British Journal of Dermatology (1990) 122, 817-820.
Trial of nedocromil sodium in atopic eczema E.C.BENTON, H.A.F.MCFARLANE AND R.ST.C.BARNETSON* University Department of Dermatology, Royal Infirmary, Edinburgh EH3 9YW, U.K. Accepted for publication 15 December 1989
SUMMARY
The efficacy of orally administered nedocromil sodium, a mast-cell stabilizer, was assessed in the treatment of adults with atopic eczema plus food allergy. Twenty adults with atopic eczema and allergy to hens' eggs, cows' milk or wheat took part in this double-blind, cross-over study of nedocromil sodiiom versus placebo, each treatment period lasting 4 weeks. No significant differences were found between the two treatments on clinical assessment, or by measurement of total and specific IgE levels.
Approximately 25% of adults with severe atopic eczema have associated IgE-mediated food allergy.' Although in some patients this only causes angioedema, in others it may be associated with delayed exacerbation of the eczema over the following 2-24 h. Patients can usually easily avoid allergens such asfishor nuts, but those allergic to common foods such as hens' eggs, cows' milk or wheat may unwittingly be ingesting small amounts in prepared foods such as sauces or confectionery. The rationale behind the use of orally administered mast-cell stabilizers in atopic eczema associated with food allergy is that, by stabilizing the small intestinal mucosal mast cells, inflammation precipitated by the presence of an allergen is prevented, and this results in its decreased absorption. Previous studies with the mast-cell stabilizer sodium cromoglycate have proved disappointing.^ Nedocromil sodium has been shown to be markedly more active in vitro than sodivim cromoglycate in stabilizing mucosal mast cells.'' It has been shown, in vivo, to be as effective as sodium cromoglycate in asthma*'^ and in suppressing allergic conjunctivitis when instilled into the eye.^ In this study we assessed the efficacy of orally administered nedocromil sodium in the management of patients with atopic eczema associated with IgE-mediated food allergy. METHODS
Adults between the ages of 16 and 65 years with moderate or severe atopic dermatitis were chosen for the study, and all had a history of allergy to the common foods, hens' eggs, cows' milk Correspondence: Dr E.C.Benton. * Present address: Department of Dermatology, University of Sydney, Australia. 817
E.C.Benton et al. or wheat, confirmed by positive skin-prick test (> 5 mm weal) or by a strongly positive radioallergosorbent test (3 or 4). Patients on regular oral steroid therapy were excluded. It was a double-blind, placebo-controlled cross-over study lasting 4 months. After a 4-week baseline period the patients were randomly assigned to nedocromil sodium 100 mg three times daily or to placebo (matching dextrose tablets) for 4 weeks. At the end of this period they were switched to the alternative treatment. The trial was completed after a 4-week follow up. Throughout the study patients continued on their normal diet which was assessed by a dietitian to see whether food allergens were totally, partially or not excluded. All patients were monitored at monthly intervals using a grading system 0-6 to record the severity of the eczema, and a modification of the rule of nines system was used to find the extent of body involvement. Patients also kept a daily diary card to record symptoms of itching, redness and weeping of the skin using a o-io linear analogue scale. Topical therapy was standardized to betamethasone valerate 0-02% and 1% hydrocortisone and the amount used was weighed for each i-month period. Full blood counts and tests of renal and hepatic function were performed each month to determine any drug toxicity. The scores were compared for the final 2 weeks of each 4-week period in order to minimize any possible carry-over effect. The results were analysed using a non-parametric analysis for cross-over trials and a parametric analysis of variance with a factor for order, period and treatment. 8i8
RESULTS
Twenty patients (six male, 14 female; age range 17-61 years, median 29 years) completed the study. Two additional women were enrolled but proceeded no further than their first visit; one failed to return and the other became pregnant. All patients were food allergic, hens' eggs being the commonest allergen (16 patients), then fish (6), cows' milk (6), pork (2) and wheat (i). Dietary assessment demonstrated that six patients totally avoided foods to which they were known to be allergic, 12 patients partially avoided and two did not avoid the allergens. Compliance was good with only one patient withdrawing early while on placebo because of uncontrolled eczema, and two on nedocromil sodium, one because of uncontrolled eczema and the other because of persistent diarrhoea. Analysis of the clinician's overall opinion of the severity of the eczema and the body chart TABLE I. Parametric analysis of scores for body chart symptoms
Mean score for Variable Overall severity Erythema Excoriation Dryness Proportion body involved
Baseline 3'13 2-69 2-09 1-42 0-41
Nedocromil — placebo Nedocromil Placebo Follow-up Mean (95% confidence interval) P value 2-87 2-58 1-81 1-37 0-38
3-09 2-51 1-97 1-38 0-38
2-78 2-28 1-62 1-16 0-40
-0-22 + 0-07 -0-16 -o-oi 0
(-0-71-0-26) (-0-33-0-46) ( — 0-50-0-18) (-0-47-0-45) (-0-07-0-07)
Symptom scale: o, none; i, minimal; 2, mild; 3, moderate; 4, moderate-severe; 5, severe; 6, very severe.
