Updates on Psoriasis and Cutaneous Oncology

PSORIASIS UPDATE 2017

THE UNVEIL STUDY, a randomized, placebo-controlled, double-blind, multicenter, Phase 4 study ( NCT02425826) of the efficacy and safety of apremilast for the treatment of moderate plaque psoriasis was recently published.1 Apremilast is a novel immunomodulatory medication approved for treatment of both psoriasis and psoriatic arthritis. It inhibits the activity of phosphodiesterase 4 (PDE4), which is active in immune system cells as well as in keratinocytes. Reducing PDE4 may decrease production of proinflammatory cytokines. To enroll in the study, adults (≥18 years) had to have chronic plaque psoriasis for at least six months prior to screening. Chronic plaque psoriasis was defined as a body surface area (BSA) of 5 to 10 percent and a score on the Static Physician’s Global Assessment (sPGA) of 3 on a scale of 0 to 5. The product of these two scores accordingly could range from 15 to 30 at screening and baseline. Patients were included when they had not previously been exposed to conventional systemic or biologic therapy for psoriatic arthritis, psoriasis, or any indication which might impact psoriasis assessment. The main exclusionary criterion was any inflammatory and/or dermatologic condition other than plaque psoriasis (including other forms of psoriasis). In the UNVEIL study, patients were randomized in a 2:1 scheme to receive apremilast or placebo for the first 16 weeks; at Week 16, placebo patients were switched to apremilast. All patients then continued on apremilast in open-label treatment until the end of the study (Week 52).

The primary efficacy endpoint was the mean percentage change from baseline at Week 16 in sPGA × BSA. The sPGA score was calculated for all plaques in all involved areas, erythema severity, scaling, and plaque elevation; these scores were then averaged and rounded to the nearest whole number. The secondary efficacy endpoints were the mean percentage change from baseline in the Psoriasis Area and Severity Index (PASI) score, the percentage of patients who could achieve at least a 75-percent reduction from baseline of the sPGA × BSA, as well as the percentage of patients who scored 0 (clear) or 1 (almost clear) in sPGA response with at least a two-point reduction from baseline.

A total of 221 patients were enrolled in the study. At 16 weeks, the mean percentage change of the sPGA × BSA was 48.1 percent for the apremilast group versus 10.2 percent of the placebo patients. sPGA × BSA that showed at least a 75-percent reduction over baseline was achieved by 35.1 percent of apremilast patients compared to 12.3 percent of placebo patients. About one-third of apremilast patients (30.4%) had a PGA score of 0 or 1 after 16 weeks, compared to 9.6 percent of placebo patients.

Adverse events occurred in 62.6 percent of apremilast and 47.9 percent of placebo patients, most of which were not serious or severe; three serious and three severe adverse events occurred in the apremilast group compared to one severe adverse event in the placebo group. The rate of study discontinuation owing to adverse events was 4.1 percent for placebo patients versus 3.4 percent for the apremilast group. The most frequently reported adverse effects were diarrhea (29.3% vs. 16.4% for apremilast vs. placebo, respectively), headache (20.4% vs. 11.0%), nausea (17.7% vs. 9.6%), upper respiratory tract infections (6.8% vs. 4.1%), decreased appetite (4.1% vs. 5.5%), and vomiting (6.1% vs. 2.7%).

Certolizumab pegol (CZP), infliximab, adalimumab, golimumab, and etanercept are five anti-tumor-necrosis-factor-alpha (anti-TNFα) drugs approved by the United States Food and Drug Administration (FDA) for treating psoriatic arthritis. At the late-breaking sessions of the 2017 American Academy of Dermatology Scientific Sessions, Gottlieb et al presented results of two randomized, double-blind, placebo-controlled, multicenter, 16-week, Phase 3 studies evaluating CZP in chronic plaque psoriasis patients: CIMPASI-1 (An Efficacy and Safety Study of Two Dose Levels of Certolizumab Pegol [CZP] in Subjects With Plaque Psoriasis [PSO] NCT02326298) and CIMPASI-2 (A Study to Evaluate the Efficacy and Safety of Two Dose Levels of Certolizumab Pegol [CZP] in Subjects With Plaque Psoriasis [PSO] NCT02326272).2 Upon enrollment, patients were randomized in the 16-week, double-blind phase to placebo, CZP 200mg every two weeks (with a loading dose of CZP 400mg at Weeks 0, 2, and 4), or CZP 400mg every two weeks in a 1:2:2 ratio. The primary endpoints were the percentage of patients who, after 16 weeks of treatment, achieved a 75-percent reduction in their PASI score (PASI 75) and a PGA score of 0 (clear) or 1 (almost clear) on a 0-to-5 scale with at least a two-category improvement over baseline.

At 16 weeks, patients moved into the maintenance phase (Weeks 16–48) and placebo patients were migrated to the LD-CZP group. Nonresponders, defined as those with less than a PASI 50 score, had the opportunity to withdraw at Weeks 32, 40, and 48 and progress to the next group or “escape” to 400mg CZP every two weeks. At 48 weeks, all patients remaining in the study were administered CZP 200mg every two weeks in an open-label treatment phase, which ran to 144 weeks. A safety follow-up phase continued to Week 152.

There were significantly more responders in the CZP groups (both 200 and 400mg) versus placebo in terms of PASI 75 and PASI 90 rates, as well as PGA responder rates.

The CIMPACT study (Efficacy and Safety Study of Certolizumab Pegol [CZP] Versus Active Comparator and Placebo in Subjects With Plaque Psoriasis [PSO] NCT02346240) evaluated placebo, 200mg CZP, 400mgCZP (every two weeks for both doses), and etanercept 50mg twice weekly (for 12 weeks) as an active comparator. Patients were randomized in a 1:3:3:3 scheme (1 for placebo) to enter an initial, 16-week, double-blind treatment phase. The primary endpoint was PASI 75 at 12 weeks. After 16 weeks, patients entered the maintenance phase and from Week 48 to 144, followed by an open-label treatment phase. The CZP groups had significantly more PASI 75 and PASI 90 scores at Weeks 12 and 16 than placebo patients (Table 1).3

NEW AND EMERGING PSORIASIS TREATMENTS

From new studies on old drugs to innovative new agents, the systemic treatment of psoriasis remains in an exciting period of breakthroughs.

Methotrexate. A new, randomized, double-blind, placebo-controlled, Phase 3 clinical trial from Europe (METOP [Trial in Patients With Psoriasis Treated With Methotrexate Using an Optimized Treatment Schedule NCT02902861]) enrolled 149 methotrexate-naïve plaque psoriasis patients with moderate-to-severe disease.4 Patients were randomized 3:1 to receive subcutaneous methotrexate (starting at 17.5mg/week with dose escalation in first eight weeks allowed up to a maximum of 22.5mg/week) or placebo over 16 weeks, then entered a maintenance phase of 36 more weeks, in which all patients were administered subcutaneous methotrexate. All patients received 5mg/week of folic acid throughout the study. By the 16th week, 41 percent of methotrexate and 10 percent of placebo patients had achieved a score of PASI 75 (relative risk 3.9, 95% confidence interval [CI]: 31–11.81, p=0.0026). In the methotrexate arm, 31 percent had their dose escalated to the maximum of 22.5mg/week. An sPGA score of 0 (clear) or 1 (almost clear) was achieved by 27 percent in the methotrexate and seven percent in the control groups. In this study, there were no patient deaths, no major adverse cardiac events (MACE), and no malignancies, but adverse events occurred in 82 percent of the methotrexate and 93 percent of placebo patients during the double-blind phase and then in 78 percent of methotrexate and 77 percent of placebo patients during the open-label phase. These findings contribute to the data about subcutaneous methotrexate and its potential efficacy and safety.

Second-generation biologics: Tumor necrosis factor-α antagonists. Biologics are the mainstay of systemic psoriasis treatment. Tumor necrosis factor (TNF)α antagonists include adalimumab, etanercept, infliximab, golimumab, and certolizumab. Biosimilars for infliximab, adalimumab, and etanercept have been approved or have been unanimously recommended to the FDA for approval.

Since psoriasis is inherently associated with increased cardiovascular risk, a retrospective study was conducted to evaluate the time to a MACE in patients receiving a TNFα inhibitor versus those receiving methotrexate. Data from the first quarter of 2000 to the third quarter of 2011 were evaluated, and adult psoriasis patients with two or more prescriptions for either a TNFα antagonist or methotrexate were included (n=17,729).5 Overall, those who used TNFα antagonists had a lower incidence of cardiovascular adverse events compared to methotrexate users (hazard ratio [HR]: 0.55, p<0.01); at 12 months; those using TNFα inhibitors had fewer cardiovascular events than those taking methotrexate (Figure 2). The time to first MACE among psoriasis patients showed that cumulative exposure to TNFα blockade lessens cardiovascular risk over time compared to methotrexate.5 The hazard reductions dropped by 21.3, 38.0, and 51.2 percent for one, two, and three years, respectively, of TNFα blockade. Further, cumulative exposure to TNFα blockade could be associated with an overall reduced risk for MACE.5

Interleukin-23 p19 subunit inhibitors. Tildrakizumab. Interleukin (IL)-23 p19 subunit inhibitors include tildrakizumab, guselkumab, and risankizumab. Reich et al reported results from the reSURFACE1 trial (A Study to Evaluate the Efficacy and Safety of Subcutaneous MK-3222, Followed by an Optional Long-Term Safety Extension Study, in Participants With Moderate-to-Severe Chronic Plaque Psoriasis [MK-3222-010] NCT01722331) and reSURFACE2 trial (A Study to Evaluate the Efficacy and Safety/Tolerability of Subcutaneous Tildrakizumab [SCH 900222/MK-3222] in Participants With Moderate-to-Severe Chronic Plaque Psoriasis Followed by a Long-term Extension Study [MK-3222-011] NCT01729754), demonstrating that tildrakizumab achieved rates of PASI 90 in almost 60 percent and PASI 100 in 24 percent of patients with moderate-to-severe plaque psoriasis who were treated for 28 weeks.6 The reSURFACE2 study had four arms: tildrakizumab 200mg, tildrakizumab 100mg, etanercept 50mg, and placebo. At 12 weeks, placebo patients transitioned to one of the two tildrakizumab groups and remained there until Week 28. Compared head-to-head, tildrakizumab offered significant improvements in the percentage of patients achieving PASI 75 versus both placebo (p<0.001) and etanercept (p<0.05), and while PGA scores were significantly better for tildrakizumab versus placebo, the difference achieved statistical significance versus etanercept only for tildrakizumab 200mg (p<0.05), but not the 100mg dose.6

The proportion of patients having at least one adverse event in the reSURFACE2 study was highest in the placebo group (55.1%), followed by etanercept (54.0%) and tildrakizumab 100 and 200mg (44.3% and 49.4%, respectively). Adverse events culminating in withdrawal from the study happened in less than two percent of patients in all groups (highest in etanercept group at 1.9%, lowest in both tildrakizumab groups at 1.0%, 1.3% dropout rate in placebo patients). The most commonly reported adverse events were injection-site erythema and nasopharyngitis.

Guselkumab. The results of the VOYAGE 1 trial (A Study of Guselkumab in the Treatment of Participants With Moderate to Severe Plaque-Type Psoriasis NCT02207231), a Phase 2, randomized, double-blind, placebo- and active-comparator-controlled study, were presented in 2016 and recently published.7 Psoriasis patients were randomized to be treated with guselkumab 100mg (at Weeks 0 and 4, then every 8 weeks thereafter), adalimumab (80mg at Week 0, 40mg at Week 1, then 40mg every 2 weeks), or placebo for 16 weeks, then guselkumab for the open-label phase. Compared to placebo, a significantly greater proportion of guselkumab patients scored 0 (clear) or 1 (minimal) on the five-point Investigator Global Assessment (IGA) score at 16 weeks (85.1% vs. 6.9%, respectively, p<0.001).7 A greater proportion of guselkumab patients scored PASI 90 compared to placebo patients (73.3% vs. 2.9%). Compared to adalimumab, significantly greater proportions of guselkumab patients scored 0 or 1 on the IGA at Weeks 16, 24, and 48 (85.1% vs. 65.9%, 84.2% vs. 61.7%, and 80.5% vs. 55.4%, respectively) and significantly more guselkumab patients achieved PASI 90 at Weeks 16, 24, and 48 (73.3% vs. 49.7%, 80.2% vs. 53.0%, and 76.3% vs. 47.9%, respectively). The VOYAGE2 trial (A Study of Guselkumab in the Treatment of Participants With Moderate to Severe Plaque-Type Psoriasis With Randomized Withdrawal and Retreatment NCT02207244)8 reported better persistence of response in the guselkumab maintenance group versus the withdrawal arm of the study (p<0.001) from Weeks 28 to 48. About two-thirds of the adalimumab nonresponders (66.1%) who were switched to guselkumab at Week 28 achieved PASI 90 at Week 48. The rate of adverse events was similar among groups for both VOYAGE1 and VOYAGE2.

Risankizumab. Risankizumab is a novel anti-IL-23 monoclonal antibody (BI 655066) that was recently studied for safety, efficacy, and pharmacokinetic properties in a first-in-human, proof-of-concept study, designed as a single-rising-dose, randomized, double-blind, placebo-controlled trial.9 Eighteen patients with moderate-to-severe plaque psoriasis received 0.01, 0.05, 0.25, 1, 3, or 5mg/kg of risankizumab intravenously (IV), 0.25 or 1mg/kg risankizumab subcutaneously (n=13), or matched placebo (n=8). Adverse events were similar in the active and control groups. Risankizumab was associated with clinical improvement commencing around Week 2 and maintained by 33 percent of those treated up to 66 weeks after treatment. PASI 75, PASI 90, and PASI 100 scores were achieved at 12 weeks by 87, 58, and 16 percent of risankizumab patients, respectively; no placebo patients scored in this range.7 As such, risankizumab may be considered an “immunologic disrupter.”

Third-generation biologics. IL-17 inhibitors. IL-17 inhibitors include secukinumab, ixekizumab, and brodalumab. There are clear differences in these three agents in terms of structure and signaling,10 although all three may be considered next-generation biologics (Figure 1).

Secukinumab. The SCULPTURE study (Efficacy and Safety of Subcutaneous Secukinumab [AIN457] for Moderate to Severe Chronic Plaque-type Psoriasis Assessing Different Doses and Dose Regimens [SCULPTURE] NCT01406938), presented at the European Academy of Dermatology and Venereology Congress in Vienna in 2016 by Bissonnette et al, demonstrated durable effectiveness of secukinumab in a four-year observed analysis.11 At the end of Year 4 (n=131), 88.5, 66.4, and 43.5 percent of secukinumab patients had PASI 75, PASI 90, and PASI 100 scores, which were similar to first-year results (n=162) of 88.9, 68.5, and 43.8 percent, respectively. The rate of treatment-emergent adverse events remained similar over the years (78.0% at Year 1, 75.0% at Year 2, 69.4% at Year 3, 62.0% at Year 4) with the most frequently reported adverse events being nasopharyngitis, upper respiratory tract infection, headache, and pharyngitis. Neither MACE nor opportunistic infections (other than candida infections) occurred in four years.11

Ixekizumab. Ixekizumab has been the focus of numerous recently published studies.12 The long-term results from a Phase 2 study (A Study in Participants With Moderate to Severe Psoriasis NCT01107457) of five-year safety and efficacy were recently presented at the American Association of Dermatology (AAD) scientific sessions. Subcutaneous ixekizumab was administered six times at Weeks 0, 2, 4, 8, 12, and 16; patients with plaque psoriasis for six or more months involving at least 10 percent of BSA then entered a treatment- free period up to Week 32; those whose response was better than PASI 75 at Week 32 were eligible to enter the open-label extension phase. In this phase, patients received 120mg of subcutaneous ixekizumab every four weeks up to Week 88, and then 80mg of subcutaneous ixekizumab every four weeks thereafter to Week 240 (data on file with Eli Lilly and Company).

Adverse events caused 10.8 percent of reported adverse events included alanine aminotransferase increase, hepatic enzyme increase, hidradenitis, invasive ductal breast carcinoma, nonsmall-cell lung metastatic cancer, osteomyelitis, psoriatic arthropathy, pyelonephritis, rectal adenocarcinoma, rectal adenoma, or a urinary tract obstruction (all <1%) or due to pregnancy (1.7%). No deaths were reported. Treatment-emergent adverse events decreased from 60.0 percent in the first year to 50.0 percent in the fourth year, but serious adverse events increased from 5.8 percent in the first year to 10.5 percent in the fourth year. Serious infections occurred in 5.0 percent of patients.

Brodalumab. In two Phase 3 studies (the AMAGINE2 (Study of Efficacy and Safety of Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe Plaque Psoriasis Subjects NCT01708603) and AMAGINE3 (Study of Efficacy and Safety of Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe Plaque Psoriasis Subjects NCT01708629), patients with moderate-to-severe psoriasis were randomized into one of four groups: brodalumab 210mg every two weeks, brodalumab 140mg every two weeks, ustekinumab 45mg or 90mg depending on patient weight, or placebo.13 After 12 weeks, brodalumab patients were randomized again to a maintenance dose of brodalumab of either 210mg every two weeks, 140mg every two weeks, 140mg every four weeks, and 140mg every eight weeks. Ustekinumab patients continued to receive their regimen unchanged, while placebo patients were migrated to the 210mg brodalumab group. At 12 weeks, PASI 75 response was higher in both 210mg and 140mg brodalumab groups (86% and 67%, respectively) than placebo (8%), p<0.001. The number of brodalumab patients with sPGA scores of 0 and 1 was significantly higher than placebo patients (p<0.001). At 12 weeks, PASI 100 scores were achieved by significantly more brodalumab 210mg patients than ustekinumab patients in both studies (44% vs. 22%, respectively, and 37% vs. 19%, respectively, for AMAGINE2 and AMAGINE3, p<0.001 for both). For adverse events, neutropenia was more common with active treatments than placebo, and mild-to-moderate candidate infections occurred more often in brodalumab patients than ustekinumab or placebo patients.13

Safety concerns have arisen about brodalumab and its possible associations with depression and suicidality. In Phase 3 trials, the drug sponsor, Amgen (Thousand Oaks, California), introduced a psychological survey instrument to better assess patients who might be at risk for these outcomes, but the intervention was not successful in identifying patients at risk. Despite robust efficacy results, studies were halted and Amgen stopped developmental activities in the second quarter of 2015. Amgen’s partners continued development and submitted brodalumab to the FDA where it was reviewed in July of 2016. At the Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC) on July 19, 2016, 18 panelists recommended approval and 14 recommended a risk evaluation and mitigation strategy program (REMS) for brodalumab. Thus, brodalumab was approved in February 2017 with a black-box warning, and a REMS program was established to restrict access. Patients who are prescribed brodalumab must be counseled and made aware of the mental health risks, and any new or worsening symptoms of depression or suicidality must be reported and patients will be referred, as appropriate, to competent mental health professionals. Patients must sign a patient-prescriber agreement in order to take brodalumab, which only certified pharmacies may dispense. Brodalumab is contraindicated in patients with Crohn’s disease.14

It has long been reported in the literature that psoriasis patients are at elevated risk for suicidality apart from any particular course of treatment. In a 1993 study, a survey of 217 psoriasis patients revealed that 9.7 percent said they had a wish to be dead and 5.5 percent had active suicidal ideation at the time of the survey.15 These traits could be associated with a higher score for depression (p<0.0001) and higher self-ratings of severity of psoriasis (p<0.05). This important association between psoriasis and suicidality plus the potential risk factors specifically associated with brodalumab remain to be further elucidated.

