Genetics and immunology of alopecia areata

Genetics and immunology of alopecia areata


WELCOME TO THE WEDNESDAY AFTERNOON LECTURE. TODAY WE HAVE DR. ANGELA CHRISTIANO, WHO WILL BE TALKING ON GENETICS AND IMMUNOLOGY OF ALOPECIA AREATA. ANGELA GOT HER PH.D. IN MICROBIOLOGY AND MOLECULAR GENETICS AT RUTGERS AND DID HER POSTDOCTORAL WORK AT THE DEPARTMENT OF DERMATOLOGY THOMAS JEFFERSON UNIVERSITY. SHE’S HAD HER OWN LABORATORY AS A RESEARCH ASSISTANT PROFESSOR AT THOMAS JEFFERSON AND LATER BECAME PROFESSOR AT ROCKEFELLER IN 1995, SHE MOVED TO COLUMBIA UNIVERSITY WHERE SHE WAS ASSOCIATE PROFESSOR AND IS PRESENTLY THE RICHARD AND MILDRED RHODEBECK PROFESSOR AT THE DEPARTMENTS OF DERMATOLOGY AND GENETICS AND DEVELOPMENT. SHE’S THE DIRECTOR OF THE CENTER FOR HUMAN GENETICS AND THE VICE CHAIR FOR RESEARCH OF THE DEPARTMENT OF DERMATOLOGY. SHE IS ALSO CURRENTLY THE PRESIDENT OF THE SOCIETY OF DERMATOLOGY AND SERVES AS THE DEPUTY EDITOR FOR THE JOURNAL OF INVESTIGATIVE DERMATOLOGY. ANGELA’S RESEARCH HAS FOCUSED ON UNDERSTANDING THE MOLECULAR PROCESSES THAT LEAD TO INHERITED SKIN AND HAIR DISORDERS IN HUMANS. SHE’S MADE REALLY BEAUTIFUL FINDINGS AND SEMINOLE FINDINGS STARTING WITH THE DISCOVERY OF GENETIC MUTATIONS THAT ARE ASSOCIATED WITH BLISTERING SKIN DISORDERS. SHE HAS ALSO PIONEERED THE RESEARCH IN THE UNDERLYING GENETIC CAUSES OF HAIR LOSS AND IDENTIFICATION OF POTENTIAL THERAPIES FOR ALOPECIA AREATA, AN AUTOIMMUNE FORM OF HAIR LOSS. SHE WILL BE PRESENTING THIS AREA OF HER WORK TODAY AND THE TITLE OF HER PRESENTATION IS GENETICS AND IMMUNOLOGY OF ALOPECIA AREATA. PLEASE JOIN ME IN WELCOMING DR. ANGELA CHRISTIANO. [APPLAUSE] THANK YOU SO MUCH FOR THE BEAUTIFUL INTRODUCTION AND FOR THE OPPORTUNITY TO BE HERE SPEAKING IN THIS AMAZING LECTURE SERIES. SO I’M HONORED TO ATTEND AND IT’S WONDERFUL TO SEE SO MANY FRIENDS AND COLLEAGUES OUT HERE IN THE AUDIENCE AS WELL AS SOME OF THE PEOPLE WHOSE WORK WE FOLLOWED FOR QUITE SOME TIME NOW, AND I HOPE THAT I CAN DO JUSTICE TO ACKNOWLEDGING EVERYONE APPROPRIATELY ALONG THE WAY. SO THANK YOU FOR HAVING ME. I’M GOING TO TALK TO YOU TODAY ABOUT AN AUTOIMMUNE FORM OF HAIR LOSS CALLED ALOPECIA AREATA. IT IS WITHIN THE DETERMINE TOE LOGIC DISEASES SO THIS FALLS WITHIN THE NIAMS MISSION HERE AT NIH. I’M A PH.D. GENETICIST SO I’M JOINED IN THIS WORK BY TWO CLINICAL COLLEAGUES, JULIAN MACKAY-WIGGAN WHO AND RAFAEL
CLYDES, HE REALLY HELPED US MOVE THIS PROGRAM INTO PRE-CLINICAL MODELS AND WITH JULIAN’S HELP INTO THE CLINIC. OUR WORK REALLY STEMS FROM A REGISTRY THAT WAS ESTABLISHED BY NIAMS IN ABOUT YEAR 2000 OR SO CALLED THE NATIONAL ALOPECIA AREATA REGISTRY, AND IT WAS THAT GROUP OF PATIENTS THAT REALLY FORMED THE BASIS OF ALLOWING US TO DO THE GENETIC STUDIES THAT I’LL TALK ABOUT TODAY, AND I’M JOINED HERE BY MY COLLEAGUES AT THE OTHER REGISTRY SITES. THIS WAS FOUNDED AND THE HOMESITE WAS AT MD ANDERSON IN HOUSTON FOLLOWED BY SITES AT THESE INSTITUTIONS AND AT OUR OWN AT COLUMBIA, SO WITHOUT THIS IMPORTANT PATIENT REGISTRY, A LOT OF WHAT YOU’RE GOING TO HEAR TODAY PROBABLY WOULD NOT BE ABLE TO HAPPEN, SO AGAIN I HAVE LOTS OF GRATITUDE TO THANK FOLKS UP FRONT FOR HELPING US DO THIS. SO JUST TO INTRODUCE YOU TO THE PHENOTYPES, SO ALOPECIA AREATA IS A VERY COMMON AUTOIMMUNE FORM OF HAIR LOSS AFFECTING ABOUT 6 MILLION PEOPLE IN THE UNITED STATES, ROUGHLY 1 TO 2% LIFETIME RISK. IT CAN SOMETIMES START AS SMALL PATCHES OF HAIR LOSS ON THE SCALP, SOMETIMES ON THE BEARD IN MALES, IT CAN PROGRESS TO COVER THE ENTIRE SCALP, SOMETIMES OCCURS IN UNUSUAL PATTERNS. ONE THING THAT WE THINK WE KNOW ABOUT IT IS THAT IT PREFERENTIALLY ATTACKS PIGMENTED HAIR SO IT SPARES THE WHITE HAIRS, OFTEN LEAVING BEHIND A PATCH LIKE THIS, AND IT COULD EVENTUALLY PROGRESS TO COVER THE ENTIRE SCALP, IN WHICH CASE IT’S CALLED AL PIZZA T ALOPECIA
TOTALIS. WHEN IT PROGRESSES TO THAT LATE STAGE IT TENDS TO BE RESISTANT TO CONVENTIONAL THERAPIES. WHEN WE BEGAN THIS WORK, THERE HAD BEEN 20 OR SO YEARS OF LITERATURE IN THE FIELD DESCRIBING AN AUTOIMMUNE INFILTRATE SURROUNDING FOLLICLES, IN A PATTERN CALLED A SWARM OF BEES. FOR MANY YEARS, THE COMPOSITION AND NATURE OF THIS SWARM OF BEES WASN’T WELL UNDERSTOOD, SO THINKING ABOUT WAYS TO TARGET THIS SPECIFICALLY WAS STILL A LITTLE BIT OUT OF REACH SO THE STANDARD OF CARE OF TREATMENT FOR ALOPECIA AREATA STILL TODAY IS STEROIDS, EITHER INJECTED INTERLEAGUESLY INTERLESIONLY INTO THE SCALP OR OCCASIONALLY ORAL STEROIDS, BUT AGAIN, WITHOUT KNOWLEDGE OF THE DETAILS OF THIS PROCESS, IT WAS VERY DIFFICULT OVER THE YEARS TO COME UP WITH WAYS TO TARGET THIS. I’LL ALSO MAKE ONE OTHER DISCLOSURE AT THE BEGINNING THAT MY INTEREST IN ALOPECIA IS PERSONAL AS WELL AS PROFESSIONAL, SO THE TOP MIDDLE PANEL HERE IS MYSELF. I DEVELOPED ALOPECIA AREATA IN 1996, SHORTLY AFTER ARRIVING AT COLUMBIA, AND THIS IS REALLY WHAT SPARCED OUR INTEREST IN TRYING TO DISSECT THE GENETICS OF THIS COMPLEX DISEASE. AND SO LET ME TELL YOU A BIT ABOUT OUR BASIC BIOLOGICAL CONTEXT OR PROBLEM, AND THAT IS THAT IN NORMAL CONDITIONS, THE HAIR FOLLICLE EXISTS IN A STATE OF RELATIVE IMMUNE PRIVILEGE, WHERE IT REMAINS CLOAKED IF YOU WILL GUARDIANS OF THE IMMUNE SYSTEM THAT KEEP IT FROM BEING RECOGNIZED BY IMMUNE CELLS, THAT’S PART OF ITS SPECIAL PRIVILEGE IN THE SITE. AND SO FOR REASONS WE DON’T YET UNDERSTAND ENTIRELY IN TERMS OF TRIGGERING EVENTS, THIS HAIR FOLLICLE LOSES THAT IMMUNE PRIVILEGE AND BEGINS TO EXPRESS SIGNS OF DANGER SO IT UPREGULATES MHD CLASS 1 AND 2, OTHER DANGER SIGNALS, THAT BEGIN TO RECRUIT IN THIS MIXED INFLAMMATORY INFILTRATE. OVER THE YEARS, THIS HAS BEEN SHOWN TO CONTAIN CD4 CELLS, CD8 CELLS, BUT THIS PROCESS, ONCE IT BEGIN, SORT OF BECOMES A VICIOUS CYCLE. THE HAIR FOLLICLE SECRETES MORE AND MORE DANGER, RECRUITING AGAIN THIS INFILTRATE AND IT KEEPS THIS PROCESS GOING. SO EVEN THOUGH IT’S A COMPLEX PROBLEM MODEL TO THINK ABOUT, IT ALSO PRESENTS OPPORTUNITY AT TWO LEVELS. ONE IS TO THINK ABOUT WAYS OF TREATING THE IMMUNE INFILTRATE AND SORT OF DAMPENING DOWN THAT RESPONSE, BUT THE SECOND INVOLVES TRYING TO RESTORE THIS RELATIVE IMMUNE PRIVILEGE STATE OF THE HAIR FOLLICLE. SO IF WE THINK ABOUT INTERVENTIONS, WE CAN POTENTIALLY THINK ABOUT DOING BOTH OF THOSE THINGS, BOTH RESTORING THE IMMUNE COMPONENTS AND ALSO RESTORING THE HAIR FOLLICLES. SO WHEN I SHOW YOU LATER SOME OF OUR TREATMENT WORK IN MICE AND TO THIS MODEL AND TALK ABOUT HOW WE’VE MANAGED TO TRY AND DO SOME OF THIS. SO OUR WORK REALLY BEGAN AS MANY OTHERS HAVE IN COMPLEX DISEASE GENETICS, AND THAT WAS TO TRY AND BUILD AN UNBIASED GENETIC MAP OF ALOPECIA AREATA FOR THE FIRST TIME. AGAIN THIS WAS COMING ALONG AT THE TIME IN HISTORY WHEN GWAS GENOME WIDE ASSOCIATION STUDIES WERE JUST BECOMING POPULAR, SO AGAIN, BECAUSE THIS IS A COMPLEX DISEASE INVOLVING BOTH GENES AND ENVIRONMENTAL TRIGGERS, WE FOLLOWED THE FOOTSTEPS OF OTHER DISEASES BEFORE US THAT HAD REALLY PAVED THE WAY FOR USING THIS APPROACH AND THINKING ABOUT WAYS TO USE THE GENETIC MAPS TO FIND POTENTIALLY NEW TARGETS THAT COULD BE USED POTENTIALLY WITH ALREADY FDA-APPROVED DRUGS AND TESTING THOSE IN CLINICAL TRIALS. SO THIS MAP OF FUNCTIONAL GENOMICS IS BORROWED FROM MY COLLEAGUE AT COLUMBIA, WHO I THINK HAS DONE ALSO A GREAT JOB OF HELPING US TO THINK ABOUT WAYS TO LINK OUR GENETICS TO SOME OF THE MECHANISMS AND THINK ABOUT NEW DRUGS. SO I’M GOING TO TALK IN FOUR AREAS TODAY, A LITTLE BIT ABOUT THE GENETICS, SOME WORK ON OUR IMMUNOLOGY IN ALOPECIA AREATA, AND THEN FINALLY TALK ABOUT OUR WORK TO DEVELOP NEW BIOMARKERS SO WE COULD TRACK THE PROGRESS AND RESPONSE OF PATIENTS TO SOME OF THE NEW DRUGS AND THEN FINALLY, AT THE END, SOME WORK FROM OUR CLINICAL TRIALS. SO THE RESULTS OF OUR GENOME WIDE ASSOCIATION STUDY, THIS WAS FROM ABOUT 2000 OR SO PATIENTS ROUGHLY 1500 CASES, 3500 CONTROLS, THIS IS VERY SMALL GENOME WIDE ASSOCIATION STUDY, SO NOW DAYS YOU SEE NUMBERS IN SOME DISEASES WELL OVER 100,000 CASES AND CONTROLS, SO THIS IS A VERY MODEST SIZE STUDY. WE TAKE A FEW THOUSAND CASE, SPARE THEIR MARKERS TO A FEW THOUSAND CONTROLS AND WE LOOK FOR AREAS OF THE GENOME WHERE WE SEE SKEWING OR OVERREPRESENTATION OF CERTAIN GENETIC MARKERS IN THE CASES RELATIVE TO CONTROLS, AND WHEN WE DO THAT, THIS RED LINE IS STATISTICAL SIGNIFICANCE, ANYTHING THAT RISES ABOVE THAT LINE SUGGESTS TO US THAT THERE IS A LOCUS THERE THAT MAY BE CONTRIBUTING TO DISEASE. SO THE HLA IS A NICE POSITIVE CONTROL TO HAVE FOR ANY AUTOIMMUNE DISEASE, BUT PARTICULARLY IN ALOPECIA AREATA, THERE HAD BEEN MANY CAPPED DATE GENE ASSOCIATION STUDIES HERE IN THE PAST, AND SOME OF THESE OTHER GENES IN BLACK ARE ONES THAT ARE SHARED AMONGST OTHER AUTOIMMUNE DISEASES, SO AGAIN, NICE CONTROLS THAT WE’RE HITTING UPON GENES THAT SHOULD HAVE INTEREST IN THE DISEASE. BUT WHAT EVERY CAN GENETICIST REALLY WANTS IS THE SMOKING GUN, THE GENE THAT’S UNIQUE TO YOUR DISEASE THAT HAS THE GREATEST POTENTIAL USUALLY OF GUIDING YOU TOWARDS A MECHANISM THAT MIGHT HELP UNDERSTAND PATHOGENESIS. SO IN OUR CASE, THIS JEAN GENE, THE ULBP3 AND 6 CLUSTER IS THE MOST SIGNIFICANT HIT IN ALOPECIA, AND IMPORTANTLY IT’S ALSO UNIQUE TO ALOPECIA AREATA, SO TO DATE, THERE ARE STILL NO OTHER AUTOIMMUNE DISEASES THAT HAVE THIS GENE AS A CANDIDATE GENE, SO SIMILAR TO INSULIN IN DIABETES, FOR EXAMPLE, IT’S USUALLY THE GENES THAT ARE UNIQUE TO YOUR DISEASE THAT ARE THE ONES THAT ARE THE MOST INSTRUCTIVE ABOUT PATHOGENESIS. THE OTHER REASON THIS GENE WAS EXCITING IS BECAUSE IT HAPPENS TO BE A DANGER SIGNAL. IT’S A LIGAND FOR A RECEPTOR CALLED NKG2D THAT’S EXPRESSED ON ACTIVATED CD8 EFFECTOR CELLS AND WHEN THOSE TWO ENGAGE, THE CD8 EFFECTORS CAN TARGET AND KILL CELLS THAT ARE EXPRESSING THIS LIGAND. SO FOR BOTH OF THOSE REASONS, THIS GENE BECAME QUITE AN INTEREST FOR US IN THE LAB. ONE OF THE OTHER SURPRISES THAT CAME OUT OF THIS WORK EARLY ON WAS THE ALIGNMENT OF ALOPECIA WITH SOME UNEXPECTED GENETIC DISEASES. SO WE AS I THINK MANY PEOPLE EXPECTED ALOPECIA AREATA TO CLOSELY RESEMBLE VIE PSORIASIS
IN TERMS OF ITS GENETIC MAKEUP. YOU’LL SEE THAT’S NOT THE CASE AND INSTEAD WHAT WE SEE IS A STRONG ALIGNMENT WITH THIS CLASS OF AUTOIMMUNE DISEASES. SO THIS WAS AGAIN A SURPRISE, IT TOOK US A WHILE TO SORT OF GET OUR MINDS AROUND THIS, BUT WHEN WE WENT TO THE LITERATURE, IT TURNED OUT THAT THERE WAS A RICH HISTORY IN THIS CLASS OF DISEASES FOR UNDERSTANDING WHAT MAKES THEM SIMILAR AND MOST OF THAT CONVERGES ON THIS NKG2D AXIS. SO AGAIN SOMETHING GENETICISTS LOVE TO DO IS REPLICATE OUR INITIAL GWAS STUDIES AND OFTENTIMES WE HAVE TO COMBINE COLLEAGUES AROUND THE WORLD ALSO DOING GWAS STUDIES TO GET EVEN MORE CANDIDATE GENES, SO WE’RE VERY LUCKY TO COLLABORATE WITH REGINA BETZ AND MARKUS NOTHEN TO COMBINE OUR GWAS WITH THAI WE NOW HAVE 10,000 CASES AND CONTROLS, AND WHAT WE SEE IS AN IMPROVEMENT IN OUR HLA SIGNAL HERE AS WELL AS ULBP3 AND 6 AND SOME OF THE OTHERS, SO WE FULLY REPLY DATED OUR INITIAL GWAS IN THIS META-ANALYSIS IN ADDITION TO FINDING SEVERAL OTHER NEW CANDIDATE GENES. YOU CAN SEE THE COMPILED LIST HERE. SO SOME OF THE STATISTICS ON THIS ARE GETTING IMPRESSIVE, THE ULBP GENES YOU SEE HERE AGAIN ARE HOLDING UP AT 10 TO THE MY MINUS 24, SUGGESTING ONCE AGAIN THAT THIS MIGHT BE A PLACE TO FOCUS FOR MECHANISM. WAVE ALSO RESOLVED OUR HLA SIGNAL TO A FEW PARTICULAR AMINO ACIDS WITHIN HLDRB1, SO AMINO ACID 13 AND 37 AS WELL AS A QTL SNP HERE, SO MOST OF OUR SIGNAL IS COMING FROM DRB1. THIS COMPARES NICELY TO REUM TIED OR THRIETS, TO PSORIASIS, WHICH HAVE ALSO DONE THIS TYPE OF ANALYSIS WITH THE HELP OF PAUL DEBAKER TO REALLY RESOLVE THESE SIGNALS DOWN TO A VERY SMALL NUMBER OF AMINO ACIDS AND AGAIN THESE ALSO ALIGN CLOSELY WITH THOSE IN CELIAC DISEASE AND THOSE IN TYPE 1 DIABETES. SO WE PUT THIS ALL TOGETHER AND OUR GOAL NOW IS TO CONTINUE ALONG THE GENETICS. WE’RE NOW DOING WHOLE EXOME SEQUENCING WITH CUSTOM CAPTURE IN OUR GWAS READINGS TO IDENTIFY THE FUNCTIONAL VARIANCE AND THE GOAL IS TO ADVANCE THIS TO WELL OVER 10,000 INDIVIDUALS. SO I’M NOT GOING TO GO MUCH FURTHER ON THE GENETICS TODAY, BUT SOMETIMES MY FRIENDS LIKE TO SAY THAT WE’VE GOTTEN SO DISTRACTED BY THIS FIVE YEARS OF I MEU NOLG THAT WE’RE FINALLY COMING BACK TO DOING WHAT WE STARTED, WHICH WAS TO GO FURTHER INTO THE GENETICS, BUT I WON’T GO ANY FURTHER THERE TODAY EXCEPT JUST TO — I’VE PUT IN CONTEXT A LITTLE BIT, THIS IS ALOPECIA AREATA AND THESE ARE SOME OF THE OTHER AUTOIMMUNE DISEASES. THIS IS A LITTLE BIT OUT OF DATE NOW. THESE ARE NUMBER OF PATIENTS IN GWAS STUDIES AND AGAIN MANY OF THESE ARE OVER 100,000 NOW. WHAT HAPPENS IS AS YOU MOVE TO THE LEFT HERE, YOU BEGIN TO PICK UP MORE AND MORE AND MORE SUSCEPTIBILITY GENE, SO YOU CAN SEE THAT YOU BEGIN TO GET MANY MORE GENES WITH SMALL EFFECT SIZES HERE AS YOU ADD PATIENTS TO THESE GWAS STUDIES. SO WE’RE AT THIS LEVEL, BUT I’M HOPING WHAT I CAN SHOW YOU TODAY IS THAT EVEN WITH KNOWLEDGE OF THE VERY LOWEST HANGING FRUIT, THE GENES THAT ARE EASIEST TO FIND HERE, THAT EVEN WITH THAT INFORMATION, WE’VE BEEN ABLE TO MAKE SOME INTERESTING FUNCTIONAL OBSERVATIONS. SO WHAT I HOPE TO AGAIN SEND YOU HOME WITH TODAY IS A LITTLE BIT OF APPRECIATION HOW THE GENETICS HAVE OPENED UP A NEW WINDOW INTO UNDERSTANDING THEIR DISEASE PATHOLOGY AND THEN ALSO HOW WE’VE TRIED TO LEVERAGE THAT TO CHOOSING AND REPURPOSING SOME EXISTING DRUGS TO TRY IN THIS DISEASE. SO AGAIN, TAKING A PAGE FROM WHAT’S COME BEFORE US, WE’VE STUDIED WITH GREAT CARE THE BEAUTIFUL