Andrea Becker-Merok

B-lymphocyte activating factor in systemic lupus erythematosus and rheumatoid arthritis in relation to autoantibody levels, disease measures and time

Overexpression of B-lymphocyte activating factor (BAFF) results in arthritis, glomerulonephritis and autoantibody formation in mice, but its role in human autoimmune disease is less obvious. Serum BAFF levels in patients with systemic lupus erythematosus (SLE) (n = 42) and rheumatoid arthritis (RA) (n = 60) were related to levels of disease activity, anti-dsDNA Ab, anti-ENA Ab, rheumatoid factor (RF) and anti-CCP Ab. BAFF levels were also followed over time in 19 SLE patients. BAFF levels correlated inversely with age, were higher in SLE than RA (median 2.7 versus 1.4 ng/mL, P < 0.01) and more SLE than RA patients had increased BAFF levels (57% versus 10%, P ≤ 0.01). In SLE, BAFF levels correlated with SLEDAI scores but not with anti-dsDNA Ab levels. SLE patients with increased BAFF levels had higher SLEDAI and CRP levels. In RA, BAFF levels correlated weakly with anti-CCP levels (Rs 0.27, P = 0.07), but not with joint counts, ESR, CRP or RF levels. Longitudinal BAFF levels remained unaltered in two thirds of SLE patients and changes in BAFF levels were unrelated to disease flares. These findings suggest that BAFF stimulation of B-cells may contribute to SLE by other mechanisms than autoantibody production.

Levels of Transforming Growth Factor-β 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 1β (IL-1β), IL-4, IL-6, IL-10, IL-12, IL-17, monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 1 (MIP-1α), MIP-1β, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and total transforming growth factor-β1 (TGF-β1) 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-β1 (p = 0.01) and IL-1β (p = 0.0004) compared to controls. TGF-β1 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-β1 was the most consistent cytokine abnormality in patients with SLE. The associations with disease activity, lymphocyte subsets, and damage suggest that TGF-β1 may be a therapeutic target of interest in SLE.

Prevalence, predictors and outcome of vascular damage in systemic lupus erythematosus.

Despite improved prognosis, patients with systemic lupus erythematosus (SLE) remain at increased risk for early death. Vascular events (VE) occur with increased frequency and contribute to premature death in SLE patients. As conventional cardiovascular risk factors do not fully explain this hazard, this study investigated the contribution of disease-specific features to VE development. Documented VE were classified as atherothrombotic, venous thrombotic, arterial thrombotic or tissue loss inducing vasculitis during a mean follow-up of nearly 12 years in the Tromsø Lupus cohort (n = 158). The impact of disease-specific factors (organ manifestations, laboratory findings, drug treatment, weighted average SLE Disease Activity Index (WAS) and cumulative Damage Index) was assessed by odds ratios for VE in multivariate analysis. A total of 41 patients (26%) developed VE, and atherothrombotic events were most common (73%). Overall, VE prevalence was 3.5/100 patient years, and VE risk increased linearly over time, reaching 35% after 20 years. WAS scores >3 increased, and use of hydroxychloroquine and antihypertensive medication reduced overall VE risk. Age >40 years was the main risk factor for atherothrombotic events. VE nearly quadrupled the risk of death. VE occurred in 26% of SLE patients, predominantly as atherothrombotic disease. VE prevalence increased linearly over time leading to a four-fold risk of mortality. Strategies for reducing disease activity, including treatment with antimalarials and antihypertensive drugs, are most likely to reduce the risk associated with VE in SLE.

Interleukin-6 promotes arthritis and joint deformation in patients with systemic lupus erythematosus

The underlying mechanisms for the subsets of self-limiting, intermittent or chronic and deforming arthritis in systemic lupus erythematosus (SLE) are not well understood. We performed a cross-sectional analysis of pro-inflammatory cytokines (IL-1β, IL-2, IL-6, IL-8 and TNF-α) and joint status in 47 SLE patients (79% females, age 42 years, disease duration 8.6 years). All cytokines levels were significantly elevated in SLE patients compared with controls, but only IL-2 and IL-8 levels were higher than in patients with rheumatoid arthritis. SLE patients with ongoing synovitis (19%) and joint deformities (11%) had increased erythrocyte sedimentation rate (ESR), IL-6 and anti-dsDNA Ab levels. IL-6 levels correlated with ESR, anti-dsDNA Ab and haemoglobin, but not with C-reactive protein levels. Arthritis constitutes a considerable burden of disease in SLE over time, and joint deformations are associated with longstanding disease and arthritis flare rates. IL-6 is a potential biomarker and therapeutic target in the prevention of joint damage in SLE arthritis.

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.

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.

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.

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

This study investigated the overall clinical impact of anti-α-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-α-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 α-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), Wegeners 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 Sjøgrens syndrome (SS) patients had significantly higher levels of anti-α-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-α-actinin antibodies. Within the SLE cohort, anti-α-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-α-actinin antibodies. Of these, 36% had SLE, while 64% suffered from other, mostly autoimmune, disorders. Antibodies binding to α-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.

Circulating interferon-α2 levels are increased in the majority of patients with systemic lupus erythematosus and are associated with disease activity and multiple cytokine activation

Mutations in interferon (IFN) regulatory factor genes and the biological activity of type I IFN on expression of specific genes that are induced by IFN have been associated with various aspects of systemic lupus erythematosus (SLE). Circulating levels of IFN-α in SLE has not been extensively studied because of limited sensitivity of available ELISA assays. We performed a cross-sectional case-control study where circulating levels of IFN-α2 were measured by a highly sensitive, solution phase multiplex magnetized bead assay and investigated the relation of IFN-α2 with autoantibody profiles, clinical disease activity and levels of inflammatory cytokines in SLE patients (n = 87). Cytokine levels were determined on stored sera aliquots with cut-off levels determined by the geometric mean + 2SD in healthy controls (n = 27). IFN-α2 levels were increased in 64% of SLE patients, who displayed more renal disease and higher disease activity (p = 0.06) and had a significantly higher sum of activated cytokines (median 4.5, range 7) compared to patients with normal IFN-α2 (median one, range 3; p < 0.001). Solution phase micro-bead assay thus identified increased IFN-α2 levels in two-thirds of SLE patients with longstanding disease. The association with clinical disease and activation of multiple inflammatory cytokines supports a role for IFN-α2 in disease perpetuation in a large subset of SLE patients.

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.