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Low-dose cyclosporin therapy of ocular inflammation: Preliminary report of a long-term follow-up study
Journal of Autoimmunity (1992) 5 (Supplement A), 259-264
Low-dose Cyclosporin Therapy of Ocular Inflammation: P r e l i m i n a r y Report of a L o n g - t e r m Follow-up Study
Hamish
M. A. T o w l e r , *
Susan
L. Lightman*
and John V. Forrestert
*Department of Clinical Ophthalmology, Moorfields Eye Hospital, London and ~fDepartment of Ophthalmology, University of Aberdeen, Aberdeen, UK
C y c l o s p o r i n A ( C s A ) is a n effective t h e r a p y f o r s e v e r e i n t r a o c u l a r i n f l a m m a t i o n b u t n e p h r o t o x i c i t y a n d h y p e r t e n s i o n a r e m a j o r s i d e effects e v e n in low d o s e in c o m b i n a t i o n w i t h o r a l c o r t i c o s t e r o i d s a n d c l i n i c a l s t u d i e s on t h e l o n g - t e r m effects o f l o w - d o s e C s A t h e r a p y o u t s i d e t h e field o f o r g a n transplantation are lacking. This multicentre, open, longitudinal study has b e e n e s t a b l i s h e d to e v a l u a t e t h e l o n g - t e r m efficacy a n d s i d e effects o f l o w d o s e C s A t h e r a p y ( i n i t i a l d o s e ~<5 m g ] k g ] d a y , w i t h a m a x i m u m d o s e o f 7 m g / k g ] d a y , a n d t o t a l t r e a t m e n t d u r a t i o n > 3 m o n t h s ) in s e v e r e o c u l a r i n f l a m m a t i o n w h e r e c o n v e n t i o n a l t h e r a p y h a d f a i l e d to c o n t r o l t h e d i s e a s e o r c a u s e d i n t o l e r a b l e s i d e effects. V i s u a l r e s p o n s e to t r e a t m e n t , c l i n i c a l s i g n s a n d s y m p t o m s o f s i d e effects, b i o c h e m i c a l a n d h a e m a t o l o g i c a l parameters have been recorded at 3-monthly intervals since January 1987 a n d will c o n t i n u e u n t i l D e c e m b e r 1993. D a t a f o r 74 p a t i e n t s (age 35.5 _ 16.6 y e a r s ) a n d 293 f o l l o w u p v i s i t s a r e p r e s e n t e d in t h i s p r e l i m i n a r y report.
[Mean + SEM]
Serum creatinine (ltmol/l)
Creatinine clearance (ml/min)
Blood pressure (mmHg) Systolic Diastolic
Pre-treatment During treatment
88.4 _+2.30 99.2 _+1.67
130.5 + 12.2 71.9 + 10.5
123.3 _+2.00 130.2 + 1.48
78.6 + 1.37 83.5 + 0.98
O t h e r s i d e effects i n c l u d e ( % o f a l l visits): h y p e r t r i c h o s i s (4.2), h e a d a c h e (2.8), c r a m p s (1.8), a r t h r o p a t h y (1.8), p a r a e s t h e s i a e (1.8), a b d o m i n a l p a i n (1.5), w e a k n e s s (1.5), d y s p e p s i a (1.4), n a u s e a (1.4), o t h e r s (4).
Introduction D u r i n g t h e last 8 years, C s A has b e c o m e f i r m l y e s t a b l i s h e d as an effective t r e a t m e n t for severe s i g h t - t h r e a t e n i n g o c u l a r i n f l a m m a t i o n w h i c h has p r o v e d e i t h e r r e f r a c t o r y 259 0896-8411/92/0A0259 + 06 $03.00/0
© 1992 Academic Press Limited
260
H . M . A . T o w l e r e t al.
