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Fulltext Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians

Molineros JE, Looger LL, Kim K, Okada Y, Terao C, Sun C, et al.

PLoS Genet, 2019 04;15(4):e1008092.
PMID: 31022184 DOI: 10.1371/journal.pgen.1008092

Human leukocyte antigen (HLA) is a key genetic factor conferring risk of systemic lupus erythematosus (SLE), but precise independent localization of HLA effects is extremely challenging. As a result, the contribution of specific HLA alleles and amino-acid residues to the overall risk of SLE and to risk of specific autoantibodies are far from completely understood. Here, we dissected (a) overall SLE association signals across HLA, (b) HLA-peptide interaction, and (c) residue-autoantibody association. Classical alleles, SNPs, and amino-acid residues of eight HLA genes were imputed across 4,915 SLE cases and 13,513 controls from Eastern Asia. We performed association followed by conditional analysis across HLA, assessing both overall SLE risk and risk of autoantibody production. DR15 alleles HLA-DRB1*15:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB1*06:02 (P = 7.4x10-23, OR = 1.55) formed the most significant haplotype (OR = 2.33). Conditioned protein-residue signals were stronger than allele signals and mapped predominantly to HLA-DRB1 residue 13 (P = 2.2x10-75) and its proxy position 11 (P = 1.1x10-67), followed by HLA-DRB1-37 (P = 4.5x10-24). After conditioning on HLA-DRB1, novel associations at HLA-A-70 (P = 1.4x10-8), HLA-DPB1-35 (P = 9.0x10-16), HLA-DQB1-37 (P = 2.7x10-14), and HLA-B-9 (P = 6.5x10-15) emerged. Together, these seven residues increased the proportion of explained heritability due to HLA to 2.6%. Risk residues for both overall disease and hallmark autoantibodies (i.e., nRNP: DRB1-11, P = 2.0x10-14; DRB1-13, P = 2.9x10-13; DRB1-30, P = 3.9x10-14) localized to the peptide-binding groove of HLA-DRB1. Enrichment for specific amino-acid characteristics in the peptide-binding groove correlated with overall SLE risk and with autoantibody presence. Risk residues were in primarily negatively charged side-chains, in contrast with rheumatoid arthritis. We identified novel SLE signals in HLA Class I loci (HLA-A, HLA-B), and localized primary Class II signals to five residues in HLA-DRB1, HLA-DPB1, and HLA-DQB1. These findings provide insights about the mechanisms by which the risk residues interact with each other to produce autoantibodies and are involved in SLE pathophysiology.

Matched MeSH terms: Lupus Erythematosus, Systemic/etiology*
Fulltext Puerperal acquired factor VIII inhibitor causing a von Willebrand-like syndrome in a patient with anti-DNA antibodies

Jackson N, Hashim ZA, Zainal NA, Jamaluddin N

Singapore Med J, 1995 Apr;36(2):230-1.
PMID: 7676276

A 30-year-old Malay lady, with no previous or family history of bleeding, presented with severe gum bleeding 25 days post-partum. The factor VIII:c was 0.03 iu/ml with evidence of a slow-acting factor VIII inhibitor. Von Willebrand factor antigen (VWF:age) varied from less that 0.05 to 0.17 iu/ml, and there was absent ristocetin-induced platelet aggregation. Anti-nuclear and anti-DNA antibodies were present, but there were no other features of systemic lupus erythematosus. There was some clinical response to cryoprecipitate and tranexamic acid, and slight improvement with corticosteroid. Fifteen months later, the patient has no active bleeding problem, and her VWF-ag is increasing spontaneously. However, factor VIII:c is less than 0.01 iu/ml and her factor VIII inhibitor titre is still > 20 Bethesda units/ml.

