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Serum anti-immunoglobulins in psoriatic arthritis as compared with rheumatoid arthritis.

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Serum Anti-Immunoglobulins in Psoriatic Arthritis as
Compared with Rheumatoid Arthritis
Francisco J. Tapanes, Arnold J. Rawson and Joseph L. Hollander
With the technical assistance of Mary S. Roth
Serum anti-immunoglobulinsof IgG, IgA and IgM types were measured in
patients with rheumatoid arthritis, patients with psoriatic arthritis, and
normal subjects by absorption on cross-linked IgG, with subsequent
elution. Relatively elevated values of all three types of serum anti-immunoglobulins were found in seropositive rheumatoids, and elevated values of
anti-immunoglobulinsof the IgG type were found in seronegative rheumatoids. Values in patients with psoriatic arthritis fell within the normal range.
Whether or not psoriatic arthritis is a variant
of rheumatoid arthritis has long been a subject
of controversy. The distinction between these
two diseases is made difficult by variation in
clinical presentation. Although most rheumatologists consider psoriatic arthritis a separate
disease entity on the basis of asymmetry, distal
joint involvement, and joint mutilation, others
remain reluctant to accept this distinction because of pathologic and clinical resemblance
between the two. While the sheep cell and latex
agglutination tests are usually negative in psoriatic arthritis they are also negative in about
15% of definite and classic rheumatoid arthritis (RA), and in most cases ofjuvenile RA.
From the Department of Medicine (Arthritis Section)
and the Department of Pathology, University of Pennsylvania, Philadelphia, Pa.
Supported by grants from the Barsumian Memorial
Fund, the Lederle Laboratories, the McCabe Fund, and the
Arthritis Foundation.
FRANCISCO J . TAPANES, MD: Fellow in Rheumatology,
Hospital of the University of Pennsylvania, Philadelphia,
Pa. ARNOLD J. RAWSON, MD, SCD: Professor of Pathology,
School of Medicine, University of Pennsylvania, Philadelphia, Pa. JOSEPH L. HOLLANDER, MD: Professor of Medicine,
School of Medicine, University of Pennsylvania, Philadelphia, Pa.
Reprint requests should be addressed to Dr. Hollander.
Submitted for publication June 29, 1971; accepted October 6, 1971.
Recent studies by Kunkel (l), Winchester
(2), and Hannestad (3,4), have implicated
anti-immunoglobulins of IgG as well as IgM
types as factors in the pathogenesis of RA, and
indeed I& anti-immunoglobulins have been
found in seronegative as well as seropositive
forms of RA, in a concentration well above the
normal range, by Torrigiani and Roitt (5-7)
and by Schur et a1 (8). Anti-immunoglobulins
of IgG type have been measured by exposure of
serum to insoluble cross-linked IgG as immunoadsorbent with subsequent elution of the
specific antibody and quantification by radial
immunodiffusion. Roitt suggested that the
usual agglutination tests are dependent mainly
on IgM rheumatoid factor and may fail to detect IgG or IgA anti-immunoglobulins. T h e
purpose of the present study was to determine
whether IgG, IgA and IgM antiimmunoglobulins are found in the serum of patients
with psoriatic arthritis in the same range as
in RA.
MATERIALS AND METHODS
Source of sera Sera were obtained from 42 patients
with RA, all of whom were seropositive and had been
diagnosed as definite or classic RA. according to ARA
criteria. All of these patients were over 40 years of age. In
Arthritis and Rheumatism, Vol. 15, NO. 2 (March-April 1972)
153
TAPANES ET AL
addition, sera were obtained from 3 seronegative adult patients with definite or classic RA and from 2 seronegative
patients with juvenile rheumatoid arthritis (JRA).
There were also sera from 32 patients with psoriatic arthritis. All but 3 of these patients were over 40 years of age
and most had moderate to severe activity of the joints as
well as skin lesions. All patients had negative latex fixation
tests and typical psoriatic arthritis, as defined by Wright
and Moll (1 I), including nail involvement and lesions predominantly affecting the distal interphalangeal joint with
synovial thickening, swelling and erosion of bone.
