A recent study in the North American White population has documented the association of a common STAT4 haplotype (tagged by rs7574865) with risk for rheumatoid arthritis (RA) and systemic lupus erythematosus. To replicate this finding in the Korean population, we performed a case-control association study. We genotyped 67 single nucleotide polymorphisms (SNPs) within the STAT1 and STAT4 regions in 1123 Korean patients with RA and 1008 ethnicity-matched controls. The most significant four risk SNPs (rs11889341, rs7574865, rs8179673, and rs10181656 located within the third intron of STAT4) among 67 SNPs are identical with those in the North American study. All four SNPs have modest risk for RA susceptibility (odds ratio 1.21–1.27). A common haplotype defined by these markers (TTCG) carries significant risk for RA in Koreans [34 percent versus 28 percent, P = 0.0027, OR (95 percent CI) = 1.33 (1.10–1.60)]. By logistic regression analysis, this haplotype is an independent risk factor in addition to the classical shared epitope alleles at the HLA-DRB1 locus. There were no significant associations with age of disease onset, radiographic progression, or serologic status using either allelic or haplotypic analysis. Unlike several other risk genes for RA such as PTPN22, PADI4, and FCRL3, a haplotype of the STAT4 gene shows consistent association with RA susceptibility across Whites and Asians, suggesting that this risk haplotype predates the divergence of the major racial groups.
Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10−8, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans.
Systemic lupus erythematosus (SLE), a debilitating autoimmune disease characterized by the production of pathogenic autoantibodies, has a strong genetic basis. Variants of the IL10 gene, which encodes cytokine interleukin-10 (IL-10) with known function of promoting B cell hyperactivity and autoantibody production, are associated with SLE and other autoimmune diseases, and serum IL-10 levels are elevated in SLE patients correlating with increased disease activity. In this study, to discover SLE-predisposing causal variant(s), we assessed variants within the genomic region containing IL10 and its gene family member IL19, IL20 and IL24 for association with SLE in case and control subjects from diverse ancestries. We identified SLE-associated SNP rs3122605 located at 9.2 kb upstream of IL10 as the most likely causal variant in subjects of European ancestry. The SLE-risk allele of rs3122605 was dose-dependently associated with elevated IL10 expression at both mRNA and protein levels in peripheral blood samples from SLE patients and controls, which could be explained, at least in part, by its preferential binding to Elk-1, a transcription factor activated in B cells during active disease of SLE patients. Elk-1-mediated IL-10 overexpression could be downregulated by inhibiting activation of mitogen-activated protein kinases, suggesting a potential therapeutic target for SLE.
We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10−34, OR = 1.43[1.26–1.60]) and rs1234317-T (P = 1.16×10−28, OR = 1.38[1.24–1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5′ region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5′ risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.
Systemic lupus erythematosus (SLE/lupus) is a complex disease in which the body's immune cells cause inflammation in one or more systems to cause the associated morbidity. Hormones, the environment and genes are all causal contributors to SLE and over the past several years the genetic component of SLE has been firmly established. Several genes which are regulators of the immune system are associated with disease risk. We have established one of these, the tumour-necrosis family superfamily member 4 (TNFSF4) gene, as a lupus susceptibility gene in Northern Europeans. A major obstacle in pinpointing the marker(s) at TNFSF4 which best explain the risk of SLE has been the strong correlation (linkage disequilibrium, LD) between adjacent markers across the TNFSF4 region in this population. To address this, we have typed polymorphisms in several populations in addition to the European groups. The mixed ancestry of these populations gives a different LD pattern than that found in Europeans, presenting a method of pinpointing the section of the TNFSF4 region which results in SLE susceptibility. The Non-European populations have allowed identification of a polymorphism likely to regulate expression of TNFSF4 to increase susceptibility to SLE.
Patient reported outcomes (PROs) are especially useful in assessing treatments for rheumatoid arthritis (RA) since they measure dimensions of health-related quality of life that cannot be captured using strictly objective physiological measures. The aim of this study was to compare the effects of combination etanercept and methotrexate (ETN + MTX) versus combination synthetic disease modifying antirheumatic drugs (DMARDs) and methotrexate (DMARD + MTX) on PRO measures among RA patients from the Asia-Pacific region, a population not widely studied to date. Patients with established moderate to severe rheumatoid arthritis who had an inadequate response to methotrexate were studied.
