Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift

Deane, Kevin D.; Holers, V. Michael

doi:10.1002/art.41417

Cited by 147 publications

(109 citation statements)

References 78 publications

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“…The region of interest (ROI) in this study is indicated in the open black circle. (C) As illustrated, arthritis-induced joint pathology was assessed in this study, including cartilage, bone erosion, and osteoclast number (1,4), pannus formation (2), synovitis and cellular infiltration (3,5). The density of sympathetic nerves was evaluated using the ratelimiting enzyme for norepinephrine synthesis, tyrosine hydroxylase, as a marker for these nerves.…”

Section: Animal Sacrifice and Tissue Preparationmentioning

confidence: 99%

“…Rheumatoid arthritis (RA) afflicts about 1% of adults worldwide. RA is a debilitating chronic inflammatory autoimmune disease of the joints, with no cure and no strategy for prevention (1). In RA, inflammation, immune cell infiltration into the synovium of affected joints and circulating proinflammatory cytokines are characteristic features of disease.…”

Section: Introductionmentioning

confidence: 99%

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Driving β2- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis

et al. 2021

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ObjectiveHypersympathetic activity is prominent in rheumatoid arthritis, and major life stressors precede onset in ~80% of patients. These findings and others support a link between stress, the sympathetic nervous system and disease onset and progression. Here, we extend previous research by evaluating how selective peripherally acting α/β2-adrenergic drugs affect joint destruction in adjuvant-induced arthritis.MethodsComplete Freund’s adjuvant induced inflammatory arthritis in male Lewis rats. Controls received no treatment. Arthritic rats then received vehicle or twice-daily treatment with the α-adrenergic antagonist, phentolamine (0.5 mg/day) and the β2-adrenergic agonist, terbutaline (1200 µg/day, collectively named SH1293) from day (D) of disease onset (D12) through acute (D21) and severe disease (D28). Disease progression was assessed in the hind limbs using dorsoplantar widths, X-ray analysis, micro-computed tomography, and routine histology on D14, D21, and D28 post-immunization.ResultsOn D21, SH1293 significantly attenuated arthritis in the hind limbs, based on reduced lymphocytic infiltration, preservation of cartilage, and bone volume. Pannus formation and sympathetic nerve loss were not affected by SH1293. Bone area and osteoclast number revealed high- and low-treatment-responding groups. In high-responding rats, treatment with SH1293 significantly preserved bone area and decreased osteoclast number, data that correlated with drug-mediated joint preservation. SH1293 suppressed abnormal bone formation based on reduced production of osteophytes. On D28, the arthritic sparing effects of SH1293 on lymphocytic infiltration, cartilage and bone sparing were maintained at the expense of bone marrow adipocity. However, sympathetic nerves were retracted from the talocrural joint.Conclusion and SignificanceOur findings support a significant delay in early arthritis progression by treatment with SH1293. Targeting sympathetic neurotransmission may provide a strategy to slow disease progression.

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Section: Animal Sacrifice and Tissue Preparationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Driving β2- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis

et al. 2021

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“…Although not necessarily required for the development of RA, autoAbs can readily be found many years before the onset of symptomatic disease in the evolution model of RA [ 107 , 108 , 109 ]. During the presymptomatic phase of the disease, B cells undergo a series of selection, expansion, epitope spreading and antibody maturation processes [ 22 , 29 ], providing physicians an opportunity for early detection and prevention of the disease.…”

