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SCIENCE SUMMARY
ANTI-POLYMER ANTIBODIES and FIBROMYALGIA SYNDROME
| The Anti-Polymer Antibody Assay, or APA Assay, detects an
abnormal immune system response in most fibromyalgia patients.
In a recent study, the titers of the antibodies detected
correlated with nine separate clinical measures of fibromyalgia
severity, including fatigue, stiffness, anxiety and depression.
The APA Assay appears to be the first practical laboratory test
for fibromyalgia, and the correlation between antibody titers
and symptomatology appears to provide the first direct evidence
that fibromyalgia syndrome is in fact a unique disease which is
based on a physiological, and not a psychological, pathology. |
INTRODUCTION
The APA Assay has been shown in two previously published studies
to detect anti-polymer antibodies in the blood of a large percentage
of patients with fibromyalgia and fibromyalgia-like symptoms. New
data presented in September 2001 at the International Myopain
Society's 5th World Conference on Myofascial Pain and Fibromyalgia
revealed statistically significant relationships between the titers
of these antibodies and nine different clinical measures of
fibromyalgia severity.
The data presented in September 2001 was obtained from a study of
well-characterized fibromyalgia patients which was conducted at the
University of Texas Health Science Center in San Antonio (the "San
Antonio study"). The San Antonio investigators were Yang-Ming Xiao,
M.D., Ph.D., I. Jon Russell, M.D., Ph.D., and Joel E. Michalek, Ph.D.
Dr. Russell is one of several world-recognized fibromyalgia experts,
and Dr. Michalek is the principal investigator for the Air Force
Ranch Hand Study, which is the largest and longest-running
epidemiological study in the United States. Manuscripts describing
the San Antonio study are now being prepared for publication.
The APA Assay appears to be the first practical blood test for
fibromyalgia. Data from the San Antonio study is now being used to
prepare clinical testing protocols to propose to the U.S. Food and
Drug Administration as part of the process of winning FDA approval
of the APA Assay as a diagnostic test for fibromyalgia. The
published results suggest that the APA Assay may objectively
contribute to distinguishing between patients with fibromyalgia and
patients with connective tissue diseases such as systemic lupus
erythematosus, systemic sclerosis, Sjögren's syndrome, rheumatoid
arthritis, and poly/dermatomyosis.
In part because of the historical absence of laboratory evidence
to the contrary, many physicians currently feel that fibromyalgia is
not a physically-based illness. These physicians instead believe
that fibromyalgia is either a psychological disorder or that
fibromyalgia symptoms are the product of some other disease which
has not yet been correctly diagnosed. By directly associating immune
response with symptomatology, the APA Assay demonstrates that
fibromyalgia is in fact a unique physical disorder, or, in lay
terminology, "a real disease."
The data from the San Antonio study suggests that anti-polymer
antibodies might play a direct role in the fibromyalgia disease
process. Data from this study as well as the two previously
published studies indicate that approximately two-thirds of primary
fibromyalgia patients test positive for anti-polymer antibodies.
Primary fibromyalgia syndrome is believed by many researchers to
have more than one cause, and it is entirely possible that
fibromyalgia patients who test positive for anti-polymer antibodies
represent a very large and previously unrecognized group of
fibromyalgia patients whose disease is the result of one particular
cause.
Drugs which modulate a patient's immune response are frequently
prescribed by physicians to help alleviate symptoms in autoimmune
disease patients. The APA Assay shows that an abnormal immune
response is present in most fibromyalgia patients, and physicians
could choose to interpret this finding as an indication that such
drugs might also be useful in treating fibromyalgia patients.
The titers of the antibodies detected by the APA Assay correlate
with nine measures of severity of symptoms of fibromyalgia. In
contrast, other immunological test results rarely show any
correlation at all between antibody titers and symptoms in any
rheumatic disease. Because such correlations can in fact be explored
by using the APA Assay, the Assay may also prove to be a valuable
aid to physicians who wish to monitor flare and other on-going
conditions in their fibromyalgia patients.
THE RESEARCH STUDIES
An article published in the February 1999 issue of The Journal of
Rheumatology(1) entitled "Anti-Polymer Antibody Reactivity in a
Subset of Patients with Fibromyalgia Correlates with Severity" shows
that 47% of patients with fibromyalgia and 61% of patients with
severe symptoms of fibromyalgia were seroreactive on the APA Assay.
The pain thresholds, as determined by dolorimeter scores, for
seropositive patients in the study were significantly lower than
those of seronegative patients, demonstrating that APA Assay
reactivity correlates with severity of symptoms. No other reported
laboratory measure has been found to correlate with severity of
symptoms in patients with fibromyalgia.
An earlier study of a different group of patients with
fibromyalgia-like symptoms showed similar results. In an article
published in the February 15, 1997 issue of The Lancet(2) entitled
"Use of Anti-Polymer Antibody in Recipients of Silicone Breast
Implants," 68% of patients with advanced fibromyalgia-like symptoms
exhibited APA Assay seroreactivity. The results of these two studies
suggest that the presence of anti-polymer antibodies may serve as a
laboratory marker for an illness that is the same or similar in both
groups of patients. The APA Assay was also shown to be a very
specific test, with a level of APA reactivity among patients known
not to have any fibromyalgia symptoms of approximately 3%.
Both articles also present results showing that APA reactivity is
markedly lower (p<0.05) in patients with diffuse connective tissue
diseases than in patients with fibromyalgia or fibromyalgia-like
symptoms alone. Such connective tissue diseases include rheumatoid
arthritis, systemic lupus erythematosus and systemic sclerosis/scleroderma,
and it can be difficult, particularly in severe cases of
fibromyalgia, to differentiate fibromyalgia from these diseases.
