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Rheumatoid factors in patients with silicosis with round nodular fibrosis of the lung in the absence of rheumatoid arthritis. With a note on the failure to induce such factors in animals

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Rheumatoid Factors in Patients with Silicosis with Round
Nodular Fibrosis of the Lung in the Absence
of Rheumatoid Arthritis
With a Note on the Failure to Induce Such Factors in Animals
By WALTERSCHROEDER,
EDWARD
C. FRANKLIN
AND CURRIER
MCEWEN
Sera of 10 patients with silicosis and
round nodular fibrosis of the lung in
the absence of rheumatoid arthritis had
positive rheumatoid factor tests. The
proteins responsible for this were identical or at least closely related to those
seen in patients with rheumatoid arthritis. It was not possible to induce “rheumatoid factor-like’’ proteins in rats and
guinea pigs by prolonged injections of
silica. The possible significance of these
proteins in the pathogenesis of the disease is discussed,
Le sero de 10 patientes con silicosis e
fibrosis a nodulos ronde del pulmon in
le absentia de arthritis rheumatoide
habeva positive tests pro factor rheumatoide. Le proteinas responsabile pro isto
esseva identic o a1 minus intimemente
relationate con illos vidite in patientes
con arthritis rheumatoide. I1 non esseva
possibile inducer proteinas de “typo
factor rheumatoide” in rattos e porcos
de India per prolongate injectiones de
silice. Es discutite le signification possibile de iste proteinas in le pathogenese
del morbo.
P
ULMONARY LESIONS have been described in patients with rheumatoid
arthritis (R.A.) and have on occasion been the first and even the sole
manifestation of rheumatoid disease.1-3Serologic studies of a group of such
patients with diffuse interstitial pulmonary fibrosis in the absence cf rheum3toid arthritis have revealed the presence of rheumatoid factor in about 50
per cent.5
In 1953 Caplan described the presence of diffuse round nodular fibrosis of
the lung, generally consisting of multiple well defined round opacities 0.55.0 cm. in diameter, in coal miners with R.A.6 Subsequent studies have
demonstrated conclusively that this association is not fortuitous and have
suggested that this form of silicosis is related to the rheumatoid process.7l4
The frequency of Caplan’s syndrome and of R.A. in coal miners is shown in
table 1. Similar pulmonary lesions have been noted also in coal miners in
the absence of arthritis,8 or have preceded the onset of arthritis by several
years. The relationship of these typical pulmonary infiltrates to rheumatoid
disease has been further documented by Miehlke, Dickmans and Fritze15 who
found positive tests for rheumatoid factor in approximately 50 per cent of
miners with the typical pulmonary lesions but without evidence of arthritis,
compared to an incidence of less than 10 per cent in the control population and
Frmn the Department of Medicine and the Rheumatic Ciseases Study Group, New York
University College of Medicine, New York, N . Y.
Supported by Grants #A-2594, A-5064jC3) und A-1 431 ( C 3 ) from the National Institute
of Arthritis and Metabolic Diseases, U . S. Pubiic Health Seruice, and by The Arthritis
and Rheumatism Foundation.
10
ARTHRITIS kr RHEUMATISM,VOL.5, No. 1 (FEBRUARY),1962
11
RHEUMATOID FACTORS IN PATIENTS WITH SILICOSIS
Table 1.-Incidence of Rheumatoid Arthritis in Coal Miners
Author
Caplan (1952)
Miall (1955)
Fritze-Dickmans
(1959)
Number of
coal-miners
Number of cases
with R.A.
Number of cases
with silicosis
and R.A.
Number of cases
with Caplan’s
syndrome
14000
6513
51 (0.4% )
54 (0.7%)
51
54
13 (2570)
19 (35%)
7323
26 ( 0.37 701
26
8 (30%)
in subjects with uncomplicated silicosis. In order to delineate more clearly
the relationship of “rheumatoid factors” seen in these subjects to those cncountered in patients with rheumatoid arthritis and to evaluate their possible
role in the pathogenesis of the disease, detailed physicochemical studies havc
been performed Qn the sera of 10 such selected patients with the typical
pulmonary lesions in the absence of arthritis, some of whom have been included previously by Miehlke et a1.I: These studies, reported in the first part
of. this paper, demonstrate a close similarity between these factors and those
seen in patients with rheumatoid arthritis.
