Subject(s)
Thymoma , Thymus Neoplasms , Humans , Thymoma/complications , Thymus Neoplasms/complications , Female , Male , Immunologic Deficiency Syndromes/complications , Middle Aged , AdultSubject(s)
Dermatomyositis , Lung Diseases, Interstitial , Humans , Dermatomyositis/drug therapy , Autoantibodies , Antibodies, Monoclonal/therapeutic use , Disease Progression , Lung Diseases, Interstitial/diagnostic imaging , Lung Diseases, Interstitial/drug therapy , Interferon-Induced Helicase, IFIH1 , Retrospective StudiesABSTRACT
We report 2 patients who first developed cutaneous manifestations, followed by autoimmune phenomena, infections, and hypogammaglobulinemia. They were initially diagnosed with common variable immunodeficiency; however, the diagnosis was revised to cytotoxic T-lymphocyte antigen 4 haploinsufficiency after genetic and functional testing.
ABSTRACT
The underlying immunological mechanisms of immediate-type hypersensitivity reactions (HSR) to COVID-19 vaccines are poorly understood. We investigate the mechanisms of immediate-type hypersensitivity reactions to the Pfizer BNT162b2 vaccine and the response of antibodies to the polyethylene glycol (PEG)ylated lipid nanoparticle after two doses of vaccination. Sixty-seven participants, median age 35 and 77.3% females who tolerated two doses of the BNT162b2 vaccine (non-reactors), were subjected to various blood-sampling time points. A separate group of vaccine reactors (10 anaphylaxis and 37 anonymised tryptase samples) were recruited for blood sampling. Immunoglobulin (Ig)G, IgM and IgE antibodies to the BNT162b2 vaccine, biomarkers associated with allergic reaction, including tryptase for anaphylaxis, complement 5a(C5a), intercellular adhesion molecule 1 (ICAM-1) for endothelial activation and Interleukin (IL)-4, IL-10, IL-33, tumour necrosis factor (TNF) and monocyte chemoattractant protein (MCP-1), were measured. Basophil activation test (BAT) was performed in BNT162b2-induced anaphylaxis patients by flow cytometry. The majority of patients with immediate-type BNT162b2 vaccine HSR demonstrated raised C5a and Th2-related cytokines but normal tryptase levels during the acute reaction, together with significantly higher levels of IgM antibodies to the BNT162b2 vaccine (IgM 67.2 (median) vs. 23.9 AU/mL, p < 0.001) and ICAM-1 when compared to non-reactor controls. No detectable IgE antibodies to the BNT162b2 vaccine were found in these patients. The basophil activation tests by flow cytometry to the Pfizer vaccine, 1,2-dimyristoyl-rac-glycero-3-methoxypolyethylene glycol (DMG-PEG) and PEG-2000 were negative in four anaphylaxis patients. Acute hypersensitivity reactions post BNT162b2 vaccination suggest pseudo-allergic reactions via the activation of anaphylatoxins C5a and are independent of IgE-mechanisms. Vaccine reactors have significantly higher levels of anti-BNT162b2 IgM although its precise role remains unclear.
ABSTRACT
INTRODUCTION: There is a paucity of information on the cytokine, complement, endothelial activation, and coagulation profiles of multisystem inflammatory syndrome in adults (MIS-A), a rare but serious complication following recovery from SARS-CoV-2 infection. We aim to examine the immune biomarker and coagulation profiles in association with the clinical presentation and course of MIS-A. METHOD: The clinical features of MIS-A patients admitted to our tertiary hospital were documented. Their levels of interleukin (IL)-1ß, IL-6, IL-10, IL-17, IL-18, interferon-α (IFN-α), IFN-γ, interferon gamma-induced protein 10 (IP-10), tumour necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, complement activation product (complement 5a [C5a]), and endothelial biomarker intercellular adhesion molecule-1 (ICAM-1) levels were assayed. The haemostatic profile was assessed with standard coagulation testing and thromboelastography. RESULTS: Three male patients were diagnosed with MIS-A at our centre from January to June 2022 with a median age of 55 years. All had tested positive for SARS-CoV-2 12-62 days prior to MIS-A presentation, with gastrointestinal and cardiovascular systems as the most commonly involved. Levels of IL-6, IL-10, IL-18, IP-10 and MCP-1 were raised whereas IL-1ß, IFN-α, IFN-γ, IL-17 and TNF-α remained normal. Markedly elevated levels of C-reactive protein (CRP), ferritin and ICAM-1 were present in all. C5a was elevated in 2 patients. A hypercoagulable state was demonstrated by raised levels of D-dimer, factor VIII, von Willebrand factor antigen, and ristocetin cofactor with corresponding raised parameters in thromboelastography in the 2 patients who had their coagulation profile assessed. CONCLUSION: MIS-A patients demonstrate activation of pro-inflammatory cytokines, endotheliopathy, complement hyperactivation and hypercoagulability.
