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Hypocomplementemia in Rheumatoid Arthritis.

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Hypocomplementemia in Rheumatoid Arthritis
Alejandro E. Franco* and Peter H. Schur
Hypocomplementemia has rarely been noted in patients with rheumatoid arthritis
(RA). Eleven of 250 patients studied consecutively were found to have serum
complement levels below the normal range. These 11 patients, as a group, had
more severe disease, including greater functional impairment and more frequent
positive latex tests and subcutaneous nodules, than did patients with rheumatoid
arthritis and normal or elevated complement levels. Episodes of hypocomplementemia usually were associated with an acute flare of multiple joints, vasculitis or
rheumatoid pleuritis. It is evident that RA is not necessarily associated with
normal or elevated CH,, levels. In fact, severe RA, with marked destructive
changes and multiple complications, is sometimes associated with markedly low
CH,, levels.
I n 1951, serum whole hemolytic complement (CH,,) levels were reported by
Vaughan et al (1) to be normal or elevated
in patients with rheumatoid arthritis (RA).
Subsequently,
other
authors
(2-4)
confirmed these findings. Schubart in 1965
( 5 ) , in a longitudinal study, demonstrated
that CH,, levels may fluctuate during active RA. When abnormal values occurred,
they tended to be elevated. Recently, Mongan et al (6) noted that CH,, levels were
somewhat lower i n patients with seroposiFrom the Robert B. Brigham Hospital and the
Department of Medicine, Harvard Medical School,
Boston, Mass.
Supported by USPHS Grants AM 11414, AM
05577, AM 12051 and AM 5076.
ALEJANDRO E. FRANCO, MD: Former Postdoctoral Fellow at Harvard Medical School, Robert B. Brigham
Hospital, Boston, Mass. Presently Clinical Instructor
of Pharmacology, School of Medicine, University of
Puerto Rico, San Juan, PR. PETER H. SCHUR, MD:
Assistant Professor of Medicine, Harvard Medical
School, Robert B. Brigham Hospital, Boston, Mass.
Reprint requests should be addressed to Peter
H. Schur, MD.
Submitted for publication Sept 3, 1970; accepted
Nov 2, 1970.
*Clinical Fellow of the NIAMD.
Arthritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
tive RA than i n patients with seronegative
RA, but were still normal.
Levels of CH,, below normal range in
RA patients have been noted only sporadically ( 3 , 7 , 8 ) . This paper presents a clinical
and immunologic analysis of 11 cases of
RA with CH,, levels lower than normal,
and compares these to patients with normal and elevated CH,, values.
MATERIALS AND METHODS
T h e serum hemolytic complement level was determined in 250 consecutive cases of RA seen at the
Robert B. Brigham Hospital. All of the patients
had probable, definite or classic RA by the criteria
of the American Rheumatism Association (9).
CH, levels were determined by the method of
Kent and Fife (10) (normal 200 50 p/ml). Eleven
patients who were found to have values below 150
@/ml were designated the low complement group.
Twenty patients with markedly elevated CH,
levels (ie, over 285 @/rnl) were called the high
complement group: 40 patients were selected at
random (every fifth case in alphabetic order) from
those with normal CH, values to form the normal
complement group. Another group of 20 patients
with RA was matched for disease duration with the
low complement group, and was designated the
prolonged disease duration group.
*
231
FWNCO & SCHUR
percent of the group had values within the
normal range (150-250 p/ml), with a mean
of 213 p/ml. Levels above 250 p/ml were
present in 31% of the patients, and values
below 150 p/ml, in 4y0 (11 patients). I n
the group with prolonged disease duration
the mean value for CH,, was 236 p/ml.
T h e sex ratio in the low complement
group was 2.7 F : lM, while for the normal
and high complement groups, it was 3.6
and 4 F’s : lM, respectively. T h e ratio of
4F : 1M is the sex ratio for the RA patients
admitted to this hospital. Mean ages for
each group as well as mean duration of
disease, functional class and grade of the
RA diagnosis, are presented in Table 1. A
reduction in complement levels from high
to normal to low levels coincided with a
more frequent occurrence of classic RA, as
well as a greater impairment in functional
activity, longer mean duration of illness
and higher frequency of subcutaneous nodules.
