Corneal Transplantation and Immunologic Tolerance

Corneal Transplantation and Immunologic Tolerance
C. Stephen Foster, M.D., F.A.C.S., F.A.C.R.

Corneal transplants, more often than not, are “tolerated (i.e., not rejected), unlike solid organ transplants such as heart, lung, kidney and skin. For 40 years it was imagined that this phenomenon occurred because of the lack of blood vessels and lymphatics in the cornea, resulting in antigen “invisibility” of the foreign material (i.e., piece of cornea from an unrelated donor), from the recipient patient immune system, and therefore the lack of an immune response against the corneal transplant. Indeed, a British immunologist was awarded the Nobel Prize in Medicine in the early 1950’s for his experiments on this topic, and his description of the phenomenon of immunologic tolerance.

It turns out, however, that the high success rate enjoyed by most corneal transplants is more complex than imagined 40 years ago. The foreign corneal antigens or proteins on the transplanted cornea are not invisible for the recipient’s immune system, but rather are recognized very rapidly by the recipient’s immune system. The thing is, however, rather than an “attack-and-destroy” immune response, a curious (and lucky for us) immune response develops in which regulatory cells which actively discourage the development of “attack-and-destroy” cells in the immune system are rapidly developed, and it is the continued activity of these regulatory cells which accounts for the tolerance of most corneal transplants. Tolerance can be interrupted or broken if the immune system is perturbed, particularly if it is “reved up” through an upper respiratory infection or immunization, with the result that “attack-and-destroy” types of immunologic cells suddenly do begin to attack the corneal transplant. In most instances, the patient and ophthalmologist will recognize this quickly, will treat the eye with frequent application of steroid eye drops, and will eventually be able to stop those eye drops, despite the fact that it is quite clear that the recipient immune system has now unquestionably recognized that foreign corneal transplant, and has made an immune response against it. But the temporary use of the steroid drops has allowed the brief perturbation in the immune system to subside and has enabled the patient’s regulatory cells to once again gain the upper hand, mediating the continued freedom from transplant rejection.

The take home lessons most important from this story for patients are:

  1. Corneal transplants have an extraordinarily high degree of success today;
  2. Even if the patient develops an episode of corneal transplant rejection, recognition of the earliest signs and symptoms of that by the patient (discomfort, light sensitivity, redness, decrease in vision,) with prompt presentation to the ophthalmologist and recognition by that ophthalmologist that the earliest phases of a transplant rejection exist, will result in aggressive treatment of the transplant with steroid drops, and salvage of the transplant 90% of the time.

Systemic Treatment of Ocular Inflammatory Disease (OID)

Systemic Treatment of Ocular Inflammatory Disease (OID)
C. Stephen Foster, M.D., F.A.C.S., F.A.C.R

Most eye diseases which are treatable are treated with eye drops. In fact, the number of instances in which patients attending a general ophthalmologist’s office might be prescribed a systemic medication (i.e., one which is taken, for example, by mouth) is vanishingly small. Perhaps because of this and other factors, most ophthalmologists eventually consider treating patients with an eye problem only rarely with systemic medication. And while this is usually perfectly appropriate, in some instances, such as in the care of patients with uveitis, we believe that to neglect strong consideration of systemic therapy for the condition is to ensure that no progress will be made in reducing the prevalence of blindness secondary to the disease. Indeed, the evidence on the subject of the uveitis is clear: the prevalence of blindness caused by this disease has not been reduced in the past thirty years; it remains the number three cause of preventable blindness in the United States.

Eye drops (steroids) remain the mainstay and cornerstone of treatment of patients with uveitis. But some patients with uveitis continue to have episodes of active inflammation each time the topical steroid drops are reduced and discontinued. All ophthalmologists realize that they cannot keep their patient with uveitis and other forms of OID on topical steroids indefinitely; cataract is a guaranteed side effect from the chronic use of steroid eye drops; glaucoma is a significant possibility from such use; and increased susceptibility to eye infections, including those from herpes simplex virus, is also a risk. The all-too-frequent scenario, therefore, is:

Treatment of the uveitis with steroid drops, resolution of the uveitis, tapering and discontinuation of the steroid drops, recurrence of the uveitis, reinstitution of steroid eye drop therapy, etc.

We believe that there is a better way, and, in fact, the “outcomes” study data show that this is so. Our philosophy, over the past few decades has been to not tolerate even low-grade chronic uveitis, but also not to tolerate endless amounts of steroid use. We achieve this goal through a “stepladder” approach in aggressiveness of therapy. The next “step” on this stepladder, after topical steroids, is oral nonsteroidal anti-inflammatory drug therapy. This class of drug, nonsteroidal anti-inflammatory drugs, is typified by aspirin, ibuprofen, naproxen, etc. Unless a patient has a contraindication to the use of such medications chronically by mouth (for example, history of peptic ulcer disease), we place the patient on prescription strength nonsteroidal anti-inflammatory drugs, and then attempt to taper the topical steroid drops, expecting the oral nonsteroidal medication to keep the uveitis from recurring. This strategy, in our hands, is effective in approximately 70% of selected patients. In those 30% who do not respond to this strategy, we then advance to systemic immunosuppressive/immunomodulatory therapy, sometimes referred to as “chemotherapy.” I place this word in quotation marks simply because it is not the kind of chemotherapy that most patients think of when they hear that word, i.e., cancer-type therapy. Rather, it is the type of chemotherapy typically used by rheumatologists in their care of patients with severe rheumatoid arthritis, and by dermatologists in their care of patients with severe psoriasis, or in their care of patients with certain blistering dermatitis diseases. This is the area in systemic drug therapy for ocular disease in which the vast majority of ophthalmologists are uncomfortable, primarily out of ignorance (and I do not mean that in a pejorative way, but rather in a factual way.) Ophthalmologists are not used to using these medications, and carry with them the “baggage” learned in Medical School about the risks of immunosuppressive chemotherapy drugs, typically as they are used in solid organ transplant patients and in patients with malignant disease. And those risks are simply not the same as the risks associated with the low-dose, single-agent immunosuppressive chemotherapeutic programs that rheumatologists, dermatologists, and ocular immunologists use in their care of patients with non-malignant inflammatory disease. The potential for drug-induced “mischief” exists; but, used correctly, the likelihood of a significant drug-induced problem is quite small. The drugs, of course, must be managed by an individual who is, by virtue of training and experience, an expert in their use, in a patient who is responsible, keeps his or her appointments, etc.

We believe that unless or until increasing numbers of ophthalmologists embrace the idea of systemic therapy for certain blinding ocular diseases, the prevalence of blindness from such diseases will go unchanged, as it has over the past 30 years.

Cost of Care of Patients with Uveitis

C. Stephen Foster MD

Increasingly restrictive “gate keeping” policies of health maintenance organizations, insurance companies, and other medical insurance plans have created increasing pressure on ophthalmologists to be parsimonious in their use of medical services in both the diagnostic and therapeutic care of patients with a variety of medical disorders, including those with uveitis. These pressures are particularly prominent in the physician’s care of patients with chronic disorders, and ophthalmologists caring for patients with uveitis are increasingly experiencing this restrictive pressure. We wondered what the cost of diagnostic and therapeutic care of a patient with uveitis might be, given what we, as a uveitis referral center, see as appropriate yet fiscally prudent care. The cost of care obviously varies greatly, depending on the underlying cause and on the severity of the patient’s uveitis and associated complications. As a first step in estimating the total annual direct cost in the care of patients with uveitis we restricted our analysis to patients with HLA-B27 associated uveitis. We also restricted our analysis to the direct medical cost of caring for such patients, recognizing that direct non-medical costs, indirect morbidity costs, and other intangible economic loss costs, disability payments, absences from work, etc. are real but difficult to measure costs of the total cost of the patient’s illness. Direct medical costs are transactions and expenditures for medical products and services, including diagnostic studies, physician fees, hospitalization costs, surgical costs, rehabilitation and subsequent long-term care costs.

