Authors: Rita Baron-Faust,Jill Buyon
As with Evelyn, it often takes years before a woman is properly diagnosed. Sometimes the symptoms are blamed on aging, says Ann Parke, MD, a noted rheumatologist who specializes in Sjögren’s at St. Francis Hospital and Medical
Center in Hartford, Connecticut. “I have patients who come in and say they were perfectly fine until age 40 or 45, and that’s when they start to develop their complaints. But frequently they are not diagnosed for another 10 years. To a certain extent we associate dry eyes, dry mouth, and dry vagina with aging, but I think a lot of people don’t take these complaints seriously,” says Dr. Parke, a member of the Sjögren’s Foundation medical and scientific advisory board. “The fatigue associated with Sjögren’s also complicates things. Women go in to see their primary care physicians and say, ‘I’m tired,’ and they are labeled as having ‘empty-nest syndrome’ or being depressed. They are not asked the important questions: ‘Do you have dry eyes? Do you have a dry mouth? Do you sleep OK?’ It’s a major problem.”
According to the 2015 screening guidelines from the Sjögren’s Syndrome Foundation, patients answering “yes” to any of the following questions need a full ocular examination:
8
Other causes of the symptoms associated with Sjögren’s must also be ruled out, such as the drying effects of drugs, eye diseases or infection, the effects of allergies (and allergy medications), and lymphoma (which can sometimes involve the salivary glands).
A workup should begin with a complete history and physical to assess the possibility of autoimmune, connective tissue, or glandular diseases. Your eyes, mouth, skin, and glands in your face and neck should be carefully examined.
After an assessment of your symptoms, a number of blood tests can help confirm a diagnosis of Sjögren’s, the most important of which are autoantibodies reactive with SSA/Ro and SSB/La. Other tests may include an
erythrocyte sedimentation rate
(
ESR
, a general indication of inflammation, see
page 33
), as well as measuring levels of blood proteins called
immunoglobulins
. An elevation of the ESR and total IgG levels are often observed in patients with Sjögren’s but are not specific.
Specific antibody tests that are performed include:
Antinuclear antibodies (ANAs)
are a group of antibodies that react against the components of a cell nucleus. ANAs are present in a variety of autoimmune diseases, including lupus, but about 70 percent of patients with Sjögren’s will also have a positive ANA test (see
page 72
).
Rheumatoid factor (RF),
an antibody associated with rheumatoid arthritis, is found in 60 to 70 percent of people with Sjögren’s (see
page 32
).
Sjögren’s syndrome-associated A antigen (SSA/Ro) and Sjögren’s syndrome-associated B antigen (SSB/La)
are separate autoantibodies. Anti-SSA/Ro antibodies react with intracellular proteins that can be found in the cytoplasm (white of a cell as in an egg) or the nucleus (yellow center). Anti-SSB/La reacts with a nuclear protein. These antibodies are often found in pairs, but anti-SSA/Ro is more common. It is seen in the majority of patients with SS and in about 40 percent of patients with SLE. Anti-SSB/La is also seen in the majority of patients with SS but only about 15 percent of patients with SLE.
Recent research indicates that ANAs and other autoantibodies may be present years before obvious symptoms even appear.
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Antithyroid antibody and thyroid stimulating hormone (TSH)
levels will be checked, since autoimmune thyroid diseases can cluster with Sjögren’s and
share symptoms like dry skin and fatigue. Therefore tests will be done to measure antithyroid antibodies and assess thyroid function, including the level of TSH.
The 2015 screening guidelines from the Sjögren’s Syndrome Foundation include the following tests to evaluate dry eye.
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The Schirmer test
is the simplest and most common eye test to assess tears and tear production. Small pieces of filter paper are placed between your eyeball and lower lid, and the amount of wetting produced within five minutes indicates the level of tear production. No anesthetic is required. A result of less than 5 mm would be strongly suggestive of Sjögren’s.
