Treating Early Inflammatory Arthritis: What are the Latest Options?
Associate Attending Rheumatologist, Hospital for Special Surgery
Associate Professor of Clinical Medicine, Weill Medical College of Cornell University
The management of inflammatory arthritis has moved to a completely different plane than it was 20 years ago. The literature provides clear and copious evidence of the benefits of treating early inflammatory arthritis preemptively. In addition, with the availability of the biologic agents for rheumatoid arthritis since 1998, our therapeutic options are dramatically improved, and our choices expanded. This presentation will review the spectrum of options in the treatment of rheumatoid arthritis as of the end of 2005 and review some of the agents on the near horizon which should even further improve our armamentarium.
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The following case is one where all would agree with the diagnosis of rheumatoid arthritis:
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This presentation will look at the “state-of-the art” in the active, aggressive management of rheumatoid arthritis and other types of inflammatory arthritis, and focus especially on the options for early treatment. Of special concern is the ability of early treatment to prevent joint damage and ultimate disability.
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Several features of rheumatoid arthritis, the most common of the inflammatory types of arthritis, make it a major problem for individuals and for society. It is fortunate that there have been major improvements in our therapeutic options.
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Because joint damage often occurs early in rheumatoid arthritis, medications that can stop that damage are crucial. Identifying those patients at higher risk for later disability is key to making the right therapeutic decisions.
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There are a variety of “non-invasive” options for rheumatoid arthritis, which need to be individualized to the patient. Essentially all patients with rheumatoid arthritis benefit from at least some physical therapy and from learning proper exercise techniques to do at home. Some patients are greatly helped, for example, by wrist splints or by paraffin bath therapy for the hands.
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In the present era, all patients with rheumatoid arthritis benefit from medications of some type, and usually require a combination of medications. Analgesics such as acetaminophen are are almost universally used by patients with RA. Most patients with RA end up requiring DMARD‘s (Disease-Modifying anti-Rheumatic Drugs, also called “slow acting agents”) and many benefit from having such agents started quite early in their course.
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Analgesics for prn use are important to get RA patients through times of significant pain. While it is desirable to control RA with medications that not only stop pain but also help prevent joint damage, a role for analgesics is clearly present in this disease.
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Examples of available analgesics are listed below. While trying to use the mildest analgesic for the shortest period of time, patients should be made comfortable with the concept that these medications, used in closely watched doses while awaiting better control of their arthritis, have an acceptable risk/benefit profile.
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Non-steroidal anti-inflammatory agents (NSAID’s) make a big difference in daily function for some patients with RA, especially until their long-acting agents can take effect. However, we now know that patients with RA are at higher risk of atherosclerotic heart disease, making it more difficult to use long-term high-dose non-steroidal anti-inflammatory agents. Also, RA is associated with a higher-than-average risk of peptic ulcer disease, even without the use of NSAID’s. NSAID’s also can raise blood pressure and cause ankle swelling. Considering all this, the ideal is to use NSAID’s (and the COX-2 inhibitor celecoxib) at the lowest dose and for the shortest time possible. The new long-term treatments for RA often make this possible. However, some patients need to try a number of long-term treatments before they get their arthritis under control, and in such patients the use of NSAID’s, in full therapeutic doses, may be needed to allow them to function.
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Corticosteroids continue to be used in managing inflammatory arthritis. Their side-effects are very dose-related, and below 7.5mg daily of prednisone, it appears that there is not a major effect on bone density. Certainly corticosteroids are often used while waiting for long-acting agents to work, and they are often used in fairly high - but brief - courses for major flares. The literature remains controversial as to whether corticosteroids are “disease-modifying” in the sense of being able to decrease joint erosion. The weight of the evidence seems to favor some disease-modifying effect. Use of corticosteroids in RA needs to be highly individualized in view of the potential for toxicity.
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Slow-acting agents for rheumatoid arthritis have been the mainstay of management of RA for many years. Their combination with, and at times replacement by, biologic agents is a new development starting in 1998 with the introduction of etanercept. Not all “slow-acting” agents have been shown to be “disease-modifying” – if that term is defined as “slowing or stopping joint damage.” The agents marked with three stars (***) are those where there is literature support for their ability to decrease joint damage (as demonstrated on serial x-ray review).
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Hydroxychloroquine continues to be used in RA in view of documented clinical benefit and relatively low toxicity. It has not been demonstrated to slow joint damage. If doses are kept below 6.5mg/kg/day, the risk of retinal toxicity has been shown to be quite low.
