Rheumatoid Arthritis: Turesson C

Turesson C, Matteson EL. · Department of Rheumatology, Malmo University Hospital, Malmo, Sweden. · Curr Opin Rheumatol. · Pubmed #19077716 No free full text.

Abstract: 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.

Turesson C, Jacobsson LT, Matteson EL. · Department of Rheumatology, Malmö University Hospital, Malmö, Sweden. · Vasc Health Risk Manag. · Pubmed #18827910 links to  free full text

Abstract: Patients with rheumatic disorders have an increased risk of cardiovascular disease (CVD). This excess co-morbidity is not fully explained by traditional risk factors. Disease severity is a major risk factor for CVD in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Shared disease mechanisms in atherosclerosis and rheumatic disorders include immune dysregulation and inflammatory pathways, which are potential targets for therapy. Lessons from RA and SLE may have implications for future research on the pathogenesis of atherosclerotic vascular disease in general. Recent data indicate that suppression of inflammation reduces the risk of CVD morbidity and mortality in patients with severe RA. The modest, but clinically relevant, efficacy of atorvastatin treatment in RA adds to the evidence for important anti-inflammatory properties for statins. There is increased recognition of the need for structured preventive strategies to reduce the risk of CVD in patients with rheumatic disease. Such strategies should be based on insights into the role of inflammation in CVD, as well as optimal management of life style related risk factors. In this review, the research agenda for understanding and preventing CVD co-morbidity in patients with rheumatic disorders is discussed.

Turesson C, Matteson EL. · Department of Rheumatology, Malmö University Hospital, Malmö, Sweden. · Curr Opin Rheumatol. · Pubmed #17278937 No free full text.

Abstract: PURPOSE OF REVIEW: There is increased recognition of an excess risk of cardiovascular disease in patients with rheumatic disorders. Physical inactivity is a frequent complication of arthritis, and also common in the general population. In this review, we highlight recent findings on risk factors for cardiovascular disease in patients with rheumatic diseases, and explore the role of physical activity for the prevention of cardiovascular disease. RECENT FINDINGS: Inflammatory mechanisms are clearly involved in cardiovascular disease in patients with systemic lupus erythematosus and rheumatoid arthritis. In rheumatoid arthritis, disability is also a major predictor of cardiovascular disease. A sedentary lifestyle increases the risk of cardiovascular disease in the general population, and high physical activity prevents cardiovascular disease mortality and morbidity. Successful treatment of rheumatic disease with control of inflammation and improved functional capacity may also reduce the risk of cardiovascular disease. SUMMARY: As part of the effort to prevent vascular comorbidity, regular exercise should be encouraged in patients with rheumatic diseases, and structured interventions to reduce adverse lifestyle factors scientifically evaluated.

Turesson C, Matteson EL. · Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, Minn 55905, USA. · Mayo Clin Proc. · Pubmed #16438485 links to  free full text

Abstract: Rheumatoid arthritis (RA) is a heterogeneous autoimmune disorder of unknown cause with variable clinical expression. About 70% of patients are women. Genetic factors play an important role and likely account for about 60% of disease susceptibility and expression. The association with the HLA-DRB1 gene is the best understood, although several non-HLA loci have been linked to RA, including the 18q21 region of the TNFRSR11A gene, which encodes the receptor activator of nuclear factor kappaB, important in bone resorption in RA. Genetic factors are also important in the treatment of RA because the activity of enzymes relevant in the metabolism of drugs such as methotrexate and azathioprine, including methylenetetrahydrofolate reductase and thiopurine methyltransferase, are in part genetically determined.

Turesson C, Weyand CM, Matteson EL. · Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Arthritis Rheum. · Pubmed #15478157 links to  free full text

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Turesson C, Jacobsson LT. · Department of Rheumatology, Malmö University Hospital, Lund University, Sweden. · Scand J Rheumatol. · Pubmed #15163106 No free full text.

Abstract: 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.

Turesson C, Matteson EL. · Division of Rheumatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. · Curr Opin Rheumatol. · Pubmed #15103246 No free full text.

