Clinical Course and Prognosis
The course of RA is quite variable and difficult to predict in an individual patient. The current therapeutic approach of early aggressive intervention appears to have mitigated the clinical course of RA, resulting in less persistent inflammation, disability, joint damage, and mortality. Classically, most patients had experienced persistent but fluctuating disease activity, accompanied by a variable degree of joint abnormalities and functional impairment. After 10-12 years, <20% of patients had no evidence of disability orjoint abnormalities. Moreover, within 10 years, ~50% of patients had work disability. All of these outcomes are thought to be positively influenced by early aggressive intervention. A number of features are correlated with a greater likelihood of developing joint abnormalities or disabilities. These include the presence of >20 inflamed joints, a markedly elevated ESR, radiographic evidence of bone erosions, the presence of rheumatoid nodules, high titers of serum rheumatoid factor or anti-CCP antibodies, the presence of functional disability, persistent inflammation, advanced age at onset, the presence of comorbid conditions, low socioeconomic status or educational level, or the presence of HLA-DR,1*0401 or -DR,*0404. The presence of one or more of these implies the presence of more aggressive disease with a greater likelihood of developing progressive joint abnormalities and disability. Persistent elevation of the ESR, disability, and pain on longitudinal follow-up are good predictors of work disability, whereas persistent synovitis of >12 weeks is associated with an increased likelihood of developing bone erosions. Patients who lack these features have more indolent disease with a slower progression to joint abnormalities and disability. The pattern of disease onset does not appear to predict the development of disabilities. Approximately 15% of patients with RA will have a short-lived inflammatory process that remits without major disability. These individuals tend to lack the aforementioned features associated with more aggressive disease.
Several features of patients with RA appear to have prognostic significance. Remissions of disease activity are most likely to occur during the first year. White females tend to have more persistent synovitis and more progressively erosive disease than males. Persons who present with high titers of rheumatoid factor, anti-CCP antibodies, C-reactive protein, and haptoglobin also have a worse prognosis, as do individuals with subcutaneous nodules or radiographic evidence of erosions at the time of initial evaluation. Sustained disease activity of >1 year’s duration portends a poor outcome, and persistent elevation of acute-phase reactants appears to correlate strongly with radiographic progression. Before the use of early aggressive therapy, a large proportion of inflamed joints manifested erosions within 2 years, whereas the subsequent course of erosions was highly variable; however, in general, radiographic damage appears to progress at a constant rate in patients with RA. Foot joints are affected more frequently than hand joints. Despite the decrease in the rate of progressive joint damage with time, functional disability, which develops early in the course of the disease, continues to worsen at the same rate, although the most rapid rate of functional loss occurs within the first 2 years of disease. Early in the course of RA, disability is more associated with pain and inflammation, whereas later in the course of the disease, damage to articular structures makes a greater contribution.
The median life expectancy of persons with RA is shortened by 3-7 years. Of the 2.5-fold increase in mortality rate, RA itself is a contributing feature in 15-30%. The increased mortality rate seems to be limited to patients with more severe articular disease and can be attributed largely to infection and gastrointestinal bleeding and an increased risk of cardiovascular disease. Recent evidence has emphasized the important role of cardiovascular disease in the increased mortality of RA patients, and this appears to diminish with effective anti-inflammatory therapy. Drug therapy may also play a role in the increased mortality rate seen in individuals with RA. Factors correlated with early death include disability, disease duration or severity, persistent inflammation, glucocorticoid use, age at onset, and low socioeconomic or educational status.
Diagnosis
The diagnosis of RA can be delayed because of the nonspecific nature of initial symptoms. The diagnosis of RA is easily made in persons with typical established dis-ease.The typical picture of bilateral symmetric inflammatory polyarthritis involving small and large joints in both the upper and lower extremities with sparing of the axial skeleton except the cervical spine suggests the diagnosis. Constitutional features indicative of the inflammatory nature of the disease, such as morning stiffness, support the diagnosis. Demonstration of subcutaneous nodules is a helpful diagnostic feature. Additionally, the presence of rheumatoid factor, anti-CCP antibodies, inflammatory synovial fluid with increased numbers of PMNLs, and radiographic findings of juxtaarticular bone demineralization and erosions of the affected joints substantiate the diagnosis.
