Box 23.1 AMERICAN COLLEGE OF RHEUMATOLOGY 1987 CLASSIFICATION CRITERIA FOR RHEUMATOID ARTHRITIS

    In 2010, new RA classification criteria were published representing the culmination of a collaborative multinational effort between the ACR and European League Against Rheumatism (table 23.1). These new criteria stress the presence of inflammatory arthritis and deemphasize late changes of RA (e.g., erosions and rheumatoid nodules). Thus they permit an earlier diagnosis of RA, allowing for earlier aggressive DMARD therapy in an effort to preserve joint structure and function. It should be emphasized that, strictly speaking, classification criteria are designed for the purposes of clinical research studies and not for day-to-day office practice; some patients with RA may not meet established criteria.

CLINICAL MANIFESTATIONS OF RA

RA most commonly presents as a symmetric inflammatory arthritis of the small joints of the upper and lower extremities. The presentation may be of an acute polyarthritis, but it can also present as an indolent process. Patients with RA experience painful, swollen, red joints, usually with a morning stiffness that exceeds 30 minutes upon awakening and improves with physical activity. Tendons and bursae may also be involved, because the lining of these structures is similar to synovial tissue. Tenosynovitis in the wrist can cause median nerve impingement and carpal tunnel syndrome (CTS), which manifests as numbness and paresthesia of the volar surface of the first through fourth fingers. An analogous process can occur in the ankle to cause tarsal tunnel syndrome.

    The distribution of involved joints is useful in the differential diagnostic considerations of patients presenting with polyarthritis. RA can affect almost any joint in the body, often in a symmetric fashion but not exclusively so. Hands, wrists, and feet are most commonly involved, whereas the lumbar spine is rarely if ever affected. In the hands, RA tends to affect the proximal interphalangeal (PIP) joints, metacarpal phalangeal (MCP) joints, and wrists. It typically spares the distal interphalangeal joints. Low back or distal interphalangeal disease suggests a condition other than RA, such as osteoarthritis or spondyloarthritis-like psoriatic arthritis. In less than 10% of patients with RA, arthritis may manifest as a chronic, sterile, inflammatory monoarthritis. Box 23.2 lists the differential diagnosis of RA. The other inflammatory disorders that should be distinguished from RA include psoriatic arthritis, microcrystalline disorders (e.g., gout and pseudogout), and polymyalgia rheumatica.

    Hallmarks of RA upon physical examination include the presence of erythema, warmth, and swelling of the involved joints. Chronic RA can lead to specific deformities in the hand, such as wrist fusion and the classic swan neck and boutonniere deformities that occur upon joint subluxation at the MCPs and PIPs. The symptoms of CTS can be reproduced by forced flexion of the wrist (Phalen’s sign) or by sharply percussing the volar wrist over the median nerve (Tinel’s sign). Focal posterior knee swelling, calf swelling, or a dependent ecchymosis in the ankle may be indicative of a Baker’s cyst (or rupture), which can occur in patients with RA and large knee effusions. Notably, patients may misinterpret their disability as muscle weakness rather than joint pain, which can confound the diagnostic workup. Hoarseness and odynophagia can indicate cricoarytenoid arthritis, which can cause laryngeal obstruction in patients following extubation. Tenosynovitis of the extraocular superior oblique muscle tendon can impair eye adduction during upward gaze, a condition known as Brown’s syndrome. The cervical spine may also be involved, with particular involvement to the C1-2 articulation. This may cause basilar invagination or C1-2 subluxation producing myelopathic symptoms in extreme cases. Cervical disc disease is also commonly manifested in patients with RA.

LABORATORY TESTING

No single laboratory test should be used to diagnose RA in the absence of clinical findings. Laboratory studies are used to support the diagnosis of RA in a patient with suggestive symptoms, to monitor RA disease activity, and to rule out other possible causes of arthritis.

    Serum rheumatoid factor (RF) testing is highly useful in the diagnostic workup of patients with polyarthritis, as approximately 80% of patients with RA have RF detectable in the serum (termed “seropositive”). The remaining 20% of RA patients never develop detectable RF levels (termed “seronegative”), so the absence of RF does not rule out the presence of RA. Routine RF analysis tests for IgM antibodies that have specificity directed against the constant (Fc) region of other antibodies. Many other medical conditions can cause an elevated RF (box 23.3), thereby limiting the test’s specificity.

Box 23.2 DIFFERENTIAL DIAGNOSIS OF RHEUMATOID ARTHRITIS

Box 23.3 CONDITIONS ASSOCIATED WITH AN ELEVATED SERUM RHEUMATOID FACTOR

    More recently, RA has been associated with the presence of anti-citrullinated peptide antibodies (ACPAs), a subset of which are the more commonly termed anti-cyclic citrullinated peptide (anti-CCP) antibodies. Like RF, these ACPAs are present in the serum of 70–80% of patients with RA. When present, the specificity of ACPAs in RA approaches 95%. Importantly, ACPAs are rarely found in the conditions listed in box 23.3; thus, a diagnosis of RA in a patient with ACPAs can be made with greater certainty. As with RF, 20–30% of patients with RA will never develop ACPAs, so the absence of these antibodies again does not rule out the presence of RA.

