IPSIndian Journal of Pharmacology
Home  IPS  Feedback Subscribe Top cited articles Login 
Users Online : 2472 
Small font sizeDefault font sizeIncrease font size
Navigate Here
  Search
 
  
Resource Links
 »  Similar in PUBMED
 »  Search Pubmed for
 »  Search in Google Scholar for
 »Related articles
 »  Article in PDF (231 KB)
 »  Citation Manager
 »  Access Statistics
 »  Reader Comments
 »  Email Alert *
 »  Add to My List *
* Registration required (free)

 
In This Article
 »  Abstract
 » Introduction
 » Case Report
 » Discussion
 » Conclusion
 »  References

 Article Access Statistics
    Viewed1538    
    Printed45    
    Emailed1    
    PDF Downloaded118    
    Comments [Add]    
    Cited by others 1    

Recommend this journal

 


 
 Table of Contents    
DRUG WATCH
Year : 2014  |  Volume : 46  |  Issue : 6  |  Page : 649-650
 

Autoimmune hepatitis as an adverse effect of long-term methotrexate therapy


1 Department of Pharmacology, School of Medecine of Sfax, Tunisia
2 Department of Rheumatology, CHU Hedi Chaker Sfax, Tunisia

Date of Submission14-Jun-2014
Date of Decision09-Sep-2014
Date of Acceptance21-Sep-2014
Date of Web Publication18-Nov-2014

Correspondence Address:
Kamilia Ksouda
Department of Pharmacology, School of Medecine of Sfax
Tunisia
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0253-7613.144940

Rights and Permissions

 » Abstract 

Methotrexate (MTX) is one of the most commonly used medicines in the treatment of psoriatic arthritis. The drug can produce steatosis and cirrhosis. Autoimmune hepatitis is a rare and serious adverse effect. We describe the case of a 53-year-old woman who developed autoimmune hepatitis after a long-term use of MTX for psoriatic arthritis. Hepatitis was completely resolved 4 months after stopping this drug. The pathophysiologic mechanisms of a drug-induced autoimmunity are unclear and complex. This report confirms the need to monitor liver enzymes carefully in patients using long-term treatment with MTX for psoriasis or rheumatoid arthritis.


Keywords: Autoimmune hepatitis, drug-induced autoimmunity, methotrexate, psoriatic arthritis


How to cite this article:
Ksouda K, Affes H, Atheymen R, Ezzeddine M, Zeghal K, Hammami S. Autoimmune hepatitis as an adverse effect of long-term methotrexate therapy . Indian J Pharmacol 2014;46:649-50

How to cite this URL:
Ksouda K, Affes H, Atheymen R, Ezzeddine M, Zeghal K, Hammami S. Autoimmune hepatitis as an adverse effect of long-term methotrexate therapy . Indian J Pharmacol [serial online] 2014 [cited 2019 Aug 17];46:649-50. Available from: http://www.ijp-online.com/text.asp?2014/46/6/649/144940



 » Introduction Top


Methotrexate (MTX) is a folic acid antagonist with antiproliferative and antiinflammatory properties. It is one of the most commonly used medicines in the treatment of rheumatoid arthritis or psoriatic arthritis. [1],[2] Potential liver toxicity of MTX is characterized by hepatic fibrosis. Autoimmune hepatitis is a rare and serious adverse-effect. It is idiosyncratic and is classified as type B adverse drug reaction. [3] We report the case of an adult woman with psoriatic arthritis who developed acute severe hepatitis following long-term treatment with MTX.


 » Case Report Top


A 53-year-old woman was diagnosed with psoriatic arthritis in the year 2000. She received 15 mg MTX weekly, with a satisfactory clinical response. The periodic biological monitoring of liver enzymes: Alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), gamma-glutamyl transpeptidase (gamma-GT) performed every 6 months did not reveal any abnormalities. MTX was stopped in the year 2005 due to remission of the disease. In 2009, it was reintroduced at a dose of 15 mg/week due to decompensation of the disease. Monitoring of liver enzymes performed every 6 months showed an elevation <2 times the normal levels on average of ASAT and ALAT since 2010. Assessing the risk-benefit ratio and given the severe decompensation of the disease, MTX was continued. In May 2013, patient presented with jaundice following the development of asthenia and weight loss. Laboratory investigation showed the following results: Prothrombin time (71%), ASAT 580 U/L, ALAT 620 U/L, serum gamma-GT 146 IU/L, serum alkaline phosphatase 170 IU/L and total serum bilirubin 12 mg/dl. Antimitochondrial antibodies (titer >1/40) and antinuclear antibodies (titer of 1/640) were detected in serum. Serum gamma-globulin was 16.9 g/L, serum albumin was 34.9 g/L and IgG was 16.6 g/L. Routine laboratory investigations for infection with hepatitis A, B, and C viruses and serology for cytomegalovirus and Epstein-Barr virus were negative. Abdominal ultrasound detected no anomalies. Patient denied ingestion of any herbal medicines or drugs other than MTX.

Methotrexate was stopped, and therapy with oral methylprednisolone (80 mg/day) was initiated. A significant improvement in the following parameters was observed a week later: Prothrombin time (88%), ASAT 270 U/L, ALAT 340 U/L, S. gamma-GT 122 IU/L, and S. alkaline phosphatase 173 IU/L. After 4 months, all laboratory parameters had normalized, and serum was negative for antimitochondrial and antinuclear antibodies. Methylprednisolone was gradually withdrawn after 5 months of treatment.


