WASHINGTON – Multiple biologic failure in a minority of patients with psoriasis may have several causes, from genetic endotypes and immunologic factors to lower serum drug levels, the presence of anti-drug antibody levels, female sex, and certain comorbidities, Wilson Liao, MD, said at the annual research symposium of the National Psoriasis Foundation.
“Tough-to-treat psoriasis remains a challenge despite newer therapies ... Why do we still have this sub-population of patients who seem to be refractory?” said Dr. Liao, professor and associate vice chair of research in the department of dermatology at the University of California, San Francisco, who coauthored a 2015-2022 prospective cohort analysis that documented about 6% of patients failing two or more biologic agents of different mechanistic classes.
“These patients are really suffering,” he said. “We need to have better guidelines and treatment algorithms for these patients.”
A significant number of patients with psoriatic arthritis (PsA), meanwhile, are inadequate responders to tumor necrosis factor (TNF) inhibition, Christopher T. Ritchlin, MD, PhD, professor of medicine in the division of allergy/immunology and rheumatology and the Center of Musculoskeletal Research at the University of Rochester (N.Y.), said during another session at the meeting.
The long-term “persistence,” or usage, of first-line biologics in patients with PsA – and of second-line biologics in patients who failed one TNF-inhibitor – is low, but the literature offers little information on the reasons for TNF-inhibitor discontinuation, said Dr. Ritchlin, who coauthored a perspective piece in Arthritis & Rheumatology on managing the patient with PsA who fails one TNF inhibitor.
Dr. Ritchlin and his coauthors were asked to provide evidence-informed advice and algorithms, but the task was difficult. “It’s hard to know what to recommend for the next step if we don’t know why patients failed the first,” he said. “The point is, we need more data. [Clinical trials] are not recording the kind of information we need.”
Anti-drug antibodies, genetics, other factors in psoriasis
Research shows that in large cohorts, “all the biologics do seem to lose efficacy over time,” said Dr. Liao, who directs the UCSF Psoriasis and Skin Treatment Center. “Some are better than others, but we do see a loss of effectiveness over time.”
A cohort study published in 2022 in JAMA Dermatology, for instance, documented declining “drug survival” associated with ineffectiveness during 2 years of treatment for each of five biologics studied (adalimumab [Humira], ustekinumab [Stelara], secukinumab [Cosentyx], guselkumab [Tremfya], and ixekizumab [Taltz]).
“There have been a number of theories put forward” as to why that’s the case, including lower serum drug levels, “which of course can be related to anti-drug antibody production,” he said.
He pointed to two studies of ustekinumab: One prospective observational cohort study that reported an association of lower early drug levels of the IL-12/23 receptor antagonist with lower Psoriasis Area and Severity Index (PASI) scores, and another observational study that documented an association between anti-drug antibody positivity with lower ustekinumab levels and impaired clinical response.
“We also now know ... that there are genetic endotypes in psoriasis, and that patients who are [HLA-C*06:02]-positive tend to respond a little better to drugs like ustekinumab, and those who are [HLA-C*06:02]-negative tend to do a little better with the TNF inhibitors,” Dr. Liao said. The human leukocyte antigen (HLA) allele HLA-C*06:02 is associated with susceptibility to psoriasis.
In a study using a national psoriasis registry, HLA-C*06:02-negative patients were 3 times more likely to achieve PASI90 status in response to adalimumab, a TNF-alpha inhibitor, than with ustekinumab treatment. And in a meta-analysis covering eight studies with more than 1,000 patients with psoriasis, the median PASI75 response rate after 6 months of ustekinumab therapy was 92% in the HLA-C*06:02-positive group and 67% in HLA-C*06:02-negative patients.
The recently published cohort study showing a 6% rate of multiple biologic failure evaluated patients in the multicenter CorEvitas Psoriasis Registry who initiated their first biologic between 2015 and 2020 and were followed for 2 or more years. Investigators looked for sociodemographic and clinical differences between the patients who continued use of their first biologic for at least 2 years (“good response”), and those who discontinued two or more biologics of different classes, each used for at least 90 days, because of inadequate efficacy.
Of 1,039 evaluated patients, 490 (47.2%) had good clinical response to their first biologic and 65 (6.3%) had multiple biologic failure. All biologic classes were represented among those who failed multiple biologics. The first and second biologic classes used were attempted for a mean duration of 10 months – “an adequate trial” of each, Dr. Liao said.
In multivariable regression analysis, six variables were significantly associated with multiple biologic failure: female sex at birth, shorter disease duration, earlier year of biologic initiation, prior nonbiologic systemic therapy, having Medicaid insurance, and a history of hyperlipidemia. The latter is “interesting because other studies have shown that metabolic syndrome, of which hyperlipidemia is a component, can also relate to poor response to biologics,” Dr. Liao said.
The most common sequences of first-to-second biologics among those with multiple biologic failure were TNF inhibitor to IL-17 inhibitor (30.8%); IL-12/23 inhibitor to IL-17 inhibitor (21.5%); TNF inhibitor to IL-12/23 inhibitor (12.3%); and IL-17 inhibitor to IL-23 inhibitor (10.8%).
The vast majority of patients failed more than two biologics, however, and “more than 20% had five or more biologics tried over a relatively short period,” Dr. Liao said.