Psoriasis

The etiology of psoriasis is multifactorial, and it is attributed to both genetic and environmental components.¹ One of the lesser-studied aspects of psoriasis pathogenesis is the involvement of the nervous system. It is thought that the pathogenesis involves inflammation of the cutaneous nerves,² and cutaneous denervation has been shown to improve acanthosis and IL-23 expression in mice with psoriasiform skin.³ There also have been reports of psoriasis remission following peripheral and central nervous system injury from surgical nerve resection⁴ as well as cerebrovascular accident.⁵ We present a case of total psoriasis clearance following ischemic stroke.

Case Report

A 52-year-old man with psoriasis presented to the dermatology clinic for follow-up. The patient had been using topical clobetasol and apremilast with limited success but had not previously tried biologics. On physical examination he was noted to have erythematous, scaly, indurated papules and plaques on the chest, abdomen, back, arms, and legs, consistent with psoriasis. Affected body surface area was approximately 10%. Ustekinumab was prescribed, but the patient did not pick it up from the pharmacy.

Approximately 1 month later, the patient presented to the emergency department with left-sided weakness and numbness. He was hospitalized for treatment of stroke. During hospitalization, the patient was started on lisinopril, aspirin, and atorvastatin. He also was given subcutaneous enoxaparin with plans to initiate warfarin as an outpatient. His psoriasis was not treated with topical or systemic medications during the course of his admission. He was discharged to a skilled nursing facility after 3 days.

Three months following discharge, the patient returned to the dermatology clinic for follow-up. After his stroke, he reported that his psoriasis had cleared and had not returned. On physical examination his skin was clear of psoriatic lesions.

Comment

The nervous system is thought to play an important role in the pathophysiology of psoriasis. Evidence for this involvement includes the exacerbation of psoriasis with stress and the often symmetric distribution of psoriatic lesions.⁶

Moreover, numerous neuropeptides have been identified in the pathophysiology of psoriasis. Farber et al⁷ first proposed that release of substance P (SP) from cutaneous sensory nerve fibers causes a local neurogenic response that triggers psoriasis in predisposed individuals. The role of SP in psoriasis is unclear, as there have been reports of both higher⁸ and lower⁹ levels in involved and noninvolved skin of psoriatic patients compared to skin in healthy individuals. It has been suggested that numerous other neuropeptides, including nerve growth factor (NGF), calcitonin gene-related peptide, and vasoactive intestinal peptide, play a part in psoriasis.^2,10 Specifically, NGF prevents apoptosis of keratinocytes¹¹ and is found in higher levels in psoriatic skin compared to controls.¹² Calcitonin gene-related peptide has been shown to stimulate keratinocyte proliferation¹³ and has been found at increased levels in psoriatic skin.¹⁴ Vasoactive intestinal peptide-positive nerve fibers in the epidermis and dermis are found in higher quantities in psoriatic plaques compared to nonlesional and normal skin.⁸

Neuropeptides also might play a role in the itching and Köbner phenomenon that accompany psoriasis. Increased levels of NGF in nonlesional skin of patients with psoriasis is thought to contribute to the development of psoriatic plaques following trauma by inducing an inflammatory response that upregulates other neuropeptides, such as SP and calcitonin gene-related peptide. These neuropeptides induce keratinocyte proliferation, which further increases NGF expression, thus creating a cycle of inflammation and formation of psoriatic lesions.⁶ Moreover, there is a notable correlation between pruritus severity and density of NGF-immunoreactive keratinocytes, high-affinity NGF receptors, protein gene product 9.5–immunoreactive intraepidermal fibers, and immunoreactive vessels for E-selectin.¹⁵

Spontaneous remission of psoriasis after cerebrovascular accident was first reported in 1998.⁵ Moreover, there have been cases of protective effects from psoriasis and psoriatic arthritis in limbs affected by poliomyelitis.^16,17 In cases in which patients regained neurologic function, Zhu et al¹⁰ found that recurrence of skin lesions in areas corresponding to nervous system injury also occurred. However, in cases of permanent nerve damage, psoriasis did not return,¹⁰ confirming the role of peripheral nerves in the pathogenesis of psoriasis. It is thought that peripheral nerve damage results in decreased secretion of neuropeptides³ and that central nervous system injury also can cause similar downstream effects.¹⁰

Other reasons for the patient’s remission also were considered. Although it is possible that the sudden change in the patient’s usual environment could have induced remission of psoriasis, it seems more likely that the stress of the situation would have worsened his symptoms. Medications used during the patient’s hospitalization also were considered as reasons for symptom improvement. One study using a case-control and case-crossover design found psoriasis to be associated with nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors (odds ratio, 4.0 and 2.1, respectively).¹⁸ Atorvastatin has been investigated as a potential treatment of psoriasis, though no therapeutic benefit has been proven.^19,20 Heparin has been shown in case reports to improve psoriasis symptoms but was used in addition to standard psoriasis therapies and not as monotherapy.²¹

A more thorough understanding of which neuropeptides are directly implicated in the neurologic-mediated clearance of psoriasis might contribute to better targeted therapies. For example, infusion of peptide T, a vasoactive intestinal peptide analogue, was shown to have some effect in clearing the skin in 14 psoriasis patients.²² Although this finding has not been replicated, it demonstrates the potential utility of therapies targeted toward the neurologic aspects of psoriasis. More research is needed to evaluate the potential of targeting other neuropeptides for treatment of psoriatic plaques.

The etiology of psoriasis is multifactorial, and it is attributed to both genetic and environmental components.¹ One of the lesser-studied aspects of psoriasis pathogenesis is the involvement of the nervous system. It is thought that the pathogenesis involves inflammation of the cutaneous nerves,² and cutaneous denervation has been shown to improve acanthosis and IL-23 expression in mice with psoriasiform skin.³ There also have been reports of psoriasis remission following peripheral and central nervous system injury from surgical nerve resection⁴ as well as cerebrovascular accident.⁵ We present a case of total psoriasis clearance following ischemic stroke.

Case Report

A 52-year-old man with psoriasis presented to the dermatology clinic for follow-up. The patient had been using topical clobetasol and apremilast with limited success but had not previously tried biologics. On physical examination he was noted to have erythematous, scaly, indurated papules and plaques on the chest, abdomen, back, arms, and legs, consistent with psoriasis. Affected body surface area was approximately 10%. Ustekinumab was prescribed, but the patient did not pick it up from the pharmacy.

Approximately 1 month later, the patient presented to the emergency department with left-sided weakness and numbness. He was hospitalized for treatment of stroke. During hospitalization, the patient was started on lisinopril, aspirin, and atorvastatin. He also was given subcutaneous enoxaparin with plans to initiate warfarin as an outpatient. His psoriasis was not treated with topical or systemic medications during the course of his admission. He was discharged to a skilled nursing facility after 3 days.

Three months following discharge, the patient returned to the dermatology clinic for follow-up. After his stroke, he reported that his psoriasis had cleared and had not returned. On physical examination his skin was clear of psoriatic lesions.

Comment

The nervous system is thought to play an important role in the pathophysiology of psoriasis. Evidence for this involvement includes the exacerbation of psoriasis with stress and the often symmetric distribution of psoriatic lesions.⁶

Moreover, numerous neuropeptides have been identified in the pathophysiology of psoriasis. Farber et al⁷ first proposed that release of substance P (SP) from cutaneous sensory nerve fibers causes a local neurogenic response that triggers psoriasis in predisposed individuals. The role of SP in psoriasis is unclear, as there have been reports of both higher⁸ and lower⁹ levels in involved and noninvolved skin of psoriatic patients compared to skin in healthy individuals. It has been suggested that numerous other neuropeptides, including nerve growth factor (NGF), calcitonin gene-related peptide, and vasoactive intestinal peptide, play a part in psoriasis.^2,10 Specifically, NGF prevents apoptosis of keratinocytes¹¹ and is found in higher levels in psoriatic skin compared to controls.¹² Calcitonin gene-related peptide has been shown to stimulate keratinocyte proliferation¹³ and has been found at increased levels in psoriatic skin.¹⁴ Vasoactive intestinal peptide-positive nerve fibers in the epidermis and dermis are found in higher quantities in psoriatic plaques compared to nonlesional and normal skin.⁸

Neuropeptides also might play a role in the itching and Köbner phenomenon that accompany psoriasis. Increased levels of NGF in nonlesional skin of patients with psoriasis is thought to contribute to the development of psoriatic plaques following trauma by inducing an inflammatory response that upregulates other neuropeptides, such as SP and calcitonin gene-related peptide. These neuropeptides induce keratinocyte proliferation, which further increases NGF expression, thus creating a cycle of inflammation and formation of psoriatic lesions.⁶ Moreover, there is a notable correlation between pruritus severity and density of NGF-immunoreactive keratinocytes, high-affinity NGF receptors, protein gene product 9.5–immunoreactive intraepidermal fibers, and immunoreactive vessels for E-selectin.¹⁵

Spontaneous remission of psoriasis after cerebrovascular accident was first reported in 1998.⁵ Moreover, there have been cases of protective effects from psoriasis and psoriatic arthritis in limbs affected by poliomyelitis.^16,17 In cases in which patients regained neurologic function, Zhu et al¹⁰ found that recurrence of skin lesions in areas corresponding to nervous system injury also occurred. However, in cases of permanent nerve damage, psoriasis did not return,¹⁰ confirming the role of peripheral nerves in the pathogenesis of psoriasis. It is thought that peripheral nerve damage results in decreased secretion of neuropeptides³ and that central nervous system injury also can cause similar downstream effects.¹⁰

Other reasons for the patient’s remission also were considered. Although it is possible that the sudden change in the patient’s usual environment could have induced remission of psoriasis, it seems more likely that the stress of the situation would have worsened his symptoms. Medications used during the patient’s hospitalization also were considered as reasons for symptom improvement. One study using a case-control and case-crossover design found psoriasis to be associated with nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors (odds ratio, 4.0 and 2.1, respectively).¹⁸ Atorvastatin has been investigated as a potential treatment of psoriasis, though no therapeutic benefit has been proven.^19,20 Heparin has been shown in case reports to improve psoriasis symptoms but was used in addition to standard psoriasis therapies and not as monotherapy.²¹

A more thorough understanding of which neuropeptides are directly implicated in the neurologic-mediated clearance of psoriasis might contribute to better targeted therapies. For example, infusion of peptide T, a vasoactive intestinal peptide analogue, was shown to have some effect in clearing the skin in 14 psoriasis patients.²² Although this finding has not been replicated, it demonstrates the potential utility of therapies targeted toward the neurologic aspects of psoriasis. More research is needed to evaluate the potential of targeting other neuropeptides for treatment of psoriatic plaques.

The etiology of psoriasis is multifactorial, and it is attributed to both genetic and environmental components.¹ One of the lesser-studied aspects of psoriasis pathogenesis is the involvement of the nervous system. It is thought that the pathogenesis involves inflammation of the cutaneous nerves,² and cutaneous denervation has been shown to improve acanthosis and IL-23 expression in mice with psoriasiform skin.³ There also have been reports of psoriasis remission following peripheral and central nervous system injury from surgical nerve resection⁴ as well as cerebrovascular accident.⁵ We present a case of total psoriasis clearance following ischemic stroke.

Case Report

A 52-year-old man with psoriasis presented to the dermatology clinic for follow-up. The patient had been using topical clobetasol and apremilast with limited success but had not previously tried biologics. On physical examination he was noted to have erythematous, scaly, indurated papules and plaques on the chest, abdomen, back, arms, and legs, consistent with psoriasis. Affected body surface area was approximately 10%. Ustekinumab was prescribed, but the patient did not pick it up from the pharmacy.

Approximately 1 month later, the patient presented to the emergency department with left-sided weakness and numbness. He was hospitalized for treatment of stroke. During hospitalization, the patient was started on lisinopril, aspirin, and atorvastatin. He also was given subcutaneous enoxaparin with plans to initiate warfarin as an outpatient. His psoriasis was not treated with topical or systemic medications during the course of his admission. He was discharged to a skilled nursing facility after 3 days.

Three months following discharge, the patient returned to the dermatology clinic for follow-up. After his stroke, he reported that his psoriasis had cleared and had not returned. On physical examination his skin was clear of psoriatic lesions.

Comment

The nervous system is thought to play an important role in the pathophysiology of psoriasis. Evidence for this involvement includes the exacerbation of psoriasis with stress and the often symmetric distribution of psoriatic lesions.⁶

Moreover, numerous neuropeptides have been identified in the pathophysiology of psoriasis. Farber et al⁷ first proposed that release of substance P (SP) from cutaneous sensory nerve fibers causes a local neurogenic response that triggers psoriasis in predisposed individuals. The role of SP in psoriasis is unclear, as there have been reports of both higher⁸ and lower⁹ levels in involved and noninvolved skin of psoriatic patients compared to skin in healthy individuals. It has been suggested that numerous other neuropeptides, including nerve growth factor (NGF), calcitonin gene-related peptide, and vasoactive intestinal peptide, play a part in psoriasis.^2,10 Specifically, NGF prevents apoptosis of keratinocytes¹¹ and is found in higher levels in psoriatic skin compared to controls.¹² Calcitonin gene-related peptide has been shown to stimulate keratinocyte proliferation¹³ and has been found at increased levels in psoriatic skin.¹⁴ Vasoactive intestinal peptide-positive nerve fibers in the epidermis and dermis are found in higher quantities in psoriatic plaques compared to nonlesional and normal skin.⁸

Neuropeptides also might play a role in the itching and Köbner phenomenon that accompany psoriasis. Increased levels of NGF in nonlesional skin of patients with psoriasis is thought to contribute to the development of psoriatic plaques following trauma by inducing an inflammatory response that upregulates other neuropeptides, such as SP and calcitonin gene-related peptide. These neuropeptides induce keratinocyte proliferation, which further increases NGF expression, thus creating a cycle of inflammation and formation of psoriatic lesions.⁶ Moreover, there is a notable correlation between pruritus severity and density of NGF-immunoreactive keratinocytes, high-affinity NGF receptors, protein gene product 9.5–immunoreactive intraepidermal fibers, and immunoreactive vessels for E-selectin.¹⁵

Spontaneous remission of psoriasis after cerebrovascular accident was first reported in 1998.⁵ Moreover, there have been cases of protective effects from psoriasis and psoriatic arthritis in limbs affected by poliomyelitis.^16,17 In cases in which patients regained neurologic function, Zhu et al¹⁰ found that recurrence of skin lesions in areas corresponding to nervous system injury also occurred. However, in cases of permanent nerve damage, psoriasis did not return,¹⁰ confirming the role of peripheral nerves in the pathogenesis of psoriasis. It is thought that peripheral nerve damage results in decreased secretion of neuropeptides³ and that central nervous system injury also can cause similar downstream effects.¹⁰

Other reasons for the patient’s remission also were considered. Although it is possible that the sudden change in the patient’s usual environment could have induced remission of psoriasis, it seems more likely that the stress of the situation would have worsened his symptoms. Medications used during the patient’s hospitalization also were considered as reasons for symptom improvement. One study using a case-control and case-crossover design found psoriasis to be associated with nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors (odds ratio, 4.0 and 2.1, respectively).¹⁸ Atorvastatin has been investigated as a potential treatment of psoriasis, though no therapeutic benefit has been proven.^19,20 Heparin has been shown in case reports to improve psoriasis symptoms but was used in addition to standard psoriasis therapies and not as monotherapy.²¹

A more thorough understanding of which neuropeptides are directly implicated in the neurologic-mediated clearance of psoriasis might contribute to better targeted therapies. For example, infusion of peptide T, a vasoactive intestinal peptide analogue, was shown to have some effect in clearing the skin in 14 psoriasis patients.²² Although this finding has not been replicated, it demonstrates the potential utility of therapies targeted toward the neurologic aspects of psoriasis. More research is needed to evaluate the potential of targeting other neuropeptides for treatment of psoriatic plaques.

Psoriasis is a chronic, immune-mediated, inflammatory disease affecting almost 2% of the population.^1-3 It is characterized by patches of raised reddish skin covered by silvery-white scales. Most patients have limited disease (<5% body surface area [BSA] involvement) that can be managed with topical agents.⁴ Topical corticosteroids (TCSs) are considered first-line therapy for mild to moderate disease because of the inflammatory nature of the condition and often are used in conjunction with systemic agents in more severe psoriasis.⁴

As many as 20% to 30% of patients with moderate to severe plaque psoriasis have inadequate disease control.⁵ Several factors may affect patient outcomes; however, drug selection and patient adherence are important given the chronic nature of the disease. A survey of 1200 patients with psoriasis reported nonadherence rates of 73% with topical therapy.⁶ In addition, patients tend to apply less than the recommended dose or abandon treatment altogether if rapid improvement does not occur^7,8; it is not uncommon for patients with psoriasis to mistakenly believe treatment will improve their condition within 1 to 2 weeks.⁹ Patient satisfaction with topical treatments is low, partly because of these false expectations and formulation issues. Treatments can be greasy and sticky, with unpleasant odors and the potential to stain clothes and linens.^7,10 Safety concerns with TCSs also limit their consecutive use beyond 2 to 4 weeks, which is not ideal for a disease that requires a long-term management strategy.

