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.     

The influence of patch tests with clobetasol propionate on adjacent patch test reactions

Contact allergy to corticosteroids now seems frequent among patients being patch tested. As corticosteroids are intrinsically anti-inflammatory, we investigated whether patch tests with a potent corticosteroid might suppress simultaneous adjacent patch test reactions to another allergen. Nickel-sensitive subjects were patch tested with an aqueous dilution series of nickel in duplicate, adjacent to patch tests with clobetasol propionate 1% in ethanol and with ethanol, respectively. Statistical evaluation of the results obtained in 2 different centers, using their own patch test techniques, did not reveal any suppression of the positive nickel patch test reactions.     

Detection of contact hypersensitivity to topical corticosteroids with hydrocortisone-17-butyrate

We showed earlier that most patients with contact dermatitis due to corticosteroids show cross-reactions when patch tested with hydrocortisone-17-butyrate (H-17-B). To test whether H-17-B could be used for detecting topical corticosteroid allergy, we screened patients undergoing routine patch testing with H-17-B. Patients with clearly allergic or doubtful/mildly irritant patch test reactions to H-17-B, and with a history suggesting topical corticosteroid allergy, were further tested with a large panel of steroid preparations. 20 out of 4039 patients (0.5%) showed definite allergic test reactions to corticosteroids. A further 165 patients with clinically suspected corticosteroid allergy were directly tested with a panel of steroid preparations; 14 patients showed positive patch test reactions. Altogether, 33 out of 34 patients with corticosteroid allergy had positive test reactions to H-17-B. Inclusion of 1.0% H-17-B in ethanol in the standard patch test series improves the diagnosis of topical corticosteroid hypersensitivity.     

FS14.6Oral lichenoid reactions and amalgams: no topographical relationship

Objective:  To study the usefulness of a trivalent gold salt, gold trichloride (GTC), as a marker for contact allergy to gold. Method: Patients patch test positive or negative to gold sodium thiosulfate (GSTS), 13 subjects of each, were patch‐tested with dilution series of GTC and equimolar concentrations of GSTS; each series started at 0.03 mM and contained 5 steps. In order to avoid false positive and false negative test reactions the salts were dissolved in an alkaline buffer and placed on van der Bend® polypropene chambers. The tests were applied for 48 h; reading was blinded and performed on D3 and D7.
Results:  Allergic reactions were observed in 9/13 gold‐allergic patients with GSTS and in 2/13 with GTC. The sum of positive reactions was 18 with GSTS and 5 with GTC. Primary toxic reactions: 0 with GSTS and 2 with GTC among the gold‐allergic patients; and 2 with GSTS and 1 with GTC among the controls.
Conclusion:  GTC can elicit positive patch test reactions in patients with gold allergy but to a lesser degree than GSTS. GTC cannot be recommended for patch testing.     

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.     

The benefit of patch testing with a corticosteroid at a low concentration.

BACKGROUND: Patch testing with corticosteroid marker molecules is advocated because testing with all available corticosteroids is impossible in clinical practice. Most commonly used are budesonide, tixocortol pivalate, and hydrocortisone-17-butyrate. We have been patch testing not only with the three markers, but also with two corticosteroid mixes, each consisting of different concentrations of the three markers. OBJECTIVE: We describe a patient allergic to tixocortol pivalate, who was diagnosed by using a lower patch test concentration that recommended, 0.1% in petrolatum, as well as a weak corticosteroid mix, 0.202%. METHODS: The patient was patch tested to a standard series, including the two corticosteroid mixes and its three constituents. RESULTS: None of the corticosteroid preparations were positive on the first ordinary reading day, day 3, whereas both tixocortol pivalate at 0.1% and the corticosteriod mix at 0.202% were positive on the second ordinary reading day, day 7, whereas all tested corticosteroids in the standard series gave positive reactions on d10. CONCLUSION: The possible benefit of patch testing with a corticosteroid at a low concentration is supported, as is the significance of late readings beyond D4.     

Screening for corticosteroid contact hypersensitivity

To evaluate which corticosteroids are most useful for the detection of corticosteroid contact allergy in our population, 2123 patients were patch tested with a series of 6 corticosteroids in parallel with a standard series, and other relevant investigations, 127 patients (5.98%) were allergic to one or more corticosteroids; 96 to tixocortol pivalate, 51 to hydrocortisone butyrate, 47 to budesonide, 11 to betamethasone valerate, 11 to clobetasone butyrate and 8 to clobetasol propionate, 511 patients with negative patch tests to the limited corticosteroid series were in addition tested to a further 12 corticosteroids; only 1 of these patients reacted to a corticosteroid. A combination of tixocortol pivalate and budesonide thus detected 91.3% of corticosteroid-allergic subjects. We believe that both these allergens should be included in the standard series and that there may be a case for extending this further.     

