MicroRNA-21a-5p inhibition alleviates systemic sclerosis by targeting STAT3 signaling.

BACKGROUND: MicroRNA (miRNA)-21-5p participates in various biological processes, including cancer and autoimmune diseases. However, its role in the development of fibrosis in the in vivo model of systemic sclerosis (SSc) has not been reported. This study investigated the effects of miRNA-21a-5p overexpression and inhibition on SSc fibrosis using a bleomycin-induced SSc mouse model. METHODS: A murine SSc model was induced by subcutaneously injecting 100 µg bleomycin dissolved in 0.9% NaCl into C57BL/6 mice daily for 5 weeks. On days 14, 21, and 28 from the start of bleomycin injection, 100 µg pre-miRNA-21a-5p or anti-miRNA-21a-5p in 1 mL saline was hydrodynamically injected into the mice. Fibrosis analysis was conducted in lung and skin tissues of SSc mice using hematoxylin and eosin as well as Masson's trichrome staining. Immunohistochemistry was used to examine the expression of inflammatory cytokines, phosphorylated signal transducer and activator of transcription-3 (STAT3) at Y705 or S727, and phosphatase and tensin homologue deleted on chromosome-10 (PTEN) in skin tissues of SSc mice. RESULTS: MiRNA-21a-5p overexpression promoted lung fibrosis in bleomycin-induced SSc mice, inducing infiltration of cells expressing TNF-α, IL-1ß, IL-6, or IL-17, along with STAT3 phosphorylated cells in the lesional skin. Conversely, anti-miRNA-21a-5p injection improved fibrosis in the lung and skin tissues of SSc mice, reducing the infiltration of cells secreting inflammatory cytokines in the skin tissue. In particular, it decreased STAT3-phosphorylated cell infiltration at Y705 and increased the infiltration of PTEN-expressing cells in the skin tissue of SSc mice. CONCLUSION: MiRNA-21a-5p promotes fibrosis in an in vivo murine SSc model, suggesting that its inhibition may be a therapeutic strategy for improving fibrosis in SSc.

Predictors of renal relapse in Koreans with lupus nephritis after achieving complete response: a 35-years of experience at a single center.

BACKGROUND/AIMS: Renal relapse has known to be a poor prognostic factor in patients with lupus nephritis (LN), but there were few studies that identified the risk factors of renal relapse in real world. We conducted this study based on 35-years of experience at a single center to find out predictors of renal relapse in Korean patients with LN after achieving complete response (CR). METHODS: We retrospectively analyzed the clinical, laboratory, pathologic and therapeutic parameters in 296 patients of LN who reached CR. The cumulative risk and the independent risk factors for renal relapse were examined by Kaplan-Meier methods and Cox proportional hazards regression analyses, respectively. RESULTS: The median follow-up period from CR was 123 months. Renal relapse had occurred in 157 patients. Renal relapse occurred in 38.2%, 57.6% and 67.9% of patients within 5-, 10-, and 20-year, respectively. The age at diagnosis of SLE and LN were significantly younger, and the proportions of severe proteinuria and serum hypoalbuminemia were higher in patients with renal relapse. Interestingly, the proportion of receiving cytotoxic maintenance treatment was higher in patients with renal relapse. In Cox proportional hazards regression analyses, only young-age onset of LN (by 10 years, HR = 0.779, p = 0.007) was identified to independent predictor of renal relapse. CONCLUSION: Young-age onset of LN was only independent predictor and the patients with severe proteinuria and serum hypoalbuminemia also tended to relapse more, despite of sufficient maintenance treatment. Studies on more effective maintenance treatment regimens and duration are needed to reduce renal relapse.

A single-centre retrospective study of factors affecting steroid-free remission of immunoglobulin G4-related disease conducted in South Korea: A notable outcome after complete resection.

