Reactions to corticosteroids: some new aspects regarding cross-sensitivity

Patch test results obtained with corticosteroid allergic patients tested with a large corticosteroid series validated the earlier classification of corticosteroid molecules in four groups of cross-reacting molecules: i.e., group A (hydrocortisone type), group B (acetonides), group C (betamethasone type-non esterified) and group D (esters). The latter group can now be subclassified into 2 groups, i.e., group D1 (halogenated and with C16 substitution) and group D2 (the "labile" prodrug esters without the latter characteristics).     

C(16)-methyl corticosteroids are far less allergenic than the non-methylated molecules

Background. It has been confirmed that binding to amino acids in skin proteins takes place at C₂₁ after oxidation of the corticosteroid molecule, which gives to the constituents of the D‐ring an essential role in cross‐reactivity patterns. In 2000, Matura et al. subdivided the corticosteroid esters of the D‐group into two subgroups: D1, the ‘stable’ esters; and D2, the ‘labile’ esters. Recent data have indicated that non‐methylated corticosteroids selectively react with arginine to form stable cyclic adducts, which are probably implicated in sensitization to corticosteroids. Objectives. To compare the patch test results and reactivity of C₁₆‐methylated and non‐methylated corticosteroids. Methods. Three hundred and fifteen subjects with a proven corticosteroid contact allergy underwent patch testing with an extended corticosteroid series. Statistical analysis was performed with the Wilcoxon signed rank test to compare the number of reactions to molecules with and without C₁₆‐methyl substitution. Results. Positive patch test reactions to corticosteroid molecules without C₁₆‐methyl substitution groups A and D2, were, with statistical significance, much more frequently observed than to those with a C₁₆‐methyl group, groups D1 and C. Conclusions. C₁₆‐methyl substitution, interfering with protein binding, and halogenation, seem to reduce the allergenicity of corticosteroid molecules. Hence, when indicated, C₁₆‐methylated corticosteroids should be preferentially prescribed.     

Identification of cross-reaction patterns in allergic contact dermatitis from topical corticosteroids

Contact allergy to topical corticosteroids occurs more frequently than previously supposed. Cross-allergic phenomena are common. On the basis of a review of the literature and our own patch test data on 15 patients, we conclude that positive patchtests to corticosteroids occur approximately six to seven times more frequently in well-defined groups of structurally-related substances than between corticosteroids of different groups. An analogous substitution pattern on the steroid D-ring or the carbon side chain (C20, C21) seems to have a significant influence on the association of positive patchtest results. This is not the case for other structural variables, such as the presence of a double bond in the steroid A-ring or fluoride substitutions on the B-ring. The effect of other factors such as concomitant sensitization and steroid metabolism in the skin on the development of a corticosteroid polyallergy are analysed, and the specificity and sensitivity of cross-allergy phenomena are evaluated. These are important in the selection of a topical steroid in the future treatment of a corticosteroid sensitive patient.     

Pemphigoid gestationis: treatment by topical class I corticosteroid]

BACKGROUND: Systemic corticosteroid is the main treatment of severe forms of pemphigoid gestationis. We report a case of generalised pemphigoid gestationis successfully treated with very potent topical corticosteroid. CASE: A 37-year-old woman developed during her third pregnancy with a new partner an urticated generalised eruption associated with bullous lesions. The diagnosis of pemphigoid gestationis was confirmed by direct immunofluorescence which detected a linear C3 deposition along the basement membrane zone and the positivity of Herpes Gestationis Factor (10 units). Local treatment with potent corticosteroid (betamethasone dipropionate 0.05 p. 100) failed and the patient was successfully treated by clobetasol propionate 0.05 p. 100 cream. The infant, in good health, was not delivered prematurely. DISCUSSION: Severe form of pemphigoid gestationis are currently treated with 0.5 to 1 mg/kg/day of systemic corticosteroids, with maternal and pediatric possible side effects. As in bullous pemphigoid, this observation underlines the efficiency and good tolerance of very potent corticosteroid in severe forms of pemphigoid gestationis.     

