Biological insights into systemic lupus erythematosus through an immune cell-specific transcriptome-wide association study.

OBJECTIVE: Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. METHODS: We built gene expression predictive models in blood B cells, CD4+ and CD8+ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. RESULTS: TWAS identified 171 genes for SLE (p<1.0×10-5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10-8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10-9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. CONCLUSIONS: Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

Novel susceptibility loci for steroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus.

Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE.

Early control of C-reactive protein levels with non-biologics is associated with slow radiographic progression in radiographic axial spondyloarthritis.

AIM: Predicting radiographic progression is vital for assessing the prognosis of patients with radiographic axial spondyloarthritis, and C-reactive protein (CRP) may be a valuable biomarker for this purpose. This study aimed to investigate the relationship between changes in the CRP level and spinal radiographic progression in patients with radiographic axial spondyloarthritis who were initially treated with non-biologics. METHODS: Patients with radiographic axial spondyloarthritis who were followed up for 18 years at a single center and initially treated with nonsteroidal anti-inflammatory drugs and/or conventional disease-modifying antirheumatic drugs for 3 months were included. Patients with a CRP level of <0.8 mg/dL or 50% of the baseline CRP at 3 months were assigned to the controlled CRP group (n = 351), and the remaining patients were assigned to the uncontrolled CRP group (n = 452). A generalized estimating equation was used to analyze the differences in the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) between the 2 groups. RESULTS: The increase in the mSASSS was slower in the controlled CRP group than in the uncontrolled CRP group (interaction term ß = -.499, 95% confidence interval -0.699 to -0.300). CONCLUSION: Controlled CRP achieved in response to initial treatment with non-biologic agents for 3 months was significantly associated with a slower rate of spinal radiographic change in patients with radiographic axial spondyloarthritis. The CRP level at 3 months after initial non-biologic treatment is a good predictor of radiographic progression.

Use of Quantitative Vertebral Bone Marrow Fat Fraction to Assess Disease Activity and Chronicity in Patients with Ankylosing Spondylitis.

OBJECTIVE: We quantitatively measured the fat fraction (FF) in the vertebrae of patients with ankylosing spondylitis (AS) using magnetic resonance imaging (MRI) and investigated the role of FF as an indicator of both active inflammation and chronicity. MATERIALS AND METHODS: A total of 52 patients with AS who underwent spinal MRI were retrospectively evaluated. The FF values of the anterosuperior and anteroinferior corners of the bone marrow in the L1-S1 spine were assessed using the modified Dixon technique. AS activity was measured using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), AS Disease Activity Score (ASDAS), and serum inflammatory marker levels. AS disease chronicity was assessed by AS disease duration and the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Univariable and multivariable regression analyses were conducted to investigate the correlation between FF and other clinical characteristics. RESULTS: The mean FF ± standard deviation of the total lumbar spine was 43.0% ± 11.3%. At univariable analysis, spinal FF showed significant negative correlation with BASDAI (ß = -0.474, p = 0.002) and ASDAS with C-reactive protein (ASDAS-CRP; ß = -0.478, p = 0.002) and a significant positive correlation with AS disease duration (ß = 0.440, p = 0.001). After adjusting for patient age, sex, and total mSASSS score, spinal FF remained significantly negatively correlated with BASDAI (ß = -0.543, p < 0.001), ASDAS-CRP (ß = -0.568, p < 0.001), and ASDAS with erythrocyte sedimentation rate (ß = -0.533, p = 0.001). Spinal FF was significantly lower in patients with very high disease activity (ASDAS-CRP > 3.5) than in those with only high disease activity (2.1 ≤ ASDAS-CRP ≤ 3.5) (p = 0.010). CONCLUSION: Spinal FF may help assess both AS disease activity and chronicity.

Excess mortality persists in patients with rheumatoid arthritis.

