The Role of Musculoskeletal Ultrasound Versus Serum Survivin and Lubricin Levels in Evaluation of Disease Activity in Juvenile Idiopathic Arthritis

Background:

Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases which encompasses all forms of arthritis of unknown etiology lasting for at least 6 weeks and with onset before the age of 16. The International League of Associations for Rheumatology (ILAR) has defined seven subtypes of JIA.

Understanding of the JIA pathogenesis over the last two decades have revolutionized therapy, reduced morbidity, and improved quality of life for those affected . Various autoantibodies have been associated with JIA, including anti-nuclear antibodies (ANA), rheumatoid factor (RF), anti-citrullinated protein autoantibodies (ACPA), and others. Although the ANA test is not used to diagnose JIA, it is of high prognostic value with respect to the risk of uveitis. ANA positivity among the JIA subtypes is the highest in patients with oligoarticular JIA (up to 70%) and is particularly more prevalent in young, female patients. The prevalence of RF in patients with JIA is very low (< 5%), and it confers a worse prognosis. In particular, RF-positive polyarticular patients are at higher risk of a more aggressive disease course and bone erosion. ACPA positive children with JIA are recommended for earlier and more aggressive therapy. Nevertheless, the diagnosis of JIA still depends mainly on clinical characteristics, imaging examination, and exclusion of other, more common causes of persistent arthritis with low serological support. Therefore, it is necessary to establish alternate methods or discover new biomarkers to further improve precise JIA diagnosis at the early stage of the disease.

Lubricin, encoded by the proteoglycan 4 (PRG4) gene, is a mucin-like molecule and includes proline, serine and threonine that provides a scaffold for glycosylation, high viscosity and low friction . It is suggested to have protective effects against synovial hyperplasia and cartilage deterioration in the joint spaces. Experimental models of osteoarthritis showed that lubricin retards cartilage degeneration, enhances cartilage repair and reduces chondrocyte apoptosis.Lubricin levels were also diminished in synovial fluid of inflammatory arthritis. Furthermore, lubricin was recently suggested to act as an antagonist for Toll like receptor (TLR 2)and (TLR 4), preventing its activation in inflammatory arthritis.Moreover, a recent study proposed a new mechanism of lubricin, including inhibition of interleukin 1β (IL-1β) and tumor necrosis factor-α (TNF-α) via CD44 binding.

Survivin is an anti-apoptotic oncoprotein, known as a tissue marker of cancer. During recent years, the role of survivin in non-malignant cells was intensively explored. Survivin has been shown essential for the differentiation, growth, and regeneration of healthy tissues. Due to its role in apoptosis and proliferation, it plays important roles in the pathogenesis of autoimmune diseases. At the preclinical phase of JIA, high levels of survivin correlate with cytokines and anticipate the formation of aggressive T helper cells (Th1) and (Th17) cells. In patients after JIA diagnosis, survivin predicts joint destructive course of the disease and resistance to anti-rheumatic treatment. Survivin has been suggested as a predictive marker of a severe course of adult RA and could be used for preclinical recognition of the disease. Survivin positive patients have poor outcomes if treated with methotrexate (MTX) monotherapy. A decrease in serum survivin concentration is associated with a better clinical response to treatment.