Higher odds of periodontitis in systemic lupus erythematosus compared to controls and rheumatoid arthritis: a systematic review, meta-analysis and network meta-analysis.

Introduction: Periodontitis as a comorbidity in systemic lupus erythematosus (SLE) is still not well recognized in the dental and rheumatology communities. A meta-analysis and network meta-analysis were thus performed to compare the (i) prevalence of periodontitis in SLE patients compared to those with rheumatoid arthritis (RA) and (ii) odds of developing periodontitis in controls, RA, and SLE. Methods: Pooled prevalence of and odds ratio (OR) for periodontitis were compared using meta-analysis and network meta-analysis (NMA). Results: Forty-three observational studies involving 7,800 SLE patients, 49,388 RA patients, and 766,323 controls were included in this meta-analysis. The pooled prevalence of periodontitis in SLE patients (67.0%, 95% confidence interval [CI] 57.0-77.0%) was comparable to that of RA (65%, 95% CI 55.0-75.0%) (p>0.05). Compared to controls, patients with SLE (OR=2.64, 95% CI 1.24-5.62, p<0.01) and RA (OR=1.81, 95% CI 1.25-2.64, p<0.01) were more likely to have periodontitis. Indirect comparisons through the NMA demonstrated that the odds of having periodontitis in SLE was 1.49 times higher compared to RA (OR=1.49, 95% CI 1.09-2.05, p<0.05). Discussion: Given that RA is the autoimmune disease classically associated with periodontal disease, the higher odds of having periodontitis in SLE are striking. These results highlight the importance of addressing the dental health needs of patients with SLE. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/ identifier CRD42021272876.

High-density lipoprotein cholesterol subfraction HDL2 is associated with improved endothelial function in systemic lupus erythematosus.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) have increased risk of premature atherosclerosis but the exact mechanisms remains unclear. Flow-mediated dilatation (FMD) is an established non-invasive assessment of vascular endothelial function. Lipoprotein subfractions may be better predictors of FMD than conventional cholesterol measurements. We tested the hypothesis that lipoprotein subfractions are independently associated with FMD. METHODS: Forty-one consecutive adult patients with SLE without known cardiovascular risk factors or disease were recruited in this cross-sectional study. Endothelial function and early atherosclerosis were assessed by brachial FMD and common carotid artery (CCA) intima-media thickness (IMT). High-density lipoprotein (HDL)/low-density lipoprotein (LDL) subfractions were measured. Machine learning models were also constructed to predict FMD and CCA IMT. RESULTS: Median FMD was 4.48% (IQR 5.00%) while median IMT was 0.54 mm (IQR 0.12 mm). Univariate analysis showed lower LDL1 (r=-0.313, p<0.05) and higher HDL2 subfractions (r=0.313, p<0.05) were significantly associated with higher log-transformed FMD. In a multiple linear regression model, HDL2 (ß=0.024, SE=0.012, p<0.05) remained an independent predictor of higher FMD after adjusting for age, body mass index, LDL1 and systolic blood pressure. The machine learning model included parameters such as HDL2 (positive association), prednisolone dose, LDL cholesterol and LDL1 for prediction of FMD (r=0.433, p<0.01). Age, LDL cholesterol and systolic blood pressure were independently associated with higher CCA IMT after adjusting for body mass index and HDL2. CONCLUSIONS: HDL 2, a large HDL particle, was independently associated with greater FMD and may be a biomarker of vascular health in SLE.

