[ Applause ] >> All right, well thankyou very much for having me.
It really is a pleasureand an honor.
I work with all of these people, and I get to see them allthe time, and I'm still — every time I see everyone speaktogether I'm really amazed at the continuity of the program and how much stuff isreally going on here.
So very pleased tobe a part of it.
Also, first time ever I've beenaccused of being best dressed or possibly [laughter]remotely in the running for best dressed, anything of the sort.
So I'm going to betalking about weight loss and calorie restrictiontoday in pain management.
And just a little bit of aheads up, we're really — this is a somewhat newfield in some ways.
I probably will raisemore questions than I will give youanswers, but I still think that this is a veryexciting new area.
I have no conflicts of interestor commercial relationships that I need to disclose to you.
So in exploring a relationshipbetween obesity and pain, it's important to know that there is a prettywell-established relationship in the sense that we knowthat people who are overweight or obese are more likelyto experience pain.
So generally speaking ourreally high-quality surveys of the public will findthat maybe about one out of five people report havingchronic pain or persistent pain.
The chances of you fallinginto that group go up about 30% if you are overweight, meaning that you have a BMIbetween 25 and 30.
If you have a BMI of 30 orabove, then the chances go up to about 60%, and an oddsratio of about 1.
6, which is really I think asignificant increased risk.
And when obesity is alreadypresent in an individual who has a pain condition, we see something veryinteresting happen, which is that most of thesymptoms tend to get worse, even if we can trace the originof the pain condition to a time when the person was notoverweight or obese.
So in a nice study of 215fibromyalgia patients, it was shown that thosepatients who were overweight or obese had muchhigher levels of fatigue, much greater sleep disruption, but they were alsomore sensitive to pain on manual palpationof tender points, which suggests somethinga little bit different than just pain, say, inthe knees, or the ankles, or the hips, or the places thatwe classically expect to see it, but actually more of thiscentral sensitization phenomenon may be part of obesity.
In the classic view ofhow obesity promotes pain, we really borrow prettyheavily, actually, from sort of physicalengineering to describe why wethink it's happening.
And you'll actually hear thisterm “mechanical load” a lot to describe why patientswho are overweight or obese are reportinga lot more pain in areas like the lower back, the hips, the knees, and the ankles.
These are, of course, the load-bearing joints of the human body, and they'rethe ones that are most taxed by extra weight, extra adipose tissue.
But there's something I thinkthat is missing from this, which is that ifyou actually think about your clinical experience– and I am not a clinician.
I say that very openly.
I help no one.
I rely on all of you [laughter]to do that kind of work.
But if you think about yourpatients, what I always hear is that this really doesn'tdescribe the phenomenon of overweight and obesepeople and the kinds of pain that they experience.
And actually, high-qualitydata has started to come out to show us that thatis definitely not true, that it's confined to thoseweight-bearing joints.
In fact, people who areoverweight and obese are at much greater risk of havingmigraine; tension-type headache.
They're more likely tohave abdominal pain with and without symptomsthat are similar to irritable bowel syndrome.
They're more likely to havetemporomandibular joint disorder, which primarilypresents as pain in the jaw, in the musculature of the face.
I would contend that those kinds of pains are not very easilyexplained by something like mechanical load, and that we need to kind of expand our thinking about whythese connections might exist.
So let me give you onepossible alternative view of why this happens.
Adipose tissue isnot neutral as far as our immune systemsare concerned.
Adipose tissue tendsto pull immune cells, cause them to migrate into thetissue, especially monocytes, which are the greatchameleons of the immune system.
Monocytes are there when a person is experiencing avery severe inflammatory event, and they're thereduring wound healing.
They can take on both roles inthe immune system of the body.
So what happens is that inadipose-derived inflammation, we tend to have those monocytesmigrate into the fat tissue, and then they startto take on more of a proinflammatory phenotype.
That is the monocytesthat we can actually pull out of adipose tissue are goingto look a lot like the monocytes that we would findin infected wounds.
