Background

Atopic dermatitis is a common eczematous condition which is defined primarily by clinical signs and symptoms. It is highly pruritic or itchy and characterized by erythematous patchy rash. There is a definite familial clustering of cases.

EPIDEMIOLOGIC ASSOCIATIONS	CHARACTERIZATION
INCIDENCE	7-12% of school age children
Clinical features of atopic dermatitis at two years of age: a prospective, population-based case-control study. Bohme M, Svensson A, Kull I, Nordvall SL, Wahlgren CF. Department of Dermatology, Karolinska Hospital and Institute, Stockholm, Sweden.	Acta Derm Venereol 2001 Jun-Jul;81(3):193-7 Abstract quote While atopic dermatitis (AD) usually presents early in life, few prospective studies focus on young children with AD. The objective of this study was to characterize, phenotypically and prospectively, young children with AD. From a community birth cohort of 2,256 children, consecutive children with AD (n = 221) were followed to 2 years of age, when they were re-examined and screened for atopic sensitization (skin-prick test to foods; Phadiatop). Ninety-nine controls were also examined. AD debuted during the first year in 88% of cases. At the 2-year examination, when the children had already undergone topical treatment, 157/221 (71%) had ongoing eczema ranging among mild (45%), moderate (53%) and severe (2%). Airway problems indicating asthma had occurred in 9% of cases and 6% of controls (not significant), and allergic rhinoconjunctivitis in 5% and 0%, respectively (p<0.05). The skin-prick test to common food allergens was positive in 27% of cases and Phadiatop was positive in 15%. In 67% both tests were negative. Eczema severity did not differ between sensitized and non-sensitized children. Positive Phadiatop was more common in boys than in girls with ongoing AD (22% vs 3%, p<0.01), and more boys than girls had ongoing AD (82% vs 59%, p<0.001); otherwise, no differences attributable to gender were found.
In the United States, blacks and asian/pacific islanders are more likely than whites to seek medical care for atopic dermatitis. Janumpally SR, Feldman SR, Gupta AK, Fleischer AB Jr. Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC 27157.	Arch Dermatol 2002 May;138(5):634-7 Abstract quote BACKGROUND: There have been population-based studies conducted in England and the United States that suggest an increase in prevalence of atopic dermatitis among black and/or Asian children. OBJECTIVE: To assess whether health care utilization for atopic dermatitis differs among different ethnic groups in the United States. DESIGN: Weighted data on representative office visits by whites, blacks, and Asian/Pacific Islanders were analyzed using a cross-sectional study, the National Ambulatory Medical Care Survey (NAMCS), from 1990 through 1998 using statistical software. SETTING: The NAMCS is an ongoing data collection effort by the Division of Health Care Statistics, National Center for Health Statistics, Centers for Disease Control and Prevention. The survey samples representative visits to US office-based physicians during a representative week of practice. PATIENTS: All outpatient visits were analyzed and compared with those for patients diagnosed as having atopic dermatitis (International Classification of Diseases, Ninth Revision, Clinical Modification, code 691.80). MAIN OUTCOME MEASURE: Diagnosis of atopic dermatitis by race. RESULTS: Of 570 million estimated visits for skin conditions, 7.9 million were for atopic dermatitis. The numbers of per capita visits for atopic dermatitis among blacks and Asian/Pacific Islanders were 2-fold and 6-fold higher, respectively, than among whites. The odds ratios (95% confidence intervals) for atopic dermatitis visits by blacks and Asian/Pacific Islanders relative to whites were 3.4 (2.5-4.7) and 6.7 (4.8-9.5), respectively. CONCLUSIONS: Blacks and Asian/Pacific Islanders are much more likely to visit physicians for atopic dermatitis than are whites and may benefit from education and early intervention efforts concerning the disease.

 

DISEASE ASSOCIATIONS	CHARACTERIZATION
Myelitis associated with atopic disorders in Japan: a retrospective clinical study of the past 20 years. Kira J, Horiuchi I, Suzuki J, Osoegawa M, Tobimatsu S, Murai H, Minohara M, Furue M, Ochi H. Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka.	Intern Med 2001 Jul;40(7):613-9 Abstract quote OBJECTIVE: To clarify the clinical features of myelitis associated with atopic disorders in Japanese patients. SUBJECTS AND METHODS: We retrospectively studied the clinical, immunological and electrophysiological features of 68 consecutive patients with myelitis of acute or subacute onset diagnosed at Kyushu University Hospital during the past 20 years. RESULTS: While only 2 of 28 (7%) patients with myelitis diagnosed between 1979 and 1993 had either atopic dermatitis (AD) or bronchial asthma (BA), 19 of 40 (48%) patients with myelitis diagnosed between 1994 and 1998 did. Among the 40 patients with myelitis diagnosed between 1994 and 1998, 19 patients with either AD or BA as well as 21 patients without either disease showed a significantly higher level of serum total IgE, higher frequency of hyperIgEaemia and higher frequency of mite antigen-specific IgE than 82 healthy controls. Myelitis patients with AD presenting as persistent paresthesia/dysesthesia in all four limbs showed cervical cord lesions on MRI and abnormalities in upper limb motor evoked potentials but no abnormalities in the cerebrospinal fluid (CSF), while myelitis patients with BA showed preferential involvement of the lower motor neurons clinically and electromyographically. In addition, 12 patients with myelitis who had hyperIgEaemia and mite antigen-specific IgE but neither AD nor BA showed incomplete transverse myelitis with mild motor disability and few CSF abnormalities. CONCLUSION: The clinical features of myelitis associated with atopic disorders were in part distinguished by the type of preceding atopic disorder, and also were different from those of hyperIgEaemic myelitis with no preceding atopic disorders.