The diagnosis is somewhat more difficult early in the course when only constitutional symptoms or intermittent arthralgias or arthritis in an asymmetric distribution may be present. A period of observation may be necessary before the diagnosis can be established. A definitive diagnosis of RA depends predominantly on characteristic clinical features and the exclusion of other inflammatory processes. The isolated finding of a positive test for rheumatoid factor, anti-CCP antibody, or an elevated ESR or C-reactive protein (CRP), especially in an older person with joint pains, should not itself be used as evidence of RA.
In 1987, the American College of Rheumatology developed revised criteria for the classification of RA (Table 5-1). These criteria demonstrate a sensitivity of 91-94% and a specificity of 89% when used to classify patients with RA compared with control subjects with rheumatic diseases other than RA. Although these criteria were developed as a means of disease classification for investigational purposes, they can be useful as guidelines for establishing the diagnosis.
TABLE 5-1
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THE 1987 REVISED CRITERIA FOR THE CLASSIFICATION OF RA |
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1. Guidelines for classification |
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a. |
Four of seven criteria are required to classify a patient as having rheumatoid arthritis (RA). |
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b. |
Patients with two or more clinical diagnoses are not excluded. |
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2. Criteriaa |
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a. |
Morning stiffness: Stiffness in and around the joints lasting 1 h before maximal improvement. |
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b. |
Arthritis of three or more joint areas: At least three joint areas, observed by a physician simultaneously, have soft tissue swelling or joint effusions, not just bony overgrowth. The 14 possible joint areas involved are right or left proximal interphalangeal, metacarpophalangeal, wrist, elbow, knee, ankle, and metatarsophalangeal joints. |
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c. |
Arthritis of hand joints: Arthritis of wrist, metacarpophalangeal joint, or proximal interphalangeal joint. |
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d. |
Symmetric arthritis: Simultaneous involvement of the same joint areas on both sides of the body. |
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e. |
Rheumatoid nodules: Subcutaneous nodules over bony prominences, extensor surfaces, or juxtaartic-ular regions observed by a physician. |
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f. |
Serum rheumatoid factor: Demonstration of abnormal amounts of serum rheumatoid factor by any method for which the result has been positive in less than 5% of normal control subjects. |
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g. |
Radiographic changes: Typical changes of RA on posteroanterior hand and wrist radiographs that must include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints. |
aCriteria a-d must be present for at least 6 weeks. Criteria b-e must be observed by a physician.
Failure to meet these criteria, however, especially during the early stages of the disease, does not exclude the diagnosis. Indeed, these criteria do not effectively differentiate patients with new-onset RA from those with a variety of other forms of early inflammatory arthritis. Moreover, in patients with early arthritis, the criteria do not discriminate effectively between patients who subsequently develop persistent, disabling, or erosive disease and those who do not.
Treatment:
Rheumatoid Arthritis
GENERAL PRINCIPLES The goals of therapy for RA are (1) relief of pain, (2) reduction of inflammation, (3) protection of articular structures, (4) maintenance of function, and (5) control of systemic involvement. Since the etiology of RA is unknown, the pathogenesis is not completely delineated,and the mechanisms of action of some of the therapeutic agents employed are uncertain, therapy remains somewhat empirical. None of the therapeutic interventions is curative, and therefore all must be viewed as palliative, aimed at relieving the signs and symptoms of the disease.The various therapies employed are directed at nonspecific suppression of the inflammatory or immunologic process with the expectation of ameliorating symptoms and preventing progressive damage to articular structures.
