Hydroxychloroquine Therapy in Massive Total Doses Without Retinal Toxicity

Hydroxychloroquine Therapy in Massive Total Doses Without Retinal Toxicity Mark W. Johnson, M . D . , and A n d r e w K. V i n e , M . D .

To assess the relationship between hydroxychloroquine retinal toxicity and total dose, we selectively reviewed the histories of patients who had received an additive dose exceeding 1,000 g. No retinopathy was found in nine patients treated with massive total hydroxychloroquine doses ranging from 1,054 to 3,923 g. Eight of these patients were taking recommended daily doses of 400 mg/day or less and showed no evidence of toxicity. The remaining patient treated with 600 mg/day showed evidence of preretinopathy in one eye. THE ANTIMALARIAL DRUGS chloroquine and hydroxychloroquine have been used since the early 1950s in the treatment of rheumatoid arthritis, systemic lupus erythematosus, discoid lupus, and other rheumatologic and dermatologic disorders. A recent report 1 advocates expansion of the role for chloroquine in the treatment of the calcium abnormalities of sarcoidosis. Since chloroquine retinopathy was first described by Hobbs, Sorsby, and Freedman in 1959,2 the fear of retinal toxicity has been a significant deterrent to the use of antimalarial drugs in chronic disease. Many investigators have primarily related the incidence of retinopathy to the total or cumulative drug dose.3"6 It is generally accepted that a cumulative dose of 100 g of chloroquine can cause retinopathy and that the risk of retinopathy increases significantly when the additive dose exceeds 300 g. 36 " Several recent reports, however, have suggested that patients who are followed u p closely on recommended daily doses of antimalarial

Accepted for publication April 23, 1987. From the Department of Ophthalmology, W. K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan. Reprint requests to Andrew K. Vine, M.D., Retina Service, W. K. Kellogg Eye Center, 1000 Wall St., Ann Arbor, MI 48105-1994.

drugs may tolerate large cumulative doses with little or no toxicity. 811 These studies question the relation between cumulative dosage and retinopathy, but minimal experience with massive total doses has been reported. 1213 In order to determine the incidence and severity of retinopathy in patients treated with massive total doses, we selectively reviewed those patients examined at our institution who had received a total dose of hydroxychloroquine exceeding 1,000 g.

Patients and Methods We reviewed the records of all patients followed up in our institution's hydroxychloroquine clinic w h o had received a cumulative hydroxychloroquine dose that exceeded 1,000 g. The initial examination included a medical history, visual acuity testing by Snellen chart, Amsler grid testing, color vision testing using Ishihara plates, and the Farnsworth-Munsell 100-hue test, automated (Humphrey) central field testing with a red test object, ophthalmoscopy, color fundus photographs, and, in selected patients, fluorescein angiography. Patients were followed up at four- to six-month intervals. In each patient, total dose calculations and examination results from the most recent clinic visit were evaluated. The Farnsworth-Munsell 100-hue test was administered monocularly under a lamp, which generated average daylight or Type C illumination. In grading the results, consideration was given to the total error score as well as to the distribution of errors. Total error scores were evaluated using parameters suggested by Verriest, Laethem, and Uvijls.14 Central visual fields were tested by Humphrey automated static threshold perimetry. A size III (4 mm2) red test object was displayed against background illumination of 31.5 apostilbs. A grid pattern of 56 points in a 7

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x 8 array with an interpoint distance of 4 degrees was used to cover the central 10 degrees of visual field. Criteria for abnormality were chosen as follows: two or more adjacent points of 5 dB loss each, or a single point of 10 dB loss (where loss refers to the difference between the measured and expected threshold values).

