Interview with Dr. Clawu from NEMSN Newsletter

Through personal contacts by NEMSN and a constituent Ken Kleemier, Representative Ralph Regula of Ohio sent this response to Mr. Kleemier in January 2002:" As you may know, I am the chairman of the House Subcommittee on Labor, Health and Human Services and Education, and in this position I have jurisdiction over the budget for National Institutes of Health (NIH).... Specifically, the National Institute on Musculosckeletal and Skin Diseases, (NIMSD) the lead institute within the NIH on EMS research, received $448.865 million in funding, an increase of $52 million. In addition, the final bill urged the NIMSD to enhance research efforts to identify the cause of EMS and develop a better understanding of the characterization of the pathophysiological events leading to the chronic phase of the disease." This is the first research funding opportunity not associated with Showa Denko, the company whose product Tryptophan was implicated with the initial epidemic of this disease.

NEMSN members are urged to send a letter of thanks to their Congressperson and Representative Regula and request support for continuation funding. The addresses for members of Congress can be found at our Website www.nemsn.org.

Contacts to agencies within NIH are being made by members of the NEMSN board. Dr. Susanna Serrata-Sztein, Director of the Rheumatic Diseases Branch, a key administrator, said: "there has not been much research going on in this area and it may be that there is not enough interest." However, Robin Straughn, Budget Affairs Director for NIH suggested NEMSN can help by encouraging a "conference be convened to determine the major research questions to be answered."

Dr. Gerald Gleich a scientist who has been engaged in research into the cause of EMS is "enthusiastic about helping to convene such a conference ." and identified key people in the field to be contacted. NEMSN is contacting its' Medical Advisory panel and others doing research or treatment of persons who have EMS and will initiate this effort by setting up a teleconference early this summer. The next step will be to convene a conference sometime in the fall devoted to identifying the important current research issues.

NEMSN is interested in promoting research into the cause of EMS and treatment of current patients. We will be including physicians and scientists from disciplines of rheumatology, neurology, internal medicine, and specialists in specific classic chronic symptoms such as scleroderma and pulmonary disorders. Other Institutes and agencies within NIH are being contacted to generate interest in EMS research including: Allergy and Infectious Diseases, Alternative Medicine, Environmental Health, and Dietary Supplements.

by Joe Hayes and Sharron Lobaugh

When we first saw this head line on a special paper that was sent to NEMSN by a member, it gave us hope that this could be something that could help our members. After reading the article, on the study, it became clear that it was beyond our knowledge of understanding how the Gold Standard may be able to help us. We decided that it deserved to be posted on our web site for our members but needed some clarification. We ask Dr. Clauw M.D. a Professor of Medicine, in the Division of Rheumatology, at the University of Michigan serveing as the Executive Director of the Chronic Pain and Fatigue Research Center if he would answer questions about the study so that we could report to our members the essence of the study. He gratefully accepted and we put together some questions that should help us understand the complexity of the study. We only have room for an excerpt of the article and will publish the complete article on our web site www.nemsn.org. The complete study took 6 years and was supported by many professionals in the medical field as you will see in the credits. Because of limited space we will have the continuation of the interview in our next Newsletter.

Phillip A. Hertzman, MD; Daniel J. Clauw, MD; Joseph Duffy, MD; Thomas A. Medsger, Jr, MD; Alvan R. Feinstein, MD

Los Alamos Medical Center, Los Alamos, NM (Dr Hertzman); Division of Rheumatology, Immunology, and Allergy Department of Medicine.

Georgetown University School of Medicine, Washington, DC (Dr Clauw); Division of
Rheumatology

Department of Internal Medicine, Mayo Clinic, Rochester, Minn (Dr Duffy); Division of Rheumatology and Clinical Immunology

Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa (Dr
Medsger)

Department of Internal Medicine and Epidemiology, Yale
University School of Medicine, New Haven, Conn (Dr Feinstein).
Corresponding author and reprints: Phillip A. Hertzman, MD, Los Alamos Medical Center, Suite 130, West Road, Los Alamos, NM 87544

Background: Constructing diagnostic criteria, a common problem in clinical medicine, is particularly difficult for diseases that lack a pathognomonic
"gold standard." To develop an improved strategy for constructing such criteria, we used the eosinophilia-myalgia syndrome as an example. The goal, for research classifications, was to construct validated clinically sensible criteria and to develop improved methods that can be used for other disorders.
Methods: Using a "pattern-based" approach with data from several separate sources, a committee of investigators first prepared and informally tested criteria for the diagnosis of eosinophilia-myalgia syndrome. A gold standard challenge set of reports of cases and noncases was independently generated and separately validated by an external panel of clinical experts. The
criteria were then tested using the gold standard set, and interobserver variability and diagnostic accuracy were determined.

