large Korean RA case-control population. METHODS: We newly generated genome-wide variant data in two independent Korean cohorts comprising 4068 RA cases and 36 487 controls, followed by a whole-genome imputation and a meta-analysis of the disease association results in the two cohorts. By integrating publicly available omics data with the GWAS results, a series of bioinformatic analyses were conducted to prioritise the RA-risk genes in RA loci and to dissect biological mechanisms underlying disease associations. RESULTS: We identified six new RA-risk loci (SLAMF6, CXCL13, SWAP70, NFKBIA, ZFP36L1 and LINC00158) with pmeta<5×10-8 and consistent disease effect sizes in the two cohorts. A total of 122 genes were prioritised from the 6 novel and 13 replicated RA loci based on physical distance, regulatory variants and chromatin interaction. Bioinformatics analyses highlighted potentially RA-relevant tissues (including immune tissues, lung and small intestine) with tissue-specific expression of RA-associated genes and suggested the immune-related gene sets (such as CD40 pathway, IL-21-mediated pathway and citrullination) and the risk-allele sharing with other diseases. CONCLUSION: This study identified six new RA-associated loci that contributed to better understanding of the genetic aetiology and biology in RA.

Altered distribution and enhanced osteoclastogenesis of mucosal-associated invariant T cells in gouty arthritis.

OBJECTIVE: This study was designed to investigate the role of mucosal-associated invariant T (MAIT) cells in gouty arthritis (GA) and their effects on osteoclastogenesis. METHODS: Patients with GA (n = 61), subjects with hyperuricaemia (n = 11) and healthy controls (n = 30) were enrolled in this study. MAIT cells, cytokines, CD69, programmed death-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) levels were measured by flow cytometry. In vitro osteoclastogenesis experiments were performed using peripheral blood mononuclear cells in the presence of M-CSF and RANK ligand. RESULTS: Circulating MAIT cell levels were significantly reduced in GA patients. However, their capacities for IFN-γ, IL-17 and TNF-α production were preserved. Expression levels of CD69, PD-1 and LAG-3 in MAIT cells were found to be elevated in GA patients. In particular, CD69 expression in circulating MAIT cells was increased by stimulation with MSU crystals, suggesting that deposition of MSU crystals might contribute to MAIT cell activation. Interestingly, MAIT cells were found to be accumulated in synovial fluid and infiltrated into gouty tophus tissues within joints. Furthermore, activated MAIT cells secreted pro-resorptive cytokines (i.e. IL-6, IL-17 and TNF-α) and facilitated osteoclastogenesis. CONCLUSION: This study demonstrates that circulating MAIT cells are activated and numerically deficient in GA patients. In addition, MAIT cells have the potential to migrate to inflamed tissues and induce osteoclastogenesis. These findings provide an important role of MAIT cells in the pathogenesis of inflammation and bone destruction in GA patients.

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.

Anti-Sm Antibody, Damage Index, and Corticosteroid Use Are Associated with Cardiac Involvement in Systemic Lupus Erythematosus: Data from a Prospective Registry Study.

BACKGROUND: Disease-specific factors that predispose patients to diverse cardiac diseases in systemic lupus erythematosus (SLE) have been established. The aim of this study was to identify risk factors for cardiac involvement in patients with SLE drawn from the Korean Lupus Network (KORNET) registry. METHODS: A total of 437 patients with SLE recruited from the KORNET registry were included in the analysis. The Cox proportional hazard model was used to identify risk factors for the development of cardiac involvement during the follow-up period. The hazard ratios for risk factors of cardiac involvement were assessed using Kaplan-Meier curves and log-rank test. RESULTS: Of 437 patients with SLE, 12 patients (2.7%) developed new cardiac involvement during a median follow-up period of 47.6 months. Frequencies in men and in patients with anti-Sm antibody, anti-Ro antibody, and at least one Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI) score in patients with cardiac involvement were higher, compared to those without cardiac involvement (P < 0.001, P = 0.026, P = 0.015, and P < 0.001, respectively). Men gender, older age, anti-Sm antibody, SDI, and corticosteroid dosage were potent predictors for cardiac involvement in patients with SLE in the determination of risk factors for cardiac involvement. Men, anti-Sm antibody positivity, and SDI ≥ 1 increased incidence rates of cardiac involvement for (P < 0.001, P = 0.036, and P < 0.001, respectively). CONCLUSION: The results of this study reveal that SLE-related factors such as anti-Sm antibody, SDI, and corticosteroid dosage at baseline are risk factors for cardiac involvement in SLE.

Efficacy and Safety of Rituximab in Korean Patients with Refractory Inflammatory Myopathies.

BACKGROUND: Rituximab (RTX), a monoclonal antibody that selectively binds to CD20+ B cells, showed favorable outcomes in patients with idiopathic inflammatory myopathies (IIM) in small case series, but the evidence is still not enough. Our goal was to determine the efficacy and safety of RTX for Korean patients with refractory IIM. METHODS: We retrospectively analyzed the medical records of 16 patients with refractory IIM treated with RTX in seven tertiary rheumatology clinics in the Korea. The efficacy of RTX was evaluated with the improvement of serum creatine phosphokinase (CPK) level and physician's global assessment (PGA), and daily corticosteroid dose reduction. A > 25% decrease in CPK level, corticosteroid dose, or PGA was considered significant. A complete response (CR) was designated by meeting three efficacy criteria and a partial response (PR) by only two criteria. RESULTS: Sixteen patients with IIM were evaluated (13 female; median age, 51.8 years). All patients had received at least one conventional immunosuppressive agent (median, 3.6 [2.0-5.0]) and concomitant corticosteroids. The median CPK level and median dose of prednisolone was 421.0 units/L and 20.0 mg/day respectively. Eleven patients were treated with intravenous immunoglobulin. Seven patients received 2,000 mg of RTX and the others received lower dose. Twenty-four weeks after RTX treatment, 11 patients achieved a > 25% reduction in corticosteroid dose and CPK levels, and nine showed improved PGA. The overall response rate was 68.8% (11 patients). At the end of follow-up (median 24 weeks), 12 (75.0%) patients responded overall: four (25.0%) and eight (50.0%) patients achieved CR and PR, respectively. Baseline muscle enzyme levels were higher in responders than non-responders, but disease duration, RTX dose, ESR and serum CRP were not significantly different between the two groups. The rate of adverse event was 25.4/1,000 person-years. CONCLUSION: RTX could be an effective and relatively safe therapeutic option in patients with refractory IIM.