polymyalgia rheumatic drugs

so my name is rebecca manno, and i'm a rheumatologistat johns hopkins. so first i'd like tothank the organizers for the invitation to be here,and to talk about a very big, but very relevant topic,which is autoimmunity. so, as i mentioned,i'm a rheumatologist. i'm not an immunologist,i'm a clinician. i take care of patients, and theresearch that i do is clinical research, so i don'thave mice with arthritis.

i don't work in a lab,but i work with people. and i work with peoplewith autoimmune diseases. and i see this every single day. and i see howdevastating they can be. but i've also beendoing this for long enough that i seehow far we have come. and it's a great timeto be a rheumatologist. and i always tellmedical students and residents who are thinkingabout, maybe what

are some of the more glamorousfields, cardiology and surgery. and maybe they haven't thoughtabout rheumatology before. but it's a great timeto be a rheumatologist. because we understand more aboutthe immune system and more about the clinical phenotypes thatoccur because of dysregulation of the immune system thanwe ever understood before. and most importantly, we actually have treatments now,whereas even 20, 30, 50 years ago, we didn't haveanything to offer our patients.

we now have fdaapproved treatments. we have treatmentsin the pipeline and a lot of discovery for how to manage some of these veryrare and not so rare diseases. so, once again, thank you for the invitation to speakabout autoimmunity. autoimmunity is important,why is it important? there's a whole lot moreof it now than there was. and if you look at the datain terms of the epidemiologic

studies that are lookingat autoimmune disease and the incidence and the prevalence, almostuniversally there's an increase. there's some discrepancy as tohow much that increase is, if it's 3% or 5%, but universallythere has been an increase. and the reason for that,why is there an increase, there's a lot ofdiscussion in the field. maybe it's becausewe're living longer, that may have somethingto do with it.

just as you were hearingabout the increase incidents of cancers with age. some of that may have to do withall the autoimmune d as well. some of it has to do withthe ability to detect autoimmune diseases. we're understanding more aboutwhat our patients look like so we can identify them clinically. we have better biomarkers, and i'm gonna talk a little bitabout those serum biomarkers

that help us in diagnostics andin following our patients. but even if we take thatbias out of the picture, the fact that we understandthese diseases better, we're recognizing them better, theincidence is still increasing. and without a doubt,almost universally, whatever autoimmune diseasethat you wanna talk about, these disproportionatelyaffect women, almost every single one,with very, very few exceptions. so these are incrediblyimportant for women to be aware

of, to understand somethingabout these toxic diseases. and that we start thinking aboutin the future how to tailor our treatments specificallytowards women as well. so, before we talk aboutautoimmunity we have to talk a little bit about the immunesystem, what is it, what does it do? obviously, we all need one. the goal of your immunesystem is to protect you from the big and bad environment.

and specifically, the microbes in the environmentthat want to do you harm. so there's two big partsof the immune system, so this is very basic immunology. there's the innateimmune system, this is your prehistoricimmune system. it's been around fora really really long time. it comes after thingswith a sledgehammer. and then there's youradaptive immune system.

and this is made of differentpopulations of cells, t-cells and b-cells. and this is a reallysophisticated part of your immune system. and it has come up with a wholerepertoire of cells that can recognize foreign antigens. antigens are anything thattriggers an immune response. and the goal of this partof the immune system, is if it finds a cell that'sinfected with something,

it notices it, andit destroys it. there's also another part ofthis adaptive immune system that can secrete things that arecalled antibodies or proteins. and if it sees a foreignerin the milieu of the host, these immune cells cansecrete these antibodies. the antibodies can attach onto the bacteria or the virus, tell the rest of the immunesystem, get this bug, and they destroy it. i'm making it sound very simple,it's not.

it's very sophisticated,but it works. and most of the timeit works really well. and it protects us from all ofthe microbes that are trying to do us harm in the environment. while your immune system isdeveloping, it becomes smart. and some of thesesophisticated t-cells and b-cells develop somethingthat's called tolerance, which is itrecognizes you as you. and it says, that's notsomething that i want to destroy

or that i wanna mess with. and so when your cells developtolerance, then they're not going to cause problems withyour own body's tissues. so what is autoimmunity? autoimmunity is a misdirectedimmune response. where all of a sudden, or gradually over time theset-cells, b-cells become reactive to yourself, become reactiveto self-host antigens. there's a breakdown inthe sophisticated system

