S.-C. Bae

Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a complex pathogenesis in which genetic, hormonal and environmental factors have a role. Rare mutations in the TREX1 gene, the major mammalian 3′–5′ exonuclease, have been reported in sporadic SLE cases. Some of these mutations have also been identified in a rare pediatric neurological condition featuring an inflammatory encephalopathy known as Aicardi–Goutières syndrome (AGS). We sought to investigate the frequency of these mutations in a large multi-ancestral cohort of SLE cases and controls. A total of 40 single-nucleotide polymorphisms (SNPs), including both common and rare variants, across the TREX1 gene, were evaluated in ∼8370 patients with SLE and ∼7490 control subjects. Stringent quality control procedures were applied, and principal components and admixture proportions were calculated to identify outliers for removal from analysis. Population-based case–control association analyses were performed. P-values, false-discovery rate q values, and odds ratios (OR) with 95% confidence intervals (CI) were calculated. The estimated frequency of TREX1 mutations in our lupus cohort was 0.5%. Five heterozygous mutations were detected at the Y305C polymorphism in European lupus cases but none were observed in European controls. Five African cases incurred heterozygous mutations at the E266G polymorphism and, again, none were observed in the African controls. A rare homozygous R114H mutation was identified in one Asian SLE patient, whereas all genotypes at this mutation in previous reports for SLE were heterozygous. Analysis of common TREX1 SNPs (minor allele frequency (MAF)>10%) revealed a relatively common risk haplotype in European SLE patients with neurological manifestations, especially seizures, with a frequency of 58% in lupus cases compared with 45% in normal controls (P=0.0008, OR=1.73, 95% CI=1.25–2.39). Finally, the presence or absence of specific autoantibodies in certain populations produced significant genetic associations. For example, a strong association with anti-nRNP was observed in the European cohort at a coding synonymous variant rs56203834 (P=2.99E−13, OR=5.2, 95% CI=3.18–8.56). Our data confirm and expand previous reports and provide additional support for the involvement of TREX1 in lupus pathogenesis.

Atherosclerotic vascular events in a multinational inception cohort of systemic lupus erythematosus

To describe vascular events during an 8‐year followup in a multicenter systemic lupus erythematosus (SLE) inception cohort and their attribution to atherosclerosis.

Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus

Objective Neuropsychiatric events occur unpredictably in systemic lupus erythematosus (SLE) and most biomarker associations remain to be prospectively validated. This study examined a disease inception cohort of 1047 SLE patients to determine which autoantibodies at enrolment predicted subsequent neuropsychiatric events. Methods Patients with a recent SLE diagnosis were assessed prospectively for up to 10 years for neuropsychiatric events using the American College of Rheumatology case definitions. Decision rules of graded stringency determined whether neuropsychiatric events were attributable to SLE. Associations between the first neuropsychiatric event and baseline autoantibodies (lupus anticoagulant (LA), anticardiolipin, anti-β2 glycoprotein-I, anti-ribosomal P and anti-NR2 glutamate receptor) were tested by Cox proportional hazards regression. Results Disease duration at enrolment was 5.4±4.2 months, follow-up was 3.6±2.6 years. Patients were 89.1% female with mean (±SD) age 35.2±13.7 years. 495/1047 (47.3%) developed one or more neuropsychiatric event (total 917 events). Neuropsychiatric events attributed to SLE were 15.4% (model A) and 28.2% (model B). At enrolment 21.9% of patients had LA, 13.4% anticardiolipin, 15.1% anti-β2 glycoprotein-I, 9.2% anti-ribosomal P and 13.7% anti-NR2 antibodies. LA at baseline was associated with subsequent intracranial thrombosis (total n=22) attributed to SLE (model B) (HR 2.54, 95% CI 1.08 to 5.94). Anti-ribosomal P antibody was associated with subsequent psychosis (total n=14) attributed to SLE (model B) (HR 3.92, 95% CI 1.23 to 12.5, p=0.02). Other autoantibodies did not predict neuropsychiatric events. Conclusion In a prospective study of 1047 recently diagnosed SLE patients, LA and anti-ribosomal P antibodies are associated with an increased future risk of intracranial thrombosis and lupus psychosis, respectively.

Genetic associations of LYN with systemic lupus erythematosus.

We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case–control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P=1.1 × 10−4, odds ratio (OR)=0.81 (95% confidence interval: 0.73–0.90)). This single nucleotide polymorphism (SNP) is located in the 5′ untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P=1.5 × 10−3, OR=0.75 (95% CI: 0.62−0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.