Treatment targets. The AAD published treatment targets for plaque psoriasis in 2017 that recommended BSA as the preferred assessment metric and that treatments ought to attain an improvement of at least 75 percent every three months or the equivalent of achieving three percent BSA improvement every three months.16 The target response would be less than one percent of BSA achieved at six months and then maintained every six months thereafter.16 In order to meet this goal, dermatologists must select highly effective drugs for their psoriasis patients. An important metric for appropriate drug selection is the number needed to treat (NNT), which defines the average number of patients who must be treated to achieve one additional good outcome. In clinical trials, the NNT is the number of patients who are treated to get one patient to benefit when compared to a control patient.17 Fortunately, based on prescribing information provided in product labeling and clinical trials, it is possible to know the NNT scores for a variety of psoriasis drugs for various outcomes (Table 2).

The old treatment paradigm for psoriasis modeled a stepwise progression starting with over-the-counter (OTC) products, such as emollients, and advancing to prescription topicals (including topical steroids, vitamin D analogs, retinoids), phototherapy options, and finally systemic therapy. In this traditional treatment scheme, patients had to move step by step through the system and could not advance to the next step until they had failed the current step. In other words, patients could not get phototherapy until they had failed prescription topicals. This has given way to our emerging psoriasis treatment model, which commences with topical therapy; if a patient fails topical therapy (OTC or prescription products), the patient may be advanced to phototherapy, traditional systemic agents (such as apremilast, acitretin, methotrexate), or biologics, based on the individual patient’s preferences and condition.

PSORIATIC ARTHRITIS UPDATE

The societal costs of psoriatic arthritis (PsA) have been and remain enormous. In a nationwide cohort study from Denmark using data from January 1998 through December 2014, 10,525 PsA patients were matched with 20,777 comparators from the general population.18 At baseline, compared to the general population, PsA patients had more comorbid conditions: cardiovascular disease (odds ratio [OR] 1.70, 95% CI: 1.54–1.6), respiratory disease (OR 1.73, 95% CI: 1.54–1.96), and infectious diseases (OR 2.03, 95% CI: 1.69–2.42). PsA patients had higher total healthcare costs and significantly lower income than people in the general population. Perhaps most concerning is the fact that five years prior to PsA diagnosis, PsA patients were at greater risk of being on disability (risk ratio [RR] 1.36, 95% CI: 1.24–1.4) than individuals in the general population, but that risk increased to 1.60 (95% CI: 1.49–1.72) at the time of diagnosis, and then increased to RR 2.69 (95% CI: 2.40–3.02) 10 years after diagnosis. In fact, a decade after the PsA diagnosis, 22 percent of PsA patients were on disability insurance.18

About 2 to 3 percent of the population has cutaneous psoriasis, and, of that population, about 30 percent will develop PsA.19 Thus, it becomes important to the healthcare system to better identify those psoriasis patients who are most at risk of developing PsA, to allow for earlier and potentially more effective intervention. The question remains unanswered as to why some patients with psoriatic skin disease do not develop PsA. It has been speculated that PsA may exist in all patients with cutaneous psoriasis but it remains subclinical in most. Better understanding of this so-called “occult PsA” and the transition from psoriatic skin disease to PsA will allow for development of better therapeutic targets. In a study of 85 subjects (55 psoriasis patients and 30 healthy control subjects), high-field magnetic resonance imaging (MRI) scans were used to evaluate patients with psoriasis for synovitis, osteitis, tenosynovitis, and periarticular inflammation based on the PsA MRI scoring (PsAMRIS) criteria.10 At least 47 percent of these patients had at least one inflammatory lesion visible on MRI. The frequencies of the observed lesions were 38 percent inflammatory, 11 percent osteitis, four percent tenosynovitis, and four percent periarticular inflammation. In psoriasis patients with subclinical synovitis and arthralgia-associated symptoms, the risk for developing PsA was as high as 55.5 percent, but was 15.3 percent for those patients with normal MRI scans and no reported arthralgia symptoms.20

C-C-X motif ligand (CXCL) 10 is a chemokine which is secreted by a variety of cells, including lymphocytes, monocytes, keratinocytes, fibroblasts, and endothelial cells in response to interferon-γ (IFNγ) and TNF.21 It has been speculated that CXCL10 may be a potential biomarker for PsA. In a prospective study of patients with skin psoriasis but without PsA, baseline levels of serum CXCL10 messenger RNA were evaluated as a potential biomarker for PsA.22 Patients in whom PsA developed were designated in this study as “converters,” compared to “nonconverters” (who did not develop PsA). CXCL10 serum levels were significantly higher in converters (493pg/mL) than nonconverters (371pg/mL), p=0.005, but serum levels of C-reactive protein were similar between groups.22 After PsA developed, patients exhibited lower levels of CXCL10. This both implicates CXCL10 as a predictive biomarker for PsA in psoriasis patients and suggests that it may play a role in the pathogenesis of PsA.

A new population-based study by Lewinson et al23 has found depression increases the risk that a patient with cutaneous psoriasis will develop PsA. Since systemic inflammation increases the risk of PsA in psoriasis patients and since major depressive disorder (MDD) is associated with increased levels of systemic inflammation, investigators hypothesized that patients with psoriasis who suffer from MDD were more at risk of developing PsA than those without MDD. A retrospective analysis using the Health Improvement Network identified psoriasis patients (n=73,447) who were followed for 25 years until either PsA was diagnosed or the censor date. Using Cox proportional hazards models, those psoriasis patients who developed MDD had a significantly increased risk of subsequently developing PsA compared to those psoriasis patients who did not have MDD (HR: 1.37, 95% CI: 1.05–1.80, p=0.021).23

There are numerous treatment options for PsA, including adjunctive treatments (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs]), physical therapy, topical agents (e.g., topical corticosteroids), disease-modifying antirheumatic drugs (DMARDs) (e.g., methotrexate), biologics, and new experimental agents (e.g., Janus-kinase [JAK] inhibitors, α-IL-23 monoclonal antibodies, and other anti-IL-17 agents).

Early and effective treatment of PsA is crucial to reduce joint damage, improve outcomes, prevent disability, and enhance patient quality of life. As many as 20 to 50 percent of patients with PsA are unemployed and 16 to 39 percent are legally disabled.24 Patients with PsA who are employed may suffer from presenteeism (i.e., ability to go to work but at a diminished capacity), absenteeism (i.e., taking time off from work for medical reasons), and productivity loss (i.e., combination of presenteeism plus abstenteeism).25 A multicenter, observational cohort study enrolled patients with PsA who were either starting or switching to an anti-TNF therapy or conventional synthetic DMARD (csDMARD) for PsA.25 At baseline, 57 percent of the study population was employed and 24 percent of those of working age were not employed. At six months of therapy, there were significant improvements in the csDMARD group (n=164) in terms of presenteeism (10%, p=0.007) and work-related productivity (15%, p=0.001). The improvements were more pronounced in the anti-TNF therapy group (n=65), with proportions of patients achieving significantly less presenteeism (30%, p<0.001) and greater work productivity (40%, p<0.001). Clinical improvement was greater in the anti-TNF group compared to the csDMARD group.25

Obesity is a frequently observed comorbidity with PsA and may exacerbate its course.27 Obesity is associated with inflammation, and studies of other rheumatic patients suggest that anti-TNF therapy adherence is low in patients with obesity.26,27 An observational cohort study evaluated patients with PsA over a median 1.5 years (n=1,943).28 Of this population, 32 percent were obese (n=408), defined as body mass index (BMI) of 30kg/m² or more. Adherence was defined as the number of years that the patient maintained treatment with the first TNF inhibitor, although temporary interruptions in treatment (<3 months) were allowed. TNF inhibition therapy was shorter in patients with obesity compared to patients without obesity (2.5 years vs. 5.9 years). Good or moderate response on the European League Against Rheumatism (EULAR) scale was achieved by 55 percent of obese and 65 percent of nonobese patients at six months (p=0.02), and obesity was associated with greater degree of disease activity, increased risk of discontinuation of TNF inhibition therapy, and decreased treatment response. Obesity had a significant effect on patients in this study irrespective of sex, particular type of TNF inhibitor, and patient nationality.28

