Adult Rheumatoid Arthritis

heumatoid arthritis (RA) is a chronic inflammatory disease that is probably triggered by an antigen and presents

as an inflammatory reaction against the synovium in the joint (Fig. 1).

Figure 1
Pathogenesis of RA is complex, involving immune processes lead by T cells, cytokine-driven events (responsible for most of the erosive events), and fibroblast-like synoviocyte transformation, resulting in pan- nus formation, hypercellularity, and hyperplasia.
(Reproduced from Recklies AD, Poole AR, Banerjee S, et al: Pathophysiologic aspects of inflammation in diarthrodial joints, in Buckwalter JA, Einhorn TA, Simon SR (eds): Ortho- paedic Basic Science: Biology and Biomechanics of the Musculoskeletal System, ed 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2000, pp 489-530.)

This immune process leads to a proliferative synovitis (pannus formation), which proceeds to destroy the joint. Clinically, RA follows a course of waxing and waning, but it results in progressive disability over time. Patients with RA may be disabled from the disease beyond its effect in the joints. For example, RA can cause systemic manifestations, such as fatigue, weight loss, or anemia. In addition, RA is often treat- ed with potent drugs; thus, patients are potentially exposed to complications from medications.

The initial effects of RA in the joint are manifest as stiffness, and the disease may progress to complete destruction of the articular surfaces. The damage is inflicted by the proliferative synovium itself, which tends to physically invade the joint space, as well as by enzymes that the synovium and reactive white blood cells release. RA also affects the ligaments of the joint; therefore, instability and deformity are characteristic (Fig. 2)

Figure 2
Advanced RA. Note that the fingers are deviated toward the ulnar side of the hand because synovitis destroys the tendon sheath. A, Clinical appearance. B, Radiographic appearance.
(Reproduced from Greene WB: Essentials of Musculoskeletal Care, ed 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2001, p 213.


RA represents the intersection between musculoskeletal medicine and the basic sci- ence of immunology and inflammation. It is therefore a rich and, at times, recondite subject. This chapter perforce is but an overview.


RA affects approximately 1% of the population in the United States. Approximately two of every three patients with RA are female.1 RA typically occurs in patients between the ages of 40 and 60 years, although there is a juvenile form that can be found in those younger than 16 years. There appears to be a genetic susceptibility to this condition, as a monozygotic twin of a patient with RA is more likely to have the condition than a dizygotic twin. However, genes are not the only factor affecting susceptibility because even a mono- zygotic twin has only approximately a 15% chance of having RA when the twin has it.


The exact etiology of RA is not known. It is thought that exposure to an antigen in a genetically susceptible host leads to an antibody production directed against the synovium. In this model, the antigen activates T cells, which produce cytokines. These mediators stimulate antibody production by B cells.4-6 Among these antibodies is the classic rheumatoid factor that binds to IgG. These antibodies are then deposited as immune complexes in the synovium and in cartilage. Activation of other white blood cells promotes a chronic inflammatory state (Fig. 3).

Figure 3
Cytokines found in the joint initiate and perpetuate many different inflam- matory processes. TNF -α is thought to control many of the processes attributed to inflammatory cells in the joint fluid, and IL-1 is thought to act within the articular cartilage itself. The role of IL -15 in this hierarchy is currently hypothetical, but existing data suggest that IL-15 may act to initiate the T-cell driven autoimmune process.
(Reproduced from Recklies AD, Poole AR, Banerjee S, et al: Pathophysiologic aspects of inflammation in diarthrodial joints, in Buckwalter JA, Einhorn TA, Simon SR (eds): Ortho- paedic Basic Science: Biology and Biomechanics of the Musculoskeletal System, ed 2. Rosemont, IL, American Academy of Orthopaedic Surgeons, 2000, pp 489-530.)

Synovial proliferation follows this immune activation, a process called pannus formation. The pannus is hyperplastic synovium with fibroblasts, blood vessels, macrophages, and lymphocytes. The synovial cavity of the joint becomes filled with fluid (an inflammatory effusion). The pannus itself, synovial fluid inflammatory cells, and bone-based osteoclasts attack cartilage and bone, resulting in joint destruction.7-9 This destruction produces two characteristic radiographic features of RA: marginal ero- sions and symmetric narrowing of the joint space medially and laterally. Osteoarthritis, by contrast, tends to produce asymmetric joint space narrowing, beginning on the point of maximal force bearing or previous trauma.

Extra-articular manifestations of RA can occur, the most common of which is a sub- cutaneous nodule found near the joint. Rheumatoid nodules contain granulation tissue and inflammatory white blood cells. The synovitis of RA often extends to the tendon sheath as well, leading to its destruction. In patients with RA of the hand, loss of the tendon sheath causes ulnar deviation of the fingers because the tendons no longer remain tethered to the digit. In some patients with RA, inflammation in the heart, lung, or blood vessels may also occur.

The destruction of the joint in patients with RA is modulated by various factors. These include various cytokines as well as specific matrix-destroying enzymes.10 These factors are elaborated from the synovial macrophages and invading T cells. The activation of these cells is thought to be responsi- ble for the extra-articular manifestations of the disease.