A potent/superpotent TCS that is administered once daily and has a safety profile that affords longer-term, once-daily treatment in an aesthetically pleasing formulation would seem ideal. Herein, we investigate the safety and tolerability of a novel low-concentration (0.01%) lotion formulation of halobetasol propionate (HP), reporting on the pooled data from 2 phase 3 clinical studies in participants with moderate to severe psoriasis.

METHODS
Study Design

We conducted 2 multicenter, double-blind, randomized, parallel-group phase 3 studies to assess the safety, tolerability, and efficacy of HP lotion 0.01% in participants with a clinical diagnosis of moderate to severe psoriasis with an investigator global assessment (IGA) score of 3 or 4 and an affected BSA of 3% to 12%. Participants were randomized (2:1) to receive HP lotion or vehicle applied topically to the affected area once daily for 8 weeks.

Inclusion and Exclusion Criteria
The studies included individuals of either sex aged 18 years or older. A target lesion was defined primarily to assess signs of psoriasis, measuring 16 to 100 cm², with a score of 3 (moderate) or higher for 2 of 3 different psoriasis signs—erythema, plaque elevation, and scaling—and summed score of 8 or higher, with no sign scoring less than 2. Participants who had pustular psoriasis or used phototherapy, photochemotherapy, or systemic psoriasis therapy within the prior 4 weeks or biologics within the prior 3 months, or those who were diagnosed with skin conditions that would interfere with the interpretation of results were excluded from the studies.

Study Oversight
Participants provided written informed consent before study-related procedures were performed, and the protocol and consent were approved by institutional review boards or ethics committees at all investigational sites. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki.

Efficacy Assessment

A 5-point scale ranging from 0 (clear) to 4 (severe) was used by the investigator at each study visit to assess the overall psoriasis severity of the treatable areas. Treatment success (the percentage of participants with at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]) was evaluated at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Signs of psoriasis at the target lesion were assessed at each visit using individual 5-point scales ranging from 0 (clear) to 4 (severe). Treatment success was defined as at least a 2-grade improvement from baseline score for each of the key signs—erythema, plaque elevation, and scaling—and reported at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Affected BSA also was evaluated at each visit. In addition, an IGA×BSA composite score was calculated by multiplying the IGA by the BSA (range, 9–48 [eg, maximum IGA=4 and maximum BSA=12]) at each time point. The mean percentage change in IGA×BSA from baseline was calculated for each study visit. Additional end points included the achievement of a 50%, 75%, and 90% or greater reduction from baseline IGA×BSA score—IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90—at week 8.

Safety Assessment

Safety evaluations including adverse events (AEs), local skin reactions (LSRs), vital signs, laboratory evaluations, and physical examinations were performed. Information on reported and observed AEs was obtained at each visit. Routine safety laboratory tests were performed at screening, week 4, and week 8. An abbreviated physical examination was performed at baseline, week 8 (end of treatment), and week 12 (end of study). Treatment areas also were examined by the investigator at baseline and each subsequent visit for the presence or absence of marked known drug-related AEs including skin atrophy, striae, telangiectasia, and folliculitis.

LSR Assessment
Local skin reactions such as itching, dryness, and burning/stinging were evaluated at each study visit using 4-point scales ranging from 0 (clear) to 3 (severe). Given the nature of the disease, the presence of LSRs and symptoms at baseline is commonplace, and as such, these evaluations identified both improvement and any emergent issues.

Statistical Analysis

The primary study goal was to assess differences in treatment efficacy between HP lotion and vehicle with respect to IGA. All statistical processing was performed using SAS unless otherwise stated; statistical tests were 2-sided and performed at the 0.05 level of significance. Markov Chain Monte Carlo multiple imputation was the primary method used to handle missing efficacy data. No imputations were made for missing safety data. All participants were randomized, and the dispensed study drug was included in the intention-to-treat analysis set. This analysis was considered primary for the evaluation of efficacy. Data were analyzed using Cochran-Mantel-Haenszel tests, stratified by analysis center.

Body surface area data were analyzed in a post hoc analysis of covariance with factors of treatment and analysis center and baseline BSA as a covariate. P values for comparisons of percentage change in IGA×BSA were derived from a Wilcoxon rank sum test. For IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90, P values were derived from a Cochran-Mantel-Haenszel test. Last observation carried forward was used to impute data for IGA and BSA through week 8 prior to analysis.

The primary safety analysis was conducted at week 8 using the safety analysis set, which included all participants who were randomized, received at least 1 confirmed dose of the study drug, and had at least 1 postbaseline safety assessment. Adverse events were recorded and classified using the Medical Dictionary for Regulatory Activities (MedDRA, Version 18.0). A post hoc Wilcoxon rank sum test was conducted to compare itching, dryness, and burning/stinging scores at week 8 for HP lotion versus vehicle.

RESULTS
Participant Disposition

Overall, 430 participants were randomized (2:1) to HP lotion (n=285) or vehicle (n=145)(eFigure 1) and included in the intention-to-treat population. Across the 2 studies, 93.3% (n=266) of participants treated with HP lotion and 89.7% (n=130) of participants treated with vehicle completed treatment. The main reasons for study discontinuation with HP lotion were lost to follow-up (3.2%; n=9), participant request (1.8%; n=5), and AEs (1.4%; n=4). Participant request (4.8%; n=7), lost to follow-up (4.1%; n=6), and AEs (1.4%; n=2) also were the main reasons for treatment discontinuation in the vehicle arm.

A total of 426 participants were included in the safety population, with no postbaseline safety evaluation in 4 participants.

Baseline Participant Demographics
Demographic data were comparable across the 2 studies. The mean age (SD) was 52.6 (14.13) years. Overall, the majority of participants were male (58.8%; n=253) and white (86.5%; n=372)(eTable 1).

Efficacy Evaluation

IGA of Disease Severity
Halobetasol propionate lotion was consistently more effective than its vehicle in achieving treatment success (at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]). Halobetasol propionate lotion demonstrated statistically significant superiority over vehicle as early as week 2 (P=.003). By week 8, 37.43% of participants in the HP lotion group achieved treatment success compared with 10.03% in the vehicle group (P<.001)(Figure 1).

Overall, 39% of participants who had moderate disease (IGA score, 3) at baseline were treatment successes with HP lotion at week 8 compared with 11.53% of participants treated with vehicle; 27.97% of participants with severe disease (IGA score, 4) were treatment successes, with at least a 3-grade improvement in IGA. No participants with severe psoriasis who were treated with vehicle achieved treatment success at week 8. Efficacy was similar in female and male participants, allowing for vehicle effects.

Severity of Signs of Psoriasis (Erythema, Plaque Elevation, and Scaling) at Target Lesion Site
Halobetasol propionate lotion was statistically superior to vehicle in reducing the psoriasis signs of erythema, plaque elevation, and scaling at the target lesion from week 2. At week 8, treatment success (at least a 2-grade improvement from baseline) was achieved by 51.48% (erythema), 57.64% (plaque elevation), and 58.98% (scaling) of participants compared with 17.85%, 23.61%, and 22.82%, respectively, with vehicle (all P<.001)(Figure 2).

Safety Evaluation

Adverse event reports were low and similar between the active and vehicle groups. Overall, 61 participants (21.5%) treated with HP lotion reported AEs compared with 34 participants (23.9%) treated with vehicle (Table). The majority of participants treated with HP lotion (90.2%) had AEs that were mild or moderate. There was 1 AE of telangiectasia, not considered treatment related. There were 5 treatment-related AEs for HP lotion, all at the application site: dermatitis (0.7%; n=2), infection (0.4%; n=1), pruritus (0.4%; n=1), and discoloration (0.4%; n=1). There were no AE reports of skin atrophy or folliculitis.

Local Skin Reactions
Most LSRs at baseline were mild to moderate in severity. Itching was the most common, present in 76.8% of participants. Participant-reported burning/stinging was less common, reported by 40.6% of participants. Investigator-reported dryness was noted in 65.7% of participants. There was a rapid improvement in participant-reported itching as early as week 2 that was sustained to the end of the studies, with more gradual improvements in skin dryness and burning/stinging.

COMMENT

Plaque psoriasis is a chronic condition. The rationale behind the development of HP lotion 0.01% was to provide optimal topical treatment of moderate to severe psoriasis, allowing for the potential of prolonged use beyond the 2-week consecutive use normally applied to HP cream 0.05% in a light, once-daily, aesthetically pleasing lotion formulation that patients would prefer.

Treatment success was rapid and achieved in more than 37% of participants by week 8, with significant improvements in psoriasis signs and symptoms (erythema, plaque elevation, and scaling) compared with vehicle. However, IGA does not consider BSA involvement, a key aspect of disease severity,^11,12 and improvements in psoriasis signs of erythema, plaque elevation, and scaling were only assessed at the target lesion. Recently, the product of the IGA and BSA involvement (IGA×BSA) has been proposed as a simple alternative for assessing response to therapy that has been consistently shown to be highly correlated with the psoriasis area and severity index.^13-19 Halobetasol propionate lotion 0.01% achieved a 50% reduction in IGA×BSA score by week 8. This efficacy compares well with results reported with apremilast in patients with moderate plaque psoriasis.²⁰

Achieving clinically meaningful outcomes is an important aspect of disease management, especially in psoriasis with its disease burden and detriment to quality of life. It has been suggested that achieving a 75% or greater reduction from baseline IGA×BSA score (IGA×BSA-75) is an appropriate clinical goal.²⁰ In our investigation, IGA×BSA-75 was achieved by 39% of participants treated with HP lotion by week 8, which again compares favorably with 35% of participants in the apremilast study who achieved IGA×BSA-75 at week 16.²⁰

Physicians continue to have long-term safety concerns with TCSs,^4,11,12 participants remain concerned about the risk for skin thinning,¹³ and product labelling restricts HP cream 0.05% consecutive use to 2 weeks. In clinical experience, HP cream 0.05% is well tolerated, with potential local AEs similar to those experienced with other superpotent TCSs. In short-term clinical trials, local AEs at the site of application were reported in up to 13% of patients^21-26; itching, burning, or stinging were the most common local AEs (reported in 4.4% of patients).²⁷

There were minimal safety concerns in our 2 studies using an 8-week, once-daily treatment regimen with HP lotion 0.01%. Local AEs at the application site were reported in less than 1% of participants. Baseline itching, dryness, and burning/stinging all improved with treatment.

CONCLUSION

Halobetasol propionate lotion 0.01% provides rapid improvement in disease severity. Halobetasol propionate lotion was consistently more effective than vehicle in achieving treatment success; reducing the BSA affected by the disease; reducing erythema, plaque elevation, and scaling at the target lesion; and improving IGA×BSA score over 8 weeks, which is a realistic time frame to see improvement in psoriasis with a topical steroid. There were minimal safety concerns with prolonged use. Halobetasol propionate lotion may provide an effective and reasonable treatment option in patients with moderate to severe plaque psoriasis.

Acknowledgment
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of this article. Ortho Dermatologics funded Mr. Bulley’s activities pertaining to this article.

Psoriasis is a chronic, immune-mediated, inflammatory disease affecting almost 2% of the population.^1-3 It is characterized by patches of raised reddish skin covered by silvery-white scales. Most patients have limited disease (<5% body surface area [BSA] involvement) that can be managed with topical agents.⁴ Topical corticosteroids (TCSs) are considered first-line therapy for mild to moderate disease because of the inflammatory nature of the condition and often are used in conjunction with systemic agents in more severe psoriasis.⁴

As many as 20% to 30% of patients with moderate to severe plaque psoriasis have inadequate disease control.⁵ Several factors may affect patient outcomes; however, drug selection and patient adherence are important given the chronic nature of the disease. A survey of 1200 patients with psoriasis reported nonadherence rates of 73% with topical therapy.⁶ In addition, patients tend to apply less than the recommended dose or abandon treatment altogether if rapid improvement does not occur^7,8; it is not uncommon for patients with psoriasis to mistakenly believe treatment will improve their condition within 1 to 2 weeks.⁹ Patient satisfaction with topical treatments is low, partly because of these false expectations and formulation issues. Treatments can be greasy and sticky, with unpleasant odors and the potential to stain clothes and linens.^7,10 Safety concerns with TCSs also limit their consecutive use beyond 2 to 4 weeks, which is not ideal for a disease that requires a long-term management strategy.

A potent/superpotent TCS that is administered once daily and has a safety profile that affords longer-term, once-daily treatment in an aesthetically pleasing formulation would seem ideal. Herein, we investigate the safety and tolerability of a novel low-concentration (0.01%) lotion formulation of halobetasol propionate (HP), reporting on the pooled data from 2 phase 3 clinical studies in participants with moderate to severe psoriasis.

METHODS
Study Design

We conducted 2 multicenter, double-blind, randomized, parallel-group phase 3 studies to assess the safety, tolerability, and efficacy of HP lotion 0.01% in participants with a clinical diagnosis of moderate to severe psoriasis with an investigator global assessment (IGA) score of 3 or 4 and an affected BSA of 3% to 12%. Participants were randomized (2:1) to receive HP lotion or vehicle applied topically to the affected area once daily for 8 weeks.

Inclusion and Exclusion Criteria
The studies included individuals of either sex aged 18 years or older. A target lesion was defined primarily to assess signs of psoriasis, measuring 16 to 100 cm², with a score of 3 (moderate) or higher for 2 of 3 different psoriasis signs—erythema, plaque elevation, and scaling—and summed score of 8 or higher, with no sign scoring less than 2. Participants who had pustular psoriasis or used phototherapy, photochemotherapy, or systemic psoriasis therapy within the prior 4 weeks or biologics within the prior 3 months, or those who were diagnosed with skin conditions that would interfere with the interpretation of results were excluded from the studies.

Study Oversight
Participants provided written informed consent before study-related procedures were performed, and the protocol and consent were approved by institutional review boards or ethics committees at all investigational sites. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki.

Efficacy Assessment

A 5-point scale ranging from 0 (clear) to 4 (severe) was used by the investigator at each study visit to assess the overall psoriasis severity of the treatable areas. Treatment success (the percentage of participants with at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]) was evaluated at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Signs of psoriasis at the target lesion were assessed at each visit using individual 5-point scales ranging from 0 (clear) to 4 (severe). Treatment success was defined as at least a 2-grade improvement from baseline score for each of the key signs—erythema, plaque elevation, and scaling—and reported at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Affected BSA also was evaluated at each visit. In addition, an IGA×BSA composite score was calculated by multiplying the IGA by the BSA (range, 9–48 [eg, maximum IGA=4 and maximum BSA=12]) at each time point. The mean percentage change in IGA×BSA from baseline was calculated for each study visit. Additional end points included the achievement of a 50%, 75%, and 90% or greater reduction from baseline IGA×BSA score—IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90—at week 8.

Safety Assessment

Safety evaluations including adverse events (AEs), local skin reactions (LSRs), vital signs, laboratory evaluations, and physical examinations were performed. Information on reported and observed AEs was obtained at each visit. Routine safety laboratory tests were performed at screening, week 4, and week 8. An abbreviated physical examination was performed at baseline, week 8 (end of treatment), and week 12 (end of study). Treatment areas also were examined by the investigator at baseline and each subsequent visit for the presence or absence of marked known drug-related AEs including skin atrophy, striae, telangiectasia, and folliculitis.

LSR Assessment
Local skin reactions such as itching, dryness, and burning/stinging were evaluated at each study visit using 4-point scales ranging from 0 (clear) to 3 (severe). Given the nature of the disease, the presence of LSRs and symptoms at baseline is commonplace, and as such, these evaluations identified both improvement and any emergent issues.

Statistical Analysis

The primary study goal was to assess differences in treatment efficacy between HP lotion and vehicle with respect to IGA. All statistical processing was performed using SAS unless otherwise stated; statistical tests were 2-sided and performed at the 0.05 level of significance. Markov Chain Monte Carlo multiple imputation was the primary method used to handle missing efficacy data. No imputations were made for missing safety data. All participants were randomized, and the dispensed study drug was included in the intention-to-treat analysis set. This analysis was considered primary for the evaluation of efficacy. Data were analyzed using Cochran-Mantel-Haenszel tests, stratified by analysis center.

Body surface area data were analyzed in a post hoc analysis of covariance with factors of treatment and analysis center and baseline BSA as a covariate. P values for comparisons of percentage change in IGA×BSA were derived from a Wilcoxon rank sum test. For IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90, P values were derived from a Cochran-Mantel-Haenszel test. Last observation carried forward was used to impute data for IGA and BSA through week 8 prior to analysis.

The primary safety analysis was conducted at week 8 using the safety analysis set, which included all participants who were randomized, received at least 1 confirmed dose of the study drug, and had at least 1 postbaseline safety assessment. Adverse events were recorded and classified using the Medical Dictionary for Regulatory Activities (MedDRA, Version 18.0). A post hoc Wilcoxon rank sum test was conducted to compare itching, dryness, and burning/stinging scores at week 8 for HP lotion versus vehicle.

RESULTS
Participant Disposition

Overall, 430 participants were randomized (2:1) to HP lotion (n=285) or vehicle (n=145)(eFigure 1) and included in the intention-to-treat population. Across the 2 studies, 93.3% (n=266) of participants treated with HP lotion and 89.7% (n=130) of participants treated with vehicle completed treatment. The main reasons for study discontinuation with HP lotion were lost to follow-up (3.2%; n=9), participant request (1.8%; n=5), and AEs (1.4%; n=4). Participant request (4.8%; n=7), lost to follow-up (4.1%; n=6), and AEs (1.4%; n=2) also were the main reasons for treatment discontinuation in the vehicle arm.

