Anakinra is a recombinant version of the interleukin 1 receptor antagonist (IL1-RA). Anakinra differs from native human IL-1Ra in that it has the addition of a single methionine residue at its amino terminus  Anakinra blocks the biologic activity of naturally occurring IL-1, including inflammation and cartilage degradation associated with rheumatoid arthritis, by competitively inhibiting the binding of IL-1 to the Interleukin-1 type receptor, which is expressed in a large number of tissues and organs. IL-1 is produced in response to inflammatory stimuli and mediates various physiologic responses, including inflammatory and immunologic reactions. IL-1 additionally stimulates bone resorption and induces tissue damage like cartilage degradation as a result of loss of proteoglycans. In patients with rheumatoid arthritis the natural IL-1 receptor antagonist isn't found in effective concentrations in synovium and synovial fluid to counteract the elevated IL-1 concentrations in these patients.
Anakinra isn't considered a 'disease-modifying antirheumatic drug' (DMARD) but rather a 'biological response modifier' (BRM) because its able to selectively target the pathologic element of the disease.
Basic chemical, pharmacological and marketing data
The anakinra molecule is a recombinant, non-glycosylated version of human IL-1RA (RA for receptor antagonist) prepared from cultures of genetically modified Escherichia coli using recombinant DNA technology. It consists of 153 amino acids and has a molecular weight of 17,257.6 g/mol (approx. 17.3 kilodaltons) and differs from native human IL-1RA in that it has the addition of a single methionine residue on its amino terminus.
Anakinra had an absolute bioavailability of 95 percent for healthy adults (n = 11) after a 70 mg subcutaneous bolus injection. Peak plasma concentrations of anakinra generally occurred 3 to 7 hours after s.c. administration of clinically relevant doses (1 to 2 mg/kg: n = 18) for patients with rheumatoid arthritis. The terminal half-life ranged from 4 to 6 hours. After daily s.c. dosing for up to 24 weeks, no unexpected accumulations of anakinra were observed in the plasma samples of rheumatoid arthritis patients.
This drug is sold under the tradename "Kineret" and is produced by the pharmaceutical company Amgen. Since 15 December 2008, Swedish Orphan Biovitrum AB is the global market authorisation holder for Kineret on the indication adult rheumatoid arthritis. It is delivered as injection concentrate containing 100 mg each single dose.
Anakinra is indicated for the management of signs and symptoms of rheumatoid arthritis and to inhibit the progression of structural damage associated with the disease in adults with moderately to severely active disease who have had an absence of clinical improvement of symptoms or inadequate response in therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs). It is used as monotherapeutic agent or in combination with DMARDs. Anakinra shouldn't be used in combination with anti-TNF agents like etanercept (Enbrel), infliximab (Remicade) or adalimumab (Humira).
Anakinra showed moderate but statistically significant therapeutic efficacy; in most studies methotrexate was administered concomitantly. In the methotrexate plus anakinra group 38 percent of 250 patients reached an improvement/relief of symptoms of at least twenty percent within 24 weeks. In the control group of 251 patients under methotrexate treatment alone response was seen in twenty-two percent only. The clinical response was measured according to ACR-criteria (20, 50, and 70).
There are no direct studies comparing anakinra with TNF-α inhibitors, but indirect data suggests that anakinra might be inferior to TNF-α inhibitors. However a review of the literature has suggested that TNF-α inhibitors might be superior then anakinra. In a study with infliximab plus methotrexate fifty percent of all patients had significant remission (according to at least ACR 20 criteria) after a 30-week treatment period.
Anakinra might have applications for treating lupus nephritis. Inflammatory reactions caused by anti-dsDNA complexes with extracellular DNA in the glomerular basement membrane cause macrophage IL-1 release onto neighbouring mesangial cell IL-1 receptors.
Contraindications and precautions
- Hypersensitivity to anakinra, additional E. coli derived proteins, or to any additional ingredient (absolute contraindication).
- Preexisting malignant diseases (e.g., solid cancers, leukemia): absolutely contraindicated (anakinra might worsen already existing malignancies).
- Patients with neutropenia due to any reason : absolutely contraindicated. Neutrophil counts should be obtained before initiating therapy and regularly thereafter (see recommended laboratory tests).
- Severely impaired renal function (creatinine clearance less than 30 ml/minute): absolutely contraindicated.
