Remission is a primary end point of in clinical practice and trials of treatments for rheumatoid arthritis (RA). The 2011 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria were developed to provide a consensus definition of remission. This study aimed to assess the concordance between the new remission criteria and the physician’s clinical judgment of remission and also to identify factors that affect the discordance between these two approaches. A total of 3,209 patients with RA were included from the KORean Observational Study Network for Arthritis (KORONA) database. The frequency of remission was evaluated based on each approach. The agreement between the results was estimated by Cohen’s kappa (κ). Patients with remission according to the 2011 ACR/EULAR criteria (i.e. the Boolean criteria) and/or physician judgment (n = 855) were divided into three groups: concordant remission, the Boolean criteria only, and physician judgment only. Multinomial logistic regression analysis was used to identify factors responsible for the assignment of patients with remission to one of the discordant groups rather than the concordant group. The remission rates using the Boolean criteria and physician judgment were 10.5% and 19.9%, respectively. The agreement between two approaches for remission was low (κ = 0.226) and the concordant remission rate was only 5.5% (n = 177). Pain affected classification in both discordant groups, whereas fatigue was associated with remission only by physician clinical judgment. The Boolean criteria were more stringent than clinical judgment. Patient subjective symptoms such as pain and fatigue were associated with discordance between the two approaches.
Arthritis, Rheumatoid; Remission; Discordance
The aim of this study was to investigate the prevalence of osteoporosis in rheumatoid arthritis (RA) patients and to analyze the risk factors in these patients using the KORean Observational study Network for Arthritis (KORONA) database.
Among the RA patients in the KORONA who were recruited between July 2009 and December 2011, postmenopausal women with bone mineral density (BMD) results within one year from the time of KORONA enrollment were included in this study. The baseline characteristics of patients in three groups, defined by BMD results, were compared. The BMD measurement rates and prevalence of osteoporosis in the study patients were calculated in accordance with age and gender subgroups. Multivariable logistic regression analysis was used to explore the association between osteoporosis and demographics and disease-related risk factors.
Of 1322 postmenopausal woman patients with RA in whom BMD was measured within one year of study enrollment, 619 patients (46.8 %) were in the osteoporosis group (T-score ≤ −2.5 SD). RA patients with osteoporosis had a higher frequency of previous fractures than those in other groups, especially fractures of the femur (p = 0.004) and wrist (p = 0.042). Advanced age (≥70 years; OR = 2.28, 95 % CI: 1.40–3.58), lower body mass index (<25; OR = 2.14, 95 % CI:1.52–3.02), longer disease duration (≥10 years; OR = 1.46, 95 % CI: 1.07–2.00), higher cumulative glucocorticoid dose (OR = 1.03, 95 % CI: 1.01–1.05), and higher Health Assessment Questionnaire score (OR = 1.37, 95 % CI:1.11–1.69) were independent risk factors for osteoporosis.
A large percentage (90.8 %) of RA patients enrolled in the KORONA cohort had osteoporosis and osteopenia. Nevertheless, BMD measurement rates in this population remained low, despite high risk groups of fractures.
Osteoporosis; Rheumatoid arthritis; Frequency; Risk factors
A classic T-cell phenotype in Systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters TCR signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multi-ethnic population. We typed 44 contiguous CD247 SNPs in 8 922 SLE patients and 8 077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99×10−4
We have previously demonstrated that semimature dendritic cell- (smDC-) based immunotherapy is effective for the treatment of collagen-induced arthritis (CIA) prior to disease onset. In the present study, we examined the efficacy of combination therapy with smDCs and methotrexate (MTX) in advanced CIA with a score of 2-3. Combination therapy with low-dose MTX and type II collagen- (CII-) pulsed smDCs (CII-smDCs) was more effective in inhibiting disease progression than high or low-dose MTX alone or a combination of high dose MTX and CII-smDCs. The effect of CII-smDCs alone was also comparable to the combination therapy. CD4+Foxp3+ Treg populations and IL-10 secretion markedly increased, and CII-specific autoreactive T cells decreased in mice treated with CII-smDCs alone or in combination with MTX. Combination therapy reduced the secretion of interferon-γ (IFN-γ) and IL-17 with little influence on the IL-4 secretion in the mixed leukocyte reaction. These results imply that the combination therapy with low-dose MTX and smDCs is effective in controlling advanced CIA by enhancing Treg population and suppresses antigen-specific Th1/Th17 immunity, rather than initiating Th1 to Th2 immune deviation. Our findings provide a better understanding of the DC therapy in combination with MTX for the treatment of patients with rheumatoid arthritis (RA).
