Increased resting energy expenditure (REE) in rheumatoid arthritis (RA) patients is thought to be caused by hypermetabolism associated with production of proinflammatory cytokines. Our aim in the present study was to explore the possible association between REE and disease activity in females with RA.
A total of 499 female RA patients were recruited to this cross-sectional study assessing REE scores on disease activity indices (the routine assessment of patient index data 3 [RAPID3], the disease activity score 28, and the clinical/simplified disease activity index [CDAI/SDAI]) and the levels of RA-associated autoantibodies (rheumatoid factor and anticyclic citrullinated peptide [anti-CCP] antibodies). Age-matched healthy female controls (n = 131) were also enrolled.
REE did not differ between RA patients (all patients, and those in remission or not) and controls, or between RA patients in remission or not (p > 0.05 for all comparisons). Increased REE in total RA patients was associated with younger age and a higher body mass index (BMI) (p < 0.001 and p < 0.001, respectively), but not with disease activity index scores on any of RAPID3, CDAI, or SDAI. BMI was the only clinical parameter exhibiting a significant relationship with REE quartiles (Q1 to Q4; p < 0.001); none of disease duration, functional status, or anti-CCP antibody titer in RA patients was significantly related to REE, based on analysis of covariance.
We found no association between REE and disease activity in RA patients, implying that energy metabolism in RA patients might be independent of RA-associated systemic inflammation.
Arthritis, rheumatoid; Resting energy expenditure; Disease activity index
The variability of cardiovascular abnormalities is one of the characteristics of systemic lupus erythematosus (SLE). Among the cardiovascular manifestations, hypertension is reported in 14% to 58.1% of patients in diverse ethnic populations, and remains a clinically important issue due to its close relationship with early mortality in patients with SLE. The development of hypertension in patients with SLE has been associated with advanced lupus-related renal disease and the medications used for the treatment of lupus. Malignant hypertension is a serious complication of hypertension; it rarely occurs in patients with SLE. However, it can occur in patients with other complicated medical conditions such as the antiphospholipid antibody syndrome (APS) or cardiac tamponade. Here, we report the case of a patient with SLE and malignant hypertension with hypertensive retinopathy that initially presented without clinical evidence of APS or hypertensive nephropathy.
Lupus erythematosus, systemic; Hypertension, malignant
Serum creatinine level is the most commonly used indices for assessment of glomerular filtration rate (GFR), even though these indices have been shown to have some limitations in clinical practice. We investigated the diagnostic efficacy of serum cystatin C compared to that of serum creatinine levels and identified the relating factors associated with changes in serum cystatin C levels in gout patients with renal impairment. A total of 68 gouty patients with renal impairment were enrolled in this study. Diagnostic efficacy of serum cystatin C levels was evaluated through non-parametric receiver operating characteristic (ROC) analysis. The risk factors for changes in serum cystatin C levels were confirmed using multivariate regression analysis. With 24-hr urine creatinine clearance (Ccr) as the reference for GFR, 1/cystatin C (r=0.702, P<0.001) showed a significantly higher correlation with Ccr than 1/creatinine (r=0.665, P<0.001). Multivariate correlation analysis demonstrated that the clinical parameters for increased serum cystatin C are a higher stage of chronic kidney disease, older age, use of allopurinol, and lower high density lipoprotein-cholesterol. The area under the curve (AUC) at ROC plots identified that of serum cystatin C was significantly greater than that of serum creatinine (AUC 0.804 of cystatin C and AUC 0.745 of creatinine). The study suggests that serum cystatin C is a reliable endogenous marker for the assessment of renal function or GFR in gout patients with renal impairment.
Cystatin C; Gout; Creatinine; Kidney Failure; Glomerular Filtration Rate
The concurrence of ankylosing spondylitis (AS) in a patient with mixed connective tissue disease (MCTD) is rarely described in the literature. Significant and sustained efficacy with tumor necrosis factor (TNF)-α blockers has been demonstrated in AS patients. However, evidence to date has revealed associated side effects, including antinuclear antibody induction and development of a lupus-like syndrome. Several authors have reported lupus-like manifestations in MCTD patients treated with TNF-α blockers used to control peripheral polyarthritis. In our case report, we demonstrate a good response to etanercept therapy for refractory sacroiliitis in a patient with coexisting AS and MCTD, without development of a lupus-like syndrome. This demonstrates that etanercept therapy may be an appropriate therapeutic agent for sacroiliitis in MCTD patients, as it is in AS alone.
