Psoriasis: New Data for 2018

Based on the Maui Derm 2018 presentation by Bruce E. Strober, MD, PhD, Professor and Chair, University of Connecticut Health Center, Department of Dermatology, Farmington, Connecticut

Article by Jo Ann LeQuang and the Journal of Clinical and Aesthetic Dermatology

Four significant studies emerge when perusing the new data from 2017, all of which can help guide clinical care of patients with psoriasis. The first involves treating psoriasis in pregnant and lactating women. Treating psoriasis in any special population can pose clinical challenges, but new and encouraging answers are available for certolizumab pegol. Second, the prevalent and distressing condition of genital psoriasis has always been difficult for patients and prescribers. New 2017 data on ixekizumab as a potential course of treatment holds promise. Third, novel treatments for psoriasis seem to abound but the issue of durability of results is relevant to patients and prescribers. This year, long-term data on secukinumab durability are available to help guide clinical decision-making. Finally, the risk of non-melanoma skin cancer (NMSC) and other cutaneous malignancies has been further studied in order to better understand what contributory role biologics might play in their development.

Certolizumab pegol in pregnancy. Pregnant women represent an important special population in which inflammatory diseases can be particularly difficult to treat due to the risk of transference to the child in utero. CRIB was a prospective, multicenter, post-market, pharmacokinetic study that evaluated the placental transfer of certolizumab pegol (CZP).1 Sixteen pregnant women were entered into and completed the study. The patients had to be at least 30 weeks pregnant, with a diagnosis of an approved CZP indication—psoriatic arthritis, rheumatoid arthritis, Crohn’s disease, or ankylosing spondylitis—and receive the last dose of CZP 35 days or less before delivery. Blood samples for measurement of CZP plasma concentration were taken from mothers, umbilical cords, and neonates at delivery; blood was drawn again from the infants at four and eight weeks post-delivery. At delivery, maternal CZP plasma levels from the 16 patients fell within the anticipated therapeutic range (24.4µg/mL, range 5.0– 49.4). Sixteen neonates were included in the study, but two were excluded from per-protocol datasets, one because of missing data at birth, the other because of implausible pharmacokinetic data. Of the 14 neonates in the per-protocol study, there was no quantifiable level of plasma CZP in 13 infants (<0.032µg/mL) and a minimal level in one (0.042µg/mL). At Weeks 4 and 8, none of the infants had quantifiable plasma levels of CZP. Umbilical cord samples were taken from the 16 patients but one was excluded due to missing data; of the 15 included umbilical cords, three had quantifiable levels of CZP, the highest of which was 0.048µg/mL. Thus, the CRIB clinical trial demonstrated that there was little to no CZP transfer from mother to child and that there was no fetal exposure to CZP during the third trimester of pregnancy. These findings suggest that CZP can be safely administered to pregnant women, when appropriate, without the risk of placental transfer.

Ixekizumab in genital psoriasis. Genital psoriasis affects up to 63 percent of all patients with psoriaris2 and can be difficult to treat. A recent randomized, double-blind, placebo-controlled Phase IIIb study (IXORA-Q)3 evaluated the potential of ixekizumab for the treatment of genital psoriasis. A total of 149 patients with moderate-to-severe genital psoriasis with body surface area (BSA) greater than one percent were randomized to receive either placebo (n=74) or ixekizumab at recommended doses (n=75). Moderate-to-severe genital psoriasis was defined by the Physician’s Global Assessment of Genitalia (sPGA-G) as having a score of three or higher. The primary endpoints were patients who score zero or one on the sPGA-G, the overall sPGA score, a three-point or more improvement over baseline on the itching numeric rating scale, and response to Item 2 on the Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ), which asked if genital psoriasis limited sexual activity (Table 1). The ixekizumab group received the United States Food and Drug Administration (FDA)-approved psoriasis dosing of 160mg of ixekizumab at Week 0, then 80mg every two weeks through Week 12; the placebo group received placebo on the same schedule. After 12 weeks, patients entered an open-label treatment phase for a total of 52 weeks. Most of the IXORA-Q patients were male (75.8%). The mean age of patients was 43.7± 2.7 years and mean weight was 93.5±24.7kg. Among the participants, 52.3 percent had previously used non-biologic systemic therapies, and19.5 percent had previously used biologic systemic therapies to treat their psoriasis. By Week 12, significantly more patients in the ixekizumab group had clear or almost clear genital-area skin compared to placebo (73.3% vs. 8.1%, p<0.001). Fifty-six percent of ixekizumab patients had completely clear genital-area skin at 12 weeks compared to placebo (5.4%), p<0.001. Patients also reported at Week 12 a clinically meaningful relief from itchiness over baseline with ixekizumab versus placebo (59.7% vs. 8.3%, p<0.001), with a statistically significant difference emerging at Week 2. Item 2 on the GenPs-SFQ (Table 1) found that significantly more patients in the ixekizumab group reported that genital psoriasis never or rarely limited sexual activity at Week 12 versus placebo (78.4% vs. 21,4%, p<0.001) with the difference achieving statistical significance by Week 1 (21.6% vs. 4.8%, p=0.036). Treatment-emergent adverse events (TEAEs) were more frequent with ixekizumab than placebo; most were mild to moderate. The most commonly reported TEAEs with ixekizumab were respiratory tract infection, injection site reactions, oropharyngeal pain, pruritus, back pain, eczema, and hypertension. Severe TEAEs occurred more frequently among the placebo group than the ixekizumab group (4.1% placebo vs. 1.3% ixekizumab). Six patients discontinued the study (6.8% of placebo group and 1.3% of ixekizumab group) because of adverse effects.3

Secukinumab durability. In 2014, the results of two Phase III studies, Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis (ERASURE, N=738) and Full-year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis (FIXTURE, N=1,306) were published.4 Patients with moderate-to-severe plaque psoriasis were recruited. Patients in the FIXTURE study were randomized to receive subcutaneous secukinumab 300mg or 100mg once a week for five weeks, then every four weeks thereafter; etanercept 50mg twice a week for 12 weeks, then weekly thereafter; or placebo. The study objective was to show the superiority of secukinumab over placebo at 12 weeks (defined as Psoriasis Area and Severity Index Score [PASI] of at least 75 percent over baseline [PASI75] and a score of “clear” or “almost clear,” that is, 0 or 1, on a five-point PGA). More patients in the secukinumab group at both doses achieved PASI75 at 12 weeks compared to patients in the placebo group or etanercept group ( Table 2).

