865
SUMMARY OF MEASUREMENT OF ACA* BY FOUR LABORATORIES
been investigated in published placebo-controlled trials: the largest number of patients entered into trials on any one agent is 293 (for halcinonide); the other three agents combined have been tested in fewer than 200; and no trial lasted for more than 4 weeks, which is not enough for drugs with side-effects that are likely to be used for many years.
Epogam has thus been more thoroughly studied than any other atopic eczema; it has fewer side-effects than many alternative treatments; and it permits reduced steroid use and relieves itch without causing drowsiness. Furthermore epogam is the only treatment which has a rational basis in the reversal of a biochemical abnormality probably present from birth.8-1° It is therefore not surprising that clinical improvement takes time. Those reviewing the evidence for epogam, the only fundamentally new approach to atopic eczema in the past twenty years, should compare their findings with the paucity of hard evidence on the efficacy and safety of most other agents used to treat atopic eczema. treatment for
Scotia Pharmaceuticals Ltd, Guildford, Surrey GU1 1 BA, UK
DAVID F. HORROBIN CHARLES STEWART
1. Morse PF, Horrobin DF, Manku MS, et al. Meta-analysis of placebo-controlled studies of the efficacy of Epogam in the treatment of atopic eczema: relationship
between plasma essential fatty acid changes and treatment response. Br J Dermatol 1989; 121: 75-90. 2. Wright S, Burton JL. Oral evening primrose oil improves atopic eczema. Lancet 1982; it: 1120-22. 3. Schalin-Karrila M, Mattila L, Jansen CT, Uotila P. Evening primrose oil in the treatment of atopic eczema: effect on clinical status, plasma phospholipid fatty acids and circulating blood prostaglandins. Br J Dermatol 1987; 117: 11-19. 4. Bordoni A, Biagi PL, Masi M, et al. Evening primrose oil (Efamol) in the treatment of children with atopic eczema. Drugs Exp Clin Res 1987; 14: 291-97. 5. Peto R. Why do we need systematic overviews of randomized trials? Stat Med 1987; 6: 233-40. 6. Bamford JTM, Gibson RW, Renier CM. Atopic eczema unresponsive to evening primrose oil (linoleic and gamma-linolenic acids). J Am Acad Dermatol 1985; 13: 959-65. 7. Frosch PJ, Schwanitz HJ, Macher E. A double blind trial of H, and H, receptor antagonists in the treatment of atopic dermatitis. Arch Dermatol Res 1984; 276: 36-40. 8. Strannegard I-L, Svennerholm L, Strannegard O. Essential fatty adds in serum lecithin of children with atopic dermatitis and in umbilical cord serum of infants with high or low IgE levels. Int Arch Allergy Appl Immunol 1987; 82: 422-23. 9. Melnik BC, Plewig G. Is the origin of atopy linked to deficient conversion of omega-6 fatty adds to prostaglandin E1? J Am Acad Dermatol 1989; 21: 557-63. 10. Galli E, Picardo M, De Luca C, et al. Essential fatty acids in cord blood lymphocytes of infants at risk for atopy. Pediatric Res 1989; 26: 519.
Interlaboratory inconsistencies in detection of anticardiolipin antibodies
*In SD above mean. tln units reported by G IgG isotype; M =
=
laboratory as substantially raised. IgM isotype, - = negative.
