Course Authors
Chaim Putterman, M.D., and Peter Barland, M.D.
Dr. Putterman is Assistant Professor of Medicine at the Albert Einstein College of Medicine and the Director of the Arthritis Clinic at Montefiore Medical Center. Drs. Putterman and Barland report no commercial conflicts of interest.
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
Upon completion of this Cyberounds®, you should be able to:
Describe the role of TNF and IL-1b in the pathogenesis of rheumatoid arthritis
Discuss the mechanism of action, dosing, major side effects and indications for the use of leflunomide, infliximab, etanercept and anakinra in rheumatoid arthritis
Enumerate the differences between infliximab and etanercept
Discuss the potential effects of biologic agents on structural damage to cartilage and bone in rheumatoid joints.
Rheumatoid arthritis (RA) is a common rheumatologic condition, affecting about one percent of the population. One diagnostic feature of the disease is the presence of joint erosions, which can result in progressive morbidity and significant disability. The clinical course of RA is highly variable. Rarely, the disease will remit after the first episode. More commonly, however, RA is characterized by a chronic course requiring long-term medication, with periods of disease exacerbation alternating with periods of disease quiescence.
Treatment Protocols
Historically, the treatment protocol recommended for RA was based on a therapeutic pyramid, in which the physician employed increasingly potent (and potentially toxic) medications in a step-wise manner. Patients with RA were started on non-steroidal anti-inflammatory drugs (NSAIDs) and were often switched between different drugs of this class if the initial response was unsatisfactory. Other patients began receiving potent anti-rheumatic therapy, so-called disease-modifying anti-rheumatic drugs [DMARDS], only after many weeks or months of active disease.
In recent years, there has been a paradigm shift, with rheumatologists treating RA patients with second and third line medications earlier and earlier in the disease course. Several factors, in combination, have led to the tendency for earlier aggressive treatment. First, physicians are attempting to intervene before irreversible damage occurs to the joints, or before the inflammatory lesions have begun to self perpetuate. Second, the increasing recognition of the favorable benefit/risk ratio of low dose oral methotrexate (< 25 mg/week) has led to earlier introduction of this medication in the disease course, alone and in combination. Methotrexate, with proper monitoring, has been notably effective in the management of RA, while boasting a record of tolerability and safety not found with older DMARDs.
Yet, is methotrexate indeed a DMARD? While signs and symptoms of active disease are generally diminished by methotrexate (MTX), is the disease itself modified? Can erosions (and progressive joint destruction) be arrested by MTX therapy? The results from available studies are not conclusive. Therefore, the search for safe, effective and well-tolerated drugs for RA that would really modify disease has continued at full pace.
New Drugs
Several new drugs that were recently approved for the therapy of rheumatoid arthritis are the focus of this session of Cyberounds®. The first medication we will discuss is leflunomide (Arava®). Although not a biologic agent, Arava® also has a novel mechanism of action not found in currently used DMARDs. We will then discuss the use of TNF inhibitors -- the first group of targeted biological agents that successfully made the difficult leap from the "bench to bedside" in the field of rheumatic diseases. The two TNF inhibitors that we will review are etanercept (Enbrel®) and infliximab (Remicade®). While both medications inhibit TNF, their structure, mechanism of action and kinetics are different. We will clarify these differences later on. The notable clinical success of these new medications, combined with rapid progress in understanding crucial disease pathways, ensures that the introduction of additional biologic agents for the treatment of RA is not far off. Finally we will discuss a new biological agent, anakinra® that acts by inhibiting IL-1b -- another proinflammatory cytokine.
Leflunomide (Arava®)
Mechanism of Action
Leflunomide belongs to a new class of therapeutic agents, the isoxazol derivatives.(1) Leflunomide, itself, is a pro-drug (active form of the medication is the metabolite); A77 1726, the active component in vivo, is the primary metabolite of the drug. Leflunomide has been shown to have a variety of anti-inflammatory, immunosuppressive and immunomodulatory effects in vitro, and was demonstrated to be beneficial in a variety of autoimmune disease models.
However, the exact mechanism of action of leflunomide is still under active investigation.(2) Purine and pyrimidine nucleotides (needed for synthesis of DNA, RNA and for other important cellular processes) can be generated via two metabolic pathways: 1) a salvage pathway, using preformed nucleic acid bases and 2) de novo synthesis from glutamine. Leflunomide has been shown to inhibit dihydroorotate dehydrogenase, a key enzyme in the de novo pyrimidine synthesis pathway.
Activated T cells predominantly use pyrimidines synthesized de novo and, as such, are particularly sensitive to the effects of leflunomide. Leflunomide also inhibits protein tyrosine kinases, which play a key role in signal transduction pathways. More recently, leflunomide was shown to block NF-kappa B activation from a wide variety of inflammatory stimuli.(3) Activation of NF-kappa B is an upregulator of several pro-inflammatory genes.
