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Anakinra (brand name Kineret) is a drug used to treat rheumatoid arthritis.^[1] It is an interleukin 1 (IL1) receptor antagonist.

Mechanism

Anakinra is a recombinant version of the interleukin receptor antagonist 1 (IL1-RA).^[2] Anakinra differs from native human IL-1Ra in that it has the addition of a single methionine residue at its amino terminus ^[3] 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 many 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 is not found in effective concentrations in synovium and synovial fluid to counteract the elevated IL-1 concentrations in these patients.

Anakinra is not 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% 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.

Indications

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 should not be used in combination with anti-TNF agents such as 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% of 250 patients reached an improvement/relief of symptoms of at least 20% within 24 weeks. In the control group of 251 patients under methotrexate treatment alone response was seen in 22% 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 may be inferior to TNF-α inhibitors. However a review of the literature has suggested that TNF-α inhibitors may be superior then anakinra.^[4] In a study with infliximab plus methotrexate 50% of all patients had significant remission (according to at least ACR 20 criteria) after a 30-week treatment period.

Contraindications and precautions

Hypersensitivity to anakinra, other E. coli derived proteins, or to any other ingredient (absolute contraindication).
Preexisting malignant diseases (e.g., solid cancers, leukemia): absolutely contraindicated (anakinra may 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 may 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.
Pediatric patients: no well controlled human data exists in patients under age 18. Therefore, therapy is contraindicated in those patients.

Precautions:

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 is not available. The drug should be applied to pregnant women only if clearly indicated.
Mild to moderately impaired renal function: caution.

Side-effects

Gastrointestinal tract : Frequently, nausea (8%), diarrhea (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 also 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 neutralizing 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), usually during first 4 weeks of therapy, reversible within 1 to 2 weeks. These reactions are reasons why many patients discontinue therapy.

Recommended laboratory tests

In patients receiving anakinra a decrease in neutrophil counts may be found. In the placebo-controlled studies 8% of patients receiving anakinra had decreases in neutrophil counts of at least 1 World Health Organization (WHO) toxicity grade compared with 2% 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.

Malignancies

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. However, the 'natural' incidence of lymphomas in patients with rheumatoid arthritis is considerably increased and may even be higher in patients with high disease activity.

Additionally, 37 solid tumors 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; http://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD005121/pdf_standard_fs.html) 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 randomized 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 are not serious. Each of the trials reviewed measured prevalence of malignancies and found no evidence that these are increased amongst patients taking anakinra.

Interactions

TNF-Blocking Agents:

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 other agents blocking TNF (alpha) (e.g., adalimumab, infliximab). Therefore, combined drug therapy with anakinra and any TNF-blocking agent is not recommended and should be avoided. Moreover, in a 24-week clinical study a regime with anakinra and etanercept did not provide any additional benefit to the patients.

Methotrexate:

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.

Vaccines:

Live-virus vaccines should not be given to patients during anakinra treatment. Information is not 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 other effect of vaccination on patients receiving the drug. Due to the fact that anakinra decreases the immune response to antigens in general, vaccine efficacy may be reduced in patients receiving anakinra.

Dosage regimen

The usual dosage is 100 mg subcutaneously once a day. Dose reduction to 100 mg subcutaneously every other 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 other 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 may be anticipated in patients with inflammatory joint diseases such as psoriatic arthritis, and spondylarthritis. Possibly, anakinra may even benefit patients with destructive osteoarthritis in inflammatory phases. Clinical studies have not been initiated so far regarding these diseases. Currently, the use of anakinra in these patients is therefore not recommended.

