.
OPEN LETTER
TO FIBROMYALGIA PATIENTS
On Fibromyalgia Awareness Day, May 12, 1999
SCIENCE AND FIBROMYALGIA
A Review of Recent Research
In February of this year, an article in a scientific
journal announced the discovery that a new immune system antibody had been
found to be associated with many cases of fibromyalgia.
This marked the first time that laboratory evidence of an immunological
process involving fibromyalgia had ever been detected,
and it is one of the most exciting developments in recent years concerning
a disorder that may affect as many as 15% to 20% of adult
women, and many men, in the United States.
What Is Fibromyalgia?
Fibromyalgia syndrome, or FM, is a chronic pain and fatigue
disorder. Together with widespread pain and "tender points" in
various areas of the body, signs and symptoms of FM include
fatigue, sleep disorder, morning stiffness, headache, memory loss,
disjointed thought processes, irritable bowel syndrome,
and other symptoms. Millions of individuals, most of whom are women, in
many countries throughout the world have been diagnosed
with FM, and millions more have fibromyalgia-like symptoms that
parallel but do not precisely meet the standards needed
to be given a formal diagnosis of FM.
The direct medical costs of fibromyalgia in the United
States alone have been estimated by one expert to be more than $16 billion
per year. A large portion of this cost falls directly
upon the patients.
The cause or causes of fibromyalgia are not currently
known, but researchers have suggested that trauma, infection, and exposure
to environmental factors may all trigger the development
of this debilitating illness. Research has recently shown that there is
a
hereditary element in FM, and it is possible that susceptible
individuals develop the disorder in response to one or more of these
triggers.
In the United States, some 3% to 5% of adult women meet
the strict diagnostic research criteria of the American College of
Rheumatology for fibromyalgia, but as many as 15% to
20% of adult women may actually have fibromyalgia-like symptoms. For
example, the strict diagnostic criteria for FM include
tenderness to the touch in at least eleven of eighteen specific musculoskeletal
points on the body, so tenderness in only ten of these
points would mean that the patient did not meet the strict criteria for
receiving a diagnosis of FM.
Why Are Antibodies Important?
Fibromyalgia has always been difficult to diagnose, in
part because it involves many different symptoms and seems to have
multiple causes. FM symptomatology includes pain that
changes and migrates, a characteristic of pain that doesn't fit neatly
into
every medical textbook. And there has in the past been
no confirming laboratory test for FM. For these and other reasons, not
everyone in the health care system has felt that FM is
a "real" disorder that involves a unique physiological process.
Many physicians practicing today think that fibromyalgia
is a product of aging, the result of a psychological problem, or a part
of
some other process, and they do not believe that FM is
a distinct disorder. Because of this, fibromyalgia patients frequently
find
they need to prove, to themselves or to others, that
they do have a "real" disorder and that they are not just being whiners,
malingerers, or slackers. This problem extends from the
home and family into the workplace, and it often becomes an issue in
disability insurance claims, where the absence of objective
proof of illness can be a major barrier to claim settlement.
The discovery of the new antibodies in many FM patients
is the first hard evidence that an immunological response is under way
in
these patients. FM patients can't "imagine" antibodies
into existence, and the presence of the new antibodies does not correlate
with the existence of other diseases, so the antibodies
in the FM patients' blood serve as an objective laboratory marker for
fibromyalgia and demonstrate that FM is a "real" disorder
that involves a physiological disease process.
Together with the medical benefits that can be expected
to result from this discovery, there may be other practical applications
for
FM patients. One attorney who is experienced in handling
fibromyalgia disability cases believes that disability insurers will have
to
look at FM much differently from the way they have in
the past. "Now that this laboratory test is available, the absence of
objective evidence can no longer be routinely cited as
a reason for disallowing a claim," he said.
What Are these Antibodies and What Do They Mean?