Matched MeSH terms: Lupus Erythematosus, Systemic/complications
Fulltext An interesting case of systemic lupus erythematosus presenting with hypercalcemia: A diagnostic dilemma

Abdul Gafor AH, Cader RA, Das S, Masir N, Wahid FA

Am J Case Rep, 2013;14:1-3.
PMID: 23569551 DOI: 10.12659/AJCR.883849

BACKGROUND: Hypercalcemia is common in primary hyperparathyroidism malignancies and even in tuberculosis. Interestingly, systemic lupus erythematosus (SLE) rarely presents with hypercalcemia.
CASE REPORT: We describe an interesting case of SLE in a patient who was otherwise thought to have either tuberculosis or a malignancy. The patient initially presented with feeling unwell, with generalized lymphadenopathy, bilateral pleural effusion, and bilateral corneal calcium deposits secondary to severe hypercalcemia. The diagnosis of SLE was made based on positivity of antinuclear antibodies (ANA) and anti-dsDNA, the presence of serositis, lymphadenopathy, autoimmune hemolytic anemia, and constitutional symptoms. She was treated with steroids, with tremendous improvement in her general well-being, resolution of lymphadenopathy and pleural effusion, and normalization of her hemoglobin and serum calcium. The atypical presentation of SLE with hypercalcemia with pleural effusion is discussed.
CONCLUSIONS: SLE should be one of the differential diagnoses in patients presenting with severe hypercalcemia.
KEYWORDS: atypical presentation; hypercalcemia; systemic lupus erythematosus

Matched MeSH terms: Lupus Erythematosus, Systemic
Fulltext A case report of severe Ascariasis infection in systemic lupus erythematosus patient

Tan J. Y. S., R. Surendran, Mohd Noh Malehah, Shaila Kabir, Chong Y. Y. Eleen

Malaysian Journal of Medicine and Health Sciences, 2019;15(106):53-53.
MyJurnal

Introduction: Ascariasis is a parasitic infection, which commonly affects immunocompromised patients. Most pa-tients remained asymptomatic during the early larval migration stage and respond well with conventional anti-hel-minthic drugs. Previous literature had reported symptomatic Ascaris infection mimicking bacterial pneumonia and the typical eosinophilia found in Loeffler syndrome was absent in patients on corticosteroids. Thus, a high index of suspicion for ascariasis is needed for immunosuppressed patients presented with infection. We present here a case of severe ascariasis infection in a systemic lupus erythematosus patient. Case description: A 16-year-old boy presented with fever, generalized maculopapular rash associated with neutropenia and thrombocytopenia. He was treated initially as Dengue Fever initially. However his symptoms did not resolve at even day 14 of admission. On further assessment, we were convinced he has SLE based upon presence of malar rash, oral ulcers, urinary protein-uria, persistent leucopenia, thrombocytopenia with low complements and ANA positive. He was promptly started on IV hydrocortisone. He showed a good progress in the first few days. On day 5 of admission, he coughed out a round worm which later identified as Ascarisis lumbricoides. He was started on Albendazole. Unfortunately he developed hemoptysis and respiratory compromisation where he required intubation. Post intubation he went into cardiac arrest, which required CPR. Following that event, his condition further deteriorated with multi organ failure. He succumbed to his illness three days later. Conclusion: Immunocompromised patients are prone to opportunistic infections including parasitic infections. we present here a case of ascariasis in an SLE patient who unfortunately succumbed to the illness. Due to the variable clinical symptoms that mimic other infections, screening for parasitic infections needs to be considered especially if the patients do not respond to antibiotics and routine treatments.

Matched MeSH terms: Lupus Erythematosus, Systemic
Fulltext Buccal swab as a suitable source of genomic DNA for screening of selected human leukocyte antigen (HLA) alleles