Control sera were obtained from 23 normal blood bank
donors, all over 40 years of age. All of these individuals had
negative latex fixation tests. In all 3 groups, most sera were
fresh, but a few had been maintained frozen for several
months.
Quantitative immunoadsorptwn of antiimmunoinsoluble cross-linked preparation
globulins. An
of human Cohn Fraction 11. was made with glutaraldehyde, 2.5%, 1 ml for each 250 mg of Cohn Fraction 11, according to the method of Avrameas (9). Complete crosslinking was obtained after 2 hours at room temperature.
The cross-linked material was homogenized in glycineHCI, p H 2.5, washed three times with phosphate-buffered
saline (PBS), p H 7.2, stored in 1 M glycine overnight and
again washed five times in PBS. No protein was detectable
in any of the supernates subsequent to the homogenization,
using the method of Daughaday et al. (10).
Twenty milligrams of this insoluble immunoadsorbent,
suspended in 1 ml of PBS, was incubated at 37" C for 1
hour with 0.5 ml of serum and kept at 4" C overnight. The
adsorption capacity of 20 mg of this insoluble antigen was
shown by Avrameas to be approximately 20 mg of antiimmunoglobulin. The adsorbed antibody was eluted with
glycine-HC1 at p H 2.5. After neutralization with 0.03 ml of
0.5 M NaOH, the anti-immunoglobulins were determined
as IgG, IgM or IgA by the single radial immunodiffusion
method, using Hyland low level immunoplates. Four
standard solutions were used in each immunoplate, as well
as one positive control (RA); one negative control (normal
blood bank donor) and one reagent control (phosphate buffered saline p H 7.2). Reagent controls were uniformly negative. By this method, the standard deviations on multiple
measurements of the same test sera were as follows: for
IgG, 203 rg/ml SD = 44; 43 rg/ml SD = 9; for IgA, 63
&ml SD = 12; for IgM, 42 g / m l SD = 17. The optimal ranges for the plates used were as follows: IgG,
50-1200 rg/ml; IgA, 40-400 rgjml; IgM, 40-300 pg/
ml .
~
* Pentex, Miles Labs, Inc, Kankakee, Ill.
154
RESULTS
IgG concentration in eluates from seropositive RA sera ranged from 46 to 21 3 &ml. The
concentration of IgG in eluates from sera of
normal controls was less than 53 &ml. IgG in
all eluates from sera of patients with psoriatic
arthritis was within the normal range (Fig 1A).
IgG concentration in eluates from seronegative
RA, including JRA, ranged from 62 to 115
pg/ml.
Anti-IgG of the IgA type in eluates from
seropositive RA sera ranged from 18 to 360
pg/ml. The concentration of IgA in normal
controls ranged from negative to 47 pg/ml, indicating some overlap between the two groups.
Psoriatic arthritis patients were within the
normal range (Fig 1B).
Anti-IgG of the IgM type in eluates from
seropositive RA sera ranged from 20 to 140
g / m l in two-thirds of the cases and was insufficient to measure in the remainder. By contrast, in all normal controls the eluates contained insufficient IgM to measure. The eluates
from psoriatic sera were similar to the normals
(Fig 1C).
In the case of anti-IgG of the IgG type, the
mean value for the seropositive rheumatoid
group was 108 g / m l while the corresponding
value for the normal group was 34 pg/ml and
for the psoriatic group, 32 &ml. The difference between the means of RA and normal and
those of RA and psoriatic arthritis were highly
significant with P < 0.001. (Student's t test).
T h e difference in means between normal and
psoriatics was not significant. In the case of
anti-IgG of the IgA type, the mean value of the
seropositive rheumatoid group was 64 g / m l
while the corresponding value for the normal
group was 16 pg/ml and the psoriatic group
was 16 pg/ml. T h e difference in means between RA and normals and RA and psoriatic
arthritis was satistically significant, P < 0.001.
In the case of anti-IgG of IgM type the mean
value of the seropositive rheumatoid group was
38 pg/ml, as compared with zero for the other
Arthritis and Rheumatism,Vol. 15, No. 2 (March-April 1972)
SERUM ANTI-IMMUNOGLOBULINS IN ARTHRITIS
Rhoum'8toid
Rheumotoid
IgG
Irglrnl 3 0 0
Normal
Paorialic
Normol
Psoriatic
0
200
0
I00
SO
80
70
60
so
0
40
?
