Anticollagen type II antibodies are associated with an acute onset rheumatoid arthritis phenotype and prognosticate lower degree of inflammation during 5 years follow-up.
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.
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala Sweden.
Vivek Anand
VA
Manivel
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala Sweden.
Mohammed
M
Mullazehi
Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
Leonid
L
Padyukov
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Helga
H
Westerlind
Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
Lars
L
Klareskog
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Lars
L
Alfredsson
Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
Saedis
S
Saevarsdottir
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala Sweden.
Johan
J
Rönnelid
D000208:Acute Disease; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D001323:Autoantibodies / Q000276:immunology*; D001799:Blood Sedimentation; D002097:C-Reactive Protein / Q000276:immunology; D016022:Case-Control Studies; D024043:Collagen Type II / Q000276:immunology*; D005260:Female; D005500:Follow-Up Studies; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016015:Logistic Models; D008297:Male; D016017:Odds Ratio; D010456:Peptides, Cyclic / Q000276:immunology*; D010641:Phenotype; D012042:Registries; D012720:Severity of Illness Index; D012907:Smoking / Q000276:immunology; D013548:Sweden
D001323:Autoantibodies; D024043:Collagen Type II; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide; D002097:C-Reactive Protein
DAS28; Outcomes research; Rheumatoid Arthritis