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The significance of antinuclear factors in rheumatoid arthritis.

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The Significance of Antinuclear Factors
in Rheumatoid Arthritis
By
JOHN J. CONDEMI,
EUGENE
V. BARNETT,EDWARD
C. AnvArER,
RALPHF. JACOX, EDWARD
S. MONGANAND JOHN H. VAUGHAN
Sixty-eight patients with definite or classic rheumatoid arthritis were studied to
determine the significance of the presence of antinuclear factors. The patients
with positive antinuclear factor determinations were those with more severe
disease. These patients almost always
had subcutaneous nodules, which were
not always associated with a high latex titer for rheumatoid factor. Necrotizing vasculitis occurred in both antinuclear factor positive and negative
patients. Our data do not support the
notion that a positive antinuclear factor
test or a positive L.E. cell test should
be used to exclude the diagnosis of
rheumatoid arthritis.
Sexanta-octo patientes con definite o
classic arthritis rheumatoide esseva
studiate con le objectivo de determinar
le signification del presentia de factores
antinuclear. Esseva constatate que le
patientes in qui le determinationes de
factor antinuclear esseva positive esseva
etiam le patientes con grados sever del
morbo. Iste patientes habeva in quasi
omne le casos nodulos subcutanee le
quales esseva non semper associate con
un alte titro a latex pro factor rheumatoide. Vasculitis necrotisante occurreva
in patientes tanto positive como etiam
negative pro factor antinuclear. Nostre
datos non supporta le these que un
positive test pro factor antinuclear o un
positive test pro cellulas de L.E. pote
esser usate in excluder un diagnose de
arthritis rheumatoide.
T
HE APPLICATION O F Coon's immunofluorescence method' to demonstrate the presence of antinuclear factor^^-^ in the serums of patients
with systemic lupus erythematosus (SLE) has made available both a valuable research tool and a useful diagnostic test. It soon became obvious, however, that the technique was revealing these factors to be present in other
diseases, such as rheumatoid arthritis (RA), juvenile rheumatoid arthritis,
discoid lupus, scleroderma, dermatomyositis, polyarteritis nodosum, liver disease, ulcerative colitis, thyroid disease, myasthenia gravis, and 5 per cent
of normal people.
Although the incidence of antinuclear factors (ANF) in systemic lupus
erythematosus has been reported to be from 97-100 per cent by most workers,
From the Departmmt of Medicine, Uniuersity of Rochester School of Medicine and
Dentistry, Rochester, N . Y.
Supported b y research grants AI 02349 and AM 02443 from the National Institutes of
Health and from the National Foundation, Bethesda, Md.
JOHN J. CONDEMI,
M.D.: Senior Instructor in Mediche, Assistant Physician; EUGENE
V.
BARNETT,M.D.: Assistant Professor of Medicine, Associate Physician; EDWARD
C. ATWATER, M.D.: Assistant Professor of Medicine, Associate Physician; EDWARD
S . MONGAN,
M.D.: Assistant Professor of Medicine, Associate Fhysician; RALPH F. JACOX, M.D.:
Professor of Medicine, Physician; and JOHN H. VAUGHAN,M.D.: Professor of Medicine,
Physician, Recipient, Research Career Award from the National Institutes of Health,
Bethesda, Md., all at Strong Memorial Hospital, Rochester, N . Y.
1080
.dRlHRITIS AND RHEUi%fAlISM, VOr
. 8, NO. 6
(I)kC EhiAEA),
I!i)65
SI(;NIE’ICANCE:OF ANTINUCLEAR
FACrOHS
1081
there has been a wide variation in the reported incidence of ANF in rheumatoid arthritis-e.g., less than 10 per cent by Friou,5 16 per cent by Weir
arld Holbrow,c 16 per cent by Rothfield et al.,‘ 36 per cent by Hall et al.,s
36 per cent by Witebsky,s and 65 per cent by Alexander et a1.I0 This variation has most often been attributed to differences in sensitivity of the systems
employed to demonstrate ANF. Another explanation may be patient selection. Alexander, Bremmer, and Duthie,lo who reported the highest incidence,
included in their series only patients with disease of 8 or more years’ duration. The number of patients with Felty’s syndrome in any series may also
increase the number of positive reactions obtained.ll
With these differences in reported incidences of ANF in patients with
rheumatoid arthritis and the uncertainty of the significance of the test in
classification, treatment, and prognoses, we decided to study a group of
patients with RA from our clinic to determine the incidence in them of ANF
as we measure it, and to assess its clinical significance.
