cyclosporine: immunology, pharmacology and therapeutic uses

SURVEY OF OPHTHALMOLOGY VOLUME 31 . NUMBER 3. NOVEMBER-DECEMBER 1986

THERAPEUTIC REVIEW JOEL MINDEL AND SAIICHI MISHIMA, EDITORS

Cyclosporine: Immunology, Pharmacology Therapeutic Uses

ROBERT B. NUSSENBLATT, M.D., AND ALAN G. PALESTINE, M.D.

and

Abstract. Human and animal investigations since the mid- 1970s have demonstrated thr ellec- tiveness of qclosporine (Cs,\) as an immunosuppressive agent. In the area of transplantation immunity, it has been shown to enhance success of renal, hone marrow. and li\,er transplantation. Moreover. certain models of autoimmune disease have heen effectively treated with CL\. and a number of studies have reported encouraging results \vith CsA therapy for ocular inflammatory disorders. notably BehCet’s disease. The most serious side effects of CsA are nephrotosi- city and hypertension; thus. conservative dosages of the drug and careful monitoring of renal function during treatment are recommended. The purpose of this review is to provide clinicians and researchers with a clear perspective of both the potential benefits and shortcomings of this .tgent (Surv Ophthalmol 31:159-169, 1986)

Key words. cyclosporine l cornea1 transplantation l immunoloqy l

immunosuppressive agents l ocular inflammatory disorders

Cyclosporine (CA) has presented the clinician

and researcher with a twofold opportunity, opening

the possibility of new treatments for ocular inflammatory disorders and providing a new tool for prob-

ing the immune system. Cyclosporine’s story begins in 1969-70 in the Microbiology Department of San-

doz, Ltd., in Basel, Switzerland, when two new strains of fungi imperfecti were isolated from soil

samples taken from Wisconsin and Norway.12 The fungal extracts showed a narrow spectrum of anti- fungal activity and were low in toxicity. Because of

these observations, compound 24-556 entered into a screening program. In <January 1972, Jean Bore1 discovered the marked immunosuppressive effects of this metabolite, and so began a most interesting saga. This review summarizes current information concerning this agent, so that the ophthalmic re-

searcher and clinician can better put into perspec-

tive its great potential as well as its shortcomings.

Pharmacology and Metabolism

Cvclosporinc (Fig. 1) is a cyclic peptide contain-

ing eleven amino acids with a total molecular weight

of 1202.“,!“’ Uncharged at physiologic pH and in-

soluble in water, it is soluble in ethanol or it can be

dissolved in olive or sesame oil at 60°C:. It will then

remain in solution at room temperature. These solu-

bility characteristics substantially influence the

clinical use of this drug. The oral preparation is an

olive oil solution with 12.5% ethanol which must be

dispersed in juice or milk before ingestion.“” Conse-

quently, oral absorption is variable and slow. Ap-

proximately 30% of the oral dose is absorbed, with a

peak blood level 2-4 hours after ingestion.’ “I How-

159

160 Surv Ophthalmol 3 l(3) November-December 1986 NUSSENBLATT, PALESTINE

C”39

!

C”3\ ,C”3 H’ \cH2 I

f” C”3 C”3 HO CH

7”2 f”3 ‘$ \/\

CH3 F” C”3

CHj- ~-CH-CO-N-CH-C-~-CH-CO-

C”3, co

C”3

,CH-CH2-iH

CH3 : I

Ii

OC-CH - N-CO-CH-ti-CO-CH-N-

iH3 ii LH*

CH3 CH3

b

i-C”3

ti I

ii-CH-k-CO-C”

,tH CH3 ‘CH3

iH2

tH

c& ‘cti3

Fig. I. Structure of cyclosporine A, a cyclic peptide.

ever, the absorption may vary between 4% and 60%, and it appears to improve after extended use

in some patients. A single 600 mg oral dose will

produce a peak plasma concentration of 240 to 1250 ng/ml (mean 538 ng/ml).6 Therefore, absorption

varies among individuals as well as over time in a

single patient. The variability in oral drug availabil-

ity is one of the factors which influences individual adjustment of the dose for each patient. A relation-

ship of absorption to meals has not been reliably

established,3gJ5 but bile and the enterohepatic circu-

lation do affect absorption. An intravenous formula-

tion containing ethanol and polyoxyethylated castor oil is available, but is rarely needed in the treatment

of autoimmune diseases. ‘O No commercially avail-

able topical cyclosporine formulation is currently

available. Although this has potential use in ophthalmology, the lipid solubility and uncharged na-

ture of the molecule make ocular penetration difli-

cult and prevent the use of the usual ophthalmic vehicles.

A radioimmune assay is available to measure

nannogram concentrations of CsA, which, in the blood, is largely bound to erythrocytes.50 This binding is temperature-dependent and can markedly in-

fluence the results of a plasma CsA concentration assay. CsA leaves the erythrocyte as the temperature decreases.5* It is therefore important to either assay whole blood CsA concentrations or to always allow the blood to equilibrate at 25°C for two hours prior to plasma separation so that the plasma concentration consistently reflects the “true” blood concentration. At 25”C, the blood concentration is approximately live times the measured plasma concentration. 6’ Erythrocyte CsA binding is saturated

above 5000 nglml, which is considerably above the therapeutic range. There is a biphasic decrease in

blood and tissue concentrations of CsA; the mean elimination half-lives are 1.2 hours and 27 hours in

normal individuals.‘j An elevated serum bilirubin

and associated liver dysfunction will prolong the

half-life, and the elimination of CsA is not affected

by renal disease. The clearance of the drug is 6-7 ml/min/kg.83J4

CsA is most highly concentrated in lipid contain-

ing tissues. The highest concentrations are in the

fat, breast, pancreas, liver, kidney and lymphoid

tissue whereas the lowest concentrations are in brain and muscle.‘J8 The concentration in the fat is

approximately 10 times the plasma concentration.

Hence, a large reserve of drug is present. The con-

centration in the aqueous humor in patients with chronic flare is 40% of the plasma concentration.

CsA is in extremely low and non-therapeutic con-

centrations in the cerebrospinal fluid.77 CsA metabolism involves oxidative alterations by

the cytochrome P-450 microsomal enzymes of the

liver.5J3 The ring structure remains intact during metabolism. A number of the side-chains of the amino acids are hydroxylated or N-demethylated; over 15 metabolites of CsA have been identified. Only

0.1% of the CsA is excreted unchanged.25,g8 Excre- tion occurs primarily through the bile and intes- tines, although a small amount (6%) of the drug and its metabolites are excreted in the urine.25

The pharmacology ofCsA relates to possible drug interactions. The recommended clinical plasma concentration was initially 100-300 ng/ml. How- ever, in view of side-effects such as nephrotoxicity, this has been lowered to 50-100 ng/ml. Drugs such

CYCLOSPORINE

as phenobarbital or phenytoin, which increase the

activity of the hepatic microsomal enzymes, will in-

crease the rate of metabolism of the drug, thereby lowering plasma concentrations.“.” Isoniazid, ri-

fampin, and intravenous sulpha/trimethoprim have

also been reported to decrease circulating GSA concentrations.‘“.‘” Ketoconazole is an inhibitor of the

hepatic microsomal enzymes and therefore will in-

crease the plasma GSA concentration when admin-

istered concomitantly.” Cimetidine and erythromy-

tin may also increase the plasma concentration.“’ CsA has an additive toxic effect with known nephro-

toxic drugs. Renal toxicity is the major clinical side-

effect of cyclosporine and drugs such as gentamicin,

amphotericin B, co-trimoxazole, and nonsteroidal

antiinflammatory agents will markedly enhance

CsA induced nephrotoxicity.“H.q” These drugs may

be clinically necessary at times, but should be avoid-

ed if alternate compounds are clinically acceptable.

Mechanism of Action of Cyclosporine

CsA has been an effective immunologic probe which has been used to dissect the immune rc-

sponse. The major effect of this agent centers about the basic events concerning T-cell activation (Pig.

2). The activation of noncommitted, resting T-ccalls

requires both specific antigen and nonspecific sig-

nals.” This activation will lead to the expression 01‘ various receptors on the cell membrane of the T-

cell. Of major import is the lymphokine interlrukin 2 (IL-2). This factor is thought to be the primar).

path by which T-cells continue to recruit and acti-

vate new T-cells. The expression of IL-2 receptors is

critical for the T-cell’s capacity to respond to this

lymphokine. It should be stressed that other factors, such as gamma-interferon, are being produced at the same time during the extremely complex (‘as-

cadc of immunoreactive f’actor production. Lars-

son” compared the perturbation of this system b)

CsA and dexamethasone. She observed that, in the

murine model she utilized, CsA appeared to block

the acquisition of responsiveness to mitogen of resting cells (i.e., the formation of IL-2 receptors), but

that the proliferation of activated T-cells (already

bearing IL-2 receptors) in the presence of IL-2 could not be blocked. Dexamethasone, howeLTer.

was f‘elt to block IL-2 release but not the expression

of IL-2 receptors on the cell membrane. Bunjes and coworkers” have reached very ditI’er-

ent conclusions in that their observations supported the notion that IL-2 release by T-cells was inhibited while the acquisition of receptors permitting these cells to respond was not inhibited. Kaufman and

coworkers3’ evaluated this question in a unique system utilizing T-cell hybridomas, some of which do not bear IL-2 receptors. but produce IL-2. They

161

a 0 YACROPtlAQE

INTERLEUKIN I

INDUCER T CELL

IL-2 RECEPTOR

/

+ CYCLOSPORINE INTERLEUKIN 2 t-4

(IL-2)

. EFFECTOR T CELL

Fig. 2. Mode of action of’cyclosporine. This agent’s major effect centers around its perturbation ofthe T-cell’s ability to produce Interleukin 2 (11,-Z) or to rrspond to IL-2, hy prevrnting the formation of specific I L-2 receptors.

observed that CsA blocked both the stimulation of

IL-2 and its ongoing production. They concluded

that CsA blocked the binding of an antigen to its

appropriate receptor, leading to the events de-

scribed above. Bendtzen and Dinarello’ have con-

jectured, however, that the agent’s interference oc-

curred at earlier events in the T-cell activation

process. They noted that Cspl may prevent the up- takr of IL-1 (macrophage produced) by T-cells. This monokine is needed in the process of T-cell

activation, and its less efficient binding to T cells

would ultimately lead to the decrease or prevention of IL-2 production. These similar but still quite dif-

ferent observations were unified by the observations of DOS Reis and Shevach.‘LY Working in a guinea pig

model, they felt that the site at which CsA affects T- cell functioning varied depending on the nature of

the T-cell stimulus and the differentiation state of the cell itself: It is clear from the available informa-

tion that CsA is unique in mediating its action at a specific portion of the immune system, and that all evidence agrees that its major effect centers about IL-2 production and responsiveness. However, it is clear that various T-cell subsets and the state of’ their activation may render them less susceptible to

the effects of CsA.” The alterations in T-cell functioning seem to

translate in a differential effect on various cellular


components of the immune system. The presence of CsA has a variable effect on B-cell functioning. Lil-

lehoj et a15’ found that CsA had no effect on B-cell

proliferation to T-cell independent antigens, nor did

it inhibit the expression of B-cell activation markers. In the S-antigen model for uveitis, Chan and col-

leagues9 noted that specific antibody production

was not inhibited by GSA administration, but rather

that the time needed to reach peak levels was some- what longer than that needed in control animals.

Cytotoxic cells have been noted to be affected by CsA administration, apparently preventing the in-

duction of this T-cell subset.‘O’ We have noted that

the number of inducer T-cells in the draining lymph

node of the site of antigen immunization was mark-

edly diminished by CsA therapy.@ Of interest has

been the sparing of suppressor cells by CsA. Leap- man and coworkers4’ felt that in humans, while oth-

er subpopulations were inhibited, suppressor cells

were spared but not induced when CsA was added

in vitro. Hutchinson and colleagues”” noted a spar-

ing of donor-specific suppressor cells in rats receiv-

ing heart allografts. Others, however, have suggest-

ed that CsA administration may induce suppressor

cells, Wang and colleagues”’ felt that this mecha-

nism explained the longlasting unresponsiveness

seen in CsA-treated mice immunized vsith target

cells, which usually induce highly cytolytic cells.

Further, Hess and coworkers, studying human cells,

observed a nylon-wool adherent suppressor cell

which was induced by CsA administration30

The molecular basis for these effects has only recently begun to be elucidated. The evidence to date

would not suggest that a specific CsA receptor exists on T-cell membranes. 48 However, Merker and

Handschumacher 54 have reported a cytoplasmic macromolecule that does appear to bind with CsA.

It is clear that CsA’s effect is not just at the mem-

brane. CsA has been shown to inhibit lymphokine- specific mRNA and new protein synthesis.“‘,R’

Animal Studies

Calm and White,” as well as Green and Allison,‘8 noted the extensive prolongation of renal allografts

with CsA therapy, while others have shown similar results with cardiac allografting.~g,4’ In experimen-

tal lung transplantation in dogs, the addition ofCsA

leads to longterm normal lung function and no evi-

dence of rejection in some animalsg7 CsA treatment was also most effective in altering graft-versus-host

and host-versus-graft responses in rats-j2

An area ofgreat interest has been the basic under-

lying perturbations of the immune system which Iead to the clinical entity recognized as an autoim-

mune condition. Experimental allergic encephalo-

myelitis (EAE), induced by immunization with cen-

tral nervous system derived basic protein, a

paralytic condition, has been studied extensively. Bore1 and coworkers” demonstrated that CsA effec-

tively prevented the expression of EAE. Several re-

searchers have confirmed these observations, with

dosages usually at 15 mglkgfday. Cs.4 has also been noted to have a beneficial effect even when adminis-

tered with a delay of several days after immuniza-

tion,” and the agent was effective in preventing the

adoptive transfer of EAE with activated lympho-

cytes.’

The effect of CsA on the naturally occurring lu- pus-like disorder in certain mice has also been inves-

tigated. CsA treatment of NZB/W mice appears to

suppress anti-DNA titers normally noted in these

animals as they develop disease. Jones and Harris””

have also reported that CsA therapy improved the survival of NZB/W mice. A most important area of

investigation was carried out by Laupacis and colleagues,+j who evaluated BB Wistar rats for their

spontaneous development ofdiabetes. In this study,

75% of control animals developed insulin-depen-

dent diabetes between 60 and 120 days of age while none of the 40 CsA treated rats became diabetic.

While control rats developed partial or complete

destruction of their islets of Langerhans by lympho- cytic infiltration, CsA-treated rats had normal pan-

creases.

Two major areas of investigation revolve around

the effects of CsA administration on transplantation models and those of autoimmunity, both induced and naturally occurring. This discussion will deal separately with the nonocular and ocular observations.

NONOCU~R ANIMAL STUDIES

It should be emphasized that some models of pu-

tative autoimmune disease were not effectively treated with CsA; such an example is the spontaneous autoimmune thyroiditis seen in the obese strain

of chickens. Wick and colleagues’02 observed that CsA therapy led to the development of much more severe disease as well as higher titers of thyroglobu-

lin autoantibodies. Transplantation immunity has been an area in-

fluenced greatly by CsA. Bore1 and coworkers” OCULAR ANIMAL STUDIES _ _,

early on demonstrated the effectiveness of CsA in The usefulness of CsA in preventing cornea1 graft delaying skin graft rejection in mice and graft-ver- rejection has been extensively evaluated. Coster and sus-host disease in mice and rats. Organ transplant Shepherd and their colleagues’0,g3 treated one group studies are too numerous to fully list. However, of outbred Dutch rabbits with 25 mg/kg/day of CsA

CYCLOSPORINE

after 6 mm penetrating grafts. Another group re-

ceived a 1 O/O CsA eye drop five times a day. Addi-

tionally, skin grafts were performed to ensure rejection. In this study, prolongation ofthe cornea1 grafts were seen in all animals receiving systemic therapy.

This observation was confirmed by Bell and colleagues.’ However, the topically applied CsA did

not appear to prolong cornea1 graft survival, but this was thought to he related to the need for skin graft-

ing to initiate the rejection. Salishury and Geh-

hardt’“’ gave a single retrobulbar injection ofCsA to

New Zealand white rabbits at the end of kerato-

plasty. Four (45%) of nine allografts treated with

Csi4 survived more than 70 days, while all untreated eyes rttjcctchd within 40 days. They observed that

CsA was less effective in suppressing allograft rqjec-

tion in heavily vascularized, inflamed graft sites.

Hunter and coworkers,” reported that a 1% CsA solution in arachis oil given topically five times dail)

significantly prolonged graft survisal. Kana and as-

sociates, using both a subconjunctival and topical route, confirmed the above observations? Roussel

and colleagues”’ took the novel approach of’deli\.cr-

ing a L 9’0 CM solution locally to the cornea bl- using

a polypropylene tube connected to a subcutaneous

osmotic pump. This method delivered CsA to the cornea1 surface at a continuous rate of 2.5 &%r (2.5

~gihr) fbr 28 day-s. This approach signi~ca~ltl~ de-

layed graft re_jection compared to controls. Addi-

tionally. this topical s!‘stem, when delivering a markedly higher CM dose (500 pgihr) appeared to

reverse cornea1 graft rcjrction after it began.“” How-

ever, because of‘thr relatively large ocular surface in the rabbit. systemic absorption can occur. thcrch)

making these results difficult to interpret without

systemic. blood levels, w*hich were not performed. An important consideration has been the ocular

penetration of local Cs/\ administration. Mosteller

and colleaguesi” observed that a 10% GSA ointment

preparation could obtain a peak of900 ng/ml in the cornea three hours after administration. Relatively-

low lrvc~ls were measured in the aqueous humor.

suggesting a cornea1 strctmal pooling of this hydro- phobic agent. Wiederhott and coworkers”” felt that therapeutic levels could be found in the aqueous

humor as well as the u\:ea/retina. \Ve”’ have noted,

as have Mosteller and colleagues,‘” that relativel)

low levels or‘ C&A penetrated intraocularly, and not at a therapeutically cfiactive dose.

The effects of CS~~ on an experimental herprtic

stromal keratitis model \vas investigated by Boisjol) and colleagues.’ They noted that the severity of stro- ma1 disease was significantly decreased in eyes treatt%d with a comhiIlation GSA/steroid topical preparation. but the incidence and duration of positive cultures was increased in this group as com-

2.6

“‘~,~~ f??

10.0

9.0

6.0

70

6.0

~~

5.0

40

3.0

2.0

10

10 11 12 13 14

Blood

Daily Therapy

W Oil

M CsA

Lymph Node

Davs Post immunization

Fig. 3. In vitro prol%erative responses to the S-Ar: of lymphocytes iiom lymph node and blood frnm Lewis rats

receiving rither CsA or oil. Significant proliferative IT-

sponses to this antigen were seen onI>- in the blood of rats rcvG\-.ing oil injections. (Reprinted from Nussenhlatt RB et al”’ with permission from Inll Arch ;1lI~1;gv Appr hmunol-

OgY)

pared to controls. A combination of systemic and

intravitreal CsA therapy also proved effective in suppressing secondary herpes simplex uveitis, a

condition thought to be due to an interaction between herpes antigen as well as various components of the immune system.”

The effect of &A on retinal S-antigen induced experimental autoimmune uveitis (EAU) has been investigated extensively. This agent prevented the expression of EAU when S-antigen-immunized rats were treated with 10 mgikgiday CsA when begun on day 0, and at 40 m,g/k,q when CsA was begun on

164 Surv Opht~lmol 3 l(3) November-December 1986 NUSSENB~~, PALESTINE

day 7 after immunization.6g Similar observations

have been recently noted by Striph and associatesg” Neither cell-mediated nor antibody responses were

abrogated, but a delay in the time needed to obtain

peak responses was observed. Additionally, lym-

phocytes carrying immune memory for the S-Ag were not observed in the circulation in those ani-

mals receiving CsA’O (Fig. 3). At higher dosages of

the agent, some rats were noted not to develop EAU

even when evaluated weeks (4-5) after the abroga-

tion of therapy. 68 The transfer of EAU to naive rats

by cells from S-Ag-immunized donors could be sup- pressed by daily injections of CSA.~” The topical

application of GSA did not prove to be effective in preventing EAU as long as circulating CsA levels

could not be measured, suggesting that effect ofCsA is mediated through systemic mechanisms.~’ How-

ever, when su~ciently high amounts of the drug are

placed into the vitreous, the eye can be protecred

from EAU, while the contralateral, untreated eye

will express disease.

Human Studies

NONOCULAR HUMAN STUDIES

The usefulness of CsA in almost all aspects of

transplantation immunology has been extensively evaluated. Calne and colleagues’7 reported the use-

fulness of CsA in patients receiving renal allografts

from cadaver donors. In a European multicenter trial, renal transplant survival was superior in pa-

tients immunosuppressed with CsA as opposed to the standard azathioprine and steroid prophylax-

is.87 GSA has been used to prevent graft-versus-host disease in humans after allogeneic bone marrow

transplantation. ” Although toxic side effects were

noted, the agent appeared effective in preventing serious complications, The era of liver transplanta-

tion has perhaps undergone the most dramatic change with the use of CsA. As Starzl and col-

leagues wrote, “The purgatory in which liver transplantation was mired has ended in the cyclosporine era.“g4 Starzl reported that of the first 67 recipients

in the CsA series in its first two years, 42 passed the

one-year mark. This was almost as many patients as survived the one-year mark for the 17 years prior to

CsA therapy. Comparing the 66 patients undergoing cardiac transplantation at Stanford University

who received CsA to the 99 receiving azathioprine, the incidence of rejection was not significantly different between the two groups. However, since rejection episodes were less severe, mortality related to these episodes was reduced to near zero in the CsA group and therefore afforded distinct improve- ments in terms of survival, rehabilitation, and hos- pital costs.‘”

The use of CsA in a multitude of auto~mrnLine

diseases has begun in order to investigate its poten-

tial usefulness in some very problematic diseases. As of this writing, most studies are pilot in nature, with

randomized studies just getting started or projected.

Amor and Dougados’ have reported their experi-

ence in an open trial utilizing CsA in the treatment of rheumatoid arthritis. Their impression, using

several clinical and laboratory parameters, was that

the drug was a beneficial agent for this disorder. A

pilot study in the treatment of recently diagnosed

Type 1 diabetes mellitus patients with CsA resulted

in the observation that this therapy enhanced or

preserved endogenous secretion of insulinZ3 and

that results from a recently completed randomized study will support this observation (Dr. Beat von

Graffenreid, personal communication). It should be emphasized that controlled clinical trials are still

needed to fully evaluate these and other observa-

tions.

OCULAR HUMAN STUDIES

Experimental cornea1 transplantation data would

suggest that CsA may be a logical therapeutic agent for the enhancement of graft survival. Hoffman and

Wiederholt”2 have reported their experience in util-

izing a 2% CsA castor oil eye drop solution combined with dexamethasone drops as a therapeutic

regimen for 25 patients. In this open, nonrandom-

ized study, 21125 grafts remained clear with a mean follow-up period of ten months. They noted that all

patients on this regimen developed a punctate keratitis and a slight conjunctivitis. A masked random-

ized study using systemic CsA is presently under-

way in the United States.

We have reported the beneficial effects of CsA on patients with severe, sight-threatening intermediate

and posterior uveitis.“2.67 An initial sixteen patients ranged in age from 20 to 67 years and all had pre- viously received systemic corticosteroids and/or cy-

totoxic agents. These individuals, who had not had a positive therapeutic effect or intolerable side ef-

fects to these agents, were treated with CsA. Of the

16 patients, 15 had positive clinical responses to CsA therapy. Ofinterest, patients with cystoid mac-

ular edema demonstrated an improvement in visual acuity before the resolution of their edema could be demonstrated by fluorescein angiography. Resoiu- tion was, however, seen later in the therapeutic course (Fig. 4).62 While vitreal cells appear to linger, vitreal haze tends to dissipate more rapidly and can

be quantified.“.’ In longterm follow-up study of 52 patients treated with CsA, 41 of 52 patients (79%) were considered therapeutic successes at three months, and 63% (22 of 35) of those with one year’s follow-up were considered successfully treated as well.“’ Graham and associates” have noted similarb

CYCLOSPORINE

Fig. 4. Fluorescein angiograms of 41-year-old white female with intermediate uvcitis and long standing cystoid madar

edema. A. Pretherapy cystoid macular edema. I’a ~~/20(~. B. After one year on cyclosporine therapy. the cystoid ~~~cu~~~

edema has essentially resolved, and there is a visual acuity of 20/M. ‘I‘his patient’s visual acuity had reached this level of acuity after S months, with continued presence of the cystoid macula edema still noted. ‘I%P patient hx been ofi

cyclosporine for 2 years with li~aintenance of good visual acuity in that eye.

beneficial ocular effects in all patients they treated. abrogated the acute attack, and totally pre\.ented or However, significant toxic effects obviated their markedly reduced the number of recurrences. This

continuing this therapeutic regimen. A sirnilal observation has been corroboratrd by a recently

experience was reported by LeHoang and Fon- complctcd double-masked randomized study in .Ja- taine. !” Nissen and colleagues reported their posi- pan, which “clearly verified that . . Ck4 is superior tive experience in treating 17 uveitis patients with to that of colchicine not only in the suppression of

CsA who had not done well on oral corticostcroids ocular in\~o~ven~~ilts but also in other systemic

or cytotoxic agents.“’ It was their feeiing that CsA symptoms. “” In our studies, we ha\,e observed that was as efficient, if not more so, than steroids and laser interferometry is an effective aid in determin-

cytotoxic agents in the treatment of uveitis. Of note, ing which patients may ultinlatel~ have a significant one of’ their patients developed an Epstein-Barr improvrment in vision. Patients with active inflam- virus infection and one Herpes zoster, which was matory disease who had a disparity of three lines or

successfully treated with acyclovir. Of particular more between Snellen acuity and visual acuity as note was the efTect of&A on the course of the ocular detrrmined by laser interferometry had an 86%

disease in Behqet’s disease patients.h’ CsA therap) chance of increasing their visual acuity bx at least


three lines with CsA therapy.74 Of interest as well

has been the excellent clinical response to CsA of a

patient with a severe scleral melt that was unrespon-

sive to cytotoxic agents (Fig. 5).

Toxicity and Side Effects

Although cytosporine has a relatively specific ef-

fect on the immune system, its use is associated with

a number of subjective side effects.45*76 Mild numb-

ness and tingling of the extremities as well as tem-

perature hypersensitivity are noted within several

days of starting on CsA by 90% of the patients.

Nausea and gastrointestinal distress beginning with

the first dose are noted in 2O%, but only in rare

individuals does this alter the patient’s ability to use the drug. This adverse reaction is responsive to a

decrease in dose. Increased hair growth is another

commonly observed side effect. It is usually noted

during the first several months of therapy. Gingival hyperplasia similar to phenytoin toxicity is noted in

25% of patients within the first several months of

therapy. Its severity is exacerbated by poor oral

hygiene and can largely be controlled by careful

attention to periodontal disease. Rarely, periodon-

tal surgery has been necessary. A fine hand tremor occurs in the early months of treatment, but this will

frequently improve during therapy. Oechslin et al”

reported cotton wool exudates in three bone marrow

recipients treated prophylactically with CsA for graft-versus-host disease. However, these aiter- ations were not noted in renal transplant patients

receiving CsA.”

Although CsA is not a cytotoxic drug and does

not cause leukopenia, a normochromic, normocytic

anemia is noted in 25% of patients. The hematocrit

rarely falls below 30%. It is important to rule out other causes of anemia. The cause of this anemia is

not known. Another unexplained side-effect is an increase in the erythrocyte sedimentation rate. A

significant increase is seen in 40% of patients in spite of an apparent clinical improvement in the underlying in~ammatory disease. This increase

may complicate treatment of diseases in which the sedimentation rate is an important clinical param- eter. Hepatic toxicity has not been a serious adverse reaction. Mild, dose-dependent elevations of serum transaminases and serum bilirubin have been noted.

Nephrotoxicity and hypertension have been the two major serious clinical toxicities of CsA therapy. Depending on the definition of renal toxicity, 75% or more of patients have some degree of renal func- tional change.26,76,78 A significant rise in the serum creatinine can be noted in treated patients. This is accompanied by a corresponding fall in glomerular filtration.‘” Initially this toxicity appears to be dose-

dependent and reversible; lowering of the dose will lead to a normalization of renal function within 4-6

weeks. However, chronic alterations in renal mor-

phology consisting of interstitial fibrosis and tubu-

lar atrophy have been noted in a large percentage of heart transplant patients treated for one year in

whom the serum creatinine was permitted to remain markedly elevated for extended periods of time.” In

our experience, this has also occurred in a patient

population where the dose of CsA was continually lowered to maintain a serum creatinine of less than

double the pretreatment serum creatinine.75 How-

ever, the initial dose of cyclosporine was 10 mg/kg and many patients received higher doses during

their treatment. It appeared that patients had more histologic evidence of renal toxicity if their serum creatinine was 50% above baseline for longer than

four months. Clinical monitoring of renal toxicity

does not fully reflect the underlying pathology. The patients in this study had a mean creatinine of 1.5

mg/dL in spite of the significant morphologic

changes.7” The significant irreversible renal toxicity

has led to recommendations of lower CsA doses and

the addition of other immunosuppressive drugs such as corticosteroids. It is further recommended

that creatinine not rise more than 20-30% above

the pretherapy level during CsA therapy. It is not

yet clear whether CsA nephrotoxicity is due to a

direct tubular toxic effect of the drug or whether it is due to decreased renal blood flow from an effect on

the sympathetic nervous system or on prostacyclin synthesis.7’

Systemic hypertension occurs in 25% of pa-

tients,7H more frequently in those patients with clinical alterations in renal function. It is responsive to

dose-reduction and to treatment with antihyperten-

sive regimens such as hydrochlorothiazide/alpha-

methyl dopa in combination with beta blocking

agents or prazosin. Reports of lymphoma caused initial concern

about the use of CsA.’ Lymphoma occurs no more frequently in organ transplant recipients receiving

CsA and prednisone than in similar patients treated

with other immunosuppressive agents. Forty-nine lymphomas occurred in 5000 transplant recipients followed for five yearsg’ Most of these deveiop in the first several months of therapy, and discontinuation

of therapy results in regression of the lymphoma. The incidence of lymphoma in patients receiving this drug for autoimmune disease is probably less than the above statistic, and to date we have seen none in our patients, nor are we aware of any reported.

Current Status The guidelines for the use of CsA in ocular in-

CYCLOSPORINE

flammatory diseases are undergoing modification as

new information concerning the mechanism of ac-

tion and the toxicity becomes available. Currently, CsA appears to be effective in diseases such as Beh- Get’s syndrome and in spite of the apparent nephro-

toxicity, probably has fewer severe side effects than

cytotoxic agents. In other inflammatory conditions, it is still a drug to be considered primarily in pa-

tients who have done poorly on high-dose cortico-

steroids or who cannot tolerate an effective mainte- nance dose of corticosteroids. In view of the

alterations in renal function, we have decreased the

starting dose of CsA to 6 mgfkglday and we contin-

ue the patient on low-dose corticosteroids. Renal

function should be carefully monitored by serum

creatinine and inulin or creatinine clearances. The amount of acceptable alteration in renal function

has not yet been determined; however, our current

guidelines suggest no more than a 30% increase in serum creatinine. CsA represents a first generation

drug of agents that will be effective on subsets of the immune system. In spite of its toxicity, organ trans-

plant survival has been dramatically improved.

Succeeding generations of CsA derivatives may of-

fer more specific action with less toxicity. For example, initial evaluation of Cyclosporine G has shown

that the nephrotoxicity is considerably less with this

drug, while the efficacy is only slightly reduced.“-b” In addition, an improved understanding of the

nephrotoxicitv may lead to the use ofvasodilators or

other drugs to decrease this side effect without af-

fecting the immunosuppressive action. Lastly. it

may be possible to reduce the required dose of CsA

by enhancing its effectiveness through the co-administration of other drugs. The final goal is the

control of immune-mediated inflammatory disease with minimal adverse effects.

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CYCLOSPORINE

cyclosporine: immunology, pharmacology and therapeutic uses

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