- Email: [email protected]
Prophylactic therapy in children with hereditary angioedema
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claudin 8 (CLDN8), leptin (LEP), and peroxisome proliferatoractivated receptor g (PPARG), with the latter 2 known to have important roles in lipid metabolism and immune activation. To determine functional sets of genes that were altered with NB-UVB, we measured the average improvement for canonical pathways using the Gene Set Enrichment Analysis software from the Molecular Signatures Database (see Table E3 in this article’s Online Repository at www.jacionline.org). Pathways with less than 75% improvement include the cytokine and cytokine receptor interaction and chemokine receptor pathways, which improved by 67% and 58%, respectively. The PPAR signaling pathway, which is involved in lipid signaling, cellular proliferation and differentiation, and inflammatory responses, improved by only 30%. We further detected lack of improvement in selected structural genes through immunohistochemical staining (Fig 1, B-E), which contrasts with the clinical resolution of AD lesions (Fig 1, A). Levels of AQP7, an aquaglyceroporin similar to AQP3, an important determinant of epidermal hydration,4 are decreased in AD lesions and do not return to normal levels with treatment (Fig 1, B). CLDN8, a tight junction protein, also lacks improvement (Fig 1, C). Tight junction proteins (ie, claudin 1) are downregulated in patients with AD, contribute to barrier dysfunction, and inversely correlate with TH2 activation.5 PPARG, which has emerged as an important structural element with reduced expression in patients with AD and a functional negative immune regulator of DCs in the onset of AD,6 does not improve to normal levels (Fig 1, D). Leptin, another structural protein primarily involved in lipid metabolism, shows decreased epidermal expression and increased dermal cellular expression that did not return to normal levels (Fig 1, E-F). Leptin is a known pleotropic cytokine that binds to its receptor on all immune cells, upregulates adhesion molecules, induces release of cytokines and chemokines, and stimulates proliferation and survival of various immune cells.7 The reduced epidermal leptin might have no effect on the skin, as suggested by transgenic mice studies,8 or could potentially contribute to increased fatty acid oxidation in the epidermal barrier, whereas the increased dermal expression (Fig 1, F) likely promotes immune activation after treatment. Lesions with clinical resolution after NB-UVB treatment maintain a residual genomic disease phenotype, with incomplete suppression of inflammatory mediators and residual structural and lipid abnormalities (Table I) contributing to persistent epidermal deficits. This RDGP should be considered in the development of AD treatments. For example, the concomitant use of PPARG activators (ie, thiazolidinediones), which have demonstrated efficacy in AD,9 could be considered. Although some of these residual changes might be specific to NB-UVB treatment, which has known effects on keratinocytes,10 it is crucial to define and compare RDGP across various therapeutic agents. It is important to note, as seen in Fig 1, G, that although lesional AD skin significantly improved compared with nonlesional skin, both lesional and nonlesional skin demonstrate minor improvement compared with normal skin (see Tables E4 and E5 in this article’s Online Repository at www.jacionline.org), representing a ‘‘background’’ phenotype that must also be considered in the development of AD therapeutics. Without specifically targeting background skin, as well as the RDGP of AD, lesions will likely continue to recur after treatment. Mayte Su arez-Fari~ nas, PhDa,b* Julia K. Gittler, BAa,c*
Avner Shemer, MDd Irma Cardinale, MSca James G. Krueger, MD, PhDa Emma Guttman-Yassky, MD, PhDa,e* From athe Laboratory for Investigative Dermatology and bthe Center for Clinical and Translational Science, Rockefeller University, New York, NY; cAlbert Einstein College of Medicine, Bronx, NY; dthe Department of Dermatology, Tel-Hashomer Hospital and Tel-Aviv University, Tel Aviv, Israel; and ethe Department of Dermatology, Mount Sinai School of Medicine, New York, NY. E-mail: [email protected]. *These authors contributed equally to this work. J.G.K. and M.S.-F. were supported by grant no. 5UL1RR024143-02 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research. E.G.-Y. was supported by the Dermatology Foundation Physician Scientist Career Development Award. Disclosure of potential conflict of interest: J. G. Krueger has been a consultant for Janssen, Eli Lilly, and Pfizer; has received grants or has grants pending for anti-TNF from Amgen, anti-p40 and anti–IL-23 from Janssen, anti–IL-17 from Eli Lilly, anti–IL-23 from Merck, and CP690, 550 from Pfizer. E. Guttman-Yassky has received grants from the Dermatology Foundation, Regeneron, and Merck to the Mount Sinai School of Medicine and has been a consultant for Regeneron, Celgene, Merck, Pfizer, and Stiefel. The rest of the authors declare that they have no relevant conflicts of interest.