Breast-feeding and the onset of atopic dermatitis in childhood: A systematic review and meta-analysis of prospective studies Michael Gdalevich, MD, MPH Daniel Mimouni, MD Michael David, MD Marc Mimouni, MD Tel Aviv, Israel	J Am Acad Dermatol 2001;45:520-7 Abstract quote Background: Despite the numerous studies on the possible protective effect of breast-feeding against the onset of atopic dermatitis during childhood, this issue remains controversial. Objective: We conducted a systematic review with meta-analysis of prospective studies that evaluated the association between exclusive breast-feeding during the first 3 months after birth and atopic dermatitis. Methods: A comprehensive search of the 1966-2000 MEDLINE database and review of the reference lists of relevant articles identified 18 prospective studies that met the predefined inclusion criteria. By means of a standardized approach, 2 of the investigators independently assessed the methodologic quality of the studies, duration and exclusivity of breast-feeding, outcome measures, and control for potential confounding factors. The same approach was applied during data abstraction and evaluation of the estimates of association. Summary measures of association were then calculated. Results: The summary odds ratio (OR) for the protective effect of breast-feeding in the studies analyzed was 0.68 (95% confidence interval [CI], 0.52-0.88). This effect estimate was higher in the group of studies wherein children with a family history of atopy were investigated separately (OR = 0.58; CI, 0.41-0.92) than in those of combined populations (OR = 0.84; CI, 0.59-1.19). A small subset of studies of children without a history of atopy in first-degree relatives showed no association between breast-feeding and the onset of atopic dermatitis (OR = 1.43; CI, 0.72-2.86). Conclusion: Exclusive breast-feeding during the first 3 months of life is associated with lower incidence rates of atopic dermatitis during childhood in children with a family history of atopy. This effect is lessened in the general population and negligible in children without first-order atopic relatives. Breast-feeding should be strongly recommended to mothers of infants with a family history of atopy, as a possible means of preventing atopic eczema.

 

PATHOGENESIS	CHARACTERIZATION
Linkage and association to candidate regions in Swedish atopic dermatitis families. Soderhall C, Bradley M, Kockum I, Wahlgren CF, Luthman H, Nordenskjold M. Department of Molecular Medicine, CMM 02, Karolinska Institutet, SE- 171 76 Stockholm, Sweden.	Hum Genet 2001 Aug;109(2):129-35 Abstract quote We have studied, in 406 families with at least two siblings affected with atopic dermatitis (in total 1514 individuals) from the Swedish population, linkage and association to five chromosomal regions (2q35, 5q31-33, 6p21, 11q13 and 14q11) previously implicated in atopic diseases. The region on 14q11 gave evidence for linkage to atopic dermatitis (NPL-score: 2.36, P<0.009). In the 11q13 region, there was a clear association to an intragenic marker in the beta-subunit of the high-affinity IgE receptor for raised allergen-specific serum IgE levels (P<0.009). When a quantitative variable for the severity of atopic dermatitis was studied, evidence was found in favour of linkage to the 5q31-33 region, with the highest Z-score (2.06) close to the marker D5S458 (P<0.005).
CD4+ CD8+ (thymocyte-like) T lymphocytes present in blood and skin from patients with atopic dermatitis suggest immune dysregulation. Bang K, Lund M, Wu K, Mogensen SC, Thestrup-Pedersen K. Department of Dermatology, Marselisborg Hospital, DK-8000 Aarhus C., Denmark.	Br J Dermatol 2001 Jun;144(6):1140-7 Abstract quote BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease expressed early in life. Disease development is primarily determined by as yet unknown genetic factors, leading to the accumulation of activated T lymphocytes in the skin. OBJECTIVES: To investigate the nature of these T cells. METHODS: T-cell lines could be established from AD skin biopsies, but not from normal skin or AD peripheral blood, when placed in RPMI 1640 medium with 10% human AB serum, antibiotics, and the T-lymphocyte growth factors interleukins 2 and 4. The cell lines were subjected to phenotypic analysis using a fluorescence-activated cell sorter and compared with lymphocytes from AD and normal control peripheral blood. RESULTS: T-cell lines from 22 of 24 consecutive skin biopsies taken from 24 adult patients with AD were established. All cells were T lymphocytes expressing several activation markers. A significant proportion of the lymphocytes had stable expression of a CD4+ CD8+ phenotype (26% +/- 6%; mean +/- SEM). Such double-positive T lymphocytes are normally only seen in the thymus and not in the peripheral immune system. CD4+ CD8+ cells in peripheral blood of the patients (12.5% +/- 3.3%) were also detected. CONCLUSIONS: We suggest that a basic pathophysiological change in AD may be a faulty maturation of the T-lymphocyte system, leading to skin inflammation with CD4+ CD8+ T lymphocytes resembling immature T cells. This is likely to lead to skewing of many immune reactions in the patients.
