CME #133 December 2007
Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for one category 1 physician credit hour. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee.
In our year-end look back at dermatology in 2007, author Aaron Loyd, M.D., covers the year’s highlights, including the continuing struggles of iPLEDGE, the increasingly worrisome epidemic of MRSA, and the latest studies regarding therapies for psoriasis, atopic dermatitis, and acne.
At the end of this article, you’ll find an exam. Mark your responses in the designated area, then fax page 52 to NACCME at (610) 560-0501.
We’ll also post this course on our Web site, which you can access at www.skinandaging.com. I hope this CME contributes to your clinical skills.
Amy McMichael, M.D.
CME Editor
Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC.
Principal Faculty: Aaron Loyd, M.D.
Method of Participation: Physicians may receive 1 AMA PRA Category 1 Credit™ by reading the article on pages 45 through 50 and successfully answering the questions found on page 51. A score of 70% is required for passing. Submit your answers and evaluation via fax; or you may log on to our Web site at www.skinandaging.com.
Estimated Time to Complete Activity: 1 hour
Date of Original Release: December 1, 2007
Expiration Date: November 30, 2008
Accreditation Statement: This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NACCME designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.™ Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.
Off-Label/Unapproved Usage Discussion: This educational activity contains discussion of published and/or investigational uses of agents that are not indicated by the FDA. Neither NACCME, Genentech/Biogen Idec nor Roche recommends the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Disclosures: All those with control over the content of continuing education programs sponsored by NACCME are expected to disclose whether they do or do not have any real or apparent conflict(s) of interest or other relationships related to the content of their presentation(s). It is not assumed that these relationships will have an adverse impact on presentations; they are simply noted here to fully inform participants.
Dr. Loyd has disclosed that he has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of his article.
All those involved in the planning and editing of this educational activity have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of this educational activity.
Sponsor: This activity is sponsored by the North American Center for Continuing Medical Education.
Learning Objectives:
1. Identify major studies, new therapeutic interventions and updates on currently used medications from this past year.
2. Identify possible applications of new information from 2007 in an effort to improve therapeutic strategies for patients with skin disease.
Target Audience: Dermatologists
Commercial Support: None
Sponsor: NACCME
Year in Review
This year proved another exciting episode in dermatology, full of new therapeutics, new genes and new regulations. New regulatory issues, beyond the obvious drug approval apparatus, are affecting our specialty and should be familiar to all dermatologists. New genetic findings are driving more targeted therapies, from psoriasis to resistant bacterial infections. Finally, new therapeutics provide broader options with which to practice the art of dermatology and improve patient satisfaction.
INFECTIOUS DISEASE: Community Threat
S. aureus Resistance Update
A growing consensus has emerged in 2007 in the battle with methicillin-resistant Staphylococcus aureus (MRSA).
In July of this year, Hankin published a review of evidence for antibiotic use in abscesses, the most common presentation of MRSA.1 The bulk of the evidence, including the only two randomized controlled trials, suggests that incision and drainage is sufficient. In cohort studies, incorrect empiric antibiotics with incision and drainage produced the same results as correct antibiotics with incision and drainage. Nevertheless, lesions larger than 5 cm and patients with comorbidities or systemic symptoms may require antibiotic therapy and/or hospitalization.
Complicated Case Therapy
Antibiotics remain important adjuncts to incision and drainage in complicated cases, and better understanding of Staphylococcus aureus allows appropriate selection of therapy. MRSA prevalence is increasing, and in many urban areas may now be more common than methicillin-sensitive (MSSA) species.2,3 MRSA is categorized as community-associated (CA-MRSA) and hospital-associated, the prior having the small mec IV resistance cassette. Due to its small size, multi-drug resistant CA-MRSA is rare, and treatment with tetracycline or sulfa drugs should be the primary empiric drug therapy for community patients with a pus-containing lesion. Panton-Valentine leukocidin is the major virulence factor.
Patients with respiratory symptoms and close or personal contact with MRSA abscesses should be evaluated for MRSA pulmonary syndrome.
Colonization Reduction
While colonization does not correlate closely with infection, patients who develop infection should be treated to reduce colonization, as relapse is common. Skin surface colonization is at least as important as nasal colonization.3
Triclosan- and alcohol-based cleansers appear to be more effective than chlorhexidine. Mupirocin applied for 5 days to nares reduced nasal carriage by 44% compared with 23% for vehicle ointment in one study, while other studies have demonstrated that mupirocin resistance is rising. General good hygiene should be advocated.
Topical Antibiotics
The first of the pleuromutilin class of topical antibiotics has been approved in 20074 for staphylococcal and streptococcal impetigo in both pediatric and adult populations, with a dosage of twice daily for 5 days. Pleuromutilins are broad-spectrum antibiotics with novel anti-ribosomal activity.
Retapamulin (Altabax) was more effective than placebo in treating impetigo in a Phase III trial with clinical success rates of 85.6% (119/139) versus 52.1% (37/71) for placebo in the intent-to-treat (ITT) population (p<0.001).5 Additional Phase III trials have demonstrated noninferiority compared with sodium fusidate, with response rates of 94.8% versus 90.1% for retapamulin and sodium fusidate, respectively. In this trial, retapamulin was also effective for methicillin- and mupirocin-resistant strains of Staphylococcus aureus, 8/8 and 6/6, respectively.5
ACNE: Filling the Gap
iPLEDGE’s First Year
In October 2006 the iPLEDGE system was updated, with FDA approval, to rescind the 23-day "lockout" period for males and females of non-childbearing potential.6 This allowed these low-risk populations to receive immediate prescriptions for the drug after the 7-day window, provided the registration and counseling obligations were again fulfilled. Dermatologists had lobbied for this change from the initial mandatory inception of the system in March 2006.
Generally, the system has undergone significant streamlining, with long wait times and frequent server errors now uncommon.
However, the system is far from perfect. In July 2007, iPLEDGE’s first-year data was released.7 The news of 122 isotretinoin-associated pregnancies was sobering, although comparisons to previously reported numbers are unfair, given the increased scope of this monitoring system. All 122 for whom records were available had received and acknowledged appropriate counseling. Generally, when fault could be determined, failure was due either to contraceptive failure or using less than the recommended two forms of birth control.
Two events in August further underscore the need for change:
First, the FDA released a warning and Web site links concerning online purchasing of isotretinoin.8 This highlights the problem of unsupervised isotretinoin use. Although difficult to quantify, this fallout may significantly undermine the purpose of the iPLEDGE system, which is to reduce fetal exposure to isotretinoin.
Second, an FDA advisory panel voted unanimously to further relax the regulations of iPLEDGE.9 Specifics were not delineated, but proposed changes include allowing women of childbearing potential to obtain a prescription after the 7-day window if an additional pregnancy test is negative.
Adapalene (Differin) 0.3% Approval
Topical retinoid therapy remains the foundation of acne therapy. Variable concentrations are helpful for tailoring skin-type-specific regimens, and titrating strength of action. A higher concentration of adapalene received FDA approval in June 2007.
In a Phase III trial,10 635 patients were randomized to daily application of one of the three comparison compounds in a double-blind manner. Inflammatory lesions were reduced by 62.5%, 57.8% and 47.2% for adapalene 0.3%, 0.1% and vehicle gel respectively, all of which were statistically significant (p<0.015). Noninflammatory lesions showed 52.1%, 43.4% and 29.3% reduction, which did not reach significance between the adapalene 0.3% and 0.1% (p=0.061). There was some increase in dry skin (14% versus 7%) and skin discomfort (6% versus 5%) with the adapalene 0.3% gel versus 0.1% gel, which subsided by 4 weeks. Therapy was discontinued due to irritation in three, two and one patient(s) in the 0.3%, 0.1% and vehicle groups, respectively.
With superior efficacy and relative tolerability, adapalene 0.3% gel is a welcome addition to acne therapy.
Drospirenone/Ethinyl Estradiol (Yaz): New Acne Indications
In women of childbearing potential with inflammatory acne, alternative treatment options are sorely needed.
Yaz (3 mg DSP/20 mcg EE) is the first drug to be approved as oral contraceptive with two other indications: the treatment of acne vulgaris and premenstrual dysphoria.
FDA approval11 in January was based on two randomized blinded controlled trials involving approximately 1,000 patients with moderate acne, which demonstrated significant reductions in lesion counts as well as a two- to four-fold increase in total success (clear or almost clear) versus placebo (15% to 21% versus 4% to 9%).12 In separate trials,13,14 drospirenone (3 mg with 30 mcg EE) has been found to be at least as effective for acne as cyproterone (active ingredient in Diane) and norgestimate (active ingredient in Ortho Tri-Cyclin). As the effect of 3 mg of drospirenone is equated with 25 mg of spironolactone, some patients must be monitored for hyperkalemia.
Incyclinide in Early Trials
A blinded, controlled, Phase II dose-finding trial15 provided modest evidence of efficacy of the new tetracycline derivative incyclinide in treating acne. At 20-mg daily, results at 3 and 6 weeks were 25.9% and 36.1% reduction in inflammatory lesions versus 9.4% and 17.5% with placebo, respectively (p<0.07). A subsequently initiated cohort at 40 mg daily experienced at least one case of significant phototoxicity and has been suspended.