The ERASURE and FIXTURE studies were then extended to evaluate long-term control of moderate-to-severe psoriasis following the withdrawal of secukinumab.4 PASI75 responders in the secukinumab 300mg and 150mg groups entered the study and were randomized to be treated for two years with secukinumab (same dose as original study) or placebo. Patients were monitored monthly and could not use any other psoriasis medications. Relapse in placebo patients, defined as greater than 50-percent loss of the previous gain in PASI score reduction, was treated by switching the patients to the secukinumab group. Among the placebo patients, 14 percent and 21 percent of the patients in the previous secukinumab 150mg and 300mg groups, respectively, did not relapse in the first year without medication; in the second year, six percent and 10 percent of the placebo patients who had previously been treated with secukinumab 150mg and 300mg, respectively, did not relapse. The meaning of these data is controversial and should not be interpreted to mean that the typical patient treated with secukinumab will achieve “remitted” control of his or her skin disease. In fact, without an active control group, it is impossible to know if this type of response is typical of many different therapies for psoriasis.

Risk of non-melanoma skin cancer (NMSC) with biologics versus methotrexate. The Psoriasis Longitudinal Assessment and Registry (PSOLAR) database was evaluated to determine the potential risk of NMSC in patients who used biologic therapy compared to those who were eligible for biologic treatment but took methotrexate instead.5 Collection of data was cut stopped on August 23, 2015, and was pooled from 12,090 patients representing 48,870 patient-years of follow-up. Within this group, 6,350 patients used biologics and 432 used methotrexate. Most of the patients in this registry study were Caucasian. This was a well-performed analysis with a comparator group. There were 72 new diagnoses of NMSC (48 basal cell carcinoma [BCC], 24 squamous cell carcinoma [SCC]). This signals a declining rate of BCC with ustekinumab and a trend toward increasing rates of SCC with TNF-inhibitors. That said, the risk of skin cancer with all biologic drugs remains very low, and targeted monitoring of high-risk patients remains the sensible approach.

Risk of malignancy with systemic psoriasis treatment. Using the PSOLAR data, a retrospective, nested case-control analysis6 was conducted on the risk of malignancy for individuals who received systemic psoriasis treatment; this analysis was based on 12,090 registry participants who were followed for 4.2 years, with a maximum follow-up period of 8.2 years. The analysis included patients with newly diagnosed malignancies (other than NMSC) and excluded those with a history of cancer (other than NMSC). Four randomly chosen control patients were matched with each case by age at index date (±6 months), sex, geographical region, and date of enrollment. For the purposes of this study, “exposure” was defined as having received a dose of the study therapy within one year of the index date and stratified by the duration of therapy into three discreet categories: greater than 0 and less than three months; three months to less than 12 months; and 12 months or longer. A total of 252 malignancy cases were found and matched to a total of 1,008 controls. Treatment of psoriasis using methotrexate or ustekinumab for any of the three discreet time periods was not associated with an increased risk of malignancy compared with no exposure to these drugs. However, TNF inhibitors, when used longer term (12 months or longer) were associated with an increased risk of cancer (odds ratio [OR]1.54, 95% confidence interval [CI], range 1.10– 2.15, p=0.01). This risk for TNF inhibitors disappeared when the analysis solely focused on patients receiving these agents as monotherapy. Also, the use of TNF inhibitors for shorter exposure periods (<12 months) was not associated with an increased risk of malignancy.6

References

1. Mariette X, Förger F, Abraham B, et al. Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study. Ann Rheum Dis. 2018;77(2): 228–233.

2. 1Ryan C, Sadlier M, De Vol E, et al. Genital psoriasis is associated with significant impairment in quality of life and sexual functioning. J American Acad Dermatol. 2015;72(6):978–983.

3. Ryan C, Menter A, Guenther L, et al. Efficacy and safety of ixekizumab in a randomized, double-blinded, placebo-controlled Phase 3b study of patients with moderate-to-severe genital psoriasis. Br J Dermatol. 2018 May 10. doi: 10.1111/bjd.16736. [Epub ahead of print].

4. Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N Engl J Med. 2014;371(4):326–338.

5. Fiorentino D, Ho V, Lebwohl M, et al. Risk of malignancy associated with biologic therapy and methotrexate (MTX) in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). Poster Abstract B221. Presented at the American Academy of Dermatology. Orlando, Florida. 3–7 March 2017. J Am Acad Dermatol. 2017;76:(6 Suppl).

6. Fiorentino D, Ho V, Lebwohl MG, et al. Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry. J Am Acad Dermatol. 2017;77(5):845–854.e845.

New Drugs, New Devices

By Ted Rosen, MD

The year 2017 saw many new drugs and devices introduced that show considerable promise for dermatology patients. A fast round-up of what was approved in 2017 (including one December 2016 entry) appears in Table 1.

Table 1.

