Methotrexate for psoriasis in the era of biological therapy

R. B. Warren, R. J. G. Chalmers, C. E. M. Griffiths and A. Menter*
Department of Dermatological Sciences, Salford Royal Hospital, University of Manchester, Manchester, UK; and *Baylor Research Institute, Dallas, Texas, USA

Summary
Methotrexate’s traditional role as a first line agent for moderate to severe psoriasis is being challenged by the rapid and growing use of biological therapies. A recent study comparing adalimumab with methotrexate showed significantly superior efficacy of adalimumab over methotrexate over 16 weeks. Although it is inexpensive, the future use of methotrexate may be compromised by its unpredictable response and toxicity, and by the introduction of newer, more effective biological therapies. However, recent advances in the screening of liver fibrosis by monitoring serum levels of the aminoterminal peptide fragment of type III procollagen have reduced the need for liver biopsy. Furthermore, the potential for personalized methotrexate use by application of modern pharmacogenetics and pharmacokinetics may ensure its place as a first-line agent for the treatment of psoriasis for the foreseeable future.

Introduction
Currently methotrexate is one of the most commonly used systemic therapies worldwide in dermatology. Its main use is in the treatment of psoriasis but benefit has been shown in a number of other dermatoses including pemphigus vulgaris, cutaneous sarcoidosis and derma- tomyositis.1–3 The use of methotrexate in dermatology was the result of a chance finding in 1951 when Gubner noted the rapid clearance of psoriasis in patients treated with aminopterin (a folate antagonist) for carcinoma.4 This led to the development of the more stable derivative methotrexate and its introduction in 1971 for the treatment of severe psoriasis.

The place of methotrexate as a first-line agent for moderate to severe psoriasis is now being challenged by the rapid and growing use of biological therapies for this condition. Furthermore, biological agents are now being compared head to head with methotrexate. In one recent study, adalimumab, showed both superior efficacy and lower rates of treatment discontinuation due to adverse events compared with methotrexate.5 This review assesses the future place of methotrexate in the era of biological therapies and highlights developments that may facilitate prediction of its efficacy and toxicity.

Mechanism of action of methotrexate
Significant advances in the understanding of the mech- anism of action of methotrexate have allowed several

Correspondence: Dr Richard B Warren, Department of Dermatological Sci- ences, Salford Royal NHS Foundation Trust, University of Manchester, Manchester, M6 8HD, UK.
E-mail: [email protected]
Conflict of interest: CEM Griffiths is a paid Consultant for Abbott, Centcor and Schering-Plough. RBW has received speaking or consulting fees from Abbott and Schering-Plough. AM has served on the advisory board; as a Consultant; as an Investigator; and ⁄ or as a Speaker; and has received compensation from Abbott, Amgen, Astellas, Centocor, Galderma, Genentech, Warner Chilcott and Wyeth.
Accepted for publication 23 June 2008
areas of its metabolic pathway to be targeted in an attempt to allow more refined prescription of this drug. A postulated mechanism of action of methotrexate is shown in Fig. 1.

Clinical utility and efficacy of methotrexate
Methotrexate is given as a once-weekly dose, starting with a test dose of 5–7.5 mg, and if tolerated, increasing to a maximum dose of 30 mg dependent on response. It

all patients receiving the drug should undergo periodic

ADORA 1/2a
liver biopsy to detect the onset and ⁄ or progression of

MTX
Influx SLC19A1 Efflux ABCC1-C4/ABCG2
hepatic fibrosis.9 In recent years there has been increasing recognition that the need for liver biopsy

Cell membrane can be greatly reduced by monitoring serum levels of
MTX

GGH FPGS MTX polyglutamates

Adenosine
the aminoterminal peptide fragment of type III procol- lagen (P3NP). Several studies have shown that the risk

