Philip H. Li

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.

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.

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, Crohns 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.

Lack of Association of TYK2 Gene Polymorphisms in Chinese Patients with Systemic Lupus Erythematosus

To the Editor: We read with interest the study of Hellquist, et al 1 showing tyrosine kinase 2 ( TYK2 ) is associated with systemic lupus erythematosus (SLE). Similar results have been reported in different Caucasian populations2,3,4, but not in a recently published Japanese study5. Interestingly, we also found TYK2 polymorphisms were not associated with SLE in Hong Kong Chinese, although subphenotype analysis revealed it may be associated with the development of photosensitivity and discoid rash. Our study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster. The study included 669 patients with SLE and 2538 controls, as reported6,7. Genotyping with the Illumina 610-Quad Human Beadchip (Illumina, San Diego, CA, USA) from 612 patients and 2193 healthy controls included 9 single-nucleotide polymorphisms (SNP) within 10 kilobases spanning TYK2 . Additional genotyping by direct sequencing on 150 patients and 345 healthy controls was performed for rs12720270, rs2304356, and rs2304255, which were not included … Address correspondence to Dr. Lau; E-mail: lauylung{at}hkucc.hku.hk

Sesame allergy in adults: Investigation and outcomes of oral food challenges

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Epidemiology: The effects of AIDS on the prevalence of rheumatic diseases

The transition of HIV and AIDS from a death sentence to a chronic disease has not come without problems. Rheumatologists need to be aware of the full spectrum of rheumatic diseases seen in patients with HIV and AIDS, and know the best strategies for disease management.

Immunoglobulin G4–related disease in Hong Kong: clinical features, treatment practices, and its association with multisystem disease

INTRODUCTION Immunoglobulin G4-related disease remains an under-recognised and evolving disease. Local data are sparse and previous publications have been limited to individual case reports or case series only. We conducted this study to review the clinical features, treatment practices, and factors associated with multisystem involvement in Hong Kong. We described the clinical features and treatment modalities of the largest cohort of immunoglobulin G4-related disease in our locality thus far. METHODS We retrospectively evaluated all patients with immunoglobulin G4-related disease between January 2003 and December 2015 in Queen Mary Hospital and combined this with patient data extracted from previous local publications. We analysed the clinical features, treatment practices, and factors associated with the number of organ systems involved. RESULTS A total of 104 patients (55 from Queen Mary Hospital and 49 from literature review) were identified. Patients were predominantly older men (mean [standard deviation] age, 61.9 [12.7] years; male-to-female ratio=3:1) and 94.4% had elevated pre-treatment serum immunoglobulin G4 levels. Hepatobiliary and pancreatic system (40.4%), salivary gland (33.7%), lymph node (29.8%), and eye (19.2%) were the most common organ systems involved. Lymphadenopathy was associated with glucocorticoid use (odds ratio=2.65; 95% confidence interval, 1.08-6.54; P=0.034). Pre-treatment serum immunoglobulin G4 levels correlated with the number of organ systems involved (β=0.347; P=0.004) and, specifically, more associated with patients having salivary gland involvement than those without (mean, 1109 mg/dL vs 599 mg/dL; P=0.012). CONCLUSION We identified pre-treatment serum immunoglobulin G4 to be associated with multisystem disease, especially with salivary gland involvement, highlighting its potential for disease prognostication and monitoring. Increased physician awareness and multidisciplinary efforts are required for early diagnosis and optimal management of this masquerading disease.

