Prevalence of pulmonary hypertension in an unselected, mixed connective tissue disease cohort: results of a nationwide, Norwegian cross-sectional multicentre study and review of current literature.

OBJECTIVES: The aim of this study was to assess the overall prevalence of pulmonary hypertension (PH) in an unselected MCTD cohort and review the current knowledge with a systematic database search. METHODS: A nationwide multicentre cohort of 147 adult MCTD patients were initially screened for PH by echocardiography, high-resolution computed tomography (HRCT), pulmonary function tests and N-terminal pro-brain natriuretic peptide (NT-proBNP) and then followed up for a mean of 5.6 years. Right-sided heart catheterization was performed when estimated pulmonary artery systolic pressure was >40 mmHg on echocardiography. PH was diagnosed according to the 2009 European Society of Cardiology and European Respiratory Society guidelines. RESULTS: At inclusion, 2.0% (3/147) had established PH. Two additional PH patients were identified during follow-up, giving a total PH frequency in the cohort of 3.4% (5/147). All five had elevated serum NT-proBNP. Two had isolated pulmonary arterial hypertension (PAH) and three PH associated with interstitial lung disease (PH-ILD). Three PH patients died during follow-up. Nine other patients in the cohort also died, but none of them had echocardiographic signs of PH prior to death. CONCLUSION: The data from the current unselected MCTD cohort suggest that the prevalence of PH is much lower than expected from previous studies but confirm the seriousness of the disease complication.

Prevalence and severity of interstitial lung disease in mixed connective tissue disease: a nationwide, cross-sectional study.

BACKGROUND: Mixed connective tissue disease (MCTD) is an immune-mediated, systemic disorder of unknown cause. OBJECTIVE: To assess the prevalence, pattern and severity of interstitial lung disease (ILD) in a cross-sectional study of the nationwide, Norwegian MCTD cohort. METHODS: 126 patients with MCTD were systematically examined for ILD by high-resolution CT (HRCT), pulmonary function tests (PFT), 6 min walk test (6MWT) and by the New York Heart Association (NYHA) functional classification of dyspnoea. The extent and type of HRCT lung abnormalities were scored according to the CT criteria of ILD recommended by the Fleischner Society. RESULTS: All 126 patients were Caucasian, 75% women. At the time of the cross-sectional ILD study, the patients had a mean disease duration of 9.0 years. 52% of the patients had abnormal HRCT findings, most commonly reticular patterns consistent with lung fibrosis (35%). Lung fibrosis was quantified as minor in 7%, moderate in 9% and severe in 19% of the patients. Fibrosis was uniformly concentrated in the lower parts of the lungs and was not associated with smoking. Patients with severe lung fibrosis had lower PFT values, shorter 6MWT and a higher mean NYHA functional class. After a mean 4.2 years' follow-up, overall mortality was 7.9%. Mortality in patients with normal HRCT was 3.3%, as compared with 20.8% in patients with severe lung fibrosis (p<0.01). CONCLUSIONS: Severe lung fibrosis is common in MCTD, has an impact on pulmonary function and overall physical capacity and is associated with increased mortality.

Susceptibility for Lupus Nephritis by Low Copy Number of the FCGR3B Gene Is Linked to Increased Levels of Pathogenic Autoantibodies.

Low copy number (CN) of the FCGR3B gene reduces FCGR3B membrane expression on neutrophils and results in clearance of a smaller amount of immune complex. We investigated FCGR3B CN in relation to the clinical phenotype in a Caucasian SLE cohort (n = 107). FCGR3B CN was determined by three different qPCR parameter estimations (Ct-, Cy0, and cpD1) and confirmed by the FCGR2C/FCGR2A paralog ratio test. Clinical and serological data were then analyzed for their association with FCGR3B CN. Low FCGR3B CN (<2) was more frequent in SLE patients than in healthy controls (n = 162) (20% versus 6%, OR 4.15, P = 0.003) and associated with higher disease activity scores (SLEDAI 10.4 versus 6.1, P = 0.03), lupus nephritis (LN) (25 versus 5%, P = 0.03), and increased levels of antibodies against dsDNA (81 versus 37 IU, P = 0.03), C1q (22 versus 6 IU, P = 0.003), and ribosomal P (10 versus 5 IU, P = 0.01). No such associations were seen with antibodies against extractable nuclear antigens or high FCGR3B CN (>2). In multivariate analyses, LN was independently associated with anti-C1q-Ab levels (P = 0.03) and low FCGR3B CN (P = 0.09). We conclude that the susceptibility for LN in patients with low FCGR3B CN is linked to increased levels of pathogenic autoantibodies.