Patients were randomized to either ETN + MTX (N = 197) or DMARD + MTX (N = 103) in an open-label, active-comparator, multicenter study, with PRO measures designed as prospective secondary endpoints. The Health Assessment Questionnaire (HAQ), Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue), Medical Outcomes Short Form-36 Health Survey (SF-36), Hospital Anxiety and Depression Scale (HADS) and the Work Productivity and Activity Impairment Questionnaire: General Health (WPAI:GH) were used.
Significantly greater improvements were noted for the ETN + MTX group at week16 for HAQ mean scores and for proportion of patients achieving HAQ score ≤ 0.5, compared to patients in the DMARD + MTX group. SF-36 Summary Scores for physical and mental components and for 6 of 8 health domains showed significantly greater improvements at week16 for the ETN + MTX group; only scores for physical functioning and role-emotional domains did not differ significantly between the two treatment arms. Greater improvements at week16 were noted for the ETN + MTX group for FACIT-Fatigue, HADS, and WPAI:GH mean scores.
Combination therapy using ETN + MTX demonstrated superior improvements using a comprehensive set of PRO measures, compared to combination therapy with usual standard of care DMARDs plus MTX in patients with established rheumatoid arthritis from the Asia-Pacific region.
clintrials.gov # NCT00422227
Patient reported outcomes; Etanercept; Rheumatoid arthritis; Asia-Pacific; Health outcomes assessments
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.
The genetic association of the major histocompatibility complex (MHC) to rheumatoid arthritis risk has commonly been attributed to HLA-DRB1 alleles. Yet controversy persists about the causal variants in HLA-DRB1 and the presence of independent effects elsewhere in the MHC. Using existing genome-wide SNP data in 5,018 seropositive cases and 14,974 controls, we imputed and tested classical alleles and amino acid polymorphisms for HLA-A, B, C, DPA1, DPB1, DQA1, DQB1, and DRB1 along with 3,117 SNPs across the MHC. Conditional and haplotype analyses reveal that three amino acid positions (11, 71 and 74) in HLA-DRβ1, and single amino acid polymorphisms in HLA-B (position 9) and HLA-DPβ1 (position 9), all located in the peptide-binding grooves, almost completely explain the MHC association to disease risk. This study illustrates how imputation of functional variation from large reference panels can help fine-map association signals in the MHC.
T cells from patients with SLE express increased amounts of PP2Ac which contribute to decreased production of IL-2. Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac.
We conducted a trans-ethnic study consisting of 8,695 SLE cases and 7,308 controls from four different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across the PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time PCR.
A 32-kb haplotype comprised of multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans (HA), European Americans (EA) and Asians but not in African-Americans (AA). Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, EA and HA populations (pmeta=3.8×10−7, OR=1.3[1.14–1.31]). In EA, the largest ethnic dataset, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-dsDNA and anti-RNP antibodies. PPP2CA expression was approximately 2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying GG genotype (p = 0.008).
Our data provide the first evidence for an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in EA, HA and Asians.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by autoantibody production and organ damage. Lupus nephritis (LN) is one of the most severe manifestations of SLE. Multiple studies reported associations between renal diseases and variants in the non-muscle myosin heavy chain 9 (MYH9) and the neighboring apolipoprotein L 1 (APOL1) genes. We evaluated 167 variants spanning MYH9 for association with LN in a multiethnic sample. The two previously identified risk variants in APOL1 were also tested for association with LN in European-Americans (EAs) (N = 579) and African-Americans (AAs) (N = 407). Multiple peaks of association exceeding a Bonferroni corrected p-value of p < 2.03 × 10−3 were observed between LN and MYH9 in EAs (N=4620), with the most pronounced association at rs2157257 (p = 4.7 × 10−4; odds ratio [OR]=1.205). A modest effect with MYH9 was also detected in Gullah (rs8136069, p = 0.0019, OR = 2.304). No association between LN and MYH9 was found in AAs, Asians, Amerindians or Hispanics. This study provides the first investigation of MYH9 in LN in non-Africans and of APOL1 in LN in any population and presents novel insight into the potential role of MYH9 in LN in EAs.
