Feature: CME #113 – December 2002: Dermatologic Therapeutic Advances of 2002 - By J. Alhariri, M.D., and Simon Yoo, M.D. A review of the diseases and their respective treatments that have made the news this year. 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 one physician credit hours. As a reader of Skin & Aging, this course is free for you. You don’t need to pay a processing fee. This past year has probably been a busy one for you — a number of new drugs and therapies have been developed or modified to treat a variety of dermatologic conditions. J. Alhariri, M.D., and Simon Yoo, M.D., review the new therapies and some of the best treatments for the conditions we treat every day — from acne to warts. At the end of this article you’ll find a 10-question exam. Mark your responses on the postage-paid postcard and return it to HMP Communications. About 1 month after the publication date, we’ll post this course on Skin & Aging’s Web site, which you can access at www.skinandaging.com. I hope this CME contributes to your clinical skills. Cordially, Steven R. Feldman, M.D., Ph.D. CME Editor CME Guidelines -Steven R. Feldman, M.D., CME Editor Principal faculty: J. Alhariri, M.D., and Simon Yoo, M.D. Method of Participation: Physicians may receive two category 1 credits by reading the article on pages 40 to 45 and successfully answering the questions found on p. 46. A score of 70% is required for passing. Use the postage-paid card provided to submit your answers and evaluation or log on to www.skinandaging.com and respond electronically. Estimated time to complete the educational activity: 2 hours Dates of original release: December 2002 — Expiration Date: December 2003 This activity has been planned and produced in accordance with the ACCME essentials. Accreditation Statement: HMP Communications, LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Designation Statement: HMP Communications, LLC, designates this continuing medical education activity for a maximum of 1 credit hour in category 1 credit toward the AMA Physician’s Recognition Award. Each physician should claim only those hours of credit that he/she actually spent in the educational activity. Disclosure Policy: All faculty participating in continuing medical education programs sponsored by HMP Communications are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. Faculty Disclosures: Drs. Alhariri and Yoo have disclosed that they have no significant financial relationship with any organization that could be perceived as a real or apparent conflict of interest in the contexts of the subject of their presentation. Learning Objectives: At the conclusion of this educational activity, the participants should be able to: • identify skin disorders and their pathophysiology and the treatment options available — whether FDA approved, off-label or still in the clinical trial phase • identify new treatment options for chronic skin disorders when faced with treatment resistance or adverse effects • understand the importance of keeping abreast of the therapeutic advances in the field of dermatology. Target Audience: Dermatologists, Plastic Surgeons, Internists Commercial support: None T herapeutics in dermatology is ever-changing with new drugs and therapies being discovered and modified often. And as dermatologists and researchers have learned more and developed a better understanding of the etiology and pathophysiology of the different diseases we treat, we’ve been better able to use available advanced technology. This year we’ve added to our therapeutic armamentarium with new drugs that have gained FDA approval for treating a number of skin diseases. In addition, using drugs approved for non-dermatologic conditions that share similar underlying pathophysiology to conditions we treat in dermatology has led to major scientific breakthroughs and has helped in engineering new therapeutics. Many clinical trials this year have focused on skin disorders that are models for a multitude of systemic inflammatory disorders, which has positively reinforced the emergence of novel dermatologic treatments. Here, we’ll review the promising treatments that have been recently approved or are evolving as novel therapies for the diseases and conditions