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Objective: The aims of this study were to evaluate whether treatment with tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis (RA) affects the risk of developing severe extraarticular rheumatoid arthritis (ExRA) manifestations and to investigate potential predictors for developing ExRA., Methods: A dynamic community-based cohort of patients with RA was studied (n = 1977). Clinical records were reviewed and cases of severe ExRA were identified. Information on exposure to TNF inhibitors was obtained from a regional register. Exposure to TNF inhibitors was analyzed in a time-dependent fashion and the incidence of severe ExRA in exposed patients was compared with the incidence in unexposed patients. Cox regression models were used to assess potential predictors of severe ExRA., Results: During treatment with TNF inhibitors, there were 17 patients with new onset of severe ExRA in 2400 person-years at risk (PY; 0.71/100 PY, 95% CI 0.41-1.13) compared with 104 in 15,599 PY (0.67/100 PY, 95% CI 0.54-0.81) in patients without TNF inhibitors. This corresponded to an incidence rate ratio of 1.06 (95% CI 0.60-1.78). The age- and sex-adjusted HR for ExRA in anti-TNF-treated patients was 1.21 (95% CI 1.02-1.43), with similar findings in models adjusted for time-dependent Health Assessment Questionnaire and propensity for anti-TNF treatment. Male sex, positive rheumatoid factor (RF), long disease duration, and greater disability were predictors for ExRA., Conclusion: This study suggests that patients treated with TNF inhibitors are at a slightly increased risk of developing severe ExRA. RF-positive patients with disabling disease of long duration were more likely to develop severe ExRA.

Purpose of Review: To discuss recent findings on the epidemiology and pathogenesis of extra-articular manifestations in rheumatoid arthritis (RA), and provide an update on the literature on treatment of patients with extra-articular RA (ExRA) manifestations., Recent Findings: ExRA is associated with increased comorbidity and mortality. Several surveys suggest that some ExRA manifestations, in particular vasculitis, occur less frequently than previously reported. This is probably due to improved overall control of disease activity. Active RA with high disease activity is associated with increased risk of severe ExRA manifestations. Studies on the impact of treatment with biologics on the occurrence of ExRA are inconclusive. Circulating immune complexes and T cells have been implicated in the pathogenesis of ExRA. The genetic background and related disease mechanisms may be somewhat different in manifestations such as vasculitis and interstitial lung disease. Limited data support a benefit from treatment with cyclophosphamide, TNF-inhibitors or rituximab in patients with severe ExRA., Summary: ExRA remains a major diagnostic and therapeutic challenge in some patients. Further studies of the pathogenesis of systemic involvement and on the effect of treatment on such mechanisms may be helpful for further improvement of the management of RA.

Objectives: To determine the incidence of severe extra-articular rheumatoid arthritis (ExRA) in a community-based cohort of RA patients, and to evaluate whether treatment with tumour necrosis factor (TNF) inhibitors has any effect on the risk of ExRA., Methods: In a review of clinical records from 1 July 1997 to 31 December 2004, severe ExRA manifestations were classified according to predefined criteria. Patients were censored at the development of ExRA, death, emigration, or 31 December 2004. Exposure to anti-TNF treatment has continuously and independently been recorded as part of a regional follow-up system., Results: During treatment with TNF inhibitors, there were two patients with new onset of ExRA in 408 person-years at risk (pyr) [0.49/100 pyr, 95% confidence interval (CI) 0.06-1.77]. Among those without anti-TNF treatment there were 63 patients with ExRA in 5425 pyr (1.16/100 pyr, 95% CI 0.89-1.49). The relative risk comparing those treated to those not treated with TNF inhibitors was 0.42 (95% CI 0.10-1.73)., Conclusion: Our data show a lower incidence of ExRA in patients treated with TNF inhibitors but further studies with a larger sample size are needed for a more accurate estimate of the size of the effect.

