Authors
Neal Bhatia, MD Harbor UCLA Medical Center Torrance, California
Andrew Blauvelt, MD, MBA Oregon Medical Research Center Portland, Oregon
Marc Brown, MD University of Rochester School of Medicine and Dentistry Rochester, New York
Whitney High, MD, JD, MEng University of Colorado School of Medicine Denver, Colorado
Craig T. Leonardi, MD St. Louis University School of Medicine St. Louis, Missouri
Ted Rosen, MD Baylor College of Medicine Houston, Texas
Linda Stein Gold, MD Henry Ford Hospital Detroit, Michigan
Eggert Stockfleth, MD Skin Cancer Center Charité Berlin, Germany
Bruce Strober, MD, PhD University of Connecticut Health Center Farmington, Connecticut
Neil A. Swanson, MD Oregon Health & Science University Portland, Oregon
George Martin, MD Dermatology Laser Center Maui Kihei, Hawaii
The MauiDerm annual educational meeting, sponsored by Advances in Cosmetic and Medical Dermatology, aims to increase physician knowledge in the areas of both medical and cosmetic dermatology. MauiDerm’s world-renowned experts have discussed significant advances in the diagnosis, management, and treatment of both medical and cosmetic dermatologic conditions at a very high scientific level. This supplement to The Journal of Clinical and Aesthetic Dermatology is based upon the proceedings from the cutaneous oncology sessions and the psoriasis and psoriatic arthritis sessions that took place at the 2014 MauiDerm Meeting. SC2 SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY [JULY 2014 • VOLUME 7 • NUMBER 7]
Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2014 MauiDerm Meeting
Updates on Psoriasis and Cutaneous Oncology Proceedings from the 2014 MauiDerm Meeting Psoriasis Update Psoriasis Therapy The treatment paradigm for moderate-to-severe psoriasis has evolved into a non-stepwise approach in which, essentially, all patients should initially be considered for one of three approaches (phototherapy, traditional systemic agents, or biologics). If a large body surface area (BSA) is affected, topical monotherapy becomes impractical. In addition, previous failure of topical therapy, high degree of impact on quality of life, disease in sensitive or difficult-to-treat areas (e.g., the palms), and presence of psoriatic arthritis (PsA) also make patients candidates for systemic therapy. For these patients, choice of systemic therapy has to be individualized and payer considerations come into play. Conventional agents. The three main conventional “go to” agents for psoriasis are methotrexate, acitretin, and cyclosporine, which are not interchangeable. Methotrexate is a mainstay agent, and many payers require it be used prior to biologic therapy. Acitretin may work well in certain patients (e.g., those with palmoplantar psoriasis or pustular psoriasis) or as an adjunct treatment to phototherapy. Cyclosporine can be highly effective, but is more broadly immunosuppressive than other choices and has known renal toxicity; unlike methotrexate or acitretin, cyclosporine should rarely be prescribed as a long-term agent. Biologics. Biologic agents are the main focus of current psoriasis drug development. Etanercept, infliximab, and adalimumab are tumor necrosis factor (TNF) inhibitors and are highly effective in treating psoriasis. When prescribing these drugs, route of administration must be considered; infliximab is an effective agent, but its intravenous administration makes it impractical for some patients. Ustekinumab is a biologic that inhibits interleukin (IL)-12 and IL-23, and is also highly effective. Ustekinumab is dosed by body weight with patients under 100kg prescribed 45mg at Week 0, Week 4, and then every 12 weeks thereafter for maintenance; those weighing over 100kg are dosed at 90mg on the same schedule.1 Note that payers should be consulted when prescribing ustekinumab for overweight or obese patients, as some require a 45mg dose to fail before advancing to 90mg. Reimbursement for biologics varies by geographical region, patients, and payers.
Overall, biologics are well tolerated by a wide range of patients. While infections are a known risk factor of TNF blockers, ustekinumab is not associated with an increased risk of infection. Patients receiving TNF blockers should be counseled about their elevated risk for infection, and if an infection occurs but can be resolved, the patient may resume taking the same biologic. Patients with a history of frequent infections may not be the best candidates for TNF blocker use. Well-managed human immunodeficiency virus (HIV) patients with an undetectable viral load may be suitable candidates for all types of biologic therapy. Biologics can be very effective. Infliximab results in a Psoriasis Area and Severity Index (PASI) 75 response in four out of every five patients (80%) at 10 weeks. Adalimumab and ustekinumab have results of 70 percent PASI 75 at 12 to 16 weeks, whereas results approach 80 percent for ustekinumab at Weeks 24 to 28. About 50 to 55 percent of patients achieve PASI 75 at 12 to 24 weeks after step-down therapy with etanercept. All biologics when used as monotherapy, may lose response over time. Should this happen, other therapies can be added or agents rotated. This possibility should be discussed with patients prior to treatment. Dose escalation also may work in some cases, but not all payers may approve of this approach due to increased costs. Immunogenicity often plays a role in loss of response. All biologics are recognized as foreign by the immune system, and thus all biologics are associated with some degree of immunogenicity. Patients who demonstrate detectable neutralizing anti-drug antibodies will more rapidly clear drug out of their bodies, resulting in lower serum drug levels, which can correlate with loss of clinical responses. Concomitant administration of methotrexate can suppress anti-drug antibody development and reduce immunogenicity. Indeed, psoriasis patients on both etanercept and methotrexate exhibit augmented clinical responses.2 One acceptable treatment strategy for psoriasis is to initiate therapy with oral or injectable methotrexate at a standard dose of 10 to 25mg per week; after 8 to 12 weeks, PASI 75 is achieved by approximately 35 percent of patients. If there is no response, a biologic may then be added to methotrexate, even if the patient is a methotrexate nonresponder. If, however, the goal is to get to biologic monotherapy, it is best to allow an overlap period where the patient receives two drugs for some time.
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Psoriasis Immunology: Understanding the Basis for Targeted Therapy Growing understanding of psoriasis pathogenesis has influenced the choice of drug targets over time. Before 1980, psoriasis was believed to be a disease of keratinocyte dysfunction and was treated with methotrexate, ultraviolet (UV) B radiation therapy, psoralen plus UVA treatment (PUVA), or retinoids. In the 1980s, psoriasis was found to be an immunological disease, with cyclosporine then becoming a novel treatment. In the 1990s and early 2000s, psoriasis was known as a disease mediated by IL-12 and T-helper (Th) 1 cells, which brought into consideration treatments such as alefacept, efalizumab, and TNF-α blockers. Psoriasis is now considered an IL-23 and Th-17 cell-mediated disease. Ustekinumab and novel agents that block IL-17A function work via inhibiting this immunological pathway. The current pharmacological pipeline for psoriasis includes the so-called “generic biologics” or TNF-α biosimilars as well as specific IL-23 blockers, IL-17A blockers, IL-17RA receptor blockers, oral Janus kinase (JAK) inhibitors, and a phosphodiesterase-4 (PDE4) inhibitor. To understand these new agents, it is important to understand both the normal and pathological function of each of these targets. Myeloid dendritic cells, Th-17 cells, keratinocytes, and many other cells produce TNF-α. Its production represents a “danger signal” for inflammation. TNF-α also is involved in systemic immunity to numerous pathogens. Genetic polymorphisms in TNF-responsive genes that lead to its overproduction have been associated with psoriasis, and it is found in abundance in psoriatic lesional skin. As mentioned above, etanercept, adalimumab, and infliximab target TNF-α. Another potential target is IL-23, composed of two protein subunits (p19 and p40). Tildrakizumab, guselkumab, and BI 655066 specifically block IL-23 function by binding to the p19 subunit. Myeloid dendritic cells produce IL-23 after they have
been activated by such pathogens as Candida albicans and Staphylococcus aureus. Normally, IL-23 acts “upstream” by promoting the activation, proliferation, and survival of Th-17 cells. Genetic polymorphisms in both p19 and p40 have been associated with psoriasis, and excess levels of IL-23 are also found in psoriatic lesional skin. IL-17A is a “midstream” target produced by Th-17 cells after activation by IL-23. Normally, IL-17A protects skin and mucosa from pathogens, such as C. albicans and S. aureus, by stimulating activation and proliferation of keratinocytes and neutrophils. The new psoriasis drugs secukinumab and ixekizumab selectively block IL-17A and, in turn, block abnormal activation and proliferation of keratinocytes and neutrophils characteristically found within psoriatic plaques. IL-17RA is a “downstream” target in that it is expressed on cell surfaces of keratinocytes, neutrophils, and other cells. It mediates the effects of IL-17A and other IL-17 isoforms, including IL-17C and IL-17E. IL-17RA is a subunit component of the IL-17A receptor (IL-17RA + IL-17RC = IL-17A receptor). There is excess expression of IL-17RA in psoriatic skin. Brodalumab, another new agent being studied for psoriasis, is a selective IL-17RA blocker. The distinction between IL-17A blockers (secukinumab and ixekizumab) and IL-17RA blockers (brodalumab) is shown in Figure 1. The intracellular signaling protein JAK is involved in relaying information after extracellular cytokines bind to cellsurface receptors. JAK signaling occurs for numerous cytokines—IL-6, IL-12, IL-15, IL-17A, IL-20, IL-21, IL-22, IL23, interferon (IFN)-α, and IFN-γ. Following cytokine binding to receptor, JAK is activated via phosphorylation. Signal transducers and activators of transcription (STATs) are then activated, and these molecules promote new expression of pro-inflammatory genes within nuclei. The novel psoriasis drug tofacitinib blocks phosphorylation of JAK, which leads to relatively broad anti-inflammatory and immunosuppressive effects following its use. A final target to consider is a phos-phodiesterase type 4 inhibitor (PDE4), which is an intracellular enzyme prevalent in immune cells that degrades cyclic adenosine 3', 5'-monophosphate (cAMP) levels. Decreased cAMP levels lead to decreased protein kinase A, which, in turn, increases pro-inflammatory cytokines production (such as TNF-α and IL17A) and decreases anti-inflammatory cytokine production (such as IL-10). By blocking PDE4, the new psoriasis drug apremilast reverses these processes, leading to an overall decrease in inflammation.
