New treatments, personalized care are just some of the exciting advancements to come
To understand the future of dermatologic therapies, we need to understand where we have been.
The biologic revolution in the treatment of dermatologic disease began in January 2002, when the tumor necrosis factor receptor blocker etanercept (Enbrel) was approved for the treatment of psoriatic arthritis. The revolution rolled forward with the approval of other biologic agents that blocked TNF alpha to treat psoriatic arthritis and psoriasis, and seven years after etanercept’s approval, a new pathway for the treatment of psoriatic disease was approved.
Since that time, an explosion of new biologic treatments for psoriatic disease has occurred, and dermatologists now have 12 branded biologics approved for the treatment of psoriasis and psoriatic arthritis in both children and adults.
Biologic medications have been approved for the treatment of atopic dermatitis, hidradenitis suppurativa and pemphigus vulgaris, and more are in development for these disease states, as well as cutaneous and systemic lupus, scleroderma, alopecia areata and pustular psoriasis. In addition, small molecules available as oral medications have been approved for psoriasis, psoriatic arthritis and alopecia areata, with impending approvals for atopic dermatitis.
The pace of development of new therapeutics for dermatologic diseases in the past decade has been astonishing, and it represents both impressive innovation in pharmaceuticals and a deeper appreciation of the toll of dermatologic disease on our patients. With these new treatments has come an understanding not only of the psychosocial and physical burden of skin disease but also much deeper insight into the systemic effects of inflammatory skin disease.
As new medications were discovered to treat psoriasis, the National Psoriasis Foundation and the American Academy of Dermatology discovered a huge unmet need. Patients were desperate for treatment, and it soon became clear that the burden of skin disease had been terribly underestimated by all clinicians, including dermatologists.
A seminal paper in 2015 showed the impact of psoriasis on quality of life was similar to the impact of severe heart disease and cancer, and in some areas more severe. Further research showed that the disease of psoriasis itself increased the risk of early death and other serious medical problems, including heart disease, diabetes, stroke and hypertension. Suddenly, a new slogan arose: psoriasis was more than skin deep.
But we’ve known for centuries that skin disease correlates with internal disease. Lupus erythematosus, dermatomyositis, scleredema and scleroderma are all skin signs of internal disease. Paraneoplastic syndromes, tripe palms, even itching are all external clues to internal disease. While other fields have had great advances in imaging, robotic surgery and invasive procedures, dermatologists have always remained true to the physical exam.
Now that we know how far we’ve come in less than two decades, let’s look ahead to the future.
The idea of defining a disease by its specific protein abnormalities is the root of all biologic therapy. As molecular biology has allowed us to identify thousands of cytokines, dermatologists and bench scientists have worked to elucidate the exact cytokine profile of inflammatory skin disease and cancer.
We are still at the dawn of therapy. At this stage, we simply identify elevated protein expression and lower it. Likewise, biologic immunotherapy for melanoma and other cancers non-specifically activates the immune system. The future of biologic therapy for inflammatory disease will involve both personalized medicine and a remittive or even permanent normalization of the immune system. The same is true for cancer, where harnessing the immune system specifically to the genetics of the patient and the tumor itself should one day provide cures, rather than remissions, without the cost of autoimmunity or other side effects we associate with cancer immunotherapy today.
In the immediate future, dermatologists can anticipate the approval of a new IL-17 inhibitor that blocks both IL17-A and F and has the potential to rapidly achieve PASI100 (or full clearance of disease) with better control of psoriatic arthritis than any other agent to date. Two IL-13 inhibitors are in Phase III clinical trials for adolescent and adult atopic dermatitis, and an IL-31 inhibitor shows promise for atopic dermatitis and primary pruritus.
The discovery that lack of the IL-13 receptor antagonist led to familial pustular psoriasis prompted the development of an IL-36 inhibitor that has shown dramatic rapid resolution of generalized pustular psoriasis and is being studied in palmar plantar pustulosis. These diseases have been notoriously difficult to manage and prior to the burst of new therapeutics were treated with broad and nonspecific immunosuppressants with limited efficacy and often unacceptable side effects. For hidradenitis suppurativa, monoclonal antibodies against IL-1, IL-17, and IL-23 are in late stage development, with more novel antibodies in earlier development.
