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Clustering of Extraarticular Manifestations in Patients with Rheumatoid Arthritis

To the Editor:

Rheumatoid arthritis (RA) is a chronic, inflammatory disorder associated with a number of extraarticular manifestations. Extraarticular RA (ExRA) tends to be more frequent in patients with severe disease1. We previously reported from a study of a community based sample of patients with RA that ExRA manifestations of some kind occur in about 40% of all patients, and that 15% develop severe ExRA manifestations at some time2. Different manifestations may share different pathogenetic mechanisms, including vascular abnormalities3, and it has been shown that rheumatoid nodules predict severe extraarticular disease4. Based on this, it would be expected that some extraarticular manifestations tend to occur together, but this has never been formally tested. Further, the preferential time periods for onset of various manifestations have not been studied systematically.

We analyzed data from a community based RA cohort, in which the occurrence of ExRA manifestations was thoroughly investigated5. Using the resources of the Rochester Epidemiology Project, all incident cases of RA residing in Rochester, Minnesota, USA, with disease onset between January 1, 1955, and December 31, 1994, were identified (n = 609)6. The date of RA diagnosis was defined as the date of fulfillment of the 1987 American College of Rheumatology (ACR) criteria for RA. A structured review of all medical records from all care providers in the area was performed as described5. ExRA manifestations were identified and classified according to predefined criteria2,5. The date of first onset was noted for each manifestation. Patients were followed from diagnosis of RA until death, loss to followup, or December 31, 2000. ExRA manifestations were classified into the following groups: serositis (pericarditis or pleuritis), vasculitis (major cutaneous lesions or internal organ vasculitis), neuropathy (mono- or polyneuropathy), rheumatoid lung disease (interstitial lung disease or bronchiolitis obliterans organizing pneumonia), severe eye manifestations (scleritis/episcleritis/retinal vasculitis), Felty's syndrome, rheumatoid nodules, and secondary Sjögren's syndrome. The observed frequency of coexisting ExRA manifestations was compared to the expected, based on the marginal frequency of each manifestation. P values are based on Fisher's exact tests. The median time from fulfillment of the ACR criteria for RA to first diagnosis of ExRA was calculated for each manifestation.

ExRA manifestations occurred in 260 patients (42.7%) during a median followup of 11.8 years. The most frequent manifestation diagnosed was occurrence of rheumatoid nodules. The median time from the diagnosis of RA to onset of ExRA manifestations varied from 3.3 years for nodules to 11.5 years for pericarditis (Table 1). Vasculitis occurred in 20 cases, and these patients were significantly more likely than expected to also have neuropathy (p < 0.001), rheumatoid lung disease (p = 0.008), and nodules (p < 0.001; Table 2). Patients with rheumatoid nodules were more likely to have vasculitis, serositis, severe eye manifestations (p < 0.001, respectively) and rheumatoid lung disease (p = 0.001); Table 2). About 90% of RA patients with vasculitis or severe eye disease also had rheumatoid nodules. In addition, rheumatoid nodules occurred more frequently than expected in patients with Felty's syndrome (p = 0.02), secondary Sjögren's syndrome (p = 0.007), and neuropathy (p = 0.10).

Table 1. Duration of RA at diagnosis of individual extraarticular manifestations in the RA cohort (n = 609).

Table 2. Clustering of extraarticular manifestations in the RA cohort (n = 609).

Our findings support the concept that different ExRA manifestations often coexist in patients with severe RA. The clustering of vasculitis with neuropathy and rheumatoid lung disease suggests shared disease mechanisms. Studies of nerve biopsy specimens from patients with RA-associated neuropathy have revealed signs of necrotizing vasculitis7. Further, rheumatoid nodules are characterized by early vascular changes resembling vasculitis8. As we found rheumatoid nodules to cluster with virtually all other ExRA manifestations studied, and nodules often precede other manifestations, this may indicate that vascular pathogenetic mechanisms are important in all types of ExRA. Immunoglobulin deposition, high inflammatory load, and systemic endothelial activation3 have been implicated in ExRA. The influence of inflammation on the vasculature in systemic RA is of particular interest, given the association between RA and cardiovascular comorbidity9, with a particularly increased risk in patients with severe ExRA10. The mechanisms underlying these associations should be studied further.

The major strength of this study is the community based approach, which limits selection of severe RA cases and enables an estimate of the true burden of extraarticular disease in the community. One limitation is due to the retrospective method, which limits the analysis to case-record data collected by the managing physician. On the other hand, this means that the observations made reflect manifestations considered clinically relevant.

We have demonstrated that severe ExRA manifestations cluster in patients with RA in a community based sample. Vasculitis is particularly associated with neuropathy, rheumatoid lung disease, and nodules. Rheumatoid nodules are associated with all other ExRA manifestations, and often precede the onset of severe ExRA. These findings suggest shared disease mechanisms in systemic manifestations of RA.

CARL TURESSON, MD, PhD, Department of Rheumatology, Malmö University Hospital, Malmö, Sweden, and Division of Rheumatology, Mayo Clinic College of Medicine; ROBYN L. McCLELLAND, PhD, Department of Biostatistics, University of Washington, Seattle, Washington; TERESA CHRISTIANSON, BSc, Department of Health Sciences Research; ERIC MATTESON, MD MPH, Division of Rheumatology, Mayo Clinic College of Medicine, Minneapolis, Minnesota, USA. Address reprint requests to Dr. C. Turesson, Department of Rheumatology, Malmö University Hospital, 205 02 Malmö, Sweden. E-mail:

Supported in part by the US National Institutes of Health (grant K24 AR 47578-01A1), the Swedish Rheumatism Association, and the Swedish Society for Medicine.


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1. Gordon DA, Stein JL, Broder I. The extra-articular features of rheumatoid arthritis. A systematic analysis of 127 cases. Am J Med 1973;54:445-52.

2. Turesson C, O'Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis. J Rheumatol 2002;29:62-7. [MEDLINE]

3. Turesson C, Englund P, Jacobsson LT, et al. Increased endothelial expression of HLA-DQ and interleukin 1 alpha in extraarticular rheumatoid arthritis. Results from immunohistochemical studies of skeletal muscle. Rheumatology Oxford 2001;40:1346-54. [MEDLINE]

4. Voskuyl AE, Zwinderman AH, Westedt ML, Vandenbroucke JP, Breedveld FC, Hazes JM. Factors associated with the development of vasculitis in rheumatoid arthritis: results of a case-control study. Ann Rheum Dis 1996;55:190-2. [MEDLINE]

5. Turesson C, O'Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis 2003;62:722-7. [MEDLINE]

6. Doran MF, Pond GR, Crowson CS, O'Fallon WM, Gabriel SE. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum 2002;55:625-31.[MEDLINE]

7. Puechal X, Said G, Hilliquin P, et al. Peripheral neuropathy with necrotizing vasculitis in rheumatoid arthritis. A clinicopathologic and prognostic study of thirty-two patients. Arthritis Rheum 1995;38:1618-29. [MEDLINE]

8. Sokoloff L, McCluskey RT, Bunim JJ. Vascularity of the early subcutaneous nodule of rheumatoid arthritis. Arch Pathol 1953;55:475-95.

9. Solomon DH, Karlson EW, Rimm EB, et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003;107:1303-7. [MEDLINE]

10. Turesson C, McClelland RL, Christianson TJ, Matteson EL. Severe extra-articular disease manifestations are associated with an increased risk of first-ever cardiovascular events in patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66:70-5. [MEDLINE]

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