Update on Emerging Systemic Therapies for Psoriasis
Figure 1. Targets in biologic drug development. Note that both secukinumab and ixekizumab block IL-17A while brodalumab blocks IL-17RA. S6
It is important for practitioners to find the best medicine for their psoriasis patients, especially since drugs come and go and sometimes fall by the wayside. Many of the second-generation
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Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2014 MauiDerm Meeting
biologics were developed with specific cytokines in mind (Figure 2). Below is a review of some of the emerging systemic therapies in the treatment of psoriasis. Certolizumab pegol. Certolizumab pegol (CZP), a pegylated antibody fragment (Fab), was initially approved for Crohn’s disease and subsequently approved for the treatment of rheumatoid arthritis, PsA, and ankylosing spondylitis. In 2005, a large Phase 2 psoriasis trial of 176 patients with 10 percent BSA and PASI 12 was conducted in Germany and France.3 There were three treatment arms: 200mg subcutaneously every other week, 400mg subcutaneously every month, and placebo. PASI 75 results demonstrated 75 percent, 83 percent, and seven percent, respectively. Physician’s global assessment (PGA) results (clear–almost clear) showed 53 percent, 72 percent, and two percent, respectively, among all treatment arms. There were no unexpected safety issues. These data, first presented in 2007 at the American Academy Figure 2. Cytokines and cytokine inhibitors in chronic inflammation of Dermatology Annual Meeting, tell us that CZP is both efficacious and safe for the treatment of moderate-to-severe plaque psoriasis. CZP is also approved for PsA. Currently, UCB, the maker of CZP, has again taken an interest in this medication, as there is some development effort and a psoriasis trial on the horizon. Targeting the IL-12/23 pathway. Both ustekinumab (IL-12) and briakinumab (IL-23) block the shared p40 subunit.4 When IL-12 is blocked, a set of cytokines from the Th1 pathway downregulate, including IFN-γ, IL-2, and TNF-α. When IL-23 is blocked, IL-17 alpha, IL-17F, IL-6, TNF-α, IL-21, and IL-22 downregulate (Figure 3). Ustekinumab. Ustekinumab is a highperforming drug for psoriasis patients. The data at Week 28 in both the PHOENIX 15 and PHOENIX 26 studies show about 70 to 79 percent of patients are achieving a PASI 75; this is a huge achievement for these patients (Figure 4). Third-generation biologics. There is a downstream effect from anti-IL-23 blockade Figure 3. Function of the Th17 effector cytokines feeding into IL-17 and downregulating IL-22. Many pharmaceutical companies have been studying evaluated secukinumab doses of 150 and 300mg in a placebothis pathway; there are two, possibly three, IL-23 inhibitors controlled study. PASI 75 response rates in the secukinumab currently in clinical trials. There are also two anti-IL-17 groups reached a peak at Week 16 (80–90% range). IGA scores inhibitors and an IL-17 receptor antagonist and there was an of “clear or almost clear” were reported in 60 to 75 percent of IL-22 blocker that came and went7—an indication that this is a very rich developmental pathway with many promises. patients. Treatment benefit was maintained through Week 52 IL-17 antagonists. The Phase 2 studies of secukinumab, on q4-week injections following an induction period. Other a human IgG1 monoclonal IL-17A antibody, demonstrated that Phase 3 trials included the FIXTURE study in which the 150mg and 300mg doses were statistically significant as etanercept was an active control.9 In this comparator study, 8 compared to placebo at Week 12. Between 80 and 90 percent patients showed a more rapid response to secukinumab versus of those taking the 300mg dose achieved PASI 75. etanercept (3 vs. 8 weeks) to achieve PASI 50, and a greater The results of secukinumab’s pivotal Phase 3 data were number of patients achieved PASI 90 (72.4 vs. 41.5%). The released in the Fall of 2013 at the European Academy of third secukinumab Phase 3 trial, SCULPTURE, compared Dermatology and Venereology meeting. The ERASURE study fixed-interval maintenance dosing every four weeks with a [JULY 2014 • VOLUME 7 • NUMBER 7] SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY
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Figure 4. Ustekinumab Phase 3 PASI response over 28 weeks
“retreatment-as-needed” regimen. Data from follow-up to Week 52 showed fixed interval therapy with SEC 300 and 150mg every four weeks sustained significantly greater PASI 75, 90, and 100 clearance rates over one year compared to “retreatment-as-needed.” Although we have not seen any of the safety results from the secukinumab Phase 3 trials, the drug was well tolerated overall, according to the Phase 2 data. Ixekizumab. Ixekizumab is another anti-IL-17 monoclonal antibody that is a high-performance, skin-clearing drug based on Phase 2 data.10,11 Studies looking at 10, 25, 75, and 150mg demonstrated that at the two highest doses, 80 percent of patients were at the PASI 75 range. There were no serious adverse events in this trial, and the drug had a remarkable safety profile. The biostatisticians at Eli Lilly, the makers of ixekizumab, utilized Youden’s Index to create a sensitivity and specificity assay. They determined that if they looked at the PASI 50 response at Week 4, they could make accurate predictions on the chances of success downstream. The likelihood of achieving PASI 75 and PASI 90 correlated with the PASI 50 response. Brodalumab. Brodalumab is an anti-IL-17 receptor antibody that blocks not only Il-17A, but also IL-17E and IL17C. It is another high-performance drug for the treatment of psoriasis. The Phase 2 studies, which were completed some time ago, demonstrated positive efficacy results along with a good safety profile.12,13 The long-term maintenance of clinical response with brodalumab has been demonstrated through Week 96 of an open-label extension study.14 Positive results were also seen with sPGA over 96 weeks. The one caveat with this open-label extension study is that it is an observed analysis, not an intent-to-treat approach to the data. The patients who came out of the trial are those who are not doing well, so as the trial moves on, the population continues to improve. S8
Interleukin 23. The p19 subunit is not shared; therefore, an anti-P19 molecule will block just IL-23. Tildrakizumab, a novel anti-IL-23p19 monoclonal antibody, demonstrated good results in a 16-week Phase 2B trial.15 There were four doses at Weeks 0 and 4 (5mg, 25mg, 100mg, and 200mg) versus placebo. PASI 75 was achieved in 35, 65.5, 67.1, and 76.2 percent of patients, respectively, versus 4.9 percent in the placebo arm, and PASI 90 was achieved in 11.9, 24.4, 38.2, and 51.2 percent of patients versus 2.2 percent in the placebo arm. Tildrakizumab appears to be generally safe and well tolerated. Small molecules. Apremilast is a novel, small molecule that inhibits PDE4. It has a variety of immunosuppressive effects in that it reduces TNFα, IL-2, IFN-γ, and several leukotrienes. In Phase 3 studies (ESTEEM I and II), apremilast (30mg BID) has achieved a PASI 75 rate of 33 percent (Figures 5 and 6).16 Importantly, scalp, nail, and pruritus scores were superior in the apremilast patients compared to controls. Phase 3 results also demonstrated greater improvements from baseline Dermatology Life Quality Index versus placebo. The majority of adverse events (AEs) were not serious and included mild gastrointestinal side effects: nausea 16 percent and diarrhea 19 percent. Apremilast also has Phase 3 PsA results that are statistically significant versus placebo although not quite as robust as the TNF inhibitors.17,18 United States Food and Drug Administration (FDA) approval for apremilast for the treatment of PsA was announced during the American Academy of Dermatology’s Annual Meeting in March of 2014. Laboratory monitoring of the patient was not required in the apremilast package insert. Tofacitinib, a novel, oral JAK inhibitor approved for the treatment of rheumatoid arthritis, is currently being investigated as a treatment for psoriasis among other indications.19 At Week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25% (2mg), 40.8% (5mg), and 66.7% (15mg), compared with placebo (2%).19 There has been an explosion of new biologics in the marketplace, with most of the drugs targeting the IL-23 pathway. With the unresolved issue of major adverse cardiovascular events (MACE), some feel that there is a signal at the IL-12/23 blockade level. It will be interesting to see if the MACE signal populates the IL-17 blockers. There has also been an emergence of a wide variety of novel small molecules demonstrating moderate-to-robust efficacies, and the safety profiles for some of these products are promising. Additionally, there has been a move to explore the JAK inhibitor in a topical formulation to treat psoriasis. Psoriasis patients are now the “model” of choice in the treatment of chronic inflammatory disease and practitioners caring for these patients are getting new and emerging therapies earlier now than ever before. Many psoriasis drugs have fallen by the wayside for efficacy and/or safety reasons.
SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY [JULY 2014 • VOLUME 7 • NUMBER 7]
Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2014 MauiDerm Meeting
Figure 5. Apremilast Phase 3 (ESTEEM 1): PASI-75 by prior treatment experience at Week 16
Dermatologists need to consider that short- and long-term safety issues do exist; however, the benefit/risk ratio in emerging systemic therapies for psoriasis appears to be favorable overall. Our treatment paradigm for psoriasis has shifted from a stratified approach (i.e., patients must fail the previous “step” of therapy before initiating a more “aggressive” therapy) to an approach whereby the choice of therapy depends upon individual patient characteristics.
