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Getting the chemistry right in trials
COMMENTARY
patients, compared with a frequency of approximately 40% in all SLE patients.5 Ro/SS-A autoantibodies are even more highly associated with cases of drug-induced SCLE.5 Drugs that have been implicated in inducing SCLE include calcium-channel blockers, captopril, penicillamine, glibenclamide, griseofulvin, hydrocholorothiazide, and procainamide.6-8 Drug-induced SCLE differs from drug-induced SLE in several ways and is thought to arise from different pathogenetic mechanisms.7 Antibodies to histone, which serve as a useful clinical marker for drug-induced SLE, have not been reported with increased frequency in druginduced SCLE. To date there are no reported cases of drug-induced DLE. Photosensitivity is a common complaint among SCLE patients, and in laboratory experiments exposure to ultraviolet A or ultraviolet B light can induce SCLE lesions in these patients. Chlebus and colleagues found that ultraviolet B was much more likely to induce cutaneous lupus lesions in SCLE patients than in SLE patients (70% vs 21%).3 This finding is similar to what has previously been reported.9,10 Prolonged erythema at the exposed site was also commoner among SCLE than SLE patients (93% versus 59%). In one study ultraviolet light induced LE skin lesions in 40% of DLE patients, although it sometimes took 1–2 weeks for lesions to develop.10 Protective measures against exposure to ultraviolet A or B light are thus highly advisable for all LE patients but especially for SCLE patients, A minority of LE patients will manifest more than one type of LE-specific skin disease.11 Chlebus and colleagues found that fewer than 20% of SCLE patients had DLE skin lesions.3 Although SCLE skin lesions can later develop in a patient who has previously been diagnosed as having another subtype of LE, Chlebus and colleagues found that the first sign of LE in 80% of their SCLE patients was SCLE skin lesions.3 Although dermatopathologists cannot reliably distinguish between the different types of lupus-specific skin disease on the basis of histopathological findings,12 the clinician should be able to do so from gross morphological features. Distinguishing between the various lupus subsets provides additional prognostic and therapeutic insight that can positively influence the way in which these patients are managed.
Daniel P McCauliffe Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7283, USA 1
2 3
4
5 6
7
8
Sontheimer RD, Thomas JR, Gilliam JN. Subacute cutaneous lupus erythematosus: a cutaneous marker for a distinct lupus erythematosus subset. Arch Dermatol 1979; 115: 1409–15. Sontheimer RD. Subacute cutaneous lupus erythematosus: a decade’s perspective. Med Clin N Am 1989; 73: 1073–90. Chlebus E, Wolska H, Blaszczyk M, Jablonska S. Subacute cutaneous lupus erythematosus versus systemic lupus erythematosus: diagnostic criteria and therapeutic implications. J Am Acad Dermatol 1998; 38: 405–12. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–77. McCauliffe DP. Cutaneous disease in adults associated with antiRo/SS-A autoantibody production. Lupus 1997; 6: 158–66. McCauliffe DP, Sontheimer RD. Subacute cutaneous lupus erythematosus. In: DJ Wallace, BH Hahn eds. Dubois’ lupus erythematosus. Philadelphia: Lea & Febiger, 1993: 302–09. Crowson AN, Magro CM. Subacute cutaneous lupus erythematosus arising in the setting of calcium channel blocker therapy. Human Pathol 1997; 28: 67–73. Reed BR, Huff JC, Jones SKL, Orton PW, Lee LA, Norris DA.
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Subacute cutaneous lupus erythematosus associated with hydrochlorothiazide therapy. Ann Intern Med 1985; 103: 49–51. 9 Wolska H, Blaszczyk M, Jablonska S. Phototests in patients with various forms of lupus erythematosus. Int J Dermatol 1989; 28: 98–103. 10 Lehmann P, Holzle E, Kind P, Goerz G, Plewig G. Experimental reproduction of skin lesions in lupus erythematosus by UVA and UVB radiation. J Am Acad Dermatol 1990; 22: 181–87. 11 Sontheimer RD. Clinical manifestations of cutaneous lupus erythematosus. In: Walker DJ, Halam BH, eds. Dubois’ lupus erythematosus, Philadelphia: Lea & Febiger, 1993: 285–301. 12 Bielsa I, Herrero C, Collado A, Copbos A, Palou J, Mascaro JM. Histopathologic findings in cutaneous lupus erythematosus. Arch Dermatol 1994; 130: 54–58.
