Preclinical Rheumatoid
Arthritis: Identification,
Evaluation, and Future
Directions for
Investigation
Kevin D. Deane, MDa,*, Jill M. Norris, MPH, PhDb,
V. Michael Holers, MDa
‘‘When the rheumatic poison is in the system, any disturbing circumstance, even
of temporary duration, such as over fatigue, anxiety, grief or anger, by rendering
the system more susceptible of its influence, may prove the accidental or exciting
cause of the disease’’
Henry William Fuller in ‘‘On Rheumatism, Rheumatic Gout, and Sciatica’’
Publishers: Samuel S & William Wood, New York, 1854.
The discovery of genetic and environmental factors associated with rheumatoid
arthritis (RA), and elevations in autoantibodies and inflammatory markers prior to
the onset of symptomatic disease, coupled with similar findings in other autoimmune
diseases including type 1 diabetes mellitus (T1DM), has led to the creation of a shared
model of autoimmune disease development. In this model, the development of RA
follows a natural history divided into phases wherein genetic and environmental interactions initially lead to a period of asymptomatic autoimmunity, evidenced by the
presence of RA-related autoantibodies, that later evolves into clinically apparent
disease. It is the initial phases of risk and asymptomatic autoimmunity that encompass
‘‘preclinical’’ RA.
To understand the genetic and environmental influences that are important to the
evolution of RA, as well as develop predictive models and preventive strategies for
a Division of Rheumatology, University of Colorado School of Medicine, 1775 Aurora Court,
Mail Stop B-115, Aurora, CO 80045, USA
b Department of Epidemiology, Colorado School of Public Health, University of Colorado,
13001 East 17th Place, Aurora, CO 80045, USA
* Corresponding author.
E-mail address: Kevin.Deane@UCDenver.edu
KEYWORDS
Rheumatoid arthritis Preclinical period
Anticyclic citrullinated peptide antibodies
Rheum Dis Clin N Am 36 (2010) 213–241
doi:10.1016/j.rdc.2010.02.001 rheumatic.theclinics.com
0889-857X/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved.
future symptomatic disease, this preclinical period must be investigated. Herein are
discussed the following issues related to preclinical RA: (1) what is known about the
preclinical development of autoimmunity and inflammation in RA as well as other autoimmune diseases that may follow a similar model of development as RA, (2) how RA
development can be modeled based on studies in preclinical RA and other autoimmune diseases, (3) practical issues related to the challenge of defining for research
studies ‘‘preclinical’’ RA, as compared with clinically apparent disease, and (4) what
aspects of RA evolution including genetic and environmental influences, and predictive and preventive models, could be addressed in studies of the preclinical period.
Finally, potential methodologies and areas of focus going forward for research into
preclinical RA are discussed.
PART 1. AUTOANTIBODIES AND INFLAMMATION IN PRECLINICAL RHEUMATOID
ARTHRITIS AS WELL AS OTHER AUTOIMMUNE DISEASES
Studies of Preclinical Rheumatoid Arthritis
Multiple studies have shown that RA-related autoantibodies are present years before
the diagnosis of RA (Table 1).1–11 del Puente and colleagues,1 who investigated RA in
the Pima Indians in the Southwestern United States, showed that rheumatoid factor
was present before the onset of clinically apparent RA. Aho and colleagues,2,12–14
who investigated preclinical RA in Finland using a biobank of stored prediagnosis
samples, and Jonsson and colleagues,15 who used Icelandic biobank samples, also
demonstrated that rheumatoid factor (RF) (by various methodologies) was present
prior to the onset of clinically apparent RA. Also, in a prospective study of initially
healthy family members of patients with RA, Silman and colleagues11 showed that
the presence of RF preceded the onset of clinically apparent RA.
Later studies also showed preclinical RA positivity for RF, as well as positivity for
the highly RA-specific antibodies to citrullinated protein antigens (ACPAs). Again
using a Finnish biobank, Aho and colleagues3,4 demonstrated preclinical RA positivity
of antikeratin (AKA) and antiperinuclear factor (APF) antibodies, and antifillagrin antibodies (AFA)6—autoantibody targets that, based on later findings, represented citrullinated antigens.16 Using stored blood samples available through the Medical
Biobank of Northern Sweden, Rantapaa-Dahlqvist and colleagues7 evaluated for
elevations of RF isotypes (immunoglobulins [Ig] M, G and A) and the anticyclic citrullinated peptide (anti-CCP) antibody in 98 preclinical samples from 83 RA patients,
collected a median of 2.5 years prior to symptomatic disease onset. In this study,
approximately 34% of patients were positive for anti-CCP within 1.5 years prior to
diagnosis of RA, and the prevalence of RF isotype positivity ranged from about
17% to 34% during this same period. In addition, in comparison to controls, a combination of both anti-CCP and any RF isotype was highly specific (99%) for the future
development of classifiable RA. This report was followed by a similarly designed
retrospective cohort study by Nielen and colleagues8 that evaluated preclinical RA
RF and anti-CCP positivity using pre-RA diagnosis samples stored in a Dutch blood
donor biobank. In this study, 79 RA patients with stored prediagnosis samples were
identified, with a median of 13 preclinical samples per case. Of these 79 cases,
approximately 28% and 41% had pre-RA diagnosis elevation of RF (IgM isotype) or
anti-CCP, respectively. RF was positive a median of 2.0 years prior to RA diagnosis
(range 0.3–10.3 years), and anti-CCP was positive a median of 4.5 years prior to
RA diagnosis (range 0.1–13.8 years).
