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Svärd, Anna
Publications (7 of 7) Show all publications
Roos, K., Martinsson, K., Ziegelasch, M., Sommarin, Y., Svärd, A., Skogh, T. & Kastbom, A. (2016). Circulating secretory IgA antibodies against cyclic citrullinated peptides in early rheumatoid arthritis associate with inflammatory activity and smoking. Arthritis Research & Therapy, 18(119)
Open this publication in new window or tab >>Circulating secretory IgA antibodies against cyclic citrullinated peptides in early rheumatoid arthritis associate with inflammatory activity and smoking
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2016 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 18, no 119Article in journal (Refereed) Published
Abstract [en]

Background: A possible association between mucosal immunization and inflammation, as well as the initiation and propagation of rheumatoid arthritis (RA), is attracting renewed interest. The aim of this study was to evaluate the possible occurrence and clinical correlations of circulating secretory immunoglobulin A (SIgA) antibodies against the second-generation cyclic citrullinated peptides (CCP) among patients with recent-onset RA followed prospectively over 3 years. Methods: Baseline serum samples from 636 patients with recent-onset RA were analyzed for SIgA anti-CCP antibodies by using an enzyme-linked immunosorbent assay with a secondary antibody directed against secretory component. SIgA anti-CCP status at baseline was analyzed in relation to smoking, HLA-DRB1/shared epitope (SE), and the disease course over 3 years. Significant findings were evaluated in regression analysis that included age, sex, smoking, and SE. Results: Seventeen percent of the patients tested positive for circulating SIgA anti-CCP, and the occurrence was confirmed by detection of secretory component in an affinity-purified IgA anti-CCP fraction. SIgA anti-CCP positivity at baseline was associated with slightly higher baseline erythrocyte sedimentation rate (ESR) (mean 38 vs. 31 mm/first hour, p = 0.004) and C-reactive protein (CRP) (mean 30 vs. 23 mg/L, p = 0.047). During follow-up, SIgA anti-CCP-positive patients had a higher mean AUC regarding ESR (adjusted p = 0.003), although there were no significant differences regarding CRP, tender and swollen joint counts, or radiological joint damage (median Larsen progression 1.0 vs. 1.0, p = 0.22). SIgA anti-CCP was associated significantly with smoking (79 % ever smokers among SIgA anti-CCP-positive patients vs. 59 % in SIgA anti-CCP-negative patients, adjusted OR 2.19, 95 % CI 1.01-4.37, p = 0.027) but not with carriage of the SE (80 % vs. 73 %, p = 0.62). Conclusions: Circulating SIgA anti-CCP, which is present in a subgroup of patients with early RA, is not related to SE, but it is environmentally linked to cigarette smoking. This finding strengthens the hypothesis that immunization against citrullinated peptides and/or proteins may occur at mucosal surfaces of the airways. Analysis of SIgA antibodies in serum may be a convenient and more versatile means to investigate the "mucosal connection" in RA compared with analyses in mucosal fluid samples.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2016
Keywords
Rheumatoid arthritis; Anticitrullinated protein antibodies; Secretory immunoglobulin A; Mucosal immunity
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:liu:diva-129493 (URN)10.1186/s13075-016-1014-1 (DOI)000376373100001 ()27215344 (PubMedID)
Note

Funding Agencies|King Gustav Vs 80-year Foundation; Swedish Medical Society; Reinhold Sund Foundation; Ostergotland County Council

Available from: 2016-06-20 Created: 2016-06-20 Last updated: 2017-11-28
Svärd, A., Skogh, T., Alfredsson, L., Ilar, A., Klareskog, L., Bengtsson, C. & Kastbom, A. (2015). Associations to smoking and shared epitope differ between IgA and IgG class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis. Arthritis & Rheumatology, 67(8), 2032-2037
Open this publication in new window or tab >>Associations to smoking and shared epitope differ between IgA and IgG class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis
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2015 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, no 8, p. 2032-2037Article in journal (Refereed) Published
Abstract [en]

Background Smoking and HLA-DRB1/shared epitope (SE) are well-known interacting risk factors for developing rheumatoid arthritis (RA) with IgG anticitrullinated protein/peptide antibodies (ACPA). It remains unknown to what extent SE-genes and smoking associate with mucosal immune responses.

