A Review of the Diagnostic and Therapeutic Gaps in Rosacea Management: Consensus Opinion.

Rosacea is a common, chronic inflammatory disease characterized by both fluctuating and fixed heterogeneous signs such as facial erythema, papules/pustules, telangiectasia, acute vasodilation (flushing), and phymatous changes, and symptoms such as cutaneous stinging and burning. The shift to a phenotype-based approach to rosacea management has improved the consistency of recommendations across recent published guidelines. Consistent and thorough guidance for the classification, diagnosis, and management of the disease is difficult, as the mechanisms underlying the development of rosacea are still not completely understood nor universally accepted. Here, we provide a critical review of current published guidance, and gaps in the knowledge and management of rosacea. We present the recently approved microencapsulated benzoyl peroxide as an effective topical treatment option for papulopustular rosacea. Benzoyl peroxide (BPO) has been used in acne management for many years; however, many clinicians perceive treatment of rosacea with any BPO formulation to be counterintuitive because of concerns of potential skin irritation, while the lack of an accepted mechanism of action on rosacea pathophysiology means that others may be hesitant to use BPO as a treatment. Minocycline foam 1.5% is also an option for the treatment of inflammatory lesions in rosacea, with a decreased risk of systemic adverse events compared with oral minocycline.

Stasis Dermatitis: The Burden of Disease, Diagnosis, and Treatment.

Stasis dermatitis (SD), an inflammatory dermatosis occurring on the lower extremities, is a cutaneous manifestation of chronic venous insufficiency (CVI). SD is associated with a significant burden of disease. Symptoms such as pain, swelling, and itching can be debilitating for patients, leading to poor sleep, loss of mobility, and the inability to perform daily activities, and can interfere with work and leisure activities. Moreover, SD is a progressive disease with serious secondary complications such as ulcerations, which increase the patients' morbidity, reduce their quality of life, and increase health care burden. Challenges in diagnosing patients may have both short- and long-term sequalae for the patients due to unnecessary treatment and management. In addition, misdiagnosis may result in hospitalizations, placing additional burden on health care professionals in terms of time and financial burden on the health care system. Compression therapy and leg elevation represent the mainstay of treatment for CVI; however, it is also difficult to self-manage, which places a substantial burden on patients and caregivers. Moreover, compression therapy may cause discomfort and exacerbate itching. Subsequent nonadherence may result in disease progression that places additional burden on the physicians who manage these patients and the health care system in terms of resources required and costs incurred. A large proportion of patients with SD develop allergic contact dermatitis because of innate immune signals and altered skin barrier predisposing to sensitization to topical prescriptions, over-the-counter medications, and compression devices used to treat SD. Other than topical corticosteroids, there are no approved pharmacological options to treat inflammation in SD.

Narrative Review of the Pathogenesis of Stasis Dermatitis: An Inflammatory Skin Manifestation of Venous Hypertension.

INTRODUCTION: Stasis dermatitis (SD), also known as venous dermatitis, is a form of inflammatory dermatitis of the lower extremities that typically occurs in older individuals and represents a cutaneous manifestation of venous hypertension. Venous hypertension (also known as sustained ambulatory venous pressure) is most often due to retrograde blood flow, which occurs due to calf muscle pump failure. This failure is most commonly secondary to incompetent venous valves, valve destruction, or obstruction of the venous system. Many of the common symptoms associated with SD are caused by inflammatory processes. METHODS: This review summarizes the pathogenesis and key role of inflammation in SD by reviewing inflammatory biomarkers associated with SD. The literature was selected though a high-level PubMed search focusing on keywords relating to inflammation associated with SD. RESULTS: Venous reflux at the lower extremities causes venous hypertension, which leads to chronic venous insufficiency. High venous pressure due to venous hypertension promotes the local accumulation and extravasation of inflammatory cells across the vascular endothelium. Leukocyte trapping in the microcirculation and perivascular space is associated with trophic skin changes. Cell adhesion molecules are linked with the perpetuated influx of activated leukocytes into inflammatory sites. Here, inflammatory cells may influence the remodeling of the extracellular matrix by inducing the secretion of proteinases such as matrix metalloproteinases (MMPs). The increased expression of MMPs is associated with the formation of venous leg ulcers and lesions. Phosphodiesterase 4 activity has also been shown to be elevated in individuals with inflammatory dermatoses compared to healthy individuals. DISCUSSION: Because inflammation is a key driver of the signs and symptoms of SD, several of the highlighted biomarkers of inflammation represent potential opportunities to target and interrupt molecular pathways of cutaneous inflammation and, therefore, remediate the signs and symptoms of SD. CONCLUSION: Understanding the pathogenesis of SD may help clinicians identify drivers of inflammation to use as potential targets for the development of new treatment options.

