Lee Reichman: This Web-based seminar will specifically cover screening diagnosis and
treatment and management in patients who are taking anti-tumor necrosis
factor agents or TNF-alpha inhibitors as they are more commonly known.
Slide 2 The seminar will consist of an overview of the interaction between TNF-alpha
inhibitors and TB infection and disease and a review of the latest
recommendations from physicians prescribing these agents as well as
physicians diagnosing and treating TB in patients already taking TNF-alpha
Slide 3 Our faculty members today are Ms. Lynelle Phillips from the Heartland
National Tuberculosis Center and the University of Missouri and Dr. Gerry
Jacquette from the New Jersey Medical School Global Tuberculosis Institute.
Slide 4 After this introduction, Ms. Phillips will provide a review of TNF-alpha
inhibitor treatment in Tuberculosis.
This will be followed by Dr. (Jacquette) who will present the case who will
then have time for questions and discussion.
Slide 5 And now we’re going to begin with Ms. Lynelle Phillips. Lynelle is a nurse
consultant with the Heartland National Tuberculosis Center, is on the faculty
at the Sinclair School of Nursing at the University of Missouri.
She spent several years at CDC, first in their vaccine program and then as a
TB public health advisor and has published extensively in the field of TB
Lynelle Phillips: Thank you Dr. Reichman for that introduction. I will be talking about TNF-
alpha inhibitor treatment as part of this webinar…
Slide 6 …and specifically on the objectives.
We’re going to talk about what is TNF-alpha anyway and why do we care
about it in our world of TB infection and disease prevention and control and
then we’re going to review the screening and treatment recommendations so
that we can best assure that patients taking these medications are as protected
as they can be against tuberculosis.
Slide 7 Okay, so first let’s learn about TNF-alpha, what is it anyway, and why are we
concerned about it?
Slide 8 Here is the diagram of taking us back to our biochemistry days. At the cellular
level in the cell-mediated immune response system the TNF-alpha does play a
critical role in the whole cascade of events that needs to happen as part of
your immune response.
It’s early in the process and as you can see here we have an invading micro
organism, in this case the TB bacilli and the macrophage phagocytes, the
invading bacteria and then that release TNF-alpha into the process.
Slide 9 As the macrophage consumes the TB bacilli it basically takes one for the team
and it’s for - the easiest way to describe it is it’s killed at this point and thus
suspending whatever activity the invading microorganism was about to
So, certainly this is an important process and what this all adds up to is
basically granuloma formation, which in the world of TB control that’s a very
good thing. This is what latent TB infection is and this is what keeps our
patients from activating their TB. So we like for this to happen.
Slide 10 However, in patients with diseases such as rheumatoid arthritis certainly the
TNF-alpha process that I just described has basically gone haywire, and these
patients have produced too much TNF-alpha. It’s found in very high
concentrations in a rheumatoid joint, for instance, and a drug that is able to
inhibit this process would be a very good thing for these folks because they
certainly have too much of it going on and they’re suffering greatly from that.
In vitro has shown that it induces cytokines in the synovial cytokine network
and experimental models demonstrate that arthritis is suppressed by TNF
inhibitors and this is early information for our rheumatoid arthritis patients.
But basically it inhibits the formation of too much granuloma.
Slide 11 So, the mechanism of action here, as we discussed, TNF alpha induces
macrophage, apoptosis or death after bacillary infection. This is needed for the
formation of granuloma and for patients undergoing treatment with TNF-
alpha inhibitors. The granulomas don’t form and in the case of the M. tb, the
latent TB infection, there is a failure of the body’s ability to keep this
infection in check. And certainly the unfortunate thing that has happened is
that we’ve seen some big bad cases of active TB and high mortality rates.
So, what you have is a person that is suffering from rheumatoid arthritis,
Crohn’s disease, or psoriasis from the autoimmune diseases involved with the
malfunctioning of this system and they also have the misfortune to have latent
TB infections. So they’re sort of caught in a paradox at this point or a catch 22
where - for one reason you certainly would want to assure that the TNF-alpha
process is not inhibited and for another reason you do want to inhibit the TNF-
alpha formation. So very difficult patients to sort of treat and know what to
Slide 12 Here we have a picture of what goes on here. The TNF-alpha inhibitors are
these substances right here. They bind with TNF-alpha and in the event that
your system is making too much of this stuff then certainly this would be a
great medication for you to be able to take.