Autoantibodies in systemic lupus erythematosus: comparison of historical and current assessment of seropositivity

Systemic lupus erythematosus (SLE) is characterized by multiple autoantibodies and complement activation. Recent studies have suggested that anti-nuclear antibody (ANA) positivity may disappear over time in some SLE patients. Anti-double-stranded DNA (dsDNA) antibody titers and complement levels may vary with time and immunosuppressive treatment, while the behavior of anti-extractable nuclear antigen (ENA) over time is less well understood. This study sought to determine the correlation between historical autoantibody tests and current testing in patients with SLE. Three hundred and two SLE patients from the ACR Reclassification of SLE (AROSE) database with both historical and current laboratory data were selected for analysis. The historical laboratory data were compared with the current autoantibody tests done at the reference laboratory and tested for agreement using percent agreement and Kappa statistic. Serologic tests included ANA, anti-dsDNA, anti-Smith, anti-ribonucleoprotein (RNP), anti-Ro, anti-La, rheumatoid factor (RF), C3 and C4. Among those historically negative for immunologic markers, a current assessment of the markers by the reference laboratory generally yielded a low percentage of additional positives (3–13%). However, 6/11 (55%) of those historically negative for ANA were positive by the reference laboratory, and the reference laboratory test also identified 20% more patients with anti-RNP and 18% more with RF. Among those historically positive for immunologic markers, the reference laboratory results were generally positive on the same laboratory test (range 57% to 97%). However, among those with a history of low C3 or C4, the current reference laboratory results indicated low C3 or C4 a low percentage of the time (18% and 39%, respectively). ANA positivity remained positive over time, in contrast to previous studies. Anti-Ro, La, RNP, Smith and anti-dsDNA antibodies had substantial agreement over time, while complement had less agreement. This variation could partially be explained by variability of the historical assays, which were done by local laboratories over varying periods of time. Variation in the results for complement, however, is more likely to be explained by response to treatment. These findings deserve consideration in the context of diagnosis and enrolment in clinical trials.

Predictors of poor response to methotrexate in polyarticular-course juvenile idiopathic arthritis: analysis of the PRINTO methotrexate trial

Objectives To determine whether baseline demographic, clinical, articular and laboratory variables predict methotrexate (MTX) poor response in polyarticular-course juvenile idiopathic arthritis. Methods Patients newly treated for 6 months with MTX enrolled in the Paediatric Rheumatology International Trials Organization (PRINTO) MTX trial. Bivariate and logistic regression analyses were used to identify baseline predictors of poor response according to the American College of Rheumatology pediatric (ACR-ped) 30 and 70 criteria. Results In all, 405/563 (71.9%) of patients were women; median age at onset and disease duration were 4.3 and 1.4 years, respectively, with anti-nuclear antibody (ANA) detected in 259/537 (48.2%) patients. With multivariate logistic regression analysis, the most important determinants of ACR-ped 70 non-responders were: disease duration >1.3 years (OR 1.93), ANA negativity (OR 1.77), Childhood Health Assessment Questionnaire (CHAQ) disability index>1.125 (OR 1.65) and the presence of right and left wrist activity (OR 1.55). Predictors of ACR-ped 30 non-responders were: ANA negativity (OR 1.92), CHAQ disability index>1.14 (OR 2.18) and a parents evaluation of childs overall well-being ≤4.69 (OR 2.2). Conclusion The subgroup of patients with longer disease duration, ANA negativity, higher disability and presence of wrist activity were significantly associated with a poorer response to a 6-month MTX course.

FcγRIIa/IIIa polymorphism and its association with clinical manifestations in Korean lupus patients

The aim of this study was to determine the distribution of the FcgRIIa and FcgRIIIa polymorphisms and their association with clinical manifestations in Korean lupus patients. Three hundred SLE (systemic lupus erythematosus) patients (48 male, 252 female) meeting 1982 ACR criteria and 197 Korean disease-free controls were enrolled. Genotyping for FcgRIIa 131 R/H and FcgRIIIa 176 F/V was performed by PCR of genomic DNA using allele-specific primers and the FcgRIIIa genotype was confirmed by direct sequencing of PCR product in some cases. There was significant skewing in the distribution of the three FcgRIIa genotypes between the SLE and the controls (P=0.002 for R =R131 vs R/H131 and H/H131, OR 2.5 (95% CI 1.4–4.5), but not in FcgRIIIa genotypes. FcgRIIa-R allele was a significant predictor of lupus nephritis, as compared with SLE patients without nephritis (P=0.034 for R131 vs H131, OR 1.4 (95% CI 1.03–1.9)), but proliferative nephritis (WHO class III and IV) was less common in patients with FcgRIIa-R/R131 and in FcgRIIa-R allele. In 300 SLE patients, high binding allele combination H131=V176 was less common in SLE with nephritis than in SLE without nephritis. Hemolytic anemia was less common in R131=F176 allele combination among four FcgRIIa/FcgRIIIa allelic combinations. Male SLE patients showed a higher frequency of renal involvement, serositis, thrombocytopenia, malar rash and discoid rash than female SLE, and male SLE had a higher frequency of FcgRIIa-R/R131 or R131-allele than male controls, but FcgRIIa or FcgRIIIa genotypes had no association with renal involvement in male SLE patients. FcgRIIa-H/H131 showed a higher frequency of hemolytic anemia and less pulmonary complications in male SLE. Female SLE patients showed higher frequency of any hematologic abnormality, lymphopenia, anti-cardiolipin antibody (/) and anti-Ro antibody (/) than male SLE, and had earlier onset of first symptoms. There was no skewing in FcgRIIa or FcgRIIIa genotypes between female SLE and female controls, but FcgRIIa-R131 allele showed skewing between female SLE with nephritis and female SLE without nephritis. The age at onset of thrombocytopenia was earlier in FcgRIIa-R/R131 among three FcgRIIa genotypes, and serositis in FcgRIIIa-F/F176 among three FcgRIIIa genotypes. FcgRIIa-R131 homozygote was a major predisposing factor to the development of SLE and FcgRIIa-R131 homozygote and R131 allele were a predisposing factor, and H131=V176 was a protective allele combination in lupus nephritis. In contrast to other ethnic patients, in our study cohort, clinical manifestation was different between male and female, and FcgRIIa and FcgRIIIa showed somewhat different clinical associations between the genders.