All patients in each group had evidence
of active arthritis at the time of the CH,,
determination. Two to 5 joints were sym-
CH, in synovial fluid was determined in 6 of 11
patients of the low CH, group, and in 13 of 20
patients of the high CH, group. Patients in each
group were evaluated clinically, emphasizing duration of disease, functional class ( l l ) , presence of
subcutaneous nodules, number of joints involved,
and complications secondary to RA. Radiographs of
the joints were classified on the basis of narrowing
of articular cartilage, bony erosions, demineralization, subluxations, dislocations and fusions.
Laboratory studies performed on each patient
included complete blood count, sedimentation index (12), serum protein electrophoresis, latex
fixation test (13) and antinuclear factors test (14).
For those with antinuclear antibodies, tests were
also performed for precipitating antibodies to calf
thymus deoxyribonucleic acid (DNA), heat denatured DNA (HDNA), calf thymus soluble nuclear
extract (CTN), rabbit liver ribosomes (Rb) (15)
and ribonucleic acid (RNA) (16). LE preparations
were done on most of the patients. Sera were tested
for Clq (8), C4 and C3 (17) protein levels by
radial immunodiffusions (18). Serial CH, determinations were done on several patients.
RESULTS
T h e serum CH5, levels of 250 patients
with RA ranged from 450 p/ml to 58 p/ml
with a mean value of 209 p/ml. Sixty-five
Table 1. Clinical Characteristics
Group
High CH5a
Mean
No.
Mean disease
of
age duration
patients (yr)
(Y
20
54
4.7
Normal CHso
LOWCHso
40
11
57
59
10
13.6
Prolonged
disease
duration
20
52
14
Diagnosis by ARA
criteria (%)
Prob
Def
Class
40
25
35
10
32.5
0
18
5
65
Subcutaneous
nodules
Functional class (%)
I
10
(3)
(1)
10
57.5
0
82
(1) (2) (3) (4)
0
39
(2) (3) (4)
I1
45
(3)
47.5
9
(3) (4)
55
(4
Ill
15
5
(5)
40
73
(5)
2.5
18
(5
25
(%I
IV
40
30
45
(5 \
20
35
Comparison of frequency of classic RA in high vs low CHN: (1):P < 0.02; comparison of frequency of
classic RA in low CHN vs prolonged disease duration: (2):P < 0.05; comparison of frequency of class I
and I 1 RA in high vs low CH50: (3): P < 0.05; comparison of frequency of class I and I1 RA in low CHS vs
prolonged disease duration: (4):P < 0.05; and comparison of frequency of class I l l and IV RA in high vs
IOWCHN: (5):P < 0.02.
232
Arthritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
HYPOCOMPLEMENTEMIA
metrically involved in the low complement
group at the time the low CH50 value was
obtained; only 0 to 2 joints were similarly
involved at the time the CH50 levels returned to normal.
T h e synovial fluid CH,, of the low
CH,, groups ranged from 0 to 40 r/ml,
with a mean of 14 p/ml. For this group of
6 patients, the mean serum CH,, was 111
p/ml. The synovial fluid CH,,, of the high
CH,, groups ranged frcm 19 to 216 p/ml
with a mean of 87 ,/ml-while
the mean
serum CH,, for these 13 patients was 219
P/ml.
Among the groups, no striking differTable 2.
Group
ences were noted regarding complete blood
counts and sedimentation index. Leucopenia of less than 4000 WBC/cu mm was
not present in any patient. Persistent eosinophilia of more than 8%. not related to
any known specific cause, was present in 2
cases from .the high complement group and
in 4 from the low complement group.
Demineralization, subluxations, fusions
and/or dislocations were seen more frequently in the low complement group (Table 2).
Gamma globulin levels were elevated in
the low complement and long disease duration groups (Table 3). A positive latex
Radiologic Characteristics
Demineralization
Cartilage
narrowing
Erosions
Subluxations.
dislocations
and/or fusions
(%)
(%I
(%I
(%I
65
50
5
80
100
72
100
27
54
94
78
42
15
High CHW
(1)
Normal CHW
LOWCHso
35
82
Prolonged disease duration
57
(2)
(1)
(2)
Comparison of frequency of demineralization in high vs low CHw: (1):P
quency of subluxations in high vs low CHW:(2):P < 0.01.
Table 3.
