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sidepatients suffering from endogenous posterior uveitis (EPU). However, the therapeuticbenefits of CsA are partially outweighed by its many side effects, most notably nephro-

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372toxicity and hypertension. Low-dose CsA regimens have reduced toxicity but have not beenable to completely eliminate this problem. New therapeutic approaches, such as anti-tumor necrosis factor treatment or immunosuppression with drugs including tacrolimus,sirolimus, and interleukin-2 receptor antibodies, are currently under evaluation. Hopefullysuch strategies will further reduce the morbidity of EPU and minimize the adverse effectsassociated with conventional therapies.

HE POSSIBILITY OF using cyclosporine A (CsA) forthe treatment of autoimmune disease was recognized

early as 1976. In the original paper on the immunosup-ssive effects of CsA, Jean-Francois Borel and colleagues

monstrated that the drug was not only effective inventing skin allograft rejection and graft-versus-hostease in mice and rats, but that the drug also inhibitederimental allergic encephalitis and Freunds adjuvantuced arthritis.1 Ever since, CsA has been tested in

tually every known autoimmune disease in man, rangingm systemic lupus erythematosus (SLE), psoriasis, andammatory bowel disease to rheumatoid arthritis andhma. This review will focus on one of the autoimmuneorders in which the effects of CsA have been studiedst extensively, namely endogenous (or noninfectious)

sterior uveitis (EPU).

EITIS

eitis is the term used to describe inflammation of theddle coat of the eye (uvea), which consists of the iris,

ciliary body, and choroid.2,3 In practice, inflammatory pro-cesses of the retina and vitreous body are also included inthis group of diseases. Uveitis can be caused by infection,trauma, and malignancy, but in more than 50% of patientsno exact cause can be identified. These cases of so-calledidiopathic uveitis can occur as isolated ocular disease oras a manifestation of a systemic disorder. Examples of theformer are serpiginous choroidopathy, birdshot retinocho-roidopathy, and sympathetic ophthalmia, while the latterinclude sarcoidosis, Behcets disease, Vogt-Koyanagi-Harada (VKH) syndrome, and SLE, all of which are

From the Departments of Internal Medicine, Renal TransplantUnit (D.A.H.), Ophthalmology (R.W.A.M.K.), and Clinical Immu-nology (P.M.V.H.), Erasmus Medical Center, Rotterdam, theNetherlands, and Department of Ophthalmology (G.S.B.), EyeHospital Rotterdam, Rotterdam, the Netherlands.

Address reprint requests to D.A. Hesselink, Room Ee 563a,Department of Internal Medicine, Renal Transplant Unit, Eras-mus Medical Center, Dr. Molewaterplein 50, 3015 GE Rotter-dam, The Netherlands. E-mail: [email protected] With Cyclosporine in En

A. Hesselink, G.S. Baarsma, R.W.A.M. Kuijpers, an

ABSTRACT

Treatment with cyclosporine (CsA) has con1-1345/04/$see front matter:10.1016/j.transproceed.2004.01.003

S Tragenous Uveitis Posterior

.M. van Hagen

rably improved the visual prognosis of 2004 by Elsevier Inc. All rights reserved.360 Park Avenue South, New York, NY 10010-1710

nsplantation Proceedings, 36 (Suppl 2S), 372S377S (2004)

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CYCLOSPORINE AND ENDOGENOUS UVEITIS POSTERIOR 373Sieved to result from an autoimmune process. Apart froms etiologic classification (infectious vs noninfectious),itis is frequently categorized based upon its anatomicalalization into anterior uveitis, intermediate uveitis, pos-ior uveitis, and panuveitis. Pathogenetically and clinicallyse are distinct diseases. Anterior uveitis often has ante onset, is self-limiting, and responds rapidly to therapy,

ereas posterior uveitis tends to be a chronic relapsingorder that progressively damages vision.2,3 In 35% of alles of uveitis, the disease will eventually lead to blindnesssevere visual impairment, which is most often caused bytoid macular edema. Other sight-threatening complica-ns of uveitis include glaucoma, cataract formation, vitre-s opacities, and retinal vascular abnormalities.4 It isimated that uveitis alone is responsible for 3% to 15% ofcases of blindness in the Western world. The socioeco-

mic impact of uveitis is highlighted further by the factt 70% to 90% of patients are affected during their activerking life, costing an annual $242.6 million in the USAne.5

TIONALE FOR CYCLOSPORINE IN ENDOGENOUSEITIS POSTERIOR

though the pathogenesis of EPU is still incompletelyderstood, it has become clear that the disease resultsm an autoimmune process in which T lymphocytesy a central role.6 Not surprisingly, treatment withmunosuppressive drugs has been the only effectiverapy for this group of inflammatory disorders. Beforeintroduction of CsA, drug treatment for EPU con-

ted mainly of corticosteroids, sometimes used in com-ation with azathioprine, methotrexate, or cytotoxicnts such as cyclophosphamide and chlorambucil.wever, these immunosuppressants frequently fail totrol EPU adequately and need to be high dosed,

ulting in a high incidence of toxicity. Corticosteroidsparticular have many unwanted side effects, such asistribution of body fat, loss of muscle mass, mood

ings and insomnia, decreased bone density, hyperten-n, glucose intolerance, and gastric ulceration. In ad-ion, prolonged therapy with this class of drugs canult in cataract formation, increased ocular pressure,paired wound healing, and increased susceptibility tolar surface infection. Side effects of azathioprine,thotrexate, and cytotoxic agents include bone marrow

pression, hepatotoxicity, and an increased risk of de-oping malignancy. In contrast to the above-mentionedgs, the immunosuppressive actions of CsA are (rela-

ely) specific for T lymphocytes. In these cells, CsAcks several intracellular signaling processes, causing a

creased transcription of the interleukin (IL)-2, IL-4,40L, and -interferon genes, which finally results ininhibition of T-lymphocyte activation and prolifera-

n.7 Because of the limitations of conventional therapy,T-lymphocyte specificity of CsA, and the excellentults that were obtained with this drug in the field of cleid organ transplantation, it was not long before thecacy of CsA was studied in EPU.

INICAL TRIALS WITH CYCLOSPORINE INOPATHIC UVEITIS

ssenblatt and coworkers,8,9 demonstrated that CsA (10/kg daily, begun on the day of immunization) was able tovent S antigen (S-Ag)-induced uveitis in Lewis rats, anerimental model that resembles the human condition ofpathethic ophthalmia. More importantly, CsA was able

completely suppress established ocular disease, albeit atigher dose of 40 mg/kg daily.8,9 Encouraged by theseults, Nussenblatt et al were the first to use CsA for theatment of uveitis in humans.10 Eight patients with bilat-l, sight-threatening uveitis of noninfectious origin, who

d all been previously treated unsuccesfully with cortico-roids or cytotoxic agents, received CsA as the solemunosuppressant in a dose of 10 mg/kg daily. CsArapy resulted in an improvement of both visual acuity

d ocular inflammation in seven of the eight patients (15the 16 eyes). In the majority of patients a measurableprovement in visual acuity occurred within 10 days ofrting therapy. Side effects were reported as mild. Onetient had a rise in serum creatinine that normalized afterse reduction. Several other patients had moderate liverzyme abnormalities or gingival hyperplasia or experi-ced transient tingling sensations in the extremities andund the mouth.10 Successful treatment of refractoryitis of various etiologies (including Behcets disease,H syndrome, birdshot retinochoroidopathy, and parsnitis) with CsA was subsequently confirmed by severaler uncontrolled, nonrandomized studies and by a num-of double-masked, randomized controlled clinical tri-

1117 (Table 1). De Vries et al16 randomized 27 patientsh severe chronic idiopathic uveitis to treatment withcebo or a single daily dose of 10 mg/kg CsA. All patientseived low-dose prednisone as well. The efficacy resultsre in favor of CsA, with more months of successfulrapy in this patient group. However, the positive effect of

A did not last after dose reduction and did not reachtistical significance, probably because of the small num-

of patients16 (Table 1). In another double-masked,domized clinical trial, the efficacy of high-dose CsA wasectly compared with that of corticosteroids.17 After 3nths, treatment success was comparable between the twoups, with 46% of patients in each treatment arm showing

proved visual acuity or vitreal haze. Importantly, anditional 13% of patients improved after crossing over to

alternative therapy, and a further 14% was successfullyated when CsA and corticosteroids were combined.17 Inhcets disease, 10 mg/kg CsA proved to be superior tochicine15 or conventional treatment with corticosteroidschlorambucil14 in decreasing the severity of ocularammation and the frequency of ocular attacks and in

proving visual acuity.he efficacy of CsA in the treatment of EPU, which wasarly demonstrated in these trials, offered new hope for

374STable 1. Cyclosporine in Noninfectious Endogenous Uveitis

First author andreference n Type of ocular disease

Previoustreatment Study type Treatment Outcome Side effects Other

10Nussenblatt 8 Miscellaneous UP andUI

CS/cytotoxagents

Case series CsA 10 mg/kg 7/8 patients improved visual acuityand ocular inflammation

1/8 nephrotoxicity

Nussenblatt11 16 Miscellaneous UP andUI

CS/cytotoxagents

Case series CsA 10 mg/kg 15/16 patients improved visual acuityand ocular inflammation

5/16 nephrotoxicity

Binder12 12 Behcet syndrome CS/cytotoxagents

Case series CsA 10 mg/kg 10/12 improved visual acuity; 12/12improved ocular inflammation

12/12 nephrotoxicity,5/12 HT

Relapse in all patients afterdose reduction

BenEzra14 40 Behcet syndrome None Double-blindRCT

CsA 10 mg/kg vsconventionaltherapy (CS orchlorambucil)

CsA group better visual acuity andless ocular inflammation


Le Hoang13 21 Birdshotretinochoroidopathy

CS/cytotoxagents

Case series CsA 10 mg/kg CS

81% stable/improved visual acuity 9/21 nephrotoxicity

Masuda15 96 Behcet syndrome NR Double-blindRCT

CsA 10 mg/kg vscolchicine 1 mg

CsA group reduced frequency andseverity of ocular attacks

11/47 nephrotoxicity Nonocular symptomsbetter with CsA

de Vries16 27 Miscellaneous UP andUI

CS/cytotoxagents

Double-blindRCT

CS CsA 10mg/kg vs CS placebo

CsA group more months of succesfultherapy

1/27 nephrotoxicity,4/27 hypertension

13/14 relapsed after CsAdose reduction

Towler23 13 Miscellaneous UP andUI

CS Case series CsA 5 mg/kg CS

10/13 improved visual acuity 10/13 nephrotoxicity,4/13 HT

Nussenblatt17 56 Miscellaneous UP andUI

NR Double-blindRCT

CsA 10 mg/kgvs CS

Improved visual acuity and ocularinflammation in 46% of eachtreatment groups

Nephrotoxicity and HTmore frequent inCsA group

13% improved aftercrossover to alternativetherapy, 14% improvedwith CsA CS

Hooper24 5 Serpiginouschoroidopathy

CS Case series CsA 5 mg/kg Aza CS

Remission in all patients 1/5 HT 2/5 relapsed after dosereduction

Whitcup25 19 Behcet syndrome CS Case series 10 CsA (mean 8.6mg/kg), 9 CsA(mean 6.2 mg/kg) CS

Of all patients 75.7% stable/improvedvisual acuity, 73.6% decreasedocular inflammation


Trend toward greaterefficacy and less renaltoxicity with CsA CS

Vitale26 19 Birdshotretinochoroidopathy

CS Case series 8 low-dose CsA(25 mg/kg), 6low-dose CsA Aza, 6perlocularsteroids only

Ocular inflammation controlled in88.5% of CsA group vs 25% in CSgroup. Stable/improved visualcuityin 83.3% and 45.5% of CsA andCS groups, respectively

2/19 nephrotoxicity,2 HT

Frequent relapse afterdose reduction

Vitale27 50 Miscellaneous, UP andUI

CS/cytotoxagents

Case series CsA 2.55 mg/kg CS Aza

88% improved/stable visual acuity,73.9% controlled ocularinflammation, 82.1%improved/stable visual acuity


Walton29 15 Miscellaneous UP andUI

CS Pediatric caseseries

CsA 2.510 mg/kg CS

Ocular inflamm decreased from 2 to0.5 at 6 months

9/15 nephrotoxicity, 2HT

Kilmartin30 14 Miscellaneous UP andUI

CS Pediatric caseseries

CsA 5 mg/kg Aza CS

92% improved/stable visual acuity,76% improved inflammatory score

4/14 nephrotoxicity, 1HT

Ozdal28 52 Behcet syndrome CS/cytotoxagents/colchicine

Case series CsA 5 mg/kg CS

69.2% improved/stable visual acuity 5/52 nephrotoxicity,3/52 HT

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

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CYCLOSPORINE AND ENDOGENOUS UVEITIS POSTERIOR 375Stients and ophthalmologists. In the pre-CsA era, thelity to effectively control uveitis, despite heavy immuno-pressive therapy, had been limited. As a result, many

tients suffered from severe visual loss or side effects ofmunosuppressants, and frequently from both. However,

initial enthusiasm that surrounded CsA was somewhatpered by the high incidence of CsA toxicity. Already infirst clinical trials studying the effectiveness of the drug,side-effect profile became clear: the development ofertension and hypercholesterolemia, the induction ofcose intolerance, gingival hyperplasia, hirsutism, hypo-gnesemia, tremor, and paresthesia. In addition, CsA is

phrotoxic. The adverse effects of CsA on renal functionits most dreaded complication and form the major

itation to its use. The pathogenesis of CsA nephrotox-y is still incompletely understood, but we can discrimi-

te an acute and chronic form. Acute nephrotoxicityurs within the first weeks after the initiation of treatment

d is usually reversible with dose reduction. It is caused bystriction of afferent glomerular arterioles, probablysed by alterations in the metabolism and secretion ofstaglandins, nitric oxide, and endothelin, as well as anreased adrenergic activity. In contrast, chronic CsAphrotoxicity is irreversible and is accompanied by severetologic alterations.1820

alestine et al21 evaluated renal histopathological alter-ons in patients who had received CsA for uveitis. Renalpsy specimens of 17 patients who had been treated for

toimmune uveitis with a starting dose of 10 mg/kg CsAan average of 2 years were compared with 37 renal

psy specimens from controls with idiopathic hematuriat had been read as nondiagnostic. Compared with con-ls, kidney biopsies of CsA-treated patients showed moreerstitial fibrosis, tubular atrophy, and glomerular ab-rmalities, resulting in a significantly higher chronicityex. Importantly, chronic pathologic alterations were

served in patients who had normal renal functionsessed by serum creatinine and inulin clearance mea-ements) at the time of biopsy and its severity did notrelate with the average or cummulative CsA dose.21

e high incidence of nephrotoxicity in these first trialspartly be explained by the high CsA doses (10

/kg) that were administered. Later studies therefored lower doses of CsA (2.5 to 5 mg/kg), either as thee immunosuppressant or combined with prednisone orer immunosuppressive agents2230 (Table 1). Lower-the dose of CsA appears to result in a lower incidence

side effects without reduced therapeutic efficacy, but adomized, controlled clinical trial comparing high-h low-dose CsA regimens is needed to fully answers question. Such a trial has not been performed yet. Indition, trials studying the safety of early CsA doseuction or complete cessation after induction of remis-n in EPU have generally shown disappointing resultsh a high relapse rate after CsA weaning.12,16,24,26

ally, strategies using lower CsA doses have not been

le to completely eliminate the problem of CsA neph- spooxicity.25,31 Isnard Bagnis et al31 studied 41 uveitistients treated with CsA between 1986 and 1997 in adomized, open-label, prospective study. All patients

d normal renal function before entry into the study.an CsA daily dose was 4.3 1.6 mg/kg, which wasdually tapered to 1.8 0.9 mg/kg at 5 years follow-

. Even this low-dose CsA regime induced a significante in plasma creatinine and a deterioration of theatinine clearance and glomerular filtration rate. In 11

tients who underwent serial renal biopsies, histologicmination showed a significant increase in interstitial

rosis, tubular atrophy, glomerular sclerosis, and thick-ing of Bowmans capsule after 2 years of CsA treat-nt compared to baseline. Interestingly, of all histologic

rameters, only the number of obsolescent gomerulis related to the initial daily dose of CsA. Whentients enrolled before 1990 (who received CsA dosesove 3.16 mg/kg) were compared with patients enrolleder 1990 (who received doses of CsA below 3.16 mg/kg),

former had a significantly worse renal function.wever, even patients treated with the lowest CsA

ses had histopathologic evidence of renal damage.31

ERAPEUTIC DRUG MONITORING

ug dosage based on blood concentrations rather thandy weight is known as therapeutic drug monitoringDM). In the field of solid organ transplantation, thisctice is widely applied for many immunosuppressants,luding CsA, tacrolimus, mycophenolate mofetil, andolimus. Dosage of these drugs is adjusted to reach certaindefined target concentrations that have been deter-

ned empirically and are associated with optimal treat-nt outcomes. For CsA, the traditional parameter forM has been the predose or trough concentration.32 Ineral, TDM is not routinely performed for patients

ated with CsA for autoimmune disease. This can belained by the fact that in autoimmune disease the

munologic process is already in full swing at the time ofgnosis and inititation of treatment, whereas in the trans-nt situation, drug therapy is started to prevent theurrence of an immunologic reaction. Therefore, immu-

suppressive drugs used in the treatment of autoimmunitybe titrated to their biological effect. Moreover, in

toimmunity time is less critical as most of these diseasesnot acutely life-threatening, while this is clearly not the

e when a transplanted patient suffers from an acuteection. Nevertheless, there are some situations in whichtients with autoimmune disease may benefit from TDM.st, such a situation arises when therapy is started with ag that has a large intra- and interindividual pharmaco-etic variability, as this may result in therapeutic failure oricity on standard dosing. The pharmacokinetics of CsAnotoriously unpredictable, showing marked differences

ween individuals or within a single patient over time.erefore, uveitis patients who are classified as nonre-

nders may in fact suffer from low CsA blood concentra-

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376S HESSELINK, BAARSMA, KUIJPERS ET ALns caused by a high first-pass metabolism of the drug.33

ce versa, in patients who suffer from severe toxicity, theg may be withdrawn too early, while a much lower dose

uld have minimized side effects yet maintained adequatemunosuppression. Second, TDM may be beneficial whentors are present that interfere with drug pharmacokinet-or pharmacodynamics. Such factors include diet andedication. The pharmacokinetic interactions of CsA

h many drugs are well known as they frequently result inered CsA blood concentrations (Table 2). Prescription ofse drugs is not uncommon in uveitis patients and the

hthalomologist needs to be familiar with these interac-ns. Finally, TDM can be used to check patient compli-ce.

o date few studies have systematically studied thessible advantages of TDM in uveitis. In an uncontrolledl, Rocha et al34 treated eight patients who were resistantconventional immunosuppressive therapy with CsA.se adjustments were made based on CsA blood concen-tions 6 hours after administration of the morning dose6). Treatment with CsA monitored by C6 resulted in anprovement of ocular inflammation in all patients, ander a mean follow-up of 16 10 months renal functions not statistically different from baseline. In addition,od pressure and potassium, uric acid, and magnesiumum concentrations remained stable throughout follow-.34 Whether such a favorable outcome could have beenieved if a CsA dose reduction had been performed

espective of blood concentrations remains open to ques-n. In conclusion, TDM is currently not advocated forA therapy in uveitis patients and unless randomizedtrolled trials demonstrate a significant benefit of such a

Table 2. Drugs With Clinically Relevant PharmacokineticInteractions With Cyclosporine

ibioticslarithromycinoxycyclinrythromycinifampiniconvulsantsarbamazepinehenytoinihypertensives/antiarrhythmicsmiodaroneiltiazemicardipineifedipineerapamilimycoticstraconazoleluconazoleetoconazoleerrotease inhibitorsheophyllinorticosteroidsategy, treatment guidelines are unlikely to change. None- 197less, there are several situations in which TDM may bebenefit and the ophthalmologist should keep an open eyesuch occasions.

TURE CONSIDERATIONS

A is an effective second-line agent that has considerablyproved the visual prognosis of patients with EPU. How-r, despite low-dosing regimens, CsA toxicity remains an

portant problem that forms the major limitation tocessful long-term treatment. In addition, a significant

mber of uveitis patients are refractory to this powerfulmunosuppressant. Thus, there has been a continuinged to further optimize drug therapy for uveitis. In thest decade, a number of novel immunosuppressants thatre originally introduced into the fields of transplantationd rheumatology have been studied for the treatment ofU. Drugs that have shown encouraging results in animaldies and small trials in humans include tacrolimus,olimus, and antibodies that block the IL-2 receptor.3537

e of the most promising new therapies is anti-tumorcrosis factor (TNF) treatment. Both the monoclonalti-TNF antibody, infliximab, as well as the TNF fusiontein, etanercept, have shown remarkable efficacy in

proving the symptoms of sight-threatening EPU in pa-nts refractory to conventional therapy.3840 Except forld injection-site reactions and one case of tuberculosis,adverse effects were noted in these preliminary trials. It

to be expected that in the near future, the efficacy andety of this new generation of immunosuppressants will bether investigated in randomized, controlled clinical trialslarger patient groups. Most likely they will be studied intients with CsA-refractory EPU or compared head-to-ad with CsA. Another possibility is to combine thesegs with (low-dose) CsA. However, until such trials

monstrate clear advantages of these novel immunosup-ssants, CsA will remain the mainstay of immunosuppres-

e therapy in patients with corticosteroid-refractory EPU.

NCLUSIONS

U is a sight-threatening autoimmune disease that fre-ently fails to respond to treatment with high doses ofticosteroids. CsA has proved to be an effective second-

e agent for such patients. However, the success of CsAs been hampered by side effects, most notably nephro-icity. Low-dose CsA regimens have minimized toxicitybeen unable to completely eliminate it. Currently, the

cacy and safety of novel immunosuppressants are beingestigated in a number of clinical trials. Hopefully, thesegs will provide means to reduce CsA toxicity whileintaining its full therapeutic benefit.

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