Inflammatory Arthritis - RA

Anakinra
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On November 14, 2001 the Food and Drug Administration (FDA) approved Amgen's new product anakinra, a recombinant form of the naturally occurring interleukin-1 receptor antagonist (IL-1ra).  This product is indicated for use in patients with moderate to severe rheumatoid arthritis who have not had an adequate response to conventional DMARD therapy. The drug may be used as monotherapy or in combination with methotrexate or other DMARDs. Anakinra is a biologic response modifier that acts by antagonizing the biologic effects of IL-1.
 
IL-1 is a 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 tissues of patients with 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 been correlated with disease severity. Like tumor necrosis factor (TNF), IL-1 is a pleiotropic 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 (nitric oxide, cyclooxygenase 2, PAF); synoviocyte proliferation; expression of adhesion molecules (on vascular endothelium) and RANK ligand; resorption of bone and degradation of cartilage.
 
 IL-1ra is a counter-regulatory cytokine that rises in an acute phase fashion in response to IL-1 production and competes with IL-1b for binding to type I IL-1 receptors. Thus, anakinra is a competitive inhibitor of IL-1 and must be present in large amounts to abrogate the biologic effects of IL-1. Human IL-1ra has been isolated from human monocytes and has been cloned and expressed in E. coli. Anakinra is a nonglycosylated, recombinant human IL-Ra and differs from endogenous human IL-1ra by the addition of an N-terminal methionine. It binds with the same avidity as native IL-1ra and IL-1b.  It is 153 amino acids and 17.3 kD in size and has a biologic half-life of 4-6 hours. It is self-administered by patients as a daily subcutaneous injection using prefilled 100 mg syringes.
 
Anakinra has been studied in several RA clinical trials and has been shown to have a satisfactory efficacy and safety profile. FDA approval has been based on 5 separate randomized placebo-controlled clinical trials involving 2932 RA patients. In these trials the ACR20 response rates were 38-42%. ACR50 and ACR70 response rates ranged from 11-24% and 1-10%, respectively.
 
A monotherapy trial of anakinra in 472 RA patients showed significant reduction in radiographic progression after 24 and 48 weeks of therapy1. In these trials, withdrawal rates ranged from 12.1-27.1%, with more withdrawals for adverse events than lack of efficacy. In these clinical trials both fixed doses (75 or 150 mg qd) or adjusted doses (1 or 2 mg/kg/d) were studied.  The recommended dose will be 100 mg qd, administered subcutaneously using prefilled 100 mg syringes. Although higher doses have been studied, dose related benefits were not uniformly observed and more frequent injection site reactions (ISRs) have been seen at higher doses.
 
Nearly 1500 patients have received anakinra 100 mg qd for between 6-12 months. Over 60 patients have been on anakinra for 4 years or longer. During clinical trials, patient compliance was observed to be >95%. The primary adverse event noted in clinical trials was ISRs.  These were usually observed in the first 4 weeks, disappeared within days to weeks and required patient reassurance and no further treatment. ISRs were usually described as erythema , rash, urticaria, ecchymoses, with either no complaint or complaint of dysesthesia or mild pruritis. These were described as mild-moderate in nearly 95% of patients.
 
Other infrequent adverse reactions included mild reductions in neutrophil counts, headache and an increase in URIs. Anakinra was originally studied in sepsis. While it did not show a protective effect, it was not associated with increased infectious risk or mortality.  Infections were infrequently seen with anakinra. The serious infection (according to FDA definition of serious adverse event) was 1.8% vs. 0.7% for those receiving 100 mg/d vs. placebo respectively. Pneumonia (N=14) was the most common serious infection noted.
 
Analysis of all patients revealed a slightly higher rate of pulmonary infections for those with asthma and COPD - thus caution should be exercised when using this agent in such patients. Therapy with anakinra should not be initiated in patients who have active infections. The combined use of anakinra and a TNF inhibitor was tested in a small pilot study of 58 RA patients who had active synovitis despite etanercept therapy and were then given anakinra 100 mg qd along with etanercept 25 mg BIW. While many of these patients did improve, 4 of 58 (7%) had serious infections (2 cellulitis, 2 pneumonia).
 
