Ocular Tuberculosis Diagnosis Through Biomarkers: Clinical Relevance of Serum C1q and Whole Blood Interferon Gene Signature Score.

PURPOSE: To assess the clinical relevance of pathophysiology-based biomarkers, specifically serum C1q and whole blood interferon gene signature score (IGSS), in ocular tuberculosis (OTB) diagnosis by conducting an integrative analysis of clinical presentations and treatment response. METHODS: This retrospective cohort study analysed data from 70 patients with suspected OTB at a tertiary care uveitis practice in Indonesia. Serum C1q levels and whole blood IGSS were quantified. Patients were categorized into four quadrants based on their biomarker profiles: quadrant 1 (high C1q & low IGSS), quadrant 2 (high C1q & high IGSS), quadrant 3 (low C1q & high IGSS), and quadrant 4 (low C1q & low IGSS). Characteristics of clinical presentations, work-up results, and treatment outcomes were explored according to the predefined quadrants. RESULTS: We identified that the majority of OTB patients diagnosed with concurrent active pulmonary TB were in quadrant 1, 2, or 3 (20/23, 87.0%). Twenty-seven patients (27/47, 57.4%) with clinically undifferentiated uveitis were in quadrant 4 (p < 0.001). Among patients in quadrants 1, 2, and 3, completion of a full course of antitubercular treatment (ATT) was associated with a lower number of patients showing persistence or recurrence of ocular inflammation compared to those who were not fully treated with ATT (14.3% vs 85.7%, p = 0.001). CONCLUSIONS: Based on the analysis of clinical features and treatment outcomes, patients with elevated levels of either or both serum C1q and whole blood IGSS may reflect active TB disease in the eye, necessitating full ATT management.

Bioinformatic meta-analysis reveals novel differentially expressed genes and pathways in sarcoidosis.

Introduction: Sarcoidosis is a multi-system inflammatory disease of unknown origin with heterogeneous clinical manifestations varying from a single organ non-caseating granuloma site to chronic systemic inflammation and fibrosis. Gene expression studies have suggested several genes and pathways implicated in the pathogenesis of sarcoidosis, however, due to differences in study design and variable statistical approaches, results were frequently not reproducible or concordant. Therefore, meta-analysis of sarcoidosis gene-expression datasets is of great importance to robustly establish differentially expressed genes and signalling pathways. Methods: We performed meta-analysis on 22 published gene-expression studies on sarcoidosis. Datasets were analysed systematically using same statistical cut-offs. Differentially expressed genes were identified by pooling of p-values using Edgington's method and analysed for pathways using Ingenuity Pathway Analysis software. Results: A consistent and significant signature of novel and well-known genes was identified, those collectively implicated both type I and type II interferon mediated signalling pathways in sarcoidosis. In silico functional analysis showed consistent downregulation of eukaryotic initiation factor 2 signalling, whereas cytokines like interferons and transcription factor STAT1 were upregulated. Furthermore, we analysed affected tissues to detect differentially expressed genes likely to be involved in granuloma biology. This revealed that matrix metallopeptidase 12 was exclusively upregulated in affected tissues, suggesting a crucial role in disease pathogenesis. Discussion: Our analysis provides a concise gene signature in sarcoidosis and expands our knowledge about the pathogenesis. Our results are of importance to improve current diagnostic approaches and monitoring strategies as well as in the development of targeted therapeutics.

Clinical Features and Predictors of Treatment Outcome in Patients with Ocular Tuberculosis from the Netherlands and Indonesia: The OculaR TB in Low versus High Endemic Countries (ORTEC) Study.