WORK OF THOMAS WALDMAN WHO’S HERE IN THE AUDIENCE — WHO WORKS ON CELIAC DISEASE — OWE SHEA WHO’S HERE IN THE AUDIENCE, AND MANY OF THE FOLKS WHO HAVE COME BEFORE US HAVE DONE SEMINOLE WORK IN THESE PATHWAYS IN THE ROW LATED AUTOIMMUNE DISEASES AND WE’VE BEEN INSPIRED BY THEIR COLLECTIVE SCHOLARSHIP TO TRY AND BORROW SOME OF THESE PRINCIPLES AND APPLY THEM TO ALOPECIA AREATA, OF COURSE WITH THE GOAL OF FINDING SOME SHARED TREATMENT. SO TO COME BACK TO OUR FAVORITE CANDIDATE GENE, ULBP3, AGAIN WHEN WE FIRST FOUND THIS, WE WEREN’T QUITE SURE HOW TO INTERPRET IT, WHAT TO MAKE OF IT, SO WE BEGAN TO GO THROUGH THIS LITERATURE AND WHAT CAME THROUGH WAS THAT IN THE OTHER THREE RELATED DISEASE STATES, THERE WAS THE SIMILAR UPREGULATION OF A — IN THE END ORGAN OF THE OTHER DISEASES, SO IN RHEUMATOID ARTHRITIS — IN THE NOD MICE, THE NOMENCLATURE GETS A LEL MESSY ABOUT — ARE RELATIVES OF THE SAME CLASS OF ULBP3 LIGANDS. SO OUR QUESTION WAS DO WE SEE THE SAME IN ALOPECIA AREATA HAIR FOLLICLES. SO THE BLUE IS AN OUTLINE OF NORMAL CELLS IN THE CONTROL HAIR FOLLICLE. THE RED IS STAINING FOR ULBP3. WE ALWAYS SEE A LITTLE BIT OF STAINING EVEN IN CONTROLS, BUT IN ALOPECIA AREATA PATIENTS, WE SEE A MASSIVE UPREGULATION OF ULBP3 IN THE OUTER MOST PART OF THE HAIR FOLLICLE IN THIS CASE, IN THE DERMAL SHEATH, POSITIONING IT AT THE RIGHT PLACE IN THE ANATOMY OF THE HAIR FOLLICLE TO INTERACT WITH THE NK — RECEPTOR COMING IN FROM THE SURROUNDING IMMUNE CELLS. SO THIS CHARACTERISTIC REALLY I THINK BEGINS TO GIVE SOME FUNCTIONAL SIGNIFICANCE TO OUR CANDIDATE GENE. SO IF WE HAVE THE LIGAND ON THE HAIR FOLLICLE, WE EXPECT TO SEE THE RECEPTOR ON THE INFILTRATE, SO THIS IS CO-STAINING FOR CD8 AND NK IM. 2DKG2D — LIKELY
INVOLVED IN DISEASE. SO REMEMBER AT THE BEGINNING I MENTIONED THIS SORT OF SWARM OF BEES PATHOLOGY THAT WAS KNOWN UP UNTIL NOW, AND IT WAS REALLY AT THIS POINT THAT I WAS ABLE TO ENLIST THE HELP OF MY CLAB COLLABORATOR TO REALLY HELP FIGURE THIS OUT. WHEN RAFAEL LOOKED AT THIS PICTURE HE SAID THIS LOOKS LIKE TYPE 1 DIABETES OF THE HAIR FOLLICLE, SO THAT SORT OF BECAME OUR WORKING MODEL FOR TRYING TO BUILD OUT OUR STUDIES ON THE IMMUNOLOGY. OH SO LET ME INTRODUCE YOU TO THE MOUSE MODEL USED THROUGHOUT OUR WORK. SO THIS IS AN INBRED STRAIN OF MICE CALLED C3H/HEJ. THIS IS A STRAIRN STRAIN THAT’S
KEPT AT JACKSON LABS, THEY DEVELOPED SPONTANEOUS ALOPECIA AREATA IN ABOUT 15% FEMALES AT ABOUT A YEAR, SO IT’S NOT A VERY TRACTABLE MODEL TO DO EITHER PREVENTION OR TREATMENT STUDIES WAITING AROUND ALL THIS TIME. SO THEY DEVELOPED A GRAFT MODEL WHERE THEY CAN TAKE SMALL BITS OF SKIN FROM AFFECTED AA MICE AND GRAFT THEM ON THE BACK OF C3H RECIPIENTS, THEY START TO LOSE HAIR ON THE BELLY FIRST, AND THEN IF YOU LET THIS PROGRESS TO THREE OR FOUR MONTHS, THEY’LL LOSE HAIR EVERYWHERE ON THE BACK, AND ON THE REST OF THE BODY. SO THIS MODEL IS VERY STEREOTYPICAL, IT’S EASY TO USE FOR TESTING, AND SO WE CAN DO TWO THINGS WITH IT, WE CAN GIVE DRUGS AT THE TIME OF THE GRAFT AND WE CAN TRY TO PREVENT THE ONSET OF ALOPECIA, THAT’S THE EASIER MODEL, OR WE CAN LET THE MICE LOSE THEIR HAIR, EITHER EARLY OR LATE DISEASE, AND THEN GIVE DRUG AND TRY TO REVERSE THE MODEL AND ACTUALLY SET UP A TREAT M-TYPE TREATMENT-TYPE STUDY AND THAT’S OF COURSE MORE CHALLENGING. SO TO TRY AND PROVE THAT THE MOUSE WAS A GOOD MODEL FOR HUMAN ALOPECIA, JUST A FEW QUICK STUDIES, SO THIS IS AT THE GENE EXPRESSION LEVEL. THIS IS HUMAN COMPARED TO MOUSE ALOPECIA AREATA. YOU CAN SEE UPREGULATION OF SOME OF THE INTERFERON CYTOKINES HERE, SOME MARKERS OF CD8 CYTOTOXIC CELLS, CD8 HERE, WE’LL GO THROUGH THIS IN A LOT MORE DETAIL LATER BUT ROUGH SIMILARITIES IN TERMS OF GENE EXPRESSION. DO WE SEE SIMILAR UPREGULATION OF AN NK LIGAND IN THE MOUSE? SO THIS IS HUMAN ULBP3 IN THE STRESSED FOLLICLE, AND THIS IS C3H MOUSE BEFORE GRAFTING. YOU CAN SEE THAT THIS LIGAND, H60, IS ALREADY UPREGULATED AT BASELINE COMPARED TO BLACK 6 MICE AND HERE IT IS AFTER TRANSFER OF THE SKIN GRAFT SHOWING EVEN MORE UPREGULATION, SO GOOD CONSISTENCY THERE. DO WE SEE THE SIMILARITIES AT THE LEVEL OF THE T-CELLS? SO IN HUMAN AGAIN CD8, NKG2D CELLS, HERE IN THE MOUSE, THE SAME MARKING INFILTRATE WITH THIS TWO MARKERS IN THESE KILLER CELLS. INTERESTINGLY, THIS PHENOTYPE OF CD8 NKG2D CELLS MAKES UP A FULL 20% OF THE T-CELLS IN THE SKIN OF LESIONAL ALOPECIA IN THE MIKE SO THIS BECOMES A VERY CONVENIENT BIOMARKER IF YOU WILL IF WE CAN MEASURE THE DISAPPEARANCE OF THESE CELLS FROM THE SKIN, IT WOULD SUGGEST TO US THAT WE’RE HITTING THE RIGHT TARGET, AND WE’LL SEE THAT AGAIN LATER. SO THE CRITICAL EXPERIMENT REALLY WAS TO SHOW THAT THE CD CD8 — WERE NECESSARY AND SUFFICIENT. SO HERE WE’RE TRANSFERRING TOTAL — INTO AN UNAFFECTED RECIPIENT AND THAT MOUSE LOSES ITS HAIR. IF WE ACCEPT SEPARATE THE NKG2D NEGATIVE FROM POSITIVE CELLS, YOU CAN SEE HE DEPLETED CELLS, THE MICE RETAIN THEIR HAIR AND IT’S ONLY THE POSITIVE CELLS THAT LOSE THEIR HAIR, SO THIS GAVE US REALLY THE FIRST WINDOW OF TRYING TO UNDERSTAND AGAIN A LITTLE BIT MORE SPECIFICALLY WHAT’S IN THAT INFILTRATE AND IF WE COULD SELECTIVELY TARGET THOSE CELLS MAYBE GIVE US A CHANCE TO INTERYOU WANTINTERRUPT
THE DISEA
SE PROCESS. THERE ARE MANY, MANY WAYS TO THINK ABOUT DOING THAT. AGAIN, THIS IS A RICH LITERATURE IN TERMS OF TARGETING THESE CELLS, BUT HERE WE START TO THINK ABOUT THE RISK-BENEFIT FOR A DISEASE LIKE ALOPECIA AREATA WHERE THESE PATIENTS DON’T HAVE LIFE-THREATENING COMPLICATIONS FROM THEIR DISEASE, IN MANY CASES, IN MOST CASE, IN FACT, HAIR LOSS IS THEIR ONLY MEDICAL PROBLEM, SO THE RISK-BENEFIT OF USING POTENT IMMUNOSUPPRESSIVE DRUGS FOR A DISORDER LIKE ALOPECIA AREATA BECOMES A QUESTION THAT WE ASK AND ALSO TO MAKE THIS INTO A VIABLE TREATMENT FOR PATIENTS, WE NEED ABOUT WHAT’S THE RIGHT WAY TO GO HERE. SO EVEN THOUGH THERE WAS A RICH LITERATURE IN THE CYTOKINE WORLD, OUR QUESTION REALLY BEGAN TO FOCUS A LITTLE MORE ON HOW COULD WE MAYBE COULD DO THIS