Dosage and Administration
The active metabolite of leflunomide has a very long half-life (about two weeks). Therefore, to achieve a more rapid pharmacokinetic steady state, a loading dose of leflunomide is usually given. Leflunomide is available in 10, 20, and 100 mg tablets. One loading dose that has been used is 100 mg a day for three days but the same 300 mg total loading dose can also be achieved by giving 60 mg a day for five days. Following the loading dose, the usual adult daily dose is 10 or 20 mg.
Important Side Effects
The most common side effect of this drug is diarrhea, which may necessitate lowering the dose or stopping the medication altogether. The most important side effects of leflunomide are hematologic toxicity, immunosuppression and hepatotoxicity. Elevations of AST and ALT (generally reversible) were seen in a significant number of patients treated with leflunomide in clinical trials.
The American College of Rheumatology (ACR) has not yet published guidelines for the monitoring and follow-up of patients treated with leflunomide. Because its toxicity profile is similar to methotrexate's, we have been using the ACR guidelines for methotrexate to follow our patients on leflunomide. In cases of leflunomide toxicity or when it is necessary to reduce the concentrations of active metabolite in plasma, we can do so using elimination with cholestyramine or activated charcoal. It is also important to note the teratogenic potential of leflunomide; its use is contraindicated in women who are, or may become, pregnant. Effective contraception is indicated for women of childbearing age in whom this drug is being considered.
Clinical Trials
To study the efficacy of leflunomide in RA, this drug has been compared in clinical trials to the gold standard of DMARDs - methotrexate, as well as to placebo and sulfasalazine (another second line agent). In a randomized, double blind, controlled study, 482 patients with active RA in the US and Canada were treated with methotrexate (182 patients), placebo (118 patients) and leflunomide (182 patients).(4) After 52 weeks of treatment, leflunomide and methotrexate each significantly increased the rate of patients meeting ACR criteria for a 20 percent response (a common standard used in RA drug trials) versus placebo. No significant differences were found between the responses to methotrexate and leflunomide.
Significantly, patients on leflunomide not only improved clinically, but also had slowing of disease progression, as shown by analysis of bony erosions on X-rays. Diarrhea occurred in about one-quarter of the patients on leflunomide, and elevated liver function tests in 15 percent. In another study, 358 patients received leflunomide, sulfasalazine, or placebo. Leflunomide was significantly more effective than placebo in the treatment of RA and demonstrated comparable efficacy to sulfasalazine.(5) Significant improvements in measurements of disease activity were found already four weeks after initiating leflunomide therapy. Finally, in a small multicenter open label study,(6) adding leflunomide to methotrexate had significant benefit in patients that remained active on methotrexate alone, without excessive toxicity. After one year, 16 patients (53%) met ACR 20 response criteria.
Clinical Use
Leflunomide is indicated for patients with active RA to reduce signs and symptoms of disease and to retard disease progression. In practical terms, leflunomide should be considered in those situations in which a DMARD is being added to the therapeutic regimen. Overall, the efficacy of leflunomide seems comparable to methotrexate. The side effect profile of these medications also has many areas of overlap. Therefore, many rheumatologists would still choose methotrexate as the first DMARD to be used in a patient with RA, based on many accumulated patient-years of positive experience with this drug. Patients with inadequate benefit from methotrexate, unacceptable toxicity or contraindications to methotrexate use may be considered for leflunomide therapy.
Inhibitors of Tumor Necrosis Factor-alpha
Mechanism of Action
TNF-alpha, secreted by macrophages, is thought to be a pivotal cytokine in the pathogenesis of RA. The biological effects of TNF are mediated by nuclear regulatory factors that are generated after TNF binds to its membrane bound receptor. TNF has many important pro-inflammatory effects, including enhanced proliferation of B and T cells, induction of adhesion molecules on endothelial cells and stimulation of synovial cells to synthesize IL-1, metalloproteinases and prostaglandins. Interruption of the effects of TNF might therefore be expected to downregulate joint inflammation in RA.
Two types of TNF inhibitors are currently available for clinical use. Infliximab is a chimeric IgG1 monoclonal antibody, which binds to TNF-alpha with high affinity. In this molecule, a mouse variable region was grafted onto a human antibody constant region, thus creating a hybrid molecule with less immunogenicity than a murine antibody with no human elements. A completely human monoclonal antibody to TNFa is currently in clinical trials. Etanercept is a "designer molecule": a dimer of recombinant p75 TNF receptor hooked up to an Fc domain of a human IgG1 molecule (to extend the in vivo half-life of the soluble receptor).