Abstract: PURPOSE OF REVIEW: To discuss the rationale for various treatment strategies in rheumatoid arthritis with extra-articular manifestations, and to review advances in understanding the impact of extra-articular rheumatoid arthritis and its management. RECENT FINDINGS: Recent epidemiologic studies of extra-articular rheumatoid arthritis manifestations have emphasized their major role as predictors of premature mortality in patients with rheumatoid arthritis, and provide a rationale for aggressive ant-rheumatic treatment of extra-articular rheumatoid arthritis. Previous uncontrolled or nonrandomized studies favor the use of cyclophosphamide in patients with systemic rheumatoid vasculitis, and methotrexate in the case of other manifestations of extra-articular rheumatoid arthritis. Recent case reports indicate that patients with rheumatoid lung disease may respond to cyclosporine or tumor necrosis factor inhibitors, and that tumor necrosis factor blocking therapy also may be successful in cases of treatment-resistant vasculitis. By contrast, it has been suggested that tumor necrosis factor inhibitors may induce some manifestations of extra-articular rheumatoid arthritis. Data indicating a high risk of serious infections and cardiovascular disease in patients with extra-articular rheumatoid arthritis underline the importance of carefully monitoring such patients. SUMMARY: Extra-articular rheumatoid arthritis is a serious condition, and rheumatoid arthritis patients with extra-articular manifestations should be aggressively treated and monitored. Advances in the understanding of the pathogenesis of rheumatoid arthritis and developments of new, more specific drugs may be of particular benefit to patients with extra-articular disease.

Turesson C. · Department of Rheumatology, Malmö University Hospital, Malmö, Sweden. · Curr Pharm Des. · Pubmed #14754393 No free full text.

Abstract: Major histocompatibility complex (MHC) class II molecules are up-regulated on endothelial cells in human allografts, and are thought to be involved in graft rejection. The MHC class II subtypes HLA-DR, DQ and DP regulate T cell dependent immune responses, and aberrant expression could be important in autoimmunity. Increased endothelial MHC class II expression has been demonstrated in several autoimmune diseases, including myocarditis with dilated cardiomyopathy, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Recent data suggest that there is an association between endothelial expression of MHC class II molecules and diffuse endothelial dysfunction, which may be part of the explanation of the increased risk of cardiovascular disease in patients with RA, SLE and other chronic inflammatory conditions. MHC class II transcription is in part genetically determined. Cytokine induced up-regulation of MHC class II molecules can be inhibited in vitro by antioxidants and different drugs, such as cyclosporin and statins. Research on the development of new treatments for systemic autoimmune diseases and cardiovascular disease should include evaluation of effects on endothelial activation, including MHC class II expression. This review also discusses the genetic basis of MHC class II expression and its implications for understanding MHC genotype associations with autoimmune diseases. Recent studies of interactions between endothelial cells and T cells are reviewed. Such interactions could be of major importance in the pathogenesis of autoimmune and vascular diseases.

Nyhäll-Wåhlin BM, Petersson IF, Nilsson JA, Jacobsson LT, Turesson C, Anonymous00073. · Department of Rheumatology, Falun Hospital, Falun, Sweden. · Rheumatology (Oxford). · Pubmed #19213849 No free full text.

Abstract: OBJECTIVES: To identify patients with severe extra-articular RA (ExRA) in an early RA cohort and to investigate potential risk factors. METHODS: From a cohort (n = 2900) in a structured programme for newly diagnosed RA, 40 patients with severe ExRA after RA diagnosis were identified. Disease activity score (DAS28), functional disability (HAQ) and treatment with glucocorticosteroids (GCs) and DMARDs were assessed regularly. Cases with ExRA were compared with RA controls from the same cohort matched for age, sex and duration of symptoms at inclusion. RESULTS: Patients who developed severe ExRA were more often current smokers and had higher mean DAS28, HAQ and CRP at baseline. Among the ExRA cases, 93% had a positive RF vs 59% of the controls. The area under the curve (AUC) of DAS28 odds ratio (OR) 7.79/S.D.; 95% CI 3.04, 19.95, HAQ (OR 2.30/S.D.; 95% CI 1.37, 3.88) and CRP (OR 3.05/S.D.; 95% CI 1.77, 5.26) during the first 2 years of follow-up were strong predictors of subsequent development of ExRA. The most frequently used DMARDs were MTX and SSZ, with similar frequency and duration of treatment among cases and controls. The cases were treated with GC before onset of ExRA more frequently (73 vs 47%; P = 0.005) and with higher mean cumulative dose (3667 vs 2037 mg, P = 0.015). CONCLUSIONS: High levels of disease activity and disability during the first 2 years after RA diagnosis, smoking and RF predict the development of severe extra-articular RA.

