Anakinra

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Anakinra
Anakinra.png
Clinical data
Trade names Kineret
AHFS/Drugs.com Monograph
MedlinePlus a602001
License data
Pregnancy
category
  • AU:B1
Routes of
administration 		Subcutaneous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 95%
Metabolism predominantly kidney
Elimination half-life 4-6 hrs
Identifiers
  • Recombinant human Interleukin-1 receptor antagonist protein; syn. N2-l-methionyl-interleukin 1 receptor antagonist (human isoform x reduced)
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
Formula C759H1186N208O232S10
Molar mass 17257.66 g·mol−1
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Anakinra, sold under the brand name Kineret, is a biopharmaceutical medication used to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, familial Mediterranean fever, and Still's disease. [3] It is a slightly modified recombinant version of the human interleukin 1 receptor antagonist protein. [3] It is marketed by Swedish Orphan Biovitrum. [1] Anakinra is administered by subcutaneous injection. [2]

Contents

Medical uses

It is used as a second line treatment to manage symptoms of rheumatoid arthritis after treatment with a disease-modifying antirheumatic drug (DMARD) has failed. [1] [2] It can be used in combination with some DMARDs. [1] [2] [5]

It is administered subcutaneously to patients diagnosed with a cryopyrin-associated periodic syndrome, including neonatal-onset multisystem inflammatory disease. [1] [2]

It is used to treat Schnitzler's syndrome (off label in the US). [6] Its response rate is such that it has been suggested that "Treatment failures should lead to reconsider the diagnosis." [7]

Off label, it is used to treat systemic juvenile idiopathic arthritis (SJIA), gout, calcium pyrophosphate deposition (CPPD), Behçet's disease, ankylosing spondylitis, uveitis, and other auto-inflammatory syndromes. [8]

In December 2021, the European Medicines Agency authorized the use of anakinra "to treat COVID-19 in adults with pneumonia requiring supplemental oxygen (low or high flow oxygen) and who are at risk of developing severe respiratory failure, as determined by blood levels of a protein called suPAR (soluble urokinase plasminogen activator receptor) of at least 6 ng per ml." [3] [9] [10] In November 2022, the United States FDA approved its use under an emergency use authorization "for the treatment of COVID-19 in hospitalized adults with pneumonia requiring supplemental oxygen (low- or high-flow oxygen) who are at risk of progressing to severe respiratory failure and likely to have an elevated plasma soluble urokinase plasminogen activator receptor (suPAR)." [11] [12]

Safety

It was not tested in pregnant women, but appeared to be safe in animal studies. [2]

It should not be used in people who have active infections[ clarification needed ] or latent tuberculosis, or who are taking TNF inhibitors. [2]

Adverse reactions

More than ten percent of people taking Anakinra have injection site reactions, headaches, and have increased cholesterol levels. [1] Recipients have eight percent more patients decrease white blood cells counts, two percent more patients decrease platelets counts, one percent more patients get severe infections (4.5% for patients with asthma compared to 0% placebo patients with asthma). [1] It is unclear if taking Anakinra increases cancer risk; studies are complicated by the fact that people with rheumatoid arthritis already face higher cancer risk. [1] [5]

Chemistry

Anakinra differs from the sequence of Interleukin 1 receptor antagonist by one methionine amino acid added to its N-terminus; it also differs from the human protein in that it is not glycosylated, as it is manufactured in Escherichia coli . [2]

History

It was approved for medical use in the US in 2001, [2] and in the European Union in 2002. [1] [3]

In 2018, NHS England published a Clinical Commissioning Policy: Anakinra to treat periodic fevers and autoinflammatory disorders (all ages) allowing Anakinra to be commissioned as a first-line treatment for Schnitzler's syndrome and in cases where the first-line treatment is not effective for Familial Mediterranean fever, Hyper-IgD syndrome also known as Mevalonate kinase deficiency, and TNF receptor associated periodic syndrome (TRAPS), [13] and a Clinical Commissioning Policy: Anakinra/tocilizumab for the treatment of Adult-Onset Still's Disease refractory to second-line therapy (adults), allowing Anakinra to be commissioned for adult-onset Still's disease "as a third line treatment where patients are refractory to steroid-sparing effect DMARDs". [14]

In December 2020, Anakinra was approved by the US Food and Drug Administration for the treatment of deficiency of the interleukin-1–receptor antagonist (DIRA), a rare autoinflammatory disease of infancy. [15] In 2021, it was announced that the Ministry of Health of the Russian Federation had approved the use of Anakinra for the treatment of CAPS. [16]