The results emphasise the discrepancies in reporting of ACA positive values from various laboratories. Although published work suggests
an
association between ACA and
recurrent
spontaneous
abortion, there is debate about the predictability of pregnancy loss. Lockshin5 found a positive ACA to have a predictive value of 0.562 for fetal death. The data presented here and the low predictive value call into question the usefulness of a single ACA ELISA test in the diagnosis of wolnen with RSA. These data also highlight the frustrations of the clinician who wishes to use the results in the management of patients. The appropriateness of applying these irreproducible results to clinical treatment deserves consideration. Center for Reproduction and Transplant Immunology, Methodist Hospital of Indiana, Indianapolis, IN 46202, USA, and Foundation for Blood Research,
Scarborough, Maine
CAROLYN B. COULAM JOHN A. MCINTYRE DAWN WAGENKNECHT NEAL ROTH
ML, Goei S, et al. Antibody to cardiolipin asa predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl J Med 1985; 313: 152-56. 2. Triplett DA. Antiphospholipid antibodies and recurrent pregnancy loss. Am J Reprod Immunol 1989; 20: 52-67. 3. Harris EN, Hughes GRV. Standardising the anticardiolipin antibody test. Lancet 1987; i: 277. 4. Loizou S, McCrea JD, Rudge AC, Reynolds R, Boyle CC, Harris EN. Measurement of anticardiolipin by an enzyme linked immunosorbent assay (ELISA): standardization and quantitation of results. Clin Exp Immunol 1985; 62: 738-45. 5. Lockshin MD. Anticardiolipin antibodies in pregnant patients with systemic lupus erythematosus. N Engl J Med 1986; 314: 1392-93. 1. Lockshin MD, Druzin
SIR,-Raised concentrations of anticardiolipin antibodies (ACA) associated with recurrent spontaneous abortion and fetal death.1,2 Although Harris and Hughes3 reported the need for standardisation of the ACA test, neither the usefulness nor the reproducibility of ACA assays has been assessed in the diagnosis of women with recurrent spontaneous abortion (RSA). To establish the reproducibility of tests for ACA, blood samples from 20 women with a history of RSA were sent to four independent laboratories, including two commercial laboratories (Speciality Laboratories, Santa Monica, CA, USA; and Smith Kline and French Reference Laboratories, Van Nuys, CA) and two research laboratories (Center for Reproduction and Transplantation Immunology, Methodist Hospital of Indiana, Indianapolis, IN; and Foundation for Blood Research, Scarborough, ME). ACA were measured by ELISA with a modification of Loizou and colleagues’ method.4 A total of 80 assays for ACA were analysed (4 samples for each woman). 10 (12-5%) of these were over 5 SD above the mean for that laboratory and were interpreted as positive. These 10 positive results were obtained from 8 (40%) women. The table summarises the results of ACA testing in these 8 women. In only 2 were positive ACA results shown by two laboratories. The 6 other women had a positive ACA reported by one laboratory and negative results by three. Of the 10 positive samples 7 had raised IgG concentrations and 4 had increased IgM. In 1 sample both IgG and IgM were are
raised (patient 8). 1 patient (no 4) who was reported positive by two laboratories also had a raised activated partial thromboplastin time.
risk of anaphylactic shock during surgery for spina bifida SIR,-Slater1 has reported two patients with spina bifida who had latex-induced anaphylactic shock during surgery. In 1989 we observed three identical cases; two of the patients were also sensitised to ethylene oxide (table), used to sterilise latex gloves. Two of these patients have an allergic background. We think it is reasonable to suspect an abnormal frequency of sensitisation to latex and ethylene oxide, which are recognised allergens, in children with spina bifida who undergo multiple operations and sometimes daily catheterisation, bringing them into contact with these substances. We obtained sera from eight children with spina bifida to test for atopy and for specific IgE RAST (table). None of these children has had anaphylactic shock. The results uphold our hypothesis since two of the eight children were sensitised to latex and two to ethylene oxide, and four were atopic (table). Atopy predisposes to latex allergy.2 In spida bifida, we believe, there is a much higher risk of anaphylactic shock than in other patients.3-’ We would emphasise the need for screening to detect these sensitisations-by skin prick tests for latex and by RAST for latex and ethylene oxide. For prevention, we recommend the sterilisation of catheters and surgical gloves by gamma-rays and
High
avoidance of the
use
of latex.
866
DETAILS OF SPINA BIFIDA PATIENTS WITH ANAPHYLACTIC SHOCK OR WHO WERE SYMPTOM-FREE
*By ’Phadiatop’ test (Pharmacia) NSA!D=non-stero!da! antt-inflammatory drugs; TAO = trtacetyloleandomycin.
