Rheumatoid arthritis typically presents in subacute fashion with symmetric polyarthritis, although atypical forms include monoarticular and asymmetric disease. The most common sites are the wrists, proximal interphalangeal (PIP) joints, and metacarpophalangeal (MCP) joints, but elbows, neck, hips, knees, ankles, and feet may also be involved. Extra-articular manifestations include vasculitis, pulmonary nodules or interstitial fibrosis, mononeuritis multiplex, Sjögren syndrome, and Felty syndrome (splenomegaly, anemia, thrombocytopenia). Fatigue may dominate the early clinical presentation and precede the onset of joint symptoms. Other systemic symptoms (fever, weight loss) are prominent in severe cases. Women are more often affected than are men. Morning stiffness is almost universal, with Raynaud phenomenon a common accompaniment. Rheumatoid factor (RF) is found in approximately 75% of cases and is associated with skin nodules and more aggressive articular and extra-articular disease. Tendinous inflammation and joint destruction may ensue, producing characteristic changes (subluxation, swan neck deformities of the fingers, ulnar deviation
of the wrists). Because no single clinical feature or test finding is definitive, the diagnosis requires the presence of a constellation of findings (see later discussion and Tables 146-2A and 146-2B).

Lupus usually occurs in young women, with a high prevalence in blacks. Malar rash, symmetric polyarthralgias, and nondeforming arthritis are characteristic, as is multisystem involvement, but morning stiffness and joint destruction are not as prominent as in RA. Both large- and small-vessel vasculitis may occur. Oral ulcers are common. Serositis leading to pleuritis, effusion, or pericarditis develops in about one third of patients with systemic lupus erythematosus (SLE). Hematologic manifestations include leukopenia, immune thrombocytopenia, and hemolytic anemia. The most serious complications are glomerulonephritis and cerebritis.

The appearance of autoantibodies is characteristic of lupus and typically predates the development of clinical disease by years; however, their presence is not diagnostic in the absence of clinical findings and does not reliably predict the development of clinical disease. Characteristic serologic findings include positivity for antinuclear antibody (ANA), antibody to native doublestranded DNA (anti-dsDNA), and anti-Smith (anti-Sm) antibody. Additional serologic features may include antiphospholipid antibodies (associated with an increased risk of thrombosis and a false-positive test for syphilis), antiribonucleoprotein (anti-RNP, associated with manifestations of scleroderma), and anti-Ro and anti-La antibodies (also found in persons with Sjögren syndrome).

Scleroderma initially presents as hand arthralgias, mild inflammatory hand arthritis, or Raynaud phenomenon. Florid joint inflammation is uncommon. Skin thickening, a hallmark of the condition, follows several months later. Two clinical variants are described. One is a very slowly progressive form in which visceral involvement does not become significant until after decades of activity. It is manifested by the CREST syndrome: subcutaneous calcinosis of the digits, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia. In the more aggressive form, skin thickening progresses rapidly to extend to the proximal limbs and trunk (hence the term scleroderma), and the onset of visceral involvement is accelerated (i.e., kidneys, lung, heart, and gastrointestinal tract). The results of ANA testing are positive in most patients with diffuse organ system disease, and a speckled pattern is characteristic and disease-specific when it corresponds to antibody to the nuclear enzyme topoisomerase (anti-Scl-70); the presence of anti-nuclear ribonucleoprotein antibodies is also associated with the condition.

Asymmetric polyarthritis may occur as a consequence of vasculitis, from underlying rheumatoid disease (e.g., RA, SLE), one of the antineutrophil cytoplasmic antibody (ANCA)-associated conditions (e.g., granulomatosis with polyangiitis [formerly referred to as Wegener granulomatosis], microscopic polyangiitis, Churg-Strauss disease, and necrotizing pauci-immune glomerulonephritis), or ANCA-negative disease (e.g., polyarteritis nodosum).