Researchers don't yet understand the disease process itself,
but they can indeed detect the antibodies associated with it. Called
anti-polymer antibodies, they were discovered several
years ago by scientists studying silicone breast implant patients at Tulane
University Medical Center in New Orleans. The scientists
were surprised to find that blood samples from a large number of breast
implant patients who were ill with fibromyalgia-like
symptoms contained what seemed to be a new antibody. After carefully
checking and rechecking their results they found that
the antibody was in fact previously unknown, and they decided to call it
an
anti-polymer antibody. They named the test that detects
the antibody the Anti-Polymer Antibody Assay, or APA Assay. They
published their findings in The Lancet in 1997, and Tulane
later obtained several patents on the APA Assay.
Tulane licensed the APA Assay to Autoimmune Technologies
LLC, a small New Orleans biomedical research and development
company. Autoimmune Technologies continued to do research
into anti-polymer antibodies and began a study of FM patients who
did not have breast implants or other implants of any
kind. The researchers found that a large percentage of FM patients had
these
antibodies and found that the presence of anti-polymer
antibodies correlated with the severity of the patients' FM symptoms. The
antibodies were found in only small numbers of patients
with other diseases, such as lupus, who did not also have FM. As a result,
these researchers found that the APA Assay served as
a blood test for fibromyalgia. Their work was published in the February
1999 issue of The Journal of Rheumatology.
The researchers also found that anti-polymer antibodies
were not present in all FM patients. This finding supports the concept
that
there may be multiple triggers of fibromyalgia, and the
researchers surmise that anti-polymer antibodies are associated with one
particular trigger of FM. They are now conducting additional
research to test that theory as well as to further explain the disease
process.
If You Don't Have the Antibodies, Does that Mean You Don't
Have FM?
No, not having the antibodies doesn't mean that a patient
doesn't have fibromyalgia. In the published studies, anti-polymer
antibodies were found in fewer than 70% of patients with
the most severe FM symptoms and in about 50% of patients who had
ever received a diagnosis of fibromyalgia.
There is a saying that medical testing is like prospecting
for gold: finding something proves that it is there, but not finding something
doesn't prove that it isn't there. Not finding anti-polymer
antibodies might mean that a patient is not currently producing the
antibodies, or it might mean that the patient's symptoms
are associated with an FM trigger that is not related to the antibodies,
or it
might mean something else. It does NOT mean that the
patient does not have FM.
Another example of this is the test for rheumatoid arthritis
that looks for a protein called Rheumatoid Factor, or RF, which is
associated with that disorder. About 20% of rheumatoid
arthritis patients test negative for RF, but the negative test results
do not
mean that those patients don't have rheumatoid arthritis.
Research in the United States
The APA Assay detects the presence of anti-polymer antibodies,
and Autoimmune Technologies is now designing the research
protocols to use in asking the U.S. Food and Drug Administration
to approve diagnostic use of that information. The company is
continuing its work to define the disease process associated
with anti-polymer antibodies and to demonstrate which FM trigger
may be associated with the antibodies. The company has
also initiated studies to determine whether certain drugs are working
better in patients who test positive on the APA Assay
than on patients who do not.
Research in Europe
After the publication of the article in The Lancet in
1997, scientists in The Netherlands approached Autoimmune Technologies
and
expressed an interest in conducting research there using
the APA Assay. Dutch scientists subsequently found the APA Assay to
be reproducible and useful for evaluating the presence
of anti-polymer antibodies in human serum, and the APA Assay was
introduced into the National Institute of Public Health
and the Environment, or RIVM, in 1998. Antibody research using the APA
Assay is now under way in The Netherlands.
Is the Test Available Yet?
At present, any physician in the U.S. or any other country
may order the APA Assay from Autoimmune Technologies to
determine if a patient's blood contains anti-polymer
antibodies, although it remains the responsibility of the physician ordering
the
APA Assay to decide how to make use of the results of
the test in his or her investigation into the patient's condition. In the
United States, a combination of U.S. Food and Drug Administration
regulations and patent laws prohibit any other labs from
conducting the APA Assay until it has been put into a
portable kit format and the diagnostic value of the kit and the information
that the APA Assay conveys about anti-polymer antibodies
has been approved by the FDA. Such a test kit is now being
developed by Autoimmune Technologies. In most European
and other countries the physicians make their own determinations of
the diagnostic values of such tests, and the test kit
will be made available in those countries as soon as it is ready.
