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OBJECTIVES: To compare the incidence of major adverse cardiovascular events (MACEs), cancer and infective complications in RA patients using Janus kinase (JAKis) and TNF (TNFis) inhibitors. METHOD: A retrospective analysis of data from the Hong Kong Biologics Registry 2008-2021 was performed. RA patients who had ever used JAKis or TNFis were included. The incidence of MACEs, cancer and infections were compared between the two groups, with adjustment for confounding factors. RESULTS: A total of 2471 courses of JAKis (n = 551) and TNFis (n = 1920) were used in 1732 RA patients (83.7% women, age 53.8 [12.5] years; follow-up 6431 patient-years). JAKi users had significantly older age, more atherosclerotic risk factors and higher frequency of past malignancies. A total of 15 and 40 MACEs developed in the JAKi and TNFi users, respectively (incidence 1.34 vs 0.75 per 100 patient-years; P = 0.22). There was no significant difference in the incidence of cancers between the two groups (0.81 [JAKi] vs 0.85 [TNFi] per 100 patient-years; P = 0.25). The adjusted hazard ratios of MACE and cancer in the JAKi users were 1.36 (95% CI: 0.62, 2.96) (P = 0.44) and 0.87 (95% CI: 0.39, 1.95) (P = 0.74), respectively. Rates of infections were significantly higher in the JAKi than TNFi users (16.3 vs 9.9 per 100 patient-years; P = 0.02), particularly herpes zoster (3.49 vs 0.94 per 100 patient-years; P < 0.001). CONCLUSIONS: In a real-life setting, there is no increase in MACEs or cancers in users of JAKis compared with TNFis. However, the incidence of non-serious infections, including herpes zoster, was increased in users of JAKis.
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Antirreumáticos , Artritis Reumatoide , Productos Biológicos , Herpes Zóster , Neoplasias , Humanos , Femenino , Persona de Mediana Edad , Masculino , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Productos Biológicos/efectos adversos , Estudios Retrospectivos , Hong Kong/epidemiología , Antirreumáticos/efectos adversos , Factor de Necrosis Tumoral alfa , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/epidemiología , Artritis Reumatoide/complicaciones , Herpes Zóster/inducido químicamente , Herpes Zóster/epidemiología , Quinasas Janus , Sistema de Registros , Neoplasias/inducido químicamenteRESUMEN
OBJECTIVES: To report the 10-year outcome of lupus nephritis (LN) treated with mycophenolate mofetil (MMF) or tacrolimus (TAC) induction in a randomised controlled trial. METHODS: Patients with active LN were treated with MMF or TAC combined with high-dose prednisolone. Responders were switched to azathioprine (AZA) at month 6. Clinical outcomes at 10 years (renal flares, renal function decline and mortality) were assessed. Factors affecting prognosis were studied by Cox regression. Urine protein-to-creatinine ratio (uPCr) and estimated glomerular filtration rate (eGFR) at different time points were evaluated for their prediction of a poor prognosis by receiver operating characteristic (ROC) analysis. RESULTS: 150 patients were studied (age 35.5±12.8 years). Complete renal response rate was similar between MMF (59%) and TAC-treated patients (62%; p=0.71). AZA maintenance was given to 79% patients. After 118.2±42 months, proteinuric and nephritic renal ï¬ares occurred in 34% and 37% of the MMF, and 53% and 30% of the TAC groups of patients, respectively (p=0.49). The cumulative incidence of a composite outcome of ↓eGFR ≥30%, chronic kidney disease stage 4/5 or death at 10 years was 33% in both groups (p=0.90). Factors independently associated with a poor renal prognosis were first-time LN (HR 0.12 (0.031 to 0.39); p=0.01), eGFR (HR 0.98 (0.96 to 0.99); p=0.008) and no response at month 6 (HR 5.18 (1.40 to 19.1); p=0.01). ROC analysis revealed an uPCr >0.75 and eGFR of <80 mL/min at month 18 best predicted a poor renal prognosis. CONCLUSIONS: Long-term data confirmed non-inferiority of TAC to MMF as induction therapy of LN. An uPCr≤0.75 and eGFR of ≥80 mL/min at month 18 best predicted a favourable 10-year outcome and may be suitable targets for induction/consolidation therapy. TRIAL REGISTRATION NUMBER: NCT00371319.
