Maternal Smoking During Pregnancy and Lactation Increases the Risk for Atopic Eczema in the Offspring
Introduction.—Maternal smoking during pregnancy may cause immunologic changes in the offspring. The influence of smoking on atopy is not well defined. The influence of air pollutants on the manifestations of atopy were assessed in 678 preschool children.
Methods.—The parents of 5- to 6-year-old preschool children from areas with varying degrees of air pollution in Bavaria completed a questionnaire regarding their child’s history of atopic diseases and other relevant factors. Children underwent skin-prick testing for common allergens.
The outdoor and indoor exposures to sulfur dioxide and nitrogen oxide were measured using a passive sampler. Atopy was defined as, “personal history of atopic disease or positive prick test to either grass pollen, house dust mite, or cat.”
Results.—Overall, 38.9% of children bad at least one manifestation of atopy. In children of smoking (12.6% of mothers smoked during pregnancy and 26.8% smoked during lactation) and nonsmoking mothers, respectively, 52.5% and 35.7% had manifestations of atopy. The only factor significantly associated with maternal smoking during pregnancy and lactation was a history of atopic eczema. There was an inverse correlation between indoor nitrogen oxide exposure and manifestations of atopy in smoking mothers. It is not known why this occurred. Children residing in the so-called clean-air areas had significantly fewer manifestations of atopy, compared to other groups.
Conclusion.—Maternal smoking during pregnancy and lactation was correlated with an increased risk of 2.3 of atopic eczema in the offspring. There were fewer manifestations of atopy in the so-called clean-air regions.
- This study from Germany assesses the association, if any, between maternal smoking during pregnancy and lactation and the development of atopic diseases. The authors attempted to control for indoor and outdoor pollutants (sulfur dioxide and nitrogen oxide) as well as for the regions in which the participants lived, which are known to have different air pollution patterns. They performed various statistical analyses including a classification and regression tree. There was an increased risk of atopic eczema in the offspring of mothers who smoked during pregnancy and lactation. The authors also cite previous articles that have suggested a deleterious effect of maternal smoking on children’s health.
Granulocyte Macrophage Colony-stimulating Factor Is Overproduced by Keratinocytes in Atopic Dermatitis: Implications for Sustained Dendritic Cell Activation in the Skin
Background.—High numbers of dendritic cells with enhanced capacity to stimulate T lymphocytes are present in the lesional skin of atopic dermatitis (AD). Local cytokine expression plays a key role in governing the nature, extent, and persistence of inflammation in AD. Keratinocytes can release many different cytokines with a modulatory effect on skin immune responses. Among these is granulocyte-macrophage colony-stimulating factor (GM-CSF), which plays an essential role in the development and function of dendritic cells. Production of GM-CSF by keratinocytes in AD skin was studied.
Findings.—Skin specimens from 8 patients with moderate-to-severe chronic AD, as well as from unaffected controls, were studied. In both the epidermal and dermal compartments, the skin of AD lesions stained heavily for GM-CSF. In culture, keratinocytes from the uninvolved skin of patients with AD showed highly increased release of GM-CSF, compared with keratinocytes from nonatopic controls. Both spontaneous and PMA- stimulated release of GM-CSF were significantly increased. Constitutive and PMA-induced GM-CSF gene expression were also significantly in-creased in keratinocytes from AD patients. The AD keratinocytes showed increased production of GM-CSF in response to interleukin-1 (IL-1), but not after lipopolysaccharide, lipoteichoic acid, or staphylococcal entero- toxin B stimulation. Peripheral blood mononuclear cell proliferation was strongly stimulated in a GM-CSF-dependent fashion by supernatants from atopic keratinocytes. Also, maturation of peripheral blood precursors into dendritic cells was supported by conditioned medium from PMA-treated AD keratinocytes, with the addition of exogenous IL-4.
Conclusions.—Keratinocytes from AD skin show enhanced production of GM-CSF. This could play an important role in the establishment and chronicity of AD lesions, particularly in terms of the number, activation, and antigen-presenting functions of dendritic cells. Epithelial cells may be an important target of glucocorticoid drugs, which downregulate the expression of signals involved in attracting and activating inflammatory cells.
The Association of Atopy With a Gain-of-Function Mutation in the a Subunit of the lnterleukin-4 Receptor
Objective.—Some of the recently identified atopy susceptibility genes, including interleukin-4, regulate the production of IgE. Whether interleukin-4 receptor a regulates production of IgE by gain-of-function mutations or deletions that enhance receptor signaling was investigated.
