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Rheumatoid arthritis with serologic evidence suggesting systemic lupus erythematosusClinical serologic and chromatographic studies.

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Rheumatoid Arthritis with Serologic Evidence Suggesting
Systemic Lupus Erythematosus: Clinical, Serologic
and Chromatographic Studies
By ROBERTF. WILLKENS
AND JOHN L. DECKER
Fourteen patients with antinuclear activity demonstrable in their serum were
studied in detail. All had severe, deforming rheumatoid arthritis with visceral manifestations, and eight had
chronic leg ulcers. Serum protein chromatography provided evidence that, in
these patients, macromolecular globulins comprised a greater proportion of
the antinuclear activity than was true
in systemic lupus erythematosus. The
factors were considered to be a manifestation of rheumatoid arthritis possibly provoked by chronic bacterial infection.
Dece-quatro patientes con activitate antinucleari demonstrabile in le sero esseva studiate in detalio. Omnes habeva
sever grados de deformante arthritis
rheumatoide con manifestationes visceral, e octo habeva chronic ulceres de
gamba. Chromatographia del proteinas
del sero provideva evidentia que in iste
patientes le globulinas macronucleari
comprendeva un plus grande proportion del activitate antinucleari que in
patientes con systemic lupus erythematose. Esseva opinate que le factores esseva un manifestation de arthritis rheumatoide, provocate possibilemente per
chronic infection bacterial.
T
HE PATIENT with rheumatoid arthritis whose serum is found to produce L.E. cells defies classification as either rheumatoid arthritis or systemic lupus erythematosus. The American Rheumatism Association criteria
for the diagnosis of rheumatoid arthritis (R.A.) exclude those patients with
a significantly positive L.E. cell preparati0n.l This exclusion has been interpreted to support the opposite view that the appropriate diagnosis is systemic lupus erythematosus ( S.L.E.) . The difficulty is compounded b y the
fact that these patients frequently exhibit visceral manifestations which are
uncommon in rheumatoid disease but regularly seen in systemic l u p ~ s . ~ ? ~
Rather than classify these individuals, some authors have simply dealt
with them descriptively and labeled them as rheumatoid arthritics with a
positive L.E. cell preparation. More frequently the interpetation has been that
It i s , in some measure, the inclusion of this type
these patients have S.L.E.4*5
o f patient in the diagnostic category of systemic lupus which has produced
a modification of the concept of S.L.E. as a more chronic disease than heretofore conceived. While it is recognized that a chronic false positive serologic
tests for syphilis, idiopathic thrombocytopenic purpura, or a convulsive disorder may presage the much later onset of frank S.L.E.,such “tagged patients
seldom exhibit chronically active disease, which is the hallmark of the
arthritic patient considered here.
Some authors have preferred to place these individuals in a borderline zone
~~
From the Department of Medicine, University of Washington, Seattle, Wash.
Supported in part by Grants A-2663 and ZA-5157 of the National Institute of’ Arthritis
and Metubolic Diseases, U.S.P.H.S.
720
ARTHRITIS AND RHEUMATISM, VOL.
6, NO. 6 (DECEMBER),
1963
721
R.A. AND EVIDENCE OF S.L.E.
somewhere between the two major disease entities.6 Indeed, the point has
been made that a clear distinction between these disorders is little more
than a semantic exercise.? Insofar as there is validity in distinguishing among
any of the “collagen diseases,” these patients appear to require separate consideration. They are sufficiently numerous in the rheumatic population to
have a very pronounced effect upon etiologic, descriptive, or therapeutic
studies or analyses of either S.L.E. or R.A.
In attempting to answer the question of what these chronic arthritics with
positive L.E.cell preparations represented, we have analyzed the clinical
course of 14 such patients currently under our observation.
They were selected from a much larger group of patients with R.A. on the
basis of the demonstration of some form of antinuclear serologic activity as
defined below. Their clinical records were analyzed in detail, four postmortem
examinations were re-evaluated, and their sera were studied with a series of
procedures including anion-exchange chromatography in six instances.