T a b l e 1. Endogenous ocular inflammatory diseases
treated with cyclosporin Intermediate uveitis/pars planitis Idiopathic retinal vasculitis Behqet's disease Posterior uveitis Scleritis Panuveitis Sympathetic ophthalmia Birdshot choroidopathy Sarcoidosis Corneal graft rejection Geographic choroiditis Acute retinitis Corneal melting Mooren's ulcer
19 13 10 8 7 4 3 2 2 2 1 1 1 1
to corticosteroids alone or where the dose or side effects of corticosteroids have been unacceptable [1-3]. M o s t of the clinical data regarding the efficacy of CsA therapy has come f r o m open, uncontrolled studies [1-3] and the only two double-masked studies of CsA treatment of uveitis [4, 5] have employed a dose of 10 mg/kg/day which is associated with a high incidence of nephrotoxicity and hypertension [6, 7]. L o w - d o s e CsA treatment ( ~<5 mg/kg/day), in combination with corticosteroids or alone, has been shown to be successful in the m a n a g e m e n t of intra-ocular inflammation but nephrotoxicity and hypertension remain the major dose-limiting side effects, particularly in older patients [8]. F u r t h e r m o r e , the chronic nature of m a n y of these diseases demands long-term therapy and the m a x i m u m safe dose and duration of CsA therapy in non-organ transplant disorders remains to be established. This open, multicentre study was designed to assess the side effect profile, long-term safety and clinical efficacy of low-dose CsA treatment in patients with differing forms of severe inflammatory eye disease.
Methods
Patients with endogenous ocular inflammatory diseases (Table 1) treated with an initial CsA dose of ~<5 mg/kg/day, m a x i m u m CsA dose ~<7 mg/kg/day, and for m o r e than 3 months were eligible for entry into the study. Concomitant treatment with other anti-inflammatory agents including corticosteroids was permitted. T h e visual response to treatment, signs and s y m p t o m s of side effects, biochemical and haematological monitoring parameters, and concurrent drug therapy were recorded at 3monthly intervals on standardized forms from three participating centres. T h e maintenance CsA dose was adjusted to achieve the lowest dose compatible with control of inflammation, minimal nephrotoxicity and specific target CsA levels in whole blood. Prospective data from entry into the study and retrospective data from January 1987 recorded for 74 patients and a total of 293 follow-up visits are presented.
Cyclosporin for ocular i n f l a m m a t i o n
3
•
CF
261
6/60 PRE TREATMENT VISUAL ACUITY
HMt
|
6/36
6/24 --
6/18 -- • 6/12 ~
OiO •
•
•
•
000
•
•
•
•
•
I~
6/9
6/6
:
-
~ 6/6
6/9
6/12
6/18
6/24
6/36
6/60
CF
HM
POST-TREATMENT VISOAL ACUITY
Figure 1. Visual outcomeduring CsA treatment at 6 months. PL
.J-
HM CF 6/60 PRE TREATMENT VISUAL ACUITY
6/36 6/24 6/18 6/12
S
6/9
•
6/6 6/6
6/9
6/12
6/18
6/24
POST T R E A T M ~
6/36
6/60
CF
HM
VISUAL ACUITY
Figure 2. Visual outcomeduring CsA treatment at 12 months. Results
T h e resuhs of visual outcome during the first 2 years of CsA therapy are shown in Figures 1-4. On average during this period, 52 Yo of patients showed an improvement in visual acuity of at least one Snellen line, 33% remained stable and 19Yo deteriorated. Vitreous opacification diminished in 45%, remained the same in 52Yo and increased in only 3 %. T h e mean ( + SEM) serum creatinine rose significantly during CsA treatment from 88.4_+ 2.30 to 99.2 + 1.67 ( P < 0.001, Student's t-test) though remaining within the reference range during the first year of treatment (Figure 5). T h e mean systolic blood pressure rose from 123.5_+ 1.88 to 133.4_+ 1.31 m m H g ( P < 0 . 0 0 1 , Student's t-test) and the mean diastolic pressure from 78.8_+ 1.28 to 84.6 + 0.85 m m H g ( P < 0.001, Student's t-test) during CsA treatment. Patients who
262
H . M . A . Towler e t al. PL HM •
CF
• •
@
•
• 4
6/60 PRETREATM]~IT VISUAL ACUITY
6/36
|
*
6/9
6/12
.
/
6/24 6/18 6/12 6/9 6/6 6/6
6/18
6/24
POST-TREATM2~WT
6/36
6/60
CF
HM
PL
VISUAL ACUITY
Figure 3. Visual outcome during CsA treatment at 18 months. PL HM
../
CF 6/60 PRETREATMENT VISUAL ACUITY
6/36 6/24 6/18 6/12 6/9 6/6 6/6
6/9
6/12
6/18
6/24
6/36
6/60
CF
HM
PL
POST-TREATMENT VISUAL ACUITY
Figure 4. Visual outcome during CsA treatment at 24 months.
developed hypertension (systolic pressure > 160 m m H g and/or diastolic pressure > 95 m m H g ) showed a significantly greater rise in mean serum creatinine over the first 2 years of C s A treatment than those in w h o m the blood pressure remained normal (Figure 6). D o c u m e n t e d side effects are listed in Table 2. W h o l e blood CsA levels showed no correlation with changes in serum creatinine levels or the development of any side effects (data not shown).
