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DRUG RECORD

 

METHOTREXATE

OVERVIEW
Methotrexate

 

Introduction

Methotrexate is an antineoplastic and immunosuppressive agent widely used in the therapy of leukemia, lymphoma, solid tumors, psoriasis and rheumatoid arthritis.  When given in high intravenous doses, methotrexate can cause acute elevations in serum enzymes, and long term methotrexate therapy has been associated with frequent but mild elevations in serum liver enzymes and, more importantly, with development of chronic liver injury, progressive fibrosis, cirrhosis and portal hypertension.

 

Background

Methotrexate (meth" oh trex' ate) is an antifolate and antimetabolite that is used extensively in the therapy of leukemia, lymphoma and several solid organ tumors.  It also has potent activity against psoriasis and has immunomodulatory activity against inflammatory bowel disease and the inflammatory arthritidies.  Methotrexate is considered a disease modifying antirheumatic drug (DMARD) and used widely in rheumatoid arthritis and other autoimmune diseases.  Methotrexate acts by inhibition of folate metabolism, blocking dihydrofolic acid reductase, thereby inhibiting synthesis of purines and pyrimidines and decreasing DNA and RNA synthesis.  Recent results suggest that methotrexate also leads to increase and release of adenosine, which may mediate its immunosuppressive activity.  Folic acid antagonists (aminopterin) were developed in the late 1940s and introduced into clinical medicine shortly thereafter.  Aminopterin was later replaced by methotrexate because of its better tolerance and lower rate of toxicity.  Methotrexate was approved for use in cancer in the United States in 1955, for psoriasis in 1972 and rheumatoid arthritis in 1988 and is still widely used for these indications.  Methotrexate is available in generic forms and under the brand names of Rheumatrex and Trexall in tablets of 2.5, 5, 7.5, 10 and 15 mg, and in both powdered and liquid-for-injection forms in vials of various strengths for intravenous, intramuscular or intrathecal injection.  The dose regimen varies by indication; high, short term doses being used in treatment of cancer and chronic, lower doses for autoimmune conditions.  The typical maintenance dose used to treat psoriasis and rheumatoid arthritis is 7.5 to 25 mg once weekly either orally or by injection.  Side effects are mostly dose related and include stomatitis, oral ulcers, hair loss, fatigue, headache, gastrointestinal upset, nausea, diarrhea and bone marrow suppression.

 

Hepatotoxicity

Methotrexate is well known to cause serum aminotransferase elevations and long  term therapy has been linked to development of fatty liver disease, fibrosis and even cirrhosis.  The literature on methotrexate is extensive, but with great variability in rates of liver test and biopsy abnormalities at different doses, dose regimens and durations of therapy.

With high dose intravenous methotrexate, serum ALT levels can rise to 10 to 20 times the upper limit of normal (ULN) within 12 to 48 hours, but levels then fall rapidly to normal with only rare instances of jaundice or symptoms of liver injury.  With long term, low-to-moderate dose methotrexate therapy, elevations in serum ALT or AST values occur in 15 to 50% of patients, but are usually mild and self-limiting.  Approximately 5% of patients have elevations greater than twice normal and these abnormalities resolve rapidly with discontinuation or dose modification, but can resolve even with continuation at the same dose level.  The reported rate of ALT elevations during therapy has varied considerably, perhaps because of differences in frequency of determinations (every month vs every 3, 6 or 12 months) and due to the timing of the blood sampling (whether just before or soon after the once weekly dose).  Finally, coadministration of folic acid has been shown to decrease the frequency of serum enzyme elevations and now is commonly used.

Long term therapy with methotrexate has been associated with development of fatty liver and hepatic fibrosis and, in rare instances, portal hypertension and symptomatic cirrhosis.  Symptoms are usually absent until cirrhosis is present, and liver tests are typically normal or minimally and transiently elevated.  Routine monitoring of patients with regular liver biopsies done at 1 to 2 year intervals or with cumulative methotrexate doses of 1 to 10 grams demonstrates that approximately 30% of patients develop mild-to-moderate histological abnormalities (fat, cellular unrest, mild inflammation, nuclear atypical) and 2 to 20% of patients develop some degree of hepatic fibrosis.  Well documented cases of cirrhosis arising during long term methotrexate therapy have been reported, but cirrhosis is rare in prospective series, even with routine histological monitoring.  Patients who develop fibrosis on long term methotrexate therapy often have other risk factors for fatty liver disease, including excessive alcohol use, obesity, diabetes and concurrent administration of other potentially hepatotoxic agents.  Use of high doses and daily methotrexate dosing is particularly associated with development of hepatic fibrosis and rates of cirrhosis of greater than 20% after 5 to 10 years of treatment.  With more modern dose regimens (5 to 15 mg in one dose weekly with folate supplementation), fibrosis and clinically apparent liver disease are rare even with long term use.  The hepatic fibrosis and cirrhosis due to methotrexate typically arise after 2 to 10 years of treatment and can present with ascites, variceal hemorrhage or hepatosplenomegaly.  Some patients present with signs and symptoms of portal hypertension, yet have only moderate degrees of fibrosis, suggesting that methotrexate may also cause nodular regeneration.  Patients who develop portal hypertension and cirrhosis usually have had minimal or no elevations in serum aminotransferase or alkaline phosphatase levels, and monitoring using serum enzymes appears to be poorly predictive of fibrosis development.  Noninvasive markers of hepatic fibrosis, such as serial platelet counts, serum procollagen III aminoterminal peptide (PIIIP), serum bile acids, hepatic ultrasound, advanced imaging techniques and transient elastography may be more efficient in screening for fibrosis in patients on long term methotrexate, but the reliability and accuracy of these approaches has not been documented prospectively.  Patients with cirrhosis due to methotrexate are often asymptomatic and the condition tends to be non progressive, even in those who restart low dose therapy.  Rare instances of hepatocellular carcinoma have been reported in patients with suspected methotrexate induced cirrhosis.

Low dose, long term methotrexate therapy has also been implicated in rare instances of reactivation of hepatitis B in patients with rheumatoid arthritis or psoriasis who were HBsAg carriers, without HBeAg and with normal ALT levels and no detectable or low levels of HBV DNA before starting methotrexate.  The frequency of reactivation with methotrexate is unknown, but is probably low.  Reactivation typically presents after years of therapy with methotrexate and most published cases were also receiving corticosteroids.  The clinical presentation is characterized by insidious onset of fatigue, nausea and jaundice accompanied by marked elevations in serum ALT levels and, in some instances, progressive and severe liver injury and liver failure. In some instances, reactivation occurred when methotrexate was withdrawn.  Reactivation has also been described in patients with antibodies to HBV without HBsAg (reverse seroconversion) treated with methotrexate and prednisone.  The cases of reactivation of hepatitis B published in the literature have mostly resulted in death or emergency liver transplantation, perhaps reflecting publication bias for more severe cases.  These cases have led to recommendations for routine screening for HBsAg before starting long term methotrexate therapy and prophylaxis with antiviral agents or careful monitoring for rises in HBV DNA levels if methotrexate is used.  However, whether methotrexate on its own, without prednisone, can cause reactivation of hepatitis B is not clear.

 

Mechanism of Injury

The mechanism of liver injury with methotrexate is believed to be direct toxicity, though inhibition of RNA and DNA synthesis in the liver and producing cellular arrest.  Methotrexate therapy has been shown to increase hepatic stellate cell numbers, but the mechanism by which fibrosis is induced has not been clearly elucidated.  Concurrent therapy with folate has been shown to reduce the rate of serum enzyme elevations during low dose methotrexate therapy.

 

Outcome and Management

Methotrexate can lead to serious liver disease, portal hypertension, fibrosis and cirrhosis, usually with long term use particularly when given in daily regimens and in higher doses.  Various guidelines have been developed and refined for monitoring of patients with psoriasis or rheumatic disorders during long term methotrexate use, although the effectiveness and necessity of these approaches are often debated.  At present, both the American Academy of Dermatology and the American College of Rheumatology recommend careful evaluation of patients before initiating methotrexate therapy for evidence of liver disease and risk factors for developing fatty liver.  While a pretreatment liver biopsy is no longer recommended for all patients, a biopsy is recommended in patients with any evidence of liver disease or significant risk factor (excessive alcohol use, chronic viral hepatitis, elevations in serum enzymes, and in selected patients with diabetes and obesity).  Patients should be told to avoid alcohol use, and abstinence is often recommended.  Concurrent administration of folic acid (~1 mg daily) has been shown to decrease the rate of liver test abnormalities on therapy without apparently affecting the efficacy of methotrexate.  On-treatment monitoring of serum aminotransferase levels is recommended on a monthly basis for at least 6 months and then every 3 months, with more intensive monitoring and withdrawal of therapy if aminotransferase levels rise and stay above 3 times the ULN.  Routine liver biopsy after a cumulative dose of 1, 3 and 8 grams of methotrexate is considered prudent, but guidelines from different societies vary on this issue.  Alternatively, monthly aminotransferase levels can be monitored and patients with raised values at least 50% of the time might be candidates for surveillance liver biopsy.  A system for grading of liver biopsies has been developed and widely used (Roenigk Scale).  Patients with Roenigk IIIb (advanced fibrosis) or IV (cirrhosis) are advised to stop therapy.  With improvement in noninvasive tests for liver fibrosis, recommendations for surveillance liver biopsies will undoubtedly be relaxed.  There does not appear to be cross reactivity in hepatic side effects between methotrexate and other disease modifying antirheumatic drugs (DMARDs) such as leflunomide, hydroxychloroquine, azathioprine, etanercept, or infliximab.

 

Drug Class:  Antineoplastic Agents; Antirheumatic Agents

 

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CASE REPORT
Methotrexate

 

Case 1.  Cirrhosis and ascites after long term therapy with methotrexate.
[Modified from:  Clegg DO, Furst DE, Tolman KG, Pogue R. Acute, reversible hepatic failure associated with methotrexate treatment of rheumatoid arthritis. J Rheumatol 1989; 16: 1123-6. PubMed Citation: Patient 1]


A 38 year old woman with rheumatoid arthritis who had been treated with prednisone, d-penicillamine and gold was switched to methotrexate (7.5 mg/week) and salicylate (3.9 g/day) because of poor response to the other agents.  Her serum enzymes and bilirubin levels were normal and serum albumin 3.7 g/dL.  Her arthritis symptoms improved on methotrexate therapy, and the dose was raised to 15 mg/week.  After two years of methotrexate therapy, she underwent a routine surveillance liver biopsy which showed changes of steatosis and mild portal inflammation (Roenigk grade 1).  Serum AST and alkaline phosphatase were still normal, but albumin levels had decreased to 3.2 g/dL.  One year later, a repeat surveillance liver biopsy showed mild fibrosis and steatosis (Roenigk grade IIIA).  A third liver biopsy done after 4 years of therapy (total dose 2.2 g) again showed moderate activity, steatosis and mild fibrosis.  Serum aminotransferase and alkaline phosphatase levels were normal.  One year later (year 5 of therapy), she presented with weight gain, peripheral edema and ascites.  Serum ALT was 17 U/L, AST 35 U/L, bilirubin 0.2 mg/dL, albumin 2.4 g/dL and prothrombin time 18.4 seconds.  She denied alcohol use or previous history of liver disease or exposures to viral hepatitis.  Tests for hepatitis A and B were negative as were routine autoantibodies.  A liver biopsy showed bridging fibrosis and moderate inflammation (Roenigk grade IIIB), but not frank cirrhosis.  Methotrexate and salicylate were stopped and she improved clinically with resolution of the peripheral edema and ascites.  Serum albumin levels rose and prothrombin time fell into the normal range.  She was later maintained on salicylate alone.


Key Points

Medication:Methotrexate (15 mg/week) for 5 years
Pattern: Undefined (minimal or no serum enzyme elevation)
Severity: 4+ (ascites)
Latency: 5 years
Recovery:Clinical improvements over the ensuing 4-6 months
Other medications:Salicylate 3.9 g/day, prednisone 7.5 mg/day

Comment

Long term, low dose methotrexate is associated with insidious development of hepatic fibrosis in at least 5% of patients, which in some instances leads to cirrhosis and liver decompensation.  The absence of serum enzyme elevations accompanying this progressive fibrosis makes it difficult to monitor patients short of performing routine surveillance liver biopsies at 1 to 2 year intervals.  As shown in this example, even surveillance liver biopsies may not adequately reflect the severity of the liver injury and allow for stopping therapy before onset of serious fibrosis.  Somewhat typical of fibrotic liver injury caused by methotrexate was the lack of accompanying clinical symptoms and the clinical improvement that occurred when methotrexate was stopped.  The fact that the liver biopsy did not show frank cirrhosis, suggests that the portal hypertension may have been due in part to nodular regeneration.  Salicylates decrease renal elimination of methotrexate and displace methotrexate from protein binding, and thus may increase the likelihood of toxicity.

 

Case 2.  Cirrhosis after long-term therapy with methotrexate.
[Modified from:  Weinblatt ME, Dixon JA, Falchuk KR. Serious liver disease in a patient receiving methotrexate and leflunomide. Arthritis Rheum 2000; 43: 2609-11. PubMed Citation]


A 51 year old man with active rheumatoid arthritis was treated with methotrexate at an initial dose of 7.5 mg weekly, increasing to 15 mg weekly with daily folic acid and low doses of prednisone (5 mg daily) for four years with only partial control of his arthritis.  He was then enrolled in an open label trial of the combination of methotrexate and leflunomide (10 mg/day).  He had significant improvement and continued on both drugs for a total of 3.5 years.  During the first year of therapy, he had minor and transient serum ALT elevations, but none were more than 3 times the upper limit of normal (ULN) (Table).  Six months into combination therapy, however, his platelet count began to fall, and it remained low despite a decrease in the dose of methotrexate to 5 mg weekly.  After 3.5 years of combination therapy, an abdominal ultrasound showed mild hepatomegaly, splenomegaly with increased echogenicity of the liver suggestive of fatty infiltration.  He denied alcohol use and any history or risk factors for liver disease.  He had been treated with methotrexate for 7.5 years and received a cumulative dose of 4.5 g.  Tests for hepatitis A, B and C were negative as were routine autoantibody tests.  Liver tests including serum aminotransferase levels, alkaline phosphatase, bilirubin and albumin were normal and prothrombin time was not increased.  A percutaneous liver biopsy showed marked fibrosis, early cirrhosis, mild steatosis and nuclear variability without inflammation or obvious necrosis.

 

Key Points

Medication:Methotrexate (5-15 mg/week) for 7.5 years (total dose 4.5 g)
Pattern: Undefined (no serum enzyme elevation)
Severity: 4+ (cirrhosis)
Latency: ~5 years
Recovery:Not mentioned
Other medications:Leflunomide (10 mg/day for 3 years), folic acid, prednisone (5 mg/day)

Laboratory Values

Years After Starting ALT (U/L) Alk P (U/L) Platelets  (per μL) Other
4.0 38 101 181,000 Leflunomide started
4.2 39 119 206,000
4.4 57 111 150,000
4.6 28 105 129,000
4.8 27 111 109,000
5.0 38 106 105,000 Methotrexate dose reduced
5.5 37 117 98,000
6.0 32 107 103,000
6.5 28 101 96,000
7.0 73 109 92,000 Bilirubin and albumin normal
7.5 21 115 148,000 Liver biopsy
Normal <44 <111 >160,000

Comment

This case demonstrates how significant hepatic fibrosis and portal hypertension can arise during methotrexate therapy without accompanying symptoms or significant elevations in serum aminotransferase levels.  Also characteristic was the mild and nonprogressive nature of the cirrhosis despite continuation of methotrexate.  A possible noninvasive marker for the development of significant fibrosis in this case was the decrease in platelet count, which fell from 181,000/μL at baseline to 105,000 μ/L one year later–a 47% decline and a “platelet slope” of -74,000/year.  In analyses of serial platelet count determinations in patients who developed portal hypertension, a platelet slope of -9,000/year was found to be indicative of the development of portal hypertension and hepatic dysfunction.  Whether leflunomide contributed to the toxicity of methotrexate is not clear, but the findings are compatible with the duration and total dose of methotrexate received.  The patient did not have typical risk factors for developing methotrexate related fibrosis such as excessive alcohol use, underlying viral hepatitis, renal insufficiency or diabetes (no mention is made of body weight or presence of obesity).  While this patient did not qualify for undergoing surveillance liver biopsies (according to the criteria of the American College of Rheumatology), noninvasive tests such as PIIIP, hepatic imaging or elastography would have been appropriate and would likely have suggested the presence of significant fibrosis much earlier.

 

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PRODUCT INFORMATION
Methotrexate


REPRESENTATIVE TRADE NAMES
Methotrexate – Generic, Trexall®


DRUG CLASS
Antineoplastic Agents

Antirheumatic Agents


COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Methotrexate 59-05-2 C20-H22-N8-O5 Methotrexate Chemical Structure

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REFERENCES
Methotrexate

 

References Last Updated: 08 April 2013

  1. Zimmerman HJ. Methotrexate. Oncotherapeutic and immunosuppressive agents. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 681-7.  (Expert review of hepatotoxicity of methotrexate published in 1999).

  2. Aithal GP. Hepatotoxicity related to methotrexate. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 593-604. (Review of clinical features, course and outcome of methotrexate hepatotoxicity with discussion and comparison of guidelines for monitoring).

  3. Chabner BA, Bertino J, Cleary J, Ortiz T, Lane A, Supko JG, Ryan DP. Antimetabolites. Folic acid analogs. Cytotoxic agents. In, Brunton LL, Chabner B, Knollman B, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1690-4.  (Textbook of pharmacology and therapeutics).

  4. Colsky J, Greenspan EM, Warren TN. Hepatic fibrosis in children with acute leukemia after therapy with folic acid antagonists. AMA Arch Pathol 1955; 59: 198-206. PubMed Citation  (Five children with acute leukemia who had remission with aminopterin or methotrexate therapy developed cirrhosis within 8 months to 1.5 years of starting therapy).

  5. Hutter RVP, Shipkey FH, Tan CTC, Murphy ML, Chowdhury M. Hepatic fibrosis in children with acute leukaemia: a complication of therapy. Cancer 1960; 13: 288-307. PubMed Citation  (Review of liver histology from autopsies on 273 children with leukemia; rate of fibrosis increased with introduction of chemotherapy, including antifolates aminopterin and methotrexate from 31% [usually mild] to 84% [29% moderate and 1% severe]).

  6. Ryan TJ, Vickers HR, Salem SN, Callender ST, Badenoch J. The treatment of psoriasis with folic acid antagonists. Br J Dermatol 1964; 76: 555-64. PubMed Citation  (Among 14 patients with psoriasis treated with aminopterin or methotrexate using a daily schedule and rest periods, 4 had elevations in ALT [62-122 U/L], rapidly returning to normal upon stopping; liver biopsy in one patient showed steatosis).

  7. O''Rourke RA, Eckert GE. Methotrexate-induced hepatic injury in an adult. A case report. Arch Intern Med 1964; 113: 191-4. PubMed Citation  (62 year old with psoriasis treated with methotrexate for 2 years [25-50 mg/week] had AST 66 U/L, Alk P 1.5 times ULN, bilirubin 0.6 mg/dL, and liver biopsy showing mild fatty change and periportal fibrosis).

  8. Taft LI. Methotrexate induced hepatitis in childhood leukemia. Isr J Med Sci 1965; 1: 823-7. PubMed Citation  (Among 32 Australian children with acute leukemia treated with methotrexate for more than a month, 7 developed evidence of cirrhosis [ascites in 6, jaundice in 1] which was documented by liver biopsy in 3; after only 3-10 months of therapy, improving clinically with stopping therapy).

  9. Hersh EM, Wong VG, Henderson ES, Freireich EJ. Hepatotoxic effects of methotrexate. Cancer 1966; 19: 600-6. PubMed Citation  (Analysis of 22 patients given high doses of methotrexate [2-4 five-day courses at 10-22 mg/m2], ALT levels rose in ~90% of patients, peak levels of 37-1100 U/L, resolving with stopping therapy; biopsies in 12 patients showed portal inflammation in 6, fatty change in 5, fibrosis in 1).

  10. Talerman A, Thompson RB. Hepatic fibrosis in a child possibly due to prolonged methotrexate. J Clin Pathol 1966; 19: 81-2. PubMed Citation  (11 year old child with leukemia treated with methotrexate for 3 years [total dose 2.5 g] died of leukemic relapse and had hepatomegaly with extensive hepatic fibrosis and steatosis on autopsy).

  11. Fry L. The treatment of psoriasis with parenteral methotrexate. Br J Dermatol 1966; 78: 282-8. PubMed Citation  (Among 15 patients treated for psoriasis with weekly parenteral methotrexate doses of 25-100 mg for 1-6 months, 9 developed raised AST levels [58-208 U/L], usually lasting for less than 7 days after an injection, all resolving with stopping).

  12. Coe RO, Bull FE. Cirrhosis associated with methotrexate treatment of psoriasis. JAMA 1968; 206: 1515-20. PubMed Citation  (Three patients developed cirrhosis during methotrexate therapy for psoriasis with insidious onset after 1, 2 and 5.5 years with minimal elevations in ALT [peak 53-132 U/L], Alk P [1.2-2 times ULN], and bilirubin [0.9-1.9 mg/dL], presenting with peripheral edema, ascites and hepatomegaly).

  13. Auerbach R. Cirrhosis and methotrexate treatment of psoriasis. JAMA 1969; 208: 155. PubMed Citation  (Letter in response to Coe and Bull questioning relationship of liver injury and methotrexate).

  14. Roenigk HH Jr, Fowler-Bergfeld W, Curtis GH. Methotrexate for psoriasis in weekly oral doses. Arch Dermatol 1969; 99: 86-93. PubMed Citation  (Among 204 patients with psoriasis treated with oral methotrexate [25 mg weekly], AST elevations occurred in 6.8%, but liver biopsies done on patients with abnormal liver tests found "no significant pathologic changes").

  15. Baker H, Dahl MG. Methotrexate and the liver. Br J Dermatol 1969; 81: 465-7. PubMed Citation  (Description of 3 patients who developed hepatic fibrosis on oral methotrexate for psoriasis for up to 2.5 years).

