The natural history of RA is complex and affected by a number of factors including age of onset, gender, genotype, phenotype (i.e., extraarticular manifestations or variants of RA), and comorbid conditions, which make for a truly heterogeneous disease. There is no simple way to predict the clinical course. It is important to realize that as many as 10% of patients with inflammatory arthritis fulfilling ACR classification criteria for RA will undergo a spontaneous remission within 6 months (particularly seronegative patients). However, the vast majority of patients will exhibit a pattern of persistent and progressive disease activity that waxes and wanes in intensity over time. A minority of patients will show intermittent and recurrent explosive attacks of inflammatory arthritis interspersed with periods of disease quiescence. Finally, an aggressive form of RA may occur in an unfortunate few with inexorable progression of severe erosive joint disease, although this highly destructive course is less common in the modern treatment era of biologics.
TREATMENT Rheumatoid Arthritis
The amount of clinical disease activity in patients with RA reflects the overall burden of inflammation and is the variable most influencing treatment decisions. Joint inflammation is the main driver of joint damage and is the most important cause of functional disability in the early stages of disease. Several composite indices have been developed to assess clinical disease activity. The ACR 20, 50, and 70 improvement criteria (which corresponds to a 20%, 50%, and 70% improvement, respectively, in joint counts, physician/patient assessment of disease severity, pain scale, serum levels of acute-phase reactants [ESR or CRP], and a functional assessment of disability using a self-administered patient questionnaire) are a composite index with a dichotomous response variable. The ACR improvement criteria are commonly used in clinical trials as an endpoint for comparing the proportion of responders between treatment groups. In contrast, the Disease Activity Score (DAS), Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI) are continuous measures of disease activity. These scales are increasingly used in clinical practice for tracking disease status and, in particular, for documenting treatment response.
Several developments during the past two decades have changed the therapeutic landscape in RA. They include (1) the emergence of methotrexate as the disease-modifying antirheumatic drug (DMARD) of first choice for the treatment of early RA; (2) the development of novel highly efficacious biologicals that can be used alone or in combination with methotrexate; and (3) the proven superiority of combination DMARD regimens over methotrexate alone. The medications used for the treatment of RA may be divided into broad categories: nonsteroidal anti-inflammatory drugs (NSAIDs); glucocorticoids, such as prednisone and methylprednisolone; conventional DMARDs; and biologic DMARDs (Table 380-2). Although disease for some patients with RA is managed adequately with a single DMARD, such as methotrexate, the situation in most cases demands the use of a combination DMARD regimen that may vary in its components over the treatment course depending on fluctuations in disease activity and emergence of drug-related toxicities and comorbidities. NSAIDs
NSAIDs were formerly viewed as the core of all other RA therapy, but they are now considered to be adjunctive therapy for management of symptoms uncontrolled by other measures. NSAIDs exhibit both analgesic and anti-inflammatory properties. The anti-inflammatory effects of NSAIDs derive from their ability to nonselectively inhibit cyclooxygenase (COX)-1 and COX-2. Although the results of clinical trials suggest NSAIDs are roughly equivalent in their efficacy, experience suggests that some individuals may preferentially respond to a particular NSAID. Chronic use should be minimized due to the possibility of side effects, including gastritis and peptic ulcer disease as well as impairment of renal function. GLUCOCORTICOIDS
Glucocorticoids may serve in several ways to control disease activity in RA. First, they may be administered in low to moderate doses to achieve rapid disease control before the onset of fully effective DMARD therapy, which often takes several weeks or even months. Second, a 1- to 2-week burst of glucocorticoids may be prescribed for the management of acute disease flares, with dose and duration guided by the severity of the exacerbation. Chronic administration of low doses (5–10 mg/d) of prednisone (or its equivalent) may also be warranted to control disease activity in patients with an inadequate response to DMARD therapy. Low-dose prednisone therapy has been shown in prospective studies to retard radiographic progression of joint disease; however, the benefits of this approach must be carefully weighed against the risks. Best practices minimize chronic use of low-dose prednisone therapy owing to the risk of osteoporosis and other long-term complications; however, the use of chronic prednisone therapy is unavoidable in many cases. High-dose glucocorticoids may be necessary for treatment of severe extraarticular manifestations of RA, such as ILD. Finally, if a patient exhibits one or a few actively inflamed joints, the clinician may consider intraarticular injection of an intermediate-acting glucocorticoid such as triamcinolone acetonide. This approach may allow for rapid control of inflammation in the setting of a limited number of affected joints. Caution must be exercised to appropriately exclude joint infection, as it often mimics an RA flare.