Pikwer M, Bergström U, Nilsson JA, Jacobsson L, Berglund G, Turesson C. · Department of Rheumatology, Malmö University Hospital, 205 02 Malmö, Sweden. · Ann Rheum Dis. · Pubmed #18477739 No free full text.

Abstract: OBJECTIVE: To determine whether breast feeding or the use of oral contraceptives (OCs) affects the future risk of rheumatoid arthritis (RA) in a community-based prospective cohort. METHODS: A community-based health survey (18 326 women) was linked to regional and national registers, and incident cases of RA were identified. All women with a diagnosis of RA after inclusion in the health survey (n = 136) and four female controls for every case, who were alive and free from RA when the index person was given a diagnosis of RA, were included in a case-control study. Data on lifestyle factors at baseline were derived from a self-administered questionnaire. Potential predictors were examined in logistic regression models. RESULTS: 136 women with incident RA were compared with 544 age-matched controls. A longer history of breast feeding was associated with a reduced risk of RA (OR 0.46 (95% CI 0.24 to 0.91) for women who had breast fed for >/=13 months and OR 0.74 (95% CI 0.45 to 1.20) for those who had breast fed for 1-12 months, compared with those who had never breast fed). The protective effect of longer breast feeding remained significant after adjustment for smoking and level of education in multivariate models, and point estimates were protective also when the analyses were restricted to parous women. Neither parity nor OC use had any significant effect on the risk of RA. CONCLUSION: In this study, long-term breast feeding, but not OC use, was associated with a significant reduction in the risk of RA.

Michel JJ, Turesson C, Lemster B, Atkins SR, Iclozan C, Bongartz T, Wasko MC, Matteson EL, Vallejo AN. · Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA. · Arthritis Rheum. · Pubmed #17195207 links to  free full text

Abstract: OBJECTIVE: T cells deficient in CD28 expression have been implicated in the pathogenesis of rheumatoid arthritis (RA). Given that CD28-null T cells are functionally heterogeneous, we undertook this study to screen for novel receptors on these cells. METHODS: Seventy-two patients with RA (ages 35-84 years) and 53 healthy persons (32 young controls ages 19-34 years, 21 older controls ages 39-86 years) were recruited. Phenotypes and proliferative capacity of T cells from fresh leukocytes and of long-term cultures were monitored by flow cytometry. Lung biopsy specimens from patients with RA-associated interstitial pneumonitis (IP) were examined by immunohistochemistry. Receptor functionality was assessed by crosslinking bioassays. RESULTS: Chronic stimulation of CD28(+) T cells in vitro yielded progenies that lacked CD28 but that gained CD56. Ex vivo analysis of leukocytes from patients with extraarticular RA showed a higher frequency of CD56(+),CD28-null T cells than in patients with disease confined to the joints or in healthy controls. CD56(+),CD28-null T cells had nil capacity for proliferation, consistent with cellular senescence. CD56(+) T cells had skewed T cell receptor (TCR) alpha/beta-chain usage and restricted TCR third complementarity-determining region spectra. Histologic studies showed that CD56(+) T cells were components of cellular infiltrates in RA-associated IP. CD56 crosslinking on T cells sufficiently induced cytokine production, although CD56/TCR coligation induced higher production levels. CONCLUSION: Chronic activation of T cells induces counterregulation of CD28 and CD56 expression. The loss of CD28 is accompanied by the gain of CD56 that confers TCR-independent and TCR-dependent activation pathways. We propose that accumulation of CD56(+) T cells in RA contributes to maladaptive immune responses and that CD56(+) T cells are potential targets for therapy.

Jacobsson LT, Turesson C, Nilsson JA, Petersson IF, Lindqvist E, Saxne T, Geborek P. · Department of Rheumatology, Malmö University Hospital, S-205 02 Malmö, Sweden. · Ann Rheum Dis. · Pubmed #17158824 No free full text.

Abstract: OBJECTIVE: To assess mortality in patients with rheumatoid arthritis (RA) treated with tumour necrosis factor (TNF) inhibitors, compared with a standard RA population. METHODS: Patients were recruited from a regional register, which includes over 90% of patients with RA treated with TNF blockers in the area in 1999 or later, and a local community-based cohort of patients with RA, established in 1997. Of a total of 1430 patients in the combined cohort <80 years old, 921 received treatment with TNF inhibitors during the study period. The total cohort was linked with the national register for cause of death. Overall mortality in those treated versus those not treated with TNF blockers was estimated using standardised mortality ratios and time-dependent Cox proportional hazards. RESULTS: There were 188 deaths per 7077 person-years at risk in the total cohort. Controlling for age, sex, disability and baseline comorbidity, the adjusted HR for death was 0.65 (95% CI 0.46 to 0.93) in those treated with anti-TNF versus those not treated. The effect was significant in women (HR = 0.52, 95% CI 0.33 to 0.82) but not in men (HR = 0.95, 95% CI 0.52 to 1.71). CONCLUSION: After adjusting for disease severity, treatment with TNF inhibitors was found to be associated with a reduced mortality in women but not men with RA. These findings are compatible with a critical role for inflammation in RA-associated premature mortality.