Additional studies using stored biobank samples have also demonstrated preclinical
RA positivity for autoantibodies. Using stored pre-RA samples from 83 United States
214 Deane et al
military subjects with RA, Majka and colleagues9 demonstrated pre-RA diagnosis positivity for RF and anti-CCP. In addition, they demonstrated that individuals that were
older at the time of diagnosis of RA had longer duration of preclinical positivity of autoantibodies, a finding that was supported by work by Bos and colleagues.17 Chibnik and
colleagues18 utilized the Nurses’ Health Study (NHS) biobank to demonstrate anti-CCP
positivity prior to RA diagnosis, and showed that a lower cut-off value for anti-CCP than
the kit suggested was also highly specific for future RA.
Multiple studies have also evaluated elevations of inflammatory markers prior to
diagnosis of RA, with varying results (see Table 1).19–24 In their Finnish biobank study,
Aho and colleagues25 found no significant elevation of C-reactive protein (CRP) in preRA diagnosis samples, although the time of sample collection prediagnosis was not
reported. Using the same Medical Biobank of Northern Sweden as in the study of
pre-RA RF and anti-CCP positivity, Rantapaa-Dahlqvist and colleagues21 showed
a significant elevation of monocyte chemoattractant protein-1 (MCP-1) in 92 pre-RA
cases versus controls, but not secretory phospholipase A2 (sPLA2), high-sensitivity
CRP (hsCRP) or interleukin (IL)-6. Nielen and colleagues19 demonstrated, in the Dutch
pre-RA sample cohort described above, that CRP was elevated in the pre-RA period,
most commonly about 2 years before diagnosis, regardless of prediagnosis autoantibody positivity, although these investigators were unable in this study to demonstrate
the chronologic sequence of appearance of CRP versus autoantibodies. Nielen and
colleagues20 later additionally demonstrated pre-RA elevation of sPLA2 in this cohort,
but were unable to determine whether CRP or sPLA2 preceded autoantibodies in the
preclinical period, and they concluded that the temporal development of autoantibodies and these 2 markers were probably similar. Jorgensen and colleagues24
utilized samples from a Norwegian biobank to examine in 49 cases with RA prediagnosis elevations of autoantibodies (RF and anti-CCP) and multiple cytokines. These
investigators found that RF and anti-CCP were elevated in RA cases prediagnosis;
however, they could not demonstrate any cytokine elevations prior to 5 years before
disease onset, and only tumor necrosis factor a (TNFa) was statistically significantly
elevated in cases (vs controls) during the 5-year period just before diagnosis of
RA.24 Using a single pre-RA diagnosis blood sample from 90 incident RA cases
(case status confirmed by chart review) identified in the Women’s Health Study
(WHS), Shadick and colleagues23 were unable to demonstrate significant elevations
in CRP levels in cases versus controls (with case samples available a mean of 6.6
years prior to diagnosis), and they were unable to use a single CRP level to predict
future RA. However, in a later study using 170 RA cases from a combination of the
NHS and WHS cohorts, the same group22 was able to demonstrate statistically significant elevations of soluble tumor necrosis factor receptor II (sTNFRII) prior to RA diagnosis, but not IL-6 or hsCRP. Most recently, Rantaapa-Dahlqvist and colleagues used
an expanded sample set from their Swedish Biobank, to demonstrate elevations of
multiple cytokines and chemokines prior to the diagnosis of RA, with these elevations
likely indicating pre-clinical RA activity of Th1, Th2, and T regulatory processes.26
There are caveats when interpreting the data regarding pre-clinical elevations of
biomarkers. Certainly the prospective studies by del Puente and colleagues1 and Silman and colleagues11 suggest that autoantibodies are truly elevated before the onset
of clinically apparent disease. However, in the studies of preclinical autoantibody and
inflammatory marker elevations using stored samples from biobanks, there were not
detailed joint-directed questionnaires or examinations performed at baseline or over
time to ensure that no clinically apparent arthritis was present at the time of presumed
preclinical RA blood collections. As such, it may be that the duration of pre-RA diagnosis autoantibody positivity is overestimated in the studies utilizing stored biobank
Preclinical Rheumatoid Arthritis 215
Table 1
Summary of selected studies of preclinical rheumatoid arthritis (RA)
Study Study Design
Biomarkers
Assessed Findings
Implications for Prediction
of Future RA
del Puente et al,
19881
Prospective; Native Americans,
Southwest United States
RF RF precedes diagnosis of RA Increased incidence of RA in RF1
individuals. Rates 2.4–48.3 per
1000 person-years, with highest
rates in those with highest RF
titers at baseline
Silman et al,
199211
Prospective; British; FDRs from
families with R2 RA cases
RF RF precedes diagnosis of RA Average incidence of RA 8 per
1000 person-years in FDRs;
highest rate in FDRs with RF1: