Methotrexate users get a break from liver biopsies

[Nick]

Good news for all psoriasis sufferers using methotrexate (MTX)

In the past MTX users have had the added pain and suffering of having to undergo liver biopsies. Now thanks to a new serum, procollagen III aminopeptide or PIIINP may deliver monitoring without the need for biopsies.


Methotrexate

Methotrexate is an effective antipsoriatic agent1. It is especially useful in acute, generalised, pustular psoriasis, psoriatic erythroderma, psoriatic arthritis, and for extensive chronic plaque psoriasis in patients who are inadequately controlled by topical therapy alone. It has not been formally compared with other treatments for severe psoriasis, such as cyclosporin or psoralen photochemotherapy. In comparison with other systemic therapies for psoriasis, it is inexpensive. It can be used either as a short term option, to gain control of unstable psoriasis such as pustular psoriasis or erythroderma before returning to the other modes of treatment, or, more often, as long term maintenance treatment. The most important potential side effect is acute marrow suppression, which is the cause of most of the rare deaths attributable to methotrexate therapy of psoriasis. Long term treatment carries with it a risk of hepatic fibrosis and cirrhosis, which is related to the dosage regimen employed2, and is increased by exposure to other hepatic toxins, in particular alcohol. The correlation between the cumulative lifetime dose of methotrexate and the risk of development of hepatic fibrosis or cirrhosis is not clear-cut3-6.
Safety, side-effects and patient acceptability

Haematological or renal abnormality: Methotrexate should be avoided in patients with significant haematological abnormalities including severe anaemia, leucopenia or thrombocytopenia. Methotrexate should also be avoided, in all but exceptional circumstances, in patients with significant renal impairment. Because methotrexate is eliminated largely via the kidneys, toxic levels may build up rapidly in patients with renal impairment, and even low doses of the drug may then produce acute myelosuppression7 . This is particularly liable to occur in the elderly when concomitant drug administration or illness, such as fever or diarrhoea, may result in the sudden deterioration of renal function. Of the 24 fatalities associated with methotrexate treatment for psoriasis reported to the United Kingdom Committee on Safety of Medicines (CSM) between 1969 and 1994, myelosuppression was given as the cause of death in 19 (information supplied by CSM). Elderly patients especially, should be warned to omit methotrexate doses whenever they are at risk of acute dehydration (e.g. from acute fever, vomiting or diarrhoea).

Drug Interactions: Certain drugs may increase the toxicity of methotrexate by increased antifolate effect (e.g. sulphonamindes, trimethoprim and phenytoin), or by decreasing renal elimination (e.g. aspirin, NSAIDs, probenecid and cyclosporin)8. As life-threatening myelosuppression may result from interactions between methotrexate, and such drugs, great care must be taken to ensure that all medical attendants are made aware when a patient is receiving methotrexate and patients should be advised to check with their pharmacist on the safety of any new drug prescription they receive.

Liver disease and alcohol: Methotrexate should be administered with great caution, if at all, to patients with significant current or previous liver disease, especially if due to alcohol. Any patient suspected of alcohol abuse is usually unsuitable for methotrexate, although many dermatologists allow patients receiving methotrexate to continue taking small amounts of alcohol (e.g. 4-6 units weekly).

Fertility: Because methotrexate is both abortifacient9 and teratogenic,10,11 it is strictly contraindicated in pregnancy. Adequate contraceptive measures must be taken by women of child-bearing potential during methotrexate therapy, and for at least one menstrual cycle after stopping the drug12. Although methotrexate is not mutagenic, and normal children have been born when the father was taking methotrexate at the time of conception,9,13 the drug may affect spermatogenesis14 . It is customary to advise men to avoid fathering children during therapy and for at least three months after12.

