Meta-analysis of GWAS on two Chinese populations followed by replication identifies novel genetic variants on the X chromosome associated with systemic lupus erythematosus.

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.

Three SNPs in chromosome 11q23.3 are independently associated with systemic lupus erythematosus in Asians.

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.

Meta-analysis followed by replication identifies loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with systemic lupus erythematosus in Asians.

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases.

Genome-wide search followed by replication reveals genetic interaction of CD80 and ALOX5AP associated with systemic lupus erythematosus in Asian populations.

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 1 659 cases and 3 398 controls in the discovery stage and 2 612 cases and 3 441 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.

ELF1 is associated with systemic lupus erythematosus in Asian populations.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic involvement. The susceptibility genes identified so far can only explain a small proportion of disease heritability. Through a genome-wide association in a Hong Kong Chinese cohort and subsequent replication in two other Asian populations, with a total of 3164 patients and 4482 matched controls, we identified association of ELF1 (E74-like factor 1) with SLE (rs7329174, OR = 1.26, joint P= 1.47 × 10(-8)). ELF1 belongs to the ETS family of transcription factors and is known to be involved in T cell development and function. Database analysis revealed transcripts making use of three alternative exon1s for this gene. Near equivalent expression levels of distinct transcripts initiated from alternative exon1s were detected in peripheral blood mononuclear cells from both SLE patients and healthy controls. Although a direct association of rs7329174 with the three forms of transcripts for this gene was not detected, these findings support an important role of ELF1 in SLE susceptibility and suggest a potentially tight regulation for the expression of this gene.

Epistatic interaction between genetic variants in susceptibility gene ETS1 correlates with IL-17 levels in SLE patients.

T-helper cells that produce IL-17 (Th17 cells) are a subset of CD4(+) T-cells with pathological roles in autoimmune diseases including systemic lupus erythematosus (SLE), and ETS1 is a negative regulator of Th17 cell differentiation. Our previous work on genome-wide association study (GWAS) identified two variants in the ETS1 gene (rs10893872 and rs1128334) as being associated with SLE. However, like many other risk alleles for complex diseases, little is known on how these genetic variants might affect disease pathogenesis. In this study, we examined serum IL-17 levels from 283 SLE cases and observed a significant correlation between risk variants in ETS1 and serum IL-17 concentration in patients, which suggests a potential mechanistic link between these variants and the disease. Furthermore, we found that the two variants act synergistically in influencing IL-17 production, with evidence of significant genetic interaction between them as well as higher correlation between the haplotype formed by the risk alleles and IL-17 level in patient serum. In addition, the correlation between ETS1 variants and IL-17 level seems to be more significant in SLE patients manifesting renal involvement, dsDNA autoantibody production or early-onset.

Relationship between autoantibody clustering and clinical subsets in SLE: cluster and association analyses in Hong Kong Chinese.

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.

Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus.

Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33x10(-11), OR = 1.29; WDFY4: rs7097397, P = 8.15x10(-12), OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.

Dietary Intake in Law Enforcement Personnel: Occupation Is an Additional Challenge for Changing Behavior.

BACKGROUND: Law enforcement is a dangerous, stressful, and health-threatening occupation. This study investigated the association between demographic factors including sex, age, and types of law enforcement occupation and described self-reported barriers to healthy and enjoyable diets within a cohort of law enforcement personnel. METHODS: This mixed-methods study explored cross-sectional data from the Perceived Barriers to Healthy Eating validated survey. The survey included eight questions obtaining quantitative data and two open ended question obtaining qualitative data. A framework thematic analysis using the theory of planned behavior was undertaken to describe self-reported barriers to a healthy and enjoyable dietary intake. RESULTS: 159 participants (median age = 27 (range 19-60) years; 74% males) were surveyed. In general, demographic factors are not associated with the dietary beliefs and behavior of law enforcement personnel. Self-reported barriers (generated themes) to a healthy and enjoyable diet included individual preferences, social influences, internal drive, capacity to change and occupational influences, which broadly aligned with the theory of planned behavior. CONCLUSIONS: Dietary intake in law enforcement personnel is impacted by occupational considerations, including busy schedules, long working hours, inconsistent meal breaks, tiredness, and shift work. The study provides useful information to support dietary interventions.

