Mycoplasmic Theory of Rheumatoid Disease

According to Thomas McPherson Brown, M.D.

by
Anthony di Fabio, Harold W. Clark,
Ph.D. (Mycoplasma Research Institute) Joseph
Mercola, D.O.
©2000

Introduction
When I (Anthony di Fabio) first suffered from
"galloping” rheumatoid arthritis my family
doctor knew only to provide me with pain
relievers while the damage to my joints
"galloped” on, and the pain intensified daily.
I eventually learned of the Roger Wyburn-
Mason, Ph.D., M.D. treatment based on the
theory that an amoeba was the culprit of the
disease. We were never able to prove Wyburn-
Mason’s theory, but we did know that he’d been
treating folks on a worldwide basis since the
1960s, and getting them well. I got well in six
weeks.
Then, later, after a number of medical doctors
and I had founded the Rheumatoid Disease
Foundation/The Arthritis Trust of America, we
all learned of the Thomas McPherson Brown,
MD. treatment based on his theory that a
mycoplasma was the chief culprit in those who
suffered from rheumatoid arthritis.

Since the Roger Wyburn-Mason treatment took

only six weeks — at best twelve weeks — to test
out, and the McPherson Brown treatment took
as long as a year or even two years, it always
seemed foolish that most medical doctors
leaned toward the Brown treatment first.
It mattered not to our new foundation which
theory was correct. I believe I speak for all
rheumatoid disease victims everywhere when I
say that we don’t care which theory is correct.
We only want the joint damage to stop and the
pain to quit, which also means that we’re only
barely interested in symptomatic treatment as
offered by the majority of medical practitioners.
The following, therefore, is considered by us
to be another method of getting well. There
can never be too many such methods in our
opinion.
Roger Wyburn-Mason, Ph.D., M.D. treatment
protocol for rheumatoid disease is rather well
defined in his The Causation of Rheumatoid
Disease and Many Human Cancers.

Nature of the Disease

The progressive immunologic rheumatoid

diseases are characterized by periodic and
chronic symptoms. The discovery of more
effective forms of sustained therapy is
handicapped by one significant fact: in
nearly all forms of chronic arthritis, the
causative factors although suspected remain
unknown. An infectious agent has long been
thought to initiate rheumatoid arthritis and
related diseases previously designated "chronic
infectious disorders” and "collagen vascular
disorders.” As recommended for many years
high priority should be given to an intensive
search for latent, slow-acting microbes such
as the ubiquitous and unique mycoplasmas
that as a viable irritant could cause persistent
inflammation.
In the immunologic disorders, such as the
rheumatoid diseases that may incubate for
years, the immune system becomes over-
reactive. In their efforts to destroy the irritating
agents the influx of digestive enzymes from
the activated white blood cells (WBC) start to
destroy the surrounding tissues causing the
inflammatory symptoms. The WBCs are also
activated to produce neutralizing antibodies
against the invading germs. The antibodies
combine with the germs in their effort
to help contain the infection. When the
antibodies combine with the germs or antigens
they form “immune complexes” that activate
the Complement enzyme system which in
turn can also destroy both irritating germs
and surrounding tissues. Both Lupus and
rheumatoid arthritis are characterized by the
deposition of immune complex in kidneys and
other tissues along with the erosion of blood
vessels.

Mechanistic Treatment

By eliminating the cause(s) the mechanistic

approach can be more effective and less
costly in controlling and preventing chronic
disease activity. This is unlike the symptomatic
treatment approach that temporarily relieves
symptoms. Basically there are three therapeutic
targets: 1) to search for and eliminate the
microbial cause(s) and metabolic defects. 2) to
identify and block immune complex formation,
and 3) to control and eliminate inflammation,
pain, and fatigue. The elimination of the
microbial root cause should be the primary
target. The less pathogenic or nonvirulent
microbes would be less reactive requiring less
antibiotic treatment.

Three-Prong Prescription

1. Antibiotics; such as minocyclines, in low

pulsed doses should be directed at inhibiting
the microbial cause and preventing the
disease. The multi-prong tetracyclines can also
act as antioxidants, immunosuppressants, and
protein synthesis inhibitors.
2. Immunosuppressants; that come in many
different forms of alternatives including low
dose prednisone that blocks the immune-
complex formation and the activation
of Complement which promotes tissue
destructive inflammation.
3. Anti-inflammatory antioxidants; such as
dietary supplements and the nonsteroidal
antiin-fiammatory drugs (NSAIDs) to eliminate
and prevent the tissue destructive
inflammation.
Several other major contributing factors
affecting the occurrence and severity of the
rheumatoid disorders must also be considered
in selecting the most effective treatment.
These include variable factors such as: Health,
Diet, Exposure, physical & mental Stress.
The most effective treatment is Good Health
that is individually controlled by ones’ Diet,
and exposures to physical and mental Stress.
The goal of many alternative therapies is
helping to achieve maximum good health
with natural dietary supplements and both
physical and mental stimulants. In addition
fixed factors that include: Age, Gender, and
Genetic susceptibility, all of which can help,
hinder or predispose the therapeutic success.
The treatment, for optimum benefits, should be
individually adjusted for ones’ age, body size,
and gender.
Even though the symptoms on the surface
are similar the underlying mechanisms can be
different.
(From the book: “Why Arthritis? Searching for
the Cause and the Cure of Rheumatoid Diseases"
Copyright by Harold W. Clark, Ph.D., used by
permission.)