High CHS
Ant in uclear
antibodies
serum dil.)
Hypergammaglobulinemia
(96)
(%I
Mean CHu
(P/ml)
25
319
23
30
210
54
100
116
57
236
(xo
(%I
40
16
(3)
(1)
Normal CHM
0.01; comparison of fre-
Laboratory Results
Positive
latex test
Group
<
60
(2)
Low CH50
82
(1) (2)
Prolonged disease duration
60
9
(”
Comparison of frequency of positive latex test in high vs low CHW: (1):P < 0.01; comparison of frequency of positive latex test in normal vs low CHm: (2): P < 0.02; comparison of frequencyof antinuclear
antibodies in high vs low CHW:(3):P < 0.01.
Arthritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
233
80
30
s
2
s
b
6o
'2
40
$
h'
2 20
8
8
0
Negative
32 02 560
20-160
LATEX
5 12040,960
81,920-
655,360
nrms
Fig 1. Percentage of patients with low, normal or high complement levels who either had a negative
serum latex fixation test for rheumatoid factor or had a positive titer.
fixation test was most prevalent in the low
complement group (Fig 1). Mean latex
titers for the low complement group were
three times higher than those for the normal complement group, and five times
higher than those for the high complement
group. Antinuclear antibodies were detected (1/ 10 serum dilution) in twice as many
patients in the low complement group as in
the other groups (Table 2). One patient
(AB) from the low complement group, with
classic RA-by
the criteria of ,the ARA,
including: subcutaneous nodules, pannus
Table 4.
~
Complement Values
~~~
Mean
serum C H W
Group
High CHW
LOWCHso
Normals
234
formation, loss of cartilage, erosions, multiple subluxations and dislocations, and pathologic examination of synovial tissuehad precipitating antibodies against DNA
and HDNA. T w o patients with classic R A
from the low complement group had rare
LE cells. None of the patients had photosensitivity, alopecia, rashes, renal disease
or neurologic symptoms.
Results of the complement components
Clq, C4 and C3 protein studies are
presented in Table 4. T h e complement
components tended to be low in the low
G/mU
318
117
200 f 50
Mean
synovial CHm
( P / W
97
14
-
Mean
serum Clq
(fig C l q N/mO
Mean
serum C4
(dml)
Mean
serum C3
(mg/100 ml)
29.9
22.1
25.2 f 6.4
536
230
422 f 214
231
123
145 j=44
Arthritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
HYPOCOMPLEMENTEMIA
complement group and high in the high
complement group, but remained within
the normal range, except for C3 in the
high complement group. I n 1 patient (Table 5), the CH,, dropped twice over a
period of 2 years, first with an episode of
vasculitis, skin ulcers and rheumatoid pleuritis, and second with multiple soft tissue
abscesses and vasculitis of the skin, as well
as a second episode of pleuritis. I n another
patient, the drop in CH,, was associated
with the development of Felty’s syndrome
and skin lesions of vasculitis; he died of a
pulmonary embolism. I n the other 9 patients in the low complement group, decrease in CH,, was associated with an
acute flare of the RA, involving multiple
joints. Close follow-up of CH,, levels revealed a return to normal values associated
with improvement in the rheumatoid condition or the complication.
When the low complement group was
compared with the group of similar disease
duration, statistically significant differences
were observed. A greater frequency of classic RA (P<0.05), and a lower number of
cases in class I and I1 of functional activity
(P<0.02) were found in the low complement group. Although differences in other
parameters, such as presence of subcutaneTable 5.
ous nodules, positive latex fixation test,
presence of antinuclear antibodies and hypergammaglobulinemia are apparent, it
was not possible to establish the statistical
significance of the differences, due to the
small number of observations (Table 1 and
3).
There was no striking difference in the
therapy received by each group. Steroids in
low dose (prednisone, 5-10 mg/day) were
given to 2 patients in the low complement
group and to 3 patients in the high complement group. Salicylates, hydroxychloroquine and gold were received in various
doses and in different combinations by each
patient.
DISCUSSION
Low levels of serum complement in RA
patients have received scant attention.
Rather, most studies have emphasized elevated or normal levels. I n the present
study, 11 of 250 patients with RA had
CH,, levels below the normal range.
These patients had more severe RA than
did patients with normal or elevated complement levels.
