Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial.

BACKGROUND: Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin-13, a key driver of atopic dermatitis (AD). OBJECTIVES: To evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate-to-severe AD who were candidates for systemic therapy. METHODS: This was a double-blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator's Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks. RESULTS: At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% [difference (95% confidence interval): 12·4% (2·9-21·9); P = 0·015] and EASI 75: 56·0% vs. 35·7% [20·2% (9·8-30·6); P < 0·001]. Of the patients who were tralokinumab responders at week 16, 89·6% and 92·5% of those treated with tralokinumab Q2W and 77·6% and 90·8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30·5% and 55·8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events was similar across treatment groups. CONCLUSIONS: Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate-to-severe AD.

Adalimumab for nail psoriasis: efficacy and safety over 52 weeks from a phase-3, randomized, placebo-controlled trial.

BACKGROUND: Few clinical trials have evaluated long-term treatment of nail psoriasis with biologics. OBJECTIVE: Safety and efficacy of adalimumab [ADA; Humira AbbVie Inc, North Chicago, IL, USA)] long-term treatment (52 weeks) was evaluated in a phase-3, randomized trial in patients with moderate-to-severe plaque psoriasis and concomitant moderate-to-severe fingernail psoriasis. Results from the first 26 weeks (Period A) have been reported. METHODS: Patients receiving 40 mg ADA every other week or placebo in Period A, continued with or switched to 40 mg ADA every-other-week treatment in the subsequent 26-week open-label extension (OLE) period. Main efficacy evaluations were ≥75% improvement in total-fingernail modified Nail Psoriasis Severity Index (mNAPSI 75) and achievement of Physician's Global Assessment for Fingernail Psoriasis of clear or minimal disease (PGA-F 0/1) with a ≥2-grade improvement from baseline, across the trial for patients who continued ADA from Period A through the OLE (Continuous-ADA Population). Safety was evaluated during the OLE and for patients receiving ADA at any time during the study (All-ADA Population). RESULTS: Of the 217 patients initially randomized in Period A, 188 (86.6%; 94 in each treatment group) entered the OLE after completion of or early escape from Period A. For the Continuous-ADA Population (N = 109), endpoint achievement rates improved from OLE entry (Week 26) to Week 52, including total-fingernail mNAPSI 75 (47.4-54.5%); PGA-F 0/1 (51.1-55.6%) and total-fingernail mNAPSI = 0 (6.6-17.9%). Serious adverse event and serious infection rates for the All-ADA Population (N = 203) were 6.9% and 3.4%, respectively. CONCLUSIONS: In this population of psoriasis patients with concomitant, moderate-to-severe nail psoriasis, long-term efficacy and improvement in signs and symptoms of nail disease were demonstrated after every-other-week ADA treatment, including incremental improvements in rate of total clearance of nail disease. No new safety risks were identified for patients receiving at least one ADA dose across 52 weeks.

Human polyomavirus-7-associated eruption successfully treated with acitretin.

Advances in molecular technologies have led to the discovery of several novel human polyomaviruses (HPyVs), including human polyomavirus-7 (HPyV-7). Although low levels of HPyV-7 are shed from apparently normal skin, recent reports have described clinically significant cutaneous infection in immunocompromised patients that manifests as generalized pruritic plaques. The pruritus can be severe, and treatment options have not been described. Herein we report HPyV-7 cutaneous infection in a heart transplant patient who experienced temporary improvement with intravenous cidofovir, and complete remission with acitretin. We report a case of HPyV-7 cutaneous infection demonstrating a good response to treatment.

Efficacy, safety and tolerability of topical terbinafine nail solution in patients with mild-to-moderate toenail onychomycosis: results from three randomized studies using double-blind vehicle-controlled and open-label active-controlled designs.

