772 nor whether this was unfortunate. The statement in editorial in the British Medical ,ournal,3 that ascertainment through affected boys "would allow most carriers to be identified", is also unlikely to be true. The yield in Lyons of 9/109,000 affected boys,’ leading to 25 uncertain and 3 certain carriers, may seem a good one. However, 6 boys without a family history are unlikely to define more than twice as many true carriers, and most of the 25 women "who have taken or will take advantage of the genetic information provided in this way" are likely to be non-carriers on purely statistical grounds. Any response, until safe and reliable fetal diagnosis is available, is likely to involve the great majority of those consequently unborn being unaffected. With such a poor yield at so high a cost it is tempting to extend screening to the female. However, this temptation must be resisted until techniques improve. Little is known of the creatine-kinase levels in infancy of either normal girls or carriers, and carriers cannot at present have their status confirmed unless they reproduce; small girls cannot do this for ten
leagues,2
Letters
to
the Editor
an
EARLY DIAGNOSIS OF DUCHENNE’S DISEASE
SIR,-Dellamonica and colleagues’ join Beckman et al. in recommending neonatal screening as a means of preventing Duchenne disease. The implications of screening one child so that another, as yet unborn, might benefit by not being born, can only be justified if those responsible are adequately informed, if the various contingencies of response are explicit, and if the magnitude of the various types of error anticipated is estimated. As the few dozen people with adequate knowledge and experience in this difficult area are far from in accord, I present my own estimate of the effects of such policies on the incidence of the disease and on the cost (casualty-rate) as reflecting the proportion of normal children among those conse-
quently unborn. First we must clarify the language since the distinct concepts of prevention, non-conception, abortion, abortion of males, and abortion of affected males are often confounded. The term secondary case is inappropriate in a non-infective disorder and familial is simpler. In practice most avoidable familial cases will be brothers of affected boys: many will be conceived before the first is diagnosed, and it is this group which it is the aim of screening procedures to intercept before conception or before birth. Prevention involves a reduction in the mutation-rate of the offending unit, whose nature is unknown; the inexorable similarity of incidence in various places adequately studied suggests that the prospect of prevention may be slight. Since prevention is, at any rate with present knowledge, impossible, we can expect about 100 new cases and 200-400 newly mutated units per year in the UK. Without intervention these will become lost:
(1) By chance,
with
or
without
a
harmless passage
through
one or
more women.
(2) By causing the death without progeny of a male without the mediation of any female carrier. (3) By causing the death of one male via one or more female carriers. (4) By causing the death of several males via one or more female
years or more.
Studies of
a
strictly observational
nature on a
local
girls’
school4 (the girls and their parents were assured that no reports would be issued and the identities have now been destroyed) yielded a "carrier-rate", on the levels suggested by Beckman and his colleagues, which was some hundredfold the likely carrier-rate. Any successful attempt to discourage the reproduction of such girls would have yielded hundreds of nonbirths for each Duchenne not born. The discrimination is so poor in this age-group that even sisters of affected boys could well benefit from not being tested until puberty. In view of the intellectual and physical resources now being diverted to this disorder there would seem every prospect of a reliable carrier test by the time most small girls, and most sisters of newly diagnosed boys, reach puberty. Infant
Development Unit, Department of Clinical Genetics, Birmingham Maternity Hospital, Birmingham B15 2TG
J. H. EDWARDS
DITHRANOL OR PHOTOCHEMOTHERAPY FOR PSORIASIS?
carriers.
