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Chapter 28 Rheumatoid Arthritis

Manual of Rheumatology and Outpatient Orthopedic Disorders

Chapter 28 Rheumatoid Arthritis

Dror Mevorach and Stephen A. Paget

Epidemiology
Genetic factors
Pathogenesis
Clinical presentation
Laboratory studies and imaging
Diagnosis
Global assessment of functional status and disease
Treatment

Rheumatoid arthritis (RA) is a chronic, systemic, autoimmune, inflammatory disorder in which an erosive, symmetric joint disorder maintains the center stage accompanied by a variable, but at times prominent, degree of extraarticular involvement. The term was introduced by Garrod in 1859 and relates today to a disorder occurring in about 1% of the world's population, with a twofold to threefold female predominance before 60 years of age and greater equity between the sexes thereafter. Rheumatoid factor (RF), an immunoglobulin M (IgM) auto-antibody against the Fc portion of an IgG molecule first described by Waaler in 1940, is the main serologic marker, found in 75% to 80% of patients .

During the past 10 years, epidemiologic studies have unearthed disturbing information about the true potential of this disease, which now guides our modern therapeutic approach; RA is a chronic disease that leads to joint damage within the first 2 years, causes marked functional limitation and a 30% loss of work within the first 5 years, and shortens life by 5 to 7 years. This aggressive disorder demands the early institution of an equally aggressive therapeutic approach. A treatment plan should be individually crafted that is based on patient-specific clinical and functional parameters and employs a wide range of effective medications and physical therapeutic modalities aimed at altering the disease course and maintaining function.

As our concepts about the pathogenesis and clinical realities of RA have crystallized and been coupled with refined methods derived from biotechnology, promising biologics have been developed. Monoclonal antibodies, recombinant cytokines, cytokine receptor fusion proteins , and other biologics have moved from the status of novel reagents studied in phase I trials to validated therapeutic tools in widespread use. With the development of these extraordinary agents , a new era in the focused treatment of RA has begun.

I. Epidemiology. Whereas the worldwide prevalence rate of RA is about 1%, higher rates are found in certain groups, such as 5.3% in certain Native-American tribes. RA is two to three times more common in women than in men, but in persons over 50 years of age, the disease frequency becomes more equal. Although the onset of disease is most common between the ages of 40 and 60, in one-third of patients, RA develops after the age of 60.

II. Genetic factors in RA are important in defining disease susceptibility and severity.

  1. Family studies have demonstrated an increased risk for disease in siblings of persons affected with RA. Concordance has been found to be 12% to 15% in monozygotic and 4% in dizygotic twins, strong evidence for a major influence of genetic factors in disease causation.
  2. The major histocompatibility complex (MHC) is a region of genes whose MHC I and II products provide a system for displaying antigenic peptides to T cells . RA was shown to be associated with the HLA-DR4 and -DR1 haplotypes; on further molecular characterization, the association was confined to a short sequence in the HLA-DRB1 gene that codes for the RA epitope in amino acid positions 67 through 74. Some of the HLA-DRB1 alleles (HLA-DRB1*0401, *0404, and *0408 in general populations and some others in specific ethnic populations) are RA-associated alleles. These MHC genes are related not only to the initiation of the disease but also to its course and severity. For instance, patients with non-DR4 disease-associated genes have milder, seronegative disease, and patients with two (homozygous) DRB1*04 alleles have more severe and extraarticular disease.
  3. Other genetic factors are not as well defined, but because the HLA association represents less than 30% of the genetic risk, several candidate genes coding for cytokines, chemokines, and signal transduction factors may influence disease initiation, severity, and progression.

III. Pathogenesis

  1. No clear etiology has been defined. Although there are no convincing studies demonstrating a specific infectious etiology in RA, some studies support the possibility that an infectious agent may be responsible for the disease in a genetically predisposed host. Immune responses initially generated against such immunogens would be sustained by cross-reactivity to host antigens within the synovial joints, leading to a breakdown of normal immunologic tolerance and a chronic destructive autoimmunity. Candidate infectious agents include viruses (e.g., parvovirus B19, Epstein-Barr virus), Mycoplasma, and other bacteria (e.g., streptococci). Possible auto-antigens include type 2 collagen, proteoglycan, chondrocyte antigens, heat shock proteins, and immunoglobulins.
  2. Histopathology. In the early months of RA, edema, angiogenesis, hyperplasia of synovial lining , and inflammatory infiltrate are already present. Once the disease enters a more chronic phase, massive hyperplasia, mainly of type A synovial cells, and subintimal mononuclear cell infiltration are prominent. The synovium of RA assumes the appearance of a reactive lymph node because of the extensive infiltration by plasma cells, macrophages, and lymphocytes in the form of large lymphoid follicles. The histologic appearance of the synovium in RA, however, is not specific, as a similar picture is seen in other inflammatory arthritides, such as psoriatic arthritis and Reiter's syndrome. One characteristic feature of RA is the invasion of and damage to cartilage, bone, and tendons by an infiltrating inflammatory synovial tissue mass called the pannus.
  3. Cellular immunity. CD4+ T lymphocytes in the form of aggregates or diffuse infiltrates are found in the subintimal area. B cells, although in low numbers , evolve into plasma cells and produce RF. Activated macrophages and dendritic cells are intermixed with other immunoreactive cells and are thought to be important in antigen presentation. Neutrophils, mainly localized to the synovial fluid and not the synovial membrane , are prominent effectors of inflammation , and cartilage is damaged by the various enzymes they release.
  4. Cytokines, chemokines, growth factors, enzymes, and other soluble mediators. Cytokines and growth factors bind to cell surface receptors and transmit a signal to the cell, with a resultant shift in activation. In this way, they play an integral role in the initiation and perpetuation of synovitis. Interleukin-1 (IL-1), IL-6, tumor necrosis factor-alpha (TNF- a ), and colony stimulating factor-1 (CSF-1) are produced by macrophages and fibroblasts; they have broad effects on many cells that lead to cell proliferation , increased release of prostaglandins and matrix-degrading proteases, fever , and bone resorption. IL-2, IL-3, IL-4, IL-6, and interferons are produced in T cells and lead to activation and amplification of cellular and humoral immune responses. Enzymes such as metalloproteinases (collagenase, stromelysin), which degrade matrix proteins, and complement proteins, which participate in acute inflammation, are effector molecules and as such have the ability to alter the environment directly. The relative contribution of each arm probably depends on the degree of chronicity, extent of therapeutic interventions, and other poorly defined factors. Because of the highly complex interrelationships between these cells, it is unlikely that therapies aimed at only one aspect of the axis will succeed in all patients.
  5. Auto-antibodies. RFs are anti-globulin antibodies that bind to the Fc portions of IgG. The mechanisms initiating RF secretion and its exact role in disease pathogenesis have not been established. RF is found in the serum of 75% to 80% of RA patients, is locally produced in rheumatoid synovial tissue, and may be present in the serum of patients with other disease characterized by B-cell or immune hyperreactivity, such as systemic lupus erythematosus (SLE) and bacterial endocarditis. The presence of high RF titers is associated with severe, erosive disease, a worse functional outcome, rheumatoid nodules, other extraarticular disease manifestations , and HLA-DR4 positivity.

IV. Clinical presentation

  1. Disease criteria. The 1987 revised American Rheumatology Association criteria for the classification of RA were developed for epidemiologic purposes. However, because of the high sensitivity and specificity of these criteria in the classification of RA, they are useful to consider at the time of diagnosis. Of the seven criteria, the presence of four is sufficient for classifying a patient as having RA. The first four criteria must be present for at least 6 weeks. They include the following:
    1. Morning stiffness or stiffness after rest lasting longer than 1 hour .
    2. Polyarthritis of at least three joints in 14 areas, including right and left proximal interphalangeal (PIP) joints, metacarpophalangeal (MCP) joints, wrists, elbows, knees, ankles, and metatarsophalangeal (MTP) joints.
    3. Arthritis of hands, wrists, MCP joints, or PIP joints; symmetric arthritis.
    4. Simultaneous arthritis in both sides of the body.
    5. Subcutaneous rheumatoid nodules.
    6. Serum RF.
    7. Hand radiographic changes typical of RA, including erosions or periarticular osteoporosis.
  2. Joint, tendon, and bursal involvement. Symmetric polyarthritis with variable degrees of damage and inflammation of the hands and feet, mainly the wrists, MCP joints, PIP joints, MTP joints, elbows, knees, ankles, and shoulders is characteristic of RA. Early changes include ulnar styloid prominence, and later deformities resulting from combinations of joint and tendon damage may evolve, including ulnar deviation, boutonniere and swan neck deformities. Flexor tenosynovitis can lead to triggering of the fingers and may eventuate in rupture of tendons. Extensor tenosynovitis is seen as swelling over the dorsum of the wrist, and flexor tenosynovitis can lead to carpal tunnel syndrome from median nerve entrapment. Olecranon bursitis often presents as swelling at the tip of the elbow ; synovial extensions, known as Baker's cysts, appearing from the knee to the medial calf region may mimic phlebitis. Spinal disease is limited to the cervical region and, in patients with severe disease, may lead to atlanto- axial subluxation and even cord compromise.
  3. Disease presentation and course. The gradual onset of symmetric polyarthritis is most common, occurring in at least 50% of patients; a sudden onset is seen in 10% to 25% of patients. Other patterns of presentation include monarticular disease; palindromic (short-lived and episodic) disease; extraarticular features, such as nodules; and a proximal type resembling polymyalgia rheumatica. Whatever the onset is, the subsequent course may be brief or episodic, prolonged and progressive, or something intermediate. A monocyclic course is a single cycle with remission for at least 1 year, seen in 10% of patients. A polycyclic course is seen in 70% of patients, with either intermittent or continuing subtypes . The latter group shows smoldering activity with incomplete remission or progression. A progressive pattern with increasing joint damage and extraarticular manifestations is seen in about 10% of patients. Included in this group are patients with malignant RA, a polyarteritis nodosa-like disorder.
  4. Extraarticular presentation. Although the joint disease dominates the clinical picture, constitutional symptoms such as fatigue and extraarticular features such as serositis, sclerosis, subcutaneous nodules, and rheumatoid vasculitis may be prominent, dominant, or life- threatening . Subcutaneous nodules appear in 20% to 30% of seropositive patients. Nodules develop mostly in pressure areas such as the elbows, finger joints, Achilles tendon, and occipital scalp and are associated with active and more severe disease. Interestingly, methotrexate treatment may cause an increase in nodulosis, especially in the fingers. Nailfold infarcts may be seen when rheumatoid vasculitis develops. Pulmonary involvement is common, with pleurisy, pleural effusion, parenchymal nodules, interstitial alveolitis, fibrosis, and bronchiolitis obliterans organizing pneumonia. Cardiac manifestations include pericarditis, myocarditis, valvulitis, nodule formation with arrhythmia, amyloidosis, and vasculitis. Ocular keratoconjunctivitis sicca is the most common eye abnormality, but sclerosis and scleromalacia may be associated with extensive disease activity. The median, ulnar, and posterior tibial nerves may become entrapped by neighboring sites of joint inflammation or damage. Peripheral neuropathies and central nervous system disease can be manifestations of rheumatoid vasculitis. Felty's syndrome (granulocytopenia, splenomegaly, recurrent infection) and Sj gren's syndrome may coexist with RA and often occur in patients with active, systemic disease.

V. Laboratory studies and imaging

  1. Laboratory studies. IgM RF is detected in the serum of about 75% to 80% of RA patients. High titers are associated with more severe and extraarticular disease. The fact that 20% of RA patients are seronegative highlights the fact that the diagnosis of RA is based on clinical, not laboratory, data. An elevated erythrocyte sedimentation rate (ESR) and levels of C-reactive protein are commonly found in RA and correlate well with disease activity in most patients. Normochromic normocytic anemia of chronic disease is frequently seen in active RA; it may be complicated, however, by other conditions, such as drug-induced suppression of bone marrow and blood loss. Thrombocytosis is a frequent correlate of active RA; thrombocytopenia and leukopenia may be seen in drug-induced bone marrow suppression or in Felty's syndrome. Elevated alkaline phosphatase is common in severe disease, but elevation of other liver enzymes more likely is related to treatment with nonsteroidal antiinflammatory drugs (NSAIDs), steroids, or methotrexate.
  2. Imaging techniques are employed in defining the diagnosis, severity, progression, extent of disease, response to therapy , and presurgical state of RA patients. The most common plain radiographic findings are soft-tissue swelling, periarticular osteoporosis, marginal erosions, joint space narrowing, and joint deformities.

VI. Diagnosis. A careful clinical examination (history plus physical examination) is a powerful diagnostic tool; it should focus on the pattern and severity of joint inflammation and damage, the presence and extent of constitutional and extraarticular manifestations, modifying medical and psychosocial factors, coexistent medical illnesses, and family history.

  1. Differential diagnosis
    1. Systemic lupus erythematosus and other connective tissue disorders. The symmetric joint inflammation of RA and SLE may be indistinguishable. However, in SLE, erosions do not develop, and the joint disease is commonly accompanied by such manifestations of SLE as fever, serositis, nephritis, dermatitis, cytopenias, and antinuclear antibody (ANA) and anti-DNA seropositivity. Other connective tissue disorders, such as scleroderma and the vasculitides, may present with an RA-like polyarthritis, or this may develop later.
    2. Polymyalgia rheumatica. Especially in the elderly, it is at times very difficult to differentiate between late-onset (>60 years) RA that is seronegative and polymyalgia rheumatica. At times, RA may present with prominent soreness and stiffness in the shoulder and pelvic girdles. The presence of temporal arteritis symptoms or signs supports the diagnosis of polymyalgia rheumatica.
    3. Seronegative spondyloarthropathies characteristically present with asymmetric inflammatory disease of the large joints of the lower extremities, often with low-back disease and telltale manifestations such as psoriasis, urethritis, uveitis, or inflammatory bowel disease.
    4. Crystal deposition arthritis. Both gout and pseudogout may present in a polyarticular, RA-like fashion. Careful history, radiographs, and joint fluid analysis are helpful in defining these diagnoses.
    5. Osteoarthritis . In the setting of severe, RA-related joint damage, secondary osteoarthritis may develop and be a contributing factor to joint dysfunction and the need for hip or knee replacement. Osteoarthritis itself can easily be differentiated from RA by a late age of onset, localization in the distal and proximal interphalangeal joints, monarticular involvement of a single hip or knee, the propensity to involve the neck and low back, and the absence of joint inflammation and constitutional features.
    6. Infectious arthritis
      1. Viral arthritides may present as a self-limited, RA-like disorder. This is particularly true in the setting of rubella infection or immunization and parvovirus B19 infection. Associated symptoms and signs, serologies, and course establish the diagnosis. Hepatitis C-associated RA-like disease is another consideration. The finding of RF in hepatitis C-associated cryoglobulinemia makes it distinguishable only on documentation of hepatitis C infection. Early hepatitis B may present as a self-limited RA-like disease in the pre-icteric phase.
      2. Spirochetal arthritis. Lyme disease rarely presents in an RA-like fashion. Early Lyme disease may present with arthralgias and myalgias in the setting of the erythema chronicum migrans rash and history of tick bite. Late ( tertiary ) Lyme presents with a waxing and waning monarticular synovitis or oligoarthritis (four or fewer joints) that often involves the knees.
      3. Bacterial arthritides. Whipple's disease may present as a peripheral, symmetric, migratory, non-deforming seronegative polyarthritis, simultaneously with or long before gastrointestinal manifestations and lymphadenopathy.
      4. Reactive arthritis associated with group A b -hemolytic streptococcal infection. Rheumatic fever must be considered in children and adults of all socioeconomic strata. The telltale clinical presentation is a migratory polyarthritis, particularly in the setting of a recent sore throat. Almost invariably, the patient will have an elevated anti-streptolysin O titer and sedimentation rate.