Methods.—Single-strand conformation polymorphism (SSCP) analysis and sequencing was employed to discover mutations in the a subunit of the interleukin-4 receptor in 10 patients, 3 with hyper-IgE syndrome and 7 with severe atopic dermatitis and in 50 healthy volunteers. Patients on immunotherapy were excluded. Peptide conjugation, binding assays, and immunoblotting studies were performed. Flow cytometry was used to analyze CD23 expression.
Results.—An alteration in the SSCP profile of one cDNA segment was identified where guanine was substituted for adenine at nucleotide 1902 resulting in a change from glutamine to arginine residue at position 576. This latter substitution alters the binding of the adjacent phosphorylated tyrosine residue. This mutant interleukin-4 receptor .allele was found in 3 of 3 patients with hyper-IgE syndrome and in 4 of 7 patients with severe atopic dermatitis. This R576 allele occurs with a frequency of 20% in the group with atopy and 10% in the group without atopy. The presence of this allele carries a relative risk of atopy of 9.3 and is associated with higher levels of CD23 expression.
Conclusion.—The mutant R576 allele of the interleukin-4 receptor a segregates with atopy by causing enhanced signaling of the receptor that decreases the binding of the phosphotyrosine phosphatase SHP-1.
- Recent work by Hershey et al. and Pastore et al. help to define the complex role of cytokines in the pathogenesis of atopic dermatitis. The work by Hershey et al. (Abstract 1-3) provides compelling evidence that atopic dermatitis is associated with a gain-of-function mutation of the IL-4 receptor, which in turn is linked to the production of IgE. This occurs because IL-4 mediates B-cell surface molecule CD40 function in switching isotype production to IgE. Pastore et al. (Abstract 1-2) have demonstrated that the development of dermal dendritic cell morphology is co-mediated by IL-4 and GM-CSF. Dermal and epidermal dendritic cells are very potent antigen- presenting cells for the activation of T cells and are present in increased numbers in patients with atopic dermatitis. These authors also demonstrate that GM-CSF is overproduced in keratinocytes from patients with atopic dermatitis and that such production is up-regulated by IL-1 alpha but not by staphylococcal enterotoxin B, lipoteichoic acid or lipopolysaccharides. Therefore, taken together, these two papers suggest that IL-4 and GM-CSF may play a synergistic role in the expression of dermal dendritic cells and recruitment of other inflammatory cells into the skin of patients with atopic dermatitis.
Elevated Levels of Soluble HLA Class I (sHLA-l) in Children With Severe Atopic Dermatitis
Introduction.—Atopic dermatitis is distinguished by increased production of IgE and interleukin-4, immediate skin test reactivity to allergens, increased expression of CD23 on mononuclear cells, and reduced production of interferon-y. Elevation of soluble HLA class I (sHLA-I) molecule levels is observed in conditions where T cells are activated, such as viral infection, autoimmune diseases, mycobacterial infection, chronic renal disease, and bone marrow and organ transplantation. Fourteen children with atopic dermatitis were assessed to determine whether sHLA-I heterodimers were elevated and if sHLA-I elevations correlated with disease activity.
Methods.—All children had atopic dermatitis resistant to conventional therapy. Children were followed during an 8-week period of an ongoing treatment trial with topical sodium cromoglycate. Patients were evaluated at baseline for extent of skin involvement, disease severity, absolute eosinophil counts, IgE and sHLA-I levels. Soluble HLA-I levels were also obtained at 4 and 8 weeks after therapy.
Results.—Mean sHLA-I levels were significantly higher in patients with atopic dermatitis compared with 55 healthy controls. Nine of 14 patients (64%) with atopic dermatitis had elevated sHLA-I antigens. The sHLA-I levels did not correlate with extent of disease, disease severity score, eosinophil count, or IgE levels. Even in the presence of marked clinical improvement, the sHLA-I levels remained consistently similar at baseline and at 4 and 8 weeks of therapy.
Conclusion.—Soluble HLA-I levels are increased in patients with atopic dermatitis, even with clinically effective therapy; this suggests persistent activation of the immune system in this disease. Prolonged preventive and treatment measures are recommended for these patients.
- The 14 children with atopic dermatitis in this study experienced clinical improvement after treatment with topical sodium cromoglycate. The authors found that soluble HLA-I heterodimers were elevated in these patients when compared with controls, and they remained elevated despite clinical improvement. They postulate that this reflects continuing subclinicai inflammation even during periods of clinical remission. There is a parallel with asthmatic patients whose lungs remain inflamed even during times of apparent clinical remission. Based on these findings, ongoing and long-term therapeutic management is necessary for patients with atopic dermatitis.