CERAMIDE-DOMINANT BARRIER
Ceramide-dominant barrier repair lipids alleviate childhood atopic dermatitis: Changes in barrier function provide a sensitive indicator of disease activity. Chamlin SL, Kao J, Frieden IJ, Sheu MY, Fowler AJ, Fluhr JW, Williams ML, Elias PM. Departments of Dermatology and Pediatrics, University of California, San Francisco, and Dermatology Service, Veterans Affairs Medical Center, San Francisco.	J Am Acad Dermatol 2002 Aug;47(2 Pt 1):198-208 Abstract quote BACKGROUND: It is currently fashionable to consider atopic dermatitis (AD), like other inflammatory dermatoses, as immunologic in pathogenesis ("inside-outside" hypothesis). Accordingly, topical glucocorticoids and other immunosuppressive agents are mainstays of therapy, but the risk of toxicity from these agents is not insignificant, particularly in children. Alternatively, because stratum corneum (SC) permeability barrier function is also abnormal in AD, it has been hypothesized that the barrier abnormality could drive disease activity. Yet commonly used emollients and moisturizers do not correct the SC ceramide deficiency, the putative cause of the barrier abnormality. OBJECTIVES: We assessed the efficacy of a newly developed, ceramide-dominant, physiologic lipid-based emollient, when substituted for currently used moisturizers, in 24 children who were also receiving standard therapy for stubborn-to-recalcitrant AD. METHODS: All subjects continued prior therapy (eg, topical tacrolimus or corticosteroids), only substituting the barrier repair emollient for their prior moisturizer. Follow-up evaluations, which included severity scoring of atopic dermatitis (SCORAD) values and several biophysical measures of SC function, were performed every 3 weeks for 20 to 21 weeks. RESULTS: SCORAD values improved significantly in 22 of 24 patients by 3 weeks, with further progressive improvement in all patients between 6 and 20 or 21 weeks. Transepidermal water loss levels (TEWL), which were elevated over involved and uninvolved areas at entry, decreased in parallel with SCORAD scores and continued to decline even after SCORAD scores plateaued. Both SC integrity (cohesion) and hydration also improved slowly but significantly during therapy. Finally, the ultrastructure of the SC, treated with ceramide-dominant emollient, revealed extracellular lamellar membranes, which were largely absent in baseline SC samples. CONCLUSION: These studies suggest that (1) a ceramide-dominant, barrier repair emollient represents a safe, useful adjunct to the treatment of childhood AD and (2) TEWL is at least as sensitive an indicator of fluctuations in AD disease activity as are SCORAD values. These studies support the outside-inside hypothesis as a component of pathogenesis in AD and other inflammatory dermatoses that are accompanied by a barrier abnormality.
PROSTAGLANDINS
Prostaglandin E2 induces vasodilation and pruritus, but no protein extravasation in atopic dermatitis and controls. Neisius U, Olsson R, Rukwied R, Lischetzki G, Schmelz M. Department of Dermatology, University of Erlangen/Nurnberg, Universitatstrasse 17, 91054 Erlangen, Germany.	J Am Acad Dermatol 2002 Jul;47(1):28-32 Abstract quote BACKGROUND: Prostaglandin E(2) (PGE(2)) has well-established vasodilatory effects, whereas its effects on protein extravasation and its sensory effects are less clear. OBJECTIVE: Vasoactive effects of PGE(2) were correlated to its ability to evoke pain or itch in healthy volunteers and patients with atopic dermatitis (AD). METHODS: Intradermal microdialysis was used to apply PGE(2) (10(-8)-10(-4) M) via microdialysis capillaries in 8 patients and 8 controls. Large pore size membranes (3000 kd) enabled simultaneous analysis of protein extravasation. Itch and pain sensations were measured psychophysically, and superficial blood flow was measured by laser Doppler imaging. RESULTS: PGE(2) dose dependently provoked intense local vasodilation, weak pruritus, and pain, but no protein extravasation. No differences were found between patients with AD and controls for any parameter. CONCLUSION: We conclude that PGE(2) is a potent vasodilator and a weak pruritic agent in normal skin and in patients with AD, but does not provoke increased protein extravasation.