  16. Dubin HV, Harrell ER. Absorption of methotrexate and hepatotoxicity. JAMA 1969; 210: 1104. PubMed Citation  (Letter in response to Baker and Dahl raising issue of variability in absorption of methotrexate as basis for variability in rates of hepatotoxicity).

  17. Epstein EH Jr, Croft JD Jr. Cirrhosis following methotrexate administration for psoriasis. Arch Dermatol 1969; 100: 531-4. PubMed Citation  (46 year old man with psoriasis developed cirrhosis after 5 years of methotrexate therapy [10-80 mg/week] with jaundice, [bilirubin 7.4 mg/dL, ALT 35 U/L, Alk P 1.5 times ULN], ascites and hepatomegaly; dying 4 months later of end stage liver disease and autopsy showing small nodular liver with diffuse fibrosis and fatty change).

  18. McDonald CJ, Bertino JR. Parenteral methotrexate in psoriasis. A report on the efficacy and toxicity of long-term intermittent treatment. Arch Dermatol 1969; 100: 655-68. PubMed Citation  (Results of methotrexate therapy in 36 patients with psoriasis; side effects included elevations in AST in 4 patients, 2 of whom had cirrhosis, but both were alcoholic and improved with stopping alcohol intake).

  19. Muller SA, Farrow GM, Martalock DL. Cirrhosis caused by methotrexate in the treatment of psoriasis. Arch Dermatol 1969; 100: 523-30. PubMed Citation  (Two cases of cirrhosis arising in patients with psoriasis on methotrexate; 37 and 52 year old men treated for 7 and 5 years with normal AST levels and improvement on stopping therapy).

  20. Sharp H, Nesbit M, White J, Krivit W. Methotrexate liver toxicity. J Pediatr 1969; 74: 818-9. PubMed Citation  (Prospective study of 10 children receiving methotrexate [7 on daily and 4 on intermittent therapy for leukemia] found hepatic fibrosis and fat even without liver test abnormalities, often improving after stopping therapy).

  21. Psoriasis, methotrexate, and cirrhosis. JAMA 1970; 212: 314-5. PubMed Citation  (Editorial recommending caution in using methotrexate particularly because "results of liver-function tests may be deceiving because transient abnormalities frequently occur in the absence of significant hepatotoxicity, while irreversible liver damage may exist despite normal results").

  22. Bender AS. Hazards of prolonged low-dose methotrexate therapy. Va Med Mon(1918) 1970; 97: 218-9. PubMed Citation

  23. Dubin HV, Harrell ER. Liver disease associated with methotrexate treatment of psoriatic patients. Arch Dermatol 1970; 102: 498-503. PubMed Citation  (Three men with psoriasis, ages 23, 41 and 51 years, treated with methotrexate for 2-8 years had liver biopsies showing fibrosis, ballooning degeneration and inflammation, with poor correlation to AST elevations which were intermittent and mild).

  24. Holst R, Mobacken H. [Liver damage during methotrexate treatment of psoriasis]. Nord Med 1970; 84: 1193-6. Swedish. PubMed Citation  (Three patients with psoriasis on methotrexate had abnormal liver biopsy findings of inflammation and steatosis).

  25. Weinstein GD, Cox JW, Suringa DW, Millard MM, Kalser M, Frost P. Evaluation of possible chronic hepatotoxicity from methotrexate for psoriasis. Arch Dermatol 1970; 102: 613-8. PubMed Citation  (Analysis of liver biopsies done on 29 patients with psoriasis; among 21 on methotrexate, 16 had steatosis, 2 had fibrosis and 1 cirrhosis [78 year old woman treated for 2 years]; among 8 on no therapy 4 had steatosis but none had fibrosis and all had normal ALT and AST levels).

  26. Almeyda J, Baker H, Levene GM, Barnardo D, Landells JW. Methotrexate, alcohol, and liver damage. Br Med J 1971; 2: 167. PubMed Citation  (Among 39 patients with psoriasis on methotrexate undergoing liver biopsy, 12 had fibrosis and 3 cirrhosis [all 3 were heavy drinkers]; among 20 patients not on methotrexate, 3 had fibrosis).

  27. Almeyda J, Barnardo D, Baker H. Drug reactions XV. Methotrexate, psoriasis and the liver. Br J Dermatol 1971; 85: 302-5. PubMed Citation  (Review of hepatotoxicity of methotrexate in psoriasis based upon 7 publications; among 130 biopsies done before therapy 29% were normal, 57% had mild or nonspecific changes, 5% fibrosis and 1.5% cirrhosis often corresponding to alcohol history; among 193 biopsies done during methotrexate therapy, 21% were normal, 23% had fibrosis and 11% cirrhosis, with marked variability in rates of cirrhosis [5-16%]; alcohol could not explain all hepatic fibrosis associated with methotrexate therapy).

  28. Baker H. Liver damage and methotrexate. Br Med J 1971; 2: 776. PubMed Citation  (Comments on drug levels with daily versus weekly dosing of methotrexate).

  29. Dahl MG, Gregory MM, Scheuer PJ. Liver damage due to methotrexate in patients with psoriasis. Br Med J 1971; 1: 625-30. PubMed Citation  (Among 37 patients with psoriasis treated with methotrexate who were not heavy drinkers, cirrhosis was present in 7 [19%], fibrosis in 10 [27%] and minor abnormalities in 17 [46%] including fat, ballooning degeneration and inflammation; fibrosis appeared only after 10 months and correlated with duration of therapy; nonspecific findings of fat and inflammation can be seen in pretreatment biopsies; AST elevations occurred in almost all patients, but were mild and transient and did not predict the severity of biopsy changes).

  30. Filip DJ, Logue GL, Harle TS, Farrar WH. Pulmonary and hepatic complications of methotrexate therapy of psoriasis JAMA 1971; 216: 881-2. PubMed Citation  (49 year old man with psoriasis developed pulmonary toxicity and liver disease [biopsy showing fat and fibrosis] after 5 years of methotrexate therapy, improving on withdrawal).

  31. Price LA. Liver damage and methotrexate. Br Med J 1971; 2: 464. PubMed Citation  (Letter arguing for use of folinic acid when using methotrexate even in oral low dose therapy).

  32. Roenigk HH Jr, Bergfeld WF, St Jacques R, Owens FJ, Hawk WA. Hepatotoxicity of methotrexate in the treatment of psoriasis. Arch Dermatol 1971; 103: 250-61. PubMed Citation  (Liver biopsies in 50 patients with psoriasis; 7 of 13 had abnormal histology before therapy which correlated with alcohol history; 28 of 37 taken during methotrexate therapy were abnormal including 6 with cirrhosis; initial scoring system proposed with 1=normal; 2=minor steatosis; 3=moderate-to-severe steatosis and inflammation; 4=fibrosis; 5=cirrhosis).

  33. Tashima CK. Methotrexate and hepatic disease. JAMA 1971; 216: 2018. PubMed Citation  (70 year old woman with psoriasis presented with cirrhosis and end stage liver disease after being treated with methotrexate for 4 years; alcohol history unclear).

  34. Vogler WR, Jacobs J. Toxic and therapeutic effects of methotrexate-folinic acid(Leucovorin) in advanced cancer and leukemia. Cancer 1971; 28: 894-901. PubMed Citation  (Toxicity of high dose methotrexate followed by leucovorin rescue in patients with cancer and leukemia; little on hepatotoxicity).

  35. Zachariae H, Schiodt T. Liver biopsy in methotrexate treatment. Acta Derm Venereol 1971; 51: 215-20. PubMed Citation  (Analysis of 57 liver biopsies from 36 patients with psoriasis on methotrexate therapy showed high rate of findings in pretreatment biopsies and no significant change except for increase in steatosis on treatment; ALT elevations occurred but liver biopsies often showed no abnormalities; no mention of fibrosis).

  36. Almeyda J, Barnardo D, Baker H, Levene GM, Landells JW. Structural and functional abnormalities of the liver in psoriasis before and during methotrexate therapy. Br J Dermatol 1972; 87: 623-31. PubMed Citation  (Liver biopsies on 67 patients with psoriasis comparing 25 not on therapy to 42 on methotrexate [for 0.3-7 years]: 56% vs 40% were normal, 28% vs 24% had nonspecific, mild changes, 16% vs 29% had fibrosis and 0% vs 7% had cirrhosis; fibrosis more common with daily dose regimens and in alcoholics).

  37. Dahl MG, Gregory MM, Scheuer PJ. Methotrexate hepatotoxicity in psoriasis--comparison of different dose regimens. Br Med J 1972; 1: 654-6. PubMed Citation  (Analysis of liver biopsies from 44 patients with psoriasis treated with methotrexate, found 6 with cirrhosis [13%] and 11 fibrosis [25%]; presence of fibrosis correlating with duration of therapy and with daily [12 of 22] rather than weekly [2 of 14] dosing).

  38. Griesman FA, Hammer CJ, Fenster LF. Methotrexate-associated liver disease in psoriatic patients. Northwest Med 1972; 71: 609-12. PubMed Citation

  39. Ryan TJ, Sadler GH, Guerrier C, Vickers HR. Methotrexate hepatotoxicity in psoriasis. Br Med J 1972; 2: 296. PubMed Citation  (Among 4 patients with psoriasis on methotrexate for more than 10 years using daily regimens, 2 had cirrhosis, but 2 had no fibrosis on biopsy).

  40. Robeson JA, Spenney J, Hirschowitz BI. Cirrhosis following prolonged treatment of psoriasis with methotrexate orally. South Med J 1972; 65: 453-6. PubMed Citation  (60 year old non-drinking woman with psoriasis on methotrexate for 9 years presented with cirrhosis and ascites [bilirubin 1.0 mg/dL, AST 25, Alk P 2.5 times ULN, albumin 2.7, prothrombin index 63]; patient improved clinically on withdrawal).

  41. Roenigk H, Maibach H, Weinstein G. Guidelines on methotrexate therapy for psoriasis. Arch Dermatol 1972; 105: 363-5. PubMed Citation  (Recommended liver biopsy before starting methotrexate and repeat liver biopsy based upon abnormal liver tests and proposed a five-point grading system from normal [Grade I] to cirrhosis [Grade 5]).

  42. Roenigk H, Maibach H, Weinstein G. Methotrexate therapy for psoriasis: guideline revisions. Arch Dermatol 1973; 108: 35. PubMed Citation  (Change in grading system to: Grade I=normal or mild fatty infiltration, nuclear variability and portal inflammation; II=moderate changes; III=fibrosis [with septa]; IV=cirrhosis; with recommendations not to use or continue methotrexate in patients with Grade III changes and to perform a liver biopsy before starting therapy).

  43. Weinstein G, Roenigk H, Maibach H, Cosmides J, Halprin K, Millard M. Psoriasis-liver-methotrexate interactions. Arch Dermatol 1973; 108: 36-9. PubMed Citation  (Cooperative study with analysis of 742 biopsies from 550 patients with psoriasis on methotrexate from 10 clinical centers; ALT levels elevated in 12% before and 13% after methotrexate; moderate-severe fibrosis in 7% vs 13%, cirrhosis in 1.5% vs 2.6%, fibrosis correlating with duration and cumulative dose, daily dosing, alcohol intake, obesity and diabetes).

  44. Coughlin GP, Henderson DW, Reid JG, Grant AK. Cirrhosis following methotrexate administration for psoriasis. Med J Aust 1973; 2: 499-501. PubMed Citation  (52 year old with psoriasis [non-drinker] treated with methotrexate [daily regimens] for 3 years presented with large liver, AST 50 U/L, Alk P 1.5 times ULN, albumin 30 gm/dL, platelets 37,000/μL, and biopsy showing cirrhosis; improved clinically upon withdrawal).

  45. Horvath E, Kovacs K, Ross RC. Liver ultrastructure in methotrexate treatment of psoriasis. Arch Dermatol 1973; 108: 427-8. PubMed Citation  (Analysis of 9 biopsies from patients with psoriasis on methotrexate which had only mild, nonspecific changes on light microscopy but showed increase in Ito cells by electron microscopy).

  46. Kraus Z, Vortel V, Fixa B, Komárková O. [Liver of psoriatic patients treated with methotrexate]. Cesk Dermatol 1973; 48: 255-62. Czech. PubMed Citation

  47. Moldenhauer E, Dabels J, Diwok K, Leithäer W, Nowotny P. [Incidence of liver diseases in psoriatic patients with special reference to methotrexate therapy]. Dermatol Monatsschr 1973; 159: 242-8. German. PubMed Citation

  48. Pai SH, Werthamer S, Zak FG. Severe liver damage caused by treatment of psoriasis with methotrexate. N Y State J Med 1973; 73: 2585-7. PubMed Citation  (32 year old with psoriasis treated with methotrexate for 3 years [0.5 g] presented with fever, coma and acidosis; autopsy showed advanced fibrosis; no liver tests or alcohol history provided).

  49. Palmer HM. Hepatotoxicity of methotrexate in the treatment of psoriasis. Practitioner 1973; 211: 324-8. PubMed Citation  (Analysis of 37 patients with psoriasis on long term methotrexate, usually 5 days a week for 2 months to 6 years; 4 of 23 biopsies showed fibrosis and 3 cirrhosis [after 1.8-2.8 g total dose]).

  50. Podurgiel BJ, McGill DB, Ludwig J, Taylor WF, Muller SA. Liver injury associated with methotrexate therapy for psoriasis. Mayo Clin Proc 1973; 48: 787-92. PubMed Citation  (Among 35 patients with psoriasis treated with methotrexate for 1 to 8 years, liver biopsies showed fibrosis in 5 [14%] and cirrhosis in 4 [11%]; presence of fibrosis correlated with AST elevations, >2 years of therapy, and daily administration).

  51. Tobias H, Auerbach R. Hepatotoxicity of long-term methotrexate therapy for psoriasis. Arch Intern Med 1973; 132: 391-6. PubMed Citation  (Liver biopsy results on 88 patients with psoriasis treated with methotrexate found increase in fibrosis and cirrhosis after cumulative dose of 2 g; rates higher in alcoholics; fat was present in 64% of 14 untreated versus 61% of 41 treated non-users of alcohol; nuclear changes found in most treated patients; ALT and AST usually normal).

  52. Millward-Sadler GH, Ryan TJ. Methotrexate induced liver disease in psoriasis. Br J Dermatol. 1974; 90: 661-7. PubMed Citation  (Among 19 patients with psoriasis treated with methotrexate for 1-10 years, 2 had fibrosis and 3 cirrhosis; fibrosis correlated with duration of therapy and was more common with daily vs weekly regimens; serum liver tests were not helpful in identifying patients with fibrosis).

  53. Reese LT, Grisham JW, Aach RD, Eisen AZ. Effects of methotrexate on the liver in psoriasis. J Invest Dermatol 1974; 62: 597-602. PubMed Citation  (Among 102 liver biopsies done in 70 patients with psoriasis, fibrosis was present in 1 of 35 [3%] untreated versus 3 of 35 [9%] on methotrexate [1 with cirrhosis], but nonspecific changes were found equally in the two groups, and serum enzyme elevations did not correlate with histological findings).

  54. Ruszczak Z, Prószynska-Kuczynska W, Krajewski C. [Side effects of methotrexate in the treatment of skin diseases]. Wiad Lek 1974; 27: 1083-6. Polish. PubMed Citation

  55. Shapiro HA, Trowbridge JO, Lee JC, Maibach HI. Liver disease in psoriatics - an effect of methotrexate therapy? Arch Dermatol 1974; 110: 547-51. PubMed Citation  (Among 67 patients with psoriasis, liver fibrosis and fat did not correspond with methotrexate therapy; cirrhosis present in 4 of 20 [20%] before therapy and 5 of 46 [12%] on methotrexate; amount of fat and liver tests abnormalities were also similar in untreated and treated patients).

  56. Delbrück H, Schaison G, Chelloul N, Bernard J. [Carcinoma of the liver in a child after seven-year complete remission of acute lymphoblastic leukaemia(author's transl)]. Dtsch Med Wochenschr 1975; 100: 1792-7. PubMed Citation  (12 year old girl on maintenance methotrexate and mercaptopurine for 7 years after remission in acute leukemia presented with hepatocellular carcinoma).

  57. Warin AP, Landells JW, Levene GM, Baker H. A prospective study of the effects of weekly oral methotrexate on liver biopsy. Br J Dermatol 1975; 93: 321-7. PubMed Citation  (25 patients with psoriasis underwent 192 liver biopsies before and after 1-5 years of weekly oral methotrexate therapy showed no increase in fibrosis or inflammation; pretreatment liver biopsies in 66 patients were normal in 67%, had nonspecific changes in 26%, fibrosis in 6% and cirrhosis in 1 alcoholic patient).

  58. Nyfors A, Svejgaard A. The relation of HL-A antigens to liver histology in methotrexate-treated psoriatics. Acta Dermatovener(Stockholm) 1976 56: 235-8. PubMed Citation  (In 45 patients with psoriasis on methotrexate therapy [14 with cirrhosis or fibrosis], no association was found between HLA-A and liver histological findings).

  59. Hopwood D, Nyfors A. Effect of methotrexate therapy in psoriatics on the Ito cells in liver biopsies, assessed by point-counting. J Clin Pathol 1976; 29: 698-703. PubMed Citation  (Among 24 patients with psoriasis treated with methotrexate, light and electron microscopy of liver tissue showed increase in hepatic stellate cells [mean volume density rising from 0.25% to 0.66%] with methotrexate therapy, not correlating with dose and decreasing rapidly with stopping; morphology of stellate cells did not change).

  60. Nyfors A, Poulsen H. Liver biopsies from psoriatics related to methotrexate therapy. 1. Findings in 123 consecutive non-methotrexate treated patients. Acta Pathol Microbiol Scand A 1976; 84: 253-61. PubMed Citation  (Among 123 liver biopsies in patients with psoriasis not on methotrexate, 49% were normal, 37% had fatty change, 12% had nonspecific findings, 1% fibrosis and 1% cirrhosis; abnormalities correlating with raised AST [high specificity, low sensitivity], alcohol history, age and obesity).

  61. Nyfors A, Poulsen H. Liver biopsies from psoriatics related to methotrexate therapy. 2. Findings before and after methotrexate therapy in 88 patients. A blind study. Acta Pathol Microbiol Scand A 1976; 84: 262-70. PubMed Citation  (Among 88 patients with psoriasis undergoing liver biopsy before and after 2-72 months [175-4590 mg] of weekly doses of methotrexate, 6 [7%] developed cirrhosis and 5 [6%] fibrosis with little correlation with dose, alcohol history, AST elevations or pretreatment liver histology).

  62. Nyfors A. Liver biopsies from psoriatics related to methotrexate therapy. 3. Findings in post-methotrexate liver biopsies from 160 psoriatics. Acta Pathol Microbiol Scand A 1977; 85: 511-8. PubMed Citation  (Among 160 patients with psoriasis treated with methotrexate, 92 had a single liver biopsy on therapy of whom 1% had cirrhosis and 7% fibrosis [correlated with alcohol intake and age but not total dose]; among 68 with two liver biopsies on therapy [total dose 175-5568 mg], 21% had cirrhosis and 24% fibrosis, fibrosis correlating with alcohol intake during therapy, obesity and older age, but cirrhosis found almost only in patients with >2 g methotrexate exposure).

  63. Nyfors A, Hopwood D. Liver ultrastructure in psoriatics related to methotrexate therapy. 1. A prospective study of findings in hepatocytes from 24 patients before and after methotrexate treatment. Acta Pathol Microbiol Scand A 1977; 85: 787-800. PubMed Citation  (Liver biopsies taken before and during methotrexate therapy in 24 patients with psoriasis showed increase in hepatocyte membrane whorls and vacuoles and increase in autophagic vacuoles, but no correlation with duration of therapy or total dose).

  64. Hopwood D, Nyfors A. Liver ultrastructure in psoriatics related to methotrexate therapy. 2. Findings in bile ducts from 11 methotrexate treated psoriatics and 2 controls. Acta Pathol Microbiol Scand A 1977; 85: 801-11. PubMed Citation  (Bile duct histology was studied by light and electron microscopy in 11 patients with psoriasis on methotrexate and 2 controls showed increase in autophagic vacuoles in biliary epithelial cells and nonspecific findings of mitochondrial damage and membrane whorls and particulate debris in lumen).

  65. Horvath E, Kovacs K, Ross RC, Saibil F, Kerenyi NA. Desmosomal abnormalities in the liver of methotrexate-treated psoriatics. Experientia 1977; 33: 1202-4. PubMed Citation  (Among 50 liver biopsies from patients with psoriasis on methotrexate for 0.1 to 15 years, detachment of desmosomes was found in half of cases along with microfilaments anchored to mitochondria).

  66. Nyfors A, Poulsen H. Morphogenesis of fibrosis and cirrhosis in methotrexate-treated patients with psoriasis. Am J Surg Pathol 1977; 1: 235-43. PubMed Citation  (Analysis of progression of fibrosis using 31 liver biopsies from 8 patients with psoriasis treated with methotrexate [4 developed fibrosis, 4 cirrhosis]; early changes were focal interface hepatitis, followed by entry of fibrous septa, that then linked portal areas, that could lead to micronodular cirrhosis).

  67. McIntosh S, Davidson DL, O'Brien RT, Pearson HA. Methotrexate hepatotoxicity in children with leukemia. J Pediatr 1977; 90: 1019-21. PubMed Citation  (8 children treated with methotrexate [1-11 g/m2] for leukemia underwent liver biopsy, and 5 had fibrosis; all had at least transient AST elevations [peak 49-400 U/L]).

  68. Ruymann FB, Mosijczuk AD, Sayers RJ. Hepatoma in a child with methotrexate-induced hepatic fibrosis. JAMA 1977; 238: 2631-3. PubMed Citation  (11 year old girl with acute leukemia treated with methotrexate for 6 years died of recurrence; found on autopsy to have hepatic steatosis, fibrosis, nodular liver and a small hepatocellular carcinoma).

  69. Chan H, Evans WE, Pratt CB. Recovery from toxicity with high-dose methotrexate: prognostic factors. Cancer Treat Rep 1977; 61: 797-804. PubMed Citation  (Among 65 patients with cancer given high dose methotrexate with leucovorin rescue, 6 had severe toxicity marked by neutropenia and infections and 3 died with multiorgan failure and sepsis with jaundice and ALT elevations).