While both infliximab and etanercept bind avidly to TNF and inhibit the downstream effects of this cytokine, there are several important differences between the two drugs. One pharmacological difference (which has not yet shown to have clinical significance) is that etanercept binds to lymphotoxin-alpha, as well as to TNF-alpha, while infliximab binds to TNF-alpha alone. Another important difference between etanercept and infliximab, with practical implications, is the mode of administration, further discussed below.
Dosage and Administration
Infliximab is supplied as 100 mg vials of lyophilized powder intended for single use. Infliximab is given at a dose of 3 mg/kg as an intravenous infusion, followed by additional 3 mg/kg doses at two and six weeks after the initial dose and every six to eight weeks thereafter. The clinical response appears to correlate with the serum levels of infliximab which can vary greatly. Many patients may require higher doses (up to 10 mg/kg).
The standard dose of etanercept for adults is 25 mg, administered twice weekly by subcutaneous injection.
One important benefit, common to both infliximab and etanercept, is the rapid response to beginning treatment. As opposed to older DMARDs (which were also known as SAARD - slow acting anti-rheumatic drugs), patients that will respond to this intervention can usually be identified in just a few weeks.
Important Side Effects
Joint inflammation is not the only disease pathway in which TNF has been shown to be an important mediator. Infliximab, for example, is also approved for the treatment of fistulizing Crohn's disease. However, the multifaceted molecular roles of TNF lead to several areas of concern in treating patients with TNF inhibitors. While the most frequent infection reported in patients on TNF inhibitors are upper respiratory tract infections, anecdotal reports have also described the occurrence of severe infection in patients with RA treated with TNF inhibition. Several cases of reactivation of tuberculosis, many of which have been extra-pulmonic, have been reported in patients on infliximab. It is now recommended that prior to starting infliximab patients should screened with a PPD or chest xray. Positive PPD responders who have not been previously treated should receive appropriate treatment before beginning infliximab. These drugs should not be used in patients with active infection. Use of TNF inhibitors in patients with a history of recurrent infections, or with predisposing factors for developing infection, can be dangerous and should be done cautiously only after carefully analyzing the risk/benefit potential of this intervention.
The long-term risk of developing malignancy from TNF-inhibitors is also of concern. Obviously, the short time these agents have been on the market may not be sufficient for detection of even a significant increase in risk, especially since patients with RA have a higher background risk of neoplastic disorders because of the disease or its treatment. Whether or not TNF inhibitors will increase the risk for malignancy is being closely looked at in long-term safety follow-up studies.
Inhibition of TNF in animal models is a predisposing factor for the development of autoimmunity. Indeed, treatment of humans with etanercept and infliximab is associated with an increased risk of developing anti-nuclear antibodies. Perhaps, even more worrisome is the fact that up to 15 percent of TNF inhibitor-treated patients also developed more specific autoantibodies -- anti-double stranded DNA antibodies. This is an area of concern, particularly with the report of a mild drug-induced lupus syndrome in several patients (which resolved with treatment and withdrawal of the medication). The clinical significance of these early reports will need to be confirmed in larger groups of patients. Etanercept use has also been reported to exacerbate multiple sclerosis, another autoimmune disease, and therefore should be avoided in such patients. A few cases of a de novo demyelinating disorder have also been reported in patients on etanercept
Clinical Trials
There have been several large clinical trials documenting the efficacy of anti-TNF-alpha agents in the treatment of rheumatoid arthritis. In the multicenter ATTRACT (Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy) study, 428 patients with active RA, despite treatment with methotrexate, were given one of four different regimens of infliximab or placebo (while methotrexate was being continued).(7) At 30 weeks, about 50 percent of patients treated with the combination of infliximab and methotrexate met the ACR 20 response criteria versus only 20 percent in the group receiving methotrexate and placebo. Of the patients receiving infliximab, 25-30 percent met the ACR 50% response criteria versus five percent in the placebo group. Serious side effects and infections were not significantly different between the treatment and placebo groups.
Moreland et al(8) studied 180 patients with refractory RA in a double blind, multicenter study -- the investigators randomized patients to twice weekly subcutaneous injections of placebo versus three different doses of etanercept. Treatment continued for three months and resulted in a dose-dependent improvement in disease activity in patients treated with active drug. At the end of the study, 75 percent of patients receiving etanercept at a dose of 16 mg per square meter of body-surface area met ACR 20 percent response criteria versus only 14 percent in the placebo group. The most common side effects were injection site reactions and upper respiratory tract symptoms. Finally, Weinblatt et al(9) studied if addition of etanercept to concomitant methotrexate therapy would result in additional benefit in patients with persistently active disease. Eighty-nine patients were randomized to subcutaneous injections of 25 mg of etanercept twice weekly versus placebo for 24 weeks. At the end of the study, 71 percent and 39 percent of the patients receiving etanercept met ACR 20 and ACR 50 response criteria versus only 27 percent and three percent, respectively, of patients in the control group.