 

PROGNOSIS AND TREATMENT	CHARACTERIZATION
TREATMENT
ANTIBIOTICS
Age-related prevalence and antibiotic resistance of pathogenic staphylococci and streptococci in children with infected atopic dermatitis at a single-specialty center. Arkwright PD, Daniel TO, Sanyal D, David TJ, Patel L. Academic Unit of Child Health, University of Manchester , Booth Hall Children's Hospital, Ward 3, Charlestown Road, Blackley, Manchester M9 7AA, England.	Arch Dermatol 2002 Jul;138(7):939-41 Abstract quote BACKGROUND: Skin staphylococci and streptococci are known to exacerbate atopic dermatitis, but the prevalence changes that occur with age are unknown. This study examined the age-related prevalence and antibiotic resistance of these pathogenic bacteria in children with atopic dermatitis and suspected skin infections. OBSERVATIONS: Medical records of 150 children with atopic dermatitis referred to a regional center, who had skin swabs taken for suspected infection, were studied retrospectively. All patients carried Staphylococcus aureus. The prevalence of methicillin sodium-resistant (P =.05) and fusidic acid-resistant (P =.001) S aureus tripled from infancy to school age. Lancefield groups A and G streptococci were the other pathogens found. The prevalence of group A streptococci was highest in children aged 3 to 6 (53%), compared with 11% of infants and 21% of patients aged 9 to 16 (P =.002). CONCLUSIONS: Significant differences in the age-related prevalence of group A streptococci skin carriage and antibiotic resistance of S aureus isolates occurred in this group of children with atopic dermatitis and suspected skin infections. Skin swabs to determine bacterial type and antibiotic sensitivities provide an important guide to antibiotic prescribing in these children.
CORTICOSTEROIDS, TOPICAL
Safety of fluticasone propionate cream 0.05% for the treatment of severe and extensive atopic dermatitis in children as young as 3 months S. F. Friedlander, MD A. A. Hebert, MD D. B. Allen, MD for the Fluticasone Pediatrics Safety Study Group* San Diego, California, Houston, Texas, and Madison, Wisconsin	J Am Acad Dermatol 2002;46:387-93 Abstract quote Background: Topical corticosteroids are useful for the treatment of pediatric dermatoses. However, concerns regarding possible systemic and topical toxicities have limited the use of moderate-potency corticosteroids in children. Objective: Our purpose was to characterize the safety of fluticasone propionate cream in children. Methods: Children between 3 months and 5 years 11 months (n = 32) and 3 up to 6 years of age (n = 19) with moderate to severe atopic dermatitis (35% body surface area; mean body surface area treated, 64%) were treated with fluticasone propionate cream, 0.05% twice daily for 3 to 4 weeks. Serum cortisol response, fluticasone levels, skin changes, and adverse events were analyzed. Results: Mean cortisol levels were similar at baseline (13.76 ± 6.94 µg/dL prestimulation and 30.53 ± 7.23 µg/dL poststimulation) and at end of treatment (12.32 ± 6.92 µg/dL prestimulation and 28.84 ± 7.16 µg/dL poststimulation). Only 2 of 43 children had end-treatment poststimulation values less than 18.0 µg/dL. No significant adverse cutaneous effects were noted. Conclusion: Fluticasone propionate cream 0.05% appears to be safe for the treatment of severe eczema for up to 4 weeks in children 3 months of age and older.
COST
Cost of atopic dermatitis and eczema in the United States Charles N. Ellis, MD Lynn A. Drake, MD Mary M. Prendergast, MBA, etal. Ann Arbor, Michigan; Boston, Massachusetts; Deerfield, Illinois; Dallas, Texas; Denver, Colorado; Jackson, Mississippi; New York, New York; Cleveland, Ohio; Farmington, Connecticut; and San Francisco, California	J Am Acad Dermatol 2002;46:361-70 Abstract quote Background: Atopic dermatitis/eczema (AD/E) is a common disease. Few studies have attempted to quantify the cost to third-party payers. Objective: Our purpose was to identify the annual cost of medical services and prescription drugs for the treatment of AD/E to private insurance and Medicaid payers in the United States. Methods: We used a retrospective study design employing claims data from 1997 and 1998 from a private insurer and a state Medicaid program to analyze costs incurred. Beneficiaries were considered to have AD/E if they had at least one claim in 1997 with a primary or secondary listing of 1 of 3 diagnosis codes: 691.8, other atopic dermatitis and related conditions; 692.9, contact dermatitis and other eczema when no cause is specified; or 373.3, noninfectious dermatoses of eyelid. Patients who did not meet the diagnosis criteria served as a control group in each payer for comparisons of expenditures with the AD/E group. Results: Disease prevalence was 2.4% (private insurer) to 2.6% (Medicaid) of all eligible beneficiaries, and 3.5% to 4.1% of patients submitted at least one health care claim during the study period. Medicaid-insured patients used outpatient hospital visits and hospitalizations at a greater rate than did privately insured patients; neither used emergency departments extensively. The third-party payer cost of illness for AD/E ranged from $0.9 billion to $3.8 billion when projected across the total number of persons younger than 65 years insured by private insurers and Medicaid in the United States. More than one fourth of all health care costs for patients with AD/E may be attributed to AD/E and co-morbid conditions. Conclusions: Annual costs of AD/E are similar to those of other diseases such as emphysema, psoriasis, and epilepsy. Patients incur significant costs associated with AD/E and co-morbid conditions.