Vivek Prasad, Lam Yan Shim, Sethu Thakachy Subha, Fazlina Nordin, Maha Abdullah

Malaysian Journal of Medicine and Health Sciences, 2019;15(108):46-46.
MyJurnal

Introduction: Human leukocyte antigens (HLA) are a group of unique transmembrane glycoproteins that are ex-pressed on the surface of virtually all types of cells within the human body. These molecules are encoded by a set of highly polymorphic gene sequences known also as the major histocompatibility complex (MHC) and play an essential role in the presentation of antigenic peptides to immune cells for recognition and response. In recent years, various HLA alleles have been found to be associated with different autoimmune and inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE) and allergic rhinitis. Identification of these alleles via HLA typing is necessary for initial screening and diagnosis purposes. Besides that, HLA typing is also used to determine compatibility matching between a donor and a recipient for tissue/organ transplantations in order to prevent graft rejection. Therefore, good quality and quantity of genomic DNA is required. In most scenarios, peripheral blood is chosen as the most reliable source of DNA for analysis, however this approach is seen as invasive and may cause pain and anxiety among the patients, particularly young children and weak subjects. Hence, derivation of genomic DNA from buccal cells as an alternative source material is becoming increasingly popular, especially in PCR-based genetic assays. Some of the most commonly described methods to collect buccal cells include using oral swabs, cytological brushes, mouthwashes and treated cards. Each technique yields varying quantities of DNA with diverse purity levels. In this study, we aim to evaluate the amount and purity of genomic DNA extracted from buccal swabs and brushes as well as blood for screening of selected HLA class II alleles. Methods: Cheek cell samples were col-lected using sterile foam tipped buccal swabs (Whatman) and buccal collection brushes (Gentra Puregene) whereas peripheral blood samples were withdrawn following routine venipuncture techniques. All samples were subjected to DNA extraction according to modified commercial kit protocols. Screening of selected HLA-DRB1 alleles was con-ducted via PCR with sequence-specific primers as established by Bunce et al. 1995. Results: There was no significant difference (p > 0.05) in the total DNA yield obtained from blood and buccal swab samples, which were 17.57μg (± 8.66) and 13.28μg (± 4.81), respectively. All samples exhibited similar 260/280 ratios of about ~1.80 (p > 0.05). However, buccal brush samples contributed the least amount of DNA (0.29μg, ± 0.12) compared to other sources (p < 0.05). The pure genomic DNA isolated from both blood and buccal swab samples were successfully typed for low resolution HLA-DRB1 alleles. Conclusion: Buccal swabs provide good quantity and quality of DNA for screening of HLA alleles with high accuracy and thus can be utilized as a non-invasive substitute for venipuncture.

Matched MeSH terms: Lupus Erythematosus, Systemic
Fulltext Detection of anti-cell membrane DNA antibodies by indirect immunoflouresencence technique in systemic lupus erythematosus

Faten Nurul Amira Awing Kechik, Maha Abdullah, Masriana Hassan, Masita Arip, Hasni Mahayidin

Malaysian Journal of Medicine and Health Sciences, 2019;15(108):28-28.
MyJurnal

Introduction: Systemic lupus erythematosus (SLE) has a broad spectrum of clinical presentations. The diagnosis of SLE remains a challenge and largely depends on the presence of several serum autoantibodies including anti-nuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA) and anti-Smith antibody (anti-Sm). ANA, a highly sensitive but not specific marker is used for SLE screening Anti-dsDNA and anti-Sm are SLE-specific biomarkers but has lower sensitivity of 80% and 30% for SLE, respectively. However, it is noted that there are SLE patients who are persistently negative for SLE-specific autoantibodies. Anti-dsDNA and anti-Sm were reported to be negative in up to 51.2% and 62.4% of SLE, respectively. This limitation can lead to misdiagnosis and halter proper treatment to SLE patients. Previous studies have suggested that cell membrane DNA (cmDNA) can act as a specific target for the autoantibodies in SLE patients. Autoantibodies towards cmDNA (anti-cmDNA) were reported to have promis-ing value as a reliable biomarker for SLE. In this study, we would like to determine the usefulness of anti-cmDNA in diagnosing SLE as compared to the standard SLE-specific autoantibodies. Methods: Serum samples from 83 SLE patients, 86 other connective tissue diseases and 61 healthy subjects were included in this study. The other connec-tive tissue diseases include samples from 10 Sjogren’s syndrome, 56 rheumatoid arthritis, 12 scleroderma and eight mixed connected tissues disease (MCTD) patients. All samples were analysed by indirect immunofluorescence (IIF) technique using Raji cells as substrate to detect the presence of anti-cmDNA. Anti-cmDNA was reported as positive if there was presence of a fluorescent ring, either continuous or punctate. Sera from SLE patients were also tested for anti-dsDNA and anti-Sm antibodies by using enzyme-immunoassays. Results: Anti-cmDNA positivity was highest in SLE (55.4%) than in other connective tissue diseases (9.3%) and healthy subjects (0%). Anti-cmDNA was 100% spe-cific at differentiating SLE from healthy subjects and 90.7% specific at differentiating SLE from other connective tissue diseases. There was no difference in the sensitivity (55.4%) of anti-cmDNA at differentiating SLE from both groups. Anti-cmDNA were present in 46 SLE samples negative for standard SLE-specific autoantibodies. It was detected in 11 (42.3%) of anti-dsDNA, 23 (63.9%) of anti-Sm and 8 (12.9%) of both anti-Sm and anti-dsDNA negative samples. Conclusion: The high specificity of anti-cmDNA detection using IIF method makes it an excellent diagnostic tool for SLE. Anti-cmDNA is potentially a very useful biomarker for SLE with negative anti-dsDNA or/and anti-Sm antibodies.

Matched MeSH terms: Lupus Erythematosus, Systemic
Vitamin D status in patients with systemic lupus erythematosus (SLE): A systematic review and meta-analysis

Islam MA, Khandker SS, Alam SS, Kotyla P, Hassan R

Autoimmun Rev, 2019 Sep 11.
PMID: 31520805 DOI: 10.1016/j.autrev.2019.102392

BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease where chronic inflammation and tissue or organ damage is observed. Due to various suspected causes, inadequate levels of vitamin D (a steroid hormone with immunomodulatory effects) has been reported in patients with SLE, however, contradictory.
AIMS: The aim of this systematic review and meta-analysis was to evaluate the serum levels of vitamin D in patients with SLE in compared to healthy controls.
METHODS: PubMed, SCOPUS, ScienceDirect and Google Scholar electronic databases were searched systematically without restricting the languages and year (up to March 2, 2019) and studies were selected based on the inclusion criteria. Mean difference (MD) along with 95% confidence intervals (CI) were used and the analyses were carried out by using a random-effects model. Different subgroup and sensitivity analyses were conducted. Study quality was assessed by the modified Newcastle-Ottawa Scale (NOS) and publication bias was evaluated by a contour-enhanced funnel plot, Begg's and Egger's tests.
RESULTS: We included 34 case-control studies (2265 SLE patients and 1846 healthy controls) based on the inclusion criteria. Serum levels of vitamin D was detected significantly lower in the SLE patients than that in the healthy controls (MD: -10.44, 95% CI: -13.85 to -7.03; p 

Matched MeSH terms: Lupus Erythematosus, Systemic
Fulltext Childhood-Onset Systemic Lupus Erythematosus: Southeast Asian Perspectives

Tang SP, Lim SC, Arkachaisri T

J Clin Med, 2021 Feb 03;10(4).
PMID: 33546120 DOI: 10.3390/jcm10040559

Childhood onset systemic lupus erythematosus is a rare disease that is more common amongst Southeast Asian children compared to the West. It is typified by a peripubertal onset and a female preponderance, which increases with advancing age. Organs commonly involved at diagnosis include haematological, renal, and mucocutaneous. Fever, malar rash, and cutaneous vasculitis are common. Lupus nephritis is typically proliferative especially Class IV and contributes to both disease activity and damage. Antinuclear antibody and anti-dsDNA positivity are both prevalent in this region. Disease activity is higher than Western cohorts at onset but responds to therapy reducing to low disease activity by six months. However, organ damage occurs early and continues to accumulate over the time, a consequence of both active disease (neurological and renal systems) and steroid-related complications especially in the eye (cataract and glaucoma) and musculoskeletal systems (avascular necrosis). Infections remain the leading cause of death and mortality in this region is highly variable contributed by the heterogeneity in social economic status, healthcare access, and availability of paediatric rheumatology expertise in the region.

Matched MeSH terms: Lupus Erythematosus, Systemic
Early damage as measured by SLICC/ACR damage index is a predictor of hospitalization in systemic lupus erythematosus (SLE)

Raman L, Yahya F, Ng CM, Sockalingam S, Ramasamy K, Ratnam R, et al.

