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(Updated 08/03/99)
. Living
with fibromyalgia: One woman's story
By Ann Marie Brauner
(WebMD) -- One day, shortly after
the birth of her second baby, Nancy,*
then 39, collapsed into a chair in her
home. It wasn't quite noon, yet she
was already exhausted. She had been
noticing that she didn't have as much
energy with her second child as she
had had with her first. Today was no
different than the days before: Her
muscles ached and she wasn't
sleeping well.
Nancy would eventually learn the reason for her pain and lack of energy:
fibromyalgia syndrome, or FMS.
A muscular condition that affects mostly women
"FMS is a chronic muscular condition that causes widespread pain in
multiple tender points at the juncture between muscles and tendons," says
Dr. Andre Barkhuizen, assistant professor of rheumatology at Oregon
Health Sciences University. "In FMS patients, the central nervous system
perceives as pain what most people think of as pressure."
The American College of Rheumatology estimates that fibromyalgia affects
3 to 6 million Americans (about 2 percent of the U.S. population). The
patients are predominantly women; a 1995 study published in the journal
Arthritis and Rheumatism found that women are seven times more likely to
develop fibromyalgia than men. Barkhuizen says perhaps 10 percent to 20
percent of FMS sufferers have cases as severe as Nancy's.
Getting a diagnosis
Nancy's condition progressed from mild aches and general tiredness to the
point where she had trouble walking from room to room. "It was December
of 1989," recalls Nancy, now 49. "I tried to stand up and felt excruciating
pain in my arms, legs and neck. I couldn't even make it out of the room."
Nancy visited her internist, who referred her to a specialist in rheumatoid
arthritis. "The doctor reviewed my x-rays and did an 18-point trigger test,
which is one of the ways they diagnose fibromyalgia. I had soreness in
all
18 trigger points. He then made the diagnosis of FMS."
Nancy was lucky to have her condition diagnosed. Many of the women she
has encountered in online FMS support groups have not met with the same
quality of care as she has. "Many are told it's all psychological," she
says.
"Because the symptoms are invisible, people assume it's all in their minds.
They look fine on the outside, so what could be wrong?" Not all physicians
are convinced of the existence of the disorder.
"Individuals who believe they may be suffering from FMS symptoms should
be seen by a physician who believes in the syndrome," Barkhuizen says.
Nancy agrees. She suggests that sufferers contact a qualified rheumatologist
for advice and treatment.
Treatment plans vary
Taking medication by itself does little to ease the symptoms. Nancy takes
a
prescription-strength painkiller and uses a small muscle stimulation unit,
Transcutaneous Electrical Nerve Stimulation (TENS), to aid in pain
management. TENS, used for many types of chronic pain, sends electrical
impulses to nerves and helps block the transmission of pain signals to
the
brain. It also increases the production of endorphins, the body's natural
painkillers.
Physical exercise is one therapeutic approach to FMS. For patients with
symptoms less severe than Nancy's, light exercise can help to loosen painful
joints and improve flexibility. For more severe cases where physical activity
is painful, doctors recommend light stretching or hydrotherapy. Nancy
regularly sits in a hot tub with airjets, which helps relax her muscles
and
provides temporary pain relief.
To combat "fibrofog," the name inner circles give to such FMS symptoms
as short-term memory loss and the inability to concentrate, Nancy does
puzzles and writes in a journal. "FMS impairs your sense of thinking,"
she
says. "I push myself to do things that will stimulate me mentally."
Nancy also takes a mild antidepressant to help her sleep more deeply.
Most FMS patients are notoriously poor sleepers and some doctors think
fibromyalgia symptoms are linked to abnormalities in deep sleep.
Shrouded in mystery
"No one single thing has been proven to be the cause of FMS," says
Barkhuizen. "A variety of circumstances may cause an individual with
predisposed pain to develop FMS." These factors include a previous injury
that never quite healed, a lack of REM sleep, abnormalities in the spinal
cord or even a tendency toward depression.
