Uzma J. Haque
Joan M. Bathon
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown cause that primarily targets the peripheral joints. The articular inflammation has a variable course, but the usual presentation is an additive, progressive, symmetrical polyarthritis that, if inadequately treated, will lead to joint destruction, deformity, and loss of function. Extra-articular features and systemic symptoms are recognized as an integral part of the disease and may antedate the onset of inflammatory arthropathy.
In the last 10 years, a confluence of discoveries from many areas of research has greatly affected our approach to the treatment of RA. Recognition that joint destruction and disability begin early, and that survival in RA is reduced, has led to a much more aggressive approach than in decades past. Advances in immunology and biotechnology have yielded more effective and better-tolerated agents. More than ever, it is imperative for clinicians to make the diagnosis rapidly, identify patients with poor prognosis, and institute an appropriate and effective therapeutic plan.
P.1255
Epidemiology
The prevalence of RA worldwide is approximately 1% to 2%. However, this figure differs significantly in some populations. For example, Native Americans have a high prevalence of 3.5% to 5.3%, and among rural South African blacks and Japanese the prevalence is only 0.1% (1). The prevalence of RA increases with age, approaching 5% in women older than 55 years. The average annual incidence in the United States is approximately 70 per 100,000 people (1). Both the incidence and the prevalence of RA are two to three times greater in women than in men. Although RA may manifest at any age, it most commonly affects individuals in the fourth to sixth decades.
Genetic influences on disease frequency and severity are suggested by an increased incidence of the human class II histocompatibility antigens human leukocyte antigen (HLA)-DR4 and HLA-DR1 in patients with RA, compared with a matched control population (2). The HLA-DR molecule consists of an α chain and a β chain, with the various HLA-DR specificities determined by heterogeneity at the three hypervariable regions of the HLA-DRβ chain. The molecular basis for the HLA association with RA is defined by a specific sequence of amino acids at positions 70–74 in the third hypervariable region of the DRβ chain. The presence of this shared structural element or “shared epitope” correlates with an increased risk for development of RA and/or greater disease severity (3).
Pathogenesis
The normal diarthrodial joint is surrounded by a thin connective tissue structure called the synovium. The synovium is the primary site of pathology in RA. Normal synovium is a thin, somewhat amorphous structure consisting of a lining layer one to three cells thick and a sublining layer that is hypocellular but vascularized. Synovial lining cells bear markers of fibroblast and macrophage lineage and secrete joint lubricants such as hyaluronic acid and lubricin. The vascularized sublining area provides nutrients to nearby avascular cartilage. The pathologic hallmark of RA consists of profound hypertrophy of the synovium via increased cellularity in both the lining and sublining areas into a tumorlike structure called the pannus. This hypertrophied structure, which consists of lymphocytes, plasma cells, macrophages, and fibroblasts, invades and erodes contiguous cartilage and bone via the elaboration of proinflammatory and degradative enzymes and cytokines (4). The event(s) or factor(s) that triggers the recruitment of inflammatory cells to the joint remains unknown. Local production of rheumatoid factor-containing immune complexes activates complement and attracts inflammatory cells. The predominance and persistence of CD4+ T cells in the rheumatoid synovium suggest an antigen-driven, cell-mediated inflammatory process. The inflammatory process is amplified by a number of macrophage- and fibroblast-derived cytokines found in large quantities in the rheumatoid joint, including tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor (5). These cytokines drive the recruitment of additional inflammatory cells and subsequent release of destructive enzymes. Enzymes such as collagenase and stromelysin destroy cartilage and bone, leading to loss of normal joint architecture.
History
RA usually is recognized by its articular manifestations. However, systemic symptoms such as weight loss, fever, and malaise may predate or accompany the onset of joint symptoms, and extraarticular manifestations may occur relatively early. Most commonly, RA presents insidiously over several months with a progressive, additive polyarthritis. Occasionally, patients experience an explosive polyarticular onset over 24 to 48 hours. A relatively uncommon presentation is termed palindromic rheumatoid arthritis in which a series of acute, self-limited attacks of inflammatory arthritis occur, usually in a single joint. Regardless of the initial presentation, the usual course is a relentless inflammatory polyarthritis involving small and large joints that is highly destructive and debilitating. The American College of Rheumatology criteria for the diagnosis of RA (6) are outlined in Table 77.1 and are discussed here.
Signs and symptoms of joint inflammation provide the definitive clues to the diagnosis of RA. One of the earliest symptoms is stiffness in the joints in the morning upon awakening. The stiffness usually lasts several hours and is accompanied by pain on movement. Patients often volunteer that they warm their hands in warm water or take prolonged showers in order to relieve the debilitating stiffness. Stiffness and pain in the balls of the feet (metatarsalgia) upon arising from bed is another common presenting symptom. Similar stiffness can occur after long periods of sitting or inactivity (gel phenomenon). In contrast, patients with degenerative arthritis complain of stiffness that lasts only 5 to 30 minutes (see Chapter 75). Unlike a patient with gout (see Chapter 76), a patient with RA can bear weight and move the inflamed joint but has a persistent, deep, gnawing discomfort. Severe pain in a patient with established RA, particularly if limited to one joint, should suggest a superimposed infection or an acute structural problem. The number of joints involved initially is highly variable, but almost always the process is eventually polyarticular, involving at least five joints. RA is an additive polyarthritis, with the sequential addition of involved joints, in contrast to the migratory or
P.1256
self-limited arthritis that can be seen in gout and rheumatic fever.
|
TABLE 77.1 1987 American College of Rheumatology Revised Criteria for Classification of Rheumatoid Arthritis |
||||||||||||||||||
|
||||||||||||||||||
The other hallmark symptom of RA is swelling of the joints as a result of inflammation. Swelling may be accompanied by warmth and mild erythema. Patients complain of inability to remove rings from their fingers and the need to purchase shoes of increased width and size to accommodate their swollen forefeet. The arthritis typically is symmetrical, involving the same distribution of joints on the right and left sides of the body. Most typically, the small joints of the hands and feet are affected first. The larger joints also become affected as the disease progresses. The joints involved most often are the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the hands, the wrists (particularly at the ulnar styloid articulation), shoulders, elbows, knees, ankles, and metatarsophalangeal (MTP) joints. The hips are involved in only approximately 20% of patients with RA. The distal interphalangeal (DIP) joints are nearly always spared, as is the axial skeleton except for the C1–2 articulation (discussed below).
Constitutional symptoms, such as fatigue, weight loss, low-grade fever (37°C –38°C), and malaise, are not uncommon as presenting symptoms and may even precede the arthritis by weeks to months. A higher fever, however, should suggest another illness such as an infection.
It is not unusual for articular symptoms of RA to wax and wane, especially at the beginning of the illness. Furthermore, because patients initially may present only with systemic symptoms and/or transient articular complaints that mimic other musculoskeletal conditions, the diagnosis may be delayed by several months. Atypical presentations include intermittent joint inflammation that can be confused with gout or pseudogout (see Chapter 76), proximal muscle pain and tenderness mimicking polymyalgia rheumatica, and diffuse musculoskeletal pain as seen in fibromyalgia (see Chapter 74).
During the time of diagnostic uncertainty, the physician can best serve the patient by providing reassurance, taking careful interval histories, performing periodic physical examinations (see Physical Examination), and, if appropriate, performing selected tests. Symptomatic treatment with anti-inflammatory drugs can be instituted during this period.
Physical Examination
Patients with suspected RA should undergo an initial complete physical examination and then a limited examination every 2 to 4 months. The physical examination is important not only to make the diagnosis but to establish a baseline against which to assess the response to treatment and acceleration of both articular and extra-articular disease. The primary focus of examinations in the physician's office is the joints. Serial joint examinations should be performed with careful records of the status of affected joints, as determined by history and previous examinations (Table 77.2).
Inflammation of the joints, manifested by swelling and sometimes warmth and mild erythema, is the signature physical finding of RA. Swelling is usually, but not always, symmetrical in distribution. The swelling is generally confined to the joint capsule, in contrast to gout, for example, in which a tremendous amount of subcutaneous edema is seen as well. In the hands, where the disease often is first manifested, typical fusiform swelling of the PIP joints is often observed (Fig. 77.1). The MCP joints, wrists, and MTP joints often become swollen as well, and involvement of
P.1257
these joints is more specific for an inflammatory arthropathy. Careful palpation of the joints is necessary to distinguish the swelling of joint inflammation from the bony enlargement seen in osteoarthritis. The elbows, knees, and ankles are other common sites of disease where swelling may be readily apparent. In contrast to gout (see Chapter 76) or septic arthritis, intense erythema of affected joints is not a prominent feature of RA.
|
TABLE 77.2 Components To Be Assessed at Each Clinic Visit |
|
|
|
|
FIGURE 77.1. Hand deformities in rheumatoid arthritis. A: Typical fusiform swelling of the proximal interphalangeal (PIP) joints. Note synovial swelling of the wrist and metacarpophalangeal joints. B: Ulnar deviation of the fingers. C: Swan-neck deformity (hyperextension of the PIP joint). D: Boutonnière deformity (flexion contracture of the PIP joint and hyperextension of the distal interphalangeal joint). |
Pain on palpation and with passive motion of the joints, although not specific for RA, is another indicator of joint inflammation. When examining a joint, it is important to apply gentle but firm pressure at the joint line so that tenderness caused by inflammation is elicited. Inflamed joints usually are warmer than normal joints.
