In 2002, the FDA approved etanercept (Enbrel) for the treatment of psoriatic arthritis. The next year, alefacept (Amevive) and efalizumab (Raptiva) were approved for plaque psoriasis, followed by etanercept in 2006 and adalimumab (Humira) in 2008.
The completion of my dermatology residency at Emory University in 2002 coincided with the introduction of these drugs. Emory’s department of dermatology clinical trials unit was involved in treating patients with these early biologics, so we had a small glimpse at what they could do. However, most of us were unaware that we were witnessing a revolution in the treatment of inflammatory skin disease.
Dermatologists who had finished training before us had no experience with these medications. The pharmaceutical-sponsored drug talks were standing room only when the clinical researchers came to present their findings. These men and women, generally more comfortable in labs and lecture halls, were suddenly rock stars. Patients with these diseases became highlights of our day rather than dreaded appointments in which we would have to admit that treatment for their disease carried significant risks with little hope of dramatic or sustainable improvement.
Now, 20 years later, dermatologists have 11 FDA-approved biologic treatments for plaque psoriasis, one biologic each for atopic dermatitis, hidradenitis suppurativa, chronic idiopathic urticaria and pemphigus vulgaris. Dozens more are in clinical development. We have progressed from measuring plaque psoriasis based on 50% improvement to realistically expecting 90%-100% clearance of disease.
These medications, unlike prior treatments, target specific components of the immune system and have a favorable safety profile, without evidence of end organ damage. We no longer have to monitor kidney or liver function in these patients, many of whom have comorbidities that put them at increased risk of liver, kidney and cardiac disease.
Despite these welcome and dramatic advances, the biologic revolution in dermatology is incomplete. We still have many inflammatory diseases that have no targeted treatment. Though the existing biologics are highly efficacious, they do not generally lead to a cure of disease. They carry a high price tag, and, since they are proteins, they must be administered by injection or intravenously.
The first biologics were likely developed for psoriasis based on two principles: its prevalence and the serendipitous observation that patients on these medications who had psoriasis saw their skin disease improve. For business reasons, pharmaceutical companies prefer to develop drugs for common and lifelong diseases rather than short or curable problems.
Psoriasis is estimated to affect 3% of Americans; up to a third of those patients have moderate to severe psoriasis, eligible for treatment with biologics. All currently available biologics for psoriasis are specifically designed for patients with at least 10% body surface area psoriasis that is determined to be a 3 or 4 in severity on a scale of 0-4.
Studies have shown specific efficacy for certain types of psoriasis, for example psoriasis on the scalp, hands and feet, and genitals. Prior to the introduction of biologics, when the mainstays of treatment for psoriasis were ultraviolet therapy, methotrexate, acitretin and cyclosporine, patients with low disease burden were generally not considered candidates for systemic therapy. The risks were judged to outweigh the benefits.
In the last 20 years, however, as patients have advocated for themselves and patient organizations like the National Psoriasis Foundation have shown that even small disease burdens can dramatically impact patients’ quality of life, treatment of psoriasis, especially with biologics, has extended beyond the original 10% body surface area criteria.
At this time, there are four categories of biologics for psoriasis: those targeting tumor necrosis factor alpha (adalimumab, etanercept, certolizumab, infliximab), those targeting interleukins 12 and 23 (ustekinumab), targeting interleukin 17 (brodalumab, ixekizumab, secukinumab) and targeting interleukin 23 alone (guselkumab, risankizumab, tildrakizumab). Many, but not all, of these medications are also approved for psoriatic arthritis.
These drugs have specific advantages and disadvantages relative to each other. While anti-TNF agents have been on the market the longest and have great efficacy in both psoriasis and psoriatic arthritis, they have black box warnings for infections, including tuberculosis and fungal infections, and can exacerbate heart failure and multiple sclerosis. IL-17 inhibitors are similarly highly effective for both psoriasis and psoriatic arthritis but have a safety signal in regard to increased risk of candidiasis and rare cases of new onset inflammatory bowel disease, while IL-23 inhibitors are not approved for psoriatic arthritis. None of these medications are intended to induce remission or cure of disease, and all biologics carry, to varying extents, the risk of loss of response, particularly if there is interruption of treatment. New biologics, both within these categories and inhibitors of novel interleukins, are in development, including a monoclonal antibody to interleukin 36 intended for use in generalized and localized pustular psoriasis.
Thus far all biologics for psoriasis have the same basic design – they identify a protein that is elevated in the disease state and lower it. Newer approaches, however, may focus on normalizing the inflammatory state by activating regulatory cytokines or being used in sequence. The long-term goal of biologics in psoriasis should focus not only on remission and cure but prevention of comorbid diseases, including not only psoriatic arthritis but the well-established risks of heart disease, stroke, malignancy, inflammatory bowel disease and liver and renal dysfunction. Biologics have driven home the fact that psoriasis is more than a skin disease.