Slide 13 So, the TNF-alpha inhibitors, what are they? We have Enbrel here that was
the first one licensed in 1988, Remicade, licensed shortly after that in 1999
and Humira was licensed in 2002.
They all inhibit the TNF-alpha mechanism. They’re licensed for treatment for
rheumatoid arthritis, juvenile rheumatoid arthritis and other autoimmune
diseases involving too much granuloma formation.
Remicade has been a wonderful treatment for Crohn’s disease. So the patients
that are suffering from these types of conditions very much are appreciating
that these drugs are on the market.
Slide 14 Here we have an overview of some of the conditions that these drugs can
treat, in summary…
Slide 15 …and here’s a slide on effectiveness. And if you’ve ever had a friend or a
family member that has rheumatoid arthritis or Crohn’s disease you know that
they do suffer. The wonderful thing that this slide shows is that in
combination with methotrexate we’re seeing much improved quality of life
So, these are all statistically significant improvements in quality of life and
certainly if you’ve known any of the patients that have taken these drugs you
know that they feel much better having taken them. Patients with these
conditions will very much want to be candidates for TNF-alpha inhibitor
Slide 16 Some of the off label uses; anything involving too much granuloma formation
so here are some examples of those conditions.
Slide 17 Just briefly, any autoimmune diseases seem to be responding to this treatment.
Slide 18 Some of our transplant patients are benefiting from this so certainly several
off-label uses for these drugs as well.
Slide 19 Okay, so what happened? The world started prescribing TNF-alpha inhibitors
and did not perceive up front that this may muck up the system maintaining
latent TB infection and the active TB disease cases started rolling in.
Slide 20 The FDA has a post licensing adverse event monitoring system. Some of you
are familiar with it as MedWatch and then in the not to distant future they had
70 reports of active TB come in which flagged a signal in the system that
maybe we have something going on here.
Forty-seven were in rheumatoid arthritis patients, 18 in Crohn’s patients and 5
in others as we talked about some of these off label uses that are possible for
Slide 21 So, what was interesting was not only the number of TB patients that were
reported but sort of their epidemiological picture here. Fifty-six percent of
them were extrapulmonary and this is unusual. For those of you that deal with
TB surveillance data at the end of the year when you’re reporting your
caseload typically 15, 20% of your patients will be extrapulmonary and here
we had over half of them where extrapulmonary, so unusual.
Twenty-four percent where disseminated cases of TB, that means that TB
infection was flourishing in all different parts of the body and very dangerous
situation, very potentially deadly situation.
And look at the mortality rate down here; 17% of these patients died. That’s
terrible. That’s a much higher mortality rate then we typically see with TB
Early on there was some recognition too that the Enbrel patients seemed to
have less problems with active TB than the Remicade patients.
So, early on we suspected that maybe there’s a different mechanism for our
Enbrel patients that led to them only having nine reported cases out of these
So, anyway, important surveillance data. Always important to report adverse
events to the FDA MedWatch system so we can find these things post
Slide 22 Another interesting finding here with these 70 cases was their time of onset of
disease. And look at this; we never see this in TB. We had people coming now
with rip roaring cases of TB two to four weeks into treatment, the median was
Most of the patient’s were already sick within 18 weeks. This is really unusual
for TB as we know it. We’re usually looking at active disease happening 3 to
12 to 24 months after exposure and here this was very unusual. So all kinds
of signals here that something needed to be addressed for TB control with
Slide 23 In the United States we weren’t the only ones picking up on this. This is post
licensure surveillance state out of Portugal, Sweden and Spain and look at
these numbers of these case rates in 100,000 person years much higher than
we see with TB patients.
And then again, the Enbrel a little bit lower than the others; still a problem but
boy these are mighty high case rates for active TB, much more than we
Slide 24 So, in summary we were seeing 4 to 11 fold increase in the risk of TB in these
patients, onset typically within 18 weeks which is really unusual and really
high mortality rates with lots of extra pulmonary and disseminated disease;
very difficult to diagnosis and treat. Certainly not a good situation.
Slide 25 And, again, the Enbrel - little bit less active TB with these folks but still
happening. The thought was that perhaps Enbrel, those complexes that I
showed you earlier where the drug binds with TNF-alpha, (Canadian) Enbrel
those complexes are a little bit less stable.