we treat on a daily basis from acne vulgaris to warts. Psoriasis In the past few years, there’s been a great deal of research into the development of new therapeutic modalities for treating psoriasis. Research has focused on targeting specific cell receptors or cytokines that will diminish the effects of moderate to severe psoriasis, including redness, flaking and itching. Multiple topical and systemic drugs for psoriasis have evolved in the past years, but all with multiple side effects. These effects range from local irritation to tachyphylaxis to more severe side effects with the systemic drugs, such as hepatotoxicity, nephrotoxicity, bone marrow toxicity and increased risk of lymphoproliferative disorders and skin cancers. Aiming for fewer side effects, and more specific targets, etanercept (Enbrel), infliximab (Remicade), alefacept (Amevive), and efalizumab (Xanelin) among others, are agents currently being studied for psoriasis. T cells in psoriatic plaques are mainly effector T cells that were previously activated. This is demonstrated by their expression of the T-cell marker CD45RO. These cells secrete cytokines of the TH1 pattern demonstrated in psoriatic plaques. Let’s discuss a therapy that’s directed to reduce the number of pathogenic T cells, to inhibit their migration and activation or to block the activity of their inflammatory cytokines. Alefacept (LFA-3TIP) is a fusion protein combining the binding site of lymphocyte function associated antigen-3 (LFA-3) with the Fc portion of human IgG. Alefacept binds to CD2 (the ligand to LFA-3) expressed on CD45RO T cells. Patients treated with this drug showed 50% to 75% improvement and remission for as long as 8 months.1 Efalizumab (anti CD11a) is a humanized monoclonal antibody aimed at binding CD11a on T cells, which is a component of LFA1. CD11a inhibits LFA1-ICAM-1 interaction on antigen presenting cells necessary for T-cell activation and cellular migration. At a dose of 0.3 mg/kg per week intravenously (I.V.) efalizumab produced significant improvement of 45% in PASI scores (see “Understanding PASI,” at right) of treated patients.2 Etanercept and infliximab are anti-tumor necrosis factor alpha agents. Etanercept, a fusion protein using the extracellular domain of the TNF-alpha receptor, is given at doses of 25 mg twice a week. Infliximab, a monoclonal antibody derived from mice and directed against human TNF-alpha, is given as an I.V. infusion. Etanercept, which has FDA approval for psoriatic arthritis, resulted in 46% improvement in PASI score of treated patients.3 Infusion reactions, or injection site reactions, as well as other adverse skin effects have been reported. Neutralizing antibodies have also been a concern with infliximab. A major recent concern is infections — recent reports of mycobacterial infections and reactivation of latent tuberculosis have been documented.4 As efalizumab and alefacept complete clinical trials in psoriasis, we’ll have considerable information on how effective they are in more than 1,000 patients. We’ll also have safety information on these clinical trial subjects. We have much less information on the efficacy of TNF inhibitors in psoriasis, but they not only appear promising they are already on the market and can be prescribed for patients now. Moreover, we do have considerably more information on the safety of TNF inhibitors since they’ve been used in more than 100,000 patients. Other biologic agents such as the following are also currently under study. Denileukin diftitox (Ontak) is a fusion protein that combines IL2 and diphtheria toxin and selectively eliminates activated T cells. In addition, IL10, a TH2 cytokine, also downregulates TH1 response. Lastly, two other agents, anti-Interferon gamma, which is an anti-CD 80, and anti-IL8 are also under study. Understanding PASI -Steven R. Feldman, M.D., CME Editor Dermatologists who want to keep abreast of the information on new treatments for psoriasis need to be well versed in how to interpret measures of psoriasis. The primary measure used to evaluate psoriasis is the Psoriasis Area and Severity Index (PASI). The PASI is a measure of how thick, red and scaly the lesions of psoriasis are and a measure of the area of the body covered