Drug Brand Approval Date Indication/Area What’s New
Crisaborole Eucrisa® 12/14/16 Atopic dermatitis Good safety data, no limit on therapy duration, safe for use on face and eyelids, etc.
Dupilumab Dupixent® 3/28/17 For moderate-to-severe atopic dermatitis, approved for adults only, minimal adverse events
Guselkumab Tremfya® 7/13/17 Psoriasis Superior to adalimumab for achieving PASI75, PASI90, and PASI100 (44% achieved PASI100 at 24 weeks)
Brodalumab Siliq® 2/15/17 Similar results as guselkumab
Blue Control Device

 

 7/13/17 Wearable blue light for psoriasis
Delafoxaciin Baxdela® 6/19/17 Antibiotic Fluorinated quinolone, wide spectrum
Ozenoxacin Xepi® 12/14/17 Non-fluorinated quinolone, cream for impetigo
Oxymetazoline Rhofade® 1/19/17 For persistent facial erythema of rosacea
Benznidazole Not branded 8/29/17 Chagas disease Oral agent to treat tropical disease
Avelumab Bavencio® 3/23/17 Merkel cell carcinoma New treatment for aggressive neuroendocrine cancer
Pembrolizumab Keytruda® 3/14/17 Hodgkin lymphoma Expanded indication for adult and pediatric Hodgkin lymphoma
H202 40% Eskata® 12/17/17 Seborrheic keratosis Topical solution, 40% solution most effective, 41.3% of lesions clear or near-clear
HZ/su Vaccine Shingrix® 10/20/17 Shingles vaccine May be more effective than current vaccine
Dignicap Cooling Cap 7/3/2017 Chemotherapy-induced alopecia 70% of chemotherapy patients expected to lose all of their hair retained at least 50% of scalp hair
DermaPACE device 12/28/17 Diabetic ulcers 48% of patients had >90% healing at 20 weeks

Note that trademarks and registered trademarks are the property of their respective owners.

 

The “libraries” of therapeutic options for many conditions are being expanded, such as the treatments for atopic dermatitis, psoriasis, and cutaneous cancers. With the wealth of new options comes the need to learn how to best deploy these new drugs and devices for use in our patients. A few highlights follow.

Crisaborole

Atopic dermatitis can be a lifelong condition and one that distresses patients by its appearance as well as by itching. Crisaborole, a nonsteroidal phosphodiesterase-4 (PDE-4) inhibitor, is indicated for patients with atopic dermatitis of at least two years duration. There is no skin atrophy, so it may be safely used on the face, eyelids, skin folds, and external genital areas. It is to be used twice a day and there is no limit on how long therapy may persist.1 See Figure 1 for atopic dermatitis patients treated with crisaborole by the author.

Atopic Dermatitis Crisaborole

Figure 1. Monotherapeutic regimen with crisaborole in an adult woman with atopic dermatitis.

 

Dupilumab

Dupilumab is indicated for moderate to severe atopic dermatitis in adults; it is a monoclonal antibody that works against subunit 4Rα of the interleukin (IL)-4 and IL-13 receptors. It reduced pruritus markedly compared to placebo and the once-weekly and twice-weekly regimens provided about equal effectiveness.2

Avelumab

Avelumab is an anti-programmed cell death (PD)-ligand (L)1 immunotherapeutic agent that has been approved for use in pediatric (≥ 12 years) and adult patients with metastatic Merkel cell carcinoma, an aggressive neuroendocrine cancer with high morbidity and mortality rates. Complete response occurred in 10/88 patients in a phase II trial and 19/88 had partial responses with median overall survival rates of 12.9 months.3

Cemiplimab

This anti-PD-L1 monoclonal antibody is used to treat unresectable locally advanced or metastatic cutaneous squamous cell carcinoma. It is not yet approved but early results hold great promise as the objective response rate in phase I was 46.1%. A phase II pivotal study is currently enrolling. The most commonly reported side effects are fatigue, arthralgia, and nausea.4

Important Trends in 2017

  • The armamentarium of agents is building up, giving us more choices and likely improving treatment for patients
  • Many drugs are now being tested against active comparators—these head-to-head studies provide relevant and valuable clinical information (such as the study that showed guselkumab was superior to adalimumab in achieving PASI75, PASI90, and PASI100)
  • Indications may expand, for example, guselkumab is being investigated now for its potential utility in treating psoriatic arthritis

 

References

  1. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. Journal of the American Academy of Dermatology. 2016;75(3):494-503.e494.
  2. Beck LA, Thaci D, Hamilton JD, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. The New England journal of medicine. 2014;371(2):130-139.
  3. Joseph J, Zobniw C, Davis J, Anderson J, Trinh VA. Avelumab: A Review of Its Application in Metastatic Merkel Cell Carcinoma. The Annals of pharmacotherapy. 2018:1060028018768809.
  4. Kaplon H, Reichert JM. Antibodies to watch in 2018. mAbs. 2018;10(2):183-203.

 

Pediatric Acne: Putting Best Practices into Actual Practice

By Lawrence F. Eichenfield, MD

Restaurants do it all of the time—something changes and the restaurant must understand the change, adapt to it, and make changes to its system. Changes may seem unimportant—a decrease in local foot traffic, changes in customer preferences for certain foods—but they can impact business. When the change is well managed, the restaurant recognizes it and responds accordingly. If it does this well, the consumer experience remains optimal, the restaurant retains or expands its business, costs are controlled, and outcomes remain favorable.

Why don’t we do this in healthcare? Specifically, why don’t we do this in the field of pediatric acne?

 

Here’s what has changed:

A great deal has been elucidated recently about the preadolescent acne microbiome. Preadolescents with acne tend to be colonized with a greater diversity of cutaneous bacteria than control patients; in particular, Streptococcus species are more prevalent. See Figure 1.

 

Pediatric-Acne

Figure 1. Preadolescent microbiome for acne for healthy controls, acne patients treated with benzoyl peroxide (BP), and those treated with tretinoin. Note that 1 and 2 indicate first visit and pretreatment while 2 indicates the second visit.1

 

In a study of girls between the ages of 7 and 12 with at least six acneiform lesions performed by Ahluwalia et al, patients were treated with benzoyl peroxide (BP) 4% for six weeks (range four to 8 weeks). They were administered a swab to assess the microbiome at week 0 and then at the end of their treatment. This study found that patients with more acneiform lesions were significantly more likely to have more P. acnes bacteria and there were trends toward decreased S. mitis and increased S. epidermis.  This has led to the intriguing observation that P. acnes seems to create a hostile environment for certain pathogens—but allows Staphylococcal strains like S. epidermis to flourish.1 This seems to suggest that early preadolescent acne may involve a shift from a dominant S. mitis in the microbiome to a dominant P. acnes, which is then accompanied by more acne lesions.

