Complement Activation
Interaction of rheumatoid factors with normal IgG activates complement and thereby starts a chain of events that includes production of anaphylatoxins and chemotactic factors. Polymor-phonuclear leukocytes then engulf the rheumatoid factor-IgG-complement complexes and release lysosomal enzymes and other products. Complexes of IgG rheumatoid factor with IgG and complement components are readily detected in the synovium, synovial fluid, and extra-articular lesions. Although the synovi-um is a rich source of complement production, the levels in rheumatoid synovial fluid are low because of local consumption. Deposits of immunoglobulin and complement have been identified in avascular cartilage and other collagenous tissues of rheumatoid joints and may play a role in the formation of the destructive lesion of RA. These deposits, which are highly specific for RA, may be an attractant for the invasive pannus.
Cytokines
Early studies suggested an unrestricted abundance of cy-tokines in the rheumatoid joint. However, later experiments demonstrated a relative paucity of many T cell-derived cy-tokines, including IL-2, IL-4, and TNF-|.29 One exception is IL-17, which can regulate cartilage metabolism and may be produced by CD4+ T cells in the joint.30 T cells can also potentially contribute to macrophage and synoviocyte activation by inducing metalloproteinase gene expression via direct cell-cell contact.
T helper cells can be divided into subsets that mediate distinct functions of the immune system. T helper type 1 (Th1) cells produce interferon gamma and IL-2 but not IL-4, IL-5, or IL-10; T helper type 2 (Th2) cells produce the opposite cytokine profile. Th1 overactivity predominates in most animal models of autoim-munity, whereas Th2 cytokines mediate disease suppression.31 The small amounts of T cell cytokines that can be detected in RA are biased toward the Th1 phenotype, including IL-17. In contrast, Th2 cytokines (especially IL-4) are virtually absent from the joint. Some IL-10 is present but is derived mainly from mac-rophages, and the amount is not sufficient to suppress Th1 cy-tokine production.32 The relative lack of suppressive Th2 cy-tokines may contribute to the pathogenesis of rheumatoid syn-ovitis. Levels of other suppressive cytokines, such as the natural IL-1 receptor antagonist (IL-1ra), are also low in RA joint tissues.33
Macrophage- and fibroblast-derived cytokines (e.g., IL-1, IL-6, TNF-a, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) are abundantly expressed in the rheumatoid joint.34 Although many of these cytokines are involved in the pathogen-esis of RA, TNF-a and IL-1 are major pathogenic factors: both can induce synoviocyte proliferation, collagenase production, and prostaglandin release; overexpression of either TNF-a or IL-1 can induce arthritis in animal models. IL-15 is produced by macrophages but shares many activities of the T cell-derived cy-tokine IL-2. It increases the ability of T cells to induce TNF-a production by macrophages through an antigen-independent mechanism that involves cell-cell contact.35 IL-18 is also present in the RA joint and can bias T cell responses toward Th1 or directly activate macrophages to produce proinflammatory medi-ators.36 Cytokine networks can potentially establish paracrine or autocrine networks that can perpetuate arthritis long after the etiologic agent has been cleared. Recent studies suggest that anti-cytokine therapy (including therapy with IL-1, TNF-a, and IL-6) is effective in severe RA and demonstrates the importance of fi-broblast and macrophage products in chronic synovitis.
Diagnosis
Clinical features and disease course
The onset of RA in adults may be either acute or insidious. In the latter case, systemic manifestations may precede overt symptoms of arthritis by months. In some patients, external events (e.g., major infections, surgical procedures, trauma, or childbirth) precede the clinical onset. How these events relate to pathogene-sis is unknown. Small joints of the hands and feet are usually involved at the outset, although large joints (e.g., knees and ankles) are sometimes affected first. In about 10% of cases, monoarthritis of a large joint can presage progression to polyarticular RA.
An insidious onset followed by progression to polyarticular involvement is the most common course. Most patients experience some degree of joint stiffness, especially in the morning after awakening, which may accompany or precede joint swelling or pain. These symptoms are hallmarks of disease activity and help distinguish RA from noninflammatory diseases such as os-teoarthritis. However, joint stiffness and swelling are not specific for RA and can occur with other types of inflammatory arthritis. RA patients frequently complain of morning stiffness that lasts more than 30 minutes (often up to several hours).
Examination of the joints reveals varying degrees of swelling, warmth over the involved joint, tenderness to palpation, and limitation of active and passive range of motion. Swelling may be caused by thickening, edema, and increased vascularity of the synovium; by synovial effusions; or by combinations of these factors. In small joints, such as metacarpophalangeal joints, effusions may be difficult to detect: the presence of synovial thickening causes loss of the anatomic landmarks and can obscure the peaks and valleys formed by the joints. In large joints, especially the knees, effusions are usually easy to demonstrate. Unlike acute inflammatory arthritides (e.g., gout or septic arthritis), RA tends not to cause marked erythema, and swelling usually does not extend far beyond the articulation. In elderly patients, the most prominent manifestation may be diffuse swelling of the hands accompanied by aching and marked stiffness in the absence of erythema. This can be difficult to distinguish from polymyalgia rheum-atica, especially in patients lacking rheumatoid factor.
