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DRUG RECORD

 

ANAKINRA

OVERVIEW
Anakinra

 

Introduction

Anakinra is a recombinant interleukin-1 (IL-1) receptor antagonist having antiinflammatory and immunomodulatory actions and used in the therapy of rheumatoid arthritis and other inflammatory arthritidies.  Anakinra is associated with a low rate of serum enzyme elevations during therapy and with rare instances of clinically apparent, acute liver injury.

 

Background

Anakinra (an a kin’ ra) is used to treat serious inflammatory conditions such as rheumatoid arthritis and cryopyrin-associated periodic syndromes (CAPS).  IL-1 like tumor necrosis factor alpha (TNF) is a proinflammatory cytokine that plays a major role in the immune responses underlying local and systemic inflammation.  IL-1 also is the dominant cartilage destructive cytokine.  Circulating IL-1 receptor antagonists (IL-1Ra) modulate the effects of IL-1 and are synthesized in response to inflammatory reactions, acting to prevent binding of circulating IL-1 to its receptor and thus helping to terminate the proinflammatory reaction.  Anakinra is a recombinant version of IL-1Ra produced in E. coli, differing from the natural cytokine antagonist only in being nonglycosylated and having the addition of a single amino acid (methionine) on its amino terminus.  Anakinra has been shown to be a disease modifying antirheumatologic drug (DMARD) and to improve signs and symptoms and decrease cartilage destruction in rheumatoid arthritis.  Anakinra was approved for use in the United States in 2001 and its current formal indications are for severe rheumatoid arthritis and the autoinflammatory conditions known as cryopyrin-associated periodic syndomres (CAPS).  It is used off label for idiopathic juvenile arthritis and other autoimmune forms of arthritis such as adult onset Still disease.  Anakinra must be given parenterally daily and is available under the brand name Kineret in prefilled syringes of 100 mg per 0.67 mL, which allow for doses between 20 and 100 mg.  A typical regimen is 100 mg subcutaneously each day.  Common side effects are local skin reactions, gastrointestinal upset, headahce, arthraglias and possibly an increased incidence of bacterial infections.

 

Hepatotoxicity

In large registration trials, ALT elevations occurred in <1% of patients taking anakinra, a rate not different from that in placebo recipients, and no cases of clinically apparent liver injury with jaundice were reported.  Since its approval and more wide scale use, however, anakinra has been linked to several instances of acute liver injury.  The onset was within a few weeks to up to 6 months after starting subcutaneous injections of anakinra and thetypical clinical presentation resembled acute viral hepatitis, with a hepatocellular pattern of serum enzyme elevations, high levels of ALT and AST and mild to moderate jaundice.  Immunoallergic features were not reported and autoantibodies were considered due to the underlying conditions being treated.  Liver biopsies demonstrated an acute hepatocellular injury with prominence of eosinophils.  Most patients recovered within 2 to 8 weeks of stopping anakinra without evidence of residual injury, but some cases have been severe, protracted and associated with transient features of hepatic failure.  Not all published cases of anakinra-associated acute liver injury have been very convincing; virtually all have occurred in patients with Still's disease in which acute liver injury can be a manifestation of the underlying condition.  Furthermore, in many of the published instances, patients were taking other drugs capable of causing acute liver injury (such as high dose methylprednisolone).  Anakinra has not been linked to reactivation of hepatitis B or exacerbation of chronic hepatitis C. 

 

Likelihood score: C (probable cause of clinically apparent acute liver injury).

 

Mechanism of Injury

Anakinra binds to circulating IL-1 and is metabolized peripherally, probably largely in macrophages.  It is a polypeptide and has minimal hepatic metabolism.  The mechanism by which it causes liver injury is unknown, but may be the result of its effects on the immune system.

 

Outcome and Management

The hepatic injury caused by anakinra is usually self-limited and resolves within a few weeks of stopping the medication, although some cases have been severe and protracted.  Cases of fatal, acute liver failure, chronic hepatitis and vanishing bile duct syndrome have not been reported with its use.  There is no reason to suspect that there may be cross sensitivity to hepatic injury between anakinra and other immune modulating biologic agents including agents that modulate IL1 such as canakinumab and rilonacept.


