Can we accurately predict the development of rheumatoid arthritis in the preclinical phase?

Majka, Darcy S.; Holers, V. Michael

doi:10.1002/art.11224

Cited by 58 publications

(39 citation statements)

References 56 publications

(78 reference statements)

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“…These sites become potential targets for IgG antibodies (53). Recent studies have suggested that the target epitopes in synovium are citrullinated vimentin or variants of the α and β chains of fibrin that have been subjected to posttranslational deimination (50,53,(56)(57). Deposits of fibrin and fibrin-related extracellular and intracellular deposits have long been recognized in inflamed rheumatoid synovium (58).…”

Section: Citrullinated Proteins Link Rheumatoid and Periodontal Inflamentioning

confidence: 98%

Hypothesis: The Humoral Immune Response to Oral Bacteria Provides a Stimulus for the Development of Rheumatoid Arthritis

et al. 2004

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Rheumatoid arthritis (RA) and adult periodontitis share common pathogenetic mechanisms and immunologic and pathological findings. One oral pathogen strongly implicated in the pathogenesis of periodontal disease, Porphyromonas gingivalis, possesses a unique microbial enzyme, peptidylarginine deiminase (PAD), the human equivalent of which has been identified as a susceptibility factor for RA. We suggest that individuals predisposed to periodontal infection are exposed to antigens generated by PAD, with de-iminated fibrin as a likely candidate, which become systemic immunogens and lead to intraarticular inflammation. PAD engendered antigens lead to production of rheumatoid factor-containing immune complexes and provoke local inflammation, both in gingiva and synovium via Fc and C5a receptors.

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Section: Citrullinated Proteins Link Rheumatoid and Periodontal Inflamentioning

confidence: 98%

Hypothesis: The Humoral Immune Response to Oral Bacteria Provides a Stimulus for the Development of Rheumatoid Arthritis

et al. 2004

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“…Routine screening with a high sensitivity RF IgM ELISA and anti-CCP tests 31,32 , followed by isotype determination 5,8,33 , may lead to early diagnosis of RA even before the onset of clinical symptoms. For those very likely to have or develop RA, early diagnosis may change the outcome and may drastically reduce the cost of treatment 23,34 . Based on the data presented here and previously 5,8,10,14,15,19,31,32,33 , an algorithm is proposed for the most efficient use of RF test by ELISA in the diagnosis of RA ( Figure 5).…”

Section: Rheumatologymentioning

confidence: 99%

Relationship Between Rheumatoid Factor Isotypes and IgG Anti-Cyclic Citrullinated Peptide Antibodies