Presence of Specific IgE Antibodies to Staphylococcal Enterotoxins in Patients With Atopic Dermatitis
Introduction.—A number of environmental factors influence the clinical course of atopic dermatitis, including colonization of the skin with Staphylococcus aureus. The disease is characterized as a pruritic, eczematous dermatosis. A combination of corticosteroid and antibiotic therapy produces a better response in patients with atopic dermatitis than does topical corticosteroid therapy alone. Treatment with a very potent corticosteroid alone, however, can eliminate S. aureus. In serum from patients with atopic dermatitis, the presence of specific IgE antibodies to staphylococcal enterotoxins was demonstrated. Their possible roles in disease exacerbation, through IgE-mediated immunoreactions, were discussed.
Methods.—There were 96 patients (mean age 20.2 years) with mild-to- severe atopic dermatitis. Serum samples were obtained and analyzed for specific IgE antibodies against staphylococcal enterotoxin A (SEA) and enterotoxin B (SEB) and for total serum IgE. Control serum samples were obtained from 11 non-atopic patients with eczematous lesions such as contact dermatitis, as well as from 11 healthy patients.
Results.—Specific IgE antibodies against SEA and SEB were found in 77 of 96 patients (80.2%). Twenty-three of 27 patients (85.2%) with severe atopic dermatitis had both antibodies. Anti-SEA IgE antibodies were found in 48 of 58 patients (82.8%) with high serum IgE levels, and 51 of 58 patients (87.9%) had anti-SEB IgE antibodies. The atopic dermatitis patients with higher levels of total serum IgE had a higher incidence of positive specific IgE antibodies. In the control groups, only 1 of the serum samples was positive to SEA alone.
Conclusions.—In the exacerbation and prolongation of the inflammation of atopic dermatitis, staphylococcal enterotoxins may play an important role through an IgE-mediated immunoresponse. This may lead to a more severe dermatitis in a subset of patients.
- Although its exact contribution remains somewhat unclear, there is growing evidence for a role for S. aureus in the pathogenesis and exacerbation of atopic dermatitis. The skin of atopies is frequently heavily colonized with S. aureus, and use of antibiotics often results in clinical improvement. Staphylococci are known to secrete a variety of toxins that can function as superantigens, causing a widespread, T-cell-mediated immune response. It has been suggested in several studies that this may explain at least part of the inflammatory response occurring in atopic dermatitis. In this study, the presence of serum IgE antibodies to several specific staphylococcal enterotoxins was detected in patients with atopic dermatitis. The detection of antibodies did not correlate with disease severity, and it is impossible to state with certainty from this study that these antibodies contribute in any way to the pathogenesis of the disease. This finding does, however, suggest that immediate hypersensitivity allergic reactions to staphylococcal toxins may be important in atopic dermatitis. This implies new and exciting therapeutic possibilities for this most challenging condition.
Adult Height in Patients With Childhood Onset Atopic Dermatitis
Introduction.—There is cross-sectional evidence linking atopic dermatitis to growth impairment in children. However, without longitudinal data, it is unclear whether any such growth impairment is temporary or permanent. If permanent, then the final height of children with atopic dermatitis should be reduced. Final height was evaluated in adults with atopic dermatitis, compared with healthy controls.
Methods.—The controlled, cross-sectional study included 35 individuals—20 women and 15 men, mean age 26 years—with a history of childhood atopic dermatitis. All children had atopic dermatitis before 5 years of age, with the condition continuing into adulthood. In each case, the disease was severe enough to warrant specialist care. For comparison, 35 adults with adult-onset contact dermatitis or psoriasis were studied; all were free of childhood skin disease. For the childhood atopic dermatitis group, the age at onset of disease, age at onset of topical corticosteroid treatment, and potency of topical corticosteroids were analyzed. Standing height and other anthropometric findings were compared for the 2 groups.
Findings.—The 2 groups were similar in standing height standard deviation (SD) score, midparental height SD score, sitting height SD score, subischial leg length SD score, and body mass index. Within the atopic dermatitis group, height was no different for those with disease affecting more or less than 50% of body surface area. The potency of topical corticosteroids given during childhood was deemed mild in 7 patients, moderate in 2, potent in 16, and very potent in 10, with no height differences between groups. One patient—the shortest in the group— received topical corticosteroids under occlusion.