A cohort of 105 patients with HLA-B27 associated uveitis were studied in 2002. The diagnosis in each instance was established on our Service, and a minimum follow-up of two years existed for each patient. The medical records were reviewed for the diagnostic studies and costs of each performed, the physician and hospital fees associated with visits and/or surgery, in the cost of medical therapy. The average direct annual cost per patient per year was calculated. A stepladder approach to therapy was employed in an effort to eliminate recurrences of uveitis. The first step on the stepladder was the use of steroids, through any route required to achieve the goal of quieting the uveitis. Oral non-steroidal anti-inflammatory agents were added, if recurrence typically continued despite the use of steroids. Immunosuppressive chemotherapy was employed if patients continued to have recurrence of inflammation despite the use oral non-steroidals. Ten patients eventually required the use long-term oral immunosuppressive agents, and 30 patients were on chronic oral non-steroidal anti-inflammatory drugs. The average annual cost of care of the patients with HLA-B27 associated uveitis was $4,108.60 (range $433 to $9,683.18). These results reflect an average cost of caring for a cohort of patients with recurrent HLA-B27 associated uveitis of varying severity. The results may serve as an indicator, to health maintenance organizations and other pooled-risk insurers, of the cost of prudent care of patients with this form of uveitis. We would emphasize that we were very cautious and parsimonious in our use of laboratory tests and frequency of return visits, striving for the greatest degree of economy, while at the same time striving for the best possible outcomes (for outcomes analysis studies performed on these and other patients with uveitis, please refer to the Bibliography section of this Web Site). Clearly, patients with recurrent or chronic uveitis require significant expenditure of the health care dollar. It is, however, money well spent, since the preservation of sight from modern care of such patients profoundly reduces the prevalence of blindness secondary to uveitis, and hence reduces the economic burden on our society in total.

Did you know the Connection between Arthritis and Ocular Disease?

Connection Between Arthritis and Ocular Disease
C. Stephen Foster, M.D.

The eye is made up primarily of collagen, as are ligaments, tendons, and tissue within joint spaces. It is, perhaps, primarily because of this similarity in composition that the eye is often affected by many of the same diseases which affect joints. Some of these disorders include Juvenile Rheumatoid Arthritis, Adult Rheumatoid Arthritis, Systemic Lupus Erythematosus, Relapsing Polycondritis, Behcet’s Disease, Wegener’s Granulomatosis, Polyarteritis Nodosa, and Scleroderma or systemic sclerosis. Additionally, the type of vasculature that is present in the eye has special characteristics that produce an extraordinarily sensitive “barometer” or “sentinel canary” in the eye for potentially lethal vasculitis that can be associated with the aforementioned collagen vascular diseases. Specifically, we know from considerable experience that, despite the fact that a patient’s rheumatoid arthritis may be “burned out” as far as active inflammation of the joints in concerned, nonetheless, the patient may well have subclinical rheumatoid vasculitis affecting various internal organ systems. The eye is a very potent indicator of such subclinical potentially lethal vasculitis, and if the eye becomes involved with retinal vasculitis, uveitis, scleritis, or peripheral ulcerative keratitis in such a patient, we take that as a very strong signal that the patient must be evaluated extremely carefully for potentially underlying vasculitis affecting viscera and we also take such a potentially blinding ocular lesion very seriously from the standpoint of the need for aggressive systemic immunomodulatory therapy in order to prevent permanent damage to the eye from such lesions.

For example, we have seen many instances in which patients with systemic lupus erythematosus appear, systemically, to be doing quite well (indeed, the patient’s Rheumatologist has told her that she is doing very well) despite the fact that new-onset uveitis, scleritis, or retinal vasculitis has developed in one eye. We have seen this story evolve to life-threatening central nervous system vasculitis and/or lupus renal disease when the onset of the ocular inflammation was not taken as an indication for increasing the vigor of systemic therapy. We have tried diligently, therefore, over the past 15 years to raise the consciousness, not only of ophthalmologists worldwide, but also of rheumatologists and other internists of the valuable indicator that the eye can be with respect to seriousness of associated arthritic/collagen vascular disease.

Pediatric Uveitis

Uveitis is the third leading cause of blindness in America, and 5% to 10% of the cases occur in children under the age of 16. But Uveitis in children blinds a larger percentage of those affected than in adults, since 40% of the cases occurring in children are posterior uveitis, compared to the 20% of posterior Uveitic cases in the adult Uveitis population.