OBJECTIVES: Few studies have examined factors affecting steroid-free remission (SFR) in patients with immunoglobulin G4-related disease (IgG4-RD). The aim of this study was to investigate clinical factors affecting SFR in IgG4-RD. METHODS: The medical records of 68 patients who met the 2020 revised comprehensive diagnostic criteria for IgG4-RD were reviewed retrospectively. SFR was defined as remission maintained for at least 6 months without corticosteroids. Cox regression analysis was performed to examine the associations between SFR and various clinical factors. The relapse rate after SFR was examined using the log-rank test. RESULTS: After a median follow-up of 36 months, 30.9% (21/68) of patients with IgG4-RD achieved SFR. Multivariate Cox regression analysis revealed that IgG4-RD diagnosed by complete resection rather than by common diagnostic procedures was the only factor positively associated with SFR (hazard ratio, 7.41; 95% confidence interval, 2.23-24.60; P = .001). Furthermore, relapse after attainment of SFR was significantly less common in the group that underwent complete resection than in the group that did not undergo complete resection (log-rank P = .006). CONCLUSIONS: Patients with IgG4-RD diagnosed by complete resection had a higher likelihood of achieving SFR and a lower rate of relapse after attaining SFR.

Characteristics of patients with psoriatic arthritis in Korea: focusing on axial involvement.

BACKGROUND/AIMS: We aimed to clarify the clinical characteristics of psoriatic arthritis (PsA) in Korean patients focusing on PsA with axial involvement. METHODS: A retrospective medical chart review was performed to identify PsA patients at a single tertiary center. Cases of AS patients with psoriasis were recruited from a prospective AS registry of the same center. Demographics, laboratory findings, and radiologic characteristics were assessed. RESULTS: A total of 69 PsA patients were identified. In PsA patients, spondylitis (46.4%) was the most common form. Compared to AS patients with psoriasis, PsA patients with radiographic axial involvement were older (50.9 vs. 32.4 years; p < 0.001) and showed greater peripheral disease activity (peripheral arthritis 78.1 vs. 12.5%, p < 0.001; enthesitis 50.0 vs. 6.3%, p = 0.003). AS patients with psoriasis presented a higher rate of HLA-B*27 positivity (81.3 vs. 17.2%; p < 0.001) and a more frequent history of inflammatory back pain (100.0 vs. 75.0%; p = 0.039) than PsA patients with radiographic axial involvement. Significant proportions of PsA patients with radiographic axial involvement had cervical spine involvement (10/18, 55.6%) and spondylitis without sacroiliitis (10/23, 43.5%). CONCLUSION: We demonstrate that axial involvement is common in Korean PsA patients, and its characteristics can be distinct from those of AS.

SARS-CoV-2 spike protein accelerates systemic sclerosis by increasing inflammatory cytokines, Th17 cells, and fibrosis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) induces a dysfunctional immune response, inflammation, autoantibody production, and coagulopathy, which are symptoms that bear resemblance to those of autoimmune diseases, including systemic sclerosis (SSc). METHODS: While there is a single case report suggesting an association between COVID-19 and SSc, the effects of COVID-19 on SSc are not yet fully understood. Human embryonic kidney 293 (HEK293) cells were transfected with the SARS-CoV-2 spike protein gene, in the presence of TGF-ß. The expression levels of fibrosis-related proteins were measured via Western blotting. A bleomycin (BLM)-induced SSc mouse model was employed, wherein mice were injected with the gene encoding the SARS-CoV-2 spike protein and the ACE2 receptor. The levels of fibrosis, autoantibodies, thrombotic factors, and inflammatory cytokines in tissues and serum were analyzed. RESULTS: In vitro, the expression levels of fibrosis marker proteins were elevated in the spike protein group compared to the control group. In vivo, the skin thickness of SSc mice increased following exposure to the SARS-CoV-2 spike protein. Furthermore, the levels of autoantibodies and thrombotic factors, such as anti-phospholipid antibodies (APLA), were significantly increased in the presence of the protein. Flow cytometry analysis revealed increased expression of the proinflammatory cytokine IL-17 in the skin, lungs, and blood. Moreover, tissue fibrosis and levels of inflammatory cytokines in skin and lung tissues were markedly escalated in SSc mice subjected to the protein. CONCLUSION: COVID-19 may accelerate the development and progression of SSc by intensifying fibrosis through the upregulation of inflammation, autoantibody production, and thrombosis.

Predictors for future development of systemic lupus erythematosus in Korean Sjögren's syndrome patients.

