Circulating anti-citrullinated protein antibodies containing secretory component are prognostic for arthritis onset in at-risk patients

Ljungberg, Karin; Martinsson, Κjell; Wetterö, Jonas; Svärd, Anna; Kastbom, Alf

doi:10.1111/cei.13591

Cited by 6 publications

(3 citation statements)

References 25 publications

(40 reference statements)

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“…IgA1 ACPA were associated with a higher risk of developing RA within the following 14 months. This finding is in concordance with recent studies showing that elevated levels of ACPA containing secretory component (which partially include IgA ACPA) are associated with RA development in IgG ACPA positive individuals with musculoskeletal pain31 and that serum IgA ACPA levels are increased in at-risk individuals with clinically suspect arthralgia 23. However, in the former study, IgA ACPA positivity was not different between RA progressors and non-progressors, which might be related to the high cut-off used in that study.…”

Section: Discussionsupporting

confidence: 93%

Antibodies against citrullinated proteins of IgA isotype are associated with progression to rheumatoid arthritis in individuals at-risk

et al. 2023

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ObjectiveEvents triggering disease outbreak in individuals at-risk for rheumatoid arthritis (RA at-risk) remain unclear, and the role of the various anticitrullinated protein antibody (ACPA) isotypes in this process is still to be established. We aimed to investigate the prevalence of IgA ACPA in RA at-risk individuals, their role in the transition from the RA at-risk status to RA and their dynamics during this transition.MethodsCross-sectional measurement of serum IgA1 and IgA2 ACPA levels was conducted in healthy controls, RA at-risk individuals and patients with RA and compared with the frequency of RA development in at risk individuals during a follow-up of 14 months. In addition, longitudinal measurements of serum IgA1 and IgA2 ACPA levels prior to, at and after the onset of RA were performed.ResultsApproximately two-thirds of RA at-risk individuals were positive for serum IgA1 and IgA2 ACPA in levels comparable to IgG ACPA positive patients with RA. IgA1, but not IgA2 ACPA positivity was associated with the transition from the RA at-risk state to RA within the following 14 months. Interestingly, during this transition process, IgA1 ACPA levels declined at RA onset and also thereafter during the early phase of RA. This decline was confirmed in a second, independent cohort.ConclusionBoth IgA1 and IgA2 ACPA are present in RA at-risk individuals, but only IgA1 ACPA are associated with the progression to RA. The observed decline in serum IgA1 ACPA levels before the onset of RA might indicate starting barrier leakiness prior to disease outbreak.

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Section: Discussionsupporting

confidence: 93%

Antibodies against citrullinated proteins of IgA isotype are associated with progression to rheumatoid arthritis in individuals at-risk

et al. 2023

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“…However, growing evidence from prospective studies on symptomatic at-risk patients suggest otherwise. In fact, studies published so far show that RF and ACPA (including nonclassical isotypes) appear stable during the symptomatic prearthritic phase, both in terms of levels and seroconversion, and without apparent association with arthritis onset (99,108,109).…”

Section: Is There a Value Of Repeated Autoantibody Testing In Symptomatic At-risk Patients?mentioning

confidence: 99%

Autoantibodies in Rheumatoid Arthritis – Laboratory and Clinical Perspectives

2021

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Measurement of two groups of autoantibodies, rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) have gained increasing significance in the diagnosis and classification of rheumatoid arthritis (RA) over the last 65 years. Despite this rising importance of autoimmune serology in RA, there is a palpable lack of harmonization between different commercial RF and ACPA tests. While a minimal diagnostic specificity has been defined for RF tests, which almost always are related to an international reference preparation, neither of this applies to ACPA. Especially assays with low diagnostic specificity are associated with very low positive predictive values or post-test probabilities in real world settings. In this review we focus on issues of practical bearing for the clinical physician diagnosing patients who potentially have RA, or treating patients diagnosed with RA. We advocate that all clinically used assays for RF and ACPA should be aligned to a common diagnostic specificity of 98-99% compared to healthy controls. This high and rather narrow interval corresponds to the diagnostic specificity seen for many commercial ACPA tests, and represents a specificity that is higher than what is customary for most RF assays. Data on antibody occurrence harmonized in this way should be accompanied by test result-specific likelihood ratios for the target diagnosis RA on an ordinal or interval scale, which will provide the clinical physician with more granular and richer information than merely relating numerical values to a single cut-off point. As many physicians today are used to evaluate autoantibodies as positive or negative on a nominal scale, the introduction of test result-specific likelihood ratios will require a change in clinical mindset. We also discuss the use of autoantibodies to prognosticate future arthritis development in at-risk patients as well as predict severe disease course and outcome of pharmacological treatment.

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“…However, their formation requires free SC which, to our knowledge, is produced by epithelial cells only (25), and therefore, their origin most likely remains related to the mucosa. Given that SC‐containing ACPAs occur in joint fluid and may be formed in serum, where they predict arthritis onset among at‐risk patients (30), we believe that these autoantibodies may be involved in triggering arthritis. Therefore, functional characterization of SC‐containing ACPAs should be addressed in future work, facilitated by the methods of in vitro SC‐containing ACPA formation described here.…”

Section: Discussionmentioning

confidence: 99%

Extramucosal Formation and Prognostic Value of Secretory Antibodies in Rheumatoid Arthritis

Martinsson

Kling

Ljungberg

et al. 2022

Arthritis & Rheumatology

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Objective To investigate levels and possible extramucosal formation of secretory Ig, including anti–citrullinated protein antibodies (ACPAs), in rheumatoid arthritis (RA). Methods Three patient groups were studied: 1) ACPA‐positive patients with musculoskeletal pain without clinical arthritis, 2) patients with recent‐onset RA, and 3) patients with established RA. In baseline serum samples (groups 1 and 2) and paired synovial fluid samples (group 3), we analyzed total secretory IgA, total secretory IgM, free secretory component (SC), and SC‐containing ACPA. Extramucosal formation of SC‐containing ACPA was investigated by preincubating RA sera and affinity‐purified ACPA with recombinant free SC. Results Compared to healthy controls, serum levels of total secretory IgA and total secretory IgM were increased both in patients with early RA and at‐risk patients (P < 0.05). Patients with early RA with elevated total secretory Ig had significantly higher disease activity during the 3‐year follow‐up period compared to those without increased levels. At‐risk patients who developed arthritis during follow‐up (39 of 82) had higher baseline total secretory IgA levels compared to those who did not (P = 0.041). In established RA, total secretory IgA and total secretory IgM levels were higher in serum than in synovial fluid (P < 0.0001), but SC‐containing ACPAs adjusted for total secretory Ig concentration were higher in synovial fluid (P < 0.0001). Preincubation with recombinant free SC yielded increased SC‐containing ACPA reactivity in sera as well as in affinity‐purified IgA and IgM ACPA preparations. Conclusion Circulating secretory Ig are elevated before and at RA onset. In the presence of free SC, secretory Ig may form outside the mucosa, and SC‐containing ACPAs are enriched in RA joints. These findings shed important new light on the mucosal connection in RA development.

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Circulating anti-citrullinated protein antibodies containing secretory component are prognostic for arthritis onset in at-risk patients

Cited by 6 publications

References 25 publications

Antibodies against citrullinated proteins of IgA isotype are associated with progression to rheumatoid arthritis in individuals at-risk

Antibodies against citrullinated proteins of IgA isotype are associated with progression to rheumatoid arthritis in individuals at-risk

Autoantibodies in Rheumatoid Arthritis – Laboratory and Clinical Perspectives

Extramucosal Formation and Prognostic Value of Secretory Antibodies in Rheumatoid Arthritis

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