371
microscopy, and fundal examination under mydriasis. In some patients additional tests included visual-field testing to a red
Controversy
target
IS CHLOROQUINE OBSOLETE IN TREATMENT OF RHEUMATIC DISEASE?
J. S. MARKS Rheumatism Research Cen tre, Royal Infirmary, Manchester M13 9WL
B. J. POWER* Manchester
testing visual acuity, fundal examination, visual field testing, and by a photostress test (macula dazzled by a bright light and time taken for restoration of best pre-dazzle level of visual acuity recorded).
Royal Eye Hospital, Manchester M13 9WL
changes associated with chloroin 22 out of 222 patients quine on long-term therapy for rheumatic diseases and were related to patient age, total dose, and duration of treatment. Ophthalmic review showed progression of the retinopathy with deteioration of visual acuity in only 1
Summary
(150 cases), fluorescein fundal angiography (22), colour
vision (12), and electro-retinography (4). The patients’ age and the total dose and duration of treatment at the time of their last ophthalmic assessment was recorded. Those patients who had been advised to discontinue treatment because of a suspected chloroquine retinopathy were re-examined for evidence of progression of the retinopathy by
Retinal
occurred
RESULTS
The 222 patients had received a mean total dose of 210 g of chloroquine with a mean duration of treatment of 29 months. TABLE I-RELATION BETWEEN RETINOPATHY AND AGE
case while the remainder retained normal Vision. The results suggest that the risks of ocular toxicity related to chloroquine therapy are acceptablylow.
INTRODUCTION THE beneficial eff-CL ch1on:’quinè in the treatment of rheumatoid 2. ’thT!1 is was established by long-term falling z controlle£ ed trals controlled trials _: but out it7f.., ’? ;falling mio io disfavour because of its ocular side effects The British National Formulary 1976-1978 states that ’Chloroquine is rarely elective andd toxic effectsare frequent and serincluding irreversible retinal damage: it is now regarded as obsolete’’. Recent reviews of drug therapy in rheumatoid arthritis have either omitted any reference to its value4or have condemned its use.5 There is dis-_ about the role of agreement agre ement among among rheumatologists rheumatologists chlroquine in the treatment of the rheumatic diseases and a postal enquiry among.g British rheumatologists indicated that while one third used it. often, 100 or more patients each ye?.’’, the remainder rarely did SO.6 Manchester is oneof few centres in which large numbers of patients are still iteated with chloroquine and we have reviewed these patients in order to assess the freof chloroquine-induced quency and ocular complicatatiorsS ‘
ious,
Chloroquine corneal deposits were an incidental finding on slit-lamp examination in 33 patients (15%) and were not considered an indication for stopping therapy. Corneal deposits were more frequent in older patients but
were
unrelated
to
the total dose
or
duration of treat-
ment.
22 patients (10%) were thought to have a quine-induced retinopathy and treatment was tinued. The mean total dosage of chloroquine
chlorodisconin this
B,..
the
natural history
PATTENTS AND METHODS
The dosage policy in Manchester is to use chloroquine phosphate (‘Avloclor’) 250 ng dailyfor 1 year in the tirst instance If there ia relapse on ster pine therapy chloroquine is often restarted and
attempts
to wean
,_ .’
patients
Fig. 1--Relationship of retinopathy to total dose of chloroquine. Figures abpve columns refer to number of patients treated in that doserange.
on to an
alternate-day or thrice weakly Ophthalmic assessments are then arranged at 6-monthintervals The case records of all --.":’-."" attending the rheumatology outpatient dinics at the disorder Royal Intirmary, Withington Hospital, and the ;- _ , as there Royal Hospital, Buxton, between September, ’- ’’ . --.1 August 1977. were examined to obtain tkt detailassessment on chlorouse quine-treated pattern There were 22 "? , .-_o the study and these included 202 with seropositiver’-’:".’ ’.-.’"’7’ ’’*.::’:; and 20 with systemicic assessment in all cases lupus erythematses ’’." consisted of theeuity,slit-lamp corneal -.