OBJECTIVE: This study determined the impact of demographic factors, clinical manifestations, disease activity, and serological tests at baseline on future SLE development in Sjögren's syndrome (SS) patients. METHODS: This retrospective study assessed 1,082 SS patients without other autoimmune diseases at baseline who visited our hospital between January 2012 and March 2021. We analyzed demographic features, extra-glandular manifestations (EGMs), clinical indices, and laboratory values at baseline between the two groups divided per future SLE development (SS/SLE group vs SS group). The probability and predictors of SLE development in SS patients were estimated using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: The median follow-up duration was 1083.5 days. Forty-nine patients (4.5%) developed SLE that met the 2012 Systemic Lupus International Collaborating Clinics or 2019 EULAR/ACR classification criteria. The baseline EULAR SS disease activity index (ESSDAI) score was significantly higher in the SS/SLE group (p < .001). The SS/SLE group had more lymphadenopathy and renal involvement (p = .015 and p = .017, respectively). Shorter SS disease duration (<3 years) (hazard ratio [HR] = 2.12, p = .0328), high ESSDAI (HR = 8.24, p < .0001), leukopenia (HR = 4.17, p = .0005), thrombocytopenia (HR = 3.38, p = .0059), hypocomplementemia (HR = 29.06, p<.0001), and positive for anti-dsDNA (HR = 13.70, p < .0001), anti-ribonucleoprotein (RNP) (HR = 3.82, p = .0027), and anti-ribosomal P (HR = 6.70, p = .0002) at baseline were SLE development predictors in SS patients. CONCLUSION: Shorter disease duration and higher disease activity of SS at baseline may be risk factors for future SLE development. Serologic predictors of SLE development are hypocomplementemia, leukopenia, thrombocytopenia, and positivity for anti-dsDNA, anti-RNP, and anti-ribosomal P antibodies. If the above factors are observed, close monitoring will be necessary during the follow-up period, considering the possibility of future SLE development.

A newly developed PLD1 inhibitor ameliorates rheumatoid arthritis by regulating pathogenic T and B cells and inhibiting osteoclast differentiation.

Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine to phosphatidic acid and choline, plays multiple roles in inflammation. We investigated the therapeutic effects of the newly developed PLD1 inhibitors A2998, A3000, and A3773 in vitro and in vivo rheumatoid arthritis (RA) model. A3373 reduced the levels of LPS-induced TNF-α, IL-6, and IgG in murine splenocytes in vitro. A3373 also decreased the levels of IFN-γ and IL-17 and the frequencies of Th1, Th17 cells and germinal-center B cells, in splenocytes in vitro. A3373 ameliorated the severity of collagen-induced arthritis (CIA) and suppressed infiltration of inflammatory cells into the joint tissues of mice with CIA compared with vehicle-treated mice. Moreover, A3373 prevented systemic bone demineralization in mice with CIA and suppressed osteoclast differentiation and the mRNA levels of osteoclastogenesis markers in vitro. These results suggest that A3373 has therapeutic potential for RA.

Faecalibacterium prausnitzii alleviates inflammatory arthritis and regulates IL-17 production, short chain fatty acids, and the intestinal microbial flora in experimental mouse model for rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease that leads to joint destruction and functional disability due to the targeting of self-antigens present in the synovium, cartilage, and bone. RA is caused by a number of complex factors, including genetics, environment, dietary habits, and altered intestinal microbial flora. Microorganisms in the gut bind to nod-like receptors and Toll-like receptors to regulate the immune system and produce various metabolites, such as short-chain fatty acids (SCFAs) that interact directly with the host. Faecalibacterium prausnitzii is a representative bacterium that produces butyrate, a well-known immunomodulatory agent in the body, and this microbe exerts anti-inflammatory effects in autoimmune diseases. METHODS: In this study, F. prausnitzii was administered in a mouse model of RA, to investigate RA pathology and changes in the intestinal microbial flora. Using collagen-induced arthritic mice, which is a representative animal model of RA, we administered F. prausnitzii orally for 7 weeks. RESULTS: The arthritis score and joint tissue damage were decreased in the mice administered F. prausnitzii compared with the vehicle-treated group. In addition, administration of F. prausnitzii reduced the abundance of systemic immune cells that secrete the pro-inflammatory cytokine IL-17 and induced changes in SCFA concentrations and the intestinal microbial flora composition. It also resulted in decreased lactate and acetate concentrations, an increased butyrate concentration, and altered compositions of bacteria known to exacerbate or improve RA. CONCLUSION: These results suggest that F. prausnitzii exerts a therapeutic effect on RA by regulation of IL-17 producing cells. In addition, F. prausnitzii modify the microbial flora composition and short chain fatty acids in experimental RA mouse model.