Combining multimodal magnetic resonance brain imaging and machine learning to unravel neurocognitive function in non-neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: To study whether multimodal brain MRI comprising permeability and perfusion measures coupled with machine learning can predict neurocognitive function in young patients with SLE without neuropsychiatric manifestations. METHODS: SLE patients and healthy controls (HCs) (≤40 years of age) underwent multimodal structural brain MRI that comprised voxel-based morphometry (VBM), magnetization transfer ratio (MTR) and dynamic contrast-enhanced (DCE) MRI in this cross-sectional study. Neurocognitive function assessed by Automated Neuropsychological Assessment Metrics was reported as the total throughput score (TTS). Olfactory function was assessed. A machine learning-based model (i.e. glmnet) was constructed to predict TTS. RESULTS: Thirty SLE patients and 10 HCs were studied. Both groups had comparable VBM, MTR, olfactory bulb volume (OBV), olfactory function and TTS. While after correction for multiple comparisons the uncorrected increase in the blood-brain barrier (BBB) permeability parameters compared with HCs did not remain evident in SLE patients, DCE-MRI perfusion parameters, notably an increase in right amygdala perfusion, was positively correlated with TTS in SLE patients (r = 0.636, false discovery rate P < 0.05). A machine learning-trained multimodal MRI model comprising alterations of VBM, MTR, OBV and DCE-MRI parameters mainly in the limbic system regions predicted TTS in SLE patients (r = 0.644, P < 0.0005). CONCLUSION: Multimodal brain MRI demonstrated increased right amygdala perfusion that was associated with better neurocognitive performance in young SLE patients without statistically significant BBB leakage and microstructural abnormalities. A machine learning-constructed multimodal model comprising microstructural, perfusion and permeability parameters accurately predicted neurocognitive performance in SLE patients.

Platelet TLR7 is essential for the formation of platelet-neutrophil complexes and low-density neutrophils in lupus nephritis.

OBJECTIVES: Platelets and low-density neutrophils (LDNs) are major players in the immunopathogenesis of SLE. Despite evidence showing the importance of platelet-neutrophil complexes (PNCs) in inflammation, little is known about the relationship between LDNs and platelets in SLE. We sought to characterize the role of LDNs and Toll-like receptor 7 (TLR7) in clinical disease. METHODS: Flow cytometry was used to immunophenotype LDNs from SLE patients and controls. The association of LDNs with organ damage was investigated in a cohort of 290 SLE patients. TLR7 mRNA expression was assessed in LDNs and high-density neutrophils (HDNs) using publicly available mRNA sequencing datasets and our own cohort using RT-PCR. The role of TLR7 in platelet binding was evaluated in platelet-HDN mixing studies using TLR7-deficient mice and Klinefelter syndrome patients. RESULTS: SLE patients with active disease have more LDNs, which are heterogeneous and more immature in patients with evidence of kidney dysfunction. LDNs are platelet bound, in contrast to HDNs. LDNs settle in the peripheral blood mononuclear cell (PBMC) layer due to the increased buoyancy and neutrophil degranulation from platelet binding. Mixing studies demonstrated that this PNC formation was dependent on platelet-TLR7 and that the association results in increased NETosis. The neutrophil:platelet ratio is a useful clinical correlate for LDNs, and a higher NPR is associated with past and current flares of LN. CONCLUSIONS: LDNs sediment in the upper PBMC fraction due to PNC formation, which is dependent on the expression of TLR7 in platelets. Collectively, our results reveal a novel TLR7-dependent crosstalk between platelets and neutrophils that may be an important therapeutic opportunity for LN.

Prevalence and factors associated with flares following COVID-19 mRNA vaccination in patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis: a national cohort study.

OBJECTIVE: To determine prevalence and factors associated with flares post Coronavirus disease 2019 (COVID-19) mRNA vaccination in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA). METHODS: A retrospective multi-centre study was conducted (January 2021 to February 2022). Data were collected during index visit, defined as first post-vaccine visit in which the patient had a physician-defined flare, or if at least 3 months had elapsed since first vaccine dose, whichever came first. Factors associated with flares were identified using mixed effects Cox regression and expressed as hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Total of 2377 patients were included (1563 RA, 415 PsA and 399 SpA). Among patients with RA, PsA and SpA, 21.3%, 24.1% and 21.8% experienced a flare respectively. Of those who experienced a flare, only 10.2%, 11.0% and 14.9% were severe in patients with RA, PsA and SpA respectively. Patients with low or moderate/high disease were more likely to flare compared to those in remission in patients with RA only (HR: 1.68, 95% CI 1.22-2.31; HR: 2.28, 95% CI 1.50-3.48, respectively). Receiving the Moderna vaccine was associated with a higher HR of flare compared to the Pfizer vaccine in patients with PsA only (HR: 2.21, 95% CI 1.20-4.08). Patients who had two vaccine doses were found to be less likely to flare (HR: 0.08, 95% CI 0.06-0.10). HRs of flares were not significantly different among RA, PsA and SpA. CONCLUSION: About one-fifth of patients experienced a disease flare post COVID-19 mRNA vaccination, but most flares were non-severe. Patients with active disease prior to vaccination should be monitored closely for disease flares, especially in patients with RA.