Results Nine patients had received a total dose of hydroxychloroquine exceeding 1,000 g (Table 1). Seven women were receiving hydroxychloroquine for systemic lupus erythematosus. Two men had rheumatoid arthritis. Patient age ranged from 27 to 60 years. Total hydroxychloroquine dose varied from 1,054 to 3,923 g, and duration of treatment ranged from seven to 26 years. At the time of last examination, all patients were receiving a daily dose of 400 mg of hydroxychloroquine or less, except Patient 3 who was taking 600 mg per day. Two other patients had received daily doses in excess of 400 mg previously but not within the last ten years. Daily dosage adjusted for weight was based on actual body weight at the time of the last examination (Table 1). At the last examination all patients were asymptomatic except Patient 3 who reported intermittent photopsias. Visual acuity was

20/20 in all eyes (Table 2). Amsler grid and Ishihara color plate tests were normal in all patients tested. Results of fluorescein angiography were normal in the two patients tested (Patients 1 and 7). Farnsworth-Munsell 100-hue tests were graded using age-related critical values for abnormality, as suggested by Verriest, Laethem, and Uvijls.14 All eyes had normal values by these criteria except the right eye of Patient 3. This eye had a total error score that was borderline abnormal; the distribution of errors was nonspecific.15 Automated static perimetry of the central 10-degree visual fields with a red test object was normal in all patients except Patient 3. This patient, who had a history of a right hemispheric cerebrovascular accident associated with surgical clipping of a cerebral aneurysm, had an incongruous left homonymous hemanopia. Additionally, there was a small, shallow, superior paracentral depression in the right eye. Ophthalmoscopy disclosed normal macular pigmentation in five patients. In the other four patients (Patients 3, 4, 5, and 9), biomicroscopy showed subtle, fine granularity of the macular pigment epithelium. All of these patients had been referred to the hydroxychloroquine clinic after initiation of therapy, and the pigment granularity had been noted on the first visit. It was therefore not possible to determine wheth-

TABLE 1 PATIENT CHARACTERISTICS AND HYDROXYCHLOROQUINE DOSAGE DATA DAILY DOSE PATIENT

ADJUSTED FOR WEIGHT

NO.. AGE (YRS),

SEX

1,39, F 2, 60, M

(MG/KQ BODY

DURATION

TOTAL DOSE

(MG)

WEIGHT/DAY)

(YRS)

(G)

7.1 2.9

9 25

1,278 3,923

6.3 6.3

9 26

1,971 3,902

4.9 4.2 7.4 4.0 3.9

7 14 15 13 10

1,054 3,400 1,990 1,190 1,460

DIAGNOSIS*

SLE RA

3,44, F 4,44, F

SLE SLE

5,51, 6, 50, 7, 43, 8, 27, 9, 45,

RA SLE SLE SLE SLE

M F F F F

DAILY DOSE

400 800 600 200 600 600 400 400 300 400 250 400

X X X

X X

4 yrs 9 yrs 12 yrs* 16 yrs 10 yrs'

* SLE, systemic lupus erythematosus; RA, rheumatoid arthritis. ' Current dosage listed last.

Hydroxychloroquine Therapy

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TABLE 2 EXAMINATION RESULTS*

PATIENT NO.

VISUAL ACUITY

AMSLER GRID

ISHIHARA COLOR PLATES

20/20

Normal

10/10

20/20

Normal

10/10

RED FM-100f

CENTRAL FIELDS

OPHTHALMOSCOPY

Normal

Normal

Normal

Normal

R.E.: 189

Paracentral depression

Pigment granularity

L.E.: 161

Normal

R.E.:

75

Normal

Pigment granularity

L.E.:

96 Normal

Pigment granularity

Normal

Normal

Normal

Normal

Normal

Normal

Normal

Pigment granularity

R.E.:

24

L.E.:

28

R.E.: 106 L.E.:

20/20 20/20 20/20 20/20 20/20 20/20 20/20

— Normal Normal Normal Normal Normal Normal

10/10 10/10 10/10 10/10 10/10 10/10

99

R.E.: 108 L.E.:

74

R.E.:

80

L.E.:

