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Circulating antibodies against citrullinated peptides are highly specific for rheumatoid arthritis (RA), and associated with RA disease progression.1 ,2 We have previously reported that antibodies to cyclic citrullinated peptides (anti-CCP) are associated with severe extra-articular RA (ExRA) manifestations, although rheumatoid factor (RF) levels seemed to be more important in active ExRA than anti-CCP levels.3
Another RA-related antibody, the anti-Sa antibody, which has been associated with severe joint damage in RA,4 reacts with citrullinated vimentin.5 Most studies have shown that antibodies to modified citrullinated vimentin (anti-MCV) have a higher sensitivity but a lower specificity for RA than anti-CCP, although there are conflicting results.6 To our knowledge, no studies have previously reported on the relation between anti-MCV and severe ExRA.
We enrolled 35 consecutive patients from a single centre, with a recent clinical diagnosis of severe ExRA manifestations according to predefined criteria.7 For each patient with ExRA, two controls with RA but no evidence for current or previous ExRA, individually matched to extra-articular subjects for age, sex and disease duration, were selected.3 Blood was drawn directly after ExRA was diagnosed and before any new treatment was started. Samples were stored at −80°C after centrifugation. The study was approved by the regional ethical review board in Lund, Sweden.
Anti-MCV levels were measured in duplicate using a commercial ELISA kit (Orgentec Diagnostika, Mainz, Germany).8 Values above the standard curve were further diluted to obtain quantitatively definite values. Anti-CCP were measured with ELISA (Eurodiagnostica, Malmö, Sweden; second generation test), and RF was detected and quantified using nephelometry, as previously described.3
Patients with ExRA had higher swollen joint counts and C reactive protein levels compared with RA controls (table 1). Anti-MCV (p=0.001), RF (p=0.006) and anti-CCP (p=0.03) were all detected more frequently among those with ExRA manifestations (table 1). Among patients with ExRA, 34/35 were positive for anti-MCV. The anti-MCV negative individual with ExRA (pleuritis) was also negative for anti-CCP and RF. The other anti-CCP negative cases with ExRA had pleuritis (n=4), pericarditis (n=2) or neuropathy (n=1).
Anti-MCV levels were significantly higher among patients with ExRA compared with RA controls (p=0.02) (table 2). Also, patients with Felty's syndrome and patients with major cutaneous vasculitis had significantly higher anti-MCV levels compared with RA controls (table 2). As previously reported,3 there was a trend towards higher anti-CCP levels in the ExRA group compared with RA controls (p=0.09), and RF levels were higher in the ExRA group (p=0.0002) (table 2). In analyses restricted to positive individuals, cases with ExRA had significantly higher levels of RF, but not of anti-MCV and anti-CCP (data not shown).
In conclusion, anti-MCV was strongly associated with severe, active ExRA. This is in agreement with previous findings of a closer relation for anti-MCV than anti-CCP with disease activity in early RA.9 Thereby, anti-MCV behaves more like RF than like anti-CCP. The results of this study may have been affected by the limited sample. The role of anti-MCV in systemic complications and associated disease mechanisms in RA should be further investigated.
The authors would like to thank Dr Bo Holmgren, Dr Ylva Lindroth, Dr Lida Marsal and Dr Ingemar Petersson for valuable aid in patient recruitment.
Contributors Study concept and design: CT, LTHJ, GS, JR; acquisition of data: CT, LM, LTHJ, JR; analysis and interpretation of data: CT, LM, LTHJ, GS, JR; drafting of manuscript: CT, JR. All authors contributed to critical revision of the manuscript for important intellectual content.
Funding The Swedish Research Council (2010–2891), Lund University, the Åke Viberg foundation and the Swedish Rheumatism Association.
Competing interests None.
Ethics approval Regional Ethical Review Board in Lund, Sweden.
Provenance and peer review Not commissioned; externally peer reviewed.
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