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 two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee.
As 2006 nears its end, Christina L. Haverstock, M.D., and Nina F. Abraham, B.A., look back on the year in dermatology. And, 2006 was an exciting, and somewhat controversial, year — the HPV vaccine was released, iPLEDGE was introduced, several drugs were approved for new indications, and old favorites received new warnings. The authors highlight the many changes dermatology has experienced over the past year.
At the end of this article, you’ll find an exam. Mark your responses in the designated area, then fax page 49 to HMP Communications 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: Christina L. Haverstock, M.D., and Nina F. Abraham, B.A.
Method of Participation: Physicians may receive two category 1 credits by reading the article on pp. 41 to 47 and successfully answering the questions found on pp. 48 to 49. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to our Web site at www.skinandaging.com.
Estimated Time to Complete Activity: 2 hours
Date of Original Release: December 2006
Expiration Date: December 2007
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.
Designation Statement: NACCME designates this continuing medical education activity for a maximum of 2 category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity.
This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies
Disclosure Policy: All those with control over the content of continuing education programs sponsored by the North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. It is not assumed that these financial interests or affiliations will have an adverse impact on presentations; they are simply noted here to fully inform participants.
Faculty Disclosures: Dr. Haverstock and Ms. Abraham have disclosed that they has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the contexts of the subject of this article.
Learning Objectives:
1.Identify major studies and their implications, new therapeutic interventions and updates on currently used medications from this past year.
2. Identify possible applications of new information from 2006 in an effort to improve dermatologic care and therapeutic strategies.
Target Audience: Dermatologists, Plastic Surgeons, Internists
Commercial Support: None
Sponsor: NACCME
2006 YEAR IN REVIEW
The year 2006 was monumental for medicine and dermatology. The HPV vaccine was released, iPLEDGE was introduced, several drugs were approved for new indications, and old favorites received new warnings. Here, we’ll highlight the exciting, innovative, and routine changes the field of dermatology has experienced over the past year — covering everything from infectious diseases to psoriasis to pediatric dermatology.
Infectious Diseases
HPV Vaccine. Certainly one of the most exciting things to happen in medicine this year was the release of the human papillomavirus (HPV) vaccine Gardasil.
The HPV vaccine was approved by the FDA in June 2006 after numerous studies demonstrated its safety and efficacy.1 It is a quadrivalent vaccine composed of proteins from the L1 capsid from HPV strains 6, 11, 16 and 18 (no live virus) — the strains of HPV responsible for 70% of cervical cancer.
Cervical cancer remains an important cause of morbidity and mortality in the United States and worldwide. More than 9,000 new cases of cervical cancer are diagnosed every year, and this cancer is responsible for 3,700 deaths annually in this country.2 The vaccine has been shown to be 100% effective in preventing pre-cancerous lesions of the cervix and vulva as well as genital warts, as long as the patient has not been previously infected with one of the strains of HPV.2-3
The time course of the studies was not sufficient to demonstrate a decrease in the rate of cervical cancer from the new vaccine; however, it is felt that there will be an inevitable decrease as the vaccine use becomes part of regular medical practice.
Gardasil is currently approved for use in females aged 9 to 26 years, and when administered on a more regular basis, will result in a decrease in the number of genital warts that dermatologists and all practitioners see and treat in female patients. Since genital warts are the most common sexually transmitted disease in the United States it would be ideal to have a similar prevention strategy for male counterparts.4
Zoster vaccine. Zostavax, a vaccine designed to decrease the risk of herpes zoster (see photo 1), was also FDA approved this year.5 The vaccine contains live virus and is indicated in persons older than 60 years. Shingles is caused by reactivation of dormant herpes zoster virus and is rarely a threat to life; however, the incidence and severity of herpes zoster reactivation increases with age. In addition, zoster is associated with morbidity secondary to post herpetic neuralgia (PHN) and chronic pain after reactivation. The risk of PHN also increases with age.
In trials, Zostavax was administered to more than 38,000 patients and was shown to decrease the incidence of zoster by 51% and decrease the incidence of PHN by 66%.6 Guidelines for regular use of the vaccine have not yet been released.
iPledge
iPLEDGE. If you asked general dermatologists what changed their practice the most this year and they were prescribers of isotretinoin (Accutane, Amnesteem, Claravis, Sotret), most would probably say iPLEDGE.
Despite a large outcry from many dermatologists, March 2006 marked the beginning of the iPLEDGE program, designed to monitor the prescription and side effects of isotretinoin in the United States.7
Registration with iPLEDGE is mandatory in order for a physician to prescribe the medication. The program was instituted in hopes that the guidelines would reduce the number of pregnancies in women taking isotretinoin. As a result, female patients must be enrolled in and access the iPLEDGE system, have two forms of birth control for 30 days, enter those two forms of birth control in the computer system and have two negative pregnancy tests 30 days apart. The birth control methods must match those entered by physician’s offices, and results of pregnancy tests must be entered monthly by the physician’s office.8
The start of the iPLEDGE program was marked by confusion, conflicting information, and changes in rules in the system without notification to prescribers, resulting in initial frustration for both patients and physicians.
Restrictions on males and females not able to conceive are much less stringent now. Male patients must also be registered in the iPLEDGE system, but are able to receive isotretinoin immediately once registered. In addition, in October, the lockout period of 30 days was eliminated for males and females of non-childbearing potential, making the program easier to use for these patients.
Whether iPLEDGE will result in a decrease in the number of pregnancies in patients taking isotretinoin remains to be seen, but data for the first year should be available soon. Overall effects the system will have on the practice of dermatology and the prescription of isotretinoin also remain to be seen.
Most of the concerns expressed by dermatologists so far surround excess time and resources required, without compensation, as well as limitations of access to the computer system/wait time when calling to rectify problems. Dermatologists have been assured that these issues are being worked out, but many remain skeptical of the overall benefit iPLEDGE will have for patients and prescribers. More information on iPLEDGE can be found at the Web site: www.ipledgeprogram.com.8
More Acne News
Adapalene 0.3% gel. Thiboutot et al published data this year supporting the efficacy of a stronger adapalene gel. Patients were randomized to receive either vehicle alone, adapalene 0.1% (Differin) or adapalene 0.3% gel. The higher concentration gel significantly reduced percentage of inflammatory lesions when compared to the 0.1% and vehicle alone, and also reduced non-inflammatory lesions, though this did not achieve statistical significance when compared to adapalene 0.1% gel (p = 0.061).
Adverse effects of scaling, erythema, dryness and burning were similar between the lower and higher concentration groups, and both treatments were well tolerated. The Phase III trial contributes to the data in support of hopeful FDA approval of adapalene 0.3% gel.9
Clindamycin/tretinoin hydrogel. In January, Leyden et al reported the results of two well-designed vehicle controlled trials of the use of a clindamycin/tretinoin hydrogel currently in development.
They found that the combination gel significantly reduced the inflammatory lesion counts, noninflammatory lesion count, and the global assessment scale was improved as compared with clindamycin, tretinoin or vehicle gel alone. The combination hydrogel was safe with the most common adverse effects being dryness, burning, peeling, redness and pruritus.
Clindamycin and tretinoin are both commonly prescribed medications for the treatment of acne and the combination gel would be well received as a simplification of the acne treatment regimen.10
Psoriasis Treatment and Malignancy Risk
Biologics and Lymphoma. In the May 17, 2006, edition of the Journal of the American Medical Association (JAMA), a meta-analysis was published assessing the risk of malignancy and infection in patients with rheumatoid arthritis (RA) treated with anti-TNF antibody therapy. The meta-analysis was a retrospective look at nine randomized, placebo-controlled trials of infliximab (Remicade) and adalimumab (Humira) when used for more than 12 weeks. The study reported that the odds ratios (OR) in the biologic group for malignancy and severe infections were 3.3 and 2.0, respectively. In addition, researchers reported the number needed to harm for biologics was 154 for malignancy and 59 for infections.11
Following its publication, the JAMA article received a great deal of media attention, generating concern among patients and prescribers alike.
The American College of Rheumatology (ACR) responded to these concerns by directly addressing the JAMA publication. The ACR proposed that although the authors report a statistically significant difference in malignancy occurrence in treatment groups, the risk of malignancy remains rare in patients treated with biologic agents. In addition, the ACR cautions against grouping patients with different types of rheumatoid arthritis together, as was done in the analysis.12
It is important as dermatologists and prescribers of these medications to understand how they affect our patients. The anti-TNF agents have shown great benefit in many patients, but we must continue to understand the serious adverse effects of these medications. Just this year, infliximab (Remicade) was granted approval for use in the pediatric and adolescent population for Crohn’s disease while simultaneously adding a warning about the increased risk of hepatosplenic T-cell lymphoma in this same age group.13
For dermatological use, the jury is still out whether there is a risk of malignancy in psoriasis patients receiving these drugs. As always, the risk of treatment must be balanced against the risk of uncontrolled disease.