Anakinra may be effective in pediatric patients with juvenile rheumatoid arthritis (JRA), also known as Juvenile Idiopathic Arthritis (JIA) or Still's Disease.^[5]

A 2005 article published in Arthritis & Rheumatism reported rapid improvement in four patients with Adult-Onset Still's Disease who were treated with Anakinra.^[6] 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".^[7]

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.^[8] A few studies have looked at the effectiveness of anakinra in some 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 other inflammatory lung diseases." ^[9] There is anecdotal evidence suggesting that IL-1 inhibitors may indeed be effective in gouty arthritis,and this approach is currently under study.^[10]

In 2008, an article in the European Journal of Pediatrics discussed treatment of colchicine-resistant Familial Mediterranean Fever with anakinra.^[11]

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. (http://medicalxpress.com/news/2012-07-treatments-reality.html)

On July 23, 2012 an article in the journal Annals of Neurology reported anakinra may be useful in epilepsy. The article stated that "anakinra rapidly terminated seizures, prevented their recurrence, and resolved seizure-associated BBB breakdown." (http://onlinelibrary.wiley.com/doi/10.1002/ana.23567/abstract)

The Nijmegen ME/CFS centre is starting a RCT to study the effects of Anakinra treatment in 46 female ME/CFS patients.

References

^ Fleischmann RM, Tesser J, Schiff MH et al. (August 2006). "Safety of extended treatment with anakinra in patients with rheumatoid arthritis". Annals of the rheumatic diseases 65 (8): 1006–12. doi:10.1136/ard.2005.048371. PMC 1798263. PMID 16396977.
^ Mertens, M; Singh, JA (21 January 2009). "Anakinra for rheumatoid arthritis.". The Cochrane database of systematic reviews (1): CD005121. doi:10.1002/14651858.CD005121.pub3. PMID 19160248.
^ |url=http://www.kineretrx.com/fileadmin/user_upload/pdfs/Kineret_100_mg_PatientInformation_US.PDF
^ "The future of the IL-1 receptor antagonist anakinra: from rheumatoid arthritis to adult-onset Still's disease and systemic-onset juvenile idiopathic arthritis.". Expert Opin Investig Drugs 17 (3): 349–59. Mar 2008. doi:10.1517/13543784.17.3.349. PMID 18321234.
^ "Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade". Rockefeller University Press. 2005-04-25. Retrieved 2012-10-13.
^ "Rapid responses to anakinra in patients with refractory adult-onset Still's disease.". Wiley. 2005-06-02. Retrieved 2012-10-13.
^ "Anti-Interleukin-1 Agents in Adult Onset Still's Disease.". Hindawi. 2012-02-07. Retrieved 2012-10-13.
^ "New type of drug helpful in type 2 diabetes". Reuters. 2007-04-12. Retrieved 2011-04-28.
^ Dostert, Catherine; Virginie Pétrilli; Robin Van Bruggen; Chad Steele; Brooke T. Mossman; Jürg Tschopp (2008-05-02). "Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica". Science 320 (5876): 674–7. doi:10.1126/science.1156995. PMC 2396588. PMID 18403674. Retrieved 2011-04-28.
^ Arthur Kavanaugh. "Gout:Treatment Reaction to Allopurinol- - What Next?". Medscape Rheumatology.
^ Calligaris, Lorenzo; Federico Marchetti; Alberto Tommasini; Alessandro Ventura (2008-06-01). "The efficacy of anakinra in an adolescent with colchicine-resistant familial Mediterranean fever". European Journal of Pediatrics 167 (6): 695–6. doi:10.1007/s00431-007-0547-3. PMC 2292480. PMID 17588171. Retrieved 2011-04-28.

