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Objective: Interstitial lung disease (ILD) is one of the most common pulmonary manifestations of rheumatoid arthritis (RA), but its prevalence has not been investigated in psoriatic arthritis (PsA). The role of methotrexate (MTX) in ILD development remains under debate. This study (1) compares the incidences of ILD in patients with RA or PsA initiating a first biologic disease-modifying antirheumatic drug (bDMARD) to that in the general population, and (2) investigates the role of MTX comedication on ILD incidence., Methods: Patients were identified in 5 rheumatology registries. Demographics, MTX use, and disease activity were retrieved. Matched subjects from the general population were available from 4 countries. Incidence of ILD during follow-up of up to 5 years was assessed through national patient registries. Subjects with prior ILD were excluded. Adjusted hazard ratios (HRs) were calculated for ILD incidence in patients vs the general population, and for MTX users vs nonusers., Results: During follow-up of 29,478 patients with RA and 10,919 patients with PsA initiating a first bDMARD and 362,087 population subjects, 225, 23, and 251 cases of ILD were identified, respectively. HRs for ILD (vs population subjects) were 9.7 (95% CI 7.97-11.91) in RA and 4.4 (95% CI 2.83-6.97) in PsA. HRs for ILD with MTX comedication (vs nonuse) were 1.0 (95% CI 0.72-1.25) in RA and 0.9 (95% CI 0.38-2.05) in PsA., Conclusion: Among patients with RA and PsA initiating a bDMARD, the risk of ILD was higher than in the general population, and was highest in RA. MTX comedication was not a risk determinant for ILD., (Copyright © 2024 by the Journal of Rheumatology.)

A deeper understanding of the molecular processes underlying late-onset Alzheimer's disease (LOAD) could aid in biomarker and drug target discovery. Using high-throughput serum proteomics in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik Study (AGES) cohort of 5,127 older Icelandic adults (mean age, 76.6 ± 5.6 years), we identified 303 proteins associated with incident LOAD over a median follow-up of 12.8 years. Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status, were implicated in neuronal processes and overlapped with LOAD protein signatures in brain and cerebrospinal fluid. We identified 17 proteins whose associations with LOAD were strongly dependent on APOE-ε4 carrier status, with mostly consistent associations in cerebrospinal fluid. Remarkably, four of these proteins (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated due to LOAD, a finding replicated in external cohorts and possibly reflecting a response to disease onset. These findings highlight dysregulated pathways at the preclinical stages of LOAD, including those both independent of and dependent on APOE-ε4 status., (© 2024. The Author(s).)

Background: Impact of Merkel cell polyomavirus (MCPyV) associated Merkel cell carcinoma (MCC) has not been assessed in the Icelandic population, nor in a whole population elsewhere., Objectives: The primary objective was to assess trends in the incidence of MCC in Iceland and the association with MCPyV. Secondary objectives aimed to analyze MCC outcomes., Methods: In this retrospective cohort study, patients diagnosed with MCC between 1981 and 2021 were identified from the Icelandic Cancer Registry. Patients were separated into 2 groups based on MCPyV immunochemistry staining. Age-standardized incidence was calculated and Joinpoint analysis was used to assess incidence trends. A Cox proportional hazards model was used to assess survival differences between the 2 groups., Results: Overall incidence of MCC increased from 0.015 to 0.26 per 100,000 persons, though the incidence of MCPyV positive cases recently decreased while negative cases increased. MCPyV negative tumors were associated with sun exposure ( P  < .01), a history of keratinocyte carcinoma, smaller tumor size, and lower overall survival., Limitations: Even with population-level data, comprehensively investigating associations with MCC is difficult due to its rarity., Conclusion: MCPyV negative MCC tumors were associated with lower survival despite smaller tumor size. Thus, MCPyV status could be an important prognostic biomarker., Competing Interests: None disclosed., (© 2024 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

Background: A decline in forced expiratory volume (FEV1) is a hallmark of respiratory diseases that are an important cause of morbidity among the elderly. While some data exist on biomarkers that are related to FEV1, we sought to do a systematic analysis of causal relations of biomarkers with FEV1., Methods: Data from the population-based AGES-Reykjavik study were used. Serum proteomic measurements were done using 4782 DNA aptamers (SOMAmers). Data from 1479 participants with spirometric data were used to assess the association of SOMAmer measurements with FEV1 using linear regression. Bi-directional two-sample Mendelian randomisation (MR) analyses were done to assess causal relations of observationally associated SOMAmers with FEV1, using genotype and SOMAmer data from 5368 AGES-Reykjavik participants and genetic associations with FEV1 from a publicly available GWAS (n = 400,102)., Results: In observational analyses, 530 SOMAmers were associated with FEV1 after multiple testing adjustment (FDR < 0.05). The most significant were Retinoic Acid Receptor Responder 2 (RARRES2), R-Spondin 4 (RSPO4) and Alkaline Phosphatase, Placental Like 2 (ALPPL2). Of the 257 SOMAmers with genetic instruments available, eight were associated with FEV1 in MR analyses. Three were directionally consistent with the observational estimate, Thrombospondin 2 (THBS2), Endoplasmic Reticulum Oxidoreductase 1 Beta (ERO1B) and Apolipoprotein M (APOM). THBS2 was further supported by a colocalization analysis. Analyses in the reverse direction, testing whether changes in SOMAmer levels were caused by changes in FEV1, were performed but no significant associations were found after multiple testing adjustments., Conclusions: In summary, this large scale proteogenomic analyses of FEV1 reveals circulating protein markers of FEV1, as well as several proteins with potential causality to lung function., (© 2024. The Author(s).)

