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    2013: The year in review

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    As 2013 came to a close, Dermatology Times asked some of its editorial advisory board members what they considered to be some of the most clinically relevant advances in the past year. Not surprisingly, their answers encompassed recently approved treatment modalities and promising agents that are at various stages in the investigational pipeline. The developments capturing their attention, however, also included some that fall under the category of “what’s old is new again.”

    The approval of oral vismodegib (Erivedge, Genentech) for the treatment of metastatic and locally advanced basal cell carcinoma (BCC) was one of the top news stories in dermatology in 2012, and the drug continued to be a focus of major interest in 2013 as dermatologists looked to its potential to solve other challenging BCC clinical scenarios. Ronald Wheeland, M.D., notes that while vismodegib is unlikely to replace standard excision or Mohs surgery for BCC management, it seems to be a valuable alternative to these surgical techniques in a variety of situations.

    “Vismodegib will certainly be useful in elderly patients who may not be good candidates for invasive surgery. In addition, it might be very helpful for treating patients with multiple recurrent BCCs, tumors located in a surgically-challenging anatomic site, or very large lesions on the trunk or limbs,” says Dr. Wheeland, who practices in Tucson, Ariz.

    James Spencer, M.D., of St. Petersburg, Fla., also notes there is significant interest in using vismodegib as an adjuvant treatment for patients with large BCCs, administering the drug prior to Mohs surgery in order to reduce tumor burden, and he is involved in a clinical study investigating that indication.

    Two of the five new dermatology drugs approved in 2013 were for the treatment of unresectable or metastatic melanoma with BRAF mutations (trametinib, Mekinist; and dabrafenib, Tafinlar; GlaxoSmithKline), and these advances in therapies for metastatic melanoma were also identified as highlights of the year. Dr. Spencer says it is important for dermatologists to know about the new therapeutic options for metastatic melanoma even though they are not using them directly.

    Norman Levine, M.D., observes that while the BRAF inhibitors and ipilimumab (Yervoy, Bristol-Myers Squibb) provide only a modest improvement in overall survival versus older therapies, they are a noteworthy development because they represent an entirely different approach for treating patients with advanced cancers and likely herald future developments that may have greater measurable benefit.

    The list of new drug approvals in dermatology also included topical brimonidine 0.33 percent gel (Mirvaso, Galderma) for the treatment of rosacea-associated facial erythema. Both Dr. Spencer and Zoe Draelos, M.D., identified it as one of the year’s important developments, considering it addresses a previously unmet therapeutic need for a very common problem.

    Investigational agents

    Drug development for atopic dermatitis was another area of progress in 2013, according to Elaine Siegfried, M.D., who says there are currently no approved drugs for severe atopic dermatitis. Therefore, a report of promising data for dupilumab (Sanofi/Regeneron), a subcutaneously administered interleukin-4 receptor alpha antibody, was particularly exciting. In addition, topical AN2728 (Anacor), an anti-inflammatory phosphodiesterase 4 (PDE4) inhibitor, will soon enter phase 3 studies evaluating its use to treat mild-to-moderate disease.

    Also in looking at the pediatric dermatology therapeutic pipeline, Dr. Siegfried identifies ongoing clinical trials evaluating topical rapamycin as treatment for facial angiofibromas in patients with tuberous sclerosis complex as an item of interest.

    “Tuberous sclerosis complex is a rare disease, but facial angiofibromas are a very disfiguring manifestation for which there are no good treatments,” Dr. Siegfried says.

    She also highlighted groundbreaking research involving a recombinant ectodysplasin-A1 replacement protein (EDI200, Edimer Pharmaceuticals) for the treatment of X-linked hypohidrotic ectodermal dysplasia (XLHED). A phase 2 trial investigating EDI200 for the treatment of affected neonates began in October 2013. The study was undertaken after positive results were achieved in both a preclinical proof of concept study and a phase 1 clinical study enrolling adults with XLHED. Ultimately, a study of antenatal administration is planned.

    “This research represents entry into a brave new world,” Dr. Siegfried says.

    Gene discovery

    On the topic of genetic disorders, Dr. Siegfried notes that genetic mutations underlying both Sturge-Weber syndrome and nevus sebaceous were recently found.

    “Gene discovery is an incredibly important emerging field. While the beginning focus is on rare disorders, in the long run we can expect it will help us learn more about the pathogenesis of more common diseases and provide a basis for new therapeutic interventions,” Dr. Siegfried says.

    Based on the scope of ongoing research, Dr. Levine says he believes dermatologists can expect to see major advances in the not-too-distant future in treatments for psoriasis. In 2013, new data were reported for the oral PDE4 inhibitor apremilast (Celgene), as well as for new biologics targeting interleukin-17 and for both oral and topical Janus kinase inhibitors.

    Pediatric care

    The efficacy of propranolol for the treatment of infantile hemangioma was not breaking news in 2013. However, an international, multicenter, phase 3, prospective, double-blind, placebo-controlled trial has been completed, demonstrating remarkable efficacy and bringing a new formulation of the drug much closer to approval by the Food and Drug Administration, says Dr. Siegfried, who believes propranolol treatment for hemangioma is one of the biggest innovations that has occurred in pediatric dermatology during the past decade, if not her entire career.

