The ultimate destruction of cartilage, bone, tendons, and ligaments probably results from a combination of proteolytic enzymes, metalloproteinases, and soluble mediators. Collagenase, produced at the interface of pannus and cartilage, is probably largely responsible for the typical bony erosions.

CLINICAL FEATURES.

The mode of onset of RA is highly variable. In the majority of cases, joint pain and/or stiffness develops insidiously over several weeks to months. One or more small joints of the hands, wrists, shoulders, or knees and/or the metatarsophalangeal (MTP) joints are frequently the 1st symptomatic areas. Malaise and fatigue, occasionally with low-grade fever, may accompany musculoskeletal discomfort. As the disease progresses, joint swelling, tenderness, and a red or bluish discoloration become apparent (Fig. 286-2) . The pattern of joint involvement is typically polyarticular and symmetrical and involves the proximal interphalangeal (PIP), metacarpophalangeal (MCP), wrist, elbow, shoulder, knee, ankle, and MTP joints. The distal interphalangeal (DIP) joints of the fingers are usually spared. Joint stiffness, especially if lasting more than 1 hour in the morning and after inactivity, is prominent. So characteristic is this symptom that the duration of morning stiffness is often used as a quantitative guide to the activity of the inflammatory process in both clinical practice and research studies. Over time the patient may experience increasing difficulty with pain and stiffness, as well as impaired joint function. The simple activities of daily living may be severely compromised, and the