Dr. Brown’s Antibiotic Treatment Plans

In his medical practice the late Thomas

McPherson Brown, M.D. seemed to have a
treatment protocol, a plan, for each rheumatoid
patient that included some form of anti-
mycoplasma antibiotics.
Using different medications and dosages made
it difficult to statistically compare and evaluate
any single therapy. Medications were often
changed trying to find both a tolerable
and effective therapy. As new drugs became
available they were continuously evaluated. For
example tetracycline dosages varied from 10
mg. to 1000 mg. or from daily to weekly with
oral and intravenous administration including
several days of hospitalization. A significant
study of 98 hospitalized rheumatoid arthritis
patients treated over a five year period found
that over 70 were substantially improved using
the variable antibiotic treatment plan which
was anything but the standard infection plan of
1 gm./day for 10 days.
The protocols weren’t just drugs and antibiotics
as Dr. Brown was also interested in the psycho-
social aspects of illness and patient care. With
extensive interviews the treatment also focused
on both the patient and their family and not
simply the disease. He worked extensively with
a team of rehabilitation experts in helping
to alleviate and solve the underlying patient
problems. A good example of comprehensive
medicine was the support by John L. Lewis,
president of the Miners Union, that provided
total care of the West Virginia miners’ medical
problems. Although not discussed in his book
The Road Back Dr. Brown was also the director
of a multi-discipline medical Rehabilitation
Center that also pursued the causes and the
solutions to the related physical and mental
health problems associated with rheumatoid
diseases. The Allied Health staff proved
essential for the therapeutic effectiveness.
Like their diverse rheumatoid patients, doctors
after leaving school and with experience
developed their own theories and philosophy of
patient care that are a little different from their
professor’s and others. A consensus of what is
the right medicine, a protocol for all patients,
is not the question or the issue as medicine is
more of an art than a science. There are many
skilled artists and also 171
different wide ranging forms of arthritis. Most
symptoms have suspected or unknown causes
and become chronic or are short lived with
periods of spontaneous remission. Because
of the many different kinds and severity
of symptoms many will require more than
antimicrobials for control and eradication.
Eventually with control comes prevention
of the various forms of arthritis with
regulated living and application of improved
and alternative therapies. In his treatment
plans Dr. Brown promoted a Mechanistic
approach in searching for the cause and
cure of rheumatoid diseases. Because of the
many targets Symptomatic treatment requires
multiple medications that further complicate
the protocol and the evaluation of safe and
effective results. Prescribing a treatment for
the primary causes provides a direction for
the evaluation of effectiveness. For nearly forty
years Dr. Brown was considered a maverick
whose antibiotic treatment plan was criticized
as unproven quackery and whose strong
personality convinced patients they were
better. Now today after the antibiotic approach
has been extensively tested and proven to be
safe and effective in rheumatoid diseases both
doctors and patients are finding the treatment
beneficial.
Dr. Thomas McPherson Brown [was] the
chairman of the Arthritis Clinic of Northern
Virginia. A world-renowned leader in arthritis
research and treatment, Dr. Brown has served as
a consultant to the White House and has been
a member of the National Research Council and
the Food and Drug Administration’s Arthritis
Advisory Committee.
He is a graduate of Swarthmore College and
Johns Hopkins Medical School. Dr Brown has
served as Chief Resident in Medicine at Johns
Hopkins and as a Resident at the Rockefeller
Institute Hospital.
He has held several prestigious positions,
including Director of Arthritis Research at
the Veterans Hospital in Washington, D.C.,
and Chairman of the Department of Medicine
at George Washington University School of
Medicine for a twenty year period. He founded
the Arthritis Institute of the National Hospital
for Orthopaedics and Rehabilitation in 1970.
His work on rheumatoid arthritis dates back
to the late 1930’s during his tenure at the
Rockefeller Institute when a colleague, Dr.
Albert Sabin, found a strain of mycoplasma
in a mouse while studying the disease,
Toxoplasmosis. Dr. Sabin injected another
mouse with this mycoplasma strain and the
second mouse contracted arthritis. During this
same period, Dr. Brown had been researching
for an unknown virus in rheumatic tissues. No
virus was found but one culture of joint fluid
revealed mycoplasma. Subsequently, he found
the same agents in the cultures from the genital
tracts of men and women.
Dr. Sabin had found that the mouse strain of
mycoplasma was susceptible to gold salts and
Dr.
Brown and his coworkers found this to be
true of human strains as well. This prompted
the search for a non-toxic antimycoplasma
substance to substitute for gold. Such
a substance was found with tetracycline
antibiotics.
These findings suggested the initial use of
antibiotic therapy in rheumatoid arthritis. A
clinical finding which encouraged the pursuit
of this approach was the Herxheimer reaction
common to both gold and tetracycline with the
initiation of treatment.
The concept of an infectious agent as a trigger
of autoimmune diseases is not new. Indeed
cross-reactions between group A streptococcal
antigens and human myocardium elicit auto
antibodies that have been associated with
acute rheumatic fever. Several microorganisms
(bacteria, mycoplasmas and viruses) have
been proposed as likely etiologic agents for
rheumatoid arthritis and animal arthritis.
In particular the swine arthritis that mimics
the disease in humans is known to be caused by
a mycoplasma.
The recent report that Lyme arthritis, (which
is known to result from a bacterial infection),
can demonstrate rheumatoid arthritis-like
symptoms, and can be treated with antibiotics,
has once again stimulated interest in the
infectious theory.
Dr. Brown and his staff continued to conduct
research to confirm his working hypothesis.
His clinical observations throughout the years
regarding which classes and combinations
of antibiotics, and routes and intervals of
administration were more tolerable, while at
the same time providing the most effective
means of sustained control in patients is
summarized below. It is significant that the
only antibiotics effective in the long term
management of rheumatoid disease are also the
only antibiotics effective against mycoplasmas.
Arthritis affected tissues are very reactive, and
early cases of arthritis respond to treatment
much better than the most severe long standing
cases.

Dosage and administration of drugs

Tetracycline: (250 mg. dosages in capsule form)

are administered once a day, three times a week
at the onset of treatment.
Non-steroidal Anti-inflammatory Drugs
(NSAIDs): The concomitant use of NSAIDs
varies. Aspirin is often given initially, followed
by a variety of substitutes for cortisone.
Cortisone: To reduce the inflammatory barrier
and allow penetration of the antibiotics, 7 to
5 mg. of prednisone may be administered to
the patient simultaneously with the antibiotic.
Preferably, no more than 10 mg. should be
administered for flares. Larger doses when
required should be given in short interrupted
courses. It is of interest that the concomitant
use of antibiotics with the steroids makes
steroid withdrawal easier. The dosage of the
drug must be kept low to avoid interfering with
the immune system but high enough to reduce
the hypersensitivity or allergic inflammatory
reactions of the disease.
The therapeutic outline can be modified by the
physician at any time using the following major
guideline:
1. Titration of the antibiotic dosage
2. Treatment complex to be given in interrupted
fashion
3. Aim to phase out steroids in time
Ampicillin: in the presence of streptococcal
infection as determined by the presence of an
ASO
titer, and/or a strong history of streptococcal
infection, 250 mg. of ampicillin to be taken
once daily (preferably in the evenings) twice or
three times a week is administered.
As treatment progresses, a gradual increase in
the tetracycline dose, up to 500 mg. one to
three times a day, three times a week, (Monday,
Wednesday and Friday) is administered. Care
should be taken not to administer the drug at
too high a dosage too fast, to avoid an allergic
reaction by the patient.
When remission becomes established, the
antibiotics may be gradually phased out. When
flare-ups occur, short courses of antibiotics,
should be given until no longer needed.
Intravenous Therapy
For patients who usually do not tolerate oral
antibiotics, or those patients with a history of
drug resistance from earlier treatment with a
variety of drugs (e.g. gold, penicillamine, etc.),
an intravenous regimen is followed.
Cleocin (the least irritating effective antibiotic
for intravenous use) is given daily in the course
of 5
to 7 days in the following manner: 300 mgm.
Cleocin in 250 cc. 5% dextrose solution given by
intravenous drip for a period of 40 minutes for
the first two days. The dose is increased to 600
mgm and finally 900 mgm on subsequent days.
Following the courses of intravenous therapy,
the oral medication is usually more effective
and acceptable. Thus the intravenous therapy
serves as a booster.
Some patients are likely to develop a Jarisch-
Herxheimer (J-H) reaction. The most likely
candi-dates are those who present at the onset
of the disease with high levels of gamma
globulin, C-reactive protein, BFT titer, anemia
and low white cell count. When this J-
H reaction occurs, it is best to discontinue
treatment, and to administer cortisone (not to
exceed a maximum of 10 mg. to relieve flares) as
well as symptomatic remedies.
The Jarisch-Herxheimer reaction is rather brief,
and when the symptoms subside, treatment
should proceed by using a carefully titrated
course of tetracyclines; e.g. starting with
doxycycline, 50 mg. three times a day, and
gradually increasing the dosage to 100 mg.
When it is determined that the patient’s
symptoms have stabilized as may be
observed by improvement in laboratory tests,
(i.e. ESR, CBC, gamma globulin, BFT titer
(bentonite flocculation test; Rheumatoid Factor
determination, etc.) the higher dose of
antibiotics, i.e. tetracycline, 250 mg. to 500 mg.
three times a week, etc. can be administered.
Anemia may be induced either by a
spontaneous or drug related flare. Thus,
the hemoglobin or hematocrit serves as a
good therapeutic guide. Concurrently with
the treatment, the patient’s blood chemistry
is monitored. This includes CBC, the platelet
count: ESR, BFT, and C-reactive protein.
Urinalysis screening is also performed.
Tests for MCF (mycoplasma complement fixing
antibodies), BFT and Kunkel Globulin (gamma
globulin) determination are available for this
analysis.
In his four decades of experience with
antibiotics. Dr. Brown notes that significant
benefits from this type of treatment require on
the average one to two years. Some patients do
experience a worsening of the condition during
the first few months prior to improvement;
however; some patients were able to notice
a dramatic improvement in their situation:
as early as six weeks. The length of therapy
varies widely depending on the extensiveness
of the disease. In severe cases, it may take
up to thirty months for the patient to gain
sustained improvement, and the achievement
of remission may take 3 to 5 years.
The primary importance of the antibiotic
approach is that once remission is established
it is generally permanent unlike the experience
with other treatment approaches. It appears
that the absence of drug toxicity allows
suppression of antigen long enough for the
body’s immune system to take over.
Persistence is usually required in seeking the
right combination of antibiotic dosage and
method of administration in the difficult cases
that require reduction of sensitization to the
antigen.
Although the antibiotic treatment approach is
still considered experimental, Dr. Brown treat
e d hundreds of patients successfully over a 40
year period, bringing many of them back from
hopelessness to living healthy and productive
lives.
Dr. Brown's Modified Protocol For Using
Antibiotics In The Treatment Of Rheumatic
Diseases Presented at the 32nd International
Congress of the Great Lakes College of Clinical
Medicine Baltimore, Maryland, September 25,
1999 by Joseph Mercola, D.O.