TACROLIMUS
Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part I, efficacy. Hanifin JM, Ling MR, Langley R, Breneman D, Rafal E. Oregon Health Sciences University, Portland, USA.	Am Acad Dermatol 2001 Jan;44(1 Suppl):S28-38 Abstract quote A total of 632 adults with atopic dermatitis applied tacrolimus ointment (0.03% or 0.1%) or vehicle twice daily for up to 12 weeks in two randomized, double-blind studies. This report focuses on the efficacy of tacrolimus ointment in these studies. The mean percent body surface area (%BSA) affected at baseline was 45%, and 56% of patients had severe atopic dermatitis. Evaluations included a physician's global evaluation of clinical response, %BSA affected, individual signs of atopic dermatitis, the Eczema Area and Severity Index (EASI) score, and the patient's assessment of pruritus. A 90% or greater improvement from baseline in disease status was observed for 6.6%, 27.5%, and 36.8% of patients in the vehicle, 0.03% tacrolimus ointment, and 0.1% tacrolimus ointment groups, respectively (P<.001), and 50% or better improvement was observed for 19.8%, 61.6%, and 72.7% of patients, respectively. Tacrolimus ointment-treated patients showed significantly greater improvement than vehicle-treated patients for all efficacy parameters evaluated, including the %BSA affected, the total score and individual scores for signs of atopic dermatitis, the patient's assessment of pruritus, and EASI score. The 0.1% concentration was more effective than the 0.03% concentration, particularly in patients with severe disease and/or extensive BSA involvement at baseline and in African Americans. Tacrolimus ointment is an effective therapy for the treatment of adult patients with atopic dermatitis on all skin regions including the head and neck.
Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part II, safety. Soter NA, Fleischer AB Jr, Webster GF, Monroe E, Lawrence I. New York University School of Medicine, Department of Dermatology, NY 10016-6451, USA	J Am Acad Dermatol 2001 Jan;44(1 Suppl):S39-46 Abstract quote In two randomized, double-blind, multicenter studies, a total of 631 adult patients with moderate to severe atopic dermatitis applied tacrolimus ointment (0.03% or 0.1%) or vehicle twice daily for up to 12 weeks. The mean percent body surface area (%BSA) affected at baseline was 45%, and 56% of patients had severe atopic dermatitis. As previously reported, these studies showed that tacrolimus ointment was superior to vehicle for all efficacy parameters measured. This report focuses on the safety of tacrolimus ointment in these studies. The most common adverse events were the sensation of skin burning, pruritus, flu-like symptoms, skin erythema, and headache. Skin burning and pruritus were more common among patients with severe or extensive disease; these events were usually brief and were resolved during the first few days of treatment. Common adverse events with a significantly higher incidence in one or both of the tacrolimus ointment groups than in the vehicle group included skin burning, flu-like symptoms, and headache. More patients in the vehicle group discontinued the study because of an adverse event than in either of the tacrolimus ointment groups. There were no notable or consistent changes in any laboratory variables. Tacrolimus was not detected in 80% of blood samples collected. Measurable concentrations of tacrolimus were transitory and were not associated with adverse events. Tacrolimus ointment is a safe therapy for the treatment of adult patients with atopic dermatitis on the face, neck, or other body regions.
Long-term safety and efficacy of tacrolimus ointment for the treatment of atopic dermatitis in children. Kang S, Lucky AW, Pariser D, Lawrence I, Hanifin JM. University of Michigan Medical Center, Ann Arbor 48109-0314, USA.	J Am Acad Dermatol 2001 Jan;44(1 Suppl):S58-64 Abstract quote Tacrolimus ointment is a nonsteroidal topical immunomodulator that was formulated specifically for the treatment of atopic dermatitis. A total of 255 children, 2 to 15 years of age, with moderate to severe atopic dermatitis applied 0.1% tacrolimus ointment twice daily for up to 12 months to assess long-term safety and efficacy. Patients on average were treated with tacrolimus ointment for 279 days or 87% of study days. Substantial improvements in the signs and symptoms of atopic dermatitis, percent body surface area affected, and the patient's or parent's assessment of pruritus were observed during the first week of treatment and were maintained throughout the study. Transient skin burning and itching were the most common drug application site adverse events. Occurrence of these symptoms decreased after the first few days of treatment. There was no increased incidence of infections or other significant adverse events. Effectiveness of tacrolimus was maintained with prolonged daily use. Tacrolimus ointment (0.1%) is safe and effective for long-term treatment of atopic dermatitis in children.
Opposing effects of UVA1 phototherapy on the expression of bcl-2 and p53 in atopic dermatitis. Breuckmann F, Pieck C, Kreuter A, Bacharach-Buhles M, Mannherz HG, Altmeyer P, von Kobyletzki G. Department of Dermatology, Ruhr-University, Bochum, Germany.	Arch Dermatol Res 2001 Apr;293(4):178-83 Abstract quote Recently, medium-dose UVA1 phototherapy (50 J/cm2) has been introduced as an effective treatment for severe atopic dermatitis (AD). In order to further elucidate the mechanisms by which medium-dose UVA1 irradiation leads to an improvement in skin status in patients with AD, biopsy specimens from ten patients before and after treatment were analysed immunohistochemically for features of apoptosis. We sought to determine the extent to which UVA1 irradiation was able to modulate the balance between p53 and bcl-2 expression in vivo using monoclonal antibodies labelling these proteins. As compared with lesional skin of patients with AD before UVA1 irradiation, the number of dermal cells, apparently lymphocytes, that were positive for p53 had significantly increased after treatment and, in addition, some basal keratinocytes showed slight positive staining for p53. An increased expression of the bcl-2 gene before treatment in predominately dermal lymphocytes was significantly downregulated by UVA1 therapy. The increase in p53+ cells and the decrease in bcl-2+ cells were closely linked to a significant reduction in dermal T cells (CD3+) and a substantial clinical improvement in skin condition. In summary, medium-dose UVA1 irradiation led to a marked modulation of the expression of p53 and bcl-2, and this plays a key role in regulating UVA1-induced apoptosis.