Pathogenesis in ANCA-positive vasculitis is believed to involve autoimmune, genetic, and environmental factors. Target antigens include proteinase 3 (more common in granulomatosis with polyangiitis) and myeloperoxidase (more typical of microscopic polyangiitis). Risk of developing antibodies to these proteins and clinical disease appears linked to specific gene mutations, suggesting these antibodies are not only markers but also pathogenic factors. Whether the clinical presentation becomes one of granulomatosis with polyangiitis (with greater involvement of the upper respiratory tract) or microscopic polyangiitis appears to depend on additional factors yet to be determined.

The resulting vascular compromise leads to multisystem injury and a broad array of symptoms. In persons with vasculitis unassociated with rheumatoid disease, arthralgias of large joints occur in up to 50% of cases, but true synovitis develops in only a minority of patients. Skin changes (e.g., palpable purpura, livedo reticularis, ulceration) ensue due to inflammatory injury to small dermal blood vessels (see Chapter 179). The lungs and the glomeruli are commonly involved in ANCA-associated disease, but the lungs are spared in polyarteritis nodosa. Patients with ANCA-associated disease may present with hematuria, proteinuria, hemoptysis, or pulmonary nodularity. Other features of ischemic injury include abdominal pain and peripheral neuropathy (including mononeuritis multiplex, in which there is infarction of long individual peripheral nerves such as the peroneal, ulnar, or sural).

This designation describes an indistinct clinical syndrome that contains features of systemic sclerosis, lupus, and Sjögren syndrome. With time, the presentation usually evolves into one of these three conditions, so that some investigators have concluded that this is not a unique condition but rather an early, nonspecific clinical presentation.

Psoriatic disease has both peripheral and axial forms. The peripheral form is asymmetric, oligoarticular, and often erosive. The distal interphalangeal (DIP) joints are most often affected, and the nails are pitted. Sausage-shaped digits and a pencil-in-cup radiologic appearance of the affected joints caused by erosion are found in advanced disease. Psoriatic skin changes (see Chapter 187) usually predate the onset of arthritis, often by months to years, but they can be subtle. The spondylitic form of the disease (associated with HLA-B27 positivity) may resemble ankylosing spondylitis, but the extent of spinal involvement is less.

This condition is primarily a disease of young men. Oligoarthritis, nongonococcal urethritis, and ocular inflammation (i.e., conjunctivitis, iritis) are the defining features. The latter two features may be fleeting and nonconcurrent. Dermatologic features include circinate balanitis (shallow, painless ulcers of the glans penis) and keratoderma blennorrhagicum (a hyperkeratosis of the feet). Onset sometimes follows a recent bacillary dysentery or chlamydial urethritis, which has led to speculation that the condition represents an immunologic cross-response in genetically predisposed hosts. HLA-B27 positivity is common and is believed to be related to the pathogenesis (i.e., shared antigenicity with the infectious agents). Joint involvement is asymmetric and affects the lower extremities. Heel pain with plantar fasciitis and calcaneal periostitis is distinctive. Mild spondylitis is common. ANA is absent.

The presentation begins insidiously and affects young men most severely, producing inflammation of the spinal joints and connective tissue with subsequent calcification and ossification. Characteristic radiographic findings include sacroiliitis and a diffuse proliferation of syndesmophytes leading to spinal fusion. Peripheral arthritis does occur, more often in women. In men, it tends to develop only after spinal disease has become evident. Large proximal joints such as the hips or the knees are the predominant peripheral sites. Uveitis and HLA-B27 positivity are
found, but their presence is not necessary for the diagnosis to be made. The arthritis of inflammatory bowel disease has many of the same features (see also Chapter 147).

When gout presents polyarticularly as an acute process, it almost always occurs in patients with a prior history of monoarticular or oligoarticular gouty attacks, although hyperuricemia is not always present. The acute arthritis may be migratory but usually is confined to the lower extremities. The diagnosis is made by the finding of urate crystals in synovial fluid (see Chapter 145). A chronic arthritis occurs in patients with tophaceous disease. Acute attacks may be superimposed (see Chapter 158).

Like gout, pseudogout is mostly an acute monoarticular disease, but on occasion, the presentation is polyarticular. Patients are usually elderly, with degenerative disease of the knees. The finding of calcium pyrophosphate crystals in the synovial fluid is diagnostic, although cartilage calcification can be seen on radiography. A subacute form, referred to as “pseudorheumatoid” arthritis, has been described, characterized by morning stiffness, synovial thickening, an elevated erythrocyte sedimentation rate (ESR), and low titers of RF.