PURPOSE: To describe and compare clinical features, treatment approaches, and treatment outcomes of ocular tuberculosis (OTB) patients in the Netherlands, a low tuberculosis (TB)-endemic country, and Indonesia, a high TB-endemic country. We also aimed to identify predictors of treatment outcomes. METHODS: A medical chart review of 339 OTB patients (n = 93 from the Netherlands and n = 246 from Indonesia) was performed. The primary outcome was response to treatment, whether with or without anti-tubercular treatment, after six months of treatment initiation (good versus poor responders). RESULTS: Indonesian OTB patients displayed a higher prevalence of chest radiograph findings indicative of TB infection (p < 0.001) and concurrent active systemic TB (p = 0.011). Indonesian cohort exhibited a more acute and severe disease profile, including uveitis duration ≤ 3 months (p < 0.001), blindness (p < 0.001), anterior chamber (AC) cells ≥ 2+ (p < 0.001), and posterior synechiae (p < 0.001). Overall proportions of good responders to treatment were 67.6% in the Netherlands and 71.5% in Indonesia. Presence of AC cell ≥ 2+ (adjusted odds ratio (aOR): 2.12, 95% CI: 1.09-4.14), choroidal lesions other than serpiginous-like choroiditis (SLC) or tuberculoma (aOR: 4.47, 95% CI: 1.18-16.90), and retinal vasculitis (aOR: 2.32, 95% CI: 1.10-4.90) at baseline were predictors for poor response to treatment. CONCLUSIONS: Despite a more severe initial clinical presentation in the Indonesian cohort, the overall treatment outcomes of OTB was comparable in both cohorts. Three baseline clinical features were identified as predictors of treatment outcomes.

Relapse in ocular tuberculosis: relapse rate, risk factors and clinical management in a non-endemic country.

AIMS: To assess the risk of uveitis relapse in ocular tuberculosis (OTB) following clinical inactivity, to analyse clinical factors associated with relapses and to describe the management strategies for relapses. METHODS: A retrospective study was conducted on a 10-year patient registry of patients with OTB diagnosed at Erasmus MC in Rotterdam, The Netherlands. Time-to-relapse of uveitis was evaluated with Kaplan-Meier curve and risk factors for relapses were analysed. RESULTS: 93 OTB cases were identified, of which 75 patients achieved clinical inactivity following treatment. The median time to achieve uveitis inactivity was 3.97 months. During a median follow-up of 20.7 months (Q1-Q3: 5.2-81.2) after clinical inactivity, uveitis relapse occurred in 25 of these 75 patients (33.3%). Patients who were considered poor treatment responders for their initial uveitis episode had a significantly higher risk of relapse after achieving clinical inactivity than good responders (adjusted HR=3.84, 95% CI: 1.28 to 11.51). 13 of the 25 relapsed patients experienced multiple uveitis relapse episodes, accounting for 78 eye-relapse episodes during the entire observation period. Over half (46 out of 78, 59.0%) of these episodes were anterior uveitis. A significant number of uveitis relapse episodes (31 episodes, 39.7%) were effectively managed with topical corticosteroids. CONCLUSIONS: Our results suggest that approximately one-third of patients with OTB will experience relapse after achieving clinical inactivity. The initial disease course and poor response to treatment predict the likelihood of relapse in the long-term follow-up. Topical corticosteroids were particularly effective in relapse presenting as anterior uveitis.

EZH2 as a major histone methyltransferase in PDGF-BB-activated orbital fibroblast in the pathogenesis of Graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is an extra-thyroidal complication of Graves' disease which can lead to vision loss in severe cases. Currently, treatments of GO are not sufficiently effective, so novel therapeutic strategies are needed. As platelet-derived growth factor (PDGF)-BB induces several effector mechanisms in GO orbital fibroblasts including cytokine production and myofibroblast activation, this study aims to investigate the roles of histone lysine methyltransferases (HKMTs) in PDGF-BB-activated GO orbital fibroblasts by screening with HKMTs inhibitors library. From the total of twelve selective HKMT inhibitors in the library, EZH2, G9a and DOT1L inhibitors, DZNeP, BIX01294 and Pinometostat, respectively, prevented PDGF-BB-induced proliferation and hyaluronan production by GO orbital fibroblasts. However, only EZH2 inhibitor, DZNeP, significantly blocked pro-inflammatory cytokine production. For the HKMTs expression in GO orbital fibroblasts, PDGF-BB significantly and time-dependently induced EZH2, G9a and DOT1L mRNA expression. To confirm the role of EZH2 in PDGF-BB-induced orbital fibroblast activation, EZH2 silencing experiments revealed suppression of PDGF-BB-induced collagen type I and α-SMA expression along with decreasing histone H3 lysine 27 trimethylation (H3K27me3) level. In a more clinically relevant model than orbital fibroblast culture experiments, DZNeP treated GO orbital tissues significantly reduced pro-inflammatory cytokine production while slightly reduced ACTA2 mRNA expression. Our data is the first to demonstrate that among all HKMTs EZH2 dominantly involved in the expression of myofibroblast markers in PDGF-BB-activated orbital fibroblast from GO presumably via H3K27me3. Thus, EZH2 may represent a novel therapeutics target for GO.

