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“Early Arthritis” Centers have been organized for several years in Europe and Canada. Patients with new onset symptoms of undifferentiated, new onset, inflammatory arthritis are seen and have been enrolled in cohorts and followed for the development of RA. Cohorts followed in these clinics have demonstrated that early use of aggressive disease-modifying therapy for early rheumatoid arthritis (RA) can effectively halt or slow the progression of joint destruction1, 2. In the U.S., patients are still commonly referred to rheumatology practices after inflammatory arthritis has persisted for months or even years. Thus, substantial clinical momentum is now being directed at identifying potential early RA and starting appropriate treatment as early as possible in the disease course3.
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 influence4. 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 symptoms5, 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 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 RA7. Anti-citrullinated peptide autoantibodies (ACPA) are strongly associated with 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) Classification Criteria for RA do not reliably identify “early RA” for either research and clinical purposes10. The sensitivity of the current classification criteria for RA ranges from 25-90% and specificity from 60-90% for new onset disease11-13. 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, 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 two different methods for the identification of subjects with inflammatory arthritis and/or high-risk for developing RA(refs- Deane and Kolfenbach). Deane and colleagues sought to identify subjects with early inflammatory arthritis with high likelihood of being RA through community health fair screening. 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)14, and underwent a joint examination and a blood draw. They aimed to identify individuals with inflammatory arthritis, defined as having just one or more swollen joint(s). The health fair took place at five sites in Colorado and was visited by approximately 91,000 people, of which 601 participants were screened: 84 (14%) had inflammatory arthritis by this definition, 15 (2.5%) were found to have inflammatory arthritis and RF and/or ACPA, and 9 (1.5%) met current ACR criteria for the classification of RA, but had no prior diagnosis of RA.
Also in this issue Kolfenbach and colleagues, report the establishment of a cohort of subjects at high-risk subjects for developing RA, the Studies of the Etiology of RA (SERA) cohort. They recruited 1058 first-degree relatives of individuals with RA followed by rheumatologists in several U.S. cities, for SERA. Previous studies have indicated that first-degree relatives of individuals with RA are at significantly elevated risk of developing RA: the relative risk of developing RA for an offspring of an affected parent was 3 times that of the normal population15. The risk of RA was 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 epidemiological 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 follow-up.
What are the potential fruits of these two studies and the establishment of other early RA cohorts in the U.S.16? Which research questions could be optimally addressed by cohorts of high-risk individuals or pre-clinical RA subjects?
1. 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 specimen from individuals who eventually developed RA to 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 (sTNFRII) were elevated up to 12 months prior to the development of RA 17. This study employed banked blood samples from two prospective cohorts of women, the Nurses' Health Study (NHS) and the Women's Health Study (WHS), 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 prevalance of 1% 18, requires following thousands of individuals for many years. The SERA cohort allows for targeting of high-risk subjects likely to develop RA thus 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.
2. 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 19. Recent studies have demonstrated that genetic factors for ACPA-positive RA differ from those for seronegative disease; further studies promise to improve understanding of these two separate disease phenotypes, their genetics, manifestations and prognoses. Studies of families with multiple autoimmune diseases have also shed light on genes shared by multiple autoimmune diseases and their shared molecular pathways20.
3. As physicians, the advice we give to individuals with strong family histories of RA, or early non-specific 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 about the timing of initiating therapy. Efforts to develop combined clinical/genetic risk prediction tools for RA, l the Framingham Risk Score for cardiovascular disease21 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 anti-rheumatic drug therapy and followed for the development of symptomatic RA22. The prospect of such studies is exciting and should provide useful information about disease risk and the effects of early treatment.
4. 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 study of criteria validity and for their refinement over time as new data concerning autoantibodies and other clinical and serologic risk markers becomes available. High-risk and pre-clinical 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 exams and phone follow-up, paperwork, and lab testing, were estimated to be $2000 per person. Different staged strategies in which lab testing were 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 and colleagues 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 follow-up 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 cohorts23.
Identifying and studying subjects with pre-clinical 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.
Dr. Liao is supported by NIH grant T32 AR 055885. Dr. Costenbader is supported by NIH grant P60 AR047782.