Osteoporosis ranks as an important long-term complication of chronic prednisone use. The ACR recommends primary prevention of glucocorticoid-induced osteoporosis with a bisphosphonate in any patient receiving 5 mg/d or more of prednisone for greater than 3 months. Although prednisone use is known to increase the risk of peptic ulcer disease, especially with concomitant NSAID use, no evidence-based guidelines have been published regarding the use of gastrointestinal ulcer prophylaxis in this situation. DMARDs
DMARDs are so named because of their ability to slow or prevent structural progression of RA. The conventional DMARDs include hydroxychloroquine, sulfasalazine, methotrexate, and leflunomide; they exhibit a delayed onset of action of approximately 6–12 weeks. Methotrexate is the DMARD of choice for the treatment of RA and is the anchor drug for most combination therapies. It was approved for the treatment of RA in 1986 and remains the benchmark for the efficacy and safety of new disease-modifying therapies. At the dosages used for the treatment of RA, methotrexate has been shown to stimulate adenosine release from cells, producing an anti-inflammatory effect. The clinical efficacy of leflunomide, an inhibitor of pyrimidine synthesis, appears similar to that of methotrexate; it has been shown in well-designed trials to be effective for the treatment of RA as monotherapy or in combination with methotrexate and other DMARDs.
Although similar to the other DMARDs in its slow onset of action, hydroxychloroquine has not been shown to delay radiographic progression of disease and thus is not considered to be a true DMARD. In clinical practice, hydroxychloroquine is generally used for treatment of early, mild disease or as adjunctive therapy in combination with other DMARDs. Sulfasalazine is used in a similar manner and has been shown in randomized, controlled trials to reduce radiographic progression of disease. Minocycline, gold salts, penicillamine, azathioprine, and cyclosporine have all been used for the treatment of RA with varying degrees of success; however, they are used sparingly now due to their inconsistent clinical efficacy or unfavorable toxicity profile. BIOLOGICALS
Biologic DMARDs have revolutionized the treatment of RA over the past decade (Table 380-2). They are protein therapeutics designed mostly to target cytokines and cell-surface molecules. The TNF inhibitors were the first biologicals approved for the treatment of RA. Anakinra, an IL-1 receptor antagonist, was approved shortly thereafter; however, its benefits have proved to be relatively modest compared with the other biologicals and is rarely used for the treatment of RA with the availability of other more effective agents. Abatacept, rituximab, and tocilizumab are the newest members of this class. Anti-TNF Agents
The development of TNF inhibitors was originally spurred by the experimental finding that TNF is a critical upstream mediator of joint inflammation. Currently, five agents that inhibit TNF-α are approved for the treatment of RA. There are three different anti-TNF monoclonal antibodies. Infliximab is a chimeric (part mouse and human) monoclonal antibody, whereas adalimumab and golimumab are humanized monoclonal antibodies. Certolizumab pegol is a pegylated Fc-free fragment of a humanized monoclonal antibody with binding specificity for TNF-α. Lastly, etanercept is a soluble fusion protein comprising the TNF receptor 2 in covalent linkage with the Fc portion of IgG1. All of the TNF inhibitors have been shown in randomized controlled clinical trials to reduce the signs and symptoms of RA, slow radiographic progression of joint damage, and improve physical function and quality of life. Anti-TNF drugs are typically used in combination with background methotrexate therapy. This combination regimen, which affords maximal benefit in many cases, is often the next step for treatment of patients with an inadequate response to methotrexate therapy. Etanercept, adalimumab, certolizumab pegol, and golimumab have also been approved for use as monotherapy.
