this is a very long article from Medscape I thought some of the
Sjogrens might be interested in the current thinking on treatment. --
MZ

Sjögren's Syndrome: A Disease in Evolution
Posted 11/29/2004

Frederick B. Vivino, MD, FACR

Background and Patient Demographics
Concepts regarding the diagnosis and management of Sjögren's syndrome
(SS) have dramatically changed in the last 5-10 years. When originally
described, SS was regarded as a rare disorder and eventually was
listed in the National Organization for Rare Disorders registry.
However, on the basis of recent population studies in the United
Kingdom[1] and the high prevalence of sicca symptoms in the United
States,[2] many experts now consider SS to be the second most common
autoimmune rheumatic disease (behind rheumatoid arthritis) with an
estimated prevalence of 2-3 million people in the United States.
Because 90% of SS patients are female, SS also represents a major
women's health problem that is still largely underdiagnosed and
undertreated by the medical community. Although the typical patient
remains a perimenopausal white woman, SS is now increasingly
recognized among younger women and women of all racial and ethic
backgrounds, as well as men and pediatric patients.

Pathogenesis
The etiopathogenesis of SS was recently reviewed.[3] Genetics,
hormones, and environmental factors (eg, infection with a sialotropic
virus) may all play a role. Salivary gland dysfunction apparently
occurs due to multiple mechanisms including parenchymal loss,
autonomic neuropathy (cytokine-mediated?), and anti-M3 muscarinic
receptor blocking antibodies. Keratoconjunctivitis sicca results not
only from aqueous tear deficiency but also from ocular surface
inflammation.[4,5]

Clinical Presentations and Diagnosis
The mean duration between onset of symptoms and time of diagnosis
remains far too long, at 6 years. Eighty percent of SS patients
present with the insidious onset of sicca symptoms that evolve over a
period of several months to years, while 20% present in atypical
fashion (Table 1). Of note, in the latter group, sicca symptoms are
often minimal or nonexistent at the time that these patients are seen
by rheumatologists. Therefore, the diagnosis of SS can be easily
missed without a high index of suspicion.

The differential diagnosis of the sicca syndrome is quite extensive
(Table 2), and includes medication side effects, viral illnesses,
other systemic diseases, and disorders intrinsic to the salivary
glands, such as chronic nonspecific sialadenitis and sialadenosis.
Chronic nonspecific sialadenitis causes sicca symptoms associated with
scarring and scattered inflammation of the salivary glands, whereas
sialadenosis typically presents with sicca symptoms and parotid gland
swelling due to fatty infiltration.

Accurate diagnosis of SS necessitates not only demonstration of
objective evidence of dry eyes and mouth but also proof of
autoimmunity. Diagnosis cannot be based on symptoms alone. The
American-European consensus criteria (Table 3) for the classification
of SS were originally developed to define a homogenous population of
patients for research studies but are now also widely used for
diagnosis as well.[6] They offer several advantages over previous
classification schemes. These criteria have been validated in
prospective studies and facilitate the diagnosis or classification of
SS with 90% sensitivity and 95% specificity. They also allow for the
diagnosis of SS without a lip biopsy, as well as diagnosis in atypical
cases based on objective findings alone.

The focus scoring threshold for grading a biopsy as positive has now
been changed to greater than or equal to one focus per 4 mm2 tissue
surface area, and should lead to more frequent and earlier diagnoses.
Misinterpretation of histologic findings, however, is still a common
problem and causes frequent diagnostic errors.[7] Consequently, proper
reporting of the focus score by pathologists and adequate tissue
sampling (at least 4-5 labial minor salivary glands must be excised)
are needed to minimize this possibility.

Why Proper Diagnosis Is Crucial
SS is a systemic disease. Like lupus, it has the potential to affect
almost every organ system in the body (Table 4). Some of the problems
(eg, recurrent bronchitis or sinusitis due to dryness of the
respiratory tract) arise from exocrine dysfunction in other organs,
while other problems (eg, interstitial lung disease or interstitial
nephritis) result from the extraglandular spread of lymphocytic
infiltration. SS may also be associated with other autoimmune
diseases, particularly autoimmune thyroiditis. Therefore, determining
the precise etiology of the patient's dry mouth becomes especially
important when other health problems arise. Additionally, the
association between lymphomas and autoimmune rheumatic disease is
strongest in the SS population. Some studies indicate a 44-fold higher
incidence of lymphomas (usually non-Hodgkin's B-cell lymphomas) in SS
patients compared with age- and sex-matched controls.[8] This may
affect up to 5% of SS patients at any time during the disease course.