Maybe the route of administration is a little bit different. We’re looking at IB
bolus dosing like once a month with Remicade patients. With Enbrel patients
there’s sub q twice weekly so maybe that was part of it but little bit less active
TB activity with Enbrel than Remicade. So, that was an interesting finding.
Slide 26 So, as I mentioned the Europeans were also seeing this phenomenon and the
screening recommendations started rolling out. And why is this important?
Well, if you are a rheumatologist, a gastroenterologist, or a dermatologist and
you’re going to be interested in screening your patients for TB it depends on
which journal you read and who publishes the journal. But you may be
looking at recommendations from Europe as well as the United States and,
you know, Joe Blow, rheumatologist out there might find this very confusing.
So, I thought I’d share with you that these recommendations have come from
all over and they may differ slightly between each other and with ours.
Slide 27 Our recommendations, of course, are from the MMWR. These came out in
2004. The first one, screen patients for risk factors for TB and also TST for
latent TB infection.
So, not only are we screening for risk factors we are placing TSTs on all
patients before they start treatment. Not entirely clear how the
recommendation is written but - because we are used to screening patients for
risk factors for TB and then only testing those with risk factors. But it seems
these recommendations talk about screening patients for risk factors and
placing TSTs on all patients.
Of course we default to the diagnosis and treatment of latent TB infection, TB
disease with current guidelines; 5 millimeter cutoff. Because some of these
patients will be immunosuppressed, will already be on methotrexate or anti-
steroidals. So you’ll be cautioned in interpreting the TST. And this is a little
bit above and beyond what we typically see even if you have a negative TST,
you may still want to treat that patient for LTBI if they have risk factors or
some exposure history or some question that they would be anergic.
Anyway, very conservative interpretation of the TST. A lot of focus on
screening patients for risk factors and taking their whole picture into account
in diagnosing latent TB infection. And this is conservative, but because these
patients get such big bad cases of active TB we need to be conservative. It
kind of shifts the risk benefit decision making there. So, those are our
recommendations in the United States.
Slide 28 In an attempt to sort of summarize all the recommendations out here in 2007
they came up with a consensus statement. And, again, evaluate all patients for
LTBI before starting treatment. History of risk factor screening, physical
exam, and screening tests.
So, out there in Europe in particular they’re really talking about chest x-ray
screening as well. And we don’t typically do that in the United States, but they
have seen some success with chest x-ray screening and looking for little
granulotamous lesions on chest x-rays so, again, a very conservative approach
to latent TB infection screening.
Slide 29 Of course the best option here in developing screening processes is to attempt
to have them evidence based.
So with the lack of evidence and, again, you’re going to see this kind of
variety of things going on out there. And this compares the British and the
Americans and the Europeans and you can see the British have a kind of
complicated whole thing here with taking into account BCG which they have
to do much more often there than we do here. We just had a straight 5
millimeter cutoff. The Europeans refer local recommendations and then you
can start to see over here differences in treatment recommendations which
we’ll talk about later on.
And then chest x-ray screening certainly in some circumstances or all
circumstances depending on the recommendations.
Slide 30 So there is some variation out there. Cutoff 5 millimeter. If they’re not
immunosuppressive I think you defer to the regular recommendations. Two-
step testing, not clearly addressed. However, if you have someone that this is
their baseline test then you need to make sure it’s accurate. Something to think
Chest x-ray screening for all patients even with negative TST and then what
about our blood assay tests that are new on the scene. What’s going on with
So, still some lingering questions out there and probably a real challenge for
our colleagues who are not familiar with TB screening to interpret all of this,
as you can imagine.
Slide 31 So, again, I talked earlier about evidence based. Coming up with evidence
based screening recommendations and I don’t know how you all feel about
single payer healthcare systems that we’ve been debating in our country but
certainly they do have the advantages. Everybody is in the same electronic
medical record system and that made for wonderful surveillance data.
So this came out of Spain, out of their electronic medical records where they
can monitor kind of on an algorithm type format, what is working and what
isn’t. So this is the whole potential path a patient could take in TB screening.
And, where did they see the most cases? Well, they saw them interestingly
enough out of our patients that did not undergo two-step TB testing. So they
did not get the second test, they were erroneously diagnosed as not having
LTBI and started on treatment and eight cases came out of that group.