0-33 0-73 0-34 0-96 0-97
Nedocromil in atopic eczema 819 scores (Table i), showed no significant differences between active and placebo treatments. Neither the non-parametric analysis nor the parametric analysis of variance of cross-over data showed any significant differences; the latter is presented in Table i. Period and order effects were not statistically significant for any variable. The patient's preference for treatment was for nedocromil sodium in seven cases, placebo in nine and neither in four. The diary card symptom scores, topical steroid usage and total and specific IgE levels showed no significant differences between active and placebo treatments. No abnormalities were found in laboratory data, and the drug was well tolerated apart from one patient who developed persistent diarrhoea, which ceased on withdrawal of the drug. DISCUSSION
The pathogenesis of atopic eczema is not fully understood, but it seems likely that IgE-mediated allergy plays an exacerbating rather than intrinsic role in the disease. Patients with atopic eczema and food allergies describe a variety of reactions to food allergens. Immediate angioedema and urticaria may be the only symptoms, but this is often associated with a delayed aggravation of eczema or increased itching,^ possibly due to late phase leukotriene release. As only 3% of nedocromil sodium is absorbed into the bloodstream, the drug ingested orally would be expected to have its main effect in preventing infiammation in the small intestine, thereby suppressing absorption of food allergens. This in turn may prevent binding of the allergens to IgE on skin mast cells with consequent degranulation of these cells, release of inflammatory mediators and exacerbation of the eczema. It has been shown that patients with atopic eczema tend to have increased permeability of the small intestine to inert sugar molecules.^'' We have shown that patients with atopic eczema and proven IgE-mediated food allergy have circulating precipitating antibodies (mainly IgG and IgA) to common food allergens.' ° It has been presumed that such antibodies are formed due to increased absorption of foods, as is the case in patients with coeliac disease, who have similar circulating precipitating antibodies" and increased gut permeability. In this study nedocromil sodium administered orally appears to have had no beneficial effects in the management of patients with atopic eczema. This was the case both in patients who completely avoided incriminated foods, and those who only partially avoided them. This suggests that in adults, either allergy to common foods is not one of the major factors influencing the exacerbation of eczema, or alternatively sufficient allergen absorption may be continuing either via the buccal mucosa where the nedocromil has not been dispersed and is therefore not active, or via the small intestine because of the failure of the nedocromil to stabilize mucosal mast cells. In view of the success of'topically' administered preparations to the lung (by inhalation) and the eye, it will be of interest to see whether nedocromil sodium applied topically to the skin has any effect in suppressing exacerbations of atopic eczema. However, we conclude that oral nedocromil sodium has no part to play in the management of atopic eczema in adults. ACKNOWLEDGMENTS
We would like to thank Dr A.M.Edwards, Fisons Pharmaceuticals for his help with this study. REFERENCES I Barnetson RStC, Wright AL, Benton EC. IgE-mediated allergy in adults with severe atopic eczema. Clin Exp Allergy 1989; 19: 321-35.