Cardiometabolic Morbidities The association of severe psoriasis with cardiovascular (CV) events and metabolic comorbidities may be due to shared inflammatory pathways. Psoriasis is a chronic inflammatory condition that promotes immune dysregulation mediated by TNF and IL-17 pathways, which affect cardiometabolic processes.20 Current research suggests that people with severe psoriasis die about five years earlier than they should, factoring in all other mortality risks. Psoriasis is no trivial disorder. In a study of patients treated with disease-modifying antirheumatic drugs (DMARDs), the hazard ratio for all-cause mortality for psoriasis patients was 1.8 (1.6–2.0) compared to 1.6 (1.5–1.7) for rheumatoid arthritis (RA) patients and 0.9 (0.8–1.1) for patients with PsA.21 A recent study of the psoriasis transcriptome using 85 paired lesional and nonlesional samples from psoriasis patients found 2,725 unique known genes and functional pathways associated with metabolic and CV disease.22 An unexpected finding of this study was that metabolic and CV gene expression was higher in inflammatory disease categories. For example, psoriasis patients have higher levels of serum renin, and renin is associated with hypertension. A murine study found that skin-specific inflammation could promote aortic root inflammation and thrombosis.23
Figure 6. Apremilast Phase 3 (ESTEEM 1): Select secondary endpoints
High-density lipoproteins (HDL), or “good cholesterol,” are not as effective in psoriasis patients. Independent of traditional risk factors, psoriasis is associated with reduced HDL efflux, an increase in low-density lipoprotein (LDL) particle concentration, and decreased particle size24 as well as increased vascular inflammation, particularly of the aorta, equivalent to 10 years of aging.25 Further support of the connection between psoriasis and cardiometabolic disorders can be found in eight meta-analyses that together analyzed more than 500,000 psoriasis patients and more than 29 million controls.26–33 There are 11,500 incremental MACEs per year in the United States attributable to psoriasis.32 Patients with severe psoriasis taking systemic agents and without traditional cardiac risk factors have a 10year, six-percent risk for MACE, similar to the rate for diabetics. The Incident Health Outcomes and Psoriasis Events (iHOPE) study had general practitioners in the United Kingdom categorize 9,000 psoriasis patients as mild (≤2%), moderate (3–10%), or severe (>10%) based on BSA affected and found that risk of atherosclerotic disease increased with psoriasis severity.34 The risk of diabetes was greater for psoriasis compared to RA in a large population-based study in the United Kingdom. For example, relative risk of new onset diabetes adjusted for major risk factors, such as BMI and oral steroid use, were 1.33 (1.09, 1.61) in PsA, 1.21 (1.15, 1.27) in psoriasis, and 0.94 (0.84, 1.06) in RA.35 There is a 30-percent prevalence of metabolic syndrome in pediatric psoriasis patients,36 indicating that the association begins in childhood. Even controlling for other risk factors (e.g., diabetes and hypertension), moderate-to-severe psoriasis has also been associated with renal dysfunction, elevating patients’ risk of kidney disease two-fold and the likelihood of dialysis fourfold.37 In fact, the risk of renal dysfunction is greater for patients with moderate-to-severe psoriasis than those with diabetes. These associations depend on psoriasis severity; there is no clear association between renal or cardiometabolic
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disorders and mild psoriasis. However, with moderate and severe psoriasis, such associations emerge. Future comorbidity research will likely explore CV risk factors, such as insulin resistance, dyslipidemia, and chronic kidney disease as part of the causal pathway from long-standing psoriatic disease via atherosclerosis to CV disorders. To date, there is only mixed evidence as to whether aggressive treatment of psoriasis, PsA, and RA reduces CV morbidity and mortality. Three important ongoing trials may shed insight: • Vascular Inflammation in Psoriasis Trial (VIP) (NCT01553058). Does adalimumab or phototherapy lower vascular inflammation and improve lipid metabolism in patients with moderate-to-severe psoriasis? • Cardiovascular Inflammation Reduction Trial (CIRT) (NCT01594333). Does methotrexate lower the risk of major vascular events in patients with a history of myocardial infarction, diabetes, or metabolic syndrome? • Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) (NCT01327846). Does IL-1β inhibition reduce MACE rates in patients with stable coronary artery disease? Psoriasis patients should be considered at risk for metabolic disease and those between the ages of 20 and 79 should be screened for traditional CV risk factors every four to six years.38–42
Psoriatic Arthritis PsA refers specifically to an inflammatory arthritis that occurs among patients with skin psoriasis. A number of patients with PsA are under-treated or not under a doctor’s care; some remain undiagnosed. This will hopefully change with greater awareness and more effective treatment options. PsA may quickly cause permanent damage. A recent single-center study found that a six-month delay from initial psoriatic arthritis symptoms to rheumatologist consultation resulted in peripheral joint erosions that exacerbated longterm physical function.43 Multidisciplinary care for PsA is recommended by groups, such as the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).44 Recently, the introduction of highly effective therapies, such as TNF-α blockers, has driven interest in additional research in PsA, not only into newer treatments, but in optimal treatment approaches that can be individualized for each patient. The goals in treating PsA are to improve signs and symptoms of disease, delay or prevent joint damage, maintain functional status, and avoid complications of treatment. A number of factors affect treatment response in PsA, including obesity. Presumably because it is pro-inflammatory, obesity has been shown to attenuate responses to treatment (e.g., with TNF inhibitors).45 If obese patients who take a TNF-α inhibitor lose weight, they can achieve better outcomes. A new class of therapy that is being used already in some countries is S10
biosimilar medications. Also known as “follow-on biologics,” they possess the same amino-acid sequence and other highly similar physical properties (e.g., glycosylation patterns) of socalled originator biologics.46 The potential advantage behind the development of biosimilars is economic because the development program for such drugs may be abbreviated and hence cheaper than for novel therapies. A biosimilar infliximab is already on the market in parts of Europe.47 The United States Food and Drug Administration (FDA) under the Patient Protection and Affordable Care Act has an abbreviated licensure pathway for biosimilars.48 There are still some considerations that will be sorted out for regulatory agencies.49 Biosimilar TNF inhibitors, for example, have been given the full broad indication across diseases in some countries, whereas in other countries regulators have asked for data specific to some diseases. Ustekinumab, a drug used worldwide for psoriasis, has been studied in PsA, and recently received regulatory approval.50–52 Safety data with ustekinumab for psoriasis for five years (n=3,117 or 8,998 patient-years) have been published recently, with rates of AEs generally comparable to other biologics.53 The ongoing Psoriasis Longitudinal Assessment and Registry (PSOLAR) follows patients who are taking or are candidates for systemic psoriasis therapy.54 Currently, 9,495 patients at 266 centers around the world are followed. Mean BSA affected by psoriasis is 12.3 percent, roughly 80 percent of patients are overweight or obese, and 38.8 percent have CV comorbidities. A total of 7,476 patients in the registry have been exposed to at least one biologic agent. Rates of serious infections, malignancy, all-cause mortality, and MACE are 1.40, 0.61, 0.37, and 0.36, respectively, per 100 patient-years of follow-up. The goal for the treatment of PsA should be remission or as low a level of disease activity as possible. Tight control, that is, frequent clinical assessments with therapeutic adjustments as needed in order to try to achieve remission, is the model that has been assessed in rheumatoid arthritis; it has been proposed as a potentially useful treatment approach for PsA patients and has been shown capable of producing better outcomes.55,56
Prevalence of Psoriatic Arthritis in Psoriasis The prevalence of PsA among psoriasis patients has been estimated to be as low as six percent and as high as more than 40 percent.57–60 At present, it is generally considered that about 20 to 30 percent of psoriasis patients will develop PsA.61 Interestingly, for 80 percent or more of patients, the typical presentation is skin disease first, followed by joint involvement years later. In addition to causing joint pain and damage, PsA can drastically reduce quality of life and negatively impact work productivity.62 PsA patients are at risk for numerous comorbidities, including depression,63 metabolic syndrome, and CV disorders.61 PsA requires a clinical diagnosis, as there are no
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Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2014 MauiDerm Meeting
pathognomonic, serologic, or other diagnostic tests. The Classification of Psoriatic Arthritis (CASPAR) criteria are helpful when inflammatory arthritis is present.64 A number of screening tools have been developed for PsA, including, but not limited to, the Psoriasis Epidemiology Screening Tool (PEST), ToPAS (Toronto Psoriatic Arthritis Screening questionnaire), and PASE (Psoriatic Arthritis Screening and Evaluation).65 These are helpful, but no individual test is perfect for all patients. TNF-α inhibitors, including etanercept, infliximab, adalimumab, golimumab, and, most recently, certolizumab pegol, have changed the treatment paradigm for PsA. Rotating from one TNF-α antagonist to another may be a reasonable strategy for some patients.66,67 Ustekinumab, an IL12/23 inhibitor, has recently been approved for PsA. Aprelimast, an oral agent that inhibits PDE4, was approved in 2014 for the treatment of PsA. Other drugs under study in PsA include IL-17 inhibitors (e.g., brodalumab, ixekizumab, secukinumab). The JAK inhibitor tofacitinib is also being investigated for use in PsA.
Scalp Psoriasis Despite the scalp’s extensive vascular network, scalp psoriasis can be a recalcitrant condition, even when appropriately treated. Poor outcomes with scalp psoriasis mostly owe to poor adherence. For that reason, dermatologists treating scalp psoriasis should select topical remedies available in a patient-friendly vehicle to encourage compliance. Since most chronic plaque psoriasis patients will develop some form of scalp psoriasis, effective scalp products are important for the long-term care of the patient.68 The main treatment modalities are topical corticosteroids and vitamin D, which may be used as monotherapies.69 Adding a steroid to a vitamin D analog or other combination can improve outcomes because it leads to earlier results and thus encourages adherence. Betamethasone valerate “mousse,” a low-residue foam vehicle, was tested in 241 patients with severe scalp psoriasis as compared with betamethasone valerate lotion and the two vehicles. After four weeks of treatment, betamethasone valerate foam was more effective than the lotion-based standard treatment on scalp psoriasis (88% of patients had complete or nearly complete resolution of scaling vs. 66% using standard therapy, p5 AKs and field cancerization), and high-risk AKs (e.g., immunosuppressed and/or high-risk location). The new AK guidelines will use the following 5-point GRADE (Grading of Recommendations Assessment, Development and Evaluation) system: 1=strong recommendation for use; 2=weak recommendation for use; 3=no; 4=weak recommendation against; 5=strong recommendation against.89 The guidelines will also feature a flowchart for managing patients with AKs.
