Paediatric case series of drug reaction with eosinophilia and systemic symptoms (DRESS): 12-year experience at a single referral centre in Hong Kong and the first reported use of infliximab.

Summary: DRESS (drug reaction with eosinophilia and systemic symptoms) is a rare but potentially life-threatening disorder characterized by fever, skin eruption, haematological abnormalities and multi-organ dysfunction after drug exposure. The pathophysiology is thought to be related to interactions between culprit drugs, viral reactivation and T-lymphocytes activation. We report 4 paediatric patients with DRESS who were treated at our centre over the past 12 years. Most cases improved after corticosteroids. Other immunosuppressive medications were attempted in refractory cases with varied outcomes. Patient 3 was the first reported case that involved the use of infliximab, a TNF-α inhibitor, for DRESS. Although clinical efficacy was not observed for this one patient, a previous study demonstrated that patients with DRESS, disease progression and HHV-6 reactivation had elevated pre-treatment TNF- α and IL-6 levels. Further research is needed to explore the role of these cytokines in DRESS.

Exome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn's disease.

Inflammatory bowel disease is well recognized for a strong genetic involvement in its pathogenesis. Homozygous mutations in interleukin-10 receptor 1 (IL-10R1) identified by linkage analysis were shown to be involved in this disorder. However, the underlying molecular mechanism and the causal nature of the mutations in the disease process remain to be clarified. In this study, using whole exome sequencing, we identified novel compound heterozygous missense mutations in the extracellular domain of IL-10R1 in a Crohn's disease patient from a non-consanguineous family. These mutations did not affect IL-10R1 expression, nor IL-10 binding. However, they abrogated IL-10R1 phosphorylation induced by IL-10, therefore leading to impaired STAT3 activation and suppression of inflammatory responses. After reconstitution with wild-type IL-10R1, the patient cells showed fully restored IL-10R function including IL-10-induced STAT3 activation and expression of suppressor of cytokine signaling 3. Thus, our results demonstrated that the mutations in IL-10R1 extracellular domain impair IL-10R1 activation rather than IL-10 binding, indicating these residues are important in IL-10 signal transduction through IL-10R1. The reconstitution data also confirmed the causality of the IL-10R1 mutations.

Association of CD247 with systemic lupus erythematosus in Asian populations.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. CD247 (CD3Z, TCRZ) plays a vital role in antigen recognition and signal transduction in antigen-specific immune responses, and is known to be involved in SLE pathogenesis. Weak disease association was reported for genetic variants in this gene in Caucasian studies for SLE, Crohn's disease and systemic sclerosis, but its role as a genetic risk factor was never firmly established. METHODS: In this study, using a collection of 612 SLE patients and 2193 controls of Chinese ethnicity living in Hong Kong in a genome-wide study, single nucleotide polymorphisms (SNPs) in and around CD247 were identified as being associated with SLE. The two most significant SNPs in this locus were selected for further replication using TaqMan genotyping assay in 3339 Asian patients from Hong Kong, Mainland China, and Thailand, as well as 4737 ethnically and geographically matched controls. RESULTS: The association of CD247 with SLE in Asian populations was confirmed (rs704853: odds ratio [OR] = 0. 81, p = 2.47 × 10(-7); rs858543: OR = 1.10, p = 0.0048). Patient-only analysis suggested that rs704853 is also linked to oral ulcers, hematologic disorders and anti-double-stranded DNA (dsDNA) antibody production. CONCLUSION: A significant association between variants in CD247 and SLE was demonstrated in Asian populations. Understanding the involvement of CD247 in SLE may shed new light on disease mechanisms and development of new treatment paradigms.

Two missense variants in UHRF1BP1 are independently associated with systemic lupus erythematosus in Hong Kong Chinese.

UHRF1BP1 encodes a highly conserved protein with unknown function. Previously, a coding variant in this gene was found to be associated with systemic lupus erythematosus (SLE) in populations of European ancestry (rs11755393, R454Q, P=2.22 x 10⁻8, odds ratio=1.17). In this study, by a combination of genome-wide study and replication involving a total of 1230 patients and 3144 controls, we confirmed the association of this coding variant to SLE in Hong Kong Chinese. We also identified another coding variant in this gene that independently contributes to SLE susceptibility (rs13205210, M1098T, P=4.44 x 10⁻9, odds ratio=1.49). Cross-population confirmation establishes the involvement of this locus in SLE and indicates that distinct alleles are contributing to disease susceptibility.

