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特应性皮炎治疗指南.pdf FROM THE ACADEMY This report reflects the best available data at the time the report was prepared, but caution should be exercised in interpreting the data; the results of future studies may require alteration of the conclusions or recommendations set forth in this report. Guidelines of care for atopic dermatitis Work group: Jon M. Hanifin, MD, Chair Work Group, Kevin D. Cooper, MD, Vincent C. Ho, MD, Sewon Kang, MD, Bernice R. Krafchik, MD, David J. Margolis, MD, Lawrence A. Schachner, MD, Robert Sidbury, MD, Susan E. Whitmore, MD, Carol K. Sieck, RN, MSN, and Abby S. Van Voorhees, MD, Chair Guideline/Outcomes Task ForceDISCLAIMER Adherence to these guidelines will not ensure successful treatment in every situation. Furthermore these guidelines should not be deemed inclusive of all proper methods of care or exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific therapy must be made by the physician and the patient in light of all the circumstances presented by the individual patient. INTRODUCTION/METHODOLOGY* A work group of recognized experts was con- vened to determine the audience for the guideline, define the scope of the guideline, and identify nine clinical questions to structure the primary issues in diagnosis and management. Work group members were asked to complete a disclosure of commercial supports and this information is in the technical report. They employed an evidence-based model and the evidence was obtained primarily from a search of MEDLINE and EMBASE databases spanning the Guidelines/Outcomes Task Force: Abby Van Voorhees, MD, Chair Task Force, Mark A. Bechtel, MD, Boni E. Elewski, MD, Steven R. Feldman, MD, Cindy Francyn Hoffman, MD, Robert S. Kirsner, MD, Lawrence M. Lieblich, MD, David J. Margolis, MD, Yves P. Poulin, MD, Barbara R. Reed, MD, Dirk B. Robertson, MD, Erin W. Warshaw, MD, Daniel A. Smith, MD, and Carol K. Sieck, RN, MSN. A full technical report that provides a complete description of the methodology is available at our Web site, www.aad.org, or by request at the reprint request address. Reprint requests: American Academy of Dermatology, PO Box 4014, Schaumburg, IL 60168-4014. J Am Acad Dermatol 2004;50:391-404. 0190-9622/$30.00 © 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2003.08.003years 1990 to June 3, 2003. Additional searches were done by hand searching publications, including re- views, meta analysis and correspondence. Only En- glish-language publications were reviewed. Statisti- cal assistance was provided by Hayes, Inc, a health technology assistance assessment service. Also, there was reliance on the comprehensive “System- atic Review of Treatments for Atopic Eczema” pub- lished as a Health Technology Assessment 2000 and listed in the bibliography.1 The available evidence was evaluated using a method described by Goodman (1998). Evidence was graded on a five-point scale based on the qual- ity of methodology. In a document on healthcare technology assessment prepared for the National Information Center on Health Services Research and Health Care Technology (NICHSR) at the National Library of Medicine,1 grading of the level of evi- dence was done as follows: I Properly designed randomized controlled trial. II-1 Well-designed controlled trial without random- ization. II-2 Well-designed cohort or case-control analytic study, preferably from more than one center or research group. II-3 Time series with or without the intervention. Dramatic results in uncontrolled experiments could also be regarded as this type of evidence. III Clinical experience, descriptive studies, or re- ports of expert committees. Individual tables are included in the technical report but are also integrated into some of the dis- cussions to illustrate recommendations. Every at- tempt was made to present a balanced approach to clinical recommendations; however, high-quality randomized clinical trials were often found lacking391 ww. 392 Hanifin et al J AM ACAD DERMATOL MARCH 2004for the scope of this guideline. In these cases, con- sensus of expert opinion was used with a grading of available evidence to assist the reader in evaluating the recommendations. This guideline has been developed in accordance with the American Academy of Dermatology (AAD)/ American Academy of Dermatology Association “Administrative Regulations for Evidence-Based Clinical Practice Guidelines” which includes the op- portunity for review and comment by the entire AAD membership and final review and approval by the AAD Board of Directors. SCOPE This guideline addresses the management of those patients with AD or atopic eczema. Recom- mendations regarding smallpox vaccinations in AD patients were not addressed in this guideline. These issues are discussed at the following Web sites from the American Academy of Dermatology, American Academy of Dermatology Association, Centers for Disease Control and Prevention, and the Institute of Medicine: www.aad.org, www.aadassociation.org, w bt.cdc.gov/agent/smallpox, and www4.national academies.org/iom/iomhome.nsf. DEFINITIONS Atopic dermatitis (AD) is a chronic inflammatory pruritic skin disease which occurs most frequently in children but can occur in adults and follows a re- lapsing course. It is often associated