Discussion T h i s study has confirmed the visual benefits of CsA therapy over a sustained period in patients with severe sight threatening ocular inflammation, with 85 % showing
C y c l o s p o r i n for o c u l a r i n f l a m m a t i o n
263
150 140 130
+
120
S~UM CREATI~INE [~mol/l]
110 100 90
+**÷+
+
+
80 70
6
~
g
~
la
lg
DDRATION OF TREATMEWT
ta
.~1
.24
[months]
Figure 5. Serum creatinine changes during CsA treatment.
150
•
HYPERT~SIVE N O R M O T E N S IVE
140 130 120 S~UM CI~W~ATININE [~mol/l]
+ +
110 100 90 80 70 0
3
6
9
12
15
18
21
24
D U R A T I O N OF TREATMI~WT [months}
Figure 6. Serum creatinine changes during CsA treatment in normotensive ( • ) and hypertensive ( • ) patients.
T a b l e 2.
Cyclosporin side effects (% of all follow-up visits)
Hypertrichosis Headache Paraesthesiae Cramps Arthropathy Abdominal pain Dyspepsia Weakness Nausea Ankle swelling Skin rash Warts Vitiligo
12 8 5 5 5 5 4 4 4 3 3 2 2
(4.2%) (2.8%) (1.8%) (1.8%) (1.8%) (1.8%) (1.4%) (1.4%) (1.4%) (1.0%) (1.0%) (0.7%) (0.7%)
264
H . M . A . T o w l e r e t al.
either improvement or stabilization of visual acuity for up to 2 years compared with pre-treatment vision, and 97% showing reduction or stabilization of vitreous inflammatory infiltrate. Visual deterioration may occur because of progression of other pathological processes despite control of ocular inflammation, e.g. macular or optic nerve ischaemia, or subretinal neovascularization, and this was noted in several patients in this series. T h e confirmation of the nephrotoxic and hypertensive effects of low-dose CsA treatment emphasizes the need for close monitoring of these parameters. T h e apparently greater nephrotoxicity of CsA in patients who also develop hypertension is of considerable interest, and if this is related to changes in renal vascular resistance as clinical studies suggest [9], there may be o p p o r t u n i t y to ameliorate CsA toxicity by the use of specific pharmacological agents, e.g. calcium channel blockers. Other side effects were u n c o m m o n and generally well tolerated. Hypertrichosis was the most troublesome side effect, particularly in women, but not dose-limiting and acceptable to most patients if associated with a good visual outcome from CsA therapy. CsA blood levels were not found to be of value in predicting side effects or monitoring nephrotoxicity and from our experience there seems to be no justification in their routine use. References
1. Nussenblatt, R. B., A. G. Palestine, A. H. Rook, I. Scher, W. Wacker, and I. Gery. 1983. Treatment of intraocular inflammatory disease with Cyclosporin A. Lancet ii: 235-238 2. Nussenblatt, R. B., A. G. Palestine, and C. C. Chan. 1983. Cyclosporin A therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents. Am. J. Ophthalmol. 96:275-282 3. Binder, A. I., E. M. Graham, M. D. Sanders, W. Dinning, D. G. James, and A. M. Denman. 1987. Cyclosporin A in the treatment of severe Behqet's uveitis. Br. J. Rheumatol. 26:285-291