of tolerance. and now, your immune systemtargets certain parts of you. one of the manifestations ofthis may be the generation of autoantibodies. now you've probably all had theexperience or known somebody who said i had the lupus test orthe rheumatoid arthritis test. and it's a blood test, and so does that blood test tell youabout an autoimmune disease? and the blood tests are, most ofthe time, the blood tests that

we're looking at,are these autoantibodies. they're proteins that are madeby the immune system. and what we've learned aboutthem over the years, and as we're discovering more andmore, they help us understand where the dysregulation inthe immune system is occurring. from a clinician's standpoint,they can be an incredible powerful marker of dysregulationin the immune system, and cue me in to potentialproblems down the road. well, what we also knowabout autoantibodies, and

you've probably heardof a few of them, ana, double-stranded dna,anti-ro, anti-la. i can go down a wholelist of them, and we're constantlydiscovering more and more. what we know is that most ofthe autoantibodies do not equal an autoimmune disease. but they're tellingus something, and we're finally startingto listen, and we're starting to understandwhat they're trying to tell us.

they're telling usthere's a marker for the immune systembeing dysregulated. and as we start to follow largegroups of individuals over time, and large groups of individualsover time who have or don't have these antibodies. we can start to subset whatour patients with with autoimmune diseases, whattheir clinical phenotypes are. and we can start to understandwhat the natural history of their autoimmune disease may be.

and most importantly,how a particular therapy may or may not be effective basedon those autoantibodies. so, autoantibodies and thoseblood tests that people order all the time and they thinkabout when they think about rheumatologists, are morethan just a marker. they're really telling usabout the pathophysiology of the disease. so, why does the immunesystem become dysregulated? so, what happens?

well, we know thatthere's multiple hits. so there isn't just onething that has to happen for the immune system to go awry. and what has become very,very clear is there is absolutely a genetic component,but that's not sufficient. something else hasto happen as well. so there's lots and lots of dataabout the genetic component. and one of the best examples ofthis is in rheumatoid arthritis. so there's a genetic marker,

which has been discovered inrheumatoid arthritis, and it's something that'scalled the shared epitope. and so we know that individualswho have this genetic marker added an increased risk comparedto the general population for rheumatoid arthritis. and that was a really bigbreakthrough in the world of rheumatoid arthritis, but we also know is thatit's not sufficient. so everyone with a geneticmarker does not go on to develop

the disease. and we see this repeated timeand time and time again, whatever autoimmune diseasethat you're talking about. there has to be a second hit. so what are somepotential second hits? so, the environment, toxins. there's certainly some toxinsthat we know have been linked very, very strongly toautoimmune disease, silica being one of them.

we know thatmedications can do it. we can see this in drugreactions, where a medication is introduced into a person,into the host environment. the immune system reacts toit in a very pathogenic way, and we see the developmentof an autoimmune disease. those diseases are usually verynice to take care of cuz you get rid of the drug andthings get better. what are otherpotential triggers? uv light, so the sunlight can bea trigger in the right host for

the development ofautoimmune diseases. and then there'sthe world of infections, this world of microbes thatwe're constantly in battle with. and remember that's whatthe job of the immune system, part of the job of the immune system is to protect usfrom those microbes. and there are some infections,specifically chronic infections that we know are constantlystimulating the immune system. infections like hepatitis c,hepatitis b,

hiv, that ebv as well. that are very closely linked with very discreteimmunologic phenotypes. so how does the immunesystem become disregulated? and it's highly variable, but we know that you haveto have those two hits. we also know thatthere's a delay. so when an event happensit may be months, years before the patientpresents clinically.

and we've learned this throughthese auto antibody markers. so there's some very nicework which has been done, it's been a few decades nowwhere serum was collected in individuals who didn't have anyevidence of autoimmune disease. and they looked forautoantibodies and they found thesepeople over time and said who developsautoimmune disease? and we saw these beautifulgraphs that panned out, that showed us there can be abig lag between the development

of the autoantibody andthe clinical phenotype. and that's tellingus that there's this quiescent period and what's soexciting about that is that it's an opportunityin the future to intervene. and if we can understand what'shappening in that quiescent period between the immune systembeing activated, the generation of autoantibodies and thenthe presentation of the clinical phenotype of the patient,we really can make a difference. we can do more than justslow down these diseases,

we can solve them. getting back to the exampleof rheumatoid arthritis, i think it's a nice example onceagain, can have the genetics but you have to have something else. so i told you about the sharedepitope in rheumatoid arthritis which was a very big discovery. we also have auto-antibodiesnow for rheumatoid arthritis. anti-ccp antibody,which is very specific for but what we also have learned ismore about the environment and

