Will 14-3-3η Be a New Diagnostic and Prognostic Biomarker in Rheumatoid Arthritis? A Prospective Study of Its Utility in Early Diagnosis and Response to Treatment

Aim of the Work. To evaluate diagnostic and prognostic capacity of 14-3-3η protein in early RA, investigate its pathogenic and theragnostic role, and find its correlations with disease activity and severity in established RA patients. Subjects and Methods: 80 patients with early RA, 80 patients with established RA, and 80 healthy controls were included in this study. ROC curve analysis of RF, ACCP, and 14-3-3η in early disease was conducted, and serum levels of 14-3-3η were assessed by ELISA and reassessed in early RA patients 6 months after anti-TNF therapy. Correlation of 14-3-3η with parameters of disease activity and severity was analyzed. Results. Serum14-3-3η levels were significantly higher in all RA patients than in controls P < 0.001 , its sensitivity was 86.7% and 88.3% in early and established RA patients with a significant difference with RF and ACCP at early disease, and the specificity was 96.7%. There was a significant reduction of 14-3-3η levels 6 months after treatment in the first group p = 0.004 , and there was a significant positive correlation between serum 14-3-3η levels and parameters of disease activity and severity. Conclusion. 14-3-3η could be a novel, potent, and efficacious diagnostic, and prognostic marker for RA with high sensitivity, that may become a new therapeutic target for RA.

Factors Associated with Pediatric In-Hospital Recurrent Cardiac Arrest

The objective of this article was to identify demographic and clinical factors associated with early recurrent arrest (RA) (<48 hours) and late RA (≥48 hours) among pediatric inpatients following an initial in-hospital cardiac arrest. A retrospective cohort study of inpatients was performed in a free-standing academic quaternary care children's hospital. All inpatients were <18 years old with a cardiac arrest event requiring ≥1 minute of cardiopulmonary resuscitation with the return of spontaneous circulation sustained for ≥20 minutes at Seattle Children's Hospital from February 1, 2012 to September 18, 2019. Of the 237 included patients, 20 (8%) patients had an early RA and 30 (13%) had a late RA. Older age and severe pre-arrest acidosis were associated with a higher risk of early RA, odds ratios (OR) 1.2 (95% confidence interval [CI] 1.1–1.3) per additional year and 4.6 (95% CI 1.2–18.1), respectively. Pre-arrest organ dysfunction was also associated with a higher risk of early RA with an OR of 3.3 (95% CI 1.1–9.4) for respiratory dysfunction, OR 1.4 (95% CI 1.1–1.9) for each additional dysfunctional organ system, and OR 1.1 (95% CI 1–1.2) for every one-point increase in PELOD2 score. The neonatal illness category was associated with a lower risk of late RA, OR 0.3 (95% CI 0.1–0.97), and severe post-arrest acidosis was associated with a higher risk of late RA, OR 4.2 (95% CI 1.1–15). Several demographic and clinical factors offer some ability to identify children who sustain a recurrent cardiac arrest, offering a potential opportunity for intervention to prevent early recurrent arrest.

Study the Role and Value of Antibodies to Cyclic Citrullinated Peptide in Early Rheumatoid Arthritis

Research relevance: prognosis of early rheumatoid arthritis (RA) course remains an unresolved problem, which dictates the need to identify new factors affecting the activity and course of the disease. Research objectives: it is assumed that the cause of immunopathological reactions in early RA is a dysregulation of the immune response resulting from an imbalance in the function of T- and B-lymphocytes, namely, the immunodeficiency of the T-lymphocyte system, which leads to uncontrolled synthesis of immunoglobulins by B-lymphocytes, in particular, organo- and tissue-specific antibodies. Research methods: this article analyzes occurrence frequency, pathogenetic and clinical significance of antibodies to cyclic citrullinated peptide (ACCP) in early rheumatoid arthritis (RA). Research results: in this work, in patients with early RA, the detection rate of ACCP was 68.8%, the frequency of detection of ACCP was higher than that of rheumatoid factor. Conclusions: in the examined patients with early RA, the presence of ACCP did not depend on gender and age but depended on the duration of the disease.

