Interleukin-1 Inhibition

Introduction

Interleukin (IL)-1 is a prototypic proinflammatory cytokine. It is produced by numerous cell types (i.e., macrophages, synoviocytes, endothelial cells, chondrocytes, osteoclasts) and is found in excess in the serum, synovial fluid and synovial tissue of patients with rheumatoid arthritis (RA) and other inflammatory arthritides. In animal models, IL-1 is capable of mediating and amplifying destructive inflammatory arthritis. In RA, serum and synovial IL-1 levels have correlated with disease severity and a deficiency of the counterregulatory IL-1 receptor antagonist (IL-1Ra) has been noted in RA and other inflammatory arthritides. Like tumor necrosis factor (TNF), IL-1 is a pleotropic cytokine that has numerous biologic activities, including activation of T and B cells, induction of other cytokines and chemokines (e.g., IL-6, TNF, IL-8), release of degradative enzymes (collagenase, stromelysin, metalloproteinases) and other inflammatory mediators (inducible nitric oxide, cyclooxygenase (COX)-2, platelet-activating factor), synoviocyte proliferation, expression of adhesion molecules (on vascular endothelium) and RANK ligand, resorption of bone and degradation of cartilage.

If given exogenously in nanogram doses, IL-1 can induce fever, myalgia, arthralgia, headache, confusion, anorexia and, at higher doses, can mediate hypotension and shock. Whereas TNF appears to be a potent inducer of IL-1 and to a degree IL-6, IL-1 is a less potent inducer of TNF release but is more effective in inducing IL-6 synthesis. Thus these proinflammatory cytokines are redundant if not dependent upon each other. Moreover, animal models of arthritis have confirmed the additive or synergistic effects of coadministration of IL-1 and TNF on measures of inflammation or tissue damage. It is unknown if the differential effects of IL-1 and TNF on cartilage destruction and bony erosions in animal models will impact humans, including RA patients, in the same manner. Nonetheless, clinical studies with both inhibitors of IL-1 and TNF have shown beneficial effects on radiographic progression in RA.

IL-1 was the first proinflammatory cytokine to be identified and well characterized. In <20 years, several specific inhibitors of IL-1 have been identified and developed as therapeutic agents for controlling inflammation. Currently, only one agent, recombinant IL-1Ra (anakinra), has been extensively studied and approved for use in RA. When given in adequate amounts, this agent can abrogate IL-1–driven biologic responses. However, this is not the only means of IL-1 inhibition. Strategies to inhibit IL-1 would include the use of IL-1Ra and other natural IL-1 inhibitors, such as the type I or type II IL-1 receptors, or the use of inhibitors of caspace-1 (IL-1 converting enzyme [ICE]) or IL-1 Trap. In addition, the advent of gene therapy has been applied to RA in studies transfecting the IL-1Ra gene into patients with RA. The results of clinical research with these modalities are presented below.

Anakinra (Kineret)

Anakinra is the recombinant form of the naturally occurring IL-1Ra, a counterregulatory cytokine, levels of which increase in an acute-phase fashion in response to IL-1 production and compete with IL-1b for binding to type I IL-1 receptors. After IL-1 binds to the type I receptor, it will couple with the IL-1 accessory protein and form a heterodimer that leads to transmembrane signaling (Figure 13-1). As the recombinant form of IL-1Ra, anakinra is a biologic response modifier that similarly acts to antagonize the effects of IL-1. But unlike IL-1, anakinra and IL-1Ra will not engage the IL-1 accessory proteins required to initiate transmembrane signaling and subsequent cellular activation. Thus anakinra is a competitive inhibitor of IL-1 and must be present in large amounts to abrogate the biologic effects of IL-1.

Anakinra is a nonglycosylated, recombinant human IL-1Ra that differs from the endogenous form by the addition of an N-terminal methionine. It binds with the same avidity as native IL-1Ra and IL-1b to bind type I IL-1 receptors. Human IL-1Ra consists of 153 amino acids and is 17.3 kd in size. It has been cloned and expressed in Escherichia coli. It has a biologic half-life of 4 to 6 hours in normal volunteers and 5.9 hours in RA patients using conventional doses.

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Clinical Efficacy

Anakinra has not been studied in early RA patients and was largely developed and approved in patients with long-standing established RA. In 2001, anakinra was approved by the Food and Drug Agency (FDA) for use in adult patients (≥18 years of age) with moderately to severely active RA in whom one or more disease-modifying antirheumatic drug (DMARDs) have failed. Anakinra can be used as monotherapy or in combination with DMARDs, excluding the TNF inhibitors.

FDA approval was based on five separate, randomized, placebo-controlled clinical trials involving 2,932 RA patients. In these trials, the overall ACR20 response rates were 38% to 43% and ACR50 and ACR70 response rates ranged from 11% to 24% and 1% to 10%, respectively. A trial of anakinra monotherapy in 472 RA patients showed significant reduction in erosions and less radiographic progression as measured by Larsen scores after 24 and 48 weeks of therapy. When anakinra was added to methotrexate (MTX) in patients with an inadequate response to MTX alone, 38% of patients achieved an ACR20 response compared with 23% of placebo/MTX–treated patients (Figure 13-2).

While some have interpreted the ACR20 responses seen with anakinra to be modest, significant improvement in patient-generated outcomes (e.g., health assessment questionnaire (HAQ), patient pain, etc.) were observed in this trial. Reasons for a less dramatic response with anakinra (compared with TNF inhibition) may relate to the shorter half-life (~6 hours) for this compound. In the anakinra plus MTX study, up to 2.7% of the anakinra-treated and 1.8% of placebo-treated patients demonstrated sporadic levels of anakinra antibodies. These antibodies exhibited no neutralizing activity.

