Clinical Features

Onset

Onset of rheumatoid arthritis (RA) peaks between the ages of 30 and 50 years but can also occur in childhood or old age. In all races, women are affected nearly three times as often as men. The prevalence of this disorder increases with age, and gender differences are less pronounced in older patients. The greater prevalence of RA among women suggests that sex hormones may influence the development of the disease. This thesis is also supported by the tendency of RA to improve during pregnancy and oral contraceptive use. Unlike other types of arthritis, such as osteoarthritis (OA) and gout, RA does not appear to have existed before the industrial age. This historic evidence suggests that unknown environmental exposure(s) may account for the risk of RA in the modern world. It appears that age at onset may influence the disease outcome, as those with a very early onset and disease persistence are at high risk for damage and deformity.

In about two thirds of patients, RA appears insidiously with development of symmetric arthritis over the course of weeks to months. Patients may complain either of joint pain and stiffness or nonspecific malaise and fatigue. The initial presentation of monarticular or oligoarticular pain is soon replaced by pain in the additional joints, often in a symmetric distribution. Small, medium and large joints are equally affected during the onset of disease. Reasons for the symmetric joint distribution and preferential involvement of joints (e.g., metacarpophalangeal [MCP], wrist, knee) are unknown.

Less than 10% of patients experience an acute onset of polyarticular arthritis, sometimes with fever and prostration. Historically, this acute, febrile onset was called the Still-Chauffard variant of RA. This acute presentation of RA is thought to be most common in elderly males. Although septic arthritis and gout need to be considered with such a presentation, this more fulminant presentation may facilitate an early diagnosis in the few with such an onset.

Morning stiffness is an integral and prominent symptom that is invariably present at onset of disease. Morning stiffness is a purported surrogate measure of inflammatory activity in RA and tends to parallel the inflammatory activity in the joints. With inflammatory arthritis, it is typically prolonged, lasting hours rather than minutes each morning and tends to improve with movement, exercise, heat, or anti-inflammatory medications. Some patients will describe their morning stiffness as a soreness or pain that improves each morning. Many patients also report constitutional symptoms, such as fatigue, anorexia and low-grade fever, when inflammation is uncontrolled.

Joint Involvement

The signs of joint inflammation—pain, swelling, erythema, or warmth—are most evident early in the disease or during flares of disease activity. However, with established synovitis and disease chronicity, findings of erythema or warmth may be absent. Warmth is often a subtle finding and erythema may be temporary. Pain referred to the joint originates predominantly in the joint capsule, which is abundantly supplied with pain fibers and is exquisitely sensitive to distention caused by synovial fluid and synovial membrane hypertrophy. Thus palpable or visible joint swelling reflects the degree of active rheumatoid inflammation. Pain elicited by transverse manual compression of the metacarpophalangeal (MCP) joints is highly suggestive of RA and is known as the “MCP squeeze.”

Although RA can affect any diarthrodial joint, it has a distinct predilection for the small joints of the hand, wrist, feet, knee, and ankle. The pattern of MCP, proximal interphalangeal (PIP) and wrist involvement is highly suggestive of RA and should be distinguished from OA, psoriatic arthritis and pseudogout (Figure 2-1). Other frequently involved joints include the knee and metatarsophalangeal (MTP) joints. Although patients may complain of few specific problematic joints, a detailed joint examination may disclose additional tender or swollen joints with this typical distribution. Less common but equally symptomatic is involvement of the shoulder, elbow, ankle, tarsal (midfoot), hip, acromioclavicular, sternoclavicular, temporomandibular and cervical spine joints. Joints not typically affected by RA include the lumbar and/or thoracic spine, sacroiliac, costochondral and first carpometacarpal (CMC1, or base of the thumb) articulations.

Physical examination may disclose palpable fusiform swelling of the PIP joints that has the feel and compressibility of a ripe grape. Swelling involving the MCP, PIP, or wrist joints may cause visible bulging and, on palpation, a compressible thickening of the synovial membrane that will obscure normal joint margins and bony edges. Although distal interphalangeal (DIP) joint involvement is more characteristic of osteoarthritis, DIP pain and swelling may also be seen in some RA patients. Other common findings include swelling of extensor or flexor tendon sheaths (tenosynovitis), cystic synovitis over the wrist and dorsal tenosynovium, swan neck and boutonniere deformities and ulnar drift of the fingers at the MCP joints (Figure 2-2). The latter deformities result from inflammatory damage to periarticular structures, such as tendons and ligaments, with realignment and malposition of articulating surfaces. Rupture of the extensor tendons is not uncommon and may result in a finger drop from unopposed flexion. Rupture of such tendons may be due to nodules that erode through the tendon or the grating of extensor tendons as they pass over the bony abnormalities (e.g., erosions, osteophytes) at the wrist.