VII. Global assessment of functional status and disease. To craft an optimal therapeutic plan and establish baseline data for later comparison, the initial collection of pertinent clinical, laboratory, and functional information is mandatory. Apart from the traditional detailed history and clinical evaluation, a number of self-report questionnaires [Health Assessment Questionnaire (HAQ), Arthritis Impact Measurement Scale (AIMS)], as well as physician joint count and radiographic scores, have been developed to assess functional capacity, performance of daily activities, disease severity and progression, and response to therapy. Clinical evaluation of the amount of joint damage is based on range of motion, instability, mal-alignment, subluxation, crepitus, and radiographic changes. Negative prognostic markers (e.g., high RF titers; development of erosions, particularly early in the disease course; early or severe functional limitation; family history of severe RA; development of extraarticular disease) should be entered into the clinical and therapeutic equations.

VIII. Treatment

  1. Treatment goals in rheumatoid arthritis
    1. Control of the immunologic and inflammatory disease process.
    2. Prevention of joint damage and normalization of function and life span.
    3. Complete relief of symptoms and return to normal performance of activities of daily living.
    4. Avoidance of complications of the disease and its treatment.
    5. Education, counseling , and physical and occupational therapy.
  2. General approach to the patient with rheumatoid arthritis
    1. Patient and family education is important in the management of rheumatoid disease. Strong emphasis must be placed on the crucial role played by the patient in minimizing disability. Both the patient and the family must be taught what RA is and how it differs from other forms of arthritis. The patient should be told that RA can be a chronic, lifelong disease but that a variety of measures can lead to disease control. Such emotional support may help the patient to maintain employment or an optimal activity schedule. In addition to familiarizing patients with the concepts of chronic disease and its management, specific points must be stressed regarding individual drug and physical medicine therapies used, nutritional information, quackery, and the social services available to the patient with arthritis. Such an education program can take the form of frank discussions between the physician and the patient and family, supplemented by literature dispensed by the doctor. An optimal setting is an established patient education program that employs lecture and audiovisual material. Sex and vocational counseling should be part of the comprehensive approach to the RA patient.
    2. Exercise and rest. It is important for the RA patient to maintain a balance between resting and exercising joints that falls short of causing significant pain or fatigue. Systemic and articular rest are both important. Although the classic recommendations for short rest periods during the day (1 hour of bed rest at mid-morning and mid-afternoon) remain , they are incompatible with the work requirements of most people. At times, hospitalization may become necessary to impose a strict balance of rest and activity that cannot be followed by the patient at home. Articular inflammation may be decreased by adequate rest of the affected joints with either bed rest or splints. The purpose of splints is to provide rest for inflamed joints, relieve spasm, and prevent deformities or reduce deformities already present. Wrist splints are particularly useful during bouts of acute wrist synovitis and for the management of carpal tunnel syndrome.
    3. Regular active exercise with instructions by the physician or physical therapist is important. Exercise is most successful after heat application. A 15-minute early-morning shower or a bath at 98 ° to 100 ° will help decrease morning stiffness. Unless advanced deformity, significant joint pain, or muscle wasting is present, slow and deliberate active or active-resistive exercises should be performed twice daily for approximately 15 minutes. These exercises should involve the fingers, wrists, shoulders, and knees, which are the areas most vulnerable to deformity and functional disability (see Chapter 56 and Chapter 57). As tolerance for exercise increases and the activity of the disease decreases, progressive resistive exercises are indicated for the improvement of muscular function. Static quadriceps exercises should be performed to strengthen the muscular, ligamentous, and tendinous support of the knees. Initial therapy is 10 to 20 exercise sets in each thigh twice daily.
    4. Principles of joint protection include maintenance of muscle strength and range of motion, avoidance of positions of deformity, use of the strongest joints possible for a given task, utilization of joints in the most stable anatomic planes, avoidance of continuous use of muscles and joints in a fixed position, and avoidance of activities beyond the patient's muscular capacity. Active exercises in the form of activities that interest the patient should be provided (e.g., sculpting , clay modeling, weaving).
    5. Activities of daily living. Instruction by the occupational therapist should include self-help devices, resting and functional splints, and the demonstration of alternate methods for task performance aimed at avoiding positions that cause joint deformity. This often includes the use of simulated kitchens, bathrooms, and workplace environments that allow for improvement in functional capacity in sites germane to the patient's life-style.
  3. Medication and therapy with biologics: general information
    1. Rationale for the modern therapeutic approach
      1. RA is an aggressive disorder that demands equally aggressive and early treatment.
      2. A lack of evident joint inflammation (e.g., no evidence of disease) is highly correlated with an absence of joint damage.
      3. Disease- and damage-modifying medications with acceptable safety profiles are available.
      4. Early treatment can prevent joint damage, maintain function, prolong life, and alter the natural history of RA.
      5. Combination therapy is usually both effective and safe and is focused on multiple pathogenetic sites.
      6. Careful clinical profiling can effectively guide therapy.
      7. Careful choice of medications and monitoring for side effects improves outcome.
    2. General therapeutic concepts
      1. A well-crafted treatment regimen should begin soon after the diagnosis and be guided by the patient profile.
      2. The regimen, its rationale, potential side effects, and monitoring must be discussed with the patient.
      3. The aggressiveness of the regimen should match that of the disease.
      4. Patient comorbidities should be factored into the choice of medications.
      5. Disease activity and severity and the patient's functional status should be measured at baseline and at regular intervals.
      6. Lack of reasonable disease control demands a change in the treatment regimen.
      7. Multidrug regimens are state-of-the-art and include the following:
        1. A nonsteroidal antiinflammatory drug (NSAID).
        2. One or more disease-modifying antirheumatic drugs (DMARDs) or biologic agents.
        3. Short courses of an oral or intraarticular steroid, as needed to reset the level of inflammation, improve function, and act as a bridge for other treatments . Regular monitoring is mandatory for each medication and drug combination. Side effects or drug intolerance demands a change in the treatment approach. Collaboration with other professionals should be sought as needed to improve the outcome.
    3. Definition of the patient profile. This should be established at baseline and at regular intervals. Initial and future therapeutic decisions should be based on the following data:
      1. Quantification of the level of inflammation
        1. Intensity and extent of joint inflammation (i.e., number and intensity of red, warm, tender, swollen joints).
        2. Duration of morning stiffness, in minutes or hours.
        3. Severity of constitutional symptoms (fatigue and weight loss can be quantified ).
        4. Determination of ESR, levels of C-reactive protein and hemoglobin, platelet count.
        5. Presence or development of manifestations of extraarticular disease.
      2. Measurement of functional limitation. Use of functional instruments, including the HAQ and the AIMS2, can accurately measure function (see Chapter 7), as can use of a simple visual analog scale in which 0 represents full function and 10 the worst possible functional limitation.
      3. Measurement of joint damage. New erosions or joint deformity, as defined by physical examination and plain radiography.
    4. Treatment regimens. All regimens should include physical therapy, an educational program, optimal drug-specific monitoring, and prevention of side effects (protective medication for the stomach for patients on NSAIDs, if indicated by past medical history).
    5. Patient profile for mild disease. Mild joint inflammation (5 to 10 joints mildly swollen and tender), 20 minutes of morning stiffness, minimal functional limitation or still working full-time , no manifestations of extraarticular disease, mild elevation of ESR to 20 to 30 mm/h without anemia or thrombocytosis, no erosions or joint deformities.
      1. Recommended treatment regimen
        1. NSAID.
        2. DMARD: antimalarial drug (Plaquenil), sulfasalazine (Azulfidine), or IM gold. Some rheumatologists might add minocycline in early disease.
      2. Follow-up
        1. Assessment of disease activity and response to treatment regimen every 1 to 2 months.
        2. Lack of a 75% or better improvement or clear worsening of disease parameters within 3 months demands a reassessment of the treatment approach and possible movement to the regimen for moderate disease.
    6. Patient profile for moderate disease. Moderate joint inflammation and some limitation in range of motion (20 to 30 joints with moderately severe swelling, tenderness with some erythema), 1 hour or more of morning stiffness, moderate functional limitation with threatened loss of work, moderate fatigue that limits function, rheumatoid nodules, ESR over 50 mm/h with anemia and thrombocytosis, high RF titers, marginal erosions in hands and feet.
      1. Recommended treatment regimen
        1. NSAID.
        2. Combination DMARD: methotrexate (MTX) plus hydroxychloroquine, or IM gold plus hydroxychloroquine. Short courses of low-dose prednisone to reset the level of inflammation (e.g., 10 to 20 mg of prednisone daily in divided doses, tapered to zero over 3 to 5 days). If the patient fails to show a 75% or better improvement in response to a combination of hydroxychloroquine plus full-dose MTX (i.e., 20 to 25 mg/wk) or a 3-month course of parenteral gold, consider the following therapeutic alternatives, as guided by prior drug usge, comorbidities, and patient choice.
        3. At times, a change from oral to SC, IM, or IV routes of administration of MTX can improve the clinical response.
        4. Addition of sulfasalazine (SSZ) to MTX plus hydroxychloroquine.
        5. Addition of low-dose cyclosporine (CyA) (1 to 2.5 mg/kg daily) to 15 mg of MTX per week. Hydroxychloroquine can be continued or stopped .
        6. Addition of parenteral anti-TNF therapy to 15 mg of MTX per week, or discontinuation of MTX and use of anti-TNF therapy alone.
        7. Discontinuation of MTX and institution of 2 mg of azathioprine (AZA) per kilogram daily.
        8. Discontinuation of MTX and institution of 100 mg of leflunomide daily for 3 days, then 20 mg PO daily or combination therapy with both.
      2. Follow-up. Assessment of disease activity and response to treatment regimen every month, with changes in therapy as noted above.
    7. Patient profile for severe disease. Severe joint inflammation and deformities (20 to 30 or more red, warm, swollen, tender joints with ulnar deviation, swan neck deformities, and moderate to severe limitation in range of motion), morning stiffness lasting most of the day, loss of work, severe fatigue with weight loss, rheumatoid nodules, and possibly other extraarticular manifestations, such as sclerosis, serositis, ESR between 50 and 100 mm/h with significant anemia (hemoglobin, 9.5 g%) and thrombocytosis (platelet count, 500,000 to 600, 000/mm 3 or higher), many erosions, joint space narrowing, and joint deformities noted on plain radiography.
      1. Recommended treatment regimen
        1. NSAID.
        2. DMARD combination
          1. MTX plus hydroxychloroquine plus SSZ.
          2. MTX plus CyA.
          3. MTX plus anti-TNF agent.
        3. Short courses of prednisone (as above) or daily low-dose prednisone (5 mg/d), or intermittent minipulses of IV Solu-Medrol (250 mg/d for 1 to 2 days).
        4. If improvement is no better than 50% to 75% or if disease worsens despite the above regimens, consider the following:
          1. AZA (2 mg/kg daily) in combination with hydroxychloroquine or an anti-TNF agent.
          2. Leflunomide (100 mg daily for 3 days), then 20 mg PO daily in combination with hydroxychloroquine or MTX.
        5. In the setting of severe, refractory disease unresponsive to the above regimens, or of systemic, necrotizing vasculitis, consider the following:
          1. Cyclophosphamide (CTX) (2 mg/kg PO daily), with steroids or
          2. CTX (monthly IV dose of 0.5 g/m 2 ).
          3. Until disease control is attained, (a) or (b) can be given for 3 to 4 months, then one can switch to 20 to 25 mg of MTX per week or to alternative immunosuppressive agents such as AZA, CyA, or leflunomide.
      2. Follow-up
        1. Close follow-up monthly or more often.
        2. Vigorous program of physical therapy, emotional and vocational support.
        3. Hospitalization may be needed to balance activity and therapy optimally, institute new medications, and consider parenteral steroid treatments.
  4. Medications and biologic agents
    1. Nonsteroidal antiinflammatory drugs. NSAIDs do not appear to alter the natural history of RA, but they can contribute to control of a component of the inflammatory process. NSAIDs are appropriately used early in the course of the disease to relieve pain and decrease the amount of inflammation while the diagnosis is established. Later in the course of the disease, NSAIDs are used in combination with DMARDs. The choice of NSAIDs is quite individual, and most rheumatologists employ traditional nonacetylated salicylates and nonsalicylate NSAIDs or COX-2-specific NSAIDs rather than aspirin. This system has evolved because of the ease of dosing and despite the higher costs of non-aspirin NSAIDs. The side effect profile of some of the NSAIDs has been shown to be higher than that of some of the DMARDs. This is particularly true in the elderly. All NSAIDs can lead to gastrointestinal ulceration and renal injury , but in general, COX-2-specific NSAIDs appear to cause significantly fewer gastrointestinal problems.
      1. Indications . Although these drugs do not appear to have the capacity to induce a disease remission or prevent the formation of joint erosions, they can decrease pain and inflammation, so that the patient is better able to preserve function and range of motion.
      2. Mechanism of action. Although their dominant action relates to the ability to inhibit the cyclooxygenase enzyme and thus pro-inflammatory prostaglandins, NSAIDs also inhibit lipoxygenase and lysosomal enzyme release, antagonize kinins, and induce apoptosis. Cyclooxygenase-1 (COX-1) is present in many tissues and is responsible for the production of prostaglandins in the gastric mucosa, endothelium, platelets, and kidneys. COX-1 inhibition by NSAIDs is linked to known adverse effects, such as gastric ulceration and renal toxicity. Cyclooxygenase-2 (COX-2) is an inducible, pro-inflammatory enzyme . Although different NSAIDs vary in the degree to which they inhibit both enzymes, in many cases, both COX-1 and COX-2 are inhibited at the high doses used for clinical purposes. Two new COX-2-specific inhibitors are now in widespread use (Celebrex and Vioxx); although similar in effectiveness to other NSAIDs, they appear to cause significantly less gastrointestinal toxicity.
      3. Therapeutic approach. NSAIDs are often used in combination with one or more of the DMARDs, and at times with DMARDs and steroids. All salicylate and nonsalicylate NSAIDs share a similar toxicity profile. The elderly, however, are more vulnerable to all types of side effects in view of age-related alterations in metabolism and excretion. The presence of preexisting gastric, hepatic, or renal disease in any patient is particularly important and may predispose to increased tissue injury. Thus, if NSAIDs are needed in this group of patients, they should be used with great caution, in the lowest dose possible, and with close monitoring for adverse drug effects. Note that elderly women on NSAIDs have the highest likelihood of developing potentially life-threatening gastric ulcer disease with bleeding. Gastric protection is not indicated in every patient; however, it should be considered in high-risk patients. The use of COX-2-specific NSAIDs will protect all patients.
      4. Cost. All the non-aspirin NSAIDs are very expensive, at times costing more than $1.00 a day. This needs to be factored into the therapeutic equation when the physician is deciding on which NSAID to choose. This is particularly true in patients on a fixed budget who are taking multiple medications. However, although plain aspirin is much cheaper, the cumbersome regimen of 12 to 16 tablets per day taken in four doses must be appreciated.