Factors Predictive of Primary Resistance to Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Primary resistance to immune checkpoint inhibitors (ICI) is observed in routine clinical practice. We sought to determine factors predictive of primary resistance to ICI monotherapy, defined by the Society for Immunotherapy of Cancer (SITC) as progression within 6 months of ICI treatment with patients receiving at least 6 weeks of ICI monotherapy, in patients with advanced non-small-cell lung cancer (NSCLC). METHOD: Patients with stage IV NSCLC treated with at least 6 weeks of single-agent ICI at two tertiary hospitals in Singapore were included. A multivariate logistic regression model was utilised to elucidate factors predictive of primary resistance to ICI. RESULTS: Of the 108 eligible patients, 59 (54.6%) experienced primary resistance. The majority were male (65.7%), smokers (66.3%), Chinese (79.6%), had adenocarcinoma (76.9%), received Pembrolizumab (55.6%) and received immunotherapy treatment in the later line setting (≥2 lines) (61.1%). Female gender (aOR = 3.16, p = 0.041), a sixth-week neutrophil-to-lymphocyte ratio (NLR) of ≥3) (aOR = 3.454, p = 0.037) and a later line of immunotherapy treatment (≥2 lines) (aOR = 2.676, p = 0.040) were factors predictive of primary resistance to ICI monotherapy in patients with advanced NSCLC. CONCLUSIONS: Using SITC criteria, an elevated NLR (≥3) at 6 weeks, female gender and a later line of immunotherapy treatment (≥2 lines) were predictive factors of developing primary resistance to ICI monotherapy in patients with advanced NSCLC.

Bridging the Gap: Tailoring an Approach to Treatment in Febrile Infection-Related Epilepsy Syndrome.

Cytokine profiling before immunotherapy is increasingly prevalent in febrile infection-related epilepsy syndrome (FIRES). In this case, an 18-year-old man presented with first-onset seizure after a nonspecific febrile illness. He developed super-refractory status epilepticus requiring multiple antiseizure medications and general anesthetic infusions. He was treated with pulsed methylprednisolone and plasma exchange and started on ketogenic diet. Contrast-enhanced MRI brain revealed postictal changes. EEG findings showed multifocal ictal runs and generalized periodic epileptiform discharges. CSF analysis, autoantibody testing, and malignancy screening were unremarkable. Genetic testing revealed variants of uncertain significance in the CNKSR2 and OPN1LW genes. Initial serum and CSF cytokine analyses performed on days 6 and 21 revealed that interleukin (IL)-6, IL-1RA, monocyte chemoattractant protein-1, macrophage inflammatory protein 1ß, and interferon γ were elevated predominantly in the CNS, a profile consistent with cytokine release syndrome. Tofacitinib was initially trialed on day 30 of admission. There was no clinical improvement, and IL-6 continued to rise. Tocilizumab was given on day 51 with significant clinical and electrographic response. Anakinra was subsequently trialed from days 99 to 103 because clinical ictal activity re-emerged on weaning anesthetics but stopped because of poor response. Serial cytokine profiles showed improvement after 7 doses of tocilizumab. There was corresponding improved seizure control. This case illustrates how personalized immunomonitoring may be helpful in cases of FIRES, where proinflammatory cytokines are postulated to act in epileptogenesis. There is an emerging role for cytokine profiling and close collaboration with immunologists for the treatment of FIRES. The use of tocilizumab may be considered in patients with FIRES with upregulated IL-6.

Post-mRNA vaccine flares in autoimmune inflammatory rheumatic diseases: Results from the COronavirus National Vaccine registry for ImmuNe diseases SINGapore (CONVIN-SING).

