Torgny Smedby

Background Rheumatoid arthritis (RA) is a systemic progressive destructive joint disease with an increased risk for co-morbidity and premature death if untreated. Cardiovascular disease (CVD) is the main cause of death but also other co-morbid conditions contribute to the patient’s shorter life expectancy. Inflammation is important for the development of CVD, but knowledge of its relationship with other co-morbidities is sparse. Early disease modifying anti rheumatic drugs (DMARDs) can suppress disease activity and improve the long-term outcome. The aim of this thesis was to evaluate prospectively aspects of disease activity and severity in a large cohort of patients with early RA. Predictive and prognostic markers, e.g., antibodies against citrullinated proteins/peptides (ACPAs), occurring in early disease and with implications for disease outcome and co-morbidity were evaluated.Methods Patients with early RA (i.e., symptomatic for ≤12 months) have, since December 1995, been consecutively included in a large survey of prospective and observational studies on the progression of RA and the development of co-omorbidity. Autoantibodies, inflammatory, genetic markers and radiographs have been analyzed. In paper I, 210 RA patients and 102 controls were followed regularly for two years. The predictive value of four different ACPAs in relation to disease activity and radiological progression was evaluated. In Paper II (n = 700) and in Papers III-IV (n =950), patients with early RA from the four northern-most counties of Sweden were followed regularly for 5 years. Data on risk factors and co-morbidity was collected, according to the study protocol, from clinical records and self-reported questionnaires from patients at inclusion into the study cohort and after five years. The predictive value of traditional and potential disease related risk factors for new cardiovascular events (CVE) was evaluated (II). In Paper III, the impact of age at the onset RA, stratified as being young onset RA (<58 years; YORA) and late onset RA (≥58 years; LORA) on disease activity, severity and chosen treatment, was evaluated. In Paper IV, the development of new co-morbidities after RA onset and their relation to inflammatory activity was assessed.Results The presence of anti-mutated citrullinated vimentin (MCV ) antibodies was associated with a more severe disease course, estimated by disease activity score, erythrocyte sedimentation rate (ESR) and swollen joint count after 24 months, compared with anti-CCP2, anti-CCP3, and anti CCP3.1 antibodies. In Paper II, the incidence of a new CVE during 5 years was explained by several of the traditional CV risk factors, and potentiated by a high disease activity. Treatment with DMARDs decreased the risk. In Paper III, LORA patients were associated with greater disease activity/severity at disease onset and over time compared with YORA who were more often ACPA positive. YORA patients were treated earlier with DMARDs, whilst LORA patients were more often treated with corticosteroids and less so with DMARDs early in the course of their disease. In Paper IV, 53%of patients already had one or more co-morbidities already at the onset of RA. After 5 years, 41% of the patients had developed at least one new co-morbidity. ESR at baseline and accumulated disease activity were associated with a new co-morbidity after five years.Conclusion Early RA patients sero-positive for anti- MCV antibodies appeared to have a higher disease activity over time. The occurrence of a new CVE in early RA patients was predicted by traditional risk factors for CVD which were potentiated by a high disease activity. Treatment with DMARDs decreased the risk. Patients with young onset of RA were associated with a higher frequency of ACPA. Late onset of RA was associated with higher disease activity/severity at inclusion and over time. However, LORA patients were more often treated with corticosteroids and less so with DMARDs early in the disease course. Development of a new co-morbidity during the five years following diagnosis was related to ESR.

Background: Patients with rheumatoid arthritis (RA) suffer from co-morbidities that contribute to a shortened lifespan. Inflammation is important for the development of cardiovascular disease, but little is known on its relationship with other co-morbidities. We investigated the role of inflammation for the development of new comorbidities in early RA. Methods: Since 1995, all patients with early RA in Northern Sweden are included in a prospective study on co-morbidities, with a total of 950 patients being included. At the time for this study, 726 had been ill for ≥5 years. Data on co-morbidities, clinical and laboratory disease activity and pharmacological therapy were collected from patient records and further validated using a questionnaire at RA onset (T0) and after 5 years (T5). Results: Of the patients, 53.2 % of the patients had one or more co-morbidity at onset, the commonest being: hypertension (27.3 %), obstructive pulmonary disease (13.9 %), diabetes (8.0 %), hypothyroidi...

