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Associations to smoking and shared epitope differ between IgA and IgG class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Rheumatology.ORCID iD: 0000-0002-0153-9249
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
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2015 (English)In: Arthritis & Rheumatology, ISSN 2326-5191, E-ISSN 2326-5205, Vol. 67, no 8, 2032-2037 p.Article 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. Vol. 67, no 8, 2032-2037 p.
Keyword [en]
Rheumatoid arthritis, immunoglobulin A, ACPA, smoking, shared epitope
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:liu:diva-105986DOI: 10.1002/art.39170ISI: 000358609300007OAI: oai:DiVA.org:liu-105986DiVA: diva2:712605
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
In thesis
1. Circulating and Mucosal Antibodies to Citrullinated Antigens in Rheumatoid Arthritis
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. 78 p.
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)
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Available from: 2014-04-15 Created: 2014-04-15 Last updated: 2015-08-31Bibliographically approved

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Svärd, AnnaSkogh, ThomasKastbom, Alf

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