Chapter 4: Rheumatoid Arthritis

INTRODUCTION

• Rheumatoid arthritis (RA) is a chronic, progressive autoimmune condition that primarily affects joints and the synovium but can also have systemic manifestations.

PATHOPHYSIOLOGY

• RA results from a combination of genetic susceptibility, nongenetic factors, and a triggering event. An unknown infectious process is thought to be the primary trigger.

• Antigen-presenting cells process and present antigens to T cells; activated T cells stimulate B cells to produce autoantibodies that form large complexes that deposit throughout the body. Antibodies to immunoglobulin G (IgG) are known as rheumatoid factor (RF) and have a strong correlation to the pathogenesis and poor prognosis of RA. B cells also produce proinflammatory cytokines, including tumor necrosis factor (TNF) and the interleukin (IL) system, which induce expression of adhesion molecules on the endothelium, further enhancing T-cell proliferation and differentiation, encouraging cell migration, and regulating matrix modeling.

• Overexpression of tumor suppressor gene p53 prevents normal DNA repair and interferes with appropriate cell apoptosis and increased anti-citrullinated protein antibodies (ACPA). ACPA positivity is associated with a worse prognosis in patients with RA.

• Migration of lymphocytes, macrophages, and mononuclear cells into the synovium and synovial cavity increases synovial mass, causing hypertrophy and angiogenesis. Angiogenesis is driven by IL-8, prostaglandins, vascular endothelial growth factor, and macrophage angiogenic factor. As the vessels develop, cytokines stimulate further migration of cells into the synovium, causing inflammation. The inflamed, fibrotic synovium (pannus) invades cartilage and bone around it, promoting further destruction and dysregulation.

• Cytokines within cartilage cause generation of reactive nitrogen and oxygen species and increase chondrocyte catabolism, inhibit chondrocyte anabolism, and increase extracellular matrix destruction. Proinflammatory cytokines travel to bone, provide the source for receptor activator of NFkB ligand (RANKL), and enhance osteoclast activity, leading to bone matrix destruction.

• Chronic inflammation in vascular endothelial and visceral, cutaneous, and pleural tissues leads to complications including vasculitis, fibrosis, anemia, and renal amyloidosis.

CLINICAL PRESENTATION

• Nonspecific prodromal symptoms developing over weeks to months include fatigue, weakness, low-grade fever, anorexia, and joint pain. Stiffness and myalgias may precede development of synovitis.

• Joint involvement tends to be symmetric and affects small joints of the hands, feet, wrists, and ankles; elbows, knees, shoulders, hips, cervical spine, and temporomandibular joints may also be affected.

• Joint stiffness is typically worse in the morning, usually exceeds 30 minutes, and may persist all day.

• On examination, joint swelling may be visible or apparent only by palpation. Tissue is soft, spongy, warm, and may be erythematous. If left untreated, long-term joint inflammation may lead to bony erosions and subluxations of wrists, metacarpophalangeal joints, and proximal interphalangeal joints (swan neck deformity, boutonnière deformity, and ulnar deviation).

• Extra-articular involvement may include rheumatoid nodules, interstitial lung disease, pleural effusions, vasculitis, ocular manifestations, pericarditis, cardiac conduction abnormalities, bone marrow suppression, and lymphadenopathy.

• RF is detected in 70%–80% of patients; higher titers generally reflect a more severe disease course. ACPA antibodies are more specific for ...