    It is unclear whether RF complexes or ACPAs play a directly pathogenic role in RA. Seropositive RA patients tend to have more aggressive disease and greater numbers of extra-articular manifestations than do seronegative patients. However, serum RF and ACPA levels do not correlate with disease activity and therefore cannot be used to monitor response to therapy. Instead, this is accomplished by measuring nonspecific markers of systemic inflammation, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Improvement in these markers suggests an overall decrease in RA disease activity. Additional nonspecific markers of inflammation include a peripheral blood leukocytosis, thrombocytosis, anemia of chronic disease, and other elevated acute-phase proteins (e.g., ferritin, haptoglobin, and complements).

    Arthrocentesis of synovial fluid is used to rule out other potential causes of arthritis such as septic arthritis or microcrystalline diseases (e.g., gout and pseudogout). Synovial fluid analysis is also the most important way to differentiate inflammatory disorders from noninflammatory disorders including mechanical disorders such as osteoarthritis. Rheumatoid synovial fluid is inflammatory, with white blood cell (WBC) counts typically ranging >1500–2000 WBC/mm³. One can feel assured that the effusion is not inflammatory if the cell count is <1500 WBC/mm³; infection should be considered if the cell count is >50,000 WBC/mm³. Neutrophils are often a dominant cell type in RA synovial fluid, but they rarely comprise >90% of WBCs. Although it is rarely done, synovial biopsy may be carried out to confirm inflammatory features or rule out atypical crystal disease, occult infection, or malignancy in clinically appropriate situations.

MUSCULOSKELETAL IMAGING

Similar to laboratory tests, imaging studies aid in the diagnostic workup of RA and can be used to monitor disease progression. Plain film radiographs have been the staple of imaging for decades, while other techniques have an ever-increasing role.

    The plain film radiographic changes of RA tend to follow a uniform sequence of events, with the pace of radiographic progression depending primarily on severity and duration of disease activity. The earliest radiographic findings are soft tissue swelling and periarticular osteopenia. These are followed by joint space narrowing and marginal erosions. Joint ankylosis (fusion) can occur after long-standing inflammatory damage. Interestingly, patients with seropositive RA are more likely to develop joint erosions than patients with seronegative disease. Effective DMARD therapy slows radiographic joint progression.

    Magnetic resonance imaging (MRI), computed tomography (CT) scan, ultrasound, and bone scan are all imaging techniques that can provide additional anatomic definition in patients with RA. MRI allows visualization of preradiographic erosions, bone marrow edema, soft tissue swelling, synovitis, and tenosynovitis with much greater sensitivity than plain film radiography. Gadolinium-containing contrast agents are often used to enhance MR quality. These can be given intravascularly or intra-articularly (MR arthrogram) for definition of intra-articular structures such as ligaments and menisci. CT scan is most useful in the assessment of bony structures, especially when MRI may be contraindicated. Musculoskeletal ultrasound with power Doppler has an emerging role in identifying bone erosions and synovitis. Bone scan is a fading technology that still has limited diagnostic utility in the patient with polyarthralgias but few objective findings of RA.

SPECIAL CONSIDERATIONS

RA involvement of the cervical spine deserves special mention because of its potentially devastating consequences if unrecognized. The articulation between C1 and C2 is a synovial joint and, thus, can be affected by synovitis. Patients need not have long-standing RA to have cervical spine disease. They may not complain of neck pain but may instead present with neurologic symptoms and signs to suggest a myelopathy. Paresthesias or weakness in a RA patient with brisk reflexes, clonus, positive Hoffman’s sign, or upgoing toes on Babinski’s maneuver should prompt an immediate assessment for cervical spine disease. Flexion and extension films of the cervical spine are the most useful and readily available initial imaging study. CT scan and MRI provide additional anatomic definition of the neck. Consultation with a spine surgeon is warranted for any patient with evidence of C1–C2 instability because fusion may be required to avoid damage to the spinal cord or brainstem.

    Although RA primarily afflicts the joints, extra-articular manifestations can occur. These processes can affect almost any organ or tissue in the body and are listed in table 23.2. Constitutional symptoms of fatigue and malaise occur commonly, whereas fever, anorexia, and weight loss are less frequently present. Pulmonary and hematologic complications deserve special mention. Pulmonary complications include pleural effusions whose hallmark is a strikingly low pleural fluid glucose. The effusion is often exudative, making the differentiation between RA and empyema of importance. The hematologic complications include anemia of chronic disease, thrombocytosis, and leukopenia associated with Felty syndrome or large granular lymphocyte (LGL) syndrome.

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