The immunoglobulin (IgG) autoantibody repertoire remained diverse but did not expand in patients with systemic lupus erythematosus (SLE) over time and disease activity was associated with histone H3 and double-stranded DNA (dsDNA) autoantibody levels, according to a report published in Arthritis & Rheumatology.
Epitope spreading, a phenomenon whereby the immune system targets formerly tolerated antigens, is thought to contribute to the pathogenesis and exacerbation of systemic autoimmune diseases. However, little is known about its role in disease course or activity in established patients with SLE.
A longitudinal prospective observational trial enrolled participants with SLE (n=69; mean age, 36.96; 79.7% women; mean disease duration, 14.74 years) and compared them with healthy controls (n=45; mean age, 43; 82% women) in a long-term analysis of autoantibody repertoires. Serology was performed at baseline and at 2-year intervals thereafter, assessing IgG reactivity to 398 recombinant proteins. Flares were noted in individuals with Systemic Lupus Activity Measure (SLAM) increases >3, and new organ involvement was identified.
Outcomes included changes in mean fluorescence intensity (MFI) and total autoantibodies to separate antigens. Reactivity to known SLE fine mapping epitope targets, including ribosomal P, Sm, and U1-RNP, was also assessed. Sex- and age-adjusted linear mixed modeling with Bonferroni correction was performed.
The mean MFI, number of epitope fine mapping autoantibodies, and total autoantibodies were all significantly higher in participants with SLE vs controls (P <.0001). The SLE group displayed initial reactivity to significantly more antigens (68.5) compared with the control group (16.6; P <.0001). Over time, the mean MFI decreased in patients with SLE (P <.021), while the total number of autoantibodies to distinct antigens remained stable.
Regarding fine mapping, compared with controls, patients with SLE had a significantly greater number of Sm (P <.0005), U1-RNP (P <.0005), and ribosomal P (P =.0031) autoantibodies. The SLE group reactivity to the U1-RNP complex peaked during new organ involvement (+0.65; P =.0068).
Patients with lupus nephritis exhibited increased mean MFI compared with patients without lupus nephritis (P =.047). When MFI was time-averaged, following Bonferroni correction the SLE group had anti-dsDNA (P <.0001) and 21 other autoantibodies with increased levels compared with controls. In terms of disease activity, histone cluster 2 H3c and dsDNA MFI levels correlated with SLAM changes >3 (P <.0001).
Study strengths included long-term surveillance of a large collection of antigens and examination of antigenic complexes relevant to SLE in the context of epitope spreading. Study limitations included treatment heterogeneity, inability to exclude autoantibody expansion in less stable patients, and lack of controlling for potential antigenic cross-reactions.
“In our study, there was no general increase in the number of autoantigens over 6 years in established SLE, and the total number of recognized autoepitopes did not correlate to disease activity,” the authors concluded.
Disclosure: Three study authors are employees of Protagen AG. Please see original article for more details.