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Research Update about ACPAs

Are RA-specific ACPAs formed directly within inflamed joints?

Antibodies against mutated citrullinated vimentin (anti-MCV) and cyclic citrullinated peptides (anti-CCP) in the serum of RA patients act as highly specific indicators of rheumatoid arthritis. In addition, these antibodies indicate whether the disease is progressing aggressively. In contrast to the CCP antibodies, the anti-MCV antibodies seem to have pathogenic significance.

Earlier studies showed that the anti-CCP titre is higher in the synovial fluid of RA patients than in their serum. This study was intended to demonstrate that this is also true of anti-MCV antibodies and antibodies against other citrullinated proteins.  In addition, it was meant to clarify whether the formation of ACPAs (anti-citrullinated protein/peptide antibodies) is related to specific genetic risk factors.

The study tested 290 serum samples from RA patients for antibodies against mutated citrullinated vimentin (MCV), cyclic citrullinated peptides (CCP), citrullinated fibrinogen, alpha-enolase, type-II collagen, and vimentin. The control group included 100 healthy individuals. The HLA-DR genotype in the SE-allele (SE = shared epitope) was identified in the RA patients.

The skeleton of a human hand, pain points are highlighted

The skeleton of a human hand, pain points are highlighted

As expected, the titre of anti-MCV antibodies and antibodies against CCP were significantly higher in the synovial fluid of the RA patients than in their serum. Similar results were found for the remaining ACPAs.

The diagnostic sensitivity of the anti-MCV detection in serum was 76% (74% in the synovial fluid); the sensitivity of the anti-CCP detection was 73%. The two biomarkers do not differ in their diagnostic specificity.

It is striking that detection of antibodies against unmodified citrullinated vimentin (anti-Sa) was significantly less common in RA patients (sensitivity < 51%). Antibodies against epitopes of native vimentin were only detectible in 2.7% of patient serum samples (2% of synovial fluid samples).

RA patients who carried the HLA-DRB1*04 allele were more frequently ACPA positive than patients with the DRB1*01 allele or patients without HLA SE. Antibodies against anti-CCP or anti-MCV were detected significantly more often in all three groups than antibodies against the remaining citrullinated antigens (see table). 

  Patients with positive autoantibody result in %
Antigen no SE-allele HLA-DRB1*01 HLA-DRB1*04
CCP 54 48 85
MCV 66 48 85
Cit.-Vimentin 31 30 70
Cit.-Collagen 31 33 57
Cit.-Fibrinogen 49 45 77
Cit.-alpha-Enolase 23 20 56

 

This study shows that the titres of antibodies against various citrullinated antigens are elevated in both the serum and synovial fluid of RA patients. The authors thus conclude that ACPAs are either produced directly in the inflamed joint or accumulate there. The results of this study are another indicator that ACPAs are directly involved in the pathogenesis of rheumatoid arthritis, and support the hypothesis of a T cell/B cell dialog in the inflamed joints of RA patients.

The study also proves the relationship between the presence of an HLA-DRB1*04 allele and the formation of antibodies against mutated citrullinated vimentin (MCV) in RA. The results of this study thus confirm the theory that ACPA-positive RA and ACPA-negative RA represent two different subtypes of rheumatoid arthritis; well-defined environmental and genetic risk factors have been described for ACPA-positive RA.

Snir O et al. Antibodies to Several Citrullinated Antigens Are Enriched in the Joints of Rheumatoid Arthritis Patients. Rheumatoid Arthritis Clinical Study. Arthritis Rheum. 2010 Jan;62(1):44-52 – doi 10.1002/art.25036 – LinkOut to the abstract 

You can download this blogpost as an ORGENTEC Research Update (PDF).

Author of this article:  Tobias Stolzenberg

Foto: © Sebastian Kaulitzki, fotolia.com

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