COD
Contact Dermatitis • Original Article
Contact Dermatitis
Sensitization to omeprazole in the occupational setting Per Hamid Ghatan1 , Maritha Marcusson-Ståhl2 , Mihaly Matura3 , Carol Björkheden4 , Per Lundborg5 and Karin Cederbrant2 1 AstraZeneca,
OSHE Department, SE-151 85 Södertälje, Sweden, 2 Department of Molecular Toxicology/Immunotoxicology, Safety Assessment, AstraZeneca R&D, SE-151 85 Södertälje, Sweden, 3 Centre for Occupational and Environmental Medicine, Stockholm County Council, Solnavägen 4, SE-113 65 Stockholm and Institute of Environmental Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden, 4 Department of General Toxicology Sciences, Safety Assessment, AstraZeneca R&D, SE-151 85 Södertälje, Sweden, and 5 AstraZeneca R&D, SE-431 83 Mölndal, Sweden
doi:10.1111/cod.12305
Summary
Background. Omeprazole is a proton pump inhibitor for the treatment of gastric acid-related disorders. In recent years, reports of dermatitis upon exposure to omeprazole during manufacture have been noted. Objective. To present diagnostic findings in workers who reported suspected hypersensitivity reactions resulting from occupational exposure to omeprazole. Methods. Ninety-six workers exposed to omeprazole during the manufacturing process underwent investigation by the AstraZeneca Occupational Health Centre (Södertälje, Sweden) for suspected allergy. All subjects underwent a lymphocyte transformation test (LTT) and a skin test within 6 months of the clinical reaction. Predictive tests on guinea-pigs were conducted to establish omeprazole’s sensitizing potential. Results. Thirty-one subjects with clinical symptoms had a positive LTT result. Twenty-eight subjects had positive patch test results; of these, 23 also had a positive LTT result (sensitivity of the LTT: 82%). Fifty-six subjects had negative patch test results; 46 of these had a negative LTT result (specificity: 82%). All subjects who underwent prick testing (n = 18) had negative results. Delayed contact hypersensitivity was observed in 18 of 20 test animals. Conclusions. These findings confirm the risk of sensitization to omeprazole from occupational exposure. They are of importance for the development of new formulations of omeprazole, or its enantiomers, in light of the potential for inducing skin allergy. Key words: contact allergy; dermatitis; omeprazole; proton pump inhibitor.
Correspondence: Karin Cederbrant, Swedish Toxicology Sciences Research Center – Swetox, Forskargatan 20, 151 36 Södertälje, Sweden. Tel: +46 8 524 885 03. E-mail: [email protected] Conflict of interests: All authors apart from M. Matura were employees at AstraZeneca at the time when the data were collected. M. Matura has no conflicts of interest to declare. Statement of funding: No specific funding was given to finance this study. All investigations were performed as part of the regular procedure for diagnosing potential allergy in occupationally exposed workers at the AstraZeneca plant in Gärtuna, Sweden. The development of this article was funded
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 71, 371–375
Omeprazole (CAS no. 73590-58-6) is an oral proton pump inhibitor (PPI) for the treatment of gastric acid-related disorders such as reflux oesophagitis and peptic ulcer disease. It was originally launched in 1979, and > 1 billion treatment courses have been prescribed. From a dermatological perspective, adverse reactions such as dermatitis, pruritus and rash are uncommon side-effects of oral treatment (≥ 1/1000 to < 1/100) by AstraZeneca. Medical writing support was provided by Claire Byrne of inScience Communications, Springer Healthcare and funded by AstraZeneca. Accepted for publication 18 August 2014
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(1). However, in the occupational setting, a number of cases (including some recent cases) of dermatitis upon exposure to omeprazole during manufacture have been reported (2, 3). These reactions are probably explained by the strong skin-sensitizing capacity of this benzimidazole agent (4). Indeed, between 1989 and 1999, 96 workers who had been exposed to omeprazole during the manufacturing process directly contacted, or were referred to, the AstraZeneca Occupational Health Centre (Södertälje, Sweden) because of skin reactions on the face, hands, and neck. Other symptoms, such as rhinitis and conjunctivitis, were also observed. An interesting dichotomy therefore exists between the occupational setting, where omeprazole has been identified as a potential skin sensitizer (2, 3, 5), and the clinical setting, where few allergic reactions have been observed. The aim of this article is to present the diagnostic findings in 96 workers with suspected hypersensitivity reactions resulting from occupational exposure to omeprazole. These data were collected primarily for diagnostic purposes. The potential for skin allergy has been taken into consideration during development of the branded omeprazole formulation since the 1990s. It is important to highlight the potential of omeprazole to induce skin allergy, and this should be considered when new formulations of omeprazole or either of its enantiomers are developed. It should be noted that all data presented are the results of standard procedures used at the company at the time for occupationally exposed personnel with symptoms of hypersensitivity.