REFERENCES 1. Tintle S, Shemer A, Suarez-Fari~nas M, Fujita H, Gilleaudeau P, Sullivan-Whalen M, et al. Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response. J Allergy Clin Immunol 2011;128:583-93, e1-4. 2. Suarez-Farinas M, Fuentes-Duculan J, Lowes MA, Krueger JG. Resolved psoriasis lesions retain expression of a subset of disease-related genes. J Invest Dermatol 2011;131:391-400. 3. Suarez-Fari~nas M, Tintle S, Shemer A, Chiricozzi A, Nograles K, Cardinale I, et al. Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities. J Allergy Clin Immunol 2011; 127:954-64, e1-4. 4. Verkman AS. Aquaporins: translating bench research to human disease. J Exp Biol 2009;212:1707-15. 5. De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, et al. Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol 2011;127:773-86, e1-7. 6. Jung K, Tanaka A, Fujita H, Matsuda A, Oida K, Karasawa K, et al. Peroxisome proliferator-activated receptor g-mediated suppression of dendritic cell function prevents the onset of atopic dermatitis in NC/Tnd mice. J Allergy Clin Immunol 2011;127:420-9, e1-6. 7. Balato N, Nino M, Patruno C, Matarese G, Ayala F. ‘‘Eczemas’’ and leptin. Dermatitis 2011;22:320-3. 8. Rico L, Del Rio M, Bravo A, Ramirez A, Jorcano JL, Page MA, et al. Targeted overexpression of leptin to keratinocytes in transgenic mice results in lack of skin phenotype but induction of early leptin resistance. Endocrinology 2005;146: 4167-76. 9. Behshad R, Cooper KD, Korman NJ. A retrospective case series review of the peroxisome proliferator-activated receptor ligand rosiglitazone in the treatment of atopic dermatitis. Arch Dermatol 2008;144:84-8. 10. Hino R, Kobayashi M, Mori T, Orimo H, Shimauchi T, Kabashima K, et al. Inhibition of T helper 2 chemokine production by narrowband ultraviolet B in cultured keratinocytes. Br J Dermatol 2007;156:830-7. Available online December 21, 2012. http://dx.doi.org/10.1016/j.jaci.2012.11.010
Prophylactic therapy in children with hereditary angioedema To the Editor: Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is characterized by paroxysms of edema formation in the subcutis and/or the submucosa.1 In 50% of patients, symptoms first occur during childhood or adolescence. Timely diagnosis and appropriate management are essential because of the severe consequences of edema formation.2
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Management comprises therapy of attacks and prevention of their recurrence. Prophylaxis is a challenge for the clinicians, because of the narrow range of suitable medications and their poor safety profile, especially in children. Only case reports3 and review articles4,5 have been published to date on the prophylactic treatment of pediatric patients with HAE, and reports on long-term follow-up studies of larger populations are lacking. International guidelines provide only meager advice on the management of children.6 Our objective was to present the algorithm we have designed, in observance of international recommendations, to guide the therapy of HAE. A prospective analysis was conducted in 48 pediatric patients with HAE aged younger than 18 years. The study design is described (see this article’s Methods section in the Online Repository at www.jacionline.org). The patient group included 23 boys and 25 girls, 43 with type I and 5 with type II HAE. Their mean age at diagnosis was 7.6 years (range, 1-17 years). In 63% of these cases, the symptoms of HAE first occurred before 6 years of age, both in girls and in boys. Patients were followed from diagnosis until the age of 18 years. The presented treatment regimen summarizes the experience of 24 years (1986-2010). During the first year after diagnosis, 29 patients did not receive prophylaxis, 10 patients received intermittent prophylaxis (IMP), and 9 patients underwent long-term prophylaxis (LTP) with antifibrinolytics. The following is a discussion of the therapy since diagnosis. Twenty-nine of the 48 patients were symptom-free at diagnosis. On reevaluating the frequency and severity of the manifestations 1 year later, 7 of 29 patients needed antifibrinolytic treatment: 4 received IMP and 3 received LTP with tranexamic acid (TXA). During the second year, 2 of the 3 patients who received LTP with TXA were switched to danazol, because of an increased number of attacks (Fig 1, A). Compared with before treatment initiation, HAE attacks did not occur or followed a milder course and their duration halved during IMP with TXA initiated in 10 patients at diagnosis. In this group, the mean yearly attack number decreased from 6.8 (range, 2-36) to 4.5 (range, 1-12) after introducing therapy. In the first year, 3 of these patients were switched to LTP (1 to TXA, and 2 to danazol; Fig 1, B). In the second year, 2 of these 3 patients also received IMP with human plasma-derived C1-INH (hpdC1INH) concentrate (Berinert; CSL Behring, Marburg, Germany) as described below. Until now, they have not required further prophylactic treatment. Patient 1: Unwanted pregnancy occurred in a 15-year-old girl on LTP with TXA, which no longer controlled her attacks. We introduced intermittent substitution of hpdC1-INH concentrate (500 IU given twice weekly) for the first trimester of pregnancy, and, subsequently, attacks occurred less frequently (Fig 1, B). Patient 2: Although this patient did not experience attacks initially during LTP with danazol, the number of attacks increased subsequently. In addition, the patient developed erythrocytosis, polycythemia, thrombocytopenia, and became aggressive. We discontinued danazol and introduced IMP with hpdC1-INH concentrate (500 IU once a week) for 2 months. During this period, only mild, cutaneous edema occurred occasionally, and hematologic abnormalities resolved after discontinuation of danazol (Fig 1, B). At diagnosis, 9 of the 48 patients were receiving LTP with antifibrinolytics for frequent and severe symptoms: 2 were taking
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epsilon-aminocaproic acid and 7 were taking TXA. In this group, the mean yearly attack number decreased from 6.2 (range, 3-12) to 3 (range, 1-10) when introducing therapy on diagnosis. One year later, 5 of these 9 patients were switched from antifibrinolytics to long-term danazol therapy, because of adverse effects (2 patients) or an increased frequency of symptoms (3 patients) (Fig 2). During the second year, TXA was replaced with danazol in an additional 2 patients, because of adverse reactions or unsatisfactory efficacy (Fig 1, C). Additional results are described (see this article’s Results section in the Online Repository at www. jacionline.org). In the whole population of pediatric patients with HAE 60.4% (29/48) did not require prophylaxis after diagnosis, and 17 of 27 patients who received a diagnosis younger than age 6 years did not require prophylaxis; this was in agreement with the literature.6 At diagnosis, LTP was introduced in 18.7% (9/48) of patients, in case edematous attacks recurred frequently _1 attack per month), or the patient’s history contained life(> threatening episodes. This rate is in contrast with the management of adults, whereby 39% of our patients are receiving LTP. By the age of 18, 13 of 30 patients were receiving LTP (43%), which is similar to the rate seen in adults. According to the guidelines, antifibrinolytics are the agents of choice for prophylaxis in pediatric patients.6 Their use is seldom contraindicated; thrombophilia is the primary excluding factor. TXA had a good therapeutic effect in approximately one-third of our patients, similar to the results of Zanichelli et al.7 Nevertheless, because TXA is safer than attenuated androgens, the former was chosen to initiate prophylaxis in pediatric patients. Because TXA may not prove sufficiently effective, introducing anabolic androgens may be necessary in a proportion of cases.6 When administered at the lowest effective dose, danazol appeared well tolerated. IMP was preferred whenever allowed by the patient’s condition. During IMP with TXA in 22.9% (11/48) of our patients, edematous attacks did not occur or their duration and severity decreased. Considering that HAE is an uncommon disorder, our study is relatively large, because the data contain follow-up information from 48 patients. In our experience, the therapeutic modalities recommended for pediatric patients include the emergency therapy of attacks, as well as IMP with TXA or hpdC1-INH concentrate. We adopted individualized treatment, through many adjustments guided by regular monitoring, with the lowest effective drug doses. To obtain statistically homogeneous patient groups for comparison, these findings need confirmation in a large-scale, multicenter trial. Such a study might yield results that would justify reviewing the current treatment protocols. Henriette Farkas, MD, PhD, DSca Dorottya Csuka, MSca Zsuzsanna Zotter, MDa Lilian Varga, PhDa George F€ ust, MD, PhD, DSca From athe 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary. E-mail: [email protected]. Supported by the OTKA-NKTH 100886 grant (to H.F.). Disclosure of potential conflict of interest: H. Farkas has received research support from OTKA-NKTH; has received consultancy fees and travel support from Shire, Pharming, Viropharma, and CSL Behring; and has received lecture fees from Shire. D. Csuka has received travel grants from CSL Behring, Shire, and Viropharma. L. Varga has received travel support from CSL Behring and Shire. The rest of the authors declare that they have no relevant conflicts of interest.
