Systemic therapy of psoriasis: methotrexate

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1 CLINICAL STUDY Systemic therapy of psoriasis: methotrexate Kozub P, Simaljakova M Department of Dermatology, Faculty of Medicine, University Hospital, Bratislava, Slovakia. peter.kozub@laposte.net 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 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 treatment of psoriasis. It has immunosuppresive, cytostatic and antiinflammatory effects. In dermatology, it started to be used in Almost forty years of experience are granting good knowledge of its effects on psoriasis, but also of the side effects, incidence of which varies depending on the treatment length, methotrexate dose and supplementation of folic acid. Even thought it is on the market for a long time, its effect on psoriasis is often unpredictable. There are patients, who react on the treatment satisfactorily, 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, respective when local therapy is insufficiency. Mechanism of action of methotrexate Methotrexate (Fig. 1), like the folic acid, binds to the same transmembrane protein RFC (reduced folate carrier) and is transported into the cell. In the cell membrane, also an active transport proteins exist, that evict the methotrexate out of the cell. In cytoplasm, the methotrexate is activated by the enzyme FPGS (folylpolyglutamate syntetase) by polyglutamation. By the same enzyme, the folic acid is processed with the result of polygutamates of folic acid, which serve as the deposit for the cell. Almost 50 % of the folic acid is stored in the body in the form of polyglutamates deposited in hepatic cells. One molecule of methotrexate can bind from 2 up to 7 glutamates. This process is reversible. Methotrexate glutamates can be splintered by Department of Dermatology, Faculty of Medicine, University Hospital, Bratislava, Slovakia Address for correspondence: MUDr. Peter Kozub, Department of Dermatology, Faculty of Medicine, University Hospital, Bratislava, Slovakia. Fig. 1. Methotrexate mechanism of action (3). the influence of enzyme gama-glutamylhydrolase, resulting in the creation of the former molecule of methotrexate. The active form of methotrexate (polyglutamate) is responsible for its target effects in the cell. The most important effect of methotrexate is evoked by a blockade of dihydrofolate-reductase (DHFR). This enzyme plays an important role in the metabolism of folic acid by activating it to tetrahydrofolate (TFH). The blockade of this enzyme leads to reduction in the creation of tetrahydrofolate. Tetrahydrofolate is the important substrate for the de novo creation of purine and pyrimidine bases. This reduction is enhanced by the inhibitory effect of methotrexate on another important enzyme, tymidilate syntasis (TYMS), which is responsible for the transformation of uridilate to tymidilate. The ending result Indexed and abstracted in Science Citation Index Expanded and in Journal Citation Reports/Science Edition

2 Kozub P, Simaljakova M. Systemic therapy of psoriasis: methotrexate of inhibitory influence of methotrexate on the enzymes mentioned above is the blockade of DNA and RNA synthesis. Anti-inflammatory effect is induced by inhibition of other important enzyme, aminoimidazole-4-carboxamide ribonucleotide transformylase. Its blockade leads to accumulation of adenosine, an important anti-inflammatory factor. Pharmacokinetics of methotrexate Methotrexate is used after fasting. Two forms exist oral and parenteral. In dermatology, we use only methotrexate pills, although the recent studies with methotrexate dosed subcutaneously in patients with rheumatic arthritis (4) showed a higher efficiency of subcutaneously applied methotrexate compared to methotrexate dosed as pills and might indicate the future change. 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 diseases have to be reduced. Dosing of methotrexate The weekly dose of methotrexate in patients with psoriasis varies from 7.5 mg to 22.5 mg. It starts with the lowest, so-called test dose of 5 or 7.5 mg for week, and after a week the blood samples are taken (biochemistry and blood count) for a possible occurrence of side effects. The most dangerous is myelosuppresion, which could be lethal to the patient. If the tests are within normal levels, the dose of methotrexate could be raised. Laboratory parameters are checked frequently (blood count, hepatic enzymes, renal parameters) and the patient is checked for possible side effects on skin and mucous membranes, respective the subjective tolerance of the dose from the gastrointestinal point of view is observed. The dose is adjusted according to the needs. Two ways of dosing are used. American school prefers the drug administration split into three doses of 12 hour intervals. This type is common in our country