Optimizing the treatment of psoriasis with methotrexate; after 40 years the first dose-finding study.

Patients with moderate to severe chronic plaque type psoriasis may fail to
respond to treatment with topical and photo(chemo)therapy. The next step in the
therapeutic strategy is systemic therapy, with low-dose MTX often being the
first choice. MTX has been widely used and prescribed as a systemic treatment
for psoriasis since Gubner in 1951 first described the efficacy of folic acid
antagonists in psoriasis. It was approved by the Food and Drug Association
(FDA) for the treatment of psoriasis in 1971. Besides psoriasis there are many
other inflammatory conditions (besides label use also off-label use) in which
MTX therapy is indicated. An example is rheumatoid arthritis for label use.
Crohn`s disease and atopic dermatitis are off-label indications. Despite the
clinical value, MTX has some potentially serious side effects, such as
myelosuppression, pneumonitis and gastro- intestinal tract disorders with the
most prominent long term side effect being hepatotoxicity. In clinical practice
there is a high variety in the dosage regimen of MTX. Reviews, guidelines and
expert meetings over and over underline this gap in evidence. When treatment
with MTX is not sufficient any more, biologics are often the next option in the
treatment spectrum. However, the cost these medicines implicate creates a next
problem in financing health care and optimizing treatment with MTX might
prevent having to use biologics and in this way lower the always rising
expenses.
Taken together all the arguments mentioned above, a well performed phase IIA
(dose finding) study has to be performed. Therefore we propose a study to
determine the optimal dose of MTX with maximal clinical improvement (measured
with e.g. PASI) and the least side-effects (monitored by standard
questionnaires and blood sampling). Besides the initial dose an
increasing/decreasing regimen will be investigated.

Our aim is to optimize treatment for patients with moderate to severe psoriasis
by creating evidence for the optimal dose of MTX (on short- and long-term) with
the largest disease reduction and the least side effects.

We propose a single-blinded (outcome assessor and concealment of allocation),
randomized, clinical trial in which a total of 80 patients will be included in
2 different groups (see 5.4 in protocol: sample size calculation). Both groups
will start with a single test dose of 5 mg to detect idiosyncrasy. One group
will start with 7.5 mg MTX once a week, the other with 15 mg MTX once a week.
Doses will be increased or decreased based upon clinical improvement, with a
maximum of 25 mg once a week (see Table 1 below). Both groups will be treated
concomitantly with 5 mg of folic acid once a week, the day after MTX
administration, to prevent side effects. Patients will be recruited from the
outpatients dermatology clinic from the Academic Medical Center (Amsterdam, the
Netherlands) and the outpatients dermatology clinic from the Radboud hospital
(Nijmegen, the Netherlands), including patients referred from affiliated
outpatient clinics. Affiliated clinics will be contacted to refer suitable
patients for this study. For a detailed description of study population with
in- and exclusion criteria see protocol chapter 5. Written informed consent
should be given. Randomization will be web-based with concealment of
allocation. The trial will be performed in accordance with the ICH GCP
guidelines. We will look at short- and long-term clinical improvement and side
effects. Patients will be monitored for 52 weeks. Primary and secondary outcome
data will be analyzed according to the intention-to-treat principle. Drop-outs
will be handled by the multiple imputation method. Appropriate and non
parametric statistics will be used. In all analyses statistical uncertainties
will be expressed in 95% confidence intervals.

One group will start with 7.5 mg MTX once a week, the other with 15 mg MTX once
a week. Doses will be increased or decreased based upon clinical improvement,
with a maximum of 25 mg once a week. Both groups will be treated concomitantly
with 5 mg of folic acid once a week, the day after MTX administration, to
prevent side effects.

This study does not implicate extra visits or extra blood-sampling for
participating subjects because control will take place according to the
recently published Dutch Guideline Psoriasis (2011). The only extra is the
making of a fibroscan at baseline.