by these lesions. Four body area sections are scored separately (head, upper extremities, trunk and lower extremities). Redness, thickness and scaliness of the lesions are each scored on a scale of 0 to 4. The area covered is scored on a scale of 1 through 6 (1=<10%, 2=10% to 30%, 3=31% to 50%, etc). The sum of the redness, thickness and scaliness is then multiplied by the area score. Once the scores for each body area are obtained, they are weighted and summed to get the final PASI. Scores greater than 10 to 12 generally reflect severe disease. Changes in the PASI score are not linearly related to improvement in the disease. For example, if one has dark red, very scaly and thick plaques (4 for each for a sum of 12) spread equally on 50% of the body (area score 3), the PASI is 36. If treatment reduces the area of coverage to 1% of the body but there has been no change in the lesions, the PASI drops to 12. This means there’s been a 98% improvement in the disease but only a 66% improvement in the PASI. Typically patients who have at least 50% improvement in PASI have achieved a clinically significant improvement in their disease. Clinical trials tend to report the number of subjects who achieve 75% reduction in PASI score. This may lead clinicians to underestimate the value of treatment. One way to get a sense of PASI improvement is to consider the changes in PASI seen with methotrexate. In one small study of psoriasis patients treated for 6 months with 15 mg to 30 mg/week of methotrexate (Rheumatrex), only about 30% achieved 75% improvement in the PASI. This is not to say that methotrexate is not effective, rather it means that therapies that help 30% of patients to achieve a 75% improvement in PASI may be about as effective as methotrexate in the treatment of psoriasis. Atopic Dermatitis A new class of drugs, the topical immunodmodulators (TIMs), was developed in recent years to treat atopic dermatitis (AD). First, in 2000, tacrolimus ointment (Protopic) was FDA approved for the treatment of moderate to severe AD. And in 2002, we had a second TIM available to treat our AD patients. In December 2001, pimecrolimus (Elidel) received FDA approval for the treatment of AD. Pimecrolimus targets calcineurin and calcium-dependent phosphatase, which are necessary for T-cell activation. Pimecrolimus binds to one of the immunophilin class of cytosolic binding proteins, forming a complex that inhibits calcineurin, thereby suppressing the activation of type 1 and 2 T cells. Improvement in pruritus of skin lesions was seen as early as 8 days after therapy began. Treatment of early signs of AD in infants between 3 and 24 months of age has shown that the drug modified the disease course by reducing incidence of flares and improving overall control of AD.5 In another study of 713 patients with AD between the ages of 2 and 17 years treated for 1 year, pimecrolimus was found to be clinically tolerated and not associated with significant side effects.6 Keep in mind that topical treatment with pimecrolimus is effective in mild to moderate cases of AD, and severe cases might require more aggressive therapy such as phototherapy, cyclosporine (Neoral, Sandimmune), azathioprine (Imuran), mycophenolate mofetil (CellCept) and I.V. immunoglobulin. Actinic Keratosis Actinic keratosis (AK) may be the earliest manifestation of squamous cell carcinoma (SCC), but this remains debatable among physicians. Risk of progression of AK to SCC can be as high as 16%. Typically presenting on sun exposed areas, AKs can vary in shape, size and color from being few millimeters to several centimeters; erythematous to hyperpigmented; and hyperkeratotic to hypertrophic. We now have several new options for treating these prevalent lesions. Actinic Keratosis An AK lesion on a patient's arm. Photo courtesy of Neil Shear, M.D. Diclofenac sodium 3% in 2.5% hyaloronan gel (Solaraze) twice daily for 60 to 90 days is one such therapy. Adverse reactions were mostly localized to skin and include contact dermatitis, dry skin and exfoliation. When compared to its vehicle, hyaloronan (a glycosaminoglycan), diclofenac appears to be well tolerated and effective in decreasing the number and the size of treated AKs. Its mechanism of action appears