too. English school prioritizes drug administration in a single day in the morning and evening, with a lower dosage even one-time only (Tab. 1). Indications Tab. 1. Dosage of folic acid number of European dermatologists, using different dosage schemes (1). Dosage of folic acid Methotrexate is indicated for the treatment of nummular chronic psoriasis and psoriatic arthritis. It is not suitable for treating acute conditions (erythrodermia, generalized pustulous psoriasis, exudative psoriasis), in which systemic corticoid therapy is preferred. Methotrexate starts operating within a month and its effect fully develops after two months. From this reason it is a great additive to systemic corticoid therapy. Serious acute state is suppressed by corticoids, which are later dropped. The efficiency of methotrexate is relatively lower, but it depends on a patient s weight, dose, the speed of increasing the dose and dosage of folic acid. It has the most sovereign effect on joints among the first-line treatment. Neotigason is absolutely inadequate treatment in simultaneous joint disability. Cyclosporine also has an effect on joints, but it is achieved later than effects on skin (approximately after 2 3 months), and does not have to be sufficient. Methotrexate is the ideal drug in treatment of patients with nummular chronic psoriasis and with severe joint disabilities. Methotrexate adverse effects No. of dermatologists 5 mg daily except of MTX-day 16 5 mg daily 9 5 mg 24 hours after the lats dose of MTX 6 5 mg on the 4th day after the last dose of MTX 1 5 mg 2x per week 1 Methotrexate adverse effects could be divided into few groups: 1. myelosuppression the most feared side effect of methotrexate, which tends to occur in the beginnings of treatment. The result is attenuation of bone marrow and pancytopenia. Because of this, the starting dose of methotrexate is administered in reduced form and after a week the blood samples are checked. Pancytopenia is very rare. If it occurs, the treatment with methotrexate has to be stopped immediately, and possibly the antidote is to be administered calciumfolinate. 2. hepatotoxicity is given by increasing the hepatic enzyme levels up to 2 3 times. It occurs pretty frequently and is commonly dependent on the dose of methotrexate. The treatment has not to be interrupted and usually a lowering of dose is sufficient, or hepatoprotectives are to be added into treatment. The recommendations of world known dermatologists prevailed for a long time due to an increased risk of hepatic fibrosis during long-time dosing of methotrexate, hepatic biopsies were taken after achieving the cumulative dose of 1.5 g, but in present this recommendation is considered obsolete. Actually it is enough if the levels of hepatic enzymes are checked, abdominal ultrasound performed 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. Levels of PIIINP should be checked every 3 4 months. If the levels increase, the liver tissue samples should be taken by biopsy. 3. gastrointestinal adverse effects (diarrhea, nausea, abdominal pain) occurs mainly due to high dosage. They are relative common and when they occur, the dose of methotrexate should be decreased. 4. skin and mucous membrane adverse effects (ulcers in mouth cavity, stomatitis, cheilitis, alopecia, exanthemas) are relatively common as well and dosage-dependent. If they occur, the dosage should be adjusted. They are not the reason to terminate the treatment. 391

3 teratogenic effects contraception is required during the treatment with methotrexate, it also should be provided for the next three 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 recommended because of the possible increased risk of skin carcinoma. Restrictions during methotrexate administration (5) During the treatment, patients are prohibited to drink alcoholic beverages. They cannot use some drugs simultaneously, for example non-steroid antiflogistics, which are used frequently by patients with synchronous psoriatic arthritis. Non steroid antiflogistics increase and extent serum levels of methotrexate and could significantly increase the risk of severe hematologic and gastrointestinal toxicity. Methotrexate is bounded to albumins in serum and drugs, which interact with the same bonds (salicylates, fenylbutazone, fenytoine, sulphonamides), could increase its toxicity. Oral antibiotics (tetracycline, chloramphenicol) and non-absorbable wide-spectrum antibiotics could lower the absorption 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). During the treatment the vaccination is not recommended. Monitoring of treatment First blood samples (blood count, laboratory values) are taken after a week of treatment. Frequency of following blood checks depends on the speed of dose increment, they should be performed at least once a month in first three months of