The range of motion of each joint should be examined. Range of motion may be limited by excessive swelling, structural deformity, or both. Swelling is reversible with treatment, but joint deformities are not and may require surgical intervention; therefore, determining which process(es) is operative in any joint with limited motion is critical. Permanent deformity of the joint is a consequence of the inflammatory process and may occur in the intra-articular structures (bone and cartilage) or in the periarticular structures (ligaments and tendons). Severe loss of cartilage will limit the ability of the joint to move through its normal range of motion. This is observed clinically as loss of extension of the wrists or as contractures of the elbows and knees. Persistent inflammation of tendon sheaths, on the other hand, may lead to attrition and, ultimately, to rupture of the involved tendon. A common example is rupture of the extensor tendons of the fourth and fifth fingers, resulting in a “drooping” or inability to extend these digits. Invasion of inflamed synovium into articular bone will cause erosion of bone and loss of integrity of the articulating surface, resulting in malalignment, subluxation or frank dislocation of the joints. Physical findings typically seen in the joint examination of the upper extremities of patients with RA (Fig. 77.1) include ulnar deviation
P.1258
of the fingers at the MCP joints, hyperextension (swan-neck deformity) or hyperflexion (boutonnière deformity) of the PIP joints, flexion contractures of the elbows, and loss of extension of the wrists. In the lower extremities, dorsal subluxation of the toes (“cock-up” toes) and hallux valgus (“bunion”) are common and lead to painful plantar callosities. Rupture of the posterior tibial tendons at the ankle will lead to severe heel valgus (“flat foot” appearance) and lateral ankle pain.
Swelling of a joint or tendon may be visible as a discrete synovial cyst (rather than with diffuse swelling). Synovial cysts of the popliteal space (“Baker cysts”) are common in patients with RA (Fig. 77.2) (see Chapter 74).
|
FIGURE 77.2. Baker cyst. A: Swelling of the calf secondary to dissection of the Bakers cyst. B: Arthrogram of the knee demonstrating the cyst. |
Muscle atrophy is commonly observed in the hands of patients with advanced RA and is likely to occur in larger muscle groups as well. Although originally thought to be due to atrophy from disuse, it now is recognized to be a consequence of the effect of overproduction of inflammatory cytokines such as TNF-α (7). Assessment of muscle weakness in patients with RA is difficult, however, in the face of active joint inflammation. Muscle weakness due to inflammation of muscle (polymyositis) is uncommon in RA. Weakness in an extremity may result from muscle atrophy because of severe joint deformity and disuse; for example, atrophy of the quadriceps is frequently seen in patients with painful limited motion of the hip or knee. Neurologic impairment from subluxation at the first and second cervical vertebrae may lead to extremity weakness. Finally, the fatigue produced by the illness may contribute to an overall sense of weakness.
Laboratory Tests
Baseline diagnostic laboratory information in patients with suspected RA should include a complete blood count (CBC) and differential, a comprehensive chemistry panel, erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP), urinalysis, rheumatoid factor titer and/or anti-cyclic citrullinated peptide (anti-CCP). In selected patients, synovial fluid analysis, additional serologic studies, and appropriate radiographs also are important (as discussed below).
Hematology
Mild anemia, with hematocrit values ranging from 30% to 34%, occurs in approximately 25% to 35% of patients
P.1259
with RA (8). In most cases, the reduced red cell mass is caused by the anemia of chronic disease, a normocytic, normochromic process characterized by a low serum iron concentration, low serum iron-binding capacity, a normal or increased serum ferritin concentration, abnormal retention of iron by reticuloendothelial cells, and depressed erythropoietin concentrations (9). However, true iron-deficiency anemia occasionally develops secondary to gastrointestinal (GI) blood loss. The inflammation of RA inhibits erythropoiesis, making it difficult to differentiate anemia secondary to chronic blood loss from the anemia of chronic disease without an iron stain of the bone marrow. Nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk of GI bleeding from peptic ulcer disease and gastritis, particularly in the elderly. It is especially important to monitor for GI blood loss in patients older than 70 years, although other causes of blood loss, such as colon cancer, may be operative in this age group (see Chapter 42). The leukocyte count and platelet count usually are normal in patients with RA, but both counts can be mildly elevated secondary to inflammation. Drug reactions and Felty syndrome are rare causes of leukopenia or thrombocytopenia (see later discussion).
ESR and CRP usually are elevated in patients with RA prior to treatment and decrease and/or normalize in response to treatment. Therefore, they can be used as barometers of disease activity. Because measurement of ESR is accurate only if the blood sample is examined within the first hour or two after phlebotomy, CRP is generally favored as the inflammatory marker.
Chemistry
Serum electrolyte levels and liver and renal function tests usually are normal in RA. Nonetheless, it is important to examine baseline liver and renal function because underlying liver disease and/or renal insufficiency significantly impact on the choice of disease-modifying agents that can be used. For example, methotrexate and leflunomide cannot be used in a patient with active hepatitis B or C, and NSAIDs must be avoided in patients with renal insufficiency (discussed in greater detail under Management). In some patients, the serum albumin concentration is modestly depressed and the total protein mildly elevated (yielding a “protein gap”), as a result of IL-6–mediated effects on hepatocytes and B cells.
Serology
Autoantibodies
The two most common antibodies in RA are “rheumatoid factor” and antibodies against cyclic citrullinated peptides (anti-CCP). Rheumatoid factors are antibodies directed against the Fc portion of immunoglobulin (Ig) G. Although these antibodies may be of any subclass (IgG, IgM, IgA), IgM rheumatoid factor is the most common and commercial assay, therefore, test only for IgM. A positive test for rheumatoid factor (>40 IU/mL) by enzyme-linked immunosorbent assay (ELISA) or by latex fixation method (>1:80) is by no means pathognomonic of RA, but it is present in 70% to 90% of patients with the disease (10). However, in early disease, the rheumatoid factor may be negative in up to 25% of patients (11). The titer does not correlate with the activity of disease, but patients with a high-titer rheumatoid factor are more likely to have erosive joint disease, nodules, extra-articular manifestations, and greater functional disability over time.
Rheumatoid factors are also detectable in the serum of many patients without RA. Most of these patients have sustained chronic antigenic stimulation, such as prolonged infection (bacterial endocarditis, tuberculosis, cytomegalovirus, human immunodeficiency virus, viral hepatitis), collagen vascular disease, chronic lung disease (pulmonary fibrosis, sarcoidosis, asthma), or dysproteinemia (myeloma, macroglobulinemia, mixed cryoglobulinemia). Positive rheumatoid factors may occur transiently in normal individuals without RA after vaccination or after a self-limited viral infection. Finally, low titers of rheumatoid factors may be detected in the serum of apparently normal people, especially those older than 70 years, in whom the prevalence ranges from 10% to 25% (12).
Antibodies against citrullinated proteins have been described in patients with RA and are highly specific (>95%) for diagnosis of RA (13). Citrullination is a postsynthetic modification of arginine residues, catalyzed by the enzyme peptidyl deiminase, which can cause unfolding of proteins and thereby unmask antigenic neoepitopes. Some substrate proteins that elicit autoantibody responses in their citrullinated, but not native, state include fibrin, fibrinogen, keratin, filaggrin, and vimentin (14,15). Anti-CCP antibodies are present in >80% of patients with RA, compared to 70% to 90% positivity with rheumatoid factor (16). Some patients may be positive for either anti-CCP or rheumatoid factor antibodies as early as 8 years prior to the onset of symptoms (17). This finding suggests that the initial insult triggering the disease probably occurs years before the onset of clinically recognizable signs and symptoms. When considering the diagnosis of RA, both rheumatoid factor and anti-CCP antibodies should be obtained because one may be positive and not the other. A small percent of patients with RA will remain negative for either antibody throughout the course of their disease (“seronegative rheumatoid arthritis”).
Antinuclear antibodies (ANAs), measured by immunofluorescence techniques, are present in approximately 20% to 30% of patients with RA (18). ANAs are more common in patients with extra-articular manifestations of disease and in patients with a high titer of rheumatoid factor. In
P.1260
comparison with systemic lupus erythematosus (SLE), the titer of ANAs is lower in patients with RA, and antibodies to native deoxyribonucleic acid (DNA) or other specific nuclear antigens are uncommon. The ANA test usually is unnecessary in a patient with typical RA unless the diagnosis is in doubt or other systemic symptoms are noted.
Serum hemolytic complement (CH50) and complement components C3 or C4 usually are normal or increased in patients with RA. Complement levels may be low in some patients with severe disease or systemic vasculitis. The test is most useful in helping distinguish early RA from immune complex-mediated diseases (e.g., SLE), in which serum complement components often are markedly decreased.
Synovial Fluid
Synovial fluid should be analyzed (Table 74.2) in a patient with monoarthritis or with polyarthritis and fever, or in any patient with a joint effusion in whom the diagnosis is in doubt. Patients with known RA who develop disproportionate pain and swelling of one joint should have fluid aspirated from that joint to rule out infection. If the physician is unfamiliar or uncomfortable with arthrocentesis (see Chapter 74), the patient should be referred to a rheumatologist or orthopedic surgeon.
The rheumatoid joint has increased susceptibility to infection (19). Streptococcal or staphylococcal organisms are the most common pathogens. When a single joint flares or a flare is accompanied by fever or follows a recent invasive procedure, arthrocentesis with synovial fluid examination and culture are essential to rule out infection.
Recommended studies on fluid aspirated from the joint include cell count and differential, Gram stain, culture, and crystal examination. Joint fluid should be added immediately to a tube containing ethylenediamine tetra-acetic acid (EDTA, purple top) or heparin to prevent clotting and cell lysis. If the quantity of fluid is limited, priority is given first to culture, then to Gram stain, and finally to crystal examination. The total leukocyte count and the neutrophil count vary considerably in the synovial fluid of rheumatoid joints, but in general the total count in an inflamed joint is >2,000 cells/mm3 and consists predominantly of neutrophils. Occasionally, the leukocyte count is >75,000 cells/mm3, but values in this range should raise concern about infection. Other analyses, such as protein, glucose, enzymes, complement, immune complexes, rheumatoid factor, ANA, viscosity, turbidity, and mucin clot, are not recommended because they are neither specific nor sensitive.
Synovial biopsy is rarely necessary for the diagnosis or management of RA; therefore, it is rarely performed except for research purposes or to rule out infection.
