Systemic therapy of psoriasis: methotrexate Department of Dermatology, Faculty of Medicine, University Hospital, Bratislava, Slovakia.
Abstract: Methotrexate is the first line therapy for the treatment of moderate to severe psoriasis and psoriatic
arthritis all over the world. It has immunosupressive and anti-inflammatory effects. If we want to use it, we have
to know its mechanism of action and also its possible toxicity and how to cope with it (Tab. 3, Fig. 1, Ref. 14).
Full Text in free PDF www.bmj.sk.
Key words: methotrexate, psoriasis, folic acid.
Methotrexate is the antagonist of folic acid. It belongs to the first line treatment in Europe concerning the systemic treatmentof psoriasis. It has immunosuppresive, cytostatic and antiinflam- matory effects. In dermatology, it started to be used in 1971.
Almost forty years of experience are granting good knowledgeof its effects on psoriasis, but also of the side effects, incidenceof which varies depending on the treatment length, methotrexate dose and supplementation of folic acid. Even thought it is on themarket for a long time, its effect on psoriasis is often unpredict-able. There are patients, who react on the treatment satisfacto-rily, but also patients who do not react at all. After a 12-week treatment dosed 15 mg/week, 24 % of patients achieve PASI 75.
In a direct comparative study on the biological agent adalimumab,with slowly increasing dose from 7.5 mg up to 22.5 mg/week,only 3 % of patients achieved this in 16th week of treatment. In present, it is used for the treatment of moderate psoriasis, re-spective when local therapy is insufficiency.
Methotrexate (Fig. 1), like the folic acid, binds to the same transmembrane protein RFC (reduced folate carrier) and is trans-ported into the cell. In the cell membrane, also an active trans- Fig. 1. Methotrexate mechanism of action (3).
port proteins exist, that evict the methotrexate out of the cell. Incytoplasm, the methotrexate is activated by the enzyme FPGS the influence of enzyme gama-glutamylhydrolase, resulting in (folylpolyglutamate syntetase) by polyglutamation. By the same the creation of the former molecule of methotrexate. The active enzyme, the folic acid is processed with the result of form of methotrexate (polyglutamate) is responsible for its tar- polygutamates of folic acid, which serve as the deposit for the get effects in the cell. The most important effect of methotrexate cell. Almost 50 % of the folic acid is stored in the body in the is evoked by a blockade of dihydrofolate-reductase (DHFR). This form of polyglutamates deposited in hepatic cells. One molecule enzyme plays an important role in the metabolism of folic acid of methotrexate can bind from 2 up to 7 glutamates. This pro- by activating it to tetrahydrofolate (TFH). The blockade of this cess is reversible. Methotrexate glutamates can be splintered by enzyme leads to reduction in the creation of tetrahydrofolate.
Tetrahydrofolate is the important substrate for the de novo cre- Department of Dermatology, Faculty of Medicine, University Hospital, ation of purine and pyrimidine bases. This reduction is enhanced by the inhibitory effect of methotrexate on another important Address for correspondence: MUDr. Peter Kozub, Department of Der- enzyme, tymidilate syntasis (TYMS), which is responsible for matology, Faculty of Medicine, University Hospital, Bratislava, Slovakia.
the transformation of uridilate to tymidilate. The ending result Indexed and abstracted in Science Citation Index Expanded and in Journal Citation Reports/Science Edition Kozub P, Simaljakova M. Systemic therapy of psoriasis: methotrexate of inhibitory influence of methotrexate on the enzymes mentioned Tab. 1. Dosage of folic acid – number of European dermatologists, above is the blockade of DNA and RNA synthesis. Anti-inflam- matory effect is induced by inhibition of other important enzyme,aminoimidazole-4-carboxamide ribonucleotide transformylase.
Its blockade leads to accumulation of adenosine, an important 5 mg on the 4th day after the last dose of MTX Methotrexate is used after fasting. Two forms exist – oral and parenteral. In dermatology, we use only methotrexate pills, equate treatment in simultaneous joint disability. Cyclosporine although the recent studies with methotrexate dosed subcutane- also has an effect on joints, but it is achieved later than effects ously in patients with rheumatic arthritis (4) showed a higher on skin (approximately after 2–3 months), and does not have to efficiency of subcutaneously applied methotrexate compared to be sufficient. Methotrexate is the ideal drug in treatment of pa- methotrexate dosed as pills and might indicate the future change.
tients with nummular chronic psoriasis and with severe joint dis- After the oral dose, the maximal concentration in blood is achieved in 1–2 hours. Depending on the dose, the biological availability could be as high as 60 %. Elimination occurs mostly by urine (more than 90 %), dosing in patients with renal diseaseshave to be reduced.
