Getting them even earlier: Identifying individuals before clinical presentation with rheumatoid arthritis
Article first published online: 30 NOV 2009
Copyright © 2009 by the American College of Rheumatology
Arthritis Care & Research
Volume 61, Issue 12, pages 1620–1622, 15 December 2009
How to Cite
Liao, K. P. and Costenbader, K. H. (2009), Getting them even earlier: Identifying individuals before clinical presentation with rheumatoid arthritis. Arthritis & Rheumatism, 61: 1620–1622. doi: 10.1002/art.24991
- Issue published online: 30 NOV 2009
- Article first published online: 30 NOV 2009
- Manuscript Accepted: 31 AUG 2009
- Manuscript Received: 14 AUG 2009
- NIH. Grant Numbers: T32-AR055885, P60-AR047782
“Early arthritis” centers have been organized for several years in Europe and Canada. Patients with new onset symptoms of undifferentiated inflammatory arthritis are seen, enrolled in cohorts, and followed for the development of rheumatoid arthritis (RA). Cohorts followed in these clinics have demonstrated that early use of aggressive disease-modifying therapy for RA can effectively halt or slow the progression of joint destruction (1, 2). In the US, patients are still commonly referred to rheumatology practices after inflammatory arthritis has persisted for months or even years. Therefore, substantial clinical momentum is now being directed at identifying potential early RA and starting appropriate treatment as early as possible in the disease course (3).
In parallel with clinical efforts, RA research is aiming to better understand its underlying pathogenesis and to test the effectiveness of treatment strategies for new onset disease to prevent damage and the sequelae of chronic uncontrolled inflammation. The cause of the breakdown in immune tolerance that allows for the development of antibodies to self-targets is still unknown. Among individuals who have inherited genetic risk factors, loss of self-tolerance without clinically apparent disease may follow an exposure to an environmental trigger, such as infection, cigarette smoke, or hormonal influence (4). In this preclinical phase, autoantibodies are detectable, but inflammation and symptomatic disease may not occur for years. With time, the autoimmune response propagates, and clinical symptoms arise. The pathologic role of rheumatoid factor (RF) is not well understood, but it may be detected in the blood >5 years prior to the first RA symptoms (5, 6). More recently, autoantibodies directed against an array of citrullinated peptides have been detected years before RA symptoms, and these are now important in early RA diagnosis. These autoantibodies are highly specific for RA (sensitivity 67%, specificity 95%) (7). While the exact roles of citrullinated peptides and the autoantibodies to them in RA pathogenesis remain unclear, the presence of these autoantibodies is associated with more severe structural damage and radiographic progression among those with established RA (7). Anti–citrullinated peptide autoantibodies (ACPA) are strongly associated with the risk of developing RA in healthy individuals and have been detected up to 12 years before symptom onset (6, 8, 9).
The current 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for RA do not reliably identify “early RA” for either research or clinical purposes (10). The sensitivity range of the current classification criteria for RA is 25–90% and the specificity range is 60–90% for new onset disease (11–13). In fact, no established definition of “early RA” exists. In past studies, “early RA” ranges from a few weeks of symptoms to a few years of disease. A combined ACR and European League Against Rheumatism (EULAR) collaboration is underway to develop classification criteria that will include the identification of subjects with short durations of inflammatory arthritis at high risk for developing persistent or erosive inflammatory RA. These criteria will take into account the results of testing for ACPA, which is not currently included in the ACR criteria for RA classification.
In this issue of Arthritis Care & Research, investigators at the University of Colorado and their collaborators report the results of the development of 2 different methods for the identification of subjects with inflammatory arthritis and/or at high-risk for developing RA. Deane et al sought to identify subjects with early inflammatory arthritis with a high likelihood of developing RA through a community health fair screening (14). Individuals at the health fair were recruited to participate if they had symptoms of arthritis (joint pain, stiffness, or swelling), had a family history of RA, or were just interested in learning more about their health. Participants completed the Connective Tissue Questionnaire (CSQ) (15) and underwent a joint examination and had blood drawn. Deane et al aimed to identify individuals with inflammatory arthritis, who were defined as having ≥1 swollen joint(s). The health fair took place at 5 sites in Colorado and was visited by ∼91,000 people, of which 601 participants were screened. Of these 601 participants, 84 (14%) had inflammatory arthritis according to the above definition, 15 (2.5%) were found to have inflammatory arthritis and a positive RF and/or ACPA, and 9 (1.5%) met the current ACR criteria for the classification of RA (10), but had no prior diagnosis of RA.
Also in this issue of Arthritis Care & Research, Kolfenbach et al report the establishment of the Studies of the Etiology of RA (SERA) cohort, a cohort at high risk for developing RA (16). They recruited 1,058 first-degree relatives of individuals with RA who were followed for SERA by rheumatologists in several US cities. Previous studies have indicated that first-degree relatives of individuals with RA are at a significantly elevated risk of developing RA: for an offspring of an affected parent the relative risk of developing RA is 3 times that of the normal population (17). The risk of RA is almost 5 times higher than average for an individual with an affected sibling. For SERA, first-degree relatives were interviewed and demographic and medical history information was obtained. All subjects were examined using the 68-joint count technique and underwent blood and urine testing for future studies. In addition, they received epidemiologic questionnaires on environmental and hormonal exposures and completed the CSQ. SERA first-degree relatives, 71% of whom were female with a mean age of 47 years at enrollment, will be invited for prospective followup.