Lupus, 2020 Dec;29(14):1885-1891.
PMID: 33040647 DOI: 10.1177/0961203320962848

BACKGROUND: Hospital admissions and re-admissions in lupus patients are common occurrences that can lead to poor prognosis.
OBJECTIVES: We evaluated the leading causes of all-cause hospitalizations and their predictive factors in the Malaysian multi-ethnic SLE patients.
METHODS: This is a retrospective study involving 300 SLE patients. Demographic data and details of hospitalizations from the year 1988 until 2019 were reviewed. Baseline and latest disease activity (SLEDAI-2 K) and SLICC/ACR damage index (SDI) scores were evaluated. To be eligible for this study, their SLE diagnosis and disease duration was at least one year; this is to ensure that the baseline disease damages were measured at least after 6 months of diagnosis and subsequent disease damage indexes were captured.
RESULTS: Majority were of Chinese ethnicity 150 (50%). The cohort's median age was 48 (18-82) years and median disease duration was 13 (1-52) years. 133 (44.3%) had SDI score of ≥1 at baseline (early damage). 69 (23%) had developed new organ damage during this study period.There were 222 (74%) patients ever hospitalized from this cohort. The main cause of hospitalization was lupus flare which included concurrent infection (n = 415 admissions, 46%), followed by elective admissions for procedures and others (n = 284 admissions, 31.5%). Admissions for treatment and disease related complications were 13.8%. 8.7% of admissions were due to infections alone. Median length of stay for SLE-related cause admissions was longer compared to non-SLE related causes. Jointly predictive factors for hospitalization were anti-phospholipid syndrome (OR 5.82), anti-Smith (OR 6.30), anti-SSA (OR 3.37), serositis (OR 14.56), neurological (OR 5.52) and high baseline SDI (OR 1.74), all p

Matched MeSH terms: Lupus Erythematosus, Systemic
Fulltext Antiphospholipid syndrome in lupus retinopathy

Ng HK, Chong MF, Azhany Y, Zunaina E

Clin Ophthalmol, 2014;8:2359-63.
PMID: 25473262 DOI: 10.2147/OPTH.S71712

Systemic lupus erythematosus (SLE) is a chronic, multisystem, autoimmune disease that can affect any part of the human body including the eyes. Common blinding ocular manifestations include central retinal artery occlusion (CRAO), central retinal vein occlusion (CRVO), severe vaso-occlusive retinopathy, and optic nerve involvement. Antiphospholipid syndrome (APS) in lupus is usually associated with large vessel occlusions and needs prompt treatment with anticoagulant. We are reporting two cases of APS in SLE patients that presented with CRVO (case 1) and vaso-occlusive lupus retinopathy (case 2). Both cases were positive for antiphospholipid antibody (APA) and were treated with immunosuppression, anticoagulant, and laser treatment. Thus, screening for APA is vital in SLE patients with lupus retinopathy, as prompt treatment with anticoagulants is important to prevent further vascular thrombosis, which worsens the visual prognosis.
Study site: Ophthalmology clinic, Hospital Raja Permaisuri Bainun, Ipoh, Perak, Malaysia

Matched MeSH terms: Lupus Erythematosus, Systemic
Fulltext Retinal vasculitis in systemic lupus erythematosus: an indication of active disease

Md Noh UK, Zahidin AZ, Yong TK

Clin Pract, 2012 Mar 30;2(2):e54.
PMID: 24765453 DOI: 10.4081/cp.2012.e54

A 26-year-old woman with a recent flare-up of systemic lupus erythematosus presented with peripheral retinal hemorrhages at a routine check-up. She is on a tapering dose of immunosuppressive agents. Her visual acuity was good. Fluorescein angiogram revealed vasculitic changes with capillary non-perfusion areas. A few weeks later, she developed cerebral lupus with advanced lupus nephritis. Immunosuppressive therapy was restarted and panretinal photocoagulation was delivered. Her visual acuity remained stable, despite development of a cataract from prednisolone therapy.

Matched MeSH terms: Lupus Erythematosus, Systemic
Characteristics and outcome of autoimmune liver disease in Asian children

Lee WS, Lum SH, Lim CB, Chong SY, Khoh KM, Ng RT, et al.

Hepatol Int, 2015 Apr;9(2):292-302.
PMID: 25788179 DOI: 10.1007/s12072-014-9558-0

BACKGROUND: Little is known about autoimmune liver disease (AILD) in Asian children. We studied the clinical features and predictors of outcome in childhood AILD in an Asian population.