  70. Horvath E, Saibil FG, Kovacs K, Kerenyi NA, Ross RC. Fine structural changes in the liver of methotrexate-treated psoriatics. Digestion 1978; 17: 488-502. PubMed Citation  (Electron microscopy was done on 55 liver biopsies from 52 patients with psoriasis, 47 on methotrexate therapy; most common findings were diverse mitochondrial abnormalities, detachment of desmosomal plaques and hyperplasia of stellate cells, but these changes did not correlate with duration of therapy or hepatic injury as shown by light microscopy).

  71. Perez C, Sutow WW, Wang YM, Herson J. Evaluation of overall toxicity of high-dosage methotrexate regimens. Med Pediatr Oncol 1979; 6: 219-28. PubMed Citation  (Among 349 courses of high dose methotrexate with leucovorin rescue, AST elevations occurred after 59% with values >3 times ULN in 16%; however, all resolved).

  72. Plomteux G, Closon MT. [Hepatic tolerance of methotrexate]. Med Chir Dig 1979; 8: 385-7. French. PubMed Citation

  73. Vaughan WP, Wilcox PM, Alderson PO, Ettinger DS, Abeloff MD. Hepatic toxicity of adjuvant chemotherapy for carcinoma of the breast. Med Pediatr Oncol 1979; 7: 351-9. PubMed Citation  (Four patients being treated with cyclophosphamide, methotrexate and 5-fluouracil developed focal defects on liver scans which were thought to be metastases, but later presumed due to hepatotoxicity with only minor elevations in AST and Alk P, injury being attributed to methotrexate).

  74. Nyfors A. Methotrexate therapy of psoriasis. Effect and side effects with particular reference to hepatic changes. A survey. Dan Med Bull 1980; 27: 74-96. PubMed Citation  (Extensive review of history of development of methotrexate, changes in dosing schedules and evolution of understanding of hepatotoxicity with detailed analysis of liver histology).

  75. Parker D, Bate CM, Craft AW, Graham-Pole J, Malpas JS, Stansfeld AG. Liver damage in children with acute leukaemia and non-Hodgkin's lymphoma on oral maintenance chemotherapy. Cancer Chemother Pharmacol 1980; 4: 121-7. PubMed Citation  (36 children on maintenance chemotherapy for leukemia or lymphoma with methotrexate [25-30 mg/m2] and mercaptopurine had frequent AST and Alk P elevations; 8 had liver biopsy which were abnormal in 6 with cirrhosis in 1, no anti-HCV testing available).

  76. Robinson JK, Baughman RD, Auerbach R, Cimis RJ. Methotrexate hepatotoxicity in psoriasis. Consideration of liver biopsies at regular intervals. Arch Dermatol 1980; 116: 413-5. PubMed Citation  (Among 131 liver biopsies done in 43 patients with psoriasis on methotrexate, fibrosis [grade IIIA or B changes] found in 11 after 1-6 years of therapy [total dose 0.6-2.7 g], not predicted by ALT or AST values, but did correlate with older age and total duration of treatment).

  77. Zachariae H, Kragballe K, Søgaard H. Methotrexate induced liver cirrhosis. Studies including serial liver biopsies during continued treatment. Br J Dermatol 1980; 102: 407-12. PubMed Citation  (Analysis of 764 liver biopsies done on 328 patients with psoriasis; 2 had cirrhosis before therapy [0.6%], rising to 13.5% after 2 years and 26% after 5 years; often nonprogressive and patients tolerated continuation of therapy).

  78. Zachariae H, Kragballe K, Thestrup-Pedersen K, Kissmeyer-Nielsen F. HLA antigens in methotrexate-induced liver cirrhosis. Acta Derm Venereol 1980; 60: 165-6. PubMed Citation  (HLA-typing done on 20 patients with psoriasis and methotrexate related cirrhosis was compared to 44 treated patients without cirrhosis and 1291 controls; found a slight increase in HLA-A1+B8 [25% vs 7% vs 15%]).

  79. Wilkens RF, Watson MA, Paxson CS. Low dose pulse methotrexate therapy in rheumatoid arthritis. J Rheumatol 1980; 7: 501-5. PubMed Citation  (32 patients with rheumatoid arthritis were treated with methotrexate [7.5-15 mg/week] for 0.3-5 years; 4 had liver biopsies after 2 years of treatment; in those with liver test abnormalities, mild fatty change in 1).

  80. Eschenbach C, Schmitz-Moormann P, Gutjahr P. [Liver cell carcinoma following juvenile acute lymphoblastic leukemia. Case contribution]. Helv Paediatr Acta 1980; 35: 577-84. German. PubMed Citation  (Child with chronic hepatitis B died of hepatocellular carcinoma 5 years after chemotherapy for acute leukemia using methotrexate).

  81. Kamen BA, Nylen PA, Camitta BM, Bertino JR. Methotrexate accumulation and folate depletion in cells as a possible mechanism of chronic toxicity to the drug. Br J Haematol 1981; 49: 355-60. PubMed Citation  (Red cell folate was decreased in 9 of 12 children on methotrexate and in 3 of 5 liver samples from patients on long term methotrexate).

  82. Roenigk HH, Auerbach R, Maibach HI, Weinstein GD. Methotrexate guidelines - revised. J Am Acad Dermatol 1982; 6: 145-55. PubMed Citation  (Expert review of methotrexate and recommendations for use and monitoring; recommended liver biopsy before starting therapy, ALT testing at 3-4 month intervals and repeat liver biopsy after 1.5 g total dose and based upon relative risk, risk factors being alcohol use, previous arsenic exposure, diabetes, obesity, renal impairment and pretreatment liver pathology).

  83. Ashton RE, Millward-Sadler GH, White JE. Complications in methotrexate treatment of psoriasis with particular reference to liver fibrosis. J Invest Dermatol 1982; 79: 229-32. PubMed Citation  (Among 38 patients with psoriasis undergoing liver biopsy before and during methotrexate therapy, 7 [18%] developed fibrosis and 2 [5%] cirrhosis after 16-38 months [1-3.4 g], of whom 3 had moderate alcohol intake).

  84. Lenler-Petersen P, Søgaard H, Thestrup-Pedersen K, Zachariae H. Galactose tolerance test and methotrexate-induced liver fibrosis and cirrhosis in patients with psoriasis. Acta Derm Venereol 1982; 62: 448-9. PubMed Citation  (A total of 151 galactose elimination tests were done on 45 patients with psoriasis and fibrosis undergoing liver biopsies during methotrexate therapy; abnormal results were found in 6% of 46 patients with normal biopsy, 14% of 105 with fibrosis and 20% of 41 with cirrhosis).

  85. Zachariae H, Bjerring P. Methotrexate in psoriasis with and without leucovorin: effect of different dosage schedules on acute liver toxicity. Acta Derm Venereol 1982; 62: 446-8. PubMed Citation  (Comparison of patients with psoriasis given varying regimens of methotrexate [5 mg over 3 days vs 25 mg once weekly, orally vs intramuscularly, with and without leucovorin] found no difference in AST increase during week after dosing [110-187% increase compared to baseline]).

  86. Geronemus RG, Auerbach R, Tobias H. Liver biopsies upsilon liver scans in methotrexate-treated patients with psoriasis. Arch Dermatol. 1982; 118: 649-51. PubMed Citation  (Technetium 99m sulfur-colloid scans were not accurate in detecting fibrosis in patients with psoriasis on methotrexate, being abnormal in 6 of 17 patients with normal liver histology and 2 of 5 with fibrosis).

  87. Lawrence CM, Strange RC, Summerly RA, Scriven AJ, Elmahallowy M, Wood A, Fletcher PJ, et al. Assessment of liver function using fasting bile salt concentrations in psoriasis prior to and during methotrexate therapy. Clin Chim Acta 1983; 129: 341-51. PubMed Citation  (Fasting bile acid levels were measured in 18 patients with psoriasis before therapy and 21 receiving long term methotrexate; elevations in bile acids were more accurate than routine liver tests in predicting severe histological abnormalities, but were not sufficiently reliable to detect moderate or severe histological changes).

  88. Beck HI, Foged EK. Toxic hepatitis due to combination therapy with methotrexate and etretinate in psoriasis. Dermatologica 1983; 167: 94-6. PubMed Citation  (47 year old with psoriasis who had been on oral weekly methotrexate for 10 years with normal liver tests, developed fever, jaundice and ascites 4 months after adding 25-75 mg/day etretinate [AST 460 U/L, Alk P 1.5 times ULN, bilirubin 17 mg/dL, prothrombin index 27%], with resolution 2 months after stopping both agents; liver biopsy later showed cirrhosis).

  89. Breithaupt H, Küenzlen E. High-dose methotrexate for osteosarcoma: toxicity and clinical results. Oncology 1983; 40: 85-9. PubMed Citation  (9 patients with osteosarcoma received 122 infusions of high dose methotrexate with leucovorin rescue; "Mild to moderate elevations of serum transaminases have been recorded in nearly each course, usually returning to normal values within 1 week." One patient developed nausea with ALT 1090 U/L and normal bilirubin and with recurrence on re-infusion).

  90. Groff GD, Shenberger KN, Wilke WS, Taylor TH. Low dose oral methotrexate in rheumatoid arthritis: an uncontrolled trial and review of the literature. Semin Arthritis Rheum 1983; 12: 333-47. PubMed Citation  (Retrospective analysis of 28 patients with rheumatoid arthritis treated with methotrexate for 4-30 months; 3 had liver biopsies for elevated serum enzymes and all 3 were normal).

  91. Hoffmeister RT. Methotrexate therapy in rheumatoid arthritis: 15 years experience. Am J Med 1983; 75: 69-73. PubMed Citation  (Retrospective analysis of 78 patients with rheumatoid arthritis treated with methotrexate for up to 15 years; 34 patients underwent 67 liver biopsies, 50 biopsies were normal and 17 showed mild abnormalities with fat and inflammation, 7 with portal fibrosis but none with cirrhosis).

  92. Hilgers RD, Alberts DS, Standefer JC, Skipper BE, Miles NJ, Borst J. Phase II and pharmacokinetics study of high-dose methotrexate in the treatment of advanced gynecologic malignancy. Gynecol Oncol 1984; 18: 62-70. PubMed Citation  (Among 15 patients with gynecological malignancies given several courses of high dose intravenous methotrexate [0.5-8 g/m2] with leucovorin rescue, AST elevations occurred during 6% of courses, but all were asymptomatic and resolved).

  93. Haim N, Kedar A, Robinson E. Methotrexate-related deaths in patients previously treated with cis-diamminedichloride platinum. Cancer Chemother Pharmacol 1984; 13: 223-5. PubMed Citation  (6 patients with cancer receiving high dose methotrexate [40 mg/m2] and cis-diamminedichloride platinum [CDDP] died with severe stomatitis, fever and leucopenia followed by renal and hepatic failure; the CDDP perhaps causing excessive methotrexate toxicity because of its nephrotoxicity).

  94. Birnie GG, Fitzsimons CP, Czarnecki D, Cooke A, Scobie G, Brodie MJ. Hepatic metabolic function in patients receiving long-term methotrexate therapy: comparison with topically treated psoriatics, patient controls and cirrhotics. Hepatogastroenterology 1985; 32: 163-7. PubMed Citation  (Indocyanine green and antipyrine clearance were measured in 11 patients with psoriasis on long term methotrexate [iv every 2 weeks for 1-16 years] and 14 patients not on therapy and compared to routine liver tests; patients on methotrexate had lower clearances, but there was complete overlap with normal subjects).

  95. Hendel J, Poulsen H, Nyfors B, Nyfors A. Changes in liver histology during methotrexate therapy of psoriasis correlated to the concentration of methotrexate and folate in erythrocytes. Acta Pharmacol Toxicol (Copenh) 1985; 56: 321-6. PubMed Citation  (Among 31 patients with psoriasis on methotrexate therapy, liver biopsies showed mild to moderate fatty change and none had progression of fibrosis, but abnormalities that did occur correlated with lower red cell folate and higher methotrexate levels).

  96. Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, Trentham DE. Efficacy of low dose methotrexate in rheumatoid arthritis. N Engl J Med 1985; 312: 818-22. PubMed Citation  (Placebo controlled crossover trial of methotrexate [7.5-15 mg/week] for 24 weeks in 33 patients with severe rheumatoid arthritis; abnormal ALT or AST occurred in 21% on drug and 3% on placebo, all episodes resolving rapidly with holding the dose).

  97. van de Kerkhof PC, Hoefnagels WH, van Haelst UJ, Mali JW. Methotrexate maintenance therapy and liver damage in psoriasis. Clin Exp Dermatol 1985; 10: 194-200. PubMed Citation  (Among 44 patients with psoriasis treated with methotrexate for 3 to 15 years, 7 [16%] had fibrosis and 2 [4.5%] cirrhosis, no correlation with ALT or AST elevations and poor correlation with total dose; more common in elderly; all received >2 g total dose).

  98. Williams HJ, Willkens RF, Samuelson CO Jr, Alarcon GS, Guttadauria M, Yarboro C, Polisson RP, et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthritis Rheum 1985; 28: 721-30. PubMed Citation  (Controlled trial of methotrexate [7.5-15 mg/week] vs placebo for 18 weeks in 189 patients with rheumatoid arthritis; ALT elevations >2 times ULN occurred in 19% of 95 patients on methotrexate vs 3% of 94 on placebo; most common cause of drug withdrawal).

  99. Lanse SB, Arnold GL, Gowans JD, Kaplan MM. Low incidence of hepatotoxicity associated with long-term, low-dose oral methotrexate in treatment of refractory psoriasis, psoriatic arthritis, and rheumatoid arthritis. An acceptable risk/benefit ratio. Dig Dis Sci 1985; 30: 104-9. PubMed Citation  (Serial liver biopsies among 30 patients with psoriasis or rheumatoid arthritis treated with oral methotrexate weekly showed normal results in 50% and all remained normal on repeat biopsy 1-10 years later; among 11 with fat and 4 with mild fibrosis initially, 4 worsened, 8 were unchanged and 3 were better in follow up and none developed cirrhosis).

  100. Mackenzie AH. Hepatotoxicity of prolonged methotrexate therapy for rheumatoid arthritis. Cleve Clin Q 1985; 52: 129-35. PubMed Citation  (Among 60 patients with rheumatoid arthritis being treated with methotrexate who underwent liver biopsy, none had fibrosis; and rates of steatosis [50% vs 44%] and portal inflammation [18% vs 20%] were not increased compared to controls).

  101. Pestana A, Halprin KM, Taylor JR, Schiff ER, Esquenazi V, Comerford M, Gomez C. Predictive value of HLA antigen for methotrexate-induced liver damage in patients with psoriasis. J Am Acad Dermatol 1985; 12(1 Pt 1): 26-9. PubMed Citation  (Among 32 patients with psoriasis treated with methotrexate for at least 4 years who had variable degrees of hepatic fibrosis, HLA typing showed no association with degree of fibrosis or cirrhosis).

  102. Tolman KG, Clegg DO, Lee RG, Ward JR. Methotrexate and the liver. J Rheumatol Suppl 1985; 12 Suppl 12: 29-34. PubMed Citation  (Analysis of liver biopsies in 29 patients with rheumatoid arthritis on weekly methotrexate for at least 2 years, found 24% normal, 41% with mild changes, 34% with fibrosis and none with cirrhosis; ALT levels did not predict more severe histologic changes; hypoalbuminemia and persistent ALT elevations were somewhat predictive and significant abnormalities found only after 1.5 g total dose).

  103. Weinstein A, Marlowe S, Korn J, Farouhar F. Low-dose methotrexate treatment of rheumatoid arthritis. Long-term observations. Am J Med 1985; 79: 331-7. PubMed Citation  (Among 25 patients with rheumatoid arthritis treated with methotrexate for 0.5 to 5 years, ALT elevations found in 48% at least once; 6 of 17 [35%] had fibrosis on liver biopsy but none had cirrhosis; histology having a poor correlation with ALT elevations).

  104. Miller JA, Dodd H, Rustin MHA, Lees WR, Levene GM, Kirby JD, Munro DD. Ultrasound as a screening procedure for methotrexate-induced hepatic damage in severe psoriasis. Br J Dermatol 1985; 113: 699-705. PubMed Citation  (Among 82 patients with psoriasis on methotrexate, abnormal ultrasound findings [moderate-severe fat or fibrosis] found in 22% of those with normal [n=49], 73% of those with abnormal liver biopsies without fibrosis [n=30] and all with fibrosis [n=8]).

  105. Jones SK, Aherne GW, Campbell MJ, White JE. Methotrexate pharmacokinetics in psoriatic patients developing hepatic fibrosis. Arch Dermatol 1986; 122: 666-9. PubMed Citation  (Pharmacokinetic studies on 7 patients with psoriasis with fibrosis due to methotrexate and 12 without fibrosis showed no differences in peak levels of methotrexate or rates of clearance).

  106. Kremer JM, Lee JK. The safety and efficacy of the use of methotrexate in long-term therapy for rheumatoid arthritis. Arthritis Rheum 1986; 29: 822-31. PubMed Citation  (Among 29 patients with rheumatoid arthritis treated with methotrexate for 7-54 months, 69% had at least one AST elevation, occurring randomly and not requiring dose change; comparison of 29 baseline and 31 follow up liver biopsies showed minimal worsening and no correlation with AST elevations).

  107. Kremer JM, Galivan J, Streckfuss A, Kamen B. Methotrexate metabolism analysis in blood and liver of rheumatoid arthritis patients: association with hepatic folate deficiency and formation of polyglutamates. Arthritis Rheum 1986; 29: 832-5. PubMed Citation  (Among 29 patients with rheumatoid arthritis, measurement of folate metabolites in liver tissue showed evidence of folate deficiency in all patients on methotrexate which was restored by oral folate therapy).

  108. Reynolds FS, Lee WM. Hepatotoxicity after long-term methotrexate therapy. South Med J 1986; 79: 536-9. PubMed Citation  (Among 14 patients with psoriasis who underwent liver biopsy, 4 [27%] had fibrosis all of whom had been treated for more than 5 years).

  109. Berkowitz RS, Goldstein DP, Bernstein MR. Ten years' experience with methotrexate and folinic acid as primary therapy for gestational trophoblastic disease. Gynecol Oncol 1986; 23: 111-8. PubMed Citation  (Among 185 patients with gestational trophoblastic disease treated with methotrexate and leucovorin rescue, sustained remission in 82% with one course; hepatotoxicity occurred in 14% but abnormalities returned to normal within 2 weeks).

  110. Rademaker M, Webb JA, Lowe DG, Meyrick-Thomas RH, Kirby JD, Munro DD. Magnetic resonance imaging as a screening procedure for methotrexate induced liver damage. Br J Dermatol 1987; 117: 311-6. PubMed Citation  (Among 51 patients with psoriasis on methotrexate therapy, magnetic resonance imaging liver parameters did not correlate with either steatosis or fibrosis on liver biopsy).

  111. Gispen JG, Alarcón GS, Johnson JJ, Acton RT, Barger BO, Koopman WJ. Toxicity of methotrexate in rheumatoid arthritis. J Rheumatol 1987; 14: 74-9. PubMed Citation  (Among 72 patients with rheumatoid arthritis treated with oral methotrexate weekly, 55% had benefit and 74% had side effects, usually minor, but 7 were serious and 2 patients died both related to leukopenia and infection and not to liver injury).

  112. Leonard PA, Clegg DO, Carson CC, Cannon GW, Egger MJ, Ward JR. Low dose pulse methotrexate in rheumatoid arthritis: an 8-year experience with hepatotoxicity. Clin Rheumatol 1987; 6: 575-82. PubMed Citation  (Among 163 patients with rheumatoid arthritis treated with methotrexate for 0.3-7 years [total dose 0.1-3.1 g], serum enzyme elevations occurred at least once in 58% but led to discontinuation in only 5%; elevations did not correlate with alcohol use, age, dose or days relative to methotrexate dose).

  113. Williams CN, McCauley D, Malatjalian DO, Turnbull GK, Ross JB. The aminopyrine breath test, an inadequate early indicator of methotrexate-induced liver disease in patients with psoriasis. Clin Invest Med 1987; 10: 54-8. PubMed Citation  (Among 32 patients with psoriasis on methotrexate therapy, aminopyrine breath tests were abnormal [<7%] in none of 24 without fibrosis and 3 of 8 with fibrosis and, thus, were not accurate enough to replace liver biopsy in assessing progressive injury).

  114. Shepard KV, Levin B, Faintuch J, Doria MI, DuBrow RA, Riddell RH. Hepatitis in patients receiving intraarterial chemotherapy for metastatic colorectal carcinoma. Am J Clin Oncol 1987; 10: 36-40. PubMed Citation  (Among 51 patients with metastatic colon cancer treated with hepatic intra-arterial floxuridine [FUDR] and dichloromethotrexate or mitomycin, 47% developed liver injury and 25% were jaundiced, usually within 1-8 weeks of the first cycle [ALT 26-710 U/L, bilirubin 3-12.5 mg/dL], resolving in 1 week to 3 months, but two developed biliary stricture, cause likely to be FUDR).

  115. Fried M, Kalra J, Ilardi CF, Sawitsky A. Hepatocellular carcinoma in a long-term survivor of acute lymphocytic leukemia. Cancer 1987; 60: 2548-52. PubMed Citation  (28 year old woman presented with hepatocellular carcinoma and cirrhosis 22 years after diagnosis of acute leukemia treated successfully with mercaptopurine and methotrexate [6 years: total dose 4 g], with ALT 90 U/L, Alk P 538 U/L, bilirubin 1.3 mg/dL; no other cause of cirrhosis found, but published before availability of tests for hepatitis C).

  116. Szanto E, Sandstedt B, Kollberg B. Hepatotoxicity associated with low-dose, long-term methotrexate treatment of rheumatoid arthritis. Scand J Rheumatol 1987; 16: 229-34. PubMed Citation  (Among 17 patients with rheumatoid arthritis treated with methotrexate for 1-5 years, liver biopsies were normal in 16 with only mild fatty change and nuclear variability; 1 patient had mild fibrosis [0.6 g total dose and normal ALT levels]).