There are, at any one time, approximately 115,000 cases of Pediatric Uveitis in the United States, with 2,250 new cases occurring each year. Spread across the entire U.S. population, therefore, and across all offices of Ophthalmic practitioners, the likelihood that any one individual practitioner will care for a patient with Pediatric Uveitis is relatively small, and the likelihood that any single individual will have significant experience in caring for large numbers of cases over a long period of time is vanishingly small. This accounts, we believe, at least in part for the sub-optimal care that many of our children with Uveitis appear to be receiving, even in these “modern” times. The stakes are incredibly high, for the child, for the parents who will be faced with (usually) many years of dealing with this health problem in their child, and for society at large because of the life-time of dependence which occurs in those who eventually reap substantial visual handicap as the result of sub-optimal treatment.

We believe that current epidemiologic data emphasize two critically important goals for all of us in Ophthalmology, acting together, in an effort to change the current prevalence of blindness caused by Pediatric Uveitis:

  1. Repeatedly emphasizing to parents, other medical colleagues, especially Pediatricians, and school personnel the critical importance of routine (annual) vision screening for all children.
  2. The critical importance of beating back the frontiers of general ignorance and mind sets, eliminating the all-too-common pronouncement by physicians to parents of a child with Pediatric Uveitis that:
  3. “He’ll (She’ll) out grow it.”
  4. “The drops will get him (her) through it.”
  5. “It’s just the eye; systemic therapy is not warranted.”

Statements (a) and (b) are true, but too often pull the doctor, and patient, and family into the seduction of nearly endless amounts of topical steroid therapy. It is generally true that the child will in fact “out grow” the Uveitis, i.e., that the Uveitis will no longer be a problem eventually. The pity is, however, that so often by the time the child “out grows it”, permanent structural damage to retina, optic nerve, or aqueous outflow pathways has already occurred, and the blinding consequences are now permanent. It is also true that for any individual episode of Uveitis, the steroid drops usually will get the patient through it. But the fact is that so many children with Pediatric Uveitis have recurrent episodes of Uveitis such that the cumulative damage caused by each episode of Uveitis and the steroid therapy for each episode eventually produces vision-robbing damage. And item (c) is simply the result of the common myopic viewpoint of Ophthalmologists: that it is just an eye problem, and therefore should simply be treated with eye medications. Nothing could be further from the truth! And unless and until large numbers of Ophthalmologists reframe this socially and epidemiologically important matter, the prevalence of blindness secondary to Pediatric Uveitis is not going to change.

The differential diagnosis of Pediatric Uveitis is relatively vast, and therefore the detective work required to properly pursue the underlying diagnosis is complex. The job can be slightly simplified by “playing the odds”, categorizing the case as carefully as possible into anterior non-granulomatous; anterior granulomatous; intermediate; posterior, with vasculitis; posterior, without vasculitis; and categorizing it into the general age groups of Infancy (0 to 2 years), Toddler-School Age (2 to 10 years), and Adolescence (10 to 20 years).

The most common etiologic groups in children segregated into these groups are shown in Tables 1-6

TABLE 1 (Anterior Non-Granulomatous)

Idiopathic

HLA-B27 associated

Juvenile Rheumatoid Arthritis

Ankylosing Spondylitis

Reiter’s disease

Psoriasis

Inflammatory bowel disease

Nephritis

Systemic lupus erythematosus

Herpes Simplex virus

Lyme disease

Leukemia

Drug-induced

TABLE 2 (Anterior Granulomatous Uveitis)

Sarcoidosis

Inflammatory bowel disease

Syphilis

Herpes simplex virus

Tuberculosis

Bechet’s disease

Multiple Sclerosis

Fungal disease

Whipple’s disease

Leprosy

TABLE 3 (Intermediate Uveitis)

JRA

Pars Planitis

Multiple Sclerosis

Lyme disease

Sarcoidosis

TABLE 4 (Posterior Uveitis, without vasculitis)

Toxocariasis

Toxoplasmosis

Leukemia

Tuberculosis

Intraocular Foreign Body

Vogt-Koyanagi Harada Syndrome

TABLE 5 (POSTERIOR UVEITIS, with vasculitis)

Posterior Uveitis with vasculitis

Cytomegalovirus

HSV/VZV

Inflammatory bowel disease

Syphilis

Bechet’s disease

Systemic lupus erythematosus

Kowasaki’s disease

Sarcoidosis

Polyarteritis nodosa

Wegener’s granulomatosis

TABLE 6 (most common causes of Uveitis in infants)