Stasis dermatitis is a skin disease that affects the legs, most often of older people, with chronic venous insufficiency. Chronic venous insufficiency is when veins cannot return blood from the legs back to the heart. This leads to high blood pressure in veins and causes blood in those veins to flow backwards. If stasis dermatitis is left untreated, complications, including skin ulcers, can result. Other skin symptoms of stasis dermatitis include itchiness, scaling, and discoloration. Such skin symptoms can have a negative effect on a person's quality of life. Inflammation that lasts a long time is likely the main link between the skin changes seen in people with stasis dermatitis and the increased pressure in leg veins. Several molecules are associated with the inflammation observed in stasis dermatitis, including white blood cells, matrix metalloproteinases, phosphodiesterase 4, and interleukin-31. Treatment for stasis dermatitis should focus both on the underlying chronic venous insufficiency and the associated skin issues. Identifying inflammatory markers and pathways could help treat the signs and symptoms associated with stasis dermatitis, including the skin symptoms.

Unmet needs for patients with seborrheic dermatitis.

Seborrheic dermatitis (SD) is a common skin disease with signs and symptoms that may vary by skin color, associated medical conditions, environmental factors, and vehicle preference. Diagnosis of SD is based on presence of flaky, "greasy" patches, and/or thin plaques accompanied by erythema of the scalp, face, ears, chest, and groin and is associated with pruritus in many patients. The presentation may vary in different skin types and hyper- or hypopigmentation may occur, with or without erythema and minimal or no scaling. While the pathogenesis is not certain, 3 key factors generally agreed upon include lipid secretion by sebaceous glands, Malassezia spp. colonization, and some form of immunologic dysregulation that predisposes the patient to SD. Treatment involves reducing proliferation of, and inflammatory response to, Malassezia spp. Topical therapies, including antifungal agents and low potency corticosteroids, are the mainstay of treatment but may be limited by efficacy and side effects. Few novel treatments for SD are currently being studied; however, clinical trials assessing the use of topical phosphodiesterase-4 inhibitors have been completed. Improving outcomes in SD requires recognizing patient-specific manifestations/locations of the disease, including increased awareness of how it affects people of all skin types.

Evaluation of a First-in-Class Proteasome Inhibitor in Patients With Moderate to Severe Rosacea.

BACKGROUND: Novel, effective, affordable therapies for rosacea are needed. Innovative methods of assessing response for rosacea treatments are needed as well. This trial was designed to evaluate efficacy and safety of ACU-D1, a novel inhibitor of the 26S protea-some for the treatment of moderate to severe rosacea in a first in human pilot study. In addition, this is the first trial to our knowledge to use Canfield imaging to quantitatively assess responses. METHODS: This was a 14-week, randomized, double-blinded, placebo-controlled study, performed at two well established rosacea clini-cal trial sites, which randomized 40 adult subjects with moderate to severe rosacea (Investigator’s Global Assessment [IGA]=3/4) to either ACU-D1 (27) or comparator vehicle (13) twice daily. In addition, Canfield imaging was used to assess responses both qualitatively and quantitatively Results: A total of 39 subjects participated, with 38 completing the study. ACU-D1 displayed efficacy in 92% (25 of 27) of patients in reducing inflammatory lesions and a 2 plus grade IGA reduction of clear to near clear in 27% of patients. There was a trend toward improvement in erythema as well in the active arm. CONCLUSION: This study demonstrates that topical ACU-D1 is safe and well-tolerated by patients in the study and demonstrates efficacy in reducing inflammatory lesions and erythema in patients with rosacea. Improvement was also noted on Canfield imaging, and this modality is likely to be used as an objective measure in the future. Further studies are warranted based on these initial positive results. ClinicalTrials.gov Identifier: NCT03064438 J Drugs Dermatol. 2021;20(6):660-664. doi:10.36849/JDD.5925.

