| 41. |
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| 42. |
- Frodlund, Martina, 1978-
(författare)
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Antinuclear and antiphospholipid antibodies versus disease manifestations and clinical outcomes in systemic lupus erythematosus
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE) has an exceptionally heterogeneous clinical spectrum, ranging from mild disease limited to skin and joints to severe manifestations with renal disorder, central nervous system disease, severe cytopenias and thromboembolic events. Important clinical challenges include the prediction of disease flares and the identification of individuals that are likely to evolve severe disease with accrual of organ damage and worse prognosis. Autoantibodies, i.e. antinuclear antibodies (ANA) and antiphospholipid antibodies (aPL), and interferon alpha (IFN-α) that contribute to formation of immune complexes with nuclear antigens, are hallmarks considered to drive the disease in a vicious circle of antigen exposure, autoantibody production, inflammation and organ damage. There are few good biomarkers to predict severe SLE and organ damage. The aim of this PhD project was thus to increase the knowledge regarding ANA as well as aPL, and other potential biomarkers in relation to clinical features and disease outcomes in SLE.As expected, we found that the homogeneous ANA staining pattern was most common, and that it was associated with the occurrence of the ‘immunological disorder’ criterion. Speckled ANA was the second most common staining pattern, and it was inversely associated with arthritis, the ‘immunological disorder’ criterion and organ damage (Paper I). We also demonstrated that a considerable proportion of the patients lost ANA-positivity over time, whereas consistent staining patterns were most frequent (Paper V).Survival of patients with SLE has improved. Yet, in comparison to the general population, irreversible organ damage and increased mortality remains a critical concern. In Paper II, our cross-sectional analysis showed that more than a quarter of the patients had any aPL isotype (IgG, IgM or IgA class), and 14% were classified with antiphospholipid antibody syndrome (APS). A positive lupus anticoagulant (LA) test and/or IgG aPL tests were associated with most APS-related events and organ damage. Lupus nephritis, tobacco smoking, LA-positivity and the use of statins and/or corticosteroids were strongly associated with damage accrual, while hydroxychloroquine seemed to be protective. IgA aPL was not uncommon (16%) in Swedish cases of SLE, and analysis of IgA aPL may add information among clinically suspected APS-patients testing negative for LA and other aPL isotypes.Despite modern management and tax-funded health care with universal access, almost two thirds of the patients accrued organ damage over time, and the main causes of death were identified as malignancy, infection, and cardiovascular disease. We could confirm well established risk factors for organ damage such as APS, hypertension, and/or the use of corticosteroids, but we also observed that other factors such as pericarditis, haemolytic anaemia, lymphopenia and myositis seems to be of importance in this view (Paper IV).We also demonstrated that levels of the extracellular matrix protein osteopontin (OPN) was correlated with disease activity in patients with recent-onset SLE. In addition, OPN levels reflected global organ damage and were associated with APS and could have potential as a valuable biomarker in SLE (Paper III).Additional studies are warranted to further establish the clinical and mechanistic relevance of ANA seroconversion, OPN, as well as the importance of IgA aPL. Vigilance for malignancies, a restricted use of corticosteroids and prevention of cardiovascular disease and APS events are among modifiable factors to prevent organ damage and premature mortality.This thesis emphasizes the importance of autoantibodies in the pathogenesis, and diagnosis, of SLE. The autoantibody profile can be of great importance for tailored therapy in order to minimize the risk of organ damage accrual, morbidity as well as mortality.
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| 43. |
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| 44. |
- Frodlund, Martina, et al.