Radiology
Structural damage to the bone and cartilage components of rheumatoid joints can be recognized radiographically as erosions and joint space narrowing, respectively. These radiographic changes, once believed to be a late manifestation, now are recognized to begin early in disease (20). Erosions on baseline radiographs are also a prognostic indicator of more severe disease (21). Radiographs of the hands and feet are recommended at presentation to evaluate the extent of disease and to serve as a baseline against which subsequent films can be compared. Structural joint damage tends to progress in an unrelenting fashion in RA unless an effective disease-modifying treatment is initiated. Followup radiographs of the hands and feet can be obtained 12 to 24 months after initiating a therapy to ensure that no additional radiographically evident joint damage has occurred (Fig. 77.3). Clinical trials in RA have shown that radiographic progression may occur even in the face of clinically well-controlled disease. However, the converse also is true: radiographic damage can be stabilized even when clinical features of disease remain active (22). The primary care physician should seek the counsel of the rheumatology consultant when using serial radiographs to guide therapeutic decisions.
|
FIGURE 77.3. Radiographic changes in rheumatoid arthritis. A: Joint space narrowing in the second and third metacarpophalangeal (MCP) joints. B: Cystic changes, erosions, and further bony proliferation in the second and third MCP joints. C: Periarticular osteoporosis, most noticeable in the interphalangeal joints, and numerous marginal erosions and cysts in the carpal bones and metacarpal heads. D: Juxta-articular erosions in a proximal interphalangeal joint. |
In end-stage disease, bony proliferation may occur because of degenerative changes that follow inflammation. Thus, RA and other inflammatory arthritides are causes of “secondary” osteoarthritis (see Chapter 75).
RA-related structural changes, such as synovitis and erosion of bone and cartilage, can be visualized earlier by magnetic resonance imaging (MRI) and ultrasound than by plain radiograph (23,24). These techniques can be used in patients with confusing clinical presentations to determine whether or not an inflammatory process is present. MRI also is useful to investigate internal joint derangement or injury to a supporting structure, such as a torn rotator cuff of the shoulder or meniscal tear of the knee. MRI has largely replaced arthrography for the diagnosis of these problems. Computed tomography (CT) or MRI is important in the evaluation of cord compression secondary to atlantoaxial (C1/C2) subluxation.
Extra-Articular Disease
Although the joints almost always are the principal organ affected by RA, other organ systems also may be involved (25). Extra-articular manifestations of RA (Table 77.3) occur most often in seropositive patients with more severe joint disease. Extra-articular manifestations can occur in later stages of the disease, when there is little active synovitis (“burnt-out” disease). Extra-articular manifestations of RA appear to be linked with excess mortality in RA (26). Although there may be a trend toward a decline in
P.1261
P.1262
organ-specific extra-articular disease, the overall incidence of any extra-articular manifestation continues to be high (26). With an emphasis on aggressive management with combination therapy and the introduction of the TNF inhibitors (see Management), this frequency may be reduced over time.
|
TABLE 77.3 Systemic Manifestations of Rheumatoid Arthritis |
|
|
Rheumatoid Nodules
The subcutaneous nodule is the most frequent extra-articular lesion in patients with RA (Fig. 77.4), occurring in 20% to 30% of cases and almost exclusively in seropositive patients. They vary in size from a few millimeters to several centimeters and either are fixed to surrounding tissue or are freely movable beneath the skin. They are located most commonly on the extensor surfaces of the elbows, in the region of the Achilles tendon, and on the fingers. Rheumatoid nodules also may arise within tendons or ligaments and can lead to dysfunction or rupture. Rarely, nodules arise in visceral organs such as lungs, heart, or sclera of the eye. Nodules may regress spontaneously. The course of nodule formation and regression does not seem to parallel that of joint inflammation. Although the nodules usually are asymptomatic, they can be painful and may ulcerate, requiring surgical excision. They frequently recur at sites of resection. Methotrexate has been associated with a higher occurrence of rheumatoid nodules (27).
|
FIGURE 77.4. Rheumatoid nodules along the extensor surface of the forearm. |
Pleuropulmonary Disease
The pulmonary manifestations of RA include pleurisy with or without effusion, pleural and parenchymal nodules, rheumatoid pneumoconiosis (Caplan syndrome), diffuse
P.1263
interstitial fibrosis, and, rarely, bronchiolitis obliterans, pneumothorax, or pulmonary arteritis (28). Common findings on pulmonary function testing are a restrictive ventilatory defect with reduced lung volumes and a decreased diffusing capacity for carbon monoxide. Obstructive airways disease (in the absence of a significant smoking history) is described in patients with RA. Extrathoracic upper airway obstruction may occur secondary to involvement of the cricoarytenoid joints of the larynx.
Pulmonary involvement may precede by months the onset of arthritis. Pleurisy, the most common problem, is clinically apparent in 5% of patients, but pleural thickening and inflammation are found in 50% of autopsy cases. Pleural effusions, either unilateral or bilateral, usually are exudates. Even in transudates the glucose concentration of the fluid usually is low (<30 mg/100 mL), a finding otherwise seen only in pleural space infections. The first approach to the management of a pleural effusion includes a diagnostic aspiration and pleural biopsy to exclude infection and malignancy.
Rheumatoid nodules in the lung usually are asymptomatic, but cavitation simulating cancer or infection may occur. Therefore, appropriate diagnostic steps should be taken to ensure that pleural or pulmonary nodules in a patient with RA are not malignant. Interstitial pneumonitis or fibrosing mononuclear alveolitis precedes progressive pulmonary fibrosis, the most severe form of rheumatoid lung disease. Fine dry crackles are heard on auscultation of the lung, and reticulonodular infiltrates are seen on chest radiographs.
Case reports have reported success in treating rheumatoid lung with glucocorticoids and a variety of immunosuppressive regimens, including methotrexate, cyclosporin, cyclophosphamide, and azathioprine. However, no information from controlled clinical trials is available. Patients with symptomatic pleural or pulmonary manifestations of RA should be monitored in consultation with a rheumatologist and a pulmonologist.
Cardiac Disease
Pericarditis is the most common cardiac manifestation of RA (29). In older series, echocardiographic studies demonstrate pericardial effusion in 55% of patients with subcutaneous nodules and 15% of patients without nodules. Patients with symptomatic pericarditis usually present with fever, chest pain, and a pericardial rub that resolve spontaneously. Recurrent or persistent pericardial disease, complicated by tamponade or constriction, is rare. Other unusual cardiac manifestations include nonspecific valvulitis, nodule formation in a valve cusp, myocarditis, and conduction abnormalities secondary to nodule formation in the heart. The treatment of patients with symptomatic cardiac disease is best done in consultation with a rheumatologist and a cardiologist.
Patients with RA now are recognized to have a shorter lifespan than age- and gender-matched controls (30,31). The majority of this increased risk for early mortality results from cardiovascular disease (myocardial infarctions, strokes, and congestive heart failure) (32). Rheumatoid inflammation may initiate or aggravate atherosclerotic lesions and probably constitutes a lifetime independent risk factor (above and beyond conventional cardiovascular risk factors) for the accelerated progression of cardiovascular disease (33). Aggressive control of rheumatoid synovitis and management of conventional cardiovascular risk factors hopefully will reduce cardiovascular morbidity and mortality in patients with RA.
Ocular Disease
Keratoconjunctivitis of Sjögren syndrome is the most common ocular manifestation of RA (see Sjogren Syndrome and Chapter 109). Symptoms include a sensation of dryness and grittiness and can be relieved by artificial tears. Episcleritis occurs occasionally and is manifested by mild pain and intense redness of the affected eye. Ordinarily, episcleritis is a self-limited process of a few weeks’ duration. Scleritis and corneal ulcerations are rarer but more serious problems. Unlike episcleritis, scleritis is a slowly progressive, often bilateral process that may lead to perforation and loss of vision. It is characterized by nodularity, intense redness, and often severe pain. The distinction between episcleritis and scleritis is difficult (see Chapter 109), and all patients with a red, painful eye should be referred to an ophthalmologist.
Neurologic Disease
The most common neurologic manifestation of RA is a mild, primarily sensory peripheral neuropathy that usually is more marked in the lower extremities. Entrapment neuropathies (e.g., carpal tunnel syndrome, tarsal tunnel syndrome) sometimes occur in patients with RA because of compression of a peripheral nerve by inflamed, swollen tissue (see Chapter 92). Cervical myelopathy secondary to atlantoaxial subluxation is an uncommon but particularly worrisome complication potentially causing permanent, even fatal neurologic damage. Approximately 30% of patients with RA in a referral practice had atlantoaxial subluxation without symptoms, but few of them developed neurologic dysfunction (see Ruddy et al., at http://www.hopkinsbayview.org/PAMreferences). Imaging of the cervical spine (e.g., MRI) should be performed if neurologic signs and symptoms are present, and neurosurgical consultation should be pursued. A patient with RA who may have sustained cervical injury or is at risk for a neck manipulation (e.g., during general anesthesia) should have flexion/extension cervical spine radiographs so that
P.1264
special caution can be exercised if subluxation, even without symptoms, is present.
Felty Syndrome
Felty syndrome is characterized by RA, splenomegaly, and leukopenia, predominantly granulocytopenia (34). Patients with this syndrome usually are older, and they have high titers of rheumatoid factor and ANA, severe arthritis, and other extra-articular manifestations of the disease. Recurrent bacterial infections and chronic refractory leg ulcers are the major complications. Patients with suspected Felty syndrome should see a rheumatologist urgently because therapy is difficult.
Rheumatoid Vasculitis
Evidence of vasculitis is found in 10% to 25% of autopsy patients with RA. The most common clinical manifestations of vasculitis are small digital infarcts along the nail beds. A syndrome of accelerated vasculitis is seen in fewer than 1% of patients. It is characterized by distal cutaneous ulcerations, gangrene, peripheral polyneuropathy, and visceral (intestinal, renal, cardiac, cerebral) ischemia. The abrupt onset of an ischemic mononeuropathy (mononeuritis multiplex) or progressive scleritis is typical of rheumatoid vasculitis. The syndrome ordinarily emerges after years of seropositive, persistently active RA; however, vasculitis may occur when joints are inactive. Immediate consultation with a rheumatologist and immunosuppressive therapy usually are indicated.
