A 62-year-old woman comes to the office due to a 3-month history of painful, swollen wrists and knees. She also has joint stiffness, which is worse upon wakening and limits her daily activities. Review of systems is positive for fatigue. The patient's only other medical condition is hypothyroidism for which she takes levothyroxine. She smoked a pack of cigarettes daily for 20 years and quit 15 years ago. Vitals signs are within normal limits. Physical examination shows symmetric, moderate swelling of the wrists and knees. The joints are tender and warm. Range of motion is intact but painful. Plain radiographs of the symptomatic joints show joint space narrowing and marginal erosions. Which of the following cytokines are primarily involved in the pathogenesis of this patient's joint destruction?

Question

A 62-year-old woman comes to the office due to a 3-month history of painful, swollen wrists and knees.  She also has joint stiffness, which is worse upon wakening and limits her daily activities.  Review of systems is positive for fatigue.  The patient's only other medical condition is hypothyroidism for which she takes levothyroxine.  She smoked a pack of cigarettes daily for 20 years and quit 15 years ago.  Vitals signs are within normal limits.  Physical examination shows symmetric, moderate swelling of the wrists and knees.  The joints are tender and warm.  Range of motion is intact but painful.  Plain radiographs of the symptomatic joints show joint space narrowing and marginal erosions.  Which of the following cytokines are primarily involved in the pathogenesis of this patient's joint destruction?

Quizplus · Accepted Answer

This patient has chronic, symmetric, inflammatory arthritis associated with significant morning stiffness and overt synovitis (swelling, warmth, tenderness). In association with the radiographic findings of joint space narrowing and marginal joint erosions, this presentation is typical for rheumatoid arthritis (RA). RA is a progressive autoimmune disorder that has a peak incidence at age 50-75 but can occur at any age; women are affected more often than men. Systemic symptoms (eg, fatigue, fever) are common. The pathogenesis of RA involves both humoral (eg, autoantibodies against citrullinated polypeptides) and cell-mediated immunity; activation of CD4⁺ T cells, especially Th1 and Th17, occurs early in the disease process. Macrophages release proinflammatory cytokines critical for the development and progressive articular destruction seen in RA. These include: Tumor necrosis factor-alpha (TNF-alpha) stimulates the proliferation of inflammatory cells and causes expression of inflammatory factors (eg, collagenase, prostaglandins) by synovial cells. IL-1 induces synthesis of matrix metalloproteinases and enhances T-cell immune responses. The proteases (eg, collagenase, metalloproteinase) contribute to cartilage destruction. In addition, both cytokines indirectly activate osteoclasts, resulting in bony erosions. Monoclonal antibodies that inhibit TNF-alpha (eg, adalimumab, etanercept) or IL-1 receptors (eg, anakinra) are widely used in the treatment of RA and can slow progression of the disease. (Choice B) Activated Th1 cells produce significant quantities of IL-2 and interferon gamma, among other cytokines. Although Th1 cells and interferon gamma play a role in the pathogenesis of RA, IL-2 is less prominent. These cytokines are present in higher quantities in granulomatous diseases (eg, tuberculosis, sarcoidosis). (Choice C) IL-4 and IL-5 are involved prominently in mast cell function and play a role in the pathogenesis of atopic disorders (eg, asthma). (Choice D) Transforming growth factor-beta and IL-10 are antiinflammatory cytokines that downregulate lymphocyte activation and proliferation and reduce the production of proinflammatory cytokines (eg, TNF-alpha). These cytokines are likely protective of the joint destruction seen in RA. (Choice E) IL-12 and IL-23 are produced by activated T cells and play a prominent role in the pathogenesis of psoriasis. Educational objective: The pathogenesis of rheumatoid arthritis involves early activation of CD4⁺ T cells (especially Th1 and Th17 subsets) with release of cytokines such as tumor necrosis factor-alpha and IL-1 that cause destruction of cartilage and bone. Monoclonal antibodies that inhibit tumor necrosis factor-alpha or IL-1 receptors can slow progression of the disease. __________ References: Pathogenetic insights from the treatment of rheumatoid arthritis. (http://www.ncbi.nlm.nih.gov/pubmed/28612747)

A 62-Year-Old Woman Comes to the Office Due to a 3-Month