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FIG 2. Therapeutic algorithm of prophylaxis in pediatric patients with HAE once the diagnosis had been established. The initial doses were based on a stepwise management strategy, for both the duration of treatment and the dose administered, as follows: intermittent or long-term TXA, 20 mg/kg per day; intermittent or long-term danazol, 100 mg every other day; and intermittent hpdC1-INH concentrate, 500 IU, 1-2 times/week (Berinert; CSL Behring, Marburg, Germany).
REFERENCES 1. Agostoni A, Aygoren-Pursun E, Binkley KE, Blanch A, Bork K, Bouillet L, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004;114(3 Suppl):S51-131. 2. Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 2006;119:267-74. 3. Barakat A, Castaldo AJ. Hereditary angioedema: danazol therapy in a 5-year-old child. Am J Dis Child 1993;147:931-2. 4. Sardana N, Craig TJ. Recent advances in management and treatment of hereditary angioedema. Pediatrics 2011;128:1173-80. 5. Farkas H, Varga L, Szeplaki G, Visy B, Harmat G, Bowen T. Management of hereditary angioedema in pediatric patients. Pediatrics 2007;120:e713-22. 6. Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Zuraw B, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol 2010;6:24. 7. Zanichelli A, Vacchini R, Badini M, Penna V, Cicardi M. Standard care impact on angioedema because of hereditary C1 inhibitor deficiency: a 21-month prospective study in a cohort of 103 patients. Allergy 2011;66:192-6. Available online September 24, 2012. http://dx.doi.org/10.1016/j.jaci.2012.08.001
TGF-b1 polymorphisms and asthma severity, airway inflammation, and remodeling
:
To the Editor: The development and progression of asthma are determined by multiple genetic and environmental factors. A relatively new hypothesis is that chronic injury by environmental irritants and/or
defective repair of the airway epithelium leads to the release of cytokines and growth factors.1 These factors drive chronic airway inflammation and remodeling seen in asthma. Airway inflammation and remodeling are 2 important pathologic features associated with airway hyperresponsiveness (AHR) and fixed airflow obstruction.2 TGF-b1 is a cytokine whose level increases in asthma.3 It is involved in airway pathology.4 The release of TGF-b1 in the submucosa, mainly by eosinophils, is stimulated by environmental factors such as allergens and cigarette smoke. Experimental studies show that exposure to cigarette smoke increases TGFB1 gene expression5 and decreases eosinophil migration in the airway.6 Single nucleotide polymorphisms (SNPs) in the TGFB1 gene have been associated with asthma development, yet only a few studies have investigated associations with asthma severity and the underlying airway inflammation7 and none with FEV1 decline and airway remodeling in asthma. Our aim was to investigate associations between TGFB1 SNPs and asthma severity (ie, AHR, FEV1 level, asthma remission, FEV1 decline) and features of airway wall inflammation and remodeling in 2 asthma populations. In addition, we assessed interactions between TGFB1 SNPs and smoking. Details on the clinical assessment, outcome definitions, immunochemistry and quantification procedures, genotypic information, and statistical analysis are presented in this article’s Online Repository at www.jacionline.org. The study was approved by the
FIG 1. This flowchart represents our management strategy during the initial 2 years after diagnosis. A, Follow-up of patients not receiving treatment at the time of diagnosis. B, Follow-up of patients undergoing IMP with antifibrinolytics at the time of diagnosis. C, Follow-up of patients undergoing LTP with antifibrinolytics at the time of diagnosis. Dg, Diagnosis; EACA, epsilon-aminocaproic acid; Hct, hematocrit; hpdC1-INH concentrate, human plasma-derived C1-INH concentrate; RBC, red blood cell.