Objectives This study was done to explore relations between cigarette smoking habits and SE versus circulating IgA and IgG anti-cyclic citrullinated peptide antibodies (anti-CCP) among early RA patients.

Methods Patients from two early-RA cohorts were analysed, EIRA-1 (n=1663) and TIRA-2 (n=199). The patients were grouped into four subsets based on anti-CCP: IgG-/IgA-, IgG-/IgA+, IgG+/IgA- and IgG+/IgA+. Interaction between smoking and SE was calculated by the attributable proportion due to deviation from additivity. Analyzed controls (n=1100) were randomly selected from the EIRA-1 study base.

Results Anti-CCP occurrence was similar in the two cohorts. Only in EIRA was IgA anti-CCP detected alone in a minority of cases (3%). Smoking was significantly overrepresented among IgA anti-CCP+ patients with or without IgG-class anti-CCP, but not with IgG anti-CCP alone. Presence of SE genes was overrepresented among IgG anti-CCP+ patients with or without IgA-class anti-CCP, but not with IgA anti-CCP alone. Smoking and SE interacted regarding the risk of IgG+/IgA+ RA (AP=0.5, 95 % CI=0.4-0.6), whereas no significant interaction was observed regarding IgG-/IgA+ or IgG+/IgA- RA.

Conclusions Association between cigarette smoking and anti-CCP is limited to cases with IgA-class antibodies in addition to IgG anti-CCP. This suggests a causal relation between chronic mucosal irritation/inflammation, induction of a systemic IgA anti-CCP response and subsequent development of RA.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2015
Keywords
Rheumatoid arthritis, immunoglobulin A, ACPA, smoking, shared epitope
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:liu:diva-105986 (URN)10.1002/art.39170 (DOI)000358609300007 ()
Note

At the defence date the status of this publication was Manuscript.

Supported by the Centre for Clinical Research-Dalarna, the Swedish Research Council, the Swedish Association Against Rheumatism, King Gustaf V's 80-Year Foundation, the County Council of Ostergotland, the Reinhold Sund Foundation, the Swedish Society of Medicine, the Medical Research County Council of South-East Sweden, the Swedish Research Council for Health, Working Life, and Welfare, AFA Insurance, the Swedish Rheumatic Foundation, and the Innovative Medicines Initiative (BTCure).

Available from: 2014-04-15 Created: 2014-04-15 Last updated: 2017-12-05Bibliographically approved
Svärd, A. (2014). Circulating and Mucosal Antibodies to Citrullinated Antigens in Rheumatoid Arthritis. (Doctoral dissertation). Linköping: Linköping University Electronic Press
Open this publication in new window or tab >>Circulating and Mucosal Antibodies to Citrullinated Antigens in Rheumatoid Arthritis
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation and subsequent destruction of cartilage and bone. The etiology is largely unknown, although genetic as well as environmental factors are involved. The manifestations and consequences of RA differ between individuals. This makes it important to find early markers for the disease course, in order to enable the most suitable treatment. IgG antibodies to cyclic citrullinated peptides (CCP) have high specificity for RA, but only around 60% of RA patients test positive for IgG anti-CCP.

The aim of this thesis was to evaluate the usefulness of serum IgA anti-CCP as a diagnostic maker compared to IgG anti-CCP, and to assess IgA versus IgG anti-CCP status in relation to smoking habits and genetic background. Another aim was to evaluate signs of mucosal immunization by analyzing salivary IgA anti-CCP.

