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New Options In the Treatment of Rheumatoid Arthritis
• Available Therapeutic Options • Important Breakthroughs in Patient Care • Economic Implications for Health Plans • Discussion: Step-Care Algorithm To Optimize Patient Benefits and Economic Impact
Volume 10, No. 7 July 2001
About this publication
Thomas E. Scott, M.D. Mid-America Rheumatology Consultants Leawood, Kan. Joel M. Kremer, M.D. Director of Research The Center for Rheumatology Albany, N.Y. Joseph J. Doyle, R.Ph., M.B.A. Senior Manager, Health Economics & Outcomes Research Aventis Pharmaceuticals Bridgewater, N.J.
Q&A/Discussion Session Participating Faculty
David C. Calabrese, R.Ph., M.P.H. Director of Pharmacy Provider Service Network Eric Cannon, Pharm.D. Director of Pharmacy Intermountain Health Care / IHC Health Plans Jeffrey J. Casberg, R.Ph., M.S. Director of Pharmacy ConnectiCare Imelda C. Coleman, Pharm.D. Clinical Pharmacist Ochsner Clinic Mauro J. Florentine, R.Ph. Director of Pharmacy Humana Mark R. Harris Consultant MRH Associates Robert Konop, Pharm.D. Senior Clinical Pharmacist Pharmacotherapy Assessment & Policy Prime Therapeutics Inc. Terry K. Maves, R.Ph. Director of Pharmaceutical Services Touchpoint Health Plans Libby Meske, R.Ph. Clinical Pharmacy Manager PacifiCare of Colorado Burton I. Orland, R.Ph. Corporate Director of Pharmacy Harvard Pilgrim Health Care Yvonne Southwell, R.Ph. Vice President, Pharmaceutical Services Caremark Inc. David M.Yoder, Pharm.D., M.B.A. Senior Director Mid-Atlantic Medical Services Inc.
his MANAGED CARE special supplement, “New Options in the Treatment of Rheumatoid Arthritis,” is supported by an unrestricted educational grant from Aventis Pharmaceuticals.The material in this publication stems from a meeting that took place April 17–18, 2001, in Tampa, Fla.The program brought together leading experts in the field of rheumatology to discuss new and exciting treatment options for rheumatoid arthritis. The goal of the meeting was to create a new step-care algorithm for treating patients affected by this debilitating illness that is associated with substantial morbidity and mortality.Thomas E. Scott, M.D., Joel M. Kremer, M.D., and Joseph J. Doyle, R.Ph., M.B.A., described recent developments in combination treatment, using new agents that are radically improving patient care, bringing a significant reduction in disease-related disability, measurable improvements in quality of life, and a substantial decrease in economic losses.The clinical measures for rheumatoid arthritis, which are based on the standard instruments recommended by the FDA in all clinical trials, demonstrate that leflunomide is superior to older agents in combination with methotrexate, the previous gold standard for rheumatoid arthritis treatment. The material in this special supplement has been independently peer reviewed.The sponsor played no role in reviewer selection. The opinions expressed in this special report are those of the participants and authors and do not necessarily reflect the views of the sponsor, publisher, editor, or editorial board of MANAGED CARE. Clinical judgment must guide each clinician in weighing the benefits of treatment against the risk of toxicity. Dosages, indications, and methods of use for products referred to in this special supplement may reflect the clinical experience of the authors or may reflect the professional literature or other clinical sources and may not necessarily be the same as indicated in the approved package insert. Please consult the complete prescribing information on any products mentioned in this special supplement before administering.
Thomas Scott, M.D., acknowledges that he has an affiliation with Aventis Pharmaceuticals as a member of its advisory board panel on rheumatology. Neither Aventis Pharmaceuticals nor Dr. Scott perceives this affiliation as a conflict of interest for the presentation of scientific and medical information. Joel Kremer, M.D., acknowledges that he has been a consultant to, and has received honoraria for his work from Aventis Pharmaceuticals, Amgen, Immunex, and Centocor. He also acknowledges having done research with grant support from these companies. Neither these companies nor Dr. Kremer perceive these affiliations as conflicts of interest for the presentation of scientific and medical information. Joseph Doyle, R.Ph., M.B.A., acknowledges that he is currently employed by Aventis Pharmaceuticals as a senior manager in health economics and outcomes research. Aventis Pharmaceuticals does not perceive this affiliation as a conflict of interest for the presentation of scientific and medical information.
PHOTOGRAPHS BY PHELAN EBENHACK/MERCURY PICTURES
STEZZI Publisher Economic and Quality-of-Life Impact Of Rheumatoid Arthritis Joseph Doyle. 275 Phillips Blvd. Trenton. SEARCH.Editorial staff Editor SPECIAL SUPPLEMENT JOHN A. Kremer. MARCILLE Managing Editor MICHAEL D.D.B. HILLMAN. J. N. M. Issue 7. Letters may be edited for length and clarity.A.D.A. M. $120 per year elsewhere. Philadelphia Group Publisher 2 Combination DMARD Therapy For Rheumatoid Arthritis Joel M.” is supported by an unrestricted educational grant from Aventis Pharmaceuticals. J. MediMedia USA. DENNING MIKE FOLIO. MANAGED CARE. Midwest Sales Manager Discussion/Development of Treatment Algorithm Presenters and participants TERRY HICKS Senior Account Manager SCOTT MACDONALD Account Manager SCOTT OLSON Director of Production Services WANETA PEART MANAGED CARE (ISSN 1062-3388) is published monthly by MediMedia USA Inc. 275 Phillips Blvd. .D. DALZELL Senior Editor FRANK DIAMOND Senior Science Editor PAULA R.. 15 19 TIMOTHY P.D. at 275 Phillips Blvd.D. 10 TIMOTHY J.PH. JEFFREY J.J.B. NJ 08618. This MANAGED CARE Special Supplement.. R.“New Options in the Treatment of Rheumatoid Arthritis. R. fax (609) 882-3213. Copyright ©2001 by MediMedia USA Inc. Phone: (609) 671-2100. SIROIS Senior Contributing Editor Care July 2001 M A N A G E D PATRICK MULLEN Contributing Editors BOB CARLSON JOHN CARROLL DAVID COLEMAN. J... Senior Fellow Center for Health Policy Leonard Davis Institute of Health Economics University of Pennsylvania. circulation inquiries.com. Trenton. Prices: $10 per copy. $93 per year in the USA. (609) 671-2100.D... Trenton. Periodicals postage paid at Trenton. M. POSTMASTER: Send address changes to MANAGED CARE. NJ 08618. M. and at additional mailing offices. This is Volume 10. NJ 08618. Send letters to the editor c/o Frank Diamond. MICHAEL LEVIN-EPSTEIN JACK MCCAIN KAREN TRESPACZ. E-mail: editors@managedcaremag. PHILIP DENLINGER Editorial Advisory Board Chairman ALAN L.Ph. Design Director New Options In the Treatment Of Rheumatoid Arthritis Pharmaceutical Agents for the Treatment Of Rheumatoid Arthritis Thomas E. M. Scott.
is a new agents. which can include the potential for pericarditis and pleurisy to develop. with elevated platelets and low serum iron. which presents as a symmetric arthritis but shows no erosion on radiograph. Patients generally report pain and fatigue in their initial office visits. RA is expensive to treat. Joint erosions are characteristic of RA. and to ascertain whether there is radiographic evidence of erosion. The criteria for studies of RA define it as a symmetrical inflammatory polyarthritis (meaning it affects both sides of the body equally). and a higher titer serum 2 MANAGED CARE / SUPPLEMENT . isconceptions about rheumatoid arthritis (RA) abound. significant dollars will be saved — given that a total hip or knee arthroplasty costs upwards of $16. Mo. a clinical assistant professor of as well as total joint medicine at the University of replacement. Many primary care physicians do not fully recognize how devastating RA really is. and that it is a systemic disorder affecting multiple organs. The common estimate is that 1 percent of the adult population is affected by RA. disability. with the Center for Rheumatic can prevent disabil. Patients with RA often have abnormalities in blood counts.. The total perpatient costs are not quite as high as those for coronary artery disease. and the losses associated with quality of life are considered.Disease in Kansas City. Because other conditions are characterized by symptoms similar to those associated with RA.1 A high percentage of these M patients are within Class IV. He is ity and joint damage. to look carefully at the lab studies to determine if the patient has a positive serum rheumatoid factor. M. An astute clinician who sees a patient with ankle and knee inflammation and no involvement of the hands and wrists would question a diagnosis of RA. RA is a progressive and systemic inflammatory disorder of unknown etiology to which multi-system extra-articular manifestations are linked.2 Defining severity and progression Assessing a patient’s prognosis is important for determining the treatment program. using the patient’s functional status (Table 1). it is important to discern whether the condition is symmetric. there are problems with vasculitis — inflammation of the small blood vessels that can lead to stroke. SCOTT. RA has been approached as a condition that the patient can learn to live with. and vasculitic skin lesions. Patients often have organ inflammation. Additionally. Scott.Consultants and is currently tor (TNF) inhibitors. yet costs rise substantially when joint replacement. then Kansas School of Medicine. the most advanced stage of rheumatoid arthritis as described by the American College of Rheumatology (ACR).Pharmaceutical Agents For the Treatment Of Rheumatoid Arthritis THOMAS E.000 exclusive of postoperative care and rehabilitation. Certain indicators are useful in identifying patients whose disease is likely to become severe. The fatigue is attributable to the systemic inflammation. and may be anemic. M. neuritis. Forty to sixty percent of these patients typically survive five years or less following diagnosis. such as lupus. The available diagnostic tools can help the physician differentiate this disease from others sharing similar symptoms.D. If Thomas E. even among physicians.D. such as practicing rheumatologist with leflunomide and the Mid-America Rheumatology tumor necrosis fac. Rather than being a disease characterized by tender and swollen joints. Generally viewed as a benign disease with manageable symptoms. which diminishes their energy. these symptoms almost always involve the hands and wrists. Serum rheumatoid factor is positive in approximately 75 percent of RA patients. the so-called extraarticular manifestations of RA. with prolonged morning stiffness.
