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Fixed drug eruption caused by lactose in an injected botulinum toxin preparation
Journal of the American Academy of Dermatology Volume 40, Number 2, Part 1
Brief communications 263
Fixed drug eruption caused by lactose in an injected botulinum toxin preparation Neil H. Cox, FRCP,a Philip Duffey, MRCP,b and Janice Royle, MRCGPc Carlisle and Newcastle upon Tyne, United Kingdom
Cutaneous eruptions resulting from botulinum toxin preparations are uncommon. We describe a novel case of fixed drug eruption (FDE) to a botulinum toxin preparation and the investigations that proved this was caused by a minor excipient. CASE REPORT A 64-year-old woman described a predictable skin reaction on the nasal tip, which had occurred 4 weeks after each of 11 treatments (including the first) with botulinum toxin (Dysport, Speywood Pharmaceuticals) for severe blepharospasm. On each occasion she had experienced an inflamed plaque with subsequent blistering and crusting, initially healing after a month but more recently lasting about 6 weeks. Each treatment had followed the manufacturer’s dosage and injection site protocols, using 3 injection sites (medial and lateral orbicularis oculi of the upper eyelid, and lateral orbicularis oculi of the lower eyelid) and 50 U of botulinum toxin, administered by an operator experienced with this technique. No additional medications had been taken in conjunction with any of the episodes. The interval between injection and reaction had gradually decreased to 3 weeks with repeated exposures. Examination revealed a smooth erythematous and edematous plaque of about 2 cm diameter at the nasal tip (Fig 1). A punch biopsy specimen demonstrated a dense, predominantly lymphocytic, dermal infiltrate with patchy spongiosis and some intraepidermal lymphocytes consistent with the clinical diagnosis of FDE. Treatment with a potent topical corticosteroid produced prompt clearing and was used subsequently to abolish the reaction in its early stages. No antibodies to botulinum toxin were detected in the patient’s serum by toxin neutralization test. Use of an alternative brand (Botox, Allergan) did not provoke From the Department of Dermatology, Cumberland Infirmary, Carlisle,a Regional Rehabilitation Centre, Newcastle upon Tyne,b and The Surgery, Brampton, Carlisle.c Reprint requests: Neil H. Cox, FRCP, Department of Dermatology, Cumberland Infirmary, Carlisle CA2 7HY, England. J Am Acad Dermatol 1999;40:263-4. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/54/94096
the reaction but neither did it have clinical benefit. The patient was unwilling to try this brand again. Challenge at a forehead injection site with the manufacturer’s placebo, which contains human serum albumin (HSA) and lactose, provoked the same nasal tip reaction 2 weeks after administration. Challenge with HSA alone, obtained from the same original supplier (Immuno Ltd), was negative. The FDE was therefore caused by lactose, either alone or in combination with albumin. DISCUSSION
Rashes of any sort are uncommon with any brand of botulinum toxin and, to our knowledge, this is the only recorded case of FDE. Generalized pruritus occurred in 0.3% of patients treated for blepharospasm1 and rash (type not specified) in 1 of 96 patients treated for oromandibular dystonia.2 A 1996 review of botulinum toxin3 documented that no allergic or urticarial reactions had occurred during cosmetic procedures. In the United Kingdom, the Committee on Safety of Medicines (a voluntary adverse reaction reporting agency) has had reports of 1 case of urticaria, 4 nonspecified rashes, and 2 nonspecified allergic reactions (personal communication, July 1997, to N. H. C.). In the department where our patient was treated, no such reactions have occurred in approximately 800 patients. The clinical appearance, consistent site, and reproducibility of eruption in this case were all typical of FDE, but there were unusual features. Most FDEs occur with orally administered rather than injected drugs, although there are other cases in which injected drugs have been implicated.4 There was no residual pigmentation (a pattern described as nonpigmenting FDE5,6), and the nose is an uncommon site for FDE. The interval of 4 weeks between exposure and skin reaction is longer than occurs with typical causative drugs, which generally trigger FDE within a few hours.7 The significance of all of these unusual features remains uncertain.
264 Brief communications
Fig 1. Fixed drug eruption on tip of nose.