Clinical relevance of positive patch test reactions to the 26 EU-labelled fragrances

Background: Fragrance mix I (FM I) and fragrance mix II (FM II) in the European baseline series are used as screening tools for fragrance contact allergy. In 2005 the European Union (EU) required labelling of 26 fragrances when present in cosmetic products. INCI nomenclature is obligatory for such labelling.
Objectives: To describe frequencies of contact allergy to these 26 fragrance substances, and to evaluate clinical relevance of these positive reactions.
Methods: Three hundred and twenty patients with eczema suspected of being contact allergy to fragrances or cosmetics were patch tested with the EU-declared fragrance chemicals, FM I and FM II.
Results: There were 76 positive reactions in 33 patients. Most reactions were to hexyl cinnamal and hydroxyisohexyl 3-cyclohexene carboxaldehyde in 3.1%, followed by Evernia furfuracea (2.5%) and cinnamyl alcohol (2.5%). Twelve reactions to FM I and II were not confirmed by separate ingredients. Clinical relevance of positive reactions to fragrances was certain in 20/33 (61%).
Conclusions: 10.3% of the patients had positive patch tests in the EU-list. Hydroxyisohexyl 3-cyclohexene carboxaldehyde, a component of FM II, was the most frequent allergen, followed by Evernia furfuracea . Since Evernia furfuracea is not part of FM I or FM II, relevant reactions can be missed when only the European baseline series is used.     

Patch testing with budesonide in serial dilutions: the significance of dose,occlusion time and reading time*

Budesonide is advocated as a marker molecule for corticosteroid contact allergy. When patch testing corticosteroids, one must consider their sensitizing potential but also their anti-inflammatory properties, as well as the possibility of different time courses for such properties. The dose-response relationship for budesonide was therefore investigated with regard to dose, occlusion time, and reading time. 10 patients were patch tested with budesonide in ethanol in serial dilutions from 2.0% down to 0.0002% with occlusion times of 48, 24, and 5 h. Readings were on D2, D4, and D7. The 48-h occlusion picked up most positive reactors, 8/10. The D4 reading (48-h occlusion) detected most positive reactors, 8/10, and here 0.002% picked up most contact allergies. Late readings favoured high concentrations. The “edge effect” was noted for several concentrations at early readings. Due to the individual corticosteroid reactivity, the dose-response relationship and the time courses of the elicitation and the anti-inflammatory capacity, several features may be explained, i.e., that lower concentrations may detect budesonide allergy better at early readings, that patients with an “edge reaction” can have positive reactions to lower concentrations.     

Cross-reactivity patterns to budesonide

Allergic contact dermatitis from topical corticosteroids is not uncommon. Budesonide has been included in the European standard series as a marker for corticosteroid allergy, though little is known of its cross-reactivity with other corticosteroids. Twelve patients previously positive to budesonide on patch testing were given further patch and intradermal tests to a range of corticosteroids. Six patients previously negative to budesonide on patch testing were used as a control group. Budesonide cross-reacts with hydrocortisone-21-sodium phosphate and triamcinolone acetonide. Patients positive to budesonide should therefore avoid hydrocortisone and triamcinolone acetonide. Patch testing, unfortunately, is an inaccurate method of determining cross-reactivity patterns among corticosteroids.     

Topical corticosteroid allergy in an urban Australian centre

The reported prevalence of allergic contact dermatitis from topical corticosteroids in clinical populations, in the period 1993-2002, varied from 0.55 to 5.98%. This study is a retrospective analysis of 1153 individuals undergoing routine patch testing in an Occupational Dermatology Clinic in Melbourne, Australia. We report a rate of 0.52% for positive patch test reactions to 5 corticosteroids. Corticosteroids tested were betamethasone-17-valerate, budesonide, Diprosone cream (betamethasone diproprionate 0.05%) (Essex-Pharma, a division of Schering-Plough Pty Ltd, Sydney, Australia), tixocortol-21-pivalate and triamcinolone acetonide. Population characteristics were described using the MOAHL (M = percentage of males tested; O = occupational; A = atopics; H = patients with hand eczema; L = patients with leg ulcers or stasis eczema) index. Prescribing patterns, rate of referral and rate of relevant positive patch test reactions were characterized for the region. These results were compared to the rates of corticosteroid allergy and patch testing methodologies from published international studies. It was noted that many high-sensitization potential corticosteroids were not available in our region. Although a low percentage of leg ulcers and stasis dermatitis may be associated with a lower rate of corticosteroid allergy, this association may be confounded by regional factors such as prescribing habits and the local availability of corticosteroids. We conclude that the low rate of topical corticosteroid contact allergy reported by our clinic is associated with regional availability and prescribing practices and the scarcity of stasis dermatitis and leg ulcers in our clinic population.     