to inhibit angiogenesis and induce neovascular regression in inflammatory tissues and stimulate apoptosis. Hyaloronan appears to depot and hold diclofenac in the epidermis, thereby prolonging its pharmacokinetic half-life.7,8 Imiquimod 5% (Aldara) cream is an immune-response modifier that results in locally increased levels of INF-alpha, TNF-alpha, and interleukins 6 and 8 upon application to the skin. Reports and small studies have shown it to be effective in treating basal cell carcinoma (BCC) as well as SCC. A recent study has shown that the average number of AKs decreased by 40% after 3-times-per-week treatments with imiquimod for a total of 8 weeks. The most frequent reactions to this treatment, which were seen in more than 80% of treated patients, were erythema, itching and scabbing, but all were reported to be mild to moderate and tolerable.9 We also have photodynamic therapy (PDT), which is based on the application of aminolevulinic acid (ALA) and subsequent illumination of a skin lesion with light, to treat AKs. For this treatment, ALA is converted to protoporphyrin IX, a photosensitizer that sensitizes the involved cells to the destructive action of the light. A recent study comparing PDT with cryotherapy showed that the overall response rate was 69% for PDT and 75% for cryotherapy, but with a better cosmetic outcome in the PDT treatment group.10 There is no long-term data about cure rate with PDT treatment, whereas a 99% cure rate is achieved with cryotherapy in patients followed for as long as 8 years post treatment. ALA 20% (Levulan Kerastick) is the first approved topical photosensitizer for the treatment of AKs. The practical aspects of its use, the time span between the application and illumination, the potential for discomfort, and the cost of the therapy, are factors to be considered in using PDT. We also have topical 5-fluorouracil (5-FU) creams to treat AKs. 5-FU 0.5% (Carac) is applied once a day and is used for 1,2 or up to 4 weeks, which is a shorter treatment period than some of our other options. It has been associated with greater initial irritation. However, it allows us to see pre-clinical lesions that weren’t visible before within about 7 days of treatment. Mycosis Fungoides Mycosis Fungoides (MF) is the most common primary cutaneous T-cell lymphoma, a heterogeneous group of low-grade Non-Hodgkin’s lymphomas that manifest primarily in the skin. It’s characterized by the accumulation of clonal population of CD4 positive T cells in the skin. In its early stages, IA through IIA, CTCL is typically limited to the skin. Mycosis Fungoides Acruate patches and thin plaques of MF. Photo courtesy of Seth Stevens, M.D. Conservative treatment with skin-directed therapies is the standard as aggressive systemic chemotherapy has shown minimal or no effect on skin limited disease. Traditional therapy with topical steroids, topical mechlorethamine (Mustargen, Nitrogen Mustard, Chlorethazine, Chlormethine, HN2, Mustine), topical carmustine (BCNU), electron beam irradiation, psoralen-UVA (PUVA) and UVB are all effective in treating patients with MF. Inconvenience, hypersensitivity reactions, as well as increased risk of secondary skin cancers, are all limiting factors to treatment. Bexarotene gel (Targretin) received FDA approval in June 2000 as a therapy for stage IA through IIA CTCL, which expanded the armamentarium of available therapy. Bexarotene gel is a retinoid X receptor-selective ligand whose exact mechanism of action in CTCL is not yet defined. It’s speculated to work on already transformed T cells directly or indirectly through cytokine modulation or receptor induction in the CTCL lesions. In a study of 67 patients with stage IA through IIA MF, an overall response rate (partial remission) of 63% and a complete response rate (total remission) of 21% were achieved. Median treatment duration was 10.5 months. The most common adverse effect was erythema, which was prevalent in 87% of patients. Systemic blood levels of bexarotene were negligible.11 Since MF in early stages tends to be chronic, sequential therapy as used in the treatment of psoriasis might be necessary. Bexarotene gel seems to be efficacious and safe and should be added to the list of available topical