MYH9; APOL1; lupus nephritis; systemic lupus erythematosus; multiethnic association study
Systemic Lupus Erythematosus (SLE, OMIM 152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic resequencing in ethnically diverse populations we fully characterized the TNFAIP3 risk haplotype and isolated a novel TT>A polymorphic dinucleotide associated with SLE in subjects of European (P = 1.58 × 10−8; odds ratio (OR) = 1.70) and Korean (P = 8.33 × 10−10; OR = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex comprised of NF-κB subunits with reduced avidity. Furthermore, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.
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
Anti-cyclic citrullinated peptide autoantibodies (anti-CCP) are the most specific serologic marker for rheumatoid arthritis (RA). Genetic polymorphisms in a citrullinating (or deiminating) enzyme, peptidyl arginine deiminase type IV (PADI4) have been reproducibly associated with RA susceptibility in several populations. We investigated whether PADI4 polymorphisms contribute to anti-CCP-negative as well as -positive RA, whether they influence disease severity (erosive joint status), and whether they interact with two major risk factors for RA, Human Leukocyte Antigen-DRB1 (HLA-DRB1) shared epitope (SE) alleles and smoking, depending on anti-CCP and erosive joint status.
All 2,317 unrelated Korean subjects including 1,313 patients with RA and 1,004 unaffected controls were genotyped for three nonsynonymous (padi4_89, padi4_90, and padi4_92) and one synonymous (padi4_104) single-nucleotide polymorphisms (SNPs) in PADI4 and for HLA-DRB1 by direct DNA sequence analysis. Odds ratios (OR) were calculated by multivariate logistic regression. Interaction was evaluated by attributable proportions (AP), with 95% confidence intervals (CI).
A functional haplotype of the three fully correlated nonsynonymous SNPs in PADI4 was significantly associated with susceptibility to not only anti-CCP-positive (adjusted OR 1.73, 95% CI 1.34 to 2.23) but also -negative RA (adjusted OR 1.75, 95% CI 1.15 to 2.68). A strong association with both non-erosive (adjusted OR 1.62, 95% CI 1.29 to 2.05) and erosive RA (adjusted OR 1.62, 95% CI 1.14 to 2.31) was observed for PADI4 haplotype. Gene-gene interactions between the homozygous RA-risk PADI4 haplotype and SE alleles were significant in both anti-CCP-positive (AP 0.45, 95% CI 0.20 to 0.71) and -negative RA (AP 0.61, 95% CI 0.29 to 0.92). Theses interactions were also observed for both non-erosive (AP 0.48, 95% CI 0.25 to 0.72) and erosive RA (AP 0.46, 95% CI 0.14 to 0.78). In contrast, no interaction was observed between smoking and PADI4 polymorphisms.
A haplotype of nonsynonymous SNPs in PADI4 contributes to development of RA regardless of anti-CCP or erosive joint status. The homozygous PADI4 haplotype contribution is affected by gene-gene interactions with HLA-DRB1 SE alleles.
Recent studies have identified a number of novel rheumatoid arthritis (RA) loci in Caucasian populations. In this study, we sought to determine whether the genetic variants at 4q27, 6q23, CCL21, TRAF1/C5, and CD40 identified in Caucasians are also associated with RA in a Korean case-control collection. We also comprehensively evaluated the genetic variation within PTPN22, a well established autoimmune disease-associated gene.
We designed a Sequenom iPlex experiment to thoroughly evaluate the PTPN22 linkage disequilibrium region using tag SNPs and disease-associated SNPs at 5 other previously reported Caucasian RA-associated loci in 1123 RA Korean RA patients and 1008 ethnically matched controls. We also re-sequenced the PTPN22 gene to look for novel coding variants that might be contributing to disease in this population.
None of the Caucasian RA susceptibility loci contributed significantly to disease in Koreans. Tag SNPs covering the PTPN22 linkage disequilibrium block, while polymorphic, did not reveal any disease association and re-sequencing did not identify any new common coding region variants in this population. The 6q23 and 4q27 SNPs assayed were non-polymorphic in this population and the TRAF1/C5, CD40, and CCL21 SNPs did not show any evidence for association.
Caucasian and Korean rheumatoid arthritis have different genetic risk factors. While patients of different ethnic groups share the HLA region as a major genetic risk locus, most other genes shown to be significantly associated with disease in Caucasians appear not to play a role in Korean RA.