56

R.E.:

66

L.E.:

93

R.E.:

72

L.E.:

98

R.E.: 111 L.E.: 104

"Results were the same for both eyes unless listed separately. 'FM-100, Farnsworth-Munsell 100-huetest.

er the pigment patterns were related to drug therapy, aging, or normal variation. Patient 4 elected with her referring physician to stop hydroxychloroquine therapy rather than undergo fluorescein angiography; her macular appearance was unchanged at the six-month follow-up examination. Patient 5 had shown no change in macular pigmentation since his initial fundus photographs one year earlier and was considered normal. Patient 9 had not been receiving hydroxychloroquine for six months because he no longer required treatment and did not expect to resume treatment. Patient 3, who showed borderline abnormalities of color vision and red central field in the right eye and had fine macular pigment granularity bilaterally, exhibited signs of possible early toxicity. The patient refused fluorescein angiography and the referring physician discontinued hydroxychloroquine therapy. The patient did not return for follow-up testing.

Discussion Estimates of the overall incidence of antimalarial retinopathy vary widely depending on

the criteria used to define it. Voipio's 3 review of the literature found incidence figures ranging from less than 1% to 22%. Bernstein's 16 review presented estimates ranging from less than 1% to 16%, but stressed that most series showed a low retinopathy incidence of less than 1% to 2%. Most of the more than 200 reported cases of antimalarial retinopathy have been chloroquine-induced, reflecting the predominant use of chloroquine during the years when higher doses were commonly used. Much of the literature regarding retinopathy is therefore based on experience with chloroquine despite the much greater current use of hydroxychloroquine. Early studies suggested that the incidence of chloroquine retinopathy is related to the total dose and duration of treatment. Reed and Campbell 17 reported that a total dose of 100 g can be retinopathic. Voipio3 concluded that the practical risk of retinopathy begins with a total dose of 100 g or duration of treatment greater than one year. This conclusion was supported by the finding of Carr, Gouras, and Gunkel 4 that perifoveal retinal thresholds were significantly increased when the total chloroquine dose exceeded 100 g. Nylander 6 suggested that

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the risk of retinopathy increases significantly with a total dose greater than 300 g, and reported a 58% incidence of retinopathy with total doses exceeding 900 g. In 1965, Scherbel and associates 18 suggested that excessive daily dosage, rather than cumulative dose or duration of therapy, may be the critical determinant in chloroquine retinopathy. In a large series of patients treated with moderate daily doses of antimalarial drugs (250 mg of chloroquine, 400 mg of hydroxychloroquine) they found no cases of definite retinopathy despite high total doses. Young and associates 19 reported that in a series of 1,000 patients receiving chloroquine, those treated with 500 mg/day had a much greater incidence of retinopathy than those receiving 250 mg/day, despite higher total doses in the latter group. In his review, Bernstein 16 found no patients with retinopathy who had received doses less than 250 mg/day, noting that most reported cases had occurred at a daily dose of 500 mg or greater. Numerous reports subsequently emphasized that in patients treated with the recommended chloroquine dose of 250 mg/day, the incidence of retinopathy with visual loss is negligible.8,9'n'20"23 The first well-documented case of maculopathy secondary to hydroxychloroquine was reported by Crews in 1964.2i Shearer and Dubois 12 found one case of retinopathy among 94 patients treated with an average dose of 800 mg daily. Although Mills, Beck, and Power25 reported a 29% incidence of mild macular pigmentary changes in high total-dose patients receiving daily doses of 200 to 600 mg, subsequent studies on patients receiving doses of 400 mg per day or less have shown no cases of definite retinopathy. 26 ' 28 Tobin, Krohel, and Rynes 1013 reported the results of a prospective, seven-year follow-up study of 99 patients treated with 400 mg of hydroxychloroquine daily (total doses ranging up to 1,255 g). Only four patients developed evidence of early toxicity, which was reversible when therapy was discontinued. They found no relationship between toxicity and total dose. Mackenzie 11 detected no retinopathy in over 900 patients treated with less than 4.0 mg/kg of body weight/day of chloroquine or less than 6.5 mg/kg of body weight/day of hydroxychloroquine, even when total doses exceeded 1,000 g. Finding a highly significant difference between the daily dosage rate of patients without retinopathy and patients with retinopathy, he suggested a daily dosage threshold for reti-