Neuropathy, which may also be associated with RA, must be included in the differential diagnosis of finger dysfunction. Elbow contractures may be seen in both early and late disease and provide evidence of prior or existing inflammatory synovitis. Elbow effusions or synovitis will produce a bulge in the lateral olecranon groove (Figure 2.3). This is easily distinguished from a swollen olecranon bursa that will protrude off the olecranon process and be mobile to palpation. The olecranon bursa may be swollen with inflammatory fluid or contain rheumatoid nodules. Septic olecranon bursitis should be suspected when fever, overlying warmth or erythema, or purulent bursal fluid is present. Rheumatoid nodules are most commonly found over the olecranon, ulna, or extensor tendons of the fingers and hand.

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Upper Extremity Involvement

Although the most obvious clinical manifestations of RA are seen in the hands and wrists, the clinician should ask the patient about functional problems or disability due to upper extremity arthritis and whether this interferes with occupation, daily activities, self-care, or avocational activities (i.e., hobbies, sports, etc.). Shoulder involvement in RA may be particularly painful and rapidly lead to a loss of motion (from adhesive capsulitis) and function if not recognized. Rotator cuff damage is a common consequence of chronic glenohumeral inflammatory arthritis and should be further evaluated in those RA patients with chronic shoulder pain.

Upper extremity function can be partially assessed by observing the patient rise from a chair, carry or lift a newspaper or handbag, undress (i.e., shirt buttons, zippers, etc.) and grasp a pen and write. Most patients with moderate to severe RA will complain of a deterioration of their penmanship.

Lower Extremity Involvement

Knee pain and swelling are often painful and can markedly limit mobility. Early in the disease, the accumulation of inflammatory synovial fluid results in an effusion that obscures normal bony margins and distends the suprapatellar pouch above the knee as a buoyant compressible mass. Small to moderate effusions can be detected by demonstrating a bulge sign, elicited by milking joint fluid downward and laterally from the suprapatellar pouch. A visible bulge (or shift in fluid) may be seen medially after applying pressure to the lateral aspect of the knee. In some individuals, synovial pressure may rise and lead to the out-pouching of the synovial membrane to form a popliteal or Baker cyst. Popliteal cysts are formed as the swollen synovium acts as a one-way valve, forcing synovial fluid into the posterior aspect of the knee. A popliteal cyst may be localized to the popliteal space or dissect down the calf where it may cause venous obstruction or rupture leading to an intense local inflammatory reaction that can mimic an acute deep vein thrombosis. The diagnosis is best ascertained by Doppler venous flow studies and ultrasound of the popliteal fossa. Eventually, synovial fluid is replaced by proliferative synovium and pannus. Inflammation and destruction of intraarticular and periarticular structures may give rise to quadriceps atrophy, joint laxity, or meniscal cartilage damage.

Hip involvement is less common but occurs in those with well-established RA. Hip disease can have a devastating effect on ambulation and function. With inflammation of the hip joint, pain is felt anteriorly with radiation into the groin. Palpable swelling is rare. Hip involvement may be suggested by pain or limitation of internal or external rotation or abduction. True hip involvement should be distinguished from trochanteric bursitis (felt laterally over the greater trochanter) and referred pain from lumbosacral spine (felt as gluteal pain). Both hip and knee arthritis should be assessed with standing radiographs to assess the degree of joint space loss (and cartilage damage). In RA, both will demonstrate concentric and symmetric loss of joint space, juxtaarticular osteopenia and subchondral cysts. Articular erosions may be common in the hand and foot but are seldom seen in the hip and knee. Advanced hip disease may result in protrusion acetabula where the acetabulum has eroded, reorganized and collapsed into the pelvic canal. Surgical reconstruction is very difficult at this stage.

