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Rheumatology Advance Access originally published online on May 12, 2008
Rheumatology 2008 47(7):939-941; doi:10.1093/rheumatology/ken158
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EDITORIALS

Psoriatic arthritis, methotrexate and the liver—are rheumatologists putting their patients at risk?

K. Lindsay and A. Gough

Harrogate and District NHSFT, Harrogate, N Yorkshire, UK

Correspondence to: K. Lindsay, Harrogate and District NHSFT, Lancaster Park Road, Harrogate, N Yorkshire HG2 7SX, UK. E-mail: Karen.Lindsay{at}anhst.nhs.uk

It seems hard to believe that in the early 1990s MTX use by a respected group of UK rheumatologists in nine hospitals only represented 3% of all DMARDs used for a cohort of patients presenting with early RA [1]. It is now the most widely used DMARD, not only for RA, but is effective for both psoriasis and PsA [2, 3]. It has also become our principal anchor drug in combination therapy, including the anti-TNF agents, where recent data suggests that their combination is our best treatment option yet in RA [4]. As a cheap, effective and usually well-tolerated drug it is not surprising that prescribing it worldwide has continued to rise exponentially and that the patients may be on it commonly for >5 yrs.

Hepatotoxicity with MTX has always been a concern. In the 1970s, this was the predominant reason for MTX falling out of favour in the UK. Fortunately for patients, good long-term follow-up studies continued in the USA proving not only that it is safe but also that it may improve survival in patients with RA [5, 6]. Further data shows that it is more likely to be continued at 5 yrs than any of the traditional DMARDs and is now the most frequently prescribed in Europe too [3].

The introduction of regular folate supplementation has been a key advance, not only in reducing aphthous ulceration, hair loss and nausea, but also reducing haematological toxicity. There is also some evidence to suggest that this reduces liver toxicity too [7]. However, even without this, long-term studies have suggested that liver damage is minimal in RA patients, as long as regular monitoring of liver transaminases is undertaken. Thus, treatment of RA with MTX and folate has become widely accepted, with very little toxicity reported. Even hepatologists now use MTX to treat conditions such as primary biliary cirrhosis [8].

Rheumatologists have moved on to use MTX for PsA, knowing that our dermatology colleagues have used it successfully to treat psoriasis for many years. Although effective for both conditions, the dermatologists have always had concern for its potential for liver damage. The American Academy of Dermatology guidelines still recommend that sequential liver biopsies are performed at a cumulative dose of 1.5 g (i.e. every 2 yrs at a weekly dose 15 mg) [9].

The concern for liver toxicity in psoriasis has been supported by research suggesting that significant liver damage is three times more likely in these patients when compared with patients with RA at the same dosage and that liver cirrhosis may occur without significant increases in transaminase [10, 11]. Reasons suggested for this are the confounding effect of alcohol from which abstinence has been strongly emphasized in rheumatology practice; a systemic effect of psoriasis per se; more frequent and regular serial testing of liver function tests (LFTs) with dose reduction in rheumatology practice; folic acid co-prescription that reduces liver function test abnormalities; and finally anti-inflammatory medication and other DMARDs, such as SSZ and steroids, which suppress fibrogenesis within the liver [12].

Rheumatologists treating PsA usually monitor their patients in the same way as RA and do not quantify cumulative dose or treatment duration. This may suggest that rheumatologists are putting their patients at risk particularly after 5 yrs treatment when there is a dearth of evidence that this is safe. Significantly, liver function tests are thought to be insensitive at predicting the development of liver fibrosis in psoriasis by dermatologists, whereas rheumatologists feel that serial monitoring of transaminases is sufficient. The caveat to this is that a referral to a gastroenterologist for liver biopsy is made if five out of nine aspartamine transferase (AST) estimations are elevated in 1 yr or if hypoalbuminaemia in the absence of active inflammatory arthritis occurs [9, 13]. From a rheumatologist's point of view this rarely occurs. A recent review of Irish practice confirms that monitoring remains very different between the two specialties when treating people with psoriasis [14].

From this two key questions arise. First, as PsA is more likely to be like psoriasis than RA, are patients with PsA on MTX in rheumatology departments at risk of long term progressive undetected liver damage. Second, can we find a reliable non-invasive way of monitoring our MTX-treated patients without having to do regular liver biopsies? With the known complications of liver biopsy, both patients and clinicians are very keen to find an answer to this [15].

Whilst there is no doubt that MTX causes hepatotoxicity, to what degree it does in the absence of other risk factors is not clear. There are numerous clinical cases of MTX-induced cirrhosis and death, though typically in the presence of confounding factors [16, 17]. An experimental rat model demonstrates hepatic necrosis with low-dose daily MTX [18] but cannot be reproduced in weekly dosages even at very high doses. Non-alcoholic fatty liver disease (NAFLD), a hitherto unrecognized and largely ignored disease has become the focus of intense research as it may well be the most common form of liver disease in the western world. A proportion of cases develop inflammation, non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis and hepatocellular carcinoma [19]. Similar to MTX hepatotoxicity the risk factors for NASH are obesity and diabetes. The mainstay of treatment of NASH is aggressive risk factor management and weight loss [20]. Whilst difficult to quantify, MTX contributes to liver fibrosis and no doubt a proportion of reported cases of MTX-induced hepatotoxicity cases can retrospectively be ascribed to NASH. MTX can lead to NASH-like appearances on histology in the absence of obesity or diabetes [21].