A slit-lamp examination
measures the amount of tears produced by the eye in its normal resting state. A lamp indirectly illuminates your eye to avoid producing reflex tears, and magnifies the surface so the normal layer of tears along the lower eyelid can be seen. The tear film may appear thickened with excessive debris. There may be inflammation of the conjunctiva.
Rose Bengal staining
determines the quality of the mucin layer of the tear film and its distribution over the surface of the eye.
Rose Bengal
is a harmless vegetable dye. A single drop is administered after rinsing with a preservative-free tear preparation; reddish stain remains on the cells that have lost their mucin coating, a pattern of staining characteristic of keratoconjunctivitis sicca syndrome. The number of cells is counted, or scored. Another test, using a dye called
lissamine green
, can reveal scratches on the surface of the eye.
The degree of severity is graded, based on the results of ocular staining. Fluctuations in vision, decreased vision, and sensitivity to light also factor into the severity grading.
8
A dentist or oral pathologist may also measure your saliva production. As in Evelyn’s case, this is done by stimulating saliva production using an acidic or sour substance, and then measuring the amount of saliva produced.
Salivary gland biopsy
may be performed in some cases. The procedure involves making a small incision in the lower lip and removing five to ten tiny salivary glands, which are examined under a microscope for immune cell infiltration. Ultrasound to examine the salivary glands may provide additional information.
In cases of severe neuropathic pain, a small “punch” biopsy to count these fibers may be done
(epidermal nerve fiber density, ENFD)
. A lower nerve fiber count is considered diagnostic.
10
A combination of symptoms, positive antibody tests, and positive tests for dry eye and/or decreased salivary production substantiate the diagnosis of Sjögren’s. However, there’s no single standard for diagnosis. American College of Rheumatology (ACR) has proposed simple criteria that your rheumatologist may use:
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Two of these tests should be positive for a diagnosis of Sjögren’s syndrome, according to the ACR.
10
However, many patients do not want to undergo salivary gland biopsies. In some clinical settings physicians will diagnose Sjögren’s based on three or more of the following (provided that there is also some objective clinical testing).
As many as 60 percent of pre- and postmenopausal women suffer from dry eyes. While estrogen appears to play a role in some autoimmune diseases, androgen deficiency appears to be a more critical factor in dry eye.
3
“Premenopausal women normally make about two-thirds of the amount of androgen than men do, and we have found that women with Sjögren’s are
androgen deficient. We have also learned that androgens are important for optimal lacrimal and meibomian gland function,” says Dr. Sullivan. “Androgens can significantly influence the nature of the lipids produced in the meibomian glands, and they appear to promote the formation of the tear film lipid layer, thereby enhancing tear film stability. Consequently, androgen deficiency may promote the development of dry eye.”
Androgen deficiency can occur with aging, during menopause (peak years for Sjögren’s), and with certain autoimmune diseases, like lupus and Sjögren’s. Androgens seem to dampen inflammation; studies indicate that dry eye improves in people given androgens. Dr. Sullivan adds. “In contrast, estrogen may worsen inflammation of the lacrimal glands, and may suppress meibomian gland function.”
In fact, a 2001 study coauthored by Dr. Sullivan found the risk for dry eye was greater among women taking postmenopausal hormones. Researchers from the Schepens Eye Research Institute and Brigham and Women’s Hospital in Boston looked at data from the Women’s Health Initiative (WHI), which included 25,665 postmenopausal women, and found that almost 7 percent of women taking HT reported dry eye syndrome (keratoconjunctivitis sicca, KCS). More than 9 percent of women using estrogen therapy (ET) alone had KCS. The longer a woman used hormones, the greater the risk; for each three years that women used HT there was a 15 percent increase in the likelihood of being diagnosed with KCS or having severe symptoms.
12
However, the study was limited since diagnostic tests were not done.
Dry eyes can also occur in women with
autoimmune premature ovarian failure (POF)
, now called
primary ovarian insufficiency
(
POI
, see
page 231
). While women with premature menopause (before age 40) seem to have worse symptoms and more ocular damage, they don’t appear to have reduced tear production.