Sjögren Syndrome
Approximately 10% to 15% of patients with RA, mostly women, develop Sjögren syndrome, a chronic inflammatory disorder characterized by lymphocytic infiltration of lacrimal and salivary glands. This leads to impaired secretion of saliva and tears and results in the sicca complex:dry mouth (xerostomia) and dry eyes (keratoconjunctivitis sicca). Patients should use lubricating eye drops. They also should be monitored by an ophthalmologist to prevent corneal ulcerations and monitored closely by a dentist to prevent dental caries. Artificial saliva preparations are available, but patients often dislike them because of their taste. Oral pilocarpine derivatives (pilocarpine HCl [Salagen] and cevimeline [Evoxac]) are available for treatment of xerostomia but carry the troublesome side effects of hyperhidrosis and diarrhea.
Other exocrine glands can be affected, manifested clinically as dry skin, decreased perspiration, dry vaginal membranes, or a nonproductive cough. Commonly, a polyclonal lymphoproliferative reaction, characterized by lymphadenopathy and occasionally splenomegaly, is seen. This can mimic and, rarely, transform into a malignant lymphoma. Sjögren syndrome may be associated with a number of other systemic manifestations, including vasculitis, peripheral neuropathy, and thyroiditis.
Course
The course of RA, like that of most chronic diseases, cannot be predicted in any individual patient. Several patterns of activity have been described: spontaneous remission, particularly in the seronegative patient; recurrent explosive attacks followed by periods of quiescence, most commonly in the early phases; and the usual pattern of persistent and progressive disease activity that waxes and wanes in intensity.
A self-limited course with spontaneous remission is rare in RA, especially after 6 months of active disease. If long-term remission occurs without disease-modifying antirheumatic drug (DMARD) therapy, the diagnosis should be called into question. Some patients early in the course of the disease, however, will have a course characterized by remissions and exacerbations, each lasting several months. This usually transitions into the typical picture of RA, manifested as sustained joint pain and swelling. Occasionally patients with newly diagnosed RA have severe rapidly progressive disease that leads to early joint destruction and disability. Risk factors for more aggressive disease include high titers of rheumatoid factor and/or anti-CCP antibodies, the presence of radiographic erosions, and markedly elevated inflammatory markers (ESR and/or CRP) at presentation, as well as the presence of the “shared epitope” (35). Patients with one or more of these risk factors should be treated aggressively (see Management) and monitored carefully for signs of advancing joint damage. RA in women may go into remission during pregnancy, but disease activity usually increases again several weeks after childbirth.
Significant morbidity from RA has long been recognized. Approximately 60% of patients with RA were unable to work 10 years after the onset of their disease (36). Only recently, however, have studies demonstrated an increased mortality rate in rheumatoid patients. Median life expectancy was shortened by an average of 7 years for men and 3 years for women, compared with control populations; in >5,000 patients with RA from four centers, the mortality rate was two times greater than in the control population (32). Patients at higher risk for shortened survival are those with systemic extra-articular involvement, low functional capacity, low socioeconomic status, low education, and long-term prednisone use. The role of cardiovascular disease in the observed increase in mortality rate in patients with RA was discussed earlier.
|
TABLE 77.4 Outline of a Diagnostic Approach to Polyarthritis |
|
|
P.1265
Differential Diagnosis
The difficulty of diagnosing early RA emphasizes the importance of a systematic approach to patients with arthritis (Table 77.4). The patient's age, sex, ethnic background, and family history influence the likelihood of disease. Therefore, a clear definition of host features forms a framework to begin the evaluation of the patient with arthritis. Table 77.5 outlines examples of the differential diagnosis of polyarthritis based on age and sex. The characteristics of the arthritis itself provide important clues to the differential diagnosis (Tables 77.6 and 77.7).
|
TABLE 77.5 Differential Diagnosis of Polyarthritis Based on Age and Sex |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Management
Overview
RA is a chronic, inflammatory arthritis that can cause joint destruction, significant disability, and increased mortality if adequate treatment is not initiated early and is not appropriately managed throughout the course of the disease (37). Past treatment was based on a pyramid approach beginning with “less potent” NSAIDs, reserving disease-modifying agents only for patients with joint destruction and disability. Thus, institution of appropriate therapeutic intervention often was significantly delayed. We now recognize that articular damage begins early and may progress more rapidly early in the course of the disease (20). Radiologic evidence of bone erosions is apparent in approximately 75% of patients during first 2 years of disease by radiographs (20) and within months if MRI techniques are applied (38).
Several studies have shown that early initiation of treatment leads to less joint damage in long-term followup (39,40). In a comparison study of early versus delayed
P.1266
therapy in patients with RA, less radiographic damage was noted in the early treatment group after 2 years of followup (40). These and similar data suggest that there is a “window of opportunity” during which therapeutic intervention may have greatest impact on disease progression and may potentially “switch” off the disease process if initiated in the first few weeks or months of disease. Thus, in the last 2 decades, there has been a critical shift from the “wait-and-see” paradigm of treatment toward early aggressive intervention to control inflammation and to possibly modify future disease course.
|
TABLE 77.6 Assessment of Joint Involvement |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
TABLE 77.7 Diagnostic Clues Provided by Arthritis of Specific Joints |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
The recognition in the 1990s of the safety and efficacy of methotrexate has led to widespread acceptance of this drug as the “first-line” treatment of RA and as the “gold standard” against which new therapies are compared. Moreover, combination of methotrexate with other DMARDs has been demonstrated to provide cumulative benefit without incurring any unexpected synergistic toxicities (41, 42, 43). Thus, one or more DMARDs, conventional or biologic, can be added to methotrexate in a “step-up” approach if treatment with methotrexate alone does not achieve adequate control of disease activity. This “step-up” approach is the most commonly used treatment strategy in clinical practice and in clinical trials of RA to date. An alternate approach that has been used primarily in clinical trials, and is also highly effective, is an “induction” approach. In this strategy, multiple DMARDs are started simultaneously and then “stepped down” over 6 months to a single DMARD (43,44). Fortunately, the traditional approach of sequential monotherapy, in which one DMARD is replaced with another until an effective treatment is found, has been abandoned in favor of step-up and induction approaches.
P.1267
The advent of biologic agents that block the effects of TNF-α and IL-1 has been a major breakthrough in the treatment of RA and other selected inflammatory disorders. These biologic agents have been shown to be effective in reducing disease activity and improving radiologic outcomes in patients with RA, when used alone or in combination with methotrexate (45, 46, 47). Thus, the availability of these new agents, combined with the conceptual advances of early, aggressive treatment and combination therapy, have revolutionized the treatment of RA in the last 10 years.
General Principles
When the diagnosis of inflammatory arthritis is in question, rapid referral of the patient to a rheumatologist is recommended. Delay in therapy can lead to irreversible joint damage and disability. Thus, every effort should be made to prevent delay by referral and access to specialist care. Once the diagnosis is established, the primary goals of treatment of RA are to reduce pain, enhance function and quality of life, and reduce long-term damage to the joints. This is achieved by aggressively suppressing synovitis with pharmacologic therapies and by providing physical and occupational therapy and psychological support to the patient. Treatment usually commences with an NSAID and a DMARD. In cases of very aggressive synovitis and/or disabling systemic symptoms, low-dose prednisone is added. The rapid onset of action of the NSAID and corticosteroid provides some immediate relief while allowing the slower-acting DMARD to exert its effects. Commonly prescribed DMARDs include hydroxychloroquine, sulfasalazine, methotrexate, leflunomide, and TNF inhibitors (etanercept, infliximab, and adalimumab). Older agents, such as gold, penicillamine, and azathioprine, and the newer biologic anakinra (Kineret) are much less commonly prescribed because of their lower rates of efficacy and/or higher rates of toxicity compared to the more commonly prescribed agents.
The choice of the initial DMARD depends to some extent on the cost of the drugs, side-effect profile, comorbidities of the patient, and preferences of the patient and physician. As noted above, however, methotrexate is generally recommended as the initial treatment given its high benefit–risk ratio (48,49). The Early Rheumatoid Arthritis (ERA) trial introduced a dosing schedule for methotrexate that now is widely accepted. The schedule consists of rapid-dose increase over 8 weeks, from 10 mg/week to 20 to 25 mg/week or to maximal tolerated dose (50). If disease activity is not well controlled by 3 to 4 months (allowing for the slow onset of action of methotrexate), a second DMARD should be added. The addition of sulfasalazine and/or hydroxychloroquine to methotrexate is effective and well tolerated. The combination of all three agents, commonly known as “triple therapy,” is generally well tolerated (41) but does involve a complicated dosing schedule that may decrease patient adherence over time. Alternatively, an anti-TNF agent may be added to methotrexate, and this combination probably is the most common approach among rheumatologists for patients in whom methotrexate monotherapy is insufficient. The combination of a TNF inhibitor with methotrexate has been demonstrated to be superior to methotrexate monotherapy, for both clinical and radiographic outcomes, for all three available anti-TNF agents (47,51,52). Anakinra, an IL-1 inhibitor, also reduces clinical symptoms and retards radiographic progression when added to methotrexate in patients with RA, but it is a considerably weaker agent than the TNF inhibitors (53). Addition of leflunomide to methotrexate monotherapy is another acceptable combination approach that results in improved clinical outcomes compared to methotrexate alone and is generally well tolerated (54). However, radiographic outcomes comparing this combination to methotrexate alone have not been examined.
Inhibitors of TNF are generally not used as first-line therapy for RA because of their expense and limited data regarding long-term safety. However, first-line treatment with an anti-TNF agent or sulfasalazine is the preferred therapy in certain patients, such as those with chronic liver disease, renal insufficiency, or sulfa allergy, and patients anticipating a pregnancy.
In patients with a mild disease phenotype, seronegativity, and absence of poor prognostic factors, a weaker DMARD such as hydroxychloroquine or minocycline may be sufficient as first-line therapy. However, the disease-modifying potential of these drugs (i.e., to slow or halt joint damage) has not been rigorously proven. Therefore, careful monitoring to evaluate the need to “step-up” the therapy is important.