Classically, RA is symmetrical. When RA is progressive and unremitting, nearly every peripheral joint may eventually be affected, although the thoracic, lumbar, and sacral spine are usually spared. This clinical presentation is observed in perhaps 10% of patients. In about 75%, the disease waxes and wanes over a period of years. In the remaining patients, complete remissions may be achieved with no evidence of inflammation. Remissions may be only partial, with mild clinical disease persisting despite clear improvement. When the course is progressive, the periods of remission may become shorter, and less impressive decreases in symptoms and findings may occur.
A relatively favorable course with long remissions tends to be associated with age less than 40 years, acute onset restricted to a few large joints, disease duration less than 1 year, and negative test results for rheumatoid factor. Conversely, an unfavorable prognosis is often associated with insidious onset, constitutional symptoms (e.g., weight loss, low-grade fever, and profound fatigue), rapid appearance of rheumatoid nodules, and high titers of rheumatoid factor. Homozygosity for the QKRAA sequence in the HLA-DR locus is also associated with more severe disease with extra-articular manifestations. The duration and intensity of inflammation correlates with long-term disability, and there is a significant relationship between persistent elevations in the level of C-reactive protein and poor outcome. The appearance of bone erosions early in the course of disease also portends a worse prognosis.
Pregnancy often relieves the symptoms of RA in the second or third trimester through a poorly clarified mechanism. One possible explanation is that the placenta produces large amounts of the suppressive cytokine IL-10. The risk of developing RA appears to be lower in women who have been pregnant. The effect of oral contraceptives on disease susceptibility is controversial; the effect, if any, is probably small.37 In long-term studies, multiple pregnancies or the use of oral contraceptives did not significantly alter the course of RA.38
Mortality is higher in RA patients than in the normal population. For the most part, RA patients die of the same causes as the general public, albeit earlier. In severe RA, mortality can approach that of severe congestive heart failure or Hodgkin disease, thereby justifying aggressive early management. Cardiovascular disease accounts for about 40% to 45% of deaths in RA patients; cancer, about 15%; and infection, about 10%. The inflammatory response, especially when associated with an increase in C-reac-tive protein and the use of proatherogenic treatments such as cor-ticosteroids, correlates with an increased incidence of coronary artery disease.39 The incidence of lymphoproliferative diseases is increased in patients with RA; non-Hodgkin lymphoma, leukemia, multiple myeloma, and Hodgkin disease account for most excess malignancies.
Specific Joint Disease
Hands and wrists Involvement of the hands and wrists is the most characteristic finding. Swelling and tenderness are usually noted first at the metacarpophalangeal and proximal interphalangeal joints [see Figure 3]. Fusiform swelling at the proximal interphalangeal joints is typical. Distal interpha-langeal joints are usually spared. Grip strength is decreased because of pain and mechanical derangement. Flexor tenosynovi-tis is common; progressive flexion limitation prevents the making of a fist.
Depending on the site and severity of the rheumatoid lesions, varying degrees of ulnar deviation and subluxation at the metacarpophalangeal joints result. These deformities are, in large part, caused by inflammation and radial deviation at the wrist. As the wrist abnormalities progress, the extensor tendons apply torque across the metacarpophalangeal joints and tend to pull the digits into the classic ulnar deviation position. Other changes in the phalanges include (1) hyperextension at the prox- imal interphalangeal joint and flexion at the distal interpha-langeal joint (so-called swan-neck deformity) and (2) flexion at the proximal interphalangeal joint and extension at the distal in-terphalangeal joint (boutonniere deformity). Several deformities also affect the thumb and interfere with grasp and pinch. In extreme instances, the fingers are markedly deformed and flail as a result of destruction of cartilage and bone.
Figure 3 The hand and wrist are common sites of synovitis in rheumatoid arthritis. Marked swelling in the wrist and metacarpo-phalangeal joints is caused by synovial proliferation. Modest ulnar deviation of the fingers is also present.
Figure 4 Rheumatoid nodules commonly form near the extensor surface of the elbow. They can be fixed to the underlying periosteum or can be freely mobile.
In early RA, relatively painless swelling of the dorsum of the wrist may be noted. Most often, the wrist is painful and is the source of functional limitations (e.g., inability to remove the lid from a jar). At the volar aspect, median nerve compression caused by synovial expansion can produce carpal tunnel syndrome. On the dorsal surface, synovial proliferation may erode and rupture the extensor tendons of the fingers, rendering the patient unable to extend the fingers actively at the metacar-pophalangeal joints. Decreased dorsiflexion and plantar flexion of the wrist caused by fusion of carpal bones is common in severe disease. Volar subluxation and radial deviation are also common deformities; the ulnar styloid is often one of the first sites of bone erosion.
