iPLEDGE Weaknesses: Is It Time to Address the Flaws?

BACKGROUND: The observance during acne follow-ups that information stored within iPLEDGE was discordant with medical charts prompted this study. OBJECTIVE: To evaluate the information acquired and stored within iPLEDGE as it compares to medical charts with a goal of assessing the efficacy of iPLEDGE as a database. METHODS: This is a multicenter retrospective chart review analyzing congruence and discrepancies between medical chart documentation and iPLEDGE data for all patients who received at least a single dose of isotretinoin from the primary investigators between January 2006 and November 2010. RESULTS: A total of 357 charts were analyzed. Overall congruence between medical chart documentation and iPLEDGE data was observed in only 73.1% of cases. The discrepancy (N=96) was due to a missed dose (prescription recorded in chart but not in iPLEDGE) in 81.4% of cases, or an addition (medication dispensed per iPLEDGE without corresponding chart documentation) in the remainder of cases. Of note, several charts had multiple discrepancies (N=249 total discrepancies). LIMITATIONS: Retrospective chart review study. CONCLUSION: Given the large percentage of discordant data, our findings question the efficacy of the iPLEDGE system, which is designed to monitor every dispensed isotretinoin dose.

Dermatologic manifestation of hyperandrogenism: a retrospective chart review.

Several studies have described a wide spectrum of hyperandrogenism diseases, many of which are difficult to distinguish from each other. In order to better understand diseases of hyperandrogenism, the authors performed a retrospective study of the cutaneous features and metabolic findings in women with hyperandrogenism. A retrospective chart analysis compiled by three dermatologists in both academic and private settings was performed, including patients presenting with > or = 2 manifestations of hyperandrogenism. Relevant dermatologic and associated manifestations and laboratory and imaging study findings were reviewed. Moderate to severe acne was the most common manifestation. Other common manifestations that patients first presented with include hirsutism, acanthosis nigricans, androgenic alopecia, and skin tags. Oligomenorrhea was the most common systemic presenting sign. Statistical analysis of various clinical markers revealed correlations with hyperandrogenemia. Acanthosis nigricans and hirsutism were found to be useful clinical markers for hyperandrogenism, whereas androgenic alopecia was not. This study provides some insights into the presentation and diverse manifestations seen in hyperandrogenism.

Modulation of cytokine and nitric oxide production by keratinocytes, epithelial cells, and mononuclear phagocytes in a co-culture model of inflammatory acne.

INTRODUCTION: Ultraviolet B (UVB, 290 nm to 320 nm) has been reported to modulate the cytokine-mediated inflammatory process in various inflammatory skin conditions, including production of TNF-α, IL-1α, IL-6, IL-8, and IL-10. We constructed an in vitro model system involving co-culture of different cell types to study the effect of UVB on the inflammatory process using nitric oxide (NO) and tumor necrosis factor (TNF)-α as markers of inflammation. OBJECTIVE: This study was conducted to quantitatively assess the products secreted by human epithelial keratinocytes in the presence and absence of macrophages/monocytes. METHODS: Cells were exposed to UVB radiation (50 mJ to 200 mJ per cm2) or treated with bacterial lipopolysaccharide (LPS) as stimulator of inflammatory response. Nitric oxide (NO) was measured by modified Griess assay and TNF-α was measured by quantitative ELISA. For the co-culture system, SC monocytes were seeded in a 24-well Transwell tissue culture plate whereas irradiated keratinocytes were seeded in the individual baskets subsequently placed on top of the monocyte cultures, and samples of culture supernatants were collected at 1 to 6 days. RESULTS: When primary human epidermal keratinocytes (NHEK) were irradiated with UVB, a dose-dependent stimulation of TNF-α production was observed (33% to 200% increase). TNF-α production was not changed significantly in SC monocytes/NHEK co-culture. In contrast, when macrophages were irradiated with UVB, significant inhibition of NO production (40% suppression, P<0.001) was seen. CONCLUSION: This improved model of cutaneous inflammation could use multiple cells to study their interactions and to offer convenience, reproducibility, and a closer approximation of in vivo conditions.