USING SMALL MOLECULES. SO AGAIN DEFINED BY DR. WALDMAN WHO’S HERE IN THE ROOM AND HIS COLLEAGUES, THE IL-15 PATHWAY WE KNOW IS THE KEY COMPONENT OF KEEPING THE CD8 CYTOTOXIC CELLS ALIVE AND THAT WITHOUT AN ACTIVE IL-15 SIGNAL, THESE CELLS REALLY DON’T SURVIVE WELL. SO I WON’T SHOW YOU THE WHOLE STORY BUT SUFFICE TO SAY THAT WE HAVE STRONG UPREGULATION OF IL-15 PATHWAY IN ALOPECIA AREATA, BOTH IN THE HAIR FOLLICLE, SO WE NEED TWO COMPONENTS ON THE SENDING CELL, IN ALOPECIA AREATA, WE HAVE EXPRESSION OF IL-15RA, THE CHAPERONE RECEPTOR, AS WELL AS IL-15, THE CYTOKINE ITSELF, AND IN THE RECEIVING CELL, THE GAMMA CHAIN AND BETA CHAIN CYTOKINE HERE, SO WE HAVE ALL FOUR COMPONENTS IN ALOPECIA, SUGGESTING THAT THIS, IN FACT, COULD BE THOUGHT OF AS TARGETING WITH A DOWNSTREAM JACK INHIBITOR. AGAIN AS MANY YOU HAVE KNOW ON THE CAMPUS, DR. ROCHET’S LAB HAS BEEN ONE OF THE PIONEERS THE FIELD ESTABLISHING MANY OF THE CORE CONCEPTS, SO AGAIN, IT WAS RAFAEL’S SUGGESTION TO THINK ABOUT USING THESE JACK INHIBITORS IN PLACE OF SOME OF THESE MORE BROAD IMMUNE SPRE SELF MOLECULES AS A WAY TO TARGET FOR ALOPECIA. SO HERE YOU SEE THAT IL-15 SIGNAL IN AN AFFECTED HAIR FOLLICLE, IT’S VERY STROK, ALSO IN. SO OUTER LAYERS AGAIN SUGGESTING IT’S AT THE RIGHT PLACE TO BE ACTIVE. I’LL SHOW YOU LATER BUT ALSO WE HAVE THE STRONG EVIDENCE FOR THE INTERFERON SIGNATURE THAT YOU SAW A BIT EARLIER, SO THESE TWO CYTOKINE PATHWAYS ARE REALLY OUR TWO MAJOR AXES IN ALOPECIA AREATA, INHIBITION OF JACK 1-2 OR JACK 1-3 TO TRY AND BLOCK ONE OR BOTH OF THESE SIGNATURES. SO AS IT TURNED OUT, THE JAK INHIBITORS IN OUR STORY ACTUALLY HAD A DUAL PURPOSE, SO WE CAN BE THINKING ABOUT IT. HERE’S OUR IL-15 SIGNAL COMING FROM THE HAIR FOLLICLE BACK TO THE T-CELL, HERE YOU SEE BLOCKADE BY SOME JAK INHIBITORS, BUT WE ALSO UNEXPECTEDLY HAVE A SECOND OPPORTUNITY TO INTERRUPT THE INTERFERON SIGNAL HERE THAT ACTUALLY FUNCTIONS AT THE LEVEL OF THE HAIR FOLLICLE, SO THIS WAS UNEXPECTED, WE SORT OF GOT A GIFT WITH PURCHASE HERE, AND AGAIN WORK THAT I WON’T GO TOO MUCH INTO, WE KNOW NOW THAT THE J ASM K INHIBITORS HAVE A DUAL EFFECT NOT JUST ON BLOCKING IMMUNE RESPONSE BUT ALSO DIRECT ACTIVATION OF FOLLICLE STEM CELLS SO AGAIN, THAT WAS UNEXPECTED. AT THE TIME WE STARTED, THERE WERE — STILL ARE, I THINK, ONLY TWO FDA-APPROVED JAK IMHIN TORES HERE IN THE U.S., ONE WAS TOFA TOFACINIB, AND — TOFA IS CALLED A PAN JAK INHIBITOR, TARGETS ALL THREE, AND RUXO IS SPECIFIC TO JAK 1 AND 2, ALSO — JOHN TOLD ME TODAY BEEN APPROVED IN EUROPE FOR R.A. SO A LOT OF ACTIVITY AND DEVELOPMENT IN THIS AREA FOR MANY DIFFERENT AUTOIMMUNE DISEASES AND CANCERS. SO AGAIN, THE WAY WE USE THESE DRUGS IN THE MODEL, SOME WE GIVE AT THE TIME OF GRAFTING TO PREVENT DISEASE, AND OTHERS WE GIVE AFTER THE MICE HAVE ESTABLISHED ALOPECIA AREATA TO TRY AND REVERSE IT. SO LET ME SHOW YOU SOME EXAMPLES. THIS IS SYSTEMIC DELIVERY OF BOTH RUXO AND TOFA. SO HERE WE GIVE TOFA AT THE TIME OF GRAFTING, AND YOU CAN SEE THAT MICE THAT RECEIVED TOFA RETAPED THEIR HAIR, WHEREAS THE RETAINED THEIR HAIR, THE TREATED MICE HAVE THICK, HEALTHY FOLLICLES HERE, STILL IN THE ANTIGEN OR GROWTH PHASE, WHEREAS THE UNTREATED MICE HAVE A STRONG IMMUNE INFILTRATE AND DYSTROPHIC HAIRS, NOT MAKING MUCH OF A HAIR SHAFT, THEIR LYMPH NODES STAY SMALL, SUGGESTING THE CELLS BASICALLY DON’T GET STARTED, THEY REALLY DON’T GET BORN IN THE TREATED ANIMALS. THE SAME RESULT IS TRUE FOR RUXO, SO THE TREATED MICE RETAIN THEIR HAIR AND THE UNTREATED MICE LOSE THEIR HAIR. THESE ARE STRONG HEALTHY FOLLICLES IN ANTIGEN AND DYSTROPHIC FOLLICLES WITH IMMUNE INFILTRATE SURROUNDING THE FOLLICLE IN THE SAME RESULT HERE. SO IF WE COMPARE THAT TO WHAT WE GET WHEN WE BLOCK WITH AN IL-15 BLOCKING ANTIBODY, YOU CAN SEE THAT IN THE TOP ROW OF EACH IL-15 BLOCKADE OR TO FA OR RUXO, EACH CAN REVERSE THE MARKERS START TO GO AWAY, YOU SEE THESE BLACK INDICATORS OF HAIR FOLLICLE REGROWTH SO THOSE ARE THE HAIR SHAFTS GOING BACK INTO ANTIGEN OR GROWTH PHASE, SO WE’VE REVERSED, IF YOU WILL, OUR DANGER SIGNALS OR RESTORING IMMUNE PRIVILEGE AT THE HAIR FOLLICLE LEVEL. IN THE UNTREATED MICE, THEERS ARE THESE ARE OUR KILLER CELLS IN THE TOP RIGHT QUADRANTS, BOTH IL-15 AND JAK3 IN TOFA CONTROLS, BUT WHEN WE LOOK AT THE TREATED MICE, THESE QA THESE QUADRANTS ARE BASICALLY EMPTY, SUGGESTING THEY NEVER HAD A CHANCE TO GET GOING, SO GIVING US I THINK GOOD EVIDENCE THAT WE’RE HITTING TARGET AND THAT WE’RE BEGINNING TO AFFECT THE CELLS AS WELL AS THE END ORGAN PHENOTIME IN A POSITIVE DIRECTION. SO I’LL FAST FORWARD AND JUST SHOW YOU, WE’VE DONE THIS NOW WITH MANY DIFFERENT JAK INHIBITOR, BOTH WITH SYSTEMIC AND MORE RECENTLY TOPICAL DELIVERY, SO THIS IS WHAT IT LOOKS LIKE TOPICALLY, SO THESE CONTROL MICE ARE TREATED WITH THE VEHICLE CREAM BEFORE AND FOR ONE MONTH AND FOR TWO MONTHS, AND THEN THIS IS TOFA BEFORE ONE MONTH, TWO MONTHS, AND THE SAME FOR RUXO. SO YOU SEE THIS IS A DRAMATIC INCREASE IN HAIR GROWTH AFTER JUST TWO MONTHS OF TREATMENT. WE CAN WITHDRAW THE TREATMENT AND SHOW IT’S DURABLE SO WHEN WE TAKE THE DRUG AWAY, THEY ONLY REGROW WHERE WE TREAT THEM, THESE MICE WERE TREATED ON THEIR BACK, THE DRUGS TO NOT SEEM TO PASS SYSTEMICALLY WHEN WE USE IT TOPICALLY. WE’VE REVERTED SOME OF OUR IMMUNE PRIVILEGE MARKERS BACK TO THE NORMAL SITUATION, AND IMPORTANTLY, WE’VE BEEN ABLE TO CLEAR THESE CELLS FROM TREATED SKIN, SO HERE’S OUR 20% OR SO OF NKG2D POSITIVE CELLS BEFORE TREATMENT AND THEN AFTER THE TOPICAL TREATMENT, THESE GO BACK TO A BASELINE LEVEL. SO THIS IS ENCOURAGING AND SUGGESTS THAT AGAIN FOR DIFFERENT MODALITIES THAT WE MIGHT BE ABLE TO THINK ABOUT INCORPORATING TOPICAL TREATMENT INTO THE ARSENAL FOR TREATMENT OF ALOPECIA AREATA. SO JUST A QUICK ASIDE, LET’S CHANGE GEARS AND LOOK AT SOME OF THE WORK WE’VE BEEN TRYING TO DO TO DEVELOP A CONCOMITANT BIOMARKER PLAN THAT WE COULD USE IN TANDEM WITH OUR CLINICAL TRIALS TO BEGIN TO GIVE US BIOLOGICAL INDICATIONS OF RESPONSE TO TREATMENT EVEN BEFORE WE’RE ABLE TO SEE THE HAIR GROWING. SO AGAIN ENCOURAGED BY NIAMS, WHO WAS BEHIND US REALLY 100% IN THIS WORK. WE HAD A SMALL R21 GRANT TO BEGIN TO DEVELOP SOME OF THESE GENE EXPRESSION BIOMARKERS. SO IN ADDITION TO THE GENETICS, WE’VE DONE NOW EXTENSIVE TRANSCRIPTIONAL ANALYSIS, BOTH IN THE BLOOD AND ALSO IN SKIN, SO I’LL SHOW YOU SOME OF OUR GENE EXPRESSION WORK. THE GOAL IS SEVERAL FOLD. ONE IS TO TRY AND THINK ABOUT STRATIFICATION OF PATIENTS WHEN THEY COME IN WITH ALOPECIA AREATA FOR THE FIRST TIME. SO THE MOST COMMON PRESENTATION FOR PATIENTS IS JUST A SINGLE PATCH OF HAIR LOSS, AND IT’S REALLY — IT’S UNKNOWN TO THE PATIENT AND THEIR PRACTITIONER WHETHER THAT PATIENT WILL GO ON TO GET BETTER, GET WORSE OR STAY THE SAME. AND IT’S ACTUALLY A HUGE FRUSTRATION BOTH FOR TREATING AND ALSO A HUGE SOURCE OF ANXIETY FOR PATIENTS TO KNOW IF THEY’RE LIKELY TO SPONTANEOUSLY REMIT OR LIKELY TO HAVE LONG TERM PATCHY DISEASE OR LIKELY TO PROGRESS. SO IN THE LONG TERM, WE’D LIKE TO HAVE A GENOTYPE RISK SCORE THAT COULD HELP US AT BASELINE KNOW HOW MANY SUSCEPTIBILITY GENES A PATIENT WILL CARRY. WE’D LIKE TO HAVE SOME SERUM MARKERS SO WE COULD TRACK THESE CHANGES NON-INVASIVELY, NOT HAVE TO DO A SCALP BIOPSY EACH TIME, THEN FINALLY WHAT I WILL SHOW YOU IS A GENE EXPRESSION CLASS FIRE TO MARK AGAIN THEIR RESPONSE TO TREATMENT. SO WE’D LIKE IT KNOW, AGAIN, COULD WE USE THESE PROGNOSTICLY AND ALSO COULD WE STRATIFY GIVEN PATIENTS TO A PARTICULAR TREATMENT. SO IF WE TAKE BIOPSIES FROM ALOPECIA AREATA SCALP, AND WE DO SORT OF AN UNSUPERVISED CLASSIFICATION, THESE ARE CONTROL SCAL PS, THESE ARE MILD PATCHY DISEASE IN THE MIDDLE, AND THIS IS SEVERE, TOTALIS, YOU CAN SEE THEY NICELY úDIFFERENT STATES OF DISEASE. IF WE ANALYZE THESE, IT’S ON ONE END THE INTERFERON SIGNATURE AND THE CYTOTOXIC T-CELL SIGNATURE THAT’S MOST EXTREMELY UPREGULATED, WHEREAS ON THE OTHER SIDE, IT’S THE KERATINS AND SOME OF THE OTHER STRUCTURE HAIR GENES THAT ARE DOWNREGULATED SO STATISTICALLY, WE’D LIKE TO HAVE BOTH ENDS OF THIS REPRESENTED SO WHEN OUR INTERFERON SCORES GO DOWN, OUR HAIR KERATIN SCORES GO UP AND WE CAN MEASURE RECOVERY IN THESE DIFFERENT WAYS. SO HERE’S A CLOSER VIEW. SO IN NORMAL CONTROL SUBJECT SCALP, WE SEE VERY LOW EXPRESSION OF OUR CYTOTOXIC T-CELL SIGNATURE OR OUR INTERFERON SIGNATURE, AND THE RED INDICATES VERY STRONG SIGNATURE OF NORMAL HAIR GROWTH. IF WE CONTRAST THAT TO ALOPECIA TOTALIS SSH/UNIVERSALIS, AND