Other Skin Cancers and Benign Tumors Sebaceous hyperplasia. Sebaceous hyperplasia involves enlarged but benign sebaceous glands, which develop round papules with a central dell; these papules are generally less than 3mm in diameter. The papules may appear yellow. Telangiectasia may be visible on the surface and the appearance can mimic that of basal cell carcinoma (BCC). Sebaceous hyperplasia is often located around a central hair follicle or duct that can create a donut-shaped appearance. The prevalence of sebaceous S14
hyperplasia is greater among individuals 40 years of age or older, and risk increases with age. They typically appear on the face and are most common in people who have always had oily skin. There are no particular predilections by race, ethnicity, or gender. Sebaceous hyperplasia is associated with Muir-Torre syndrome, Cowden syndrome, and Gardner’s syndrome. Although sebaceous hyperplasia is relatively common, effective, non-scarring permanent removal is lacking. Most therapies target only the superficial component of the lesion. A new 1,720nm laser has been shown to effectively treat the entire sebaceous hyperplasia lesion in one or two treatments with crusting resolving in about 10 days.90 This treatment is based on the observation that human fat has absorption peaks at 1,210 and 1,720nm and this laser selectively treats at 1,720nm. Low-dose isotretinoin is an effective way of reducing the size of sebaceous hyperplasia. It should be commenced at 10mg/week and then titrated to 20mg/week, 30mg/week, and so on. Isotretinoin is a known teratogenic agent, and US patients must be enrolled in the national iPLEDGE program in order to receive isotretinoin therapy. Treatment considerations of sebaceous hyperplasia are provided in Table 2. Nevus sebaceous of Jadassohn. Nevus sebaceous of Jadassohn (NSJ), sometimes called Jadassohn Nevus, organoid nevus, or nevus sebaceous, is a smooth, hairless, yellow-orange variant of epidermal nevus. Nevus sebaceous regions contain sebaceous glands, hair follicles, apocrine glands, and connective tissue. They are mainly found on the scalp or the forehead in proximity to the scalp and more rarely on the face and neck. A differential diagnosis of NSJ must consider aplasia cutis, mastocytoma, and juvenile xanthogranuloma (JXG). NSJ occurs about equally in men and women with no particular ethnic predilections. Most NSJ patients have NSJ at birth, but lesions may grow more prominent over time. There is low risk for other tumors growing within the nevus sebaceous area, including BCC and sebaceous carcinoma. Associated syndromes include epidermal nevus syndrome, Schimmelpenning syndrome, proteus syndrome, and CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects, a condition that occurs only in females). There are two main schools of thought for the treatment of NSJ. The first is a “watch and wait” approach where clinicians intervene only if a tumor develops within the lesion. The other approach is prophylactic excision that should occur before puberty. The latter avoids the problems associated with a larger lesion should a tumor develop and cosmetic benefits for the child. If a malignant tumor develops, Mohs surgery is the recommended treatment. The cumulative incidence of malignant tumors developing in NSJ patients is approximately two percent.91 Sebaceous gland carcinoma (SGC). Sebaceous gland carcinoma (SGC) is a relatively uncommon, but aggressive cutaneous neoplasm that arises from the sebaceous glands in the skin, three-quarters of which occur in the periocular region. These tumors arise from the sebaceous glands around the eyes: Meibomian glands (tarsal plates, 50–70%), glands of Zeis (eyelash cilia, 10%), or more rarely the glands of caruncle. About 12 to 15 percent of these tumors have a multicentric origin. They develop as painless, yellow-to-pink nodules that enlarge slowly.
SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY [JULY 2014 • VOLUME 7 • NUMBER 7]
Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2014 MauiDerm Meeting
There is a high risk for local recurrence. The risk for metastasis is controversial but significant. SGC ocular tumors comprise less than one percent of all eyelid tumors and about 1 to 5 percent of all eyelid malignancies. They are 2 to 3 times more common in the upper than lower eyelid, occur more often in women than men, and are more common among Asians. They typically occur in people around 60 to 70 years of age and rarely in children. Because they mimic benign eye conditions, including keratoconjunctivitis, chalazion, blepharoconjunctivitis, and ocular pemphigoid, diagnosis is typically delayed 1 to 3 years. SGC ocular tumors can have a similar appearance to periocular BCC or SCC, but the latter are more likely to occur on the lower lid. Clinicians should suspect SGC with chalazions that do not heal, loss of cilia, yellow streaks on the conjunctiva, increased vascularity of the eye, and chronic unilateral eye inflammation. Chalazion is the most common misdiagnosis of sebaceous carcinoma. Pagetoid or intraepithelial spread into the conjunctiva can result in keratoconjunctivitis or blepharoconjunctivitis, which is often misdiagnosed as blepharitis. Extraocular SGC composes about a quarter of all sebaceous gland cancers and most commonly presents on the parotid gland, head, or neck as a yellow, tan, or pink nodule or papule. It is rare, but possible for extraocular SGC to appear on the genitalia, ear canal, breast, nasal vestibule, or axilla. A retrospective study of 91 cases showed recurrence in 29 percent and metastasis in 21 percent of cases.92 Muir-Torre syndrome. Muir-Torre syndrome (MTS), identified independently by two investigators in 1967, is a rare autosomal dominant genodermatosis caused by a mutation in one of the mismatch repair genes (MLH1, MSH2, MSH6). This results in a concurrent or sequential development of sebaceous neoplasms with an internal malignancy; the cancer is often a multiple, low-grade, visceral malignancy, such as colorectal (most common), genitourinary, breast, or hematological cancer. A study of 120 patients with MTS reported that 24 percent of patients with MTS developed sebaceous carcinoma. Patients can be screened for Muir-Torre syndrome by testing sebaceous lesions for microsatellite instability or by use of immunohistochemical staining to look for mismatch repair genes. Gorlin syndrome (basal cell nevus syndrome). Gorlin syndrome, also known as basal cell nevus syndrome, is a rare hereditary condition that predisposes the patient to develop multiple BCCs.93 It occurs in people with one defective copy (autosomal dominant) of the PTCH1 gene. Clinical manifestations include BCCs, cysts on the jaw (odontogenic keratocysts), palmar and/or plantar pits, and ectopic calcifications.94 It is associated with numerous congenital defects, including, but not limited to, polydactyly, macroencephaly, broad faces, immobile thumbs, and others.95 Metastatic basal cell carcinoma. Until recently, metastatic BCC has been treated with systemic chemotherapy, such as cisplatin or cisplatin with doxorubicin or targeted therapy with cetuximab, an epidermal growth factor receptor antibody.96 A new and novel therapy for the treatment of locally advanced and metastatic BCC is vismodegib (Erivedge®,
Genentech), a recently approved agent to treat BCC that has metastasized, relapsed after surgery, or cannot be treated by surgery or radiation. It is the first drug that targets the so-called hedgehog signaling pathways. Hedgehog signaling occurs along signaling pathways that transmit information to embryonic cells required for development; BCC is associated with hedgehog signaling malfunctions. Adult stem cells require hedgehog signaling in the regulation and maintenance of adult tissues. Sonic hedgehog (SHH) is the best studied ligand of the vertebrate pathway. The hedgehog pathways include hedgehog ligands (encoded by the hedgehog gene), a patched molecule (PTCH) controlled by a PTCH gene (thought to be an inhibitory receptor or tumor suppressor), a smoothened (SMO) molecule or signaling receptor or oncogene, and the Gli family of transcription factors. When signaling is inactive, PTCH inhibits SMO activity (Figure 7).97 The hedgehog pathway is activated by the hedgehog ligand binding to PTCH, which removes the SMO’s inhibitory effect and eventually will result in gene expression (Figure 8). Ninety percent of sporadic BCCs have inactivating mutations in the PTCH genes, while 10 percent of sporadic BCCs have activating mutations in the SMO gene. Gorlin syndrome is a disorder of the germ-line heterozygous mutations in the PTCH gene. These mutations are associated with basal cell carcinomas (Figures 9A and 9B). Vismodegib is a hedgehog pathway inhibitor (HPI), a small molecule that binds to SMO1–4 where it acts as a highly potent, selective SMO inhibitor. The drug is available in oral capsules for once-daily dosing (150mg/day), and micromolar plasma concentrations were achieved with one oral dose of 150mg.98 Vismodegib binds to SMO, directly blocking the hedgehog signaling pathway in BCC that are driven by either inactivating mutations of PTCH or activating mutations of SMO. Vismodegib inhibits signal transduction so there is no targeted gene expression and, in so doing, it inhibits the tumor. It does not matter if the mutation is PTCH or SMO; vismodegib inhibits both mutations. The ERIVANCE BCC was the pivotal Phase 2 trial of vismodegib in the treatment of advanced BCC.99 The study had two patient cohorts: metastatic BCC patients (with BCC that was measurable by imaging) and patients with locally advanced BCC. Locally advanced BCC was defined in the study as a BCC tumor that was either inoperable or where surgery was inappropriate with tumors more than 1cm in diameter and characterized by two or more recurrences following surgery, rendering curative resection unlikely or only possible with substantial morbidity and/or deformity from surgery. All patients were treated with vismodegib 150mg daily until disease progression or withdrawal from the study for toxicity or other reasons. Responses were assessed in the metastatic cohort using imaging and Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Responses were measured in the local BCC cohort using a novel composite endpoint that included measurable diameter and ulceration of the visible tumor along with RECIST measures of the deeper tumor component (when present). The primary endpoint was the objective response rate, with secondary endpoints being duration of response, progression-free survival, and absence of residual BCC on biopsy for the local BCC patient cohort. Tumor regression, measured as
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Figure 7. In the absence of the hedgehog ligand, PTCH inhibits SMO and the hedgehog signaling pathway is suppressed.