Another change has been the switch of BP from a prescription medication to an over-the-counter (OTC) product, as well as the introduction of OTC retinoids (adapalene). OTC products are a cornerstone of acne treatment, but patients seem somewhat less consistent at acquiring OTC products as compared to prescriptions.. In a cohort study of 84 patients (ages 12 to 45) seen in a dermatology clinic for acne, patients were contacted by phone two weeks after their appointment. All patients had been counseled by the dermatologist to purchase an OTC BP product as part of their treatment. Only 20% of the patients remembered what OTC product was recommended and about a third (36%) did not purchase any OTC products, although 93% picked up their prescriptions. Of the 64% of patients who reported that they did buy an OTC acne product as recommended, only 32% of these products contained BP.2

 

Here’s what we can do:

Knowing more about the microbiome, better and more targeted medications can be developed. The antimicrobial effects of BP have been shown to be equivocal.1 Nevertheless, BP is a key part of acne treatment.  BP is now available OTC and patients must be educated that it is an important element in acne treatment and that they must read labels or follow instructions to be sure to get the right OTC product. Some ideas to improve this situation are samples for patients to take home and handouts or other printed materials with product images so the patient purchases the right OTC product.

Pediatric acne guidelines are in place.3 There is a large body of evidence in the medical literature about how to treat pediatric acne. However, in medicine, there is often a time lag between the validation of medical evidence (including published clinical trials and updated guidelines) and their implementation. For example, it took over 15 years for the use of beta-blockade following myocardial infarction to translate into practice as a standard of care for the average heart attack survivor.

Pediatricians are on the frontlines of caring for pediatric acne. While patients can be referred to a dermatologist, it may be more efficient and convenient for patients if the pediatrician could manage these cases efficiently. To that end, these pearls are offered.

  • Pediatricians and the clinicians who work with them should be trained with respect to the guidelines on pediatric acne
  • Training materials for patients should be developed—it would be ideal if these could be ordered via electronic medical records
  • In particular, training materials should offer images of OTC products, if recommended, to assure patients select the right medications

References

  1. Coughlin CC, Swink SM, Horwinski J, et al. The preadolescent acne microbiome: A prospective, randomized, pilot study investigating characterization and effects of acne therapy. Pediatric dermatology. 2017;34(6):661-664.
  2. Huyler AH, Zaenglein AL. Adherence to over-the-counter benzoyl peroxide in patients with acne. Journal of the American Academy of Dermatology. 2017;77(4):763-764.
  3. Eichenfield LF, Krakowski AC, Piggott C, et al. Evidence-based recommendations for the diagnosis and treatment of pediatric acne. Pediatrics. 2013;131 Suppl 3:S163-186.

Atopic Dermatitis: Epidemiology & Beyond

By Jonathan I. Silverberg, MD, PhD, MPH

The global prevalence of atopic dermatitis (AD) has been estimated at about 15% to 20% in pediatric and 1% to 10% of adult populations. The prevalence has increased in the past few decades in many regions.

Atopic Dermatitis Prevalence

Figure 1. Reported prevalence rates of AD vary between adults and children and, for pediatric patients, are higher in developing nations than the industrialized world

It was thought that AD prevalence has increased primarily in the developed world, but it is not possible to draw clear lines of demarcation.1 Sometimes national variations can be striking and seem to defy explanation.

For example, among pediatric patients in the age range of 6 to 7 years, the prevalence of AD was, from lowest to highest, 0.9% in India and 22.5% in Ecuador.2 Among older children (aged 13 to 14), prevalence was lower in China, Asia-Pacific, the Middle East, India, and parts of Latin America but higher in some parts of Africa, Northern and Eastern Europe, and Oceania.2 The prevalence rates for AD vary broadly by developed versus developing nation and are higher for children than adults, see Figure 1.

Factors that may help to explain the global variations in AD prevalence:

  • Genetic factors
  • Environmental factors
  • Microbial exposures
  • Immune dysfunction
  • Definitions of AD, eczema, diagnostic criteria3

Most cases of childhood AD start in in the first five years of life. Approximately, 20-50% of childhood AD persists into adulthood.4 However, adult onset AD is quite common, with one in four adults with AD report adult-onset of their disease.5

Emerging data suggest that family structure may play a role in AD rates. Using multivariable logistic regression and adjusting for socio-demographic factors, it was found that US children from single-adult households, families with a mother but no father present, families with unmarried mothers, and families with non-biological fathers had increased odds of developing AD.6 Other risk factors for AD include cigarette smoking and exposure to second-hand smoke.7 Moreover, both adults and children with AD have higher rates of mental health symptoms, such as depression and anxiety.8,9

AD is characterized by a dysregulation of the immune system and a disruption in the skin’s barrier function. These conditions may set the stage for AD-associated comorbidities. Some of these comorbidities may be interrelated and their exact association with AD may not be yet entirely elucidated.10

  • Cutaneous infections, including extra-cutaneous infections (such as sepsis)
  • Disturbed sleep, sleep inefficiency, fatigue
  • Cardiovascular conditions, such as atherosclerosis, myocardial infarction, congestive heart failure
  • Cerebrovascular disorders, including stroke
  • Obesity
  • Hypertension
  • Hyperlipidemia
  • Diabetes type II

The burden of AD is not trivial. Patients experience severe and sometimes relentless pruritus, may have skin pain11 experience sleep and mental health disturbances, and suffer from an unsightly rash that may cause embarrassment and social isolation. Most AD patients (88%) report the daily presence of itchy skin and 69% report that the itchiness lasts at least 12 hours a day. Fifty percent of AD patients report pain accompanies pruritus and 69% describe the itchiness as being severe or unbearable. Most AD patients (90%) report that their AD disrupts sleep at least one night per week.12-14

AD is a highly prevalent condition associated with serious comorbidities, a high disease burden, and great costs to the healthcare system.