Management of patients with RA involves an interdisciplinary approach, which attempts to deal with the various problems that these individuals encounter with functional as well as psychosocial interactions.A variety of physical therapy modalities may be useful in decreasing the symptoms of RA. Rest ameliorates symptoms and can be an important component of the total therapeutic program. In addition, splinting to reduce unwanted motion of inflamed joints may be useful. Exercise directed at maintaining muscle strength and joint mobility without exacerbating joint inflammation is also an important aspect of the therapeutic regimen. A variety of orthotic and assistive devices can be helpful in supporting and aligning deformed joints to reduce pain and improve function. Education of the patient and family is an important component of the therapeutic plan to help those involved become aware of the potential impact of the disease and make appropriate accommodations in lifestyle to maximize satisfaction and minimize stress on joints.
Medical management of RA involves five general approaches. The first is the use of nonsteroidal antiinflammatory drugs (NSAIDs) and simple analgesics to control the symptoms and signs of the local inflammatory process. These agents are rapidly effective at mitigating signs and symptoms, but they appear to exert minimal effect on the progression of the disease. Recently, specific inhibitors of the isoform of cyclooxy-genase (COX) that is upregulated at inflammatory sites (COX-2) have been developed.COX inhibitors (known as Coxibs), which selectively inhibit COX-2 and not COX-1, have been shown to be as effective as classic NSAIDs, which inhibit both isoforms of COX, but to cause significantly less gastroduodenal ulceration. However, these agents are associated with an increased risk of cardiovascular events,and therefore their use must be guided by a careful assessment of risk/benefit ratio. An important additional second line of therapy involves the use of low-dose oral glucocorticoids. Although low-dose glucocorticoids have been widely used to suppress signs and symptoms of inflammation, recent evidence indicates that they may also retard the development and progression of bone erosions. In addition, the use of low-dose glucocorticoids increases the anti-inflammatory effects of agents such as methotrexate as well as the protective effect of these agents on bone damage. An initial course of low-dose glucocorticoids should be considered in patients either alone or when therapy with disease modifying anti-rheumatic drugs (DMARDs) is considered. Intraarticular glucocorticoids can often provide transient symptomatic relief when systemic medical therapy has failed to resolve inflammation.The third line of agents includes the DMARDs just mentioned. These agents appear to have the capacity to decrease elevated levels of acute-phase reactants in treated patients and, therefore, are thought to modify the inflammatory component of RA and thus its destructive capacity. These agents include methotrexate, sulfasalazine, hydroxychloroquine, gold salts, or D-penicillamine, although the latter two are now used infrequently. Combinations of DMARDs appear to be more effective than single agents in controlling the signs and symptoms of RA.A fourth group of agents are the biologics, which include TNF-neutralizing agents (infliximab,etanercept,and adalimumab), IL-1-neutraliz-ing agents (anakinra), those that deplete B cells (ritux-imab), and those that interfere with T cell activation (abatacept). These agents have been shown to have a major impact on the signs and symptoms of RA and also to slow progressive damage to articular structures. A fifth group of agents are the immunosuppressive and cytotoxic drugs, including leflunomide, cyclosporine, azathioprine, and cyclophosphamide, that have been shown to ameliorate the disease process in some patients.Additional approaches have been employed in an attempt to control the signs and symptoms of RA. Substituting omega-3 fatty acids, such as eicosapen-taenoic acid found in certain fish oils,for dietary omega- 6 essential fatty acids found in meat has also been shown to provide symptomatic improvement in patients with RA. A variety of nontraditional approaches have also been claimed to be effective in treating RA, including diets, plant and animal extracts, vaccines, hormones, and topical preparations of various sorts. Many of these are costly, and none has been shown to be effective. However, belief in their efficacy ensures their continued use by some patients.
Drugs
Disease-Modifying Anti-Rheumatic Drugs
Clinical experience has delineated a number of agents— the DMARDs—that appear to have the capacity to alter the course of RA. Despite having no chemical or pharmacologic similarities, in practice these agents share a number of characteristics. They exert minimal direct nonspecific anti-inflammatory or analgesic effects, and therefore NSAIDs must be continued during their administration, except in a few cases when true remissions are induced with them.The appearance of benefit from DMARD therapy is usually delayed for weeks or months. As many as two-thirds of patients develop some clinical improvement as a result of therapy with any of these agents, although the induction of true remissions is unusual. In addition to clinical improvement, there is frequently an improvement in serologic evidence of disease activity, and titers of rheumatoid factor and C-reactive protein and the ESR frequently decline. Moreover, DMARD therapy, especially early in the disease course, retards the development of bone erosions.