Drug Class:  Antirheumatic Agents


Other Drugs in the Subclass, Interleukin Receptor Antagonists:  Canakinumab, Rilonacept, Tocilizumab

 

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CASE REPORT
Anakinra

 

Case 1.  Acute liver injury due to anakinra.
[Modified from:  Diallo A, Mekinian A, Boukari L, Mouas H, Zamy M, Nahon P, Gérin M, et al. [Severe hepatitis in a patient with adult-onset Still's disease treated with anakinra]. Rev Med Interne 2013; 34:168-70. French. PubMed Citation]

 

A 22 year old woman with suspected adult onset Still disease was treated with anakinra, which resulted in a marked improvement in the inflammatory arthritis, but was followed by the development of jaundice 3 weeks after starting the daily injections.  Before starting anakinra, the patient had presented with a systemic inflammatory condition marked by fever, skin rash and polyarthritis that was diagnosed as being adult onset Still disease, based upon the clinical presentation and laboratory findings of an elevated erythrocyte sedimentation rate and serum ferritin in the absence of autoantibodies or rheumatoid factor.  She was treated with high doses of methylprednisolone followed by oral prednisone (1 mg/kg) with little change in symptoms, and persistent fever and arthralgias.  Anakinra was started in a subcutaneous dose of 100 mg daily, which was followed by symptomatic improvement and fall of ESR to normal within a week.  The dose of prednisone was decreased to 30 mg daily and anakinra was continued.  Three weeks after starting the IL-1ra therapy she developed fatigue and jaundice.  She had no previous history of liver disease, alcohol abuse or risk factors for viral hepatitis.  When she initially presented with fever and polyarthritis, serum aminotransferase levels were mildly elevated (Table).  At the time of presentation with jaundice, the serum total bilirubin was 6.8 mg/dL (6.6 direct), ALT 3346 U/L, AST 2386 U/L, GGT 538 U/L and alkaline phosphatase 300 U/L.  Tests for hepatitis A, B and C were negative and abdominal ultrasound was normal, with no evidence of biliary obstruction.  A liver biopsy showed an acute hepatitis with marked inflammation and necrosis without fibrosis or signs of hemophagocytosis.  Stopping anakinra was followed by a rapid improvement in the liver injury, but two weeks later the reappearance of symptoms and signs of adult onset Still disease prompted treatment with intravenous immunoglobulin which led to a remission in disease.

 

Key Points

Medication:Anakinra (100 mg daily)
Pattern: Hepatocellular (R=32)
Severity:3+ (jaundice, hospitalization)
Latency:3 weeks
Recovery:~2 weeks
Other medications:Prednisone, folate

Comment

This patient developed acute hepatitis with jaundice 3 weeks after starting daily doses of anakinra for adult onset Still's disease.  The pattern and course of the liver injury was quite typical of idiosyncratic drug induced liver injury and compatible with the type of injury that has been reported with anakinra with a 2 to 6 week latency and a hepatocellular or mixed pattern of liver enzyme elevations.  The pathogenesis is unknown.  Anakinra is a recombinant protein and is unlikely to be inherently hepatotoxic, but rather more likely to toe trigger the acute liver injury indirectly by its action against IL-1 or on the immune system.  Patients with adult onset Still disease often have hepatic involvement.

 

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REPRESENTATIVE TRADE NAMES
Anakinra – Kineret®

 

DRUG CLASS
Antirheumatic Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NO. MOLECULAR FORMULA STRUCTURE
Anakinra 143090-92-0 C759-H1186-N208-O232-S10 Protein

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REFERENCES
Anakinra

 

References updated: 05 July 2017

  1. Zimmerman HJ. Drugs used to treat rheumatic and musculospastic disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 517-53.  (Expert review of hepatotoxicity published in 1999 before the availability of anakinra).