  117. Weber BL, Tanyer G, Poplack DG, Reaman GH, Feusner JH, Miser JS, Bleyer WA. Transient acute hepatotoxicity of high-dose methotrexate therapy during childhood. NCI Monogr 1987; 5: 207-12. PubMed Citation  (Among 24 children with acute leukemia treated with 75 cycles of very high dose methotrexate [33.6 g/24 hr] and leucovorin rescue, ALT elevations occurred in 30% after first course but in >92% after 3 courses, values reaching 1500 U/L, Alk P and bilirubin elevations peaking later, sometimes with symptoms, but without any long term clinically apparent consequences).

  118. Zachariae H, Schrøder H, Foged E, Søgaard H. Methotrexate hepatotoxicity and concentrations of methotrexate and folate in erythrocytes - relation to liver fibrosis and cirrhosis. Acta Derm Venereol 1987; 67: 336-40. PubMed Citation  (Assessment of red cell folate levels and liver histology in 30 patients with psoriasis receiving long term methotrexate therapy found no correlation of folate levels with severity of liver injury, duration of therapy or dose).

  119. Zachariae H, Søgaard H. Methotrexate-induced liver cirrhosis. A follow-up. Dermatologica 1987; 175: 178-82. PubMed Citation  (Analysis of 113 liver biopsies from 25 patients with psoriasis who developed cirrhosis on methotrexate therapy; cirrhosis found after 0.6-10 g [mean=3.1 g] of methotrexate; 21 patients were continued on therapy [at lowest possible dose and with prohibition against alcohol] for up to 9 years without evidence of worsening liver disease or clinical decompensation).

  120. Hendel J, Poulsen H, Nyfors A. Changes in liver histology during methotrexate therapy of psoriasis correlated to the concentration of methotrexate and folate in erythrocytes. Acta Pharmacol Toxicol (Copenh) 1987; 56: 321-6.  (Letter in response to Zachariae et al. [1987] stressing the need to monitor serial red blood cell folate levels in assessing methotrexate hepatotoxicity).

  121. Aponte J, Petrelli M. Histopathologic findings in the liver of rheumatoid arthritis patients treated with long-term bolus methotrexate. Arthritis Rheum. 1988; 31: 1457-64. PubMed Citation  (Among 23 patients with rheumatoid arthritis treated with methotrexate for more than 1 years [total dose 4.7-10.2 g] using weekly regimens, 52% had serum enzyme elevations and 21 underwent liver biopsy which was normal in 68% and showed mild fibrosis in 24%; none had severe fibrosis or cirrhosis).

  122. Paramsothy H, Strange R, Shariff H, Collins M, Shaw P, Lawrence CM. The use of antipyrine clearance to measure liver damage in patients receiving methotrexate. Br J Dermatol 1988; 119: 761-5. PubMed Citation  (Among 15 patients with psoriasis on methotrexate, aminopyrine saliva clearance tests correlated with degree of liver abnormality, but without clear demarcation of abnormal result).

  123. Banerjee AK, Lakhani S, Vincent M, Selby P. Dose-dependent acute hepatitis associated with administration of high dose methotrexate. Hum Toxicol 1988; 7: 561-2. PubMed Citation  (18 year old girl with osteosarcoma given high dose methotrexate [20 g] and leucovorin rescue had rise of ALT to 908 U/L at day 10, rapidly falling to normal with minimal rise with subsequent dose of 0.8 g intravenously).

  124. Bjorkman DJ, Hammond EH, Lee RG, Clegg DO, Tolman KG. Hepatic ultrastructure after methotrexate therapy for rheumatoid arthritis. Arthritis Rheum 1988; 31: 1465-72. PubMed Citation  (Liver biopsy analyses in 26 patients treated with methotrexate for 1 to 10 years, most had some abnormality and all had increased collagen in space of Disse by electron microscopy; by light microscopy, 62% had steatosis, 12% inflammation and 15% mild pericentral fibrosis not seen in control biopsy material).

  125. Kevat S, Ahern M, Hall P. Hepatotoxicity of methotrexate in rheumatic diseases. Med Toxicol Adverse Drug Exp 1988; 3: 197-208. PubMed Citation  (Detailed review of liver histology changes associated with methotrexate use and authors' recommendations for liver biopsy before and during therapy [after 1.5 g and every 2 years thereafter]).

  126. Lewis JH, Schiff E. Methotrexate-induced chronic liver injury: guidelines for detection and prevention. The ACG Committee on FDA-related matters. American College of Gastroenterology. Am J Gastroenterol 1988; 83: 1337-45. PubMed Citation  (Review of methotrexate induced liver disease and recommendations for monitoring).

  127. Kremer JM, Lee JK. A long-term prospective study of the use of methotrexate in rheumatoid arthritis. Update after a mean of fifty-three months. Arthritis Rheum 1988; 31: 577-84. PubMed Citation  (Further follow up on cohort of 29 patients with rheumatoid arthritis treated with methotrexate for average of 4 years [2.5-6 years] found sustained improvements in 25 patients, 22 had at least one elevation in AST levels).

  128. Risteli J, Sød H, Oikarinen A, Risteli L, Karvonen J, Zachariae H. Aminoterminal propeptide of type III procollagen in methotrexate-induced liver fibrosis and cirrhosis. Br J Dermatol. 1988; 119: 321-5. PubMed Citation  (Among 24 patients with psoriasis on methotrexate therapy, PIIIP elevations found in none of 9 with normal liver biopsy, 5 of 9 with fibrosis and 2 of 5 with cirrhosis).

  129. Shergy WJ, Polisson RP, Caldwell DS, Rice JR, Pisetsky DS, Allen NB. Methotrexate-associated hepatotoxicity: retrospective analysis of 210 patients with rheumatoid arthritis. Am J Med 1988; 85: 771-4. PubMed Citation  (Analysis of 538 liver biopsies done on 399 patients with various diagnoses being monitored during methotrexate therapy, found 2 with cirrhosis and 12 with fibrosis; but only 6 of 210 patients with rheumatoid arthritis had fibrosis and none had cirrhosis; the 6 with fibrosis included 5 with obesity, 3 with diabetes, but only one with liver test abnormalities [all <2 times ULN]).

  130. Weinblatt ME, Trentham DE, Fraser PA, Holdsworth DE, Falchuk KR, Weissman BN, Coblyn JS. Long-term prospective trial of low-dose methotrexate in rheumatoid arthritis. Arthritis Rheum 1988; 31: 167-75. PubMed Citation  (Among 26 patients with rheumatoid arthritis treated long term, 8 [31%] had ALT or AST elevations >2 times ULN, but all resolved and none required permanent discontinuation; liver biopsies done in 17 showed no fibrosis, but minor degrees of fat and inflammation [15 grade I, 2 grade II Roenigk changes]).

  131. Roenigk HH Jr, Auerbach R, Maibach HI, Weinstein GD. Methotrexate in psoriasis: revised guidelines. J Am Acad Dermatol 1988; 19: 145-56. PubMed Citation  (Expert advice and guidelines for use of methotrexate in psoriasis; recommends pretreatment liver biopsy, serum enzymes every 3-4 months, biopsy after 1.5 g total dose and repeat biopsies based upon liver test abnormalities and second biopsy results; discusses Roenigk grading system of I-IV and recommends stopping methotrexate if grades IIIB or IV are found).

  132. Alarcón GS, Tracy IC, Blackburn WD Jr. Methotrexate in rheumatoid arthritis. Toxic effects as the major factor in limiting long-term treatment. Arthritis Rheum 1989; 32: 671-6. PubMed Citation  (Among 152 patients with rheumatoid arthritis started on methotrexate, only 50% remained on long-term [>5 year] therapy; toxicity accounted for 60% of discontinuations; none were hepatic and liver biopsies in 9 showed no fibrosis).

  133. McKendry RJ, Cyr M. Toxicity of methotrexate compared with azathioprine in the treatment of rheumatoid arthritis. A case-control study of 131 patients. Arch Intern Med 1989; 149: 685-9. PubMed Citation  (Among 131 patients with rheumatoid arthritis treated for up to 5 years, elevated liver tests > twice the ULN occurred in 14% of 94 patients on methotrexate vs none of 37 on azathioprine).

  134. Bridges SL Jr, Alarcón GS, Koopman WJ. Methotrexate-induced liver abnormalities in rheumatoid arthritis. J Rheumatol 1989; 16: 1180-3. PubMed Citation  (Editorial on hepatotoxicity of methotrexate in rheumatoid arthritis comments on the infrequency of significant fibrosis in cohorts studied from the United States and recommends that routine pretreatment and during-treatment liver biopsies are not needed in patients with normal liver tests and no risk factors for liver disease).

  135. Clegg DO, Furst DE, Tolman KG, Pogue R. Acute, reversible hepatic failure associated with methotrexate treatment of rheumatoid arthritis. J Rheumatol 1989; 16: 1123-6. PubMed Citation  (Two women with rheumatoid arthritis developed liver disease on methotrexate; 38 year old developed steatosis and fibrosis after 4 years and cirrhosis with ascites after 5 years, improving on stopping therapy: Case 1; 54 year old with mild fibrosis on liver biopsy before therapy developed ascites and jaundice after two years, improving on stopping methotrexate).

  136. O'Connor GT, Olmstead EM, Zug K, Baughman RD, Beck JR, Dunn JL, Seal P, et al. Detection of hepatotoxicity associated with methotrexate therapy for psoriasis. Arch Dermatol 1989; 125: 1209-17. PubMed Citation  (Retrospective analysis of 147 liver biopsies done in 78 patients with psoriasis treated with methotrexate found fibrosis or cirrhosis in 5 [10%] before and 23 [24%] on therapy; individual liver tests had poor sensitivity and specificity for detecting fibrosis, but authors developed an algorithm with reasonable accuracy; final model included age, sex, AST, Alk P, cholecystitis history and cumulative dose).

  137. Kremer JM, Lee RG, Tolman KG. Liver histology in rheumatoid arthritis patients receiving long-term methotrexate therapy: a prospective study with baseline and sequential biopsy samples. Arthritis Rheum 1989; 32: 121-7. PubMed Citation  (27 patients with rheumatoid arthritis treated with methotrexate for 1-6 years underwent 101 liver biopsies; no patient had fibrosis on pretreatment biopsy, but rates increased to 8% at 2, 16% at 3, and 40% at 4 years; correlated with duration of therapy, patient age and history of alcohol use, but not AST or ALT elevations which were often raised; no cirrhosis).

  138. Kremer JM, Kaye GI. Electron microscopic analysis of sequential liver biopsy samples from patients with rheumatoid arthritis: correlation with light microscopic findings. Arthritis Rheum 1989; 32: 1202-13. PubMed Citation  (Analysis of 52 liver biopsies from 22 patients with rheumatoid arthritis treated with methotrexate for 2-6 years found only minor, nonspecific changes by electron microscopy).

  139. Rau R, Karger T, Herbern G, Fernzel H. Liver biopsy findings in patients with rheumatoid arthritis undergoing long-term treatment with methotrexate. J Rheumatol 1989; 16: 489-93. PubMed Citation  (Analysis of liver biopsies from 60 patients with rheumatoid arthritis, comparing 60 from before therapy to 40 taken during therapy [mean total dose 1.3 g] found no significant difference using a semiquantitative analysis of 10 features including fibrosis, fat, ballooning, necrosis and inflammation; normal findings in 68% before vs 58% on therapy, fibrosis in 15% vs 25%; ALT elevations in 15% vs 50%).

  140. Newman M, Auerbach R, Feiner H, Holzman RS, Shupack J, Migdal P, Culubret M, et al. The role of liver biopsies in psoriatic patients receiving long-term methotrexate treatment improvement in the abnormalities after cessation of treatment. Arch Dermatol 1989; 125: 1218-24. PubMed Citation  (Retrospective analysis of 364 liver biopsies from 168 patients with psoriasis treated with methotrexate for 0 to 19 years [mean=4 years]; among 83 biopsies before therapy, 80% were normal, 20% had fibrosis, none cirrhosis [those with cirrhosis were not treated]; during treatment, fibrosis scores increased but rarely by much and most improved with subsequent withdrawal of therapy).

  141. Brick JE, Moreland LW, Al-Kawas F, Chang WWL, Layne RD, DiBartolomeo AG. Prospective analysis of liver biopsies before and after methotrexate therapy in rheumatoid arthritis patients. Semin Arthritis Rheum 1989; 19: 31-44. PubMed Citation  (Among liver biopsies done in 96 patients with rheumatoid arthritis before or after methotrexate therapy, fibrosis was found in 3% of 62 pretreatment and 10-12% of 88 posttreatment biopsies, cirrhosis was found in 2 patients, but alcohol was blamed in one instance).

  142. Zacchariae H, Sogaard H, Heikendorff L. Serum aminoterminal propeptide of type III procollagen: a non-invasive test for liver fibrogenesis in methotrexate-treated psoriasis. Acta Derm Venereol 1989; 69: 241-4. PubMed Citation  (Serum PIIIP levels were assessed in 72 patients with psoriasis before or during methotrexate therapy; mean levels were higher in patients with fibrosis [5.2 vs 3.3 µg/L] but considerable overlap in values; serial results in 11 patients were normal in most).

  143. Drosos AA, Psychos D, Andonopoulos AP, Stefanaki-Nikou S, Tsianos EB, Moutsopoulos HM. Methotrexate therapy in rheumatoid arthritis. A two year prospective follow-up. Clin Rheumatol 1990; 9: 333-41. PubMed Citation  (Among 130 Greek patients with rheumatoid arthritis treated with methotrexate [7.5-15 mg/week] for up to 2 years, 25% developed raised serum enzymes, requiring discontinuation in 4%; liver biopsies in 41 patients [mean total dose 1550 mg] showed mild fibrosis in 15%, no cirrhosis and no correlation with ALT elevations).

  144. Fries JF, Singh G, Lenert L, Furst DE. Aspirin, hydroxychloroquine, and hepatic enzyme abnormalities with methotrexate in rheumatoid arthritis. Arthritis Rheum 1990; 33: 1611-9. PubMed Citation  (Among "nearly" 2,600 patients with rheumatoid arthritis in the ARAMIS database, abnormal ALT values were present in <5%, highest rates in those on salicylates [7.6%], sulindac [8.3%], methotrexate [9.5%] and lowest in those on hydroxychloroquine even in combination with methotrexate and salicylates).

  145. Flowers MA, Heathcote J, Wanless IR, Sherman M, Reynolds WJ, Cameron RG, Levy GA, et al. Fulminant hepatitis as a consequence of reactivation of hepatitis B virus infection after discontinuation of low-dose methotrexate therapy. Ann Intern Med 1990; 112: 381-2. PubMed Citation  (57 year old woman with rheumatoid arthritis and inactive HBsAg carrier state, developed severe hepatitis 22 days after stopping methotrexate [given for 7 years] for pulmonary toxicity with appearance of HBV DNA and IgM anti-HBc, progression to hepatic failure and successful liver transplantation after which she remained HBsAg positive; use of corticosteroids not mentioned).

  146. Gilbert SC, Klintmalm G, Menter A, Silverman A. Methotrexate-induced cirrhosis requiring liver transplantation in three patients with psoriasis. A word of caution in light of the expanding use of this 'steroid-sparing' agent. Arch Intern Med 1990; 150: 889-91. PubMed Citation  (Three patients with psoriasis underwent liver transplantation for methotrexate induced cirrhosis; ages 39, 46 and 59 years, treated for 5, 10 and 12 years, total doses of 9.5-26 g, presenting with anasarca, liver failure and variceal hemorrhage, two survived and had excellent remission in psoriasis; none had undergone surveillance liver biopsies; no mention of hepatitis C testing or alcohol history).

  147. Kaito K, Katayama T, Yoshida M, Saito A, Kobayashi M, Ochiai S, Masuoka S, et al. [Fulminant hepatic failure induced by intermediate dose methotrexate in a case of non-Hodgkin's lymphoma]. Rinsho Ketsueki 1990; 31: 1862-7. Japanese. PubMed Citation

  148. Keim D, Ragsdale C, Heidelberger K, Sullivan D. Hepatic fibrosis with the use of methotrexate for juvenile rheumatoid arthritis. J Rheumatol 1990; 17: 846-8. PubMed Citation  (17 year old girl with juvenile rheumatoid arthritis had a normal liver biopsy after 1.5 years of methotrexate therapy, but had mild fibrosis (Roenigk IIIA) on biopsy after 3.5 years and methotrexate was stopped; AST levels were minimally and transiently elevated during the first 2 years of therapy and repeatedly normal thereafter).

  149. Gabriel S, Cregsen E, O'Fallen WM, Jaquith J, Bunch T. Treatment of rheumatoid arthritis with higher dose intravenous methotrexate. J Rheumatol 1990; 17: 460-5. PubMed Citation  (Pilot study of intravenous, higher dose methotrexate for resistant rheumatoid arthritis; AST values increased by an average of 13 U/L; maximum level was 50 U/L).

  150. Furst DE, Erickson N, Clute L, Koehnke R, Burmeister L, Kohler J. Adverse experience with methotrexate during 176 weeks of a long-term prospective trial in rheumatoid arthritis patients. J Rheumatol 1990; 17: 1628-35. PubMed Citation  (Among 45 patients with rheumatoid arthritis treated with methotrexate for up to 3 years, 97% had side effects leading to dose modifications in 71%; ALT elevations above 3 times ULN occurred in 33% of patients, but were usually not a reason for changing the dose on their own).

  151. Mitchell D, Smith A, Rowan B, Warnes TW, Haboubi NY, Lucas SB, Chalmers RJ. Serum type III procollagen peptide, dynamic liver function tests and hepatic fibrosis in psoriatic patients receiving methotrexate. Br J Dermatol 1990; 122: 1-7. PubMed Citation  (PIIIP levels were measured in 51 patients with psoriasis on methotrexate for 1-13 years [10 with fibrosis, 3 cirrhosis] and controls; levels were often raised in treated patients [69%], but with somewhat poor correlation to hepatic histology and serum enzyme elevations; BSP and galactose clearance tests were similarly poorly predictive and of limited practicality).

  152. Wilkens RF, Leonard PA, Clegg DO, Tolman KG, Ward JR, Marks CR, Greene ML, et al. Liver histology in patients receiving low dose pulse methotrexate for the treatment of rheumatoid arthritis. Ann Rheum Dis 1990; 49: 591-3. PubMed Citation  (Liver biopsies were done on 52 patients with rheumatoid arthritis treated with methotrexate [7.5-15 mg/week] for 2-8 years [773-3913 mg]; fibrosis found in 29%, cirrhosis in none, and only 2 were normal; grade of abnormality did not correlate with age, duration of treatment, total dose or serum enzyme elevations [elevated at least once in 90%]).

  153. Odeh M. Methotrexate, liver abnormalities and RA. J Rheumatol 1990; 17: 853-4. PubMed Citation  (Letter in response to Rau et al. [1989] arguing against the conclusion that methotrexate does not induce liver injury; reply by the authors).

  154. Kujala GA, Shamma'a JM, Chang WL, Brick JE. Hepatitis with bridging fibrosis and reversible hepatic insufficiency in a woman with rheumatoid arthritis taking methotrexate. Arthritis Rheum 1990; 33: 1037-41. PubMed Citation  (58 year old woman with rheumatoid arthritis on oral methotrexate 10 mg weekly for 6 years [2.7 g total dose] developed ascites with bilirubin 1.6 mg/dL, Alk P 100 U/L, ALT 12 U/L, albumin 3 g/dL, platelets 133,000 μ/L, liver biopsy showing bridging fibrosis, responding to diuretics).

  155. Zachariae H. Methotrexate side-effects. Br J Dermatol 1990; 122 Suppl 36: 127-33. PubMed Citation  (Review of side effects of methotrexate; table showing results of 25 patients with psoriasis who developed cirrhosis after 1-10 years of therapy [total dose 0.5-6.5 g], many of whom were able to continue methotrexate for another 1-8 years).

  156. Weinblatt ME, Kaplan H, Germain BF, Merriman RC, Solomon SD, Wall B, Anderson L, et al. Low-dose methotrexate compared with auranofin in adult rheumatoid arthritis. A thirty-six-week, double-blind trial. Arthritis Rheum 1990; 33: 330-8. PubMed Citation  (Among 281 patients with rheumatoid arthritis treated for 36 weeks, those treated with methotrexate had higher, earlier and better clinical responses; ALT elevations >2 times ULN occurred in 24% of methotrexate- vs 7% of gold-treated patients, requiring discontinuation in 6% vs 1.4%).

  157. Schmiegelow K, Pulczynska M. Prognostic significance of hepatotoxicity during maintenance chemotherapy of childhood acute leukemia. Br J Cancer 1990; 61: 767-72. PubMed Citation  (Among 115 children on maintenance chemotherapy for leukemia with methotrexate and mercaptopurine, ALT levels were on average elevated [>40 U/L] in 60% and this group had a lower rate of relapse; elevations tended to decrease over time during long-term therapy).

  158. Rose CD, Singsen B, Eichenfield AH, Goldsmith DP, Athreya BH. Safety and efficacy of methotrexate therapy for juvenile rheumatoid arthritis. J Pediatr 1990; 117: 653-9. PubMed Citation  (29 children with juvenile rheumatoid arthritis were treated with methotrexate [~7 mg/m2/week] for 8 to 39 months; >80% response rate and only 1 child had ALT elevations, which were transient, resolving with dose reduction).

  159. Martini A, Ravelli A, Viola S, Burgio RG. Methotrexate hepatotoxic effects in children with juvenile rheumatoid arthritis. J Pediatr 1991; 119: 333-4. PubMed Citation  (Letter in response to Rose et al. [1990]; authors treated 27 children with methotrexate for 6 to 30 months [~9 mg/m2] with 74% response rate; 56% had ALT elevations, all self-limiting or resolving with stopping).