Is this frequent sensitisation due only to repeated contacts with these substances? In over ten years’ investigation we have not observed anaesthesia-induced shock in children with repeated surgical procedures but without spina bifida.5 We suggest that this condition is correlated with a predisposition to formation of specific IgE for proteins and haptens. Although spina bifida develops in the embryo with no known anomaly of the genome, the possible existence of a link between this condition and atopy is worthy of consideration. Medicine D (Immunoallergology), Hôpital de Brabois, 54511 Vandoeuvre Nancy, France
D. A. MONERET-VAUTRIN E. MATA
Unité Inserm 308, Faculte de Medecine, Vandoeuvre Nancy
J. L. GUEANT
Centre d’Education Motrice, Grenoble
D. TURGEMAN
Department of Anaesthesia, Hôpital Central, Nancy
M. C. LAXENAIRE
1. Slater JE. Rubber anaphylaxis. N Engl J Med 1989; 320: 1126-30. 2. Turjanmaa K. Incidence of immediate allergy to latex gloves in hospital personnel. Contact Dermatiits 1987; 17: 270-75. 3. Gerber AC, Jorg W, Zbinden S, Seger RA, Dangel PH. Severe intraoperative anaphylaxis to surgical gloves: latex allergy, an unfamiliar condition. Anesthesiology 1989; 71: 800-02. 4. Leynadier F, Pecquet C, Dry J. Anaphylaxis to latex during surgery. Anaesthesia 1989; 44: 547-50. 5. Laxenaire MC, Moneret-Vautrin DA, Verdloet D. The French experience of anaphylactoid reactions. Int Anesthesiol Clin 1985; 23: 145-60.
Cyclosporin monitoring in psoriasis SIR,-Dr Bos
and
colleagues (Dec 23/30, p 1500), reporting on cyclosporin (’Sandimmun’ 3 mg/kg daily) in psoriasis, suggest monthly measurement of trough concentrations of this drug. We have evaluated cyclosporin trough levels as predictors of clinical events in 134 adults with severe disabling psoriasis who were treated with cyclosporin 2-5 mg/kg daily in two doses. The dose remained unchanged for the first month so weeks 1-4 were selected for the analysis. Cyclosporin levels were measured in whole blood by radioimmunoassay, with a monoclonal antibody specific to the parent compound and a tritium-labelled tracer (sandimmun kit). The mean of four consecutive blood level low-dose
treatment with
Reduction in PASI (panel A) and increase in serum creatinine over baseline (panel B) at week 4 by specific cyclosporin blood level.
Each circle represents 1 patient and is the value of four (at weeks 1, 2, 3, and 4). Total number of patients 134
measurements
1,2,3, and 4) was calculated and correlated efficacy and renal dysfunction at week 4. The mean cyclosporin level was 103 (SEM 5) ng/ml. Inter-individual variability was 53%. Efficacy was assessed by the percentage reduction (39 [3]%) in psoriasis activity and severity index (PASI)1 and renal dysfunction was evaluated by the percentage change in serum creatinine from baseline level (6 [1]%). As shown in the figure, no significant correlation was found between cyclosporin levels and efficacy or renal dysfunction. On the basis of experience with maintenance cyclosporin in transplantation, a cut-off of 100 ng/ml was selected for efficacy and 200 ng/ml for renal dysfunction.4 10 out of 53 patients (19%) with levels of 100 ng/ml or more had success at week 4 (75% or more reduction in PASI) compared with 5/81 (6%) with lower cyclosporin levels (p 0-040, Fisher’s exact test). The frequency of renal dysfunction (creatinine increase 30% or more above baseline) was 1/10 where the cyclosporin level was 200 ng/ml or more and 7/124 for lower levels (not significant). On the one hand, the cyclosporin level had significant but low predictive value for efficacy and no predictive value for renal
measurements (at weeks to
=
SUMMARY OF MEASUREMENT OF ACA* BY FOUR LABORATORIES
been investigated in published placebo-controlled trials: the largest number of patients entered into trials on any one agent is 293 (for halcinonide); the other three agents combined have been tested in fewer than 200; and no trial lasted for more than 4 weeks, which is not enough for drugs with side-effects that are likely to be used for many years.