Figure 8. Hedgehog signaling pathway overview; target gene expression is initiated by hedgehog ligand binding to patch.
change in lesion diameter as a percentage, was marked. Among metastatic BCC patients (n=33), the independently assessed response rate was 30 percent (95% CI, 16–48, p=0.001) compared to the local BCC cohort with an independently assessed response rate of 43 percent (95% CI, 31–56, p
Neal Bhatia, MD Harbor UCLA Medical Center Torrance, California
Andrew Blauvelt, MD, MBA Oregon Medical Research Center Portland, Oregon
Marc Brown, MD University of Rochester School of Medicine and Dentistry Rochester, New York
Whitney High, MD, JD, MEng University of Colorado School of Medicine Denver, Colorado
Craig T. Leonardi, MD St. Louis University School of Medicine St. Louis, Missouri
Ted Rosen, MD Baylor College of Medicine Houston, Texas
Linda Stein Gold, MD Henry Ford Hospital Detroit, Michigan
Eggert Stockfleth, MD Skin Cancer Center Charité Berlin, Germany
Bruce Strober, MD, PhD University of Connecticut Health Center Farmington, Connecticut
Neil A. Swanson, MD Oregon Health & Science University Portland, Oregon
George Martin, MD Dermatology Laser Center Maui Kihei, Hawaii
The MauiDerm annual educational meeting, sponsored by Advances in Cosmetic and Medical Dermatology, aims to increase physician knowledge in the areas of both medical and cosmetic dermatology. MauiDerm’s world-renowned experts have discussed significant advances in the diagnosis, management, and treatment of both medical and cosmetic dermatologic conditions at a very high scientific level. This supplement to The Journal of Clinical and Aesthetic Dermatology is based upon the proceedings from the cutaneous oncology sessions and the psoriasis and psoriatic arthritis sessions that took place at the 2014 MauiDerm Meeting. SC2 SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY [JULY 2014 • VOLUME 7 • NUMBER 7]
Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2014 MauiDerm Meeting
Updates on Psoriasis and Cutaneous Oncology Proceedings from the 2014 MauiDerm Meeting Psoriasis Update Psoriasis Therapy The treatment paradigm for moderate-to-severe psoriasis has evolved into a non-stepwise approach in which, essentially, all patients should initially be considered for one of three approaches (phototherapy, traditional systemic agents, or biologics). If a large body surface area (BSA) is affected, topical monotherapy becomes impractical. In addition, previous failure of topical therapy, high degree of impact on quality of life, disease in sensitive or difficult-to-treat areas (e.g., the palms), and presence of psoriatic arthritis (PsA) also make patients candidates for systemic therapy. For these patients, choice of systemic therapy has to be individualized and payer considerations come into play. Conventional agents. The three main conventional “go to” agents for psoriasis are methotrexate, acitretin, and cyclosporine, which are not interchangeable. Methotrexate is a mainstay agent, and many payers require it be used prior to biologic therapy. Acitretin may work well in certain patients (e.g., those with palmoplantar psoriasis or pustular psoriasis) or as an adjunct treatment to phototherapy. Cyclosporine can be highly effective, but is more broadly immunosuppressive than other choices and has known renal toxicity; unlike methotrexate or acitretin, cyclosporine should rarely be prescribed as a long-term agent. Biologics. Biologic agents are the main focus of current psoriasis drug development. Etanercept, infliximab, and adalimumab are tumor necrosis factor (TNF) inhibitors and are highly effective in treating psoriasis. When prescribing these drugs, route of administration must be considered; infliximab is an effective agent, but its intravenous administration makes it impractical for some patients. Ustekinumab is a biologic that inhibits interleukin (IL)-12 and IL-23, and is also highly effective. Ustekinumab is dosed by body weight with patients under 100kg prescribed 45mg at Week 0, Week 4, and then every 12 weeks thereafter for maintenance; those weighing over 100kg are dosed at 90mg on the same schedule.1 Note that payers should be consulted when prescribing ustekinumab for overweight or obese patients, as some require a 45mg dose to fail before advancing to 90mg. Reimbursement for biologics varies by geographical region, patients, and payers.
Overall, biologics are well tolerated by a wide range of patients. While infections are a known risk factor of TNF blockers, ustekinumab is not associated with an increased risk of infection. Patients receiving TNF blockers should be counseled about their elevated risk for infection, and if an infection occurs but can be resolved, the patient may resume taking the same biologic. Patients with a history of frequent infections may not be the best candidates for TNF blocker use. Well-managed human immunodeficiency virus (HIV) patients with an undetectable viral load may be suitable candidates for all types of biologic therapy. Biologics can be very effective. Infliximab results in a Psoriasis Area and Severity Index (PASI) 75 response in four out of every five patients (80%) at 10 weeks. Adalimumab and ustekinumab have results of 70 percent PASI 75 at 12 to 16 weeks, whereas results approach 80 percent for ustekinumab at Weeks 24 to 28. About 50 to 55 percent of patients achieve PASI 75 at 12 to 24 weeks after step-down therapy with etanercept. All biologics when used as monotherapy, may lose response over time. Should this happen, other therapies can be added or agents rotated. This possibility should be discussed with patients prior to treatment. Dose escalation also may work in some cases, but not all payers may approve of this approach due to increased costs. Immunogenicity often plays a role in loss of response. All biologics are recognized as foreign by the immune system, and thus all biologics are associated with some degree of immunogenicity. Patients who demonstrate detectable neutralizing anti-drug antibodies will more rapidly clear drug out of their bodies, resulting in lower serum drug levels, which can correlate with loss of clinical responses. Concomitant administration of methotrexate can suppress anti-drug antibody development and reduce immunogenicity. Indeed, psoriasis patients on both etanercept and methotrexate exhibit augmented clinical responses.2 One acceptable treatment strategy for psoriasis is to initiate therapy with oral or injectable methotrexate at a standard dose of 10 to 25mg per week; after 8 to 12 weeks, PASI 75 is achieved by approximately 35 percent of patients. If there is no response, a biologic may then be added to methotrexate, even if the patient is a methotrexate nonresponder. If, however, the goal is to get to biologic monotherapy, it is best to allow an overlap period where the patient receives two drugs for some time.
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Psoriasis Immunology: Understanding the Basis for Targeted Therapy Growing understanding of psoriasis pathogenesis has influenced the choice of drug targets over time. Before 1980, psoriasis was believed to be a disease of keratinocyte dysfunction and was treated with methotrexate, ultraviolet (UV) B radiation therapy, psoralen plus UVA treatment (PUVA), or retinoids. In the 1980s, psoriasis was found to be an immunological disease, with cyclosporine then becoming a novel treatment. In the 1990s and early 2000s, psoriasis was known as a disease mediated by IL-12 and T-helper (Th) 1 cells, which brought into consideration treatments such as alefacept, efalizumab, and TNF-α blockers. Psoriasis is now considered an IL-23 and Th-17 cell-mediated disease. Ustekinumab and novel agents that block IL-17A function work via inhibiting this immunological pathway. The current pharmacological pipeline for psoriasis includes the so-called “generic biologics” or TNF-α biosimilars as well as specific IL-23 blockers, IL-17A blockers, IL-17RA receptor blockers, oral Janus kinase (JAK) inhibitors, and a phosphodiesterase-4 (PDE4) inhibitor. To understand these new agents, it is important to understand both the normal and pathological function of each of these targets. Myeloid dendritic cells, Th-17 cells, keratinocytes, and many other cells produce TNF-α. Its production represents a “danger signal” for inflammation. TNF-α also is involved in systemic immunity to numerous pathogens. Genetic polymorphisms in TNF-responsive genes that lead to its overproduction have been associated with psoriasis, and it is found in abundance in psoriatic lesional skin. As mentioned above, etanercept, adalimumab, and infliximab target TNF-α. Another potential target is IL-23, composed of two protein subunits (p19 and p40). Tildrakizumab, guselkumab, and BI 655066 specifically block IL-23 function by binding to the p19 subunit. Myeloid dendritic cells produce IL-23 after they have
been activated by such pathogens as Candida albicans and Staphylococcus aureus. Normally, IL-23 acts “upstream” by promoting the activation, proliferation, and survival of Th-17 cells. Genetic polymorphisms in both p19 and p40 have been associated with psoriasis, and excess levels of IL-23 are also found in psoriatic lesional skin. IL-17A is a “midstream” target produced by Th-17 cells after activation by IL-23. Normally, IL-17A protects skin and mucosa from pathogens, such as C. albicans and S. aureus, by stimulating activation and proliferation of keratinocytes and neutrophils. The new psoriasis drugs secukinumab and ixekizumab selectively block IL-17A and, in turn, block abnormal activation and proliferation of keratinocytes and neutrophils characteristically found within psoriatic plaques. IL-17RA is a “downstream” target in that it is expressed on cell surfaces of keratinocytes, neutrophils, and other cells. It mediates the effects of IL-17A and other IL-17 isoforms, including IL-17C and IL-17E. IL-17RA is a subunit component of the IL-17A receptor (IL-17RA + IL-17RC = IL-17A receptor). There is excess expression of IL-17RA in psoriatic skin. Brodalumab, another new agent being studied for psoriasis, is a selective IL-17RA blocker. The distinction between IL-17A blockers (secukinumab and ixekizumab) and IL-17RA blockers (brodalumab) is shown in Figure 1. The intracellular signaling protein JAK is involved in relaying information after extracellular cytokines bind to cellsurface receptors. JAK signaling occurs for numerous cytokines—IL-6, IL-12, IL-15, IL-17A, IL-20, IL-21, IL-22, IL23, interferon (IFN)-α, and IFN-γ. Following cytokine binding to receptor, JAK is activated via phosphorylation. Signal transducers and activators of transcription (STATs) are then activated, and these molecules promote new expression of pro-inflammatory genes within nuclei. The novel psoriasis drug tofacitinib blocks phosphorylation of JAK, which leads to relatively broad anti-inflammatory and immunosuppressive effects following its use. A final target to consider is a phos-phodiesterase type 4 inhibitor (PDE4), which is an intracellular enzyme prevalent in immune cells that degrades cyclic adenosine 3', 5'-monophosphate (cAMP) levels. Decreased cAMP levels lead to decreased protein kinase A, which, in turn, increases pro-inflammatory cytokines production (such as TNF-α and IL17A) and decreases anti-inflammatory cytokine production (such as IL-10). By blocking PDE4, the new psoriasis drug apremilast reverses these processes, leading to an overall decrease in inflammation.