A total of 426 participants were included in the safety population, with no postbaseline safety evaluation in 4 participants.

Baseline Participant Demographics
Demographic data were comparable across the 2 studies. The mean age (SD) was 52.6 (14.13) years. Overall, the majority of participants were male (58.8%; n=253) and white (86.5%; n=372)(eTable 1).

Efficacy Evaluation

IGA of Disease Severity
Halobetasol propionate lotion was consistently more effective than its vehicle in achieving treatment success (at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]). Halobetasol propionate lotion demonstrated statistically significant superiority over vehicle as early as week 2 (P=.003). By week 8, 37.43% of participants in the HP lotion group achieved treatment success compared with 10.03% in the vehicle group (P<.001)(Figure 1).

Overall, 39% of participants who had moderate disease (IGA score, 3) at baseline were treatment successes with HP lotion at week 8 compared with 11.53% of participants treated with vehicle; 27.97% of participants with severe disease (IGA score, 4) were treatment successes, with at least a 3-grade improvement in IGA. No participants with severe psoriasis who were treated with vehicle achieved treatment success at week 8. Efficacy was similar in female and male participants, allowing for vehicle effects.

Severity of Signs of Psoriasis (Erythema, Plaque Elevation, and Scaling) at Target Lesion Site
Halobetasol propionate lotion was statistically superior to vehicle in reducing the psoriasis signs of erythema, plaque elevation, and scaling at the target lesion from week 2. At week 8, treatment success (at least a 2-grade improvement from baseline) was achieved by 51.48% (erythema), 57.64% (plaque elevation), and 58.98% (scaling) of participants compared with 17.85%, 23.61%, and 22.82%, respectively, with vehicle (all P<.001)(Figure 2).

Safety Evaluation

Adverse event reports were low and similar between the active and vehicle groups. Overall, 61 participants (21.5%) treated with HP lotion reported AEs compared with 34 participants (23.9%) treated with vehicle (Table). The majority of participants treated with HP lotion (90.2%) had AEs that were mild or moderate. There was 1 AE of telangiectasia, not considered treatment related. There were 5 treatment-related AEs for HP lotion, all at the application site: dermatitis (0.7%; n=2), infection (0.4%; n=1), pruritus (0.4%; n=1), and discoloration (0.4%; n=1). There were no AE reports of skin atrophy or folliculitis.

Local Skin Reactions
Most LSRs at baseline were mild to moderate in severity. Itching was the most common, present in 76.8% of participants. Participant-reported burning/stinging was less common, reported by 40.6% of participants. Investigator-reported dryness was noted in 65.7% of participants. There was a rapid improvement in participant-reported itching as early as week 2 that was sustained to the end of the studies, with more gradual improvements in skin dryness and burning/stinging.

COMMENT

Plaque psoriasis is a chronic condition. The rationale behind the development of HP lotion 0.01% was to provide optimal topical treatment of moderate to severe psoriasis, allowing for the potential of prolonged use beyond the 2-week consecutive use normally applied to HP cream 0.05% in a light, once-daily, aesthetically pleasing lotion formulation that patients would prefer.

Treatment success was rapid and achieved in more than 37% of participants by week 8, with significant improvements in psoriasis signs and symptoms (erythema, plaque elevation, and scaling) compared with vehicle. However, IGA does not consider BSA involvement, a key aspect of disease severity,^11,12 and improvements in psoriasis signs of erythema, plaque elevation, and scaling were only assessed at the target lesion. Recently, the product of the IGA and BSA involvement (IGA×BSA) has been proposed as a simple alternative for assessing response to therapy that has been consistently shown to be highly correlated with the psoriasis area and severity index.^13-19 Halobetasol propionate lotion 0.01% achieved a 50% reduction in IGA×BSA score by week 8. This efficacy compares well with results reported with apremilast in patients with moderate plaque psoriasis.²⁰

Achieving clinically meaningful outcomes is an important aspect of disease management, especially in psoriasis with its disease burden and detriment to quality of life. It has been suggested that achieving a 75% or greater reduction from baseline IGA×BSA score (IGA×BSA-75) is an appropriate clinical goal.²⁰ In our investigation, IGA×BSA-75 was achieved by 39% of participants treated with HP lotion by week 8, which again compares favorably with 35% of participants in the apremilast study who achieved IGA×BSA-75 at week 16.²⁰

Physicians continue to have long-term safety concerns with TCSs,^4,11,12 participants remain concerned about the risk for skin thinning,¹³ and product labelling restricts HP cream 0.05% consecutive use to 2 weeks. In clinical experience, HP cream 0.05% is well tolerated, with potential local AEs similar to those experienced with other superpotent TCSs. In short-term clinical trials, local AEs at the site of application were reported in up to 13% of patients^21-26; itching, burning, or stinging were the most common local AEs (reported in 4.4% of patients).²⁷

There were minimal safety concerns in our 2 studies using an 8-week, once-daily treatment regimen with HP lotion 0.01%. Local AEs at the application site were reported in less than 1% of participants. Baseline itching, dryness, and burning/stinging all improved with treatment.

CONCLUSION

Halobetasol propionate lotion 0.01% provides rapid improvement in disease severity. Halobetasol propionate lotion was consistently more effective than vehicle in achieving treatment success; reducing the BSA affected by the disease; reducing erythema, plaque elevation, and scaling at the target lesion; and improving IGA×BSA score over 8 weeks, which is a realistic time frame to see improvement in psoriasis with a topical steroid. There were minimal safety concerns with prolonged use. Halobetasol propionate lotion may provide an effective and reasonable treatment option in patients with moderate to severe plaque psoriasis.

Acknowledgment
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of this article. Ortho Dermatologics funded Mr. Bulley’s activities pertaining to this article.

Psoriasis is a chronic, immune-mediated, inflammatory disease affecting almost 2% of the population.^1-3 It is characterized by patches of raised reddish skin covered by silvery-white scales. Most patients have limited disease (<5% body surface area [BSA] involvement) that can be managed with topical agents.⁴ Topical corticosteroids (TCSs) are considered first-line therapy for mild to moderate disease because of the inflammatory nature of the condition and often are used in conjunction with systemic agents in more severe psoriasis.⁴

As many as 20% to 30% of patients with moderate to severe plaque psoriasis have inadequate disease control.⁵ Several factors may affect patient outcomes; however, drug selection and patient adherence are important given the chronic nature of the disease. A survey of 1200 patients with psoriasis reported nonadherence rates of 73% with topical therapy.⁶ In addition, patients tend to apply less than the recommended dose or abandon treatment altogether if rapid improvement does not occur^7,8; it is not uncommon for patients with psoriasis to mistakenly believe treatment will improve their condition within 1 to 2 weeks.⁹ Patient satisfaction with topical treatments is low, partly because of these false expectations and formulation issues. Treatments can be greasy and sticky, with unpleasant odors and the potential to stain clothes and linens.^7,10 Safety concerns with TCSs also limit their consecutive use beyond 2 to 4 weeks, which is not ideal for a disease that requires a long-term management strategy.

A potent/superpotent TCS that is administered once daily and has a safety profile that affords longer-term, once-daily treatment in an aesthetically pleasing formulation would seem ideal. Herein, we investigate the safety and tolerability of a novel low-concentration (0.01%) lotion formulation of halobetasol propionate (HP), reporting on the pooled data from 2 phase 3 clinical studies in participants with moderate to severe psoriasis.

METHODS
Study Design

We conducted 2 multicenter, double-blind, randomized, parallel-group phase 3 studies to assess the safety, tolerability, and efficacy of HP lotion 0.01% in participants with a clinical diagnosis of moderate to severe psoriasis with an investigator global assessment (IGA) score of 3 or 4 and an affected BSA of 3% to 12%. Participants were randomized (2:1) to receive HP lotion or vehicle applied topically to the affected area once daily for 8 weeks.

Inclusion and Exclusion Criteria
The studies included individuals of either sex aged 18 years or older. A target lesion was defined primarily to assess signs of psoriasis, measuring 16 to 100 cm², with a score of 3 (moderate) or higher for 2 of 3 different psoriasis signs—erythema, plaque elevation, and scaling—and summed score of 8 or higher, with no sign scoring less than 2. Participants who had pustular psoriasis or used phototherapy, photochemotherapy, or systemic psoriasis therapy within the prior 4 weeks or biologics within the prior 3 months, or those who were diagnosed with skin conditions that would interfere with the interpretation of results were excluded from the studies.

Study Oversight
Participants provided written informed consent before study-related procedures were performed, and the protocol and consent were approved by institutional review boards or ethics committees at all investigational sites. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki.

Efficacy Assessment

A 5-point scale ranging from 0 (clear) to 4 (severe) was used by the investigator at each study visit to assess the overall psoriasis severity of the treatable areas. Treatment success (the percentage of participants with at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]) was evaluated at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Signs of psoriasis at the target lesion were assessed at each visit using individual 5-point scales ranging from 0 (clear) to 4 (severe). Treatment success was defined as at least a 2-grade improvement from baseline score for each of the key signs—erythema, plaque elevation, and scaling—and reported at weeks 2, 4, 6, and 8, with a posttreatment follow-up at week 12.

Affected BSA also was evaluated at each visit. In addition, an IGA×BSA composite score was calculated by multiplying the IGA by the BSA (range, 9–48 [eg, maximum IGA=4 and maximum BSA=12]) at each time point. The mean percentage change in IGA×BSA from baseline was calculated for each study visit. Additional end points included the achievement of a 50%, 75%, and 90% or greater reduction from baseline IGA×BSA score—IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90—at week 8.

Safety Assessment

Safety evaluations including adverse events (AEs), local skin reactions (LSRs), vital signs, laboratory evaluations, and physical examinations were performed. Information on reported and observed AEs was obtained at each visit. Routine safety laboratory tests were performed at screening, week 4, and week 8. An abbreviated physical examination was performed at baseline, week 8 (end of treatment), and week 12 (end of study). Treatment areas also were examined by the investigator at baseline and each subsequent visit for the presence or absence of marked known drug-related AEs including skin atrophy, striae, telangiectasia, and folliculitis.

LSR Assessment
Local skin reactions such as itching, dryness, and burning/stinging were evaluated at each study visit using 4-point scales ranging from 0 (clear) to 3 (severe). Given the nature of the disease, the presence of LSRs and symptoms at baseline is commonplace, and as such, these evaluations identified both improvement and any emergent issues.

Statistical Analysis

The primary study goal was to assess differences in treatment efficacy between HP lotion and vehicle with respect to IGA. All statistical processing was performed using SAS unless otherwise stated; statistical tests were 2-sided and performed at the 0.05 level of significance. Markov Chain Monte Carlo multiple imputation was the primary method used to handle missing efficacy data. No imputations were made for missing safety data. All participants were randomized, and the dispensed study drug was included in the intention-to-treat analysis set. This analysis was considered primary for the evaluation of efficacy. Data were analyzed using Cochran-Mantel-Haenszel tests, stratified by analysis center.

Body surface area data were analyzed in a post hoc analysis of covariance with factors of treatment and analysis center and baseline BSA as a covariate. P values for comparisons of percentage change in IGA×BSA were derived from a Wilcoxon rank sum test. For IGA×BSA-50, IGA×BSA-75, and IGA×BSA-90, P values were derived from a Cochran-Mantel-Haenszel test. Last observation carried forward was used to impute data for IGA and BSA through week 8 prior to analysis.

The primary safety analysis was conducted at week 8 using the safety analysis set, which included all participants who were randomized, received at least 1 confirmed dose of the study drug, and had at least 1 postbaseline safety assessment. Adverse events were recorded and classified using the Medical Dictionary for Regulatory Activities (MedDRA, Version 18.0). A post hoc Wilcoxon rank sum test was conducted to compare itching, dryness, and burning/stinging scores at week 8 for HP lotion versus vehicle.

RESULTS
Participant Disposition

Overall, 430 participants were randomized (2:1) to HP lotion (n=285) or vehicle (n=145)(eFigure 1) and included in the intention-to-treat population. Across the 2 studies, 93.3% (n=266) of participants treated with HP lotion and 89.7% (n=130) of participants treated with vehicle completed treatment. The main reasons for study discontinuation with HP lotion were lost to follow-up (3.2%; n=9), participant request (1.8%; n=5), and AEs (1.4%; n=4). Participant request (4.8%; n=7), lost to follow-up (4.1%; n=6), and AEs (1.4%; n=2) also were the main reasons for treatment discontinuation in the vehicle arm.

A total of 426 participants were included in the safety population, with no postbaseline safety evaluation in 4 participants.

Baseline Participant Demographics
Demographic data were comparable across the 2 studies. The mean age (SD) was 52.6 (14.13) years. Overall, the majority of participants were male (58.8%; n=253) and white (86.5%; n=372)(eTable 1).

Efficacy Evaluation

IGA of Disease Severity
Halobetasol propionate lotion was consistently more effective than its vehicle in achieving treatment success (at least a 2-grade improvement in baseline IGA score and a score of 0 [clear] or 1 [almost clear]). Halobetasol propionate lotion demonstrated statistically significant superiority over vehicle as early as week 2 (P=.003). By week 8, 37.43% of participants in the HP lotion group achieved treatment success compared with 10.03% in the vehicle group (P<.001)(Figure 1).

Overall, 39% of participants who had moderate disease (IGA score, 3) at baseline were treatment successes with HP lotion at week 8 compared with 11.53% of participants treated with vehicle; 27.97% of participants with severe disease (IGA score, 4) were treatment successes, with at least a 3-grade improvement in IGA. No participants with severe psoriasis who were treated with vehicle achieved treatment success at week 8. Efficacy was similar in female and male participants, allowing for vehicle effects.

Severity of Signs of Psoriasis (Erythema, Plaque Elevation, and Scaling) at Target Lesion Site
Halobetasol propionate lotion was statistically superior to vehicle in reducing the psoriasis signs of erythema, plaque elevation, and scaling at the target lesion from week 2. At week 8, treatment success (at least a 2-grade improvement from baseline) was achieved by 51.48% (erythema), 57.64% (plaque elevation), and 58.98% (scaling) of participants compared with 17.85%, 23.61%, and 22.82%, respectively, with vehicle (all P<.001)(Figure 2).

Safety Evaluation

Adverse event reports were low and similar between the active and vehicle groups. Overall, 61 participants (21.5%) treated with HP lotion reported AEs compared with 34 participants (23.9%) treated with vehicle (Table). The majority of participants treated with HP lotion (90.2%) had AEs that were mild or moderate. There was 1 AE of telangiectasia, not considered treatment related. There were 5 treatment-related AEs for HP lotion, all at the application site: dermatitis (0.7%; n=2), infection (0.4%; n=1), pruritus (0.4%; n=1), and discoloration (0.4%; n=1). There were no AE reports of skin atrophy or folliculitis.

Local Skin Reactions
Most LSRs at baseline were mild to moderate in severity. Itching was the most common, present in 76.8% of participants. Participant-reported burning/stinging was less common, reported by 40.6% of participants. Investigator-reported dryness was noted in 65.7% of participants. There was a rapid improvement in participant-reported itching as early as week 2 that was sustained to the end of the studies, with more gradual improvements in skin dryness and burning/stinging.

COMMENT

Plaque psoriasis is a chronic condition. The rationale behind the development of HP lotion 0.01% was to provide optimal topical treatment of moderate to severe psoriasis, allowing for the potential of prolonged use beyond the 2-week consecutive use normally applied to HP cream 0.05% in a light, once-daily, aesthetically pleasing lotion formulation that patients would prefer.

Treatment success was rapid and achieved in more than 37% of participants by week 8, with significant improvements in psoriasis signs and symptoms (erythema, plaque elevation, and scaling) compared with vehicle. However, IGA does not consider BSA involvement, a key aspect of disease severity,^11,12 and improvements in psoriasis signs of erythema, plaque elevation, and scaling were only assessed at the target lesion. Recently, the product of the IGA and BSA involvement (IGA×BSA) has been proposed as a simple alternative for assessing response to therapy that has been consistently shown to be highly correlated with the psoriasis area and severity index.^13-19 Halobetasol propionate lotion 0.01% achieved a 50% reduction in IGA×BSA score by week 8. This efficacy compares well with results reported with apremilast in patients with moderate plaque psoriasis.²⁰

Achieving clinically meaningful outcomes is an important aspect of disease management, especially in psoriasis with its disease burden and detriment to quality of life. It has been suggested that achieving a 75% or greater reduction from baseline IGA×BSA score (IGA×BSA-75) is an appropriate clinical goal.²⁰ In our investigation, IGA×BSA-75 was achieved by 39% of participants treated with HP lotion by week 8, which again compares favorably with 35% of participants in the apremilast study who achieved IGA×BSA-75 at week 16.²⁰

Physicians continue to have long-term safety concerns with TCSs,^4,11,12 participants remain concerned about the risk for skin thinning,¹³ and product labelling restricts HP cream 0.05% consecutive use to 2 weeks. In clinical experience, HP cream 0.05% is well tolerated, with potential local AEs similar to those experienced with other superpotent TCSs. In short-term clinical trials, local AEs at the site of application were reported in up to 13% of patients^21-26; itching, burning, or stinging were the most common local AEs (reported in 4.4% of patients).²⁷

There were minimal safety concerns in our 2 studies using an 8-week, once-daily treatment regimen with HP lotion 0.01%. Local AEs at the application site were reported in less than 1% of participants. Baseline itching, dryness, and burning/stinging all improved with treatment.