Evolution of anti-modified protein antibody responses can be driven by consecutive exposure to different post-translational modifications

Background Besides anti-citrullinated protein antibodies (ACPA), rheumatoid arthritis patients (RA) often display autoantibody reactivities against other post-translationally modified (PTM) proteins, more specifically carbamylated and acetylated proteins. Immunizing mice with one particular PTM results in an anti-modified protein antibody (AMPA) response recognizing different PTM-antigens. Furthermore, human AMPA, isolated based on their reactivity to one PTM, cross-react with other PTMs. However, it is unclear whether the AMPA-reactivity profile is “fixed” in time or whether consecutive exposure to different PTMs can shape the evolving AMPA response towards a particular PTM. Methods Longitudinally collected serum samples of 8 human individuals at risk of RA and 5 with early RA were tested with ELISA, and titers were analyzed to investigate the evolution of the AMPA responses over time. Mice (13 per immunization group in total) were immunized with acetylated (or carbamylated) protein (ovalbumin) twice or cross-immunized with an acetylated and then a carbamylated protein (or vice versa) and their serum was analyzed for AMPA responses. Results Human data illustrated dynamic changes in AMPA-reactivity profiles in both individuals at risk of RA and in early RA patients. Mice immunized with either solely acetylated or carbamylated ovalbumin (AcOVA or CaOVA) developed reactivity against both acetylated and carbamylated antigens. Irrespective of the PTM-antigen used for the first immunization, a booster immunization with an antigen bearing the other PTM resulted in increased titers to the second/booster PTM. Furthermore, cross-immunization skewed the overall AMPA-response profile towards a relatively higher reactivity against the “booster” PTM. Conclusions The relationship between different reactivities within the AMPA response is dynamic. The initial exposure to a PTM-antigen induces cross-reactive responses that can be boosted by an antigen bearing this or other PTMs, indicating the formation of cross-reactive immunological memory. Upon subsequent exposure to an antigen bearing another type of PTM, the overall reactivity pattern can be skewed towards better recognition of the later encountered PTM. These data might explain temporal differences in the AMPA-response profile and point to the possibility that the PTM responsible for the initiation of the AMPA response may differ from the PTM predominantly recognized later in time.

Comparing longitudinal patient-reported outcome measures between Swedish patients with recent-onset systemic lupus erythematosus and early rheumatoid arthritis

The onset of rheumatic disease affects each patient differently and may impact quality of life with progression. We investigated the relationship between patient-reported outcome measure (PROM) scores and organ damage in patients with recent-onset systemic lupus erythematosus (SLE) and those with early rheumatoid arthritis (RA). Patients with recent-onset SLE without prior organ damage from the Clinical Lupus Register in Northeastern Gothia and patients with early RA from the observational 2nd Timely Interventions in Early RA study, Sweden, were included. Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (SDI) was used to assess organ damage. PROM (visual analog scale [VAS]: pain, fatigue, well-being, Health Assessment Questionnaire, and EQ-5D-3L) scores were captured at months 0, 6, 12, 24, 36, 48, and 60 after diagnosis. Statistical tests included Pearson correlation coefficients and t-tests. Forty-one patients with recent-onset SLE and 522 with early RA were included. Numerical differences were seen in age and sex. PROMs were worse for patients with RA versus SLE but improved by month 6 following diagnosis, while SLE PROMs remained stable. The incidence of organ damage in SLE was 13.6 per 100 patient-years. SDI significantly correlated with EQ-5D-3L (− 0.48, P = 0.003), VAS fatigue (0.44, P = 0.009), and well-being (0.41, P = 0.01) at month 24. As illustrated, the complexity of disease burden in patients with SLE is clear and may result from disease-related multiorgan system effects and slower symptom resolution compared with RA. This underscores the need for improved multiprofessional interventions to manage all aspects of SLE. Key Points• We observed an evident discrepancy in patient-reported outcome measures (PROMs) between patients with recent-onset SLE and early RA.• Despite differences in PROMs between patients with recent-onset SLE and early RA, both groups had prominent self-reported disability during the study period.• PROM scores for patients with RA were generally worse than those with SLE but improved by month 6, whereas PROM scores for patients with SLE remained stable over time.• Our findings underline the need of new therapeutic options and interventions for SLE disease management, including pharmacologic and multiprofessional aspects.