Most of the existing literature on TNF inhibitor safety relates to the use of these drugs in patients with RA. Risk assessment of developing lymphomas in patients with psoriasis utilizing TNF inhibitors is ongoing.
Longer-term follow-up of psoriasis patients treated with biologics will provide important information in helping to resolve these issues in the future.
Psoriasis and the Biologics
Infliximab approved for psoriasis indication. In October 2006, the FDA approved infliximab for use in psoriasis. In a Phase III, double-blind, placebo-controlled study, infliximab was shown to be highly effective. At a dose of 5mg/kg, the percent of patients achieving PASI 90 was 57% at 10 weeks, and 80% of patients achieved a PASI 75 at week 10. Lastly, 26% of patients achieved a PASI of 0 (complete skin clearing).
Nail disease, often one of the most difficult aspects of psoriasis to manage, also responded to treatment in some patients.
The most common side effect during the trial was upper respiratory infection, but infusion reaction, headache, fatigue, pruritus, elevated liver transaminases are among other minor side effects that occurred. Serious side effects during the trial include one fatality from necrotizing fasciitis.14
For some patients infliximab is a good option since it has a high efficacy and many patients do not like to self-administer injections; however, for others, having to spend hours at an infusion center to get the medication prohibits its use. Nonetheless, with the new indication it gives dermatologists an additional option for treatment of extensive or recalcitrant psoriasis.
Adalimumab (Humira) approved for psoriatic arthritis. Adalimumab is a human monoclonal TNF alpha antibody that has long been used in rheumatoid arthritis. The efficacy of adalimumab in treating psoriatic arthritis was demonstrated in the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT) that ultimately led to FDA approval of adalimumab for psoriatic arthritis in October 2005.15
The current recommended dose for treating psoriatic arthritis is 40 mg every other week by subcutaneous injection, which has added a second option (in addition to etanercept [Enbrel]) for patients to treat themselves at home.
Common side effects of adalimumab include injection site reactions, headache, upper respiratory infections, abdominal pain, nausea, rash, urinary tract infections and fever. Potential serious side effects include opportunistic and other serious infections, such as reactivation of tuberculosis, congestive heart failure, lupus-like syndrome, possible increased risk of malignancy, pancytopenia, CNS demyelinating disease such as multiple sclerosis, and hypersensitivity reactions.16,17
Adalimumab also received an expanded indication for treating psoriatic arthritis last month. It is now also approved for inhibiting structural joint damage and improving physical function in patients with psoriatic arthritis. For more details, see “FDA Approvals and News” on page 15 of this issue.
Trials evaluating the safety and efficacy of adalimumab in the treatment of psoriasis are also currently underway, with the drug on schedule for potential approval by the FDA for the psoriasis indication within the next 1 to 2 years.
Other Psoriasis News
Taclonex Approval. Calcipotriene hydrate 0.005% and betamethasone dipropionate 0.064% (Taclonex) ointment is a new combination topical therapy approved by the FDA in January 2006 for the treatment of plaque psoriasis. It is intended for the treatment of initial or recurrent disease in adults 18 years of age and older.
Taclonex ointment combines the effects of calcipotriene hydrate, a synthetic vitamin D analog, with betamethasone dipropionate, a class III intermediate potency corticosteroid, in an ointment base of mineral oil, polypropylene glycol-15 stearyl ether, d1-alpha tocopheral, and white petrolatum.18 Neither drug on its own is new, but the combination is novel.
It is recommended as a once-daily application to affected areas for up to 4 weeks, excluding the face, axillae and groin. The maximum weekly dose should not exceed 100 g and treatment of more than 30% of body surface area is not recommended. Since studies in psoriasis patients demonstrate a high rate of non-compliance, it is plausible that the ease of a once-a-day application will help some patients adhere to the recommended treatment regimens.19
Adverse reactions include pruritus, headache, nasopharyngitis, erythema and pain or burning at the site of application.20,21 The risk of hypercalcemia with long-term use is unknown. Its use is contraindicated in patients with known or suspected disorders of calcium metabolism.
In addition, Taclonex ointment is contraindicated in patients with erythrodermic, exfoliative, or pustular psoriasis and patients with a history of hypersensitivity to any of the components. Safety and efficacy have not been established in the pediatric population. Taclonex ointment is listed as pregnancy category C.21
Clobex Spray. This year Galderma Laboratories released Clobex spray, a formulation of clobetasol propionate 0.05% in a spray vehicle to aid in ease of application and increase the likelihood of patient compliance. It is FDA approved for the treatment of moderate to severe plaque psoriasis affecting up to 20% of body surface area in adults
18 years of age and older.22
Clobex spray is applied and rubbed into affected areas twice daily, excluding the face, axillae and groin. It is recommended that physicians assess patients’ improvement after 2 weeks and continue treatment for an additional 2 weeks only in areas that did not respond. The maximum weekly dosage should not exceed one 59-ml bottle.
The most common reported adverse reaction is burning at the site of application. However, hypothalamic-axis suppression is a concern. Clobex spray is listed as pregnancy category C.23
This new formulation is expensive when compared with other clobetasol vehicles;24 however, if patient compliance increases as a result of the more acceptable vehicle, then perhaps patients will present to their physicians less often, lessening the cost burden on the healthcare system.
Cosmetic Dermatology
Fillers. A number of fillers await approval from the FDA. A recent study investigated the effectiveness of Radiesse for soft tissue augmentation. Radiesse is composed of calcium hydroxylapatite microspheres in a gel vehicle. Since it is not animal derived, there is no need for prior skin testing, and it is believed to last up to 2 years — longer than the human-based dermal products.
Currently, Radiesse is approved for assisting in radiographic imaging, for laryngoplasty, and for correction of maxillofacial defects. In this study, the investigators enrolled 82 patients who sought augmentation. Patient follow-up was 6 months in most cases. Patients underwent treatment to one of four sites: melolabial fold, infracommissural fold, upper lip, and lower lip. Patients and physicians both gauged the effectiveness using a scale of 1 to 5 (1 = unsatisfactory, 5 = excellent). The mean ratings at 3 and 6 months from the patients were 4.6 and 4.8, respectively. Physician mean ratings were 4.5 at both 3 and 6 months for appearance. The most common adverse effect was submucosal nodules in the patients receiving lip augmentation, and these were treated either by intralesional triamcinolone or excision, without lasting cosmetic effect.27
If studies continue to demonstrate safety and efficacy, Radiesse is on schedule to receive FDA approval for tissue augmentation.
ArteFill also awaits approval from the FDA as a tissue augmentation agent. ArteFill is a filler containing both bovine collagen and polymethylmethacrylate microspheres. A large multi-center study of more than 200 patients who received treatment for wrinkles of the glabella, nasolabial folds, upper lip lines and corners of the mouth was conducted. The results of the study showed that there was significant improvement at 6 months, by both physician and patient scales, with the ArteFill vs. collagen, and in 111 patients, the beneficial effect of the ArteFill was still evident at the 12-month follow-up point, again, longer than the effects of collagen alone.
Side effects were similar to the other dermal fillers: ranging from mild lumpiness at the sites of treatment to more severe nodular lesions. In both treatments, the percentage of patients with adverse effects was low, and adverse effects were easily managed by either intralesional corticosteroid or intraoral excision of nodules. A 4- to 5-year follow-up of a small number of the patients helped to demonstrate the long-term safety of the product.28
Pediatric Dermatology
New FDA Labeling for Topical Calcineurin Inhibitors. Currently there are two topical calcineurin inhibitors approved for the treatment of atopic dermatitis (see photo 3) in the United States.
In December 2000, tacrolimus (Protopic) was FDA approved for moderate to severe atopic dermatitis in patients 2 years of age and older. Pimecrolimus (Elidel) was FDA approved in December 2001 for mild to moderate atopic dermatitis in patients 2 years of age and older.29 These agents were intended for short-term and intermittent treatment of disease in non-immunocompromised hosts who fail to respond to, or are intolerant of other eczema treatments.30,31
On Jan. 19, 2006, the FDA approved updated labeling for both of the calcineurin inhibitors. The new labeling includes a boxed warning concerning theoretical malignancy risk of topical calcineurin inhibitors and a Medication Guide (FDA approved patient labeling) distributed to each patient with his or her prescription. In addition, the new labeling clarifies that these agents are intended as second-line treatment.30,31
Several factors contributed to this action by the FDA. Animal studies have demonstrated an increased risk of malignancy and a dose-dependent development of lymphoma in mice models treated with systemic tacrolimus and pimecrolimus, though these results have not been substantiated with use of the topical preparations of either medication.30,31,32 Moreover, since their approval, 19 malignancy-related events in tacrolimus and 10 malignancy-related events in pimecrolimus have been reported,33,34 though these cases were reported after the concerns of malignancy were publicized. The majority of these cases of malignancy were not compatible with immunosuppression-caused disease. While animal studies show that oral intake of pimecrolimus induces lymphomas, doses achieved in these cases are 30 times in excess of those achieved with topical use alone.35
It is important to recognize that although a plausible scenario exists for malignancy development, a clear causal relationship between topical calcineurin inhibitors and malignancy has not been established in humans. Cases of malignancy-related events are rare given the volume of patients utilizing these drugs. From January 2001 through August 2004, 3.2 million prescriptions were written for tacrolimus, and from January 2001 through August 2004, 7.7 million prescriptions were written for pimecrolimus.33,34
Further studies and analyses are underway by the manufacturers of both drugs to help establish the long-term safety and efficacy of these drugs in the pediatric population.