BACKGROUND: Terbinafine nail solution (TNS) was developed for the treatment of onychomycosis. OBJECTIVE: To assess the efficacy of TNS vs. vehicle and amorolfine 5% nail lacquer. METHODS: Subjects with mild-to-moderate toe onychomycosis (25% to ≤75% nail-involvement, matrix uninvolved) were randomized to receive either TNS or vehicle in two double-blind studies, and to TNS or amorolfine in an active-controlled, open-label study. Primary endpoint was complete cure (no residual clinical involvement and negative mycology) at week 52. Secondary endpoints were mycological cure (negative mycology defined as negative KOH microscopy and negative culture) and clinical effectiveness (≤10% residual-involvement and negative mycology) at week 52. RESULTS: Complete cure was not different between TNS vs. vehicle and amorolfine. Mycological cure was higher with TNS vs. vehicle, as was clinical effectiveness with TNS vs. vehicle, and TNS and amorolfine were not different for secondary efficacy endpoints. Patients achieving mycological cure had a better clinical outcome, and efficacy was improved in subjects with milder disease. Post hoc analysis suggests that nail thickness is an important prognostic factor. Moreover, mycological cure may require 6 months of treatment regimen while complete cure and clinical effectiveness may be achievable only after 10 months. A simulation study suggests that longer treatment duration would have resulted in higher complete cure with TNS vs. vehicle. Study treatments were well-tolerated. CONCLUSION: Primary efficacy objectives were not met in the studies reported herein. Possible reasons for failure to achieve significant outcomes include insufficient length of treatment; stringency of primary endpoint and severity of nail involvement of study population.

Rosacea - global diversity and optimized outcome: proposed international consensus from the Rosacea International Expert Group.

BACKGROUND: The absence of specific histological or serological markers, the gaps in understanding the aetiology and pathophysiology of rosacea, and the broad diversity in its clinical manifestations has made it difficult to reach international consensus on therapy guidelines. OBJECTIVES: The main objective was to highlight the global diversity in current thinking about rosacea pathophysiology, classification and medical features, under particular consideration of the relevance of the findings to optimization of therapy. METHODS: The article presents findings, proposals and conclusions reached by the ROSacea International Expert group (ROSIE), comprising European and US rosacea experts. RESULTS: New findings on pathogenesis provide a rationale for the development of novel therapies. Thus, recent findings suggest a central role of the antimicrobial peptide cathelicidin and its activator kallikrein-5 by eliciting an exacerbated response of the innate immune system. Cathelicidin/kallikrein-5 also provide a rationale for the effect of tetracyclines and azelaic acid against rosacea. Clinically, the ROSIE group emphasized the need for a comprehensive therapy strategy - the triad of rosacea care - that integrates patient education including psychological and social aspects, skin care with dermo-cosmetics as well as drug- and physical therapies. Classification of rosacea into stages or subgroups, with or without progression, remained controversial. However, the ROSIE group proposed that therapy decision making should be in accordance with a treatment algorithm based on the signs and symptoms of rosacea rather than on a prior classification. CONCLUSION: The ROSIE group reviewed rosacea pathophysiology and medical features and the impact on patients and treatment options. The group suggested a rational, evidence-based approach to treatment for the various symptoms of the condition. In daily practice this approach might be more easily handled than prior subtype classification, in particular since patients often may show clinical features of more than one subtype at the same time.

Onychomycosis and diabetes.

OBJECTIVE: This study aims to discuss factors specific to diabetics in the diagnosis and treatment of onychomycosis. DISCUSSION: Onychomycosis has the potential to cause severe complications in diabetics and should be treated promptly. The existence of comorbid conditions and potential for drug-drug interactions complicates the selection of an appropriate treatment regimen. The role of Candida in onychomycosis is controversial but may be of increased significance in the diabetic population due to an underlying vulnerability to this organism. CONCLUSIONS: Terbinafine is an excellent choice in diabetics due to its low risk of drug-drug interaction and proven efficacy against the typical pathogens that cause onychomycosis. Itraconazole, while an effective treatment for onychomycosis, is not a first-choice therapy due to its black-box cardiac warning and numerous drug interactions. Larger studies are needed in diabetics to determine the frequency of candidal nail infections.

Rosacea: a review of current topical, systemic and light-based therapies.