Update on Emerging Systemic Therapies for Psoriasis
Figure 1. Targets in biologic drug development. Note that both secukinumab and ixekizumab block IL-17A while brodalumab blocks IL-17RA. S6
It is important for practitioners to find the best medicine for their psoriasis patients, especially since drugs come and go and sometimes fall by the wayside. Many of the second-generation
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Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2014 MauiDerm Meeting
biologics were developed with specific cytokines in mind (Figure 2). Below is a review of some of the emerging systemic therapies in the treatment of psoriasis. Certolizumab pegol. Certolizumab pegol (CZP), a pegylated antibody fragment (Fab), was initially approved for Crohn’s disease and subsequently approved for the treatment of rheumatoid arthritis, PsA, and ankylosing spondylitis. In 2005, a large Phase 2 psoriasis trial of 176 patients with 10 percent BSA and PASI 12 was conducted in Germany and France.3 There were three treatment arms: 200mg subcutaneously every other week, 400mg subcutaneously every month, and placebo. PASI 75 results demonstrated 75 percent, 83 percent, and seven percent, respectively. Physician’s global assessment (PGA) results (clear–almost clear) showed 53 percent, 72 percent, and two percent, respectively, among all treatment arms. There were no unexpected safety issues. These data, first presented in 2007 at the American Academy Figure 2. Cytokines and cytokine inhibitors in chronic inflammation of Dermatology Annual Meeting, tell us that CZP is both efficacious and safe for the treatment of moderate-to-severe plaque psoriasis. CZP is also approved for PsA. Currently, UCB, the maker of CZP, has again taken an interest in this medication, as there is some development effort and a psoriasis trial on the horizon. Targeting the IL-12/23 pathway. Both ustekinumab (IL-12) and briakinumab (IL-23) block the shared p40 subunit.4 When IL-12 is blocked, a set of cytokines from the Th1 pathway downregulate, including IFN-γ, IL-2, and TNF-α. When IL-23 is blocked, IL-17 alpha, IL-17F, IL-6, TNF-α, IL-21, and IL-22 downregulate (Figure 3). Ustekinumab. Ustekinumab is a highperforming drug for psoriasis patients. The data at Week 28 in both the PHOENIX 15 and PHOENIX 26 studies show about 70 to 79 percent of patients are achieving a PASI 75; this is a huge achievement for these patients (Figure 4). Third-generation biologics. There is a downstream effect from anti-IL-23 blockade Figure 3. Function of the Th17 effector cytokines feeding into IL-17 and downregulating IL-22. Many pharmaceutical companies have been studying evaluated secukinumab doses of 150 and 300mg in a placebothis pathway; there are two, possibly three, IL-23 inhibitors controlled study. PASI 75 response rates in the secukinumab currently in clinical trials. There are also two anti-IL-17 groups reached a peak at Week 16 (80–90% range). IGA scores inhibitors and an IL-17 receptor antagonist and there was an of “clear or almost clear” were reported in 60 to 75 percent of IL-22 blocker that came and went7—an indication that this is a very rich developmental pathway with many promises. patients. Treatment benefit was maintained through Week 52 IL-17 antagonists. The Phase 2 studies of secukinumab, on q4-week injections following an induction period. Other a human IgG1 monoclonal IL-17A antibody, demonstrated that Phase 3 trials included the FIXTURE study in which the 150mg and 300mg doses were statistically significant as etanercept was an active control.9 In this comparator study, 8 compared to placebo at Week 12. Between 80 and 90 percent patients showed a more rapid response to secukinumab versus of those taking the 300mg dose achieved PASI 75. etanercept (3 vs. 8 weeks) to achieve PASI 50, and a greater The results of secukinumab’s pivotal Phase 3 data were number of patients achieved PASI 90 (72.4 vs. 41.5%). The released in the Fall of 2013 at the European Academy of third secukinumab Phase 3 trial, SCULPTURE, compared Dermatology and Venereology meeting. The ERASURE study fixed-interval maintenance dosing every four weeks with a [JULY 2014 • VOLUME 7 • NUMBER 7] SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY
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Figure 4. Ustekinumab Phase 3 PASI response over 28 weeks
“retreatment-as-needed” regimen. Data from follow-up to Week 52 showed fixed interval therapy with SEC 300 and 150mg every four weeks sustained significantly greater PASI 75, 90, and 100 clearance rates over one year compared to “retreatment-as-needed.” Although we have not seen any of the safety results from the secukinumab Phase 3 trials, the drug was well tolerated overall, according to the Phase 2 data. Ixekizumab. Ixekizumab is another anti-IL-17 monoclonal antibody that is a high-performance, skin-clearing drug based on Phase 2 data.10,11 Studies looking at 10, 25, 75, and 150mg demonstrated that at the two highest doses, 80 percent of patients were at the PASI 75 range. There were no serious adverse events in this trial, and the drug had a remarkable safety profile. The biostatisticians at Eli Lilly, the makers of ixekizumab, utilized Youden’s Index to create a sensitivity and specificity assay. They determined that if they looked at the PASI 50 response at Week 4, they could make accurate predictions on the chances of success downstream. The likelihood of achieving PASI 75 and PASI 90 correlated with the PASI 50 response. Brodalumab. Brodalumab is an anti-IL-17 receptor antibody that blocks not only Il-17A, but also IL-17E and IL17C. It is another high-performance drug for the treatment of psoriasis. The Phase 2 studies, which were completed some time ago, demonstrated positive efficacy results along with a good safety profile.12,13 The long-term maintenance of clinical response with brodalumab has been demonstrated through Week 96 of an open-label extension study.14 Positive results were also seen with sPGA over 96 weeks. The one caveat with this open-label extension study is that it is an observed analysis, not an intent-to-treat approach to the data. The patients who came out of the trial are those who are not doing well, so as the trial moves on, the population continues to improve. S8
Interleukin 23. The p19 subunit is not shared; therefore, an anti-P19 molecule will block just IL-23. Tildrakizumab, a novel anti-IL-23p19 monoclonal antibody, demonstrated good results in a 16-week Phase 2B trial.15 There were four doses at Weeks 0 and 4 (5mg, 25mg, 100mg, and 200mg) versus placebo. PASI 75 was achieved in 35, 65.5, 67.1, and 76.2 percent of patients, respectively, versus 4.9 percent in the placebo arm, and PASI 90 was achieved in 11.9, 24.4, 38.2, and 51.2 percent of patients versus 2.2 percent in the placebo arm. Tildrakizumab appears to be generally safe and well tolerated. Small molecules. Apremilast is a novel, small molecule that inhibits PDE4. It has a variety of immunosuppressive effects in that it reduces TNFα, IL-2, IFN-γ, and several leukotrienes. In Phase 3 studies (ESTEEM I and II), apremilast (30mg BID) has achieved a PASI 75 rate of 33 percent (Figures 5 and 6).16 Importantly, scalp, nail, and pruritus scores were superior in the apremilast patients compared to controls. Phase 3 results also demonstrated greater improvements from baseline Dermatology Life Quality Index versus placebo. The majority of adverse events (AEs) were not serious and included mild gastrointestinal side effects: nausea 16 percent and diarrhea 19 percent. Apremilast also has Phase 3 PsA results that are statistically significant versus placebo although not quite as robust as the TNF inhibitors.17,18 United States Food and Drug Administration (FDA) approval for apremilast for the treatment of PsA was announced during the American Academy of Dermatology’s Annual Meeting in March of 2014. Laboratory monitoring of the patient was not required in the apremilast package insert. Tofacitinib, a novel, oral JAK inhibitor approved for the treatment of rheumatoid arthritis, is currently being investigated as a treatment for psoriasis among other indications.19 At Week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25% (2mg), 40.8% (5mg), and 66.7% (15mg), compared with placebo (2%).19 There has been an explosion of new biologics in the marketplace, with most of the drugs targeting the IL-23 pathway. With the unresolved issue of major adverse cardiovascular events (MACE), some feel that there is a signal at the IL-12/23 blockade level. It will be interesting to see if the MACE signal populates the IL-17 blockers. There has also been an emergence of a wide variety of novel small molecules demonstrating moderate-to-robust efficacies, and the safety profiles for some of these products are promising. Additionally, there has been a move to explore the JAK inhibitor in a topical formulation to treat psoriasis. Psoriasis patients are now the “model” of choice in the treatment of chronic inflammatory disease and practitioners caring for these patients are getting new and emerging therapies earlier now than ever before. Many psoriasis drugs have fallen by the wayside for efficacy and/or safety reasons.
SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY [JULY 2014 • VOLUME 7 • NUMBER 7]
Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2014 MauiDerm Meeting
Figure 5. Apremilast Phase 3 (ESTEEM 1): PASI-75 by prior treatment experience at Week 16
Dermatologists need to consider that short- and long-term safety issues do exist; however, the benefit/risk ratio in emerging systemic therapies for psoriasis appears to be favorable overall. Our treatment paradigm for psoriasis has shifted from a stratified approach (i.e., patients must fail the previous “step” of therapy before initiating a more “aggressive” therapy) to an approach whereby the choice of therapy depends upon individual patient characteristics.