SOME HAIR IS STILL LEFT IN THESE PATIENTS. SO WE’VE TRIED TO QUANTITATE THIS AS SORT OF WHAT WE CALL A DISTANCE TO HEALTH CALCULATION, WHERE WE CAN MEASURE COMPOSITE SCORE OF ALL OF THE GENE EXPRESSION IN AN RNA SCWEENS
SEQUENCING. THIS IS OUR MOST SEVERE PHENOTYPE, THIS IS PATCHY DISEASE IN THE MIDDLE, AND THESE ARE CONTROLLED SO THE GOAL IS WHEN WE TREAT WITH A DRUG THAT HITS THE TARGETS, WE EXPECT TO SEE THESE GENE EXPRESSION SIGNATURES MOVE THIS WAY TO SORT OF RESOLVE TOWARDS THE NORMAL QUADRANT WHICH WE SEE DOWN HEERY GRES REGRESS TO NORMAL. ONE THING THAT WAS SURPRISING TO US, US, WE ACTUALLY AS YOU SAW EARLIER SEE AN EXAGGERATED PROFILE IN THE SEVERE DISEASE COMPARED TO PATCHY. SO NOW THAT WE LOOK PACK BACK ON
T MAYBE THIS MAKES SENSE, BUT FOR A LONG TIME IN OUR FIELD, IT’S BEEN SUGGESTED THAT THESE PATIENTS ACTUALLY HAVE WHAT THEY CALL BURNED OUT DISEASE, MEANING THEY’RE REALLY NOT TREATABLE BECAUSE THE THINKING WAS THAT THIS IMMUNE INFILTRATE HAD LONG DISAPPEARED FROM THE SCALP. BUT IN FACT OUR BIOPSY STUDY ACTUALLY INDICATES THE OPPOSITE, THAT THESE PATIENTS HAVE THE HIGHEST LEVELS OF INFILTRATE SIGNATURES SO THIS SUGGESTS TO US THAT EVEN THOUGH FOR CONVENTIONAL THERAPIES LIKE STEROIDS, THESE PATIENTS WERE RESISTANT, BUT FOR THE JAK INHIBITORS OR OTHERS, THEY MAY ACTUALLY BE TARGETABLE. SO IN THE LAST SECTION, I’LL JUST TELL YOU ABOUT OUR TWO OPEN LABEL STUDIES THAT HAVE BEEN DONE AGAIN LED BY JULIAN AT COLUMBIA. WE STUDIED A SMALL STUDY OF 10 TO 12 PATIENTS AS WELL AS A VERY SMALL SERIES OF 10 TO 12 PATIENTS IN AN OPEN LABEL STUDY. SO I’LL SHOW YOU SOME OF OUR RESULTS. SO AGAIN THESE ARE SINGLE ARM PILOT STUDIES. IN THIS STUDY, RUXO, WE STARTED WITH 10 MODERATE TO SEVERE PATIENTS AND ADVANCED THIS TO TWO TOTALIS PATIENTS, THESE ARE 20 BID FOR THREE TO SIX MONTHS AND WE FOLLOWED THEM WITH PHOTOGRAPHY AND REPORTING AND BIOMARKERS DURING THIS STUDY. SO OVERALL, 9 OUT OF OUR 12 PARENTS ACHIEVED 12 PATIENTS ACHIEVED THEIR PRIMARY OUT COME OF AT LEAST 50% OF REGROWTH MEASURED BY SALT SCORE. THE RESPONSE WAS SEEN AS EARLY AS ONE MONTH. THE REGROWTH WAS PROGRESSIVE, ONE PATIENT WAS A LITTLE BIT SLOWER THAN THE OTHERS BUT EVENTUALLY CAUGHT UP. SO I’LL JUST SHOW YOU SOME EXAMPLES. HERE’S A PATIENT WITH MODERATE IF YOU WOULD TO SEVERE PATCHY ALOPECIA, THIS IS AFTER 20 WEEKS ON STUDY. THIS IS ANOTHER PATIENT AT BASELINE AFTER ABOUT FOUR MONTHS, SHE GOT SOME HAIR EXTENSIONS BECAUSE SHE WAS VERY EXCITED TO HAVE HER HAIR BACK SO THIS RUINED OUR PICTURES A LITTLE BIT, BUT NONETHELESS, SHE WAS VERY HAPPY. THIS GENTLEMAN HAD LONG-STANDING ALOPECIA AREATA. THIS IS A TATTOO OF HIS EYEBROW AND HE HAD LOST ALL OF HIS FACIAL HAIR AS WELL AS THE HAIR IN THE BACK OF HIS HEAD, AND THIS IS HIM AFTER SIX MONTHS ON RUXO SO HE REGAINED ALL OF HIS FACIAL AND BODY HAIR AS WELL AS HIS SCALP HAIR, SO COMPLETE ESSENTIALLY COMPLETE RESPONSE. THIS GENTLEMAN ALSO NICE RESPONSE, THIS IS SHOWN IN SERIES HERE BECAUSE YOU CAN SEE HIS HAIR IS COMING BACK IN GRAY, HERE ON TOP BUT HE DID MEET OUR END POINT AND IF YOU’RE LOOKING CAREFULLY, THE DERMATOLOGISTS IN THE ROOM ARE NOTICING HIS FOREHEAD IS ALSO REPIGMENTING, SO THIS GENTLEMAN HAD — AS WELL AS ALOPECIA AREATA, CAME TO US FROM JOHN HARRIS’ GROUP AND HIS VINILIGO ALSO RESPONDED WELL TO TREATMENT WITH RUXO. WE KNOW FROM JOHN’S WORK THAT THE SAME TYPE OF IMMUNE INFILTRATE IS SIMILAR AND YOU CAN SEE IT RESPONDING. SO THE HAIRLINE IN ALOPECIA IS VERY DIFFICULT TO REGROW. HERE YOU SEE NICE FILLING IN OF THAT HAIRLINE. HERE’S A PATIENT AGAIN ESSENTIALLY COMPLETE ALOPECIA TOTALIS AFTER SIX MONTHS. THIS IS OUR SLOWER RESPONDER SO AT BASELINE AND EVENTUALLY CAUGHT UP TO MEET OUR END POINT OF MORE THAN 50% AND HERE’S ANOTHER EXAMPLE JUST SHOWING FROM THE SIDE, AGAIN A NICE RESPONSE AFTER SIX MONTHS. SO THIS GENTLEMAN HAD AGAIN LONG STANDING ALOPECIA UNIVERSEALIS FOR A VERY LONG TIME AND HAD COMPLETE REGROWTH. SO THE — WE DON’T HAVE A CLEAR UNIFYING HYPOTHESIS YET. ONE OF THEM ALSO FAILED INTRALESIONAL STEROIDS, ANOTHER HAD BIOPSY PROVEN ALOPECIA BUT ALSO HAD SOME FEMALE PATTERN HAIR LOSS AND ANOTHER ALSO HAD MALE PATTERN HAIR LOSS BUT ALSO CLEARLY AA SO WE’RE NOT SURE EXACTLY WHAT WENT ON HERE. ALL THREE OF THEM HAPPEN TO BE FROM AFRICAN-AMERICAN OR HISPANIC DESCENT BUT I THINK THAT’S A COINCIDENCE BECAUSE A LOT OF OUR RESPONDERS ARE FROM THOSE GROUPS. SO THIS IS AT BASELINE, THIS LOOKS LIKE REGROWTH BUT HE SIMPLY DIDN’T SHAVE IN THIS PICTURE SO IT’S ACTUALLY NO CHANGE FROM BASELINE. HERE’S ANOTHER ONE, BASELINE, THEN 16 WEEKS. NO CHANGE AGAIN. THIS PATTERN MIGHT BE A LITTLE DIFFERENT THIS, IS A MORE DIFFUSE TYPE. THEN FINALLY THIS PATIENT IS THE ONE WHO HAD FAILED STEROIDS, AND THIS IS THE OPHIASIS PATTERN THAT SURROUNDS THE HAIRLINE, A VERY CHALLENGING PATTERN TO GET TO RE-GROW. SO THIS IS THEIR SALT SCORE SO AT BASELINE AGAIN UP TO 100% HAIR LOSS, SO THE HAIR LOSS SCORE GOES DOWN. THIS DASHED LINE IS AFTER WE STOPPED TREATMENT, THIS IS THE OTHER WAY, THIS IS PERCENT REGROWTH OVER TIME. SO THIS IS THE HAIR RETURNING, THIS IS AT THE END OF THE TREATMENT PERIOD, THEN THE DASHED LINES INDICATE THE RELAPSE AFTER TREATMENT STOPPED AND HERE’S SOME OF THE NON-RESPONDERS DOWN HERE. SO RELAPSES ARE COMMON, THEY OCCUR BETWEEN TWO AND THREE MONTHS IF YOU WILL AFTER THE TREATMENT HAS ENDED. IT CAN BE SEVERE, IT CAN GO BACK TO BASELINE, SOME SOME REPORT
