Presence of autoantibodies in “seronegative” rheumatoid arthritis associates with classical risk factors and high disease activity
Abstract Background Rheumatoid arthritis (RA) is classified as seropositive or seronegative, depending on the presence/absence of rheumatoid factor (RF), primarily IgM RF, and/or anti-citrullinated protein antibodies (ACPA), commonly detected using anti-cyclic citrullinated peptide (CCP) assays. Kno...
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doaj-9e44246f67784c6896472dab7aa00d192020-11-25T03:47:11ZengBMCArthritis Research & Therapy1478-63622020-07-0122111110.1186/s13075-020-02191-2Presence of autoantibodies in “seronegative” rheumatoid arthritis associates with classical risk factors and high disease activityEvan Reed0Anna Karin Hedström1Monika Hansson2Linda Mathsson-Alm3Boel Brynedal4Saedis Saevarsdottir5Martin Cornillet6Per-Johan Jakobsson7Rikard Holmdahl8Karl Skriner9Guy Serre10Lars Alfredsson11Johan Rönnelid12Karin Lundberg13Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University HospitalInstitute of Environmental Medicine, Karolinska InstitutetDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University HospitalThermo Fisher ScientificInstitute of Environmental Medicine, Karolinska InstitutetDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University HospitalUnité Différenciation Epithéliale et Autoimmunité Rhumatoïde, Université de Toulouse-INSERM UMR 1056Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University HospitalSection for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska InstitutetDepartment of Rheumatology and Clinical Immunology, Charité UniversityUnité Différenciation Epithéliale et Autoimmunité Rhumatoïde, Université de Toulouse-INSERM UMR 1056Institute of Environmental Medicine, Karolinska InstitutetDepartment of Immunology Genetics and Pathology, Uppsala UniversityDivision of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University HospitalAbstract Background Rheumatoid arthritis (RA) is classified as seropositive or seronegative, depending on the presence/absence of rheumatoid factor (RF), primarily IgM RF, and/or anti-citrullinated protein antibodies (ACPA), commonly detected using anti-cyclic citrullinated peptide (CCP) assays. Known risk factors associate with the more severe seropositive form of RA; less is known about seronegative RA. Here, we examine risk factors and clinical phenotypes in relation to presence of autoantibodies in the RA subset that is traditionally defined as seronegative. Methods Anti-CCP2 IgG, 19 ACPA fine-specificities, IgM/IgG/IgA RF, anti-carbamylated-protein (CarP) antibodies, and 17 other autoantibodies, were analysed in 2755 RA patients and 370 controls. Antibody prevalence, levels, and co-occurrence were examined, and associations with risk factors and disease activity during 5 years were investigated for different antibody-defined RA subsets. Results Autoantibodies were detected in a substantial proportion of the traditionally defined seronegative RA subset, with ACPA fine-specificities found in 30%, IgA/IgG RF in 9.4%, and anti-CarP antibodies in 16%, with a 9.6% co-occurrence of at least two types of RA-associated autoantibodies. HLA-DRB1 shared epitope (SE) associated with the presence of ACPA in anti-CCP2-negative RA; in anti-CCP2-positive RA, the SE association was defined by six ACPA fine-specificities with high co-occurrence. Smoking associated with RF, but not with ACPA, in anti-CCP2-negative RA. Presence of ACPA and RF, but not anti-CarP antibodies, in conventionally defined “seronegative” RA, associated with worse clinical outcome. Conclusions “Seronegative” RA is not truly a seronegative disease subset. Additional screening for ACPA fine-specificities and IgA/IgG RF defines a group of patients that resembles seropositive patients with respect to risk factors and clinical picture and may contribute to earlier diagnosis for a subset of anti-CCP2−/IgM RF− patients with a high need for active treatment.http://link.springer.com/article/10.1186/s13075-020-02191-2Rheumatoid arthritis (RA)AutoantibodiesAnti-citrullinated protein antibodies (ACPA)Cyclic citrullinated peptide (CCP)Rheumatoid factor (RF)Anti-carbamylated protein antibodies (anti-CarP) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Evan Reed Anna Karin Hedström Monika Hansson Linda Mathsson-Alm Boel Brynedal Saedis Saevarsdottir Martin Cornillet Per-Johan Jakobsson Rikard Holmdahl Karl Skriner Guy Serre Lars Alfredsson Johan Rönnelid Karin Lundberg |