Ankylosing spondylitis; mixed connective tissue disease; etanercept
Behçet's disease (BD) is a systemic vasculitis involving diverse sizes of arteries and veins. We performed this study to evaluate the vascular changes by assessment of the arterial stiffness and intima-media thickness (IMT) of carotid artery in Korean patients with BD. Forty-one patients with BD and age-, and sex-matched 53 healthy subjects were recruited in this study. Carotid arterial stiffness and IMT were assessed by using high-resolution B-mode ultrasonography. Arterial stiffness parameters such as carotid arterial distensibility coefficient, stiffness index, and incremental elastic modulus (Einc) were significantly increased in BD patients compared with those in healthy subjects, but not in IMT. Positive relationship was noted between age and IMT, whereas age of onset was significantly associated with arterial stiffness in BD. This finding suggests impaired endothelial function before visible structural changes of arterial wall in BD. Age and age of onset may be an independent risk factor for carotid IMT and arterial stiffness, respectively. Further studies in more large populations are required to confirm our results.
Arterial Stiffness; Intima-media Thickness; Carotid Artery; Behçet's Disease
A 40-year-old Korean man presented with painful swelling and tenderness of both ankle joints as well as the plantar surfaces of both feet, along with inflammatory back pain, and a purulent discharge from the urethral orifice. The patient also complained of sicca-like symptoms including dry eyes and dry mouth. An immunological analysis revealed a high titer of rheumatoid factor, positive results for antinuclear antibody and anti-Ro antibody, and a positive result for HLA-B27. An antibody titer for Chlamydia was also significantly increased. Positive results of the Schirmer's test and for keratoconjunctivitis sicca were confirmed by an ophthalmologist. These clinical manifestations were compatible with Chlamydia-induced reactive arthritis (ReA) accompanied by Sjögren's syndrome (SS). This is the first report of the combination of these two distinct disease entities in the Korean population.
Reactive arthritis; Sjögren's syndrome
A highly polygenic etiology and high degree of allele-sharing between ancestries have been well-elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data.
We analyzed Korean rheumatoid arthritis case-control samples using the Immunochip and GWAS array to search for new risk alleles of rheumatoid arthritis with anti-citrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data, for a total sample size of 9,299 Korean and 45,790 European case-control samples.
We identified 8 new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1–FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10−8), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the 7 new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of SNPs that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs.
This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.
Rheumatoid arthritis; Gene polymorphism; Anti-CCP
Activation of spinal glial cells plays a crucial role in the pathogenesis of neuropathic pain. An administration of oxaliplatin, an important anticancer drug, often induces acute neuropathic cold hypersensitivity and/or mechanical hypersensitivity in patients. Gyejigachulbu-tang (GBT), a herbal formula comprising Cinnamomi Cortex, Paeoniae Radix, Atractylodis Lanceae Rhizoma, Zizyphi Fructus, Glycyrrhizae Radix, Zingiberis Rhizoma, and Aconiti Tuber, has been used in East Asia to treat various pain symptoms, especially in cold patients. This study investigated whether and how GBT alleviates oxaliplatin-induced cold and mechanical hypersensitivity in rats. The behavioral signs of cold and mechanical hypersensitivity were evaluated by a tail immersion test in cold water (4°C) and a von Frey hair test, respectively. The significant cold and mechanical hypersensitivity were observed 3 days after an oxaliplatin injection (6 mg/kg, i.p.). Daily oral administration of GBT (200, 400, and 600 mg/kg) for 5 days markedly attenuated cold and mechanical hypersensitivity. Immunoreactivities of glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker) in the spinal dorsal horn were significantly increased by an oxaliplatin injection, which were restored by GBT administration. These results indicate that GBT relieves oxaliplatin-induced cold and mechanical hypersensitivity in rats possibly through the suppression of spinal glial activation.
Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disease of unknown origin, which exhibits a complex heterogeneity in its pathophysiological background, resulting in differential responses to a range of therapies and poor long-term prognosis. RA synovial fibroblasts (RASFs) are key player cells in RA pathogenesis. Identification of DNA methylation biomarkers is a field that provides potential for improving the process of diagnosis and prognosis of various human diseases. We utilized a genome-wide technique, methylated DNA isolation assay (MeDIA), in combination with a high resolution CpG microarray for discovery of novel hypermethylated genes in RASFs. Thirteen genes (APEX1, EBF3, EGR2, EN1, IRX1, IRX6, KIF12, LHX2, MIPOL1, SGTA, SIN3A, TOLLIP, and ZHX2) with three consecutive hypermethylated probes were isolated as candidate genes through two CpG microarrays. Pyrosequencing assay was performed to validate the methylation status of TGF-β signaling components, EBF3 and IRX1 genes in RASFs and osteoarthritis (OA) SFs. Hypermethylation at CpG sites in the EBF3 and IRX1 genes was observed with a high methylation index (MI) in RASFs (52.5% and 41.4%, respectively), while a lower MI was observed in OASFs and healthy SFs (13.2% for EBF3 and 4.3% for IRX1). In addition, RT-PCR analysis showed a remarkable decrease in their mRNA expression in the RA group, compared with the OA or healthy control, and their reduction levels correlated with MI. The current findings suggest that methylation-associated down-regulation of EBF3 and IRX1 genes may play an important role in a pathogenic effect of TGF-β on RASFs. However, further clinical validation with large numbers of patients is needed in order to confirm our findings.
EBF3; hypermethylation; IRX1; rheumatoid arthritis; synovial fibroblast
This study investigated whether the calcineurin inhibitor, tacrolimus, suppresses receptor activator of NF-κB ligand (RANKL) expression in fibroblast-like synoviocytes (FLS) through regulation of IL-6/Janus activated kinase (JAK2)/signal transducer and activator of transcription-3 (STAT3) and suppressor of cytokine signaling (SOCS3) signaling.
The expression of RANKL, JAK2, STAT3, and SOCS3 proteins was assessed by western blot analysis, real-time PCR and ELISA in IL-6 combined with soluble IL-6 receptor (sIL-6R)-stimulated rheumatoid arthritis (RA)-FLS with or without tacrolimus treatment. The effects of tacrolimus on synovial inflammation and bone erosion were assessed using mice with arthritis induced by K/BxN serum. Immunofluorescent staining was performed to identify the effect of tacrolimus on RANKL and SOCS3. The tartrate-resistant acid phosphatase staining assay was performed to assess the effect of tacrolimus on osteoclast differentiation.
We found that RANKL expression in RA FLS is regulated by the IL-6/sIL-6R/JAK2/STAT3/SOCS3 pathway. Inhibitory effects of tacrolimus on RANKL expression in a serum-induced arthritis mice model were identified. Tacrolimus inhibits RANKL expression in IL-6/sIL-6R-stimulated FLS by suppressing STAT3. Among negative regulators of the JAK/STAT pathway, such as CIS1, SOCS1, and SOCS3, only SOCS3 is significantly induced by tacrolimus. As compared to dexamethasone and methotrexate, tacrolimus more potently suppresses RANKL expression in FLS. By up-regulating SOCS3, tacrolimus down-regulates activation of the JAK-STAT pathway by IL-6/sIL-6R trans-signaling, thus decreasing RANKL expression in FLS.
These data suggest that tacrolimus might affect the RANKL expression in IL-6 stimulated FLS through STAT3 suppression, together with up-regulation of SOCS3.
This study determined the prevalence and determinants of seropositivity for rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) antibody, and anti-mutated citrullinated vimentin (anti-MCV) antibody in unaffected first-degree relatives (FDRs) of rheumatoid arthritis (RA) patients.
A total of 337 subjects (135 with RA and 202 FDRs) were enrolled in this case-control study. Serum RF, anti-CCP antibody, and anti-MCV antibody were assayed. Subjects in multicase families (≥ 2 affected FDRs within the same family) were identified. Multivariate logistic regression analysis was used to identify risk factors associated with RA-related autoantibodies.
