SupplemeNt to the September 2013 iSSue of
www.jcadonline.com
A PEER-REVIEWED JOURNAL PROVIDING EVIDENCE-BASED INFORMATION TO PRACTICING CLINICIANS
Vol. 6, No. 9 (SupplemeNt) • September 2013
Updates on Psoriasis and Cutaneous Oncology Proceedings from the 2013 MauiDerm Meeting
Scan this QR code with your QR reader for the digital edition of this JCAD supplement.
Support provided2013 by •Janssen Inc. and Medicis [SEPTEMBER VOLUME 6Pharmaceuticals, • NUMBER 9 ] SUPPL EMENT TO THE JOURNAL
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OF CLINICAL AND AESTHETIC DE RMATOLOGY
Authors
Andrew Blauvelt, MD, MBA Oregon Medical Research Center, Portland, Oregon
Marc Brown, MD University of Rochester School of Medicine and Dentistry, Rochester, New York
Kenneth B. Gordon, MD Northwestern University, Feinberg School of Medicine, Chicago, Illinois
Arthur Kavanaugh, MD University of California, San Diego, San Diego, California
Craig T. Leonardi, MD St. Louis University School of Medicine, St. Louis, Missouri
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
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. The dermatology landscape is ever changing and there have been significant advances in the diagnosis, management, and treatment of both medical and cosmetic dermatologic conditions. MauiDerm’s world-renowned experts have discussed these topics 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 2013 MauiDerm meeting in January 2013. George Martin, MD Dermatology Laser Center Maui, Kihei, Hawaii
Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2013 MauiDerm Meeting
Updates on Psoriasis and Cutaneous Oncology Proceedings from the 2013 MauiDerm Meeting
Introduction Psoriasis. There are 41 genetic susceptibility loci identified with considerable overlap to other autoimmune disorders. The pathogenesis of psoriasis involves the interplay between innate immune response and acquired immunity related to the interleukin (IL)-23 and Th17 pathway. New agents in Phase 3 trials include IL-17 and IL17 receptor blockers (secukinumab, ixekizumab, brodalumab). So-called “third-generation” drugs for psoriasis include those that block proteins in the IL-23/Th17 pathway, including ustekinumab and those under development (tildrakizumab, guselkumab, secukinumab, ixekizumab, and brodalumab). Recent long-term safety data on ustekinumab report rates of adverse events lower or similar to those of other biologic agents. Phosphodiesterase-4 (PDE-4) inhibitors, such as apremilast, are in late-stage clinical trials. Additional new small-molecule therapy includes tofacitinib, a drug that blocks the Janus kinase (JAK) pathway, implicated in inflammation. Pharmacological therapy effective in treating psoriatic arthritis can be used to treat skin psoriasis, but with varying levels of effectiveness and tolerability. Indeed, dermatologists may be able to leverage the use of a variety of drugs used for other rheumatologic conditions to treat psoriasis (and vice versa). In 1997, the World Health Organization (WHO) declared that obesity was a global epidemic and, this year, in 2013, the American Medical Association has classified obesity as a disease. Obesity affects about 500 million adults globally; in the United States, about 30 to 35 percent of the population is obese. Obesity is comorbid with many heath conditions, including, but not limited to, osteoarthritis, obstructive sleep apnea, diabetes, cardiovascular disease, and other diseases associated with
chronic inflammation. This chronic inflammation may play a role in psoriasis and may explain why obese individuals have lower response rates to certain psoriasis therapies, such as occurred in the PSUMMIT1 trial. Given the prevalence of obesity, the connection between obesity and psoriasis will be an important clinical focus in the future. Recent investigations and meta-analyses confirm the association between psoriasis and diabetes mellitus type 2 along with other cardiovascular risk factors, such as hypertension, hyperlipidemia, and coronary artery disease. These diseases may share certain genetic susceptibility. However, it cannot be overlooked that the psoriasis population has a higher rate of independent risk factors for heart disease, such as smoking, alcohol misuse, and obesity. The so-called “psoriatic march” suggests that psoriasis drives heart disease. However, an older retrospective Veterans Affairs (VA) study suggests that reducing chronic inflammation via methotrexate may reduce cardiovascular risk as well as treat psoriasis. More recently, studies have shown that biologic use is also associated with fewer cardiovascular events over time. Cutaneous oncology. Mohs micrographic surgery remains an important mainstay in dermatology although not every patient with basal cell carcinoma should be considered a candidate. The risks associated with Mohs surgery can be highly individual, depending on the location of the cancer, the nature of the tumor, and whether or not the patient is immunosuppressed. Prevalent and challenging to treat, squamous cell carcinoma requires careful evaluation and a detailed personalized care plan for optimal outcomes. The location of the tumor, the depth of the invasion, and whether or not perineural invasion has occurred may significantly impact surgical success. Immunosuppressed patients are at greater risk of metastases. When the tumor and location are high risk, adjunct radiation therapy may be indicated.