Subject(s)
COVID-19 , Connective Tissue Diseases , Hemostatics , Humans , Adult , Male , Middle Aged , COVID-19/complications , Interleukin-10 , Interleukin-18 , Intercellular Adhesion Molecule-1 , Interleukin-17 , Chemokine CXCL10 , Interleukin-6 , SARS-CoV-2ABSTRACT
Since the introduction of coronavirus disease 2019 (COVID-19) messenger ribonucleic acid (mRNA) vaccines, there have been multiple reports of post-vaccination myocarditis (mainly affecting young healthy males). We report on four patients with active autoimmune rheumatic diseases (ARDs) and probable or confirmed myocarditis following COVID-19 mRNA vaccination managed at a tertiary hospital in Singapore; we reviewed the literature on post-COVID-19 mRNA vaccination-related myocarditis and ARD flares. Three patients had existing ARD flares (two had systemic lupus erythematosus (SLE), one had eosinophilic granulomatosis polyangiitis (EGPA)), and one had new-onset EGPA. All patients recovered well after receiving immunosuppressants comprising high-dose glucocorticoids, cyclophosphamide, and rituximab. Thus far, only one case of active SLE with myocarditis has been reported post-COVID-19 mRNA vaccination in the literature. In contrast to isolated post-COVID-19 mRNA vaccination myocarditis, our older-aged patients had myocarditis associated with ARD flares post-COVID-19 vaccination (that occurred after one dose of an mRNA vaccine), associated with other features of ARD flares, and required increased immunosuppression to achieve myocarditis resolution. This case series serves to highlight the differences in clinical and therapeutic aspects in ARD patients, heighten the vigilance of rheumatologists for this development, and encourage the adoption of risk reduction strategies in this vulnerable population.
ABSTRACT
OBJECTIVES: The Montreal Cognitive Assessment (MoCA) is an increasingly used screening tool for cognitive impairment. The aim of this study was to examine how MoCA performed in identifying cognitive impairment (CI) domains in SLE patients compared with formal standardized neuropsychological testing (NPT). Factors related to SLE disease, immunologic and psychological state associated with CI were also explored. METHODS: This cross-sectional study recruited 50 SLE patients without overt neuropsychiatric manifestations from April 2017 to May 2018. The patients were evaluated with MoCA, formal NPT and the Depression, Anxiety, and Stress Scales (DASS) 42-item self-report questionnaire. Values of sensitivity and specificity were computed for different cut-offs of MoCA within each cognitive domain of NPT and descriptive analysis was used to identify the factors affecting cognitive function. RESULTS: The median score for MoCA was 27.5 (range 22-30). Using a MoCA cutoff of <26, 18 (36%) were identified to have CI using NPT compared to 8 (16%) using MoCA. The most frequently affected cognitive domain was executive functioning with 15 affected patients. Sensitivities and specificities of the MoCA range from 50% to 100% and 5.7% to 16.7%, respectively, across cognitive domains. A lower MoCA cutoff of <25 improve sensitivity of identifying impairment in executive functioning from 60% to 80%. In univariate analysis, DASS scores, disease activity, presence of antiphospholipid antibodies, presence of concurrent autoimmune disease, current, and cumulative corticosteroid therapy did not predict cognitive performance. CONCLUSION: MoCA may be a useful screening tool to identify the most frequently affected cognitive domain which is executive functioning using a lower cutoff of <25 in SLE patients without overt neuropsychiatric manifestations.