Treating Inflammation in Rosacea: Current Options and Unmet Needs.

Rosacea is a disease resulting from dysregulation of innate, adaptive, and neurovascular immune systems. Inflammatory pathways activated in rosacea can explain many of its signs and symptoms. Current treatments address some of these inflammatory processes, alleviating erythema and decreasing papules and pustules. However, for the majority of patients, complete clearance of these features is not currently achievable even with combination therapy. There is a need to address the spectrum of inflammatory processes involved in rosacea and for more efficacious agents with the goal of providing complete clearance for patients. J Drugs Dermatol. 2020;19(6): doi:10.36849/JDD.2020.5187.

A randomized phase 3b/4 study to evaluate concomitant use of topical ivermectin 1% cream and doxycycline 40-mg modified-release capsules, versus topical ivermectin 1% cream and placebo in the treatment of severe rosacea.

BACKGROUND: Randomized controlled studies of combination therapies in rosacea are limited. OBJECTIVE: Evaluate the efficacy and safety of combining ivermectin 1% cream (IVM) and doxycycline 40-mg modified-release capsules (ie, 30-mg immediate-release and 10-mg delayed-release beads) (DMR) versus IVM and placebo for treatment of severe rosacea. METHODS: This 12-week, multicenter, randomized, investigator-blinded, parallel-group comparative study randomized adult subjects with severe rosacea (Investigator's Global Assessment [IGA] score, 4) to receive either IVM and DMR (combination arm) or IVM and placebo (monotherapy). RESULTS: A total of 273 subjects participated. IVM and DMR displayed superior efficacy in reduction of inflammatory lesions (-80.3% vs -73.6% for monotherapy [P = .032]) and IGA score (P = .032). Combination therapy had a faster onset of action as of week 4; it significantly increased the number of subjects achieving an IGA score of 0 (11.9% vs 5.1% [P = .043]) and 100% lesion reduction (17.8% vs 7.2% [P = .006]) at week 12. Both treatments reduced the Clinician's Erythema Assessment score, stinging/burning, flushing episodes, Dermatology Life Quality Index score, and ocular signs/symptoms and were well tolerated. LIMITATIONS: The duration of the study prevented evaluation of potential recurrences or further improvements. CONCLUSION: Combining IVM and DMR can produce faster responses, improve response rates, and increase patient satisfaction in cases of severe rosacea.

Efficacy and Safety of Apremilast in Systemic- and Biologic-Naive Patients With Moderate Plaque Psoriasis: 52-Week Results of UNVEIL.

BACKGROUND: Many patients with moderate plaque psoriasis are undertreated despite broadening treatment options. In the phase IV UNVEIL study, oral apremilast demonstrated efficacy and safety in systemic-naive patients with chronic moderate plaque psoriasis with lower psoriasis-involved body surface area (BSA; 5%-10%) during the 16-week, double-blind, placebo-controlled phase. We describe efficacy and safety of apremilast in this population through week 52 in UNVEIL.

