O24 Low level detection of CTD-associated autoantibodies in patients with idiopathic pulmonary fibrosis confirms this as a robust phenotype when diagnosed on clinical grounds alone

Abstract

Background: Interstitial lung disease (ILD) represents a disease spectrum comprised of many heterogeneous subgroups, the commonest being idiopathic pulmonary fibrosis (IPF). In IPF approximately 50% of patients succumb within only three-five years of ILD onset, and corticosteroids are not only ineffective, but actually also harmful. In contrast, most patients with connective tissue disease ILD (CTD-ILD) can respond to corticosteroid-based immunosuppression, even if their HRCTs exhibit changes similar to those of IPF. Given these treatment response differences, which in turn likely reflect differential aetiopathologies, having the ability to reliably exclude a CTD pathology in every IPF patient has become an imperative. Recent serological studies have demonstrated that many CTD-ILD patients produce characteristic autoantibodies which are increasingly regarded as key diagnostic biomarkers for their CTD-ILD. In view of the lack of a gold standard biomarker for IPF, and the resulting inability to always differentiate IPF from CTD-ILD patients, who may initially present with ILD as their only CTD feature, this study utilised comprehensive CTD serology to study a large cohort of IPF patients to quantify how frequently the detection of a CTD-associated autoantibody would identify a misdiagnosis. Methods: 250 IPF patients, diagnosed according to the 2011 ATS/ ERS/JRS/ALAT guidelines and recruited via the UK-BILD collaboration, were screened for autoantibodies by immunoprecipitation, using radio-labelled K562 cell extracts and 9% SDS-PAGE. Known autoantibodies were identified by direct comparison with positive disease controls, and unknown novel bands were characterised using the molecular weights of known proteins co-immunoprecipitated on the same gel. Results: Known CTD-associated autoantibodies were identified in five IPF patients (2.0%); these included one patient with anti-Ku, two with an anti-tRNA synthetase (one anti-KS and one anti-OJ), one with anti-mitochondrial autoantibodies and one patient with anti-RNA polymerase II. These patients were indistinguishable from antibody negative patients when gender, age at diagnosis and smoking history were compared. A further 99 IPF patients (39.6%) had strong unknown bands on immunoprecipitation, but which did not correspond to any known CTD autoantigen. Conclusion: Whilst previous studies have demonstrated CTD-ILD patients to have a high prevalence of characterised autoantibodies, the finding here that only 2% of 250 IPF patients had a recognised CTD-associated autoantibody, by the gold standard of immunoprecipitation, confirms a low level of misdiagnosis between CTD-ILD and IPF, when the latter is diagnosed by dedicated chest physicians using the currently available clinical screening methods. However, the finding that almost 40% of IPF patients did have autoantibodies characterising various unknown antigen targets suggests that an immunological aetiological component may be relevant in IPF pathogenesis. Further discovery studies into these novel, unknown bands may potentially improve IPF diagnostics, provide further insights into IPF pathogenesis, and thus also lead to more targeted future treatments for this difficult and rapidly lethal disease.