Table of Contents:
ANNOUNCEMENT: LDANJ Fund-raiser: "Great Imitator" Family Masquerade
BARRONS: Drugs on Trial: The Growing Role of Washington's Advisory
WISCONSIN STATE JOURNAL: Lyme Overdiagnosed
SPECIAL NEWS ANALYSIS: Dr. Paul Mitchell's Radio Comments
ABSTRACT: (Proc Natl Acad Sci) Evasion of Protective Immunity By
Borrelia Burgdorferi by Truncation of Outer Surface Protein B
THE VANCOUVER SUN: Woman with Symptoms Relieved as Official Reveals
B.C. Contractions Possible
ABSTRACT: (Arthritis Rheum) The Polymerase Chain Reaction for the
Detection of Borrelia burgdorferi in Human Body Fluids
BOOK REVIEWS: 1. Lyme Disease: A Mother's Perspective
2. Coping with Lyme Disease: A Practical Guide to Dealing
with Diagnosis and Treatment
* Lyme Disease Electronic Mail Network *
* LymeNet Newsletter *
Volume 1 - Number 20 - 8/24/93
III. News from the Wires
IV. Book Reviews
V. Jargon Index
VI. How to Subscribe, Contribute and Get Back Issues
I. ***** INTRODUCTION *****
Let me begin by welcoming our newest Contributing Editor. Frank Demarest has
been consistently submitting timely information to the newsletter for several
months. Many of the news items published in the past few months were
researched by Frank. It is only fitting that we officially make him a
Contributing Editor. Thanks for all your help, Frank!
On a technical note, I am pleased to announce that back issues are now
available by anonymous FTP. See the signature at the end of this
newsletter for FTP site and path information.
Many of you are probably interested in hearing information about the Senate
hearing on LD earlier this month. I was hoping to have complete transcripts
available by this time. However I don't have them yet due to circumstances
beyond my control. I will try to have material ready for the next issue.
Now... on to business. We begin with an announcement for a fund-raiser to
raise money for research.
The first piece of News from the Wires is disappointing. We find out that
Glaxo attempted to win approval from the FDA to market Ceftin, an oral
cephalosporin, as an effective drug to treat LD. Glaxo conducted two trials
to show Ceftin is more effective than Doxycycline. An FDA panel appointed
to review the application will not recommend that it be approved. Some
readers will notice factual errors in the article. Relevant sections
of the long piece are reprinted.
The next piece of News from the Wires is put in perspective. Once again,
a researcher has made claims to have a 100% accurate test for LD. When he
is questioned, we find out how he can make this claim. Thanks to Lora
Mermin for sending in a recording of Dr. Paul Mitchell's comments.
Towards the end of the issue, we present reviews of two newly published books
on LD. Both volumes are well written and worth reading.
II. ***** ANNOUNCEMENTS *****
Sender: The Lyme Disease Association of New Jersey, Inc.
Subject: LDANJ Fund-raiser: "Great Imitator" Family Masquerade Party
The past year has been difficult for Lyme sufferers. We have been denied
insurance, treatment and even a diagnosis. Without research to prove the
"persistence of infection," these rights will continue to be denied. Your
generous donations can enable this research to happen.
New Jersey suffers between 12% and 20% of the total cases nationwide each
year, and you or your children can contract the disease by simply walking out
your front door.
As in the past who years, LDANJ will send proceeds from our fund-raiser to the
Lyme Disease Research Project of the Fox Chase Cancer Center, directed by
Manfred Bayer, M.D. These respected researchers will continue their
important investigation of Lyme disease pathophysiology.
The LDANJ operates using volunteers ONLY. We have never hired professional
fund-raisers and have no intention of doing so in the future. Therefore, all
proceeds go directly toward the goal of our organization, i.e. education and
fundraising. We are proud of our fundraising efforts and will gladly share
our financial statements with anyone concerned about the expenditure of their
Please work with us to make this fund-raiser a huge success and eventually
find relief for the thousands of Lyme disease sufferers. Remember, this
disease can strike any family member, friend, employee, costing families
and businesses millions per year.
