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Noninvasive monitoring for methotrexate hepatotoxicity

The advent of targeted biological treatments for psoriasis has challenged the safety and efficacy of established systemic treatments. Methotrexate has been used for psoriasis since the late 1950s and is still the most widely prescribed drug for severe psoriasis worldwide. Its effectiveness in treating psoriasis was first detected by chance in a patient being treated for arthritis whose coincident psoriasis was observed to improve. This started a trend of serendipity in drug development for psoriasis, being subsequently followed by ciclosporin, vitamin D and infliximab. As methotrexate has been in use for almost 50 years it predates the development of randomized controlled trials, and high-quality data concerning its efficacy are sparse. Consequently there is considerable variability in the recommended weekly dose, the route of administration (oral, intramuscular, intravenous and subcutaneous) and the need for, and dosing of, concomitant folic acid. With improvements in our understanding of the immunopathogenesis of psoriasis, it has become apparent that the mechanism of action in psoriasis (originally attributed to the inhibition of the enzyme dihydrofolate reductase, disrupting DNA synthesis and interrupting epidermal cell division) is probably related to effects on T cells, rather than keratinocytes. Use of methotrexate is restricted by the risk of organ toxicity. Major concerns are myelosuppression, hepatotoxicity and pulmonary fibrosis, of which myelosuppression is the most important. Of the 164 fatalities associated with methotrexate therapy reported to the U.K. Committee on the Safety of Medicines (CSM) between 1969 and 2004, 67 were associated with myelosuppression. In contrast, 30 deaths occurred in association with pulmonary complications and only eight as a result of liver complications (CSM, personal communication, 2004). It is possible that there is under-reporting of cases to the CSM, as a survey in 1992 of 278 U.K. dermatologists treating approximately 10 000 patients with methotrexate over a mean period of 12 years reported 23 deaths as a result of liver failure and five as a result of liver biopsy. Prescribing error is a particular problem and this may increase in the U.K. with a shift in monitoring of methotrexate to primary care. The National Patient Safety Agency recorded 137 patient safety incidents in the U.K. over the last 10 years, including 25 deaths and 26 cases of serious harm to the patient as a consequence of methotrexate administration (http://www.npsa.nhs.uk, accessed 21 December 2004). Two-thirds of incidents were prescribing errors, 19% were due to a lack of, or poor monitoring, and 7% were due to misidentification of tablets by professionals or patients. Most incidents involved primary care clinicians. Among dermatologists, there is particular concern about the long-term hepatotoxic potential of methotrexate. Interestingly, this concern is not shared to the same extent by other specialities. It seems quite possible that the risk of hepatotoxicity varies in different diseases. For instance, patients with rheumatoid arthritis are more frequently treated with oral corticosteroids than are patients with psoriasis, and it is conceivable that this reduces hepatic inflammation. Psoriatic patients have a greater tendency to drink alcohol to excess, which may contribute. Among patients with psoriasis receiving methotrexate, rates of hepatic fibrosis as high as 25–50% have been published athough recent estimates are lower, at 0–4%. The cause of methotrexate-induced fibrosis is unknown. Methotrexate may also be an independent risk factor for nonalcoholic steatohepatitis (NASH), the most common cause of chronic liver disease in the developed world. Folate supplementation reduces the frequency of raised liver enzymes without altering efficacy, suggesting that this aspect of methotrexate toxicity may be divorced from its therapeutic efficacy. Understanding of liver fibrosis and cirrhosis has advanced significantly over recent years. Hepatic stellate cells (HSCs) are now known to be the final common pathway in the production of collagens. In hepatic fibrosis, HSCs are upregulated to become myofibroblast-like and produce collagen. Gliotoxin, which stimulates apoptosis of HSCs, promotes reversal of liver fibrosis in animal models. Research into the mechanisms of activation of HSCs by chemokines and cytokines may allow for therapeutic intervention in the future. Understanding of the role of metalloproteinases, which degrade collagen, may also provide a therapeutic target to reverse fibrosis. Ideally, individuals at particular risk of hepatotoxicity would be identified prior to treatment. Early pharmacogenetic studies have demonstrated an A1298C polymorphism in the methylenetetrahydrofolate reductase gene which may protect against methotrexate-related adverse effects, while a C667T polymorphism in the same gene correlates with methotrexate hepatotoxicity. These studies assessed tolerability of methotrexate and derangement of liver enzymes rather than progression to fibrosis, but hopefully this aspect will also be addressed. Environmental factors predisposing to methotrexate hepatotoxicity include exposure to other hepatotoxins such as alcohol, and also the various factors associated with NASH, such as obesity and diabetes. Many issues need to be considered in deciding a policy for screening for methotrexate hepatotoxicity, but it is important that the procedures used are not only accurate, but are also proportionate to the frequency and severity of this complication. It is widely accepted that elevations in liver enzymes are a poor guide to the development of liver fibrosis. However, although liver enzymes rise in the days following