New oral and small molecule therapeutics will also soon be available. Janus kinase inhibitors are in Phase III trials for alopecia areata and atopic dermatitis and in Phase II for lupus, dermatomyositis and hidradenitis suppurativa. An oral retinoic acid-related orphan receptor shows promise as an immunomodulatory treatment for psoriasis and will be developed for other disease states.
As with psoriasis, the emergence of these new therapeutics has led to increased recognition of the need for safe, effective and aggressive treatment of skin disease. While inflammatory skin disease is rarely life-threatening, it is life altering, and patients have eagerly embraced the opportunity for new and effective treatment.
Regulatory authorities like the Food and Drug Administration are increasingly embracing the importance of the patient experience, and while dermatologists may have been reluctant to offer aggressive treatment for atopic dermatitis, psoriasis or hidradenitis in the past, fearing the side effects, patients have learned to advocate for themselves. As exciting as it is to have new treatments, it is more exciting to see this patient advocacy, and physicians in turn should be advised to listen to patients and offer a broad range of therapeutic options rather than pre-judging which diseases warrant treatment.
Looking further down the horizon, innovations in cheaper diagnostic testing will allow for more personalized medicine, more of the science and less of the art of medicine. In clinical trials, patients frequently undergo biopsies for extraction of messenger RNA from lesional skin. This mRNA and protein expression both in the blood and lesions can be used to predict response or failure to treatment. With longer follow up, it may also be able to predict complications and comorbidities.
As clinicians, we would love to be able to predict which of our psoriasis patients is high risk for cardiovascular disease, which of our hidradenitis suppurativa patients is high risk for inflammatory bowel disease and which lupus patients are likely to develop renal disease. Similarly, we may also be able to predict complications from the treatment itself.
Personalized medicine has been a buzzword for decades, but we are closer to making it a reality now than we have ever been. And in the midst of a pandemic, it is of even more vital importance. The varied responses to COVID-19, from no symptoms to acute respiratory distress and death, show that heterogeneous immune responses literally mean the difference between life and death. Now more than ever, it is imperative to define and predict these variations, and dermatology offers great insight into our understanding of what has been a black box of immunology for centuries.
Finally, emerging therapeutics are aiming for the holy grail not of disease management but of a cure, restoring the immune system to normal function and tolerance. As chemokines and interleukins were discovered and named (and misnamed, as in tumor necrosis factor alpha), we have also found that these proteins can have different functions depending on the company they keep. Using more than one biologic or small molecule in succession or using biologics not to suppress the inflammatory component of the immune system but rather to enhance the regulatory and anti-inflammatory arms offers a chance to restore homeostasis.
Cynically I have said that pharmaceutical companies want a drug that works perfectly, has no side effects and that you take forever, but I am happy to say that I have been proven wrong. While we are only at the early stage, treatments in development for inflammatory disease now carry the possibility of long-term remittance and even a cure.
The joke I learned about dermatology in medical school – our patients never die and are never cured – has never really made sense. We know that dermatology patients can die of melanoma, Merkel cell carcinoma and squamous cell carcinoma. We further know that the chronic inflammatory state of many of our diseases can be a cause of early death, not to mention the well-documented psychosocial effects that increase rates of substance abuse, depression and suicide.
The last 20 years of drug development in dermatology has been nothing short of miraculous, but the next 20 – or 10 or even two years – looks to be even more exciting. The skin is the largest immunological organ. Now more than ever, treatment of immune-mediated skin disease is gratifying to the physician and life-changing for our patients.
When we were enrolling patients for a pediatric atopic dermatitis study last year, a six-year-old boy with severe involvement, relentless itching and essentially no normal skin came to start treatment. He had been treated with strong immunosuppressants including cyclosporine. He had been hospitalized for whirlpool baths, IV antibiotics and IV corticosteroids, along with traditional wet wraps and topical steroids, all treatments that I used in residency at the end of the last century.
Nothing offered him long term relief. His mother was holding his new baby brother, and he told us, “I say my prayers every night. I pray that my brother doesn’t have eczema like me.”
His skin is now 90% improved. He has joined his first-ever soccer team. His little brother recently learned to walk, and he told us, “It’s ok if he gets eczema because if he does, you will make it better.”