Although humoral immunity is not generally thought to explain FDE,7 we excluded antibodies to botulinum toxin as a cause in our patient. The positive placebo reaction demonstrated that the base constituents of the botulinum toxin preparation were the cause of FDE, but did not distinguish between lactose (0.25 mg total each exposure) and HSA (0.0125 mg per exposure) as the implicated excipient. We could not provoke the FDE with an alternative brand, which also contained HSA but no lactose, nor could we provoke it with HSA alone. We were unable to perform a direct challenge to lactose because pharmaceutical regulations in the United Kingdom prohibit ad hoc manufacture of injectable pharmaceuticals in sterile form, and we could not obtain a sterile supply of lactose from other sources. However, the series of challenge tests performed clearly implicated lactose (or lactose in conjunction with albumin) as the cause of the FDE. Lactose is a constituent of numerous foodstuffs and orally administered medicines, but is metabolized in the bowel. The only cutaneous reaction to ingested lactose that we have identified is a case of chronic eczema in a patient with lactose intolerance, in whom the eczema cleared after introduction of a lactose-free diet.8 However, our patient tolerates ingested lactose in milk. FDE may be related to foods or food additives9,10 rather than medications, but it is unlikely that ingested lactose is a significant cause of FDE because it is such a common dietary constituent; it is more likely that the route of administration was important in our
Journal of the American Academy of Dermatology February 1999
patient. FDE has been reported as occurring in situations in which a combination of constituents was required to provoke the reaction,11 and we suggest that this may be true of our case. A possible explanation is that albumin acts as a carrier protein and lactose as a hapten when they are injected together, in a manner similar to that described with nickel12; this would also explain the delay in onset of the reaction if an immunologic response is required. However, the mechanism must be more complicated than simply having lactose and human albumin together in the skin because lactosuria (and therefore presumably lactosemia and increased tissue lactose) is common during lactation, whereas FDE is not. The precise mechanism of this reaction therefore remains unproved. We are grateful to Dr A. W. Popple for histology, to Lesley Maughan and Alex Obzanska at Speywood Pharmaceuticals Ltd for their help and for the botulinum antibody assay, to Baxter Healthcare (Immuno Ltd) for HSA, and to the Committee on Safety of Medicines for permission to use their data. REFERENCES 1. Dutton JJ, Buckley EG. Long term results and complications of botulinum A toxin in the treatment of blepharospasm. Ophthalmology 1988;95:1529-34. 2. Brin MF, Blitzer A, Herman S, Stewart C. Oromandibular dystonia: treatment of 96 patients with botulinum toxin type A. In: Jankovic J, Hallett M, editors. Therapy with botulinum toxin. New York: Marcel Dekker; 1994. p. 429-35. 3. Carruthers A, Kiene K, Carruthers J. Botulinum A exotoxin use in clinical dermatology. J Am Acad Dermatol 1996;34:788-97. 4. Sigal-Nahum M, Konqui A, Gauliet A, Sigal S. Linear fixed drug eruption. Br J Dermatol 1988;118:849-51. 5. Shelley WB, Shelley ED. Nonpigmenting fixed drug reaction pattern: examples caused by sensitivity to pseudoephedrine hydrochloride and tetrahydrolozine. J Am Acad Dermatol 1987;17:403-7. 6. Valsecchi R, Cainelli T. Nonpigmenting fixed drug reaction to piroxicam. J Am Acad Dermatol 1989;21:1300. 7. Breathnach SM, Hintner H. Adverse drug reactions and the skin. Oxford: Blackwell Scientific Publications; 1996. p. 72-8. 8. Grimbacher B, Peters T, Peter HH. Lactose-intolerance may induce severe chronic eczema. Int Arch Allergy Immunol 1997;113:516-8. 9. Kelso JM. Fixed food eruption. J Am Acad Dermatol 1996;35:638-9. 10. Hatzis J, Noutsis K, Hatzidakis E, et al. Fixed drug eruption in a mother and her son. Cutis 1992;50:50-2. 11. Verbov J. Fixed drug eruption due to a drug combination but not to its constituents. Dermatologica 1985;171:60-1. 12. Veien NK, Christiansen AH, Svejgaard E, Kaaber K. Antibodies against nickel-albumin in rabbits and man. Contact Dermatitis 1979;5:378-83.