Methotrexate adverse effects could be divided into few 1. myelosuppression – the most feared side effect of methotrex- ate, which tends to occur in the beginnings of treatment. The The weekly dose of methotrexate in patients with psoriasis result is attenuation of bone marrow and pancytopenia. Because varies from 7.5 mg to 22.5 mg. It starts with the lowest, so-called of this, the starting dose of methotrexate is administered in re- test dose of 5 or 7.5 mg for week, and after a week the blood duced form and after a week the blood samples are checked.
samples are taken (biochemistry and blood count) for a possible Pancytopenia is very rare. If it occurs, the treatment with meth- occurrence of side effects. The most dangerous is myelosuppre- otrexate has to be stopped immediately, and possibly the anti- sion, which could be lethal to the patient. If the tests are within dote is to be administered – calciumfolinate.
normal levels, the dose of methotrexate could be raised. Labora- 2. hepatotoxicity – is given by increasing the hepatic enzyme tory parameters are checked frequently (blood count, hepatic levels up to 2–3 times. It occurs pretty frequently and is com- enzymes, renal parameters) and the patient is checked for pos- monly dependent on the dose of methotrexate. The treatment sible side effects on skin and mucous membranes, respective the has not to be interrupted and usually a lowering of dose is suffi- subjective tolerance of the dose from the gastrointestinal point cient, or hepatoprotectives are to be added into treatment. The of view is observed. The dose is adjusted according to the needs.
recommendations of world known dermatologists prevailed for Two ways of dosing are used. American school prefers the drug a long time – due to an increased risk of hepatic fibrosis during administration split into three doses of 12 hour intervals. This long-time dosing of methotrexate, hepatic biopsies were taken type is common in our country too. English school prioritizes after achieving the cumulative dose of 1.5 g, but in present this drug administration in a single day in the morning and evening, recommendation is considered obsolete. Actually it is enough if with a lower dosage even one-time only (Tab. 1).
the levels of hepatic enzymes are checked, abdominal ultrasoundperformed and the level of aminoterminal peptide procolagene III (PIIINP) in serum observed. If the normal levels are achieved repeatedly, the risk of significant hepatic fibrosis is negligible.
Methotrexate is indicated for the treatment of nummular Levels of PIIINP should be checked every 3–4 months. If the chronic psoriasis and psoriatic arthritis. It is not suitable for treat- levels increase, the liver tissue samples should be taken by bi- ing acute conditions (erythrodermia, generalized pustulous pso- riasis, exudative psoriasis), in which systemic corticoid therapy 3. gastrointestinal adverse effects (diarrhea, nausea, abdomi- is preferred. Methotrexate starts operating within a month and nal pain) – occurs mainly due to high dosage. They are relative its effect fully develops after two months. From this reason it is common and when they occur, the dose of methotrexate should a great additive to systemic corticoid therapy. Serious acute state is suppressed by corticoids, which are later dropped. The effi- 4. skin and mucous membrane adverse effects (ulcers in mouth ciency of methotrexate is relatively lower, but it depends on cavity, stomatitis, cheilitis, alopecia, exanthemas) – are relatively a patient’s weight, dose, the speed of increasing the dose and common as well and dosage-dependent. If they occur, the dos- dosage of folic acid. It has the most sovereign effect on joints age should be adjusted. They are not the reason to terminate the among the first-line treatment. Neotigason is absolutely inad- 390– 3945. teratogenic effects – contraception is required during the treat- Tab. 2. Peroral methotrexate available in Slovakia since 1.10.2009 (14).
ment with methotrexate, it also should be provided for the nextthree months after the end of treatment. The frequency of menses is checked and pregnancy test should be taken if suspicious.
6. mutagenic effects – continuous phototherapy is not recom- mended because of the possible increased risk of skin carcinoma.