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nopathy below which the drugs are safe. He emphasized that overdosage may occur with standard doses (400 mg/day of hydroxychloroquine, 250 mg/day of chloroquine) if lean body weight is not taken into account. There was no information given on how patients were followed up ophthalmologically or how retinopathy was defined. In a study of antimalarial drug dosage in children, Laaksonen, Koskiahde, and Juva29 found the frequency of side effects to be related to the daily, rather than total, dose. Suggested values for maximum safe daily doses, adjusted for weight, were virtually identical to Mackenzie's 11 values. Additional experimental support for this concept was reported by Frisk-Holmberg and associates, 30 who found a relationship between side effects and serum concentrations but not the total dose of chloroquine. The term premaculopathy has been used by many authors 0 ' 10 - 21 to describe subtle, asymptomatic macular changes which are reversible on discontinuation of the drug. These consist of macular pigment mottling, loss of the foveal light reflex, and paracentral scotomata to a red but not a white test object. Of these, red central field changes are the most reliable and sensitive indicators of reversible premaculopathy. 10,21,31 Early chloroquine-related pigment granularity and changes in the light reflex are frequently impossible to distinguish from normal variations, aging changes, or manifestations of connective tissue disease, 18 particularly when there are no baseline (pretreatment) studies. Our series supports the conclusion that patients receiving daily doses of hydroxychloroquine of less than 6.5 mg/kg of body weight/day may tolerate massive total doses without the development of functionally significant retinal toxicity. We found no retinopathy in nine patients receiving a total dose ranging from 1,054 to 3,923 g of hydroxychloroquine. In one patient (Patient 3) a shallow red central field depression in one eye as well as borderline color vision abnormality and macular pigment granularity was indicative of premaculopathy. Subtle pigment granularity in three patients with normal red central fields was not ascribed to hydroxychloroquine toxicity since no interval change was observed in these patients during treatment and since red field testing was considered a more reliable indicator of premaculopathy. All patients in this series were taking recommended daily doses of hydroxychloroquine

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(400 m g / d a y or less) except Patient 3 w h o took 600 m g / d a y . All p a t i e n t s h a d a daily d o s a g e rate a d j u s t e d for w e i g h t (Table 1) below t h e r e t i n o toxic t h r e s h o l d (7.8 m g / k g of b o d y w e i g h t / d a y ) s u g g e s t e d by Mackenzie. 1 1 W h e n a d j u s t e d for lean b o d y w e i g h t (from M e t r o p o l i t a n Life Ins u r a n c e C o m p a n y tables), o n l y t h e daily d o s age rate of Patient 3 (9.8 m g / k g of b o d y w e i g h t / day) e x c e e d e d t h e t h r e s h o l d . We also c o m p a r e d d o s a g e d a t a of t h e p a t i e n t s in o u r series to t h o s e of p a t i e n t s w i t h k n o w n hydroxychloroquine maculopathy. The only patient with retinopathy w h o had undergone the b a t t e r y of tests in o u r h y d r o x y c h l o r o q u i n e clinic w a s a 43-year-old w o m a n w i t h r h e u m a toid arthritis referred for a s e c o n d o p i n i o n r e g a r d i n g h e r m a c u l o p a t h y . She h a d b e e n t r e a t e d w i t h a total d o s e of 730 g of h y d r o x y c h l o r o q u i n e over four y e a r s at a n a v e r a g e daily d o s e of 500 m g . O n e x a m i n a t i o n , visual acuity w a s R.E.: 20/25 a n d L.E.: 20/20. F a r n s w o r t h M u n s e l l 100-hue test r e s u l t s w e r e n o r m a l , p e r i central s c o t o m a s w e r e p r e s e n t , a n d bilateral bull's-eye p i g m e n t a r y m a c u l o p a t h y w a s s e e n by o p h t h a l m o s c o p y a n d fluorescein a n g i o g r a p h y (Figure). A l t h o u g h h e r total d o s e w a s well below t h a t of o u r n i n e p a t i e n t s , h e r daily d o s e a d j u s t e d for w e i g h t w a s 10.6 m g / k g of b o d y w e i g h t / d a y c o m p a r e d w i t h a n a v e r a g e of 5.7 m g / k g of b o d y w e i g h t / d a y for o u r p a t i e n t s . H e r daily d o s a g e rate a d j u s t e d for w e i g h t w a s well a b o v e t h e retinotoxic t h r e s h o l d s u g g e s t e d by Mackenzie. 1 1 We c o n c l u d e d t h a t p a t i e n t s receiving r e c o m -