Biologics able to inhibit the IL-17A pathway have been explored for their potential role in treating PsA as well as other disorders. IL-17A has been implicated in the pathogenesis of multiple immunoinflammatory diseases, including psoriasis, PsA, and rheumatoid arthritis (RA).29 IL-17 is a cytokine family of six subunits (A, B, C, D, E, F). IL-17A may be described as a principal effector of T-helper type (Th) 17 cells; high levels may be found at diseased cutaneous sites and in diseased joints.29 In results presented at the 2016 meeting of the American College of Rheumatology, secukinumab at multiple dosages offered sustained improvements in signs and symptoms in various clinical domains at three years in 606 PsA patients.30

Other IL-17A inhibitors currently being evaluated for PsA treatment include ixekizumab, bimerkizumab (this monoclonal antibody antagonizes both IL-17A and IL-17F), a dual-variable domain (DVD) drug that inhibits TNF and IL-17 (ABT-122), and guselkumab. A novel selective T-cell costimulator (abatacept) used to treat rheumatoid arthritis and juvenile idiopathic arthritis was recently evaluated in the ASTRAEA trial (Efficacy and Safety of Subcutaneous Abatacept in Adults With Active Psoriatic Arthritis [ASTRAEA] NCT01860976) and was shown to be effective against PsA and well tolerated, even in patients previously exposed to TNF inhibitors.31

New agents that help to inhibit JAK pathways are being explored for their potential role in treating psoriasis and rheumatic diseases.32 The two best known JAK inhibitors are tofacitinib and ruxolitinib. In a randomized placebo- and active-controlled, double-blind, Phase 3 study, PsA patients were randomized to one of five groups: oral tofacitinib 5mg twice daily (n=107), tofacitinib 10mg daily (n=104), subcutaneous adalimumab 40mg once every two weeks (n=106), placebo patients who were migrated to tofacitinib 5mg twice daily at the end of three months (n=52), and placebo patients who were migrated at three months to 10mg of tofacitinib twice daily (n=53).33 Tofacitinib was significantly superior to placebo on the American College of Rheumatology and 20-percent improvement (ACR20) response rates and improved scores on the Health Assessment Questionnaire Disability Index at three months. Safety was similar in all groups.

The OPAL BEYOND trial (Tofacitinib In Psoriatic Arthritis Subjects with Inadequate Response to TNF Inhibitors NCT01882439) examined tofacitinib’s effectiveness in 395 patients with PsA who did not respond to TNF inhibition therapy.34 Effectiveness with tofacitinib was superior to placebo in ACR20 response and improved scores on the Health Assessment Questionnaire Disability Index with superiority becoming evident as early as the first assessment (Week 2). No new safety risks emerged in this study.

TOPICAL THERAPIES FOR PSORIASIS

The vehicle for topical products plays a large role in effectiveness, safety, and patient satisfaction. For example, topical calcipotriene produced marked improvement in more patients (70%) as an ointment compared to solution (31%), foam (41%), or cream (50%). However, skin irritation is markedly lower in the solution and foam formulations; calcipotriene ointment and cream have rates of skin irritation around 10 to 15 percent. This gives rise to the question as to whether “designer vehicles” can be created to help optimize drug penetration into the skin, skin permeation rates, and how well the active ingredients are absorbed into the receptor fluid.

To this end, a novel betamethasone dipropionate (BD) emollient spray was formulated, aimed at gaining better epidermal penetration in skin affected by psoriasis while minimizing systemic absorption. This new formulation was compared with super-potent augmented BD 0.05% lotion in adults with moderate plaque psoriasis.35 Patients in this study (n=351) were randomized to receive augmented BD or the new emollient spray or vehicle alone to be applied twice a day to affected areas for two weeks. The primary endpoint was an IGA score of 0 or 1 and at least two-grade improvement over baseline. At baseline, the mean BSA affected by psoriasis in patients was about 13 percent. The primary endpoint was achieved at two weeks in 19.0 percent of the emollient spray patients, 18.9 percent of the superpotent augmented BD lotion patients, and 2.3 percent in the vehicle patients (spray was significantly better than placebo, p<0.001). Response was rapid, with 10 percent of patients responding to the emollient spray at eight days versus 6.7 percent of augmented BD patients and 1.2 percent of vehicle patients. All products were well tolerated but significantly more patients reported burning or stinging with augmented BD compared to the emollient spray (13.6% vs. 4.1%, p=0.006). 35

Combination therapy may be an important consideration in topical therapy of psoriasis. The rationale behind combination therapy is to enhance efficacy by using multiple products with complementary mechanisms of action while, when possible, reducing side effects by using lower doses of each medication.36 For example, topical combination therapies have been proposed with the aim of reducing steroid use while still providing safe, effective treatment. In a three-arm study of calcipotriene ointment 0.005% applied mornings and halobetasol propionate 0.05% ointment applied evenings, this combination therapy was compared to the twice-daily use of either product alone (n=127).37 At two weeks, the calcipotriene/halobetasol combination group had significantly improved results in the treatment of psoriasis and fewer cutaneous adverse effects than either of the two components applied in monotherapy. Lesional or perilesional irritation, a side effect sometimes reported with calcipotriene ointment monotherapy, did not occur in the combination group.37 This study terminated at two weeks. To assess the durability of therapies, a double-blind, placebo-controlled study of the 40 patients in the prior study who achieved 50-percent or greater improvement were then randomized to receive either halobetasol ointment twice daily on weekends and calcipotriene ointment twice daily on week days (n=20) or halobetasol ointment twice daily on weekends and placebo ointment twice daily on weekdays (n=20). At six months, 66 percent of the combination patients were able to maintain remission compared to 40 percent of the control patients.38

The drawback with combination therapy that relies on two different products is that it may be too complex, inconvenient, or burdensome for patients to manage self-application over the long term. A fixed combination product, which combines calcipotriol and BD into a single ointment, can be applied once daily. In a clinical trial of 1,603 patients with psoriasis randomized to one of four treatment arms (combination, betamethasone only, calcipotriol only, or vehicle), the mean percentage change in PASI scores at the end of four weeks of treatment was -71.3 for combination therapy compared to -57.2, -46.1, and -22.7 for betamethasone monotherapy, calcipotriol monotherapy, or vehicle, respectively.39 The mechanism of action behind this combination calcipotriol/BD product is thought to be based on the fact that the combination suppresses both TNFα and the IL-23/IL-17 axis more effectively than BD monotherapy.40

The ability of a topical product to penetrate the stratum corneum may improve its bioavailability. The only substance that can penetrate the skin barrier is the dissolved active ingredient (not crystalline substances), and the rate of cutaneous penetration is proportional to the amount of dissolved active ingredient. Thus, if the solubility of active ingredients could be improved and delivered in a vehicle that patients preferred, this could increase not just the drug’s usability but also its clinical effectiveness. The efficacy of the fixed-combination calcipotriene/BD product in an aerosol foam formulation compared to an ointment was studied in a multicenter, prospective randomized trial (n=376); this study was investigator-blinded only (not double-blinded) as there were formulation differences that could not be masked. At four weeks, psoriasis patients had significantly greater improvement with the combination foam product (54.6%) compared to combination ointment (41.0%, p=0.025) and vehicles (foam 6.1%, ointment 7.8%).41

Tazarotene is an effective topical retinoid available in 0.1% and 0.05% cream and gel formulations. Side effects, including pruritus and erythema, are reported in up to 30 percent of patients. Combining tazarotene with topical steroids has long been observed to enhance efficacy while reducing potential adverse events.42 A fixed-combination product of halobetasol propionate lotion 0.01% together with tazarotene 0.045% (HP/TAZ) was evaluated in the treatment of moderate-to-severe plaque psoriasis.43 In a randomized, double-blind, vehicle-controlled, Phase 2 study of 212 patients with moderate-to-severe psoriasis, subjects were randomized to one of four groups: HP/TAZ, HP monotherapy, TAZ monotherapy, or vehicle.43 All products were applied once a day for eight weeks. Efficacy was at least two-grades improvement over baseline in IGA score and a score of “clear” or “almost clear.” At two weeks, HP/TAZ was statistically significantly superior to vehicle, and by the conclusion of the study, 52.5 percent of the combination patients (HP/TAZ) had achieved treatment success compared to HP only (33.3%), TAV only (18.6%), and vehicle (9.7%) groups. Adverse events most frequently reported were application-site reactions.43 The proportion of patients reporting at least one adverse event was 33.9, 21.0, 46.6, and 22.6 percent for HP/TAZ, HP monotherapy, TAZ monotherapy, and vehicle, respectively. A related Phase 3 study was completed that randomized 215 patients with moderate-to-severe plaque psoriasis to a combination lotion (halobetasol propionate 0.01% combined with tazarotene 0.045%) versus vehicle with primary outcomes defined as two-grade improvement or more from baseline in IGA score and an IGA score of 0 (clear) or 1 (almost clear). Results indicated that the combination product was significantly more effective than the vehicle (results on file with LS Gold, a presenter at MauiDerm 2017 whose presentation is one of which portions of this article are based). Overall, the combination product was well tolerated.