Although fibromyalgia is chronic, the symptoms may cycle through various
stages of severity. Nancy says she slips in and out of "remission" often.
"Today is a good day," she says, "but I never know what will happen next.
At any given moment, I might experience pain that impairs me to the point
of debilitation. I just have to take each day as it comes."
*This woman's name has been changed in order to protect her privacy.
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
(Posted 05/25/99)
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)
(Posted 05/25/99)
NEW LAB
MARKERS FOR CHRONIC FATIGUE
SYNDROME
What is Chronic Fatigue and Immune Dysfunction
Syndrome?
Chronic Fatigue and Immune Dysfunction Syndrome
CFS/CFIDS is the new onset of persistent and debilitating
fatigue in a person who has no previous history of similar
symptoms. According to the revised case definition of chronic
fatigue syndrome by CDC, chronic fatigue is defined as
self-reported persistent fatigue lasting six months or longer.
Patient is classified having chronic fatigue if:
A. Criteria for severity of fatigue are met, and
B. Four or more of the following symptoms are concurrently
presents for six months or more
1.Impaired memory or concentration
2.Sore throat
3.Tender cervical and axillary lymph nodes
4.Muscle pain
5.Multi-joint pain
6.New headaches
7.Unrefreshing sleep
8.Post exertion malaise
The precise nature and cause of CFIDS is not clear at
this time. However, recent studies have shown:
A. Clinical and serological association of CFS with all of the
human herpes viruses, particularly EBV and the recently
discovered Human B-lymphotropic Virus (HBLV) or Human
Herpes-6, Human T-lymphotropic virus (HTLV) types I and II,
foamy or Spuma virus, and possibly mycoplasma incognitus.
B. CFIDS Syndrome might be due to physiological
manifestations of neurological influences on immune function
by neurohormones or other immunomodulators of
T-lymphocyte function, including the above-mentioned viruses.
Apparently, viruses, upon binding to different lymphocyte
surface markers, induce a secretion of several lymphokines.
This interaction may interfere with the regulation of immune
response including mucosal, humoral and cellular immunity.
C. Chronic Fatigue and Immune Dysfunction Syndrome
patients may have T-Helper 1 and/or T-Helper 2
dysregulation.
T lymphocytes have been subdivided into naive cells and
memory cells or CD4+ T cells that respond to recall antigen.
As lymphocytes develop into memory cells following antigenic
stimulation, they cease to express CD45RA and begin to
express CD45RO on their surface. The memory CD4+ T cell
population has been subdivided further into two functionally
distinct subsets, T helper-1 and T helper-2. The Th1 cells
produce IFN-Gamma and IL-2 but not IL-4 nor IL-5, whereas
Th2 cells produce IL-4 and IL-5 but not IFN-Gamma nor IL-2.
The Th1 cytokines induce important cellular responses that
are central to the elimination of intracellular pathogens. The
Th2 cytokines induce distinct responses as well, most notably
the induction of IgE, eosinophilia and allergic reaction.
Measuring these parameters recently we have been able to
demonstrate T helper-1 and/or T helper-2 imbalance and
immune dysregulation in patients with CFIDS. Since CD4+ T
cells play a key role in regulating the function of the immune
system and immunological diseases are greatly influenced by
the pattern of T cell activation, the ability to measure T
helper-1, T helper-2 imbalance is likely to provide a basis for
diagnosis and treatment of such diseases.
D. The other immune abnormalities, such as the decrease of
natural killer (NK) cell activity, lymphocyte mitogenic assay,
changes in the ratio of T-helper to T-suppressor cells, and
changes in CD11b/CD8, HLADR/CD8 and CD38/CD8 have
been continuously observed in CFIDS patients.
