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CHaPtEr 52 Rheumatoid Arthritis 717

TABLE 52.2 2010 aCr/EULar Insights Into the Preclinical Phase of Disease
Classification Criteria for rheumatoid arthritis ON tHE HOrIZON
Weighted The Preclinical Phase of Rheumatoid Arthritis
Domain Score
Joint Involvement (0–5) • High-risk individuals include those with inflammatory joint pain (arthralgia)
and serum RA–associated autoantibodies. From 40–50% of those
1 medium to large joint 0 with high-titer ACPAs (with or without rheumatoid factor) may develop
2–10 medium to large joints 1 clinical synovitis within 24 months.
1–3 small joints 2 • Targeting these high-risk individuals with preventative strategies
4–10 small joints 3 provides the best chance of achieving cure. Trials of rituximab,
>10 joints (with at least one small joint) 5 abatacept, or hydroxychloroquine are ongoing.
• In-depth molecular and cellular studies for characterizing the preclinical
Serology (0–3) phase of disease will be critical to the success of this endeavor.
Neither RF- or ACPAs-positive (≤ULN) 0 • Models for progression to RA have identified the following phases:
At least one test, low positive titer (>1 ≤3 × ULN) 2 (I) Genetic risk
At least one test, high positive titer (>3 × ULN) 3 (II) Genetic risk with autoimmunity (e.g., ACPAs, rheumatoid factor)
(III) Genetic risk with autoimmunity and arthralgia (but absence of
Duration of Synovitis (0–1) clinically apparent synovitis)
<6 weeks 0 (IV) Undifferentiated arthritis (clinically apparent synovitis, not fulfilling
≥6 weeks 1 RA classification criteria)
(V) Early RA (fulfilling disease criteria; need for DMARDs)
acute-Phase reactants (0–1) • Stratification of risk, including genetic, serological, and demographic
factors, will permit the identification of subjects most suitable for
Neither ESR or CRP abnormal 0 intervention studies.
Abnormal ESR or CRP 1 • Studying the impact of lifestyle modifications, e.g., diet, stopping
TOTAL (≥6 indicates definite RA): ______ smoking, would be of great interest.
• Reestablishing immune homeostasis and/or induction of immune
ACPAs, antibodies to citrullinated protein antigens; ACR, American College of
Rheumatology; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; tolerance may provide the best chance of achieving cure in subjects
EULAR, European League Against Rheumatism; RF, rheumatoid factor; ULN, upper during the preclinical phase of disease. Early-phase studies of peptide
limit of normal. immunotherapy indicate that this approach is well tolerated.
• Establishing robust assays for signatures of immune tolerance (e.g.,
immune phenotyping by flow cytometry, extended autoantibody
have prognostic value in terms of radiographic progression, and serotyping, multiplex assays for detection of inflammatory mediators
titers may alter with therapy. The new-generation anti-CCPs in serum, whole-blood transcriptomic profiles) that reflect a healthy
immune system will greatly facilitate these endeavors.
kits have demonstrated diagnostic sensitivity of 80% and specific-
ity of 98%. As the range of RA-associated autoantigens has ACPAs, antibodies to citrullinated protein antigens; DMARDs,
expanded and the repertoire of citrullinated target autoantigens disease-modifying antirheumatic drugs; RA, rheumatoid arthritis.
has become better defined, multiplex assays of serum autoantibod-
ies are likely to play an increasingly important role in the diagnosis
and prognosis of subsets of autoantibody-positive inflammatory
arthritides.
The identification of a preclinical phase of RA, through the
detection in serum of autoantibodies up to 14 years before disease
onset, has sparked considerable interest in characterizing the
CLINICaL PEarLS RA prodrome in more detail. Work has centered around evaluation
Predictors of Poor Outcome in of acute-phase proteins and serum cytokines and chemokines,
Rheumatoid Arthritis which appear to rise 1–2 years before onset of clinical disease;
ACPAs isotype usage and epitope spreading; whole-blood gene
• Chronic, unremitting disease onset, especially at advanced age expression analysis, which shows similarities to patients with
• High disease activity scores at baseline established disease (including type I interferon-inducible gene
• Female gender
• Poor functional status as determined by validated functional disability signatures in a subset); imaging by MRI and ultrasonographic
indices such as the Stanford Health Assessment Questionnaire (HAQ) modalities; and, most recently, analysis of lymph node immune
and the Arthritis Impact Measurement Scale (AIMS) phenotypes, showing evidence of lymphocyte activation. The
• Low socioeconomic status strongest predictors of progression in those at-risk subjects are
• Systemic and extraarticular features joint pains without clinically detectable synovitis (arthralgia)
• Depression and anxiety combined with the presence of high-titer ACPAs and RF auto-
• Comorbidity, e.g., infection, cardiovascular disease, renal
impairment antibodies. Risk scores, which take into account other demographic
• Early erosive disease (in first 6–12 months; may be associated with factors, have been developed and are currently being evaluated.
+
ACPAs autoantibodies) Progression rates for ACPAs arthralgia patients with subclinical
• Persistent acute-phase response (e.g., time-integrated CRP levels) synovitis detected by ultrasound examination are of the order
• Autoantibodies (RF and ACPAs) and HLA-DRB1 status (SE ) of 20% over a median of 28 months, while arthritis-free survival
+
44
• Significant delay in early use of DMARDs and corticosteroids curves suggest that 40–50% of those at highest risk will develop
ACPAs, antibodies to citrullinated protein antigens; CRP, C-reactive clinically apparent synovitis in 2–3 joints within 24 months.
protein; DMARDs, disease-modifying antirheumatic drugs; RF, This rate of progression is considered to be sufficient to justify
rheumatoid factor; SE, shared epitope. secondary prevention intervention studies. Somewhat surprisingly,