Figure (Johnson and Vine). Fluorescein angiogram of left macula in patient with hydroxychloroquine retinopathy.

143

m e n d e d daily d o s e s (400 m g / d a y or 6.5 m g / k g of b o d y w e i g h t / d a y , w h i c h e v e r is less) 11 m a y tolerate m a s s i v e total d o s e s of h y d r o x y c h l o r o quine without developing retinopathy. Our findings s u p p o r t t h e t h e o r y t h a t daily d o s e is a m o r e i m p o r t a n t d e t e r m i n a n t of retinal toxicity t h a n c u m u l a t i v e d o s e . C o n t r a r y to w i d e l y h e l d belief, t h e r e a p p e a r s to b e n o u p p e r limit o n the total h y d r o x y c h l o r o q u i n e d o s e t h a t can be u s e d safely in p a t i e n t s receiving j u d i c i o u s daily doses w h o are followed-up regularly.

References 1. O'Leary, T. J., Jones, G., Yip, A., Lohnes, D., Cohanim, M., and Yendt, E. R.: The effects of chloroquine on serum 1,25-dihydroxyvitamin D and calcium metabolism in sarcoidosis. N. Engl. J. Med. 315:727, 1986. 2. Hobbs, H. E., Sorsby, A., and Freedman, A.: Retinopathy following chloroquine therapy. Lancet 2:478, 1959. 3. Voipio, H.: Incidence of chloroquine retinopathy. Acta Ophthalmol. 44:349, 1966. 4. Carr, R. E., Gouras, P., and Gunkel, R. D.: Chloroquine retinopathy. Early detection by retinal threshold test. Arch. Ophthalmol. 75:171, 1966. 5. Arden, G. B., and Kolb, H.: Antimalarial therapy and early retinal changes in patients with rheumatoid arthritis. Br. Med. J. 1:270, 1966. 6. Nylander, U.: Ocular damage in chloroquine therapy. Acta Ophthalmol. 45(suppl. 92):5, 1967. 7. Bernstein, H. N.: Ophthalmologic considerations and testing in patients receiving long-term antimalarial therapy. Am. J. Med. 75(1A):25, 1983. 8. Elman, A., Gullberg, R., Nilsson, E., Rendahl, I., and Wachtmeister, L.: Chloroquine retinopathy in patients with rheumatoid arthritis. Scand. J. Rheumatol. 5:161, 1976. 9. Marks, J. S.: Is chloroquine obsolete in the treatment of rheumatic disease? Lancet 1:371, 1979. 10. Rynes, R. I.: Ophthalmologic safety of longterm hydroxychloroquine sulfate treatment. Am. J. Med. 75(1A):35, 1983. 11. Mackenzie, A. H.: Dose refinements in longterm therapy of rheumatoid arthritis with antimalarials. Am. J. Med. 75(1A):40, 1983. 12. Shearer, R. V., and Dubois, E. L.: Ocular changes induced by long-term hydroxychloroquine (Plaquenil) therapy. Am. J. Ophthalmol. 64:245, 1967. 13. Tobin, D. R., Krohel, G. B., and Rynes, R. L.: Hydroxychloroquine. Seven-year experience. Arch. Ophthalmol. 100:81, 1982. 14. Verriest, G., Laethem, J. V., and Uvijls, A.: A new assessment of the normal ranges of the