Association of BANK1 and TNFSF4 with systemic lupus erythematosus in Hong Kong Chinese.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. Recently, single nucleotide polymorphisms (SNPs) in BANK1 and TNFSF4 have been shown to be associated with SLE in Caucasian populations, but it is not known whether they are also involved in the disease in other ethnic groups. Recent data from our genome-wide association study (GWAS) for 314 SLE cases and 920 controls collected in Hong Kong identified SNPs in and around BANK1 and TNFSF4 to be associated with SLE risk. On the basis of the results of the reported studies and our GWAS, SNPs were selected for further genotyping in 949 SLE patients (overlapping with the 314 cases in our GWAS) and non-overlapping 1042 healthy controls. We confirmed the associations of BANK1 and TNFSF4 with SLE in Chinese (BANK1, rs3733197, odds ratio (OR)=0.84, P=0.021; BANK1, rs17266594, OR=0.61, P=4.67 x 10(-9); TNFSF4, rs844648, OR=1.22, P=2.47 x 10(-3); TNFSF4, rs2205960, OR=1.30, P=2.41 x 10(-4)). Another SNP located in intron 1 of BANK1, rs4522865, was separately replicated by Sequenom in 360 cases and 360 controls and was also confirmed to be associated with SLE (OR=0.725, P=2.93 x 10(-3)). Logistic regression analysis showed that rs3733197 (A383T in ankyrin domain) and rs17266594 (a branch point-site SNP) from BANK1 had independent contributions towards the disease association (P=0.037 and 6.63 x 10(-8), respectively). In TNFSF4, rs2205960 was associated with SLE independently from the effect of rs844648 (P=6.26 x 10(-3)), but not vice versa (P=0.55). These findings suggest that multiple independent genetic variants may be present within the gene locus, which exert their effects on SLE pathogenesis through different mechanisms.

Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese.

In this study, we compared the association of several newly discovered susceptibility genes for systemic lupus erythematosus (SLE) between populations of European origin and two Asian populations. Using 910 SLE patients and 1440 healthy controls from Chinese living in Hong Kong, and 278 SLE patients and 383 controls in Thailand, we studied association of STAT4, BLK and PXK with the disease. Our data confirmed association of STAT4 (rs7574865, odds ratio (OR) =1.71, P=3.55 x 10(-23)) and BLK (rs13277113, OR=0.77, P=1.34 x 10(-5)) with SLE. It was showed that rs7574865 of STAT4 is also linked to hematologic disorders and potentially some other subphenotypes of the disease. More than one genetic variant in STAT4 were found to be associated with the disease independently in our populations (rs7601754, OR=0.59, P=1.39 x 10(-9), and P=0.00034 when controlling the effect of rs7574865). With the same set of samples, however, our study did not detect any significant disease association for PXK, a risk factor for populations of European origin (rs6445975, joint P=0.36, OR=1.06, 95% confidence interval: 0.93-1.21). Our study indicates that some of the susceptibility genes for this disease may be population specific.

Recurrent major infections in juvenile-onset systemic lupus erythematosus--a close link with long-term disease damage.

OBJECTIVES: We postulate that patients with systemic lupus erythematosus (SLE) having recurrent infections are more likely to have poorer disease outcome. The aim of this study is to describe the pattern of infections and disease damage that occurred in a cohort of patients with juvenile-onset SLE, and to find out whether cumulative disease damage was associated with recurrent infections in these patients. METHOD: We retrospectively reviewed (1988-2004) the clinical characteristics, infective complications, and disease damage as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index (SDI) in 47 juvenile-onset SLE patients. Potential risk factors for disease damage were evaluated by univariate analysis and logistic regression. The correlation between number of major infections and disease damage was determined. RESULTS: Thirty-two (68.1%) patients had lupus nephropathy and 16 patients (34%) had neuropsychiatric lupus. Sixty-one episodes of major infections, defined as infections requiring more than 1 week of antimicrobial agents, occurred in 27 patients (57.4%), and 18 patients (31.4%) had recurrent major infections (>/= 2 episodes). Organ damage (SDI >/= 1) was documented in 21 subjects (44.7%). By logistic regression, occurrence of major infections (P < 0.001) was the only significant risk factor for disease damage. There was a positive correlation between SDI score with the number of recurrent major infections (Spearman's correlation coefficient = 0.50, P < 0.001). CONCLUSION: Infections and disease damage are common co-morbidities in juvenile-onset SLE. Recurrent infections could predict poorer disease outcome and associated organ damage in SLE.

Relationship between carotid intima-media thickness and arterial stiffness in children after Kawasaki disease.