METHODS: Patients with moderate plaque psoriasis (BSA 5%-10%; static Physician's Global Assessment [sPGA] score of 3 [moderate]) and naive to systemic therapies for psoriasis were randomized (2:1) to receive apremilast 30 mg twice daily or placebo for 16 weeks. At week 16, patients continued on apremilast (apremilast/apremilast) or were switched from placebo to apremilast (placebo/apremilast) through week 52 (open-label apremilast treatment phase). Efficacy assessments included the product of sPGA and BSA (PGAxBSA) (mean percentage change from baseline; ≥75% reduction from baseline [PGAxBSA-75]), sPGA response (achievement of score of 0 [clear] or 1 [almost clear]), and the Dermatology Life Quality Index (DLQI; mean change from baseline).

RESULTS: A total of 136 patients completed the 52-week analysis period (placebo/apremilast, n=50/64; apremilast/apremilast, n=86/121). At week 52, improvements in all efficacy end points observed at week 16 were maintained in the apremilast/apremilast group (mean percentage change from baseline in PGAxBSA: -55.5%; PGAxBSA-75: 42.1%; sPGA response: 33.1%; mean change from baseline in DLQI score: -4.4); similar improvements emerged in the placebo/apremilast group after switching to apremilast. The most common adverse events (≥5% of patients) through week 52 were diarrhea (28.0%), nausea (19.0%), headache (15.2%), nasopharyngitis (10.4%), upper respiratory tract infection (7.1%), vomiting (5.7%), and decreased appetite (5.2%).

CONCLUSIONS: Apremilast was effective in systemic-naive patients with moderate plaque psoriasis with BSA 5%-10%; efficacy was sustained through week 52. No new safety signals emerged with continued apremilast exposure.

ClinicalTrials.gov: NCT02425826

J Drugs Dermatol. 2018;17(2):221-228.

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DFD-01 Reduces Transepidermal Water Loss and Improves Skin Hydration and Flexibility.

INTRODUCTION: In plaque psoriasis, the benefit of topical steroids is well established. The vehicle formulation of topical steroids may also provide benefit in addition to the effects of the steroid itself. DFD-01 (betamethasone dipropionate spray, 0.05%) is a formulation composed of a topical steroid in an emollient-like vehicle that enhances penetration to the target site of inflammation in the skin. The aim of this study was to assess the effect of DFD-01 and its vehicle on skin hydration and barrier function in compromised skin and to evaluate its effect on flexibility in healthy skin. METHODS: Eighteen healthy white volunteers were enrolled in each of two studies. In Study 1, dry shaving of volar forearms created a compromised skin barrier, through which transepidermal water loss (TEWL) was measured using an evaporimeter. Capacitance, a measure of epidermal hydration, was also measured at baseline and at 1, 2 and 4 h after application of DFD-01 or its vehicle formulation. In Study 2, intact skin flexibility was tested with a cutometer before and at 1, 2 and 4 h after application of DFD-01 or vehicle. RESULTS: In Study 1, both DFD-01 and its vehicle were effective at reducing TEWL through the compromised stratum corneum. Capacitance measurements confirmed this finding; razor-chafed skin treated with either DFD-01 or vehicle exhibited levels of skin hydration similar to unshaved control skin. Study 2 found softening and greater flexibility of normal skin treated with either DFD-01 or vehicle compared with nontreated control skin samples. CONCLUSIONS: These tests suggest that the DFD-01 formulation and its vehicle are each effective at retaining moisture within a damaged skin barrier and for softening and increasing the flexibility of intact skin. FUNDING: Dr. Reddy's Laboratories.

Efficacy and Safety of Apremilast in Patients With Moderate Plaque Psoriasis With Lower BSA: Week 16 Results from the UNVEIL Study.

INTRODUCTION: Many options are available for patients with moderate to severe plaque psoriasis. Patients with moderate disease, however, are often undertreated and do not achieve satisfactory clearance. UNVEIL (NCT02425826) assessed efficacy and safety of apremilast in patients with chronic moderate plaque psoriasis.

METHODS: Patients with psoriasis body surface area (BSA) 5% to 10% and static Physician's Global Assessment (sPGA) score of 3 (moderate) without prior exposure to systemics were randomized (2:1) to apremilast 30 mg twice daily or placebo for 16 weeks. The primary efficacy endpoint was mean percentage change in the product of sPGA and BSA scores (PGAxBSA).