Anti-TNF agents should be avoided in patients with active infection or a history of hypersensitivity to these agents and are contraindicated in patients with chronic hepatitis B infection or class III/IV congestive heart failure. The major concern is the increased risk for infection, including serious bacterial infections, opportunistic fungal infection, and reactivation of latent tuberculosis. For this reason, all patients are screened for latent tuberculosis according to national guidelines prior to starting anti-TNF therapy (Chap. 202). In the United States, patients are skin tested using an intradermal injection of purified protein derivative (PPD); individuals with skin reactions of more than 5 mm are presumed to have had previous exposure to tuberculosis and are evaluated for active disease and treated accordingly. The QuantiFERON IFN-γ release assay may also be used in selected circumstances to screen for previous exposure to tuberculosis. Anakinra
Anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist. Although anakinra has seen limited use for the treatment of RA, it has enjoyed a resurgence of late as an effective therapy of some rare inherited syndromes dependent on IL-1 production, including neonatal-onset inflammatory disease, Muckle-Wells syndrome, and familial cold urticaria, as well as systemic juvenile-onset inflammatory arthritis and adult-onset Still’s disease. Anakinra should not be combined with an anti-TNF drug due to the high rate of serious infections as observed with this regimen in a clinical trial. Abatacept
Abatacept is a soluble fusion protein consisting of the extracellular domain of human CTLA-4 linked to the modified portion of human IgG. It inhibits the co-stimulation of T cells by blocking CD28-CD80/86 interactions and may also inhibit the function of antigen-presenting cells by reverse signaling through CD80 and CD86. Abatacept has been shown in clinical trials to reduce disease activity, slow radiographic progression of damage, and improve functional disability. Many patients receive abatacept in combination with methotrexate or another DMARD such as leflunomide. Abatacept therapy has been associated with an increased risk of infection. Rituximab
Rituximab is a chimeric monoclonal antibody directed against CD20, a cell-surface molecule expressed by most mature B lymphocytes. It works by depleting B cells, which in turn, leads to a reduction in the inflammatory response by unknown mechanisms. These mechanisms may include a reduction in autoantibodies, inhibition of T cell activation, and alteration of cytokine production. Rituximab has been approved for the treatment of refractory RA in combination with methotrexate and has been shown to be more effective for patients with seropositive than seronegative disease. Rituximab therapy has been associated with mild to moderate infusion reactions as well as an increased risk of infection. Notably, there have been isolated reports of a potentially lethal brain disorder, progressive multifocal leukoencephalopathy (PML), in association with rituximab therapy, although the absolute risk of this complication appears to be very low in patients with RA. Most of these cases have occurred on a background of previous or current exposure to other potent immunosuppressive drugs. Tocilizumab
Tocilizumab is a humanized monoclonal antibody directed against the membrane and soluble forms of the IL-6 receptor. IL-6 is a proinflammatory cytokine implicated in the pathogenesis of RA, with detrimental effects on both joint inflammation and damage. IL-6 binding to its receptor activates intracellular signaling pathways that affect the acute-phase response, cytokine production, and osteoclast activation. Clinical trials attest to the clinical efficacy of tocilizumab therapy for RA, both as monotherapy and in combination with methotrexate and other DMARDs. Tocilizumab has been associated with an increased risk of infection, neutropenia, and thrombocytopenia; however, the hematologic abnormalities appear to be reversible upon stopping the drug. In addition, this agent has been shown to increase LDL cholesterol; however, it is not known as yet if this effect on lipid levels increases the risk for development of atherosclerotic disease. SMALL-MOLECULE INHIBITORS
Because some patients do not adequately respond to conventional DMARDS or biologic therapy, other therapeutic targets have been investigated to fill this gap. Recently, drug development in RA has focused attention on the intracellular signaling pathways that transduce the positive signals of cytokines and other inflammatory mediators that create the positive feedback loops in the immune response. These synthetic DMARDs aim to provide the same efficacy as biological therapies in an oral formulation. Tofacitinib
Tofacitinib is a small-molecule inhibitor that primarily inhibits JAK1 and JAK3, which mediate signaling of the receptors for the common γ-chain-related cytokines IL-2, -4, -7, -9, -15, and -21 as well as IFN-γ and IL-6. These cytokines all play roles in promoting T and B cell activation as well as inflammation. Tofacitinib, an oral agent, has been shown in randomized, placebo-controlled clinical trials to improve the signs and symptoms of RA significantly over placebo. Major adverse events include elevated serum transaminases indicative of liver injury, neutropenia, increased cholesterol levels, and elevation in serum creatinine. Its use is also associated with an increased risk of infections. Tofacitinib can be used as monotherapy or in combination with methotrexate.