Cardiometabolic Morbidities The association of severe psoriasis with cardiovascular (CV) events and metabolic comorbidities may be due to shared inflammatory pathways. Psoriasis is a chronic inflammatory condition that promotes immune dysregulation mediated by TNF and IL-17 pathways, which affect cardiometabolic processes.20 Current research suggests that people with severe psoriasis die about five years earlier than they should, factoring in all other mortality risks. Psoriasis is no trivial disorder. In a study of patients treated with disease-modifying antirheumatic drugs (DMARDs), the hazard ratio for all-cause mortality for psoriasis patients was 1.8 (1.6–2.0) compared to 1.6 (1.5–1.7) for rheumatoid arthritis (RA) patients and 0.9 (0.8–1.1) for patients with PsA.21 A recent study of the psoriasis transcriptome using 85 paired lesional and nonlesional samples from psoriasis patients found 2,725 unique known genes and functional pathways associated with metabolic and CV disease.22 An unexpected finding of this study was that metabolic and CV gene expression was higher in inflammatory disease categories. For example, psoriasis patients have higher levels of serum renin, and renin is associated with hypertension. A murine study found that skin-specific inflammation could promote aortic root inflammation and thrombosis.23
Figure 6. Apremilast Phase 3 (ESTEEM 1): Select secondary endpoints
High-density lipoproteins (HDL), or “good cholesterol,” are not as effective in psoriasis patients. Independent of traditional risk factors, psoriasis is associated with reduced HDL efflux, an increase in low-density lipoprotein (LDL) particle concentration, and decreased particle size24 as well as increased vascular inflammation, particularly of the aorta, equivalent to 10 years of aging.25 Further support of the connection between psoriasis and cardiometabolic disorders can be found in eight meta-analyses that together analyzed more than 500,000 psoriasis patients and more than 29 million controls.26–33 There are 11,500 incremental MACEs per year in the United States attributable to psoriasis.32 Patients with severe psoriasis taking systemic agents and without traditional cardiac risk factors have a 10year, six-percent risk for MACE, similar to the rate for diabetics. The Incident Health Outcomes and Psoriasis Events (iHOPE) study had general practitioners in the United Kingdom categorize 9,000 psoriasis patients as mild (≤2%), moderate (3–10%), or severe (>10%) based on BSA affected and found that risk of atherosclerotic disease increased with psoriasis severity.34 The risk of diabetes was greater for psoriasis compared to RA in a large population-based study in the United Kingdom. For example, relative risk of new onset diabetes adjusted for major risk factors, such as BMI and oral steroid use, were 1.33 (1.09, 1.61) in PsA, 1.21 (1.15, 1.27) in psoriasis, and 0.94 (0.84, 1.06) in RA.35 There is a 30-percent prevalence of metabolic syndrome in pediatric psoriasis patients,36 indicating that the association begins in childhood. Even controlling for other risk factors (e.g., diabetes and hypertension), moderate-to-severe psoriasis has also been associated with renal dysfunction, elevating patients’ risk of kidney disease two-fold and the likelihood of dialysis fourfold.37 In fact, the risk of renal dysfunction is greater for patients with moderate-to-severe psoriasis than those with diabetes. These associations depend on psoriasis severity; there is no clear association between renal or cardiometabolic
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disorders and mild psoriasis. However, with moderate and severe psoriasis, such associations emerge. Future comorbidity research will likely explore CV risk factors, such as insulin resistance, dyslipidemia, and chronic kidney disease as part of the causal pathway from long-standing psoriatic disease via atherosclerosis to CV disorders. To date, there is only mixed evidence as to whether aggressive treatment of psoriasis, PsA, and RA reduces CV morbidity and mortality. Three important ongoing trials may shed insight: • Vascular Inflammation in Psoriasis Trial (VIP) (NCT01553058). Does adalimumab or phototherapy lower vascular inflammation and improve lipid metabolism in patients with moderate-to-severe psoriasis? • Cardiovascular Inflammation Reduction Trial (CIRT) (NCT01594333). Does methotrexate lower the risk of major vascular events in patients with a history of myocardial infarction, diabetes, or metabolic syndrome? • Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) (NCT01327846). Does IL-1β inhibition reduce MACE rates in patients with stable coronary artery disease? Psoriasis patients should be considered at risk for metabolic disease and those between the ages of 20 and 79 should be screened for traditional CV risk factors every four to six years.38–42
Psoriatic Arthritis PsA refers specifically to an inflammatory arthritis that occurs among patients with skin psoriasis. A number of patients with PsA are under-treated or not under a doctor’s care; some remain undiagnosed. This will hopefully change with greater awareness and more effective treatment options. PsA may quickly cause permanent damage. A recent single-center study found that a six-month delay from initial psoriatic arthritis symptoms to rheumatologist consultation resulted in peripheral joint erosions that exacerbated longterm physical function.43 Multidisciplinary care for PsA is recommended by groups, such as the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).44 Recently, the introduction of highly effective therapies, such as TNF-α blockers, has driven interest in additional research in PsA, not only into newer treatments, but in optimal treatment approaches that can be individualized for each patient. The goals in treating PsA are to improve signs and symptoms of disease, delay or prevent joint damage, maintain functional status, and avoid complications of treatment. A number of factors affect treatment response in PsA, including obesity. Presumably because it is pro-inflammatory, obesity has been shown to attenuate responses to treatment (e.g., with TNF inhibitors).45 If obese patients who take a TNF-α inhibitor lose weight, they can achieve better outcomes. A new class of therapy that is being used already in some countries is S10
biosimilar medications. Also known as “follow-on biologics,” they possess the same amino-acid sequence and other highly similar physical properties (e.g., glycosylation patterns) of socalled originator biologics.46 The potential advantage behind the development of biosimilars is economic because the development program for such drugs may be abbreviated and hence cheaper than for novel therapies. A biosimilar infliximab is already on the market in parts of Europe.47 The United States Food and Drug Administration (FDA) under the Patient Protection and Affordable Care Act has an abbreviated licensure pathway for biosimilars.48 There are still some considerations that will be sorted out for regulatory agencies.49 Biosimilar TNF inhibitors, for example, have been given the full broad indication across diseases in some countries, whereas in other countries regulators have asked for data specific to some diseases. Ustekinumab, a drug used worldwide for psoriasis, has been studied in PsA, and recently received regulatory approval.50–52 Safety data with ustekinumab for psoriasis for five years (n=3,117 or 8,998 patient-years) have been published recently, with rates of AEs generally comparable to other biologics.53 The ongoing Psoriasis Longitudinal Assessment and Registry (PSOLAR) follows patients who are taking or are candidates for systemic psoriasis therapy.54 Currently, 9,495 patients at 266 centers around the world are followed. Mean BSA affected by psoriasis is 12.3 percent, roughly 80 percent of patients are overweight or obese, and 38.8 percent have CV comorbidities. A total of 7,476 patients in the registry have been exposed to at least one biologic agent. Rates of serious infections, malignancy, all-cause mortality, and MACE are 1.40, 0.61, 0.37, and 0.36, respectively, per 100 patient-years of follow-up. The goal for the treatment of PsA should be remission or as low a level of disease activity as possible. Tight control, that is, frequent clinical assessments with therapeutic adjustments as needed in order to try to achieve remission, is the model that has been assessed in rheumatoid arthritis; it has been proposed as a potentially useful treatment approach for PsA patients and has been shown capable of producing better outcomes.55,56
Prevalence of Psoriatic Arthritis in Psoriasis The prevalence of PsA among psoriasis patients has been estimated to be as low as six percent and as high as more than 40 percent.57–60 At present, it is generally considered that about 20 to 30 percent of psoriasis patients will develop PsA.61 Interestingly, for 80 percent or more of patients, the typical presentation is skin disease first, followed by joint involvement years later. In addition to causing joint pain and damage, PsA can drastically reduce quality of life and negatively impact work productivity.62 PsA patients are at risk for numerous comorbidities, including depression,63 metabolic syndrome, and CV disorders.61 PsA requires a clinical diagnosis, as there are no
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Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2014 MauiDerm Meeting
pathognomonic, serologic, or other diagnostic tests. The Classification of Psoriatic Arthritis (CASPAR) criteria are helpful when inflammatory arthritis is present.64 A number of screening tools have been developed for PsA, including, but not limited to, the Psoriasis Epidemiology Screening Tool (PEST), ToPAS (Toronto Psoriatic Arthritis Screening questionnaire), and PASE (Psoriatic Arthritis Screening and Evaluation).65 These are helpful, but no individual test is perfect for all patients. TNF-α inhibitors, including etanercept, infliximab, adalimumab, golimumab, and, most recently, certolizumab pegol, have changed the treatment paradigm for PsA. Rotating from one TNF-α antagonist to another may be a reasonable strategy for some patients.66,67 Ustekinumab, an IL12/23 inhibitor, has recently been approved for PsA. Aprelimast, an oral agent that inhibits PDE4, was approved in 2014 for the treatment of PsA. Other drugs under study in PsA include IL-17 inhibitors (e.g., brodalumab, ixekizumab, secukinumab). The JAK inhibitor tofacitinib is also being investigated for use in PsA.
Scalp Psoriasis Despite the scalp’s extensive vascular network, scalp psoriasis can be a recalcitrant condition, even when appropriately treated. Poor outcomes with scalp psoriasis mostly owe to poor adherence. For that reason, dermatologists treating scalp psoriasis should select topical remedies available in a patient-friendly vehicle to encourage compliance. Since most chronic plaque psoriasis patients will develop some form of scalp psoriasis, effective scalp products are important for the long-term care of the patient.68 The main treatment modalities are topical corticosteroids and vitamin D, which may be used as monotherapies.69 Adding a steroid to a vitamin D analog or other combination can improve outcomes because it leads to earlier results and thus encourages adherence. Betamethasone valerate “mousse,” a low-residue foam vehicle, was tested in 241 patients with severe scalp psoriasis as compared with betamethasone valerate lotion and the two vehicles. After four weeks of treatment, betamethasone valerate foam was more effective than the lotion-based standard treatment on scalp psoriasis (88% of patients had complete or nearly complete resolution of scaling vs. 66% using standard therapy, p5 AKs and field cancerization), and high-risk AKs (e.g., immunosuppressed and/or high-risk location). The new AK guidelines will use the following 5-point GRADE (Grading of Recommendations Assessment, Development and Evaluation) system: 1=strong recommendation for use; 2=weak recommendation for use; 3=no; 4=weak recommendation against; 5=strong recommendation against.89 The guidelines will also feature a flowchart for managing patients with AKs.