  2. Krensky AM, Bennett WM, Vincenti F. Immunosuppressants, tolerogens, and immunostimulants. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1005-29.  (Textbook of pharmacology and therapeutics).

  3. Bywaters EG. Still's disease in the adult. Ann Rheum Dis 1971; 30: 121-33. PubMed Citation  (Clinical description of 14 patients with adult onset Still disease seen at a single referral center in the UK over a 25 year period; all woman, ages 17-35 years, presenting with urticarial, macular rash, high fevers, fatigue and arthritis, high ESR but no rheumatoid factor, the majority ultimately recovering completely without residual arthritis or problems).

  4. Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, Emery P, Nuki G, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998; 41: 2196-204. PubMed Citation  (Among 472 patients with rheumatoid arthritis enrolled in a controlled trial comparing anakinra [30, 75 or 150 mg] vs placebo, both given subcutaneously once daily for 24 weeks, the most frequent side effect was injection site reactions [50%-81% vs 25% with placebo]; "no other important adverse effects were detected in the laboratory analyses").

  5. Nuki G, Bresnihan B, Bear MB, McCabe D; European Group Of Clinical Investigators. Long-term safety and maintenance of clinical improvement following treatment with anakinra(recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis; extension phase of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46: 2838-46. PubMed Citation  (Among 309 patients with rheumatoid arthritis who entered an extension phase after a controlled trial of anakinra [Bresnihan 1998] and were treated for up to 76 weeks, the only common adverse event being injection site reactions; no mention of ALT elevations or clinically apparent liver injury).

  6. Fleischmann RM, Schechtman J, Bennett R, Handel ML, Burmester GR, Tesser J, Modafferi D, et al. Anakinra, a recombinant human interleukin-1 receptor antagonist(r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial. Arthritis Rheum 2003; 48: 927-34. PubMed Citation  (Among 1414 patients with rheumatoid arthritis treated for 24 weeks with anakinra [100 mg] or placebo given subcutaneously once daily, serum biochemistry testing indicated "no evidence of hepatotoxicity").

  7. Andrès E, Kurtz JE, Perrin AE, Pflumio F, Ruellan A, Goichot B, Dufour P, et al. Retrospective monocentric study of 17 patients with adult Still's disease, with special focus on liver abnormalities. Hepatogastroenterology 2003; 50: 192-5. PubMed Citation  (Among 17 patients with adult onset Still disease seen at a single French referral center, mean age was 27 years and 76% had "moderate liver dysfunction" with hepatomegaly in 47%, bilirubin 0.6-1.3 mg/dL, ALT 32-252 U/L; all ultimately had "complete recovery").

  8. Hawkins PN, Lachmann HJ, McDermott MF. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome. N Engl J Med 2003; 348: 2583-4. PubMed Citation  (Two patients with Muckle-Wells syndrome, a hereditary autoinflammatory disease, had a dramatic and sustained response to therapy with anakinra).

  9. Furst DE. Anakinra: review of recombinant human interleukin-I receptor antagonist in the treatment of rheumatoid arthritis. Clin Ther 2004; 26: 1960-75. PubMed Citation  (Systematic review of literature on anakinra therapy of rheumatoid arthritis concluded that it was "mildly to moderately effective and well tolerated", the frequency of side effects other than injection site reactions being no different than that among placebo recipients).

  10. Fleischmann RM, Tesser J, Schiff MH, Schechtman J, Burmester GR, Bennett R, Modafferi D, et al. Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis 2006; 65: 1006-12. PubMed Citation  (Summary of an open label extension trial of anakinra in 1346 patients with rheumatoid arthritis who had participated in a randomized controlled trial [Fleischmann 2002], mentions that 5 patients [0.4%] had elevated serum enzymes, but no details of levels or outcomes given; among 15 deaths, there were none attributed to liver disease).