Despite these significant advances in therapeutics, individual response to treatment is variable, requiring “trial and error” strategy and frequent reassessment of adequacy of response. Even with an aggressive combination approach, therapeutic response may decline over a period of time, making long-term management of this chronic disease a challenge to physicians. Future research in the field of pharmacogenomics may enhance our ability to predict the probability of response to DMARDs and “tailor” treatment to each individual patient.
In addition to aggressive pharmacologic control of synovitis, other important goals of treatment include preservation of joint function, management of pain and disability associated with chronic deformities, and improvement of overall quality of life. To achieve these goals, it is essential that the patient and the patient's family be educated about the nature and course of the disease, the specific causes of the pain, and the goals, problems, and expectations of treatment.
Reduction of joint stress is a critical part of protection of inflamed joints and is accomplished by a number of
P.1268
practical measures that do not depend on the use of drugs. Because obesity stresses the musculoskeletal system, ideal body weight should be achieved and maintained. When the joints are actively inflamed, vigorous activity (heavy work, brisk exercise) should be avoided because of the danger of intensifying joint inflammation or causing traumatic injury to structures weakened by inflammation. On the other hand, patients should be urged to maintain a modest level of activity to prevent joint laxity and muscular atrophy. Splinting of acutely inflamed joints, particularly at night, and the use of walking aids (canes, walkers) are all effective means of reducing stress on specific joints. Specially designed furniture and household utensils can help not only to relieve stress on joints but also to maintain independent function. Such aids are provided on recommendation of the consultant rheumatologist, orthopedist, physiatrist, physical therapist, or occupational therapist and are obtained from an orthotics appliance store.
A consultation with a physical therapist and an occupational therapist is recommended early in the course of treating a patient with RA. These therapists can effectively design a program of balanced rest and activity that is appropriate for the stage of disease. Passive exercise (moving the joints through a full range of motion) is used when inflammation is active and poorly controlled. An active exercise program, when tolerated, can be designed to prevent contractures and muscular atrophy. The application of local heat, the use of various supporting aids, education on joint protection, and maintenance of good joint function are all part of the therapist's role. The occupational therapies will also assess the patient's need for devices to aid in the performance of activities of daily living, such as buttoning blouses and removing lids from jars.
Specific Pharmacologic Agents
Nonsteroidal Anti-inflammatory Drugs
In the presence of acute or chronic inflammation, it is appropriate to prescribe NSAIDs in patients with RA. The major effect of these agents is to reduce acute inflammation, thereby decreasing pain and improving function. However, NSAIDs are not disease modifying and hence have no role as monotherapy in treatment of RA. They usually are used in conjunction with other DMARDs to reduce pain. All of these drugs have mild to moderate analgesic properties independent of their anti-inflammatory effect.
Aspirin is the oldest drug of the nonsteroidal class. However, because of its higher rate of GI toxicity, the narrow window between toxic and anti-inflammatory serum levels, and the inconvenience of multiple daily doses, aspirin has largely been replaced by NSAIDs. Nonacetylated salicylates (Disalcid, Trilisate) are less potent anti-inflammatory agents but have the advantage of less GI toxicity, lack of inhibition of platelet aggregation, and decreased incidence of NSAID-induced angioedema reactions.
NSAIDs inhibit prostaglandin synthesis by blocking cyclooxygenase enzymes. Prostaglandins are important mediators of pain and inflammation. The two isoforms of cyclooxygenase are COX-1 and COX-2. COX-1 is expressed under basal conditions in the stomach, platelets, and kidney. Because of its tissue localization, COX-1 is thought to play physiologic roles in gastric cytoprotection and platelet aggregation. COX-2 expression is highly restricted under basal conditions and is induced in inflammatory cells by inflammatory or noxious stimuli. Prostaglandins produced by COX-2 mediate symptoms of pain, inflammation, and fever. Conventional NSAIDs inhibit both COX-1 and COX-2, thus putting the patient at higher risk for GI ulcers and bleeding. Selective COX-2 agents are associated with a lower rate of GI ulcers but are associated with a higher rate of acute cardiovascular events presumably mediated by promotion of clotting. A large number of NSAIDs are available from which to choose (Table 77.8), and at full dosage all may be equally effective. However, there is a great deal of variation in tolerance and response to a particular NSAID. Long-acting NSAIDs that allow once- or twice-daily dosing improve compliance. The selective COX-2 inhibitors (celecoxib, rofecoxib, valdecoxib) have been shown to be as efficacious as the older, nonselective NSAIDs, with less GI toxicity and less bleeding (55,56). However, rofecoxib and valdecoxib have now been removed from the market because of the problem with cardiovascular toxicity (see Side Effects).
Dosage
A full dosage of an NSAID should be prescribed for active inflammation (Table 77.8). However, a lower dosage should be used if inflammation is mild and if the patient is elderly or at risk for toxicity (see Side Effects). If a particular NSAID is ineffective after a 4-week trial or is not tolerated, another NSAID can be initiated. An individual patient's response to NSAIDs with respect to both tolerance and effectiveness is unpredictable and varied. Combinations of NSAIDs should be avoided because of the potential for increased toxicity.
Usual Time to Maximal Effect
Although these agents achieve therapeutic blood levels and analgesic effects within hours to days after the first dose, the full anti-inflammatory effect may take several weeks. In the absence of side effects, a reasonable trial period is 1 month.
Side Effects
The most common toxicity of NSAIDs is GI disturbance (57, 58, 59) (Table 77.9). The term NSAID gastropathy describes a variety of gastric lesions, including mucosal erythema, gastric erosions, and frank ulcerations,
P.1269
although NSAID-related lower GI bleeding also has been described (60). Serious complications of NSAID-induced peptic ulcers include obstruction, bleeding, and perforation, which may be life threatening. Risk factors for these serious complications include age over 70 years, RA, concomitant use of steroids or anticoagulants, prior history of ulcer-related GI bleed, and comorbid cardiopulmonary disease (61). NSAID-induced gastropathy is caused by reduced production of gastroprotective prostaglandins by the stomach lining as a result of COX-1 inhibition. Patients should be carefully monitored for GI symptoms and evidence of GI blood loss while receiving NSAIDs. For patients at risk for NSAID-related gastropathy, management strategies may include lower doses of NSAIDs (although this strategy may not provide adequate pain control), coadministration of a gastroprotective agent, or use of an NSAID that selectively inhibits COX-2.
|
TABLE 77.8 Nonsteroidal Anti-Inflammatory Drugs |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Although the relative efficacies of the latter two strategies have never been compared head to head, independent clinical trials have demonstrated that both reduce the risk of serious NSAID-induced ulcer complications (55,56). Proton pump inhibitors such as omeprazole and the prostaglandin analogue misoprostol, for example, decrease the incidence of new endoscopic and/or symptomatic gastric ulcers and their complications in NSAID users (62,63). Furthermore, healing of pre-existing, endoscopically documented peptic ulcers occurs at a high rate without discontinuing NSAID treatment if a proton pump inhibitor or H2 blocker is added (64). As for the COX-2 selective NSAIDs, several large clinical trials in arthritis patients have demonstrated a 50% reduction in risk of serious ulcer complications (perforation, bleeding, and obstruction) in patients receiving these agents compared to those receiving nonselective NSAIDs (55,56). It should be noted that the gastropathy is not completely eliminated
P.1270
with the use of the COX-2 agents, and continued caution is needed in patients at risk for GI bleeding. Furthermore, the protective GI effect of COX-2 selective agents is largely lost if the patient is taking concomitant low-dose aspirin for cardiovascular prophylaxis (65). In these cases, COX-2 selective agents have no apparent advantage over a nonselective NSAID.
|
TABLE 77.9 Side Effects of Nonsteroidal Anti-Inflammatory Drugs |
||||||||||||||||||||||||||||||||||||||||||||||||
|
Unlike aspirin and nonselective NSAIDs, COX-2 selective NSAIDs do not inhibit platelet clotting because the prostanoid product that promotes platelet aggregation (thromboxane B2) is produced by platelet COX-1. However, COX-2 agents do inhibit production of the anticlotting, vasodilatory prostanoid (prostacyclin) produced by endothelium. An increase in thromboxane/prostacyclin ratio in the vasculature in patients receiving selective COX-2 agents is likely to occur and may be responsible for the increase in acute coronary events and/or cerebrovascular events that were observed in several clinical trials and population studies of patients treated with COX-2 agents compared to nonselective NSAIDs (56,66,67). This serious complication of COX-2 treatment has led to the removal of two of the three Food and Drug Administration (FDA)-approved COX-2 selective NSAIDs (rofecoxib and valdecoxib) from the market, leaving only celecoxib at this time. In adenoma prevention trials, celecoxib showed inconsistent results with regard to cardiovascular toxicity. Although a dose-related increase in acute cardiovascular events was noted with celecoxib use (400 and 200 mg bid) in the Adenoma Prevention with Celecoxib (APC) trial, this effect was not seen in the Prevention of Spontaneous Adenomatous Polyposis (PreSAP) trial (68,69).
Thus, before prescribing celecoxib, the relative benefit (GI protection) versus risk (cardiovascular toxicity) of selective COX-2 inhibition, as well as alternative strategies (e.g., conventional NSAID with proton pump inhibitor), must be weighed carefully for each individual patient (56,66). Celecoxib should be reserved for patients at high risk for recurrent bleeding ulcers, those taking warfarin, and those with significant GI discomfort taking conventional NSAIDs who cannot be managed effectively with gastroprotective agents such as misoprostol or proton pump inhibitors. Celecoxib should be avoided in patients at high risk for new or recurrent cardiovascular events; however, if it is selected as the optimal NSAID, concomitant low-dose aspirin should be continued.