We aimed to evaluate the safety and clinical responses in Korean ankylosing spondylitis (AS) patients after three months of etanercept therapy. AS patients satisfying the Modified New York Criteria were enrolled. They were assessed for safety and clinical responses at enrollment and after three months of etanercept therapy. A total of 124 patients completed the study. After three months, the rate of ASsessment in AS International Working Group 20% improvement (ASAS 20) response was 79.8%. The rates of ASAS 40 and ASAS 5/6 responses were 58.5 and 62.8%, respectively. Significant improvement of Korean version of Bath AS Disease Activity Index (KBASDAI) (p<0.0001), Bath AS Functional Activity Index (BASFI) (p<0.0001), and Bath AS Metrology Index (BASMI) (p=0.0009) were achieved after three months. Quality of life was also significantly improved after three months, as demonstrated by scores for SF-36 (p<0.0001) and EQ-5D (p<0.0001). Erythrocyte sedimentation rate and C-reactive protein were significantly decreased (p<0.0001, p<0.0001, respectively). None of the patients developed tuberculosis and there were no serious adverse event. AS patients with inadequate response to conventional therapy showed significant clinical improvement without serious adverse events after three months of etanercept therapy.
Spondylitis, Ankylosing; TNFR-Fc Fusion Protein; Clinical Effectiveness; Safety
This paper provides an overview of the Korean Burden of Disease (KBoD) study, which was the first such study to assess the national burden of disease using disability-adjusted life years (DALYs) in an advanced Asian country. The KBoD study generally followed the approach utilized in the original Global Burden of Disease study (GBD), with the exception of the disease classification and epidemiological data estimation methods used, and the relative weightings of disabilities. The results of the present study reveal that the burden of disease per 100,000 of the Korean population originates primarily from; cancer (1,525 Person Years, PYs), cardiovascular disease (1,492 PYs), digestive disease (1,140 PYs), diabetes mellitus (990 PYs), and certain neuro-psychiatric conditions (883 PYs). These results are largely consistent with those of developed countries, but also represent uniquely Korean characteristics.
Mortality; Morbidity; Korea; Burden of Disease
Recently, two studies provided convincing evidence that IFN regulatory factor 5 (IRF5) gene polymorphisms are significantly associated with systemic lupus erythematosus (SLE) in several white populations. To replicate the association with SLE in an Asian population, we examined the genetic effects in our SLE cohort from a Korean population. A total of 1,565 subjects, composed of 593 cases and 972 controls, were genotyped using the TaqMan® (Applied Biosystems, Foster City, CA, USA) method. The genetic effects of polymorphisms on the risk of SLE were evaluated using χ2 tests and a Mantel–Haenszel meta-analysis. Statistical analysis revealed results in the Korean population were similar to the previous reports from white populations. The rs2004640 T allele had a higher frequency in SLE cases (0.385) than controls (0.321; odds ratio (OR) = 1.32, P = 0.0003). In combined analysis, including all seven independent cohorts from the three studies so far, robust and consistent associations of the rs2004640 T allele with SLE were observed. The estimate of risk was OR = 1.44 (range, 1.34–1.55), with an overall P = 1.85 × 10-23 for the rs2004640 T allele. The haplotype (rs2004640T–rs2280714T) involved in both the alternative splice donor site and the elevated expression of IRF5 also had a highly significant association with SLE (pooled, P = 2.11 × 10-16). Our results indicate that the genetic effect on the risk of SLE mediated by IRF5 variants can be generally accepted in both white and Asian populations.
Rheumatoid arthritis (RA) is a common autoimmune disease with a complex genetic etiology. Herein we identify a single-nucleotide polymorphism (SNP) in the promoter region of FcRH3, a member of the Fc receptor homolog family, that is associated with RA susceptibility (OR=2.15, P=0.00000085). This polymorphism alters the binding affinity of nuclear factor-κB and regulates FcRH3 expression. High FcRH3 expression on B-cells and augmented autoantibody production were observed in individuals with the disease-susceptible genotype. Associations were also found between the SNP and susceptibility to autoimmune thyroid disease and systemic lupus erythematosus. FcRH3 may thus play a pivotal role in autoimmunity.
