Morgan Lilly

Background: Rheumatoid arthritis (RA) is an autoimmune disorder marked by joint inflammation, pain, stiffness, and damage.¹ Its origins are multifactorial, with over 100 genetic variations contributing to disease susceptibility, resulting in diverse pathogenic mechanisms.² RA is categorized into seropositive and seronegative subtypes, with the presence of anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF) indicating seropositive RA.² Despite treatment options, many patients experience disease progression and symptoms, highlighting the need for further RA stratification. Peptidylarginine deiminase 4 (PAD4) is a potential marker for RA, present in 2 to 17.7% of seronegative RA patients.³ PAD4 catalyzes calcium-dependent citrullination and auto-citrullination reactions, resulting in antigenic targets for ACPAs.⁴

Methods: PubMed and ScienceDirect search terms included: Rheumatoid Arthritis, PAD4, ACPAs, and RA Pathophysiology.

Results: Multiple genetic associations between variants of the PAD4 gene and RA are known. The single nucleotide polymorphism rs2240335 increases RA risk in North American and East Asian populations, while 89GG, 90TT, and 92GG sequences increase risk in western Mexico. ⁵ ⁶ Animal studies reveal that injection of citrullinated PAD4 into the knee joints of mice markedly increased synovial inflammation, characterized by significantly more mononuclear cells and polymorphonuclear leukocytes and greater increases in knee circumferences compared to injections with buffer solution or unmodified PAD4.⁷ The absence of swelling in the healthy and unmodified PAD4 groups but the presence of swelling in the citrullinated PAD4 group implies that citrullinated PAD4 may exhibit chemotactic properties for inflammatory cells.⁷ Research also indicates that 30-40% of RA patients produce antibodies targeting PAD4.³ This phenomenon is not observed in healthy individuals, highly specific to RA, and potentially attributable to a loss of immune tolerance.³ ⁸ Small-molecule inhibitors of PAD4 show promise in reducing RA severity in mice, but their lack of specificity results in binding the active site of multiple human PAD isoforms.⁹ Antibodies targeting PAD4 offer a selective approach, potentially inhibiting only extracellular PAD4, without impacting essential functions like histone citrullination. Additionally, interventions targeting PAD4 dimerization or calcium-binding could reduce enzyme activity, offering therapeutic benefits with improved specificity.⁹

Conclusions: The involvement of PAD4 in RA encompasses its citrullinated products as ACPA antigens, potential chemotactic properties attracting immune cells, and the loss of immune tolerance resulting in the emergence of anti-PAD4 antibodies that contribute to inflammation. ⁹ ¹⁰ ¹¹ Further investigation into PAD4-targeted therapies, namely inhibition of PAD4 dimerization or calcium-binding, could address persistent symptoms experienced by a significant subset of RA patients.

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