Materials and Methods Subjects
Between 1989 and 1999, 96 workers (mean age, 33 years) who reported possible hypersensitivity-type reactions/symptoms resulting from occupational exposure to omeprazole during the manufacturing process underwent investigation by AstraZeneca Occupational Health Centre (Södertälje, Sweden) for suspected allergy. The total number of employees working with omeprazole at AstraZeneca Södertälje during this time is unknown. Skin reactions constituted the primary presentation in the majority of individuals, but a few cases of ocular and nasopharyngeal reactions (suggesting type I allergic reactions) were also observed (Table 1). All subjects underwent a lymphocyte transformation test (LTT) and/or a skin test as described below, performed within 6 months of the clinical reaction. Other individuals who worked in the same occupational environment
372
Table 1. Symptoms observed in workers exposed to omeprazole
(n = 96a) Symptomsb
Number of subjects
Itchy/dry skin Erythema Oedema around the eyes Rhinitis Conjunctivitis Pruritus Urticaria Nasal congestion Swollen throat Fever Shortness of breath Swollen lips Dry skin
43 19 4 5 3 19 3 4 2 1 1 1 5
a Some subjects presented with more than one symptom. b Sixty-nine
subjects reported facial symptoms; 38 of these reported symptoms in the area around the eyes.
as the above-mentioned 96 subjects, and who had similar exposure but did not have hypersensitivity reactions, were asked to participate as healthy exposed controls. Twenty-one of these individuals (mean age, 41 years) agreed to give a blood sample and underwent an LTT, thereby acting as a ‘control’ group. Lymphocyte transformation test
The LTT was performed with the MELISA® (Memory Lymphocyte Immuno-Stimulation Assay) procedure (6). The sensitivity and specificity of the LTT were calculated with the patch test as a reference. ‘Sensitivity’ describes the true positive rate, that is, the proportion of positive subjects who were correctly identified as having an allergic response to omeprazole: Sensitivity = number of true positives (number of true positives + number of false negatives) ‘Specificity’, on the other hand, is used to describe the proportion of subjects who were correctly identified as having a negative response: Specificity = number of true negatives (number of true negatives + number of false positives) Patch tests
Patch testing was performed in 84 of the 96 subjects with Finn Chambers® on Scanpor® tape; occlusion was performed for 2 days (7). An omeprazole sodium salt in saline
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 71, 371–375
OCCUPATIONAL SENSITIZATION TO OMEPRAZOLE • GHATAN ET AL.
300
250
Stimulation index
solution at 0.1%, 0.5% and 1% was employed. One patch test reading was taken, and subjects removed the patches themselves after 48 hr. Reactions were evaluated by the dermatologist 24 hr later, and were rated as either ‘positive’ or ‘negative’. These tests were performed between 1989 and 1999. Prick testing was also performed in 18 subjects who reported symptoms (mainly on the eyes and facial area) with the same concentrations and vehicle as used for the patch test. Readings were performed 15 min after exposure, and possible late reactions were checked at the time point at which patch test reading was performed. A histamine reference was used as a positive control for the prick tests.
200
150
100
50
0 0.62
1.25
2.5
5
278
Guinea pig maximization test (GPMT)
This test was conducted to establish the sensitizing potential of omeprazole by following Organization for Economic Co-operation and Development (OECD) 406 from 1981 (this guideline was subsequently deleted from the OECD list in 2010) and the procedures outlined by Magnusson and Kligman (8). First, concentrations of omeprazole in liquid paraffin were identified for (i) induction purposes (mildly irritating following intradermal and topical administration) and (ii) challenge purposes (non-irritating on topical administration). Induction was initiated in a test group of 20 male albino guinea pigs by administration of three pairs of intradermal injections of 0.1 ml, one from each pair on opposite sides of a skin area in the scalpular region. The formulations administered consisted of (i) Freund’s complete adjuvant diluted 50:50 with water for injection, (ii) 7.5% wt/wt omeprazole in liquid paraffin, and (iii) 7.5% wt/wt omeprazole in a 50:50 mixture of Freund’s complete adjuvant and liquid paraffin. One week later, a patch of Whatman No. 3 filter paper saturated with 50% wt/wt omeprazole in liquid paraffin was placed over the same skin area, secured with an impermeable dressing, and left in place for 24 hr. Twenty control animals underwent identical induction procedures, with the exception that omeprazole was excluded from the formulations. After a further 2 weeks, both the test and control animals were challenged topically with 0.2 ml of 5% and 10% wt/wt omeprazole in liquid paraffin on shaved skin sites on the flank, by using small patches of Whatman No. 3 paper. These patches were left in place for 24 hr under an impervious dressing, after which the dermal reaction was graded with a five-point scale for erythema and/or oedema at 24, 48 and 72 hr after patch removal.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 71, 371–375
10
20
40
80
Omeprazole concentration (µg/mL) 275
256
Fig. 1. Stimulation index values at each omeprazole concentration among the 3 subjects (nos. 256, 275, and 278) with the strongest lymphocyte transformation test response.