Sodium nitroprusside (SNP), a widely used nitric oxide donor, has recently been shown to mediate chondrocyte apoptosis by generating reactive oxygen species, whereas more potent nitric oxide donors do not induce chondrocyte apoptosis. The present study was performed to investigate the protective effect of a low concentration of SNP upon the cytotoxicity of chondrocytes to higher concentrations of SNP, and to elucidate the underlying mechanism. Human osteoarthritis chondrocytes were cultured as monolayers, and first-passage cells were used for the experiments. Chondrocyte death induced by 1 mM SNP was completely inhibited by pretreating with 0.1 mM SNP. This protective effect of SNP was replicated by the guanosine-3',5'κ-cyclic monophosphate analog, DBcGMP. Protection from chondrocyte death conferred by 0.1 mM SNP was mediated by heme oxygenase 1 (HO-1), as was revealed by the increased expression of HO-1 in 0.1 mM SNP pretreated chondrocytes and by the reversal of this protective effect by the HO-1 inhibitor, zinc protoporphyrin. SNP-mediated chondrocyte protection correlated with the downregulation of both extracellular signal-regulated protein kinase 1/2 and p38 kinase activation. SNP at 0.1 mM induced significant NF-κB activation as revealed by electrophoretic mobility shift assays, and the inhibition of NF-κB by MG132 or Bay 11-7082 nullified 0.1 mM SNP-mediated chondrocyte protection. The upregulation of p53 and the downregulation of Bcl-XL and Mcl-1 by 1 mM SNP were reversed by 0.1 mM SNP pretreatment at the protein level by western blotting. Our study shows that priming with 0.1 mM SNP confers complete protection against cell death induced by 1 mM SNP in human articular chondrocytes. This protective effect was found to be correlated with the upregulation of both HO-1 and NF-κB and with the concomitant downregulation of both extracellular signal-regulated protein kinase 1/2 and p38 activation.
Severe systemic manifestations of adult onset Still's disease (AOSD) are often fatal and occasionally related to hemophagocytic syndrome (HS). We describe the case of a 49-yr-old woman with AOSD presenting with non-remitting high fever, confusion, jaundice, hepatosplenomegaly, serositis, azotemia, pancytopenia, coagulopathy with disseminated intravascular coagulation (DIC), hyperferritinemia, acute acalculous cholecystitis and ileocolitis noted in computed tomographic images. The patient had a history of herpes zoster developed prior to the admission, but there is no history of diarrhea or abdominal pain. Although bone marrow examination was not performed due to hemorrhagic diathesis, we suspected AOSD-associated HS on the basis of clinical course without detectable infectious agents in cultures or serologic studies. Intravenous immunoglobulin, pulse methylprednisolone, oral cyclosporine A (CsA) and ceftriaxone brought about transient improvement of fever and confusion, but the disease progressed. After increasing CsA dose, all previously mentioned abnormalities disappeared rapidly. Accordingly, we believe that DIC and multiple organ dysfunctions might have been the complications of HS but not that of sepsis, and that CsA can be used as a first-line therapy in case of life-threatening situations.
Still's Disease, Adult-onset; Hemophagocytic Syndrome; Cyclosporins
The aim of our study was to develop a Korean rheumatic diseases-screening questionnaire. The questionnaire was constructed based on American College of Rheumatology criteria for rheumatic diseases and a connective tissue diseases screening questionnaire. Two groups of patients were selected and completed the questionnaire: (i) those with osteoarthritis (n=46), rheumatoid arthritis (n=52), systemic lupus erythematosus (n=50), scleroderma (n=8), polymyositis or dermatomyositis (n=7), Sjogren's disease (n=4), and mixed connective-tissue disease (n=9) as case subjects; and (ii) those with fibromyalgia (n=8) and general disease without evidence of any rheumatic disease (n=72) as controls. Laboratory results were analyzed for correlation with actual data using kappa (kappa) statistics. Test-retest reliability was performed in 12 patients, and showed strong agreement between the first and second interviews (kappa=0.91). The sensitivity of the questionnaire ranged from 77.8 to 100%, and specificity ranged from 68.8 to 95.0%. Negative predictive values were very high in the general population, from 98.4 to 99.99%. The kappa statistic for agreement between laboratory items was 0.22-0.56, except for rheumatoid factor, antinuclear antibody test, and muscle enzyme level. We have developed a simple and sensitive Korean rheumatic diseases-screening questionnaire for the epidemiologic study of rheumatic diseases in Korea.