Table of Contents

Introduction

My Experience with Dr. Brown's Protocol

Nutritional Considerations

Antibiotic Therapy With Minocin

Clindamycin

What To Do If Severe Patients Fail To Respond

Anti-Inflammatories

Prednisone

Remission

Preliminary Laboratory Evaluation For Non-

Rheumatologists

Fibromyalgia

Signs And Symptoms of Fibromyalgia

Pain Location
Treatment Of Fibromyalgia

Exercise For Rheumatoid Arthritis

The Infectious Cause Of Rheumatoid Arthritis

Culturing Mycoplasmas From Joints Animal

Evidence for The Protocol The Science of Why
Minocycline Is Used

Clinical Studies

Criteria For Classification Of Rheumatoid

Arthritis

Bibliography

Introduction

Rheumatoid arthritis affects about 1 percent

of our population and at least two
million Americans have definite or classical
rheumatoid arthritis. It is a much more
devastating illness than previously appreciated.
Most patients with rheumatoid arthritis have
a progressive disability. More than 50% of
patients who were working at the start of
their disease are disabled after five years of
rheumatoid arthritis. The annual cost of this
disease in the U.S. is estimated to be over $1
billion.
There is also an increased mortality rate. The
five-year survival rate of patients with more
than thirty joints involved is approximately
50%. This is similar to severe coronary artery
disease or stage IV
Hodgkin's disease.
Thirty years ago, one researcher concluded that
there was an average loss of eighteen years
of life in patients who developed rheumatoid
arthritis before the age of 50.
Most authorities believe that remissions rarely
occur. Some experts feel that the term
"remission-inducing" should not be used to
describe ANY current rheumatoid arthritis
treatment. A review of contemporary treatment
methods shows that medical science has not
been able to significantly improve the long-
term outcome of this disease.

My Experience with the Dr. Brown's Protocol

I first became aware of Doctor Brown's protocol

in 1989 when I saw him on 20/20 on ABC.
This was shortly after the introduction of his
first edition of The Road Back. The newest
version is The New Arthritis Breakthrough that is
written by Henry Scammel. Unfortunately, Dr.
Brown died from prostate cancer shortly after
the 20/20 program so I never had a chance to
meet him. By the year 2000,1 will have treated
over 1,500 patients with rheumatic illnesses,
including SLE, scleroderma, polymyositis and
dermatomyositis.
My application of Dr. Brown's protocol
has changed significantly since I first
started implementing it. Initially, I followed
Dr.Brown'swork rigidly with very
little modification other than shifting the
tetracycline choice to Minocin. I believe I was
one of the first people who recommended the
shift to Minocin, which seems to have been
widely adopted at this time.
In the early 90s, I started to integrate the
nutritional model into the program and noticed
a significant improvement in the treatment
response. I cannot emphasize strongly enough
the importance of this aspect of the program.
It is absolutely an essential component of the
revised Dr. Brown protocol. One may achieve
remission without it, but the chances are
much improved with its implementation. The
additional benefit of the dietary changes is that
they severely reduce the risk of the two to six
month worsening of symptoms that Dr. Brown
described in his book.
In the late 80s, the common retort from other
physicians was that there was "no scientific
proof" that this treatment works. Well, that
is certainly not true today. If one peeks
ahead at the bibliography, one will find over
200 references in the peer-reviewed medical
literature that supports the application of
Minocin in the use of rheumatic illnesses. The
definitive scientific support for minocycline in
the treatment of rheumatoid arthritis came
with the MIRA trial in the United States.
This was a double blind randomized placebo
controlled trial done at six university centers
involving 200 patients for nearly one year. The
dosage they used (100 mg twice daily) was
much higher and likely less effective than what
most clinicians currently use. They also did not
employ any additional antibiotics or nutritional
regimens, yet 55% of the patients improved.
This study finally provided the "proof" that
many traditional clinicians demanded before
seriously considering this treatment as an
alternative regimen for rheumatoid arthritis.
Dr. Thomas Brown's effort to treat the
chronic mycoplasma infections believed to
cause rheumatoid arthritis is the basis
for this therapy. Dr. Brown believed that
most rheumatic illnesses respond to this
treatment. He and others used this therapy
for SLE, ankylosing spondylitis, scleroderma,
dermatomyositis and polymyositis.
Dr. Osier was also a preeminent figure of
his time (1849-1919). Many regard him as
the consum-mate physician of modern times.
An excerpt from a commentary on Dr.
William Osier provides a useful perspective on
application of alternative medical paradigms:
Osier would be receptive to the cautious
exploration of nontraditional methods of
treatment, particularly in situations in which
our present science has little to offer. From his
reading of medical history, he would know that
many pharmacologic agents were originally
derived from folk medicine.
He would also remember that in the 19th
century physicians no less intelligent than
those in our own day initially ridiculed the
unconventional practices of Semmelweis and
Lister.
Osier would caution us against the arrogance
of believing that only our current medical
practices can benefit the patient. He would
realize that new scientific insights might
emerge from as yet unproved beliefs. Although
he would fight vigorously to protect the
public against frauds and charlatans, he
would encourage critical study of whatever
therapeutic approaches were reliably reported
to be beneficial to patients.

Nutritional Considerations

Limiting sugar is a critical element of

the treatment program. Sugar has multiple
significant negative influences on a person's
biochemistry. Its major mode of action is
through elevation of insulin levels. However, it
has a similarly severe impairment of intestinal
microflora. Patients who are unable to decrease
their sugar intake are far less likely improved.
One of the major benefits of implementing the
dietary changes is that one does not seem to
develop worsening of symptoms the first three
to six months that is described in Dr. Brown's
book. Most of my patients tend to not worsen
once they start the antibiotics. I believe this is
due to the beneficial effects that the diet has on
the immune response. I ask all new patients to
read my 6-page handout on the dietary changes.
Rather than repeat it here, one could obtain the
current version on my web site at
www.mercola.com under the tab heading on
the left side of the page entitled Read This First.