Anti pruritic effects of topical crotamiton, capsaicin, and a corticosteroid on pruritogen-induced scratching behavior

Itch accompanies various skin diseases. As a number of mediators other than histamine can be involved in the itch sensation, H1 receptor antagonists are not necessarily effective in treating itch. External application of antipruritic drugs is occasionally used as an alternative therapy for pruritic skin conditions, such as pruritus on primary non-diseased, non-inflamed skin. Even so, the actual effects of these drugs on the itch sensation have yet to be studied in detail. To verify the antipruritic effects of crotamiton, capsaicin, and a corticosteroid on the itch sensation, we examined the inhibitory effects of these drugs on various pruritogen-induced scratching behaviors in mice. Topical application of 10% crotamiton moderately inhibited histamine-, serotonin-, and PAR-2 agonist-induced scratching behaviors. Topical capsaicin (0.025%) also exerted a moderate suppressive effect on histamine-, substance P-, and PAR-2 agonist-induced itch responses. Notably, topical corticosteroid (0.05% clobetasol propionate) remarkably inhibited the scratching behaviors induced by all of the pruritogenic agents tested. Therapeutic effects of capsaicin on substance P-induced pruritus did not seem to be mediated by desensitization of the TRPV1 (+) C fibers and/or by altered responsiveness of the mast cells. In addition, the antipruritic effects of crotamiton and corticosteroid appear to be, at least partly, associated with a TRPV1-independent pathway. This study examined the itch responses to pruritogens and demonstrated the mode of action of the externally applied antipruritic drugs.     

Reactions to other corticosteroids in patients with allergic contact dermatitis from hydrocortisone

It has been proposed that corticosteroid cross-reactions occur more frequently within structurally well-defined groups. To test this hypothesis we have compared the patch-test reactions to other corticosteroids in 96 patients allergic to hydrocortisone. We found that our data did not agree with the previously proposed classification. The presence of a substitution at the C₆ or C₉ position was the most important factor in determining whether a patient would be allergic to another corticosteroid. This information should facilitate the choice of an alternative corticosteroid in patients allergic to hydrocortisone, if facilities for patch testing to other corticosteroids are not available.     

Erythema-multiforme-like lesions from triamcinolone acetonide

Triamcinolone acetonide is a class B corticosteroid of Coopman et al. (1), characterized by a C16, C17-cis ketal or diol structure. To the best of our knowledge, only 3 cases of contact allergy to it have been reported (2, 3).     

Pharmacokinetics and ‘bioactivation’ of MPA

In order to display its pharmacological and therapeutic effects, a local corticosteroid has to be bioavailable at its target site in the skin. The intensity and duration of its activity depend on the time course of its concentration in the target tissue, the number of receptors within this, tissue and on the intrinsic pharmacological activity of the molecule respectively of its active metabolite(s). It is commonly accepted that the desired and the adverse corticosteroid effects are mediated by receptor mechanisms. Since all nucleated cells contain corticosteroid receptors with the same specifity yet in different numbers, a dissociation between wanted anti-inflammatory and unwanted local and systemic effects is not achievable at the receptor level. A certain dissociation seems to be possible pharmacokinetically: structural modification of the corticosteroid molecule, especially introduction of suitable side chains, can lead to high concentrations of the active principal at the site of the desired effect and to low levels at the site of undesired effects. In the following, the most important pharmacokinetic properties of methylprednisolonaceponate (MPA), the active ingredient of Advantan® are presented: MPA is a di-ester of the non-halogenated methylprednisolone with a propionate group at C-atom 17 and an acetate group at C-atom 21. The introduction of both ester groups increase markedly the lipophilicity of the molecule and thus penetration into the skin. In addition the acetate side chain at C21 prevents a so-called acyl-migration of the propionic acid from C17 to C21 and thus stabilizes the molecule. After penetration out of the formulation into the living skin, MPA is hydrolized by the esterases in the epidermis and dermis at position 21, leading to the formation of methylprednisolone-17-propionate (MP-17-Prop). MP-17-Prop binds more strongly to the corticosteroid receptor than the parent substance MPA and represents the active principle in the skin. This so-called ‘bioactivation’ proceeds distinctly faster in damaged and inflamed skin compared to healthy skin. After percutaneous absorption MP-17-Prop is inactivated by conjugation with glucuronic acid and is excreted mainly in the urine.     