Where did the second most cases come out of? And these were in patients that
did not receive a baseline chest x-ray.
So, two screening recommendations that are not particularly emphasized in
our recommendations and this is where the most cases came out of.
So I thought that was interesting, sort of evidence based information that we
can perhaps take into account as we screen our TB patients or our TNF-alpha
Slide 32 Now what about blood assay tests? Well, since 2004 when CDC issued their
recommendation we learned a lot about blood assay tests and thankfully, folks
have seen fit to publish in the literature.
Slide 33 And this one intrigued me the most. This was an experience with a
QuantiFERON Gold screening at a rheumatology clinic in the United
Kingdom and they decided to whole hog abandon TST screening in favor of
QuantiFERON Gold, kind of a daring thing to do. They’re in a rheumatology
clinic, they had 101 patients. They screened them all with QuantiFERON
They were very wary of having to deal with positive TSTs where they weren’t
sure if they were BCG related or not. And they followed these patients
prospectively for 30 months. And as you recall if you’re going to see TB show
up in these patients you’re looking at 12 to 18 weeks typically. So, they
followed them up to 30 months, average of 18 months. So certainly if they
were having breakthrough TB they would have seen it.
They did not see any breakthrough TB; they had no new cases of active TB in
their negative QuantiFERON group. So good news, good positive information
that in evidence that QuantiFERON Gold may be a reasonable test to screen
particularly BCG vaccinated populations.
Slide 34 And here are these data. They were very excited that their positivity rate
dropped to only 10% here, and, again, the negative - no new TB in this group
so that’s good news. Of course with QuantiFERON now you’re dealing with
indeterminates and they had 10% of their folks they screened where
indeterminate on the first test.
Slide 35 But here is their conclusion - the QuantiFERON Gold is a good screening tool
for rheumatoid arthritis patients due to start TNF-alpha inhibitor treatment.
This foremost appears to be unaffected by their relative immune competence
and it’s useful and potentially cost effective particularly in a BCG vaccinated
So they had very positive things to say.
Slide 36 Here’s another study that just came out in 2008 and this was interesting.
Again, these are 70 rheumatic patients due to start TNF-alpha inhibitor
treatment. Sixteen positive on Elispot, 27 were positive up front on the TST
and so we’ve seen this. We’ve all seen this out there. Overall the agreement,
not so good; 73% between Elispot and TST and even here note that four
Elispot positives came out of the 43 TST negatives.
Slide 37 So interesting finding there that we had some false negative TSTs. So, this
villager kind of put it all together for us in a chart. What are the advantages
and disadvantages of using the various screening tests? So basically good
sensitivity, good specificity with both and here we go. Here’s the big one,
influenced by prior BCG vaccination, yes, but with our new blood assay test,
no and no.
So, good summary information there. What about indeterminates? We’ll talk
about that in a second.
Slide 38 One thing we want to note here in reviewing these screening tools is that you
may be - if you use TSTs for screening of BCG vaccinated population you
may be over treating the false positives and even perhaps under treating the
So using TSTs you’re basically at risk with some over treatment and some
under treatment. Clearly this author was coming out in favor of using blood
assay tests for screening for LTBI in this population.
Slide 39 Okay, so what about the indeterminates? Well, here was (press) take on the
whole thing that he’d much rather deal with a few indeterminates from
QuantiFERON Gold testing than all the confusion that results from using
TSTs in a BCG vaccinated population.
And then Villager more recently talked about maybe a 1 to 11% indeterminate
rate with our quantiFERON Gold folks that are screened and maybe more so
for quantiFERON Gold than (T) spot just because their mechanisms are
And Villager talked about that maybe perhaps this is incorrect handling of the
probe. You’ve got to shake it vigorously or perhaps some immunosuppression
here brought on by treatment.
So, still need to be careful interpreting those. Still not gold standard but seems
to be a better option.
Slide 40 Okay, suppose you have a patient diagnosed with latent TB infection and still
very much wants to try one of these drugs in the TNF-alpha inhibitor class.
What are the treatment recommendations? And, again, our physicians out
there, depending on the journal they read, they might be reading treatment
recommendations from Europe, the United Kingdom, or USA so be aware that
they vary out there depending on what you read.