Thyroid stimulating immunoglobulin concentration is associated with disease activity and predicts response to treatment with intravenous methylprednisolone in patients with Graves' orbitopathy.

Background: Thyroid stimulating immunoglobulins (TSI) play a central role in the pathogenesis of Graves' orbitopathy (GO), while soluble interleukin-2 receptor (sIL-2R) is a marker for T-cell activity. We investigated TSI and sIL-2R levels in relation to thyroid function, disease activity and severity and response to treatment with intravenous methylprednisolone (IVMP) in patients with GO. Methods: TSI (bridge-based TSI binding assay), sIL-2R, TSH and fT4 levels were measured in biobank serum samples from 111 GO patients (37 male, 74 female; mean age 49.2 years old) and 25 healthy controls (5 male, 20 female; mean age 39.8 years old). Clinical characteristics and response to treatment were retrospectively retrieved from patient files. Results: Higher sIL-2R levels were observed in GO patients compared to controls (p < 0.001). sIL-2R correlated with fT4 (r = 0.26), TSH (r = -0.40) and TSI (r = 0.21). TSI and sIL-2R concentrations were higher in patients with active compared to inactive GO (p < 0.001 and p < 0.05, respectively). Both TSI and sIL-2R correlated with total clinical activity score (CAS; r = 0.33 and r = 0.28, respectively) and with several individual CAS items. Cut-off levels for predicting active GO were 2.62 IU/L for TSI (AUC = 0.71, sensitivity 69%, specificity 69%) and 428 IU/mL for sIL-2R (AUC = 0.64, sensitivity 62%, specificity 62%). In multivariate testing higher TSI (p < 0.01), higher age (p < 0.001) and longer disease duration (p < 0.01) were associated with disease activity. TSI levels were higher in patients with a poor IVMP response (p = 0.048), while sIL-2R levels did not differ between responders and non-responders. TSI cut-off for predicting IVMP response was 19.4 IU/L (AUC = 0.69, sensitivity 50%, specificity 91%). In multivariate analysis TSI was the only independent predictor of response to IVMP (p < 0.05). Conclusions: High TSI levels are associated with active disease (cut-off 2.62 IU/L) and predict poor response to IVMP treatment (cut-off 19.4 IU/L) in GO. While sIL-2R correlates with disease activity, it is also related to thyroid function, making it less useful as an additional biomarker in GO.

Serum immunoglobulins and biomarkers of dementia: a population-based study.

BACKGROUND: Inflammation plays a key role in the development of dementia, but its link to early biomarkers, particularly those in plasma or neuroimaging, remains elusive. This study aimed to investigate the association between serum immunoglobulins and biomarkers of dementia. METHODS: Between 1997 and 2009, serum immunoglobulins (IgA, IgG and IgM) were measured in dementia-free participants of the population-based Rotterdam Study. A random subset of participants had assessment of biomarkers in plasma (total tau (t-tau), neurofilament light chain (NfL), amyloid-ß40 (Aß-40), amyloid-ß42 (Aß-42), while another subset of participants underwent neuroimaging to quantify brain volume, white matter structural integrity and markers of cerebral small vessel disease. Linear regression models were constructed to determine cross-sectional associations between IgA, IgG, IgM and biomarkers of dementia, with adjustment for potential confounders. Multiple testing correction was applied using the false discovery rate. As a sensitivity analysis, we re-ran the models for participants within the reference range of immunoglobulins, excluding those using immunomodulating drugs, and conducted a stratified analysis by APOE-ε4 carriership and sex. RESULTS: Of 8,768 participants with serum immunoglobulins, 3,455 participants (65.8 years [interquartile range (IQR): 61.5-72.0], 57.2% female) had plasma biomarkers available and 3,139 participants (57.4 years [IQR: 52.7-60.7], 54.4% female) had neuroimaging data. Overall, no associations between serum immunoglobulins and biomarkers of dementia remained significant after correction for multiple testing. However, several suggestive associations were noted: higher serum IgA levels concurred with lower plasma levels of Aß-42 (standardized adjusted mean difference: -0.015 [95% confidence interval (CI): -0.029--0.002], p = 2.8 × 10-2), and a lower total brain volume, mainly driven by less gray matter (-0.027 [-0.046--0.008], p = 6.0 × 10-3) and more white matter hyperintensities (0.047 [0.016 - 0.077], p = 3.0 × 10-3). In sensitivity analyses, higher IgM was linked to lower t-tau, Aß-40, and Aß-42, but also a loss of white matter microstructural integrity. Stratified analyses indicate that these associations potentially differ between carriers and non-carriers of the APOE-ε4 allele and men and women. CONCLUSIONS: While associations between serum immunoglobulins and early markers of dementia could not be established in this population-based sample, it may be valuable to consider factors such as APOE-ε4 allele carriership and sex in future investigations.