The results constitute the body of this report. The data best conformed to
the notion that these patients have rheumatoid arthritis. Within this diagnosis
these patients were distinguishable by the high frequency of rheumatoid
nodules, splenomegaly, leg ulcers, serositis, and high titers of the rheumatoid
factor. The antinuclear activity in these patients was distinguishable to some
extent from that found in a group of patients with unequivocal systemic
lupus. While the reason for the presence of this antinuclear activity remains
unknown, it is suggested that it results from the altered immunologic status
known to exist in patients with R.A.
METHODS
Clinical
In addition to the patients described below, sera from six patients with active S.L.E. were
studied. All were women between 22 and 43 years of age. All had had nondefoming
arthritis, fever of unknown origin, serositis, skin involvement and positive L.E. cell preparations. Four had renal disense, including two with the nephrotic syndrome. The diagnosis
was substantiated in two cases by postmortem examination.
.4ntinuclear Activity
( 1 ) L.E. ceZE preparation. The direct method of Hargraves was used without an anticoagulant, the fibrin being whipped out with a swab stick.8 The indirect method of Davis
and Eisensteing was used on sera. The smears were examined by US.
(2) DNA-RBC. Desoxyribonucleic acid ( D N A ) obtained from salmon sperm (Nutritional
Biochemical Corp., Cleveland, Ohio) was dissolved in phosphate buffered saline (pH
8.0) (PBS) to make a 0.1 per cent solution. Sheep whole blood was drawn into Alsever’s
solution and stored for periods up to 10 days at 4 C. When needed, the red cells were
washed 3 times in PBS and exposed for 10 minutes at 37 C . to a 1:60,000 solution of
tannic acid in PBS.10 They were rewashed 3 times in PBS and suspended at poncentration
of 25 per cent in fresh PBS. One volume of this suspension wa5 added to 2 volumes of the
0.1 per cent DNA solution and the mixture incubated for 30 minutes at 37 C. The cells
were washed once with PBS and resuspended at 0.20 per cent.
All sera were heat inactivated ( 3 0 min., 56 C . ) and absorbed with washed, packed sheep
red cells overnight at 4 C. Serial dilutions of the serum or serum fraction to be tested were
made up with a final volume of 0.5 ml. in each tube with 1 per cent normal rabbit serum
>
722
WILLKENS AND DECKER
Table 1.-Phosphate
Chamber
Number
Buger Volumes in Mixing Chambers
_____
Volume (ml.)
p H 8.0, 0.1M
p H 4.6, 0.3M
75
75
0
0
15
60
75
15
75
30
75
0
0
60
0
45
0
75
in PBS. An equal volume of the sensitized cell suspension was added to each tube. Thc
tests were kept overnight at 4 C., and resd without shaking. Appropriate controls including
tanned cells only, DNA sensitized cells only, and the full system with known negative and
known positive sera were run. The method is similar to those described by others.llJ2
(3) AT-RBC. A 1M sodium chloride solution of nncleoprotein, extracted from frozen calf
thymus by the method of Chargaff13 was diluted 1:20 with PBS. With vigorous shaking
and mechanical disruption, a faintly cloudy suspension resulted. This was incubated for
30 minutes at 37 C. with half the volnine of a 25 per cent suspension of tanned sheep
cells in PBS. The cells were then washed ancl handled as described in (2) above.
( 4 ) NP-Lx. This was performed as prescribed by the manufacturer (Hyland Laboratories, Los Angeles ) .