(författare)
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Associations between antinuclear antibody staining patterns and clinical features of systemic lupus erythematosus: analysis of a regional Swedish register
- 2013
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 3, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- Objective Antinuclear antibody (ANA) analysis by immunofluorescence (IF) microscopy remains a diagnostic hallmark of systemic lupus erythematosus (SLE). The clinical relevance of ANA fine-specificities in SLE has been addressed repeatedly, whereas studies on IF-ANA staining patterns in relation to disease manifestations are very scarce. This study was performed to elucidate whether different staining patterns associate with distinct SLE phenotypes.Design Observational cohort study.Setting One university hospital rheumatology unit in Sweden.Participants The study population consisted of 222 cases (89% women; 93% Caucasians), where of 178 met ≥4/11 of the 1982 American College of Rheumatology (ACR-82) criteria. The remaining 20% had an SLE diagnosis based on positive IF-ANA (HEp-2 cells) and ≥2 typical organ manifestations at the time of diagnosis (Fries’ criteria).Outcome measures The IF-ANA staining patterns homogenous (H-ANA), speckled (S-ANA), combined homogenous and speckled (HS-ANA), centromeric (C-ANA), nucleolar (N-ANA)±other patterns and other nuclear patterns (oANA) were related to disease manifestations and laboratory measures. Antigen-specificities were also considered regarding double-stranded DNA (Crithidia luciliae) and the following extractable nuclear antigens: Ro/SSA, La/SSB, Smith antigen (Sm), small nuclear RNP (snRNP), Scl-70 and Jo-1 (immunodiffusion and/or line-blot technique).Results 54% of the patients with SLE displayed H-ANA, 22% S-ANA, 11% HS-ANA, 9% N-ANA, 1% C-ANA, 2% oANA and 1% were never IF-ANA positive. Staining patterns among patients meeting Fries’ criteria alone did not differ from those fulfilling ACR-82. H-ANA was significantly associated with the 10th criterion according to ACR-82 (‘immunological disorder’). S-ANA was inversely associated with arthritis, ‘immunological disorder’ and signs of organ damage.Conclusions H-ANA is the dominant IF-ANA pattern among Swedish patients with SLE, and was found to associate with ‘immunological disorder’ according to ACR-82. The second most common pattern, S-ANA, associated negatively with arthritis and organ damage.
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| 45. |
- Frodlund, Martina, et al.
(författare)
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Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus : associations with disease phenotypes, vascular events and damage accrual
- 2018
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Ingår i: Clinical and Experimental Immunology. - : WILEY. - 0009-9104 .- 1365-2249. ; 194:1, s. 27-38
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Tidskriftsartikel (refereegranskat)abstract
- Immunoglobulin (Ig) G- and IgM-class anti-cardiolipin antibodies (aCL) and lupus anti-coagulant (LA) are included in the 1997 update of the American College of Rheumatology (ACR-97) systemic lupus erythematosus (SLE) criteria. Despite limited evidence, IgA-aCL and IgA anti-(2)-glycoprotein-I (anti-(2)GPI) were included in the 2012 Systemic Lupus International Collaborating Clinics criteria. The present study aimed to evaluate IgG-/IgA-/IgM-aCL and anti-(2)GPI occurrence in relation to disease phenotype, smoking habits, pharmacotherapy, anti-phospholipid syndrome (APS) and organ damage among 526 Swedish SLE patients meeting ACR-97. Patients with rheumatoid arthritis (n=100), primary Sjogren's syndrome (n=50) and blood donors (n=507) served as controls. Anti-phospholipid antibodies (aPL) were analysed by fluoroenzyme-immunoassays detecting aCL/anti-(2)GPI. Seventy-six (14%) SLE cases fulfilled the Sydney APS-criteria, and 1 aCL/anti-(2)GPI isotype (IgG/IgA/IgM) occurred in 138 SLE patients (26%). Forty-five (9%) of the SLE cases had IgA-aCL, 20 of whom (4%) lacked IgG-/IgM-aCL. Seventy-four (14%) tested positive for IgA anti-(2)GPI, 34 (6%) being seronegative regarding IgG/IgM anti-(2)GPI. Six (1%) had APS manifestations but were seropositive regarding IgA-aCL and/or IgA anti-(2)GPI in the absence of IgG/IgM-aPL and LA. Positive LA and IgG-aPL tests were associated with most APS-related events and organ damage. Exclusive IgA anti-(2)GPI occurrence associated inversely with Caucasian ethnicity [odds ratio (OR)=021, 95% confidence interval (CI)=006-072) and photosensitivity (OR=019, 95% CI=005-072). Nephritis, smoking, LA-positivity and statin/corticosteroid-medication associated strongly with organ damage, whereas hydroxychloroquine-medication was protective. In conclusion, IgA-aPL is not rare in SLE (16%) and IgA-aPL analysis may have additional value among SLE cases with suspected APS testing negative for other isotypes of aPL and LA.
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| 46. |
- Frodlund, Martina, 1978-, et al.
