Anakinra

Drug News

Joint destruction begins as early as 3 to 6 months after disease onset. In fact, joint destruction may progress despite clinical signs of improvement that result from symptomatic therapy and some disease-modifying antirheumatic drugs.

Although the direct cause of rheumatoid arthritis (RA) remains unknown, researchers continue to define and label its pathophysiologic characteristics to correlate functional changes to signs and symptoms and x-ray progression. A chronic, systemic, inflammatory disorder, RA results in function loss.1 Characteristics associated with pathogenesis include genetic profile, inflammatory response mechanisms, immune system responses, bone resorption mechanism, endogenous hormonal response, and neuronal response mechanisms. 1-5

Traditionally, pharmacologic treatment of RA proceeded gradually-one drug at a time-when prescribing first-- line, symptomatic-relief therapy or when changing symptomatic therapy (see Table "RA Drug Categories and Classifications"). Studies have shown, however, that joint destruction begins as early as 3 to 6 months after disease onset.6 In fact, joint destruction may progress despite clinical signs of improvement that result from symptomatic therapy and some disease-- modifying antirheumatic drugs (DMARDs).3 According to long-term outcomes of conventional, stepped therapy, we haven't achieved protection from joint destruction.7

A growing consensus among rheumatologists points to changing the stepped, pyramid approach to an inverted pyramid paradigm of early, aggressive intervention (within 2 to 3 months of diagnosis).8 For patients who fail to respond effectively to DMARD therapy and have moderate to severe disease, drugs from the biologic response modifiers (BRMs) classification may prove more effective in the fight to preserve bone, prevent cartilage erosion, and promote joint form and function.

* Standard Pharmacotherapy

The American Academy of Family Physicians and the American College of Rheumatology (ACR) group RA pharmacologic therapies into two categories: symptomatic-relief drugs and disease-modifying drugs. RA disease-- modifying drugs have two subset classifications: DMARDs and the new subset classification of BRMs, which also have disease modification activity.8

Symptomatic relief drugs reduce joint pain, swelling, and stiffness, but don't alter joint destruction progression and bone and cartilage erosion. In the past 2 years, the Food and Drug Administration (FDA) approved four drugs for RA treatment: the DMARD leflunomide (Arava) and the BRMs etanercept (Enbrel), infliximab (Remicade), and anakinra (Kineret).9 DMARDs reduce some inflammation effects, and specific drugs within the class may help delay the progression of joint destruction. Most, however, don't prevent or arrest the progressive cartilage and bone erosion characteristics of RA.

Use BRMs in patients whose disease hasn't responded effectively to DMARDs. BRMs inhibit or antagonize proinflammatory cytokines (for example, tumor necrosis factor [TNF], interleukin-1) and related enzymes involved in producing joint destruction. Most importantly, researchers associate DMARDs and some BRMs with toxicities and increased risk of serious adverse events. Etanercept and infliximab can have serious adverse effects, such as infection, sepsis, tuberculosis reactivation, demyelination, and blood dyscrasia.

* Pharmacology and Pharmacokinetics

Anakinra (Kineret), an exogenous, recombinant, human IL- 1 receptor antagonist (rhIL- 1 ra), counterbalances the detrimental effects of the disease-- heightened activity of IL-1 in inflammation, bone erosion, and cartilage destruction. Preliminary studies of anakinra show 95% bioavailability when administered S.C., a mean half-- life of 6 hours and a duration compatible with once-daily dosing.10

In a test of anakinra pharmacokinetics, Yang and colleagues found that anakinra distribution volume and plasma clearance increased with increasing body weight. They also validated the kidney as the major organ of clearance for anakinra and noted that plasma clearance rates were higher in men than in women and higher in younger subjects than in older subjects.11

Anakinra blocks IL- 1-induced synovial inflammatory-cell infiltration, specifically reducing synovial tissue macrophage and T-cell infiltration.2 IL-- 1b mediates joint destruction, which stimulates cartilage and bone resorption and inhibits the synthesis of articular collagen and proteoglycan.12

Anakinra blocks IL-1b binding, limiting or regulating these activities. Anakinra's protective effects on the bone erosion of joint destruction occur at a slower rate than do the effects on cartilage degradation.

Dose-ranging study data on anakinra have yet to provide information on maximum dosing regimens for initiating treatment or for dose titration based on disease-severity indices; however, once-daily dosing by S.C. injection (rotating the injection sites) appears to give the greatest benefit over weekly or three times per week dosing.12

* Clinical Trials

Campion and colleagues tested the safety of anakinra (IL-1ra) at different doses and dose frequencies in 175 patients with active RA in a 7-week, randomized, multicenter, double-blind clinical trial.10 Assessed changes indicated that daily dosing provided greater benefit than weekly dosing in all dose-- level groups. Researchers, however, failed to establish optimal or appropriate dose levels because of the small sample sizes, the number of baseline variables, and the lack of a placebo arm.10

Anakinra is the first BRM targeted against IL-1 activity that demonstrates a beneficial effect (reduction) in the rate of joint destruction and bone and cartilage erosion in patients with active, severe RA.13 Anakinra not only reduces inflammation, pain, and disease activity, it also improves quality of life when administered as monotherapy or in combination with methotrexate. These properties render anakinra a valuable treatment option for patients with all stages of RA.