A Serum Biomarker Panel of exomiR-451a, exomiR-25-3p and Soluble TWEAK for Early Diagnosis of Rheumatoid Arthritis

BackgroundThe etiology of rheumatoid arthritis (RA) remains poorly understood. Early and accurate diagnosis still difficult to achieve. Inflammatory related molecules released into the circulation such cytokines and exosome-derived microRNAs (exomiRNAs) could be good candidates for early diagnosis of autoimmune diseases. We sought to discover a serum biomarker panel for the early detection of RA based on exomiRNAs and inflammatory markers.MethodsA 179 miRNAs-microarray panel was analyzed in a pilot study (4 early RA and 4 controls). Validation of deregulated exomiRNAs was performed in a larger cohort (24 patients with early RA and 24 controls). miRNet software was used to predict exomiRNA gene-targets interactions. Potentially altered pathways were analyzed by Reactome pathway database search. STRING database was used to predict protein-protein interaction networks. Enzyme-linked immunosorbent assay was used to measure serum levels of sTWEAK and sCD163. Signature biomarker candidates were statistical analyzed.ResultsWe detected 11 differentially expressed exomiRNAs in early RA pilot study. Validation analysis revealed that 6/11 exomiRNAs showed strong agreement with the pilot microarray data (exomiR-144-3p, -25-3p, -15a-5p, -451a, -107 and -185-5p). sTWEAK and sCD163 biomarkers were significantly elevated in the serum of patients with early RA. Receiver operating characteristic (ROC) analysis showed that the best panel to diagnose early RA contained exomiR-451a, exomiR-25-3p and sTWEAK, and could correctly classify 95.6% of patients, with an area under the ROC curve of 0.983 and with 100% specificity and 85.7% sensitivity. The YWHAB gene was identified as a common target of the putative miRNA-regulated pathways.ConclusionA novel serum biomarker panel composed of exomiR-451a, exomiR-25-3p and serum levels of sTWEAK may have use in the early clinical diagnosis of RA. A new predicted exomiRNA-target gene YHWAB has been identified and may have a relevant role in the development of RA.

C-Reactive Protein-to-Albumin Ratio: A Novel Inflammatory Marker and Disease Activity Sign in Early Rheumatoid Arthritis

Objective A novel inflammation-based score, C-reactive protein (CRP)-to-albumin ratio (CAR), has been shown to have an association with the inflammatory status in several diseases. We aimed to analyse the association between CAR and disease activity in patients with early rheumatoid arthritis (RA) and to determine the cut-off value of CAR in early and established RA. Methods A total of 177 patients with RA and 111 age and gender-matched healthy controls were included in this study. Cases with a disease duration of less than 1 year were classified as early RA. Serum albumin, CRP, erythrocyte sedimentation rate (ESR), Disease Activity Score-28 (DAS-28-ESR), Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire (HAQ) scores were recorded. Results CAR was 2.44 (0.21–30.83) in the RA group and 0.45 (0.21–10.47) in the control group (p<0.001). Eighty-seven (49.15%) of the RA cases were classified as early RA. The analyses indicated that the ESR, CRP and CAR values were higher in patients with early RA than in those with established RA and controls. CAR was correlated with albumin, CRP, ESH, DAS-28 and HAQ scores in both early RA and established RA groups. The receiver operating characteristic curves revealed a CAR cut-off value of 2.67 (80% sensitivity and 85% specificity) and 1.63 (77% sensitivity and 72% specificity) for the prediction of early and established RA, respectively. Conclusion CAR, a formulated ratio, has been described as a predictor for disease activity in patients with early RA as well as in those with established RA. However, CAR has higher sensitivity and specificity for early RA than for established RA.

Treatment response and several patient-reported outcomes are early determinants of future self-efficacy in rheumatoid arthritis

Background Self-efficacy, or patients’ confidence in their ability to control disease and its consequences, was recently prioritised in EULAR recommendations for inflammatory arthritis self-management strategies. However, it remains unclear which factors influence self-efficacy in early rheumatoid arthritis (RA). Methods Data were analysed from the 2-year RCT Care in early RA (CareRA), which studied remission-induction treatment regimens for early RA. Participants completed the Arthritis Self-Efficacy Scale (ASES), Short-Form 36 (SF-36), Revised Illness Perception Questionnaire (IPQ-R), Utrecht Coping List (UCL), RAQoL and Health Assessment Questionnaire (HAQ). Depending on time to first remission (DAS28-CRP < 2.6) and persistence of remission, treatment response was defined as persistent response, secondary failure, delayed response, late response or non-response. The association between ASES scores and clinical/psychosocial factors was explored with Spearman correlation and multivariate linear mixed models. Baseline predictors of week 104 ASES were identified with exploratory linear regression followed by multiple regression of significant predictors adjusted for DAS28-CRP, HAQ, treatment arm, treatment response, cumulative CRP/SJC28 and demographic/serologic confounders. Results All 379 patients had a recent diagnosis of RA and were DMARD-naïve at study initiation. Most patients were women (69%) and RF/ACPA-positive (66%), and the mean (SD) age was 52 (13) years. For all tested outcome measures, better perceived health correlated with higher self-efficacy. While patient-reported factors (HAQ, SF-36, RAQoL, IPQ-R, pain, fatigue and patient’s global assessment) showed moderate/strong correlations with ASES scores, correlations with physician-reported factors (physician’s global assessment, SJC28), TJC28 and DAS28-CRP were weak. Only more favourable outcomes on patient-reported factors and DAS28-CRP were associated with higher ASES scores at each time point. An earlier, persistent treatment response predicted higher ASES scores at both weeks 52 and 104. Significant baseline predictors of week 104 ASES included HAQ; SF-36 mental component score, vitality, mental health and role emotional; IPQ-R illness coherence, treatment control, emotional representations and consequences; UCL Passive reacting; and the RAQoL. Conclusions Patient-reported outcomes and treatment response were early determinants of long-term self-efficacy in an early RA trial. These results provide further relevance for the window of opportunity in an early treat-to-target strategy and could help to timely identify patients who might benefit from self-management interventions. Trial registration EudraCT 2008-007225-39