  11. Efthimiou P, Georgy S. Pathogenesis and management of adult-onset Still's disease. Semin Arthritis Rheum 2006; 36: 144-52. PubMed Citation  (Adult onset Still disease is a rare, systemic inflammatory disorder of unknown cause characterized by fever, distinctive skin rash, arthritis and multiorgan involvement).

  12. Kötter I, Wacker A, Koch S, Henes J, Richter C, Engel A, Günaydin I, Kanz L. Anakinra in patients with treatment-resistant adult-onset Still's disease: four case reports with serial cytokine measurements and a review of the literature. Semin Arthritis Rheum 2007; 37: 189-97. PubMed Citation  (Description of 4 patients with chronic or relapsing adult onset Still disease who had an immediate, dramatic response to anakinra therapy, having failed to respond to corticosteroids, methotrexate, TNF antagonists and leflunomide; ALT and AST values improved with treatment as well).

  13. Mylona E, Golfinopoulou S, Samarkos M, Fanourgiakis P, Papadakos V, Skoutelis A. Acute hepatitis in adult Still's disease during corticosteroid treatment successfully treated with anakinra. Clin Rheumatol 2008; 27: 659-61. PubMed Citation  (46 year old man with adult onset Still disease developed worsening liver tests during prednisone taper [bilirubin 1.5 mg/dL, ALT 3009 U/L, Alk P 185 U/L, INR normal] that improved when anakinra was added, with remission in disease and fall of all liver tests into the normal range).

  14. Mertens M, Singh JA. Anakinra for rheumatoid arthritis: a systematic review. J Rheumatol. 2009; 36: 1118-25. PubMed Citation  (Systematic review of literature on efficacy and safety of anakinra in rheumatoid arthritis identified 5 clinical trials involving 2846 patients; the major adverse events were injection site reactions [71% vs 28% with placebo], nonsignificant increase in serious infections, but no mention of liver injury or ALT elevations).

  15. Canna S, Frankovich J, Higgins G, Narkewicz MR, Nash SR, Hollister JR, Soep JB, et al. Acute hepatitis in three patients with systemic juvenile idiopathic arthritis taking interleukin-1 receptor antagonist. Pediatr Rheumatol Online J 2009; 7: 21. PubMed Citation  (Description of 3 patients with systemic juvenile rheumatoid arthritis who developed symptomatic hepatitis 1-8 months after starting anakinra [bilirubin not given, AST ~1200 to 3000 U/L], resolving once anakinra was stopped).

  16. Zhu G, Liu G, Liu Y, Xie Q, Shi G. Liver abnormalities in adult onset Still's disease: a retrospective study of 77 Chinese patients. J Clin Rheumatol 2009; 15: 284-8. PubMed Citation  (Retrospective analysis of clinical features of 77 patients with adult onset Still disease presenting at a single referral center in China reported hepatomegaly in 12%, ALT or AST elevations in 62%, values >5 times ULN in 16% [some on therapy], hepatitis with jaundice in 8%; 2 patients developed acute liver failure and one died, the rest recovered without residual injury).

  17. Furst DE. The risk of infections with biologic therapies for rheumatoid arthritis. Semin Arthritis Rheum 2010; 39: 327-46. PubMed Citation  (Review of the excess risk of infections during biologic therapy of rheumatoid arthritis mentions that infection was 2.1% in treated patients vs 0.4% in controls; infections were primarily pneumonia and skin infections, none were fatal and few were opportunistic).

  18. Mahamid M, Paz K, Reuven M, Safadi R. Hepatotoxicity due to tocilizumab and anakinra in rheumatoid arthritis: two case reports. Int J Gen Med 2011; 4: 657-60. PubMed Citation  (49 year old woman with rheumatoid arthritis and nonalcoholic fatty liver disease developed fatigue and mild serum enzyme elevations 2 months after starting anakinra [bilirubin normal, ALT 50 U/L, Alk P 161 U/L], resolving rapidly upon stopping).