 

References

 

  1. Nutten S. Atopic dermatitis: global epidemiology and risk factors. Annals of nutrition & metabolism. 2015;66 Suppl 1:8-16.
  2. Odhiambo JA, Williams HC, Clayton TO, Robertson CF, Asher MI. Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three. The journal of allergy and clinical immunology. 2009;124(6):1251-1258.e1223.
  3. Dizon MP, Yu AM, Singh RK, et al. Systematic review of atopic dermatitis disease definition in studies using routinely collected health data. The British journal of dermatology. 2018;178(6):1280-1287.
  4. Kim JP, Chao LX, Simpson EL, Silverberg JI. Persistence of atopic dermatitis (AD): A systematic review and meta-analysis Journal of the American Academy of Dermatology, Vol. 75, Issue 4, p681–687.e11. Published online: August 18, 2016
  5. Lee HH, Patel KR, Singam V, et al. A systematic review and meta-analysis of the prevalence and phenotype of adult-onset atopic dermatitis. Journal of the American Academy of Dermatology. Published online: June 1, 2018
  6. McKenzie C, Silverberg JI. Association of family structure with atopic dermatitis in United States children. Journal of the American Academy of Dermatology. 2018.
  7. Kantor R, Dalal P, Cella D, Silverberg JI. Research letter: Impact of pruritus on quality of life—A systematic review. Journal of the American Academy of Dermatology, Vol. 75, Issue 5, p885–886.e4. Published online: August 28, 2016
  8. Yaghmaie P, Koudelka CW, Simpson EL. Mental health comorbidity in patients with atopic dermatitis. The Journal of allergy and clinical immunology. 2013;131(2):428-433.
  9. Yu SH, Silverberg JI. Association between Atopic Dermatitis and Depression in US Adults. The Journal of investigative dermatology. 2015;135(12):3183-3186.
  10. Silverberg JI. Associations between atopic dermatitis and other disorders. F1000Research. 2018;7:303.
  11. Vakharia PP, Chopra R, Sacotte R, et al. Burden of skin pain in atopic dermatitis Annals of Allergy, Asthma & Immunology, Vol. 119, Issue 6, p548–552.e3. Published in issue: December 2017
  12. Simpson EL, Bieber T, Eckert L, et al. Patient burden of moderate to severe atopic dermatitis (AD): Insights from a phase 2b clinical trial of dupilumab in adults. Journal of the American Academy of Dermatology. 2016;74(3):491-498.
  13. Dawn A, Papoiu AD, Chan YH, Rapp SR, Rassette N, Yosipovitch G. Itch characteristics in atopic dermatitis: results of a web-based questionnaire. The British journal of dermatology. 2009;160(3):642-644.
  14. O’Neill JL, Chan YH, Rapp SR, Yosipovitch G. Differences in itch characteristics between psoriasis and atopic dermatitis patients: results of a web-based questionnaire. Acta dermato-venereologica. 2011;91(5):537-540.

 

Cutaneous tolerability of a novel topical minocycline gel for the treatment of rosacea

Cutaneous tolerability of a novel topical minocycline gel for the treatment of rosacea

Presenters: Bhatia N1, Ahmadyar M1, Hansra H2, Del Rosso J3, Baldwin H4, Daniels AM5

Affiliations: 1Therapeutics Clinical Research, San Diego, CA; 2BioPharmX, Inc., Menlo Park, CA; 3JDR Dermatology Research, LLC, Las Vegas, NV; 4The Acne Treatment and Research Center, Morristown, NJ

Background/Objective: Rosacea is a chronic and relapsing skin disorder that primarily involves the central face. Affecting at least 16 million people in the United States alone, rosacea can develop via genetic, immunologic, inflammatory, vascular, or environmental pathways. The papulopustular subtype resembles acne vulgaris in its formation of inflammatory papules, pustules, and plaques.

Minocycline is effective as a first-line systemic therapy for rosacea. It is thought that, like other tetracyclines, its anti-inflammatory properties are responsible. Unfortunately, oral and/or long-term use, as required in a chronic condition such as rosacea, might contribute to antibiotic resistance. Additionally, significant side effects such as gastrointestinal distress and vertigo might make oral minocycline intolerable. Therefore, another form of delivery is needed.

Methods: This was a Phase II feasibility study of 1% and 2% formulations of a novel topical minocycline gel. Nineteen adults with moderate-to-severe papulopustular rosacea participated. Skin diseases, prohibited comorbidities and treatments, and pregnancy were exclusionary.

Treatment was open-label and nonrandomized. Subjects applied the assigned gel to the face once per day for 12 weeks. Numbers of facial lesions and their severity were assessed throughout the study. Safety endpoints were also recorded, as were ratings of the cutaneous tolerability (4-point severity scales, investigator- and subject-reported).

Results: The treatment was well tolerated. According to ratings for erythema, scaling/peeling, and edema, none of the subjects experienced worsening of rosacea. Ratings for burning, stinging, tightness, and itching showed that the majority of the subjects improved or were unchanged. Only a single subject reported severe cutaneous irritation at Week 12 (burning, stinging, and itching). Additionally, there were no study-related adverse events or clinically significant changes in laboratory values. Additionally, for both formulations, lesion count and severity were reduced with rapid onset. Clinically meaningful improvements were reported after just four weeks of treatment. The majority of subjects stated they would use the minocycline gel again.

Conclusion: Both formulations of the novel topical minocycline gel demonstrated improvement in treating rosacea and had good cutaneous tolerability profiles. Because cutaneous symptoms such as erythema, edema, burning, and stinging are commonly reported symptoms of rosacea itself, it is to be expected that these were reported with some frequency at baseline. Improvements, which were observed for the majority of subjects in most measures, might therefore be indicative of an improvement in the underlying condition as well as a lack of treatment reaction. Additionally, safety endpoints were met and there was evidence for the effectiveness of treatment in the rapid reduction in number and severity of facial lesions. Although generalizability is limited by the study’s small size and open-label, single-center design, this new therapy shows promise as a new treatment option for rosacea. An important advantage of the topical minocycline formulation might be in reduction of risks associated with systemic exposure to this antibiotic. Next-phase clinical studies are planned.