MILD SHED BUG NOT TOTALLY SIGNIFICANT. ADVERSE EVENTS IN OUR PATIENTS IN THIS STUDY WERE ESSENTIALLY MILD TO NON-EXISTENT. NONE OF THE THINGS THAT WE WERE AFRAID OF LOOKING OUT FOR REALLY SHOWED UP HERE. ONE PATIENT DROPPED THEIR HEMOGLOBIN JUST A LITTLE BIT, WE ADJUSTED THE DOSE AND IT RECOVERED ON ITS OWN. SO FOR THE BIOMARKERS, AGAIN WE WANTED TO LOOK AND SEE IF WE COULD NOTICE THE RESPONSE TO TREATMENT EVEN BEFORE THE HAIR WAS GROWING BACK. SO HERE’S OUR TWO EXAMPLE PATIENTS AT BASELINE, SO THE RED BEGIN GWEN VERY HIGH INTERFERON SCORES AND ESSENTIALLY NO HAIR SIGNATURE. IF WE COMPARE THOSE TO THE THREE NORMALS HERE ON THE RIGHT, AGAIN, LOW IMMUNE INFILTRATES AND A LOT OF HAIR. THIS WAS THEM AFTER 12 WEEKS. SO YOU CAN SEE THE IMMUNE INFILTRATE IS LARGELY RESOLVED AND THE HAIR HAS BEGUN TO RECOVER, AND IF WE LOOK AT OUR BIOMARKERS, THESE ARE BEFORE TREATMENT AND THESE ARE AFTER TREATMENT, AND WE’VE SEEN A NICE CORRECTION OF OUR MARKERS AND THE BLACK AGAIN INDICATES THAT THESE HAIRS HAVE GONE BACK INTO THEIR GROWTH PHASE. SO IF WE EXPAND THAT TO LOOK AT THE WHOLE COHORT, THOOS ARE OUR RUXO RESPONDERS IN THE MIDDLE SO THESE ARE NINE RESPONDERS AT TIME ZERO, HERE THEY ARE AFTER 12 WEEKS. SO AGAIN AT BASELINE, A HIGH IMMUNE SIGNATURE, NOT MUCH HAIR, THEN AFTER TREATMENT, A MUCH LOWER IMMUNE SCORE AND THE RED INDICATES THE RETURN OF THEIR HAIR MUCH LIKE THESE CONTROLS. BUT HERE’S TWO NON-RESPONDERS. SO INTERESTINGLY, I THINK THESE TWO NON-RESPONDERS ACTUALLY DID NOT HAVE A STRONG INTERFERON GAMMA SCORE OR CYTOTOXIC — SCORE AT BASELINE SO THIS GIVES US A HINT, I THINK, THAT SOMETHING MUST BE GOING ON WITH THESE NON-RESPONDERS THAT’S DIFFERENT, THEY EITHER HAVE A DIFFERENT FORM OF ALOPECIA AREATA OR THE FORM THAT THEY HAVE IS DRIVEN BY A DIFFERENT SET OF CYTOKINES BUT AS WE GET MORE AND MORE OF THESE COLLECTED, I THINK THIS WILL BE INFORMATIVE FOR US TO — HOW TO APPROACH THESE IN THE FUTURE. SO HERE’S AGAIN OUR RESPONDERS AT BASELINE AND OUR RESPONDERS IN PURPLE AFTER 12 WEEKS, AND THEN THE NON-RESPONDERS IN BLUE BEFORE TREATMENT, AND IN YELLOW AFTER TREATMENT, AGAIN SHOWING NOT MUCH CHANGE IN THEIR MOLECULAR SIGNATURE. SO JUST VERY BRIEFLY, THE TOFA STUDY, SIMILAR, 12 PATIENTS, THIS TIME SIX MODERATE TO SEVERE AND SIX SEVERE. WE HAD TO ESCALATE OUR DOSE FROM 5 MILLIGRAMS BID TO 10, AND YOU’LL SEE HOW THAT PLAYED OUT DURING THE STUDY. AGAIN THE SAME MONITORING WAS DONE FOR ALL. SO HERE’S A PATIENT AT BASELINE AND HERE’S WEEK 40. SO THESE ARE LONGER. THE NUMBERS ON THE BOTTOM ARE HOW LONG THEY SPENT AT THE LOW DOSE, SO FIVE MONTHS AT THE LOW DOSE, TWO MONTHS AT A MEDIUM DOSE, AND THREE MONTHS AT THE HIGHEST DOSE BEFORE GOING DOWN IN A SALT SCORE FROM 100% TO 39%, SO THE STEP WISE ESCALATION IN THEIR DOSE. AGAIN, FIVE MONTHS AT LOW DOSE, TWO MONTHS AT MEDIUM DOSE, TWO MONTHS AT HIGH DOSE, AND AS YOU PUSH THE DOSE, THEY BEGIN TO GET A STRONGER RESPONSE. HERE’S ANOTHER ONE EVENTUALLY CAUGHT UP AND IS FILLED IN. THIS WAS OUR ONLY PATIENT WHO RESPONDED COMPLETELY ONLY AT THE LOW DOSE, SO SHE ONLY GOT 5 MILLIGRAMS BID FOR SIX MONTHS AND HAD A FULL RESPONSE. THIS IS WHAT THE TIME COURSE LOOKS LIKE, SO YOU CAN SEE THE HAIR IS ACTUALLY BEGINNING TO FILL IN DURING THE COURSE OF TREATMENT. AND IN THESE PATIENTS, AGAIN, GROWING THE FAISHT HAIR FACIAL
HAIR IS VER
Y DIFFICULT AND HERE YOU CAN SEE THE EYELASHES AND EYEBROWS AS WELL AS THE FRONTAL HAIRLINE. SO THE SAME IS TRUE FOR OUR BIOMARKER, THEY WORKED VERY WELL IN SORT OF PREDICTING HOW THESE PATIENTS WOULD RESPOND. HERE WE’RE JUST — RUXO FOR COMPARISON IN THIS LANE, AND AFTER TREATMENT, AND HERE’S A TOFA. BUT THE DIFFERENCE HERE IS THAT THIS TOFA STUDY WAS DONE AT FOUR WEEKS SO ALREADY YOU CAN BEGIN TO SEE IN FOUR WEEKS THAT THESE PATIENTS ARE BEGINNING TO HAVE A MOLECULAR RESPONSE VERY, VERY EARLY, SO THAT MEANS IF WE TESTED EARLY, WE BEGIN TO MAYBE PICK UP A RESPONSE SIGNATURE AND NOW THEY WOULD EITHER, A, RESPONDS TO THE DRUG AT ALL, B, WOULD THEIR DOSE HAVE TO BE ESCALATED OR C, IF THEY’RE NOT RESPONDING, TO SWITCH THEM TO SOMETHING ELSE. AND HERE YOU JUST SEE THAT WE CAN GIP TO BEGIN TO TRACK THIS
IN SERUM SO THIS IS A FOUR-WEEK TREATMENT LOOKING AT CLCX10 IN SERUM, SO WE’D LIKE TO BEGIN TO MOVE THIS TO A NONINVASIVE MARKER WHERE WE COULD TRACK IMMEDIATE AND EARLY RESPONSE AND FINALLY WE’VE GONE ON TO DO THIS NOW FOR THE ENTIRE SERIES LOOKING FROM TIME ZERO TO TIME FOUR WEEK TO TIME 12 WEEK AND THIS IS NORMAL SCALP ON THE RIGHT SO YOU CAN SEE THE BLUE CHANGING AND CHANGING OVER SO THAT AFTER 12 WEEKS IT BEGINS TO LOOK VERY MUCH LIKE NORMAL SCALP. SO AGAIN, SALT SCORES OVER TIME, AGAIN, THIS WAS THE DOSE ESCALATION SO THEY LOOK FLAT UNTIL WE CHANGE THE DOSE AND THEN THEY TEND TO RESPOND. HERE’S THE ONE THAT RESPONDED AT LOW DOSE. AGAIN, THE OTHER WAY AROUND, THIS IS REGROWTH SO THAT’S THE PATIENT WHO RESPONDED AT LOW DOSE, THE REST OF THEM REQUIRED DOSE ESCALATION AROUND HERE BEFORE THEY EFFICIENTLY CAUGHT
EVENTUALLY
CAUGHT UP. SO WE’RE NOT TOTALLY SURE WHAT’S DRIVING THAT DOSE ESCALATION BUT WE DO HAVE SOME HYPOTHESIS. SO AGAIN NO SERIOUS ADVERSE EVENTS REALLY IN THIS STUDY. ONE PATIENT HAD A LITTLE BIT OF HYPERTENSION, ONE PATIENT HAD INCREASED ALCOHOL INTAKE AND SO HER LIVER FUNCTION WAS A LITTLE BIT OUT OF LINE AND SOME PATIENTS HAVE A FEW G.I. PROBLEMS. ALMOST ALL OF OUR PATIENTS REPORT WEIGHT GAIN, BUT SOME OF THEM SAY THAT THEY’RE JUST VERY HAPPY TO BE OUT IN THE WORLD WITHOUT THEIR WIGS OR WITHOUT THEIR HATS AND THEY’RE JUST FEELING BETTER AND SOCIAL. SO JUST OUR STATISTICS, AND JUST TO SAY THAT NOW MANY OTHER CENTERS ARE USING THESE DRUGS IN THEIR PATIENTS, SO YALE HAS DONE SEVERAL HUNDRED PATIENTS, STANFORD IS OVER A HUNDRED, AND WHAT’S INTERESTING IS, THE RESPONSE RATE IS VERY CONSISTENT ACROSS THE DIFFERENT GROUPS THAT ARE USING THESE DRUGS, SO 65, 70, 75% RESPONSE IS NOT UNCOMMON. AND SO AGAIN, THE NEXT STEP HERE WOULD BE TO DO A PROPER PLACEBO CONTROLLED STUDY AND I HOPE THAT THAT WILL BE ON THE RADAR FOR ONE OF THE GROUPS IN THE FUTURE. SO JUST AS A COMPARATOR ABOUT THE DOSING FOR TOFACITINIB, PFIZER’S OWN STUDY IN 2015 ALSO SHOWED THIS DIFFERENCE THAT WHEN TOFA IS GIVEN AT LOW DOSE TWICE A DAY, ONLY ABOUT 40% OF PSORIASIS PATIENTS RESPOND AND THAT IF YOU TAKE IT TO 10 MILLIGRAMS TWICE A DAY, IT GOES UP TO ABOUT 60% OR GREATER, SO THIS IS PRETTY SIMILAR, I THINK, TO WHAT WE’RE SEEING IN ALOPECIA AREATA SO MAYBE SUGGESTING THAT MORE OF A DOSE IS NEEDED TO GET THIS DRUG INTO THE SKIN AND MAYBE A HIGHER LOCAL CONCENTRATION IN THE SCALP OR SKIN IS NEEDED TO TARGET SOME OF OUR DISORDER. SO THIS IS FROM ONE OF MY FAVORITE REVIEWS WRITTEN BY JOHN O’SHEA AND HIS TEAM HERE, AND SO THIS REALLY IS SAYING FOR THE FUTURE, WHAT’S THE THINKING IN THE FIELD, AND I THINK UP TO NOW, WE’VE TALKED ABOUT PAN JAK INHIBITORS, ONE THAT TARGET JAK 1, 2 AND 3 TOGETHER LIKE TOFA, SO THE IDEA I THINK FOR THE FUTURE IS TO TRY AND FIND MORE AND MORE SPECIFIC AND SELECTIVE ISOFORMS AND FIGURE OUT IF POSSIBLE WHICH OF THESE JAK INHIBITORS IS CONTROLLING WHICH PART OF DISEASE, AND AGAIN, THE THINKING