Infantile Hemangiomas – Predicting Complications and Need for Treatment. In the September 2006 issue of Pediatrics, a large prospective study was published identifying clinical characteristics of infantile hemangiomas associated with complications and need for treatment.
The authors of this study recognized the challenge physicians face in determining which hemangiomas need treatment and which are at risk for complications. For the study, 1,058 subjects with infantile hemangiomas were enrolled and were followed for a minimum of 8 months to 23 months. Subjects were 12 years of age and younger. The location, size, and morphological subtype were documented for no more than four hemangiomas per patient. The morphological subtypes included segmental, localized, indeterminate and multifocal hemangiomas.36
In this study, morphological subtype was the strongest prognostic indicator for treatment need and complications.36 This finding is consistent with two previous retrospective studies.37,38 After controlling for size, segmental hemangiomas were 8 times more likely to receive treatment and 11 times more likely to develop complications than localized hemangiomas (OR: 8.4; 95% CI: 5.8 to 12.2; OR:11.5; 95% CI: 7.8 to 17).
In addition, the authors reported a greater need for treatment and higher rates of complications for indeterminate hemangiomas when compared with localized hemangiomas.
Size and location were also found to be important predictors of outcome. The complicated mean hemangioma size was 37.3 cm2 compared with 19.1 cm2 for hemangiomas without complications. Moreover, the mean size of hemangiomas requiring treatment was 30.4 cm2 compared with 19.3 cm2 for hemangiomas not needing therapeutic intervention. With regard to location, perineal hemangiomas had the highest rate of complication (52%) and need for treatment (47.9%), followed by facial hemangiomas with a complication rate of 22.9% and need for treatment of 43% for facial hemangiomas.36
Overall, 24% of subjects enrolled experienced complications, including ulceration (23.2%), visual compromise (6.9%), airway obstruction (1.8%), auditory canal obstruction (1.1%) and cardiac compromise (0.4%).36 Also, 38% received some form of treatment during the study, including systemic therapy, wound care, and laser and surgical excision.
Although most infantile hemangiomas spontaneously regress, it is important to recognize that a significant minority do progress and may lead to scarring and possible disfigurement. The clinical characteristics described here may serve as guidelines in helping to predict clinical outcomes of infantile hemangiomas.
Loss-of-function Mutations in Filaggrin Gene Predispose to Atopic Dermatitis. In the April 2006 issue of Nature Genetics, Palmer et al identified filaggrin as a key protein in the pathogenesis of atopic dermatitis (AD). Two association studies and a prospective study reported in this publication provided the evidence for a heritable genetic defect common to AD and associated asthma.39 The two filaggrin mutations implicated, R501X and 2282del4, are localized to chromosome 1q21 in the epidermal differentiation complex.40,41 Previously, filaggrin mutations were also identified as the causative factor in ichthyosis vulgaris, a prevalent inherited disorder of keratinization.42 Both R501X and 2282del4 are loss-of-function mutations that result in complete loss of filaggrin expression in the epidermis.42
Filaggrin is a protein that plays a role in terminal differentiation of the epidermis and formation of the stratum corneum, which prevents water loss, keeps out allergens and irritants, and protects against infectious agents.39,42
In a cohort study of 52 Irish pediatric patients with AD, the combined allele frequency for filaggrin R501X and 2282del4 variants in an anonymous unselected Irish control population (n=189) was 0.042 compared with a combined allele frequency of 0.330 established in the AD cohort (OR=13.4; 95% CI: 6.2-27.5; p< 0.0001). Nearly half of the patients with AD had documented asthma.
In a second cohort study, Palmer et al genotyped 1,008 Scottish school children with unknown disease and 604 Scottish school children and adolescents with asthma. The combined carrier frequency for the two filaggrin mutations in the control group was 9.6% compared with 15.7% in the asthma cohort. Moreover, 72% of children in the asthma cohort carrying a filaggrin null allele had AD compared with 46% of those without a filaggrin null allele.
These results demonstrate R501X and 2282del4 variants are predisposing factors for asthma only in the context of AD. The results were replicated in a prospective study examining the children of asthmatic mothers. In this study, 372 Danish children were genotyped for the two variants. The combined filaggrin variants were over-represented in the children with atopic dermatitis compared with children without disease (hazards ratio = 2.8; 95% CI: 1.7 to 4.5, P< 0.0001).39
A family-based analysis by Weidinger et al of 476 white German families with AD supported the associations found in Palmer et al’s cohort and prospective studies.43 Combined, the studies establish a strong association between the loss-of-function filaggrin mutations, R501X and 2282del4, and atopic dermatitis. Impairment of the epidermal barrier is now recognized as a primary defect that facilitates the pathogenesis in atopic dermatitis.
A Good Year for Dermatology
As this article has discussed, 2006 was a busy year for dermatology and medicine in general. The introduction and use of the HPV vaccine is sure to have a profound effect in medicine and society in the years and decades to come. Other approvals and changes this year were met with less enthusiasm, and as dermatologists we will continue to navigate the intricacies of iPLEDGE because we believe in isotretinoin and the benefits it provides to our patients. Overall, it’s been a great year, and we’re all looking forward to what next year will bring.
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 two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee.
As 2006 nears its end, Christina L. Haverstock, M.D., and Nina F. Abraham, B.A., look back on the year in dermatology. And, 2006 was an exciting, and somewhat controversial, year — the HPV vaccine was released, iPLEDGE was introduced, several drugs were approved for new indications, and old favorites received new warnings. The authors highlight the many changes dermatology has experienced over the past year.
At the end of this article, you’ll find an exam. Mark your responses in the designated area, then fax page 49 to HMP Communications 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: Christina L. Haverstock, M.D., and Nina F. Abraham, B.A.
Method of Participation: Physicians may receive two category 1 credits by reading the article on pp. 41 to 47 and successfully answering the questions found on pp. 48 to 49. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to our Web site at www.skinandaging.com.
Estimated Time to Complete Activity: 2 hours
Date of Original Release: December 2006
Expiration Date: December 2007
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.
Designation Statement: NACCME designates this continuing medical education activity for a maximum of 2 category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity.
This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies
Disclosure Policy: All those with control over the content of continuing education programs sponsored by the North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. It is not assumed that these financial interests or affiliations will have an adverse impact on presentations; they are simply noted here to fully inform participants.
Faculty Disclosures: Dr. Haverstock and Ms. Abraham have disclosed that they has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the contexts of the subject of this article.
Learning Objectives:
1.Identify major studies and their implications, new therapeutic interventions and updates on currently used medications from this past year.
2. Identify possible applications of new information from 2006 in an effort to improve dermatologic care and therapeutic strategies.
Target Audience: Dermatologists, Plastic Surgeons, Internists
Commercial Support: None
Sponsor: NACCME
2006 YEAR IN REVIEW
The year 2006 was monumental for medicine and dermatology. The HPV vaccine was released, iPLEDGE was introduced, several drugs were approved for new indications, and old favorites received new warnings. Here, we’ll highlight the exciting, innovative, and routine changes the field of dermatology has experienced over the past year — covering everything from infectious diseases to psoriasis to pediatric dermatology.
Infectious Diseases
HPV Vaccine. Certainly one of the most exciting things to happen in medicine this year was the release of the human papillomavirus (HPV) vaccine Gardasil.
The HPV vaccine was approved by the FDA in June 2006 after numerous studies demonstrated its safety and efficacy.1 It is a quadrivalent vaccine composed of proteins from the L1 capsid from HPV strains 6, 11, 16 and 18 (no live virus) — the strains of HPV responsible for 70% of cervical cancer.
Cervical cancer remains an important cause of morbidity and mortality in the United States and worldwide. More than 9,000 new cases of cervical cancer are diagnosed every year, and this cancer is responsible for 3,700 deaths annually in this country.2 The vaccine has been shown to be 100% effective in preventing pre-cancerous lesions of the cervix and vulva as well as genital warts, as long as the patient has not been previously infected with one of the strains of HPV.2-3
The time course of the studies was not sufficient to demonstrate a decrease in the rate of cervical cancer from the new vaccine; however, it is felt that there will be an inevitable decrease as the vaccine use becomes part of regular medical practice.
