SLIRP promotes autoimmune diseases by amplifying antiviral signaling via positive feedback regulation.

The abnormal innate immune response is a prominent feature underlying autoimmune diseases. One emerging factor that can trigger dysregulated immune activation is cytosolic mitochondrial double-stranded RNAs (mt-dsRNAs). However, the mechanism by which mt-dsRNAs stimulate immune responses remains poorly understood. Here, we discover SRA stem-loop interacting RNA binding protein (SLIRP) as a key amplifier of mt-dsRNA-triggered antiviral signals. In autoimmune diseases, SLIRP is commonly upregulated, and targeted knockdown of SLIRP dampens the interferon response. We find that the activation of melanoma differentiation-associated gene 5 (MDA5) by exogenous dsRNAs upregulates SLIRP, which then stabilizes mt-dsRNAs and promotes their cytosolic release to activate MDA5 further, augmenting the interferon response. Furthermore, the downregulation of SLIRP partially rescues the abnormal interferon-stimulated gene expression in autoimmune patients' primary cells and makes cells vulnerable to certain viral infections. Our study unveils SLIRP as a pivotal mediator of interferon response through positive feedback amplification of antiviral signaling.

All-cause and cause-specific mortality in patients with Behçet disease versus the general population.

BACKGROUND: The comparative risk of cause-specific mortality in patients with Behçet disease (BD) vs. the general population is not known. OBJECTIVES: To compare the risk of all-cause and cause-specific mortality in patients with BD vs. the general population. METHODS: Using data from the Korea National Health Insurance Service database for the period 2002-20, we conducted a cohort study comparing patients with BD with the general population, matched according to age and sex (1 : 4 ratio). We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality. Subgroup analyses by age and sex were done. RESULTS: We included 24 669 patients with BD and 98 676 age- and sex-matched controls [mean (SD) age 40.5 (12.9) years; 34% male]. During a mean follow-up of 11.9 years, the incidence rate (IR) of death per 100 person-years was 0.36 in patients with BD and 0.29 in controls [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.20-1.38]. The risk of mortality was highest in the first year after BD diagnosis (HR 2.66, 95% CI 2.09-3.40). Patients with BD died more often in this period as a result of malignancy (HR 1.96, 95% CI 1.30-2.98); cardiovascular (HR 2.68, 95% CI 1.45-4.97), gastrointestinal (HR 3.50, 95% CI 1.35-9.07) and respiratory disease (HR 5.00, 95% CI 1.34-18.62); and infection (HR 3.33, 95% CI 1.02-10.92). Mortality as a result of neurological (HR 1.58, 95% CI 1.06-2.35) or genitourinary disease (HR 2.20, 95% CI 1.43-3.37) was also more common in patients with BD during the overall follow-up. Subgroup analyses showed consistent results. The risk of cardiovascular mortality vs. the general population was higher in younger patients (P = 0.006) and the risk of gastrointestinal mortality was increased in women vs. men (P = 0.04). CONCLUSIONS: This population-based cohort study revealed that the first year after diagnosis is the highest risk period for excess mortality in people with BD. The mortality burden in BD derives from a wide spectrum of organ involvement and should serve as a warning to clinicians about the systemic nature of the disease.

Behçet disease (BD) is a multisystem vasculitis (inflammation of the blood vessels) of unknown origin that commonly results in oral and genital ulcers, uveitis (eye inflammation) and skin lesions. BD is most prevalent in people from the Mediterranean to East Asia, affecting 0.4% of people in this area. Most lesions go away with time, but more severe forms that involve the cardiovascular and neurological systems can lead to death. It is estimated that people with BD have 1.4 times the risk of dying than the general population. Using large insurance databases in Korea, we investigated the risk of death in people with BD versus age- and sex-matched controls (i.e. people without the disease) from the general population. We found that patients with BD had a 28% greater risk of death than controls over 11.9 years of follow-up, with the highest risk being in first year after diagnosis. Top causes of death in people with BD included cancer, and cardiovascular, gastrointestinal, neurological, genitourinary, respiratory and infectious disease. Further analyses of the data showed that the risk of death in BD is affected by age and sex. In particular, younger patients were more susceptible to death as a result of cardiovascular disease and women were more susceptible to dying of gastrointestinal disease. Our study suggests that there could be an increased risk of death within the first year of being diagnosed with BD and highlights how BD is a systemic disease (i.e. the involvement of any internal organ system could lead to an increase in mortality). Finally, there were unique patterns of cause-specific deaths across subgroups of people with BD.