820
E.C.Benton et al.
2 Atherton DJ, Soothill JF, Elvidge J. A controlled trial of oral sodium cromoglycate in atopic eczema. BrJ Dermatol 1982; 106: 681-5. 3 Orr TSC, Jackson DM, Greenwood B et al. Nedocromil sodium (Tilade): a selective mucosal mast cell stabiliser. In: Asthma—Clinical Pharmacology and Therapeutic Progress. (Kay AB et al., eds), Oxford: Blackwell Scientific Publications, 1986; 265-73. 4 Lai S, Malhotra S, Gribben D, Hodder D. Nedocromil sodium: a new drug for the management of bronchial asthma. Thorax 1984; 39: 802-12. 5 Shaw RJ, Kay AB. Nedocromil, a mucosal and connective tissue mast cell stabiliser inhibits exercise-induced asthma. Br J Dis Chest 1985; 79: 385-9. 6 Dockhorn R, Smith R, Blumenthal M et al. Nedocromil sodium 2% (Tilavist) versus placebo in the treatment of ragweed seasonal allergic conjunctivitis. J Allergy Clin Immunol 1989; 83: 301. 7 Benton EC, Barnetson RStC. Skin reactions to foods in patients with atopic dermatitis. Acta Derm Venereol (Stockh) 1985; Suppl 114: 129-32. 8 Jackson PG, Lessof MH, Baker RWR et al. Intestinal permeability in patients with eczema and food allergy. Lancet 1981 i: 1285-6. 9 Pike MG, Heddle RJ, Boulton P et al. Increased intestinal permeability in atopic eczema. J Invest Dermatol 1986; 86: 101-4. 10 Barnetson RStC, Drummond H, Ferguson A. Precipitins to dietary proteins in atopic eczema. BrJ Dermatol 1983; 109: 653-5. 11 Ferguson A, Carswell F. Precipitins to dietary proteins in serum and upper intestinal secretions of coeliac children. Br MedJ 1972; i: 75-7.
Trial of nedocromil sodium in atopic eczema E.C.BENTON, H.A.F.MCFARLANE AND R.ST.C.BARNETSON* University Department of Dermatology, Royal Infirmary, Edinburgh EH3 9YW, U.K. Accepted for publication 15 December 1989
SUMMARY
The efficacy of orally administered nedocromil sodium, a mast-cell stabilizer, was assessed in the treatment of adults with atopic eczema plus food allergy. Twenty adults with atopic eczema and allergy to hens' eggs, cows' milk or wheat took part in this double-blind, cross-over study of nedocromil sodiiom versus placebo, each treatment period lasting 4 weeks. No significant differences were found between the two treatments on clinical assessment, or by measurement of total and specific IgE levels.
Approximately 25% of adults with severe atopic eczema have associated IgE-mediated food allergy.' Although in some patients this only causes angioedema, in others it may be associated with delayed exacerbation of the eczema over the following 2-24 h. Patients can usually easily avoid allergens such asfishor nuts, but those allergic to common foods such as hens' eggs, cows' milk or wheat may unwittingly be ingesting small amounts in prepared foods such as sauces or confectionery. The rationale behind the use of orally administered mast-cell stabilizers in atopic eczema associated with food allergy is that, by stabilizing the small intestinal mucosal mast cells, inflammation precipitated by the presence of an allergen is prevented, and this results in its decreased absorption. Previous studies with the mast-cell stabilizer sodium cromoglycate have proved disappointing.^ Nedocromil sodium has been shown to be markedly more active in vitro than sodivim cromoglycate in stabilizing mucosal mast cells.'' It has been shown, in vivo, to be as effective as sodium cromoglycate in asthma*'^ and in suppressing allergic conjunctivitis when instilled into the eye.^ In this study we assessed the efficacy of orally administered nedocromil sodium in the management of patients with atopic eczema associated with IgE-mediated food allergy. METHODS