[SEPTEMBER 2013 • VOLUME 6 • NUMBER 9 ] SUPPL EMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DE RMATOLOGY
S9
Psoriasis Update Immunology and Psoriasis Psoriasis genetics and pathogenesis are far more complex than originally thought, with 15 new genetic susceptibility loci identified, to be added to the 26 known loci. These 41 genetic signals account for about 22 percent of estimated psoriasis heritability.1 These known psoriasis genes have considerable overlap with genes associated with other autoimmune disorders, such as Crohn’s disease, ulcerative colitis, celiac disease, ankylosing spondylitis, rheumatoid arthritis, systemic lupus, multiple sclerosis, and diabetes types 1 and 2.2 For example, Crohn’s disease shares 11 of the 41 susceptibility genes with psoriasis and 6 of those 11 are related to interleukin-23 (IL-23) and T-helper-17 (Th17) signaling (IL12B [p40], IL23R, TYK2, JAK2, SOCS, and STAT3). This suggests that Crohn’s disease may respond to IL-23/Th17 blockade.3 All of the known psoriasis genes can be grouped into five main functional categories (Table 1). Mutations in the IL-36 receptor antagonist lead to generalized pustular psoriasis.4 In contrast, decreased IL-36 receptor antagonist activity leads to an increase in IL-36 signaling and increased pro-inflammatory cytokine production by keratinocytes. In a large genetic study, a mutation in CARD14 (G to A) at position 349 in chromosome 17 was seen in all individuals with psoriasis from two large cohort families.5 CARD14 mutations lead to increased nuclear factor-kappaB (NF-kB) activity and increased pro-inflammatory cytokine production by keratinocytes. Numerous CARD14 variations have been associated with psoriasis, all of which translate into increased NF-kB activity in keratinocytes. In humans, the IL23R R381Q gene variant protects against immune-system-mediated diseases by impairing the IL-23induced Th17 effector response.6 At IL-23R, position 38, the GG variant increases IL-23 signaling, increases IL-17A
production, and can result in psoriasis. The GA variant results in intermediate IL-23 signaling and IL-17A production. However, the AA variant decreases IL-23 signaling and IL-17A levels, conferring a protective effect against psoriasis. Polymorphisms in p19, p40, and IL-23R have been linked to both protection from and susceptibility to psoriasis. Thus, the pathogenesis of psoriasis represents a complex interplay between innate and mostly skin-specific immune responses and acquired immunity, often associated with the IL-23/Th17 pathway.7 The IL-23 and IL-17A pathways involve activation of Th17 leading to pro-inflammatory cytokine production, antimicrobial peptide production, neutrophil accumulation, and a proliferation of keratinocytes (Figure 1). IL-23-induced epidermal hyperplasia is dependent upon IL-17A and IL-22, although neither IL-17A nor IL-22 by itself is sufficient to cause IL-23-mediated epidermal hyperplasia.8 IL17A plays an essential role in cell activation and inflammatory gene circuits in psoriasis patients. In a study of ixekizumab (an anti-IL-17A mAb agent) compared to etanercept, ixekizumab led to a greater down-modulation of psoriasis-related gene expression than the comparator.9 IL-23 is blocked selectively by three new anti-p19 mAb drugs: tildrakizumab (Merck, Phase 3 studies recently underway), guselkumab (Janssen, recently completed Phase 2 studies), and AMG 139 (Amgen, now in Phase 1 studies). Selective IL-17A blockers include secukinumab and ixekizumab, whereas brodalumab selectively blocks the IL17RA receptor (Table 2). These new agents are currently being studied and results in terms of safety and efficacy in the treatment of psoriasis appear promising. Acquired T-cell immunity is associated with a continuum of immunological responses in skin with regard to extracellular pathogens, such as Candida and Staphylococcus (Figure 2). Excessive Th17 response can result in psoriasis, while a lack of Th17 response prevents psoriasis, but may lead to the development of chronic mucocutaneous infection. Job syndrome, also known as hyperimmunoglobulin E
TABLE 1. Known psoriasis genes by categories CATEGORY
DESCRIPTION
IL-23/Th17 cell activation
Acquired
Antigen presentation
Acquired
Type I interferon induction
Innate
NF-kB signaling
Innate
Skin barrier function
Innate
Of note, genes that are exclusively specific to psoriasis (that is, have no other disease associations) are mostly associated with innate immunity.