    Furthermore, the serendipitous discovery of propranolol’s benefit fostered active research looking at other alternatives for medical treatment of hemangioma of infancy, including the use of various beta-blockers administered orally or topically, as well as topical brimonidine.

    In addition, it allowed for an expanded role of laser surgery. According to Roy Geronemus, M.D., use of the pulsed dye laser with oral propranolol to treat infantile hemangiomas, having a superficial component is one of the major advances in laser surgery.

    “The addition of the laser appears to be helpful for both limiting the duration of oral propranolol treatment and achieving a more complete response,” says Dr. Geronemus, who practices in New York.

    Other laser advances

    Both Drs. Geronemus and Spencer highlighted the availability of the picosecond laser (PicoSure, Cynosure) for tattoo removal as an important development. Dr. Geronemus conducted the clinical research leading to FDA clearance of the device in 2012.

    “This first picosecond laser expedites tattoo treatment and particularly for tattoos with blue and green colors that have been extremely difficult to remove. Using the picosecond laser, tattoo removal in many patients can now be completed in just one to three sessions,” Dr. Geronemus says.

    According to Dr. Geronemus, other important developments in laser surgery include use of the 1,927 nm thulium laser (Fraxel Dual, Solta Medical) to clear actinic keratoses with minimal downtime or recovery and of ablative fractional resurfacing to improve burn, traumatic and surgical scars.

    “Ablative fractional resurfacing for scar treatment in military veterans has been an especially gratifying application of this technology,” Dr. Geronemus says.

    Dr. Wheeland also identifies the expansion in applications of fractional laser technology as an important development in dermatology.

    “Fractional treatments using newer wavelengths, including 1,927; 1,550; and 1,440 nm, to induce tissue remodeling can improve the appearance of scarred or aging skin and with less pain, faster healing, and better results compared with older technologies,” Dr. Wheeland says.

    Pearls from the literature

    In compiling his list of the year’s important developments, Dr. Levine also references some reports in the literature on uses of older drugs. He highlighted a prospective study that provides support for azathioprine as a steroid-sparing, long term treatment for severe, recalcitrant atopic dermatitis in children (Caufield M, Tom WL. J Am Acad Dermatol. 2013;68(1):29-35).

    “Clinicians have been reluctant to use azathioprine based on the perception that it has too many side effects. However, in children with severe atopic dermatitis that is unresponsive to topical therapies, azathioprine represents an excellent alternative to chronic systemic steroids,” Dr. Levine says. “Monitoring for side effects is easier for azathioprine than with steroids. Furthermore, most of the adverse reactions to azathioprine are reversible if caught early, whereas many side effects of prednisone are permanent.”

    He also notes there have been multiple reports on the use of oral glycopyrrolate for the treatment of hyperhidrosis.

    “Anticholinergic therapy for hyperhidrosis is not a new concept, but there are new data showing glycopyrrolate is safe and effective when used in a low dose regimen,” Dr. Levine says. “With just modest side effects and seemingly favorable safety with long-term use, perhaps it may replace more costly and difficult treatments such as iontophoresis , sympathectomy and even onabotulinumtoxinA (Botox, Allergan) injections.”

    Treatments with neurotoxins

    On the topic of the neurotoxin, Dr. Levine says there is emerging data on its use for treating vasomotor symptoms in patients with Raynaud’s phenomenon.

    “There are now reasonably good data supporting onabotulinumtoxinA as a safe and effective option for what has been a very difficult-to-treat disorder. Based on this information and the fact that there are few good alternatives, onabotulinumtoxinA seems to be something worth considering,” he says.

    Another publication that caught Dr. Levine’s interest as providing practical information was a report by Elston et al showing favorable long-term outcomes in patients with incompletely excised dysplastic nevi (Hocker TL, Alikhan A, Comfere NI, Peters MS. J Am Acad Dermatol. 2013;68(4):545-551).

    “Many pathologists recommend that mild-to-moderately dysplastic nevi be re-excised if the margins are involved,” Dr. Levine says. “The data presented in this article indicate re-excision is unnecessary, and they provide further support for the idea that atypical moles are mostly benign lesions not requiring aggressive surgical therapy.”

    In addition, Dr. Levine says he thought a retrospective case-control study by Summers et al was worth highlighting (Summers EM, Bingham CS, Dahle KW, et al. JAMA Dermatol. 2013;149(7):814-818). These investigators demonstrated an association between calcium channel blocker use and chronic eczema in adults, thus suggesting that discontinuation of this medication may be a strategy to consider in patients with intractable eczema of uncertain etiology.

    Finally, Dr. Siegfried identifies the occurrence of a second North American outbreak of eczema coxsackium during 2013 as a noteworthy event because of its medical and socioeconomic impact.

    “Children affected with eczema coxsackium were flooding emergency rooms, and they were sometimes misdiagnosed with epidermolysis bullosa, eczema herpeticum or bullous impetigo and then treated with antiviral or antibiotic therapy,” Dr. Siegfried says. “Dermatologists and other providers to whom these children are likely to present need to be aware of the disease so that they will make the proper diagnosis and not prescribe unnecessary medications.”

    Cheryl Guttman Krader
    Cheryl Guttman Krader is a contributor to Dermatology Times, Ophthalmology Times, and Urology Times.

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