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Inmunosupresores/uso terapéutico , Quimioterapia de Inducción/métodos , Nefritis Lúpica/tratamiento farmacológico , Ácido Micofenólico/uso terapéutico , Tacrolimus/uso terapéutico , Adulto , Azatioprina/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Quimioterapia de Mantención/métodos , Masculino , Persona de Mediana Edad , Prednisolona/uso terapéutico , Brote de los Síntomas , Tiempo , Resultado del TratamientoRESUMEN
Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects mainly females. What role the X chromosome plays in the disease has always been an intriguing question. In this study, we examined the genetic variants on the X chromosome through meta-analysis of two genome-wide association studies (GWAS) on SLE on Chinese Han populations. Prominent association signals from the meta-analysis were replicated in 4 additional Asian cohorts, with a total of 5373 cases and 9166 matched controls. We identified a novel variant in PRPS2 on Xp22.3 as associated with SLE with genome-wide significance (rs7062536, OR = 0.84, P = 1.00E-08). Association of the L1CAM-MECP2 region with SLE was reported previously. In this study, we identified independent contributors in this region in NAA10 (rs2071128, OR = 0.81, P = 2.19E-13) and TMEM187 (rs17422, OR = 0.75, P = 1.47E-15), in addition to replicating the association from IRAK1-MECP2 region (rs1059702, OR = 0.71, P = 2.40E-18) in Asian cohorts. The X-linked susceptibility variants showed higher effect size in males than that in females, similar to results from a genome-wide survey of associated SNPs on the autosomes. These results suggest that susceptibility genes identified on the X chromosome, while contributing to disease predisposition, might not contribute significantly to the female predominance of this prototype autoimmune disease.
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Pueblo Asiatico/genética , Cromosomas Humanos X/genética , Genes Ligados a X , Lupus Eritematoso Sistémico/genética , Ribosa-Fosfato Pirofosfoquinasa/genética , China , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
Systemic lupus erythematosus (SLE) has a complex etiology and is affected by both genetic and environmental factors. Although more than 40 loci have shown robust association with SLE, the details of these loci, such as the independent contributors and the genes involved, are still unclear. In this study, we performed meta-analysis of two existing genome-wide association studies (GWASs) on Chinese Han populations from Hong Kong and Anhui, China, and followed the findings by further replication on three additional Chinese and Thailand cohorts with a total of 4254 cases and 6262 controls matched geographically and ethnically. We discovered multiple susceptibility variants for SLE in the 11q23.3 region, including variants in/near PHLDB1 (rs11603023, P(_combined) = 1.25E-08, OR = 1.20), DDX6 (rs638893, P(_combined) = 5.19E-07, OR = 1.22) and CXCR5 (rs10892301, P(_combined) = 2.51E-08, OR = 0.85). Genetic contributions from the newly identified variants were all independent of SNP rs4639966, whose association was reported from the previous GWAS. In addition, the three newly identified variants all showed independent association with the disease through modeling by both stepwise and conditional logistic regression. The presence of multiple independent variants in this region emphasizes its role in SLE susceptibility, and also hints the possibility that distinct biological mechanisms might be involved in the disease involving this genomic region.
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Cromosomas Humanos Par 11 , ARN Helicasas DEAD-box/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Lupus Eritematoso Sistémico/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas/genética , Receptores CXCR5/genética , Pueblo Asiatico/genética , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Modelos Logísticos , Lupus Eritematoso Sistémico/diagnósticoRESUMEN
OBJECTIVES: Genetic interaction has been considered as a hallmark of the genetic architecture of systemic lupus erythematosus (SLE). Based on two independent genome-wide association studies (GWAS) on Chinese populations, we performed a genome-wide search for genetic interactions contributing to SLE susceptibility. METHODS: The study involved a total of 1â 659 cases and 3â 398 controls in the discovery stage and 2â 612 cases and 3â 441 controls in three cohorts for replication. Logistic regression and multifactor dimensionality reduction were used to search for genetic interaction. RESULTS: Interaction of CD80 (rs2222631) and ALOX5AP (rs12876893) was found to be significantly associated with SLE (OR_int=1.16, P_int_all=7.7E-04 at false discovery rate<0.05). Single nuclear polymorphism rs2222631 was found associated with SLE with genome-wide significance (P_all=4.5E-08, OR=0.86) and is independent of rs6804441 in CD80, whose association was reported previously. Significant correlation was observed between expression of these two genes in healthy controls and SLE cases, together with differential expression of these genes between cases and controls, observed from individuals from the Hong Kong cohort. Genetic interactions between BLK (rs13277113) and DDX6 (rs4639966), and between TNFSF4 (rs844648) and PXK (rs6445975) were also observed in both GWAS data sets. CONCLUSIONS: Our study represents the first genome-wide evaluation of epistasis interactions on SLE and the findings suggest interactions and independent variants may help partially explain missing heritability for complex diseases.