Atrial fibrillation induced by gabapentin: a case report.

BACKGROUND: Gabapentin is commonly prescribed for the treatment of neuropathic pain, restless leg syndrome, and partial-onset seizures. Although the most frequent side effects of gabapentin are associated with the central nervous system, gabapentin can also affect the cardiovascular system. Case reports and observational studies have showed that gabapentin can be associated with increased risk of atrial fibrillation. However, all the evidence is concentrated in patients older than 65 years old with comorbidities that predispose them to the development of arrhythmias. CASE PRESENTATION: We describe a case of an African American male in his 20s that presented to our chronic pain clinic with lumbar radiculitis and developed atrial fibrillation 4 days after being started on gabapentin. Laboratory workup did not show significant abnormalities, including normal complete blood count, comprehensive metabolic panel, toxicology screen, and thyroid-stimulating hormone. Transthoracic and transesophageal echocardiography showed a patent foramen ovale with right-to-left shunt. The patient was initially treated with diltiazem for heart rate control and apixaban. Direct current cardioversion with successful conversion to sinus rhythm was performed 24 hours after admission. The patient was then discharged on apixaban and diltiazem. Apixaban was changed to low-dose aspirin 1 month after discharge. CONCLUSION: With rapidly increasing usage of gabapentin for approved and off-label indications, it is important to identify unintended adverse effects of this drug as they are considered safe alternatives to opioids. New-onset atrial fibrillation could be induced by gabapentin in young individuals.

Lactobacillus acidophilus and propionate attenuate Sjögren's syndrome by modulating the STIM1-STING signaling pathway.

BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disease characterized by inflammation of the exocrine gland. An imbalance of gut microbiota has been linked to SS. However, the molecular mechanism is unclear. We investigated the effects of Lactobacillus acidophilus (L. acidophilus) and propionate on the development and progression of SS in mouse model. METHODS: We compared the gut microbiomes of young and old mice. We administered L. acidophilus and propionate up to 24 weeks. The saliva flow rate and the histopathology of the salivary glands were investigated, and the effects of propionate on the STIM1-STING signaling pathway were evaluated in vitro. RESULTS: Lactobacillaceae and Lactobacillus were decreased in aged mice. SS symptoms were ameliorated by L. acidophilus. The abundance of propionate-producing bacterial was increased by L. acidophilus. Propionate ameliorated the development and progression of SS by inhibiting the STIM1-STING signaling pathway. CONCLUSIONS: The findings suggest that Lactobacillus acidophilus and propionate have therapeutic potential for SS. Video Abstract.

Bifidobacterium longum BORI inhibits pain behavior and chondrocyte death, and attenuates osteoarthritis progression.

Osteoarthritis (OA), the most common form of arthritis, is characterized by pain and cartilage damage; it usually exhibits gradual development. However, the pathogenesis of OA remains unclear. This study was undertaken to improve the understanding and treatment of OA. OA was induced in 7-week-old Wistar rats by intra-articular injection of monosodium iodoacetate (MIA); subsequently, the rats underwent oral administration of Bifidobacterium longum BORI (B. BORI). The effects of B. BORI were examined in chondrocytes and an MIA-induced OA rat model. In the rats, B. BORI-mediated effects on pain severity, cartilage destruction, and inflammation were recorded. Additional effects on mRNA and cytokine secretion were analyzed by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Paw withdrawal threshold, paw withdrawal latency, and weight-bearing assessments revealed that pain severity in MIA-induced OA rats was decreased after B. BORI treatment. Histopathology analyses and three-dimensional surface renderings of rat femurs from micro-computed tomography images revealed cartilage protection and cartilage loss inhibition effects in B. BORI-treated OA rats. Immunohistochemical analyses of inflammatory cytokines and catabolic markers (e.g., matrix metalloproteinases) showed that the expression levels of both were reduced in tissue from B. BORI-treated OA rats. Furthermore, B. BORI treatment decreased the expression levels of the inflammatory cytokine monocyte chemoattractant protein-1 and inflammatory gene factors (e.g., inflammatory cell death markers) in chondrocytes. The findings indicate that oral administration of B. BORI has therapeutic potential in terms of reducing pain, progression, and inflammation in OA.

Identification of gut dysbiosis in axial spondyloarthritis patients and improvement of experimental ankylosing spondyloarthritis by microbiome-derived butyrate with immune-modulating function.