ITGAM is associated with disease susceptibility and renal nephritis of systemic lupus erythematosus in Hong Kong Chinese and Thai.

ITGAM was recently found to be associated with systemic lupus erythematosus (SLE) in populations of not only European ancestry, but also in Hispanic- and African-Americans, Mexicans and Colombians. The risk alleles in the gene, however, were found to be monomorphic in two Asian populations examined: Japanese and Korean. In this study, using a collection of 910 SLE patients and 2360 controls from Chinese living in Hong Kong, analyzed by both genome-wide association and direct sequencing, we confirmed the association of the same risk alleles in ITGAM with the disease. These findings were further replicated in the Thai population with 278 patients and 383 ethnicity- and geography-matched controls. Subphenotype stratification analyses showed significantly more involvement of the gene in patients with renal nephritis and neurological disorders. Although our results support a pivotal role by rs1143679 (R77H) in disease association, our data also suggests an additional contribution from rs1143683, another non-synonymous polymorphism in this gene (A858V). Therefore, despite the low-allele frequencies of the risk alleles of the gene in our two Asian populations, ITGAM was confirmed to be a risk factor related to disease susceptibility and probably severe manifestations of SLE.

Free-Living Dietary Intake in Tactical Personnel and Implications for Nutrition Practice: A Systematic Review.

Tactical personnel (including military, law enforcement, and fire and rescue) are responsible for ensuring national and public safety. Dietary intake is an important consideration to support optimal health and performance. The aims of this systematic review were to: (1) describe the reported free-living dietary intake (energy and macronutrients) of tactical personnel, and (2) describe the practical implications of reported dietary intakes to support the physical and dietary requirements of tactical personnel. A systematic search of databases (MEDLINE, EMBASE, CINAHL and Web of Science) was conducted following the PRISMA guidelines. English and full text research articles were identified and screened against inclusion and exclusion criteria. Demographic and dietary intake data were extracted, tabulated, and synthesized narratively. The quality of the studies was assessed using the Academy of Nutrition and Dietetics Quality Criteria Checklist. Twenty-two studies (15 military, 4 law enforcement, and 2 fire and rescue) were eligible to inform this review. The volume of evidence suggested that tactical personnel met dietary protein and exceeded dietary fat recommendations but failed to meet energy and carbohydrate recommendations. Therefore, practical approaches to support optimized energy, fat and carbohydrate intake in tactical personnel is important.

Rheumatoid arthritis management in the APLAR region: Perspectives from an expert panel of rheumatologists, patients and community oriented program for control of rheumatic diseases.

Rheumatoid arthritis (RA) is a major health burden in Asia Pacific affecting the quality of life of patients and consuming healthcare resources. According to recent estimates from the World Health Organization-International League Against Rheumatism-Community Oriented Program for Control of Rheumatic Diseases, prevalence is around 0.3%-0.5%. Management guidelines have helped to improve treatment across this diverse region. To gain better insight into current real-world management applications in view of these guidelines, virtual meetings were conducted in mid-2020 to explore perspectives of rheumatologists and patients, as well as discuss the impact of coronavirus disease 2019 on RA management. Patients and rheumatologists from Hong Kong, Malaysia, Singapore, the Philippines, Thailand, India, Pakistan, and Taiwan were included, representing a diverse mix of healthcare systems, wealth, ethnicity and culture. Despite many countries having prospered in recent years, similar challenges in RA diagnosis and treatment were identified. The daily impact and patient experience of RA were also similar across countries, marked by "silent" pain and disability, and universal misunderstanding of the disease. Late diagnosis and treatment, and barriers to access to appropriate treatment, remain problematic. The experience shared by Taiwan offers a glimmer of hope, however, wherein patient advocacy groups have succeeded in being included in policy-making decisions and securing access to advanced treatment. Real-world solutions that pay heed to the unique local needs and diversity of Asia Pacific are required to improve RA management, which will take time. In the interim, help can be sought from the trained, non-rheumatologist community to reduce some of the disease burden.