DNA dTMP

dUMP

TYMS

FH
2

DHFR
FH4

5,10-CH -THF
2
MTHFR
5-CH -THF
3

ATIC
accumulation
of overlooking significant liver fibrosis in patients with consistently normal serum levels of P3NP is negligi-
10,11
ble.
Clinical factors such as renal impairment, significant haematological abnormalities or abnormal liver func- tion may limit the appropriateness of methotrexate for

Figure 1 A postulated mechanism of action of methotrexate (MTX) in psoriasis. MTX is transported into the cell via the
solute carrier family 19, member 1 (SLC19A1). It can be actively transported out of the cell by the adenosine triphosphate (ATP)- binding cassette transporters including the ATP-binding cassette, subfamily C (CFTR ⁄ MRP), member 1–4 (ABCC1-4) and ATP- binding cassette, subfamily G, member 2 (ABCG2). Within the cell, it undergoes polyglutamation (activation) under the enzymatic control of folypolyglutamyl synthase (FPGS). This is a dynamic process where glutamate residues can be removed by gamma- glutamyl hydrolase (GGH). In the polyglutamated form, MTX inhibits aminoimidazole-4-carboxamide ribonucleotide transform- ylase (ATIC), which is likely to account for some of its anti- inflammatory effects via an intracellular rise in adenosine,
which is known to interact with a number of adenosine receptors (ADORA), including ADORA A1 and 2a. Inhibition of the folate pathway may not be as important for mechanism of action of MTX in psoriasis as previously thought, but MTX also influences the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR)
which catalyses the conversion of 5,10-methylenetetrahydrofolate 5,10-CH2-THF to 5-methyltetrahydofolate (5-CH3-THF), a cosub- strate for homocysteine remethylation. The polyglutamated form of MTX also inhibits thymidylate synthase (TYMS), which converts deoxyuridylate (dUMP) to deoxythymidylate (dTMP) in the de novo pyrimidine biosynthetic pathway.

is usually prescribed alongside folic acid in doses of 1–5 mg daily. This regimen is likely to diminish potential side-effects without affecting efficacy, although both the ability of folic acid to reduce side-effects without affecting the efficacy of methotrexate,6 and the frequency of the folic acid dosing remain contro- versial.7 Although methotrexate is normally adminis- tered orally, it is of interest that a recent randomized, double-blind, phase IV study of patients with rheuma- toid arthritis (RA) treated with either oral or subcuta- neous methotrexate showed the latter to have superior efficacy.8 An equivalent study has not as yet been undertaken in patients with psoriasis.
A significant impediment to widespread use of meth- otrexate in psoriasis has been the recommendation that
many patients. It is important to note that methotrexate is both teratogenic and mutagenic, so appropriate counselling to patients of both genders should be given before commencing the drug.
Despite a paucity of randomized controlled trials (RCTs), retrospective data has shown methotrexate to be effective in 70–80% of patients, while around 30% may experience toxicity, which is usually mild.12,13 In recent years, however, the efficacy of systemic therapies for psoriasis has come to be judged by the percentage of patients obtaining a 75% reduction in the baseline clinical severity as assessed by the Psoriasis Area and Severity Index (PASI 75). To date, the only published study comparing a biological agent (adalimumab) with methotrexate for treatment of moderate to severe psoriasis is the CHAMPION (Comparative Study of Humira vs. Methotrexate vs. Placebo In Psoriasis Patients) study.5 This study found that 79.6% of patients achieved a PASI 75 response after 16 weeks of adalimumab treatment compared with 35.5% of the patients on methotrexate. Furthermore, the drop-out rate was higher in the methotrexate group. Such marked differences in both efficacy and possibly short- term tolerability of these two drugs raise questions about the future role of methotrexate, particularly its continuance as one of the first-line treatments for moderate to severe psoriasis. Other biological agents, such as infliximab and ustekinumab, achieve PASI 75 responses that are similar if not superior to ada- limumab;14,15 however, they have not as yet been compared directly with methotrexate.
Before methotrexate is ‘written off’, it should be noted that the CHAMPION study was only 16 weeks in duration and that methotrexate was started in the lower dose ranges. Likewise, the placebo response (PASI 75) was high at 18.9%, perhaps suggesting that the PASI 75 for methotrexate in this study is unreliable. Certainly, previous data from two RCTs comparing methotrexate with ciclosporin found that the PASI 75