(författare)
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Longitudinal anti-nuclear antibody (ANA) seroconversion in systemic lupus erythematosus : a prospective study of Swedish cases with recent-onset disease
- 2020
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Ingår i: Clinical and Experimental Immunology. - : WILEY. - 0009-9104 .- 1365-2249. ; 199:3, s. 245-254
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Tidskriftsartikel (refereegranskat)abstract
- Serum immunoglobulin (Ig)G anti-nuclear antibodies (ANA) detected by indirect immunofluorescence (IF) microscopy remains a hallmark of systemic lupus erythematosus (SLE). Whether or not IF-ANA status varies over time is controversial. We therefore designed a prospective study with longitudinal follow-up of patients with recent-onset SLE. The study population consisted of 54 recently diagnosed SLE cases, all meeting the 1982 American College of Rheumatology (ACR) and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. Clinical follow-up data, including disease activity, organ damage and sera, were collected from clinical onset of SLE and onwards, in most cases yearly (0-96 months). IF-ANA was analysed on human epithelial cells-2 (HEp-2) cells and categorized regarding staining patterns. Using an addressable laser bead assay (FIDIS (TM) Connective profile), we measured IgG-ANA fine specificities against Ro52/SSA, Ro60/SSA, Sjogren's syndrome type B antigen (La/SSB), Smith antigen (Sm), Smith antigen/ribonucleoprotein (Sm/RNP), U1 RNP (U1RNP), dsDNA, ribosomal-P protein and histone. At baseline, all patients were judged ANA-positive at an abnormal titre corresponding to the 95th percentile of healthy blood donors, but seven of 54 patients (13%) lost ANA-positivity over time. Homogeneous (AC-1; 46%) and speckled (AC-4 or 5; 31%) were the most frequently observed patterns at inclusion, whereas 7% switched pattern at least once during follow-up. Established associations between ANA fine specificities and clinical data were confirmed. Levels of anti-Sm/RNP, but not of anti-dsDNA, correlated with clinical disease activity [modified SLE disease activity 2000 (mSLEDAI-2K)]. Our data indicate that a considerable proportion of Swedish patients with SLE lose ANA-positivity over time, whereas consistent staining patterns were frequent. The clinical and mechanistic relevance of ANA seroconversion remains uncertain. Further prospective evaluations in larger SLE populations with more diverse ethnicities are warranted.
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| 47. |
- Ge, Changrong P, et al.
(författare)
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Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage
- 2017
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Ingår i: JCI INSIGHT. - : AMER SOC CLINICAL INVESTIGATION INC. - 2379-3708. ; 2:13
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Tidskriftsartikel (refereegranskat)abstract
- Today, it is known that autoimmune diseases start a long time before clinical symptoms appear. Anti-citrullinated protein antibodies (ACPAs) appear many years before the clinical onset of rheumatoid arthritis (RA). However, it is still unclear if and how ACPAs are arthritogenic. To better understand the molecular basis of pathogenicity of ACPAs, we investigated autoantibodies reactive against the C1 epitope of collagen type II (CII) and its citrullinated variants. We found that these antibodies are commonly occurring in RA. A mAb (ACC1) against citrullinated C1 was found to cross-react with several noncitrullinated epitopes on native CII, causing proteoglycan depletion of cartilage and severe arthritis in mice. Structural studies by X-ray crystallography showed that such recognition is governed by a shared structural motif "RG-TG" within all the epitopes, including electrostatic potential-controlled citrulline specificity. Overall, we have demonstrated a molecular mechanism that explains how ACPAs trigger arthritis.
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| 48. |
- Ge, Changrong, et al.
(författare)
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Structural Basis of Cross-Reactivity of Anti-Citrullinated Protein Antibodies
- 2019
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Ingår i: Arthritis & Rheumatology. - : WILEY. - 2326-5191 .- 2326-5205. ; 71:2, s. 210-221
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Tidskriftsartikel (refereegranskat)abstract
- Objective Anti-citrullinated protein antibodies (ACPAs) develop many years before the clinical onset of rheumatoid arthritis (RA). This study was undertaken to address the molecular basis of the specificity and cross-reactivity of ACPAs from patients with RA. Methods Antibodies isolated from RA patients were expressed as monoclonal chimeric antibodies with mouse Fc. These antibodies were characterized for glycosylation using mass spectrometry, and their cross-reactivity was assessed using Biacore and Luminex immunoassays. The crystal structures of the antigen-binding fragment (Fab) of the monoclonal ACPA E4 in complex with 3 different citrullinated peptides were determined using x-ray crystallography. The prevalence of autoantibodies reactive against 3 of the citrullinated peptides that also interacted with E4 was investigated by Luminex immunoassay in 2 Swedish cohorts of RA patients. Results Analysis of the crystal structures of a monoclonal ACPA from human RA serum in complex with citrullinated peptides revealed key residues of several complementarity-determining regions that recognized the citrulline as well as the neighboring peptide backbone, but with limited contact with the side chains of the peptides. The same citrullinated peptides were recognized by high titers of serum autoantibodies in 2 large cohorts of RA patients. Conclusion These data show, for the first time, how ACPAs derived from human RA serum recognize citrulline. The specific citrulline recognition and backbone-mediated interactions provide a structural explanation for the promiscuous recognition of citrullinated peptides by RA-specific ACPAs.