  160. Zachariae H, Aslam HM, Bjerring P, Sogaard H, Zachariae E, Heickendorff L. Serum aminoterminal propeptide of type III precollagen in psoriasis and psoriatic arthritis: relation to liver fibrosis and arthritis. J Am Acad Dermatol 1991; 25: 50-3. PubMed Citation  (PIIIP levels were assessed in 170 patients with psoriasis being treated with methotrexate; levels were usually elevated in those with psoriatic arthritis [38% without fibrosis], but elevations in those with psoriasis alone were reliable markers for fibrosis or cirrhosis on liver biopsy [67% of 24] vs nonspecific or normal findings [4% of 52]; no correlation between ALT and PIIIP levels).

  161. Mehdi A, Marteau P, Lavergne A, Molho-Sabatier P, Cochand-Priollet B, Caen J, Rambaud JC. [Hepatocellular carcinoma in a patient with psoriasis and methotrexate-induced cirrhosis]. Gastroenterol Clin Biol 1991; 15: 464-5. French. PubMed Citation  (64 year old man with psoriasis presented with 16 cm hepatocellular carcinoma having a history of 2 years of therapy with methotrexate [total dose 3 g] and arsenic [1.5 g] 20 years earlier; negative for HCV, HBV and iron markers).

  162. Scully CJ, Anderson CJ, Cannon GW. Long-term methotrexate therapy for rheumatoid arthritis. Semin Arthritis Rheum 1991; 20: 317-31. PubMed Citation  (Analysis of 124 patients with rheumatoid arthritis treated with methotrexate, 39 for more than 5 years; elevated serum enzymes in 70% which resulted in stopping in 7%; 57 liver biopsies done in 40 patients after mean of 2.7 years [1.3 g] of which 17 [30%] showed fibrosis but none cirrhosis, but only 2 of these stopped therapy).

  163. Hall PD, Ahern MJ, Jarvis LR, Stoll P, Jenner MA, Harley H. Two methods of assessment of methotrexate hepatotoxicity in patients with rheumatoid arthritis. Ann Rheum Dis 1991; 50: 471-6. PubMed Citation  (Comparison of two methods of assessing collagen in serial liver biopsies from 18 patients with rheumatoid arthritis on methotrexate for 1-12 years; mild increases in pericellular collagen were best shown by computerized morphometry, but presence of collagen did not correlate with total methotrexate dose).

  164. Ahern MJ, Kevat S, Hill W, Hayball PJ, Harley H, Hall PD. Hepatic methotrexate content and progression of hepatic fibrosis: preliminary findings. Ann Rheum Dis 1991; 50: 477-80. PubMed Citation  (Among 16 patients with rheumatoid arthritis treated with methotrexate for 1-6 years undergoing paired liver biopsies and quantitative assessment of fibrosis [image analysis], the 3 patients with the most progression [>3.5%] had high levels of methotrexate and its glutamates in liver).

  165. Wolfe F, Cathey MA. The effect of age on methotrexate efficacy and toxicity. J Rheumatol 1991; 18: 973-7. PubMed Citation  (Among 235 patients with rheumatoid arthritis treated with methotrexate, at least one AST elevation occurred in 26% of 51 elderly [>65 years] compared to 31% of 184 younger patients).

  166. Whiting-O'Keefe QE, Fye KH, Sack KD. Methotrexate and histologic hepatic abnormalities: a meta-analysis. Am J Med 1991; 90: 711-6. PubMed Citation  (Meta analysis of 15 studies of liver histology during long term, low dose methotrexate therapy in psoriasis [n=299] and rheumatoid arthritis [n=334]; progression in one Roenigk score after each gram of methotrexate in 6.9% of patients, correlating with cumulative dose and alcohol use; advanced fibrosis [Roenigk IIIB and IV] in 5%, higher in alcoholics and in psoriasis).

  167. Singh G, Fries JF, Williams CA, Zatarain E, Spitz P, Bloch DA. Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis. J Rheumatol 1991; 18: 188-94. PubMed Citation  (Analysis of side effects of 7 agents from the ARAMIS database including 2,479 patients with rheumatoid arthritis [497 on methotrexate for 735 person-years] reported 41 instances of liver abnormalities and 2 of jaundice in patients on methotrexate, rates higher than gold, hydroxychloroquine, penicillamine, azathioprine and cyclosphosphamide).

  168. Watson RG, Smallwood RA. Low-dose methotrexate therapy and hepatotoxicity. The view of the hepatologist. Med J Aust 1991; 155: 428-30. PubMed Citation  (Editorial on hepatotoxicity of long term, low dose methotrexate therapy stressed the lack of progression of fibrosis found in many publications and that 0-22% of patients had fibrosis and 0-1.5% had cirrhosis even before therapy; "the balance of evidence indicates that the risk of liver damage is small").

  169. Grosflam J, Weinblatt ME. Methotrexate: mechanism of action, pharmacokinetics, clinical indications, and toxicity. Current Opin Rheumatol 1991; 3: 363-8. PubMed Citation  (Review of recent literature on mechanism of action, pharmacokinetics, clinical indications and toxicity; summary of 7 papers on hepatotoxicity).

  170. Korman MG. Low-dose methotrexate therapy and hepatotoxicity. Med J Aust 1992; 156: 221. PubMed Citation  (Letter in response to Watson and Smallwood [1991] questioning wisdom of using routine liver tests to monitor for methotrexate liver injury).

  171. Aponte J, Petrelli M, von Dawson N. Liver enzyme levels in arthritis patients treated with long-term bolus methotrexate. Arthritis Rheum 1992; 35: 126-8. PubMed Citation  (Analysis of ALT, AST and GGT levels in 40 patients treated with methotrexate for more than 10 years found no difference in serum enzymes or liver histology in patients with or without concurrent hydroxychloroquine treatment).

  172. Kremer JM, Phelps CT. Long term prospective study of the use of methotrexate in the treatment of rheumatoid arthritis: update after mean of 90 months. Arthritis Rheum 1992; 35: 138-45. PubMed Citation  (Update on clinical trial of long term methotrexate in 29 patients with rheumatoid arthritis, including 18 patients still on therapy [for 6-9 years; total dose ~6 g]; no discussion of hepatotoxicity).

  173. Kremer JM. Liver biopsies in patients with rheumatoid arthritis receiving methotrexate. Where are we going? J Rheumatol 1992; 19: 189-91. PubMed Citation  (Editorial on liver biopsy recommendations for patients with rheumatoid arthritis receiving methotrexate; recommended baseline biopsy only for patients with abnormal liver tests or at high risk for having liver disease and repeat biopsy on therapy for repeated AST elevations or decrease in serum albumin, stopping therapy if significant fibrosis is found [Roenigk grade IIIB or IV]).

  174. Tishler M, Caspi D, Halperin Z, Baratz M, Moshkowitz M, Yaron M. A prospective analysis of liver biopsies in rheumatoid arthritis patients receiving long term methotrexate therapy. Rheumatol Int 1992; 12: 39-41. PubMed Citation  (Analysis of paired liver biopsies from 10 patients with rheumatoid arthritis before and after methotrexate therapy for 4-7.5 years [total dose 1.4 to 7.5 g], showed no progression in fibrosis, despite AST elevations in 30%; 1 patient had mild fibrosis before therapy and amount did not change).

  175. Graham LD, Myones BL, Rivas-Chacon RF, Pachman LM. Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. J Pediatr 1992; 120: 468-73. PubMed Citation  (Among 62 children with juvenile rheumatoid arthritis treated with methotrexate for 1-6 years, 9 had ALT elevations [119-1500 U/L], resolving with stopping but no recurrence on restarting; liver biopsy in 12 [after 0.8 to 1.4 g] found none with fibrosis).

  176. Locasciulli A, Mura R, Fraschini D, Gornati GL, Scoven E, Gervasoni A, Uderzo C, et al. High-dose methotrexate administration and acute liver damage in children treated for acute lymphoblastic leukemia. A prospective study. Haematologica 1992; 77: 49-53. PubMed Citation  (Among 68 children with acute leukemia treated with high dose methotrexate monitored with liver tests before and 1 and 2 weeks after each of 272 courses, 88% had ALT elevations during induction courses and 38% during consolidation; 85% had mild indirect hyperbilirubinemia, but only 1 patient had hepatotoxicity [peak ALT 700 U/L and jaundice], which resolved rapidly).

  177. Phillips CA, Cera PJ, Mangan TF, Newman ED. Clinical liver disease in patients with rheumatoid arthritis taking methotrexate. J Rheumatol 1992; 19: 229-33. PubMed Citation  (Among 134 patients with rheumatoid arthritis treated with methotrexate, 3 [2%] developed histologic signs of severe liver disease; ages 58-68 years, treated for 2-4 years [total dose 1.3-1.6 g] with biopsy showing advanced fibrosis [n=2] or cirrhosis [n=1], 2 with ascites, 1 died; none were alcoholic, 2 had normal pretreatment biopsy; AST levels elevated on therapy in 2, GGT in the third).

  178. Themido R, Loureiro M, Pecegueiro M, Brandão M, Campos MC. Methotrexate hepatotoxicity in psoriatic patients submitted to long-term therapy. Acta Derm Venereol 1992; 72: 361-4. PubMed Citation  (Analysis of paired liver biopsies done in 30 Portuguese patients with psoriasis before and on methotrexate [0.2-7 g], 8 had fibrosis before therapy; 7 [23%] developed fibrosis and 3 [10%] cirrhosis on treatment).

  179. McHenry PM, Bingham EA, Callender ME, Delvin PB, O'Hara MD, Ferguson WR, Laird JD, et al. Dynamic hepatic scintigraphy in the screening of patients for methotrexate-induced hepatotoxicity. Br J Dermatol 1992; 127: 122-5. PubMed Citation  (Among 63 patients with psoriasis having 87 dynamic scintigraphy scans during methotrexate therapy, 20 scans were abnormal, including 83% of 6 with moderate-severe fibrosis and 22% of 81 without fibrosis).

  180. Weinblatt ME, Weissman BN, Holdsworth DE, Fraser PA, Maier AL, Falchuk KR, Coblyn JS. Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis: 84-month update. Arthritis Rheum 1992; 35: 129-37. PubMed Citation  (26 patients with rheumatoid arthritis enrolled in study of methotrexate [7.5-15 mg weekly], liver biopsies showed no fibrosis at 2 years [n=17; mean dose 1.1 g], one at 4 years [n=15; 2.0 g], and another at 6 years [n=10, 3.1 g]; both cases were Roenigk IIIA only, but both had normal biopsy previously).

  181. Arias JM, Morton KA, Albro TE, Patch GG, Valdivia S, Greenberg HE, Christian PE, et al. Comparison of methods for identifying early methotrexate-induced hepatotoxicity in patients with rheumatoid arthritis. J Nucl Med 1993; 34: 1905-9. PubMed Citation  (Analysis of 16 patients undergoing 22 sets of noninvasive tests of liver disease while on methotrexate for 0.5 to 8 years; comparing 13 patients with minimal or no histologic changes to 9 patients with Roenigk II and III changes, liver enzymes were elevated in 0% vs 22%, aminopyrine breath tests 54% vs 55%, hepatic technitium scans 0% vs 11%; none being adequately sensitive and specific compared to liver biopsy).

  182. Walker AM, Funch D, Dreyer NA, Tolman KG, Kremer JM, Alarcón GS, Lee RG, et al. Determinants of serious liver disease among patients receiving low-dose methotrexate for rheumatoid arthritis. Arthritis Rheum 1993; 36: 329-35. PubMed Citation  (In a survey of 107 US rheumatologists, they identified 24 verifiable cases of cirrhosis attributable to methotrexate and compared them to 39 matched controls; patients with cirrhosis were older [54 vs 42 years], received a higher cumulative dose [1.9 vs 0.7 g], but did not differ by body weight, diabetes, sex, other medication use or recorded alcohol use; estimated rate of serious liver disease as 0.1% after 5 years of methotrexate use).

  183. Minocha A, Dean HA, Pittsley RA. Liver cirrhosis in rheumatoid arthritis patients with long-term methotrexate. Vet Human Toxicol 1993; 35: 45-8. PubMed Citation  (Among 25 patients with rheumatoid arthritis undergoing 29 surveillance liver biopsies during methotrexate therapy [1-5 years], 1 had fibrosis and 2 cirrhosis [both had elevations in serum enzymes and were obese and diabetic]).

  184. Brass EP. Hepatic toxicity of antirheumatic drugs. Cleve Clin J Med 1993; 60: 466-72. PubMed Citation  (Short review of hepatotoxicity of nonsteroidals, salicylates, methotrexate, penicillamine and gold).

  185. Nohlgard C, Rubio CA, Kock Y, Hammar H. Liver fibrosis quantified by image analysis in methotrexate-treated patients with psoriasis. J Am Acad Dermatol 1993; 28: 40-5. PubMed Citation  (Sirius red staining on 46 liver biopsies from 26 patients with psoriasis analyzed by image analysis found higher percent of fibrosis in patients with psoriasis than controls [0.9%], but no correlation with methotrexate therapy, total dose, nor with Roenigk classification [Grade I with 11.4%, IIIA with 9.3%, IIIB 24% and IV 11.8%]).

  186. Carvallo A, Wolff C, Armas R, Villanueva P, Donoso G, Náira N, Lobo G, et al. [Rheumatoid arthritis. Therapeutic efficacy of methotrexate and its hepatotoxic effects]. Rev Med Chil 1993; 121: 777-84. Spanish. PubMed Citation

  187. Lacki JK, Samborski W, Machiewicz SH. Transient increase of aminotransferases in RA patients treated with methotrexate. Z Rheumatol 1993; 52: 232-5. PubMed Citation

  188. Shiroky JB, Neville C, Esdaile JM, Choquette D, Summer M, Hazeltine M, Bykerk V, et al. Low-dose methotrexate with leucovorin(folinic acid) in the management of rheumatoid arthritis. Results of a multicenter randomized, double-blind, placebo-controlled trial. Arthritis Rheum 1993; 36: 795-803. PubMed Citation  (Among 92 patients with rheumatoid arthritis treated with methotrexate and either placebo or folinic acid, there were fewer side effects in those on folate [60% reduction in enzyme elevations] with no difference in efficacy).

  189. McKendry RJ, Dale P. Adverse effects of low dose methotrexate therapy in rheumatoid arthritis. J Rheumatol 1993; 20: 1850-6. PubMed Citation  (Among 144 patients with rheumatoid arthritis starting methotrexate therapy, 75% stopped therapy before 5 years; 53% for adverse events, 14% for elevated liver tests, usually in first 2 years).

  190. Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, Koopman WJ, et al. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind placebo-controlled trial. Ann Intern Med 1994; 121: 833-41. PubMed Citation  (79 patients with rheumatoid arthritis treated with methotrexate were given placebo or 5 or 27.5 mg of folate weekly; efficacy was similar, but side effects were less with folate treatment, particularly at higher dose; also prevented folate deficiency which occurred by one year in placebo recipients).

  191. Kremer JM, Alarcon GS, Lightfoot RW, Wilkens RF, Furst DE, Willliams HJ, Dent PB, et al. Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. Arthritis Rheum 1994; 37: 316-28. PubMed Citation  (Review of hepatotoxicity of methotrexate in rheumatoid arthritis and delineation of guidelines; among 295 biopsies taken before therapy, only 3.7% had fibrosis and none cirrhosis, compared to fibrosis rates of 15% and cirrhosis of 0.3% on treatment; ALT elevations >2 times ULN occurred in 3.4% on methotrexate vs 0.4% on placebo or gold usually during first 2-3 years; recommend pretreatment biopsy only in patients with raised enzymes or risk factors for liver disease, regular liver test monitoring at 4-8 week intervals and repeat liver biopsy if AST elevations occur [at least 5] or albumin levels fall; discontinue if Roenigk grade IIIB or IV or if AST elevations present and unable to do liver biopsy).

  192. Petrazzuoli M, Rothe MJ, Grin-Jorgensen C, Ramsey WH, Grant-Kels JM. Monitoring patients taking methotrexate for hepatotoxicity. J Am Acad Dermatol 1994; 31: 969-77. PubMed Citation  (Survey of 70 gastroenterologists in practice; only 33% were monitoring patients with psoriasis or rheumatoid arthritis on methotrexate therapy).

  193. Breithaupt H. [Drug-induced liver damage caused by antirheumatic drugs - antirheumatic therapy in pre-existing liver damage]. Z Rheumatol 1994; 53: 250-4. German. PubMed Citation

  194. Exadaktylos P, Reiss T, Schobess R, Hommann M, Höhne S, Beck A. [Acute hepatotoxicity with intermediate-dose methotrexate in children with leukemia and non-Hodgkin's lymphoma]. Klin Padiatr 1994; 206: 315-8. German. PubMed Citation

  195. Fabbri A, Motta E, Ferrari S, Longhi C, Marchi E, Bacci G, Figus E, et al. High-dose methotrexate treatment and liver function in patients with osteosarcoma. J Intern Med 1994; 236: 209-14. PubMed Citation  (Among 14 patients with osteosarcoma who had received high dose methotrexate therapy [30-57 g/m2], galactose elimination decreased minimally while aminopyrine clearance and routine liver tests did not change between baseline and end of therapy).

  196. Goodman TA, Polisson RP. Methotrexate: adverse reactions and major toxicities. Rheum Dis Clin North Am 1994; 20: 513-28. PubMed Citation  (Review of side effects of methotrexate therapy in rheumatoid arthritis).

  197. Schnabel A, Reinhold-Keller E, Willmann V, Gross WL. Tolerability of methotrexate starting with 15 or 25 mg/week for rheumatoid arthritis. Rheumatol Int 1994; 14: 33-8. PubMed Citation  (Controlled trial of methotrexate starting at either 15 or 25 mg/week in 168 patients with rheumatoid arthritis found slightly higher side effects with higher initial dose, but similar withdrawal rates [~23%] at 12 months; ALT or AST elevations occurred in 38% starting with 15 mg/week and 44% with 25 mg/week).

  198. Van Dooren-Greebe RJ, Kuijpers AL, Mulder J, De Boo T, Van de Kerkhof PC. Methotrexate revisited: effects of long-term treatment in psoriasis. Br J Dermatol 1994; 130: 204-10. PubMed Citation  (Retrospective analysis of 113 patients with psoriasis treated with methotrexate [7.5-15 mg/week] for an average of 9 years [mean total dose 4.8 g]; methotrexate was discontinued in 71 patients, 12 [17%] for liver test abnormalities; 105 liver biopsies done oin 55 patients, 7 [13%] had fibrosis and 2 [4%] cirrhosis with poor correlation with total dose, duration of therapy or abnormal liver tests).

  199. Chandran G, Ahern MJ, Hall PD, Geddes R, Smith MD, Hill W, Harley JH. Cirrhosis in patients with rheumatoid arthritis receiving low dose methotrexate. Br J Rheumatol 1994; 33: 981-4. PubMed Citation  (Three cases; 68-70 year old men with long standing rheumatoid arthritis treated with methotrexate for 5, 7 and 11 years [3.9, 7.2 and 10 g total dose] presented with varices or ascites; 2 had no alcohol use and all had minimally and only intermittently abnormal AST values during long term monitoring).

  200. Berquist SR, Felson DT, Prashker MJ, Freedberg KA. The cost-effectiveness of liver biopsy in rheumatoid arthritis patients treated with methotrexate. Arthritis Rheum 1995; 38: 326-33. PubMed Citation  (Cost effectiveness of liver biopsy during methotrexate therapy was dependent on the likelihood of cirrhosis and was $52,000 per year of life saved at 10 years, but $1.9 million per year of life saved at 5 years).

  201. Kremer JM, Kaye GI, Kaye NW, Ishak KG, Axiotis CA. Light and electron microscopic analysis of sequential liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy: follow up over long treatment intervals and correlation with clinical and laboratory variables. Arthritis Rheum 1995; 38: 1194-203. PubMed Citation  (Analysis of 170 liver biopsies from 27 patients with rheumatoid arthritis treated with methotrexate for 2 to 11 years [0.8-10.4 g]; there were minimal increases in average Roenigk score [1.8 at baseline to 2.3 at year 3 and 2.4 at year 6] and no significant change in semiquantitative estimates of electron microscopic features of fat, bile, collagen or smooth endoplasmic reticulum).

  202. Oogarah PK, Rowland PC, Mitchell DM, Smith A, Chalmers RIG, Rowan B, Haboubi NY. Abnormalities of serum type III procollagen aminoterminal peptide in methotrexate-treated psoriatic patients with normal liver histology do not correlate with hepatic ultrastructural changes. Br J Dermatol 1995; 1: 512-8. PubMed Citation  (Electron microscopic analysis of liver biopsies described by Mitchell et al. [1990] showed no correlation of changes with PIIIP levels; collagen in space of Disse present in 82% of biopsies and amount did not correlate with light microscopic or PIIIP elevations).

  203. al-Lamki Z, Thomas E, el-Banna N, Jaffe N. Acute urticaria and hepatitis complicating high-dose methotrexate therapy. Med Pediatr Oncol 1995; 24: 137-40. PubMed Citation  (3.5 year old girl with osteosarcoma given 22 courses of methotrexate with leucovorin rescue with excellent response, but then had anaphylactic reaction with 23rd course with urticaria, facial edema, and jaundice [bilirubin 19.7 mg/dL, ALT 4278 U/L, LDH 10,968 U/L, protime 15.3 sec], resolving in 4 weeks with immediate erythema and nausea on brief methotrexate rechallenge).

  204. Boffa MJ, Chalmer RJ, Haboubi NY, Shomaf M, Mitchell DM. Sequential liver biopsies during long-term methotrexate treatment for psoriasis: a reappraisal. Br J Dermatol 1995; 133: 774-8. PubMed Citation  (Analysis of 124 liver biopsies taken from 49 patients with psoriasis treated with methotrexate; between the initial and last biopsy, 24% improved, 57% did not change and 18% worsened, but none developed cirrhosis and rates of fibrosis fell from 22% to 20% despite another average 2.4 g of methotrexate).