Other precautions: Other important contraindictions to the use of methotrexate in psoriasis include active peptic ulceration, active infectious disease, such as tuberculosis or immunodeficiency states, and patient unreliability.
Efficacy

Initiation of therapy: The risks and benefits of therapy should be clearly explained to the patient, both verbally and in writing. A clear record of the history (including previous therapy), and the extent of psoriasis, should be made. Adequate contraceptive measures must be commenced where appropriate. A full blood count and tests of renal and hepatic function (see below) should be performed. If there are no contradications, then therapy may be commenced. The dose of methotrexate must be individually assessed for each patient. Most serious problems and the rare deaths associated with methotrexate usage in psoriasis arise because of an absolute or relative overdosage.

Methotrexate is usually given orally but may be administered by the intramuscular or intravenous route. It should be given as a single weekly dose as it is well-established that the toxicity for a given total dose is considerably increased when it is administered daily2. Unambiguous instructions, including which day of the week the tablets are to be taken, should be given to the patient and specified on the prescription. The rationale proposed for giving methotrexate in three divided doses once weekly15 , is now thought unlikely to be valid16. As this schedule is undoubtedly more open to error on the part of the patient and may, perhaps, be associated with a greater risk of hepatic fibrosis17 , it should be abandoned, except for the few patients in whom drug-induced nausea may be lessened by changing to the divided dose regimen.

A small test dose, usually 5mg, should be given in order to detect those patients who may be unduly sensitive to the drug. If the full blood count is stable, at seven days, then methotrexate may be continued. Subsequent doses may be gradually increased, usually by 2.5-5 mg steps, according to clinical response and any accompanying toxicity. The aim of therapy should not be to induce complete clearance of psoriasis but to achieve sufficient control that it may be more readily managed with topical therapy. Most patients are adequately controlled on doses of 7.5-15mg weekly and few patients require more than 20mg. Even lower doses may suffice, particularly in the elderly.

Monitoring therapy: Initially, patients should be assessed weekly by examination and laboratory measurement of the full blood count, plasma urea, electrolytes and creatinine, and liver enzyme tests. The interval between visits may be gradually increased until therapy has been stabilised, after which continuing assessments should be performed every two to three months. The exact time intervals will vary according to circumstance. Mechanisms should be in place to ensure that further supplies of the drug are dispensed only if appropriate monitoring has been carried out, and that blood test results are reviewed promptly after each visit so that any necessary action, such as dosage reduction, can be taken without delay. In any individual the dose of methotrexate required to maintain adequate control of psoriasis will vary from time to time, and should be adjusted accordingly.

As alcohol abuse greatly increases the risks of liver damage in patients receiving methotrexate, they should be reminded regularly of the need to restrict or avoid alcohol intake. Liver damage cannot be reliably detected by standard liver enzyme tests18, or by imaging techniques 19, and regular liver biopsy for all patients receiving low dose methotrexate for psoriasis is still advocated by several authorities12,20. Several studies suggest, however, that the risk of serious liver damage in carefully monitored patients receiving once weekly low dose methotrexate is small5,21,22, and that the cost and morbidity of repeated liver biopsy may be difficult to justify when compared with the low yield of significant liver pathology. It is, thus, reasonable to recommend that liver biopsy need no longer be performed routinely. If there are concerns about pre-existing liver damage, it may be appropriate to obtain a liver biopsy as a baseline soon after successful methotrexate therapy has been established. The best practice for liver biopsy is for this to be done, by radiologists, under ultrasound control. A number of investigators have examined the place of serological markers of fibrosis, particularly the aminoterminal peptide of type III procollagen (PIIINP), in assessing liver damage from methotrexate. A recent study has concluded that patients whose PIIINP levels (Orion Diagnostica7) are consistently normal are very unlikely to have significant liver damage, and that follow-up biopsy may be restricted to the small minority in whom PIIINP levels are repeatedly elevated23 . If the PIIINP assay is available, it should be performed three monthly and liver biopsy should then be considered for patients in whom it is persistently abnormal (i.e. greater than 4.2ng/ml for the Orion assay).

Management of problems: Nausea is the commonest side effect reported by patients and may affect up to a quarter of all patients treated24. It usually appears within 12 hours of methotrexate ingestion and may last up to three days24. It is usually mild, but in some patients, it is sufficiently severe enough to necessitate withdrawal of therapy. No measures are guaranteed to relieve symptoms. Folic acid, at a dose of 5mg daily, has been found to be more helpful than the use of antiemetics, taking methotrexate with the evening meal, or dividing the dose (in a once weekly course of 3 doses at 12 hour intervals) 24, although any of these manoeuvres may help some patients.