Aim: To examine the ability of serum proteins in predicting future heart failure (HF) events, including HF with reduced or preserved ejection fraction (HFrEF or HFpEF), in relation to event time, and with or without considering established HF-associated clinical variables., Methods and Results: In the prospective population-based Age, Gene/Environment Susceptibility Reykjavik Study (AGES-RS), 440 individuals developed HF after their first visit with a median follow-up of 5.45 years. Among them, 167 were diagnosed with HFrEF and 188 with HFpEF. A least absolute shrinkage and selection operator regression model with non-parametric bootstrap were used to select predictors from an analysis of 4782 serum proteins, and several pre-established clinical parameters linked to HF. A subset of 8-10 distinct or overlapping serum proteins predicted different future HF outcomes, and C-statistics were used to assess discrimination, revealing proteins combined with a C-index of 0.80 for all incident HF, 0.78 and 0.80 for incident HFpEF or HFrEF, respectively. In the AGES-RS, protein panels alone encompassed the risk contained in the clinical information and improved the performance characteristics of prediction models based on N-terminal pro-B-type natriuretic peptide and clinical risk factors. Finally, the protein predictors performed particularly well close to the time of an HF event, an outcome that was replicated in the Cardiovascular Health Study., Conclusion: A small number of circulating proteins accurately predicted future HF in the AGES-RS cohort of older adults, and they alone encompass the risk information found in a collection of clinical data. Incident HF events were predicted up to 8 years, with predictor performance significantly improving for events occurring less than 1 year ahead, a finding replicated in an external cohort study., (© 2023 European Society of Cardiology.)

Aims: Atrial fibrillation (AF) is associated with high risk of comorbidities and mortality. Our aim was to examine causal and predictive relationships between 4137 serum proteins and incident AF in the prospective population-based Age, Gene/Environment Susceptibility-Reykjavik (AGES-Reykjavik) study., Methods and Results: The study included 4765 participants, of whom 1172 developed AF. Cox proportional hazards regression models were fitted for 4137 baseline protein measurements adjusting for known risk factors. Protein associations were tested for replication in the Cardiovascular Health Study (CHS). Causal relationships were examined in a bidirectional, two-sample Mendelian randomization analysis. The time-dependent area under the receiver operating characteristic curve (AUC)-statistic was examined as protein levels and an AF-polygenic risk score (PRS) were added to clinical risk models. The proteomic signature of incident AF consisted of 76 proteins, of which 63 (83%) were novel and 29 (38%) were replicated in CHS. The signature included both N-terminal prohormone of brain natriuretic peptide (NT-proBNP)-dependent (e.g. CHST15, ATP1B1, and SVEP1) and independent components (e.g. ASPN, AKR1B, and LAMA1/LAMB1/LAMC1). Nine causal candidates were identified (TAGLN, WARS, CHST15, CHMP3, COL15A1, DUSP13, MANBA, QSOX2, and SRL). The reverse causal analysis suggested that most AF-associated proteins were affected by the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide improved the prediction of incident AF events close to baseline with further improvements gained by the AF-PRS at all time points., Conclusion: The AF proteomic signature includes biologically relevant proteins, some of which may be causal. It mainly reflects an NT-proBNP-dependent consequence of the genetic liability to AF. N-terminal prohormone of brain natriuretic peptide is a promising marker for incident AF in the short term, but risk assessment incorporating a PRS may improve long-term risk assessment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Age-related macular degeneration (AMD) is one of the most common causes of visual impairment in the elderly, with a complex and still poorly understood etiology. Whole-genome association studies have discovered 34 genomic regions associated with AMD. However, the genes and cognate proteins that mediate the risk, are largely unknown. In the current study, we integrate levels of 4782 human serum proteins with all genetic risk loci for AMD in a large population-based study of the elderly, revealing many proteins and pathways linked to the disease. Serum proteins are also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study identifies several proteins that are causally related to the disease and are directionally consistent with the observational estimates. In this work, we present a robust and unique framework for elucidating the pathobiology of AMD., (© 2022. The Author(s).)

Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases., (© 2022. The Author(s).)

Background: Psoriatic arthritis mutilans (PAM) is the most severe phenotype of psoriatic arthritis (PsA)., Purpose: To describe the radiological features in PAM and explore whether existing scoring systems for radiological damage in psoriatic arthritis are applicable for PAM., Material and Methods: Radiographs were scored according to the modified Sharp-van der Heijde (mSvdH) and the Psoriatic Arthritis Ratingen Score (PARS) systems for PsA., Results: At inclusion, 55 PAM patients (49% women, mean age 58 ± 12 years) had conventional radiographs of both hands and feet. A total of 869 PAM joints were detected and 193 joints with ankylosis. The mean total mSvdH score was 213.7 ± 137.8 (41% of maximum) with a higher score for hands than for feet: 136.6 ± 90.1 vs. 79.1 ± 60.9. However, the total score was relatively higher in the feet than in the hands when compared to the highest possible scoring (47% vs. 38% of max). The mean total PARS score was 126.3 ± 79.6 (35% of max). Scoring for joint destruction was higher than for proliferation (22% vs. 11% of max). Strong correlation was found between mSvdH and PARS (r 2  = 0.913). A significant correlation was found between scoring and duration of arthritis and the Health Assessment Questionnaire. History of smoking, BMI, and gender did not influence the scoring values., Conclusions: The two scoring systems studied may not be ideal to indicate progression of PAM in advanced disease since they reach ceiling effects rather early. Therefore, reporting early signs suggestive of PAM, e.g. signs of pencil-in-cup deformities or osteolysis, is crucial. This would reveal the presence of PAM and might lead to improved treatment in order to minimize joint damage., (© The Foundation Acta Radiologica 2020.)