Subject(s)
Cognitive Dysfunction , Lupus Erythematosus, Systemic , Humans , Cross-Sectional Studies , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/psychology , Mental Status and Dementia Tests , Cognitive Dysfunction/etiology , Cognitive Dysfunction/complications , Executive Function , Neuropsychological TestsABSTRACT
During the initial rollout of coronavirus disease 2019 (COVID-19) vaccination in Singapore, the Ministry of Health (MOH) issued a recommendation that patients with a history of any previous vaccine allergy be referred to an allergist for further review of their suitability to proceed with mRNA-based COVID-19 vaccines. Patients fulfilling the above criterion were divided into three groups: immediate reaction (Group A), delayed reaction (Group B) and no/irrelevant reaction (Group C). They were subjected to either a skin prick test (SPT) and intradermal test (IDT) with polyethylene glycol (PEG) or polysorbate-containing products; direct injection with the Pfizer BNT162b2 vaccine in the allergy clinic; or injection at community vaccination centres, respectively. Groups A and B were also invited to complete a questionnaire survey on post-vaccination reactions, and blood sampling pre-vaccination and 1 h after the first dose of the BNT162b2 vaccine to measure immunoglobulin (Ig) G, IgM and IgE antibodies to the Pfizer BNT162b2 vaccine via ELISA assays immobilised with the BNT162b2 vaccine, as well as levels of allergic cytokines interleukin (IL)-4 and IL-33, complement C5a and the endothelial activation marker intercellular adhesion molecule-1 (ICAM-1). Groups A and B comprised 62 (20.5%) patients each. In Group A, two subjects (3.2%) with equivocal IDT results tolerated both doses of the BNT162b2 vaccine without major allergic reactions. The remaining 60 (96.8%) in Group A and 62 (100%) in Group B completed both doses of BNT162b2 vaccination without major adverse reactions. Among the 99 who completed the questionnaire survey, 13 (13%) patients reported mild allergic reactions after the first dose of the vaccine. Immunoglobulin (Ig) G and M antibodies, but not IgE antibodies to the Pfizer BNT162b2 vaccine were detected in 67 subjects prior to vaccination. The presence of anti-Pfizer BNT162b2 IgG and IgM prior to vaccination did not result in major allergic reactions nor increases in Th2-related cytokines (IL-4, IL-33), complement activation products (C5a) or endothelial activation (ICAM-1). The majority of those with suspected reactions to non-COVID-19 polysorbate-containing vaccines tolerated the BNT162b2 vaccine. Excipient skin tests for PEG and polysorbate prior to vaccination are unnecessary.
ABSTRACT
Sustained hypercoagulability and endotheliopathy are present in convalescent COVID-19 patients for up to 4 months from recovery. The hemostatic, endothelial, and inflammatory profiles of 39 recovered COVID-19 patients were evaluated up to 16 months after recovery from COVID-19. These values were compared with a control group of healthy volunteers (n = 124). 39 patients (71.8% males, median age 43 years) were reviewed at a mean of 12.7 ± 3.6 months following recovery. One patient without cardiovascular risk factors had post COVID-19 acute ischaemic limb. Elevated D-dimer and Factor VIII levels above normal ranges were noted in 17.9% (7/39) and 48.7% (19/39) of patients respectively, with a higher median D-dimer 0.34 FEU µg/mL (IQR 0.28, 0.46) (p < .001) and Factor VIII 150% (IQR 171, 203) (p = .004), versus controls. Thrombin generation (Thromboscreen) showed a higher median endogenous thrombin potential (ETP) of 1352 nM*min (IQR 1152, 1490) (p = .002) and a higher median peak height of 221.4 nM (IQR 170.2, 280.4) (p = 0.01) and delayed lag time 2.4 min (1.42-2.97) (p = 0.0002) versus controls. Raised vWF:Ag and ICAM-1 levels were observed in 17.9% (7/39) and 7.7% (3/39) of patients respectively, with a higher median VWF:Ag 117% (IQR 86, 154) (p = 0.02) and ICAM-1 54.1 ng/mL (IQR 43.8, 64.1) (p = .004) than controls. IL-6 was noted to be raised in 35.9% (14/39) of patients, with a higher median IL-6 of 1.5 pg/mL (IQR 0.6, 3.0) (p = 0.004) versus controls. Subgroup analysis stratifying patients by COVID-19 severity and COVID-19 vaccination preceding SARS-CoV-2 infection did not show statistically significant differences. Hypercoagulability, endothelial dysfunction, and inflammation are still detectable in some patients approximately 1 year after recovery from COVID-19.
Subject(s)
COVID-19 , Thrombophilia , Adult , COVID-19/complications , COVID-19 Vaccines , Factor VIII , Female , Humans , Inflammation , Intercellular Adhesion Molecule-1 , Male , SARS-CoV-2 , Thrombin , Thrombophilia/etiology , von Willebrand FactorABSTRACT
VEXAS syndrome, an autoinflammatory syndrome due to a Ubiquitin Like Modifier Activating Enzyme 1 (UBA1) somatic mutation, has a high thrombotic burden. We report a case of a 69-year-old male that was diagnosed with VEXAS syndrome who developed venous thromboembolism (VTE). Review of literature of existing VEXAS syndrome cases showed a high thrombotic burden, with the reported incidence of VTE (36.4%) being markedly higher than arterial thrombosis (1.6%), with deep vein thrombosis being more common than pulmonary embolism. Somatic mutation in the UBA1 gene results in decreased ubiquitylation which is a key driver in the development of thrombosis in VEXAS syndrome, due to chronic inflammation and cytokine release from abnormal crosstalk between the intrinsic effector mechanism of innate immune cells, platelets and endothelium resulting in dysregulated haemostasis and endothelial dysfunction. Targeting endothelial dysfunction and reducing inflammatory milieu causing hypercoagulability with immunosuppressants and immunomodulatory agents, together with anticoagulation may be the strategy to prevent recurrent thrombotic events.
