Bo Baslund

Genetically Distinct Subsets within ANCA-Associated Vasculitis

BACKGROUNDnAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegeners granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis.nnnMETHODSnA genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria.nnnRESULTSnWe found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding α(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P=6.2×10(-89), P=5.6×10(-12,) and P=2.6×10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P=2.1×10(-8)).nnnCONCLUSIONSnThis study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.).

EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis

Objectives The systemic vasculitides are multiorgan diseases where early diagnosis and treatment can significantly improve outcomes. Robust nomenclature reduces diagnostic delay. However, key aspects of current nomenclature are widely perceived to be out of date, these include disease definitions, classification and diagnostic criteria. Therefore, the aim of the present work was to identify deficiencies and provide contemporary points to consider for the development of future definitions and criteria in systemic vasculitis. Methods The expert panel identified areas of concern within existing definitions/criteria. Consequently, a systematic literature review was undertaken looking to address these deficiencies and produce ‘points to consider’ in accordance with standardised European League Against Rheumatism (EULAR) operating procedures. In the absence of evidence, expert consensus was used. Results There was unanimous consensus for re-evaluating existing definitions and developing new criteria. A total of 17 points to consider were proposed, covering 6 main areas: biopsy, laboratory testing, diagnostic radiology, nosology, definitions and research agenda. Suggestions to improve and expand current definitions were described including the incorporation of anti-neutrophil cytoplasm antibody and aetiological factors, where known. The importance of biopsy in diagnosis and exclusion of mimics was highlighted, while equally emphasising its problems. Thus, the role of alternative diagnostic tools such as MRI, ultrasound and surrogate markers were also discussed. Finally, structures to develop future criteria were considered. Conclusions Limitations in current classification criteria and definitions for vasculitis have been identified and suggestions provided for improvement. Additionally it is proposed that, in combination with the updated evidence, these should form the basis of future attempts to develop and validate revised criteria and definitions of vasculitis.

Increased morbidity from ischemic heart disease in patients with Wegener's granulomatosis

OBJECTIVEnExperimental studies indicate that patients with Wegeners granulomatosis (WG) experience accelerated atherosclerosis. The purpose of this study was to investigate whether the occurrence of overt ischemic heart disease (IHD) is increased in WG.nnnMETHODSnA total of 293 WG patients were included in the study. Information on all hospitalizations for IHD in Denmark from 1977 to 2006 was obtained from the Danish National Hospital Register. The WG patients were compared with the Danish background population with respect to rates of hospitalization for clinical manifestations of IHD after the date of vasculitis diagnosis by calculating standardized ratios of observed to expected (O:E) events.nnnRESULTSnSixty-three first IHD events were registered in the WG group during the 2,482 patient-years of followup, corresponding to a significantly increased O:E ratio for IHD of 1.9 (95% confidence interval [95% CI] 1.4-2.4). A significantly increased risk was found for acute myocardial infarction (MI) (O:E ratio 2.5 [95% CI 1.6-3.7]), but not for angina pectoris (O:E ratio 1.3 [95% CI 0.7-2.1]). In analyses stratified according to the time between the diagnosis of vasculitis and the cardiovascular event, increased O:E ratios were found for IHD and acute MI occurring <5.0 years after WG diagnosis (2.1 [95% CI 1.4-3.0] for IHD and 3.6 [95% CI 2.0-5.9] for acute MI) and for IHD occurring > or =10.0 years after WG diagnosis (2.2 [95% CI 1.3-3.4]). Significantly increased O:E ratios for IHD and acute MI were found in patients who were > or =50.0 years of age at the time of diagnosis of WG, in male patients, and in patients who received high cumulative doses of cyclophosphamide.nnnCONCLUSIONnCompared with the background population, WG patients seem to experience an increased number of both early and late cardiovascular events due to IHD.

