AUTOIMMUNE DISEASE

Experience With Cyclosporine in Endogenous Uveitis Posterior

D.A. Hesselink, G.S. Baarsma, R.W.A.M. Kuijpers, and P.M. van Hagen
ABSTRACT
Treatment with cyclosporine (CsA) has considerably improved the visual prognosis of
patients suffering from endogenous posterior uveitis (EPU). However, the therapeutic
benefits of CsA are partially outweighed by its many side effects, most notably nephrotoxicity and hypertension. Low-dose CsA regimens have reduced toxicity but have not been
able to completely eliminate this problem. New therapeutic approaches, such as antitumor necrosis factor treatment or immunosuppression with drugs including tacrolimus,
sirolimus, and interleukin-2 receptor antibodies, are currently under evaluation. Hopefully
such strategies will further reduce the morbidity of EPU and minimize the adverse effects
associated with conventional therapies.

HE POSSIBILITY OF using cyclosporine A (CsA) for

the treatment of autoimmune disease was recognized
as early as 1976. In the original paper on the immunosuppressive effects of CsA, Jean-Francois Borel and colleagues
demonstrated that the drug was not only effective in
preventing skin allograft rejection and graft-versus-host
disease in mice and rats, but that the drug also inhibited
experimental allergic encephalitis and Freunds adjuvant
induced arthritis.1 Ever since, CsA has been tested in
virtually every known autoimmune disease in man, ranging
from systemic lupus erythematosus (SLE), psoriasis, and
inflammatory bowel disease to rheumatoid arthritis and
asthma. This review will focus on one of the autoimmune
disorders in which the effects of CsA have been studied
most extensively, namely endogenous (or noninfectious)
posterior uveitis (EPU).
UVEITIS

Uveitis is the term used to describe inflammation of the

middle coat of the eye (uvea), which consists of the iris,
0041-1345/04/$see front matter
doi:10.1016/j.transproceed.2004.01.003
372S

ciliary body, and choroid.2,3 In practice, inflammatory processes of the retina and vitreous body are also included in
this group of diseases. Uveitis can be caused by infection,
trauma, and malignancy, but in more than 50% of patients
no exact cause can be identified. These cases of so-called
idiopathic uveitis can occur as isolated ocular disease or
as a manifestation of a systemic disorder. Examples of the
former are serpiginous choroidopathy, birdshot retinochoroidopathy, and sympathetic ophthalmia, while the latter
include sarcoidosis, Behcets disease, Vogt-KoyanagiHarada (VKH) syndrome, and SLE, all of which are
From the Departments of Internal Medicine, Renal Transplant
Unit (D.A.H.), Ophthalmology (R.W.A.M.K.), and Clinical Immunology (P.M.V.H.), Erasmus Medical Center, Rotterdam, the
Netherlands, and Department of Ophthalmology (G.S.B.), Eye
Hospital Rotterdam, Rotterdam, the Netherlands.
Address reprint requests to D.A. Hesselink, Room Ee 563a,
Department of Internal Medicine, Renal Transplant Unit, Erasmus Medical Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: d.a.hesselink@erasmusmc.nl
2004 by Elsevier Inc. All rights reserved.
360 Park Avenue South, New York, NY 10010-1710
Transplantation Proceedings, 36 (Suppl 2S), 372S377S (2004)

CYCLOSPORINE AND ENDOGENOUS UVEITIS POSTERIOR

believed to result from an autoimmune process. Apart from

this etiologic classification (infectious vs noninfectious),
uveitis is frequently categorized based upon its anatomical
localization into anterior uveitis, intermediate uveitis, posterior uveitis, and panuveitis. Pathogenetically and clinically
these are distinct diseases. Anterior uveitis often has an
acute onset, is self-limiting, and responds rapidly to therapy,
whereas posterior uveitis tends to be a chronic relapsing
disorder that progressively damages vision.2,3 In 35% of all
cases of uveitis, the disease will eventually lead to blindness
or severe visual impairment, which is most often caused by
cystoid macular edema. Other sight-threatening complications of uveitis include glaucoma, cataract formation, vitreous opacities, and retinal vascular abnormalities.4 It is
estimated that uveitis alone is responsible for 3% to 15% of
all cases of blindness in the Western world. The socioeconomic impact of uveitis is highlighted further by the fact
that 70% to 90% of patients are affected during their active
working life, costing an annual $242.6 million in the USA
alone.5
RATIONALE FOR CYCLOSPORINE IN ENDOGENOUS
UVEITIS POSTERIOR