Slide 41 And, here’s the other question that comes up. Do you have them take the
whole nine months of treatment prior to starting treatment with TNF-alpha
inhibitors or can they start it somewhere in the midst of taking nine months of
treatment? And, of course, your patients will be pressuring you to take it as
soon as possible. The recommendations get kind of fuzzy here. We’ve got
language like it would be prudent to wait but you don’t have. They sort of
leave it in the judgment of the physician.
It should be made by a thoracic or ID physician. So this is why we’re all
getting a lot of calls in public health. What do I do with these patients and can
they start treatment with a TNF-alpha inhibitor before they’re done with their
nine months? And how does this work?
Slide 42 What is the MMWR say? Preferably you would want to get all nine months in
there and consider postponing but, again, there’s not a lot of evidence based
information out there to make a decision.
Our great observational work from Spain indicates that probably one month of
INH before starting the TNF-alpha inhibitor treatment.
Slide 43 The National Psoriasis Foundation has weighed in on this one and, again, this is
what the most definitive thing I saw was may start immunosuppressive therapy
one to two months into INH treatment. So, again, a variety of things out there.
You’ll probably get called.
Slide 44 This is the post licensure evaluation from Spain and, look here, we only have one
case arise out of the INH treatment group and what this could be, it could be a
drug resistant case, a drug resistant organism that’s resistant to INH. So, not
seeing a lot of breakthrough cases in that group.
Slide 45 Okay, but what all this brings up is sort of an interesting discussion of what
happens out there in the medical world in following public health
recommendations. And in their post licensure surveillance we talked - the
authors of the article from Spain talked about why did they have this sort of
myriad of things happening when their screening recommendations where
And, in fact again, this is electronic medical record system so when it pops up
that they’re screening someone for TB prior to treatment, the
recommendations appear right on the electronic medical system. So, they
were a bit flummoxed that there was all this variation happening with what the
physicians out there were supposed to be doing.
Here are some of their thoughts on the matter so they didn’t have a
straightforward explanation. They believe that perhaps this had to do a lot of
work and a big ordeal to get them through TB screening. The two-step testing
appeared to be a major barrier. They didn’t feel that was necessary in
complying recommendations and then more importantly this is probably quite
true that things where sort of ambiguous or softly supported with evidence.
So all the more reason it was important that they publish this information. But,
you can see that the recommendations are a little bit ambiguous. So we’ve
typically, hopefully, will get a lot of questions about what needs to be done.
Slide 46 In the United States the FDA took this opportunity to sort of track what
happens when they have new screening recommendations come out on a post
licensing situation on a new drug.
So they kind of broke it down into three phases here and there. In the second
phase they had package insert warnings and some presentations and so forth.
But when they realized how serious a problem this was they had kind of a
third phase of recommendations and they sent every doctor a letter and they
got a New England Journal of Medicine article and box warning. This is when
we started seeing the commercials on television and so forth.
They kind of tracked, in these three phases, how effective were…
Slide 47 …. here’s what they found in the first cohort, of course, very little was known
about TB screening so not much happening there but look down here. This is
the third cohort where they have pretty much pulled out all the stops and done
all the recommendations they could and we still have less than 40% of our
TNF-alpha inhibitor patients being screened for TB prior to treatment.
Kind of a bummer here. We wish we were having more compliance with these
recommendations and, of course, all of us out in public health know this
because we saw all the active TB cases.
Slide 48 Then they compared disciplines. The rheumatologists where first to sort of
recognize the TB risk with their rheumatoid arthritis patients then the GI guys
came along and they’re treating Crohn’s patients and they recognize the risk.
So you can see that just by timing wise the rheumatologists where much more
likely, well slightly more likely, to embrace the recommendations than the GI
And then the dermatologists, they’re not even on the map yet. They were sort
of the last to come along in considering TNF-alpha inhibitors for treatment of
Slide 49 So, here were some conclusions here. The federal risk communication efforts
did seem to double the TST screening rates. They found that the dear doctor
letters, it’s like who reads the mail anymore so that wasn’t too effective and
despite all of this risk communication including - even my kids heard about
TB on the Remicade commercials. They said, “Hey mom, they just mentioned
TB on television.” Despite all that, we’re still seeing not entirely embracing
our TST screening recommendations. However, that doesn’t diminish the fact
that the FDA risk communication was very helpful in getting the word out.