S1 0
Figure 1. IL-23 and IL-17A pathways implicated in psoriasis.
SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AE STHETIC DERMAT OLOGY [SE PTE MBER 201 3 • VOL UME 6 • NUMBE R 9]
Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2013 MauiDerm Meeting
TABLE 2. New agents that block the actions of IL-17A AGENT
DESCRIPTION
INVESTIGATION/PUBLICATION
MANUFACTURER
Secukinumab
Fully human anti-IL-17A mAb
Phase 3, phase 2 studies have been published10,11
Novartis
Ixekizumab
Humanized anti-IL-17A mAb
Phase 3, phase 2 studies published12–14
Lilly
Brodalumab
Fully human anti-IL-17RA receptor mAb
Phase 3, phase 2 study published15
Amgen
syndrome, occurs in patients with a defect in STAT3, making their Th1 cells normal, their Th2 cells active, and their Th17 cells absent. Job syndrome is characterized by severe eczema-like skin disease (but no psoriasis), frequent staphylococcal infections of the skin, and chronic candidiasis.16 In addition, IL-17A plays a role in the pathogenesis of atherosclerosis.17 Drugs that block IL-17A may reduce atherosclerotic disease, which may explain why fewer than Figure 2. Acquired T-cell immunity and the spectrum of clinical disease manifestations expected major adverse cardiac events (MACE) occurred in a study following psoriatic patients who took ustekinumab for issues must be considered (Table 3). four years.18 Ustekinumab is a human monoclonal antibody that binds Future research is needed to explore whether drugs that with high affinity to shared p40 protein subunits of IL-12 and inhibit IL-23 and/or IL-17 might cause or worsen skin and IL-23. These cytokines, especially the latter, are thought to mucosal infections. Moreover, more investigation is needed as play key roles in the inflammatory cascade of psoriasis. IL-12 to whether these agents might decrease systemic antiand IL-23 production by dendritic cells results in the upinflammatory activity, that is, whether they might decrease regulation of many downstream cytokines, resulting in the atherosclerosis and, if so, the clinical ramifications of this stimulation of keratinocyte proliferation and secretion of decrease. antimicrobial peptides; this could explain the reduction in The pathogenesis of plaque psoriasis is incompletely psoriasis-related skin infections.22 In the PHOENIX I elucidated, but it appears to depend on the interaction of randomized, double-blind, placebo-controlled, multicenter environmental factors with genetic factors, leading to a trial (n=766), patients received ustekinumab 45mg or 90mg at dysregulated immune response in which the cytokine IL-17 Weeks 0 and 4 and then every 12 weeks or placebo (with appears to play a key role.19 It is likely that agents targeting IL17 will be of growing importance in the pharmacologic crossover to ustekinumab at 12 weeks).22 Psoriasis area and management of psoriasis, whether these agents neutralize ILseverity index (PASI)-75 scores at Week 12 were achieved by 17A (secukinumab and ixekizumab) or antagonize its receptor 67.1 and 66.4 percent of the ustekinumab 45mg and 90mg (brodalumab).20 Indeed, the history of drug development for patients, respectively, compared to 3.1 percent of placebo the treatment of plaque psoriasis parallels our growing patients. Adverse events occurred in 54.5 percent of understanding of the disease mechanisms. ustekinumab and 48.2 percent of placebo patients; serious Drug development for psoriasis falls into two distinct adverse events occurred in 1.2 and 0.8 percent of these periods. From 1987 to 2001, drugs to treat psoriasis included patients, respectively. Results were maintained for at least a etretinate, acitretin, and cyclosporine. From 2002 to the year in PHOENIX patients who received ustekinumab for 12 present, several first-generation biologics entered the market, weeks; such durable effects were not seen in those who such as alefacept and efalizumab, but these agents have since discontinued treatment before 12 weeks. In the PHOENIX II been withdrawn. Second-generation psoriasis biologics trial (n=1,230) dosing intensification of ustekinumab 90mg included etanercept, infliximab, and adalimumab. These drugs every eight weeks elicited response from certain patients who target tumor necrosis factor alpha (TNF-α). Third-generation did not respond fully to the initial regimen (45 or 90mg at