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Study |

A Double-blind Randomized Trial of 0.1% Tacrolimus vs 0.05% Clobetasol for the Treatment of Childhood Vitiligo FREE

Veronica Lepe, MD; Benjamin Moncada, MD; Juan Pablo Castanedo-Cazares, MD; Maria Bertha Torres-Alvarez, MD; Carlos A. Ortiz; Antonio B. Torres-Rubalcava, MD
[+] Author Affiliations

From the Dermatology Department, Hospital Central "Dr Ignacio Morones Prieto" (Drs Lepe, Moncada, Castanedo-Cazares, and Torres-Alvarez), Public Health Department (Dr Torres-Rubalcava), School of Medicine, and the Graphic Design School (Mr Ortiz), Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico. The authors have no relevant financial interest in this article.


Arch Dermatol. 2003;139(5):581-585. doi:10.1001/archderm.139.5.581.
Text Size: A A A
Published online

Objective  To assess the safety and efficacy of topical 0.1% tacrolimus vs 0.05% clobetasol propionate.

Design  Randomized double-blind trial.

Setting  Department of Dermatology, Hospital Central "Dr Ignacio Morones Prieto," San Luis Potosí, México.

Participants  From 20 children with vitiligo, 2 symmetrical lesions of about the same size and evolution time were selected. They were devoid of any topical or systemic therapy for 2 months prior to inclusion.

Interventions  Treatment with topical tacrolimus and clobetasol for a 2-month period.

Main Outcomes Measures  The grade of repigmentation was evaluated by color slides at baseline and again at every 2-week visit. The slides were analyzed by 2 clinicians unrelated to the study and by a morphometric digitalized computer program. Characteristics of pigment, time of response, symptoms, telangiectasias, and atrophy were evaluated every 2 weeks.

Results  Eighteen (90%) of the 20 patients experienced some repigmentation. The mean percentage of repigmentation was 49.3% for clobetasol and 41.3% for tacrolimus. Lesions in 3 patients using clobetasol presented atrophy, and 2 lesions incurred telangiectasias; tacrolimus caused a burning sensation in 2 lesions.

Conclusions  Tacrolimus proved almost as effective as clobetasol propionate to restore skin color in lesions of vitiligo in children. Because it does not produce atrophy or other adverse effects, tacrolimus may be very useful for younger patients and for sensitive areas of the skin such as eyelids, and it should be considered in other skin disorders currently treated with topical steroids for prolonged periods.

Figures in this Article

VITILIGO IS a common idiopathic, acquired, depigmenting disease of the skin and hair that affects 0.5% of the world's population.1 Controversy still exists about its pathogenesis because factors other than immunologic ones have been implicated, such as the early cell death of vitiligo melanocytes related to their increased sensitivity to oxidative stress.2 The idea that nitric oxide could lead to autodestruction of melanocytes resulting in skin depigmentation has been raised.3 Also, the monoaminergic system has been implicated because of increased activity of some of its components and higher levels of catecholamine and its metabolites.4 Neuropeptide Y may play certain roles in the pathogenesis of vitiligo via neuroimmunity mechanisms or neuronal effects on the melanocytes.5 More recently, reports of the participation of 1,25-dihydroxy-vitamin D3 in the regulation of melanin synthesis and the demonstration of the receptors in the melanocytes for this vitamin have opened a new direction in therapy.6

However, experimental evidence shows that abnormal humoral and cell-mediated immune mechanisms are probably the most commonly involved aspect of pathogenesis in this disease.710 The relative success of clinical use of topical corticosteroids (a widespread therapeutic approach with response rates between 50% and 70%) supports this theory.11 Tacrolimus is an immunosuppressor macrolide lactone capable of inhibiting the activation and maturation of T cells by means of blocking the action of calcineurin and interleukin (IL) 2, IL-4, and IL-5 transcription.12,13 It also enhances T-cell apoptosis in vitro and down-regulates IL-8 keratinocyte surface receptors.14 Systemic tacrolimus has been used in a number of applications, particularly to avoid graft rejection.15 Topical tacrolimus is a safe and effective treatment for inflammatory skin diseases, particularly atopic dermatitis, psoriasis, pyoderma gangrenosum, alopecia areata, and other illnesses with immunologic disarrangement.16