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METHODS Study design After diagnosis, we asked the patients and their relatives to record disease symptoms to accumulate clinical information on the frequency, severity, duration, and localization of attacks, as well as on their triggering factors. Data on the symptoms were collected from patient diaries and medical charts. When a new drug was introduced, the patient was requested to record the name and dosage of the medication continuously, in the diary. In addition, patients were asked to record the consumption of hpdC1-inhibitor concentrate (Berinert; CSL Behring, Marburg, Germany) used either during attacks or as prophylaxis. hpdC1-inhibitor concentrate has been available in Hungary since 1986 (authorized for marketing in 1996). The clinical data thus obtained, as well as the findings of laboratory and imaging studies, were entered into the National HAE Registry. Follow-up visits were scheduled at 6-month to 1-year intervals. Patients on intermittent or long-term prophylaxis were examined as follows. In case of danazol prophylaxis, laboratory tests (complete blood count, liver and renal function tests, blood coagulation, serum lipid profile, and urinalysis) were repeated initially at 3-month intervals. Abdominal ultrasound scanning was performed semiannually during the first 2 years of treatment. Subsequently, asymptomatic persons or patients with mild symptoms were checked every 6 to 12 months to detect potential liver damage. Anthropometric assessments of growth were repeated every 6 months (comparison of body height and weight development to age-specific reference values and bone age determination with hand x-rays, when necessary). In addition, the development of secondary sexual characteristics, somatic and mental parameters, as well as the time of the onset of puberty, were compared with a control population. The somatic development of children with HAE was monitored regularly by family pediatricians, and the medical professionals employed by educational institutions. The tool used for this purpose was a percentile calculator that was based on reference data from the National Longitudinal Child Development Study conducted in Hungary. In case of prophylaxis with antifibrinolytics, complete blood count, liver and renal function tests, blood coagulation, creatine kinase level, and urinary parameters were monitored just as with danazol. An ophthalmology review was performed semiannually during the initial 2 years of treatment and annually thereafter. In case of intermittent prophylaxis with hpdC1-INH concentrate, virus serology tests for blood-borne pathogens (hepatitis B and C, HIV, parvovirus B19) were performed at baseline and during follow-up, at the annual control visits.
Treatment The national HAE protocol, developed by our center, has been in use since 1992 for the diagnosis, management, and follow-up of patients. The therapeutic strategy was reassessed at the annual control visits. 1. Long-term prophylaxis (LTP) _1 We recommended LTP if the edematous attacks recurred frequently (> attack per month), or the patient’s history contained life-threatening episodes. An antifibrinolytic was proposed as the initial choice, unless the use of this agent was contraindicated. a) Tranexamic acid (TXA) TXA (Exacyl; Sanofi-Synthelabo Produtos Farmaceuticos SA, Porto Salvo, Portugal) 20 to 40 mg/kg initial daily was administered in 2 or 3 divided doses (maximum of 3 g/day). Epsilon-aminocaproic acid (EACA; 0.17-0.43 g/kg daily) had been used previously, when TXA was not yet available. The efficacy of these drugs was similar; however, EACA was not tolerable by the patients because of gastrointestinal side effects. Antifibrinolytics were avoided in suspected, active thromboembolic disease, or if the family history was positive for thrombophilia.
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Treatment was initiated with the lowest available dose of danazol (100 mg) taken every other day and titrated to the lowest effective maintenance dose (range, 33-200 mg/day, administered every 1-3 days). Potential adverse effects, such as decreased growth rate, hirsutism, behavioral disturbances, menstruation irregularities during puberty, myalgia, headache, elevation of serum transaminase levels, and changes of the lipid profile, were monitored. 2. We chose intermittent prophylaxis (IMP) a) in cases, with an increasing number and severity of edematous attacks (in comparison with that experienced previously), where the suspected underlying cause of this change was transient or could not be eliminated immediately; as well as b) when the patient was entering a period of increased attack frequency (examinations, flu season, wintertime, family crises, puberty, pregnancy). Medicinal products conventionally used for LTP were administered but for shorter periods of time (the median duration of IMP was 2 weeks and the range was 1-12 weeks) occasionally in combination with intermittent hpdC1-INH concentrate substitution (500 IU 1-2 times/week; maximum, 1000 IU 2 times/week). In addition, IMP with hpdC1-INH concentrate was introduced when the discontinuation of danazol became necessary because of the lack of effect or the occurrence of undesirable effects. IMP is not mentioned in the international guidelines, although this term was used in relation to danazol treatment by Agostoni et al in 1978.E1 3. Alternative short-term prophylaxis was started 1 to 2 days before the expected date of each menses and continued for a week.
RESULTS In the case of 30 patients, the observation period ended because these subjects turned 18 years of age. At this time, 3 of them were receiving an antifibrinolytic, and 10 were taking danazol for LTP. In our pediatric patient population, the mean age of patients starting prophylactic treatment with androgens was 11.4 years (range, 5-18 years). These 10 patients received danazol for an average of 5.8 years, in a mean dose of 86 mg/day, whereas the 3 other patients received antifibrinolytics for 2.5 years on average, in a mean dose of 1262 mg/day. The patients were followed for 6 years (range, 1-12 years) on average (median duration of follow-up was 7 years [interquartile range, 4-9 years]) from diagnosis until they turned 18 years of age. Nine patients had never received IMP/LTP during follow-up. The distribution of therapies in the individual age groups is shown in Table E1. In regard to the safety profile of the medicinal products administered, some patients taking antifibrinolytics experienced gastrointestinal symptoms (such as abdominal discomfort, diarrhea, stomach ache, nausea), whereas irregular menstruation, erythrocytosis, polycythemia, and thrombocytopenia occurred in subjects who received danazol. Two of 17 patients (12%) taking TXA, 2 of 2 patients (100%) on EACA, and 2 of 11 patients (18%) receiving danazol experienced adverse events. Compared with the age-specific percentiles of the Hungarian population, the somatic and mental development, the time of the appearance of secondary sexual characteristics, and the onset of puberty were normal in all patients taking danazol for LTP. Adverse events or seroconversion (regarding the viruses listed earlier) did not occur after treatment with hpdC1-INH concentrate.
b) Danazol (Danoval; KRKA, Novo Mesto, Slovenia) If antifibrinolytics failed to mitigate the frequency and severity of symptoms or caused serious adverse effects, we introduced an attenuated androgen.
REFERENCE E1. Agostoni A, Marasini B, Cicardi M, Martignoni GC. Intermittent therapy with danazol in hereditary angioedema. Lancet 1978;1:453.
