Rheumatoid arthritis is associated with an increased mortality compared with the general population.1 Disability2 and severe extra‐articular rheumatoid arthritis (ExRA) manifestations3 predict mortality in patients with rheumatoid arthritis. In a previous study of a community‐based sample of patients with rheumatoid arthritis, we showed that ExRA was a strong predictor of mortality, whereas the survival of patients with rheumatoid arthritis without severe ExRA was not largely different from the background population.4 We have now studied the effect of multiple ExRA manifestations on mortality.
Using the resources of the Rochester Epidemiology Project, all patients with rheumatoid arthritis residing in Rochester, Minnesota, with a disease onset between 1 January 1955 and 31 December 1994 were identified (n = 609;5 table 1). A structured review of all medical records from all care providers in the area was carried out and ExRA manifestations were identified and classified according to predefined criteria, as previously described.6 Severe ExRA manifestations included pericarditis, pleuritis, vasculitis, peripheral neuropathy, Felty's syndrome, glomerulonephritis and scleritis or episcleritis. Patients were followed up from the time of rheumatoid arthritis diagnosis until death, loss to follow‐up or 31 December 2000.
Table 1 Clinical characteristics of the rheumatoid arthritis cohort.
| Male sex, n (%) | 164 (26.9) |
| Age at diagnosis, mean (SD) | 58.0 (15.1) |
| RF positive at diagnosis, n (%) | 185 (30.4) |
| Smokers at diagnosis, n (%)* | 317 (55.2) |
| BMI at diagnosis, mean (SD) (kg/m2) | 25.6 (4.9) |
| Any ExRA manifestation, n (%)† | 260 (42.7) |
| Severe ExRA manifestation,‡ n (%)† | 82 (13.5) |
| Rheumatoid nodules, n (%)† | 183 (30.0) |
| Pulmonary fibrosis, n (%)† | 36 (5.9) |
Cox proportional hazards were used to assess the effect on mortality of ExRA, as well as the effect on morality of new ExRA manifestations, controlling for the presence of previously existing ExRA. ExRA manifestations were modelled as time‐dependent covariates and the models were adjusted for age, sex, smoking at diagnosis of rheumatoid arthritis, body mass index (BMI (weight (kg)/height2 (m2))) at diagnosis and rheumatoid factor.
ExRA manifestations occurred in 260 (42.7%) patients during a median follow‐up of 11.8 years. ExRA was associated with increased mortality in the fully adjusted model (p<0.001; table 2). Additional ExRA manifestations occurred in 121 patients and further increased the risk of death (adjusted hazards ratio (HR) 1.91; 95% confidence interval (95% CI) 1.36 to 2.69). Onset of a first severe ExRA manifestation (n = 82) was particularly associated with premature mortality (adjusted HR 4.45; 95% CI 3.29 to 6.00). In patients with severe ExRA, the occurrence of a second severe ExRA manifestation (n = 17) further increased the risk of death (table 2), and the development of rheumatoid nodules (p = 0.001) or pulmonary fibrosis (p = 0.019) in patients with previously identified severe ExRA contributed significantly to increased mortality in adjusted models (table 2).
Table 2 Effect of ExRA manifestations on mortality in patients with rheumatoid arthritis.
| HR* | 95% CI | |
|---|---|---|
| First ExRA manifestation (any) | 2.20 | 1.73 to 2.82 |
| Second ExRA manifestation (any, controlling for first) | 1.91 | 1.36 to 2.69 |
| First severe ExRA manifestation† | 4.45 | 3.29 to 6.00 |
| Second severe ExRA manifestation (controlling for first) | 1.70 | 0.90 to 3.19 |
| Rheumatoid nodules after severe ExRA manifestation‡ | 1.60 | 1.21 to 2.12 |
| Pulmonary fibrosis after severe ExRA manifestation‡ | 1.83 | 1.10 to 3.04 |
ExRA, extra‐articular rheumatoid arthritis.
*The separate models were adjusted for age, sex, rheumatoid factor positivity at disease onset, smoking at disease onset and body mass index.
†Severe ExRA was defined according to the Malmö criteria.6,9
‡This model was adjusted for the presence of severe ExRA.
We found that the presence of multiple ExRA manifestations is associated with an increased overall mortality in rheumatoid arthritis. This is not explained by potential confounding factors such as smoking, rheumatoid factors and BMI. Smoking and rheumatoid factors are associated with increased comorbidity and mortality and are considered predictors of ExRA.6 Low BMI, presumably related to disease severity, is associated with increased mortality in patients with rheumatoid arthritis.7 However, the association between multiple ExRA manifestations and mortality remained significant in multivariate models adjusted for these factors.
Patients with severe ExRA have an increased risk of severe infections8 and cardiovascular disease.9 The role of rheumatoid arthritis‐associated pathomechanisms in comorbidities needs to be studied further. We suggest that the extent of systemic involvement is a major determinant of survival in patients with rheumatoid arthritis.
Acknowledgements
This study was supported by the National Institutes of Health (grant K24 AR 47578‐01A1), the Swedish Rheumatism Association, the Swedish Society for Medicine and a grant by the Mayo Clinic.
Footnotes
This study was approved by the Mayo Clinic Institutional Review Board.
Competing interests: None declared.
References
- 1.Wolfe F, Mitchell D M, Sibley J T, Fries J F, Bloch D A, Williams C A.et al The mortality of rheumatoid arthritis. Arthritis Rheum 199437481–494. [DOI] [PubMed] [Google Scholar]
- 2.Pincus T, Brooks R H, Callahan L F. Prediction of long‐term mortality in patients with rheumatoid arthritis according to simple questionnaire and joint count measures. Ann Intern Med 199412026–34. [DOI] [PubMed] [Google Scholar]
- 3.Gabriel S E, Crowson C S, Kremers H M, Doran M F, Turesson C, O'Fallon W M.et al Survival in rheumatoid arthritis: a population‐based analysis of trends over 40 years. Arthritis Rheum 20034854–58. [DOI] [PubMed] [Google Scholar]
- 4.Turesson C, O'Fallon W M, Crowson C S, Gabriel S E, Matteson E L. Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis. J Rheumatol 20022962–67. [PubMed] [Google Scholar]
- 5.Doran M F, Pond G R, Crowson C S, O'Fallon W M, Gabriel S E. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty‐year period. Arthritis Rheum 200246625–631. [DOI] [PubMed] [Google Scholar]
- 6.Turesson C, O'Fallon W M, Crowson C S, Gabriel S E, Matteson E L. Extra‐articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis 200362722–727. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Kremers H M, Nicola P J, Crowson C S, Ballman K V, Gabriel S E. Prognostic importance of low body mass index in relation to cardiovascular mortality in rheumatoid arthritis. Arthritis Rheum 2004503450–3457. [DOI] [PubMed] [Google Scholar]
- 8.Doran M F, Crowson C S, Pond G R, O'Fallon W M, Gabriel S E. Predictors of infection in rheumatoid arthritis. Arthritis Rheum 2002462294–2300. [DOI] [PubMed] [Google Scholar]
- 9.Turesson C, Jacobsson L, Bergstrom U. Extra‐articular rheumatoid arthritis: prevalence and mortality. Rheumatology (Oxford) 199938668–674. [DOI] [PubMed] [Google Scholar]