Antibiotic Therapy With Minocin

There are three different tetracyclines available:

simple tetracycline, doxycycline, or Minocin
(minocycline).
Minocin has a distinct and clear advantage over
tetracycline and doxycycline in three important
areas.
1. Extended spectrum of activity
2. Greater tissue penetrability
3. Higher and more sustained serum levels
Bacterial cell membranes contain a lipid layer.
One mechanism of building up a resistance to
an antibiotic is to produce a thicker lipid layer.
This layer makes it difficult for an antibiotic to
penetrate.
Minocin's chemical structure makes it the most
lipid soluble of all the tetracyclines.
This difference can clearly be demonstrated
when one compares the drugs in the treatment
of two common clinical conditions. Minocin
gives consistently superior clinical results in
the treatment of chronic prostatitis. In other
studies, Minocin was used to improve between
75-85% of patients whose acne had become
resistant to tetracycline. Strep is also believed
to be a contributing cause to many patients
with rheumatoid arthritis. Minocin has shown
significant activity against treatment of this
organism.
There are several important factors to consider
when using Minocin. Unlike the other
tetracyclines, it tends not to cause yeast
infections. Some infectious disease experts
even believe that it even has a mild anti-yeast
activity.
Women can be on this medication for several
years and not have any vaginal yeast infections.
Nevertheless, it would be prudent to have
patients on prophylactic oral Lactobacillus
acidophilus and bifidus preparations. This will
help to replace the normal intestinal flora that
is killed with the Minocin.
Another advantage of Minocin is that it tends
not to sensitize patients to the sun. This
minimizes the risk of sunburn and increased
risk of skin cancer. However, one must
incorporate several precautions with the use of
Minocin. Like other tetracyclines, food impairs
its absorption. However, the absorption is much
less impaired than with other tetracyclines.
This is fortunate because some patients cannot
tolerate Minocin on an empty stomach.
They must take it with a meal to avoid GI side
effects. If they need to take it with a meal,
they will still absorb 85% of the medication,
whereas tetracycline is only 50% absorbed. In
June of 1990, a pelletized version of Minocin
became available. This improved absorption
when taken with meals.
This form is only available in the non-generic
Lederle brand and is a more than reasonable
justifica-tion to not substitute for the generic
version. Clinical experience has shown that
many patients will relapse when they switch
from the brand name to the generic. It is
strongly advised that only the non-generic
brand name Minocin by Lederle be used.
However, many patients are on NSAID's which
contribute to micro-ulcerations of the stomach
which cause chronic blood loss. It is certainly
possible they can develop a peptic ulceration
contributing to their blood loss. In either event,
patients frequently receive iron supplements to
correct their blood counts. IT IS IMPERATIVE
THAT MINOCIN NOT BE GIVEN WITH IRON.
Over 85% of the dose will bind to the iron
and pass through the colon unabsorbed. If iron
is taken, it should be at least one hour before
the minocin or two hours after. One recent
uncommon complication of Minocin is a cell-
mediated hypersensitivity pneumonitis.
Most patients can start on Minocin 100 mg.
every Monday, Wednesday, and Friday evening.
Doxycycline can be substituted for patients
who cannot afford the more expensive Minocin.
It is important to not give either medication
daily, as this does not seem to provide as great a
clinical benefit.
Tetracycline type drugs can cause a permanent
yellow-grayish brown discoloration of the
teeth.
This can occur in the last half of pregnancy and
in children up to eight years old. One should
not routinely use tetracycline in children. If
patients have severe disease, one can consider
increasing the dose to as high as 200 mg
three times a week. Aside from the cost of
this approach, several problems may result
from the higher doses. Minocin can cause quite
severe nausea and vertigo. Taking the dose
at night does tend to decrease this problem
considerably.
However, if one takes the dose at bedtime, one
must tell the patient to swallow the medication
with TWO glasses of water. This is to insure
that the capsule doesn't get stuck in the throat.
If that occurs, a severe chemical esophagitis
can result which can send the patient to the
emergency room.
For those physicians who elect to use
tetracycline or doxycycline for cost or
sensitivity reasons, several methods may
help lessen the inevitable secondary yeast
overgrowth. Lactobacillus acidophilus will help
maintain normal bowel flora and decrease the
risk of fungal overgrowth. Aggressive avoid-
ance of all sugars, especially those found in
non-diet sodas will also decrease the substrate
for the yeast's growth. Macrolide antibiotics
like Biaxin or Zithromax may be used if
tetracyclines are con-traindicated. They would
also be used in the three pills a week regimen.

Clindamycin

The other drug used to treat rheumatoid

arthritis is clindamycin. Dr. Brown's book
discusses the uses of intravenous clindamycin.
It is important to use the IV form of treatment if
the disease is severe.
Nearly all scleroderma patients should take
an aggressive stance and use IV treatment.
Scleroderma is a particularly dangerous form of
rheumatic illness that should receive aggressive
intervention.
A major problem with the IV form is the cost.
The price ranges from $100 to $300 per dose
if administered by a home health care agency.
However, if purchased directly from Upjohn,
significant savings will be appreciated. A case
of two-dozen 900 mg prefilled IV bags can be
purchased directly from Upjohn for about $200.
(2000 prices)
For patients with milder illness, the oral form is
preferable. If the patient has a mild rheumatic
illness (the minority of cases), it is even possible
to exclude this from their regimen. Initial
starting doses for an adult would be a 1200
mg dose once a week. Patients do not seem to
tolerate this medication as well as Minocin. The
major complaint seems to be a bitter metallic
type taste, which lasts about 24 hours after the
dose. Taking the dose after dinner does seem
to help modify this complaint some-what. If
this is a problem, one can lower the dose and
gradually increase the dose over a few weeks.
Concern about the development of C.
difficile pseudomembranous enterocolitis as a
result of the clindamycin is appropriate.
This complication is quite rare at this
dosage regimen, but it certainly can occur.
It is important to warn all patients
about the possibility of developing a severe
uncontrollable diarrhea. Administration of the
acidophilus seems to limit this complication by
promoting the growth of the healthy gut flora.
If one encounters a resistant form of rheumatic
illness, intravenous administration should be
considered. Generally, weekly doses of 900 mg
are administered until clinical improvement is
observed.
This generally occurs within the first ten doses.
At that time, the regimen can be decreased to
every two weeks with the oral form substituted
on the weeks where the IV is not taken.

What To Do If Severe Patients Fail To Respond

The most frequent reason for failure to respond

to the protocol is lack of adherence to the
dietary guidelines. Most patients will be eating
too many grains and sugars, which disturb
insulin physiology.
It is important that patients adhere as strictly
as possible to the guidelines. A small minority,
generally under 15%, of patients will fail to
respond to the protocol described above despite
rigid adherence to the diet. These individuals
should already be on the IV Clindamycin.
It appears that the hyaluronic acid, which is
a potentiating agent commonly used in the
treatment of cancer, may be quite useful. It
seems that hyaluronic acid has very little to no
direct toxicity but works in a highly synergistic
fashion when administered directly in the IV
bag with the Clindamycin. Hyaluronic acid is
also used in orthopedic procedures. The dose is
generally from 2 to 10 cc into the IV bag.
Hyaluronic acid is not inexpensive as the cost
may range up to $10 per cc. One does need
to exert some caution with its use as it
may precipitate a significant Herxheimer flare
reaction.
Patients will frequently have emotional
traumas that worsen their illness. Severe
emotional traumas can seriously impair the
immune response to this treatment. A
particularly useful and rapid technique called
Neuro Emotional Technique (NET) can be used
to resolve this problem. Practitioners using this
technique can be found by calling the One
Foundation. The ONE Research Foundation,
144 West D
Street, Suite 107, Encinitas, CA 92024,
Telephone: 800-638-1411 or 760-944-7383.