In the preceding clinical studies, discontinuation rates ranged from 12.1% to 27.1%, with more withdrawals for adverse events than for lack of efficacy. Variable dosing regimens were used in these trials (fixed doses [75 or 150 mg qd] or adjusted doses [1 or 2 mg/kg/day]), but the currently recommended dose is 100 mg qd, administered subcutaneously using prefilled 100-mg syringes. Although higher doses have been studied, dose-related benefits were not observed and more frequent injection site reactions (ISRs) have been seen at higher doses. Patients must receive instruction on the proper administration of this parenteral therapy and safe disposal of used needles and syringes. The manufacturer supplies a specially designed self-injector device (called the Simpleject) at no charge to the patient.

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Safety in RA

During clinical trials, patient compliance with daily administration of medication was observed to be >95%. The primary adverse events noted in clinical trials were injection site reaction (ISRs). Although ISRs occurred in nearly 70% of patients in clinical trials, less than one third experienced ISRs in clinical practice. Cutaneous lesions were usually observed in the first 4 to 6 weeks but then disappeared within 10 to 14 days and seldom required treatment (Figure 13-3). ISRs are mild to moderate in 95% of patients and have been described as erythema, rash, urticaria, ecchymoses and sometimes with dysesthesia or mild pruritus. Other infrequent adverse reactions included mild reductions in neutrophil counts (8%), headache (12%) and upper respiratory infections (13%).

Severe neutropenia (absolute neutrophil count ≤1000 cells/mm³) was seen in 0.3% of patients. Less than 1% of patients withdrew from clinical trials because of leukopenia (white blood cell count <3500 cells/mm³). Only two cases of drug-related neutropenia have resulted in infectious events and these potentially related events occurred in two of 58 patients treated in a 6-month open-label anakinra-plus-etanercept trial. With this treatment, monthly monitoring of leukocyte counts is recommended for the first 3 months and then quarterly thereafter.

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Infection

Anakinra was originally studied for the treatment of sepsis. While it did not show a protective effect, it was not associated with an increased risk of infection or mortality. In RA clinical trials, infections were infrequently seen with anakinra. The incidence of serious infection (according to FDA definition of serious adverse event) was 1.8% vs 0.7% for those receiving 100 mg/day vs placebo, respectively. Pneumonia, which occurred in 14 patients, was the most common serious infection noted. Less common were reports of cellulitis, osteomyelitis, septic arthritis and septic bursitis. Analysis of all patients revealed a significantly higher rate of pulmonary infections in those with asthma and chronic obstructive pulmonary disease; thus caution should be exercised when using this agent in such patients. Therapy with anakinra should not be initiated in patients who have active or recurrent serious infections. No reports of Mycobacterium tuberculosis or other opportunistic infections have been observed in clinical trials in the United States or Europe.

The combined use of an IL-1 inhibitor (e.g., anakinra) and a TNF inhibitor (e.g., infliximab or etanercept) was expected to be highly beneficial based on in vitro and animal models showing the additive or synergistic effects of inhibiting both proinflammatory cytokines. However, the use of this combination in RA patients has only yielded negative outcomes.

A small, open-label, pilot, safety trial has been completed in 58 patients with active RA despite prior therapy with etanercept for over a mean of 1.2 years. Patients remained on etanercept twice weekly and were then given anakinra 1 mg/kg/day subcutaneously for 6 months. During this trial, there were no deaths but there was a 12.1% serious adverse event rate and a 6.8% incidence of serious infections (two cases each of cellulitis and pneumonia). Moreover, two of these patients with serious infections also experienced neutropenia that may have contributed to their risk of infection. One third of patients were unable to complete the 6-month study and half of these withdrawals were for adverse events.

A larger phase 4 controlled trial compared the effects of etanercept alone against anakinra plus etanercept. In this trial, the combination of anakinra plus etanercept failed to show added clinical benefit but did show a higher rate (7.4%) of serious infectious adverse events. Thus this combination should not be used since data indicate a safety concern and increased risk of serious infection when IL-1 and TNF inhibition are employed concomitantly.

Dosage and Administration

The recommended dose of anakinra for the treatment of RA is 100 mg/day administered by subcutaneous injection, at approximately the same time each day. Since anakinra is excreted by the kidneys, the risk for toxic reactions to this drug may be greater in patients with impaired renal function. Physicians should consider a dose of 100 mg administered every other day for patients with RA who have severe renal insufficiency or end-stage renal disease.

Anakinra should not be used in combination with TNF-blocking agents due to a greater risk for serious infection. Anakinra should not be initiated in patients with active infections and should be discontinued if a serious infection develops. Live vaccines should not be given concurrently with anakinra. Neutrophil counts should be assessed prior and during treatment with anakinra, each month for the first 3 months and every 3 months thereafter for a period of up to 1 year.

Practical Issues

The use of anakinra in RA has dwindled since its release in 2001. Reasons for this may be the daily injections, higher rate of ISRs, and the observation of fewer dramatic or complete clinical responses when compared with other expensive biologic agents (e.g., TNF inhibitors). The potential advantages of this agent may well rest with its relatively shorter half-life of 5.9 hours in RA patients. While shorter duration of effect may translate into less efficacy in some patients, it may well yield a better safety profile in others. In an effort to maximize clinical efficacy, appropriate timing of dosing may prove advantageous for some patients. Since IL-1 and several other proinflammatory cytokines are normally secreted in a circadian fashion with late-night peak production, nightly dosing may be more efficacious, although this remains an untested hypothesis.