Concurrent administration of ivermectin 1% cream with brimonidine 0.33% gel improves efficacy and tolerability in treatment of moderate-to-severe rosacea

Concurrent administration of ivermectin 1% cream with brimonidine 0.33% gel improves efficacy and tolerability in treatment of moderate-to-severe rosacea

Presenters: Gold LS1, Papp K2, Lynde C3, Lain E4, Gooderham M5, Johnson S6, Kerrouche N7, Schäfer G8

Affiliations: 1Department of Dermatology, Henry Ford Medical Center, Detroit, MI; 2K. Papp Clinical Research, Probity Medical Research, Waterloo, ON, Canada; 3Lynde Institute for Dermatology, Markham, ON, Canada; 4Austin Institute for Clinical Research, Pflugerville, TX; 5SKiN Centre for Dermatology, Probity Medical Research and Queen’s University Peterborough, ON, Canada; 6Johnson Dermatology, Fort Smith, AR; 7Galderma R&D, Sophia Antipolis, Biot, France, 8Galderma International, Paris, France

Background/Objective: Multiple studies have demonstrated the efficacy of ivermectin 1% (IVM) cream (inflammatory lesions) and brimonidine 0.33% (BR) gel (persistent erythema). This prospective study evaluated the efficacy and safety of IVM and BR versus their vehicles in moderate-to-severe rosacea.

Methods: This was a multicenter, randomized, double-blind, vehicle-controlled study in moderate-to-severe rosacea (Investigator Global Assessment [IGA] ?3). The study comprised three arms. The two active treatment arms were: 1) once-daily BR (morning) and IVM (evening) for 12 weeks (IVM+BR/12W; n=49); or 2) Once-daily BR vehicle for four weeks, followed by once-daily BR for eight weeks (morning), and once-daily IVM for 12 weeks (evening; IVM+BR/8W; n=46). The the vehicle arm stipulated once-daily BR vehicle (morning) and IVM vehicle (evening), 12 weeks (n=95). A general skin care regimen (cleanser/moisturizer/sunscreen) was provided/recommended. IGA (0–4), Clinician’s Erythema Assessment (CEA; 0–4), percent change from baseline inflammatory lesion count (ILC), percentage of subjects with 10- percent IL reduction, subject global rosacea improvement, and facial appearance questionnaire. Adverse events (AEs) were monitored throughout the study.

Results: The total IVM and BR population showed superior efficacy (Week 12, Hour 3; IGA success [clear/almost clear]) versus vehicle (55.8% vs. 36.8%, p=0.007); IVM and BR/12W showed better efficacy versus vehicle (61.2% vs. 36.8%, p=0.003) than IVM and BR/8W (50% vs. 36.8%, p=0.135). At Week 12, success increased for IVM and BR/12W (32.7%, Hour 0 [pre-BR application]; 61.2%, Hour 3 [post-BR application) and IVM and BR/8W (28.3%, Hour 0; 50%, Hour 3). CEA and median percent change in ILC improved with IVM and BR/12W and IVM and BR/8W vs vehicle (p<0.01). IVM and BR/12W trended toward higher efficacy. Eight treatment-related AEs in six subjects (3.2%) were reported (including treatment-related worsening of rosacea: 1 with IVM and BR, 3 with vehicle).

Conclusion: Administration of IVM cream with BR gel demonstrated good efficacy and safety. Early introduction of BR (Day 1; with a complete daily skin care regimen) might benefit efficacy and accelerate treatment success without impairing tolerability.

Funding: This analysis was funded by Galderma R&D. G. Schäfer and N. Kerrouche are employees of Galderma.

Secukinumab achievement of psoriatic arthritis disease activity score- (PASDAS) related remission: two-year results from a Phase III study

Secukinumab achievement of psoriatic arthritis disease activity score- (PASDAS) related remission: two-year results from a Phase III study

Presenters: Coates LC1, Gladman DD2, Nash P3, Fitzgerald O4, Kavanaugh A5, Rasouliyan L6, Pricop L7, Ding K7, Gaillez C8 (on behalf of the FUTURE 2 Study Group)

Affiliations: 1Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK; 2Toronto Western Hospital, Toronto, ON, Canada; 3University of Queensland, Brisbane, Australia; 4St. Vincent’s University Hospital, Dublin, Ireland; 5UC San Diego School of Medicine, La Jolla, CA; 6RTI Health Solutions, Barcelona, Spain; 7Novartis Pharmaceuticals Corporation, East Hanover, NJ; 8Novartis Pharma AG, Basel, Switzerland.

Background/Objective: Psoriatic Arthritis Disease Activity Score (PASDAS) assessing multiple facets of psoriatic arthritis (PsA) has been shown to distinguish treatment effect and perform better in statistical terms than traditional joint-only indices and could be used as a treatment target in clinical trials in PsA. Secukinumab significantly improved the signs and symptoms of PsA over 104 weeks in the FUTURE 2 study. This post-hoc analysis assessed the ability of secukinumab to achieve low disease activity (LDA) or remission (REM) using PASDAS through 104 weeks in the FUTURE 2 study.

Methods: The FUTURE 2 study design was previously published. PASDAS index is derived from Physician’s Global Visual Analog Scale, patient’s global VAS, SF-36 PCS, tender and swollen joint counts, Leeds enthesitis count, dactylitis count and c-reactive protein level with validated cut-points for high disease activity (HDA ?5.4), moderate disease activity (3.2< MoDA <5.4), 1.9<LDA ?3.2 and REM ?1.9.3