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Proteínas Activadoras de la 5-Lipooxigenasa/genética , Pueblo Asiatico/genética , Antígeno B7-1/genética , Epistasis Genética/genética , Lupus Eritematoso Sistémico/genética , Adulto , Estudios de Casos y Controles , Femenino , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Proteínas de Fusión Oncogénica/genética , Polimorfismo de Nucleótido Simple , Tetraspaninas , Receptor fas/genéticaRESUMEN
OBJECTIVE: This study aims to identify the existence of, and relationship between autoantibody clusters and clinical subsets in Chinese SLE patients. METHODS: Data from 1928 SLE patients from Hong Kong were analysed. Using cluster analysis, patients were grouped by autoantibodies into clusters. The frequencies of various clinical manifestations were then compared between each cluster. Separate association analyses between individual autoantibodies and clinical manifestations as well as between clinical manifestations were also performed without any prior clustering. RESULTS: Three separate autoantibody clusters were identified, each with significantly different clinical manifestations. Cluster 1 was characterized by anti-dsDNA and the greatest prevalence of renal disorder but the lowest frequencies of other clinical manifestations. Cluster 2 was represented by the predominance of anti-Smith, anti-RNP and aPL, with greater prevalence of malar rash, oral ulcers, arthritis and serositis. Cluster 3 was characterized by anti-Ro and anti-La with greater prevalence of discoid rash, photosensitivity and haematological involvement. Individual association analysis also revealed similar findings. Patients of clusters 2 and 3 were more closely related, while cluster 1 was more distinct, associated with renal disorder only and negatively associated or not associated with other manifestations. CONCLUSION: We conclude that autoantibody clustering and clinical subsets exist in SLE patients of our locality. These clusters may be viewed as a bipolar spectrum of related autoantibody and clinical manifestations. At one end are patients with over-representation of anti-dsDNA and renal disorder, while at the other end are two distinct autoantibody clusters (anti-Sm/anti-RNP/aPL and anti-Ro/anti-La) with overlapping of other clinical manifestations.
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Autoanticuerpos/sangre , Lupus Eritematoso Sistémico/inmunología , Adolescente , Adulto , Anticuerpos Antinucleares/sangre , Pueblo Asiatico/etnología , Análisis por Conglomerados , Estudios Transversales , Femenino , Hong Kong/epidemiología , Humanos , Lupus Eritematoso Sistémico/etnología , Masculino , Prevalencia , Estudios Retrospectivos , Adulto JovenRESUMEN
OBJECTIVE: To study the bone mineral density (BMD) and body composition in men with systemic lupus erythematosus (SLE). METHODS: Consecutive male patients who fulfilled > or =4 ACR criteria for SLE and age-matched healthy men were recruited for measurement of BMD and body composition by DXA scan. Risk factors for low BMD in SLE patients were evaluated. RESULTS: 40 male SLE patients were studied (age 42.6+/-12 years; disease duration 84.7+/-79 months). 34 (85%) patients were treated with long-term glucocorticoids. Compared with 40 controls, SLE patients had a significantly lower BMD at the lumbar spine (0.96+/-0.16 vs 1.03+/-0.11 g/cm2; p=0.02) and the hip (0.87+/-0.14 vs 0.94+/-0.12 g/cm2; p=0.04). At the spine, 12 (30%) SLE patients had Z scores< - 2.0 and 2 (5%) had osteoporotic fractures. At the hip, 3 (7.5%) patients had Z scores< - 2.0 but none had hip fractures. The BMD Z scores at the femoral neck and spine were significantly lower in SLE patients than controls. The total lean body mass was also lower in patients than control subjects (46.4+/-7.3 vs 50.5+/-5.9 kg; p=0.01). Multiple regression revealed increasing age, habitual drinking, lower BMI and use of high-dose prednisolone were unfavorably associated with lower BMD at the spine in SLE patients. CONCLUSIONS: Reduced BMD and lean body mass are prevalent in men with SLE. Appropriate measures against osteoporosis should be undertaken, especially in older patients with low BMI who receive high-dose glucocorticoids.
