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The present status of antinuclear antibody serology.

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543
COMhIUNICATIONS
Editor’s Note
The statements in the following letters
represent the consensus of the Committee
on Serology Standardization of the American Rheumatism Association. The letter
from Dr. Epstein presents a minority
opinion on antiglobulin (rheumatoid) factors.
Serological Reactions of the Rheumatoid Factors
Sir:
There is a growing feeling that the antibodies
commonly called rheumatoid factors found in high
titer in the serum of patients with rheumatoid
arthritis and the antiglobulin antibodies found in
the serum of normal individuals may represent similar immune responses of different intensity. The
myriad variability of these responses is expressed
not only by differences in titer but also by the
ability of these antibodies to react differently with
rabbit or human gamma globulin, by differences
in antibody specificity to inherited antigenic components of isologous gamma globulin (Gm groups),
by single or multiple specificities of the antibodies
(Snagg and Ragg), by differences in the various
globulins participating in antibody production
(IgM and IgC), and finally by the autoreactivity
of some of the antibodies and the strictly isoreactivity of others.
It is postulated that these antibodies may represent an immune potential of all capable individuals and that the intensity and duration of the
response may reflect the different antigenic stimuli.
This is not to disregard the opinions of those who
feel that these antibodies are an intense secondary or auxiliary response to an unknown antibody
of sharply defined specificity.
There is little doubt that the measure of an
antibody response of variable specificity, associated
most closely with a disease of unknown etiology
and ill-defined pathogenesis, has inherent difficulties in standardization. The suggestion has been
made that a standardized test should include both
the consideration of specificity and of sensitivity.
The selected test must therefore be primarily one
of great sensitivity capable of detecting all varieties of antiglobulin antibodies even when pres-
ent in low titer. This test could be standardized
so that “diagnostic titers” could be established.
There are three test systems at the present time
which could be standardized with these objectives
in mind: (1) tube latex test, ( 2 ) F I1 hemagglutination test, and (3) the sensitized sheep cell
test. It is of concern that this test be reproducible
with due regard to ease of performance. Unless
these criteria are met, the test will be slow to meet
with acceptance.
An alternate suggestion is to have two tests:
( 1 ) a quick simple test of great sensitivity to be
used as a screening test (the slide latex test has
met with wide acceptance for this purpose); ( 2 ) a
test which will give a titer of reactivity (this test
could either be a tube test or a slide test).
The serology standardization committee of the
American Rheumatism Association is attempting
to solve this problem in two ways: (1) by evaluating all popular test systems, and ( 2 ) by providing a reference laboratory where individuals
may send problem bloods for evaluation by a
variety of test procedures, and where they may
direct any questions they have about rheumatoid
serology.
In the meantime, members of the serology
committee feel that clinicians and investigators
should realize that these tests are measuring exaggerated responses of what may be observed in
the normal state and that, as with the tests for
antinuclear antibodies, positive results should not
override or alter a diagnostic impression made on
the basis of clinical signs and symptoms.
MAFUONWALLER,PH.D.
Medical College of Virginia
Richmond, Va.
The Present Status of Antinuclear Antibody Serology
Sir:
It has been 20 years since the original description of the lupus erythematosus (LE) cell
phenomenon and more than 10 years since immunofluorescence technics have been applied to
the detection of antinuclear antibodies. During
this period clinicians have received considerable
aid in the confirmation of the diagnosis of systemic
lupus erythematosus by use of these technics.
However, it has been fully appreciated that antinuclear antibodies, whether detected by the
immunofluorescent technic or in LE cell preparations, may be associated with disease entities other
than systemic lupus erythematosus. Indeed, if the
544
most highly sensitive tests are used, antinuclear
antibodies of one or another immunoglobulin class
and of specificity for a wide variety of nuclear
antigens may be detected in sera from many
asymptomatic individuals. The incidence of such
serologic phenomena unassociated with clinical
disease has been shown to increase with advancing age. Diagnostic criteria recently proposed for
systemic lupus erythematosus do not include tests
for antinuclear factor. This omission was brought
about by the lack of data on antinuclear antibodies available at the time data were compiled
for the purpose of defining the criteria. Not including antinuclear antibodies among the criteria
for the diagnosis of systemic lupus erythematosus
merely reflects the absence of data on tests for
antinuclear factor at the time criteria were analyzed and in no way excludes such tests from
being of diagnostic significance.