13
Evelyn’s story continues:
The hardest thing for me are the social interactions. I always feel so self-conscious; I feel like everyone can see how dry I am. When I start a conversation with someone, and I don’t have water with me, I can’t have a conversation. It’s impossible; I can’t talk long without water. And it certainly affects eating. I have to have lots of liquid. At a cocktail party, I kind of
ignore the food because I need to have something to drink and I can’t juggle a plate and a glass. But I manage. I have it easier than people who also have arthritis or other painful syndromes. I have found ways to cope with the dryness. I have tried artificial saliva, and the sprays, but I can’t stand the taste, and they are very short-acting. I took pilocarpine for two years, but it had a lot of side effects. The biggest way Sjögren’s affects me is actually the fatigue. By nine o’clock at night, I just collapse.
While there’s no cure, there are a variety of treatment options for symptoms of Sjögren’s syndrome.
For some women, over-the-counter “artificial tears” can temporarily soothe dry eyes. However, these lubricating drops don’t have lasting effects and, in severe cases, must be used frequently, increasing the risk of problems from preservatives says Janine Austin Clayton, MD, director of the Office of Research on Women’s Health at the National Institutes of Health (NIH). Ocular lubricant ointments can be helpful if used before bedtime but can blur vision, causing problems during the day, so apply only a small amount.
Use preservative-free eyedrops (drops used to relieve redness and allergies often contain preservatives and can cause rashes under the eye). OTC drops include
Refresh Tears
,
Bion Tears
, and
TheraTears
.
14
TheraTears has also been shown to increase production of mucin in a rabbit model, adds Dr. Clayton, who served as deputy clinical director of the National Eye Institute at NIH. Some products provide the staying power of an ointment without blurring vision.
Several new gels have a consistency somewhere between eyedrops and ointment.
GenTeal
is a water-based gel and is among the lubricants and eyedrops containing “disappearing preservatives,” which break down once the product is exposed to air.
“
Lacrisert
is a very tiny pellet, kind of like ointment in a pellet that is placed between the eye and the lower lid, and it dissolves over a 24-hour
period. But it’s only effective in patients who have some tears, because it needs tears to dissolve,” explains Dr. Clayton.
A prescription eyedrop formulation of the anti-inflammatory drug
cyclosporine A (Restasis)
is the first therapy specifically aimed at dampening the underlying inflammation of dry eye.
15
Approved for treating Sjögren’s and other forms of dry eye, Restasis appears to prevent T cell activation on the ocular surface and in the lacrimal gland. The drops increase tear production (as measured in a Schirmer test).
Corticosteroid eyedrops (such as
Pred Forte
,
Pred Mild
,
Lotemax
) can also reduce inflammation.
12
However, they can cause glaucoma and cataracts and are not safe to use for long periods. They are generally used as a short-term therapy for people who have not responded to other treatments. “If the eye is extremely inflamed, other measures won’t work. If you can bring down the inflammation, other treatments may have a better chance of helping,” says Dr. Clayton, an ophthalmologist who has researched dry eye and other ocular disorders.
A prescription eye “cleanser” called
Avenova (hypochlorous acid)
, for people with meibomian gland dysfunction and inflammation (
meibomitis
), can relieve symptoms of dry eye such as a gritty sandy feeling, crusted lids on awakening, and meibomian cysts (
chalazions
).
16
It is
not
a treatment for dry eye or for Sjögren’s, however.
Tiny silicone plugs (called
punctal plugs
) can be placed in your tear ducts near the corner of the eyes and can help tears stay around longer. “In women with Sjögren’s who have very low tear flow, punctal plugs may make things worse. If you have no outflow of tears, as the tears evaporate, inflammatory proteins can concentrate on the surface of the eye and cause discomfort. So you need to use other measures to keep the surface of the eye lubricated and flushed,” explains Dr. Clayton. In rare cases, the plugs can become contaminated and cause infections, and ducts may become damaged.