Anti-Inflammatories

The first non-aspirin NSAID (non-steroidal

anti-inflammatory drug), indomethacin was
introduced in 1963. Now more than 30
are available. Relafen is one of the better
alternatives as it seems to cause less of an
intestinal dysbiosis. If cost is a concern, generic
ibuprofen can be used. Unfortunately, recent
studies suggest this drug is more damaging to
the kidneys. One must be especially careful to
monitor renal function studies periodically. It
is important for the patient to understand and
accept the risks associated with these more
toxic drugs.
Unfortunately, these drugs are not benign.
Every year, they do enough damage to the
GI tract to kill 2,000 to 4,000 patients
with rheumatoid arthritis alone. That is ten
patients EVERY DAY. At any given time patients
receiving NSAID therapy have gastric ulcers
in the range of 10-20%. Duodenal ulcers
are lower at 2-5%. Patients on NSAIDs are
at approximately three times greater relative
risk for developing serious gastrointestinal side
effects than are non-users.
Approximately 1.2% of patients taking NSAIDs
are hospitalized for upper GI problems per
year of exposure. One study of patients
taking NSAIDs showed that a life-threatening
complication was the first sign of ulcer in more
than half of the subjects.
Celebrex has received much recent press due
to its decreased toxicity to the gut. That is
certainly a step in the right direction. Celebrex
inhibits a specific type of prostaglandin and is
called a COX2
inhibitor. A similar new drug introduced in
1999 is Vioxx. There was a report in early 1999
in the Proceedings of the National Academy of
Science, which showed that these drugs might
increase the risk of heart attack, stroke and
blood clotting disorders.
Researchers found that the drugs suppress
production of prostacyclin, which is needed
to dilate blood vessels and inhibit clotting.
Earlier studies had found that mice
genetically engineered to be unable to use
prostacyclin properly were prone to clotting
disorders. Anyone who is at increased
risk of cardiovascular disease should steer
clear of these two new medications. Ulcer
complications are certainly potentially life-
threatening, but, heart attacks are a much more
common and likely risk, especially in older
individuals.
Risk factor analysis helps to discriminate those
that are at increased danger of developing these
complications.
Those associated with a higher frequency of
adverse events are: 1. Old age
2. Peptic ulcer history
3. Alcohol dependency
4. Cigarette smoking
5. Concurrent prednisone or corticosteroid use
6. Disability
7. High dose of the NSAID
8. NSAID known to be more toxic
Studies clearly show that the non-acetylated
salicylates are the safest NSAIDs. Celebrex and
Vioxx likely cause the least risk for peptic
ulcer. But as mentioned, they pose an increased
risk for heart disease. Factoring these newer
medications out would leave the following
less toxic NSAIDs: Relafen, Daypro, Voltaren,
Motrin, and Naprosyn. Meclomen, Indocin,
Orudis, and Tolectin are among the most toxic
or likely to cause complications.
They are much more dangerous than the
antibiotics or non-acetylated salicylates. One
should run an SMA at least once a year on
patients who are on these medications. One
must monitor the serum potassium levels if
the patient is on an ACE inhibitor as these
medications can cause hyperkalemia.
One should also monitor their kidney function.
The SMA will also show any liver impairment
that the drugs might cause.
These medications can also impair
prostaglandin metabolism and cause papillary
necrosis and chronic interstitial nephritis.
The kidney needs vasodilatory prostaglandins
(PGE2 and prostacycline) to coun-terbalance
the effects of potent vasoconstrictor hormones
such as angiotensin II and catecholamines.
NSAIDs decrease prostaglandin synthesis
by inhibiting cyclooxygenase, leading to
unopposed constriction of the renal arterioles
supplying the kidney.
One might consider the use of non-acetylated
salicylates such as salsalate, sodium salicylate
and magnesium salicylate (i.e., Salflex, Disalcid,
or Trilisate). They are the drugs of choice
if there is renal insufficiency. They have
minimal interference with anticyclooxygenase
and other prostaglandins.
Additionally, they will not impair platelet
inhibition of those patients who are on
every other day aspirin to decrease their risk
for stroke or heart disease. Unlike aspirin,
they do not increase the formation of
products of lipoxygenase-mediated metabolism
of arachidonic acid. For this reason, they may
be less likely to precipitate hypersensitivity
reactions. These drugs have been safely used
in patients with reversible obstructive airway
disease and a history of aspirin sensitivity.
They also are much gentler on the stomach then
the other NSAIDs and are the drug of choice
if the patient has problems with peptic ulcer
disease. Unfortunately, all these benefits are
balanced by the fact they may not be as effective
as the other agents and are less convenient to
take. One need to push them to 1.5-2 grams bid
and tinnitus is a frequent complication.
One should warn patients of this complication
and explain that if tinnitus does develop they
need to stop the drugs for a day and restart with
a dose that is half a pill per day lower. They
repeat this until they find a dose that relieves
their pain and doesn't give them any ringing.

Prednisone

One can give patients with severe disease a

prescription for prednisone 5 mg. They can take
one of them a day if they develop a severe flare-
up as a result of going on the antibiotics. They
can use an additional tablet at night if they
are in really severe flare. Explain to all patients
that the prednisone is very dangerous and every
dose they take decreases their bone density.
However, it is a trade-off. Since they will only
be on it for a matter of months, its use may be
justifiable. This is the first medicine they should
try to stop as soon as their symptoms permit.
Blood levels of cortisol peak between 3 and 9 am.
It would, therefore, be safest to administer the
prednisone in the morning. This will minimize
the suppression on the hypothalamic-pituitary-
adrenal axis. Patients often ask the dangers of
these medications. The most significant one is
osteoporosis.
Other side effects that usually occur at
higher doses include adrenal insufficiency,
atherosclerosis acceleration, cataract
formation, Cushing's syndrome, diabetes,
ulcers, herpes simplex and tuberculosis
reactivation, insomnia, hypertension,
myopathy and renal stones.
One also needs to be concerned about
the increased risk of peptic ulcer disease
when using this medicine with conventional
non-steroidal anti-inflammatories. Persons
receiving both of these medicines may have a
15 times greater risk of developing an ulcer.
If a patient is already on prednisone, it is helpful
to give them a prescription for 1 mg tablets so
they can wean themselves off of the prednisone
as soon as possible. Usually one lowers the dose
by about 1
mg per week. If a relapse of the symptoms
occurs, than further reduction of the
prednisone is not indicated.
Remission

