Yoon-Kyoung Sung

Biologic discontinuation studies: a systematic review of methods

Objectives We conducted a systematic review to assess the design and ‘failure definition’ in studies of biologic discontinuation in rheumatoid arthritis (RA). Methods We found 403 studies on PubMed, and included nine published papers and five abstracts from scientific meetings. We used a structured extraction form to collect information regarding study design and outcome (failure) definition. Results Three types of studies were found: randomised controlled trials, long-term extension studies of clinical trials and prospective discontinuation studies. The largest study had 196 subjects in the discontinuation arm. Most studies allowed concomitant use of non-biologic drugs at biologic discontinuation. Heterogeneity was also found in the failure definition. Although all studies used measures of disease activity, the threshold for failure and the time point of assessment differed among studies. Few studies incorporated changing use of non-biologic drugs or glucocorticoids into the failure definition. Conclusions Although many studies have examined the outcome of biologic discontinuation, they have all been relatively small. Typical practice studies from registries may add important information but will likely need to rely on a broader failure definition.

Genetic studies of systemic lupus erythematosus in Asia: where are we now?

There have been many genetic studies of systemic lupus erythematosus (SLE) in Asia, but the status of SLE in Asia remains unclear. Genes that have been associated with SLE in Caucasians have shown both consistent and inconsistent results in Asians. This prompted us to review studies of SLE-associated genes and compare the degree of consistency according to ethnicity in Asia. We searched PubMed and the national databases in Korea and Japan for SLE genetic studies. A total of 755 articles were found and after applying various exclusion criteria, 442 studies including 17 linkage studies, 2 genome-wide association studies and 423 candidate-gene analyses were reviewed. Nine linkage loci were confirmed to be associated with SLE susceptibility in non-Asians, but the risk locus (16q12) has been identified in only one Asian study. A total of 156 candidate genes were analyzed, of which 92 were studied in Asians. Although there were allelic (HLA-DRB1 and IRF5) or genetic heterogeneity (FCGR gene family), HLA-DRB1, the FCGR gene family, IRF5, STAT4 and MECP2 showed consistent associations with SLE susceptibility across ethnicities. In conclusion, genetic associations often vary with ethnicity, requiring validation in different ethnic groups, and hence future SLE genetic studies will require strong worldwide collaborations.

A regulatory SNP at position −899 in CDKN1A is associated with systemic lupus erythematosus and lupus nephritis

The CDKN1A gene encoding a cell cycle inhibitor, p21(WAF1/CIP1), is located in the systemic lupus erythematosus (SLE) susceptibility locus on chromosome 6p21.2. Decreased cellular levels of p21 are associated with SLE. Here, we examine four single-nucleotide polymorphisms (SNPs) within the promoter and two in the first intron of CDKN1A for association with SLE susceptibility. A comparison of 742 Korean SLE patients with 1017 controls disclosed that one SNP (rs762624 C>A at position −899), located at a putative Myb-binding site in the promoter, was associated with SLE susceptibility (P=0.00047). This association was independent of the SLE-association signal of HLA-DRB1 on 6p21.3, as it was significant after adjustment for SLE-risk DRB1 alleles (P=0.0012). The same SNP was associated with lupus nephritis (P=0.000014). The risk allele-carrying promoter sequence displayed ∼15% lower activity than the non-risk sequence upon fusion to the luciferase gene (P=0.025). Endogenous CDKN1A mRNA levels measured in Epstein–Barr virus-transformed B cells established from 16 control subjects were linearly correlated with a decreasing copy number of the risk allele (P=0.024). Accordingly, we conclude that the minor allele A at −899 of CDKN1A is associated with increased susceptibility to SLE and lupus nephritis, and decreased cellular levels of p21.

Precuneus hypoperfusion plays an important role in memory impairment of patients with systemic lupus erythematosus

The present study was designed to identify regional cerebral blood flow (rCBF) abnormalities in systemic lupus erythematosus (SLE) patients with memory impairments. Nineteen SLE patients (mean age 36.1u2009±u20098.6 years, range 17–47) with subjective memory complaints underwent brain single-photon emission computed tomography (SPECT). The Korean Wechsler Adult Intelligence Scale (K-WAIS) and the Rey–Kim Memory Test (RKMT) were used objectively to evaluate cognitive functions in these patients. On the basis of the Intelligence Quotient–Memory Quotient (IQ-MQ) difference score, patients were classified into two groups: those with below one standard deviation (SD) from the mean for normal subjects of comparable age and education (memory impairment, nu2009=u20096) and those with without memory impairment (non-memory impairment, nu2009=u200913). Their brain SPECT images were analyzed by statistical parametric mapping (SPM) for group comparisons. The group of SLE patients with memory impairment showed significant hypoperfusion in the right precuneus compared with those with non-memory impairment (pu2009<u20090.001). Hypoperfusion of the precuneus may play a significant role in the memory function of SLE patients. SPM analysis of brain SPECT images could be a useful and objective tool for identifying abnormal rCBF in SLE patients with memory impairment.