IgA anti-CCP was present in a subgroup of RA patients with high levels of IgG anti-CCP and a slightly more severe disease course. Similar results were found regarding IgA class antibodies to modified citrullinated vimentin (MCV). IgG anti-MCV had slightly higher sensitivity for RA than IgG anti-CCP, thus identifying a group of IgG anti-CCP negative patients with an unfavourable disease course. However, the lower diagnostic specificity of IgG anti-MCV limits its usefulness.

Among 63 patients with established RA, salivary IgA anti-CCP was found in 22% and was associated with a more favourable outcome regarding erosive joint disease at follow-up. IgA anti-CCP in serum was strongly associated with smoking, and the earlier known interaction between smoking and shared epitope (SE) was here shown to be valid only for subjects positive for IgA anti-CCP in combination with IgG anti-CCP.

In conclusion, IgG anti-CCP is still the most useful serologic marker of RA, but IgA anti-CCP should be further investigated as a prognostic marker. The association between smoking and IgA anti-CCP strongly indicates a pathogenic role for smoking and IgA anti-CCP, supporting the possibility that RA may originate from chronic airway irritation. The less erosive disease in patients positive for salivary IgA anti-CCP indicates a protective role of secretory IgA anti-CCP.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. p. 78
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1404
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-105987 (URN)10.3384/diss.diva-105987 (DOI)978-91-7519-342-7 (ISBN)
Public defence
2014-05-15, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2014-04-15 Created: 2014-04-15 Last updated: 2015-08-31Bibliographically approved
Svärd, A., Kastbom, A., Sommarin, Y. & Skogh, T. (2013). Salivary IgA antibodies to cyclic citrullinated peptides (CCP) in rheumatoid arthritis. Immunobiology, 218(2), 232-237
Open this publication in new window or tab >>Salivary IgA antibodies to cyclic citrullinated peptides (CCP) in rheumatoid arthritis
2013 (English)In: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 218, no 2, p. 232-237Article in journal (Refereed) Published
Abstract [en]

Circulating IgG anti-cyclic citrullinated peptide antibodies (CCP) are highly specific for rheumatoid arthritis (RA) and prognostic of poor outcome. Serum IgA anti-CCP occurs in a subset of IgG-positive cases and relates to still more aggressive disease. Mucosal IgA-class antibodies, however, are generally associated with anti-inflammatory actions and systemic tolerance induction. In the present study, unstimulated salivary samples from 63 patients with established RA and 20 healthy persons were analysed by enzyme-linked immunoassay for the presence of IgA anti-CCP antibodies. To ensure antigen specificity, IgA-reactivity with the corresponding uncitrullinated antigen, cyclic arginine peptide (CAP), was analysed and anti-CCP/anti-CAP ratios calculated. Retrospective data regarding disease activity and radiological outcome were achieved via medical records. Salivary IgA anti-CCP was found in 14/63 (22%) patients and one (5%) control (positive test = anti-CCP/anti-CAP ratio andgt; 1.5). Salivary IgA reactivity was dose-dependently inhibited by pre-incubation with soluble CCP to a degree strongly correlating with anti-CCP/anti-CAP ratio. In salivary IgA anti-CCP positive patients, joint erosions within 6 years of diagnosis was significantly lower (p = 0.043), and at the time for diagnosis there was a trend towards lower erythrocyte sedimentation rate (p = 0.071) and C-reactive protein (p = 0.085). Contrasting to circulating IgG and IgA anti-CCP, our results imply that salivary IgA antibodies may be associated with a less severe outcome of RA. Hypothetically, this relates to an anti-inflammatory and protective immunomodulating role of secretory IgA-class autoantibodies against citrullinated antigens presented at mucosal surfaces.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Citrullinated peptides, IgA, Rheumatoid arthritis, Saliva, Mucosal immunity
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-90205 (URN)10.1016/j.imbio.2012.04.011 (DOI)000315312000013 ()
Note

