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 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 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 its importance? What is the history of its therapy?
Uveitis Therapy Through the Ages The Ebers Papyrus (1500 BC) - Egypt Hippocratic Corpus (4 th 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 6 th 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
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.