EVENT: Third annual "Great Imitator" Family Masquerade Party
DATE: Sunday, October 17, 1993
PLACE: Jenkinson's Pavilion in Point Pleasant Beach, NJ
[To receive a copy of the registration form by mail, please send your name
and address to [email protected] (or the Newsletter's USPS address or FAX #)]
III. ***** NEWS FROM THE WIRES ******
HEADLINE: Drugs on Trial: The Growing Role of Washington's Advisory Panels
SOURCE: BARRON'S (B) 08/09/93, p8
BYLINE: By Edward A. Wyatt
[...The following are relevant paragraphs from the 1,500 word article...]
...The young and inexperienced aren't alone in their susceptibility to
stumbling during the FDA approval process. Even companies that have
been going through the routine for years can run aground, as was aptly
demonstrated last month by the Anti-Infective Drugs Advisory
Committee, which met to consider a Glaxo Inc. application to sell
Ceftin, a prescription antibiotic, as a treatment for Lyme disease....
...For all the public attention focused on Lyme disease in recent
years, no drugs are currently approved to treat the ailment. But
doctors in regions where the disease is rampant have found that a
regimen of widely available antibiotics, particularly doxycycline or
amoxicillin, are effective, especially when the disease is caught in
its early stages. In fact, because those two off-patent, generic drugs
work so well, no company has deemed it worthwhile to conduct the
clinical trials needed to get an approval -- it simply wouldn't be
Glaxo, however, thought otherwise, seeing a significant niche
opportunity for its patented antibiotic. Ceftin is Glaxo's fifth-
largest drug, with sales of about $447 million last year. To Glaxo,
the exclusive right to promote a cure for Lyme disease could be
incredibly lucrative: At retail prices, Ceftin would cost a Lyme-
disease sufferer about $235 for a 20-day dose, compared with $50 for a
20-day regimen of doxycycline.
The Centers for Disease Control reported fewer than 10,000
confirmed cases of Lyme disease last year. But because there's no
reliable diagnostic test for the disease, tens of thousands more
patients are treated with antibiotics, even though they don't actually
have a Lyme infection. Doctors diagnose the disease based on a
patient's report of flu-like symptoms, as well as a characteristic
rash. But the rash itself shows up in less than three-quarters of
confirmed cases. And a study published in April in the Journal of the
American Medical Association reported that only one of every four
patients referred to the New England Medical Center from 1987 to 1991
for treatment of Lyme actually had the illness.
In other words, Lyme disease is severely overdiagnosed and
overtreated -- a superb prospect for a company looking to sell an
...Following public comments, the committee will sometimes hear a
background session, if necessary, on the topic at hand, as it did at
the Glaxo meeting. Because most of the panel members had never treated
a Lyme-disease patient, they invited a researcher from Long Island,
near the heart of Lyme disease country (the ailment is named for a
town in Connecticut where it was first diagnosed), to discuss the
manifestations of the disease and briefly review the published
literature. The agenda continues with the company's presentation of
its clinical trial data, the FDA's review of the findings, and the
committee's discussion and vote.
In testing Ceftin for Lyme disease, Glaxo conducted two trials, a
year apart, in which half of the 355 patients were given Ceftin and
half received doxycycline. Jeffrey Collins, associate director of anti-
infectives at Glaxo's Allen & Hanbury's division, reported that more
than 90% of the patients given Ceftin responded satisfactorily,
meaning that they were cured or showed significant improvement in
symptoms of the disease. According to Glaxo's data, that equaled the
positive response rate produced in patients given the generic
After its presentation, the Glaxo officials ably fielded a few
queries from the committee. They explained, for example, that Glaxo
couldn't test the drug against a placebo, as is common practice in
most drug trials, because with an available effective treatment of
generic antibiotics, it would be unethical to give a patient with Lyme
disease a dummy pill. Glaxo also measured up in a ritual common to the
advisory committee meetings: a sort of data scavenger hunt, wherein a
committee member asks about some obscure subset of the study, and the
company officials scramble through reams of paper and slides to
produce the appropriate factoid and statistical breakdown.