OBJECTIVES: To investigate the causes and risk of death in a large cohort of Korean patients with rheumatoid arthritis (RA). METHODS: Patients in the Hanyang BAE (Bae registry of Autoimmune diseases for Epidemiology) RA cohort who fulfilled the American College of Rheumatology criteria were analyzed. A total of 2355 patients were enrolled from October 2001 to December 2015. Mortality data were derived by linking with data from the Korean National Statistical Office. Standardized mortality ratio was estimated by dividing observed deaths by expected number of deaths in the general population. RESULTS: Over the observation period, 225 deaths were reported. Total age- and sex-adjusted standardized mortality ratio was 1.65 (95% confidence interval 1.44-1.87). The most common cause of death was malignancy (40 cases; 17.8%), followed by respiratory disease (38 cases; 16.9%) and cardiovascular disease (32 cases; 14.2%). Mortality rate and causes of death differed according to year and age of RA onset. Compared with survivors, individuals who died were more likely to be male, smokers, diagnosed with RA at an older age, and to have long disease duration, higher erythrocyte sedimentation rate and C-reactive protein, higher rheumatoid factor positivity rate, more severe radiographic damage, and more comorbidities. CONCLUSION: The mortality rate of patients with RA remains higher than that of the general population. Therefore, to improve the survival of patients with RA, attention should be paid to the management of comorbidities as well as to the RA itself.

Clinical and Genetic Risk Factors Associated With the Presence of Lupus Nephritis.

Objective: To elucidate whether clinical features and the weighted genetic risk score (wGRS) were associated with the presence of lupus nephritis (LN). Methods: We retrospectively divided patients with systemic lupus erythematosus (SLE, n=1,078) into biopsy-proven LN (n=507) and non-LN groups (non-LN, n=571) Baseline clinical features, serologic markers, and the wGRS were collected The wGRS was calculated from 112 non-human leukocyte antigen (non-HLA) loci and HLA-DRß1 amino acid haplotypes for SLE Associations among clinical features, wGRS, and the presence of LN were identified. Results: In the multivariate analysis, patients with LN were younger at diagnosis (odds ratio [OR]=0.97, p<0.001), had more pleuritis (OR=2.44, p<0.001) and pericarditis (OR=1.62, p=0.029), had a higher detection rate of anti-double stranded deoxyribonucleic acid (anti-dsDNA antibodies, OR=2.22, p<0.001), anti-Smith antibodies (anti-Sm antibodies, OR=1.70, p=0.002), low level of complement (OR=1.37, p=0.043) and absence of antiphospholipid antibodies (aPL antibodies, OR=1.60, p=0.002), and had higher wGRS (OR=1.16, p=0.012) Mediation analysis suggested that anti-Sm antibodies and low complement could be mediators in the relationship between high wGRS and the presence of LN. Conclusion: Onset age, pleuritis, pericarditis, several serologic markers, and wGRS were associated with the presence of LN Anti-Sm antibodies and low complement appeared to mediate the indirect relationship between wGRS and the presence of LN.

Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations. METHODS: We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations. RESULTS: We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10-8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=-0.242) and non-albumin protein (rg=0.238). CONCLUSION: This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

Efficacy and Safety of Rituximab in Korean Patients with Refractory Inflammatory Myopathies.

BACKGROUND: Rituximab (RTX), a monoclonal antibody that selectively binds to CD20+ B cells, showed favorable outcomes in patients with idiopathic inflammatory myopathies (IIM) in small case series, but the evidence is still not enough. Our goal was to determine the efficacy and safety of RTX for Korean patients with refractory IIM. METHODS: We retrospectively analyzed the medical records of 16 patients with refractory IIM treated with RTX in seven tertiary rheumatology clinics in the Korea. The efficacy of RTX was evaluated with the improvement of serum creatine phosphokinase (CPK) level and physician's global assessment (PGA), and daily corticosteroid dose reduction. A > 25% decrease in CPK level, corticosteroid dose, or PGA was considered significant. A complete response (CR) was designated by meeting three efficacy criteria and a partial response (PR) by only two criteria. RESULTS: Sixteen patients with IIM were evaluated (13 female; median age, 51.8 years). All patients had received at least one conventional immunosuppressive agent (median, 3.6 [2.0-5.0]) and concomitant corticosteroids. The median CPK level and median dose of prednisolone was 421.0 units/L and 20.0 mg/day respectively. Eleven patients were treated with intravenous immunoglobulin. Seven patients received 2,000 mg of RTX and the others received lower dose. Twenty-four weeks after RTX treatment, 11 patients achieved a > 25% reduction in corticosteroid dose and CPK levels, and nine showed improved PGA. The overall response rate was 68.8% (11 patients). At the end of follow-up (median 24 weeks), 12 (75.0%) patients responded overall: four (25.0%) and eight (50.0%) patients achieved CR and PR, respectively. Baseline muscle enzyme levels were higher in responders than non-responders, but disease duration, RTX dose, ESR and serum CRP were not significantly different between the two groups. The rate of adverse event was 25.4/1,000 person-years. CONCLUSION: RTX could be an effective and relatively safe therapeutic option in patients with refractory IIM.

