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Background: Dermatomyositis is an inflammatory muscle disease caused by immune-mediated muscle injury, and central core disease (CCD) is a congenital myopathy associated with disturbed intracellular calcium homeostasis and excitation-contraction coupling. To date, CCD has not been reported to have autoantibodies or coexist with inflammatory myopathy., Case Presentation: Here, we described the case of a 25-year-old woman who had progressive proximal muscle weakness, myalgia, pruritic macular rash, skin ulcers, and calcinosis. Dermatomyositis was initially suspected based on the clinical symptoms accompanied by elevated muscle enzyme levels, electromyography abnormalities, and a positive antinuclear antibody test. However, the patient's muscle biopsy revealed the characteristic findings of both dermatomyositis and CCD, suggesting that dermatomyositis occurred in this patient with previously asymptomatic CCD. The patient did not have any pathogenic gene mutations associated with congenital myopathy, including RYR1 and SEPN1 in targeted next-generation sequencing. She received high-dose glucocorticoid therapy and azathioprine with a significant improvement in muscle strength., Conclusions: We present a case of rare coexistence of dermatomyositis and CCD. Clinicians should be aware that patients with CCD may have inflammatory myopathy that responds well to immunosuppressive therapy.

Background/aims: Myelodysplastic syndrome (MDS) is caused by genetic and epigenetic alteration of hematopoietic precursors and immune dysregulation. Approximately 20% of patients with MDS develop an autoimmune disease (AID). Here, we investigated whether particular genetic mutations are associated with AID in patients with MDS., Methods: Eighty-eight genetic mutations associated with myeloid malignancy were sequenced in 73 MDS patients. The association between these mutations and AID was then analyzed., Results: The median age of the 73 MDS patients was 70 years (interquartile range, 56 to 75), and 49 (67.1%) were male. AID was observed in 16 of 73 patients (21.9%). Mutations were detected in 57 (78.1%) patients. The percentage (68.8% vs. 80.7%, p = 0.32) and the mean number of mutations (1.8 ± 1.6 vs. 2.2 ± 1.8, p = 0.34) in MDS patients with or without AID were similar. However, the ten-eleven translocation- 2 (TET2) mutation rate was significantly higher in patients with AID than in those without (31.3% vs. 5.3%, respectively; p = 0.001). All TET2 mutations were variants of strong clinical significance., Conclusion: Mutation of TET2 in patients with MDS may be associated with increased risk of developing AID.

Autoimmune manifestations (AIMs) are common in patients with myelodysplastic syndrome (MDS). This study aimed to investigate whether AIMs are associated with a specific cytogenetic abnormalities and worse survival in patients with MDS. A total of 67 MDS patients with AIMs and 134 age- and sex-matched MDS patients without AIMs, all of whom received medical care at Seoul National University Hospital from January 2000 through July 2014, were enrolled. The clinical features, chromosomal abnormalities, and outcomes were examined. The effect of AIMs on mortality was estimated after adjusting for age, sex, and the International Prognostic Scoring System. The mean age (±SD) at the time of MDS diagnosis was 54.5 ± 17.1 years, and 44.8% of patients were male. Neutrophilic dermatosis (ND; Sweet syndrome and pyoderma gangrenosum) was the most prevalent AIM (n = 24 36%]), followed by Behcet disease (10 [15%]), rheumatoid arthritis (9 [13%]), vasculitis (8 [12%]), myositis (3 [4%]), spondyloarthropathy (3 [4%]), and systemic lupus erythematous (2 [3%]). ND and vasculitis occurred at the time of MDS diagnosis, whereas other AIMs occurred years after MDS diagnosis. Deletion of 5q was associated with ND (P = 0.001), whereas trisomy 8 was associated with Behcet disease (P = 0.015). Strikingly, ND was associated with a 1.8-fold increase in mortality (95% CI 1.033-3.093; P = 0.038). Certain AIMs in MDS patients are associated with distinctive karyotypes and worse survival. A larger study is needed to confirm whether the presence of AIMs influences disease outcome in MDS., Competing Interests: The authors have no competing interests to declare. The authors have no conflicts of interest to disclose.