This form of bacterial arthritis is most likely to present in polyarticular fashion. Fever is usually present, and a papulovesicular rash indicative of disseminated disease develops in about two thirds of cases. Initially, the patient may have diffuse polyarticular symptoms, and signs of tenosynovitis may be found in the wrists, fingers, ankles, and toes. These manifestations are followed by a purulent arthritis in a limited number of joints, usually confined to the wrists, knees, or ankles (see Chapter 137).

Lyme disease may begin with migratory polyarthralgias and progress about 6 months after infection in untreated patients to attacks of asymmetric oligoarthritis in large joints (especially the knees). Later, a chronic monoarticular or oligoarticular arthritis may follow. The knees are a common site of chronic involvement. Erythema chronica migrans, the diagnostic annular red lesion at the site of the tick bite, occurs in 50% to 80% of cases during the early phase of illness. The diagnosis of late disease can be difficult because serologic testing is imprecise (see later discussion and also Chapter 160).

Hepatitis B and other viral infections may present with an immune polyarthritis, often in conjunction with urticaria. The condition is symmetric, affecting the proximal joints of the hands. Onset in hepatitis B is during the preicteric phase. The condition clears spontaneously (see also Chapter 70).

Endocarditis can produce an immune-mediated polyarthritis similar to that noted with hepatitis B. Fever, petechiae, splinter hemorrhages, heart murmur, and hematuria may be seen.

If streptococcal infection is not treated, acute rheumatic fever may ensue 2 to 3 weeks after infection. The abrupt onset of arthritis and fever are the predominant manifestations in adults. Both synovitis and periarticular inflammation occur, especially in the knees and ankles. Erythema of the overlying skin may be noted. The clinical presentation may be dominated by complaints of migratory joint pain +/- signs of joint inflammation. Such migratory polyarthritis in conjunction with carditis, chorea, erythema marginatum, and subcutaneous nodules constitutes the major Jones criteria for diagnosis of acute rheumatic fever. Minor criteria are fever, arthralgia, elevated levels of acute-phase reactants, and prolonged PR interval on electrocardiogram. Two major criteria or one major criterion and two minor are required for diagnosis. A history of recent sore throat is often absent. Although rheumatic fever is increasingly rare in the United States, it may be present among recent immigrants and should be considered in the differential of migratory polyarthritis.

This granulomatous inflammatory disease can present with an acute arthritis of the knees, wrists, PIP joints, and ankles, accompanied by fever, simulating an infectious arthritis. Erythema nodosum, hilar adenopathy, and periarticular involvement help to differentiate the condition from other etiologies. A destructive arthritis develops in a few persons; it is asymmetric and relapsing.

These conditions produce joint pain with few of the manifestations of inflammation, although sometimes a small effusion or mild synovial thickening may be noted.

The arthritis of degenerative joint disease typically presents as deep, aching joint pain that is aggravated by motion and weight bearing and by periods of inactivity. The involved joint can be enlarged as a result of osteophyte formation, but swelling is usually inconsequential because soft tissue involvement and inflammation are minimal. In later stages, pain occurs on motion and at rest in conjunction with stiffness. Nocturnal pain after vigorous activity is common. Patients with advanced disease have pain on weight bearing and joint instability. Examination often reveals crepitus and discomfort on movement of the joint. Occasionally, slight warmth is noted in severely affected weightbearing joints, but erythema and marked warmth are absent. Limitation of motion, malalignment, and bony protuberances from spurs are frequent findings. The joints most commonly affected include the DIP joints of the hands (with formation of Heberden nodes), the MPC joint at the base of the thumb, hips, knees, and cervical and lumbosacral vertebral joints.

This condition is associated with diffuse bony pain in the lower extremities that is worsened by dependency. New bone formation and periostosis are the source of discomfort. Articular and periarticular symptoms may be encountered. Clubbing is a hallmark, although it is not readily evident in about 25% of cases. Intrapulmonary disease is an important precipitant (see Chapter 45).