treatment. After balancing the dose and physiological levels in blood samples, these intervals could be elongated. In the blood count we follow the numbers of erythrocytes, leucocytes, neutrophiles, the middle volume of erythrocyte and from the laboratory values hepatic and renal parameters. In the case of rising levels of the middle volume of erythrocytes, we can check the levels of folic acid and B12. At least once a year patient should undergo abdominal ultrasound. Also, aminopeptide procolagene III is not the part of routine check, but after repeatedly higher levels of hepatic enzymes and positive hepatic ultrasound it should be evaluated (Tabs 2 and 3). Methotrexate and folic acid Methotrexate is an antagonist of folic acid. Methotrexate and folic acid competes against each other to bind on the same receptor. Folic acid has been added into the treatment to lower the possible undesirable side-effects. By adding the folic acid we also lower the immunosuppressive and anti-inflammatory effect of methotrexate. Commonly the axiom states that 5 mg of folic acid is administered per day, missing out on days when methotrexate is dosed. If we assume that methotrexate is dosed once or twice per week, other days the folic acid should be taken. In our Tab. 2. Peroral methotrexate available in Slovakia since (14). Name of agent No of pills Price Surcharge Surcharge in package (Euro) (Euro) (%) Methotrexat Teva mg Trexan 2.5 mg Trexan 2.5 mg Trexan 10 mg Trexan 10 mg Methotrexate Lachema 2.5 mg Methotrexate Ebewe 2.5 mg Methotrexate Ebewe 5 mg Tab. 3. Folic acid available in Slovakia since (14). Name of agent No of pills Price Surcharge Surcharge in package (Euro) (Euro) (%) Acidum folicum mg 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 because the pills does not have the splitting gap. Other problem could result from the weekly dose of folic acid. It is different, when patient takes 30 mg of folic acid during the methotrexate dosage of 7.5 mg/week or 15 mg/week. In the first case we significantly reduce the risk of potential side effects, but at a cost of lowering its effect. In the second case the effect should be better, but its toxicity could rise. Due to that, the dosage of folic acid should be adjusted to individual needs of patient. In the case that patient is treated by methotrexate only, serum levels of folic acid could decrease and secondarily the middle volume of erythrocytes could rise. Heavy pancytopenia could occur from a grave deficit of folates. Despite that not every dermatologist uses the folic acid. During the spring symposium EADV 2009 in Bucurest the practice of European dermatologists was presented (6): Only 32 % of dermatologists commonly use the folic acid daily during treatment with methotrexate, next 32 % only during specific circumstances (i.e. a rise in the middle volume of erythrocytes) and the rest 36 % does not use the folic acid at all. Various weekly dosages of folic acid were presented; the results are to be seen in the Table 1. In the results it is shown that even European dermatologists are consistent about the dose of folic acid (in most European countries the dosage of 5 mg is available in single pills, instead of Slovakia), the weekly dose is not uniform and probably the randomized blinded trials will be needed to get the results of optimal dosage scheme. Dermatologists have agreed that the supplementation of folic acid during the treatment with methotrexate should be realized during the whole time of treatment. If the higher levels of middle volume 392

4 Kozub P, Simaljakova M. Systemic therapy of psoriasis: methotrexate of erythrocytes over 106 fl persist, treatment with methotrexate should be stopped. The majority of patients with psoriasis has lower levels of folic acid and a higher middle volume of erythrocytes. The comparative trial CHAMPION, in which the effects of adalimumab and methotrexate were evaluated, supports the fact that only folic acid by itself in monotherapy could bring some benefit for the patient. The dose of methotrexate was increased from 7.5 mg up to 22.5 mg in 16th week when needed. Together with methotrexate, the folic acid was administered in a dose of 5 mg/day. Patients dosed with placebo also received the folic acid treatment in a dose of 5 mg/day. The last group of patients reached PASI 75 in 16th week as high as 18.9 %. It is too high number for the placebo group, but these patients also received the folic acid treatment, high probability is that the folic acid itself has some positive 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 phototherapy. Other trials are needed to confirm the beneficial effect of folic acid on psoriasis. Folic acid was added to methotrexate treatment to lower the possible side effects. French authors Prey and Paul (7) analyzed 6 double blinded placebo controlled trials focused on