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Treatment failure and relapse are common in diseases of chronic inflammation, and psoriasis is no exception.

It is unclear if failure rates are higher in psoriasis than in other immune-mediated conditions such as inflammatory bowel disease (IBD) and rheumatoid arthritis (RA), according to Nicholas D. Brownstone, MD, of Temple University Hospital in Philadelphia. "While psoriasis/IBD/RA are all immune-mediated, they're inherently different disease states, and it's difficult to compare studies because of factors that cannot be accounted for across all disease states, such as high or low rheumatoid factor in RA," he noted.

Goal of Treatment

According to the National Psoriasis Foundation's the aim of successful therapy is a 1% psoriasis-affected body surface area within 3 months of treatment initiation.

"There is some wiggle room such that if you have experienced a significant improvement of 75% or better or are at 3% affected body surface area, a little more time can be taken -- but we have very good treatments nowadays and we really should be able to get the psoriasis to a minimal level on the body," said George Z. Han, MD, PhD, of the Zucker School of Medicine at Hofstra/Northwell in New Hyde Park, New York.

Primary and Secondary Failure

Han makes a distinction between primary and secondary treatment failures, as the reasons can differ significantly. "With a primary treatment failure, we think of certain factors -- such as heavier weight and prior non-response to biologics -- as risk factors for not improving on a biologic within a time frame of 3 to 6 months."

Brownstone noted that "obesity is a pro-inflammatory state and therefore, in theory, obese patients may have a larger burden of inflammation." Furthermore, pharmacokinetic studies have shown that excessive body weight could negatively affect volume of distribution and drug metabolism, challenging a medication's efficacy and leading to a high rate of treatment failure.

"It's good for providers to know that ustekinumab [Stelara], a biologic therapy FDA-approved for both psoriasis and psoriatic arthritis, also has an FDA approval for an increased dose for higher patient weights," Brownstone said.

Secondary non-response is somewhat harder to define, Han noted, as multiple mechanisms may be at play. "Perhaps the easiest mechanism to understand would be the development of anti-drug antibodies, which could, if neutralizing, inactivate the medicine itself. This has been shown to reduce efficacy in clinical practice."

Another possibility is that the psoriasis simply worsens on its own owing to the natural progression of the disease. "A lot of attention has been focused on figuring out why this may be, if perhaps some alternative inflammatory pathways could be activated, enabling the psoriasis to be more active again," Han explained.

Despite these susceptibilities, rates of primary treatment failure are quite low, thanks to modern drugs. "We're talking about PASI [Psoriasis Area and Severity Index]-75 rates, that is, improvement of at least 75% from baseline, in 90% or more of patients, with a mean improvement in the 95% range," Han said. "However, this does mean that a small percentage of patients -- roughly 10% -- don't get a great response, so there is still some work to be done."

Han added that in real life, the so-called drug survival rates for patients on medications out to longer time points can be quite disappointing, with rates of drug survival going below 50% at 2 years for some drugs. "This may be due to various reasons, not all efficacy-related, such as a change in insurance, patients moving to other areas, and the such," he said. "But there is still work to be done in making sure our patients get on good medicines that work for the long term."

After an initial response, how long does it typically take for vulnerable patients to stop responding?

"I've had patients respond well, then relapse in 6 to 12 months, but this is the exception rather than the rule," Han said. "If a patient is able to stay on the medication -- that is, if you look at long-term 5-year efficacy data -- these medicines have maintenance of efficacy rates in the 90% range."

He cautioned, however, that this is generally reported as observed data, so patients who stop the medicine are not counted. "Which is why real-world evidence of patients stopping medicine 1 to 2 years after starting is important to consider," he said.

Predictors of Refractory Patients

Two of the main predictors are failure of a previous biologic and heavier weight. "I have patients who have been on up to nine different biologics," Han said. "Our study findings are that female patients, shorter duration of psoriasis, prior systemic therapy use, and history of hyperlipidemia were all factors influencing multi-biologic failure."

found that other risk factors such as acne, inverse psoriasis initially in the gluteal cleft, and erythrodermic psoriasis were associated with the need to use three or more biologics. "This is an area of active study and one that we certainly need more information on because as effective as our treatments are overall, there are still patients in need of better or different therapies," Han said.

identified female sex, shorter psoriasis duration, earlier year of biologic initiation, previous non-biologic systemic therapy, history of hyperlipidemia, and Medicaid insurance as being significantly associated with multiple biologic failure.