Bresnihan and colleagues tested the efficacy and safety of anakinra at three-- dose levels (30, 70, or 150 mg/day) in 472 patients with active, severe RA. Using the ACR composite index as an improvement measure, investigators found that 43% of patients who received the highest anakinra dose achieved an ACR response as opposed to 27% of the placebo group. Injection site reactions, the most common adverse event, occurred in 50% of the 30-- mg group, 73% of the 75-mg group, and 81% of the 150-mg group of anakinra group as opposed to 25% of the placebo group.13 Most reactions were mild and brief in duration. Severe adverse events (neutropenia, neoplasia, and infection) occurred rarely and resulted in less than 2% of patients withdrawing from any treatment group.

In a crossover study, Bresnihan and colleagues looked at the effects of three doses of anakinra on progressive joint destruction in patients with severe RA.

After 12 months of treatment, they determined that patients treated with either 75 mg/day or 150 mg/day of anakinra for the entire 12 months showed significant reduction in joint destruction compared to patients treated with placebo for the first 6 months.14

In a preliminary, prospective, randomized, double-blind, placebo-- controlled clinical trial of 12 patients with severe RA, Cunnane and colleagues assessed the effects of anakinra on synovial tissue at 30 mg/day and 150 mg/day. Biopsies taken at baseline and at trial end showed a notable reduction in intimal layer and subintimal layer macrophages and lymphocytes (150 mg/day). Anakinra reduced mononuclear-cell infiltration of synovial membranes, representing in vivo inhibition of IL- 1-mediated joint destruction.15

Furthermore, tenant and colleagues investigated the effects of anakinra on joint destruction by x-ray in a subset population from 472 patients at 24 weeks and 48 weeks. They reported that placebo patients who were randomized to anakinra doses for the second-phase 24 weeks showed significant reduction in the joint destruction rate. Patients who remained on the same dose of anakinra for the entire 48 weeks showed an accelerated benefit in slowed progression in the second-phase 24 weeks, above that seen in the first phase.16

Jiang and colleagues evaluated x-ray progression and radiologic scores assessed by the Genant and Larsen methods in a multicenter, double-blind, dose-ranging, randomized, placebo-- controlled clinical study of anakinra treatment for RA patients. Assessment of hand x-rays taken at baseline, 24 weeks, and 48 weeks of treatment demonstrated reduced progression of bone and cartilage destruction. The resuits indicate that RA treatment with anakinra retards radiologic disease progression.17 Anakinra is the first of the biologics to exhibit this effect.

In a combination study, Cohen and colleagues randomized 419 patients with active disease into six treatment groups to evaluate the efficacy and safety of anakinra in combination with methotrexate. Measurement of ACR20 responses showed significantly greater clinical benefit in patients treated with anakinra in combination with methotrexate over those treated only with methotrexate.18

*Indications and Use

The FDA approved anakinra in November 2001 as a daily S.C. injection of 100 mg for treating moderate to severe, active RA in patients ages 18 and older. The FDA hasn't approved anakinra for treating juvenile rheumatoid arthritis. Animal studies of anakinra revealed no adverse effects on fertility and fetal development; however, researchers haven't conducted human studies to assure safety in pregnant women. Contraindications include hypersensitivity to Escherichia coli-derived proteins, Kineret, or any components of the product.19

* Adverse Reactions

The drug's most common adverse reaction was injection site reactions. Serious adverse reactions included serious infection and neutropenia. Serious infections occurred in 1.8% of anakinra-treated patients and 0.6% in placebo-treated patients.19 Cellulitis, pneumonia, and bone and joint infections comprised the majority of infections. Researchers found an increased rate of neutropenia and serious infection with combination therapy with TNF blocking agents such as etanercept; therefore, they don't advise combination therapy with TNF-blocking agents.

* Dosing and Administration

The recommended dose of anakinra for RA treatment is 100 mg/day administered daily by S.C. injection. Higher doses don't result in a higher response. Administer the dose the same time each day.

The manufacturer provides anakinra in a single-use, 1-ml, prefilled, glass syringe. Protect the drug from light, refrigerate it at 36 deg to 46 deg F (2 deg to 8 deg C), and discard any unused portions. Don't freeze or shake the syringes.