Although the pathogenesis of EPU is still incompletely

understood, it has become clear that the disease results
from an autoimmune process in which T lymphocytes
play a central role.6 Not surprisingly, treatment with
immunosuppressive drugs has been the only effective
therapy for this group of inflammatory disorders. Before
the introduction of CsA, drug treatment for EPU consisted mainly of corticosteroids, sometimes used in combination with azathioprine, methotrexate, or cytotoxic
agents such as cyclophosphamide and chlorambucil.
However, these immunosuppressants frequently fail to
control EPU adequately and need to be high dosed,
resulting in a high incidence of toxicity. Corticosteroids
in particular have many unwanted side effects, such as
redistribution of body fat, loss of muscle mass, mood
swings and insomnia, decreased bone density, hypertension, glucose intolerance, and gastric ulceration. In addition, prolonged therapy with this class of drugs can
result in cataract formation, increased ocular pressure,
impaired wound healing, and increased susceptibility to
ocular surface infection. Side effects of azathioprine,
methotrexate, and cytotoxic agents include bone marrow
depression, hepatotoxicity, and an increased risk of developing malignancy. In contrast to the above-mentioned
drugs, the immunosuppressive actions of CsA are (relatively) specific for T lymphocytes. In these cells, CsA
blocks several intracellular signaling processes, causing a
decreased transcription of the interleukin (IL)-2, IL-4,
CD40L, and -interferon genes, which finally results in
the inhibition of T-lymphocyte activation and proliferation.7 Because of the limitations of conventional therapy,
the T-lymphocyte specificity of CsA, and the excellent
results that were obtained with this drug in the field of

373S

solid organ transplantation, it was not long before the

efficacy of CsA was studied in EPU.
CLINICAL TRIALS WITH CYCLOSPORINE IN
IDIOPATHIC UVEITIS

Nussenblatt and coworkers,8,9 demonstrated that CsA (10

mg/kg daily, begun on the day of immunization) was able to
prevent S antigen (S-Ag)-induced uveitis in Lewis rats, an
experimental model that resembles the human condition of
sympathethic ophthalmia. More importantly, CsA was able
to completely suppress established ocular disease, albeit at
a higher dose of 40 mg/kg daily.8,9 Encouraged by these
results, Nussenblatt et al were the first to use CsA for the
treatment of uveitis in humans.10 Eight patients with bilateral, sight-threatening uveitis of noninfectious origin, who
had all been previously treated unsuccesfully with corticosteroids or cytotoxic agents, received CsA as the sole
immunosuppressant in a dose of 10 mg/kg daily. CsA
therapy resulted in an improvement of both visual acuity
and ocular inflammation in seven of the eight patients (15
of the 16 eyes). In the majority of patients a measurable
improvement in visual acuity occurred within 10 days of
starting therapy. Side effects were reported as mild. One
patient had a rise in serum creatinine that normalized after
dose reduction. Several other patients had moderate liver
enzyme abnormalities or gingival hyperplasia or experienced transient tingling sensations in the extremities and
around the mouth.10 Successful treatment of refractory
uveitis of various etiologies (including Behcets disease,
VKH syndrome, birdshot retinochoroidopathy, and pars
planitis) with CsA was subsequently confirmed by several
other uncontrolled, nonrandomized studies and by a number of double-masked, randomized controlled clinical trials1117 (Table 1). De Vries et al16 randomized 27 patients
with severe chronic idiopathic uveitis to treatment with
placebo or a single daily dose of 10 mg/kg CsA. All patients
received low-dose prednisone as well. The efficacy results
were in favor of CsA, with more months of successful
therapy in this patient group. However, the positive effect of
CsA did not last after dose reduction and did not reach
statistical significance, probably because of the small number of patients16 (Table 1). In another double-masked,
randomized clinical trial, the efficacy of high-dose CsA was
directly compared with that of corticosteroids.17 After 3
months, treatment success was comparable between the two
groups, with 46% of patients in each treatment arm showing
improved visual acuity or vitreal haze. Importantly, an
additional 13% of patients improved after crossing over to
the alternative therapy, and a further 14% was successfully
treated when CsA and corticosteroids were combined.17 In
Behcets disease, 10 mg/kg CsA proved to be superior to
colchicine15 or conventional treatment with corticosteroids
or chlorambucil14 in decreasing the severity of ocular
inflammation and the frequency of ocular attacks and in
improving visual acuity.
The efficacy of CsA in the treatment of EPU, which was
clearly demonstrated in these trials, offered new hope for