Conclusions.—Final height for children with atopic dermatitis appears to be no different than for adults with no history of childhood skin disease. If growth is impaired in children with atopic dermatitis, the effect is likely a temporary one. Pubertal delay, as seen in children with asthma, is still possible. Growth should be closely monitored in children receiving topical corticosteroids because individual susceptibility may vary.
- Although topical corticosteroids may not affect ultimate height, it should be recognized that growth suppression from long-term systemic corticosteroid treatment may have a more significant effect on stature.
Time-dependent Variations of the Skin Barrier Function in Humans: Transepidermal Water Loss, Stratum Corneum Hydration, Skin Surface pH, and Skin Temperature
Objective.—Skin barrier function of the epidermis, in particular the stratum corneum, is important for topical drug permeability. Yet few studies have examined the effect of circadian rhythm on permeability. The effect of circadian rhythm on stratum corneum water content, transepidermal water loss (TEWL), stratum corneum pH, and skin temperature at different anatomic sites over 24 hours was investigated using rhythmometric methods.
Methods.—Forehead, upper back, forearm, and shin measurements were made every 2 hours during 8-hour day and night sessions in a 24-hour day, and were repeated 1 week later, in 16 healthy volunteers (7 women), aged 23-53. Twelve samples were taken of each variable except TEWL which was measured only at night with an evaporimeter. A corne- ometer was used to measure stratum corneum hydration, a pH meter was used to measure skin surface pH, and a digital infrared thermometer was used to measure skin temperature. Differences were compared statistically using cosinor analysis and analysis of variance.
Result.—Transepidermal water loss at all sites, shin and forearm pH, and skin temperature at all sites were time-dependent. Stratum corneum hydration did not vary over time. Peak to trough differences were detected at all sites. Relative peak-trough differences were significant. Whereas the acrophase values of skin temperature at different sites were correlated, TEWL and skin temperature were not.
Conclusion.—Skin permeability in most sites appears to be higher at night. Stratum corneum hydration did not vary over time.
- The authors conclude their paper with a brief discussion of chronopharmacology, the timing of administration of medications. This is based on the observation that drugs may have different therapeutic effects or side effects depending on the time of day they are given. Chronopharmacologic variables may be important in the treatment of cancer, and immunologic and endocrinologic disorders.’ The data presented by Yosipovitch et al. may have clinical relevance in determining the optimal time for topical drug application.
Topically Applied Aspirin Rapidly Decreases Histamine-induced Itch
Introduction.—Hyperalgesia results from the effects of prostaglandin in sensitizing the small nerve fiber endings to various mediators. This effect is inhibited by aspirin, which accounts for its analgesic effect. The authors have developed an experimental model of histamine-induced itch, which causes increased warm sensation thresholds, a C fiber-mediated sensation. Using this model, the effects of topical aspirin on the magnitude and duration of itch were investigated. Aspirin’s effects on C fibers were examined as well.
Methods.—Itch was produced by histamine injection in 16 volunteers, who were then treated with either topical 3% aspirin or its vehicle, dichloromethane. The response of itch to treatment was measured by a visual analogue scale. The effects on C fibers wefe assessed using a computerized thermal testing device.
Results.—Aspirin significantly reduced the duration and magnitude of itch, compared with vehicle. Warmth sensation threshold was significantly elevated after histamine injection, whereas cold and heat pain thresholds were unaffected. Neither aspirin nor vehicle altered thermal or pain thresholds during histamine-induced itch.
Conclusions.—Topical aspirin significantly relieves histamine-induced itch. The clinical relevance of this finding is uncertain, hut topical application of high-dose aspirin in the area of cutaneous nociceptors could be an effective antipruritic therapy.
- The clinical importance of these data is uncertain. Most clinicians have observed that systemic antihistamines are often of marginal benefit, even in disorders in which histamine is the putative mediator of the pruritus. A previous study has shown that oral aspirin does not affect itching, and another has found that oral aspirin may actually aggravate histamine-induced itch. Interestingly, the use of topical aspirin in chloroform has been shown to alleviate the pain of postherpetic neuralgia.
The Effects of Topical Doxepin on Responses to Histamine, Substance P and Prostaglandin E2 in Human Skin
Objective.—Doxepin is a tricyclic antidepressant with known H1 and H2 antihistaminic effects. A preparation of 5% doxepin cream is now being marketed for short-term use in the treatment of eczematous dermatoses. Previous reports have suggested that topical doxepin increases the histamine-induced itch threshold while decreasing itch caused by various clinical conditions. The effects of topical doxepin on skin responses to histamine, substance P, and prostaglandin E2 (PGE2) were investigated, including a comparison with the effects of the antihistamine terfenadine.
