Hans Nossent

Epidemiology of Wegener's granulomatosis in northern Norway

OBJECTIVE To determine if changes in the incidence, prevalence, and clinical presentation of Wegeners granulomatosis (WG) have occurred in the stable population of northern Norway during a 15-year period. METHODS We performed a retrospective cohort study using hospital discharge records from all 11 hospitals in the region and the databases of the 2 pathology departments in the area. Only patients fulfilling the American College of Rheumatology 1990 criteria for WG were included in the study, and demographic and clinical data at diagnosis were recorded. Incidence, point prevalence, and period prevalence rates were estimated for three 5-year periods. RESULTS Fifty-five patients (62% male) with a median age at diagnosis of 50 years (range 10-84 years) fulfilled the inclusion criteria. The annual incidence/ million population increased from 5.2 (95% confidence interval [95% CI] 2.7-9.0) during 1984-1988 to 12.0 (95% CI 8.0-17.3) during 1994-1998. The point prevalence/million increased from 30.4 (95% CI 16.6-51.0) to 95.1 (95% CI 69.1-129.0). The highest incidence rate occurred in men ages 65-74 years. There were no significant period differences in age, first organ involved, delay of diagnosis, or disease activity, but fewer patients had malaise and renal insufficiency during the earliest time period. No seasonal variation in the onset of WG was present, although we noted a pattern of annual fluctuation. CONCLUSION The prevalence of WG has tripled in northern Norway over the last 15 years. While more efficacious therapy may explain part of this increase, we also found a significant trend toward increased incidence over that period. The incidence rate over the last 5 years is the highest reported so far, while the clinical presentation has remained unchanged.

Epidemiology of vasculitis in Europe

We recently compared the annual incidence of primary systemic vasculitis (PSV) in two different regions of Europe (Norwich, UK (latitude 52°N) and Lugo, Spain (latitude 43°N)).1Wegeners granulomatosis (WG) was more common in Norwich (10.6/million) than in Spain (4.9/million), though the overall incidence of PSV was similar. This supports the idea that environmental factors may be important in the aetiopathogenesis of PSV. To extend our observations we have now studied the incidence of PSV in northern Europe (Tromso, Norway (latitude 70°N)). …

Anti-DNA antibody subpopulations and lupus nephritis.

As a consequence of increased insight into the cellular and molecular mechanisms responsible for induction of B cell and T cell autoimmunity to DNA and nucleosomes, there is an obvious need to reconsider the dogma stating that anti-dsDNA antibodies serve as marker antibodies for SLE and also that anti-dsDNA antibodies per se are responsible for the initiation of lupus nephritis. Given that the potential to produce anti-dsDNA antibodies is an inherent property of the normal immune system and that few anti-DNA antibodies have nephritogenic potential, we must try to solve the problem whether it is avidity for DNA, specificity for unique DNA structures or cross-reactivity with non-DNA molecules, that make such antibodies pathogenic and thus potential markers for SLE and lupus nephritis. In this review, we will summarize contemporary problems related to these questions; (1) try to focus on phenotypic differences with respect to the ability to produce anti-dsDNA antibodies between individuals suffering from SLE and those not belonging to this diagnostic group, and (2) to describe differences between pathogenic and non-pathogenic anti-dsDNA antibodies.

Antinuclear antibody screening in this new millennium: farewell to the microscope?

ANA testing by immunofluorescence technique (F-ANA) is nowadays still performed in much the same way as 45 years ago when the test was introduced. Due to its low specificity the F-ANA test has a poor predictive value for systemic autoimmune diseases and in addition has proven difficult to standardise. In the meantime, many of the nuclear and cytoplasmatic auto-antigens, related to specific types of autoimmune disease, have been characterised and can be tested for in specific ELISA assays (E-ANA). These assays are in large part automated and enable the large volume testing required, by the current attitude, to use ANA-testing for its high negative predictive value in the exclusion of systemic autoimmune disease. In addition, E-ANA assays give specific results for clinically relevant autoantibodies, while its test repertoire can be altered at any given time to reflect changes in current thinking on relevant auto-antigens. Thus, we suggest that the unspecific F-ANA test should no longer be considered the gold standard for the detection of clinically relevant autoantibodies.ANA testing by immunofluorescence technique (F-ANA) is nowadays still performed in much the same way as 45 years ago when the test was introduced. Due to its low specificity the F-ANA test has a poor predictive value for systemic autoimmune diseases and in addition has proven difficult to standardise. In the meantime, many of the nuclear and cytoplasmatic auto-antigens, related to specific types of autoimmune disease, have been characterised and can be tested for in specific ELISA assays (E-ANA). These assays are in large part automated and enable the large volume testing required, by the current attitude, to use ANA-testing for its high negative predictive value in the exclusion of systemic autoimmune disease. In addition, E-ANA assays give specific results for clinically relevant autoantibodies, while its test repertoire can be altered at any given time to reflect changes in current thinking on relevant auto-antigens. Thus, we suggest that the unspecific F-ANA test should no longer be considered the gold standard for the detection of clinically relevant autoantibodies.

