A 48-year-old woman comes to the office with a 4-month history of pain, stiffness, and swelling of her hands, feet, and knees that is associated with daily fatigue. She has taken over-the-counter nonsteroidal anti-inflammatory agents, but they only temporarily relieve the pain. The patient has no other medical issues. She does not use tobacco, alcohol, or illicit drugs and is not sexually active. Vital signs are within normal limits. BMI is 35 kg/m². The patient walks with a limp due to pain in the foot. There is symmetric swelling, tenderness, and restricted range of motion involving the wrists, ankles, forefeet, and knees. There is no skin rash. Laboratory studies show anemia. Which of the following is most likely to be the earliest finding during the development of this patient's condition?

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11ec160b_3a69_3f2d_9249_ffb78db5a57c_MD0001_00 This patient has a chronic, symmetric, polyarticular arthritis with joint swelling and stiffness consistent with early rheumatoid arthritis (RA). RA is a progressive autoimmune disorder that is often associated with signs of systemic inflammation (eg, fatigue, fever, anemia). It has a peak incidence at age 50-75 but can occur at any age; women are affected more commonly than men. The pathogenesis of RA begins with activation of T lymphocytes in response to rheumatoid antigens (eg, citrullinated peptides, type II collagen). Activated T cells release cytokines that cause synovial hyperplasia with recruitment of additional mononuclear cells. The accelerated metabolic rate of the inflamed synovial tissue leads to local hypoxia and increased production of hypoxia-inducible factor 1 and vascular endothelial growth factor by local macrophages and fibroblasts, resulting in synovial angiogenesis (neovascularization). As the disease progresses, new blood vessels provide nutrients that facilitate expansion of inflammed synovium into a rheumatoid pannus, an invasive mass composed of fibroblast-like synovial cells, granulation tissue, and inflammatory cells. Over time, the pannus encroaches into the joint space and can destroy the articular cartilage and erode the underlying subchondral bone (Choice C). Ossification of the pannus can lead to fusion of the bones across the affected joint (bony ankylosis). (Choices A and D) Osteoarthritis is characterized by progressive fibrillation (ie, fissuring, fracturing) and erosion of articular cartilage due to increased biomechanical stress. Periarticular findings include osteophyte formation and subchondral sclerosis due to extensive bone remodelling. In contrast, RA is more frequently associated with periarticular bone erosions. (Choice B) Late-stage RA is characterized by widespread joint deformities. Characteristic findings include ulnar deviation at the metacarpophalangeal joints, swan-neck deformities (hyperextension at the proximal interphalangeal joints with flexion at the distal interphalangeal joints) in the digits, and additional deformities (eg, volar subluxation of the carpus, radial drift) at the wrists. Educational objective: Rheumatoid arthritis is characterized by synovial hyperplasia with inflammatory infiltrates. The accelerated metabolic rate of the inflamed synovium causes local hypoxia, which leads to synovial angiogenesis. As the disease progresses, the joint space is replaced by a rheumatoid pannus (an invasive mass of fibroblast-like synovial cells, granulation tissue, and inflammatory cells) which can destroy the articular cartilage and underlying subchondral bone. __________ References: The pathogenic role of angiogenesis in rheumatoid arthritis. (http://www.ncbi.nlm.nih.gov/pubmed/26198292)

A 48-Year-Old Woman Comes to the Office with a 4-Month