External links

Kineret homepage
http://www.rheuma-online.de/medikamente/anakinra-kineret/anakinra-zb-kineret/tumorrisiko.html (on the risk of cancerogenity (in German))
http://www.rheuma-online.de/medikamente/anakinra-kineret/anakinra-zb-kineret/ausblicke-moegliche-zukuenftige-anwendungen-von-anakinra-kineret.html (same site on future indications)
http://www.rheuma-online.de/medikamente/anakinra-kineret/anakinra-zb-kineret/anakinra-kineret-in-der-kinderrheumatologie.html (same site on possible pediatric indications)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. リウマチ性疾患における生物学的製剤の概要 overview of biologic agents in the rheumatic diseases
2. リウマチ性疾患を有する男性における抗炎症剤および免疫抑制剤が性腺機能に及ぼす影響 effects of antiinflammatory and immunosuppressive drugs on gonadal function in men with rheumatic diseases
3. IL-1、IL-6、およびRANKLを抑制する生物学的製剤の関節リウマチにおける
ランダム化臨床試験 randomized clinical trials in rheumatoid arthritis of biologic agents that inhibit il 1 il 6 and rankl
4. 急性痛風の治療 treatment of acute gout
5. 全身型若年性特発性関節炎：治療 systemic onset juvenile idiopathic arthritis treatment

English Journal

Effectiveness and tuberculosis-related safety profile of interleukin-1 blocking agents in the management of Behçet's disease.

Cantarini L1, Lopalco G2, Caso F3, Costa L4, Iannone F2, Lapadula G2, Anelli MG2, Franceschini R5, Menicacci C5, Galeazzi M6, Selmi C7, Rigante D8.
Autoimmunity reviews.Autoimmun Rev.2015 Jan;14(1):1-9. doi: 10.1016/j.autrev.2014.08.008. Epub 2014 Aug 22.
Behçet's disease (BD) is a multi-systemic disorder of unknown etiology characterized by relapsing oral-genital ulcers, uveitis, and involvement of the articular, gastrointestinal, neurologic, and vascular systems. Although the primum movens of this condition remains unknown, a tangled plot combinin
PMID 25151975

Neutrophilic dermatosis: disease mechanism and treatment.

Maalouf D1, Battistella M, Bouaziz JD.
Current opinion in hematology.Curr Opin Hematol.2015 Jan;22(1):23-9. doi: 10.1097/MOH.0000000000000100.
PURPOSE OF REVIEW: The purpose of this review is to describe the physiopathological and therapeutic aspects of neutrophilic dermatosis, taking into account their most frequent associated conditions.RECENT FINDINGS: In autoinflammatory syndromes featuring neutrophilic dermatosis, the role of interleu
PMID 25394310

Resistant or recurrent acute pericarditis: A new therapeutic opportunity?

Massardier C1, Dauphin C2, Eschalier R1, Lusson JR1, Soubrier M3.
International journal of cardiology.Int J Cardiol.2014 Dec 15;177(2):e75-7. doi: 10.1016/j.ijcard.2014.09.192. Epub 2014 Oct 5.
PMID 25449496

Japanese Journal

Muckle-Wells 症候群の1例

大橋敦子,林宏一,岡田まゆみ,小林法元,上松一永,小池健一,宇原久,奥山隆平
日本小児皮膚科学会雑誌 = Journal of pediatric dermatology 31(2), 107-111, 2012-06-30
NAID 10030802187

W4-4 Cryopyrin-associated periodic syndromeの治療：本邦におけるcanakinumab臨床試験及びアナキンラ疫学調査について

西小森隆太,井澤和司,河合朋樹,八角高裕,平家俊男
日本臨床免疫学会会誌 35(4), 307b-307b, 2012
… てCAPSに対する治療薬として承認された．またCanakinumab承認まで抗IL-1療法として個人輸入で使用されてきたanakinraのCAPSに対する治療効果について，本邦でanakinraが治療として用いられたCAPS患者を対象に疫学調査を行った．本レビュートークでは，Canakinumabの臨床試験とanakinraの疫学調査についてのべることにより，本邦におけるCAPSに対する治療の実際についてあきらかにし，今後 …
NAID 130003364006

IL-1βR antagonist (特集糖尿病とその合併症の新薬の現状と未来)

