Dr. Baker: Thank you very much. Can we have Allen Steere come to the podium please?
Dr. Allen Steere: Thanks for this opportunity to speak with you about the IDSA treatment guidelines. I think that these guidelines reflect the best information available about the treatment of this infection. During the past thirty four years I have studied each of the manifestations of Lyme disease and have conducted treatment studies of each manifestation. However my talk today is about late manifestations of the disorder. This is where I and my colleagues began thirty four years ago with the evaluation of a cluster of children in Lyme, Connecticut who were thought to have juvenile rheumatoid arthritis. Lyme arthritis in these patients was characterized by intermittent or persistent swelling and pain in a few large joints specially the knee over a period of several years. Some of the children or their parents remembered an initial skin lesion before the arthritis. We began to follow such patients perspectively and it was from that work that I saw the complete range of the disease before antibiotic therapy and before the cause of the disease was known. Within weeks about 15% of the patients developed neurologic involvement, meningitis, cranial neuritis, or [Indiscernible] [0:01:59] or some combination. About 5% developed cardiac abnormalities which was primarily AV nodal block.
This part of the disease was often accompanied by many other symptoms a lot of systemic symptoms initially that could include myalgias, arthralgias, fever. But over period of months the disease seemed to change and people generally felt much better with few if any systemic symptoms but it was in that period the joint involvement began to occur months after disease onset. We now know that this clinical picture is caused by Borrelia burgdorferi infection or synovial tissue in joints this is the most common late manifestation of the illness and I think I didn’t mention this is about 60% of untreated patients. We then became aware that there could be late neurologic syndromes giving you a percentage is somewhat difficult because of problems with definition of late neurologic involvement of Lyme disease. But even in untreated patients I would say that the maximum is 5% it is probably more like 1% or less. So I think now with antibiotic therapy generally early disease is recognized all of these percentages of later manifestations of the disease have become much less. So you ask why is it a problem to find patients with even acute neurologic involvement of the disease. Well they are there one can come up with them finding patients with late neurologic involvement who you can really document Borrelia burgdorferi that is quite rare today. This picture of knee [Indiscernible] [0:03:52] involvement of several large joints we still see. The recommendation and the IDSA treatment guidelines Lyme arthritis can be treated successfully with any microbial agents administered orally doxycycline, amoxicillin, or Ceftin for 28 days as recommended in adult patients without clinical evidence of neurologic disease. That recommendation is based primarily on this study I‘m sorry but I thought because the screen would be bigger.
Dr. Allen Steere: But I’m still [Indiscernible] [0:04:30].
Speaker: Yes.
Dr. Allen Steere: From 1986 through 1981 eighteen of twenty patients 90% randomized to receive doxycycline for 28 days or sixteen of eighteen patients 89% randomized to receive amoxicillin and Probenecid for 28 days. Have the resolution of arthritis within one to three months after the initiation of antibiotics. This didn’t work for everyone. More patients had little improvement in their arthritis with these oral regimens. In addition neurobrucellosis later developed in five patients four of whom received the amoxicillin and Probenecid regimen. Despite these limitations of former cost effective this analysis concluded but oral antibiotics were preferred to IV antibiotics for the initial treatment of Lyme arthritis in the absence of [indiscernible] neurologic involvement. Because they are often effective they are less likely to result in serious complications and they are substantially less expensive. The second part of the recommendation, patients who have persistent and recurrent joint swelling after recommended course of oral antibiotic therapy should be retreated with another four week course of oral antibiotics if their arthritis is substantially improved but not yet completely absolved, resolved, or with a two to four week course of IV ceftriaxone if there has not been substantial improvement.