Restrictions during methotrexate administration (5) During the treatment, patients are prohibited to drink alco- holic beverages. They cannot use some drugs simultaneously, for example non-steroid antiflogistics, which are used frequently by patients with synchronous psoriatic arthritis. Non steroid anti- flogistics increase and extent serum levels of methotrexate and could significantly increase the risk of severe hematologic and gastrointestinal toxicity. Methotrexate is bounded to albuminsin serum and drugs, which interact with the same bonds (salicy- lates, fenylbutazone, fenytoine, sulphonamides), could increase Tab. 3. Folic acid available in Slovakia since 1.10.2009 (14).
its toxicity. Oral antibiotics (tetracycline, chloramphenicol) and non-absorbable wide-spectrum antibiotics could lower the ab- sorption of methotrexate by gastrointestinal tract. Penicillin could also reduce the renal excretion of methotrexate. Higher attention should be paid to patients using other potentially hepatotoxic drugs (leflunomid, azathioprine, retinoids, sulphasalazine). Dur-ing the treatment the vaccination is not recommended.
practice such a dosing is unreal due to dosage of folic acid only by 10 mg and small pills, which could not be split easily becausethe pills does not have the splitting gap. Other problem could First blood samples (blood count, laboratory values) are taken result from the weekly dose of folic acid. It is different, when after a week of treatment. Frequency of following blood checks patient takes 30 mg of folic acid during the methotrexate dosage depends on the speed of dose increment, they should be per- of 7.5 mg/week or 15 mg/week. In the first case we significantly formed at least once a month in first three months of treatment.
reduce the risk of potential side effects, but at a cost of lowering After balancing the dose and physiological levels in blood its effect. In the second case the effect should be better, but its samples, these intervals could be elongated. In the blood count toxicity could rise. Due to that, the dosage of folic acid should we follow the numbers of erythrocytes, leucocytes, neutrophiles, be adjusted to individual needs of patient.
the middle volume of erythrocyte and from the laboratory val- In the case that patient is treated by methotrexate only, se- ues hepatic and renal parameters. In the case of rising levels of rum levels of folic acid could decrease and secondarily the middle the middle volume of erythrocytes, we can check the levels of volume of erythrocytes could rise. Heavy pancytopenia could folic acid and B12. At least once a year patient should undergo occur from a grave deficit of folates. Despite that not every der- abdominal ultrasound. Also, aminopeptide procolagene III is not matologist uses the folic acid. During the spring symposium the part of routine check, but after repeatedly higher levels of EADV 2009 in Bucurest the practice of European dermatolo- hepatic enzymes and positive hepatic ultrasound it should be gists was presented (6): Only 32 % of dermatologists commonly use the folic acid daily during treatment with methotrexate, next32 % only during specific circumstances (i.e. a rise in the middle volume of erythrocytes) and the rest 36 % does not use the folicacid at all. Various weekly dosages of folic acid were presented; Methotrexate is an antagonist of folic acid. Methotrexate and the results are to be seen in the Table 1. In the results it is shown folic acid competes against each other to bind on the same re- that even European dermatologists are consistent about the dose ceptor. Folic acid has been added into the treatment to lower the of folic acid (in most European countries the dosage of 5 mg is possible undesirable side-effects. By adding the folic acid we available in single pills, instead of Slovakia), the weekly dose is also lower the immunosuppressive and anti-inflammatory effect not uniform and probably the randomized blinded trials will be of methotrexate. Commonly the axiom states that 5 mg of folic needed to get the results of optimal dosage scheme. Dermatolo- acid is administered per day, missing out on days when methotr- gists have agreed that the supplementation of folic acid during exate is dosed. If we assume that methotrexate is dosed once or the treatment with methotrexate should be realized during the twice per week, other days the folic acid should be taken. In our whole time of treatment. If the higher levels of middle volume Kozub P, Simaljakova M. Systemic therapy of psoriasis: methotrexate of erythrocytes over 106 fl persist, treatment with methotrexate It is also important to remember, that even though the supple- mentation of folic acid lowers the efficiency of methotrexate, it The majority of patients with psoriasis has lower levels of primarily lowers the immunosuppressive effect. Anti-inflamma- folic acid and a higher middle volume of erythrocytes. The com- tory effect of methotrexate is not bonded to folate metabolism, parative trial CHAMPION, in which the effects of adalimumab but probably to inhibition of aminoimidazole karboxamide ribo- and methotrexate were evaluated, supports the fact that only folic nucleotide transformylamylase, which results in accumulation acid by itself in monotherapy could bring some benefit for the of adenosine, which is one of the main elements of the anti-in- patient. The dose of methotrexate was increased from 7.5 mg up to 22.5 mg in 16th week when needed. Together with methotrex- Adjuvant therapy with folic acid during the methotrexate ate, the folic acid was administered in a dose of 5 mg/day. Pa- treatment definitely has its meaning. It significantly reduces the tients dosed with placebo also received the folic acid treatment hepatotoxicity and mildly the gastrointestinal and skin respec- in a dose of 5 mg/day. The last group of patients reached PASI tive mucosal adverse effects and only minimally influence the 75 in 16th week as high as 18.9 %. It is too high number for the methotrexate efficiency. It is necessary to adequately adjust the placebo group, but these patients also received the folic acid treat- dosages of both drugs to actual needs of patient.
