Do autoantibody-responses mature between presentation with arthralgia suspicious for progression to rheumatoid arthritis and development of clinically apparent inflammatory arthritis? A longitudinal serological study.

Several nested case-control studies have shown that autoantibody-response maturation in rheumatoid arthritis (RA) precedes clinical arthritis development.1–3 This suggests a role in disease triggering. However, nested case-control studies have, similar to case-control studies, the disadvantage that controls are selected and that prospective data from non-progressing patients in a similar predisease stage are absent. The phase preceding clinically apparent inflammatory arthritis (IA) can be distinguished into an asymptomatic and symptomatic (ie, clinically suspect arthralgia, CSA) subphase. It is unknown whether autoantibody-response maturation occurs in the symptomatic phase. Likewise, its role in progression to clinical arthritis is undetermined; if autoantibody-response maturation relates to disease development, maturation is expected to be more pronounced in patients with CSA that progress compared with patients with CSA that do not. To better understand the relation between autoantibody-response maturation in time and development of clinical arthritis (RA/IA), we performed a longitudinal study on autoantibody-response maturation in patients with CSA that did and did not progress. In serum from 147 patients with CSA, we determined with in-house ELISAs the presence and levels of IgM, IgG, IgA anti-citrullinated, anti-carbamylated and anti-acetylated protein antibodies (ACPA, anti-CarP, AAPA), resulting in nine autoantibody measurements per patient per timepoint. Autoantibody-response maturation was defined as increase in number of autoantibody reactivities or isotypes, and/or increase in autoantibody levels. Patients with CSA with paired samples at first presentation at the outpatient clinic and at IA development (n=55) or else after 2 years (n=92) were selected. Analyses were repeated with the outcome RA (the subgroup of patients with IA that fulfilled …