The largest study of late Lyme disease was this randomized study of two versus four weeks of intravenous Ceftriaxone which [Indiscernible] [0:06:10] was the principal investigator 143 patients in a multi center randomized trial with late Lyme disease were randomized to receive IV Ceftriaxone for two or four weeks. 76% of patients in the two week group and 70% of patients in the four-week group were cured that’s the information that we were given. This study has limitations the one that I find most difficult is that I don’t really know what these patients had. I would like to know what manifestation of late involvement they had. [Indiscernible] [0:06:46] says most had Lyme arthritis because that’s the most common late manifestation of the disease. But then this also goes onto to say the most common persistent symptoms were arthralgia, malaise, and fatigue. I said earlier Lyme arthritis becomes a localized disease for the most part with few or any systemic symptoms and I don’t see Arthralgia, malaise, and fatigue in this group of patients after antibiotic treatment. It makes me think in some of the patients who veered into this trial had what we might call post Lyme disease syndrome today. The next piece of information five patients in the two- week group had no apparent response to therapy compared with none in the four-week group. Well I also have trouble with that is that Lyme arthritis is that a swollen knee and five in the two-week group didn’t have a response but everyone in the four-week group did have a response. So a greater proportion of patients in the four-week treatment group had therapy prematurely discontinued because of the adverse events the downside of treating with four weeks rather than two weeks. What I think now is there are patients it’s a rare syndrome characterized by localized proliferative synovitis lasting months to several years after two to three months of oral and IV antibiotics for Lyme arthritis. This is usually a swollen knee in which one can show proliferative synovitis generally without other symptoms. Patients generally feel well except that they have a proliferative synovitis in one knee. The pathogenesis of antibiotic-refractory Lyme arthritis is debated. Hypothesis to explain this disease cause have included persistent infection or infection induced tissue specific autoimmunity. I would want to underscore that I do not think this is systemic
autoimmunity. And I’m also not saying that this is applicable to any other manifestation of Lyme disease it is simply that synovial tissue which was infected remains proliferative and inflamed for some period of months to several years after two to three months of oral and IV antibiotics. So the recommendation is if patients have no resolution of arthritis despite intravenous antibiotic therapy and if PCR results per sample of synovial fluid are negative symptomatic treatment is recommended which may include NSAIDs or DMARDs such as [Indiscernible] [0:09:40]. Arthroscopic synovectomy may reduce the duration of joint inflammation. The type of information that we have about this outcome synovial tissue obtained from these patients of synovectomy has shown uniformly negative culture and PCR results. I would add QPCR and MRNA result or [indiscernible] DNA. This outcome is associated with particular HLADR [Indiscernible] [0:10:13] particularly the [Indiscernible] [0:10:18]which are primarily HLADR [indiscernible] associated with rheumatoid arthritis. This is however a different clinical picture than rheumatoid arthritis. And is also associated with declining cellular and humeral immune responses to [Indiscernible] [0:10:35] except for one patient treated with hydroxyl [Indiscernible] [0:10:38] breakthrough cases of persistent infection had not been noted with [Indiscernible] [0:10:46] therapy. This is included with both methotrexate and TNF inhibitors. These findings suggest that proliferative synovitis may persist in genetic re-susceptible individuals after the near or total eradication of B Burgdorferi from the joints. An observational study of twenty patients who underwent arthroscopic synovectomy for the treatment of antibiotic-refractory Lyme arthritis sixteen had the resolution of arthritis without recurrence.
I want to comment on seronegative late Lyme disease a number of people have so I want to as well. The principal study you have heard in 1998 so this was based on patients seen before that. Seventeen patients were described to receive short courses of antibiotic therapy for early Lyme disease and subsequently developed arthritis, arthralgia, peripheral neuropathy, headache, or fatigue. These symptoms were accompanied by positive proliferative responses of PBMC B Burgdorferi [indiscernible] [0:11:48] without an antibody response. Rather quickly specificity of the proliferation assay was called in question. We worked hard I know trying to standardize this assay it’s difficult and I think it’s a test that is quite problematic in that regard. I think we now also think that the role of CD4 positive T cells in this disease is to help T cells to produce antibody. So if one has a C4 positive T cell response one is also going to start seeing an antibody response to this agent.
[Indiscernible] [0:12:36] system mice inoculated with [ developed an antibody response. I do not know of any exceptions for that. And in patients with Lyme arthritis or neurologic manifestations of the disorder where it has been possible to get culture or PCR evidence another way of documenting B Burgdorferi infection they have been seropositive that’s our experience. I think reports about PCR positivity alone without any other findings related to problems of doing PCR testing in the earlier days of doing it. Now we are sequencing and other ways of really documenting that one is dealing with B Burgdorferi in my experience these patients are seropositive. So I would say current experiences that all patients with late manifestations of Lyme disease are seropositive by
the two test approach of [Indiscernible] [0:13:43] western block recommended by the center for disease control.