-,
*Present address: Department of Wales, Cardiff CF4 4XW
of
Ophtalmology, University
Hospital
Fig. 2-Relationship of retinopathy to total dose of chloroquine. Figures above columns refer to number of patients treated for that duration.
372 group was 286 g with a mean duration of therapy of 36 months. The incidence of retinopathy increased with the patients’ age (table I) and with both the total dose and duration of chloroquine therapy (figs 1 and 2). The patients who had a retinopathy were reviewed in more detail (table n). All had evidence of abnormal pigmentation around one or both maculx. In 5 cases there was a characteristic ring or bull’s-eye lesion and in 17 patients there was pigmentary mottling or a speckled appearance around the macula, referred to as stippling. 1 patient (case 22) had a paracentral scotoma but visualfield testing in the remainder was normal. None of the patients had any impairment of visual acuity that could be related to the retinopathy. The patients with a retinopathy were reviewed at intervals which varied from 5 to 96 months after stopping chloroquine, to assess whether there had been any progression of the retinopathy (table III). In 9 patients macular appearance had returned to normal and this included 2 patients previously thought to have a bull’s-eye macula. 12 patients had stippling around the maculae including 2 patients with a bull’s-eye macula on initial assessment. 1 patient (case 22) had a typical chloroquine bull’s-eye macula which remained unchanged and she was the only patient with abnormal visual fields and deterioration in visual acuity. The photostress test was abnormal in 3 patients with an otherwise normal ophthalmic assessment (cases 2, 5, 6) but was normal when measured in the patients with mild pigment changes.
TABLE III-FOLLOW-UP OF CASES WITH SUSPECTED
RETINOPATHY
M.S.:
macular stippling
DISCUSSION TABLE II——SUMMARY OF DATA ON PATIENTS WITH SUSPECTED RFTTNnPATT4V
*
Patients with systemic lupus erythematosus. All other patients had rheumatoid arthritis. Patient 22 had paracentral scotoma. Visual fields were full in all other patients. t Patients with bull’s-eye lesion(s). All other patients had macular stip-
pling.
Deposits of chloroquine in the cornea were first described in 19587 and their frequency in other series has varied from 7%8to 68%.9 The deposits occasionally cause photophobia or halo phenomena around lights but usually induce no symptoms and in this study deposits were an incidental finding in 15% of cases and were not considered an indication for stopping treatment. There is no relation between the occurrence of corneal deposits and the development of a retinopathy. The major hazard associated with chloroquine is retinal damage. Chloroquine-induced retinopathy was first described in 195710 and has subsequently been demonstrated in several series. 11-17 The incidence of a retinopathy in different series has varied from less than 1 %18 to more than 15%’9 depending on the definition of what constitutes a retinopathy and the method used for its detection. In this study 22 patients (10%) were first thought to have a retinopathy on the basis of abnormal macular pigmentation but there was a typical bull’s-eye distribution of pigment in only 5 patients and the remainder showed fine pigmentary mottling at the macula which may be an age-related change.16 The recording of central fields to red targets has been recommended as the most reliable index of impending retinal toxicity7 and was used as a screening test in 150 patients. It has been shown in other studies that typical paracentral scotomas may occur without any corresponding macular abnormality2O 21 but in this study there were no visual-field abnormalities in the patients with normal macula; and even in the group with definite macular pigmentary changes the visual fields were usually normal, suggesting that the value of the visualfield test for screening may have been over-emphasised. The frequency of retinopathy increased with patients’
373 age and may indicate that many patients had incipient macular degeneration rather than a chloroquine retinopathy, although another study has suggested that chloroquine therapy may be more hazardous in the elderly. 17 Other studies have shown that the total amount of drug received is the most important risk factor13 22 and we also found that there was a clear relationship between total dose of chloroquine and retinal changes, with 10% of those receiving a total dose of less than 200 g of chloroquine developing retinal changes as opposed to 50% of those receiving more than 600 g.