As the panel prepared to break for lunch, Glaxo clearly appeared to
have the momentum in its favor. Then came one of those telling hints
that to the astute observer are signs of an impending deluge. Just
before the break, a panel member asked Glaxo if the FDA had approved
the design of its trials. Glaxo's Collins responded yes, the company
had submitted to the FDA, as required, the protocol-outlining how the
company would enroll patients, determine whether they got Ceftin or
the generic drug and, most important, how it defined what was a
To that point, the FDA staff had been nearly silent as the
committee took in the company presentation. But Glaxo's response to
this final question prompted the FDA to point out that Glaxo didn't
request a meeting to discuss the study's design, as is often common,
particularly for diseases for which no drug has ever been approved.
Instead, Glaxo took advantage of an FDA rule stating that if the
agency doesn't object to a drug trial's design within 30 days of
notification, the company is free to commence testing.
Dr. Murray M. Lumpkin, head of the FDA's anti-infective drugs
division, emphasized that while those routine submissions are reviewed
for safety concerns, "there was no implied agreement with the Glaxo
design for efficacy."
The impact of that statement wasn't lost on Glaxo. As the meeting
reconvened for the afternoon session, Collins was overheard advising
an aide to begin rescheduling the Glaxo officials' flights home. "It
looks like we're in for a long afternoon," he said glumly.
He was right. Dr. Janice Soreth, the FDA medical officer who
reviewed Glaxo's data, walked the committee through her analysis,
which firmly concluded that each of Glaxo's two clinical trials "does
not demonstrate clinically or statistically that Ceftin is equivalent
to doxycycline in the treatment of early Lyme disease."
Soreth's conclusion, as hinted in the morning session, stemmed from
some obvious problems in the study design and execution. Under
standard FDA procedures, the agency hadn't briefed the advisory
committee on its reviewer's conclusions beforehand, to prevent pre-
meeting bias. Her well-argued review was so decidedly negative that,
when she finished, several panel members looked stunned, and a numbing
quiet hung in the room.
That compelled Lumpkin, who as head of the division reviewing
Glaxo's application was Soreth's boss, to remind the panel that
Soreth's conclusions hadn't been adopted as the FDA's official
position and didn't mean the agency necessarily was ready to reject
Glaxo's drug. "There obviously is a difference of opinion between her
and the sponsor Glaxo," Lumpkin said, but he assured the group that
the agency still needed advice about whose analysis was more valid,
given how little is known about Lyme disease.
Glaxo's back was clearly against the wall. During the subsequent
discussion, some committee members did challenge parts of Soreth's
review. And Glaxo and its hired guns -- three consulting physicians
with vast experience treating Lyme disease -- argued vociferously
against Soreth's reasoning, particularly her questioning of whether
all the patients who entered into the trial did, in fact, have Lyme
In the end, however, the committee's decision was unanimous that
Glaxo hadn't proven its drug a safe and effective treatment for Lyme
disease. For its three years and several million dollars worth of
studies, Glaxo's only success was in demonstrating the safety and
efficacy of doxycycline, the generic antibiotic. Dr. Thomas R. Beam,
chairman of the advisory committee, remarked after the meeting
"Even if the company's studies had shown their drug was effective, the
committee probably would have recommended that the agency approve both
Ceftin and the generic drug."
That, perhaps, is the most significant outcome of the advisory
session: Any company seeking approval for a Lyme-disease treatment
will have to test it against the generic therapies. And if a company
wants to avoid getting the less-costly alternative approved at the
same time, it will need to prove that its own drug is much more
effective than the current standard.