Although liver enzyme tests are an unreliable indicator of liver fibrosis, an acute rise in liver enzymes may indicate hepatic inflammation. If aspartate or alanine aminotransferase levels rise to greater than three times the upper limit of normal, most authorities would recommend that methotrexate be discontinued. If PIIINP levels are repeatedly abnormal over a twelve month period, then liver biopsy should be considered. The decision to discontinue methotrexate depends not only on the results of liver biopsy, but also on the ease with which an individual patient's psoriasis may be managed by other means. In general, severe fibrosis and cirrhosis are considered contraindications to further methotrexate therapy. Nevertheless some dermatologists have continued treatment in patients with documented cirrhosis without encountering significant deterioration of liver disease20. In patients with hepatic inflammation or mild to moderate fibrosis without cirrhosis, continuation of methotrexate therapy is probably still safe, as long as alcohol is strictly avoided and patients are closely monitored. If PIIINP remains elevated, then a further liver biopsy should be considered, after twelve months to two years of continued therapy.

A rise in the mean corpuscular volume (MCV) is common in patients receiving long term methotrexate, and usually indicates relative folate deficiency. Some authorities advise supplementary folic acid for all patients treated with the drug25, but others consider that it need be given only if the MCV rises above the upper limit of normal. If this occurs, it is important to exclude other causes of macrocytosis, in particular vitamin B12 deficiency, but usually it will indicate folate deficiency. Patients will normally be advised to take folic acid 5mg daily for as long as methotrexate is continued. If the MCV rises above 106 fl, despite folate replacement, then further methotrexate therapy is probably contraindicated26. It is important to note that folate therapy does not appear to reduce the therapeutic effect of methotrexate in psoriasis24.

Absolute or relative overdosage of methotrexate can result in acute toxicity, manifested clinically by myelosuppression, mucosal ulceration and, rarely, cutaneous necrolysis. The metabolic effects of methotrexate can be bypassed by the administration of folinic acid, which should be readily available to any dermatologist prescribing methotrexate. As soon as overdose is suspected, serum should be collected for measurement of methotrexate levels and folinic acid should be administered intravenously. The dose of folinic acid should be at least as high as the total dose of methotrexate thought to be responsible for the overdose and should in any event not be less than 20 mg. Subsequent doses (which may be taken orally if no more than 20 mg), should be given at 6 hourly intervals until the serum methotrexate is less than 0.01 FM/L. The dose of folinic acid required will vary according to the serum methotrexate concentration. Twenty milligrams suffices where the concentration is 0.5 FM/L or less but at higher concentrations the dose can be calculated at 100 mg for every 1 FM/L of measured serum methotrexate concentration 12 . Adequate hydration is essential to ensure maximal renal elimination and, in cases of massive overdose, alkalinisation of the urine with sodium bicarbonate may be required to prevent precipitation of methotrexate in the renal tubules. In patients with poor drug excretion or delayed drug absorption, methotrexate levels can remain dangerously elevated for several days after an overdose and folinic acid should be continued until it is certain that all methotrexate has been excreted. If plasma methotrexate levels are unavailable folinic acid should be continued until the blood count has returned to normal and the mucosae have healed. Clinical oncologists and haematologists who are familiar with high-dose methotrexate regimens may be a useful source of advice on the management of acute methotrexate toxicity. Early treatment may be life-saving Every dermatologist using methotrexate should know how to manage overdosage.
Synergy with other treatments

Most forms of topical treatment can be continued in a patient on methotrexate. Systemic immunosuppressive drugs and UV radiation are not usually administered concurrently with methotrexate.
Cost implications

The annual drug cost of methotrexate 15 mg/week is ,34. The cost of blood tests and clinic visits is extra. A liver biopsy, if performed, has an estimated cost of ,588.



Courtesy of The British Association of Dermatologists