  205. Erickson AR, Reddy V, Vogelgesang SA, West SG. Usefulness of the American College of Rheumatology recommendations for liver biopsy in methotrexate-treated rheumatoid arthritis. Arthritis Rheum 1995; 38: 1115-9. PubMed Citation  (Using the initial Psoriatic Task Force recommendations, 66 of 112 patients with rheumatoid arthritis treated with methotrexate underwent 110 liver biopsies and 5 were found to have advanced fibrosis or cirrhosis [Roenigk IIIB or IV], whereas applying the new American College of Rheumatology guidelines only 15 would have undergone 18 biopsies and 4 of the 5 with advanced fibrosis would have been identified, the case of cirrhosis missed being a patient with diabetes and perhaps deserving histological monitoring).

  206. Lower EE, Baughman RP. Prolonged use of methotrexate for sarcoidosis. Arch Intern Med 1995; 155: 846-51. PubMed Citation  (Among 50 patients with sarcoidosis treated with methotrexate for 2-6 years, liver biopsy histology became abnormal in 6 [15%], but findings were not reflected in serum enzyme elevations).

  207. Reiff A, Shaham B, Wood BP, Bernstein BH, Stanley P, Szer IS. High dose methotrexate in the treatment of refractory juvenile rheumatoid arthritis. Clin Exp Rheumatol 1995; 13: 113-8. PubMed Citation  (Use of higher doses of methotrexate in 21 children with severe juvenile rheumatoid arthritis was beneficial in only 33% of patients; transient ALT or AST elevations occurred in 38% and all resolved with holding dose, not requiring permanent discontinuation).

  208. Tamaro G, Danek GM, Mangiarotti MA, Tamaro P, Zanazzo GA. Methotrexate therapy and liver fibrosis: are human prolyl hydroxylase and type IV collagen reliable and sensitive markers? Int J Clin Lab Res 1995; 25: 55. PubMed Citation  (Among 13 children with leukemia treated with high dose methotrexate, 62% had elevations in serum prolyl hydroxylase and type IV collagen, suggesting that these tests may identify patients with significant liver injury; but histological verification was not done).

  209. Salaffi F, Carotti M, Sartini A, Cervini C. A prospective study of the long-term efficacy and toxicity of low-dose methotrexate in rheumatoid arthritis. Clin Exp Rheumatol 1995; 13: 23-8. PubMed Citation  (Among 51 Italian patients with rheumatoid arthritis treated with methotrexate weekly for up to 3 years, 14% had transient ALT or AST elevations, all resolving spontaneously or with dose modification).

  210. Franck H, Rau R, Herborn G. Thrombocytopenia in patients with rheumatoid arthritis on long-term treatment with low dose methotrexate. Clin Rheumatol 1996; 15: 163-7. PubMed Citation  (Among 315 patients with rheumatoid arthritis treated with methotrexate, 13 developed thrombocytopenia [<100,000/μL], after 1-100 [mean=41] months of therapy [mean total dose 1.9 g], most instances improved when methotrexate or other medications were withdrawn).

  211. ter Borg EJ, Seldenrijk CA, Timmer R. Liver cirrhosis due to methotrexate in a patient with rheumatoid arthritis. Neth J Med 1996; 49: 244-6. PubMed Citation  (49 year old woman with rheumatoid arthritis underwent liver biopsy after ~8 years of methotrexate therapy [total dose 6 g] with ALT 52 U/L, Alk P 180 U/L, albumin 3.5 g/dL, and platelet count 76,000/μL; ultrasound showed splenomegaly; biopsy [previously normal] showing early cirrhosis; liver tests fell to normal on stopping methotrexate but platelets remained low [124,000/μL]).

  212. Dufour JF, Kaplan MM. Methotrexate therapy and liver disease. N Engl J Med 1996; 335: 898-9. PubMed Citation  (Patient with sclerosing cholangitis started on methotrexate had an increase in ALT [rising from 51 to 467 U/L] for two months, but a liver biopsy showed no change from earlier specimen and ALT levels subsequently fell to normal).

  213. Furuya T, Totokawa S, Nakajima A, Suzuki T, Kashiwazaki S. [Adverse effects of low-dose methotrexate therapy in rheumatoid arthritis]. Ryumachi 1996; 36: 746-52. Japanese. PubMed Citation

  214. Kawabe Y, Eguchi K, Tsuboi M, Kita M, Tsukada T, Takashima H, Mizokami A, et al. [Untoward effects of low dose methotrexate therapy in rheumatoid arthritis]. Ryumachi 1996; 36: 514-21. Japanese. PubMed Citation

  215. Malatjalian DA, Ross JB, Williams CN, Colwell SJ, Eastwood BJ. Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up. Can J Gastroenterol 1996; 10: 369-75. PubMed Citation  (Among 104 patients with psoriasis treated with methotrexate for 1-11 years undergoing 477 liver biopsies, 7% had mild fibrosis before treatment; 46% developed fibrosis [26% mild, 20% moderate] and 3% cirrhosis; progression to fibrosis correlating with diabetes, but not social alcohol intake).

  216. Kugathasan S, Newman AJ, Dahms BB, Boyle JT. Liver biopsy findings in patients with juvenile rheumatoid arthritis receiving long-term, weekly methotrexate therapy. J Pediatr 1996; 128: 149-51. PubMed Citation  (Nine children with juvenile rheumatoid arthritis treated for at least 3 years with weekly methotrexate [total dose 0.8-2.3 g] underwent liver biopsy and all were normal [Roenigk I], and only one had mild steatosis).

  217. Van Doore-Greebe R, Kuijpers A, Buigs W, Kniest PHM, Corstens FHM, Nagengast FM, de Boo T, et al. The value of dynamic hepatic scintigraphy and serum aminoterminal propeptide of type III procollagen for early detection of methotrexate-induced hepatic damage in psoriasis patients. Br J Dermatol 1996; 134: 481-7. PubMed Citation  (25 patients with psoriasis treated with methotrexate [total dose 0.2-11 g; mean 3.9 g] underwent liver biopsy, PIIIP testing and dynamic scintigraphy; only 1 patient had fibrosis [Roenigk IIIA] who had both an elevated PIIIP and abnormal scan).

  218. Biasi D, Bambara LM, Carletto A, Casaril M, Capra F, Caramaschi P, Corrocher R. Effects on fibrogenesis markers of rheumatoid arthritis therapy with methotrexate. J Rheumatol 1996; 23: 453-4. PubMed Citation  (Among 20 patients with rheumatoid arthritis treated with methotrexate for 1 year, PIIIP levels were slightly higher than controls before therapy but actually decreased on average during therapy, while laminin levels did not change).

  219. Jaskewicz K, Voigt H, Blakolmer K. Increased matrix proteins, collagen and transforming growth factor are early markers of hepatotoxicity in patients on long-term methotrexate therapy. J Toxicol Clin Toxicol 1996; 34: 301-5. PubMed Citation  (76 liver biopsies from 36 patients with psoriasis treated with methotrexate for 1-5 years were studied by immunohistochemistry showing slight and progressive increases in laminin, fibronectin and collagen in biopsies, with minimal or no changes by light microscopy).

  220. Rebora A. Is methotrexate liver toxicity modest worldwide? Br J Dermatol 1996; 135: 1003-4. PubMed Citation  (Letter in response to Boffa et al. [1995] raising issue of hepatitis C contributing to apparent hepatotoxicity of methotrexate; reply by authors that HCV testing was not done but is rare in Manchester UK).

  221. Weinblatt ME. Methotrexate in rheumatoid arthritis: toxicity issues. Br J Rheumatol 1996; 35: 403-5. PubMed Citation  (Editorial on methotrexate hepatotoxicity and guidelines for monitoring).

  222. Zachariae H, Sød H, Heickendorff L. Methotrexate-induced liver cirrhosis. Clinical, histological and serological studies - a further 10-year follow-up. Dermatology 1996; 192: 343-6. PubMed Citation  (Long term follow up on 25 patients with psoriasis who developed cirrhosis on methotrexate therapy [reported in 1987]; the majority continued on lower doses of methotrexate and tolerated therapy well; 13 died, but only one of liver failure [all with autopsies had cirrhosis]; 13 appeared not to have cirrhosis on follow up liver biopsy and PIIIP levels were largely normal, suggesting that methotrexate induced cirrhosis is rarely progressive even with continuing therapy, at least at low doses).

  223. Boffa MJ, Smith A, Chalmer RJG, Mitchell DM, Rowan B, Warnes TW, Shomaf M, et al. Serum type III procollagen aminopeptide for assessing liver damage in methotrexate-treated psoriasis patients. Br J Dermatol 1996; 135: 538-44. PubMed Citation  (Serum PIIIP levels were measured at time of 147 liver biopsies in 87 patients with psoriasis on methotrexate; raised PIIIP levels found in 18% of 28 patients with a normal biopsy, 42% of 12 with steatosis, 54% of 26 with inflammation, 78% of 18 with fibrosis and 100% of 3 with cirrhosis; among 17 patients followed serially, elevations in PIIIP occurred in all 6 with progression vs only 3 of 11 without).

  224. Kremer JM, Furst DE, Weinblatt ME, Blotner SD. Significant changes in serum AST across hepatic histological biopsy grades: prospective analysis of 3 cohorts receiving methotrexate therapy for rheumatoid arthritis. J Rheumatol 1996; 23: 459-61. PubMed Citation  (Among 94 patients with rheumatoid arthritis treated with methotrexate who underwent 354 liver biopsies, AST levels were higher in those with higher Roenigk scores and elevations were associated with abnormal liver biopsy grade).

  225. Bologna C, Viu P, Picot MC, Jorgensen C, Sany J. Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate: an open retrospective, observational study. Br J Rheumatol 1997; 36: 535-40. PubMed Citation  (Among 453 French patients with rheumatoid arthritis treated with methotrexate given weekly for an average of 3 years [0.3 to 9 years], 13% had elevated liver tests leading to withdrawal in 2.3%; no deaths from liver disease and no mention of cirrhosis or liver biopsies).

  226. Beyeler C, Reichen J, Thomann SR, Lauterburg BH, Gerber NJ. Quantitative liver function in patients with rheumatoid arthritis treated with low-dose methotrexate: a longitudinal study. Br J Rheumatol 1997; 36: 338-44. PubMed Citation  (Among 117 patients with rheumatoid arthritis treated with methotrexate and monitored yearly with galactose elimination, aminopyrine breath tests and bile acids, there was a decline in liver function tests with little correlation with routine test abnormalities; elevations in ALT occurred in 8%, GGT in 23%, bile acid levels in 2.4%; no correlation found between Roenigk score and decline in liver function tests in 16 patients with liver biopsy).

  227. Hashkes PJ, Balistreri WF, Bove KE, Ballard ET, Passo MH. The long-term effect of methotrexate therapy on the liver in patients with juvenile rheumatoid arthritis. Arthritis Rheum 1997; 40: 2226-34. PubMed Citation  (Liver biopsies done on 14 children with juvenile rheumatoid arthritis treated with long term methotrexate found no fibrosis but minor changes found in 13, anisonucleosis, mild portal or lobular inflammation, and 3 with mild steatosis).

  228. Kremer JM. Safety, efficacy, and mortality in a long-term cohort of patients with rheumatoid arthritis taking methotrexate: followup after a mean of 13.3 years. Arthritis Rheum 1997; 40: 984-5. PubMed Citation  (Further follow up on initial cohort of 29 patients with rheumatoid arthritis [Kremer 1986] treated with long term methotrexate; 52% of patients remained on therapy for >10 years; 9 of the cohort had died, none of liver disease; among 10 still actively followed [mean total dose 9.7 g], none had clinically apparent liver disease).

  229. Lewis JH. Monitoring for methotrexate hepatotoxicity in patients with rheumatoid arthritis: another hepatologist's perspective. J Rheumatol 1997; 24: 1459-60. PubMed Citation  (Editorial on methotrexate hepatotoxicity in rheumatoid arthritis endorsing the use of serial ALT and AST determinations to identify patients at risk of developing significant fibrosis during therapy and thus avoiding liver biopsy in most patients).

  230. Stein CM, Brooks RH, Pincus T. Effect of combination therapy with cyclosporine and methotrexate on liver function test results in rheumatoid arthritis. Arthritis Rheum 1997; 40: 1721-3. PubMed Citation  (No differences in ALT elevations between patients on methotrexate alone [3%] vs its combination with cyclosporine [2%] for 24 weeks).

  231. Kremer JM. Liver toxicity does not have to follow methotrexate therapy of patients with rheumatoid arthritis. Am J Gastroenterol 1997; 92: 184-96. PubMed Citation  (Editorial on issue of monitoring patients with rheumatoid arthritis on methotrexate therapy suggested that frequent determinations of ALT and AST [at least 9 per year] allows for identification of patients at risk for developing progressive fibrosis; those with >50% of values elevated based upon results from Kremer et al. 1996).

  232. West SG. Methotrexate hepatotoxicity. Rheum Dis Clin North Am 1997; 23: 883-915. PubMed Citation  (Extensive review of methotrexate hepatotoxicity with discussion of both Psoriasis Task Force and American College of Rheumatology recommendations).

  233. Ahern MJ, Smith MD, Roberts-Thomson PJ. Methotrexate hepatotoxicity: what is the evidence? Inflamm Res 1998; 47: 148-51. PubMed Citation  (Editorial on American College of Rheumatology recommendations for monitoring for liver injury during methotrexate therapy of rheumatoid arthritis, guidelines prudent but of unproven benefit).

  234. Hakim NS, Kobienia B, Benedetti E, Bloomer J, Payne WD. Methotrexate-induced hepatic necrosis requiring liver transplantation in a patient with rheumatoid arthritis. Int Surg 1998; 83: 224-5. PubMed Citation  (40 year old man with rheumatoid arthritis developed acute liver failure after 6 months of methotrexate therapy when he presented with rapid rise in ALT ["levels of several thousands"] and presence of HBsAg without anti-HBc in serum requiring liver transplantation, but no information on HBsAg status in follow up).

  235. Narváez J, Rodriguez-Moreno J, Martinez-Aguilá MD, Clavaguera MT. Severe hepatitis linked to B virus infection after withdrawal of low dose methotrexate therapy. J Rheumatol 1998; 25: 2037-8. PubMed Citation  (67 year old man with rheumatoid arthritis treated with methotrexate [7.5 mg/week] and prednisone [5 mg/day] for 2 years [previous HBsAg status not known] developed acute hepatitis 3 weeks after stopping methotrexate because of pulmonary toxicity [bilirubin 1.8 mg/dL, ALT 252 U/L, Alk P 135 U/L, presence of HBsAg, IgM anti-HBc, anti-HBe, and HBV DNA], progressing to hepatic failure and death 6 months later).

  236. Roenigk HH Jr, Auerbach R, Maibach H, Weinstein G, Lebwohl M. Methotrexate in psoriasis: consensus conference. J Am Acad Dermatol 1998; 38: 478-85. PubMed Citation  (Update of recommendations for use of methotrexate and monitoring for side effects; pretreatment liver biopsy recommended for patients with evidence of liver disease or significant risk factors; monitoring of liver chemistries every 4-8 weeks; liver biopsy on treatment after each 1.5 g of therapy and more frequent if liver tests are abnormal).

  237. Hashkes PJ, Balistreri WF, Bove KE, Ballard ET, Passo MH. The relationship of hepatotoxic risk factors and liver histology in methotrexate therapy for juvenile rheumatoid arthritis. J Pediatr 1999; 134: 47-52. PubMed Citation  (Among 33 liver biopsies from 25 patients with juvenile rheumatoid arthritis treated with methotrexate for 1.5-12 years [total dose 0.5-8.4 g], 82% were normal and 6% had fibrosis [Roenigk IIIA only]; obesity and ALT or AST elevations were found to be risk factors for abnormal histology).

  238. Locatelli M, Colleoni M, Noberasco C, Nolé F, Orlando L, Munzone E, Peruzzotti G, et al. Hepatic toxicity from cyclophosphamide, methotrexate, fluorouracil(CMF regimen). Ann Oncol 1999; 10: 1394-5. PubMed Citation  (Among 264 patients given methotrexate and fluorouracil intravenously twice monthly and oral cyclophosphamide for breast cancer, 40% had ALT elevations, 19% above 5 times ULN, but all resolved within 30 days).

  239. Suzuki Y, Uehara R, Tajima C, Noguchi A, Ide M, Ichikawa Y, Mizushima Y, et al. Elevation of serum hepatic aminotransferases during treatment of rheumatoid arthritis with low-dose methotrexate. Risk factors and response to folic acid. Scand J Rheumatol 1999; 28: 273-81. PubMed Citation  (Among 14 patients with rheumatoid arthritis treated with methotrexate who were started on folate [5 mg weekly, 36 hours after dosing], serum ALT levels fell in all within 3 months; two had exacerbations of arthritis and stopped folate).

  240. Haustein UF, Rytter M. Methotrexate in psoriasis: 26 years' experience with low-dose long-term treatment. J Eur Acad Dermatol Venereol 2000; 14: 382-8. PubMed Citation  (Retrospective analysis of clinical experience using methotrexate in 157 patients treated for up to 15 years [mean=5 years]; abnormal liver tests arose in 40 [25%] leading to stopping in 22 [14%], but no clinically apparent liver disease or cirrhosis).

  241. Mok MY, Ng WL, Yuen MF, Wong RW, Lau CS. Safety of disease modifying anti-rheumatic agents in rheumatoid arthritis patients with chronic viral hepatitis. Clin Exp Rheumatol 2000; 18: 363-8. PubMed Citation  (Among 29 Chinese patients with rheumatoid arthritis and chronic hepatitis [23 HBV; 6 HCV], ALT elevations occurred in 41% on hydroxychloroquine, 30% on methotrexate and 14% on gold vs 14% of 94 control patients without viral hepatitis).

  242. Hirshberg B, Muszkat M, Schlesinger O, Rubinow A. Safety of low dose methotrexate in elderly patients with rheumatoid arthritis. Postgrad Med J 2000; 76: 787-9. PubMed Citation  (Retrospective analysis of 33 patients with rheumatoid arthritis above age of 65 treated with methotrexate for at least 2 years; two patients stopped because of raised serum enzymes, but none developed clinically apparent liver injury).

  243. Richard S, Guerret S, Gerard F, Tebib JG, Vignon E. Hepatic fibrosis in rheumatoid arthritis patients treated with methotrexate: application of a new semi-quantitative scoring system. Rheumatology 2000; 39: 50-4. PubMed Citation  (Analysis of 74 liver biopsies from 57 patients with rheumatoid arthritis before or during methotrexate therapy using a new scoring system for fibrosis [graded at 4 sites giving scores of 0 to 35] found good correlation with Roenigk score, but no change in scores with methotrexate therapy).

  244. Kuijpers AL, van de Kerkhof PC. Risk-benefit assessment of methotrexate in the treatment of severe psoriasis. Am J Clin Dermatol 2000; 1: 27-39. PubMed Citation  (Review article on mechanism of action, pharmacology, efficacy and safety of methotrexate in psoriasis; in a study of 55 patients who underwent liver biopsy on therapy, 4% had cirrhosis and 13% fibrosis).

  245. Lémann M, Zenjari T, Bouhnik Y, Cosnes J, Mesnard B, Rambaud J-C, Modigliani R, et al. Methotrexate in Crohn's disease: long-term efficacy and toxicity. Am J Gastroenterol 2000; 95: 1730-4. PubMed Citation  (Among 49 patients with Crohn disease treated with methotrexate for more than 6 months, serum enzyme elevations occurred in 10 leading to withdrawal in 2 patients; liver biopsies showed mild steatosis in 1 and mild fibrosis in two others).

  246. Zachariae H. Liver biopsies and methotrexate: a time for reconsideration? J Am Acad Dermatol 2000; 42: 531-4. PubMed Citation  (Review of role of liver biopsy in monitoring methotrexate hepatotoxicity in patients with psoriasis and rheumatoid arthritis; PIIIP levels may provide a means of reducing number of biopsies, restricting surveillance biopsies to patients with high risk of having fibrosis).

  247. Te HS, Schiano TD, Kuan SF, Hanauer SB, Conjeevaram HS, Baker AL. Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease. Am J Gastroenterol 2000; 95: 3150-6. PubMed Citation  (Among 32 patients with Crohn disease treated with methotrexate for 1-4 years, 20 underwent liver biopsy after 1.5-5.4 g of therapy given for 1-5 years; only 1 had fibrosis which was mild, and ALT and AST elevations were rare).

  248. Weinblatt ME, Dixon JA, Falchuk KR. Serious liver disease in a patient receiving methotrexate and leflunomide. Arthritis Rheum 2000; 43: 2609-11. PubMed Citation  (51 year old man with rheumatoid arthritis was treated with leflunomide and methotrexate and had several ALT elevations and decline in platelet count during first 1-2 years of therapy and, after 3.5 years [total dose 4.5 g], a liver biopsy showed cirrhosis and mild steatosis without inflammation: Case 2).

  249. Langman G, Hall PM, Todd G. Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury. J Gastroenterol Hepatol 2001; 16: 1395-401. PubMed Citation  (Retrospective review of paired liver biopsies from 24 patients with methotrexate associated liver injury; 17 had features suggestive of nonalcoholic steatohepatitis [NASH] of whom 13 had risk factors such as obesity and diabetes).

  250. Wollina U, Ständer K, Barta U. Toxicity of methotrexate treatment in psoriasis and psoriatic arthritis - short- and long-term toxicity in 104 patients. Clin Rheumatol 2001; 20: 406-10. PubMed Citation  (Analysis of adverse events occurring in 104 patients with psoriasis treated with methotrexate for undefined period, ALT and AST elevations were the most frequent adverse event both during early and long term therapy).

  251. Van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar MA, van Denderene CJ, Westgeest TAA, et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 2001; 44: 1515-24. PubMed Citation  (Randomized controlled trial of folic acid [1 mg/day] vs folinic acid [7.5 mg/week] vs placebo in 434 patients with rheumatoid arthritis treated with methotrexate [7.5-25 mg/week] for 48 weeks, found higher toxicity related withdrawals with placebo [38%] compared to folate [17%] or folinic acid [12%]; elevated ALT levels occurred in 26% on placebo, 4% on folic acid and 4% on folinic acid; no differences in efficacy).

  252. Zachariae H, Heickendorff L, Sogaard H. The value of amino-terminal propeptide of type III collagen in routine screening for methotrexate-induced liver fibrosis: a 10-year follow-up. Br J Dermatol 2001; 144: 100-3. PubMed Citation  (Retrospective analysis of 70 patients with psoriasis on methotrexate therapy who were monitored with PIIIP levels after an initial liver biopsy; only 4 [6%] developed fibrosis, all of whom had elevations in PIIIP levels compared to only 2 of 66 who did not develop fibrosis).