In October 2021, NHS England published Clinical Commissioning Policy: Anakinra for Haemophagocytic Lymphohistiocytosis (HLH) for adults and children in all ages, allowing Anakinra to be used in the treatment of HLH. [17]

Society and culture

Approvals
Condition
CountryRACAPSFMFAOSDSchnitzler'sMKDTRAPSDIRAHLH
US20012020
UK20182018201820182021
EU200220022002
Russia2021

Research

Anakinra effectively treated meningitis caused by a rare genetic mutation in the gene NALP3 in a 67-year-old man enrolled in the Undiagnosed Diseases Network. [18] Researchers at Johns Hopkins University announced in 2019 that anakinra given to pregnant mice with Zika virus had reduced fetal deaths and birth defects. [19] In November 2019, researchers at the University of Manchester reported that Anakinra might have a use in preventing breast cancer from spreading to the bones. [20] [21]

In 2021, it was reported that Anakinra appeared to reduce the neuropathic pain experienced by patients undergoing chemotherapy with vincristine, saying that "repurposing anakinra may be an effective co-treatment strategy to prevent vincristine-induced peripheral neuropathy". [22] [23]

A review published in 2022 found that "Anakinra appears to show efficacy for numerous dermatologic conditions, with the strongest evidence for hidradenitis suppurativa, Behçet's disease, Muckle–Wells syndrome, and SAPHO syndrome." and concluded that "Overall, anakinra appears to be a promising option in the treatment of numerous dermatologic inflammatory conditions refractory to first line therapies, but further and higher-quality data is needed to clarify its therapeutic role." [24]

In 2023, researchers at Columbia University explored the effect of Anakinra on the ageing of Hematopoietic stem cells in mice. They concluded "that targeting IL-1 as a key mediator of niche inflammation is a tractable strategy to improve blood production during ageing" and were reported to have said "that their findings could pave the way for science to delay aging and even lengthen the lifespan of humans". [25] [26] [27]

A 2023 preliminary study on the use of Anakinra in the treatment of endometriosis concluded that "there is justification for a larger study" and that "Anakinra may be a particularly impactful option for women desiring fertility." [28]

COVID-19

Anakinra is undergoing multiple clinical trials to treat COVID-19 patients, by targeting mechanisms in patients with hyperinflammation. [29] In 2021 a review and meta-analysis of 9 studies involving 1,119 cases concluded that "Available evidence shows that treatment with anakinra reduces both the need for invasive mechanical ventilation and mortality risk of hospitalized non-intubated patients with COVID-19 without increasing the risk of adverse events." [30]

As of July 2021, the European Medicines Agency (EMA) is evaluating an application to extend the use of anakinra to include treatment of COVID-19 in adults with pneumonia who are at risk of developing severe respiratory failure (inability of the lungs to work properly). [31] According to study results published in September 2021 in Nature Medicine , hospitalized COVID-19 patients at increased risk for respiratory failure showed significant improvement after treatment with Anakinra. [32] [33]

Related Research Articles

<span class="mw-page-title-main">Arthritis</span> Type of joint disorder

Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In some types of arthritis, other organs are also affected. Onset can be gradual or sudden.

<span class="mw-page-title-main">Rheumatoid arthritis</span> Type of autoimmune arthritis

Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involved, with the same joints typically involved on both sides of the body. The disease may also affect other parts of the body, including skin, eyes, lungs, heart, nerves, and blood. This may result in a low red blood cell count, inflammation around the lungs, and inflammation around the heart. Fever and low energy may also be present. Often, symptoms come on gradually over weeks to months.

Rheumatology is a branch of medicine devoted to the diagnosis and management of disorders whose common feature is inflammation in the bones, muscles, joints, and internal organs. Rheumatology covers more than 100 different complex diseases, collectively known as rheumatic diseases, which includes many forms of arthritis as well as lupus and Sjögren's syndrome. Doctors who have undergone formal training in rheumatology are called rheumatologists.

<span class="mw-page-title-main">Methotrexate</span> Chemotherapy and immunosuppressant medication

Methotrexate, formerly known as amethopterin, is a chemotherapy agent and immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancies. Types of cancers it is used for include breast cancer, leukemia, lung cancer, lymphoma, gestational trophoblastic disease, and osteosarcoma. Types of autoimmune diseases it is used for include psoriasis, rheumatoid arthritis, and Crohn's disease. It can be given by mouth or by injection.

<span class="mw-page-title-main">Disease-modifying antirheumatic drug</span> Category of drugs

Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroidal anti-inflammatory drugs and steroids.