* Anakinra in Practice

Limited knowledge of the heterogeneous clinical syndrome in RA patients has led clinicians to take a conservative, empirical approach to treatment; however, evolving knowledge of RA genetic predisposition and the potential for early onset bolster the rationale for altering treatment approaches. Modifying the most detrimental aspects of the disease along specific, biologic response pathways reinforces the need for changes in treatment approaches that may offer patients a reprieve from disease progression.

REFERENCES

1. Straub RH, Cutolo M: Involvement of the hypothalamic-pituitaryadrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis, viewpoint based on a systemic pathogenetic role. Arthritis Rheum 2001;44(3):493-507.

2. Bresnihan B, Cunnane G: Interleukin- 1 receptor antagonist. Rheum Dis Clin North Am 1998;24(3):615-28.

3. Cunnane G, Fitzgerald 0, Summers CA, et aL: Early joint erosions and serum levels of matrix metalloproteinase (MMP)- 1, MMP-3 and tissue inhibitor of metalloproteinases- 1 (TIMP) in rheumatoid arthritis. Arthritis Rheum 2000;43(suppl 9):abstract 507.

4. Goldring SR, Gravallese EM: Pathogenesis of bone erosions in rheumatoid arthritis. Curr Opin Rheumatol 2000;12(3):195-99.

5. Kaneko M, Tomita T, Nakase T, et al.: Expression of proteinases and inflammatory cytokines in subchondral bone regions in the destructive joint of rheumatoid arthritis. Rheumatology 2001;40(3):247-55.

6. St. Clair EW, Smith JA: Changing management of rheumatoid arthritis in clinical practice, new data, new options. [8 March 2002].

7. Willke WS, Sweeney TJ, Calabrese LH: Early, aggressive therapy for rheumatoid arthritis: Concerns, descriptions, and estimate of outcome. Semin Arthritis Rheum 1993;23(2 suppl 1):26-41.

8. Chatham W, Casebeer L, Kristofco R: Advances in the management of osteoarthritis and rheumatoid arthritis. A CME program. [8 February 2002].

9. Kremer JM: Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Ann Intern Med 2001;134(8):695-706.

10. Campion GV, Lebsack ME, Lookabaugh J, et al.: Dose-range and dose-frequency study of recombinant human interleukin- 1 receptor antagonist in patients with rheumatoid arthritis. The IL- 1 Ra Arthritis Study Group. Arthritis Rheum 1996;39(7):1092-101.

11. Yang BB, Frazier J, McCabe D, et al.: Population pharmacokinetics of recombinant interleukin- 1 receptor antagonist (anakinra) in subjects with rheumatoid arthritis (RA). Arthritis Rheum 2000;43(suppl 9):abstract 519.

12. Bresnihan B: Treatment of rheumatoid arthritis with interleukin-I receptor antagonist. Ann Rheum Dis 1999;8(suppl 1):196-98.

13. Bresnihan B, Alvaro-Gracia JM, Cobby M, et al.: Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998;41(12):2196-2204. Comment in Arthritis Rheum 1999;42(8):1781-2.

14. Bresnihan B, Newmark RD, Robbins S, et aL: Anakinra reduces the rate of joint destruction after I year of treatment in a randomized controlled cohort

of patients with rheumatoid arthritis. Arthritis Rheum 2000;43(supp] 9):abstract 1332.

15. Cunnane G, Madigan A, Murphy E, et al.: The effects of treatment within interleukin-1 receptor antagonist on the inflamed synovial membrane in rheumatoid arthritis. Rheumatology 2001;40(1):62-69.

16. Genant HK, Bresnihan B, Ng W, et al.: Treatment with anakinra reduces the of joint destruction and shows accelerated benefit in the second 6 months of treatment for patients with rheumatoid arthritis. Arthristis Rheum 2000;43(; pl 9):abstract 1333.

17. Jiang Y, Genant HK, Watt I, et al.: A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin- 1 receptor antagonist in patients with rheumatoid arthritis: Radiologic progression and correlation of Genant and Larsen scores. Arthritis Rheum

2000;43(5):1001-09.

18. Cohen S, Hurd E, Cush J, et al.: Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin- 1 receptor antagonist in combination with methotrexate: Results of a twenty-four week, multicenter, randomized, double-blind, placebo-controlled trail. Arthritis Rheum 2002;46:614-24.

19. Amgen, Inc.: Kineret (anakinra) prescribing information. Thousand Oaks, Calif: Amgen Inc., November, 2001. [8 February 2002].

Deborah Kupecz, NP, PhD

Candace Berardinelli, ANP, PhD

Drug News Co-Editors

Lisa Kastanek RN

ABOUT THE AUTHOR

Lisa Kastanek is clinical research supervisor, Arthritis Center of Nebraska, Lincoln.

Copyright Springhouse Corporation Apr 2002
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