      5. Routine use and dosage regimen. The choice of NSAID is quite individual, varies greatly from physician to physician, and often depends on the presence of preexisting medical problems. The general approach is to choose an NSAID and treat for 3 to 4 weeks, the usual time period needed to define the efficacy and side effect profile of a drug. If there is no clinical response, or if the patient cannot tolerate the drug, an alternative NSAID is started. Often, four to five such cycles are carried out, and then the patient is placed on the most effective of the drugs tried. Patients vary greatly with regard to their propensity to improve clinically or suffer side effects. The physician's choice should be guided by an appreciation of the patient's age and medical history. Patient compliance is highest with once-daily dosing or a twice-daily regimen.
      6. Specific agents. Carboxylic acids, enolic acids, and non-acidic compounds are the three chemical classes of NSAIDs. Carboxylic acids comprise the largest family, and salicylates (aspirin), acetic acid (diclofenac, indomethacin), proprionic acids (ibuprofen, naproxen), enolic acids (piroxicam), and substituted pyrozoles (celecoxib, rofecoxib) are commonly used.
        1. Salicylates were, historically, the initial treatment of choice for RA. Aspirin (acetylsalicylic acid) is antiinflammatory in therapeutic dosages of 3.6 to 6.0 g/d (12 to 16 300-mg tablets per day; serum salicylate levels of 15 to 25 mg/dL) and analgesic at lower dosages (fewer than eight 300-mg tablets per day). Salicylates are administered at dosages of 600 to 1,200 mg every 4 to 6 hours, usually with meals or with antacid to minimize gastric irritation. Constant serum drug levels can be achieved in most patients with this dosage interval. The dosages needed to achieve therapeutic concentrations vary widely, especially in the elderly. Salicylate levels can be used to monitor compliance. Hepatic metabolic pathways may become saturated at higher levels. Therefore, a small dosage increase can result in a very large elevation of the serum salicylate level and salicylism. Similarly, when the dose is decreased, small decreases may bring about rapid decreases in the salicylate level. The maximum tolerated dosage should be approached slowly because it may take as long as a week after each dosage change to achieve a new, steady level. Rectal suppositories are available; however, rectal absorption is incomplete.
        2. Other nonsteroidal antiinflammatory drugs. These agents are equipotent to aspirin and are thought to exert their antiinflammatory action by modifying prostaglandin metabolism. Most rheumatologists use nonsalicylate NSAIDs rather than plain aspirin. Major attributes of this class of drugs include ease of administration (especially in the once- or twice-daily regimens), the potential for improved compliance, and COX-2 specificity. This has to be balanced against their high cost relative to aspirin. More than a dozen NSAIDs are available. The complete list is found in Appendix E. The agents listed below have been successfully used at our institution.
          1. Celecoxib. The first of the class of COX-2-specific inhibitors, it is well tolerated and indicated for treatment of RA in a dosage of 200 to 400 µg/d (tablet sizes of 100 µg and 200 mL). As discussed below, the COX-2-specific inhibitors offer analgesic and antiinflammatory efficacy comparable to that of the older NSAIDs but are significantly safer with regard to the GI tract .
          2. Naproxen. Well tolerated; twice-daily regimen or slow-release tablets for once-a-day use encourage compliance; tablet sizes are 250 mg, 375 mg, and 500 mg; the dosage schedule is defined by the severity of joint disease.
          3. Piroxicam. Generally well tolerated; once-daily dosage schedule encourages compliance; capsule sizes are 10 mg and 20 mg; usual dosage is 20 mg/d PO (sometimes taken as an evening dose for patients with severe morning stiffness or 10 mg PO twice daily); doses larger than 20 mg/d are probably associated with increased gastrointestinal toxicity. NSAIDs with a long half-life, such as piroxicam (Feldene), should be used with greater caution in elderly patients because of the increased propensity for side effects.
          4. Sulindac. Generally well tolerated; twice-daily regimen encourages compliance; tablet sizes are 150 mg and 200 mg; usual dosage is 150 to 200 mg PO twice daily.
          5. Indomethacin is effective in the control of acute flares of RA. Capsule sizes are 25 mg and 50 mg; the usual dosage regimen is 25 mg three to four times daily. A slow-release preparation is available; the 75-mg dose is equivalent to 25 mg three times daily; two 75-mg doses are equivalent to 50 mg three times daily.
          6. Ibuprofen. 200 to 800 mg. The therapeutic dosage is usually 300 to 800 mg three to four times daily. Shorter-acting NSAIDs may be safer in the elderly. A 200-mg tablet is available over the counter.
          7. Diclofenac is available as 25- to 75-mg tablets, as 100-mg extended-release tablets, and in combination with misoprostol (arthrotec). The usual effective dosage is 50 to 100 mg twice daily.
      7. Common side effects
        1. Gastrointestinal effects. The most common side effects of NSAIDs include dyspepsia, peptic ulceration (gastric more often than duodenal), hemorrhage, and perforation. Protective techniques include the following:
          1. Avoidance of nonsteroidal antiinflammatory drugs and treatment with alternative modalities (i.e., oral or intraarticular steroids, pain medications, physical therapy, DMARDs). This is particularly true in high-risk patients, including the elderly, those with a past history of peptic ulcer disease or significant NSAID-related dyspepsia, patients on steroids, and those with comorbidities such as cardiac disease.
          2. Taking nonsteroidal inflammatory drugs with meals will reduce the incidence and severity of dyspepsia but does not reduce occult bleeding (2 to 10 mL/d in 70% of patients taking usual aspirin doses). Guaiac-positive stools (trace to 1+) are common during aspirin therapy. A gastrointestinal evaluation is performed when clinically indicated by persistent gastrointestinal reflux, abdominal discomfort, significant decrease in hemoglobin levels, syncope, or melena.
          3. Use of medications to protect the stomach. Misoprostol, a synthetic prostaglandin E 1 analog, acid pump inhibitors, and histamine 2 inhibitors have all been shown to protect the gastric mucosa from the irritative effects of NSAIDs. The first two medications are probably the most effective. The main side effects of misoprostol include the potential to cause abortion, teratogenicity (congenital facialis), and diarrhea and bloating soon after institution. These agents should be employed only in those high-risk patients noted above.
          4. Use of cyclooxygenase-2-specific inhibitors. These drugs may be employed first, especially in higher-risk patients. It must be noted that although they are safer, these drugs do not appear to be more effective than other NSAIDs.
        2. Tinnitus or deafness is usually the earliest indication of salicylate toxicity in adults and is reversible with a small (one or two tablets) decrease in daily dosage. There is an inverse relationship between plasma salicylate levels at which auditory symptoms appear and the age of the patient. Other NSAIDs can also cause tinnitus.
        3. Central nervous system symptoms such as headache , vertigo, nausea, vomiting, irritability, and even psychosis can occur, especially in the elderly. These symptoms can be quite severe with indomethacin treatment. NSAID-induced aseptic meningitis has been reported .
        4. Hepatic abnormalities. Transient and asymptomatic transaminase elevations are commonly seen in patients on NSAIDs and often resolve with or without drug discontinuation. The drug should be stopped if the serum level is more than three times the upper limits of normal. Significant hepatitis may also occur, especially in patients with juvenile RA and active SLE. Acute hepatic cellular injury can occur, particularly when aspirin is taken in the setting of a viral illness (Reye's syndrome).
        5. Platelet and hematologic abnormalities. Platelet adenosine diphosphate release, adhesiveness, and aggregation are inhibited for as long as 72 hours after a single 300-mg dose of aspirin, probably as a result of irreversible acetylation of platelet membrane proteins. COX-1 is also found on platelets, and inhibition of COX-1 by the nonspecific NSAIDs will inhibit platelet aggregation. This side effect should be taken into consideration before and after surgery and in the final weeks of pregnancy . This effect does not occur with salsalate and is reversible with other traditional NSAIDs. NSAIDs should be stopped at least 3 to 5 days before surgical procedures. COX-2-specific NSAIDs do not cause these platelet effects but can increase the prothrombin time (international normalized ratio) via protein binding effects. Other, less common adverse hematologic effects include aplastic anemia and neutropenia. The presence of unexplained anemia should stimulate an assessment for blood loss.
        6. Acute bronchospasm can be induced by aspirin and other NSAIDs in asthmatic patients and patients with nasal polyposis. Patients in whom this problem develops with one NSAID should avoid others.
        7. Dermatologic abnormalities. A wide spectrum of skin lesions can be caused by the broad array of NSAIDs, including exfoliative dermatitis.
        8. Drug interactions. These occur either through competition for albumin binding or overlapping drug effects. With oral anticoagulants, the effect of warfarin (Coumadin) can be increased, and an NSAID-induced platelet defect can further increase the risk for bleeding. Gastrointestinal bleeding can occur in the setting of NSAID-related gastric mucosal defects. Decreased renal clearance resulting from NSAIDs and albumin-binding competition can lead to increased levels of lithium and an increased risk for hypoglycemia in patients taking oral hypoglycemic drugs.
    2. Corticosteroids. Although these drugs are highly potent antiinflammatory agents, they are associated with a high incidence of cumulative toxicity when administered on a long-term basis. It is for this reason that the physician and patient must be aware that optimal therapy in RA involves the lowest dose for the shortest period of time. Steroids can be used in short courses systemically or intraarticularly to control acute disease flares, as bridge therapy until DMARDs begin to act, or on a long-term basis.
      1. Indications. The indications for corticosteroids in RA include the following:
        1. Active synovitis in a single joint out of proportion to all others: intraarticular steroids are quite effective in this setting. The dose of Depo-Medrol (40 mg/cc) is proportional to the size of the joint. The full 40 mg is injected into knee joints in the same syringe with 1 cc of 1% xylocaine without epinephrine. Note: Steroids should not be injected if there is a possibility of joint infection.
        2. Multiple joints are inflamed and markedly limited in function despite the active use of nonsteroidal antiinflammatory drugs and disease-modifying antirheumatic drugs. In this setting, a short course of oral prednisone (a 4-day course beginning with 20 mg and tapered by 5 mg/d to zero over 4 days) may be very helpful in rapidly resetting the level of inflammation and improving function. At times, minipulses of IV Solu-Medrol (250 mg/d for 1 to 3 days) are needed to bring severe disease under control rapidly .
        3. Bridge therapy is needed to control disease until a recently started DMARD begins to work. This can be in the form of short (2 to 4 days) courses of prednisone or a daily, low-dose (5 mg/d) regimen. The physician should attempt to taper the steroids once the DMARD begins to control the disease.
        4. Severe flares of polyarthritis with any attempt to taper steroids may occur while a patient appears to be doing well on a combination drug regimen of NSAIDs and DMARDs. At times, these patients will be relegated to long-term steroid therapy. If that is the case, the safest dose is 5 mg or less daily. This possible scenario must be appreciated when steroids are started. Long-term steroid use requires increased monitoring for and prophylaxis against side effects such as osteoporosis.
        5. Prominent constitutional or extraarticular manifestations. At times, manifestations such as fatigue, weight loss, serositis (pleurisy or pericarditis), or a polyarteritis nodosa-like vasculitis dominate the clinical picture. Although DMARDs will be employed to control these problems in the long run, steroids are often needed acutely to regain disease control and function.
        6. Fatigue, weight loss, fever. (Note: Fever is not a common manifestation of active RA.) Low doses of prednisone (10 to 20 mg initially, then 5 mg/d) are often sufficient to control these problems that have not been suppressed by NSAIDs. DMARDs are also aimed at such problems but take longer to act.
        7. Rheumatoid vasculitis (malignant rheumatoid arthritis). Fortunately rare, rheumatoid vasculitis is a polyarteritis nodosa-like disorder that occurs in patients who have had chronic, severe, deforming, seropositive, nodular RA. Presentations might include fever, neuropathy, leg ulcers, and ischemic disease of the intestines, heart, and nerves. This is often an organ- or life-threatening disorder and thus demands aggressive treatment. Steroid dosage varies and is guided by the severity of the disorder. Prednisone (40 to 60 mg/d in divided doses; 20 mg three times daily with meals) or pulses of Solu-Medrol (250 to 1, 000 mg/d for 1 to 3 days) followed by prednisone are employed and titrated in proportion to disease control. Steroids are commonly employed along with immunosuppresive agents such as cyclophosphamide in the setting of active, systemic vasculitis.
      2. Mechanism of action. Corticosteroids attach to cell membrane receptors and trigger an increased synthesis of lipocortin. This substance inhibits the release of phospholipase A 2 and therefore the production of pro-inflammatory prostaglandins, leukotrienes, and oxygen radicals. Corticosteroids inhibit cytokines such as IL-I, IL-2, TNF, and a -interferon as well as some pro-inflammatory enzymes such as elastase and plasminogen activator. Corticosteroids induce apoptosis of lymphocytes in vitro and in vivo and inhibit lymphocyte proliferation and delayed-type hypersensitivity in vitro. Inhibition of antigen presentation and reduced expression of Fc receptors may represent additional mechanisms of action.
      3. Therapeutic approach. Steroids continue to be the most powerful antiinflammatory agents available today. However, because of their well-defined side effects, one should always try to taper steroids as much as possible and use alternative disease-controlling, steroid- sparing agents (i.e., NSAIDs, DMARDs, physical and occupational therapy, and intraarticular steroids). Remember that starting a patient on steroids does not commit the physician to continuing it forever. And, with an understanding of other medications in the RA armamentarium, the physician can prescribe steroids in an enlightened manner and prevent their long-term side effects.
      4. Steroid preparations and administration
        1. Prednisone is the preferred oral agent because its cost and mineralocorticoid activity are low. Scored tablets come in many sizes, so that the patient can mix and match them as disease control is attempted and the dose is tapered. Tablet sizes include 1 mg, 2.5 mg, 5 mg, 10 mg, and 20 mg. For suppression of disease manifestations, the optimal and safest maintenance regimen is no more than 5.0 to 7.5 mg of prednisone, preferably in a single morning dose. In patients with severe disease and incapacitating morning symptoms, the dose can be taken with dinner, or a split schedule with dosing at breakfast and dinner may be best. The total dose should be the smallest possible needed to relieve symptoms. At times, a severe and incapacitating acute flare of RA may require ambulatory or in-hospital management with the institution of 20 mg of prednisone per day for 3 to 5 days and tapering thereafter. Rheumatoid vasculitis, if manifested by mesenteric and other internal organ ischemia, is an indication for 40 to 60 mg of prednisone per day because of its malignant, life-threatening nature.
        2. Prednisolone and methylprednisolone are alternative types of steroids. Some physicians favor these because of the fact that prednisone is metabolized in the liver to prednisolone, the active steroid agent. These drugs are a bit more expensive than prednisone but have less mineralocorticoid effect (i.e., less fluid and salt retention), and they may be absorbed better and work effectively in some patients. Four milligrams of these agents equals 5 mg of prednisone. Pulse, high-dose Solu-Medrol (250 to 1,000 mg/d for 1 to 3 days IV) is sometimes administered to patients with severe, active disease unresponsive to other treatment modalities, or patients with rheumatoid vasculitis. At times, this therapy can bring about disease control, which can then be maintained with low-dose oral steroids, DMARDs, and NSAIDs. Particular surveillance for hypertension, arrhythmia, hyperkalemia, serum glucose elevation, and infection is indicated in patients receiving this form of treatment. This should not be considered part of the routine management of RA patients.
