Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.

Comparison of diagnostic spectrum between inflammation of unknown origin and fever of unknown origin: A systematic review and meta-analysis.

BACKGROUND: Patients with inflammation of unknown origin (IUO) and fever of unknown origin (FUO) are commonly considered a single population. Differences in underlying causes between both groups may steer the diagnostic work-up. METHODS: PubMed, Embase, Web of Science, and ClinicalTrials.gov were searched from July 2009 through December 2023. Studies including both FUO and IUO patients with a sample size of ≥20 were considered. The primary outcome was the difference in the rate of patients affected by predefined diagnostic categories according to meeting FUO or IUO criteria. Data were pooled using random-effects models. RESULTS: A total of 8 studies met criteria for inclusion, with a total of 1452 patients (466 with IUO and 986 with FUO). The median rate of IUO patients among the included studies was 32 % (range 25-39 %). Patients with IUO had a lower likelihood of infection (OR 0.59 [95 % CI; 0.36-0.95]; I2 0 %). There were no significant differences in the rate of noninfectious inflammatory disorders, malignancies, miscellaneous disorders, or remaining undiagnosed. Comparison of diagnostic subgroups revealed that IUO patients were less likely to have systemic autoinflammatory disorders (OR 0.17 [95 % CI, 0.05-0.58]; I2 42 %) and more likely to have vasculitis (OR 2.04 [95 % CI, 1.23-3.38]; I2 21 %) and rheumatoid arthritis or spondylarthritis (OR 3.52 [95 % CI, 1.16-10.69]; I2 0 %). CONCLUSION: Based on our findings, there is little reason to assume that FUO and IUO patients would benefit from a different initial diagnostic approach.

Detection of pre-existing neutralizing antibodies against Ad26 in HIV-1-infected individuals not responding to the Ad26.COV2.S vaccine.

PURPOSE: The Ad26.COV2.S vaccine is a replication-incompetent human adenovirus type 26 vector encoding the SARS-CoV-2 spike protein. In a phase 1-2a trial, a single dose of Ad26.COV2.S induced SARS-CoV-2 spike-specific antibodies in ≥ 96% of healthy adults. To investigate vaccine immunogenicity in HIV-1-infection, we measured SARS-CoV-2 spike-specific antibodies in Ad26.COV2.S vaccinated HIV-1-infected patients and analyzed the presence of pre-existing Ad26 neutralizing antibodies. METHODS: We included all Ad26.COV2.S vaccinated HIV-1-infected patients of Erlangen HIV cohort fulfilling all inclusion criteria. The study cohort consisted of 15 HIV-1-infected patients and three HIV-1-uninfected subjects who received the Ad26.COV2.S vaccine between April and November 2021. Pre-vaccination sera were collected between October 2014 and June 2021, post-vaccination sera between June and December 2021. Neutralizing antibodies towards Ad26 were determined by a FACS-based inhibition assay measuring the expression of SARS-CoV-2 spike and adenoviral proteins in HEK293T cells after in-vitro transduction with Ad26.COV2.S or the control ChAdOx1-S. RESULTS: Six out of 15 HIV-1-infected patients failed to develop SARS-CoV-2-specific antibodies and four patients developed weak antibody responses after vaccination with Ad26.COV2.S. Pre-vaccination sera of four of the six vaccine non-responders showed neutralizing activity towards Ad26.COV2.S but not toward the ChAdOx1-S vaccine at 1:50 dilution. After Ad26.COV2.S vaccination, 17 of the 18 subjects developed strong Ad26-neutralizing activity and only one of the 18 subjects showed neutralizing activity towards the ChAdOx1-S vaccine. CONCLUSION: Ad26.COV2.S vaccination showed a high failure rate in HIV-1-infected patients. Pre-existing immunity against Ad26 could be an important contributor to poor vaccine efficacy in a subgroup of patients.

Cinematic rendering in rheumatic diseases-Photorealistic depiction of pathologies improves disease understanding for patients.

Background: Patient education is crucial for successful chronic disease management. Current education material for rheumatic patients however rarely includes images of disease pathologies, limiting patients' disease understanding. Cinematic rendering (CR) is a new tool that allows segmentation of standard medical images (DICOMs) into pictures that illustrate disease pathologies in a photorealistic way. Thus CR has the potential to simplify and improve the explanation of disease pathologies, disease activity and disease consequences and could therefore be a valuable tool to effectively educate and inform patients about their rheumatic and musculoskeletal disease (RMD). Objectives: To examine the feasibility of creating photorealistic images using CR from RMD patients depicting typical rheumatic disease pathologies and, in a second step to investigate the patient-perceived educational potential of these photorealistic images in clinical routine. Methods: We selected conventional, high-resolution (HR) and positron emission tomography (PET) computed tomography (CT) images of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), and giant cell arteritis (GCA) that showed typical respective disease pathologies. These images were segmented using CR technique. In a prospective study, physicians used CR-enhanced and conventional original images to explain the depicted pathognomonic pathologies to patients with the respective rheumatic disease. Patients were then asked to complete a questionnaire evaluating the perceived usefulness of being presented with CR-enhanced images to better understand their underlying disease. Results: CR images were successfully generated from above mentioned CT methods. Pathologies such as bone erosions, bony spurs, bone loss, ankylosis, and PET-based inflammation could be visualized in photorealistic detail. A total of 79 patients (61% females) with rheumatic diseases (RA 29%, PsA 29%, axSpA 24%, GCA 18%) were interviewed and answered the quantitative questionnaire. Mean age was 55.4 ± 12.6 years. Irrespective of disease, all patients agreed or highly agreed that CR-based images help to improve disease understanding, should be shown at disease onset, provide a rationale to regularly take medication and would like to have access to their own CR-enhanced images. Conclusion: Conventional disease images can successfully be turned into photorealistic disease depictions using CR. Patients perceived CR images as a valuable addition to current patient education, enabling personalized disease education and potentially increased medication adherence.

Impact of Cytokine Inhibitor Therapy on the Prevalence, Seroconversion Rate, and Longevity of the Humoral Immune Response Against SARS-CoV-2 in an Unvaccinated Cohort.

OBJECTIVE: To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). METHODS: Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave. RESULTS: In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]). CONCLUSION: IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.