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TABLE E1. Distribution of therapies administered at specific ages
LTP with danazol LTP with TXA IMP with danazol IMP with TXA No prophylactic therapy
6 Years of age, no.
12 Years of age, no.
18 Years of age, no.
3 2 0 5 17
8 4 0 12 6
10 3 4 9 4
J ALLERGY CLIN IMMUNOL VOLUME 131, NUMBER 2
claudin 8 (CLDN8), leptin (LEP), and peroxisome proliferatoractivated receptor g (PPARG), with the latter 2 known to have important roles in lipid metabolism and immune activation. To determine functional sets of genes that were altered with NB-UVB, we measured the average improvement for canonical pathways using the Gene Set Enrichment Analysis software from the Molecular Signatures Database (see Table E3 in this article’s Online Repository at www.jacionline.org). Pathways with less than 75% improvement include the cytokine and cytokine receptor interaction and chemokine receptor pathways, which improved by 67% and 58%, respectively. The PPAR signaling pathway, which is involved in lipid signaling, cellular proliferation and differentiation, and inflammatory responses, improved by only 30%. We further detected lack of improvement in selected structural genes through immunohistochemical staining (Fig 1, B-E), which contrasts with the clinical resolution of AD lesions (Fig 1, A). Levels of AQP7, an aquaglyceroporin similar to AQP3, an important determinant of epidermal hydration,4 are decreased in AD lesions and do not return to normal levels with treatment (Fig 1, B). CLDN8, a tight junction protein, also lacks improvement (Fig 1, C). Tight junction proteins (ie, claudin 1) are downregulated in patients with AD, contribute to barrier dysfunction, and inversely correlate with TH2 activation.5 PPARG, which has emerged as an important structural element with reduced expression in patients with AD and a functional negative immune regulator of DCs in the onset of AD,6 does not improve to normal levels (Fig 1, D). Leptin, another structural protein primarily involved in lipid metabolism, shows decreased epidermal expression and increased dermal cellular expression that did not return to normal levels (Fig 1, E-F). Leptin is a known pleotropic cytokine that binds to its receptor on all immune cells, upregulates adhesion molecules, induces release of cytokines and chemokines, and stimulates proliferation and survival of various immune cells.7 The reduced epidermal leptin might have no effect on the skin, as suggested by transgenic mice studies,8 or could potentially contribute to increased fatty acid oxidation in the epidermal barrier, whereas the increased dermal expression (Fig 1, F) likely promotes immune activation after treatment. Lesions with clinical resolution after NB-UVB treatment maintain a residual genomic disease phenotype, with incomplete suppression of inflammatory mediators and residual structural and lipid abnormalities (Table I) contributing to persistent epidermal deficits. This RDGP should be considered in the development of AD treatments. For example, the concomitant use of PPARG activators (ie, thiazolidinediones), which have demonstrated efficacy in AD,9 could be considered. Although some of these residual changes might be specific to NB-UVB treatment, which has known effects on keratinocytes,10 it is crucial to define and compare RDGP across various therapeutic agents. It is important to note, as seen in Fig 1, G, that although lesional AD skin significantly improved compared with nonlesional skin, both lesional and nonlesional skin demonstrate minor improvement compared with normal skin (see Tables E4 and E5 in this article’s Online Repository at www.jacionline.org), representing a ‘‘background’’ phenotype that must also be considered in the development of AD therapeutics. Without specifically targeting background skin, as well as the RDGP of AD, lesions will likely continue to recur after treatment. Mayte Su arez-Fari~ nas, PhDa,b* Julia K. Gittler, BAa,c*
Avner Shemer, MDd Irma Cardinale, MSca James G. Krueger, MD, PhDa Emma Guttman-Yassky, MD, PhDa,e* From athe Laboratory for Investigative Dermatology and bthe Center for Clinical and Translational Science, Rockefeller University, New York, NY; cAlbert Einstein College of Medicine, Bronx, NY; dthe Department of Dermatology, Tel-Hashomer Hospital and Tel-Aviv University, Tel Aviv, Israel; and ethe Department of Dermatology, Mount Sinai School of Medicine, New York, NY. E-mail: [email protected]. *These authors contributed equally to this work. J.G.K. and M.S.-F. were supported by grant no. 5UL1RR024143-02 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research. E.G.-Y. was supported by the Dermatology Foundation Physician Scientist Career Development Award. Disclosure of potential conflict of interest: J. G. Krueger has been a consultant for Janssen, Eli Lilly, and Pfizer; has received grants or has grants pending for anti-TNF from Amgen, anti-p40 and anti–IL-23 from Janssen, anti–IL-17 from Eli Lilly, anti–IL-23 from Merck, and CP690, 550 from Pfizer. E. Guttman-Yassky has received grants from the Dermatology Foundation, Regeneron, and Merck to the Mount Sinai School of Medicine and has been a consultant for Regeneron, Celgene, Merck, Pfizer, and Stiefel. The rest of the authors declare that they have no relevant conflicts of interest.