What are the potential fruits of these 2 studies and the establishment of other early RA cohorts in the US (18)? Which research questions could be optimally addressed by cohorts of high-risk individuals or preclinical RA subjects?
Although our knowledge is growing about the biology of the insidious development of RA over time, we still have a lot to learn. Cohorts such as SERA could enable research studies on what molecular events may be taking place prior to the onset of RA. Biospecimen banking in SERA will allow researchers to analyze specimens from individuals who eventually developed RA and compare differences in levels of biomarkers prior to the onset of disease. Karlson and colleagues showed that levels of soluble tumor necrosis factor receptor II were elevated up to 12 months prior to the development of RA (19). This study employed banked blood samples from 2 prospective cohorts of women, the Nurses' Health Study and the Women's Health Study, which together follow more than 270,000 female health professionals. As demonstrated by the large number of women in the study, studying RA, with an estimated prevalence of 1%, requires following thousands of individuals for many years (20). The SERA cohort allows for targeting of high-risk subjects likely to develop RA, thereby focusing on and prospectively following a smaller group of individuals. Obtaining exposure information and medical history prior to the onset of disease circumvents the threat of recall bias that can occur in incident and retrospective RA cohort studies.
The genetics of RA susceptibility, and relationships with susceptibility to other autoimmune diseases and to environmental exposures such as cigarette smoking and crystalline silica exposure, offer an equally ripe area for research. RA susceptibility appears to be heavily influenced by environmental exposures and interaction between RA risk alleles and the environment (21). Recent work has demonstrated that genetic factors for ACPA-positive RA differ from those for seronegative disease; further studies promise to improve understanding of these 2 separate disease phenotypes and their genetics, manifestations, and prognoses. Studies of families with multiple autoimmune diseases have also shed light on the genes shared by these diseases as well as their shared molecular pathways (22).
As physicians, the advice we give to individuals with strong family histories of RA or early nonspecific arthritis symptoms is not evidence-based and can be vague and random. Data from such early and high-risk RA cohorts can improve our ability to accurately estimate disease risk and counsel patients about their risk factors and the timing of initiating therapy. Efforts to develop combined clinical/genetic risk prediction tools for RA, such as the Framingham Risk Score for cardiovascular disease (23) have begun. Who knows, perhaps in the near future rheumatologists will be calculating 10-year RA risk scores for patients in their offices. Moreover, a small randomized trial is getting underway in Europe in which asymptomatic first-degree relatives deemed at high-risk of developing RA will be randomized to a mild disease-modifying antirheumatic drug therapy and followed for the development of symptomatic RA (Finckh A: personal communication). The prospect of such studies is exciting and should provide useful information about disease risk and the effects of early treatment.
With the anticipated completion of new ACR/EULAR criteria for classification of RA, which will include early “high-likelihood-of-RA inflammatory arthritis,” cohorts like these will be essential for the study of criteria validity and for their refinement over time as new data concerning autoantibodies and other clinical and serologic risk markers become available. High-risk and preclinical RA cohorts could also serve as potential groups for recruitment into trials of therapies in early RA.
Community-wide screening for RA in the healthy population is not likely to prove a cost- or time-efficient strategy for future research or clinical efforts. For the 601 individuals screened at the Colorado health fair by Deane and colleagues, the total costs, including personnel time for examinations, phone followup, paperwork, and laboratory testing, were estimated to be $2,000 per person. Different staged strategies in which laboratory testing is performed only on those who screened positive, could decrease the cost per subject, but would reduce the performance of the screening to various amounts as well. Deane et al did demonstrate the potential feasibility and high specificity of their screening strategy, which could be adopted for other populations. Recruiting first-degree relatives of RA cases enriches the population for RA susceptibility, but it is still unclear how many individuals will need to be followed and for how long to have adequate power to assess environmental associations with disease. The SERA cohort followup should answer these questions. Studies of interactions between genetic and environmental risk factors in determining RA risk, which would be extremely interesting in this setting, notoriously demand thousands of individuals. New methods for investigating gene-environment interactions in autoimmune disease susceptibility may be developed, employing data from high-risk family cohorts (24).
Identifying and studying subjects with preclinical RA should improve our understanding of the events occurring in the very early stages of RA. The major challenges are recruiting sufficient numbers of subjects and following them prospectively for long enough to ensure a well-powered study at a reasonable cost.
- 1FIN-RACo Trial Group. Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: five-year experience from the FIN-RACo Study. Arthritis Rheum 2004; 50: 2072–81., , , , , , et al, for the
- 13Ability of the American College of Rheumatology 1987 criteria to predict rheumatoid arthritis in patients with early arthritis and classification of these patients two years later. Arthritis Rheum 2001; 44: 2485–91., , , , , , et al.
- 21Epidemiological Investigation of Rheumatoid Arthritis Study Group. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA–DR (shared epitope)–restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006; 54: 38–46., , , , , , et al, and the
- 23The Framingham Study: historical insight on the impact of cardiovascular risk factors in men versus women. J Gend Specif Med 2002; 5: 27–37..
- 24On the use of sibling recurrence risks to select environmental factors liable to interact with genetic risk factors. Eur J Hum Genet 2009. E-pub ahead of print., , , .