Chi Chiu Mok

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 = 2.33×10−11, OR = 1.29; WDFY4: rs7097397, P = 8.15×10−12, 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.

Interleukin‐10 promoter polymorphisms in Southern Chinese patients with systemic lupus erythematosus

OBJECTIVE To study the genetic association of interleukin-10 (IL-10) promoter polymorphisms in Southern Chinese patients with systemic lupus erythematosus (SLE), and to investigate possible associations with clinical manifestations of the disease. METHODS DNA was extracted from 88 Chinese patients with SLE and 83 ethnically matched controls. The IL-10 promoter region between positions -533 and -1120 was amplified by polymerase chain reaction, and polymorphisms were detected by restriction-enzyme cleavage. RESULTS No significant difference in the allele or haplotype frequencies between SLE patients and controls could be demonstrated. The *A and *C alleles at the -597 position were linked to the *T and *C alleles at the -824 position, respectively. However, when clinical features were examined, the *A allele at the -597 position and the *T allele at the -824 position were significantly associated with lupus nephritis, by chi-square analysis (P < 0.001, odds ratio 4.19, 95% confidence interval 2.02-8.71). Similarly, the haplotype -1087*A/-824*T/-597*A was also associated with renal involvement (P < 0.001, odds ratio 3.62, 95% confidence interval 1.80-7.31). CONCLUSION IL-10 promoter polymorphisms are not strong determinants of susceptibility to the development of SLE, per se, in Southern Chinese individuals. However, IL-10 genotypes are strongly associated with certain clinical manifestations of SLE and may have a role in predicting disease prognosis.

Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy

OBJECTIVE To determine the incidence of ovarian failure after cyclophosphamide (CYC) treatment for systemic lupus erythematosus (SLE) and to identify the risk factors for this complication. METHODS The records of 70 premenopausal female SLE patients treated with CYC were reviewed retrospectively. Information on demographic features, autoantibody profiles, and CYC treatment was obtained, and comparisons were made between those who developed ovarian failure and those who did not. Data on the CYC-treated patients were also compared with data on 2 control groups of non-CYC-treated SLE patients. RESULTS Eighteen patients developed ovarian failure after CYC treatment, for an overall incidence of 26%. The incidence of ovarian failure showed a linear trend of increase with increasing age at the start of CYC (P = 0.007). The cumulative CYC dose was significantly higher in the patients with ovarian failure than in those without (28.3 gm versus 15.4 gm; P = 0.004). The risk of ovarian failure also showed a linear trend of increase with increasing cumulative CYC dose (P < 0.001). Using multiple logistic regression, the age at the time of CYC treatment initiation (beta = 0.37, SE = 0.11, P = 0.001) and the cumulative dose of CYC received (beta = 0.69, SE = 0.29, P = 0.02) were found to be independent risk factors for CYC-induced ovarian failure. CONCLUSION In our population of female SLE patients, CYC-induced ovarian toxicity is a significant problem, particularly in patients above the age of 40. The age at the start of CYC therapy and the cumulative dose are the major determinants for the development of this complication. For older patients with SLE in whom the use of CYC is warranted, a shorter course and lower dosage should be considered.

Long-term survival of southern Chinese patients with systemic lupus erythematosus: a prospective study of all age-groups.

Abstract: We conducted the current study to determine the clinical determinants of survival and the survival rates in an unselected cohort of Chinese patients with new-onset systemic lupus erythematosus (SLE), including all age-groups. Patients were those newly diagnosed as having SLE or referred within 6 months of diagnosis to the departments of medicine, geriatrics, and pediatrics at Tuen Mun Hospital, Hong Kong, between 1991 and 2003. Patients under the care of all specialists were included for analysis. We obtained demographic data, presenting and cumulative clinical features, disease activity, and serial damage scores. For patients who died or were lost to follow-up, data were censored at the last clinic visit. Survival over time was studied by the Kaplan-Meier method, and factors predictive of mortality were evaluated by the Cox proportional hazard model. We studied 285 new-onset SLE patients (92% women). All were ethnic Chinese and fulfilled at least 4 of the American College of Rheumatology criteria for SLE. The mean age of SLE onset was 30.0 ± 13.5 years. Fifty (18%) patients had first onset of SLE before the age of 16 years (childhood onset), and 22 (8%) had disease onset after the age of 50 years (late onset); 213 (75%) patients had disease onset between the ages of 16 and 50 years (adult onset). Twenty-nine (10%) patients died (4 from the childhood-onset group, 6 from the late-onset group, and 19 from the adult-onset group) and 18 (6%) patients were lost to follow-up. The overall 5-, 10-, and 15-year survival rates were 92%, 83%, and 80%, respectively. Survival was significantly worse in late-onset patients: 5-, 10-, and 15-year survival rates were 66%, 44%, and 44%, respectively; p < 0.0001. Infection was the main cause of death (55%), followed by cardiovascular (17%) and cerebrovascular complications (14%). Unfavorable factors for survival on univariate analysis were increasing age, damage scores at 1 year, and the use of high-dose corticosteroids. Cox regression revealed that damage scores at 1 year and hematologic manifestations were independent predictors of mortality. Long-term survival of Chinese SLE patients is comparable to that reported for white patients in the 1990s. Late-onset SLE patients have the worst prognosis. Early damage predicts mortality. Abbreviations: ACR = American College of Rheumatology, SDI = Systemic Lupus International Collaborating Clinics Damage Index, SELENA-SLEDAI = Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index, SLE = systemic lupus erythematosus.

Life expectancy, standardized mortality ratios, and causes of death in six rheumatic diseases in Hong Kong, China.