Methods.—A total of 8 patients with atopic dermatitis and 8 healthy controls were studied. The participants received 7 intradermai injections of histamine, 1 or 10 pg; substance P, 10, 100, or 200 pmol; PGE2, 2 nmol; or saline. Injections were given before and after treatment with topical 5% doxepin or oral terfenadine. The effects on wheal and flare responses were evaluated.
Results.—In both groups of individuals, both treatments significantly reduced the wheal volume and flare area responses to histamine. At a 10- μg dose of histamine, doxepin reduced the mean flare area by 54% in nonatopic individuals vs. 89% in atopic individuals, compared with 48% and 60%, respectively, with terfenadine. Doxepin reduced mean wheal volume by 96% in nonatopic individuals vs. 89% in atopic individuals; with terfenadine, the reductions were 70% and 63%, respectively. In both groups, both treatments reduced the flare response to substance P, although not the wheal response. Neither treatment altered the skin response to PGE2. Doxepin inhibited skin reactions at least as effectively as terfenadine. In normal individuals, doxepin produced greater inhibition of the wheal response to histamine and in the flare response to substance P than did terfenadine. The 2 groups of individuals were not significantly different in the percentage reduction of skin responses by the 2 treatments. The first 3 individuals receiving topical doxepin showed a marked sedative response; subsequent subjects received a lower dosage.
Conclusions.—For inhibiting histamine-induced and axon-reflex-mediated cutaneous responses, topical doxepin was at least as effective as oral terfenadine. In some situations, doxepin was more effective. However, doxepin had a definite sedative effect, which may limit its clinical applicability.
- Overall, topical doxepin appears to be as or more effective than oral terfenadine in the treatment of many of the physiologic responses that occur as part of the urticarial reaction. Conspicuously absent in either group was an effect on the cutaneous response to PGE2 . I personally have found antihistamines to be of only partial benefit in treating chronic urticaria. Perhaps more aggressive use of drugs that inhibit enzymes and products of the arachidonic acid cascade would augment the rather limited clinical benefits of antihistamines.
Comparison of the Influence of Cyclosporine and Topical Betametha- sone-17, 21-dipropionate Treatment on Quality of Life in Chronic Hand Eczema
Introduction.—Hand eczema has a great socioeconomic impact and can have a detrimental effect on the quality of life. In medical interventions, the assessment of quality of life is often neglected. In several eczematous diseases of severe grade, cyclosporine provides a treatment alternative. In the treatment of chronic hand eczema, cyclosporine, 3 mg/kg/day for 6 weeks, was shown to be as effective as topical betamethasone-17,21- dipropionate. The impacr of both treatment modalities was evaluated on the quality of life of the patients.
Methods.—Forty-one patients were treated either with cyclosporine or betamethasone for 6 weeks. Those who had failure were switched to the other treatment for another 6 weeks. The Eczema Disability Index was used to assess the quality of life at baseline and at the end of both treatment periods.
Results.—Both groups had a significant decrease in the total Eczema Disability Index score. The cyclosporine group decreased from a mean value of 30.5 to 20.9, and the betamethasone-17,21-dipropionate group decreased from a mean value of 27.2 to 18.9. There was no significant difference at the end of the first treatment period between the two groups in the components of the Eczema Disability Index: daily activity, school/ work, personal relationships, leisure, or treatment. There was a slight further decrease in the total score at the end of the second treatment period, but there was still no difference between the two groups. Changes in the clinical assessments, such as extent of the disease, disease activity, itch, sleep disturbances, and use of emollients correlated significantly with changes in the total Eczema Disability Index score.
Conclusions.—Although the strong correlation between the total Eczema Disability Index score and clinical assessment could indicate that clinical assessment gives a complete picture of the outcome, some aspects of the score are not covered by clinical measures. Subtle differences in a patient’s state of well-being could be picked up by a modified Eczema Disability Index.