Incyclinide may provide adjunctive treatment for inflammatory acne without inducing antimicrobial resistance common with other tetracyclines.
High Glycemic Diet and Acne
The effect of diet on acne has been a question in the medical community for some time. Many patients hold common beliefs that certain foods cause acne, but no studies have ever demonstrated this. However, a randomized, controlled pilot study was released in August16 that revealed a possible role for diet in acne severity.
A group in Australia divided over 40 patients aged 16 to 25 with mild to moderate inflammatory acne into a specific low-glycemic index diet with food training and menu suggestions and a control group where normal carbohydrate-rich diets were encouraged. Only a gentle cleanser (Cetaphil) was allowed as topical therapy, in both arms.
At 12 weeks, a significant (p=0.01) reduction in acne lesions (22% versus 14%) was seen in the treatment group.
ECZEMA: New Hope for Chronic Disease
Resistant/RecalcitrantAtopic Dermatitis Therapy
In a study published this year, mycophenolate mofetil therapy was assessed in severe, resistant atopic dermatitis in pediatric patients, a group that has not been studied before with this drug. Of 14 patients, only one failed to respond while most (64%) achieved almost complete or complete clearance.17 No adverse effects were noted. While the study was small and uncontrolled, the relatively benign adverse effect profile of mycophenolate encourages further exploration of a possibly very helpful therapy.
In a systematic review released this year,18 cyclosporine was recommended as first-line therapy for recalcitrant atopic dermatitis, showing the most consistent and highest efficacy, generally at or above 50% reduction in severity at a dose of 3 to 5mg/kg/day.
Other therapies that demonstrate efficacy are azathioprine and interferon-gamma and mycophenolate mofetil.
Alitretinoin Phase III Trials for Hand Dermatitis
Company-released results of a Phase III, randomized double-blind placebo-controlled trial19 confirmed that alitretinoin, an oral retinoid, provides dose-related relief for sufferers of chronic and recalcitrant hand dermatitis.
With success defined as clear or almost-clear, 48% of patients treated with 30 mg daily, 28% treated with 10 mg, and 17% treated with placebo achieved success (p<0.001). A follow-up study revealed that 80% of patients previously treated successfully with alitretinoin cleared with retreatment for flares. Adverse effects were similar to other retinoids, with dryness, headaches and lipid elevations most common. Teratogenicity is the most important toxicity.
With the positive data, a new drug application is likely by the end of 2007.
PSORIASIS: A Horizon of Possibilities
Clobetasol in Emollient Foam Vehicle (Olux-E) Approved
A new treatment option is available for atopic dermatitis and psoriasis. Olux-E consists of clobetasol 0.05% in an emollient yet foam-delivered vehicle.
Randomization of approximately 400 patients with moderate to severe atopic dermatitis demonstrated that 52% of subjects treated with Olux-E versus 14% in vehicle arm achieved success, which was defined as clear or almost clear by Investigator’s Static Global
Assessment score and at least two grades of improvement from baseline.20
A similar randomized study for mild-to-moderate plaque-type psoriasis also confirmed efficacy. In the study, 41 of 253 treatment patients (16%) versus 18 of 126 vehicle subjects (4%) achieved the endpoint of success, defined as per the atopic study above. Both studies limited the study population to patients 12 years of age and older.20
Beyond clinical studies, it is believed that the foam vehicle may support patient compliance due to ease of use. Also, the emollient-based foam directly aids the barrier dysfunction of psoriasis and atopic dermatitis.
Efalizumab for Palmoplantar Psoriasis
Phase IV study data of efalizumab (Raptiva) for hand and foot psoriasis was presented in February.21 Eighty patients were randomized to receive either efalizumab at standard 1-mg/kg/week dosage or placebo.
In a double-blinded 12-week follow-up, 46.2% versus 17.9% (p=0.015) of patients in the respective groups achieved at least clearance to the point of mild. Perhaps more poignant is the 32.7% versus 7.1% (p=0.013) of those patients who received a grade of clear or almost clear. Many of the patients had previously failed other biologic therapies. These data indicate that nearly one-third of patients with recalcitrant palmoplantar psoriasis can expect near clearance with efalizumab.
Efalizumab is a kappa isotype human monoclonal antibody to the CD11a chain of LFA-1, a receptor on T cells that plays a prominent role in transmigration and activation. It was approved in 2005 for moderate to severe plaque psoriasis for which systemic or phototherapy is indicated.22 While the risk of infection and malignancy may be lower than with other biologics, a unique risk is immune-mediated thrombocytopenia.22
Interleukin 12 and 23 Monoclonal Antibody Drugs in Trials
A dose-finding trial with over 300 patients involving a new monoclonal antibody infusion for psoriasis (CNTR 1275) has shown robust efficacy.23 At the highest dose, 90 mg weekly infusion, 75% improvement in psoriasis area-and-severity index was achieved in 81% after 12 weeks versus 2% for placebo (p<0.001); 52% of these achieved 90% improvement. Even at this dose, side effects were generally well tolerated with serious adverse effects in 4% of the treatment group versus 1% of placebo (p=0.069). With these promising results, studies now need to ensure safety on a large scale.
Interleukin 12 has been extensively studied24 and is a known promoter of the Th1 system, directly increasing CD4+ Th1 helper T cells and inducing tumor necrosis factor alpha and interferon gamma, among other inflammatory mediators. Interleukin 12 and its receptor share subunits with interleukin 23 and its receptor.
Newer research on interleukin 23 demonstrates induction of interleukin 17, which acts as a co-promotor of inflammation. Interestingly, human and murine subjects deficient in these interleukins exhibit increased susceptibility to infections, but current studies have not shown the antibodies to induce a significant risk of infection.
Two other anti-IL-12/IL-23 compounds are being developed and are currently in human trials for psoriasis.24
AUTOIMMUNE DERMATOLOGY: Blocking the B Lymphocyte
Rituximab: Wide-Reaching Applications
Rituximab, a chimeric monoclonal antibody to CD20 that induces a 6-month depletion of peripheral B lymphocytes, is showing promise in several rheumatologic diseases. Effectively able to markedly reduce humoral immunity, and thereby antibody-mediated immune disorders, rituximab is being investigated in multiple disorders, and in 2007 much new information was released.
For Pemphigus
Perhaps the most exciting application of rituximab for dermatologists is in pemphigus. The anti-desmoglein antibodies central to pemphigus vulgaris and foliaceous pathophysiology have prompted pilot studies.
Two case series25,26 involving a total of 33 patients with pemphigus reported 29 patients (88%) with complete responses after a single cycle of four weekly infusions at 375 mg per square meter of body surface. All patients responded to some degree, and most were able to reduce or stop other immunosuppressant medications. Some patients relapsed after a mean of 18 months, and a second course again cleared the disease. Only two serious infections, including fatal septicemia, were reported and both were more than 1 year after treatment.
For Dermatomyositis
By contrast, the results for dermatomyositis were less impressive.27 In a pilot study published in June, three of eight patients exhibited improvement in muscle strength, as defined by an objective measure (manual muscle testing). However, there was no significant change in creatine kinase levels or skin severity levels (as defined by the Dermatomyositis Skin Severity Index) in any patient. Patients were given two 1-g infusions of rituximab 2 weeks apart, while continuing other stable immunosuppressant therapies.
For Other Disorders
Rituximab has long been used in B-cell lymphomas, but has also demonstrated efficacy in rheumatoid arthritis and systemic lupus erythematosus.28
A systematic review28 concerning antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, such as Wegener granulomatosis and microscopic polyangiitis, was released this year and pointed to rituximab and infliximab as two therapeutic methods with high promise, although with low levels of evidence to date. Specifically, rituximab has been used in two small open pilot studies in cyclophosphamide- and prednisone-resistant ANCA cases, with complete remission in 95% of patients at 3 to 6 months.
Vitiligo Gene Described
From defensins to toll-like receptors, the innate arm of the immune response is becoming increasingly appreciated. In another important discovery this year, NALP1 has been connected with vitiligo, and by association, several other autoimmune disorders.29 NALP1 encodes NACHT leucine-rich-repeat protein 1, which catalyzes interleukin 1 and 18 production in response to uncharacterized signals, likely of bacterial or viral origin. NALP3 is known to be associated with cold urticaria and Muckle-Wells syndrome.
With this knowledge, targeted vitiligo therapy, such as interleukin 1 blockage, can now be attempted.30
DRUG REACTIONS: Not Your Classic Drug Rash
Gadolinium-Based Agents Receive FDA Warning
In May of this year, after mounting evidence31 linked nephrogenic systemic fibrosis (NSF) to gadolinium exposure, the FDA posted a warning concerning use of several gadolinium-based contrast agents (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, and ProHance) for magnetic resonance imaging in patients with renal impairment.30 The vast majority of NSF cases have occurred after gadodiamide (Omniscan) exposure, and some feel that the FDA warning should have been more explicit on this point.