Results Lymphocyte transformation test
A total of 31 of the 96 LTT-tested subjects with clinical symptoms (32%) had a positive LTT result (that is, symptoms could not be verified as omeprazole allergy by the LTT in 68% of subjects), as compared with 2 control subjects [9.5%; stimulation indices (SIs) of 3.0 and 9.8]. Individual omeprazole concentration–response relationships for lymphoproliferative intensity were observed, and were exemplified by the 3 subjects with the strongest LTT results (SIs of 126, 186, and 226; Fig. 1). Patch tests and prick tests
Positive patch test results were obtained for 28 of the 84 patch tested individuals with clinical symptoms (33%). Overall, a good association with positive LTT findings was apparent (Fig. 2). The 18 subjects who underwent prick testing had negative results in this test. Sensitivity and specificity of the LTT with the patch test as the reference method. Of the 28 subjects with positive patch test
results, 23 also had a positive LTT result (Fig. 2), yielding a sensitivity of 82% for the LTT. Fifty-six subjects had negative patch test results; 46 of these had a negative LTT result, yielding a specificity of 82%. Combining the LTT and patch test in the diagnostic procedure. When both the patch test and the LTT were combined, eight further symptomatic individuals were identified as being allergic to omeprazole.
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250
200
animals showed thickening, dryness and sloughing of the epidermis (evidence of hyperkeratinization) that partially or completely obscured the erythema.
150
100
SI value
50
10 9 8 7 6 5 4 3 2 1 0 Positive patch test result Negative patch test result Occupationally exposed; symptom–free
Fig. 2. Relationship between lymphocyte transformation test findings [as measured by stimulation indices (SI)] with omeprazole and patch test results (96 subjects with clinical symptoms and 21 controls). The horizontal line denotes the cut-off for a positive LTT result (SI of 3.0). Twelve subjects with clinical symptoms [two of whom had an SI of >3.0 (5.6 and 13.1)] were not patch tested, and are therefore not shown. Occupationally exposed symptom-free subjects were not patch tested.
Overall, 58 symptomatic subjects had neither a positive LTT result nor a positive patch test result. For the majority of these subjects, no further information was available on other diseases or allergies as a cause of their symptoms. For a small number of these subjects, the probable cause of symptoms could be identified as: psoriasis; allergy to nickel, quinidine, rubber, formaldehyde, or p-phenylenediamine; and recurrent urticaria, seborrhoeic eczema, or folliculitis.
Guinea pig maximization test
The challenge reaction was more marked and/or more persistent than the maximum reaction seen in the controls in 18 of the 20 test animals, constituting clear evidence of a delayed contact hypersensitivity potential for omeprazole. An erythema score of 3 (moderate erythema) was evident in the majority of these animals, and a score of 2 (well-defined oedema) was the most common grade for oedema. At the 72-hr time point, the majority of the test
374
Discussion In this dataset, approximately one-third of the individuals with symptoms associated with occupational exposure were diagnosed with omeprazole-specific allergy (with either the patch test or the LTT as the diagnostic procedure). Drug-specific T cells in peripheral blood represent a valuable biomarker for the diagnosis and confirmation of allergic disease (9), irrespective of allergy type, as these cells drive the fundamental mechanism behind this type of immunologically mediated reaction. Although the LTT is considered to be a widely used standard in vitro method (10), a careful analysis of sensitivity and specificity with the intended drug is always required. The chemical properties of tested compounds may interfere with cell proliferative capacity and cause false-positive results (11, 12), for example when metal salts are used as test antigens. In the present dataset, we chose to compare the LTT results with the patch test results (the ‘gold standard’), as this procedure is usually applied as a stand-alone test for type IV-related allergy in the occupational setting. The 82% sensitivity and specificity observed in this sample confirms that the LTT is a suitable diagnostic tool for identifying occupational allergy to omeprazole. The SI values in Fig. 1 show that individuals show different SIs at different omeprazole concentrations. These results reinforce the need to use a test concentration curve that is wide enough to capture all individual responses. Overall, our results are consistent with the strong sensitizing potential of omeprazole seen in animals, manifesting itself in humans as contact allergy type IV. The data from the GPMT reinforce the LTT and patch test data, suggesting that omeprazole does have the potential to cause contact allergy in humans. It should be noted that, on the basis of this GPMT, omeprazole, esomeprazole and salts thereof are classed as allergens from a notification (i.e. transportation of bulk product) point of view [Health and Safety Executive classification: risk phase 43 (may cause sensitization by skin contact)] (13, 14). Reports of allergic reactions with the clinical use of omeprazole are rare; severe hypersensitivity reactions have included urticaria/angioedema and anaphylaxis (15, 16). In contrast to our occupational sample, eczematous symptoms are less common in patients receiving omeprazole as oral treatment. Direct omeprazole contact with skin would normally be avoided, for instance by using enteric-coated formulations. However, this
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 71, 371–375
OCCUPATIONAL SENSITIZATION TO OMEPRAZOLE • GHATAN ET AL.
