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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Natalizumab

Last Update: April 15, 2020.

OVERVIEW

Introduction

Natalizumab is a monoclonal antibody to human alpha-4 integrin which has potent immune suppressive activity and is used in the therapy of severe inflammatory bowel disease and relapsing multiple sclerosis. Natalizumab has been linked to rare instances of idiosyncratic acute liver injury that has features of autoimmunity and seen largely in patients being treated for multiple sclerosis.

Background

Natalizumab (na" ta liz' ue mab) is a humanized monoclonal antibody to alpha-4 integrin, which binds avidly to the cellular adhesion molecule found on leukocytes blocking their ability to migrate to inflammatory foci. Inhibition of alpha-4 integrin activity leads to modulation of inflammatory pathways that are activated in autoimmune disorders. Natalizumab was shown to improve vision and motor function in patients with multiple sclerosis and to decrease inflammation, symptoms and relapses in patients with Crohn disease. Natalizumab was approved for use in the United States in 2005 and indications included severe Crohn disease and relapsing multiple sclerosis. However, after its general availability, natalizumab was linked to several instances of progressive multifocal leukoencephalopathy (PML), a severe neurological condition which is believed to be due to reactivation of the JC virus in neural cells. Because of this severe complication (which is often fatal), natalizumab has been restricted in use and is available only by a special program that requires thorough assessment of risks and careful monitoring and reporting. Natalizumab is available in 15 mL vials of 300 mg under the brand name Tysabri. The recommended dose is 300 mg intravenously every 4 weeks. Common side effects include headache, fatigue and infusion reactions. Natalizumab is also capable of causing immune suppression, resulting in an increased susceptibility to severe viral and bacterial infections as well as immune reconstitution reactions when it is withdrawn.

Hepatotoxicity

In large clinical trials, serum aminotransferase elevations occurred in an average of 5% of patients on natalizumab therapy and in a slightly lower, although similar proportion (~3%) of those who received placebo. While there were no individual case reports of liver injury attributed to natalizumab therapy, at least 59 instances of hepatic injury were reported to the Adverse Event Reporting System maintained by the FDA within 4 years of its initial approval. In a report summarizing six clinically apparent cases of liver injury attributable to natalizumab, all were associated with jaundice and all occurred in patients receiving natalizumab for multiple sclerosis. The onset of injury followed the initial infusion of natalizumab in 4 patients, and after 5 and 12 courses of treatment in the other two reported cases. The pattern of liver injury was hepatocellular in 5 cases and cholestatic in one. Several cases were accompanied by autoantibodies and were treated with corticosteroids (Case 1), but autoimmune features were not prominent and immunoallergic features (fever, rash, eosinophilia) were not reported. The clinical cases were moderate in severity and no patient developed acute liver failure or progressed to chronic liver injury or vanishing bile duct syndrome. Since that initial summary, several more case reports of clinically apparent liver injury attributable to natalizumab have appeared, many of which have features of autoimmunity and almost all arising in patients with multiple sclerosis. Natalizumab can cause immune suppression and has been linked to bacterial and viral infections, but interestingly has not been reported to cause reactivation of tuberculosis or hepatitis B.

Likelihood score: B (likely cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of liver injury caused by natalizumab is probably immunologically mediated, perhaps as a result of its effects on leukocyte function. It is a monoclonal antibody and like other proteins it is taken up by cells by endocytosis and is metabolized into amino acids.

Outcome and Management

The hepatotoxicity of natalizumab is usually moderate in severity and reversible with discontinuation of infusions. Recurrence of injury with a shorter latency and more severe course has been reported. In cases with persistent injury, the addition of prednisone has appeared to hasten recovery, but in most instances, corticosteroid therapy can ultimately be discontinued. There is little information about cross sensitivity to liver injury with other monoclonal antibodies or immune modulating agents, but in most instances other disease modifying agents have been tolerated without recurrence of injury, although many of these are capable of causing liver injury on their own.

Drug Class: Gastrointestinal Agents, Inflammatory Bowel Disease Agents; Monoclonal Antibodies, Multiple Sclerosis Agents

CASE REPORT

Case 1. Acute hepatocellular injury due to natalizumab.(1)

A 43 year old man with multiple sclerosis developed fatigue, fever and back pain 8 days after the fifth monthly dose of natalizumab. On hospital admission, he was found to have elevations in serum enzymes but was not jaundiced. Serum ALT was 410 U/L, AST 134 U/L, INR 1.17 and bilirubin 0.4 mg/dL. Over the next several days, his liver tests worsened, serum bilirubin peaking at 3.0 mg/dL. A liver biopsy showed acute lobular and portal hepatitis with mild fibrosis. Recovery was slow and prednisone was given. Natalizumab was not continued. Over the next 6 months liver tests returned to normal, whereupon natalizumab was restarted. After the second monthly infusion, however, he redeveloped fatigue and jaundice and liver tests were again abnormal: ALT 3494 U/L, AST 1259 U/L and bilirubin 13.4 mg/dL. The antinuclear antibody, which was negative during the first episode, was positive in titers >1:320. Natalizumab was again stopped and prednisone was given with subsequent improvement.