the environmental influenceson the immune system. an enlarged epidemiologicstudies when they look to say, whose got the shared appetite,whose got this auto antibody and what really increases yourrisk of developing an auto immune disease if you havetwo those things, smoking. the risk associated with smokingfor developing rheumatoid arthritis, i don't thinkanybody could predict. we all know smoking is bad forlots and lots of reasons but this really spoke to us assaying there's something very

unique about the environmentthat that changed the risk ten-fold for the developmentof rheumatoid arthritis. so how does the immune systembecomes disregulated, and the analogy i like to use wheni'm explaining it to my patients is what i callthe campfire analogy. so if you want tobuild a camp fire, you have to have wood, right? so you make the pile of wood,okay? and you can soak that pile ofwood in gasoline, but you're

still not gonna have a campfire,you need to have a spark. so something has to light it,and you can think of the wooden self as being thegenes that you were born with. you can think of the gasolinethat maybe you pour on the fire as something in the environmentthat sets the stage, but then you have to have the spark. and maybe that's an infection,and maybe that's a drug, we're not sure butnow you've got the campfire. but also remember with many ofour auto immune diseases these

are not a self limited processthese become chronic diseases. so something has tocontinue to feed that fire. cuz otherwise it will burn out,and now you have gottarebuild the camp fire. but something is a continuoussource of antigen to stimulate the immunesystem on and on and on. and so maybe that isa chronic infection, maybe that isa chronic exposure, maybe that is the target tissueof whatever the immune system is

responding to that is the fuelthat continues to feed the fire. so, why are these autoimmunediseases increasing? why are we seeing more of them? and as i mentioned before, i don't think anyoneis really sure. no one can say,this is exactly it. and that's probably becauseit's complicated, and there's multiple influences. but there's a lot ofinteresting thought so

certainly the aging population, many of our auto-immune diseasesdo occur in older individuals. certainly we see autoimmunityin children as well but it's rare compared to adults. and many of our diseases, if welook at the age distribution, it's shifted towards fifty and older, there's somevariability there. there's a really interestingbody of literature that's continuing to grow calledthe hygiene hypothesis,

which you've probably heardabout or read about and it's all over the popular press. which is maybe we'rebeing too sterile, maybe we aren'texposing ourselves and our children to enough ofthe microbes in the environment. because we know whenwe look at mice, and there's a lot of differencesbetween mice and humans. but if we look at mice and we keep them in a sterileenvironment, there's actually

higher risks of certain typesof autoimmune diseases. and interesting, there's a wholegrowing body of literature in terms of parasites that inindividuals where parasites like hookworms are very, very commonthere's a lower incidence of autoimmune diseases. so there's something about thisinteraction between the immune system and microbes thatwe don't understand yet. the microbiome in terms of allof the bugs that is in your gi tract in particular isa very hot area of research and

investigation. and i'll tell you how howinteresting it has become at the american college ofrheumatology annual meeting last year they had an entire twohour session just dedicated to the microbiome andhow to sequence out bacteria in stool and how different itis in different populations. it's different in people whohave crohn's disease compared to people who have lupus comparedto people who don't have there's something to it.

we don't understand enough aboutit but the more that we are able to have sophisticationmeasuring techniques, such as we were just hearingabout, with gene sequencing, now we're able to actually look atthese microscopic particles and try to understand whatthe patterns are. and maybe this is goingto be a key to why we see a difference between women andmen in auto immunity and i think that there's a growingbody of evidence that suggests that may be the case.

cuz certainly, hormones havesomething to do with it. but if that was all that it tookin terms of that differential between men and women, then wewould never see any autoimmune disease in men and that's notthe case, it's just less common. but maybe it's the interactionbetween our microbiome and the hormones andother environmental triggers. but you're starting to seethe layers of complexity when you're dealingwith the immune system. so autoimmunity and cancer, dr.nelson touched on this, and it's

something as a rheumatologisti think about all of the time. we've known about therelationship between the immune system and cancer fordecades and decades. there's certain autoimmunediseases where this became very, very obvious. so dermatomyositis isan autoimmune condition that can affect the skin andit can effect the muscles and it's driven by the immunesystem causing weakness in the muscles andit can cause a skin rash.

and what became very clear,this is well described even back when the diseasewas first described, was that people withthis autoimmune condition had a markedly increasedrisk of cancer. as we started to followindividuals over time, we saw that the risk of cancerincreased around that five year time frame whenindividuals are diagnosed. and this gets back to thisidea that your immune system, yes it's designed to protect youfrom viruses and bacteria and

the external world. but it's also trying toprotect you from cancers. we all make cancercells every day, but your immune systemgets rid of it, notices those genetic defectsand gets rid of those cells. but a cancer can also stimulatethe immune system and sometimes maybe the cancer grows,stimulates the immune system, the immune system's successful,it eradicates the cancer but the autoimmunitycontinues to propagate.