Slide 50 Here we go, in sort of researching all of this they did a questionnaire on over
6000 Remicade treated patients; 60% of them completed a skin test
questionnaire and reported having a TST so even a little bit better than the
previous finding but they still had four active cases.
And unfortunately three had a previously positive finding for TB on TST and
one had even had active TB in the past probably and none of those patients
So, still some education work out there for us public health folks to do.
Slide 51 So, what are our challenges? Clearly, effectively, promoting
recommendations, getting rid of as much ambiguity as possible. Ideally they
should be clear and consistent and then be aware of our colleagues in specialty
areas that haven’t thought about TB probably since medical school. So just
letting them know you’re out there and that they can certainly approach you
for professional advice is a really important thing to do.
I took away from this and perhaps you too, that the blood assay tests are quite
an asset for us for the BCG-vaccinated patients; that really being able to
assure those are available because certainly these folks are suffering from very
debilitating diseases. They’re going to very much want this treatment and to
put them off for one, two, nine months with the positive TST that they might
not even think is credible.
I think the better option here is to have these blood assay tests available
particularly for that population. We in public health we really need to make
sure LTBI treatment is completed. Really high index of suspicion, even if you
do everything right the active TB disease in these patients is just tremendously
horrible and they are in mortal danger.
And continue to report all cases of TB to FDA MedWatch system. Here’s the
Web site. It’s because of this post licensure pass of surveillance that we
learned everything that we did.
So very important to keep reporting any problems you have with active TB in
Slide 52 Okay, well, that’s what I had here for today. Thank you so much for you
Slide 53 Below here I have the very hard work of my M.P.H. graduate student Dr.
Craig Lewis who was very helpful in completing the medical - the literature
Slide 54 So, thanks again for your attention, I think I’ll hand it off at this point.
Lee Reichman: Okay, thank you very much Lynelle for sharing your knowledge and
experience and excellent review.
Lee Reichman: We now have some time for discussion. So, do we have any questions or
comments? The floor is open?
Mary Louise: This is Mary Louise calling from Erie County Department of Health in Erie
Lee Reichman: Hi Mary Louise. Go ahead.
Mary Louise: I have a question. The information from Lynelle’s talk seems to be only
talking about Isoniazid as far as treatment before or starting any other therapy.
Why is Rifampin not mentioned?
Lee Reichman: Okay, Lynelle?
Lynelle Phillips: The treatment recommendations are basically just defer to the typical
treatment recommendations we use for LTBI.
So Isoniazid is mentioned more because it’s the number one ideal choice.
Although I think folks are starting to use Rifampin more and more but
basically the treatment recommendations just defer to what CDC is currently
Mary Louise: Okay, so there’s nothing in particular that would say when we’re making
these recommendations in treatment it has to be INH?
Lynelle Phillips: No, no. Certainly we just recommend following the treatment
recommendations as they’re laid out currently by CDC.
Lee Reichman: I think that’s a good question, this is Reichman, because Rifampin is an
acceptable alternative and then now at least three or four articles in the
literature including one from our institution that recommend Rifampin
preferably and it should work. It can be used for a shorter period of time.
All the articles do not suggest it be used in HIV-infected patients but they
don’t say anything about people on TNF-alpha inhibitors.
Mary Louise: Okay, we....
Lee Reichman: Other questions...Okay, go ahead.
Mary Louise: No, I was going to say we have in fact used four months of Rifampin so that
someone who had rheumatoid arthritis could initiate therapy sooner than it
would have been with the INH.
Lee Reichman: I think that’s an excellent reason for using the shorter regimen. Good point.
Mary Louise: Thank you sir.
(Lee Reichman): Any more questions?
Dr. Hwang): This is Dr. Hwang from LA County. Are there any reports of atypical chest x-
ray presentations on TNF-antagonist recipients in terms of TB manifestation
besides the typical reactivation upper lobe cavitation?
Gerry Jacquette: Yes. Just like with AIDS patients there are a lot of atypical presentations and
the recommendation is made that physicians become familiar with these
atypical presentations. Yes, there can be minimal infiltrate and get a positive
Lynelle Phillips: Yeah, because you’re on these drugs you’ve wiped out the bodies ability for
granuloma formation which is what you see in sick wall cavities and so forth.
If you wipe that out and so the disease can disseminate very easily and brings
us back to the point that having a very high index of suspicion for TB in these
patients is really important because it won’t present the same way.