Ankle and foot abnormalities are common in RA and may cause problems with ambulation and lead to deformity. Synovial tissue or effusion is best palpated around the medial and lateral malleoli. With protracted or progressive synovitis, loss of movement may be seen as a reduction in plantar and dorsiflexion (at the tibiotalar joint) or inversion and eversion (at the subtalar joint) of the heel. The Achilles tendon may be inflamed and painful in some patients or else there may be palpable rheumatoid nodules within the tendon. Tarsal involvement is not uncommon and, early on, may present as midfoot pain, swelling, or warmth and later, as spreading of the metatarsals. Posterior tibialis tendonitis or rupture may result in eversion of the ankle and midfoot and flattening of the arch. If it is severe or progressive, such patients may benefit from corrective orthotic shoe inserts or surgery. Involvement of the MTP joints is very common in RA and may manifest either as a hallux valgus deformity (Figure 2-2), MTP erosions, MTP, or subluxations. The interphalangeal joint of the toes may also be affected by synovitis or deformity with possible ankylosis, cock-up toe, hammer toe, or overriding toe deformities.

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Cervical Involvement

Neck pain and pain on movement are common in RA, and may result from arthritis of the atlantoaxial joint (C1-C2) or the posterior apophyseal joints. The atlantoaxial joint is a synovial-lined joint that can be affected in RA. Normally, the posterior transverse ligament holds the odontoid process of C2 tight against the anterior arch of C1, such that both move together with flexion and extension. However, erosive disease at C1-C2 and erosion of the transverse ligament may result in ligamentous laxity and C1-C2 subluxation, wherein the atlantoaxial interval (distance) is >3 mm in the neutral or flexed position. A large percentage of patients with long-standing, erosive RA will have asymptomatic changes of C1-C2 subluxation on routine cervical radiography. This may be clinically important in the evaluation of RA patients with neck pain, such that the larger the atlantoaxial interval, the greater the risk for spinal cord compromise. Patients with chronic RA undergoing tracheal intubation should also be assessed radiographically for C1-C2 subluxation to avoid spinal cord or brain stem injury during the procedure.

Cervical subluxation may also occur below C1-C2 and is referred to as subaxial subluxation. Malalignment and bony abnormalities may result in nerve root impingement (or radiculopathy). The C2 nerve root is most commonly affected, although such lesions may occur at any level. Aching or sharp radicular pain may result. The spinal cord is rarely involved at this level but may give rise to features including weakness, sphincter dysfunction, hyperreactive reflexes and sensory deficits.

The cricoarytenoid joints are small amphiarthroses that permit movement of the vocal cords. Arthritis of these joints may manifest as throat pain on swallowing and speaking, or may result in hoarseness, progressive shortness of breath and inspiratory stridor. The latter is a medical emergency and may require the use of high-dose corticosteroids (e.g., prednisone 60 mg/day) or tracheal intubation to avoid further respiratory distress.

Rheumatoid Deformities

Damage to articular and periarticular structures may result in joint destruction and deformities, the most feared complications of RA. Deformities can substantially impair mobility and ability to perform activities of daily living (e.g., preparing food, bathing, dressing). The most common deformities due to RA affect the hands and feet of those with long-standing aggressive disease. The swan neck deformity (hyperextension at the PIP joints and flexion at the DIP joints of the fingers) is commonly seen in second through fifth digits (Figure 2-4). The boutonniere deformity (flexion at the PIP joint and hyperextension at the DIP joint) may occur in all digits of the hand, including the thumb, where it is referred to as a zeta deformity (Figure 2-5). Ulnar drift manifests as deviation of the fingers (at the MCP joint) toward the ulnar side of the hand. A piano key deformity is detected by manual compression of the ulnar styloid with prominent up and down laxity due to damage at the radioulnar joint. A bent-fork deformity of the wrist may produce a step-down appearance over the dorsum of the wrist due to collapse of the carpal bones with subluxation at the CMC joints (Figure 2-6). In the foot, a hallux valgus deformity affects the first MTP joint, with medial displacement at the MTP joint and lateral deviation of the first toe bilaterally (Figure 2-2).

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Extra-articular Manifestations

Although arthritis may be its most prominent clinical feature, RA is a systemic disease that may cause a variety of extra-articular problems. Extra-articular manifestations are almost exclusively seen in patients with high serum titers of rheumatoid factor (RF), those with established (long-standing) erosive arthritis and deformity. Some manifestations are common and usually do not require treatment; these include subcutaneous rheumatoid nodules and some pulmonary and vasculitic manifestations. Some extra-articular manifestations, such as vasculitis and Felty’s syndrome, are rare and may require specific therapy. Extra-articular manifestations of RA are not always accompanied by active synovitis and may arise in patients with burnt-out or active disease.