Turesson C, Schaid DJ, Weyand CM, Jacobsson LT, Goronzy JJ, Petersson IF, Dechant SA, Nyähll-Wåhlin BM, Truedsson L, Sturfelt G, Matteson EL. · Department of Rheumatology, Malmö University Hospital, Malmö, Sweden. · Arthritis Rheum. · Pubmed #16947780 links to  free full text

Abstract: 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.

Turesson C, Jacobsson LT, Sturfelt G, Matteson EL, Mathsson L, Rönnelid J. · Department of Rheumatology, Malmö University Hospital, Södra Förstadsgatan 101, S-205 02 Malmö, Sweden. · Ann Rheum Dis. · Pubmed #16901955 No free full text.

Abstract: OBJECTIVE: To study antibodies to cyclic citrullinated peptides (anti-CCP) and rheumatoid factor in patients with active, severe extra-articular rheumatoid arthritis (ExRA) compared with controls without ExRA. METHODS: 35 consecutive patients with severe ExRA manifestations according to predefined criteria were studied. 70 patients with rheumatoid arthritis, but no ExRA manifestations, individually matched for age, sex and disease duration, served as controls. Patients were included when ExRA was diagnosed, before any new treatment was started. Anti-CCPs were detected with ELISA, rheumatoid factor was quantified using nephelometry and anti-nuclear antibodies (ANA) were investigated using indirect immune fluorescence. RESULTS: Anti-CCPs were detected in 77% of patients with ExRA versus 56% of controls without ExRA (p = 0.03). Anti-CCP levels also tended to be higher in patients with ExRA (p = 0.09). Rheumatoid factor was detected in 94% v 71% of patients and controls, respectively (p = 0.006), and rheumatoid factor levels were higher in patients with ExRA (median interquartile range (IQR) 245 IU/ml (94-604) v 73 IU/ml (not detected-165); p = 0.001). Levels and occurrence of ANA did not differ between patients with ExRA and controls. Patients with ExRA had higher swollen joint counts and C reactive protein levels, but no correlations were found between anti-CCP or rheumatoid factor levels and these measures within the ExRA group. CONCLUSION: Rheumatoid factor is strongly associated with severe ExRA manifestations in patients with rheumatoid arthritis, and a similar but weaker association exists for anti-CCPs. This suggests a role for rheumatoid factor and anti-CCP in the pathogenesis of ExRA.

Turesson C, McClelland RL, Christianson TJ, Matteson EL. · Division of Rheumatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Ann Rheum Dis. · Pubmed #16877533 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis is associated with increased cardiovascular mortality and morbidity. OBJECTIVE: To assess the effect of severe extra-articular rheumatoid arthritis (ExRA) manifestations on the risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis. METHODS: Patients with ExRA (n = 81) according to predefined criteria and controls (n = 184) without evidence of extra-articular disease were identified from a large research database of patients with rheumatoid arthritis. In a structured review of the medical records, the occurrence and the date of onset of clinically diagnosed CVD events were noted. Cox proportional hazards models were used to estimate the effect of ExRA on the risk of first ever CVD events after the diagnosis of rheumatoid arthritis. ExRA manifestations were modelled as time-dependent covariates, with adjustment for age, sex and smoking at the diagnosis of rheumatoid arthritis. Onset of erosive disease and rheumatoid factor seropositivity were entered as time-dependent variables. Patients were followed until onset of CVD, death or loss to follow-up. RESULTS: ExRA was associated with a significantly increased risk of first ever CVD events (p<0.001), and also with an increased risk of new-onset coronary artery disease, adjusted for age, sex and smoking (hazard ratio (HR): 3.16; 95% confidence interval (95% CI: 1.58 to 6.33). The association between ExRA and any first ever CVD event remained significant when controlling for age, sex, smoking, rheumatoid factor and erosive disease (HR: 3.25; 95% CI: 1.59 to 6.64). CONCLUSION: Severe ExRA manifestations are associated with an increased risk of CVD events in patients with rheumatoid arthritis. This association is not due to differences in age, sex, smoking, rheumatoid factor or erosive joint damage. It is suggested that systemic extra-articular disease is a major determinant of cardiovascular morbidity in rheumatoid arthritis.