Aminoacyl-tRNA synthetase-interacting multifunctional protein 1 (AIMP1; previously known as p43) is a multifunctional protein that was initially found in multitRNA synthetase complex. In the present study, screening of the AIMP1-binding proteins revealed that AIMP1 can form a molecular complex with heat shock protein gp96. AIMP1 enhances gp96 dimerization and the interaction between gp96 and KDEL receptor-1 (KDELR-1), which mediates the retrieval of KDEL-containing proteins from Golgi to the endoplasmic reticulum (ER). The interaction between gp96 and KDELR-1 was reduced in AIMP1-deficient cells, and this disturbed ER retention of gp96 and increased its cell surface localization. Moreover, this localization of gp96 at the cell surface was suppressed by its interaction with AIMP1 and enhanced by the depletion of endogenous AIMP1. In addition, AIMP1-deficient mice showed dendritic cell activation attributable to increased gp96 surface presentation and lupus-like autoimmune phenotypes. These results suggest that AIMP1 acts as a regulator of the ER retention of gp96 and provide a new perspective of the regulatory mechanism underlying immune stimulation by gp96.

ObjectivePrimary Sjögren's syndrome (pSS) is the second most common chronic autoimmune connective tissue disease. Autoantibodies, immunoglobulin (IgG) anti-SSA/Ro, in serum is a key diagnostic feature of pSS. Since pSS is a disease of the salivary gland, we investigated anti-SSA/Ro52 in saliva.MethodsUsing a novel electrochemical detection platform, Electric Field-Induced Release and Measurement, we measured IgG/M/A, IgG, IgA, IgA isotypes (IgA1 and IgA2) and IgA1 subclasses (polymeric and monomeric IgA1) to anti-SSA/Ro52 in saliva supernatant of 34 pSS, 35 dry eyes and dry mouth (patients with Sicca) and 41 health controls.ResultsSaliva IgG/M/A, IgG, IgA, IgA isotypes and IgA1 subclasses to anti-SSA/Ro52 differed significantly between pSS, non-pSS Sicca and healthy subjects. Elevated monomeric IgA1 was observed in patients with non-pSS Sicca while elevated polymeric IgA1 (pIgA1) was observed in patients with pSS. Salivary polymeric but not monomeric IgA1 (mIgA1) isoform correlated with focus score (r2=0.467, p=0.001) CONCLUSIONS: Salivary anti-Ro52 polymeric IgA1 isoform is associated with glandular inflammation in pSS, while salivary monomeric IgA1 is associated with Sicca. Whether IgA1 isotope switching plays a role in the progression of the Sicca to pSS warrants further investigation.

Background: We investigated the mortality and disability rate, as well as the healthcare expenditure, for patients with newly diagnosed seropositive rheumatoid arthritis (RA) who were followed-up for up to 10 years, compared to the general population in Korea. Methods: We conducted a nationwide population-based study using a National Health Insurance Service-National Sample Cohort of the Korean population, consisting of 1 million individuals who submitted medical care claims between 2002 and 2013. RA was identified using as the International Classification of Diseases code M05 (seropositive RA), with prescription of any disease-modifying anti-rheumatic drug (DMARD). Our analysis was based on the data of 1655 patients with incident seropositive RA and 8275 non-RA controls. The controls were matched to the RA cohort by sex, age at the time of diagnosis, duration of follow-up, geographic region, type of social security, and household income. Results: The most commonly used conventional synthetic DMARDs were hydroxychloroquine (71.30%) and methotrexate (69.5%), with adalimumab being the most commonly used biologic DMARD (2.54%). The mortality rate was significantly higher in the RA than the control group (incidence rate ratio [IRR] 1.29, 95% confidence interval [CI] 1.02–1.64) in the first 10 years after diagnosis. Specifically, mortality due to infectious diseases (IRR 4.41, 95% CI 1.60–12.17) and pneumonia (IRR 3.92, 95% CI 1.46–10.53) was significantly higher in the RA than control group. The disability rate was higher in the RA than control group over the first 10 years of the disease (IRR 2.27, 95% CI 1.77–2.92), which was attributed to a higher incidence of physical disability (IRR 3.81, 95% CI 2.81–5.15). Annual health expenditure was greater for the RA than the control group. Conclusions: Therefore, the rate of mortality and disability, as well as healthcare expenditure, are higher for patients with RA over the first 10 years of the disease onset, than the general population of Korea. The use of claim data has limited the quality of information and there is a limit to the observation period, and we expect the prospective national-wide multicenter cohort for longer period to overcome these limitations. [ABSTRACT FROM AUTHOR]