Gardasil is currently approved for use in females aged 9 to 26 years, and when administered on a more regular basis, will result in a decrease in the number of genital warts that dermatologists and all practitioners see and treat in female patients. Since genital warts are the most common sexually transmitted disease in the United States it would be ideal to have a similar prevention strategy for male counterparts.4
Zoster vaccine. Zostavax, a vaccine designed to decrease the risk of herpes zoster (see photo 1), was also FDA approved this year.5 The vaccine contains live virus and is indicated in persons older than 60 years. Shingles is caused by reactivation of dormant herpes zoster virus and is rarely a threat to life; however, the incidence and severity of herpes zoster reactivation increases with age. In addition, zoster is associated with morbidity secondary to post herpetic neuralgia (PHN) and chronic pain after reactivation. The risk of PHN also increases with age.
In trials, Zostavax was administered to more than 38,000 patients and was shown to decrease the incidence of zoster by 51% and decrease the incidence of PHN by 66%.6 Guidelines for regular use of the vaccine have not yet been released.
iPledge
iPLEDGE. If you asked general dermatologists what changed their practice the most this year and they were prescribers of isotretinoin (Accutane, Amnesteem, Claravis, Sotret), most would probably say iPLEDGE.
Despite a large outcry from many dermatologists, March 2006 marked the beginning of the iPLEDGE program, designed to monitor the prescription and side effects of isotretinoin in the United States.7
Registration with iPLEDGE is mandatory in order for a physician to prescribe the medication. The program was instituted in hopes that the guidelines would reduce the number of pregnancies in women taking isotretinoin. As a result, female patients must be enrolled in and access the iPLEDGE system, have two forms of birth control for 30 days, enter those two forms of birth control in the computer system and have two negative pregnancy tests 30 days apart. The birth control methods must match those entered by physician’s offices, and results of pregnancy tests must be entered monthly by the physician’s office.8
The start of the iPLEDGE program was marked by confusion, conflicting information, and changes in rules in the system without notification to prescribers, resulting in initial frustration for both patients and physicians.
Restrictions on males and females not able to conceive are much less stringent now. Male patients must also be registered in the iPLEDGE system, but are able to receive isotretinoin immediately once registered. In addition, in October, the lockout period of 30 days was eliminated for males and females of non-childbearing potential, making the program easier to use for these patients.
Whether iPLEDGE will result in a decrease in the number of pregnancies in patients taking isotretinoin remains to be seen, but data for the first year should be available soon. Overall effects the system will have on the practice of dermatology and the prescription of isotretinoin also remain to be seen.
Most of the concerns expressed by dermatologists so far surround excess time and resources required, without compensation, as well as limitations of access to the computer system/wait time when calling to rectify problems. Dermatologists have been assured that these issues are being worked out, but many remain skeptical of the overall benefit iPLEDGE will have for patients and prescribers. More information on iPLEDGE can be found at the Web site: www.ipledgeprogram.com.8
More Acne News
Adapalene 0.3% gel. Thiboutot et al published data this year supporting the efficacy of a stronger adapalene gel. Patients were randomized to receive either vehicle alone, adapalene 0.1% (Differin) or adapalene 0.3% gel. The higher concentration gel significantly reduced percentage of inflammatory lesions when compared to the 0.1% and vehicle alone, and also reduced non-inflammatory lesions, though this did not achieve statistical significance when compared to adapalene 0.1% gel (p = 0.061).
Adverse effects of scaling, erythema, dryness and burning were similar between the lower and higher concentration groups, and both treatments were well tolerated. The Phase III trial contributes to the data in support of hopeful FDA approval of adapalene 0.3% gel.9
Clindamycin/tretinoin hydrogel. In January, Leyden et al reported the results of two well-designed vehicle controlled trials of the use of a clindamycin/tretinoin hydrogel currently in development.
They found that the combination gel significantly reduced the inflammatory lesion counts, noninflammatory lesion count, and the global assessment scale was improved as compared with clindamycin, tretinoin or vehicle gel alone. The combination hydrogel was safe with the most common adverse effects being dryness, burning, peeling, redness and pruritus.
Clindamycin and tretinoin are both commonly prescribed medications for the treatment of acne and the combination gel would be well received as a simplification of the acne treatment regimen.10
Psoriasis Treatment and Malignancy Risk
Biologics and Lymphoma. In the May 17, 2006, edition of the Journal of the American Medical Association (JAMA), a meta-analysis was published assessing the risk of malignancy and infection in patients with rheumatoid arthritis (RA) treated with anti-TNF antibody therapy. The meta-analysis was a retrospective look at nine randomized, placebo-controlled trials of infliximab (Remicade) and adalimumab (Humira) when used for more than 12 weeks. The study reported that the odds ratios (OR) in the biologic group for malignancy and severe infections were 3.3 and 2.0, respectively. In addition, researchers reported the number needed to harm for biologics was 154 for malignancy and 59 for infections.11
Following its publication, the JAMA article received a great deal of media attention, generating concern among patients and prescribers alike.
The American College of Rheumatology (ACR) responded to these concerns by directly addressing the JAMA publication. The ACR proposed that although the authors report a statistically significant difference in malignancy occurrence in treatment groups, the risk of malignancy remains rare in patients treated with biologic agents. In addition, the ACR cautions against grouping patients with different types of rheumatoid arthritis together, as was done in the analysis.12
It is important as dermatologists and prescribers of these medications to understand how they affect our patients. The anti-TNF agents have shown great benefit in many patients, but we must continue to understand the serious adverse effects of these medications. Just this year, infliximab (Remicade) was granted approval for use in the pediatric and adolescent population for Crohn’s disease while simultaneously adding a warning about the increased risk of hepatosplenic T-cell lymphoma in this same age group.13
For dermatological use, the jury is still out whether there is a risk of malignancy in psoriasis patients receiving these drugs. As always, the risk of treatment must be balanced against the risk of uncontrolled disease.
Most of the existing literature on TNF inhibitor safety relates to the use of these drugs in patients with RA. Risk assessment of developing lymphomas in patients with psoriasis utilizing TNF inhibitors is ongoing.
Longer-term follow-up of psoriasis patients treated with biologics will provide important information in helping to resolve these issues in the future.
Psoriasis and the Biologics
Infliximab approved for psoriasis indication. In October 2006, the FDA approved infliximab for use in psoriasis. In a Phase III, double-blind, placebo-controlled study, infliximab was shown to be highly effective. At a dose of 5mg/kg, the percent of patients achieving PASI 90 was 57% at 10 weeks, and 80% of patients achieved a PASI 75 at week 10. Lastly, 26% of patients achieved a PASI of 0 (complete skin clearing).
Nail disease, often one of the most difficult aspects of psoriasis to manage, also responded to treatment in some patients.
The most common side effect during the trial was upper respiratory infection, but infusion reaction, headache, fatigue, pruritus, elevated liver transaminases are among other minor side effects that occurred. Serious side effects during the trial include one fatality from necrotizing fasciitis.14
For some patients infliximab is a good option since it has a high efficacy and many patients do not like to self-administer injections; however, for others, having to spend hours at an infusion center to get the medication prohibits its use. Nonetheless, with the new indication it gives dermatologists an additional option for treatment of extensive or recalcitrant psoriasis.
Adalimumab (Humira) approved for psoriatic arthritis. Adalimumab is a human monoclonal TNF alpha antibody that has long been used in rheumatoid arthritis. The efficacy of adalimumab in treating psoriatic arthritis was demonstrated in the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT) that ultimately led to FDA approval of adalimumab for psoriatic arthritis in October 2005.15
The current recommended dose for treating psoriatic arthritis is 40 mg every other week by subcutaneous injection, which has added a second option (in addition to etanercept [Enbrel]) for patients to treat themselves at home.
Common side effects of adalimumab include injection site reactions, headache, upper respiratory infections, abdominal pain, nausea, rash, urinary tract infections and fever. Potential serious side effects include opportunistic and other serious infections, such as reactivation of tuberculosis, congestive heart failure, lupus-like syndrome, possible increased risk of malignancy, pancytopenia, CNS demyelinating disease such as multiple sclerosis, and hypersensitivity reactions.16,17
Adalimumab also received an expanded indication for treating psoriatic arthritis last month. It is now also approved for inhibiting structural joint damage and improving physical function in patients with psoriatic arthritis. For more details, see “FDA Approvals and News” on page 15 of this issue.
Trials evaluating the safety and efficacy of adalimumab in the treatment of psoriasis are also currently underway, with the drug on schedule for potential approval by the FDA for the psoriasis indication within the next 1 to 2 years.
Other Psoriasis News
Taclonex Approval. Calcipotriene hydrate 0.005% and betamethasone dipropionate 0.064% (Taclonex) ointment is a new combination topical therapy approved by the FDA in January 2006 for the treatment of plaque psoriasis. It is intended for the treatment of initial or recurrent disease in adults 18 years of age and older.