Recurrent focal myofasciitis of Behçet syndrome mimics infectious myofasciitis: a case report.

Behçet syndrome (BS) is a chronic inflammatory disease with multiorgan manifestations. However, muscular involvement in BS has rarely been reported. Herein, we report the case of a 30-year-old male with BS who had recurring pain and swelling of the lower legs. The patient was administered antibiotics on several occasions as the condition was misinterpreted to be infectious myositis. Magnetic resonance imaging revealed myofascial involvement with focal necrotic lesions, and muscle biopsy revealed acute suppurative myositis with perivascular infiltration of polymorphonuclear leukocytes. His symptoms improved after treatment with corticosteroids. Azathioprine and colchicine therapy was beneficial for preventing further relapse after short-term corticosteroid treatment. Therefore, BS should be considered in the differential diagnosis of focal suppurative myofasciitis.

Comparative risk of infections between JAK inhibitors versus TNF inhibitors among patients with rheumatoid arthritis: a cohort study.

BACKGROUND: To compare infectious risk between JAK inhibitors (JAKis) versus TNF inhibitors (TNFis) among rheumatoid arthritis (RA) patients in Korea. METHODS: Using 2009-2019 Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating a JAKi or TNFi. The primary outcomes were herpes zoster (HZ), serious bacterial (SBI), and opportunistic infections (OI). Propensity-score fine-stratification (PSS) and weighting were applied to adjust for > 70 baseline covariates. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing JAKi versus TNFi users. RESULTS: We included 2963 JAKi initiators PSS-weighted on 5169 TNFi initiators. During a follow-up of 1.16 years, the most frequent type of infections was HZ with incidence rate (IR) per 100 person-years of 11.54 and 4.88 in JAKi and TNFi users, respectively. The IR of SBI was 1.39 and 1.32, respectively. The OI was rare with a majority being tuberculosis and showed an IR of 0.11 and 0.49 in JAKi and TNFi users, respectively. The PSS-weighted HR (95% CI) for individual types of infections was 2.37 (2.00-2.80) for HZ, 1.04 (0.71-1.52) for SBI, and 0.25 (0.09-0.73) for OI. CONCLUSIONS: This population-based cohort study on RA patients treated with JAKi or TNFi in Korea showed an exceptionally high IR of HZ in both treatment groups compared to that from Western countries, with an approximately doubled risk associated with JAKi versus TNFi use. The risk of SBI was comparable, but the risk of OI, particularly tuberculosis, was less among JAKi than TNFi initiators.

Anterior and Lateral Femoroacetabular Excursion Angles Are Helpful for Assessing Femoroacetabular Impingement Syndrome: A Cross-Sectional Cohort Study.

PURPOSE: To develop a radiographic measurement to evaluate the femoroacetabular space using 3-dimensional (3D) hip models in asymptomatic hips, and to evaluate the reliability and validity of the femoroacetabular excursion angle (FAEA) in symptomatic patients. METHODS: From January 2020 to December 2020, we recruited patients with healthy hips to establish 3D models. Through the simulation of 14 activities of daily living (ADLs), anterior and lateral impingement-free FAEAs were measured. Another cross-sectional cohort was formed from consecutive symptomatic subjects with impingement signs during the same period. In the validation cohort, anterior and lateral FAEAs were assessed on modified Dunn's and anteroposterior views of the hip, respectively. We evaluated the reliability and clinical implications of the FAEAs. RESULTS: In the discovery cohort (n = 33), hips with collisions tended to have smaller computed tomography-based FAEAs than collision-free hips, although alpha and lateral center-edge (CE) angles were comparable. Additionally, hips with a lower quartile of FAEAs had a significantly higher number of ADLs with collisions. In the validation cohort (n = 411), the FAEA measurement was highly reliable (kappa statistics >0.95 for both interobserver and intraobserver reliabilities). The femoroacetabular impingement syndrome (FAIS) group (n = 165) showed significantly smaller anterior and lateral FAEAs than the non-FAIS group (all P < .001, Cramer V = .420). The optimal cut-off values for anterior and lateral FAEAs were 32.6° and 48.9°, respectively. In univariate regression, anterior (odds ratio [OR] = 0.91; 95% confidence interval [CI] = 0.89-0.94) and lateral (OR = 0.91; 95% CI = 0.89-0.93) FAEAs were significantly associated with FAIS. Moreover, in multivariate regression adjusted for alpha and lateral CE angles, anterior FAEA remained a significant predictor (OR = 0.96; 95% CI = 0.93-0.99), and small FAEA was an independent risk factor for FAIS (OR = 1.99; 95% CI = 1.06-3.71) for any small FAEA (OR = 2.88; 95% CI = 1.32-6.31) for both small FAEAs. CONCLUSION: The FAEA is a valid measurement for FAIS with high reliability. Small FAEA was an independent risk factor for FAIS in the multivariate regression model, even after adjusting for alpha and lateral CE angles. LEVEL OF EVIDENCE: Level III, diagnostic study.