Information on the Web
The National Fibromyalgia Awareness Campaign maintains
a Web site at http://members.xoom.com/nfac/home.htm that provides
a good starting point for exploring the many excellent
fibromyalgia sites and related medical sites on the Internet. The Web
address of Autoimmune Technologies is www.autoimmune.com.
To Fibromyalgia Patients
The scientists and physicians involved in this research
all hope that their work will eventually lead to better treatments for,
and
ultimately to a cure for, fibromyalgia. Today, on Fibromyalgia
Awareness Day, they offer their thoughts to all of the patients who
are living with FM and wish them well.
For more information about our research on fibromyalgia,
see Science Summary
and News Release
of February 10, 1999.
For information about having us perform the APA Assay,
see
Requisition
Form.
Go to the
Autoimmune Technologies Home Page
Low-Dose
Hydrocortisone for Chronic
Fatigue Syndrome
.
Letters - May 26, 1999
To the Editor: Dr McKenzie and colleagues[1] suggest that
hydrocortisone, despite its effectiveness against chronic fatigue syndrome
(CFS), should not be used as a prolonged treatment for CFS because they
found that "cautious hormonal supplementation" consisting of "low-dose"
hydrocortisone caused a significant degree of adrenal suppression. Such
suppression, however, may simply indicate that the dosage of
hydrocortisone was neither cautiously low nor suitable for CFS patients.
Hydrocortisone in dosages greater than 22 mg/d may harm even subjects
with bilateral adrenalectomies,[2] whose adrenal insufficiency is axiomatically
absolute. Therefore, the 25- to 35-mg/d hydrocortisone dosage
administered by McKenzie et al clearly represents an inappropriately high
dosage for CFS patients, whose adrenal insufficiency is mild, since those
authors report that "CFS patients excreted, on average, about 30% less
cortisol in 24-hour urine collections than healthy, matched controls."[1]
During the twice-daily regimen of glucocorticoid replacement therapy, the
second daily dose is usually administered in the evening.[2] Therefore,
it is
unclear why McKenzie and colleagues administered the second daily dose
of hydrocortisone at about 2 PM. This is even more surprising if we consider
that they cite a study in which some authors of their group reported that
basal cortisol levels of CFS patients were significantly reduced in the
evening. In view of the many undesirable consequences of overtreatment
with glucocorticoids,[2] it is likely that 10 to 15 mg/d of hydrocortisone,
split
as 5 to 10 mg at 8 AM and 5 mg at 6 PM, would have provided greater
benefit for McKenzie and coworkers' subjects, without producing adrenal
suppression.
McKenzie and colleagues state that "mere supplementation of cortisol is
not
sufficient" in the treatment of CFS and propose future pharmacological
options. Surprisingly, however, they fail to mention an available option
I
proposed 3 years ago[3] and appears promising, namely, hydrocortisone
plus fludrocortisone acetate. This mineralocorticoid, if administered
properly,[4] appears to improve CFS symptoms substantially.[3] Scott and
colleagues[5] support the view that hydrocortisone plus fludrocortisone
may
benefit CFS patients, writing that "replacement therapy may more
appropriately involve not only glucocorticoid, but mineralocorticoid
supplements also."
The rationale for using both hydrocortisone and fludrocortisone in the
treatment of CFS lies primarily in the similarity between CFS and Addison
disease, which shares 26 features with CFS[4] and is routinely treated
with
hydrocortisone plus fludrocortisone.[2] Hormonal supplementation,
however, could hardly benefit patients meeting the "Oxford" criteria for
CFS
because they have hypercortisolism.[6]
Riccardo Baschetti, MD
Padua, Italy
1. McKenzie R, O'Fallon A, Dale J, et al. Low-dose hydrocortisone for
treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA.
1998;280:1061-1066.