Tumour necrosis factor inhibitors slow radiographic progression in patients with ankylosing spondylitis: 18-year real-world evidence.

OBJECTIVES: Tumour necrosis factor inhibitors (TNFis) have been suggested to slow radiographic progression in patients with ankylosing spondylitis. However, limitations such as variations in disease activity, complex drug administration and short follow-up duration make it difficult to determine the effect of TNFis on radiographic progression. The aim of the study was to investigate whether long-term treatment with TNFis can reduce radiographic progression in patients with ankylosing spondylitis using 18-year longitudinal real-world data. METHODS: This retrospective study was conducted between January 2001 and December 2018 at a single centre. Among the 1280 patients whose electronic medical records were reviewed, data of 595 patients exposed to TNFis at least once were included. Among them, time intervals of TNFi exposure or non-exposure were determined in 338 patients ('on the TNFis' or 'off the TNFis' intervals, respectively). The difference in the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) change rate between 'on the TNFis' and 'off the TNFis' intervals was investigated. RESULTS: We obtained 2364 intervals of 338 patients (1281 'on the TNFis' and 1083 'off the TNFis' intervals). In the marginal structural model for inverse probability of treatment weighting, the change rate of mSASSS significantly decreased with the use of TNFis (ß=-0.112, p=0.004), and the adjusted mSASSS changes were 0.848 and 0.960 per year during 'on the TNFis' and 'off the TNFis' intervals, respectively. CONCLUSION: Compared with treatment without TNFis, treatment with TNFis slowed radiologic progression significantly.

Identifying damage clusters in patients with systemic lupus erythematosus.

AIM: Systemic lupus erythematosus (SLE) causes irreversible damage to organ systems. Recently, evidence has been obtained for subphenotypes of SLE. This study aimed to identify damage clusters and compare the associated clinical manifestations, SLE disease activity, mortality, and genetic risk scores (GRS). METHODS: The study was conducted on the Hanyang BAE lupus cohort. Patients with disease duration <5 years were excluded to minimize confounding effects of disease duration. They were grouped into 3 clusters based on the Systemic Lupus International Collaborating Clinics Damage Index using k-means cluster analysis. RESULTS: Among the 1130 analyzed patients, musculoskeletal damage was most prevalent (20.2%), followed by ocular (11.4%), renal (10.5%), and neuropsychiatric damage (10.2%). Three significantly different damage clusters were identified. Patients in cluster 1 (n = 824) showed the least damage. Cluster 2 (n = 195) was characterized by frequent renal (55.4%) and ocular (58.0%) damage, and cluster 3 (n = 111) was dominated by neuropsychiatric (100%) and musculoskeletal damage (35.1%). Cluster 2 had the highest adjusted mean AMS (adjusted mean SLE Disease Activity Index score; mean ± SD: 5.4 ± 2.9), while cluster 3 had the highest mortality (14.4%). Weighted GRS did not differ significantly between the clusters. CONCLUSION: Patients in prevalent renal and ocular damage cluster had the highest AMS scores, while the cluster with frequent neuropsychiatric damage had the highest mortality.

Relationship between cerebral microbleeds and white matter MR hyperintensities in systemic lupus erythematosus: a retrospective observational study.