The clinical picture of late neurologic involvement of Lyme disease this is the most problematic area. Two people really worked describing this in the 1980s. First John Harper who was at Stony Brook at the time and Eric Largegan [Indiscernible] [0:14:04] both described Lyme neuropathy as a subtle I want to emphasize that subtle sensory neuropathy causing distal paresthesia or radicular pain usually without much in the way of systemic symptoms or other neurologic symptoms. In addition to seropositivity the EMG showed an [Indiscernible] [0:14:33] neuropathy affecting proximal and distal nerve segments that is not a specific finding for B Burgdorferi infection. It’s simply saying that the EMG actually looked worse than the symptoms did. So why isn’t this perhaps due to diabetic neuropathy or peripheral neuropathy that’s idiopathic. These patients were treated with intravenous Ceftriaxone and improved. It was based on two or four week courses. Lyme encephalopathy was certainly moré problematic. How was it defined in the study of Eric Largegan headed up with some observational case studies because there weren’t many patients. There is a subtle syndrome of memory impairment characterized by previous classic manifestations of Lyme disease, verbal, or visual memory impairment is demonstrated by a score of at least two standard deviations below [Indiscernible] [0:15:28] on four subjects on three tests that were part of this. And a positive serologic test for Lyme disease and often in most patients evidence of intrathecal antibody production to B Burgdorferi . I tried to say before that I think these are rare outcomes of B Burgdorferi infection become even rare presumably due to effective therapy of early manifestations of Lyme disease. But the recommendation adult patients with late neurologic disease affecting the central or peripheral nervous system should be treated with IV Ceftriaxone 2 grams per day for two to four weeks. And these were the observational case series twenty five patients with Lyme neuropathy who were treated with IV Ceftriaxone for two weeks nineteen were clinically improved six months after treatment. In a case series of eighteen patients with Lyme encephalopathy were treated with IV Ceftriaxone fourteen of the fifteen patients examined in six months then improvement in symptoms and verbal memory scores and CF of protein values were significantly less. At twelve to twenty four months all eighteen patients rated themselves as back to normal or improved and this improvement was sustained.
It was concluded from these studies that Lyme neuropathy or encephalopathy maybe associated with active infection of the nervous system and can be treated successfully in most patients with a four week course of IV Ceftriaxone. Clinically the major differential point that I would made is that these were subtle contained symptoms in patients with very little in the way of systemic symptoms that is different from the more dramatic and diffused pain and fatigue syndromes and we have been hearing about today. However it’s problematic to try to differentiate these syndromes clinically really is dependent on test results. So in the neuropathy groove I want to know that the EMG shows a diffused axonal neuropathy affecting both proximal and distal nerve segments. And in a patient with Lyme encephalopathy I really like to see that there is evidence of intrathecal antibody production as shown by antibody capture EIA. If one defines this in this way we ask each other on the panel how many such patients have you seen in the last ten
years we were each able to come up with a few but less than a total of ten over a ten year period thank you very much.
Dr. Baker: Thank you Dr. Steere does the panel have questions?
Dr Charini: Yeah.
Dr. Baker: Dr. Charini.
Dr. Charini: I have several questions some of them you are talking others just to tap your expertise on this. Well actually one thing I wanted to ask you about one critique as far as the two tier testing goes is that for the diagnosis of late Lyme disease arthritis or neurologic manifestations is that that there may be some circular reasoning the Baker paper pointed out that in order for the patients to be defined as having late Lyme disease they have to have a positive [Indiscernible] [0:19:15] test and if they have a positive future [Indiscernible] [0:19:17] test then hundred percent of the level [indiscernible] and so because there is no goal standard how do you address that.
Dr. Steere: As I mentioned there are cases though where we have culture evidence of B Burgdorferi infection and in the majority of patients with Lyme arthritis before antibody treatment it is possible to show QPCR evidence MRNA evidence of B Burgdorferi infection. Anyone who has had those results in my experience has been seropositive even strongly seropositive. High antibody responses to [Indiscernible] [0:19:59] with antibody reactivity with many [indiscernible] block. And then in animal [Indiscernible] [0:20:08] systems where one can control what’s going on in B Burgdorferi injected to my knowledge the animals become seropositive.
Dr. Charini: So much of the diagnosis is being based on the two tier test and the guidelines, what do you make of this phenomenon of immune complexes and is that something that.