Response to: ‘Biologic discontinuation studies: a systematic review of methods’ by van der Maas et al

We would like to thank van der Maas and colleagues1 for their interest in, and useful feedback on, our review.2 They raise several important points. First, regarding the interpretation of the studies included in the review, we focused on studies examining discontinuation of biologic disease modifying antirheumatic drugs (DMARDs) that examined patient outcomes. Thus, we had difficulty in …

AB0726 Systemic review: agreement between tuberculin skin test (TST) and-gamma release assay (IGRA) blood test for latent tb screening among patients with rheumatic diseases

Background The accuracy of screening tests for latent tuberculosis infection (LTBI) such as TST and IGRAs and their agreement are varied according to study. Objectives We conducted meta-analysis on the positivity of LTBI screening tests and the level of agreement between them in the patients prior to use of anti-TNF agents. Then, we further analyzed the difference in agreement according to underlying rheumatic diseases and the prevalence of TB in each country. Methods OVID-MEDLINE, EMBASE, and Cochrane Library were searched for LTBI screening in patients with rheumatic diseases, including RA, AS, JIA, and PsA, through Nov 21st 2012. Among 135 literatures retrieved, 18 English original research articles were selected excluding non-FDA approved method, non-rheumatic disease(e.g. IBS, autoimmune diseases), and screenings after TNF-alpha inhibitor use. Heterogeneity was evaluated using the Cochran Q statistic. A random effect model was constructed in STATA 10®. Results In the pooled analysis, 4764 patients across all rheumatic diseases underwent both TST and one of IGRAs (4334 patients measured by QFT-GIT, and 711 by TSPOT) prior to use of anti-TNF agents. The positivity of TST (>5mm), TSPOT, and QFT-GIT among all patients were estimated as 34.7% [95% CI: 25.7-43.6], 16.1% [7.0-25.1], and 20.7% [14.8-26.6], respectively. The percent agreement between TST and QFT-GIT was 69.8% [64.3-75.3]. In low-to moderate endemic subjects (n=854), positive rate of TST, TSPOT, and QFT-GIT were35.6% [23.3-47.9], 15.5%[10.1-20.8], and 17.5% [9.5-25.5], wherease those of high endemic subjects (n=1010) were 33.6% [24.2-43.0], 23.9% [12.6-38.8], and 30.5% [23.6-37.3], respectively. Percent agreement between TST and QTF-GIT was lower in low-to-moderate endemic area than high endemic area (66.1% [56.5-75.6] vs. 72.7% [65.8-79.6]). In RA subjects (n=1073 patients of 8 studies), the positivity of TST, TSPOT, and QFT-GIT was 31.3% [25.0-37.6], 22.2% [3.0-41.4] and 27.3% [20.1-34.6]. In AS patients (n=317 patients of 3 studies; all high endemics), the positivity of TST, and QFT-GIT was 56.8% [35.0-78.7], and 26.3% [13.5-39.2], and agreement between TST and QFT-GIT was 54.9% [43.9-65.9]. Only sub-analyses by underlying diseases presented non-heterogeneities across literatures measured by Q statistics. Conclusions Among patients with rheumatic diseases, the screening results of TST and IGRAs are inconsistent across the underlying disease and endemic area. Specifically, a lower level of agreement between TST and IGRAs was found among patients with JIA and AS than RA population. Also, populations originated from low-to-moderate endemic regions, presented more disagreements, mainly due to similar positive rates of TST with lower rates by IGRAs, than patients of high endemic origins. It suggests different strategies are needed for each patient group to detect LTBI in clinical settings considering endemic origins. Disclosure of Interest None Declared

SAT0040 Prevalence and Predictors for Sustained Remission in Rheumatoid Arthritis

Background Disease progression of RA is unpredictable and recurrence occurs frequently even in patients in remission. Since patients with short term remission are more likely to experience radiographic structural progression compared with those achieving long-term remission, sustained remission is likely to improve patient outcomes and quality of life. Therefore, understanding the prevalence and predictors of sustained remission in typical clinical settings is important for physicians and patients to plan treatment strategies. Objectives In this study, we aimed to investigate the prevalence of sustained remission in established RA patients and to identify the predictors for sustained remission. Methods The study cohort consisted of subjects with RA from the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) and the Korean Observational Study Network for Arthritis (KORONA). We analyzed subjects with remission in 2009 with 2 years of annual follow-up. Remission was assessed according to the Disease Activity Score 28 (DAS28-CRP) and sustained remission was defined as three consecutive annual visits with remission 2009-2011. Predictors for sustained remission were identified by multivariate logistic regression analysis. Results A total of 465 subjects with remission in 2009 were analyzed, and sustained remission was achieved by 53 of 92 (57.5%) in BRASS and by 198 of 373 (53.1%) in KORONA. In multivariate analyses, baseline predictors of sustained remission were: disease duration less than 5 years [odds ratio (OR) 1.96, 95% confidence interval (95% CI) 1.08-3.58], Modified Health Assessment Questionnaire (MHAQ) score of 0 (OR 1.80, 95% CI 1.18-2.74), and non-use of oral glucocorticoid (OR 1.58, 95% CI 1.01-2.47). Conclusions More than half of RA subjects in remission in 2009 remained in remission through 2011. Short disease duration, no disability, and non-use of oral glucocorticoid at baseline were associated with sustained remission. Acknowledgements This study had no specific support. However, BRASS is supported by grants from Crescendo Biosciences, Medimmune, and Briston Myers Squib. KORONA receives support from the Korea Healthcare technology R&D Project, Ministry for Health and Welfare, Republic of Korea (A102065). Disclosure of Interest None Declared