Of note, recent population-based studies have implicated the conventional NSAIDs in promoting acute ischemic events (70). In 2004, the National Institutes of Health (NIH) terminated the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) because of an apparent increase in cardiovascular events noted in patients taking naproxen compared to placebo. No increased risk was seen with celecoxib in this trial (FDA webcast). This potential adverse effect of nonselective NSAIDs has not been confirmed in any prospective long-term study, and available data are insufficient to draw any definite conclusion. Thus, the long-term cardiovascular safety of both selective and nonselective NSAIDs need to be evaluated in future trials.
Because renal prostaglandins from both COX-1 and COX-2 pathways play a role in the regulation of renal blood flow and maintenance of glomerular filtration, both nonselective and COX-2 selective NSAIDs have the potential to impair renal function (71). Patients at highest risk are those with fluid imbalances or compromised renal function (e.g., heart failure, diuretic use, cirrhosis, dehydration, renal insufficiency) (72). If an NSAID is prescribed for such patients, it should be initiated at low dose, and renal function should be monitored early on and throughout the course of treatment. The drugs should be stopped if there is a rise in serum creatinine concentration or increased edema. Usually, the creatinine concentration returns to normal within 1 or 2 weeks. Rarely, an interstitial nephritis develops in association with a sustained rise in
P.1271
serum creatinine concentration and eosinophiluria. Urinalysis usually is normal.
|
TABLE 77.10 Nonsteroidal Anti-Inflammatory Drugs and Drug Interactions |
||||||||||||||||||||||
|
||||||||||||||||||||||
Fewer than 5% of patients develop a hypersensitivity reaction, usually a rash, to an NSAID. This reaction usually is specific to a particular drug, so another NSAID of a different class can be substituted. Rarely, an anaphylactoid reaction or worsening asthma can occur (seeChapter 30) that can be intrinsic to the mechanism of prostaglandin inhibition. If anaphylaxis or worsening asthma occurs with NSAID therapy, subsequent exposure to all classes of NSAIDs (including aspirin) is contraindicated. If NSAID therapy is deemed essential in the case of anaphylaxis, an allergy consultation is recommended for evaluation and possible desensitization. Although theoretically a selective COX-2 inhibitor might be safe in these instances, this has not been conclusively proven.
Significant drug interactions can occur with any of the NSAIDs (Table 77.10).
Corticosteroids
Glucocorticoids are potent anti-inflammatory agents that inhibit the cascade of inflammatory and immune mechanisms at multiple levels. They have a rapid onset of action and thus are very useful as “bridging therapy” for patients with early debilitating RA. In this context, treatment with low-dose oral prednisone is initiated early on to reduce pain and inflammation while waiting for the delayed action of a coadministered DMARD(s) to take full effect. Once the DMARD effect is evident, prednisone should be tapered slowly to the smallest tolerated dose or, preferably, discontinued entirely. Low-dose prednisone (7.5 mg/day) has been shown to have disease-modifying effects compared to placebo, with retardation of joint damage (73,74), but this effect is relatively modest compared to DMARDs such as methotrexate and the TNF inhibitors. Furthermore, significant side effects associated with chronic steroid use limit their long-term use, and every effort should be made to use the smallest required dose of these agents. Chronic low-dose prednisone as the sole disease-modifying therapy is not acceptable treatment. Indications for oral prednisone use in RA therefore include (a) short-term use in early disease until the DMARD effect is realized; (b) short-term use for disease flares; and (c) chronic use only in patients with severe, difficult-to-treat disease.
Corticosteroids can be administered by other systemic routes (intravenously and intramuscularly) or by local route (intra-articularly). Intra-articular steroid injection is indicated when the disease is under excellent control except for one or two joints; however, infection as the cause of the synovitis must be ruled out via arthrocentesis and culture prior to the steroid injection. Intra-articular injections can circumvent the need for systemic glucocorticoids and their side effects. Generally, the same joint should not be injected with a corticosteroid more than three to four times per year because of the risk for deterioration of intra-articular cartilage, although it must be recognized that uncontrolled joint inflammation also can cause rapid deterioration of cartilage.
High doses of intravenous glucocorticoids, or so-called “pulse therapy” (methylprednisolone 100 mg intravenously daily on 3 consecutive days), for management of severe flares usually are reserved for patients for whom most other therapies have failed and who are experiencing a great deal of functional disability. A randomized clinical trial showed equivalent efficacy of 100 versus 1,000 mg of intravenous methylprednisolone daily for 3 days; consequently, the 100-mg dose is preferred (75).
Weight gain and cushingoid appearance are common complaints with high-dose steroids, although their frequency at a chronic low dose of prednisone (<10 mg/day) are unclear. Because of the proatherogenic and bone-resorbing effects of steroids, increased cardiovascular risk and accelerated osteoporosis have been described in association with prednisone, particularly at dosages >10 mg/day (76). RA itself is a risk factor for osteoporosis (77); consequently, patients receiving corticosteroids should undergo baseline bone densitometry to assess fracture risk. Bisphosphonates are recommended to prevent glucocorticoid-induced osteoporosis in all patients
P.1272
on chronic glucocorticoid therapy (see Chapters 84 and 103). Other clinically significant side effects include premature cataracts, increased intraocular pressure (78), and glucose intolerance.
|
TABLE 77.11 Toxicities and Monitoring of Commonly Used Disease-Modifying Antirheumatic Drugs |
|||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||
Disease-Modifying Antirheumatic Drugs
Table 77.11 lists the toxicities and monitoring of commonly used disease-modifying antirheumatic drugs.
Hydroxychloroquine
An antimalarial agent derived from the bark of the cinchona tree, hydroxychloroquine is rapidly absorbed, safe, well tolerated, and has been used for decades for treatment of RA. In several randomized controlled clinical trials, hydroxychloroquine was shown to be effective in reducing joint pain and swelling, improving physical functioning, however, its effects, particularly on progression of joint damage, are less potent than those of the other DMARDs (48,79). For this reason, hydroxychloroquine as monotherapy usually is reserved for patients with very mild disease. Its greatest use in clinical practice is as adjunctive therapy with other DMARDs, as discussed above.
Mechanism.
The mechanism of action of hydroxychloroquine in the treatment of patients with RA is unknown.
Dosage.
The usual daily dosage is 400 mg (two tablets). Initial loading with 1,200 mg/day followed by 400 mg/day has been shown to hasten the onset of action (80); however, the long-term safety of this approach is not known. Nonetheless, long-term toxicity is unusual if the chronic daily dose is <6 mg/kg.
Side Effects.
The most important toxicity is deposition of hydroxychloroquine in the retina, potentially leading to blindness. This is rare, however, if the drug is used at the recommended doses. Nonetheless, a baseline ophthalmologic examination and a followup examination every 1 to 2 years are recommended during the period of treatment. GI upset, pigmentation changes, leukopenia, and a variety of neurologic side effects are seen rarely.
Methotrexate
Methotrexate is a folic acid antagonist. Its long track record of safety, tolerability and efficacy have made it the first choice for monotherapy of RA and the “anchor” drug for various combinations of DMARDs (48,49). Methotrexate therapy should be considered in all patients who have active disease with one or more risk factors for poor prognosis (see Management).
Mechanism.
Although the immunosuppressive and cytotoxic effects of methotrexate are caused by the inhibition of dihydrofolate reductase, the anti-inflammatory effects in RA appear to be unrelated to this mechanism of action. This is evidenced by its continued efficacy in the face of supplementation with folic acid (81). The anti-inflammatory mechanism remains unclear but may be caused by increases in extracellular adenosine, a potent inhibitor of inflammation.
Dosage.
Methotrexate (available as a 2.5-mg tablet) is prescribed on a weekly basis. Folic acid (1 mg/day) should be administered with methotrexate. Rapid dose increment to a maximal tolerated dose of 20 to 25 mg/wk was well tolerated in the ERA trial (50), and this regimen has now gained wide acceptance in clinical practice. In this protocol, methotrexate is initiated at a dose of 10 mg/wk and
P.1273
then increased by 5 mg every 4 weeks until a dose of 20 mg/wk is attained. Escalation can be interrupted if a side effect occurs. The total dose can be further escalated to 25 mg/wk if efficacy is not achieved at 20 mg/wk. Because of the slow onset of action, a 4- to 6-week period is required after a dose change before a clinical response is seen. For patients with intolerable GI side effects at higher doses of this medication, substituting intramuscular methotrexate (available as a 25-mg/mL solution) at an equivalent dose may be better tolerated, although this conclusion has been called into question (82).
Contraindications to therapy include renal insufficiency, acute or chronic liver disease, (including chronic hepatitis B and C infection), alcohol abuse, leukopenia, thrombocytopenia, untreated folate deficiency, pregnancy, and breast-feeding. Trimethoprim inhibits folate synthesis and should be avoided or used cautiously in patients receiving methotrexate to avoid cumulative toxicity.
Side Effects.
Most side effects of low-dose methotrexate are relatively mild and resolve with a dose adjustment or addition of folic acid; rarely do they require complete discontinuation of the drug. Before starting methotrexate, baseline studies should include a CBC, liver chemistries, serum creatinine concentration, and hepatitis B and C serologies. The need for a baseline chest radiograph is more controversial. American College of Rheumatology (ACR) guidelines call for monitoring of CBC and analysis of concentrations of liver transaminases, serum albumin, and serum creatinine every 8 weeks during therapy (83).
Stomatitis, mild alopecia, and GI upset may occur in 20% to 70% of patients treated with methotrexate, are related to folic acid antagonism, and are improved with folic acid supplementation (81). Folic acid supplementation (1 mg/day by prescription) does not appear to decrease the efficacy of methotrexate (81).
Significant hepatotoxicity from methotrexate is rare as long as patients with pre-existing liver disease, alcohol abuse, or hepatic dysfunction are excluded from treatment and as long as liver function tests are periodically checked. Elevated concentrations of liver enzymes (usually transaminases), up to twice the normal value, have been reported in 5% to 9% of patients receiving methotrexate in different clinical trials (84). Transaminitis may be reduced by cotreatment with folic acid (85). Patients are advised to limit alcohol consumption to one to two alcoholic beverages per week while taking methotrexate. Elevated concentrations of liver enzymes often are transient, returning to baseline either spontaneously or with brief discontinuation of the medication. Methotrexate may be restarted at the same dose; however, if the elevation occurs a second time, the dose should be reduced. Persistent elevation of enzyme concentrations have been associated with mild fibrotic changes in the liver (86), but frank progression to cirrhosis is exquisitely rare. Baseline or surveillance liver biopsies are not indicated unless pre-existing liver disease is suspected in a patient who is not a candidate for alternative DMARDs.