4. Masuda, K., A. Nakajima, A. Urayama, A. Nakae, M. Kogure, and G. Inaba. 1989. Double-masked trial of cyclosporin versus colchicine and long-term open study of cyclosporin in Behqet's disease. Lancet i: 1093-1096 5. de Vries, J., G. S. Baarsma, M J. W. Zaal, T. N. Boen-Tan, A. Rothova, H. J. Buitenhuis, C. M. C. Schweitzer, R. J. W. de Keizer, and A. Kijlstra. 1990. Cyclosporin in the treatment of severe chronic idiopathic uveitis. 74:344-349 6. Palestine, A. G., R. B. Nussenblat, and C. C. Chan. 1984. Side effects of systemic cyclosporin in patients not undergoing transplantation. Am. J. Med. 77" 652-656 7. Deray, G., P. Le Hoang, P. Cacoub, B. Aupetit, A. Mertani, F. Martinez, and J. Rottembourg. 1988. Renal function and blood pressure in patients treated with cyclosporin A for uveitis. Eur. J. Clin. Pharmacol. 34:601-604 8. Towler, H. M. A., P. H. Whiting, and J. V. Forrester. 1990. Combination low-dose cyclosporin A and steroid therapy in chronic intraocular inflammation. Eye 4:514-520 9. McNally, P. G., J. Feehally, and J. Walls. 1989. Nifedipine increases GFR in chronic cyclosporin treated renal transplant recipients. Nephr. Dial. Transpl. 4" 515
Low-dose Cyclosporin Therapy of Ocular Inflammation: P r e l i m i n a r y Report of a L o n g - t e r m Follow-up Study
Hamish
M. A. T o w l e r , *
Susan
L. Lightman*
and John V. Forrestert
*Department of Clinical Ophthalmology, Moorfields Eye Hospital, London and ~fDepartment of Ophthalmology, University of Aberdeen, Aberdeen, UK
C y c l o s p o r i n A ( C s A ) is a n effective t h e r a p y f o r s e v e r e i n t r a o c u l a r i n f l a m m a t i o n b u t n e p h r o t o x i c i t y a n d h y p e r t e n s i o n a r e m a j o r s i d e effects e v e n in low d o s e in c o m b i n a t i o n w i t h o r a l c o r t i c o s t e r o i d s a n d c l i n i c a l s t u d i e s on t h e l o n g - t e r m effects o f l o w - d o s e C s A t h e r a p y o u t s i d e t h e field o f o r g a n transplantation are lacking. This multicentre, open, longitudinal study has b e e n e s t a b l i s h e d to e v a l u a t e t h e l o n g - t e r m efficacy a n d s i d e effects o f l o w d o s e C s A t h e r a p y ( i n i t i a l d o s e ~<5 m g ] k g ] d a y , w i t h a m a x i m u m d o s e o f 7 m g / k g ] d a y , a n d t o t a l t r e a t m e n t d u r a t i o n > 3 m o n t h s ) in s e v e r e o c u l a r i n f l a m m a t i o n w h e r e c o n v e n t i o n a l t h e r a p y h a d f a i l e d to c o n t r o l t h e d i s e a s e o r c a u s e d i n t o l e r a b l e s i d e effects. V i s u a l r e s p o n s e to t r e a t m e n t , c l i n i c a l s i g n s a n d s y m p t o m s o f s i d e effects, b i o c h e m i c a l a n d h a e m a t o l o g i c a l parameters have been recorded at 3-monthly intervals since January 1987 a n d will c o n t i n u e u n t i l D e c e m b e r 1993. D a t a f o r 74 p a t i e n t s (age 35.5 _ 16.6 y e a r s ) a n d 293 f o l l o w u p v i s i t s a r e p r e s e n t e d in t h i s p r e l i m i n a r y report.
[Mean + SEM]
Serum creatinine (ltmol/l)
Creatinine clearance (ml/min)
Blood pressure (mmHg) Systolic Diastolic
Pre-treatment During treatment
88.4 _+2.30 99.2 _+1.67
130.5 + 12.2 71.9 + 10.5
123.3 _+2.00 130.2 + 1.48
78.6 + 1.37 83.5 + 0.98
O t h e r s i d e effects i n c l u d e ( % o f a l l visits): h y p e r t r i c h o s i s (4.2), h e a d a c h e (2.8), c r a m p s (1.8), a r t h r o p a t h y (1.8), p a r a e s t h e s i a e (1.8), a b d o m i n a l p a i n (1.5), w e a k n e s s (1.5), d y s p e p s i a (1.4), n a u s e a (1.4), o t h e r s (4).
Introduction D u r i n g t h e last 8 years, C s A has b e c o m e f i r m l y e s t a b l i s h e d as an effective t r e a t m e n t for severe s i g h t - t h r e a t e n i n g o c u l a r i n f l a m m a t i o n w h i c h has p r o v e d e i t h e r r e f r a c t o r y 259 0896-8411/92/0A0259 + 06 $03.00/0
© 1992 Academic Press Limited
260
H . M . A . T o w l e r e t al.