Bongartz T, Cantaert T, Atkins SR, Harle P, Myers JL, Turesson C, Ryu JH, Baeten D, Matteson EL. · Division of Rheumatology, Mayo Clinic College of Medicine, 200 1St St SW Rochester, MN 55905, USA. · Rheumatology (Oxford). · Pubmed #16782731 links to  free full text

Abstract: BACKGROUND: Anti-citrullinated protein antibodies have been detected with high specificity in serum of patients with rheumatoid arthritis (RA), and citrullination of proteins may play a key role in the pathogenesis of RA. We therefore investigated the presence of citrullination in two extra-articular manifestations of RA, interstitial pneumonia (IP) and rheumatoid nodules. METHODS: Open-lung biopsy specimens from patients with RA-associated IP (n = 18), idiopathic IP (n = 20) and controls (n = 10), as well as specimens of rheumatoid nodules from 26 patients, were examined. All sections were incubated with an anti-modified citrulline antibody. Masked scoring of stained sections and analysis of results by stratification according to demographic and clinical characteristics was performed. RESULTS: Presence of citrulline could be detected in eight lung specimens of patients with RA-associated IP (44%) and nine patients with idiopathic IP (46%). Conversely, lung tissue from control patients showed weak extracellular citrullination in only two cases (20%). Citrullination did not show any significant associations with demographic or clinical characteristics such as age, gender, smoking habits, disease severity, histological subtype, degree of inflammation or steroid use. Rheumatoid nodules were citrulline positive in a majority of cases (70%). CONCLUSION: Citrullination is present in extra-articular manifestations of RA such as IP and nodules. In contrast to the high specificity of anti-citrulline antibodies in RA, citrullination is not only restricted to RA but can also be observed in idiopathic IP. Whether citrullination significantly contributes to the initiation or perpetuation of autoimmunity or merely reflects ongoing inflammation remains to be clarified.

Atkins SR, Turesson C, Myers JL, Tazelaar HD, Ryu JH, Matteson EL, Bongartz T. · Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. · Arthritis Rheum. · Pubmed #16447242 links to  free full text

Abstract: OBJECTIVE: B lymphocytes are emerging as important elements in the events leading to joint destruction in rheumatoid arthritis (RA). However, B lymphocytes have not been studied in rheumatoid arthritis (RA)-associated lung disease. We performed a morphologic and quantitative analysis of B lymphocytes and plasma cells in RA-associated interstitial pneumonia (IP) in comparison with idiopathic IP and normal lungs. METHODS: Open-lung biopsy specimens from patients with RA-associated IP (n = 18), patients with idiopathic IP (n = 21), and control subjects (n = 11) were stained with antibodies to CD20 and CD138. Morphologic patterns of stained specimens were characterized and staining was quantified using computer-assisted image analysis. RESULTS: In RA-associated IP, marked follicular B cell hyperplasia was detected, which was limited almost entirely to peribronchiolar lymphoid aggregates. Plasma cells were also present in large numbers, but showed a more diffuse tissue infiltration. Quantification of B cells demonstrated higher cellularity in RA-associated IP (median 2.0%, interquartile range [IQR] 1.0-5.7) as compared with idiopathic IP (0.9%, IQR 0.5-2.1). Control specimens showed a significantly smaller number of B cells compared with both diseases (0.4%, IQR 0.1-1.3). In RA patients who were smokers and in those who were male, the proportion of CD20+ tissue areas further increased to 4.3% (IQR 1.0-5.8) and 3.9% (IQR 0.7-6.9), respectively. CONCLUSION: We demonstrated a significant follicular B cell hyperplasia in RA-associated IP. The differences between RA-associated IP and idiopathic IP imply a differential emphasis of B cell-mediated mechanisms in the 2 diseases despite radiologic and histologic similarities and provide a rationale for studying functional aspects of B cell involvement in the pathogenesis of RA-associated IP.