BACKGROUND: Studies of flares of autoimmune inflammatory rheumatic diseases (AIIRD) after COVID-19 mRNA vaccination are limited by small sample size, short follow up or at risk of selection bias. METHODS: A national retrospective cohort study of consecutive AIIRD patients ≥12 years old, across 8 hospitals who received at least one dose of a COVID-19 mRNA vaccine. Patients were included from the date of 1st vaccine dose and censored at the time of flare or on the date of the clinic visit at least 3 months from cohort entry, whichever came first. Predictors of flare were determined by Cox proportional hazards analysis. FINDINGS: 4627 patients (73% Chinese, 71% female) of median (IQR) age 61 (48, 70) years were included; 42% Rheumatoid arthritis, 14% Systemic lupus erythematosus and 11% Psoriatic arthritis. 47% were in remission, 41% low disease activity, 10% moderate disease activity and 1% in high disease activity. 18% patients flared, of which 11.7% were within the 3-month period of interest. 11.8% patients improved. Median (IQR) time-to-flare was 60 (30, 114) days. 25% flares were self-limiting, 61% mild-moderate and 14% severe. Older patients (53-65 years and >66 years) had a lower risk of flare [HR 0.6 (95% CI 0.5-0.8) and 0.7 (0.6-0.8) respectively]. Patients with inflammatory arthritis and with active disease had a higher risk of flare [HR 1.5 (1.2-2.0) and 1.4 (1.2-1.6), respectively]. Treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), immunosuppression and prednisolone was also associated with an increased risk of flare [HR 1.5 (1.1-2), 1.2 (1.1-1.4) and 1.5 (1.2-1.8) for prednisolone ≤7.5 mg respectively]. INTERPRETATION: There was a moderately high rate of AIIRD flares after mRNA vaccination but also improvement in several patients. Severe flares and hospitalisation were rare. Thus, vaccination remains safe and highly recommended.

Latent Class Analysis Identifies Distinct Phenotypes of Systemic Lupus Erythematosus Predictive of Flares after mRNA COVID-19 Vaccination: Results from the Coronavirus National Vaccine Registry for ImmuNe Diseases SINGapore (CONVIN-SING).

We recently reported that messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination was associated with flares in 9% of patients with systemic lupus erythematosus (SLE). Herein, we focused our analysis on patients from a multi-ethnic Southeast Asian lupus cohort with the intention of identifying distinct phenotypes associated with increased flares after mRNA COVID-19 vaccination. METHODS: Six hundred and thirty-three SLE patients from eight public healthcare institutions were divided into test and validation cohorts based on healthcare clusters. Latent class analysis was performed based on age, ethnicity, gender, vaccine type, past COVID-19 infection, interruption of immunomodulatory/immunosuppressive treatment for vaccination, disease activity and background immunomodulatory/immunosuppressive treatment as input variables. Data from both cohorts were then combined for mixed effect Cox regression to determine which phenotypic cluster had a higher risk for time to first SLE flare, adjusted for the number of vaccine doses. RESULTS: Two clusters were identified in the test (C1 vs. C2), validation (C1' vs. C2') and combined (C1″ vs. C2″) cohorts, with corresponding clusters sharing similar characteristics. Of 633 SLE patients, 88.6% were female and there was multi-ethnic representation with 74.9% Chinese, 14.2% Malay and 4.6% Indian. The second cluster (C2, C2' and C2″) was smaller compared to the first. SLE patients in the second cluster (C2 and C2') were more likely to be male, non-Chinese and younger, with higher baseline disease activity. The second cluster (C2″) had more incident flares (hazard ratio = 1.4, 95% confidence interval 1.1-1.9, p = 0.014) after vaccination. A higher proportion of patients in C2″ had immunomodulatory/immunosuppressive treatment interruption for vaccination as compared to patients in C1″ (6.6% vs. 0.2%) (p < 0.001). CONCLUSION: We identified two distinct phenotypic clusters of SLE with different patterns of flares following mRNA COVID-19 vaccination. Caution has to be exercised in monitoring for post-vaccination flares in patients with risk factors for flares such as non-Chinese ethnicity, young age, male gender and suboptimal disease control at the time of vaccination.