biologics, such as ustekinumab and the pipeline drugs Weeks 0 and 4, then every 12 weeks).23 The primary endpoint, 21 mentioned earlier, target the IL-23/Th17 pathway. Today, a PASI-75, was achieved initially by 66.7 and 75.7 percent of the plethora of new drugs are in development, including both oral ustekinumab 45mg and 90mg groups, respectively (versus and topical formulations. While the risk/benefit ratio of these 3.7% of placebo patients) and significantly more partial agents still favors the patient, short-term and long-term safety responders achieved the PASI-75 score with the accelerated [SEPTEMBER 2013 • VOLUME 6 • NUMBER 9 ] SUPPL EMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DE RMATOLOGY
S11
TABLE 3. A brief history of drug development for the treatment of psoriasis TARGET
DRUG
BRAND NAME, COMPANY
HISTORY
First Generation Biologics
Efalizumab
Raptiva, Genentech
Approved 2003, withdrawn 2009 due to progressive multifocal leukoencephalopathy
T-cell inhibitors
Alefacept
Amevive, Biogen Astellas
Approved 2002, withdrawn 2012 for lack of use
Adalimumab
Humira, Abbott/Abbvie
Approved 2002 for rheumatoid arthritis; its indication for psoriasis was the drug’s fifth indication, approved in 2008
Certolizumab pegol
Cimzia, UCB
Approved in 2008 for Crohn’s disease and in Europe in 2009 for rheumatoid arthritis
Etanercept
Enbrel, Amgen
TNF-receptor fusion protein approved for psoriasis in 2004
Infliximab
Remicade, Centocor
Approved in 1998 for rheumatoid arthritis; psoriasis is the most recently approved indication
Ustekinumab (IL-12 and -23)
Stelara, Centocor
Approved in 2009 for psoriasis
ABX-IL8 (IL-8)
Abgenix, subsequently acquired by Amgen
Oprelvikin (IL-11)
Neumega, Wyeth
Second Generation
TNF-α, cytokine inhibitors
Third Generation
Indicated for severe thrombocytopenia
Not named (IL-18-BP) Serono Interleukin (IL) cytokine inhibitors
Tildrakizumab
Merck
Phase 3 studies recently underway
Guselkumab
Janssen
Recently completed Phase 2 studies
Secukinumab
Novartis
Phase 3 studies recently underway
Ixekizumab
Eli Lilly
Phase 3 studies recently underway
Brodalumab
Amgen
Phase 3 studies recently underway
eight-week 90mg dosing regimen.22 Adverse events with ustekinumab appear to be stable over time and occur at a low rate. A meta-analysis of MACE with ustekinumab and other biologics (n=183, 22 randomized clinical trials) found no significant difference in the MACE rates among patients taking anti-IL-12, IL-23, and anti-TNF-α agents.24 Ustekinumab has an acceptable safety profile for up to five years of exposure.25 Pooled safety data from four ustekinumab studies in psoriasis patients (n=3,117 patients and 8,998 patient-years) treated for up to five years revealed no dose-related or cumulative toxicity, even with prolonged exposure; rates of adverse events were generally comparable S1 2
to those of other biologic agents approved for treatment of moderate-to-severe psoriasis.26 For doses of 45mg and 90mg, the reported serious adverse events were 7.0 and 7.2 percent, respectively; serious infections were 0.98 and 1.19 percent, respectively; and MACEs were 0.56 and 0.36 percent, respectively. Mortality and malignancy rates were comparable to the general population. New developments include drugs that target IL-17A, namely ixekizumab, secukinumab, and the IL-17RA receptor (brodalumab), which targets the receptor for IL-17A, F, and C. In a Phase II, double-blind, placebo-controlled trial (n=142), patients with moderate-to-severe plaque psoriasis received
SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AE STHETIC DERMAT OLOGY [SE PTE MBER 201 3 • VOL UME 6 • NUMBE R 9]
Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2013 MauiDerm Meeting
subcutaneous injections of 10, 25, 75, or 150mg of ixekizumab or placebo at 0, 2, 4, 8, 12, and 16 weeks.12 At Week 12, 82.1 percent of 150mg patients, 82.8 percent of 75mg, and 76.7 percent of 25mg patients had achieved the primary endpoint of a PASI-75 score or better compared to 7.7 percent of placebo patients (p
www.jcadonline.com
A PEER-REVIEWED JOURNAL PROVIDING EVIDENCE-BASED INFORMATION TO PRACTICING CLINICIANS
Vol. 6, No. 9 (SupplemeNt) • September 2013
Updates on Psoriasis and Cutaneous Oncology Proceedings from the 2013 MauiDerm Meeting
Scan this QR code with your QR reader for the digital edition of this JCAD supplement.