Interleukin‐1β and interleukin‐1 receptor antagonist gene polymorphisms in Korean patients with adult‐onset Still's disease

Objective. Interleukin‐1 (IL‐1) has been implicated in the pathogenesis of several rheumatic inflammatory diseases, including adult‐onset Stills disease (AOSD) and systemic‐onset juvenile idiopathic arthritis (SoJIA). Several clinical trials also suggest that anakinra, a human recombinant interleukin‐1 receptor antagonist (IL‐1Ra), is effective in patients with AOSD and SoJIA. We have therefore investigated whether IL‐1β and IL‐1Ra gene polymorphisms are associated with the development and clinical features of AOSD. Methods. Genomic DNA was isolated from 83 AOSD patients and 144 healthy controls. Genotyping of the two IL‐1β gene (IL‐1B+3954 and IL‐1B–511) polymorphisms was performed using polymerase chain reaction restriction fragment length polymorphism (PCR‐RFLP). Genotyping of the IL‐1Ra gene (intron 2, VNTR) polymorphism was performed using PCR‐based analysis. To compare genotype and allele frequencies, the χ2‐test or Fishers exact test was used. Haplotype frequencies and pairwise linkage disequilibrium were also estimated. A p‐value <0.05 was considered significant. Results. There were no significant differences in the genotype and allele frequencies of the IL‐1β and IL‐1Ra gene polymorphisms. No differences were also found in the IL‐1 gene cluster haplotypes between both groups. IL‐1 gene cluster polymorphisms had no effect on the clinical course and joint involvement pattern. Nevertheless, the IL‐1B–511 and IL‐1RN (VNTR) polymorphic sites were in linkage disequilibrium. Conclusion. These results suggest that IL‐1β and IL‐1Ra gene polymorphisms are not associated with the development and clinical features of AOSD in Korean patients.

Palisaded neutrophilic granulomatous dermatitis presenting as an unusual skin manifestation in a patient with Behçet's disease

A 32‐year‐old Korean woman with painful oral ulcers and a sore throat presented with multiple erythematosus papules on both legs. Histological examination of the papular lesions on the legs demonstrated palisaded granuloma with degeneration of collagen fibres in the dermis, compatible with palisaded neutrophilic granulomatous dermatitis (PNGD). This condition is known to be an unusual disease entity associated with various systemic autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, other connective tissue diseases, and systemic vasculitis. To our knowledge a case with typical Behçets disease coinciding with PNGD among systemic autoimmune diseases has not been described before.

Autoantibodies and neuropsychiatric events at the time of systemic lupus erythematosus diagnosis

OBJECTIVE To examine, in an inception cohort of systemic lupus erythematosus (SLE) patients, the association between neuropsychiatric (NP) events and anti-ribosomal P (anti-P), antiphospholipid (lupus anticoagulant [LAC], anticardiolipin), anti-beta2-glycoprotein I, and anti-NR2 glutamate receptor antibodies. METHODS NP events were identified using the American College of Rheumatology case definitions and clustered into central/peripheral and diffuse/focal events. Attribution of NP events to SLE was determined using decision rules of differing stringency. Autoantibodies were measured without knowledge of NP events or their attribution. RESULTS Four hundred twelve patients were studied (87.4% female; mean +/- SD age 34.9 +/- 13.5 years, mean +/- SD disease duration 5.0 +/- 4.2 months). There were 214 NP events in 133 patients (32.3%). The proportion of NP events attributed to SLE varied from 15% to 36%. There was no association between autoantibodies and NP events overall. However, the frequency of anti-P antibodies in patients with central NP events attributed to SLE was 4 of 20 (20%), versus 3 of 107 (2.8%) in patients with other NP events and 24 of 279 (8.6%) in those with no NP events (P = 0.04). Among patients with diffuse NP events, 3 of 11 had anti-P antibodies (27%), compared with 4 of 111 patients with other NP events (3.6%) and 24 of 279 of those with no NP events (8.6%) (P = 0.02). Specific clinical-serologic associations were found between anti-P and psychosis attributed to SLE (P = 0.02) and between LAC and cerebrovascular disease attributed to SLE (P = 0.038). There was no significant association between other autoantibodies and NP events. CONCLUSION Clinically distinct NP events attributed to SLE and occurring around the time of diagnosis were found to be associated with anti-P antibodies and LAC. This suggests that there are different autoimmune pathogenetic mechanisms, although low sensitivity limits the clinical application of testing for these antibodies.