CONCLUSION

Halobetasol propionate lotion 0.01% provides rapid improvement in disease severity. Halobetasol propionate lotion was consistently more effective than vehicle in achieving treatment success; reducing the BSA affected by the disease; reducing erythema, plaque elevation, and scaling at the target lesion; and improving IGA×BSA score over 8 weeks, which is a realistic time frame to see improvement in psoriasis with a topical steroid. There were minimal safety concerns with prolonged use. Halobetasol propionate lotion may provide an effective and reasonable treatment option in patients with moderate to severe plaque psoriasis.

Acknowledgment
We thank Brian Bulley, MSc (Konic Limited, United Kingdom), for assistance with the preparation of this article. Ortho Dermatologics funded Mr. Bulley’s activities pertaining to this article.

Plaque psoriasis is a chronic inflammatory disease with a complex pathogenesis. Cutaneous dendritic cells drive the activation and proliferation of T cells with production of several immunomodulators, such as tumor necrosis factor (TNF) α, IL-17, IL-12, and IL-23. Because multiple systemic therapies are efficacious, treatment selection depends on side-effect profiles, availability, and patient preference. Activation of the TNF-α pathway is not unique to psoriasis. Tumor necrosis factor α plays a key role in multiple inflammatory conditions, including psoriatic arthritis, rheumatoid arthritis, and hidradenitis suppurativa. One study in mice demonstrated that TNF-α drives endothelial and vascular wall dysfunction in sickle cell anemia. In this study, use of the TNF-α blocker etanercept in mice with homozygous sickle cell anemia (HbSS) disease resulted in amelioration of TNF-mediated clinical features shared by sickle mice and humans.¹

Sickle cell anemia is caused by a structural defect in hemoglobin that results in hemolysis and chronic anemia. The most common type of hemoglobin in adults without sickle cell anemia is HbAA. Homozygous sickle cell anemia patients carry 2 abnormal S alleles, whereas in sickle cell trait, patients carry both the S and normal A alleles (HbSA). Hemoglobin C is a structural variant of HbA that results in lower solubility in red blood cells. Patients with hemoglobin SC disease (HbSC) have S and C alleles.² We present a case of a patient with moderate to severe plaque psoriasis and heterozygous sickle cell anemia treated with adalimumab.

Case Report

A 31-year-old woman presented with moderate to severe plaque psoriasis (70% body surface area) and HbSC. She reported chronic dull arthralgia in the ankles that was worse at night. Radiographs of the feet and ankles showed erosive changes of the distal tarsal row and metatarsal bases. The diffuse bone pain had gradually worsened over the years and was treated by hematology with ibuprofen and ketorolac. At presentation, her HbSC pain was 8/10 on a visual analog scale. She described her sickle cell pain crises as sharp 10/10 pain in the back, elbows, and ankles, associated with mild edema lasting 1 to 2 days. Radiographs of the spine, hands, and ankles were unremarkable.

Adalimumab was chosen as a systemic therapy for psoriasis based on the potential for improvement in HbSC. Within 17 weeks of starting adalimumab, the psoriasis body surface area decreased from 70% to 40%, and the HbSC pain decreased from 8/10 to 4/10 at 8-week follow-up and to 0/10 at 17-week follow-up. After initiation of adalimumab, she reported decreased use of pain medication with no sickle cell pain crises.

 

 

Comment

Tumor necrosis factor α blockers are commonly used for moderate to severe plaque psoriasis. To our knowledge, there have been no reported human studies showing TNF-α blockade as a potential treatment of sickle cell disease. Increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and severity of sickle cell disease by playing an integral role in the development of vascular wall dysfunction and ischemia.³ Inflammatory mediators in HbSS disease, such as heparan sulfate from the endothelial glycocalyx and heme from hemolysis, act on monocytes to release TNF-α.¹ Through this effect on the endothelium, TNF-α impedes blood flow during sickle cell crisis, leading to worsening ischemia and resultant painful infarction.³ Analysis of cytokine levels in HbSS patients showed significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in comparison to nondiseased controls (HbAA), indicating a possible role of TNF-α in the pathogenesis of the crisis state.³ These studies suggest that TNF-α inhibition may reduce the initiation of vaso-occlusive crisis and decrease the subsequent ischemia related to a sickle cell crisis.

Although these findings were observational and limited to a single patient, the 50% decrease in pain level and use of pain medications reported to her hematologist independent of her dermatology visits coincided with the initiation of adalimumab. Although radiographs showed possible psoriatic changes of the distal metatarsal row, her described sickle cell pain and pain crises were atypical for psoriatic arthralgia. Tumor necrosis factor α inhibitors could be the drug of choice to treat patients with psoriasis with concomitant HbSS or HbSC disease due to the blockade of a common inflammatory mediator. Further studies are indicated to analyze the in vivo role of TNF-α inhibition in sickle cell disease.

Plaque psoriasis is a chronic inflammatory disease with a complex pathogenesis. Cutaneous dendritic cells drive the activation and proliferation of T cells with production of several immunomodulators, such as tumor necrosis factor (TNF) α, IL-17, IL-12, and IL-23. Because multiple systemic therapies are efficacious, treatment selection depends on side-effect profiles, availability, and patient preference. Activation of the TNF-α pathway is not unique to psoriasis. Tumor necrosis factor α plays a key role in multiple inflammatory conditions, including psoriatic arthritis, rheumatoid arthritis, and hidradenitis suppurativa. One study in mice demonstrated that TNF-α drives endothelial and vascular wall dysfunction in sickle cell anemia. In this study, use of the TNF-α blocker etanercept in mice with homozygous sickle cell anemia (HbSS) disease resulted in amelioration of TNF-mediated clinical features shared by sickle mice and humans.¹

Sickle cell anemia is caused by a structural defect in hemoglobin that results in hemolysis and chronic anemia. The most common type of hemoglobin in adults without sickle cell anemia is HbAA. Homozygous sickle cell anemia patients carry 2 abnormal S alleles, whereas in sickle cell trait, patients carry both the S and normal A alleles (HbSA). Hemoglobin C is a structural variant of HbA that results in lower solubility in red blood cells. Patients with hemoglobin SC disease (HbSC) have S and C alleles.² We present a case of a patient with moderate to severe plaque psoriasis and heterozygous sickle cell anemia treated with adalimumab.

Case Report

A 31-year-old woman presented with moderate to severe plaque psoriasis (70% body surface area) and HbSC. She reported chronic dull arthralgia in the ankles that was worse at night. Radiographs of the feet and ankles showed erosive changes of the distal tarsal row and metatarsal bases. The diffuse bone pain had gradually worsened over the years and was treated by hematology with ibuprofen and ketorolac. At presentation, her HbSC pain was 8/10 on a visual analog scale. She described her sickle cell pain crises as sharp 10/10 pain in the back, elbows, and ankles, associated with mild edema lasting 1 to 2 days. Radiographs of the spine, hands, and ankles were unremarkable.

Adalimumab was chosen as a systemic therapy for psoriasis based on the potential for improvement in HbSC. Within 17 weeks of starting adalimumab, the psoriasis body surface area decreased from 70% to 40%, and the HbSC pain decreased from 8/10 to 4/10 at 8-week follow-up and to 0/10 at 17-week follow-up. After initiation of adalimumab, she reported decreased use of pain medication with no sickle cell pain crises.

 

 

Comment

Tumor necrosis factor α blockers are commonly used for moderate to severe plaque psoriasis. To our knowledge, there have been no reported human studies showing TNF-α blockade as a potential treatment of sickle cell disease. Increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and severity of sickle cell disease by playing an integral role in the development of vascular wall dysfunction and ischemia.³ Inflammatory mediators in HbSS disease, such as heparan sulfate from the endothelial glycocalyx and heme from hemolysis, act on monocytes to release TNF-α.¹ Through this effect on the endothelium, TNF-α impedes blood flow during sickle cell crisis, leading to worsening ischemia and resultant painful infarction.³ Analysis of cytokine levels in HbSS patients showed significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in comparison to nondiseased controls (HbAA), indicating a possible role of TNF-α in the pathogenesis of the crisis state.³ These studies suggest that TNF-α inhibition may reduce the initiation of vaso-occlusive crisis and decrease the subsequent ischemia related to a sickle cell crisis.

Although these findings were observational and limited to a single patient, the 50% decrease in pain level and use of pain medications reported to her hematologist independent of her dermatology visits coincided with the initiation of adalimumab. Although radiographs showed possible psoriatic changes of the distal metatarsal row, her described sickle cell pain and pain crises were atypical for psoriatic arthralgia. Tumor necrosis factor α inhibitors could be the drug of choice to treat patients with psoriasis with concomitant HbSS or HbSC disease due to the blockade of a common inflammatory mediator. Further studies are indicated to analyze the in vivo role of TNF-α inhibition in sickle cell disease.

Plaque psoriasis is a chronic inflammatory disease with a complex pathogenesis. Cutaneous dendritic cells drive the activation and proliferation of T cells with production of several immunomodulators, such as tumor necrosis factor (TNF) α, IL-17, IL-12, and IL-23. Because multiple systemic therapies are efficacious, treatment selection depends on side-effect profiles, availability, and patient preference. Activation of the TNF-α pathway is not unique to psoriasis. Tumor necrosis factor α plays a key role in multiple inflammatory conditions, including psoriatic arthritis, rheumatoid arthritis, and hidradenitis suppurativa. One study in mice demonstrated that TNF-α drives endothelial and vascular wall dysfunction in sickle cell anemia. In this study, use of the TNF-α blocker etanercept in mice with homozygous sickle cell anemia (HbSS) disease resulted in amelioration of TNF-mediated clinical features shared by sickle mice and humans.¹

Sickle cell anemia is caused by a structural defect in hemoglobin that results in hemolysis and chronic anemia. The most common type of hemoglobin in adults without sickle cell anemia is HbAA. Homozygous sickle cell anemia patients carry 2 abnormal S alleles, whereas in sickle cell trait, patients carry both the S and normal A alleles (HbSA). Hemoglobin C is a structural variant of HbA that results in lower solubility in red blood cells. Patients with hemoglobin SC disease (HbSC) have S and C alleles.² We present a case of a patient with moderate to severe plaque psoriasis and heterozygous sickle cell anemia treated with adalimumab.

Case Report

A 31-year-old woman presented with moderate to severe plaque psoriasis (70% body surface area) and HbSC. She reported chronic dull arthralgia in the ankles that was worse at night. Radiographs of the feet and ankles showed erosive changes of the distal tarsal row and metatarsal bases. The diffuse bone pain had gradually worsened over the years and was treated by hematology with ibuprofen and ketorolac. At presentation, her HbSC pain was 8/10 on a visual analog scale. She described her sickle cell pain crises as sharp 10/10 pain in the back, elbows, and ankles, associated with mild edema lasting 1 to 2 days. Radiographs of the spine, hands, and ankles were unremarkable.

Adalimumab was chosen as a systemic therapy for psoriasis based on the potential for improvement in HbSC. Within 17 weeks of starting adalimumab, the psoriasis body surface area decreased from 70% to 40%, and the HbSC pain decreased from 8/10 to 4/10 at 8-week follow-up and to 0/10 at 17-week follow-up. After initiation of adalimumab, she reported decreased use of pain medication with no sickle cell pain crises.

 

 

Comment

Tumor necrosis factor α blockers are commonly used for moderate to severe plaque psoriasis. To our knowledge, there have been no reported human studies showing TNF-α blockade as a potential treatment of sickle cell disease. Increased levels of TNF-α have been shown to contribute to the onset of sickle cell crises and severity of sickle cell disease by playing an integral role in the development of vascular wall dysfunction and ischemia.³ Inflammatory mediators in HbSS disease, such as heparan sulfate from the endothelial glycocalyx and heme from hemolysis, act on monocytes to release TNF-α.¹ Through this effect on the endothelium, TNF-α impedes blood flow during sickle cell crisis, leading to worsening ischemia and resultant painful infarction.³ Analysis of cytokine levels in HbSS patients showed significantly (P<.05) elevated levels of TNF-α during sickle cell crises and at baseline in comparison to nondiseased controls (HbAA), indicating a possible role of TNF-α in the pathogenesis of the crisis state.³ These studies suggest that TNF-α inhibition may reduce the initiation of vaso-occlusive crisis and decrease the subsequent ischemia related to a sickle cell crisis.

Although these findings were observational and limited to a single patient, the 50% decrease in pain level and use of pain medications reported to her hematologist independent of her dermatology visits coincided with the initiation of adalimumab. Although radiographs showed possible psoriatic changes of the distal metatarsal row, her described sickle cell pain and pain crises were atypical for psoriatic arthralgia. Tumor necrosis factor α inhibitors could be the drug of choice to treat patients with psoriasis with concomitant HbSS or HbSC disease due to the blockade of a common inflammatory mediator. Further studies are indicated to analyze the in vivo role of TNF-α inhibition in sickle cell disease.

In an era when we have access to a dizzying array of biologics for psoriasis treatment, it is easy to forget that topical therapies are still the bread and butter of treatment. For the majority of patients living with psoriasis, topical treatment is the only therapy they receive; indeed, a recent study examining a large national payer database found that 86% of psoriasis patients were managed with topical medications only.¹ Thus, it is extremely important to understand how to optimize topical treatments, recognize pitfalls in management, and utilize newer agents that can been added to our treatment armamentarium for psoriasis.

In general, steroids have been the mainstay of topical treatment of psoriasis. Their broad anti-inflammatory activity works well against both the visible signs and symptoms of psoriasis as well as the underlying inflammatory milieu of the disease; however, these treatments are not without their downsides. Hypothalamic-pituitary-adrenal (HPA) axis suppression, especially in higher-potency topical steroids, is a serious concern that limits their use. In one study comparing lotion and cream formulations of clobetasol propionate, HPA axis suppression was seen in 80% (8/10) of adults in the lotion group and 30% (3/10) in the cream group after 4 weeks of treatment.² These findings are not new; a 1987 study found that patients using less than 50 g of topical clobetasol per week, which is considered a low dose, could still exhibit HPA axis suppression.³ Severe HPA axis suppression may occur; one study of various topical steroids found some degree of HPA axis suppression in 38% (19/50) of patients, with a direct correlation with topical steroid potency.⁴ Additionally, cutaneous side effects such as striae formation, atrophy, and the possibility of tachyphylaxis must be considered. Various treatment regimens have been developed to limit topical steroid use, including steroid-sparing medications (eg, calcipotriene) used in conjunction with topical steroids, systemic treatments (eg, phototherapy) added on, or higher-potency topical steroids rotated with lower-potency steroids. Implementing other agents, such as topical retinoids or keratolytics, into the treatment regimen also is an important consideration in the overall approach to topical psoriasis therapy.

Notably, a number of newly approved topical treatments for psoriasis have emerged, and more are in the pipeline. When evaluating these agents, important considerations include safety, length of treatment course, and efficacy. Several of these agents hold promise for patients with psoriasis.

The newest agent, halobetasol propionate lotion 0.01%, was approved for treatment of psoriasis in October 2018. Compared to halobetasol 0.05% cream or ointment, halobetasol propionate lotion 0.01% has one-fifth the concentration of the active ingredient with the same degree of success in efficacy scores.⁹ This reduction in drug concentration is possible because the proprietary lotion base allows for better drug delivery of the active ingredient. Importantly, HPA axis suppression was assessed over an 8-week period of use and no suppression was noted.⁹ Generic class I steroids should only be used for 2 weeks, which is the standard treatment period used in comparator trials; however, many patients will still have active lesions on their body after 2 weeks of treatment, and if using generic clobetasol or betamethasone dipropionate, the choice becomes whether to keep applying the medication and risk HPA axis suppression and cutaneous side effects or switch to a less effective treatment. However, some of the newer agents are indicated for 4 to 8 weeks of treatment.

Utilizing other classes of agents such as retinoids and keratolytics in our treatment armamentarium for psoriasis often is helpful. It has long been known that tazarotene can be combined with topical steroids for increased efficacy and limitation of the irritating effects of the retinoid.¹⁰ Similarly, keratolytics play a role in allowing a topically applied medication to penetrate deep enough to affect the underlying inflammation of psoriasis. Medications that include salicylic acid or urea may help to remove ostraceous scales from thick psoriasis lesions that would otherwise prevent delivery of topical steroids to achieve clinically meaningful results. For scalp psoriasis, there are salicylic acid solutions as well as newer agents such as a dimethicone-based topical product.¹¹

Nonsteroidal topical anti-inflammatories also have been used off label for psoriasis treatment. These agents are especially useful in patients who were not successfully treated with calcipotriene or need adjunctive therapy. Although not extremely effective against plaque psoriasis, topical tacrolimus in particular seems to have a place in the treatment of inverse psoriasis where it can be utilized without concern for long-term side effects.¹² Crisaborole ointment, a topical medication approved for treatment of atopic dermatitis, was studied in phase 2 trials, but development has not progressed for a psoriasis indication.¹³ It is reasonable to consider this medication in the same way that tacrolimus has been used, however, considering that the mechanism of action—phosphodiesterase type 4 inhibition—has successfully been implemented in an oral medication to treat psoriasis, apremilast.