The package insert warns that the combined use of TNF inhibitors and anakinra "should only be done with extreme caution and when no satisfactory alternatives exist". Other larger controlled trials of anakinra plus etanercept are in progress. To date there have been no reports of mycobacterial or other opportunistic infections in clinical trial patients receiving anakinra in the USA or Europe.
 
Patients will have the option of self-injecting 100 mg prefilled syringes or loading these into a specially designed injector device, called Simpleject. This prescription device will be provided to rheumatologists along with a patient education kit and is designed to work with anakinra 100 mg prefilled syringes and will not work with other injectable medicines (ie, etanercept).  Patients will also be given travel packs and are advised to keep anakinra refrigerated at 2-8oC (36-48oF) until planned use at room temperature.

The cytokine chemical interleukin-1 (IL-1),along with TNF-alpha,is considered to be central to the inflammatory and destructive processes of RA. In fact,IL-1 can induce the production of TNF-alpha,and vice-versa. Included among the nasty effects of IL-1 are an increase in COX-2,the enzyme that enhances inflammation (and is the target of the new anti-inflammatory drug Celebrex. IL-1 also stimulates the production of molecules that line the blood vessels and grab onto passing white blood cells,luring them to enter the irritated tissues and contribute to the inflammation.
 
This cytokine also contributes to the eventual breakdown of bone tissue in the joints. Its actions go beyond the joints and contribute to more general reactions such as loss of appetite,and fatigue. Again,it's important to remember that all these effects of this cytokine and others released by the body's immune system are part of a natural,complex set of events designed to defend against injury and infection. When these responses  are excessive and prolonged,as in the case of RA,they provoke and maintain inflammatory disease.
 
IL-1 acts by being recognized by special receptors on cell surfaces. Those receptors,which are proteins,will act as a lock into which the IL-1 molecule easily fits. Once this meeting takes place,a cascade of reactions is set off within the cell,genes are turned,and the cell can then make substances that contribute to inflammation,such as destructive enzymes. As it turn out,the body makes another slightly different form of IL-1,which also can fit the receptor locks. This form is interleukin-1 receptor antagonist (IL-1ra). The crucual difference between IL-1 and IL-1ra is that when IL-1ra fits into the receptors,the cascade of reactions does not take place inside the cell.
 
Il-1ra is a natural control the body uses to balance the inflammatory effect of IL-1. It's as though the IL-1 receptor sites were reserved parking sites. The IL-1ra molecules park there instead.leaving nowhere for the IL-1 molecules to park and get on with their work of inflammation.  However,it takes relatively high concentrations of IL-1ra to counteract the effects of IL-1. Studies have shown that the natural levels of IL-1ra in people with RA are not sufficient to control the disease.

The medication,anakinra (Kineret), is the first of a new class of RA medication. It is a "recombinant" form of human IL-ra,which means that scientistists at Amgen have used the human gene that makes IL-1ra and put the gene into batches of cells growing in the laboratory. The cells dutifully follow the instructions of the gene and make IL-1ra,offering an ample supply for medical  use. This is another example of genetic engineering. Extensive clinical trials of injections of this recombinant human IL-ra have shown it to be an effective treatment that can both reduce inflammation and slow bone and cartilage destruction.  There are different ways for foiling the IL-1 molecule and these other different methods are under study.

IL-1ra is a rational therapeutic target for use in the treatment of RA As part of the body's attempt to maintain a balanced state, it naturally produces a blocker of IL-1, called IL-1 receptor antagonist (IL-1ra).  Unfortunately, in RA, too much IL-1 is produced and too little IL-1ra is available to counter its activity. Anakinra was developed as a recombinant form of the human IL-1 receptor antagonist to re-set the inflammatory thermostat and inhibit inflammation, pain and joint damage. Both clinical markers of joint inflammation and the progression of joint damage have been significantly improved with this new biologic agent.
 