<span class="mw-page-title-main">Psoriatic arthritis</span> Long-term inflammatory arthritis

Psoriatic arthritis (PsA) is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. This often happens in association with changes to the nails such as small depressions in the nail (pitting), thickening of the nails, and detachment of the nail from the nailbed. Skin changes consistent with psoriasis frequently occur before the onset of psoriatic arthritis but psoriatic arthritis can precede the rash in 15% of affected individuals. It is classified as a type of seronegative spondyloarthropathy.

Adalimumab, sold under the brand name Humira and others, is a disease-modifying antirheumatic drug and monoclonal antibody used to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, plaque psoriasis, hidradenitis suppurativa, and uveitis. It is administered by subcutaneous injection. It works by inactivating tumor necrosis factor-alpha (TNFα).

<span class="mw-page-title-main">Leflunomide</span> Chemical compound

Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug (DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor that works by inhibiting dihydroorotate dehydrogenase.

A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma, so TNF inhibitors may be used in their treatment. The important side effects of TNF inhibitors include lymphomas, infections, congestive heart failure, demyelinating disease, a lupus-like syndrome, induction of auto-antibodies, injection site reactions, and systemic side effects.

Tocilizumab, sold under the brand name Actemra among others, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis, cytokine release syndrome, COVID‑19, and systemic sclerosis-associated interstitial lung disease (SSc-ILD). It is a humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). Interleukin 6 (IL-6) is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases, such as autoimmune diseases, multiple myeloma and prostate cancer. Tocilizumab was jointly developed by Osaka University and Chugai, and was licensed in 2003 by Hoffmann-La Roche.

<span class="mw-page-title-main">Canakinumab</span> Pharmaceutical drug

Canakinumab, sold under the brand name Ilaris, is a medication for the treatment of systemic juvenile idiopathic arthritis, active Still's disease, including adult-onset Still's disease, gout flares. It is a human monoclonal antibody targeted at interleukin-1 beta. It has no cross-reactivity with other members of the interleukin-1 family, including interleukin-1 alpha.

Adult-onset Still's disease (AOSD) is a form of Still's disease, a rare systemic autoinflammatory disease characterized by the classic triad of fevers, joint pain, and a distinctive salmon-colored bumpy rash. The disease is considered a diagnosis of exclusion. Levels of the iron-binding protein ferritin may be extremely elevated with this disorder. AOSD may present in a similar manner to other inflammatory diseases and to autoimmune diseases, which must be ruled out before making the diagnosis.

Rilonacept, sold under the brand name Arcalyst, is a medication used to treat cryopyrin-associated periodic syndromes, including familial cold autoinflammatory syndrome, and Muckle–Wells syndrome; deficiency of interleukin-1 receptor antagonist; and recurrent pericarditis. Rilonacept is an interleukin 1 inhibitor.

Schnitzler syndrome or Schnitzler's syndrome is a rare disease characterised by onset around middle age of chronic hives (urticaria) and periodic fever, bone pain and joint pain, weight loss, malaise, fatigue, swollen lymph glands and enlarged spleen and liver.

A Janus kinase inhibitor, also known as JAK inhibitor or jakinib, is a type of immune modulating medication, which inhibits the activity of one or more of the Janus kinase family of enzymes, thereby interfering with the JAK-STAT signaling pathway in lymphocytes.

<span class="mw-page-title-main">Secukinumab</span> Monoclonal antibody against IL-17

Secukinumab, sold under the brand name Cosentyx among others, is a human IgG1κ monoclonal antibody used for the treatment of psoriasis, ankylosing spondylitis, and psoriatic arthritis. It binds to the protein interleukin (IL)-17A and is marketed by Novartis.

Sarilumab, sold under the brand name Kevzara, is a human monoclonal antibody medication against the interleukin-6 receptor. Regeneron Pharmaceuticals and Sanofi developed the drug for the treatment of rheumatoid arthritis (RA), for which it received US FDA approval on 22 May 2017 and European Medicines Agency approval on 23 June 2017.

Olokizumab (OKZ) sold under the name Artlegia, is an immunosuppressive drug, used for the treatment of rheumatoid arthritis and COVID-19. It is a humanized monoclonal antibody against the interleukin-6 (IL-6). IL-6 is a cytokine that plays an important role in immune response and is implicated in the pathogenesis of many diseases. Olokizumab is the first interleukin-6 (IL-6) inhibitor approved for treatment of rheumatoid arthritis which blocks directly cytokine instead of its receptor. Olokizumab specifically binds to IL-6 at Site 3, blocking IL-6 ability to form hexameric complex. Olokizumab was developed by R-Pharm group, and was launched in 2020.