APPROACH TO THE PATIENT: Rheumatoid Arthritis
The original treatment pyramid for RA is now considered to be obsolete and has evolved into a new strategy that focuses on several goals: (1) early, aggressive therapy to prevent joint damage and disability; (2) frequent modification of therapy with utilization of combination therapy where appropriate; (3) individualization of therapy in an attempt to maximize response and minimize side effects; and (4) achieving, whenever possible, remission of clinical disease activity. A considerable amount of evidence supports this intensive treatment approach.
As mentioned earlier, methotrexate is the DMARD of first choice for initial treatment of moderate to severe RA. Failure to achieve adequate improvement with methotrexate therapy calls for a change in DMARD therapy, usually transition to an effective combination regimen. Effective combinations include: methotrexate, sulfasalazine, and hydroxychloroquine (oral triple therapy); methotrexate and leflunomide; and methotrexate plus a biological. The combination of methotrexate and an anti-TNF agent, for example, has been shown in randomized, controlled trials to be superior to methotrexate alone not only for reducing signs and symptoms of disease, but also for retarding the progression of structural joint damage. Predicting which patients will ultimately show radiologic joint damage is imprecise at best, although some factors such as an elevated serum level of acute-phase reactants, high burden of joint inflammation, and the presence of erosive disease are associated with increased likelihood of developing structural injury.
In 2012 a joint task force of the ACR and EULAR updated the treatment guidelines for RA. They do make a distinction between patients with early RA (<6 months of disease duration) and patients with established RA. These guidelines highlight the need to switch or add DMARD therapy after 3 months of worsening or persistent moderate/high disease activity. If disease still persists after 3 months of intense DMARD therapy, addition of a biologic agent is warranted. Treatment with a biologic agent or aggressive combination DMARD therapy was also recommended as initial therapy in certain patients with high disease activity and poor prognosis. However, it has not been clearly established that this more intensive initial approach is superior to starting with methotrexate alone and, in the absence of an inadequate therapeutic response, moving rapidly to combination therapy.
Some patients may not respond to an anti-TNF drug or may be intolerant of its side effects. Initial responders to an anti-TNF agent that later worsen may benefit from switching to another anti-TNF agent. The 2012 guidelines recommend that with loss or lack of effectiveness of anti-TNF after 3 months, one should switch to another anti-TNF or non-TNF biologic agent. In patients with high disease activity and a serious adverse event from an anti-TNF agent, a non-TNF drug should be used.
Studies have also shown that oral triple therapy (hydroxychloroquine, methotrexate, and sulfasalazine) is a reasonable first step for the treatment of early RA, including its use as a step-up strategy where treatment is initiated with methotrexate alone and then combined at 6 months with hydroxychloroquine and sulfasalazine if the disease is not adequately controlled.