ABNORMAL NK CYTOTOXIC ACTIVITY IS ONE OF THE
MOST RELIABLE TESTS FOR THE DIAGNOSIS OF
CHRONIC FATIGUE IMMUNE DYSFUNCTION
SYNDROME.
Natural killer (NK) cells appear to play a role in a variety of
human diseases. Compromised or absent natural immunity,
as measured in vitro by decreased NK activity and/or
depressed absolute numbers of circulating NK cells, has
been linked to the development and progression of cancer,
chronic and acute viral infections, including the acquired
immunodeficiency syndrome (AIDS), chronic fatigue
syndrome, psychological dysfunction, various
immunodeficiencies, and certain autoimmune diseases.
Recent evidence indicates that NK cells may be involved in
multiple effector, regulatory, and developmental activities of
the immune system and that deficiencies or abnormalities in
NK cell function may contribute to, or be a biologic
marker for disease. Furthermore, recent evidence
indicates that there is a relationship between an
individual's reaction to emotional stress and NK activity.
Attempts are being made to define the mechanism
responsible for low NK activity in individuals who have
difficulties in handling stress and in those suffering from
behavioral disorders.
The role of NK cells in viral disease has been known for a
long time. The correlation between low NK activity and
serious viral infections in immunocompromised hosts, e.g., in
AIDS, after transplantation and in certain congenital
immuno-deficiencies, has been well documented.
Abnormalities in NK function have been described in a variety
of autoimmune diseases and, since these diseases are
frequently associated with serious viral infections and
malignancy, low levels of NK activity may be biologically
important in individuals with autoimmune disorders. Finally,
chronic fatigue immune dysfunction syndrome (CFIDS)
is characterized by a number of immunologic
abnormalities, the most consistent being a significant
depression of NK activity. Recently, a similar phenomenon
(low NK cytotoxic activity) was reported by our laboratory in
patients who have a history of toxic chemical exposure. For
the above reasons, it is important to detect
abnormalities in NK cell function.
E. Defects in the 2-5A Synthetase/RNAse L Pathways:
A key regulatory enzyme in the interferon induced antiviral
defense mechanism is 2-5A Synthetase. In the presence of
dSRNA (provided by the virus), the 2-5A synthetase catalyzes
production of 2',5'-oligoadenylates (2-5A) from ATP. The
2-5A binds to and activates a 2-5A-dependent endonuclease
(RNaseL). Activated RNase L cleaves single-stranded
regions of RNA which leads to inhibition of viral protein
synthetase. Recently the levels of 2-5A synthetase,
intracellular 2-5A, and RNase L have been measured in
individuals with chronic fatigue immune dysfunction syndrome
(CFIDS). In addition to low natural killer cytotoxic activity, it
was shown that this critical enzyme is not functioning properly
in patients with CFIDS. Specifically, compared to controls,
activated 2-5A synthetase was increased up to 10 fold,
intracellular levels of bioactive 2-5A was increased up to 220
fold, and RNase L was elevated up to 45 fold. Therefore,
measurements of these enzymes, especially the protein level
and the message are of great importance for the diagnosis of
viral induced chronic fatigue or other immune dysfunction
syndromes.
F. PKR or Protein Kinase P1
Another interferon-induced anti-viral gene is the PKR. PKR is
a serine-threonine kinase activated by dSRNA in the
presence of ATP and divalent cations. Upon activation, PKR
is autophosphorylated and Phosphorylates the Alpha subunit
of eukaryotic initiation factor 2-Alpha (eIF-2). Phosphorylation
of the Alpha subunit of eIF-2 by PKR inhibits translation
initiation by impairing the beta catalyzed guanine nucleotide
exchange reaction, a key regulatory reaction in protein
synthesis. In healthy individuals, the activity of the protein
kinase P1 or PKR remains constant. In contrast, the activity of
this protein kinase is enhanced significantly in patients with
viral infections (please see figure depicted below) and is
decreased during the course of the disease in parallel with
clinical ameliorations and reversal of clinical symptoms. There
is a strong correlation between the enhanced levels of the
protein kinase activity and another interferon-mediated
enzyme, 2-5A synthetase. Both of these enzymes, therefore,
could be used as markers to evaluate the state of the disease
and recovery. The anti-viral activity of this protein kinase and
its similarity to 2-5A synthetase and their role in inhibition of
protein synthesis is presented in the attached figure 7.