MAY COME THAT SPECIFIC IS BETTER, BUT PERHAPS AS JOHN AND I TALKED ABOUT THIS MORNING, MAYBE FOR THE EARLY STAGES OF DISEASE, HAVING SOMETHING THAT COVERS BROADLY ACROSS MANY OF THE CYTOKINE PATHWAYS MIGHT BE USEFUL BECAUSE I DON’T THINK THAT IL-15 AND INTERFERON GAMMA ARE THE WHOLE STORY FOR ALOPECIA AREATA, CERTAINLY NOT, AND MORE WORK TO BE DONE THERE. SO JUST IN THE LAST TWO MINUTES, I’LL JUST SHARE A LITTLE BIT OF UNPUBLISHED DATA, JUST TO SAY WE’VE BEEN THINKING A LOT ABOUT THE YES. TICS BUT THE JE HE? TICS BUT ALSO THE ENVIRONMENTAL FACTOR, SO GIVEN ALL THE EXCITEMENT ABOUT — A ROLE FOR MICROBIOME SO DON’T THINK I NEED TO TALK ABOUT HOW IMPORTANT THIS HAS BECOME, THERE’S A HUGE EFFORT HERE ON CAMPUS, AGAIN, SOME OF THE GREAT STUDIES IN THIS FIELD IN SKIN HAVE COME FROM HERE, FROM JEWIAN AND OTHERS, MICROBIOME IN SKIN, PARTICULARLY IN SOME OF THE AUTOIMMUNE DISEASES LIKE R.A., DIFFERENT MICROORGANISMS AGAIN ARE NOW SHOWING UP AS BEING OVERREPRESENTED IN PATIENTS AT LEAST IN R.A. AT THE ONSET OF DISEASE, AND SO WE’VE BEGUN TO SORT OF AGAIN MODEL OUR WORK, OUR THINKING AFTER THE WORK OF DAN LITMAN AND OTHERS WHO HAVE ALREADY PAVED THIS PATH FOR RHEUMATOID ARTHRITIS SO WE’VE JUST DONE A COUPLE VERY SIMPLE SPAISHTS BUT BASICALLY WE JUST WANTED TO ASK IF WE COULD MANIPULATE THE MICROBIOME AND SEE IF WE COULD GET AN EFFECT ON ALOPECIA AREATA. SO WE USED OUR SKIN GRAFT MODEL AND WE GAVE THE CONVENTIONAL ANTIBIOTIC COCKTAIL THAT’S USED TO DEPLETE THE MICROBIOME, PRIMARILY IN THE GUT, AND SO WHEN WE DO THAT, WE TREAT OUR MICE BEFORE GRAFTING AND KEEP GOING. THIS WAS ABOUT TWO MONTHS AFTER GRAFTING, AND THE CONTROL MICE ARE LOSING THEIR HAIR RIGHT ON TIME, BUT THE ANTIBIOTIC-TREATED MICE RETAIN THEIR HAIR, AND THIS IS THE COCKTAIL AGAIN, USED IN MANY OF THE MICROBIOME STUDIES. SO WE PUSHED IT FURTHER SO NOW THIS IS ABOUT FOUR MONTHS AFTER GRAFTING, THE UNTREATED MICE HAVE LOST THEIR HAIR AND THE ANTIBIOTIC TREATED MICE STILL HAVEN’T LOST THEIR HAIR. SO WE’VE DONE THIS NOW A NUMBER OF TIMES OVER RELATIVELY CONFIDENT THAT THERE’S AN EFFECT HERE, A TON MORE WORK TO BE DONE. WE’VE SEQUENCED THE SKIN MICROBIOME FROM THESE TREATED MICE AND WE DON’T SEE ANY DIFFERENCE IN THEIR SKIN AND WE’VE NOW BEGUN TO WORK THROUGH THEIR GUT MICROBIOME TO UNDERSTAND IF, IN FACT, THIS EFFECT MAY BE COMING FROM THE GUT. SO AGAIN HERE’S OUR CONTROLS, HERE’S OUR TREATMENTS AND AFTER GIVING THOSE ANTIBIOTICS, THE TREATED MICE AGAIN RETAIN THEIR HAIR IN 100% OF CASES. SO MORE WORK TO BE DONE. IS IT SKIN, IS IT GUT, IS IT BOTH? HOW DOES THIS WORK? IS IT PRIMING AT A DISTANT SITE? THIS IS JUST THE BEGINNING OF THE STORY, BUT I JUST WANTED TO GIVE YOU A LITTLE FLAVOR OF EXCITEMENT FOR SOME OF THE WORK THAT WE’RE NOW DOING TO TRY AND COMBINE OUR GENETICS WORK WITH BOTH NEW TREATMENTS AND ALSO NEW WAYS OF LOOKING AT THE ENVIRONMENTAL EFFECTS. SO I’LL CLOSE BY JUST SAYING THAT IT’S BEEN A REALLY EXCITING COUPLE OF YEARS FOR JAK INHIBITORS IN SKIN, AND HERE’S JUST SOME OF THE EXAMPLES OF CASES THAT HAVE COME IN THE LITERATURE IN THE PAST FEW YEARS. ESPECIALLY THIS CANDLE SYNDROME STUDY THAT’S ONGOING HERE AT THE NIH. I LEARNED TODAY FROM ED ABOUT GRAPH VERSUS HOST DISEASE WHICH I DIDN’T KNOW AT ALL, SO THIS IS OUR WORK ON ALOPECIA AREATA AND I THINK IN THE HAIR FIELD, THIS WORK IS NOW EXPANDING INTO OTHER FORMS OF INFLAMMATORY ALOPECIA INCLUDING THE SCARRING ALOPECIAS THAT ALSO HAVE NO SUITABLE TREATMENTS AT THE MOMENT, ARE EVEN LESS WELL UNDERSTOOD THAN ALOPECIA AREATA, BUT BECAUSE OF SOME OF THE EARLY WORK FROM OTHERS IN THE FIELD, RALPH AND HIS COLLEAGUES ESPECIALLY, HAVE BEGUN TO DEFINE THIS EARLY IMMUNE INFILTRATE, SUGGESTING THAT A JACK INHIBITOR MIGHT WORK HERE TOO AND WE HAVE SOME DATA NOW THAT WILL BE PRESENTED AT THE SID MEETING ABOUT THIS, SUGGESTING THAT AGAIN THESE DRUGS MAY HAVE A BROADER USE IN THE FIELD. SO THIS IS JUST A SUMMARY OF EVERYTHING WE’VE TESTED IN THE ALOPECIA AREATA MOUSE MODEL. THE ONES IN GREEN HAVE I THINK MADE IT ALL THE WAY INTO HUMAN CLINICAL PROOF OF CONCEPT. WE HAVE AGAIN 12 PATIENTS WITH RUXO, THERE’S ONE CASE REPORT OF RUXO TOPICAL — ONE PATIENT HERE IN THE NIH CANDLE STUDY WHO HAD ALOPECIA AREATA WITH RAH FEEL AND RECOVERED THEIR ALOPECIA AREATA. TOFA, THIS IS NOW WELL OVER SEVERAL HUNDRED, AGAIN AS SOME OF THESE ADVANCE HOPEFULLY INTO THE CLINIC, THIS HUMAN SIDE OF THE TABLE WILL FILL OUT MORE. SO AGAIN, MORE WORK TO BE DONE BUT JUST A SORT OF OVERVIEW OF HOW THINGS ARE LOOKING. SO I THINK COMING BACK FULL CIRCLE, HISTORICALLY CLINICAL TRIALS IN ALOPECIA REALLY HAVE BEEN SORT OF, IF LU, ONE OFF STUDIES, REPURPOSING STUDIES FROM PSORIASIS DRUGS MAINLY, AND THESE HAVE BEEN PARTICULARLY UNFRUITFUL FOR ALOPECIA AREATA, AND I THINK NOW THAT WE UNDERSTAND THE GENETICS AND A BIT ABOUT THE IMMUNOLOGY, WE CAN SEE WHY. THERE’S NOT MUCH OVERLAP IN THE PATHWAYS THAT ARE INVOLVED IN BOTH DISEASES, AND SO I’M VERY GRATIFIED THAT AFTER SUCH A SHORT TIME REALLY OF THIS WORK COMING OUT, THAT THERE’S BEEN A TREMENDOUS UPTAKE OF INTEREST ON THE PART OF THE PHARMACEUTICAL PARTNERS TO BRING THESE DRUGS INTO STUDIES, SPECIFICALLY FOR ALOPECIA AREATA, AND THAT REALLY IS A CHANGE IN THE WAY THAT THIS DISEASE HAS BEEN STUDIED IN THE PAST. THIS IS THE FIRST TIME HISTORICALLY THAT ANY OF THESE FOLKS HAVE TAKEN AN INTEREST IN ALOPECIA FOR ITS OWN SAKE AND NOT AS A SECOND INDICATION FOR A PSORIASIS DRUG, SO I’M EXTREMELY ENCOURAGED BY ALL OF THIS ACTIVITY. THERE’S INTEREST IN TOPICAL DRUGS, THERE’S INTEREST IN ORAL DRUGS, THERE’S PAN JAKS, THERE’S SINGLE ISOFORMS. I THINK THIS IS GOING TO BE A REALLY EXCITING SPACE. AND HOPEFULLY ONE THAT WILL LEAD TO AN APPROVAL FOR THIS INDICATION SOMETIME IN THE FUTURE. SO I’LL JUST CLOSE BY SAYING A WORD OF THANKS BEING HERE AT THE NIH. OUR WORK HAS BEEN SUPPORTED BY NIAMS FROM THE BEGINNING, STARTING WITH THE FOUNDING OF THE AA REGISTRY IN 2001, EVEN BEFORE THAT FOR ME PERSONALLY, BUT THIS IS REALLY THE TIMELINE OF WORK THAT’S GONE ON LARGELY AGAIN SUPPORTED AT DIFFERENT TIMES BY NIAMS, HERE’S OUR CONTRACT, HERE’S OUR INITIAL R21, HERE’S OUR UO1, FINALLY MUCH MORE RECENTLY, OUR CENTER GRANT WHICH JUST STARTED, AND THEN ON THE BOTTOM, THIS IS AGAIN THE CLINICAL TIMELINE, BUT THIS IS REALLY LOBBIED BACK AND FORTH BETWEEN LAB FINDINGS AND MOVING THEM INTO THE CLINIC, AND I THINK AGAIN WITHOUT MY EXTREMELY WONDERFUL COLLEAGUES AT COLUMBIA, THIS WOULD NOT HAVE COME TO PASS AND WE’VE HAD TREMENDOUS FOUNDATION SUPPORT FROM NAF AND ALSO THE LOCKS OF LOVE FOUNDATION THAT HAVE REALLY HELPED AGAIN JUMP START SOME OF THOSE EARLY STUDIES. RIGHT NOW IN 2016, AT LEAST, THIS HAS BEEN A MILESTONE FOR US, SO JUST THIS PAST FALL, OUR TEAM AT COLUMBIA HAS