OCULAR INFLAMMATORY DISEASE

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OCULAR INFLAMMATORY DISEASE

• C. Stephen Foster, MD, FACS, FACR
• Harvard Medical School
• Massachusetts Eye Research and Surgery Institution

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Ocular Inflammatory Disease

• By far, the number one cause of blindness,
  worldwide
• Infection
• Trauma
• Cancer
• Autoimmunity

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UVEITIS

• What is it?
• What is its importance?
• What is the history of its therapy?
• What does the future hold?

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UVEITIS

• What is it?

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Etymology

• Uvea, from uva (Latin grape)
• itis, (Greek inflammation)
• Therefore, inflammation of the uvea
• Ophthalmia and flegmoni, general terms

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Anatomy

• The uvea or uveal tract is the middle, highly
  vascular layer of the eyeball
• Iris
• Ciliary body
• Choroid

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UVEITIS

• What is it?
• What is its importance?

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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

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The Problem

• Uveitis is the third leading cause of preventable
  blindness in developed countries

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How Does Uveitis Blind?

• Glaucoma

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How Does Uveitis Blind?

• Glaucoma
• Hypotony
• Maculopathy
• Edema

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How Does Uveitis Blind?

• Glaucoma
• Hypotony
• Maculopathy
• Edema
• Cysts/holes

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How Does Uveitis Blind?

• Glaucoma
• Hypotony
• Maculopathy
• Edema
• Cysts/holes
• Membrane

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How Does Uveitis Blind?

• Glaucoma
• Hypotony
• Maculopathy
• Edema
• Cysts/holes
• Membrane
• Optic neuropathy

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How Does Uveitis Blind?

• Glaucoma
• Hypotony
• Maculopathy
• Edema
• Cysts/holes
• Membrane
• Optic neuropathy
• Retinopathy

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How Does Uveitis Blind?

• Glaucoma
• Hypotony
• Maculopathy
• Edema
• Cysts/holes
• Membrane
• Optic neuropathy
• Retinopathy
• Neovascularization

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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.
  1966Suppl166
• Kanski JJ. JRA and uveitis. Surv Ophthalmol.
  199034253-67
• 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

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UVEITIS

• What is it?
• What is its importance?
• What is the history of its therapy?

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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

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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)

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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).

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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

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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.

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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.

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Uveitis Therapy Through the Ages

• Roman period 2ndC BC 4thC AD
• Cannabis, opium, plant extracts
• Cathartics and enemas

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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

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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

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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

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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 fathers
  saddle shop.
• Sympathetic ophthalmia uveitis blinded the other
  eye by the time the child was 9 years old

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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 1950s

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Uveitis Therapy Through the Ages

• 1949 Hensch Corticosteroid therapy
• 1950 Dan Gordon Cornell University, New York
  City

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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

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The History of Immunosuppressive Therapy for
Uveitis

• Wong 1965
• Newell 1966
• Moore 1968
• Gills 1970

• Mamo 1970
• Godfrey 1974
• Andrash - 1978
• Martinez - 1978

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Prevalence of Visual Disability and Blindness
Despite Corticosteroid TherapyIts 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?

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Steroid MonotherapyStuck in second gear

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

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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

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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.

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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

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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

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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
gtgt By Carol A. Wallace, MD
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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

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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

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So, Where Are We Today?

• IMMUNOMODULATORY THERAPY
• Clear evidence for insufficient employment of
  such therapy by ophthalmologists worldwide

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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

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A View to the Future

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

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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.

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A View to the Future

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

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A View to the Future

• Basic research on the immune system and
  mechanisms of regulation

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A View to the Future

• My fantasy
• Re-education and autoregulation

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Re-educaton and Autoregulation

• Identification of target molecule involved in the
  autoimmune inflammation

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OCP Target Antigen Identification

• We have identified the ß-4 subunit of a-6/ ß-4
  integrin as the target antigen in patients with
  ocular cicatricial pemphigoid

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IFs
b4
PLECTIN
BP230
a6
BP180
Plasma Membrane
?
Laminin 5
Collagen VII
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Disassociation of hemidesmosome components
PLECTIN
BP230
b4
Add Antibodies
BP180
?
a6
Plasma Membrane
Laminin 5
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Re-educaton and Autoregulation

• Isolation of patient white blood cell lymphocyte
  popluation

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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

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Re-educaton and Autoregulation

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

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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

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Re-educaton and Autoregulation

• Alternatively, what about this?

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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.

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Re-education and Autoregulation

• Sir Medawars 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

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Re-education and Autoregulation

• Sir Medawars 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 1970s by Baruj Benacerraf of a
  unique popluation of white blood cells now called
  regulatory or suppressor T lymphocytes

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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.

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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?

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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

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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.

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