Volume: 1 Table of Contents: ANNOUNCEMENT: LDANJ Fund-raiser: "Great Imitator" Family Masquerade Party BARRONS: Drugs on Trial: The Growing Role of Washington's Advisory Panels 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 Newsletter: ***************************************************************************** * Lyme Disease Electronic Mail Network * * LymeNet Newsletter * ***************************************************************************** Volume 1 - Number 20 - 8/24/93 I. Introduction II. Announcements 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. -Marc. 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 generous contribution. 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 profitable. 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 expensive antibiotic... ...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 antibiotic. 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 successful treatment. 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 disease. 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 Paul Mitchell. Mitchell, based at the Marshfield Clinic, said Lyme may be one of the most overdiagnosed ailments in history, leading to unnecessary and costly treatments. "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 antibiotic therapy." 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 Lyme disease." 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 of infection." [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 ABSTRACT: 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 possible 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 the ticks. 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 believe her. 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 research. 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 symptoms. 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, said Banerjee. *****=***** 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 ABSTRACT: 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 was 3.6%. 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 physicians. 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 uttered. "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 shape. Western Blot - A more precise antibody test. VI. ***** HOW TO SUBSCRIBE, CONTRIBUTE AND GET BACK ISSUES ***** SUBSCRIPTIONS: Anyone with an Internet address may subscribe. Send a memo to [email protected] in the body, type: subscribe LymeNet-L <Your Real Name> FAX subscriptions are also available. Send a single page FAX to 215-974-6410 for further information. DELETIONS: Send a memo to [email protected] in the body, type: unsubscribe LymeNet-L CONTRIBUTIONS: Send all contributions to [email protected] or FAX them to 215-974-6410. All are encouraged to submit questions, news items, announcements, and commentaries. BACK ISSUES: Available via 2 methods: 1. E-Mail: Send a memo to [email protected] in the first line of the body, type: get LymeNet-L/Newsletters x-yy (where x=vol # and yy=issue #) example: get LymeNet-L/Newsletters 1-01 (will get vol#1, issue#01) 2. Anonymous FTP: ftp.Lehigh.EDU:pub/listserv/lymenet-l/Newsletters ----------------------------------------------------------------------------- LymeNet - The Internet Lyme Disease Information Source ----------------------------------------------------------------------------- Editor-in-Chief: Marc C. Gabriel <[email protected]> FAX: 215-974-6410 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) ----------------------------------------------------------------------------- WHEN COMMENTS ARE PRESENTED WITH AN ATTRIBUTION, THEY DO NOT NECESSARILY REPRESENT THE OPINIONS/ANALYSES OF THE EDITOR. ----------------------------------------------------------------------------- THIS NEWSLETTER MAY BE REPRODUCED AND/OR POSTED ON BULLETIN BOARDS FREELY AS LONG AS IT IS NOT MODIFIED OR ABRIDGED IN ANY WAY. ----------------------------------------------------------------------------- SEND ALL BUG REPORTS TO [email protected]. ----------------------------------------------------------------------------- |
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