SELECTIONOF PATIENTS
AND METHODOF STUDY
During a two-year period (1961-1963), we began utilizing the immuncfluorescence method for detecting ANF and obtained positive results in 18
of 20 patients with SLE, 36 of 132 patients with adult RA, 5 of 15 with
juvenile RA, 3 of 75 normal people, and 18 of 143 with a variety of other
diseases (Table 1 ) . Among the 316 patients with negative tests in the miscellaneous group were cases of dermatomyositis, Laennec’s cirrhosis, viral
hepatitis, Behcet’s syndrome, drug reactions, chronic infections, rheumatic
fever, rheumatic heart disease, syphilis, serum sickness, thyroid disease, and
solar dermatitis. The patients’ sera were examined because they were sent
to 11s by the attending physicians, who considered that autosensitivity might
have been playing a role in the patients’ illnesses. The two cases of systemic
liipus erythematosus with negative ANF determinations in Table 1 were
well-documented cases in which earlier sera had exhibited positive L.E. cell
tests, but had been in long remissions when the sera were taken for ANF
testing.
For the present study, 68 patients from the Arthritis Clinic were investigated. About one-half were on corticosteroids at the time the study was
performed. The remainder had never been on corticosteroids or had not received steroids for at least one year. An equal number of the patients were
in anatomical Stages I or I1 or in Stages I11 or IV by Steinbrocker’s classification12 ( p. 271 ) . Patients on corticosteroids were equally distributed between
the groups with mild disease (Stages I and 11) and the groups with more
severe disease (Stages I11 and IV). All patients fulfilled the ARA diagnostic
criteria fur definite RA12 (p. 234), except that a positive L.E. cell preparation did not exclude a patient from the study.
Each patient was given a questionaire about onset and duration of disease,
joints involved, sun sensitivity, nervous system symptoms, leg ulcers, Raynauds phenomenon, and family history. A complete examination was then
performed by one of our group. The laboratory studies included a complete
CONDEMI ET AL.
1082
Table 1.-Zncidence
of
Antinuclear Factors in Disease
TESTED
DIA6NOSIs
POSITIVE
PER CENT
POSITIVE
20
18
90
RHEUMATOID ARTHRITIS
I32
36
27
JUVENILE RHEUMATOID ARTHRITIS
IDIOPATHIC THROYBOCYTOPENIC WRPURA
15
5
33
8
3
ULCERATIVE COLITIS
8
2
DISCOID LUPUS ERYTHEMATOSUS
6
2
SCLERODERMA
5
2
MYASTHENIA GRAVIS
5
2
SYSTEMIC LUPUS ERYTHEMATOSUS
7
I
OSTEOARTHRITIS
31
2
ASTHMA
20
I
KIDNEY DISEASE
28
I
IDIOPATHIC PERlCARDlTlS
II
I
MYLERAN-TREATED CHRONIC
MYOLOGENOUS LEUKEYIA
I4
I
TOTAL
310
NORMALS
71
POLYARTERITIS
NDDOSUY
blood count, urine analysis, sedimentation rate, paper electrophoresis, Wassermann test, chest x-ray, electrocardiogram, and biopsy to confirm the
diagnosis of vasculitis whenever possible.
MATERIALSAND METHODS
To demonstrate the presence of antinuclear factors, peripheral smears were made from
the bloods of hospitalized patients with elevated peripheral blood leukocyte counts but
with no evidence of autosensitivity diseases. The smears were dried for one hour before
a fan and fixed in 95 per cent ethanol at 37 C. for 10 minutes. They were dried again at
37 C. for 30 minutes and used immediately or frozen at -20 C. for future use.
Prior to testing, the slides were thawed before a fan and rinsed in buffered saline. The
test serum was applied for 30 minutes, with care taken to prevent drying. The excess
serum was then Iremoved by washing for 20 minutes with two changes of phosphate
buffered saline. Fluorescein-labeled rabbit antihuman gamma globulin was then applied
for 30 minutes. This was also washed with two changes of saline and then covered with
a 90 per cent glycerin solution and overlayed with a cover slip.
The rabbit antihuman gamma globulin for labeling was prepared by immunization with
alum-precipitated Cohn Fr. 11.13 The antisera reacted only with y G globulin on immnnoelectrophoresis against normal serum. By Ouchterlony analysis, there were cross reactions
with gamma A and gamma M globulins.*
*According to the new convention, the terms yG. yA, and yM are used in preference
to the prior terms y2 ( y s s ) , ylA ( B2A), and ylM (B,M) respectively.14
1083
SIGNIFICANCE OF ANTINUCLEAR FACTORS
Table 2.-Relationship
X.
