Psoriasis research advances treatments for inflammatory skin diseases

“It took decades for us to get from relatively primitive treatments of psoriasis to the very advanced perfected treatments that we currently have...The advent of the biologics around the turn of the century has changed the treatment and management of inflammatory skin diseases forever," says Mark Lebwohl M.D., FAAD

The treatment of inflammatory skin diseases of late has been advanced due to a better understanding in the mechanics of the individual disease. Continued research and development of therapeutic avenues for psoriasis has led to a translational revolution, the lessons of which can now also be observed in other common inflammatory diseases such as atopic dermatitis, alopecia areata, vitiligo, hidradenitis suppurativa, acne, and rosacea. According to one expert, the journey has been arduous but the future is bright for patients with inflammatory skin diseases mostly due to the years-long work on psoriasis.

Atopic dermatitis and psoriasis are inflammatory skin diseases characterized by immune-mediated inflammation and abnormal keratinocyte differentiation and although their T-cell infiltration characterizes both diseases, T-cell polarization differs. Because of their similarities, however, the therapeutics for atopic dermatitis in particular has shown to benefit from continued psoriasis research.

“It took decades for us to get from relatively primitive treatments of psoriasis to the very advanced perfected treatments that we currently have available, and we can clear almost everybody with these therapies. The advent of the biologics around the turn of the century has changed the treatment and management of inflammatory skin diseases forever,” said Mark Lebwohl MD, FAAD, Sol and Clara Kest Professor and Chairman of the Department of Dermatology at the Mount Sinai School of Medicine, New York, New York.

Cyclosporine worked well but it basically knocked out the whole immune system, Dr. Lebwohl said, making patients more susceptible to an increase in cancers, opportunistic infections, as well as a host of other side effects. Current advanced treatment approaches include targeted therapies that target individual molecules in the immune system and lead to the clearing of inflammatory skin diseases that are immunologically mediated, without disrupting the whole immune system.

“The first biologics like alefacept were only modestly effective and they targeted the activation of lymphocytes. These agents were designed to target just a tiny fraction of the immune system, which ultimately allowed us to treat psoriasis much more effectively," Dr. Lebwohl said.

The TNF (tumor necrosis factor) blockers also proved to be effective and although TNF is a much smaller target in the immune system compared to what cyclosporine targets, these agents still block a fair amount of the immune system, leading to an increase in opportunistic infections and a slight increase in skin cancers. It was the realization of the critical importance of the IL-17 and 23 pathways, Dr. Lebwohl said, that has led to the development of numerous therapies that specifically target and block only a very small part of the immune system, resulting in extraordinary clinical outcomes with very few side effects.

“IL-12 has once been likened to the master switch of psoriasis. Today, we know now that blocking IL-12 also blocks IL-23. They share p40 a common molecule, and the antibodies to IL-12 are the same ones to IL-23,” Dr. Lebwohl said.

As the only biologic currently FDA-approved for atopic dermatitis, dupilumab (Regeneron Pharmaceuticals) is the first and only IL-4 and IL -13 antibody used for patients with atopic dermatitis, with early results showing that it can achieve dramatic clinical outcomes at the lowest dose. Following the success with dupilumab, a host of other biologic agents including tralokinumab and lebrikizumab were then developed to target IL-13, also achieving positive clinical outcomes with minimal side effects.

The role of IL-31 has also been well established in patients with pruritus and atopic dermatitis, and the levels of IL-31 are elevated in atopic dermatitis and correlate with disease severity. According to Dr. Lebwohl, other promising systemic agents that have recently become available for the treatment of atopic dermatitis are those that target IL-31 including nemolizumab, several JAK inhibitors such as baricitinib (Eli Lilly) and upadacitinib (AbbVie Inc.), JAK inhibitor PF04965842 from Pfizer, as well as the JAK-SYK inhibitor ASN002 from Asana. Developed by Kiniksa Pharmaceuticals Corp., KPL-716 is a fully-human monoclonal antibody that in addition to blocking oncostatin M (OSM) also inhibits IL-31, which according to Dr. Lebwohl has also achieved remarkable clinical results in preliminary clinical trials, particularly in the reduction of pruritus.

Some based on the same concept, a number of topical therapies have also recently become available for atopic dermatitis patients including topical JAK inhibitor ointments such as crisaborole (Pfizer). According to Dr. Lebwohl, crisaborole is the first phosphodiesterase 4 (PDE4) inhibitor on the market that has shown to be very effective in controlling inflammation in atopic skin.     

“After almost a century of relatively primitive treatment options including systemic steroids, cyclosporine and a number of other immunosuppressant drugs all associated with sometimes significant side effects, we now have a whole host of innovative therapies that due to their smaller target can improve the symptoms of atopic dermatitis with minimal side effects. In similar to a growing list of other inflammatory skin diseases, the future is very bright for atopic dermatitis patients, as these new and exciting agents have been shown to help clear patients, particularly when recalcitrant to other tried therapies,” Dr. Lebwohl said.

Disclosures:

AbbVie – I(Grants/Research Funding); Allergan, Inc. – C(H); Almirall – C(H); Amgen – I(Grants/Research Funding); Arcutis, Inc. – C(H); AstraZeneca – I(Grants/Research Funding); Boehringer Ingelheim – C(H), I(Grants/Research Funding); Bristol-Myers Squibb – C(H); Celgene Corporation – I(Grants/Research Funding); Clinuvel – I(Grants/Research Funding); Corrona, Inc. – O(H); Dr. Reddy – C(H); Eli Lilly and Company – I(Grants/Research Funding); Foundation for Research & Education of Dermatology – O(H); Incyte Corporation – I(Grants/Research Funding); Janssen Research & Development, LLC – I(Grants/Research Funding); Kadmon Corporation, LLC – I(Grants/Research Funding); Leo Pharma Inc – C(H); LEO Pharma, US – I(Grants/Research Funding); Medimmune – I(Grants/Research Funding); Menlo Therapeutics – C(H); Mitsibushi Pharma – C(H); Neuroderm LTD – C(H); Novartis Pharmaceuticals Corp. – I(Grants/Research Funding); Ortho Dermatologics – I(Grants/Research Funding); Pfizer Inc. – I(Grants/Research Funding); SCIderm – I(Grants/Research Funding); Theravance Biopharma – C(H); UCB – I(Grants/Research Funding); Verrica Pharmaceuticals Inc – C(H); Vidac Pharma – I(Grants/Research Funding)