the effects of folic acid ror foline acid on the safety and efficiency of methotrexate treatment in patients with rheumatoid arthritis and with psoriasis with or without psoriatic arthritis. They founded that gastrointestinal (diarrhea, nausea, abdominal pain) and skin (respective mucosal) adverse effects (ulcers in mouth cavity, stomatitis, alopetia, exanthemas) were only mildly lowered, but hepatotoxicity, defined as elevation of alaninaminotraspherase up to double the normal levels, was significantly reduced thanks to the supplementation with folic and foline acid by 35.8 %. Hematological adverse effects (neutropenia, lymphopenia, and anemia) could not be evaluated because of its rare occurrence, but the significant reduction was not reached depending on dosage or not of folic/foline acid in the patients that expressed these hematological side effects. The results showed that the supplementation of folic/foline acid significantly decreased the hepatotoxicity of methotrexate and mildly decreased its gastrointestinal, resp. skin/mucosal adverse effects. The influence on the myelotoxicity was not significant. The dosage of folic acid used in the mentioned studies was either 1 or 5 mg daily and the foline acid 1 5 mg/week. Concurrently the effect of these acids on the methotrexate efficiency was observed. The results showed that in patients with rheumatoid arthritis both acids had mildly negative effect on methotrexate, but in patients with psoriasis this effect was not so clear. Authors also dealt with the dosage of acids. Only in one trial the two doses of folic acid (27.5 mg/week vs 5 mg/week) were compared, but it was not achieved that the higher dose is more efficient than lower dose. Some results suggested that patients with higher weight need either the higher dose of methotrexate or lower doses of folic acid. Other trials are needed to confirm these observations. It is on the dermatologist himself to adjust the dose of methotrexate and folic acid depending on the patient s needs. It is also important to remember, that even though the supplementation of folic acid lowers the efficiency of methotrexate, it primarily lowers the immunosuppressive effect. Anti-inflammatory effect of methotrexate is not bonded to folate metabolism, but probably to inhibition of aminoimidazole karboxamide ribonucleotide transformylamylase, which results in accumulation of adenosine, which is one of the main elements of the anti-inflammatory response (Fig. 1) )8). Adjuvant therapy with folic acid during the methotrexate treatment definitely has its meaning. It significantly reduces the hepatotoxicity and mildly the gastrointestinal and skin respective mucosal adverse effects and only minimally influence the methotrexate efficiency. It is necessary to adequately adjust the dosages of both drugs to actual needs of patient. Methotrexate and biological treatment Methotrexate has an irreplaceable role in biological treatment of psoriasis and psoriatic arthritis. It is used mainly during the treatment with TNFá blockers, especially treatment with infliximab. With its cytostatic effect, methotrexate blocks B-lymphocytes and decreases the production of antibodies against infliximab. Antibodies against infliximab have neutralizing character and are able to lower the efficiency of methotrexate, but also can induce infusion reactions. Even if the concentration of antibodies against infliximab is not examined as a standard, its increased values could result in decreasing of its effect. During the treatment with infliximab, two ways of failure can occur: (1) infliximab does not tighten up its effect meaning that patient will get better after the infusion dosage, but this improvement lasts only 4 6 weeks, after which the gradual deterioration occurs, but after the next infusion, the patient will get temporarily better again, (2) infliximab effect is not adequate patient does not get better despite the infusion treatment, vice-versa to worse manifestation. The solving of the first case is based on shortage in intervals of infusion dosage to 4 6 weeks, solving the second case is the methotrexate. Adding of methotrexate lowers the concentration of neutralizing antibodies against infliximab, also its immunosuppressive and anti-inflammatory effect takes place. Similarly as in the methotrexate monotherapy, we start with an induction dose of 7.5 mg/week. If after one week, the bone marrow attenuation is not observed, the dosage is increased adequately. The possible preventive effect of methotrexate on the infusion reactions for a long time during the treatment with infliximab is considered. Many studies have proved its benefit, even if the infusion reactions did not occur in the group of patients treated by methotrexate. Time factor is very important. The full effect of methotrexate can be expected as soon as in two months. Crandall and Mackner found out that the risk of infusion reactions was significantly lower after 4 months of simultaneous therapy with methotrexate and infliximab (9). After adding the methotrexate to infliximab or other TNFá blocker, we pay more attention to the levels of hepatic enzymes, because the combination of two increases the risk of hepatotoxicity. 393