Epogam has thus been more thoroughly studied than any other atopic eczema; it has fewer side-effects than many alternative treatments; and it permits reduced steroid use and relieves itch without causing drowsiness. Furthermore epogam is the only treatment which has a rational basis in the reversal of a biochemical abnormality probably present from birth.8-1° It is therefore not surprising that clinical improvement takes time. Those reviewing the evidence for epogam, the only fundamentally new approach to atopic eczema in the past twenty years, should compare their findings with the paucity of hard evidence on the efficacy and safety of most other agents used to treat atopic eczema. treatment for
Scotia Pharmaceuticals Ltd, Guildford, Surrey GU1 1 BA, UK
DAVID F. HORROBIN CHARLES STEWART
1. Morse PF, Horrobin DF, Manku MS, et al. Meta-analysis of placebo-controlled studies of the efficacy of Epogam in the treatment of atopic eczema: relationship
between plasma essential fatty acid changes and treatment response. Br J Dermatol 1989; 121: 75-90. 2. Wright S, Burton JL. Oral evening primrose oil improves atopic eczema. Lancet 1982; it: 1120-22. 3. Schalin-Karrila M, Mattila L, Jansen CT, Uotila P. Evening primrose oil in the treatment of atopic eczema: effect on clinical status, plasma phospholipid fatty acids and circulating blood prostaglandins. Br J Dermatol 1987; 117: 11-19. 4. Bordoni A, Biagi PL, Masi M, et al. Evening primrose oil (Efamol) in the treatment of children with atopic eczema. Drugs Exp Clin Res 1987; 14: 291-97. 5. Peto R. Why do we need systematic overviews of randomized trials? Stat Med 1987; 6: 233-40. 6. Bamford JTM, Gibson RW, Renier CM. Atopic eczema unresponsive to evening primrose oil (linoleic and gamma-linolenic acids). J Am Acad Dermatol 1985; 13: 959-65. 7. Frosch PJ, Schwanitz HJ, Macher E. A double blind trial of H, and H, receptor antagonists in the treatment of atopic dermatitis. Arch Dermatol Res 1984; 276: 36-40. 8. Strannegard I-L, Svennerholm L, Strannegard O. Essential fatty adds in serum lecithin of children with atopic dermatitis and in umbilical cord serum of infants with high or low IgE levels. Int Arch Allergy Appl Immunol 1987; 82: 422-23. 9. Melnik BC, Plewig G. Is the origin of atopy linked to deficient conversion of omega-6 fatty adds to prostaglandin E1? J Am Acad Dermatol 1989; 21: 557-63. 10. Galli E, Picardo M, De Luca C, et al. Essential fatty acids in cord blood lymphocytes of infants at risk for atopy. Pediatric Res 1989; 26: 519.
Interlaboratory inconsistencies in detection of anticardiolipin antibodies
*In SD above mean. tln units reported by G IgG isotype; M =
=
laboratory as substantially raised. IgM isotype, - = negative.
