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
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
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
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
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
Bee venom has been used to relieve pain and to treat inflammatory diseases, including rheumatoid arthritis, in humans. To better understand the mechanisms of the anti-inflammatory and anti-atherosclerosis effect of bee venom, gel electrophoresis and mass spectrometry were used to identify proteins whose expression was altered in human Vascular Smooth Muscle Cells (hVSMCs) stimulated by tumor necrosis factor alpha after 12 h in the presence of melittin.
To obtain valuable insights into the anti-inflammatory and anti-atherosclerosis mechanisms of melittin, two-dimensional (2-D) gel electrophoresis and MALDI-TOF/TOF were used. The proteome study, we showed 33 significant proteins that were differentially expressed in the cells treated with tumor necrosis factor alpha and melittin. Thirteen proteins were significantly increased in the cells treated with tumor necrosis factor alpha, and those proteins were reduced in the cells treated with melittin. Five of the proteins that showed increased expression in the cells treated with tumor necrosis factor alpha are involved in cell migration, including calreticulin, an essential factor of development that plays a role in transcription regulation. The proteins involved in cell migration were reduced in the melittin treated cells. The observed changes in the expression of GRP75, prohibitin, and a select group of other proteins were validated with reverse transcribed-PCR. It was confirmed that the observed change in the protein levels reflected a change in the genes level. In addition, the phosphorylation of EGFR and ERK was validated by analyzing the protein pathway.
Taken together, these data established that the expression of some proteins was significantly changed by melittin treatment in tumor necrosis factor alpha stimulated the cells and provided insights into the mechanism of the melittin function for its potential use as an anti-inflammatory agent.
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.
Objective. Although two recent randomized placebo-controlled trials of rituximab (RTX) failed to demonstrate efficacy in systemic lupus erythematosus (SLE), clinicians continue to use off-label RTX for cases refractory to current treatments. We evaluated the effectiveness and safety of rituximab for patients with refractory SLE in Korea. Methods. We retrospectively analyzed multicenter patients treated with RTX in Korea. Results. 39 SLE patients treated with RTX were included in the following manner: lupus nephritis 43.6%, hematologic 33.3%, arthritis 7.8%, myositis 7.8%, and others 7.7%. All patients had responded poorly to at least one conventional immunosuppressive agent (mean 2.5 ± 1.1, cyclophosphamide 43.6%, mycophenolate mofetil 48.7%, and other drugs) before RTX. Clinical improvements (complete or partial remission) occurred in patients with renal disease, hematologic disease, arthritis, myositis, and other manifestations at 6 months after RTX. The SLEDAI score was significantly decreased from 10.8 ± 7.1 at baseline to 6.7 ± 4.0 at 6 months, 6.2 ± 4.1 at 12 months, and 5.5 ± 3.6 at 24 months after RTX (P < 0.05). Among 28 clinical responders, 4 patients experienced a relapse of disease at 25 ± 4 months. Infections were noted in 3 patients (7.7%).
Conclusion. RTX could be an effective and relatively safe therapeutic option in patients with severe refractory SLE until novel B-cell depletion therapy is available.
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
We performed a multicenter cross-sectional study of 134 sexually active systemic lupus erythematosus (SLE) patients to investigate the prevalence of and risk factors for high risk human papilloma virus (HPV) infection and cervical cytological abnormalities among Korean women with SLE. In this multicenter cross-sectional study, HPV testing and routine cervical cytologic examination was performed. HPV was typed using a hybrid method or the polymerase chain reaction. Data on 4,595 healthy women were used for comparison. SLE patients had greater prevalence of high-risk HPV infection (24.6% vs. 7.9%, P<0.001, odds ratio 3.8, 95% confidence interval 2.5-5.7) and of abnormal cervical cytology (16.4 vs. 2.8%, P<0.001, OR 4.4, 95% CI 2.5-7.8) compared with controls. SLE itself was identified as independent risk factors for high risk HPV infection among Korean women (OR 3.8, 95% CI 2.5-5.7) along with ≥2 sexual partners (OR 8.5, 95% CI 1.2-61.6), and Pap smear abnormalities (OR 97.3, 95% CI 6.5-1,456.7). High-risk HPV infection and cervical cytological abnormalities were more common among Korean women with SLE than controls. SLE itself may be a risk factor for HPV infection among Korean women, suggesting the importance of close monitoring of HPV infections and abnormal Pap smears in SLE patients.
Systemic Lupus Erythematosus, Human Papilloma Virus; Cervical Cytological Abnormalities
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
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
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
It has been suggested that hyperuricemia and possibly gout are associated with the metabolic syndrome, but there have been no direct studies. This study was undertaken to obtain the prevalence of the metabolic syndrome in patients with gout and to compare it with those from the general population studies. This was a 4-institutional case-historical control study composed of 168 patients with gout. We assessed the prevalence of metabolic syndrome according to the ATP III criteria and compared the prevalence with that of the historical controls. To elucidate the factors in gout that were associated with metabolic syndrome, a multivariate analysis was done. The age-adjusted prevalence of metabolic syndrome in gout patients was 43.6%, which was significantly higher than that of the Korean control population (5.2%) from the previous studies. Patients with gout had more components of metabolic syndrome than did the controls. Body mass index (BMI, OR=1.357 (95%CI 1.111-1.657)) and high density lipoprotein (HDL, OR=0.774 (95%CI 0.705-0.850)) were the variables most significantly associated with the occurrence of metabolic syndrome in gout, but alcohol consumption did not show such associations. Gout is associated with the metabolic syndrome, and furthermore, obesity and dyslipidemia were the factors most associated with the syndrome in these patients.
Gout; Metabolic Syndrome X; Hyperuricemia
Inflammatory arthritis is associated with the release of a network of key cytokines. In T cell receptor transgenic K/BxN mice interleukin (IL)-1 plays a key role in joint swelling and destruction, as suggested by the ability of anti–IL-1receptor (IL-1R) antibody treatment to delay the onset and slow the progression of this disease. This mechanism is dependent on the signaling pathway intermediary myeloid differentiation factor 88 (MyD88), such that neither IL-1R nor MyD88-deficient mice developed visually detectable synovitis after transfer of arthritogenic sera. The Toll-like receptors (TLRs) share the same signaling pathway through MyD88 as the IL-1R. The administration of a TLR-4 ligand, lipopolysaccharide, concomitant with arthritogenic serum in IL-1 receptor–deficient mice resulted in acute paw swelling, but not in MyD88-deficient mice. Also, serum transferred arthritis was not sustained in TLR-4 mutant mice compared with controls. These results suggest that innate immune functions via TLR-4 might perpetuate inflammatory mechanisms and bypass the need for IL-1 in chronic joint inflammation.
animal model; lipopolysaccharide; rheumatoid arthritis; autoantibody; Toll-like receptor