Women are as much as 50 times more likely to suffer from certain autoimmune diseases than men, and these diseases often have ocular manifestations that ophthalmologists should be aware of when examining their female patients, experts say.

“Autoimmune diseases are the No. 1 example of the higher risk” women carry for certain diseases due to sex, said Janine A. Smith, MD, of the National Eye Institute. “There are a lot of autoimmune diseases, and nearly every single one affects women more than men.”

There is no definitively known reason for this disparity between the sexes, she said.

Dr. Smith said Sjögren’s syndrome, with its symptoms of dry eye and dry mouth, is a prime example of an autoimmune disease seen more often in women. In addition, she said, systemic lupus erythematosus, rheumatoid arthritis and thyroid disease all disproportionately affect women, and all can have ophthalmic manifestations.

“The immune system between men and women is different,” Dr. Smith explained. “Even the way men respond to viruses and women respond to infections, there are differences.”

One theory, she said, is that because estrogens are naturally proinflammatory and androgens, specifically testosterone, are considered anti-inflammatory, women are more prone to developing autoimmune problems.

OSN spoke with Dr. Smith and other experts regarding the ocular complications of autoimmune disorders, what can be done to treat them and how to work with internal medicine specialists and others in management of patients with these diseases.

Lupus

Systemic lupus erythematosus, a collagen vascular disease, affects women nine times as often as men. Typically young, middle-aged women are affected, said C. Stephen Foster, MD.

Lupus often causes dry eye, for which treatment is much like that for Sjögren’s syndrome, but there are other possible ocular complications as well. Usually, Dr. Foster said, these complications are inflammatory.

“It might be something as relatively trivial as a rash, a low grade subtle dermatitis on the lid, or something that is directly relating to the eyeball itself with episodes of superficial inflammation,” he said. “This superficial inflammation may be affecting only the conjunctiva or, more prominently, it will be episodic inflammation of the tissues deeper to the conjunctiva like the episclera or sclera.”

Recurring episcleritis is a “trivial” but common ocular complication of lupus, Dr. Foster said. While it rarely requires aggressive therapy, episodes are often treated with corticosteroid drops, which can have long-term consequences, he explained.

“Eventually there is a price to pay, most particularly with respect to development to cataract,” he said. “We believe taking an oral nonsteroidal anti-inflammatory medication is the most productive and appropriate way to address that.”

Keratitis is another ocular manifestation of lupus. Patients can develop peripheral keratitis or multifocal superficial corneal inflammation, leaving small nebulae in the superficial cornea stroma.

“Both of them are associated with light sensitivity and photophobia. Both are important because they both carry with them a little more prognostic significance than does episcleritis or conjunctivitis,” Dr. Foster explained. “Both are fairly disabling because of the photophobia.”

Kathryn Colby

He said, again, corticosteroids are usually used for treatment, but the long-term solution for keratitis is to address the underlying lupus with systemic medication.

The systemic manifestations of lupus make it a potentially life threatening disorder, said Kathryn Colby, MD, PhD.

“The treatment is first identification of the systemic disease associated with it,” she said. “Often, management of the systemic disease will help with the ocular manifestations.”

Unfortunately, Drs. Colby and Foster said, Plaquenil (hydroxychloroquine, Sanofi Winthrop), the traditional systemic treatment for lupus, can cause damage to the retina when used in high dosage.

“There is a danger dose, which is measured in milligrams per kilogram, so a smaller person would be more likely to be at that danger dose using a regular dose of Plaquenil,” Dr. Colby said. “It causes a retinopathy, basically dysfunction of the retina cells.”

The site for some of the most serious ocular complications of lupus is the retina, Dr. Foster said.

“Patients with lupus can develop an immune complex vasculitis with the lodging of immune complexes forming in the vasculature, both in the choroid and in the retinal vasculature itself,” he explained.

This ophthalmic emergency can cause permanent vision loss, but it can also be a prompt for systemic lupus testing in an as yet undiagnosed patient or a sign of similar immune complexes in other areas of the body.

“Ophthalmologists have a spectacular opportunity not only to influence the situation but also to be lifesavers as well if they make the diagnosis of lupus in the patient,” Dr. Foster said. “The presence of lupus retinopathy with retinal vasculitis or choroidopathy is a terrifically reliable hallmark of the presence of these immune complexes lodging in other areas as well, most particularly the brain and the kidney. The likelihood of the patient dying from one of those sites being affected by lupus nephropathy or lupus affecting the central nervous system is very high in the patient with lupus retinopathy who is not properly, appropriately and aggressively treated.”

Rheumatoid arthritis

Rheumatoid arthritis, another collagen vascular disease, is four times more common in women than men and presents problems similar to those with lupus, including dry eye.

“You can also get scleritis and pretty severe inflammatory disorders, things like melting of the peripheral cornea,” Dr. Colby said. “There’s a lot of overlap with lupus.”

Dr. Foster said the approach to treating dry eye or secondary Sjögren’s in rheumatoid arthritis patients is much like that in lupus, including the use of Restasis (cyclosporine ophthalmic emulsion, Allergan) along with heat and massage to improve the function of the meibomian glands.

In addition, he said, the ophthalmologist must be aware of the patient’s systemic disease management to best treat its ocular manifestations.

“See if there is any evidence of the underlying rheumatoid disease being active, so to speak, even if it’s not active in the joints,” Dr. Foster said. “Are there markers in the blood that would indicate that chronic low-grade inflammatory activity is afoot? If so, deal with that systemically with a sprucing up of the systemic medication program.”