  253. Ito S, Nakazono K, Murasawa A, Mita Y, Hata K, Saito N, Kikuchi M, et al. Development of fulminant hepatitis B(precore variant mutant type) after the discontinuation of low-dose methotrexate therapy in a rheumatoid arthritis patient. Arthritis Rheum 2001; 44: 339-42. PubMed Citation  (75 year old with rheumatoid arthritis and HBsAg carrier state [normal ALT and no HBeAg] was treated with methotrexate and prednisone for 3 years, but discontinued when ALT began to rise [112 U/L], and within a few weeks she presented with acute hepatitis [bilirubin 9.7 mg/dL, ALT 1016 U/L, prothrombin index 32%, presence of HBeAg and HBV DNA polymerase], dying of hepatic failure a few weeks later).

  254. Cutolo M, Seriolo B, Pizzorni C, Craviotto C, Sulli A. Methotrexate in psoriatic arthritis. Clin Exp Rheumatol 2002; 20(6 Suppl 28): S76-80. PubMed Citation  (Review of status of methotrexate therapy in psoriatic arthritis, makes claim that folate therapy reduces efficacy of methotrexate).

  255. Kumar B, Saraswat A, Kaur I. Short-term methotrexate therapy in psoriasis: a study of 197 patients. Int J Dermatol 2002; 41: 444-8. PubMed Citation  (Retrospective review of 243 short term cycles of methotrexate therapy in 197 patients with psoriasis in India, with low rate of serum enzyme elevations [1.2%], and no evidence of progressive liver injury in 8 patients who underwent paired liver biopsy).

  256. Lahdenne P, Rapola J, Ylijoki H, Haapasaari J. Hepatotoxicity in patients with juvenile idiopathic arthritis receiving longterm methotrexate therapy. J Rheumatol 2002; 29: 2442-5. PubMed Citation  (Among 10 patients with juvenile rheumatoid arthritis undergoing liver biopsy during methotrexate therapy, all had fat, 5 had inflammation but none had fibrosis; Roenigk scores were 1-2 only).

  257. van Outryve S, Schrijvers D, van den Brande J, Wilmes P, Bogers J, van Marck E, Vermorken JH. Methotrexate-associated liver toxicity in a patient with breast cancer: case report and literature review. Neth J Med 2002; 60: 216-22. PubMed Citation  (60 year old woman with breast cancer developed fatigue and mild ALT elevations [64 to 98 U/L] during cycles 2 to 4 of methotrexate-fluorouracil-cyclophosphamide, resolving when methotrexate was replaced by mitoxantrone; biopsy showed centrolobular fat and ballooning).

  258. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002; 359: 1173-7. PubMed Citation  (In a retrospective analysis of a large cohort of patients with rheumatoid arthritis, methotrexate use was associated with decrease in all-cause mortality and particularly cardiovascular).

  259. Kwoh CK, Anderson LG, Greene JM, Johnson DA, O'Dell JR, Robbins ML, Roberts WN Jr, et al.; American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum 2002; 46: 328-46. PubMed Citation  (Guidelines for management of rheumatoid arthritis; recommended serial monitoring during methotrexate therapy with routine liver tests and liver biopsy in those with risk factors of liver disease or persistent liver test abnormalities).

  260. Ros S, Juanola X, Condom E, Cañas C, Riera J, Guardiola J, Del Blanco J, et al. Light and electron microscopic analysis of liver biopsy samples from rheumatoid arthritis patients receiving long-term methotrexate therapy. Scand J Rheumatol 2002; 31: 330-6. PubMed Citation  (Analysis of liver biopsies by light and electron microscopy taken from 42 Spanish patients with rheumatoid arthritis before and after 4 years of methotrexate found mild fibrosis in 14% at baseline vs 12% at year 4; mild increase in steatosis, smooth endoplasmic reticulum, and number of lysosomes after therapy, but no change in amount of collagen in the space of Disse).

  261. Penalva Polo JC, Gómez Andrés A, Vela P, Niveiro M. [Acute liver failure in a patient with methotrexate therapy]. Rev Esp Enferm Dig 2002; 94: 440-1. Spanish. PubMed Citation

  262. Fathi NH, Mitros F, Hoffman J, Straniero N, Labreque D, Koehnke R, Furst DE. Longitudinal measurement of methotrexate liver concentrations does not correlate with liver damage, clinical efficacy, or toxicity during a 3.5 year double blind study in rheumatoid arthritis. J Rheumatol 2002; 29: 2092-8. PubMed Citation  (40 patients enrolled in a controlled trial of methotrexate in varying weekly oral doses underwent liver biopsy before and after 1, 2 and 3.5 years; at least one ALT abnormality occurred in ~50%, and AST ~25% of patients; the average Roenigk and "Iowa" histological scores did not change, but 13% developed some degree of fibrosis [none cirrhosis], abnormalities did not correlate with methotrexate concentrations in liver, use of folic acid, but some correlation was found between AST values and worsening of Iowa score).

  263. Yazici Y, Erkan D, Paget SA. Monitoring methotrexate hepatic toxicity in rheumatoid arthritis: is it time to update the guidelines? J Rheumatol 2002; 29: 1586-9. PubMed Citation  (Among 182 patients with rheumatoid arthritis treated with methotrexate, 17% had at least one abnormal liver test, but no instances of cirrhosis or clinically apparent liver disease arose; authors questioned the need of extensive monitoring).

  264. Kremer JM. Not yet time to change the guidelines for monitoring methotrexate liver toxicity: they have served us well. J Rheumatol 2002; 29: 1590-2. PubMed Citation  (Review of the data that supported initial guidelines for monitoring serum enzymes during methotrexate therapy of rheumatoid arthritis suggesting that any elevation may be indicative of hepatic injury and that monitoring reduces occurrence of severe fibrosis).

  265. Farrell GC. Drugs and steatohepatitis. Semin Liver Dis 2002; 22: 185-94. PubMed Citation  (Hepatic changes similar to nonalcoholic steatohepatitis [NASH] occur with long term use of amiodarone, methotrexate and some nucleoside analogues; in contrast, corticosteroids, estrogens and tamoxifen appear to cause fatty liver by exacerbating pre-existing NASH).

  266. Hoekstra M, van Ede AE, Haagsma CJ, van de Laar MAFJ, Huizinga TWJ, Kruijsen MWM, Laan RFJM. Factors associated with toxicity, final dose, and efficacy of methotrexate in patients with rheumatoid arthritis. Ann Rheum Dis 2003; 62: 423-6. PubMed Citation  (Randomized trial of 48 weeks of methotrexate with or without folate supplementation in 411 patients with rheumatoid arthritis; ALT elevations >3 times ULN occurred in 26% of placebo vs 4% of folate supplemented groups; hepatotoxicity also more common with higher body weight index; folate did not affect efficacy but decreased withdrawals because of toxicity).

  267. Hoekstra M, van de Laar MAFJ, Bernelot Moens HJ, Kruijsen MW, Haagsma CJ. Longterm observational study of methotrexate use in a Dutch cohort of 1022 patients with rheumatoid arthritis. J Rheumatol 2003; 30: 225-9. PubMed Citation  (Retrospective analysis of database on 1022 Dutch patients with rheumatoid arthritis treated with methotrexate, 64% remained on therapy for 5 and 50% after 9 years; factors favoring continuing therapy included folic acid supplementation; reason for stopping was liver test abnormalities in 14%).

  268. Heydendael VMR, Spuls PhI, Opmeer BC, de Borgie CA, Saccozzi R, Luini A, Agullar M, et al. Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis. N Engl J Med 2003; 349: 658-65. PubMed Citation  (Controlled trial of 16 weeks of cyclosporine vs methotrexate in 88 patients with psoriasis found similar efficacy, but high drop out rate because of raised ALT levels in methotrexate group [27%]).

  269. Vanhoof J, Landewe S, Van Wijngaerden E, Geusens P. High incidence of hepatotoxicity of isoniazid treatment for tuberculosis chemoprophylaxis in patients with rheumatoid arthritis treated with methotrexate or sulfasalazine and anti-tumour necrosis factor inhibitors. Ann Rheum Dis 2003; 62: 1241-2. PubMed Citation  (Among 88 patients with rheumatoid arthritis receiving disease modifying therapies, 8 were given isoniazid for latent tuberculosis half of whom developed hepatotoxicity, ALT levels rising to 82-330 U/L after 7-16 weeks and resolving 4-11 weeks after stopping; none were clinically apparent).

  270. Baughman RP, Koehler A, Bejarano PA, Lower EE, Weber FL Jr. Role of liver function tests in detecting methotrexate-induced liver damage in sarcoidosis. Arch Intern Med 2003; 163: 615-20. PubMed Citation  (Among 68 patients with sarcoidosis undergoing 100 liver biopsies during 2-8 years of methotrexate therapy, 14% showed evidence of mild methotrexate toxicity, but no association found with ALT, AST or Alk P elevations or total dose).

  271. Hytiroglou P, Tobias H, Saxena R, Abramidou M, Papadimitrian CS, Theise ND. The canals of Hering might represent a target of methotrexate hepatic toxicity. Am J Clin Pathol 2004; 121: 324-9. PubMed Citation  (Analysis of 16 liver biopsies from 7 patients receiving methotrexate for psoriasis using special stains [cytokeratin 7] to identify the canals of Hering found a reduction of these structures in 13 patients with fibrosis due to methotrexate, the fibrosis following the distribution of the canals).

  272. Boffa MJ. Methotrexate for psoriasis: current European practice. J Eur Acad Dermatol Venereol 2004; 19: 196-202. PubMed Citation  (Survey of 69 European dermatologists on use of methotrexate in psoriasis; 59 [85%] used methotrexate but none requested baseline liver biopsies and <20% monitored patients with biopsies during therapy; among 10 fatalities attributed to methotrexate, 8 were caused by myelosuppression and two from liver failure).

  273. Kent PD, Luthra HS, Michet C Jr. Risk factors for methotrexate-induced abnormal laboratory monitoring results in patients with rheumatoid arthritis. J Rheumatol 2004; 31: 1727-31. PubMed Citation  (Retrospective chart review of 483 patients with rheumatoid arthritis treated with methotrexate [average 5 years], 4.6% of patients discontinued therapy because of liver test abnormalities, correlated with lack of folate supplementation, high BMI and untreated hyperlipidemia).

  274. Whittle SL, Hughes RA. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. Rheumatology 2004; 43: 267-71. PubMed Citation  (Review of publications on folate supplementation during weekly methotrexate therapy of rheumatoid arthritis found no evidence that folate decreased efficacy, but clear evidence of fewer side effects including lower rates of ALT elevations; authors recommend 5 mg of folic acid weekly on the day after methotrexate is taken).

  275. Kremer JM. Toward a better understanding of methotrexate. Arthritis Rheum 2004; 50: 1370-2. PubMed Citation  (Review of proposed mechanism of action and toxicity of methotrexate in autoimmune diseases; may cause increase in intracellular and extracellular adenosine levels which bind to its cellular membrane receptors and increase intracellular cyclic AMP which has immunosuppressive consequences).

  276. Hagiyama H, Kubota T, Komano Y, Kurosaki M, Watanabe M, Miyasaka N. Fulminant hepatitis in an asymptomatic chronic carrier of hepatitis B virus mutant after withdrawal of low-dose methotrexate therapy for rheumatoid arthritis. Clin Exp Rheumatol 2004; 22: 375-6. PubMed Citation  (72 year old with rheumatoid arthritis and HBsAg carrier state [normal ALT and no HBeAg] developed elevations in serum ALT [246 U/L] 2 years after starting methotrexate [4 mg/week] and prednisone [5 mg daily]; 2 months after stopping, she presented with acute liver failure [ALT 569 U/L, prothombin index 65%, presence of HBeAg and HBV DNA] and died).

  277. Ortiz-Alvarez O, Morishita K, Avery G, Green J, Petty RE, Tucker LB, Malleson PN, et al. Guidelines for blood test monitoring of methotrexate toxicity in juvenile idiopathic arthritis. J Rheumatol 2004; 31: 2501-6. PubMed Citation  (Monitoring liver enzymes in 89 children with juvenile rheumatoid arthritis at monthly intervals for an average of 3 years, identified 13 instances [15%] of ALT or AST elevations >2 times ULN, all resolved rapidly and methotrexate was either continued or restarted without recurrence).

  278. Heydendael VM, Spuls PI, Bossuyt PM, Bos JD, de Rie MA. Analysis of risk factors in psoriatic patients with methotrexate-induced increases in transaminase levels. Arch Dermatol 2004; 140: 1289-90. PubMed Citation  (Reanalysis of high rate [28%] of ALT elevations in controlled trial of methotrexate vs cyclosporine A, inconclusive results).

  279. Aithal GP, Haugk B, Das S, Card T, Burt AD, Record CO. Monitoring methotrexate-induced hepatic fibrosis in patients with psoriasis: are serial liver biopsies justified? Aliment Pharmacol Ther 2004; 19: 391-9. PubMed Citation  (Analysis of 121 biopsies from 66 patients with psoriasis treated with methotrexate for average of 5.4 years found advanced fibrosis arose in 2.6% of biopsies after 1.4-3 g, 8.2% after 4.5-6 g, and 32% after 10 g total dose; total number of cases uncertain; Roenigk score has less helpful than Ishak or Scheuer fibrosis scales).

  280. Suissa S, Ernst P, Hudson M, Bitton A, Kezouh A. Newer disease-modifying antirheumatic drugs and the risk of serious hepatic adverse events in patients with rheumatoid arthritis. Am J Med 2004; 117: 87-92. PubMed Citation  (Case-control analysis of hepatic events in two US cohorts of 41,885 patients with rheumatoid arthritis treated with disease modifying agents, found no increase in cases of serious or non-serious events with leflunomide [rate ratio 0.9] compared to methotrexate, but higher rates with etanercept and infliximab [rate ratio 5.3]).

  281. Gupta R, Gupta SK. Severe hepatotoxicity in a rheumatoid arthritis patient switched from leflunomide to methotrexate. MedGenMed 2005; 7: 9. PubMed Citation  (44 year old woman with rheumatoid arthritis found to have elevated ALT [341 U/L] 9 months after starting leflunomide, resolving within 2 months of stopping, but recurring after 3 months of oral methotrexate which was tolerated for many years in the past [bilirubin 3.5 mg/dL, ALT 1297 U/L], resolving within 4 weeks of stopping).

  282. Kinder AJ, Hassell AB, Brand J, Brownfield A, Grove M, Shadforth MF. The treatment of inflammatory arthritis with methotrexate in clinical practice: treatment duration and incidence of adverse drug reactions. Rheumatology(Oxford) 2005; 44: 61-6. PubMed Citation  (Among 673 patients with rheumatic diseases treated with methotrexate between 1986 and 1999, 74% continued on therapy for 5 years or more; 37 patients stopped because of abnormal liver tests; 25 patients died, but none from liver disease).

  283. Mathew J, Leong MY, Morley N, Burt AD. A liver fibrosis cocktail? Psoriasis, methotrexate and genetic hemochromatosis. BMC Dermatol 2005; 5: 12. PubMed Citation  (Two patients with hemochromatosis and psoriasis on long term methotrexate had minor abnormalities on liver biopsy without fibrosis).

  284. Nieminen U, Höök-Nikanne J, Kärkäinen P, Niemelä S. [Liver damage in methotrexate-treated patients. When liver biopsy is necessary in the follow-up?]. Duodecim 2005; 121: 2680-8. Finnish. PubMed Citation

  285. Yazici Y, Erkan D, Harrison MJ, Nikolov NP, Paget SA. Methotrexate use in rheumatoid arthritis is associated with few clinically significant liver function test abnormalities. Clin Exp Rheumatol 2005; 23: 517-20. PubMed Citation  (Retrospective analysis of 182 patients with rheumatoid arthritis treated with methotrexate between 1985-1999; 16.5% had at least 1 abnormal ALT or AST, but only 2 discontinued drug for these findings and no patient developed clinically apparent liver injury; routine liver biopsies were not done).

  286. Yazici Y, Sokka T, Kautiainen H, Swearingen C, Kulman I, Pincus T. Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities. Ann Rheum Dis 2005; 64: 207-11. PubMed Citation  (Among 248 patients with rheumatoid arthritis treated with methotrexate, 79% continued for at least 5 years; AST elevations occurred in 7% per year, but usually transient and <2 times ULN, none requiring permanent discontinuation).

  287. Zachariae H. Have methotrexate-induced liver fibrosis and cirrhosis become rare? A matter for reappraisal of routine liver biopsies. Dermatology 2005; 211: 307-8. PubMed Citation  (Editorial on issue of monitoring for liver fibrosis in patients with psoriasis on methotrexate; rates of cirrhosis in treated patients have decreased but major rates of cirrhosis were in those treated for >10 years, often with other hepatotoxic exposures).

  288. Thomas JA, Aithal GP. Monitoring liver function during methotrexate therapy for psoriasis. Are routine biopsies really necessary? Am J Clin Dermatol 2005; 6: 357-63. PubMed Citation  (Review of role liver biopsy in monitoring patients with psoriasis on low dose methotrexate therapy; authors recommend pretreatment liver biopsy only in patients with evidence for liver disease or risk factors and routine surveillance biopsy only after total dose of 4 g, and use of Ishak or Scheuer fibrosis staging systems rather than Roenigk scale).

  289. Maurice PD, Maddox AJ, Green CA, Tatnall F, Schofield JK, Stott DJ. Monitoring patients on methotrexate : hepatic fibrosis not seen in patients with normal serum assays of aminoterminal peptide of type III procollagen. Br J Dermatol 2005; 152: 431-8. PubMed Citation  (Among 38 patients with psoriasis on methotrexate undergoing 70 liver biopsies and routine PIIIP testing, 4 patients had fibrosis and all 4 had at least one abnormal PIIIP level as did half of patients with normal liver biopsies; in 23 patients undergoing 2 biopsies, 4 worsened and all 4 had at least one abnormal PIIIP as did 63% of patients with no change; 46% of patients had persistently normal PIIIP values and none had fibrosis or worsening histology and might have avoided need for liver biopsy).

  290. Chalmers RJG, Kirby B, Smith A, Burrows P, Little R, Horan M, Hextall JM, et al. Replacement of routine liver biopsy by procollagen III aminopeptide for monitoring patients with psoriasis receiving long-term methotrexate: a multicentre audit and health economic analysis. Br J Dermatol 2005; 152: 444-50. PubMed Citation  (Comparison of costs between UK centers using PIIIP monitoring versus routine liver biopsy at different total methotrexate doses suggested seven-fold decrease in need for liver biopsy with serum fibrosis marker).

  291. Berends MA, Snoek J, de Jong EM, van de Kerkhof PC, van Oijen MG, van Krieken JH, Drenth JP. Liver injury in long-term methotrexate treatment in psoriasis is relatively infrequent. Aliment Pharmacol Ther 2006; 24: 805-11. PubMed Citation  (125 patients with psoriasis treated with methotrexate for average of 4.4 years underwent 278 liver biopsies; 71% did not change from baseline; 15% developed fibrosis including 2% with cirrhosis; poor correlation of fibrosis with ALT and AST elevations; over half had risk factors such as obesity, diabetes or alcohol use).

  292. Khan S, Subedi D, Chowdhury MMU. Use of amino terminal type III procollagen peptide(P3MP) assay in methotrexate therapy for psoriasis. Postgrad Med J 2006; 82: 353-4. PubMed Citation  (Retrospective analysis on 15 patients with psoriasis on long-term methotrexate who had abnormal PIIIP levels and underwent liver biopsy; one showing cirrhosis and two fibrosis).

  293. Goujon C, Bérd F, Dahel K, Guillot I, Hennino A, Nosbaum A, Saad N, et al. Methotrexate for the treatment of adult atopic dermatitis. Eur J Dermatol 2006; 16: 155-8. PubMed Citation  (20 patients with atopic dermatitis were treated with methotrexate, 15 having a response at 3 months and continuing therapy [7.5-25 mg/week], 10% had serum enzyme elevations, but none required stopping).

  294. La Montagna G, Tirri R, Vitello R, Malesci D, Buono R, Mennillo G, Valentini G. [Safety of methotrexate in rheumatoid arthritis: a retrospective cohort study in clinical practice]. Reumatismo 2006; 58: 261-7. Italian. PubMed Citation  (Among 224 patients with rheumatoid arthritis treated with methotrexate for an average of 4 years, 9 [4%] had ALT or AST elevations requiring discontinuation).

  295. Tilling L, Townsend S, David J. Methotrexate and hepatic toxicity in rheumatoid arthritis and psoriatic arthritis. Clin Drug Investig 2006; 26: 55-62. PubMed Citation  (Prospective study of 550 patients with rheumatoid arthritis and 69 with psoriasis treated with methotrexate [1-30 mg/week] for up to 13 years [mean=3 years], rise in ALT or AST to >3 times ULN occurred in 14.5% of psoriasis vs 7.5% of rheumatoid arthritis patients; differences and most abnormalities were not explained by differences in alcohol use).

  296. Berends MA, van Oijen MG, Snoek J, van de Kerkhof PC, Drenth JP, Han van Krieken J, de Jong EM. Reliability of the Roenigk classification of liver damage after methotrexate treatment for psoriasis: a clinicopathologic study of 160 liver biopsy specimens. Arch Dermatol 2007; 143: 1515-9. PubMed Citation  (Among 160 liver biopsies from 95 patients with psoriasis treated with oral methotrexate, reading for Roenigk score gave highly concordant results with initial local readings).

  297. Correa G H, Paredes S N. [Serum liver tests in patients treated with methotrexate. A retrospective analysis]. Rev Med Chil 2007; 135: 1002-8. Spanish. PubMed Citation  (Among 63 patients with psoriasis treated with methotrexate in Chile, 32% had elevation in liver tests; 10% had ALT values above 2 times ULN [97-321 U/L], most were transient, one resolved rapidly with stopping).