Concurrent application of tretinoin (retinoic acid) partially protects against corticosteroid-induced epidermal atrophy

Summary Cutaneous atrophy arising from prolonged use of potent topical corticosteroids has long been a concern. Thus, it would be advantageous to find an agent which protects against atrophy produced by corticosteroids but at the same time does not impair their anti-inflammatory effects. Recent work shows that topical all- trans retinoic acid (tretinoin) prevents skin atrophy in mice treated with topical corticosteroids, but such studies have not been performed in humans. We performed an 8-week clinical, histological and biochemical study to test the ability of tretinoin to enhance efficacy and inhibit atrophogenicity of topical corticosteroids, when used in the treatment of psoriasis. In each of 20 psoriasis patients, one plaque, and its perilesional skin, was treated once daily with betamethasone dipropionate and tretinoin 0·1%, and one plaque, and its perilesional skin, treated with once daily betamethasone dipropionate and tretinoin vehicle. There was no difference in the speed or degree of improvement in plaques treated with either the topical corticosteroid/tretinoin combination or with corticosteroid alone. Light microscopy revealed a 19% reduction in epidermal thickness, in corticosteroid-treated perilesional skin, as compared with a slight (1%) increase in corticosteroid/ tretinoin-treated perilesional areas (P= 0.067). Western blot analysis showed a 55% reduction in procollagen I aminopropeptide in perilesional skin treated with corticosteroid alone, as compared with a 45% reduction in corticosteroid/tretinoin-treated perilesional skin. These data indicate that the addition of tretinoin does not impair the efficacy of a topical corticosteroid, in the treatment of psoriasis, and partially ameliorates epidermal atrophy produced by the topical corticosteroid.     

Contact allergy to corticosteroids in asthma/rhinitis patients

Patients with asthma and/or rhinitis, when using inhalers or nasal sprays containing corticosteroids, may experience mucosal symptoms, such as congestion of the nose, itching, nose bleeding and worsening of rhinitis, but also eczema of the face sometimes spreading to flexures, and sometimes the corticosteroid simply does not help. Few patients with such symptoms have been found to be allergic to their inhaled corticosteroids (1), and no report on whether contact allergy to corticosteroids could explain treatment failures is available. This issue was investigated in 2 ways: (i) by testing asthma/rhinitis patients for corticosteroid allergy, (ii) by looking at the prevalence of tixocortol pivalate allergy among dermatitis patients with and without asthma/rhinitis, respectively.     

Hypersensitivity to topical corticosteroids

Contact hypersensitivity from topical corticosteroids is becoming increasingly recognized; it is present in 2–5% of the patients attending contact dermatitis clinics. The use of a corticosteroid series containing tixocortal pivalate 1% (petrolatum), to detect hypersensitivity to hydrocortisone, and other steroids 1% (ethanol), depending on local corticosteroid usage, detects the majority of cases of corticosteroid hypersensitivity. In selected cases, the use of intradermal tests further improves the diagnosis of corticosteroid hypersensitivity. Corticosteroid hypersensitivity occurs most frequently among patients with stasis dermatitis. However, corticosteroid hypersensitivity is also common in other types of dermatitis, occurring as frequently as hypersensitivity to several allergens (e.g. wool alcohols and colophony) in the European standard battery. Although hypersensitivity has mainly been reported with corticosteroids applied to the skin, reactions may also occur on mucosal surfaces, following systemic administration and with sex steroids.     