REFERENCES 1. Tintle S, Shemer A, Suarez-Fari~nas M, Fujita H, Gilleaudeau P, Sullivan-Whalen M, et al. Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response. J Allergy Clin Immunol 2011;128:583-93, e1-4. 2. Suarez-Farinas M, Fuentes-Duculan J, Lowes MA, Krueger JG. Resolved psoriasis lesions retain expression of a subset of disease-related genes. J Invest Dermatol 2011;131:391-400. 3. Suarez-Fari~nas M, Tintle S, Shemer A, Chiricozzi A, Nograles K, Cardinale I, et al. Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities. J Allergy Clin Immunol 2011; 127:954-64, e1-4. 4. Verkman AS. Aquaporins: translating bench research to human disease. J Exp Biol 2009;212:1707-15. 5. De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, et al. Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol 2011;127:773-86, e1-7. 6. Jung K, Tanaka A, Fujita H, Matsuda A, Oida K, Karasawa K, et al. Peroxisome proliferator-activated receptor g-mediated suppression of dendritic cell function prevents the onset of atopic dermatitis in NC/Tnd mice. J Allergy Clin Immunol 2011;127:420-9, e1-6. 7. Balato N, Nino M, Patruno C, Matarese G, Ayala F. ‘‘Eczemas’’ and leptin. Dermatitis 2011;22:320-3. 8. Rico L, Del Rio M, Bravo A, Ramirez A, Jorcano JL, Page MA, et al. Targeted overexpression of leptin to keratinocytes in transgenic mice results in lack of skin phenotype but induction of early leptin resistance. Endocrinology 2005;146: 4167-76. 9. Behshad R, Cooper KD, Korman NJ. A retrospective case series review of the peroxisome proliferator-activated receptor ligand rosiglitazone in the treatment of atopic dermatitis. Arch Dermatol 2008;144:84-8. 10. Hino R, Kobayashi M, Mori T, Orimo H, Shimauchi T, Kabashima K, et al. Inhibition of T helper 2 chemokine production by narrowband ultraviolet B in cultured keratinocytes. Br J Dermatol 2007;156:830-7. Available online December 21, 2012. http://dx.doi.org/10.1016/j.jaci.2012.11.010
Prophylactic therapy in children with hereditary angioedema To the Editor: Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is characterized by paroxysms of edema formation in the subcutis and/or the submucosa.1 In 50% of patients, symptoms first occur during childhood or adolescence. Timely diagnosis and appropriate management are essential because of the severe consequences of edema formation.2
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Management comprises therapy of attacks and prevention of their recurrence. Prophylaxis is a challenge for the clinicians, because of the narrow range of suitable medications and their poor safety profile, especially in children. Only case reports3 and review articles4,5 have been published to date on the prophylactic treatment of pediatric patients with HAE, and reports on long-term follow-up studies of larger populations are lacking. International guidelines provide only meager advice on the management of children.6 Our objective was to present the algorithm we have designed, in observance of international recommendations, to guide the therapy of HAE. A prospective analysis was conducted in 48 pediatric patients with HAE aged younger than 18 years. The study design is described (see this article’s Methods section in the Online Repository at www.jacionline.org). The patient group included 23 boys and 25 girls, 43 with type I and 5 with type II HAE. Their mean age at diagnosis was 7.6 years (range, 1-17 years). In 63% of these cases, the symptoms of HAE first occurred before 6 years of age, both in girls and in boys. Patients were followed from diagnosis until the age of 18 years. The presented treatment regimen summarizes the experience of 24 years (1986-2010). During the first year after diagnosis, 29 patients did not receive prophylaxis, 10 patients received intermittent prophylaxis (IMP), and 9 patients underwent long-term prophylaxis (LTP) with antifibrinolytics. The following is a discussion of the therapy since diagnosis. Twenty-nine of the 48 patients were symptom-free at diagnosis. On reevaluating the frequency and severity of the manifestations 1 year later, 7 of 29 patients needed antifibrinolytic treatment: 4 received IMP and 3 received LTP with tranexamic acid (TXA). During the second year, 2 of the 3 patients who received LTP with TXA were switched to danazol, because of an increased number of attacks (Fig 1, A). Compared with before treatment initiation, HAE attacks did not occur or followed a milder course and their duration halved during IMP with TXA initiated in 10 patients at diagnosis. In this group, the mean yearly attack number decreased from 6.8 (range, 2-36) to 4.5 (range, 1-12) after introducing therapy. In the first year, 3 of these patients were switched to LTP (1 to TXA, and 2 to danazol; Fig 1, B). In the second year, 2 of these 3 patients also received IMP with human plasma-derived C1-INH (hpdC1INH) concentrate (Berinert; CSL Behring, Marburg, Germany) as described below. Until now, they have not required further prophylactic treatment. Patient 1: Unwanted pregnancy occurred in a 15-year-old girl on LTP with TXA, which no longer controlled her attacks. We introduced intermittent substitution of hpdC1-INH concentrate (500 IU given twice weekly) for the first trimester of pregnancy, and, subsequently, attacks occurred less frequently (Fig 1, B). Patient 2: Although this patient did not experience attacks initially during LTP with danazol, the number of attacks increased subsequently. In addition, the patient developed erythrocytosis, polycythemia, thrombocytopenia, and became aggressive. We discontinued danazol and introduced IMP with hpdC1-INH concentrate (500 IU once a week) for 2 months. During this period, only mild, cutaneous edema occurred occasionally, and hematologic abnormalities resolved after discontinuation of danazol (Fig 1, B). At diagnosis, 9 of the 48 patients were receiving LTP with antifibrinolytics for frequent and severe symptoms: 2 were taking
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epsilon-aminocaproic acid and 7 were taking TXA. In this group, the mean yearly attack number decreased from 6.2 (range, 3-12) to 3 (range, 1-10) when introducing therapy on diagnosis. One year later, 5 of these 9 patients were switched from antifibrinolytics to long-term danazol therapy, because of adverse effects (2 patients) or an increased frequency of symptoms (3 patients) (Fig 2). During the second year, TXA was replaced with danazol in an additional 2 patients, because of adverse reactions or unsatisfactory efficacy (Fig 1, C). Additional results are described (see this article’s Results section in the Online Repository at www. jacionline.org). In the whole population of pediatric patients with HAE 60.4% (29/48) did not require prophylaxis after diagnosis, and 17 of 27 patients who received a diagnosis younger than age 6 years did not require prophylaxis; this was in agreement with the literature.6 At diagnosis, LTP was introduced in 18.7% (9/48) of patients, in case edematous attacks recurred frequently _1 attack per month), or the patient’s history contained life(> threatening episodes. This rate is in contrast with the management of adults, whereby 39% of our patients are receiving LTP. By the age of 18, 13 of 30 patients were receiving LTP (43%), which is similar to the rate seen in adults. According to the guidelines, antifibrinolytics are the agents of choice for prophylaxis in pediatric patients.6 Their use is seldom contraindicated; thrombophilia is the primary excluding factor. TXA had a good therapeutic effect in approximately one-third of our patients, similar to the results of Zanichelli et al.7 Nevertheless, because TXA is safer than attenuated androgens, the former was chosen to initiate prophylaxis in pediatric patients. Because TXA may not prove sufficiently effective, introducing anabolic androgens may be necessary in a proportion of cases.6 When administered at the lowest effective dose, danazol appeared well tolerated. IMP was preferred whenever allowed by the patient’s condition. During IMP with TXA in 22.9% (11/48) of our patients, edematous attacks did not occur or their duration and severity decreased. Considering that HAE is an uncommon disorder, our study is relatively large, because the data contain follow-up information from 48 patients. In our experience, the therapeutic modalities recommended for pediatric patients include the emergency therapy of attacks, as well as IMP with TXA or hpdC1-INH concentrate. We adopted individualized treatment, through many adjustments guided by regular monitoring, with the lowest effective drug doses. To obtain statistically homogeneous patient groups for comparison, these findings need confirmation in a large-scale, multicenter trial. Such a study might yield results that would justify reviewing the current treatment protocols. Henriette Farkas, MD, PhD, DSca Dorottya Csuka, MSca Zsuzsanna Zotter, MDa Lilian Varga, PhDa George F€ ust, MD, PhD, DSca From athe 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary. E-mail: [email protected]. Supported by the OTKA-NKTH 100886 grant (to H.F.). Disclosure of potential conflict of interest: H. Farkas has received research support from OTKA-NKTH; has received consultancy fees and travel support from Shire, Pharming, Viropharma, and CSL Behring; and has received lecture fees from Shire. D. Csuka has received travel grants from CSL Behring, Shire, and Viropharma. L. Varga has received travel support from CSL Behring and Shire. The rest of the authors declare that they have no relevant conflicts of interest.
