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In vitro IgM and IgM rheumatoid factor production and response to remittive agents in rheumatoid arthritis.

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LETTERS
In vitro IgM and IgM rheumatoid factor production
and response to remittive agents in rheumatoid
arthritis
To the Editor:
We have been interested in the relationship between
in vitro patterns of IgM and IgM rheumatoid factor (IgM-RF)
production in patients with rheumatoid arthritis (RA), and
the response to remittive agents. Our previous studies,
carried out on a cross-sectional sample of our RA patients,
failed to show any significant relationship between the
quantity of IgM-RF or IgM produced and the remittive
agents the patients were receiving at the time of the study
(1,2). Nonetheless, in vivo data have shown that serum
immunoglobulin levels, including RF titers, are reduced
during treatment with gold salts (GS) (3,4). Therefore, it was
of interest to perform a prospective in vitro study of IgM and
IgM-RF production in a group of patients undergoing chrysotherapy.
Eleven patients with seropositive classic or definite
RA (5) undergoing a 1-gm loading dose of GS (Myochrysine:
7 patients, Solganal: 4 patients) were studied. Peripheral
blood was obtained at the initiation (To)and at the completion (TI)of the GS loading dose (mean interval: 22 weeks).
Peripheral blood mononuclear leukocytes (MNL) were prepared by Ficoll-Hypaque density centrifugation, cultured for
7 days in the presence and absence of the polyclonal B cell
activator pokeweed mitogen (PWM), and the culture supernatants were assayed for total IgM and IgM-RF using
methods previously described in detail (6).
Each patient was examined by one of us (GSA) at To
and T1, and clinical activity was assessed using both duration of morning stiffness and number of swollen and tender
joints (modified Ritchie Index [7]). If a patient had at least a
two-thirds reduction in both indices of disease activity at T1,
he or she was considered a responder to GS therapy.
The results of these studies are summarized in Table
1. Spontaneous in vitro production of IgM-RF was observed
at TO in only 4 of 11 of the gold-treated patients. These
patients were equally divided between those who responded
and those who did not respond to GS. MNL from each of
these individuals spontaneously synthesized less RF at T1
than at To. Although the numbers were too few to permit
definite conclusions regarding the true effect of chrysotherapy on spontaneous in vitro IgM-RF production, it is noteworthy that RF production by 11 RA control patients on
stable therapeutic regimens did not differ between To and T I
(data not shown). Spontaneous in vitro production of IgM
was observed for each of the gold-treated patients at To, but
did not demonstrate significant changes at TI. Results with
the RA control patients on stable therapeutic regimens were
comparable.
In contrast with spontaneous in vitro synthesis,
MNL from most (10 of 11) of the gold-treated patients
exhibited in vitro IgM-RF production when stimulated with
PWM at To (mean +- SD = 50 2 57 ng/106cells). A significant
decrease in RF synthesis was observed at T I (14.5 10.0; P
< 0.05). This decrease was apparent for all patients, whether
responders or nonresponders. Similarly, PWM-stimulated in
vitro IgM production was less at T I than at To (P < 0.01),
regardless of response to therapy. Significant changes in
PWM-stimulated in vitro IgM-RF and IgM production were
not observed for the RA control group on stable therapeutic
regimens.
*
Table 1. Spontaneous and pokeweed mitogen (PWM)-induced IgM and IgM rheumatoid factor (IgMRF) production in relation to clinical response, in rheumatoid arthritis patients undergoing
chrysotherapy, at initiation (time 0) and completion (time I ) of loading dose
IgM-RF (ng/106 cells)*
IgM (ng/lOh cells)
Spontaneous
TimeO
Responder
patients
42
I
2
306
330
3
4
171
5
222
54
6
7
42
Nonresponder
patients
8
42
9
142
10
360
11
414
PWM-induced
Time 1
Time0
Time 1
140
232
94
78
240
156
15
1,200
4,300
1,400
3,800
2,450
390
1,000
500
535
380
150
125
142
580
83
79
138
96
1,255
1,500
5,000
4,750
875
850
2,000
1,050
* Sensitivity of the assay: 210 ng/lO" cells.
Arthritis and Rheumatism, Vol. 28, No. 3 (March 1985)
Spontaneous
TimeO
Time 1
10
28
42
<I0
< 10
< 10
< 10
< 10
<I0
< 10
< 10
<to
< 10
93
208
< 10
< 10
< 10
PWM-induced
TimeO
Time 1
16
61
42
80
29
14
43
11
I1
18
< 10
< 10
< 10
37
16
61
11
< 10
< 10
< 10
17
218
<I0
31
<I0
11
LETTERS
357
Our results suggest that spontaneous in vitro production of IgM-RF by peripheral blood MNL is not a useful
indicator of response to chrysotherapy, as suggested by
Olsen et al (S), for 2 reasons. First, many RA patients (64%
in the present series) do not demonstrate significant in vitro
IgM-RF production in the absence of PWM stimulation.
Second, decreases in spontaneous in vitro RF production
were observed regardless of response to therapy, although
the number of patients studied was too small to permit
statistical analysis. Decreases in PWM-induced in vitro IgM
and IgM-RF production by peripheral blood MNL following
GS therapy occurred with most of our patients, but were
comparable in patients who showed clinical improvement
and those who did not.
