GOTHENBURG, SWEDEN - New evidence identifying the optimal dosing regimen for methotrexate in psoriasis comes from a just-completed year-long randomized clinical trial.

"There's a huge long-standing discussion about which is the best dosing regimen for methotrexate. I think we will be able to give you an answer today," promised Dr. Kristian Reich.

That he did, highlighting the oral methotrexate arm of a new phase-III randomized trial of briakinumab, an investigational, fully human monoclonal antibody–targeting interleukin-12 and interleukin-23, in which the biologic agent was compared to oral methotrexate used in a dosing regimen designed to minimize potential toxicities.

The take-home messages regarding methotrexate from the M10-255 study:

• Nearly 60% of psoriasis patients who are started on methotrexate will discontinue the drug during the first year due to lack of efficacy.

• A starting dose of 15 mg once weekly is well tolerated and effective; in only a small percentage of patients is up-titration beneficial.

• Patients who show a good response to methotrexate 15 mg/week by week 6-8 have a high probability of having a full PASI 75 response after 52 weeks.

• Methotrexate’s safety profile in psoriasis patients is better than it’s often painted, based upon the favorable results of the briakinumab study and phase-III trials of two other biologic agents featuring methotrexate arms.

• The peak response to methotrexate is seen by week 16-20 and thereafter declines steadily.

"I think that for many dermatologists there was a perception that the longer we give methotrexate, the better this drug is going to be. Wrong!" declared Dr. Reich, professor of dermatology at the University of Göttingen, Germany.

Confirmation on this score comes from the methotrexate arm of the phase-III Raptiva (efalizumab) Evaluation of Safety and Treatment Optimization (RESTORE) study. The highest PASI 75 response rate to methotrexate in RESTORE was seen at week 16, when patients were on 15 or 20 mg/week. This was followed by a nearly 12% absolute decline in PASI 75 responders between weeks 16 and 26, he added at the satellite symposium supported by Abbott.

"I think these studies may change the way we view methotrexate," Dr. Reich observed.

The M10-255 trial involved 317 psoriasis patients with a mean baseline PASI score of 18 and a 19-year history of the disease. They were randomized to briakinumab or to oral methotrexate with folic acid on the following schedule: 5 mg of methotrexate on week 1, 10 mg during week 2, 15 mg/week for weeks 3-9, and then an increase to 20 mg/week if a PASI 75 wasn’t achieved on week 10. If a PASI 75 was not reached by week 16, the weekly dose could be further increased to 25 mg.

Of the patients in the methotrexate arm, 72% had discontinued the drug by week 52, with lack of efficacy the reason for 80% of dropouts. Only 6% of subjects discontinued methotrexate due to adverse events.

A PASI 75 efficacy end point was achieved in 40% of patients in the methotrexate arm at 24 weeks and in 24% at week 52.

"In only a low percentage of patients was the week-10 increase to 20 mg/week necessary and helpful to make them achieve a PASI 75 response. And there is no evidence that the further increase to 25 mg is doing any good to the patient," Dr. Reich reported.

This 40% PASI 75 response at week 24 is quite similar to what was seen earlier in the methotrexate arms of the RESTORE and Comparative Study of Humira vs. Methotrexate vs. Placebo in Psoriasis Patients (CHAMPION) trials, which recorded week-16 PASI 75s of 36% and 42%, respectively.

"These three trials used three different methotrexate dosing regimens. Let's get this straight: The methotrexate efficacy was independent of the dosing regimens. No matter if you started with a low dose of 5 mg or with 15 mg straight away, the efficacy was the same. The safety profile of methotrexate was also very similar across these trials," the dermatologist continued.

Dr. Reich said these three trials have changed the way he approaches methotrexate therapy in psoriasis.

"I will no longer use the Weinstein regimen or start with a 5-mg test dose. I think it's fair to say, based on these data, that we can start with 15 mg right away. However, it is now for me absolutely clear that methotrexate is going to produce a good response in 35%-40% of patients, and that's it. And it's not true that the longer we give methotrexate the higher the clinical response will be. We are going to see a decrease, as with every psoriasis drug, beyond week 16-20," according to Dr. Reich.

He disclosed that he has served as a consultant and speaker for and/or participated in clinical trials sponsored by Abbott, which funded the M10-255 trial, as well as Biogen Idec, Bristol-Myers-Squibb, Centocor, Merck Serono, Schering-Plough, UCB Pharma, and Wyeth.

New Evidence Defines Optimal Methotrexate Dosing Regimen in Psoriasis