A highly polygenic etiology and high degree of allele-sharing between ancestries have been well-elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data.
We analyzed Korean rheumatoid arthritis case-control samples using the Immunochip and GWAS array to search for new risk alleles of rheumatoid arthritis with anti-citrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data, for a total sample size of 9,299 Korean and 45,790 European case-control samples.
We identified 8 new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1–FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10−8), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the 7 new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of SNPs that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs.
This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases.
Rheumatoid arthritis; Gene polymorphism; Anti-CCP
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with significant immune system aberrations resulting from complex heritable genetics as well as environmental factors. TRAF6 is a candidate gene for SLE, which has a major role in several signaling pathways that are important for immunity and organ development.
Fifteen single-nucleotide polymorphisms (SNPs), across TRAF6 were evaluated in 7,490 SLE and 6,780 control subjects from different ancestries. Population-based case-control association analyses and meta-analyses were performed. P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated.
Evidence of associations in multiple SNPs was detected. The best overall p values were obtained for SNPs rs5030437 and rs4755453 (p=7.85×10−5 and p=4.73×10−5, respectively) without significant heterogeneity among populations (p=0.67 and p=0.50 in Q-statistic). In addition, rs540386 previously reported to be associated with RA was found to be in LD with these two SNPs (r2= 0.95) and demonstrated evidence of association with SLE in the same direction (meta-analysis p=9.15×10−4, OR=0.89, 95%CI=0.83–0.95). Thrombocytopenia improved the overall results in different populations (meta-analysis p=1.99×10−6, OR=0.57, 95%CI=0.45–0.72, for rs5030470). Finally evidence of family based association in 34 African-American pedigrees with the presence of thrombocytopenia were detected in one available SNP rs5030437 with Z score magnitude of 2.28 (p=0.02) under a dominant model.
Our data indicate the presence of association of TRAF6 with SLE in agreement with the previous report of association with RA. These data provide further support for the involvement of TRAF6 in the pathogenesis of autoimmunity.
TRAF6; polymorphism; systemic lupus erythematosus
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.
Systemic lupus erythematosus (SLE; OMIM 152700) is a chronic autoimmune disease for which the aetiology includes genetic and environmental factors. ITGAM, integrin αΜ (complement component 3 receptor 3 subunit) encoding a ligand for intracellular adhesion molecule (ICAM) proteins, is an established SLE susceptibility locus. This study aimed to evaluate the independent and joint effects of genetic variations in the genes that encode ITGAM and ICAM.
The authors examined several markers in the ICAM1–ICAM4–ICAM5 locus on chromosome 19p13 and the single ITGAM polymorphism (rs1143679) using a large-scale case–control study of 17 481 unrelated participants from four ancestry populations. The single marker association and gene–gene interaction were analysed for each ancestry, and a meta-analysis across the four ancestries was performed.
The A-allele of ICAM1–ICAM4–ICAM5 rs3093030, associated with elevated plasma levels of soluble ICAM1, and the A-allele of ITGAM rs1143679 showed the strongest association with increased SLE susceptibility in each of the ancestry populations and the trans-ancestry meta-analysis (ORmeta=1.16, 95% CI 1.11 to 1.22; p=4.88×10−10 and ORmeta=1.67, 95% CI 1.55 to 1.79; p=3.32×10−46, respectively). The effect of the ICAM single-nucleotide polymorphisms (SNPs) was independent of the effect of the ITGAM SNP rs1143679, and carriers of both ICAM rs3093030-AA and ITGAM rs1143679-AA had an OR of 4.08 compared with those with no risk allele in either SNP (95% CI 2.09 to 7.98; p=3.91×10−5).
These findings are the first to suggest that an ICAM–integrin-mediated pathway contributes to susceptibility to SLE.
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.
Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE.
systemic lupus erythematosus; leptin pathway; gene polymorphisms
We report a 25-year-old Korean woman with Adult onset Still’s disease (AOSD) presented with renal amyloidosis, which had developed four years after disease onset. We successfully treated her with prednisolone, colchicine and cyclophosphamide. A review of the literature uncovered about 10 cases, most of which were treated by various regimens that resulted in poor outcomes. Renal amyloidosis should be suspected in patients with AOSD who have unexplained proteinuria. Although the mechanism of renal amyloid deposition is not well known, earlier histopathologic diagnosis and choice of regimen may affect prognosis.
