Table Of ContentOptimal Use of Sandimmun
®
in Endogenous Uveitis
D. BenEzra, R. B. Nussenblatt, P. Timonen
With 37 Figures and 1 Table
Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
BenEzra D, M.D., Ph.D.,
Department of Ophthalmology, Hadassah University Hospital,
Jerusalem, Israel
Nussenblatt RB, M.D.
National Eye Institute, National Institutes of Health,
Bethesda, Maryland, USA
Timonen P, M.B.
International Clinical Research, Sandoz Ltd,
Basle, Switzerland
ISBN·13: 978·3·540·18878·0 e·ISBN·13: 978·3·642·83368·7
001: 10.1007/978·3·642·83368·7
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© Sandoz Ltd, Basle 1988
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Editorial
From past experience and in the clinical judgement of Careful evaluation of the results achieved in both un
ophthalmologists dealing with endogenous uveitis, it is controlled and controlled studies has made the formula
clear that there is a need for alternative treatments. tion of these guidelines possible. They are a reflection
Since the beginning of the 80s, Sandimmun ® (ciclo of clinical experience extending over 6 years, which
sporin) has become the immunosuppressant of choice has led, in particular, to the conviction that the use of
in organ transplantation. The rationale for the use of the lower doses of Sandimmun ® than were initially consid
drug is its selective effects on T-cell subsets, making ered necessary results in a superior risk/benefit ratio.
Sandimmun ® the first representative of a new genera Research on the optimal use of Sandimmun ® in en
tion of immunomodulator drugs. dogenous uveitis will continue, providing us with
As early as 1981, R. B. N ussenblatt reported the inhi greater insight into the selection of those patients who
bition of experimental autoimmune uveitis in rats by will derive the greatest benefit from the treatment.
Sandimmun® (1. Clin. Invest. 67, 1228). Many centres The results already achieved, as documented here,
all over the world have since been involved in clinical are encouraging. We hope this booklet will contribute
trials and the drug has recently been approved in Japan to the attainment of the most important objective: to
and other countries for clinical use in Beh~et's disease provide our patients with the best possible treatment of
involving the posterior segment of the eye. their sight-threatening disease.
Erik Wiskott, Ph. D.
Basle, December 1987
Nomenclature:
Sandimmun®
Sandimmune (US regd.)
Cic1osporin (INN prop.)
Cyc1osporin (BAN)
Cyc1osporine (USAN)
Cyc1osporin-A (scientific name)
Table of Contents
Editorial (E. Wiskott) V 3. Present Experience with Sandimmun 9
1. Introduction: Endogenous Uveitis 1 4. Patient Selection for Sandimmun Treatment 16
1.1 Anterior Uveitis 1
5. Suggested Treatment Schedule with
1.2 Intermediate and Posterior Uveitis I
Sandimmun 17
1.3 Immune Mechanisms in Endogenous Uveitis 2
5.1 Management of Exacerbations 19
2. Treatment of Endogenous Uveitis 6
6. Safety Precautions 20
2.1 Anterior Uveitis 6
2.2 Intermediate and Posterior Uveitis 6 7. Summary 21
2.3 Need for More Effective Treatment Modalities 7
8. References 22
2.4 Rationale for Use of Sandimmun 7
1. Introduction: Endogenous Uveitis
An inflammatory reaction triggered by various specific neal endothelium to form keratic precipitates (KP's)
and non-specific factors, uveitis, denotes that the princi (Fig. 3) or result in hypopyon formation (Fig. 4).
pal, although by no means the only, involved tissue is The sequelae of anterior uveitis may be acute,
the uvea (iris, ciliary body and choroid). Uveitis, uni manifested by posterior synechiae (adhesions of the iris
or bilateral, may be the sole clinical manifestation in an at the pupillary margin to the anterior capsule of the
otherwise "healthy" patient or a symptom accompany lens; Fig. 5) and angle closure glaucoma (Fig. 6), or
ing a systemic disease. Specific pathogens (viruses, bac chronic as cataract formation, chronic angle closure
teria, fungi and parasites) can be identified as causative glaucoma (with or without anterior synechiae), fixed
agents in some cases. In most, however, non-specific pupil and iris atrophy (Fig. 7). Neovascularization of
(primary or secondary) inflammatory reactions de the iris and angle with or without corneal decompen
termine the characteristics and the clinical manifes sation are late sequelae and, when present, are a poor
tations of the disease. In both the "specific" and "non prognostic sign.
specific" uveitis the perpetuation of the inflammatory
processes and their chronicity are influenced by endoge
nous host factors in which the patient's immune system 1.2 Intermediate and Posterior Uveitis
plays a major pivotal role. In cases where the inflamma
tory reaction is confined to the iris (iritis), the ciliary Although some inflammation of the anterior uvea may
body (cyclitis) or both (iridocyclitis), the manifestation be present and a slightly "red eye" observed in a few in
is coined anterior uveitis. Localization of the inflamma stances, characteristically the bulk of reaction is local
tory reaction to the pars plana and peripheral fundus ized in the pars plana (Fig. 8) and peripheral fundus
(pars planitis) as well as vitreous (vitritis) is coined in (intermediate uveitis; Fig. 9) or in the choroid including
termediate uveitis, while posterior uveitis denotes in the posterior pole (posterior uveitis). Cellular infiltrates
volvement of the choroid (choroiditis). The vitreous are usually detected within the vitreous (Fig. 31). The
and the retina (retinitis) or its vessels (vasculitis) may presenting symptom in most cases is a blurring of vision
be involved during the disease process of intermediate with or without decrease in visual acuity. The decrease
and posterior uveitis. When both the anterior and pos in visual acuity is associated with the intensity of the in
terior uvea are involved, the condition is referred to as flammatory reaction in the vitreous and may be very
panuveitis. profound if macular edema develops.
Intermediate, posterior or panuveitis may be an ex
pression of a phenomenon solely confined to the ocular
1.1 Anterior Uveitis tissues as in sympathetic ophthalmia (Fig. 18), birdshot
chorioretinopathy (Figs. 17, 25), acute posterior mul
The manifestations are characterized by a red and often tifocal placoid pigment epitheliopathy (Figs. 19, 20),
painful eye, photophobia and tearing. It may be an serpiginous choroiditis (Fig. 26) and presumed ocular
isolated phenomenon or part of a systemic manifes histoplasmosis. Very frequently the ocular manifes
tation as in ankylosing spondylitis (Fig. 1), Reiter's syn tations are part of a systemic disorder, being the pre
drome (Fig. 2) and Crohn's disease, and is therefore the senting symptom in most cases of Beh~et's disease (Figs.
type of uveitis most often encountered by the internist 10, 21, 22), sarcoidosis (Fig. 14) and Vogt-Koyanagi
or a general practitioner. The examining physician will Harada disease (Figs. IS, 16).
find in the anterior chamber the presence of cells and a Exacerbations and remissions of the inflammatory
Tyndall effect (flare) induced by an increased concen processes are unpredictable. A high percentage of these
tration of proteins in the aqueous humor. The pupil will cases become chronic and are a challenge for the treat
be constricted (myosis) with poor response to changes ing ophthalmologist. The triggering factors for inter
in illumination. At times, especially in the presence of mediate and posterior uveitis remain elusive in most
macrophages, cellular precipitates can settle on the cor- cases. In all, however, the immunocompetent cells
2 I. Introduction: Endogenous Uveitis
Fig. 1. Unilateral acute anterior uveitis in the right eye of a Fig. 2. Bilateral iridocyclitis with marked ciliary injection in a
patient with ankylosing spondylitis patient with Reiter's syndrome
(directly or via the secretion of lymphokines and terphotoreceptor retinoid binding protein (IRBP) [3].
monokines) take an active role in the perpetuation of Similar cellular immune mechanisms have been ob
the inflammatory processes. Early sequelae are retinal served in sympathetic ophthalmia (the classical and
vascular sheathing (Figs. 10-12, 21, 22), retinal and unique manifestation of organ specific autoimmunity in
macular edema, vitreous organization and opacification humans) [4] and experimental autoimmune uveitis in
of the posterior capsule of the lens. Later, chronic cys rats [5] and monkeys [6].
toid macular edema with the formation of a partial Furthermore, experimental autoimmune uveitis has
thickness, macular hole or cyst may be the cause of the been transferred to naive Lewis rats by T-cell lines de
very poor visual acuity (Fig. 13). rived from immunized Lewis rats of the same strain,
Total lens opacification and traction retinal de while active induction of the disease was not possible in
tachment may be amenable to surgical treatment if the the T-cell deficient nude rats [7]. The role of specific
inflammation can be controlled. N eovascularization of HLA types in endogenous uveitis is still elusive. A defi
the peripheral fundus, posterior pole, optic nerve head nite increased incidence of HLA B27 is found in acute
and vitreous are grave prognostic signs and the reason anterior uveitis [8] and a strong association between
for recurrent hemorrhages. If unabated, the chronic in HLA A29 and birdshot chorioretinopathy has been re
traocular inflammation induces a progressive im corded [9]. In Behr;et's disease, an association with
pairment of choroidal and retinal blood flow leading to HLA B51 has been demonstrated [10] while the corre
retinal and optic nerve atrophy, resulting in total blind lation between this haplotype and ocular manifestations
ness (Fig. 22). of the disease awaits further clarifications. Although
still elusive, the role of specific HLA types in endog
enous uveitis is probably linked to the presentation and
1.3 Immune Mechanisms in Endogenous
recognition of specific autologous ocular antigens by
Uveitis the local immunocompetent cells. Recently, a high con
centration of interleukin-l (IL-I) and interleukin-2
As stated earlier, endogenous uveitis may be an acute (IL-2) has been detected in aqueous humor and vitreous
phenomenon triggered by various specific (viruses, taps from patients with Behr;et's disease [11].
Fig. 27; bacteria, parasites, Figs. 23, 24; fungi) and non These findings, along with the clinical manifestations
specific (endotoxins and other mediators of inflamma observed in endogenous uveitis, strongly support the
tion) agents. However, after the initial reactions have idea of a pivotal role for the host immune responses in
subsided, the chronicity of the process is mediated by these diseases.
the involvement of the host immune mechanism. The
perpetuation of uveitis follows an imbalance of the
regulatory immune system and relentless autoimmune
processes [I]. During the last decade, evidence for the
involvement of the immune system in endogenous
uveitis has been accumulating. Experimental autoim
mune uveitis (EAU) has been induced in rats following
immunization against retinal S-antigen [2] or in-
I. Introduction: Endogenous Uveitis 3
Fig.3. Keratic precipitates on corneal
endotheli urn and flare in the anterior
chamber
Fig. 4. Anterior uveitis with hypopyon for
mation in a patient with Behc;et's disease
involving the eye
Fig. 5. Posterior synechiae with irregular
pupil
Fig. 6. Acute angle closure glaucoma following anterior uveitis in a patient with pauci Fig. 7. Fixed myotic pupil, posterior
articular juvenile rheumatoid arthritis. The shallowness of the anterior chamber is visualized synechiae and formation of a complicated
by the slit lamp light reflection on the cornea and the iris. The band keratopathy of the cataract
cornea is a classic feature of the ocular affection in this disease
Fig. 8. Pars planitis and "snow balls" in an
I ~ --.
eye with intermediate uveitis
Fig. 9. Vitritis in an eye with intermediate '
I
uveitis. The intense vitreous haze is visu
alized by the slit lamp reflection
.
!~
i
Fig. 10. Vasculitis of retinal vessels in a Fig. 11. Retinal vasculitis and choroidal Fig. 12. Choroiditis with involvement of
patient with Behc;et's disease involving the infiltrates in a patient with endogenous the retinal vessels next to the optic nerve
eye. The sheathing and the sausage-like posterior uveitis. The fundal details are head
dilation of the veins are accompanied by remarkably blurred by the vitreous haze
discrete hemorrhages
4 I. Introduction: Endogenous Uveitis
Fig. 13. Chronic macular edema with for
mation of macular cyst leading to a pro
found loss of visual acuity in a patient with
endogenous uveitis
Fig. 14. Lesions in the macular area in a
patient with sarcoidosis
Fig. 16. Fundal lesions in a patient suffer
ing from Vogt-Koyanagi-Harada disease.
The lesions are similar to those observed in
patients with sympathetic ophthalmia
Fig. 15. Bilateral panuveitis in a patient with Vogt-Koyanagi-Harada disease. Vitiligo poli
osis and alopecia are accompanying symptoms
Fig. 17. Peripheral choroidal lesions in a
patient with birdshot chorioretinopathy
Fig. 18. Choroidal lesions in a patient with
sympathetic ophthalmia. The Dalen-Fuchs
nodules of varying size resemble the lesions
observed in patients with Vogt-Koyanagi
Harada disease and birdshot chorio
retinopathy
Fig. 19. Early fundal changes in a patient
with acute posterior multifocal placoid pig
ment epitheliopathy
Fig. 20. Late fundal changes in a patient
with acute posterior multifocal placoid pig
ment epitheliopathy