Background: Ankylosing spondylitis (AS) is an inflammatory rheumatic disease typically diagnosed in young age and follows a chronic progressive course. Its impact on the patient is life-long and the burden that AS exerts on society is increasing cumulatively every year. We aimed to quantify the burden of AS and to identify the factors associated with comorbidity, disability, and healthcare expenditure in Korean AS patients. Methods: We conducted a nationwide, population-based study using health insurance data (2003–2013). The analysis included individuals with incident AS (1,111 patients) and controls (5,555 patients) matched by age, sex, income, and geographic region. The incidence rates of extra-articular manifestations (EAMs), comorbidities, mortality, and disability (type and severity) were compared between AS patients and controls. Annual health expenditure per patient was also analyzed. Associations were expressed as odds ratios (ORs) with 95% confidence intervals (95%CIs). Results: During the follow-up, 28% of AS patients experienced at least one EAM. AS diagnosis was significantly associated with Charlson comorbidity index ≥3 (OR 2.18, 95% CI 1.91–2.48). Disability rate was higher in AS patients than in controls regardless of cause and severity (OR 2.94, 95% CI 2.48–3.48), but crude incidence rate ratios for mortality were not significantly higher. On multivariate analysis, male sex (OR 3.18, 95% CI 2.13–4.75), presence of an EAM (OR 1.63, 95% CI 1.15–2.32), and older age at diagnosis (OR 1.27, 95% CI 1.20–1.35) were evidently associated with increased disability in AS. Presence of an EAM was also associated with increased AS-unrelated expenditures in biologic-naïve patients (median, 1112 vs. 877 USD per person, P < 0.05). Conclusions: In patients with AS, demographic factors and systemic manifestations including EAMs and other comorbidities were associated with increased disability and healthcare expenditures. [ABSTRACT FROM AUTHOR]

Objective: To investigate the impact of dose reduction of tumor necrosis factor inhibitor (TNFi) on radiographic progression in ankylosing spondylitis (AS). Methods: One hundred and sixty-five patients treated with etanercept or adalimumab were selected from a consecutive single-center observational cohort based on the availability of radiographs at baseline and after two- and/or four-years of follow up. Radiographs were assessed by two blinded readers using the modified Stokes AS Spinal Score (mSASSS). Radiographic progression in patients treated with standard-dose TNFi (standard-dose group, n = 49) was compared with patients whose dosage was tapered during the treatment (tapering group, n = 116) using linear mixed models. Results: Baseline characteristics between two groups were comparable except for higher BASDAI (7.1 vs. 6.3, p = 0.003) in the standard-dose group. At two years after the treatment, mean dose quotient (S.D.) of the tapering group was 0.59 (0.17). During follow up, rate of radiographic progression in overall patients was 0.90 mSASSS units/year. Radiographic progression over time between the two groups was similar at the entire group level. However, in the subgroup of patients with baseline syndesmophytes, progression occurred significantly faster in the tapering group after the adjustment for baseline status (1.23 vs. 1.72 mSASSS units/year, p = 0.023). Results were consistent when radiographic progression was assessed by the number of newly developed syndesmophytes (0.52 vs. 0.73/year, p = 0.047). Sensitivity analysis after multiple imputation of missing radiographs also showed similar results. Conclusion: A dose tapering strategy of TNFi is associated with more rapid radiographic progression in AS patients who have syndesmophytes at baseline. [ABSTRACT FROM AUTHOR]