Public Health
MICRO-PROCESSORS, MACRO-ECONOMIC POLICY, AND PUBLIC HEALTH PETER DRAPER JOHN DENNIS JENNY GRIFFITHS JAMES PARTRIDGE JENNIE POPA
Some authors have commented on the irreversibility23 progression 24 of the retinopathy after discontinuing therapy and this has been a major argument against the use of chloroquine. We therefore re-examined all the patients who had discontinued chloroquine because of a suspected retinopathy. The visual acuity, fundal appearance, and visual fields were re-examined in all patients and some had a photostress test.
Unit for the
or
There was deterioration of visual acuity in only 1 patient (case 22) and this was associated with a bull’s-eye macula and a paracentral scotoma. This patient had received more chloroquine than any of the other patients who had a retinopathy and had also exceeded the daily recommended dose of 250 mg with a mean daily dose of 600 mg. There was regression of macular changes in the other 4 patients initially found to have bull’s-eye maculæ with 2 showing minor pigment changes (caseses 10, 21) and 2 with normal maculae (cases 1, 2). There was no progression of retinal changes in the 17 patients who initially showed mild pigmentary disturbance of the macula and, on later review, in 7 of these patients the maculae were thought to be normal. A delay in recovery time in excess of 40 s after a photostress test has been claimed to be a sensitive index of macular function25 but we could not show any dose correlation between the photostress test and fundal abnormalities. These results show that retinal changes due to chloroare dose-related and are reversible in the early stages; even patients who show the bull’s-eye maculae which are regarded as a feature of advanced chloroquine retinopathy may have reversible changes if visual acuity is normal and there are no visual-field defects.
quine
The risks associated with theuse of chloroquine in the of rheumatoid arthritis should be balanced against the risk of fatal marrow suppression or nephrotoxicity which may occur when drugs of similar effectiveness, such as gold or penicillamine, are used. This study indicates that the ocular hazards associated with long-term chloroquine therapy are low and does not support the view that chloroquine should be regarded as
Study of Health Policy, Department of
Community Medicine, Guy’s Hospital Medical School, London SE1 1YR
"In West Germany, where the micro-processor is known the ’job-killer’, a study by the electrical giant, Siemens, suggests that office employment could fall by 40 per cent by 1990-that, incidentally, is two million jobs." "It was in 1975 that British unemployment began its miserable march toward the plateau of 1.5 million. It has stayed there for a couple of years now, despite job creation schemes and temporary employment subsidies ... Both the Think Tank and the Manpower Services Commission _admit that rising unemployment is the expectation in the medium term (up to ten years)."-The Micro-electronic Revolution. TOM FORESTER, New Society, Nov. 16, 1978. as
Whether the optimists or the pessimists will be proved right about the impact of micro-processors on employment, it is remarkable how those involved in health care in Britain have remained apparently untouched by the public debates on unemployment and what to do about it. High levels of unemployment raise two broad issues in relation to health care: the damage (and, of course, any benefits) to health caused by involuntary unemployment and relative poverty; and the waste of potentially useful employment. First, is there any evidence of damage to health caused by unemployment? Probably the largest and most statistically elaborate inquiries into the effects of unemployment on health and other social indicators in different countries (including the U.K.) has been carried out by an American medical sociologist, Dr Harvey Brenner, and his colleagues of
treatment
obsolete.
6. Popert, A. J. Rheum. Rehab. 1976, 15, 235. 7. Hobbs, H., Calnan, C. Lancet, 1958, i, 1207. 8. Abels, D. J., O’Keefe, T. N., Smith, D., Gutow, R., Falls, H. F., Duff, I. F. Arthrt. Rheum. 1963, 6, 258. 9. Henkind, P., Rothfield, N. F. New Engl. J. Med. 1963, 269, 432. 10. Cambiaggi, A.Archs Ophthal. 1957, 57, 451. 11. Ellsworth, R., Zeller, R. ibid. 1961, 66, 269. 12. Hobbs, H. E., Eadie, S. P., Somerville, F. Br. J. Ophthal. 1961, 45, 284. 13. Scherbel, A. L., Mackenzie, A. H., Nousek, J. E., Atdjian, M. New Engl. J.