Prevalence and factors associated with flares following COVID-19 mRNA vaccination in patients with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis: a national cohort study

Abstract Objective To determine prevalence and factors associated with flares post Coronavirus disease 2019 (COVID-19) mRNA vaccination in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA). Methods A retrospective multi-centre study was conducted (January 2021 to February 2022). Data were collected during index visit, defined as first post-vaccine visit in which the patient had a physician-defined flare, or if at least 3 months had elapsed since first vaccine dose, whichever came first. Factors associated with flares were identified using mixed effects Cox regression and expressed as hazard ratio (HR) and 95% confidence interval (CI). Results Total of 2377 patients were included (1563 RA, 415 PsA and 399 SpA). Among patients with RA, PsA and SpA, 21.3%, 24.1% and 21.8% experienced a flare respectively. Of those who experienced a flare, only 10.2%, 11.0% and 14.9% were severe in patients with RA, PsA and SpA respectively. Patients with low or moderate/high disease were more likely to flare compared to those in remission in patients with RA only (HR: 1.68, 95% CI 1.22-2.31; HR: 2.28, 95% CI 1.50-3.48, respectively). Receiving the Moderna vaccine was associated with a higher HR of flare compared to the Pfizer vaccine in patients with PsA only (HR: 2.21, 95% CI 1.20-4.08). Patients who had two vaccine doses were found to be less likely to flare (HR: 0.08, 95% CI 0.06-0.10). HRs of flares were not significantly different among RA, PsA and SpA. Conclusion About one-fifth of patients experienced a disease flare post COVID-19 mRNA vaccination, but most flares were non-severe. Patients with active disease prior to vaccination should be monitored closely for disease flares, especially in patients with RA.

Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency.

Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/ß (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23-dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.

Real-world experience of consolidation durvalumab after concurrent chemoradiotherapy in stage III non-small cell lung cancer.

BACKGROUND: Durvalumab consolidation is associated with improved survival following concurrent chemoradiotherapy (CCRT) in patients with stage III non-small cell lung cancer (NSCLC). Given the heterogeneity of stage III NSCLC patients, in this study we evaluated the efficacy and safety of durvalumab in the real-world setting. METHOD: Unresectable stage III NSCLC patients were retrospectively studied: one cohort received CCRT, another had CCRT-durvalumab. Primary endpoints were progression-free survival (PFS) and overall survival (OS), secondary endpoints were relapse rate and safety. In CCRT-durvalumab cohort, association between blood markers with survival and pneumonitis risk were analyzed. RESULTS: A total of 84 patients were enrolled: 45 received CCRT, and 39 received CCRT-durvalumab. Median PFS was 17.5 months for CCRT-durvalumab and 8.9 months for CCRT-alone (HR 0.47, p = 0.038). Median OS was not-reached for CCRT-durvalumab and 22.3 months for CCRT-alone (HR 0.35, p = 0.024). Both EGFR-positive and wild-type (WT) patients had numerically improved PFS with durvalumab consolidation compared to CCRT-alone, 17.5 versus 10.9 months and 11.8 versus 6.63 months, respectively (interaction p-value = 0.608). Grade 2+ pneumonitis was detected in 25% of patients in the durvalumab cohort. Most pneumonitis occurred at 3.5 weeks after durvalumab initiation. Baseline neutrophil-to-lymphocyte ratio (NLR) ≥ 3 and ≥5 were associated with shorter PFS with durvalumab. Week 6 platelet-lymphocyte-ratio ≥ 180 was associated with a lower risk of pneumonitis. CONCLUSION: In this real-world study, durvalumab consolidation post CCRT was associated with a statistically significant improvement in PFS and OS. Effect of durvalumab on PFS was not modified by EGFR status. Active surveillance for pneumonitis is crucial. Baseline NLR may help to predict the benefit of treatment with durvalumab.

Insights into the role of neutrophils in neuropsychiatric systemic lupus erythematosus: Current understanding and future directions.

Central nervous system (CNS) involvement of systemic lupus erythematosus (SLE), termed neuropsychiatric SLE (NPSLE), is a major and debilitating manifestation of the disease. While patients with SLE mostly complain of common neuropsychological symptoms such headache and mild mood disorders that may not even be technically attributed to SLE, many SLE patients present with life-threatening NPSLE syndromes such as cerebrovascular disease, seizures and psychosis that are equally challenging in terms of early diagnosis and therapy. While we are just beginning to unravel some mysteries behind the immunologic basis of NPSLE, advancements in the mechanistic understanding of the complex pathogenic processes of NPSLE have been emerging through recent murine and human studies. The pathogenic pathways implicated in NPSLE are multifarious and various immune effectors such as cell-mediated inflammation, autoantibodies and cytokines including type I interferons have been found to act in concert with the disruption of the blood-brain barrier (BBB) and other neurovascular interfaces. Beyond antimicrobial functions, neutrophils are emerging as decision-shapers during innate and adaptive immune responses. Activated neutrophils have been recognized to be involved in ischemic and infective processes in the CNS by releasing neutrophil extracellular traps (NETs), matrix metalloproteinase-9 and proinflammatory cytokines. In the context of NPSLE, these mechanisms contribute to BBB disruption, neuroinflammation and externalization of modified proteins on NETs that serve as autoantigens. Neutrophils that sediment within the peripheral blood mononuclear cell fraction after density centrifugation of blood are generally defined as low-density neutrophils (LDNs) or low-density granulocytes. LDNs are a proinflammatory subset of neutrophils that are increased with SLE disease activity and are primed to undergo NETosis and release cytokines such as interferon-α and tumor necrosis factor. This review discusses the immunopathogenesis of NPSLE with a focus on neutrophils as a core mediator of the disease and potential target for translational research in NPSLE.