The following criteria can help establish

remission:
*A decrease in duration of morning stiffness to
no more than 15 minutes
* No pain at rest
* Little or no pain or tenderness on motion
* Absence of joint swelling
* A normal energy level
* A decrease in the ESR to no more than 30
* A normalization of the patient's CBC. Generally
the HGB, HCT, & MCV will increase to
normal and their "pseudo"-iron deficiency will
disappear
* ANA, RF, & ASO titers returning to normal
The natural course of rheumatoid arthritis is
quite remarkable. Less than 1% of patients
who are rheumatoid factor seropositive have a
spontaneous remission. Some disability occurs
in 50-70% of patients within five years after
onset of the disease. Half of the patients will
stop working within 10
years. This devastating natural prognosis is
what makes the antibiotic therapy so exciting.
Approximately one third of patients have been
lost to follow-up for whatever reason and have
not continued with treatment. The remaining
patients seem to have a 60-90% likelihood of
improvement on this treatment regimen.
That is quite a stark contrast to the numbers
quoted above.
There are many variables associated with an
increased chance of remission or improvement.
The younger the patient is the better they seem
to do. The more closely they follow the diet,
the less likely they are to have a severe flare-
up and the more likely they are to improve.
Smoking seems to be negatively associated with
improvement.
The longer the patient has had the illness and
the more severe the illness the more difficult it
seems to treat.
If patients discontinue their medications before
all of the above criteria are met, there is a
greater risk that the disease will recur. If the
patient meets the above criteria, one can have
them to try to stop their anti-inflammatory
medication once they start to experience
these improvements. If the improvements
are stable for six months, then discontinue
the clindamycin. If the improvements are
maintained for the next six months, one can
then discontinue their Minocin and monitor
for recurrences. If symptoms should recur, it
would be wise to restart the previous antibiotic
regimen.
Overall, nearly 80% of the patients
do remarkably better with this program.
Approximately 5% of the patients continued to
worsen and required conventional agents, like
methotrexate, to relieve their symptoms.
Approximately 15% of the patients who started
the treatment dropped out of the program and
were lost to follow-up. The longer and more
severe the illness, the longer it takes to cure.
Smokers tend not to do as well with this
program. Age and competency of the person's
immune system are also likely important
factors.
Dr. Brown successfully treated over 10,000
patients with this protocol. He found that
significant benefits from the treatment require
on the average one to two years. I have treated
nearly over 1,500
patients and find that the dietary modification I
advocate accelerates the response rate to several
months.
The length of therapy can vary widely. In severe
cases, it may take up to thirty months for the
patients to gain sustained improvement. One
requires patience because remissions may take
up to 3 to 5 years.
Dr. Brown's pioneering approach represents
a safer less toxic alternative to many
conventional regimens and results of the NIH
trial have finally scientifically validated this
treatment.

Preliminary Laboratory Evaluation

For Non-Rheumatologists

It is important to evaluate patients to

determine if indeed they have rheumatoid
arthritis. Most patients will have received
evaluations and treatment by one or more
board certified rheumatologists. If this is the
case, the diagnosis is rarely in question and
one only needs to establish some baseline
laboratory data.
However, patients will frequently come in
without having any appropriate workup done
by a physician. Arthritic pain can be an
early manifestation of 20-30 different clinical
problems. These include not only rheumatic
disease, but also metabolic, infectious and
malignant disorders. These patients will
require a more extensive laboratory analysis.
Rheumatoid arthritis is a clinical diagnosis for
which there is not a single test or group
of laboratory tests which can be considered
confirmatory. When a patient hasn't been
properly diagnosed, then one needs to establish
the diagnosis with the standard Rheumatism
Association's criteria found in the table at the
end of the article.
One must also make certain that the first four
symptoms listed in the table are present for six
or more weeks.
These criteria have a 91-94% sensitivity and
89% specificity for the diagnosis of rheumatoid
arthritis. However, these criteria were designed
for classification and not for diagnosis. One
must make the diagnosis on clinical grounds.
It is important to note that many patients
with negative serologic tests can have a strong
clinical picture for rheumatoid arthritis.
The metacarpophalangeal joints, proximal
interphalangeal and wrists joints are the first
joints to become symptomatic. In a way, the
hands are the calling card of rheumatoid
arthritis. If the patient completely lacks hand
and wrist involvement, even by history, the
diagnosis of rheumatoid arthritis is doubtful.
Rheumatoid arthritis rarely affects the hips and
ankles early in its course.
Fatigue may be present before the joint
symptoms begin. Morning stiffness is a
sensitive indicator of rheumatoid arthritis. An
increase in fluid in and around the joint
probably causes the stiffness. The joints are
warm, but the skin is rarely red. When the
joints develop effusions, the patients hold them
flexed at 5 to 20 degrees as it is too painful to
extend them fully.
The general initial laboratory evaluation should
include a baseline ESR, CBC, SMA, U/A, and an
ASO titer. One can also draw RF and ANA titers
to further objectively document improvement
with the therapy. However, they seldom add
much to the assessment.
Follow-up visits can be every two months
for patients who live within 50 miles, and
every three to four months for those who
live farther away. An ESR at every visit is an
inexpensive and reliable objective parameter of
the extent of the disease. However, one should
run this test within several hours of the blood
draw. Otherwise, one cannot obtain reliable
and reproducible results. This is nearly impos-
sible with most clinical labs that pick up your
specimen at the office.
Inexpensive disposable ESR kits are a practical
alternative to the commercial or hospital labs.
One can then run them in the office, usually
within one hour of the blood draw. One must
be careful to not run the test on the same
countertop as your centrifuge. This may cause a
falsely elevated ESR due to the agitation of the
ESR measuring tube.
Many patients with rheumatoid arthritis have a
hypochromic, microcytic CBC. This is probably
due to the inflammation in the rheumatoid
arthritis impairing optimal bone marrow
utilization of iron. This type of anemia does
NOT respond to iron. Patients who take iron
can actually worsen if they don't need it as the
iron serves as a potent oxidant stress. Ferritin
levels are generally the most reliable indicator
of total iron body stores. Unfortunately it is
also an acute phase reactant protein and will
be elevated anytime the ESR is elevated. This
makes ferritin an unreliable test in patients
with rheumatoid arthritis.

Fibromyalgia

One needs to be very sensitive to this

clinical problem when treating patients with
rheumatoid arthritis. It is frequently a
complicating condition. Many times, patients
will confuse the pain from it with a flare-up of
their arthritis. One needs to aggressively treat
this problem. If this problem is ignored, the
likelihood of successfully treating the arthritis
is significantly diminished.
Fibromyalgia is a very common problem. Some
experts believe that 5% of people are affected
with it. Over 12% of the patients at the Mayo
Clinic's Department of Physical Medicine and
Rehabilitation have this problem. It is the third
most common diagnosis by rheumatologists in
the outpatient setting.
Fibromyalgia affects women five times as
frequently as men.
Signs And Symptoms of Fibromyalgia
One of the main features of fibromyalgia is the
morning stiffness, fatigue, and multiple areas
of tenderness in typical locations. Most patients
with fibromyalgia complain of pain over many
areas of the body, with an average of six to
nine locations. Although the pain is frequently
described as being all over, it is most prominent
in the neck, shoulders, elbows, hips, knees, and
back.
Tender points are generally symmetrical and
on both sides of the body. The areas of
tenderness are usually small (less than an inch
in diameter) and deep within the muscle. They
are often located in sites that are slightly tender
in normal people. Patients with fibromyalgia,
however, differ in having increased tenderness
at these sites than normal persons. Firm
palpation with the thumb (just past the point
where the nail turns white) over the outside
elbow will typically cause a vague sensation
of discomfort. Patients with fibromyalgia will
experience much more pain and will often
withdraw the arm involuntarily.
More than 70% of patients describe their pain
as profound aching and stiffness of the muscles.
Often it is relatively constant from moment to
moment, but certain positions or movements
may mo-mentarily worsen the pain.
Other terms used to describe the pain are
dull and numb. Sharp or intermittent pain is
relatively uncommon.
Patients with fibromyalgia often complain that
sudden loud noises worsen their pain. The
general-ized stiffness of fibromyalgia does not
diminish with activity, unlike the stiffness of
rheumatoid arthritis, which lessens as the day
progresses.
Despite the lack of abnormal lab tests, patients
can suffer considerable discomfort. The fatigue
is often severe enough to impair activities
of work and recreation. Patients commonly
experience fatigue on arising and complain of
being more fatigued when they wake up then
when they went to bed. Over 90% of patients
believe the pain, stiffness, and fatigue are made
worse by cold, damp weather. Overex-ertion,
anxiety and stress are also factors.
Many people find that localized heat, such as
hot baths, showers, or heating pads, give them
some relief. There is also a tendency for pain to
improve in the summer with mild activity or
with rest.
Some patients will date the onset of their
symptoms to some initiating event. This is
often an injury, such as a fall, a motor vehicle
accident, or a vocational or sports injury.
Others find that their symptoms began with a
stressful or emotional event, such as a death
in the family, a divorce, a job loss, or similar
occurrence.