may not extend to developmental formulations utilizing non-enteric-coated drug products including omeprazole powder, in simple solutions or suspensions (17, 18). The data reported in this communication were collected primarily for diagnostic purposes, and AstraZeneca has worked continuously with occupational safety to reduce the incidence of allergies throughout the omeprazole-manufacturing period, starting in approximately 1989, when the first reports of occupational allergy were noted. For example, omeprazole production was moved to an ‘encapsulated’ environment, which prevents workers from coming into contact with omeprazole or any of its enantiomers. Today, 1–2 employees per year (of ∼ 300 involved in the production of omeprazole) are diagnosed with contact dermatitis resulting from occupational exposure to omeprazole. However, as our data highlight the potential of omeprazole to induce skin allergy, they are important to consider when new formulations are being developed or when the manufacturing process of omeprazole, or of either of its enantiomers, is being considered. Cross-reactivity with other PPIs was not assessed in our dataset. However, some cases of cross-reactivity have been reported in the literature (16). No cross-sensitivity information appears to have been reported for topical exposure. One should also consider the fact that control
subjects with positive LTT and negative patch test results were not followed up, and the possibility that they may have developed symptoms later on can therefore not be excluded.
Conclusion The results of this dataset confirm the sensitizing potential of omeprazole from occupational exposure. Such results are potentially of importance when new formulations are developed or the manufacturing process of omeprazole, or either of its enantiomers, is considered in the light of this potential for inducing skin allergy.
Acknowledgements The authors would like to thank: Dr Hannes Freyman and nurse Mia Westberg from AstraZeneca; Dr Vera Stejskal, the developer of the MELISA® test; BMA Anette Wallstedt for performing the MELISA® tests; Dr Margit Forsbeck (deceased) for performing the skin tests; and Ann-Charlotte Cederlund, who was involved in the investigation of contact dermatitis during this period. The authors would like to thank Claire Byrne of inScience Communications, Springer Healthcare, for providing medical writing support in the preparation of this manuscript.
References 1 AstraZeneca. 2012. Available at: http://www.medicines.org.uk/EMC/ searchresults.aspx?term=losec+ capsules&searchtype=QuickSearch (last accessed 31 July 2014). 2 Conde-Salazar L, Blancas-Espinosa R, Perez-Hortet C. Occupational airborne contact dermatitis from omeprazole. Contact Dermatitis 2007: 56: 44–46. 3 Sanz-Gallén P, Nogué S, Herrera-Mozo I, Delclos G L, Valero A. Occupational contact allergy to omeprazole and fluoxetine. Contact Dermatitis 2011: 65: 118–119. 4 Hausen B M, Lucke R, Rothe E, Erdogan A, Rinder H. Sensitizing capacity of azole derivatives: part III. Investigations with anthelmintics, antimycotics, fungicides, antithyroid compounds, and proton pump inhibitors. Am J Contact Dermat 2000: 11: 80–88. 5 Meding B. Contact allergy to omeprazole. Contact Dermatitis 1986: 15: 36–51. 6 Stejskal V D, Cederbrant K, Lindvall A, Forsbeck M. MELISA – an in vitro tool for
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the study of metal allergy. Toxicol in Vitro 1994: 8: 991–1000. Pirila V. Chamber test versus patch test for epicutaneous testing. Contact Dermatitis 1975: 1: 48–52. Magnusson B, Kligman A M. The identification of contact allergens by animal assay. The guinea pig maximization test. J Investig Dermatol 1969: 52: 268–276. Beeler A, Pichler W J. In vitro tests of T cell-mediated drug hypersensitivity. Expert Rev Clin Immunol 2006: 2: 887–900. Beeler A, Pichler W. In vitro tests of T-cell-mediated drug hypersensitivity. In: Drug Hypersensitivity, Pichler W J (ed.): Basel, Kerger, 2007: pp. 380–390. Cederbrant K, Gunnarsson L G, Hultman P, Norda R, Tibbling-Grahn L. In vitro lymphoproliferative assays with HgCl2 cannot identify patients with systemic symptoms attributed to dental amalgam. J Dent Res 1999: 78: 1450–1458. Cederbrant K, Hultman P, Marcusson J A, Tibbling L. In vitro lymphocyte
