Raymond Woon Sing Wong

Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis

Background The combination of cyclophosphamide and prednisolone is effective for the treatment of severe lupus nephritis but has serious adverse effects. Whether mycophenolate mofetil can be substi...

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.

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.

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.

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.

Lupus nephritis in Southern Chinese patients: clinicopathologic findings and long-term outcome.

Despite the improvement in survival of patients with systemic lupus erythematosus (SLE) and associated nephritis in the past 20 years, few studies of the long-term outcome of large cohorts of patients with well-defined histological classes of lupus nephropathy are available. We examined the long-term outcome of 183 patients with lupus nephritis (LN) followed up by the Division of Rheumatology at Queen Mary Hospital (Hong Kong) between 1976 and 1997. Their renal biopsies were classified according to World Health Organization (WHO) criteria. There were 27 men and 156 women. Initial renal biopsy showed the following WHO classes of LN: 2 patients (1%), class I; 9 patients (5%), class II; 46 patients (25%), class III; 101 patients (55%), class IV; and 25 patients (14%), class V. The mean duration of follow-up from the renal biopsy was 130.7 +/- 5.9 months (range, 13 to 260 months). The overall 5-, 10-, and 15-year survival and renal survival (survival without dialysis) rates were 98.9%, 94.4%, and 94.4% and 92.1%, 81.2%, and 75.2%, respectively. Univariate analysis showed class IV nephritis, hypertension, impaired renal function (glomerular filtration rate < 50 mL/min), nephrotic syndrome at time of renal biopsy, and failure of complete remission in the first year of treatment were unfavorable predictors for renal survival. Multivariate analysis using the Cox regression model also showed persistent hypertension, class IV nephritis, and incomplete renal remission in the first year were independent risk factors for renal failure. Our results showed the renal survival rate of our patients from South China with LN was similar to that of most reported series of white patients. Prospective randomized studies with well-defined treatment protocols are needed to delineate the optimal treatment strategy for LN.

Sequential Therapy for Diffuse Proliferative and Membranous Lupus Nephritis: Cyclophosphamide and Prednisolone Followed by Azathioprine and Prednisolone

A retrospective single-center cohort study was conducted on 35 patients with diffuse proliferative (WHO type IV) and/or membranous (type V) lupus nephritis (22 with type IV, 6 with type V, and 7 with type IV plus V) who had been treated with a sequential regimen comprising prednisolone and cyclophosphamide during active disease, followed by low-dose prednisolone and azathioprine maintenance. The follow-up period was 33.2 +/- 4.5 months. At presentation, 32 (91.4%) patients were nephrotic, and an abnormal serum creatinine level was noted in 14 (48.3%) patients with type IV changes. Cyclophosphamide was given for 26.8 +/- 2.8 weeks. 33 (94.3%) patients achieved complete or partial renal remissions: 77.3 and 22.7% of the type IV patients, 16.7 and 66.6% of the type V patients, and 14.3 and 71.4% of the type IV plus V patients, respectively (p < 0.0001 for type IV versus type V and for type IV versus type IV plus V). The duration of therapy before renal remissions and normalization of C3 were attained was similar among the three groups of patients. Disease relapse occurred in 4 (18.2%) of 22 IV patients and in 1 of the 5 type V patients in remission. Mortality was not observed, and none of the patients had an increase in serum creatinine level to double the baseline value. Adverse effects related to therapy included: hair loss (42.9%), transient amenorrhea (53.6%), leukopenia (11.4%), febrile episodes (14.3%), and herpes zoster(28.6%). We conclude that sequential use of prednisolone and cyclophosphamide followed by low-dose prednisolone and azathioprine can achieve favorable therapeutic results in the majority of patients with diffuse proliferative and/or membranous lupus nephritis, without excessive toxicities.

Anti‐cyclic citrullinated peptide: diagnostic and prognostic values in juvenile idiopathic arthritis and rheumatoid arthritis in a Chinese population

Objective: The incidence and clinical significance of anti‐cyclic citrullinated peptide (CCP) antibodies in a cohort of Chinese patients with juvenile idiopathic arthritis (JIA) and adults with rheumatoid arthritis (RA) were studied. Methods: Anti‐CCP antibodies were determined by enzyme‐linked immunosorbent assay (ELISA) in 59 patients with JIA, 129 adult RA patients, 48 children with diseases other than JIA, 68 adult patients with rheumatic diseases other than RA, and 60 normal adults. Associations between anti‐CCP antibodies and clinical and laboratory parameters were determined by Fishers exact test. Results: Six of 59 (10.2%) patients with JIA and 71 of 129 (55%) patients with RA were positive for anti‐CCP. Four of five RF‐positive JIA patients and two of 54 RF‐negative JIA patients were positive (p<0.001). One paediatric patient with allergy (0.9%) and two adult patients with rheumatic diseases other than RA (2.3%) were positive. All healthy controls were negative for anti‐CCP. The specificity was 99.1% for JIA and 98.4% for RA. The sensitivity was 10.2% for JIA and 55% for RA. Positive predictive values were 85.7% for JIA and 97.3% for RA and negative predictive values were 66.9% for JIA and 68.5% for RA. Conclusion: The anti‐CCP antibody assay is a valuable tool for the diagnosis of RA and a subset of JIA in Chinese patients. It could be a useful predictive test for joint erosion in JIA of the polyarticular RF‐positive subset and may be influential in the choice of the best therapeutic strategy in patients with recent‐onset arthritis.

OVARIAN FAILURE AND FLARES OF SYSTEMIC LUPUS ERYTHEMATOSUS

OBJECTIVE To study the effects of ovarian failure on disease flares in systemic lupus erythematosus (SLE). METHODS Fifty-four female premenopausal SLE patients who were under the age of 45 years and treated with continuous oral cyclophosphamide (CYC) for no more than 12 months were studied. All patients had been followed up for >5 years following CYC treatment. Demographic characteristics, clinical and serologic profiles, and information concerning disease flares were recorded. Comparison of the number of severe and mild/moderate flares during the first 5 years after CYC treatment was made between patients who developed CYC-induced ovarian failure and those who did not. RESULTS Fourteen SLE patients had documented ovarian failure with hypoestrogenemia within 2 years after CYC treatment. Compared with the menstruating group of patients, those who developed ovarian failure were significantly older at the time of CYC therapy (mean 37.9 versus 25.5 years; P < 0.001), but otherwise no significant differences in organ manifestations and autoantibody profiles between the 2 groups were observed. Both the ovarian failure group and menstruating group of patients had similar SLE Disease Activity Index scores at the time of CYC treatment (mean 15.6 versus 17.7; P = 0.16), and had comparable treatment durations (mean 8.2 versus 7.8 months; P = 0.68) and cumulative doses of CYC (mean 20.4 versus 17.9 grams; P = 0.34). Flares of SLE were uncommon during the first year following CYC administration. However, during the 5-year followup period, patients who developed CYC-induced ovarian failure had significantly fewer severe flares (mean 0.014 versus 0.075 flares/patient-year; P = 0.01) and smaller total number of flares (mean 0.128 versus 0.250 flares/patient-year; P = 0.03) when compared with those who were still menstruating. CONCLUSION This study provides an important clinical observation to support the notion that ovarian failure with hypoestrogenemia is protective against lupus flares and emphasizes the importance of estrogen status in the determination of disease activity in SLE.