Key Points

Medication:Natalizumab (300 mg infusions monthly for 5 months)
Pattern:Hepatocellular (R=21.5)
Severity:3+ (jaundice, hospitalization)
Latency:11 days after 5th monthly infusion initially; shortly after second monthly infusion on rechallenge 6 months later
Recovery:6 months initially, unknown upon rechallenge
Other medications:Spirulina (food supplement), multivitamins, prednisone

Comment

This patient developed clinically apparent acute hepatocellular injury within 2 weeks of receiving his fifth monthly infusion of natalizumab for relapsing multiple sclerosis. The injury was moderate in severity, but slow to resolve. Liver histological features suggested an element of autoimmunity, and he was treated with prednisone but tolerated its withdrawal and had normal liver tests six months later. Upon reexposure, he redeveloped the liver injury with a shorter latency and with a more severe course. At this point, he was found to have high titers of ANA and prednisone was restarted. Although compatible with spontaneous autoimmune hepatitis (which has been reported in patients with multiple sclerosis), the timing of onset and recurrence of similar injury upon reexposure is reasonably convincing evidence that it was due to natalizumab, perhaps an autoimmune hepatitis that was triggered by the immunomodulatory therapy. This example was case 2 from the six case series reported by the FDA, which were based upon review of spontaneous adverse event reports during the first 4 years of general availability of natalizumab. The six cases were selected as the clinically apparent examples among a total of 59 separate reports of liver injury. The authors estimated the frequency of idiosyncratic clinically apparent liver injury from natalizumab to be 17 per 100,000 exposed patients. Events occurring at this low rate are unlikely to be detected in premarketing studies. Interestingly, virtually all of the published cases of natalizumab-hepatotoxicity have occurred in patients with multiple sclerosis, an autoimmune condition in which spontaneous autoimmune hepatitis is not infrequent.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Natalizumab – Tysabri®

DRUG CLASS

Gastrointestinal Agents; Multiple Sclerosis Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Natalizumab189261-10-7Monoclonal AntibodyNot Available

CITED REFERENCE

1.
Bezabeh S, Flowers CM, Kortepeter C, Avigan M. Clinically significant liver injury in patients treated with natalizumab. Aliment Pharmacol Ther. 2010;31:1028–35. [PubMed: 20163378]

ANNOTATED BIBLIOGRAPHY

References updated: 15 April 2020

Abbreviations: TNF, tumor necrosis factor; PML, progressive multifocal leukoencephalopathy.