Liang KP, Liang KV, Matteson EL, McClelland RL, Christianson TJ, Turesson C. · Mayo Clinic and Mayo Graduate School of Medicine, Rochester, Minnesota, USA. · Arthritis Rheum. · Pubmed #16447212 links to  free full text

Abstract: OBJECTIVE: To investigate the incidence of noncardiac vascular disease in patients with rheumatoid arthritis (RA) and its relationship to systemic extraarticular disease in a community-based cohort. METHODS: A retrospective medical record review of 609 patients with incident RA diagnosed during 1955-1994 was carried out in Olmsted County, Minnesota. Patients were followed up from 1955 to 2000 (median followup 11.8 years). Incident noncardiac vascular disease and severe extraarticular RA manifestations (including pericarditis, pleuritis, and vasculitis) were recorded according to predefined criteria, and incidence rates were estimated. Using Cox proportional hazards models, the risk (hazard ratio [HR]) of developing vascular events was assessed in patients with and without severe extraarticular RA. RESULTS: Cerebrovascular and peripheral arterial events occurred in 139 patients (22.8%). The 30-year cumulative incidence rates of peripheral arterial events, cerebrovascular events, and venous thromboembolic events were estimated to be 19.6%, 21.6%, and 7.2%, respectively. The presence of severe extraarticular RA manifestations was found to be associated with all subgroups of noncardiac vascular disease except cerebrovascular disease alone (HR 2.3, 95% confidence interval [95% CI] 1.2-4.3 for peripheral arterial events; HR 3.7, 95% CI 1.3-10.3 for venous thromboembolic events; HR 1.5, 95% CI 0.7-3.2 for cerebrovascular events) after adjusting for age, sex, body mass index, smoking, and rheumatoid factor status. CONCLUSION: This is the first study to assess the incidence of noncardiac vascular disease in RA. Severe extraarticular RA was associated with all forms of noncardiac vascular disease except cerebrovascular disease alone. Similar to cardiac disease, the excess risk of noncardiac vascular disease in RA is likely to be related, in part, to the systemic inflammation associated with the extraarticular manifestations of RA.

Turesson C, Schaid DJ, Weyand CM, Jacobsson LT, Goronzy JJ, Petersson IF, Sturfelt G, Nyhäll-Wåhlin BM, Truedsson L, Dechant SA, Matteson EL. · Department of Rheumatology, Malmö University Hospital, Södra Förstadsgatan 101, 205 02 Malmö, Sweden. · Arthritis Res Ther. · Pubmed #16277691 links to  free full text

Abstract: The objective of this study was to examine HLA-DRB1 and HLA-DQB1 genotypes in patients with severe extra-articular rheumatoid arthritis (ExRA) and to compare them with the genotypes of rheumatoid arthritis (RA) patients without extra-articular manifestations. Patients with severe ExRA were recruited from a large research database of patients with RA, from two cohorts of prevalent RA cases, and from a regional multicenter early RA cohort. Cases with ExRA manifestations (n = 159) were classified according to predefined criteria. Controls (n = 178) with RA but no ExRA were selected from the same sources. Cases and controls were matched for duration of RA and for clinical center. PCR based HLA-DRB1 and HLA-DQB1 genotyping was performed using the Biotest SSP kit, with additional sequencing in order to distinguish DRB1*04 subtypes. Associations between alleles and disease phenotypes were tested using multiple simulations of random distributions of alleles. There was no difference in global distribution of HLA-DRB1 and HLA-DQB1 alleles between patients with ExRA and controls. DRB1*0401 (P = 0.003) and 0401/0401 homozygosity (P = 0.002) were more frequent in Felty's syndrome than in controls. The presence of two HLA-DRB1*04 alleles encoding the shared epitope (SE) was associated with ExRA (overall odds ratio 1.79, 95% confidence interval 1.04-3.08) and with rheumatoid vasculitis (odds ratio 2.44, 95% confidence interval 1.22-4.89). In this large sample of patients with ExRA, Felty's syndrome was the only manifestation that was clearly associated with HLA-DRB1*0401. Other ExRA manifestations were not associated with individual alleles but with DRB1*04 SE double dose genotypes. This confirms that SE genes contribute to RA disease severity and ExRA. Other genetic and environmental factors may have a more specific impact on individual ExRA manifestations.

