Toward More Uniform Methotrexate Dosing in Psoriasis

With overwhelming support from some 200 experts worldwide, dosing of methotrexate (MTX) for psoriasis should start at 15 mg/week for most adults, though lower in those considered

"vulnerable" and in children, according to a new consensus statement.

That may not seem like big news, as it's in line with most dermatologists' and rheumatologists' practice. But in fact, surveys have shown wide variation in physicians' approach to MTX dosing

in psoriasis. The authors of the consensus statement, led by Astrid M. van Huizen, MD, of the University of Amsterdam, noted that some doctors prescribe as little as 5 mg/week or as much as

22 mg/week for initial dosing in adults.

"The variability in treatment regimens might have contributed to suboptimal treatment with MTX or early discontinuation of treatment because of limited efficacy or, in the case of

overtreatment, adverse effects," van Huizen and colleagues wrote in their statement, appearing in JAMA Dermatology.

Consequently, the Skin Inflammation and Psoriasis International Network (SPIN), comprising some 4,500 professionals in the field, asked its members to participate in a series of three

surveys about their beliefs and recommendations for methotrexate dosing. Just over 200 did so for the first round and 180 completed all three; 58 also participated in a consensus meeting

where proposals not achieving consensus through this process were discussed and refined further.

Seven SPIN leaders from Britain and continental Europe formed a working group to identify the main issues around MTX dosing that need standardization. They came up with seven topics -- test

dose, start dose, dosage adjustment, maximum dose, form of administration, switching formulations, and use of folic acid -- with consideration of how they might differ among adults,

"vulnerable patients," and children.

Proposed consensus statements included, for example: "Usually, MTX is administered in a single weekly dose," and "When starting MTX in vulnerable patients, start with a dosage of 7.5-10

mg/wk." In each survey round, participants rated their agreement with the statements on a nine-point scale: 1-3 indicated disagreement, 7-9 reflected agreement, and 4-6 was considered

neither agreeing nor disagreeing. Voters were asked to avoid the middle range whenever possible, as such votes would make it more difficult to achieve consensus.

At each round, participants could also propose their own new or reworded statements. In the end, 21 statements were brought forward to the third round, and 16 achieved what SPIN had defined

as consensus (no more than 15% of voters disagreeing).

Both of the two quoted above were agreed to. Others included: "Folic acid should be supplemented in all patients"; "Usually, MTX is administered orally"; and "In case of inefficacy or

insufficient effect, according to the treatment goals, it is preferred to switch the MTX route of administration from oral to subcutaneous."

Also achieving consensus were the preferred dosage for children ("around 10 mg/m2/wk"), more items on folic acid dosing, and a stipulation that efficacy shouldn't be assessed until patients

have been on the drug "at least 3-4" months.

Five proposals went to the consensus meeting for further discussion and voting, with four gaining consensus there. Two of these stated that test doses aren't needed for vulnerable patients

or children, respectively; one set the maximum weekly MTX dose at 25 mg for vulnerable patients, the same as for other adults; and the fourth called for folic acid to be given once weekly.

The one statement not achieving final consensus was, "The dosage of folic acid should be increased when increasing the dosage of MTX." Fully 93% of meeting participants disagreed with it,

which looks very much like consensus, but under SPIN's rules it had to be considered non-achieved.

This so-called eDelphi procedure had some limitations, van Huizen and colleagues noted. "Most participants were from Europe," the authors wrote, whereas the group had hoped to attract input

more widely. Their definition of consensus was somewhat arbitrary, and the focus on MTX and folic acid dosing meant that some related issues such as safety monitoring went unaddressed.

Perhaps most importantly, the agreed-upon statements are expert opinion, considered the weakest form of evidence for guidelines. SPIN leaders did link the proposals to published reports from

randomized trials, so they were founded to some extent on hard science. Nevertheless, the selections were not necessarily systematic or comprehensive.

John Gever was Managing Editor from 2014 to 2021; he is now a regular contributor.

Many of the roughly 200 authors reported relationships with pharmaceutical companies and other commercial entities.