NEW ORLEANS – Clinically successful biologic therapy for psoriasis reverses roughly 70% of the molecular disease profile, leaving behind more than 1,200 dysregulated genes whose expression is either markedly increased or reduced, compared with nonlesional skin.
"Even highly effective treatments for psoriasis don't restore gene expression to levels seen in control skin biopsies. This suggests the possibility of a 'molecular scar' of psoriasis, even in clinically resolved psoriatic lesions," Dr. James G. Krueger said at the annual meeting of the American Academy of Dermatology.
Dr. James G. Krueger
Many of these residual dysregulated genes are involved in promoting what he called "smoldering inflammation."
"This could be the reason why psoriasis tends to recur in focal clinical regions. It's very common if you have bad plaque psoriasis that it comes back in the same spot after it’s effectively treated," noted Dr. Krueger, professor and head of the laboratory of investigative dermatology at Rockefeller University in New York.
He reported on 85 patients with moderate to severe plaque psoriasis who participated in a larger randomized clinical trial and underwent skin biopsies of lesional and nonlesional skin at baseline and again after 12 weeks of etanercept therapy. Another 85 patients were biopsied before and after 12 weeks on ustekinumab. In all, 21 etanercept-treated patients achieved a PASI 75 score (a 75% improvement over baseline on the Psoriasis Area and Severity Index), as did 19 on ustekinumab. In addition, skin biopsies were obtained from 25 normal, healthy volunteers. The specimens from all subjects were subjected to gene microarray analysis.
In all, 4,175 genes were differentially expressed (that is, either upregulated or downregulated) at baseline in lesional – compared with nonlesional – skin from psoriasis patients. Following 12 weeks of successful biologic therapy in patients who achieved a PASI 75 response, 2,922 of these genes were essentially normalized in lesions that were resolved clinically and histologically on hematoxylin and eosin stain, meaning that the genes' activity improved by at least 75% with treatment.
For the most part, both biologic agents normalized the same dysregulated genes; however, 7.7% of dysregulated genes were uniquely normalized by ustekinumab, and 14.7% were modulated only by etanercept.
Most of the dysregulated genes that were present in lesional skin whose functionality improved after 12 weeks of treatment were involved in keratinization, cyclin production, and formation of structural proteins. They were largely responsible for creating the classic hyperplasia phenotype of psoriasis which melts away both clinically and histologically in biologic therapy responders. But in addition, there was a high rate of improvement in genes that were involved in inflammatory pathways.
The molecular disease remnant that remained unchanged by the two biologics – that is, the 30% of dysregulated genes that were not normalized in response to clinically successful treatment – were to a considerable extent concerned with interferon pathway suppression and other residual inflammatory pathways. A probing of the tissue structure of these clinically resolved psoriatic lesions demonstrated subtle pathology, specifically in the lymphatics, which were "completely collapsed," according to Dr. Krueger.
"The idea that there is altered tissue structure caused by psoriasis perhaps puts it into the same category of scarring diseases as psoriatic arthritis and rheumatoid arthritis in that we don’t have totally benign and reversible disease of the skin," he said.
Further analysis of the molecular disease remnants that are present after clinically successful biologic therapy, and the pathways in which the involved genes lie, may lead to identification of novel therapeutic targets in psoriasis, Dr. Krueger added.
Nonlesional skin of patients with psoriasis contained roughly 2,000 genes that were significantly dysregulated, compared with their activity in normal skin from healthy controls.
Dr. Krueger said that he plans to rebiopsy patients again as they continue on etanercept or ustekinumab.
"It becomes really important to know whether we need to treat this disease for a very long time to maximize benefit," he noted. "With gene microarray analysis, we now have a tool set where we can ask if we can improve treatment ... by starting earlier, treating longer, or using smart combinations of agents."
Dr. Krueger said that this study was supported by Centocor, a company with which he holds an intellectual property arrangement.