The forefront of topical research involves new molecules able to disrupt the many and varied intracellular signal-transduction pathways used by cytokines. Cytokines, chemokines, antibodies, and antigens bind to receptors on the surface of the cell, causing the receptors to polymerize, which enables their auto-activation or allows them to recruit binding partners.44 This, in turn, results in a cascade of signaling activity, which lead to the altered expression of the genes involved in inflammation, degradation of the extracellular matrix, apoptosis, and other cellular processes. Many of these signaling pathways are currently known, and more are being discovered. Among the pathways known to play a role in psoriasis are the mitogen-activated protein kinase (MAPK) pathway, the spleen-tyrosine kinase (Syk) pathway, the phosphoinositide 3-kinase (P13K0 pathway), the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathways, the protein kinase C (PKC) pathway, the nuclear-factor-κ light-chain-enhancer of activated B-cells (NF-κB) pathway, and, perhaps most discussed currently, the JAK pathway.44,45

A cytokine binding to a receptor can activate JAK, a tyrosine kinase. Activated JAK acts as a docking station for signal-transducer and activator of transcription (STAT) factor, which induces pro-inflammatory cytokine gene transcription. Once the STAT is docked, it is phosphorylated by the activated receptor-associated JAK. There are four JAK enzymes (JAK1, JAK2, JAK3, JAK4) that pair up in various combinations to integrate signaling from almost 40 different cytokines and growth factors.

When cytokines bind to the cell-surface receptors, the JAKs dimerize and are autophosphorylated. STAT proteins are bound and are phosphorylated by the activated JAKs. Phosphorylated STAT proteins then are translocated to the nucleus where they initiate gene transcription and secretion of the specific cytokine that activated the receptor. When the signaling processes are disrupted, some proinflammatory cytokines may be overproduced; increased cell proliferation may occur; and there may be an increase in multiple cellular processes, including growth/maturation of lymphoid cells and the differentiation/homeostasis of T-cells and B-cells.46–50

Tofacitinib is a new small molecule that can be applied in an ointment formulation for the treatment of plaque psoriasis based on the inhibition of JAK1/JAK3. In a randomized, double-blind, parallel-group, vehicle-controlled Phase 2b study over 12 weeks, tofacitinib ointment in two strengths (2% and 1%) was applied once or twice daily in adults with mild-to-moderate plaque psoriasis.51 A total of 430 patients were treated; tofacitnib ointment 2% applied once or twice a day was associated with greater effectiveness than the vehicle at Week 8 but not Week 12; about half of patients (44.2%) experienced adverse events but the higher rate of adverse events occurred in the vehicle rather than active-treatment group.51

A novel agent, known currently as INCB018424, is a powerful JAK1/JAK2 inhibitor that is able to block signal transduction of several pro-inflammatory cytokines. Topical INCB018424 phosphate 1% or 1.5% cream was applied once or twice daily for four weeks over 2 to 20 percent of the BSA in five sequential cohorts of five patients each. Target lesions were rated on a scale of 0 to 4 for erythema, scaling, and thickness; the Physician’s Global Assessment was also used to assess overall disease activity. Both formulations improved lesion scores.52

Another new small module, GSK2894512, has undergone a dose-finding Phase 2 study set up as a double-blind, vehicle-controlled, six-arm, parallel-group trial. More small molecules will likely be tested soon for topical delivery.

UPDATE ON PSORIASIS COMORBIDITIES

Psoriasis is associated with many comorbidities that may affect prescribing considerations. It has been known that psoriasis is comorbid with many cardiometabolic conditions (e.g., atherosclerosis, atrial fibrillation, diabetes, dyslipidemia, hypertension, metabolic syndrome, obesity, and peripheral vascular disease) as well as noncardiovascular conditions (e.g., anxiety, asthma, chronic kidney disease, chronic obstructive pulmonary disorder, depression, migraines, multiple sclerosis, and uveitis).53 New and ongoing research continues to associate other conditions with psoriatic disease.

A family history of cardiovascular disease may predict MACE in patients with psoriasis. In a retrospective study from data drawn from the Danish National Patient Register (n=2,722,375),54 investigators found that patients who had both psoriasis and a family history of cardiovascular disease had an adjusted incidence rate ratio for MACE of 1.28 for mild disease (95% CI: 1.12–1.46) and 1.62 for severe disease (95% CI: 1.14–2.30). Patients with psoriasis of any degree of severity but without a family history of cardiovascular disease had no incremental risk for MACE.

Abnormalities in liver enzyme levels are commonly reported in patients with psoriasis.55 To investigate a potential association between psoriasis and autoimmune hepatitis, a retrospective Danish nationwide cohort study (n=5,404,503) observed 56,739 people with mild and 10,909 with severe psoriasis.56 The adjusted incidence rate ratio for autoimmune hepatitis was 2.64 (95% CI: 1.70–4.11) and 3.05 (95% CI: 0.98–9.47) for mild and severe psoriasis, respectively (p<0.001 for mild psoriasis vs. reference population, p=0.054 for severe psoriasis vs. reference population).56

Chronic pancreatitis may develop following episodes of acute pancreatitis. It is an irreversible inflammatory disease of the pancreas and confers a risk of morbidity and mortality.57 A retrospective analysis of the Taiwan National Health Insurance Research Database (n=48,430 people with psoriasis and n=193,720 without psoriasis) found the incidence of chronic pancreatitis to be 0.61 per 1,000 person-years in patients with psoriasis compared to controls over a mean of 6.6 years.58 Patients with mild psoriasis had significantly higher risk of chronic pancreatitis (crude hazard ratio 1.81, 95% CI: 1.53–2.15), and the risk appears to be similar with severe psoriasis (crude hazard ratio 1.68, 95% CI: 1.02–2.89). Data in this study were analyzed two ways: once including patients with psoriasis and PsA and once excluding the patients with PsA from the psoriasis group. Results did not differ significantly.

Avascular necrosis (AVN), sometimes called osteonecrosis, is an ischemic bone necrosis that can occur when blood supply to the bone is lost or diminished. In a retrospective study based on the Taiwanese National Health Insurance Research Database, 28,268 patients with psoriasis were identified and then matched to 113,072 randomly selected controls without psoriasis.59 Patients with psoriasis had higher adjusted hazard ratio for AVN than control patients (HR: 1.96, 95% CI: 1.62–2.38), and men with psoriasis had significantly higher adjusted hazard ratio for AVN than women. The risk for AVN occurs in both mild and severe psoriasis disease (although severe psoriasis confers a greater risk than mild psoriasis) and in patients with and without PsA (although those with PsA had a greater risk for developing AVN). The risk for AVN was greater in patients under age 30 years than other age groups (adjusted HR 2.64, 95% CI: 1.24–5.61).

Endothelial dysfunction, considered an early phase of atherogenesis, is a systemic and pathological state of the endothelium that results from an imbalance between vasodilating and vasoconstricting substances produced by and/or acting on the inner lining of blood vessels. Accelerated atherosclerosis has been recognized as a comorbidity of moderate to severe psoriasis.60,61,62 A new study explored whether the use of TNFα inhibitors in patients with moderate-to-severe psoriasis (n=29 consecutive patients) would improve endothelial function measured by brachial artery reactivity measuring flow-mediate dilatation (FMD%).63 Patients had completed six months treatment with adalimumab. FMD% values increased (improved) from 6.19±2.44 percent at the commencement of adalimumab therapy to 7.46±2.43 percent after six months (p=0.008).

Arterial stiffness is considered an independent predictor of cardiovascular disease, and it was likewise found that after six months of treatment with adalimumab, patients with moderate-to-severe psoriasis showed significant improvement. Carotid arterial stiffness was assessed using pulse wave velocity (PWV) at baseline and then at six months. PWV decreased (improved) from 6.28±1.04m/sec at baseline to 5.69±1.31m/sec at six months (p=0.03).63

In a single-center, prospective, observer-blinded, controlled study, noncontrast coronary artery calcium computed tomography (CT) scans along with contrast-enhanced coronary CT angiography were performed at baseline and again at 13 months in 28 patients with severe psoriasis treated with adalimumab, etanercept, infliximab, or ustekinumab.64 Patients could rotate to different drugs from this list over the 13 months of the study at the discretion of their physicians in order to control inflammation. Noncontrast coronary artery calcium scores remained stable in the active-treatment group but progressed in the control group (p=0.02). Luminal narrowing remained unchanged in the intervention group but worsened in the control group.64 Thus, these biologics could be associated with a reduction in coronary artery disease progression in patients with severe psoriasis.

To compare the risk of MACE in patients treated with TNFα inhibitors versus those treated with methotrexate, a retrospective claims-based analysis was conducted using data from the Truven Health Analytics MarketScan^® databases with data from the first quarter of 2000 through the third quarter of 2011).65 In this large study (n=382,059 psoriasis patients), TNFα inhibition was associated with greater reduction of various cardiovascular risks in psoriasis patients than methotrexate (Figure 2, Table 3).

THE CENTRAL IMPORTANCE OF THE IL-23/TH17 PATHWAY IN THE PATHOGENESIS AND TREATMENT OF PSORIASIS

The evolution in thinking about the pathogenesis of psoriasis. The inflammatory immune system has long been implicated in psoriatic disease.66 In the past decades, tremendous advances have been made in understanding the pathogenesis of psoriasis.