(5) ANFZ. Antinuclear fluorescence was demonstrated using normal humin white blood
cells. Capi!lary blood smears were de-Hemoglobinized by exposure to 0.1NHCl and washed
with saline 3 times. Serum was then layered on the slide which was incubated for 20 minutes
at 37 C. The slides were again thrice washed, layered with a 1:5 dilution of horse antihuman gamma globulin conjugated with fluorescein isothiocyanate ( Sylvana Corporation,
Orange, N. J . ) , and incubated for 20 minutes at 37 C. The slides were thoroughly washed,
mounted in 25 per cent glycerine, and examined using a Leitz microscope, an Osram HBO
200 mercury vapor arc light source, and BG12 barrier (Corning) and 5840 objective
( Leitz) filters. Slides were studied withont knowledge of the clinical pictures by two
observers; known negative and positive controls were prepared and examined in each
series of tests.
Rhseunicitoid Factor
The Singer-Plotz latex test (F-I1 LP) was nwd throughout.14
Chromatography
Anion-exchange cellulose column chromatography was carried out on diethylaminoethyl
cellulose. Three Gm.of absorbent were packed to a height of 25 cni. in a tube of 1.1 cm.
internal diameter. Heat inactivated, sheep red cell absorbed serum in 3 ml. amounts was
chromatographed. A phosphate buffer gradient elution system was produced with a ninechambered mixing device.15 A total volume of 675 ml. of phosphate buffers was divided
into individual chamber volumes as shown in table 1. The runs were carried out at 4 C.
and required about 24 hours.
A total of approximateIy 150 tubes was collected and combined into five large fractions
as diagrammed in figure 1. Our previous experience and the work of others16 has shown
that proteins coming off the column early contain primarily 7 s gamma globulins and
723
R.A. AND EVIDENCE OF S.L.E.
TUBE
NUMBERS
Fig. 1.-Schematic diagram of serum partition obtained by anion-exchange
chromatography on diethylaminoethyl cellulose. The fraction cutoff points were
selected individually after inspection of each diagram.
wbsequently albumin. The gamma globulins were in fraction I and the albumins in I1 and
111. Following the albumin, a variety of proteins were eluted including 19s gamma globulins contained largely in fraction V. The fractions were concentrated by negative pressure
dialysis using heavy cellophane membranes to a final volume ranging from 2 to 4 ml. The
concentrated fractions were dialyzed against PBS overnight at 4 C. prior to testing for
antinuclear activity.
Recoveries, evaluated on the basis of the total optical densities absorbed and eluted,
were in the area of 60-70 per cent. Protein determinations by a biuret method on the
concentrated fractions showed values in the range of 0.9 Gm. per rent for fractions I and
11, 0.6 Gm. per cent for fractions 111 and IV, and 0.2 Gm. per cent for fraction V.
RESULTS
The 14 patients studied are described in tabular form in table 2 with summary data at the bottom. The group consisted of 11 females and 3 males.
The average age of onset was 39 years and the mean duration was 15 years.
Our experience with them ranged from 1% months to 5 years, and averaged
2.4 years.
In the majority the illness was first manifested as a symmetrical small joint
disease, although in two the first sign was leg ulcer and in another it was
pericarditis. Applying the Steinbrocker criteria the entire group was found
to be Stage I11 or IV. With a single exception, all exhibited both small diid large
joint involvement with erosive x-ray changes. Notwithstanding thesr changes,
w.
F 11
.__.
F 79
F 70
F 45
F 59
M 67
F 60
F 54
F 35
F 60
F 55
F 56
F 67
M 47
M 41
56
15
9
25
20
20
10
15
6
15
15
8
18
15
10
40
-.
Ihration
(years)
___
...
.-
In-IV
2.8
IV 4
111 2
111 4
IV 4
IV 3
IV 4
IV 4
111 2
I11 2
111 2
1112
Iv2
111 2
111 2
Stage/Class
-
-.
-
11
+
0
0
+
-t
-1-
+
+
+
0
+
+
+
+
-
.
.-
..
7
-
-
6
6.5
~--.
4.0
8.8
2.6
1.6
5.0
1.9
5.2
0
-
6
-
-.
8
0
0
0
0
0
0
T
+
+
+
+
+
+
+
.
-.
-
4
~.
0
0
0
0
0
0
+
-
- Tbc..