Adult onset Still’s disease; Amyloidosis
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a strong genetic component. Our aim was to perform the first genome-wide association study on individuals from the Americas enriched for Native American heritage.
MATERIALS and METHODS
We analyzed 3,710 individuals from four countries of Latin America and the Unites States diagnosed with SLE and healthy controls. Samples were genotyped with the HumanOmni1 BeadChip. Data of out-of-study controls was obtained for the HumanOmni2.5. Statistical analyses were performed using SNPTEST and SNPGWA. Data was adjusted for genomic control and FDR. Imputation was done using IMPUTE2, and HiBAG for classical HLA alleles.
The IRF5-TNPO3 region showed the strongest association and largest odds ratio (OR) (rs10488631, Pgcadj = 2.61×10−29, OR = 2.12, 95% CI: 1.88–2.39) followed by the HLA class II on the DQA2-DQB1 loci (rs9275572, Pgcadj = 1.11 × 10−16, OR = 1.62, 95% CI: 1.46–1.80; rs9271366, Pgcadj=6.46 × 10−12, OR = 2.06, 95% CI: 1.71–2.50). Other known SLE loci associated were ITGAM, STAT4, TNIP1, NCF2 and IRAK1. We identified a novel locus on 10q24.33 (rs4917385, Pgcadj =1.4×10−8) with a eQTL effect (Peqtl=8.0 × 10−37 at USMG5/miR1307), and describe novel loci. We corroborate SLE-risk loci previously identified in European and Asians. Local ancestry estimation showed that HLA allele risk contribution is of European ancestral origin. Imputation of HLA alleles suggested that autochthonous Native American haplotypes provide protection.
Our results show the insight gained by studying admixed populations to delineate the genetic architecture that underlies autoimmune and complex diseases.
We aimed to investigate the prevalence and possible causes of hypouricemia in the Korean population and to compare our findings with published results of other populations.
We examined the serum uric acid levels of 30,757 subjects who had their uric acid values measured at least once during a 1-year period. All individuals with hypouricemia (serum uric acid < 2.0 mg/dL, n = 424) were reviewed with respect to medical drug history and concomitant diseases previously identified as being associated with hypouricemia.
The prevalence of hypouricemia was 4.14% (299/7,223) among inpatients and 0.53% (125/23,534) among outpatients, for an overall prevalence of 1.39% (424/30,757). Possible causes associated with hypouricemia were found to be solid or hematologic malignancies (n = 86), diabetes mellitus (n = 56), and therapeutic drugs (n = 29). The medications were allopurinol (n = 11), angiotensin II receptor blockers (n = 10), salicylates (n = 6), febuxostat (n = 1), and warfarin (n = 1). In the remaining 226 individuals, the cause of hypouricemia was not identified.
Hypouricemia is relatively common in the Korean population compared to those of other countries. The possible causes associated with hypouricemia are related to underlying diseases and medications.
Hypouricemia; Uric acid
The concerns about the development of adverse events (AEs) in elderly RA patients as a result of age-related changes in drug metabolism and the presence of comorbid illnesses are emphasizing due to increasing prevalence of rheumatoid arthritis (RA) in old age. However, they tend to be inadequately represented in RA clinical trials because of the exclusion criteria that are commonly applied. The tolerability and safety of TNF inhibitors in elderly patients have not been also evaluated in clinical practice. This study aimed to evaluate the retention rate and safety of TNF inhibitors (TNFI) in elderly RA patients.
Total 429 RA patients (838 person-years [PYs]) treated with TNFI from a retrospective biologic DMARDs registry. Patients were divided into an elderly (age ≥60 years) and a younger group (<60 years). The drug retention rates of both groups were compared using Kaplan-Meier curves. Potential predictors of TNFI discontinuation in the elderly were examined using Cox regression analysis. The incidence rate (IR) of serious adverse events (SAEs) in the elderly group was compared to that of the young group.
Of the patients, 24.9 % (n = 107, 212 PYs) were in the elderly group. Regarding the retention rates of TNFI in 3 years, there was no significant difference between the elderly and younger group (p = 0.33). The major cause of discontinuation in elderly patients was AE (34.3 %), whereas that was drug ineffectiveness (41.7 %) in younger patients. Age (HR 1.09, CI 1.02-1.16) was a predictor of discontinuation, while the presence of comorbidity (HR 0.37, CI 0.15-0.91) had a protective effect against drug discontinuation in the elderly. The IR of SAEs in the elderly (6.13/100 PYs) was higher than in the younger group (5.11/100 PYs).