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Composición Corporal/fisiología , Densidad Ósea/fisiología , Lupus Eritematoso Sistémico/fisiopatología , Adulto , Autoanticuerpos/inmunología , Peso Corporal , Estudios de Casos y Controles , Cadera/fisiopatología , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Masculino , Obesidad/fisiopatología , Prednisolona/administración & dosificación , Prednisolona/uso terapéutico , Análisis de Regresión , Columna Vertebral/fisiopatología , Delgadez/fisiopatologíaRESUMEN
INTRODUCTION: Systemic lupus erythematosus (SLE) is a heterogeneous disease with a diverse spectrum of clinical symptoms, ranging from skin rash to end-organ damage. 22q11.21 has been identified as a susceptibility region for several autoimmune diseases, including SLE. However, detailed information for SLE association and the underlying functional mechanism(s) is still lacking. METHODS: Through meta-analysis of two genome-wide association studies (GWAS) on Han Chinese populations, comprising a total of 1,659 cases and 3,398 controls matched geographically, we closely examined the 22q11.21 region, especially on the reported single-nucleotide polymorphisms (SNPs) associated with different autoimmune diseases and their relationships. We further replicated the most significant associations of SNPs with SLE using 2,612 cases and 2,323 controls of Asian ancestry. RESULTS: All reported SNPs in the 22q11.21 region with different autoimmune diseases were examined using the two GWAS data and meta-analysis results, and supportive evidence of association with SLE was found (meta-analysis: P_meta ≤ 7.27E-05), which might require further investigation. SNP rs2298428 was identified as the most significant SNP associated with SLE in this region (P_meta =2.70E-09). It showed independent effects through both stepwise and conditional logistic regression, and there is no evidence of other independent association signals for SLE in this region. The association of rs2298428 was further replicated in three cohorts from Hong Kong, Anhui and Thailand comprising a total of 2,612 cases and 2,323 controls (joint analysis of GWAS and replication result: P_all =1.31E-11, odds ratio =1.23). SNP rs2298428 was shown to be an expression quantitative locus for UBE2L3 gene in different cell types, with the risk allele (T) being correlated with higher expression of UBE2L3. This is consistent with earlier reports on higher expression of UBE2L3 in patients with SLE. CONCLUSIONS: Association with distinct autoimmune diseases highlights the significance of this region in autoreactive responses and potentially shared functional mechanisms in these diseases.
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Alelos , Pueblo Asiatico/genética , Cromosomas Humanos Par 22/genética , Predisposición Genética a la Enfermedad/genética , Lupus Eritematoso Sistémico/genética , Vigilancia de la Población , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/genética , Predisposición Genética a la Enfermedad/epidemiología , Estudio de Asociación del Genoma Completo/métodos , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/epidemiología , Factores de RiesgoRESUMEN
OBJECTIVE: Previous genome-wide association studies (GWAS), which were mainly based on single-variant analysis, have identified many systemic lupus erythematosus (SLE) susceptibility loci. However, the genetic architecture of this complex disease is far from being understood. The aim of this study was to investigate whether using a gene-based analysis may help to identify novel loci, by considering global evidence of association from a gene or a genomic region rather than focusing on evidence for individual variants. METHODS: Based on the results of a meta-analysis of 2 GWAS of SLE conducted in 2 Asian cohorts, we performed an in-depth gene-based analysis followed by replication in a total of 4,626 patients and 7,466 control subjects of Asian ancestry. Differential allelic expression was measured by pyrosequencing. RESULTS: More than one-half of the reported SLE susceptibility loci showed evidence of independent effects, and this finding is important for understanding the mechanisms of association and explaining disease heritability. ANXA6 was detected as a novel SLE susceptibility gene, with several single-nucleotide polymorphisms (SNPs) contributing independently to the association with disease. The risk allele of rs11960458 correlated significantly with increased expression of ANXA6 in peripheral blood mononuclear cells from heterozygous healthy control subjects. Several other associated SNPs may also regulate ANXA6 expression, according to data obtained from public databases. Higher expression of ANXA6 in patients with SLE was also reported previously. CONCLUSION: Our study demonstrated the merit of using gene-based analysis to identify novel susceptibility loci, especially those with independent effects, and also demonstrated the widespread presence of loci with independent effects in SLE susceptibility genes.