Support provided2013 by •Janssen Inc. and Medicis [SEPTEMBER VOLUME 6Pharmaceuticals, • NUMBER 9 ] SUPPL EMENT TO THE JOURNAL
SC1 www.jcadonline.com
OF CLINICAL AND AESTHETIC DE RMATOLOGY
Authors
Andrew Blauvelt, MD, MBA Oregon Medical Research Center, Portland, Oregon
Marc Brown, MD University of Rochester School of Medicine and Dentistry, Rochester, New York
Kenneth B. Gordon, MD Northwestern University, Feinberg School of Medicine, Chicago, Illinois
Arthur Kavanaugh, MD University of California, San Diego, San Diego, California
Craig T. Leonardi, MD St. Louis University School of Medicine, St. Louis, Missouri
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
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. The dermatology landscape is ever changing and there have been significant advances in the diagnosis, management, and treatment of both medical and cosmetic dermatologic conditions. MauiDerm’s world-renowned experts have discussed these topics 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 2013 MauiDerm meeting in January 2013. George Martin, MD Dermatology Laser Center Maui, Kihei, Hawaii
Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2013 MauiDerm Meeting
Updates on Psoriasis and Cutaneous Oncology Proceedings from the 2013 MauiDerm Meeting
Introduction Psoriasis. There are 41 genetic susceptibility loci identified with considerable overlap to other autoimmune disorders. The pathogenesis of psoriasis involves the interplay between innate immune response and acquired immunity related to the interleukin (IL)-23 and Th17 pathway. New agents in Phase 3 trials include IL-17 and IL17 receptor blockers (secukinumab, ixekizumab, brodalumab). So-called “third-generation” drugs for psoriasis include those that block proteins in the IL-23/Th17 pathway, including ustekinumab and those under development (tildrakizumab, guselkumab, secukinumab, ixekizumab, and brodalumab). Recent long-term safety data on ustekinumab report rates of adverse events lower or similar to those of other biologic agents. Phosphodiesterase-4 (PDE-4) inhibitors, such as apremilast, are in late-stage clinical trials. Additional new small-molecule therapy includes tofacitinib, a drug that blocks the Janus kinase (JAK) pathway, implicated in inflammation. Pharmacological therapy effective in treating psoriatic arthritis can be used to treat skin psoriasis, but with varying levels of effectiveness and tolerability. Indeed, dermatologists may be able to leverage the use of a variety of drugs used for other rheumatologic conditions to treat psoriasis (and vice versa). In 1997, the World Health Organization (WHO) declared that obesity was a global epidemic and, this year, in 2013, the American Medical Association has classified obesity as a disease. Obesity affects about 500 million adults globally; in the United States, about 30 to 35 percent of the population is obese. Obesity is comorbid with many heath conditions, including, but not limited to, osteoarthritis, obstructive sleep apnea, diabetes, cardiovascular disease, and other diseases associated with
chronic inflammation. This chronic inflammation may play a role in psoriasis and may explain why obese individuals have lower response rates to certain psoriasis therapies, such as occurred in the PSUMMIT1 trial. Given the prevalence of obesity, the connection between obesity and psoriasis will be an important clinical focus in the future. Recent investigations and meta-analyses confirm the association between psoriasis and diabetes mellitus type 2 along with other cardiovascular risk factors, such as hypertension, hyperlipidemia, and coronary artery disease. These diseases may share certain genetic susceptibility. However, it cannot be overlooked that the psoriasis population has a higher rate of independent risk factors for heart disease, such as smoking, alcohol misuse, and obesity. The so-called “psoriatic march” suggests that psoriasis drives heart disease. However, an older retrospective Veterans Affairs (VA) study suggests that reducing chronic inflammation via methotrexate may reduce cardiovascular risk as well as treat psoriasis. More recently, studies have shown that biologic use is also associated with fewer cardiovascular events over time. Cutaneous oncology. Mohs micrographic surgery remains an important mainstay in dermatology although not every patient with basal cell carcinoma should be considered a candidate. The risks associated with Mohs surgery can be highly individual, depending on the location of the cancer, the nature of the tumor, and whether or not the patient is immunosuppressed. Prevalent and challenging to treat, squamous cell carcinoma requires careful evaluation and a detailed personalized care plan for optimal outcomes. The location of the tumor, the depth of the invasion, and whether or not perineural invasion has occurred may significantly impact surgical success. Immunosuppressed patients are at greater risk of metastases. When the tumor and location are high risk, adjunct radiation therapy may be indicated.