Inflammatory acne management with a novel prescription dietary supplement.

BACKGROUND: Inflammatory acne, particularly in post-adolescent women, is increasing in incidence. The most effective therapeutic modality for treatment of this type of acne has been the administration of oral tetracyclines. Long-term acne treatment with such drugs, however, is frequently accompanied by undesirable adverse reactions, including gastrointestinal disturbances, antianabolic effects, headaches, tinnitus, and photosensitivity. OBJECTIVE: To assess the usefulness of a novel dietary supplement in the overall management of patients with inflammatory acne vulgaris. METHODS: 235 patients with inflammatory acne vulgaris were enrolled by dermatologists in a multicenter, open-label, 8-week, prospective study evaluating the effects of adding NicAzel, 1 to 4 tablets daily, to their current acne treatment regimen. RESULTS: A statistically significant (P<.0001) number of patients demonstrated improvement over their previous acne treatment regimens after both 4 and 8 weeks of NicAzel (nicotinamide, azelaic acid, zinc, pyridoxine, copper, folic acid; Elorac Inc, Vernon Hills, IL) use. At week 8, 88% of the patients experienced a visible reduction in inflammatory lesions, and 81% of the patients rated their appearance as much or moderately better compared with baseline. Three-quarters (76%) of the patients thought NicAzel was at least as effective as previous treatment with oral antibiotics. CONCLUSION: Patients with inflammatory acne showed significant improvement in acne severity and overall appearance when NicAzel was added to their existing treatment regimen.

A multicenter, double-blind study to evaluate the efficacy and safety of 2 treatments in participants with mild to moderate acne vulgaris.

Acne treatment regimens have changed due to the recent over-the-counter (OTC) switch of all prescription benzoyl peroxide (BPO) topical preparations. The elimination of prescription single-agent BPO products means that dermatologists must select from a variety of OTC formulations to utilize the time-tested efficacy of BPO in the treatment of mild to moderate acne. Our research compared the efficacy and safety of an OTC BPO 5.5% formulation with lipohydroxy acid and tretinoin cream 0.025% with prescription clindamycin 1%-BPO 5% gel and tretinoin cream 0.025%. Parity was demonstrated between the 2 treatment regimens at 12 weeks.

Clinical applications of non-antimicrobial tetracyclines in dermatology.

There are many proposed non-antimicrobial actions of tetracyclines. Pathways affected by these medications are often overexpressed in various dermatologic conditions. Matrix metalloproteinases (MMPs) are enzymes best known for breaking down connective tissue proteins and are upregulated in conditions involving dermal destruction. Inhibition of MMPs by tetracyclines has been emphasized as one major non-antimicrobial action. Other effects of tetracyclines that are important in dermatology include inflammatory cytokine regulation, inhibition of leukocyte chemotaxis and activation, and anti-oxidation. Dermatologists have utilized the non-antimicrobial benefits of using tetracycline, through their success in treating disorders that do not have a primary infectious etiology such as rosacea. Even in acne, there is believed to be overactive inflammation to a normally commensal organism which is inhibited by tetracyclines. These medications have also been reported as successful in cases of less common skin conditions, such as pyoderma gangrenosum and bullous pemphigoid, both of which involve inflammation and dermal destruction which are inhibited by tetracyclines. The pathologic mechanisms of several dermatologic conditions are reviewed, followed by evidence of how tetracyclines and chemically modified tetracyclines (CMTs; structurally altered tetracyclines to remove antimicrobial properties while retaining non-antimicrobial properties) affect these pathways. Clinical testing of sub-antimicrobial doxycycline, in both 20mg twice daily and 40 mg once daily (controlled release; 30 mg immediate release, 10mg delayed release) forms, in rosacea and acne is reviewed as evidence that non-antimicrobial actions are valuable for treatment. Chemically modified tetracycline-3 (CMT-3) for Kaposi's sarcoma is highlighted as the only clinical evidence available for CMTs in dermatology. Certain evidence of success using antimicrobial tetracyclines in inflammatory conditions of the skin is reviewed as well, because they are likely working through non-antimicrobial properties. Finally, dermatologic side effects of non-antimicrobial tetracyclines are assessed.