Rheumatoid Nodules

Rheumatoid nodules are found in up to 35% of RA patients. They can be identified as discrete, often painless, nodular masses that tend to appear over the extensor surface of joints or over pressure points. Thus they are typically found over the olecranon (or in olecranon bursa) (Figure 2-3), proximal ulna, fingers (Figure 2-5), Achilles, or extensor tendons and are seldom found over the sacrum and occiput. Nodules are rarely found in the vocal cords, pulmonary parenchyma, pleura, pericardium, myocardium, or leptomeninges of the central nervous system. They may appear as a solitary mass or less commonly as a cluster of nodules. They are usually subcutaneous, mobile, and possess a rubbery consistency. A minority will be bound to periosteum and will feel firm or hard on palpation. Nodular masses may also be seen in other disorders including gout (tophi), rheumatic fever, xanthomatosis, multicentric reticulocytosis, granuloma annulare, sarcoidosis, and leprosy. In contrast with gouty tophi, rheumatoid nodules rarely erode or ulcerate through the overlying skin. There is a very strong correlation between rheumatoid nodules and high levels of serum rheumatoid factor (RF). Thus finding a nodule in an RF-negative individual should suggest gout (or other nodular disorders) rather than RA as the primary diagnosis.

The diagnosis of rheumatoid nodule is made on clinical grounds and rarely requires biopsy confirmation. Nodules may or may not resolve with control of the RA using disease-modifying antirheumatic drugs (i.e., gold, penicillamine, methotrexate [MTX] and anti–TNF agents). Paradoxically, some patients treated with MTX sometimes experience worsening of nodules with resultant “MTX nodulosis.” Surgical removal of nodules should be discouraged since they frequently recur.

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Rheumatoid Vasculitis

This rare complication of RA is considered one of its more serious extra-articular manifestations. It is usually associated with aggressive, long-standing disease and affects patients who also have other extra-articular manifestations (i.e., nodules, Sjogren’s). It is observed in both males and females and nearly all patients have high-titer IgM-RF. This complication appears to be decreasing in incidence, possibly due to earlier diagnosis and more aggressive treatment regimens. Autopsy studies suggest that the true incidence of vasculitis is higher than that clinically observed, although most of these cases are subclinical and not detected during life. The etiology is not completely understood, but it is presumed to involve RF-containing immune complexes that are passively deposited on the vessel wall of small- to medium-sized vessels. Lesions range from mild leukocytoclastic vasculitis to severe necrotizing vasculitis.

Clinically, vasculitis typically presents as limited cutaneous lesions rather than severe necrotizing vasculitis affecting nerves or organs. Systemic manifestations (i.e., fever, weight loss) are common during the onset of rheumatoid vasculitis. Palpable purpura on the extremities or fingertip lesions (e.g., infarction, splinter hemorrhages, tender macules) are most common and usually indicate a leukocytoclastic vasculitis. Larger vessel involvement often presents as nonhealing ulcers in the lower extremities (over the malleolus of the ankle) but may also affect nerves and organs. Peripheral neuropathy may be the sole manifestation of rheumatoid vasculitis and most commonly presents as a mononeuritis multiplex (multiple individual nerves involved) with wrist or footdrop. Rarely, involvement of large arteries will result in infarction of the myocardium, bowel, or lung. The diagnosis should be supported by laboratory evidence of high-titer IgM-RF levels, decreased serum complement (C3, C4), leukocytosis, anemia of chronic disease and possibly cryoglobulinemia. The diagnosis can be confirmed by tissue biopsy (e.g., sural nerve or leg ulcer biopsy) or nerve conduction velocity testing that indicates a mononeuritis multiplex. It is important to note that like other extra-articular manifestations, rheumatoid synovitis may be relatively inactive and the degree of active joint inflammation does not correlate with the activity of the vasculitis.

A proven diagnosis of rheumatoid vasculitis may significantly alter therapy. Vasculitis involving medium- to large-sized vessels should be treated aggressively with cyclophosphamide as a daily oral dose or as an intermittent intravenous bolus infusion. Concomitant treatment with moderate doses of prednisone is required. Foot- and wrist-drop can also be managed with splints and physiotherapy. Patients with vasculitis limited to the fingertip lesions generally do well, whereas involvement of major nerves or organs tends to be associated with a poorer prognosis.