No characteristic features of patients have emerged that predict responsiveness to a DMARD. Moreover, the indications for the initiation of therapy with one of these agents are not well defined. Recently, evidence has emerged that the initiation of DMARD therapy early in the course of RA clearly has a major impact on the development of bone erosions and the progression to disability. It is now felt that DMARD therapy should be begun as soon as the diagnosis of RA is established, especially in those with any evidence of aggressive disease with a poor prognosis.
Which DMARD should be the drug of first choice remains controversial, and trials have failed to demonstrate a consistent advantage of one over the other. Despite this, methotrexate has emerged as the DMARD of choice especially in individuals with risk factors for development of bone erosions or persistent synovitis of >3 months’ duration, because of its relatively rapid onset of action, its capacity to effect sustained improvement with ongoing therapy, and the higher level of patient retention on therapy. Methotrexate is usually employed on a weekly schedule of 7.5-25 mg given either orally in divided doses or, if necessary, SC or IM to avoid gastrointestinal toxicity. Recent trials have documented the efficacy of methotrexate and have indicated that its onset of action is more rapid than other DMARDs, and patients tend to remain on therapy with methotrexate longer than they remain on other DMARDs because of better clinical responses and less toxicity. Long-term trials have indicated that methotrexate does not induce remission but rather suppresses symptoms while it is being administered. Maximal improvement is observed after 6 months of therapy, with little additional improvement thereafter. Major toxicity includes gastrointestinal upset,oral ulceration,and liver function abnormalities that appear to be dose related and reversible and hepatic fibrosis that can be quite insidious, requiring liver biopsy for detection in its early stages. Drug-induced pneumonitis has also been reported. Liver biopsy is recommended for individuals with persistent or repetitive liver function abnormalities. Concurrent administration of folic acid or folinic acid may diminish the frequency of some side effects, although efficacy may be diminished somewhat. In this regard, each of the DMARDs is associated with toxicity, and therefore careful patient monitoring is necessary.Toxic-ity of the various agents also becomes important in determining the drug of first choice. Of note, failure to respond or development of toxicity to one DMARD does not preclude responsiveness to another.Thus,a similar percentage of RA patients who have failed to respond to one DMARD will respond to another when it is given as the second disease-modifying drug.
GLUCOCORTICOID THERAPY Systemic glucocorticoid therapy can provide effective symptomatic therapy in patients with RA. Low-dose (<7.5 mg/d) prednisone is a useful additive therapy to control symptoms. Moreover, recent evidence suggests that low-dose glucocorticoid therapy may retard the progression of bone erosions and that an initial course of low-dose glucocorticoids may have a long-term protective effect against bone damage. Monthly pulses with high-dose glucocorticoids may be useful in some patients and may hasten the response when therapy with a DMARD is initiated. Finally, a course of low-dose oral glucocorticoids combined with DMARD therapy can be beneficial in controlling signs and symptoms rapidly and affording long-term retardation of bone erosion.