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Farnsworth-Munsell 100-hue test scores. Am. J. Ophthalmol. 93:635, 1982. 15. Farnsworth, D.: The Farnsworth-Munsell 100hue Test for the Examination of Color Discrimination. Baltimore, Munsell Color Company, Inc., 1957. 16. Bernstein, H. N.: Chloroquine ocular toxicity. Surv. Ophthalmol. 12:415, 1967. 17. Reed, H., and Campbell, A. A.: Central scotomata following chloroquine therapy. Can. Med. J. 86:176, 1962. 18. Scherbel, A. L., Mackenzie, A. H., Nousek, J. E., and Atdjian, M.: Ocular lesions in rheumatoid arthritis and related disorders with particular reference to retinopathy. N. Engl. J. Med. 273:360, 1965. 19. Young, P., Isbey, E. K., Briggs, H. H., and Bronson, D. W.: Chloroquine retinopathy. A preliminary report of a five-year study. Arthritis Rheum. 9:552, 1966. 20. Percival, S. P. B., and Meanock, I.: Chloroquine. Ophthalmological safety, and clinical assessment in rheumatoid arthritis. Br. Med. J. 3:579, 1968. 21. Percival, S. P. B., and Behrman, J.: Ophthalmological safety of chloroquine. Br. J. Ophthalmol. 53:101, 1969. 22. Petrohelos, M. A.: Chloroquine-induced ocular toxicity. Ann. Ophthalmol. 6:615, 1974. 23. Marks, J. S.: Chloroquine retinopathy. Is there a safe daily dose? Ann. Rheum. Dis. 41:52, 1982.

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24. Crews, S. J.: Chloroquine retinopathy with recovery in early stages. Lancet 2:436, 1964. 25. Mills, P. V., Beck, M., and Power, B. J.: Assessment of the retinal toxicity of hydroxychloroquine. Trans. Ophthalmol. Soc. U.K. 101:109, 1981. 26. Frenkel, M.: Safety of hydroxychloroquine (correspondence). Arch. Ophthalmol. 100:841, 1982. 27. Mantyjarvi, M.: Hydroxychloroquine treatment and the eye. Scand. J. Rheumatol. 14:171, 1985. 28. Finbloom, D. S., Silver, K., Newsome, D. A., and Gunkel, R.: Comparison of hydroxychloroquine and chloroquine use and the development of retinopathy. J. Rheumatol. 12:692, 1985. 29. Laaksonen, A., Koskiahde, V., and Juva, K.: Dosage of antimalarial drugs for children with juvenile rheumatoid arthritis and systemic lupus erythematosis. Scand. J. Rheumatol. 3:103, 1974. 30. Frisk-Holmberg, M., Bergkvist, Y., DomeijNyberg, B., Hellstrom, L., and Jansson, F.: Chloroquine serum concentration and side effects. Evidence for dose-dependent kinetics. Clin. Pharmacol. Ther. 25:345, 1979. 31. Hart, W. M., Burde, R. M., Johnston, G. P, and Drews, R. C : Static perimetry in chloroquine retinopathy. Perifoveal patterns of visual field depression. Arch. Ophthalmol. 102:377, 1984. 32. Abramowicz, M. (ed.): Drugs for rheumatoid arthritis. Med. Lett. Drugs Ther. 29:21, 1987.