Nyhäll-Wåhlin BM, Jacobsson LT, Petersson IF, Turesson C, Anonymous00001. · Department of Rheumatology, Falun Hospital, SE-791 82 Falun, Sweden. · Ann Rheum Dis. · Pubmed #16166104 links to  free full text

Abstract: OBJECTIVE: To examine whether smoking is a risk factor for rheumatoid nodules in early rheumatoid arthritis, and if so to determine the quantitative effect of smoking. METHODS: From a cohort (n = 1589) in a structured programme for follow up of newly diagnosed cases of rheumatoid arthritis (symptoms of swollen joints < or =12 months), 112 individuals with rheumatoid nodules at inclusion were identified. Nodular patients were each compared with two age and sex matched controls without nodules from the same cohort. A detailed self administered tobacco use questionnaire was answered by 210 patients (63%). RESULTS: Seventy patients were current smokers, 71 former smokers, and 69 had never smoked. Current smoking and former smoking were more common in patients with rheumatoid nodules compared with controls (86% v 59%) in both sexes. Positive rheumatoid factor (RF) was found more often among cases with nodules than controls (78% v 64%). Using detailed information from the questionnaires with conditional logistic regression analyses, ever having smoked was associated with an increased risk of the presence of rheumatoid nodules (odds ratio (OR) = 7.3 (95% confidence interval, 2.3 to 23.6); p = 0.001). The risk of having nodules was not obviously dose dependent when smoking duration as well as smoking amount were examined. A stratified analysis showed that only RF positive smokers had an increased risk of rheumatoid nodules. Smoking was associated with rheumatoid nodules among both men (p = 0.006) and women (p = 0.001). Tobacco use other than smoking (n = 31) was not associated with an increased risk of nodules (OR = 0.8 (0.2 to 3.4); p = 0.813). CONCLUSIONS: There is a strong association between smoking and rheumatoid nodules in early seropositive rheumatoid arthritis.

Jacobsson LT, Turesson C, Gülfe A, Kapetanovic MC, Petersson IF, Saxne T, Geborek P. · Department of Rheumatology, Malmö University Hospital, Malmö, Sweden. · J Rheumatol. · Pubmed #15996054 No free full text.

Abstract: OBJECTIVE: To investigate the risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) treated with tumor necrosis factor (TNF) inhibitors, compared to a standard RA population. METHODS: Patients were recruited from a regional register, which includes over 90% of patients with RA started on TNF blockers in 1999 or later, and a local community based cohort of RA patients, established in 1997. Of a total of 983 patients in the combined cohort, 531 received treatment with etanercept or infliximab during the study period. The total cohort (n = 983) was linked with national registers for inpatient care and cause of death through December 31, 2001. CVD was defined as the first inpatient care or death from CVD without inpatient care for CVD prior to study entry. First CVD events in those treated versus not treated with TNF blockers were estimated, using age and sex adjusted incidence density computations with treatment and disease severity markers as time-dependent covariates. RESULTS: In the anti-TNF-treated patients, the age-sex adjusted incidence rate of first CVD event was 14.0/1000 person-years at risk (95% CI 5.7-22.4), compared with 35.4/1000 person-years (95% CI 16.5-54.4) in those not treated. Controlling for disability, the age-sex adjusted rate ratio was 0.46 (95% CI 0.25-0.85, p = 0.013) in anti-TNF-treated versus not treated. CONCLUSION: These findings suggest that the risk of developing CVD is lower in patients with RA treated with TNF blockers. This is compatible with the hypothesis that inflammation contributes to the development of cardiovascular events.

Turesson C, Jacobsson L, Rydén Ahlgren A, Sturfelt G, Wollmer P, Länne T. · Department of Rheumatology, Malmö University Hospital, Södra Förstadsgatan 101, 205 02 Malmö, Sweden. · Rheumatology (Oxford). · Pubmed #15784628 links to  free full text

Abstract: OBJECTIVE: To study the distensibility and the diameter of the abdominal aorta and the common carotid artery (CCA) in patients with rheumatoid arthritis (RA), and investigate the relation between mechanical properties of these arteries and disease severity. METHODS: One hundred and one patients with RA (33 consecutive cases with extra-articular manifestations, and 68 subjects with non-extra-articular disease, matched for age, sex and disease duration) were investigated. Echo-tracking ultrasonography was used to measure stiffness and mean diameter of the abdominal aorta and the CCA. The patients were compared with healthy individuals from the corresponding age group (n=74 for measurements of the aorta, n=64 for the CCA). Predicted values for stiffness and mean diameter, based on age and sex, were calculated. RESULTS: Stiffness of the abdominal aorta was increased in women with RA [mean percentage of predicted value (% predicted) 180; 95% confidence interval (95% CI) 150-211] but not in men (% predicted 99; 95% CI 75-122). CCA stiffness was less markedly increased, and mean diameters of the aorta and the CCA were not different from the expected. In the RA cohort, patients with extra-articular manifestations tended to have greater stiffness of the aorta (P=0.11), and disability, as indicated by a higher Health Assessment Questionnaire score, was associated with increased aortic stiffness (P=0.04). CONCLUSION: RA is associated with decreased distensibility of the abdominal aorta in females, and such changes seem to correlate with disease severity. We suggest that arterial stiffness is an important factor in cardiovascular co-morbidity in RA.

