Background and Objective In established RA, autoantibodies (AAB) to human citrullinated fibrinogen (AhFibA) were demonstrated to be mainly composed of two subfamilies of AAB directed to immunodominant epitopes borne by the fibrin peptides α36-50Cit38,42 and β60-74Cit60,72,74,respectively. Serum reactivity toward those peptides defines subgroups of patients. In the present study, we investigated whether AhFibA, anti-α36-50Cit38,42 and β60-74Cit60,72,74 AAB, have different predictive values for disease outcome in very early RA. We also analysed whether these AAB differentially associate with SE and tobacco exposure.
Materials and Methods The French ESPOIR cohort is comprised of very early RA and of undifferentiated arthritides (UA) of less than 6-month duration. AhFibA, anti-α36-50Cit38,42 and anti-β60-74Cit60,72,74 AAB were assayed by ELISA at baseline. After 3-year follow up, 701 patients were diagnosed RA according to the ACR/EULAR 2010 criteria. Relationships between SE HLA-DR alleles, tobacco exposure and the 3 AAB were analysed on those patients. Disease activity (DAS28, HAQ) and radiographic damage (SHS) were evaluated at baseline, and after 2- or 3-year follow up. Associations with clinical parameters and predictive value of each AAB were investigated.
Results AhFibA, anti-α36-50Cit38,42 and anti-β60-74Cit60,72,74 AAB were detected in 349/701 (50%), 203/701 (29%), and 257/701 (37%), RA sera, respectively. Their positive predictive values for RA (72%, 82%, and 79%, respectively) were not significantly different. The presence and titre of each AAB were associated with SE HLA-DR alleles without significant additional effect of tobacco exposure. When 2 vs 0 copies of SE alleles were present, the odds ratios for AhFibA, anti-α36-50Cit38,42 and anti-β60-74Cit60,72,74 AAB presence reached 8.0, 6.1 and 9.5, respectively. Neither the presence nor the titres of AhFibA, α36-50Cit38,42 and β60-74Cit60,72,74 AAB were associated with DAS28 or HAQ at baseline and after 2 years. However, for the 3 AAB, patients whose sera contained one or several AAB had a progression of SHS during the first 3 years (medians from 6 to 8 depending on the subgroup), significantly higher than the AhFibA-negative patients (median = 4). Nevertheless, no significant correlation was observed between the titres of AAB and radiographic progression.
Conclusion Not only AhFibA but also their anti-α36-50Cit38,42 and anti-β60-74Cit60,72,74 AAB subfamilies, are prognostic markers for bone erosion in RA. Moreover, AhFibA, anti-α36-50Cit38,42 and anti-β60-74Cit60,72,74 AAB are similarly associated to HLA-DR and to tobacco exposure.