Introduction: Dysbiosis is an environmental factor that affects the induction of axial spondyloarthritis (axSpA) pathogenesis. In the present study, we investigated differences in the gut microbiota of patients with axSpA and revealed an association between specific gut microbiota and their metabolites, and SpA pathogenesis. Method: Using 16S rRNA sequencing data derived from feces samples of 33 axSpA patients and 20 healthy controls (HCs), we examined the compositions of their gut microbiomes. Results: As a result, axSpA patients were found to have decreased α-diversity compared to HCs, indicating that axSpA patients have less diverse microbiomes. In particular, at the species level, Bacteroides and Streptococcus were more abundant in axSpA patients than in HCs, whereas Faecalibacterium (F). prausnitzii, a butyrate-producing bacteria, was more abundant in HCs. Thus, we decided to investigate whether F. prausnitzii was associated with health conditions by inoculating F. prausnitzii (0.1, 1, and 10 µg/mL) or by administrating butyrate (0.5 mM) into CD4+ T cells derived from axSpA patients. The levels of IL-17A and IL-10 in the CD4+ T cell culture media were then measured. We also assessed osteoclast formation by administrating butyrate to the axSpA-derived peripheral blood mononuclear cells. The CD4+ IL-17A+ T cell differentiation, IL-17A levels were decreased, whereas IL-10 was increased by F. prausnitzii inoculation. Butyrate reduced CD4+ IL-17A+ T cell differentiation and osteoclastogenesis. Discussion: We found that CD4+ IL-17A+ T cell polarization was reduced, when F. prausnitzii or butyrate were introduced into curdlan-induced SpA mice or CD4+ T cells of axSpA patient. Consistently, butyrate treatment was associated with the reduction of arthritis scores and inflammation levels in SpA mice. Taken together, we concluded that the reduced abundance of butyrate-producing microbes, particularly F. prausnitzii, may be associated with axSpA pathogenesis.

SARS-CoV-2 spike protein promotes inflammatory cytokine activation and aggravates rheumatoid arthritis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) induces inflammation, autoantibody production, and thrombosis, which are common symptoms of autoimmune diseases, including rheumatoid arthritis (RA). However, the effect of COVID-19 on autoimmune disease is not yet fully understood. METHODS: This study was performed to investigate the effects of COVID-19 on the development and progression of RA using a collagen-induced arthritis (CIA) animal model. Human fibroblast-like synoviocytes (FLS) were transduced with lentivirus carrying the SARS-CoV-2 spike protein gene in vitro, and the levels of inflammatory cytokine and chemokine expression were measured. For in vivo experiments, CIA mice were injected with the gene encoding SARS-CoV-2 spike protein, and disease severity, levels of autoantibodies, thrombotic factors, and inflammatory cytokine and chemokine expression were assessed. In the in vitro experiments, the levels of inflammatory cytokine and chemokine expression were significantly increased by overexpression of SARS-CoV-2 spike protein in human FLS. RESULTS: The incidence and severity of RA in CIA mice were slightly increased by SARS-CoV-2 spike protein in vivo. In addition, the levels of autoantibodies and thrombotic factors, such as anti-CXC chemokine ligand 4 (CXCL4, also called PF4) antibodies and anti-phospholipid antibodies were significantly increased by SARS-CoV-2 spike protein. Furthermore, tissue destruction and inflammatory cytokine level in joint tissue were markedly increased in CIA mice by SARS-CoV-2 spike protein. CONCLUSIONS: The results of the present study suggested that COVID-19 accelerates the development and progression of RA by increasing inflammation, autoantibody production, and thrombosis. Video Abstract.

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.

Impact of Acupuncture on Hot Flashes in Breast Cancer Patients Receiving Adjuvant Antiestrogen Therapy with Tamoxifen: A Randomized Controlled Trial.