Anakinra is recombinant, nonglycosylated form of the human IL1ra. It differs from the native nonglycosylated IL1ra by the addition of an Nterminal methionine. Anakinra blocks the biologic activity of IL1 by binding to IL-1R type I with the same affinity as IL1b. The recommended dose of anakinra is 100 mg/day administered daily by subcutaneous injection. The dose should be administered at approximately the same time each day.
 
The most commonly observed side effect in all of the clinical trials with anakinra to date is injection site reactions, occurring in approximately twothirds of patients at the FDAapproved daily dose of 100 mg administered subcutaneously. These reactions are generally mild, present as erythema, itching, and discomfort and resolve over one to two months.  A modest increase in the risk of serious infection was observed in RA patients treated with anakinra in combination with DMARDS other than TNF inhibitors, compared to placebo with DMARDs (2 % vs 1%). The risk of serious infections of anakinra in combination with a TNF inhibitor is unknown, but preliminary data in a small-uncontrolled study of 58 RA patients suggest an increase (7%) relative to anakinra alone.
 
In the placebocontrolled trials, 8% of patients receiving anakinra had mild to moderate decreases in absolute neutrophil counts, compared to 2% in the placebo groups. 0.3% of anakinra treated patients experienced severe neutropenia (< 1x 109/L). In the combination anakinra/etanercept study, two of 58 points (3%) experienced severe neutropenia.  The rate of malignancies in anakinra treated patients was not increased relative to expected rates in the general population. Neutralizing antibodies were rare, and the presence of antibodies did not appear to correlate with clinical response or adverse events.
 
In another double blind, placebo-controlled study, the efficacy and safety of IL1-ra added to background methotrexate (MTX) was evaluated. 419 people with moderate to severe active RA despite treatment with MTX (mean dose 16-17 mg/wk) were randomized to placebo or IL-Ira (0.04, 0.1,0.4,1.0 or 2.0 mg/kg) administered daily by subcutaneous injection. The ACR 20 response rates in the 1.0 and 2.0 mg/kg groups (46% and 38%) were statistically significantly greater than the placebo group (19%). Similar results were observed at 24 weeks.
 
Generally, IL-1ra was safe and well tolerated. Injection site reactions occurred in 28% of placebo subjects, and in 19%, 38%, 56%, 64%, and 63% of subjects in the IL-1ra 0.04, 0.1, 0.4, 1.0 and 2.0 mg/kg groups, respectively. Injection site reactions led to early withdrawal of 7% and 10% of subjects at the 1.0 mg/kg and 2.0 mg/kg groups, respectively. This study indicated that IL1ra can be added safely to background MTX and may confer additional efficacy at the higher doses.
 
A long-term safety trial of huIL-1ra (anakinra) is currently in progress. 1414 subjects with RA who were receiving a variety of concurrent disease-modifying agents (DMARDs) other than the TNF inhibitors, Enbrel® and Remicade®, were randomized to receive IL-1ra (100 mg/day) or placebo. Patients with a predisposition to infection were not excluded. Preliminary results at six months  indicated a modest increase in incidence of serious infection in the anakinra group relative to placebo (approximately 2 vs. 1%, respectively). The long-term data from this study are expected at a later date.
 
IL1 and TNF have very similar biological actions and act synergistically to promote inflammation in vitro. Consequently, a therapeutic approach in which inhibitors of both IL1 and TNF-a are combined could represent a very potent treatment for RA. Bendele et al explored this approach in mice with collagen induced arthritis (CIA) and rats with adjacent induced arthritis (AIA). Various doses of IL-1ra (20 or 100mg/kg) in slow release hyaluronic acid and PEGylated soluble TNF receptor type I (PEG sTNFRI) (0.3, 1, 3mg/kg) were given alone or in combination.
 
Treatment effects were measured by sequential caliper measurements of the ankle joints; paw volume, final paw weight, and evaluation of bone and cartilage legions. The 20-mg/kg dose of IL-1ra provided no benefit alone, whereas a dose related effect was observed with sTNFR alone. However, in combination with any dose of sTNFRI, the 20mg/kg dose of IL-1ra displayed efficacy.
 
