The realization of the critical importance of the IL-17 and 23 pathways have led to the development of numerous therapies that target parts of the immune system.
Continued research and development in psoriasis has led to a translational revolution - the lessons from which can now 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, due to the years-long work on psoriasis, the future is bright for patients with inflammatory skin diseases.
Atopic dermatitis and psoriasis are 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, have benefitted 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,” says Mark Lebwohl M.D., FAAD, Sol and Clara Kest professor and chairman of the department of dermatology at Mount Sinai School of Medicine, New York, New York.
Cyclosporine worked well but it basically knocked out the whole immune system, Dr. Lebwohl says, making patients more susceptible to cancers, opportunistic infections, as well as a host of other side effects. Current advanced treatment approaches include 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 immune system as a whole.
“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 says.
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 IL-23 pathways that led to the development of numerous therapies that target and block only a very small part of the immune system, Dr. Lebwhohl says. And this has resulted in extraordinary clinical outcomes with very few side effects.
“IL-12 has once been likened to the master switch of psoriasis. Today, we know 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 says.
As the only biologic currently approved by the U.S. Food and Drug Administration for atopic dermatitis, dupilumab (Dupixent, Sanofi Regeneron Pharmaceuticals) is the first and only IL-4 and IL -13 antibody used for patients with atopic dermatitis. Early results show that it can achieve dramatic clinical outcomes at the lowest dose. Following the success with dupilumab, a host of other biologic agents including tralokinumab (Leo Pharma) and lebrikizumab (Dermira) were developed to target IL-13, and are achieving positive clinical outcomes in trials with minimal side effects.
The role of IL-31 has also been well established in patients with pruritus and atopic dermatitis. Levels of IL-31 are elevated in atopic dermatitis and correlate with disease severity.
Other promising systemic agents for the treatment of atopic dermatitis are those that target this pathway, according to Dr. Lebwohl, including nemolizumab (Galderma), several JAK inhibitors: baricitinib (Olumiant, Eli Lilly), upadacitinib (ABT-494, AbbVie Inc.), Pfizer’s PF04965842, and 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 results in preliminary clinical trials, particularly in the reduction of pruritus.
The topical JAK inhibitor crisaborole (Eucrisa, Pfizer) is the first phosphodiesterase 4 (PDE4) inhibitor on the market that has demonstrated efficacy in controlling inflammation in atopic skin, according to Dr. Lebwohl.
“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,” Dr. Lebwohl says. “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 reports associations with the following companies: 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).