Long-Term Follow-Up of Patients with Scleritis After Rituximab Treatment Including B Cell Monitoring.

PURPOSE: We report the long-term effect of rituximab (RTX) in scleritis and determine the value of B-cell monitoring for the prediction of relapses. METHODS: We retrospectively studied 10 patients with scleritis, who were treated with RTX. Clinical characteristics were collected, and blood B-cell counts were measured before the start of RTX, and at various time points after treatment. RESULTS: Clinical activity of scleritis decreased after RTX treatment in all patients within a median time of 8 weeks (range 3-13), and all reached remission. The median follow-up was 101 months (range 9-138). Relapses occurred in 6 out of 10 patients. All relapses, where B-cell counts were measured (11 out of 19), were heralded by returning B cells. However, B cells also returned in patients with long-term remissions. CONCLUSIONS: RTX is a promising therapeutic option for scleritis. Recurrence of B cells after initial depletion does not always predict relapse of scleritis.

Diagnosis and biomarkers for ocular tuberculosis: From the present into the future.

Tuberculosis is an airborne disease caused by Mycobacterium tuberculosis (Mtb) and can manifest both pulmonary and extrapulmonary disease, including ocular tuberculosis (OTB). Accurate diagnosis and swift optimal treatment initiation for OTB is faced by many challenges combined with the lack of standardized treatment regimens this results in uncertain OTB outcomes. The purpose of this study is to summarize existing diagnostic approaches and recently discovered biomarkers that may contribute to establishing OTB diagnosis, choice of anti-tubercular therapy (ATT) regimen, and treatment monitoring. The keywords ocular tuberculosis, tuberculosis, Mycobacterium, biomarkers, molecular diagnosis, multi-omics, proteomics, genomics, transcriptomics, metabolomics, T-lymphocytes profiling were searched on PubMed and MEDLINE databases. Articles and books published with at least one of the keywords were included and screened for relevance. There was no time limit for study inclusion. More emphasis was placed on recent publications that contributed new information about the pathogenesis, diagnosis, or treatment of OTB. We excluded abstracts and articles that were not written in the English language. References cited within the identified articles were used to further supplement the search. We found 10 studies evaluating the sensitivity and specificity of interferon-gamma release assay (IGRA), and 6 studies evaluating that of tuberculin skin test (TST) in OTB patients. IGRA (Sp = 71-100%, Se = 36-100%) achieves overall better sensitivity and specificity than TST (Sp = 51.1-85.7%; Se = 70.9-98.5%). For nuclear acid amplification tests (NAAT), we found 7 studies on uniplex polymerase chain reaction (PCR) with different Mtb targets, 7 studies on DNA-based multiplex PCR, 1 study on mRNA-based multiplex PCR, 4 studies on loop-mediated isothermal amplification (LAMP) assay with different Mtb targets, 3 studies on GeneXpert assay, 1 study on GeneXpert Ultra assay and 1 study for MTBDRplus assay for OTB. Specificity is overall improved but sensitivity is highly variable for NAATs (excluding uniplex PCR, Sp = 50-100%; Se = 10.5-98%) as compared to IGRA. We also found 3 transcriptomic studies, 6 proteomic studies, 2 studies on stimulation assays, 1 study on intraocular protein analysis and 1 study on T-lymphocyte profiling in OTB patients. All except 1 study evaluated novel, previously undiscovered biomarkers. Only 1 study has been externally validated by a large independent cohort. Future theranostic marker discovery by a multi-omics approach is essential to deepen pathophysiological understanding of OTB. Combined these might result in swift, optimal and personalized treatment regimens to modulate the heterogeneous mechanisms of OTB. Eventually, these studies could improve the current cumbersome diagnosis and management of OTB.

The immune response in tubercular uveitis and its implications for treatment: From anti-tubercular treatment to host-directed therapies.