- Preexisting active tuberculosis (disease might be worsened – see side-effects).
- Concomitant application of live-virus vaccines (see Interactions).
- Lactation: it is unknown if anakinra is distributed into human milk. Nursing mothers should either discontinue the drug or breast-feeding, taking into account the importance of the drug to the mother.
- Geriatric patients (over 65 yrs of age): risk of infections is increased.
- Asthma: increased risk of severe infections.
- Women of childbearing potential should use effective contraception methods.
- Pregnancy: animal studies showed no adverse effects. Human data isn't available. The drug should be applied to pregnant women only if clearly indicated.
- Mild to moderately impaired renal function: caution.
- Gastrointestinal tract : Frequently, nausea (8%), diarrhoea (7%), unspecific abdominal pain (5%).
- Gastrointestinal tract : elevated liver transaminases
- Allergy : Rare cases of allergic reactions including severe anaphylaxis have been noticed. If necessary, the usual symptomatic therapy with corticosteroids, epinephrine, antihistamines and intravenous fluid correction should be initiated as soon as possible. Rare cases of allergic skin rash have additionally been seen.
- Respiratory tract : Frequently, infections of upper respiratory tract (13%), sinusitis (7%), flu-like syndrome (6%), Infrequently, pneumonia and tuberculosis.
- Skin : Frequently ecchymoses, infrequently skin mycosis, lupus erythematosus-like syndrome, urticaria, and isolated cases of melanoma (see malignancies).
- Immune system : Frequently, infections (40%, severe in 2%). Infrequently, production of antibodies with neutralising activity.
- Blood and blood forming organs : Frequently, decrease in neutrophil counts (8% under anakinra, placebo 2%), infrequent significant neutropenia (0.4% under anakinra), moderate eosinophilia, moderately low platelet count, and malignant lymphomas (0.12 cases/patient year) (see malignancies).
- Musculoskeletal system : Infrequently seen are arthritic symptoms, arthritic symptoms associated with inflammation, bony infections.
- Pain, inflammation, and erythema at injection sites : Very frequently (70% of patients), most of the time throughout first 4 weeks of therapy, reversible within 1 to 2 weeks. These reactions are reasons why a large number of patients discontinue therapy.
Recommended laboratory tests
In patients receiving anakinra a decrease in neutrophil counts might be found. In the placebo-controlled studies eight percent of patients receiving anakinra had decreases in neutrophil counts of at least 1 World Health Organization (WHO) toxicity grade compared with two percent in the placebo control group. anakinra-treated patients experienced defined neutropenia (ANC < 1 x 109/L) in 0.4%.
Neutrophil counts should be assessed prior to initiating anakinra treatment, and while receiving anakinra, monthly for 3 months, and thereafter quarterly for a period up to 1 year.
Among 5,300 rheumatoid arthritis patients treated with anakinra in clinical trials for a mean of 15 months (approximately 6,400 patient years of treatment), 8 cases of lymphomas were observed resulting in a rate of 0.12 cases/100 patient years. This is 3.6 fold higher than the rate of lymphomas expected in the general population. Notwithstanding the 'natural' incidence of lymphomas in patients with rheumatoid arthritis is considerably increased and might even be higher in patients with high disease activity.
Additionally, 37 solid tumours of different origination have been found. Of these, the number of 3 melanomas reported in study 4 is significant (1 case expected), but the clear association to anakinra therapy remains unclear.
The Cochrane Collaboration (www.cochrane.org) is an independent body which produces systematic literature reviews to a high academic standard. The Cochrane review entitled, ‘Anakinra for rheumatoid arthritis’ (Mertens and Singh, 2009; ) evaluates the clinical effectiveness and safety of anakinra in adult patients with rheumatoid arthritis, using data from 2876 patients, from five trials which constituted in total 781 randomised to placebo and 2065 to anakinra. The authors conclude, “There were no statistically significant differences noted in most safety outcomes with treatment with anakinra versus placebo - including number of withdrawals, deaths, adverse events (total and serious), and infections (total and serious). Injection site reactions were significantly increased, occurring in 1235/1729 (71%) versus 204/729 (28%) of patients treated with anakinra versus placebo, respectively”. These injection site reactions last for no more than four months and aren't serious. Each of the trials reviewed measured prevalence of malignancies and found no evidence that these are increased amongst patients taking anakinra.
