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 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. 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. 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. 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.
CME #113 – December 2002: Dermatologic Therapeutic Advances of 2002
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 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. 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. 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. 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.
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 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. 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. 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. 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.