Pain Location

Patients with fibromyalgia have pain in at least

11 of the following 18 tender point sites (one on
each side of the body):
1. Base of the skull where the suboccipital
muscle inserts.
2. Back of the low neck (anterior intertransverse
spaces ofC5-C7).
3. Midpoint of the upper shoulders (trapezius).
4. On the back in the middle of the scapula.
5. On the chest where the second rib attaches to
the breastbone (sternum).
6. One inch below the outside of each elbow
(lateral epicondyle).
7. Upper outer quadrant of buttocks.
8. Just behind the swelling on the upper leg
bone below the hip (trochanteric prominence).
9. The inside of both knees (medial fat pads
proximal to the joint line).

Treatment Of Fibromyalgia

There is a persuasive body of emerging

evidence that indicates that patients with
fibromyalgia are physically unfit in terms
of sustained endurance. Some studies show
that cardiovascular fitness training programs
can decrease fibromyalgia pain by 75%.
Sleep is critical to the improvement. Many
times, improved fitness will correct the sleep
disturbance.
Allergies, especially to mold, seem to be another
common cause of fibromyalgia. There are some
simple interventions using techniques called
Total Body Modification (TBM) 800-243-4826
or Neuro Emotional Technique (NET)
800-638-1411. These maybe helpful in rapidly
resolving the problem.

Exercise For Rheumatoid Arthritis

It is very important to exercise or increase

muscle tone of the non-weight bearing
joints. Experts tell us that disuse results in
muscle atrophy and weakness. Additionally,
immobility may result in joint contractures and
loss of range of motion (ROM). Active ROM
exercises are preferred to passive. There is some
evidence that passive ROM exercises increase
the number of WBCs in the joint. If the joints are
stiff, one should stretch and apply heat before
exercising. If the joints are swollen, application
of ten minutes of ice before exercise would be
helpful.
The inflamed joint is very vulnerable to
damage from improper exercise, so one must be
cautious.
People with arthritis must strike a delicate
balance between rest and activity. They must
avoid activities that aggravate joint pain.
Patients should avoid any exercise that strains a
significantly unstable joint.
A good rule of thumb is that if the pain lasts
longer than one hour after stopping exercise,
the patient should slow down or choose
another form of exercise. Assistive devices are
also helpful to decrease the pressure on affected
joints. Many patients need to be urged to take
advantage of these. The Arthritis Foundation
has a book, Guide to Independent Living, which
instructs patients about how to obtain them.
Of course, it is important to maintain
good cardiovascular fitness. Walking with
appropriate supportive shoes is also another
important consideration.

The Infectious Cause Of Rheumatoid Arthritis

It is quite clear that autoimmunity plays a

major role in the progression of rheumatoid
arthritis.
Most rheumatology investigators believe that
an infectious agent causes rheumatoid
arthritis. There is little agreement as to the
involved organism. Investigators have proposed
the following infectious agents: Human T-
cell lymphotropic virus Type I, rubella
virus, cytomegalovirus, herpes virus, amoeba
and mycoplasma. This review will focus on
the evidence supporting the hypothesis that
mycoplasma is a common etiologic agent of
rheumatoid arthritis.
Mycoplasmas are the smallest self-replicating
prokaryotes. They differ from classical bacteria
by lacking rigid cell wall structures and are
the smallest known organisms capable of
extracellular existence. They are considered to
be parasites of humans, animals, and plants.
In 1939, Dr. Sabin, the discoverer of the polio
vaccine, first reported a chronic arthritis in
mice caused by a mycoplasma. He suggested
this agent might cause human rheumatoid
arthritis.
Dr. Thomas Brown was a rheumatologist who
worked with Dr. Sabin at the Rockefeller
Institute.
Dr. Brown trained at John Hopkins Hospital
and then served as chief of medicine at George
Washington Medical School before serving
as chairman of the Arthritis Institute in
Arlington, Virginia. He was a strong advocate of
the mycoplasma infectious theory for over fifty
years of his life.

Culturing Mycoplasmas From Joints

Mycoplasmas have limited biosynthetic

capabilities and are very difficult to culture and
grow from synovial tissues.
They require complex growth media or a
close parasitic relation with animal cells. This
contributed to many investigators failure to
isolate them from arthritic tissue. In reactive
arthritis immune complexes rather than viable
organisms localize in the joints. The infectious
agent is actually present at another site. Some
investigators believe that the organism binding
in the immune complex contributes to the
difficulty in obtaining positive mycoplasma
cultures.
Despite this difficulty some researchers
have successfully isolated mycoplasma from
synovial tissues of patients with rheumatoid
arthritis. A British group used a leucocyte-
migration inhibition test and found two-thirds
of their rheumatoid arthritis patients to be
infected with Mycoplasma fermentens.
These results are impressive since they did not
include more prevalent Mycoplasma strains like
M.
salivarium, M. ovale, M. hominis, and M.
pneumonia.
One Finnish investigator reported a 100%
incidence of isolation of mycoplasma from
27 rheumatoid synovia using a modified
culture technique. None of the non-rheumatoid
tissue yielded any mycoplasmas. The same
investigator used an indirect hemagglutination
technique and reported mycoplasma antibodies
in 53% of patients with definite rheumatoid
arthritis. Using similar techniques other
investigators have cultured mycoplasma in
80-100% of their rheumatoid arthritis test
population.
Rheumatoid arthritis follows some
mycoplasma respiratory infections. One study
of over 1000
patients were able to identify arthritis in nearly
1% of the patients. These infections can be
associated with a positive rheumatoid factor.
This providesadditional support for
mycoplasma as an etiologic agent for
rheumatoid arthritis.
Human genital mycoplasma infections have
also caused septic arthritis.
Harvard investigators were able to culture
mycoplasma or a similar organism, ureaplasma
urealyticum, from 63% of female patients with
SLE and only 4% of patients with CFS. The
researchers chose CFS
as these patients shared similar symptoms as
those with SLE, such as fatigue, arthralgias, and
myalgias.