RESULTS: Of 221 patients (placebo, n=73; apremilast, n=148), >80% had received prior topical therapy. At week 16, apremilast yielded a significantly greater percentage change from baseline in PGAxBSA (-48.1%) vs placebo (-10.2^; P less than 0.0001). Dermatology Life Quality Index scores were significantly improved with apremilast (-4.8) vs placebo (-2.4; P=0.0008). Mean improvements in the Treatment Satisfaction Questionnaire for Medication, version II, were greater with apremilast vs placebo for global satisfaction (63.2 vs 48.7; P less than 0.0001) and treatment effectiveness (57.3 vs 38.8; P less than 0.0001). Most adverse events were mild or moderate; most common were diarrhea, headache, nausea, upper respiratory tract infection, decreased appetite, and vomiting.

CONCLUSION: Apremilast was effective and well tolerated, significantly improved quality of life, and was associated with high patient satisfaction in systemic-naive, post-topical patients with moderate plaque psoriasis.

ClinicalTrials.gov: NCT02425826

J Drugs Dermatol. 2017;16(8):801-808.

Defining treatment success in rosacea as 'clear' may provide multiple patient benefits: results of a pooled analysis.

BACKGROUND: Rosacea treatment success is usually defined as a score of 1 ('almost clear') or 0 ('clear') on the 5-point Investigator Global Assessment (IGA) scale. OBJECTIVE: To evaluate whether, after successful treatment, 'clear' subjects had better outcomes than 'almost clear' subjects. METHODS: A pooled analysis was performed on 1366 rosacea subjects from four randomized controlled trials with IGA before and after treatment (ivermectin, metronidazole or vehicle). Assessments included the Dermatology Life Quality Index (DLQI) questionnaire and subject assessment of rosacea improvement. In one trial, patients were followed after the treatment period to measure time to relapse (IGA score ≥2). RESULTS: At end of treatment, more 'clear' than 'almost clear' subjects had a clinically meaningful difference in DLQI (59% vs. 44%; p < .001) and a final DLQI score of 0-1 indicating no effect on quality of life (84% vs. 66%; p < .001). More 'clear' subjects reported an 'excellent' improvement in their rosacea (77% vs. 42%; p < .001). The median time to relapse was more than 8 months for 'clear' vs. 3 months for 'almost clear' subjects (p < .0001). CONCLUSIONS: Achieving an endpoint of 'clear' (IGA 0) vs. 'almost clear' (IGA 1) is associated with multiple positive patient outcomes, including delayed time to relapse.

Improvement in Extensive Moderate Plaque Psoriasis With a Novel Emollient Spray Formulation of Betamethasone Dipropionate 0.05.

BACKGROUND: A novel formulation of 0.05% betamethasone dipropionate in an emollient spray vehicle (DFD-01) was developed to deliver steroid to the skin layers most affected by psoriasis. OBJECTIVE: To compare the efficacy and safety of DFD-01 to its vehicle for the treatment of moderate plaque psoriasis over 4 weeks. METHODS: Two Phase 3 trials enrolled adults with moderate psoriasis (Investigator Global Assessment [IGA]=3; 10-20% body surface area [BSA]) and randomized them 2:1 to DFD-01 or Vehicle. Products were applied twice daily to affected areas for 28 days. Treatment success was defined as an IGA=0 or 1 and ≥ 2-grade improvement from baseline. Primary endpoint was the proportion of subjects achieving treatment success at day 15. RESULTS: Moderate psoriasis subjects were enrolled in Study 1 (174 DFD-01; 87 Vehicle) and Study 2 (182 DFD-01; 95 Vehicle). Mean BSA was 13-14%. Treatment success was achieved in significantly more subjects using DFD-01 than Vehicle at day 15 in both Study 1 (P<0.001) and Study 2 (P=0.002), and at day 29 (both studies P<0.001). Treatment success with DFD-01 was significant at day 8 in Study 1 (P=0.003) but not in Study 2 (P=0.156). Erythema, scaling, and plaque elevation scores of target lesions were significantly reduced as early as day 4 with DFD-01. Adverse events were similar between groups, with no increase between 2 and 4 weeks. CONCLUSION: These studies demonstrate DFD-01's excellent efficacy and safety for the treatment of extensive psoriasis (10-20% BSA). DFD-01 achieved treatment success in significantly more subjects than Vehicle after 2 and 4 weeks of treatment, and showed early onset of action with improved signs of erythema, scaling and elevation of target lesions after 4 days of treatment. This medium potency formulation provides a safe and effective choice for topical steroid treatment of psoriasis.