The results emphasise the discrepancies in reporting of ACA positive values from various laboratories. Although published work suggests
an
association between ACA and
recurrent
spontaneous
abortion, there is debate about the predictability of pregnancy loss. Lockshin5 found a positive ACA to have a predictive value of 0.562 for fetal death. The data presented here and the low predictive value call into question the usefulness of a single ACA ELISA test in the diagnosis of wolnen with RSA. These data also highlight the frustrations of the clinician who wishes to use the results in the management of patients. The appropriateness of applying these irreproducible results to clinical treatment deserves consideration. Center for Reproduction and Transplant Immunology, Methodist Hospital of Indiana, Indianapolis, IN 46202, USA, and Foundation for Blood Research,
Scarborough, Maine
CAROLYN B. COULAM JOHN A. MCINTYRE DAWN WAGENKNECHT NEAL ROTH
ML, Goei S, et al. Antibody to cardiolipin asa predictor of fetal distress or death in pregnant patients with systemic lupus erythematosus. N Engl J Med 1985; 313: 152-56. 2. Triplett DA. Antiphospholipid antibodies and recurrent pregnancy loss. Am J Reprod Immunol 1989; 20: 52-67. 3. Harris EN, Hughes GRV. Standardising the anticardiolipin antibody test. Lancet 1987; i: 277. 4. Loizou S, McCrea JD, Rudge AC, Reynolds R, Boyle CC, Harris EN. Measurement of anticardiolipin by an enzyme linked immunosorbent assay (ELISA): standardization and quantitation of results. Clin Exp Immunol 1985; 62: 738-45. 5. Lockshin MD. Anticardiolipin antibodies in pregnant patients with systemic lupus erythematosus. N Engl J Med 1986; 314: 1392-93. 1. Lockshin MD, Druzin
SIR,-Raised concentrations of anticardiolipin antibodies (ACA) associated with recurrent spontaneous abortion and fetal death.1,2 Although Harris and Hughes3 reported the need for standardisation of the ACA test, neither the usefulness nor the reproducibility of ACA assays has been assessed in the diagnosis of women with recurrent spontaneous abortion (RSA). To establish the reproducibility of tests for ACA, blood samples from 20 women with a history of RSA were sent to four independent laboratories, including two commercial laboratories (Speciality Laboratories, Santa Monica, CA, USA; and Smith Kline and French Reference Laboratories, Van Nuys, CA) and two research laboratories (Center for Reproduction and Transplantation Immunology, Methodist Hospital of Indiana, Indianapolis, IN; and Foundation for Blood Research, Scarborough, ME). ACA were measured by ELISA with a modification of Loizou and colleagues’ method.4 A total of 80 assays for ACA were analysed (4 samples for each woman). 10 (12-5%) of these were over 5 SD above the mean for that laboratory and were interpreted as positive. These 10 positive results were obtained from 8 (40%) women. The table summarises the results of ACA testing in these 8 women. In only 2 were positive ACA results shown by two laboratories. The 6 other women had a positive ACA reported by one laboratory and negative results by three. Of the 10 positive samples 7 had raised IgG concentrations and 4 had increased IgM. In 1 sample both IgG and IgM were are
raised (patient 8). 1 patient (no 4) who was reported positive by two laboratories also had a raised activated partial thromboplastin time.
risk of anaphylactic shock during surgery for spina bifida SIR,-Slater1 has reported two patients with spina bifida who had latex-induced anaphylactic shock during surgery. In 1989 we observed three identical cases; two of the patients were also sensitised to ethylene oxide (table), used to sterilise latex gloves. Two of these patients have an allergic background. We think it is reasonable to suspect an abnormal frequency of sensitisation to latex and ethylene oxide, which are recognised allergens, in children with spina bifida who undergo multiple operations and sometimes daily catheterisation, bringing them into contact with these substances. We obtained sera from eight children with spina bifida to test for atopy and for specific IgE RAST (table). None of these children has had anaphylactic shock. The results uphold our hypothesis since two of the eight children were sensitised to latex and two to ethylene oxide, and four were atopic (table). Atopy predisposes to latex allergy.2 In spida bifida, we believe, there is a much higher risk of anaphylactic shock than in other patients.3-’ We would emphasise the need for screening to detect these sensitisations-by skin prick tests for latex and by RAST for latex and ethylene oxide. For prevention, we recommend the sterilisation of catheters and surgical gloves by gamma-rays and
High
avoidance of the
use
of latex.
866
DETAILS OF SPINA BIFIDA PATIENTS WITH ANAPHYLACTIC SHOCK OR WHO WERE SYMPTOM-FREE
*By ’Phadiatop’ test (Pharmacia) NSA!D=non-stero!da! antt-inflammatory drugs; TAO = trtacetyloleandomycin.