Quantitative interstitial lung disease scores in idiopathic inflammatory myopathies: longitudinal changes and clinical implications.

OBJECTIVES: To investigate computer-aided quantitative scores from high-resolution CT (HRCT) images and determine their longitudinal changes and clinical significance in patients with idiopathic inflammatory myopathies (IIMs)-related interstitial lung disease (IIMs-ILD). METHODS: The clinical data and HRCT images of 80 patients with IIMs who underwent serial HRCT scans at least twice were retrospectively analysed. Quantitative ILD (QILD) scores (%) were calculated as the sum of the extent of lung fibrosis, ground-glass opacity, and honeycombing. The individual time-estimated ΔQILD between two consecutive scans was derived using a linear approximation of yearly changes. RESULTS: The baseline median QILD (interquartile range) scores in the whole lung were 28.1% (19.1-43.8). The QILD was significantly correlated with forced vital capacity (r = -0.349, P = 0.002) and diffusing capacity for carbon monoxide (r = -0.381, P = 0.001). For ΔQILD between the first two scans, according to the visual ILD subtype, QILD aggravation was more frequent in patients with usual interstitial pneumonia (UIP) than non-UIP (80.0% vs 44.4%, P = 0.013). Multivariable logistic regression analyses identified UIP was significantly related to radiographic ILD progression (ΔQILD >2%, P = 0.015). Patients with higher baseline QILD scores (>28.1%) had a higher risk of lung transplantation or death (P = 0.015). In the analysis of three serial HRCT scans (n = 41), dynamic ΔQILD with four distinct patterns (improving, worsening, convex and concave) was observed. CONCLUSION: QILD changes in IIMs-ILD were dynamic, and baseline UIP patterns seemed to be related to a longitudinal progression in QILD. These may be potential imaging biomarkers for lung function, changes in ILD severity and prognosis in IIMs-ILD.

Comparative risk of blindness and vision-threatening ocular comorbidities in patients with Behçet's disease versus the general population.

OBJECTIVE: To compare the risk of blindness and vision-threatening ocular comorbidities in patients with Behçet's disease (BD) vs the general population. METHODS: Using 2002-2017 Korea National Health Insurance Service database, we did a population-based cohort study comparing newly diagnosed BD patients and age- and sex-matched non-BD controls at a 1:5 ratio. The primary outcome was blindness, defined as a best-corrected visual acuity of ≤20/500 in the better-seeing eye. Secondary outcomes were vision-threatening ocular comorbidities (cataract, glaucoma and retinal disorders) that require surgical interventions and incident uveitis. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. We performed subgroup analyses by sex and BD diagnosis age. RESULTS: We included 31 228 BD patients and 156 140 controls. During a follow-up of 9.39 years, the incidence rate of blindness per 1000 person-years was 0.24 in BD and 0.02 in controls with an HR of 10.73 (95% CI 7.10, 16.22). The HR for secondary outcomes was 2.06 (95% CI 1.98, 2.15) for cataract surgery, 5.43 (4.57, 6.45) for glaucoma surgery and 2.71 (2.39, 3.07) for retinal surgery. The HR of incident uveitis was 6.19 (95% CI 5.83, 6.58). Males suffered a disproportionately higher risk of blindness than females due to greater severity rather than a lower incidence of uveitis. The risk of uveitis and blindness decreased as BD diagnosis age increased. CONCLUSIONS: In this large population-based cohort study, BD patients compared with the general population have a 10.73-fold risk of blindness in 10 years and also a substantially higher risk of diverse ocular comorbidities that pose potential threats to vision.

Association between sarcopenia defined as low lean mass by dual-energy X-ray absorptiometry and comorbidities of rheumatoid arthritis: Results of a nationwide cross-sectional health examination.