Anger and disappointment among the Glaxo officials was palpable
after the meeting, but like most companies that know they'll come
before the FDA again, Glaxo wouldn't discuss the outcome. Perhaps it
can take some small comfort in the fact that the FDA doesn't always
follow the advisory panel's advice -- although, for Ceftin, that
doesn't seem likely.
SOURCE: Wisconsin State Journal
DATE: June 9, 1993
People might worry too much about Lyme disease, according to microbiologist
Mitchell, based at the Marshfield Clinic, said Lyme may be one of the most
overdiagnosed ailments in history, leading to unnecessary and costly
"In earlier years, many who were thought to have it didn't," Mitchell said.
"Just suspecting a patient has Lyme disease is not enough for big-gun
The Marshfield Clinic is one of the few sites that uses a culture test to
diagnose Lyme disease with 100 percent accuracy, Mitchell said, Testing
has found that only half the suspects are positive, he added.
Some people who were unnecessarily treated with antibiotics developed
other infections, he said...
SPECIAL NEWS ANALYSIS:
[Lora Mermin, author of "Lyme Disease 1991: Patient/Physician Perspectives
from the U.S. and Canada" sent me the State Journal article and an audio
cassette transcript of Dr. Mitchell being interviewed on Wisconsin Public
Radio (6-14-93). Here are a few of Dr. Mitchell's comments:]
PM -- "Personally, I don't think there is a problem with underdiagnosing
Interviewer -- "Why not?"
PM -- "Because the patients that clinically fit the descriptions that have
been established through the years for Lyme disease are very easy to diagnose
and consequently to treat."
PM -- "The tests are not falsely negative. The problems we have are with
the false positive assays."
PM -- "Personally, I do not believe in seronegative Lyme disease -- Unless
a patient has been treated with antibiotics extremely early in the course
[Dr. Mitchell went on to discuss his "100% accurate" method of diagnosis --
the skin culture. He explained that it had to be performed early during the
infection when the EM rash is still present.]
Interviewer -- "If you don't have a skin lesion, then you're out of luck?"
PM -- "Well -- That's correct."
TITLE: Evasion of protective immunity by Borrelia burgdorferi by truncation
of outer surface protein B.
AUTHORS: Fikrig E; Tao H; Kantor FS; Barthold SW; Flavell RA
ORGANIZATION: Section of Immunobiology, Yale University School of Medicine
REFERENCE: Proc Natl Acad Sci U S A 1993 May 1; 90 (9): 4092-6
We analyzed variability in outer surface protein B (OspB) from Borrelia
burgdorferi (Bb), the causative agent of Lyme disease, to determine how Bb
escapes immune destruction. We have shown that vaccination with OspB from Bb
strain B31 protected mice from infection with Bb B31 but not against Bb N40.
The present study demonstrates that Bb N40 spirochetes which evade vaccination
immunity to OspB have a truncated form of OspB, due to a TAA stop codon at
nucleotide 577. In contrast, Bb N40 spirochetes that express full-length OspB
are unable to infect mice immunized with OspB, analogous to our previous
studies with Bb B31. Mapping of the OspB antibody response shows that
epitopes in the C terminus of OspB are surface-exposed and bind protective
monoclonal and polyclonal antibodies. This suggests that the C terminus of
OspB is important for eliciting a protective immune response to OspB.
Truncation or modification of outer surface proteins that do not bind
protective antibody may be a means by which Bb evades host defenses.
SOURCE: The Vancouver Sun, pA3
DATE: Tuesday, June 15, 1993
HEADLINE: Woman with symptoms relieved as official reveals B.C. contractions
BYLINE: REBECCA WIGOD; VANSUN
People can indeed get Lyme disease in B.C. [Canada], health authorities
admitted for the first time Monday.
"It is very likely we have this organism," Dr. John Millar, the acting
provincial health officer, said at a Vancouver press conference.
