Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects synovial joints, leading to pain, swelling, and progressive joint damage. Early diagnosis is critical to prevent irreversible disability. However, up to 30% of RA patients are seronegative for conventional markers such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies, creating a diagnostic challenge. This study aims to evaluate the diagnostic performance of serum anti-procollagen C-endopeptidase enhancer (anti-PCOLCE) antibodies in RA patients, with a particular focus on seronegative cases. We will conduct a case-control study involving RA patients and age- and sex-matched healthy controls. Clinical assessments, disease activity scoring, functional disability evaluation, and laboratory testing will be performed. The findings may provide evidence for anti-PCOLCE as a novel biomarker for improved RA diagnosis.

Rheumatoid arthritis (RA) is an inflammatory disease that primarily affects synovial joints through an autoimmune mechanism. If not treated properly, the disease can lead to bone erosion, joint deformities, and disability. Arthritis can also cause serious extra-articular disorders, including interstitial lung disease, vasculitis, and lymphoma.

The global prevalence of RA is 1%, with 44% of patients incapacitated within ten years. Increasing evidence indicates that early diagnosis and treatment of RA are crucial in preventing or delaying progression to erosive disease.

The production of antibodies to modified self-antigens is a hallmark in RA damage to synovial joints. The diagnosis of RA is based on a combination of clinical, radiographic, and serological findings. Among serological biomarkers, the most widely used are rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies. While anti-CCP antibodies are relatively specific for RA and are included in the 2010 ACR/EULAR classification criteria, they are not present in all patients. Approximately 20-30% of RA patients may test negative for both RF and anti-CCP, is termed seronegative RA (SNRA) emphasizing the need for additional, more sensitive and specific biomarkers, especially in early and seronegative RA.

Antibodies to citrullinated and carbamylated proteins are of particular interest in RA because of their high prevalence, specificity, association with erosive disease, and appearance during the preclinical phase of RA. Citrullination is a physiological posttranslational modification (PTM) best known for its role in gene regulation and skin keratinization. During this process, arginine residues are converted to citrulline by the activity of the peptidylarginine deiminase (PAD) enzymes.

Procollagen C-protease enhancer protein (PCOLCE) is a secretory glycoprotein, which plays an important role in enhancing the activity of procollagen C-Protease and promoting the reconstruction of extracellular matrix.

PCOLCE essential for the maturation of collagen, particularly types I and II. These collagen types are major components of articular cartilage and connective tissues. In the inflammatory environment of RA, PCOLCE can undergo citrullination, potentially converting it into a novel autoantigen.

Emerging evidence suggests that PCOLCE may elicit an autoimmune response in RA patients. Detecting autoantibodies directed against PCOLCE (anti- PCOLCE ) could therefore provide a new serological tool for RA diagnosis. These antibodies may not only enhance diagnostic accuracy particularly in patients who are seronegative for conventional markers but also shed light on novel mechanisms in RA pathophysiology.

Inclusion criteria Adults (≥18 years old).

Patients clinically diagnosed with rheumatoid arthritis according to the 2010 ACR/EULAR classification criteria:

Exclusion criteria Patients with other autoimmune or connective tissue diseases (e.g., SLE, SS). Patients with chronic infections or malignancies. Patients less than 18 years old.

Two groups will be included: rheumatoid arthritis patients attending the Rheumatology, Rehabilitation and Physical Medicine Department at Assiut University Hospital, and age- and sex-matched healthy controls recruited from the community.