Geborek P, Bladström A, Turesson C, Gulfe A, Petersson IF, Saxne T, Olsson H, Jacobsson LT. · Department of Rheumatology, Lund University Hospital, SE 221 85 Lund, Sweden. · Ann Rheum Dis. · Pubmed #15695534 links to  free full text

Abstract: OBJECTIVE: To determine whether TNF blockers increase tumour risk in patients with RA. MATERIALS AND METHODS: The South Swedish Arthritis Treatment Group register (SSATG) comprises over 90% of anti-TNF treated patients with RA in the area. 757 patients treated with etanercept or infliximab included between 1 February 1999 and 31 December 2002 were identified. 800 patients with conventional antirheumatic treatment in a community based cohort served as a comparison cohort. Tumours and deaths were identified in the cancer registry and population census registers. Patients were followed up from initiation of anti-TNF treatment or 1 July 1997 for the comparison group, until death or 31 December 2002. RESULTS: In the anti-TNF group, 16 tumours (5 lymphomas) were identified in 1603 person-years at risk, and in the comparison group 69 tumours (2 lymphomas) in 3948 person-years. Standardised incidence ratios (SIRs) for total tumour relative risk for the anti-TNF group and the comparison group were 1.1 (95% confidence interval (CI) 0.6 to 1.8) and 1.4 (95% CI 1.1 to 1.8), respectively. The lymphoma relative risk (RR) was 11.5 (95% CI 3.7 to 26.9) and 1.3 (95% CI 0.2 to 4.5), respectively The total tumour RR excluding lymphoma was 0.79 (95% CI 0.4 to 1.42) and 1.39 (95% CI 1.08 to 1.76), respectively. Proportional hazard analysis for lymphomas yielded RR 4.9 (95% CI 0.9 to 26.2) in anti-TNF treated versus untreated patients. CONCLUSION: Community based patients with RA treated conventionally had an increased overall tumour risk compared with the background population. A possible additional increased risk for lymphoma associated with TNF blockers was based on few cases and needs confirmation.

Turesson C, Matteson EL, Colby TV, Vuk-Pavlovic Z, Vassallo R, Weyand CM, Tazelaar HD, Limper AH. · Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. · Arthritis Rheum. · Pubmed #15641082 links to  free full text

Abstract: OBJECTIVE: To study lymphocyte markers in rheumatoid arthritis (RA)-associated interstitial pneumonitis (IP) compared with idiopathic IP. METHODS: Paraffin-embedded lung biopsy specimens from patients with RA (n = 15) and from those without RA (n = 16), all of whom had a diagnosis of either nonspecific IP or usual IP, were studied. Tissue sections from each patient were reviewed by a pathologist, who was blinded to the clinical data. Age and pulmonary function test results were similar in RA and non-RA patients. After high-temperature antigen unmasking, sections were incubated with mouse monoclonal antibodies directed against CD3, CD4, CD8, CD16, and CD20. All slides were coded, and digital images (100x magnification) of the entire tissue area were obtained. Staining was quantified using computer-assisted image analysis. RESULTS: Staining for CD4 was more prominent in patients with RA than in the non-RA comparison group (median 9.3 cells/mm(2), interquartile range [IQR] 5.5-27.3 versus 0.6 cells/mm(2), IQR 0.2-1.9; P = 0.002). CD4+ cell counts were increased in RA patients with nonspecific IP as well as in RA patients with usual IP, with no major difference between these groups. Results were similar for quantification of CD3 (P = 0.012). There was a less striking trend toward more CD8+ cells in RA patients (P = 0.27 versus those with non-RA lung disease). CONCLUSION: IP lesions in patients with RA are characterized by an increased number of CD4+ cells, as compared with that in patients with idiopathic IP. This finding suggests that CD4+ T cells are critical for the development of pulmonary manifestations in RA, and may have implications for the treatment of RA-associated lung disease.

Turesson C, McClelland RL, Christianson TJ, Matteson EL. · Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Arthritis Rheum. · Pubmed #15529357 links to  free full text

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