Funding Agencies|Centre for Clinical Research in Dalarna||Swedish Research Council|2008-2832|Swedish Association Against Rheumatism||King Gustaf Vth 80-Year Foundation||County Council of Ostergotland Research Foundations||Medical Research County Council of South-East Sweden (FORSS)||

Available from: 2013-03-21 Created: 2013-03-21 Last updated: 2017-12-06
Svärd, A., Kastbom, A., Sommarin, Y. & Skogh, T. (2012). A disease-modifying role for mucosal IgA antibodies to citrullinated antigens?. Paper presented at 32nd European Workshop for Rheumatology Research Stockholm, FEB 23-25, 2012. Annals of the Rheumatic Diseases, 71(Issue suppl. 1), A38-A39
Open this publication in new window or tab >>A disease-modifying role for mucosal IgA antibodies to citrullinated antigens?
2012 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, no Issue suppl. 1, p. A38-A39Article in journal, Meeting abstract (Refereed) Published
Abstract [en]

Objective

The aim of this study was to investigate whether immunoglobulin A (IgA) antibodies to cyclic citrullinated peptides CCP) can be detected in saliva of patients with established heumatoid arthritis (RA) and if it relates to clinical manifestations.

Methods

Salivary samples were collected (by ‘passive drooling’) from 63 consecutive patients with established RA at a visit to the rheumatology outpatient clinic (Falun, Sweden), and from 20 healthy persons (hospital staff). The samples were centrifuged and kept frozen at −70°C until analysis. IgA-class anti-CCP antibodies in saliva were analysed by adaptation of commercial ELISA (Immunoscan RA, Euro-Diagnostica AB, Malmo, Sweden) using polyclonal rabbit antihuman α-chain specific antibodies conjugated with horseradish peroxidase(DakoCytomation, Glostrup, Denmark) as secondary antibody. To ensure specificity of the reaction, a corresponding ELISA was set up to analyse IgA antibodies to control antigen(cyclic arginine peptide, CAP), and anti-CCP/anti-CAP ratios were calculated. Also, inhibition studies were performed by preincubation of sera with soluble CCP or CAP. Clinical and laboratory data on disease activity, that is, C reactive protein (CRP), erythrocyte sedimentation rate (ESR), and 28-joint count disease activity score (DAS28) as well as radiological outcome (occurrence or absence of erosions as judged by a radiologist in diagnostic routine) were achieved retrospectively via the patients’ medical records.

Results

Background reactivity against CCP was found in virtually all patients and healthy subjects, whereas a positive anti-CCP/anti-CAP ratio (≥1.5) was found in 14 out of 63 RA patients (22%) and in one healthy subject (5%). Salivary IgA-reactivity with CCP was dose-dependently inhibited by soluble CCP (but not with CAP) in sera with anti-CCP/anti- CAP ratios ≥1.5. No IgG-reactivity to CCP was found in saliva, although all patients with salivary IgA anti-CCP tested IgG anti-CCP-positive in serum. Furthermore, less than half of those testing IgA-positive in saliva were IgA anti-CCP positive in serum, strongly arguing against passive leakage of anti-CCP antibodies from blood to saliva. The patients testing positive for salivary IgA antibodies had lower average disease activity measures (CRP, ESR, DAS28) at presentation and fewer developed bony erosions within 6 years after presentation (p=0.043, Fisher’s exact test).

Conclusion

Salivary IgA antibodies to citrullinated proteins were found in a subset of IgG anti-CCP positive RA patients. In contrast to their serum counterparts, salivary IgA antibodies may associate with a milder/less destructive disease course. This accords with the notion that secretory IgA antibodies exert anti-inflammatory actions, and that they may be associated with induction of systemic tolerance (oral tolerance). The possible disease-modifying role of mucosal immunity to citrullinated proteins needs further investigation!