treatments. Vitiligo Various treatment modalities for vitiligo have been described. Surgical modalities (split-thickness epidermal grafting, epidermal blister grafting and grafting of cultured melanocytes), corticosteroids, topical psoralen plus UVA, oral psoralen plus UVA and narrow-band UVB are all unsatisfactory. An optimal treatment of vitiligo is not yet available. Variable results with PUVA, which still is the primary therapy, have been reported. Gastrointestinal side effects, phototoxicity and long-term carcinogenic effects are all potential risks. Receptors for 1,25-dihydroxyvitamine D3 have been demonstrated on melanocytes and recent advances in the pathophysiology of vitiligo have demonstrated defective calcium hemostasis in depigmented skin. Recently, studies and case reports of successful treatment of vitiligo with calcipotriene (Dovonex) suggest that 1,25-dihydroxyvitamine D3 may be involved in the regulation of melanin synthesis. A study comparing the use of twice-daily application of calcipotriene as a monotherapy in comparison to calcipotriene and oral or topical 8-methoxypsoralen UVA combination showed favorable results. Of those patients with calcipotriene monotherapy, 77% showed a 30% to 100% improvement after 3 to 9 months of therapy, with no adverse effects.12 In another placebo controlled double-blinded study, combination treatment of calcipotriene 1 hour prior to PUVA therapy resulted in a significantly higher percentages of repigmentation compared with placebo and PUVA. This indicates that topical calcipotriene potentiates the efficacy of PUVA if used as an adjunctive treatment of vitiligo and lowers the total UVA dosage needed for repigmentation.13 Acne Vulgaris Acne vulgaris affects a large number of adolescents and imposes a tremendous amount of stress on the affected patients leading sometimes to social and psychological dysfunction. Acne is a multifactorial disease and treatments over the past several decades have targeted the different etiologic and pathogenic factors of this disease. Successful treatment, which can be challenging for you as the physician and frustrating to the patient, should address one or more of the following: sebaceous glands and sebum production, follicular hyperkeratinization, abnormal hormonal states and hyperandrogenism, Propionibacterium acnes (P. acnes), and resulting scarring and hyperpigmentation. The armamentarium of acne therapy keeps enlarging, and sequential as well as combination therapy is usually needed to achieve good results. Recently, tazarotene (Tazorac), a newer retinoid that’s converted in the epidermis to tazarotenic acid, was approved in higher concentrations (0.1%) to treat acne. (It’s also available in a 0.05% concentration.) This synthetic retinoid has selective binding to RAR beta and RAR gamma. Its efficacy and tolerability as compared to both adapalene 0.1% (Differin) and tretinoin 0.1% (Retin-A) was assessed in two studies. Tazarotene 0.1% was associated with a significantly greater incidence of treatment success and significant reduction of non-inflammatory as well as inflammatory lesion count as compared to adapalene and tretinoin. The mean usage per application of tazarotene was also significantly lower, resulting in a decreased cost per treatment success in both studies. Tolerability was also assessed, with burning, erythema, itching and peeling occurring early on during treatment.14,15 A more important limiting factor to its use is its labeling as a category X drug, and caution should be applied in its use in adolescent females or any females who are at risk for pregnancy. We’ve also known, for a long time, that phototherapy improves acne. ClearLight (Lumenis) was FDA approved in August 2002 for the treatment of acne. It produces a narrow band blue light (410 nm to 420 nm) that will excite the porphyrins produced by P. acnes and destroy the bacteria. Patients should be treated for 15 minutes twice a week. Irradiation of light seems also to have some anti-inflammatory effect. Also, recently, a number of lasers have been developed for the treatment of acne. The 1320 nm, 1450 nm and 1540 nm, mid-infrared lasers have all been used. These wavelengths cause a peak thermal damage in the upper dermis