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There is some evidence that sulfasalazine can decrease joint damage over time. This medication is widely used for RA in Europe and is used for this indication in the U.S. as well. The WBC count needs to be closely followed for the first 3 months after starting therapy with sulfasalazine since acute drops in WBC have been reported. Combination regimens with sulfasalazine, methotrexate, and hydroxychloroquine have been described as effective in RA.
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Azathioprine and cyclosporine have had disease-modification demonstrated, but they are used less, and often after other agents in view oftoxicity. Penicillamine was commonly used 25 years ago, but toxicity has essentially removed it from standard usage for RA. Minocycline can help the symptoms of RA but has not been demonstrated to slow the destructive process.
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Methotrexate is the most commonly used long-term agent for RA and is also the most common agent used in combination with other agents, such as the biologics. Although liver toxicity has been demonstrated, when given in the regimen shown below, the risk has been relatively small. Follow-up of liver function tests has been recommended in published guidelines to be done at approximately 5 week intervals, although some rheumatologists feel that this can be done less frequently. An acute lung toxicity of an apparently allergic type can occur with significant dyspnea and requiring corticosteroid therapy, but fortunately this is rare.
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Leflunomide has also been shown to slow damage in RA joints. Liver toxicity risk, as with methotrexate, required close laboratory follow-up. Leflunomide has a long half-life, and patients with side-effects with this agent at times need a “wash-out” process, involving large doses of cholestyramine to remove it from its enterohepatic circulation.
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The inflammatory process in RA and other types of inflammatory arthritis can be thought of as a tipping of the cytokine balance in favor of pro-inflammatory cytokines. Among the most important pro-inflammatory cytokines in the RA joint appear to be TNF-alpha, IL-1, and IL-6. Agents already exist which can block the effects of TNF-alpha and IL-1, and an agent which blocks IL-6 is under active study.
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It is worthwhile to be aware of how long each of the biologic agents has been available in the U.S. Patients are especially concerned with medication for which there is short-duration clinical experience. We now have 10 years of experience with etanercept, the first biologic approved for RA (in 1998). Of the four agents listed below, three are subcutaneous, and infliximab is intravenous. Three are anti-TNF agents, and anakinra is an IL-1 receptor antagonist. The intervals of treatment are different for these agents: anakinra is used daily, etanercept once a week, adalimumab once every 2 weeks, and infliximab is infused, after a loading period, once every 2 months. These intervals are changed, at times, with some of these agents related to patient response.
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The pathogenesis of RA is complex, involving activation of T- and B-cells, antibody production, immune complex generation, complement activation, osteoclast activation, and the formation of locally erosive pannus on the surface of cartilage.
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The biologic agents outlined above, being all the biologic agents presently approved by the FDA for RA, work in the area circled below – by blocking the effects of either TNF-alpha or IL-1.
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Etanercept was the first biologic agent approved for RA and is given by self-injection most commonly once a week. It is also approved for use in psoriatic arthritis and ankylosing spondylitis.
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The combination of etanercept with methotrexate has been shown to be more effective in producing clinical response and decreasing joint damage than either agent alone.
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Infliximab was the second biologic agent approved for RA. This agent is given intravenously. There is extensive world-wide experience with this agent, since it has been used for Crohn’s disease in addition to RA. It is also used for psoriatic arthritis and ankylosing spondylitis.Infliximab, like etanercept, has been shown more effective when combined with methotrexate.
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Adalimumab was approved for RA in 2002 and is also approved for use in psoriatic arthritis. Patients inject themselves once every two weeks. Like etanercept and infliximab, adalimumab is more effective when combined with methotrexate.
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Anakinra is the only IL-1 blocker presently approved by the FDA for use in RA. It requires daily self-injection, and local reactions are a problem for some patients. It seems somewhat less potent than the anti-TNF agents for RA, but seems less likely to cause infections as a side-effect.
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A variety of infections have been described associated with the use of anti-TNF agents. Most common has been tuberculosis. For this reason, before any anti-TNF agent is used, the patient should have a PPD skin test. If positive, and if the patient is previously untreated, Isoniazid is begun before the patient is given an anti-TNF agent. There is controversy as to whether the course of treatment needs to be completed (9 months) before starting the agent, but in general, the case needs to be individualized. See this article for further discussion of this issue. Anakinra seems less likely to activate tuberculosis than the anti-TNF agents.
Other side-effects of biologic agents are listed below. Due to worsening of multiple sclerosis in patients treated with biologic agents, and rare cases of new multiple sclerosis-like lesions developing in patients not symptomatic prior to starting a biologic agent, it is advised not to use anti-TNF agents in patients with multiple sclerosis.