Rosacea is a common chronic inflammatory disorder of the facial skin characterized by periods of exacerbation, remission and possible progression. The principle subtypes include erythematotelangiectatic rosacea, papulopustular rosacea, phymatous rosacea and ocular rosacea. Although the pathogenesis is unknown, rosacea is largely recognized as an inflammatory disorder. Individual subtypes are likely a result of different pathogenic factors and respond best to different therapeutic regimens. The non-pharmacologic approach to therapy is adequate skin care, trigger avoidance and photoprotection; in addition, there are several topical, herbal, systemic and light based therapies available. Standard Food and Drug Administration (FDA) approved treatments include topical sodium sulfacetamide, metronidazole, and azelaic acid. Anti-inflammatory dose doxycycline, a controlled-release 40 mg formulation offers a non-antibiotic, anti-inflammatory treatment option. Combination of azelaic acid or topical metronidazole with anti-inflammatory doxycycline appears to have a synergistic effect. Oral isotretinoin may be effective for phymatous rosacea and treatment resistant rosacea. Light based therapies with pulsed dye laser and intense pulsed light are effective in treatment of erythema and telangiectasias. As our knowledge of rosacea and its therapeutic options expand, a multifaceted approach to treatment is warranted.

Hendersonula toruloidea and Scytalidium hyalinum. Review and update.

Hendersonula toruloidea and Scytalidium hyalinum are opportunistic organisms that can produce tinea pedis, tinea manuum, and tinea unguium. These infections, which clinically mimic those caused by dermatophytes but are caused by nondermatophyte agents, are correctly called dermatomycoses. When examined microscopically with potassium hydroxide, the agents of these disorders resemble those of dermatophytosis, showing narrow, septate, branching hyphae. It, therefore, becomes important to culture samples taken from sites with these tineas on cycloheximide-free agars even if they are potassium hydroxide-positive to rule out nondermatophyte mycoses. Correct identification becomes imperative since neither H toruloidea nor S hyalinum responds to conventional therapy. We review these diseases with emphasis on clinical appearance and differentiation from dermatophytosis. We also report four cases of S hyalinum infection of the nail or feet.

Restructuring dermatology education at Cleveland medical centers affiliated with Case Western Reserve University.

We describe our response to the changing needs for dermatologic education and training at Cleveland medical centers affiliated with Case Western Reserve University School of Medicine (CWRU) located in Cleveland, Ohio. Our departmental plan for change is a multifaceted approach that alters the number of dermatology residents we train and also the way we interact with and educate our generalist colleagues. Like many other dermatologists, we have both idealistic and practical reasons for increasing our involvement in interdisciplinary education. One of our primary objectives is maximizing quality of care for dermatologic patients in our community. Traditionally, the majority of skin care in the United States has been provided by nondermatologists, and with the growth of managed care, this proportion is increasing. This has motivated us to increase our medical student teaching activities and to support the American Academy of Dermatology in its current efforts to develop a dermatology core curriculum for students. We should also be involved in the education of generalist physicians, since prior studies have suggested that their knowledge of dermatology needs improvement. Our goals should be both to improve the direct patient care skills of primary care physicians and to teach clinically appropriate referral thresholds. The American Academy of Dermatology has recently issued guidelines for the referral of dermatology patients in managed care settings to help ensure that our specialty has input into this process. In addition, teaching gatekeeper physicians to use appropriate referral criteria is important to many dermatologists in capitated managed care systems who often prefer limited as opposed to unrestricted access to their services.

Onychomycosis. Treatment, quality of life, and economic issues.