There are numerous topical medications in the pipeline that are being developed to treat psoriasis. Of them, the most relevant is a fixed-dose combination of halobetasol propionate 0.01% and tazarotene 0.045% in a proprietary lotion vehicle. A decision from the US Food and Drug Administration is expected in the first quarter of 2019. This medication capitalizes on the aforementioned synergistic effects of tazarotene and a superpotent topical steroid to achieve improved efficacy. Similar to halobetasol lotion 0.01%, this product was evaluated over an 8-week period, and no HPA axis suppression was observed. Efficacy was significantly improved versus both placebo and either halobetasol or tazarotene alone.¹⁴

Overall, it is promising that after a long period of relative stagnancy, we have numerous new agents available and upcoming for the topical treatment of psoriasis. For the vast majority of patients, topical medications still represent the mainstay of treatment, and it is important that we have access to better, safer medications in this category.

In an era when we have access to a dizzying array of biologics for psoriasis treatment, it is easy to forget that topical therapies are still the bread and butter of treatment. For the majority of patients living with psoriasis, topical treatment is the only therapy they receive; indeed, a recent study examining a large national payer database found that 86% of psoriasis patients were managed with topical medications only.¹ Thus, it is extremely important to understand how to optimize topical treatments, recognize pitfalls in management, and utilize newer agents that can been added to our treatment armamentarium for psoriasis.

In general, steroids have been the mainstay of topical treatment of psoriasis. Their broad anti-inflammatory activity works well against both the visible signs and symptoms of psoriasis as well as the underlying inflammatory milieu of the disease; however, these treatments are not without their downsides. Hypothalamic-pituitary-adrenal (HPA) axis suppression, especially in higher-potency topical steroids, is a serious concern that limits their use. In one study comparing lotion and cream formulations of clobetasol propionate, HPA axis suppression was seen in 80% (8/10) of adults in the lotion group and 30% (3/10) in the cream group after 4 weeks of treatment.² These findings are not new; a 1987 study found that patients using less than 50 g of topical clobetasol per week, which is considered a low dose, could still exhibit HPA axis suppression.³ Severe HPA axis suppression may occur; one study of various topical steroids found some degree of HPA axis suppression in 38% (19/50) of patients, with a direct correlation with topical steroid potency.⁴ Additionally, cutaneous side effects such as striae formation, atrophy, and the possibility of tachyphylaxis must be considered. Various treatment regimens have been developed to limit topical steroid use, including steroid-sparing medications (eg, calcipotriene) used in conjunction with topical steroids, systemic treatments (eg, phototherapy) added on, or higher-potency topical steroids rotated with lower-potency steroids. Implementing other agents, such as topical retinoids or keratolytics, into the treatment regimen also is an important consideration in the overall approach to topical psoriasis therapy.

Notably, a number of newly approved topical treatments for psoriasis have emerged, and more are in the pipeline. When evaluating these agents, important considerations include safety, length of treatment course, and efficacy. Several of these agents hold promise for patients with psoriasis.

The newest agent, halobetasol propionate lotion 0.01%, was approved for treatment of psoriasis in October 2018. Compared to halobetasol 0.05% cream or ointment, halobetasol propionate lotion 0.01% has one-fifth the concentration of the active ingredient with the same degree of success in efficacy scores.⁹ This reduction in drug concentration is possible because the proprietary lotion base allows for better drug delivery of the active ingredient. Importantly, HPA axis suppression was assessed over an 8-week period of use and no suppression was noted.⁹ Generic class I steroids should only be used for 2 weeks, which is the standard treatment period used in comparator trials; however, many patients will still have active lesions on their body after 2 weeks of treatment, and if using generic clobetasol or betamethasone dipropionate, the choice becomes whether to keep applying the medication and risk HPA axis suppression and cutaneous side effects or switch to a less effective treatment. However, some of the newer agents are indicated for 4 to 8 weeks of treatment.

Utilizing other classes of agents such as retinoids and keratolytics in our treatment armamentarium for psoriasis often is helpful. It has long been known that tazarotene can be combined with topical steroids for increased efficacy and limitation of the irritating effects of the retinoid.¹⁰ Similarly, keratolytics play a role in allowing a topically applied medication to penetrate deep enough to affect the underlying inflammation of psoriasis. Medications that include salicylic acid or urea may help to remove ostraceous scales from thick psoriasis lesions that would otherwise prevent delivery of topical steroids to achieve clinically meaningful results. For scalp psoriasis, there are salicylic acid solutions as well as newer agents such as a dimethicone-based topical product.¹¹

Nonsteroidal topical anti-inflammatories also have been used off label for psoriasis treatment. These agents are especially useful in patients who were not successfully treated with calcipotriene or need adjunctive therapy. Although not extremely effective against plaque psoriasis, topical tacrolimus in particular seems to have a place in the treatment of inverse psoriasis where it can be utilized without concern for long-term side effects.¹² Crisaborole ointment, a topical medication approved for treatment of atopic dermatitis, was studied in phase 2 trials, but development has not progressed for a psoriasis indication.¹³ It is reasonable to consider this medication in the same way that tacrolimus has been used, however, considering that the mechanism of action—phosphodiesterase type 4 inhibition—has successfully been implemented in an oral medication to treat psoriasis, apremilast.

There are numerous topical medications in the pipeline that are being developed to treat psoriasis. Of them, the most relevant is a fixed-dose combination of halobetasol propionate 0.01% and tazarotene 0.045% in a proprietary lotion vehicle. A decision from the US Food and Drug Administration is expected in the first quarter of 2019. This medication capitalizes on the aforementioned synergistic effects of tazarotene and a superpotent topical steroid to achieve improved efficacy. Similar to halobetasol lotion 0.01%, this product was evaluated over an 8-week period, and no HPA axis suppression was observed. Efficacy was significantly improved versus both placebo and either halobetasol or tazarotene alone.¹⁴

Overall, it is promising that after a long period of relative stagnancy, we have numerous new agents available and upcoming for the topical treatment of psoriasis. For the vast majority of patients, topical medications still represent the mainstay of treatment, and it is important that we have access to better, safer medications in this category.

In an era when we have access to a dizzying array of biologics for psoriasis treatment, it is easy to forget that topical therapies are still the bread and butter of treatment. For the majority of patients living with psoriasis, topical treatment is the only therapy they receive; indeed, a recent study examining a large national payer database found that 86% of psoriasis patients were managed with topical medications only.¹ Thus, it is extremely important to understand how to optimize topical treatments, recognize pitfalls in management, and utilize newer agents that can been added to our treatment armamentarium for psoriasis.

In general, steroids have been the mainstay of topical treatment of psoriasis. Their broad anti-inflammatory activity works well against both the visible signs and symptoms of psoriasis as well as the underlying inflammatory milieu of the disease; however, these treatments are not without their downsides. Hypothalamic-pituitary-adrenal (HPA) axis suppression, especially in higher-potency topical steroids, is a serious concern that limits their use. In one study comparing lotion and cream formulations of clobetasol propionate, HPA axis suppression was seen in 80% (8/10) of adults in the lotion group and 30% (3/10) in the cream group after 4 weeks of treatment.² These findings are not new; a 1987 study found that patients using less than 50 g of topical clobetasol per week, which is considered a low dose, could still exhibit HPA axis suppression.³ Severe HPA axis suppression may occur; one study of various topical steroids found some degree of HPA axis suppression in 38% (19/50) of patients, with a direct correlation with topical steroid potency.⁴ Additionally, cutaneous side effects such as striae formation, atrophy, and the possibility of tachyphylaxis must be considered. Various treatment regimens have been developed to limit topical steroid use, including steroid-sparing medications (eg, calcipotriene) used in conjunction with topical steroids, systemic treatments (eg, phototherapy) added on, or higher-potency topical steroids rotated with lower-potency steroids. Implementing other agents, such as topical retinoids or keratolytics, into the treatment regimen also is an important consideration in the overall approach to topical psoriasis therapy.

Notably, a number of newly approved topical treatments for psoriasis have emerged, and more are in the pipeline. When evaluating these agents, important considerations include safety, length of treatment course, and efficacy. Several of these agents hold promise for patients with psoriasis.

The newest agent, halobetasol propionate lotion 0.01%, was approved for treatment of psoriasis in October 2018. Compared to halobetasol 0.05% cream or ointment, halobetasol propionate lotion 0.01% has one-fifth the concentration of the active ingredient with the same degree of success in efficacy scores.⁹ This reduction in drug concentration is possible because the proprietary lotion base allows for better drug delivery of the active ingredient. Importantly, HPA axis suppression was assessed over an 8-week period of use and no suppression was noted.⁹ Generic class I steroids should only be used for 2 weeks, which is the standard treatment period used in comparator trials; however, many patients will still have active lesions on their body after 2 weeks of treatment, and if using generic clobetasol or betamethasone dipropionate, the choice becomes whether to keep applying the medication and risk HPA axis suppression and cutaneous side effects or switch to a less effective treatment. However, some of the newer agents are indicated for 4 to 8 weeks of treatment.

Utilizing other classes of agents such as retinoids and keratolytics in our treatment armamentarium for psoriasis often is helpful. It has long been known that tazarotene can be combined with topical steroids for increased efficacy and limitation of the irritating effects of the retinoid.¹⁰ Similarly, keratolytics play a role in allowing a topically applied medication to penetrate deep enough to affect the underlying inflammation of psoriasis. Medications that include salicylic acid or urea may help to remove ostraceous scales from thick psoriasis lesions that would otherwise prevent delivery of topical steroids to achieve clinically meaningful results. For scalp psoriasis, there are salicylic acid solutions as well as newer agents such as a dimethicone-based topical product.¹¹

Nonsteroidal topical anti-inflammatories also have been used off label for psoriasis treatment. These agents are especially useful in patients who were not successfully treated with calcipotriene or need adjunctive therapy. Although not extremely effective against plaque psoriasis, topical tacrolimus in particular seems to have a place in the treatment of inverse psoriasis where it can be utilized without concern for long-term side effects.¹² Crisaborole ointment, a topical medication approved for treatment of atopic dermatitis, was studied in phase 2 trials, but development has not progressed for a psoriasis indication.¹³ It is reasonable to consider this medication in the same way that tacrolimus has been used, however, considering that the mechanism of action—phosphodiesterase type 4 inhibition—has successfully been implemented in an oral medication to treat psoriasis, apremilast.

There are numerous topical medications in the pipeline that are being developed to treat psoriasis. Of them, the most relevant is a fixed-dose combination of halobetasol propionate 0.01% and tazarotene 0.045% in a proprietary lotion vehicle. A decision from the US Food and Drug Administration is expected in the first quarter of 2019. This medication capitalizes on the aforementioned synergistic effects of tazarotene and a superpotent topical steroid to achieve improved efficacy. Similar to halobetasol lotion 0.01%, this product was evaluated over an 8-week period, and no HPA axis suppression was observed. Efficacy was significantly improved versus both placebo and either halobetasol or tazarotene alone.¹⁴

Overall, it is promising that after a long period of relative stagnancy, we have numerous new agents available and upcoming for the topical treatment of psoriasis. For the vast majority of patients, topical medications still represent the mainstay of treatment, and it is important that we have access to better, safer medications in this category.

GRAND CAYMAN, CAYMAN ISLANDS – Guselkumab bested secukinumab in a 48-week-long study of plaque psoriasis, with 84.5% of patients on the interleukin (IL)-23 blocker hitting at least a 90% improvement in their Psoriasis Area Severity Index (PASI), compared with 70% of those taking secukinumab, which blocks IL-17.

The difference in the PASI 90 response, the primary endpoint, was guselkumab’s largest effect over the comparator in the phase 3 trial, which also had six secondary endpoints. The drug was numerically, but not significantly, better than secukinumab in the PASI 75 response at weeks 12 and 48 (84.6% for guselkumab at both time points vs. 80.2% for secukinumab at both time points). This finding on the primary secondary endpoint knocked the P values of the other five into “nominally significant” ranges. But the responses were still good enough for researchers to tag guselkumab as noninferior to its competitor, Jeffrey M. Sobell, MD, said at the meeting provided by Global Academy for Medical Education.

The difference also speaks to the difference in the drugs’ onset of action and its peak efficacy, said Dr. Sobell, of the department of dermatology at Tufts University, Boston.

“In both groups, the PASI 90 increased similarly in the first month,” to about 20%, he commented. “But at week 12 and after, it was consistently higher in guselkumab, peaking around week 28. Secukinumab peaked around weeks 16 to 20 and then slowly declined.”

Despite not being statistically significant, the other secondary efficacy endpoints were certainly enough to pique the audience’s attention. At week 48, guselkumab topped secukinumab in both PASI 100 (58.2% vs. 48.4%, respectively) and Investigator’s Global Assessment (IGA) scores of 0 (62.2% vs. 50.4%) and 0-1 (85% vs. 74.9%).

ECLIPSE randomized 1,048 patients with moderate to severe plaque psoriasis to 100-mg subcutaneous guselkumab at weeks 0, 4, and 12, followed by dosing every 8 weeks, or to 300-mg subcutaneous secukinumab administered by two subcutaneous injections of 150 mg at weeks 0, 1, 2, 3, and 4, followed by dosing every 4 weeks. The primary endpoint of the study was the proportion of patients achieving a PASI 90 response at week 48. Secondary endpoints were assessed at weeks 12 and 48, with safety monitoring through week 56.

The mean baseline Body Surface Area score was 24, and the mean PASI score was 20. Patients had already been treated with phototherapy (51.8%), nonbiologic systemic medications (53.7%), and biologics (29%). About 37% were naive to both nonbiologics and biologics.

Both drugs were well tolerated, with no unanticipated adverse events. Through week 44, the discontinuation rates were 5% for guselkumab and 9% for secukinumab. Adverse events were common in both arms (77.9% and 81.6%, respectively). Serious adverse events occurred in 6.2% and 7.2%, respectively. These included serious infections in six patients taking guselkumab and five taking secukinumab. Superficial Candida infections occurred in 2% of the guselkumab group and 5.7% of the secukinumab group; Tinea infections occurred in 1.7% and 4.5%, respectively.

The session was sponsored by Janssen, the manufacturer of guselkumab (Tremfya). Dr. Sobell is a consultant for Janssen and also disclosed relationships with AbbVie, Amgen, Celgene, Eli Lilly, Merck, Novartis, Regeneron, and Sun Pharma. Secukinumab is marketed as Cosentyx.

Global Academy and this news organization are owned by the same parent company.

This article was updated 2/1/19.

msullivan@mdege.com

GRAND CAYMAN, CAYMAN ISLANDS – Guselkumab bested secukinumab in a 48-week-long study of plaque psoriasis, with 84.5% of patients on the interleukin (IL)-23 blocker hitting at least a 90% improvement in their Psoriasis Area Severity Index (PASI), compared with 70% of those taking secukinumab, which blocks IL-17.

The difference in the PASI 90 response, the primary endpoint, was guselkumab’s largest effect over the comparator in the phase 3 trial, which also had six secondary endpoints. The drug was numerically, but not significantly, better than secukinumab in the PASI 75 response at weeks 12 and 48 (84.6% for guselkumab at both time points vs. 80.2% for secukinumab at both time points). This finding on the primary secondary endpoint knocked the P values of the other five into “nominally significant” ranges. But the responses were still good enough for researchers to tag guselkumab as noninferior to its competitor, Jeffrey M. Sobell, MD, said at the meeting provided by Global Academy for Medical Education.

The difference also speaks to the difference in the drugs’ onset of action and its peak efficacy, said Dr. Sobell, of the department of dermatology at Tufts University, Boston.

“In both groups, the PASI 90 increased similarly in the first month,” to about 20%, he commented. “But at week 12 and after, it was consistently higher in guselkumab, peaking around week 28. Secukinumab peaked around weeks 16 to 20 and then slowly declined.”

Despite not being statistically significant, the other secondary efficacy endpoints were certainly enough to pique the audience’s attention. At week 48, guselkumab topped secukinumab in both PASI 100 (58.2% vs. 48.4%, respectively) and Investigator’s Global Assessment (IGA) scores of 0 (62.2% vs. 50.4%) and 0-1 (85% vs. 74.9%).

ECLIPSE randomized 1,048 patients with moderate to severe plaque psoriasis to 100-mg subcutaneous guselkumab at weeks 0, 4, and 12, followed by dosing every 8 weeks, or to 300-mg subcutaneous secukinumab administered by two subcutaneous injections of 150 mg at weeks 0, 1, 2, 3, and 4, followed by dosing every 4 weeks. The primary endpoint of the study was the proportion of patients achieving a PASI 90 response at week 48. Secondary endpoints were assessed at weeks 12 and 48, with safety monitoring through week 56.

The mean baseline Body Surface Area score was 24, and the mean PASI score was 20. Patients had already been treated with phototherapy (51.8%), nonbiologic systemic medications (53.7%), and biologics (29%). About 37% were naive to both nonbiologics and biologics.