An increased incidence of serious infections and an increased risk of neutropenia have been seen when anakinra and etanercept were used concomitantly in patients with rheumatoid arthritis. Similar interactions can be anticipated for the combination therapy of anakinra together with additional agents blocking TNF (alpha) (e.g., adalimumab, infliximab). Therefore, combined drug therapy with anakinra and any TNF-blocking agent isn't recommended and should be avoided. Moreover, in a 24-week clinical study a regime with anakinra and etanercept didn't provide any additional benefit to the patients.
Methotrexate has been coadministered with anakinra in quite extended clinical studies. Neither specific drug interactions nor increased toxicity of anakinra and/or methotrexate have been noticed. In animal models (rats) studying the effects of both drugs when coadminstered, no effects on clearing of both drugs form plasma or on the respective toxicologic properties have been seen. Therefore, the concomitant use of both disease modifiers in patients with rheumatoid arthritis can be regarded as safe.
Live-virus vaccines shouldn't be given to patients throughout anakinra treatment. Information isn't available, if anakinra would affect the rate of secondary transmission of vaccine virus (e.g., measles or poliomyelitis viruses) following administration of a live virus vaccine or regarding any additional effect of vaccination on patients receiving the drug. Due to the fact that anakinra decreases the immune response to antigens in general, vaccine efficacy might be reduced in patients receiving anakinra.
The usual dosage is 100 mg subcutaneously once a day. Dose reduction to 100 mg subcutaneously every additional day should be considered in patients with severe renal impairment, if these are treated in exceptional cases (see contraindications and precautions). No additional benefits of doses exceeding 100 mg daily have been seen.
Duration of treatment
In the pre-clinical and clinical studies the usual duration of therapy was 24 weeks. It is possible to extend therapy to 48 weeks in patients with satisfying remission after 24 weeks to maintain clinically evident improvements. Under continued therapy anakinra has been shown to slow progression of disease over a period of at least 12 month evidenced by X-ray studies or additional clinical examinations. Some experience with 48 to 60 weeks (15 months) treatment duration has already been gained and no evidence has been seen regarding additional toxicity.
Possible future indications
Due to the specific mechanism of action of anakinra, a possible efficiency might be anticipated in patients with inflammatory joint diseases like psoriatic arthritis, and spondylarthritis. Possibly, anakinra might even benefit patients with destructive osteoarthritis in inflammatory phases. Clinical studies haven't been initiated so far regarding these diseases. Currently, the use of anakinra in these patients is therefore not recommended.
A 2005 article published in Arthritis & Rheumatism reported rapid improvement in four patients with Adult-Onset Still's Disease who were treated with Anakinra. Authors of a 2012 review article published in the International Journal of Inflammation concluded that "a growing number of evidences supports the utilisation of anakinra in Adult-Onset Still's Disease".
On April 12, 2007 an article in the New England Journal of Medicine discussed the possibility of using anakinra for treatment of type 2 diabetes. A few studies have looked at the effectiveness of anakinra in a few familial periodic fever syndromes.
On May 2, 2008 an article in the review Science discussed the possibility of using anakinra for treatment of asbestosis. "Since Anakinra (IL-1ra) is efficiently used in the clinical treatment of autoinflammatory syndromes as well as gout patients, the present study suggests a potential use of Anakinra in order to slow down progression of asbestosis, silicosis and possibly additional inflammatory lung diseases."  There is anecdotal evidence suggesting that IL-1 inhibitors might indeed be effective in gouty arthritis,and this approach is currently under study.
In July 2012, the University of Manchester scientists have demonstrated the effectiveness of the drug Anakinra (IL-1Ra), which is already used for rheumatoid arthritis in experimental studies of stroke: MRI scans revealed that the rats that were given IL-1Ra (Anakinra) up to three hours after the stroke, had only about half the brain damage of the placebo group. ()
On July 23, 2012 an article in the journal Annals of Neurology reported anakinra might be useful in epilepsy. The article stated that "anakinra rapidly terminated seizures, prevented their recurrence, and resolved seizure-associated BBB breakdown." ()
The Nijmegen ME/CFS centre is starting a RCT to study the effects of Anakinra treatment in 46 female ME/CFS patients.