Adults between the ages of 16 and 65 years with moderate or severe atopic dermatitis were chosen for the study, and all had a history of allergy to the common foods, hens' eggs, cows' milk Correspondence: Dr E.C.Benton. * Present address: Department of Dermatology, University of Sydney, Australia. 817
E.C.Benton et al. or wheat, confirmed by positive skin-prick test (> 5 mm weal) or by a strongly positive radioallergosorbent test (3 or 4). Patients on regular oral steroid therapy were excluded. It was a double-blind, placebo-controlled cross-over study lasting 4 months. After a 4-week baseline period the patients were randomly assigned to nedocromil sodium 100 mg three times daily or to placebo (matching dextrose tablets) for 4 weeks. At the end of this period they were switched to the alternative treatment. The trial was completed after a 4-week follow up. Throughout the study patients continued on their normal diet which was assessed by a dietitian to see whether food allergens were totally, partially or not excluded. All patients were monitored at monthly intervals using a grading system 0-6 to record the severity of the eczema, and a modification of the rule of nines system was used to find the extent of body involvement. Patients also kept a daily diary card to record symptoms of itching, redness and weeping of the skin using a o-io linear analogue scale. Topical therapy was standardized to betamethasone valerate 0-02% and 1% hydrocortisone and the amount used was weighed for each i-month period. Full blood counts and tests of renal and hepatic function were performed each month to determine any drug toxicity. The scores were compared for the final 2 weeks of each 4-week period in order to minimize any possible carry-over effect. The results were analysed using a non-parametric analysis for cross-over trials and a parametric analysis of variance with a factor for order, period and treatment. 8i8
RESULTS
Twenty patients (six male, 14 female; age range 17-61 years, median 29 years) completed the study. Two additional women were enrolled but proceeded no further than their first visit; one failed to return and the other became pregnant. All patients were food allergic, hens' eggs being the commonest allergen (16 patients), then fish (6), cows' milk (6), pork (2) and wheat (i). Dietary assessment demonstrated that six patients totally avoided foods to which they were known to be allergic, 12 patients partially avoided and two did not avoid the allergens. Compliance was good with only one patient withdrawing early while on placebo because of uncontrolled eczema, and two on nedocromil sodium, one because of uncontrolled eczema and the other because of persistent diarrhoea. Analysis of the clinician's overall opinion of the severity of the eczema and the body chart TABLE I. Parametric analysis of scores for body chart symptoms
Mean score for Variable Overall severity Erythema Excoriation Dryness Proportion body involved
Baseline 3'13 2-69 2-09 1-42 0-41
Nedocromil — placebo Nedocromil Placebo Follow-up Mean (95% confidence interval) P value 2-87 2-58 1-81 1-37 0-38
3-09 2-51 1-97 1-38 0-38
2-78 2-28 1-62 1-16 0-40
-0-22 + 0-07 -0-16 -o-oi 0
(-0-71-0-26) (-0-33-0-46) ( — 0-50-0-18) (-0-47-0-45) (-0-07-0-07)
Symptom scale: o, none; i, minimal; 2, mild; 3, moderate; 4, moderate-severe; 5, severe; 6, very severe.