Both drugs were well tolerated, with no unanticipated adverse events. Through week 44, the discontinuation rates were 5% for guselkumab and 9% for secukinumab. Adverse events were common in both arms (77.9% and 81.6%, respectively). Serious adverse events occurred in 6.2% and 7.2%, respectively. These included serious infections in six patients taking guselkumab and five taking secukinumab. Superficial Candida infections occurred in 2% of the guselkumab group and 5.7% of the secukinumab group; Tinea infections occurred in 1.7% and 4.5%, respectively.

The session was sponsored by Janssen, the manufacturer of guselkumab (Tremfya). Dr. Sobell is a consultant for Janssen and also disclosed relationships with AbbVie, Amgen, Celgene, Eli Lilly, Merck, Novartis, Regeneron, and Sun Pharma. Secukinumab is marketed as Cosentyx.

Global Academy and this news organization are owned by the same parent company.

This article was updated 2/1/19.

msullivan@mdege.com

GRAND CAYMAN, CAYMAN ISLANDS – Guselkumab bested secukinumab in a 48-week-long study of plaque psoriasis, with 84.5% of patients on the interleukin (IL)-23 blocker hitting at least a 90% improvement in their Psoriasis Area Severity Index (PASI), compared with 70% of those taking secukinumab, which blocks IL-17.

The difference in the PASI 90 response, the primary endpoint, was guselkumab’s largest effect over the comparator in the phase 3 trial, which also had six secondary endpoints. The drug was numerically, but not significantly, better than secukinumab in the PASI 75 response at weeks 12 and 48 (84.6% for guselkumab at both time points vs. 80.2% for secukinumab at both time points). This finding on the primary secondary endpoint knocked the P values of the other five into “nominally significant” ranges. But the responses were still good enough for researchers to tag guselkumab as noninferior to its competitor, Jeffrey M. Sobell, MD, said at the meeting provided by Global Academy for Medical Education.

The difference also speaks to the difference in the drugs’ onset of action and its peak efficacy, said Dr. Sobell, of the department of dermatology at Tufts University, Boston.

“In both groups, the PASI 90 increased similarly in the first month,” to about 20%, he commented. “But at week 12 and after, it was consistently higher in guselkumab, peaking around week 28. Secukinumab peaked around weeks 16 to 20 and then slowly declined.”

Despite not being statistically significant, the other secondary efficacy endpoints were certainly enough to pique the audience’s attention. At week 48, guselkumab topped secukinumab in both PASI 100 (58.2% vs. 48.4%, respectively) and Investigator’s Global Assessment (IGA) scores of 0 (62.2% vs. 50.4%) and 0-1 (85% vs. 74.9%).

ECLIPSE randomized 1,048 patients with moderate to severe plaque psoriasis to 100-mg subcutaneous guselkumab at weeks 0, 4, and 12, followed by dosing every 8 weeks, or to 300-mg subcutaneous secukinumab administered by two subcutaneous injections of 150 mg at weeks 0, 1, 2, 3, and 4, followed by dosing every 4 weeks. The primary endpoint of the study was the proportion of patients achieving a PASI 90 response at week 48. Secondary endpoints were assessed at weeks 12 and 48, with safety monitoring through week 56.

The mean baseline Body Surface Area score was 24, and the mean PASI score was 20. Patients had already been treated with phototherapy (51.8%), nonbiologic systemic medications (53.7%), and biologics (29%). About 37% were naive to both nonbiologics and biologics.

Both drugs were well tolerated, with no unanticipated adverse events. Through week 44, the discontinuation rates were 5% for guselkumab and 9% for secukinumab. Adverse events were common in both arms (77.9% and 81.6%, respectively). Serious adverse events occurred in 6.2% and 7.2%, respectively. These included serious infections in six patients taking guselkumab and five taking secukinumab. Superficial Candida infections occurred in 2% of the guselkumab group and 5.7% of the secukinumab group; Tinea infections occurred in 1.7% and 4.5%, respectively.

The session was sponsored by Janssen, the manufacturer of guselkumab (Tremfya). Dr. Sobell is a consultant for Janssen and also disclosed relationships with AbbVie, Amgen, Celgene, Eli Lilly, Merck, Novartis, Regeneron, and Sun Pharma. Secukinumab is marketed as Cosentyx.

Global Academy and this news organization are owned by the same parent company.

This article was updated 2/1/19.

msullivan@mdege.com

PARIS – The more comorbid conditions present in patients with moderate to severe plaque psoriasis, the less likely they are to achieve complete clearance in response to biologic therapy, according to the results of the prospective observational PSO-BIO-REAL study.

Bruce Jancin/MDedge News

“I think this reflects a picture that has been seen in other studies,” noted Mr. Ziegler, director of global patient access at Leo Pharma in Ballerup, Denmark.

The purpose of the 12-month PSO-BIO-REAL (PSOriasis treated with BIOlogics in REAL life) study was to assess the effectiveness of a variety of biologic agents in a real-world population typical of patients encountered in routine clinical practice, as opposed to more restrictive format of often-cited randomized trials, which generally feature a lengthy list of exclusions. One-third of participants were from the United States, with the rest drawn from four Western European countries. Their mean age was 47 years, with an 18.4-year history of psoriasis and a baseline Psoriasis Area and Severity Index (PASI) score of 14.3.

Sixty percent of participants were starting treatment with a biologic agent for the first time. The other 40% had prior biologic experience. At physician discretion, 61% of enrollees were put on a tumor necrosis factor inhibitor, either etanercept (Enbrel), adalimumab (Humira), or infliximab (Remicade); 30% initiated treatment with the interleukin-12/23 inhibitor ustekinumab (Stelara); and 9% received secukinumab (Cosentyx), an interleukin-17 inhibitor.

The five most common comorbid conditions present at baseline were hypertension, present in 33.5% of participants; psoriatic arthritis (PsA), present in 28.1%; hyperlipidemia, 20.9%; diabetes, 13.9%, and depression, present in 13.7% of the psoriasis patients.

Baseline comorbidities were significantly more common among the biologic-experienced patients. For example, their prevalence of hypertension was 42%, compared with 28% in the biologic-naive group. PsA was present in 35% of the biologic-experienced and 23% of the biologic-naive patients. Nineteen percent of biologic-experienced patients had diabetes at baseline, as did 11% of the biologic-naive group.

During the 12-month study, 3.7% of patients developed a new comorbidity, the most common being anxiety, hypertension, PsA, depression, and hyperlipidemia.

The primary outcome in the study was the complete clearance rate – a PASI 100 response – at 6 months. It ranged from a high of 31% in patients with no baseline comorbid conditions to a low of 16.5% in those with three or more. The results were similar at 12 months.

Conversely, an inadequate therapeutic response as defined by a PASI 50 or less at 6 months occurred in 15% of psoriasis patients with no baseline comorbidities, 27% with one, 35% with two comorbid conditions, and 28% with three or more.

The major caveat regarding this study is that the observed association between comorbid conditions and complete clearance rates doesn’t prove causality, Mr. Ziegler noted.

The PSO-BIO-REAL study was sponsored by Amgen, AstraZeneca, and Leo Pharma. Mr. Ziegler is a Leo executive.

bjancin@mdedge.com

SOURCE: Ziegler F. EADV Congress, Abstract FC04.01.

PARIS – The more comorbid conditions present in patients with moderate to severe plaque psoriasis, the less likely they are to achieve complete clearance in response to biologic therapy, according to the results of the prospective observational PSO-BIO-REAL study.

Bruce Jancin/MDedge News

“I think this reflects a picture that has been seen in other studies,” noted Mr. Ziegler, director of global patient access at Leo Pharma in Ballerup, Denmark.

The purpose of the 12-month PSO-BIO-REAL (PSOriasis treated with BIOlogics in REAL life) study was to assess the effectiveness of a variety of biologic agents in a real-world population typical of patients encountered in routine clinical practice, as opposed to more restrictive format of often-cited randomized trials, which generally feature a lengthy list of exclusions. One-third of participants were from the United States, with the rest drawn from four Western European countries. Their mean age was 47 years, with an 18.4-year history of psoriasis and a baseline Psoriasis Area and Severity Index (PASI) score of 14.3.

Sixty percent of participants were starting treatment with a biologic agent for the first time. The other 40% had prior biologic experience. At physician discretion, 61% of enrollees were put on a tumor necrosis factor inhibitor, either etanercept (Enbrel), adalimumab (Humira), or infliximab (Remicade); 30% initiated treatment with the interleukin-12/23 inhibitor ustekinumab (Stelara); and 9% received secukinumab (Cosentyx), an interleukin-17 inhibitor.

The five most common comorbid conditions present at baseline were hypertension, present in 33.5% of participants; psoriatic arthritis (PsA), present in 28.1%; hyperlipidemia, 20.9%; diabetes, 13.9%, and depression, present in 13.7% of the psoriasis patients.

Baseline comorbidities were significantly more common among the biologic-experienced patients. For example, their prevalence of hypertension was 42%, compared with 28% in the biologic-naive group. PsA was present in 35% of the biologic-experienced and 23% of the biologic-naive patients. Nineteen percent of biologic-experienced patients had diabetes at baseline, as did 11% of the biologic-naive group.

During the 12-month study, 3.7% of patients developed a new comorbidity, the most common being anxiety, hypertension, PsA, depression, and hyperlipidemia.

The primary outcome in the study was the complete clearance rate – a PASI 100 response – at 6 months. It ranged from a high of 31% in patients with no baseline comorbid conditions to a low of 16.5% in those with three or more. The results were similar at 12 months.

Conversely, an inadequate therapeutic response as defined by a PASI 50 or less at 6 months occurred in 15% of psoriasis patients with no baseline comorbidities, 27% with one, 35% with two comorbid conditions, and 28% with three or more.

The major caveat regarding this study is that the observed association between comorbid conditions and complete clearance rates doesn’t prove causality, Mr. Ziegler noted.

The PSO-BIO-REAL study was sponsored by Amgen, AstraZeneca, and Leo Pharma. Mr. Ziegler is a Leo executive.

bjancin@mdedge.com

SOURCE: Ziegler F. EADV Congress, Abstract FC04.01.

PARIS – The more comorbid conditions present in patients with moderate to severe plaque psoriasis, the less likely they are to achieve complete clearance in response to biologic therapy, according to the results of the prospective observational PSO-BIO-REAL study.

Bruce Jancin/MDedge News

“I think this reflects a picture that has been seen in other studies,” noted Mr. Ziegler, director of global patient access at Leo Pharma in Ballerup, Denmark.

The purpose of the 12-month PSO-BIO-REAL (PSOriasis treated with BIOlogics in REAL life) study was to assess the effectiveness of a variety of biologic agents in a real-world population typical of patients encountered in routine clinical practice, as opposed to more restrictive format of often-cited randomized trials, which generally feature a lengthy list of exclusions. One-third of participants were from the United States, with the rest drawn from four Western European countries. Their mean age was 47 years, with an 18.4-year history of psoriasis and a baseline Psoriasis Area and Severity Index (PASI) score of 14.3.

Sixty percent of participants were starting treatment with a biologic agent for the first time. The other 40% had prior biologic experience. At physician discretion, 61% of enrollees were put on a tumor necrosis factor inhibitor, either etanercept (Enbrel), adalimumab (Humira), or infliximab (Remicade); 30% initiated treatment with the interleukin-12/23 inhibitor ustekinumab (Stelara); and 9% received secukinumab (Cosentyx), an interleukin-17 inhibitor.

The five most common comorbid conditions present at baseline were hypertension, present in 33.5% of participants; psoriatic arthritis (PsA), present in 28.1%; hyperlipidemia, 20.9%; diabetes, 13.9%, and depression, present in 13.7% of the psoriasis patients.

Baseline comorbidities were significantly more common among the biologic-experienced patients. For example, their prevalence of hypertension was 42%, compared with 28% in the biologic-naive group. PsA was present in 35% of the biologic-experienced and 23% of the biologic-naive patients. Nineteen percent of biologic-experienced patients had diabetes at baseline, as did 11% of the biologic-naive group.

During the 12-month study, 3.7% of patients developed a new comorbidity, the most common being anxiety, hypertension, PsA, depression, and hyperlipidemia.

The primary outcome in the study was the complete clearance rate – a PASI 100 response – at 6 months. It ranged from a high of 31% in patients with no baseline comorbid conditions to a low of 16.5% in those with three or more. The results were similar at 12 months.

Conversely, an inadequate therapeutic response as defined by a PASI 50 or less at 6 months occurred in 15% of psoriasis patients with no baseline comorbidities, 27% with one, 35% with two comorbid conditions, and 28% with three or more.

The major caveat regarding this study is that the observed association between comorbid conditions and complete clearance rates doesn’t prove causality, Mr. Ziegler noted.

The PSO-BIO-REAL study was sponsored by Amgen, AstraZeneca, and Leo Pharma. Mr. Ziegler is a Leo executive.

bjancin@mdedge.com

SOURCE: Ziegler F. EADV Congress, Abstract FC04.01.

PARIS – The interleukin-17 receptor inhibitor brodalumab achieved complete clearance of moderate-to-severe psoriasis far faster and more frequently than the interleukin-12/23 inhibitor ustekinumab.

Bruce Jancin/MDedge News

That’s according to a post hoc pooled analysis of the phase 3 randomized AMAGINE-1 and -3 trials that Kristian Reich, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Other interleukin-17 inhibitors have also outperformed ustekinumab (Stelara) in head-to-head, randomized trials. What’s unique about this new secondary analysis of the AMAGINE trials is the demonstration that the complete clearance rate – that is, 100% improvement in Psoriasis Area and Severity Index (PASI) – with brodalumab (Siliq) was consistent, regardless of a psoriasis patient’s prior treatment history, according to Dr. Reich, professor of dermatology at Georg-August-University in Göttingen, Germany, and a partner at the Dermatologikum Hamburg.

“I don’t want to niche brodalumab as a rescue drug; but if you need a response in a patient who has failed a biologic, then obviously, this is a pretty good choice,” he said.

Typically, psoriasis patients who have previously failed to respond favorably to a biologic agent have a substantially lower complete clearance rate when placed on another biologic than do those who are biologic naive or haven’t been on a nonbiologic systemic therapy.

“I think it’s interesting that there is very little impact of previous treatment response with regard to this analysis when it comes to brodalumab,” the dermatologist observed. “It goes down a little bit, but if you compare it to ustekinumab, you see a very good robustness despite previous therapy.”

His presentation focused on the 339 AMAGINE-2 or AMAGINE-3 participants randomized to brodalumab at the approved dose of 210 mg by subcutaneous injection every 2 weeks, or to subcutaneous ustekinumab at the approved dose of 45 mg or 90 mg, depending upon body weight, on day 1, week 4, and then every 12 weeks in the 52-week trials.

It took 14 weeks for 50% of patients assigned to brodalumab to achieve a PASI 100 response, and 44 weeks to accomplish the same in the ustekinumab group. At 52 weeks, the PASI 100 response rate was 76% for brodalumab and 52% for ustekinumab.

This was a competing-risk analysis – a methodology relatively new to dermatology – in which the coprimary endpoint was inadequate response to treatment, as defined by a static Physician’s Global Assessment score of 3 or more or two consecutive sPGAs of at least 2 over a 4-week interval at any point from week 16 on. The inadequate response rate was 20% in the brodalumab group and 40% with ustekinumab.

Looking in the brodalumab group at PASI 100 response rates in relation to prior treatments, the complete clearance rate at week 52 was 76% in those with no prior systemic treatment at study entry, 78% in those with a history of nonbiologic systemic treatment, 75% in patients who hadn’t experienced treatment failure when previously on another biologic agent, and 70% in those with a baseline history of failure on a different biologic.

The corresponding PASI 100 rates in the ustekinumab group were strikingly lower, at 58%, 55%, 41%, and 30%.

Leo Pharma funded Dr. Reich’s post hoc analysis; Leo markets brodalumab in Europe. Dr. Reich reported receiving research funding from and serving as a consultant to that pharmaceutical company and numerous others involved in developing new drugs for psoriasis and atopic dermatitis.

bjancin@mdedge.com

SOURCE: Reich K. EADV Congress, Abstract #FC03.06.

PARIS – The interleukin-17 receptor inhibitor brodalumab achieved complete clearance of moderate-to-severe psoriasis far faster and more frequently than the interleukin-12/23 inhibitor ustekinumab.

Bruce Jancin/MDedge News

That’s according to a post hoc pooled analysis of the phase 3 randomized AMAGINE-1 and -3 trials that Kristian Reich, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Other interleukin-17 inhibitors have also outperformed ustekinumab (Stelara) in head-to-head, randomized trials. What’s unique about this new secondary analysis of the AMAGINE trials is the demonstration that the complete clearance rate – that is, 100% improvement in Psoriasis Area and Severity Index (PASI) – with brodalumab (Siliq) was consistent, regardless of a psoriasis patient’s prior treatment history, according to Dr. Reich, professor of dermatology at Georg-August-University in Göttingen, Germany, and a partner at the Dermatologikum Hamburg.

“I don’t want to niche brodalumab as a rescue drug; but if you need a response in a patient who has failed a biologic, then obviously, this is a pretty good choice,” he said.