0
0
0
0
-.
+
-i
+
__
.
..
Ulcer
1.W
....
-.
.____
0
0
0
.t
f
0
0
-
0
0
i'
+
Serositis
-
5.8
lcukopenic
_ _ _ ~-
0
0
0
0
+
+
+
+
0
0
i
t
0
-1-
-
WBC
.
Features
Clinkal Manifestations
- (r1000) -.
7.6
1.5
1.5
9.4
3.7
-SPlc?llOrncxaly
__
-
Nodules
-.
-
Table P.-CZinicaZ
- = Adequate data unobtainable.
'The serositis noted was detected only at postmortem examination.
Summary
A. W.
K. D.
M. G.
E. T.
C. B.
I. H.
P. M.
€3.
P. A.
R. F.
Y.G.
M.H.
H. K.
Y. R.
Ser/Age
._
..
~
7
0
.t0
0
+
+
0
+
+
0
+
+
0
0
-
~
.
-
-.
Albuminuria
-.
.
-
10
+
0
+
+
'1 .
0
+
.+
1-
+
0
+
+
Steroid
6
+
0
0
-
+
0
0
0
+
0
i
+
+
Gold
-
Therapy
-.
-__
-
-
4
0
0
0
0
+
0
0
+
0
+
0
0
0
+
Death
_-
_ -
U
7.
r
v)
b5:
$
E
R.A. AKD EVIDENCE OF S.L.E.
725
Fig. 2.-The opening of a fistulous tract overlying the right elbow of Y. G.
The tract led to a rheumatoid nodule of long standing. At the time of photography,
5-10 ml. of purulent material had been draining daily for 3 months.
over half were well enough to be in Functional Class 2, only five patients
being severely incapacitated.
Eleven patients had subcutaneous nodules. In addition to the usual olecranon site, several of them had tiny seed-like nodules over metacarpal-phalangeal joints. Three patients (P. A., Y. G., and Y. R . ) showed nodular breakdown, infection and drainage from sites overlying the olecranon, a state described as fistulous rheumatismli (fig. 2 ) . Splenomegaly, apparent in seven
patients, was only minimal to moderate in degree but was associated with
leukopenia in five. In one patient the duration of splenomegaly was known
to exceed 5 years.
Most of the leukopenic group showed neutropenia with the polymorphonuclear proportion ranging from 10 to 50 per cent. Serositis was noted historically or on examination during life in four patients. In three the pleura and
the pericardium were involved and in the other peritonitis was demonstrated
at laparotomy. Clinically there was no evidence of peripheral neuropathy nor
pulmonary fibrosis.
The leg ulcers, noted in eight patients, initially appeared as hemorrhagic
papules or bullae 2 mm. in diameter. With gradual enlargement, the center
became white and was surrounded by an erythematous halo; the appearance
was that of an infarcted central area (fig. 3). The entire lesion then became
WILLKENS AKD DECKER
Fig. %-Early phase of recurrent ulceration of right ankle (P. A.). Previous lesion
shows as atrophic scar at lower border of photograph. In the recent past the area
had showii desquamatioii h i t was clcar of the multiple, circular darkened areas.
necrotic and, with removal of the slough, a shallow ulcer crater was apparent.
Sucli ulcers often gradually enlarged and coalesced with neighboring lesions
to form ii still larger crater (fig. 4 ) . By the time they were 5 to 10 cm. in
diameter, they were generally infected with a variety of organisms. Although
these ulcers, when seen late, were similar to those associated with venous
R.A. AND EVIDENCE OF S.L.E.
727
Fig. 4.-Same area as in figure 3, 2 weeks later. The darkened areas have
sloughed leaving multiple, coalescent ulcers.
stasis in that they were found over the malleoli and anterior tibia (fig. 5) and
recurred readily, the patients failed to demonstrate evidence of peripheral
venous disease. In all instances the ulcers were greater than 2 cm. in diameter
and their duration exceeded 3 months.
