UNLABELLED: Methotrexate is used to manage moderate to severe psoriasis and psoriatic arthritis. Methotrexate acts by inhibiting the enzymes involved in nucleotide synthesis. Methotrexate polyglutamates (MTXPGs) have a higher potency to inhibit Dihydrofolate reductase (DHFR), 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC), and thymidylate synthase (TS), compared to naïve methotrexate. Among all the MTXPGs, methotrexate polyglutamate three (MTXPG-3) is a more potent inhibitor of DHFR, ATIC, and TS enzymes. MTXPG-3 is anticipated to allow therapeutic drug monitoring in immune-mediated inflammatory diseases. We aim to study MTXPG-3 levels as a biomarker for both efficacy and adverse events among psoriatic patients treated with methotrexate monotherapy. We used the LC-MS/MS (Liquid Chromatography Mass Spectrophotometry) system for measuring erythrocyte MTXPG-3. We recruited 106 patients with psoriasis who were treated with methotrexate. Sixty-one of them had psoriatic arthritis (concomitant or in the past). The mean age was 45.08 ± 13.04 years. After twenty-four weeks of methotrexate treatment, 73(69%) were responders, and 33(31%) were non-responders. Thirty-nine (36%) experienced adverse effects, and 67(64%) did not experience any adverse effects. We observed a significant positive correlation between erythrocyte MTXPG-3 and methotrexate dose per week at weeks 12 and 16 but not at week 24. Erythrocyte MTXPG-3 did not correlate with response or adverse effects. It can be used as a marker of compliance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12291-024-01269-x.

• Publication type
• Journal Article MeSH

BACKGROUND: Clinical studies of low-dose oral methotrexate (MTX) in the treatment of psoriasis and rheumatoid arthritis document a large interpatient variability in the pharmacokinetics of MTX, including its polyglutamates (MTXPGs) in erythrocytes (RBC). This can be a factor contributing to the variability of therapeutic and toxic effects. AIM: This pilot trial aimed to investigate the MTXPG concentrations in RBC as well as their relation to therapeutic and adverse effects during the initial 4 months of pharmacokinetically guided therapy with a divided-dose schedule (three doses of MTX separated by 12-h intervals once a week). SUBJECTS AND METHODS: Sixteen psoriatic patients (4 men and 12 women; mean age, 53 years; range, 28-69 years) with moderate-to-severe chronic plaque psoriasis [mean Psoriasis Area and Severity Index (PASI) = 24; range, 9-42] were enrolled in the study. Concentrations of plasma MTX and that of MTXPGs in RBC were assayed using liquid chromatography methods. The area under the concentration-time curve of plasma MTX in the interval 0-8 h post-dose (AUC(0-8 h)) was measured after a test bolus dose of 10 mg, and the starting weekly dose was individualized in order to achieve the target AUC(0-8 h) of 1800 nmol.h/L. The PASI, biochemistry, and haematology tests and MTXPGs levels in RBC were evaluated at baseline and at 4-week intervals. RESULTS: The AUC(0-8 h )achieved 1360 +/- 425 nmol.h/L (mean +/- SD: range, 778-2400 nmol.h/L). The mean (range) of individualized doses was 14.5 mg/week (7.5-22.5 mg). The mean (SD) steady-state concentration of total MTXPGs observed between days 85 to 110 reached 113 (34.6) nmol/L (range, 66.1-174 nmol/L). The PASI decreased from 24.0 +/- 8.0 (mean +/- SD) at baseline to 8.0 +/- 6.1 at day 110 (P < 0.001). Thirteen patients (87%) achieved a greater than 50% improvement in baseline PASI, and seven (47%) experienced a greater than 75% improvement. There was no relationship between the percent improvement from baseline PASI and the steady-state concentration of MTXPGs in RBC. All patients tolerated MTX well. Throughout the study period, there was a continuous increasing trend in the geometric mean values of the mean corpuscular volume from 92.6 to 96.4 fL (P < 0.001) and of plasma homocysteine from 9.5 to 12.3 micromol/L (P < 0.005). The geometric mean serum alanine aminotransferase (ALT) activity slightly increased from 0.49 to 0.80 microkat/L (P < 0.05). However, only two patients had the ALT activity transiently elevated above twice the upper limit of normal. CONCLUSION: Results of this pilot trial show that the steady-state levels of MTXPGs in RBC vary less than threefold between patients and did not correlate with the change in PASI observed after 4 months of therapy with an individualised weekly dose of MTX. Whether pharmacokinetically guided dosing can improve the results of psoriasis therapy with MTX should be prospectively tested in large controlled studies.

