Currently there is no simple diagnostic test for Sjgrens, nor are there
universally accepted diagnostic and classification criteria. However,
those physicians skilled in caring for patients with Sjgrens know that
early and accurate diagnosis in the hands of such a physician can greatly
benefit a patient with Sjgrens syndrome.
The hallmark clinical findings are dryness of the eyes and mouth and,
often, dryness of the nose, throat, vagina, and skin. Many other organ systems
may show evidence of dysfunction. The syndrome may develop alone
(primary Sjgrens) or in association with almost any of the rheumatic
or autoimmune diseases (secondary Sjgrens). Chronic immune system
stimulation plays a central role in the pathogenesis of Sjgrens. This
chronic immune stimulation is manifested by hyperreactivity of B-cells
expressed by increased antibody production and the presence of lymphoplasmacytic
infiltrates in the affected glands and organs.The trigger and the processes that perpetuate the infiltration of lymphocytes
and production of increased antibodies are not known. Though a
genetic predisposition has been suggested by a number of studies, no clearcut
identifiable gene that can be tested for has been found to be associated
with Sjgrens. A variety of viruses have been looked at, but none have
been clearly identifiable in the pathogenesis of this disease. Alterations of
the number and kinds of cytokines that immune cells produce have been
looked at as well, but no pattern is clearly associated with Sjgrens.
There are non-organ-specific antibodies that are found in both primary
and secondary Sjgrens (anti-Ro/SSA and anti-La/SSB) that have clinical
significance and are used in the diagnostic criteria for Sjgrens. Organspecific
antibodies have been found (antibodies against carbonic anhydrase,
alpha-fodrin, proteasomal subunits, and M3 muscarinic receptors)
but these currently are not being included in any of the criteria for diagnosis
of Sjgrens.
Why is it important for there to be consistent criteria for the diagnosis
of Sjgrens syndrome? Since the cause of Sjgrens is unknown, for physicians
to properly treat patients with Sjgrens, we need to have data on
how patients with this disease will respond to a specific treatment. To date
there are very few clinical studies showing a particular therapy is efficacious
for Sjgrens patients. One of the problems is the lack of universally
acceptable diagnostic criteria.
There has been an evolution in the criteria for making the diagnosis
of Sjgrens. The universally accepted gold standard in helping with the
diagnosis is the labial gland biopsy showing a characteristic infiltrate of
lymphocytes and plasma cells in aggregates (foci) throughout the salivary
glands. The problem has been that similar infiltrates can be seen with
HIV, hepatitis C, sarcoidosis, and lymphoma. So although the finding of
lymphocytic infiltrates is essential in making the diagnosis of Sjgrens, it
is not specific for Sjgrens. In the past 30 years there have been multiple
attempts to establish a set of diagnostic and classification criteria. European
Study Group criteria allowed Sjgrens to be diagnosed on the basis
of symptoms and signs of dry mouth and dry eyes. Labial gland biopsy
findings and the presence of autoantibodies were among the criteria but
were not required for the diagnosis. In contrast, the more stringent San
Diego criteria required evidence of autoantibodies or the characteristic
pathology. The Europe Study Group criteria were criticized for including
a group of non-Sjgrens patients without immunologically active disease.
The Sjgrens Syndrome Foundation organized and sponsored meetings
between the European and American group, and a revised European criterion
was proposed by the American-European Consensus Group. This criterion
is very important for defining a group of patients with Sjgrens that
could be included in studies for the purpose of looking at pathogenesis,disease course, and response to treatment. However,
on a day-to-day basis, a practicing physician encounters
patients with Sjgrens who need care but may not
fit the American European Consensus Criteria.
First lets look at the criteria. In order to meet them,
a patient must have four positive out of the following
six, as long as the labial gland biopsy and the autoantibodies
are not both negative, and none of the exclusions
may apply.The American-European Consensus Criteria
Subjective dry eyes (my eyes are dry, feel gritty
and I have difficulty making tears)
Objective dry eyes (positive Schirmers test, positive
Rose-Bengal staining)
Subjective dry mouth (my mouth is dry; I have
altered taste and dysesthesias)
Objective dry mouth (decreased salivary flow
tests, positive sialography)
Positive autoantibodies (SSA, SSB antibodies)
Positive labial gland biopsy
Exclusions: anti-cholinergic drugs, HIV, Hepatitis
C, lymphoma, sarcoidosis, radiation therapy
I would like to tell you about some of the problems
with using the American-European criteria for making
the diagnosis in clinical practice. We know that many
patients have the disease for many years before it is
properly diagnosed. I have a patient in my practice
who has Sjgrens, but she came to me many years after
she had symptoms and was not treated aggressively
during that time. About five years ago she was diagnosed
as having a B-cell lymphoma and was successfully
treated by a local oncologist. By the time she saw
me, she clearly had had manifestations of Sjgrens for
many years, but because her lymphoma was diagnosed
first, she was excluded by the American-European
Consensus due to her lymphoma history. Sjgrens is
strongly associated with B-cell lymphoma. It is more
likely to occur in patients who are SSA positive and
have hypergammaglobulinemia, as my patient did.
Elderly women in my community often are taking
anticholinergic medications for bladder control. These
can contribute to dry eyes and dry mouth. In order to
qualify for the consensus criteria, these patients have
to be tested off of their medication. Otherwise they
must be excluded according to the criteria.
There are many patients with hepatitis C who
exhibit signs and symptoms of Sjgrens, yet they are
excluded by the consensus criteria. Do they have primary
or secondary Sjgrens? Since we dont know yet
what causes Sjgrens, doesnt this group of patients
provide a valuable human model for study?
I have found that there are many clues in a patients
history that can lead to the diagnosis of Sjgrens,
sometimes before significant symptomatic sicca (dry
eye and dry mouth) symptoms are present. Thyroid
disease, esophageal dysfunction, neuropathies, joint
pain, hoarseness, recurrent respiratory problems,
fatigue, lymph node enlargement, and rashes are all
clues to possible systemic problems associated with
Sjgrens. A physician who pays attention to these
findings, along with the findings of autoantibodies andelevated markers of inflammation such as an elevated
sed rate or C-reactive protein, may suspect that the
patient has an autoimmune disease or Sjgrens. If the
patient has a positive SSA or SSB antibody and the
features of the disease, the physician usually will make
the diagnosis. If the SSA and SSB antibodies are not
present, a labial gland biopsy will be essential to help
make the diagnosis.
Making the diagnosis of Sjgrens syndrome is
important to allow the physician to offer the patient
early therapy that may help the symptoms and delay
progression of the disease. The key to the diagnosis is
to have an index of suspicion that the condition may
be present. If your physician is not familiar with the
manifestations of Sjgrens, it is unlikely that he or she
will be able to diagnose this disease, especially if the
SSA and SSB antibodies are not present or their presence
has not been determined due to a lack of laboratory
testing. n