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13 14 15
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proliferation as compared to patch test using gold, palladium and nickel. Int Arch Allergy Immunol 1997: 112: 212–217. AstraZeneca. Omeprazole safety data sheet, 2012. AstraZeneca. Esomeprazole safety data sheet, 2012. Abdul Razzak E, Tomas M, Tornero P, Herrero T. Nine cases of allergy to omeprazole. J Investig Allergol Clin Immunol 2012: 22: 228–230. Lobera T, Navarro B, Del Pozo M D, Gonzalez I, Blasco A, Escudero R, Venturini M, Alarcon E. Nine cases of omeprazole allergy: cross-reactivity between proton pump inhibitors. J Investig Allergol Clin Immunol 2009: 19: 57–60. Alwan W, Banerjee P, White I R. Occupational contact dermatitis caused by omeprazole in a veterinary medicament. Contact Dermatitis 2014: 71: 376. Al–Falah K, Schachter J, Sasseville D. Occupational allergic contact dermatitis caused by omeprazole in a horse breeder. Contact Dermatitis 2014: 71: 377–378.
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Contact Dermatitis • Original Article
Contact Dermatitis
Sensitization to omeprazole in the occupational setting Per Hamid Ghatan1 , Maritha Marcusson-Ståhl2 , Mihaly Matura3 , Carol Björkheden4 , Per Lundborg5 and Karin Cederbrant2 1 AstraZeneca,
OSHE Department, SE-151 85 Södertälje, Sweden, 2 Department of Molecular Toxicology/Immunotoxicology, Safety Assessment, AstraZeneca R&D, SE-151 85 Södertälje, Sweden, 3 Centre for Occupational and Environmental Medicine, Stockholm County Council, Solnavägen 4, SE-113 65 Stockholm and Institute of Environmental Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden, 4 Department of General Toxicology Sciences, Safety Assessment, AstraZeneca R&D, SE-151 85 Södertälje, Sweden, and 5 AstraZeneca R&D, SE-431 83 Mölndal, Sweden
doi:10.1111/cod.12305
Summary
Background. Omeprazole is a proton pump inhibitor for the treatment of gastric acid-related disorders. In recent years, reports of dermatitis upon exposure to omeprazole during manufacture have been noted. Objective. To present diagnostic findings in workers who reported suspected hypersensitivity reactions resulting from occupational exposure to omeprazole. Methods. Ninety-six workers exposed to omeprazole during the manufacturing process underwent investigation by the AstraZeneca Occupational Health Centre (Södertälje, Sweden) for suspected allergy. All subjects underwent a lymphocyte transformation test (LTT) and a skin test within 6 months of the clinical reaction. Predictive tests on guinea-pigs were conducted to establish omeprazole’s sensitizing potential. Results. Thirty-one subjects with clinical symptoms had a positive LTT result. Twenty-eight subjects had positive patch test results; of these, 23 also had a positive LTT result (sensitivity of the LTT: 82%). Fifty-six subjects had negative patch test results; 46 of these had a negative LTT result (specificity: 82%). All subjects who underwent prick testing (n = 18) had negative results. Delayed contact hypersensitivity was observed in 18 of 20 test animals. Conclusions. These findings confirm the risk of sensitization to omeprazole from occupational exposure. They are of importance for the development of new formulations of omeprazole, or its enantiomers, in light of the potential for inducing skin allergy. Key words: contact allergy; dermatitis; omeprazole; proton pump inhibitor.