FEMALES
2
4
ANF to Stage* of Disease
n.
et
13
3
8
4
6
5
5
13
30
33
5
J
m.
m.
TOTAL
of
J
5
13
J
5
4
27
5 5
5
54
*ANATOMICAL STAGE AS MFINEO BY STEINBROCKER. 12
fONE
OF THESE
EXHIBITED
A POSITIVE ANF OETERYINA1,TK)N ONLY WITH ALTERED CELLS.
The modification of Marshall et al.,15 was used in coupling fluorescein isothyocyanate
to globulin. Nonspecific staining was removed by absorption with acetone-dried rabbit
liver powder.16 A Zeiss microscope with an OSRAM HBO 200 W. mercury arc light
source was used. In viewing the slides, a BG 12 exciting filter and 500 blocking filter
were used.
The sera tested were used iininediately or stored for short periods of time at -20 C.
Titers were determined by twofold dilutions of serum and are expressed as reciprocals of
the highest dilution giving a pozitive reaction. The latex fixation test was a modification of
the Singer and Plotz method as described by Atwater.17 The L.E. cell preparations were
generally performed on the same bleeding as the ANF test and the defibrinationls method
was used. In one patient with a positive L.E. cell preparation the ANF were demonstrated
in the serum only when altered nuclear material was used19 Titers were not performed
on this sera.
RESULTS
Of the 68 patients studied there were 24 who were ANF positive and 44
who were ANF negative (Table 2 ) . Eleven of 25 males and 13 of 43 females
were ANF positive. The frequency of males and females in this series of
patients with rheumatoid arthritis is within expected limits. The greater
frequency of occurrence of ANF in males over females is statistically significant only at the 10-20 per cent level. Of 34 patients in Stages I11 and IV,
18 were ANF positive, while only 6 positive tests were seen in 34 patients
who were in Stages I and 11. This difference of distribution is significant at
the 1 per cent level. The highest ANF titers (32 and above) occurred in
patients with disease in Stage I11 or IV. As can be seen, however, there were
also patients in Stages I11 and IV who had low titers of ANF.
Table 3 shows that there was also an increased incidence of positive ANF
tests in patients in functional Class 111 or IV. Thirty-eight patients were in
Class I11 or IV and 18 were ANF positive, while of 30 in Class I or I1 only
6 were ANF positive. This difference is significant at the 1 per cent level.
CONDEMI ET AL.
1084
Table 3.-Relationship
of
ANF to Class"
of Disease
MALES
FEMALES
I ~ T A 1L 1
1
3
3
0
1
I
I
I
I
I
I
I
I
~~
*FUYCTIOWAL CLASS AS DEFINED BY STEINBRDCKER. ' 2
tDNE OF THESE EXHIBITED A POSITIVE ANF DETERMIMATIOW ONLY WITH ALTERED CELLS.
Table 4.-Relationship
of
(o
ANF to Age of Patient
MA1-ES
FEMALES
ONE OF THESE EXHIBITED A POSITIVE ANF DETERYINATION ONLY WITH ALTERED CELLS. Is
1085
SIGNIFICANCE OF ANTINUCLEAR FACTORS
Table 5.-Relationship of ANF to Duration of Disease
I
MALES
FEMALES
IN ONE OF THESE, A POSITIVE ANF MTERHINATION
OCCURRED ONLY WITH
ALTERED CELLS. 19
The correlation between positive A N F determinations and more advanced
stages and classes of disease was more marked in males. There was no
correlation between titer of A N F and functional class of rheumatoid arthritis.
The patients’ ages, recorded in Table 4, are the ages attained at the time
of the study. As can be seen, the men were all over 40, and the incidence of
positive ANF tests increased with age. This changing incidence, however, is
not statistically significant. The women had disease at earlier ages, and no
significant correlation was noted between presence of ANF and age. However, it may be noted that in the combined sexes, 9/19 (47 per cent) of
patients over 60 years were ANF positive, while only 15/49 (30 per cent)
who were under 60 years were A N F positive.
In Table 5 the duration of disease is compared to the presence of ANF.
In neither sex could the presence of A N F be correlated with greater duration of disease at a high probability, but in each sex the highest incidence
occurred in those with disease of longest duration.