to reduce pain and morning stiffness. cyclooxygenase. fewer gastrointestinal bleeds. and fewer daily life. These agents do not reduce disavoid more severe stages of this disease. Rheumatolproblems with platelet inhibition and anemia. have generated substantial misundersive treatment. activities. rheumatoid nodules. The COX-2 inhibitors are associated Patients should be able to perform their activities of with fewer ulcers. Radical changes to adhere to one another. and even play sports. Like NSAIDs. which selectively inhibit COX-2 to a greater extent disability. and the older DMARDs). as a result of direct-toChanging pharmacologic goals consumer advertising. The various nonsteroidal antiindicate a worse prognosis.3 inflammatory drugs (NSAIDs) have long been a mainFunctional status is highly predictive of severity and stay of RA treatment because they control inflammation and pain to some degree. With the introease progression or deformities and erosions.. Traditional NSAIDs as a result of new pharmacotherapeutic options that such as naproxen and ibuprofen inhibit the proinflammake early treatment possible and the avoidance of dismator y prostaglandins as well as the “good” ability a realistic goal. ognizes the overriding importance of controlling inNew nonsteroidal agents such as celecoxib and rofeflammation early to avert irreversible joint damage and coxib. standing among patients. limited clinically apparent physical factors in vocational/avocational activities patients with the systemic disease.7 Their bention. Early. Structural daming the “housekeeping” prostaglandins. COX-1 and Because RA is not a benign disorder. vocational/avocational activities neurological symptoms. early diagnosis COX-2. self-care. such patients may be found to have pleurisy Class IV Limited ability to perform usual self-care and or pericarditis. aggressive treatment Prostaglandins mediate pain as well as inflammation. compared with agents that inhibit both control disease activity in a large proportion of patients. and the criteria for this assessment can be efprove mobility and quality of life in only a low percentfectively used to measure improvement in the effort to age of patients with RA. The COX-2 enzyme produces in treatment approaches to RA have recently developed proinflammatory prostaglandins. which are inflammation indica(e. The COX-1 enzyme is responsible for producand aggressive treatment are important. because they offer quick rethese lines. sion. Such extra-articular manifestations Nonsteroidal agents. Corticosteroids also are which have produced measurable improvements along overused in RA treatment. renal blood flow — and also allow platelets ease has been linked to early treatment. which produces prostaglandins.8 Also. An inflammatory disease involving the eye (the “sicca” syndrome) also is common steroidals. These needs are being met more often with the Corticosteroids. For patients presenting with Classification Specifications extremely high elevations of C-reactive protein and erythrocyte sedimentation Class I Complete ability to perform usual activities rate. corticosteroids.6. limited avocational activities Extra-articular manifestations are Class III Ability to perform usual self-care activities.g. which is problematic. Early diagnosis is thus essential.rheumatoid factor tends to predict TABLE 1 ACR criteria for assessing functional status in RA severity. RA treatment was aimed at decreasing traditional NSAIDs with respect to relieving signs and swelling and tenderness and increasing range of mosymptoms of RA4. their work. paogists want to maximize the patient’s quality of life and tients on COX-2 drugs can take warfarin and not be at to see radiographic demonstration of slowed progresan increased risk of bleeding. The medical profession now recprostaglandins. zyme. or vasculitic skin rashes. Cyclooxygenase exists as two isoforms.Yet they reduce swelling and imoutcome. in patients with RA. and slower progression of this dissome degree. They are not disease-modifying agents. vocational/avocational) tors. Steroids have been used to bridge gaps during treatagents in the context of the traditional agents (nonment while waiting for other medications to become ef- SUPPLEMENT / MANAGED CARE 3 . more aggressive treatment and Class II Ability to perform usual self-care and vocational close patient monitoring are needed.5 or osteoarthritis (OA). therapy aims to prevent the Nonsteroidal agents function by inhibiting an enadvanced disease state associated with Class IV status. which maintain age and disability can occur within the first two to three mucosal integrity in the gastrointestinal tract — and to years of the disease. as is aggresthan COX-1. corticosteroids are not newer agents — leflunomide and the anti-TNF agents — disease-modifying drugs. The following discussion places the newer lief. duction of the newer agents. and they have not been shown to be superior to Historically. These goals have been expanded to include the maintenance of funcefits lie in their relatively rapid onset of action and retional status through the use of extremely safe agents that duced toxicity. COX-1 and COX-2.
daily 1. sulfasalazine. many are noted for their toxicity. every 2–4 weeks Moderate 200 mg. Arava prescribing information. proteinuria. In addition. rash. and rash. oral Gold. Steroids may be beneficial in the long term and are inexpensive. proteinuria Myelosuppression. gastrointestinal Cyclosporine Gold. proteinuria. Steroid injections are highly effective for targeting a specific joint. Like most of the older agents. twice daily 20 mg. daily or twice daily High Low 25–50 mg IM. even by the American College of Rheumatology. Rheumatologists no longer use penicillamine. and approximately 35 percent of patients on gold therapy experience side effects that often lead to discontinuation of the drug. however. hydroxychloroquine. a metabolite of penicillin. myelosuppression Myelosuppression. Sulfasalazine seems to work better in combination therapy and for patients with inflammatory bowel disease who get arthritis. proteinuria Macular damage Hepatotoxicity. Parenteral gold is now recognized to have limited effectiveness. The older DMARDs are characterized above all by their relatively slow onset of action — anywhere from one to six months is needed before a clinical benefit can be discerned (Table 2). 2 or 3 times daily High Low Sources: Guidelines for the management of rheumatoid arthritis. A small percentage of patients would do well on hydroxychloroquine alone. penicillamine. although in some patients diarrhea is exacerbated by this drug. thrombocytopenia.5–15 mg. although it is used as an off-label treatment for scleroderma.39:713–722. and azathioprine also have generally been referred to as DMARDs. Even low doses (≤10 mg daily) of long-term oral prednisone can lead to osteoporosis. In the past. 1996. Penicillamine is highly toxic and can lead to druginduced lupus. The older DMARDs include methotrexate. hyperuricemia Myelosuppression.TABLE 2 Selection of an initial DMARD Drug Azathioprine Approximate time to benefit 2–3 months Usual maintenance dose 50–150 mg. to treat RA. DMARDs Disease-modifying antirheumatic drugs (DMARDs) interfere with the inflammatory process by a variety of mostly unclear mechanisms. parenteral 2–4 months 4–6 months 3–6 months 1. they are not true disease-modifying agents be- cause they do not reduce erosions and disability. hepatotoxicity. per week Low Low Moderate Hydroxychloroquine 2–4 months Leflunomide Methotrexate 2–4 months 1–2 months D-penicillamine Sulfasalazine 3–6 months 1–2 months 250–750 mg. Hydroxychloroquine is generally perceived as a drug for mild disease. rash. Although oral gold. which mandates frequent monitoring. daily Toxicity Moderate Toxicities to monitor Myelosuppression. gastrointestinal Myelosuppression. pulmonary. an option that most primary care physicians cannot offer. Arthritis Rheum. Cyclosporine is an immunosuppressive agent associ- 4 MANAGED CARE / SUPPLEMENT . lymphoproliferative Renal. fective. and injectable gold salts.000 mg.0–2. cyclosporine.5 mg/kg/d 3 mg. used with sulfasalazine and methotrexate. this treatment choice was more common in combination therapy. 2000. The osteoporosis can be prevented with bisphosphonates. gastrointestinal Hepatotoxicity. a drug that originated as a treatment for malaria. loss of taste. it does not halt disease progression. Hydroxychloroquine raises concerns about macular damage.9 and it can be challenging to taper the dose of these drugs without a recurrence of symptoms. daily 7. and it is now used more in the treatment of lupus than RA.
both infliximab and etanercept are effective at lower doses. because RA often affects women in their childbearing years. vs 27 percent of patients receiving methotrexate plus placebo. effectiveness decreases after six weeks if not used with methotrexate. TNF-α production rises sharply. it has immunosuppressive and cytotoxic effects that are due to the inhibition of dihydrofolate reductase. and negative effects are considerably reduced. urticaria. intravenous etanercept acted more rapidly than oral methotrexate to decrease symptoms and slow joint damage. If a drug can prevent TNF-α from binding with its receptors. chills. which was reported in two RA patients receiving infliximab in clinical trials (and which resolved following the cessation of therapy and appropriate medical treatment). TNFα has two types of receptors. Methotrexate: the treatment standard After more than 15 years of extensive clinical experience. acute infusion reactions (headache. A fair number of patients also develop lung toxicity from this drug. whose treatment may be high doses of methotrexate (≥20 mg/week). 71 percent of patients receiving the etanerceptmethotrexate combination met the ACR-20 criteria. which leads to sharp rises in cost. and serum creatinine. etanercept. methotrexate remains an effective tool in the armamentarium against RA. There is increasing recognition that the dose of infliximab must continue to be increased to maintain efficacy throughout the treatment of RA. rather than have the patient come to the office every four weeks for treatment. p55 and p75. swelling. Toxicity concerns are high in the patient population. As a practical issue. Patients on methotrexate must be diligent about having their liver function monitored every four to eight weeks to avoid serious toxicities that can lead to cirrhosis in rare cases.ated with increased risk of infection and renal insufficiency. Complications commonly occur with compliance and follow-up when monitoring is done outside the physician practice. Anti-TNF therapies Tumor necrosis factor-alpha (TNF-α) appears to be an extremely important mediator of RA. offers the added advantage of using methotrexate at lower doses that are better tolerated due to the reduction in toxicity. Concomitant treatment with methotrexate can reduce the incidence of the formation of antibodies against infliximab. improvement in some patients was observed after the first infusion. Toxicity can generally be prevented with daily folic acid supplementation. If left unchecked. Two anti-TNF agents are available. antibodies against infliximab have been associated with drug-induced lupus. TNF-α affects the lining of the synovium. SUPPLEMENT / MANAGED CARE 5 . particularly the elderly. it can block these negative effects downstream. Combination therapy. Essentially. which can result in a diminished therapeutic response over time. In a study using methotrexate and infliximab at 3 mg/kg every eight weeks and 10 mg/kg every eight weeks.10 There was an upward curve in improvement. The chimeric nature of infliximab is important clinically because human antibodies to infliximab can develop.12 After 24 weeks. as well as bone and cartilage. The myelosuppressive drug azathioprine can control RA for 10 years but the risk of lymphoma and liver toxicity is heightened.11 The combination of subcutaneous etanercept and methotrexate provided greater clinical benefit than methotrexate alone in patients with persistent RA. Infliximab is a chimeric IgG1 monoclonal antibody. the dose can be increased to 5 mg/kg. For the small subset of patients who do not achieve as good a response with time. Significant myelosuppression may develop in RA patients. versus 7 percent of those receiving placebo. In three-year follow-up safety studies. with no drop-off at 54 weeks. it affects various cellular pathways that lead to inflammation. and many RA patients will be on long-term medication. Although its mechanism of action relative to its anti-inflammatory effects remains unclear. treatment challenges increase with patients who continue to ingest alcohol. Etanercept has been shown in clinical trials to be efficacious when used alone or in combination with methotrexate. enabling cells to infiltrate joints. Moreover. and does well in the overall clinical parameters. composed of human constant and murine variable regions. fever. Etanercept consists of two recombinant p75 soluble receptors attached to the Fc portion of human IgG1. Combination studies. chest pain) have been seen in 17 percent of patients receiving infliximab. and even joint destruction. including X-ray data. Used in combination with methotrexate. Routine toxicity monitoring should include a complete blood cell count (CBC). or leflunomide. In a 12-month study of patients with early RA. Produced by macrophages and T-cells. In addition. Methotrexate is a proven agent in reducing painful and swollen joints. the options are to either increase the dose or reduce the dosage interval. thus necessitating an infusion or a dose increase that may lead to greater adverse effects. using methotrexate with infliximab. Methotrexate is not as effective as the TNF inhibitors and leflunomide in reducing the incidence of erosions. serum albumin. both agents act as sponges to soak up circulating TNF-α before it can bind with its cell-surface receptors and deliver its signal. both of which occur as cell-surface receptors and in soluble forms. leading to pain. because the infusion takes two to three hours. It also increases permeability through its effects on the endothelium of blood vessels. liver profile. etanercept and infliximab. With drugs such as infliximab.