The retention rate of TNFI in the elderly was comparable with that in younger patients. The major cause of discontinuation in the elderly patients was AEs, while it was drug ineffectiveness in younger patients. The IR of SAEs in the elderly was higher than in the younger patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s12891-016-1185-6) contains supplementary material, which is available to authorized users.
Rheumatoid arthritis; TNF inhibitor; Elderly; Safety; Drug retention rate
To determine the frequency, clinical and autoantibody associations and outcome of mood disorders in a multi-ethnic/racial, prospective, inception cohort of SLE patients.
Patients were assessed annually for mood disorders (4 types as per DSM-IV) and 18 other neuropsychiatric (NP) events. Global disease activity (SLEDAI-2K), SLICC/ACR damage index (SDI) and SF-36 subscale, mental (MCS) and physical (PCS) component summary scores were collected. Time to event, linear and ordinal regressions and multi-state models were used as appropriate.
Of 1,827 SLE patients, 88.9% were female, 48.9% Caucasian, mean ± SD age 35.1±13.3 years, disease duration 5.6±4.8 months and follow-up 4.73±3.45 years. Over the study 863 (47.2%) patients had 1,627 NP events. Mood disorders occurred in 232/1827 (12.7%) patients and 98/256 (38.3%) events were attributed to SLE. The estimated cumulative incidence of any mood disorder after 10 years was 17.7% (95%CI=[15.1%,20.2%]). There was a greater risk of mood disorder in patients with concurrent NP events (p ≤ 0.01) and lower risk with Asian race/ethnicity (p=0.01) and immunosuppressive drugs (p=0.003). Mood disorders were associated with lower mental health subscale and MCS scores but not with SLEDAI-2K, SDI scores or lupus autoantibodies. Antidepressants were used in 168/232 (72.4%) patients with depression. 126/256 (49.2%) mood disorders resolved in 117/232 (50.4%) patients.
Mood disorders, the second most frequent NP event in SLE patients, have a negative impact on HRQoL and improve over time. The lack of association with global SLE disease activity, cumulative organ damage and lupus autoantibodies emphasize their multifactorial etiology and a role for non-lupus specific therapies.
Systemic lupus erythematosus; Mood disorders; Inception cohort; Outcomes research
Osteonecrosis of the femoral head (ONFH) is a complex and multifactorial disease that is influenced by a number of genetic factors in addition to environmental factors. Some autoimmune disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD), are associated with the development of ONFH. Complement receptor type 2 (CR2) is membrane glycoprotein which binds C3 degradation products generated during complement activation. CR2 has many important functions in normal immunity and is assumed to play a role in the development of autoimmune disease. We investigated whether CR2 gene polymorphisms are associated with risk of ONFH in SLE patients. Eight polymorphisms in the CR2 gene were genotyped using TaqMan™ assays in 150 SLE patients and 50 ONFH in SLE patients (SLE_ONFH). The association analysis of genotyped SNPs and haplotypes was performed with ONFH. It was found that three SNPs, rs3813946 in 5′-UTR (untranslated region), rs311306 in intron 1, and rs17615 in exon 10 (nonsynonymous SNP; G/A, Ser639Asn) of the CR2 gene, were associated with an increased risk of ONFH under recessive model (P values; 0.004~0.016). Haplotypes were also associated with an increased risk (OR; 3.73~) of ONFH in SLE patients. These findings may provide evidences that CR2 contributes to human ONFH susceptibility in Korean SLE patients.
Considerable sharing of disease alleles among populations is well-characterized in autoimmune disorders (e.g., rheumatoid arthritis), but there are some exceptional loci showing heterogenic association among populations. Here we investigated genetic variants with distinct effects on the development of rheumatoid arthritis in Asian and European populations. Ancestry-related association heterogeneity was examined using Cochran’s homogeneity tests for the disease association data from large Asian (n = 14,465; 9,299 discovery subjects and 5,166 validation subjects; 4 collections) and European (n = 45,790; 11 collections) rheumatoid arthritis case-control cohorts with Immunochip and genome-wide SNP array data. We identified significant heterogeneity between the two ancestries for the common variants in the GTF2I locus (PHeterogeneity = 9.6 × 10−9 at rs73366469) and showed that this heterogeneity was due to an Asian-specific association effect (ORMeta = 1.37 and PMeta = 4.2 × 10−13 in Asians; ORMeta = 1.00 and PMeta = 1.00 in Europeans). Trans-ancestral comparison and bioinfomatics analysis revealed a plausibly causal or disease-variant-tagging SNP (rs117026326; in linkage disequilibrium with rs73366469), whose minor allele is common in Asians but rare in Europeans. In conclusion, we identified largest-ever effect on Asian rheumatoid arthritis across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant.