All of the patients with low complement
levels had definite or classic RA; most of
them were in functional class I11 and IV
Clinical Laboratory Correlation in Patient A 6
Precipitating antibodies
Date
Nov27, 1968
Dec 30, 1968
May2,1969
June 4, 1969
July 6,1969
Aug25, 1969
Sept 3,1969
Dec 31, 1969
April 12, 1970
CHm
(p/ml)
54
72
129
172
150
37
10
38
125
RNA
NP
CTN
0
+
+
+
+0
0
0
0
0
+
+
0
0
HDNA
+
+
0
0
0
+
+
0
0
DNA
Clinical picture
Vasculitis, skin ulcers, arthritis
Pleural effusion
Pleura cleared, skin clearing
Skin cleared
Pleural effusion
Pleural effusion, skin ulcers
More skin ulcers
Skin and pleura cleared
Normal = 200 f 50
Arthritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
235
FRANC0 & SCHUR
(91%) and 45y0 of them had subcutaneous
nodules, Most of them had positive latex
fixation tests (82y0),and 54y0 had antinuclear antibodies. Elevated gamma globulin
levels by electrophoresis were common. At
the time of the low CHao level, all the
patients had multiple joint involvement,
and some had complications of the disease,
such as vasculitis, Felty’s syndrome or rheumatoid pleuritis. As a group, narrowing of
joint spaces and erosions were common.
T h e presence of antinuclear antibodies,
including antibodies to DNA, and hypocomplementemia have been associated with
systemic lupus erythematosus (15). T h e coexistence of many serologic and clinical
features of both rheumatoid arthritis and
systemic lupus erythematosus has been
noted (19). I n spite of these serologic abnormalities, the patients described herein
had the typical clinical features of definite
or classic rheumatoid arthritis; and, on
clinical grounds, they were not thought to
have systemic lupus erythematosus.
By contrast, patients with normal or elevated complement levels had less functional impairment, less frequent subcutaneous
nodules, lower frequency of positive latex
fixation and antinuclear antibodies, and
less radiologic evidence of joint involvement, Patients with elevated complement
levels tended to have less severe disease
than did those with normal complement
levels.
T h e possibility that the disease duration
contributes to the low CHSo levels was unlikely, as the mean CHbo for the group of
patients with the same disease duration was
much higher (236 p/ml) than that of the
low complement group (mean CH,,, 116
p/ml). Disease duration has been found to
be unrelated to most of the clinical manifestations of RA (20). O n the other hand,
Ellis (3) showed a trend from elevated to
normal CH,, levels, associated with advanc236
ing stages of the disease. Nevertheless, he
did not attribute clinical significance to the
low CH,,, values, and explained them on
the basis of anticomplementary activity.
Depression of the early complement
components suggests activation of the complement system and fixation by an immune
mechanism. T h e more pronounced depression of complement levels in the synovial
fluid of patients with low serum CH5, most
probably represents increased complement
consumption in the joint cavity. This is
supported by the fact that in the low CH,,
group, the synovial fluid CH,, level was
13% of the serum level, while in the high
CH,, group, the synovial fluid level was
44y0 of the serum level. Such complement
activation has been shown to be present in
the synovial space of many patients with
seropositive RA (2 1-23). Complement levels
are also depressed i n rheumatoid pleural
effusions (24). It is possible that if enough
complement were to be consumed in the
joint or pleural cavities, it would be reflected by a low serum level. In addition, deposition of antigen antibody complexes in
blood vessels might cause a vasculitis and
thus deplete complement (6). In these respects, the basis of hypocomplementemia
associated with RA might be similar to that
in nephritis associated with systemic lupus
erythematosus. I n lupus nephritis, hypocomplementemia is also associated with
complement-fixing immune complexes in a
local inflammatory site-ie, the kidney.
It is clear that some patients with severe,
active rheumatoid arthritis, without evidence of the coexistence of another disease
process, may have low levels of serum complement. Although low levels of joint h i d
complement were often associated with low
serum levels, it is not clear whether the low
serum levels in the patients reported here
reflect the formation of complexes localized
elsewhere, the low levels of complement
Arthritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
HYPOCOMPLEMENTEMIA
production or t h e destruction of complement by other mechanisms.
of reagents for complement fixation. Amer
J Trop Med Hyg 12:103-116, 1963
11. Landsbury J: Methods for Evaluating
ACKNOWLEDGMENTS
The authors are grateful to the staff a t
Robert B. Brigham Hospital, Boston, Mass,
being allowed to study their patients; and to
A. Hall for his helpful criticism in evaluating
study and manuscript.
the
for
Dr.