Patch,prick or intradermal tests to detect delayed hypersensitivity to corticosteroids?

Background. Contact allergy to topical corticosteroids is usually detected by patch testing. Objectives. This study compares the test results obtained with patch, prick and intradermal testing, to assess the most sensitive method for diagnosing corticosteroid hypersensitivity. Patients/Methods. Nineteen corticosteroid‐allergic subjects and three control subjects were included. Patch, prick and intradermal tests were performed with five commercial corticosteroid preparations, as well as with the respective active principles diluted in ethanol. The test readings were performed at different time points, i.e. at 8, 24, 48 and 96 hr, and at 7 days. Results. Patch tests with ethanolic preparations produced more positive reactions than the commercial ones. The intradermal tests became positive earlier than the patch tests, a concordance between patch and intradermal tests being found in 11/15 (two positive intradermal test results with negative patch test results and vice versa). However, several subjects developed skin atrophy (14/22) at intradermal injection sites. Conclusion. Patch testing with the active principles diluted in ethanol remains the diagnostic method of choice for the detection of delayed hypersensitivity to corticosteroids. Intradermal tests with late readings, despite detecting additional contact allergy cases, should not be routinely performed, because of an important risk of atrophy, particularly with corticosteroid suspensions.     

Relevance and reproducibility of patch-test reactions to corticosteroids

We present our patch test findings with dermatocorticosteroids during the period 1995-1999. We retrospectively studied the % of doubtful and positive reactions to each allergen in our corticosteroid series and assessed the relevance of these reactions. To assess reproducibility, we retested 15 patients with doubtful or positive reactions in 1999. The % of + or ++ reactions on D2-D3 and D7 ranged from 0.0% to 0.9% for most of the compounds tested. Hydrocortisone acetate 1% alc.abs./DMSO 50/50 showed a much higher % of positive reactions. Most of these reactions were not relevant and therefore probably due to the irritant nature of the vehicle. An overall reproducibility of 47.2% was obtained. 100.0% of the non-reproducible patch test reactions were not relevant. Definite relevance was much higher in the reproducible + or ++ reactions than in the reproducible doubtful reactions: 100.0% and 18.2%, respectively. We conclude that the mean % of + and ++ reactions to the corticosteroid series on D2-D3 is 0.5%, with an overall reproducibility of 47.2%. Tixocortol pivalate and budesonide proved to be important markers for dermatocorticosteroid allergy.     

FS02.8Patch testing with gold trichloride can give false test results

Background:  Hydrochloric acid is formed in water solutions of gold trichloride. Hydrochloric acid in contact with aluminium generates hydrogen gas which can reduce and transform trivalent gold to elemental gold.
Objective:  To investigate whether patch testing with aqueous gold trichloride can cause false positive (irritant) reactions in patients without contact allergy to gold and false negative reactions in patients with gold allergy.
Methods:  13 patients with and 13 patients without positive patch test reactions to gold sodium thiosulfate were tested with gold trichloride in 2 different vehicles, water and alkaline buffer, using 2 different test techniques, the Finn Chamber technique with aluminium chambers and van der Bend technique with polypropene chambers.
Results:  Irritant patch test reactions were obtained with aqueous gold trichloride tested in van der Bend chambers in 10 patients without gold allergy. In gold‐allergic patients no positive test reactions were obtained from aqueous gold trichloride in Finn chambers while 2 positive test reactions were obtained from gold trichloride in alkaline buffer tested in van der Bend chambers.
Conclusion:  If gold trichloride is patch tested in wrong vehicle and with wrong test technique irritant test reactions may occur which can be misinterpreted as positive allergic reactions in patients without gold allergy as well as negative reactions in patients with gold allergy.     

Investigation of contact allergy to dental metals in 206 patients

Background:  Contact allergy to dental materials is poorly understood; clinical manifestations are heterogeneous.
Objective:  To analyse positive patch test reactions to metals (as their alloys or salts) used in dentistry together with clinical symptoms and possible relevance to dental fillings.
Methods:  We retrospectively analysed 206 patients who underwent patch testing with metals used in dentistry because of suspected contact allergy to them.
Results:  Twenty-eight of 206 patients had positive patch test reactions to metals used in dentistry. The number of positive patch test reactions was highest for gold sodium thiosulfate, palladium chloride, and nickel sulfate ( n  = 10, respectively), followed by amalgam, ammoniated mercury, and cobalt chloride ( n  = 4, respectively) and amalgam-mixed metals (including copper, tin, zinc, and silicon), and ammonium tetrachloroplatinate ( n  = 1). Only 14 (7%) of 206 patients had a clinically relevant contact allergy with conditions of the oral mucosa ( n  = 7 with lichen planus and n  = 7 with stomatitis) and positive patch test reactions to dental metals containing the suspected allergen. Improvement of symptoms was assessed in one patient with amalgam contact allergy 2 weeks after removal of dental fillings.
Conclusions:  Clinically relevant contact allergies to dental metals are infrequent. Gold sodium thiosulfate and palladium chloride presented the most frequent contact allergens.     