Section: Predictive Values Of Rf Acpa and Anti-carp Ab In The Diamentioning

confidence: 99%

From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis

Yang

Luo

et al. 2021

IJMS

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Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease mainly involving synovial inflammation and articular bone destruction. RA is a heterogeneous disease with diverse clinical presentations, prognoses and therapeutic responses. Following the first discovery of rheumatoid factors (RFs) 80 years ago, the identification of both anti-citrullinated protein antibodies (ACPAs) and anti-carbamylated protein antibodies (anti-CarP Abs) has greatly facilitated approaches toward RA, especially in the fields of early diagnosis and prognosis prediction of the disease. Although these antibodies share many common features and can function synergistically to promote disease progression, they differ mechanistically and have unique clinical relevance. Specifically, these three RA associating auto-antibodies (autoAbs) all precede the development of RA by years. However, while the current evidence suggests a synergic effect of RF and ACPA in predicting the development of RA and an erosive phenotype, controversies exist regarding the additive value of anti-CarP Abs. In the present review, we critically summarize the characteristics of these autoantibodies and focus on their distinct clinical applications in the early identification, clinical manifestations and prognosis prediction of RA. With the advancement of treatment options in the era of biologics, we also discuss the relevance of these autoantibodies in association with RA patient response to therapy.

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“…To effectively utilize the huge data sets that can now be generated through autoantibody and other biomarker analytics, machine learning and artificial intelligence (AI) in the setting of precision health (PH) are major drivers for biomarker use in clinical practice (2,(4)(5)(6). For example, autoantibodies combined with other multi-analyte "omic" profiles are now beginning to form the basis of predicting disease thus allowing for disease prevention strategies and earlier and effective personalized interventions for established disease (7)(8)(9)(10). As medical intervention continues to move toward disease prediction and a model of "intent to PREVENT" morbidity and mortality (11), futuristic diagnostics will take into consideration symptoms and risks, as opposed to an established disease and organ involvement approach.…”

Section: Overviewmentioning

confidence: 99%

Autoantibody Discovery, Assay Development and Adoption: Death Valley, the Sea of Survival and Beyond

et al. 2021

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Dating to the discovery of the Lupus Erythematosus (LE) cell in 1948, there has been a dramatic growth in the discovery of unique autoantibodies and their cognate targets, all of which has led to the availability and use of autoantibody testing for a broad spectrum of autoimmune diseases. Most studies of the sensitivity, specificity, commutability, and harmonization of autoantibody testing have focused on widely available, commercially developed and agency-certified autoantibody kits. However, this is only a small part of the spectrum of autoantibody tests that are provided through laboratories world-wide. This manuscript will review the wider spectrum of testing by exploring the innovation pathway that begins with autoantibody discovery followed by assessment of clinical relevance, accuracy, validation, and then consideration of regulatory requirements as an approved diagnostic test. Some tests are offered as “Research Use Only (RUO)”, some as “Laboratory Developed Tests (LDT)”, some enter Health Technology Assessment (HTA) pathways, while others are relegated to a “death valley” of autoantibody discovery and become “orphan” autoantibodies. Those that achieve regulatory approval are further threatened by the business world’s “Darwinian Sea of Survival”. As one example of the trappings of autoantibody progression or failure, it is reported that more than 200 different autoantibodies have been described in systemic lupus erythematosus (SLE), a small handful (~10%) of these have achieved regulatory approval and are widely available as commercial diagnostic kits, while a few others may be available as RUO or LDT assays. However, the vast majority (90%) are orphaned and languish in an autoantibody ‘death valley’. This review proposes that it is important to keep an inventory of these “orphan autoantibodies” in ‘death valley’ because, with the increasing availability of multi-analyte arrays and artificial intelligence (MAAI), some can be rescued to achieve a useful role in clinical diagnostic especially in light of patient stratification and precision medicine.

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Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift

Cited by 147 publications

References 78 publications

Driving β2- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis

Driving β2- While Suppressing α-Adrenergic Receptor Activity Suppresses Joint Pathology in Inflammatory Arthritis

From Rheumatoid Factor to Anti-Citrullinated Protein Antibodies and Anti-Carbamylated Protein Antibodies for Diagnosis and Prognosis Prediction in Patients with Rheumatoid Arthritis

Autoantibody Discovery, Assay Development and Adoption: Death Valley, the Sea of Survival and Beyond

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