Limited data are available about topical bioavailability in humans when tacrolimus is applied to normal skin, although a number of studies have assessed blood levels following application to diseased skin. In a phase 1 study of patients with atopic dermatitis, the topical absorption of 0.3% tacrolimus ointment was found to be less than 4% of an equivalent oral dose given for immunosuppression. Pruritus, burning sensation, and erythema are the adverse reactions observed from topically applied tacrolimus.17

We hypothesized that given its immunomodulatory properties and safer profile than corticosteroids, tacrolimus ointment might carry an improved benefit–toxic effect ratio18 and provide a new therapeutic alternative to topical corticosteroids in children with vitiligo. We know from experience that clobetasol is the most effective topical corticoid therapy for vitiligo because it very often produces pigmentation where other topical steroids have failed. For that reason we selected clobetasol propionate rather than other midpotency steroids for this trial.

PATIENTS

Twenty patients younger than 18 years with vitiligo but otherwise healthy were selected for the study. They all had a vitiligo index of disease activity (VIDA) greater than 3; VIDA is a useful measure to assess the activity of the disease and takes into account recentness or remoteness of the onset of lesions (a VIDA of +4 indicates a lesion duration of 6 weeks; +3, a duration of 3 months; +2, six months; and +1, one year).19 Our patients had not had any vitiligo therapy for 2 months prior to the study. Patients with segmental and mucosal vitiligo were excluded.

A total of 20 patients were recruited; there were 16 girls and 4 boys. Only 2 patients had a positive family history. The mean age was 9.5 years (range, 4-17 years). The mean duration of disease was 2.2 years. The mean percentage of total area affected by vitiligo was 12.2%. The localization of vitiligo was variable. Fifteen patients (75%) had a VIDA of +4, and the other 5 had a VIDA of +3.

Information collected in the routine clinical history included patient sex, location and distribution of the disease, percentage of depigmentation, age at onset, family history, and disease activity. Informed consent was obtained from all patients, and the study was approved by the local institutional review board.

Two lesions similar to each other in size and time of evolution were selected to apply either 0.1% tacrolimus ointment (Protopic Ointment, Fujisawa Healthcare Inc, Deerfield, Ill) or 0.05% clobetasol propionate (Lobevat Cream; Stiefel Laboratories Inc, Coral Gables, Fla) twice a day, in a double-blind randomized way. The medications were in exactly the same containers, packed by a person unaware of the study. The total amount of medication used ranged between 20 and 40 g. Patients were evaluated every 2 weeks, and repigmentation and adverse effects were recorded.

Color slides of the lesions were taken at the beginning and end of the treatment period. The slides were analyzed visually by 2 clinicians not involved in the study and by computer using Corel Draw, version 9.0 (Corel Corporation, Ottawa, Ontario). For the computer analysis, each of the digitalized pictures was subjected to morphometry analysis (Figure 1). The entire lesion was given a 0% score at the beginning of the study to indicate a baseline of no repigmentation. A second percentage value was assigned at the end of the study to represent the level of repigmentation. The categories of repigmentation were as follows: none (0%), poor (1%-25%), moderate (26%-50%), good (51%-75%), and excellent (>75%).20

Place holder to copy figure label and caption
Figure 1.

Vitiligo-depigmented eyelids (in red) before (A) and after (B) treatment with one of the study medications. The patient's right eyelid and brow were treated with clobetasol propionate and showed 40.3% repigmentation; the patient's left eyelid and brow were treated with tacrolimus, and showed 36.0% repigmentation.

Graphic Jump Location
STATISTICAL ANALYSIS

To assess the size of the sample, we hypothesized that 95% of patients using clobetasol and 40% of patients using tacrolimus would reach some degree of repigmentation; using these figures, we determined that we needed 20 subjects.21 The method of randomization was the technique of permuted block randomization for right or left selection.22 Evaluation of the new pigment was done by the Kolmogorov-Smirnov test for clinical observation and the paired t test for digital observation. We compared the clinicians' visual evaluations and the digitalization-morphometry findings using the κ test of consistency.23 The error differences between the medications had a normal distribution (W=0.965; P =.65); then a paired t test was applied (P =.005).24

Eighteen (90%) of our 20 patients achieved some repigmentation with each treatment (Figure 2). Both medications were very well tolerated during the 2 months of the study. The percentage of repigmentation with clobetasol was 49.3% vs 41.3% with tacrolimus. With both treatments, the new pigment was conserved and the best effects of repigmentation were observed in the face and areas with greater density of hair follicles. Neither treatment produced pigment on the dorsum of the hands or areas devoid of hair follicles.