Objective: In order to identify putative biomarkers in lipoprotein, we compared lipid and lipoprotein properties between rheumatoid arthritis (RA) patients and control with similar age. Methods: We analyzed four classes of lipoproteins (VLDL, LDL, HDL2, HDL3) from both male (n = 8, 69±4 year-old) and female (n = 25, 53±7 year-old) rheumatoid arthritis (RA) patients as well as controls with similar age (n = 13). Results: Although RA group showed normal levels of total cholesterol (TC), low-density lipoprotein (LDL)-cholesterol, and glucose, however, the RA group showed significantly reduced high-density lipoprotein (HDL)-C level and ratio of HDL-C/TC. The RA group showed significantly elevated levels of blood triglyceride (TG), uric acid, and cholesteryl ester transfer protein (CETP) activity. The RA group also showed elevated levels of advanced glycated end (AGE) products in all lipoproteins and severe aggregation of apoA-I in HDL. As CETP activity and TG contents were 2-fold increased in HDL from RA group, paraoxonase activity was reduced upto 20%. Electron microscopy revealed that RA group showed much less HDL2 particle number than control. LDL from the RA group was severely oxidized and glycated with greater fragmentation of apo-B, especially in female group, it was more atherogenic via phagocytosis. Conclusion: Lipoproteins from the RA patients showed severely altered structure with impaired functionality, which is very similar to that observed in coronary heart patients. These dysfunctional properties in lipoproteins from the RA patients might be associated with high incidence of cardiovascular events in RA patients. [ABSTRACT FROM AUTHOR]

T helper 17-related cytokines have been implicated in rheumatoid arthritis (RA) pathogenesis. The study aimed to identify cytokines associated with the treatment response of RA patients to tocilizumab (TCZ), a humanized monoclonal antibody against the interleukin- (IL-) 6 receptor. As an independent substudy of the 24-week, randomized, double-blinded CWP-TCZ301 trial of TCZ in RA patients with an inadequate response to disease-modifying antirheumatic drugs, serum levels of cytokines including tumor necrosis factor-alpha, IL-17A, IL-21, IL-23, IL-6, and soluble IL-6 receptor were measured. Baseline IL-17A levels were significantly lower in RA patients who achieved disease activity score 28 (DAS28) remission at 12 weeks of TCZ treatment, compared to patients not in remission. Patients were stratified into IL-17A low group and IL-17A high group. Significantly more patients in the IL-17A low group achieved remission as compared to the IL-17A high group (47.6 versus 17.4%, P=0.032). DAS28 improvement was significantly better in the IL-17A low group than in the IL-17A high group at 12 weeks (P=0.045) and 24 weeks (P=0.046) after adjustment. Other baseline cytokines were not associated with treatment response to TCZ. The data demonstrate that low baseline IL-17A levels are associated with better clinical response to TCZ treatment in RA patients. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the efficacy and safety of trimethoprim/sulfamethoxazole (TMP-SMX) as primary prophylaxis for pneumocystis pneumonia (PCP) in patients with rheumatic diseases receiving high-dose steroids.Methods: The study included 1522 treatment episodes with prolonged (≥4 weeks) high-dose (≥30 mg/day prednisone) steroids in 1092 patients over a 12-year period. Of these, 262 treatment episodes involved TMP-SMX (prophylaxis group) while other episodes involved no prophylaxis (control group). Differences in 1-year PCP incidence and its mortality between the two groups were estimated using Cox regression. To minimise baseline imbalance, propensity score matching was performed and efficacy outcome was mainly assessed in the postmatched population (n=235 in both groups).Results: During a total of 1474.4 person-years, 30 PCP cases occurred with a mortality rate of 36.7%. One non-fatal case occurred in the prophylaxis group. TMP-SMX significantly reduced the 1-year PCP incidence (adjusted HR=0.07(95% CI 0.01 to 0.53)) and related mortality (adjusted HR=0.08 (95% CI 0.0006 to 0.71)) in the postmatched population. The result of the same analysis performed in the whole population was consistent with that of the primary analysis. Incidence rate of adverse drug reactions (ADR) related to TMP-SMX was 21.2 (14.8-29.3)/100 person-years. Only two serious ADRs (including one Stevens-Johnson syndrome case) occurred. The number needed to treat for preventing one PCP (52 (33-124)) was lower than the number needed to harm for serious ADR (131 (55-∞)).Conclusion: TMP-SMX prophylaxis significantly reduces the PCP incidence with a favourable safety profile in patients with rheumatic disease receiving prolonged, high-dose steroids. [ABSTRACT FROM AUTHOR]