First experience of topical SDZ ASM 981 in children with atopic dermatitis. Harper J, Green A, Scott G, Gruendl E, Dorobek B, Cardno M, Burtin P. Department of Paediatric Dermatology, Great Ormond Street Hospital for Children, London WC1 3JH, UK.	Br J Dermatol 2001 Apr;144(4):781-7 Abstract quote BACKGROUND: SDZ ASM 981 is a selective inhibitor of inflammatory cytokine release under development for the topical treatment of atopic dermatitis. OBJECTIVES: This first paediatric study was designed to measure the systemic exposure to SDZ ASM 981 in young children with atopic dermatitis treated on extensive skin areas. METHODS: Children 1-4 years of age referred to a tertiary care centre for their atopic dermatitis were treated twice daily for 3 weeks with 1% SDZ ASM 981 cream. SDZ ASM 981 blood concentrations were measured on day 4 and 22 (last day) of treatment, and 1 week after the last application, using a radioimmunoassay with a limit of quantification of 0.5 ng mL(-1). Efficacy was assessed by the Eczema Area Severity Index (EASI). RESULTS: The 10 patients included had 23-69% of their body surface area (BSA) affected at baseline. Of the 63 SDZ ASM 981 blood concentrations measured, 63% were < 0.5 ng mL(-1); the maximum value observed was 1.8 ng mL-1. No accumulation was evidenced between days 4 and 22. The first two patients experienced a flare of atopic dermatitis that was not controlled by the study medication. In the other patients, the EASI improved by 8-89% at 3 weeks of treatment. CONCLUSIONS: In these children 1-4 years of age, blood concentrations of SDZ ASM 981 during topical treatment with the 1% cream were consistently low even in the children with the most extensive areas treated (up to 69% of their BSA).
ASM 981: an emerging safe and effective treatment for atopic dermatitis. Luger T, Van Leent EJ, Graeber M, Hedgecock S, Thurston M, Kandra A, Berth-Jones J, Bjerke J, Christophers E, Knop J, Knulst AC, Morren M, Morris A, Reitamo S, Roed-Petersen J, Schoepf E, Thestrup-Pedersen K, Van Der Valk PG, Bos JD. Department of Dermatology, University of Muenster, Germany.	Br J Dermatol 2001 Apr;144(4):788-94 Abstract quote BACKGROUND: SDZ ASM 981 is a selective inhibitor of the production of pro-inflammatory cytokines from T cells and mast cells in vitro. It is the first ascomycin macrolactam derivative under development for the treatment of inflammatory skin diseases. OBJECTIVES: This study was designed to determine the safety and efficacy of SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6% and 1.0% in the treatment of patients with atopic dermatitis and to select the concentration to be used in phase III studies. METHODS: This was a double-blind, randomized, parallel-group, multicentre dose-finding study. A total of 260 patients were randomly assigned to treatment with SDZ ASM 981 cream at concentrations of 0.05%, 0.2%, 0.6%, or 1.0%, matching vehicle cream, or the internal control 0.1% betamethasone-17-valerate cream (BMV). Treatment was given twice daily for up to 3 weeks. RESULTS: A clear dose-response relationship for SDZ ASM 981 was evident, with 0.2%, 0.6% and 1.0% SDZ ASM 981 creams all being significantly more effective than vehicle (P = 0.041, 0.001 and 0.008, respectively) in terms of baseline to end-point changes in the Eczema Area Severity Index (EASI) and pruritus score. The 1.0% cream was the most effective SDZ ASM 981 concentration. BMV was more effective than the SDZ ASM 981 creams tested in this study. It appears that the efficacy plateau was not reached with the SDZ ASM 981 creams within 3 weeks treatment. SDZ ASM 981 was well tolerated. Burning or a feeling of warmth were the only adverse events reported more frequently in the 0.6% and 1.0% SDZ ASM 981 treatment groups than in the vehicle treatment group (42.9%, 48.9% and 34.9%, respectively). Few systemic adverse events were reported during the study (headache was the most frequent systemic event reported by 15 of 252 patients) and none was considered to be related to treatment. The local tolerability profile of the 1.0% cream was similar to that of the lower concentrations. CONCLUSIONS: 1.0% SDZ ASM 981 cream, which was shown to be safe, well tolerated and the most effective concentration in this study, was selected as the concentration to be further developed in phase III studies.