Because of the well known ability of quartz to interact with a number of
proteinsl’j and to induce the formation of several agglutinating substances,li
experiments were designed to study the possible role of quartz in eliciting
the appearance of proteins with the properties of rheumatoid factor. In these
studies, attempts have been made to induce the appearance of such suhstances in rats and guinea pigs by the injection of quartz-either
alone or
with a protein antigen. However, neither antibodies to homologous or heterologous gamma-globulins ncr evidence of delayed hypersensitivity to these
proteins was obtained in these animals, some of which were injected with
quartz for periods as long as 10 months. The results of these studies are
briefly discussed in the second part of this report.
Part I-Clinical and Serologic Studies of 10 Subjects with
Silicosis with Round Nodular Pulmonary Infiltrates
in the Absence of Rheumatoid Arthritis
MATERIALS
AND PV~ETHODS
A. Sera Sera* were obtained from 10 coal miners with round pulmonary foci, but without evidence of arthritis, selected from a larger group of patients. Their exposure to dust
ranged from 12 to 33 years, and their ages from 48 to 63 years. In all subjects, specimens
of sputum, gastric lavage and laryngeal washings were examined on several occasions for
tubercle bacilli, but with negative results.
B. Serologic Tests: The sera were inactivated at 56 C. for 30 minutes and absorbed repeatedly with packed sheep cells for 60 minutes at 37 C. until they no longer agglutinated
unsensitized sheep cells. Englobulin fractions were obtained by dialysis, as described by
Ziff and co-workers.18
The agglutination of sensitized sheep cells by tht‘ euglobulin fraction (SCA), and the
*The sera used in this study were kindly provided by Dr. H. Dicknians, Med. Klinik,
Bergmannsheil, Bochum, Germany.
12
SCHROEDER, FRANKLIN AND MC EWEN
inhibition by the euglobulin of agglutination of a positive rheumatoid serum, were carried out according to the method of Ziff and co-workers.l*
The latex fixation test was performed following the method of Singer and Plotzlg and
the capillary latex test as described by Tanner and Ziff.20 Gamma globulin was determined
by using the modification of the zinc turbidity test21 and by paper electrophoresis.
C. Ultracentrifugation: Analytical examination of sera containing the highest titers by
each of the serologic tests was carried out in a Spinco Model E ultracentrifuge using cells
with double sector centerpieces.22 Preparative density gradient ultracentrifugation was
performed in a Spinco Model L ultracentrifuge in a SW-39 swinging bucket rotor through
a NaCl gradient formed with 21, 14 and 7 per cent saline. The amount of protein in each of
the fractions was estimated by the modified Folin technic23 and 7 s and 19s gamma globulins
were located with specific antisera to 7s and 19s gamma globulin. The determination of
agglutinating activity of the fractions was carried out using the sensitized sheep cell agglutination reaction and the latex fixation test18219 after removal of salt by dialysis.
RESULTS
In table 2 are listed the results of the serologic tests obtained with the sera
from these 10 subjects. Each of them had far advanced round nodular fibrosis
of the lung (silicosis stage HI), and none had any clinical evidence of arthritis, other collagen disease or liver disease which might conceivably account
for these findings.
All 10 sera were positive with the sheep cell inhibition test, and eight were
positive by the SCA test. Similarly, when human gamma globulin was used
in the latex fixation or capillary latex test, eight of 10 sera were positive.
Five of the 10 subjects had elevated levels of gamma globulin.