Purpose of Review: To examine the occurrence and pathophysiology of vasculitis in rheumatoid arthritis (RA), describe the epidemiology and clinical features, and provide a therapeutic perspective., Recent Findings: With improved control of RA over the past two decades, the risk of severe outcomes such as vasculitis may be decreasing. Rheumatoid vasculitis continues to be associated with longstanding, erosive, seropositive disease, and it has recently been shown to be more frequent among patients with antibodies to cyclic citrullinated peptides. Apart from circulating immune complexes, expansion of cytotoxic CD28null T cells and circulating proinflammatory cytokines also play a role in the pathogenesis. The role of agents directed against the tumor necrosis factor (TNF) in the occurrence and management of rheumatoid vasculitis remains unclear, as rheumatoid vasculitis may be both associated with and treated with anti-TNF agents, once it has appeared., Summary: Vasculitis in RA is generally associated with longstanding disease, has an important impact on a patient's well being, and markedly influences patient life expectancy. Advances in therapies for RA will likely continue to reduce the incidence of vasculitis, and improved management of cardiovascular comorbidity in patients with RA will be of particular benefit to those who suffer from vasculitis and other extraarticular manifestations.

Objective: To compare HLA-C genotypes and smoking habits in patients with vasculitis or other severe extraarticular manifestations of rheumatoid arthritis (ExRA) with those in RA patients without extraarticular disease., Methods: Patients were recruited from a large research database of patients with RA at the Mayo Clinic, from 2 Swedish cohorts of prevalent RA cases, and from a regional Swedish early RA cohort. Patients with severe ExRA (n = 159) and control patients with RA but no history of ExRA (non-ExRA controls) (n = 178) were matched for duration of RA and for clinical center. Data on smoking at RA onset, rheumatoid factor (RF) status, and antinuclear antibodies (ANAs) were extracted from the medical records. Polymerase chain reaction-based HLA-C genotyping was performed using a sequence-specific primer kit., Results: The distribution of HLA-C alleles was significantly different between patients with RA-associated vasculitis and non-ExRA controls (P = 0.014). This was mainly due to a positive association of the HLA-C3 allele with vasculitis (allele frequency 0.411 in vasculitis patients versus 0.199 in non-ExRA controls; P < 0.001) and a decreased frequency of HLA-C7 (0.122 and 0.243, respectively; P = 0.018). The association between HLA-C3 and vasculitis was not due to linkage disequilibrium with HLA-DRB1. Smoking (P = 0.001), RF positivity (P < 0.0001), and presence of ANAs (P < 0.0001) were all associated with ExRA. HLA-C3 and smoking were both significant predictors of vasculitis in a multivariate model., Conclusion: Vasculitis in RA is associated with HLA-C3. Smoking is an independent predictor of vasculitis and other types of severe ExRA. Our results suggest that these variables are among the genetic and environmental factors that contribute significantly to the pathomechanisms of systemic RA.

Extra-articular RA (ExRA) includes a wide variety of disease manifestations. Although rheumatologists in general are aware that such events are clinically important, the heterogeneity of available data, including discrepancies in case definitions, has complicated constructive discussions on this aspect of the RA disease phenotype. In recent years, there has been a growing recognition of the importance of co-morbidity in patients with RA. ExRA manifestations are not uncommon, explain excess mortality in RA and are predicted by smoking and autoantibodies. Further studies of the mechanisms underlying these associations are likely to be important in improving our understanding of the systemic nature of RA. This article discusses the methodological issues involved in the study of ExRA manifestations, presents suggested criteria that have been used in clinical studies, and reviews important surveys of the epidemiology of extra-articular RA.

Objective: The prevalence and distribution of extra-articular manifestations of rheumatoid arthritis (ExRA) and associated mortality were studied retrospectively in a cohort of RA patients admitted to University Hospital, Malmö, Sweden, during the period 1990-94., Results: Of 489 patients who fulfilled the 1987 ACR criteria for RA, 37 manifested onset of ExRA, predominantly serositis and cutaneous vasculitis, during the period, corresponding to a cumulative incidence of 7.9%. The occurrence of ExRA was independent of disease stage. Among patients with ExRA, 1 death/4.3 person-years at risk (pyr) occurred, as compared with 1 death/11.4 pyr in the non-ExRA subgroup. The age- and sex-adjusted mortality rate ratio was 2.49 (95% confidence interval 1.43-4.03). The major cause of death among ExRA cases was heart disease, which occurred in 9/13 cases (69%) in comparison to the expected 2.4 cases., Conclusion: In this series, serositis and cutaneous vasculitis were predominant extra-articular manifestations of RA; and mortality was greater in the ExRA than in the non-ExRA subgroup, perhaps due to a high frequency of associated heart disease.