Studies of blood histamine levels during topical corticosteroid therapy compared with those during systemically administered corticosteroids

Blood histamine levels during topical corticosteroid therapy have not been reported, although decreased blood histamine levels are known to occur after the systemic administration of corticosteroid. Blood histamine levels and serum 11-hydroxycorticosteroids (11-OHCS) after systemic corticosteroid were compared with those after topical corticosteroid. Both blood histamine and serum 11-OHCS levels decreased in a parallel and dose-dependent manner during systemic administration of 0.5-1.0 mg/day of betamethasone. Blood histamine levels increased and serum 11-OHCS levels decreased during systemic administration of 0.25 mg/day to the betamethasone and topical corticosteroid group. Changes in blood histamine levels in the topical corticosteroid group appeared between 0.25 and 0.5 mg/day of systemically administered betamethasone. Fifteen cases of dermatological inpatients suffering from wide-spread eczema or exfoliative dermatitis were treated with the topical corticosteroids betamethasone 17-valerate, budesonide and diflorasone diacetate. In each case, blood histamine levels were examined and an equipotent dose of oral administeration of betamethasone was calculated. Thirteen cases in whom blood histamine levels were measured fell into the dosage range from 0.1 to 0.5 mg/day. In each case, serum 11-OHCS levels were also examined and an equipotent dose of oral administration of betamethasone was calculated by the same method. Fourteen cases in whom serum 11-OHCS levels were measured compared to a dose of less than 1.0 mg/day of betamethasone. Blood histamine levels in rats treated with 20 or 50 mg/kg/day of prednisolone were decreased significantly, and peripheral total leukocytes, lymphocytes, neutrophils and basophils were also decreased significantly.     

Successful treatment of pemphigus vegetans by addition of etretinate to systemic steroids

Pemphigus vegetans is a rare variant of pemphigus vulgaris and is characterized by flaccid bullae, which become eroded and form vegetations or papillomatous proliferations, especially in the intertriginous areas. ¹ Oral administration of corticosteroids alone does not always induce disease remission in pemphigus vegetans. We report a 44-year-old Japanese man with pemphigus vegetans. Although corticosteroid therapy resulted in healing of the oral ulcers and skin bullae, verrucous vegetations continued to develop. In contrast, by combining corticosteroid with etretinate, verrucous vegetations improved. Thus we propose that the combination therapy of steroid and etretinate might be an effective adjunct in the therapy of pemphigus vegetans.     

Stevens-Johnson综合征及中毒性表皮坏死松解症61例回顾性分析

目的 探讨Stevens-Johnson综合征（SJS） 及中毒性表皮坏死松解症（TEN）患者的病因及治疗经验。方法 回顾性分析1994年7月至2007年5月确诊为SJS和TEN的61例患者的临床资料,根据治疗分为静脉滴注免疫球蛋白联合糖皮质激素组（简称IVIG组）16例及糖皮质激素组（简称激素组）45例,采用SCORTEN评分评价病情严重程度及预后。比较激素初始量、最大控制量、减量前激素总量、IVIG总量、激素减量前时间、住院时间等指标。结果 引起SJS和TEN常见致敏药物依次为非甾体抗炎药类（26例）、抗癫痫药（15例）、抗生素类（10例）,其中最多的为卡马西平（13例）。IVIG组SCORTEN评分（1.44 ± 1.21）显著高于激素组（0.80 ± 1.10）,两组差异有统计学意义（P < 0.05）。IVIG组减量前激素总量、减量前时间及住院治疗时间（分别为12.06 ± 4.32 mg/kg,7.81 ± 2.29 d,18.00 ± 5.92 d）与激素组（分别为12.52 ± 8.29 mg/kg,8.29 ± 4.18 d,21.07 ± 13.36 d）比较,差异均无统计学意义。11例SCORTEN评分等于2的患者联用IVIG及激素能使住院治疗时间从（27.57 ± 9.90） d缩短至（14.50 ± 2.38） d（P < 0.05）。IVIG组并发症发生率（43.8％）高于激素组（24.4％）（P < 0.05）。IVIG组与激素组实际死亡率分别为12.5％及4.4％,均低于预期死亡率（分别为12.9％及7.9％）。结论 激素及IVIG治疗SJS和TEN有效。     