Place holder to copy figure label and caption
Figure 2.

Extent of the vitiligo-depigmented area before (A) and after (B) treatment with one of the study medications is outlined in red in the top photographs and fully red shaded in the bottom. The patient's left eye was treated with tacrolimus and the right eye, clobetasol propionate. Both treatments resulted in significant improvement.

Graphic Jump Location

With clobetasol, perifollicular islands of pigment were observed after 3 weeks; more than 75% overall repigmentation was seen in 5 (25%) of the clobetasol-treated patients. Of these, none showed complete repigmentation. Most of the patients using clobetasol (40%) experienced from 51% to 75% repigmentation in areas such as the axillae, legs, and abdomen—areas where clobetasol showed an advantage over tacrolimus. No change of coloration was observed in 2 patients (10%); these 2 cases involved the dorsal hand areas.

Tacrolimus produced more than 75% repigmentation in 5 patients, most of this on facial areas (Figure 3). Two patients (10%), the same 2 who showed no repigmentation from clobetasol, showed no change of pigmentation with tacrolimus. For those patients who experienced repigmentation, it first appeared after the third week, and the new pigment color was a mix between the color of the patient's normal skin and the color of the lesion. It was homogeneous and in centripetal form (Figure 4).

Place holder to copy figure label and caption
Figure 3.

A, Vitiligo depigmentation is apparent on the brows and lids of this patient before treatment. B, The condition is much improved after treatment. Both the clobetasol (patient's right eye) and tacrolimus (left eye) treatments produced excellent (>75%) repigmentation.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Eighteen (90%) of the 20 patients experienced some improvement of skin color with both treatments. Comparison between the 2 medications shows similar results except in the "good" category (51%-75% repigmentation).

Graphic Jump Location

Clinical evaluation of the results showed no statistically significant differences between treatments (P>.05, Kolmogorov-Smirnov test). However, computerized morphometric evaluation showed that tacrolimus was a significantly more effective treatment (P = .005, paired t test). The results obtained by the 2 clinicians not related to the study were compared and subjected to the test of consistency,23 with the following results: κ = 0.70 for clobetasol; κ = 0.64 for tacrolimus. To prove the dependability of the computer program, the results of these 2 clinicians were compared against the computer results, with the following outcome: κ = 0.93 and 0.79 for clobetasol; κ = 0.74 and 0.51 for tacrolimus. These data show agreement for both kinds of observations.

Atrophy was reported in 3 patients (15%) and telangiectasias in 2 (10%) after the eighth week of treatment with clobetasol, when approximately 20 to 30 g of medication had been consumed. Burning sensations (that did not preclude continuation of therapy) were reported in 2 (10%) of the patients treated with tacrolimus during the first 2 weeks of treatment (Table 1).

Table Graphic Jump LocationCharacteristics of Patients, Repigmentation, and Adverse Effects

For the past 2 decades, monotherapy with topical steroids has been the most common treatment for vitiligo in children. The range of response has been between 20% and 90% improvement, usually not a complete cure.11 Adverse effects and poor efficacy have led to the search for new alternatives. While treatment with combinations of steroids and retinoids can avoid atrophy, retinoids are not well tolerated by children because of skin irritation. Therapy with systemic psoralens and UV-A irradiation is not used in children, and the topical variant is cumbersome and carries some risk. The new phototherapeutic approach with narrow-band UV-B irradiation may prove useful for children with vitiligo.25

The search for substances with the benefits of topical steroids but without the well-known adverse effects seems to be producing results: calcipotriol for psoriasis and tacrolimus and other macrolides for inflammatory dermatoses.26 Calcipotriol has also been shown to be 77% effective in treating adults with vitiligo, but there are no data for children with this disease.27

In the present study, we compared treatment with tacrolimus and clobetasol propionate for repigmenting different areas of the body affected by vitiligo and found very similar results. The risk for adverse effects with both drugs was reduced due to frequent observation and the short duration of the study.

Additionally, the hyperpigmented borders frequently seen in the repigmented skin of patients treated with clobetasol did not occur in those treated with tacrolimus. The tacrolimus repigmentation was homogeneous and not composed of confluent spots. Certainly the main point in the comparison made in this study was the absence of atrophy in lesions treated with tacrolimus. Regarding the question of tacrolimus penetration into noninflamed skin, the fact that pigmentation was obtained with this medication speaks in favor of penetration. Certainly there is no hyperkeratosis in vitiligo that could preclude incursion of the drug into the skin.