Table 1. Cyclosporine in Noninfectious Endogenous Uveitis

10

Nussenblatt

Nussenblatt11
Binder12
BenEzra14

Le Hoang13
Masuda15

Previous
treatment

Type of ocular disease

8 Miscellaneous UP and CS/cytotox

UI
agents
16 Miscellaneous UP and CS/cytotox
UI
agents
12 Behcet syndrome
CS/cytotox
agents
40 Behcet syndrome
None

Case series

21 Birdshot
CS/cytotox
retinochoroidopathy
agents
96 Behcet syndrome
NR

Case series

de Vries16

27 Miscellaneous UP and CS/cytotox

UI
agents

Towler23

13 Miscellaneous UP and CS
UI
56 Miscellaneous UP and NR
UI

Nussenblatt17

Hooper24

Study type

Case series
Double-blind
RCT

Double-blind
RCT
Double-blind
RCT
Case series
Double-blind
RCT

Case series

CS

Case series

Vitale26

19 Birdshot
CS
retinochoroidopathy

Case series

Vitale27

50 Miscellaneous, UP and CS/cytotox

UI
agents

Case series

Walton29

15 Miscellaneous UP and CS
UI
14 Miscellaneous UP and CS
UI
52 Behcet syndrome
CS/cytotox
agents/
colchicine

Pediatric case
series
Pediatric case
series
Case series

Kilmartin30
Ozdal28

CsA 10 mg/kg

Outcome

7/8 patients improved visual acuity

and ocular inflammation
CsA 10 mg/kg
15/16 patients improved visual acuity
and ocular inflammation
CsA 10 mg/kg
10/12 improved visual acuity; 12/12
improved ocular inflammation
CsA 10 mg/kg vs CsA group better visual acuity and
less ocular inflammation
conventional
therapy (CS or
chlorambucil)
CsA 10 mg/kg
81% stable/improved visual acuity
CS
CsA 10 mg/kg vs CsA group reduced frequency and
colchicine 1 mg severity of ocular attacks
CsA group more months of succesful
CS CsA 10
mg/kg vs CS therapy
placebo
CsA 5 mg/kg 10/13 improved visual acuity
CS
CsA 10 mg/kg
Improved visual acuity and ocular
vs CS
inflammation in 46% of each
treatment groups

Side effects

Other

1/8 nephrotoxicity
5/16 nephrotoxicity
12/12 nephrotoxicity,
5/12 HT
9/40 nephrotoxicity,
12/40 HT