When immunocompetent cells in exacerbating, untreated psoriatic skin were subjected to immunophenotyping using monoclonal antibodies in a two-stage immunoperoxidase technique, numerous epidermal changes were reported: accumulation of immunoglobulins in the stratum corneum, focal accumulation of OKM-1 positive but Mo-2 negative cells in the epidermis, reflecting granulocytes in Munro’s abscesses, decreased epidermal Langerhans cells, and sporadic exocytosis of mainly T-lymphocytes (T1, T8).67 When quantified in patients with a variety of skin conditions, including but not limited to cutaneous psoriasis, epidermal infiltration of T-cells was most pronounced in psoriasis and least pronounced in atopic dermatitis.67 In normal and diseased skin, the so-called “memory” T-lymphocytes (CD4+, CDw29+) were more numerous than “naïve” (virgin) T-cells (CD4+, CD45R+). A memory T-cell is one that has been activated by an antigen in the presence of antigen-presenting cells at some time after export from the thymus; this differentiation between a memory and a naïve cell also is associated with a change in the CD45 gene product. This predominance of memory cells over naïve cells suggests that most of the T-cells in diseased and normal skin are already primed and have met their specific ligand.67

In the early 1990s, it was thought that the primary pathogenesis of psoriasis involved keratinocytes and T-cells. A fusion protein made up of IL-2 and fragment of diphtheria toxin (DAB₃₈₉IL-2) had been tested.68 DAB₃₈₉IL-2 selectively blocked activated lymphocytes (but not keratinocytes) and resulted in marked clinical improvement in psoriasis, with a concomitant reduction in intraepidermal CD3+ and CD8+ T-cell noted.68 A T-cell model for psoriasis evolved at the time. In healthy skin, there was homeostasis with relatively low proliferation and complete differentiation. Activated CD25+ T-cells interacting with keratinocytes could trigger epidermal hyperplasia, leading to the characteristic high proliferation and incomplete differentiation observed in skin psoriasis along with a concomitant induction of immune-related surface proteins. The strength of this model was reinforced when it was observed that depletion of T-cells by DAB₃₈₉IL-2 could clear psoriasis.

Thinking changed around 2003 when two biologic agents targeting T-cells (alefacept and ealizumab) were approved by the FDA. Both of these drugs were able to improve psoriasis and achieved scores of PASI 75 in more than half of all patients treated. However, there was no characterization of pathogenic T-cell subsets, associated cytokines, or cellular/molecular drivers of pathogenic immunity. It was then learned that CD4+ and CD8+ T-cells are activated by a dendritic antigen-presenting cell (APC) and an antigen. For example, CD8+ T-cells require that an antigen be presented by an APC known as MCH-1. MCH-1 favors intracellular antigens, such as viruses. Meanwhile, CD4+ T-cells are activated by MCH-2, which favors extracellular antigens, such as bacteria. Thus, psoriasis was once thought to be the result of dysregulation of the keratinocyte signaling system. This was later revised to a model that implicated autoimmune T-cell-mediated pathways. The introduction of new biologic agents, such as alefacept, ought to have confirmed the T-cell hypothesis, but instead alefacept was associated with a narrow therapeutic index, limited efficacy, and side effects. In retrospect, neither alefacept nor efalizumab were specific for any T-cell driven pathway. Instead, subsequent agents targeted TNFα and were more effective and better tolerated. Indeed, the introduction of TNFα blockade has revolutionized our current thinking about psoriasis and helped to clarify the crucial role of Th17 in psoriasis pathogenesis.69

Further elucidation indicates that there are multiple mechanisms that can activate dendritic cells, which initiate the psoriasis cascade. The dendritic cells can be induced to produce interferon-α by antimicrobial peptides (LL-37), which can complex with self-RNA and DNA to activate endosomal toll-like receptors (TLR) 7, 8, and 9.70,71 Localized in psoriatic lesional skin, plasmacytoid dendritic cells naturally produce IFN-α and might drive early Th1 cytokine expression before differentiating into tissue-resident dendritic cells or myeloid dendritic cells.72 Resident in tissue cells, there may be a subpopulation of myeloid dendritic cells that express CD11c but not CD1c and produce inducible iNOS, IL-20, and IL-23. TNFα blockade inhibits IL-20 and IL-23,73,74,75 and it is known that IL-23 levels correlate with psoriatic plaque development.76 IL-6 and transforming growth factor β1 upregulate the IL-23 in naïve T-cells, which allow some to differentiate into the Th17 subtype, so named because they produce IL-17.77,78

Research suggests that Th17 cells are crucial to psoriasis pathogenesis. IL-17, a cytokine of the Th17 family, induces an inflammatory response that can be seen in psoriatic skin by the presence of neutrophils.79 TNF-α acts with IL-17 in a synergistic fashion on keratinocytes, but IL-17 inhibition down-regulates these synergistic genes more extensively than TNFα inhibition.80 This likewise points to the key role of Th17 in psoriasis,81 with IL-17 contributing to the associated inflammation. It is likely IL-22 (secreted from Th17 and Th22 cells) induces the epidermal proliferation and de-differentiation of cells characteristic of psoriatic skin disease.82–84 Furthermore, IL-22 up-regulates keratin-17, which has been associated with psoriasis, by way of JAK-STAT.85 Today, psoriasis is one of the best understood autoimmune diseases.

Psoriasis features explained by Th17. A transcriptome may be considered a disease road map that shows the genes and pathways involved in a particular condition. From skin biopsies of patients with psoriasis, today we can identify 4,175 probe sets representing 2,725 unique, known genes associated with psoriasis, compared to only 159 in 2001.86,87

IL-22 is a cytokine produced by activated Th1 and other cells; IL-22 acts on epithelial cells and regulates the expression of only a few genes in keratinocytes.88 These IL-22-regulated genes include psoriasin (S100A7), calgranulin A (S100A8), calgranulin B (S100A9), profilaggrin, keratin 1, keratin 10, kallikrein 7, matrix metalloproteinease (MMP) 1, MMP3, and desmocollin.89 The effects of IL-22 are transcriptional and may be independent of protein synthesis and secretion or mediated via a secreted protein. Inflammation may enhance and amplify the effects of IL-22. Although classified as an interleukin, IL-22 does not appear to influence immune cells because IL-22R1 expression is evident in neither resting nor activated immune cells.89 Patients with psoriasis exhibit elevated plasma levels of IL-22, which can be correlated with disease severity. Psoriasis therapy reduces the expression of IL-22 and IL-22-regulated genes. Cytokines of the IL-10 family (IL-19, IL-20, IL-22, IL-24, and IL-26) are up-regulated in psoriatic skin and may induce acanthosis in reconstituted human epidermis in a dose-dependent fashion.90 Thus, IL-22 promotes acanthosis and impairs terminal differentiation.

By contrast, IL-17 up-regulates numerous genes in keratinocytes including innate defense molecules (DEFB4, S100A7, S100A12, S100A8, and S100A9), cytokines (IL-1F9, IL-8, IL-1β), and chemokines (CCL20, CXCL6, CXCL1, CXCL2, CXCL3, and CXCL5).91 Together, IL-17 and IL-22 induce key molecular features of psoriasis. Keratinocytes have unique responses to IL-17 and IL-22, which are distinct from reactions to Th1 cytokines. In fact, Th1, Th17, and Th22 are the T-cells that drive cellular and molecular features of psoriasis by activating complex cytokine circuits.92

Ustekinumab is a human monoclonal antibody to the human IL-12 p40 subunit (thus, an anti-IL-12p40 agent), which was found to be effective in treatment of plaque psoriasis. In a study of 18 patients with psoriasis covering at least three percent of the BSA, 67 percent of the patients achieved at least 75-percent improvement in their PASI score over the course of the 16-week study.93 Subsequent studies (PHOENIX 1 and 2) align with these results, where ustekinumab 45mg or 90mg produced PASI 75 at 12 weeks in 67 and 66 percent of patients, respectively (p<0.001 compared to placebo, 3%),94 and in 67 and 76 percent of patients, respectively (p<0.001 compared to placebo 4%).95 Histology likewise confirms the resolution of psoriasis with ustekinumab treatment.

The contributions of Th1 versus Th22 versus Th17 to psoriatic disease. Some clinical trials advance medical science by what they do not show. Humanized anti-IFN-γ (fontolizumab) was studied for its effectiveness in the treatment of psoriasis. IFN-γ is a proinflammatory cytokine that has been implicated in psoriasis and in other conditions, such as Crohn’s disease. However, the study ended in near total failure with 9 out of 10 of the patients treated with high doses of fontolizumab having no major improvement in psoriasis.96 This led to the conclusion that IFN-γ (Th1 T-cells) may not be important in maintaining psoriasis.

This, in turn, led to a series of discoveries that pointed to the role of IL-17 in the psoriasis cellular/molecular phenotype in vivo. Direct antagonism of IL-17 began with IL-17 antibodies first introduced around 2009. IL-17 adapted for host-protective functions, but it appears that deranged IL-17 signaling may be associated with immunopathologies.97 IL-17 blockade emerged as an important therapeutic target for psoriasis treatment as well as the treatment of other conditions, such as rheumatoid arthritis and Crohn’s disease. A short summary of the IL-17 family appears in Table 4.