They're very proinflammatory;they're spitting out cytokines.
And what can happen even is thatthose monocytes and other cells that are in the adiposetissue begin to secrete proinflammatorycytokines at a sufficient concentrationto actually start to change the rest of theimmune system, and even maybe to start to signal the brain.
These are just some basicpoints about the qualities of the immune cellsin adipose tissue.
But how is it that these immunefactors would sensitize the central nervous system, if this is true? So this is the question Iprobably get asked the most because I usually talkabout inflammation and the immune system andhow it relates to the brain.
People often say this to me, “How is it that theimmune system and the cytokines areaffecting the brain?” Most of us learned, right, thatthere's something called the “blood-brain barrier”that serves as a barrier and protectant againstperipheral inflammation.
And that is absolutely true, the blood-brain barrier is there to keep out those nastycytokines and signals of sickness from theperiphery of the body.
But our brain and ourimmune system engage in constant bidirectionalcommunication.
We would not surviveor function very well if our brain didn'tknow what was happening in the peripheral immune system.
They're constantly talking.
So one of the thingsthat can happen is that if cytokines reach asufficient concentration in blood, they canactually diffuse across the blood-brainbarrier directly into the brain and spinal cord.
And that means that you allof the sudden have [inaudible] and tumor necrosis factor[inaudible] beta talking to the immune cellsin your brain.
Now, this normally only happens when somebody isreally quite sick.
This is something that's mostlyassociated with septic shock or something like that.
But there's another routethat we know a lot less about, but we've learned more aboutin maybe the last ten years.
The immune cellsthemselves, not the cytokines, those monocytes themselves, can actually cross over through our vasculature inthe brain and enter our brain and set up residence there.
If you label themin animal models and then stress the animal, you can subsequently see them in various parts of thebrain that are associated with anxiety, anddepression, and pain.
So that means that those immunecells that are not supposed to be getting up hereare in fact doing that.
They're getting up thereand they're staying there, and they're changing thecharacteristics of the brain in a way that could promotea lot of these symptoms that we think are really nasty.
And in case there's any doubtabout this, this is something that I'm really happyabout and proud of — actually my friend Neil Basu[assumed spelling] played a major role in this analysis.
But when Neil came here, welooked at some RA patients, we did an analysis of the levelsof inflammation in the periphery in a group of RA patients, andwe looked at how that seemed to be associated with the brain.
And what we see are profoundchanges in the function and structure of the brain in anindividual who has high levels of peripheral inflammation.
And this is obviously just aproof of the basic concept, because this is not in obesity.
But I think it's very importantto say that evidence is mounting that as those levels of peripheral informationare increasing, so the brain is respondingin a commensurate way.
So in order to addressthis question of obesity inflammation, weightloss calorie restriction, again, like I said before, I have toreally, really take my hat off to the clinicians who areinvolved in these projects.
And Amy Rothberg is somebodywho's in family medicine here.
She has been doinga fantastic job of running a weightmanagement program here at the University of Michigan.
At this point, several thousandpatients have actually passed through the program.
And what it is primarilydesigned to do is give peoplean opportunity to lose weight very rapidly, and then actually get additionalsupport for another 21 months to take a person out to twoyears where they have a period of intense weight loss, andthen they get that maintenance and that additionalsupport with a nutritionist and seeing the clinicianregularly for a long period after that to actually helpthem maintain the weight loss, which we know iscritical to success here.
The weight loss itselfis induced through a very low-energy diet.
That's another way of justsaying you don't eat very much.
You have a very lowlevel of calorie intake, typically something like six toeight hundred calories a day.
That is enough to keep yourinternal organs healthy and not much else.
That is enough tokeep you going, and after that it isessentially a loss.
Of course, any energyyou expend above six to eight hundredcalories per day, which most of us do just being, is going to end upbeing weight loss.
And that occurs forabout 12 weeks.
After that, they enter themaintenance phase of the program where they'll get to regularlymeet with a nutritionist and try to maintain the lossthat they have achieved.