a similar percentage may not respond to infliximab. Significantly.16 (On the HAQ. patients are 30 focusing on improvements in their quality of life and ability to function. I have * more patients on a combination of metho* trexate and leflunomide than on either agent 40 alone. and methomide has a relatively rapid onset of action of four to trexate.agents used in the past. In some patients. gression of disability. but a two-year radiographic comparison clearly shows fewer erosions with leflunomide. an improvement with 0 time that was even greater than that seen with ACR responders† ACR success** methotrexate. the probability of adverse events is reduced. treatment with both of these drugs together may be synergistic. 6 MANAGED CARE / SUPPLEMENT . Some patients receiving leflunomide may experience mild gastrointestinal reactions. a 10 recent study shows patients on leflunomide did better than placebo. Some evidence indicates its onset of action tient who shows ≥20 percent improvement) in a combination of responses. unlike some of the other RA demonstrating that leflunomide was as good or better therapies. Some patients who cannot tolerate methoLeflunomide Placebo Methotrexate trexate do well on leflunomide alone. toward a specific part of the immune response: T-cells A primary goal in RA therapy is to reduce the prothat proliferate and turn on the immune response in the gression of disease to an extent that is visible on radiojoints. test abnormalities. Increasingly. Disease progression. trexate14 in these early studies. **ACR “success” is defined as a patient who completed ity show improvement with leflunomide (Fig12 months’ treatment and is classified as an ACR responder at endpoint. careful blood monitoring is necessary during treatment with leflunomide. Because leflunomide selectively targets autoimmune lymphocytes. ment is represented by a larger negative The anti-TNF therapies are inaccurately viewed by some as a cure for RA. using ACR-20 responder criteria (defined as a paeight weeks. leflunomide is directed than methotrexate was an extremely important finding. This was particularly exLeflunomide is well tolerated by most patients. that takes care of all patients. 15 FIGURE 1 Efficacy of leflunomide. such as methotrexate. have to be discontinued due to persistent liver function leflunomide is a viable alternative in the treatment of RA. * Quality of life. Adding an NSAID to the mix could afLeflunomide: a breakthrough agent fect liver function. leflunoprogression with leflunomide. Early studies compared disease Compared with some of the older DMARDs. Approximately 25 percent of patients may not respond to etanercept. Also. and an extremely small percentage of patients specifically for RA. and methotrexate Methotrexate reduces disease progression as based on ACR-responder index well. Patient quality of life and work productiv*P ≤. rather than on the 20 treatment of isolated symptoms. Some patients cannot tolerate the diIt is the first of the new agents to have been designed arrhea. To avoid hepatic toxicity. than placebo13 (Figure 1) and was superior to methothe data on leflunomide demonstrate that the drug works as well at two years as it does initially. leflunomide is more selective than the graphic examination. Serious infections have been reported in patients receiving TNF inhibitors.0001 vs placebo. an improvein disease progression. or combination therapy. placebo. and citing news. maximiz* 50 ing the beneficial effects. Importantly. The release of these data came at a time many studies with leflunomide have shown safety and efwhen methotrexate was considered the gold standard. placebo. Leflunomide performed much better may be sooner than that of methotrexate. Randomized controlled trials of leflunomide have revealed that it definitely slows radiographic progression of RA. leflunomide will Less costly than either of these new biological agents. ficacy over two years. There is still no single agent. Questions remain about the long-term use of these drugs. yet for 60 most patients. †ACR responder is defined as a patient who shows ≥20 percent improvement ures 2 and 3). In my practice. Treatment with the combination of leflunomide and methotrexate also necessitates monitoring the liver. Using the Health Assessment Questionnaire (HAQ) or the modified HAQ as an outcome measure. and it has been shown to halt prowith alopecia drop off the drug.
Increased disability is averted. have persistent swelling and erosions. perhaps a benefit of synergistic effects. rheumatologists generally choose methotrexate.5 *† * *† * Selecting a treatment option In evaluating the available treatment options. as radiographic examination reveals that inflammatory changes in the joints resolve. In the old paradigm.0001 leflunomide vs placebo. For patients with refractory disease.4 –0. SF-36. a positive change is much harder to achieve.01 leflunomide vs methotrexate. This slowing is clinically apparent. it is important to seek data showing decreased progression of joint erosions and the resulting reduction in deformity and disability. and in one. Negative values for PET indicate improvement. PET = Problem Elicitation Technique (weighted top 5 scores). and begin to get deformities.0001 vs placebo. with early and aggressive combination therapy. methotrexate and leflunomide may be the combination of choice.number.1 0 –0. the old pyramid has been inverted.) In all three of these outcome measures — work productivity. better than methotrexate.2 –0.3 –0. and problem elicitation technique — leflunomide was better than placebo. With the advent of leflunomide. ‡P ≤. MHAQ = Modified Health Assessment Questionnaire. †P ≤.01 leflunomide vs methotrexate. Today.1 –0.] More and more. HAQ-DI = Health Assessment Questionnaire (disability index). Kremer’s discussion on the synergistic potential of the leflunomide-methotrexate combination. SUPPLEMENT / MANAGED CARE 7 . however. positive values for SF-36 and work productivity indicate improvement. rheumatologists are using methotrexate in combination as first-line therapy. **P ≤. DMARDs such as methotrexate and leflunomide actually slow disease progression and improve functional status. in contrast to Short Form 36. etanercept. The introduction of the newer agents initially led many rheumatologists to switch patients away from methotrexate. FIGURE 2 Functional activities and health-related quality-of-life parameters in active RA Lef lunomide Placebo Methotrexate 0.01 leflunomide vs placebo. where improved work productivity is indicated by a positive number. MHAQ HAQ-DI *P ≤. Negative values indicate improvement. Once erosions are present in a Class III or IV patient. treatment began with anti-inflammatory agents — lowdose prednisone. †P ≤. FIGURE 3 Functional activities and health-related quality-of-life parameters in active RA (continued) Leflunomide (n=166) Placebo (n=101) Methotrexate (n=169) 10 8 6 4 2 0 –2 –4 –6 –8 PET SF-36 Work productivity *‡ *† ** *P ≤. yet increasingly they are realizing that patients do better on methotrexate in combination with leflunomide or one of the anti-TNF agents. page 10. The new treatment paradigm is shown in Figure 4.001 leflunomide vs methotrexate. SF-36 = Medical Outcomes Survey Short Form 36 (physical component). and infliximab. when patients fail NSAIDs. possibly gold or hydroxychloroquine — and then progressed to the more powerful agents. [See Dr.
Arnett FC. 5. JAMA. Caldwell JR. Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison.000 to $2. Higher-dose steroids biologic response modifiers. Day R. Simon LS. 7. Arthritis Rheum. Leflunomide costs approximately $300 a month and methotrexate about $75 per month. leflunomide and the anti-TNF agents offer improved gastrointestinal tolerability and reduced renal insufficiency compared to the older agents. Ann Intern Med.000 per month. Rational use of new and existing diseasemodifying agents in rheumatoid arthritis. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis.000 or more (infliximab is dosed by weight). 1999.354:2106–2111. Celecoxib Long-term Arthritis Safety Study. Lawrence RC. Zeidler H. Graham DY. Goldstein JL. 2000.39:713–722. Antiinflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis. 4. et al. 6. which is over $1. et al. and these patients often have additional coverage for the other 20 percent. sulfasalazine. 1999. For many patients. Arch Intern Med. 8. Weaver AL. 1998. it is important to look at the long term. non-acetylated salicylates. The CLASS study: A randomized controlled trial. From a strict cost perspective. Arthritis Rheum. for flares or extra-articular disease D-penicillamine. hydroxychloroquine. for many patients the leflunomide-methotrexate combination is an excellent choice. and other NSAIDs Intra-articular steroids Occupational therapy Physical therapy Severe disease at onset Simple analgesic SOURCE:WEAVER AL. Infliximab is often prescribed for Medicare patients. with clinical efficacy comparable with that of diclofenac sodium: results of a one-year. Guidelines for the management of rheumatoid arthritis. References 1. Rofecoxib/Ibuprofen Comparator Study Group. Morrison B. 2001. Holt P. Rofecoxib Phase III Protocol 035 Study Group. methotrexate.284:1247–1255. and infliximab. 1998. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. however. with a monthly cost that can range from $1. Lancet. 8 MANAGED CARE / SUPPLEMENT . The TNF inhibitors also provide a fast response that is gratifying for both patient and physician. 2000. JAMA. Kvien TK.41:778–799. and there are no clear data on which combination is better. clinical trial in patients with osteoarthritis of the knee and hip. as opposed to etanercept. 1996. Rofecoxib. because they generally do not have secondary insurance that covers medications.160:1781–1787. a specific inhibitor of cyclooxygenase 2. Faich G. what happens at two years with respect to costs. Partly due to cost considerations. Cannon GW. 2000. Nevertheless. et al. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines.43:978–987. Luza A. et al.FIGURE 4 The new treatment paradigm New experimental agents and procedures Orthopedic surgery Azathioprine. et al. which can be exacerbated by the potential need to increase dosages. Emery P. Kremer JM. et al. 3. There has yet to be a comparative study of methotrexate and leflunomide vs methotrexate plus either infliximab or etanercept. A randomized controlled trial. cyclosporine alone or in combination with other DMARDs Leflunomide. 2. the difference between leflunomide and the antiTNF therapies argues for using leflunomide in combination with methotrexate first.134:695–706. 80 percent of the cost of infliximab is covered by Medicare. A randomized trial of the efficacy and tolerability of the COX-2 inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. gold alone or in combination with other DMARDs Low-dose corticosteroids Mild disease at onset Patient education Salicylates. The patient’s insurance coverage makes a difference in private practice. randomized.282:1921–1928. Silverstein FE. Helmick CG. Arthritis Rheum.