METHODS: Retrospective review of AILD [autoimmune hepatitis type 1 and 2 (AIH1, AIH2), primary sclerosing cholangitis (PSC) and autoimmune sclerosing cholangitis (ASC)] seen at two pediatric liver units in Malaysia.

RESULTS: At presentation, 17 (56%) of the 32 children [19 females, 59%; median (range) age 7.7 (1.8-15.5) years] with AILD (AIH1 = 18, AIH2 = 5, PSC = 0, ASC = 9) had liver cirrhosis. At final review [median (range) duration of follow-up 4.8 (0.4-12) years], 24 patients (75%) survived with a native liver. Twenty-one (66%) were in remission; 19 (AIH1 = 11; AIH2 = 4, ASC = 4) were on prednisolone and/or azathioprine, one on cyclosporine and another on mycophenolate mofetil. Three (AIH1 = 3) were in partial remission. Of the two who underwent liver transplantation (LT; 6.5%; both ASC), one died of primary graft failure after LT. Six patients (19%) died without LT (acute liver failure, n = 1; end-stage liver disease, n = 5). The overall survival rate (native liver and survival post-LT) was 78%. A delay in seeking treatment adversely affected the final outcome [survival with native liver vs. LT or death (duration between onset of disease and treatment; median ± standard error) = 2.5 ± 2.9 months vs. 24.0 ± 13.3 months; p = 0.012].

CONCLUSIONS: Although remission was achieved in the majority of patients with prednisolone and/or azathioprine therapy, delay in seeking diagnosis and treatment adversely affects the outcome of childhood AILD in Malaysia.

Matched MeSH terms: Lupus Erythematosus, Systemic/complications
Fulltext Pyoderma gangrenosum and cobalamin deficiency in systemic lupus erythematosus: a rare but non fortuitous association

Teoh SC, Sim CY, Chuah SL, Kok V, Teh CL

BMC Rheumatol, 2021 Mar 03;5(1):7.
PMID: 33653418 DOI: 10.1186/s41927-021-00177-4

BACKGROUND: Pyoderma gangrenosum (PG) is an uncommon, idiopathic, ulcerative neutrophilic dermatosis. In many cases, PG is associated with a wide variety of different disorders but SLE in association with PG is relatively uncommon. In this article we present the case of a middle aged patient with PG as the initial clinical presentation of SLE. We also provide a brief review of cobalamin deficiency which occurred in our patient and evidence-based management options.
CASE PRESENTATION: A 35 years old man presented with a 5 month history of debilitating painful lower limb and scrotal ulcers. This was associated with polyarthralgia and morning stiffness involving both hands. He also complained of swallowing difficulties. He had unintentional weight loss of 10 kg and fatigue. Physical examination revealed alopecia, multiple cervical lymphadenopathies, bilateral parotid gland enlargement and atrophic glossitis. There was Raynaud's phenomenon noted over both hands and generalised hyper-pigmented fragile skin. Laboratory results disclosed anaemia, leukopenia, hyponatraemia and hypocortisolism. Detailed anaemic workup revealed low serum ferritin and cobalamin level. The autoimmune screen showed positive ANA, anti SmD1, anti SS-A/Ro 52, anti SSA/Ro 60, anti U1-snRNP with low complement levels. Upper gastrointestinal endoscopy with biopsies confirmed atrophic gastritis and duodenitis. Intrinsic factor antibodies and anti-tissue transglutaminase IgA were all negative. Punch biopsies of the leg ulcer showed neutrophilic dermatosis consistent with pyoderma gangrenosum. Based on the clinical findings and positive immunologic studies, he was diagnosed as systemic lupus erythematosus. His general condition improved substantially with commencement of corticosteroids, immunosuppressants and vitamin supplements.
CONCLUSIONS: We report a case of PG as the first manifestation of SLE which was treated successfully with immunosuppressants and vitamin supplements. Our report highlighted the need to consider connective tissue diseases such as SLE in a patient presenting with PG in order for appropriate treatment to be instituted thereby achieving a good outcome.

Matched MeSH terms: Lupus Erythematosus, Systemic

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