Low-dose cyclosporin A microemulsion in children with severe atopic dermatitis: clinical and immunological effects. Bunikowski R, Staab D, Kussebi F, Brautigam M, Weidinger G, Renz H, Wahn U. Charite Campus Virchow-Klinikum, Department of Pediatric Pneumology and Immunology, Humboldt University of Berlin, Berlin, Germany.	Pediatr Allergy Immunol 2001 Aug;12(4):216-23 Abstract quote Cyclosporin A (CsA) is an effective and well-tolerated treatment for severe childhood atopic dermatitis (AD). By starting at a low dose, the therapeutic safety should be further increased. The aim of this study was to evaluate low-dose CsA in childhood AD with respect to clinical outcome and modulation of T-cell dysregulation. In an open prospective study, 10 children (age: 22-106 months) with severe AD (mean objective SCORAD score > 40 on two baseline measurements at a minimum interval of 2 weeks) were treated with CsA solution for 8 weeks. All patients received a starting dose of 2.5 mg/kg/day, which was increased stepwise in non-responders to a maximum of dose of 5 mg/kg/day. Disease activity was monitored using the SCORAD index. The frequency of cytokine-producing peripheral blood T lymphocytes was analyzed by intracellular cytokine staining, and T-cell numbers were measured by fluorescence-activated cell sorter (FACS) analysis. Twenty healthy age-matched children were included as controls for the immunological data. Nine of the 10 patients had a SCORAD reduction of at least 35%. In seven patients this was achieved with low-dose CsA at 2.5 mg/kg/day (n = 4) and 3.5 mg kg/day (n = 3). Seven of the nine responders experienced no relapse within the 4-week follow-up period. At baseline the percentage of interleukin-4 (IL-4), IL-13, and human leucocyte antigen (HLA)-DR-positive CD3(+) cells was higher in the patient group than in the controls. After CsA treatment there was a significant reduction in interferon-gamma (IFN-gamma), IL-2, IL-4, IL-13, and HLA-DR-positive CD3(+) cells. Hence, in severe pediatric AD, CsA microemulsion, when started at a low dose (2.5 mg/kg/day), improves clinical measures of disease, reduces T-lymphocyte cytokine production, and regulates T-cell activation.
High-dose versus medium-dose UVA1 phototherapy for patients with severe generalized atopic dermatitis Stanislava Tzaneva, MD Arno Seeber, MD Martina Schwaiger, DScTechc Herbert Hönigsmann, MD Adrian Tanew, MD Vienna and Seibersdorf, Austria	J Am Acad Dermatol 2001;45:503-7 Abstract quote Background: Several studies have demonstrated the efficacy of UVA1 (340-400 nm) phototherapy for patients with severe atopic dermatitis. However, the optimum treatment dose has yet to be determined. Although in seminal investigations high UVA1 doses were used, comparable results were reported in recent studies with a medium-dose regimen. Objective: Our purpose was to compare the efficacy of high-dose with medium-dose UVA1 phototherapy for patients with severe generalized atopic dermatitis. Methods: Ten adult patients with a median baseline SCORAD score of 67 were enrolled in an investigator-blinded, bilateral comparison study. Treatment was given 5 times weekly over a period of 3 weeks on an outpatient basis. Irradiation was performed by exposing one half of the patient's body to high-dose UVA1 (130 J/cm2), and the contralateral body side received only half that dose. The clinical response was assessed after 5, 10, and 15 treatments. After completion of the study, patients were followed up for 6 months to evaluate the duration of clinical improvement. Results: All but one patient responded favorably to treatment. High-dose UVA1 led to a decrease of the median SCORAD score by 33.4% after 1 week, 38.4% after 2 weeks, and 34.7% after 3 weeks. The respective values for the medium-dose regimen were 29.7%, 36.4%, and 28.2%. The difference in efficacy between the two dosages remained below the level of significance at all time points. Relapses occurred after a median of 4 weeks. Time of onset and severity of relapse were the same for both doses. Conclusion: Our data support previous uncontrolled observations that medium-dose UVA1 is comparably as effective as high-dose treatment for patients with severe generalized atopic dermatitis. Irrespective of the dose regimen, follow-up examinations revealed early relapse in the majority of patients.
Macrolactam immunomodulators for topical treatment of inflammatory skin diseases Elke Bornhövd, MD Walter H. C. Burgdorf, MD Andreas Wollenberg, MD Munich, Germany	J Am Acad Dermatol 2001;45:736-43 Abstract quote The immunomodulatory macrolactams provide an alternative to glucocorticosteroids for the topical treatment of atopic dermatitis and other inflammatory dermatoses. Tacrolimus (FK506), as well as the newer ascomycin derivative ASM 981 (pimecrolimus), penetrate the inflamed epidermis and are suitable for topical therapy. Both substances inhibit the transcription of proinflammatory cytokine genes such as interleukin 2, which are dependent on the nuclear factor NF-AT. They block the catalytic function of calcineurin, which leads to the inhibition of the transport of the cytoplasmic component of NF-AT to the cell nucleus. Multicenter, randomized, double-blind clinical trials with topical formulations have shown the efficacy of both substances in moderate to severe atopic dermatitis. A review is presented of the biochemical and cell biologic properties, mode of action, pharmacokinetic data, side effects, results of the clinical trials, and further indications for tacrolimus and ASM 981, along with an overview of the related substances cyclosporine and sirolimus (rapamycin).