- This report appears to be a follow-up to a previous study by several of the same authors’ in which they demonstrated comparable efficacy of cyclosporine and topical betamethasone-17, 21-dipropionate in the treatment of chronic hand eczema. This article addresses more specifically quality-of-life issues during therapy. Improvement in patients’ clinical status correlated significantly with improvement in their quality of life. The degree of improvement was comparable between the 2 treatments. As a clinician, I think this article would best be read in conjunction with the authors’ previous article in which they detail the specifics about the clinical efficacy of the treatments. Moreover, the study period was relatively short, covering only 6 weeks, and it is unclear whether the quality-of-life parameters would remain similar in these 2 patient groups for a more extended period because potential complications of therapy might arise.
Cyclosporine in Severe Childhood Atopic Dermatitis: A Multicenter Study
Background.—Severe atopic dermatitis (AD), which significantly lowers the quality of life for children and adults, is still difficult to treat. Cyclosporine has been found to be effective in adults. The efficacy, safety, and tolerability of cyclosporine were investigated in children with severe refractory AD.
Methods.-Twenty-seven children aged 2-16 years were enrolled in the open study. Cyclosporine, 5 mg/kg/day, was given for 6 weeks. Every 2 weeks, disease activity was assessed using sign scores, visual analogue scales for symptoms, and quality-of-life questionnaires. Five-point scales were used to determine efficacy and tolerability.
Outcomes.—All measures of disease activity were improved in this series. Twenty-two of the 27 children had substantial improvement or total clearing. In addition, quality of life was improved for the children and their families. Twenty-five children rated tolerability as good or very good.
Conclusions.—Cyclosporine appears to be an effective treatment for children with severe AD. It is fairly well tolerated and safe, at least in the short term. Further studies are needed to better define the optimal dose, duration of treatment, and manner of drug withdrawal.
- Obviously, cyclosporine therapy for childhood AD can be recommended only in highly selected individuals. Its greatest value may be in short-term use to allow other therapeutic interventions to take hold. It is also possible that gradual tapering of the dose to avoid a quick rebound may be more appropriate than abrupt withdrawal.
A Highly Sensitive Enzyme-linked Immunosorbent Assay for the Determination of Tacrolimus in Atopic Dermatitis Patients
Introduction.—The macrolide immunosuppressant agent tacrolimus has shown activity against autoimmune diseases in animals, and as such may be a useful treatment for immunologically mediated inflammatory skin diseases. A tacrolimus ointment has been studied for use in adults and children with atopic dermatitis. However, the circulating blood levels of tacrolimus produced by this formulation are below the level of detection of currently available assays. A sensitive new enzyme-linked immunosorbent assay (ELISA) for the measurement of tacrolimus in blood samples is reported.
Methods and Findings.—The ELISA was based on a previously reported assay, but modified for better sensitivity. Tacrolimus was first extracted using methanol and sulfosalicylic acid. Then a Nunc Maxisorb plate precoated with polyclonal antibody for nonspecific binding was used to incubate the blood samples for 2 hours at room temperature. In human blood to which tacrolimus was added in concentrations of 0.02-5.0 ng/ mL, the ELISA showed precision and accuracy over a 6-day period. The coefficients of variation with the ELISA were 6.0% to 28.9% between days and 3.9% to 15.2% within days. Its lower level of quantitation was 0.05 ng/mL.
The ELISA was subsequently used to measure blood tacrolimus concentrations in patients treated with 0.3% tacrolimus ointment. Mean concentration-time profile varied with the size of the treated area. Pharmacokinetic studies suggest that systemic tacrolimus exposure increased in a relatively linear fashion. Topical tacrolimus had a bioavailability of less than 1%, compared with historical data on IV tacrolimus.
Discussion.—A sensitive, specific, and accurate ELISA for the measurement of tacrolimus levels in blood is reported. This technique is useful in patients being treated with tacrolimus ointment; these patients have lower tacrolimus concentrations than transplant recipients or patients receiving oral tacrolimus.
A Short-term Trial of Tacrolimus Ointment for Atopic Dermatitis
Background.—Atopic dermatitis is typically treated with topical corticosteroids, but their use is associated with unpleasant side effects. Thus drugs with more acceptable side effect profiles are constantly being sought. One such drug may be tacrolimus, which causes local immunosuppression when applied topically. The efficacy of topical tacrolimus was compared with placebo in treating moderate to severe atopic dermatitis.
Methods.—After a 1-week washout phase, an ointment of placebo (n = 54) or tacrolimus in concentrations of 0.03% (n = 54), 0.1% (n = 54), or 0.3% (n = 51) was administered twice daily to 200-1,000 cm2 of skin for 3 weeks. Baseline and follow-up studies (for 1 week after the end of treatment) included assessments of erythema, edema, pruritus, oozing or crusting, excoriation, lichenification, and the dryness of uninvolved skin. The change from baseline to the end of treatment in the sum of the scores for erythema, edema, and pruritus (i.e., summary score 1) was the primary endpoint; the change in the sum of all the symptom scores (i.e., summary score 2) was also calculated.