BACKGROUND: To examine the association between sarcopenia and comorbidities among patients with rheumatoid arthritis (RA). METHODS: We selected RA patients and age- and sex-matched non-RA controls at a 1:5 ratio from 2008-2011 Korea National Health and Nutrition Examination Survey database. Sarcopenia was defined by appendicular skeletal muscle mass. After investigating associations between sarcopenia and individual comorbidities among RA patients, we performed a stratified analysis comparing three subgroups (RA/sarcopenia, RA/non-sarcopenia, non-RA/sarcopenia) versus a non-RA/non-sarcopenia subgroup to evaluate interactive as well as independent effects of sarcopenia and RA on comorbidities. Health-related behaviors (exercise, smoking, drinking, and diet) were also examined. The weighted logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for age, sex, and income. RESULTS: We included 400 RA patients and 2,000 non-RA controls (mean age 57.4 years, 79.6% female). Sarcopenia was observed in 20.5% of RA and 19.3% of non-RA group. Among RA patients, sarcopenia was associated with obesity (OR 2.61, 95% CI 1.42-4.83), dyslipidemia (3.09, 1.37-6.99), diabetes (2.07, 0.99-4.33), chronic obstructive pulmonary disease (18.77, 2.40-146.55), and hepatitis B ever-infection (8.69, 1.15-65.58). Among three stratified subgroups, only a RA/sarcopenia subgroup was associated with such comorbidities, cardiovascular diseases, and depression compared to a non-RA/non-sarcopenia subgroup. Health-related behaviors were comparable between patients with and without sarcopenia. CONCLUSIONS: In this nation-wide cross-sectional study, a wide spectrum of comorbidities were preferentially found among RA patients with sarcopenia than without, suggesting that sarcopenia is significantly associated with RA-related comorbidities. Particular attention should be paid to comorbidities of sarcopenic RA patients.

Cardiovascular safety associated with febuxostat versus allopurinol among patients with gout: Update with accumulated use of febuxostat.

BACKGROUND: To re-evaluate comparative cardiovascular (CV) safety of febuxostat versus allopurinol among patients with gout following recent accumulated use of febuxostat. METHODS: Using 2011-2019 Korea National Health Insurance database, we conducted a cohort study comparing gout patients initiating febuxostat versus allopurinol, 1:1 matched on a propensity-score (PS) for >60 covariates. The primary outcome was a composite endpoint of myocardial infarction, coronary revascularization, and stroke. Secondary outcomes were individual components of the primary outcome, hospitalized heart failure, and all-cause mortality. Subgroup analyses were done for those at high CV risk, long-term users (follow-up >3 years), and those without chronic kidney disease. We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We included 160,930 PS-matched pairs of febuxostat and allopurinol users (mean age 59.3 years, 79.6% male). Incidence rates of the primary outcome were 2.06 and 2.27 per 100 person-years for febuxostat and allopurinol users, respectively, with a HR [95% CI] of 1.03 [0.95-1.12] comparing febuxostat versus allopurinol initiators. We also observed similar risks for secondary outcomes, except for reduced all-cause mortality among febuxostat users (HR [95% CI] of 0.84 [0.78-0.91]). Subgroup analyses also showed non-inferior CV safety of febuxostat. CONCLUSION: In this population-based cohort study including the largest number of febuxostat users to date, we found non-inferior CV safety of febuxostat versus allopurinol. There was a 16% reduction in all-cause mortality among febuxostat users.

Infectious risk of add-on leflunomide or tacrolimus versus TNF inhibitors among patients with rheumatoid arthritis receiving background methotrexate: A population-based cohort study.

BACKGROUND: To compare infectious risk between leflunomide versus TNF inhibitors (TNFi), and between tacrolimus versus TNFi among rheumatoid arthritis (RA) patients receiving methotrexate (MTX). METHODS: Using Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating TNFi, leflunomide, or tacrolimus. The primary outcome was any serious infections defined as a composite endpoint of serious bacterial, opportunistic, and herpes zoster infections. Secondary outcomes were individual components of the primary outcome. Propensity-score fine-stratification (PSS) and weighting were applied to adjust for confounding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing leflunomide versus TNFi, and tacrolimus versus TNFi. RESULTS: Among 72,516 RA patients receiving MTX, we identified 3,336 TNFi initiators, 11,122 leflunomide initiators, and 5,136 tacrolimus initiators. Two study cohorts were 10,992 leflunomide initiators PSS-weighted on 1,623 TNFi initiators and 5,126 tacrolimus initiators PSS-weighted on 2,521 TNFi initiators. The incidence rate per 100 person-years of herpes zoster infection (3.70-4.27) was beyond 3-times that of serious bacterial infection (1.12-1.36), but opportunistic infection was relatively rare (0.11-0.23). The PSS-weighted HR [95% CI] for any serious infection was 1.03 [0.89-1.22] comparing leflunomide versus TNFi, and 0.91 [0.77-1.08] comparing tacrolimus versus TNFi. Analyses on the secondary outcomes showed consistent results. CONCLUSION: In this nation-wide cohort study, we did not find a significant difference in the risk of serious infections (i.e., serious bacterial, opportunistic, and herpes zoster infections) between leflunomide versus TNFi, and between tacrolimus versus TNFi among RA patients receiving background MTX.