A preliminary open-label safety study in a small number of patients with RA treated with the combination of etanercept (sTNF-RII) and sHuIL-1ra was reported recently.  The observed incidence of serious infections was high however (7 %) and may be a dose-limiting problem with this therapeutic approach. A double-blind controlled trial is now underway in a number of larger patients.
 
A possible limitation to the successful use of IL-1ra as a treatment for RA is its short (six hours) half-life in plasma. Daily injections are required to sustain a therapeutic effect. Additionally, a large excess of IL-1ra is required to block the effect of IL-1.  Eventually, the use of gene therapy may be a more efficient method to provide sustained high local concentrations of IL-1ra. Feasibility studies have been performed in which synovial fibroblasts were transfected with the gene for human IL-1ra and subsequently injected into the joints of animals. IL-1ra was successfully produced but expression tapered off after several weeks.
 
In humans, the IL-1ra gene was introduced into the joints of three patients prior to arthroplasty (joint replacement) in the hands. Analysis of the joint tissue following arthroplosty demonstrated successful induction of IL-1ra expression. Methods for sustaining long-term expression of genetically induced proteins are still in their infancy, however.

Interleukin-1 and TNF-alpha: IL-1 has been shown to be a dominant cytokine associated with RA. IL-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses including inflammatory and immunological responses. IL-1 has a broad range of activities including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption.
 
The pathogenesis of RA is a complex process that leads to significant and chronic joint inflammation. Interleukin-1 (IL-1) is a central mediator in RA and is a critical proinflammatory cytokine that has been found to be abundant in the synovial fluid of RA patients. IL-1 and TNF- are thought to share several biologic actions. IL-1 and TNF- induce the production of each other, and they act synergistically.  In the RA joint, production of IL-1 cannot be sufficiently countered by endogenous IL-1Ra. This imbalance allows IL-1 to bind to IL-1 receptors at a more aggressive rate and perpetuate the proinflammatory response.
 
Kineret (IL-1 inhibitor) exerts its action in the same manner as endogenous IL-1Ra. Kineret is a recombinant, nonglycosylated form of IL-1Ra. Kineret neutralizes the biologic activity of IL-1 by competitively inhibiting IL-1 binding to IL-1RI. Kineret is well absorbed following subcutaneous injection. It has a half-life of approximately 4 to 6 hours. In rheumatoid arthritis (RA) patients, no unexpected accumulation of Kineret was observed after daily subcutaneous (SC) doses for up to 24 weeks.
 
The safety and efficacy of Kineret have been established in three large, pivotal, randomized, placebo-controlled trials. Patients treated with Kineret were more likely to achieve an American College of Rheumatology (ACR) response rate of ACR20 or higher (ACR50 or ACR70) than patients treated with placebo. Clinical responses to Kineret were seen by week 4 in 3 pivotal studies and most were seen by week.
 
The data described herein reflect exposure to Kineret in 2606 patients, including 1812 exposed for at least 6 months and 570 exposed for at least one year. Studies 1 and 4 used the recommended dose of 100 mg per day. The patients studied were representative of the general population of patients with rheumatoid arthritis. The most common and consistently reported treatment-related adverse event associated with Kineret is injection-site reaction (ISR). The majority of ISRs were reported as mild. These typically lasted for 14 to 28 days and were characterized by 1 or more of the following: erythema, ecchymosis, inflammation, and pain. In studies 1 and 4, 71% of patients developed an ISR, which was typically reported within the first 4 weeks of therapy. The development of ISRs in patients who had not previously experienced ISRs was uncommon after the first month of therapy.
 
Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice. In studies 1 and 4 combined, the incidence of infection was 40% in the Kineret-treated patients and 35% in placebo-treated patients. The incidence of serious infections in studies 1 and 4 was 1.8% in Kineret-treated patients and 0.6% in placebo-treated patients over 6 months. These infections consisted primarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections, rather than unusual, opportunistic, fungal, or viral infections. Patients with asthma appeared to be at higher risk of developing serious infections; Kineret 5% vs. placebo <1%. Most patients continued on study drug after the infection resolved. There were no on-study deaths due to serious infectious episodes in either study.
 