Contact allergy to corticosteroids and Malassezia furfur in seborrhoeic dermatitis patients

Background Seborrhoeic dermatitis (SD) is a chronic skin disease, requiring long‐term treatment, which might promote sensitization. Malassezia furfur (Mf) plays an important role in seborrhoeic dermatitis. Objectives The aim of this study was to determine the frequency of contact sensitivity in SD patients. Patients and methods A total of 100 patients and 20 healthy controls (HC) were investigated: 50 suffering from SD with no previous local corticosteroid treatment (SDN), 50 SD patients treated with local corticosteroids (SDC). Mycological examination for Mf was performed. All patients were patch tested with the baseline standard, corticosteroid series, with 12 commercial corticosteroid preparations frequently used in Croatia; and also with Mf. Results Malassezia furfur was found in 44 (88%) SDN, 37 (74%) SDC, and in 4 (20%) HC; patch test reaction to Mf was positive in one SDN and in three SDC. Positive patch tests to standard allergens were observed in 17 (34%) SDN, 33 (66%) SDC and 2 (10%) HC. Patch tests to the corticosteroid series revealed positive reactions in 4 SDC and to commercial corticosteroids in seven patients, i.e. 2 SD and 5 SDC. Conclusions Patch tests to the baseline series and to both individual corticosteroid and commercial corticosteroid preparations should be performed in SD patients with persistent dermatitis, as contact‐allergic reactions may complicate their dermatitis. Sensitization to Mf was found to be infrequent.     

Contact allergy to corticosteroids in patients using inhaled or intranasal corticosteroids for allergic rhinitis or asthma.

BACKGROUND: Patients using topically applied corticosteroids are at risk of developing allergic contact hypersensitivity. OBJECTIVE: To assess prevalence of allergic contact hypersensitivity reactions to inhaled or intranasal corticosteroids. METHODS: A prospective study of 30 adult patients using inhaled or intranasal corticosteroids for conditions such as allergic rhinitis was performed. We used epicutaneous patch testing to determine the prevalence of allergic contact hypersensitivity to corticosteroids and common additives (propylene glycol and benzalkonium chloride) in inhaled and nasal corticosteroid preparations in this population. RESULTS: Of 30 patients, 4 (13%) had positive patch test results. 3 (10%) were allergic reactions and 1 (3%) was an irritant reaction. Half of the reactions were to a corticosteroid (budesonide) and half were to a common preservative in nasal preparations (benzalkonium chloride). CONCLUSION: This study supports other clinical evidence that contact dermatitis/mucositis from inhaled or intranasal corticosteroid products can occur. The corticosteroids or added agents such as preservatives can be causative and may result in allergic or irritant reactions, which can be relevant to clinical symptoms.     

Corticosteroids

Up to 5% of dermatitis patients are allergic to corticosteroids. Because such allergy may be difficult to suspect due to the anti-inflammatory action of the corticosteroid, markers for corticosteroid allergy should be present in any standard series. Budesonide and tixocortol pivalate are two such markers, and they seem to detect a majority of corticosteroid allergy. The patch test concentration for a given corticosteroid may be crucial. A false-negative reaction may follow despite the patient being allergic, if too high a test concentration is used, because of the anti-inflammatory action of the corticosteroid. Patch test readings must be performed not only on Day 3 or Day 4 but also on a late occasion, i.e., Day 7 after test application, also because the anti-inflammatory action may suppress an allergic reaction at an early reading. Once a patient has reacted to a corticosteroid, an extended corticosteroid series should be tested, so that information may be given on which corticosteroids to use and, above all, which corticosteroids to avoid.     

Results of routine patch testing with corticosteroid series in 2073 patients

The patch test results of 61 patients allergic to at least 1 corticosteroid molecule are presented. These contact allergies were detected by testing with several corticosteroids included in our standard patch test series between February 1988 and December 1990. Whenever possible, further investigations were conducted by means of a more complete corticosteroid series. We found corticosteroids to be the 7th most frequent allergen, positive results being obtained in 2.9% of all patients referred to our contact dermatitis unit. In this series, budesonide was the most common allergen and often gave simultaneous reactions with other corticosteroids.