[SEPTEMBER 2013 • VOLUME 6 • NUMBER 9 ] SUPPL EMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DE RMATOLOGY
S9
Psoriasis Update Immunology and Psoriasis Psoriasis genetics and pathogenesis are far more complex than originally thought, with 15 new genetic susceptibility loci identified, to be added to the 26 known loci. These 41 genetic signals account for about 22 percent of estimated psoriasis heritability.1 These known psoriasis genes have considerable overlap with genes associated with other autoimmune disorders, such as Crohn’s disease, ulcerative colitis, celiac disease, ankylosing spondylitis, rheumatoid arthritis, systemic lupus, multiple sclerosis, and diabetes types 1 and 2.2 For example, Crohn’s disease shares 11 of the 41 susceptibility genes with psoriasis and 6 of those 11 are related to interleukin-23 (IL-23) and T-helper-17 (Th17) signaling (IL12B [p40], IL23R, TYK2, JAK2, SOCS, and STAT3). This suggests that Crohn’s disease may respond to IL-23/Th17 blockade.3 All of the known psoriasis genes can be grouped into five main functional categories (Table 1). Mutations in the IL-36 receptor antagonist lead to generalized pustular psoriasis.4 In contrast, decreased IL-36 receptor antagonist activity leads to an increase in IL-36 signaling and increased pro-inflammatory cytokine production by keratinocytes. In a large genetic study, a mutation in CARD14 (G to A) at position 349 in chromosome 17 was seen in all individuals with psoriasis from two large cohort families.5 CARD14 mutations lead to increased nuclear factor-kappaB (NF-kB) activity and increased pro-inflammatory cytokine production by keratinocytes. Numerous CARD14 variations have been associated with psoriasis, all of which translate into increased NF-kB activity in keratinocytes. In humans, the IL23R R381Q gene variant protects against immune-system-mediated diseases by impairing the IL-23induced Th17 effector response.6 At IL-23R, position 38, the GG variant increases IL-23 signaling, increases IL-17A
production, and can result in psoriasis. The GA variant results in intermediate IL-23 signaling and IL-17A production. However, the AA variant decreases IL-23 signaling and IL-17A levels, conferring a protective effect against psoriasis. Polymorphisms in p19, p40, and IL-23R have been linked to both protection from and susceptibility to psoriasis. Thus, the pathogenesis of psoriasis represents a complex interplay between innate and mostly skin-specific immune responses and acquired immunity, often associated with the IL-23/Th17 pathway.7 The IL-23 and IL-17A pathways involve activation of Th17 leading to pro-inflammatory cytokine production, antimicrobial peptide production, neutrophil accumulation, and a proliferation of keratinocytes (Figure 1). IL-23-induced epidermal hyperplasia is dependent upon IL-17A and IL-22, although neither IL-17A nor IL-22 by itself is sufficient to cause IL-23-mediated epidermal hyperplasia.8 IL17A plays an essential role in cell activation and inflammatory gene circuits in psoriasis patients. In a study of ixekizumab (an anti-IL-17A mAb agent) compared to etanercept, ixekizumab led to a greater down-modulation of psoriasis-related gene expression than the comparator.9 IL-23 is blocked selectively by three new anti-p19 mAb drugs: tildrakizumab (Merck, Phase 3 studies recently underway), guselkumab (Janssen, recently completed Phase 2 studies), and AMG 139 (Amgen, now in Phase 1 studies). Selective IL-17A blockers include secukinumab and ixekizumab, whereas brodalumab selectively blocks the IL17RA receptor (Table 2). These new agents are currently being studied and results in terms of safety and efficacy in the treatment of psoriasis appear promising. Acquired T-cell immunity is associated with a continuum of immunological responses in skin with regard to extracellular pathogens, such as Candida and Staphylococcus (Figure 2). Excessive Th17 response can result in psoriasis, while a lack of Th17 response prevents psoriasis, but may lead to the development of chronic mucocutaneous infection. Job syndrome, also known as hyperimmunoglobulin E
TABLE 1. Known psoriasis genes by categories CATEGORY
DESCRIPTION
IL-23/Th17 cell activation
Acquired
Antigen presentation
Acquired
Type I interferon induction
Innate
NF-kB signaling
Innate
Skin barrier function
Innate
Of note, genes that are exclusively specific to psoriasis (that is, have no other disease associations) are mostly associated with innate immunity.