‘More than just chitchat’: a qualitative study concerning the need and potential format of a peer mentor programme for patients with early rheumatoid arthritis

BackgroundPatients recently diagnosed with rheumatoid arthritis (RA) have specific educational and supportive needs. These could partly be addressed with mentoring by other patients living with RA. This qualitative study explores stakeholder perceptions towards peer mentoring in early RA care.MethodsTwo focus groups with patients with early RA (n=10), one with patient organisation representatives (n=5), one with rheumatologists (n=8) and one with rheumatology nurses (n=5) were held. Two patient research partners supported analysis and interpretation.ResultsFour overarching themes were found: added value, experience with peer mentoring, concerns and need in daily care. Patients and patient organisation representatives confirmed the potential of peer mentoring especially regarding sensitive topics not easily discussed with professionals. Patients felt it could provide additional understanding and recognition. Nurses and rheumatologists were less convinced of the added value of peer mentoring because patients never mentioned it and they were concerned about the loss of control over correct information provision. The need for peer mentoring was perceived as person and disease phase-dependent and should therefore be optional, rather than a care standard. The requirements for a peer mentorship programme remained challenging to define for stakeholders. However, all expressed the need for supervision by healthcare professionals and that peer mentors should be carefully selected, educated and matched to newly diagnosed patients.ConclusionPeer mentoring and its implementation remain vague concepts, especially for healthcare providers. However, patients are interested in mentoring by peers, and the current results may support in effectively implementing such programmes early in the disease.

The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual “window of treatment success” in RA patients

Background There is a need for biomarker to identify patients “at risk” for rheumatoid arthritis (risk-RA) and to better predict the therapeutic response and in this study we tested the hypothesis that novel native and citrullinated heterogeneous nuclear ribonucleoprotein (hnRNP)-DL autoantibodies could be possible biomarkers. Methods Using protein macroarray and ELISA, epitope recognition against hnRNP-DL was analysed in sera from different developed RA disease and diagnosed SLE patients. Toll-like receptor (TLR) 7/9 and myeloid differentiation primary response gene 88 (MyD88)-dependency were studied in sera from murine disease models. HnRNP-DL expression in cultivated cells and synovial tissue was analysed by indirect immunofluorescence, immunoblot and immunohistochemistry. Results HnRNP-DL was highly expressed in stress granules, citrullinated in the rheumatoid joint and targeted by autoantibodies either as native or citrullinated proteins in patient subsets with different developed RA disease. Structural citrullination dependent epitopes (SCEs) of hnRNP-DL were detected in 58% of the SLE patients although 98% of these sera were α-CCP-2-negative. To obtain a specific citrullinated signal value, we subtracted the native antibody value from the citrullinated signal. The citrullinated/native index of autoantibodies against hnRNP-DL (CNDL-Index) was identified as a new value for an “individual window of treatment success” in early RA and for the detection of RF IgM/α-CCP-2 seronegative RA patients (24–46%). Negative CNDL-index was found in SLE patients, risk-RA and early RA cohorts such as EIRA where the majority of these patients are DAS28-responders to methotrexate (MTX) treatment (87%). High positive CNDL-values were associated with more severe RA, shared epitope and parenchymal changes in the lung. Specifically, native α-hnRNP-DL is TLR7/9-dependent, associated with pain and ROC analysis revealed an association to initial MTX or etanercept treatment response, especially in seronegative RA patients. Conclusion CNDL-index defines people at risk to develop RA and the “window of treatment success” thereby closing the sensitivity gap in RA.