The presence or absence of ANF is correlated in Table 6 with several
clinical signs considered to reflect the vasculitis of rheumatoid arthritis. As
can be seen, nodules21 occurred in 20 of 24 patients with positive tests but
in only 15 of 44 with negative tests. This difference is significant at the 1
per cent level. Symptoms or signs of peripheral neuropathy, including paresthesias, decreased vibratory or pinprick sensation, or absent reflexes occurred
without a significant difference in ANF-positive and ANF-negative groups.
Nail fold thrombi22 (Fig. 1) occurred in 2 of 24 A N F positive patients and
1086
CONDEMI ET AL.
Table 6.-Euidence
of
Vasculitis
in 4 of 44 of the ANF-negative patients. Two patients (R. C . ) and (L. R.)
had foot drop and positive biopsies for vasculitis (Figs. 3 and 5 ) . Both had
gangrenous changes in the lower extremities (Figs. 2 and 4 ) . Patient L. R.
was ANF negative; patient R. C. was ANF positive.
The ANF-positive patients were also compared to the ANF negative patients for the incidence of infection, Raynauds phenomenon, drug sensitivity,
sun sensitivity, family history of rheumatic disease, gamma globulin level,
sedimentation rate, hematocrit, blood count, urine protein and sediment,
Wassermann test, and steroid treatment. No significant differences were
Fig. 1.-Nail
fold thrombi.
SIGNIFICANCE OF ANTINUCLEAR FACTORS
Fig. 2.-A
1087
gangrenous leg ulcer in a patient (R. C.) who was ANF positive.
noted. There were 14 positive ANF tests in 35 patients taking corticosteroids
and 10 positive tests in 33 patients not on steroids.
In Table 7 the ANF titers of patients with RA are compared to those of
patients with SLE. In general, it can be seen that patients with SLE had
higher ANF titers than did patients with RA. When the RA patients with
positive L.E. cell tests were studied by the three layer immunofluorescent
test for specific immune globulins, nearly all had rG ANF.20 The 7 G ANF
titers were significantly lower in the RA patients than in those with SLE.
The two groups did not differ significantly in their r M ANF titers. Only 3
of the 7 patients with RA and positive L.E. cell tests had evidence of vasculitis. All 3 had leg ulcers and peripheral neuropathy. One of the 3 also
had nail fold thrombi.
Table 8 demonstrates the relationships existing among F I1 latex titers,
ANF titers, nodules, and L.E. cell tests. It is obvious from the spread of the
points that there is no correlation between titers of ANF and of F I1 latex
flocculation. In the 44 patients with negative ANF tests (left column) ncdules occurred more frequently in those with higher latex titers (640 and
1088
CONDEMI ET AL.
Fig. 3.-The vasculitis noted in patient (R. C.) at postmortem examination.
There is a perivascular mononuclear inflammatory reaction with necrosis and hyaline
degeneration of the media.
above). In the ANF-positive group, the presence of nodules was not related
to high F I1 latex titers. In 3 patients with negative ANF tests and 3 patients
with positive ANF tests, nodules were noted in the past but were not found
at the time of this study. The patients with nodules had either positive F I1
latex tests or ANF tests or both. Positive L.E. cell tests were limited to patients with positive ANF determinations, but they occurred more frequently
if the patient also exhibited a strongly positive latex test. Only 1 of 7 patients with positive L.E. cell tests failed to exhibit nodules. In our series we
did not observe positive F I1 latex tests in patients with active systemic lupus
erythematosus, although others have reported positive tests in up to 25 per
cent of SLE patients7
DISCUSSION
The presence of ANF in patients with RA has been correlated in other
studies with severity of disease, duration of disease, vasculitis and infection.
SIGNIFICANCE O F ANTINUCLEAR FACTORS
Fig. 4.-A
1089
gangrenous toe in a patient (L. K . ) who was ANF negative.
This study confirms the impression of Alexander et al.'" and Hall et a1.,8 that
ANF is more apt to be present in the serums of RA patients with severe
disease, but we could not correlate it with the presence of vasculitis or
infection.
were able to find a positive correlation between the
Alexander et
presence of ANF and duration of disease. Hall et a1.8 stated that their patients with RA and positive ANF tests had a mean duration of disease of
8.4 years and those with negative ANF tests had a mean duration of 7.4
years. Although we found the highest percentage of positive ANF tests in
patients with disease of longer duration, many positive tests were also seen
in patients with disease of shorter duration. It is to be noted, however, that
17 of the 34 patients in our group in Stage I11 or IV had disease of less than
4 years duration. There were 7 positive ANF tests in this group of 17 patients. Because Alexander and Duthie selected for their study patients with
disease of 8 or more years' duration, patients with early rapidly progressing
active disease were excluded. This emphasizes to us that severity of disease
is probably a more important correlate of positive ANF tests than duration.