Examination of four of the sera with the highest titers (Gl, Me, Ni, Ho) in
the analvtical ultracentrifuge revealed a small amount of a peak sedimenting
ahead of the 19s peak in only one. None of the other three contained detectable amounts of a 22s peak or peaks with s rates intermediate between 7s
and 19s. This low incidence of detectable 22s material is probably due to tlle
lack of sensitivity of the ultracentrifuge as an analytical tool since previous
studies have shown that it generally can detect these peaks only in high titer
sera.22In order to study further the physicocochemical properties of the agTable B.-Serologic
Name
HO
GR
SCHO
WA
DI
NI
ME
GL
SCHI
BE
Normal
Sheep cell
agglutination
reaction
reciprocal
titer
112
28
14
56
112
224
224
224
14
28
<14
Findings in Ten Selected Coal Miners with Round
Nodular Pulmonary Infiltrates
Sheep cell
inhibition
reciprocal
titer
Capillary latex
fixation test
0
0
0
0
0
0
0
0
0
0
>7
+
negative
negative
negative
Latex
fixation test
reciprocal
titer
Zinc
turbidity
640
320
20
20
80
2560
1280
2560
20
20
21
30
27
20
10
9
22
16
11
20
<20
________
(U)
13
RHEUMATOID FACTORS I N PATIENTS WITH SILICOSIS
Table 3.-Fractionation
Tube
TOP
10
9
8
Anti 7 S
gammaglobulin
-
+
++
+++
+++
+++
++
7
6
5
4
Bottom
3
2
1
of 3 Sera from Patients with Advanced Silicosis
Anti 19 S
gammaglobulin
-
+
+++
+++
++f
3=
i
&
-+
SCA
0
0
0
0
0
0
0
0
0
7
GL
Latex
0
0
0
0
0
0
10
20
10
0
SCA
NI
Latex
SCA
ME
Latex
0
0
0
0
0
0
0
0
0
0
7
0
0
0
0
0
0
0
20
20
0
0
0
0
0
0
0
0
0
28
14
14
7
0
0
20
20
10
7
0
glutinating factors, five of the sera were separated into fractions with different sedimentation properties by centrifugation in a saline density gradient.
The location of the different fractions was determined with specific antisera
to albumin, 7s gamma globulin and 19s gamma globulin. After dialysis to
remove the excess salt, each of the fractions was tested by the SCA and latex
fixation test. In each of the sera examined, serologic activity by both tests was
found in the more rapidly sedimenting fractions containing the 19s gamma
globulin, and none of the activity remained in the upper part of the tube
which contained, however, the bulk of the protein. The results obtained with
three of the sera are shown in table 3. Since it is well recognized that this
group of proteins is readily dissociated into 7s units which are no longer
serologically active by treatment with sulfhydryl r e a g e n t ~ , 2 ~each
J ~ of the
sera was treated with 0.1 M 2 mercaptoethanol and then tested by the serologic tests. In each of the sera there was complete loss of serologic activitv
following reductive cleavage, thus adding further evidence that these pr -teins belonged to the 19s class of gamma globulins and were similar in all
respects to rheumatoid factors in patients with rheumatoid arthritis.
Part II-Experimental Studies
To determine the possible relationship between silicosis and the presence
of rheumatoid factor, experiments were performed in rats and guinea pigs
in an effort to induce similar factors experimentally by the administration of
quartz particles. Previously, many investigatorsz6-36have studied the effects
in animals of the injection of quartz and have demonstrated the presence, in
sera of some of these, factors that agglutinate quartz particles, zymozanl7 and
possibly also factors that react specifically with proteins known to coat quartz
If the injection of quartz would cause the production of rheuparticle~.l6*~"-""
matoid factor-like substances in animals, it would be strong evidence for its
possible role in the production of such substances in man. Negative resuIts,
while not conclusive per se, would favor the concept that rheumatoid factor
may have antedated the silicosis and may simply reflect a predisposition of
the subject to react to certain exogenous stimuli in an unusual way.
14
SCHROEDER, FRANKLIN AND MC EWEN
Table 4.-Course of Injection and Results of Fraction 11 Test and Skin Test
in Guinea Pigs
Number
of
guinea
pigs
Injection
of cristobalite
i.p.
21
50mg.
14
75 mg.
12
40
20
Total: 107
Table 5.-Course
Number
of rats
27
10
7
Injection
Injection of tridymite
of NaCl
i.v. after
i.p.
27 wks.
10 my.
10 mg.
1.0 cc.
1.0 c c .
negative
negative
neaatioe
1.0 cc.
of
Skin test for delayed
hypersensitivity
after
8,16,38
after
weeks
7 % weeks
Fraction I1 Test
( Heller et al. )
after
6,13,27,38
after
weeks
R weeks
40 ma.
negative
negative
negative
negative
negative
negative
negative
Injection and Results of Fraction I1 Test and Skin Test in Rats
Injection of
cristobalite
i.p.
i.v.
50mg.
30mg.
Injection
of NaCl
i.v. after
27 wks.
Injection
of 1 mg.
ovalbumin
2 x weekly for
2 months
2nd Injection of
cristobalite
i.p. after
8 weeks
50 mg.