Conclusions: The proposed criteria are accurate and reproducible, and can be used in future clinical investigations of the eosinophilia-myalgia syndrome.
The new strategy and methods developed for this challenge can be valuable for solving analogous problems in constructing criteria for other clinical
disorders.
Arch Intern Med. 2001;161:2301-2306

Stages:

The project involved 4 stages: (1) construction and modification of preliminary criteria via consensus and informal testing by the coordinating committee, (2) development of a gold standard set of EMS cases and noncases by an independent panel of experts, (3) formal evaluation of the reproducibility and accuracy of the criteria when tested against the gold standard set, and (4) preparation of the final version of the criteria.

Q. Dr. Clauw what are the "supplementary features" referred to in the publication which were not included as components in the criteria that could be potentially useful in diagnosing the conditions of the individual patients?

Note: At this point Dr Clauw thought that we were asking a question about the supplementary information in the following paragraph of the paper so we let it continue because it was of some interest.

"Together with the cited supplementary information, the criteria can enhance communication about
EMS and can provide a starting point for diagnosing the conditions of individual patients."

When we went through the information, it was in the original criteria. Iit was developed primarily for set up of public health when the Center for Disease Control developed those criteria, they did so very rapidly with the information that they had at time. The purpose for the Center for Disease Control’s studies and actions was to, as quickly as possible,
identify what was causing eosinophilia myalgia syndrome. The criteria didn’t turn out to be very extremely useful in clinical practice in that some people who met those criteria didn’t have what we would consider to be EMS and some people who had EMS didn’t meet those criteria. New criteria which were
developed with a lot more knowledge after six or seven years, was an attempt to
develop criteria that more accurately described the syndrome as we knew it and took into account, what was called Pattern One. Pattern One was really an attempt to get rid of the problem that there were some people who met the EMS criteria who didn’t have EMS. So for example, there were multiple examples of people who had muscle pain which is an incredibly common problem in the general population. 15 or 20% of the population might have muscle pain at any one time and for one reason or another, had eosinophilia. Maybe they had an allergic reaction. Maybe they had hay fever or asthma or something like that. There are also a number of people who at any given time, will have eosinophilia. So Pattern One, by adding the third component which was requirement for rash, edema, pulmonary involvement or neuropathy, it was an attempt
to make the original CDC criteria more specific. Pattern Two was really typed to do the opposite which was to say that there were probably people who had EMS that didn’t the have the high eosinophil count or in whom the eosinophil count wasn’t done at the right time to find out if they had a high eosinophil count because we know that eosinophil count only stayed high in most people with EMS for three or four months at most. So criteria with two or Para two as its called in the paper, was an attempt to lift some features of the illness that were distinguishing enough that even in the absence of a high eosinophil, it could still be reasonably comfortable in making the diagnosis.

Dr. Clauw let me repeat the question and present the quote from the paper so that you might understand the question.

Q. What are the "supplementary features" referred to in the publication which were not included as components in the criteria that could be potentially useful in diagnosing the conditions of the individual patients?

The question is derived from the following paragraph within the article .

"In a separate publication, we will present a supplementary list of features, not included as components in the criteria, that can be potentially useful in diagnosing the conditions of individual
patients. We will also (1) describe difficult cases that evoked diagnostic errors and (2) compare the performance of the new criteria with that of the Centers for Disease Control and Prevention surveillance criteria."

DR: Okay, I see what you’re saying there. That was basically the, no, there hasn’t been another
publication because it took way longer to get this publication published than anyone ever thought it would. It took about three years to get it published. To get it published it took two submissions to the Archives of Internal Medicine and was sent to the New England Journal and the Journal of the American
Medical Association before it was sent to the Archives of Internal Medicine, so this took maybe even more than that, but I know it took at least three years to get this published. As you probably know, unfortunately, with the exception of Terry Goik who is still doing a little bit of work on eosinophilia myalgia syndrome now in Utah and a couple small groups in Germany,little research is being done. There really isn’t anyone still doing work in the EMS and then the problem became that it got
harder and harder to get articles published. Alvin Feinstein is considered to be sort of a grandfather of clinical medicine in the United States and the fact that it took so long to get an article published with Alvin Feinstein being the co-author spoke to the fact that people just were really not that interested in eosinophilia myalgia syndrome.

