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Circulating and Mucosal Antibodies to Citrullinated Antigens in Rheumatoid Arthritis
Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
2014 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2014. , s. 78
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1404
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-105987DOI: 10.3384/diss.diva-105987ISBN: 978-91-7519-342-7 (tryckt)OAI: oai:DiVA.org:liu-105987DiVA, id: diva2:712609
Disputas
2014-05-15, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2014-04-15 Laget: 2014-04-15 Sist oppdatert: 2015-08-31bibliografisk kontrollert
Delarbeid
1. Presence and utility of IgA-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis: the Swedish TIRA project
Åpne denne publikasjonen i ny fane eller vindu >>Presence and utility of IgA-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis: the Swedish TIRA project
2008 (engelsk)Inngår i: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 10, nr 4Artikkel i tidsskrift (Fagfellevurdert) 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.

HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-44398 (URN)10.1186/ar2449 (DOI)76502 (Lokal ID)76502 (Arkivnummer)76502 (OAI)
Tilgjengelig fra: 2009-10-10 Laget: 2009-10-10 Sist oppdatert: 2017-12-13bibliografisk kontrollert
2. A Comparison Between IgG- and IgA-class Antibodies to Cyclic Citrullinated Peptides and to Modified Citrullinated Vimentin in Early Rheumatoid Arthritis and Very Early Arthritis
Åpne denne publikasjonen i ny fane eller vindu >>A Comparison Between IgG- and IgA-class Antibodies to Cyclic Citrullinated Peptides and to Modified Citrullinated Vimentin in Early Rheumatoid Arthritis and Very Early Arthritis
Vise andre…
2011 (engelsk)Inngår i: Journal of Rheumatology, ISSN 0315-162X, E-ISSN 1499-2752, Vol. 38, nr 7, s. 1265-1272Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Objective. Because of their slightly higher sensitivity, it has been argued that antibodies to modified citrullinated vimentin (anti-MCV) are superior to antibodies to cyclic citrullinated peptides (anti-CCP), while others claim that anti-CCP is preferable because of higher diagnostic specificity for rheumatoid arthritis (RA). We evaluated IgG- and IgA-class anti-MCV and anti-CCP as diagnostic and prognostic markers in early arthritis. less thanbrgreater than less thanbrgreater thanMethods. Two Swedish arthritis populations were examined: 215 patients with early RA (andlt;= 12 months duration) from the Swedish TIRA-1 cohort, and 69 patients with very early arthritis (andlt;= 3 months duration) from the Kronoberg Arthritis Incidence cohort, in which 22% were diagnosed with RA. IgG anti-CCP and anti-MCV antibodies were analyzed with commercial kits. These tests were modified for IgA-class antibody detection. less thanbrgreater than less thanbrgreater thanResults were related to disease course, smoking habits, and shared epitope status. Results. In the TIRA-1 cohort, occurrence of IgG anti-MCV and IgG anti-CCP showed a 93% overlap, although IgG anti-MCV had higher diagnostic sensitivity. Twenty-four percent tested positive for IgA anti-MCV compared to 29% for IgA anti-CCP. In the Kronoberg Arthritis Incidence cohort, 15% tested positive for IgG anti-MCV and 6% for IgA anti-MCV, compared to 10% positive for IgG anti-CCP and 3% positive for IgA anti-CCP, revealing that anti-CCP had higher diagnostic specificity for RA. As previously reported for IgA anti-CCP, IgA anti-MCV antibodies occurred in a small proportion of high-level IgG antibody-positive sera and were associated with a more aggressive disease course. Smokers were more often positive for antibodies to citrullinated proteins, most strikingly among the patients who were IgA anti-MCV-positive. less thanbrgreater than less thanbrgreater thanConclusion. The occurrences of IgG-class anti-MCV and anti-CCP in early RA largely overlap. The sensitivity of anti-MCV is slightly higher, while the diagnostic specificity is higher for anti-CCP. In both instances a positive test predicts an unfavorable disease course, possibly slightly more so for anti-MCV. Although associated with a more active disease over time, IgA-class anti-CCP or anti-MCV do not add any diagnostic advantage.

sted, utgiver, år, opplag, sider
Journal of Rheumatology, 2011
Emneord
ANTICYCLIC CITRULLINATED PEPTIDE ANTIBODIES, VIMENTIN, EARLY ARTHRITIS, RHEUMATOID ARTHRITIS, IgA
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-70512 (URN)10.3899/jrheum.101086 (DOI)000293041600009 ()
Merknad

Funding Agencies|Center for Clinical Research in Dalarna||Swedish Research Council||Swedish Society Against Rheumatism||Gustaf Vth 80-year Foundation||Karin Svensson, Siv Olsson||Gunnar Trosell Foundations for rheumatology research||Reinhold Sund Foundation||Tore Nilson Foundation||Abbott||

Tilgjengelig fra: 2011-09-12 Laget: 2011-09-12 Sist oppdatert: 2017-12-08bibliografisk kontrollert
3. Salivary IgA antibodies to cyclic citrullinated peptides (CCP) in rheumatoid arthritis
Åpne denne publikasjonen i ny fane eller vindu >>Salivary IgA antibodies to cyclic citrullinated peptides (CCP) in rheumatoid arthritis
2013 (engelsk)Inngår i: Immunobiology, ISSN 0171-2985, E-ISSN 1878-3279, Vol. 218, nr 2, s. 232-237Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Elsevier, 2013
Emneord
Citrullinated peptides, IgA, Rheumatoid arthritis, Saliva, Mucosal immunity
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-90205 (URN)10.1016/j.imbio.2012.04.011 (DOI)000315312000013 ()
Merknad

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)||

Tilgjengelig fra: 2013-03-21 Laget: 2013-03-21 Sist oppdatert: 2017-12-06
4. Associations to smoking and shared epitope differ between IgA and IgG class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis
Åpne denne publikasjonen i ny fane eller vindu >>Associations to smoking and shared epitope differ between IgA and IgG class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis
Vise andre…
2015 (engelsk)Inngår i: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, nr 8, s. 2032-2037Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
Wiley-Blackwell, 2015
Emneord
Rheumatoid arthritis, immunoglobulin A, ACPA, smoking, shared epitope
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-105986 (URN)10.1002/art.39170 (DOI)000358609300007 ()
Merknad

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).

Tilgjengelig fra: 2014-04-15 Laget: 2014-04-15 Sist oppdatert: 2017-12-05bibliografisk kontrollert

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