Taclonex ointment combines the effects of calcipotriene hydrate, a synthetic vitamin D analog, with betamethasone dipropionate, a class III intermediate potency corticosteroid, in an ointment base of mineral oil, polypropylene glycol-15 stearyl ether, d1-alpha tocopheral, and white petrolatum.18 Neither drug on its own is new, but the combination is novel.
It is recommended as a once-daily application to affected areas for up to 4 weeks, excluding the face, axillae and groin. The maximum weekly dose should not exceed 100 g and treatment of more than 30% of body surface area is not recommended. Since studies in psoriasis patients demonstrate a high rate of non-compliance, it is plausible that the ease of a once-a-day application will help some patients adhere to the recommended treatment regimens.19
Adverse reactions include pruritus, headache, nasopharyngitis, erythema and pain or burning at the site of application.20,21 The risk of hypercalcemia with long-term use is unknown. Its use is contraindicated in patients with known or suspected disorders of calcium metabolism.
In addition, Taclonex ointment is contraindicated in patients with erythrodermic, exfoliative, or pustular psoriasis and patients with a history of hypersensitivity to any of the components. Safety and efficacy have not been established in the pediatric population. Taclonex ointment is listed as pregnancy category C.21
Clobex Spray. This year Galderma Laboratories released Clobex spray, a formulation of clobetasol propionate 0.05% in a spray vehicle to aid in ease of application and increase the likelihood of patient compliance. It is FDA approved for the treatment of moderate to severe plaque psoriasis affecting up to 20% of body surface area in adults
18 years of age and older.22
Clobex spray is applied and rubbed into affected areas twice daily, excluding the face, axillae and groin. It is recommended that physicians assess patients’ improvement after 2 weeks and continue treatment for an additional 2 weeks only in areas that did not respond. The maximum weekly dosage should not exceed one 59-ml bottle.
The most common reported adverse reaction is burning at the site of application. However, hypothalamic-axis suppression is a concern. Clobex spray is listed as pregnancy category C.23
This new formulation is expensive when compared with other clobetasol vehicles;24 however, if patient compliance increases as a result of the more acceptable vehicle, then perhaps patients will present to their physicians less often, lessening the cost burden on the healthcare system.
Cosmetic Dermatology
Fillers. A number of fillers await approval from the FDA. A recent study investigated the effectiveness of Radiesse for soft tissue augmentation. Radiesse is composed of calcium hydroxylapatite microspheres in a gel vehicle. Since it is not animal derived, there is no need for prior skin testing, and it is believed to last up to 2 years — longer than the human-based dermal products.
Currently, Radiesse is approved for assisting in radiographic imaging, for laryngoplasty, and for correction of maxillofacial defects. In this study, the investigators enrolled 82 patients who sought augmentation. Patient follow-up was 6 months in most cases. Patients underwent treatment to one of four sites: melolabial fold, infracommissural fold, upper lip, and lower lip. Patients and physicians both gauged the effectiveness using a scale of 1 to 5 (1 = unsatisfactory, 5 = excellent). The mean ratings at 3 and 6 months from the patients were 4.6 and 4.8, respectively. Physician mean ratings were 4.5 at both 3 and 6 months for appearance. The most common adverse effect was submucosal nodules in the patients receiving lip augmentation, and these were treated either by intralesional triamcinolone or excision, without lasting cosmetic effect.27
If studies continue to demonstrate safety and efficacy, Radiesse is on schedule to receive FDA approval for tissue augmentation.
ArteFill also awaits approval from the FDA as a tissue augmentation agent. ArteFill is a filler containing both bovine collagen and polymethylmethacrylate microspheres. A large multi-center study of more than 200 patients who received treatment for wrinkles of the glabella, nasolabial folds, upper lip lines and corners of the mouth was conducted. The results of the study showed that there was significant improvement at 6 months, by both physician and patient scales, with the ArteFill vs. collagen, and in 111 patients, the beneficial effect of the ArteFill was still evident at the 12-month follow-up point, again, longer than the effects of collagen alone.
Side effects were similar to the other dermal fillers: ranging from mild lumpiness at the sites of treatment to more severe nodular lesions. In both treatments, the percentage of patients with adverse effects was low, and adverse effects were easily managed by either intralesional corticosteroid or intraoral excision of nodules. A 4- to 5-year follow-up of a small number of the patients helped to demonstrate the long-term safety of the product.28
Pediatric Dermatology
New FDA Labeling for Topical Calcineurin Inhibitors. Currently there are two topical calcineurin inhibitors approved for the treatment of atopic dermatitis (see photo 3) in the United States.
In December 2000, tacrolimus (Protopic) was FDA approved for moderate to severe atopic dermatitis in patients 2 years of age and older. Pimecrolimus (Elidel) was FDA approved in December 2001 for mild to moderate atopic dermatitis in patients 2 years of age and older.29 These agents were intended for short-term and intermittent treatment of disease in non-immunocompromised hosts who fail to respond to, or are intolerant of other eczema treatments.30,31
On Jan. 19, 2006, the FDA approved updated labeling for both of the calcineurin inhibitors. The new labeling includes a boxed warning concerning theoretical malignancy risk of topical calcineurin inhibitors and a Medication Guide (FDA approved patient labeling) distributed to each patient with his or her prescription. In addition, the new labeling clarifies that these agents are intended as second-line treatment.30,31
Several factors contributed to this action by the FDA. Animal studies have demonstrated an increased risk of malignancy and a dose-dependent development of lymphoma in mice models treated with systemic tacrolimus and pimecrolimus, though these results have not been substantiated with use of the topical preparations of either medication.30,31,32 Moreover, since their approval, 19 malignancy-related events in tacrolimus and 10 malignancy-related events in pimecrolimus have been reported,33,34 though these cases were reported after the concerns of malignancy were publicized. The majority of these cases of malignancy were not compatible with immunosuppression-caused disease. While animal studies show that oral intake of pimecrolimus induces lymphomas, doses achieved in these cases are 30 times in excess of those achieved with topical use alone.35
It is important to recognize that although a plausible scenario exists for malignancy development, a clear causal relationship between topical calcineurin inhibitors and malignancy has not been established in humans. Cases of malignancy-related events are rare given the volume of patients utilizing these drugs. From January 2001 through August 2004, 3.2 million prescriptions were written for tacrolimus, and from January 2001 through August 2004, 7.7 million prescriptions were written for pimecrolimus.33,34
Further studies and analyses are underway by the manufacturers of both drugs to help establish the long-term safety and efficacy of these drugs in the pediatric population.
Infantile Hemangiomas – Predicting Complications and Need for Treatment. In the September 2006 issue of Pediatrics, a large prospective study was published identifying clinical characteristics of infantile hemangiomas associated with complications and need for treatment.
The authors of this study recognized the challenge physicians face in determining which hemangiomas need treatment and which are at risk for complications. For the study, 1,058 subjects with infantile hemangiomas were enrolled and were followed for a minimum of 8 months to 23 months. Subjects were 12 years of age and younger. The location, size, and morphological subtype were documented for no more than four hemangiomas per patient. The morphological subtypes included segmental, localized, indeterminate and multifocal hemangiomas.36
In this study, morphological subtype was the strongest prognostic indicator for treatment need and complications.36 This finding is consistent with two previous retrospective studies.37,38 After controlling for size, segmental hemangiomas were 8 times more likely to receive treatment and 11 times more likely to develop complications than localized hemangiomas (OR: 8.4; 95% CI: 5.8 to 12.2; OR:11.5; 95% CI: 7.8 to 17).
In addition, the authors reported a greater need for treatment and higher rates of complications for indeterminate hemangiomas when compared with localized hemangiomas.
Size and location were also found to be important predictors of outcome. The complicated mean hemangioma size was 37.3 cm2 compared with 19.1 cm2 for hemangiomas without complications. Moreover, the mean size of hemangiomas requiring treatment was 30.4 cm2 compared with 19.3 cm2 for hemangiomas not needing therapeutic intervention. With regard to location, perineal hemangiomas had the highest rate of complication (52%) and need for treatment (47.9%), followed by facial hemangiomas with a complication rate of 22.9% and need for treatment of 43% for facial hemangiomas.36
Overall, 24% of subjects enrolled experienced complications, including ulceration (23.2%), visual compromise (6.9%), airway obstruction (1.8%), auditory canal obstruction (1.1%) and cardiac compromise (0.4%).36 Also, 38% received some form of treatment during the study, including systemic therapy, wound care, and laser and surgical excision.
Although most infantile hemangiomas spontaneously regress, it is important to recognize that a significant minority do progress and may lead to scarring and possible disfigurement. The clinical characteristics described here may serve as guidelines in helping to predict clinical outcomes of infantile hemangiomas.