Measurements of these enzymes and detection of their
mRNA level are very important in studying mechanism
of interference with signal transduction in lymphocytes
of patients with chronic fatigue and other immune
dysfunction syndromes.
G. Absence or low RNase L inhibitor in patients with
chronic fatigue
The 2-5A/RNase L system is considered as a central pathway
of interferon action and could possibly play a more general
physiological role as for instance in the regulation of RNA
stability in mammalian cells.
Recently, a new type of endonuclease inhibitor was cloned
and characterized. By using the polymerase chain reaction
we measured the level of this RNase L inhibitor in patients
with CFIDS. It was found that this inhibitor either is absent or
very low in these patients. Low levels or absence of RNase L
inhibitor may be the mechanisms by which RNase L is
induced. This enzyme has the capacity to degrade single
stranded RNA of hypotethical virus involved in the pathway of
interferon action. Measurements of RNAase L inhibitor along
with PKR may confirm virus as a cause of chronic fatigue
syndrome.
H. Protein Kinase-C and Its Isozymes
Protein Kinase-C (PKC) is a signal transducing enzyme
which is playing an important role in cellular communication
and in the mechanism of cell mediated cytotoxicity. Levels of
protein Kinase-C were found to be abnormal in patients with
low NK activity. Measurements of PKC are very important in
studying the mechanism of interference with signal
transduction in lymphocytes of patients with chronic fatigue
and other immune dysfunction syndromes. This signal
transduction system which consists of eleven different
isozymes, gets activated upon ligand-stimulation of
transmembrane receptors by hormones, neurotransmitters,
and growth factors.
Since each isozyme has a different biological function in the
immune system, analysis of the eleven PKC isozymes in
lymphocytes by western blot assay will help in the early
diagnosis and follow the treatments of patients with CFIDS.
Different level of
protein kinase P1
or PKR in normal
control (A) and
classical patient
with chronic fatigue
syndrome (B). Note
presence of peak
number 2 and
enhancement of
peak in chronic
fatigue patient.
IMMUNOSCIENCES LAB., INC. http://www.immuno-sci-lab.com/fatigue.html
(Posted 02/22/99)
Study Shows Supplement
Helps Chronic Fatigue
WASHINGTON (Reuters) -- A
nutritional supplement based on an
energy-giving natural enzyme can help
in some cases of chronic fatigue
syndrome, researchers said Monday.
A team at Georgetown University in
Washington tested the supplement,
Enada, and found it helped as many
as 72 percent of patients with the
baffling condition.
More than 500,000 Americans have been diagnosed with chronic fatigue
syndrome, and an estimated 2 million people believe they have it.
In the Georgetown study, approved by the U.S. Food and Drug
Administration, Dr. Joseph Bellanti and colleagues said they tested 26
patients in the equivalent of a Phase II safety and efficacy trial.
For four weeks half the patients got Enada and half got placebos. For the
next month both groups got nothing, then the groups were switched -- and
the volunteers who got Enada the first time got a placebo for the next
four
weeks, while the second group got the supplement.
Neither group knew which they were getting at the time, placebo or
supplement.
Writing in the Annals of Allergy, Asthma and Immunology, Bellanti's team
said 31 percent of the patients said their symptoms got better while they
took Enada, as opposed to 8 percent of those on placebo.
Then the researchers opened the trial, allowing all the volunteers to
knowingly take Enada. After a year, 72 percent reported improvement.
Natural energy high
Enada is the brand name of the company's version of a natural |