0-33 0-73 0-34 0-96 0-97
Nedocromil in atopic eczema 819 scores (Table i), showed no significant differences between active and placebo treatments. Neither the non-parametric analysis nor the parametric analysis of variance of cross-over data showed any significant differences; the latter is presented in Table i. Period and order effects were not statistically significant for any variable. The patient's preference for treatment was for nedocromil sodium in seven cases, placebo in nine and neither in four. The diary card symptom scores, topical steroid usage and total and specific IgE levels showed no significant differences between active and placebo treatments. No abnormalities were found in laboratory data, and the drug was well tolerated apart from one patient who developed persistent diarrhoea, which ceased on withdrawal of the drug. DISCUSSION
The pathogenesis of atopic eczema is not fully understood, but it seems likely that IgE-mediated allergy plays an exacerbating rather than intrinsic role in the disease. Patients with atopic eczema and food allergies describe a variety of reactions to food allergens. Immediate angioedema and urticaria may be the only symptoms, but this is often associated with a delayed aggravation of eczema or increased itching,^ possibly due to late phase leukotriene release. As only 3% of nedocromil sodium is absorbed into the bloodstream, the drug ingested orally would be expected to have its main effect in preventing infiammation in the small intestine, thereby suppressing absorption of food allergens. This in turn may prevent binding of the allergens to IgE on skin mast cells with consequent degranulation of these cells, release of inflammatory mediators and exacerbation of the eczema. It has been shown that patients with atopic eczema tend to have increased permeability of the small intestine to inert sugar molecules.^'' We have shown that patients with atopic eczema and proven IgE-mediated food allergy have circulating precipitating antibodies (mainly IgG and IgA) to common food allergens.' ° It has been presumed that such antibodies are formed due to increased absorption of foods, as is the case in patients with coeliac disease, who have similar circulating precipitating antibodies" and increased gut permeability. In this study nedocromil sodium administered orally appears to have had no beneficial effects in the management of patients with atopic eczema. This was the case both in patients who completely avoided incriminated foods, and those who only partially avoided them. This suggests that in adults, either allergy to common foods is not one of the major factors influencing the exacerbation of eczema, or alternatively sufficient allergen absorption may be continuing either via the buccal mucosa where the nedocromil has not been dispersed and is therefore not active, or via the small intestine because of the failure of the nedocromil to stabilize mucosal mast cells. In view of the success of'topically' administered preparations to the lung (by inhalation) and the eye, it will be of interest to see whether nedocromil sodium applied topically to the skin has any effect in suppressing exacerbations of atopic eczema. However, we conclude that oral nedocromil sodium has no part to play in the management of atopic eczema in adults. ACKNOWLEDGMENTS
We would like to thank Dr A.M.Edwards, Fisons Pharmaceuticals for his help with this study. REFERENCES I Barnetson RStC, Wright AL, Benton EC. IgE-mediated allergy in adults with severe atopic eczema. Clin Exp Allergy 1989; 19: 321-35.
820
E.C.Benton et al.
2 Atherton DJ, Soothill JF, Elvidge J. A controlled trial of oral sodium cromoglycate in atopic eczema. BrJ Dermatol 1982; 106: 681-5. 3 Orr TSC, Jackson DM, Greenwood B et al. Nedocromil sodium (Tilade): a selective mucosal mast cell stabiliser. In: Asthma—Clinical Pharmacology and Therapeutic Progress. (Kay AB et al., eds), Oxford: Blackwell Scientific Publications, 1986; 265-73. 4 Lai S, Malhotra S, Gribben D, Hodder D. Nedocromil sodium: a new drug for the management of bronchial asthma. Thorax 1984; 39: 802-12. 5 Shaw RJ, Kay AB. Nedocromil, a mucosal and connective tissue mast cell stabiliser inhibits exercise-induced asthma. Br J Dis Chest 1985; 79: 385-9. 6 Dockhorn R, Smith R, Blumenthal M et al. Nedocromil sodium 2% (Tilavist) versus placebo in the treatment of ragweed seasonal allergic conjunctivitis. J Allergy Clin Immunol 1989; 83: 301. 7 Benton EC, Barnetson RStC. Skin reactions to foods in patients with atopic dermatitis. Acta Derm Venereol (Stockh) 1985; Suppl 114: 129-32. 8 Jackson PG, Lessof MH, Baker RWR et al. Intestinal permeability in patients with eczema and food allergy. Lancet 1981 i: 1285-6. 9 Pike MG, Heddle RJ, Boulton P et al. Increased intestinal permeability in atopic eczema. J Invest Dermatol 1986; 86: 101-4. 10 Barnetson RStC, Drummond H, Ferguson A. Precipitins to dietary proteins in atopic eczema. BrJ Dermatol 1983; 109: 653-5. 11 Ferguson A, Carswell F. Precipitins to dietary proteins in serum and upper intestinal secretions of coeliac children. Br MedJ 1972; i: 75-7.