Extracellular pyruvate kinase M2 promotes osteoclastogenesis and is associated with radiographic progression in early rheumatoid arthritis.

Extracellular PKM2 (exPKM2) levels have been reported to be increased in several cancers and inflammatory diseases, including rheumatoid arthritis (RA). This study aimed to investigate the association of circulating exPKM2 levels with radiographic progression in RA patients and the effect of exPKM2 on osteoclastogenesis. Plasma and synovial fluid exPKM2 levels were significantly elevated in RA patients. Plasma exPKM2 levels were correlated with RA disease activity and were an independent predictor for radiographic progression in RA patients with a disease duration of ≤ 12 months. CD14+ monocytes but not RA fibroblast-like synoviocytes secreted PKM2 upon stimulation with inflammatory mediators. Recombinant PKM2 (rPKM2) increased the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinuclear cells and resorption pit in osteoclast precursors, dose-dependently, even in the absence of receptor activator of nuclear factor-kappa B ligand (RANKL). rPKM2 treatment upregulated the expression of dendrocyte-expressed seven transmembrane protein (DC-STAMP) and MMP-9 via the ERK pathway. Although rPKM2 did not directly bind to RAW264.7 cells, extracellular application of pyruvate, the end-product of PKM2, showed effects similar to those seen in rPKM2-induced osteoclastogenesis. These results suggest that exPKM2 is a potential regulator of RA-related joint damage and a novel biomarker for subsequent radiographic progression in patients with early-stage RA.

All-cause and cause-specific mortality of patients with rheumatoid arthritis in Korea: A nation-wide population-based study.

OBJECTIVE: To compare all-cause and cause-specific mortality between rheumatoid arthritis (RA) patients versus the general population of Korea. METHODS: A nationally representative RA population aged≥40 years was identified from Korea National Health Insurance Service (KNHIS) database. We estimated age- and sex-adjusted all-cause and cause-specific standardized mortality ratios (SMRs) with 95% confidence intervals (CIs), comparing RA patients to the general population. Subgroup analyses were done by sex, age group, calendar year, and biologics use. RESULTS: We identified 79,352 RA patients with 6404 deaths during 2011-2016. The all-cause SMR [95% CI] of RA patients compared to the general population was 1.53 [1.49-1.56]. The top five causes of death were cancer (19.5%), respiratory disease (19.1%), cardiovascular disease (18.8%), systemic rheumatic diseases (9.5%, 9.1% due to RA), and infection (6.1%). Cause-specific SMRs [95% CI] were 0.95 [0.90-1.01] for cancer, 3.34 [3.15-3.52] for respiratory disease, 1.26 [1.18-1.33] for cardiovascular disease, 3.41 [3.08-3.75] for infection, and 4.88 [3.10-6.65] for non-RA systemic rheumatic disease. The SMR of RA population was slightly higher among men than women, and highest in their 60s and 70s. The yearly SMR increased from 1.10 [1.01-1.18] in 2011 to 1.85 [1.75-1.95] in 2016 due to population aging and comorbidity accumulation. Users of biologics showed a higher SMR than non-users (1.82 [1.69-1.96] vs. 1.50 [1.46-1.54]), due to higher RA activity, and more comorbidities despite a younger mean age. CONCLUSION: RA patients in Korea experienced 1.5-fold increase in all-cause mortality compared to the general population. Except for cancer, the top five causes of death were associated with excess mortality among RA patients. RA-associated mortality was largely determined by age, RA activity, and comorbidity status.

Fucoxanthin Suppresses Osteoclastogenesis via Modulation of MAP Kinase and Nrf2 Signaling.