Nephrogenic systemic fibrosis is a serious, multi-organ fibrosing disorder, and dermatologists often play a role in its diagnosis. Recent studies have demonstrated gadolinium in affected skin32 and bone marrow and support the primacy of this compound in inducing NSF, although renal insufficiency seems to be a requisite cofactor.
CTLA4 Blockers With Immune-Related Adverse Effects
A new therapy showing promise in melanoma has a high incidence of autoimmune-like reactions.33 Two drugs now in clinical trials are monoclonal antibodies to cytotoxic T lymphocyte antigen 4 (CTLA4). Blocking CTLA4 essentially leads to T-cell proliferation and persistence of immune responses, which may induce tumor rejection but also autoimmune phenomena.
Interestingly, response rates in Phase II trials were higher in patients experiencing these immune-related adverse effects. Dermatologists will likely be asked to recognize this highly variable type of drug reaction, which may mimic vitiligo or mycosis fungoides. Autoimmune adrenal crisis and enterocolitis are other common adverse effects.
CUTANEOUS ONCOLOGY: Melanoma Matters
PQRI Pay for Performance Measures
The Physician's Quality Reporting Initiative went into effect on July 1, 2007.34 This pilot program aims to reward physicians and other healthcare providers for reporting the execution of 140 quality measures, which have been developed by peer consensus as standard guidelines for improving patient outcomes and thereby reducing overall health spending.
Measure numbers 25, 26, and 27 are the only measures relevant to dermatology. They specifically require reporting of adequate history, exam and counseling for patients with a history of malignant melanoma. The history must include asking about new or changing moles; the exam must be a full- skin exam; the counseling must include recommending monthly skin self exams.
The reward for 80% reporting of these measures in patients with melanoma history is a 1.5% bonus on all CMS payments. This would amount to $2,500 for the average dermatologist.35
The program has advocates and opponents. These measures are considered standard, appropriate practice, and for most will not be difficult to implement. However, as more such measures are likely to be implemented while CMS payments are slowly reduced, incentives may dominate medical practice.
A short- term concern is the source and reliability of this year’s 1.5% bonus payment, which would amount to millions of dollars across all health care.35
New Sunscreen Labeling
Although still far from implementation, new proposed guidelines for sunscreen labeling were released by the FDA in August.36 Most dermatologists welcome this long-awaited move, as current sun protection factor (SPF) labeling relates only to UVB exposure and not to overall skin damage and cancer protection.
The new system would utilize four stars to indicate the level of UVA protection, with four stars equaling best UVA protection and zero stars labeled as “no UVA protection.” Under the proposed system, SPF would be specified as “SPF UVB” with the addendum “low,” “medium” or “high.” Testing for UVA and UVB would be required, but the means of testing would not be mandated.
New Biologics for Advanced Melanoma
After several decades of unsuccessful therapy for advanced melanoma, several drugs now in clinical trials are providing hope.
The most promising of these are the CTLA4 blockers, as mentioned previously. Several large studies are now examining the effect of CTLA4 blockers, both as monotherapy and in combination with chemotherapy and melanoma vaccine, in stage IV melanoma.
Ipilimumab, one of these CTLA4 blockers, was granted FastTrack status by the FDA in December 2006. Phase II studies released this year demonstrated 10% to 15% tumor response and 30% to 40% stabilization of disease.37 A slow onset of action is common, with many demonstrating a response only after 12 weeks.
Oblimersen, an antisense oligonucleotide, down-regulates Bcl-2 and narrowly missed FDA approval for treatment of late-stage melanoma. In large Phase III trials, the combination of oblimersen with DTIC had no overall survival benefit, but in the subset of patients with normal lactate dehydrogenase levels, it did achieve significant improvement in survival. Repeat Phase III trials are planned.38
Sorafenib, an antiangiogenesis protein kinase inhibitor with theoretic targeting of the BRAF mutation present in 70% of melanoma, has shown mixed results. A Phase II study with 101 patients demonstrated impressive progression-free survival, but there was no overall survival benefit when used as adjuvant to dacarbazine. A Phase III study with 270 patients showed no advantage to adjuvant sorafenib with paclitaxel-carboplatin.38
COSMETIC DERMATOLOGY: The Palette Expands
Hyaluronic Acid Update
Hyaluraonic acid (HA), a polysaccharide, is an important component of the extracellular matrix that maintains hydration, forms proteoglycans, and is involved in regulatory functions including cell proliferation.39 It is common to all living organisms, reducing concerns for immune reactions compared with collagen fillers. Currently manufactured HA products are either animal-stabilized (rooster combs) or non-animal (streptococcal-derived). The major factor for longevity and viscosity is cross-linkage, as natural HA is quickly degraded in vivo. Cross-linkage quantity and type vary by product. The excellent viscosity allows for softer, smoother filling than some collagen fillers.
Elevess is the first commercial HA product for aesthetic filling that incorporates lidocaine, and was FDA-approved in 2007.40 It is also the most concentrated cross-linked HA available among the current dermal fillers. Pain with injection, although traditionally less than with collagen fillers, has remained an issue for HA fillers and this product may be an important option in more pain-intolerant patients. The manufacturer, Anika Therapeutics, hopes to launch Elevess in the first half of 2008.
The FDA has approved the HA-based filler Perlane for deep dermal injection to correct facial folds and wrinkles such as nasolabial folds.41 Perlane differs from Restylane, a cousin compound from the same company, by the larger size of its hyaluronate particles, making it more amenable to larger, deeper defects.
Juvéderm is another hyaluronic acid product that received a change in FDA-indicated duration of action from 6 months to 1 year.42 Most other forms of HA are approved to endure for 6 months.
Great Strides in 2007
We have reviewed the highlights of another good year for skin medicine. The rapid advances in medical science are producing fascinating new therapies, and we as professionals have the responsibility of applying these therapies, with due caution, to our patients.
CME #133 December 2007
Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for one category 1 physician credit hour. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee.
In our year-end look back at dermatology in 2007, author Aaron Loyd, M.D., covers the year’s highlights, including the continuing struggles of iPLEDGE, the increasingly worrisome epidemic of MRSA, and the latest studies regarding therapies for psoriasis, atopic dermatitis, and acne.
At the end of this article, you’ll find an exam. Mark your responses in the designated area, then fax page 52 to NACCME at (610) 560-0501.
We’ll also post this course on our Web site, which you can access at www.skinandaging.com. I hope this CME contributes to your clinical skills.
Amy McMichael, M.D.
CME Editor
Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC.
Principal Faculty: Aaron Loyd, M.D.
Method of Participation: Physicians may receive 1 AMA PRA Category 1 Credit™ by reading the article on pages 45 through 50 and successfully answering the questions found on page 51. A score of 70% is required for passing. Submit your answers and evaluation via fax; or you may log on to our Web site at www.skinandaging.com.
Estimated Time to Complete Activity: 1 hour
Date of Original Release: December 1, 2007
Expiration Date: November 30, 2008
Accreditation Statement: This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NACCME designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.™ Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.
Off-Label/Unapproved Usage Discussion: This educational activity contains discussion of published and/or investigational uses of agents that are not indicated by the FDA. Neither NACCME, Genentech/Biogen Idec nor Roche recommends the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Disclosures: All those with control over the content of continuing education programs sponsored by NACCME are expected to disclose whether they do or do not have any real or apparent conflict(s) of interest or other relationships related to the content of their presentation(s). It is not assumed that these relationships will have an adverse impact on presentations; they are simply noted here to fully inform participants.
Dr. Loyd has disclosed that he has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of his article.
All those involved in the planning and editing of this educational activity have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of this educational activity.
Sponsor: This activity is sponsored by the North American Center for Continuing Medical Education.
Learning Objectives:
1. Identify major studies, new therapeutic interventions and updates on currently used medications from this past year.
2. Identify possible applications of new information from 2007 in an effort to improve therapeutic strategies for patients with skin disease.
Target Audience: Dermatologists
Commercial Support: None
Sponsor: NACCME
Year in Review
This year proved another exciting episode in dermatology, full of new therapeutics, new genes and new regulations. New regulatory issues, beyond the obvious drug approval apparatus, are affecting our specialty and should be familiar to all dermatologists. New genetic findings are driving more targeted therapies, from psoriasis to resistant bacterial infections. Finally, new therapeutics provide broader options with which to practice the art of dermatology and improve patient satisfaction.
INFECTIOUS DISEASE: Community Threat
S. aureus Resistance Update
A growing consensus has emerged in 2007 in the battle with methicillin-resistant Staphylococcus aureus (MRSA).
In July of this year, Hankin published a review of evidence for antibiotic use in abscesses, the most common presentation of MRSA.1 The bulk of the evidence, including the only two randomized controlled trials, suggests that incision and drainage is sufficient. In cohort studies, incorrect empiric antibiotics with incision and drainage produced the same results as correct antibiotics with incision and drainage. Nevertheless, lesions larger than 5 cm and patients with comorbidities or systemic symptoms may require antibiotic therapy and/or hospitalization.