BIOLOGICS A range of biologic agents that bind and neutralize TNF are available. One of these is a TNF type II receptor fused to IgG1 (etanercept),the second is a chimeric mouse/human monoclonal antibody to TNF (infliximab), a third is a fully human antibody to TNF (adalimumab), and a fourth is a humanized monoclonal antibody that neutralizes TNF (golimumab). Clinical trials have shown that parenteral administration of any of these TNF-neutralizing agents is remarkably effective at controlling signs and symptoms of RA in patients who have failed DMARD therapy, as well as in DMARD-naïve patients. Repetitive therapy with these agents is effective with or without concomitant methotrexate, although combination therapy with methotrexate or another DMARD appears to provide the greatest benefit. These agents not only are effective in persistently controlling signs and symptoms of RA in a majority of patients, but they have also been shown to slow the rate of progression of joint damage assessed radiographically and to improve disability. Side effects include the potential for an increased risk of serious infections. Particularly notable is the capacity of TNF blockade to increase the risk of developing reactivation of dormant tuberculosis. It is prudent to carry out tuberculin skin testing and, if necessary, further evaluation with chest radiographs before beginning therapy with an anti-TNF agent to limit the chance of inciting reactivation of tuberculosis. Anti-TNF therapy also has the potential to increase the risk of lymphoma and possibly other malignancies in treated patients. TNF-neutralizing therapy can also induce the development of anti-DNA antibodies, but rarely is there associated evidence of signs and symptoms of systemic lupus erythematosus. Other side effects include infusion or injection site reactions and rarely the development of demyelinating central nervous system disease.Although these side effects are uncommon, their occurrence mandates that TNF-neutralizing therapy be supervised by physicians with experience in their use.
Anakinra is a recombinant IL-1 receptor antagonist that competitively blocks the binding of IL-1 β and IL-1 α to the IL-1 receptor and thereby inhibits the activity of these two related proinflammatory cytokines. Anakinra has been shown to improve the signs and symptoms of RA,to decrease disability,and to slow progression of articular damage assessed radiographically. It can be given as monotherapy or in combination with methotrexate.The major side effects are injection site reactions. In general, the clinical impact of anakinra appears to be less than that of TNF-neutralizing therapy, but it may be used in those in whom TNF-neutralizing therapy is precluded. It is rarely effectivein thosewho havefailedTNF-neutralizing therapy. Combining anakinra with a TNF-blocking agent does not increase efficacy and is associated with an increased frequency of infection and, therefore, is not recommended.
Rituximab, a chimeric antibody directed to CD20 that depletes mature B cells, has been approved for treatment of RA patients who have failed anti-TNF therapy. In combination with methotrexate, this therapy can improve signs and symptoms in these patients and also retard the progress of bone damage. The major adverse events relate to transfusion reactions that can be controlled with glucocorticoids. Although the optimal regimen has not been established, therapy can be repeated usually at 6-month intervals when circulating B cells return.
Abatacept is a fusion protein consisting of CTLA4 and the Fc portion of IgG1. It inhibits T cell activation by competitively inhibiting the co-stimulation of T cells that results from interaction of T cell-expressed CD28 and CD80/86 expressed by antigen-presenting cells. It can be used with or without methotrexate, although its efficacy is greater as co-therapy with methotrexate. It has a positive effect on signs and symptoms of RA and also retards progressive bone damage. It is usually reserved for patients who have failed TNF-neutralizing therapy or in those who have contraindications to TNF blockade. Abatacept is tolerated quite well. Combining abatacept with a TNF-blocking agent does not increase efficacy, and is associated with more adverse events,including serious infections,and,therefore,is not recommended.
IMMUNOSUPPRESSIVE THERAPY The immunosuppressive drugs azathioprine, leflunomide, cyclosporine,and cyclophosphamide have been shown to be effective in the treatment of RA and to exert Approach to the Patient:
Rheumatoid Arthritis
An approach to the medical management of patients with RA is depicted in Fig. 5-3. The principles underlying care of these patients reflect the value of early appropriately aggressive intervention, the variability of the disease, the frequent persistent nature of the inflammation and its potential to cause disability, the relationship between sustained inflammation and bone erosions and mortality, and the need to reevaluate therapeutic effects similar to those of the DMARDs. However, these agents appear to be no more effective than the DMARDs. Moreover, they cause a variety of toxic side effects, and cyclophosphamide appears to predispose patients to the development of malignant neoplasms. Therefore, these drugs have been reserved for patients who have clearly failed therapy with DMARDs and biologics. On occasion, extraarticular disease such as rheumatoid vasculitis may require cytotoxic immunosuppressive therapy.