Getting the chemistry right in trials The report of an independent review of a pilot trial in which babies with severe birth asphyxia received about twice the intended dose of magnesium sulphate should give all clinical trialists pause for thought. The pilot phase of the Randomised Asphyxia Study (RAST) was stopped in 1996 after two unexpected adverse events. Investigation of the treatment group revealed unexpectedly high serum magnesium concentrations. Animal studies show that magnesium ions can protect against hypoxic injury. RAST was designed to test the hypothesis that early administration of magnesium sulphate would reduce the likelihood of severe handicap or death in babies with birth asphyxia. A pilot study to test the feasibility of a double-blind placebo-controlled intervention trial started in 1995. 56 babies had been recruited from nine countries by the time the pilot trial was suspended on Sept 26, 1996. How did the excessive concentrations of magnesium sulphate come about? The problem was that at the time the UK had no agreed convention between the medical and pharmaceutical professions as to how magnesium sulphate should be described or prescribed. A dose of 250 mg/kg bodyweight had been selected for the pilot trial on the basis of results of a preliminary pharmacokinetic study for which the magnesium sulphate came from a hospital pharmacy. In accordance with standard practice, the pharmacy supplied solution based on the hydrated form of the molecule (MgSO4.7H2O). However, the source of the solution used in the pilot study was not a hospital pharmacy, but an external company. “125 mg/mL of magnesium sulphate” was ordered; each infant would be given 2 mL of this solution. The trial coordinators did not know that the order should have specified use of hydrated magnesium sulphate. Unfortunately, the solution that the company provided was equivalent to 125 mg/mL of anhydrous magnesium sulphate (MgSO4)—a solution that was effectively twice as “strong” as that used in the pharmacokinetic study. The review recommends independent follow-up of the RAST babies and that, if the RAST hypothesis is to be tested again, a second pilot study should be done before a full-scale trial is contemplated. Perhaps the most obvious recommendation is that the UK Medicines Control Agency should ensure that there is a uniform convention for expressing doses of magnesium sulphate, based on molecular weight. Without this simple safeguard, how many other trial coordinators would be alert to the possibility of a potentially dangerous error being made?
Sarah Ramsay The Lancet, London WC1B 3SL, UK 1
Review group. Report of an independent group established to review the conduct and monitoring of the Randomised Asphyxia Study (RAST). Leeds: University of Leeds, April, 1998.
THE LANCET • Vol 351 • May 23, 1998
patients, compared with a frequency of approximately 40% in all SLE patients.5 Ro/SS-A autoantibodies are even more highly associated with cases of drug-induced SCLE.5 Drugs that have been implicated in inducing SCLE include calcium-channel blockers, captopril, penicillamine, glibenclamide, griseofulvin, hydrocholorothiazide, and procainamide.6-8 Drug-induced SCLE differs from drug-induced SLE in several ways and is thought to arise from different pathogenetic mechanisms.7 Antibodies to histone, which serve as a useful clinical marker for drug-induced SLE, have not been reported with increased frequency in druginduced SCLE. To date there are no reported cases of drug-induced DLE. Photosensitivity is a common complaint among SCLE patients, and in laboratory experiments exposure to ultraviolet A or ultraviolet B light can induce SCLE lesions in these patients. Chlebus and colleagues found that ultraviolet B was much more likely to induce cutaneous lupus lesions in SCLE patients than in SLE patients (70% vs 21%).3 This finding is similar to what has previously been reported.9,10 Prolonged erythema at the exposed site was also commoner among SCLE than SLE patients (93% versus 59%). In one study ultraviolet light induced LE skin lesions in 40% of DLE patients, although it sometimes took 1–2 weeks for lesions to develop.10 Protective measures against exposure to ultraviolet A or B light are thus highly advisable for all LE patients but especially for SCLE patients, A minority of LE patients will manifest more than one type of LE-specific skin disease.11 Chlebus and colleagues found that fewer than 20% of SCLE patients had DLE skin lesions.3 Although SCLE skin lesions can later develop in a patient who has previously been diagnosed as having another subtype of LE, Chlebus and colleagues found that the first sign of LE in 80% of their SCLE patients was SCLE skin lesions.3 Although dermatopathologists cannot reliably distinguish between the different types of lupus-specific skin disease on the basis of histopathological findings,12 the clinician should be able to do so from gross morphological features. Distinguishing between the various lupus subsets provides additional prognostic and therapeutic insight that can positively influence the way in which these patients are managed.
