Actas Dermo-Sifiliográficas (English Edition) Actas Dermo-Sifiliográficas (English Edition)
Actas Dermosifiliogr 2017;108:603-4 - Vol. 108 Num.6 DOI: 10.1016/j.adengl.2016.12.024
Case and Research Letter
Split doses of Methotrexate in patients with moderate to severe Psoriasis
Dosis divididas de metotrexato en pacientes con psoriasis moderada a severa
M.J.M. Rodríguez-Zúñigaa,b,, , , F. Cortez-Francoa, E. Qujiano-Gomeroa
a Servicio de Dermatología del Hospital Nacional Daniel Alcides Carrión, Callao, Peru
b Universidad Nacional Mayor de San Marcos, Lima, Peru
Dear Editor,

Psoriasis is the most common inflammatory skin condition with a worldwide prevalence of 2%. Systemic or topical treatment is decided according to the severity of the disease.1 For systemic treatment, Methotrexate (MTX) remains effective and medically accessible: it is widely used in hospitals in Latin America, where biological therapy is still limited for economic reasons.2

The article: “Methotrexate in Moderate to Severe Psoriasis: Review of the Literature and Expert Recommendations”3 outlines very important and interesting recommendations on the use of this drug in Psoriasis. However, one point that has not been taken into account is the split of MTX in two or three weekly doses, with the benefit of both efficacy and reduced side effects.

The benefits of fractional doses are listed below. As indicated in the article, MTX has significant gastrointestinal adverse effects that hinder its use, and increases with higher oral doses; but can be avoided or reduced with parenteral route, and with folates.3 In addition, a divided dose of MTX is an alternative for reducing gastrointestinal side effects in patients with Psoriasis.4 Second, with high MTX enteral doses, bioavailability decreases (for limiting absorption); therefore it is beneficial to divide MTX into smaller doses and thus increase its concentration systemically,5 increasing efficiency without worsening adverse effects.6

Although MTX experience with divided doses for Psoriasis has been well known and accepted7 for several decades,8 it is based on a limited number of studies.5,9 Thus, further experience with divided doses of MTX has been carried out in rheumatologic patients, but these are also limited.

Weinstein and Frost9 first proposed the divided dose of MTX for Psoriasis in 1971. They showed that small doses of 2.5–7.5mg of MTX given at intervals of 12h for a total of three doses every week had an improvement from 75% to 100% in 26 patients with severe Psoriasis, with minimal adverse effects (nausea, oral ulcers and hives).

Chladek et al.5 conducted a study that related the pharmacodynamics and pharmacokinetics of divided doses (2.5mg and 5mg three times a week) and weekly full doses (7.5mg and 15mg) of MTX with the Psoriasis Area Severity Index of 41 patients with severe disease. They concluded that split doses of MTX were associated with greater efficacy and lower risk of acute adverse effects during anti-psoriatic therapy.

In the rheumatology field, Dhaon et al.6 randomly divided 135 patients with rheumatoid arthritis into three groups: group 1 on split 7.5mg doses of oral MTX two or three times weekly; group 2 on single 15–22.5mg of oral MTX weekly; and group 3 on single intramuscular 15–22.5mg dose of MTX weekly. Clinical efficacy of split and intramuscular doses was superior to single oral dose, but intramuscular administration lead to greater discomfort on patients. In addition, split doses group showed the lowest rates of gastrointestinal side effects, with higher levels of alopecia.

Pharmacokinetic studies demonstrate enhanced bioavailability of the drug with multiple dosing, supporting the clinical superiority of divided doses compared to single oral dose. Hoekstra et al.,10 compared blood samples of 10 rheumatoid arthritis patients with fluorescence polarization immunoassay technique who received a single oral dose of 25–35mg MTX, and after one week, divided two or three doses every 8h. Bioavailability of split doses was 28% significantly higher than single doses and similar to that of subcutaneous doses, obtained from a previous study. The authors concluded that when high-dose of MTX is needed, the divided dose is an effective and comparable alternative to subcutaneous administration.

After demonstrating and bringing up the efficacy and safety of MTX split oral doses in patients with Psoriasis, it is important to remember that there are limitations and drawbacks in their use, mainly with delivery errors. Because patients must take three weekly doses of 2.5mg or 5mg, and MTX tablets are mainly available at 2.5mg and 10mg in this region, patients may accidentally fail in both: reduncing or increasing the dose. However, in our experience this accident is very uncommon.

In conclusion, MTX remains as a first-line treatment for severe Psoriasis, and accessible in many Latin American countries. Enteral and parenteral weekly divided doses of MTX show similar efficacy and safety in several studies both in psoriatic and rheumatologic patients. Therefore, we should continue proposing low split oral doses in future guidelines and consensus, in comparison to the single oral dose, with the benefit of achieving greater adherence by reducing adverse effects, taking into account their limitations.

Conflict of interest

The authors declare no conflict of interest.

R. Parisi,D.P. Symmons,C.E. Griffiths,D.M. Ashcroft,Identification and Management of Psoriasis and Associated ComorbidiTy (IMPACT) project team
Global epidemiology of psoriasis: a systematic review of incidence and prevalence
J Invest Dermatol, 133 (2013), pp. 377-385
R. Gyulai,M. Bagot,C.E. Griffiths,T. Luger,L. Naldi,C. Paul
Current practice of methotrexate use for psoriasis: results of a worldwide survey among dermatologists
J Eur Acad Dermatol Venereol, 29 (2015), pp. 224-231
J.M. Carrascosa,P. de la Cueva,M. Ara,L. Puig,X. Bordas,G. Carretero
Methotrexate in moderate to severe psoriasis: review of the literature and expert recommendations
Actas Dermosifiliogr, 107 (2016), pp. 194-206
G. Carretero,L. Puig,L. Dehesa,J.M. Carrascosa,M. Ribera,M. Sanchez-Regana
Metotrexato: guia de uso en psoriasis
Actas Dermosifiliogr, 101 (2010), pp. 600-613
J. Chladek,J. Grim,J. Martinkova,M. Simkova,J. Vaneckova
Low-dose methotrexate pharmacokinetics and pharmacodynamics in the therapy of severe psoriasis
Basic Clin Pharmacol Toxicol, 96 (2005), pp. 247-248
P. Dhaon,S.K. Das,R. Srivastava,G. Agarwal,A. Asthana
Oral Methotrexate in split dose weekly versus oral or parenteral Methotrexate once weekly in Rheumatoid Arthritis: a short-term study
Int J Rheum Dis, (2016),
M. Czarnecka-Operacz,A. Sadowska-Przytocka
The possibilities and principles of methotrexate treatment of psoriasis – the updated knowledge
Postepy Dermatol Alergol, 31 (2014), pp. 392-400
H.H. Roenigk Jr.,R. Auerbach,H. Maibach,G. Weinstein,M. Lebwohl
Methotrexate in psoriasis: consensus conference
J Am Acad Dermatol, 38 (1998), pp. 478-485
G.D. Weinstein,P. Frost
Methotrexate for psoriasis. A new therapeutic schedule
Arch Dermatol, 103 (1971), pp. 33-38
M. Hoekstra,C. Haagsma,C. Neef,J. Proost,A. Knuif,M. van de Laar
Splitting high-dose oral methotrexate improves bioavailability: a pharmacokinetic study in patients with rheumatoid arthritis
J Rheumatol, 33 (2006), pp. 481-485

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Actas Dermosifiliogr 2017;108:603-4 - Vol. 108 Num.6 DOI: 10.1016/j.adengl.2016.12.024