In our study, the results were evaluated by digital morphometry, which we believe provides a high degree of certainty. Pigment obtained in the study was sustained throughout the period of observation. It remains to be seen whether the newly formed color remains over the long term. We believe that the present study is the first to show the usefulness of tacrolimus in treating vitiligo in children. It would be interesting to see whether longer periods of therapy, combinations of tacrolimus with other topical agents, or increased concentrations of tacrolimus could produce better results than those obtained in this series and whether the negative results obtained in acral areas could be overturned with any of these approaches.

Corresponding author and reprints: Benjamin Moncada, MD, Dermatology Department, School of Medicine, Universidad Autónoma de San Luis Potosí, 2405 V Carranza Ave, Zona Universitaria, 78210, San Luis Potosí, SLP, Mexico (e-mail: moncadab@uaslp.mx).

Accepted for publication November 12, 2002.

This study was supported in part by the Dermatology Department at the Universidad Autónoma de San Luis Potosí, San Luis Potosí, Mexico.

Kovacs  SO Vitiligo. J Am Acad Dermatol. 1998;38647- 666
Link to Article
Jimbow  KChen  HPark  JSThomas  PD Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase-related protein in vitiligo. Br J Dermatol. 2001;14455- 65
Link to Article
Rocha  IMGuillo  LA Lipopolysaccharide and cytokines induce nitric oxide synthetase and produce nitric oxide in cultured normal human melanocytes. Arch Dermatol Res. 2001;293245- 248
Link to Article
Cucchi  MLFrattini  PSantagostino  GOrecchia  G Higher plasma catecholamine and metabolite levels in the early phase of nonsegmental vitiligo. Pigment Cell Res. 2000;1328- 32
Link to Article
Lazarova  RHristakieva  ELazarov  NShani  J Vitiligo-related neuropeptides in nerve fibers of the skin. Arch Physiol Biochem. 2000;108262- 267
Link to Article
Ameen  MExarchou  VChu  AC Topical calcipotriol as monotherapy and in combination with psoralens plus ultraviolet A in the treatment of vitiligo. Br J Dermatol. 2001;145476- 479
Link to Article
Ghoneum  MGrimes  EPGill  GKelly  AP Natural cell-mediated cytotoxicity in vitiligo. J Am Acad Dermatol. 1987;17600- 605
Link to Article
Naughton  GKReggiardo  DBystryn  JC Correlation between vitiligo antibodies and extent of depigmentation in vitiligo. J Am Acad Dermatol. 1986;15978- 981
Link to Article
Halder  RMWalters  CSJohnson  ABChakrabarti  SGKenney  JA  Jr Aberration in T lymphocytes and natural killer cells in vitiligo: a flow cytometric study. J Am Acad Dermatol. 1986;14733- 737
Link to Article
Grimes  PEGhoneum  MStockton  TPayne  CKelly  APAlfred  L T cell profiles in vitiligo. J Am Acad Dermatol. 1986;14196- 201
Link to Article
Njoo  MDSpuls  PIBos  JDWesterhof  WBossuyt  PM Nonsurgical repigmentation therapies in vitiligo. Arch Dermatol. 1998;1341532- 1540
Duncan  JL Differential inhibition of cutaneous T-cell mediated reactions and epidermal cell proliferation by cyclosporine A, FK-506, and rapamycin. J Invest Dermatol. 1994;10284- 88
Link to Article