Objectives: The aim of this study was to evaluate the impact of acupuncture on hot flashes in breast cancer patients taking tamoxifen as an adjuvant antiestrogen therapy in Korea. Design: This trial was a randomized, no-treatment-controlled, single-blind, multi-center trial. Participants were randomized 1:1 into the acupuncture group or into the no-treatment control group. Location: This trial was conducted at Daegu Catholic University Hospital and Daegu Haany University Korean Medicine Hospital in Daegu, Republic of Korea. Participants: Patients with moderate to severe symptoms of hot flashes while receiving adjuvant antiestrogen therapy using tamoxifen after surgery for breast cancer were included. Interventions: In the acupuncture group, acupuncture was performed three times a week for 4 consecutive weeks at five predetermined points. The control group received no treatment during the study period. Study Outcome Measures: As a primary outcome, the severity of hot flashes was measured on the visual analogue scale (VAS) and total hot flash score. In addition, the quality of life (QoL) of participants was assessed as a secondary outcome. Results: A total of 30 patients were included in this study, 15 each in the acupuncture group and the control group. The participants in the acupuncture group significantly decreased the severity of hot flashes evaluated with both VAS and total hot flash scores compared with participants in the control group. Also, the acupuncture group showed improved score of a global health status/QoL scale and functional scales assessed with the European Organisation for Research and Treatment of Cancer QoL questionnaire-core questionnaire, compared with those in the control group. This trend was maintained 4 weeks after acupuncture treatment. No adverse events have been reported in this study. Conclusions: Acupuncture was effective and safe in improving hot flashes in Korean breast cancer patients receiving adjuvant antiestrogen therapy with tamoxifen, and it improved the QoL. Clinical Trial Registration: KCT0007829.

Population genetic structure of a recent insect invasion: a gall midge, Asynapta groverae (Diptera: Cecidomyiidae) in South Korea since the first outbreak in 2008.

Outbreaks of Asynapta groverae, an invasive mycophagous gall midge, in South Korea have been repeatedly reported since the first occurrence in 2008. This species is a nuisance to residents owing to its mass emergence from newly built and furnished apartments. Here, the levels of genetic diversity, divergence, and structure of invasive A. groverae populations were investigated to understand their ability to survive in novel locations. Population genetic analyses were performed on seven invasive populations, including the first outbreak, sporadically emerged, and two laboratory-isolated (quarantined) populations, using the mitochondrial COI sequences and the ten novel microsatellite markers developed in this study. Non-indigenous A. groverae managed to maintain their populations for 12 years despite decreased genetic polymorphisms resulting from multiple incidences of founder effects by a small number of colonists. Additionally, the advantageous sustainability of A. groverae in the particle boards from which they emerge suggests that human-mediated dispersal is plausible, which may allow for the successful spread or invasion of A. groverae to new locations. This study is one of the few examples to demonstrate that an insect species successfully invaded new regions despite exhibiting decreased genetic diversity that was maintained for a decade. These findings indicate that the high genetic diversity of the initial founding population and asexual reproduction would contribute to the successful invasion of A. groverae in novel environments.

Costovertebral joint involvement in patients with axial spondyloarthritis.

OBJECTIVES: To evaluate costovertebral joint involvement in patients with axial spondyloarthritis (axSpA) and to assess its association with disease features. METHODS: We included 150 patients from the Incheon Saint Mary's axSpA observational cohort who underwent whole spine low-dose computed tomography (ldCT). Costovertebral joint abnormalities were scored by two readers on a scale of 0-48 based on the presence or absence of erosion, syndesmophyte, and ankylosis. The interobserver reliability of costovertebral joint abnormalities was assessed using intraclass correlation coefficients (ICCs). Associations between costovertebral joint abnormality scores and clinical variables were evaluated using a generalized linear model. RESULTS: Two independent readers found costovertebral joint abnormalities in 74 (49%) patients and 108 (72%) patients. The ICCs of scores for erosion, syndesmophyte, ankylosis, and total abnormality were 0.85, 0.77, 0.93, and 0.95, respectively. For both readers, total abnormality score was correlated with age, symptom duration, Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath AS functional index (BASFI), CT syndesmophyte score (CTSS), and number of bridging spines. Multivariate analyses showed age, ASDAS, CTSS to be independently associated with total abnormality scores in both readers. The frequency of ankylosed costovertebral joint was 10.2% (reader 1) and 17.0% (reader 2) in patients without radiographic syndesmophytes (n=62), and 10.3% (reader 1) and 17.2% (reader 2) in patients without radiographic sacroiliitis (n=29). CONCLUSIONS: Costovertebral joint involvement was common in patients with axSpA, even in the absence of radiographic damage. LdCT is recommended for evaluating structural damage in patients with clinically suspected costovertebral joint involvement.

A green-lipped mussel prevents rheumatoid arthritis via regulation of inflammatory response and osteoclastogenesis.