T a b l e 1. Endogenous ocular inflammatory diseases
treated with cyclosporin Intermediate uveitis/pars planitis Idiopathic retinal vasculitis Behqet's disease Posterior uveitis Scleritis Panuveitis Sympathetic ophthalmia Birdshot choroidopathy Sarcoidosis Corneal graft rejection Geographic choroiditis Acute retinitis Corneal melting Mooren's ulcer
19 13 10 8 7 4 3 2 2 2 1 1 1 1
to corticosteroids alone or where the dose or side effects of corticosteroids have been unacceptable [1-3]. M o s t of the clinical data regarding the efficacy of CsA therapy has come f r o m open, uncontrolled studies [1-3] and the only two double-masked studies of CsA treatment of uveitis [4, 5] have employed a dose of 10 mg/kg/day which is associated with a high incidence of nephrotoxicity and hypertension [6, 7]. L o w - d o s e CsA treatment ( ~<5 mg/kg/day), in combination with corticosteroids or alone, has been shown to be successful in the m a n a g e m e n t of intra-ocular inflammation but nephrotoxicity and hypertension remain the major dose-limiting side effects, particularly in older patients [8]. F u r t h e r m o r e , the chronic nature of m a n y of these diseases demands long-term therapy and the m a x i m u m safe dose and duration of CsA therapy in non-organ transplant disorders remains to be established. This open, multicentre study was designed to assess the side effect profile, long-term safety and clinical efficacy of low-dose CsA treatment in patients with differing forms of severe inflammatory eye disease.
Methods
Patients with endogenous ocular inflammatory diseases (Table 1) treated with an initial CsA dose of ~<5 mg/kg/day, m a x i m u m CsA dose ~<7 mg/kg/day, and for m o r e than 3 months were eligible for entry into the study. Concomitant treatment with other anti-inflammatory agents including corticosteroids was permitted. T h e visual response to treatment, signs and s y m p t o m s of side effects, biochemical and haematological monitoring parameters, and concurrent drug therapy were recorded at 3monthly intervals on standardized forms from three participating centres. T h e maintenance CsA dose was adjusted to achieve the lowest dose compatible with control of inflammation, minimal nephrotoxicity and specific target CsA levels in whole blood. Prospective data from entry into the study and retrospective data from January 1987 recorded for 74 patients and a total of 293 follow-up visits are presented.
Cyclosporin for ocular i n f l a m m a t i o n
3
•
CF
261
6/60 PRE TREATMENT VISUAL ACUITY
HMt
|
6/36
6/24 --
6/18 -- • 6/12 ~
OiO •
•
•
•
000
•
•
•
•
•
I~
6/9
6/6
:
-
~ 6/6
6/9
6/12
6/18
6/24
6/36
6/60
CF
HM
POST-TREATMENT VISOAL ACUITY
Figure 1. Visual outcomeduring CsA treatment at 6 months. PL
.J-
HM CF 6/60 PRE TREATMENT VISUAL ACUITY
6/36 6/24 6/18 6/12
S
6/9
•
6/6 6/6
6/9
6/12
6/18
6/24
POST T R E A T M ~
6/36
6/60
CF
HM
VISUAL ACUITY
Figure 2. Visual outcomeduring CsA treatment at 12 months. Results
T h e resuhs of visual outcome during the first 2 years of CsA therapy are shown in Figures 1-4. On average during this period, 52 Yo of patients showed an improvement in visual acuity of at least one Snellen line, 33% remained stable and 19Yo deteriorated. Vitreous opacification diminished in 45%, remained the same in 52Yo and increased in only 3 %. T h e mean ( + SEM) serum creatinine rose significantly during CsA treatment from 88.4_+ 2.30 to 99.2 + 1.67 ( P < 0.001, Student's t-test) though remaining within the reference range during the first year of treatment (Figure 5). T h e mean systolic blood pressure rose from 123.5_+ 1.88 to 133.4_+ 1.31 m m H g ( P < 0 . 0 0 1 , Student's t-test) and the mean diastolic pressure from 78.8_+ 1.28 to 84.6 + 0.85 m m H g ( P < 0.001, Student's t-test) during CsA treatment. Patients who
262
H . M . A . Towler e t al. PL HM •
CF
• •
@
•
• 4
6/60 PRETREATM]~IT VISUAL ACUITY
6/36
|
*
6/9
6/12
.