Sjogren’s Syndrome

Keratoconjunctivitis sicca, also known as Sjogren’s syndrome, is the most common ocular manifestation in RA. Sjogren’s is a chronic autoimmune syndrome characterized by inflammatory damage of exocrine glands, especially the lacrimal and salivary glands, with resultant dry eyes and dry mouth. It may occur as a primary autoimmune disorder or in patients with another established autoimmune disease, such as RA. Salivary gland biopsies show infiltration of predominantly CD4⁺ helper T lymphocytes in interstitial and periductal areas. Infiltrating lymphocytes mediate destruction and dysfunction of the glandular tissue, resulting in characteristic symptoms. Dry mouth may result in difficulty swallowing (upper pharyngeal dysphagia) or progressive dental caries. Dry eyes may manifest as redness or the sensation of sand or “grit” in the eye. Patients will excessively blink or rub their eyes. Parotid gland enlargement is found in a minority of patients. Uncommonly, renal involvement, with resultant tubular dysfunction and renal tubular acidosis, will manifest as weakness and hypokalemia. Central nervous system involvement (e.g., headaches and altered mentation) is rare.

Patients with secondary Sjogren’s syndrome are strongly positive for RF and a majority will possess other autoantibodies, such as antinuclear antibodies (ANAs) or antibodies against SS-A (also known as anti-Ro) or SS-B (also known as anti-La). The diagnosis of keratoconjunctivitis sicca can be further established using quantitative measures of tear production. Schirmer’s test uses adsorbent paper strips inserted into the lower palpebral fold to measure the amount of wetting or tear production. Alternatively, the ophthalmologist can facilitate the diagnosis by performing a rose bengal test. Rose bengal is a vital stain that is retained within nonviable cells and is used to evaluate corneal abnormalities in patients with symptomatic or suspected keratoconjunctivitis sicca. Biopsy of glandular tissue (i.e., minor salivary gland of the lip or parotid gland) is the most definitive means of diagnosis but is infrequently necessary. Histology should reveal the characteristic lymphocytic infiltration (with a focus score >1) that is diagnostic of Sjogren’s syndrome.

Treatment must focus on education, frequent dental care, the use of topical ophthalmic and oral lubricants, and avoidance of activities or medications that promote mucosal dryness. A variety of artificial tear- and saliva-substitute preparations are available. Agents such as pilocarpine (Salagen) and cevimeline (Evoxac) (given tid or qid) are effective in augmenting salivary flow. Systemic therapies (i.e., nonsteroidal anti-inflammatory drugs [NSAIDs], steroids, immunosuppressives, MTX, TNF inhibitors) are not effective in the management of the sicca symptoms. A topical ocular formulation of the T-cell inhibitor cyclosporine has been approved for use in Sjogren’s syndrome.

Other Ocular Findings

Episcleritis and scleritis are rare but serious complications of systemic rheumatoid inflammation. The episclera of the eye is highly vascularized, located over the limbus and may become acutely inflamed, raised and intensely red, which tends not to be painful but rather uncomfortable. Scleritis causes a focal intense ocular pain with a dark red discoloration. If left untreated, it can result in resorption of the sclera—a condition known as scleromalacia perforans (so-called scleral melt). Management of scleritis and episcleritis often requires high-dose corticosteroids and immunosuppressives (e.g., cyclosporine, azathioprine, cyclophosphamide). TNF inhibitors have anecdotally been used with some success.

Pulmonary Complications

Pulmonary disorders are uncommon in RA but may include pleuritis, pulmonary nodules, Caplan’s syndrome, interstitial lung disease, and bronchiolitis obliterans. Pleural effusions are clinically observed in 1% to 5% of patients and in nearly 20% of autopsied patients. Thus, in most, pleuritis is asymptomatic. Pleurisy can be seen at any time during the disease. Examination of the pleural fluid often reveals low glucose and complement levels, but seldom will these effusions accumulate and require thoracentesis. Pulmonary nodules are also rarely seen in RA. They may be solitary or multiple and are more commonly seen in the upper rather than lower lobes. These nodules uncommonly necrose, cavitate, or erode into airways to cause a pneumothorax. Lung nodules must be distinguished from malignant or infectious lesions using the clinical picture and, possibly, biopsy. When multiple, large pulmonary nodules are seen in patients with pneumoconiosis (e.g., coal miners, those exposed to silica or asbestos), this has been called Caplan’s syndrome.