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    (Expert review of hepatotoxicity published in 1999, well before the availability of most antibody therapies).
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  • MacNaughton WK, Sharkey KA. Pharmacotherapy of inflammatory bowel disease. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 945-54.
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    (Randomized controlled trial of natalizumab in 30 patients with mild-to-moderate Crohn's disease found no difference in side effects compared to placebo; no mention of ALT elevations or hepatotoxicity).
  • Miller DH, Khan OA, Sheremata WA, Blumhardt LD, Rice GP, Libonati MA, Willmer-Hulme AJ, et al. International Natalizumab Multiple Sclerosis Trial Group. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2003;348:15–23. [PubMed: 12510038]
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  • Bezabeh S, Flowers CM, Kortepeter C, Avigan M. Clinically significant liver injury in patients treated with natalizumab. Aliment Pharmacol Ther. 2010;31:1028–35. [PubMed: 20163378]
    (Summary of 6 clinically apparent hepatic adverse events reported to the FDA over a 4 year period included 1 man and 5 women, ages 26 to 59 years, all with multiple sclerosis, injury arising after the first to 11th dose [bilirubin 4.5 to 16.1 mg/dL, ALT 753-3494 U/L, Alk P 46-1043 U/L], all resolving, all were icteric and symptomatic and 5 were hepatocellular; 3 had autoantibodies but immune features were not prominent: Case 1).
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    (51 year old woman with multiple sclerosis on long term natalizumab [32 months] developed jaundice [bilirubin 3.4 mg/dL, ALT 1324 U/L, ALT 255 U/L] and responded to prednisone).
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    (Among 1094 patients with multiple sclerosis formerly enrolled in clinical trials of natalizumab and continued on therapy [300 mg every 4 weeks] for up to 5 years, 171 [16%] had at least one serious adverse event including 7 listed as "hepatobiliary" [without specific details] and 8 confirmed cases of PML).
  • Butzkueven H, Kappos L, Pellegrini F, Trojano M, Wiendl H, Patel RN, Zhang A, et al. TYSABRI Observational Program (TOP) Investigators. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. J Neurol Neurosurg Psychiatry. 2014;85:1190–7. [PMC free article: PMC4215289] [PubMed: 24532785]
    (Among 4821 patients with multiple sclerosis being treated with natalizumab enrolled in a prospective observational program, 3599 continued on treatment, among whom there were 465 serious adverse events including 7 were abnormal liver tests [0.1% yearly], 18 cases of PML [0.4%] and 9 deaths, but none due to liver disease).
  • Hillen ME, Cook SD, Samanta A, Grant E, Quinless J, Rajasingham J. Fatal acute liver failure with hepatitis B virus infection during natalizumab treatment in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2015; 2: e72. Erratum in Neurol Neuroimmunol Neuroinflamm. 2015;2:e97. [PMC free article: PMC4335813] [PubMed: 25815364]
    (28 year old woman with multiple sclerosis on long term natalizumab [22 months] developed acute hepatitis B [bilirubin 1.0 mg/dL, ALT 1564 U/L, Alk P 70 U/L, HBsAg positive, IgM anti-HBc positive] that progressed to acute liver failure and death).
  • Antezana A, Sigal S, Herbert J, Kister I. Natalizumab-induced hepatic injury: A case report and review of literature. Mult Scler Relat Disord. 2015;4:495–8. [PubMed: 26590653]
    (26 year old woman with multiple sclerosis developed abnormal liver tests 2 weeks after a 2nd monthly infusion of natalizumab [bilirubin 24.9 mg/dL, ALT 856 U/L, Alk P 165 U/L] with slow but eventual recovery after stopping; review of literature identified 12 cases of acute liver injury due to natalizumab, half of which were “autoimmune” in character).
  • Drugs for multiple sclerosis. Med Lett Drugs Ther. 2016;58(1496):71–4. [PubMed: 27249095]
    (Concise review of the mechanism of action, clinical efficacy, safety, costs and relative role of the medications approved for use in multiple sclerosis mentions that beta interferon and natalizumab can cause clinically apparent liver injury and that fingolimod and teriflunomide are associated with frequent serum enzyme elevations).
  • Clerico M, Artusi CA, Di Liberto A, Rolla S, Bardina V, Barbero P, De Mercanti SF, et al. Long-term safety evaluation of natalizumab for the treatment of multiple sclerosis. Expert Opin Drug Saf. 2017;16:963–72. [PubMed: 28641055]
    (Review of the literature and adverse event databases identified 12 case reports of significant liver injury attributed to natalizumab and spontaneous reports of 22 cases of liver failure to the FDA).
  • Van Obberghen EK, Cohen M, Rocher F, Lebrun-Frenay C. Multiple immune disorders after natalizumab discontinuation: After the CIRIS, the SIRIS? Rev Neurol (Paris). 2017;173:222–4. [PubMed: 28372806]
    (35 year old woman with multiple sclerosis stopped natalizumab therapy because of pregnancy and developed rash, diabetes, hypothyroidism and abnormal liver tests [values not given] most, but not all, of which resolved after delivery and restarting natalizumab, suggesting that the abnormalities were due to natalizumab withdrawal and reconstitution autoimmunity).
  • Kaufmann M, Haase R, Proschmann U, Ziemssen T, Akgün K. Real-world lab data in natalizumab treated multiple sclerosis patients up to 6 years long-term follow up. Front Neurol. 2018;9:1071. [PMC free article: PMC6292961] [PubMed: 30581413]
    (Results of routine laboratory results taken every 3 months for up to 6 years during natalizumab therapy in 120 patients with multiple sclerosis demonstrated that ALT and AST elevations were rare and usually mild; only one ALT value was above 3 times ULN, which was normal on retesting despite drug continuation).
  • Butzkueven H, Kappos L, Wiendl H, Trojano M, Spelman T, Chang I, Kasliwal R, et al. Tysabri Observational Program (TOP) Investigators. Long-term safety and effectiveness of natalizumab treatment in clinical practice: 10 years of real-world data from the Tysabri Observational Program (TOP). J Neurol Neurosurg Psychiatry. 2020 Mar 31; [Epub ahead of print] [PMC free article: PMC7279201] [PubMed: 32234967]
    (A long term observational study enrolled 6148 patients from 17 countries with multiple sclerosis as they started natalizumab with follow up for up to 11 years [median=5.2 years]; 829 patients [13.5%] had at least one serious adverse event including PML in 53 [0.9%], malignancy in 66 [1.1%] and hepatic events in 12 [0.2%] described as drug induced liver injury in 4, autoimmune hepatitis in 2 and acute liver failure, fulminant hepatitis, hepatitis and liver injury in 1 each: no specific details given).

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