Seropositivity for RF, anti-CCP antibody, or anti-MCV antibody was detected in 14.4%, 5.0%, or 13.4% of unaffected FDRs, respectively. Anti-CCP antibody seropositivity was more prevalent in FDRs in multicase families (17.8%) than in those not in multicase families (1.3%, p < 0.0001). Significant correlations between RA-associated autoantibodies were detected in the FDR group (between RF and anti-CCP antibody: r = 0.366, p < 0.0001; between RF and anti-MCV antibody: r = 0.343, p < 0.0001; and between anti-CCP antibody and anti-MCV antibody: r = 0.849, p < 0.0001). After adjustment for age and sex, anti-CCP antibody seropositivity in FDRs was significantly associated with being in a multicase family (odds ratio, 49.8; 95% confidence interval, 5.6 to 441.6).
The association between anti-CCP antibody seropositivity in unaffected FDRs and being in a multicase family suggests that genetic and/or environmental factors may increase the risk for RA development in unaffected FDRs.
Rheumatoid arthritis; First-degree relative; Rheumatoid factor; Citrullinated antigen
To determine the associating factors of fear of falling (FOF) and the correlations between FOF and quality of life (QOL) on subacute stroke patients in Korea.
Fifty hemiplegic subacute stroke patients in our clinic were recruited. We directly asked patients with their fear of falling and interviewed them with the Korean version of falls efficacy scale-international (KFES-I). We divided the participants into two groups; with FOF and without FOF. We compared these groups with the strength of hemiplegic hip abductor, knee extensor, ankle plantar flexor, functional ambulation category (FAC) scale, stroke specific quality of life (SSQOL), and hospital anxiety depression scale (HADS).
Thirty-four participants were enrolled, and more than half of the patients with subacute stroke had FOF. We compared the patients with and without FOF. According to the results, FOF was associated with the strength of hemiplegic hip abductor, knee extensor and ankle plantar flexor, FAC, total SSQOL, and domains (energy, mobility, self care, upper extremity function) of SSQOL (p<0.05). FOF was also associated with the anxiety score of HADS (p<0.05). KFES-I had a significant negative correlation with the strength of hemiplegic hip abductor, knee extensor and ankle plantar flexor, FAC, total SSQOL, and domains (energy, mobility, self care, upper extremity function) of SSQOL (p<0.01).
The FOF was associated with not only QOL but also with the physical and psychological factors, and in particular, anxiety. Therefore, further concerns about FOF in subacute stroke patients might be required.
Stroke; Fear; Falling; Anxiety; Quality of life
Fibromyalgia (FM) is a disorder characterized by chronic widespread pain and frequently associated with other symptoms. Patients with FM commonly report cognitive complaints, including memory problem. The objective of this study was to investigate the differences in neural correlates of working memory between FM patients and healthy subjects, using functional magnetic resonance imaging (MRI).
Nineteen FM patients and 22 healthy subjects performed an n-back memory task during MRI scan. Functional MRI data were analyzed using within- and between-group analysis. Both activated and deactivated brain regions during n-back task were evaluated. In addition, to investigate the possible effect of depression and anxiety, group analysis was also performed with depression and anxiety level in terms of Beck depression inventory (BDI) and Beck anxiety inventory (BAI) as a covariate. Between-group analyses, after controlling for depression and anxiety level, revealed that within the working memory network, inferior parietal cortex was strongly associated with the mild (r = 0.309, P = 0.049) and moderate (r = 0.331, P = 0.034) pain ratings. In addition, between-group comparison revealed that within the working memory network, the left DLPFC, right VLPFC, and right inferior parietal cortex were associated with the rating of depression and anxiety?
Our results suggest that the working memory deficit found in FM patients may be attributable to differences in neural activation of the frontoparietal memory network and may result from both pain itself and depression and anxiety associated with pain.
Scleroderma, systemic; Cerebrovascular disorder; Moyamoya disease
Anti-Ro autoantibody is associated with Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), and neonatal lupus syndrome (i.e., congenital complete heart block in newborns). Generally, the adult atrioventricular (AV) node is believed to be relatively resistant to the scarring effects of anti-Ro/anti-La autoantibodies. However, there have been some reports of adult complete AV block in SS and SLE patients. Here, we report a case of complete heart block in primary SS with anti-Ro autoantibodies, with no other risk factor for the development of heart block, and review their etiological association.