BACKGROUND: Evidence of premature atherosclerosis and systemic arterial stiffening in patients after Kawasaki disease is accumulating. AIM: To test the hypothesis that carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis, is associated with systemic arterial stiffness in children after Kawasaki disease. METHODS: A cohort of 72 patients was studied, comprising 26 patients with Kawasaki disease and coronary aneurysms (group I), 24 patients with Kawasaki disease and normal coronary arteries (group II) and 22 healthy age-matched children (group III). The carotid IMT, carotid artery stiffness index, brachioradial pulse wave velocity (PWV), fasting total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol were determined and compared among the three groups. RESULTS: The carotid IMT was related to indices of arterial stiffness, and significant determinants of carotid IMT were identified by multivariate analysis. The mean (standard deviation (SD)) carotid IMT of both group I (0.41 (0.04) mm) and group II (0.39 (0.04) mm) was significantly greater than that of group III (0.36 (0.04) mm; p<0.001 and p = 0.008, respectively). For the entire cohort, carotid IMT correlated positively with LDL cholesterol (r = 0.31, p = 0.009), carotid artery stiffness index (r = 0.40, p = 0.001) and brachioradial PWV (r = 0.28, p = 0.016), but not with age, body mass index, systemic blood pressure, and HDL and total cholesterol. Multiple linear regression analysis identified carotid artery stiffness index (beta = 0.25, p = 0.028) and subject grouping (beta = -0.39, p = 0.001; model R(2) = 0.29) as significant correlates of carotid IMT. CONCLUSION: The increased carotid IMT in children after Kawasaki disease is associated with systemic arterial stiffening.

Kawasaki disease in Hong Kong, 1994 to 2000.

OBJECTIVE: To describe the epidemiology, clinical characteristics, and management of Kawasaki disease in children in Hong Kong. DESIGN: Retrospective survey of medical records from July 1994 to June 1997, and prospective data collection from July 1997 to June 2000. SETTING: Hospitals with a paediatric unit in Hong Kong. PATIENTS: Patients diagnosed with Kawasaki disease between July 1994 and June 2000 in public hospitals in Hong Kong. MAIN OUTCOME MEASURES: Incidence of Kawasaki disease and coronary artery aneurysm rates. RESULTS: A total of 696 cases of Kawasaki disease were reported. There were 435 (62.5%) boys and 261 (37.5%) girls giving a male to female ratio of 1.7:1. The age ranged from 1 month to 15 years 5 months with a median of 1.7 years. Infants (<1 year) constituted the largest group of patients (223, 32.0%) and overall, 638 (91.7%) were younger than 5 years. Skin rash, conjunctivitis, and oral signs were among the principal clinical features present in over 80% of cases. Prominent cervical lymph nodes larger than 1.5 cm were less commonly found (24%). Coronary artery aneurysms or ectasia were present in 15.7% (109/696), 8.5% (59/696), and 5.0% (35/696) of patients at 2, 4, and 8 weeks, respectively. The incidence of Kawasaki disease per 100,000 children under 5 years was significantly higher in the prospective study period than in the retrospective period (39 vs 26, P<0.001). CONCLUSION: The incidence of Kawasaki disease is high in Hong Kong and is 39 per 100,000 children below 5 years of age. The coronary artery aneurysm prevalence is 5%. Intravenous gamma-globulin and high-dose aspirin is the mainstay of treatment.

Increased high sensitivity C reactive protein concentrations and increased arterial stiffness in children with a history of Kawasaki disease.

OBJECTIVES: To test the hypothesis that low grade inflammation persists after the acute phase and affects arterial stiffness in children with a history of Kawasaki disease. DESIGN AND PATIENTS: A cohort of 106 children was studied, which comprised 43 patients with Kawasaki disease with coronary aneurysms (group I), 28 patients with Kawasaki disease with normal coronary arteries (group II), and 35 healthy age matched children (group III). Their systemic blood pressure, fasting cholesterol concentrations, serum high sensitivity C reactive protein (hs-CRP) concentrations, and carotid artery stiffness index were compared. Significant determinants of serum hs-CRP concentration and carotid artery stiffness were identified and the relation between hs-CRP concentration and arterial stiffness was investigated. SETTING: Tertiary paediatric cardiac centre. RESULTS: Serum hs-CRP concentration of group I patients (median 0.39 mg/l, interquartile range 0.28-0.65 mg/l) was significantly greater than that of group II (median 0.24 mg/l, interquartile range 0.17-0.29 mg/l, p < 0.001) and of group III patients (median 0.25 mg/l, interquartile range 0.18-0.40 mg/l, p < 0.01). Likewise, carotid artery stiffness index of group I patients (mean (SD) 5.07 (1.11)) was significantly greater than that of group II (4.27 (0.83), p = 0.002), and of group III patients (4.24 (0.86), p = 0.001). For the entire cohort, the carotid artery stiffness index correlated positively with log serum hs-CRP concentration (r = 0.24, p = 0.013). In multiple linear regression analysis, age (standardised beta = 0.22, p = 0.02), systolic blood pressure (standardised beta = 0.28, p = 0.01), log serum hs-CRP concentration (standardised beta = 0.21, p = 0.017), and patient grouping (standardised beta = -0.36, p < 0.001) were all independently associated with the carotid artery stiffness index. CONCLUSIONS: These findings support the possibility of ongoing low grade inflammation late after the acute phase of Kawasaki disease in patients with coronary aneurysms. Furthermore, this low grade inflammation may have a role in increasing systemic arterial stiffness.