Ahmed  MVenkataraman  RLogar  AJ  et al.  Quantitation of immunosuppression by tacrolimus using flor cytometric analysis of interleukin-2 and interferon-gamma inhibition in CD8(-) and CD8(+) peripheral blood T cells. Ther Drug Monit. 2001;23354- 362
Link to Article
Hashimoto  YMatsuoka  AKawakami  MNakashima  KEguchi  T Novel immunosuppressive effect of FK506 by augmentation of T-cell apoptosis. Clin Exp Immunol. 2001;12519- 24
Link to Article
Ruzicka  TAssmann  THomey  B Tacrolimus: the drug for the turn of the millennium? Arch Dermatol. 1999;135574- 580
Link to Article
Azbawsi  ECostner  MCohen  JBCockerell  CJ Tacrolimus: pharmacology and therapeutic uses in dermatology. Int J Dermatol. 2000;39721- 727
Link to Article
Alaiti  SKang  SFiedler  CV  et al.  Tacrolimus (FK506) ointment for atopic dermatitis: a phase I study in adults and children. J Am Acad Dermatol. 1998;3869- 76
Link to Article
Nasr  IS Topical tacrolimus in dermatology. Clin Exp Dermatol. 2000;25250- 254
Link to Article
Njoo  MDDas  PKBos  JDWesterhof  W Association of the Köbner phenomenon with disease activity and therapeutic responsiveness in vitiligo vulgaris. Arch Dermatol. 1999;135407- 413
Khalid  MMujtaba  GTahir  SH Comparison of 0.05% clobetasol propionate cream and topical puvasol in childhood vitiligo. Int J Dermatol. 1995;34203- 205
Link to Article
Hulley  EBCummings  SR Estimating sample size and power. Browner  SWBlack  DNewman  BTHulley  BSeds.Designing Clinical Research: An Epidemiologic Approach 2nd ed. Baltimore, Md William & Wilkins1988;139- 150
Gore  SM Assessing clinical trials—restricted randomisation. Br Med J (Clin Res Ed). 1981;2822114- 2117
Link to Article
Kramer  MSFeinstein  AR Clinical biostatistics of concordance. Clin Pharmacol Ther. 1981;29111- 123
Link to Article
Sackett  DLHaynes  RBGuyatt  GHTugwell  P The clinical examination. Sackett  DLHaynes  RBGuyatt  GHTugwell  Peds.Clinical Epidemiology: A Basic Science for Clinical Medicine 2nd ed. Boston, Mass Little Brown & Co Inc1991;19- 49
Njoo  MDBos  JDWesterhof  W Treatment of generalized vitiligo in children with narrow-band (TL-01) UVB radiation therapy. J Am Acad Dermatol. 2000;42245- 253
Link to Article
Assmann  THomey  BRuzicka  T Applications of tacrolimus for the treatment of skin disorders. Immunopharmacology. 2000;47203- 213
Link to Article
Ermis  OAlpsoy  ECetin  LYilmaz  E Is the efficacy of psoralens plus ultraviolet A therapy for vitiligo enhanced by concurrent topical calcipotriol? a placebo-controlled double-blind study. Br J Dermatol. 2001;145472- 475
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Vitiligo-depigmented eyelids (in red) before (A) and after (B) treatment with one of the study medications. The patient's right eyelid and brow were treated with clobetasol propionate and showed 40.3% repigmentation; the patient's left eyelid and brow were treated with tacrolimus, and showed 36.0% repigmentation.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Extent of the vitiligo-depigmented area before (A) and after (B) treatment with one of the study medications is outlined in red in the top photographs and fully red shaded in the bottom. The patient's left eye was treated with tacrolimus and the right eye, clobetasol propionate. Both treatments resulted in significant improvement.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