Elbows and shoulders Synovitis of the elbow joint and inflammation and nodules in the olecranon bursa are frequent in established RA [see Figure 4]. Mild flexion contractures occur early; late in the disease, more severe flexion contractures cause functional disability, especially when associated with decreased shoulder abduction and rotation. Pain with decreased range of motion is commonly caused by synovitis of the glenohumeral joint; occasionally, large anterior effusions are evident. Shoulder pain commonly causes difficulty sleeping at night and functional disability. In chronic RA, the joint space becomes contracted, and rupture of the rotator cuff is very common. On physical examination, true glenohumeral joint arthritis can usually be distinguished from acromioclavicular pain, rotator cuff tendinitis, and subdeltoid bursitis.
Hips The hip is affected later than most other joints. In os-teoarthritis, the femoral head tends to migrate superiorly in the acetabulum, but in RA, symmetrical destruction of cartilage leads to axial migration. End-stage rheumatoid disease with typical cartilage loss produces acetabular protrusion of the femoral head [see Figure 5].
Knees Knee arthritis is common and is occasionally a primary manifestation in early RA. Swelling and thickening of the synovium and effusions are usually simple to detect; arthrocen-tesis readily provides synovial fluid for analysis. Occasionally, large effusions expand into the suprapatellar pouch. Atrophy of muscles around the knee, especially the quadriceps, and resultant weakness can be detected early. Persistent synovitis eventually limits walking because of cartilage destruction, ligament laxity, joint instability, and contractures.
Baker cysts of the popliteal space are lined with synovial membrane and usually communicate with the cavity of the knee joint. The high pressure generated during knee flexion may be propagated posteriorly and cause rupture or dissection of these cysts. Calf swelling, pain, and erythema result, mimicking thrombophlebitis. Rupture of cysts is not specific to RA, occurring in other forms of inflammatory synovitis as well. Diagnosis of popliteal cysts can be confirmed by ultra-sonography or arthrography. Generally, treatment of the cyst is directed toward the underlying knee synovitis. Cortico-steroid injections are usually directed into the knee rather than into the cyst.
Ankles and feet Inflammation of the ankle joints and of the small joints of the feet is common. Pain on flexion and extension is a result of tibiotalar arthritis, whereas pain on inversion and eversion is caused by subtalar disease. The metatarsophalangeal joints are sites of early synovitis, which causes pain in the ball of the foot on weight bearing [see Figure 6]. Later in the disease, there is subluxation with protrusion of the metatarsal heads, hal-lux valgus, and collapse of the arch.
Figure 5 (a) A pelvic roentgenogram of a patient with classic seropositive rheumatoid arthritis was taken early in the course of the disease. (b) Another roentgenogram taken 4 years later demonstrates marked acetabular protrusion and resorption of the femoral heads, both of which are characteristic of the disease.
Cervical spine Joints of the thoracic, lumbar, and sacral spine are relatively unaffected in adult RA, but cervical spine disease is frequent and may result in severe pain or neurologic complica-tions.40 The lesion that has received the most attention is at-lantoaxial subluxation and consequent separation at the atlanto-odontoid articulation [see Figure 7]. This deformity is best seen on lateral roentgenograms obtained with the neck flexed, so that the separation of the anterior margin of the odontoid process from the posterior margin of the anterior arch of the atlas can exceed 3 mm. When the separation is severe, the odontoid process may protrude into the foramen magnum and exert pressure on the spinal cord, causing paresthesia or even muscle weakness in the arms and hands. Often, the odontoid process itself is eroded, which minimizes pressure complications but produces instability. Prophylactic surgery to correct subluxation is usually not recommended because of the high morbidity and mortality associated with the procedure. Surgical fixation is indicated in the presence of neurologic signs and symptoms related to spinal cord compression. If the patient requires other surgical procedures, the anesthesiologist should be alerted to the presence of atlantoaxial subluxation to minimize complications of intubation.
Other cervical spine lesions are also seen, including subluxa-tion at multiple levels, erosions at end plates or apophyseal joints, or fusion at these joints. Management of cervical spine pain in the absence of significant subluxation can be frustrating. Traction can be gently applied, but one must always be cognizant of instability. Soft collars can provide some temporary relief, but if used excessively, they can exacerbate the problem by weakening the cervical muscles.
Figure 6 Erosions (arrows) are visible in the metatarsal heads and in some of the phalanges in this roentgenogram of the foot of a patient with classic seropositive rheumatoid arthritis.
Figure 7 The anterior edge of the odontoid process (O) is abnormally separated from the posterior margin of the arch of the atlas (A) in this lateral roentgenogram of the cervical spine of a patient with rheumatoid arthritis. Subluxations of the lower cervical vertebral bodies (arrows) are also visible.
Other joints Synovitis of the temporomandibular joints may produce pain on chewing and limit jaw motion. If the joint is sufficiently destroyed, posterior subluxation of the jaw may cause a receding chin. Sternoclavicular arthritis is uncommon but occurs in patients with widespread arthritis. In acute cricoarytenoid arthritis, hoarseness and pain on swallowing may accompany tenderness over the larynx.