20mg.
16mg.
16 mg.
Skin test for
Injection Fraction I1 test delayed hyperof tridymite (Heller et al.)
sensitivity
i.v. after
after 8,14,
after 5,12,
27 weeks
27.36 weeks
36 weeks
10 mg.
10 mg.
10 mg.
negative
negative
negative
negative
negative
negative
Total: 44
MATERIALS
AND METHODS
Quartz dnst (cristobalite and tridymite, approximate particle size %I0 p ) were suspended in normal saline to make a concentration of 50 mg./ml. and sterilized by autoclaving." One hundred and seven male guinea pigs weighing between 300-400 Gm. and 44
male rats weighing 200-300 Gm. were used and were bled by cardiac puncture before
injection. The course of injection and the results are listed in tables 4 and 5.
Twenty-one guinea pigs were injected intraperitoneally with 50 mg. of Cristobalite and
14 guinea pigs intraperitoneally with 75 mg. of cristobalite. Twelve guinea pigs injected
with 1.0 cc. of normal saline served as controls. After 27 weeks the same animals were
injected intravenously with 10 mg. of Tridymite and the controls with 1.0 cc. of normal
saline. The guinea pigs were bled by cardiac puncture 6, 1.3, 27 and 38 weeks after the
first injection.
Another group of 40 guinea pigs was injected with 40 mg. of tridymite intravenously
and 20 controls with 1.0 ce. of normal saline. Their sera were examined after eight weeks.
Twenty-seven rats were injected twic.e intraperitoneally with 508 mg. cristobalite during
an eight week period. After 27 weeks they received 10 mg. tridymite intravenously. Ten
rats were injected with 30 mg. of cristobalite intraperitoneally as well as 20 mg. cristobalite
intravenously at the same time, followed after 27 weeks with 10 nig. tridymite intravenously.
Seven rats served as controls and received 1.0 cc. of normal saline instead of quartz.
In view of the possible role of quartz as an adjuvant,37 the last group of 10 rats as well
as the control rats were given 1.0 nig. ovalbumin intraperitoneally twice weekly for a
period of two months. The rats were bled by cardiac puncture after 8, 14, 27 and 36 weeks
and their sera tested for ability to react with hoinologous gamma globulin as well as with
heterologous human gamma globulin.
The test with human globulin was performed with latex particles coated with Cohn
Fraction I1 (Squibb), as dericribed by Singer and Plotz.19 Attempts to use guinea pig or
rat gamma globulin in the latex fixation test were not successful since these proteins in the
native state as well as after heat inactivation at 57 C. for 30' agglutinated the parti
"We are indebted to Dr. E. Fritze, Mtd. KIinik, Bergmannsheil, Bochum, Germany, and
Dr. B. Pernis, Clinica dei Lavoro, Milan, Italy, for supplying the Cristobalite and Tridynlitc..
RHEUMATOID FACTORS I N PATIENTS WITH SILICOSIS
15
spontaneously over a p H range from 5.1 to 10.0. For this reason tanned sheep cells coated
with guinea pig or rat gamma globulin were used. These were prepared according to the
method of Heller and co-workers38 and were not agglutinated spontaneously by these
proteins.
In order to determine the development of delayed hypersensitivity to gamma globulin,
all of the animals were tested at three different periods by intradermal injection of 0.1 cc.
of a solution of 50 gamma/nil. of homologous gamma globulin, ovalbumin and normal
saline. The guinea pigs were tested after 8, 16 and 38 weeks and the rats after 5, 12 and
36 weeks. The reaction was noted 8 hours and 24 hours after each injection.
