PracticalDermatology

Within the last two decades, we have seen an explosion in systemic treatments for the treatment of a variety of conditions, particularly psoriatic disease. Biologic therapies have since made an enormous impression and are rapidly redefining how clinicians understand, approach, and manage conditions such as psoriasis and more recently atopic dermatitis. Moreover, the prominence of systemic and biologic therapy has intensified in recent years, with new classes of biologics and oral agents recently approved or moving through trials.

Indeed, the introduction of new treatment possibilities may engender a palpable sense of enthusiasm for the future of our field and heightened understanding of the systemic nature of skin disease. But these developments also raise a host of new questions and concerns that go beyond the treatment of any one condition. Given the paucity of new molecules in the field of dermatology, the recent surge of biologics should compel all of us to consider the implications this may have for our field of medical dermatology.

Does New Mean Better?

In the last 15 years, the biologic landscape has undergone significant shifting. Whereas TNF alpha inhibitors such as etanercept (Enbrel, Amgen), adalimumab (Humira, AbbVie), efalizumab (Raptiva, Genentech), infliximab (Remicade, Janssen), etc., were once the driving force of the biologic market in the treatment of psoriatic disease, the landscape has since changed significantly as interleukin pathways have deepened the biologic platform. Since the IL-12/23 agent ustekinumab (Stelara, Janssen) was approved six years ago, interest in the interleukin pathways has skyrocketed and new IL-based agents have been explored further in clinical trials. The recent approval of secukinumab (Cosentyx, Novartis), which targets the IL-17 pathway, represents a new direction within the IL realm. Two other IL-17 drugs are in the pipeline, brodalumab (Amgen) and ixekizumab (Eli Lilly) and are likely to see approval within a year.

As new research digs deeper into Th17 and the IL-17 pathways and more biologic therapies reach the market, it is important that we attempt to place these rapid changes into a larger context. In a review article of 39 new drugs from 2009-2010, Ujeyl, et al. stated: “New drugs do not always mean better.”¹ Certainly, the published data on secukinumab as well as other IL-17 agents in the pipeline have been very encouraging, with up to 50 to 60 percent of patients achieving PASI 90. However, we must bear in mind that we have very little long-term “real world” data on these agents.

In 2009, efalizumab was withdrawn from the market due to three instances reported of progressive multifocal leukoencephalopathy (PML), after over 40,000 patients had been dosed with the drug. There were no suggestions of an increased likelihood of PML in patients receiving efalizumab in clinical trials, but it’s important to note that drugs in real world use may behave very differently than in the very controlled circumstances of clinical trials. Some side effects may be few and far between, but the case of efalizumab will be a constant reminder of what can happen if those side effects are severe enough.

It is important to recognize that clinical trials represent a subset of patients often with no prior cancers or debilitating conditions who are in reasonable good health. Thus, the data we receive are limited to very specific conditions and do not account for the full range of complexities stemming from comorbidities that physicians encounter when treating patients with psoriatic disease. On other hand, we have learned in the last several years that TNF alpha inhibitors may actually have a positive effect on cardiovascular disease. In addition, a new review looking at 23,000 patients with seven differing disease states who received adalimumab for up to nine years found no new evidence of significant side effects across the board.² That doesn’t mean the controversy will fade away, but it’s important to always consider the larger context for these issues in order to reassure our psoriasis population.

Specifically regarding the IL-17 pathways, the current data is certainly reason for enthusiasm. But if past events in the biologic spectrum have taught us anything, it’s that we will always have much to learn about how these agents are to be used in practice.

Biologics: Bolstering the Specialty

Beyond the clinical data, we should also consider the broader circumstances of psoriasis severity as well as global and national health trends in our assessment of biologics. A majority of psoriasis patients worldwide—roughly 75-80 percent—have mild to moderate disease, which can be addressed by topical agents. However, a significant percentage of the remaining 20-25 percent of patients with moderate to severe disease who would be eligible for systemic treatments are not being treated adequately. In fact, a significantly lower percentage of eligible psoriasis patients are receiving biologic treatments than patients with conditions such as Crohn’s disease or rheumatoid arthritis.

The reasons for this disconnect are likely more complex than we would hope. One factor, certainly, is that psoriasis is an immune-mediated disease that is still not particularly well understood. Although the availability of several new therapies that can address the clinical nuances of the disease is a benefit to physicians and patients, we should also consider the possibility that a higher volume of therapeutic options is making the already cloudy pool even murkier for physicians and patients who are not accustomed to using these agents. Moreover, securing access to biologics can be a difficult and cumbersome process that many physicians are either not willing or equipped to take on in their practices.

The combination of these factors presents a compelling narrative for the still-lagging rate of biologic use in psoriasis. But the larger issue is how this bottom line will affect the specialty of dermatology. Thanks to the development biologics, psoriasis is now the development leader in medical dermatology and arguably bolsters the entire specialty.