Fucoxanthin (FX), a natural carotenoid present in edible brown seaweed, is known for its therapeutic potential in various diseases, including bone disease. However, its underlying regulatory mechanisms in osteoclastogenesis remain unclear. In this study, we investigated the effect of FX on osteoclast differentiation and its regulatory signaling pathway. In vitro studies were performed using osteoclast-like RAW264.7 cells stimulated with the soluble receptor activator of nuclear factor-κB ligand or tumor necrosis factor-alpha/interleukin-6. FX treatment significantly inhibited osteoclast differentiation and bone resorption ability, and downregulated the expression of osteoclast-specific markers such as nuclear factor of activated T cells 1, dendritic cell-specific seven transmembrane protein, and matrix metallopeptidase 9. Intracellular signaling pathway analysis revealed that FX specifically decreased the activation of the extracellular signal-regulated kinase and p38 kinase, and increased the nuclear translocation of phosphonuclear factor erythroid 2-related factor 2 (Nrf2). Our results suggest that FX regulates the expression of mitogen-activated protein kinases and Nrf2. Therefore, FX is a potential therapeutic agent for osteoclast-related skeletal disorders including osteoporosis and rheumatoid arthritis.

Subclinical sacroiliitis detected by abdominopelvic computed tomography in Korean patients with Crohn's disease.

BACKGROUND/AIMS: Sacroiliitis is a frequent extraintestinal manifestation of inflammatory bowel diseases (IBDs). This study aimed to assess the prevalence of sacroiliitis using a validated screening tool based on abdominopelvic computed tomography (APCT) in Korean patients with Crohn's disease (CD) and examine potential associations between clinical characteristics and sacroiliitis. METHODS: One hundred five patients with CD undergoing APCT for any indication at an IBD clinic were matched 1:1 for age and sex with 105 controls without underlying chronic illnesses. Using a validated APCT screening tool that defines sacroiliitis as either ankylosis or a total erosion score (TES) ≥ 3, all computed tomography scans were assessed by two independent, blinded radiologists. We compared the prevalence of sacroiliitis between CD patients and controls and clinical characteristics between CD patients with and without sacroiliitis. RESULTS: The prevalence of sacroiliitis was significantly higher in CD patients than in controls (13.3% vs. 4.8%, p = 0.030). All subjects with sacroiliitis had a TES ≥ 3, but no ankylosis. The assessment of sacroiliitis in APCT showed excellent interreader reliability (Cohen's kappa = 0.933 for presence of sacroiliitis). Sacroiliitis in CD patients was bilateral and asymptomatic. There were no significant associations between sacroiliitis and any demographic data or clinical characteristics in these patients. CONCLUSION: The prevalence of APCT-detected sacroiliitis in CD patients was higher than that in controls, but the condition was asymptomatic. The clinical significance of asymptomatic sacroiliitis in Korean CD patients remains unclear.

Clinical usefulness of anti-muscarinic type 3 receptor autoantibodies in patients with primary Sjögren's syndrome.

OBJECTIVES: To elucidate the clinical values of anti-M3R in Sjögren's syndrome (SS) in the largest cohort for an anti-M3R study. METHODS: The plasma of 361 subjects (156 primary SS [pSS], 62 non-SS-sicca [SICCA], 40 systemic lupus erythematosus [SLE], 50 rheumatoid arthritis [RA], and 53 healthy controls [HC]) was screened using our modified On-Cell-Western assay. Saliva from pSS (n=37) compared to SICCA (n=26) was also analysed. The sensitivity and specificity of anti-M3R and its association with comprehensive clinical and laboratory features were determined. RESULTS: Plasma-anti-M3R was higher in pSS compared to other groups, differentiating pSS with good-to-excellent diagnostic power with a specificity of 85% and a sensitivity between 75% and 98%. pSS plasma-anti-M3R was positively correlated with ocular staining scores, anti-Ro/SSA, IgG, ß2-microglobulin, ESR, and ESSDAI. It was negatively correlated with WBC, C4, and salivary scintigraphic indices. Saliva-anti-M3R was 3.59 times higher in pSS than in SICCA. Interestingly, the agreement between the 2002 American European Consensus Group criteria and the criteria substituted with plasma-anti-M3R for the lip biopsy reached 92%, with a significant kappa of 0.824. CONCLUSIONS: Anti-M3R enhances sensitivity and specificity for SS diagnosis, correlating with ocular dryness and glandular hypofunction, and the haematological/biological domains of the ESSDAI. Our findings also highlight the clinical significance of anti-M3R in SS diagnosis, especially where clinical assessments, such as lip biopsy, sialometry, or ocular evaluation, by multi-disciplinary specialists are limited.

Diffuse large B-cell lymphoma involving the left sternoclavicular joint mimicking rheumatoid arthritis flare: a case-based review.