Results: PASDAS scores at baseline was similar across the three treatment groups. In the overall population at Week 16, PASDAS REM, LDA, and MoDA were achieved in 15.6 percent, 22.9 percent, and 49.0 percent, respectively, of patients treated with secukinumab 300 mg; of patients treated with secukinumab 150mg, 15.2 percent, 19.2 percent, and 42.4 percent, respectively; and of patients given placebo, 2.3 percent, 13.8 percent, and 44.8 percent, respectively. At Week 104, REM was achieved in 22.9 percent and 14.3 percent of patients treated with secukinumab 300mg and 150mg, respectively. In anti–TNF-naïve patients at Week 16, PASDAS REM, LDA, and MoDA were achieved in 18.5 percent, 27.7 percent, and 46.2 percent, respectively, of patients treated with secukinumab 300mg; of patients treated with secukinumab 150mg, 22.2 percent, 20.6 percent, and 42.9 percent, respectively; and of patients given placebo, 3.5 percent, 14.0 percent, and 45.6 percent, respectively. At Week 104 in anti–TNF-naïve patients, REM was achieved in 29.1 percent and 17.0 percent of patients treated with secukinumab 300mg and 150mg, respectively. In anti–TNF-inadequate response (IR) patients at Week 16, PASDAS REM, LDA, and MoDA were achieved in 9.7 percent, 12.9 percent, and 54.8 percent, respectively, of patients treated with secukinumab 300mg; of patients treated with secukinumab 150mg, 2.8 percent, 16.7 percent, and 41.7 percent, respectively; of patients given placebo, 0 percent, 13.3 percent, and 43.3 percent, respectively. At Week 104 in anti–TNF-IR patients, REM was achieved in 10.7 percent and 8.3 percent of patients treated with secukinumab 300mg and 150mg, respectively. The proportion of patients achieving PASDAS REM/LDA at Weeks 16 and 104 was similar, irrespective of time since first diagnosis, for both secukinumab doses. Secukinumab treated patients achieving PASDAS REM had significantly greater improvements in function, physical- and mental-health quality of life, and fatigue compared to HDA through Week 104.

Conclusion: At Week 16, PASDAS REM and LDA were achieved in 38.5 percent and 34.4 percent of patients treated with secukinumab 300mg and 150mg, respectively, versus 16.1 percent in the placebo group, with approximately 50 percent of patients achieving PASDAS REM and LDA in both secukinumab groups at Week 104. A higher proportion of anti–TNF-naïve patients treated with secukinumab achieved PASDAS REM or LDA than those treated with anti–TNF-IR through Week 104. Secukinumab treated patients achieving PASDAS REM had significantly greater improvements in function, quality of life, and fatigue.

Funding: This research was sponsored by Novartis Pharma AG in Basel, Switzerland.

Radiographic progression of structural joint damage in patients with active psoriatic arthritis treated with ixekizumab over 52 weeks

Radiographic progression of structural joint damage in patients with active psoriatic arthritis treated with ixekizumab over 52 weeks

Presenters: van der Heijde D1, Okada M2, Lee C3, Shuler CL3, Rathmann S3, Amato D3, Lin CY3, and Mease P4

Affiliations: 1Leiden University Medical Centre, Leiden, the Netherlands; 2St. Luke’s International Hospital, Tokyo, Japan; 3Eli Lilly and Company, Indianapolis, IN; 4Swedish Medical Center and University of Washington, Seattle, WA

Background/Objective: Ixekizumab (IXE), an anti-interleukin-17A monoclonal antibody, was shown to be superior to placebo (PBO) in clinical responses and in inhibition of the progression of structural joint damage in patients with psoriatic arthritis (PsA) treated for 24 weeks. Here, we assessed progression of structural joint damage in PsA patients with IXE for up to 52 weeks.

Methods: Biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with active PsA (n=417) entered into SPIRIT-P1 (NCT01695239), a double-blind Phase III trial. Patients must have had at least one joint erosion on the hand and foot confirmed by central x-ray reading or have had a C-reactive protein level less than 6mg/L at screening. A total of 417 patients were randomized to IXE 80mg every two (Q2W; n=103) or four weeks (Q4W; n=107) following a 160mg initial dose, PBO (n=106), or adalimumab 40mg every two weeks (ADA; active reference arm; n=101) for 24 weeks. In the Extension Period (EXT; Weeks 24–52), patients on PBO and ADA were re-randomized (1:1) to IXEQ2W or IXEQ4W at Week 16 (inadequate responders) or Week 24; patients on ADA underwent a washout prior to IXE treatment. All patients were assessed for structural joint damage using the van der Heijde modified PsA Total Sharp Score (mTSS, 0–528 scale). Two readers blinded to timepoint scored X-rays at Weeks 0, 24, and 52 independently and clinical data (average of readers). The mTSS was excluded from the prespecified analysis if the radiograph was taken after the scheduled visit date. In a post-hoc analysis, mTSS from a radiograph taken after the scheduled visit date was interpolated and considered as observed data. Any missing data at Week 52, in either presentation, were imputed using a linear extrapolation if they had at least one post-baseline value.

Results: Of the patients who had active PsA at Week 0, 381 patients (91.3%) entered the EXT, with 374 (98.2%) having radiographs collected during the EXT. Week 52 mean (SD) mTSS change from baseline were 0.54 (2.11) and 0.09 (1.0) for patients randomized to IXEQ4W and IXEQ2W at baseline, respectively. Similarly, post-hoc analysis changes at Week 52 were 0.47 (1.9) and 0.09 (0.9) for the IXEQ4W and IXEQ2W groups, respectively. The majority of patients on IXEQ2W or IXEQ4W exhibited no structural progression through one year of IXE treatment. In patients who switched from PBO or ADA to IXE, the Week 52 mean change from baseline mTSS values scores ranged from -0.03 to 0.41.

Conclusion: Over a 52-week period, minimal changes in mTSS were observed in patients with PsA entering the EXT and treated with IXEQ2W or IXEQ4W.

Secukinumab for the treatment of scalp, nail, and palmoplantar psoriasis

Secukinumab for the treatment of scalp, nail, and palmoplantar psoriasis

Presenters: Hawkes JE1,2, Lebwohl M2, Elewski B3, Kircik L2,4, Reich K5, Muscianisi E6, Gottlieb A7

Affiliations: 1The Laboratory for Investigative Dermatology, The Rockefeller University, New York, NY; 2Icahn School of Medicine at Mount Sinai, New York, NY; 3University of Alabama, Birmingham, AL; 4Indiana University School of Medicine, Indianapolis, IN; 5Dermatologikum Hamburg, Hamburg, Germany; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ 7New York Medical College, Valhalla, NY

Background/Objective: Psoriasis is a chronic, immune-mediated, systemic condition that commonly affects the scalp, nails, palms, and soles. Although psoriasis in these areas accounts for a small percentage of total body surface area, it often results in significant dysfunction and quality of life impairment. For instance, the highly visible nature of scalp psoriasis can cause embarrassment and discomfort. Psoriatic nail disease is often overlooked, causing cosmetic concerns and difficulty with tasks requiring manual dexterity. Palmoplantar psoriasis causes significant functional impairment compared with other psoriasis subtypes and can be recalcitrant to traditional systemic therapies. Until recently, there has been limited clinical research focused on less common and hard-to-treat subtypes or clinical features of psoriatic disease. Secukinumab, a human monoclonal antibody that selectively binds to and neutralizes interleukin-17A, has demonstrated efficacy for chronic plaque psoriasis in a structured Phase III development plan. Here we present a review of the efficacy and safety of secukinumab in patients with psoriasis affecting the scalp, nails, palms, and soles of the feet.