16. 1999. Fleischmann RM.343:1586–1593. Strand V. Hurley F.43:495–505. Arthritis Rheum. Ruijs SH. 12. Loew-Friedrich I. placebo-controlled trial. Strand V. Weinblatt ME.38:1595–1603. Laan RF. 14. 2000. Arthritis Rheum. 13. Kremer JM.42:1870–1878. Leung H. Rozman B. Lipsky PE. Clair EW. phase II study. a recombinant tumor necrosis factor receptor:Fc fusion protein. et al. et al. 11.9. Martin RW. et al. Br J Rheumatol.343:1594–1602. 1992. Bankhurst AD. Vertebral osteoporosis in rheumatoid arthritis patients: effect of low dose prednisone therapy. Sharp JT. N Engl J Med. Bombardier C. in patients with rheumatoid arthritis receiving methotrexate. 2000:43:506–514. et al. Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Results of a randomized. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Leflunomide Rheumatoid Arthritis Investigators Group. van der Heijde DFMF. et al.340:253–259. Arthritis Rheum. van Erning LJ. van Riel PL. Domljan Z. Mladenovic V. Arthritis Rheum. Wells G. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. 2000. 1995. for the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Strand V. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. Function and health-related quality of life: results from a randomized controlled trial of leflunomide versus methotrexate or placebo in patients with active rheumatoid arthritis. Bathon JM. Tugwell P. Lemmens JA. N Engl J Med. van de Putte LB. placebo-controlled. 2000. St. Clinical improvement as reflected in measures of function and health-related quality of life following treatment with leflunomide compared with methotrexate in patients with rheumatoid arthritis: sensitivity and relative efficiency to detect a treatment effect in a twelve-month. et al. Leflunomide Rheumatoid Arthritis Investigators Group. 15. Tugwell P.31:91–96. A trial of etanercept. 10. N Engl J Med. 1999. SUPPLEMENT / MANAGED CARE 9 . Leflunomide Rheumatoid Arthritis Investigators Group.
because the burden of inflammation/immunologic activity is associated with comorbidities. nonadditive toxicity. Sixteen years later. the side effects of drugs were regarded as more severe than the so-called side effects of RA. we first must examine the recent history of therapy for patients with this disease. Kremer. rapid onset of action.D. of research at the Center for they had already enRheumatology in Albany.2 the new agents offer different possibilities and expanded pharmacotherapeutic potential when used in combination with methotrexate. described RA as primarily a benign disease with which most patients do well.Combination DMARD Therapy For Rheumatoid Arthritis JOEL M. The focus. medicine at Albany Medical It was a surprise to College.Y. and the ability to monitor and recognize liver and lung toxicity was developed. KREMER. as monotherapy.. (See Figure 1. and disability may be present. Today. N. the effects of RA are recognized to be more severe than the adverse effects associated with the pharmacological agents being used to treat patients. Kelly’s Textbook of Rheumatology. The combination of cyclosporine and methotrexate 10 MANAGED CARE / SUPPLEMENT . because disease progression is rapid in the first few years. should be on damage. At that time. when only two or three of 336 combination studies demonstrated efficacy of the agents then available. Typically. Because a wait of two to six months is necessary to determine if these interventions are effective. this is too late. including atherosclerosis. During the 1980s. and infections. RA is not a benign disease. an onHe has recently focused on the cology drug. radiographic erosion. RA has been identified as a source of increased mortality. and the so-called slow-acting antirheumatic drugs toward the apex.D. and cost-effectiveness. an acceptable dosing schedule and rate of administration. dured the disease for and he is a clinical professor of a number of years. disability.. Moreover. Clearly. the treatment of RA was traditionally depicted as a pyramid. Early fears about the side effects of methotrexate were overcome. if treatment is delayed. along with quality-of-life issues. and death. Patients die prematurely. premature coronary disease. To measure disease activity. The new treatment paradigm is combination therapy. but unlike 1990. methotrexate. the need for aggressive therapy becomes obvious. by the time patients were subjected Joel M. and no single agent is capable of halting its progression. He was one of the original investigators who developed the medical commumethotrexate. The idea has been around for a long time. rheumatologists count swollen joints and arrange them in composite scores. M. those beliefs have been abandoned. In fact.) NSAIDs and physical therapy were near the base of the pyramid. however. premature death from malig- T nancies. maximally effective dosage. but only after damage begins. During the 1980s.1 a highly regarded book. the 1985 edition of William N. The ideal combination would provide complementary biologic effects: accessible. o understand the place of the new agents in our armamentarium against rheumatoid arthritis (RA). deformity. was combinations that are being more effective than developed using new agents disease-modifying with methotrexate. anti-rheumatic drugs (DMARDs) available then. is director to these therapies. then. early RA was thought to progress slowly. M. In addition. the traditional pyramid is no longer seen to be sufficient. With growing recognition of the rapid progression of this disease. the drugs were used sequentially. describing its nity to learn that long-term safety and efficacy. Rebuilding the therapeutic pyramid Using the traditional therapeutic pyramid — which was first described more than 40 years ago — and subjecting patients to sequential monotherapy means that by the time an effective drug is used.
In vitro studies have shown that methotrexate inhibits the most proximal step in the metabolic pathway for purine nucleotide biosynthesis. In an open study of 30 patients receiving leflunomide and methotrexate. SUPPLEMENT / MANAGED CARE 11 . This would clearly be a synergistic interaction of the two drugs. plus methotrexate (n = 130) or placebo plus methotrexate (n = 133) for eight weeks. by salvage pathways within the cell. only 2 mg/kg or 3 mg/kg is used. This creates the potential for increased toxicity. the oral resin binder cholestyramine can be administered to clear it from the system within 7 to 10 days. but leflunomide limits the increase to only twofold. This is not to say that these two drugs should not be combined. which inhibits the clonal expansion of T-cells. This is accomplished by inhibiting the enzyme dihydroorotate dehydrogenase (DHODH). Nucleotides consist of a sugar (ribose [found in RNA] or deoxyribose [found in DNA]). If that can be demonstrated. • How much improvement will result from adding a new agent to methotrexate? • What are the risks from combining a new agent with methotrexate? • Why is the combination of this new agent and methotrexate being used. but that increase can be blocked by the addition of leflunomide. it would be the first case of true biochemical synergy ever reported in RA treatment. Leflunomide undergoes continuous enterohepatic recirculation. A77 1726. present. Leflunomide’s primary mechanism of action is shown in Figure 2. An eightfold increase in the precursor of this pyrimidine nucleotide* is necessary for the clonal expansion of lymphocytes. nucleotides are involved in regulatory and signaling mechanisms. whereas for the treatment of RA. Additionally. For suppression of immunity in transplant patients. either leflunomide 10 mg q. and a base. This in vitro observation needs to be expanded to prove true biochemical synergy. It is virtually 100 percent protein-bound. and future. In other words. as opposed to another combination? The combination of leflunomide and methotrexate is among the new combinations being used to treat RA. methotrexate’s area under the curve increases by 29 percent. cyclosporine cannot be used at its maximally effective dose. after a loading dose of leflunomide or placebo. FIGURE 1 The outmoded therapeutic pyramid for RA Rehabilitation Experimental Rx High-toxicity DMARDs Surgery Time Low-toxicity DMARDs ASA/NSAIDs/Low-dose steroids Patient education PT/OT Heat/Ice Rest ASA = Acetylsalicyclic Acid. When that happens. and uracil (found in RNA but not DNA). that are addressed in the following questions. at which point investigators had the option of doubling the dose * In addition to serving as the building blocks of the nucleic acids RNA and DNA. a biochemical effect of methotrexate is to increase UMP. This study served as the basis of a double-blind. Combination therapy with methotrexate and leflunomide Leflunomide has the potential for hepatotoxicity. but that practitioners using these two agents need to use extreme care in monitoring their patients on this therapeutic regimen. with the net result being the upregulation of UMP — the synthesis of which is specifically inhibited by leflunomide. PT = Physical Therapy. the conversion of phosphoribosylpyrophosphate (PRPP). Cyclosporine affects the renal clearance of methotrexate to the extent that when these drugs are used together. one or more phosphate groups. Rheumatoid arthritis: past. The purine bases are adenine and guanine.serves as an example of therapy that falls short of the ideal. thymine (found in DNA but not RNA). which initially raised the question of whether it could be used successfully with methotrexate. which means that if a patient experiences toxicity. Cornerstone of combination therapy Methotrexate is the cornerstone of modern combination therapy — and it probably will be for at least the next five years — but it presents certain challenges. the PRPP is shunted into pyrimidine pathways. the pyrimidines are cytosine. it is used at the rate of 10 mg/kg. which fall into three groups. which is a key enzyme in the de novo synthesis of uridine monophosphate (UMP). There are two kinds of nucleotide bases: pyrimidines and purines. significant improvement was observed in five clinical parameters. OT = Occupational Therapy SOURCE: Gardner GC.d. placebo-controlled trial of 24 weeks in which 263 patients with active RA and an inadequate long-term response to methotrexate received. Leflunomide — the only one of the new drugs that is administered orally — is a prodrug that is converted to an active metabolite.
89 on both ALT results in significantly greater clinical benefit than and AST for placebo and methotrexate. the algorithm for liver function tests Anti-TNF therapy (LFTs) was elaborate and fairly rigid. despite long-term treatment with methotrexate. the medication had to be discontinued. the tests were refound on the cell surface but also exist as soluble forms. placebo-controlled trial for leflunomide and methotrexate were 3. I have recommended mide monotherapy. of steroids and NSAIDS. In this study. in acshowed improvement in ACR criteria versus patients recordance with the guidelines for methotrexate that we ceiving methotrexate plus placebo. whereas one-third had achieved an Salvage Dihydroorotate Orotate adequate clinical response while repathway maining on 10 mg. taching two recombinant p75 receptors to the Fc portion Increases in LFTs of >3 times upper limits of normal durof human IgG1. pabumin in the normal range over a period of years. versus 23. with two types of receptors. p55 and p75. creases. The tests were then repeated in one or two the other more distal disease processes that can conweeks. compared to 0. Only one dosage lowering was allowed during TNF is a so-called proximal cytokine that drives many of this study. which are If they were not elevated at this range. the same rate seen in leflunomethotrexate and leflunomide. and the Short Form DNA/RNA synthesis. because methotrexate alone are nevertheless able to receive adbaseline is often abnormal in these patients due to the use ditional therapeutic benefit with combination therapy. (See Figure 3. etanercept. 36 showed that these patients improved glycosylation in the physical component.5 percent respectively.3 methotrexate alone in patients with persistently active In the open phase of a combination study.8 percent and recently showed that adding etanercept to methotrexate 1. it becomes tating withdrawal from the study were no more common necessary to adjust the dosage of either methotrexate or in the combination group than in the placebo group. the results could be confirmed within 72 ercept and infliximab are also effective for treating RA.) transferase (ALT) and aspartate aminotransferase (AST) A six-month. as with leflunomide. Provided the transaminases Two-year follow-up data show that the results are susstay in the normal range. double-blind. creased. the mean dose of prednisone dedrugs does not appear to adversely affect the liver. the medication was deProduced primarily by macrophages and monocytes. If they were confirmed. In addition. leflunomide. (See Table 1. The Health Assessment Ques+ tionnaire showed a significant improveAspartate Pyrimidine ment in the ability of patients receiving nucleotides leflunomide plus methotrexate to perform daily activities. TNF interacts times normal).3 percent among paGlutamine UMP pyrimidines + tients receiving methotrexate plus HCO3 placebo. If they remained elevated (greater than three tribute to the severity of RA. hours. If you maintain LFTs and serum alThese results indicate that. For the combination of diminishes but does not disappear. Patients inject etanercept subcutaneously ing the 24-week treatment period of alanine aminotwice weekly. If transamdiscontinue therapy. which is associated with less morbidity and morThe guidelines recommend monitoring liver enzymes tality. and if they then were greater than A fusion protein. Infectious complications necessiinases are elevated at one to two months. a tients who are incapable of further improvement on biopsy of the liver demonstrates improvement. Ordinarily. The ACR-20 reLeflunomide sponse rate for patients receiving leflunomide plus methotrexate was 51. Although 28 percent 12 MANAGED CARE / SUPPLEMENT . FIGURE 2 Leflunomide primary mechanism of action two-thirds of the patients had gone to 20 DHODH mg. Diarrhea was experienced by 25 percent of the patients receiving leflunomide plus methotrexate.4 dosage of either methotrexate or leflunomide to mainAfter 24 weeks. the patient was removed from the study.5 Extracellular percent.) published in 1994. had been created by attwice normal. the combination of these two tained. By the end of the study. patients receiving the combination tain the liver function tests in the normal range. peated at the next visit. I adjust the RA. The mean weekly dosage of methotrexate also every four to eight weeks. If transaminase enzymes were elevated to two to five times the upper limit Tumor necrosis factor (TNF) inhibitors such as etanof normal.to 20 mg daily. This side effect is fairly easily treated monthly LFTs for about six months — and that an elewith antidiarrheal agents and usually is not a reason to vation in transaminases is not to be ignored.