Tuberculosis was present in four patients. Two patients were receiving
steroids at the time the infection was demonstrated; one never received
728
WILLKENS AND DECKER
Fig. 5.-Chronic, 6 cm. skin ulcer (R.Fa), Bone and muscle were exposed but
no osteomyelitis was detected. Progressive healing was observed on anticoagulant
therapy.
steroids. In three the infection was primarily pulmonary while in one of
the steroid treated patients the organisms were found in a cervical node
biopsy when the patient was being evaluated for fever of unknown origin.
Seven patients showed proteinuria but in none was it persistent or profound. In five a combination of chronic renal infection and nephrosclerosis
provided adequate explanation. In two patients the albuminuria was not
clearly explained, although in one of these the protein was related to congestive heart failure.
Four of the patients died and the postmortem findings are summarized in
table 3. Special sections of the kidneys were made and these, in addition to
myocardial, lymph node, and splenic sections, were studied in detail. No
findings compatible with a histologic diagnosis systemic lupus were demonstrated.
The reactivity of the sera for rheumatoid factor and antinuclear activity
is shown in table 4. Only three patients had rheumatoid factor titers below
1:5120. All but one (M. H.) had definite hypergammaglobulinemia. None had
729
R.A. AND EVIDENCE OF S.L.E.
Table 3.-Postmortem
-
-___
Cause of Death
R. F.
H. K.
B. W.
M. G .
Rupture of great
vein of Galen while
on anticoagulant
therapy for chronic
leg ulcer: prothrombin time 22% 7 days
before death.
Old and recent myocardial infarctions
with congestive
heart failure.
Gram positive
eoccal septicemia
originated from
chronic leg deer.
Rheumatoid arteritis with pseudomonas septicemia
origi~ted
from
extensive decubital
ulcers.
Findings
. _ _
Myocardium
__-___
Serous Surfaces
Round cell
infiltrates.
Obliterated perieardium; minimal
pleural adhesions.
Spleen
Kidney
-.______
Nephmmicroscopic
sclerosis
normal
Round cell
infiltrates
with rheumatoid nodule
at base of
mitral valve.
Normal.
Chronic, active
pencarditis with
200 ml. fibrinous
fluid; obliterated
pleura.
180 Gm.,
microscopic
normal
Nephrosclerosis
Minimal pericardial adhesions:
obliterated pleura.
250 Gm..
microscopic
normal
NephTsclerosis
Round cell
infiltrates.
Chronic, active
perkarditis: obliterated right
pleura; flbrous
peritonitis.
330 Gm..
acute arteritia with
evidence of
sepsis.
Acute
arteritis.
pyelonephritis, and
nephrosclerosis.
425 Gm..
Table- 4.--Serum
Proteins and
Reactivity.__
______
-___
..___.
Serum Proteins
Antinuclear Activity
(Gm.%)
F-I1 LP
Titer
P. A.
R. F.
Y. G.
M. H.t
H. K .
Y. R.
B. W.?
A. W.t
K. D.
M. G.t
E. T.
C. B.7
I. H.
P. M.7
40,960
10,240
20,480
40,960
20,480
6.120
40.960
10,240
20.480
10,240
2,560
10,240
640
2,660
L.E. Prep
DNA-RBC NP-RBC
Gamma -___Total globulin* Direct Indirect
titer
titer
7.1
6.7
6.4
5.8
6.6
7.7
7.2
8.7
6.4
6.0
8.8
6.1
7.0
:
1.7
3.6
1.9
1.8
$
NP-Lx
ANFl
-
1.9
2.0
1.7
0.6
l.?
1.6
2.0
2.0
1.3
-
224
-
3684
-
-
448
3684
896
448
-
++
t-
3584
896
224
896
3684
448
4-
224
448
-
-
-
*Determined by paper eleetrophoreais and densitometric proportionality.
?These sera were subjected to anion-exchange chromatography.