Dr. Foster said that scleritis and peripheral keratitis are all “absolutely dreadful” ocular manifestations of rheumatoid disease that require systemic therapy, often aggressive.

Dr. Colby added, “The important thing with the systemic diseases is, the better the systemic diseases are managed, the easier it is to manage the ophthalmic manifestations. I can treat someone’s rheumatoid-associated dry eye all I want, but if their systemic rheumatoid disease is not under control it’s like sticking your finger in the dike.”

Scleroderma

Three times as many women as men experience scleroderma, or progressive systemic sclerosis, a connective tissue disease.

C. Stephen Foster

“Scleroderma is a very different beast from lupus and rheumatoid disease, with less known about it and less discovered thus far in terms of a routinely highly effective therapy,” Dr. Foster said. “Breakthroughs are being made, and there are increasing levels of optimism among the medical community with respect to being able to prevail over some of the more relentless manifestations of scleroderma.”

Patients with scleroderma are likely to develop dry eye, which is treated as in other autoimmune diseases. The condition also causes shrinkage of areas of the skin, including the conjunctiva, Dr. Foster said.

“Patients sometimes develop shrinkage of the conjunctiva with a shortening of the inferior fornix,” he said. “It probably has to do with laying down new collagen, perhaps type 3 collagen or embryonic collagen. This contracts and you get shrinkage.”

Choroidopathy and vascular occlusion can also occur.

“Just as in lupus, this is a wake-up call that the patient’s scleroderma has taken a nasty turn,” Dr. Foster said.

Unfortunately, he said, there is no treatment for conjunctival shrinkage, and clinical trials for treatment of vascular occlusions are “maddeningly difficult” because of the small number of patients in any one center.

“One could speculate that the same approach that has been employed in the scleroderma lung research, namely with high dose cyclophosphamide therapy intravenously and other kinds of aggressive immunosuppressive therapy, might be beneficial in patients who are developing the scleroderma choroidopathy, but frankly it’s not known,” Dr. Foster said.

Hyperthyroiditis

Hyperthyroiditis affects women seven times as often as men. Its main ocular manifestation is Graves’ orbitopathy.

“That often is relatively mild and basically cosmetic,” Dr. Foster said, “but it is graded and assigned different grades, with severity and vision threat being greater the higher the grade of the thyroid eye disease is.”

Dr. Colby explained that in Graves’ orbitopathy infiltration of inflammatory cells within the extraocular muscles causes proptosis.

“You can have exposure of the cornea, which can lead to corneal ulcers. More seriously, if the muscles are very infiltrated, “crowding” of the orbit can compress the optic nerve of the eye, which can cause vision loss,” she said. “Graves’ disease can also cause double vision because if the muscles are very infiltrated they don’t move properly.”

Mild exposure can be treated with ointment or taping of the lids, Dr. Colby said. More advanced disease may require partial tarsorrhaphy. In extreme cases, orbital decompression surgery may be called for.

Dr. Foster said, “As the space occupied by the infiltrating cells, the proliferating fibroblasts, steadily increases, there is only so much space in the orbit, and the optic nerves can get increasingly compressed. That’s something that is typically tackled surgically with decompression surgery.”

Working with other physicians

Given that ocular manifestations of autoimmune disease are related to the status of the systemic disease, Drs. Foster and Colby said ophthalmologists must maintain relationships with the patient’s ocular immunologist or rheumatologist during treatment.

“With any of those diseases, the systemic management is really key,” Dr. Colby said. “Often if the eye is out of control, it means the body is out of control, even if the patient is not having systemic symptoms.”

She suggested that ophthalmologists make sure to speak clearly with collaborating physicians, using terms that the other specialist will understand.

“It’s important to really be convinced of the concept that appropriate systemic management will only make the ophthalmologist’s life easier and make it easier to manage patients’ problems,” Dr. Colby said.

“Communication is critical,” Dr. Foster agreed.

He said good communication will come into play when the eye reveals deeper problems in the body. If this is the case, it is the responsibility of the ophthalmologist to demonstrate that to the rheumatologist and to ensure that the patient receives proper systemic care.

“The patient, from a rheumatologist’s standpoint, may still be in remission,” Dr. Foster said. “The ophthalmologist is duty-bound, in my judgment, to convince that rheumatologist that this is not so – that the eye, although it may seem trivial, is extremely important and is telling you, ‘Wake up, pay attention, increase the aggressive therapy.’ If you don’t, you’re going to be sorry 6 months from now because the kidney or the lung is going to be in trouble.”

For more information:

Janine A. Smith, MD, can be reached at the National Eye Institute 31 Center Drive, MSC 2510, Bethesda, MD, 20892; 301-496-9058; fax: 301-496-2297.

Kathryn Colby, MD, PhD, can be reached at the Massachusetts Eye and Ear Infirmary, 243 Charles St., Suite 808, Boston, MA 02114; 617-573-5537; fax: 617-573-3364. Dr. Colby has no direct financial interest in the products discussed in this article, nor is she a paid consultant for any companies mentioned.

C. Stephen Foster, MD, can be reached at Ocular Immunology and Uveitis Foundation, Massachusetts Eye Research Surgery Institute, 5 Cambridge Center, Eighth Floor, Cambridge, MA 02142; 617-742-6377; fax: 617-227-1185.

Katrina Altersitz is an OSN Staff Writer who covers all aspects of ophthalmology.

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