A clinical state defined as low disease activity or remission is the optimal goal of therapy, although most patients never achieve remission despite every effort to achieve it. Composite indices, such as the Disease Activity Score-28 (DAS-28), are useful for classifying states of low disease activity and remission; however, they are imperfect tools due to the limitations of the clinical joint examination in which low-grade synovitis may escape detection. Complete remission has been stringently defined as the total absence of all articular and extraarticular inflammation and immunologic activity related to RA. However, evidence for this state can be difficult to demonstrate in clinical practice. In an effort to standardize and simplify the definition of remission for clinical trials, the ACR and EULAR developed two provisional operational definitions of remission in RA (Table 380-3). A patient may be considered in remission if he or she (1) meets all of the clinical and laboratory criteria listed in Table 380-3 or (2) has a composite SDAI score of <3.3. The SDAI is calculated by taking the sum of a tender joint and swollen joint count (using 28 joints), patient global assessment (0–10 scale), physician global assessment (0–10 scale), and CRP (in mg/dL). This definition of remission does not take into account the possibility of subclinical synovitis or that damage alone may produce a tender or swollen joint. Ignoring the semantics of these definitions, the aforementioned remission criteria are nonetheless useful for setting a level of disease control that will likely result in minimal or no progression of structural damage and disability. PHYSICAL THERAPY AND ASSISTIVE DEVICES
All patients should receive a prescription for exercise and physical activity. Dynamic strength training, community-based comprehensive physical therapy, and physical-activity coaching (emphasizing 30 min of moderately intensive activity most days a week) have all been shown to improve muscle strength and perceived health status. Foot orthotics for painful valgus deformity decrease foot pain and resulting disability and functional limitations. Judicious use of wrist splints can also decrease pain; however, their benefits may be offset by decreased dexterity and a variable effect on grip strength. SURGERY
Surgical procedures may improve pain and disability in RA—most notably the hands, wrists, and feet, typically after the failure of medical therapy with varying degrees of reported long-term success. For large joints, such as the knee, hip, shoulder, or elbow, total joint arthroplasty is an option for advanced joint disease. A few surgical options exist for dealing with the smaller hand joints. Silicone implants are the most common prosthetic for MCP arthroplasty and are generally implanted in patients with severe decreased arc of motion, marked flexion contractures, MCP joint pain with radiographic abnormalities, and severe ulnar drift. Arthrodesis and total wrist arthroplasty are reserved for patients with severe disease who have substantial pain and functional impairment. These two procedures appear to have equal efficacy in terms of pain control and patient satisfaction. Numerous surgical options exist for correction of hallux valgus in the forefoot, including arthrodesis and arthroplasty, as well as primarily arthrodesis for refractory hindfoot pain. OTHER MANAGEMENT CONSIDERATIONS Pregnancy
Up to 75% of female RA patients will note overall improvement in symptoms during pregnancy, but often will flare after delivery. Flares during pregnancy are generally treated with low doses of prednisone; hydroxychloroquine and sulfasalazine are probably the safest DMARDs to use during pregnancy. Methotrexate and leflunomide therapy are contraindicated during pregnancy due to their teratogenicity in animals and humans. The experience with biologic agents has been insufficient to make specific recommendations for their use during pregnancy. Most rheumatologists avoid their use in this setting; however, exceptions are considered depending on the circumstances. Elderly Patients
RA presents in up to one-third of patients after the age of 60; however, older individuals may receive less aggressive treatment due to concerns about increased risks of drug toxicity. Studies suggest that conventional DMARDs and biologic agents are equally effective and safe in younger and older patients. Due to comorbidities, many elderly patients have an increased risk of infection. Aging also leads to a gradual decline in renal function that may raise the risk for side effects from NSAIDs and some DMARDS, such as methotrexate. Renal function must be taken into consideration before prescribing methotrexate, which is mostly cleared by the kidneys. To reduce the risks of side effects, methotrexate doses may need to be adjusted downward for the drop in renal function that usually comes with the seventh and eighth decades of life. Methotrexate is usually not prescribed for patients with a serum creatinine greater than 2 mg/dL.