of patients were able to stop methotrexate. This argues for using the least-expensive drug. Currently.6 Most patients with RA should receive methotrexate unless it is contraindicated. at some point the patient reports not feeling as well. By comparison. On the basis of the clinical response rate and overall toxicity reported so far. A 100-mg vial of infliximab costs approximately $500 wholesale and $620 retail. neither leflunomide. the FDA approved using the higher dosage more frequently. This decision has important implications with respect to cost.000 and $22. first. The chimeric (mouse and human) antibody against TNF. If a patient requires three vials for dosing at the 3 mg/kg rate. and methotrexate (15 mg/wk).400. TABLE 1 Percentage of patients meeting ACR criteria after 24 weeks Etanercept + methotrexate (n = 59) ACR 20 ACR 50 ACR 70 71% 39% 15% Placebo + methotrexate (n = 30) 27% 3% 0% SUPPLEMENT / MANAGED CARE 13 . I have used each combination for four years.5 Using a higher dose at the greater frequency did not produce a significantly different effect than did the lower dose at the less-frequent interval. the cost will be about $1. a chimeric monoclonal antibody to TNF (darker areas represent human component. about $650 to $900 (prices for all products vary from region to region). Thus far. administered every four weeks or every eight weeks.000. one year of etanercept therapy can cost between $14. As an attempt is made to taper and discontinue methotrexate. nor etanercept is better than the others when used in combination with methotrexate. In January. and I cannot distinguish between them in terms of their effects. increasing the dose to 6 mg/kg or 10 mg/kg will cause costs to double or triple. In a 54-week. double-blind study. the cost of one year of infliximab therapy can be between $8. has been used in combination with methotrexate to treat RA. moving to etanercept or infliximab will depend on the patient’s insurance coverage or preference. leflunomide (10 or 20 mg/day). If that level of intervention is insufficient. leflunomide. infliximab. I am treating about 40 patients with the methotrexate-leflunomide combination and another 40 with the methotrexate-etanercept combination.800 retail per treatment. two recombinant p75 TNF receptors linked to the Fc portion of the human IgG molecule two different doses of infliximab were studied: 3 mg/kg and 10 mg/kg. If the combination of methotrexate and leflunomide fails. hence the need for combination therapy. Thus. Regional prices of the leading DMARDs and recommendations for their rational use are presented in a recent article in Annals of Internal Medicine. The availability of different combinations is necessary because some patients do not respond to methotrexateleflunomide and others do not respond to methotrexateetanercept.000. Infliximab is given intravenously in the office. about $3. lighter areas represent mouse component) p75 Extracellular domain IgG1 Fc region FIGURE 3c Depiction of the structure of etanercept.O N H CH3 N H N in vivo F F F Active Metabolite (A77 1726) HO O F H N F F O Leflunomide (HWA 486) FIGURE 3a Structure of leflunomide and its active metabolite Mouse Binding site for TNFa Human IgG1 K K FIGURE 3b Depiction of the structure of infliximab. no randomized studies have compared these particular combinations. 72 percent could not discontinue it.500 and $20. however. infliximab. This led the FDA to initially recommend using 3 mg/kg every eight weeks.
The use of combinations of disease-modifying antirheumatic agents in rheumatoid arthritis. St.19:126–128. Kremer JM. and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Perhaps 25 percent of patients have RA that is sufficiently benign not to necessitate the intervention of a rheumatologist. Kremer JM. make appropriate treatment decisions. Clin Exp Rheumatol. or NSAIDs and sulfasalazine. poorly controlled hypertension is unlikely to be entrusted to a primary care doctor.17(6 Suppl 18):S66–S68. 1994.131:768–774. refractory. et al. Arthritis Rheum. leukemia. 2001. Coblyn JS. The complexity of the issues associated not only with methotrexate but also with adding other agents makes it clear that perhaps 80 percent of patients with RA should not be managed by primary care physicians. 1999. for the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Mroczkowski PJ. It is not ethical or moral to withhold effective therapies that provide significantly enhanced therapeutic value. Combination therapy with multiple disease-modifying antirheumatic drugs in rheumatoid arthritis: a preventive strategy. Kremer JM. J Am Acad Dermatol. Kremer JM. rheumatologists are highly likely to respond to a request from a primary care physician to see a patient with RA. References 1. clinicians will be able to consider other novel agents for treating RA. — and at least three fourths of patients will require methotrexate — then a level of sophistication is needed that is unlikely to be found in a primary care physician. Pincus T. it tends to diminish over time. Additional Sources Kremer JM. et al. et al. 1999. Combination therapy can be used successfully to avoid the long-term morbidities and mortalities that accompany RA. Most primary care physicians lack the experience and expertise needed to use these drugs. O’Dell JR.343:1594–1602. which is unfair to the patient. In terms of actual outcomes. Weinblatt ME.org». 6. There is a shortage of rheumatologists.eular. and it can take two or three months for a patient to get an appointment. Conclusion Until recently. 2nd ed. Rational use of new and existing diseasemodifying agents in rheumatoid arthritis. Such patients are easily monitored by a primary care physician. The onus is on the primary care physician.33:113–120.134:695–706. Nevertheless. Kelly WN. These patients can be maintained with NSAIDs and hydroxychloroquine. van der Helijde. Kremer JM. Although the TNF antagonists produce an almost-euphoric early effect. N Engl J Med. in patients with rheumatoid arthritis receiving methotrexate. Alarcon GS.37:316–328. Suggested guidelines for monitoring liver toxicity. 3. A trial of etanercept. 4 5. Additionally. possibly with periodic visits to a rheumatologist. Weinblatt ME. Arthritis Rheum. If the primary care physician calls the rheumatologist. Paulus HE. Methotrexate and leflunomide combination therapy for patients with active rheumatoid arthritis. Now. so should the management of most cases of RA be reserved for specialists.Some rheumatologists perceive the TNF antagonists as providing a larger initial effect than the other DMARDs. N Engl J Med. which rheumatologists regard as being different from back pain or fibromyalgia. 14 MANAGED CARE / SUPPLEMENT . Another TNF inhibitor being developed is D2E7. as well as moral. Abstract THU0192. The argument that it is not cost-effective to add extra agents to avoid lifelong disability and deformity is suspect on ethical. 2000. Weinblatt ME. FDA approval is expected within the next year for anakinra. 1999. No physician should accept mere improvement or stability in the face of a clinically meaningful persistent disease state.42:1322–1328. 1999. a so-called fully humanized monoclonal antibody that is in Phase III studies. or severe. 1988. Textbook of Rheumatology. Ann Intern Med. the TNF agents appear to be the equivalent of the methotrexate-leflunomide combination. Kremer J. American College of Rheumatology. a recombinant tumor necrosis factor receptor: Fc fusion protein. Kremer JM. however. the patient will be seen. Available at: «www. Pharmacokinetics. et al. an interleukin-1 receptor antagonist (IL-1ra) given subcutaneously on a daily basis. Weinblatt ME. DMFM. although there are no studies to demonstrate that they are — or are not — equivalent. In the near future. Lipsky PE. Philadelphia: Saunders. and be familiar with the complexities of management. et al. Bankhurst AD. however. Just as the management of a solid tumor. Cannon GW. Combination therapy of leflunomide (LEF) and methotrexate (MTX) is effective and well tolerated in rheumatoid arthritis (RA) patients inadequately responding to methotrexate alone. PCP or rheumatologist? The question of who should manage patients with RA is critical. 1985. grounds. 1990. Genovese M.340:253–259. Ann Intern Med. et al. 2. Methotrexate for rheumatoid arthritis. Rheumatologists are motivated to see RA patients early. evidence-based medicine demonstrates that combination therapy enables negative outcomes to be avoided. Once methotrexate has become part of the regimen. Lightfoot RW Jr. safety. Methotrexate in rheumatoid arthritis. no effective treatment was available for patients with persistent synovitis. Clair EW. Arthritis Rheum.
especially with the use of claims data.5 The treatment of RA patients thus has major economic consequences within the health care system. R.000 hospitalizations annually. with over 250. 68 percent of the cost of strokes.2 Social impact of RA Among RA patients. Costs of RA In 1998. substantial economic improvements are associated with these changes. with survival shortened by 3 to 18 years. In evaluating these data. and substantial income losses are associated with this disease. DOYLE. Further. and female life expectancy is shortened by three years. estimated at 50 percent for men and 63 percent for women.PH. Additionally. the total national cost of RA was estimated at $14 billion. 1. as measured by Short Form 36 (SF-36). The HAQ was administered in all three pivotal trials of leflunomide. the rate of depression has been estimated to be between 14 and 43 percent.2 The prevalence of this debilitating disease increases with age.B. the above-cited figure may well be an underestimate due to the challenges associated with measuring the cost of disability. The data presented by the American College of Rheumatology (ACR) Ad Hoc Committee on Clinician Guidelines (1996) in “Guidelines for the Management of Rheumatoid Arthritis” reveal that more than 9 million physician visits per year are traceable to RA..2 SUPPLEMENT / MANAGED CARE 15 . R. The divorce rate of 70 percent among patients with RA is also significantly higher.5 to 1 percent of the worldwide population. Important data are emerging from clinical trials with the newer diseasemodifying antirheumatic drugs (DMARDs) signifying the potential to radically enhance millions of affected lives. and relative to health-related quality of life (HRQoL). Moreover. Nearly one-third to twothirds of these patients have a reduced work capacity. with the highest incidence occurring in females between ages 30 and 50.Ph.. Joseph Doyle.A. systemic inflammatory disorder of the joints that is associated with progressive decline in physical function and disability. the prevalence of this disease continually grows as America ages.6 The direct costs of treating an RA patient are three times more than those costs associated with treating a patient who does not have this disease.A.S. M.2 A comparison of the lifetime direct and indirect costs of RA with those associated with other diseases clearly demonstrates the high cost of this disease.. while SF-36 was administered in one of the three trials (US301). Leflunomide has been found to provide significant improvements in physical function and HRQoL. clearly demonstrated relative to improvements in physical function. goals of treatment and patient-reported outcomes can be clearly identified using these two measuring tools. and further. RA has lifetime costs that are approximately 82 percent of those of coronary artery disease. Food R and Drug Administration to determine the extent of patient improvement in clinical trials.Economic and Quality-of-Life Impact Of Rheumatoid Arthritis JOSEPH J. significantly higher than that seen in the general population. and 49 percent of the cost of cancer. M. RA affects approximately 0.3 The data further reveal that male life expectancy is shortened by seven years. heumatoid arthritis (RA) is a chronic.B. These instruments have been adopted by both the Outcomes Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) and the U. as measured by the Health Assessment Questionnaire (HAQ).4 In spite of such sobering statistics. RA costs are five times greater than the lifetime costs associated with motor vehicle accidents. new treatment options are yielding measurable improvements with respect to physical function and quality of life. Recent advances in is a senior manager of health pharmacotherapeutic economics and outcomes approaches to treatresearch at Aventis Pharmament of RA can be ceuticals. and life expectancy is severely affected by RA.