Methotrexate in the biological era • R. B. Warren et al.

for methotrexate was >60% in both cases,17,18 and in one of the studies there was no significant difference between the treatment success of methotrexate and ciclosporin.18

Methotrexate pharmacokinetics: focus on polyglutamation
Methotrexate is best considered as a prodrug, being converted by the enzyme folylpolyglutamyl synthetase) to polyglutamyl derivatives, which are then preferen- tially retained within cells.19 This is a dynamic process with removal of glutamate residues under the control of gammaglutamyl hydrolase. Up to seven glutamate residues may be added to methotrexate.20
The pharmacokinetic process of polyglutamation is variable in both patients with psoriasis and those with RA receiving low-dose methotrexate therapy.21,22 Poly- glutamation is considered a key step in the mechanism of action of methotrexate in inflammatory diseases, because it is the higher-order methotrexate polygluta- mates that promote a sustained build-up of adenosine, thus mediating some of methotrexate’s anti-inflamma- tory actions.23
In a study of patients with RA treated with metho- trexate, a link between ‘good glutamater’ and efficacy of methotrexate was detected.22 A smaller study of 16 patients with moderate to severe psoriasis failed to replicate this finding, with no relationship detected between higher glutamation status and the percentage improvement in PASI.21 This is an important area of ongoing research. Rapid determination of glutamate status from erythrocytes is possible and it may thus be possible to predict efficacy by checking in the early weeks of treatment whether a patient is a ‘good glutamaters’ of methotrexate.

Methotrexate pharmacogenetics
Pharmacogenetics, a term suggested by Vogel in 1959, is the study of relationships between genetic polymorphisms and drug response.24 The most fre- quent type of polymorphism is a single-nucleotide polymorphism (SNP); however, these can take a number of forms, including nucleotide repeat se- quences. Polymorphisms producing an alteration of expression or function of drug-metabolizing enzymes can result in altered efficacy or toxicity of a given drug. Two recent studies have suggested that it may be possible to predict both the efficacy and toxicity of
porters ABCC1 and ABCG2, which are responsible for some of the active transportation of methotrexate from the cell. Commonly occurring SNPs within ABCC1 were linked to both efficacy and toxicity of methotrexate, while SNPs of ABCG2 were linked to methotrexate efficacy. Interestingly, variation within the genes responsible for the glutamation of metho- trexate were not predictive of response. This occurs despite the key role that glutamation plays in the mechanism of action of methotrexate.27

The future
The treatment of moderate to severe psoriasis has improved significantly over the past several years. There is little question that most biological therapies have superior efficacy to traditional systemic agents such as methotrexate in the short term. However, the significant cost differential (£55 ⁄ $110 for methotrexate compared to £10,000 ⁄ £20,000 for biological per annum) and current lack of long-term (>3 years) safety data for biological agents mean that drugs such as methotrexate are likely to remain one of the first-line choices for the foreseeable future. Furthermore, the potential of pharmacogenetic testing28 alongside effi- cient, inexpensive pharmacokinetic tests suggests that methotrexate will be used on a personalized basis in the years to come.

Learning points
•Routine liver biopsy to detect hepatic fibrosis has been replaced by monitoring serum levels of the aminoterminal peptide fragment of type III procol- lagen.
•There is a need for a study comparing the efficacy and toxicity of oral vs. subcutaneous methotrexate in patients with psoriasis.
•Methotrexate use may be personalized in future due to the application of pharmacogenetics.
•Identification of methotrexate responders may be possible by measuring methotrexate glutamates in erythrocytes.

Acknowledgement
R. B. Warren is in receipt of a Clinical Research Training

methotrexate in patients with psoriasis.
25,26
Of Fellowship from the Medical Research Council.

particular interest were the methotrexate efflux trans-

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