The spectrum of nephrocutaneous diseases and associations: Genetic causes of nephrocutaneous disease.

There are a significant number of diseases and treatment considerations of considerable importance relating to the skin and renal systems. This emphasizes the need for dermatologists in practice or in clinical training to be aware of these associations. Part I of this 2-part continuing medical education article reviews the genetic syndromes with both renal and cutaneous involvement that are most important for the dermatologist to be able to identify, manage, and appropriately refer to nephrology colleagues. Part II reviews the inflammatory syndromes with relevant renal manifestations and therapeutic agents commonly used by dermatologists that have drug-induced effects on or require close consideration of renal function. In addition, we will likewise review therapeutic agents commonly used by nephrologists that have drug-induced effects on the skin that dermatologists are likely to encounter in clinical practice. In both parts of this continuing medical education article, we discuss diagnosis, management, and appropriate referral to our nephrology colleagues in the context of each nephrocutaneous association. There are a significant number of dermatoses associated with renal abnormalities and disease, emphasizing the need for dermatologists to be keenly aware of their presence in order to avoid overlooking important skin conditions with potentially devastating renal complications. This review discusses important nephrocutaneous disease associations with recommendations for the appropriate urgency of referral to nephrology colleagues for diagnosis, surveillance, and early management of potential renal sequelae.

The spectrum of nephrocutaneous diseases and associations: Inflammatory and medication-related nephrocutaneous associations.

There are a significant number of dermatoses associated with renal abnormalities and disease, and dermatologists need to be keenly aware of their presence in order to avoid overlooking important skin conditions with potentially devastating renal complications. This review discusses important nephrocutaneous disease associations and recommendations for the appropriate urgency of referral to nephrology colleagues for diagnosis, surveillance, and early management of potential renal sequelae. Part II of this 2-part continuing medical education article addresses inflammatory and medication-related nephrocutaneous associations.

The role of brimonidine tartrate gel in the treatment of rosacea.

Rosacea is a chronic cutaneous condition with a prevalence rate ranging from 9.6% to 22% in recent studies. Facial erythema (transient and permanent) is considered a common denominator that is frequently observed in all subtypes of rosacea and is estimated to affect more than 40 million people worldwide. Brimonidine tartrate is a selective α2-adrenergic receptor agonist and is the first topical treatment approved for facial erythema of rosacea. Clinical trials have demonstrated that brimonidine tartrate provided significantly greater efficacy, compared to vehicle, for the treatment of moderate to severe erythema of rosacea. In addition, brimonidine tartrate has demonstrated a rapid onset of effect, duration of action throughout the day, and good safety profile in studies of up to 1 year. This review critically discusses the role of brimonidine tartrate for the treatment of facial erythema of rosacea by examining both clinical study data and real-world dermatologist experiences across a wide spectrum of treated patients, and concludes that it is a significant therapeutic option in the management of an unmet need of this chronic condition.

Current Understanding of Seborrheic Keratosis: Prevalence, Etiology, Clinical Presentation, Diagnosis, and Management.