where sebaceous glands are located, and these wavelengths show epidermal preservation, thereby using the selective photothermolysis concept.16 Availability and cost may be limiting factors. Finally, the increasing therapeutic options that are rendered available to treat acne widen our choices for treatment selection, but it’s important to keep treatment protocols simple to reinforce patient compliance and decrease treatment resistance. Warts We know that the human papillomavirus (HPV) causes common warts (verruca vulgaris), flat warts, genital warts, epidermodysplasia verruciformis and SCC. Here, I’ll discuss common warts, which are mostly caused by HPV type 2, 4, 27 and 29. Treatment is diverse, although cryotherapy remains the first line of therapy. Recently, immunologic manipulation has been used more, especially when patients are presenting with resistant warts that failed with some of the more traditional measures. Immunotherapy has long relied on application of sensitizer chemical compounds in a sensitization phase followed by application of the sensitizer to the surface of the wart. Dinitrochlorobenzene, diphencyprone, and squaric acid have all been used as chemical sensitizers. Imiquimod 5% (Aldara) cream, which is successful in the treatment of external anogenital warts in more than 50% of cases, has been used to treat hyperkeratotic verruca vulgaris. Its application varied from once daily for 4 weeks to twice daily for up to 16 weeks in treated cases, in some reported case series.17 A novel immunomodulatory approach consists of injecting Candida albicans skin test antigens into the warts of immune individuals. In one study where C. albicans or mumps intralesional antisera (0.1 ml to 0.3 ml ) were injected into warts, there was complete clearing of the treated warts in 74% of cases. A large percentage (78%) of patients also had clearing of distant untreated warts, which might be caused by systemic HPV-directed immunity.18 Finally, one study found duct tape to be more effective than cryotherapy; however this method needs further evaluation by larger scale studies. If it proves effective, though, it would be a rather cheap and painless therapeutic intervention.19 A Busy Year In summary, multiple FDA approved drugs have recently emerged in dermatology, and we’ve been able to apply their uses to treat other skin disorders sharing similar pathophysiology. Also, lessons learned from the use of some drugs in other specialties such as rheumatology and hematology have helped tremendously in providing new considerations for the treatment of some well-known chronic skin disorders. In Other FDA News from 2002 -Steven R. Feldman, M.D., CME Editor One of the biggest news stories in dermatology this year was that botulinum toxin type A (Botox Cosmetic) was approved by the FDA in April 2002 for the treatment of moderate to severe glabellar lines in adult men and women ages 65 and younger. The drug works by blocking nerve impulses to relax the contraction of two major forehead muscles. Botox A blocks neuromuscular transmission by binding to acceptor sites on motor nerve terminals, entering the nerve terminals and inhibiting the release of acetylcholine. The inhibition occurs as the neurotoxin clears SNAP 25, a protein integral to the successful docking and release of acetylcholine from vesicles situated within nerve endings. The toxin produces partial chemical denervation of the muscle resulting in a localized reduction in muscle activity. In a study where patients with moderate to severe glabellar lines received 20 units Botox A into five glabellar sites, a significant reduction in glabellar lines severity was noted, with the effect being maintained for 120 days. Mild blepharoptosis was a minor complication.20 Botox is also approved for treatment of several neurological disorders including strabismus, blepharospasm and cervical dystonia. It’s also been used in aerodigestive, genitourinary, autonomic nervous system and pain disorders. In dermatology, it’s also used for axillary hyperhydrosis and hand dyshydrotic vesicular dermatitis. Test Questions and evaluation forms are available for PDF download only at the present time. Click on the following links to print the PDF forms or right click the following link and select "save download as" to save the forms to your computer. Submission instructions are on the forms. <Download here>PDF Format References: 1. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med. 2001;345:248-255. 2. Gottlieb A, Krueger JG,Wittkowski K, Dedrick R, Walicke PA, Garovoy M. Psoriasis as a model for T-cell mediated disease. Immunobiologic and clinical effects of treatment with multiple doses of Efalizumab, an anti-CD11a antibody. Arch Dermatol. 2002;138:591-600. 3. Mease PJ, Goffe BS, MetzJ, VanderStoep A, Finck B, Burge DJ. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomized trial. Lancet. 2000;356:3385-390. 4. Keane J, Gershon S, wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001;345:1098-1104. 5. Kapp A, Papp K, Bingham A, Folster-Holst R, Ortonne JP, Potter PC, Gulliver W, Paul C, Molloy S, Barbier N, Thurston M, de Prost Y; Long-term management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J Allergy Clin Immunol 2002 Aug;110(2):277-84. 6. Wahn U, Bos JD, Goodfield M, Caputo R, Papp K, Manjra A, Dobozy A, Paul C, Molloy S, Hultsch T, Graeber M, Cherill R, de Prost Y. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 2002 Jul;110(1 Pt 1):e2 7. Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Wolf JE Jr, Taylor JR, Tschen E, Kang S. Int J Dermatol 2001 Nov;40(11):709-13. 8. Moore AR, Willoughby DA. Hyaluronan as a drug delivery system for diclofenac: a hypothesis for mode of action. Int J Tissue React 1995;17(4):153-6. 9. Persaud AN, Shamuelova E, Sherer D, Lou W, Singer G, Cervera C, Lamba S, Lebwohl MG. Clinical effect of imiquimod 5% cream in the treatment of actinic keratosis. J Am Acad Dermatol 2002 Oct;47(4):553-6. 10. Szeimies RM, Karrer S, Radakovic-Fijan S, Tanew A, Calzavara-Pinton PG, Zane C, Sidoroff A, Hempel M, Ulrich J, Proebstle T, Meffert H, Mulder M, Salomon D, Dittmar HC, Bauer JW, Kernland K, Braathen L. Photodynamic therapy using topical methyl 5-aminolevulinate compared with cryotherapy for actinic keratosis: A prospective, randomized study. J Am Acad Dermatol 2002 Aug;47(2):258-62. 11. Breneman D, Duvic M, Kuzel T, Yocum R, Truglia J, Stevens VJ. Phase 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma. Arch Dermatol 2002 Mar;138(3):325-32. 12. Ameen M, Exarchou V, Chu AC. Topical calcipotriol as monotherapy and in combination with psoralen plus ultraviolet A in the treatment of vitiligo. Br J Dermatol 2001 Sep;145(3):476-9. 13. Yalcin B, Sahin S, Bukulmez G, Karaduman A, Atakan N, Akan T, Kolemen F. Experience with calcipotriol as adjunctive treatment for vitiligo in patients who do not respond to PUVA alone: a preliminary study. J Am Acad Dermatol 2001 Apr;44(4):634-7. 14. Webster GF, Guenther L, Poulin YP, Solomon BA, Loven K, Lee J. A multicenter, double-blind, randomized comparison study of the efficacy and tolerability of once-daily tazarotene 0.1% gel and adapalene 0.1% gel for the treatment of facial acne vulgaris. Cutis 2002 Feb;69(2 Suppl):4-11. 15. Leyden JJ, Tanghetti EA, Miller B, Ung M, Berson D, Lee J. Once-daily tazarotene 0.1 % gel versus once-daily tretinoin 0.1 % microsponge gel for the treatment of facial acne vulgaris: a double-blind randomized trial. Cutis 2002 Feb;69(2 Suppl):12-9. 16. Paithankar DY, Ross EV, Saleh BA, Blair MA, Graham BS. Acne treatment with a 1,450 nm wavelength laser and cryogen spray cooling. Lasers Surg Med 2002;31(2):106-14. 17. Grussendorf-Conen EI, Jacobs S, Rubben A, Dethlefsen U. Topical 5% imiquimod long-term treatment of cutaneous warts resistant to standard therapy modalities. Dermatology 2002;205(2):139-45. 18. Johnson SM, Roberson PK, Horn TD. Intralesional injection of mumps or Candida skin test antigens: a novel immunotherapy for warts. Arch Dermatol 2001 Apr;137(4):451-5. 19. Focht DR 3rd, Spicer C, Fairchok MP. The Efficacy of Duct Tape vs Cryotherapy in the Treatment of Verruca Vulgaris (the Common Wart). Arch Pediatr Adolesc Med 2002 Oct;156(10):971-4. 20. Carruthers JA, Lowe NJ, Menter MA, Gibson J, Nordquist M, Mordaunt J, Walker P, Eadie N; A multicenter, double-blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol 2002 Jun;46(6):840-9. Skin & Aging - ISSN: 1096-0120 - Volume 10 - Issue 12 - December 2002 - Pages: 39 - 46