5 Farmacogenetics of methotrexate Farmacogenetics of methotrexate deals with the response on treatment and genetically based variability. It follows simple nucleotide polymorphisms (SNP) of genes of those enzymes, transport proteins, effector proteins or receptors, which are the part of the drug effect. It also follows their relationship to efficiency and toxicity of the drug. In case of methotrexate (used to treatment of psoriasis), the following proteins and their polymorphism were examined: FPGS polymorphism without influencing the efficiency or toxicity (10), GGH polymorphism without influencing the efficiency or toxicity (10), MTHFR polymorphism C677T, A1298C without influencing the efficiency or toxicity (10), compared to patients with rheumatoid arthritis, where both polymorphisms are associated with an increased risk of adverse effects, ATIC polymorphism C347G without influencing the efficiency or toxicity (10), more frequent end of treatment (12), ABCC1 (transmembrane protein evicting the methotrexate out of the cell) polymorphism in the area of this gene is associated with good response on methotrexate (11), ABCG2 (other transmembrane protein evicting the methotrexate out of the cell) polymorphism in the area of this gene is associated with good response on methotrexate and early incidence of side effects (11), RFC (reduced folate carrier) polymorphism 80A increased risk of side effects (12). Other methods then pharmacogenetic are used to evaluate an increased or decreased efficiency of methotrexate, respective to distinguish the responders from non-responders during the treatment of psoriasis vulgaris. Czech authors (13) expressed the possibility to evaluate the concentration of methotrexate polyglutamates in erythrocytes and correlate this concentration with efficiency and toxicity of methotrexate. Their pilot study did not confirm a direct correlation of levels of methotrexate polyglutamates with the changes of PASI (Psoriasis Area and Severity Index). Conclusion Methotrexate belongs to the first line of therapy in a systemic treatment of psoriasis. It does not belong to the most efficient antipsoriatic drugs, but its advantage is very good effect on potential psoriatic arthritis. Other advantage is the price. Compared to acitreine or ciclosporine it is much cheaper. With a good management it is relatively safe, even though the occurrence of possible adverse effects is higher and dose-dependent. Despite that the patients with coincident joint pain and biologically treated patients profit from the treatment with methotrexate. In both cases the methotrexate has an irreplaceable position. References 1. Flytstrom I et al. Methotrexate vs. ciclosporin in psoriasis: effectiveness, quality of life and safety. A randomized controlled trial. Br J Dermatol 2008; 158: Saurat JH et al. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158: Hughes LB et al. Recent advances in rheumatoid arthritis therapy and management: recent advances in predictors of efficacy and toxicity Braun J et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-months, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum 2008; 58: Methotrexat-Lachema, súhrn charakteristických vlastností lieku (SPC), 6. Boffa M. Methotrexate for psoriasis an update. Spring symposium EADV Bucharest Prey S, Paul C. Effect of folic or folinic acid supplementation on methotrexate-associated safety an efficacy in inflammatory disease: a systematic review. Br J Dermatol 2009; 160: Dervieux T et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase and thymidilate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum 2004; 50: Crandall WV, Mackner LM. Infusion reactions to infliximab in children and adolescents: frequency, outcome and a predictive model. Aliment Pharmacol Ther 2003; 17: Warren RB et al. Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms. Br J Dermatol 2009; 160: Warren RB et al. Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis. J Inv Dermatol 2008; 128: Campalani E et al. Polymorphisms in folate, pyrimidine and purine metabolism are associated with efficacy and toxicity of methotrexate in psoriasis. J Inv Dermatol 2007; 127: Hroch M et al. A pilot study of pharmacokinetically guided dosing of oral methotrexate in the initial phase of psoriasis treatment. JEADV 2007; 22: MZ SR. Zoznam liekov a lieèiv plne uhrádzaných alebo èiastoène uhrádzaných na základe verejného zdravotného poistenia: Received February 28, Accepted March 18,