Loss-of-function Mutations in Filaggrin Gene Predispose to Atopic Dermatitis. In the April 2006 issue of Nature Genetics, Palmer et al identified filaggrin as a key protein in the pathogenesis of atopic dermatitis (AD). Two association studies and a prospective study reported in this publication provided the evidence for a heritable genetic defect common to AD and associated asthma.39 The two filaggrin mutations implicated, R501X and 2282del4, are localized to chromosome 1q21 in the epidermal differentiation complex.40,41 Previously, filaggrin mutations were also identified as the causative factor in ichthyosis vulgaris, a prevalent inherited disorder of keratinization.42 Both R501X and 2282del4 are loss-of-function mutations that result in complete loss of filaggrin expression in the epidermis.42
Filaggrin is a protein that plays a role in terminal differentiation of the epidermis and formation of the stratum corneum, which prevents water loss, keeps out allergens and irritants, and protects against infectious agents.39,42
In a cohort study of 52 Irish pediatric patients with AD, the combined allele frequency for filaggrin R501X and 2282del4 variants in an anonymous unselected Irish control population (n=189) was 0.042 compared with a combined allele frequency of 0.330 established in the AD cohort (OR=13.4; 95% CI: 6.2-27.5; p< 0.0001). Nearly half of the patients with AD had documented asthma.
In a second cohort study, Palmer et al genotyped 1,008 Scottish school children with unknown disease and 604 Scottish school children and adolescents with asthma. The combined carrier frequency for the two filaggrin mutations in the control group was 9.6% compared with 15.7% in the asthma cohort. Moreover, 72% of children in the asthma cohort carrying a filaggrin null allele had AD compared with 46% of those without a filaggrin null allele.
These results demonstrate R501X and 2282del4 variants are predisposing factors for asthma only in the context of AD. The results were replicated in a prospective study examining the children of asthmatic mothers. In this study, 372 Danish children were genotyped for the two variants. The combined filaggrin variants were over-represented in the children with atopic dermatitis compared with children without disease (hazards ratio = 2.8; 95% CI: 1.7 to 4.5, P< 0.0001).39
A family-based analysis by Weidinger et al of 476 white German families with AD supported the associations found in Palmer et al’s cohort and prospective studies.43 Combined, the studies establish a strong association between the loss-of-function filaggrin mutations, R501X and 2282del4, and atopic dermatitis. Impairment of the epidermal barrier is now recognized as a primary defect that facilitates the pathogenesis in atopic dermatitis.
A Good Year for Dermatology
As this article has discussed, 2006 was a busy year for dermatology and medicine in general. The introduction and use of the HPV vaccine is sure to have a profound effect in medicine and society in the years and decades to come. Other approvals and changes this year were met with less enthusiasm, and as dermatologists we will continue to navigate the intricacies of iPLEDGE because we believe in isotretinoin and the benefits it provides to our patients. Overall, it’s been a great year, and we’re all looking forward to what next year will bring.
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 two category 1 physician credit hours. As a reader of Skin & Aging, this course is brought to you free of charge — you aren’t required to pay a processing fee.
As 2006 nears its end, Christina L. Haverstock, M.D., and Nina F. Abraham, B.A., look back on the year in dermatology. And, 2006 was an exciting, and somewhat controversial, year — the HPV vaccine was released, iPLEDGE was introduced, several drugs were approved for new indications, and old favorites received new warnings. The authors highlight the many changes dermatology has experienced over the past year.
At the end of this article, you’ll find an exam. Mark your responses in the designated area, then fax page 49 to HMP Communications 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: Christina L. Haverstock, M.D., and Nina F. Abraham, B.A.
Method of Participation: Physicians may receive two category 1 credits by reading the article on pp. 41 to 47 and successfully answering the questions found on pp. 48 to 49. A score of 70% is required for passing. Submit your answers and evaluation via fax or log on to our Web site at www.skinandaging.com.
Estimated Time to Complete Activity: 2 hours
Date of Original Release: December 2006
Expiration Date: December 2007
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.
Designation Statement: NACCME designates this continuing medical education activity for a maximum of 2 category 1 credit(s) toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity.
This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies
Disclosure Policy: All those with control over the content of continuing education programs sponsored by the North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. It is not assumed that these financial interests or affiliations will have an adverse impact on presentations; they are simply noted here to fully inform participants.
Faculty Disclosures: Dr. Haverstock and Ms. Abraham have disclosed that they has no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the contexts of the subject of this article.
Learning Objectives:
1.Identify major studies and their implications, new therapeutic interventions and updates on currently used medications from this past year.
2. Identify possible applications of new information from 2006 in an effort to improve dermatologic care and therapeutic strategies.
Target Audience: Dermatologists, Plastic Surgeons, Internists
Commercial Support: None
Sponsor: NACCME
2006 YEAR IN REVIEW
The year 2006 was monumental for medicine and dermatology. The HPV vaccine was released, iPLEDGE was introduced, several drugs were approved for new indications, and old favorites received new warnings. Here, we’ll highlight the exciting, innovative, and routine changes the field of dermatology has experienced over the past year — covering everything from infectious diseases to psoriasis to pediatric dermatology.
Infectious Diseases
HPV Vaccine. Certainly one of the most exciting things to happen in medicine this year was the release of the human papillomavirus (HPV) vaccine Gardasil.
The HPV vaccine was approved by the FDA in June 2006 after numerous studies demonstrated its safety and efficacy.1 It is a quadrivalent vaccine composed of proteins from the L1 capsid from HPV strains 6, 11, 16 and 18 (no live virus) — the strains of HPV responsible for 70% of cervical cancer.
Cervical cancer remains an important cause of morbidity and mortality in the United States and worldwide. More than 9,000 new cases of cervical cancer are diagnosed every year, and this cancer is responsible for 3,700 deaths annually in this country.2 The vaccine has been shown to be 100% effective in preventing pre-cancerous lesions of the cervix and vulva as well as genital warts, as long as the patient has not been previously infected with one of the strains of HPV.2-3
The time course of the studies was not sufficient to demonstrate a decrease in the rate of cervical cancer from the new vaccine; however, it is felt that there will be an inevitable decrease as the vaccine use becomes part of regular medical practice.
Gardasil is currently approved for use in females aged 9 to 26 years, and when administered on a more regular basis, will result in a decrease in the number of genital warts that dermatologists and all practitioners see and treat in female patients. Since genital warts are the most common sexually transmitted disease in the United States it would be ideal to have a similar prevention strategy for male counterparts.4
Zoster vaccine. Zostavax, a vaccine designed to decrease the risk of herpes zoster (see photo 1), was also FDA approved this year.5 The vaccine contains live virus and is indicated in persons older than 60 years. Shingles is caused by reactivation of dormant herpes zoster virus and is rarely a threat to life; however, the incidence and severity of herpes zoster reactivation increases with age. In addition, zoster is associated with morbidity secondary to post herpetic neuralgia (PHN) and chronic pain after reactivation. The risk of PHN also increases with age.
In trials, Zostavax was administered to more than 38,000 patients and was shown to decrease the incidence of zoster by 51% and decrease the incidence of PHN by 66%.6 Guidelines for regular use of the vaccine have not yet been released.
iPledge
iPLEDGE. If you asked general dermatologists what changed their practice the most this year and they were prescribers of isotretinoin (Accutane, Amnesteem, Claravis, Sotret), most would probably say iPLEDGE.
Despite a large outcry from many dermatologists, March 2006 marked the beginning of the iPLEDGE program, designed to monitor the prescription and side effects of isotretinoin in the United States.7
Registration with iPLEDGE is mandatory in order for a physician to prescribe the medication. The program was instituted in hopes that the guidelines would reduce the number of pregnancies in women taking isotretinoin. As a result, female patients must be enrolled in and access the iPLEDGE system, have two forms of birth control for 30 days, enter those two forms of birth control in the computer system and have two negative pregnancy tests 30 days apart. The birth control methods must match those entered by physician’s offices, and results of pregnancy tests must be entered monthly by the physician’s office.8
The start of the iPLEDGE program was marked by confusion, conflicting information, and changes in rules in the system without notification to prescribers, resulting in initial frustration for both patients and physicians.
Restrictions on males and females not able to conceive are much less stringent now. Male patients must also be registered in the iPLEDGE system, but are able to receive isotretinoin immediately once registered. In addition, in October, the lockout period of 30 days was eliminated for males and females of non-childbearing potential, making the program easier to use for these patients.
Whether iPLEDGE will result in a decrease in the number of pregnancies in patients taking isotretinoin remains to be seen, but data for the first year should be available soon. Overall effects the system will have on the practice of dermatology and the prescription of isotretinoin also remain to be seen.