Q. So it doesn’t look promising that this separate publication will ever come about.

A. No, I don’t think it will because Phil Hertzman would be the only one that would, if he decided to be the driving force behind it. He’d be the only one that
would do it. Some of us that have moved on to other things with respect to research would probably be willing to help him with it but we all have piles of
things that we’re behind in getting published that are more relevant to the work that we’re now doing. I’m not disinterested, it’s always just an issue of sort of prioritization and they’re always trying to get a manuscript. There’s always sort of one driving force and Phil Hertzman was clearly that driving force for this manuscript. He was the one that championed this cause and in spite of getting rejected so many time, kept persevering.

Q. Do you have any concerns about the reliability of physician’s record given that the condition of EMS is systematic in that the chronic phases of the illness are showing in varied pattern with manifestations widely varying, such as gum and mouth tissue degeneration, GIRD and other autoimmune disorders?
A. I would say yes and no. One of the fundamental issues with this whole discussion is, how important is it thirteen years after developing the illness to
diagnose someone with EMS rather than have them continue to carry a label with something like fibromyalgia. I’m just going to play the devil’s advocate. I understand that for patients that they might want to know, but the reality is, is that from a
medical standpoint, it doesn’t make a difference with respect to what we do for treatment. One of the reasons is, patients don’t like to carry diagnoses like fibromyalgia in that there’s a sense that fibromyalgia as an illness isn’t taken very seriously. As someone who now devotes my life to studying fibromyalgia, it’s an incredibly disabling illness as well and so I think that, sometimes patient’s would rather have the EMS label than the fibromyalgia label if they indeed have EMS. I can understand that their sort of want and desire, if you will, get it right. But it doesn’t affect treatment. There isn’t anything that we specifically do for people with EMS thirteen years after. We don’t given them steroids, we don’t treat that as an autoimmune or inflammatory disease in the late stages of disease. So the treatment of someone isn’t really affected by whether they’re labeled as having fibromyalgia or they’re labeled as having EMS. You try to treat each of the specific symptoms whether it’s dry mouth or muscle pain or fatigue, any of the number of symptoms that might occur in either fibromyalgia or EMS. I’m only sort of answering the question but that’s how I would answer it. Doctor’s records aren’t necessarily going to be accurate but the issue is, how important is it that we get it right, and the answer is, it’s not that important. From a medical standpoint it’s not that important. From a patient’s standpoint it might be important for one reason or another.

Q. A follow-up on that. I know one of those treatments that you recommended for EMS was magnesium. I use that myself. I found it really helpful to take care of the muscle cramping. Would you recommend that treatment for fibro as well. Is that common to both?
A. There’s some data suggesting that it works in fibromyalgia and although it’s not listed as a
first line therapy, it’s listed as one of the things that can help some people and there are some people that I recommend it, these are people that have
significant cramping. So I think that is useful in both conditions. It’s more useful in EMS because the cramping in EMS is an order of magnitude more severe and more common than the cramping that occurs in fibromyalgia. But for either illness and it’s even
recommended for like nocturnal leg cramps, the kind of cramps of people that have neither EMS nor fibromyalgia can get, where they wake up in the middle of the night with severe leg cramps. Magnesium is one of the over-the-counter or nutritional supplements that’s been recommended for that. So it’s something that generically seems to be helpful for cramps and because of the severity of the cramps in EMS where they can be so debilitating and in some cases, cause people to fracture bones and things like that. Then it’s a treatment that tends to be more useful in EMS than in fibromyalgia.

Dr. Claw, that concludes all of our questions that we have for this issue of the newsletter. Is there anything else that you’d like to add that wasn’t presented to you, either about your research at the hospital, your new location, or about EMS in particular?

DR: I think the people who have EMS should realize and understand that although most of all of us who were initially on the study have sort of moved on to other things. It doesn’t mean that we’ve forgotten these patients or forgotten this problem. Many of us are studying things like fibromyalgia that although at face value appear to somewhat dissimilar because fibromyalgia is not an autoimmune disease and was not caused by exposure to a toxin. The advances that we make in treating fibromyalgia are likely to very applicable to treating EMS. The most severe problems that people with EMS have, late in the phase of EMS like pain and fatigue and cognitive problems, are all incredibly common problems in fibromyalgia as well. So again, people should have some sense that there is still a lot of work being done in understanding the mechanisms of and treatments of the types of symptoms that they’re experiencing, even though there isn’t any work being done on EMS per se at this time.

investigations of the eosinophilia-myalgia syndrome."

Results: The 92 reports submitted by external panelists included 68 women and 24 men (mean age, 46.8 yrs.). Of the 92 reports, 47 were submitted as instances of EMS and the other diagnoses included eosinophilia fascititis, fibromyalgia, systemic sclerosis, Churg-Strauss arteritis, generalized vasculitis, systemic lupus erythermatosus, undifferentiated connective tissue disease, eosinophilic leukemia, idiopathic thrombocytopenic purpura, coronary artery disease, hypothyroidism, polymyalgia rheumaticia, giant cell arteriritis, chronic pain syndrome and indeterminate cause."