Complicated Case Therapy
Antibiotics remain important adjuncts to incision and drainage in complicated cases, and better understanding of Staphylococcus aureus allows appropriate selection of therapy. MRSA prevalence is increasing, and in many urban areas may now be more common than methicillin-sensitive (MSSA) species.2,3 MRSA is categorized as community-associated (CA-MRSA) and hospital-associated, the prior having the small mec IV resistance cassette. Due to its small size, multi-drug resistant CA-MRSA is rare, and treatment with tetracycline or sulfa drugs should be the primary empiric drug therapy for community patients with a pus-containing lesion. Panton-Valentine leukocidin is the major virulence factor.
Patients with respiratory symptoms and close or personal contact with MRSA abscesses should be evaluated for MRSA pulmonary syndrome.
Colonization Reduction
While colonization does not correlate closely with infection, patients who develop infection should be treated to reduce colonization, as relapse is common. Skin surface colonization is at least as important as nasal colonization.3
Triclosan- and alcohol-based cleansers appear to be more effective than chlorhexidine. Mupirocin applied for 5 days to nares reduced nasal carriage by 44% compared with 23% for vehicle ointment in one study, while other studies have demonstrated that mupirocin resistance is rising. General good hygiene should be advocated.
Topical Antibiotics
The first of the pleuromutilin class of topical antibiotics has been approved in 20074 for staphylococcal and streptococcal impetigo in both pediatric and adult populations, with a dosage of twice daily for 5 days. Pleuromutilins are broad-spectrum antibiotics with novel anti-ribosomal activity.
Retapamulin (Altabax) was more effective than placebo in treating impetigo in a Phase III trial with clinical success rates of 85.6% (119/139) versus 52.1% (37/71) for placebo in the intent-to-treat (ITT) population (p<0.001).5 Additional Phase III trials have demonstrated noninferiority compared with sodium fusidate, with response rates of 94.8% versus 90.1% for retapamulin and sodium fusidate, respectively. In this trial, retapamulin was also effective for methicillin- and mupirocin-resistant strains of Staphylococcus aureus, 8/8 and 6/6, respectively.5
ACNE: Filling the Gap
iPLEDGE’s First Year
In October 2006 the iPLEDGE system was updated, with FDA approval, to rescind the 23-day "lockout" period for males and females of non-childbearing potential.6 This allowed these low-risk populations to receive immediate prescriptions for the drug after the 7-day window, provided the registration and counseling obligations were again fulfilled. Dermatologists had lobbied for this change from the initial mandatory inception of the system in March 2006.
Generally, the system has undergone significant streamlining, with long wait times and frequent server errors now uncommon.
However, the system is far from perfect. In July 2007, iPLEDGE’s first-year data was released.7 The news of 122 isotretinoin-associated pregnancies was sobering, although comparisons to previously reported numbers are unfair, given the increased scope of this monitoring system. All 122 for whom records were available had received and acknowledged appropriate counseling. Generally, when fault could be determined, failure was due either to contraceptive failure or using less than the recommended two forms of birth control.
Two events in August further underscore the need for change:
First, the FDA released a warning and Web site links concerning online purchasing of isotretinoin.8 This highlights the problem of unsupervised isotretinoin use. Although difficult to quantify, this fallout may significantly undermine the purpose of the iPLEDGE system, which is to reduce fetal exposure to isotretinoin.
Second, an FDA advisory panel voted unanimously to further relax the regulations of iPLEDGE.9 Specifics were not delineated, but proposed changes include allowing women of childbearing potential to obtain a prescription after the 7-day window if an additional pregnancy test is negative.
Adapalene (Differin) 0.3% Approval
Topical retinoid therapy remains the foundation of acne therapy. Variable concentrations are helpful for tailoring skin-type-specific regimens, and titrating strength of action. A higher concentration of adapalene received FDA approval in June 2007.
In a Phase III trial,10 635 patients were randomized to daily application of one of the three comparison compounds in a double-blind manner. Inflammatory lesions were reduced by 62.5%, 57.8% and 47.2% for adapalene 0.3%, 0.1% and vehicle gel respectively, all of which were statistically significant (p<0.015). Noninflammatory lesions showed 52.1%, 43.4% and 29.3% reduction, which did not reach significance between the adapalene 0.3% and 0.1% (p=0.061). There was some increase in dry skin (14% versus 7%) and skin discomfort (6% versus 5%) with the adapalene 0.3% gel versus 0.1% gel, which subsided by 4 weeks. Therapy was discontinued due to irritation in three, two and one patient(s) in the 0.3%, 0.1% and vehicle groups, respectively.
With superior efficacy and relative tolerability, adapalene 0.3% gel is a welcome addition to acne therapy.
Drospirenone/Ethinyl Estradiol (Yaz): New Acne Indications
In women of childbearing potential with inflammatory acne, alternative treatment options are sorely needed.
Yaz (3 mg DSP/20 mcg EE) is the first drug to be approved as oral contraceptive with two other indications: the treatment of acne vulgaris and premenstrual dysphoria.
FDA approval11 in January was based on two randomized blinded controlled trials involving approximately 1,000 patients with moderate acne, which demonstrated significant reductions in lesion counts as well as a two- to four-fold increase in total success (clear or almost clear) versus placebo (15% to 21% versus 4% to 9%).12 In separate trials,13,14 drospirenone (3 mg with 30 mcg EE) has been found to be at least as effective for acne as cyproterone (active ingredient in Diane) and norgestimate (active ingredient in Ortho Tri-Cyclin). As the effect of 3 mg of drospirenone is equated with 25 mg of spironolactone, some patients must be monitored for hyperkalemia.
Incyclinide in Early Trials
A blinded, controlled, Phase II dose-finding trial15 provided modest evidence of efficacy of the new tetracycline derivative incyclinide in treating acne. At 20-mg daily, results at 3 and 6 weeks were 25.9% and 36.1% reduction in inflammatory lesions versus 9.4% and 17.5% with placebo, respectively (p<0.07). A subsequently initiated cohort at 40 mg daily experienced at least one case of significant phototoxicity and has been suspended.
Incyclinide may provide adjunctive treatment for inflammatory acne without inducing antimicrobial resistance common with other tetracyclines.
High Glycemic Diet and Acne
The effect of diet on acne has been a question in the medical community for some time. Many patients hold common beliefs that certain foods cause acne, but no studies have ever demonstrated this. However, a randomized, controlled pilot study was released in August16 that revealed a possible role for diet in acne severity.
A group in Australia divided over 40 patients aged 16 to 25 with mild to moderate inflammatory acne into a specific low-glycemic index diet with food training and menu suggestions and a control group where normal carbohydrate-rich diets were encouraged. Only a gentle cleanser (Cetaphil) was allowed as topical therapy, in both arms.
At 12 weeks, a significant (p=0.01) reduction in acne lesions (22% versus 14%) was seen in the treatment group.
ECZEMA: New Hope for Chronic Disease
Resistant/RecalcitrantAtopic Dermatitis Therapy
In a study published this year, mycophenolate mofetil therapy was assessed in severe, resistant atopic dermatitis in pediatric patients, a group that has not been studied before with this drug. Of 14 patients, only one failed to respond while most (64%) achieved almost complete or complete clearance.17 No adverse effects were noted. While the study was small and uncontrolled, the relatively benign adverse effect profile of mycophenolate encourages further exploration of a possibly very helpful therapy.
In a systematic review released this year,18 cyclosporine was recommended as first-line therapy for recalcitrant atopic dermatitis, showing the most consistent and highest efficacy, generally at or above 50% reduction in severity at a dose of 3 to 5mg/kg/day.
Other therapies that demonstrate efficacy are azathioprine and interferon-gamma and mycophenolate mofetil.
Alitretinoin Phase III Trials for Hand Dermatitis
Company-released results of a Phase III, randomized double-blind placebo-controlled trial19 confirmed that alitretinoin, an oral retinoid, provides dose-related relief for sufferers of chronic and recalcitrant hand dermatitis.
With success defined as clear or almost-clear, 48% of patients treated with 30 mg daily, 28% treated with 10 mg, and 17% treated with placebo achieved success (p<0.001). A follow-up study revealed that 80% of patients previously treated successfully with alitretinoin cleared with retreatment for flares. Adverse effects were similar to other retinoids, with dryness, headaches and lipid elevations most common. Teratogenicity is the most important toxicity.
With the positive data, a new drug application is likely by the end of 2007.
PSORIASIS: A Horizon of Possibilities
Clobetasol in Emollient Foam Vehicle (Olux-E) Approved
A new treatment option is available for atopic dermatitis and psoriasis. Olux-E consists of clobetasol 0.05% in an emollient yet foam-delivered vehicle.
