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The aim of this survey was to determine current practice throughout Europe regarding use and monitoring of methotrexate therapy for psoriasis. A structured questionnaire with questions on methotrexate prescribing and monitoring was mailed to 150 dermatologists in 32 European countries in June 2002. Dermatologists' names were chosen at random from the 2001 European Academy of Dermatology and Venereology membership directory. A reply was received from 69 dermatologists of whom 59 prescribed methotrexate regularly. In those patients receiving systemic treatment for psoriasis, methotrexate was the most widely used drug (4.4 patients of every 10) followed by acitretin (3.2) and cyclosporin (1.6). Myelosuppression was the commonest reported fatal side-effect of methotrexate (eight of a total of 10 cases). None of the respondents routinely requested a baseline liver biopsy before starting methotrexate treatment and of every 10 of their patients on long-term methotrexate it was estimated that less than two had had a liver biopsy some time during treatment. Serum measurement of the amino-terminal peptide of type III procollagen (PIIINP) was used routinely to detect liver fibrosis by 12 (20%) of the 59 respondents who regularly prescribed methotrexate. This survey demonstrates that, despite the advent of new therapies, methotrexate retains a central role in the treatment of severe psoriasis in Europe. The responses demonstrated variation in, among others, the methotrexate dose regimen utilized and the use of folate supplementation, confirming the need for randomized controlled studies to address these issues.

Methotrexate is an effective antipsoriatic agent and has been widely used to treat severe psoriasis since the 1960s. It is especially useful in acute generalized 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, however, been formally compared with other systemic treatments for severe psoriasis such as cyclosporin, retinoids or photochemotherapy with psoralen and UVA (PUVA), but in comparison with these other therapies it is inexpensive, with correct use, its safety profile is favourable. In summary, therefore, it can be used as a short-term option to gain control of unstable psoriasis such as pustular psoriasis or erythroderma before returning to other modes of treatment, or more often, as long-term maintenance treatment. The most important potential side-effect is acute myelosuppression, which is the cause of most of the rare deaths attributable to this therapy for psoriasis. Myelosuppression is more likely in the elderly, in patients with renal impairment and/or folate depletion, and with overdose or drug interactions. Long-term therapy carries with it a risk of liver fibrosis which is related to the dosage regimen employed, and is increased by exposure to other hepatic toxins, particularly alcohol. The correlation between the risk of development of liver fibrosis, cumulative lifetime dose and duration of treatment with methotrexate is not clear-cut, but may have been overstated in some studies.

This study was designed to establish whether measurement of a serological marker of fibrosis might reduce the need for liver biopsy in psoriatic patients receiving methotrexate (MTX). Levels of type III procollagen aminopeptide (PIIINP-O and PIIINP-B) and laminin P1 (LamP1-B) were measured in 147 serum samples taken at the time of liver biopsy in 87 patients receiving long-term MTX treatment for severe psoriasis. Biopsies were classified as: (1) normal, (2) steatosis, (3) inflammation, (4) fibrosis, or (5) cirrhosis. Groups 3-5 were considered to show clinically relevant abnormality. Compared with controls, PIIINP-O was significantly raised in the group of MTX-treated psoriatics (P < 0.001). Within this group, levels were significantly higher in patients with inflammation, fibrosis or cirrhosis compared with those with normal histology or steatosis alone (P < 0.0001). In contrast, PIIINP-B and LamP1-B did not distinguish between controls and MTX-treated patients or between histological groups. Forty-two patients had two or more biopsies with simultaneous PIIINP-O measurement. PIIINP-O levels at the time of the first biopsy were normal in six of the seven patients whose histology was initially normal and subsequently became abnormal. A single measurement of PIIINP-O thus did not predict which patients might develop abnormal histology following further MTX. In a group of 17 patients, PIIINP-O was measured 3-monthly for up to 6 years during MTX treatment. PIIINP-O was elevated at some time during follow-up in all three patients who developed abnormal histology but was consistently normal in eight of the 11 patients whose histology remained or became normal. Our findings indicate that PIIINP-O is of value in detecting liver damage and, particularly if measured serially, may reduce the need for liver biopsy in MTX-treated patients. Although the test does not detect all patients with fibrosis, it would appear that the risk of missing significant liver damage in patients with persistently normal PIIINP-O is low.

One hundred and eighty-two liver biopsies were performed over a 10-year period on patients receiving long-term, low-dose, once weekly oral methotrexate (MTX) for severe psoriasis. Forty-nine patients had two or more biopsies during continued treatment and formed the study population for our analysis. The first and last biopsies were compared to determine progression of any histological abnormalities. Liver biopsies were assessed without knowledge of the MTX dose and allocated to one of five groups according to the severity of the histological abnormalities. These were defined as: (1) normal; (2) steatosis alone; (3) inflammation without fibrosis; (4) fibrosis; and (5) cirrhosis. The mean cumulative dose of MTX at the time of the first biopsy was 2743 mg (range 315-10,024), given over 275 weeks (range 26-738). In the interval between the first and last biopsies, patients received, on average, a further 2362 mg (range 390-7155) over 225 weeks (range 60-460). There was improvement in the histological assessment in 12 patients, no change in 28 patients, and deterioration in nine patients. None developed cirrhosis. Liver biopsy findings prompted discontinuation of MTX in four of the 49 patients on long-term treatment. This has to be weighed against the cost and morbidity of the 124 biopsies performed in these patients. Our results suggest that, with careful follow-up, the risk of development or progression of liver disease in patients receiving long-term, low-dose, once weekly oral MTX for psoriasis is modest, and that the requirement for performing routine liver biopsies in these patients needs to be reconsidered.