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Frodlund, Martina
Publications (4 of 4) Show all publications
Frodlund, M. (2020). Antinuclear and antiphospholipid antibodies versus disease manifestations and clinical outcomes in systemic lupus erythematosus. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Antinuclear and antiphospholipid antibodies versus disease manifestations and clinical outcomes in systemic lupus erythematosus
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2020. p. 80
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1731
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:liu:diva-164957 (URN)10.3384/diss.diva-164957 (DOI)9789179298951 (ISBN)
Public defence
2020-04-29, Belladonna, Växthuset, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Rheumatism AssociationRegion ÖstergötlandSwedish Society of MedicineSwedish Society for Medical Research (SSMF)Swedish Heart Lung Foundation
Note

Ytterligare forskingsfinansiärer: Ingegerd Johanssons donation, Selanders stiftelse, Ingrid Asps stiftelse, StiftelsenProfessor Nanna Svartz fond, Stiftelsen Konung Gustaf V:s 80-årsfond och Konung Gustaf V:s och Drottning Victorias Frimurarstiftelse.

Available from: 2020-04-07 Created: 2020-04-07 Last updated: 2020-04-16Bibliographically approved
Frodlund, M., Wetterö, J., Dahle, C., Dahlström, Ö., Skogh, T., Ronnelid, J. & Sjöwall, C. (2020). Longitudinal anti-nuclear antibody (ANA) seroconversion in systemic lupus erythematosus: a prospective study of Swedish cases with recent-onset disease. Clinical and Experimental Immunology, 199(3), 245-254
Open this publication in new window or tab >>Longitudinal anti-nuclear antibody (ANA) seroconversion in systemic lupus erythematosus: a prospective study of Swedish cases with recent-onset disease
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2020 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 199, no 3, p. 245-254Article in journal (Refereed) Published
Abstract [en]

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, Sjogrens 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.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2020
Keywords
autoantibodies; autoimmunity; complement; human; systemic lupus erythematosus
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-164196 (URN)10.1111/cei.13402 (DOI)000513952100007 ()31778219 (PubMedID)2-s2.0-85076720021 (Scopus ID)
Note

Funding Agencies|the Swedish Society of Medicine; Swedish Society of Medicine; the County Council of Ostergotland; Swedish Rheumatism Association; the Swedish Rheumatism Association; the King Gustaf V and Queen Victorias Freemasons foundation; the King Gustaf Vs 80-year Anniversary foundation

Available from: 2020-03-11 Created: 2020-03-11 Last updated: 2020-04-09Bibliographically approved
Frodlund, M., Vikerfors, A., Grosso, G., Skogh, T., Wetterö, J., Elvin, K., . . . Sjöwall, C. (2018). Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus: associations with disease phenotypes, vascular events and damage accrual. Clinical and Experimental Immunology, 194(1), 27-38
Open this publication in new window or tab >>Immunoglobulin A anti-phospholipid antibodies in Swedish cases of systemic lupus erythematosus: associations with disease phenotypes, vascular events and damage accrual
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2018 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 194, no 1, p. 27-38Article in journal (Refereed) Published
Abstract [en]

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 Sjogrens 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.

Place, publisher, year, edition, pages
WILEY, 2018
Keywords
anti-phospholipid antibodies; anti-phospholipid syndrome; autoantibodies; immunoglobulin A; systemic lupus erythematosus
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-151933 (URN)10.1111/cei.13180 (DOI)000445601500004 ()30208508 (PubMedID)
Note

Funding Agencies|Swedish Society for Medical Research; Swedish Rheumatism Association; Swedish Society of Medicine; King Gustaf Vs 80-year foundation; King Gustaf V and Queen Victorias Freemasons foundation; Swedish Heart-Lung Foundation; Swedish Research Council; County Council of Stockholm; County Council of Uppsala; County Council of Ostergotland

Available from: 2018-10-16 Created: 2018-10-16 Last updated: 2020-04-07
Parodis, I., Gomez, A., Frodlund, M., Jönsen, A., Zickert, A., Sjöwall, C., . . . Gunnarsson, I. (2018). Smoking reduces the efficacy of belimumab in mucocutaneous lupus.. Expert Opinion on Biological Therapy, 18(8), 911-920
Open this publication in new window or tab >>Smoking reduces the efficacy of belimumab in mucocutaneous lupus.
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2018 (English)In: Expert Opinion on Biological Therapy, ISSN 1471-2598, E-ISSN 1744-7682, Vol. 18, no 8, p. 911-920Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Recently, we demonstrated a negative impact of smoking on belimumab efficacy in patients with systemic lupus erythematosus (SLE). Here, we particularly investigated clinical effects of belimumab and a potential impact of smoking in mucocutaneous and articular SLE.

METHODS: We surveyed 62 SLE patients treated between 2011 and 2017. Evaluation included the mucocutaneous descriptors of SLEDAI-2K (rash, alopecia, mucosal ulcers; mcSLEDAI-2K), CLASI, the arthritis SLEDAI-2K descriptor (arSLEDAI-2K) and the 28-joint count.

RESULTS: mcSLEDAI-2K and CLASI activity decreased from baseline to month 6 and 12 (P<0.001 for all). No worsening in CLASI damage was observed. Current or previous smokers displayed a higher probability of unchanged/worsened mcSLEDAI-2K compared to never smokers (OR: 6.4; 95% CI: 1.5-27.4; P=0.012), also after adjustment for antimalarial agents. arSLEDAI-2K scores had decreased at month 6 (P<0.001) and 12 (P<0.001). Likewise, tender and swollen 28-joint counts had improved at month 6 (P=0.010 and P<0.001, respectively) and 12 (P=0.001 for both). We observed no impact of smoking on belimumab efficacy in articular SLE.

CONCLUSION: We observed a negative impact of smoking on the efficacy of belimumab in mucocutaneous SLE. In contrast, no impact of smoking on belimumab efficacy was seen in patients with articular manifestations.

Place, publisher, year, edition, pages
Informa Healthcare, 2018
Keywords
belimumab, biological agents, drug efficacy, rheumatology, systemic lupus erythematosus
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:liu:diva-149494 (URN)10.1080/14712598.2018.1494719 (DOI)000445196000008 ()29958508 (PubMedID)
Available from: 2018-07-03 Created: 2018-07-03 Last updated: 2019-04-10
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