Randomization of approximately 400 patients with moderate to severe atopic dermatitis demonstrated that 52% of subjects treated with Olux-E versus 14% in vehicle arm achieved success, which was defined as clear or almost clear by Investigator’s Static Global
Assessment score and at least two grades of improvement from baseline.20
A similar randomized study for mild-to-moderate plaque-type psoriasis also confirmed efficacy. In the study, 41 of 253 treatment patients (16%) versus 18 of 126 vehicle subjects (4%) achieved the endpoint of success, defined as per the atopic study above. Both studies limited the study population to patients 12 years of age and older.20
Beyond clinical studies, it is believed that the foam vehicle may support patient compliance due to ease of use. Also, the emollient-based foam directly aids the barrier dysfunction of psoriasis and atopic dermatitis.
Efalizumab for Palmoplantar Psoriasis
Phase IV study data of efalizumab (Raptiva) for hand and foot psoriasis was presented in February.21 Eighty patients were randomized to receive either efalizumab at standard 1-mg/kg/week dosage or placebo.
In a double-blinded 12-week follow-up, 46.2% versus 17.9% (p=0.015) of patients in the respective groups achieved at least clearance to the point of mild. Perhaps more poignant is the 32.7% versus 7.1% (p=0.013) of those patients who received a grade of clear or almost clear. Many of the patients had previously failed other biologic therapies. These data indicate that nearly one-third of patients with recalcitrant palmoplantar psoriasis can expect near clearance with efalizumab.
Efalizumab is a kappa isotype human monoclonal antibody to the CD11a chain of LFA-1, a receptor on T cells that plays a prominent role in transmigration and activation. It was approved in 2005 for moderate to severe plaque psoriasis for which systemic or phototherapy is indicated.22 While the risk of infection and malignancy may be lower than with other biologics, a unique risk is immune-mediated thrombocytopenia.22
Interleukin 12 and 23 Monoclonal Antibody Drugs in Trials
A dose-finding trial with over 300 patients involving a new monoclonal antibody infusion for psoriasis (CNTR 1275) has shown robust efficacy.23 At the highest dose, 90 mg weekly infusion, 75% improvement in psoriasis area-and-severity index was achieved in 81% after 12 weeks versus 2% for placebo (p<0.001); 52% of these achieved 90% improvement. Even at this dose, side effects were generally well tolerated with serious adverse effects in 4% of the treatment group versus 1% of placebo (p=0.069). With these promising results, studies now need to ensure safety on a large scale.
Interleukin 12 has been extensively studied24 and is a known promoter of the Th1 system, directly increasing CD4+ Th1 helper T cells and inducing tumor necrosis factor alpha and interferon gamma, among other inflammatory mediators. Interleukin 12 and its receptor share subunits with interleukin 23 and its receptor.
Newer research on interleukin 23 demonstrates induction of interleukin 17, which acts as a co-promotor of inflammation. Interestingly, human and murine subjects deficient in these interleukins exhibit increased susceptibility to infections, but current studies have not shown the antibodies to induce a significant risk of infection.
Two other anti-IL-12/IL-23 compounds are being developed and are currently in human trials for psoriasis.24
AUTOIMMUNE DERMATOLOGY: Blocking the B Lymphocyte
Rituximab: Wide-Reaching Applications
Rituximab, a chimeric monoclonal antibody to CD20 that induces a 6-month depletion of peripheral B lymphocytes, is showing promise in several rheumatologic diseases. Effectively able to markedly reduce humoral immunity, and thereby antibody-mediated immune disorders, rituximab is being investigated in multiple disorders, and in 2007 much new information was released.
For Pemphigus
Perhaps the most exciting application of rituximab for dermatologists is in pemphigus. The anti-desmoglein antibodies central to pemphigus vulgaris and foliaceous pathophysiology have prompted pilot studies.
Two case series25,26 involving a total of 33 patients with pemphigus reported 29 patients (88%) with complete responses after a single cycle of four weekly infusions at 375 mg per square meter of body surface. All patients responded to some degree, and most were able to reduce or stop other immunosuppressant medications. Some patients relapsed after a mean of 18 months, and a second course again cleared the disease. Only two serious infections, including fatal septicemia, were reported and both were more than 1 year after treatment.
For Dermatomyositis
By contrast, the results for dermatomyositis were less impressive.27 In a pilot study published in June, three of eight patients exhibited improvement in muscle strength, as defined by an objective measure (manual muscle testing). However, there was no significant change in creatine kinase levels or skin severity levels (as defined by the Dermatomyositis Skin Severity Index) in any patient. Patients were given two 1-g infusions of rituximab 2 weeks apart, while continuing other stable immunosuppressant therapies.
For Other Disorders
Rituximab has long been used in B-cell lymphomas, but has also demonstrated efficacy in rheumatoid arthritis and systemic lupus erythematosus.28
A systematic review28 concerning antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, such as Wegener granulomatosis and microscopic polyangiitis, was released this year and pointed to rituximab and infliximab as two therapeutic methods with high promise, although with low levels of evidence to date. Specifically, rituximab has been used in two small open pilot studies in cyclophosphamide- and prednisone-resistant ANCA cases, with complete remission in 95% of patients at 3 to 6 months.
Vitiligo Gene Described
From defensins to toll-like receptors, the innate arm of the immune response is becoming increasingly appreciated. In another important discovery this year, NALP1 has been connected with vitiligo, and by association, several other autoimmune disorders.29 NALP1 encodes NACHT leucine-rich-repeat protein 1, which catalyzes interleukin 1 and 18 production in response to uncharacterized signals, likely of bacterial or viral origin. NALP3 is known to be associated with cold urticaria and Muckle-Wells syndrome.
With this knowledge, targeted vitiligo therapy, such as interleukin 1 blockage, can now be attempted.30
DRUG REACTIONS: Not Your Classic Drug Rash
Gadolinium-Based Agents Receive FDA Warning
In May of this year, after mounting evidence31 linked nephrogenic systemic fibrosis (NSF) to gadolinium exposure, the FDA posted a warning concerning use of several gadolinium-based contrast agents (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, and ProHance) for magnetic resonance imaging in patients with renal impairment.30 The vast majority of NSF cases have occurred after gadodiamide (Omniscan) exposure, and some feel that the FDA warning should have been more explicit on this point.
Nephrogenic systemic fibrosis is a serious, multi-organ fibrosing disorder, and dermatologists often play a role in its diagnosis. Recent studies have demonstrated gadolinium in affected skin32 and bone marrow and support the primacy of this compound in inducing NSF, although renal insufficiency seems to be a requisite cofactor.
CTLA4 Blockers With Immune-Related Adverse Effects
A new therapy showing promise in melanoma has a high incidence of autoimmune-like reactions.33 Two drugs now in clinical trials are monoclonal antibodies to cytotoxic T lymphocyte antigen 4 (CTLA4). Blocking CTLA4 essentially leads to T-cell proliferation and persistence of immune responses, which may induce tumor rejection but also autoimmune phenomena.
Interestingly, response rates in Phase II trials were higher in patients experiencing these immune-related adverse effects. Dermatologists will likely be asked to recognize this highly variable type of drug reaction, which may mimic vitiligo or mycosis fungoides. Autoimmune adrenal crisis and enterocolitis are other common adverse effects.
CUTANEOUS ONCOLOGY: Melanoma Matters
PQRI Pay for Performance Measures
The Physician's Quality Reporting Initiative went into effect on July 1, 2007.34 This pilot program aims to reward physicians and other healthcare providers for reporting the execution of 140 quality measures, which have been developed by peer consensus as standard guidelines for improving patient outcomes and thereby reducing overall health spending.
Measure numbers 25, 26, and 27 are the only measures relevant to dermatology. They specifically require reporting of adequate history, exam and counseling for patients with a history of malignant melanoma. The history must include asking about new or changing moles; the exam must be a full- skin exam; the counseling must include recommending monthly skin self exams.
The reward for 80% reporting of these measures in patients with melanoma history is a 1.5% bonus on all CMS payments. This would amount to $2,500 for the average dermatologist.35
The program has advocates and opponents. These measures are considered standard, appropriate practice, and for most will not be difficult to implement. However, as more such measures are likely to be implemented while CMS payments are slowly reduced, incentives may dominate medical practice.
A short- term concern is the source and reliability of this year’s 1.5% bonus payment, which would amount to millions of dollars across all health care.35
New Sunscreen Labeling
Although still far from implementation, new proposed guidelines for sunscreen labeling were released by the FDA in August.36 Most dermatologists welcome this long-awaited move, as current sun protection factor (SPF) labeling relates only to UVB exposure and not to overall skin damage and cancer protection.
The new system would utilize four stars to indicate the level of UVA protection, with four stars equaling best UVA protection and zero stars labeled as “no UVA protection.” Under the proposed system, SPF would be specified as “SPF UVB” with the addendum “low,” “medium” or “high.” Testing for UVA and UVB would be required, but the means of testing would not be mandated.
New Biologics for Advanced Melanoma
After several decades of unsuccessful therapy for advanced melanoma, several drugs now in clinical trials are providing hope.
The most promising of these are the CTLA4 blockers, as mentioned previously. Several large studies are now examining the effect of CTLA4 blockers, both as monotherapy and in combination with chemotherapy and melanoma vaccine, in stage IV melanoma.
