Background Anti-collagen II antibody (anti-CII) positive RA patients present with early but not persistent signs of inflammation and joint erosions. This early anti-CII-dependent phenotype coincides with high anti-CII levels around the time of RA diagnosis, whereafter anti-CII levels drop. Our previous studies showed that this phenotype is associated with in vitro cytokine production by monocytes, activation of granulocytes, and enhanced chemokine production by monocyte/granulocyte cocultures, stimulated with anti-CII containing immune complexes. These in vitro findings argue that elevated anti-CII levels at time of RA diagnosis are functionally related to the corresponding acute onset RA phenotype.
Objectives Our previous comparison done in a small RA cohort (n=274) describe that anti-cyclic citrullinated peptide 2 (anti-CCP2) positive patients have a severe long-term prognosis but anti-CII positive patients have transient inflammation. In the present study we wanted to extend this in a large RA cohort with clinical follow-up data, and to relate to HLA-DRB1* alleles.
Methods Anti-CII and anti-CCP2 were measured at baseline in 773 patients from the Swedish Epidemiological Investigations in Rheumatoid Arthritis (EIRA) study with clinical follow-up data from the Swedish Rheumatology Quality (SRQ) registry, and 1476 patients with HLA-DRB1* information. Comparisons were done concerning CRP, ESR, TJC, SJC, DAS28, DAS28CRP, pain-VAS, global-VAS and HAQ at 8 occasions during 5 years, and association to HLA-DRB1* alleles.
Results Anti-CII was detected in 6.6% (97/1476), and anti-CCP2 in 57.9% (855/1476) of the patients. There was no significant difference in treatment strategy at diagnosis for patients with and without those antibodies. Anti-CII associated with elevated CRP, ESR, SJC, DAS28 and DAS28CRP at diagnosis and up to six 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 also in anti-CII/anti-CCP2 double positive patients. Compared to baseline levels, anti-CII was asscociated with improvements in CRP, ESR, SJC, TJC and DAS28 over time, whereas anti-CCP2 was associated with deteriorations in SJC and DAS28 over time, compared to antibody negative patients. Anti-CII positive patients achieved EULAR good or moderate response more often than negative patients whereas the opposite was found for anti-CCP2 positive patients (figure). Anti-CII was positively associated with HLADRB1*01 and HLADRB1*03, with significant interaction, and double positive individuals had >14 times higher mean anti-CII levels than HLA double negatives. Whereas smoking associated with elevated anti-CCP2 levels, smokers has 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 ACPA. Although not diagnostically useful, early anti-CII determinations predict favourable inflammatory outcome in RA. The combined analysis of anti-CII and ACPA/anti-CCP2 may be a new two-dimensional tool for predicting the prognosis and chosing therapy in newly diagnosed RA patients.
Disclosure of Interest None declared
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