BackgroundCardiovascular (CV) risk stratification for patients with rheumatoid arthritis (RA) should facilitate evidence-based management. Prior work has derived an internally validated a CV risk score, the Expanded Cardiovascular Risk Prediction Score for Rheumatoid Arthritis (ERS-RA), using US data. The aim of this study was to perform an external validation among unselected patients with RA from Europe.MethodsThree large, partially overlapping, cohorts of patients with RA from the Swedish Rheumatology Quality register were identified for external validation, two with information on smoking and two with close to 10 years of median follow-up. The 10 -year rate of first CV events was assessed using the Kaplan-Meier method. The performance of ERS-RA was assessed using C-index and comparisons of observed versus predicted risks.ResultsThe C-index for ERS-RA varied across the three RA cohorts, from 0.75 to 0.78. Predicted risks corresponded well to observed risks among individuals with ...

ABSTRACT Background In the general population several inflammatory cytokines, for example pentraxin3 (ptx3), monocyte chemoattractant protein 1 (MCP-1), interleukin 6 (IL-6), TNF-receptor 1 (TNFR1), TNFR2, endoglin, VCAM and ICAM, have been found to be associated with an increased risk of cardiovascular disease (CVD). In most studies these biomarkers are elevated in patients with rheumatoid arthritis (RA), however they are not well studied with regard of the development of atherosclerosis among patients with RA. After five years of follow-up in patients with a recent onset of RA, we have found sub-clinical atherosclerosis, when measured as intima media thickness (IMT) and flow-mediated dilation (FMD), to be more progressive than in controls. Objectives The aim of the present study was to investigate whether this sub-clinical atherosclerosis in the patients with RA could be associated with cytokines associated with an increased risk of CVD. Methods Patients from northern Sweden diagnosed with early RA are followed in an ongoing prospective study of co-morbidity. From these patients a subgroup aged ≤60 years (n=71), was consecutively included for measurements of IMT of a. carotis communis and FMD of a. brachialis. 40 age/sex matched controls were included. The ultrasound measurements were taken at inclusion (T0) and after 5 years (T5). The patients were clinically assessed (DAS28, TJC, SJC, DMARDs, ESR and CRP) and blood was drawn from all individuals at T0 and T5 for analysis of cholesterol, HDL-cholesterol, triglycerides, ptx3, MCP-1, IL-6. At T5 also s-VCAM, s-ICAM, TNFR1, TNFR2 and endoglin were analysed. SCORE and Reynolds Risk Score were calculated at T0 and T5. Results At the follow up at 5 years, i.e. at T5, patients with RA had significantly higher levels of ptx3 (0.996 vs 0.69, p<0.05), VCAM (365.7 vs 325.7, p<0.05) and TNFR2 (7369.1 vs 4364.0, p<0.001) compared with the controls. There were no difference between patients with RA and controls regarding any of the other biomarkers measured. In simple linear regression models at T5 among patients with RA the inflammatory cytokines were significantly associated with several other variables at T5: ptx3 with area under the curve (AUC) for DAS28 over 60 months; IL-6 with AUC for CRP over 60 months (p<0.001); MCP-1 with cholesterol (p<0.05); s-ICAM with IMT, FMD (inversely), age and Reynolds Risk score (p<0.01); s-VCAM with Reynolds Risk score (p<0.05); TNFR2 with ESR (p<0.05); endoglin inversely with DAS28 and ESR (p<0.05). None of the cytokines measured at T0 were significantly associated with the atherosclerosis neither at T0 nor at T5. Conclusions The extent of atherosclerosis among patients with RA after 5 years follow-up was associated with the adhesion molecule s-ICAM. Moreover, several of the inflammatory cytokines associated with an increased risk of CVD in the general population were associated with conventional markers of disease activity among the patients with RA. Again, this emphasise the necessity of an optimal treatment of these patients, also for the prevention of co-morbidities like CVD. Disclosure of Interest None Declared