Med. 1965, 273, 360
Reprint requests should be addressed
to
J. S.
M.
14. Arden, K. B., Kolb, J. Br. med. J. 1966, i, 270. 15. Nylander, U. Acta ophthal. 1967, suppl. 92, p. 5. 16. Percival, S. P. B., Meanock, I. Br. med. J. 1968, iii, 579. 17. Elman, A., Gullberg, R., Nilsson, E., Rendahl, I., Wachmeister, L. Scand.
J. Rheumat. 1976, 5, 161.
REFERENCES 18.
1 Freedman, A., Steinburg, V. L. Ann. rheum. Dis. 1960, 19, 243. 2 Popert, A. J., Meijers, K. A. E., Sharp, J., Bier, F. ibid. 1961, 20, 18. 3. Mainland, D., Sutcliffe, M. I. Bull. rheum. Dis. 1962, 12, 287. 4 Clins rheum Dis. 1975, 1, 2. S Brooks, P M., Watson Buchanan, W. in Recent Advances in Rheumatology pan 2) (edited by W. Watson Buchanan, W. Carson Dick); p. 59. Edin-
burgh, 1976.
Fuld, H. Lancet, 1959, ii, 617. 19. Kornzweig, A. L., Felstein, M., Schneider, J. Am. J. Ophthal. 1957, 44, 29. 20. Percival, S. P. B., Behman, J. Br. J. Ophthal. 1969, 53, 101. 21. Reed, H., Campbell, A. Can. med. Ass. J. 1962, 86, 176. 22. Nazik, R. A., Weinstock, F. J., Vignos, P. J. Am. J. Ophthal. 1964, 58, 774. 23. Mayer, W. ibid. 1962, 53, 769. 24. Okun, E., Gouras, P., Bernstein, H. N., Van Sallman, L. Archs Ophthal. 1963, 69, 59. 25. Carr, R. E., Henkind, P., Rothfield, N., Siegal, I. M. Am. J. Opthal. 1968, 66, 738.
microscopy, and fundal examination under mydriasis. In some patients additional tests included visual-field testing to a red
Controversy
target
IS CHLOROQUINE OBSOLETE IN TREATMENT OF RHEUMATIC DISEASE?
J. S. MARKS Rheumatism Research Cen tre, Royal Infirmary, Manchester M13 9WL
B. J. POWER* Manchester
testing visual acuity, fundal examination, visual field testing, and by a photostress test (macula dazzled by a bright light and time taken for restoration of best pre-dazzle level of visual acuity recorded).
Royal Eye Hospital, Manchester M13 9WL
changes associated with chloroin 22 out of 222 patients quine on long-term therapy for rheumatic diseases and were related to patient age, total dose, and duration of treatment. Ophthalmic review showed progression of the retinopathy with deteioration of visual acuity in only 1
Summary
(150 cases), fluorescein fundal angiography (22), colour
vision (12), and electro-retinography (4). The patients’ age and the total dose and duration of treatment at the time of their last ophthalmic assessment was recorded. Those patients who had been advised to discontinue treatment because of a suspected chloroquine retinopathy were re-examined for evidence of progression of the retinopathy by
Retinal
occurred
RESULTS
The 222 patients had received a mean total dose of 210 g of chloroquine with a mean duration of treatment of 29 months. TABLE I-RELATION BETWEEN RETINOPATHY AND AGE
case while the remainder retained normal Vision. The results suggest that the risks of ocular toxicity related to chloroquine therapy are acceptablylow.