The organism - a spiral-shaped bacterium found in ticks that infest mice,
deer, squirrels and other animals - can cause Lyme disease in people bitten by
Infection often starts with a bull's-eye-like rash around the bite, followed
by flu-like symptoms, a stiff neck, nausea and swollen glands.
If untreated, it can go on to produce arthritic-like pain in the joints and
have lasting effects on the heart and nervous system.
Diane Kindree feels vindicated by Monday's announcement. The 40-year-old West
Vancouver woman had Lyme disease in the late 1980s but few doctors would
Health authorities have long maintained the disease is not endemic in B.C.,
but Kindree steadfastly refused to believe it would be found on the U.S. West
Coast but stop at the border.
"What we have experienced right across this country is a basic head-in-the-
sand attitude," said Kindree, who founded a support group to press for more
She said she has largely recovered, apart from "residual arthritic effects."
Satyendra Banerjee, the microbiologist who heads the provincial laboratory's
serology section, has been looking for the bacterium in ticks since 1986.
Two years ago, he hadn't found it. But research conducted between February
and May of this year isolated the bacterium from 13 ticks and one mouse on which
tick larvae had been feeding.
Banerjee said there have been 23 confirmed cases of Lyme disease in B.C.
since 1988. Six were people who had not traveled outside the province. He
admitted the problem could be larger because many sufferers may not report their
However, Millar urged British Columbians not to worry unduly about Lyme
disease. Deer ticks, which carry the bacterial culprit, account for only half
of the ticks in the province, and only one per cent of deer ticks are infected.
"The tick has to be on you for more than 24 hours before it can transmit an
infection to a human," he said.
Victoria will be funding research into Lyme disease for the next five years,
TITLE: The polymerase chain reaction for the detection of Borrelia
burgdorferi in human body fluids.
AUTHOR: Liebling MR; Nishio MJ; Rodriguez A; Sigal LH; Jin T; Louie JS
ORGANIZATION: Division of Rheumatology, Harbor-University of California,
Los Angeles Medical Center.
REFERENCE: Arthritis Rheum 1993 May; 36 (5): 665-75
OBJECTIVE. To analyze clinical fluids for the presence of Borrelia
burgdorferi DNA using the polymerase chain reaction (PCR).
METHODS. We utilized a modified, nested PCR to detect the presence of
Borrelia DNA in 99 samples of serum, urine, cerebrospinal fluid (CSF),
or synovial fluid obtained from 44 patients with various stages of Lyme
disease and 47 control subjects. Primer specificity was corroborated by
examining 2 DNA data banks, testing against DNA from other organisms, and
confirming results with a second set of nested primers.
RESULTS. Nested PCR was capable of detecting DNA from fewer than 10 organisms
in 1 ml of fluid. The specificity of this technique was 96.4%, with a
sensitivity of 76.7%. Although the specificity was uniformly high, the
sensitivity was dependent upon the body fluid being tested: CSF 100%, urine
100%, synovial fluid 80%, and serum 59%. The rate of false-positive results
CONCLUSION. These data demonstrate the potential utility of PCR in confirming
the clinical diagnosis of Lyme disease as well as providing insight into the
pathogenesis of various stages of this disorder.
IV. ***** BOOK REVIEWS *****
Sender: [email protected] (Marc Gabriel)
Angotti, Karen, "Lyme Disease: A Mother's Perspective," Anerak Publications,
(c) 1993, ISBN 0-9633902-3-6, 97 pages.
In a well written paperback, Karen recounts how Lyme disease invaded her
household in the summer of 1990. It all began when her son David became
infected near their new home in Tennessee. The book documents each
humiliating encounter with misinformed health care professionals and
David is diagnosed 34 pages into the book by Dr. Ed Masters from Cape
Girardeau, MO, to whom the book is dedicated. But the story does not end
there. The nightmare continues as nearly every family members succumbs
to the spirochete.