Approximately equal numbers of newly mutated units may expected to leave mankind through these four exits, but in (4), there are several deaths per mutant and, with the British parity structure, about half the cases will be in this category
be
-i.e., about 50 cases will involve carriers and 30 or so will follow a previous victim of the same mutant unit. If every woman who had an affected son diagnosed at birth had no more children then, since the expectation of a baby chosen at random being followed by another is just over a half and being followed by a brother just over a quarter, and since well below a half of such brothers are affected, such a strategy would lead to over 10 non-births of normal children for each Duchenne child not born. If such a prognosis suppressed conception this would reduce the incidence from about 100 to about 70 births and deaths a year. In practice carrier detection, though uncertain, would lower this casualty-rate, as would selective abortion. On the other hand, a proportion of women would certainly respond to this prognosis by attempting to have at least one surviving child, or even at least one surviving son. Local experience suggests that a bad prognosis inhibits, but does not prevent, conception. This position will improve when the acquisition of fetal blood becomes safer and the reliability of fetal diagnosis is confirmed. It is not clear what advice was given in the first case by Beckman and his colDellamonica, Ch., Robert, J. M., Cotte, J., Collombel, C., Dorche, C. Lancet, 1978, ii, 1100. 2. Beckman, R., Sauer, M., Ketelsen, U-P., Scheuerbrandt, G. ibid. 1978, ii,
SIR,-The report by Dr Rogers and her colleagues, (March 3, p. 455) comparing dithranol and P.U.V.A. (therapy with
psoralens and long-wave ultraviolet) in the treatment of chronic psoriasis is a valuable contribution to our knowledge of the management of this disabling disease. Some of the results reported, however, and certain conclusions drawn may not apply to the management of patients in other centres. The report seems to compare erythematous apples with hyperpigmented oranges-all the patients to be treated with the Ingram dithranol routine were admitted to hospital whereas the P.U.V.A. group were outpatients. Any comparison of the two treatments thus becomes unrealistic. Exin the largest teaching hospital in Novia Scotia has shown that daily outpatient treatment with the Ingram routine has been enthusiastically accepted by almost all patients, since they are able to proceed to their day’s work after the treatment, which takes about an hour in the morning. The average daily cost of this outpatient treatment is around$20;$200 per day is the current cost of inpatient treatment. The duration of treatment does not differ significantly between those treated as inpatients or as outpatients. Very few of our patients have objected to the staining produced by dithranol, or to the minor inconvenience of wearing the covering suit, and they quickly overcome their reluctance when they observe the satisfactory results of this treatment. Nevertheless,
of the
costs
perience
1.
105.
3. British Medical Journal, 1979, 4. Bundey, S., Crawley, M. G., (in the press).
i, 215. Edwards, J. H., Westhead, R. J. med Genet.
773 RESULTS OF INITIAL AND MAINTENANCE TREATMENT
hypersensitivity to dithranol (almost always temporary), and experience some treatment failures. The joint Newcastle/London report does not tell us the we
do
encounter
length of the remissions obtained after successful clearing of the psoriasis. Workers in other centres have stated that recurrences of psoriasis are relatively common after p.u.v.A. treatment, and that many patients require booster treatments every two weeks, or even weekly, for an indefinite period to control their psoriasis. This significantly increases the amount of exposure to long-wave ultraviolet light, with its attendant potential hazards. The conclusion of the report that "P.U.V.A. cannot be recommended as the first line of treatment" is in our present state of ignorance of long-term effects, most appropriate, and so also is the recommendation that the use of P.U.V.A. should be limited to a few centres until more is known of its long-term effects. It would be tragic if we provoked skin cancer in a large number of patients as a result of treating them for a disabling but relatively benign disease. Victoria General Hospital, Halifax, Nova Scotia, Canada
D. R. S. HOWELL
ULTRAVIOLET B PHOTOTHERAPY FOR PSORIASIS IN SUNLIGHT-RESPONSIVE PATIENTS
*Drop-outs from treatment (see text). tEvery 4 days.