INTRODUCTION THE beneficial eff-CL ch1on:’quinè in the treatment of rheumatoid 2. ’thT!1 is was established by long-term falling z controlle£ ed trals controlled trials _: but out it7f.., ’? ;falling mio io disfavour because of its ocular side effects The British National Formulary 1976-1978 states that ’Chloroquine is rarely elective andd toxic effectsare frequent and serincluding irreversible retinal damage: it is now regarded as obsolete’’. Recent reviews of drug therapy in rheumatoid arthritis have either omitted any reference to its value4or have condemned its use.5 There is dis-_ about the role of agreement agre ement among among rheumatologists rheumatologists chlroquine in the treatment of the rheumatic diseases and a postal enquiry among.g British rheumatologists indicated that while one third used it. often, 100 or more patients each ye?.’’, the remainder rarely did SO.6 Manchester is oneof few centres in which large numbers of patients are still iteated with chloroquine and we have reviewed these patients in order to assess the freof chloroquine-induced quency and ocular complicatatiorsS ‘
ious,
Chloroquine corneal deposits were an incidental finding on slit-lamp examination in 33 patients (15%) and were not considered an indication for stopping therapy. Corneal deposits were more frequent in older patients but
were
unrelated
to
the total dose
or
duration of treat-
ment.
22 patients (10%) were thought to have a quine-induced retinopathy and treatment was tinued. The mean total dosage of chloroquine
chlorodisconin this
B,..
the
natural history
PATTENTS AND METHODS
The dosage policy in Manchester is to use chloroquine phosphate (‘Avloclor’) 250 ng dailyfor 1 year in the tirst instance If there ia relapse on ster pine therapy chloroquine is often restarted and
attempts
to wean
,_ .’
patients
Fig. 1--Relationship of retinopathy to total dose of chloroquine. Figures abpve columns refer to number of patients treated in that doserange.
on to an
alternate-day or thrice weakly Ophthalmic assessments are then arranged at 6-monthintervals The case records of all --.":’-."" attending the rheumatology outpatient dinics at the disorder Royal Intirmary, Withington Hospital, and the ;- _ , as there Royal Hospital, Buxton, between September, ’- ’’ . --.1 August 1977. were examined to obtain tkt detailassessment on chlorouse quine-treated pattern There were 22 "? , .-_o the study and these included 202 with seropositiver’-’:".’ ’.-.’"’7’ ’’*.::’:; and 20 with systemicic assessment in all cases lupus erythematses ’’." consisted of theeuity,slit-lamp corneal -.
-,
*Present address: Department of Wales, Cardiff CF4 4XW
of
Ophtalmology, University
Hospital
Fig. 2-Relationship of retinopathy to total dose of chloroquine. Figures above columns refer to number of patients treated for that duration.
372 group was 286 g with a mean duration of therapy of 36 months. The incidence of retinopathy increased with the patients’ age (table I) and with both the total dose and duration of chloroquine therapy (figs 1 and 2). The patients who had a retinopathy were reviewed in more detail (table n). All had evidence of abnormal pigmentation around one or both maculx. In 5 cases there was a characteristic ring or bull’s-eye lesion and in 17 patients there was pigmentary mottling or a speckled appearance around the macula, referred to as stippling. 1 patient (case 22) had a paracentral scotoma but visualfield testing in the remainder was normal. None of the patients had any impairment of visual acuity that could be related to the retinopathy. The patients with a retinopathy were reviewed at intervals which varied from 5 to 96 months after stopping chloroquine, to assess whether there had been any progression of the retinopathy (table III). In 9 patients macular appearance had returned to normal and this included 2 patients previously thought to have a bull’s-eye macula. 12 patients had stippling around the maculae including 2 patients with a bull’s-eye macula on initial assessment. 1 patient (case 22) had a typical chloroquine bull’s-eye macula which remained unchanged and she was the only patient with abnormal visual fields and deterioration in visual acuity. The photostress test was abnormal in 3 patients with an otherwise normal ophthalmic assessment (cases 2, 5, 6) but was normal when measured in the patients with mild pigment changes.
TABLE III-FOLLOW-UP OF CASES WITH SUSPECTED
RETINOPATHY
M.S.:
macular stippling
DISCUSSION TABLE II——SUMMARY OF DATA ON PATIENTS WITH SUSPECTED RFTTNnPATT4V
*
Patients with systemic lupus erythematosus. All other patients had rheumatoid arthritis. Patient 22 had paracentral scotoma. Visual fields were full in all other patients. t Patients with bull’s-eye lesion(s). All other patients had macular stip-
pling.