Finally, it has become increasingly apparent that significant and
costly morbidity results when xerostomia and keratoconjunctivitis
sicca go unrecognized and untreated.[9] Complications of untreated dry
mouth may include accelerated caries, loss of dentition, poorly
fitting dentures, recurrent oral candidiasis, sialolithiasis,
bacterial sialadenitis, weight loss, malnutrition, and chronic sleep
disruption. Sleep deprivation from untreated sicca symptoms may also
explain the coexistence of fibromyalgia in up to 50% of SS cases.[10]
Conversely, patients diagnosed with fibromyalgia will sometimes have
early SS because clinical features of both disorders (eg, morning
stiffness, sicca symptoms, musculoskeletal pain, profound fatigue)
greatly overlap. Complications of untreated dry eyes can include
corneal melting, ulceration or perforation, loss of vision, bacterial
conjunctivitis, or keratitis. Blepharitis is also associated with dry
eyes.

Treatment Goals
Many studies suggest that the poor quality of life among SS patients
is comparable to that associated with other rheumatic disease
groups.[11,12] Depression, anxiety, and fibromyalgia are frequent
comorbid illnesses.[10] Therefore, a comprehensive management approach
must address several issues, including symptom palliation, improvement
in quality of life, prevention of complications, and recognition and
treatment of internal organ manifestations and associated
comorbidities.

Management of Dry Eyes
Measurement of tear production by Schirmer testing and assessment of
the integrity of the ocular surface with vital dye staining (eg, rose
bengal or lissamine green) should be repeated every 6-12 months to
assess the effectiveness of treatment. Symptoms alone do not always
indicate morbidity because many patients lose sensitivity in the
cornea as the disease progresses. In mild cases of dry eyes, the use
of preservative-containing artificial tears as needed up to 3 times
daily is usually sufficient. More frequent use may lead to allergic or
hypersensitivity reactions induced by preservatives.[13]

Treatment of moderate-to-severe dry eyes necessitates a switch to
preservative-free artificial tears given 4 times daily up to hourly.
Many tear preparations have similar names, so patients are advised to
look for labeling with the words "preservative-free" or to use
mini-dose applicators. Because artificial tears stay on the ocular
surface for only 15-45 minutes, the regular use of an ocular lubricant
at bedtime for better nighttime relief is highly recommended. The 4
available types of ocular lubricant include preservative-free,
preservative-containing, lanolin-free, and lanolin-containing
preparations. Patients should also be counseled to discontinue the use
of all medications with anticholinergic side effects.

Individuals with persistent symptoms may have untreated ocular surface
inflammation. These patients also benefit from the short-term (ie, no
longer than 1 month) use of steroid eye drops or administration of
0.05% topical cyclosporine. The latter treatment not only helps
symptoms but also heals ocular surface damage.[14] In SS patients with
little or no tear production, tear preservation with punctal plugs or
punctal cautery (inferior lacrimal canaliculi always done first) may
provide additional relief. A recent study also suggests that
pilocarpine tablets, particularly at doses higher than 20 mg/day, may
further alleviate various dry-eye symptoms and decrease the need for
artificial tears.[15] Patients whose dry eyes are sensitive to
environmental factors also benefit from using moisture chamber glasses
or glasses with windshields. Some ophthalmologists hold the view that
regular use of nutritional supplements containing polyunsaturated
fatty acids (eg, Thera Tears Nutrition 2 orally twice daily, HydroEye
1 orally twice daily) can be helpful.

Management of Dry Mouth With Secretagogues
The regular use of secretagogues (agents that stimulate flow)
currently provides the best strategy for palliating symptoms and
preventing complications. Successful treatment depends on residual
glandular function, and this can be estimated using salivary
scintigraphy or whole-mouth sialometry. The duration of symptoms is
not a good predictor of response to therapy. Treatment is indicated
when symptoms are troublesome enough to justify taking medications,
when the whole-mouth salivary flow rate is low (< 0.3 mL/min), or if
the patient has a history of oral/ocular complications.

Pilocarpine was the first muscarinic agonist approved by the US Food
and Drug Administration for symptomatic treatment of SS-related dry
mouth. It is currently available in 5-mg and 7.5-mg tablets. Most
patients require at least 20 mg/day in divided doses for therapeutic
response,[16] with further improvement in symptoms and salivary flow
at 30 mg/day.[15] Cevimeline 30-mg tablets are also approved for the
same indication and typically are taken 3 times daily.[17,18]

In order to minimize cholinergic side effects, pilocarpine and
cevimeline are best taken after meals. Patients are started at the
lowest dose (ie, 1 tablet daily after dinner) and advanced on a weekly
basis to the maximum daily dose. Improvement in salivary flow is
usually seen after 1 or 2 doses, but symptomatic improvement typically
lags behind by weeks or months. Although muscarinic agonists are not
approved for other indications, data from clinical studies suggest
other benefits from these agents.[15-18] Pilocarpine may also improve
dryness of the eyes, skin, nose, and vagina, while cevimeline may
alleviate symptoms of dry eyes and whole-body dryness.[15-18]
Comparison of both medications reveals subtle differences in
biochemical characteristics (eg, half-life, binding affinity to animal
muscarinic receptors, etc.), and failure to respond to one
secretagogue does not always predict failure to respond to the other.