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting primarily joints and an increased risk of developing malignant lymphomas in RA has been well reported. However, primary lymphoma in a joint in RA patient is rare. We report the case of a 65-year-old man with RA suffering from pain and swelling of left sternoclavicular (SC) joint, which was not relieved by adding low-dose glucocorticoid. Magnetic resonance imaging (MRI) showed a para-osseous soft tissue swelling around the SC joint and a fracture of proximal clavicle. Histology of the soft tissue demonstrated diffuse large B-cell lymphoma and the patient subsequently underwent R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy. He was successfully treated with six cycles of R-CHOP chemotherapy, with discontinuation of MTX, resulting in a complete response. We performed a literature review and identified nine cases of lymphoma which involved joints in patients with rheumatoid arthritis. This is the first described case of a primary large B-cell lymphoma involving the unilateral SC joint in a patient with RA, which was initially confused with aggravation of RA. Therefore, malignant lymphoma should be considered in the differential diagnosis when a RA patient develops monoarthritis with spontaneous fracture, even without B symptoms.

Impact of Tumor Necrosis Factor Inhibitor Versus Nonsteroidal Antiinflammatory Drug Treatment on Radiographic Progression in Early Ankylosing Spondylitis: Its Relationship to Inflammation Control During Treatment.

OBJECTIVE: To investigate the impact of tumor necrosis factor inhibitor (TNFi) treatment and inflammation control on radiographic progression in early ankylosing spondylitis (AS) over 4 years. METHODS: We included a total of 215 patients with early AS (symptom duration <10 years) treated with TNFi (the TNFi group; n = 135) or with nonsteroidal antiinflammatory drugs (NSAIDs) (the control group; n = 80). Two blinded readers assessed radiographic progression using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Inflammation control was inferred from C-reactive protein (CRP) levels time-averaged between 2 radiologic assessments. Linear mixed modeling was used to estimate mSASSS changes over radiographic intervals as well as the impact of clinical factors on outcomes. RESULTS: The TNFi group had longer disease duration, a higher baseline CRP level, and a higher Bath Ankylosing Spondylitis Disease Activity Index than did controls. The time-averaged CRP level over radiographic intervals was lower with TNFi treatment than with NSAID treatment (mean ± SD 0.27 ± 0.30 mg/dl versus 0.61 ± 0.68 mg/dl; P < 0.001). Overall, mean ± SD mSASSS change over the 2-year interval was 1.30 ± 2.97 units. In the multivariable model adjusted for age, smoking status, baseline CRP level, and the presence of syndesmophytes at baseline, the TNFi group showed less mSASSS change over the 2-year interval (ß = -0.90 [95% confidence interval {95% CI} -1.51, -0.29]). However, when a time-averaged CRP level was additionally included, it significantly influenced the mSASSS change (ß = 1.02 [95% CI 0.32, 1.71]), decreasing the estimated group difference (ß = -0.52 [95% CI -1.17, 0.14]). NSAID indices of both groups were not associated with either time-averaged CRP levels or mSASSS changes. CONCLUSION: Effective suppression of inflammation by TNFi treatment decreases radiographic progression in early AS.

PIM-1 kinase is a novel regulator of proinflammatory cytokine-mediated responses in rheumatoid arthritis fibroblast-like synoviocytes.

Objectives: This study investigated the expression of proviral-integration site for Moloney murine leukaemia virus (PIM) -1 kinase in RA synovium and RA fibroblast-like synoviocytes (FLSs) along with its impact on RA-FLS aggressiveness. Methods: The expression of PIM kinases was assessed in synovial tissues by immunohistochemistry and double IF. After PIM-1 inhibition using either small-interfering RNA or the chemical inhibitor AZD1208, we performed proliferation and migration assays and measured the levels of MMPs and IL-6 released from RA-FLSs under stimulation with proinflammatory cytokines (TNF-α, S100A4 and IL-6/soluble IL-6 receptor). Additionally, PIM-1-associated downstream signalling pathways were analysed by immunoblotting. Results: Three isoforms of PIM kinases were immunodetected in the synovial tissues from patients with RA or OA. Specifically, PIM-1 and PIM-3 were upregulated in RA synovium and PIM-1 was expressed in T cells, macrophages and FLSs. Additionally, upon stimulation of RA-FLSs with TNF-α, S100A4 and IL-6/sIL-6R, PIM-1 and PIM-3, but not PIM-2, were significantly inducible. Moreover, PIM-1 knockdown or AZD1208 treatment significantly suppressed basal or cytokine-induced proliferation and migration of RA-FLS and the secretion of MMPs from stimulated RA-FLSs. PIM-1 knockdown significantly affected the phosphorylation levels of extracellular signal-regulated kinase and cAMP responsive element binding protein in RA-FLSs. Conclusion: PIM-1 was upregulated in RA synovial tissues and RA-FLSs and its inhibition significantly reduced the proliferation, migration and MMP production of RA-FLSs in vitro. These findings suggest PIM-1 as a novel regulator of the aggressive and invasive behaviour of RA-FLSs and indicate its potential as a target for RA treatment.