S1 0
Figure 1. IL-23 and IL-17A pathways implicated in psoriasis.
SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AE STHETIC DERMAT OLOGY [SE PTE MBER 201 3 • VOL UME 6 • NUMBE R 9]
Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2013 MauiDerm Meeting
TABLE 2. New agents that block the actions of IL-17A AGENT
DESCRIPTION
INVESTIGATION/PUBLICATION
MANUFACTURER
Secukinumab
Fully human anti-IL-17A mAb
Phase 3, phase 2 studies have been published10,11
Novartis
Ixekizumab
Humanized anti-IL-17A mAb
Phase 3, phase 2 studies published12–14
Lilly
Brodalumab
Fully human anti-IL-17RA receptor mAb
Phase 3, phase 2 study published15
Amgen
syndrome, occurs in patients with a defect in STAT3, making their Th1 cells normal, their Th2 cells active, and their Th17 cells absent. Job syndrome is characterized by severe eczema-like skin disease (but no psoriasis), frequent staphylococcal infections of the skin, and chronic candidiasis.16 In addition, IL-17A plays a role in the pathogenesis of atherosclerosis.17 Drugs that block IL-17A may reduce atherosclerotic disease, which may explain why fewer than Figure 2. Acquired T-cell immunity and the spectrum of clinical disease manifestations expected major adverse cardiac events (MACE) occurred in a study following psoriatic patients who took ustekinumab for issues must be considered (Table 3). four years.18 Ustekinumab is a human monoclonal antibody that binds Future research is needed to explore whether drugs that with high affinity to shared p40 protein subunits of IL-12 and inhibit IL-23 and/or IL-17 might cause or worsen skin and IL-23. These cytokines, especially the latter, are thought to mucosal infections. Moreover, more investigation is needed as play key roles in the inflammatory cascade of psoriasis. IL-12 to whether these agents might decrease systemic antiand IL-23 production by dendritic cells results in the upinflammatory activity, that is, whether they might decrease regulation of many downstream cytokines, resulting in the atherosclerosis and, if so, the clinical ramifications of this stimulation of keratinocyte proliferation and secretion of decrease. antimicrobial peptides; this could explain the reduction in The pathogenesis of plaque psoriasis is incompletely psoriasis-related skin infections.22 In the PHOENIX I elucidated, but it appears to depend on the interaction of randomized, double-blind, placebo-controlled, multicenter environmental factors with genetic factors, leading to a trial (n=766), patients received ustekinumab 45mg or 90mg at dysregulated immune response in which the cytokine IL-17 Weeks 0 and 4 and then every 12 weeks or placebo (with appears to play a key role.19 It is likely that agents targeting IL17 will be of growing importance in the pharmacologic crossover to ustekinumab at 12 weeks).22 Psoriasis area and management of psoriasis, whether these agents neutralize ILseverity index (PASI)-75 scores at Week 12 were achieved by 17A (secukinumab and ixekizumab) or antagonize its receptor 67.1 and 66.4 percent of the ustekinumab 45mg and 90mg (brodalumab).20 Indeed, the history of drug development for patients, respectively, compared to 3.1 percent of placebo the treatment of plaque psoriasis parallels our growing patients. Adverse events occurred in 54.5 percent of understanding of the disease mechanisms. ustekinumab and 48.2 percent of placebo patients; serious Drug development for psoriasis falls into two distinct adverse events occurred in 1.2 and 0.8 percent of these periods. From 1987 to 2001, drugs to treat psoriasis included patients, respectively. Results were maintained for at least a etretinate, acitretin, and cyclosporine. From 2002 to the year in PHOENIX patients who received ustekinumab for 12 present, several first-generation biologics entered the market, weeks; such durable effects were not seen in those who such as alefacept and efalizumab, but these agents have since discontinued treatment before 12 weeks. In the PHOENIX II been withdrawn. Second-generation psoriasis biologics trial (n=1,230) dosing intensification of ustekinumab 90mg included etanercept, infliximab, and adalimumab. These drugs every eight weeks elicited response