Rheumatoid arthritis (RA) is a systemic autoimmune disease of unknown origin, characterized by chronic joint inflammation leading to destruction of bone and cartilage, reduction of functional capacity, and increased mortality (1, 2). Since structural joint damage is irreversible, early recognition and treatment are currently being emphasized, with the goal of halting progression of the disease (3–5). However, in 36–54% of cases, patients attending arthritis clinics shortly after the onset of symptoms already have joint damage that is visible radiographically (6–8).
The pathogenesis of RA is poorly understood. There is evidence of a preclinical or asymptomatic phase of the disease. Histologic studies have demonstrated extensive synovitis in clinically uninflamed joints (9). In addition, autoantibodies can be present before the disease becomes manifest (10–15). The autoantibodies most frequently found in patients with RA are antibodies against IgG (IgM rheumatoid factor [IgM-RF]) and antibodies against citrullinated proteins. The latter were originally measured as antibodies against keratin or filaggrin and more recently as anti–cyclic citrullinated peptide (anti-CCP) (16, 17). In hospital-based groups of patients with early RA, the prevalence of RF is 50–66%, and the prevalence of anti-CCP is 41–48%; the prevalence rates of these antibodies in the absence of disease are reported to be 7–13% and 3–9%, respectively (17–19).
A number of reports have described the presence of autoantibodies in the blood of apparently healthy persons years before they developed RA. This was found not only in populations at increased risk for RA, such as multicase families (10, 15) or Pima Indians (14), but also in the general populations of Finland (11, 12) and Iceland (13). Most of the results were based on findings in single serum samples and therefore provide no information about the course of autoantibody titers in the period before the onset of symptoms of RA or about which antibodies might be most sensitive and specific to predict the disease. In the present study, the pattern of autoantibodies in the preclinical phase of RA was investigated with serial measurements, using highly specific tests, of IgM-RF and anti-CCP in blood donors before they developed RA and in control blood donors who did not develop RA.
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- PATIENTS AND METHODS
Approximately half of 79 blood donors became positive for the autoantibodies IgM-RF and/or anti-CCP before the onset of clinical symptoms of RA. The median time from the first autoantibody positivity in a serum sample to development of symptoms was 4.5 years. Among the patients with antibodies, there was at least 1 positive anti-CCP test result a median of 2.8 years before IgM-RF positivity, but anti-CCP was slightly less likely to remain positive. Both tests were found to be highly specific in this study, which implies a high risk for the development of RA in healthy persons up to age 70 years (the upper age limit of the blood donors) who have elevated serum levels of 1 or both of these antibodies.
The group studied appears to be representative of the RA population, based on the age at onset of symptoms, percentage of patients with radiographic erosions at baseline, and frequency of IgM-RF at baseline. The percentage of women in the patient group is somewhat lower than expected, but it is not likely that this influenced the results, since the controls were matched for sex and age. Blood donors are not entirely representative of the general population, because many diseases and infections that increase the risk of a positive IgM-RF test result, such as hepatitis C, lead to exclusion as a donor. This selection might lead to a slightly higher specificity of the IgM-RF test in the studied population. The anti-CCP test might also be influenced by infections such hepatitis C, although a study of antikeratin antibodies (a preliminary anti-CCP test) showed only 8% positivity in hepatitis C–infected patients (24).
Our results are in accordance with incidental earlier reports of RF or antikeratin antibodies in both high-risk (10, 14, 15) and healthy (11–13) populations. However, in the present study we were able to measure antibody levels in serially obtained samples, using 2 different tests that are highly specific for RA. The 44% frequency of positivity for RF in the Finnish population (11) corresponds to our findings, but that study yielded information from only one point in time. Autoantibody positivity prior to symptom development has also been found in other autoimmune diseases, e.g., systemic lupus erythematosus and insulin-dependent diabetes mellitus. Ten of 16 persons who developed systemic lupus erythematosus or mixed connective tissue disease were positive for antinuclear antibodies 0.7–4.5 years before the onset of symptoms (25). Antibodies to glutamic acid decarboxylase, the primary immunologic marker in insulin-dependent diabetes mellitus, were present for up to 10 years in the prediabetic period in 82% of 28 women and in none of 100 controls (26). This led to immunologic interventions to prevent the onset of diabetes in selected populations (27, 28).
The results of this study shed more light on the time sequence of events in the pathogenesis of RA. An unknown trigger activates B lymphocytes to produce RA-specific antibodies several years before the appearance of a level of inflammation that is perceived as symptoms. In the majority of patients, seropositivity, once established, is stable. The production of antibodies in itself is not essential for clinical disease, since it occurred in only half of the patients before onset of symptoms. Still, these patients proved to be the more severely affected in terms of radiologic findings, and the prevalence of antibodies increased over time and was highest in the year before the symptoms appeared. Apparently, the conversion to RF seropositivity continued after the onset of symptoms and reached the commonly reported prevalence level of 67% after 6 years.
Apart from providing insight into the pathogenesis of RA, our findings indicate that it may be possible to predict RA development in high-risk populations, as long as appropriately high upper limits of normal are set for the tests used. For example, for multicase families with RA, we have estimated that the 5-year risk of developing RA in a family member with a positive anti-CCP result is 69.4%. We believe this figure is high enough to consider a clinical trial of a medical intervention to prevent the development of RA in these individuals. Because only a small proportion (2–3%) of all patients with RA are from multicase families (29), another possible target group for intervention could be patients with arthralgia and positive serologic findings.
In conclusion, half of patients with RA have specific serologic abnormalities years before the development of symptoms. This finding should help guide our understanding of the early phases of RA and may contribute to earlier detection and more aggressive treatment of this disabling disease.