The words "YOUR SON IS A MAJOR PSYCHOTIC" are printed in a large, bold font
on the back cover. After examining David, one of the physicians the
Angottis visited made this pronouncement. Throughout the book Karen attempts
to describe how hurt and disillusioned she felt after this callous phrase was
"Lyme Disease: A Mother's Perspective" is an excellent book for anyone who
wants to understand the frustration, rage and pain felt by Lyme patients.
Patients may find it very therapeutic to read a book written by someone
who understands their plight. Health care professionals may wish to read
this volume so as to gain a better understanding of the Lyme patient's
mindset in an effort to improve their ability to recognize Lyme disease.
Lang, Denise with DeSilva, Derrick Jr. (M.D.), "Coping with Lyme Disease:
A Practical Guide to Dealing with Diagnosis and Treatment," Henry Holt &
Company, (c) 1993, ISBN 0-8050-2650-9, 256 pages.
Scheduled for wide availability on August 25.
Finally, a complete, up-to-date volume that no family should be without.
"Coping with Lyme Disease" provides the reader with a well-rounded mix
of anecdotal stories and facts that work together to paint an accurate
picture of how to deal with Lyme and how to identify it.
One of the central themes of the book is that Lyme cannot be accurately
diagnosed solely on the basis of serology or a list of symptoms. Rather,
Denise often begins chapters by describing case histories which offer the
reader a better picture of what Lyme really is and how it strikes its prey.
Denise covers all the bases in this book. She discusses the issues involved
with the undiagnosed patient, reviews the tests available and gives us an
overview of the treatment protocols. She also talks about the politics in
a well researched and clearly explained 18 page chapter. For those who don't
understand the politics of Lyme (and the significance of the politics), this
chapter will put things in perspective. This chapter alone makes the book
worth its price.
Denise divides her book into three sections: "Recognizing the Varied Aspects
of Lyme Disease," "Special Ages, Special Problems," and "Getting Treatment
and Support." She includes lists of support groups and newsletters.
"Coping with Lyme Disease" has been endorsed by the Prevent Lyme Foundation
and the Lyme Disease Network. It is an essential handbook for all Lyme
patients, their families and individuals in endemic areas. Physicians will
also tremendously benefit from the different perspectives offered in this
volume. In addition, readers of the LymeNet Newsletter who need some
background information on the controversies and dilemmas involved with Lyme
disease will want to read this book.
V. ***** JARGON INDEX *****
Bb - Borrelia burgdorferi - The scientific name for the LD bacterium.
CDC - Centers for Disease Control - Federal agency in charge of tracking
diseases and programs to prevent them.
CNS - Central Nervous System.
ELISA - Enzyme-linked Immunosorbent Assays - Common antibody test
EM - Erythema Migrans - The name of the "bull's eye" rash that appears in
~60% of the patients early in the infection.
IFA - Indirect Fluorescent Antibody - Common antibody test.
LD - Common abbreviation for Lyme Disease.
NIH - National Institutes of Health - Federal agency that conducts medical
research and issues grants to research interests.
PCR - Polymerase Chain Reaction - A new test that detects the DNA sequence
of the microbe in question. Currently being tested for use in
detecting LD, TB, and AIDS.
Spirochete - The LD bacterium. It's given this name due to it's spiral
Western Blot - A more precise antibody test.
VI. ***** HOW TO SUBSCRIBE, CONTRIBUTE AND GET BACK ISSUES *****
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All are encouraged to submit questions, news items, announcements, and
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example: get LymeNet-L/Newsletters 1-01 (will get vol#1, issue#01)
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LymeNet - The Internet Lyme Disease Information Source
Editor-in-Chief: Marc C. Gabriel <[email protected]>
Contributing Editors: Carl Brenner <[email protected]>
John Setel O'Donnell <[email protected]>
Frank Demarest <[email protected]>
Advisors: Carol-Jane Stolow, Director
William S. Stolow, President
The Lyme Disease Network of New Jersey (908-390-5027)
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