Brief Summary
Inflammatory joint diseases are major causes of invalidity and morbidity. Rheumatoid
<br /> arthritis (RA), the most frequent of chronic arthritides, affects close to 1% of the Canadian
<br /> population. Direct and indirect costs of RA represent close to 1% of the gross national
<br /> product. Recent evidence suggest that initiation of early (e.g., during the first 3-12 months
<br /> of disease) aggressive treatment decreases both mortality and long term invalidity in RA and
<br /> other chronic arthritides. However, a significant proportion of patients with early
<br /> polyarthritis (EPA) have a benign evolution, even if they fulfill criteria for RA. On the
<br /> contrary, most patients whose arthritis persist for more than 12 months have a progressive
<br /> and destructive disease. Currently available clinical, serological and genetic markers of
<br /> severity in arthritic patients perform poorly in EPA patients to identify those patients
<br /> whose arthritis is likely to persist and thus who deserve an aggressive treatment.
<br />
<br /> The Investigators propose a prospective and longitudinal study to define the contribution of
<br /> detection of rheumatoid arthritis-specific autoantibodies (RASA), either alone or in
<br /> combination with other markers of severity, in the prognostic evaluation of patients
<br /> presenting with EPA. Availability of such an effective serological tool to establish
<br /> prognosis in individual patients would improve therapeutic decisions in clinical practice.
<br /> The same prognostic tools would represent very powerful instruments to subset patients into
<br /> more homogeneous groups in clinical trials, increasing their power.
Detailed Description
Inflammatory polyarthritides are major causes of invalidity and morbidity. Treatment of
rheumatoid arthritis (RA), the most common and most severe of these diseases, is clearly more
effective when initiated early using aggressive therapeutic protocols. The recent
availability of very effective but extremely costly biologic agents may further improve our
treatment strategies. Specific arthritides (e.g., RA) were defined using sets of criteria
that are unable to define prognosis and cannot be used to select which patients, early in the
course of their disease, should be treated aggressively. A number of putative prognostic
markers of severity are available, including anti-Sa and anti-Cyclic Citrullinated peptides
(Anti-CCP) antibodies (Abs), whose presence is highly specific to RA. Anti-Cit Abs might
characterize one of the severe subsets of RA, both clinically and pathogenically. However,
these markers are not yet demonstrated to risk-stratify patients with arthritis of recent
onset.
Objectives. Our PRIMARY objectives are to evaluate the sensitivity, specificity, and positive
likelihood ratios (+LR) of anti-Sa Abs to identify among patients with early polyarthritis
(EPA) in the first 12 months of disease (median 4 months) those that will, at 18, 30, 42 and
60 months into disease : 1- have persistent arthritis; 2- satisfy American College of
Rheumatology (ACR) criteria for RA; 3- have developed a SEVERE disease (as defined by their
Sharp/van der Heijde radiological score or their modified Health Assessment Questionnaire
(M-HAQ) score, as well as by our composite index that includes both scores).
In particular, we want to evaluate the size of the ADDITIONAL independent contribution of
anti-Sa Abs to predict severe disease, when added to markers of poor prognosis in established
RA (e.g., immunoglobulin M (IgM) Rheumatoid Factor (RF), "shared epitope", persistent high
C-Reactive Protein (CRP) levels).
Our SECONDARY objectives are to evaluate the sensitivity, specificity, and +LR : 1- of
anti-CCP and anti-Sa Abs (individually and in sets) to identify among patients with EPA those
who will develop a SEVERE disease after 18, 30, 42, and 60 months; 2- of novel genetic
markers to identify among patients with EPA those that will develop a SEVERE disease after
18, 30, 42, and 60 months; 3- of anti-Sa and anti-CCP Abs to identify among patients with EPA
those patients who will require more intensive anti-rheumatic treatment (DMARD combinations
and/or biologics) at 18, 30, 42 and 60 months; and 4- of serum and urine markers of cartilage
degradation and regeneration to identify among patients with EPA those that will develop a
SEVERE disease after 18, 30, 42, and 60 months.
Methods. We set up a single-center longitudinal observational study (LOS) planned to include
390 consecutive EPA patients observed over 5 years. EPA is defined as synovitis affecting 3
or more joints for more than one month and less than 12 months, with few specific exclusions.
At inclusion, and at each pre-defined time points after disease onset, extensive (but
focused) demographic, clinical, serological, radiological and genetic data are collected,
without interference with their treatment. Treating physicians and patients remain uninformed
about the status of the patients regarding research data (genomic data, anti-Sa and anti-CCP
Abs). About 250 such patients will have been included at the time of renewal. Loss to follow
up (up to V4 in some patients) at each visit is about 5% and is mostly found in patients in
remission. Data collected are used to verify whether patients have reached predefined
outcomes including remission, persistence of arthritis, persistence of arthritis fulfilling
RA criteria, DMARD use, and SEVERE disease.
Discussion. We have now assembled a large cohort of patients with EPA that are thoroughly
reassessed at regular intervals, allowing stratification of patients using outcome measures
that have been set in advance. The information gained from this study may have very
significant therapeutic and economic implications.