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Antibodies such as rheumatoid factor and anti-CCP (anti-cyclic citrullinated antibody) are present in RA, as in the red-circled area below. The rheumatoid factor has not been proven directly pathogenic, but there is evidence that the CCP antibody may have such a direct role. Immune complexes containing rheumatoid factor circulate in RA.
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The use of the Staph A column is approved for use in RA. Its effect may relate to removal of antibodies and immune complexes.
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The agents below are the biologic agents which seem closest to potential FDA approval, and their respective mechanisms are outlined.
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B-cells appear to have a significant role in RA (see red-circled area below), and these cells have drawn increased attention in RA studies in the last several years.
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The anti-CD20 agent rituximab, which is already widely used for lymphoma and thrombocytopenia, has a depleting effect on B cells but not on plasma cells. It has been demonstrated to decrease clinical activity in RA in combination with methotrexate (and has also demonstrated to do so in combination with cyclophosphamide).
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Antigen-presenting cells activate T cells in a process which is key to the RA process (see area circled in red below) and occurs early in the chain of events that ultimately leads to the cytokine-driven joint damage that is the hallmark of RA.
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Abatacept blocks the co-stimulation of T cells, and two signals are required for this activation. By blocking the “second messenger,” this agent can dampen the RA inflammatory process. Studies have shown clinical efficacy for this agent, which as of 12/05 is under evaluation by the FDA. Studies have suggested that this agent is effective when combined with methotrexate and that it can be effective in patients who have failed anti-TNF agents.
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In the absence of abatacept, as in the figure below, the antigen-presenting cell (APC) is able to give “2 signals” of activation to the T cell. First, the MHC on the APC and the T-cell receptor become linked via antigen binding. Second, the CD 80/86 receptor on the APC binds with the CD28 receptor on the T cell. With both signals completed, the T-cell is activated.
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When abatacept is present, as in the illustration below, the CD 80/86 receptor on the APC binds with the abatacept, which acts as a “decoy” receptor. Thus, the CD80/86 receptor cannot bind to the CD28 receptor on the T-cell. There is thus only a “single signal”, and the T-cell is not activated.
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A variety of other biologic agents are under active study for RA. A number of these agents work on the cytokines in the red-circled area below – TNF-alpha, IL-1, and IL-6.
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One agent relatively far along in studies is atlizumab, an antibody to IL-6 receptor. There is excitement among rheumatologists for agents which attack other elements of RA pathogenesis than TNF, since we are now seeing patients who have failed the anti-TNF agents. There is also an interest in combination biologic therapy, although so far most combinations which have been tried appear to cause an unacceptable risk of infection.
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Below are listed some agents under active study for RA which target various aspects of its pathogenesis. PEGylation is of interest since longer half-lives can mean fewer injections for patients. Many patients dislike parenteral therapy and are eagerly awaiting oral biologic agents (but none appears ready for presentation to the FDA in the immediate future). The concept of using anti-inflammatory cytokines to tip the balance away from inflammation is intriguing, and early studies have been done. Gene therapy has also had some early trials in RA.
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It is important that long-term RA therapy be closely monitored, and it lends itself well to close collaboration between primary care practitioner and rheumatologist. Some guidelines for follow-up of commonly used agents are below, with a link to the website of the American College of Rheumatology, where such recommendations for the spectrum of anti-rheumatic agents are posted.
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The European League Against Rheumatism has provided the recommendations below for managing RA. The early evaluation and treatment that the literature has demonstrated is critical to getting RA under control. Even if a patient feels better with a NSAID or low-dose prednisone and is managing in the short term, if they do not receive an agent that can reduce joint damage (or in some cases a combination of agents), they are at long-term disability risk.
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Three biologic agents have been approved for treatment of psoriatic arthritis (see below) and two for ankylosing spondylitis.
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The European League Against Rheumatism has put forward the recommendations below for the management of ankylosing spondylitis. The biologic agents clearly represent a major step forward in this condition, because previously used agents, such as sulfasalazine and methotrexate, have shown limited benefit for the spinal inflammatory process. The TNF-blocking agents have shown benefit both for the central and the peripheral arthritis of this condition.
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The website of the American College of Rheumatology (see below) provides management guidelines for managing inflammatory arthritis and for monitoring its therapy. The HSS website, http://www.hss.edu/, offers a broad range of articles on inflammatory arthritis and its management. Rheumatoid arthritis links for patients and physicians are numerous on the site. Articles are offered on NSAID’s, anti-TNF agents and on methotrexate.
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posted 1/4/2006
