Objective Antifibrillar collagen type II (anti-CII) antibody-positive patients with rheumatoid arthritis (RA) have early but not late signs of increased inflammation and joint erosions. We wanted to replicate this in a large RA cohort, and to relate to human leukocyte antigen (HLA)-DRB1* alleles.
Methods Anti-CII and anti-cyclic citrullinated peptide (CCP)2 were measured at baseline in 773 patients with RA from the Swedish Epidemiological Investigation in Rheumatoid Arthritis (EIRA) study with clinical follow-up data from the Swedish Rheumatology Quality Register (SRQ) registry, and 1476 with HLA-DRB1* information. Comparisons were done concerning C reactive protein (CRP), erythrocyte sedimentation rate (ESR), tender joint count (TJC), swollen joint count (SJC), Disease Activity Score encompassing 28 joints based on ESR (DAS28), DAS28CRP, pain-Visual Analogue Scale (VAS), global-VAS and Health Assessment Questionnaire Score (HAQ) at eight occasions during 5 years, and association with HLA-DRB1* alleles.
Results Anti-CII associated with elevated CRP, ESR, SJC, DAS28 and DAS28CRP at diagnosis and up to 6 months, whereas anti-CCP2 associated with SJC and DAS28 from 6 months to 5 years, but not earlier. The anti-CII-associated phenotype was strong, and predominated in anti-CII/anti-CCP2 double-positive patients. Anti-CII was associated with improvements in CRP, ESR, SJC, TJC and DAS28, whereas anti-CCP2 was associated with deteriorations in SJC and DAS28 over time. Anti-CII-positive patients achieved European League Against Rheumatism good or moderate response more often than negative patients. Anti-CII was positively associated with HLA-DRB1*01 and HLA-DRB1*03, with significant interaction, and double-positive individuals had >14 times higher mean anti-CII levels than HLA double negatives. Whereas smoking was associated with elevated anti-CCP2 levels, smokers had lower anti-CII levels.
Conclusions Anti-CII seropositive RA represents a distinct phenotype, in many respects representing the converse to the clinical, genetic and smoking associations described for anticitrullinated protein peptide autoantibodies. Although not diagnostically useful, early anti-CII determinations predict favourable inflammatory outcome in RA.
- Rheumatoid Arthritis
- Outcomes research
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Handling editor Tore K Kvien
Contributors MM performed antifibrillar collagen type II ELISA measurements; LP performed HLA-DRB1* tissue typing; HW and SS provided clinical data from the Swedish Rheumatology Quality Register registry; LK and LA contributed data and analyses from the Epidemiological Investigation in Rheumatoid Arthritis study. VAM and JR conceived and planned the study, made all statistical calculations and drafted the manuscript. JR is responsible for the merged data file containing serological, genetic and clinical data. All authors have read and approved the final manuscript.
Funding This study was funded by grants from the Swedish Research Council (grant number K2014-68X-20611-07-3), the Swedish Rheumatism association, King Gustav Vth 80-year foundation and ALF grants provides by the Uppsala County Council.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Ethical board at Karolinska Institutet.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All data for the study are available in the manuscript and in the online supplementary material.
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