小宮幸次,綿田裕孝
内分泌・糖尿病・代謝内科 31(1), 62-68, 2010-07
NAID 40017666426

Related Pictures

★リンクテーブル★

リンク元	「アナキンラ」「interleukin-1 receptor antagonist protein」

「アナキンラ」

Anakinra
Systematic (IUPAC) name
	Recombinant human Interleukin-1 receptor antagonist protein; syn. N2-l-methionyl-interleukin 1 receptor antagonist (human isoform x reduced)
Clinical data
Trade names	Kineret
AHFS/Drugs.com	monograph
MedlinePlus	a602001
Pregnancy; category	AU: B1; US: B (No risk in non-human studies);
Legal status	AU: Prescription Only (S4); CA: ℞-only; UK: Prescription-only (POM); US: ℞-only;
Routes of; administration	Subcutaneous
Pharmacokinetic data
Bioavailability	95%
Metabolism	predominantly renal
Biological half-life	4-6 hrs
Identifiers
CAS Registry Number	143090-92-0
ATC code	L04AC03
DrugBank	DB00026
UNII	9013DUQ28K
KEGG	D02934
ChEMBL	CHEMBL1201570
Chemical data
Formula	C759H1186N208O232S10
Molecular mass	17,257.6 g/mol
(what is this?) (verify)

　　[★]

英: anakinra
関: インターロイキン1受容体アンタゴニストタンパク質

「interleukin-1 receptor antagonist protein」

　　[★]

インターロイキン1受容体アンタゴニストタンパク質

関: anakinra

[pmid16396977-1] Fleischmann RM, Tesser J, Schiff MH et al. (August 2006). "Safety of extended treatment with anakinra in patients with rheumatoid arthritis". Annals of the rheumatic diseases 65 (8): 1006–12. doi:10.1136/ard.2005.048371. PMC 1798263. PMID 16396977.

[2] Mertens, M; Singh, JA (21 January 2009). "Anakinra for rheumatoid arthritis.". The Cochrane database of systematic reviews (1): CD005121. doi:10.1002/14651858.CD005121.pub3. PMID 19160248.

[prescribing_information-3] |url=http://www.kineretrx.com/fileadmin/user_upload/pdfs/Kineret_100_mg_PatientInformation_US.PDF

[4] "The future of the IL-1 receptor antagonist anakinra: from rheumatoid arthritis to adult-onset Still's disease and systemic-onset juvenile idiopathic arthritis.". Expert Opin Investig Drugs 17 (3): 349–59. Mar 2008. doi:10.1517/13543784.17.3.349. PMID 18321234.

[5] "Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade". Rockefeller University Press. 2005-04-25. Retrieved 2012-10-13.

[6] "Rapid responses to anakinra in patients with refractory adult-onset Still's disease.". Wiley. 2005-06-02. Retrieved 2012-10-13.

[7] "Anti-Interleukin-1 Agents in Adult Onset Still's Disease.". Hindawi. 2012-02-07. Retrieved 2012-10-13.

[8] "New type of drug helpful in type 2 diabetes". Reuters. 2007-04-12. Retrieved 2011-04-28.

[9] Dostert, Catherine; Virginie Pétrilli; Robin Van Bruggen; Chad Steele; Brooke T. Mossman; Jürg Tschopp (2008-05-02). "Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica". Science 320 (5876): 674–7. doi:10.1126/science.1156995. PMC 2396588. PMID 18403674. Retrieved 2011-04-28.

[10] Arthur Kavanaugh. "Gout:Treatment Reaction to Allopurinol- - What Next?". Medscape Rheumatology.

[11] Calligaris, Lorenzo; Federico Marchetti; Alberto Tommasini; Alessandro Ventura (2008-06-01). "The efficacy of anakinra in an adolescent with colchicine-resistant familial Mediterranean fever". European Journal of Pediatrics 167 (6): 695–6. doi:10.1007/s00431-007-0547-3. PMC 2292480. PMID 17588171. Retrieved 2011-04-28.

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anakinra