Clinical Use
TNF inhibitors have been approved for use in patients with RA who have persistently active disease despite treatment with a previous DMARD. Infliximab is approved for use only with methotrexate for patients who demonstrate an inadequate response to methotrexate alone. Indeed, methotrexate co-therapy may be beneficial in patients receiving infliximab to decrease production of anti-chimeric protein antibodies and, perhaps, the rate of infusion reactions. Etanercept is approved as stand-alone treatment, or in combination with methotrexate, for patients who inadequately responded to one or more DMARDs.
In clinical practice, we consider the use of TNF inhibitors as a second line DMARD - after the patient has failed or has had an inadequate response to methotrexate. Although treatment with infliximab and etanercept was not directly compared, the response rates of these two treatments seem to be generally similar. The choice between the two drugs is based, at this time, on practical considerations, such as the possibility of continuing methotrexate and comfort with self-injections.
Inhibition of IL-1b with Anakinra
Like TNFa, IL-1b is a proinflammatory cytokine produced and secreted by activated macrophages, as well as by endothelial cells, chondrocytes and osteoclasts. One of the activating signals for transcription of IL-1b is the linkage of TNFa with their respective cell membrane receptors. Interleukin-1b appears to be more active than TNFa mediating the irreversible structural changes in articular cartilage and bone seen in RA. IL-1b stimulates chondrocytes to release proteolytic enzymes that degrade cartilage matrix, while at the same time it inhibits these cells from synthesizing the macromolecular proteoglycans that are critical to the structure and function of articular cartilage. In addition, IL-1b activates osteoclasts that resorb bone and are important in the development of the characteristic subarticular erosions of bone seen in RA. Levels of IL-1b are elevated in rheumatoid synovium and synovial fluid and the level of IL-1b correlates with disease activity.
Like TNFa, IL-1b acts by attaching to specific cell membrane receptors on the surface of the target cells, leading to crosslinking of the membrane receptors with other cell membrane proteins. Once this crosslinking occurs, the intracellular portions of the receptors act as kinases which catalyze the phosphorylation of cytoplasmic proteins which eventually activate nuclear transcription factors that result in new messenger RNA synthesis, thereby altering cell function. The actions of IL-1b are kept in check by at least two other molecules secreted by macrophages. One of these is a soluble form of the IL-1b receptor and the other is a molecule known as IL-1 receptor antagonist (IL-1RA) that can attach to the IL-1b receptor but prevents crosslinking and cell activation. Anakinra (Kineret®) is a recombinant non-glycosylated form of IL-1RA to which methionine has been added to its N-terminal end. When given parenterally, anakinra enters inflamed joints and inhibits IL-1b activity.
Dosage and Administration
Anakinra is supplied in preloaded syringes for subcutaneous administration, along with a unique automated injector system, Simpleject, from the drug manufacturer (Amgen). Because of its relatively short half-life, the drug is administered daily at a dose of 100 mg. It is approved for use in patients with moderate to severe RA who have not had an adequate response to other DMARD's -- usually methotrexate or leflunomide (Arava®). The drug has not been studied in patients who have failed to respond to TNFa inhibition. However, anecdotally, some of these patients have responded to IL-1b inhibition. Amgen is reported to be developing a form of the molecule polymerized to polyethylene glycol that has a significantly longer half-life.(10)
Clinical Trials
Anakinra has been studied in clinical trials involving 2932 RA patients.(11) The drug has usually been given in conjunction with methotrexate and compared with patients on methotrexate and placebo followed for 6-12 months. In these trials, the ACR20 response rate has been approximately 45% for the anakinra group compared with 13% in the placebo group. Nineteen per cent of the patients receiving anakinra achieved an ACR50 response as compared 4% of the controls. Anakinra has been used as monotherapy in a trial of 472 RA patients. There was a significant reduction in radiological progression in these patients compared with the placebo group. Anakinra has also been studied in a small number of patients in conjunction with leflunomide (Arava®) responded comparably to patients given methotrexate and anakinra.
A trial of anakinra with etanercept was halted because of a high rate of infection.
Adverse Reactions
The most frequent adverse reaction seen with anakinra has been local injection site inflammation. These reactions appear to diminish after the first several weeks of administration and have been a rare cause of drug discontinuation. Opportunistic and severe systemic infections, as well as malignancies, bone marrow dyscrasias, autoimmune syndromes and demyelinating syndromes, have not been reported to date.
Summary
Anakinra appears to be an effective second-line agent in the treatment of RA which may retard the structural damage to the joints associated with this disease. The drug appears to be relatively safe. Because of its short half-life, anakinra has to be given by daily injections. Conversely, because of its rapid metabolism, it can be withdrawn quickly in the event of an adverse reaction or if patients develop an infection. Like the other biological agents for RA, anakinra is quite expensive.