DRESS Syndrome due to benzylpenicillin with cross-reactivity to amoxicillin

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome carries a 10% mortality and is one of the severe cutaneous adverse reactions, which also includes acute generalized exanthematous pustulosis and Stevens-Johnson syndrome/toxic epidermal necrolysis. DRESS syndrome can present with an extensive maculopapular exanthema, fever, lymphadenopathy, internal organ involvement (ie, renal and hepatic), eosinophilia, and other hematological abnormalities (ie, lymphopenia and atypical lymphocytes). The diagnosis is typically reached using the RegiSCAR (European Registry of Severe Cutaneous Adverse Reaction) validation scoring criteria and can be graded accordingly (ie, possible, probable, or definite case). Treatment involves withdrawal of the likely culprit drug and corticosteroids (ie, topical or oral). Here, we present a novel case of DRESS syndrome due to benzylpenicillin with cross-reactivity to amoxicillin confirmed by delayed intradermal and patch tests. A 40-year old man with a history of coarctation of the aorta underwent extended treatment for Staphylococcus lugdunensis bacteremia associated with aortic vascular graft infection. Following initial antimicrobial treatment, which included vancomycin, gentamicin, and rifampicin for 4 weeks, he was switched onto intravenous benzylpenicillin only. Five weeks later he developed an extensive maculopapular exanthematous eruption, without facial edema or mucosal involvement. He was afebrile with no palpable lymphadenopathy. He developed an eosinophilia (1.5 10/L; normal range, [0.0-0.4] 10/L) with deranged liver function (alanine aminotransferase, 644 IU/ L; normal range, 4-59 IU/L). Renal function was not impaired and there was no other internal organ involvement. Skin biopsy was not performed. Blood cultures revealed no growth. Screening for hepatitis A/B/C/D/E, HIV, Chlamydia, and Mycoplasma was all negative. He was diagnosed with DRESS syndrome on the basis of RegiSCAR validation criteria (total score 1⁄4 4 [probable case], achieved from the following criteria: absence of fever [ 1 point], eosinophilia [2 points], rash extent, >50% body surface area [1 point], organ involvement [1 point], exclusion of other potential causes [1 point]). The benzylpenicillin was stopped 48 hours after onset of the eruption and he was treated with topical corticosteroids, which led to a full recovery after 3 weeks. Before discharge he was started on daptomycin and then switched to cephalexin, which was tolerated well. At our allergy clinic 4 months later, intradermal testing (IDT) was performed with amoxicillin (25 mg/mL [undiluted]; Bowmed Ibisqus, Wrexham, UK), in addition to the diluted (0.9% NaCl) stock solutions of benzylpenicillin (6 mg/mL [1:10 dilution]; Genus Pharmaceuticals, Huddersfield, UK), rifampicin (0.006 mg/mL [1:10,000 dilution]; Sanofi Aventis, Guildford, UK), vancomycin (0.5 mg/ mL [1:100 dilution]; Hospira UK, Maidenhead, UK) and gentamicin (0.4 mg/mL [1:100 dilution]; Sanofi Aventis). Immediate IDT result was negative when read at 15 minutes for all tested drugs. Delayed IDT result to rifampicin, vancomycin, and gentamicin was negative at day 2 (D2) and day 4 (D4) readings. However, delayed IDT result to benzylpenicillin and amoxicillin was positive with focal papules, induration, and infiltrated erythema (20 mm) observed at D4 (with a crescendo effect since D2) (Figure 1). We also performed patch testing using IQ Ultra chambers (Chemotechnique Diagnostics, Vellinge, Sweden) with rifampicin (60 mg/mL [undiluted solution]; Sanofi Aventis), vancomycin (10% aqueous), gentamicin (20% petrolatum [pet]), benzylpenicillin (10% pet), and amoxicillin (10% pet) (Chemotechnique Diagnostics). The patch tests were read on D2 and D4 in accordance with the International Contact Dermatitis Research Group criteria. Patch testing result to rifampicin, vancomycin, and gentamicin was negative at D2 and D4 readings. However, patch testing produced a strong positive reaction (þþ) to benzylpenicillin and a doubtful reaction (?þ) to amoxicillin at D4 (Figure 2), all with crescendo effects since D2. He was diagnosed with DRESS syndrome due to benzylpenicillin on the basis of clear temporal relationship, RegiSCAR scoring, and the dual positive intradermal and patch test results to benzylpenicillin. He was advised to completely avoid all penicillin class antibiotics. DRESS syndrome is a severe potentially life-threatening delayed-type drug reaction with an estimated incidence ranging from 1 in 1000 to 1 in 10,000 drug exposures. Various pathogenic mechanisms have been proposed for DRESS syndrome including viral reactivation (ie, human herpesvirus 6 & 7, EBV, cytomegalovirus), cell-mediated hypersensitivity (ie, CD4þ/ CD8þ T-cellemediated), and genetic associations (ie, HLAB*58:01 with allopurinol). A delayed onset of 2 to 6 weeks after initiation of the causative drug is typical of its clinical course. Although the RegiSCAR validation scoring criteria is frequently used for evaluating suspected DRESS syndrome (or drug-induced hypersensitivity syndrome), there are heterogeneous diagnostic criteria also available such as the Japanese consensus group diagnostic criteria, which also include human herpesvirus 6 reactivation. DRESS syndrome has been previously associated with anticonvulsants, antimicrobials, and anti-inflammatory agents. In a large retrospective literature review of DRESS syndrome, carbamazepine was the most frequently reported causative agent. Other commonly implicated drugs include allopurinol,