  298. Gwak GY, Koh KC, Kim HY. Fatal hepatic failure associated with hepatitis B virus reactivation in a hepatitis B surface antigen-negative patient with rheumatoid arthritis receiving low dose methotrexate. Clin Exp Rheumatol 2007; 25: 888-9. PubMed Citation  (59 year old woman with rheumatoid arthritis [with anti-HBs without HBsAg] who was treated with methotrexate [10 mg/week] and prednisone [5 mg/day] for 7 years developed acute hepatitis B reactivation [bilirubin 5.7 rising to 29.5 mg/dL, ALT 378 U/L, INR 3.4, presence of HBsAg, HBeAg and HBV DNA ~15 million copies/mL], progressing to hepatic failure and death within 8 weeks of onset).

  299. Shimada K, Matsui T, Kawakami M, Nakayama H, Ozawa Y, Mitomi H, Tohma S. Methotrexate-related lymphomatoid granulomatosis: a case report of spontaneous regression of large tumours in multiple organs after cessation of methotrexate therapy in rheumatoid arthritis. Scand J Rheumatol 2007; 36: 64-7. PubMed Citation  (54 year old woman with rheumatoid arthritis on methotrexate for 10 years presented with widespread lymphomatoid granulomatosis which spontaneously disappeared 3 months after stopping methotrexate).

  300. Ting TV, Hashkes PJ. Methotrexate/naproxen-associated severe hepatitis in a child with juvenile idiopathic arthritis. Clin Exp Rheumatol 2007; 25: 928-9. PubMed Citation  (2 year old girl with idiopathic arthritis treated with methotrexate and naproxen for 8 months had elevated AST [88 rising to 2372 U/L] with lethargy, hypoglycemia and high ammonia but normal bilirubin and INR and rapid recovery upon stopping methotrexate).

  301. Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, Paulus HE, et al.; American College of Rheumatology. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008; 59: 762-84. PubMed Citation  (Recommendations on use of disease modifying agents in rheumatoid arthritis including monitoring for liver disease).

  302. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, no case was attributed to methotrexate).

  303. Carneiro SC, Cássia FF, Lamy F, Chagas VL, Ramos-e-Silva M. Methotrexate and liver function: a study of 13 psoriasis cases treated with different cumulative dosages. J Eur Acad Dermatol Venereol 2008; 22: 25-9. PubMed Citation  (13 Brazilian patients with psoriasis underwent liver biopsy before and after 1-4 g of oral methotrexate therapy; fibrosis found in none of 18 who received <2 g, in 1 of 7 after 3 g, and 2 of 4 after 4 g including 2 with cirrhosis; no mention of folate supplementation).

  304. Cheng KK. Association of plasma methotrexate, neutropenia, hepatic dysfunction, nausea/vomiting and oral mucositis in children with cancer. Eur J Cancer Care(Engl) 2008; 17: 306-11. PubMed Citation  (Case control study in 28 children with leukemia given high dose iv methotrexate [5-12 g/m2]; found those with mucositis had higher serum methotrexate levels but similar rates of ALT or AST elevations as those without mucositis).

  305. Domènech E, Mañosa M, Navarro M, Masnou H, Garcia-Planella E, Zabana Y, Cabré E, et al. Long-term methotrexate for Crohn's disease: safety and efficacy in clinical practice. J Clin Gastroenterol 2008; 42: 395-9. PubMed Citation  (Retrospective analysis of 44 patients with Crohn disease treated with methotrexate for average of 2 years [total dose 1.2 g]; ALT or AST elevations developed in 30% of patients requiring stopping therapy in 7%, but none developed cirrhosis or clinically apparent liver injury).

  306. Hartmann U, Schmitt S, Reuss-Borst M. [Elevated liver enzymes in rheumatoid arthritis: differential diagnostic considerations based on a case report]. Z Rheumatol 2008; 67: 440-4. German. PubMed Citation  (Case report of apparent autoimmune hepatitis arising in 17 year old woman with rheumatoid arthritis after 18 months of leflunomide therapy, controlled with prednisone and azathioprine).

  307. Laharie D, Terrebonne E, Vergniol J, Chanteloup E, Chabrun E, Couzigou P, de Ledinghen V. [The liver and methotrexate]. Gastroenterol Clin Biol 2008; 32: 134-42. French. PubMed Citation  (Review of hepatotoxicity of methotrexate).

  308. Lapalus MG, Hot A, Fontana A, Guillaud O, Miossec P, Xcozaec J-Y, Dumorteir J. Epstein Barr virus-induced hepatitis associated with methotrexate treatment. J Clin Gastroenterol 2008; 42: 217-9. PubMed Citation  (62 year old woman with systemic lupus on methotrexate and prednisone developed ascites [bilirubin 0.5 mg/dL, ALT 42 U/L, Alk P 85 U/L, albumin 3.1 and IgM anti-EBV], biopsy showing cirrhosis and "superimposed acute hepatitis", ultimately resolving).

  309. Prey S, Paul C. Effect of folic or folinic acid supplementation on methotrexate-associated safety and efficacy in inflammatory disease: a systematic review. Brit J Dermatol 2008; 160: 622-8. PubMed Citation  (Systematic review of 6 studies of folic or folinic acid supplementation [648 patients] during methotrexate therapy of rheumatoid arthritis [n=5] or psoriasis [n=1]; significant reduction in liver adverse events by 36%, but not on other side effects and no difference between folinic or folic acid; whether folate supplemental affects effectiveness of methotrexate could not be assessed adequately).

  310. Taylor WJ, Korendowych E, Nash P, Helliwell PS, Choy E, Krueger GG, Soriano ER, et al. Drug use and toxicity in psoriatic disease: focus on methotrexate. J Rheumatol 2008; 35: 1454-7. PubMed Citation  (Survey of rheumatologists regarding use of methotrexate in psoriasis and rheumatoid arthritis found a wide variability in practice of monitoring; use of folate was not assessed; 40 respondents had observed a case of cirrhosis due to methotrexate).

  311. Dwyer N, Jones G, Kilpatrick D. Severe hepatotoxicity in a patient on bosentan upon addition of methotrexate: reversible with resumption of methotrexate without bosentan. J Clin Rheumatol 2009; 15: 88-9. PubMed Citation  (45 year old with scleroderma on bosentan therapy developed liver test abnormalities 4 months after starting escalating doses of methotrexate [bilirubin 9.5 mg/dL, ALT 1189 U/L, Alk P 550 U/L, INR 1.3], resolving in 1 month of stopping both drugs; later tolerated methotrexate alone).

  312. Katchamart W, Trudeau J, Phumethum V, Bombardier C. Efficacy and toxicity of methotrexate(MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis 2009; 68: 1105-12. PubMed Citation  (Systematic review of 19 trials comparing methotrexate alone to its combination with other disease modifying agents in 2025 patients showed no improvement in efficacy by addition of other agents to methotrexate, but an increase in toxicity with combination therapy, including increased frequency of ALT elevations).

  313. Lindsay K, Fraser AD, Layton A, Goodfield M, Gruss H, Gough A. Liver fibrosis in patients with psoriasis and psoriatic arthritis on long-term, high cumulative dose methotrexate therapy. Rheumatology(Oxford) 2009; 48: 569-72. PubMed Citation  (Retrospective analysis of liver biopsies in 54 patients with psoriasis treated with methotrexate for an average of 7 years; mild fibrosis [IIIA] was found in 22% of patients, but none had cirrhosis; history of alcohol use and PIIIP levels did not predict presence of fibrosis).

  314. Boffa MJ, Smith A, Chalmers RJ. Comment on: Liver fibrosis in patients with psoriasis and psoriatic arthritis on long-term, high cumulative dose methotrexate therapy. Rheumatology(Oxford) 2009; 48: 1464; author reply 1465. PubMed Citation  (Letter in response to Lindsay et al. [2009] suggesting that serial normal PIIIP values in patients with psoriasis on methotrexate are helpful in providing reassurance that ongoing liver fibrosis will not be missed; response by authors suggests that more studies are needed).

  315. Lu LJ, Bao CD, Dai M, Teng JL, Fan W, Du F, Yang NP, et al. Multicenter, randomized, double-blind, controlled trial of treatment of active rheumatoid arthritis with T-614 compared with methotrexate. Arthritis Rheum 2009; 61: 979-87. PubMed Citation  (T-614, a novel immunomodulatory agent, was compared to methotrexate in a randomized controlled trial of 24 weeks in 489 patients with rheumatoid arthritis; similar efficacy; ALT elevations occurred in 24% on methotrexate vs 6% to 13.5% on T-614).

  316. Neves C, Jorge R, Barcelos A. [The network of methotrexate toxicity]. Acta Rheumatol Port 2009; 34: 11-34. Portuguese. PubMed Citation  (Systematic review of methotrexate toxicities).

  317. Periánez-Párraga L, Pérez-Rodríguez O, do Pazo-Oubiña F, Crespí-Monjo M. [Acute toxicity of high doses of methotrexate in treatment of ALL in children: a case study]. Farm Hosp 2009; 33: 172-3. Spanish. PubMed Citation  (12 year old boy with acute leukemia developed raised ALT and bilirubin during high dose methotrexate therapy attributed to concurrent renal toxicity, resolving rapidly).

  318. Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis 2009; 68: 1100-4. PubMed Citation  (Systematic review of 21 prospective studies [3463 patients] on the safety of methotrexate in rheumatoid arthritis; using average dose of 9 mg/week for 3 years, 73% had at least one adverse event and 18.5% had a liver related event; overall in 769 patients followed prospectively, 20% had at least one elevation in liver enzymes, 13% above 2 times ULN, and 3.7% discontinued therapy for this reason).

  319. Varatharajan N, Lim IG, Anandacoomarasamy A, Russo R, Byth K, Spencer DG, Manolios N, et al. Methotrexate: long-term safety and efficacy in an Australian consultant rheumatology practice. Intern Med J 2009; 39: 228-36. PubMed Citation  (Retrospective analysis of outcomes of methotrexate therapy in 790 patients with chronic arthritis; therapy stopped in 18 patients [2%] because of liver test abnormalities, but no one developed cirrhosis or died of liver disease).

  320. Ongaro A, De Mattei M, Della Porta MG, Rigolin G, Ambrosio C, Di Raimondo F, Pellati A, et al. Gene polymorphisms in folate metabolizing enzymes in adult acute lymphoblastic leukemia: effects on methotrexate-related toxicity and survival. Haematologica 2009; 94: 1391-8. PubMed Citation  (Polymorphisms of the two genes involved in folate metabolism correlated with an increased rate of hepatotoxicity [odds ratio 4.6 and 5.2] which was 29% overall; no correction was made for the multiple comparisons).

  321. Amital H, Arnson Y, Chodick G, Shalev V. Hepatotoxicity rates do not differ in patients with rheumatoid arthritis and psoriasis treated with methotrexate. Rheumatology (Oxford) 2009; 48: 1107-10. PubMed Citation  (Retrospective analysis of a health management organization records on 119 patients with rheumatoid arthritis and 690 with psoriasis treated with methotrexate showing that 45% of patients had at least one abnormal liver test with no difference in rates of AST elevation between the two diagnostic groups).

  322. Collin B, Vani A, Ogboli M, Moss C. Methotrexate treatment in 13 children with severe plaque psoriasis. Clin Exp Dermatol 2009; 34: 295-8. PubMed Citation  (Retrospective analysis of 13 children with severe psoriasis treated with methotrexate for 6 weeks to 5 years [total dose 0.04-3.6 g]; 9 had transient and mild ALT elevations and 1 discontinued therapy after 6 weeks when ALT rose to 516 U/L).

  323. Lynch M, Kirby B. Comment on: Hepatotoxicity rates do not differ in patients with rheumatoid arthritis and psoriasis treated with methotrexate. Rheumatology(Oxford) 2010; 49: 196-7; author reply 197-8. PubMed Citation  (Another letter in response to Amital [2009] arguing that standard liver tests alone are insufficient in monitoring for potential hepatotoxicity).

  324. Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. PubMed Citation  (World wide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, methotrexate accounted for 134 cases [ranking 5th] with an adjusted risk odds ratio of 4.2).

  325. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute
    liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010;
    52: 2065-76. PubMed Citation  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 [11%] were attributed to drug induced liver injury none of which were thought to be due to methotrexate).

  326. Curtis JR, Beukelman T, Onofrei A, Cassell S, Greenberg JD, Kavanaugh A, Reed G, et al. Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide. Ann Rheum Dis 2010; 69: 43-7. PubMed Citation  (In a large, observational US database, ALT or AST elevations found in 17% of patients on leflunomide alone, 22% on methotrexate alone, and 31% on both; levels >2 times ULN in only 2% vs 1% vs 5% [on both]; risk factors for elevations were methotrexate dose, history of liver disease and alcohol use [1-2 drinks/day]).

  327. Toscano E, Cotta J, Robles M, Lucena MA, Andrade RJ. [Hepatotoxicity induced by new immunosuppressants]. Gastroenterol Hepatol 2010; 33: 54-65. Spanish. PubMed Citation  (Review of hepatotoxicity of different immunosuppressive agents including methotrexate).

  328. Fournier MR, Klein J, Minuk GY, Bernstein CN. Changes in liver biochemistry during methotrexate use for inflammatory bowel disease. Am J Gastroenterol 2010; 105: 1620-6. PubMed Citation  (Among 87 patients with inflammatory bowel disease treated with methotrexate for an average of 2 years, 24% had liver test abnormalities, but most resolved without dose modification and no fibrosis or cirrhosis were found in liver biopsies from 20 patients).

  329. Rogler G. Gastrointestinal and liver adverse effects of drugs used for treating IBD. Best Pract Res Clin Gastroenterol 2010; 24: 157-65. PubMed Citation  (Review of recent literature on adverse effects of drugs used to treat inflammatory bowel disease including sulfasalazine, thiopurines, methotrexate, cyclosporine and tacrolimus).

  330. Triantafyllou K, Vlachogiannakos J, Ladas SD. Gastrointestinal and liver side effects of drugs in elderly patients. Best Pract Res Clin Gastroenterol 2010; 24: 203-15. PubMed Citation  (Review of drug adverse events in the elderly; injury seems to be more severe in older subjects, but frequency has not been proven to be increased and elderly may be at increased risk of hepatic fibrosis caused by methotrexate perhaps due to impaired renal function and frequent use of other medications).

  331. Attar SM. Adverse effects of low dose methotrexate in rheumatoid arthritis patients. A hospital-based study. Saudi Med J 2010; 30: 909-15. PubMed Citation  (Abstract: Among 71 patients with rheumatoid arthritis treated with methotrexate, 14% developed liver tests elevations).

  332. Khokhar OS, Lewis JH. Hepatotoxicity of agents used in the management of inflammatory bowel disease. Dig Dis 2010; 28: 508-18. PubMed Citation  (Review of hepatotoxicity of drugs used to treat inflammatory bowel disease including sulfasalazine, thiopurines, methotrexate and anti-TNF agents).

  333. Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. PubMed Citation  (Among 624,673 adverse event reports in children between 2000 and 2006 in the WHO VigiBase, 1% were hepatic and most common agents were isotretinoin, acetaminophen, valproic acid, carbamazepine, methotrexate, minocycline, lamotrigine, zidovudine, pemoline and ceftriaxone).

  334. Barker J, Horn E, Lebwohl M, Warren R, Nast A, Rosenberg W, Smith C; International Psoriasis Council. Assessment and management of methotrexate hepatotoxicity in psoriasis patients: report from a consensus conference to evaluate current practice and identify key questions toward optimizing methotrexate use in the clinic. J Eur Acad Dermatol Venereol 2011; 25: 758-64. PubMed Citation  (Review of the issue of hepatotoxicity of methotrexate and the reliability of monitoring with comparison of US, UK, European Union, German and Dutch guidelines; folate supplementation is recommended by most; pattern of details of monitoring and use of liver biopsy is variable and there is clearly a need for more accurate and less invasive means of assessing liver injury during methotrexate therapy).

  335. Scientific Registry of Transplant Recipients. January 31, 2010. (Among 46,633 liver transplants done in the United States between 2000 and 2009 in the SRTR registry, 31 [<0.1%] had the primary diagnosis of methotrexate induced cirrhosis).

  336. Aithal GP; Medscape. Hepatotoxicity related to antirheumatic drugs. Nat Rev Rheumatol 2011; 7: 139-50. PubMed Citation  (Review of hepatotoxicity of drugs used in rheumatic diseases; methotrexate causes ALT elevations and fibrosis in variable proportions of patients, more common in those with alcohol use, obesity, hyperlipidemia, metabolic syndrome and NASH).

  337. Barbero-Villares A, Mendoza J, Trapero-Marugan M, Gonzalez-Alvaro I, Daudén E, Gisbert JP, Moreno-Otero R. Evaluation of liver fibrosis by transient elastography in methotrexate treated patients. Med Clin (Barc) 2011; 137: 637-9. PubMed Citation. (Among 53 patients with autoimmune diseases being treated with methotrexate [for 2 weeks to 10 years], transient elastography was abnormal in 4 [8%], but did not correlate with duration of therapy or total dose; liver histology was not studied).

  338. Montaudié H, Sbidian E, Paul C, Maza A, Gallini A, Aractingi S, Aubin F, Bachelez H, Cribier B, Joly P, Jullien D, Le Maître M, Misery L, Richard MA, Ortonne JP. Methotrexate in psoriasis: a systematic review of treatment modalities, incidence, risk factors and monitoring of liver toxicity. J Eur Acad Dermatol Venereol 2011; 25 Suppl 2: 12-8. PubMed Citation  (Systematic review of literature on hepatotoxicity of methotrexate in psoriasis identified 23 studies: "published studies do not confirm the incidence of hepatic fibrosis", the rate varying from 6-71% in 5 studies of 22-96 patinets each followed for 1 to 11 years).

  339. 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. PubMed Citation  (57 year old man with rheumatoid arthritis developed jaundice 3 years after starting long-term methotrexate [bilirubin 3.3 mg/dL, ALT 1715 U/L, Alk P 167 U/L, ANA 1:160 and previously negative], responding to corticosteroid therapy which was later stopped without relapse; unclear whether methotrexate was stopped).

  340. Bishnoi P, Kumari R, Thappa DM. Monitoring methotrexate hepatotoxicity in
    psoriasis. Indian J Dermatol Venereol Leprol 2011; 77: 545-8. PubMed Citation  (Review of safety and efficacy of methotrexate in psoriasis).

  341. Gupta R, Bhatia J, Gupta SK. Risk of hepatotoxicity with add-on leflunomide in rheumatoid arthritis patients. Arzneimittelforschung 2011; 61: 312-6. PubMed Citation  (Among 46 patients with rheumatoid arthritis who had leflunomide added to conventional disease modifying therapies, 22% had ALT or AST elevations, but none developed clinically apparent liver injury).

  342. Anelli MG, Scioscia C, Grattagliano I, Lapadula G. Old and new antirheumatic drugs and the risk of hepatotoxicity. Ther Drug Monit 2012; 34: 622-8. PubMed Citation  (Review of currently used antirheumatic drugs and their potential for hepatotoxicity).

  343. Santiago García D, Saturansky E, Poncino D, Ortiz V, Martínez Artola Y, Rosenberg S, Abritta G, Palermo C, Enriquez N, Cravero A. [Liver diseases in rheumatoid and psoriatic arthritis]. Acta Gastroenterol Latinoam 2012; 42: 112-9. Spanish. PubMed Citation  (Among 118 patients with inflammatory arthritis, 47 [40%] had evidence of liver disease, including 35 [30%] with nonalcoholic fatty liver and 15 [13%] drug induced liver injury).

  344. Tugnet N, Cooper SC, Douglas KM. Methotrexate therapy, rheumatoid arthritis, and life-threatening liver complications: should we be monitoring more closely? Scand J Rheumatol 2012; 41: 163-4. PubMed Citation  (26 year old woman with rheumatoid arthritis developed variceal hemorrhage after 4 years of methotrexate therapy [bilirubin 4.1 mg/dL, ALT 377 U/L, Alk P 166 U/L, platelets 80,000/μL, INR 2.4], improving after stopping and switching to etanercept).

  345. Gilani ST, Khan DA, Khan FA, Ahmed M. Adverse effects of low dose methotrexate in rheumatoid arthritis patients. J Coll Physicians Surg Pak 2012; 22: 101-4. PubMed Citation  (Methotrexate levels and clinical toxicity in 140 patients with rheumatoid arthritis on 10 mg/week found ALT or AST elevations in 2.1% and higher toxicity in those with higher levels in plasma).

  346. Khan N, Abbas AM, Whang N, Balart LA, Bazzano LA, Kelly TN. Incidence of liver toxicity in inflammatory bowel disease patients treated with methotrexate: a meta-analysis of clinical trials. Inflamm Bowel Dis 2012; 18: 359-67. PubMed Citation  (Meta analysis of trials of methotrexate for inflammatory bowel disease identified 13 trials with 632 participants treated for 2.7-18 months; risk of ALT elevations [>2 times ULN] was 0.9 per 100 person-months).

  347. Dávila-Fajardo CL, Swen JJ, Cabeza Barrera J, Guchelaar HJ. Genetic risk factors for drug-induced liver injury in rheumatoid arthritis patients using low-dose methotrexate. Pharmacogenomics 2013; 14: 63-73. PubMed Citation  (Review of pharmacogenomics of methotrexate toxicity focusing upon MTHFR).

  348. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. PubMed Citation  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, one of which was attributed to methotrexate). 

  349. 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. PubMed Citation  (Analysis of urinary protein profiles of patients on long term methotrexate therapy for psoriasis identified several urinary proteins that might serve as noninvasive markers of fibrosis progression including N-cadherin, ITIH4, haptoglobin and serotransferrin).

  350. Ng LC, Lee YY, Lee CK, Wong SM. A retrospective review of methotrexate-induced hepatotoxicity among patients with psoriasis in a tertiary dermatology center in Malaysia. Int J Dermatol 2013; 52: 102-5. PubMed Citation  (Among 66 patients with psoriasis treated with methotrexate between 2000 and 2009 at a Malaysian medical center, 58% had ALT or AST elevations during treatment, but therapy was stopped for enzyme elevations in only 6 patients and no patient developed cirrhosis).

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