Most of the concerns expressed by dermatologists so far surround excess time and resources required, without compensation, as well as limitations of access to the computer system/wait time when calling to rectify problems. Dermatologists have been assured that these issues are being worked out, but many remain skeptical of the overall benefit iPLEDGE will have for patients and prescribers. More information on iPLEDGE can be found at the Web site: www.ipledgeprogram.com.8
More Acne News
Adapalene 0.3% gel. Thiboutot et al published data this year supporting the efficacy of a stronger adapalene gel. Patients were randomized to receive either vehicle alone, adapalene 0.1% (Differin) or adapalene 0.3% gel. The higher concentration gel significantly reduced percentage of inflammatory lesions when compared to the 0.1% and vehicle alone, and also reduced non-inflammatory lesions, though this did not achieve statistical significance when compared to adapalene 0.1% gel (p = 0.061).
Adverse effects of scaling, erythema, dryness and burning were similar between the lower and higher concentration groups, and both treatments were well tolerated. The Phase III trial contributes to the data in support of hopeful FDA approval of adapalene 0.3% gel.9
Clindamycin/tretinoin hydrogel. In January, Leyden et al reported the results of two well-designed vehicle controlled trials of the use of a clindamycin/tretinoin hydrogel currently in development.
They found that the combination gel significantly reduced the inflammatory lesion counts, noninflammatory lesion count, and the global assessment scale was improved as compared with clindamycin, tretinoin or vehicle gel alone. The combination hydrogel was safe with the most common adverse effects being dryness, burning, peeling, redness and pruritus.
Clindamycin and tretinoin are both commonly prescribed medications for the treatment of acne and the combination gel would be well received as a simplification of the acne treatment regimen.10
Psoriasis Treatment and Malignancy Risk
Biologics and Lymphoma. In the May 17, 2006, edition of the Journal of the American Medical Association (JAMA), a meta-analysis was published assessing the risk of malignancy and infection in patients with rheumatoid arthritis (RA) treated with anti-TNF antibody therapy. The meta-analysis was a retrospective look at nine randomized, placebo-controlled trials of infliximab (Remicade) and adalimumab (Humira) when used for more than 12 weeks. The study reported that the odds ratios (OR) in the biologic group for malignancy and severe infections were 3.3 and 2.0, respectively. In addition, researchers reported the number needed to harm for biologics was 154 for malignancy and 59 for infections.11
Following its publication, the JAMA article received a great deal of media attention, generating concern among patients and prescribers alike.
The American College of Rheumatology (ACR) responded to these concerns by directly addressing the JAMA publication. The ACR proposed that although the authors report a statistically significant difference in malignancy occurrence in treatment groups, the risk of malignancy remains rare in patients treated with biologic agents. In addition, the ACR cautions against grouping patients with different types of rheumatoid arthritis together, as was done in the analysis.12
It is important as dermatologists and prescribers of these medications to understand how they affect our patients. The anti-TNF agents have shown great benefit in many patients, but we must continue to understand the serious adverse effects of these medications. Just this year, infliximab (Remicade) was granted approval for use in the pediatric and adolescent population for Crohn’s disease while simultaneously adding a warning about the increased risk of hepatosplenic T-cell lymphoma in this same age group.13
For dermatological use, the jury is still out whether there is a risk of malignancy in psoriasis patients receiving these drugs. As always, the risk of treatment must be balanced against the risk of uncontrolled disease.
Most of the existing literature on TNF inhibitor safety relates to the use of these drugs in patients with RA. Risk assessment of developing lymphomas in patients with psoriasis utilizing TNF inhibitors is ongoing.
Longer-term follow-up of psoriasis patients treated with biologics will provide important information in helping to resolve these issues in the future.
Psoriasis and the Biologics
Infliximab approved for psoriasis indication. In October 2006, the FDA approved infliximab for use in psoriasis. In a Phase III, double-blind, placebo-controlled study, infliximab was shown to be highly effective. At a dose of 5mg/kg, the percent of patients achieving PASI 90 was 57% at 10 weeks, and 80% of patients achieved a PASI 75 at week 10. Lastly, 26% of patients achieved a PASI of 0 (complete skin clearing).
Nail disease, often one of the most difficult aspects of psoriasis to manage, also responded to treatment in some patients.
The most common side effect during the trial was upper respiratory infection, but infusion reaction, headache, fatigue, pruritus, elevated liver transaminases are among other minor side effects that occurred. Serious side effects during the trial include one fatality from necrotizing fasciitis.14
For some patients infliximab is a good option since it has a high efficacy and many patients do not like to self-administer injections; however, for others, having to spend hours at an infusion center to get the medication prohibits its use. Nonetheless, with the new indication it gives dermatologists an additional option for treatment of extensive or recalcitrant psoriasis.
Adalimumab (Humira) approved for psoriatic arthritis. Adalimumab is a human monoclonal TNF alpha antibody that has long been used in rheumatoid arthritis. The efficacy of adalimumab in treating psoriatic arthritis was demonstrated in the Adalimumab Effectiveness in Psoriatic Arthritis Trial (ADEPT) that ultimately led to FDA approval of adalimumab for psoriatic arthritis in October 2005.15
The current recommended dose for treating psoriatic arthritis is 40 mg every other week by subcutaneous injection, which has added a second option (in addition to etanercept [Enbrel]) for patients to treat themselves at home.
Common side effects of adalimumab include injection site reactions, headache, upper respiratory infections, abdominal pain, nausea, rash, urinary tract infections and fever. Potential serious side effects include opportunistic and other serious infections, such as reactivation of tuberculosis, congestive heart failure, lupus-like syndrome, possible increased risk of malignancy, pancytopenia, CNS demyelinating disease such as multiple sclerosis, and hypersensitivity reactions.16,17
Adalimumab also received an expanded indication for treating psoriatic arthritis last month. It is now also approved for inhibiting structural joint damage and improving physical function in patients with psoriatic arthritis. For more details, see “FDA Approvals and News” on page 15 of this issue.
Trials evaluating the safety and efficacy of adalimumab in the treatment of psoriasis are also currently underway, with the drug on schedule for potential approval by the FDA for the psoriasis indication within the next 1 to 2 years.
Other Psoriasis News
Taclonex Approval. Calcipotriene hydrate 0.005% and betamethasone dipropionate 0.064% (Taclonex) ointment is a new combination topical therapy approved by the FDA in January 2006 for the treatment of plaque psoriasis. It is intended for the treatment of initial or recurrent disease in adults 18 years of age and older.
Taclonex ointment combines the effects of calcipotriene hydrate, a synthetic vitamin D analog, with betamethasone dipropionate, a class III intermediate potency corticosteroid, in an ointment base of mineral oil, polypropylene glycol-15 stearyl ether, d1-alpha tocopheral, and white petrolatum.18 Neither drug on its own is new, but the combination is novel.
It is recommended as a once-daily application to affected areas for up to 4 weeks, excluding the face, axillae and groin. The maximum weekly dose should not exceed 100 g and treatment of more than 30% of body surface area is not recommended. Since studies in psoriasis patients demonstrate a high rate of non-compliance, it is plausible that the ease of a once-a-day application will help some patients adhere to the recommended treatment regimens.19
Adverse reactions include pruritus, headache, nasopharyngitis, erythema and pain or burning at the site of application.20,21 The risk of hypercalcemia with long-term use is unknown. Its use is contraindicated in patients with known or suspected disorders of calcium metabolism.
In addition, Taclonex ointment is contraindicated in patients with erythrodermic, exfoliative, or pustular psoriasis and patients with a history of hypersensitivity to any of the components. Safety and efficacy have not been established in the pediatric population. Taclonex ointment is listed as pregnancy category C.21
Clobex Spray. This year Galderma Laboratories released Clobex spray, a formulation of clobetasol propionate 0.05% in a spray vehicle to aid in ease of application and increase the likelihood of patient compliance. It is FDA approved for the treatment of moderate to severe plaque psoriasis affecting up to 20% of body surface area in adults
18 years of age and older.22
Clobex spray is applied and rubbed into affected areas twice daily, excluding the face, axillae and groin. It is recommended that physicians assess patients’ improvement after 2 weeks and continue treatment for an additional 2 weeks only in areas that did not respond. The maximum weekly dosage should not exceed one 59-ml bottle.
The most common reported adverse reaction is burning at the site of application. However, hypothalamic-axis suppression is a concern. Clobex spray is listed as pregnancy category C.23
This new formulation is expensive when compared with other clobetasol vehicles;24 however, if patient compliance increases as a result of the more acceptable vehicle, then perhaps patients will present to their physicians less often, lessening the cost burden on the healthcare system.
Cosmetic Dermatology
Fillers. A number of fillers await approval from the FDA. A recent study investigated the effectiveness of Radiesse for soft tissue augmentation. Radiesse is composed of calcium hydroxylapatite microspheres in a gel vehicle. Since it is not animal derived, there is no need for prior skin testing, and it is believed to last up to 2 years — longer than the human-based dermal products.