Hydrocarboxyl Radical as a Product of α-Alanine Ultraviolet Photolysis.

UV photodissociation of α-alanine was studied by parahydrogen matrix isolation infrared spectroscopy. The temporal behavior of Fourier transform infrared spectra revealed that UV irradiation at 213 nm yielded the HOCO radical as a direct photoproduct from the S2 excited state. The concentration of HOCO quickly approached a steady state due to secondary photodissociation of HOCO to produce CO2 + H or CO + OH. On the other hand, no photoproducts were detected by S1 excitation at 266 nm. Irradiation of fully deuterated α-alanine at 213 nm yielded ∼2 times more cis-DOCO radicals than the lower energy isomer trans-DOCO, indicating that the conformation of the hydroxyl group is fairly well-preserved upon photodissociation of α-alanine. The present study suggests that HOCO may be a good tracer species in the search for amino acids in interstellar space.

Gene-based meta-analysis of genome-wide association study data identifies independent single-nucleotide polymorphisms in ANXA6 as being associated with systemic lupus erythematosus in Asian populations.

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.

Meta-analysis of two Chinese populations identifies an autoimmune disease risk allele in 22q11.21 as associated with systemic lupus erythematosus.

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.

Behçet's aortitis and aortic regurgitation: a report of two cases.

Behçet's disease is a rare systemic vasculitis that may lead to neurologic complications and rare manifestations of aortitis and aortic regurgitation. We report 2 cases of Behçet's aortitis and aortic regurgitation. The first patient presented with acute stroke. Recognition of acute aortitis on echocardiography led to the diagnosis of vasculitis as the cause of the cerebral event. This case highlights the echocardiographic features of aortic root pathology from acute aortitis to subsequent aortic valve perforation. In both cases, severe aortic regurgitation necessitated aortic valve replacement. Both were complicated by valve dehiscence requiring reoperation, illustrating the postoperative morbidity in this inflammatory condition.

A multinational randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis [ISRCTN25142273].

BACKGROUND: Etoricoxib is a highly selective COX-2 inhibitor which was evaluated for the treatment of rheumatoid arthritis (RA). METHODS: Double-blind, randomized, placebo and active comparator-controlled, 12-week study conducted at 67 sites in 28 countries. Eligible patients were chronic NSAID users who demonstrated a clinical worsening of arthritis upon withdrawal of prestudy NSAIDs. Patients received either placebo, etoricoxib 90 mg once daily, or naproxen 500 mg twice daily (2:2:1 allocation ratio). Primary efficacy measures included direct assessment of arthritis by counts of tender and swollen joints, and patient and investigator global assessments of disease activity. Key secondary measures included the Stanford Health Assessment Questionnaire, patient global assessment of pain, and the percentage of patients who achieved ACR20 responder criteria response (a composite of pain, inflammation, function, and global assessments). Tolerability was assessed by adverse events and routine laboratory evaluations. RESULTS: 1171 patients were screened, 891 patients were randomized (N = 357 for placebo, N = 353 for etoricoxib, and N = 181 for naproxen), and 687 completed 12 weeks of treatment (N = 242 for placebo, N = 294 for etoricoxib, and N = 151 for naproxen). Compared with patients receiving placebo, patients receiving etoricoxib and naproxen showed significant improvements in all efficacy endpoints (p<0.05). Treatment responses were similar between the etoricoxib and naproxen groups for all endpoints. The percentage of patients who achieved ACR20 responder criteria response was 41% in the placebo group, 59% in the etoricoxib group, and 58% in the naproxen group. Etoricoxib and naproxen were both generally well tolerated. CONCLUSIONS: In this study, etoricoxib 90 mg once daily was more effective than placebo and similar in efficacy to naproxen 500 mg twice daily for treating patients with RA over 12 weeks. Etoricoxib 90 mg was generally well tolerated in RA patients.