Methods: In three separate clinical trials designed specifically for each of these hard-to-treat areas, inclusion criteria included patients with moderate-to-severe scalp psoriasis (Psoriasis Scalp Severity Index [PSSI] ?12), patients with moderate-to-severe psoriasis with significant nail involvement (Nail Psoriasis Severity Index [NAPSI] ?16 with ?4 fingernails involved), and patients with moderate-to-severe palmoplantar psoriasis (palmoplantar Investigator’s Global Assessment [ppIGA] ?3), respectively. In all trials, patients received secukinumab 300mg or 150mg at baseline, Weeks 1, 2 and 3, and then every four weeks beginning at Week 4.

Results: The primary endpoint of each trial was met. In 102 patients with scalp psoriasis, PSSI 90-percent improvement response rates were significantly greater with secukinumab 300mg versus placebo at Week 12 (52.9% vs. 2.0%; P<0.001). One in 198 patients with nail psoriasis, mean NAPSI percent change from baseline to Week 16 was significantly greater in secukinumab 300mg (-45.3%) and secukinumab 150mg (-37.9%) groups compared to placebo (-10.8%; both P<0.0001). In 205 patients with nonpustular palmoplantar psoriasis, ppIGA0/1 was achieved at Week 16 by significantly more patients with secukinumab 300mg (33.3%) and secukinumab 150mg (22.1%) than with placebo (1.5%; both P<0.001). The safety of secukinumab in these trials was consistent with the safety profile observed in previous clinical trials, and no new safety signals were identified.

Conclusion: Secukinumab is a safe and effective treatment option in chronic plaque psoriasis and these hard-to-treat psoriasis subtypes as demonstrated in specifically designed prospective clinical trials.

Funding: This research was sponsored by Novartis Pharma AG, Basel, Switzerland, and Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.

Secukinumab is superior to ustekinumab in clearing skin of patients with moderate-to-severe plaque psoriasis: CLARITY, a randomized, controlled, Phase IIIb trial

Secukinumab is superior to ustekinumab in clearing skin of patients with moderate-to-severe plaque psoriasis: CLARITY, a randomized, controlled, Phase IIIb trial

Presenters: Bagel J1, Nia J2, Hashim P2, Patekar M3, de Vera A3, Hugot S3, Sheng K4, Xia S5, Muscianisi E4, Blauvelt A6, Lebwohl M2

Affiliations: 1Psoriasis Treatment Center of Central New Jersey, East Windsor, NJ; 2Icahn School of Medicine at Mount Sinai, New York, NY; 3Novartis Pharma AG, Basel, Switzerland; 4Novartis Pharmaceuticals Corporation, East Hanover, NJ; 5Novartis Beijing Novartis Pharma Co. Ltd, Shanghai, China; 6Oregon Medical Research Center, Portland, OR

Background/Objective: Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has previously demonstrated superior efficacy to ustekinumab in the Phase IIIb CLEAR study of moderate-to-severe plaque psoriasis. Here, we report 16-week results from CLARITY, the second head-to-head trial comparing secukinumab with ustekinumab.

Methods: In this ongoing multicenter, head-to-head, double-blind, parallel-group, Phase IIIb study (NCT02826603), patients were randomized 1:1 to receive subcutaneous secukinumab 300mg or ustekinumab per label. The co-primary objectives were to demonstrate the superiority of secukinumab over ustekinumab at Week 12 in relation to the proportion of patients with 1) 90-percent or more improvement from baseline Psoriasis Area and Severity Index (PASI 90) and 2) a score of 0/1 (clear/almost clear) on the Investigator’s Global Assessment (IGA mod 2011 0/1). Key secondary objectives included demonstrating the superiority of secukinumab over ustekinumab with respect to PASI 75 at Week 4; PASI 75 and 100 at Week 12; PASI 75, 90, 100; and IGA mod 2011 0/1 at Week 16. Missing values were handled by multiple imputation.

Results: At Week 12, both co-primary objectives were met, secukinumab 300 mg (n=550) was significantly superior to ustekinumab (n=552) for the proportion of patients achieving both PASI 90 (66.5% vs. 47.9%; P<0.0001) and IGA mod 2011 0/1 (72.3% vs 55.4%; P<0.0001) response rates. Additionally, all key secondary objectives were met. At Week 4, PASI 75 response rates were significantly superior with secukinumab 300mg compared to ustekinumab (40.2% vs 16.3%; P<0.0001). At Week 16, secukinumab 300mg demonstrated significantly superior response rates compared to ustekinumab for PASI 75 (91.7% vs. 79.8%; P<0.0001), PASI 90 (76.6% vs. 54.2%; P<0.0001), PASI 100 (45.3% vs. 26.7%; P<0.0001), and IGA mod 2011 0/1 (78.6% vs. 59.1%; P<0.0001). Furthermore, at Week 12, patients receiving secukinumab 300mg compared to ustekinumab had significantly greater PASI 75 (88.0% vs. 74.2%; P<0.0001) and PASI 100 (38.1% vs. 20.1%; P<0.0001) responses. Safety findings were consistent with the known safety profile of secukinumab.

Conclusion: Secukinumab demonstrated superior results with greater improvements compared to ustekinumab across all study outcomes at Weeks 4, 12, and 16 in patients with moderate-to-severe plaque psoriasis.

Funding: This research was sponsored by Novartis Pharma AG, Basel, Switzerland.