Graciela S. Alarcon, MD, MPH
William J . Koopman, MD
Ralph E. Schrohenloher, PhD
University of Alabama in Birmingham
Birmingham, A L
1 , Koopman WJ, Schrohenloher RE: Enhanced in vitro synthesis of
IgM rheumatoid factor in rheumatoid arthritis. Arthritis Rheum
23:985-992, 1980
2. Alarcon GS, Koopman WJ, Schrohenloher RE: Differential
patterns of in vitro 1gM rheumatoid factor synthesis in seronegative and seropositive rheumatoid arthritis. Arthritis Rheum
25:150-155, 1982
3. Gotlieb N L , Kiem l M , Penneys NS, Schultz DR: The influence
of chrysotherapy on serum protein and immunoglobulin levels,
rheumatoid factor and antiepithelial antibody titers. J Lab Clin
Med 86:962-972. 1975
4. Lorber A, Simon T. Leeb J , Peter A, Wilcox S: Chrysotherapy:
suppression of immunoglobulin synthesis. Arthritis Rheum
21:785-791,1978
5 . Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA: 1958
revision of diagnostic criteria for rheumatoid arthritis. Bull
Rheum Dis 9:175-176, 1958
6. Koopman WJ, Schrohenloher RE: In vitro synthesis of IgM
rheumatoid factor by lymphocytes from healthy adults. J Immunol 125:934-939, 1980
7. Ritchie DM, Boyle JA, McInnes JM, Jasani M K , Dalakos TG,
Grieveson P, Buchanan WW: Clinical studies with an articular
index for the assessment of joint tenderness in patients with
rheumatoid arthritis. Q J Med 37:393-406, 1968
8. Olsen N, Ziff M, Jasin HE: Spontaneous synthesis of IgM
rheumatoid factor by blood mononuclear cells from patients with
rheumatoid arthritis: effect of treatment with gold salts o r Dpenicillamine. J Rheumatol 1 I:l7-21, 1984
Comment on article by van der Linden et a1
To the Editor:
Van der Linden and colleagues (1) have proposed a
modification of the New York criteria (2) for the diagnosis of
ankylosing spondylitis. They elected to substitute a modified
form of the Rome pain criterion (3) for that used in the New
York counterpart.
We have long favored a more simple approach, the
use of symptomatic sacroiliitis as the key determining factor
(4). Although the modification by van der Linden et al includes
the symptoms that we described in 1977 (5). it remains
unclear why they wish to continue to include measurement
of spinal and chest mobility. Criteria should be simple,
reproducible, and readily definable. The New York criteria
that depend on measurements are none of these. By contrast, the proposed criteria for Reiter’s syndrome are indeed
simple (6). They require the occurrence of an episode of
arthritis lasting for at least 1 month, in conjunction with
urethritis or cervicitis (6).
Whatever approach is used-straightforward as with
ours (4), or more tortuous as in the New York (2) and Rome
(3) reports-all criteria demand certain exclusions, such as
brucellosis, tuberculosis, metastatic disease, and other entities that can result in sacroiliac disease and pain. In the final
analysis, the diagnosis must depend on the subjective reading of the pelvic radiograph, and however much modification
of criteria is applied, this reading will remain a subjective
phenomenon, though the sine qua non for diagnosis.
Broadly, there are 3 main reasons criteria are needed. The first is to allow comparison of different patient
groups, the second is to help the clinician reach a diagnosis,
and the third is to provide investigators with a clue as to
whether the putative “trigger” has been pulled in a genetically susceptible individual. Regarding the first reason, it is
imperative to define the entry variables used, given that
there are numerous additional demographic and clinical
features that define the patient population. With regard to
the second, a patient with sacroiliitis and back pain should
be treated, regardless of whether the spine moves to a
“normal” or lesser extent. Clearly, in terms of the last,
evidence of bilateral sacroiliitis is sufficient to define the
endpoint.
Too much time can be spent analyzing, reanalyzing,
defining, and redefining criteria.
Andrei Calin, MD, MRCP
Royal National Hospital f o r Rheumatic Diseases
Bath, U K
1. Van der Linden S, Valkenburg HA, Cats A: Evaluation of
diagnostic criteria for ankylosing spondylitis: a proposal for
modification of the New York criteria. Arthritis Rheum 27:361368, 1984
2. Bennett PH, Burch TA: Population Studies of the Rheumatic
Diseases. Amsterdam, Excerpta Medica Foundation, 1968, pp
456-457
3. Kellgren J H , Jeffrey MR, Ball J : The Epidemiology of Chronic
Rheumatism. Vol. 1. Oxford, Blackwell Scientific Publications,
1963,pp 326-327
4. Calin A: Ankylosing spondylitis, Textbook of Rheumatology.
Edited by WN Kelley, E D Harris Jr, S Ruddy, CB Sledge.
Philadelphia, WB Saunders, 1981, pp 1017-1032
5 . Calin A, Porta J , Fries J F , Schurman DJ: Clinical history a s a
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production, factors, response, igm, agenti, arthritis, vitro, rheumatoid, remittive
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