Diet and acne.

Historically, the relationship between diet and acne has been highly controversial. Before the 1960s, certain foods were thought to exacerbate acne. However, subsequent studies dispelled these alleged associations as myth for almost half a century. Several studies during the last decade have prompted dermatologists to revisit the potential link between diet and acne. This article critically reviews the literature and discusses how dermatologists might address diet when counseling patients with acne. Dermatologists can no longer dismiss the association between diet and acne. Compelling evidence exists that high glycemic load diets may exacerbate acne. Dairy ingestion appears to be weakly associated with acne, and the roles of omega-3 fatty acids, antioxidants, zinc, vitamin A, and dietary fiber remain to be elucidated. This study was limited by the lack of randomized controlled trials in the literature. We hope that this review will encourage others to explore the effects of diet on acne.

The development of antimicrobial resistance due to the antibiotic treatment of acne vulgaris: a review.

OBJECTIVE: To review recent studies on the use of antibiotics in acne vulgaris which provide insight into the development of antimicrobial resistance. DATA SOURCES: Sources for this article were identified by searching the English literature by Medline for the period 1960 to March 2009. STUDY SELECTION: The following relevant terms were used: acne, acne vulgaris, acne and antibiotic therapy, acne and antimicrobial resistance, acne and resistance mechanisms, acne and systemic infections, acne and antibiotic resistance and coagulase-negative Staphylococcus aureus (S. aureus), acne and antibiotic resistance and upper respiratory infection. DATA SYNTHESIS: Both correct and incorrect use of antibiotics for acne vulgaris can promote antimicrobial resistance. The development of this resistance is promoted by several factors, including antibiotic monotherapy, long-term administration of antibiotics, indiscriminate use outside their strict indications, dosing below the recommended levels, and the administration of antibiotics without concurrent benzoyl peroxide and/or topical retinoids. CONCLUSION: Long-term use of antibiotics in the treatment of acne vulgaris can lead to antimicrobial resistance with serious and intractable problems not limited to Propionibacterium acnes (P. acnes), the skin and acne vulgaris themselves, but also to other bacterial species, with systemic consequences. These findings suggest that antibiotics should be prescribed in combination with benzoyl peroxide and/or topical retinoids and be limited to a maximum of several months.

Dapsone gel 5% in combination with adapalene gel 0.1%, benzoyl peroxide gel 4% or moisturizer for the treatment of acne vulgaris: a 12-week, randomized, double-blind study.

PURPOSE: To evaluate the safety and efficacy of dapsone gel 5% in the treatment of acne when used in combination with adapalene gel 0.1%, benzoyl peroxide gel 4% or moisturizer. METHODS: This was a twelve-week, randomized, double-blind study. Patients aged 12 years and older (n=301) applied dapsone gel twice daily and were randomly assigned (1:1:1) to one of three additional treatments, applied once daily. RESULTS: By week 12, dapsone gel combined with any of the three additional treatments reduced the mean number of inflammatory lesions. However, the authors did not detect a significant difference in the reduction of inflammatory lesions when dapsone was used in combination with adapalene gel or with benzoyl peroxide gel compared to the dapsone plus moisturizer combination group (P=0.052 for both versus moisturizer combination). Patients treated with dapsone gel combined with adapalene showed a significantly better response in reduction in non-inflammatory and total acne lesion count than those who received the moisturizer combination. Local adverse reactions in all three treatment groups were minimal and generally mild in severity. CONCLUSION: Dapsone gel in combination with adapalene gel or benzoyl peroxide gel is safe and well tolerated for the treatment of acne vulgaris.