/
6/24 6/18 6/12 6/9 6/6 6/6
6/18
6/24
POST-TREATM2~WT
6/36
6/60
CF
HM
PL
VISUAL ACUITY
Figure 3. Visual outcome during CsA treatment at 18 months. PL HM
../
CF 6/60 PRETREATMENT VISUAL ACUITY
6/36 6/24 6/18 6/12 6/9 6/6 6/6
6/9
6/12
6/18
6/24
6/36
6/60
CF
HM
PL
POST-TREATMENT VISUAL ACUITY
Figure 4. Visual outcome during CsA treatment at 24 months.
developed hypertension (systolic pressure > 160 m m H g and/or diastolic pressure > 95 m m H g ) showed a significantly greater rise in mean serum creatinine over the first 2 years of C s A treatment than those in w h o m the blood pressure remained normal (Figure 6). D o c u m e n t e d side effects are listed in Table 2. W h o l e blood CsA levels showed no correlation with changes in serum creatinine levels or the development of any side effects (data not shown).
Discussion T h i s study has confirmed the visual benefits of CsA therapy over a sustained period in patients with severe sight threatening ocular inflammation, with 85 % showing
C y c l o s p o r i n for o c u l a r i n f l a m m a t i o n
263
150 140 130
+
120
S~UM CREATI~INE [~mol/l]
110 100 90
+**÷+
+
+
80 70
6
~
g
~
la
lg
DDRATION OF TREATMEWT
ta
.~1
.24
[months]
Figure 5. Serum creatinine changes during CsA treatment.
150
•
HYPERT~SIVE N O R M O T E N S IVE
140 130 120 S~UM CI~W~ATININE [~mol/l]
+ +
110 100 90 80 70 0
3
6
9
12
15
18
21
24
D U R A T I O N OF TREATMI~WT [months}
Figure 6. Serum creatinine changes during CsA treatment in normotensive ( • ) and hypertensive ( • ) patients.
T a b l e 2.
Cyclosporin side effects (% of all follow-up visits)
Hypertrichosis Headache Paraesthesiae Cramps Arthropathy Abdominal pain Dyspepsia Weakness Nausea Ankle swelling Skin rash Warts Vitiligo
12 8 5 5 5 5 4 4 4 3 3 2 2
(4.2%) (2.8%) (1.8%) (1.8%) (1.8%) (1.8%) (1.4%) (1.4%) (1.4%) (1.0%) (1.0%) (0.7%) (0.7%)
264
H . M . A . T o w l e r e t al.
either improvement or stabilization of visual acuity for up to 2 years compared with pre-treatment vision, and 97% showing reduction or stabilization of vitreous inflammatory infiltrate. Visual deterioration may occur because of progression of other pathological processes despite control of ocular inflammation, e.g. macular or optic nerve ischaemia, or subretinal neovascularization, and this was noted in several patients in this series. T h e confirmation of the nephrotoxic and hypertensive effects of low-dose CsA treatment emphasizes the need for close monitoring of these parameters. T h e apparently greater nephrotoxicity of CsA in patients who also develop hypertension is of considerable interest, and if this is related to changes in renal vascular resistance as clinical studies suggest [9], there may be o p p o r t u n i t y to ameliorate CsA toxicity by the use of specific pharmacological agents, e.g. calcium channel blockers. Other side effects were u n c o m m o n and generally well tolerated. Hypertrichosis was the most troublesome side effect, particularly in women, but not dose-limiting and acceptable to most patients if associated with a good visual outcome from CsA therapy. CsA blood levels were not found to be of value in predicting side effects or monitoring nephrotoxicity and from our experience there seems to be no justification in their routine use. References
1. Nussenblatt, R. B., A. G. Palestine, A. H. Rook, I. Scher, W. Wacker, and I. Gery. 1983. Treatment of intraocular inflammatory disease with Cyclosporin A. Lancet ii: 235-238 2. Nussenblatt, R. B., A. G. Palestine, and C. C. Chan. 1983. Cyclosporin A therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents. Am. J. Ophthalmol. 96:275-282 3. Binder, A. I., E. M. Graham, M. D. Sanders, W. Dinning, D. G. James, and A. M. Denman. 1987. Cyclosporin A in the treatment of severe Behqet's uveitis. Br. J. Rheumatol. 26:285-291
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