Twenty-one malignancies of various types were observed in 2531 RA patients treated in clinical trials with Kineret for up to 50 months. The observed rates and incidences were similar to those expected for the population studied. In placebo-controlled studies with Kineret, treatment was associated with small reductions in the mean values for total white blood count, platelets, and absolute neutrophil blood count (ANC), and a small increase in the mean eosinophil differential percentage. In all placebo-controlled studies, 8% of patients receiving Kineret had decreases in ANC of at least 1 WHO toxicity grade, compared with 2% of placebo patients. Six Kineret-treated patients (0.3%) developed neutropenia (ANC < 1 x 109/L).  Additional patients treated with Kineret plus etanercept (3/139, 2%) developed ANC < 1 x 109/L. While neutropenic, one patient developed cellulitis which recovered with antibiotic therapy.
 
In study 4, 28% of patients tested positively for anti-Kineret antibodies at month 6 in a highly sensitive, Kineret-binding biosensor assay. Of the 1274 subjects with available data, < 1% (n = 9) were seropositive in a cell-based bioassay for antibodies capable of neutralizing the biologic effects of Kineret . None of these 9 subjects were positive for neutraliz ing antibodies at more than 1 time point, and all of these subjects were negative for neutralizing antibodies by 9 months. No correlation between antibody development and clinical response or adverse events was observed. The long-term immunogenicity of Kineret is unknown. Antibody assay results are highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Kineret with the incidence of antibodies to other products may be misleading.
 
The recommended dose of Kineret is 100 mg administered once daily via SC injection. Kineret is formulated as a sterile, colorless-to-white, preservative-free liquid with a pH of 6.5 for daily SC injection. For patient convenience and to enhance compliance, Kineret is supplied in single-use, 1 mL prefilled glass syringes with a 27-gauge needle. Each prefilled glass syringe contains 0.67 mL (100 mg) of anakinra. Kineret is dispensed in packs containing seven syringes. It is also available in a 4 x 7 syringe dispensing pack (28 syringes). Kineret has a new mechanism of action, proven efficacy, and demonstrated safety in a broad range of RA patients, including those on concurrent DMARD therapy (excluding TNF blocking agents) and patients predisposed to infection due to a history of underlying disease. Given this clinical experience, Kineret is an important formulary addition for those patients with RA who are not adequately responding to other DMARDs.
 
KINERET® HAS BEEN ASSOCIATED WITH AN INCREASED INCIDENCE OF SERIOUS INFECTIONS (2%) vs. PLACEBO (< 1%). ADMINISTRATION OF KINERET® SHOULD BE DISCONTINUED IF A PATIENT DEVELOPS A SERIOUS INFECTION. TREATMENT WITH KINERET® SHOULD NOT BE INITIATED IN PATIENTS WITH ACTIVE INFECTIONS. THE SAFETY AND EFFICACY OF KINERET® IN IMMUNOSUPPRESSED PATIENTS OR IN PATIENTS WITH CHRONIC INFECTIONS HAVE NOT BEEN EVALUATED. IN TWO STUDIES, WHERE PATIENTS RECEIVED CONCURRENT ETANERCEPT AND KINERET® THERAPY AND WERE TREATED FOR UP TO 24 WEEKS, A 7% RATE OF SERIOUS INFECTIONS WAS OBSERVED WHICH WAS HIGHER THAN WHEN EITHER AGENT WAS USED ALONE. CONCURRENT ADMINISTRATION OF KINERET® AND ETANERCEPT HAS NOT DEMONSTRATED INCREASED CLINICAL BENEFIT. PHYSICIANS SHOULD PERFORM A RISK/BENEFIT ASSESSMENT AND MONITOR PATIENTS CAREFULLY WHEN CONSIDERING INITIATION OF KINERET® THERAPY CONCURRENTLY WITH ETANERCEPT THERAPY.