Dominant Negative TRAF3 Variant With Recurrent Mycobacterium abscessus Infection and Bronchiectasis.

Host factors leading to pulmonary nontuberculous mycobacteria (PNTM) disease are poorly understood compared with disseminated NTM disease, which is linked to the interleukin 12-interferon gamma signaling pathway. We investigated the tumor necrosis factor receptor associated factor 3 (TRAF3) R338W variant in a patient with recurrent PNTM infection, demonstrating TRAF3- and TNF-α-deficient phenotypes via ex vivo immune and cloning-transfection cellular studies.

Distinct transcriptomic and metabolomic profiles characterize NSAID-induced urticaria/angioedema patients undergoing aspirin desensitization.

BACKGROUND: There is limited data on the mechanisms of aspirin desensitization in patients with nonsteroidal anti-inflammatory drug (NSAID)-induced urticaria/angioedema (NIUA). OBJECTIVES: We sought to characterize the transcriptomic and metabolomic profiles of patients with NIUA undergoing aspirin desensitization. METHODS: PBMCs and plasma were separated from the blood of patients with NIUA undergoing aspirin desensitization for coronary artery disease and NSAID-tolerant controls. RNA was isolated from PBMCs and subjected to messenger RNA (mRNA)- and long noncoding RNA (lncRNA)-sequencing. Plasma samples were analyzed using LC-MS/MS for metabolite shifts using a semitargeted metabolomics panel. RESULTS: Eleven patients with NIUA and 10 healthy controls were recruited. The mRNA gene profiles of predesensitization versus postdesensitization and healthy control versus postdesensitization did not differ significantly. However, we identified 739 mRNAs and 888 lncRNAs as differentially expressed from preaspirin desensitization patients and controls. A 12-mRNA gene signature was trained using a machine learning algorithm to distinguish between controls, postdose, and predose samples. Ingenuity Pathway Analysis identified 5 canonical pathways that were significantly enriched in preaspirin desensitization samples. IL-22 was the most upregulated pathway. To investigate the potential regulatory roles of the differentially expressed lncRNA on the mRNAs, 9 lncRNAs and 12 mRNAs showed significantly correlated expression patterns in the IL-22 pathway. To validate the transcriptomics data, IL-22 was measured in the plasma samples of the subjects using ELISA. IL-22 was significantly higher in preaspirin desensitization patients compared with controls. In parallel, metabolomic analysis revealed stark differences in plasma profiles of preaspirin desensitization patients and healthy controls. In particular, 2-hydroxybenzoic acid (salicylic acid) was significantly lower in preaspirin desensitization patients compared with healthy controls. CONCLUSIONS: This is the first study to combine both transcriptomic and metabolomic approaches in patients with NIUA, which contributes to a deeper understanding about the pathogenesis of NIUA and may potentially pave the way toward a molecular diagnosis of NSAID hypersensitivity.

Elucidating a bidirectional association between rheumatoid arthritis and depression: A systematic review and meta-analysis.