        3. Administration of intraarticular corticosteroids is a highly effective way of controlling a disease flare concentrated in a single joint and avoids the need for systemic oral steroids. A single joint flare, out of proportion to all others, is common in RA. However, the physician must consider and rule out the possibility of infection in that single joint before injecting steroids, especially in patients who have fever or prior infections. The risk for introducing infection, although slight , is always present; thus, careful aseptic technique is required. (For technique, dosage, and preparations, see Chapter 20.) An evanescent flare in a joint after injection may occur because of inflammation induced by leukocyte ingestion of corticosteroid ester microcrystals. This possibility should be brought to the patient's attention, and the patient should be told to treat this with a pain medication and an ice pack. Within 12 to 24 hours, the injection-induced joint pain should improve, and relief may persist anywhere from a month to forever. If the initial joint pain was primarily mechanical in origin (i.e., resulting from joint damage), the improvement may be very short-lived. Frequent intraarticular corticosteroid injections (more than once in a 2- to 3-month period or more than three times a year) are not advised because there is evidence that they may lead to accelerated cartilage damage.
      5. Common adverse effects. Fifty years ago, steroids were first used for the treatment of RA. Since that time, steroids have been the model of a double-edged sword, one edge representing the most powerful antiinflammatory agent and the other a wide array of dose-related side effects. A recent study evaluated RA patients who were treated with oral steroids for more than 1 year and compared them with patients who had never received them. An average of 5 mg or less of prednisone was not associated with a higher risk for peptic ulcer, infection, or osteoporosis. However, the incidence of these side effects increased significantly as the mean steroid dosage increased, with the highest likelihood at dosages above 15 to 20 mg/d. The problem of using steroids in a chronic disorder such as RA is that the dose often has to be increased as the disease progresses. A more complete list can be found in Appendix E.
        1. Osteoporosis. In patients with RA, the combined effects of cytokine- induced bone resorption, long-term steroid therapy, the postmenopausal state, and decreased mobility can lead to severe osteoporosis. Thus, for any RA patient who is placed on steroids for more than 1 month and in whom long-term treatment is anticipated, a bone protection monitoring and treatment program should be instituted. This includes an initial bone density test (dual-energy x-ray absorptiometry), calcium and vitamin D 3 supplements, and antiresorptive medications (e.g., estrogens, bisphosphonates) if osteopenia or osteoporosis is defined by density testing. This protocol should be followed for both women and men, the latter assessed for androgen deficiency in the face of low bone density or fragility fractures. Optimal RA control is mandatory because it improves mobility, decreases levels of bone-depleting, disease-related cytokines, and allows doses of steroids to be decreased.
        2. Risk for infection. The use of steroids clearly increases the risk for all types of infection, most prominently in those patients treated with mean doses above 10 mg PO daily. RA patients are particularly prone to Staphylococcus aureus infections. Influenza and pneumococcal immunization are strongly recommended, and the presence of fever in an RA patient should always stimulate the search for an infection. Bacterial infections are particularly problematic in patients with joint replacements because of the possibility of seeding of the artificial joint.
        3. Miscellaneous. The following selected steroid-related adverse effects can further exacerbate functional limitation or shorten life:
          1. Diabetes mellitus.
          2. Hypertension.
          3. Premature atherosclerosis.
          4. Cataracts.
          5. Steroid myopathy.
    3. Disease-modifying antirheumatic drugs. Drugs in this class differ from NSAIDs and steroids in that they act slowly, during a period of 1 to 3 months. This trait has led to use of the term slow-acting antirheumatic drugs. In addition, they appear to alter the natural history of RA by causing erosions to heal and preventing new ones from developing, controlling the inflammatory state, and improving function. Many of the so-called DMARDs fall short of fulfilling this difficult-to-achieve definition, especially the ability to control the development of erosions. This general class of drugs includes gold (oral and IM), hydroxychloroquine, sulfasalazine (SSZ), D -penicillamine, immunosuppressive agents [methotrexate (MTX), azathioprine (AZA), leflunomide (LEF), cyclosporine (CyA), and cyclophosphamide (CTX)], and biologic agents. These drugs differ greatly in chemical structures and pharmacokinetics, presumed modes of action, clinical indications, positions in the treatment algorithm, and toxicity profiles. MTX, as a single agent or in combination with other DMARDs, has had a profound effect on our ability to control this aggressive disease. Its effectiveness and safety have established its central position in treatment plans, particularly in patients with moderate to severe disease. The fact that 60% of RA patients are still on MTX after a 5-year period, as opposed to only 20% on other DMARDs, attests to the excellent track record of MTX in regard to effectiveness and patient tolerance.
      1. Gold salts . Injectable (IM) gold is a slow-acting DMARD that can prevent disease progression and, in a small percentage of patients, lead to an impressive, albeit short-lived, degree of disease control. However, gold as a single drug has fallen out of favor because of the effectiveness, safety profile, and ease of administration of MTX. Because of a high rate of toxicity (minor and reversible in most patients), the need for repeated visits to the physician's office for IM injections, and a variable clinical response, most patients discontinue gold within 1 to 2 years after initiation of treatment. However, some may greatly benefit for many years from the safe weekly and eventually monthly treatment. Oral gold, although associated with fewer side effects than IM gold, is less effective, especially in patients with severe disease and functional limitation.
        1. Indications. Despite the fact that IM gold has been relegated to a secondary role in the treatment of RA, it is a useful option, and along with NSAIDs and antimalarial drugs could be an early choice in established RA. It is contraindicated in patients with a history of previous severe skin, bone marrow, or renal reactions to gold. Significant functional impairment of the kidneys or liver is a relative contraindication to gold therapy, but toxicity to these organs is rare, and with careful clinical and laboratory monitoring, serious problems can be avoided. Leukopenia was previously considered a relative contraindication, but gold-induced improvement of leukopenia has been demonstrated in patients with Felty's syndrome (RA, granulocytopenia, and splenomegaly).
        2. The mechanism of action of gold is not completely understood . At physiologic concentrations, aurothiomalate inhibits the binding of transcription factors such as AP-1, which is a dimer of jun and fos. The possible consequence is a reduction of expression of cytokines, metalloproteinases, and adhesion molecules. Another cellular action of injectable gold may be related to the formation of monomeric aurocyanide during phagocytosis.
        3. Therapeutic approach. Clinical response occurs after a cumulative dose of 400 to 600 mg and often plateaus after 800 to 1,000 mg. If toxicity occurs, it usually appears after 300 to 700 mg of gold has been administered; however, undesirable reactions may occur at any time during the course of therapy. Although the incidence of adverse reactions varies, some toxicity develops in 30% to 40% of patients receiving gold salts.
          1. Parenteral gold. Aurothioglucose (Solganal, our recommended IM gold preparation) and gold thiomalate (Myochrysine) are given by deep IM injection. The initial dose should be small (10 mg) to test for drug idiosyncrasy (e.g., rash, thrombocytopenia). If this dose is tolerated, 25 mg should be given 1 week later, and then 50 mg weekly if tolerated. Improvement is gradual and continues over a period of several weeks to months. When improvement levels off, usually at doses ranging from 800 to 1,000 mg, the frequency of administration can be decreased to 50 mg once every 2 weeks for 1 to 2 months, then gradually to 50 mg once a month. If gold is discontinued, the condition flares in some patients within several months. Therefore, if gold is tolerated, the patient is advised to continue gold injections indefinitely (some physicians reassess gold therapy at the 5-year level). The degree of improvement is proportional to the duration of treatment. However, if improvement does not occur after a total dose of 1,000 mg, the drug should be discontinued. Future courses of gold salts in such patients are unlikely to be effective. Close monitoring of the urinalysis and complete blood counts with platelet and differential evaluation is mandatory.
          2. Oral gold (auranofin). Although parenteral gold therapy has played an important role in the treatment of RA, alternative, less toxic gold preparations have been sought. Auranofin, a unique, synthetic oral gold compound, has been used in the treatment of mild RA. Although the overall toxicity of oral gold is lower, the effectiveness of parenteral gold is significantly higher. Auranofin can produce all the same toxicities as parenteral gold (skin rash, stomatitis, proteinuria, thrombocytopenia); diarrhea develops in 40% of patients, and 6% of patients discontinue the drug because of this toxicity. Auranofin comes in 3-mg capsules, and the dosage is one capsule twice a day. Toxicities other than diarrhea should be addressed by immediate drug discontinuation, just as with parenteral gold. If diarrhea is mild, a decrease in dosage to 3 mg/d may relieve the gastrointestinal complaint; if severe, discontinuation is indicated. Although the drug manufacturer recommends only monthly complete blood cell counts, platelet counts, differential counts, and urinalysis, we recommend studies at least every 2 weeks for the first 3 to 4 months of therapy with close observation for cytopenias, proteinuria, and hematuria.
        4. Common side effects include the following:
          1. Skin and mucous membrane reactions. The most common gold toxicity is dermatitis, which is invariably associated with pruritus and at times with eosinophilia. It is almost always reversible on drug discontinuation. Stomatitis, another mucocutaneous side effect, is frequently painless. The development of these side effects is an indication to withhold gold until the lesions clear. Except in the instance of a severe reaction or exfoliative dermatitis, an uncommon but serious problem, treatment may be reinstituted at a low dose such as 5 mg, with eventual slow escalation of dose. Eosinophilia without rash should alert the physician to watch more carefully for side effects.
          2. Renal effects. Because proteinuria is detectable in at least 10% of patients receiving gold therapy, a urinalysis should be performed before each gold injection. Nephritis and the nephrotic syndrome are uncommon. The most common histologic lesion is a membranous glomerulonephritis. Renal failure is rare. If minor urinary abnormalities occur (proteinuria <500 mg/d), therapy should be interrupted until the urine is normal, then reinstituted at low doses. If the abnormalities recur, gold must be stopped. Most skin and kidney reactions, particularly dermatitis and proteinuria, will clear only after discontinuation of the drug. Antihistamines (25 mg of hydroxyzine three times daily) may be useful for pruritus. Corticosteroids (40 to 60 mg of prednisone daily) are beneficial in some instances of severe rash or exfoliative dermatitis or nephritis. Treatment with heavy-metal chelators (dimercaprol or penicillamine) is usually unnecessary.
          3. Hematologic effects. The most serious side effects of gold therapy are hematologic and include thrombocytopenia, agranulocytosis, and aplastic anemia. These complications are rare. Granulocytopenia may be noted incidentally on routine blood tests or may present with fever and pharyngitis. Thrombocytopenia is not dose-related and may occur after very low cumulative doses of gold. Aplastic anemia is a rare complication and has been reported even long after the cessation of gold therapy. For the first few months of therapy, complete blood cell and platelet counts should be performed before each gold injection is given. If no changes have occurred after 3 to 4 months, the tests can be performed at 2-week intervals and, ultimately, at monthly intervals. A trend toward progressive cytopenias may be observed by making a flow sheet of the patient's laboratory data, including white blood cell count, hemoglobin level, platelet count, polymorphonuclear percentage, and absolute neutrophil count. Management of severe hematologic gold toxicity, such as thrombocytopenia, includes the administration of 60 mg of prednisone daily in three divided doses; 200 mg of anabolic steroids such as testosterone propionate IM three times weekly; and chelating agents such as dimercaprol, penicillamine, and ethylenediamine-tetraacetic acid (EDTA). N -acetylcysteine may be employed for the treatment of leukopenia and thrombocytopenia. However, it has not been proven that any of these therapies influence outcome. Granulocyte colony-stimulating factor (G-CSF) has been effective in the setting of gold-induced leukopenia.
          4. A nitritoid reaction consisting of hypotension, flushing of the face and neck, shortness of breath , tongue swelling, nausea, and vertigo can sometimes occur after administration of gold compounds, especially gold thiomalate. Management includes switching to another gold compound or decreasing the dosage and administration with the patient supine.
          5. Miscellaneous. A number of unusual adverse reactions have been ascribed to gold, including enterocolitis, intrahepatic cholestasis, skin hyperpigmentation, peripheral neuropathy, deposits of gold in the cornea (chrysiasis), and pulmonary infiltrates.
        5. Repeated treatment. Patients with severe toxicity, such as thrombocytopenia, aplastic anemia, exfoliative dermatitis, or nephropathy, should not be re-treated with gold. With milder side effects, especially mucocutaneous reactions, it may be possible to reinstitute gold beginning with low doses (e.g., 5 mg) 4 weeks after resolution of the skin reaction.
      2. Antimalarial drugs. Hydroxychloroquine (Plaquenil) is an effective, slow-acting, antimalarial DMARD with an optimal balance between positive and negative clinical effects.
        1. Indications. Hydroxychloroquine is commonly employed as a single agent in the setting of mild disease or in combination with other DMARDs in the treatment or more severe or refractory disease.
        2. The mechanism of action is probably related to accumulation of the drug in the acid vesicular lysosomal system of mononuclear cells, granulocytes, and fibroblasts. In macrophages, antimalarials may inhibit antigen presentation and IL-1 release.
        3. Therapeutic approach. Studies have demonstrated the effectiveness of hydroxychloroquine in RA following 4 to 6 months of treatment. It is considered a somewhat weaker agent than MTX or gold. However, because of its relatively low toxicity, it is often used in patients with milder courses of RA or in combination regimens. Tablet size is 200 mg. Six weeks to 6 months of therapy may be required before a therapeutic effect is evident. If objective improvement does not occur within 3 to 6 months, the drug should be discontinued or another DMARD should be added.
        4. Dosage and administration. The initial dosage (5 to 6 mg/kg daily) is given with food to decrease gastric intolerance. When a good response is obtained (4 to 12 weeks), maintenance of effect is usually satisfactory at the next lower whole-tablet dosage level. The dose can be adjusted by cutting the tablet in half (the taste can be bitter) or by taking a whole tablet on an every-other-day basis (e.g., 200 mg one day and 400 mg the next gives a mean dose of 300 mg).
        5. Side effects
          1. Eye toxicity. Antimalarial drugs, particularly chloroquine, which is a cousin of hydroxychloroquine, have a history of causing retinal toxicity. The premaculopathy phase of retinal toxicity is an early-warning period and is completely reversible. The maculopathy phase is not reversible. Such retinal changes can occur after chloroquine is stopped; this is not true of hydroxychloroquine. Because of this potentially serious retinal side effect, the patient must be seen by an ophthalmologist experienced in the use and surveillance of antimalarial drugs at least every 6 months. At the first sign of visual impairment (especially reduced sensitivity to red light), the drug should be stopped. With such close and conservative ophthalmologic follow-up and appropriate dosing, permanent retinal changes should be either nonexistent or very rare. Adherence to the following rules ensures safety:
          2. Calculation of dosage is needed. The recommended dosage for hydroxychloroquine is 5 to 6 mg/kg daily.
          3. Ophthalmologic evaluation, before initiation of treatment and every 6 months thereafter, helps to prevent visual loss by detecting early disease in a reversible stage. The daily use of a red filter allows for an early warning sign of toxicity.
          4. Normal renal and hepatic function is necessary for safe use. Fixed dosages given regardless of a patient's renal and hepatic function, size, and age are not reasonable and lead to an increased risk for side effects.
          5. Other considerations. This drug is contraindicated in patients with significant visual, hepatic, or renal impairment, or porphyria. In pregnant women, it is traditionally contraindicated; however, the safety of the drug during pregnancy has been defined via experience with patients having SLE. The most common undesirable side effects are allergic skin eruptions and gastrointestinal disturbances, including nausea, diarrhea, and unexplained weight loss.
      3. Sulfasalazine (SSZ), a compound synthesized through the linkage of 5-aminosalicylic acid (5-ASA) and sulfapyridine, was initially developed in the 1930s for the treatment of RA. Randomized controlled trials have demonstrated significant beneficial effects of this drug in RA. Although the exact mechanism of action in RA is unknown, there is evidence for antiinflammatory and immunomodulatory actions.
        1. Indications. Because of its convenient oral dosing, safety profile, and fairly rapid onset of action, SSZ may be an appropriate choice for early and mild cases of RA. It is often used before MTX and with similar clinical indications to those of antimalarial drugs. It is at times employed in combination drug regimens, such as SSZ plus hydroxychloroquine plus MTX.
        2. The mechanism of action is unknown, but possibilities include inhibition of prostaglandins, ability to modify pro-inflammatory reactive oxygen species released from activated macrophages, reduction of activated circulatory lymphocytes, and effects on the metabolism of folic acid and adenosine.
        3. Therapeutic approach. As a single agent, SSZ is somewhat interchangeable with hydroxychloroquine, primarily in the setting of mild RA. It works rapidly, with clinical benefits becoming apparent at 4 weeks. In studies in which SSZ was used in combination with gold or MTX, effectiveness was increased, but so was discontinuation because of toxicity.
        4. Dosage. Begin with a 500-mg enteric-coated tablet with breakfast for 1 week. Then, if laboratory test results are stable on a weekly basis, the dose is increased by 500 mg/wk during 4 weeks to an eventual dose of 1,000 mg with breakfast and dinner. The optimal dose range is between 2 and 3 g/d.
        5. Common side effects. SSZ ranks with antimalarial drugs and auranofin as the best tolerated of the DMARDs. Adverse effects primarily occur in the first 2 to 3 months of therapy. The most common side effects are gastrointestinal, mainly nausea and vomiting. This problem is often avoided with the use of enteric-coated tablets and administration with meals. Leukopenia has occurred in 1% to 3% of patients, and agranulocytosis, although rare, may occur early in the course of SSZ treatment. Thus, monitoring should include weekly complete blood counts and differential counts for the first month, then every 2 to 4 weeks for 3 months, and eventually every 6 to 8 weeks. Make sure that your patient is aware of the warning signs of leukopenia, such as fever and sore throat. Note: In RA patients negative for RF and positive for ANA in whom SLE is a possibility, SSZ should be avoided because sulfa drugs may lead to a flare of SLE.
      4. D -Penicillamine has been shown in controlled studies to be effective in reducing inflammatory synovitis in approximately 50% of patients with RA, a response rate similar to that of gold. Toxic side effects are common (60% of patients) and may be severe, and there is a long time period between drug institution and clinical response. For these reasons and because of the availability of other effective and well-tolerated DMARDs, D -penicillamine is no longer a first- or second-line agent for RA. D -Penicillamine may be of value when extraarticular manifestations of RA dominate the clinical picture.
        1. Indications. In the l980s, D -penicillamine was commonly used to treat moderate to severe RA. Now, it is employed as a third-line agent for patients who have been unresponsive to other DMARDs or in whom extraarticular manifestations are prominent. Close monitoring and an appreciation of the side effect profile of this drug are mandatory.
        2. The mechanism of action is not well understood but is believed to be related to immunomodulation via an effect on sulfhydryl reactions in mononuclear cells.
        3. Therapeutic approach. A history of allergy to penicillin is not a contraindication to the use of D -penicillamine, but institution of therapy in such patients should initially be carried out under close observation and with low doses, such as 125 mg. Contraindications include pregnancy and renal failure. This drug should not be prescribed for patients who are unreliable, do not have access to a telephone, or who would have difficulty in reporting potential side effects.
        4. Administration. D -Penicillamine is available as 125-mg and 250-mg tablets. Up to 12 weeks may elapse between the initiation of D -penicillamine therapy and signs of improvement. Thus, increments in dosage should be made at 12-week intervals. The initial regimen is a single daily dose of 250 mg, which is maintained for 3 months. If no clinical evidence of response is noted, the dose is doubled to 500 mg. Three-monthly increases to 750 mg and then the final dose of 1,000 mg may eventually be needed, with the understanding that higher doses are associated with an increased frequency of side effects. Rarely do patients respond to doses of less than 250 mg, and evidence of improvement usually is seen after the first 3 to 6 months of therapy. One should attempt to reduce the daily dose in decrements of 125 mg at 3-monthly intervals to determine the least amount of drug required to sustain clinical improvement.
        5. Common adverse effects include the following:
          1. Skin and mucous membranes. Pruritus and skin rash represent the most common side effects, and dermatitis may occur at any time during the course of therapy. These may be controlled by administration of an antihistamine and a moderate reduction in dosage. If rash persists despite these measures, the drug should be stopped for at least 3 months. Repeated administration of low doses (125 mg) may be possible after this. A sudden febrile response, often associated with a generalized rash, may occur within the first 3 weeks of therapy; defervescence occurs when the drug is stopped. However, in this situation, rechallenge is not recommended. Stomatitis has been observed and often clears with decreased dosage. If oral ulcers persist, the drug should be stopped permanently. Blunting or alteration in taste perception (dysgeusia) may occur during the first 6 weeks of therapy. It may gradually disappear despite continuation of therapy or may persist even after therapy is stopped.
          2. Hematologic toxicity is potentially dangerous and dictates the need for close follow-up. Mandatory testing includes complete blood cell counts, including platelet count, differential counts, and definition of the absolute neutrophil count, at 2-weekly intervals for the first 6 months of therapy and at least monthly thereafter. Recording laboratory data on flow sheets will permit early detection of downward trends in white blood cell or platelet counts. Hematologic toxicity may be sudden in onset and may occur in the interval between scheduled laboratory studies. Thus, patients must be aware that they need to report the development of sore throat, skin or mucous membrane bleeding, infection, or fever. Downward trends of white blood cell and platelet counts ( specifically a white cell count & pound ; 3,000/mm 3 or a platelet count <100,000/mm 3 ) require immediate and permanent discontinuation of D -penicillamine therapy. Leukopenia associated with thrombocytopenia or thrombocytopenia alone may indicate impending aplastic anemia.
          3. Renal toxicity. Proteinuria is encountered in up to 20% of patients on long-term therapy. If proteinuria of 2+ or more has persisted for 30 days and other causes of renal disease have been excluded, a 24-hour urine protein determination should be performed and repeated at monthly intervals. As long as the protein excretion does not exceed 1 g/d and creatinine clearance is stable, the drug may be continued. Proteinuria may clear completely with only a 125-mg reduction in the daily dose. Development of hypoalbuminemia, nephrotic syndrome, or significant hematuria requires discontinuation of the drug. Nephrosis is reversible, but urinary abnormalities may persist up to 1 year. Rechallenge will usually lead to recurrence of proteinuria.
          4. Miscellaneous. Uncommon but severe side effects include autoimmune syndromes such as drug-induced lupus, Goodpasture's syndrome, and polymyositis. They require drug discontinuation and at times disease-specific treatment, and they usually resolve after the drug is stopped.
      5. Immunosuppressive and immunomodulatory drugs. Five classes of immunosuppressive drugs are now being employed in the treatment of RA: the antimetabolite/antiinflammatory drug methotrexate (MTX), the purine analog azathioprine (AZA), the cyclic polypeptide cyclosporine (CyA), the pyrimidine inhibitor leflunomide, and the alkylating agent cyclophosphamide (CTX). Of all the DMARDs and immunosuppressive agents, MTX is now considered the central DMARD in single or multiple drug regimens.
        1. Methotrexate. Given its safety profile and tolerance by patients, relatively rapid onset of action in 4 to 6 weeks, effectiveness, and the availability of various routes of administration (PO, IM, IV, or SC), MTX has dominated the therapeutic armamentarium as a first-or second-choice disease-modifying medication in the treatment of RA. Studies have demonstrated that RA patients remain on MTX longer than on other DMARDs (45% to 62% on MTX for 3 years vs. 18% to 32% on IM gold, 35% on hydroxychloroquine, 11% to 39% on SSZ) because of a combination of effectiveness and safety. Evidence that MTX retards bony damage is provided by many of the available studies.
          1. Indications. Although MTX does not induce a complete remission, it is a highly effective drug in controlling the inflammatory process and markedly improving function in a majority of RA patients. Its position in the RA armamentarium is either as a first-line agent, started soon after the diagnosis is made, or as a powerful second-line drug added to or used in place of ineffective courses of antimalarial drugs or SSZ.
          2. Mechanism of action. MTX inhibits dihydrofolate reductase, thus interrupting purine biosynthesis and synthesis of thymidilic and inosinic acids. However, MTX is metabolized intracellularly to MTX polyglutamates, and these long-lived metabolites inhibit dihydrofolate reductase plus other folate-dependent enzymes. Other antiinflammatory effects include reduced polymorphonuclear chemotaxis and decreased production of IL-1 and IL-2 production. In vivo and in vitro studies have demonstrated inhibition of intracellular activity of 5-aminoimidazole-4-carboxamidoribonucleotide transformylase. This inhibition is associated with increased release of adenosine into the extracellular milieu. Antiinflammatory properties of adenosine are mediated by specific receptors on the surface of cells. In inflammatory arthritis, the A 3 receptor occupancy inhibits cytokine release. This mechanism may be related to some adverse effects of MTX, such as nodulosis.
          3. Therapeutic approach. The antiinflammatory effect of MTX has been repeatedly demonstrated, and one study has shown that the effect is dose-related. Although the initial dose of MTX continues to be 7.5 mg/wk, the dose at which most patients demonstrate a well-defined clinical improvement now ranges between 15 and 25 mg/wk. Most patients will profit from the addition of 1 mg of folic acid daily without any reduction in drug efficacy. The drug appears to have a steroid-like clinical effect with relatively rapid onset (4 to 6 weeks) and offset of action. The latter point must be appreciated because severe disease flares commonly occur when the drug is stopped, and at times it is difficult to regain disease control. If MTX is stopped for only 2 to 3 weeks (e.g., in the perioperative period or because of minor side effects), disease control can be maintained simply with the repeated administration of MTX. However, if MTX must be stopped permanently, an alternative DMARD, such as SSZ, hydroxychloroquine, AZA, or an anti-TNF biologic should be started to avoid disease exacerbation. Other issues that must be appreciated before MTX is started are the following:
            1. Cost and route of administration. The cost of the oral medication is high, especially when the expense of monitoring is added. The cost of parenteral MTX is much lower, and many patients are switched from the oral to the SC, IM, or IV route because of lack of response or intolerance to the oral medication. Some physicians give the less expensive parenteral solution orally in orange juice . Bioavailability studies have demonstrated that approximately 80% of the drug is absorbed via the oral route, and more than 90% by other routes. Patient acceptance of the SC route is high, and the ability to inject it themselves at home avoids an office visit.
            2. Nodulosis. In patients both with and without a history of nodular disease, MTX can lead to the development of painful new nodules. This is particularly prominent on the fingers and can further limit function. The fact that a medication that is so effective in controlling the inflammation of RA can stimulate the formation of a characteristic inflammatory symbol of the disease underscores the incompleteness of our understanding of this disease and the actions of MTX.
            3. Liver toxicity in the form of fibrosis or cirrhosis was an early concern and evolved from prior clinical experience with a daily regimen of MTX in patients with psoriasis and psoriatic arthritis. However, with the use of weekly MTX dosing, the avoidance of MTX in high-risk patients, and an optimal monitoring approach, such liver problems are uncommon in RA patients treated with long-term MTX. Studies of MTX treatment in RA patients quantifying the risk for fibrosis/cirrhosis have shown that this problem occurs in only 1 in 1,000 patients.
            4. Oncogenicity. One of the reasons why MTX has supplanted AZA in the treatment of RA has been its lack of oncogenicity. However, MTX treatment has rarely been associated with the development of non-Hodgkin's B-cell lymphomas.
          4. Common adverse effects
            1. Gastrointestinal intolerance. Nausea and vomiting occur in nearly 20% of patients, usually those on oral MTX. This can be avoided in most cases by switching to SC, IM, or IV administration. Diarrhea occurs in 10% of patients and may be avoided by altering the route of administration.
            2. Stomatitis occurs in 6% to 10% of patients and may be avoided with the use of between 1 and 5 mg of oral folic acid daily.
            3. Hypersensitivity pneumonitis. This acute pulmonary disorder, manifested by cough, dyspnea, eosinophilia, and diffuse pulmonary infiltrates, can occur in as many as 5% of MTX-treated patients. It can be quite severe, always requires the discontinuation of MTX, and may necessitate a course of high doses of steroids. Rechallenge is not recommended. This problem may be more common in patients who smoke or have had interstitial lung disease associated with RA.
            4. Teratogenicity and induction of abortion. MTX must be discontinued 3 months before any male or female patient attempts to have a child. MTX is an abortifacient, and women taking it should be made aware of this fact and counseled regarding the need to use appropriate birth control techniques while taking this medication.
            5. Oncogenicity. Based on longitudinal data from large studies of patients treated with MTX for psoriasis and choriocarcinoma, MTX was not thought to be oncogenic. However, more than 50 cases of non-Hodgkin's B-cell lymphomas have been reported worldwide in patients taking MTX. In eight of these patients, discontinuation of MTX led to spontaneous disappearance of the lymphoma, without a need for chemotherapy. Although the exact incidence of this association is unknown, it is probably low but should be discussed with patients. It must be appreciated that RA patients already have an inherent increased risk for the development of lymphoproliferative disorders. MTX may be a cofactor, along with Epstein-Barr virus, in altering immunosurveillance capability and triggering lymphomas in some RA patients.
            6. Bone marrow toxicity. This can occur on low-dose, weekly MTX but is uncommon. The synergistic toxic effects on bone marrow of taking antibiotics that contain sulfa along with MTX should be appreciated.
            7. Hepatic toxicity. The following information is important in guiding hepatic surveillance in RA patients treated with methotrexate:

              Methotrexate is relatively safe for the liver, and SGOT levels correlate with liver biopsy grade. Despite prior concepts regarding the inability of liver function test abnormalities to predict MTX-induced liver disease, recent studies in RA patients support the fact that serial elevations of aminotransferases [AST (SGOT) and ALT (SGPT)] and decreases in albumin have been found to correlate with the progression of histologic abnormalities defined by serial liver biopsies. In such liver biopsy studies, Kremer found that the overall hepatic histologic grade does increase with time. In the patients reported, minimal fibrosis was developing; however, almost half the patients had fibrosis that was not present at baseline. Among 13 patients with RA treated with MTX in whom Kremer identified fibrosis, some lost fibrosis on follow-up, seven showed fluctuation in grading, and none showed progression of fibrosis. Hence, fibrosis appeared to be an inconsistent and inconsequential feature. There were statistically significant correlations between liver function test abnormalities and liver biopsy grade after approximately 8 years of MTX. It is important to note that the extent of fibrosis correlates poorly with the extent of hepatic dysfunction.

              Note: Alcohol should be completely avoided in patients treated with MTX. The use of alcohol adds an unacceptable risk for the development of liver inflammation and damage.

              MTX-induced cirrhosis and liver failure are uncommon in RA patients. In a survey of more than 2,200 members of the American College of Rheumatology (ACR) who had treated 16,600 patients with MTX, Walker et al. found 24 cases of cirrhosis and liver failure, giving a 5-year cumulative incidence of approximately 1 in 1,000 treated patients. Late age at first use of MTX and duration of therapy with MTX were independent predictors of serious liver disease.

              Given the above data and the risks and cost of liver biopsy, the following indications for liver biopsy have been formulated:

              The ACR has published a position paper regarding liver biopsy in MTX-treated RA patients. With their interpretation of the above data, they do not recommend baseline or follow-up biopsies unless the patient, in every 6-weekly liver function test, demonstrates persistent or recurrent elevations (even minor) of transaminases or decreases in albumin. This is a clear shift in position from prior (not from the ACR) recommendations for a biopsy between a cumulative dose of 1.5 to 5.0 g or after 3 to 5 years of treatment. The physician should be aware that this stance differs greatly from that taken by dermatologists in their treatment of psoriasis with MTX, and also does not address similar questions regarding the use of MTX for psoriatic arthritis.

              If a patient is an alcoholic or has known alcoholic liver disease and every other drug has failed to control the disease, a biopsy should be performed before initiation of MTX treatment to guide therapeutic decisions.

              For patients with baseline abnormal liver function test results of unknown cause, a biopsy would be performed to define the following disorders: hepatotoxin-induced liver disease, liver damage from prior or ongoing viral infections, and occult alcoholic liver disease.

            8. Opportunistic infections have been reported in some RA patients treated with weekly, low-dose MTX. The combined immunosuppression of corticosteroids and MTX may contribute to the risk for such infection. Appropriate immunizations should be offered to RA patients taking MTX.
            9. Nodulosis. The development of multiple, new, small, painful nodules on the hands and elsewhere can be quite uncomfortable and functionally limiting. These often occur despite excellent disease control elsewhere. The addition of hydroxychloroquine or colchicine has, in rare patients, led to some control of the development of nodules.
        2. Azathioprine. This purine analog has had an excellent track record in terms of both effectiveness and safety in patients with RA. Through the years, it has been used as a second- or third-line drug for the treatment of moderate to severe RA. Presently, it is considered for patients who have failed other DMARDs, such as MTX, and may be used in combination with other medications, such as hydroxychloroquine.
          1. Indications. For established RA after failure of several DMARDs, or as a steroid-sparing and disease-controlling agent in rheumatoid vasculitis.
          2. Mechanism of action. Reduction in circulating lymphocytes, mixed lymphocyte reactivity, and immunoglobulin synthesis have been demonstrated. These are probably caused by suppression of inosinic acid synthesis and inhibition of IL-2 secretion.
          3. Therapeutic approach. AZA is an effective drug in the treatment of RA, with many studies demonstrating its similarity in efficacy to IM gold, D -penicillamine, MTX, and other DMARDs. Its use is somewhat limited by its potential oncogenicity. The long-term experience with AZA in patients with RA has proved that this drug in this population has an acceptable profile of toxicity. However, the overall oncogenic potential of this drug must be considered before it is prescribed to treat a nonmalignant disorder.
          4. Administration. AZA is available in 50-mg tablets. Therapy is begun with 50 mg/d, and the dosage is increased by weekly 50-mg increments until a maintenance dose of 2 to 3 mg/kg is reached. The usual daily dose is 100 mg. Close monitoring is indicated and includes complete blood cell counts with platelet and differential counts weekly for 1 to 2 months, then every 2 weeks for 1 to 2 months, and eventually monthly. Liver function tests should be carried out every 1 to 2 months if the patient has excessive nausea or vomiting or if a fever develops. If gastrointestinal symptoms occur following administration of the drug, it may be given in a single daily dose before bedtime to minimize this effect. If a hypersensitivity reaction develops manifested by fever, hypotension, and liver function test abnormalities, the drug should be stopped immediately and never started again. Reinstitution of AZA in this situation can be fatal.

            Caution: Allopurinol inhibits the metabolic breakdown of AZA, and if the drugs are used concomitantly, potentially toxic levels of AZA and its metabolites may accumulate. Thus, this drug combination should be avoided because of the potential for severe bone marrow suppression. If it is essential that the drugs be used together, the dose of AZA should be decreased to one-third of the usual dose. Even then, close hematologic monitoring should be carried out.