with elevated serum IgE levels and a personal or family history of type I allergies, allergic rhinitis, and asthma.2-7 Atopic eczema is synonymous with AD. ISSUES The task force identified the following clinical questions in the management of AD prevention measures during pregnancy and after birth, use of topical corticosteroids, use of other topicals in es- tablished dermatitis, use of antihistamines, dietary restrictions, non-pharmacological interventions, sys- temic immunomodulatory agents and complemen- tary/alternative therapies. Table I. Prevention measures during pregnancy and Recommendation Role of dietary intervention Un Role of aeroallergen avoidance for the mother Un Role of prolonged breast feeding Un Role of probiotics UnI. Prevention measures during pregnancy and after birth Recommendations (Table I) ● During pregnancy, there can be no global recom- mendations regarding dietary interventions and aeroallergen avoidance for the mother; there is no conclusive evidence that manipulation prevents AD either in the infant or child. ● Despite numerous studies, there has been no de- finitive evidence that exclusive breast-feeding, aeroallergen avoidance, and/or early introduction of solid foods influences the development of AD. There is suggestive evidence that prolonged breast feeding may delay the onset of AD. ● Probiotic treatment during pregnancy and nursing may delay the onset of AD in infants and chil- dren.14-17 Discussion There is a paucity of well-controlled research that examines the effect of diet, aeroallergen avoidance, and the introduction of solid feeding on the preven- tion and later onset of AD. The value of exclusive breast-feeding and exclusive diets remains elusive. More studies regarding probiotic therapy in the peri- natal period are needed to further establish the safety, efficacy, optimal dosing, duration of treat- ment, as well as the possible effects of various Lac- tobacillus preparations on the development of AD.8-17 II. Topical corticosteroids Recommendations (Table II) ● Topical corticosteroids are the standard of care to which other treatments are compared. ● Cutaneous complications such as striae, atrophy, and telangiectasia limit the long-term use of these agents. ● Despite the extensive use of topical corticoste- roids, there are limited data regarding optimal cor- ticosteroid concentrations, duration and frequency of therapy, and quantity of application; similarly, data supporting the perception that long-term cor- ticosteroid use is not associated with extracutane- ous adverse effects are lacking. irth nsus of opinion Level of evidence References us expert opinion I-II-2 8, 9, 10, 11, 13 us expert opinion I 11, 13 us expert opinion II-2 8, 9,12 us expert opinion I 14, 15,16,17after b Conse animo animo animo animo Hanifin et al 393J AM ACAD DERMATOL VOLUME 50, NUMBER 3● Altering the local environment by hydration and/or occlusion as well as varying the vehicle can impact the absorption and effect of the topical corticosteroid administered. ● Tachyphylaxis is a clinical concern, but there is no experimental documentation. ● The use of long-term intermittent application of corticosteroids appears helpful and safe in two randomized controlled studies.19,45 Independent studies of other formulations are needed. Discussion Topical corticosteroids, first introduced in the early 1950s have been the mainstay of therapy for atopic dermatitis for many years.21,35 This class of drugs is generally the standard to which other ther- apies are compared. Several fields of medicine (eg, dermatology, allergy, ophthalmology, and otolaryn- gology) have employed topical corticosteroids ther- apeutically with what appears to be acceptable ef- fectiveness and safety. Generally, dosing outside of pharmaceutical manufacturers’ recommendations cannot be recommended due to lack of data. It is the opinion of the expert work group, that less frequent application (eg, for moderately severe AD of the flexural folds) or more frequent application (eg, for AD of the hands where required frequent hand washing may prohibit optimal absorption) may oc- casionally be used without a significant resultant alteration in the manufacturers reported efficacy and safety.19,21,38,43,44 In one large systematic review, it was found that using twice-daily applications was no more effective than once-daily application.21 The approach of using short bursts of potent steroids compared to longer term use of weaker corticoste- roids demonstrated no differences in children with mild to moderate AD.38 Steroids in peanut oil vehi- cles appear to be safe for patients sensitive to pea- nuts.40-42 Physician and health care provider instruc- tions on application techniques are an important Table II. Topical corticosteroids Recommendation Use of topical corticosteroids Una Possible cutaneous complications Una Duration of therapy, frequency of application & quantity of application uncertain Una Effects of hydration/occlusion Una Possible development of tachyphylaxis Una Role of long-term intermittent application of corticosteroids Unapart in patient education. The lack of information about the amount of medications that are truly used by patients limits our knowledge of the efficacy of these agents; we encourage more precision in dos- ing in