Liver function tests are elevated in PsA compared with RA treated with MTX in a study in which the most likely confounding factor, alcohol consumption, was excluded, supporting the suggestion that psoriasis per se may increase the risk of hepatic fibrosis [11]. However, other risk factors for NAFLD were not considered and liver biopsies were not performed. Also self-reported alcohol consumption is unreliable evidence, particularly as the level increases [11].

It is useful to think of MTX as one in a group of risk factors for hepatic fibrosis, which includes alcohol. For the long-term use of MTX for PsA and even the switch to injected MTX, the ACR guidelines are not yet validated particularly after 5 yrs of therapy. The risk of cirrhosis from all potential risk factors ought to be reassessed and performance of liver biopsy or alternative tests of liver fibrosis are justified [15]. Certainly, in patients who are at risk of NASH, with diabetes and obesity, the rheumatologist may well find themselves monitoring liver function tests for this disease as well and a still more long-term safety data is needed in this group.

The second key question concerns non-invasive liver monitoring. The current ACR recommendations for RA are for pre-treatment liver biopsy if certain risk factors are present including high alcohol consumption or persistently abnormal baseline LFTs. The guidelines also state that referral to a gastroenterologist for liver biopsy should be considered if five of nine monthly AST values are elevated or if transaminases become three times that of normal value or if the albumen falls below normal in the absence of active arthritis [22]. For most rheumatologists, LFTs are the only method used to monitor liver function and liver biopsy after a certain cumulative dose is not considered [14]. A recent European survey showed that MTX is the most commonly prescribed DMARD for severe psoriasis (44% of all systemic therapy in randomly selected group of dermatologists from across Europe) and 20% of dermatologists using MTX for psoriasis have implemented regular testing of a collagen breakdown marker in serum called procollagen III peptide (PIIINP) [2]. The serial measurement of PIIINP is already being relied upon by many dermatologists to indicate if and when a liver biopsy is required [14]. In one convincing study, it has been shown to be normal in psoriasis patients onMTX, who have had no histological progression of hepatic fibrosis on liver biopsy [23]. It has been advocated as a replacement for liver biopsy by dermatologists on economic and safety grounds and because of patient preference [24].

Unfortunately, this new test does have some disadvantages. Serial measurement is required and it is not organ specific. A study of PIIINP levels in a group of 170 patients, with 49% having PsA, suggested that PIIINP could not be relied upon to be a safe way of preventing liver biopsy to detect liver fibrosis and that PIIINP is elevated in response to active PsA [25]. More liver biopsies may be required in patients with PsA, making it appear an unhelpful test for current rheumatology practice. PIIINP is markedly raised in active synovial inflammation in RA and may in fact be proportional to disease activity, particularly in erosive or damaged joints, adding to difficulty of managing a patient with aggressive arthritis with MTX [26, 27]. Elevated PIIINP measurements are unhelpful, alarming and unlikely to imply liver damage in PsA, particularly in active disease and should not be measured in routine monitoring for hepatotoxicity in PsA [12].

Another difficulty that has to be recognized is that our gold standard, the liver biopsy itself, is far from perfect. Not only does it have a mortality of 0.01–0.1% but it is also subject to sampling error in up to 35% of the cases of advanced cirrhosis [28]. In a long-term follow-up study of 25 patients for over 10 yrs with biopsy-proven MTX-induced cirrhosis, who were obliged to continue treatment because of severe psoriatic disease, 13 biopsies taken after an interval were normal. Five of these patients subsequently had cirrhosis confirmed at autopsy. One patient died of liver failure. Thus, false positives and negatives occur even when the end organ itself is tested [15] With great improvements in imaging in recent years we might reasonably have expected this to provide accurate non-invasive information to quantify fibrotic liver disease. Unfortunately, although ultrasound has 94% sensitivity and 84% specificity in detecting steatosis, it is unhelpful in differentiating steatosis from fibrotic liver [29]. MRI has been shown to be of no value in detecting hepatic fibrosis [30].

Fortunately, in the meantime due to the rising importance of NASH, our hepatology colleagues have been strenuously involved in developing non-invasive methods of quantitative testing for hepatic fibrosis, from a battery of serum markers of fibrogenesis to combine clinical and biochemical markers seeking validation using liver biopsy [31–33]. Non-invasive markers used for staging liver fibrosis are now as accurate as liver biopsy for differentiating patients with mild fibrosis from those with significant fibrosis and some of these tests may be more accurate at detecting fibrosis than liver biopsy and this is limiting their validation [34]. Recently, a new liver test using a low-amplitude single-pulse vibration with the shear wave detected on ultrasound to assess liver stiffness has shown promise and been tested in MTX-treated Crohn's disease [35].

In summary, MTX is crucial in the long-term treatment of a number of conditions including RA, PsA and psoriasis and is likely to remain so despite the advent of biologic agents. In RA, there is enough evidence to suggest that regular monitoring of transaminases is sufficient. This may not be so in psoriasis and PsA. Whilst we still do not yet have a reliable enough non-invasive test of liver function to avoid the need for liver biopsy in all patients, further studies to evaluate the risk and validate these methods in our patients are still required. In particular, where patients have risk factors for NASH, and who have had >5 yrs of therapy, one should reconsider the risks of long-term hepatic fibrosis and consider liver biopsy.

Disclosure statement: The authors have declared no conflicts of interest.

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Accepted 31 March 2008


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K. Lindsay, A. D. Fraser, A. Layton, M. Goodfield, H. Gruss, and A. Gough
Liver fibrosis in patients with psoriasis and psoriatic arthritis on long-term, high cumulative dose methotrexate therapy
Rheumatology, May 1, 2009; 48(5): 569 - 572.
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