Influence of androgen deprivation therapy on serum urate levels in patients with prostate cancer: A retrospective observational study.

OBJECTIVES: Although estrogenic modulation of serum urate levels is well-known, the androgenic effect on urate homeostasis remains controversial. We investigated the effect of androgen deprivation therapy (ADT) on serum urate levels. METHODS: We retrospectively enrolled a total of 489 prostate cancer patients with available serum urate levels at baseline and 3 and 6 months after ADT (n = 150) or prostate surgery (n = 339). We extracted the demographic, clinical, and laboratory data from a data warehouse and compared the changes in urate levels between the two treatment groups and between the different ADT regimens (with versus without luteinizing hormone-releasing hormone (LHRH) agonists) using generalized estimating equation (GEE). RESULTS: The baseline urate levels and the proportion of hyperuricemic subjects were comparable between the two groups. After 6 months, the urate levels were significantly decreased (by -0.66 mg/dL, 95% confidence interval (CI) [-0.81 to -0.51]) in the ADT group, whereas they did not significantly change in the surgery group in the univariate GEE analysis. The ADT group (4.7% from 18.0% at baseline) had a significantly lower proportion of hyperuricemic patients than surgery group (16.5% from 15.9% at baseline) at 6-month (p < 0.001). Regardless of whether LHRH agonists were used, the serial urate levels were lowered by the ADT. Temporal changes in the urate levels were significantly associated with the treatment group, baseline hyperuricemia, and poor functional or advanced cancer status. The ADT-related serum urate level reduction also remained significant in the multivariate GEE analysis (regression coefficient = -0.43 [-0.67 to -0.19] after 3 months and -0.37 [-0.64 to -0.10] after 6 months). Moreover, propensity-score-matched analyses yielded the same results. CONCLUSIONS: Our results showed that longitudinal serum urate levels were significantly reduced in men receiving ADT. This finding suggests that androgen could have an independent role in urate homeostasis.

Circulating Semaphorin 4D as a Marker for Predicting Radiographic Progression in Patients with Rheumatoid Arthritis.

Semaphorin 3A (Sema3A) and semaphorin 4D (Sema4D) are molecules which regulate immune responses as well as bone remodeling process. The aim of this study was to evaluate the serum levels of Sema3A and Sema4D and to investigate their clinical significance in rheumatoid arthritis (RA). The serum levels of Sema3A and Sema4D were measured in 130 patients with RA and 65 sex- and age-matched healthy individuals. Circulating levels of biomarkers of RA-related inflammation and bone turnover such as tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, IL-22, IL-34, osteopontin, Dkk-1, and sclerostin were also measured. Disease activity was determined by the 28-joint disease activity score (DAS28), and radiographic joint damage was assessed by the modified Sharp van der Heijde score (SHS). The serum levels of Sema3A were significantly higher in patients with RA than those in healthy controls (p < 0.001), whereas serum4D levels did not differ between the two groups. The levels of Sema4D showed a positive correlation with C-reactive protein (p = 0.001) and IL-6 (p < 0.001) levels, whereas the levels of Sema3A showed a negative correlation with Dkk-1 (p = 0.007) and TNF-α (p = 0.001). Even though Sema3A and Sema4D levels were comparable between RA patients with DAS28> 3.2 and with DAS28 ≤ 3.2, RA patients with radiographic progression (ΔSHS change/year ≥ 1) had significantly higher baseline levels of Sema4D than those without progression (p = 0.029). Additionally, when RA patients were divided into 3 groups using tertiles of Sema4D levels, the percentage of progressors was significantly increased (p = 0.045). In multivariate logistic regression analysis, serum Sema4D levels were an independent risk factor for radiographic progression. Our results suggest that the baseline levels of Sema4D might be a useful marker to identify RA patients with subsequent radiographic progression and that Sema4D may be an active mediator involved in RA-induced joint damage.