Onychomycosis is a public health concern because of its high worldwide incidence and prevalence, and its potential for spread of fungal elements to others, as well as complications such as cellulitis, bacterial infection, pain, and extensive dermatophytic infections. The incidence of onychomycosis has been increasing, particularly in individuals over 60 years of age, patients with HIV infection, and patients with diabetes mellitus. Onychomycosis may impact upon physical, functional, psychosocial, and emotional aspects of life. Difficulty walking, wearing shoes, and embarrassment are common complaints. Quantification of such quality-of-life changes are significant to clinical practice in that many factors can affect overall patient health. In light of the potential clinical implications on physical and mental health, onychomycosis should be considered a medical condition that deserves rigorous clinical management. Onychomycosis can be treated effectively and with comparative safety with the new generation of oral antifungal agents (itraconazole, fluconazole and terbinafine). Significantly improved pharmacokinetic and pharmacodynamic profiles permit markedly reduced duration of administration, individual drug exposure, and ultimately enhanced patient compliance and satisfaction with therapy. In addition, a number of pharmacoeconomic studies have documented the cost effectiveness of these newer agents compared with both traditional pharmacologic treatment and topical therapies. The currency figures quoted are 1997 values. With regard to continuous oral antifungal regimens, terbinafine therapy has been found to be most cost effective in the treatment of toenail onychomycosis, with a drug acquisition cost of $US522.50. However, improved safety, tolerability, efficacy and cost effectiveness have been documented with itraconazole intermittent, pulse regimens. With itraconazole pulse therapy, the drug acquisition cost decreases to $US488.90. Additionally, the total cost of medical management is less for itraconazole therapy compared with that of terbinafine ($US261.00 vs $US306.00). Because sensitivity analyses for itraconazole and terbinafine have been found to be somewhat comparable in terms of mycological cure, clinical response, and relapse rates, other variables such as safety and efficacy profiles, and patient attitudes and expectations toward therapy need to be considered when formulating an onychomycosis pharmacologic treatment plan. The drug aquisition cost of fluconazole given as a 300 mg dose once weekly for 6 months is $US562.76 and given as a 150 mg dose once weekly (for 6 months) $US281.38.

Antifungal susceptibilities and genetic relatedness of serial Trichophyton rubrum isolates from patients with onychomycosis of the toenail.

Onychomycosis is a common fungal disease infecting up to 20% of the population over age 40. The major causative agent of onychomycosis is Trichophyton rubrum. Uncontrolled infection may eventually lead to penetration of the newly forming nail plate. In spite of the encouraging cure rate with recent antifungal agents such as the allylamines (terbinafine) and azoles (itraconazole and fluconazole) some patients inevitably fail therapy. In this investigation, a group of patients from a multi-center study designed to assess the efficacy of terbinafine with known cases of onychomycosis were selected for evaluation. Nail samples from this patient group were colonized with T. rubrum throughout the terbinafine therapy. Antifungal susceptibility testing was performed on these T. rubrum isolates to detect change in MIC values. Strain relatedness was examined using random amplified polymorphic DNA (RAPD) technique. Our results revealed failure of patients to clear T. rubrum is not related to the development of resistance to the drug. While species determination was possible, we were not able to identify differences that would indicate reinfection with a new strain. Analysis of patient demographic data revealed that 70% of patients were over 45 years old, 56.6% were previously treated with antifungals, 60% came from family history with onychomycosis and 13 % were diabetic. In conclusion, our data indicate that patients' failure to clear onychomycosis was not associated with resistant development. Failure of terbinafine therapy may be dependent on host-related factors.

Trichophyton rubrum onychomycosis in a 17-year-old girl.

Onychomycosis is one of the most common nail disorders seen by dermatologists. An increasing number of immunocompromised patients, in combination with an aging worldwide population, has resulted in a significant increase in the incidence of this disorder. While nearly one fifth of all occurrences are found in patients aged 40 to 60, the incidence dramatically increases in patients over 60. However, onychomycosis is very uncommon in children.

Cutaneous blastomycosis.

We report on a patient with cutaneous blastomycosis and no evidence of systemic involvement. This diagnosis was made on the basis of clinical findings and confirmed by histologic examination and results of culture. The primary lesion in blastomycosis is almost always pulmonary. However, occasionally, as in our patient, the pulmonic focus resolves spontaneously before the patient presents. Disseminated lesions occur most often in the skin, followed by bone, genitourinary tract, and central nervous system. Our patient had an excellent response to ketoconazole without adverse effects.

Comparison of an antifungal agent used alone with an antifungal used with a topical steroid in inflammatory tinea pedis.

The efficacy and safety of monotherapy with oxiconazole nitrate cream, 1 percent, a topical broadspectrum antifungal agent, were compared with those of combination therapy with oxiconazole nitrate cream, 1 percent, and fluticasone propionate cream, 0.05 percent, in a multicenter, randomized, double-blind, vehicle-controlled, parallel-group study of patients with inflammatory tinea pedis. Both combination therapy and monotherapy were associated with significantly greater proportions of mycologic and clinical cure, and a better global response than vehicle. An unexpected finding in this study was that more than 70 percent of patients with interdigital tinea pedis also had plantar or plantar plus vesiculobullous infection.