To date, six IL-17 family members have been identified, of which IL-17A and IL-17F are the best characterized. Increasing elucidation of the IL-17 cytokine family suggests there may be significant crosstalk among the various members.97,98

The first description of results obtained from a clinical trial evaluating IL-17 blockade was published by Hueber et al in 2010.99 The drug, AIN457, was later market released as secukinumab. In this first clinical trial (n=104) of 12 weeks, the active agent significantly reduced psoriasis, sometimes as early as 2 to 4 weeks. The majority of adverse events were mild to moderate, no patients discontinued treatment because of lack of tolerability, and there were no deaths.99

In 2012, Papp et al conducted a randomized Phase 2 study that investigated the effects of AMG 827 (brodalumab) on 198 patients with plaque psoriasis with a minimum of 10% BSA involved.100 IBrodalumab significantly reduced psoriasis in 12 weeks, with 72 percent of patients achieving PASI 90 scores. Adverse events occurred, the most common of which were nasopharyngitis, upper respiratory tract infection, and injection-site erythema; two cases of neutropenia were reported in the group that received brodalumab 210mg.100 Brodalumab was able to reverse gene expression across thousands of genes in psoriatic skin.101

Ixekizumab was evaluated by Leonardi et al in a 12-week Phase-2, placebo-controlled study of 142 patients with moderate-to-severe psoriasis. Significant improvement with ixekizumab versus placebo emerged in some patients in the first week.102 Secukinumab, ixekizumab, and brodalumab were all able to target IL-17 and produce dramatic results in psoriatic skin, but the question remained as to the potential impact of maximal ligand blocking to suppress the entire downstream pathway. Upstream from Th-17 (and IL-17) is IL-23. It was hypothesized that IL-23 might control the entire TH17 pathway,103 and the potential blockade of IL-23 and Th17 was proposed as a topic for further study. The humanized anti-IL-23 antibody guselkumab was evaluated in the treatment of moderate-to-severe psoriasis with promising results.104 In a 28-week study, 70.0 percent of guselkumab patients versus 2.4 percent of placebo patients achieved PASI 90 scores at 16 weeks.105 Risankizumab, a relatively new IL-23 antibody,106 was shown to markedly reduce psoriasis in a Phase 2 clinical trial (n=166), providing significantly superior results to the active comparator in the trial, ustekinumab.107 By the 12th week, the percentage of patients who achieved at least a 90-percent reduction in their baseline PASI score was 77 vs. 40 percent for risankizumab and ustekinumab, respectively (p<0.001). Serious adverse events were reported in all but one of the study arms: risankizumab 18mg (12%), risankizumab 90mg (15%), risankizumab 180mg (0), and ustekinumab 45mg or 90mg based on body weight (8%).107

Other IL-23 antagonists currently being studied include B1644066 and tildrakiuzumab. It appears that the IL-23/Th17 axis is crucial to sustaining psoriasis over time, and biologics that target this axis are showing dramatic results, which allow dermatologists to claim that psoriasis is the most effectively treated of all human autoimmune diseases.108 This has led to the elucidation of the feed-forward IL-17 pathogenesis model where autoantigens directly or indirectly mediated by IL-17 trigger IL-23/IL-17 pathways, which begin a cascade including myeloid dendritic T-cell interactions; activated T-cell subpopulations; and the production of IL-17A, IL-22, and IFNγ, which in turn allow keratinocytes to “feed-forward” the inflammatory mediators and then amplify cellular immunity and sustain chronic T-cell activation.108

Thus, psoriasis vulgaris may be regarded as the chronic and maladaptive activation of the body’s natural immune response aimed at eliminating the Candida albicans and possibly other extracellular pathogens. However, psoriasis is driven by an autoantigen rather than an exogenous one. It has long been noted that patients with psoriasis are generally highly resistant to Staphylococcus aureus infection in contrast to patients with atopic dermatitis. Indeed, the pathogenic axes of certain cutaneous diseases are distinct and defined by a type of polar axis (Table 5).

CELLULAR AND MOLECULAR PROFILING OF MILD PSORIASIS

Psoriasis occurs in all populations around the world, but frequencies vary. The disease is less prevalent in Asia than in the United States, and in the United States it is more common in Caucasians than African-Americans. There are also different subtypes of psoriasis.109,110 Asian populations are more likely to develop small plaque psoriasis compared to severe psoriasis, which is more widespread in the West. In a study of 51 patients with biopsy-confirmed psoriasis, plaque size was measured (<2cm = small plaque) and disease severity assessed by PASI. Genomic and histologic studies were done to define psoriasis subtypes. A gene set variation analysis was conducted to determine which genes were expressed in the population. These results validated that Asian small and intermediate psoriasis were phenotypes and shared a common psoriasis transcriptome and histology with Western psoriasis (psoriasis vulgaris). Disease progression was then evaluated. Psoriasis spreads by vertical growth and radial expansion. However, Asian small plaque psoriasis revealed limited spreading but with great expression of proinflammatory cytokines regulated by IL-17A and IL-17.109 In Western psoriasis, IL-17A- and IL-17-mediated cytokines were lower, but Western patients had many more T-cells and dendritic cells in their psoriatic skin areas. Both groups had diminished presence of negative immune regulators (CD69 and FAS), and both groups had incidences of arthritis and obesity, correlating with psoriasis severity. Based on this comparison, it seems that the dysregulation of T-cell expansion allows for the down-regulation of immune-negative regulators in large plaque psoriasis.109

Psoriasis is a T-cell mediated condition and autoimmune disorder, but the mechanisms by which autoantigens trigger T-cells in psoriasis continue to be elucidated.111 Dendritic cells (DCs) stimulate autoimmune T-cells, and an antimicrobial peptide (AMP), specifically LL37, is present at high levels in psoriatic lesions and has been implicated in this process.112–115 A cationic peptide, LL37 may offer antimicrobial protection to the skin, and a recent study found that LL37 could be considered an autoantigen. LL37-specific T-cells produce pathogenic cytokines, including IL-17. This may be the first example of an AMP that stimulates both the body’s innate112–114 and adaptive immune cells in the setting of autoimmune disease.111 About two-thirds of patients with moderate-to-severe plaque psoriasis have CD4(+) and/or CD8(+) T-cells specific for LL37.111

The risk gene for psoriasis is HLA-C*0.6:02 on locus PSOR1 (6p21.33).115 It has been observed that epidermal CD8(+) cells must be present for skin psoriasis to develop.116 Melanocytes have been identified as targets of the psoriatic T-cell response.116 Melanocytes are the only epidermal cells that express ADAMTSL5, an ADAMTS-like protein that acts as a melanocytic autoantigen. ADAMTSl5 stimulation also induces cytokine, IL-17A, and CD8(+) T-cells, but only in patients with psoriasis, which suggests it is a psoriatic autoantigen.116 Thus, IL-17 directly or indirectly regulates autoantigens in psoriasis.

The emerging hypotheses are that there are Type 17 T-cell clones in psoriatic lesions, probably tissue-resident memory (Trm) phenotypes. At some point, tolerance to self-antigens would be broken. It is expected that regulating functions on T-cells in patients with moderate-to-severe psoriasis is partial at most. T-cells may potentially be restrained to some degree by the expression of negative immune regulatory pathways in a process known as “checkpoint inhibition.” In a collaborative project by Clark,117 psoriasis lesions were treated to resolution with etanercept. The lesions were then subjected to T-cell antigen receptor (TCR) sequencing, because it was thought that pathogenic Trm T-cells would remain in the skin at their previous lesional location. Vβ-2, -13, and -16 clones were identified, which indicated that different clones shared the same CDR3 sequence, suggesting that they share reactivity to the same antigen.

Antigens, constitutive in normal skin, are up-regulated either directly or indirectly by IL-17 in keratinocytes or melanocytes. Trm T-cells may be reactive cells and will probably remain lifelong at their location and serve as memory for psoriasis antigens. CCL20, a substance induced by IL-17, triggers dendritic cell infiltration (both TIP-DCs and mature DCs) with potential for strong stimulation of T-cells in the skin. Note that CCL20 is also chemotactic for Th-17.

There are a number of negative immune regulators associated with psoriasis, including lymphocyte activation gene 3 (LAG3), cytotoxic T lymphocyte-associated 4 (CTLA4), indoleamine 2,3 dioxygenase (IDO1), apoptosis, programmed cell death 1 ligand (PDL1), programmed cell death 1 ligand 2 (PDL2), and IL-10. A study recently reported decreased expression of these in immunochemistry studies of psoriatic skin.118 Thus, psoriasis chronicity may be related to the absence of negative immune regulatory pathways, and these negative pathways may be potential therapeutic targets. Furthermore, the researchers hypothesize that negative immune regulation limits disease progression in mild forms of psoriasis vulgaris and in the small-plaque Asian variant of psoriasis.

When psoriasis is described as “mild,” it typically refers to a reduced BSA affected rather than specific skin pathology. In general, mild psoriasis affects less than 10 percent of the body surface, accounts for about 80 percent of all psoriasis cases, and responds to topical treatment. Moderate-to-severe psoriasis affects over 10 percent of the BSA, accounts for 20 percent of psoriasis cases, and may require systemic therapy. However, even patients with mild psoriasis are still at greater risk for cardiovascular disease than normal controls. The comorbidities associated with severe psoriasis also occur in mild psoriasis. While systemic treatment is not always appropriate for mild psoriasis, a case-by-case evaluation may be warranted, weighing the potential risks (comorbidities) and benefits for the individual patient. The high expression of negative immune regulators creates the potential to modify disease if, for example, systemic treatments targeting IL-17A/F are employed.

This leaves an important and as-yet unanswered questions about psoriasis: If one could deplete or substantially reduce effector T-cell clones in mild plaques, would there be enough checkpoint inhibition or Treg function to prevent reactivation of disease-causing clones? Our current understanding of mild psoriasis includes some important points. First, it is not always “mild” in terms of the skin reactions to underlying T-cells. Topical products are the first-line approach to mild psoriasis, but their effectiveness can be limited particularly in comparison to systemic agents. Also, patients with mild psoriasis are at increased risk for comorbidities. Given these facts, we might ask if there is a subset of mild psoriasis patients who ought to be treated with relatively safe biologics or other systemic agents.