ment, high probability is that the folic acid itself has some posi-tive effect in treatment. Theoretically it could mean that every patient (regardless the treatment) could get folic acid as a supplement to systemic, local or biological treatment or pho- Methotrexate has an irreplaceable role in biological treat- totherapy. Other trials are needed to confirm the beneficial ef- ment of psoriasis and psoriatic arthritis. It is used mainly during fect of folic acid on psoriasis. Folic acid was added to methotr- the treatment with TNFá blockers, especially treatment with exate treatment to lower the possible side effects. French au- infliximab. With its cytostatic effect, methotrexate blocks B-lym- thors Prey and Paul (7) analyzed 6 double blinded placebo con- phocytes and decreases the production of antibodies against trolled trials focused on the effects of folic acid ror foline acid infliximab. Antibodies against infliximab have neutralizing char- on the safety and efficiency of methotrexate treatment in patients acter and are able to lower the efficiency of methotrexate, but with rheumatoid arthritis and with psoriasis with or without pso- also can induce infusion reactions. Even if the concentration of riatic arthritis. They founded that gastrointestinal (diarrhea, nau- antibodies against infliximab is not examined as a standard, its sea, abdominal pain) and skin (respective mucosal) adverse ef- increased values could result in decreasing of its effect. During fects (ulcers in mouth cavity, stomatitis, alopetia, exanthemas) the treatment with infliximab, two ways of failure can occur: (1) were only mildly lowered, but hepatotoxicity, defined as eleva- infliximab does not “tighten up“ its effect – meaning that patient tion of alaninaminotraspherase up to double the normal levels, will get better after the infusion dosage, but this improvement was significantly reduced thanks to the supplementation with lasts only 4–6 weeks, after which the gradual deterioration oc- folic and foline acid – by 35.8 %. Hematological adverse effects curs, but after the next infusion, the patient will get temporarily (neutropenia, lymphopenia, and anemia) could not be evaluated better again, (2) infliximab effect is not adequate – patient does because of its rare occurrence, but the significant reduction was not get better despite the infusion treatment, vice-versa to worse not reached depending on dosage or not of folic/foline acid in manifestation. The solving of the first case is based on shortage the patients that expressed these hematological side effects. The in intervals of infusion dosage to 4–6 weeks, solving the second results showed that the supplementation of folic/foline acid sig- case is the methotrexate. Adding of methotrexate lowers the con- nificantly decreased the hepatotoxicity of methotrexate and centration of neutralizing antibodies against infliximab, also its mildly decreased its gastrointestinal, resp. skin/mucosal adverse immunosuppressive and anti-inflammatory effect takes place.
effects. The influence on the myelotoxicity was not significant.
Similarly as in the methotrexate monotherapy, we start with an The dosage of folic acid used in the mentioned studies was ei- induction dose of 7.5 mg/week. If after one week, the bone mar- ther 1 or 5 mg daily and the foline acid 1–5 mg/week. Concur- row attenuation is not observed, the dosage is increased ad- rently the effect of these acids on the methotrexate efficiency equately. The possible preventive effect of methotrexate on was observed. The results showed that in patients with rheuma- the infusion reactions for a long time during the treatment with toid arthritis both acids had mildly negative effect on methotrex- infliximab is considered. Many studies have proved its benefit, ate, but in patients with psoriasis this effect was not so clear.
even if the infusion reactions did not occur in the group of pa- Authors also dealt with the dosage of acids. Only in one trial the tients treated by methotrexate. Time factor is very important.
two doses of folic acid (27.5 mg/week vs 5 mg/week) were com- The full effect of methotrexate can be expected as soon as in pared, but it was not achieved that the higher dose is more effi- two months. Crandall and Mackner found out that the risk of infusion reactions was significantly lower after 4 months of Some results suggested that patients with higher weight need simultaneous therapy with methotrexate and infliximab (9).
either the higher dose of methotrexate or lower doses of folic After adding the methotrexate to infliximab or other TNFá acid. Other trials are needed to confirm these observations. It is blocker, we pay more attention to the levels of hepatic enzymes, on the dermatologist himself to adjust the dose of methotrexate because the combination of two increases the risk of hepato- and folic acid depending on the patient’s needs.
