Rheumatoid Arthritis: Widhe M

Klareskog L, Widhe M, Hermansson M, Rönnelid J. · Rheumatology Unit, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden. · Curr Opin Rheumatol. · Pubmed #18388522 No free full text.

Abstract: PURPOSE OF REVIEW: The purpose of this review is to describe how the current knowledge of antibodies to citrullinated protein antigens in rheumatoid arthritis and related conditions emerged; to discuss the diagnostic and prognostic value associated with antibodies to citrullinated protein antigens as a biomarker; and most importantly for this review, to discuss the potential pathogenetic significance of these antibodies. RECENT FINDINGS: Antibodies to citrullinated protein antigens have evolved from being mainly a diagnostic marker, to being recognized as something that can help us understand fundamental etiologic and pathogenetic features of rheumatoid arthritis. Fundamental in this context is the finding that rheumatoid arthritis can be divided into two distinct subsets by means of presence or absence of antibodies to citrullinated protein antigens. Thus, several genetic as well as environmental risk factors differ between these two variants of rheumatoid arthritis. From analysis of these genetic and environmental risk factors, new testable hypotheses have been produced concerning triggering of antibodies to citrullinated protein antigens, and potential pathogenicity of antibodies to citrullinated protein antigens and accompanying immune reactions. SUMMARY: The implications of the findings are that antibodies to citrullinated protein antigens can be used for early and precise diagnosis of a subset of rheumatoid arthritis with worse prognosis than other polyarthritides, and that a new basis is formed for etiologic and pathogenetic studies of antibodies to citrullinated protein antigens-positive rheumatoid arthritis.

Snir O, Widhe M, von Spee C, Lindberg J, Padyukov L, Lundberg K, Engström A, Venables PJ, Lundeberg J, Holmdahl R, Klareskog L, Malmström V. · Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Karolinska Institute, Solna, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #18635594 No free full text.

Abstract: BACKGROUND: Autoantibodies to cyclic citrullinated peptides (anti-CCP) are present in most patients with rheumatoid arthritis (RA), and associate with HLA-DRB1 shared epitope (SE) alleles. OBJECTIVE: To investigate reactivities of anti-CCP to various citrullinated proteins/peptides, which represent potential autoantigens in RA, and to examine the relationship between such antibodies, and their association with genetic variants within HLA-DRB1 SE alleles. METHODS: Serum samples from 291 patients with established RA and 100 sex- and age-matched healthy subjects were included in this study. Sera were first analysed for presence of anti-CCP antibodies and further for IgG and IgA antibodies towards candidate autoantigens in both their native and citrullinated form including: fibrinogen, alpha-enolase peptide-1 and the C1-epitope of type II collagen (C1(III)). Antibody specificity was confirmed by cross-reactivity tests. HLA-DR genotyping was performed. RESULTS: 72% of patients with RA were anti-CCP positive. Among the candidate autoantigens examined, IgG antibodies to citrullinated fibrinogen were found in 66% of patients' sera and in 41% for both citrullinated alpha-enolase peptide-1 and citrullinated C1(III). These antibodies were mainly seen in the anti-CCP-positive patient group; they were specific for their respective antigen and displayed limited cross reactivity. IgA responses were also detected, but less frequently than IgG. Anti-CCP and anti-citrullinated protein antibodies were associated with HLA-DRB1*04 rather than with HLA-DRB1*01 alleles. CONCLUSIONS: Antibodies directed against several citrullinated antigens are present in CCP-positive RA, with many patients displaying multireactivity. All specific reactivities were primarily associated with the HLA-DRB1*04 alleles, suggesting common pathways of anti-citrulline immunity.