Special goggles for outdoor use decrease tear evaporation or slow it, and some goggles have special inserts or patches that increase humidity around the eye. There are also plastic side shields for glasses and wraparound sunglasses. Humidifiers can make a big difference in the bedroom and elsewhere.
Recent research suggests that supplements containing essential fatty acids including omega-3 fats, found in fish like salmon (see
page 45
), may help
relieve dry eye.
17
Now omega-3s are being tested in a randomized clinical trial, the Dry Eye Assessment and Management (DREAM) Trial. A supplement,
Thera Tears Nutrition
, is marketed specifically for dry eye.
12
New therapies may include androgen eyedrops. “Animal data suggest that topical androgens may suppress lacrimal gland inflammation and correct the meibomian gland dysfunction in Sjögren’s syndrome, aiding tear formation and production of a lasting tear film,” explains Dr. Clayton. “It’s also thought that androgens have anti-inflammatory properties, and that there’s a relative androgen deficiency locally in the eye that may allow inflammation to progress on the surface of the eye.”
There are also receptors for androgens and estrogens in the eyelid, the conjunctiva, the cornea, the lacrimal gland, and even in the retinal pigment epithelium. “We’re learning more about how complex the ocular surface is, and it’s not something that you can just rewet. Really what’s needed is something that will produce physiologic tears,” comments Dr. Clayton.
The androgen eyedrops developed by Dr. Sullivan and his colleagues at Harvard are in clinical trials.
Tests are also under way of an experimental eyedrop preparation,
diquafosol tetrasodium (INS365)
, that acts on receptors in the eye (
P2Y2, purinergic receptors
) that regulate and stimulate secretion of tears and mucin.
18
“It causes an increase in fluid on the surface of the eye. It’s not tear fluid, but transudate, fluid that comes from underneath the conjunctiva that moves onto the surface of the eye. It results in an increase in tear volume on the surface of the eye by that mechanism. It’s the only drug that works that way,” explains Dr. Clayton. So far, studies show the drops appear to be safe and reduce some dry eye symptoms.
19
In addition, a clinical trial is also underway to test the ability of
lubricin
to alleviate the signs and symptoms of dry eye. Lubricin is the body’s antifriction and anti-adhesion protein that Dr. Sullivan and colleagues recently discovered is produced not only in joints but also by the human cornea and conjunctiva.
20
Lubricin reduces friction 20 times better than Teflon, he remarks.
However, inflammation, which typically occurs in ocular surface tissues in dry eye, is known to shut down lubricin production. This would lead to
increased stress, friction, and more inflammation. Consequently, Dr. Sullivan and colleagues have made human recombinant lubricin, which is being used in the clinical trials. So far, clinical tests show that a single drop of lubricin dramatically decreases dry eye symptoms for at least eight hours.
21
Other potential treatments in development include an
interleukin1 (IL-1)
receptor blocker
EBI005
, and
lifitegrast
, which targets another cytokine involved in ocular surface disease inflammation.
17
Salagen (pilocarpine hydrochloride)
and
Evoxac (cevimeline)
are oral medications that stimulate saliva production, helping patients chew, swallow, speak, and even sleep more easily. Evoxac is also being studied for its effect on dry eyes.
22
Salagen may have effects on dry eye, and some people using Salagen are using it in addition to other therapies.
Toothpastes containing detergents can cause mouth irritation. Detergent-free brands include
Biotene
(toothpaste and rinse) and
Oral Balance
(gel).
Artificial saliva, which contains ingredients such as methylcellulose, sorbitol or xylitol (artificial sweeteners), and salts like magnesium, can help moisten and lubricate the mouth. Preparations include lozenges (
SalivaSure
), sprays (
Aquoral
,
Biotene
), and rinses (
Biotene
,
Oasis
).
Medactive
, a saliva enhancer, is available in lozenges, gel, and spray formulations. These can also help reduce tooth enamel erosion.