The most serious complications of methotrexate therapy (interstitial pneumonitis and severe myelosuppression) are rare (87). Interstitial pneumonitis is an idiosyncratic, allergic pneumonitis that is more commonly observed in cancer patients receiving high-dose methotrexate than in patients with RA receiving relatively low doses. Nonetheless, this complication carries a high fatality rate and should be recognized and treated immediately. The patient typically presents with fever, dyspnea, nonproductive cough, hypoxia, and bilateral infiltrates on chest radiograph. Methotrexate pneumonitis can occur at any time during therapy and is not dose related. A baseline chest radiograph may be useful for comparison. Patients with poor pulmonary reserve from other causes, such as emphysema, may be excluded from therapy because of the concern for increased morbidity and/or mortality should methotrexate pneumonitis occur.
Myelosuppression is rare with low dosages of methotrexate. Increased renal insufficiency from other causes, as well as use of trimethoprim (Proloprim, Trimpex), may raise methotrexate concentrations and cause myelosuppression. In general, no conclusive evidence links low-dose methotrexate to an increased risk of infection for either common or opportunistic organisms or for postoperative infections (88). There are case reports of herpes zoster infection with methotrexate use (89). In general, methotrexate is not discontinued prior to surgery.
Lymphomas, particularly non-Hodgkin lymphoma, occur at a higher rate in RA populations compared to age- and gender-matched controls, especially in patients with severe disease (90,91). Several cases of Epstein-Barr–associated lymphomas reported in association with methotrexate therapy, interestingly, regressed completely with discontinuation of the drug without the need for chemotherapy (92). However, an overall increase in the occurrence of solid-organ malignancies or lymphomas has not been found in large population-based studies of patients with RA (93).
Based on animal studies, teratogenicity is a potential complication of methotrexate. Consequently, female RA patients of child-bearing potential and male RA patients with partners of child-bearing potential should be advised of this potential for teratogenesis and should be strongly encouraged to practice effective birth control. A washout period of at least 3 months is recommended before conception should be attempted. No detrimental effect of methotrexate on sperm production or ovarian function has been noted (94).
Sulfasalazine
Sulfasalazine is composed of a sulfapyridine moiety linked to 5-amino salicylic acid. Although it has been used
P.1274
for decades for treatment of RA, its ability to slow joint damage was demonstrated only in the last few years (95). Sulfasalazine is effective both as monotherapy and in combination with methotrexate for treatment of moderate to severe RA. A study comparing the efficacy of methotrexate with sulfasalazine showed relative efficacy of the two drugs (96).
Mechanism.
Sulfasalazine has antibiotic (sulfapyridine) and anti-inflammatory (5-amino salicylic acid) properties. Yet, its disease-modifying capacity likely is not mediated through either of these mechanisms.
Dosage.
Sulfasalazine usually is initiated at a dosage of 500 mg twice daily (available in 500-mg tablets) and increased to 2 to 3 g/day over several months. As with other oral DMARDs, its anti-inflammatory and disease-modifying effects become evident only after several months of treatment.
Side Effects.
Like methotrexate, sulfasalazine is generally well tolerated. Although side effects are reported by approximately 30% of patients who receive this drug, most can be reduced or eliminated by dose adjustment and rarely require discontinuation of the drug. Sulfasalazine should be avoided in patients with a known allergy to sulfonamide drugs or with glucose-6-phosphate dehydrogenase deficiency because reactions in these individuals can be severe. Compliance with treatment can be an issue because of the twice-daily dosing.
The most common side effect is nausea, which usually is easily managed by dose reduction or with use of the enteric-coated formulation. Rashes and other cutaneous reactions occur in up to 10% of patients, presumably as an allergic reaction to the sulfa component. In this situation, the drug should be discontinued. Serious side effects, such as myelosuppression and hepatotoxicity, are rare. Sulfasalazine is considered a safe option in patients with chronic hepatitis C infection. Reversible infertility in men treated with sulfasalazine can occur secondary to oligospermia.
Monitoring should include CBC and liver function tests at 4-week intervals for 3 months, then every 6 to 12 weeks for 6 months, and thereafter every 3 months.
Leflunomide
Leflunomide is a reversible inhibitor of pyrimidine synthesis that has disease-modifying and antidestructive effects in RA. It has been shown to have equivalent efficacy to methotrexate (97) and provides additional benefit when combined with methotrexate (54).
Mechanism.
Leflunomide selectively inhibits de novo pyrimidine ribonucleotide biosynthesis and in vitro potently inhibits lymphocyte proliferation. The primary mechanism of action of leflunomide is thought to be cell cycle arrest of pathogenic T cells in the joint by depletion of nucleotide pools and inhibition of DNA synthesis.
Dosage.
Leflunomide is a prodrug that is converted in the liver to an active metabolite. It is excreted equally in the kidney and the gut and must be used with caution in patients with hepatic or renal insufficiency. The usual starting dose is 20 mg/day, although a 3-day “loading” dose of 100 mg may be used first to hasten the attainment of therapeutic levels. Four to six weeks are required before the beneficial effects of the drug are seen. The dose should be decreased to 10 mg/day in patients who do not tolerate the higher dose. When necessary, as in the case of serious side effects, the elimination half-life can be decreased to 1 to 2 days by the administration of cholestyramine 8 g three times daily for 11 days. Leflunomide can be added safely to methotrexate, but in this case the starting dose should be 10 mg/day. If 10 mg/day is not efficacious and if the liver enzymes remain normal, the dose can be increased to 20 mg/day (54). Because of the additive potential of methotrexate and leflunomide for hepatotoxicity, regular monitoring of the liver enzymes should continue throughout the course of treatment.
Side Effects.
In clinical trials, the most commonly reported adverse events were transaminitis, alopecia, rash, and GI complaints, especially diarrhea. Diarrhea occurs in approximately 25% of patients; it usually is self-limited but may necessitate discontinuation of the drug. As with methotrexate, alanine aminotransferase and aspartate aminotransferase elevation (two to three times the upper limits of normal) occurs in 6% of patients taking leflunomide. Liver enzyme abnormalities normalize with cessation of the drug. Alopecia occurs in approximately 10% of patients (98). Some patients develop loss of appetite and weight loss. Contraindications to drug use include active or chronic liver disease and alcoholism. Like methotrexate, leflunomide is teratogenic in animals and should not be giving during pregnancy. It should be washed out prior to attempts at conception.
Monitoring should include CBC and liver enzyme testing monthly initially, followed by monitoring every 2 months.
Inhibitors of Tumor Necrosis Factor-α
Inhibitors of TNF-α include etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira). Etanercept (Enbrel) was the first TNF inhibitor approved by the FDA. It is a recombinant human TNF receptor that binds both TNF-α and lymphotoxin with high affinity. It is created by linking two molecules of the extracellular portion of TNF receptor II (p75) to the Fc portion of a human IgG1 molecule. Etanercept binds TNF-α in the circulation, thus preventing TNF-mediated activation of inflammatory cells.
P.1275
TNF-α probably is cleared from the circulation through Fc binding by the reticuloendothelial system. Although the patient may report clinical improvement within the first week or two, the maximal effect generally requires up to 3 months (99). Subcutaneously injected etanercept is slowly absorbed and has a half-life >4 days (100). It is administered as either 25 mg twice weekly or 50 mg once weekly (101).
Infliximab (Remicade) is a chimeric mouse–human anti-TNF monoclonal antibody composed of human IgG1-α coupled to the variable regions of a murine anti–human TNF-α antibody. Infliximab exhibits high affinity for TNF-α and prevents binding to cell-associated receptors (102). Infliximab therapy is initiated at a dose of 3 mg/kg by intravenous infusion at weeks 0, 2, and 6, followed by maintenance therapy at the same dose every 8 weeks. For patients with an incomplete response, dosing may be increased to a maximum of 10 mg/kg every 4 weeks. Patients may report improvement after the first or second dose; however, as with etanercept, maximal improvement usually requires several months. Because a significant portion of the infliximab molecule is of mouse origin, patients may develop human antimouse antibodies with repeat dosing, which limits response duration between doses. Methotrexate decreases the frequency of these human antimouse antibodies, and current recommendations indicate administration of infliximab concomitantly with methotrexate (103).
Adalimumab (Humira) is the latest of the TNF inhibitors to be approved by the FDA. Like infliximab, it is an anti-TNF monoclonal antibody; however, unlike infliximab, it is composed entirely of human sequences. As with the other TNF inhibitors, it binds to TNF with high affinity and specificity, preventing its binding to the cell surface receptors. It has a terminal half-life of 2 weeks (104). Although adalimumab is composed entirely of human sequences, antibodies against the drug can develop and can be suppressed by concomitant methotrexate, although there is no FDA-mandated requirement for methotrexate cotreatment. Adalimumab is initiated at a dose of 40 mg subcutaneously every 2 weeks but can be increased to 40 mg weekly if needed. As with other TNF inhibitors, patients usually experience some improvement within the first two injections, but maximal response takes several months.
Side Effects.
Injection site reactions occur in approximately 20% to 40% of patients treated with the injectable TNF inhibitors (etanercept and adalimumab) and consist of erythema and induration at the injection site (45,50,105). Reactions occur early after initiation of treatment, are generally mild and self-limited, decrease, and then resolve completely with repeated dosing. The injection site reactions are not associated with other features of hypersensitivity, and no specific therapy is generally required (99). Infusion reactions occur in approximately 20% of patients treated with infliximab and consist mainly of mild headache, nausea, and flushing. The reactions are transient and can be controlled by slowing the rate of infusion or by pretreating with antihistamines or acetaminophen. Infusion reactions do not increase over time or after multiple infusions (103). Anaphylactic reactions are rare.
