These studies have proposed a sequence of events in the development of rheumatoid arthritis: (1) An unknown causative factor (antigen), carried to the joint by the circulation, initiates synovitis. (2) The antigen is processed by antigen-presenting cells such as macrophages, dendritic cells, and even B lymphocytes to interact with T and B lymphocytes to stimulate the local production of antibodies. (3) The antigen and antibody interact, forming immune complexes, and the interaction of the resulting immune complex with rheumatoid factor in the synovium and fluid stimulates a sequence of events that generates chemotactic factors. (4) These chemotactic factors attract cellular elements of the blood into the perivascular space. (5) New blood vessels are generated in the rheumatoid synovium. (6) Large amounts of proinflammatory cytokines are produced. All of these events together lead to release of various enzymes such as matrix metalloproteinases (MMPs) to participate in the extracellular matrix degradation of the joint, cartilage damage, and, eventually, whole joint destruction.

CLINICAL COURSE AND PROGNOSIS

The clinical course of rheumatoid arthritis is characterized by remissions and relapses. In the first few months after onset, the course of the disease cannot be predicted because it is so variable (see Plate 5-9). Only repeated observation of the patient with active disease allows the physician to determine the prognosis. Factors associated with a poor prognosis include persistence of active illness for longer than a year, presence of rheumatoid nodules, high serum titers of rheumatoid factor, anti-CCP antibodies, and extra-articular manifestations.

Early and prolonged remission is more likely if the disease is mild at onset. Although partial or even complete remission may occur at any time and continue for a long time, complete remission is seldom seen after 3 or 4 years of continuously active disease.

Appropriate therapy can slow down or arrest the disease process, can relieve joint pain, allows patients to be more active, and helps to avoid disability and incapacitation. Before the early 1990s, it was true that the amount of joint damage and disability was greater after 10 years of continuously active disease than after 5 years and was greater still after 15 years. Thanks to the introduction of newer therapeutic agents, particularly biologic agents since 1998, the frequency of joint damage has been significantly reduced and joint deformities have become less prevalent, as has the need for joint replacement surgery.

DIAGNOSIS

Early in the course of the disease, when synovitis and mild systemic illness are the only clinical manifestations, it is often very difficult to distinguish rheumatoid arthritis from other rheumatic diseases. Because there is no reliable laboratory test for rheumatoid arthritis, diagnosis depends on the judgment of a well-informed physician, usually based on frequent physical examinations and laboratory studies performed over many months. The most significant diagnostic findings are synovitis in many joints (especially paired joints in the limbs); systemic signs and symptoms; elevated ESR; circulating rheumatoid factor in serum; and rheumatoid nodules. However, circulating rheumatoid factor may not be detected for many months after the onset of illness, and many patients remain seronegative. Likewise, radiographic changes become visible only after months of persistent joint inflammation.

Diagnosis is not difficult after the illness has become chronic or when any of the following manifestations are present: rheumatoid nodules; rheumatoid factor in serum; characteristic joint deformities; and radiographic evidence of articular cartilage thinning, subchondral bone destruction, joint deformity, or ankylosis.

Criteria. The following criteria, formulated by the American Rheumatism Association (ACR) in 1987, are a reliable basis for accurate diagnosis:

• Morning stiffness

• Arthritis of three or more joint areas

• Arthritis of hand joints

• Symmetric arthritis

• Rheumatoid nodules

• Serum rheumatoid factor

• Radiographic changes

A patient could be classified as having rheumatoid arthritis if at least four of these criteria were satisfied; four of the criteria must have been present for at least 6 weeks. In 2010, ACR/EULAR (European League Against Rheumatism) classification criteria were introduced to make a diagnosis of early rheumatoid arthritis among patients newly presenting with undifferentiated inflammatory synovitis. The differential diagnoses includes many other inflammatory conditions.