家族性良性天疱疮患者ATP2C1基因突变研究

目的 探讨3个家族性良性天疱疮家系和1例散发患者的ATP2C1基因突变。方法 采取家系中患病成员外周血,应用外周血细胞DNA抽提、PCR扩增和DNA直接测序等方法检测ATP2C1基因突变情况,用反向测序验证突变,用100例无血缘关系个体作正常人对照。结果 在2个家族性良性天疱疮家系和1例散发患者中发现3个未曾报道的错义突变。家系1第20外显子2048位碱基G→A,导致错义突变R619K;家系2第8外显子853位碱基A→C,导致错义突变T221P;散发患者第23外显子2323位碱基T→C,导致错义突变Y711H。家系中非患病成员和100例无血缘关系正常人均未发现这些改变。在1个家族性良性天疱疮家系未检测到基因突变。结论 发现家族性良性天疱疮3种新的ATP2C1基因突变位点。     

Comparison of Serum Gastrin Levels during Topical and Systemic Administration of Corticosteroids

Serum gastrin levels did not change during topical corticosteroid therapy with an experimental dose of 20 to 60 g/day for seven consecutive days, and serum 11-hydroxycorticosteroid levels were significantly suppressed during the treatment. On the other hand, after daily oral administration of 1.5 mg/day betamethasone for seven consecutive days in volunteers who had fasted overnight, serum gastrin levels were higher and 11-hydroxycorticosteroid levels were significantly lower. Fasting serum gastrin levels were significantly increased in rats after intraperitoneal administration of prednisolone at dosages of 2, 10, 20, or 50 mg/kg/day, but they were not significantly altered after the administration of prednisolone at 0.5 mg/kg/day. Serum gastrin levels were not significantly altered in man or rats after the administration of a histamine H₁ receptor antagonist. Therefore, serum gastrin levels are apparently not influenced by topical corticosteroid treatment although they are altered after systemic corticosteroid administration.     

Patch testing with corticosteroid mixes in Europe. A multicentre study of the EECDRG

This study investigated whether a corticosteroid mix containing tixocortol pivalate, budesonide, and hydrocortisone-17-butyrate could detect contact allergy to corticosteroids. 2 corticosteroid mixes, 1 with a high (mix I) and 1 with a low (mix II) concentration and the 3 individual constituents, each at 2 concentrations, were inserted into the standard series of 16 participating clinics. Tests were read on day (D) 3 or 4. 5432 patients were tested, and 110 (2.0%) had positive reactions to at least 1 of the 8 test preparations. Of the 8 preparations, mix I identified most allergic patients, followed by mix II, budesonide 0.10%, budesonide 0.002%, and tixocortol pivalate, both concentrations (1.0 and 0.10%) tracing the same number. With the mixes, 53.2-59.6% of tixocortol pivalate allergy was missed. 47 patients were allergic to either concentration of tixocortol pivalate, 25% of these only to 1.0% and another 25% only to 0.10%. Testing with mix I and tixocortol pivalate 0.10% picked up 98/110, testing with tixocortol pivalate 1.0% and 0.10% and budesonide 0.10% picked up 105/110. 3379 patients were read on both D3 or D4 as well as on D7. Without a late reading (D7), up to 30% of contact allergy to corticosteroid markers was missed.     