_______________________________________________________________________

Q: Dr. Clauw How does the gold
standard compare with results of the NEMSN study by Karen Tonso, PhD?

DR: They are really two different types of studies. The Tonso study is analysis of what happened to people’s symptoms over time. Our study was an attempt to look at diagnostic criteria for the illness so they weren’t the same.
Q: Could you explain the differences between the Gold Standard Study and the Tonso study?
DR: The committee compiled 45 elements considered important in the diagnosis of EMS. What we then tried to do is look at things that were unique to EMS. I suspect most of all of the 45 symptoms would have been the types of things that were found in the Tonso study. The way it was narrowed to ten, was to look at the symptoms that were in unique to EMS, so you wouldn’t consider things like fatigue for example, because that occurs so commonly in every illness that it’s not going to be a feature that is helpful in creating criteria that will allow you to pick an EMS patient out from someone with a different illness. In going from 45 to 10, we didn’t necessarily focus on the things that happened most commonly in EMS, we focused on the things were in some way, more unique in EMS or less common to other illnesses.

Q: Was there anything in the Tonso study that surprised you?
DR: It’s pretty much what I might have expected. It [NEMSN Tonso study] doesn’t represent what the average person who had EMS in 1989, but it’s probably a reasonably accurate representation of the person that still has the EMS now. But we know within the first 6 to 12 months the symptoms essentially resolved in some of the people. Those people whose symptoms didn’t resolve in the first year or two, it usually didn’t go away….They have chronic symptoms, and they’re not necessarily getting better and in many cases, they’re probably somewhat worse.

Q: Your report concludes that eosinophilic fasciitis and Churg-Strauss arthritis are considered difficult to distinguish from EMS. We are concerned because each year 20-30 new people who have been recently diagnosed with EMS after having suffered for 10 years with it, but were diagnosed incorrectly with various other diseases such fibromyalgia and chronic fatigue, arthritis or scleroderma, are contacting us to be added to the mailing list. How does the gold standard improve the patient’s ability to be diagnosed correctly?

DR: I think it does improve the patient’s ability to be diagnosed correctly because Pattern Two allows us to make the diagnosis ten years later. That was one of the things that I started to say in the beginning, was that when you develop criteria for an illness,... you try develop criteria that are as sensitive as possible and as specific as possible. Sensitive means that it picks up everyone who has the illness and specific means that it only picks up people that have the illness. It doesn’t pick up people that have other illnesses. So Pattern One was an attempt to improve the specificity of the old CDC criteria because we knew that there were people met the CDC criteria who didn’t really have EMS. Pattern Two was an attempt to improve the sensitivity because we knew there were people who didn’t meet the CDC criteria because they didn’t have documented eosinophilia. We knew they had EMS, so Pattern Two in particular, would the people who were sort of struggling with what it is that they have and thirteen years later because their physicians could look at this pattern and say, well, you know, yes, this person does in fact, meet those criteria. These criteria were pretty good at separating people with EMS from people with fibromyalgia or some of the other things. The fact that we couldn’t separate people with EMS from eosinophilic fasciitis is probably irrelevant because eosinophilic fasciitis and EMS are treated in the exact same way. The other thing is that eosinophilic fasciitis and Churg-Strauss are incredibly rare as well. It’s not likely that there are many being mislabeled with Churg-Strauss or eosinophilic fasciitis who really have EMS.

Q:. We have people who have been diagnosed with fibromyalgia and now are being rediagnosed EMS. So what specifically is the difference between fibromyalgia and EMS?
DR: None of the things that we have in Pattern Two [is subjective], they’re all objective features except one….They’re things that have to be found on a physical exam or by testing. Then myalgia and muscle cramps obviously is a subjective symptom. Then the other pattern was any two or three of again, fasciitis, myopathy, neuropathy or eosinophilia and those all are objective. Fibromyalgia patients wouldn’t have any of those objective findings. All they would have myalgia or muscle cramps, so if someone had an apparent illness that was reminiscent of EMS and they had the myalgia or muscle cramps and fibromyalgia, but they also had either fasciitis or
neuropathy, then a physician might say that thy fit Pattern Two and thus they meet criteria for investigations of the eosinophilia-myalgia syndrome."