2. Peacey SR, Guo C-Y, Robinson AM, et al. Glucocorticoid replacement
therapy: are patients overtreated and does it matter? Clin Endocrinol.
1997;46:255-261.
3. Baschetti R. Chronic fatigue syndrome and neurally mediated
hypotension. JAMA. 1996;275:359.
4. Baschetti R. Treatment for chronic fatigue syndrome. Arch Intern Med.
1998;158:2266.
5. Scott LV, Medbak S, Dinan TG. The low dose ACTH test in chronic
fatigue syndrome and in health. Clin Endocrinol. 1998;48:733-737.
6. Baschetti R. Treating chronic fatigue with exercise: results are
contradictory for patients meeting different diagnostic criteria. BMJ.
1998;317:600.
(JAMA. 1999;281:1887)
To the Editor: We congratulate Dr McKenzie and colleagues[1] on their
excellent study but would like to correct an important error and add data
that may increase the clinical utility of their study.
Our previously published pilot study[2] and the work of Jefferies[3,4]
suggests that using low-dose hydrocortisone (4 mg of hydrocortisone 1 mg
of prednisone) in CFS at dosages of 7.5 to 20 mg/d is safe and effective.
These low dosages have not caused the adrenal suppression[3,4] seen with
the higher dosages (25-35 mg/d) used by McKenzie et al. They are also less
likely to aggravate the already severe disruption of deep sleep present
in
CFS patients, as was seen in the study by McKenzie et al (P=.02 vs
placebo).
McKenzie and colleagues' reference to Jefferies' work incorrectly notes
that
"low-dose glucocorticoid replacement, defined as 20 to 40 mg [daily] of
hydrocortisone...was felt to be safe." Jefferies notes that 40 mg of
hydrocortisone per day is an optimum full-replacement dosage; it is not
the
safe or optimum dosage for treating CFS. In the cited reference,[3] Jefferies
noted that "in our clinics the term 'low-dose' has referred to oral doses
of
cortisone or hydrocortisone totaling 20 mg or less daily." Thus, McKenzie
and colleagues' underlying premise that the 25- to 35-mg/d dosage they
used was what Jefferies (and others) considered to be low dose was
incorrect.
We recently completed a randomized, double-blind study that tested the
effectiveness of treating patients with fibromyalgia and CFS for hypothalamic
dysfunction in an integrated manner (unpublished data, 1998). This included
treating suspected hormonal deficiencies (including low hydrocortisone)
and
the sleep disorder simultaneously. Using this protocol (described
previously[2] ) in 72 patients (of whom 64 completed the study) resulted
in a
significant improvement in active vs placebo group (P<.0001 for the
fibromyalgia impact questionnaire, analog scores, and tender point index).
Seven patients in our study who were treated with low-dose hydrocortisone
(eg, 2.5-20 mg/d) were given prestudy and poststudy hydrocortisone
stimulation tests. Adrenal suppression was not seen. Average hydrocortisone
levels were 386, 635, and 717 nmol/L before and 469, 635, and 717
nmol/L after hydrocortisone treatment.
These and previous data[2-4] suggest that hydrocortisone dosages of 2.5
to
20 mg/d (combined with medications that improve deep sleep) are safe. In
CFS and fibromyalgia patients who feel better when taking hydrocortisone
these dosages may result in clinically important symptomatic improvement
without causing adrenal suppression.
Jacob E. Teitelbaum, MD
Barbara Bird, MT, CLS
Alan Weiss, MD
Laurie Gould
Annapolis Research Center for Effective FMS/CFIDS Therapies
Annapolis, Md
1. McKenzie R, O'Fallon A, Dale J, et al. Low-dose hydrocortisone for
treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA.
1998;280:1061-1066.
2. Teitelbaum J, Bird B. Effective treatment of severe chronic fatigue:
a
report of a series of 64 patients. J Musculoskeletal Pain. 1995;3:91-110.
3. Jefferies WM. Low-dosage glucocorticoid therapy: an appraisal of its
safety and mode of action in clinical disorders, including rheumatoid arthritis.
