Cathrin Nikolaisen

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.

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.

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.

Diagnostic impact of contemporary biomarker assays for rheumatoid arthritis

Objective: The impetus towards early treatment for patients with rheumatoid arthritis (RA) requires more reliable disease markers than the non‐specific immunoglobulin M (IgM) rheumatoid factor (RF). To determine the accuracy of newer biomarkers for RA testing for antibody against cyclic citrullinated peptides (anti‐CCP Ab), IgA‐ and IgG‐RF and cartilage oligomeric matrix protein (COMP) levels, measured by enzyme‐linked immunosorbent assay (ELISA), were compared with IgM‐RF isotyping. Methods: Serum samples were investigated in patients with an established diagnosis of RA (n = 54), ankylosing spondylitis (AS) (n = 36), and non‐inflammatory conditions (n = 18) (cohort A), and in 234 consecutive outpatients in a blinded fashion (cohort B). Non‐parametric analysis of areas under the curve (AUC) of receiver operator characteristics were performed. Results: The presence of anti‐CCP Ab had the highest accuracy (96%) in distinguishing RA patients in cohort A and cohort B (accuracy 83%), and in both cohorts combined (accuracy 87%). This was related to the high specificity of anti‐CCP Ab for RA (95–96%), even though IgM‐RF was the most sensitive test (87–96%). Sensitivity (15–48%) and specificity (66–69%) of COMP as a marker for RA was low. Combining results of anti‐CCP Ab and IgM‐RF or any of the other assays did not increase the diagnostic accuracy for RA. Conclusion: The presence of anti‐CCP Ab is the most accurate biomarker for RA in both selected and unselected cohorts, while the COMP assay is not very useful in RA diagnosis. Combining assays for anti‐CCP Ab and IgM‐RF or IgA‐RF does not enhance RA diagnosis.

Contemporary use of disease-modifying drugs in the management of patients with early rheumatoid arthritis in Norway

Objective: As treatment options for rheumatoid arthritis (RA) are rapidly expanding, we evaluated the current use of disease‐modifying anti‐rheumatic drugs (DMARDs) in the management of patients with early RA in Norway with particular attention to the influence of risk factors for a poor disease outcome on DMARD selection. Methods: An observational multicentre study registering the type of therapy initiated in 820 DMARD‐naive patients with early active RA [67% female, mean age 51 years, disease duration 4 months, 57% rheumatoid factor (RF) positive]. The impact of baseline risk factors associated with poor prognosis (disease activity parameters and biomarkers of inflammation) on DMARD selection was analysed through odds ratios (ORs) by multivariate logistic regression. Results: Methotrexate (MTX) monotherapy was selected for 78% of patients. MTX was preferred over sulfasalazine (SSZ) monotherapy (19%), leflunomide monotherapy (2%), and combination therapy (2%) in female patients [OR 1.6, 95% confidence interval (CI) 1.1–2.5], age >50 years (OR 2.5, 95% CI 1.6–3.8), short disease duration (OR 2.7, 95% CI 1.4–5.0), ⩾10 swollen joints (OR 2.2, 95% CI 1.2–4.0), and erosive disease (OR 1.8, 95% CI 1.1–3.2). Concurrent steroid therapy was started in 73% of patients, regardless of the type of DMARD therapy initiated. Conclusion: Monotherapy with MTX is currently the DMARD treatment of choice for early RA in Norway. Disease duration, age, swollen joint count, and erosive disease have considerable impact on DMARD selection in contrast to the presence of biomarkers. Few patients with early RA in Norway receive combination DMARD therapy, while the majority of patients receive corticosteroid bridging therapy.

Rheumatoid factor by laser nephelometry and Waaler-Rose assay: prognostic value in patients with recent-onset rheumatoid arthritis.

Objective: To evaluate the prognostic value of rheumatoid factor (RF), detected in the Waaler–Rose agglutination assay and by nephelometry, in patients with recent‐onset rheumatoid arthritis (RA). Methods: Consecutive patients with new‐onset RA between 1993 and 1997 were followed for a median period of 4.7 years. Clinical data at baseline and drug use during the disease course were recorded. Outcome parameters studied were disease process, damage (erosions, joint surgery, extra‐articular manifestations, and new co‐morbidity), and death. Cut‐off levels for RF were >40 IU/mL (nephelometry) and titres ⩾1:160 (Waaler–Rose haemagglutination). Results: RF tests were negative by both methods in 22% of RA patients (RF− group), while 33% were RF positive by nephelometry only (RF+ group) and 45% were positive by Waaler–Rose and nephelometry (RF++ group). Baseline clinical and laboratory findings as well as the number of subsequently used disease‐modifying anti‐rheumatic drugs (DMARDs), the number of patients starting and the time spent on steroid therapy were similar in the three RF groups. Odd ratios for death (n = 23), erosions (n = 62), and serious extra‐articular disease manifestations (EAMs) (n = 13) as well as patient survival, erosion‐free or surgery‐free survival rates did not differ between the RF groups. Only rheumatoid nodules were more frequent in RF++ patients. Conclusion: The baseline presence of RF by either Waaler–Rose or nephelometry was not associated with differences in drug therapy, morbidity other than rheumatoid nodules, or mortality in RA patients in the first 5 years of disease. Being immunoglobulin M (IgM) RF positive thus had little impact on RA patient outcome.

Early histology in ankylosing spondylitis related spondylodiscitis supports its inflammatory origin

It is unclear whether the destructive lesions of the vertebral bodies in the spondylodiscitis of ankylosing spondylitis (AS) are related to mechanical stress or inflammation. We describe early immunohistopathological findings in an AS patient with severe symptomatic spondylodiscitis that support an inflammatory origin.