It is generally agreed that rheumatoid nodules are more commonly seen
with more severe disease. Thus, the higher incidence of rheumatoid nodules
among our patients with positive ANF tests also emphasizes the relationship
1090
Fig. 5.-The
patient (L. R.) .
CONDEMI ET AL.
perivascular inflammatory response found on muscle biopsy in
between severity of disease and the positive tests. Wilkens and Deckerz3 also
noted that patients with positive ANF tests had severe joint deformities and
rheumatoid nodules. We did not, however, find a positive correlation between presence of A N F and presence of other evidences of vasculitis or
infection as they23 and Ward et aLZ4have reported. Our experience is like
that of Halls Alexander,lo and V a l k e n b ~ r gin~ ~this regard. In Ward's study
the ANF test employed was somewhat less sensitive than ours, and so their
positive sera may have come from patients with somewhat more A N F than
ours. In the study by Wilkens and Decker, the antinuclear tests included
indirect L.E. cell preparations, nucleoprotein-coated latex particle agglutination, and DNA- and nucleoprotein-coated red blood cell agglutination in
addition to the direct L.E. cell test and the immunofluorescence method for
the detection of ANF. Wilkens and Decker obtained positive tests by immunofluorescence in only 7 of 14 patients. If this figure alone is considered,
then positive tests also occurred independently of vasculitis in their study.
In our laboratory we have been unable to find instances in which DNA- or
1091
SIGNIFICANCE OF ANTINUCLEAR FACTORS
Table 7.-ANF Titers in Systemic Lupus Erythematosus and R.A.
ANF TITER
II
m-POSITIVE
SYSTEMIC LUPUS ERYTHEMATOSUS
LE PREP.
RHEUMATOID ARTHRITIS
I
I024
512
m
256
]
X
p
J
i
128
axx
64
TIJX
xx
32
xxxx
I
lex
4
xx
2
axx
N
DXXXX
xx
0
~
*o;ONE
+ LE
PATIENT NOT INGLUDED HAD
I9
ALTERED CELLS.
PREP AND
POSITIVE ANF DETERMINATION
ONLY WITH
nucleoprotein-coated latex particles gave positive tests in the absence of a
positive test by immunofluorescence. This has also been the experience of
others.26-28In our hands, hemagglutination tests for antinuclear factors have
been uniformly unsuccessful, even with sera of high ANF titer.
We recognize that comparison of ANF data derived from various laboratories is diffxult because of differences in patient selection, sensitivity of
detection systems, and sources of antigens and antibodies used as reagentsz9
Combinations of these differences may expIain the variations in r e s ~ l t s ~ J ~ J ~ - ~ ~
appearing in the current literature.
The finding of patients with clinical RA and positive L,.E. cell tests have
in recent years led to difficulties in classification. These patients have been
classified as SLE, as RA with positive L.E. cell tests, or as an intermediate
syndrome. Among the 24 patients with positive ANF tests we noted 7 with
positive L.E. cell tests. Six of these had classic RA with subcutaneous nodules, high latex titers, and chronic symmetrical joint disease in Stage I1 or
IV. The seventh was classifiable as definite RA by the ARA criteria. This
group of 7 did not have a greater incidence of vasculitis or signs and symptoms suggestive of SLE than did the ANF-positive group. We have stated
previously that the numerous indices that might distinguish SLE from RA
were no different in the ANF-positive and the ANF-negative groups. Therefore, we are unable to justify the use of the presence of a positive ANF test
or of a positive L.E. cell test as tools of diagnostic significance in separating
1092
CONDEMI ET AL.
Table 8.-Relationship Between ANF and Latex Titers in R.A.
@
* PITIENT WITH
SUBCUTANEOUS NODULES PRESENT
ANF TtTER
POSITIVE LE CELL TEST AND POSITIVE ANF TEST
ONLY WITH ALTERED CELLS. Is
RA patients. Early in the disease, however, high titers of A N F and more specifically high titers of rG A N F may be of value in distinguishing SLE from
RA.20330These data indicate that the presence of A N F in patients with RA
at present should be considered simply a manifestation of an immunological
response that either SLE or RA patients may exhibit in the course of their
d'isease.
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J. J., Jacox, R., and Vaughan, J. H.:
Antinuclear factors in systemic lupus
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