Typically, psoriasis patients who have previously failed to respond favorably to a biologic agent have a substantially lower complete clearance rate when placed on another biologic than do those who are biologic naive or haven’t been on a nonbiologic systemic therapy.

“I think it’s interesting that there is very little impact of previous treatment response with regard to this analysis when it comes to brodalumab,” the dermatologist observed. “It goes down a little bit, but if you compare it to ustekinumab, you see a very good robustness despite previous therapy.”

His presentation focused on the 339 AMAGINE-2 or AMAGINE-3 participants randomized to brodalumab at the approved dose of 210 mg by subcutaneous injection every 2 weeks, or to subcutaneous ustekinumab at the approved dose of 45 mg or 90 mg, depending upon body weight, on day 1, week 4, and then every 12 weeks in the 52-week trials.

It took 14 weeks for 50% of patients assigned to brodalumab to achieve a PASI 100 response, and 44 weeks to accomplish the same in the ustekinumab group. At 52 weeks, the PASI 100 response rate was 76% for brodalumab and 52% for ustekinumab.

This was a competing-risk analysis – a methodology relatively new to dermatology – in which the coprimary endpoint was inadequate response to treatment, as defined by a static Physician’s Global Assessment score of 3 or more or two consecutive sPGAs of at least 2 over a 4-week interval at any point from week 16 on. The inadequate response rate was 20% in the brodalumab group and 40% with ustekinumab.

Looking in the brodalumab group at PASI 100 response rates in relation to prior treatments, the complete clearance rate at week 52 was 76% in those with no prior systemic treatment at study entry, 78% in those with a history of nonbiologic systemic treatment, 75% in patients who hadn’t experienced treatment failure when previously on another biologic agent, and 70% in those with a baseline history of failure on a different biologic.

The corresponding PASI 100 rates in the ustekinumab group were strikingly lower, at 58%, 55%, 41%, and 30%.

Leo Pharma funded Dr. Reich’s post hoc analysis; Leo markets brodalumab in Europe. Dr. Reich reported receiving research funding from and serving as a consultant to that pharmaceutical company and numerous others involved in developing new drugs for psoriasis and atopic dermatitis.

bjancin@mdedge.com

SOURCE: Reich K. EADV Congress, Abstract #FC03.06.

PARIS – The interleukin-17 receptor inhibitor brodalumab achieved complete clearance of moderate-to-severe psoriasis far faster and more frequently than the interleukin-12/23 inhibitor ustekinumab.

Bruce Jancin/MDedge News

That’s according to a post hoc pooled analysis of the phase 3 randomized AMAGINE-1 and -3 trials that Kristian Reich, MD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Other interleukin-17 inhibitors have also outperformed ustekinumab (Stelara) in head-to-head, randomized trials. What’s unique about this new secondary analysis of the AMAGINE trials is the demonstration that the complete clearance rate – that is, 100% improvement in Psoriasis Area and Severity Index (PASI) – with brodalumab (Siliq) was consistent, regardless of a psoriasis patient’s prior treatment history, according to Dr. Reich, professor of dermatology at Georg-August-University in Göttingen, Germany, and a partner at the Dermatologikum Hamburg.

“I don’t want to niche brodalumab as a rescue drug; but if you need a response in a patient who has failed a biologic, then obviously, this is a pretty good choice,” he said.

Typically, psoriasis patients who have previously failed to respond favorably to a biologic agent have a substantially lower complete clearance rate when placed on another biologic than do those who are biologic naive or haven’t been on a nonbiologic systemic therapy.

“I think it’s interesting that there is very little impact of previous treatment response with regard to this analysis when it comes to brodalumab,” the dermatologist observed. “It goes down a little bit, but if you compare it to ustekinumab, you see a very good robustness despite previous therapy.”

His presentation focused on the 339 AMAGINE-2 or AMAGINE-3 participants randomized to brodalumab at the approved dose of 210 mg by subcutaneous injection every 2 weeks, or to subcutaneous ustekinumab at the approved dose of 45 mg or 90 mg, depending upon body weight, on day 1, week 4, and then every 12 weeks in the 52-week trials.

It took 14 weeks for 50% of patients assigned to brodalumab to achieve a PASI 100 response, and 44 weeks to accomplish the same in the ustekinumab group. At 52 weeks, the PASI 100 response rate was 76% for brodalumab and 52% for ustekinumab.

This was a competing-risk analysis – a methodology relatively new to dermatology – in which the coprimary endpoint was inadequate response to treatment, as defined by a static Physician’s Global Assessment score of 3 or more or two consecutive sPGAs of at least 2 over a 4-week interval at any point from week 16 on. The inadequate response rate was 20% in the brodalumab group and 40% with ustekinumab.

Looking in the brodalumab group at PASI 100 response rates in relation to prior treatments, the complete clearance rate at week 52 was 76% in those with no prior systemic treatment at study entry, 78% in those with a history of nonbiologic systemic treatment, 75% in patients who hadn’t experienced treatment failure when previously on another biologic agent, and 70% in those with a baseline history of failure on a different biologic.

The corresponding PASI 100 rates in the ustekinumab group were strikingly lower, at 58%, 55%, 41%, and 30%.

Leo Pharma funded Dr. Reich’s post hoc analysis; Leo markets brodalumab in Europe. Dr. Reich reported receiving research funding from and serving as a consultant to that pharmaceutical company and numerous others involved in developing new drugs for psoriasis and atopic dermatitis.

bjancin@mdedge.com

SOURCE: Reich K. EADV Congress, Abstract #FC03.06.

In a review of therapeutic issues for psoriasis patients who have such chronic infections as hepatitis, HIV, or latent tuberculosis infection (LTBI) or those who fall into the category of special populations (pregnant women or children), significant concerns were directly tied to the mode of action of the drugs involved.

Courtesy NIH

In particular, “Most systemic agents for psoriasis are immunosuppressive, which poses a unique treatment challenge in patients with psoriasis with chronic infections because they are already immunosuppressed,” according to Shivani B. Kaushik, MD, a resident in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, and her colleague Mark G. Lebwohl, MD, professor and system chair of the department.

For example, the reviewers detailed a report of hepatitis B virus (HBV) and hepatitis C virus (HCV) reactivation in patients with psoriasis who were taking biologics. Virus reactivation was noted in 2/175 patients who were positive for anti-HBc antibody, 3/97 patients with HCV infection, and 8/40 patients who were positive for HBsAg (the surface antigen of HBV). From this, they concluded that “biologics pose minimal risk for viral reactivation in patients with anti-HCV or anti-HBc antibodies, but they are of considerable risk in HBsAg-positive patients.” (J Amer Acad Derm. 2019 Jan;80:43-53).

Giving a specific example, Dr. Kaushik and her colleague pointed out that the safety of ustekinumab in patients with psoriasis with concurrent HCV and HBV infection was not clear. Viral reactivation and hepatocellular cancer were reported in one of four patients with HCV and in two of seven HBsAg-positive patients; and yet, another study showed that the successful use of ustekinumab for psoriasis had no impact on liver function or viral load in a patient with coexisting HCV.

Overall, “Patients should not be treated with immunosuppressive therapies during the acute stage. However, biologic treatment can be initiated in patients with chronic or resolved hepatitis under close monitoring and collaboration with a gastroenterologist,” the researchers stated.

In addition, they pointed out that methotrexate, another commonly prescribed drug for psoriasis, is absolutely contraindicated, although the use of cyclosporine remains controversial for those patients who are HCV-antibody positive.

“Most systemic agents used in psoriasis are immunosuppressive and require appropriate screening, monitoring, and prophylaxis when used in [psoriasis] patients with chronic infections, such as hepatitis, HIV, and LTBI,” the authors concluded.

The authors reported receiving funding from a number of pharmaceutical companies.

mlesney@mdedge.com

SOURCE: Kaushik BS et al. J Amer Acad Derm. 2019;80:43-53.
 

In a review of therapeutic issues for psoriasis patients who have such chronic infections as hepatitis, HIV, or latent tuberculosis infection (LTBI) or those who fall into the category of special populations (pregnant women or children), significant concerns were directly tied to the mode of action of the drugs involved.

Courtesy NIH

In particular, “Most systemic agents for psoriasis are immunosuppressive, which poses a unique treatment challenge in patients with psoriasis with chronic infections because they are already immunosuppressed,” according to Shivani B. Kaushik, MD, a resident in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, and her colleague Mark G. Lebwohl, MD, professor and system chair of the department.

For example, the reviewers detailed a report of hepatitis B virus (HBV) and hepatitis C virus (HCV) reactivation in patients with psoriasis who were taking biologics. Virus reactivation was noted in 2/175 patients who were positive for anti-HBc antibody, 3/97 patients with HCV infection, and 8/40 patients who were positive for HBsAg (the surface antigen of HBV). From this, they concluded that “biologics pose minimal risk for viral reactivation in patients with anti-HCV or anti-HBc antibodies, but they are of considerable risk in HBsAg-positive patients.” (J Amer Acad Derm. 2019 Jan;80:43-53).

Giving a specific example, Dr. Kaushik and her colleague pointed out that the safety of ustekinumab in patients with psoriasis with concurrent HCV and HBV infection was not clear. Viral reactivation and hepatocellular cancer were reported in one of four patients with HCV and in two of seven HBsAg-positive patients; and yet, another study showed that the successful use of ustekinumab for psoriasis had no impact on liver function or viral load in a patient with coexisting HCV.

Overall, “Patients should not be treated with immunosuppressive therapies during the acute stage. However, biologic treatment can be initiated in patients with chronic or resolved hepatitis under close monitoring and collaboration with a gastroenterologist,” the researchers stated.

In addition, they pointed out that methotrexate, another commonly prescribed drug for psoriasis, is absolutely contraindicated, although the use of cyclosporine remains controversial for those patients who are HCV-antibody positive.

“Most systemic agents used in psoriasis are immunosuppressive and require appropriate screening, monitoring, and prophylaxis when used in [psoriasis] patients with chronic infections, such as hepatitis, HIV, and LTBI,” the authors concluded.

The authors reported receiving funding from a number of pharmaceutical companies.

mlesney@mdedge.com

SOURCE: Kaushik BS et al. J Amer Acad Derm. 2019;80:43-53.
 

In a review of therapeutic issues for psoriasis patients who have such chronic infections as hepatitis, HIV, or latent tuberculosis infection (LTBI) or those who fall into the category of special populations (pregnant women or children), significant concerns were directly tied to the mode of action of the drugs involved.

Courtesy NIH

In particular, “Most systemic agents for psoriasis are immunosuppressive, which poses a unique treatment challenge in patients with psoriasis with chronic infections because they are already immunosuppressed,” according to Shivani B. Kaushik, MD, a resident in the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, and her colleague Mark G. Lebwohl, MD, professor and system chair of the department.

For example, the reviewers detailed a report of hepatitis B virus (HBV) and hepatitis C virus (HCV) reactivation in patients with psoriasis who were taking biologics. Virus reactivation was noted in 2/175 patients who were positive for anti-HBc antibody, 3/97 patients with HCV infection, and 8/40 patients who were positive for HBsAg (the surface antigen of HBV). From this, they concluded that “biologics pose minimal risk for viral reactivation in patients with anti-HCV or anti-HBc antibodies, but they are of considerable risk in HBsAg-positive patients.” (J Amer Acad Derm. 2019 Jan;80:43-53).

Giving a specific example, Dr. Kaushik and her colleague pointed out that the safety of ustekinumab in patients with psoriasis with concurrent HCV and HBV infection was not clear. Viral reactivation and hepatocellular cancer were reported in one of four patients with HCV and in two of seven HBsAg-positive patients; and yet, another study showed that the successful use of ustekinumab for psoriasis had no impact on liver function or viral load in a patient with coexisting HCV.

Overall, “Patients should not be treated with immunosuppressive therapies during the acute stage. However, biologic treatment can be initiated in patients with chronic or resolved hepatitis under close monitoring and collaboration with a gastroenterologist,” the researchers stated.

In addition, they pointed out that methotrexate, another commonly prescribed drug for psoriasis, is absolutely contraindicated, although the use of cyclosporine remains controversial for those patients who are HCV-antibody positive.

“Most systemic agents used in psoriasis are immunosuppressive and require appropriate screening, monitoring, and prophylaxis when used in [psoriasis] patients with chronic infections, such as hepatitis, HIV, and LTBI,” the authors concluded.

The authors reported receiving funding from a number of pharmaceutical companies.

mlesney@mdedge.com

SOURCE: Kaushik BS et al. J Amer Acad Derm. 2019;80:43-53.
 

PARIS – Dermatologists are likely to do a double-take when they see the long-term efficacy and safety data for tildrakizumab (Ilumya), a high-affinity humanized monoclonal antibody targeting interleukin-23 p19, relative to the performance of older and more familiar biologic agents with other targets in psoriasis, Diamant Thaçi, MD, predicted at the annual congress of the European Academy of Dermatology and Venereology.

“The time to relapse [off tildrakizumab] is very different from what we are used to with other biologics; for example, the tumor necrosis factor inhibitors,” observed Dr. Thaçi, professor and chairman of the department of dermatology at the University of Lübeck (Germany).

He presented the 148-week, follow-up results of a pooled analysis of the open-label extension studies of reSURFACE 1 and reSURFACE 2, two pivotal phase 3 randomized double-blind international trials of 1,862 patients with moderate to severe chronic plaque psoriasis. The primary outcomes through week 12, which were instrumental in gaining marketing approval for tildrakizumab for treating psoriasis in 2018 from the Food and Drug Administration and the European Medicines Agency, have been published in the Lancet (2017 Jul 15;390[10091]:276-88).

Dr. Thaçi’s analysis of the 148-week outcomes was restricted to the patients who had at least a 75% improvement from baseline in Psoriasis Area and Severity Index scores (PASI 75) at week 28. Nearly 80% of patients on tildrakizumab reached that threshold at week 28 in reSURFACE 1, as did 73% in reSURFACE 2.

The question asked in the extension study was, How do responders to tildrakizumab at 28 weeks fare after nearly 3 years on the drug? And the answer was: very well. Maintenance of at least a PASI 75 response was observed at 148 weeks in 91% of patients on tildrakizumab at the approved 100-mg dose and 92% of those on the 200-mg dose. The FDA-approved regimen is 100 mg by subcutaneous injection at weeks 0 and 4, and then every 12 weeks after that.

An intriguing feature of reSURFACE 1 was that a subset of PASI 75 responders at week 28 got taken off tildrakizumab at that point and switched to double-blind placebo, then restarted on their earlier dose of tildrakizumab upon relapse, which was defined as loss of at least 50% of the achieved on-drug PASI improvement.

At week 64, fully 48 weeks after their last dose of tildrakizumab, the relapse rate was 54% in the group formerly on 100 mg of tildrakizumab and slightly better at 47% in those formerly on 200 mg. The median time to relapse was 226 days in the 100-mg group and 258 days in the higher-dose arm. Those are exceptionally long times to relapse, and it’s useful information to file away in the event a psoriasis patient needs to discontinue biologic therapy for a period of time, Dr. Thaçi observed.

At week 64 – again, off active treatment since week 16 – 63% of the tildrakizumab 100-mg group had lost their previous PASI 75 response, as had 52% who were formerly on tildrakizumab at 200 mg.

The long-term safety profile of tildrakizumab paralleled that of placebo. For example, the exposure-adjusted adverse event rates of serious infections and major adverse cardiovascular events were closely similar in the placebo, tildrakizumab 100 mg, and tildrakizumab 200 mg groups.

There were two notable between-group differences in adverse events of interest: injection site reactions occurred at a rate of 5.36 per 100 person-years with placebo, compared with 1.94 and 2.3 per 100 person-years with tildrakizumab at 100 and 200 mg, respectively; and the incidence of nonmelanoma skin cancer was 0.97 cases per 100 person-years in the placebo arm, versus 0.5 and 0.49 cases per 100 person-years in the two tildrakizumab arms.

Dr. Thaçi did not present PASI 90 response outcomes because, at the time the reSURFACE trials were planned, PASI 75 was considered state of the art. The PASI 90 data are still being crunched but will be available soon. The 4- and 5-year follow-up data from the long-term extension studies are also on their way.

The reSURFACE 1 and reSURFACE 2 trials and their extension studies were funded by Sun Pharma and Merck. Dr. Thaçi reported receiving research grants from and serving as a consultant and paid scientific advisor to those pharmaceutical companies and more than a dozen others.

PARIS – Dermatologists are likely to do a double-take when they see the long-term efficacy and safety data for tildrakizumab (Ilumya), a high-affinity humanized monoclonal antibody targeting interleukin-23 p19, relative to the performance of older and more familiar biologic agents with other targets in psoriasis, Diamant Thaçi, MD, predicted at the annual congress of the European Academy of Dermatology and Venereology.

“The time to relapse [off tildrakizumab] is very different from what we are used to with other biologics; for example, the tumor necrosis factor inhibitors,” observed Dr. Thaçi, professor and chairman of the department of dermatology at the University of Lübeck (Germany).

He presented the 148-week, follow-up results of a pooled analysis of the open-label extension studies of reSURFACE 1 and reSURFACE 2, two pivotal phase 3 randomized double-blind international trials of 1,862 patients with moderate to severe chronic plaque psoriasis. The primary outcomes through week 12, which were instrumental in gaining marketing approval for tildrakizumab for treating psoriasis in 2018 from the Food and Drug Administration and the European Medicines Agency, have been published in the Lancet (2017 Jul 15;390[10091]:276-88).