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive joint destruction. Green-lipped mussel (GLM) has chondro-modulatory and anti-inflammatory properties, but the mechanism underlying the effect of GLM on RA is unclear. To investigate the roles of GLM on the pathogenesis of RA, we examined the effects of GLM in collagen-induced arthritis (CIA) mice and osteoclast differentiation. GLM was orally administrated CIA mice at 3 weeks after chicken type II collagen (CII) immunizations. GLM reduced arthritis severity and the histologic score of CIA mice compared to vehicle. The expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-17) was decreased in the ankle joints of GLM-treated CIA mice. The expression of CD4+ IL-17+ cells decreased in ex vivo splenocytes and the spleens of GLM-treated CIA mice. Moreover, GLM inhibited TRAP+ multinucleated cells among mouse bone marrow-derived monocytes/macrophages (BMM), and the expression of osteoclast-related genes in mouse BMMs and human monocytes in vitro. These results suggest that GLM has potential as a therapeutic agent that can improve disease by controlling pathologic immune cells and osteoclastogenesis.

Prevalence and Associated Factors of Facet Joint Ankylosis in Patients With Axial Spondyloarthritis.

OBJECTIVE: To investigate the prevalence of facet joint ankylosis in the whole spine in axial spondyloarthritis (axSpA) using low-dose computed tomography (LDCT), and to identify factors associated with facet joint ankylosis. METHODS: Whole spine LDCT images from 161 patients with axSpA were examined, and the presence of facet joint ankylosis was assessed (right and left, C2-S1) by 2 readers. Facet joint ankylosis was scored from 0 to 46. Structural damage of vertebral body was assessed using CT Syndesmophyte Score (CTSS). Factors associated with ankylosed facet joint scores for the whole spine were identified using a generalized linear model with a negative binomial distribution. RESULTS: Seventy-nine patients (49%) and 70 patients (43%; reader 1 and reader 2, respectively) had ≥ 1 ankylosed facet joint. Facet joint ankylosis was most common in the thoracic spine. The mean score of facet joint ankylosis for the whole spine was 6.6 (SD 11.2) in reader 1 and 4.2 (SD 8.4) in reader 2. Whole spine facet joint ankylosis score positively correlated with Ankylosing Spondylitis Disease Activity Score (ASDAS) and CTSS. In multivariable analysis, the ankylosed facet joint score was associated with ASDAS, sacroiliitis, CTSS, and a history of uveitis in both readers. Uveitis history, ASDAS, and CTSS were associated with whole spine facet joint ankylosis score in subgroup analysis of only radiographic axSpA. CONCLUSION: The prevalence of ankylosed facet joints is high in axSpA, especially in the thoracic segment. The whole spine ankylosed facet joint score is significantly associated with a history of uveitis, ASDAS, sacroiliitis, and syndesmophyte score.

Clinical efficacy of alternative TNF inhibitor and secukinumab between primary non-responder and secondary non-responder of prior TNF inhibitor in ankylosing spondylitis.

OBJECTIVES: To compare the drug retention times and clinical efficacy of alternative tumour necrosis factor inhibitors (TNFi) and secukinumab in primary and secondary non-responders with ankylosing spondylitis (AS). METHODS: AS patients treated with biologics and enrolled in the Korean College of Rheumatology Biologics registry were examined. Patients who did not respond to previous TNFi treatment were defined as primary and secondary non-responders. Data regarding drug discontinuation and clinical efficacy were collected after 1 year. Kaplan-Meier and Cox regression analyses were performed to compare drug survival and associated factors. Logistic regression analyses were conducted to compare the clinical efficacy secukinumab with that of alternative TNFi. RESULTS: In total, 124 patients (83 receiving alternative TNFi and 41 receiving secukinumab) had biologic changes due to clinical inefficacy. Drug retention rates in the alternative TNFi and secukinumab groups were similar (P = 0.096). However, subgroup analyses including only secondary non-responders revealed that secukinumab users showed a higher hazard ratio (HR) for drug discontinuation (HR = 3.77, P = 0.045). In addition, secukinumab was negatively associated with achieving BASDAI50 or a major improvement in the ASDAS. CONCLUSION: Alternative TNFi showed better drug retention and clinical efficacy in AS patients experiencing previous TNFi failure, in secondary non-responders. Therefore, alternative TNFi may be a more suitable treatment for secondary non-responders.