This study was performed to define the clinical spectrum and disease manifestations of ankylosing spondylitis (AS) in a referral hospital setting. We identified the differences in clinical manifestations according to the sex, the age at onset, the presence of peripheral arthritis and the presence of HLA B27. A total 412 patients (357 males, 55 females) were recruited. Eighty-seven percent were men and 155 out of 412 patients (35%) were juvenile-onset. HLA B27 was detected in 385 patients (93%). Peripheral joint involvement was noted in 287 of total AS cases (juvenile- onset ankylosing spondylitis (JOAS), 82%; adult-onset ankylosing spondylitis (AOAS), 61%), and was more common than those reported in other studies. A greater portion of patients with JOAS had peripheral arthritis and peripheral enthesitis than the patients with AOAS. The patients with peripheral arthritis showed a younger age at onset and an increased tendency of having enthesitis and trauma history. The natural history of Korean AS appears largely similar to those seen in Europe and North America, except a few differences. JOAS was quite common and AS was about nine times more common in men than in women. In addition, the HLA B27 antigen frequency was 93%, which is higher than those reported in other studies.
Undifferentiated spondyloarthropathy (USpA) includes the forms that do not meet criteria for the established categories of spondyloarthropathy. The clinical spectrum of USpA is therefore wide and few studies have been published on USpA, especially peripheral arthritis. A total of 107 patients fulfilling the European Spondyloarthropathy Study Group criteria for SpA were studied retrospectively by a chart review and interview by a rheumatologist. Peripheral arthritis, excluding hip and shoulder involvement, occurred in 97 of the 107 patients (91%). Joint involvement tended to be monoarticular or pauciarticular, and most frequently developed in peripheral joints including the knee and ankle. Among the 97 patients with peripheral arthritis, only 37 (35%) had a persistent arthritis. HLA-B27 was detected in 80 patients (78%). Peripheral arthritis was found in the lower extremities regardless of symmetry or asymmetry and tended to run a benign course with only a few patients having persistent arthritis.
High-dose intravenous immunoglobulins alter the disease activity of adult-onset Still's disease (AOSD). Because activation status of FcgammaR is possibly dependent on their genetic polymorphisms, we investigated whether the polymorphisms of FcgammaR IIa and IIIa are risk factors, and affect the clinical features of AOSD. Genomic DNA was extracted from 36 patients and from 197 healthy controls. Polymerase chain reaction for FcgammaR IIa and IIIa using the allele-specific primers and direct sequencing of FcgammaR IIIa polymorphic site were performed. The frequencies of FcgammaR IIa/IIIa genotype between patients with AOSD and controls were not different. The allelic frequencies of FcgammaR IIa/IIIa between patients with AOSD and controls were not different, either. However, the FcgammaR IIa-R/R131 genotype was associated with a higher concentration of hemoglobin (p=0.04) and stable liver function (p=0.009) than the other genotypes. The FcgammaR IIIa-F/F176 genotype was associated with significantly lower titers of serum ferritin (p=0.025), and higher serum albumin (p=0.037) and cholesterol (p=0.014) concentrations than the other genotypes. This study suggest that the FcgammaR IIa and IIIa polymorphisms might not be genetic risk factors for AOSD in Korean, but contribute to the activity of disease. FcgammaR IIa-R/R131 and IIIa-F/F176 genotypes, low-binding genotypes for IgG2a and G1, may have more protective effects in acute stage of the disease than the other genotypes.
The metabolic syndrome (MetS) may contribute to increased cardiovascular risk in systemic lupus erythematosus (SLE). We aimed to examine the association of demographic factors, lupus phenotype and therapy exposure with the presence of MetS.
The Systemic Lupus International Collaborating Clinics Registry for Atherosclerosis inception cohort enrolled recently diagnosed (<15 months) SLE patients from 30 centres across 11 countries from 2000. Clinical, laboratory and therapeutic data were collected according to a standardised protocol. MetS was defined according to the 2009 consensus statement from the International Diabetes Federation. Univariate and backward stepwise multivariate logistic regression were used to assess the relationship of individual variables with MetS.