RESULTS
All of these studies were entirely negative. None of the animals developed
any substance capable of agglutinating homologous or heterologous gamma
globulins and none of the animals developed evidence of immediate or delayed hypersensitivity in spite of the presence of silicotic nodules in the lungs,
livers, spleens and peritoneum of many. Since completion of this study, essentially similar results have been published by Voisin and c o - w o r k e r ~ . ~ ~
DISCUSSION
The finding of pc\sitive rheumatoid factor tests in about one-half of 28 miners
with round nodular fibrosis of the lung in the absence of arthritis raises two
major questions: first, whether th'e proteins in these subjects are similar to
those seen in rhumatoid arthritis and, secondly, the possible role they may play
in the pathogenesis of these lesions. It was possible by using a variety of
serologic tests as well as analytic and d,ensity gradient ultracentrifugation to
demonstrate the presence of a high molecular weight protein which seems to
be identical with the rheumatoid factor. A comparison of the results obtained
from the 10 sera of coal miners and the serologic reactions and ultracentrifugal
patterns from definite rheumatoid sera indicates a close relationship between the rheumatoid factors and the proteins present in the serum of coal
miners suffering from round nodular fibrosis of the lung. The positive serologic
findings in cases of full blown Caplan's syndrome are due to the rheumatoid
arthritis. It is unlikely that the inhalation of quartz dust during a long-stsnding
exposure can be responsible for the relatively high incidence of positive serologic tests in cases found with the characteristic Caplan chest x-ray without
arthritis, since the number of positive agglutination tests occur no more frequently in coal miners with the common type of pneumoconiosis than in the
general population.15 Furthermore, it is worthy of note that none cf the laboratory animals with experimental silicosis studied over a period cf nine and onehalf months gave positive reactions after injection of concentrated and highly
active quartz. Many of these animals had gross evidence of silicotic nodules
in the lungs. liver, peritoneum and other organs, and previous studi~es29~32,33*35
have demonstrated the high incidence of silicosis in animals treated with a
similar schedule of injection.
These findings in pati,ents and in the experimental animals therefore offer
strong evidence against the hypothesis that silica in the form employed is responsible for the production of positive rheumatoid factor tests. Nevertheless
it seems possible that prolonged exposure to silica may play an as yet unde-
16
SCHROEDER, FRANKLIN AND MC EWEN
fined role in the d,evelopment of these lesions and circulating factors in view
of its ability to serve as an adjuvant,37to induce the formation of substances
agglutinating zymozan and other particles,li and to alter the antigenic prop, ~ ~ , ~the
~ j , injection
~~
into rabbits and guinea pigs
erties of p r o t e i n s . ’ ~ , z ~ ’While
of denatured autologous and homologous gamma globulins can lead to the
development of circulating antibodie~,~~)
as well as delayed hyper~ensitivity~l
directed against heterologous as well as homologous gamma globulins, silica
in the form and amount used does not appear to exert such an effect. An alternate explanation for the high correlation between rheumatoid factor and the
characteristic pulmonary lesion seen in these coal miners, as well as in subjects
with idiopathic diffuse pulmonary fibrosis, may be that the presence of rheumatoid factor may simply be an index of a predisposition to an abnormal tissue
response of the individual. There is abundant evidence from many observers
that rheumatoid factors are found in a high per cent of asymptomatic relatives
of patients with R.A. and other collagen diseases,42and it seems quite conceivable that this material may therefore be an index of an altered host response,
possibly genetically determined. Studies are currently in progress to determine
the incidence of rheumatoid factors in relatives of patients with Caplan’s syndrome as well as those with the typical pulmonary picture without arthritis
described in this report.
SUMMARY
Sera of 10 selected coal miners suffering from round nodular fibrosis of the
iung in pneumoconiosis without joint disease were chosen for serologic and
ultracentrifug,al studies.
Various serologic tests used for the diagnosis of rheumatoid arthritis gave
positive results in each case.
Bv density gradient ultracentrifugation the presence of a high molecular
weight protein complex was demonstrated. This was confirmed by a complete
loss of serologic activity after dissociation with mercaptoethanol. In one of
the cases with the highest titer which was examined in the analytical ultracentrifuge, it was possible to demonstrate a peak with a sedimentation coefficient of 22s.
The accumulated evidence suggests that the agglutinating property of the
sera examined in the present study is identical or at least closely related to the
rheumatoid factors.
After intravenous and intraperitoneal injection of fine quartz dust in 107
guinea pigs and 44 rats, 110evidence of delayed hypersensitivity or circulating
factors reactive with homologous or heterologous gamma globulin was obtained.
Possible relationships between rheumatoid arthritis and pulmonary abnormalities in coal miners with pneumoconiosis are briefly discussed.
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RHEUMATOID FACTORS I N PATIENTS WITH SILICOSIS
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silicosis, round, note, patients, induced, fibrosis, failure, factors, absence, nodular, animals, lung, arthritis, rheumatoid
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