activities.7 Economic impact A cost comparison of RA and osteoarthritis (OA) conducted by Lanes et al (1997) revealed that the total cost 16 MANAGED CARE / SUPPLEMENT . comprising eight domains measuring physical function on the following subscales: dressing. The HAQ can also be summarized as one score. swollen joint count (SJC).13 which may be attributable to the emergence of the newer agents — leflunomide.888 patients. An ACR-20 response is defined as a 20 percent or greater improvement from baseline in 5 of the following 7 criteria: tender joint count (TJC). and joint destruction can actually be more pronounced in the first years of this illness. According to the ACR Guidelines for Management of RA.7 It has been estimated that 50 percent of these patients cannot function in their job within 10 years of disease onset. Literature from 1993 to 1998 states that standard care with NSAIDs and DMARDs still results in progression of RA. It has been proven that the HAQ is more predictive of RA disease progression than any other measurement of the ACR response criteria. When using DMARDs. walking. The traditional drug therapy hierarchy. the Disability Index. As to its clinical importance. patient global assessment. The HAQ is self-administered and consists of 20 questions. but with the use of corticosteroids and NSAIDs. and hygiene. eating. over the first two years of disease. a comparison reveals that HAQ DI scores are stabilizing. joint replacement. the HAQ is a highly useful tool for correlating level of disability to cost. changes in the disease process over time can be readily seen using the HAQ. initiation of DMARD therapy should not be delayed beyond three months for any patient who has active disease in spite of adequate treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). serious disability can occur early in the disease. disability increases as measured by the HAQ DI scores. The HAQ is a valid and widely accepted instrument that allows physicians and caregivers to track disease progression and monitor the effects of drug therapy.8 Goals of therapy A major goal in the treatment of RA is to improve signs and symptoms. In addition. there is an increase in the number of points per year. These domain scores are adjusted by the patient’s use of aids and devices.6 In addition. is no longer seen as adequate in RA treatment. by measuring costs per unit of increase in HAQ score. looking at the progression of disability with standard care. costs. In a review by Scott et al.9. the FDA recommends that all RA clinical trials contain the HAQ as a component of the ACR response criteria. to maximize patient HRQoL (Table 1). gripping.14 The ARAMIS data on the effect of individual agents demonstrates. because RA is an extremely progressive and debilitating disease.9 HAQ is the best measure to predict work disability. that the use of DMARDs improves physical functioning. Whereas in 2000. which is slowing the rate of joint damage visible on Xray. Creactive protein (CRP). and the biologics Table 2). the old pyramid (page 11). disease progression and disability increase with disease duration. it has been used in many trials in which physical function is measured. Yet the DMARD trials show that disease progression can be slowed or stabilized. reaching. The HAQ is scored on a 0 to 3 basis. the HAQ allows the physician to determine for patients the level of improvement in physical function and the impact of drug therapy on physical function. In addition. recommends the use of both the HAQ and SF-36 in clinical trials. in a population of 2. physician global assessment. Though often perceived as a disease-specific questionnaire because of its use in RA trials.e. and on HRQoL. treatment aims include the prevention of disability and the maintenance of physical function. with 3 being the worst possible score and 0 being the best possible score. and premature mortality. Additionally.Disability has a major effect on day-to-day activities. commonly referred to as the HAQ DI. TABLE 1 Treatment goals of RA therapy • Improvement in signs and symptoms • Reduction in radiographic progression • Prevention of disability – Maintain physical function – Maximize HRQoL OMERACT.10 It has been estimated that an increase of one unit in the HAQ DI. a working group that provides recommendations to the FDA and to the pharmaceutical industry on the design of clinical trials.12. The reduction of these symptoms can be clinically measured using the ACR response criteria. use of DMARDs has been associated with lower long-term disability. Overall. functional disability. i.7 Clinical trial assessments: patient-reported outcomes Health Assessment Questionnaire. results in a 90 percent greater disability over the next three years. demonstrating that the patient’s disability was getting worse. Another goal is to reduce radiographic progression. Moreover. and pain-intensity assessment. arising. making it crucial to initiate patient treatment as quickly as possible. erythrocyte sedimentation rate (ESR)..11 This estimation reconfirms that the HAQ is a good predictor of future disability for patients with RA. HAQ.
Mental Component TABLE 4 Minimum clinically important differences (MCID) Score range % HAQ DI1–4 SF-362.728. 1993. Pharmacoeconomics.637 1.17 This change in score is used to measure how well patients are doing.162 703. Gardiner Fries Munro Uhlig Young 0. Arthritis Rheum. 1998.898 2. These domains are scored on a scale of 0 to 100 — 100 being the best possible score.5–5 points OMERACT 33–36% 33–36% 33–36% TABLE 3 Cost of care in managed care setting1 RA $ Cost.22. Arthritis Rheum.15 With RA.170. et al. 1997.0. Br J Rheumatol. Munro.18-21 The efficacy of leflunomide has been shown to be equivalent to methotrexate and sulfasalazine. whereas the major cost driver with OA was hospitalizations. Kosinski. 6. When calculating the score for these questionnaires. OMERACT uses a change of 33 to 36 percent across all assessments as the MCID.053 436. 7. There are two summary scores for the SF-36. For the SF-36. Arthritis Rheum. Rheumatology [Oxford].32:724–728. 4.39:616–622. SUPPLEMENT / MANAGED CARE 17 . Ann Rheum Dis.001). the physical component summary (PCS) score and the mental component summary (MCS) score.to 10-point change. et al.03 points/year1 0.22 5–10 points 2. owing to the rarity of this disease. Health-related quality of life: Short Form-36. 5. et al. SF-36 is one of the most commonly used measures of HRQoL.16. There is some overlap between the two questionnaires. Lanes SF et al. 2000. 2000.Wells. 0 being the worst possible core.509. the major cost driver was prescriptions.Thumboo.26:97–102. 1993. Guzman. 3. Interestingly.119 points/year3 Stabilized4 Stabilized5 degree of improvement in the various outcomes measures that are important and meaningful to the patient. et al. Arch Intern Med. et al. mental health. J Rheumatol. role emotional. to some extent they measure the same aspect of the patient’s HRQoL. The cost of OA was higher due to its greater prevalence in the population. et al. and role physical. Rheumatology [Oxford].39:5208.43:S140.57:88–89. An individual score can be derived on the HAQ and on the SF-36. Uhlig. This questionnaire is self-administered and contains eight domains: physical function. This difference reflects the TABLE 2 Progression of HAQ DI index with standard care 1993 1996 1998 2000 2000 1. physical function is central to quality of life Figure 1). 5. the cost in the managed care setting was relatively low for RA. The literature cited in Table 4 states that the MCID is –0. vitality.39:603–611. based on the literature. P<.674 100 62 21 16 % $ 543 4.017 points/year2 0. (See Table 3. controlled trials.43:1478–1487. the literature states that the MCID is a 5. To a patient with RA. 4. leflunomide provided significantly higher ACR-20 responder rates when compared to placebo (52 percent vs 26 percent.15:141–155. 1999. 1996.40:1475–1481 1. J Rheumatol.5–7 PCS/MCS 0–3 0–100 Mean 50±10 Direction of scoring – + + MCID Literature 0.20:557–560.5 to 5. For the PCS and MCS scores. Costs of hospital care and ambulatory care decrease after initiation of DMARD therapy.047. et al. Leflunomide in RA In large. $ per patient/year Total cost Rx Physician visits Hospital visits 2.938 115. Arthritis Rheum. et al.153:1337–1342. it is important to determine the minimum clinically important difference (MCID). 18–21 Leflunomide has also been shown to provide significant improvements in physical function and HRQoL when compared to placebo and active comparators (methoFIGURE 1 SF-36 Two-component model Physical Component Physical Role Function Physical Bodily Pain General Health Vitality Social Role Function Emotion Mental Health Gardiner.400 150. Young. social function. the MCID is 2. bodily pain. 3. 1993.425 1. but such tabulations do not hold meaning for the patient unless one calculates the change in these scores over time. that is. Arthritis Rheum. Fries. 2000. Samsa. et al. 1999.890 100 32 22 46 OA 1. 1996. et al. randomized.for RA was much less than it was for OA. Phase III. 2. 2000. Redelmeier. 2.) These results may be different since the introduction and use of the COX-2 inhibitors in OA and the use of biologics in RA. Kosinski. et al.39:732–741. et al. general health.