Correspondence: Karin Cederbrant, Swedish Toxicology Sciences Research Center – Swetox, Forskargatan 20, 151 36 Södertälje, Sweden. Tel: +46 8 524 885 03. E-mail: [email protected] Conflict of interests: All authors apart from M. Matura were employees at AstraZeneca at the time when the data were collected. M. Matura has no conflicts of interest to declare. Statement of funding: No specific funding was given to finance this study. All investigations were performed as part of the regular procedure for diagnosing potential allergy in occupationally exposed workers at the AstraZeneca plant in Gärtuna, Sweden. The development of this article was funded
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 71, 371–375
Omeprazole (CAS no. 73590-58-6) is an oral proton pump inhibitor (PPI) for the treatment of gastric acid-related disorders such as reflux oesophagitis and peptic ulcer disease. It was originally launched in 1979, and > 1 billion treatment courses have been prescribed. From a dermatological perspective, adverse reactions such as dermatitis, pruritus and rash are uncommon side-effects of oral treatment (≥ 1/1000 to < 1/100) by AstraZeneca. Medical writing support was provided by Claire Byrne of inScience Communications, Springer Healthcare and funded by AstraZeneca. Accepted for publication 18 August 2014
371
OCCUPATIONAL SENSITIZATION TO OMEPRAZOLE • GHATAN ET AL.
(1). However, in the occupational setting, a number of cases (including some recent cases) of dermatitis upon exposure to omeprazole during manufacture have been reported (2, 3). These reactions are probably explained by the strong skin-sensitizing capacity of this benzimidazole agent (4). Indeed, between 1989 and 1999, 96 workers who had been exposed to omeprazole during the manufacturing process directly contacted, or were referred to, the AstraZeneca Occupational Health Centre (Södertälje, Sweden) because of skin reactions on the face, hands, and neck. Other symptoms, such as rhinitis and conjunctivitis, were also observed. An interesting dichotomy therefore exists between the occupational setting, where omeprazole has been identified as a potential skin sensitizer (2, 3, 5), and the clinical setting, where few allergic reactions have been observed. The aim of this article is to present the diagnostic findings in 96 workers with suspected hypersensitivity reactions resulting from occupational exposure to omeprazole. These data were collected primarily for diagnostic purposes. The potential for skin allergy has been taken into consideration during development of the branded omeprazole formulation since the 1990s. It is important to highlight the potential of omeprazole to induce skin allergy, and this should be considered when new formulations of omeprazole or either of its enantiomers are developed. It should be noted that all data presented are the results of standard procedures used at the company at the time for occupationally exposed personnel with symptoms of hypersensitivity.
Materials and Methods Subjects
Between 1989 and 1999, 96 workers (mean age, 33 years) who reported possible hypersensitivity-type reactions/symptoms resulting from occupational exposure to omeprazole during the manufacturing process underwent investigation by AstraZeneca Occupational Health Centre (Södertälje, Sweden) for suspected allergy. The total number of employees working with omeprazole at AstraZeneca Södertälje during this time is unknown. Skin reactions constituted the primary presentation in the majority of individuals, but a few cases of ocular and nasopharyngeal reactions (suggesting type I allergic reactions) were also observed (Table 1). All subjects underwent a lymphocyte transformation test (LTT) and/or a skin test as described below, performed within 6 months of the clinical reaction. Other individuals who worked in the same occupational environment
372
Table 1. Symptoms observed in workers exposed to omeprazole
(n = 96a) Symptomsb
Number of subjects
Itchy/dry skin Erythema Oedema around the eyes Rhinitis Conjunctivitis Pruritus Urticaria Nasal congestion Swollen throat Fever Shortness of breath Swollen lips Dry skin
43 19 4 5 3 19 3 4 2 1 1 1 5
a Some subjects presented with more than one symptom. b Sixty-nine
subjects reported facial symptoms; 38 of these reported symptoms in the area around the eyes.
as the above-mentioned 96 subjects, and who had similar exposure but did not have hypersensitivity reactions, were asked to participate as healthy exposed controls. Twenty-one of these individuals (mean age, 41 years) agreed to give a blood sample and underwent an LTT, thereby acting as a ‘control’ group. Lymphocyte transformation test
The LTT was performed with the MELISA® (Memory Lymphocyte Immuno-Stimulation Assay) procedure (6). The sensitivity and specificity of the LTT were calculated with the patch test as a reference. ‘Sensitivity’ describes the true positive rate, that is, the proportion of positive subjects who were correctly identified as having an allergic response to omeprazole: Sensitivity = number of true positives (number of true positives + number of false negatives) ‘Specificity’, on the other hand, is used to describe the proportion of subjects who were correctly identified as having a negative response: Specificity = number of true negatives (number of true negatives + number of false positives) Patch tests
Patch testing was performed in 84 of the 96 subjects with Finn Chambers® on Scanpor® tape; occlusion was performed for 2 days (7). An omeprazole sodium salt in saline
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 71, 371–375
OCCUPATIONAL SENSITIZATION TO OMEPRAZOLE • GHATAN ET AL.