Systemic lupus erythematosus (SLE) predominantly affects women in their reproductive years and has a significant impact on childbearing. We investigated the influence of personal decision on family size among Korean women with SLE and factors that affect the decisions. A case-control study comparing childbearing history and decisions of 112 SLE patients and 135 controls was performed. Women with SLE participating in the Network for Lupus Clinical Research in South Korea and matching controls between ages of 18-45, who are/were married or living with a partner were included. Data regarding socio-demographics, reproductive history, and childbearing decisions were collected through a survey using a standardized questionnaire and medical record review. More women with SLE reported at least one pregnancy (85.7% vs. 71.9%, P = 0.009) or at least one live birth (85.7% vs. 71.9%, P = 0.003) compared with controls. Mean number of pregnancies was significantly higher (2.4 ± 1.6 vs. 1.4 ± 1.3, P < 0.001), and mean number of live births was significantly lower in women with SLE (1.2 ± 0.8 vs. 1.6 ± 0.8, P < 0.001). Significantly more women with SLE made the decision not to have children compared with controls (54.5% vs. 40.7%, P = 0.031), and health-related concerns were the major cause of the decision. Other socio-demographic factors did not influence the decision to limit childbearing in SLE women. The disease-related concerns had significant impact on family size and childbearing decisions among Korean women with SLE.
Systemic Lupus Erythematosus; Family Size; Childbearing Decisions; Korean
An association between 25-hydroxyvitamin D (25[OH]D; vitamin D) deficiency and increased cardiovascular (CV) risk factors and CV disease (CVD) has been shown in general population studies. Vitamin D deficiency has been noted in systemic lupus erythematosus (SLE), and CVD is a major cause of morbidity and mortality in SLE. The objectives of this study were to estimate the associations of 25(OH)D levels with CV risk factors and to determine whether low baseline 25(OH)D levels predict future CV events in patients participating in an international inception cohort.
Data were collected on 890 participants, including demographics, SLE activity and damage assessments, CV risk factors and events, medications, laboratory assessments of 25(OH)D levels, and inflammatory markers. Multiple logistic and Cox regressions were used to estimate the associations of baseline 25(OH)D levels with baseline CV risk factors and CVD events. The models were adjusted for age, sex, race, season, and country, with and without body mass index.
Patients in the higher quartiles of 25(OH)D were less likely to have hypertension and hyperlipidemia and were more likely to have lower C-reactive protein levels and lower Systemic Lupus Erythematosus Disease Activity Index 2000 scores at baseline when compared with the first quartile. Vitamin D levels were not independently associated with CVD event incidence; however, hazard ratios for CVD event incidence decreased with successively higher quartiles.
Lower baseline 25(OH)D levels are associated with higher risk for CV risk factors and more active SLE at baseline. There may be a trend toward a lower likelihood of CVD events in those with higher baseline 25(OH)D levels.
Many biologic disease-modifying antirheumatic drug (DMARD) discontinuation studies have been conducted, but mainly in trial settings which result in limited generalizability. Registry studies can complement the current literature of biologic DMARD discontinuation by providing more generalizable information. However, registries may need to be combined to increase power and provide a more diverse patient population. This increased power could provide us information about risk and benefits of discontinuing biologic DMARD in typical clinical practice. However, use of multiple registries is not without challenges. In this review, we discuss the challenges to combining data across multiple registries, focusing on biologic discontinuation as an example. Challenges include: 1) generalizability of each registry; 2) new versus prevalent users designs; 3) outcome definitions; 4) different health care systems; 5) different follow up intervals; and 6) data harmonization. The first three apply to each registry, and the last three apply to combining multiple registries. This review describes these challenges, corresponding solutions, and potential future opportunities.
Rheumatoid Arthritis; Antirheumatic Agents; biologic antirheumatic agents (non-MeSH); remission (non-MeSH); discontinuation (non-MeSH)
We conducted a systematic review to assess the design and “failure definition” in studies of biologic discontinuation in rheumatoid arthritis (RA).
We found 403 studies on PubMed, and included 9 published papers and 5 abstracts from scientific meetings. We used a structured extraction form to collect information regarding study design and outcome (failure) definition.
Three types of studies were found: randomized 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.
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.
biologic DMARDs; remission; discontinuation; rheumatoid arthritis