WP 3. Predictors of clinical outcome in patients with arthritis

This area of work will be lead by Partner 2 (Leiden) with input from 1 (Stockholm), Partner 3 (Berlin-Charité), Partner 4 (Vienna), Partner 5 (Dublin), partner 6 (Amsterdam), Partner 11 (Lund), Partner 12 (Umeå), Partner 13 (Prague), Partner 14 (Manchester), Partner 16 (Birmingham), Partner 18 (Evry-Paris), Partner 19 (Warsaw), Partner 20 (Heraklion), Partner 25 (BMD) and Partner 26 (Oligene). In this workpackage, we will also include subcontractors from Great Britain (Guy's Hospital, London).

The first aim in this part of the project refers to the genetic and environmental factors of importance for the chronicity in rheumatoid arthritis extending for several years and associated with various degree of structural damage. This will be evaluated in both children and adult population. The hall mark of the structural damage is development of radiographic erosions. There is considerable evidence that radiographic damage may be related to genetic factors but the genetic factors so far identified only have a limited role in predicting damage. Part of this may be the fact they are modified by a number of environmental factors. Such factors could include mechanical exposure including body weight but also needs to take on board the role of specific interventions as no patients within Europe remain untreated. It is important, as mentioned above, in evaluating the role of other treatment just for the confounding effects of disease severity. In this way it may also be possible to identify those factors associated with good treatment response, many of which are likely to be genetic in origin. Influence of gender will also be considered.

In a similar manner to that outlined in WP 2 the main focus of this part of the workplan would be to identify those large cohorts including NOAR, the Early arthritis clinic from Leiden and EIRA cohort from Sweden and other currently existing longitudinal RA cohorts within Europe which include structured and standardised clinical and laboratory information both on disease characteristics at baseline and also at outcome including the availability of radiographs which could be evaluated at five years after disease onset. Many of these cohorts are readily available without the need for further data collection.

Part of the workplan would be the centralised evaluation of the x-rays according to common scheme to take account of variation in reading locally. Another part of the plan would be to pool these datasets having examined a common database to achieve this. Results from the analyses of the pooled data of the already available clinical phenotypes, serological data and genotypes will be achieved.

Subproject on influence of a North-South gradient as to disease course of RA

Lead by partner Dimitrios Boumpas (Heraklion, Crete ) in collaboration with Gabriel Panayi ( London ) and dr Rantapää-Dahlqvist, Umeå

To study the North-South gradient on the late consequence of RA a total of 60 adult patients with rheumatoid arthritis (RA) of less than 2 year duration will be included ((from London, Crete and Umeå) to evaluate genetic and other risk factors such for development of atherosclerosis. Patients ought not to have received any other therapy except non-steroidal anti-inflammatory drugs and prednisone (less than 10 mg/day). Disease activity will be scored by the DAS (disease activity score) a validated tool for studies in RA. In addition to RA patients, 30 age- and sex-matched controls without inflammatory diseases will be also included in this study from each site (total 60 controls). Information about demographics and risk factors for atherosclerosis will be recorded. Moreover, all patients will have determinations of serum lipids, homocysteine, C-reactive protein, rheumatoid factor, IL-10, and hsp60. Blood will also be collected for isolation of DNA to be used for detection of Toll-like receptor (and other gene) polymorphisms that have been shown to correlate with atherosclerotic disease. DNA will also be typed for the presence of the DR shared epitope. RNA will be isolated from monocytes separated by Percoll gradient and will be subjected for gene analysis by DNA arrays using Affymetrics DNA chips.

Endothelial dysfunction and injury are widely accepted as primary, early events in the atherosclerosis while increased common carotid artery intima-media thickness (CCA-IMT) is thought to represent an early atherosclerotic lesion. Both patients and controls will also undergo evaluation of endothelial function and measurements of common carotid artery intima-media thickness (CCA-IMT) by ultrasonography lesion applying established techniques.

Patients and controls will be re-evaluated 2 years later using the same protocol. DAS scores will be correlated with the measures of atherosclerotic disease. Atherosclerosis will be correlated with DNA polymorphisms and gene expression.