A chewable product for dry mouth,
BasicBites
, acts in similar ways to saliva. The sugar-free chocolate soft chews contain
arginine bicarbonate
and
calcium carbonate
, which help maintain the normal pH of the mouth and protect teeth by coating them with calcium.
A lozenge containing
interferon alpha (IFNα)
that may stimulate saliva production is also in clinical trials. IFNα may treat the secretory dysfunction in the salivary glands. In clinical trials, patients using the lozenge had more than twice the increase in saliva production as a placebo group.
23
Researchers are even exploring possible gene therapy that would be delivered to the salivary glands and even implantable artificial salivary glands.
If you have dry mouth or dry eyes, avoid medications such as antihistamines, which can dry mucus membranes.
A number of vaginal moisturizers (including
Replens
,
Feminease
,
Vagisil Intimate Moisturizer
, and
KY Liquid
) can relieve dryness, itching, and burning, and a number of lubricants that can make sex more comfortable are available (see
pages 191
to
192
).
Since vaginal dryness in Sjögren’s before menopause is not due to the absence of estrogen, local estrogen therapy (such as vaginal creams or suppositories) may not help younger women. A new nonhormonal therapy,
ospemifene (Osphena)
, is a once-a-day pill that can help relieve painful intercourse (
dyspareunia
). It combats vaginal dryness and atrophy, but it can have estrogen-like effects on the lining of the uterus and may increase the risk of blood clots, as estrogen does. (For more, see
page 192
.)
Systemic therapies used for Sjögren’s include corticosteroids,
azathioprine
,
cyclophosphamide
, the antimalarial
hydroxychloroquine
,
mycophenolate mofetil
, and the B cell depleting drug
rituximab (Rituxan)
. However, none have been shown to change the course of Sjögren’s, and there are still conflicting reports on their effectiveness.
Rituximab has been shown to produce greater improvements in salivary flow, dry eye, and tear production than more conventional DMARDs.
24
But unfortunately a recent study suggested it had lesser effects in recently diagnosed patients.
25
It has been approved for treating rheumatoid arthritis, but not yet for Sjögren’s.
Many primary Sjögren’s patients find dryness, muscle and joint pain, and fatigue are improved with the DMARD
hydroxychloroquine (Plaquenil)
. However, a recent randomized 24-week study from France suggests that it may be no better than a placebo.
26
The drug only is approved for treating lupus and rheumatoid arthritis.
While studies have found Sjögren’s patients have increased levels of the inflammatory cytokine
tumor necrosis factor alpha (TNFα)
in their salivary and lacrimal glands, TNFα blockers such as
etanercept (Enbrel)
have not been shown to be effective as Sjögren’s treatments.
Studies continue of
dehydroepiandrosterone (DHEA)
in primary Sjögren’s syndrome. DHEA, a supplement, has been used to treat women with lupus and has shown some effectiveness in Sjögren’s patients.
“The thought is that androgens could affect the multiple systems involved in Sjögren’s. It could decrease inflammation in the mouth, the eyes, the joints, and perhaps in the blood for some of the inflammatory markers of Sjögren’s,” adds Dr. Clayton. However, DHEA treatment has not been approved to treat Sjögren’s.
For severe cases of small fiber neuropathy,
neuroleptic
medications (drugs originally developed for epilepsy that also relieve nerve and muscle pain) such as
gabapentin (Neurontin)
,
pregabalin (Lyrica)
, or
topiramate (Topamax)
may be recommended.
6
Evelyn’s story continues:
You have to manage dry eyes and dry mouth to prevent other health problems. You should not just accept the fact that your eyes bother you. I make sure to keep my eyes moist, and I avoid certain environments that dry out my eyes—like air-conditioned stores, which are very dry—and I wear special sunglasses that have side panels so the wind doesn’t dry my eyes. I’m careful about eating sugar and make sure to rinse my mouth or brush my teeth if I eat something sweet. I avoid eating any acidic foods, because they bother me—my tongue burns like crazy. Eventually this becomes part of you and you do things automatically.