Tubercular uveitis (TB-uveitis) remains a conundrum in the uveitis field, which is mainly related to the diverse clinical phenotypes of TB-uveitis. Moreover, it remains difficult to differentiate whether Mycobacterium tuberculosis (Mtb) is present in the ocular tissues, elicits a heightened immune response without Mtb invasion in ocular tissues, or even induces an anti-retinal autoimmune response. Gaps in the immuno-pathological knowledge of TB-uveitis likely delay timely diagnosis and appropriate management. In the last decade, the immunopathophysiology of TB-uveitis and its clinical management, including experts' consensus to treat or not to treat certain conditions with anti-tubercular treatment (ATT), have been extensively investigated. In the meantime, research on TB treatment, in general, is shifting more toward host-directed therapies (HDT). Given the complexities of the host-Mtb interaction, enhancement of the host immune response is expected to boost the effectiveness of ATT and help overcome the rising burden of drug-resistant Mtb strains in the population. This review will summarize the current knowledge on the immunopathophysiology of TB-uveitis and recent advances in treatment modalities and outcomes of TB-uveitis, capturing results gathered from high- and low-burden TB countries with ATT as the mainstay of treatment. Moreover, we outline the recent progress of HDT development in the pulmonary TB field and discuss the possibility of its applicability to TB-uveitis. The concept of HDT might help direct future development of efficacious therapy for TB-uveitis, although more in-depth research on the immunoregulation of this disease is still necessary.

COVID-19 Incidence and Disease Course Among Patients at an Allergy Department.

Background: Since the coronavirus pandemic in 2020, there is not much reported about the disease course of COVID-19 in patients with allergic diseases. Objectives: The aim of this study was to investigate the cumulative incidence and severity of COVID-19 among patients from the allergy department compared with the general Dutch population and people from their household. Design: We conducted a comparative longitudinal cohort study. Methods: In this study patients of the allergy department were included with their household members as a control group. Data from the beginning of the pandemic were systematically obtained through questionnaires by telephonic interviews and retrieved from electronic patient files between October 15, 2020 and January 29, 2021. Main outcomes were confirmed SARS-CoV-2 infection, disease duration, hospitalization, intensive care admission, and mortality. Questions regarding applied social distancing measures were inventoried as well. Results: Three hundred and eighty nine patients (median age 39.1 (18.7-84.7) years, 69.9% female) and 441 household members (median age 42.0 (18.0-91.5), 44.1% female) were included. The cumulative COVID-19 incidence in patients was higher compared with the general population (10.5% vs 5.6%, P < .001). In total, 41 (10.5%) patients attending the allergy clinic compared to 38 (8.6%) household members were infected with SARS-CoV-2 (P = .407). Median disease duration was 11.0 (0.0-61.0) days in patients compared to 10.5(1.0-232.0) days in household members (P = .996). Conclusion: The cumulative COVID-19 incidence in patients from the allergy cohort was higher compared with the general Dutch population, but similar compared with household members. There was no difference in symptoms, disease duration, or hospitalization rate between the allergy cohort and their household members.

High-titer convalescent plasma plus nirmatrelvir/ritonavir treatment for non-resolving COVID-19 in six immunocompromised patients.

OBJECTIVES: Immunocompromised patients have an increased risk of severe or prolonged COVID-19. Currently available drugs are registered to treat COVID-19 during the first 5 to 7 days after symptom onset. Data on the effectivity in immunocompromised patients with chronic non-resolving COVID-19 are urgently needed. Here, we report the outcome of patients treated with nirmatrelvir/ritonavir together with high-titer convalescent plasma (CP) in six immunocompromised patients with non-resolving COVID-19. METHODS: Immunocompromised patients with persisting COVID-19 (positive PCR with Ct values <30 for ≥20 days) received off-label therapy with nirmatrelvir/ritonavir. It was combined with CP containing BA.5 neutralizing titers of ≥1/640 whenever available. Follow-up was done by PCR and sequencing on nasopharyngeal swabs on a weekly basis until viral genome was undetectable consecutively. RESULTS: Five immunocompromised patients were treated with high-titer CP and 5 days of nirmatrelvir/ritonavir. One patient received nirmatrelvir/ritonavir monotherapy. Median duration of SARS-CoV-2 PCR positivity was 70 (range 20-231) days before nirmatrelvir/ritonavir treatment. In four patients receiving combination therapy, no viral genome of SARS-CoV-2 was detected on day 7 and 14 after treatment while the patient receiving nirmatrelvir/ritonavir monotherapy, the day 7 Ct value increased to 34 and viral genome was undetectable thereafter. Treatment was unsuccessful in one patient. In this patient, sequencing after nirmatrelvir/ritonavir treatment did not show protease gene mutations. CONCLUSIONS: In immunocompromised patients with non-resolving COVID-19, the combination of nirmatrelvir/ritonavir and CP may be an effective treatment. Larger prospective studies are needed to confirm these preliminary results and should compare different treatment durations.

The Association of Serum Immunoglobulins with Risk of Cardiovascular Disease and Mortality: the Rotterdam Study.

PURPOSE: Inflammation is implicated in cardiovascular disease (CVD), but the association of total serum immunoglobulin (Ig) A, G, and M with CVD across the whole spectrum of atherosclerosis in community-dwelling elderly is unknown. METHODS: This study was embedded in the Rotterdam Study, an ongoing population-based cohort study. We performed Cox regression for the associations of Igs with incident atherosclerotic CVD (ACVD; composite of myocardial infarction, revascularization, and stroke), cardiovascular mortality, and all-cause mortality, and multinomial logistic regression for the association between Igs and coronary artery calcification (CAC) scores. We adjusted for age, sex, lifestyle, and cardiovascular risk factors and presented results per standard deviation increase. RESULTS: We included 8767 participants (median age 62.2 years, 57% women). Higher IgG was associated with an increased ACVD risk (hazard ratio [HR]: 1.08; 95% confidence interval [95% CI]: 1.01-1.15). Higher IgA and IgG were associated with an increased cardiovascular mortality risk, mainly within Ig reference ranges, and with an increased all-cause mortality risk, although less marked. Higher IgA was associated with severe atherosclerosis, i.e., CAC score > 400 (odds ratio: 1.29; 95% CI: 1.03-1.62), while for higher IgG a trend was seen with severe atherosclerosis. CONCLUSION: In middle-aged and older individuals from the general population, higher serum IgA and IgG, but not IgM, are associated with CVD, cardiovascular mortality, and severe atherosclerosis, particularly within Ig reference ranges and independent of serum C-reactive protein. Future studies are needed to elucidate potential causality of the reported associations.

The association of serum immunoglobulins with cognition and dementia: the Rotterdam Study.

BACKGROUND: Chronic inflammation is involved in the pathophysiology of dementia, but the association of serum immunoglobulins with dementia has been understudied and longitudinal data are currently lacking. We investigated the association of serum immunoglobulin (Ig) A, G, and M with cognition and dementia in a population-based cohort. METHODS: This study was embedded in the Rotterdam Study. Participants with information on serum immunoglobulin levels, measured between 1997 and 2009, were followed for incident dementia until 2016. Assessment of cognitive function and dementia was performed according to validated tests and clinical criteria respectively. We studied the association between serum immunoglobulins with prevalent and incident dementia using logistic regression and Cox proportional hazards regression analyses respectively. We performed linear regression analyses to quantify the cross-sectional association of serum immunoglobulins with global cognition as well as separate cognitive tests. Analyses were adjusted for age, sex, lifestyle, and cardiovascular factors. RESULTS: We included 8768 participants (median age of 62.2 years, 57% women, median follow-up 10.7 years). Overall, none of the immunoglobulins was associated with prevalent or incident dementia. Higher IgG levels were associated with lower scores of global cognition (adjusted standardized mean difference - 0.04; 95% confidence interval:- 0.06; - 0.02) and separate cognitive tests. CONCLUSION: In middle-aged and older individuals from the general population, serum Igs were not associated with prevalent or incident dementia, which may imply that serum Igs are not involved in the pathophysiology of dementia. Although higher IgG levels were associated with worse cognitive function, studies with longitudinal data should exclude reverse causation.

Clinical course of COVID-19 infections in patients with Behçet's disease in The Netherlands.

OBJECTIVES: The aim of this study is to investigate the cumulative incidence and the severity of COVID-19 infections in patients with Behçet's disease. METHODS: A retrospective cohort study of patients with Behçet's disease was conducted. We obtained the data systematically from electronic patient files and through telephone interviews between February 2020 and May 1, 2021. Main outcomes were COVID-19 infection, disease duration, hospitalisation, intensive care admission and mortality. Secondary outcome was adherence to quarantine measures as recommended by the government. RESULTS: 185 Behçet's disease patients were included (mean age 42.2 years, 54% female); 58% of the patients were receiving colchicine, 30% anti-TNFα, 16% azathioprine and 8% systemic steroids. 30 patients (16.2%) were positive for COVID-19. Within our cohort, the cumulative incidence of COVID-19 was therefore 16.2% (95% CI 11.2-22.3%), which is significantly increased when compared to the general Dutch population (8.7% (95% CI 8.72-8.73%)) (p < 0.001). Four out of 30 (13%) patients were admitted to the hospital. There was no COVID-19 related mortality observed. Patients adhered to government measures; except in the period between the 1st of June and the 28th of September, this cohort received more visitors than in period 1 and 3. CONCLUSIONS: In this cohort, Behçet's disease patients have a higher risk for COVID-19 infection, without an increase of virus-related mortality. The course of COVID-19 disease in this cohort is relatively mild, with a lower admission rate than expected of patients using immunosuppressive medication.

Novel RAB27A Variant Associated with Late-Onset Hemophagocytic Lymphohistiocytosis Alters Effector Protein Binding.

Autosomal recessive mutations in RAB27A are associated with Griscelli syndrome type 2 (GS2), characterized by hypopigmentation and development of early-onset, potentially fatal hemophagocytic lymphohistiocytosis (HLH). We describe a 35-year old male who presented with recurrent fever, was diagnosed with Epstein-Barr virus-driven chronic lymphoproliferation, fulfilled clinical HLH criteria, and who carried a novel homozygous RAB27A c.551G > A p.(R184Q) variant. We aimed to evaluate the contribution of the identified RAB27A variant in regard to the clinical phenotype as well as cellular and biochemical function. The patient displayed normal pigmentation as well as RAB27A expression in blood-derived cells. However, patient NK and CD8+ T cell exocytosis was low. Ectopic expression of the RAB27A p.R184Q variant rescued melanosome distribution in mouse Rab27a-deficient melanocytes, but failed to increase exocytosis upon reconstitution of human RAB27A-deficient CD8+ T cells. Mechanistically, the RAB27A p.R184Q variant displayed reduced binding to SLP2A but augmented binding to MUNC13-4, two key effector proteins in immune cells. MUNC13-4 binding was particularly strong to an inactive RAB27A p.T23N/p.R184Q double mutant. RAB27A p.R184Q was expressed and could facilitate melanosome trafficking, but did not support lymphocyte exocytosis. The HLH-associated RAB27A variant increased Munc13-4 binding, potentially representing a novel mode of impairing RAB27A function selectively in hematopoietic cells.

Serum Immunoglobulins, Pneumonia Risk, and Lung Function in Middle-Aged and Older Individuals: A Population-Based Cohort Study.

Introduction: Immunoglobulins (Igs) play a pivotal role in host defense and prevention of pneumonia. Aging influences serum Ig levels, but the association between Igs and pneumonia in community-dwelling older individuals remains unknown. We evaluated the association of serum IgA, IgG, and IgM with pneumonia and lung function in middle-aged and older individuals. Methods: We performed Cox and negative binomial regression analyses for the association of Igs with incident pneumonia and pneumonia-related mortality, and recurrent pneumonia respectively. We performed logistic regression analyses for the association between Igs and lung function values. Associations were adjusted for age, sex, smoking, comorbidities, and serum C-reactive protein. Results: We included 8,766 participants (median age 62.2 years, 57% women, median follow-up 9.8 years). Higher IgA (hazard ratio [HR]: 1.15; 95% confidence interval [95% CI]: 1.00-1.32) and IgG (HR: 1.13; 95% CI: 1.06-1.19) were associated with an increased pneumonia risk. Higher IgG was associated with an increased risk of pneumonia-related mortality (HR: 1.08; 95% CI: 1.01-1.16) and recurrent pneumonia (incidence rate ratio: 1.04; 95% CI: 1.00-1.09). Higher IgA and IgG were also associated with lower forced expiratory volume in one second (FEV1), lower forced vital capacity (FVC), and an increased odds of preserved ratio impaired spirometry (PRISm, i.e. FEV1 <80% and FEV1/FVC ratio ≥70%). No association was seen with an obstructive spirometry pattern. Discussion: Higher serum IgA and IgG levels were associated with pneumonia, pneumonia-related mortality, and PRISm in middle-aged and older individuals from the general population. Future studies should validate our findings and elucidate underlying pathophysiology.