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OCULAR INFLAMMATORY
DISEASE
C. Stephen Foster, MD, FACS, FACR
Harvard Medical School
Massachusetts Eye Research and Surgery Institution
Ocular Inflammatory Disease
• By far, the number one cause of blindness,
worldwide
• Infection
• Trauma
• Cancer
• Autoimmunity
UVEITIS
•
•
•
•
What is it?
What is its importance?
What is the history of its therapy?
What does the future hold?
UVEITIS
• What is it?
Etymology
• Uvea, from uva (Latin = grape)
• itis, (Greek = inflammation)
Therefore, inflammation of the uvea
Ophthalmia and flegmoni, general terms
Anatomy
The uvea or uveal tract is the middle,
highly vascular layer of the eyeball
• Iris
• Ciliary body
• Choroid
UVEITIS
• What is it?
• What is its importance?
The Problem
Uveitis continues to blind people, even 60 years
after the introduction of steroid therapy.
12.3 million cases in the USA
45,000 new cases/year in the USA alone
10% of all cases of blindness
Annual costs in the USA: $242.6 million
The Problem
Uveitis is the third leading cause of preventable
blindness in developed countries
How Does Uveitis Blind?
• Glaucoma
How Does Uveitis Blind?
• Glaucoma
• Hypotony
• Maculopathy
– Edema
How Does Uveitis Blind?
• Glaucoma
• Hypotony
• Maculopathy
– Edema
– Cysts/holes
How Does Uveitis Blind?
• Glaucoma
• Hypotony
• Maculopathy
– Edema
– Cysts/holes
– Membrane
How Does Uveitis Blind?
• Glaucoma
• Hypotony
• Maculopathy
– Edema
– Cysts/holes
– Membrane
• Optic neuropathy
How Does Uveitis Blind?
• Glaucoma
• Hypotony
• Maculopathy
– Edema
– Cysts/holes
– Membrane
• Optic neuropathy
How Does Uveitis Blind?
• Glaucoma
• Hypotony
• Maculopathy
– Edema
– Cysts/holes
– Membrane
• Optic neuropathy
• Retinopathy
• Neovascularization
What Is the Evidence?
• Smith RE. 1989. Pars Planitis. In: Medical Retina,
chapter 96
• Laaksonen AL. 1966. A prognostic study of JRA.
Analysis of 544 cases. Acta Paediatr Scand.
1966;Suppl:166
• Kanski JJ. JRA and uveitis. Surv Ophthalmol.
1990;34:253-67
• Rothova A, et al. 1996. Causes and frequency of
blindness in patients with intraocular inflammatory
disease. Br J Ophthalmol. 80
• 35% of uveitic eyes: blind
UVEITIS
• What is it?
• What is its importance?
• What is the history of its therapy?
Uveitis Therapy Through the Ages
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The Ebers Papyrus (1500 BC) - Egypt
Hippocratic Corpus (4th century BC) - Greece
Galen (AD 131-201) – Rome
Aetius of Amida (AD 502-575) – Byzantium
Yves (1772) – Paris
Schmidt (1800) – Vienna
Waldrop, Saunders, Travers, MacKenzia,
Middlemore, Dalrymple (1808-1852) - England
Uveitis Therapy Through the Ages
• The Edwin Smith Surgical Papyrus
New York Academy of Medicine
1700 BC
The oldest known existing ophthalmic
document
Based upon, among other things, writings
from the time of Imhotep (2640 BC)
Uveitis Therapy Through the Ages
The Edwin Smith Surgical Papyrus contains
references to inflammatory conditions of the
eye.
Physicians with special interest in the eye were
identifiable as early as the 6th Egyptian
Dynasty (2400 BC).
Uveitis Therapy Through the Ages
Pepi-Ankh-Or-Iri, physician to the Pharaoh
The most ancient identifiable ophthalmologist
Royal Oculist
Palace Eye Physician and Guardian of the
Anus
Uveitis Therapy Through the Ages
Pepi-Ankh-Or-Iri embraced the concept of
whdw (ukedhu), “the rotten stuff par
excellence”
He subscribed to the practice of expurgation
therapy for uveitis.
This practice continued through the next 3900
years for a variety of ailments.
Uveitis Therapy Through the Ages
Additional therapies evolving through time
included employment of poltices and solutions
100 of the 237 medication recipes in the Ebers
papyrus are for eye disease
Zinc, antimony, copper, aloe, yellow ochre, red
ochre, myrrh, malachite, ink powder, galena
and djaret were predominant.
Uveitis Therapy Through the Ages
Roman period : 2ndC BC – 4thC AD
• Cannabis, opium, plant extracts
• Cathartics and enemas
Uveitis Therapy Through the Ages
Byzantine period : 4thC AD – 15thC AD
• Opium, barley, milk, honey, oil, breast milk,
egg white, iron, copper, pepper drops and
poltices
• Blood letting
• Oral and rectal administration of antidotes
Uveitis Therapy Through the Ages
Modern period (15thC AD to present)
Scarpa, 1806 : “A strong countrywoman, 35
years old, was brought into the hospital in
April 1796, on account of violent, acute
ophthalmia in both her eyes, with great
tumefaction of the eyelids, redness of the
conjunctiva, pain, and fever”
Uveitis Therapy Through the Ages
Scarpa, 1806 : “I took away blood abundantly
from the arm, foot, and also locally by means
of leeches applied near both the angles of the
eyes, and I also purged her” These remedies
helped to abate the inflammatory stage of the
violent ophthalmia.
Emollient herbs boiled in milk; quince seed
mucilage; bags of tepid mallows; blistering
Louis Braille – 1809-1852
It was during this era that a very young French
boy was blinded in one eye by an accidental
puncture of that eye with an awl in his father’s
saddle shop.
Sympathetic ophthalmia uveitis blinded the
other eye by the time the child was 9 years old
Uveitis Therapy Through the Ages
MacKenzie, 1830.
Dilation of the pupil with tincture of
belladonna, bloodletting, purging, blister
therapy
1900 – Fever therapy: fever induced by
intramuscular injections of milk and
subsequently with typhoid protein. Sometimes
fatal; persisted into the early 1950’s
Uveitis Therapy Through the Ages
1949 – Hensch – Corticosteroid therapy
1950 – Dan Gordon – Cornell University, New
York City
The History of Immunosuppressive
Therapy for Uveitis
E. Roda-Perez. El tratamiento de las uveitis de
etiologia ignota con mostaza nitrogenada.
Arch Soc Oftal Hisp Am. 1952; 12: 131-151
The History of Immunosuppressive
Therapy for Uveitis
Wong – 1965
Newell – 1966
Moore – 1968
Gills – 1970
Mamo – 1970
Godfrey – 1974
Andrash - 1978
Martinez - 1978
Prevalence of Visual Disability and
Blindness Despite Corticosteroid
Therapy:
It’s a Disgrace!
Evidence-based analysis of peer-reviewed
literature indicates that the prevalence of
visual disability and blindness secondary to
uveitis has not measurably changed in the past
40 years.
Why is that? How can that possibly be?
Steroid Monotherapy
Stuck in second gear
• Few departments of Ophthalmology have
an Ocular Immunologist on their faculty
• Therefore,
Steroid Monotherapy
Stuck in second gear
Most ophthalmologists completing their
residency training have never been
exposed to uveitis patient management
with anything other than with steroids
Lessons from Rheumatology
• Rheumatologists learned the lesson the hard
way too: steroid and NSAID therapy first,
reserving immunomodulatory therapy for
patients with advanced disease, resulted in
progressive joint damage and great disability.
Lessons from Rheumatology
• Early employment of steroid-sparing
immunomodulatory, disease-modifying agents
results in vastly superior outcomes
• The toxicity of medication side effects is less
with this approach too
Lessons from Rheumatology
• The battle-cry throughout the world of
rheumatology has, therefore, become: “The
Mission is Remission”
• Ophthalmologists can and should learn from
them
Lessons from Rheumatology
The battle-cry throughout the world of
rheumatology has, therefore, become: “The
Mission is Remission”
Disease remission should be the goal for all
rheumatologists treating childhood arthritis >> By Carol
A. Wallace, MD
Lessons from Rheumatology
• Ophthalmologists should embrace this model
of early steroid-sparing, remission-inducing
therapy with even more vigor than does
rheumatology, since the eye is so much less
forgiving of chronic inflammation than is the
joint, with profound life-altering consequences
So, Where Are We Today?
IMMUNOMODULATORY THERAPY
• Clear evidence for safety and effectiveness in
saving vision in selected populations with
uveitis patients doomed to a life of blindness
without such therapy
So, Where Are We Today?
IMMUNOMODULATORY THERAPY
• Clear evidence for insufficient
employment of such therapy by
ophthalmologists worldwide
A View to the Future
Increased emphasis on education by
subspecialty learned societies
• International Uveitis Study Group
• International Ocular Inflammation Society
• American Uveitis Society
• Uveitis Subspecialty Day – American
Academy of Ophthalmology
A View to the Future
Increased emphasis on recruitment of fellowship
trained ocular immunologists onto faculties of
departments of ophthalmology
A View to the Future
New initiatives by “Big Pharma” on clinical
trials of medications capable of affecting the
immune system and ocular inflammatory
disease.
A View to the Future
Basic tissue, cellular and molecular research on
the causes and the mechanisms of ocular
inflammatory disease eye tissue damage
A View to the Future
Basic research on the immune system and
mechanisms of regulation
A View to the Future
My fantasy
Re-education and autoregulation
Re-educaton and Autoregulation
• Identification of target molecule
involved in the autoimmune
inflammation
OCP Target Antigen
Identification
We have identified the β-4 subunit of α6/ β-4 integrin as the target antigen in
patients with ocular cicatricial
pemphigoid
IFs
b4
a6
Plasma Membrane
?
Laminin 5
Collagen VII
b4
a6
Plasma Membrane
Disassociation of
hemidesmosome
components
Laminin 5
Add Antibodies
?
b4
a6
Plasma Membrane
Laminin 5
Re-educaton and Autoregulation
• Isolation of patient white blood cell
lymphocyte popluation
Re-educaton and Autoregulation
• Incubation of patient regulatory
lymphocytes with the relevant target of
the immune inflammation attack,
combined with molecules known to
promote development of regulatory T
lymphocytes
Re-educaton and Autoregulation
Transfusion of the re-educated regulatory
T lymphocytes back into the patient
Re-educaton and Autoregulation
The newly re-educated regulatory T
lymphocytes regulate or suppress the
autoaggressive cells, thereby abrogating the
autoimmune attack on the eye.
No chemotherapy. No drugs.
Resetting the immune system
Re-educaton and Autoregulation
Alternatively, what about this?
Re-educaton and
Autoregulation
Sir Peter Medawar, a
British zoologist, was
awarded the Nobel
Prize in Physiology or
Medicine in 1960 for
his seminal work on the
immunology of the eye.
Re-education and Autoregulation
Sir Medawar’s work led to the concept of
immunologic privileged sites, the eye being
one such site, and of immunologic tolerance in
such sites, i.e., foreign material tolerated rather
than rejected when placed in such sites
Re-education and Autoregulation
Sir Medawar’s work led to an entire field of
research over the ensuing 60 years on the
mechanism of immunologic tolerance, and to
the discovery in the 1970’s by Baruj
Benacerraf of a unique popluation of white
blood cells now called regulatory or
suppressor T lymphocytes
Re-education and Autoregulation
Anterior chamber inoculation of protein can lead
to the development of very potent regulatory T
lymphocytes which regulate or suppress
inflammation directed against the protein
employed for that inoculation.
Re-education and Autoregulation
Might one be able, then, to induce immunologic
tolerance in a patient with autoimmune disease
by inoculating that patient, in the anterior
chamber of the eye, with the protein against
which the autoimmune reaction has
developed?
Summary
• Uveitis is a potentially blinding eye problem
• It is a problem of great epidemiologic and
economic importance
• Excellent therapy exists today for uveitis
• Yet far too few ophthalmolgists avail
themselves and their patients of such therapy
Conclusions
PRESCRIPTIONS FOR PROGRESS
• Training of ocular immunologists
• Training of ophthalmology residents by ocular
immunologists
• Research dedicated to uveitis; especially
identification of relevant antigen targets
• Continued research dedicated to the immune
system and to regulation of it.