Results: The 92 reports submitted by external panelists included 68 women and 24 men (mean age, 46.8 yrs.). Of the 92 reports, 47 were submitted as instances of EMS and the other diagnoses included eosinophilia fascititis, fibromyalgia, systemic sclerosis, Churg-Strauss arteritis, generalized vasculitis, systemic lupus erythermatosus, undifferentiated connective tissue disease, eosinophilic leukemia, idiopathic thrombocytopenic purpura, coronary artery disease, hypothyroidism, polymyalgia rheumaticia, giant cell arteriritis, chronic pain syndrome and indeterminate cause."
* * * * * *

Q: Dr. Clauw How does the gold
standard compare with results of the NEMSN study by Karen Tonso, PhD?

DR: They are really two different types of studies. The Tonso study is analysis of what happened to people’s symptoms over time. Our study was an attempt to look at diagnostic criteria for the illness so they weren’t the same.
Q: Could you explain the differences between the Gold Standard Study and the Tonso study?
DR: The committee compiled 45 elements considered important in the diagnosis of EMS. What we then tried to do is look at things that were unique to EMS. I suspect most of all of the 45 symptoms would have been the types of things that were found in the Tonso study. The way it was narrowed to ten, was to look at the symptoms that were in unique to EMS, so you wouldn’t consider things like fatigue for example, because that occurs so commonly in every illness that it’s not going to be a feature that is helpful in creating criteria that will allow you to pick an EMS patient out from someone with a different illness. In going from 45 to 10, we didn’t necessarily focus on the things that happened most commonly in EMS, we focused on the things were in some way, more unique in EMS or less common to other illnesses.

Q: Was there anything in the Tonso study that surprised you?
DR: It’s pretty much what I might have expected. It [NEMSN Tonso study] doesn’t represent what the average person who had EMS in 1989, but it’s probably a reasonably accurate representation of the person that still has the EMS now. But we know within the first 6 to 12 months the symptoms essentially resolved in some of the people. Those people whose symptoms didn’t resolve in the first year or two, it usually didn’t go away….They have chronic symptoms, and they’re not necessarily getting better and in many cases, they’re probably somewhat worse.

Q: Your report concludes that eosinophilic fasciitis and Churg-Strauss arthritis are considered difficult to distinguish from EMS. We are concerned because each year 20-30 new people who have been recently diagnosed with EMS after having suffered for 10 years with it, but were diagnosed incorrectly with various other diseases such fibromyalgia and chronic fatigue, arthritis or scleroderma, are contacting us to be added to the mailing list. How does the gold standard improve the patient’s ability to be diagnosed correctly?

DR: I think it does improve the patient’s ability to be diagnosed correctly because Pattern Two allows us to make the diagnosis ten years later. That was one of the things that I started to say in the beginning, was that when you develop criteria for an illness,... you try develop criteria that are as sensitive as possible and as specific as possible. Sensitive means that it picks up everyone who has the illness and specific means that it only picks up people that have the illness. It doesn’t pick up people that have other illnesses. So Pattern One was an attempt to improve the specificity of the old CDC criteria because we knew that there were people met the CDC criteria who didn’t really have EMS. Pattern Two was an attempt to improve the sensitivity because we knew there were people who didn’t meet the CDC criteria because they didn’t have documented eosinophilia. We knew they had EMS, so Pattern Two in particular, would the people who were sort of struggling with what it is that they have and thirteen years later because their physicians could look at this pattern and say, well, you know, yes, this person does in fact, meet those criteria. These criteria were pretty good at separating people with EMS from people with fibromyalgia or some of the other things. The fact that we couldn’t separate people with EMS from eosinophilic fasciitis is probably irrelevant because eosinophilic fasciitis and EMS are treated in the exact same way. The other thing is that eosinophilic fasciitis and Churg-Strauss are incredibly rare as well. It’s not likely that there are many being mislabeled with Churg-Strauss or eosinophilic fasciitis who really have EMS.

Q:. We have people who have been diagnosed with fibromyalgia and now are being rediagnosed EMS. So what specifically is the difference between fibromyalgia and EMS?
DR: None of the things that we have in Pattern Two [is subjective], they’re all objective features except one….They’re things that have to be found on a physical exam or by testing. Then myalgia and muscle cramps obviously is a subjective symptom. Then the other pattern was any two or three of again, fasciitis, myopathy, neuropathy or eosinophilia and those all are objective. Fibromyalgia patients wouldn’t have any of those objective findings. All they would have myalgia or muscle cramps, so if someone had an apparent illness that was reminiscent of EMS and they had the myalgia or muscle cramps and fibromyalgia, but they also had either fasciitis or
neuropathy, then a physician might say that thy fit Pattern Two and thus they meet criteria for