Ipilimumab, one of these CTLA4 blockers, was granted FastTrack status by the FDA in December 2006. Phase II studies released this year demonstrated 10% to 15% tumor response and 30% to 40% stabilization of disease.37 A slow onset of action is common, with many demonstrating a response only after 12 weeks.
Oblimersen, an antisense oligonucleotide, down-regulates Bcl-2 and narrowly missed FDA approval for treatment of late-stage melanoma. In large Phase III trials, the combination of oblimersen with DTIC had no overall survival benefit, but in the subset of patients with normal lactate dehydrogenase levels, it did achieve significant improvement in survival. Repeat Phase III trials are planned.38
Sorafenib, an antiangiogenesis protein kinase inhibitor with theoretic targeting of the BRAF mutation present in 70% of melanoma, has shown mixed results. A Phase II study with 101 patients demonstrated impressive progression-free survival, but there was no overall survival benefit when used as adjuvant to dacarbazine. A Phase III study with 270 patients showed no advantage to adjuvant sorafenib with paclitaxel-carboplatin.38
COSMETIC DERMATOLOGY: The Palette Expands
Hyaluronic Acid Update
Hyaluraonic acid (HA), a polysaccharide, is an important component of the extracellular matrix that maintains hydration, forms proteoglycans, and is involved in regulatory functions including cell proliferation.39 It is common to all living organisms, reducing concerns for immune reactions compared with collagen fillers. Currently manufactured HA products are either animal-stabilized (rooster combs) or non-animal (streptococcal-derived). The major factor for longevity and viscosity is cross-linkage, as natural HA is quickly degraded in vivo. Cross-linkage quantity and type vary by product. The excellent viscosity allows for softer, smoother filling than some collagen fillers.
Elevess is the first commercial HA product for aesthetic filling that incorporates lidocaine, and was FDA-approved in 2007.40 It is also the most concentrated cross-linked HA available among the current dermal fillers. Pain with injection, although traditionally less than with collagen fillers, has remained an issue for HA fillers and this product may be an important option in more pain-intolerant patients. The manufacturer, Anika Therapeutics, hopes to launch Elevess in the first half of 2008.
The FDA has approved the HA-based filler Perlane for deep dermal injection to correct facial folds and wrinkles such as nasolabial folds.41 Perlane differs from Restylane, a cousin compound from the same company, by the larger size of its hyaluronate particles, making it more amenable to larger, deeper defects.
Juvéderm is another hyaluronic acid product that received a change in FDA-indicated duration of action from 6 months to 1 year.42 Most other forms of HA are approved to endure for 6 months.
Great Strides in 2007
We have reviewed the highlights of another good year for skin medicine. The rapid advances in medical science are producing fascinating new therapies, and we as professionals have the responsibility of applying these therapies, with due caution, to our patients.
CME #133 December 2007
Skin & Aging is proud to bring you this latest installment in its CME series. This series consists of regular CME activities that qualify you for one category 1 physician credit hour. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee.
In our year-end look back at dermatology in 2007, author Aaron Loyd, M.D., covers the year’s highlights, including the continuing struggles of iPLEDGE, the increasingly worrisome epidemic of MRSA, and the latest studies regarding therapies for psoriasis, atopic dermatitis, and acne.
At the end of this article, you’ll find an exam. Mark your responses in the designated area, then fax page 52 to NACCME at (610) 560-0501.
We’ll also post this course on our Web site, which you can access at www.skinandaging.com. I hope this CME contributes to your clinical skills.
Amy McMichael, M.D.
CME Editor
Amy McMichael, M.D., is Associate Professor in the Department of Dermatology, Director of the Hair Disorders Clinic and Residency Program Director at Wake Forest University Medical Center in Winston-Salem, NC.
Principal Faculty: Aaron Loyd, M.D.
Method of Participation: Physicians may receive 1 AMA PRA Category 1 Credit™ by reading the article on pages 45 through 50 and successfully answering the questions found on page 51. A score of 70% is required for passing. Submit your answers and evaluation via fax; or you may log on to our Web site at www.skinandaging.com.
Estimated Time to Complete Activity: 1 hour
Date of Original Release: December 1, 2007
Expiration Date: November 30, 2008
Accreditation Statement: This activity is sponsored by the North American Center for Continuing Medical Education (NACCME). NACCME is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NACCME designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit.™ Physicians should only claim credit commensurate with the extent of their participation in the activity. This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.
Off-Label/Unapproved Usage Discussion: This educational activity contains discussion of published and/or investigational uses of agents that are not indicated by the FDA. Neither NACCME, Genentech/Biogen Idec nor Roche recommends the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.
Disclosures: All those with control over the content of continuing education programs sponsored by NACCME are expected to disclose whether they do or do not have any real or apparent conflict(s) of interest or other relationships related to the content of their presentation(s). It is not assumed that these relationships will have an adverse impact on presentations; they are simply noted here to fully inform participants.
Dr. Loyd has disclosed that he has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of his article.
All those involved in the planning and editing of this educational activity have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the context of this educational activity.
Sponsor: This activity is sponsored by the North American Center for Continuing Medical Education.
Learning Objectives:
1. Identify major studies, new therapeutic interventions and updates on currently used medications from this past year.
2. Identify possible applications of new information from 2007 in an effort to improve therapeutic strategies for patients with skin disease.
Target Audience: Dermatologists
Commercial Support: None
Sponsor: NACCME
Year in Review
This year proved another exciting episode in dermatology, full of new therapeutics, new genes and new regulations. New regulatory issues, beyond the obvious drug approval apparatus, are affecting our specialty and should be familiar to all dermatologists. New genetic findings are driving more targeted therapies, from psoriasis to resistant bacterial infections. Finally, new therapeutics provide broader options with which to practice the art of dermatology and improve patient satisfaction.
INFECTIOUS DISEASE: Community Threat
S. aureus Resistance Update
A growing consensus has emerged in 2007 in the battle with methicillin-resistant Staphylococcus aureus (MRSA).
In July of this year, Hankin published a review of evidence for antibiotic use in abscesses, the most common presentation of MRSA.1 The bulk of the evidence, including the only two randomized controlled trials, suggests that incision and drainage is sufficient. In cohort studies, incorrect empiric antibiotics with incision and drainage produced the same results as correct antibiotics with incision and drainage. Nevertheless, lesions larger than 5 cm and patients with comorbidities or systemic symptoms may require antibiotic therapy and/or hospitalization.
Complicated Case Therapy
Antibiotics remain important adjuncts to incision and drainage in complicated cases, and better understanding of Staphylococcus aureus allows appropriate selection of therapy. MRSA prevalence is increasing, and in many urban areas may now be more common than methicillin-sensitive (MSSA) species.2,3 MRSA is categorized as community-associated (CA-MRSA) and hospital-associated, the prior having the small mec IV resistance cassette. Due to its small size, multi-drug resistant CA-MRSA is rare, and treatment with tetracycline or sulfa drugs should be the primary empiric drug therapy for community patients with a pus-containing lesion. Panton-Valentine leukocidin is the major virulence factor.
Patients with respiratory symptoms and close or personal contact with MRSA abscesses should be evaluated for MRSA pulmonary syndrome.
Colonization Reduction
While colonization does not correlate closely with infection, patients who develop infection should be treated to reduce colonization, as relapse is common. Skin surface colonization is at least as important as nasal colonization.3
Triclosan- and alcohol-based cleansers appear to be more effective than chlorhexidine. Mupirocin applied for 5 days to nares reduced nasal carriage by 44% compared with 23% for vehicle ointment in one study, while other studies have demonstrated that mupirocin resistance is rising. General good hygiene should be advocated.
Topical Antibiotics
The first of the pleuromutilin class of topical antibiotics has been approved in 20074 for staphylococcal and streptococcal impetigo in both pediatric and adult populations, with a dosage of twice daily for 5 days. Pleuromutilins are broad-spectrum antibiotics with novel anti-ribosomal activity.
Retapamulin (Altabax) was more effective than placebo in treating impetigo in a Phase III trial with clinical success rates of 85.6% (119/139) versus 52.1% (37/71) for placebo in the intent-to-treat (ITT) population (p<0.001).5 Additional Phase III trials have demonstrated noninferiority compared with sodium fusidate, with response rates of 94.8% versus 90.1% for retapamulin and sodium fusidate, respectively. In this trial, retapamulin was also effective for methicillin- and mupirocin-resistant strains of Staphylococcus aureus, 8/8 and 6/6, respectively.5
ACNE: Filling the Gap
iPLEDGE’s First Year
In October 2006 the iPLEDGE system was updated, with FDA approval, to rescind the 23-day "lockout" period for males and females of non-childbearing potential.6 This allowed these low-risk populations to receive immediate prescriptions for the drug after the 7-day window, provided the registration and counseling obligations were again fulfilled. Dermatologists had lobbied for this change from the initial mandatory inception of the system in March 2006.
Generally, the system has undergone significant streamlining, with long wait times and frequent server errors now uncommon.
However, the system is far from perfect. In July 2007, iPLEDGE’s first-year data was released.7 The news of 122 isotretinoin-associated pregnancies was sobering, although comparisons to previously reported numbers are unfair, given the increased scope of this monitoring system. All 122 for whom records were available had received and acknowledged appropriate counseling. Generally, when fault could be determined, failure was due either to contraceptive failure or using less than the recommended two forms of birth control.
Two events in August further underscore the need for change:
First, the FDA released a warning and Web site links concerning online purchasing of isotretinoin.8 This highlights the problem of unsupervised isotretinoin use. Although difficult to quantify, this fallout may significantly undermine the purpose of the iPLEDGE system, which is to reduce fetal exposure to isotretinoin.
Second, an FDA advisory panel voted unanimously to further relax the regulations of iPLEDGE.9 Specifics were not delineated, but proposed changes include allowing women of childbearing potential to obtain a prescription after the 7-day window if an additional pregnancy test is negative.
Adapalene (Differin) 0.3% Approval
Topical retinoid therapy remains the foundation of acne therapy. Variable concentrations are helpful for tailoring skin-type-specific regimens, and titrating strength of action. A higher concentration of adapalene received FDA approval in June 2007.
In a Phase III trial,10 635 patients were randomized to daily application of one of the three comparison compounds in a double-blind manner. Inflammatory lesions were reduced by 62.5%, 57.8% and 47.2% for adapalene 0.3%, 0.1% and vehicle gel respectively, all of which were statistically significant (p<0.015). Noninflammatory lesions showed 52.1%, 43.4% and 29.3% reduction, which did not reach significance between the adapalene 0.3% and 0.1% (p=0.061). There was some increase in dry skin (14% versus 7%) and skin discomfort (6% versus 5%) with the adapalene 0.3% gel versus 0.1% gel, which subsided by 4 weeks. Therapy was discontinued due to irritation in three, two and one patient(s) in the 0.3%, 0.1% and vehicle groups, respectively.
With superior efficacy and relative tolerability, adapalene 0.3% gel is a welcome addition to acne therapy.
Drospirenone/Ethinyl Estradiol (Yaz): New Acne Indications
In women of childbearing potential with inflammatory acne, alternative treatment options are sorely needed.
Yaz (3 mg DSP/20 mcg EE) is the first drug to be approved as oral contraceptive with two other indications: the treatment of acne vulgaris and premenstrual dysphoria.
FDA approval11 in January was based on two randomized blinded controlled trials involving approximately 1,000 patients with moderate acne, which demonstrated significant reductions in lesion counts as well as a two- to four-fold increase in total success (clear or almost clear) versus placebo (15% to 21% versus 4% to 9%).12 In separate trials,13,14 drospirenone (3 mg with 30 mcg EE) has been found to be at least as effective for acne as cyproterone (active ingredient in Diane) and norgestimate (active ingredient in Ortho Tri-Cyclin). As the effect of 3 mg of drospirenone is equated with 25 mg of spironolactone, some patients must be monitored for hyperkalemia.
Incyclinide in Early Trials
A blinded, controlled, Phase II dose-finding trial15 provided modest evidence of efficacy of the new tetracycline derivative incyclinide in treating acne. At 20-mg daily, results at 3 and 6 weeks were 25.9% and 36.1% reduction in inflammatory lesions versus 9.4% and 17.5% with placebo, respectively (p<0.07). A subsequently initiated cohort at 40 mg daily experienced at least one case of significant phototoxicity and has been suspended.
Incyclinide may provide adjunctive treatment for inflammatory acne without inducing antimicrobial resistance common with other tetracyclines.
High Glycemic Diet and Acne
The effect of diet on acne has been a question in the medical community for some time. Many patients hold common beliefs that certain foods cause acne, but no studies have ever demonstrated this. However, a randomized, controlled pilot study was released in August16 that revealed a possible role for diet in acne severity.
A group in Australia divided over 40 patients aged 16 to 25 with mild to moderate inflammatory acne into a specific low-glycemic index diet with food training and menu suggestions and a control group where normal carbohydrate-rich diets were encouraged. Only a gentle cleanser (Cetaphil) was allowed as topical therapy, in both arms.
At 12 weeks, a significant (p=0.01) reduction in acne lesions (22% versus 14%) was seen in the treatment group.
ECZEMA: New Hope for Chronic Disease
Resistant/RecalcitrantAtopic Dermatitis Therapy
In a study published this year, mycophenolate mofetil therapy was assessed in severe, resistant atopic dermatitis in pediatric patients, a group that has not been studied before with this drug. Of 14 patients, only one failed to respond while most (64%) achieved almost complete or complete clearance.17 No adverse effects were noted. While the study was small and uncontrolled, the relatively benign adverse effect profile of mycophenolate encourages further exploration of a possibly very helpful therapy.
In a systematic review released this year,18 cyclosporine was recommended as first-line therapy for recalcitrant atopic dermatitis, showing the most consistent and highest efficacy, generally at or above 50% reduction in severity at a dose of 3 to 5mg/kg/day.
Other therapies that demonstrate efficacy are azathioprine and interferon-gamma and mycophenolate mofetil.
Alitretinoin Phase III Trials for Hand Dermatitis
Company-released results of a Phase III, randomized double-blind placebo-controlled trial19 confirmed that alitretinoin, an oral retinoid, provides dose-related relief for sufferers of chronic and recalcitrant hand dermatitis.
With success defined as clear or almost-clear, 48% of patients treated with 30 mg daily, 28% treated with 10 mg, and 17% treated with placebo achieved success (p<0.001). A follow-up study revealed that 80% of patients previously treated successfully with alitretinoin cleared with retreatment for flares. Adverse effects were similar to other retinoids, with dryness, headaches and lipid elevations most common. Teratogenicity is the most important toxicity.
With the positive data, a new drug application is likely by the end of 2007.
PSORIASIS: A Horizon of Possibilities
Clobetasol in Emollient Foam Vehicle (Olux-E) Approved
A new treatment option is available for atopic dermatitis and psoriasis. Olux-E consists of clobetasol 0.05% in an emollient yet foam-delivered vehicle.
Randomization of approximately 400 patients with moderate to severe atopic dermatitis demonstrated that 52% of subjects treated with Olux-E versus 14% in vehicle arm achieved success, which was defined as clear or almost clear by Investigator’s Static Global
Assessment score and at least two grades of improvement from baseline.20
A similar randomized study for mild-to-moderate plaque-type psoriasis also confirmed efficacy. In the study, 41 of 253 treatment patients (16%) versus 18 of 126 vehicle subjects (4%) achieved the endpoint of success, defined as per the atopic study above. Both studies limited the study population to patients 12 years of age and older.20
Beyond clinical studies, it is believed that the foam vehicle may support patient compliance due to ease of use. Also, the emollient-based foam directly aids the barrier dysfunction of psoriasis and atopic dermatitis.
Efalizumab for Palmoplantar Psoriasis
Phase IV study data of efalizumab (Raptiva) for hand and foot psoriasis was presented in February.21 Eighty patients were randomized to receive either efalizumab at standard 1-mg/kg/week dosage or placebo.
In a double-blinded 12-week follow-up, 46.2% versus 17.9% (p=0.015) of patients in the respective groups achieved at least clearance to the point of mild. Perhaps more poignant is the 32.7% versus 7.1% (p=0.013) of those patients who received a grade of clear or almost clear. Many of the patients had previously failed other biologic therapies. These data indicate that nearly one-third of patients with recalcitrant palmoplantar psoriasis can expect near clearance with efalizumab.
Efalizumab is a kappa isotype human monoclonal antibody to the CD11a chain of LFA-1, a receptor on T cells that plays a prominent role in transmigration and activation. It was approved in 2005 for moderate to severe plaque psoriasis for which systemic or phototherapy is indicated.22 While the risk of infection and malignancy may be lower than with other biologics, a unique risk is immune-mediated thrombocytopenia.22
Interleukin 12 and 23 Monoclonal Antibody Drugs in Trials
A dose-finding trial with over 300 patients involving a new monoclonal antibody infusion for psoriasis (CNTR 1275) has shown robust efficacy.23 At the highest dose, 90 mg weekly infusion, 75% improvement in psoriasis area-and-severity index was achieved in 81% after 12 weeks versus 2% for placebo (p<0.001); 52% of these achieved 90% improvement. Even at this dose, side effects were generally well tolerated with serious adverse effects in 4% of the treatment group versus 1% of placebo (p=0.069). With these promising results, studies now need to ensure safety on a large scale.
Interleukin 12 has been extensively studied24 and is a known promoter of the Th1 system, directly increasing CD4+ Th1 helper T cells and inducing tumor necrosis factor alpha and interferon gamma, among other inflammatory mediators. Interleukin 12 and its receptor share subunits with interleukin 23 and its receptor.
Newer research on interleukin 23 demonstrates induction of interleukin 17, which acts as a co-promotor of inflammation. Interestingly, human and murine subjects deficient in these interleukins exhibit increased susceptibility to infections, but current studies have not shown the antibodies to induce a significant risk of infection.