Other Skin Cancers and Benign Tumors Sebaceous hyperplasia. Sebaceous hyperplasia involves enlarged but benign sebaceous glands, which develop round papules with a central dell; these papules are generally less than 3mm in diameter. The papules may appear yellow. Telangiectasia may be visible on the surface and the appearance can mimic that of basal cell carcinoma (BCC). Sebaceous hyperplasia is often located around a central hair follicle or duct that can create a donut-shaped appearance. The prevalence of sebaceous S14
hyperplasia is greater among individuals 40 years of age or older, and risk increases with age. They typically appear on the face and are most common in people who have always had oily skin. There are no particular predilections by race, ethnicity, or gender. Sebaceous hyperplasia is associated with Muir-Torre syndrome, Cowden syndrome, and Gardner’s syndrome. Although sebaceous hyperplasia is relatively common, effective, non-scarring permanent removal is lacking. Most therapies target only the superficial component of the lesion. A new 1,720nm laser has been shown to effectively treat the entire sebaceous hyperplasia lesion in one or two treatments with crusting resolving in about 10 days.90 This treatment is based on the observation that human fat has absorption peaks at 1,210 and 1,720nm and this laser selectively treats at 1,720nm. Low-dose isotretinoin is an effective way of reducing the size of sebaceous hyperplasia. It should be commenced at 10mg/week and then titrated to 20mg/week, 30mg/week, and so on. Isotretinoin is a known teratogenic agent, and US patients must be enrolled in the national iPLEDGE program in order to receive isotretinoin therapy. Treatment considerations of sebaceous hyperplasia are provided in Table 2. Nevus sebaceous of Jadassohn. Nevus sebaceous of Jadassohn (NSJ), sometimes called Jadassohn Nevus, organoid nevus, or nevus sebaceous, is a smooth, hairless, yellow-orange variant of epidermal nevus. Nevus sebaceous regions contain sebaceous glands, hair follicles, apocrine glands, and connective tissue. They are mainly found on the scalp or the forehead in proximity to the scalp and more rarely on the face and neck. A differential diagnosis of NSJ must consider aplasia cutis, mastocytoma, and juvenile xanthogranuloma (JXG). NSJ occurs about equally in men and women with no particular ethnic predilections. Most NSJ patients have NSJ at birth, but lesions may grow more prominent over time. There is low risk for other tumors growing within the nevus sebaceous area, including BCC and sebaceous carcinoma. Associated syndromes include epidermal nevus syndrome, Schimmelpenning syndrome, proteus syndrome, and CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects, a condition that occurs only in females). There are two main schools of thought for the treatment of NSJ. The first is a “watch and wait” approach where clinicians intervene only if a tumor develops within the lesion. The other approach is prophylactic excision that should occur before puberty. The latter avoids the problems associated with a larger lesion should a tumor develop and cosmetic benefits for the child. If a malignant tumor develops, Mohs surgery is the recommended treatment. The cumulative incidence of malignant tumors developing in NSJ patients is approximately two percent.91 Sebaceous gland carcinoma (SGC). Sebaceous gland carcinoma (SGC) is a relatively uncommon, but aggressive cutaneous neoplasm that arises from the sebaceous glands in the skin, three-quarters of which occur in the periocular region. These tumors arise from the sebaceous glands around the eyes: Meibomian glands (tarsal plates, 50–70%), glands of Zeis (eyelash cilia, 10%), or more rarely the glands of caruncle. About 12 to 15 percent of these tumors have a multicentric origin. They develop as painless, yellow-to-pink nodules that enlarge slowly.
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Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2014 MauiDerm Meeting
There is a high risk for local recurrence. The risk for metastasis is controversial but significant. SGC ocular tumors comprise less than one percent of all eyelid tumors and about 1 to 5 percent of all eyelid malignancies. They are 2 to 3 times more common in the upper than lower eyelid, occur more often in women than men, and are more common among Asians. They typically occur in people around 60 to 70 years of age and rarely in children. Because they mimic benign eye conditions, including keratoconjunctivitis, chalazion, blepharoconjunctivitis, and ocular pemphigoid, diagnosis is typically delayed 1 to 3 years. SGC ocular tumors can have a similar appearance to periocular BCC or SCC, but the latter are more likely to occur on the lower lid. Clinicians should suspect SGC with chalazions that do not heal, loss of cilia, yellow streaks on the conjunctiva, increased vascularity of the eye, and chronic unilateral eye inflammation. Chalazion is the most common misdiagnosis of sebaceous carcinoma. Pagetoid or intraepithelial spread into the conjunctiva can result in keratoconjunctivitis or blepharoconjunctivitis, which is often misdiagnosed as blepharitis. Extraocular SGC composes about a quarter of all sebaceous gland cancers and most commonly presents on the parotid gland, head, or neck as a yellow, tan, or pink nodule or papule. It is rare, but possible for extraocular SGC to appear on the genitalia, ear canal, breast, nasal vestibule, or axilla. A retrospective study of 91 cases showed recurrence in 29 percent and metastasis in 21 percent of cases.92 Muir-Torre syndrome. Muir-Torre syndrome (MTS), identified independently by two investigators in 1967, is a rare autosomal dominant genodermatosis caused by a mutation in one of the mismatch repair genes (MLH1, MSH2, MSH6). This results in a concurrent or sequential development of sebaceous neoplasms with an internal malignancy; the cancer is often a multiple, low-grade, visceral malignancy, such as colorectal (most common), genitourinary, breast, or hematological cancer. A study of 120 patients with MTS reported that 24 percent of patients with MTS developed sebaceous carcinoma. Patients can be screened for Muir-Torre syndrome by testing sebaceous lesions for microsatellite instability or by use of immunohistochemical staining to look for mismatch repair genes. Gorlin syndrome (basal cell nevus syndrome). Gorlin syndrome, also known as basal cell nevus syndrome, is a rare hereditary condition that predisposes the patient to develop multiple BCCs.93 It occurs in people with one defective copy (autosomal dominant) of the PTCH1 gene. Clinical manifestations include BCCs, cysts on the jaw (odontogenic keratocysts), palmar and/or plantar pits, and ectopic calcifications.94 It is associated with numerous congenital defects, including, but not limited to, polydactyly, macroencephaly, broad faces, immobile thumbs, and others.95 Metastatic basal cell carcinoma. Until recently, metastatic BCC has been treated with systemic chemotherapy, such as cisplatin or cisplatin with doxorubicin or targeted therapy with cetuximab, an epidermal growth factor receptor antibody.96 A new and novel therapy for the treatment of locally advanced and metastatic BCC is vismodegib (Erivedge®,
Genentech), a recently approved agent to treat BCC that has metastasized, relapsed after surgery, or cannot be treated by surgery or radiation. It is the first drug that targets the so-called hedgehog signaling pathways. Hedgehog signaling occurs along signaling pathways that transmit information to embryonic cells required for development; BCC is associated with hedgehog signaling malfunctions. Adult stem cells require hedgehog signaling in the regulation and maintenance of adult tissues. Sonic hedgehog (SHH) is the best studied ligand of the vertebrate pathway. The hedgehog pathways include hedgehog ligands (encoded by the hedgehog gene), a patched molecule (PTCH) controlled by a PTCH gene (thought to be an inhibitory receptor or tumor suppressor), a smoothened (SMO) molecule or signaling receptor or oncogene, and the Gli family of transcription factors. When signaling is inactive, PTCH inhibits SMO activity (Figure 7).97 The hedgehog pathway is activated by the hedgehog ligand binding to PTCH, which removes the SMO’s inhibitory effect and eventually will result in gene expression (Figure 8). Ninety percent of sporadic BCCs have inactivating mutations in the PTCH genes, while 10 percent of sporadic BCCs have activating mutations in the SMO gene. Gorlin syndrome is a disorder of the germ-line heterozygous mutations in the PTCH gene. These mutations are associated with basal cell carcinomas (Figures 9A and 9B). Vismodegib is a hedgehog pathway inhibitor (HPI), a small molecule that binds to SMO1–4 where it acts as a highly potent, selective SMO inhibitor. The drug is available in oral capsules for once-daily dosing (150mg/day), and micromolar plasma concentrations were achieved with one oral dose of 150mg.98 Vismodegib binds to SMO, directly blocking the hedgehog signaling pathway in BCC that are driven by either inactivating mutations of PTCH or activating mutations of SMO. Vismodegib inhibits signal transduction so there is no targeted gene expression and, in so doing, it inhibits the tumor. It does not matter if the mutation is PTCH or SMO; vismodegib inhibits both mutations. The ERIVANCE BCC was the pivotal Phase 2 trial of vismodegib in the treatment of advanced BCC.99 The study had two patient cohorts: metastatic BCC patients (with BCC that was measurable by imaging) and patients with locally advanced BCC. Locally advanced BCC was defined in the study as a BCC tumor that was either inoperable or where surgery was inappropriate with tumors more than 1cm in diameter and characterized by two or more recurrences following surgery, rendering curative resection unlikely or only possible with substantial morbidity and/or deformity from surgery. All patients were treated with vismodegib 150mg daily until disease progression or withdrawal from the study for toxicity or other reasons. Responses were assessed in the metastatic cohort using imaging and Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Responses were measured in the local BCC cohort using a novel composite endpoint that included measurable diameter and ulceration of the visible tumor along with RECIST measures of the deeper tumor component (when present). The primary endpoint was the objective response rate, with secondary endpoints being duration of response, progression-free survival, and absence of residual BCC on biopsy for the local BCC patient cohort. Tumor regression, measured as
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Figure 7. In the absence of the hedgehog ligand, PTCH inhibits SMO and the hedgehog signaling pathway is suppressed.
Figure 8. Hedgehog signaling pathway overview; target gene expression is initiated by hedgehog ligand binding to patch.
change in lesion diameter as a percentage, was marked. Among metastatic BCC patients (n=33), the independently assessed response rate was 30 percent (95% CI, 16–48, p=0.001) compared to the local BCC cohort with an independently assessed response rate of 43 percent (95% CI, 31–56, p