353:259–266. Strand V.39:655–665. Emery P.39(suppl 1):48–56.trexate and sulfasalazine). 1991. 8. Pincus T. Smedstad LM. Arthritis Rheum. J Rheumatol. 1997. Cox N et al.2000. Yeung N. simple questionnaire and joint count measures. Lemmel EM. References 1. 4. Cohen S. 116–118. Williams CA. 110. 1996. Peloso P. The costs of rheumatoid arthritis. Terry R. A comparison of the efficacy and safety of leflunomide and methotrexate for the treatment of rheumatoid arthritis. 17. Maetzel A. Breedveld C. 1998. Young A. It has been demonstrated to improve physical function as measured by the HAQ DI. Fries JF. Arthritis Rheum. Arthritis Rheum. Martin R. et al and the Multinational Leflunomide Study Group. Resource utilization and cost of care for rheumatoid arthritis and osteoarthritis in a managed care setting: the importance of drug and surgery costs. Clinical and health status measures over time: prognosis and outcome assessment in rheumatoid arthritis. Callahan LF. 1996. 9.26–34.25:(suppl)53:8–12. Taking mortality in rheumatoid arthritis seriously — predictive markers. London. Moum T.3:S208. Fries J. Rheumatoid arthritis: Classification and epidemiology. Rheumatology. et al. Arch Intern Med. 13. Gremillion RB. Henkerius S. eds. Two-year treatment of active rheumatoid arthritis (RA) with leflunomide (LEF) compared with placebo (PL) or methotrexate (MTX). Wolfe F. J Rheumatol. the efficacy of leflunomide. Disability scores in DMARD trials: What is a clinically important change? Arthritis Rheum. Prediction of long-term mortality in patients with rheumatoid arthritis according to 18. Although RA is a disabling disease with increased mortality and an unknown cure. Lawrence RC. Kalden JR. Survival and causes of death in rheumatoid arthritis: a 25-year prospective followup. Ramey D. multicentre trial. et al. 20 21. randomised. Determining clinically meaningful improvement in SF-36 scale scores for treatment studies in rheumatoid arthritis. Singh G. Morfeld D. Vaglum P. et al and the European Leflunomide Study Group. Vandenbroucke JP. et al.122–132. and radiographic outcome after five years of follow-up. and offers practicing physicians an additional option in the treatment of RA. 2000.39:603–611. as seen at 6 and 12 months. Abstract. Kvien TK. The burden of rheumatoid arthritis: facts and figures. Rheumatology [Oxford]. Kaarela K. Cohen S.1–3:3. 2000. Dixey J.43 suppl. Pharmacoeconomics. How does functional ability in early rheumatoid arthritis affect patients and their lives? Rheumatology [Oxford]. Wolfe F. 3. 2000. 1999. double blind study. Rheumatology [Oxford]. Efficacy and safety of leflunomide in active rheumatoid arthritis. 14. 2. The economic and humanistic effects of this disease are substantial. 22. Emery P. early treatment with DMARD therapy improves patient outcomes. 2000. 1999: 42(suppl 9):S271. Pugner K. Lanza LL.18:1290–1297. Kosinski M. Mosby Year Book:1994. and HRQoL as indicated by the SF-36 data. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind. Meenan RF. Leflunomide’s effects were consistent across three studies over two years of treatment. Singh G. Lanes SF. 19. 6. 15. 1994:6:513–522. Schattenkircher M.39:732– 741. Arthritis Rheum. J Rheumatol. Hawley DJ. 1999: 42(suppl 9)S271. Radensky PW. Callahan LF. Weaver A. The course of rheumatoid arthritis and predictors of psychological. Rheumatology. Guzman J.11:158–161. Leflunomide vs sulfasalazine in RA: 24 month update of a randomized. Sibley J. Postgrad Med. Scott DL. van Vollenhoven RF.39:S318.616–622.13:841–845. Hazevoet HM. In: Klippel JH. Cathey MA. 1998. with patients becoming increasingly disabled from RA. It improves and maintains physical function and HRQoL. Arthritis Rheum. It is extremely encouraging to the rheumatology community that leflunomide provides significant and sustained improvements in clinical signs and symptoms. Gerard N. Ann Intern Med. 11. Kalden JR. Brooks RH. 1996. 18 MANAGED CARE / SUPPLEMENT . is maintained throughout two years of treatment with no long-term safety issues. Uhlig T. Callahan LF. Schiff M for the Leflunomide Study Group.40:1475–1481. J Rheumatol. 16.S140. 7.103:103–106. Guidelines for the management of rheumatoid arthritis. The links between joint damage and disability in rheumatoid arthritis. 21–23 Summary. Pincus T. 1994:120. Reduction in long-term disability in patients with rheumatoid arthritis by disease-modifying antirheumatic drug-based treatment strategies. Allaire SH. Smolen JS. 1986. socioeconomic status and comorbidity. Arthritis Rheum. Rheumatology. Scott DL. Lancet. Smolen JS. 23. physical. 10. 12. Rheumatoid arthritis: designing and implementing a treatment plan.18–21 Furthermore. 5. et al for the Leflunomide Rheumatoid Arthritis Investigators Group. Bombardier C. 1996:39.39. 2000. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum. Prashker MJ. two instruments held up as the gold standard for the assessment of patient outcomes in RA clinical trials. Schiff M. as measured by HAQ DI and SF-36. Smolen JS.3:3. Cats A. et al. 1984.159:2542–2550.39:713–722.4. Dieppe PA. 1999.
D.P.: Quality-of-life data certainly is instrumental in some of the formulary decisions we make. the participants engaged in a wide-ranging discussion in which they talked about how to apply the information about new agents for the treatment of rheumatoid arthritis to their health plans. After hearing the experts’ presentations. CALABRESE: The biggest obstacle with physicians and the combination of methotrexate and leflunomide is the LFT issues.H. R. TERRY MAVES. R. Casberg.Ph. Imelda C.B. So my point is.: They are important to a degree in differentiating one product from another. we’ve already accepted that there is a definite clinical role for drugs like leflunomide and the injectable tumor necrosis factor inhibitors. M.. They don’t have enough experience with it. YVONNE SOUTHWELL. M. but how do we bring it back home to change prescribing patterns? JEFFREY CASBERG. but if we don’t take a look at this now.Yoder.Ph. In this particular instance.Ph. Pharm. Terry K. The fact is. M.DISCUSSION Treatment Algorithm: Managing Rheumatoid Arthritis Attendees David C. our RA patients are those with multiple comorbidities. Mark R. R.A. I don’t know how much additional value SF-36 data would add. Both specialists confirmed that. do we need to know that the SF-36 indicates that leflunomide improves quality of life.S. that may be useful. R. They’re scared to be using these drugs in combination. R. who may be on a statin. is it important to know measures other than clinical measures.. R. Pharm. when we’re making formulary decisions. when we know there is a clinical improvement when leflunomide is added? It seems to me that we can make the leap of faith that if there’s a clinical improvement.D. Jeffrey J.Ph.D. R. R.: What may seem not as important at two years. Eric Cannon.Ph.. I’ll have to run it by some of the rheumatologists in my area to see if they agree. Mark Harris moderated the discussion. might make a big difference if you follow it through for 10 or 15 years. however. MARK HARRIS: Have you found SF-36 measures helpful in trying to differentiate product efficacy? DAVID CALABRESE.Ph.P. particularly in a disease that’s as symptomatic as rheumatoid arthritis.Ph. Orland. In many instances. You’re not going to have 15-year data.: How do you influence or change physicians’ prescribing patterns? The number of prescriptions for etanercept versus leflunomide is currently two to one. Harris Robert Konop. Pharm. We may not be seeing differences at this point. R. but that will not be the only consideration in the decision process. Maves.Ph. Coleman.Ph.. R.D. M. Mauro J.: I was seeking confirmation from these specialists that leflunomide is a good choice as first-line therapy. Burton I.Ph.H. Libby Meske. where there are already LFT con- SUPPLEMENT / MANAGED CARE 19 . R. IMELDA COLEMAN.D. M. Hopefully they do. who may be on glitazone. Florentine. Yvonne Southwell. or the supply of a drug. Pharm.and three-year data. David M. versus etanercept or infliximab.S.. Pharm. R. then the patient is going to get the benefit of improved quality of life.Ph. One component is quality of life. we won’t know what the differences are down the road. where all the products may show improvement in clinical efficacy? CALABRESE: When you can show that leflunomide is better outside the clinical parameters. BURTON ORLAND. The pharmacoeconomic data were good and so were the speakers. Calabrese. HARRIS: When you’re making comparisons for P&T.Ph. if you’re not collecting two.: It is interesting that some of the thought leaders are making clinical decisions based on what insurance somebody has.
when we’re negotiating a capitation rate. HARRIS: As was mentioned. because unfortunately. Actu- 20 MANAGED CARE / SUPPLEMENT . because we’re considered a center of excellence in the management of certain patient populations. it’s not always adjusted for case mix and severity. multiple sclerosis. and to say. of California. They want to keep those profitable injections within their control and return the most costly ones to the plan. We’re moving toward some higher copays on that third tier. due to the higher prices of these products. though. and our third-tier copay is either $20 or $25. As a business.cerns. the answer is cost. or cancer. R. PHARM. we’re seeing that increase to a great extent. there’s now a lot of these carve-outs for injectables management. HARRIS: Virtually all of you said that you anticipated that you were going to have to get involved in more pharmacy management of injectable products. and managed care pays the bill. How many of you are looking at those types of companies to work with you on managing physicians’ injectables? COLEMAN: These newer. asking that patients be tried on other DMARDs and leflunomide. CALABRESE: It varies from health plan to health plan. R. Moreover.Ph. our clinics have been able to profit from lower-cost injectables. It was a $300 per month medication. RIGHT. That’s going to be the biggest challenge. We do have guidelines. With newly diagnosed RA patients. to Injectable Solutions. That’s a hurdle that you’re going to have to overcome. but the physicians will contact Injectable Solutions for prior authorization and also to get the injectables delivered to their office for administration in the office. instead of their own risk. So we strive to carve these particular categories out of our risk. So it’s difficult going forward. Some of our physicians are actually carving it out of their contracts and make it the plan’s risk.. both of which have added potential for liver toxicity. To me. “I want you to use methotrexate in combination with something else. as you’re trying to get them to include these ing to include the injectables in their global capitation rate. MESKE: We are starting to look at that as well. in trying to manage that risk. HARRIS: In my past experience of working with injectable products. and now we’re talking about compounding those concerns by adding two drugs. before moving to an injectable TNF inhibitor. so $25 for a $300 medication probably is not a bad deal. and even some 50 or 60 percent coinsurances. CANNON: A question arises with respect to the plans that have leflunomide on third tier and whether that is due to its price compared to that of methotrexate. is we have many patients who already have failed four or five DMARDs. PacifiCare of Colorado is moving all the injectable prior authorizations. such as those being treated for infertility.D. In looking at the 2002 medical group and physician contracts. compared to a combination of methotrexate and etanercept. we would be placed at a major disadvantage if we did not carve it out.: Many physicians get upset with hav- IMELDA COLEMAN. before you go to the injectable TNF inhibitors. hydroxychloroquine. Beginning July 1. but we also have many RA patients who’ve been on five or six DMARDs.” is almost pushing against the next logical step.: An issue for me is that we’ve looked at the new TNF products and tried to place them in appropriate areas. right? LIBBY MESKE.. to go back to that physician where I’ve got somebody who has failed sulfasalazine. MAVES: Oncology has a huge influence on this.PH. Our goal has been to strive for carveouts. the physicians were upset with having to include the injectables in their global capitation rate. higher priced products in their reimbursement rate? HARRIS: And that’s increasing. LIBBY MESKE. Part of the problem. very expensive products affect our doctors’ capitation tremendously. and methotrexate. ORLAND: I just think the cost of injectables is getting out of hand. LEFT. Proposals to develop an injectable program were met with mixed feelings. if methotrexate is the generic choice and leflunomide is the second? For us. Why wouldn’t leflunomide be a brand on the second tier. it definitely makes sense to use the methotrexate-leflunomide combination. So not only will the members be able to get their injectables through this company. Have any of you gotten pushback from your physicians. and even the distribution of the injectables. as to whether they include this in the capitation rate or carve it out. ERIC CANNON. Pharm.D.
