EXPERT ANALYSIS FROM THE SDEF HAWAII DERMATOLOGY SEMINAR

WAILEA, HAWAII (FRONTLINE MEDICAL NEWS) – In an era when affordable health insurance could become increasingly tough to come by, it’s worth emphasizing that methotrexate is the most cost-effective way to manage extensive psoriasis – and the liquid formulation designed for intramuscular injection can be taken orally to reduce the cost even further, according to Craig L. Leonardi, MD.

“The absolute cheapest way to manage the patient who has no insurance and has bad psoriasis is to put him on methotrexate and teach him how to draw the liquid solution up in a syringe, dump it in a cup of juice, and drink it,” Dr. Leonardi said at the Hawaii Dermatology Seminar provided by the Global Academy for Medical Education/Skin Disease Research Foundation. “The bioavailability is equivalent to [that of] the tablets, and it’s only about one-tenth the cost.”

He urged his fellow dermatologists not to forget about methotrexate in the current flashy era of highly effective – and very expensive – biologic therapies for psoriasis.

“I was thinking methotrexate was going to go away, but it turns out I rely more on that drug than ever before. It’s very useful, and it’s safe if used correctly,” said Dr. Leonardi , a dermatologist at Saint Louis University and a prominent clinical trialist.

He highlighted numerous clinical scenarios in which methotrexate remains a valuable treatment in patients with moderate to severe psoriasis. He also touched on patient monitoring requirements, adverse events, and common reasons he receives referrals from physicians whose patients seem to be having problems on methotrexate – referrals that, in most cases, could be avoided, he said, if the referring physician had a fuller understanding of the drug.

“Patients are referred to me all the time for methotrexate intolerance,” Dr. Leonardi said. “When you take methotrexate, you get a brief, dramatic spike in transaminase levels that peaks within a day and then drops off. But, when you get lab tests in these patients, you want to look at trough levels. You want to see the best liver function test values for the week.

“That means you have to tell the patient what day to take the drug and what day to get labs drawn,” he continued. “I’m here to tell you that the vast majority of issues that I see where patients have elevated liver function tests involves them getting their testing done in the first 4 days after taking methotrexate. Take the time to ask about this, and I think you’ll be pleasantly surprised.

“If you just make an adjustment and get them on the right schedule, you’ll discover that the patient is tolerating the drug just fine,” Dr. Leonardi added. “We like getting labs on Monday and dosing on Tuesday.”

Methotrexate’s half-life is 3-15 hours. Psoriasis is often controlled at a methotrexate dose of about 15 mg/week.

Methotrexate’s advantages include ease of use. It’s a straightforward matter to start and stop the drug and to make small dose adjustments. Methotrexate comes in a variety of formulations: the 2.5-mg tablets, the 25 mg/mL solution for IM injection, and prefilled autoinjector devices for subcutaneous administration.

These preloaded pens for subcutaneous injection are just as effective as IM therapy, Dr. Leonardi said. Methotrexate is also better absorbed subcutaneously than it is orally. The bioavailability of oral methotrexate plateaus at a dose of about 22 mg/week, while subcutaneously delivered methotrexate does not. So, if a patient’s psoriasis isn’t adequately controlled on higher-dose oral therapy, it’s worth considering a switch to the preloaded pens.

“It’s a very simple injection, very cost-effective, and your patients may get more bang for the buck by doing that,” according to the dermatologist.

Also, nausea, vomiting, diarrhea, and abdominal pain have been shown to be significantly less frequent and intense with subcutaneous methotrexate than with the tablets. So, if a patient is experiencing limiting gastrointestinal issues on methotrexate tablets, a shift to subcutaneous therapy is often the solution.

What kind of efficacy can physicians expect with methotrexate monotherapy?

Dr. Leonardi cited the results of the European randomized, open-label RESTORE-1 trial ( Br J Dermatol. 2011 Nov;165[5]:1109-17 ) as being consistent with his own extensive clinical experience: a week-16 PASI (Psoriasis Area and Severity Index ) 75 response rate of 42% with methotrexate, compared with 78% for infliximab (Remicade).

Of course, some patients can’t receive a biologic agent because of their age, lack of insurance coverage, or medical contraindications.

“I use methotrexate a lot in Medicare patients, where, with Part D, it’s hard to get access to biologics without really good coinsurance. I think all of us who prescribe biologics understand that,” he observed.

In pediatric patients with extensive psoriasis, he turns to methotrexate as first-line systemic therapy. After 3 months, if the young patient hasn’t responded satisfactorily, Dr. Leonardi asks the insurance company for access to a biologic agent and usually gets it.

Methotrexate really shines in combination with a biologic agent. It inhibits formation of antibiologic antibodies, an important cause of loss of effectiveness of monoclonal antibody therapy.

In one study, 28% of patients on adalimumab (Humira) developed antiadalimumab antibodies during the first 3 years of therapy. These patients were more likely to drop out of therapy for lack of effectiveness.

A key finding in this study was that two-thirds of patients who developed antiadalimumab antibodies did so during the first 28 weeks of therapy ( JAMA. 2011 Apr 13;305[14]:1460-8 ). This time line has influenced Dr. Leonardi’s own clinical practice. He routinely keeps patients on methotrexate for their first 28-36 weeks on a biologic, then tapers the methotrexate in favor of biologic monotherapy.

Other benefits and guidelines

Methotrexate is also a boon in managing psoriasis flares in patients on a biologic.

“We’ve all had patients who are doing well on a biologic, they’re cruising along at 140 weeks, then they get strep throat or another infection, and, next thing you know, you have destabilized psoriasis,” Dr. Leonardi noted.

“One thing I’ll do is add methotrexate to the mix, try to get things under control, and, if we do, then we’ll try to taper the methotrexate,” he continued. “That whole episode might take 4-6 months to resolve before the patient might be able to tolerate biologic monotherapy, though. If they can’t at that point, you might consider rotating to another biologic.”

Current American Academy of Dermatology guidelines recommend that women on methotrexate limit their alcohol intake to one drink per day, two drinks for men. British Society for Rheumatology guidelines recommend a ceiling of 32 g to 64 g of ethanol per week.

“We don’t insist on abstinence. There’s no good evidence that it’s needed,” Dr. Leonardi noted. “If you dose this drug on Tuesday, you can be sure that it’s eliminated from the body on Friday, and that’s when I’ll generally green-light patients to socialize over the weekend. If you can make life a little more tolerable for your patients and they’re willing to follow your instructions, I think it’s a better deal all the way around.”

Prior to initiating methotrexate, he obtains a CBC with platelet count, liver function tests, serum urea nitrogen, creatinine, and screens for latent tuberculosis. In terms of on-treatment monitoring, he gets a CBC and liver function tests every 4-12 weeks and keeps an eye on renal function, especially in older patients, because methotrexate is eliminated renally.

“The guidelines have relaxed regarding the need for liver biopsies,” Dr. Leonardi said. “Most of us are not getting liver biopsies anymore, as is true of our friends in rheumatology.”

He reported having financial relationships with more than a dozen pharmaceutical companies. The SDEF and this news organization are owned by the same parent company.

bjancin@frontlinemedcom.com

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