In studies of the largernumbers of people who have gone through the program, theresults are really, really nice.
What you see are all sorts ofdifferent reductions in BMI, blood pressure, cardiovascularhealth risk factors, fasting, glucose, risk of diabetes, et cetera, et cetera.
Not only that, but it appearsto be very cost-effective.
I say this just in caseanybody is, you know, sort of wondering howwould this actually fits into a clinical setting, and could you ever argue that this is actuallycost-effective for your patients.
I think the answer is yes; and there's some nicedata to support that.
But what we were reallyinterested in is, “Well, so what happens whenthese patients do go through this periodof rapid weight loss? Do they experience someimprovement in pain?” So this is very muchan observational study.
And our only entrycriteria was essentially that you were taking part ofthe weight management program, and that you indicated that youhad pain in one or more areas of the body using the 19 sites on the fibromyalgiasurvey criteria, which you've all hearda lot about today.
The [inaudible] survey criteriagives us a chance to look at how widespreadpain is in the body, and it also givesus a sense of some of those other comorbid symptomsthat are really troublesome for patients like fatigue, disruption of sleep, cognitive difficulties, and someof those other symptoms as well.
So what we did is we took 123patients who had it with pain in at least one site and putthem through the program, and we just gave them thefibromyalgia survey criteria before and after.
It was really actuallythat simple.
Additionally, 31 ofthose patients agreed to have a blood draw beforeand after, so we were able to do an analysis ofproinflammatory cytokines just in serum, as well as someanti-inflammatory cytokines like interleukin 10.
So this actually showsyou the raw data of BMI as people go throughthe program.
And this is truncated to reallyfocus on the intervention phase, those first 12 weeks wherepeople are losing weight.
And what you can see, I think, is just this really nicedownward slope in BMI indicating that people are in fact losinga good amount of weight.
And if you kind of lookat the individual lines, what you can see is that ifpeople stay in the program, the vast majority of themlose quite a bit of weight.
And then during themaintenance phase, they tend to regain a littlebit, but largely maintain.
So what happened? If we look at the body map — and this is a somewhatcomplicated figure, but hopefully you can seesome of the dots showing up a little bit clearly here.
What we're doing is we'relooking at patients who lost at least ten percentof their body weight, versus those who did not.
And what the circles indicateis how many of them at baseline, the bigger the circle, saidthey had pain in that body part when they started the study.
And then the color tells youwhether or not it got better or got worse after they wentthrough the weight loss.
What we see is that allthroughout the lower limbs, and in the lower back, andespecially in the abdomen, the chest, and also somewhateven in the jaw and face, people reported painimprovement, such that they were about 20% less likely to saythat they had pain in any of those regions afterthey lost ten percent of their body weight.
There was no such effect inthose people who did not lose at least ten percentof their body weight.
Additionally — hopefullythis is going to show up a little better.
That's sort of hard to see.
Those are raw changes intheir depression scores.
On the left where it says, “Worsen, ” those are the patients who actually showed alittle bit of worsening of their depressivesymptoms, and then you can see on the other side thosewho actually improved on their depressive symptoms.
It's a really strongpreponderance of patients who are involved in the program who showed a reallysubstantial increase — or I should say “benefit”from a depression standpoint after taking partin the intervention.
Additionally, thevast, vast majority of patients either showedan improvement in fatigue, or showed no change, withvery few showing worsening of fatigue, suggesting, again, that you're also seeing somebenefit on those other symptoms.
And this was alltrue when we looked at the symptom severity score, which I'm sure Dan talked about this morning andothers, showing the sort of constellation ofsymptoms getting better.
Very interestingly, we saw no difference in proinflammatory cytokines after the interventionwas complete.
What had changed is that theanti-inflammatory cytokine, interleukin 10, had gone updramatically in the patients after they lost weight.
So what you see thereare sort of paired — each of the barsrepresents an individual.
The blue shows you what theirIL-10 levels were at baseline.
The orange shows youafter the intervention.
You can see themjust sort of spiking up patient after patient.