with or withCOLEMAN: Would you say if they tolerate the NSAIDs. Pharm. R. ORLAND: If there are comorbidities with the disease.. R.“Try methotrexate first. CASBERG: I agree. the same idea with our AIDS drugs. and a rheumatologist. Correct? that patients diagnosed with RA should be started on SOUTHWELL: That’s what I would do. methotrexate and then have leflunomide or another MAURO J. and SUPPLEMENT / MANAGED CARE 21 . Some PCPs can maintain would consider adding leflunomide.” I think that this is a good idea. Pharm.P. They agreed to a rheumatologist. though. That same idea holds true here. If authorization says it has to come through an infectious we’re motivating physicians to manage patients.. The current clinpatients on those agents. is the cost of the product. One of the things we look at. They may not get methoyou’re going through the rheumatologist. DAVID M. their patients should be encouraged to see it eats up their benefit within several months. ORLAND: Let’s say that if patients have RA.D.PH. Where YVONNE SOUTHWELL.: But I would consider DMARD added to their drug regimen before a TNF inmethotrexate as getting active therapy.A. One of teroidals. if they fit the criteria for a person ber cost-share across the pharmacy benefit. methotrexate does not appear to be managing the progression of the disease is the point at which you with the rheumatologist. with what’s going on.PH.B. but for initial prescription. weren’t they marketed as a replacement for methotrexate? At that point. jectable agent is used. the prior costs or to manage patients? That’s the key here. and then when they’re going to add the a limit to their drug benefit. FLORENTINE. tients receiving leflunomide. whether they go back to primary care. COLEMAN: One reason we put leflunomide on third tier SOUTHWELL: In our environment. both presenters concurred that methotrexate is the initial step.ally. After looking at the data that were discussed today.: So any time they want At the conclusion of the meeting. with RA. YODER. a whole population that still should probably be evalMAVES: If you’re serious enough to use this medication. PCPs can prescribe is that we have a Medicare population. sulfasalazine is less expensive. The patient may not have to stay then they suffer because they stop all their medications. leflunomide shouldn’t be viewed as a replacement for methotrexate but as an additive therapy. M. and basically. and they have methotrexate. M. this seems to make more sense. next agent.Ph.: So if they’re just on nonswhere to put a drug. the participants devised to go past NSAIDs and methotrexate. and they stop everything else. to use both of these drugs.H. they have to go a treatment algorithm for RA (see page 22). DAVID CALABRESE.. they must go through a rheumamoved into the second-tier position. you can try leflunomide. I disease specialist. So we felt that by putting it on third tier. they do. We follow trexate.. my goals is to maintain a particular amount of memORLAND: Yes. and if that doesn’t work for you. Let the rheumatologists make the decision the year. This is an edited portion of SOUTHWELL: Depending on the environment. RIGHT. protocol. they’d be more likely to stay on their medication throughout the year. MAVES: When these products came out. probably within tologist. FLORENTINE: What if they’re on sulfasalazine? You left out maybe it should be managed by a subspecialist. the patients should be referred to a rheumatologist. Methotrexate could be the trigger for referral. if ical data do not support a major disruption of this step possible. this is one of those drugs I would expect to see out comorbidities. If they go on leflunomide. they go through a rheumatologist. We priorYODER: Is it our job to motivate physicians to manage authorize all our AIDS drugs. if we’re motivating physicians to manage costs. uated by a rheumatologist. R. their discussion: you’re going to see PCPs prescribing NSAIDs for RA. CALABRESE: In this morning’s program. They also agreed that liver function YODER: Different GPs are comfortable with different testing should be encouraged — if not required — for pathings.D. They stop their leflunomide. It’s hard enough for them to keep up agree. we all said. LEFT. besides ROBERT KONOP. No one is suggesting that a patient should be started on a combination of the two.
where I grew up. and they might be quite familiar with if they’re doing well on methotrexate. Yes. though.” or intolerance or intolerance MAVES: If leflunomide costs $10. “Your doctor is right: you need methotrexate. No one goes anywhere unless they send to a rheumatologist as soon as I had the diagnosis. we can proceed on safety and correct medication. and then the primary care physician can manage that treatment plan. and so on. local. I’d let my PCP way. I agree that there aren’t many PCPs who are going to prescribe methotrexate. When you take Switch to ETANERCEPT ± methotrexate cost out. The reason we’re here. It’s not a naif for nothing other than an evaluation and a possible tional phenomenon. Health care is a local phenomenon. But then I go out to West Virrheumatology consult. $15. if I live out in Kettle. I don’t think you would. They want the rheumatologist to say to our health plan member. no primary care physician take care of everything. a rheumatologist if there’s no improvement in his FLORENTINE: I don’t think you’d know the difference. body to rheumatology. all our patients will not be able to see rheumatologists. Our primary care physicians are the COLEMAN: If I were in a major metropolitan area. yes. tinue to be seen by their primary care physicians? FLORENTINE: Would you want your primary care physiFLORENTINE: Yes. would you send the patient to a rheumatologist? Switch to ETANERCEPT Take cost out. That’s what I did. or $20. but do they want to. SOUTHWELL: The reality is. You’re going to come up with guidelines. come LEFLUNOMIDE ineffective LEFLUNOMIDE ineffective see me again. If you get worse. I’d go gatekeepers. then yes.. and the reason we all sit in rooms with Switch to INFLIXIMAB rheumatologists and medical directors. where does the rheumatologist come in? Do you need the rheumatologist to do the methotrexate. will want to prescribe drugs other than NSAIDs — YODER: I’m in Baltimore/Washington. and the PCP prescribing the intolerance inadequate response methotrexate. FLORENTINE: Would you? ORLAND: Is there a point after which a patient who has SOUTHWELL: If there are PCPs who see a lot of these pabeen taking methotrexate is eventually referred to tients. they who will not drive an hour into New Orleans to see a could. But if you took cost out. condition? SOUTHWELL: Yes. and and these guys are going to be calling the shots anythere is no rheumatologist. Mississippi. don’t have the tools to do an appropriate diagnosis? I MAVES: This all gets back to the idea that guidelines are think they would send the patient to a rheumatologist.treatment plan. we don’t want to refer everySOUTHWELL: If that’s all I was able to see. where there are few rheumatologists. But them there. Obviously we don’t have a oneDiagnosis of RA 22 MANAGED CARE / SUPPLEMENT . The second point is. they can conwhat they need to monitor. methotrexate would be in the domain of or intolerance or intolerance the primary care physician. FLORENTINE: Yes.. is beSwitch to INFLIXIMAB + methotrexate cause of cost. where you can even sulfasalazine or methotrexate — without a find rheumatologists. I don’t know many physicians ginia. given the fact that they rheumatologist. If we’re looking at a rheumatologist cian to give you methotrexate? shortage to begin with. Eventually they may. Rheumatoid arthritis treatment algorithm SOUTHWELL: PCPs may not have experience with the leflunomide. or do you need it after that? In the ETANERCEPT ineffective ETANERCEPT ineffective end. A lot of rural METHOTREXATE people are lucky to be able to see a PCP.. ± NSAIDS FLORENTINE: I agree. who would start methotrexate in a patient who isn’t COLEMAN: We have patients who live in the bayou and responding to NSAIDs and physical therapy. Switch to LEFLUNOMIDE Add LEFLUNOMIDE They’re going to want that rheumatology conor other DMARDs or other DMARDs sult. Who is going to make that diagnosis? Who is going to do all the radiography? YODER: You may have the rheumatologist doing METHOTREXATE METHOTREXATE the radiography.
if you said that everybody who is going to get methotrexate has to have it through a rheumatologist. SOUTHWELL: If PCPs don’t feel comfortable with the methotrexate. That’s a benefit design. or additional DMARDs. it’s also true that one drug may be a better choice for these patients based on Medicare’s benefit design. a lot less people are going to get methotrexate. sically comes down to a convenience issue. There’s no reason to hold back on the methotrexate. They’ve blown leflunomide in a month and a half. COLEMAN: So we’re saying to use leflunomide. and you should try leflunomide before that. in that order. so we need to develop them locally. FLORENTINE: I don’t think most people. YODER: Yes. and have the member get something rather than nothing. With a positive diagnosis of RA. “We should be doing this for our patients. ychloroquine. YODER: In our algorithm. Also. serum concentrations of infliximab were higher in RA patients who received concomitant methotrexate. I’m betting they’re highly motivated.. with your rheumatologist. Guidelines help just to say. the PCP or the rheumatologist? SOUTHWELL: In an ideal world. the treatment algorithm for RA is pretty straightforward. You don’t develop a guideline for rheumatologists. too. that’s what a guideline is for. the initial therapy is methotrexate because these patients need aggressive. It ba- are going to refuse to drive a half hour or an hour. You just don’t do it. Infliximab gets expensive very quickly. infliximab.* COLEMAN: Who will prescribe this. they have to go to a rheumatologist. plus or minus methotrexate. YODER: Infliximab is a step up in complexity from etanercept.D.” To me. leflunomide. HARRIS: While. it may be the only thing. For instance. which is unfortunate. why don’t we work our way back from infliximab as last line? Before using infliximab. not that they get one level of care if they’re in the city and another level of care if they’re in the bayou. Do we want to pay three times what we would for etanercept. Self-injectables are 30 percent coinsurance. COLEMAN: That’s the way I feel about guidelines. MAVES: We have two. M. If methotrexate does not provide adequate response or relief. you should try etanercept. and I think the guidelines would be helpful in that situation. based on diagnostic criteria set forth by ACR. SOUTHWELL: I don’t know if patient compliance is really an issue with this patient population. for the most part. And I understand that in a rural area. it would be wonderful for every patient who goes on methotrexate to automatically be referred to a rheumatologist. A lot of the data right now would lead us to say that leflunomide is probably the next logical choice. FLORENTINE: Our Medicare members have a $400 a year max pharmacy benefit. because of infusion centers and everything else. MAVES: The reality is. etanercept. then the TNF products would be appropriate. plus or minus NSAIDs for symptomatic relief. so that everyone is on the same page. some patients are simply unable to self-inject. for the same clinical benefit. but many patients probably would respond to sulfasalazine and hydrox- DAVID YODER. FLORENTINE: I wouldn’t want my PCP to give me methotrexate.size-fits-all here. managed care is not concerned with Medicare. With repeated dosing of infliximab in clinical trials.B. SUPPLEMENT / MANAGED CARE 23 . At the point when the desired response isn’t achieved with methotrexate. From both a cost * Note that the prescribing information for infliximab indicates that it should be used in combination with methotrexate to minimize antibody formation. Our goal is to make sure that every patient gets the same level of care. KONOP: But you might have an issue of patient compliance with etanercept. So infliximab is the only thing they can do. CANNON: In summary. PHARM. by all means they should be referring that patient. early treatment. given the disease. But you do develop a guideline for primary care physicians. though. I would much rather see our patients try etanercept first. Patients who cannot tolerate methotrexate can be switched to leflunomide or an additional DMARD. other issues arise within this patient group. YODER: How many rheumatologists do you have in your network? FLORENTINE: Twenty. because some health plan members don’t want to give themselves a shot? I think they should be encouraged to try etanercept first. YODER: But if anything beyond methotrexate is prescribed. leflunomide should be added.A.
and we believe that. before going to the TNF products. from a plan standpoint. because the rheumatologists in my area aren’t using a lot of combination therapy. We’ve already endorsed leflunomide in our plans. when we need input into our P&T. they’ve probably overlooked a large segment of the population that could be helping to make early diagnosis. so you can’t diagnosis and treat RA. right now initial diagnosis and initial treatment probably is being made by internal medicine.standpoint and the availability of rheumatologists. CANNON: The reality is. the reality is that not everybody is going to be able to get to a rheumatologist. Knowing that aggressive early treatment is probably the direction we want to go.” For one thing. We go to rheumatologists when we need input for guidelines. a logical step approach is to use methotrexate followed by leflunomide. Rheumatologists need to understand more about the benefits of combination therapy. They’re the clinical advisers for our P&T committees. “You’re internal medicine. I’m not willing. I don’t have enough rheumatologists. They’re overlooking part of the prescribing community that might be driving the utilization of a product that’s going to benefit all our patients. When companies say they’re going to market their products to rheumatologists and specialists only. there is really no reason they cannot start a patient on methotrexate or leflunomide. I think that for the physicians who are comfortable using the ACR criteria to make a diagnosis. to say. 24 MANAGED CARE / SUPPLEMENT .
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