spellingShingle |
Evan Reed Anna Karin Hedström Monika Hansson Linda Mathsson-Alm Boel Brynedal Saedis Saevarsdottir Martin Cornillet Per-Johan Jakobsson Rikard Holmdahl Karl Skriner Guy Serre Lars Alfredsson Johan Rönnelid Karin Lundberg Presence of autoantibodies in “seronegative” rheumatoid arthritis associates with classical risk factors and high disease activity Arthritis Research & Therapy Rheumatoid arthritis (RA) Autoantibodies Anti-citrullinated protein antibodies (ACPA) Cyclic citrullinated peptide (CCP) Rheumatoid factor (RF) Anti-carbamylated protein antibodies (anti-CarP) |
author_facet |
Evan Reed Anna Karin Hedström Monika Hansson Linda Mathsson-Alm Boel Brynedal Saedis Saevarsdottir Martin Cornillet Per-Johan Jakobsson Rikard Holmdahl Karl Skriner Guy Serre Lars Alfredsson Johan Rönnelid Karin Lundberg |
author_sort |
Evan Reed |
title |
Presence of autoantibodies in “seronegative” rheumatoid arthritis associates with classical risk factors and high disease activity |
title_short |
Presence of autoantibodies in “seronegative” rheumatoid arthritis associates with classical risk factors and high disease activity |
title_full |
Presence of autoantibodies in “seronegative” rheumatoid arthritis associates with classical risk factors and high disease activity |
title_fullStr |
Presence of autoantibodies in “seronegative” rheumatoid arthritis associates with classical risk factors and high disease activity |
title_full_unstemmed |
Presence of autoantibodies in “seronegative” rheumatoid arthritis associates with classical risk factors and high disease activity |
title_sort |
presence of autoantibodies in “seronegative” rheumatoid arthritis associates with classical risk factors and high disease activity |
publisher |
BMC |
series |
Arthritis Research & Therapy |
issn |
1478-6362 |
publishDate |
2020-07-01 |
description |
Abstract Background Rheumatoid arthritis (RA) is classified as seropositive or seronegative, depending on the presence/absence of rheumatoid factor (RF), primarily IgM RF, and/or anti-citrullinated protein antibodies (ACPA), commonly detected using anti-cyclic citrullinated peptide (CCP) assays. Known risk factors associate with the more severe seropositive form of RA; less is known about seronegative RA. Here, we examine risk factors and clinical phenotypes in relation to presence of autoantibodies in the RA subset that is traditionally defined as seronegative. Methods Anti-CCP2 IgG, 19 ACPA fine-specificities, IgM/IgG/IgA RF, anti-carbamylated-protein (CarP) antibodies, and 17 other autoantibodies, were analysed in 2755 RA patients and 370 controls. Antibody prevalence, levels, and co-occurrence were examined, and associations with risk factors and disease activity during 5 years were investigated for different antibody-defined RA subsets. Results Autoantibodies were detected in a substantial proportion of the traditionally defined seronegative RA subset, with ACPA fine-specificities found in 30%, IgA/IgG RF in 9.4%, and anti-CarP antibodies in 16%, with a 9.6% co-occurrence of at least two types of RA-associated autoantibodies. HLA-DRB1 shared epitope (SE) associated with the presence of ACPA in anti-CCP2-negative RA; in anti-CCP2-positive RA, the SE association was defined by six ACPA fine-specificities with high co-occurrence. Smoking associated with RF, but not with ACPA, in anti-CCP2-negative RA. Presence of ACPA and RF, but not anti-CarP antibodies, in conventionally defined “seronegative” RA, associated with worse clinical outcome. Conclusions “Seronegative” RA is not truly a seronegative disease subset. Additional screening for ACPA fine-specificities and IgA/IgG RF defines a group of patients that resembles seropositive patients with respect to risk factors and clinical picture and may contribute to earlier diagnosis for a subset of anti-CCP2−/IgM RF− patients with a high need for active treatment. |
topic |
Rheumatoid arthritis (RA) Autoantibodies Anti-citrullinated protein antibodies (ACPA) Cyclic citrullinated peptide (CCP) Rheumatoid factor (RF) Anti-carbamylated protein antibodies (anti-CarP) |
url |
http://link.springer.com/article/10.1186/s13075-020-02191-2 |
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