                

                                                                

Place, publisher, year, edition, pages
BMJ Publishing Group, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76965 (URN)10.1136/annrheumdis-2011-201234.16 (DOI)000302323600087 ()
Conference
32nd European Workshop for Rheumatology Research Stockholm, FEB 23-25, 2012
Available from: 2012-04-27 Created: 2012-04-27 Last updated: 2017-12-07
Svärd, A., Kastbom, A., Sommarin, Y. & Skogh, T. (2011). A Disease-Modifying Role for Mucosal IgA Antibodies to Citrullinated Antigens? in ARTHRITIS AND RHEUMATISM, vol 63, issue 10, pp S849-S849. In: ARTHRITIS AND RHEUMATISM (pp. S849-S849). Wiley-Blackwell, 63(10)
Open this publication in new window or tab >>A Disease-Modifying Role for Mucosal IgA Antibodies to Citrullinated Antigens? in ARTHRITIS AND RHEUMATISM, vol 63, issue 10, pp S849-S849
2011 (English)In: ARTHRITIS AND RHEUMATISM, Wiley-Blackwell , 2011, Vol. 63, no 10, p. S849-S849Conference paper, Published paper (Refereed)
Abstract [en]

n/a

Place, publisher, year, edition, pages
Wiley-Blackwell, 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-73351 (URN)000297621502566 ()
Available from: 2012-01-02 Created: 2012-01-02 Last updated: 2015-08-31
Svärd, A., Kastbom, A., Reckner Olsson, Å. & Skogh, T. (2008). Presence and utility of IgA-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis: the Swedish TIRA project. Arthritis Research & Therapy, 10(4)
Open this publication in new window or tab >>Presence and utility of IgA-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis: the Swedish TIRA project
2008 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 10, no 4Article in journal (Refereed) Published
Abstract [en]

Introduction

The present study was carried out to assess whether IgA-class antibodies against cyclic citrullinated peptides (IgA anti-CCP) in recent-onset rheumatoid arthritis add diagnostic and/or prognostic information to IgG anti-CCP analysis.

Methods

Serum samples were obtained from 228 patients with recent-onset (<12 months) rheumatoid arthritis at the time of inclusion in the Swedish TIRA cohort (Swedish Early Intervention in Rheumatoid Arthritis). Sera from 72 of these patients were also available at the 3-year follow-up. Disease activity and functional ability measures (erythrocyte sedimentation rate, serum C-reactive protein, 28-joint count Disease Activity Score, physician's assessment of disease activity, and the Swedish version of the Health Assessment Questionnaire) were registered at inclusion and at regular follow-ups during 3 years. An IgA anti-CCP assay was developed based on the commercially available IgG-specific enzyme immunoassay from EuroDiagnostica (Arnhem, the Netherlands), replacing the detection antibody by an anti-human-IgA antibody. A positive IgA anti-CCP test was defined by the 99th percentile among healthy blood donors.

Results

At baseline, a positive IgA anti-CCP test was observed in 29% of the patient sera, all of which also tested positive for IgG anti-CCP at a higher average level than sera containing IgG anti-CCP alone. The IgA anti-CCP-positive patients had significantly higher disease activity over time compared with the IgA anti-CCP-negative patients. After considering the IgG anti-CCP level, the disease activity also tended to be higher in the IgA anti-CCP-positive cases – although this difference did not reach statistical significance. The proportion of IgA anti-CCP-positive patients was significantly larger among smokers than among nonsmokers.

Conclusion

Anti-CCP antibodies of the IgA class were found in about one-third of patients with recent-onset rheumatoid arthritis, all of whom also had IgG anti-CCP. The occurrence of IgA-class antibodies was associated with smoking, and IgA anti-CCP-positive patients had a more severe disease course over 3 years compared with IgA anti-CCP-negative cases. Although IgA anti-CCP analysis does not seem to offer any diagnostic information in addition to IgG anti-CCP analysis, further efforts are justified to investigate the prognostic implications.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-44398 (URN)10.1186/ar2449 (DOI)76502 (Local ID)76502 (Archive number)76502 (OAI)
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2017-12-13Bibliographically approved
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