  19. Mahamid M, Mader R, Safadi R. Hepatotoxicity of tocilizumab and anakinra in rheumatoid arthritis: management decisions. Clin Pharmacol 2011; 3:3 9-43. PubMed Citation  (Description of same two patients as in Mahamid [Int J Gen Med 2011]).

  20. Carroll MB. The impact of biologic response modifiers on hepatitis B virus infection. Expert Opin Biol Ther 2011; 11: 533-44. PubMed Citation  (Review of reactivation of hepatitis B by biologic response modifiers; anakinra has not been linked to reactivation of HBV, either in the published literature or in reports to the sponsor).

  21. Lim KB, Schiano TD. Still disease and the liver-an underappreciated association. Gastroenterol Hepatol (N Y) 2011; 7: 844-6. PubMed Citation  (Concise review of liver dysfunction in adult-onset Still's disease which can vary from asymptomatic ALt elevations to acute liver failure and diagnosis of superimposed drug induced liver injury [from anakinra, methotrexate, penicillamine, leflunomide or cyclophosphamide among others] is often difficult).

  22. Nigrovic PA, Mannion M, Prince FH, Zeft A, Rabinovich CE, van Rossum MA, Cortis E, et al. Anakinra as first-line disease-modifying therapy in systemic juvenile idiopathic arthritis: report of forty-six patients from an international multicenter series. Arthritis Rheum 2011; 63: 545-55. PubMed Citation  (Retrospective analysis of 46 patients with juvenile idiopathic arthritis treated with anakinra at 11 referral centers in 4 countries; clinical responses occurred in more than 95% of patients, often within the first month; one 8 year old child developed acute hepatitis [described in Canna 2009] and two other patients had elevations in serum enzymes on treatment, but no details given).

  23. Rubbert-Roth A. Assessing the safety of biologic agents in patients with rheumatoid arthritis. Rheumatology (Oxford) 2012; 51 Suppl 5: v38-47. PubMed Citation  (Overview of safety of biologic agents in rheumatoid arthritis mentions that anakinra has not been associated with reactivation of tuberculosis, and the incidence of malignancies is not increased with its use; no mention of ALT elevations or hepatotoxicity).

  24. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012; 11: 633-52. PubMed Citation  (Review of the biologic actions of IL-1 and the clinical efficacy and safety of agents that block its activity including anakinra [IL-1Ra], canakinumab [monoclonal antibody to IL-1 beta] and rilonacept [recombinant soluble IL-1 receptor]).

  25. Drugs for rheumatoid arthritis. Treat Guidel Med Lett 2012; 10 (117): 37-44. PubMed Citation  (Concise summary on current therapies of rheumatoid arthritis states that anakinra is considered the least effective biologic DMARD and is not recommended).

  26. Miyamae T. Cryopyrin-associated periodic syndromes: diagnosis and management. Paediatr Drugs 2012; 14: 109-17. PubMed Citation  (Review of the clinical features, pathogenesis and therapy of CAPS with specific discussion of anakinra, rilonacept and canakinumab; no mention of hepatotoxicity).

  27. Moran A, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Greenbaum CJ, et al; Type 1 Diabetes TrialNet Canakinumab Study Group; AIDA Study Group. Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials. Lancet 2013; 381 (9881): 1905-15. PubMed Citation  (Two parallel trials comparing anakinra or canakinumab to placebo in 69 patients with recent onset of type 1 diabetes found no evidence of benefit and similar side effects of both drugs; no mention of ALT elevations or hepatotoxicity).

  28. Akgul O, Kilic E, Kilic G, Ozgocmen S. Efficacy and safety of biologic treatments in familial mediterranean Fever. Am J Med Sci 2013; 346: 137-41. PubMed Citation  (Systematic review of reports on biologic response modifiers in familial Mediterranean fever identified no controlled trial, but 24 single reports and 7 case series describing 59 patients, 35 on anti-TNF agents, 29 anakinra, 4 canakinumab; 2 had adverse events that required stopping but the rest seemed to have a beneficial effect; no discussion of hepatotoxicity).