Findings.—After only 3 days of treatment, all 4 groups reported decreases in the summary score for trunk and extremities compared with baselines. By the end of treatment, these decreases were significantly more in the tacrolimus group (0.03% ointment, 66.7% decrease; 0.1% ointment, 83.3% decrease; 0.3% ointment, 75% decrease) compared with placebo (22.5%). Results for the face and neck were similar (71.4%, 83.3%, 83.3%, and 2.5%, respectively), and again significantly different from the effect with placebo. For all symptoms combined (summary score 2), again a similar response and significant difference were seen for all body areas examined. Both patient and investigator ratings of improvement were higher for tacrolimus than for placebo. No dose- response effect was seen with the 3 tacrolimus concentrations. Blood tacrolimus concentrations decreased steadily over the course of the study, averaging less than 0.25 ng/mL in all drug groups. The only side effect significantly more common with tacrolimus than placebo was burning at the site of administration.
Conclusions.—Compared with placebo, tacrolimus ointment effectively treated atopic dermatitis at all the concentrations tested. The side effect of burning was also experienced by controls, which indicates that perhaps the vehicle was at least partly responsible for this side effect. These results with topical tacrolimus are promising and should be expanded in a long-term study involving a larger body area.
- A potent topical therapy for atopic dermatitis that does not cause serious side effects would certainly be welcome. In this study, blood concentrations of tacrolimus (presumably reflecting absorption) were highest at the beginning of the study and decreased over time. This suggests that systemic exposure depends on a compromised barrier function and decreases as the skin heals. In contrast to potent topical steroids, skin atrophy was not observed in this study, although the period of treatment may have been too short for clinical signs to become apparent. Interestingly, studies of topical cyclosporine as a treatment for atopic dermatitis and other dermatoses have met with little success.
A Novel Anti-inflammatory Drug, SDZ ASM 981, for the Topical and Oral Treatment of Skin Diseases: In Vivo Pharmacology
Purpose.—Safe and effective treatments are needed for psoriasis, atopic dermatitis, and other inflammatory skin diseases. Several different topical and systemic treatments have been used for psoriasis; however, each has problems related to side effects or convenience. Even fewer options are available for the treatment of atopic dermatitis. SDZ ASM 981 is a new agent, derived from ascomycin macrolactam, that has shown high levels of anti-inflammatory activity. The anti-inflammatory activity of SDZ ASM 981 was studied in a variety of animal models.
Findings.—In vivo data were reported from studies using topical or systemic SDZ ASM 981 in mouse, rat, or pig models of allergic contact dermatitis. In the pig model, the effectiveness of topical SDZ ASM 981 was equivalent to that of clobetasol-17-propionate, an ultrapotent corticoste-roid. When compared with various commercial topical corticosteroid preparations, 0.1% SDZ ASM 981 was just as effective as 0.05% clobe- tasol-17-propionate. However, SDZ ASM 981 did not cause skin atrophy in pigs, which was a problem with corticosteroids. Systemic treatment with SDZ ASM 981 inhibited allergic contact dermatitis in mouse and rat models. A study in rats found that oral SDZ ASM 981 had greater effectiveness than cyclosporine A. Rat studies of localized graft-vs.-host reaction and allogenic renal transplantation found that SDZ ASM 981 had little effect on systemic immune responses.
Discussion.—The ascomycin macrolactam derivative SDZ ASM 981 has substantial anti-inflammatory activity in animal models of allergic contact dermatitis. SDZ ASM 981 could become a well-tolerated, effective, and convenient new treatment for inflammatory skin diseases. It has a low potential to suppress systemic immune reactions, and it does not cause the skin atrophy associated with topical corticosteroid treatment.