Jaskowski¹,

Hill²,

Russo³

et al. 2010

J Rheumatol

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Objective.To validate in a general patient population (GPP) the clinical value of measuring rheumatoid factor (RF) isotypes in relationship to IgG anti-cyclic citrullinated peptide (CCP) antibodies (CCP2 and CCP3).Methods.Serum samples were obtained as follows: 1021 GPP, for whom RF was ordered for diagnosis, 137 with rheumatoid arthritis (RA), 100 healthy blood donors (HBD), and 50 with systemic lupus erythematosus. Turbidimetry and ELISA were utilized for RF screening, and individual RF isotypes and IgG anti-CCP antibodies were measured by ELISA; RF IgG was measured after pepsin digestion.Results.We validated the generally accepted 90%–98% positive predictive value (PPV) and about 68% sensitivity of the anti-CCP2 test on our diagnosed cohorts as 96% (95% CI 89–99) and 65% (95% CI 56–73), respectively. The 282 RF IgM+ specimens identified in the GPP were subdivided into 3 subsets: (1) 83 as RF IgM+ IgG+ IgA+ with 63% (95% CI 51–73) anti-CCP2+ (i.e., sensitivity similar to the RA cohort); (2) 50 as RF IgM+ IgG− IgA+ with significantly fewer anti-CCP2+ (22%; 95% CI 12–36); and (3) about half as IgM+ IgG− IgA− with just 3% (95% CI 1–8) anti-CCP2+, i.e., not significantly different from the 1% (95% CI 0–5) in HBD. Thus, the chance for a specimen in the GPP to be anti-CCP2+ (i.e., to come from an RA patient) was increased by 7- and 21-fold, respectively, by identifying RF IgA and IgG in addition to IgM. About one-third of anti-CCP− RA patients in our cohort were RF IgM+ IgG+ IgA+, reflected as 3.4% in the anti-CCP2− GPP. The agreement between anti-CCP2 and anti-CCP3 was significantly higher for RF+ RA and GPP patients, 86% (95% CI 78–93) and 83% (95% CI 73–91), respectively, than for the RF− RA (27%; 95% CI 6–61), RF− GPP (4%; 95% CI 0–19), and non-RA controls. Anti-CCP2 but not anti-CCP3 significantly distinguished the HBD from the GPP (95% CI).Conclusion.Measurement of the 3 isotypes of RF may increase by 7- to 21-fold the chance of making the serologic diagnosis of RA; a testing algorithm is proposed. The anti-CCP antibody response appears significantly less peptide-specific in the presence of IgM RF than in its absence.

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“…As pointed out by Majka and Holers [54], such studies raise the important clinical issue of identifying subjects in a stage of preclinical autoimmunity in RA, as is seen with type I diabetes mellitus. Autoimmune diseases such as RA may exhibit three phases during their development: 1) a state of susceptibility resulting from genetic risk factors that predispose to the loss of self tolerance; 2) the transition to a state of autoreactivity with autoantibody production not yet associated with clinically apparent disease, and 3) clinically apparent disease characterized by immune-mediated tissue destruction [54].…”

Section: Anti-cyclic Citrullinated Peptide Antibodiesmentioning

confidence: 97%

“…Autoimmune diseases such as RA may exhibit three phases during their development: 1) a state of susceptibility resulting from genetic risk factors that predispose to the loss of self tolerance; 2) the transition to a state of autoreactivity with autoantibody production not yet associated with clinically apparent disease, and 3) clinically apparent disease characterized by immune-mediated tissue destruction [54]. It remains to be determined whether the early appearance of RF and anti-CCP autoantibodies in RA represents a primary loss of tolerance to self antigens or a secondary response to subclinical tissue injury with exposure to novel or abundant autoantigens [54].…”

Section: Anti-cyclic Citrullinated Peptide Antibodiesmentioning

confidence: 99%

Update on autoantibodies in rheumatoid arthritis

Bridges

2004

Curr Rheumatol Rep

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Detection of rheumatoid factor (RF) in the serum of patients with rheumatoid arthritis (RA) was one of the first indications of autoimmunity in RA. The role of RF in the diagnosis of RA has been well-documented, but it has suboptimal sensitivity and specificity. Although patients with RF-positive RA generally have more severe disease than those with RF-negative RA, RF is not a reliable predictor of disease severity in individual patients. Multiple other autoantibodies have been found in RA, with recent interest focused on those directed at cyclic citrullinated peptides. Panels of autoantibodies may ultimately prove useful in preclinical diagnosis and prediction of clinical course in patients with RA and other forms of arthritis, and provide insights into the pathogenesis of the disease.

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Can we accurately predict the development of rheumatoid arthritis in the preclinical phase?

Cited by 58 publications

References 56 publications

Hypothesis: The Humoral Immune Response to Oral Bacteria Provides a Stimulus for the Development of Rheumatoid Arthritis

Hypothesis: The Humoral Immune Response to Oral Bacteria Provides a Stimulus for the Development of Rheumatoid Arthritis

Relationship Between Rheumatoid Factor Isotypes and IgG Anti-Cyclic Citrullinated Peptide Antibodies

Update on autoantibodies in rheumatoid arthritis

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