BACKGROUND: Rheumatoid arthritis (RA) and depression are conditions which commonly co-exist. Recent longitudinal studies now suggest a bidirectional association between these disorders, with inconsistent results. We conducted a systematic review and meta-analysis to examine this relationship. METHODS: Three electronic databases (PubMed, Embase and PsycINFO) were searched from inception to September 4, 2021 for cohort studies evaluating either the risk of depression in RA patients or the risk of RA in patients with depression, as well as the secondary outcome of all-cause mortality risk in RA patients with depression. A random effects model was used to summarize the included studies. RESULTS: Eleven cohort studies were included, comprising a total of 39,130 RA patients, 550,782 patients with depression and 7,802,230 controls. RA patients had a 47% greater risk of incident depression compared to controls, while patients with depression had a 34% greater risk of developing RA. Subgroup analysis by age was only significant in the ≥60 years old age group. RA patients with depression had an 80% increased risk of all-cause mortality compared to those without depression. LIMITATIONS: The results may have been confounded by factors such as differing methods of depression ascertainment across studies and overlap in presentation between the two conditions. CONCLUSION: There exists a bidirectional association between RA and depression especially in the elderly which increases mortality risk. This invites the need for clinicians to screen and be vigilant for the presence of these conditions.

Clinical Presentation of Immune-Related Endocrine Adverse Events during Immune Checkpoint Inhibitor Treatment.

The exact clinical course and factors associated with persistent endocrine immune-related adverse events (irAEs) are not well-established. Elucidation of these information will aid irAEs screening and follow-up planning for patients on immunotherapy. We analysed the clinical course of endocrine irAEs including thyroid and pituitary dysfunction and insulin-dependent diabetes mellitus (IDDM), identified factors associated with persistent thyroid dysfunction, and determined the association between endocrine irAEs and survival parameters. This retrospective observational study enrolled patients with metastatic cancer who underwent anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 treatment and developed endocrine irAE at the National University Cancer Institute, Singapore, between June 2015 and December 2020. Sixty-six patients with endocrine irAE were evaluated, with a median follow-up time of 15.7 months. The median time to onset of thyroid dysfunction, pituitary dysfunction, and IDDM was 1.8 months (range: 0.3-15.8 months), 6.8 months (range: 1.5-27.3 months), and 7.8 months (range: 1.4-9.1 months), respectively. Positive thyroperoxidase antibodies (TPOAb) and/ or thyroglobulin antibodies (TgAb) status at the time of thyroid dysfunction was associated with persistent thyroid dysfunction (OR 11.6, 95% CI 1.3-570.8, p = 0.02; OR 8.8, 95% CI 1.3-106.9, p = 0.01, respectively). All patients with pituitary irAE had central hypocortisolism. All patients with IDDM had grade 4 irAE. Patients with endocrine irAE had longer median survival times. Endocrine irAEs were associated with non-progressive disease. The screening and follow-up approach for endocrine irAEs should be tailored according to each endocrinopathy's clinical course. Early screening is imperative given its wide median time to onset.

Booster COVID-19 Vaccines for Immune-Mediated Inflammatory Disease Patients: A Systematic Review and Meta-Analysis of Efficacy and Safety.

BACKGROUND: Seroconversion and longevity of vaccine-induced immune response is blunted in immune-mediated inflammatory disease (IMID) patients owing to immunosuppressive regimens. COVID-19 booster vaccines after a primary series have been proposed with inconclusive evidence on efficacy to date. METHODS: This PROSPERO-registered systematic review (CRD42022302534) was conducted according to PRISMA guidelines. PubMed, EMBASE, CENTRAL, Web of Science, CORD-19, WHO ICTRP, and medRxiv were searched up to 28 February 2022 for eligible studies. Risk of bias was assessed using the Joanna Briggs Institute critical appraisal tools. RESULTS: From 6647 records, 17 prospective studies were included for systematic review and 12 in meta-analysis of primary series non-responders. The risk of bias was low. Pooling 340 non-responders, a booster dose proved effective with 0.47 seroconverting (95% CI: 0.32-0.63, I2 = 82%). Rituximab therapy was associated with significant impairment, with risks of 0.25 (95% CI: 0.17-0.36, I2 = 50.7%) versus 0.81 (95% CI: 0.72-0.87, I2 = 0.0%) for those without rituximab therapy. A systematic review of antibody levels against COVID-19 showed several-fold increases across studies. Incidence of local and systemic adverse events, including disease flares, were either comparable or slightly increased after the booster dose compared to primary series. No major events such as myocarditis or death were reported. CONCLUSION: Our results show that booster doses are effective in eliciting seroconversion in non-responders, bolstering immunity to COVID-19. It has also not been associated with major adverse events.