- Currently available topical and systemic therapies for chronic inflammatory skin diseases all have significant adverse effects that may limit their long-term use. The safety and efficacy in humans of derivatives of the ascomycin macrolactam class remain to be determined. A double-blind, placebo-controlled trial of a related compound, SDZ 281-240, has shown topical application of a 0.1% preparation to dramatically improve psoriatic lesions within 10 days, to a degree comparable to that obtained with the ultrapotent glucocorticoid, clobetasol-17-propionate 0.05%.’ The current study demonstrates that in animal models of skin inflammation, SDZ ASM 981 has a low potential to suppress systemic immunoreactions. After topical application, it is highly effective, and it does not cause skin atrophy. Compared with cyclosporine and SDZ 281-240, the compound has a larger therapeutic window in which skin inflammation may be treated with no adverse effects on the immune system. SDZ ASM 981 has considerable potential for the topical and oral treatment of immunologically mediated skin diseases. Obviously, much more testing in humans will be necessary before this drug comes to market.
CD4 Monoclonal Antibody Administration in Atopic Dermatitis
Background.—Atopic dermatitis (AD), a chronic inflammatory dermatosis, probably involves dysregulated activation of helper T cells, type 2 (Th2 cells). Cyclosporine treatment can control severe refractory AD. Whether short-term CD4 monoclonal antibody (mAh) treatment would be of benefit in severe AD in adults was investigated.
Methods.—Three patients with severe refractory AD received infusions of the CD4 mAb B-F5 over 2 days. Two patients with severe psoriasis were also treated to serve as control subjects.
Findings.—Despite moderate side effects after the first dose, B-F5 treatment was well tolerated. Two patients were improved clinically. The third patient experienced a dramatic worsening of symptoms 8-30 days after treatment, associated with an increased percentage of activated CD4+, CD25+, HLA-DR+, and CD45RO+ cells and peripheral blood eosinophilia. The patients with psoriasis showed marked clinical improvement of the lesions after CD4 mAb treatment.
Conclusions.—Infusion of CD4 mAb may be useful in the treatment of AD. However, the risk of aggravating the Thl/Th2 imbalance needs to be considered in future protocols.
- The authors observed that patients with AD experienced increased initial side effects and a poorer clinical response than patients with psoriasis treated with the same CD4 mAb; indeed, 1 patient with AD showed progressive worsening of disease within 2 weeks after treatment. These findings suggest that in some patients the CD4 mAb may aggravate the preexisting abnormal Th2 cell activation that is postulated to occur in AD. Other treatment schedules should be tested to assess the practical therapeutic potential, if any, of CD4 mAbs in this disease.
Treatment of Chronic Palmoplantar Eczema With Local Bath-PUVA Therapy
Background.—Plaque psoriasis can be effectively and safely treated with 8-methoxypsoralen delivered in bath water. However, there are few data on the effectiveness or side effects of local bath-(psoralen plus ultraviolet light [PUVA]) therapy for chronic palmoplantar dermatoses. This form of treatment was studied for use in patients with chronic palmoplantar eczema who had not responded to topical therapy.
Methods.—The study included 14 patients with chronic dyshidrotic eczema and 14 with chronic hyperkeratotic eczema. Each patient bathed in 37°C tap water to which an alcoholic 0.15% 8-MOP solution had been added, to achieve a final concentration of 1 mg 8-MOP/L. After 15 minutes, the palms or soles were exposed to UVA radiation by means of a Waldmann PUVA 800 unit. The maximum number of treatments was 25. Pretreatment and posttreatment photographs were used to assess the ex-tent of the lesions and to calculate the percentage surface areas of eczema.
Results.—Sixty-four percent of patients with dyshidrotic eczema had complete clearance of lesions, and 29% had substantial improvement. One patient had no change; none had a poor response. In the hyperkeratotic eczema group, 43% had lesion clearance and 43% had substantial improvement. One patient each had no change and a poor response. The average number of treatments was 12.4 in the dyshidrotic eczema group and 14.5 in the hyperkeratotic eczema group. Patients with dyshidrotic eczema received a somewhat, but not significantly, lower dosage of ultra-violet A radiation. Histologic examination confirmed lesion clearance in patients with good or excellent results. These specimens showed typical atrophy and flattening of the rete ridges and blood vessel ectasia in the papillary dermis. There were no cases of serious erythema, pruritus, blistering, or persistent light sensitivity.
Conclusion.—Bath-PUVA therapy appears to offer a high rate of good or excellent responses in patients with chronic palmar or plantar eczema. The results are better than those reported for topical PUVA therapy and similar to those reported for systemic PUVA. Surface area involvement in the patients studied was comparable to that in previous reports.
- Local bath-PUVA therapy appears to be of value in the management of chronic palmoplantar eczema resistant to standard modes of therapy. It has several advantages over topical PUVA, including the absence of phototoxic reactions, severe hyperpigmentation, and protracted photosensitivity.