$Not done.
reactivity on the venereal disease research laboratory test and cryoproteins
were not demonstrable in their sera.
The tests for antinuclear activity showed a wide variety of results. The
L.E. prep, positive in eight patients, was generally weakly positive even when
special methods to enhance sensitivity were used. In only one patient (C. B. )
was the number of cells large and their demonstration easy. In four cases,
only one of the six procedures was positive; this was true of DNA-RBC ( B. W. ) ,
NP-Lx (P. A. and K. D. ), and ANFl (Y.G.) . In three cases (M. G., C. B., and.
P. M.)five or six of the procedures were positive. Analysis of the clinical and
laboratory data pertaining to these individuals was searched for other dis-
730
WILLKEKS AND DECKER
Table 5.--Chromatographic Fraction Activity of Six Dual
and Six S.L.E. Sera __.-__
~ _ _ _ _ _ _ ~ - --
~~
Number of Dual Sera
Positive by
Number of S.L.E.Sera
Positive by
-
DNA-RHC
F-I1 LP
DNA-RBC
F-I1 LP
I
I1
111
2
1
6
0
2
4
0
4
IV
4
6
6
6
6
6
0
0
0
6
6
0
Fraction
V
_______
tinguishing features. At the time blood was obtained they all had active infections, M. G. had active rheumatoid arteritis and pseudomonas septicemia
unresponsive to antibiotics. C. B. and P. M.had active pulmonary tuberculosis
complicated in the former by laryngeal disease. However, in two further patients (H. K. and I. H . ) with active tuberculosis at the time of sampling, only
an intermediate number of positive tests for antinuclear activity were found.
Six serum samples were selected for chromatography because of the presence
of DNA-RBC agglutinating activity in the whole sera (see table 4 ) . They also
contained large amounts of rheumatoid factor and are therefore referred to
as “dual.”The resulting chromatograms and effluent tests for DNA-RBC and
F-11-LP agglutinating activity were compared to concurrent, identical experiments on six Sera from patients with active S.L.E. (table 5 ) . The whole
sera from these lupus patients was similarly reactive in the DNA-RBC test,
but did not contain rheumatoid factor.
Antinuclear reactivity was more consistently found in the post-albumin
peaks (IV and V ) of the dual sera whereas it was found in both the pre(11) and post-albumin peaks from the lupus sera. In those instances in which
pre-albumin antinuclear reactivity was demonstrated in dual sera, it was from
the patients with the greatest number of antinuclear factors. The absence of
rheumatoid factor from the L.E. sera fractions is another distinguishing
feature.
The chromatographic fractions from four of the “dual” sera and four of the
S.L.E.
sera were checked for ANFl activity. These limited results show clearly
that the ANFl and DNA-RBC activity are eluted in different fractions. In the
S.L.E. sera fraction I always showed ANFl activity, while in the “dual” sera
it was found only once.
The serum of A. W., a “dual” factor patient, was studied before and after
absorption with large amounts of aggregated gamma globulin by the method
of Christian.l*The treatment resulted in complete loss of rheumatoid factor
and a one tube drop in DNA-RBC activity in the whole serum. On chromatography after absorption, the rheumatoid factor disappeared from fractions
111, IV and V. DNA-RBC activity, originally present in fractions 111, IV and
V, persisted only in fraction 111.
DISC;USSION
Prior to the availability of the L.E. cell preparation there would have been
little question of a cliagnosis of R. A. in these patients. The finding of a
R.A. AND EVIDENCE OF S.L.E.
731
destructive, deforming polyarthritis developed over a period of 15 to 20
years associated with the presence of rheumatoid nodules would have been
irrefutable evidence in support of this conclusion. In recent years an additional
bit of evidence has become available; high titers of the rheumatoid factor,
in contrast to lower titers, have been reported in only a few conditions other
than rheumatoid arthriti~.l~-~2
The question at hand is whether the demonstration of a positive L.E. cell preparation or antinuclear activity should properly
alter this interpretation.