According to Brownstone, however, there is no convincing evidence that female sex is a risk factor for treatment failure, and real-world response to biologics was equal in both sexes in the .

But, Han countered, despite being more responsive to systemic treatments in general, women have been shown to experience more side effects from systemic treatment and to be more likely to discontinue treatment. "However, it's hard to say whether other factors -- such as a propensity to having other autoimmune diseases, for example -- play a role as well," he said.

In some studies, older age was associated with a higher likelihood of having tried multiple biologics, but since the ages of psoriasis onset were similar, older persons may simply have had more time to fail different types, Han said. "Generally speaking, I try to aim for fewer immunosuppressive medications in an older patient, whose immune system is likely less active to begin with. That does have an impact on my treatment selection; for example, avoiding tumor necrosis factor-alpha inhibitors in favor of interleukin [IL]-17 or -23 inhibitors in an older patient."

Overcoming Failure

Patients who fail multiple systemic medications ultimately find disease control from a trial-and-error approach involving switching to a different class. "And some treatment-resistant patients can get control of their disease by using both a biologic agent and systemic oral agent concurrently, at least in the short term to control flares of disease," said Brownstone.

Personalized medicine will likely play a large role in the future by reducing the amount of drug switching and identifying which cytokines are upregulated in a specific patient's psoriasis pathway.

So what is the most effective paradigm for combatting lapsed or non-response?

"First, it's important to have an honest conversation about compliance," said Han, since national prescription-fill databases indicate poor rates of filling biologics, with about half of patients filling prescriptions less frequently than the dosing regimen requires.

If the patient is being compliant, then the next step is to take a look at the characteristics of the response -- is it an overall lack of benefit? Is it only in one area?

"We do have some data on so-called special sites now, so if the patient has recalcitrant inverse psoriasis or scalp psoriasis, for example, we might choose medicines with better data in those areas," Han said. A non-biologic medicine such as methotrexate, acitretin (Soriatane), apremilast (Otezla), or deucravacitinib (Sotyktu) could then be added.

When switching biologics, it pays to think mechanistically, Han added. For example, one IL-17 inhibitor, the antibody brodalumab (Siliq) targets the receptor rather than the circulating antibody, while the antibody bimekizumab (Bimzelx) blocks IL-17A and F.

"These two medications, especially bimekizumab, have some of the highest response rates of any biologic out there, so from a pure efficacy standpoint, they could work well," Han said. "Also, thinking about the potential of a medication covering pathways that may be missed by the original medicine, these agents also make sense."

"We often see refractory cases in our practices, and there isn't yet great guidance on what to switch to," Han continued. "From my own experience and listening to the opinions of my peers, we've kind of established a general rule that if a patient has a secondary failure -- that is, responded, then lost response -- you can stay in the same class and try a different medicine targeting the same pathway, because ostensibly there was some good rationale to use the first medicine."

That scenario would imply a therapeutic failure of the particular drug, rather than a mechanistic failure of the class. "However, with primary failures where the patient never responds appropriately, you might be better off changing classes," he said. "Keep in mind that, again, the medicines that have a more complete blockade of multiple pathways in psoriasis are probably brodalumab and bimekizumab."

Both Han and Brownstone agree that insurance coverage can be an issue.

The Future

"Treatment failure will always be something we deal with to some degree until we have a cure for psoriasis, but there's a lot of development in the small-molecule world in psoriasis, including peptide drugs that in essence split the difference between a biologic and traditional small molecule," said Han. "We're excited about these medicines, as they give our patients new choices -- and keep in mind, you can't develop antibodies against small molecules as you can with biologics -- but they still work on essentially the same pathways we've identified in psoriasis, so it's not totally uncharted territory."

He pointed to newer induction studies, for example, with and , focused on giving newly diagnosed patients a higher dose of biologic to shut off the inflammatory pathway.

"Even with effective biologics, there's a subset of memory T cells that reside in the skin, such that when the treatment is stopped, the psoriasis comes back in the same place," Han explained. "There is a possibility that treating psoriasis quickly and with a very effective medication can shut down the generation of these residual inflammatory cells."

He added that much work is underway to identify the first steps to psoriasis in a patient with a genetic predisposition. "Understanding these pathways better could also help find new targets to go after in search of a cure," he said.

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