Brief communications 263
Fixed drug eruption caused by lactose in an injected botulinum toxin preparation Neil H. Cox, FRCP,a Philip Duffey, MRCP,b and Janice Royle, MRCGPc Carlisle and Newcastle upon Tyne, United Kingdom
Cutaneous eruptions resulting from botulinum toxin preparations are uncommon. We describe a novel case of fixed drug eruption (FDE) to a botulinum toxin preparation and the investigations that proved this was caused by a minor excipient. CASE REPORT A 64-year-old woman described a predictable skin reaction on the nasal tip, which had occurred 4 weeks after each of 11 treatments (including the first) with botulinum toxin (Dysport, Speywood Pharmaceuticals) for severe blepharospasm. On each occasion she had experienced an inflamed plaque with subsequent blistering and crusting, initially healing after a month but more recently lasting about 6 weeks. Each treatment had followed the manufacturer’s dosage and injection site protocols, using 3 injection sites (medial and lateral orbicularis oculi of the upper eyelid, and lateral orbicularis oculi of the lower eyelid) and 50 U of botulinum toxin, administered by an operator experienced with this technique. No additional medications had been taken in conjunction with any of the episodes. The interval between injection and reaction had gradually decreased to 3 weeks with repeated exposures. Examination revealed a smooth erythematous and edematous plaque of about 2 cm diameter at the nasal tip (Fig 1). A punch biopsy specimen demonstrated a dense, predominantly lymphocytic, dermal infiltrate with patchy spongiosis and some intraepidermal lymphocytes consistent with the clinical diagnosis of FDE. Treatment with a potent topical corticosteroid produced prompt clearing and was used subsequently to abolish the reaction in its early stages. No antibodies to botulinum toxin were detected in the patient’s serum by toxin neutralization test. Use of an alternative brand (Botox, Allergan) did not provoke From the Department of Dermatology, Cumberland Infirmary, Carlisle,a Regional Rehabilitation Centre, Newcastle upon Tyne,b and The Surgery, Brampton, Carlisle.c Reprint requests: Neil H. Cox, FRCP, Department of Dermatology, Cumberland Infirmary, Carlisle CA2 7HY, England. J Am Acad Dermatol 1999;40:263-4. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/54/94096
the reaction but neither did it have clinical benefit. The patient was unwilling to try this brand again. Challenge at a forehead injection site with the manufacturer’s placebo, which contains human serum albumin (HSA) and lactose, provoked the same nasal tip reaction 2 weeks after administration. Challenge with HSA alone, obtained from the same original supplier (Immuno Ltd), was negative. The FDE was therefore caused by lactose, either alone or in combination with albumin. DISCUSSION
Rashes of any sort are uncommon with any brand of botulinum toxin and, to our knowledge, this is the only recorded case of FDE. Generalized pruritus occurred in 0.3% of patients treated for blepharospasm1 and rash (type not specified) in 1 of 96 patients treated for oromandibular dystonia.2 A 1996 review of botulinum toxin3 documented that no allergic or urticarial reactions had occurred during cosmetic procedures. In the United Kingdom, the Committee on Safety of Medicines (a voluntary adverse reaction reporting agency) has had reports of 1 case of urticaria, 4 nonspecified rashes, and 2 nonspecified allergic reactions (personal communication, July 1997, to N. H. C.). In the department where our patient was treated, no such reactions have occurred in approximately 800 patients. The clinical appearance, consistent site, and reproducibility of eruption in this case were all typical of FDE, but there were unusual features. Most FDEs occur with orally administered rather than injected drugs, although there are other cases in which injected drugs have been implicated.4 There was no residual pigmentation (a pattern described as nonpigmenting FDE5,6), and the nose is an uncommon site for FDE. The interval of 4 weeks between exposure and skin reaction is longer than occurs with typical causative drugs, which generally trigger FDE within a few hours.7 The significance of all of these unusual features remains uncertain.
264 Brief communications
Fig 1. Fixed drug eruption on tip of nose.