Relapse in all patients after

dose reduction

9/21 nephrotoxicity
11/47 nephrotoxicity
1/27 nephrotoxicity,
4/27 hypertension

Nonocular symptoms
better with CsA
13/14 relapsed after CsA
dose reduction

10/13 nephrotoxicity,
4/13 HT
Nephrotoxicity and HT 13% improved after
crossover to alternative
more frequent in
therapy, 14% improved
CsA group
with CsA CS
CsA 5 mg/kg Remission in all patients
1/5 HT
2/5 relapsed after dose
Aza CS
reduction
10 CsA (mean 8.6 Of all patients 75.7% stable/improved 12/19 nephrotoxicity, Trend toward greater
13/19 HT
efficacy and less renal
visual acuity, 73.6% decreased
mg/kg), 9 CsA
toxicity with CsA CS
ocular inflammation
(mean 6.2 mg/
kg) CS
2/19 nephrotoxicity,
Frequent relapse after
8 low-dose CsA Ocular inflammation controlled in
2 HT
dose reduction
88.5% of CsA group vs 25% in CS
(25 mg/kg), 6
group. Stable/improved visualcuity
low-dose CsA
in 83.3% and 45.5% of CsA and
Aza, 6
CS groups, respectively
perlocular
steroids only
13/50 nephrotoxicity,
CsA 2.55 mg/kg 88% improved/stable visual acuity,
9/50 HT
CS Aza
73.9% controlled ocular
inflammation, 82.1%
improved/stable visual acuity
CsA 2.510 mg/ Ocular inflamm decreased from 2 to 9/15 nephrotoxicity, 2
kg CS
0.5 at 6 months
HT
CsA 5 mg/kg 92% improved/stable visual acuity,
4/14 nephrotoxicity, 1
Aza CS
76% improved inflammatory score
HT
CsA 5 mg/kg 69.2% improved/stable visual acuity 5/52 nephrotoxicity,
CS
3/52 HT

UP uveitis posterior; UI intermediate uveitis; CsA cyclosporine; CS corticosteroids; Aza azathioprine; RCT randomized controlled trial; HT hypertension.

HESSELINK, BAARSMA, KUIJPERS ET AL

CS

Whitcup25

5 Serpiginous
choroidopathy
19 Behcet syndrome

Case series

Treatment

374S

First author and

reference
n

CYCLOSPORINE AND ENDOGENOUS UVEITIS POSTERIOR

patients and ophthalmologists. In the pre-CsA era, the

ability to effectively control uveitis, despite heavy immunosuppressive therapy, had been limited. As a result, many
patients suffered from severe visual loss or side effects of
immunosuppressants, and frequently from both. However,
the initial enthusiasm that surrounded CsA was somewhat
tempered by the high incidence of CsA toxicity. Already in
the first clinical trials studying the effectiveness of the drug,
its side-effect profile became clear: the development of
hypertension and hypercholesterolemia, the induction of
glucose intolerance, gingival hyperplasia, hirsutism, hypomagnesemia, tremor, and paresthesia. In addition, CsA is
nephrotoxic. The adverse effects of CsA on renal function
are its most dreaded complication and form the major
limitation to its use. The pathogenesis of CsA nephrotoxicity is still incompletely understood, but we can discriminate an acute and chronic form. Acute nephrotoxicity
occurs within the first weeks after the initiation of treatment
and is usually reversible with dose reduction. It is caused by
constriction of afferent glomerular arterioles, probably
caused by alterations in the metabolism and secretion of
prostaglandins, nitric oxide, and endothelin, as well as an
increased adrenergic activity. In contrast, chronic CsA
nephrotoxicity is irreversible and is accompanied by severe
histologic alterations.18 20
Palestine et al21 evaluated renal histopathological alterations in patients who had received CsA for uveitis. Renal
biopsy specimens of 17 patients who had been treated for
autoimmune uveitis with a starting dose of 10 mg/kg CsA
for an average of 2 years were compared with 37 renal
biopsy specimens from controls with idiopathic hematuria
that had been read as nondiagnostic. Compared with controls, kidney biopsies of CsA-treated patients showed more
interstitial fibrosis, tubular atrophy, and glomerular abnormalities, resulting in a significantly higher chronicity
index. Importantly, chronic pathologic alterations were
observed in patients who had normal renal function
(assessed by serum creatinine and inulin clearance measurements) at the time of biopsy and its severity did not
correlate with the average or cummulative CsA dose.21
The high incidence of nephrotoxicity in these first trials
can partly be explained by the high CsA doses (10
mg/kg) that were administered. Later studies therefore
used lower doses of CsA (2.5 to 5 mg/kg), either as the
sole immunosuppressant or combined with prednisone or
other immunosuppressive agents2230 (Table 1). Lowering the dose of CsA appears to result in a lower incidence
of side effects without reduced therapeutic efficacy, but a
randomized, controlled clinical trial comparing highwith low-dose CsA regimens is needed to fully answer
this question. Such a trial has not been performed yet. In
addition, trials studying the safety of early CsA dose
reduction or complete cessation after induction of remission in EPU have generally shown disappointing results
with a high relapse rate after CsA weaning.12,16,24,26
Finally, strategies using lower CsA doses have not been
able to completely eliminate the problem of CsA neph-

