Methotrexate polyglutamates as a marker of patient compliance and clinical response in psoriasis: a single-centre prospective study

TY - JOUR

T1 - Methotrexate polyglutamates as a marker of patient compliance and clinical response in psoriasis: a single-centre prospective study

AU - Woolf, R. T.

AU - West, S. L.

AU - Arenas-Hernandez, M.

AU - Hare, N.

AU - van Ton, A. M. Peters

AU - Lewis, C. M.

AU - Marinaki, A. M.

AU - Barker, J. N. W. N.

AU - Smith, C. H.

PY - 2012/7

Y1 - 2012/7

N2 - Background Methotrexate is activated by the sequential addition of glutamic acid residues to form methotrexate polyglutamates (MTXPG(1-5)). MTXPG(1-5) inhibit enzymes of the folate-purine-pyrimidine pathways, and longer-chain MTXPG(3-5) species are more active.Objectives To determine the pattern of erythrocyte MTXPG(1-5) in patients initiated on oral methotrexate for psoriasis, and to investigate the potential utility of MTXPGs as markers of compliance and/or clinical response.Methods This was a single-centre, prospective study of 55 adult patients with chronic plaque psoriasis initiated on weekly oral methotrexate. Erythrocyte MTXPG(1-5) concentrations were measured (at weeks 4, 8, 12, 24 and 52) using high-performance liquid chromatography. Methotrexate responders achieved >= 50% improvement in Psoriasis Area and Severity Index or physician's global score of 'clear'/'nearly clear' at 24 weeks.Results MTXPG levels were measured in 14-33 patients at each time point. All MTXPG(1-5) species were detected at week 4 of therapy. Steady state for long-chain MTXPG(3-5) and total MTXPG(1-5) was achieved by week 24. MTXPG(3) emerged as the predominant MTXPG species (from week 12 onwards) and reflected overall polyglutamate status (correlating strongly with MTXPG(2-5), MTXPG(3-5) and MTXPG(4-5); R = 0 76-0 95, P <1.55 x 10(-5)). Age, renal function and sex were not significant determinants of MTXPG(3) concentration. No significant association was identified between MTXPG and adverse events or responder status.Conclusions This is the first study to demonstrate the prospective accumulation of MTXPG1-5 in patients with psoriasis. The detection of MTXPGs early in therapy and the establishment of a steady state with continuous treatment may offer measuring of MTXPG as a test to monitor patient compliance with therapy. Larger studies are required to determine the role of MTXPG as a potential biomarker of clinical response.

AB - Background Methotrexate is activated by the sequential addition of glutamic acid residues to form methotrexate polyglutamates (MTXPG(1-5)). MTXPG(1-5) inhibit enzymes of the folate-purine-pyrimidine pathways, and longer-chain MTXPG(3-5) species are more active.Objectives To determine the pattern of erythrocyte MTXPG(1-5) in patients initiated on oral methotrexate for psoriasis, and to investigate the potential utility of MTXPGs as markers of compliance and/or clinical response.Methods This was a single-centre, prospective study of 55 adult patients with chronic plaque psoriasis initiated on weekly oral methotrexate. Erythrocyte MTXPG(1-5) concentrations were measured (at weeks 4, 8, 12, 24 and 52) using high-performance liquid chromatography. Methotrexate responders achieved >= 50% improvement in Psoriasis Area and Severity Index or physician's global score of 'clear'/'nearly clear' at 24 weeks.Results MTXPG levels were measured in 14-33 patients at each time point. All MTXPG(1-5) species were detected at week 4 of therapy. Steady state for long-chain MTXPG(3-5) and total MTXPG(1-5) was achieved by week 24. MTXPG(3) emerged as the predominant MTXPG species (from week 12 onwards) and reflected overall polyglutamate status (correlating strongly with MTXPG(2-5), MTXPG(3-5) and MTXPG(4-5); R = 0 76-0 95, P <1.55 x 10(-5)). Age, renal function and sex were not significant determinants of MTXPG(3) concentration. No significant association was identified between MTXPG and adverse events or responder status.Conclusions This is the first study to demonstrate the prospective accumulation of MTXPG1-5 in patients with psoriasis. The detection of MTXPGs early in therapy and the establishment of a steady state with continuous treatment may offer measuring of MTXPG as a test to monitor patient compliance with therapy. Larger studies are required to determine the role of MTXPG as a potential biomarker of clinical response.

KW - JUVENILE IDIOPATHIC ARTHRITIS

KW - REDUCED FOLATE CARRIER

KW - LOW-DOSE METHOTREXATE

KW - RHEUMATOID-ARTHRITIS

KW - ORAL METHOTREXATE

KW - COMMON POLYMORPHISMS

KW - THYMIDYLATE SYNTHASE

KW - GENETIC-VARIATION

KW - PLAQUE PSORIASIS

KW - THERAPY

U2 - 10.1111/j.1365-2133.2012.10881.x

DO - 10.1111/j.1365-2133.2012.10881.x

M3 - Article

SN - 0007-0963

VL - 167

SP - 165

EP - 173

JO - British Journal of Dermatology

JF - British Journal of Dermatology

IS - 1

ER -