<span class="mw-page-title-main">Systemic-onset juvenile idiopathic arthritis</span> Medical condition

Systemic-onset juvenile idiopathic arthritis (sJIA), also known as Still disease, Still's disease, and systemic juvenile idiopathic arthritis, is a subtype of juvenile idiopathic arthritis (JIA) that is distinguished by arthritis, a characteristic erythematous skin rash, and remitting fever. Fever is a common symptom in patients with sJIA, characterized by sudden temperature rise above 39 °C and then a sudden drop. Over 80% of patients have a salmon-colored macular or maculopapular rash, which can be migratory and nonpruritic. Arthritis can develop weeks, months, or even years after onset and can affect various joints. SJIA is characterized by splenic and lymph node enlargements, with prominent symmetrical lymphadenopathy. Pericardial involvement is common, with 81% of children with active systemic symptoms having abnormal echocardiographic findings and 36% having an effusion or pericardial thickening. Around one-third of children with sJIA have occult macrophage activation syndrome (MAS), a potentially fatal illness causing T cells and macrophages to rapidly multiply and activate, resulting in a "cytokine storm."

<span class="mw-page-title-main">Antiarthritics</span> Drug class

An antiarthritic is any drug used to relieve or prevent arthritic symptoms, such as joint pain or joint stiffness. Depending on the antiarthritic drug class, it is used for managing pain, reducing inflammation or acting as an immunosuppressant. These drugs are typically given orally, topically or through administration by injection. The choice of antiarthritic medication is often determined by the nature of arthritis, the severity of symptoms as well as other factors, such as the tolerability of side effects.