375S

rotoxicity.25,31 Isnard Bagnis et al31 studied 41 uveitis

patients treated with CsA between 1986 and 1997 in a
randomized, open-label, prospective study. All patients
had normal renal function before entry into the study.
Mean CsA daily dose was 4.3 1.6 mg/kg, which was
gradually tapered to 1.8 0.9 mg/kg at 5 years followup. Even this low-dose CsA regime induced a significant
rise in plasma creatinine and a deterioration of the
creatinine clearance and glomerular filtration rate. In 11
patients who underwent serial renal biopsies, histologic
examination showed a significant increase in interstitial
fibrosis, tubular atrophy, glomerular sclerosis, and thickening of Bowmans capsule after 2 years of CsA treatment compared to baseline. Interestingly, of all histologic
parameters, only the number of obsolescent gomeruli
was related to the initial daily dose of CsA. When
patients enrolled before 1990 (who received CsA doses
above 3.16 mg/kg) were compared with patients enrolled
after 1990 (who received doses of CsA below 3.16 mg/kg),
the former had a significantly worse renal function.
However, even patients treated with the lowest CsA
doses had histopathologic evidence of renal damage.31
THERAPEUTIC DRUG MONITORING

Drug dosage based on blood concentrations rather than

body weight is known as therapeutic drug monitoring
(TDM). In the field of solid organ transplantation, this
practice is widely applied for many immunosuppressants,
including CsA, tacrolimus, mycophenolate mofetil, and
sirolimus. Dosage of these drugs is adjusted to reach certain
predefined target concentrations that have been determined empirically and are associated with optimal treatment outcomes. For CsA, the traditional parameter for
TDM has been the predose or trough concentration.32 In
general, TDM is not routinely performed for patients
treated with CsA for autoimmune disease. This can be
explained by the fact that in autoimmune disease the
immunologic process is already in full swing at the time of
diagnosis and inititation of treatment, whereas in the transplant situation, drug therapy is started to prevent the
occurrence of an immunologic reaction. Therefore, immunosuppressive drugs used in the treatment of autoimmunity
can be titrated to their biological effect. Moreover, in
autoimmunity time is less critical as most of these diseases
are not acutely life-threatening, while this is clearly not the
case when a transplanted patient suffers from an acute
rejection. Nevertheless, there are some situations in which
patients with autoimmune disease may benefit from TDM.
First, such a situation arises when therapy is started with a
drug that has a large intra- and interindividual pharmacokinetic variability, as this may result in therapeutic failure or
toxicity on standard dosing. The pharmacokinetics of CsA
are notoriously unpredictable, showing marked differences
between individuals or within a single patient over time.
Therefore, uveitis patients who are classified as nonresponders may in fact suffer from low CsA blood concentra-