SIR,-For some years now, patients with psoriasis have been treated with P.u.v.A.-i.e., oral administration of a photoac tive drug (8-methoxypsoralen) followed by exposure to longwave ultraviolet-A light (320-400 nm).1.2 During P.U.V.A. therapy the patient must protect eyes and skin from sunlight after treatment and practise contraception. Ultraviolet B phototherapy is now attracting attention. In experiments with ultraviolet in the B range (313 nm) without photoactive drugs Fischer3 obtained good results in cases with small psoriatic lesions. We have obtained promising results with U.V.B. phototherapy in fifteen selected patients with long-standing and stable psoriasis. The criterion for selection was that the psoriasis had repeatedly shown striking improvement after sunbathing. We used a panel of twelve Philips TL-12 40 W fluorescent tubes; irradiance at 50cm was 3-1mW/cm2 of 280-380 nm, peaking at 305 nm. Before treatment, light tests were carried out with the light panel to determine the minimal erythemal dose (M.E.D.) for two areas, the back and one lower leg. The U.V.B. dose used for the first treatment was equal to the highest lighttest dose that did not induce redness. Since the M.E.D. was definitely lower for the back than for the legs in all patients an additional irradiation was given on the lower legs and the elbows during the treatment in both the initial and the main-
range
phases. The dosage was increased by 30% per session unless erythema developed. The longest exposure-time for each side of the body, including the additional irradiation of lower legs and elbows, was 30 min (5-55 J/cm2) during the initial phase and 10 min (1-85 J/cm2) during the maintenance phase. During the initial (clearing) phase, four irradiations were given weekly, the total number ranging from 15 to 30 (mean 23) (see table). Thirteen of the fifteen patients showed a clearance of 80-100% of the psoriatic plaques relative to the pretreatment state, except on the scalp. The results could be maintained by administering one irradiation every 1-5 weeks (mean once every 14 days) for 6-40 weeks (mean 21 weeks). Three patients were dropped: patient 15 was found to be an alcoholic and in patients 13 and 14 a tendency to rapid relapse required a more frequent irradiation than was considered justified. Like Fischer,3 we found that the wavelengths in the U.V.B.
tenance
1
Parrish, J A., Fitzpatrick, T. B., Tanenbaum, L., Pathak, M. A. New Engl. J Med 1974, 291, 1207. 2 Rogers, S., Marks, J., Shuster, S., Briffa, D. V., Warin, A., Greaves, M. Lancet, 1979, i, 455 3 Fischer, T. Acta dermatovener. 1976, 56, 473.
(290-320 nm) are very effective for the treatment of psoriasis. The high therapeutic scores, which could generally be sustained by the maintenance treatment, are attributed to two factors-the selection of the patients, based on rapid response of the psoriasis to sunlight, and the method of irradiation, particularly the light tests for two areas, which resulted in the inclusion of an additional irradiation on the lower legs and elbows. The advantages of u.v.B. therapy over P.U.V.A. treatment include the avoidance of oral administration of photosensitisers (and the precautions that that aspect of therapy entail), the shorter exposure-times, and the possibility of home treatment with a simplified light panel. However, just as for the P.U.V.A. treatment, the long-term risk-benefit ratio (oncogenic aspects) must be extensively investigated before this kind of treatment can be recommended for use on a large scale. Department of Dermatology, University Hospital, Leiden, Netherlands
J. BOER A. A. SCHOTHORST D. SUURMOND
FAST GLYCOSYLATION OF HÆMOGLOBIN