OBJECTIVE To examine the life expectancy, standardized mortality ratios (SMRs), and causes of death in 6 groups of patients from Hong Kong with different rheumatic diseases. METHODS Patients with a diagnosis of systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), systemic vasculitis (SV), or systemic sclerosis (SSc) registered in 37 public hospitals between 1999 and 2008 were identified in the hospital registry. SMRs were calculated by comparing the mortality rate in patients with each disease with that in the general population. Life expectancy was calculated by abridged life-table analysis, and the causes of death were compared. RESULTS In 2008, data on 8,367 RA, 5,243 SLE, 2,154 AS, 1,636 SV, 778 PsA, and 449 SSc patients were available in our registry. The age- and sex-adjusted SMRs were highest for SLE (5.25 [95% confidence interval 4.79-5.70]), SSc (3.94 [95% confidence interval 3.20-4.68]), and SV (2.64 [95% confidence interval 2.36-2.93]). In female patients, the loss in life expectancy was greatest for SSc (34.1 years), SV (19.3 years), and SLE (19.7 years). In male patients, the loss in life expectancy was highest for SV (28.3 years), SLE (27 years), and SSc (16 years). There were 2,486 deaths during the study period (1999-2008), and the principal causes were infections (28%), cardiovascular complications (18%), cancer (16%), and disease activity (7%). Infection was the leading cause of death in SLE, RA, AS, and PsA, whereas deaths from disease-related activity and cardiovascular complications were most frequent in SSc. Cancer was the most common cause of death in SV. CONCLUSION Our findings indicate that patients with SLE, RA, AS, PsA, SV, and SSc have increased mortality rates and reduced life expectancy. SLE has the highest adjusted SMR, and female SSc patients have the greatest loss in life expectancy. Infection is the leading cause of death, followed by cardiovascular complications and malignancies.

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.

Prevalence of atherosclerotic risk factors and the metabolic syndrome in patients with chronic inflammatory arthritis

To evaluate the prevalence of the metabolic syndrome in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA).

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.

Late onset systemic lupus erythematosus in southern Chinese

OBJECTIVE Systemic lupus erythematosus (SLE) is a multisystem disorder that predominately affects women of the reproductive age. Onset of the disease beyond the age of 50 years is unusual. This study was undertaken to compare retrospectively the clinical and laboratory features between early and late onset (onset of disease beyond the age of 50 years) SLE patients in a Chinese population. METHODS Case records of all SLE patients who attended our rheumatology clinics between 1971 and 1997 were reviewed. Patients with a disease onset beyond the age of 50 years were identified. One hundred consecutive SLE patients who had their disease onset before the age of 50 were recruited as controls. The presenting clinical features, autoantibody profile, number of major organs involved, number of major relapses, and the use of cytotoxic agents in the two groups of patients were obtained and compared. RESULTS 25 patients with late onset SLE were identified. All the female patients in the late onset group were postmenopausal. The female to male ratio was 3.2 to 1, compared with 13.3 to 1 in the control group (p<0.02). Both groups had a comparable duration of disease. There were no significant differences in the presenting features between the two groups except for a lower prevalence of malar rash (24% v86%, p<0.0001) and a higher prevalence of rheumatoid factor (32%v 1%, p<0.0001) in the late onset patients. On subsequent visits, the late onset group had a lower prevalence of lupus nephritis (4% v 51%, p<0.001), fewer major organs involved (mean number of major organs involved; 0.3 v 0.9, p<0.02), fewer major relapses (mean number of major relapses/patient; 0.08v 0.47, p<0.002, number of major relapses/patient year; 0.009 v 0.12, p<0.001), and required fewer cytotoxic agents for disease control (percentage of patients on cytotoxic agents; 32%v 79%, p<0.002). CONCLUSION Late onset SLE in Chinese tends to run a more benign course with fewer major organ involvement and fewer major relapses. The significantly higher incidence of male sex in late onset SLE and the milder disease course in the postmenopausal female patients suggest that oestrogen status may influence disease activity.

Immunogenicity and safety of a quadrivalent human papillomavirus vaccine in patients with systemic lupus erythematosus: a case–control study

Objectives To evaluate the immunogenicity and safety of GARDASIL, a quadrivalent human papillomavirus (HPV) vaccine, in patients with systemic lupus erythematosus (SLE). Methods Women with SLE aged 18–35 years who had stable disease were recruited to receive GARDASIL vaccination and an equal number of age-matched healthy women were also vaccinated. Seroconversion rates of antibodies to HPV serotypes 6, 11, 16 and 18 at months 7 and 12 and adverse events (AEs) were compared between patients and controls. The rate of disease flares in SLE participants was compared with matched SLE controls. Results 50 patients with SLE and 50 healthy controls were studied. The mean age and disease duration of the patients was 25.8±3.9 years and 6.6±4.5 years, respectively. At month 12 the seroconversion rates of anti-HPV serotypes 6, 11, 16 and 18 in patients and controls were 82%, 89%, 95%, 76% and 98%, 98%, 98%, 80%, respectively. In patients with SLE there were no significant changes in the titres of anti-dsDNA, complements, anti-C1q and SLE Disease Activity Index scores from baseline to months 2, 7 and 12. There was one mild/moderate SLE flare at months 0–2, two mild/moderate flares at months 3–6 and six mild/moderate and two severe flares at months 7–12. Disease flares in patients with SLE occurred at a similar frequency to that of 50 matched SLE controls (0.22/patient/year vs 0.20/patient/year, p=0.81). Injection site reaction was the commonest AE (5%), and the incidence of AEs was comparable between patients with SLE and controls. Conclusions The quadrivalent HPV vaccine is well tolerated and reasonably effective in patients with stable SLE and does not induce an increase in lupus activity or flares.