Prevalence of and factors influencing sensitization to corticosteroids in a Danish patch test population

Background. Corticosteroids are used to treat dermatoses, including allergic contact dermatitis, but can also cause contact allergy. The frequency of corticosteroid allergy varies between studies and is influenced by treatment traditions and availability. Aim. To estimate the prevalence of tixocortol‐21‐pivalate, budesonide and hydrocortisone‐17‐butyrate allergy in a Danish patch test population and characterize individuals with corticosteroid allergy. Materials/methods. Three thousand five hundred and ninety‐four patients were patch tested with tixocortol‐21‐pivalate, budesonide, and hydrocortisone‐17‐butyrate. Characterization was performed according to the MOAHLFA index and duration of disease. Results. Two per cent had a steroid allergy: 0.8% had a tixocortol‐21‐pivalate allergy, 1% a budesonide allergy, and 1% a hydrocortisone‐17‐butyrate allergy. Tixocortol‐21‐pivalate and budesonide allergy were associated with atopic dermatitis in crude analyses, but only tixocortol‐21‐pivalate allergy and atopic dermatitis remained associated in adjusted analyses. Leg dermatitis was uniquely associated with tixocortol‐21‐pivalate allergy. Hydrocortisone‐17‐butyrate allergy was associated with duration of disease in both crude and adjusted analyses. Discussion/conclusion. Chronic dermatoses (atopic dermatitis and leg dermatitis) were identified as risk factors for group A corticosteroid allergy, probably because of more pronounced exposure to group A steroids resulting from ease of access that is exploited by patients with a chronic dermatosis. The duration of disease rather than the dermatosis itself seemed to be important for group B and D2 corticosteroid allergy.     

IMMUNE DEPOSITS IN THE SKIN OF REVERSED PASSIVE ARTHUS REACTION. THE EFFECTS OF THE ADMINISTRATION OF THE CORTICOSTEROID

The effects of corticosteroid administration on the immune deposits in the skin of reversed passive Arthus reaction (RPAR) using horseradish peroxidase as antigen were studied. Immune deposits were seen on vascular walls, on collagen fibers, at the dermo-epidermal junction, at perifollicular regions, on mononuclear cells and in PMN-leukocytes. By corticosteroid administration the amount of these immune deposits was most obviously reduced within the first 30 minutes after the induction of the RPAR. At 1, 4, 8, 24 and 48 hours after induction of the reaction there were no significant differences in the amount and the extent of the immune deposits on the vascular walls, on the collagen fibers and on the mononuclear cells, between the sections treated by corticosteroid and those of non-treated specimens. The infiltration of PMN-leukocytes and their uptake of immune complexes were maximum at 4 hours after the injection and the number of these infiltrated PMN-leukocytes and the amount of immune complexes which were taken by them were slightly reduced by corticosteroid administration.     

Cost‐efficacy and pharmacoeconomics of psoriatic patients in Japan: Analysis from a single outpatient clinic

Compared with topical corticosteroids, topical combined active vitamin D₃/corticosteroids and especially biologics are more expensive despite their marked efficacy in the treatment of psoriasis. The aim of the present study is to evaluate total costs as well as costs versus efficacy of various psoriasis treatments under the current Japanese health‐care insurance system. A prospective study was performed from the database of a single clinic located in Hokkaido Prefecture. Cost and quality of life of psoriatic patients were evaluated in a prospective manner during a total of 12 months from March 2017 until June 2018. Quality‐adjusted life year (QALY) of biologics was the highest among all treatments. Among the topical treatments, the cost versus efficacy of combined active vitamin D₃/corticosteroid was lowest (¥10 557/1 Psoriasis Area and Severity Index). Furthermore, incremental cost‐effectiveness ratio (ICER) of combined active vitamin D₃/corticosteroid was ¥1 024 031/QALY when compared with topical corticosteroid treatment alone. The topical combined active vitamin D₃/corticosteroid treatment showed the best cost‐efficacy in terms of medical economic burden.