30
0
0
0
t
20
0
f
0
0
IgM
Rheumotoid
Jbg/ml 300
Normol
0.
0
0
%
0.
0%
&%
Psoriatic
I
2 00
0
0
I00
Fig 1. Scattergrams of concentration of anti-immunoglobulin in a
standard volume of eluate obtained from cross-linked IgG. The
"Rheumatoid" column includes
only seropositive rheumatoids: A)
anti-immunoglobulin of IgG type B)
anti-immunoglobulin of IgA type
C) anti-immunoglobulin of IgM type.
00
80
0
70
60
so
40
30
0
20
0
_.
___I
Arthritis and Rheumatism,Voi. 15. No. 2 (March-April 1972)
155
TAPANES E l AL
2 groups. The difference in mean between
seropositive RA, on the one hand, a n d the psoriatics and normal respectively, is likewise significant, P < 0.001.
Of t h e three types of antiimmunoglobulins
measured, those of t h e IgG type seem to show
the most clear-cut separation of R A from normals and psoriatics, so that in most cases this
measurement might have some diagnostic
value.
I n order to determine whether the difference
in the mean value for anti-immunoglobulin of
the IgG type, between t h e R A a n d t h e psoriatic
group, simply reflected a higher level of total
serum IgG in the former, total serum IgG levels
were measured in each group using the immunodiffusion plate method. The average level
in the RA group w a s 9 9 3 mg/100 ml, and that
in the psoriatic group was 925 mg/lOO ml.
CONCLUSIONS
From the work of others (5,8), as well as o u r
own, anti-IgG of both IgG and IgA types appears to be consistently present in increased
amounts in both seropositive and seronegative
R A a n d JRA. According to o u r study, psoriatic
arthritis, in contrast to RA, is characterized by
a normal range of anti-IgG concentration in
serum. T h e well defined differences in antiimmunoglobulins of the IgG type may be a diagnostic aid in differentiating psoriatic arthritis
from rheumatoid arthritis.
REFERENCES
1. Kunkel HG, Muller-Eberhard H, Fudenberg
H, Tomasi TB: Gamma globulin complexes in
rheumatoid arthritis and certain other conditions. J Clin Invest 40:117, 1961
2. Winchester RJ, Agnello V, Kunkel HG: The
joint fluid gamma globulin complexes and their
relationship to intra-articular complement diminution. Ann NY Acad Sci 168:195, 1969
3. Hannestad K, Mellbye OJ: Rheumatoid factor
in synovial effusions, local production and consumption. Clin Exp Immunol2:501, 1967
4. Hannestad K: Presence of aggregated gamma
globulin in certain rheumatoid synovial effusions. Clin Exp Immunol2:511, 1967
5. Torrigiani G, Roitt IM: Antiglobulin factors in
sera from patients with rheumatoid arthritis and
normal subjects. Ann Rheum Dis 26:334, 1967
6. Torrigiani G, Ansell BM, Chown EEA, Roitt
IM: Raised IgG antiglobulin factors in Still’s
Diseases. Ann Rheum Dis 28:424, 1969
7. Torrigiani G, Roitt IM, Lloyd KN, Corbett M :
Elevated IgG antiglobulins in patients with
seronegative rheumatoid arthritis. Lancet 3: 14,
1970
8. Bianco N, Panush R, Stillman JS, Schur P:
Immunologic studies of juvenile rheumatoid arthritis. Presented at the Annual Meeting of the
American Rheumatism Association, June 20,
1970, Detroit, Michigan
9. Avrameas S, Ternynck T: The crosslinking of
proteins with glutaraldehyde and its use for the
preparation of immunoadsorbents. Immunochemistry 6:53, 1959
10. Daughaday WH, Lowry OH, Rosebrough NJ,
et al: Determination of cerebrospinal fluid protein with the Folin phenol reagent. J Lab Clin
Med 39:663,1952
11. Wright V, Moll J M H : Psoriatic arthritis. Bull
Rheum Dis21:627,1971
Arthritis and Rheumatism,Vol. 15, No. 2 (March-April 1972)
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