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

ability to continue a productive occupation is threatened. Sleep habits become disturbed, and the patient may experience depression and weight loss.

An "acute" onset occurring over 1 or several days is seen in about 20% of patients. Occasionally, an individual retires in the evening with no symptoms and awakens with acute, generalized RA. Such a rapid onset of pain involving the joints, surrounding soft tissue, and muscle can mimic and must be differentiated from acute myositis, viral syndromes, or if focal, even septic or crystal-induced arthritides. Rare patients experience recurrent (palindromic) episodes of acute monarthritis, often so severe as to mimic gout, yet lasting only 24 to 48 hours. Such patients, especially if seropositive, eventually contract the typical chronic, symmetrical polyarthritis of RA.

The course of RA, like its onset, varies widely. Fluctuating disease activity early in the disease process is usual. Ultimately, joint deformities and variable degrees of disability occur in most patients (Fig. 286-3) . Some patients have a relentlessly progressive course leading to early disability or even death, but repeated periods of some degree of remission are the rule. The American College of Rheumatology has proposed criteria for clinical remission in RA. At least five of the following requirements must be fulfilled for at least 2 consecutive months: (1) duration of morning stiffness not exceeding 15 minutes, (2) no fatigue, (3) no joint pain (by history), (4) no joint tenderness or pain on motion, (5) no soft tissue swelling in joints or tendon sheaths, or (6) an erythrocyte sedimentation rate (Westergren) less than 30 mm/hour for females or 20 mm/hour for males.

Assessment of functional capacity is frequently necessary in RA patients. Although various schemes have been proposed, the simple classification that follows serves well in most situations: