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OCULAR INFLAMMATORY DISEASE

C. Stephen Foster, MD, FACS, FACRHarvard 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?


The ProblemUveitis 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 ProblemUveitis is the third leading cause of preventable

blindness in developed countries

How Does Uveitis Blind?

• Glaucoma


• Glaucoma

• Hypotony

• Maculopathy– Edema


• Glaucoma

• Hypotony


– Cysts/holes


• Glaucoma

• Hypotony


– Cysts/holes

– Membrane


• Glaucoma• Hypotony• Maculopathy

– Edema

– Cysts/holes

– Membrane

• Optic neuropathy


• Glaucoma

• Hypotony


– Cysts/holes

– Membrane

• Optic neuropathy

• Retinopathy

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 the history of its therapy?

Uveitis Therapy Through the Ages

• 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


• 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)


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).


Pepi-Ankh-Or-Iri, physician to the Pharaoh

The most ancient identifiable ophthalmologist

Royal Oculist

Palace Eye Physician and Guardian of the Anus


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.


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.


Roman period : 2ndC BC – 4thC AD

• Cannabis, opium, plant extracts

• Cathartics and enemas


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


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”


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


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


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 MonotherapyStuck in second gear

• Few departments of Ophthalmology have an Ocular Immunologist on their faculty

• Therefore,

Steroid MonotherapyStuck 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.


• 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


• The battle-cry throughout the world of rheumatology has, therefore, become: “The Mission is Remission”

• Ophthalmologists can and should learn from them

Lessons from RheumatologyThe battle-cry throughout the world of rheumatology

has, therefore, become: “The Mission is Remission”

Disease remission should be the goal for allrheumatologists treating childhood arthritis >> By Carol A. Wallace, MD


• 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


Increased emphasis on recruitment of fellowship trained ocular immunologists onto faculties of departments of ophthalmology


New initiatives by “Big Pharma” on clinical trials of medications capable of affecting the immune system and ocular inflammatory disease.


Basic tissue, cellular and molecular research on the causes and the mechanisms of ocular inflammatory disease eye tissue damage


Basic research on the immune system and mechanisms of regulation


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 α-6/ β-4 integrin as the target antigen in patients with ocular cicatricial pemphigoid

Laminin 5

BP180

PLECTINBP230

Collagen VII

Plasma MembranePlasma Membrane

?

IFIFss

Laminin 5

BP180

PLECTINBP230


Laminin 5

BP180

PLECTINBP230


Add Antibodies

?

Disassociation of hemidesmosome components


• Isolation of patient white blood cell lymphocyte popluation


• 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


Transfusion of the re-educated regulatory T lymphocytes back into the patient


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


Alternatively, what about this?


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


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


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.


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.

Health & Medicine

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