Leflunomide is metabolized to an active metabolite that acts to inhibit dihydroorotate dehydrogenase, an essential enzyme in the pyrimidine biosynthetic pathway. Its predominant action is to inhibit the proliferation of T lymphocytes. Leflunomide has been shown to control the signs and symptoms of RA and to slow the progression of joint damage as effectively as methotrexate. Leflunomide can be given alone or with methotrexate and is the most frequently employed immunosuppressive agent used to treat patients with RA. It is used as monotherapy in patients who have had adverse reactions to methotrexate or inadequate responses to it.The major side effect is the associated increase in liver function enzymes that occurs in 5% of patients receiving leflunomide alone and in >50% of individuals taking leflunomide with methotrexate.
SURGERY Surgery plays a role in the management of patients with severely damaged joints. Although arthroplasties and total joint replacements can be done on a number of joints, the most successful procedures are carried out on hips, knees, and shoulders. Realistic goals of these procedures are relief of pain and reduction of disability. Reconstructive hand surgery may lead to cosmetic improvement and some functional benefit. Open or arthroscopic synovectomy may be useful in some patients with persistent monarthritis,especially of the knee. Although synovectomy may offer short-term relief of symptoms, it does not appear to retard bone destruction or alter the natural history of the disease. In addition, early tenosynovectomy of the wrist may prevent tendon rupture.
FIGURE 5-3
Algorithm for the medical management of rheumatoid arthritis. Coxib, COX-2 inhibitors; DMARD, disease-modifying anti-rheumatic drug; CCP, cyclic citrullinated polypeptide; MTX, methotrexate; SSA, sulfasalazine; TNF, tumor necrosis factor.
At the onset of disease it is difficult to predict the natural history of an individual patient’s illness. Therefore, the classic approach was to attempt to alleviate the patient’s symptoms with NSAIDs or Coxibs. Some patients may have mild disease that requires no additional therapy. However, most patients will require additional therapy, and the treating physician must be vigilant and prepared to institute appropriate therapy as soon as indicated. Nearly all patients will benefit from a course of low-dose glucocorticoids, and this should be considered routinely. If the patient has any evidence of aggressive disease, as described above, or persistent synovitis for >3 months, initiation of DMARD therapy should be considered as early as feasible. In RA patients there appears to be a window of opportunity early in the course of the disease, during which initiation of aggressive therapy can have a major impact on subsequent damage to articular structures and disability.
At some time during the course for most patients, the possibility of initiating DMARD therapy is entertained. The presence of risk factors for bone damage or disability or persistent synovitis of >3 months’ duration are the usual indications to initiate DMARD therapy. The decision to begin use of a DMARD and/ or low-dose oral glucocorticoids requires experience and clinical judgment as well as the ability to assess joint swelling and functional activity and the patient’s pain tolerance and expectation of therapy accurately. In this setting, the fully informed patient must play an active role in the decision to begin DMARD and/or low-dose oral glucocorticoid therapy, after careful review of the therapeutic and toxic potential of the various drugs. If DMARD therapy, usually methotrexate, fails to control signs and symptoms of RA, a decision to add or switch to a biologic agent is considered. These are quite potent at controlling signs and symptoms of RA, slowing damage to articular structures, and limiting disability, but are very expensive and associated with serious adverse events. The decision to employ these agents requires considerable experience, judgment, and the agreement of a fully informed patient.
If a patient responds to a DMARD, therapy is continued with careful monitoring to avoid toxicity. All DMARDs provide a suppressive effect and therefore require prolong administration. Even with successful therapy, local injection of glucocorticoids may be necessary to diminish inflammation that may persist in a limited number of joints. In addition, NSAIDs or Coxibs may be necessary to mitigate symptoms. Even after inflammation has totally resolved, symptoms from loss of cartilage and supervening degenerative joint disease or altered joint function may require additional treatment. Surgery may also be necessary to relieve pain or diminish the functional impairment secondary to alterations in joint function.