Seborrheic keratosis (SK) is among the most common cutaneous lesions, affecting some 83 million Americans. Biologically benign, SK lesions do not require removal for medical reasons unless histologic confirmation of the clinical diagnosis is required or the lesions are traumatized and/or become symptomatic. These macular or popular pigmented lesions are often of cosmetic concern to patients. In addition, their natural history of gradually increasing in size, thickness, and/or pigmentation often serves as the impetus compelling patients to present to a dermatologist for evaluation and skin cancer screening; SK is diagnosed and managed primarily by dermatologists. Data regarding SK prevalence and management from a survey of 594 practicing, board-certified dermatologists are summarized herein: Dermatologists report they diagnose an average of 155 patients per month with SK. Among SK patients presenting to dermatologists, 33% have more than 15 SK lesions and 67% have 15 or fewer SK lesions. On average, dermatologists treat 43% of their SK patients to remove lesions. Cryosurgery is the most common removal method. Other commonly employed removal methods include shave excision, electrodessication, curettage or a combination of these. While these procedures can be used to remove SK lesions effectively, each has potential drawbacks and careful patient selection is required to optimize cosmetic results particularly in skin of color patients and patients with thick or numerous lesions. While there is great interest from both patients and providers in a topical non-invasive treatment for SK, no effective topical therapeutic agent has been developed, and this remains an area of unmet need.

Optimizing the use of topical brimonidine in rosacea management: panel recommendations.

Rosacea is a chronic inflammatory disease with a complex pathophysiology that manifests with central facial redness with or without papulopustular lesions. Often, patients with rosacea present with a constellation of signs and symptoms; for best results, the treatment plan should take into account all symptoms manifesting in the individual patient. The first available pharmacologic treatment to address the redness associated with rosacea is topical brimonidine. In the United States, brimonidine topical gel 0.33% is indicated for persistent facial erythema of rosacea; approval was based on clinically significant efficacy and good safety data from large-scale clinical trials. Use of brimonidine in routine clinical practice has yielded new insights that elaborate on the findings from clinical trials. For example, real-world use has shown that a percentage of patients (in our experience, approximately 10 to 20%) treated with brimonidine experience a worsening of erythema that has been called "rebound." Our routine use of this agent for >1 year has yielded strategies to set patient expectations, optimize treatment initiation, and minimize potential problems; this article details those strategies. Because we believe that the term "rebound" has been used to describe several physiologically distinct events, we have also proposed more specific terminology for such events.

Improvement in facial erythema within 30 minutes of initial application of brimonidine tartrate in patients with rosacea.

BACKGROUND: Brimonidine tartrate (BT) 0.5% gel demonstrated significantly greater efficacy versus vehicle gel once-daily for the treatment of moderate to severe erythema of rosacea. OBJECTIVES: To assess the 30-minute speed of onset of topical BT 0.5% gel in reducing facial erythema in Phase III studies as measured by subject and clinician assessments of erythema. METHODS: Two Phase III, randomized, controlled studies with identical design in which subjects with moderate erythema of rosacea (study A: n=260; study B: n=293) were randomized 1:1 to apply topical BT 0.5% or vehicle gel once-daily for 4 weeks. Evaluations included severity of erythema based on Clinician's Erythema Assessment (CEA) and Patient's Self-Assessment (PSA) prior to study drug application and at 30 minutes after application on days 1, 15, and 29. RESULTS: 97.7% and 96.6% of subjects reported normal study completion for studies A and B, respectively. The percentage of subjects achieving a 1-grade improvement in both CEA and PSA was significantly increased at 30 minutes post-dosing with BT 0.5% gel compared to vehicle gel on visit days (day 1: 27.9 vs 6.9%, P <0.001; day 15: 55.9 vs 21.1%, P <0.001; Day 29: 58.3 vs 32.0%, P <0.001 for BT 0.5% gel vs vehicle) in study A. Similar results were shown for study B. CONCLUSIONS: Once-daily topical BT gel 0.5% is not only efficacious at reducing facial erythema but also exhibits response within 30 minutes of application in a significant number of patients throughout both Phase III studies.