Abstract: CXCL10 is a 10 kDa protein, which is categorized functionally as a Th1-chemokine. It binds to the receptor CXCR3 and regulates immune responses through the activation and recruitment of leukocytes, such as, T cells, eosinophils, and monocytes. Recent reports have shown that serum and/or tissue expressions of CXCL10 are increased in various autoimmune diseases like rheumatoid arthritis (RA), systemic lupus rythematosus (SLE), Sjogren syndrome (SS), systemic sclerosis (SSc), and idiopathic inflammatory myopathy (IIM). Moreover, CXCL10 and CXCR3 may have important roles in leukocyte homing to inflamed tissues and in the perpetuation of inflammation, and therefore, tissue damage. Our recent study shows that CXCL10 also has a pathogenic role in bone destruction via receptor activator of NF-κB ligand (RANKL) induction in inflamed synovial tissue of RA. In addition to its chemotactic effect, CXCL10 may have pleiotropic functions. Further research on the function of this chemokine and interactions between CXCL10 and other cytokines and chemokines may provide therapeutic targets in various autoimmune diseases. [Copyright &y& Elsevier]

Abstract: Background: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease involving multiple organs. Chemokines and their receptors play an important role in the pathogenesis of SLE. Lymphocytes expressing CXCR3, chemokine receptors of CXCL4, 9, 10, and 11, increase in patients with SLE and animal models, particularly in those with skin manifestations and nephritis. We investigated CXCR3 genetic polymorphisms in patients with SLE and their association with clinical manifestations. Methods: A total of 346 patients with SLE and 540 healthy controls were investigated for CXCR3 intron 1 polymorphisms rs2280964 and rs34334103 by Taqman analysis. Results: rs2280964 and rs34334103 were not associated with all patients with SLE, but rs34334103 showed a significant association with male patients with SLE. Among the clinical manifestations, pleuritis was associated with the rs34334103 polymorphism. Conclusion: The CXCR3 polymorphism rs34334103 was associated with male gender and pleuritis in patients with SLE. [Copyright &y& Elsevier]

Abstract: Objectives. Primary Sjögren''s syndrome (pSS) is a systemic autoimmune disease characterized by lymphocyte infiltration into the salivary and lachrymal glands, leading to dry mouth and eyes. The presence of functional autoantibodies against muscarinic type 3 receptor (M3R) has been reported in pSS patients. However, the pathological role of anti-M3R autoantibodies in pSS salivary dysfunction remains controversial. Methods. Purified IgGs were obtained from normal (control) and primary SS patients'' sera (pSS IgG). Internalization of M3R and clathrin was analyzed by biochemical assay and immunofluorescence confocal microscopy using human submandibular gland (hSMG) cells. Cytoplasmic free Ca2+ concentration ([Ca2+]i) was measured by microspectrofluorimetry. Results. Incubation of hSMG cells with pSS IgG (1mg/ml) significantly decreased M3R expression levels at the membrane. Carbachol-induced [Ca2+]i transients (CICTs) in these cells were also inhibited by pSS IgG. In contrast to pSS IgG, control IgG had no effect on both the M3R expression level and CICTs. We found that binding of pSS IgG to M3R induces phosphorylation of the receptor, and that the pSS IgG-induced M3R internalization is prevented by the lysosomal inhibitor, chloroquine. In addition, pSS IgG decreased membrane clathrin expression, which was inhibited by atropine. Our immunofluorescence study further confirmed that pSS IgG induces a co-localization of M3R with clathrin and subsequent internalization of M3R. Conclusion. pSS IgG induces internalization of M3R partly through a clathrin-mediated pathway. The results suggest M3R internalization as a potential mechanism to explain the exocrinopathy seen in pSS patients. [Copyright &y& Elsevier]

