乌鸦传媒

LAS VEGAS -- Injectable biologic therapies may have reshaped the therapeutic landscape in psoriasis, yet oral drugs -- old and new -- continue to have a major role in clinical management, a psoriasis researcher and clinician said here.

Older drugs, such as methotrexate, cyclosporine, and acitretin, still have important clinical niches. The newer agent apremilast (Otezla) has FDA approval for both psoriasis and psoriatic arthritis. Janus kinase (JAK) inhibitors are an emerging option for multiple dermatologic conditions, and investigational inhibitors of tyrosine kinase 2 (TYK2) signaling have shown promise in early clinical trials.

"So how do we sum up what we have for oral therapy?" asked Boni E. Elewski, MD, of the University of Alabama at Birmingham, at the . "We started out with methotrexate, which we're comfortable with. Cyclosporine, we might not be as comfortable with it, but it works when you have a patient in psoriatic crisis. Acitretin, for my palmar-plantar patients, my patients with pustular psoriasis."

Apremilast, an older drug by today's standards, is a good option for patients who cannot receive or do not want other forms of therapy or who want to avoid laboratory monitoring, she continued. JAK inhibitors are "very exciting," particularly the TYK2 inhibitors, which have produced promising results in early clinical trials.

Elewski said JAK inhibitors have support from a growing volume of evidence implicating the proinflammatory JAK/STAT signaling pathway in , including atopic dermatitis, alopecia areata, psoriasis, psoriatic arthritis, and vitiligo. Clinical experience with tofacitinib (Xeljanz), the first approved JAK inhibitor, illustrates the potential versatility of the drug class, as it is approved for use in rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.

JAK/Stat Inhibition

Results of provided evidence of tofacitinib efficacy in chronic plaque psoriasis. From 40%-60% of patients treated with either of two doses of the JAK inhibitor had a 75% clearance rate (PASI-75) at 16 weeks. The drug was generally well tolerated and associated with few discontinuations involving adverse events.

A recent placebo-controlled trial showed that tofacitinib significantly improved at 16 weeks (50% improvement in about 40% of patients). The number of patients with improvement continued to increase until week 28, and at 52 weeks half of the patients had at least 50% improvement from baseline.

The search for more effective ways to block JAK/Stat signaling led to TYK2 inhibitors, several of which are in development. TYK2 signaling pathways include interleukin (IL)-12 and IL-23 -- the same cytokines targeted by ustekinumab (Stelara) -- as well as type I interferons. In a recent phase II placebo-controlled trial, patients assigned to the TYK2 inhibitor BMS-986165 had 75% clearance (PASI 75) rates at 12 weeks ranging as high as 75% across five different dose groups. PASI 90 rates exceeded 40% in patients treated with the three highest doses of the drug.

BMS-986165 was well tolerated, said Elewski. The most common adverse events (≥2) were nasopharyngitis, headache, diarrhea, upper respiratory tract infection, and nausea, none of which occurred in as many as 10% of patients.

Older Options Still Viable

At the opposite end of the chronological spectrum, decades-old methotrexate remains a reliable treatment for psoriasis. A huge volume of evidence documented that the antifolate is effective in a majority of patients and generally well tolerated.

"You know its warts," said Elewski. "It has liver issues and you can't give it in renal impairment, hepatitis, alcohol abuse, pregnancy, bone marrow issues, as well as drug interactions and pneumonitis. Other than that, it's a great drug."

Methotrexate earned its clinical regard during an era with fewer effective options for psoriasis and a different perspective on psoriasis severity. Authors of a from a consensus conference said methotrexate was for patients with moderate to severe psoriasis, which they defined as ≥20% body surface area (BSA) involvement. With the introduction of biologic agents a few years later, the definition of moderate to severe psoriasis had transitioned to BSA ≥10%, Elewski noted.

Cyclosporine received a psoriasis indication from the FDA in 1997. The immunosuppressant has a rapid onset of action and has earned a clinical niche as a bridge to other therapy and as a short-term intervention for recalcitrant severe psoriasis, flares, and erythroderma, said Elewski. Nephrotoxicity and hypertension are the most common side effects, requiring regular monitoring of renal function and blood pressure during treatment.

Participants in a convened by the National Psoriasis Foundation concluded that cyclosporine is safe and effective, best used in the clinical situations described by Elewski, and requires appropriate patient selection and monitoring for side effects.

Also approved for psoriasis in 1997, the vitamin A derivative acitretin remains an option for selected patients with psoriasis, particularly in combination with phototherapy, said Elewski. The drug may be useful for patients with palmoplantar, erythrodermic, or pustular psoriasis.

Acitretin is not immunosuppressive, making it an option for patients with immunosuppressive conditions or who are at risk of immunosuppression. But the drug is teratogenic, making it contraindicated for women of childbearing potential when used within 3 years of pregnancy, as well as women who are breastfeeding.

Fast forward almost two decades to 2014, when the FDA approved the PDE-4 inhibitor apremilast for both psoriatic arthritis and plaque psoriasis, the first small-molecule oral inhibitor in the therapeutic category. The drug has proven to be particularly useful in patients who have nail psoriasis, which affects about 20% of patients with psoriasis.

"Apremilast does not require any laboratory monitoring, so it's a consideration for patients who don't want to deal with that," said Elewski.

Comment