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FIG 2. Therapeutic algorithm of prophylaxis in pediatric patients with HAE once the diagnosis had been established. The initial doses were based on a stepwise management strategy, for both the duration of treatment and the dose administered, as follows: intermittent or long-term TXA, 20 mg/kg per day; intermittent or long-term danazol, 100 mg every other day; and intermittent hpdC1-INH concentrate, 500 IU, 1-2 times/week (Berinert; CSL Behring, Marburg, Germany).
REFERENCES 1. Agostoni A, Aygoren-Pursun E, Binkley KE, Blanch A, Bork K, Bouillet L, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004;114(3 Suppl):S51-131. 2. Bork K, Meng G, Staubach P, Hardt J. Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 2006;119:267-74. 3. Barakat A, Castaldo AJ. Hereditary angioedema: danazol therapy in a 5-year-old child. Am J Dis Child 1993;147:931-2. 4. Sardana N, Craig TJ. Recent advances in management and treatment of hereditary angioedema. Pediatrics 2011;128:1173-80. 5. Farkas H, Varga L, Szeplaki G, Visy B, Harmat G, Bowen T. Management of hereditary angioedema in pediatric patients. Pediatrics 2007;120:e713-22. 6. Bowen T, Cicardi M, Farkas H, Bork K, Longhurst HJ, Zuraw B, et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol 2010;6:24. 7. Zanichelli A, Vacchini R, Badini M, Penna V, Cicardi M. Standard care impact on angioedema because of hereditary C1 inhibitor deficiency: a 21-month prospective study in a cohort of 103 patients. Allergy 2011;66:192-6. Available online September 24, 2012. http://dx.doi.org/10.1016/j.jaci.2012.08.001
TGF-b1 polymorphisms and asthma severity, airway inflammation, and remodeling
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To the Editor: The development and progression of asthma are determined by multiple genetic and environmental factors. A relatively new hypothesis is that chronic injury by environmental irritants and/or
defective repair of the airway epithelium leads to the release of cytokines and growth factors.1 These factors drive chronic airway inflammation and remodeling seen in asthma. Airway inflammation and remodeling are 2 important pathologic features associated with airway hyperresponsiveness (AHR) and fixed airflow obstruction.2 TGF-b1 is a cytokine whose level increases in asthma.3 It is involved in airway pathology.4 The release of TGF-b1 in the submucosa, mainly by eosinophils, is stimulated by environmental factors such as allergens and cigarette smoke. Experimental studies show that exposure to cigarette smoke increases TGFB1 gene expression5 and decreases eosinophil migration in the airway.6 Single nucleotide polymorphisms (SNPs) in the TGFB1 gene have been associated with asthma development, yet only a few studies have investigated associations with asthma severity and the underlying airway inflammation7 and none with FEV1 decline and airway remodeling in asthma. Our aim was to investigate associations between TGFB1 SNPs and asthma severity (ie, AHR, FEV1 level, asthma remission, FEV1 decline) and features of airway wall inflammation and remodeling in 2 asthma populations. In addition, we assessed interactions between TGFB1 SNPs and smoking. Details on the clinical assessment, outcome definitions, immunochemistry and quantification procedures, genotypic information, and statistical analysis are presented in this article’s Online Repository at www.jacionline.org. The study was approved by the
FIG 1. This flowchart represents our management strategy during the initial 2 years after diagnosis. A, Follow-up of patients not receiving treatment at the time of diagnosis. B, Follow-up of patients undergoing IMP with antifibrinolytics at the time of diagnosis. C, Follow-up of patients undergoing LTP with antifibrinolytics at the time of diagnosis. Dg, Diagnosis; EACA, epsilon-aminocaproic acid; Hct, hematocrit; hpdC1-INH concentrate, human plasma-derived C1-INH concentrate; RBC, red blood cell.