While these patients demonstrate findings compatible with a diagnosis of
rheumatoid arthritis, they also manifest features which serve to distinguish
them from the routine case of R. A. Splenomegaly and neutropenia, unusual
features of rheumatoid disease, were present in more than half of this group.
Serositis, seen in five patients, has recently been noted more frequently as a
complication of the rheumatoid disease p r o ~ e s s , 2 3but
~ ~ ~its occurrence must
still be considered unusual. The high titer of rheumatoid factor is also of note
when it is recalled that the patients were selected on the basis of antinuclear
activity. The high frequency of rheumatoid nodules present in more than
three-fourths was also noted in Friedman’s study of L.E. cell forming rheumatoids.26:
While all of the above features have been mentioned by others as aspects
of the “overlap syndrome,”* less has been said of the chronic leg ulcers so
common in our series. Study of the development and course of these indolent
lesions led to the conclusion that an arterial process was involved, that tissue
infarction caused necrosis, and that tissue ischemia coupled with chronic infection resulted in further enlargement of the ulcer crater. Biopsies showed
findings of inflammation and repair with other changes interpreted as due
to secondary infection. Indeed the presence of infection and chronic tissue
breakdown at the site of these ulcers suggested consideration of the antigenic
potential of this natural adjuvant-DNA mixture as discussed by Benjamin and
Hueston.26In any case, the presence of these relatively circumscribed lesions
distinguishes these patients from others with rheumatoid arthritis and their
nature distinguishes them from the digital and cutaneous gangrene reported in
malignant rheumatoid arthritis?‘
Three major features may be cited as evidence favoring a diagnosis of
S.L.E.-the antinuclear activity of the sera, the serositis, and the chronic
is also seen in R. A. where it
leg ulcers. The serositis, a hallmark of S.L.E.,
tends to be more chronic, less often associated with fever, and more benign
as in our cases.28Classical descriptions of S.L.E. do not include chronic leg
ulcers; the concept that they are a manifestation of that disease has developed
~ - ~majority
~
of the
since Hargrave’s first demonstration of the L.E. ~ e 1 1 . 2The
reports deal with chronically deformed, long-standing rheumatoid arthritics
often with splenomegaly and leukopenia-in other words, .the same type
of problem under consideration here. The previous diaebses have been based
primarily upon the demonstration of antinudear activity, a demonstratiboh
which is confirmed here.
All of our patients did exhibit some form of antinuclear activity during a
part of their course. Of the tests employed, no one method was consistently
732
WILLKENS AND DECKER
positive but, in our hands, the ANF1, the direct L.E.prep, and the DNARBC procedures appeared to detect the presence of antinuclear activity more
frequently than did the other methods. Nevertheless, in two cases (P. A. and
K. D., table 4 ) the only positive procedure was the NP-Lx, a method which
has been described as relatively insen~itive.~~
The concept of “sensitivity”
is probably illusory in connection with antinuclear factors. Following Robb i n ~ , 3and
~ consistent with our own findings and those of other^?^.^^ it is apparent that one is not dealing with variable amounts of a single factor, but
rather with a multiplicity of factors each with its own specificity and each
with its own independent quantitative variation. The patients (M. G., C. B.,
and P. M.) whose sera showed reactivity in most of the tests have developed
multiple factors and, in this respect but in this respect only, more nearly
parallel our findings in classic S.L.E.38The majority of our patients showed
positivity in only one, two or three of the series of antinuclear activity tests.