Is this frequent sensitisation due only to repeated contacts with these substances? In over ten years’ investigation we have not observed anaesthesia-induced shock in children with repeated surgical procedures but without spina bifida.5 We suggest that this condition is correlated with a predisposition to formation of specific IgE for proteins and haptens. Although spina bifida develops in the embryo with no known anomaly of the genome, the possible existence of a link between this condition and atopy is worthy of consideration. Medicine D (Immunoallergology), Hôpital de Brabois, 54511 Vandoeuvre Nancy, France
D. A. MONERET-VAUTRIN E. MATA
Unité Inserm 308, Faculte de Medecine, Vandoeuvre Nancy
J. L. GUEANT
Centre d’Education Motrice, Grenoble
D. TURGEMAN
Department of Anaesthesia, Hôpital Central, Nancy
M. C. LAXENAIRE
1. Slater JE. Rubber anaphylaxis. N Engl J Med 1989; 320: 1126-30. 2. Turjanmaa K. Incidence of immediate allergy to latex gloves in hospital personnel. Contact Dermatiits 1987; 17: 270-75. 3. Gerber AC, Jorg W, Zbinden S, Seger RA, Dangel PH. Severe intraoperative anaphylaxis to surgical gloves: latex allergy, an unfamiliar condition. Anesthesiology 1989; 71: 800-02. 4. Leynadier F, Pecquet C, Dry J. Anaphylaxis to latex during surgery. Anaesthesia 1989; 44: 547-50. 5. Laxenaire MC, Moneret-Vautrin DA, Verdloet D. The French experience of anaphylactoid reactions. Int Anesthesiol Clin 1985; 23: 145-60.
Cyclosporin monitoring in psoriasis SIR,-Dr Bos
and
colleagues (Dec 23/30, p 1500), reporting on cyclosporin (’Sandimmun’ 3 mg/kg daily) in psoriasis, suggest monthly measurement of trough concentrations of this drug. We have evaluated cyclosporin trough levels as predictors of clinical events in 134 adults with severe disabling psoriasis who were treated with cyclosporin 2-5 mg/kg daily in two doses. The dose remained unchanged for the first month so weeks 1-4 were selected for the analysis. Cyclosporin levels were measured in whole blood by radioimmunoassay, with a monoclonal antibody specific to the parent compound and a tritium-labelled tracer (sandimmun kit). The mean of four consecutive blood level low-dose
treatment with
Reduction in PASI (panel A) and increase in serum creatinine over baseline (panel B) at week 4 by specific cyclosporin blood level.
Each circle represents 1 patient and is the value of four (at weeks 1, 2, 3, and 4). Total number of patients 134
measurements
1,2,3, and 4) was calculated and correlated efficacy and renal dysfunction at week 4. The mean cyclosporin level was 103 (SEM 5) ng/ml. Inter-individual variability was 53%. Efficacy was assessed by the percentage reduction (39 [3]%) in psoriasis activity and severity index (PASI)1 and renal dysfunction was evaluated by the percentage change in serum creatinine from baseline level (6 [1]%). As shown in the figure, no significant correlation was found between cyclosporin levels and efficacy or renal dysfunction. On the basis of experience with maintenance cyclosporin in transplantation, a cut-off of 100 ng/ml was selected for efficacy and 200 ng/ml for renal dysfunction.4 10 out of 53 patients (19%) with levels of 100 ng/ml or more had success at week 4 (75% or more reduction in PASI) compared with 5/81 (6%) with lower cyclosporin levels (p 0-040, Fisher’s exact test). The frequency of renal dysfunction (creatinine increase 30% or more above baseline) was 1/10 where the cyclosporin level was 200 ng/ml or more and 7/124 for lower levels (not significant). On the one hand, the cyclosporin level had significant but low predictive value for efficacy and no predictive value for renal
measurements (at weeks to
=