the treatment of AD, establishment of the optimal dose and frequency of application, and the investigation of established and novel vehicles for drug efficacy and safety.19,56-59 At this time, long- term intermittent topical steroid application appears helpful and safe in two randomized controlled stud- ies.19,45 Finally, issues regarding potential non-cutaneous side effects still need further study. These include the need for investigation of whether chronic top- ical corticosteroid application may reduce the lin- ear growth rate in children and bone density in adults.22,23,46,47,57,58,60-63 Until such studies have been performed, based on unanimous expert opinion, the following should be considered: the assessment of background risk factors for subop- timal linear growth in children, and for reduced bone density in both children and adults. Also, we believe that treating physicians should remind pa- tients to ingest adequate daily calcium and vitamin D.47,60-65 The potential for topical corticosteroid therapy to suppress the hypothalamic-pituitary-adrenal axis (HPA) in pediatric patients has been investigated in a small number of studies, with inconclusive find- ings.49-52 Effects on the HPA seem to be associated with percutaneous absorption in patients with more severe disease and those less than 2 years of age.37,53-55 Additionally, there is a theoretical concern re- garding topical corticosteroid application to the eye- lids with possible increased risk of cataract forma- tion and elevated intraocular pressure cited to occur independent of other factors. While further studies are needed, surveillance ophthalmic examinations should be considered.24,48,54 sus of opinion Level of evidence References s expert opinion II-1 & III 35, 55 s expert opinion I & III 20, 21 (Appendix 3), 56 s expert opinion I-III 18, 19, 36 s expert opinion I & III 19, 37, 43, 44 s expert opinion No studies No studies s expert opinion I 19, 38,45Consen nimou nimou nimou nimou nimou nimou 394 Hanifin et al J AM ACAD DERMATOL MARCH 2004III. Other topical therapies Recommendations (Table III) ● Emollients are a standard of care, steroid-sparing, and useful for both prevention and maintenance therapy. ● Calcineurin inhibitors, pimecrolimus, and tacroli- mus have been shown to reduce the extent, sever- ity, and symptoms of AD in adults and children. ● Tar may be associated with therapeutic benefits, but is limited by compliance. ● Short-term adjunctive use of topical doxepin may aid in the reduction of pruritus, but the develop- ment of side effects may limit usefulness. Discussion Emollients. While the use of emollients is con- sidered standard therapy for the treatment of AD, few investigators have studied the effects of emol- lients alone on the severity of AD symptoms. Three clinical trials were reviewed and these demonstrated enhanced therapeutic response.35,70,71 Calcineurin inhibitors. Both tacrolimus and pimecrolimus are members of this class. There are numerous studies that demonstrate the utility of these agents in AD. The long-term (
1 year) safety, including concerns about immunosuppression and malignancy, remain unanswered.72-83,87,89-92 Tacrolimus (FK-506/Protopic). There is evi- dence that tacrolimus (FK-506/Protopic) can be ef- fective in reducing the severity of moderate to se- vere AD in both children over 2 years and adults, with few side effects reported after up to 3 years of treatment.73-83 Dropout rates in some of these stud- ies were high, but were generally highest in control groups who experienced little or no improvement. No dose-related response was demonstrated. A burning sensation at the site of application was re- ported in a number of studies and some adults reported flushing with alcohol ingestion.76 Reitamo et al81,82 compared two concentrations of tacrolimus ointment (0.03% & 0.1%) to a corticosteroid in two large, multicenter, randomized controlled trials in pediatric and adult populations. In children, both concentrations of tacrolimus ointment appeared more effective than 1% hydrocortisone acetate, with Table III. Other topical therapies Recommendations Consensus of Use of emollients Unanimous expe Use of pimecrolimus Unanimous expe Use of tacrolimus Unanimous expe Use of tar Unanimous expe Short-term use of doxepin Unanimous expethe higher concentration associated with the greatest reduction in severity.81 In adults, similar improve- ment was noted in the midpotency corticosteroid (0.1% hydrocortisone-17-butyrate ointment) and 0.1% tacrolimus ointment groups, and lesser benefit in a group using 0.03% tacrolimus ointment.82 Pimecrolimus (ASM 981/Elidel). There is ev- idence that therapy with ascomycin (ASM 981/ Elidel/pimecrolimus) is safe and effective in reduc- ing the severity of symptoms in children and adults with mild and moderate AD in studies up to 1 year’s duration. Reports of randomized clinical trials of ascomycin demonstrated efficacy in reducing symp- toms with low systemic absorption.84-88 Coal tar. Although crude coal tar and prepara- tions including coal tar derivatives have been used for many years in the treatment of AD, the significant cosmetic disadvantages of coal tar preparations are likely to make it unacceptable to patients and influ- ence compliance. There have been few scientifically