Epidemiology of Spondyloarthritis: A Review

The classification of Spondyloarthritis (SpA) has been revised with the introduction of the ASAS classification criteria. Although this has best been described in ankylosing spondylitis and psoriatic arthritis, there are population studies evaluating the epidemiology of the different subgroups of SpA. In this paper, we present data on the incidence and prevalence of the subgroups of SpA in different populations, and point to data indicating how the introduction of new classification criteria, with the altered perception of the SpA entity, might impact on the epidemiology.

Termination of human T cell tolerance to histones by presentation of histones and polyomavirus T antigen provided that T antigen is complexed with nucleosomes

OBJECTIVE To investigate whether polyomavirus T antigen linked to histones through nucleosome-T antigen complexes has the potential to terminate histone-specific T cell anergy. METHODS Blood mononuclear cells from healthy individuals were used as the source to establish T cell lines initiated and maintained by T antigen, histones, nucleosome-T antigen complexes, or nucleosomes. Proliferative responses of these lines to T antigen, histones, and nucleosomes were determined. RESULTS Whereas T cell lines could be established using T antigen or T antigen-nucleosome complexes, histones or nucleosomes did not have this potential. However, T cell lines selected by T antigen-nucleosome complexes responded subsequently to histones and nucleosomes. Identical results were obtained with murine and human nucleosomes, provided that they were complexed with T antigen. CONCLUSION T antigen-specific T cells possess the potential to proliferate when interacting with an antigen-presenting cell that presents T antigen. In the presence of T antigens complexed with nucleosomes, T antigen-specific T cells offer bystander help that may terminate histone-specific T cell anergy. These T cells may progress into functional, autoimmune T cells if histones are properly presented.

Should rheumatoid factor in rheumatoid arthritis be sent to Davy Jones's Locker?

This article reviews the characteristics and weaknesses of the rheumatoid factor (RF) assay compared with anti-citrullinated peptide antibody (ACPA) testing in the work-up of patients with synovitis. This should lead physicians to change their ordering habits and replace RF by ACPA. For RA diagnosis, good clinical judgement based on clinical history, physical examination and routine laboratory work exceeds the value of RF and ACPA assays. In settings of both low and high pretest probability, the added value of each of these assays is low. In cases with intermediate probability, ACPA assays are superior to immunoglobulin (Ig)M-RF because of their higher specificity, and they should be the first choice in a RA diagnostic work-up. Dual testing brings few additional advantages and increases costs significantly. ACPA and IgM-RF are both imperfect tests; around 30% of patients with manifest RA will test negative in both assays and therefore caution needs to be exercised when interpreting negative results. Since 2009, the anti-cyclic citrullinated peptide (anti-CCP) antibody assay has been the only assay available at our institution for RA work-up, with IgM-RF available on a case-by-case basis for non-RA diseases. This has led to a 70% reduction in RF assays performed annually.

Prior anti-dsDNA antibody status does not predict later disease manifestations in systemic lupus erythematosus

ObjectivesTo determine if the past presence of anti-double-strand (ds)DNA antibody (Ab) will predict subsequent disease activity in patients with systemic lupus erythematosus (SLE).MethodsA longitudinal study of clinical and serological disease manifestations registered during 2,412 patient months of follow-up in a well-defined lupus cohort. Organ-specific disease manifestations, the modified SLE disease activity index (M-SLEDAI) score, disease flares (M-SLEDAI increase ≥3) and predictive value of anti-dsDNA Ab testing [by enzyme-linked immunoabsorbent assay (ELISA) and Crithidia luciliae immunofluorescence (CLIFT) assays] were related to past anti-dsDNA Ab status.ResultsAnti-dsDNA Ab was previously demonstrated in 54 (57%) patients (group 1), while they were not earlier detected in 40 (43%) patients (group 2). The number of patients experiencing flares (46 vs 25%, p<0.01), the total number of flares (75 vs 17, p<0,001) as well as overall (60 vs 24 per 100 patient years, p<0,001) and organ-specific flare rate were higher in group 1. After adjustment for control frequency, group 1 remained at a higher risk for renal flares [odds ratio (OR) 2.4; confidence interval (CI) 1.5–4.1], and group 2 was at a higher risk for skin flares (OR 0.7; CI 0.5–0.8). While anti-dsDNA Ab testing overall was performed slightly more often in group 1 (OR 1.45; CI 1.0–4.6), anti-dsDNA Ab testing during flares was similar in both groups.ConclusionThe past presence of anti-dsDNA Ab identified patients with an increased risk of subsequent renal flares. However, as a new onset of anti-dsDNA Abs occurred late in the disease course, prior anti-dsDNA status was not adequate to predict disease flares.

Is closer linkage between systemic lupus erythematosus and anti-double-stranded DNA antibodies a desirable and attainable goal?

The anti-double-stranded DNA (anti-dsDNA) antibody test incorporated in the 1982 revised American College of Rheumatology criteria for the classification of systemic lupus erythematosus needs updating to reflect current insights and technical achievements, including allowance for the presence of nonpathogenic anti-dsDNA antibodies. As we need to develop at least some measure of pathogenicity of anti-dsDNA antibodies, we propose that initial anti-dsDNA antibody screening is done by sensitive ELISA and supplemented by more stringent assays. Simultaneously the relevance of anti-dsDNA antibody presence needs to be restricted to clinical manifestations, thought to be caused by anti-dsDNA antibody and within an appropriate time frame.

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.