The frequency of positive LE cell preparations
in active cases of systemic lupus erythematosus
rarely exceeds 80 per cent. The incidence of
“false negative” tests is from 15 to 20 per cent.
However, utilizing a variety of modifications for
the indirect fluorescent technics, many investigators have reported from 95 to 100 per cent
positive antinuclear antibody tests associated with
active SLE. In centers in which tests are performed, the clinicians have learned that a negative
test for antinuclear antibodies performed by the
immunofluorescent technic practically excludes the
diagnosis of active systemic lupus erythematosus.
Although there are nearly as many different
methods of performing the indirect immunofluorescent test for antinuclear antibodies as there are
investigators performing the test, the following
generalizations seem appropriate for 1969:
1. The indirect immunofluorescent technic for
antinuclear antibodies when “properly performed”
should be positive in nearly every case where the
LE cell phenomenon is positive.
2. Tests for antinuclear antibodies should be
performed on serum dilutions and a report submitted so that the clinician may infer that the
antinuclear antibodies are either absent or are at
a concentration below that usually associated with
active systemic lupus erythematosus.
3. The pattern of nuclear fluorescence should
be reported so that the clinician can interpret the
significance of the pattern: e.g., sera yielding
bright, high titer, antinuclear antibody with shaggy
or peripheral patterns are frequently from patients
with active SLE; bright, large, speckled fluorescence patterns are commonly seen in sera from
patients with systemic sclerosis.
4. At the present time, a variety of nuclear
substrates are in use in various laboratories. Since
no data are available on the comparative merits of
the various substrates, no recommendation can be
COMMUNICATIONS
made as to the substrate to be used. However, it
should be noted that differences in the results
from various laboratories may depend, in part, on
a difference in the substrate employed.
Efforts are under way under the auspices of the
World Health Organization, Medical Research
Council Division of Biologic Standards of Great
Britain, the Serology Standardization Committee
of the American Rheumatism Association, and
others to attempt definite criteria for the performance of the indirect fluorescence technic for
demonstration of antinuclear antibodies. The
groups all agree that investigators, when submitting reports for publication, should provide data
regarding: ( a ) nuclear substrate used; ( b ) the
concentration( s ) of patient’s serum used; and
( c ) specifications of the conjugate, e.g., its specificity (monovalent or multivalent), the degree of
conjugation of fluorescein isothiocyanate to the protein antibody, the units or milligrams per milliliter
of antibody present, etc. All groups agree that commercial laboratories producing conjugates for use
in the indirect fluorescent antibody technic should
provide details described under ( c ) above with
each batch of conjugate.
There are a variety of other serologic tests
available in some centers for the detection of
antinuclear antibodies. Sera from patients with
active SLE frequently have antibodies to DNA in
high titer when these are checked by a variety
of technics.
It should be emphasized that the tests for antinuclear antibodies should in no way be used to
alter a diagnostic impression made on the basis of
clinical signs and symptoms. To date, there have
been no laboratory tests without false positive and
false negative clinical correlations. The clinician
must also bear in mind that patients falling into
no clear-cut clinical diagnostic category rarely
have sera with clear-cut serologic abnormalities
sufficient to alter the diagnostic impression from
that suggested by the clinical signs and symptoms.
Furthermore, since we are at present dealing with
serologic abnormalities associated with diseases of
unknown etiology and since our present modes of
treatment are mainly symptomatic, the wise clinician should not allow himself to be tempted to
use experimental or toxic therapy not indicated by
clinical signs and symptoms even though these
may be suggested b y abnormal laboratory test
results.
EUGENEI?. BARNETT,
M.D.
University of California
at Los Angeles
Los Angeles, Calif.
NAOMIROTHFIELD,M.D.
University of Connecticut
Hartford, Conn.
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statue, present, antibody, antinuclear, serology
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