Anti-protein arginine deiminase antibodies are distinctly associated with joint and lung involvement in rheumatoid arthritis

Abstract

Objectives Rheumatoid arthritis (RA) is a chronic inflammatory disease in which possible interstitial lung disease (ILD) is an extra-articular manifestation that carries significant morbidity and mortality. Rheumatoid Factors (RF) and anti-citrullinated protein antibodies (ACPA) are included in the RA classification criteria but prognostic and diagnostic biomarkers for disease endotyping and RA-ILD are lacking. Anti-protein arginine deiminase antibodies (anti-PAD) are a novel class of autoantibodies identified in RA. This study aimed to assess clinical features, ACPA, and anti-PAD antibodies in RA patients with articular involvement and ILD. Methods We retrospectively collected joint erosions, space narrowing, clinical features, and lung involvement of a cohort of seventy-one patients fulfilling the 2010 ACR/EULAR RA classification criteria. Serum samples from these patients were tested for ACPA IgG (QUANTA Flash CCP3), and anti-PAD3 and anti-PAD4 IgG, measured with novel assays based on a particle-based multi-analyte technology (PMAT). Results Anti-PAD4 antibodies were significantly associated with radiographic injury (p= 0.027) and erosions (p= 0.02). Similarly, ACPA levels were associated with erosive disease (p= 0.014). Anti-PAD3/4 double positive patients displayed more joint erosions than patients with anti-PAD4 antibodies only or negative for both (p= 0.014 and p= 0.037, respectively). RA-ILD (15.5%, 11/71 patients) was associated with older age (p< 0.001), shorter disease duration (p= 0.045) and less erosive disease (p= 0.0063). ACPA were elevated in RA-ILD, while anti-PAD4 were negatively associated (p= 0.043). Conclusion Anti-PAD4 and anti-PAD3 antibodies identify RA-patient with higher radiographic injury and bone erosions. In our cohort, ILD is associated with lower radiographic and erosive damage, as well as low levels of anti-PAD4 antibodies.

Single-Nucleotide Variants in PADI2 and PADI4 and Ancestry Informative Markers in Interstitial Lung Disease and Rheumatoid Arthritis among a Mexican Mestizo Population

“…One of the markers used with high sensitivity and specificity for RA is anti-citrullinated peptide antibodies (ACPA). However, in the presence of ILD, there is usually no change in positivity or levels to indicate a worse prognosis [11]. ACPA are antibodies that recognize citrullinated proteins; this process is carried out by peptidyl arginine deiminases (PAD) [12,13].…”

“…Multiple SNVs in genes encoding PAD enzymes have been described in different populations, such as rs1748033 in PADI4, which has been associated with susceptibility to RA in Japanese [17,18], Korean [19], Indian [20,21], Iranian [22], and Netherlands [23] populations, as well as altered PAD4 protein levels, which correlate with the presence of anticitrullinated peptide antibodies and levels of inflammatory proteins such as rheumatoid factor and C-reactive protein [11,24].…”

Updates on interstitial lung disease and other selected extra-articular manifestations of rheumatoid arthritis

“…Studies of patient-level, and hence clinically useful, risk factors prior to RA-ILD have identified consistent associations of age, male sex, smoking status, obesity, functional status, elevated inflammatory markers and RF/CCP-positivity with development of RA-ILD [11]. While antiprotein peptidyl arginine deminase (PAD) variants are associated with joint disease, recent studies on the role of PAD4 in RA-ILD are conflicting [12,13]. MUC5 variants are associated with usual interstitial pneumonitis (UIP) in RA-ILD, while biomarkers such as Krebs von den Lungen 6, which have been shown to be diagnostic for ILD, have not been studied in prospective studies of RA-ILD [11,14].…”

Unmet needs and perspectives in rheumatoid arthritis-associated interstitial lung disease: A critical review

“…A subgroup of patients with RA possesses cross-reactive antibodies towards both PAD3 and PAD4, named anti-PAD3/4XR antibodies, that may predict ILD occurrence, especially in never-smoking patients ( 85 ), an association not found for anti-PAD3 or anti-PAD4 antibodies alone. Recent data demonstrate a possible association between double anti-PAD3 and PAD-4 positivity with both ILD and more erosive disease and the authors have hypothesized that such patients might have anti-PAD3/4XR positivity ( 112 ). Serum anti-carbamylated proteins antibodies (anti-CarP) have been reported at higher frequency in patients with RA-ILD compared to RA patients without ILD, independent of the smoking status ( 86 ).…”