Dr. Thaçi’s analysis of the 148-week outcomes was restricted to the patients who had at least a 75% improvement from baseline in Psoriasis Area and Severity Index scores (PASI 75) at week 28. Nearly 80% of patients on tildrakizumab reached that threshold at week 28 in reSURFACE 1, as did 73% in reSURFACE 2.

The question asked in the extension study was, How do responders to tildrakizumab at 28 weeks fare after nearly 3 years on the drug? And the answer was: very well. Maintenance of at least a PASI 75 response was observed at 148 weeks in 91% of patients on tildrakizumab at the approved 100-mg dose and 92% of those on the 200-mg dose. The FDA-approved regimen is 100 mg by subcutaneous injection at weeks 0 and 4, and then every 12 weeks after that.

An intriguing feature of reSURFACE 1 was that a subset of PASI 75 responders at week 28 got taken off tildrakizumab at that point and switched to double-blind placebo, then restarted on their earlier dose of tildrakizumab upon relapse, which was defined as loss of at least 50% of the achieved on-drug PASI improvement.

At week 64, fully 48 weeks after their last dose of tildrakizumab, the relapse rate was 54% in the group formerly on 100 mg of tildrakizumab and slightly better at 47% in those formerly on 200 mg. The median time to relapse was 226 days in the 100-mg group and 258 days in the higher-dose arm. Those are exceptionally long times to relapse, and it’s useful information to file away in the event a psoriasis patient needs to discontinue biologic therapy for a period of time, Dr. Thaçi observed.

At week 64 – again, off active treatment since week 16 – 63% of the tildrakizumab 100-mg group had lost their previous PASI 75 response, as had 52% who were formerly on tildrakizumab at 200 mg.

The long-term safety profile of tildrakizumab paralleled that of placebo. For example, the exposure-adjusted adverse event rates of serious infections and major adverse cardiovascular events were closely similar in the placebo, tildrakizumab 100 mg, and tildrakizumab 200 mg groups.

There were two notable between-group differences in adverse events of interest: injection site reactions occurred at a rate of 5.36 per 100 person-years with placebo, compared with 1.94 and 2.3 per 100 person-years with tildrakizumab at 100 and 200 mg, respectively; and the incidence of nonmelanoma skin cancer was 0.97 cases per 100 person-years in the placebo arm, versus 0.5 and 0.49 cases per 100 person-years in the two tildrakizumab arms.

Dr. Thaçi did not present PASI 90 response outcomes because, at the time the reSURFACE trials were planned, PASI 75 was considered state of the art. The PASI 90 data are still being crunched but will be available soon. The 4- and 5-year follow-up data from the long-term extension studies are also on their way.

The reSURFACE 1 and reSURFACE 2 trials and their extension studies were funded by Sun Pharma and Merck. Dr. Thaçi reported receiving research grants from and serving as a consultant and paid scientific advisor to those pharmaceutical companies and more than a dozen others.

PARIS – Dermatologists are likely to do a double-take when they see the long-term efficacy and safety data for tildrakizumab (Ilumya), a high-affinity humanized monoclonal antibody targeting interleukin-23 p19, relative to the performance of older and more familiar biologic agents with other targets in psoriasis, Diamant Thaçi, MD, predicted at the annual congress of the European Academy of Dermatology and Venereology.

“The time to relapse [off tildrakizumab] is very different from what we are used to with other biologics; for example, the tumor necrosis factor inhibitors,” observed Dr. Thaçi, professor and chairman of the department of dermatology at the University of Lübeck (Germany).

He presented the 148-week, follow-up results of a pooled analysis of the open-label extension studies of reSURFACE 1 and reSURFACE 2, two pivotal phase 3 randomized double-blind international trials of 1,862 patients with moderate to severe chronic plaque psoriasis. The primary outcomes through week 12, which were instrumental in gaining marketing approval for tildrakizumab for treating psoriasis in 2018 from the Food and Drug Administration and the European Medicines Agency, have been published in the Lancet (2017 Jul 15;390[10091]:276-88).

Dr. Thaçi’s analysis of the 148-week outcomes was restricted to the patients who had at least a 75% improvement from baseline in Psoriasis Area and Severity Index scores (PASI 75) at week 28. Nearly 80% of patients on tildrakizumab reached that threshold at week 28 in reSURFACE 1, as did 73% in reSURFACE 2.

The question asked in the extension study was, How do responders to tildrakizumab at 28 weeks fare after nearly 3 years on the drug? And the answer was: very well. Maintenance of at least a PASI 75 response was observed at 148 weeks in 91% of patients on tildrakizumab at the approved 100-mg dose and 92% of those on the 200-mg dose. The FDA-approved regimen is 100 mg by subcutaneous injection at weeks 0 and 4, and then every 12 weeks after that.

An intriguing feature of reSURFACE 1 was that a subset of PASI 75 responders at week 28 got taken off tildrakizumab at that point and switched to double-blind placebo, then restarted on their earlier dose of tildrakizumab upon relapse, which was defined as loss of at least 50% of the achieved on-drug PASI improvement.

At week 64, fully 48 weeks after their last dose of tildrakizumab, the relapse rate was 54% in the group formerly on 100 mg of tildrakizumab and slightly better at 47% in those formerly on 200 mg. The median time to relapse was 226 days in the 100-mg group and 258 days in the higher-dose arm. Those are exceptionally long times to relapse, and it’s useful information to file away in the event a psoriasis patient needs to discontinue biologic therapy for a period of time, Dr. Thaçi observed.

At week 64 – again, off active treatment since week 16 – 63% of the tildrakizumab 100-mg group had lost their previous PASI 75 response, as had 52% who were formerly on tildrakizumab at 200 mg.

The long-term safety profile of tildrakizumab paralleled that of placebo. For example, the exposure-adjusted adverse event rates of serious infections and major adverse cardiovascular events were closely similar in the placebo, tildrakizumab 100 mg, and tildrakizumab 200 mg groups.

There were two notable between-group differences in adverse events of interest: injection site reactions occurred at a rate of 5.36 per 100 person-years with placebo, compared with 1.94 and 2.3 per 100 person-years with tildrakizumab at 100 and 200 mg, respectively; and the incidence of nonmelanoma skin cancer was 0.97 cases per 100 person-years in the placebo arm, versus 0.5 and 0.49 cases per 100 person-years in the two tildrakizumab arms.

Dr. Thaçi did not present PASI 90 response outcomes because, at the time the reSURFACE trials were planned, PASI 75 was considered state of the art. The PASI 90 data are still being crunched but will be available soon. The 4- and 5-year follow-up data from the long-term extension studies are also on their way.

The reSURFACE 1 and reSURFACE 2 trials and their extension studies were funded by Sun Pharma and Merck. Dr. Thaçi reported receiving research grants from and serving as a consultant and paid scientific advisor to those pharmaceutical companies and more than a dozen others.

PARIS – Two-thirds of psoriasis patients with stable low disease activity while on full-dose biologic therapy can successfully undergo biologic dose reduction with long-term maintenance of disease control and no adverse consequences, Juul van den Reek, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

She presented the results of the CONDOR trial, the first-ever formal, randomized, controlled trial of tightly regulated dose reduction of biologics, compared with usual care standard-dose therapy. “Our current advice is we think you can try to reduce the dose because there are a lot of patients who benefit from this,” declared Dr. van den Reek, a dermatologist at Radboud University, Nijmegen, the Netherlands.

The advantages of this strategy are twofold: lower expenditures for this costly collection of medications and less exposure to any long-term, drug-related health risks, she noted.

CONDOR was a Dutch six-center, 12-month, open-label, unblinded, noninferiority, randomized trial including 111 patients. Participants had to have stable low disease activity as defined by both Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores of 5 or less for at least 6 months while on standard-dose etanercept (Enbrel), adalimumab (Humira), or ustekinumab (Stelara) prior to enrollment. In fact, the average baseline PASI score was less than 2, with a DLQI of 0.

Participants were randomized to usual care – the customary approved dose of biologic therapy – or a drop down to 67% of that dose, achieved through prolongation of the dosing interval. If the reduced-dose patients kept their PASI and DLQI scores at 5 or less for 3 months straight, they dropped further to 50% of their original dose. However, patients who exceeded those thresholds were immediately returned to their previously effective dose.


The primary endpoint in this noninferiority trial was the difference in mean PASI scores between the dose-reduction and usual-care groups at 12 months. The prespecified margin for noninferiority was a difference of 0.5 PASI points. And that’s where the results get dicey: The mean difference turned out to be 1.1 PASI points in favor of usual care, meaning that, according to the study ground rules, dose reduction was not statistically noninferior. In hindsight, however, that 0.5-point margin was ill-considered and too narrowly defined.

“Within the chosen margins, the dose-reduction strategy seemed inferior. But what is the clinical relevance of a mean difference of 1.1 PASI points, when the accepted minimal clinically important difference is 3.2 points?” Dr. van den Reek observed.

There was no significant between-group difference in DLQI scores at 12 months. Nor did the two study arms differ in terms of the prespecified secondary endpoint of persistent disease flares as defined by a PASI or DLQI greater than 5 for 3 consecutive months: five patients in the reduced-dose group and three in the usual-care arm experienced such flares. There were no serious adverse events or other safety signals related to the intervention.

At 12 months, 50% of patients in the dose-reduction group were well maintained on 50% of their original approved-dose biologic and another 17% were doing well on 67% of their former dose.

Session chair Dedee Murrell, MD, professor of dermatology at the University of New South Wales, Sydney, noted that neither patients nor dermatologists were blinded as to treatment status in CONDOR. She then asked the question on everybody’s minds: Was there any loss of treatment efficacy when patients in the dose-reduction arm needed to resume higher-dose therapy?

No, Dr. van den Reek replied. She added that planned future CONDOR analyses include a cost-effectiveness determination as well as measurement of serum drug levels and identification of antidrug antibodies, information that might prove helpful in identifying an enriched population of patients most likely to respond favorably to biologic dose reduction. In addition, CONDOR-X, a long-term extension study, is ongoing in order to learn how patients on reduced-dose biologics fare after the 12-month mark.

The CONDOR trial was funded by the Netherlands Organization for Health Research and Development; Dr. van den Reek reported having no financial conflicts of interest.

bjancin@mdedge.com

PARIS – Two-thirds of psoriasis patients with stable low disease activity while on full-dose biologic therapy can successfully undergo biologic dose reduction with long-term maintenance of disease control and no adverse consequences, Juul van den Reek, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

She presented the results of the CONDOR trial, the first-ever formal, randomized, controlled trial of tightly regulated dose reduction of biologics, compared with usual care standard-dose therapy. “Our current advice is we think you can try to reduce the dose because there are a lot of patients who benefit from this,” declared Dr. van den Reek, a dermatologist at Radboud University, Nijmegen, the Netherlands.

The advantages of this strategy are twofold: lower expenditures for this costly collection of medications and less exposure to any long-term, drug-related health risks, she noted.

CONDOR was a Dutch six-center, 12-month, open-label, unblinded, noninferiority, randomized trial including 111 patients. Participants had to have stable low disease activity as defined by both Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores of 5 or less for at least 6 months while on standard-dose etanercept (Enbrel), adalimumab (Humira), or ustekinumab (Stelara) prior to enrollment. In fact, the average baseline PASI score was less than 2, with a DLQI of 0.

Participants were randomized to usual care – the customary approved dose of biologic therapy – or a drop down to 67% of that dose, achieved through prolongation of the dosing interval. If the reduced-dose patients kept their PASI and DLQI scores at 5 or less for 3 months straight, they dropped further to 50% of their original dose. However, patients who exceeded those thresholds were immediately returned to their previously effective dose.


The primary endpoint in this noninferiority trial was the difference in mean PASI scores between the dose-reduction and usual-care groups at 12 months. The prespecified margin for noninferiority was a difference of 0.5 PASI points. And that’s where the results get dicey: The mean difference turned out to be 1.1 PASI points in favor of usual care, meaning that, according to the study ground rules, dose reduction was not statistically noninferior. In hindsight, however, that 0.5-point margin was ill-considered and too narrowly defined.

“Within the chosen margins, the dose-reduction strategy seemed inferior. But what is the clinical relevance of a mean difference of 1.1 PASI points, when the accepted minimal clinically important difference is 3.2 points?” Dr. van den Reek observed.

There was no significant between-group difference in DLQI scores at 12 months. Nor did the two study arms differ in terms of the prespecified secondary endpoint of persistent disease flares as defined by a PASI or DLQI greater than 5 for 3 consecutive months: five patients in the reduced-dose group and three in the usual-care arm experienced such flares. There were no serious adverse events or other safety signals related to the intervention.

At 12 months, 50% of patients in the dose-reduction group were well maintained on 50% of their original approved-dose biologic and another 17% were doing well on 67% of their former dose.

Session chair Dedee Murrell, MD, professor of dermatology at the University of New South Wales, Sydney, noted that neither patients nor dermatologists were blinded as to treatment status in CONDOR. She then asked the question on everybody’s minds: Was there any loss of treatment efficacy when patients in the dose-reduction arm needed to resume higher-dose therapy?

No, Dr. van den Reek replied. She added that planned future CONDOR analyses include a cost-effectiveness determination as well as measurement of serum drug levels and identification of antidrug antibodies, information that might prove helpful in identifying an enriched population of patients most likely to respond favorably to biologic dose reduction. In addition, CONDOR-X, a long-term extension study, is ongoing in order to learn how patients on reduced-dose biologics fare after the 12-month mark.

The CONDOR trial was funded by the Netherlands Organization for Health Research and Development; Dr. van den Reek reported having no financial conflicts of interest.

bjancin@mdedge.com

PARIS – Two-thirds of psoriasis patients with stable low disease activity while on full-dose biologic therapy can successfully undergo biologic dose reduction with long-term maintenance of disease control and no adverse consequences, Juul van den Reek, MD, PhD, reported at the annual congress of the European Academy of Dermatology and Venereology.

Bruce Jancin/MDedge News

She presented the results of the CONDOR trial, the first-ever formal, randomized, controlled trial of tightly regulated dose reduction of biologics, compared with usual care standard-dose therapy. “Our current advice is we think you can try to reduce the dose because there are a lot of patients who benefit from this,” declared Dr. van den Reek, a dermatologist at Radboud University, Nijmegen, the Netherlands.

The advantages of this strategy are twofold: lower expenditures for this costly collection of medications and less exposure to any long-term, drug-related health risks, she noted.

CONDOR was a Dutch six-center, 12-month, open-label, unblinded, noninferiority, randomized trial including 111 patients. Participants had to have stable low disease activity as defined by both Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores of 5 or less for at least 6 months while on standard-dose etanercept (Enbrel), adalimumab (Humira), or ustekinumab (Stelara) prior to enrollment. In fact, the average baseline PASI score was less than 2, with a DLQI of 0.

Participants were randomized to usual care – the customary approved dose of biologic therapy – or a drop down to 67% of that dose, achieved through prolongation of the dosing interval. If the reduced-dose patients kept their PASI and DLQI scores at 5 or less for 3 months straight, they dropped further to 50% of their original dose. However, patients who exceeded those thresholds were immediately returned to their previously effective dose.


The primary endpoint in this noninferiority trial was the difference in mean PASI scores between the dose-reduction and usual-care groups at 12 months. The prespecified margin for noninferiority was a difference of 0.5 PASI points. And that’s where the results get dicey: The mean difference turned out to be 1.1 PASI points in favor of usual care, meaning that, according to the study ground rules, dose reduction was not statistically noninferior. In hindsight, however, that 0.5-point margin was ill-considered and too narrowly defined.

“Within the chosen margins, the dose-reduction strategy seemed inferior. But what is the clinical relevance of a mean difference of 1.1 PASI points, when the accepted minimal clinically important difference is 3.2 points?” Dr. van den Reek observed.

There was no significant between-group difference in DLQI scores at 12 months. Nor did the two study arms differ in terms of the prespecified secondary endpoint of persistent disease flares as defined by a PASI or DLQI greater than 5 for 3 consecutive months: five patients in the reduced-dose group and three in the usual-care arm experienced such flares. There were no serious adverse events or other safety signals related to the intervention.

At 12 months, 50% of patients in the dose-reduction group were well maintained on 50% of their original approved-dose biologic and another 17% were doing well on 67% of their former dose.

Session chair Dedee Murrell, MD, professor of dermatology at the University of New South Wales, Sydney, noted that neither patients nor dermatologists were blinded as to treatment status in CONDOR. She then asked the question on everybody’s minds: Was there any loss of treatment efficacy when patients in the dose-reduction arm needed to resume higher-dose therapy?

No, Dr. van den Reek replied. She added that planned future CONDOR analyses include a cost-effectiveness determination as well as measurement of serum drug levels and identification of antidrug antibodies, information that might prove helpful in identifying an enriched population of patients most likely to respond favorably to biologic dose reduction. In addition, CONDOR-X, a long-term extension study, is ongoing in order to learn how patients on reduced-dose biologics fare after the 12-month mark.

The CONDOR trial was funded by the Netherlands Organization for Health Research and Development; Dr. van den Reek reported having no financial conflicts of interest.

bjancin@mdedge.com