Diffusion-weighted imaging versus short tau inversion recovery sequence: Usefulness in detection of active sacroiliitis and early diagnosis of axial spondyloarthritis

Objective To compare the utility of Diffusion weighted imaging (DWI) with short tau inversion recovery (STIR) sequence in the diagnosis of early axial spondyloarthritis (SpA). Methods Three hundred and five patients with chronic back pain were recruited consecutively from 3 rheumatology centers. Clinical, radiological and blood parameters were recorded. Patients with back pain duration no more than 3 years were classified as having early disease. STIR sequence and DWI of the sacroiliac joints were obtained and assessed using the Spondyloarthritis Research Consortium of Canada (SPARCC) method. The Assessment in Spondyloarthritis international Society definition was used to define positive STIR and DWI. Results were compared to expert diagnosed axial SpA. Results When compared to STIR sequence, DWI had similar sensitivity (STIR 0.29, DWI 0.30) and specificity (STIR 0.97, DWI 0.92) in diagnosing sacroiliitis. However, STIR sequence had better reliability (STIR 0.78, DWI 0.61). In early disease group, DWI was not better than STIR sequence in detecting active sacroiliitis (sensitivity DWI vs STIR: 0.34 vs 0.36; specificity DWI vs STIR: 0.93 vs 0.93; positive predictive value DWI vs STIR: 0.92 vs 0.92; negative predictive value DWI vs STIR: 0.36 vs 0.37). Using the Assessment in SpondyloArthritis international Society (ASAS) classification criteria, 67/98 patients with early disease (sensitivity 0.91 specificity 0.90) and 221/305 overall (sensitivity 0.90; specificity 0.92) were classified as axial SpA. Among the expert diagnosed axial SpA patients who did not meet the ASAS criteria, only 2 had positive DWI. Conclusion DWI and STIR have similar sensitivity in diagnosing axSpA in early disease. However, the use of DWI is limited by poorer reliability when compared with STIR.

Hong Kong Institute of Allergy and Hong Kong Society for Paediatric Immunology Allergy & Infectious Diseases joint consensus statement 2018 on vaccination in egg-allergic patients

Vaccination of egg-allergic individuals has been a historical concern, particularly for influenza and measles-mumps-rubella-varicella vaccines that are developed in chicken egg embryos or chicken cell fibroblasts. The egg proteins in these vaccines were believed to trigger an immediate allergic reaction in egg-allergic individuals. However, recently published international guidelines have updated their recommendations and now state that these vaccines can be safely administered to egg-allergic individuals. This joint consensus statement by the Hong Kong Institute of Allergy and the Hong Kong Society for Paediatric Immunology Allergy & Infectious Diseases summarises the updates and provides recommendations for local general practitioners and paediatricians. Hong Kong Institute of Allergy and Hong Kong Society for Paediatric Immunology Allergy & Infectious Diseases joint consensus statement 2018 on vaccination in egg-allergic patients Background.