Tacrolimus and pimecrolimus: From clever prokaryotes to inhibiting calcineurin and treating atopic dermatitis Paul Nghiem, MD, PhD Greg Pearson, MD Richard G. Langley, MD Boston, Massachusetts, Columbia, Missouri, and Halifax, Nova Scotia, Canada	J Am Acad Dermatol 2002;46:228-41 Abstract quote Tacrolimus ointment, a topical inhibitor of the phosphatase calcineurin, has recently been approved in the United States for use in the treatment of atopic dermatitis. It is the first topical immune suppressant that is not one of the hydrocortisone derivatives, important allies in dermatology for nearly 50 years. Although tacrolimus is less able to penetrate thick skin than glucocorticoids, it does not cause dermal atrophy, an important advantage over the hydrocortisone class. Pimecrolimus (ASM 981), a newer calcineurin inhibitor closely related to tacrolimus, is also being developed for atopic dermatitis therapy. Pimecrolimus has an altered skin penetration profile but the same mechanism of action as tacrolimus. In this review we chronicle the discovery of the calcineurin inhibitors, their presumed evolutionary role as a bacterial “smart bomb” against fungi, molecular and cellular mechanisms of action in the immune system, systemic and topical side effects, efficacy in atopic dermatitis, and future applications within the specialty of dermatology. Particular attention is given to the issues of systemic absorption of tacrolimus, the conditions in which absorption can become a concern, efficacy relative to glucocorticoids, and the choice of 0.03% or 0.1% tacrolimus ointment for use in adults and children.
Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. Eichenfield LF, Lucky AW, Boguniewicz M, Langley RG, Cherill R, Marshall K, Bush C, Graeber M. Pediatric and Adolescent Dermatology, Children's Hospital-San Diego, 3020 Children's Way, Mail Code 5092, San Diego, CA 92123, USA.	J Am Acad Dermatol 2002 Apr;46(4):495-504 Abstract quote BACKGROUND: The ascomycin derivative pimecrolimus (ASM 981) is a cell-selective cytokine inhibitor, specifically developed for the treatment of inflammatory skin diseases. OBJECTIVE: When applied topically, pimecrolimus cream 1% has shown promise as a treatment for inflammatory skin conditions, including atopic dermatitis (AD) in children and adults, allergic contact dermatitis, and chronic contact irritant hand dermatitis in adults. METHODS: In two independent 6-week, randomized, multicenter studies of identical design, the efficacy and safety of pimecrolimus cream 1% in children with predominantly moderate AD were compared with vehicle. Pooled data from a total of 403 patients were used in the analysis. The primary efficacy parameter was the Investigator's Global Assessment (IGA) score. Secondary parameters included Eczema Area and Severity Index (EASI) and severity of pruritus scores. Subjects were also asked to assess their disease control as uncontrolled, limited, good, or complete. RESULTS: Significant therapeutic benefits relative to vehicle were observed in the pimecrolimus-treated group at the first efficacy assessment, 8 days after initial application of the study medication (eg, relief of pruritus). At each subsequent postbaseline visit, pimecrolimus-treated patients showed significant improvement relative to controls in all efficacy measures. The medication was well tolerated. CONCLUSION: Pimecrolimus cream 1% appears to be a safe and effective alternative to currently used therapies for AD.
Tacrolimus ointment for the treatment of atopic dermatitis is not associated with an increase in cutaneous infections. Fleischer AB Jr, Ling M, Eichenfield L, Satoi Y, Jaracz E, Rico MJ, Maher RM; Tacrolimus Ointment Study Group. Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.	J Am Acad Dermatol 2002 Oct;47(4):562-70 Abstract quote OBJECTIVE: The purpose of this study was to evaluate the risk of cutaneous infection in patients with atopic dermatitis treated with tacrolimus ointment. METHODS: Data for 1554 patients with atopic dermatitis, treated with tacrolimus ointment in 5 clinical trials, were analyzed. RESULTS: In 3 controlled studies, the 12-week adjusted incidence of all cutaneous infections in patients treated with the vehicle, 0.03%, and 0.1% tacrolimus ointment, respectively, was 18.0%, 24.8%, and 17.7% for adult patients, and 20.9%, 19.6%, and 23.6% for pediatric patients. The incidence of any individual cutaneous infection was not significantly higher in the tacrolimus group than in the vehicle group, with the exception of folliculitis in adults. In two open-label studies, there was no evidence of an increased risk of cutaneous infections with long-term use of 0.1% tacrolimus ointment (up to 1 year), based on the incidence of adverse events, incidence by cumulative length of exposure, or hazard rates. CONCLUSION: Treatment with tacrolimus ointment (0.03% or 0.1%) does not increase the risk of cutaneous bacterial, viral, or fungal infections in patients with atopic dermatitis.

Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
J Allergy Clin Immunol 1998;101:587-93.

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