300
250
Stimulation index
solution at 0.1%, 0.5% and 1% was employed. One patch test reading was taken, and subjects removed the patches themselves after 48 hr. Reactions were evaluated by the dermatologist 24 hr later, and were rated as either ‘positive’ or ‘negative’. These tests were performed between 1989 and 1999. Prick testing was also performed in 18 subjects who reported symptoms (mainly on the eyes and facial area) with the same concentrations and vehicle as used for the patch test. Readings were performed 15 min after exposure, and possible late reactions were checked at the time point at which patch test reading was performed. A histamine reference was used as a positive control for the prick tests.
200
150
100
50
0 0.62
1.25
2.5
5
278
Guinea pig maximization test (GPMT)
This test was conducted to establish the sensitizing potential of omeprazole by following Organization for Economic Co-operation and Development (OECD) 406 from 1981 (this guideline was subsequently deleted from the OECD list in 2010) and the procedures outlined by Magnusson and Kligman (8). First, concentrations of omeprazole in liquid paraffin were identified for (i) induction purposes (mildly irritating following intradermal and topical administration) and (ii) challenge purposes (non-irritating on topical administration). Induction was initiated in a test group of 20 male albino guinea pigs by administration of three pairs of intradermal injections of 0.1 ml, one from each pair on opposite sides of a skin area in the scalpular region. The formulations administered consisted of (i) Freund’s complete adjuvant diluted 50:50 with water for injection, (ii) 7.5% wt/wt omeprazole in liquid paraffin, and (iii) 7.5% wt/wt omeprazole in a 50:50 mixture of Freund’s complete adjuvant and liquid paraffin. One week later, a patch of Whatman No. 3 filter paper saturated with 50% wt/wt omeprazole in liquid paraffin was placed over the same skin area, secured with an impermeable dressing, and left in place for 24 hr. Twenty control animals underwent identical induction procedures, with the exception that omeprazole was excluded from the formulations. After a further 2 weeks, both the test and control animals were challenged topically with 0.2 ml of 5% and 10% wt/wt omeprazole in liquid paraffin on shaved skin sites on the flank, by using small patches of Whatman No. 3 paper. These patches were left in place for 24 hr under an impervious dressing, after which the dermal reaction was graded with a five-point scale for erythema and/or oedema at 24, 48 and 72 hr after patch removal.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 71, 371–375
10
20
40
80
Omeprazole concentration (µg/mL) 275
256
Fig. 1. Stimulation index values at each omeprazole concentration among the 3 subjects (nos. 256, 275, and 278) with the strongest lymphocyte transformation test response.
Results Lymphocyte transformation test
A total of 31 of the 96 LTT-tested subjects with clinical symptoms (32%) had a positive LTT result (that is, symptoms could not be verified as omeprazole allergy by the LTT in 68% of subjects), as compared with 2 control subjects [9.5%; stimulation indices (SIs) of 3.0 and 9.8]. Individual omeprazole concentration–response relationships for lymphoproliferative intensity were observed, and were exemplified by the 3 subjects with the strongest LTT results (SIs of 126, 186, and 226; Fig. 1). Patch tests and prick tests
Positive patch test results were obtained for 28 of the 84 patch tested individuals with clinical symptoms (33%). Overall, a good association with positive LTT findings was apparent (Fig. 2). The 18 subjects who underwent prick testing had negative results in this test. Sensitivity and specificity of the LTT with the patch test as the reference method. Of the 28 subjects with positive patch test
results, 23 also had a positive LTT result (Fig. 2), yielding a sensitivity of 82% for the LTT. Fifty-six subjects had negative patch test results; 46 of these had a negative LTT result, yielding a specificity of 82%. Combining the LTT and patch test in the diagnostic procedure. When both the patch test and the LTT were combined, eight further symptomatic individuals were identified as being allergic to omeprazole.
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animals showed thickening, dryness and sloughing of the epidermis (evidence of hyperkeratinization) that partially or completely obscured the erythema.
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SI value
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10 9 8 7 6 5 4 3 2 1 0 Positive patch test result Negative patch test result Occupationally exposed; symptom–free
Fig. 2. Relationship between lymphocyte transformation test findings [as measured by stimulation indices (SI)] with omeprazole and patch test results (96 subjects with clinical symptoms and 21 controls). The horizontal line denotes the cut-off for a positive LTT result (SI of 3.0). Twelve subjects with clinical symptoms [two of whom had an SI of >3.0 (5.6 and 13.1)] were not patch tested, and are therefore not shown. Occupationally exposed symptom-free subjects were not patch tested.
Overall, 58 symptomatic subjects had neither a positive LTT result nor a positive patch test result. For the majority of these subjects, no further information was available on other diseases or allergies as a cause of their symptoms. For a small number of these subjects, the probable cause of symptoms could be identified as: psoriasis; allergy to nickel, quinidine, rubber, formaldehyde, or p-phenylenediamine; and recurrent urticaria, seborrhoeic eczema, or folliculitis.