Arch Intern Med. 1967;119:265-278.
4. Jefferies WM. Safe Uses of Cortisol. 2nd ed. Springfield, Ill: Charles
C
Thomas Publisher; 1996.
(JAMA. 1999;281:1887-1888)
To the Editor: Dr McKenzie and colleagues[1] continued their thorough
studies of hypothalamic-pituitary-adrenal axis dysregulation in patients
with
CFS and found that treatment with hydrocortisone mildly increased their
global wellness scale. However, several comments are in order. First,
glucocorticoids often induce a feeling of euphoria.[2] Because a control
population was not studied, the effect may not be specific to patients
with
CFS since healthy volunteers may also feel "better" when treated with
hydrocortisone.
Second, at the dosage of hydrocortisone used, significant mineralocorticoid
activity may have contributed to the beneficial effect of hydrocortisone.
We
estimate that this dosage of hydrocortisone supplies approximately 50%
of
the mineralocorticoid replacement. The authors did not provide information
on weight or orthostatic blood pressure changes, which may support the
role
of the mineralocorticoid properties of hydrocortisone on the improvement
of
CFS patients. In an open-label trial, fludrocortisone, a synthetic
mineralocorticoid, improved orthostasis and symptoms of fatigue.[3] These
findings, coupled with the high incidence of orthostasis in patients with
CFS[3] and the fact that delayed orthostasis often results in the symptom
of
fatigue,[4] further support the notion that these patients have impaired
mineralocorticoid activity.
Third, because of the heterogeneous nature of CFS, it may be important
to
select patients with mild adrenal insufficiency for hydrocortisone to be
effective. McKenzie et al excluded patients who had an onset of illness
over
a period of 6 weeks. We suspect that patients with adrenal insufficiency
(mineralocorticoid or glucocorticoid) would have an insidious onset of
illness, while patients with an infectious cause would present with a more
acute onset. Thus, the authors may have excluded the very patients who
would likely benefit from treatment.
Finally, it is noteworthy that in this and other studies, most patients
with CFS
are white. One possibility for this low representation of ethnic patients
is that
white patients consume less salt than those of other ethnicities, such
as
African American, Asian, and Hispanic. Bou-Holaigah et al[3] noted that
61% of patients with CFS in their study were following a self-imposed
sodium-restricted diet. We hypothesize that adequate salt intake may
compensate for mild mineralocorticoid insufficiency and reduce orthostasis.
Just as the corticotropin-releasing hormone-corticotropin-cortisol axis
of
patients with CFS has been well studied,[5] studying the renin-aldosterone
axis in depth in CFS patients may uncover a subset of patients with
mineralocorticoid insufficiency who would benefit from fludrocortisone
or
salt treatment.
Theodore C. Friedman, MD, PhD
Abby Adesanya
Cedars-Sinai Medical Center
Los Angeles, Calif
Russell E. Poland, PhD
Harbor-UCLA Medical Center
Torrance, Calif
1. McKenzie R, O'Fallon A, Dale J, et al. Low-dose hydrocortisone for
treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA.
1998;280:1061-1066.
2. Murphy BE. Steroids and depression. J Steroid Biochem Mol Biol.
1991;38:537-559.
3. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between
neurally mediated hypotension and the chronic fatigue syndrome. JAMA.
1995;274:961-967.
4. Streeten DHP. The nature of chronic fatigue. JAMA.
1998;280:1094-1095.
5. Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJP.
Evidence for impaired activation of the hypothalamic-pituitary-adrenal
axis in
patients with chronic fatigue syndrome. J Clin Endocrinol Metab.
1991;73:1224-1234.
(JAMA. 1999;281:1888)
In Reply: Our study of patients with CFS was designed to evaluate efficacy
and safety of hydrocortisone.[1] We reported that divided doses totaling
25
to 35 mg/d for 12 weeks provided significant but modest symptomatic relief
and also significant adrenal suppression. Our conclusion, then and now,
is
that the risks associated with low-dose hydrocortisone treatment outweigh
its potential advantages for patients with CFS.