Ro antibodies; Sjögren's syndrome; Atrioventricular block
Sjögren's syndrome (SS) is an autoimmune disorder in which lymphocytes infiltrate the exocrine glands, resulting in the development of sicca symptoms. Lymphocytes may also invade various other organs and cause diverse symptoms. Interstitial pneumonia has been observed frequently in SS patients. Typically, the pneumonia responds well to systemic steroids, and fatal cases are rare. We experienced a case of lymphocytic pneumonia accompanied by SS and treated with cyclophosphamide pulse therapy, and we present details of the case herein.
Sjögren's syndrome; Interstitial pneumonia; Lymphocytes
To examine the correlation between radiological joint damage and serological parameters in early rheumatoid arthritis (RA).
This retrospective study reviewed the records of 216 patients diagnosed with RA and classified them according to disease duration: group 1, ≤ 24 months; group 2, > 24 months; and group 3, all patients combined. The extent of joint damage was assessed from plain radiographs using a modified version of the Larsen method and compared among groups.
The mean radiographic joint damage score was significantly higher in patients who had established RA (10.1 points) compared with those who had early RA. In group 1, the inflammatory parameters, erythrocyte sedimentation rate, and C-reactive protein were positively correlated with the joint damage score, but rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody were not. A subgroup analysis revealed that the anti-CCP positive patients in groups 1 and 2 had greater joint damage scores than did the anti-CCP negative patients, but no difference in RF was observed between subgroups. Anti-CCP positivity was not significantly correlated with joint damage sores in group 3.
Anti-CCP positivity was significantly correlated with more severe joint damage at diagnosis. A correlation was observed between the radiological joint damage score and inflammatory parameters in early and established RA, indicating that anti-CCP can serve as a diagnostic tool and predict structural joint damage. These findings suggest anti-CCP positive patients should receive aggressive therapeutic intervention.
Arthritis, rheumatoid; Rheumatoid factor; Cyclic citrullinated peptide; Joint disease
Polyfibromatosis syndrome is a rare disease entity that is characterized by various clinical features such as palmar, plantar, and penile fibromatoses, keloid formations of the skin, and erosive arthropathy. Its precise pathophysiology or etiology remains unclear. In addition to distinctive diverse skin manifestations, patients with polyfibromatosis have been previously reported to show erosive arthropathy with significant limitation of movement at affected joints. However, the presence of erosive polyarthropathy in polyfibromatosis has not emphasized in previous cases. Here, we report a case of polyfibromatosis syndrome combined with painless massive structural destruction of hand and foot joints, and review the characteristics of erosive arthropathy in previous cases.
Polyfibromatosis; Erosive Arthropathy; Magnetic Resonance Imaging
Anti-inflammatory factor (AIF) is a water soluble extract of three herbs, Panax notoginseng (Burk.) F. H. Chen, Rehmannia glutinosa Libosch and Eleutherococcus senticosus. The present study aimed to investigate the safety and efficacy of herb extracts, AIF, on Korean knee osteoarthritis patients for six weeks. Fifty seven patients with knee osteoarthritis, ranging from 43 to 73 years of age, who fulfilled the "American College of Rheumatology" (ACR) classification of idiopathic osteoarthritis of knee and radiographic criteria were randomly selected and enrolled for the study. After initial screening and resting period, two capsules each of AIF (Each capsule contains; 400 mg) and similar identical placebo were administered twice a day to both groups. Pain intensity at second, fourth, and sixth weeks of study as well as one week after discontinuation of drugs was assessed by using 100 mm visual analogue scale (VAS). Changes in the Korean version of the Western Ontario and McMaster Universities (K-WOMAC) index score were compared at the initiation and completion of the study. VAS assessed by patients were significantly reduced (at visit 2; 54.64±14.72, at visit 4, 37.32±16.58, p< 0.001) after AIF administration. Results showed an improvement in the physical function of K-WOMAC scale which was significantly higher (p=0.013) in AIF than placebo group, and decreases of total K-WOMAC score were also significantly higher (p=0.030) in AIF groups than placebo group. No serious adverse effect was observed, and there was no difference in incidence of adverse effect between AIF and placebo groups. In this population of Korean patients with knee osteoarthritis, AIF was found to be safe, tolerable and effective for symptomatic improvement of pain and physical function.
Anti-inflammatory factor; Clinical trial; Herbs; Osteoarthritis; K-WOMAC