Sm,—Dr Svendsen and his colleagues (March 17, p. 603) report dissociation of HbA1c in one patient within 12 h of control of hyperglycasmia. They suggest that glycosylation of HbA is a rapidly reversible process and that estimation of glycosylated haemoglobin is thus of limited clinical value. We agree that decreases of glycosylated haemoglobin can be rapid but disagree with the suggestion that clinically significant changes occur within a matter of hours. We suggest a clinically significant decrease in HbA, is unlikely to happen in less than a week. To determine how quickly HbA1 can fall we studied eight newly diagnosed insulin-dependent diabetics serially for 3 weeks. HbAl was estimated weekly and, in two patients (cases 1 and 2), HbA1 was measured daily for the first week. HbA1 was measured by macrocolumn chromatographic technique. All the patients were in hospital for the first week. On presentation every patient had 2- glycosuria and heavy ketonuria with a mean blood-glucose of 17.5 mmol/I (range 13-1—29-0; 1 mmol/1=18 mg/dl). Subsequent random morning blood-glucoses at the time of HbA1 estimations were all less than 10-5mmol/1, and urine tests done four times daily averaged less than 2 except in case 3 (average 1’). Results of are shown in the table. All patients showed
HbA1
leagues,2
Letters
to
the Editor
an
EARLY DIAGNOSIS OF DUCHENNE’S DISEASE
SIR,-Dellamonica and colleagues’ join Beckman et al. in recommending neonatal screening as a means of preventing Duchenne disease. The implications of screening one child so that another, as yet unborn, might benefit by not being born, can only be justified if those responsible are adequately informed, if the various contingencies of response are explicit, and if the magnitude of the various types of error anticipated is estimated. As the few dozen people with adequate knowledge and experience in this difficult area are far from in accord, I present my own estimate of the effects of such policies on the incidence of the disease and on the cost (casualty-rate) as reflecting the proportion of normal children among those conse-
quently unborn. First we must clarify the language since the distinct concepts of prevention, non-conception, abortion, abortion of males, and abortion of affected males are often confounded. The term secondary case is inappropriate in a non-infective disorder and familial is simpler. In practice most avoidable familial cases will be brothers of affected boys: many will be conceived before the first is diagnosed, and it is this group which it is the aim of screening procedures to intercept before conception or before birth. Prevention involves a reduction in the mutation-rate of the offending unit, whose nature is unknown; the inexorable similarity of incidence in various places adequately studied suggests that the prospect of prevention may be slight. Since prevention is, at any rate with present knowledge, impossible, we can expect about 100 new cases and 200-400 newly mutated units per year in the UK. Without intervention these will become lost:
(1) By chance,
with
or
without
a
harmless passage
through
one or
more women.
(2) By causing the death without progeny of a male without the mediation of any female carrier. (3) By causing the death of one male via one or more female carriers. (4) By causing the death of several males via one or more female
years or more.
Studies of
a
strictly observational
nature on a
local
girls’
school4 (the girls and their parents were assured that no reports would be issued and the identities have now been destroyed) yielded a "carrier-rate", on the levels suggested by Beckman and his colleagues, which was some hundredfold the likely carrier-rate. Any successful attempt to discourage the reproduction of such girls would have yielded hundreds of nonbirths for each Duchenne not born. The discrimination is so poor in this age-group that even sisters of affected boys could well benefit from not being tested until puberty. In view of the intellectual and physical resources now being diverted to this disorder there would seem every prospect of a reliable carrier test by the time most small girls, and most sisters of newly diagnosed boys, reach puberty. Infant
Development Unit, Department of Clinical Genetics, Birmingham Maternity Hospital, Birmingham B15 2TG
J. H. EDWARDS
DITHRANOL OR PHOTOCHEMOTHERAPY FOR PSORIASIS?
carriers.