and so this observationin dermatomyositis of the proximity betweenthe development of cancer and an autoimmune disease thenstarted investigators looking at other autoimmune diseases andsaid well why would that happen? and in scleroderma was somereally amazing breakthrough research. it actually, from our division,that found that the antigen in certain tumors,there was anautoantibody that was targeted specifically againstthat antigen.

and sothe link between scleroderma and particular autoantibodies,remember those serum tests i was telling you about beforebeing a marker for the development of a malignancy,has now been confirmed. and so this link betweenthe immune system and cancers is a close one. and i think you're gonnacontinue to hear more and more about it cuz once again itgives us another opportunity to solve these diseases.

the immunotherapyto treat cancer, as dr nelson was just talkingabout, is a very interesting and very, very, exciting world. and from a rheumatologyperspective, it's interesting ina couple of ways. and one way, it gives us aninsight into the immune system because with some of thesemedications that are being used to successfully treat cancers byharnessing the immune system and targeting that cancer,some of the casualties of that

can be the development ofautoimmune phenomenon. and as we start to understandthat relationship closer, it may give us some insight then intoour other autoimmune diseases. so what doesautoimmunity look like? so what does it look like? and there's a whole hostof autoimmune diseases. you can go through every singleorgan system in the body and i can come up witha autoimmune disease. in the skin, we have psoriasis.

in the liver we haveautoimmune hepatitis, primary biliary cirrhosis. in the gastrointestinal systemwe have crohn's disease and ulcerative colitis. the musculoskeletal system,we have rheumatoid arthritis, scleroderma myositis. and what they all share,although they all look very different, is this disregulationin the immune system. but although we've grouped eachone of these diseases as their

own disease, i think we're going to start tosee more similarities between them as we understandmore about the genetics. and as we understand moreabout this feed forward loop as we learn aboutthe triggers for autoimmunity. so how do we treatthese diseases? so in 2016 right now,how do we treat these diseases? i told you that it's a great time to be a rheumatologistbecause we have treatments.

so the easiest way to treat themis if we know what the trigger is, if we know what hassparked the campfire. if it is a known infection wecan treat the infection, and we have wonderful treatmentsnow for hepatitis c. we've gotten very goodtreatments for hiv and hepatitis b and that can reallyturn off the immune response and you can solve the disease. if we know what the toxin is,we can get rid of it. and many times that'll takecare of the autoimmune disease.

the problem is that formany of the diseases, we don't know what isdriving that feed forwardly. but what we do know isthe pattern in which the immune system is responding. and if it is respondingwith certain cytokines, which are proteins madeby the immune system, and we now have therapies whichare called biologic therapies. you see them advertised ontv all of the time, yes. but what's unique about thesetherapies, as compared to our

previous approach tomany autoimmune diseases, which was shutthe immune system down. hit it with a sledgehammer. but now we're trying totarget particular pathways. and we have a whole host ofbiologic agents that block il-6, that block tnf-alpha,that deplete b cells, that jak-stat inhibitors,all these different pathways. what's interesting is thatyou'll see many of these different pathways may be usedto target a particular disease,

which once again tells youabout the layers of complexity. but what's exciting is thatby blocking these pathways, by developing moleculesthat target those pathways, we can make our patients better,so much better. and we can change the course ofthe disease, and that is really the objective, is to obtaindisease modifying therapies. not just to quiet it, not justto make someone feel better, we want that, too. but we wanna changethe course of the disease.

we wanna prevent damage fromthe immune system that's continuing to propagate. and with some of the newtherapies we think that we can actually do that. we're not so brave as to saythat any of these therapies are what we call rheumotocytal, the rheumatostatic thatthey can stop the disease. but they can changethe course of the disease. so in summary, the immunesystem really is your friend.

you want your immune system. you want it to be healthy andhappy, and do all the things thatit's supposed to do. but it certainly can go awry. there's some things thatyou can change, and a whole lot of thingsyou can't change. you can't changeyour genetic makeup. the things that we all can doin terms of, that we can change, avoiding the toxins, no smoking,having a healthy lifestyle,

having a healthy nutrition, those are the thingsthat we can change. and then, of course,being a part of the medical community as we continue tolearn about these diseases and learn about immunedisregulation. thank you for your attention. >> [applause]