390– 394Farmacogenetics of methotrexate Farmacogenetics of methotrexate deals with the response on 1. Flytstrom I et al. Methotrexate vs. ciclosporin in psoriasis: effective- treatment and genetically based variability. It follows simple ness, quality of life and safety. A randomized controlled trial. Br J Der-matol 2008; 158: 116–121.
nucleotide polymorphisms (SNP) of genes of those enzymes, transport proteins, effector proteins or receptors, which are the 2. Saurat JH et al. Efficacy and safety results from the randomized part of the drug effect. It also follows their relationship to effi- controlled comparative study of adalimumab vs. methotrexate vs. place-bo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158: ciency and toxicity of the drug. In case of methotrexate (used to treatment of psoriasis), the following proteins and their poly- 3. Hughes LB et al. Recent advances in rheumatoid arthritis therapy FPGS – polymorphism without influencing the efficiency and management: recent advances in predictors of efficacy and toxicity.
www.medscape.com GGH – polymorphism without influencing the efficiency or 4. Braun J et al. Comparison of the clinical efficacy and safety of sub- cutaneous versus oral administration of methotrexate in patients withactive rheumatoid arthritis: results of a six-months, multicenter, rando- MTHFR – polymorphism C677T, A1298C – without influ- mized, double-blind, controlled, phase IV trial. Arthritis Rheum 2008; encing the efficiency or toxicity (10), compared to patients with rheumatoid arthritis, where both polymorphisms are associated 5. Methotrexat-Lachema, súhrn charakteristických vlastností lieku with an increased risk of adverse effects, ATIC – polymorphism C347G – without influencing the ef- ficiency or toxicity (10), more frequent end of treatment (12), 6. Boffa M. Methotrexate for psoriasis – an update. Spring symposiumEADV Bucharest 2009.
ABCC1 (transmembrane protein evicting the methotrexate out of the cell) –polymorphism in the area of this gene is associ- 7. Prey S, Paul C. Effect of folic or folinic acid supplementation on ated with good response on methotrexate (11), methotrexate-associated safety an efficacy in inflammatory disease: ABCG2 (other transmembrane protein evicting the methotr- a systematic review. Br J Dermatol 2009; 160: 622–628.
exate out of the cell) – polymorphism in the area of this gene is 8. Dervieux T et al. Polyglutamation of methotrexate with common associated with good response on methotrexate and early inci- polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase and thymidilate synthase are associatedwith methotrexate effects in rheumatoid arthritis. Arthritis Rheum 2004; RFC (reduced folate carrier) – polymorphism 80A – in- 9. Crandall WV, Mackner LM. Infusion reactions to infliximab in chil-dren and adolescents: frequency, outcome and a predictive model. Ali- Other methods then pharmacogenetic are used to evaluate ment Pharmacol Ther 2003; 17: 75–84.
an increased or decreased efficiency of methotrexate, respectiveto distinguish the responders from non-responders during the 10. Warren RB et al. Outcomes of methotrexate therapy for psoriasis treatment of psoriasis vulgaris. Czech authors (13) and relationship to genetic polymorphisms. Br J Dermatol 2009; 160: possibility to evaluate the concentration of methotrexate poly-glutamates in erythrocytes and correlate this concentration with 11. Warren RB et al. Genetic variation in efflux transporters influences efficiency and toxicity of methotrexate. Their pilot study did not outcome to methotrexate therapy in patients with psoriasis. J Inv Der-matol 2008; 128: 1925–1929.
confirm a direct correlation of levels of methotrexate polyglu-tamates with the changes of PASI (Psoriasis Area and Severity 12. Campalani E et al. Polymorphisms in folate, pyrimidine and purine metabolism are associated with efficacy and toxicity of methotrexate inpsoriasis. J Inv Dermatol 2007; 127: 1860–1867.
13. Hroch M et al. A pilot study of pharmacokinetically guided dosingof oral methotrexate in the initial phase of psoriasis treatment. JEADV2007; 22: 19–24.
Methotrexate belongs to the first line of therapy in a systemic treatment of psoriasis. It does not belong to the most efficient 14. MZ SR. Zoznam liekov a lieèiv plne uhrádzaných alebo èiastoène antipsoriatic drugs, but its advantage is very good effect on po- uhrádzaných na základe verejného zdravotného poistenia: http:// tential psoriatic arthritis. Other advantage is the price. Compared to acitreine or ciclosporine it is much cheaper. With a good man- agement it is relatively safe, even though the occurrence of pos- sible adverse effects is higher and dose-dependent. Despite thatthe patients with coincident joint pain and biologically treatedpatients profit from the treatment with methotrexate. In both casesthe methotrexate has an irreplaceable position.

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