The chromatographic studies on the “dual factor” patients brought out
further contrasts. DNA-RBC activity tended to be absent from the earlier
fractions (7s globulins and albumin) in the dual patients while present in
the S.L.E. group. ANFl activity tended to be absent from fraction I (small
globulins) of the “dual sera,” but present in the S.L.E.
sera, a finding in
agreement with a recent report of Baum and Ziff.*g Taken together these
two findings suggest that antinuclear activity in this type of patient is less
likely to be found among the smaller molecular early fractions and more
likely to be found late in the elution pattern where larger globulins are
being removed while true S.L.E. sera tend to show activity throughout the
spectrum. In this regard, however, it is to be recalled that absorption of a
dual serum (A. W.) with aggregated globulin removed the 19s rheumatoid
factor but failed to eliminate the DNA-RBC agglutinating activity, thus
confirming the findings of others that the two types of activity are not present
in one and the same molecule.40*41
Clinically our patients distinguished themselves from those with S.L.E.
in a variety of ways-no skin rash nor alopecia, no oral ulcers nor stomatitis,
no unusual degree of reactivity to medications, no bleeding diatheses nor
purpura, no episodes of hemolytic anemia, no cytoid bodies nor sun sensitivity, no psychoses and no false positive serologic tests for syphilis. The absence of such findings, however, can hardly be considered conclusive in
view of their relative infrequency in S.L.E. The well recognized diffic~lty4~
of making an unequivocal diagnosis of S.L.E. on a histopathologic basis at
postmortem examination precludes a flat statement that this disease was not
present in our four autopsied cases. Nevertheless the complete absence of
hematoxylin bodies, “onion skin” changes of the splenic arterioles, and
glomerulitis is noteworthy.
Renal disease occupies an important place in the distinction since it is common and a frequent cause of death in S.L.E.43whereas it is essentially never
seen in rheumatoid arthritis,44excepting such conditions as amyloidosis and
chronic pyelonephritis. The appearance of signs of glomerulitis and particularly red blood cell casts in a patient considered to have R. A. would, indeed,
be grounds for questioning the diagnosis. None of our 14 patients, in life or
at postmortem, showed such a lesion.
733
R.A. AND EVJDENCE OF S.L.E.
In short, we conclude that these patients have rheumatoid arthritis of a
severe nature and that, for reasons unknown, such patients are likely to
develop circulating factors with antinuclear activity, factors which are generally recognized to be without pathogenetic significance. It seems to us foolish
to use the presence or absence of such factors as of diagnostic significance in
the clinical syndrome described.
The results of recent family studies have suggested that individuals with
R. A. are members of families manifesting a state of unusual immunologic
rea~tivity.4~
It might be suggested that, as the duration of active disease, the
age of the patient, and the degree of involvement advance, serologic antinuclear reactivity, usually of only one or a few types, develops presumably in
response to “antigenic stimuli” which are sommon to the normal population.
The supervention of chronic infection may be considered to increase the
variety or antigenicity of such stimuli, a notion which has been suggested
recently in studies of the rheumatoid fa~tor.4~9~7
On this hypothesis, thew
patients would be considered to show both “disturbed antibody” and “distiirbed antigen.”48
CONCLUSIONS
1. Fourteen patients with long-standing rheumatoid arthritis characterized
by severe articular deformities, subcutaneous nodules, and visceral manifestations are described. Eight had chronic ulcerative skin lesions of the lower
extremity.
2. Despite the presence of a variety of antinuclear factors in their sera, they
were not considered to have systemic lupus erythematosus.
3. Serum protein chromatography suggested that the antinuclear factors in
rheumatoid arthritis were more frequently composed of larger protein molecules than in systemic lupus erythematosus.
4. The antinuclear factors are considered to be a manifestation of rheumatoid
arthritis and clinical evidence suggested that chronic infection may have
played a role in their development.
ACKNOWLEDGMENT
The authors acknowledge with thanks the hclp and advice given by Dr Rohert Carp-nter
with regard to the fluorescent technics. Also acknowedged is the help in the performance
of laboratory tests by Maiireen O’Connor, Turid Eykeland, Joyce Luethy, and Julie Pink
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Robert F . Willkens, M.D,, Clinical Assistant Professor
Medicine, University of Washington, Seattle, Wash.
of
John L. Decker, M.D., Associate Professor of Medicine and
Head, Di&on
of Arthritis, Unioersity of Washington,
Seattle, Wash.
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