Animal Evidence for The Protocol

The full spectrum of human rheumatoid

arthritis immune responses (lymphokine
production, altered lymphocyte reactivity,
immune complex deposition, cell-mediated
immunity and development of autoimmune
reactions) occurs in mycoplasma induced
animal arthritis. Investigators have implicated
at least 31 different mycoplasma species.
Mycoplasma can produce experimental
arthritis in animals from three days to months
later. The time seems to depend on the dose
given and the virulence of the organism.
There is a close degree of similarity
between these infections and those of human
rheumatoid arthritis.
Mycoplasmas cause arthritis in animals by
several mechanisms. They either directly
multiply within the joint or initiate an
intense local immune response. Mycoplasma
produces a chronic arthritis in animals that
is remarkably similar to rheumatoid arthritis
in humans. Arthritogenic mycoplasmas
cause joint inflammation in animals by
many mechanisms. They induce nonspecific
lymphocyte cytotoxicity and antilymphocyte
antibodies as well as rheumatoid factor.
Mycoplasma clearly causes chronic arthritis in
mice, rats, fowl, swine, sheep, goats, cattle
and rabbits. The arthritis appears to be the
direct result of joint infection with culturable
mycoplasma organisms.
Gorillas have tissue reactions closer to man
than any other animal. Investigators have
shown that mycoplasma can precipitate a
rheumatic illness in gorillas. One study
demonstrated mycoplasma antigens occur in
immune complexes in great apes. The human
and gorilla IgG are very similar and express
nearly identical rheumatoid factors (IgM anti-
IgG antibodies). The study showed that when
mycoplasma binds to IgG it can cause a
conformational change. This conformational
change results in an anti-IgG antibody, which
can then stimulate an autoimmune response.

The Science of Why Minocycline Is Used

If mycoplasma were a causative factor

in rheumatoid arthritis, one would expect
tetracycline type drugs to provide some
sort of improvement in the disease.
Collagenase activity increases in rheumatoid
arthritis and probably has a role in
its cause. Investigators demonstrated that
tetracycline and minocycline inhibit leukocyte,
macrophage, and synovial collagenase.
There are several other aspects of tetracyclines
that may play a role in rheumatoid arthritis.
Investigators have shown minocycline and
tetracycline to retard excessive connective
tissue breakdown and bone resorption while
doxycycline inhibits digestion of human
cartilage. It is also possible that tetracycline
treatment improves rheumatic illness
by reducing delayed-type hypersensitivity
response.
Minocycline and doxycycline both inhibit
phosolipases which are considered
proinflammatory and capable of inducing
synovitis.
Minocycline is a more potent antibiotic than
tetracycline and penetrates tissues better.
These char-acteristics shifted the treatment
of rheumatic illness away from tetracycline
to minocycline. Minocycline may benefit
rheumatoid arthritis patients through its
immunomodulating and immunosuppressive
prop-erties. In vitro studies demonstrated a
decreased neutrophil production of reactive
oxygen intermedi-ates along with diminished
neutrophil chemotaxis and phagocytosis.
Investigators showed that minocycline reduced
the incidence of severity of synovitis in
animal models of arthritis. The improvement
was independent of minocycline's effect on
collagenase.
Minocycline has also been shown to increase
intracellular calcium concentrations that
inhibit T-cells.
Individuals with the Class II major
histocompatibility complex (MHC) DR4 allele
seem to be predisposed to developing
rheumatoid arthritis. The infectious agent
probably interacts with this specific antigen in
some way to precipitate rheumatoid arthritis.
There is strong support for the role of T cells
in this interaction. Minocycline may suppress
rheumatoid arthritis by altering T cell calcium
flux and the expression of T cell derived from
collagen binding protein. Minocycline produced
a suppression of the delayed hypersensitivity in
patients with Reiter's syndrome. Investigators
also successfully used minocycline to treat the
arthritis and early morning stiffness of Reiter's
syndrome.

Clinical Studies

In 1970 investigators at Boston University

conducted a small, randomized placebo-
controlled trial to determine if tetracycline
would treat rheumatoid arthritis. They used
250 mg of tetracycline a day.
Their study showed no improvement after one
year of tetracycline treatment. Several factors
could explain their inability to demonstrate
any benefits. Their study used only 27 patients
for a one-year trial, and only 12 received
tetracycline.
Noncompliance could have been a factor.
Additionally, none of the patients had severe
arthritis.
Patients were excluded from the trial if they
were on any anti-remittive therapy.
Finnish investigators used lymecycline to
treat the reactive arthritis in Chlamydia
trachomatous infections. The study compared
the effect of the medication in patients with
two other reactive arthritis infections Yersinia
and Campylobacter. Lymecyline produced a
shorter course of illness in the Chlamydia
induced arthritis patients, but did not affect
the other enteric infections-associated reactive
arthritis.
The investigators later published findings
that suggested lymecycline achieved its
effect through non-antimicrobial actions. They
speculated it worked by preventing the
oxidative activation of collagenase.
Breedveld published the first trial of
minocycline for the treatment of animal
and human rheumatoid arthritis. In the first
published human trial, Breedveld treated ten
patients in an open study for 16
weeks. He used a very high dose of 400
mg per day. Most patients had vestibular side
effects resulting from this dose. However, all
patients showed benefit from the treatment.
All variables of efficacy were significantly
improved at the end of the trial. Breedveld
concluded an expansion of his initial study
and observed similar impressive results. This
was a 26-week double-blind placebo-controlled
randomized trial with minocycline for 80
patients. They were given 200 mg twice a day.
The Ritchie articular index and the number of
swollen joints significantly improved (p < 0.05)
more in the minocyline group than in the
placebo group.
Investigators in Israel studied 18 patients
with severe rheumatoid arthritis for 48 weeks.
These patients had failed two other DMARD
(disease-modifying antirheumatic drugs). They
were taken off all DMARD agents and given
minocycline 100 mg twice a day. Six patients
did not complete the study, three withdrew
because of lack of improvement, and three
had side effects of vertigo or leukopenia. All
patients completing the study improved. Three
had complete remission, three had substantial
improvement of greater than 50% and six had
moderate improvement of 25% in the number
of active joints and morning stiffness.

Criteria For Classification Of Rheumatoid

Arthritis

Morning stiffness in and around joints lasting

at least one hour before maximal improvement
is noted.
Arthritis of three or more joint areas At least
three joint areas have simultaneously had soft-
tissue swelling or fluid (not bony overgrowth)
observed by a physician. There are 14 possible
joints: right or left PIP, MCP, wrist, elbow, knee,
ankle, and MTP joints.
Arthritis of hand joints
At least one joint area swollen as above in a
wrist, MCP, or PIP joint Symmetric arthritis
Simultaneous involvement of the same joint
areas (as in criterion 2) on both sides of the body
(bilateral involvement of PIPs, MCPs, or MTPs)
is acceptable without absolute symmetry. Lack
of symmetry is not sufficient to rule out the
diagnosis of rheumatoid arthritis.
Rheumatoid Nodules
Subcutaneous nodules over bony prominences,
or extensor surfaces, or in juxta-articular
regions, observed by a physician. Only about
25% of patients with rheumatoid arthritis
develop nodules, and usually as a later
manifestation.
Serum rheumatoid factor
Demonstration of abnormal amounts of serum
rheumatoid factor by any method that has been
positive in less than 5% of normal control
subjects. This test is positive only 30-40% of
the time in the early months of rheumatoid
arthritis.

Radiological Changes

Radiological changes typical of rheumatoid

arthritis on PA hand and wrist X-rays, which
must include erosions or unequivocal bony
decalcification localized to or most marked
adjacent to the involved joints (osteoarthritic
changes alone do not count).
Note: Patients must satisfy at least four of the
seven criteria listed. Any of criteria 1-4 must
have been present for at least 6 weeks. Patients
with two clinical diagnoses are not excluded.
Designations as classic, definite, or probable
rheumatoid arthritis are not to be made.
Harold W. Clark, Ph.D. adds, “I’m not sure
whether the tests (MCF, BFT, and Kunkle) are
still available but should be included.”

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