PURPOSE: White matter hyperintensities (WMH) and cerebral microbleeds (CMBs) are known to be associated with small vessel diseases (SVD) and neuroinflammation. The purpose was to investigate the relationship between CMBs and WMH in patients with systemic lupus erythematosus (SLE). METHODS: Thirty-one SLE patients with WMH and 27 SLE patients with normal brain MRI were compared. The presence, location, and grading of CMBs were assessed using susceptibility-weighted images. WMH volume was quantitatively measured. Clinical characteristics and serologic markers were compared. We also performed two separate subgroup analyses after (1) dividing WMH into inflammatory lesion vs. SVD subgroups and (2) dividing WMH into those with vs. without CMB subgroups. RESULTS: The WMH group showed more frequent CMBs than the normal MR group (p < 0.001). The WMH group showed higher SLE disease activity index, longer disease duration, and a higher incidence of antiphospholipid syndrome than the normal MR group (p = 0.02, 0.04, and 0.04, respectively). There was a moderate correlation between WMH volume and CMB grading (r = 0.49, p = 0.006). Within the WMH group, the inflammatory lesion subgroup showed more frequent CMBs and larger WMH volume than the SVD subgroup (p < 0.001 and 0.02, respectively). The WMH with CMB subgroup had larger WMH volume than the WMH without CMB subgroup (p = 0.004). CONCLUSION: In patients with SLE, CMBs could be related to large-volume WMH and inflammatory lesions. CMBs along with severe WMH could be used as an imaging biomarker of vasculitis in patients with SLE.

Impact of EUSTAR standardized training on accuracy of modified Rodnan skin score in patients with systemic sclerosis.

OBJECTIVES: To investigate the impact of European Scleroderma Trials and Research (EUSTAR) standardized training on the accuracy of modified Rodnan skin score (mRSS) in patients with systemic sclerosis (SSc). METHODS: Eight SSc patients (four diffuse, four limited) and 10 physicians (4 fellows, 6 professors) were included. Gold-standard mRSS was performed by a senior instructor. Training comprised a video presentation and a live demonstration. Each physician performed mRSS with no clinical information in all patients: (a) before training; (b) after video session; and (c) after live demonstration. Primary outcome was the change in scoring accuracy, which was defined as the difference from the gold-standard skin score, as analyzed using a linear mixed model. RESULTS: Mean (standard deviation) difference from the gold-standard score in all measurements by participants before the training was 7.7 (9.5). Completion of training significantly enhanced mRSS accuracy (adjusted ß = -7.61; 95% CI: -11.91 to -3.32). This was largely attributable to the video presentation (adjusted ß = -5.47; -9.16 to -1.78), although the live demonstration was associated with numerical reduction in the difference from the gold-standard score (adjusted ß = -2.15; -5.84 to 1.55). Effect of training was prominent in fellows whereas professors showed an increase in the difference from gold-standard score after training (P value for interaction <0.001). The intraclass correlation coefficient for physician skin scores was acceptable. However, no significant change was observed after training. CONCLUSION: New EUSTAR standardized mRSS training significantly enhanced mRSS accuracy, especially in participant with less previous experience in skin scoring.

Cross-cultural adaptation and validation of the Korean Version of the Functional Index for Hand Osteoarthritis (FIHOA).

AIM: This study aimed to translate the Functional Index for Hand Osteoarthritis (FIHOA) into Korean, and establish its reliability and validity in Korean patients with hand osteoarthritis (OA). METHOD: The FIHOA was translated into Korean (K-FIHOA) following cross-cultural adaptation guidelines. The K-FIHOA was pretested on 40 patients with hand OA. The adapted K-FIHOA was then administered to 100 consecutive hand OA patients together with the modified Health Assessment Questionnaire (mHAQ) and visual analog scale (VAS) for hand pain. The test-retest reliability of each item and total scores were assessed using Spearman's correlation coefficient and intraclass correlation coefficient (ICC). The internal consistency reliability was evaluated as Cronbach's alpha. The external construct validity was assessed using the correlation between K-FIHOA, mHAQ and hand pain VAS. RESULTS: The test-retest reliability for the total score was strong (r = 0.87 and ICC = 0.83). Cronbach's alpha was also high (0.88), which suggests that there is strong internal coherence in the test items. We identified significant correlations between K-FIHOA and mHAQ (r = 0.52, P < 0.01), mHAQ hand function score, (r = 0.57, P < 0.01) and hand pain VAS (r = 0.53, P < 0.01). CONCLUSION: The K-FIHOA is a reliable and valid instrument for evaluating functional disability in Korean hand OA patients.