• MeSH
• Administration, Oral MeSH
• Dermatologic Agents administration & dosage   pharmacokinetics   blood   MeSH
• Adult MeSH
• Erythrocytes metabolism   MeSH
• Financing, Organized MeSH
• Middle Aged MeSH
• Humans MeSH
• Methotrexate administration & dosage   pharmacokinetics   blood   MeSH
• Drug-Related Side Effects and Adverse Reactions MeSH
• Pilot Projects MeSH
• Psoriasis drug therapy   blood   MeSH
• Drug Administration Schedule MeSH
• Aged MeSH
• Severity of Illness Index MeSH
• Treatment Outcome MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Clinical Trial MeSH

OBJECTIVE: We assessed the effect of folic acid (FA) on the pharmacokinetics and pharmacodynamics of low-dose oral methotrexate (MTX) during the remission-induction phase of psoriasis treatment. METHODS: In a 32-week, open-label, two-way cross-over study, patients (n=20, seven men, aged 35-70 years) with moderate-to-severe plaque psoriasis were randomly assigned to receive MTX plus FA (20 mg/week) for 16 weeks followed by MTX monotherapy (three doses of MTX separated by 12-h intervals once a week) for an additional 16 weeks (treatment arm A, n=10) or to receive the opposite sequence of treatments (arm B, n=10). Dosing of MTX was individualised with the help of pre-study evaluation of plasma MTX pharmacokinetics. The Psoriasis Area and Severity Index (PASI), biochemistry and haematology tests and erythrocyte concentration of MTX polyglutamates (MTXPG) were evaluated throughout the study. RESULTS: In arms A and B, the mean (range) concentrations of MTXPG (nmol/L) were comparable [week 16: 96.2 (32.0-157) vs. 111 (73.7-175), P=0.32; week 32: 103 (55.8-173) vs. 83.6 (27.4-129), P=0.24]. After 16 weeks, the mean+/-SEM PASI decreased from 20.1+/-2.1 to 8.8+/-1.3 in arm A, while a greater reduction from 27.2+/-2.1 to 5.1+/-1.0 occurred in arm B (P<0.001). Positive correlations were found between the percent improvement in PASI at week 16 and the ratios of the concentration of MTXPG to plasma folate (rho=0.59, P=0.008) or RBC folate concentration (rho=0.56, P=0.013). Due to an accelerated decline in PASI in arm A and a trend to its worsening in arm B after crossing over of treatments, the mean absolute PASI scores in both arms were comparable at week 32. CONCLUSION: The antipsoriatic effect of MTX during the remission-induction phase of treatment is influenced by folate status and may be significantly less if combined treatment with FA is used, irrespective of pre-treatment folate levels. The individual tailoring of MTX dosing needs further attention because the mean percent PASI improvement from baseline was 83% and the inter-patient variability in response was low after 16 weeks of monotherapy with MTX.

• MeSH
• Patient Compliance MeSH
• Folic Acid Antagonists pharmacokinetics   adverse effects   therapeutic use   MeSH
• Administration, Oral MeSH
• Dermatologic Agents pharmacokinetics   adverse effects   therapeutic use   MeSH
• Erythrocytes metabolism   MeSH
• Financing, Organized MeSH
• Cross-Over Studies MeSH
• Folic Acid blood   adverse effects   therapeutic use   MeSH
• Polyglutamic Acid MeSH
• Middle Aged MeSH
• Humans MeSH
• Methotrexate pharmacokinetics   adverse effects   therapeutic use   MeSH
• Dietary Supplements MeSH
• Psoriasis drug therapy   MeSH
• Aged MeSH
• Vitamins blood   adverse effects   therapeutic use   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Randomized Controlled Trial MeSH