The approval of dupilumab (Dupixent) for adult and adolescent moderate to severe atopic dermatitis in 2017 and 2019 has radically changed the treatment of this terrible disease that affects both children and adults. At my research center, where we have done countless psoriasis trials, the adolescent atopic dermatitis trial was much more likely to bring tears to our eyes.
These children were teased, often to the point of choosing to be home-schooled. They had recurrent hospitalizations for staph infections; they scratched themselves until they bled and could not concentrate on tests or homework. As with psoriasis, before dupilumab was approved our treatment options were limited to light therapy and broad immunosuppression with risks of end organ toxicity. The FDA gave expedited status to dupilumab in recognition of the disease burden on these patients. The trials for children ages 6-11 have been completed, and approval from the FDA is pending.
Hidradenitis suppurativa (HS) remains a challenge to treat. Thankfully, Martin Okun, MD, at biopharmaceutical company AbbVie pushed for a clinical trial to evaluate the efficacy of adalimumab in this heart-breaking disease. Doctors had observed that some patients with inflammatory bowel disease who also had hidradenitis saw both diseases improve with use of adalimumab.
However, prior to FDA approval, it was difficult to impossible to use adalimumab in HS patients since insurance companies could point to lack of randomized controlled trial evidence to deny use of the medication. In fact, the clinical trial showed that those who used it at its FDA-approved psoriasis and Crohn’s dose schedule of every other week were undertreating patients, emphasizing the need for good clinical trial data rather than observational data.
Hidradenitis is particularly devastating because it starts in adolescence and young adulthood, involves the genitals, buttocks and axillae, often leads to potentially disabling scarring and is associated with foul odor and drainage. Just when a young man or woman is about to embark on romantic relationships, he or she develops a disease that is visible and profoundly embarrassing.
Other TNF-alpha inhibitors had shown similar efficacy, but the companies declined to pursue clinical trials, likely for economic reasons and expiring patents. Having an FDA-approved treatment for a disease that favors women, African Americans and young people has increased awareness of this tragic disease and increased patient and physician advocacy. The prevalence, moreover, appears to have been underestimated, and at the present time there are almost 10 ongoing biologic trials for the treatment of HS, including three at my clinical trial site.
The treatment for chronic urticaria was limited to antihistamines, anecdotal treatments such as dapsone or colchicine, and immunosuppression. With the approval in 2014 of omalizumab for chronic idiopathic urticaria, the use of cyclosporine – with its risks of kidney damage, hypertension and infection – has become rare.
In residency, I was called in the middle of the night about a young woman who became septic while receiving plasmapheresis for pemphigus vulgaris. Pemphigus used to carry a high disease mortality and morbidity, with patients dying from sepsis through their compromised skin barrier. Covered in blisters, with denuded skin, they were miserable. The approval of rituximab, a monoclonal antibody to CD19, for pemphigus, has transformed our treatment of this disease. Patients are rarely hospitalized, and the majority will go into remission and not require ongoing therapy.
While randomized controlled trials remain the gold standard for proving the efficacy of a treatment, many dermatologic diseases are not common enough for clinical trials. Yet all dermatologists remain frustrated by lack of good treatment for lichen planus, bullous pemphigoid, pruritus, cutaneous lupus and dermal hypersensitivity reactions. Anecdotal evidence and small trials have shown some of our existing biologic armamentarium can help some of these disease states, but more research needs to be done.
As a practicing medical dermatologist, I am grateful that I started practice at the dawn of the biologic revolution and, over the last 20 years, have seen it approach high noon. There is still much to learn, and more to treat, but our ability to treat and understand these diseases has made exponential progress.
Biologic medications have transformed and even saved the lives of dermatology patients. There is no greater joy as a physician than to have such an impact. Last week, one of my 8 year olds in the dupilumab trial told me that he got a puppy for Christmas. His mother, beaming, said that before he was on this medication they couldn’t even go to a house with a cat or a dog. On her phone, she showed me a picture of my patient with his arms around a yellow lab puppy. “His name is Charlie,” my patient said, “and I love him more than anything in the world.”
Jamie D. Weisman, MD
Dr. Weisman’s practice, Medical Dermatology Specialists, focuses on immune driven skin disorders. She is also the director of Advanced Medical Research, where she works with pharmaceutical companies to help develop new treatments for severe skin disease. She has been an author on several key publications related to biologic medications. Dr. Weisman is also an accomplished writer and is the author of the memoir, As I Live and Breathe and a recent novel, We Are Gathered.