Daniel P McCauliffe Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7283, USA 1
2 3
4
5 6
7
8
Sontheimer RD, Thomas JR, Gilliam JN. Subacute cutaneous lupus erythematosus: a cutaneous marker for a distinct lupus erythematosus subset. Arch Dermatol 1979; 115: 1409–15. Sontheimer RD. Subacute cutaneous lupus erythematosus: a decade’s perspective. Med Clin N Am 1989; 73: 1073–90. Chlebus E, Wolska H, Blaszczyk M, Jablonska S. Subacute cutaneous lupus erythematosus versus systemic lupus erythematosus: diagnostic criteria and therapeutic implications. J Am Acad Dermatol 1998; 38: 405–12. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271–77. McCauliffe DP. Cutaneous disease in adults associated with antiRo/SS-A autoantibody production. Lupus 1997; 6: 158–66. McCauliffe DP, Sontheimer RD. Subacute cutaneous lupus erythematosus. In: DJ Wallace, BH Hahn eds. Dubois’ lupus erythematosus. Philadelphia: Lea & Febiger, 1993: 302–09. Crowson AN, Magro CM. Subacute cutaneous lupus erythematosus arising in the setting of calcium channel blocker therapy. Human Pathol 1997; 28: 67–73. Reed BR, Huff JC, Jones SKL, Orton PW, Lee LA, Norris DA.
1528
Subacute cutaneous lupus erythematosus associated with hydrochlorothiazide therapy. Ann Intern Med 1985; 103: 49–51. 9 Wolska H, Blaszczyk M, Jablonska S. Phototests in patients with various forms of lupus erythematosus. Int J Dermatol 1989; 28: 98–103. 10 Lehmann P, Holzle E, Kind P, Goerz G, Plewig G. Experimental reproduction of skin lesions in lupus erythematosus by UVA and UVB radiation. J Am Acad Dermatol 1990; 22: 181–87. 11 Sontheimer RD. Clinical manifestations of cutaneous lupus erythematosus. In: Walker DJ, Halam BH, eds. Dubois’ lupus erythematosus, Philadelphia: Lea & Febiger, 1993: 285–301. 12 Bielsa I, Herrero C, Collado A, Copbos A, Palou J, Mascaro JM. Histopathologic findings in cutaneous lupus erythematosus. Arch Dermatol 1994; 130: 54–58.
Getting the chemistry right in trials The report of an independent review of a pilot trial in which babies with severe birth asphyxia received about twice the intended dose of magnesium sulphate should give all clinical trialists pause for thought. The pilot phase of the Randomised Asphyxia Study (RAST) was stopped in 1996 after two unexpected adverse events. Investigation of the treatment group revealed unexpectedly high serum magnesium concentrations. Animal studies show that magnesium ions can protect against hypoxic injury. RAST was designed to test the hypothesis that early administration of magnesium sulphate would reduce the likelihood of severe handicap or death in babies with birth asphyxia. A pilot study to test the feasibility of a double-blind placebo-controlled intervention trial started in 1995. 56 babies had been recruited from nine countries by the time the pilot trial was suspended on Sept 26, 1996. How did the excessive concentrations of magnesium sulphate come about? The problem was that at the time the UK had no agreed convention between the medical and pharmaceutical professions as to how magnesium sulphate should be described or prescribed. A dose of 250 mg/kg bodyweight had been selected for the pilot trial on the basis of results of a preliminary pharmacokinetic study for which the magnesium sulphate came from a hospital pharmacy. In accordance with standard practice, the pharmacy supplied solution based on the hydrated form of the molecule (MgSO4.7H2O). However, the source of the solution used in the pilot study was not a hospital pharmacy, but an external company. “125 mg/mL of magnesium sulphate” was ordered; each infant would be given 2 mL of this solution. The trial coordinators did not know that the order should have specified use of hydrated magnesium sulphate. Unfortunately, the solution that the company provided was equivalent to 125 mg/mL of anhydrous magnesium sulphate (MgSO4)—a solution that was effectively twice as “strong” as that used in the pharmacokinetic study. The review recommends independent follow-up of the RAST babies and that, if the RAST hypothesis is to be tested again, a second pilot study should be done before a full-scale trial is contemplated. Perhaps the most obvious recommendation is that the UK Medicines Control Agency should ensure that there is a uniform convention for expressing doses of magnesium sulphate, based on molecular weight. Without this simple safeguard, how many other trial coordinators would be alert to the possibility of a potentially dangerous error being made?
Sarah Ramsay The Lancet, London WC1B 3SL, UK 1
Review group. Report of an independent group established to review the conduct and monitoring of the Randomised Asphyxia Study (RAST). Leeds: University of Leeds, April, 1998.
THE LANCET • Vol 351 • May 23, 1998