Subject(s)
Thrombosis , Venous Thromboembolism , Aged , Humans , Male , Mutation , Syndrome , Ubiquitin-Activating Enzymes/geneticsABSTRACT
Anaphylactic reactions were observed after Singapore's national coronavirus disease 2019 (COVID-19) vaccination programme started in December 2020. We report the clinical and laboratory features of three patients in our institution who developed anaphylactic reactions after receiving the Pifzer BNT162b2 vaccine. IgM and IgG antibodies, but not IgE antibodies to the Pfizer BNT162b2 vaccine, were detected in all subjects. Similarly, mild to high elevated levels of anti-polyethylene glycol (PEG) IgG (1035-19709 U/mL, vs. vaccine-naive < 265 U/mL, vaccine-tolerant < 785 U/mL) and IgM (1682-5310 U/mL, vs. vaccine-naive < 1011 U/mL, vaccine-tolerant < 1007 U/mL) were detected in two out of three patients via commercial ELISA. High levels of serum anaphylatoxin C3a (79.0 ± 6.3 µg/mL, mean ± SD, vs. normal < 10 µg/mL) were observed in all three patients during the acute phase of the reaction, while tryptase levels, a marker of mast cell activation, were not elevated. Finally, one patient with the highest levels of anti-PEG IgG, IgM, and anti-Pfizer BNT162b2 IgG and IgM exhibited an enhanced Th2 cytokine serum profile during an acute reaction, with high levels of IL-4 (45.7 pg/mL, vs. vaccine-naive/tolerant < 2.30 pg/mL), IL-33 (86.4 pg/mL, vs. vaccine-naive/tolerant < 5.51 pg/mL) and IL-10 (22.9 pg/mL, vs. vaccine-naive/tolerant < 12.49 pg/mL) diminishing over time following corticosteroid treatment. Taken together, we propose these cases of anaphylaxis described are driven by a complement activation-related pseudoallergy (CAPRA), rather than classical IgE-mediated mechanisms.
Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19/complications , COVID-19/prevention & control , SARS-CoV-2/immunology , Venous Thrombosis/etiology , BNT162 Vaccine , COVID-19/epidemiology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Disease Management , Disease Susceptibility , Humans , Incidence , Vaccination/adverse effects , Venous Thrombosis/diagnosis , Venous Thrombosis/epidemiologySubject(s)
Arthritis, Reactive/etiology , Coronavirus Infections/complications , Coronavirus Infections/diagnosis , Knee Joint/physiopathology , Pneumonia, Viral/complications , Pneumonia, Viral/diagnosis , Arthritis, Reactive/diagnostic imaging , Arthritis, Reactive/therapy , COVID-19 , COVID-19 Testing , Clinical Laboratory Techniques , Follow-Up Studies , Humans , Male , Middle Aged , Pandemics , Risk Assessment , Severity of Illness Index , Singapore , Treatment OutcomeABSTRACT
AIM: This study was undertaken to determine the incidence and patterns of malignancies in rheumatoid arthritis (RA) patients in our cohort. METHODS: Between 2001 and 2013, we analyzed 1117 patients in the prospective Tan Tock Seng Hospital (TTSH) RA Registry. Patients who developed malignancies after the onset of RA were identified from this registry. Age- and sex-adjusted standardized incidence ratios (SIRs) were calculated to compare observed to expected numbers of malignancies based on data from the Singapore Cancer Registry. RESULTS: Out of 19 839 person-years of follow-up, 132 incident malignancies were diagnosed during the observation period. There were 114 (86.4%) solid-organ tumors and 18 (13.6%) hematological malignancies. The SIR (95% confidence interval) for all malignancies combined was 1.28 (0.88-1.87) for males and 1.21 (1.00-1.46) for females. Compared to the general population, we found a 4- to 5-fold increase in lymphoma among our RA patients compared to the general population (SIR 5.05 [1.90-13.46] for males and 3.75 [1.95-7.20] for females). The SIR of lung malignancy in male RA patients is 2.36 (1.23-4.53) and SIR of cervical malignancy in female RA patients is 3.72 (2.20-6.23). CONCLUSION: There is a trend toward an overall increased malignancy risk in our RA patients compared to the general population. Specifically, there is an increased risk of lymphomas in all RA patients, lung malignancy in male patients, and cervical malignancy in female patients, compared to the general population.