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METHODS Study design After diagnosis, we asked the patients and their relatives to record disease symptoms to accumulate clinical information on the frequency, severity, duration, and localization of attacks, as well as on their triggering factors. Data on the symptoms were collected from patient diaries and medical charts. When a new drug was introduced, the patient was requested to record the name and dosage of the medication continuously, in the diary. In addition, patients were asked to record the consumption of hpdC1-inhibitor concentrate (Berinert; CSL Behring, Marburg, Germany) used either during attacks or as prophylaxis. hpdC1-inhibitor concentrate has been available in Hungary since 1986 (authorized for marketing in 1996). The clinical data thus obtained, as well as the findings of laboratory and imaging studies, were entered into the National HAE Registry. Follow-up visits were scheduled at 6-month to 1-year intervals. Patients on intermittent or long-term prophylaxis were examined as follows. In case of danazol prophylaxis, laboratory tests (complete blood count, liver and renal function tests, blood coagulation, serum lipid profile, and urinalysis) were repeated initially at 3-month intervals. Abdominal ultrasound scanning was performed semiannually during the first 2 years of treatment. Subsequently, asymptomatic persons or patients with mild symptoms were checked every 6 to 12 months to detect potential liver damage. Anthropometric assessments of growth were repeated every 6 months (comparison of body height and weight development to age-specific reference values and bone age determination with hand x-rays, when necessary). In addition, the development of secondary sexual characteristics, somatic and mental parameters, as well as the time of the onset of puberty, were compared with a control population. The somatic development of children with HAE was monitored regularly by family pediatricians, and the medical professionals employed by educational institutions. The tool used for this purpose was a percentile calculator that was based on reference data from the National Longitudinal Child Development Study conducted in Hungary. In case of prophylaxis with antifibrinolytics, complete blood count, liver and renal function tests, blood coagulation, creatine kinase level, and urinary parameters were monitored just as with danazol. An ophthalmology review was performed semiannually during the initial 2 years of treatment and annually thereafter. In case of intermittent prophylaxis with hpdC1-INH concentrate, virus serology tests for blood-borne pathogens (hepatitis B and C, HIV, parvovirus B19) were performed at baseline and during follow-up, at the annual control visits.
Treatment The national HAE protocol, developed by our center, has been in use since 1992 for the diagnosis, management, and follow-up of patients. The therapeutic strategy was reassessed at the annual control visits. 1. Long-term prophylaxis (LTP) _1 We recommended LTP if the edematous attacks recurred frequently (> attack per month), or the patient’s history contained life-threatening episodes. An antifibrinolytic was proposed as the initial choice, unless the use of this agent was contraindicated. a) Tranexamic acid (TXA) TXA (Exacyl; Sanofi-Synthelabo Produtos Farmaceuticos SA, Porto Salvo, Portugal) 20 to 40 mg/kg initial daily was administered in 2 or 3 divided doses (maximum of 3 g/day). Epsilon-aminocaproic acid (EACA; 0.17-0.43 g/kg daily) had been used previously, when TXA was not yet available. The efficacy of these drugs was similar; however, EACA was not tolerable by the patients because of gastrointestinal side effects. Antifibrinolytics were avoided in suspected, active thromboembolic disease, or if the family history was positive for thrombophilia.
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Treatment was initiated with the lowest available dose of danazol (100 mg) taken every other day and titrated to the lowest effective maintenance dose (range, 33-200 mg/day, administered every 1-3 days). Potential adverse effects, such as decreased growth rate, hirsutism, behavioral disturbances, menstruation irregularities during puberty, myalgia, headache, elevation of serum transaminase levels, and changes of the lipid profile, were monitored. 2. We chose intermittent prophylaxis (IMP) a) in cases, with an increasing number and severity of edematous attacks (in comparison with that experienced previously), where the suspected underlying cause of this change was transient or could not be eliminated immediately; as well as b) when the patient was entering a period of increased attack frequency (examinations, flu season, wintertime, family crises, puberty, pregnancy). Medicinal products conventionally used for LTP were administered but for shorter periods of time (the median duration of IMP was 2 weeks and the range was 1-12 weeks) occasionally in combination with intermittent hpdC1-INH concentrate substitution (500 IU 1-2 times/week; maximum, 1000 IU 2 times/week). In addition, IMP with hpdC1-INH concentrate was introduced when the discontinuation of danazol became necessary because of the lack of effect or the occurrence of undesirable effects. IMP is not mentioned in the international guidelines, although this term was used in relation to danazol treatment by Agostoni et al in 1978.E1 3. Alternative short-term prophylaxis was started 1 to 2 days before the expected date of each menses and continued for a week.
RESULTS In the case of 30 patients, the observation period ended because these subjects turned 18 years of age. At this time, 3 of them were receiving an antifibrinolytic, and 10 were taking danazol for LTP. In our pediatric patient population, the mean age of patients starting prophylactic treatment with androgens was 11.4 years (range, 5-18 years). These 10 patients received danazol for an average of 5.8 years, in a mean dose of 86 mg/day, whereas the 3 other patients received antifibrinolytics for 2.5 years on average, in a mean dose of 1262 mg/day. The patients were followed for 6 years (range, 1-12 years) on average (median duration of follow-up was 7 years [interquartile range, 4-9 years]) from diagnosis until they turned 18 years of age. Nine patients had never received IMP/LTP during follow-up. The distribution of therapies in the individual age groups is shown in Table E1. In regard to the safety profile of the medicinal products administered, some patients taking antifibrinolytics experienced gastrointestinal symptoms (such as abdominal discomfort, diarrhea, stomach ache, nausea), whereas irregular menstruation, erythrocytosis, polycythemia, and thrombocytopenia occurred in subjects who received danazol. Two of 17 patients (12%) taking TXA, 2 of 2 patients (100%) on EACA, and 2 of 11 patients (18%) receiving danazol experienced adverse events. Compared with the age-specific percentiles of the Hungarian population, the somatic and mental development, the time of the appearance of secondary sexual characteristics, and the onset of puberty were normal in all patients taking danazol for LTP. Adverse events or seroconversion (regarding the viruses listed earlier) did not occur after treatment with hpdC1-INH concentrate.
b) Danazol (Danoval; KRKA, Novo Mesto, Slovenia) If antifibrinolytics failed to mitigate the frequency and severity of symptoms or caused serious adverse effects, we introduced an attenuated androgen.
REFERENCE E1. Agostoni A, Marasini B, Cicardi M, Martignoni GC. Intermittent therapy with danazol in hereditary angioedema. Lancet 1978;1:453.
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TABLE E1. Distribution of therapies administered at specific ages
LTP with danazol LTP with TXA IMP with danazol IMP with TXA No prophylactic therapy
6 Years of age, no.
12 Years of age, no.
18 Years of age, no.
3 2 0 5 17
8 4 0 12 6
10 3 4 9 4