Deposits of chloroquine in the cornea were first described in 19587 and their frequency in other series has varied from 7%8to 68%.9 The deposits occasionally cause photophobia or halo phenomena around lights but usually induce no symptoms and in this study deposits were an incidental finding in 15% of cases and were not considered an indication for stopping treatment. There is no relation between the occurrence of corneal deposits and the development of a retinopathy. The major hazard associated with chloroquine is retinal damage. Chloroquine-induced retinopathy was first described in 195710 and has subsequently been demonstrated in several series. 11-17 The incidence of a retinopathy in different series has varied from less than 1 %18 to more than 15%’9 depending on the definition of what constitutes a retinopathy and the method used for its detection. In this study 22 patients (10%) were first thought to have a retinopathy on the basis of abnormal macular pigmentation but there was a typical bull’s-eye distribution of pigment in only 5 patients and the remainder showed fine pigmentary mottling at the macula which may be an age-related change.16 The recording of central fields to red targets has been recommended as the most reliable index of impending retinal toxicity7 and was used as a screening test in 150 patients. It has been shown in other studies that typical paracentral scotomas may occur without any corresponding macular abnormality2O 21 but in this study there were no visual-field abnormalities in the patients with normal macula; and even in the group with definite macular pigmentary changes the visual fields were usually normal, suggesting that the value of the visualfield test for screening may have been over-emphasised. The frequency of retinopathy increased with patients’
373 age and may indicate that many patients had incipient macular degeneration rather than a chloroquine retinopathy, although another study has suggested that chloroquine therapy may be more hazardous in the elderly. 17 Other studies have shown that the total amount of drug received is the most important risk factor13 22 and we also found that there was a clear relationship between total dose of chloroquine and retinal changes, with 10% of those receiving a total dose of less than 200 g of chloroquine developing retinal changes as opposed to 50% of those receiving more than 600 g.
Public Health
MICRO-PROCESSORS, MACRO-ECONOMIC POLICY, AND PUBLIC HEALTH PETER DRAPER JOHN DENNIS JENNY GRIFFITHS JAMES PARTRIDGE JENNIE POPA
Some authors have commented on the irreversibility23 progression 24 of the retinopathy after discontinuing therapy and this has been a major argument against the use of chloroquine. We therefore re-examined all the patients who had discontinued chloroquine because of a suspected retinopathy. The visual acuity, fundal appearance, and visual fields were re-examined in all patients and some had a photostress test.
Unit for the
or
There was deterioration of visual acuity in only 1 patient (case 22) and this was associated with a bull’s-eye macula and a paracentral scotoma. This patient had received more chloroquine than any of the other patients who had a retinopathy and had also exceeded the daily recommended dose of 250 mg with a mean daily dose of 600 mg. There was regression of macular changes in the other 4 patients initially found to have bull’s-eye maculæ with 2 showing minor pigment changes (caseses 10, 21) and 2 with normal maculae (cases 1, 2). There was no progression of retinal changes in the 17 patients who initially showed mild pigmentary disturbance of the macula and, on later review, in 7 of these patients the maculae were thought to be normal. A delay in recovery time in excess of 40 s after a photostress test has been claimed to be a sensitive index of macular function25 but we could not show any dose correlation between the photostress test and fundal abnormalities. These results show that retinal changes due to chloroare dose-related and are reversible in the early stages; even patients who show the bull’s-eye maculae which are regarded as a feature of advanced chloroquine retinopathy may have reversible changes if visual acuity is normal and there are no visual-field defects.