Randomized comparison of the safety and efficacy of tazarotene 0.1% cream and adapalene 0.3% gel in the treatment of patients with at least moderate facial acne vulgaris.

This 16-week study evaluated once-daily tazarotene 0.1% cream and adapalene 0.3% gel in patients with moderate-to-severe acne. Patients treated with tazarotene 0.1% cream performed better in many acne efficacy measures (reduction in lesion counts, percentage of patients achieving a 50 percent lesion count reduction, overall disease severity, investigator's global assessment) than did patients treated with adapalene 0.3% gel. Reduction in postinflammatory hyperpigmentation (PIH) was also significantly greater with tazarotene 0.1% cream than with adapalene 0.3% gel (P < or = 0.018). Irritation was infrequent, generally mild and similar between treatment groups. In conclusion, both tazarotene 0.1% cream and adapalene 0.3% gel were effective and well tolerated in patients with at least moderate acne. Tazarotene 0.1% cream appeared to be more effective and nearly as well tolerated as adapalene 0.3% gel in reducing acne lesions and was more effective than adapalene 0.3% gel in reducing PIH.

Dapsone 5% gel: a review of its efficacy and safety in the treatment of acne vulgaris.

Dapsone, a synthetic sulfone that has been available for over 60 years, has been used to treat a myriad of cutaneous disorders. Prior to the general acceptance of isotretinoin, oral dapsone had been reported to be effective in the treatment of nodulocystic acne. However, the potential for systemic toxicity prevented its widespread adoption in the treatment of acne. For many years scientists explored the possibility of developing a topical formulation of dapsone for the treatment of acne in the hope of minimizing the adverse hematologic effects of oral dapsone. Such a formulation had been unavailable until recently. Dapsone 5% gel (Aczone) was recently developed to treat acne vulgaris. This topical formulation was approved in the US based on two randomized, vehicle-controlled studies. A 12-month, open-label study was also conducted to assess the safety and efficacy of topical dapsone over the long term. Finally, two open-label phase I pharmacokinetic studies were conducted to evaluate the systemic absorption of topical dapsone compared with oral dapsone. This article reports the results of these studies, which show a reduction in acne lesion count comparable to those observed in clinical trials of other approved topical acne therapies. With regard to safety, the studies demonstrated that the concentrations of dapsone and N-acetyl dapsone remain low and do not accumulate over time once steady state is reached. Of the total of 50 patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency in all the studies, only two experienced a drop in hemoglobin levels, and those shifts in values were consistent with fluctuations observed for other study participants. A recent study evaluating the risk of hemolysis in patients with G6PD deficiency found topical dapsone 5% gel to be safe to use in this patient population. Based on the observations noted in the above-mentioned studies, we conclude that topical dapsone 5% gel is safe and effective in the treatment of acne vulgaris.

New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group.

The Global Alliance to Improve Outcomes in Acne published recommendations for the management of acne as a supplement to the Journal of the American Academy of Dermatology in 2003. The recommendations incorporated evidence-based strategies when possible and the collective clinical experience of the group when evidence was lacking. This update reviews new information about acne pathophysiology and treatment-such as lasers and light therapy-and relevant topics where published data were sparse in 2003 but are now available including combination therapy, revision of acne scarring, and maintenance therapy. The update also includes a new way of looking at acne as a chronic disease, a discussion of the changing role of antibiotics in acne management as a result of concerns about microbial resistance, and factors that affect adherence to acne treatments. Summary statements and recommendations are provided throughout the update along with an indication of the level of evidence that currently supports each finding. As in the original supplement, the authors have based recommendations on published evidence as much as possible.

Changing the face of acne therapy.