from certain patients who target tumor necrosis factor alpha (TNF-α). Third-generation did not respond fully to the initial regimen (45 or 90mg at biologics, such as ustekinumab and the pipeline drugs Weeks 0 and 4, then every 12 weeks).23 The primary endpoint, 21 mentioned earlier, target the IL-23/Th17 pathway. Today, a PASI-75, was achieved initially by 66.7 and 75.7 percent of the plethora of new drugs are in development, including both oral ustekinumab 45mg and 90mg groups, respectively (versus and topical formulations. While the risk/benefit ratio of these 3.7% of placebo patients) and significantly more partial agents still favors the patient, short-term and long-term safety responders achieved the PASI-75 score with the accelerated [SEPTEMBER 2013 • VOLUME 6 • NUMBER 9 ] SUPPL EMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DE RMATOLOGY
S11
TABLE 3. A brief history of drug development for the treatment of psoriasis TARGET
DRUG
BRAND NAME, COMPANY
HISTORY
First Generation Biologics
Efalizumab
Raptiva, Genentech
Approved 2003, withdrawn 2009 due to progressive multifocal leukoencephalopathy
T-cell inhibitors
Alefacept
Amevive, Biogen Astellas
Approved 2002, withdrawn 2012 for lack of use
Adalimumab
Humira, Abbott/Abbvie
Approved 2002 for rheumatoid arthritis; its indication for psoriasis was the drug’s fifth indication, approved in 2008
Certolizumab pegol
Cimzia, UCB
Approved in 2008 for Crohn’s disease and in Europe in 2009 for rheumatoid arthritis
Etanercept
Enbrel, Amgen
TNF-receptor fusion protein approved for psoriasis in 2004
Infliximab
Remicade, Centocor
Approved in 1998 for rheumatoid arthritis; psoriasis is the most recently approved indication
Ustekinumab (IL-12 and -23)
Stelara, Centocor
Approved in 2009 for psoriasis
ABX-IL8 (IL-8)
Abgenix, subsequently acquired by Amgen
Oprelvikin (IL-11)
Neumega, Wyeth
Second Generation
TNF-α, cytokine inhibitors
Third Generation
Indicated for severe thrombocytopenia
Not named (IL-18-BP) Serono Interleukin (IL) cytokine inhibitors
Tildrakizumab
Merck
Phase 3 studies recently underway
Guselkumab
Janssen
Recently completed Phase 2 studies
Secukinumab
Novartis
Phase 3 studies recently underway
Ixekizumab
Eli Lilly
Phase 3 studies recently underway
Brodalumab
Amgen
Phase 3 studies recently underway
eight-week 90mg dosing regimen.22 Adverse events with ustekinumab appear to be stable over time and occur at a low rate. A meta-analysis of MACE with ustekinumab and other biologics (n=183, 22 randomized clinical trials) found no significant difference in the MACE rates among patients taking anti-IL-12, IL-23, and anti-TNF-α agents.24 Ustekinumab has an acceptable safety profile for up to five years of exposure.25 Pooled safety data from four ustekinumab studies in psoriasis patients (n=3,117 patients and 8,998 patient-years) treated for up to five years revealed no dose-related or cumulative toxicity, even with prolonged exposure; rates of adverse events were generally comparable S1 2
to those of other biologic agents approved for treatment of moderate-to-severe psoriasis.26 For doses of 45mg and 90mg, the reported serious adverse events were 7.0 and 7.2 percent, respectively; serious infections were 0.98 and 1.19 percent, respectively; and MACEs were 0.56 and 0.36 percent, respectively. Mortality and malignancy rates were comparable to the general population. New developments include drugs that target IL-17A, namely ixekizumab, secukinumab, and the IL-17RA receptor (brodalumab), which targets the receptor for IL-17A, F, and C. In a Phase II, double-blind, placebo-controlled trial (n=142), patients with moderate-to-severe plaque psoriasis received
SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AE STHETIC DERMAT OLOGY [SE PTE MBER 201 3 • VOL UME 6 • NUMBE R 9]
Updates on Psoriasis and Cutaneous Oncology: Proceedings from the 2013 MauiDerm Meeting
subcutaneous injections of 10, 25, 75, or 150mg of ixekizumab or placebo at 0, 2, 4, 8, 12, and 16 weeks.12 At Week 12, 82.1 percent of 150mg patients, 82.8 percent of 75mg, and 76.7 percent of 25mg patients had achieved the primary endpoint of a PASI-75 score or better compared to 7.7 percent of placebo patients (p