          5. Common adverse effects include the following:
            1. Dose-related bone marrow suppression with leukopenia and thrombocytopenia.
            2. Increased susceptibility to infection, primarily viral, such as herpes zoster, but also bacterial, and gastrointestinal intolerance, such as nausea and vomiting. AZA can lead to liver enzyme abnormalities and even clinically significant hepatitis. At times, hepatitis may be part of a hypersensitivity reaction with associated fever and hypotension. If this occurs, AZA should be stopped permanently. Pancreatitis may occur and clears when the drug is stopped.
            3. Oncogenicity. A 50-fold increase in relative risk for malignant disease, primarily non-Hodgkin's lymphoma, has been demonstrated in renal transplant patients treated with AZA. In RA, however, the related risk for lymphoma is confounded by an increased relative risk secondary to RA per se or the coexistence of Sj gren's syndrome. Overall, there appears to be a small added risk (relative risk, 1.3) for malignancy when AZA is used in patients with RA.
            4. Teratogenicity. Although there is mounting evidence demonstrating the safe use of AZA during pregnancy in patients with active SLE, the recommendation is that AZA not be used during pregnancy.
        3. Cyclophosphamide. CTX is an extraordinarily effective disease-modifying agent for the treatment of RA. However, because of its significant potential toxicities, its role is now limited to use in the most severe, refractory cases of RA or in those associated with life- and organ-threatening RA vasculitis. Only physicians experienced in the indications for and monitoring of CTX should administer this drug.
          1. Indications. Treatment with CTX should be limited to those clinical situations in which RA continues to be active and destructive despite the use of many DMARDs, including MTX, CyA, AZA, and anti-TNF biologics. It is also an effective disease-modifying agent in patients with active rheumatoid vasculitis. The physician can use CTX initially, for 3 to 6 months, to gain control of the disease, and then switch back to another medication, such as 15 to 20 mg of MTX per week, to maintain disease suppression. In this way, one employs the best possible medication initially, then changes to a safer therapeutic choice. Daily oral CTX may be more effective than monthly IV CTX, but the choice is often dictated by practical clinical considerations and patient comorbidities.
          2. Mechanism of action. The active metabolites of CTX, principally phosphoramide mustard, cross-link DNA so that it cannot replicate. CTX is cytotoxic to dividing and resting lymphocytes. It induces lymphocytopenia, with B cells more affected than T cells. It readily suppresses primary cellular and humoral immune responses. It suppresses many cell-mediated responses and also has antiinflammatory properties.
          3. Therapeutic approach. When CTX is compared with other DMARDs, its clinical effectiveness is equal to that of AZA and IM gold. In two studies, it has been shown to retard bone destruction. Although no placebo-controlled studies have been performed, daily oral CTX is thought to be the drug of choice for the treatment of necrotizing vasculitis associated with RA, so-called malignant RA. Intermittent IV CTX is also being used, but this route of administration may not be as effective as daily oral treatment.
          4. Administration. CTX (Cytoxan) tablets are 50 mg in size. The usual oral dose begins with 50 mg/d for 1 week, and then the dose is increased by 50 mg if the complete blood count is stable. The usual oral therapeutic dose is 2 mg/kg daily, or 75 to 125 mg/d. Higher doses may be needed in severe cases. Complete blood count, differential and platelet count, and urinalysis are assessed every 7 to 14 days initially, then every 2 to 4 weeks after 2 to 3 months of stable dosage. The IV regimen is 0.5 to 0.75 g/m 2 monthly. Once the patient has responded to oral and IV CTX, a switch to a less toxic DMARD, such as MTX, is appropriate to decrease the potential for oncogenicity, sterility, and other side effects. Given the renal excretion of CTX metabolites, dose adjustments and careful hematologic monitoring are needed in patients with renal insufficiency.
          5. Common adverse effects
            1. Oncogenicity. Alkylating agents in general are associated with the highest risk for tumor formation. Kinlen's experience with 643 RA patients suggests a relative risk of 12.8 for all cancers combined, a risk of 10.9 for non-Hodgkin's lymphoma, and a 10-fold increased risk for bladder cancer. There also appears to be an increased risk for acute leukemia. A major deterrent to the use of CTX in RA is the risk for cancer in treating a disease that is nonmalignant. Patients with a history of cancer should avoid CTX.
            2. Bone marrow toxicity. Dose-related marrow suppression is 6% to 32% for leukopenia and 4% for thrombocytopenia. These abnormalities tend to respond quickly to discontinuation or a decrease in dosage of CTX.
            3. Risk for infection. The overall risk is high (22%), and herpes zoster may occur in 30% of treated RA patients.
            4. Infertility, azoospermia, and amenorrhea. The risk for all of these increases with increasing duration of therapy, cumulative doses, and age in women. Once they have appeared, they are usually permanent.
            5. Bladder disorders. Hemorrhagic cystitis has been reported in one-third of patients receiving daily oral CTX, and there is a significant but lower incidence of bladder fibrosis and carcinoma . These abnormalities are caused by the CTX urinary metabolite acrolein. IV CTX is associated with a significantly lower incidence of bladder problems. Appropriate hydration, nighttime voiding , and the use of 2-mercaptoethane sulfonate can help to decrease bladder toxicity. In patients on long-term CTX, either oral or IV, monthly urinalysis is needed to monitor for hematuria. The finding of hematuria should be followed by cystoscopy. Note: the development of bladder cancer can occur many years after the institution of CTX. Thus, long-term surveillance is needed.
        4. Cyclosporine (Sandimmune, Neoral). CyA, an immunomodulating drug previously effective in preventing transplant rejection , has been found to be an effective and safe DMARD when employed in low doses and in a combination chemotherapeutic regimen with MTX. Initial concerns of renal dysfunction can be minimized by close monitoring.
          1. Indications. Short-term studies have shown the efficacy of CyA against both placebo and drugs such as AZA, hydroxychloroquine, and D -penicillamine. However, CyA is probably most effective and safest when low doses are added to MTX in treating RA patients with a suboptimal response to MTX alone. Close renal monitoring is necessary at any dose of CyA.
          2. Mechanism of action. CyA is a lipophilic cyclic polypeptide isolated from fungi. It has impressive immunosuppressive activity without causing bone marrow toxicity. CyA inhibits the transcription of DNA and thus prevents accumulation of mRNA for several cytokines. It also inhibits T-cell interaction with macrophages, leading to a decreased synthesis of IL-2, and suppresses the synthesis and release of IL-2 by helper T cells, rendering T cells unresponsive to IL-2. CyA blocks the amplification of cellular immune responses in the generation of T-cell effectors and other functions dependent on IL-2. CyA also inhibits the expression of the CD40 ligand, leading to decreased proliferation of B lymphocytes. Myeloid and erythroid lines, however, are not inhibited.
          3. Therapeutic approach
            1. Clinical use. Studies of low (2.5 mg/kg) and moderate doses of CyA have shown the drug to be effective in controlling inflammation, improving function, and retarding radiologic progression in RA. Nephrotoxicity has been the major limiting factor preventing the use of higher doses. Therefore, patients should be treated with doses no higher than 2.5 to 3.0 mg/kg daily. CyA appears to be less effective as a single agent, and when used in this way, it often is instituted as a third-line DMARD. Combination therapy with MTX and CyA is thought to be logical because of the complementary biologic and immunologic effects of the two agents. CyA was shown to be effective when added to the regimen of patients who had shown a suboptimal response to MTX alone. The combination of CyA at a mean dose of 2.97 mg/kg daily plus 15 mg of MTX weekly demonstrated no significant increase in toxicity over that seen with MTX alone.
            2. Dose initiation and increase. A dosage schedule that can optimize the careful balance between the efficacy and safety of CyA has been sought. The initial dose should be 2.5 mg/kg daily in two divided doses every 12 hours, and dose increases must follow the principle of go slow, go low. If there is no clinical response after 4 to 8 weeks, the CyA dose should be increased by 0.5 to 1.0 mg/kg at l- to 2-month intervals to a maximum dose of 5 mg/kg daily (unless this is prevented by a rise in serum creatinine ³ 30% to 50%). Caution should be exercised with doses above 4 mg/kg daily, and the safest final recommended dose range is 2 to 3 mg/kg daily. Once the largest required dosage has been reached and no further response is expected after a patient has been stable for 3 months, then the dosage can be decreased by 0.5 mg/kg to the lowest effective dose. Lack of response after 3 to 6 months should lead to a reassessment of the drug regimen or drug discontinuation.
            3. Renal function: dose reduction and monitoring. Blood pressure should be monitored every 2 weeks for the initial 3 months and then monthly if stable. More frequent monitoring will be required if the dosage is increased. If the serum creatinine level increases to 30% above the baseline on two occasions, then the daily dose should be decreased by 0.5 to 1 mg/kg. If after the dosage is lowered the creatinine level remains more than 30% above the baseline, CyA should be stopped and then resumed after 1 month only if the creatinine level returns to less than 15% above the baseline. Treatment for 6 months or 1 year seems safe under strict monitoring; after a longer administration, nephrotoxicity may not be reversible. CyA should be avoided in patients with preexisting renal disease (i.e., creatinine clearance <80 cc/min).
            4. Blood pressure. If hypertension develops (diastolic >95 mm Hg), the response should be to lower the dose of CyA or use antihypertensive agents that do not interfere with CyA metabolism.
            5. Serum cyclosporine levels. Determination is not required but may be useful to detect noncompliance or drug interactions. Indications for reducing the dose should include a decrease in renal function or an increase in blood pressure, not CyA levels. If serum creatinine increases to more than 30% above baseline, the dose should be reduced by 25% to 50%. Blood pressure and serum creatinine monitoring are indicated throughout the treatment period, with appropriate adjustment of dosage of CsA. When the dose is stable, creatinine levels should be measured every 2 to 4 weeks.
            6. Other screening tests. Liver function tests, complete blood counts, and urinalyses should be performed along with determination of serum creatinine levels.
            7. Drug interactions. CyA serum levels can be increased by drugs that decrease P-450 metabolism, including calcium antagonists, erythromycin, ketoconazole, and histamine 2 blockers. Thus, with these medications, the CyA dosage should be adjusted downward. Alternatively, anticonvulsants such as dilantin and rifampicin increase the metabolism of CyA and thus reduce the concentration.
          4. Contraindications include current or past malignancy, uncontrolled hypertension, renal dysfunction, and abnormal liver function test results with enzymes at twice baseline value. Caution should be exercised in patients who are over 65 years of age, taking NSAIDs, or lactating, and in those with controlled hypertension. CyA should be avoided during pregnancy.
          5. Drug preparations. Two different preparations are available, the initial oil and alcohol-based solutions and the newer microemulsion-based formulation Neoral, recently developed to increase the bioavailability of CyA. Neoral has more predictable absorption. Selection of the appropriate dosage of the microemulsion should take into account the enhanced bioavailability, especially with respect to the possible renal effects. When changing patients to Neoral from alternative preparations, a 1:1 dose-conversion strategy is employed. However, close creatinine and blood pressure monitoring is mandatory before and after this transition.
          6. Common side effects
            1. Renal toxicity. The renal effects of CyA are thought to be caused by the following mechanisms: vasoconstriction leading to ischemia, disruption of the mitochondrial membranes, increased procollagen synthesis, and possible coagulopathy. CyA toxicity is characterized by interstitial fibrosis, tubular atrophy, and renal arteriopathy. Dose-related decreases in glomerular filtration rate with corresponding increases in serum creatinine are common during CyA immunosuppression. This risk is increased with dosages greater than 5 mg/kg daily or with persistence of serum creatinine levels more than 30% over the baseline values. CyA doses of 10 mg/kg daily for even 2 months may lead to an irreversible loss of more than 10% of renal function in RA patients. In a study by Tugwell, serum creatinine levels failed to return to baseline during the 6-month follow-up period in only 2 of 72 patients treated with CyA at an average of 3.8 mg/kg daily for 6 months. Serum creatinine rose and creatinine clearance decreased during the period of CyA administration; however, this effect stabilized after month 4, with no further changes thereafter. After discontinuation of CyA, serum creatinine fell to within 15% of baseline in all except two patients. The safest CyA regimen consists of administration of low doses for no longer than 1 year and avoidance of the concomitant use of nephrotoxins such as NSAIDs and aminoglycosides.
            2. Elevated blood pressure occurs in one-third of RA or psoriatic arthritis patients treated with CyA. Antihypertensive agents may be needed, but potassium-sparing drugs should be avoided because CyA may increase serum potassium. Calcium channel blockers may increase CyA levels by decreasing its metabolism, and changes in CyA dosage may be needed. This effect can also be employed in an attempt to decrease the CyA dose and its attendant side effects.
            3. Oncogenicity. CyA can potentially increase the relative risk for malignancy via its immunomodulatory effects. This is particularly important when combination drug regimens are employed, such as the use of MTX along with CyA.
            4. Other side effects include hepatotoxicity with higher doses of CyA; nausea or vomiting; and neurologic symptoms such as tremor, paresthesias, and gum hyperplasia. CyA is teratogenic and should be avoided during pregnancy.
        5. Leflunomide. This oral immunosuppressive agent demonstrated a combination of effectiveness and safety in uncontrolled and placebo-controlled European studies. On this basis, it has recently been cleared for use in the United States by the Food and Drug Administration and is widely prescribed in the treatment of refractory RA. This drug does not have the track record of MTX, CyA, and AZA, but it will probably attain a similar importance in the RA armamentarium.
          1. Indications. Leflunomide will probably be employed as a second-line DMARD, after MTX alone or MTX combinations fail to control the inflammatory process.
          2. Mechanism of action. Immunosuppressant effects of leflunomide may be related to blockade of the proliferation of immune cells via inhibition of pyrimidine nucleotide synthesis in T cells. It is a pro-drug and, as such, most of its clinical immunomodulatory activity appears related to an active metabolite. It is chemically unrelated to other immunosuppressants, such as CyA, MTX, and AZA. Leflunomide functions well as an immunosuppressive and antiinflammatory medication. Its ability to decrease the development of joint erosions is at least as good as that of MTX.
          3. Therapeutic use. Oral leflunomide is effective for treating patients with RA when given daily or weekly. However, compliance with the weekly regimen is poor, and adverse effects are more frequent than with daily dosing. Once-daily oral dosing of 20 mg has been associated with significant clinical improvement. Initial therapy involves a 100-mg dose daily for 3 days, followed by 20 mg PO daily.
          4. Common side effects. Monitoring for side effects includes serial complete blood counts, liver function tests, and observation for weight loss and gastrointestinal complaints. The long half-life of leflunomide may necessitate the use of cholestyramine in patients who have severe side effects or wish to become pregnant.
            1. Gastrointestinal effects. Nausea and vomiting may occur in 15% of RA patients and do not appear to be dose-related. Weight loss may be related to these gastrointestinal symptoms. Severe diarrhea can occur.
            2. Hepatotoxicity. Elevations of serum aminotransferases are dose-related and occur in 6% of patients receiving a 25-mg dose. Severe, symptomatic liver toxicity has not been reported. Leflunomide is metabolized in the liver, and so a history of liver disease should be factored into the decision to use it. Renal impairment does not appear to influence the pharmacokinetics of the primary metabolite of leflunomide. The combined use with MTX may lead to an increased incidence of abnormalities.
            3. Alopecia. Reversible alopecia is seen occasionally and is dose-related.
            4. Skin rash. This dose-related side effect can occur in up to 8% of patients treated with the 25-mg dose. Rare anaphylactic reactions have occurred.
            5. Hematologic effects have been seen in RA patients treated with the 25-mg dose of leflunomide but are uncommon.
      6. Novel biologic agents and immunotherapy in rheumatoid arthritis. Impressive research focused on the pathogenesis of RA has discovered many new mechanisms that illustrate the complex and multicellular nature of the disease. Potential sites for therapeutic intervention include cells such as T and B lymphocytes, macrophages, fibroblasts, endothelial cells, and dendritic cells, and their many products such as cytokines and adhesion molecules. The development of these agents have already revolutionized the treatment possibilities for patients with RA. How such agents will be merged with presently accepted and effective DMARDs such as MTX will be defined by their effectiveness as disease-controlling and disease-modifying agents, their side effect profile, and their cost.
      7. Minocycline. Tetracycline derivatives have many actions that could contribute to their effectiveness in RA, including their antibiotic activity, immunomodulatory effects, and antiinflammatory and metalloproteinase inhibitory capacity. Many well-designed trials have demonstrated a significant clinical improvement in early RA patients treated with minocycline in comparison with placebo, but not with other DMARDs. Side effects include dizziness, skin rashes, gastrointestinal symptoms, and headaches . Of note is the development of SLE-like manifestations in adolescents and young adults receiving minocycline for acne. Place of minocycline in the RA armamentarium: Minocycline should not be considered a first- or second-line DMARD to be used alone in the treatment of early RA. Pending the results of ongoing trials and studies comparing minocycline with other DMARDs, some rheumatologists are using minocycline at a dosage of 100 mg twice daily for patients with early, mild disease who refuse DMARDs such as hydroxychloroquine or as part of a combination regimen in patients with severe, refractory disease.
      8. Combination disease-modifying antirheumatic drug regimens. Combinations of DMARDs are now used by most rheumatologists in the United States to treat an estimated 24% of all RA patients. This trend is increasing because (a) the effectiveness of a single DMARD often wanes with time, (b) minor clinical improvements with single DMARD regimens are unacceptable, and (c) some combinations can be given safely with greater effectiveness than monotherapy. Combination regimens have evolved in parallel with our appreciation of the aggressive nature of RA and the need to intervene quickly and effectively to prevent joint damage, normalize function, and prolong life. This approach is similar to that employed by oncologists in their war on cancer. The groupings of medications that are now used by rheumatologists have been crafted either via a knowledge of their synergistic biologic effects (e.g., MTX plus CyA) or by admixing multiple safe and effective DMARDs with the eventual aim of finding a regimen that is more effective, but not more toxic, than each individual agent. However, certain basic beliefs have guided the most commonly used regimens; MTX is considered the best single DMARD and should be a component of any multiple drug regimen, and multiple DMARD regimens should be started after the RA patient has failed to respond to a single DMARD regimen. The cost of multiple drugs and their monitoring has to be factored into these therapeutic decisions. The clinical decision to employ combinations rather than the individual drugs within them should be based on the physician's clinical experience, the patient's prior response to medications, disease severity, and the presence of comorbidities. Some rheumatologists begin these combinations at a single point; most add drugs one by one as defined by the clinical response to the prior regimen. Almost all possible combinations of DMARDs have been employed, but the regimens most commonly used include the following:
        1. Methotrexate-hydroxychloroquine. This safe regimen combining two well-known and well-tolerated medications may lead to a moderate improvement over that noted when they are given singly . The dosages are similar to those for each drug alone: an initial dose of MTX of 7.5 mg/wk, increased to 15 to 20 mg/wk, plus 200 mg of hydroxychloroquine twice daily.
        2. Methotrexate-sulfasalazine. Initial concerns about possible synergistic toxicity with these two agents have not been supported by clinical studies. Because both are folic acid inhibitors, folic acid supplementation is needed in addition to monitoring for possible bone marrow depression. Dosages are similar to those used in monotherapy.
        3. Sulfasalazine-hydroxychloroquine. This is a safe regimen with minimal additive toxicity and moderate effectiveness. Dosages are similar to those used with monotherapy. Trials have demonstrated that this combination appears to be equal in effectiveness to MTX alone.
        4. Methotrexate-sulfasalazine-hydroxychloroquine. In a study that followed 60 patients for 3.3 years, therapy with all three active drugs provided substantially greater benefit than did therapy with MTX alone. Of these patients, 73% maintained a 50% improvement, 17% failed to maintain improvement, and 10% had side effects that led to withdrawal. Although 13% of the patients fulfilled criteria for remission, in most cases no drug in their three-DMARD was tapered and withdrawn. The MTX median dosage in the study was 17.5 mg/wk; for SSZ it was 1 to 2 g/d, and for hydroxychloroquine it was 400 mg/d.
        5. Methotrexate-cyclosporin A. The evidence from combination trials suggests that CyA can be considered in patients who have exhibited a suboptimal clinical response to MTX alone. The MTX dose at which CyA was added was 15 mg/wk; the CyA dosage should start at 2.5 mg/kg daily and increase to a maximum of 3.5 mg/kg daily, as noted above. Close monitoring is mandatory.
        6. Role of biologic agents in combination DMARD regimens. Biologic agents, described below, have been released and are widely used for the treatment of RA. The ultimate place of these agents in the armamentarium remains to be elucidated. Cost and convenience will be major considerations; however, their eventual disease-modifying potential and side effect profile will define their place in the treatment protocol. Initially, they will probably be employed in RA patients unresponsive to full-dose MTX or in DMARD combination failures. They may eventually play a key role in the induction of disease control and then be balanced with less expensive and more convenient DMARDs. The most promising biologic agents now involve cytokine-based therapies and are discussed above.
          1. Elimination of lymphocytes and subsets of T cells and inhibition of cellular function. Antibodies targeted at lymphocytes (CDw52) were associated with some clinical improvement but also serious side effects resulting from cytokine release and prolonged lymphopenia. Monoclonal antibodies aimed primarily at CD4+ T cells had variable results, but the degree of clinical improvement was disappointing and the profound lymphopenia needed for minimal improvement did not justify the treatment. Future therapies targeted at the arthritogenic clones or co-stimulatory molecules may modulate T lymphocytes and be more specific and less toxic. Therapies directed toward molecules involved in the trimolecular complex (MHC plus T-cell receptor plus processed peptide antigen) will probably become increasingly important.
          2. Blocking adhesion molecules. Blocking leukocyte migration may be an important intervention at the effector phase. Initial trials with anti-ICAM-1 monoclonal antibody were reported to be encouraging.
          3. Blocking cytokine and receptor function. Blockade of cytokines or their receptors with anti-TNF- a , soluble TNF- a receptors, and anti-IL-1, or immune deviation with IL-10 and IL-4, are examples of current research directions. TNF- a inhibitors: TNF- a is a critical initiating and perpetuating pro-inflammatory molecule in rheumatoid synovitis. Two different approaches have been taken to inhibit the action of this molecule:

            Soluble tumor necrosis factor receptor fusion protein (enbrei, etanercept). Soluble TNF receptors are the shed extracellular portion of the membrane-bound molecule. Such shed receptors work as antiinflammatory molecules because they bind with and competitively inhibit the binding of the pivotal pro-inflammatory cytokine TNF- a to the cell surface TNF receptor. Two human soluble TNF receptors were linked to the Fc portion of an IgG molecule, resulting in an immunoglobulin-like molecule. This molecule had not only a high affinity for TNF- a but also a half-life that made it an ideal therapeutic agent. This agent acts as both a cytokine carrier or decoy and a TNF antagonist, rendering TNF biologically unavailable. Phase III placebo-controlled studies have demonstrated a rapid (steroid-like), significant, and prolonged clinical improvement with a significant decrease in erosion development in RA patients with active disease refractory to MTX. Seventy-one percent of patients had a 20% improvement, 39% a 50%, and 15% a 70% improvement. This was particularly impressive given the severity of the patients studied. Side effects have included development of local erythema at the site of the twice-weekly SC injection in 20% of patients, mild upper respiratory tract symptoms, and some more severe systemic infections. Six episodes of fatal sepsis occurred in the 25,000 patients treated, a number not thought to be above that expected. However, since these six patients had active infections and skin ulcers, at times in the setting of diabetes, the use of this drug in high risk patients with active infection is not recommended.This treatment has been evaluated in combination with MTX in refractory RA patients and is presently being compared with MTX in early RA. The results of these trials, long-term data regarding side effects, and the apparent capacity of this therapy to reduce or eliminate the development of joint erosions has already defined its important role in the treatment if RA.

            Anti-TNF- a monoclonal antibody therapy. This is a chimeric monoclonal antibody that consists of the variable regions of a murine anti-TNF- a monoclonal antibody engrafted onto a human IgG1 kappa molecule (Remidade, infliximab). The resulting construct is two- thirds human and has a high affinity for TNF- a . Although the clinical effectiveness of this chimeric molecule administered as a monthly IV infusion has been well defined in placebo-controlled trials, clinical benefit was transient when it was used as monotherapy. When added to 7.5 mg of MTX per week, the clinical response was sustained and the immunogenicity of the chimera was decreased. During infusion of this monoclonal antibody, minor side effects developed in some patients, including headache, fever, nausea, vasovagal reactions, and urticaria. Minor infections such as bronchitis have also occurred, but no substantial increase in infection risk has been demonstrated. Antibodies to DNA developed in nearly 10% of patients, but clinically evident SLE occurred in only one patient. Although a few cases of hematologic malignancy have occurred after treatment, the relationship of the malignancy to the monoclonal antibody has not been defined. The Food and Drug Administration has approved this new therapy for the treatment of Crohn's disease of the rectum , but, as of the time of this printing, not RA. How this drug will be employed in the treatment of RA depends on the results of further assessment and its long-term safety profile and cost. As with Enbrel, disease-modification has been demonstrated and clinical improvement impressive.

          4. Induction of oral tolerance. Type 2 collagen is one of many candidate auto-antigens that might stimulate T lymphocytes and lead to the self-perpetuating inflammatory disorder known as RA. The oral administration of type 2 collagen to animals with experimentally induced arthritis leads to suppression of the disease. One mechanism thought to be involved in this suppression of inflammation is collagen type 2-induced dormancy of T cells. The results of studies in which various doses of oral type 2 collagen were given to RA patients and compared with placebo indicated an excellent safety profile but only modest clinical improvement. Place of chicken collagen in the RA armamentarium: The theoretical aspects are interesting, but such therapy should not be considered a disease-modifying modality in RA patients, either as a single treatment or in combination with other DMARDs.
          5. Effector function blockade. Metalloproteinase inhibitors and blockade of metalloproteinase production.
          6. Modulation of growth control, apoptosis, and angiogenesis. This includes induction of apoptosis genes and gene products and inhibition of growth factors or receptors promoting angiogenesis and cellular proliferation.
  5. Surgical treatment. Orthopedic surgeons play a major role in the management of RA patients, particularly those in whom joint damage has developed. Although traditional techniques of joint fusion and synovectomy remain in the orthopedist's armamentarium, total joint arthroplasty has achieved a high level of acceptance. Surgical reconstruction in RA patients must be regarded as part of a comprehensive care plan and judiciously balanced with medical management. The pattern of joint involvement and eventual functional goals of the patient must be considered.
    1. Criteria for surgery. Many factors enter into the choice and timing of an operation. More than 40 years ago, Dr. Philip Wilson, Sr. of the Hospital for Special Surgery listed these questions to assist in forming a surgical plan:
      1. Is the arthritis still active?
      2. Is the patient in adequate physical condition to permit extensive surgical procedures?
      3. Considering the age and physical state of the patient, and the number of operations required, is the expected gain in function from the operation worth the effort and risk?
      4. Should the operation be delayed so that other therapy may be instituted?
      5. Will the patient cooperate with the proper postoperative care on leaving the hospital?
      6. Are the comprehensive facilities necessary for successful treatment available in the hospital?
      7. Will the patient be able to receive proper postoperative care on leaving the hospital?
      8. Will the patient's financial status permit independent undertaking of the entire treatment, or have community resources been mobilized to care for such treatment?
      9. In the final analysis, either intractable pain or disability requires the patient to request the operation.
    2. Surgical procedures
      1. Cervical spine. Cervical spinal instability should be considered in all patients with neck pain, occipital or lower cervical radiculopathy, patient-reported neck crepitation, instability on active motion, or signs of cervical myelopathy. Radiographic signs of cervical spinal instability may be seen in 40% of RA patients, but neurologic symptoms develop in only 10% of these.

        Important lesions include atlanto-axial subluxation, superior migration of dens, and subaxial subluxation. Subluxation of lower cervical vertebrae is most common at the C3 “4 level. These lesions can be expected to progress in 30% of patients. Lateral cervical spinal films in extension and flexion are mandatory for evaluation of instability, and magnetic resonance imaging (MRI) can best define the anatomic abnormalities. Cervical orthotics can serve as temporary stabilizing devices, but little evidence exists to suggest that they enhance autofusion. Surgical intervention is reserved for those with incapacitating pain related to spinal instability or neurologic signs of cord or root entrapment. All levels of instability should be included in a posterior cervical fusion procedure. Along with traditional wiring and autogenous bone grafting techniques, methylmethacrylate cement has proved of great value in achieving stabilization of osteoporotic bone, especially when long fusions are needed for multiple levels of instability. Postoperative care should include a rigid orthotic device until bony consolidation appears on radiography.

      2. Shoulder. Evaluation of shoulder pain in RA requires differentiating soft-tissue pain from that of articular origin. Bursitis, bicipital tendinitis, and rotator cuff tears can be discerned with a careful history, examination, diagnostic xylocaine injections, and MRI when indicated (see Chapter 13). Rotator cuff tears are difficult to repair in this group because of degenerated tissue. The presence of severe articular destruction and refractory pain and disability is an indication for total joint replacement. Shoulder prostheses are in a state of evolution, as problems of restoring rotator cuff power in the face of degenerated tissue and loosening of the glenoid component have required design adjustment.
      3. Elbow. Elbow synovectomy and radial head excision can be expected to provide good pain relief in those with persistent elbow synovitis and minimal bone loss. Total elbow replacement is reserved for patients with severe articular destruction and moderate activity expectations. It should be kept in mind that complication rates and loosening rates are relatively high in total elbow arthroplasty.
      4. Wrist and hand. Severe wrist synovitis and bony destruction are amenable to surgical therapy; the degree of involvement dictates the choice of a synovectomy and ulnar head resection (dorsal stabilization procedure), a total wrist arthroplasty, or wrist fusion. Total wrist arthroplasty retains wrist motion while providing pain relief. Wrist synovitis can attenuate and rupture extensor tendons. Wrist synovectomy is indicated in the presence of persistent boggy, dorsal swelling to prevent rupture of extensor tendons. Implants continue to play an important role in the management of thumb and MCP joint disease. Critical to success are soft-tissue balancing and prolonged dynamic postoperative splinting to prevent recurrence of ulnar drift . This procedure results in pain relief with only a slight decrease in grip strength. Although fusions are not indicated for finger MCP joints, they are often useful in advanced proximal PIP joint disease to reestablish a functional hand. Cemented PIP joint arthroplasty may prove useful in augmenting finger function. Thumb reconstruction requires careful consideration of tendon imbalance and articular destruction. A combination of tendon repositioning and joint fusion is often needed.
      5. Hip. Total hip replacement has provided consistent success in treating end-stage RA hip disease. Early problems with materials and designs, infections, and pulmonary emboli have diminished, and clinical results are excellent. The osteoporosis often found in RA patients makes the challenge of long-lasting implant fixation a formidable one.
      6. Knee
        1. Arthroscopic knee synovectomy can be expected to provide pain relief in those with persistent boggy synovitis, recurrent large painful effusions unresponsive to medical therapy, and minimal articular destruction. Long-term studies have shown that although pain relief is good, synovectomy does not prevent progression of cartilage loss. Regrowth of the synovial membrane often occurs within 3 to 5 years. Synovectomy with use of radioisotopes has been studied as a potential replacement for surgical methods.
        2. Total knee replacement can give results as good as those in total hip replacement if patients are properly selected. A variety of non- articulated condylar prostheses are available and allow for resurfacing of the femoral, tibial, and patellar surfaces. Preexisting alignment deformities (varus-valgus) or flexion contractures require experienced surgical attention for soft-tissue balancing, proper bony cuts, and component choice.
      7. Ankle and foot . Ankle pain may be caused by talotibial or subtalar disease. This differentiation is important in selecting the proper surgical procedure.
        1. Talotibial pain that is intractable is treated by ankle fusion. Rates of latent loosening in total ankle replacements have been too high to gain general acceptance.
        2. Subtalar pain, elicited by hindfoot inversion or eversion, is a result of destructive changes in the talocalcaneal, talonavicular, and calcaneocuboid joints. Triple arthrodesis, which fuses three joints, is a highly successful procedure.
        3. Forefoot pain in RA is the result of synovitis, capsular destruction, and joint subluxation giving rise to hallux valgus (bunion) or metatarsalgia. Carefully placed shoe inserts can redistribute weight and provide pain relief (see Chapter 20) Surgery is reserved for those who fail conservative treatment. Excision of the first metatarsal exostosis and the proximal half of the proximal great toe phalanx (Keller procedure) is a time-honored procedure for correction of hallux valgus in RA. Excision of the metatarsal heads (Hoffman procedure) is successful in relieving plantar metatarsal pain.

Bibliography

Day RO. SAARDs. In Klippel JH, Dieppe PA, eds. Textbook of rheumatology, 2nd ed. Philadelphia: Mosby, 1998:8.1.

Goronzy JJ, Weyand CM. Rheumatoid arthritis: epidemiology, pathology, and pathogenesis. In: Klippel JH, ed. Primer on the rheumatic diseases, 11th ed. GA: Arthritis Foundation, 1997:155.

Kelley WN, et al., eds. Rheumatoid arthritis. In: Textbook of rheumatology, 5th ed. Philadelphia: WB Saunders, 1997:851.

Klippel JH, Dieppe PA, eds. Rheumatoid arthritis. In: Textbook of rheumatology, 2nd ed. Philadelphia: Mosby, 1998.

Koopman WJ, ed. Arthritis and allied conditions, 13th ed. Baltimore: Williams & Wilkins, 1996:979.

Paget SA. Rheumatoid arthritis: treatment. In: Klippel JH, ed. Primer on the rheumatic diseases, 11th ed. GA: Arthritis Foundation, 1997:168.

Books@Ovid
Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders

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Manual of Rheumatology and Outpatient Orthopedic Disorders (LB Spiral Manuals)
Manual of Rheumatology and Outpatient Orthopedic Disorders (LB Spiral Manuals)
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Year: 2000
Pages: 315
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