Many innovations in acne therapy have evolved since the discovery in 1949 that vitamin A derivatives affected epidermal proliferation. Approval of topical tretinoin solution in 1971 was followed by modifications in the formulation to improve tolerability and provide flexibility in dosing. Identification of retinoid receptors led to research that resulted in 2 receptor-selective synthetic retinoids: adapalene and tazarotene. Today, topical retinoids are one of the cornerstones of acne therapy and are recommended as first-line therapy for all but the most severe forms of acne. They are used as monotherapy in mild comedonal acne; for inflammatory acne, topical retinoids are used in combination with benzoyl peroxide (BPO) and antibiotics (topical or oral) and/or hormonal therapy for females. Because of the high prevalence of antibiotic-resistant strains of Propionibacterium acnes, topical antibiotics should no longer be used as monotherapy. Topical retinoid monotherapy is recommended for maintenance because it prevents formation of microcomedones, the precursor lesions in acne. Combination topical retinoid/antimicrobial therapy has become the current recommended standard of care for the management of patients with acne. Combination therapy can target multiple pathogenic factors: abnormal follicular keratinization, P acnes proliferation, inflammation, and increased sebum production. A number of fixed-combination products are available. These products are effective, generally well-tolerated, and more convenient for patients than multiple individual agents. By reducing the number of medications and applications, fixed-combination products have the potential to improve patient adherence, thereby improving treatment outcomes.

A 3-step acne system containing solubilized benzoyl peroxide versus clindamycin-benzoyl peroxide.

A 3-step acne system has been developed to enhance the bioavailability and follicular penetration of benzoyl peroxide (BPO). Participants with mild to moderate facial acne vulgaris were randomly assigned to 10 weeks' facial treatment with the 3-step acne system (proprietary salicylic acid cleanser 2% twice daily, proprietary salicylic acid toner 2% once daily, and solubilized BPO gel 5% twice daily) or with control cleanser twice daily plus clindamycin 1%-BPO 5% gel (jar formulation) twice daily. Among 139 participants enrolled, the 3-step acne system was at least as effective as clindamycin-BPO in reducing noninflammatory lesion counts in the early weeks of treatment in the absence of an antibiotic (mean reductions were 27% vs 13%, 39% vs 25%, 40% vs 33%, and 42% vs 42% at weeks 2, 4, 6, and 10, respectively) (all not significant). Both regimens were associated with comparable reductions in inflammatory lesion counts at all time points. Both regimens also were generally well-tolerated with mean scores for erythema, dryness, peeling, burning/stinging, and itching less than mild in both groups at all time points. The 3-step acne system is at least as effective as clindamycin-BPO in reducing noninflammatory lesion counts in the early weeks of treatment in the absence of an antibiotic, which is likely attributed to the solubilized BPO formulation.

Guidelines of care for acne vulgaris management.

DISCLAIMER: Adherence to these guidelines will not ensure successful treatment in every situation. Furthermore, these guidelines should not be deemed inclusive of all proper methods of care or exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific therapy must be made by the physician and the patient in light of all the circumstances presented by the individual patient.

Neuropeptide (calcitonin gene-related peptide) induction of nitric oxide in human keratinocytes in vitro.

Nitric oxide (NO) is an important signaling molecule in both the central nervous system and the periphery, where it is involved in neurotransmission, vascular and bronchial tone, inflammation, and cutaneous immune function. More recently, NO has been implicated in intracellular signaling and may have a role in cellular differentiation, cytokine expression, and apoptosis. The experiments described herein examined the effect of calcitonin gene-related protein (CGRP), a cutaneous nerve neuropeptide, on NO production in human keratinocytes in vitro. CGRP stimulated two distinct increases in NO production: one within 30 minutes and a second at 24 hours. CGRP stimulated a modest increase in inducible nitric oxide synthase (iNOS) at 3-6 hours. Experimental evidence suggested that CGRP stimulated both constitutive NOS activity and generation of NO via nitrosothiol degradation within the first hour. Production of NO was paralleled by a decrease in nitrosothiol levels for 2 hour, suggesting that immediate NO release may originate from pre-existing stores. Nitrosothiols are ubiquitous molecules that comprise an important NO pool and have intracellular regulatory roles, particularly linked to oxidative stress. The present data indicate that, in addition to its known cAMP signaling pathway, CGRP may act to regulate keratinocyte biology through intracellular NO by modulation of S-nitrosothiol stores and stimulation of NOS activity.

Adapalene gel, 0.1%, as maintenance therapy for acne vulgaris: a randomized, controlled, investigator-blind follow-up of a recent combination study.

OBJECTIVE: To assess the maintenance effect of adapalene gel, 0.1%, relative to gel vehicle in subjects successfully treated in a previous 12-week study of adapalene-doxycycline, 100 mg, combination therapy. DESIGN: Multicenter, investigator-blind, randomized, controlled study. SETTING: Thirty-four US centers. SUBJECTS: A total of 253 subjects with severe acne vulgaris who showed at least moderate improvement from baseline (50% improvement from baseline) when treated with either adapalene plus doxycycline or doxycycline plus gel vehicle in a previous 12-week study. INTERVENTIONS: Subjects were randomized to receive adapalene gel, 0.1%, or gel vehicle once daily for 16 weeks. MAIN OUTCOME MEASURES: Efficacy and safety criteria included maintenance rate (subjects maintaining at least 50% improvement in lesion counts from previous therapy), lesion counts (total, inflammatory, and noninflammatory), global severity assessment, cutaneous tolerability, and adverse events. RESULTS: Adapalene maintenance therapy resulted in significantly larger maintenance rates (75% vs 54%; P<.001) and significantly lower lesion counts (total [P = .005], inflammatory [P = .01], and noninflammatory [P = .02]) compared with gel vehicle. Adapalene was safe and well tolerated in this study. Conclusion This study demonstrates a clinical benefit of continued treatment with adapalene gel, 0.1%, as a maintenance therapy for acne.

Comparison of tazarotene and minocycline maintenance therapies in acne vulgaris: a multicenter, double-blind, randomized, parallel-group study.

OBJECTIVE: To evaluate the efficacy of 3 maintenance regimens (topical tazarotene, oral minocycline hydrochloride, or both) in sustaining improvement in acne. DESIGN: Multicenter, open-label treatment phase followed by double-blind, randomized, parallel-group maintenance phase. SETTING: Ambulatory patients in research or referral centers. PATIENTS: Volunteer sample of 189 patients with moderately severe to severe acne vulgaris (110 entered maintenance phase, 90 completed, and 2 discontinued because of adverse events). INTERVENTIONS: All patients were treated with 0.1% tazarotene gel (each evening) and a 100-mg capsule (twice daily) of minocycline hydrochloride for up to 12 weeks. Patients with 75% or greater global improvement at week 12 were randomly assigned to 12 weeks of maintenance therapy with tazarotene gel plus placebo capsules, vehicle gel plus minocycline capsules, or tazarotene gel plus minocycline capsules. MAIN OUTCOME MEASURES: Overall disease severity, global improvement, and lesion counts. RESULTS: All regimens were effective in sustaining improvements in acne. After 12 weeks of maintenance therapy, the mean reductions from baseline in noninflammatory and inflammatory lesion count, respectively, were 60% and 54% with tazarotene, 52% and 66% with minocycline, and 64% and 66% with tazarotene plus minocycline. At week 24, more than 80% of patients in each group had maintained a 50% or greater global improvement from baseline, and more than 50% had maintained a 75% or greater global improvement. CONCLUSIONS: A high percentage of patients with moderately severe to severe acne can maintain improvement in their condition with topical retinoid monotherapy. Maintenance with combination tazarotene and minocycline therapy showed a trend for greater efficacy but no statistical significance vs tazarotene alone. Topical retinoid monotherapy should be considered for maintenance to help minimize antibiotic exposure.