 » Discussion Top


Patients taking MTX are more likely to discontinue therapy because of adverse drug effects rather than because of lack of efficacy. Adverse effects of MTX are, usually, mild and self-limiting, but may include serious adverse drug reactions such as hematopoietic suppression, pulmonary, and hepatotoxicity. [4]

Hepatic fibrosis is a usual adverse reaction reported with long-term use of MTX therapy in psoriatic patients. However, severe hepatic damage may occur unexpectedly. [2]

Causality assessment of the adverse drug event (ADE) was carried out using WHO-UMC criteria, [5] Naranjo's Scale, [6] and Roussel Uclaf Causality Assessment Method (RUCAM) scale. [7] In this case, patient improved on withdrawal of the drug, and there were no other confounding factors that could have caused this adverse effect. Hence, the ADE was probably caused by MTX (WHO-UMC criteria: Probable; Naranjo's Score: 7, probable; and RUCAM scale: 5).

In addition, sufficient and continuous exposure to the drug, lack of previous evidence of autoimmune disease and complete resolution of the condition within 4 months of discontinuation of the suspected drug confirmed the diagnostic criteria of drug-induced autoimmunity. [3]

The first case of autoimmune hepatitis associated with MTX was described in 2011 in a 57-year-old man after 11 years of treatment with MTX. The case was confirmed by liver biopsy. A complete normalization of laboratory parameters was obtained 5 months after stopping this drug. [8] To the best of our knowledge, this is the second case of autoimmune hepatitis reported with MTX.

The pathophysiologic mechanisms of drug-induced autoimmunity are unclear and complex. Production of autoantibodies may result from a loss of tolerance to self-antigens. This drug reaction may involve genetic, epigenetic and environmental factors. [8] It, usually, occurs at higher doses and also positively correlates with the cumulative dose of drugs. [3],[8] Other risk factors for the development of elevated liver enzymes and changes in liver biopsy include obesity, higher alcohol intake prior to commencement of MTX and persistent hepatitis B or C infection. [4] In the present case, patient was obese with a body mass index of 30.

Appearance of autoantibodies and transitory autoimmune disease associated with infliximab in a patient with psoriatic arthritis has also been documented and the preexistent serological signs of autoimmunity are believed to be a risk factor for the development of similar autoimmune reactions. [9]


 » Conclusion Top


This report confirms the need to monitor liver enzymes carefully in patients with psoriatic arthritis using long-term treatment with MTX. Clinicians must collaborate with the pharmacovigilance center to detect and notify serious adverse effects of MTX. Further research is needed to identify the exact mechanism and establish, if possible, primary means of prevention of this serious adverse effect.

 
 » References Top

1.
Alves JA, Fialho SC, Morato EF, Castro GR, Zimmermann AF, Ribeiro GG, et al. Liver toxicity is rare in rheumatoid arthritis patients using combination therapy with leflunomide and methotrexate. Rev Bras Reumatol 2011;51:141-4.  Back to cited text no. 1
    
2.
van Swelm RP, Laarakkers CM, Kooijmans-Otero M, de Jong EM, Masereeuw R, Russel FG. Biomarkers for methotrexate-induced liver injury: Urinary protein profiling of psoriasis patients. Toxicol Lett 2013;221:219-24.  Back to cited text no. 2
    
3.
Xiao X, Chang C. Diagnosis and classification of drug-induced autoimmunity (DIA). J Autoimmun 2014;48-49:66-72.  Back to cited text no. 3
    
4.
Stamp L, Roberts R, Kennedy M, Barclay M, O'Donnell J, Chapman P. The use of low dose methotrexate in rheumatoid arthritis - Are we entering a new era of therapeutic drug monitoring and pharmacogenomics? Biomed Pharmacother 2006;60:678-87.  Back to cited text no. 4
    
5.
The use of the WHO-UMC system for standardized case causality assessment [monograph on the Internet]. Uppsala: The Uppsala Monitoring Centre; 2005. Available from: Http://www.who-umc.org/Graphics/24734.pdf. [Last accessed on 2011 May 06].  Back to cited text no. 5
    
6.
Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 6
    
7.
Danan G, Benichou C. Causality assessment of adverse reactions to drugs - I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries. J Clin Epidemiol 1993;46:1323-30.  Back to cited text no. 7
    
8.
Moreno-Otero R, García-Buey L, García-Sanchez A, Trapero-Marugán M. Autoimmune hepatitis after long-term methotrexate therapy for rheumatoid arthritis. Curr Drug Saf 2011;6:197-200.  Back to cited text no. 8
    
9.
Germano V, Picchianti Diamanti A, Baccano G, Natale E, Onetti Muda A, Priori R, et al. Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis. Ann Rheum Dis 2005;64:1519-20.  Back to cited text no. 9
    



This article has been cited by
1 Methotrexate
Reactions Weekly. 2015; 1533(1): 306
[Pubmed] | [DOI]



 

Top
Print this article  Email this article
 

    

Site Map | Home | Contact Us | Feedback | Copyright and Disclaimer
Online since 20th July '04
Published by Wolters Kluwer - Medknow