valid trials of coal tar preparations that focus on the clinical efficacy in treatment of AD.66 Doxepin. There is limited evidence that the use of topical doxepin as short-term adjunctive therapy may provide slight relief of pruritus of limited dura- tion. Sedation and contact allergies may complicate use, and therefore, it is the expert opinion that it should be used for a limited duration.67,68 Phosphodiesterase inhibitors. Topical ther- apy with phosphodiesterase inhibitors may be valu- able in controlling the symptoms of AD; a recent study suggests efficacy comparable to hydrocorti- sone cream.69,93 IV. Antibiotics and antiseptics Recommendations (Table IV) ● Patients with AD are commonly colonized with Staphylococcus aureus. ● Antibiotics, both systemic and topical, temporarily reduce S aureus colonization on the skin. ● Without signs of infection, oral antibiotics gener- ally have a minimal therapeutic effect on the der- matitis. Oral antibiotics can be highly beneficial when skin infection is present. n Level of evidence References ion I 70 ion I 89-92 ion I 73-75, 81, 82 ion II-2 68 ion I 67, 68opinio rt opin rt opin rt opin rt opin rt opin Hanifin et al 395J AM ACAD DERMATOL VOLUME 50, NUMBER 3● Topical antibiotics can be effective when infection is present; however, development of resistance is a concern. Discussion Among adults, children, and infants with AD, many are colonized with S aureus in both their affected and unaffected skin.94-97 Although signifi- cant reduction of bacterial colonization in the af- fected and unaffected skin of AD patients by oral antibiotics has been demonstrated, there is little ev- idence of clinical improvement in the severity of the dermatitis.94,98 Ewing et al94 (1998) monitored com- pliance closely and documented temporary reduc- tion of colonizing organisms, but demonstrated no clinical improvement associated with oral antibiotic use. Boguniewicz et al98 (2001) demonstrated similar results. Although there are some studies about mupi- rocin that demonstrate effectiveness, the study de- sign, as well as the development of resistant strains, limits efficacy of this intervention.102 Oral antibiotics, however, can be highly beneficial when infection is present. Concerns about both oral and topical anti- biotics include the possible development of resis- tance. Studies of antiseptics showed limited effective- ness in the treatment of AD. Three studies of anti- septics or topical antibacterial agents revealed con- flicting evidence to indicate their efficacy in children.35,100,101 Stalder et al100 (1992) reported no difference between treatment of 20 children with chlorohexidine and KMn04, and attributed the im- provement in both groups to continued use of topical corticosteroids. Ainley-Walker, Patel, and David35 (1998) saw no differences in left-to-right comparisons of hospitalized children treated for AD with seven different topical antibacterials on one half of their bodies. Breneman et al101 (2000) re- ported significant improvement in patients bathing with triclocarban antibacterial soap. Table IV. Antibiotics and antiseptics Recommendation Consensus of Staph colonization of the skin Unanimous expe Role of systemic antibiotics Unanimous expe Role of topical antibiotics Unanimous expe Table V. Oral antihistamines Recommendation Conse Role of sedative antihistamines Unanimou Role of nonsedating antihistamines UnanimouCombination topical antibiotic (eg, fusidic acid) and topical steroid products have shown efficacy in one study,103 while in others, they were no more effective than topical steroid alone.21 V. Oral antihistamines Recommendations (Table V) ● There is little evidence that sedating or nonsedat- ing antihistamines are effective in relieving itch or urticarial symptoms associated with AD. ● For patients with significant sleep disruption due to itch, allergic dermatographism, or allergic rhi- noconjunctivitis, sedating antihistamines may be useful. Many patients with AD also have accom- panying allergic rhinoconjunctivitis, urticaria, and dermatographism and therefore may be benefited by the use of antihistamines. Discussion There is little evidence that sedating or nonsedat- ing antihistamines are effective in the treatment of AD. For sedating antihistamines, it can be difficult to distinguish antipruritic or other clinical effects from the sedative or soporific effect. Reported improve- ments in disease severity and quality of life may be due primarily to promotion of restful sleep rather than a reduction in symptoms.104-111 In an evidence-based review of the literature from 1966 to 1999, Klein and Clark104 remarked on the paucity of proper clinical trials and concluded that there is no evidence to support the efficacy of non-sedating antihistamines in AD. Antihistamines are safe and not associated with significant ad- verse effects, even in very young patients.106-111 Many patients with AD also have accompanying urticaria, dermatographism, and allergic rhinocon- junctivitis, and therefore they may be benefited by the use of antihistamines for these concurrent medical problems. n Level of evidence References ion I 95 ion I 96 ion I 35 opinion Level of evidence References rt opinion I 107, 108 rt opinion I 107, 108opinio rt opin rt opin rt opinnsus of s expe s expe ...