Approximately equal numbers of newly mutated units may expected to leave mankind through these four exits, but in (4), there are several deaths per mutant and, with the British parity structure, about half the cases will be in this category
be
-i.e., about 50 cases will involve carriers and 30 or so will follow a previous victim of the same mutant unit. If every woman who had an affected son diagnosed at birth had no more children then, since the expectation of a baby chosen at random being followed by another is just over a half and being followed by a brother just over a quarter, and since well below a half of such brothers are affected, such a strategy would lead to over 10 non-births of normal children for each Duchenne child not born. If such a prognosis suppressed conception this would reduce the incidence from about 100 to about 70 births and deaths a year. In practice carrier detection, though uncertain, would lower this casualty-rate, as would selective abortion. On the other hand, a proportion of women would certainly respond to this prognosis by attempting to have at least one surviving child, or even at least one surviving son. Local experience suggests that a bad prognosis inhibits, but does not prevent, conception. This position will improve when the acquisition of fetal blood becomes safer and the reliability of fetal diagnosis is confirmed. It is not clear what advice was given in the first case by Beckman and his colDellamonica, Ch., Robert, J. M., Cotte, J., Collombel, C., Dorche, C. Lancet, 1978, ii, 1100. 2. Beckman, R., Sauer, M., Ketelsen, U-P., Scheuerbrandt, G. ibid. 1978, ii,
SIR,-The report by Dr Rogers and her colleagues, (March 3, p. 455) comparing dithranol and P.U.V.A. (therapy with
psoralens and long-wave ultraviolet) in the treatment of chronic psoriasis is a valuable contribution to our knowledge of the management of this disabling disease. Some of the results reported, however, and certain conclusions drawn may not apply to the management of patients in other centres. The report seems to compare erythematous apples with hyperpigmented oranges-all the patients to be treated with the Ingram dithranol routine were admitted to hospital whereas the P.U.V.A. group were outpatients. Any comparison of the two treatments thus becomes unrealistic. Exin the largest teaching hospital in Novia Scotia has shown that daily outpatient treatment with the Ingram routine has been enthusiastically accepted by almost all patients, since they are able to proceed to their day’s work after the treatment, which takes about an hour in the morning. The average daily cost of this outpatient treatment is around$20;$200 per day is the current cost of inpatient treatment. The duration of treatment does not differ significantly between those treated as inpatients or as outpatients. Very few of our patients have objected to the staining produced by dithranol, or to the minor inconvenience of wearing the covering suit, and they quickly overcome their reluctance when they observe the satisfactory results of this treatment. Nevertheless,
of the
costs
perience
1.
105.
3. British Medical Journal, 1979, 4. Bundey, S., Crawley, M. G., (in the press).
i, 215. Edwards, J. H., Westhead, R. J. med Genet.
773 RESULTS OF INITIAL AND MAINTENANCE TREATMENT
hypersensitivity to dithranol (almost always temporary), and experience some treatment failures. The joint Newcastle/London report does not tell us the we
do
encounter
length of the remissions obtained after successful clearing of the psoriasis. Workers in other centres have stated that recurrences of psoriasis are relatively common after p.u.v.A. treatment, and that many patients require booster treatments every two weeks, or even weekly, for an indefinite period to control their psoriasis. This significantly increases the amount of exposure to long-wave ultraviolet light, with its attendant potential hazards. The conclusion of the report that "P.U.V.A. cannot be recommended as the first line of treatment" is in our present state of ignorance of long-term effects, most appropriate, and so also is the recommendation that the use of P.U.V.A. should be limited to a few centres until more is known of its long-term effects. It would be tragic if we provoked skin cancer in a large number of patients as a result of treating them for a disabling but relatively benign disease. Victoria General Hospital, Halifax, Nova Scotia, Canada
D. R. S. HOWELL
ULTRAVIOLET B PHOTOTHERAPY FOR PSORIASIS IN SUNLIGHT-RESPONSIVE PATIENTS
*Drop-outs from treatment (see text). tEvery 4 days.