The abstract of the San Antonio study which was presented in
September 2001 at the 5th World Conference on Myofascial Pain and
Fibromyalgia(3) is entitled "Anti-Polymer Antibodies [APA] in the
Serum of Patients with Fibromyalgia Syndrome [FMS]." The conclusions
recited in the abstract are as follows:
| The APA Assay kit was highly reliable. Significantly
higher anti-polymer antibody values were found in primary
fibromyalgia syndrome patients than in healthy normal controls.
These findings suggest that anti-polymer antibody testing may
have identified a previously unrecognized subgroup of primary
fibromyalgia syndrome patients. It seems reasonable to propose
that anti-polymer antibodies may be important to the
pathogenesis of that primary fibromyalgia syndrome subgroup. |
The abstract also listed the following nine statistically
significant correlations (p <= 0.05) between the optical densities
of the ELISA results (i.e., anti-polymer antibody titers) and
clinical measures of fibromyalgia severity:
Measure
|
Description
|
Scale
|
| STIFF |
Degree of stiffness severity
(VAS*) |
0 - 10 |
| FELTINAM |
Feeling from "good" to "bad" in
the morning (VAS*) |
0 - 10 |
| HOWTIRED |
Degree of fatigue severity (VAS*) |
0 - 10 |
| LIMITACT |
Symptoms-limited-activity days
experienced during the last week |
0 - 7 |
| HEADACHE |
Days in which headache was
experienced during the last week |
0 - 7 |
| ANXIOUS |
Level of anxiety (VAS*) |
0 - 10 |
| DEPRESS |
Level of depression severity
(VAS*) |
0 - 10 |
| ZUNG |
The Zung depression index |
0 - 100 |
| CESD |
The Center for Epidemiological
Studies depression index |
0 - 60 |
* As marked by the patient on a visual analog scale
In addition, the correlation between antibody titers and a tenth
clinical measure of fibromyalgia severity approached statistical
significance at p = 0.06. This tenth measure was ABDMPAIN, which
represents the number of days in which abdominal pain was
experienced during the last week.
In a separate presentation at the 5th World Conference on
Myofascial Pain and Fibromyalgia, anti-polymer antibodies were shown
to belong to the IgG2 subclass of human immunoglobulins, a subclass
of IgG composed of antibodies that typically recognize non-peptide
antigens.(4)
In the San Antonio study, APA seroreactivity was found in
approximately 26% of the population of relatively healthy normal
controls. Subsequent analysis revealed that the APA-positive members
of the control group exhibited a statistically-significant (p <=
0.05) increase in pain sensitivity as measured by dolorimeter, which
suggests that anti-polymer antibodies are present in individuals
with mild manifestations of fibromyalgia. A high APA reactivity rate
among individuals who consider themselves to be healthy corresponds
with the rate of subclinical fibromyalgia, which approached 20% of
in the adult female population in the United States, that was found
in studies by Clauw(5) and by Wolfe et al.(6)
The National Institute of Public Health and the Environment, or
RIVM, in The Netherlands has found the APA Assay to give
reproducible results and to be useful for the evaluation of the
presence of anti-polymer antibodies in human serum.(7)
The APA Assay was developed at Tulane University Medical School
and has been licensed to Autoimmune Technologies LLC of New Orleans.
The APA Assay is currently covered by U.S. and Australian patents,
and European and other patents are pending.
The San Antonio study employed the ELISA kit form of the APA
Assay. The study found the ELISA kit to be highly reliable, with a
reliability coefficient of 0.97. Though the APA Assay kit is not yet
in commercial distribution in the United States, the Assay is
available from Autoimmune Technologies as a service to interested
physicians and researchers for investigational use. The ELISA kit
form of the APA Assay will be available in the near future in other
countries.
REFERENCES
1. Wilson, R. B., O. S. Gluck, J. R. P. Tesser, J. C. Rice, A. Meyer,
and A. J. Bridges. Antipolymer Antibody Reactivity in a Subset of
Patients with Fibromyalgia Correlates with Severity. Journal of
Rheumatology 1999;26:402-407.
2. Tenenbaum, S. A., J. C. Rice, L. R. Espinoza, M. L. Cuéllar,
D. R. Plymale, D. M. Sander, L. L. Williamson, A. M. Haislip, O. S.
Gluck, J. R. Tesser, L. Nogy, K. M. Stribrny, J. A. Bevan, and R. F.
Garry. Use of Antipolymer Antibody Assay in Recipients of Silicone
Breast Implants. The Lancet 1997;349:449-454.
3. Xiao Y. M., Russell I. J., Michalek, J. E. and Wilson, R.B.
Journal of Musculoskeletal Pain 2001, Volume 9, Supplement Number
5;106
4. Wilson, R.B. Characterization of Anti-Polymer Antibodies
Present in the Serum of Patients with Fibromyalgia Syndrome. Journal
of Musculoskeletal Pain 2001, Volume 9, Supplement Number 5;105
5. Clauw, D. J. The Pathogenesis of Pain and Fatigue Syndromes,
with Special Reference to Fibromyalgia. Med Hypothesis 1995;
44:369-378
6. Wolfe, F., K. Ross, J. Anderson, I. J. Russell, and L. Hebert.
The Prevalence and Characteristics of Fibromyalgia in the General
Population. Arthritis Rheum 1995;38:19-28.
7. W. H. de Jong, S. W. Spiekstra, H. van Loveren. Detection of
Antipolymer Antibodies (APA) in Serum of Women with Silicone Breast
Implants. Introduction and Performance of the Assay in the RIVM.
Rijksinstituut voor Volksgezondheid en Milieu, National Institute of
Public Health and the Environment, Bilthoven, The Netherlands. RIVM
report 640700.001, October 1998.
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