Herpes Simplex Virus

Toxocara

Congenital Loes

Retinoblastoma

TABLE 7 (most common causes of Uveitis in Toddlers/School Children)

Toxocariasis

Toxoplasmosis

Leukemia

Vogt-Koyanagi Harada Syndrome

Diffuse Unilateral Sclerosing Neuroretinitis

Juvenile Rheumatoid Arthritis

TABLE 8 (most common causes in Adolescents)

JRA

Pars Planitis

VKH

Toxoplasmosis

HLA-B27-associated sarcoidosis

Bechet’s disease

Intraocular Foreign Body

We believe that aggressive efforts should be made to uncover the underlying cause of Uveitis in any child. If the review of systems is negative and the patient has non-recurrent anterior granulomatous Uveitis, we would not do laboratory studies. However, if review of systems is positive, we would “follow the review of systems”.

For recurrent anterior non-granulomatous Uveitis we would obtain a complete blood count and urine analysis, ANA testing, HLA-B27 testing, and would “follow the review of systems”.

The diagnostic step ladder in a pediatric patient with anterior granulomatous Uveitis, recurrent or not, would include a CBC with urine analysis, and FTA-ABS testing, Lyme disease antibody and western block, PPD analysis, chest X-ray, ANA, and angiotensin converting enzyme determination. Chest CT, and Gallium scanning would be pursued if diagnosis of sarcoidosis was strongly suspected, and, of course as usual, we would “follow the review of systems positives”.

In a patient with intermediate Uveitis, all would deserve laboratory evaluation, including CBC, urine analysis, chest X-ray, FTA-ABS, ACE, PPD, Lyme, and ANA titers.

Any patients with posterior Uveitis would deserve an extensive vasculitis work-up, if vasculitis were present, and a search for “the usual suspects” with an eye to an infectious etiology, such as that producing a granuloma in the choroid in a patient with toxocariasis or Toxoplasmosis. An audiogram or lumbar puncture would be done if positive on the review of systems were found such as tinnitus and/or meningeal signs or symptoms. Finally, a diagnostic vitrectomy would be added to the step ladder in a patient with posterior Uveitis if all non-invasive studies were unrevealing and the case was difficult to treat successfully.

On the matter of treatment, here too we believe strongly in the step ladder approach, always beginning with steroids, in any route required to achieve the desired goal, i.e., abolition of all active inflammation. Topical steroids would be followed by an examination under anesthesia with regional steroid injection therapy in a patient with granulomatous or non-granulomatous anterior Uveitis. Systemic steroids would be employed in the event that this approach did not achieve the goal of abolition of all active cells. We are extremely reluctant to get involved with long term daily systemic steroid use in a youngster, because of the obvious growth-retarding properties of such therapy. But long term oral non-steroid anti-inflammatory drug therapy, managed by a Pediatrician, can be extremely successful, in our experience in approximately 70% of children with recurrent non-granulomatous anterior Uveitis. If this strategy is not successful, then consideration of once weekly, low-dose, Methotrexate or daily Cyclosporine or CellCept would be the next considerations.

In granulomatous disease topical steroids often are not sufficient, and systemic therapy, particularly with oral non-steroidal inflammatory drugs, may be utilized sooner rather than later.

With Intermediate Uveitis topical steroids are not effective in penetrating to the level of inflammatory focus. Regional steroid injections or systemic steroids are employed to treat that area, sometimes with adjunctive topical steroids for anterior chamber “spill over” reaction. Retinal Cyropexy can be effective in selected cases of recurrent Pars Planitis, as can therapeutic Pars Plana Vitrectomy. Systemic immunomodulatory therapy, as usual, represents the final step in the step ladder approach in the aggressiveness of care.

Patients with Posterior Uveitis of course do not respond to topical therapy and therefore require systemic steroids and/or immunomodulators right from the very beginning.

We hope that this will provide some help to those Ophthalmologists who have also concluded that the usual approach to Pediatric Uveitis, i.e., steroid drops, is not always sufficient, but who are hesitant to take the initiative to commit the patient to more aggressive treatment.