YKL‐40 in giant cells and macrophages from patients with giant cell arteritis

OBJECTIVEnYKL-40, a mammalian member of the family 18 glycosyl hydrolases, is secreted by activated macrophages at a late stage of differentiation. Macrophages are present in inflammation of the arterial wall and are thought to participate in the pathogenesis of giant cell arteritis (GCA). The aim of this study was to evaluate whether macrophages and giant cells of patients with GCA produce YKL-40, and whether serum YKL-40 concentrations are elevated in these patients.nnnMETHODSnSerum YKL-40 was determined by radioimmunoassay in 19 patients with GCA and 8 patients with polymyalgia rheumatica (PMR) who were followed up prospectively during 1 year of treatment with prednisolone. Immunohistochemical staining for YKL-40 was performed in temporal artery biopsy samples that were obtained before treatment.nnnRESULTSnIn the arteritic vessels of patients with GCA, positive staining for the YKL-40 antigen was found in CD68+ giant cells and mononuclear cells located in the media. Macrophages located in the adventitia and intima were negative for YKL-40. At the time of diagnosis, patients with GCA had an increased median serum level of YKL-40 (256 microg/liter; P<0.01) compared with healthy age-matched controls (median 118 microg/liter), and the serum level of YKL-40 decreased to normal levels during prednisolone treatment (-38% after 1 month; P<0.001). Most patients with PMR had normal serum YKL-40 levels (median 158 microg/liter) and had no changes in the serum YKL-40 levels during prednisolone treatment. The observed changes in serum YKL-40 did not always parallel the changes in serum C-reactive protein levels and erythrocyte sedimentation rate during the 1-year study period.nnnCONCLUSIONnYKL-40 is found in CD68+ giant cells and mononuclear cells in the media of arteritic vessels of patients with GCA, and the concentration of serum YKL-40 may reflect the local activity of these cells in the inflamed artery.

A cross-sectional study of the Birmingham Vasculitis Activity Score version 3 in systemic vasculitis

OBJECTIVEnAssessment of disease activity in vasculitis can be achieved using the BVAS, a clinical checklist of relevant symptoms, signs and features of active disease. The aim of this study was to revalidate the BVAS version 3 (BVAS v. 3) in a cohort of patients with systemic vasculitis.nnnMETHODSnA total of 238 patients with vasculitis from seven countries in Europe were evaluated at a single time point. Spearmans correlation coefficients were calculated between BVAS v. 3 scores, vasculitis activity index (VAI), physicians global assessment (PGA), the physicians treatment decision, CRP and the vasculitis damage index (VDI) to demonstrate that the BVAS v. 3 measures disease activity.nnnRESULTSnWG (63%), Churg-Strauss syndrome (9%) and microscopic polyangiitis (9%) were the most common diagnoses. The BVAS v. 3 showed convergent validity with the VAI [ρu2009=u20090.82 (95% CI 0.77, 0.85)], PGA [ρu2009=u20090.85 (95% CI 0.81, 0.88)] and the physicians treatment decision [ρu2009=u20090.54 (95% CI 0.44, 0.62)]. There was little or no correlation between BVAS v. 3 and the CRP level [ρu2009=u20090.18 (95% CI 0.05, 0.30)] or with the VDI [ρu2009=u2009-0.10 (95% CI 0.22, 0.03)]. The inter-observer reliability was very high with an intra-class correlation coefficient (ICC) of 0.996 (95% CI 0.990, 0.998) for the total BVAS v. 3 score.nnnCONCLUSIONnThe BVAS v. 3 has been evaluated in a large cohort of patients with vasculitis and the important properties of the tool revalidated. This study increases the utility of the BVAS v. 3 in different populations of patients with systemic vasculitis.

Measurement of damage in systemic vasculitis: a comparison of the Vasculitis Damage Index with the Combined Damage Assessment Index

Objectives To compare the Vasculitis Damage Index (VDI) with the Combined Damage Assessment Index (CDA) as measures of damage from vasculitis. Methods A total of 283 patients with vasculitis from 11 European centres were evaluated in a cross-sectional study using the VDI and CDA. Results Wegeners granulomatosis (58.4%) and microscopic polyangiitis (11.0%) were the most common diagnoses. Agreement between VDI and CDA scores (Spearmans correlation) was 0.90 (95% CI 0.87 to 0.92). There was good correlation between individual comparably evaluated organ systems (Spearmans correlation 0.70–0.94). Interobserver reliability (assessed by intraclass correlation coefficient (ICC)) was 0.94 (95% CI 0.89 to 0.98) for VDI and 0.78 (95% CI 0.63 to 0.93) for CDA. Intraobserver reliability was 0.92 (95% CI 0.83 to 1.00) for VDI and 0.87 (95% CI 0.75 to 1.00) for CDA. A total of 13 items were not used in the VDI compared to 23 in the CDA. Observers agreed that the CDA covered the full spectrum of damage attributable to vasculitis but was more time consuming and thus possibly less feasible for clinical and research purposes. Conclusions The VDI and CDA capture reliable data on damage among patients with vasculitis. The CDA captures more detail but is more complex and less practical than the VDI. Further evolution of damage assessment in vasculitis is likely to include key elements from both instruments.

Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells

OBJECTIVEnTo examine if polymorphism 80G --> A in the Reduced Folate Carrier (RFC) affects uptake of MTX in B- and CD4+ T-cells.nnnMETHODSnMononuclear cells were isolated from peripheral blood of healthy persons. Real-time PCR was used to detect the RFC80 variants. FITC-labelled MTX was added to cells stimulated with Candida albicans or tetanus toxoid, and the uptake of MTX was measured by flow cytometry. A FITC-conjugated monoclonal antibody against RFC was used to detect the cellular RFC expression.nnnRESULTSnAntigen-stimulated CD4+ T cells and B cells from individuals with the GG variant (n = 9) exhibited lower uptake of MTX than individuals expressing the AA variant (n = 8), or the GA variant (n = 8). No difference could be demonstrated between the three groups with respect to the expression of RFC by CD4+ T cells and B cells, and CD4+ T cells from individuals homozygous for the G allele exhibited lower uptake of MTX per receptor than CD4+ T cells from individuals homozygous for the A allele.nnnCONCLUSIONnMTX is taken up more efficiently via the A allele than via the G allele. This difference between the variant forms of RFC suggests that genotyping could be relevant for determining the relevant dosage of MTX in the treatment of neoplastic and autoimmune disease.

Cancer preceding Wegener's granulomatosis: a case–control study

OBJECTIVEnTo investigate whether patients with WG have an increased risk of malignancies prior to and/or around the time of the vasculitis diagnosis, as suggested by previous studies.nnnMETHODSnA total of 293 WG patients were included in the study. Ten gender- and age-matched controls were selected randomly for each patient from the Danish Central Population Register. Information on malignancies was obtained through the Danish Cancer Registry. Occurrence of malignancies before WG diagnosis among patients and before WG diagnosis of their matched case among controls (reference date) was compared by calculation of prevalence odds ratios (OR).nnnRESULTSnTwenty-six patients were diagnosed with cancer before WG, while 194 controls were diagnosed with cancer before the reference date (OR 1.4; 95% CI 0.9, 2.2). Among specific malignancies, a significantly increased prevalence was found for testis cancer (OR 6.4; 95% CI 1.1, 38) based on two patients, who developed testis cancer >10 years before WG. The overall prevalence of malignancies diagnosed <2 years before WG was not significantly increased (OR: 1.6; 95% CI: 0.8, 3.4), but non-melanoma skin cancer occurred with an increased prevalence within this time interval (OR 4.0; 95% CI 1.4, 12).nnnCONCLUSIONSnWe did not find clear evidence of an increased prevalence of preceding cancer in our WG cohort, indicating that shared risk factors are of minor importance for the excess of malignancies that occur in WG patients after the vasculitis diagnosis. Furthermore, our current and previously reported latency analyses do not substantiate that serious malignancies play a significant role in the pathogenic events that trigger development of WG.

Impaired Health-related Quality of Life in Patients Treated for Wegener's Granulomatosis

Objective. To investigate whether patients with Wegener’s granulomatosis (WG) experience reduced health-related quality of life (HRQOL) after accomplishment of remission, and to study the influence of WG-associated organ damage on HRQOL. Methods. Sixty-eight patients with inactive WG and 680 randomly selected, age- and sex-matched controls of the Danish background population completed the Medical Outcomes Study Short-Form 36 (SF-36) survey for evaluation of HRQOL. Irreversible organ damage attributable to WG and/or its treatment was assessed using the Vasculitis Damage Index (VDI). Results. The median disease duration was 7.5 (range 1–26) years in the WG group, and the median total VDI score was 2.0 (range 0–7). Compared to controls, WG patients reported impaired HRQOL reflected by significantly lower SF-36 physical component summary scores (PCS) and mental component summary scores (MCS) (p < 0.001) and by significantly lower scores in 7 out of 8 SF-36 subscales (p ≤ 0.001). In the WG group, no statistically significant correlations were found between the different SF-36 scores and the total VDI score, number of organ systems affected by damage, disease duration, or number of WG relapses. Patients with organ failure or other major forms of damage did not report significantly lower HRQOL than less severely affected patients. Conclusion. WG patients experience significantly reduced HRQOL even in phases with no apparent vasculitis disease activity. Our data indicate that the level of HRQOL does not correlate well with the extent of vasculitis-associated organ damage in WG.

Anti-cardiolipin antibodies (IgG and IgA) in women with recurrent fetal loss correlate to clinical and serological characteristics of SLE

Aim of study. We investigated to which degree IgG, IgA and IgM anti‐cardiolipin antibodies (aCL) are associated in recurrent abortion or late fetal death with other signs of autoimmune disease and in particular SLE.