Diagnostic Criteria Rheumatoid Factor

This is a systemic autoimmune disorder of unknown etiology characterized by a chronic, symmetric, and erosive synovitis of peripheral joints. Characteristically, patients have elevated titers of serum rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP); however, the diagnosis may be made when RF is negative. The rheumatoid factor is not specific for RA and many other disorders are associated with a false-positive RF titer. Anti-CCP is a more specific test and may aid in diagnosis when fewer than three joints are involved. This disorder is usually progressive and the usual outcome is one of various degrees of destruction of the affected joints with associated deformity and disability. The progression of this disease also commonly involves nonarticular organ systems to be described below.

The diagnosis is probable when patients manifest swelling of three or more joints, a positive squeeze test, or morning stiffness that lasts greater than 30 minutes. Squeeze testing entails grasping the patients hand or foot across the distal metacarpals or metatarsals and applying pressure.  Tenderness with pressure is indicative of RA. This disease often affects the extremities in an asymmetric fashion and monoarthritis as the initial presentation is rare. The distal interphalangeal joints are not affected and their involvement indicates concomitant osteoarthritis.  As symptoms often begin in the small joints of the hands or feet, an increase in the space between the first and second toes (sandal sign) may be a presenting manifestation. As the disease progresses joint deformities develop and include MCP subluxations, swan-neck deformities, boutonniere deformities and ulnar deviation of the digits.

The CBC of patients with RA often reveals a normocytic anemia, thrombocytosis and examination of the WBC differential may reveal eosinophilia. Other laboratory abnormalities include hypergammaglobulinemia and hypocomplementemia. The above abnormalities are noted in patients with long standing disease and may not be present upon the initial presentation. The ESR and CRP are elevated indicative of the underlying inflammatory condition. 

Cutaneous involvement is signified by the development of subcutaneous rheumatoid nodules usually over pressure points such as the olecranon, patella, and sacrum. Nodules may also occur over the small joints of the hands, the ischial tuberosities, the Achilles tendons, and even the pulmonary parenchyma or dura. Biopsy of these nodules may aid in establishing the diagnosis, as these nodules have a characteristic histological appearance characterized by a central zone of necrotic connective tissue with surrounding palisading histiocytes, fibroblasts, and monocytes. There is an outer layer of granulation tissue which is constructed of lymphocytes, histiocytes and plasma cells. Although rheumatoid nodules are very distinct from other skin lesions, they may be difficult to distinguish histopathologically from granuloma annulare or gouty tophi.

The many potential pulmonary complications include pleural disease, pleural effusion, parenchymal nodules, interstitial lung disease, and pulmonary vasculitis. Clinically, pleural involvement is noted in 20% of cases; however, postmortem studies indicate that approximately 50% of patients are affected. Pleural fluid analysis often shows an exudate with a protein content from 3.7 to 5.5 g/dL, lymphocyte predominant cell counts ranging from 1000 to 3000 cells/mm3, low levels of glucose and complement, and elevated levels of pleural fluid RF often to levels much greater than serum values. Pulmonary nodules are similar to subcutaneous nodules on histologic examination, and these nodules do not undergo calcification. Pulmonary nodules range in size from a few millimeters to 7 centimeters and cavitation may occur. Caplan's syndrome refers to the triad of rheumatoid arthritis, nodular lung disease, and pneumoconiosis. Dyspnea, a nonproductive cough, pleurisy, fever, and clubbing may all be seen with interstitial lung disease. When interstitial disease is associated with rheumatoid arthritis, it is indistinguishable from idiopathic pulmonary fibrosis, is associated with a reticulonodular pattern on chest radiographs, and pulmonary function testing often reveals changes consistent with restrictive lung disease with a decreased diffusing capacity and resting hypoxemia.

Rheumatoid vasculitis involves mostly small arteries of various organ systems to include the cutaneous, nervous, gastrointestinal, and pulmonary systems. This complication is seen mostly in persons with long-standing, seropositive, nodular, erosive disease. Symptoms of vasculitic involvement depend on the end organs involved and include fever, weight loss, hepatosplenomegaly, purpura, ulcerations, gangrene, renal failure, or sensory and motor neuropathies. This is a potentially fatal complication and should be treated emergently.

The variable cardiovascular manifestations of RA include pericarditis, pericardial effusion, coronary arteritis, or rheumatoid granulomas of the pericardium, myocardium, or endocardium. Pericarditis is the most common complication occurring in 10% of patients. When pericardial fluid is present, analysis reveals a variable WBC, elevated protein content, low glucose, and low titers of RF. Corticosteroids may be inefficient in preventing life-threatening tamponade, which should be treated with emergency pericardiectomy. Premature coronary artery disease with resultant myocardial infarction is a common complication and patients should be screened and treated aggressively.

Neurologic complications include myelopathy secondary to subluxation of the cervical vertebrae, peripheral neuropathy, or dural nodules. Subluxation of cervical vertebrae most commonly occurs at C1-C2 but may occur throughout the cervical spine. Peripheral neuropathy may be a common complication of rheumatoid arthritis; however, a severe form of sensorimotor neuropathy may be indicative of RA associated vasculitis of the vasa nervorum. A vasculitic etiology is determined by biopsy of a pure sensory nerve (i.e., sural nerve), after delayed or absent nerve conduction has been displayed.

Pain should be controlled with NSAIDs, glucocorticoids, acetaminophen, or narcotic analgesics. Disease-modifying drugs (DMARDs) include hydroxychloroquine, sulfasalazine, methotrexate, leflunomide, tumor necrosis factor antagonists (etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab), abatacept, rituximab, tocilizumab, and anakinra. DMARDs should be started early in the disease course to limit progressive joint damage. Consultation with a rheumatologist is prudent as therapy may be adequate with a single agent in some patients and combination therapy may be required in others. Before initiation of DMARDs, assess the patients status for latent tuberculosis with PPD testing with or without a chest radiograph. Weight training and range of motion exercise programs should be undertaken by the patent to maintain joint health and function along with a weight maintenance program. Patients should be assessed as candidates for osteoporosis prophylaxis as RA is a risk factor especially in patients receiving long term corticosteroids. Smoking cessation is essential in patients addicted to tobacco products. RA patients are at increased risk for atherosclerosis secondary to the underlying inflammatory disease state and therefore should be screened and treated accordingly with regular blood pressure checks plus monitoring of glycemic and lipid status. Antiplatelet therapy should be instituted in appropriate cases.