  29. Diallo A, Mekinian A, Boukari L, Mouas H, Zamy M, Nahon P, Gérin M, et al. [Severe hepatitis in a patient with adult-onset Still's disease treated with anakinra]. Rev Med Interne 2013; 34:168-70. French. PubMed Citation  (22 year old woman with adult onset Still disease developed jaundice 3 weeks after starting anakinra which had induced a remission in disease [bilirubin 6.8 mg/dL, ALT 3346 U/L, Alk P 300 U/L], improving promptly when anakinra was stopped: Case 1). 

  30. Aly L, Iking-Konert C, Quaas A, Benten D. Subacute liver failure following anakinra treatment for adult-onset Still disease. J Rheumatol 2013; 40 (10): 1775-7. PubMed Citation  (20 year old man with adult onset Still disease developed fever and jaundice 3 months after starting anakinra and prednisone [bilirubin ~10 mg/dL, ALT ~4000 U/L, INR 2.7], with splenomegaly and ascites, improving upon stopping anakinra and increasing prednisone with eventual resolution 5 months after onset).  

  31. Néel A, Henry B, Barbarot S, Masseau A, Perrin F, Bernier C, Kyndt X, et al. Long-term effectiveness and safety of interleukin-1 receptor antagonist (anakinra) in Schnitzler's syndrome: a French multicenter study. Autoimmun Rev 2014; 13: 1035-41. PubMed Citation  (Among 42 pateints with Schnitzler's syndrome followed in 16 centers in France, 29 were treated with anankinra, all of whom had marked improvements on therapy which were maintained during an average follow up of 3 years; side effects included injection site reactions [17%], neutropenia [10%], infections [21: mostly pneumonia, 2 being fatal] and colon cancer [1 case]; no mention of hepatotoxicity or ALT elevations and no discontinuations for liver related complications),

  32. Ahmed O, Brahmania M, Alsahafi M, Alkhowaiter S, Erb S. Anakinra hepatotoxicity in a patient with adult-onset Still's disease. ACG Case Rep J 2015; 2 (3): 173-4. PubMed Citation  (46 year old woman with adult-onset Still's disease developed ALT elevations 2 weeks after starting anakinra [bilirubin  1.2 mg/dL, ALT 1202 U/L, Alk P not given], with worsening of liver injury one week after restarting anakinra [bilirubin 6.7 mg/dL, ALT 1945 U/L, GGT 696 U/L] which gradually resolved on stopping and did not recur on subsequent therapy with etanercept).

  33. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-1352.e7. PubMed Citation  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, no cases were attributed to anakinra or other interleukin 1 receptor antagonists).

  34. Kullenberg T, Löfqvist M, Leinonen M, Goldbach-Mansky R, Olivecrona H. Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology (Oxford) 2016 May 3. [Epub ahead of print] PubMed Citation  (Among 43 patients with severe cryopryin-associated periodic syndromes [84% <18 years of age] treated with anakinra for up to 5 years, adverse events were common but mostly due to the underlying condition; 14 patients [33%] had a serious adverse event, but none were liver related and there was no mention of ALT elevations or hepatotoxicity).

  35. Taylor SA, Vittorio JM, Martinez M, Fester KA, Lagana SM, Lobritto SJ, Ovchinsky N. Anakinra-induced acute liver failure in an adolescent patient with Still's disease. Pharmacotherapy 2016; 36: e1-4. PubMed Citation  (19 year old man with Still's disease developed serum ALT and AST elevations 16 days after starting high dose methylprednisone and 5 days after starting anakinra [direct bilirubin 1.7 mg/dL, ALT rising from 19 to 2002 U/L, Alk P not given, INR 1.7], biopsy showing acute hepatitis and liver test abnormalities, resolving within 30 days of stopping anakinra and switching iv methylprednisolone to oral prednisone).

 

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OTHER REFERENCE LINKS
Anakinra
  1. PubMed logoRecent References on Anakinra

  2. Clinical Trials logoTrials on Anakinra

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