Summary: To investigate the association between functional promoter polymorphisms of matrix metalloproteinase–9 (MMP-9) and systemic lupus erythematosus (SLE), we analyzed MMP-9 promoter -1562 C>T and MMP-9 -90 (CA)n repeat polymorphisms in 135 Korean SLE patients (mean age, 34.7 years; 124 female and 11 male) and in 135 gender- and age-matched healthy controls (mean age, 35.4 years). Clinical and laboratory findings were collected during the follow-up period (mean, 63.5 months; range, 3–252 months), and Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Indexes were calculated. The levels of total MMP-9 were measured in sera of SLE patients and controls by enzyme-linked immunoabsorbent assay. The serum levels of MMP-9 in SLE patients were significantly lower than those of controls (mean ± standard error of the mean, 1421.6 ± 177.4 vs 3731.4 ± 441.4 ng/ml, p = 1.2×10−5 by t test). Both functional polymorphisms were under the Hardy-Weinberg equilibrium state except (CA)n repeat polymorphisms in SLE patients (p = 2.6×10−5 by χ2 goodness-of-fit test). The distribution of the MMP-9 promoter polymorphisms or haplotypes was not significantly different in SLE patients and controls. However the frequency of alleles with low numbers of CA repeats (n < 21, 11.9% vs 7.0%, p = 0.06 by the χ2 test; odds ratio = 1.78, 95% confidence interval = 0.99−3.20) and the prevalence of low CA repeats homozygote tended to be higher in patients than in controls (5.2% vs 0.7%, p = 0.07 by logistic regression, odds ratio = 7.29, 95% confidence interval = 0.88−60.10) in the recessive model. No relationship was found between MMP-9 polymorphisms and clinical features or damage as indicated by SLICC/ACR Damage Index in the study subjects. These results suggest that genetic polymorphisms of the MMP-9 promoter regions are not associated with the development of SLE in Korea. [Copyright &y& Elsevier]

Behcet&rsquo;s disease (BD) is an autoimmune disease characterized by recurrent oral ulcers, genital ulcers, erythema nodosum, and uveitis. Genetic factors are considered important in its pathogenesis. The serum level of tumor necrosis factor (TNF) is elevated in patients with active BD, and its production is elevated in monocytes and in the &gamma;&delta; T cells of BD patients. A dramatic response to anti-TNF-&alpha; antibody treatment further supports the role of TNF in BD. In this study, we investigated genetic polymorphisms of TNF&alpha; &minus;308 G/A, TNF&beta; +252 G/A, and TNFR2 196 R/M in 94 Korean BD patients and age- and sex-matched healthy controls to investigate the role of TNF and TNF receptor polymorphisms in BD. The polymerase chain reaction&ndash;restriction fragment length polymorphism was used to identify the TNF-&alpha; promoter (G = TNFA1, A = TNFA2) and TNF-&beta; intron polymorphisms (G = TNFB1, A = TNFB2), and polymerase chain reaction&ndash;singly-strand conformation polymorphism was used to identify TNFR2 196R/M polymorphism (T = TNFR2M, G = TNFR2R). No differences were found in the TNF-&alpha;, TNF-&beta; or TNFR2 polymorphisms of the patients and the healthy controls. The allele frequencies of TNFA1/A2 were 0.94/0.06 in patients and 0.96/0.04 in healthy controls (p = 0.36, OR = 0.65, 95% CI = 0.26-1.63), for TNFB1/TNFB2 these were 0.42/0.58 in patients and 0.44/0.56 in controls (p = 0.68, OR = 0.91, 95% CI = 0.61&ndash;1.38), and for TNFR2R/TNFR2M 0.23/0.77 in patients and 0.21/0.79 in controls (p = 0.62, OR = 1.13, 95% CI = 0.69&ndash;1.84). In conclusion, this study found no differences of TNF&alpha; -308 G/A, TNF&beta; +252 G/A or of the TNFR2 196R/M polymorphisms in Korean BD patients versus healthy controls. These findings suggest that the role of TNF in BD is not genetically determined, but can be functionally explained. [Copyright &y& Elsevier]