Lee Reichman: Yeah, remember that the presentation of TB is really based on the immune
system and if the immune system is interfered with such as in HIV you get
atypical or non-typical, I should say, tuberculosis.
Gerry Jacquette: I’d just like to make a comment on that, that despite that our patient did have
granulomas shown on pathology and there are some references that suggest
that, for one thing, Etanercept may be acting by a different mechanism and
secondly that maybe granulomas are non-effective.
In the mouse model certainly if you give BCG to mice you can block their
ability to form granulomas and similarly if they already have granulomas and
you have TNF-alpha inhibitors you can have the granulomas dissolve.
So I guess there’s a whole range of what you could see in terms of granuloma
formation or effectiveness.
Lee Reichman: Thank you Gerry. We have time for a few more questions. Can we please
Jay Purshard: This is Dr. Jay Purshad from Columbia, South Carolina. A patient with a
negative PPD on Etanercept, for example, is there any recommendation for
repeating the PPD during the course of Etanercept treatment?
Lee Reichman: Gerry?
Gerry Jacquette: I’ve not seen that but I’ll just make one little caveat. I think one of the Lancet
articles talks about using the epidemiologic data on patients to decide whether
somebody with a negative skin test maybe should be given preventive therapy
or treatment of presumed latent TB infection even without a positive skin test.
So if you have a family member and a family where there’s been a lot of
transmission or some other situation where you’re concerned that there likely
was a positive test that’s now been blunted by energy that you might consider
But I’ve not heard the need to repeat the skin test. There are people who are
talking about two-step testing prior to initiating therapy. And I think that’s
been batted around a little bit and it’s not - I believe it’s not in the official
CDC recommendations, but it may be something that will be addressed in the
future whether that would be appropriate to do prior to making a decision
about whether the patient needs...
Lee Reichman: Lynelle, do you have any comments on that?
Lynelle Phillips: Well, I mean if this is a question of like sequential testing during treatment if
you have someone that’s going to be on for years, you would want to do
annual TST screening or something. I’m not sure the value of that. I don’t
know if it’s been addressed in any of the recommendations and we really
focus on upfront screening.
If there’s any concern that that patient would undergo any exposure during
treatment then certainly post exposure TST testing and then also if they have
symptoms of active disease a TST might be part of the diagnostic process.
But at this point the important thing is to do that very thorough accurate
baseline TB screening up front. That’s where the emphasis for the
Lee Reichman: I thank you for that. I agree 100% and I think that this is one of the problems
we in tuberculosis control have, is getting the outside - we have enough
trouble with our own, but imagine getting the outside community, as you so
nicely showed, to subscribe to treatment for latent tuberculosis infection in
people who don’t have objective evidence of latent tuberculosis infection
when we have enough trouble getting them to do it in people who do have
evidence of latent tuberculosis infection.
And this is all, as you said so nicely, the training and the education and the
raising of consciousness. But I think a couple of lawsuits would do an awful
lot to help this along.
Any more questions? We have a couple of more minutes left and we’d love to
entertain your question.
Ron Karpick: Lee, can you hear me?
Lee Reichman: Yep.
Ron Karpick: This is Ron Karpick in Fairfax County.
Lee Reichman: Hi Ron.
Ron Karpick: With regard to the treatment of tuberculosis, they added Moxi to the (RIPE)
therapy and that’s usually one drug to “failing regimen” once they might have
had the IRIS syndrome.
Would you address whether you would be happy to continue with just one
drug or would you add several when they were trying to rule out reactivation
Lee Reichman: Okay, this is Gerry’s case so we’ll call her.
Gerry Jacquette: Right. Actually Imipenem was on that regimen as well and we were counting
that as the second drug and she actually remained on Imipenem for a very
long time till the culture of the specimen that had been smear positive came
back. I believe it was a negative culture.
Lee Reichman: Okay, well, that’s all the time we have allotted for the seminar today. If you
have additional questions please feel free to email them to us and we will
forward them onto the speakers for answers.
We’d like to thank our excellent faculty for sharing their knowledge and
experience with all of us.
Slide 57 The New Jersey Medical School of Global Tuberculosis Institute provides
medical consultation to providers in the northeastern region, please feel free to
call us at our information line, (1-800-4TB-DOCS).
This concludes the conference, thank you for your participation.