Infections.
TNF-α plays an important role in host defense against infection and in initiation and maintenance of granuloma formation (106, 107, 108). Despite concerns, there was no increase in overall frequency of infections, nor in the frequency of serious infections, in clinical trials of TNF antagonists compared to placebo (46,50,99,109). However, postmarketing experience has revealed increased susceptibility of patients treated with TNF inhibitors to opportunistic organisms such as Mycobacterium tuberculosis, Histoplasmosis, Listeria monocytogenes,Pneumocystis carinii, and others (110,111). Infection with M. tuberculosis appears to result from TNF inhibitor-induced dissolution of pre-existing granulomas (latent infection), resulting in widespread dissemination of the organisms. Thus, patients infected with M. tuberculosisfollowing treatment with a TNF inhibitor typically have presented with atypical, extrapulmonary disease usually within the first 2 to 3 months after initiating therapy. Opportunistic infections may occur more commonly with infliximab, but the physician's index of suspicion for infection should be high for all patients treated with TNF inhibitors. Before initiation of a TNF inhibitor, all patients should be tested for latent M. tuberculosis infection with a purified peptide derivative (PPD). If the lesional induration is >0.5 cm in diameter at 24 to 48 hours, a decision should be made either to use an alternate (non-TNF inhibitor) DMARD or to begin appropriate antibiotic therapy forM. tuberculosis(usually for 1–2 months) before initiating treatment with a TNF inhibitor. Antibiotic treatment should continue for the usual recommended period of time. Most commonly, isoniazid is prescribed at a dose of 300 mg/day for a total of 9 months. Patients with active M. tuberculosisinfections should never receive treatment with a TNF inhibitor until after the active infection is adequately controlled/eradicated. Infections with Staphylococcus aureus have been reported in patients treated with TNF inhibitors, both during clinical trials and in postmarketing experience (111). Patients with a history of recurrent Staphylococcal infections should not receive a TNF inhibitor. In general, the physician should have a heightened awareness for all potential infections in patients treated with TNF inhibitors.
Malignancy.
The immune system plays an important role in the surveillance for malignancy, and increased risk of malignancy is a theoretical concern with chronic long-term TNF-α inhibition. Pooled data from clinical trials and open-label extension do not show an increased incidence of solid-organ tumors in patients treated with
P.1276
anti-TNF agents (46,50,105). However, an increased risk of lymphomas in association with anti-TNF therapy has been suggested by data from clinical trials and observational studies (112, 113, 114). Interpretation of these data is confounded, however, by the fact that RA patients, in general, are at an overall higher risk for developing lymphoma whether treated with TNF inhibitors or conventional DMARDs. Furthermore, this risk is related to the severity of RA (114). Because treatment with anti-TNF therapy tends to be reserved for patients with severe disease, it is challenging to extract and differentiate the potential effect of the TNF inhibitors from RA in assessing causality for risk of lymphoma. Until further data are available, patients with lymphomas should not be treated with TNF inhibitors, and all RA patients should be watched carefully for signs and symptoms of lymphoma.
Demyelinating Disease.
TNF appears to be an important cytokine in the pathogenesis of multiple sclerosis; however, a clinical trial using an investigational TNF inhibitor resulted in exacerbation, rather than improvement, in signs and symptoms of multiple sclerosis (115). Furthermore, in non-MS patients treated with TNF inhibitors, a small number of demyelinating syndromes have been reported (116). The most common symptoms were paresthesias, visual disturbance due to optic neuritis, and, less commonly, gait disturbance and facial palsy. Discontinuation of anti-TNF therapy led to partial or complete resolution of symptoms in some cases. However, the causal association of TNF inhibitors with these neurologic events remains unclear. Patients with multiple sclerosis or other demyelinating disease should not receive treatment with TNF inhibitors.
Autoimmunity.
Autoantibodies, bothantinuclear(ANA) and anti–double-stranded (anti-ds) DNA, have been reported in patients treated with TNF inhibitors. In clinical trials, up to 15% patients receiving etanercept or adalimumab developed new ANA (50,99,105). In the infliximab trials, up to 15% and 50% of patients developed ANA and anti-ds DNA antibodies, respectively, compared to 20% and 0% of controls (109,117). However, reports of lupus or lupuslike syndrome are relatively rare in these patients (118).
Hematologic and Bone Marrow.
No serious hematologic events occurred in controlled trials of anti-TNF agents, but rare cases of pancytopenia have been reported in postmarketing experience. Thus, although specific routine monitoring for anti-TNF agents is not required according to FDA guidelines, a CBC and chemistry profile every 3 to 6 months is prudent.
Inhibitor of Interleukin-1.
Anakinra (Kineret) is a recombinant soluble IL-1 human receptor antagonist (IL-1ra) and is the only FDA-approved IL-1 inhibitor. It has been demonstrated to improve clinical and radiographic outcomes when used alone or in combination with methotrexate (53,119,120). In general, the efficacy of anakinra is considerably more modest effect than that of the TNF inhibitors (119,120).
Anakinra binds to the IL-1 receptor, thereby preventing binding of IL-1β to its cellular receptor. The half-life of anakinra is relatively short. Anakinra is administered once daily at a dose of 100 mg by subcutaneous injection. Injection site reaction, primarily erythema and induration, is the most common side effect of anakinra, reported at a frequency of 73% compared to 33% in placebo-treated patients (119). In the controlled clinical trials as well as open-label extension data, no increase in malignancies, either solid-organ tumors or lymphomas, have been reported in anakinra-treated patients (53,119,120). Similarly, no increase in the rate of infections has been observed with either anakinra monotherapy or anakinra in combination with methotrexate, except in one trial, where a modest increase in bacterial pneumonia and cellulitis was observed in combination with other DMARDs (120). However, no increased risk of TB or other opportunistic infections has been associated with anakinra therapy.
Other Nonbiologic Disease-Modifying Antirheumatic Drugs.
Azathioprine, cyclophosphamide, intramuscular gold, oral gold, cyclosporine, and D-penicillamine are rarely used today to treat RA because of their greater toxicity, inferior efficacy, and slower onset of action in comparison with new DMARDs. Cyclophosphamide continues to be used with caution in patients with severe systemic manifestations of RA (e.g., vasculitis, interstitial lung disease). Serious risks associated with cyclophosphamide therapy include premature ovarian failure, bladder cancer, hemorrhagic cystitis, and secondary hematologic malignancies.
Analgesic Drugs.
Inflammatory joint pain is best treated by maximizing the anti-inflammatory drug regimen (see Management). However, short-term or occasional use of opioid therapy is acceptable in some situations. For example, patients in the midst of an acute flare and patients with severe destruction of one or more joints who are awaiting surgery may benefit from short-term opioid use. Patients with severe joint destruction who are not surgical candidates may require long-term opioid use. For the average RA patient, however, opioids should be avoided because they do not treat the underlying disease and have addictive potential. Side effects include diminished mental status, hypersomnolence, and constipation, particularly in the elderly. Dependency and addiction occur infrequently, but the clinician must be alert to these behavior patterns and avoid opioid therapy in patients with a history of substance abuse.
P.1277
Treatment During Pregnancy
RA therapy during pregnancy is complicated by the fact that no placebo-controlled studies have assessed the risk of specific therapies during pregnancy for any of the drugs discussed. Although signs and symptoms of RA may remit during pregnancy (121), this effect is not universal. Treatment decisions require careful consideration of the risks and benefits to the mother and fetus and should be made together with obstetric consultation.
If possible, all DMARD therapy should be stopped in women who are planning to conceive and in pregnant and lactating women. Infliximab and etanercept are pregnancy category B, whereas hydroxychloroquine is category C (122). Category B drugs are those for which animal studies have shown no adverse results and controlled human data are unavailable. Category C drugs have known adverse effects on animal fetuses but controlled human data is undocumented. Because of evidence of potential teratogenicity, methotrexate and leflunomide should be stopped in men and women who are planning conception; these drugs are category X. In the case of leflunomide, cholestyramine should be given to speed elimination (see Leflunomide). Although safety has not been proven in controlled trials, no evidence exists for risks to the fetus from low-dose prednisone (<20 mg/day) or NSAIDs used in the first and second trimesters. If necessary, joint symptoms are best managed with the lowest possible dosage of prednisone. Potential prednisone complications include worsening of maternal gestational diabetes, hypertension, and intrauterine growth retardation. NSAIDs should be avoided in the third trimester because of the potential for premature closure of the ductus, prolonged labor, and peripartum hemorrhage.
Surgery
Despite aggressive management of RA, destruction of one or more joints, leading to chronic pain and malalignment, will occur in some patients with RA and will require surgical intervention. The primary physician, the rheumatologist, and the orthopedist together can help the patient understand the risks and benefits of the surgical procedure. The decision to have surgery is complex and must take into consideration the motivation and goals of the patient, the patient's ability to undergo rehabilitation, and the patient's general medical status.
|
TABLE 77.12 Indications for Referral of Patients with Rheumatoid Arthritis for Consultation |
|
|
Total joint arthroplasties of the knee and hip are highly successful procedures as they restore function and reduce or eliminate pain. Arthroplasty of the elbow and shoulder are done primarily for pain relief, as range of motion may not significantly increase. Arthroplasty of the MCP joints also may reduce pain and improve function. Other operations include release of nerve entrapments (e.g., carpal tunnel syndrome), arthroscopic procedures, and, occasionally, removal of a symptomatic rheumatoid nodule. Synovectomy is ordinarily not recommended for patients with RA, primarily because relief is only transient. However, an exception is synovectomy of the wrist and/or extensor tendons of the fingers, which is recommended if intense synovitis persists despite medical treatment over 6 to 12 months, to prevent extensor tendon rupture.
Summary of Indications For Referral
Table 77.12 lists the indications for referral of patients with rheumatoid arthritis.
Specific References*
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
P.1278
P.1279
P.1280