Interleukin 10 is goingup in these patients, which we would expect wouldbroadly control inflammation, and might have apositive impact on some of those central pathwaysthat I was talking about.
That was true when we normalizedinterleukin 10 to levels of C reactive proteinjust to see.
So it really looks like there'sa positive inflammatory tone change in those patientsafter they lose weight.
In some secondary analyses, wesaw some interesting things.
Men tended to actually show agreater improvement in fatigue than women did, but women stillgot a nice healthy benefit in terms of improvementin depression and pain.
It really looked as ifpatients who did not reach that ten percent thresholddid not get as much benefit from the interventionover the 12-week period.
And interestingly, thatimprovement was not dependent on how much more they saidthat they were exercising; which we thought was one ofthe sort of obvious confounds or potential explanationsfor why this was happening; sleep being another one, but we did not have a goodobjective measure of sleep in this particular study, something that we'refollowing up on.
So now let me give you alittle bit more data that — this has not yet been publishedso this is a bit of sneak peek.
What we're looking at herenow is the follow-up study where we said, “Okay, we see that there's clearlysome benefit for pain.
When does it happen? How long does it take beforepeople start experiencing an improvement in pain? And when do we see theseinflammatory changes?” And so what we've done is we'veinvited people to take part in the study, but now thosewho have much more severe pain to begin with; and whatwe do is we put them on that very low-energydiet for three weeks, and then we put them ona normal diet for a week, and then we put them backon the very low-energy diet.
What we're doing is sort ofan on-again/off-again ABC — or ABAB design totry to see whether or not inflammationis going down and up, and the symptoms aregoing down and up as we're varyingtheir calorie intake.
On the left there, those areFM survey criteria scores from a small group of peoplethat we're sort of thinking of as a pilot study here.
And we've divided them up bythose who had really high levels of FMness, medium levels ofFMness, and low levels of FMness when they started thestudy, to see what happens over the first 12 weeks, with aspecial emphasis on week three.
And what you see here that Ithink is really remarkable is that the patients areshowing a dramatic improvement really quickly.
This is prior tomajor weight loss.
Most of these people havelost less than five percent of their body weight, and a lot of that body weightloss is water.
And what we're seeing here isabout a halving of FM symptoms.
I remember when I firstshowed this to Dan, he said, “We don't have any drugsthat work that well.
” That was really remarkableto me.
And it's true, wedon't have drugs that in three weeks can cutfibromyalgia symptoms in half.
What's interesting, too, is that it appears that this improvement justsort of stops at three weeks, and then is maintainedthroughout the rest of the period.
As long as they keep engagingin the diet, and they seem to continue to experiencethat benefit.
Those that actually meetfibromyalgia criteria — those are those on the right, you can see that they're showingabsolutely dramatic improvement in even just a small number ofpatients who have FM symptoms.
So this tells us somethingthat's really interesting.
It looks like weight lossper se is not necessarily the whole story.
In fact, it may be that thecalorie restriction itself is capable of inducingthese rapid changes in pain processing in the body.
And it could be throughinflammatory pathways, it could be throughcentral nervous system, neurotransmitterpathways, we're not sure.
But this is the nextstep so that we can begin to understand thisphenomenon better.
And finally, a little bit morecomplicated model suggests that we probably have increasedinflammation as a result of adiposity that isaffecting both the brain and the peripheral joints.
It's not either/or; we haveinflammation affecting both sides of the pathway.
In conclusion, it lookslike these common symptoms, the ones that youprobably see in clinic, are dramaticallyimproved by weight loss and calorie restriction.
It's possible that ananti-inflammatory activity, rather than proinflammatoryactivity, is where most of the action is occurring, why we're seeing thisangalsic benefit.
And finally, it looks likethese changes occur very early, such that a very low-energydiet by itself may be one that doesn't even have tonecessarily lead to weight loss, could be beneficialfor some patients.
And thanks again to Amyand all of her staff who actually run the study.
Happy totake any questions.
[ Applause ].