Work disability in patients with ankylosing spondylitis in Norway.

OBJECTIVE: To report the prevalence of work disability (WD) in a cross-sectional study of a large population of patients with ankylosing spondylitis (AS) and the associated demographic and clinical characteristics, including extraspinal features, that contribute to WD. METHODS: Patients with AS registered in a hospital database were invited to participate. A total of 360 patients took part. The survey period was 1998 to 2002. During an extended outpatient visit, data were collected according to a predefined data form. Demographic data were collected and a physical examination performed. RESULTS: After 22.6 years of disease duration, the cumulative prevalence of WD reached 43.6%, and an additional 8.9% of patients were nonparticipants in the labor force. Significant odds ratios indicating an independent association with WD were found for history of polyarthritis (9.6), coronary heart disease (CHD; 7.8), female sex (3.4), having children with spondyloarthritis (2.9), changing profession (2.8), lower level of education (1.4), mean score of the Bath AS Functional Index (1.2), increasing age (1.05), and increasing finger-to-floor distance (1.02). CONCLUSION: The longterm prevalence of WD among Norwegian patients with AS is considerably higher than in reports from other countries. Earlier polyarthritis and CHD were the strongest independent risk factors for WD.

Levels of transforming growth factor-beta are low in systemic lupus erythematosus patients with active disease.

OBJECTIVE: Cytokines are central regulators of the immune response but the workings of this complex network in systemic lupus erythematosus (SLE) are not fully understood. We investigated a range of inflammatory and immune-modulating cytokines to determine their value as biomarkers for disease subsets in SLE. METHODS: This was a cross-sectional study in 102 patients with SLE (87% women, disease duration 10.6 yrs). Circulating concentrations of interleukin 1ß (IL-1ß), IL-4, IL-6, IL-10, IL-12, IL-17, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 (MIP-1α), MIP-1ß, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and total transforming growth factor-ß1 (TGF-ß1) were related to disease activity (SLE Disease Activity Index; SLEDAI), lymphocyte subsets, autoantibody levels, accrued damage (Systemic Lupus International Collaborating Clinics/ACR Damage Index; SDI), and concomitant treatment. RESULTS: Patients with SLE had lower levels of TGF-ß1 (p = 0.01) and IL-1ß (p = 0.0004) compared to controls. TGF-ß1 levels were lower in patients with SLEDAI scores 1-10 and SDI > 3; and were correlated with CD4+, CD8+, and natural killer cell counts; and were independent of steroid or cytotoxic drug use. Treatment with cardiovascular drugs was associated with lower IL-12 levels. No consistent disease associations existed for the other cytokines investigated. CONCLUSION: Lower TGF-ß1 was the most consistent cytokine abnormality in patients with SLE. The associations with disease activity, lymphocyte subsets, and damage suggest that TGF-ß1 may be a therapeutic target of interest in SLE.

The influence of the 1997 updated classification criteria for systemic lupus erythematosus: epidemiology, disease presentation, and patient management.

OBJECTIVE: The 1997 update of the American College of Rheumatology classification criteria (ACR97) for systemic lupus erythematosus (SLE) has not been validated. We determined to what extent their introduction influenced the epidemiology and clinical characteristics of the disease in northern Norway. METHODS: Annual incidence and point-prevalence rates, clinical manifestations, and outcome were determined in an inception cohort of patients with SLE in northern Norway, included between 1996 and 2006, using ACR97 criteria (97acr). These findings were compared with a cohort from the same area enrolled 1978-1995 using the 1982 revised criteria ACR82 (82acr). RESULTS: The mean annual incidence of SLE was 3.00 for cohort 97acr (n = 58) versus 2.63 for cohort 82acr (n = 81) (p = 0.5). All patients in the 97acr cohort also fulfilled the 1982 criteria; however, significantly fewer patients presented with discoid rash [odds ratio (OR) 0.31)], arthritis (OR 0.24), renal (OR 0.28) or hematological disorder (OR 0.27), and significantly more with anti-dsDNA (OR 2.57) and antiphospholipid antibodies (OR 27.9). Initial treatment with intravenous pulse methylprednisolone (OR 9.23), azathioprine (OR 6.32), and low-dose aspirin (OR 20.9) was increased in cohort 97acr. Five- (95.2%) and 10-year survival (91.9%) rates were also improved for cohort 97acr. CONCLUSION: The ACR97 criteria set has construct validity compared to the ACR82 criteria set. SLE incidence remains unchanged in northern Norway, but a significant reduction of renal disease and further improvements in survival rates occurred simultaneously with increased serological surveillance with ELISA-based assays and early immunosuppressive and anticoagulant therapy.

