Precision health (PH) applied to autoimmune disease will need paradigm shifts in the use and application of autoantibodies and other biomarkers. For example, autoantibodies combined with other multi-analyte “omic” profiles will form the basis of disease prediction allowing for earlier intervention linked to disease prevention strategies, as well as earlier, effective and personalized interventions for established disease. As medical intervention moves to disease prediction and a model of “intent to PREVENT,” diagnostics will include an early symptom/risk-based, as opposed to a disease-based approach. Newer diagnostic platforms that utilize emerging megatrends such as deep learning and artificial intelligence and close the gaps in autoantibody diagnostics will benefit from paradigm shifts thereby facilitating the PH agenda.

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IntroductionThe diagnosis of rheumatoid arthritis (RA) is based on a combined approach that includes serological markers such as rheumatoid factor (RF) and anti-citrullinated peptide/protein antibodies (ACPA). The goal of this study was to evaluate the clinical performance of several RF and ACPA immunoassays for the diagnosis of RA, as well as the diagnostic value of a combinatory approach with these markers.MethodsThe study cohort included 1,655 patients from the Swiss Clinical Quality Management registry with sera from 968 patients with RA and 687 disease controls, including patients with axial spondyloarthritis (n = 450) and psoriatic arthritis (n = 237). ACPA were determined by anti-CCP2 IgG enzyme-linked immunosorbent assay (ELISA), QUANTA Flash® CCP3 IgG [chemiluminescent immunoassay (CIA)], and QUANTA Lite® CCP3 IgG ELISA. RF was determined by ELISA (QUANTA Lite® RF IgM, RF IgA, and RF IgG) and with two research use only CIAs (QUANTA Flash® RF IgM and RF IgA).ResultsAll three ACPA assays showed good discrimination between RA patients and controls and good clinical performance. Overall, CCP3 performed better than CCP2. More pronounced differences were observed between the RF assays. We observed that CIA platforms for both RF IgM and RF IgA showed better performance than the ELISA platforms. Excellent and good total agreements were found between ELISA and CIA for CCP3 (total agreement 95.3%, kappa = 0.90), and between CCP2 and CCP3 ELISA (total agreement 86.6%, kappa = 0.73), respectively. RF IgM CIA and ELISA had a good qualitative agreement (86.5%, kappa = 0.73); RF IgA CIA and ELISA showed a moderate total agreement (78.5%, kappa = 0.53). When combinatory analyses were performed, the likelihood of RA increased with dual positivity and triple positivity and combining different markers resulted in higher odds ratio than the individual markers in all cases.ConclusionACPA and RF showed good clinical performance in this large Swiss cohort of RA patients and controls. Overall, the performance of CCP3 was superior to CCP2. The combination of these biomarkers in an interval model represents a potential tool for the diagnosis of RA patients.

Objectives To analyse the predictive value of anti-carbamylated protein (anti-CarP) and anti-peptidyl-arginine deiminase type-3 (anti-PAD3) antibodies, alone or in combination with rheumatoid factors (RFs) and anti-citrullinated protein antibodies (ACPA), to identify patients at high risk of developing severe rheumatoid arthritis (RA) outcomes. Methods Patients within the « Swiss Clinical Quality Management » registry with a biobank sample were tested for RFs, ACPA, anti-CarP, and anti-PAD3 antibodies. We examined the association of each autoantibody with DAS28, HAQ and radiographic damage (Ratingen) at baseline and longitudinally. Results Analyses included 851 established RA patients and 516 disease controls [axial spondyloarthritis (axSpA = 320) and psoriatic arthritis (PsA = 196)]. Anti-CarP and anti-PAD3 antibodies were respectively present in 22.4% and 10.7% of the whole RA population, and in 13.2% and 3.8% of the RF and ACPA double seronegative patients. At baseline, RA patients with anti-PAD3 had higher DAS28 (4.2 vs 3.7; p = 0.005) and significantly more radiographic damage (14.9 vs 8.8; p = 0.02) than anti-PAD3 negative patients. In ACPA negative subgroup, baseline Ratingen scores were significantly higher in anti-PAD3 positive patients (p = 0.01). The combination of anti-PAD3, RF IgM, and ACPA was associated with significantly higher baseline radiographic scores than the double seropositive group (p = 0.04). The presence of any two of the previous autoantibodies was associated with significantly greater radiographic progression over 10 years than if all were absent (p = 0.02). There were no differences on RA outcome measures with regards to anti-CarP. Conclusions Anti-PAD3 antibodies are associated with higher disease activity and joint damage scores in RA patients.

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Objectives Rheumatoid arthritis (RA) is a chronic inflammatory disease in which possible interstitial lung disease (ILD) is an extra-articular manifestation that carries significant morbidity and mortality. Rheumatoid Factors (RF) and anti-citrullinated protein antibodies (ACPA) are included in the RA classification criteria but prognostic and diagnostic biomarkers for disease endotyping and RA-ILD are lacking. Anti-protein arginine deiminase antibodies (anti-PAD) are a novel class of autoantibodies identified in RA. This study aimed to assess clinical features, ACPA, and anti-PAD antibodies in RA patients with articular involvement and ILD. Methods We retrospectively collected joint erosions, space narrowing, clinical features, and lung involvement of a cohort of seventy-one patients fulfilling the 2010 ACR/EULAR RA classification criteria. Serum samples from these patients were tested for ACPA IgG (QUANTA Flash CCP3), and anti-PAD3 and anti-PAD4 IgG, measured with novel assays based on a particle-based multi-analyte technology (PMAT). Results Anti-PAD4 antibodies were significantly associated with radiographic injury (p= 0.027) and erosions (p= 0.02). Similarly, ACPA levels were associated with erosive disease (p= 0.014). Anti-PAD3/4 double positive patients displayed more joint erosions than patients with anti-PAD4 antibodies only or negative for both (p= 0.014 and p= 0.037, respectively). RA-ILD (15.5%, 11/71 patients) was associated with older age (p< 0.001), shorter disease duration (p= 0.045) and less erosive disease (p= 0.0063). ACPA were elevated in RA-ILD, while anti-PAD4 were negatively associated (p= 0.043). Conclusion Anti-PAD4 and anti-PAD3 antibodies identify RA-patient with higher radiographic injury and bone erosions. In our cohort, ILD is associated with lower radiographic and erosive damage, as well as low levels of anti-PAD4 antibodies.