“Rheumatoid lung” refers to the insidious onset of fibrosing alveolitis (interstitial lung disease) in RA. This progressive condition is seen in RA patients with long-standing, seropositive and erosive disease. Patients slowly develop dyspnea, dry cough, inspiratory rales and clubbing. Pulmonary function tests show a progressive decline, despite all antirheumatic therapies (including corticosteroids). RA lung is an ominous finding, as there is a 5-year mortality rate of 50%. Patients with rheumatoid lung must be distinguished from those with hypersensitivity pneumonitis due to gold, penicillamine (PCM), or MTX. Patients with hypersensitivity pneumonitis tend to be younger, with shorter disease duration and there is no association with RF or other extra-articular features of RA. The onset is acute and most patients promptly respond to drug withdrawal and corticosteroid therapy (20-60 mg/day until improved). Bronchiolitis obliterans is a rare manifestation of RA. Patients will note the acute onset and rapid decline in breathlessness, dry cough, normal chest radiographs but a small airway obstructive pattern on pulmonary function testing. This rare complication is frequently fatal, although some have responded to high-dose corticosteroid therapy.

Infectious and Malignant Complications

Patients with RA are at increased risk for infection, especially pneumonia and septic arthritis. Pneumonia is the most common infectious cause of death in RA. This increased risk is multifactorial and has been linked to the following:

• The activity or severity of RA
• Glucocorticoid use
• Comorbidities that add to this risk (i.e., diabetes, renal failure, congestive heart failure [CHF])
• Skin breakdown or chronic open lesions
• Joint replacement surgery.

A potential contributory role of disease-modifying antirheumatic drugs (DMARDs) and other immunosuppressive agents (e.g., MTX, azathioprine, biologic agents) has not been satisfactorily proven, especially when the aforementioned risk factors are already in place.

Many investigators have studied whether patients with RA are at greater risk for developing a malignancy arising from either altered immunosurveillance or immunosuppressive therapies. It appears that RA patients are at a slightly greater risk for lymphoma, especially non-Hodgkin’s lymphoma rather than Hodgkin’s disease. Overall, RA patients do not appear to be at greater risk for most solid tumors. Population-based studies suggest RA patients may be at increased risk for nonmelanomatous skin and lung cancers, but have a lower risk for breast cancer and colon cancer and adenomatous polyps due to chronic NSAID or cyclooxygenase (COX)-2 inhibitor therapy.

Hematologic complications of RA include anemia of chronic disease, hemolytic anemia, Felty’s syndrome, thrombocytosis and eosinophilia. A mild anemia of chronic disease (with normochromic, normocytic indices and normal ferritin values) is very common in the face of active inflammatory disease. In such patients, the hematocrit levels commonly range from 30% to 35% and reflect ineffective erythropoiesis. More severe forms of anemia should imply alternative etiologies, such as gastrointestinal (GI) blood loss, etc. Rarely, hemolytic anemia occurs in RA and may be due to RA, DMARD therapies, or coexistent disease. Platelet counts may be markedly elevated, with chronic inflammation. Peripheral eosinophilia is seen in nearly 40% of patients.

RA is one of the primary causes of systemic amyloidosis worldwide. Amyloid is seen in 2% to 20% of RA patients and is more prevalent in Europe than in America. Amyloid causes significant dysfunction by infiltrating various organs. In RA, this primarily manifests as renal disease with proteinuria. Amyloid may also cause carpal tunnel syndrome or GI tract deposition and be asymptomatic or cause intermittent diarrhea. Amyloid deposition has also been described in the liver, spleen, pancreas, adrenal, thyroid glands and subcutaneous fat, but is seldom symptomatic. The diagnosis is best established by rectal or abdominal fat pad biopsy.

Rheumatoid Variants

Several disorders have been linked to RA, largely based on their ability to evolve from or into RA. These rheumatoid variants are discussed below.

Undifferentiated Polyarthritis

Several studies have shown that new-onset, inflammatory oligoarthritis or polyarthritis will have a good prognosis and infrequently progresses to RA. These patients are often evaluated in the primary care setting. They present with inflammatory oligoarthritis or polyarthritis or polyarthralgia (often with a rheumatoid-like joint distribution) with prolonged morning stiffness. These patients are often diagnosed as having early RA, inflammatory, atypical arthritis, or undifferentiated polyarthritis. Very few will have rheumatoid nodules or meet the American College of Rheumatology (ACR) criteria for the diagnosis of RA. The prognosis for patients with undifferentiated polyarthritis is far more favorable than that expected for RA, especially in those who are RF-negative. Between 50% and 60% of patients with a disease duration <18 months will go into remission, <20% will go on to meet diagnostic criteria for RA and <10% will be diagnosed with another recognizable rheumatic disorder. Regardless of presentation, treatment should match the degree of synovitis and not be limited by the diagnostic label.