Several decades ago, many systemically understood diseases, such as scleroderma and lupus, were considered part of the treatment spectrum of dermatology. Psoriasis now represents one of the few systemic conditions that dermatologists still treat with some regularity. And yet, treating psoriasis has become something of a niche specialization within our field. This can be explained by the simple fact that, in our procedure-driven healthcare model, there is not a procedure for treating psoriasis in a way that other conditions may be treated.

8Like a host of other specialties, dermatology is driven by procedures, from aesthetic procedures to surgeries. There is no procedure for psoriasis. A physician can spend up to 40 minutes with a new patient talking about comorbidities, adverse event profiles of various drugs, and so on, and be reimbursed the same or less as if s/he performed cryosurgery on an actinic keratosis, which takes roughly three to four minutes.

Thus, in dermatology we are seeing a strange dichotomy developing in which biologic agents are supporting the welfare of the specialty, all the while practitioners have little incentive to use them. The recent swell of new agents arriving on the market (with several others on the cusp) is no doubt encouraging from a clinical standpoint, but the broader implications for the specialty at large are concerning.

Changing the Perception

Given the extent to which biologics are tied to the future of our specialty, ending negative perceptions of these drugs is critical. Despite the millions of dollars that are spent on direct-to-consumer advertisements encouraging patients to ask their doctors about biologics, many patients remain fearful of these drugs. This is likely tied to the fact that many physicians themselves do not prescribe biologics, presumably to avoid the headaches of dealing with specialty pharmacies and/or insurance companies, or simply because they don’t take the drugs or the condition serious enough to warrant consideration.

Biologic manufacturers have invested millions of dollars in trying to educate physicians about biologics, but it has proven an almost impossible task. In our procedure-driven system, physicians have little incentive to learn the nuances of biologics and how they work. Framed from the standpoint of our duties as clinicians, however, the discussion of biologics takes on a more serious tenor. With increasing published data linking psoriasis to cardiovascular disease, joint disease, and multiple other major medical conditions, it is our responsibility to manage and treat patients as aggressively and as safely as possible.

When it comes to educating patients, I have found that presenting patients with an information card that succinctly conveys the basics of immunomodulation rather than significant immunosuppression and how biologics work can be very productive toward putting them at ease. I also explain how researchers and physicians have become increasingly sophisticated with these drugs, particularly in how we can now target which specific cytokine in the psoriasis immunopathogenesis pathway to modulate.

But possibly the most important factor in speaking with patients—and perhaps in understanding the condition itself—is how we position adverse events. No matter how severe the psoriasis, nearly every patient with whome I’ve spoken about the potential for administering biologic therapy has been nervous about the suppression of their immune system and the risks of cancer and/or infections. Indeed, there are some risks associated with the use of biologics and we still have much to learn about their safety profiles. But the risk of living with psoriasis is conceivably far greater than those posed by treatment with biologics. It is important for both patients and physicians to consider this, fully realizing that psoriasis patients, like rheumatoid arthritis patients, have, at baseline, a slight increased risk of lymphoma.

Holding Our Heads High

We may have more questions than answers at the present time, but the evolving trajectory of biologics in our field offers a great deal of hope for patients with moderate-to-severe disease that days of relief may be ahead. Several manufacturers are deep in development with new interleukin-based agents and the results so far are very compelling. Additionally, promising new research has proposed the possibility of blending TNF alpha into a bimodal antibody and fusing two separate biologics with different methods of action to create a single molecule. This may be a long ways out, but the possibilities are exciting, particularly as clinicians try to refine treatments for certain types of psoriasis (such as palmoplantar) that do not respond well to the available systemic and biologic treatments.

But the future of biologics in medical dermatology will go beyond psoriasis, which is another cause for optimism. There are currently two biologics in development for the treatment of atopic eczema, which, if approved, could usher in a new phase of treating atopic dermatitis systemically. There are also many fascinating developments in the immune treatment of melanoma right now—for example, a new combination of specific antibodies appear to be maintaining people’s lives with multiple metastases far longer than we’ve seen in the past.

Whatever the future of biologics may be in our field, arguably the most important thing we can do as physicians is to strive for balance between being discerning and receptive to new modalities and therapies. Joining our rheumatology and gastroenterology colleagues in both the understanding and the usage of biologic agents for psoriasis and hopefully atopic dermatitis in the not-so-distant future, will hopefully allow our specialty of dermatology to hold our heads high and be considered a truly innovative and compassionate specialty in the field of medicine. n

Alan Menter, MD is Chief of the Division of Dermatology at Baylor University Medical Center in Dallas, TX.

1. Ujeyl, M et al. New drugs: evidence relating to their therapeutic value after introduction to the market. Dtsch Arztebl Int. 2012 Feb;109(7):117-23. doi: 10.3238/arztebl.2012.0117. Epub 2012 Feb 17.

2. Burmester, GR, et al. Adalimumab: long-term safety in 23,458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn’s disease. Ann Rheum Dis. 2013 Apr;72(4):517-24. Epub 2012 May 5.