The presentation of RA depends on the stage of the disease. Moreover, expression of the disease varies not only from individual to individual but also within the same individual over time. RA often begins as an acute period of non- specific complaints, such as malaise and joint pain. Characteristically, patients have diffuse joint tenderness and swelling, accompanied by morning stiffness lasting for at least 1 hour. The commonly accepted criterion is that these findings must be present for at least 6 weeks to make a diagnosis of RA (transient inflammation may have other, more benign causes). Patients with RA will demonstrate tender, warm, and swollen joints and have pain with motion. When the disease is long-standing, there will be characteristic objective findings, such as ulnar deviation of the fingers and radial deviation of the wrist caused by erosion of the extensor tendon sheath. Flexion or extension deformities of the fingers are also common.

Diagnostic Imaging

Imaging for RA in its early stages may not be diagnostic. Because RA begins by attacking soft tissue before bone, in its early stages, signs are not readily apparent on plain radiographs. As the disease progresses, osteopenia caused by increased blood flow and osteoclast activity can be detected. Marginal erosions of the bone are seen as the pannus begins to destroy bone. As the disease progresses, symmetric joint space narrowing occurs, culminating in total destruction of the articular surface (Fig. 4).

Figure 4
AP (A) and lateral (B) radiographs of the hip of a 56-year-old man with RA show moderate diffuse periarticular osteopenia, loss of joint space, and extensive acetabular cyst formation (arrow).
(Reproduced from Lachiewicz PF: Rheumatoid arthritis of the hip. J Am Acad Orthop Surg 1997;5:332-338.)

RA can cause instability of the cervical spine when tenosynovitis near the C1-C2 junction destroys the transverse ligament holding the odontoid.11,12 A cervical spine radiograph is therefore mandatory prior to elective endotracheal intubation of patients with RA.

Laboratory Studies

Laboratory studies may be helpful in the diagnosis of RA, but RA is not conclusively diagnosed on the basis of any single laboratory test result. The most useful laboratory test is probably the aspiration and analysis of the joint fluid, which is performed not so much to make the diagnosis of RA, but to exclude two other conditions that may mimic it: infectious arthritis and gout. When infectious arthritis or gout is present, bacteria or urate crystals usually are apparent on analysis of aspirated joint fluid. The fluid in RA is typically characterized by increased neutrophil concentration but only to moderate lev- els; cell counts are usually in the 5,000 to 50,000 range. A complete blood cell count of patients with RA may show an elevated white blood cell count in the peripheral circulation and anemia as well. Two useful tests for evaluating systemic inflammation involve deter- mining the serum C-reactive protein concentration and the erythrocyte sedimentation rate.

Circulating rheumatoid factor also can be measured. The sensitivity of rheumatic factor for the diagnosis of RA is approximately 80%; therefore, it is a poor screening test. However, its relatively high specificity (approximately 95%) allows it to be used as a confirmatory test. Serial monitoring of rheumatoid factor levels does not offer valuable clinical information. In general, patients with RA who do not have circulating rheumatoid factor have a more benign course.

A number of clinical features have been associated with an unfavorable prognosis. These include persistent polyarticular synovitis for more than 2 years, the presence of articular erosions, and the presence of extra-articular manifestations. Extra-articular manifestations may be general and include fatigue, low-grade fever, weight loss, or anorexia; or they may be organ-specific and include subcutaneous nodules, interstitial lung disease, pleural effusions, or neuropathy. The presence of extra-articular manifestations usually mandates aggressive antirheumatic therapy.

Treatment and Prevention

There is no known prevention for RA. Nonetheless, aggressive treatment of early forms of the disease can be viewed as a preventive measure in that damage is prevented—that is, the disease process is arrested before it is able to destroy joints.

The management of RA is centered on drug therapies, although patient education, supportive counseling, and exercise are also essential to attain a good outcome. The phar- macologic therapy of RA is directed to relieve joint pain, limit inflammation, and retard joint destruction. Because the inflammation of RA is mediated by cytokines, drugs that block them are most effective. Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonspecific inhibitors of prostaglandin synthesis. Accordingly, they can control joint pain, but they do not retard joint destruction. Corticosteroids are also used to limit inflammation. Both NSAIDs and corticosteroids ex- pose the patient to the risk of complications. NSAIDs increase the risk of gastrointestinal bleeding and renal dysfunction, whereas the long-term use of corticosteroids frequently produces osteoporosis and other serious complications.

Another category of drugs used to treat RA is called disease-modifying antirheumatic drugs (DMARDs). The goal of using DMARDs is to prevent joint destruction. The most fre- quently used DMARD is methotrexate, which can slow the progression of joint destruction in patients with RA. Methotrexate is a known inhibitor of folate metabolism; however, its precise effect on RA is not clear. Other DMARDs include immunosuppressive medications, such as sulfasalazine or cyclosporine, and newer biologic agents directed at inhibiting the actions of tumor necrosis factor (TNF)-α or interleukin-1 (IL-1).

The surgical treatment of patients with RA includes joint arthroplasty for damaged joints, fusion of unstable joints, and tenosyn ovectomy to prevent tendon rupture.

Differential Diagnosis

RA can be confused with other forms of inflammatory arthritis, such as systemic lupus erythematosus and viral arthritis. It may also be confused with septic arthritis and gout because both are inflammatory conditions that produce fluid in the joints and pain. Appropriate laboratory tests, however, should be able to differentiate these conditions from RA. RA can also be confused with seronegative spondyloarthropathies, inflammatory joint diseases that occur in the absence of rheumatoid factor (hence, the term serone- gative). These conditions affect the sacroiliac joint and frequently the spine and include ankylosing spondylitis and psoriatic arthritis. Although clinically important and scien- tifically interesting, an in-depth discussion of seronegative spondyloarthropathies is beyond the scope of this book.