Two other anti-IL-12/IL-23 compounds are being developed and are currently in human trials for psoriasis.24
AUTOIMMUNE DERMATOLOGY: Blocking the B Lymphocyte
Rituximab: Wide-Reaching Applications
Rituximab, a chimeric monoclonal antibody to CD20 that induces a 6-month depletion of peripheral B lymphocytes, is showing promise in several rheumatologic diseases. Effectively able to markedly reduce humoral immunity, and thereby antibody-mediated immune disorders, rituximab is being investigated in multiple disorders, and in 2007 much new information was released.
For Pemphigus
Perhaps the most exciting application of rituximab for dermatologists is in pemphigus. The anti-desmoglein antibodies central to pemphigus vulgaris and foliaceous pathophysiology have prompted pilot studies.
Two case series25,26 involving a total of 33 patients with pemphigus reported 29 patients (88%) with complete responses after a single cycle of four weekly infusions at 375 mg per square meter of body surface. All patients responded to some degree, and most were able to reduce or stop other immunosuppressant medications. Some patients relapsed after a mean of 18 months, and a second course again cleared the disease. Only two serious infections, including fatal septicemia, were reported and both were more than 1 year after treatment.
For Dermatomyositis
By contrast, the results for dermatomyositis were less impressive.27 In a pilot study published in June, three of eight patients exhibited improvement in muscle strength, as defined by an objective measure (manual muscle testing). However, there was no significant change in creatine kinase levels or skin severity levels (as defined by the Dermatomyositis Skin Severity Index) in any patient. Patients were given two 1-g infusions of rituximab 2 weeks apart, while continuing other stable immunosuppressant therapies.
For Other Disorders
Rituximab has long been used in B-cell lymphomas, but has also demonstrated efficacy in rheumatoid arthritis and systemic lupus erythematosus.28
A systematic review28 concerning antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, such as Wegener granulomatosis and microscopic polyangiitis, was released this year and pointed to rituximab and infliximab as two therapeutic methods with high promise, although with low levels of evidence to date. Specifically, rituximab has been used in two small open pilot studies in cyclophosphamide- and prednisone-resistant ANCA cases, with complete remission in 95% of patients at 3 to 6 months.
Vitiligo Gene Described
From defensins to toll-like receptors, the innate arm of the immune response is becoming increasingly appreciated. In another important discovery this year, NALP1 has been connected with vitiligo, and by association, several other autoimmune disorders.29 NALP1 encodes NACHT leucine-rich-repeat protein 1, which catalyzes interleukin 1 and 18 production in response to uncharacterized signals, likely of bacterial or viral origin. NALP3 is known to be associated with cold urticaria and Muckle-Wells syndrome.
With this knowledge, targeted vitiligo therapy, such as interleukin 1 blockage, can now be attempted.30
DRUG REACTIONS: Not Your Classic Drug Rash
Gadolinium-Based Agents Receive FDA Warning
In May of this year, after mounting evidence31 linked nephrogenic systemic fibrosis (NSF) to gadolinium exposure, the FDA posted a warning concerning use of several gadolinium-based contrast agents (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, and ProHance) for magnetic resonance imaging in patients with renal impairment.30 The vast majority of NSF cases have occurred after gadodiamide (Omniscan) exposure, and some feel that the FDA warning should have been more explicit on this point.
Nephrogenic systemic fibrosis is a serious, multi-organ fibrosing disorder, and dermatologists often play a role in its diagnosis. Recent studies have demonstrated gadolinium in affected skin32 and bone marrow and support the primacy of this compound in inducing NSF, although renal insufficiency seems to be a requisite cofactor.
CTLA4 Blockers With Immune-Related Adverse Effects
A new therapy showing promise in melanoma has a high incidence of autoimmune-like reactions.33 Two drugs now in clinical trials are monoclonal antibodies to cytotoxic T lymphocyte antigen 4 (CTLA4). Blocking CTLA4 essentially leads to T-cell proliferation and persistence of immune responses, which may induce tumor rejection but also autoimmune phenomena.
Interestingly, response rates in Phase II trials were higher in patients experiencing these immune-related adverse effects. Dermatologists will likely be asked to recognize this highly variable type of drug reaction, which may mimic vitiligo or mycosis fungoides. Autoimmune adrenal crisis and enterocolitis are other common adverse effects.
CUTANEOUS ONCOLOGY: Melanoma Matters
PQRI Pay for Performance Measures
The Physician's Quality Reporting Initiative went into effect on July 1, 2007.34 This pilot program aims to reward physicians and other healthcare providers for reporting the execution of 140 quality measures, which have been developed by peer consensus as standard guidelines for improving patient outcomes and thereby reducing overall health spending.
Measure numbers 25, 26, and 27 are the only measures relevant to dermatology. They specifically require reporting of adequate history, exam and counseling for patients with a history of malignant melanoma. The history must include asking about new or changing moles; the exam must be a full- skin exam; the counseling must include recommending monthly skin self exams.
The reward for 80% reporting of these measures in patients with melanoma history is a 1.5% bonus on all CMS payments. This would amount to $2,500 for the average dermatologist.35
The program has advocates and opponents. These measures are considered standard, appropriate practice, and for most will not be difficult to implement. However, as more such measures are likely to be implemented while CMS payments are slowly reduced, incentives may dominate medical practice.
A short- term concern is the source and reliability of this year’s 1.5% bonus payment, which would amount to millions of dollars across all health care.35
New Sunscreen Labeling
Although still far from implementation, new proposed guidelines for sunscreen labeling were released by the FDA in August.36 Most dermatologists welcome this long-awaited move, as current sun protection factor (SPF) labeling relates only to UVB exposure and not to overall skin damage and cancer protection.
The new system would utilize four stars to indicate the level of UVA protection, with four stars equaling best UVA protection and zero stars labeled as “no UVA protection.” Under the proposed system, SPF would be specified as “SPF UVB” with the addendum “low,” “medium” or “high.” Testing for UVA and UVB would be required, but the means of testing would not be mandated.
New Biologics for Advanced Melanoma
After several decades of unsuccessful therapy for advanced melanoma, several drugs now in clinical trials are providing hope.
The most promising of these are the CTLA4 blockers, as mentioned previously. Several large studies are now examining the effect of CTLA4 blockers, both as monotherapy and in combination with chemotherapy and melanoma vaccine, in stage IV melanoma.
Ipilimumab, one of these CTLA4 blockers, was granted FastTrack status by the FDA in December 2006. Phase II studies released this year demonstrated 10% to 15% tumor response and 30% to 40% stabilization of disease.37 A slow onset of action is common, with many demonstrating a response only after 12 weeks.
Oblimersen, an antisense oligonucleotide, down-regulates Bcl-2 and narrowly missed FDA approval for treatment of late-stage melanoma. In large Phase III trials, the combination of oblimersen with DTIC had no overall survival benefit, but in the subset of patients with normal lactate dehydrogenase levels, it did achieve significant improvement in survival. Repeat Phase III trials are planned.38
Sorafenib, an antiangiogenesis protein kinase inhibitor with theoretic targeting of the BRAF mutation present in 70% of melanoma, has shown mixed results. A Phase II study with 101 patients demonstrated impressive progression-free survival, but there was no overall survival benefit when used as adjuvant to dacarbazine. A Phase III study with 270 patients showed no advantage to adjuvant sorafenib with paclitaxel-carboplatin.38
COSMETIC DERMATOLOGY: The Palette Expands
Hyaluronic Acid Update
Hyaluraonic acid (HA), a polysaccharide, is an important component of the extracellular matrix that maintains hydration, forms proteoglycans, and is involved in regulatory functions including cell proliferation.39 It is common to all living organisms, reducing concerns for immune reactions compared with collagen fillers. Currently manufactured HA products are either animal-stabilized (rooster combs) or non-animal (streptococcal-derived). The major factor for longevity and viscosity is cross-linkage, as natural HA is quickly degraded in vivo. Cross-linkage quantity and type vary by product. The excellent viscosity allows for softer, smoother filling than some collagen fillers.
Elevess is the first commercial HA product for aesthetic filling that incorporates lidocaine, and was FDA-approved in 2007.40 It is also the most concentrated cross-linked HA available among the current dermal fillers. Pain with injection, although traditionally less than with collagen fillers, has remained an issue for HA fillers and this product may be an important option in more pain-intolerant patients. The manufacturer, Anika Therapeutics, hopes to launch Elevess in the first half of 2008.
The FDA has approved the HA-based filler Perlane for deep dermal injection to correct facial folds and wrinkles such as nasolabial folds.41 Perlane differs from Restylane, a cousin compound from the same company, by the larger size of its hyaluronate particles, making it more amenable to larger, deeper defects.
Juvéderm is another hyaluronic acid product that received a change in FDA-indicated duration of action from 6 months to 1 year.42 Most other forms of HA are approved to endure for 6 months.
Great Strides in 2007
We have reviewed the highlights of another good year for skin medicine. The rapid advances in medical science are producing fascinating new therapies, and we as professionals have the responsibility of applying these therapies, with due caution, to our patients.