Factors associated with withdrawal of the anti-TNFα biologics in the treatment of rheumatic diseases: data from the Hong Kong Biologics Registry.

OBJECTIVES: To study the factors associated with withdrawal of the and tumor necrosis factor alpha (anti-TNFα) biologics in the treatment of rheumatic diseases. METHOD: Data from the Hong Kong Biologics Registry were retrieved. The cumulative rates of withdrawal of different biological agents were studied by Kaplan-Meier plot and the incidence of serious adverse events (SAEs) was calculated. Factors associated with the withdrawal of the anti-TNFα agents were studied by Cox regression. RESULTS: Between 2005 and 2013, 2059 courses of biologics were used in 1345 patients. After 3454 patient-years, 1171 (57%) courses were terminated because of clinical inefficacy (38.1%), SAEs (22.3%) and financial reasons (15.9%). The most frequent SAEs (per 100-patient-years) were allergy (2.90), serious infections (1.34), tuberculosis (0.93) and infusion/injection site reaction (0.75). Among the anti-TNFα agents, the cumulative probability of drug withdrawal for either inefficacy or SAEs in 5 years was highest with infliximab (IFX) (64.5%), followed by etanercept (ETN) (44.2%) and adalimumab (ADA) (36.9%). The incidence of serious infections and tuberculosis (per 100 patient-years) for IFX, ETN and ADA users was 1.99, 0.85 and 0.63; and 1.68, 0.43 and 0.85, respectively. Infusion/injection site reaction was highest with IFX (1.38/100 patient-years). Cox regression revealed increasing age, female sex, not having a diagnosis of spondyloarthritis (SpA) and IFX use were significantly associated with drug withdrawal for either inefficacy or SAEs. Rheumatoid arthritis (RA) had the highest hazard ratio for drug withdrawal but SpA was favorable for drug retention, after adjustment for age, sex, disease duration and the choice of anti-TNFα agents. CONCLUSIONS: In our registry, the retention rate of the anti-TNFα agents was lowest but the incidence of tuberculosis, serious infections and infusion reaction was highest with IFX. Older female patients with RA and the use of IFX were independently associated with drug withdrawal.

Long-term outcome of diffuse proliferative lupus glomerulonephritis treated with cyclophosphamide.

PURPOSE: To report the long-term outcome of diffuse proliferative lupus nephritis (DPLN) treated with cyclophosphamide (CYC) in Chinese patients. METHODS: Patients with biopsy-proven DPLN treated with prednisolone and CYC were identified. The long-term renal outcome and treatment-related toxicities were reported. RESULTS: A total of 212 patients were studied (89% women; mean age 30.9 +/- 10.9 years; mean system lupus erythematosus [SLE] duration 36.7 +/- 55.1 months). At renal biopsy, 148 (70%) patients were nephrotic, and 78 (37%) had impaired serum creatinine. One hundred and three (49%) patients received daily oral CYC, whereas 109 (51%) received intravenous bolus CYC. At last dose of CYC, 126 (59%) patients responded completely, and 56 (26%) responded partially. In a logistic regression model, the cumulative CYC dose and histologic chronicity score predicted complete response. One hundred fifty-five (73%) patients received maintenance immunosuppression for at least 3 years (88% azathioprine). After a follow-up of 1873 patient-years, 66 patients experienced renal flares, 30 had doubling of serum creatinine, 18 developed end-stage renal failure, and 14 died. The renal survival rates were 88.7%, 82.8% and 70.7% at 5, 10 and 15 years, respectively. Failure to respond completely to CYC and the absence of maintenance immunosuppression were independent predictors of a poor renal outcome. Ovarian toxicity was more frequent with the oral CYC regimen. Increasing age and higher cumulative doses of CYC were independent risk factors. CONCLUSIONS: In Chinese patients with DPLN, the cumulative dose, rather than the route of CYC administration, determines the initial treatment response and ovarian toxicity. Maintenance immunosuppression is associated with a better long-term prognosis. The oral CYC regimen is more toxic and should be reserved for high-risk patients.