The answers to these questions are not yet clear but pose some important ideas that may potentially alter how we treat patients with mild psoriasis.

FROM UV TO SCC

Skin cancer remains by far the most common malignancy in humans in the world, including in Europe.119 In terms of tumor etiology, nonmelanoma skin cancer (NMSC) should be included, as it encompasses basal cell carcinoma (BCC), Bowen’s disease, cutaneous squamous cell carcinoma (SCC), and its early antecedent, actinic keratosis (AK).120 BCC is the most frequent form of invasive cancer around the world; in Germany, individuals approximately have a 30-percent lifetime risk of developing a BCC.121 The risk factors for skin cancer are well known and include ultraviolet (UV) radiation, the human papillomavirus (HPV), and immunosuppression.120 HPV has been implicated in benign and malignant cutaneous lesions and plays what seems to be an active role in the pathogenesis of certain cutaneous cancers.120 Papillomaviruses are small DNA viruses found in more than 20 mammalian and avian species; the genome is composed of nearly 8,000 base pairs. HPV may infect keratinocytes of the skin and mucosa.122

The genital types of HPV are distinct from cutaneous HPV in that the virus does not integrate with the host genome in the skin. Integrated E6 and E7 genes can be observed in genital forms of the HPV. HPV23 and HPV38 may be a cofactor in certain cutaneous cancers, particularly in immunosuppressed patients, such as transplant patients, HIV patients, or patients with other autoimmune disorders under pharmacological immunosuppressive therapy.

While BCC typically presents as a single tumor, AK is best described as a field cancerization, which is described as a continuum in which precancerous and cancerous cells reside in an area of skin that may be adjacent or near skin that does not appear to be involved in the cancer.123 Using the continuum paradigm, AK commences with photodamage and culminates in invasive SCC. Similar but differentially expressed genes found present in both AK and SCC suggests that AK may be a precursor lesion of SCC.124 Gene expression has been studied in photodamaged and photoaged skin. Sun exposure can prompt the down-regulation of specific genes, which starts very early with photodamage and photoaging and precedes to more overt signs of AK over time. This raises two important questions: 1) Where should treatment begin? and 2) What is the role (and timing) of prevention?

The cascade of precipitating events that occurs in the etiology of AK occurs at different stages at multiple sites, such that photodamage, early AK, AK, and SCC may occur in close proximity in the same field. The paradigm in AK treatment has changed in recent years, such that it is now deemed important to treat the entire field rather than the visible lesions alone.123 The classical pathway for AK development begins with photodamaged skin, which leads to a down-regulation of cutaneous immune response and continually expands the keratinocyte intraepidermal neoplasia (KIN). It had previously been accepted that this classical pathway involved several sequential steps, from AKI to AKII, AKIII, and finally SCC, but new evidence suggests that steps can be skipped, such that AKI can advance directly to SCC without the intervening stages.125 In fact, in Germany, AK is accepted by clinicians as a form of carcinoma in situ.

The treatment algorithms for AK vary depending on whether solitary lesions or the entire field is treated (Figure 3).127 Surgery remains the primary treatment for malignant melanoma and SCC, while noninvasive procedures are the first-line approach to AK.126 Photodynamic therapy (PDT) as field therapy for AK is an effective therapeutic option, but its clinical utility is limited by associated pain. So painful is PDT that it averages 7.8 on an analog pain scale where 0 is no pain and 10 is the worst pain imaginable. As an alternative to conventional PDT, so-called “daylight PDT” has been developed.

Regardless of the algorithm, the goal of AK treatment is to address the AK present and prevent SCC in the field with fewer side effects, better safety, enhanced efficacy (low recurrence rate, prevention of development of invasive SCC), cost-effectiveness, and with a product that optimizes patient adherence (e.g., easy to apply in a short period of time). The presence of solitary AKs indicates that the patient’s skin is photodamaged and that he or she is at risk for developing skin cancer. Thus, a topical immune response modifier (IRM) may be appropriate for field treatment in that it treats existing lesions, subclinical AK, and may prevent AK from developing into SCC.

NEXT-GENERATION IMIQUIMOD

New drugs are being developed for the safe, effective treatment of field cancerization, such as resiquimod, a next-generation imiquimod product aimed at treating AK.128 Resiquimod is an imidazoquinoline that acts by cytokine secretion from monocytes and macrophages and has been shown to be effective in BCC and SCC in both immunocompetent and immunosuppressed patients.129 Resiquimod is 100-fold more potent than imiquimod and can be used topically at 0.03% with a 90-percent complete clearance rate.130 In fact, Szeimies et al130 showed that more than 70 percent of patients achieved complete clearance after a single course of treatment. Resiquimod is applied topically for two or three days only. Adverse effects are the development of flu-like symptoms that may last up to 15 days; these were reported by 0 (0.01% gel), 3 percent (0.03% gel), 13 percent (0.06% gel), and 12 percent (0.1% gel) of patients.130 Resiquimod may also be effective in the treatment of cutaneous lymphoma.

Topical ingenol mebutate gel may be used to treat AK. In one study, patients were treated for three days with ingenol mebutate gel 0.015% on the face or scalp or for two days on the trunk or extremities with 0.05% gel.131 Of those patients who achieved complete clearance of the face or scalp lesions, most were enrolled in a 12-month study to evaluate recurrence rates. The sustained lesion reduction rates over baseline were 87.2 percent for face and scalp and 86.8 percent for trunk and extremities, with the estimated median time to recurrence set at 365 days (face/scalp) or 274 days (trunk/extremities).131 No safety concerns were reported during the follow-up period of 12 months.

A pooled analysis of ingenol mebutate gel (0.015% for face/scalp AK and 0.05% for AK on the trunk or extremities) found ingenol mebutate was significantly more effective than placebo at clearing AK on the face or scalp (42.2% vs. 3.7%, p<0.001) as well as on the trunk or extremities (34.1% vs. 4.7%, <0.001).132 Local skin responses peaked at about Day 4 and diminished to baseline by about Day 29.

Ingenol mebutate has a dual mechanism of action in the treatment of both melanoma and SCC. It acts on epidermal cells causing mitochondrial swelling and disruption of the cell membrane, culminating in apoptosis.133,134,135,136 This cascade leads to ingenol mebutate’s immunostimulatory effects and precipitation of the inflammatory response,136 namely that it increases T-cell activity, increases dendritic cell activity, activates endothelial cells, including IL-1β and TNF-α, releases cytokines135 and recruits neutrophils.134 Activated β cells release tumor-specific antibodies that are then bound to antigen-bearing tumor cells; neutrophil binding to the Fc portion of tumor cell-bound antibodies results in the activation and release of reactive oxygen species which, in turn, leads to apoptotic cell death and avoids relapses.134,135,137

Low-dose 5-fluorouracil (5-FU) 0.5% combined with salicylic acid 10% can be used as a topical treatment for hyperkeratonic AK. In a proof-of-concept study (n=15, 66 AK), treatment occurred three times weekly for four weeks. At the end of 12 weeks, 77 percent of patients had complete clearance, 21 percent had partial clearance, and two percent were nonresponders.138 When compared with diclofenac 3% in hyaluronic acid and vehicle, 5-FU 0.5% had greater histological and clinical clearance rates with durable benefits in the lesion-directed treatment of AK than the diclofenac with hyaluronic acid or vehicle.139 In a placebo-controlled, double-blind, parallel-group, multicenter trial, AK patients were randomized to topical 5-FU 0.5% gel applied once daily, vehicle treatment, or diclofenac in hyaluronic acid twice daily.140 Patients were treated for a maximum of 12 weeks, and lesion recurrence was evaluated at 6 and 12 months after the end of treatment. At 12 months, there was no recurrence of AK lesions in the 5-FU 0.5% gel group for 85.8 percent of patients compared to 79.8 percent of vehicle patients with no recurrence (p=0.04419) and 81.0 percent of patients in the diclofenac hyaluronic acid group (p=0.0246). Adverse events occurred most frequently in the 5-FU group (inflammation, burning) but generally did not cause patients to discontinue treatment.140 In a Phase 3 randomized, double-blind, vehicle-controlled multicenter study (n=166), patients with field AK were randomized to receive either 5-FU 0.5% gel combined with salicylic acid 10% or vehicle applied topically once a day for 12 weeks (contiguous areas of the skin for 25cm²).141 The first and last topical applications were performed by the study clinicians but otherwise patients applied the medication themselves. After eight weeks of treatments, the intention-to-treat and per-protocol populations of this study had significantly better results with 5-FU 0.5% gel and salicylic acid than the vehicle, 49.5 vs. 18.2 percent for intention-to-treat patients (odds ratio 3.9, 95% CI: 1.7–8.7, p=0.0006). Patients in the active-treatment group had more application and administration site reactions compared to vehicle patients (99.1% vs. 83.6%). The study results of both groups remained similar and trended in the same manner during the 12 weeks of treatment but diverged markedly in the eight weeks after treatment stopped (Figure 4).

Cryotherapy is appropriate for single, well-defined, hyperkeratonic AK lesions. Field treatment represents a paradigm shift but treats AK as carcinoma in situ and recognizes that there are subclinical lesions in the field that require treatment as well. Topical agents are particularly appropriate for field therapy in that they can treat broader areas and address the subclinical lesions as well. Increasingly, these two therapies are combined for optimal patient management.