376S
Table 2. Drugs With Clinically Relevant Pharmacokinetic
Interactions With Cyclosporine
Antibiotics
Clarithromycin
Doxycyclin
Erythromycin
Rifampin
Anticonvulsants
Carbamazepine
Phenytoin
Antihypertensives/antiarrhythmics
Amiodarone
Diltiazem
Nicardipine
Nifedipine
Verapamil
Antimycotics
Itraconazole
Fluconazole
Ketoconazole
Other
Protease inhibitors
Theophyllin
Corticosteroids

tions caused by a high first-pass metabolism of the drug.33

Vice versa, in patients who suffer from severe toxicity, the
drug may be withdrawn too early, while a much lower dose
would have minimized side effects yet maintained adequate
immunosuppression. Second, TDM may be beneficial when
factors are present that interfere with drug pharmacokinetics or pharmacodynamics. Such factors include diet and
comedication. The pharmacokinetic interactions of CsA
with many drugs are well known as they frequently result in
altered CsA blood concentrations (Table 2). Prescription of
these drugs is not uncommon in uveitis patients and the
ophthalomologist needs to be familiar with these interactions. Finally, TDM can be used to check patient compliance.
To date few studies have systematically studied the
possible advantages of TDM in uveitis. In an uncontrolled
trial, Rocha et al34 treated eight patients who were resistant
to conventional immunosuppressive therapy with CsA.
Dose adjustments were made based on CsA blood concentrations 6 hours after administration of the morning dose
(C6). Treatment with CsA monitored by C6 resulted in an
improvement of ocular inflammation in all patients, and
after a mean follow-up of 16 10 months renal function
was not statistically different from baseline. In addition,
blood pressure and potassium, uric acid, and magnesium
serum concentrations remained stable throughout followup.34 Whether such a favorable outcome could have been
achieved if a CsA dose reduction had been performed
irrespective of blood concentrations remains open to question. In conclusion, TDM is currently not advocated for
CsA therapy in uveitis patients and unless randomized
controlled trials demonstrate a significant benefit of such a
strategy, treatment guidelines are unlikely to change. None-

HESSELINK, BAARSMA, KUIJPERS ET AL

theless, there are several situations in which TDM may be

of benefit and the ophthalmologist should keep an open eye
to such occasions.
FUTURE CONSIDERATIONS

CsA is an effective second-line agent that has considerably

improved the visual prognosis of patients with EPU. However, despite low-dosing regimens, CsA toxicity remains an
important problem that forms the major limitation to
successful long-term treatment. In addition, a significant
number of uveitis patients are refractory to this powerful
immunosuppressant. Thus, there has been a continuing
need to further optimize drug therapy for uveitis. In the
past decade, a number of novel immunosuppressants that
were originally introduced into the fields of transplantation
and rheumatology have been studied for the treatment of
EPU. Drugs that have shown encouraging results in animal
studies and small trials in humans include tacrolimus,
sirolimus, and antibodies that block the IL-2 receptor.3537
One of the most promising new therapies is anti-tumor
necrosis factor (TNF) treatment. Both the monoclonal
anti-TNF antibody, infliximab, as well as the TNF fusion
protein, etanercept, have shown remarkable efficacy in
improving the symptoms of sight-threatening EPU in patients refractory to conventional therapy.38 40 Except for
mild injection-site reactions and one case of tuberculosis,
no adverse effects were noted in these preliminary trials. It
is to be expected that in the near future, the efficacy and
safety of this new generation of immunosuppressants will be
further investigated in randomized, controlled clinical trials
in larger patient groups. Most likely they will be studied in
patients with CsA-refractory EPU or compared head-tohead with CsA. Another possibility is to combine these
drugs with (low-dose) CsA. However, until such trials
demonstrate clear advantages of these novel immunosuppressants, CsA will remain the mainstay of immunosuppressive therapy in patients with corticosteroid-refractory EPU.
CONCLUSIONS

EPU is a sight-threatening autoimmune disease that frequently fails to respond to treatment with high doses of
corticosteroids. CsA has proved to be an effective secondline agent for such patients. However, the success of CsA
has been hampered by side effects, most notably nephrotoxicity. Low-dose CsA regimens have minimized toxicity
yet been unable to completely eliminate it. Currently, the
efficacy and safety of novel immunosuppressants are being
investigated in a number of clinical trials. Hopefully, these
drugs will provide means to reduce CsA toxicity while
maintaining its full therapeutic benefit.
REFERENCES
1. Borel JF, Feurer C, Gubler HU, et al: Biological effects of
cyclosporin A: a new antilymphocytic agent. Agents Actions 6:468,
1976

CYCLOSPORINE AND ENDOGENOUS UVEITIS POSTERIOR

2. Dick AD, Azim M, Forrester JV: Immunosuppressive therapy
for chronic uveitis: optimising therapy with steroids and cyclosporin
A. Br J Ophthalmol 81:1107, 1997
3. McCluskey PJ, Towler HM, Lightman S: Management of
chronic uveitis. BMJ 320:555, 2000
4. Rothova A, Suttorp-van Schulten MS, Frits Treffers W, et al:
Causes and frequency of blindness in patients with intraocular
inflammatory disease. Br J Ophthalmol 80:332, 1996
5. Suttorp-Schulten MS, Rothova A: The possible impact of
uveitis in blindness: a literature survey. Br J Ophthalmol 80:844,
1996
6. Caspi RR: Immune mechanisms in uveitis. Springer Semin
Immunopathol 21:113, 1999
7. Matsuda S, Koyasu S: Mechanisms of action of cyclosporine.
Immunopharmacology 47:119, 2000
8. Nussenblatt RB, Rodrigues MM, Wacker WB, et al: Cyclosporin A. Inhibition of experimental autoimmune uveitis in Lewis
rats. J Clin Invest 67:1228, 1981
9. Nussenblatt RB, Rodrigues MM, Salinas-Carmona MC, et al:
Modulation of experimental autoimmune uveitis with cyclosporin
A. Arch Ophthalmol 100:1146, 1982
10. Nussenblatt RB, Palestine AG, Rook AH, et al: Treatment
of intraocular inflammatory disease with cyclosporin A. Lancet
2:235, 1983
11. Nussenblatt RB, Palestine AG, Chan CC: Cyclosporin A
therapy in the treatment of intraocular inflammatory disease
resistant to systemic corticosteroids and cytotoxic agents. Am J
Ophthalmol 96:275, 1983
12. Binder AI, Graham EM, Sanders MD, et al: Cyclosporin A
in the treatment of severe Behcets uveitis. Br J Rheumatol 26:285,
1987
13. Le Hoang P, Girard B, Deray G, et al: Cyclosporine in the
treatment of birdshot retinochoroidopathy. Transplant Proc 20:
128, 1988
14. BenEzra D, Cohen E, Chajek T, et al: Evaluation of
conventional therapy versus cyclosporine A in Behcets syndrome.
Transplant Proc 20:136, 1988
15. Masuda K, Nakajima A, Urayama A, et al: Double-masked
trial of cyclosporin versus colchicine and long-term open study of
cyclosporin in Behcets disease. Lancet 1:1093, 1989
16. de Vries J, Baarsma GS, Zaal MJ, et al: Cyclosporin in the
treatment of severe chronic idiopathic uveitis. Br J Ophthalmol
74:344, 1990
17. Nussenblatt RB, Palestine AG, Chan CC, et al: Randomized, double-masked study of cyclosporine compared to prednisolone in the treatment of endogenous uveitis. Am J Ophthalmol
112:138, 1991
18. Myers BD, Ross J, Newton L, et al: Cyclosporine-associated
chronic nephropathy. N Engl J Med 311:699, 1984
19. McNally PG, Feehally J: Pathophysiology of cyclosporin A
nephrotoxicity: experimental and clinical observations. Nephrol
Dial Transplant 7:791, 1992
20. Morales JM, Andres A, Rengel M, et al: Influence of
cyclosporin, tacrolimus and rapamycin on renal function and
arterial hypertension after renal transplantation. Nephrol Dial
Transplant 16(Suppl 1):121, 2001
21. Palestine AG, Austin HA 3rd, Balow JE, et al: Renal
histopathologic alterations in patients treated with cyclosporine for
uveitis. N Engl J Med 314:1293, 1986

377S
22. Towler HM, Cliffe AM, Whiting PH, et al: Low dose
cyclosporin A therapy in chronic posterior uveitis. Eye 3:282, 1989
23. Towler HM, Whiting PH, Forrester JV: Combination low
dose cyclosporin A and steroid therapy in chronic intraocular
inflammation. Eye 4:514, 1990
24. Hooper PL, Kaplan HJ: Triple agent immunosuppression in
serpiginous choroiditis. Ophthalmology 98:944, 1991 (discussion
9512)
25. Whitcup SM, Salvo EC Jr, Nussenblatt RB: Combined
cyclosporine and corticosteroid therapy for sight-threatening uveitis in Behcets disease. Am J Ophthalmol 118:39, 1994
26. Vitale AT, Rodriguez A, Foster CS: Low-dose cyclosporine
therapy in the treatment of birdshot retinochoroidopathy. Ophthalmology 101:822, 1994
27. Vitale AT, Rodriguez A, Foster CS: Low-dose cyclosporin A
therapy in treating chronic, noninfectious uveitis. Ophthalmology
103:365, 1996 (discussion 373 4)
zdal PC, Ortac S, Taskintuna I, et al: Long-term therapy
28. O
with low dose cyclosporin A in ocular Behcets disease. Doc
Ophthalmol 105:301, 2002
29. Walton RC, Nussenblatt RB, Whitcup SM: Cyclosporine
therapy for severe sight-threatening uveitis in children and adolescents. Ophthalmology 105:2028, 1998
30. Kilmartin DJ, Forrester JV, Dick AD: Cyclosporin A therapy in refractory non-infectious childhood uveitis. Br J Ophthalmol
82:737, 1998
31. Isnard Bagnis C, Tezenas Du Montcel S, Beaufils H, et al:
Long-term renal effects of low-dose cyclosporine in uveitis-treated
patients: follow-up study. J Am Soc Nephrol 13:2962, 2002
32. Klupp J, Holt DW, van Gelder T: How pharmacokinetic and
pharmacodynamic drug monitoring can improve outcome in solid
organ transplant recipients. Transpl Immunol 9:211, 2002
33. Kahan BD: Individualization of cyclosporine therapy using
pharmacokinetic and pharmacodynamic parameters. Transplantation 40:457, 1985
34. Rocha G, Deschenes J, Cantarovich M: Cyclosporine monitoring with levels 6 hours after the morning dose in patients with
noninfectious uveitis. Ophthalmology 104:245, 1997
35. Martin DF, DeBarge LR, Nussenblatt RB, et al: Synergistic
effect of rapamycin and cyclosporin A in the treatment of experimental autoimmune uveoretinitis. J Immunol 154:922, 1995
36. Sloper CM, Powell RJ, Dua HS: Tacrolimus (FK506) in the
treatment of posterior uveitis refractory to cyclosporine. Ophthalmology 106:723, 1999
37. Nussenblatt RB, Fortin E, Schiffman R, et al: Treatment of
noninfectious intermediate and posterior uveitis with the humanized anti-Tac mAb: a phase I/II clinical trial. Proc Natl Acad Sci
U S A 96:7462, 1999
38. Reiff A, Takei S, Sadeghi S, et al: Etanercept therapy in
children with treatment-resistant uveitis. Arthritis Rheum 44:1411,
2001
39. Sfikakis PP, Theodossiadis PG, Katsiari CG, et al: Effect of
infliximab on sight-threatening panuveitis in Behcets disease.
Lancet 358:295, 2001
40. Joseph A, Raj D, Dua HS, et al: Infliximab in the treatment
of refractory posterior uveitis. Ophthalmology 110:1449, 2003