Although humoral immunity is not generally thought to explain FDE,7 we excluded antibodies to botulinum toxin as a cause in our patient. The positive placebo reaction demonstrated that the base constituents of the botulinum toxin preparation were the cause of FDE, but did not distinguish between lactose (0.25 mg total each exposure) and HSA (0.0125 mg per exposure) as the implicated excipient. We could not provoke the FDE with an alternative brand, which also contained HSA but no lactose, nor could we provoke it with HSA alone. We were unable to perform a direct challenge to lactose because pharmaceutical regulations in the United Kingdom prohibit ad hoc manufacture of injectable pharmaceuticals in sterile form, and we could not obtain a sterile supply of lactose from other sources. However, the series of challenge tests performed clearly implicated lactose (or lactose in conjunction with albumin) as the cause of the FDE. Lactose is a constituent of numerous foodstuffs and orally administered medicines, but is metabolized in the bowel. The only cutaneous reaction to ingested lactose that we have identified is a case of chronic eczema in a patient with lactose intolerance, in whom the eczema cleared after introduction of a lactose-free diet.8 However, our patient tolerates ingested lactose in milk. FDE may be related to foods or food additives9,10 rather than medications, but it is unlikely that ingested lactose is a significant cause of FDE because it is such a common dietary constituent; it is more likely that the route of administration was important in our
Journal of the American Academy of Dermatology February 1999
patient. FDE has been reported as occurring in situations in which a combination of constituents was required to provoke the reaction,11 and we suggest that this may be true of our case. A possible explanation is that albumin acts as a carrier protein and lactose as a hapten when they are injected together, in a manner similar to that described with nickel12; this would also explain the delay in onset of the reaction if an immunologic response is required. However, the mechanism must be more complicated than simply having lactose and human albumin together in the skin because lactosuria (and therefore presumably lactosemia and increased tissue lactose) is common during lactation, whereas FDE is not. The precise mechanism of this reaction therefore remains unproved. We are grateful to Dr A. W. Popple for histology, to Lesley Maughan and Alex Obzanska at Speywood Pharmaceuticals Ltd for their help and for the botulinum antibody assay, to Baxter Healthcare (Immuno Ltd) for HSA, and to the Committee on Safety of Medicines for permission to use their data. REFERENCES 1. Dutton JJ, Buckley EG. Long term results and complications of botulinum A toxin in the treatment of blepharospasm. Ophthalmology 1988;95:1529-34. 2. Brin MF, Blitzer A, Herman S, Stewart C. Oromandibular dystonia: treatment of 96 patients with botulinum toxin type A. In: Jankovic J, Hallett M, editors. Therapy with botulinum toxin. New York: Marcel Dekker; 1994. p. 429-35. 3. Carruthers A, Kiene K, Carruthers J. Botulinum A exotoxin use in clinical dermatology. J Am Acad Dermatol 1996;34:788-97. 4. Sigal-Nahum M, Konqui A, Gauliet A, Sigal S. Linear fixed drug eruption. Br J Dermatol 1988;118:849-51. 5. Shelley WB, Shelley ED. Nonpigmenting fixed drug reaction pattern: examples caused by sensitivity to pseudoephedrine hydrochloride and tetrahydrolozine. J Am Acad Dermatol 1987;17:403-7. 6. Valsecchi R, Cainelli T. Nonpigmenting fixed drug reaction to piroxicam. J Am Acad Dermatol 1989;21:1300. 7. Breathnach SM, Hintner H. Adverse drug reactions and the skin. Oxford: Blackwell Scientific Publications; 1996. p. 72-8. 8. Grimbacher B, Peters T, Peter HH. Lactose-intolerance may induce severe chronic eczema. Int Arch Allergy Immunol 1997;113:516-8. 9. Kelso JM. Fixed food eruption. J Am Acad Dermatol 1996;35:638-9. 10. Hatzis J, Noutsis K, Hatzidakis E, et al. Fixed drug eruption in a mother and her son. Cutis 1992;50:50-2. 11. Verbov J. Fixed drug eruption due to a drug combination but not to its constituents. Dermatologica 1985;171:60-1. 12. Veien NK, Christiansen AH, Svejgaard E, Kaaber K. Antibodies against nickel-albumin in rabbits and man. Contact Dermatitis 1979;5:378-83.