We studied 1686 patients, of whom 1494 (86.6%) had sufficient data to determine their MetS status. The mean (SD) age at enrolment and disease duration was 35.2 years (13.4) and 24.1 weeks (18.0), respectively. MetS was present at the enrolment visit in 239 (16%). In backward stepwise multivariable regression analysis, higher daily average prednisolone dose (mg) (OR 1.02, 95% CI 1.00 to 1.03), older age (years) (OR 1.04, 95% CI 1.03 to 1.06), Korean (OR 6.33, 95% CI 3.68 to 10.86) and Hispanic (OR 6.2, 95% CI 3.78 to 10.12) ethnicity, current renal disease (OR 1.79, 95% CI 1.14 to 2.80) and immunosuppressant use (OR 1.81, 95% CI 1.18 to 2.78) were associated with MetS.
Renal lupus, higher corticosteroid doses, Korean and Hispanic ethnicity are associated with MetS in SLE patients. Balancing disease control and minimising corticosteroid exposure should therefore be at the forefront of personalised treatment decisions in SLE patients.
Systemic Lupus Erythematosus; Cardiovascular Disease; Inflammation; Epidemiology
Protein tyrosine phosphatase non-receptor type 22 (PTPN22) is a negative regulator of T-cell activation associated with several autoimmune diseases, including systemic lupus erythematosus (SLE). Missense rs2476601 is associated with SLE in individuals with European ancestry. Since the rs2476601 risk allele frequency differs dramatically across ethnicities, we assessed robustness of PTPN22 association with SLE and its clinical sub-phenotypes across four ethnically diverse populations. Ten SNPs were genotyped in 8220 SLE cases and 7369 controls from in European-Americans (EA), African-Americans (AA), Asians (AS), and Hispanics (HS). We performed imputation-based association followed by conditional analysis to identify independent associations. Significantly associated SNPs were tested for association with SLE clinical sub-phenotypes, including autoantibody profiles. Multiple testing was accounted for by using false discovery rate. We successfully imputed and tested allelic association for 107 SNPs within the PTPN22 region and detected evidence of ethnic-specific associations from EA and HS. In EA, the strongest association was at rs2476601 (P = 4.7×10−9, OR = 1.40 (95% CI = 1.25–1.56)). Independent association with rs1217414 was also observed in EA, and both SNPs are correlated with increased European ancestry. For HS imputed intronic SNP, rs3765598, predicted to be a cis-eQTL, was associated (P = 0.007, OR = 0.79 and 95% CI = 0.67–0.94). No significant associations were observed in AA or AS. Case-only analysis using lupus-related clinical criteria revealed differences between EA SLE patients positive for moderate to high titers of IgG anti-cardiolipin (aCL IgG >20) versus negative aCL IgG at rs2476601 (P = 0.012, OR = 1.65). Association was reinforced when these cases were compared to controls (P = 2.7×10−5, OR = 2.11). Our results validate that rs2476601 is the most significantly associated SNP in individuals with European ancestry. Additionally, rs1217414 and rs3765598 may be associated with SLE. Further studies are required to confirm the involvement of rs2476601 with aCL IgG.
The Systemic Lupus Collaborating Clinics (SLICC) revised and validated the American College of Rheumatology (ACR) SLE classification criteria in order to improve clinical relevance, meet stringent methodology requirements and incorporate new knowledge in SLE immunology.
The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. SLICC validated the classification criteria in a new validation sample of 690 SLE patients and controls.
Seventeen criteria were identified. The SLICC criteria for SLE classification requires: 1) Fulfillment of at least four criteria, with at least one clinical criterion AND one immunologic criterion OR 2) Lupus nephritis as the sole clinical criterion in the presence of ANA or anti-dsDNA antibodies. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications than the current ACR classification criteria (49 versus 70, p=0.0082), had greater sensitivity (94% versus 86%, p<0.0001) and equal specificity (92% versus 93%, p=0.39). In the validation set, the SLICC Classification criteria resulted in fewer misclassifications (62 versus 74, p=0.24), had greater sensitivity (97% versus 83%, p<0.0001) but less specificity (84% versus 96%, p<0.0001).
The new SLICC classification criteria performed well on a large set of patient scenarios rated by experts. They require that at least one clinical criterion and one immunologic criterion be present for a classification of SLE. Biopsy confirmed nephritis compatible with lupus (in the presence of SLE autoantibodies) is sufficient for classification.