Thyroid dysfunction severe enough to cause myxedema is associated with symmetric peripheral joint swelling that can mimic RA clinically, but the white blood cell count in the joint
fluid is low, and no clinical signs of inflammation are present. Nonarticular neuromuscular symptoms include myalgias and hand pain related to carpal tunnel syndrome.

Synovial infiltration due to overproduction of immunoglobulin light chains can cause swelling of large joints in a symmetric distribution. Onset is gradual. An immunologic cause of arthropathy may be suspected, but the joint fluid shows no signs of inflammation or immune hyperreactivity. Concurrent involvement of skin, heart, liver, kidney, and peripheral nerves is characteristic. Carpal tunnel syndrome may be present.

Sometimes, a 2- to 3-week noninflammatory arthropathy develops affecting large joints. Swelling, tenderness, and effusion predominate. The synovial fluid is noninflammatory.

The disease polymyalgia rheumatica (PMR) develops gradually over weeks to months. Pain and stiffness of periarticular structures of the neck and shoulders are the presentation in two thirds of cases, with hip and thigh involvement accounting for the other one third. Many patients have both shoulder and thigh involvement. Morning stiffness and pain with movement are highly characteristic; muscle strength is unimpaired. Synovitis has been documented histologically; muscle biopsy specimens are usually normal or show minor inflammatory infiltrates. Sometimes, low-grade fever, weight loss, and fatigue precede the onset of musculoskeletal symptoms. The condition is usually symmetric, but if it is asymmetric, it may be mistaken for shoulder bursitis or hip arthritis. Most patients are elderly. The association with cranial arteritis makes this an important condition to recognize. Marked elevation of the ESR is characteristic. No serologic abnormalities are found (see also Chapter 161).

Myositis of any type may present as musculoskeletal pain and be confused with polyarthritis, although muscle weakness, typically proximal, is typically more prominent than pain. There are several important clinical variants.

Polymyositis is the prototypical inflammatory muscle disease, characterized by marked proximal muscle weakness, muscle soreness, and elevated levels of muscle enzymes, often in conjunction with interstitial lung involvement and myocardial dysfunction that can lead to heart failure.

Dermatomyositis, with its characteristic heliotropic rash (red or purplish discoloration of the eyelids), has a peak incidence among adults between ages 30 and 50 years. Muscle weakness is mild to moderate. Dermatomyositis (and to a lesser extent polymyositis) occurring in an older patient (age > 60 years) is associated with a two- to fourfold increase in risk of adenocarcinoma and lymphoma; risk is greater in men. In most instances, the malignancy is found to be concurrent or develops within 3 years. Screening for malignancy might be undertaken with slightly increased urgency in persons with myositis but should be based on standard criteria (see Chapter 3).

Inclusion body myositis is a disease of older white men, presenting with often asymmetric proximal and distal weakness, marked thigh atrophy relatively early in the course of disease, and weakness of the finger flexors. Dysphagia can complicate the clinical picture.

Eosinophilia-myalgia syndrome is a serious myositis observed in association with the ingestion of L-tryptophan preparations. Marked peripheral eosinophilia, muscle weakness and pain, and serum aldolase elevations comprise the initial presentation. Skin induration, pulmonary infiltrates, cardiac rhythm disturbances, and peripheral neuropathy may ensue.

This syndrome occurs predominantly in women. A central disturbance in pain processing is emerging as an important component of its pathogenesis. Characteristic manifestations include morning stiffness worsened by changes in the weather and heavy exercise, fatigue, disordered sleep, and tenderness at multiple symmetric tender points on the torso and limbs, concentrated in the upper back and the neck. The musculoskeletal discomfort is typically diffuse and poorly localized, but exacerbations caused by extremes of joint motion may produce pain referable to the joints. All hematologic and serologic parameters are normal.

This often confusing and incompletely understood condition causes diffuse musculoskeletal discomfort, swelling, weakness, and limitation of motion. A single limb is affected, usually an arm. The limb is swollen and the skin shiny, often dusky in appearance, and cool to the touch. Pain can be severe and burning. Periarticular structures are especially tender. Preceding trauma accounts for 50% of cases. A vasomotor mechanism is postulated.