Palindromic Rheumatism

Palindromic rheumatism is a very uncommon disorder that has been linked to RA. It is characterized by recurrent, afebrile attacks of severe monoarticular (occasionally polyarticular) inflammation, usually lasting hours to days. Pain, swelling and redness affect typical joints (e.g., wrists, shoulders, ankles, knees, MTP, fingers) and may be accompanied by painful subcutaneous nodules. Radiographic evidence of articular damage and clinical disability are notably absent. Less than half of patients will be seropositive for RF. The presence of RF increases the risk of developing RA. Nearly half of affected patients will experience chronic, intermittent palindromic attacks; in 30% to 40% the condition will evolve into RA; and up to 15% will go into clinical remission. With close observation and time, palindromic rheumatism can be distinguished from early RA, pseudogout, Behcet’s disease, or familial Mediterranean fever. Patients with persistent recurrent attacks may benefit from intraarticular or oral corticosteroids, gold, or antimalarial therapy.

Elderly-Onset RA

The onset of disease will occur in a substantial number of RA patients after the age of 60 years. Such patients are more likely to be male and will present with either a polymyalgia rheumatica type onset or an acute-onset polyarthritis. The onset of RA in the elderly is distinct from that of younger-onset RA, which is more rapid with markedly elevated erythrocyte sedimentation rate (ESR), less RF positivity, an equal male:female distribution, more large-joint involvement and a more favorable outcome. However, systematic reviews have indicated that these characteristics are unsubstantiated by data. Overall, the same factors are associated with the outcome and prognosis of younger patients and also apply to older-onset RA. Previously suggested differences may relate to inexact diagnoses, comorbidity and other factors.

Polyarticular Juvenile Arthritis

Polyarticular juvenile arthritis denotes the onset of inflammatory polyarthritis that affects children under the age of 16 years, usually before the age of 9 years. Females are more commonly affected than males. Nearly 30% of children diagnosed with juvenile arthritis will demonstrate a symmetric polyarthritis, with a joint distribution similar to that seen in adult RA. RF positivity is seen in 20% to 30% and ANA positivity is seen in 40% of polyarticular patients. Constitutional features of low-grade fever, weight loss and lymphadenopathy are occasionally seen. RF-positive patients are more likely to have a chronic course, significant disability, more erosions and rheumatoid nodules. Patients with polyarticular disease are at risk for micrognathia, growth retardation and cervical arthritis (especially C2-C3 apophyseal fusion). Severe erosive arthritis occurs in 50% of RF-positive and in 20% of RF-negative patients and is indistinguishable from that seen in seropositive adult RA.

Adult-Onset Still’s Disease

Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown etiology and pathogenesis. AOSD is the adult continuum of systemic-onset juvenile arthritis; hence, it usually affects young men and women under the age of 35 years. The diagnosis of AOSD is suggested by the presence of the classic triad of quotidian (daily) spiking fevers (≥39°C), evanescent salmon-pink rashes and polyarthritis. Other characteristic manifestations include a prodromal sore throat, arthralgias, myalgias, weight loss, serositis, hepatomegaly (often with elevated hepatic enzymes), splenomegaly and generalized lymphadenopathy. Laboratory tests support the inflammatory nature of the disorder with leukocytosis, anemia of chronic disease, hypoalbuminemia and hyperferritinemia, yet serum RF and antinuclear antibodies are absent. The clinical course is marked by sporadic exacerbations of systemic inflammation and/or chronic inflammatory arthritis. In nearly one quarter of patients, the condition evolves into an RA-like chronic polyarthritis with erosive disease or deformities. This is a diagnosis of exclusion based on the aforementioned characteristic features. NSAIDs (in anti-inflammatory doses) are effective in some, while many will require high-dose oral corticosteroids (e.g., prednisone 40-80 mg/day). Although MTX, azathioprine and HCQ have been successfully used as steroid-sparing agents, anakinra, a recombinant interleukin-1 receptor antagonist (see Interleukin-1 Inhibitors), is highly effective in patients with persistent or recalcitrant systemic features.