Dr. Steere: Early on there maybe immune complexes indeed I mean C125 [Indiscernible] [0:20:48] assay. There was evidence of new complexes early sometimes in blood and in the joint in patients with Lyme arthritis. But in patients with Lyme arthritis we are talking about late manifestations these patients have still been strongly seropositive. So it seems that one is producing more antibody [Indiscernible] [0:21:17]. In fact I mean we think that they are a small number of organisms left in the joint and someone who has Lyme arthritis it’s hard to show them, it’s hard to visualize them, it’s hard to culture them but takes something like PCR to amplify gene segments enough to be able to show that they are there. So I don’t think that antigen is consuming all the antibody that is being produced. Now I find the protein [Indiscernible] [0:21:45] Alan Garder quite striking he is describing that patients with Lyme arthritis have as many as responses to eighty nine different spirochete proteins antibody responses to as many as eighty nine spirochete proteins with asking for somebody to have reactivity with [Indiscernible] [0:22:04] in order to meet the complete CDC criteria. Most patients with Lyme disease have that.
Dr. Charini: one other question you mentioned in the recent paper I can’t remember the exact details but as far as the utility of the IgM western block we had in the first month of disease. And I remember reading I think it was in a paper about the C6 assay about some patients lived with confirmed Lyme disease by some other criteria but the IgM only became positive after six weeks and I wonder if you could comment on that.
Dr Steere: Yeah. I don’t think that the four weeks is absolute there are people in whom it takes six weeks or even eight weeks before one will see reactivity with five or more IgG reactivity with five or more spirochete proteins. But the number continues to expand in someone who has active infection. So I wouldn’t place it or cut off directly at four weeks and say it’s going to be everyone exactly at four weeks most people by four weeks but there are people who may take longer. By the way I think there is a very typical antibody response that goes along with early infection and that’s why the 23,39, and 41 spirochete proteins were selected. Those were the most common early responses and then with [Indiscernible] [0:23:46] as well. And ne may foresee an IgM response to that and maybe all that one sees in a patient [Indiscernible] [0:23:52] or the time there is neurologic involvement there is usually IgG reactivity with those same spirochete proteins as well. It is a very typical response that goes along with Lyme meningitis but in four weeks it may not yet be five IgG bands soon it would become.
Dr. Charini: one more quick question [Indiscernible] [0:24:18] this is important. Patients who receive antibiotic treatment early in the course of infection and then go on to develop later manifestations of Lyme disease how reliable is the two tier test in those cases?
Dr. Steere: I think people who have active infection and who develop a swollen joint they are seropositive and have reactivity with many spirochete proteins. I also think it’s rare really rare to see that clinical picture after the treatment regimens for early disease and the same thing is true with having objective neurologic involvement. Certainly we see fascia palsy is an example of meningitis developed early. Although, I must say rarely, rarely with doxycycline or with amoxicillin is primarily a complication that was observed with azithromycin. And the problem has really been the person who has fatigue, joint pain, muscle pain, where there is really disagreement about whether there is evidence of active infection in such people. I personally think it’s lacking [Indiscernible] [0:25:55] that person sure they may not see or convert at all in fact what one sees if they did sort of convert [Indiscernible] [0:25:59] that the antibody response declines and goes away, which is what we see happens if patients don’t develop subjective symptoms after Lyme disease.
Dr. Baker: Are there other questions for Dr. Steere?
Dr. Parsonnet: If there is time I have a question.
Dr. Baker: Go ahead Dr Parsonnet.
Dr. Parsonnet: what you think the statuses of some of the [Indiscernible] [0:26:26] diagnostic tests the C6 [Indiscernible] [0:26:28] you think guidelines should be updated to reflect any of those in diagnosis specially of late neurologic disease?
Dr. Steere: I think the C6 assay is a good assay and I agree with what the FBA did at saying that it could be used as a first test. I don’t personally support the idea if it’s being a standalone test for the reason that it is not [Indiscernible] [0:26:57] specific those two tier test and also in our experience not everyone with late disease has a response [Indiscernible] [0:27:06] alone.
And generally there is so much more of a response in there and it’s helpful to be able to see it. I find it helpful to be able to see it as opposed to just a single standalone test that is one in a body [Indiscernible] [0:27:21] to one protein. But I do think it’s a good test and I think it’s a good first test.
Dr. Parsonnet: some of the other assays that we have heard about today [Indiscernible] [0:27:33].
Dr. Steere: I don’t think I am not sure I know exactly there is an antibody capture assay. That’s not what you are talking about you’re talking about antigen assay such as a PCR assay in urine for example.
Dr. Parsonnet: about spinal fluid as well.
Dr. Steere: No I don’t think that any of those tests have been shown to be reliable.
Dr. Baker: Thank you very much doctor.