MSUS Versus Serum Survivin and Lubricin Levels in Evaluation of Disease Activity in JIA

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

Aim of the work The aim of this study is to compare the role of musculoskeletal ultrasound to serum Survivin and Lubricin in detection of disease activity in patients with oligoarticular and polyarticular juvenile idiopathic arthritis.

Objectives

• To assess disease activity using Juvenile arthritis disease activity score in 27 joints (JADAS 27) in the studied JIA patients.
• To identify the prevalence of functional disability in JIA children and adolescents using the childhood health assessment questionnaire (CHAQ).
• To perform MSUS on the involved joints.
• To assess Survivin in the serum and in the synovial fluid if available in JIA patients.
• To assess Lubricin in the serum and in the synovial fluid if available in JIA patients.
• To compare the disease activity across individual patients using JADAS 27, MSUS and their relation to serum level of Survivin and lubricin.

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.

Compared to clinical examination and conventional radiology, musculoskeletal ultrasound (MSUS) is a more sensitive method for detecting synovitis, tenosynovitis, and erosive bone disease. In JIA, MSUS is helpful in the detection of subclinical synovitis, early diagnosis, patient classification, disease activity monitoring, determining disease remission, and guiding intra-articular injections. MSUS is a suitable imaging modality for children as it requires neither sedation nor general anesthesia and no ionizing radiation, is easily repeated, compares between joints, and allows dynamic study and multisite assessment in the same session Despite therapy advances in JIA, patients can achieve only symptoms alleviation but cannot be completely cured. Therefore, exploring the pathogenesis of the rheumatoid process is of high importance for developing precise, personalized treatments and new drug targets.

Inclusion Criteria:

• Patients of both sexes less than 16 years at onset of disease and diagnosed with oligoarticular and polyarticular JIA, fulfilling the ILAR classification criteria of JIA, The patients will be divided according to the subtypes of JIA disease.
• Control group will include age-and-sex-matched apparently healthy children.

Exclusion Criteria:

• Patients having associated neurological or disabling diseases.
• Patients with diabetes mellitus, acute or chronic infections.
• Patients with another types of JIA other than oligoarticular and polyarticular JIA (due to different patterns and diagnostic criteria of these types of JIA)
• Patients with another causes of arthritis other than JIA