Other Treatment Measures for Oral Symptoms
Patients also benefit from measures to minimize factors that aggravate
symptoms. For example, start with medication substitution or
elimination of drying drugs. Avoid alcohol, alcohol-containing
mouthwash and fluoride rinses, smoking, and low-humidity conditions
that exacerbate dryness. Correct mouth breathing when present.
Aggressively treat oral candidiasis.

Chronic erythematous candidiasis typically presents in SS patients as
stomatopyrosis (tongue and mouth burning) or intolerance to spicy
foods, and is associated with 1 or more of the following physical
findings: atrophy of the filiform papillae, mucosal erythema, and
angular cheilitis.[19] The diagnosis can be confirmed with an oral
swab for Candida species that are typically present in normal flora
but seldom detected in oral cultures. Treat with antifungals (eg,
fluconazole 100-200 mg orally daily x 3 weeks). For patients with no
saliva, local treatment works best (eg, nystatin vaginal tablets
100,000 units 4 times daily or clotrimazole 100 mg half tablet twice
daily x 3 weeks); patients should be counseled to suck on these
lozenges with small sips of water but not to swallow them. Sterilize
dentures and use secretagogues to prevent recurrence.[20]

Every effort should be made to optimize dental hygiene. Patients with
accelerated caries are encouraged to obtain dental check-ups every 3-6
months and to use fluoride at home. For example, 1.1% neutral sodium
fluoride is applied to teeth for 30 minutes daily at bedtime instead
of toothpaste. During this interval, patients should floss between
teeth. Use of an electric toothbrush and frequent oral rinses with
water after each meal are also beneficial. Two studies also suggest
that pilocarpine may prevent or reverse caries in rat models for dry
mouth.[21,22] Therefore, stimulation of saliva flow with secretagogues
could theoretically help preserve the dentition in humans as well.
Further studies are needed to prove this hypothesis.

Other common-sense adjunctive measures sometimes provide additional
relief, especially in early cases. These include the liberal use of
sugar-free fluids or water to improve oral comfort, use of a room air
humidifier for nighttime dryness, and use of sugar-free candies or
chewing gum containing xylitol. Any type of gustatory or masticatory
stimulus (even fruit pits) may be sucked on to stimulate flow. Dietary
modification (eg, no spicy foods, more gravies to make food more
moist, etc) will ensure proper intake and adequate nutrition.

Artificial salivas may help in certain situations (nocturnal dryness,
air travel, etc.) but only last for about 30 minutes. Patients should
use 1-2 squirts orally every hour as needed while awake [13]. For
patients with no flow, vitamin E oil, mineral oil, or Oral Balance or
Orajel moisturizing gels are applied to coat the tongue and mucous
membranes twice daily after meals as needed and at bedtime. Add
long-acting guaifenesin 600-1200 mg orally twice daily for dry nose
and throat.

Use of Immunosuppressants
Immunosuppressants are mainly used for the treatment of the
extraglandular manifestations of SS. Current recommendations are based
on treatment of similar problems in other groups. Results of
randomized controlled trials and other studies suggest little benefit
for management of sicca symptoms.[23-28] Hydroxychloroquine is most
widely used and may alleviate fatigue, adenopathy, parotid swelling,
arthralgias, myalgias, and hypergammaglobulinemic purpura;
methotrexate may be used as a second-line agent. The polyarthritis and
musculoskeletal pain associated with SS is treated by following the
algorithm for rheumatoid arthritis. In contrast to rheumatoid
arthritis and scleroderma patients, interstitial pneumonitis in SS can
be successfully managed using steroids, azathioprine, or intravenous
cyclophosphamide. Treatment algorithms for central nervous system
(CNS) SS and CNS lupus are the same. Mild cases of peripheral
neuropathy sometimes spontaneously remit or can be managed with
symptomatic treatments (eg, gabapentin), while progressive cases that
affect ambulation often require use of steroids, azathioprine,
intravenous gamma globulin, or intravenous cyclophosphamide.

Patient Information
Patients empowered by medical knowledge are best equipped to cope with
the effects of a devastating illness like SS and participate more
actively in their own care. The Sjögren's Syndrome Foundation, 8120
Woodmont Avenue, Suite 530, Bethesda, MD, 20814, and its local
chapters provide a wealth of resources for patient education and
psychosocial support. For further information, providers or patients
should call 1-800-4SJOGREN or go to www.sjogrens.org.

Conclusions
Sjögren's syndrome can present in a variety of ways and be challenging
to diagnose. Proper patient identification, however, is essential in
order to avoid complications from untreated sicca symptoms, and to
treat morbidity from internal organ manifestations and associated
autoimmune diseases. As with other rheumatic disease groups, patient
involvement with care, early diagnosis, and aggressive treatment
provide the best chance for a successful outcome.

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