A, Vitiligo depigmentation is apparent on the brows and lids of this patient before treatment. B, The condition is much improved after treatment. Both the clobetasol (patient's right eye) and tacrolimus (left eye) treatments produced excellent (>75%) repigmentation.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Eighteen (90%) of the 20 patients experienced some improvement of skin color with both treatments. Comparison between the 2 medications shows similar results except in the "good" category (51%-75% repigmentation).

Graphic Jump Location

Tables

Table Graphic Jump LocationCharacteristics of Patients, Repigmentation, and Adverse Effects

References

Kovacs  SO Vitiligo. J Am Acad Dermatol. 1998;38647- 666
Link to Article
Jimbow  KChen  HPark  JSThomas  PD Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase-related protein in vitiligo. Br J Dermatol. 2001;14455- 65
Link to Article
Rocha  IMGuillo  LA Lipopolysaccharide and cytokines induce nitric oxide synthetase and produce nitric oxide in cultured normal human melanocytes. Arch Dermatol Res. 2001;293245- 248
Link to Article
Cucchi  MLFrattini  PSantagostino  GOrecchia  G Higher plasma catecholamine and metabolite levels in the early phase of nonsegmental vitiligo. Pigment Cell Res. 2000;1328- 32
Link to Article
Lazarova  RHristakieva  ELazarov  NShani  J Vitiligo-related neuropeptides in nerve fibers of the skin. Arch Physiol Biochem. 2000;108262- 267
Link to Article
Ameen  MExarchou  VChu  AC Topical calcipotriol as monotherapy and in combination with psoralens plus ultraviolet A in the treatment of vitiligo. Br J Dermatol. 2001;145476- 479
Link to Article
Ghoneum  MGrimes  EPGill  GKelly  AP Natural cell-mediated cytotoxicity in vitiligo. J Am Acad Dermatol. 1987;17600- 605
Link to Article
Naughton  GKReggiardo  DBystryn  JC Correlation between vitiligo antibodies and extent of depigmentation in vitiligo. J Am Acad Dermatol. 1986;15978- 981
Link to Article
Halder  RMWalters  CSJohnson  ABChakrabarti  SGKenney  JA  Jr Aberration in T lymphocytes and natural killer cells in vitiligo: a flow cytometric study. J Am Acad Dermatol. 1986;14733- 737
Link to Article
Grimes  PEGhoneum  MStockton  TPayne  CKelly  APAlfred  L T cell profiles in vitiligo. J Am Acad Dermatol. 1986;14196- 201
Link to Article
Njoo  MDSpuls  PIBos  JDWesterhof  WBossuyt  PM Nonsurgical repigmentation therapies in vitiligo. Arch Dermatol. 1998;1341532- 1540
Duncan  JL Differential inhibition of cutaneous T-cell mediated reactions and epidermal cell proliferation by cyclosporine A, FK-506, and rapamycin. J Invest Dermatol. 1994;10284- 88
Link to Article
Ahmed  MVenkataraman  RLogar  AJ  et al.  Quantitation of immunosuppression by tacrolimus using flor cytometric analysis of interleukin-2 and interferon-gamma inhibition in CD8(-) and CD8(+) peripheral blood T cells. Ther Drug Monit. 2001;23354- 362
Link to Article
Hashimoto  YMatsuoka  AKawakami  MNakashima  KEguchi  T Novel immunosuppressive effect of FK506 by augmentation of T-cell apoptosis. Clin Exp Immunol. 2001;12519- 24
Link to Article
Ruzicka  TAssmann  THomey  B Tacrolimus: the drug for the turn of the millennium? Arch Dermatol. 1999;135574- 580
Link to Article
Azbawsi  ECostner  MCohen  JBCockerell  CJ Tacrolimus: pharmacology and therapeutic uses in dermatology. Int J Dermatol. 2000;39721- 727
Link to Article
Alaiti  SKang  SFiedler  CV  et al.  Tacrolimus (FK506) ointment for atopic dermatitis: a phase I study in adults and children. J Am Acad Dermatol. 1998;3869- 76
Link to Article
Nasr  IS Topical tacrolimus in dermatology. Clin Exp Dermatol. 2000;25250- 254
Link to Article
Njoo  MDDas  PKBos  JDWesterhof  W Association of the Köbner phenomenon with disease activity and therapeutic responsiveness in vitiligo vulgaris. Arch Dermatol. 1999;135407- 413
Khalid  MMujtaba  GTahir  SH Comparison of 0.05% clobetasol propionate cream and topical puvasol in childhood vitiligo. Int J Dermatol. 1995;34203- 205
Link to Article
Hulley  EBCummings  SR Estimating sample size and power. Browner  SWBlack  DNewman  BTHulley  BSeds.Designing Clinical Research: An Epidemiologic Approach 2nd ed. Baltimore, Md William & Wilkins1988;139- 150
Gore  SM Assessing clinical trials—restricted randomisation. Br Med J (Clin Res Ed). 1981;2822114- 2117
Link to Article
Kramer  MSFeinstein  AR Clinical biostatistics of concordance. Clin Pharmacol Ther. 1981;29111- 123
Link to Article
Sackett  DLHaynes  RBGuyatt  GHTugwell  P The clinical examination. Sackett  DLHaynes  RBGuyatt  GHTugwell  Peds.Clinical Epidemiology: A Basic Science for Clinical Medicine 2nd ed. Boston, Mass Little Brown & Co Inc1991;19- 49
Njoo  MDBos  JDWesterhof  W Treatment of generalized vitiligo in children with narrow-band (TL-01) UVB radiation therapy. J Am Acad Dermatol. 2000;42245- 253
Link to Article
Assmann  THomey  BRuzicka  T Applications of tacrolimus for the treatment of skin disorders. Immunopharmacology. 2000;47203- 213
Link to Article
Ermis  OAlpsoy  ECetin  LYilmaz  E Is the efficacy of psoralens plus ultraviolet A therapy for vitiligo enhanced by concurrent topical calcipotriol? a placebo-controlled double-blind study. Br J Dermatol. 2001;145472- 475
Link to Article

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