quine
The risks associated with theuse of chloroquine in the of rheumatoid arthritis should be balanced against the risk of fatal marrow suppression or nephrotoxicity which may occur when drugs of similar effectiveness, such as gold or penicillamine, are used. This study indicates that the ocular hazards associated with long-term chloroquine therapy are low and does not support the view that chloroquine should be regarded as
Study of Health Policy, Department of
Community Medicine, Guy’s Hospital Medical School, London SE1 1YR
"In West Germany, where the micro-processor is known the ’job-killer’, a study by the electrical giant, Siemens, suggests that office employment could fall by 40 per cent by 1990-that, incidentally, is two million jobs." "It was in 1975 that British unemployment began its miserable march toward the plateau of 1.5 million. It has stayed there for a couple of years now, despite job creation schemes and temporary employment subsidies ... Both the Think Tank and the Manpower Services Commission _admit that rising unemployment is the expectation in the medium term (up to ten years)."-The Micro-electronic Revolution. TOM FORESTER, New Society, Nov. 16, 1978. as
Whether the optimists or the pessimists will be proved right about the impact of micro-processors on employment, it is remarkable how those involved in health care in Britain have remained apparently untouched by the public debates on unemployment and what to do about it. High levels of unemployment raise two broad issues in relation to health care: the damage (and, of course, any benefits) to health caused by involuntary unemployment and relative poverty; and the waste of potentially useful employment. First, is there any evidence of damage to health caused by unemployment? Probably the largest and most statistically elaborate inquiries into the effects of unemployment on health and other social indicators in different countries (including the U.K.) has been carried out by an American medical sociologist, Dr Harvey Brenner, and his colleagues of
treatment
obsolete.
6. Popert, A. J. Rheum. Rehab. 1976, 15, 235. 7. Hobbs, H., Calnan, C. Lancet, 1958, i, 1207. 8. Abels, D. J., O’Keefe, T. N., Smith, D., Gutow, R., Falls, H. F., Duff, I. F. Arthrt. Rheum. 1963, 6, 258. 9. Henkind, P., Rothfield, N. F. New Engl. J. Med. 1963, 269, 432. 10. Cambiaggi, A.Archs Ophthal. 1957, 57, 451. 11. Ellsworth, R., Zeller, R. ibid. 1961, 66, 269. 12. Hobbs, H. E., Eadie, S. P., Somerville, F. Br. J. Ophthal. 1961, 45, 284. 13. Scherbel, A. L., Mackenzie, A. H., Nousek, J. E., Atdjian, M. New Engl. J.
Med. 1965, 273, 360
Reprint requests should be addressed
to
J. S.
M.
14. Arden, K. B., Kolb, J. Br. med. J. 1966, i, 270. 15. Nylander, U. Acta ophthal. 1967, suppl. 92, p. 5. 16. Percival, S. P. B., Meanock, I. Br. med. J. 1968, iii, 579. 17. Elman, A., Gullberg, R., Nilsson, E., Rendahl, I., Wachmeister, L. Scand.
J. Rheumat. 1976, 5, 161.
REFERENCES 18.
1 Freedman, A., Steinburg, V. L. Ann. rheum. Dis. 1960, 19, 243. 2 Popert, A. J., Meijers, K. A. E., Sharp, J., Bier, F. ibid. 1961, 20, 18. 3. Mainland, D., Sutcliffe, M. I. Bull. rheum. Dis. 1962, 12, 287. 4 Clins rheum Dis. 1975, 1, 2. S Brooks, P M., Watson Buchanan, W. in Recent Advances in Rheumatology pan 2) (edited by W. Watson Buchanan, W. Carson Dick); p. 59. Edin-
burgh, 1976.
Fuld, H. Lancet, 1959, ii, 617. 19. Kornzweig, A. L., Felstein, M., Schneider, J. Am. J. Ophthal. 1957, 44, 29. 20. Percival, S. P. B., Behman, J. Br. J. Ophthal. 1969, 53, 101. 21. Reed, H., Campbell, A. Can. med. Ass. J. 1962, 86, 176. 22. Nazik, R. A., Weinstock, F. J., Vignos, P. J. Am. J. Ophthal. 1964, 58, 774. 23. Mayer, W. ibid. 1962, 53, 769. 24. Okun, E., Gouras, P., Bernstein, H. N., Van Sallman, L. Archs Ophthal. 1963, 69, 59. 25. Carr, R. E., Henkind, P., Rothfield, N., Siegal, I. M. Am. J. Opthal. 1968, 66, 738.