Guinea pig maximization test
The challenge reaction was more marked and/or more persistent than the maximum reaction seen in the controls in 18 of the 20 test animals, constituting clear evidence of a delayed contact hypersensitivity potential for omeprazole. An erythema score of 3 (moderate erythema) was evident in the majority of these animals, and a score of 2 (well-defined oedema) was the most common grade for oedema. At the 72-hr time point, the majority of the test
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Discussion In this dataset, approximately one-third of the individuals with symptoms associated with occupational exposure were diagnosed with omeprazole-specific allergy (with either the patch test or the LTT as the diagnostic procedure). Drug-specific T cells in peripheral blood represent a valuable biomarker for the diagnosis and confirmation of allergic disease (9), irrespective of allergy type, as these cells drive the fundamental mechanism behind this type of immunologically mediated reaction. Although the LTT is considered to be a widely used standard in vitro method (10), a careful analysis of sensitivity and specificity with the intended drug is always required. The chemical properties of tested compounds may interfere with cell proliferative capacity and cause false-positive results (11, 12), for example when metal salts are used as test antigens. In the present dataset, we chose to compare the LTT results with the patch test results (the ‘gold standard’), as this procedure is usually applied as a stand-alone test for type IV-related allergy in the occupational setting. The 82% sensitivity and specificity observed in this sample confirms that the LTT is a suitable diagnostic tool for identifying occupational allergy to omeprazole. The SI values in Fig. 1 show that individuals show different SIs at different omeprazole concentrations. These results reinforce the need to use a test concentration curve that is wide enough to capture all individual responses. Overall, our results are consistent with the strong sensitizing potential of omeprazole seen in animals, manifesting itself in humans as contact allergy type IV. The data from the GPMT reinforce the LTT and patch test data, suggesting that omeprazole does have the potential to cause contact allergy in humans. It should be noted that, on the basis of this GPMT, omeprazole, esomeprazole and salts thereof are classed as allergens from a notification (i.e. transportation of bulk product) point of view [Health and Safety Executive classification: risk phase 43 (may cause sensitization by skin contact)] (13, 14). Reports of allergic reactions with the clinical use of omeprazole are rare; severe hypersensitivity reactions have included urticaria/angioedema and anaphylaxis (15, 16). In contrast to our occupational sample, eczematous symptoms are less common in patients receiving omeprazole as oral treatment. Direct omeprazole contact with skin would normally be avoided, for instance by using enteric-coated formulations. However, this
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Contact Dermatitis, 71, 371–375
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may not extend to developmental formulations utilizing non-enteric-coated drug products including omeprazole powder, in simple solutions or suspensions (17, 18). The data reported in this communication were collected primarily for diagnostic purposes, and AstraZeneca has worked continuously with occupational safety to reduce the incidence of allergies throughout the omeprazole-manufacturing period, starting in approximately 1989, when the first reports of occupational allergy were noted. For example, omeprazole production was moved to an ‘encapsulated’ environment, which prevents workers from coming into contact with omeprazole or any of its enantiomers. Today, 1–2 employees per year (of ∼ 300 involved in the production of omeprazole) are diagnosed with contact dermatitis resulting from occupational exposure to omeprazole. However, as our data highlight the potential of omeprazole to induce skin allergy, they are important to consider when new formulations are being developed or when the manufacturing process of omeprazole, or of either of its enantiomers, is being considered. Cross-reactivity with other PPIs was not assessed in our dataset. However, some cases of cross-reactivity have been reported in the literature (16). No cross-sensitivity information appears to have been reported for topical exposure. One should also consider the fact that control
subjects with positive LTT and negative patch test results were not followed up, and the possibility that they may have developed symptoms later on can therefore not be excluded.
Conclusion The results of this dataset confirm the sensitizing potential of omeprazole from occupational exposure. Such results are potentially of importance when new formulations are developed or the manufacturing process of omeprazole, or either of its enantiomers, is considered in the light of this potential for inducing skin allergy.
Acknowledgements The authors would like to thank: Dr Hannes Freyman and nurse Mia Westberg from AstraZeneca; Dr Vera Stejskal, the developer of the MELISA® test; BMA Anette Wallstedt for performing the MELISA® tests; Dr Margit Forsbeck (deceased) for performing the skin tests; and Ann-Charlotte Cederlund, who was involved in the investigation of contact dermatitis during this period. The authors would like to thank Claire Byrne of inScience Communications, Springer Healthcare, for providing medical writing support in the preparation of this manuscript.
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