12.
this
REFERENCES
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Serum complement in rheumatoid arthritis.
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4. Jonsen J, Kass E: Complement and complement components in diseases of possible auto-immunological pathogenesis. Acta
Rheum Scand 7:21-26, 1961
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et al: Serum complement levels in rheumatoid arthritis. Ann Rheum Dis 24:439450, 1965
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study of the relation of seronegative and
seropositive rheumatoid arthritis to each
other and to necrotizing vasculitis. Amer J
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43:310-320, 1958
8. Hanauer LB, Christian CL: Clinical studies
in hemolytic complement and the 11s component. Amer J Med 42:882-890, 1967
9. Ropes M, Bennett GA, Cobb S, et al: Revision of diagnostic criteria for rheumatoid
arthritis. Arthritis Rheum 2: 16-20, 1958
10. Kent JF, Fife EH: Precise standardization
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Rourke MD, Ernestene AC: A method for
correcting the erythrocyte sedimentation
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1929- 1930
Hall AP, Mednis AD, Bayles TB: Latex
agglutination and inhibition reaction: clinical experience in diagnosis of rheumatoid
arthritis. New Eng J Med 258:731-735,
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Gonzalez EN, Rothfield NE: Immunoglobulin class and pattern of nuclear fluorescense in systemic lupus erythematosus. New
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Schur PH, Sandson J: Immunologic factors
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Schur PH, Monroe M: Antibodies to ribonucleic acid in systemic lupus erythematosus. Proc Nat Acad Sci 63: 1108-1 112, 1969
Ruddy S , Carpenter CB, Miiller-Eberhard
HJ, et al: Complement Component Levels
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Reactions. V International Immunopathology Symposium. Edited by Miescher SC
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FRANC0 & SCHUR
21. Pekin JT, Zvaifler NJ: Hemolytic complem e n t i n synovial fluid. J Clin Invest 43:
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22. Fostiropoulos G, Austen KF, Bloch JK: The
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Arch I n t e r n Med
ERRATUM
T h e fo!lowing abstract was inadvertently omitted from among the Abstracts
of Papers submitted for the Annual Meeting of the American Rheumatism
Association, June 19-20, 1970, Detroit, Mich. and published in Arthritis Rheum
13:300-360, 1970.
“Computerization” of a Rheumatic Disease Unit.
J a m s F. Fries, Stanford, California: T h e hospital chart has remained a static, traditional
method of recording and assessing clinical data even though clinical correlations, controlled
clinical trials, and devclopment of classification and prognostic criteria are important methods of
obtaining new information about Rheumatic Disease. This project revises record-keeping procedures and establishes an accessible computer databank containing all clinical information on
patients with Rheumatic Diseases seen in a University Medical Center.
Replacement of the traditional nonindexed, semichronological hospital chart with a structured
format emphasizing change in parameters with respect to time is a prerequisite for an optimally
useful computer file. T h e “Rheumatic Disease Chart” to be illustrated provides this structure
without a net increase in physician data-entry time, and with an increase in the facility with
which data may he reviewed and trends ascertained. Flexibility is maintained through an option
for narrative description when desired, and provision is made for later addition of new parameters as needed. T h e graphic nature of the information display encourages data-based management decisions. T h e information system is designed to facilitate prospective clinical trials, and
data from special laboratory projects may be added for correlation with the clinical data.
The research value of a computer databank increases exponentially as the amount of stored
data accumulates. Search possibilities early in the program are limited to general questions
covering short periods in common diseases; later searches may concern more specific questions 01
unusual conditions. Illustrative output procedures, such as a detailed computer summary of
patient status for referring physicians and outside agencies, diagnostic programs, and search
procedures for clinical and serologic correlations will be demonstrated. These operations have
been performed on the databank currently including 400 patient-visits and approximately
125,000 individual pieces of data.
238
Arthritis and Rheumatism, Vol. 14, No. 2 (March-April 1971)
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