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| >> Clinical Guidelines
Methotrexate
Methotrexate is an effective antipsoriatic agent. 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. In comparison with other systemic therapies for psoriasis, it is inexpensive and of comparable efficacy. 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 employed, 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-cut. 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 myelosuppression. 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. 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). 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 abortifacient and teratogenic 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 three months after stopping the drug. Although methotrexate is not mutagenic, and normal children have been born when the father was taking methotrexate at the time of conception the drug may affect spermatogenesis. Men should therefore be advised to avoid fathering children during therapy and for three months after. Discontinue methotrexate and refer immediately if a patient or partner discovers they are pregnant while taking methotrexate Other precautions: Other important contraindications to the use of methotrexate in psoriasis include active peptic ulceration, active infectious disease, such as tuberculosis or immunodeficiency states, and patient unreliability. Prescribing methotrexate
Initiation of therapy: The risks and benefits of therapy should be clearly explained to the patient, both verbally and in writing. In addition to the patient information leaflet on this web-site the BAD have produced a hand held patient information leaflet that complies with the National Patient Safety Agency directives for safe use of this of therapy and a hand held patient record to facilitate patient monitoring. These will be available in early 2006. 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 contradictions, 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. Recently the subcutaneous route has become more practical with the advent of the biological therapies. Details of the subcutaneous route to maximise bio-availability and improve tolerance and safety are to be found on http://www.rcn.org.uk/publications/pdf/administering-methotrexate.pdf It should be given as a single weekly dose. For oral dosing the BAD recommend all patients be prescribed the 2.5mg tablets to avoid confusion and overdosing on the 10mg tablet formulation. 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 weekly is obsolete as this schedule is more open to error and may be associated with a greater risk of hepatic fibrosis. 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. The maximum weekly dose should not exceed 30mg. Lower doses are required in the elderly and those with renal impairment. 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. Although liver biopsy is the gold standard measure for hepatic fibrosis due to methotrexate it carries significant risks and the need for this intervention can be considerably reduced by monitoring the serological markers of fibrosis, particularly the aminoterminal peptide of type III procollagen (PIIINP). Patients whose PIIINP levels are consistently normal are very unlikely to have significant liver damage, and liver biopsies may be restricted to the small minority in whom PIIINP levels are repeatedly elevated. PIIINP assay 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). Where possible, serum should be collected for PIIINP measurement prior to starting methotrexate. It should subsequently be measured every 2-3 months during continued treatment. Indications for Considering Liver Biopsy
· Elevation of pre treatment PIIINP above 8.0 mcg/l · Elevation of PIINP above normal range (1.7-4.2mcg/l) in at least three samples over a 12 month period. · Elevation of PIINP above 8.0mcg/l in two consecutive samples. Indications for considering withdrawal of methotrexate:
· Elevation of PIIINP above 10 mcg/l in at least three samples in one 12 month period. The decision whether to perform liver biopsy, withdraw or continue treatment despite raised PIIINP levels must also take into account other factors such as disease severity, patient age and the ease with which alternative therapies may be used in place of methotrexate. 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 tests. The risk of serious liver damage in carefully monitored patients receiving once weekly low dose methotrexate is small and 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. Management of problems: Nausea is the commonest side effect reported by patients and may affect up to a quarter of all patients treated. It usually appears within 12 hours of methotrexate ingestion and may last up to three days. 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. The subcutaneous administration has helped reduce problems with gastrointestinal intolerance. Folic acid, supplementation has been found to be helpful in preventing folate deficiency, reducing myelotoxicity and improving tolerance of methotrexate. It is broadly recognised that folate supplementation should be initiated with methotrexate therapy although practice varies regarding the dose. Commonly it is taken on the 6 days of the week when methotrexate is not taken. The minimum dosage recommended is 5mg taken once weekly. 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 methotrexate would normally be discontinued. The decision to discontinue methotrexate depends not only on PIIINP and/or the results of liver biopsy, but also on the ease with which an individual patient's psoriasis may be managed by other means. 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 disease. 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. If the MCV rises above the upper limit of normal, folate deficiency is likely and supplementation may be inadequate. If this occurs, it is important to exclude other causes of macrocytosis, in particular vitamin B12 deficiency. If the MCV rises above 106 fl, despite folate replacement, then further methotrexate therapy is probably contraindicated. It is important to note that folate therapy does not reduce the therapeutic effect of methotrexate. Managing overdose
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. In suspected cases of Methotrexate overdose or severe haematological toxicity consider treatment with Folinic acid. The initial dose should be at least 20 mg, given intravenously. Subsequent doses of 15 mg (which may be taken orally) should be given at 6 hourly intervals until the haematological abnormalities are improved (usually not more than 2-8 doses). If serum methotrexate is measured, a dose of 20mg usually is sufficient for a methotrexate concentration of 0.5 micromoles/l or less. 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. 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. References
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 Mar;152(3):451-8. Chalmers RJ, Kirby B, Smith A, Burrows P, Little R, Horan M, Hextall JM, Smith CH, Klaber M, Rogers S.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 Mar;152(3):444-50 Zachariae H, Heickendorff L, Sogaard H. The value of amino-terminal propeptide of type III procollagen in routine screening for methotrexate-induced liver fibrosis: a 10-year follow-up. Br J Dermatol. 2001 Jan;144(1):100-3 Boffa MJ. Methotrexate for psoriasis: current European practice. A postal survey. J Eur Acad Dermatol Venereol. 2005 Mar;19(2):196-202 Strober BE, Menon K. Folate supplementation during methotrexate therapy for patients with psoriasis. J Am Acad Dermatol. 2005 Oct;53(4):652-9 |