Damage accumulation in systemic lupus erythematosus and its relation to disease activity and mortality.

OBJECTIVE: To describe damage accrual and the interconnections between disease activity measures, damage accrual, and death in a Nordic lupus cohort. METHODS: Longitudinal study in the population-based Tromso lupus cohort. Disease activity [SLE Disease Activity Index (SLEDAI)] and disease damage [by Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI)] were recorded for each visit. Weighted average SLEDAI scores (WAS) were calculated to correct for variable observation times. Development of damage (SDI > 0), severe damage (SDI >or= 3), and death were used as separate endpoints. Univariate nonparametric analysis identified and hazard ratios (HR) by Cox regression techniques confirmed the independence of predictors for each outcome. RESULTS: Through 11.9 years of followup, 72 patients (46%) remained free of damage, 51 (32%) developed moderate damage, and 35 (22%) developed severe damage. SDI scores were higher in 37 nonsurvivors (23.4%; SDI 2.1) than in survivors (SDI 0.9; p < 0.05). Damage accrual was linear throughout the first decade of disease. The only independent predictor for SDI >/= 3 was a WAS score > 3 (hazard ratio 2.34; 95% CI 1.1-4.9). Age > 40 years at diagnosis (HR 5.6, 95% CI 2.4-12.7) and WAS > 3 (HR 2.4, 95% CI 1.2-4.9) were significant predictors for death. CONCLUSION: Damage accrual in SLE occurred in 54% of patients in a linear fashion over the first decade of disease. Global disease activity was the main determinant of damage accrual. Accrued damage was not an independent risk factor for death, which was predicted by age > 40 years and WAS > 3.

Alpha-actinin-binding antibodies in relation to systemic lupus erythematosus and lupus nephritis.

This study investigated the overall clinical impact of anti-alpha-actinin antibodies in patients with pre-selected autoimmune diseases and in a random group of anti-nuclear antibody (ANA)-positive individuals. The relation of anti-alpha-actinin antibodies with lupus nephritis and anti-double-stranded DNA (anti-dsDNA) antibodies represented a particular focus for the study. Using a cross-sectional design, the presence of antibodies to alpha-actinin was studied in selected groups, classified according to the relevant American College of Rheumatology classification criteria for systemic lupus erythematosus (SLE) (n = 99), rheumatoid arthritis (RA) (n = 68), Wegener's granulomatosis (WG) (n = 85), and fibromyalgia (FM) (n = 29), and in a random group of ANA-positive individuals (n = 142). Renal disease was defined as (increased) proteinuria with haematuria or presence of cellular casts. Sera from SLE, RA, and Sjøgren's syndrome (SS) patients had significantly higher levels of anti-alpha-actinin antibodies than the other patient groups. Using the geometric mean (+/- 2 standard deviations) in FM patients as the upper cutoff, 20% of SLE patients, 12% of RA patients, 4% of SS patients, and none of the WG patients were positive for anti-alpha-actinin antibodies. Within the SLE cohort, anti-alpha-actinin antibody levels were higher in patients with renal flares (p = 0.02) and correlated independently with anti-dsDNA antibody levels by enzyme-linked immunosorbent assay (p < 0.007) but not with other disease features. In the random ANA group, 14 individuals had anti-alpha-actinin antibodies. Of these, 36% had SLE, while 64% suffered from other, mostly autoimmune, disorders. Antibodies binding to alpha-actinin were detected in 20% of SLE patients but were not specific for SLE. They correlate with anti-dsDNA antibody levels, implying in vitro cross-reactivity of anti-dsDNA antibodies, which may explain the observed association with renal disease in SLE.