Currently, Radiesse is approved for assisting in radiographic imaging, for laryngoplasty, and for correction of maxillofacial defects. In this study, the investigators enrolled 82 patients who sought augmentation. Patient follow-up was 6 months in most cases. Patients underwent treatment to one of four sites: melolabial fold, infracommissural fold, upper lip, and lower lip. Patients and physicians both gauged the effectiveness using a scale of 1 to 5 (1 = unsatisfactory, 5 = excellent). The mean ratings at 3 and 6 months from the patients were 4.6 and 4.8, respectively. Physician mean ratings were 4.5 at both 3 and 6 months for appearance. The most common adverse effect was submucosal nodules in the patients receiving lip augmentation, and these were treated either by intralesional triamcinolone or excision, without lasting cosmetic effect.27
If studies continue to demonstrate safety and efficacy, Radiesse is on schedule to receive FDA approval for tissue augmentation.
ArteFill also awaits approval from the FDA as a tissue augmentation agent. ArteFill is a filler containing both bovine collagen and polymethylmethacrylate microspheres. A large multi-center study of more than 200 patients who received treatment for wrinkles of the glabella, nasolabial folds, upper lip lines and corners of the mouth was conducted. The results of the study showed that there was significant improvement at 6 months, by both physician and patient scales, with the ArteFill vs. collagen, and in 111 patients, the beneficial effect of the ArteFill was still evident at the 12-month follow-up point, again, longer than the effects of collagen alone.
Side effects were similar to the other dermal fillers: ranging from mild lumpiness at the sites of treatment to more severe nodular lesions. In both treatments, the percentage of patients with adverse effects was low, and adverse effects were easily managed by either intralesional corticosteroid or intraoral excision of nodules. A 4- to 5-year follow-up of a small number of the patients helped to demonstrate the long-term safety of the product.28
Pediatric Dermatology
New FDA Labeling for Topical Calcineurin Inhibitors. Currently there are two topical calcineurin inhibitors approved for the treatment of atopic dermatitis (see photo 3) in the United States.
In December 2000, tacrolimus (Protopic) was FDA approved for moderate to severe atopic dermatitis in patients 2 years of age and older. Pimecrolimus (Elidel) was FDA approved in December 2001 for mild to moderate atopic dermatitis in patients 2 years of age and older.29 These agents were intended for short-term and intermittent treatment of disease in non-immunocompromised hosts who fail to respond to, or are intolerant of other eczema treatments.30,31
On Jan. 19, 2006, the FDA approved updated labeling for both of the calcineurin inhibitors. The new labeling includes a boxed warning concerning theoretical malignancy risk of topical calcineurin inhibitors and a Medication Guide (FDA approved patient labeling) distributed to each patient with his or her prescription. In addition, the new labeling clarifies that these agents are intended as second-line treatment.30,31
Several factors contributed to this action by the FDA. Animal studies have demonstrated an increased risk of malignancy and a dose-dependent development of lymphoma in mice models treated with systemic tacrolimus and pimecrolimus, though these results have not been substantiated with use of the topical preparations of either medication.30,31,32 Moreover, since their approval, 19 malignancy-related events in tacrolimus and 10 malignancy-related events in pimecrolimus have been reported,33,34 though these cases were reported after the concerns of malignancy were publicized. The majority of these cases of malignancy were not compatible with immunosuppression-caused disease. While animal studies show that oral intake of pimecrolimus induces lymphomas, doses achieved in these cases are 30 times in excess of those achieved with topical use alone.35
It is important to recognize that although a plausible scenario exists for malignancy development, a clear causal relationship between topical calcineurin inhibitors and malignancy has not been established in humans. Cases of malignancy-related events are rare given the volume of patients utilizing these drugs. From January 2001 through August 2004, 3.2 million prescriptions were written for tacrolimus, and from January 2001 through August 2004, 7.7 million prescriptions were written for pimecrolimus.33,34
Further studies and analyses are underway by the manufacturers of both drugs to help establish the long-term safety and efficacy of these drugs in the pediatric population.
Infantile Hemangiomas – Predicting Complications and Need for Treatment. In the September 2006 issue of Pediatrics, a large prospective study was published identifying clinical characteristics of infantile hemangiomas associated with complications and need for treatment.
The authors of this study recognized the challenge physicians face in determining which hemangiomas need treatment and which are at risk for complications. For the study, 1,058 subjects with infantile hemangiomas were enrolled and were followed for a minimum of 8 months to 23 months. Subjects were 12 years of age and younger. The location, size, and morphological subtype were documented for no more than four hemangiomas per patient. The morphological subtypes included segmental, localized, indeterminate and multifocal hemangiomas.36
In this study, morphological subtype was the strongest prognostic indicator for treatment need and complications.36 This finding is consistent with two previous retrospective studies.37,38 After controlling for size, segmental hemangiomas were 8 times more likely to receive treatment and 11 times more likely to develop complications than localized hemangiomas (OR: 8.4; 95% CI: 5.8 to 12.2; OR:11.5; 95% CI: 7.8 to 17).
In addition, the authors reported a greater need for treatment and higher rates of complications for indeterminate hemangiomas when compared with localized hemangiomas.
Size and location were also found to be important predictors of outcome. The complicated mean hemangioma size was 37.3 cm2 compared with 19.1 cm2 for hemangiomas without complications. Moreover, the mean size of hemangiomas requiring treatment was 30.4 cm2 compared with 19.3 cm2 for hemangiomas not needing therapeutic intervention. With regard to location, perineal hemangiomas had the highest rate of complication (52%) and need for treatment (47.9%), followed by facial hemangiomas with a complication rate of 22.9% and need for treatment of 43% for facial hemangiomas.36
Overall, 24% of subjects enrolled experienced complications, including ulceration (23.2%), visual compromise (6.9%), airway obstruction (1.8%), auditory canal obstruction (1.1%) and cardiac compromise (0.4%).36 Also, 38% received some form of treatment during the study, including systemic therapy, wound care, and laser and surgical excision.
Although most infantile hemangiomas spontaneously regress, it is important to recognize that a significant minority do progress and may lead to scarring and possible disfigurement. The clinical characteristics described here may serve as guidelines in helping to predict clinical outcomes of infantile hemangiomas.
Loss-of-function Mutations in Filaggrin Gene Predispose to Atopic Dermatitis. In the April 2006 issue of Nature Genetics, Palmer et al identified filaggrin as a key protein in the pathogenesis of atopic dermatitis (AD). Two association studies and a prospective study reported in this publication provided the evidence for a heritable genetic defect common to AD and associated asthma.39 The two filaggrin mutations implicated, R501X and 2282del4, are localized to chromosome 1q21 in the epidermal differentiation complex.40,41 Previously, filaggrin mutations were also identified as the causative factor in ichthyosis vulgaris, a prevalent inherited disorder of keratinization.42 Both R501X and 2282del4 are loss-of-function mutations that result in complete loss of filaggrin expression in the epidermis.42
Filaggrin is a protein that plays a role in terminal differentiation of the epidermis and formation of the stratum corneum, which prevents water loss, keeps out allergens and irritants, and protects against infectious agents.39,42
In a cohort study of 52 Irish pediatric patients with AD, the combined allele frequency for filaggrin R501X and 2282del4 variants in an anonymous unselected Irish control population (n=189) was 0.042 compared with a combined allele frequency of 0.330 established in the AD cohort (OR=13.4; 95% CI: 6.2-27.5; p< 0.0001). Nearly half of the patients with AD had documented asthma.
In a second cohort study, Palmer et al genotyped 1,008 Scottish school children with unknown disease and 604 Scottish school children and adolescents with asthma. The combined carrier frequency for the two filaggrin mutations in the control group was 9.6% compared with 15.7% in the asthma cohort. Moreover, 72% of children in the asthma cohort carrying a filaggrin null allele had AD compared with 46% of those without a filaggrin null allele.
These results demonstrate R501X and 2282del4 variants are predisposing factors for asthma only in the context of AD. The results were replicated in a prospective study examining the children of asthmatic mothers. In this study, 372 Danish children were genotyped for the two variants. The combined filaggrin variants were over-represented in the children with atopic dermatitis compared with children without disease (hazards ratio = 2.8; 95% CI: 1.7 to 4.5, P< 0.0001).39
A family-based analysis by Weidinger et al of 476 white German families with AD supported the associations found in Palmer et al’s cohort and prospective studies.43 Combined, the studies establish a strong association between the loss-of-function filaggrin mutations, R501X and 2282del4, and atopic dermatitis. Impairment of the epidermal barrier is now recognized as a primary defect that facilitates the pathogenesis in atopic dermatitis.
A Good Year for Dermatology
As this article has discussed, 2006 was a busy year for dermatology and medicine in general. The introduction and use of the HPV vaccine is sure to have a profound effect in medicine and society in the years and decades to come. Other approvals and changes this year were met with less enthusiasm, and as dermatologists we will continue to navigate the intricacies of iPLEDGE because we believe in isotretinoin and the benefits it provides to our patients. Overall, it’s been a great year, and we’re all looking forward to what next year will bring.