Dr Baschetti and Dr Teitelbaum and colleagues suggest that the dosage we
used was too high. We based our regimen on our prior observation that
CFS patients secrete approximately 30% less cortisol per day than healthy
subjects.[2] Our hypothesis was that modest glucocorticoid supplementation
might ameliorate CFS symptoms.
We were aware of the work by Jefferies,[3] whose clinical experience led
him to conclude that hydrocortisone dosages totaling 10 to 20 mg/d
ameliorate fatigue. He reported, though, "...that low dosages of cortisone
partly suppress endogenous adrenocortical production of...hydrocortisone
to
a degree proportional to the dosage." Thus, low-dose exogenous
hydrocortisone treatment will not raise net glucocorticoid levels. Based
on
these considerations, we presumed that there would be no symptomatic
improvement in CFS patients unless their glucocorticoid levels could be
supplemented toward the normal range.
Perhaps, however, a lower dosage is effective. Teitelbaum et al summarize
their own trial as suggesting benefit of low-dose hydrocortisone. We
welcome a complete account of their methods and results. Since our report
appeared, though, Cleare et al[4] found that 5 to 10 mg of hydrocortisone
per day provides symptomatic relief for patients with CFS. Moreover, they
observed no evidence of adrenal suppression. Unfortunately, the extent
of
symptomatic benefit was modest, failing to achieve the study's primary
therapeutic end point. In addition, treatment was provided for only 4 weeks,
a duration that may be insufficient for such effects to be evident.
Thus, if defective glucocorticoid secretion is a primary problem in CFS,
then
low-dose replacement may, over time, worsen clinical outcome by inhibiting
the remaining endogenous glucocorticoid production. In fact, we proposed
that a more likely explanation for the findings in CFS is that peripheral
glucocorticoid secretion is a downstream indicator of a more proximal
disturbance in central nervous system function.[2] Emerging lines of evidence
regarding neuropsychological changes, psychiatric morbidity, and
neurotransmitter levels in CFS are consistent with this view.
We agree with Dr Friedman and colleagues that the benefits observed in
our
report may reflect the expected effects on general well-being of short-term
glucocorticoid administration to humans. Rather than being nonspecific
effects, they likely reflect hydrocortisone's known ability to activate
the
central nervous system. We also agree with Friedman et al, and Baschetti
that beneficial effects of hydrocortisone could have been mediated, in
part,
by its mineralocorticoid activity.[5] In this regard, we and collaborators
at
Johns Hopkins University are conducting a placebo-controlled trial of
fludrocortisone therapy in CFS. We await its completion for the insights
that
it will yield regarding the neuroendocrine disturbances in CFS and their
potential amelioration.
Stephen E. Straus, MD
National Institute of Allergy and Infectious Diseases
Bethesda, Md
Robin McKenzie, MD
Johns Hopkins University School of Medicine
Baltimore, Md
Mark A. Demitrack, MD
Lilly Research Laboratories
Indianapolis, Ind
1. McKenzie R, O'Fallon A, Dale J, et al. Low-dose hydrocortisone for
treatment of chronic fatigue syndrome: a randomized controlled trial. JAMA.
1998;280:1061-1066.
2. Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJP.
Evidence for impaired activation of the hypothalamic-pituitary-adrenal
axis in
patients with chronic fatigue syndrome. J Clin Endocrinol Metab.
1991;73:1224-1234.
3. Jefferies WM. Low-dosage glucocorticoid therapy: an appraisal of its
safety and mode of action in clinical disorders, including rheumatoid arthritis.
Arch Intern Med. 1967;119:265-278.
4. Cleare AJ, Heap E, Malhi GS, Wessley S, O'Keane V, Miell J.
Low-dose hydrocortisone in chronic fatigue syndrome: a randomised
crossover trial. Lancet. 1999;353:455-458.
5. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between
neurally mediated hypotension and the chronic fatigue syndrome. JAMA.
1995;274:961-967.
(JAMA.
1999; 281:1888-1889) (click)
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