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| 49. |
- Hallert, Eva, et al.
(författare)
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28-joint count disease activity score at 3 months after diagnosis of early rheumatoid arthritis is strongly associated with direct and indirect costs over the following 4 years: the Swedish TIRA project
- 2011
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Ingår i: Rheumatology. - Oxford : Oxford University Press. - 1462-0324 .- 1462-0332. ; 50:7, s. 1259-1267
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Tidskriftsartikel (refereegranskat)abstract
- Methods. Three-hundred and twenty patients with early (1 year) RA were assessed at regular intervals. Clinical and laboratory data were collected and patients reported health-care utilization and number of days lost from work. At 3-month follow-up, patients were divided into two groups according to disease activity, using DAS-28 with a cut-off level at 3.2. Direct and indirect costs and EuroQol-5D over the following 4 years were compared between the groups. Multivariate regression models were used to control for possible covariates. Results. Three months after diagnosis, a DAS-28 level of epsilon 3.2 was associated with high direct and indirect costs over the following 4 years. Patients with DAS-28 epsilon 3.2 at 3-month follow-up had more visits to physician, physiotherapist, occupational therapist and nurse, higher drug costs, more days in hospital and more extensive surgery compared with patients with 3-month DAS-28 less than 3.2. Number of days lost from work due to sick leave and permanent work disability was also higher in this group. The effect of disease activity on health-related quality of life was highly significant. In regression models, DAS-28 at 3-month follow-up was significantly associated with costs over the following years. Conclusions. Three months after diagnosis, DAS-28 is an important prognostic marker regarding health-care utilization and costs. Achieving remission or low disease activity 3 months after diagnosis is likely to decrease morbidity, increase quality of life and save costs for the patient and for society over the following years.
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| 50. |
- Hallert, Eva, et al.
(författare)
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Changes in sociodemographic characteristics at baseline in two Swedish cohorts of patients with early rheumatoid arthritis diagnosed 1996-98 and 2006-09
- 2015
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Ingår i: Scandinavian Journal of Rheumatology. - : Informa Healthcare. - 0300-9742 .- 1502-7732. ; 44:2, s. 100-105
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To compare baseline sociodemographic characteristics in two rheumatoid arthritis (RA) cohorts enrolled 10 years apart, and to examine differences with respect to the general population. Method: Clinical and sociodemographic data were collected in 320 early RA patients during 1996-98 (TIRA-1) and 467 patients in 2006-09 (TIRA-2). Multivariate logistic regression tests were performed and intercohort comparisons were related to general population data, obtained from official databases. Results: TIRA-2 patients were older than TIRA-1 (58 vs. 56 years). Women (both cohorts, 67%) were younger than men in TIRA-1 (55 vs. 59 years) and in TIRA-2 (57 vs. 61 years). Disease activity was similar but TIRA-2 women scored worse pain and worse on the HAQ. Approximately 73% were cohabiting, in both cohorts and in the general population. Education was higher in TIRA-2 than in TIRA-2 but still lower than in the general population. Women had consistently higher education than men. Education was associated with age, younger patients having higher education. In both cohorts, lower education was associated with increased disability pension and increased sick leave. Sick leave was lower in TIRA-2 than in TIRA-1 (37% vs. 50%) but disability pension was higher (16% vs. 10%). In TIRA-1, 9% of women had disability pension compared with 17% in TIRA-2. A similar decrease in sick leave and an increase in disability pension were also seen in the general population. Older age and a higher HAQ score were associated with increased sick leave and being in the TIRA-2 cohort was associated with decreased sick leave. Conclusions: TIRA-2 patients were slightly older, better educated, had lower sick leave and higher disability pension than those in TIRA-1. Similar changes were seen simultaneously in the general population. Belonging to the TIRA-2 cohort was associated with decreased sick leave, indicating that societal changes are of importance.
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