References

  1. 1 2 3 4 5 6 7 8 9 "Kineret 100 mg solution for injection in a pre-filled syringe - Summary of Product Characteristics (SmPC)". UK Electronic Medicines Compendium. Retrieved 2 March 2022.
  2. 1 2 3 4 5 6 7 8 9 "Kineret- anakinra injection, solution". DailyMed. 30 December 2020. Retrieved 2 March 2022.
  3. 1 2 3 4 5 "Kineret EPAR". European Medicines Agency . 17 September 2018. Retrieved 20 July 2021. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ↑ "COVID-19 medicines". European Medicines Agency (EMA). 14 October 2024. Retrieved 14 October 2024.
  5. 1 2 Singh JA, Hossain A, Tanjong Ghogomu E, Kotb A, Christensen R, Mudano AS, et al. (May 2016). "Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis". The Cochrane Database of Systematic Reviews. 2016 (5): CD012183. doi:10.1002/14651858.CD012183. PMC   7068903 . PMID   27175934.
  6. ↑ Gusdorf L, Lipsker D (August 2017). "Schnitzler Syndrome: a Review". Current Rheumatology Reports. 19 (8): 46. doi:10.1007/s11926-017-0673-5. PMID   28718061. S2CID   13780498.
  7. ↑ Néel A, Henry B, Barbarot S, Masseau A, Perrin F, Bernier C, et al. (October 2014). "Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler's syndrome: a French multicenter study" (PDF). Autoimmunity Reviews. 13 (10): 1035–1041. doi:10.1016/j.autrev.2014.08.031. PMID   25220180.
  8. ↑ "Anakinra (Kineret)". American College of Rheumatology. Retrieved 2021-11-22.
  9. ↑ "EMA recommends approval for use of Kineret in adults with COVID-19". European Medicines Agency. 16 December 2021. Retrieved 2 March 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  10. ↑ Aripaka P, Karimi A (16 December 2021). "EU regulator builds Omicron defences with approvals of GSK-Vir, Sobi drugs". Reuters. Retrieved 17 December 2021.
  11. ↑ "Sobi's Kineret granted FDA Emergency Use Authorisation for COVID-19 related pneumonia". PMNews. November 2022.
  12. ↑ "FDA roundup". Food and Drug Administration . November 15, 2022.
  13. ↑ Clinical Commissioning Policy: Anakinra to treat periodic fevers and autoinflammatory disorders (all ages) (PDF). England: National Health Service (NHS). 29 June 2018. Retrieved 9 July 2018.
  14. ↑ Clinical Commissioning Policy: Anakinra/tocilizumab for the treatment of Adult-Onset Still's Disease refractory to second-line therapy (adults) (PDF). England: National Health Service (NHS). 29 June 2018. Archived from the original (PDF) on 13 July 2018. Retrieved 13 July 2018.
  15. ↑ Kaufman MB (2 February 2021). "FDA Approves New Rituximab Biosimilar & Anakinra to Treat a Rare Disease". The Rheumatologist. Retrieved 4 February 2021.
  16. ↑ "Kineret approved in Russia for the treatment of CAPS". The Pharma Letter. 17 February 2021. Retrieved 18 February 2021.
  17. ↑ Clinical Commissioning Policy: Anakinra for Haemophagocytic Lymphohistiocytosis (HLH) for adults and children in all ages (PDF). England: National Health Service (NHS). October 2021. Archived from the original (PDF) on 13 October 2021. Retrieved 14 October 2021.
  18. ↑ Kolata G (2019-01-07). "When the Illness Is a Mystery, Patients Turn to These Detectives". The New York Times. Retrieved 2019-01-09.
  19. ↑ "Rheumatoid Arthritis Drug Diminishes Zika Birth Defects in Mice". Newsroom. Johns Hopkins Medicine. 6 May 2019. Retrieved 5 September 2019.
  20. ↑ "Arthritis drugs could be repurposed to help prevent breast cancer spreading to the bone, study suggests". Press release. University of Manchester. 20 November 2019. Retrieved 21 November 2019.
  21. ↑ Eyre R, Alférez DG, Santiago-Gómez A, Spence K, McConnell JC, Hart C, et al. (November 2019). "Microenvironmental IL1β promotes breast cancer metastatic colonisation in the bone via activation of Wnt signalling". Nature Communications. 10 (1): 5016. Bibcode:2019NatCo..10.5016E. doi:10.1038/s41467-019-12807-0. PMC   6825219 . PMID   31676788.
  22. ↑ Starobova H, Monteleone M, Adolphe C, Batoon L, Sandrock CJ, Tay B, et al. (May 2021). "Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release". The Journal of Experimental Medicine. 218 (5): e20201452. doi:10.1084/jem.20201452. PMC   7933984 . PMID   33656514.
  23. ↑ "Chemotherapy with fewer side effects may be on the way". University of Queensland. 15 March 2021. Retrieved 15 March 2021.
  24. ↑ Tegtmeyer K, Atassi G, Zhao J, Maloney NJ, Lio PA (February 2022). "Off-Label studies on anakinra in dermatology: a review". The Journal of Dermatological Treatment. 33 (1): 73–86. doi:10.1080/09546634.2020.1755417. PMID   32279586. S2CID   215749189.
  25. ↑ Caler L (1 February 2023). "This Arthritis Drug Could Rejuvenate Blood In The Elderly, Delay Aging". Medical Daily. Retrieved 6 February 2023.
  26. ↑ Mitchell CA, Verovskaya EV, Calero-Nieto FJ, Olson OC, Swann JW, Wang X, et al. (January 2023). "Stromal niche inflammation mediated by IL-1 signalling is a targetable driver of haematopoietic ageing". Nature Cell Biology. 25 (1): 30–41. doi:10.1038/s41556-022-01053-0. PMC   7614279 . PMID   36650381.
  27. ↑ Irving M (6 February 2023). "Arthritis drug mimics "young blood" transfusions to reverse aging in mice". New Atlas. Retrieved 6 February 2023.
  28. ↑ Sullender R, Agarwal R, Jacobs M, Valentine H, Foster L, Agarwal SK (November 2023). "10217 IL-1 Antagonist Anakinra for the Treatment of Endometriosis: A Placebo Controlled, Randomized Pilot Study". Journal of Minimally Invasive Gynecology. 30 (11): S107. doi:10.1016/j.jmig.2023.08.342. S2CID   264540594.
  29. ↑ "Anakinra in COVID-19: important considerations for clinical trials". Press release. May 2020. Retrieved 5 January 2021.
  30. ↑ Barkas F, Filippas-Ntekouan S, Kosmidou M, Liberopoulos E, Liontos A, Milionis H (December 2021). "Anakinra in hospitalized non-intubated patients with coronavirus disease 2019: a Systematic review and meta-analysis". Rheumatology. 60 (12): 5527–5537. doi:10.1093/rheumatology/keab447. PMC   8194671 . PMID   33999135.
  31. ↑ "EMA starts evaluating the use of Kineret in adult COVID-19 patients at increased risk severe respiratory failure". European Medicines Agency (EMA) (Press release). 16 July 2021. Retrieved 20 July 2021.
  32. ↑ Kyriazopoulou E, Poulakou G, Milionis H, Metallidis S, Adamis G, Tsiakos K, et al. (October 2021). "Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial". Nature Medicine. 27 (10): 1752–1760. doi: 10.1038/s41591-021-01499-z . PMC   8516650 . PMID   34480127.
  33. ↑ "Anakinra improved survival in hospitalized COVID-19 patients". www.mdedge.com. Retrieved 2021-09-09.
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