SIR,-For some years now, patients with psoriasis have been treated with P.u.v.A.-i.e., oral administration of a photoac tive drug (8-methoxypsoralen) followed by exposure to longwave ultraviolet-A light (320-400 nm).1.2 During P.U.V.A. therapy the patient must protect eyes and skin from sunlight after treatment and practise contraception. Ultraviolet B phototherapy is now attracting attention. In experiments with ultraviolet in the B range (313 nm) without photoactive drugs Fischer3 obtained good results in cases with small psoriatic lesions. We have obtained promising results with U.V.B. phototherapy in fifteen selected patients with long-standing and stable psoriasis. The criterion for selection was that the psoriasis had repeatedly shown striking improvement after sunbathing. We used a panel of twelve Philips TL-12 40 W fluorescent tubes; irradiance at 50cm was 3-1mW/cm2 of 280-380 nm, peaking at 305 nm. Before treatment, light tests were carried out with the light panel to determine the minimal erythemal dose (M.E.D.) for two areas, the back and one lower leg. The U.V.B. dose used for the first treatment was equal to the highest lighttest dose that did not induce redness. Since the M.E.D. was definitely lower for the back than for the legs in all patients an additional irradiation was given on the lower legs and the elbows during the treatment in both the initial and the main-
range
phases. The dosage was increased by 30% per session unless erythema developed. The longest exposure-time for each side of the body, including the additional irradiation of lower legs and elbows, was 30 min (5-55 J/cm2) during the initial phase and 10 min (1-85 J/cm2) during the maintenance phase. During the initial (clearing) phase, four irradiations were given weekly, the total number ranging from 15 to 30 (mean 23) (see table). Thirteen of the fifteen patients showed a clearance of 80-100% of the psoriatic plaques relative to the pretreatment state, except on the scalp. The results could be maintained by administering one irradiation every 1-5 weeks (mean once every 14 days) for 6-40 weeks (mean 21 weeks). Three patients were dropped: patient 15 was found to be an alcoholic and in patients 13 and 14 a tendency to rapid relapse required a more frequent irradiation than was considered justified. Like Fischer,3 we found that the wavelengths in the U.V.B.
tenance
1
Parrish, J A., Fitzpatrick, T. B., Tanenbaum, L., Pathak, M. A. New Engl. J Med 1974, 291, 1207. 2 Rogers, S., Marks, J., Shuster, S., Briffa, D. V., Warin, A., Greaves, M. Lancet, 1979, i, 455 3 Fischer, T. Acta dermatovener. 1976, 56, 473.
(290-320 nm) are very effective for the treatment of psoriasis. The high therapeutic scores, which could generally be sustained by the maintenance treatment, are attributed to two factors-the selection of the patients, based on rapid response of the psoriasis to sunlight, and the method of irradiation, particularly the light tests for two areas, which resulted in the inclusion of an additional irradiation on the lower legs and elbows. The advantages of u.v.B. therapy over P.U.V.A. treatment include the avoidance of oral administration of photosensitisers (and the precautions that that aspect of therapy entail), the shorter exposure-times, and the possibility of home treatment with a simplified light panel. However, just as for the P.U.V.A. treatment, the long-term risk-benefit ratio (oncogenic aspects) must be extensively investigated before this kind of treatment can be recommended for use on a large scale. Department of Dermatology, University Hospital, Leiden, Netherlands
J. BOER A. A. SCHOTHORST D. SUURMOND
FAST GLYCOSYLATION OF HÆMOGLOBIN
Sm,—Dr Svendsen and his colleagues (March 17, p. 603) report dissociation of HbA1c in one patient within 12 h of control of hyperglycasmia. They suggest that glycosylation of HbA is a rapidly reversible process and that estimation of glycosylated haemoglobin is thus of limited clinical value. We agree that decreases of glycosylated haemoglobin can be rapid but disagree with the suggestion that clinically significant changes occur within a matter of hours. We suggest a clinically significant decrease in HbA, is unlikely to happen in less than a week. To determine how quickly HbA1 can fall we studied eight newly diagnosed insulin-dependent diabetics serially for 3 weeks. HbAl was estimated weekly and, in two patients (cases 1 and 2), HbA1 was measured daily for the first week. HbA1 was measured by macrocolumn chromatographic technique. All the patients were in hospital for the first week. On presentation every patient had 2- glycosuria and heavy ketonuria with a mean blood-glucose of 17.5 mmol/I (range 13-1—29-0; 1 mmol/1=18 mg/dl). Subsequent random morning blood-glucoses at the time of HbA1 estimations were all less than 10-5mmol/1, and urine tests done four times daily averaged less than 2 except in case 3 (average 1’). Results of are shown in the table. All patients showed
HbA1