BEEN GRANTED A P50 GRANT FROM NIAMS AND THIS IS THE FIRST OF ITS KIND IN ALOPECIA AREATA CENTER FOR RESEARCH TRANSLATION AND WE COULDN’T BE MORE HONORED AND MORE PROUD TO BE BRINGING THIS WORK FORWARD. SO I PUT THIS SLIDE IN FOR DR. COLLINS, I HOPE THAT HE’LL SEE IT AT SOME POINT. THIS IS FROM A REVIEW THAT HE WROTE IN 2011 WHERE HE WAS TALKING ABOUT THE POTENTIAL FOR GENOME WIDE ASSOCIATION STUDIES TO UNCOVER NEW DRUG TARGETS, AND YOU CAN SEE AGAIN MANY OF THESE DISEASES WERE WELL AHEAD OF US WITH THEIR NUMBER OF GWAS HITS AND THE NUMBER OF DRUGS THAT REALLY WERE ASSOCIAED AND THAT HAVE COME THROUGH THE PIPELINE. SO I ADDED ALOPECIA TO THIS, AND EVEN WITH OUR EIGHT LITTLE GENES AT THE BEGINNING, THREE OF THOSE TURNED OUT TO BE FRUITFUL IN IDENTIFYING DRUG TARGETS. I DIDN’T TALK ABOUT ABATACREPT TODAY BUT I HOPE HE KNOWS ALOPECIA CAN TAKE ITS PLACE IN THIS TYPE OF STUDY AND BE A SUCCESS STORE O.A.R. FOE USING GENETICS TO TAKE AN UNBIASED LOOK AT A DISEASE AND BRING A NEW UNDERSTANDING TOGETHER WITH IMMUNOLOGY COLLEAGUES, CLINICAL SCIENTISTS AND HOPEFULLY SOMEDAY GET NEW APPROVALS. SO I’LL STOP AND JUST ACKNOWLEDGE AGAIN MY TWO INCREDIBLE COLLEAGUES, MY TEAM IN THE LAB THAT HAS GROWN AND CHANGED OVER THE YEARS, ESPECIALLY THESE FOLKS WHO HAVE TAKEN THE LEAD ON MANY OF THESE PROJECTS, AND ESPECIALLY AGAIN NIAMS AND SOME OF OUR OTHER SUPPORTERS FOR BELIEVING IN US AND ALLOWING US TO BRING THIS FORWARD. THANK YOU FOR HAVING ME. [APPLAUE]>>WE HAVE TIME FOR A COUPLE OF QUESTIONS.>>YES. I NOTICE UNDER THE AUTOIMMUNE DISEASES YOU DIDN’T MENTION GRAPH VERSUS HOST DISEASE IN TERMS OF DERMATOPATHOLOGY, YOU HAVE SOMETHING CALLED SAT LIE PTOSIS WHICH GOES AROUND TO SINGLE KERATIN SITE AS IT DIE, SO YOU CAN DISTINGUISH IT FROM ERYTHEMA MULTIFORUM. IT’S BEEN A LONG TIME SINCE I’VE LOOKED AT GRAPH VERSUS HOST DISEASE BUT IT CAN BE CONSIDERED IN ITS CHRONIC FORM MORE OF AN AUTOIMMUNE DISEASE. DO THEY HAVE THIS CONDITION AND WOULD THIS BE HELPFUL IN THAT CONDITION IN GRAPH VERSUS HOST DISEASE SECONDARY TO BONE MARROW TRANSPLANTATION?>>IS ED HERE? WOULD YOU LIKE TO? PLEASE. I’M NOT AN EXPERT BUT THE WORLD EXPERT IS HERE.>>SO THERE’S A LOT OF INTEREST IN ORAL AGENTS AND RUXO IS OFF LABEL FOR THE REASONS YOU SAY, AND THE SUCCESS RATE AT LEAST IN SOME OF THE PRELIMINARY TRIALS IS ON THE ORDER OF 50 TO 60%.>>FASCINATING TALK AS ALWAYS, ANGELA. SO WE TALKED ABOUT — EARLIER TODAY, I’M WONDERING ABOUT THE RELATIVE CONTRIBUTION OF CD4CD8 CELLS IN ALOPECIA AREATA MAINLY BECAUSE ALTHOUGH YOU SEE THAT GAMMA SIGNATURE, RIGHT, YOU DON’T REALLY SEE APOPTOSIS OF THE CARE SITES. AND THEN YOU SHOWED THE BEAUTIFUL IMAGE OF CD4 ILL FILTRATION INTO THE HAIR FOLLICLE, SO I’M WONDERING IF GAT MA SIGNATURE COULD BE ACTUALLY FROM CD4 T-CELLS, WONDERING WHETHER OR NOT YOU PHENOTYPED THOSE CD4 T-CELLS THAT INFILTRATE INTO THE HAIR FOLLICLES.>>IT’S A GREAT QUESTION. IT’S ONE THAT WE GET ALL THE TIME IS WHY DOES OUR MH CLASS 2 GENETICS SIGNAL AND OUR EFFECTORS ARE CD8. SO MY BEST ANSWER IS AT THIS POINT IS THAT I HOPE IT’S GOING TO TURN OUT LIKE CELIAC DISEASE, WHERE WE HAVE A SORT OF PRIMARYISH ROLE OF THE CD4 CELLS AND THEN THE EFFECTORS MAYBE BEING LESS SPECIFIC, IF YOU WILL, SO WE HAVEN’T DONE ANY OF THAT WORK YET, WE’RE JUST GETTING BACK TO DOING THE CD4 CELLS, BUT JUST TO SAY THAT THE SAME CONUNDRUM EXISTS IN PSORIASIS, SO THEIR MAIN GENETIC SIGNAL IS — 1 EVEN THOUGH A LOT OF THEIR EFFECT COMES DIFFERENTLY, SO I DON’T KNOW YET WHAT IT MEANS, BUT I WILL SAY IT’S NOT UNCOMMON AND IT DOES MIMIC WHAT’S SEEN IN CELIAC. SO WE’VE GOT A TON OF WORK TO DO. WE HAVEN’T PHENOTYPED THEM YET. WE KNOW THAT OUR CD WILL CELLS ARE EXPRESSING A LOT OF GAMMA BUT WE HAVEN’T YET STARTED DIGGING INTO THE CD4s.>>AND THE CD4 IS NOT INFILTRATING IN THE MOUSE MODEL?>>YES, THEY ARE.>>OKAY. THAT’S GOOD. THANK YOU.>>HI, I JUST WANTED TO SAY YOUR WORK VEILY COOL AND ALSO YOU MENTIONED IN THE BEGINNING THAT WHITE HAIRS DON’T FALL OUT AND I WAS WONDERING IF YOU THOUGHT THAT MAYBE THE LA KNOW SITES ARE SOMEHOW PROTECTIVE OR ARE THEY BEING SACRIFICED INSTEAD OF THE HAIR FALLING OUT OR –>>THAT’S A GREAT QUESTION. SO HISTORICALLY, IN THE DETERMINE DERM LITERATURE, YOU’LL SEE SUDDEN WHITENING OF THE HAIR, ONLY THE WHITE HAIRS STAY BEHIND, AND THAT’S THOUGHT TO BE SORT OF AN ACUTE ONSET OF ALOPECIA AREATA, SO WE DON’T KNOW WHY THEY SPECIFICALLY TARGET THOSE PIGMENTED HAIRS EXCEPT THAT THERE’S BEEN THINKING IN THE FIELD FOR A LONG TIME THAT IT MUST BE OR SHOULD BE A ME LA KNOW SITE ANTIGEN THAT COULD BE ONE OF THE PRECIP TANTS, SO THERE’S BEEN REPORTS OVER TIME ABOUT WHAT SOME OF THOSE ANTIGENS MIGHT BE, BUT DURING NORMAL REMODELS OF THE HAIR, WHEN HAIR NORMALLY GOES THROUGH — THE ME LA KNOW CITES ACTUALLY EITHER GET APOP TOIZED AND/OR YOU A TO HAVE JIEZED WHICH IS BECOMING ANOTHER MAJOR PATHWAY IN ALOPECIA AREATA, THEY UNDERGO A CONTROLLED INVOLUTION, IF YOU WILL, AND REGRESSION, SO IF SOMETHING GOES WRONG THERE AND THOSE ME LA KNOW CYTE ANTIGENS AS WELL AS SOME OF THE REST OF THE HAIR SHAFT ANTIGENS GET EXPOSED DURING THAT NORMAL CATAGEN, THERE’S SOME DEREGULATION, IT’S POSSIBLE THAT THAT COULD BE ONE OF THE UPSTREAK TRIGGERS. ALSO WORKS IN REVERSE, WHEN THE HAIR BEGINS TO RECOVER FROM ALOPECIA AREATA, WHEN IT FIRST GROWS BACK, IT TENDS TO BE CLEAR OR WHITE, AND THEN EVENTUALLY THE PIGMENT SORT OF REDEPOSITS — THE FIRST TO GO AND THE LAST TO RECOVER IN SOME WAY. SO A LOT TO BE DONE STILL, BUT ONE OF OUR CANDIDATES — ANOTHER ONE THAT’S UNIQUE TO ALOPECIA AREATA ON THE HAIR FOLLICLES, INVOLVED IN PIGMENTATION AND MELANOSOME YOU A TO AUTOPHAGY
DURING PIGMENTATION, IT CAUSES THE LOSS OF PIGMENT IN HORSE, LIPAZAANER HORSES — CAUSES THEIR COAT TO CHANGE GRAY COLOR, SO THAT’S OUR BEST — WE’RE ACTIVELY TRYING TO WORK ON THAT AS WELL.>>THANK YOU.>>SURE.>>I THINK YOUR WORK VEILY COOL TOO. SO I WAS THINKING THE ONE DRUG YOU DIDN’T MENTION WAS OWE CLA SIT ANYBODY, AND THE ONE THING I HEARD IS THAT’S MORE LIPOPHILIC, WONDERING IF IT MIGHT HAVE ADVANTAGES FOR SKIN DISEASE AND THAT SORT OF THING, BUT COUNTERING THAT, WHEN YOU DID YOUR QUADRUPLE ANTIBIOTIC EXPERIMENT, THAT — DO YOU THINK IT’S THE THE LESIONAL CELLS, AND WOULD DIFFERENT TYPES OF JA KMENT INHIBITORS MAKE A DIFFERENCE IN TERMS OF EFFICACY?>>THAT’S FANTASTIC. SO WE HAVE USED THE DOGGY JAK THANKS TO YOU AND IT WORKS WONDERFULLY IN THE MODEL SO IT WORKS GREAT TOPICALLY AS WELL AS SYSTEMICALLY. SOME OF THEM ARE ACTUALLY HARDER FOR US TO WORK WITH TOPICALLY SO SOME ARE LESS FRIENDLY, THAT ONE IS VERY FRIENDLY TOPICALLY, SO IT HAS A VERY NICE PENETRATION AND IT WORKS VERY WELL IN BOTH CONTEXTS. FOR THE TRAFFICKING EXPERIMENT FOR THE GUT PRIMING, THIS AGAIN, WE’RE JUST AT THE BEGINNING OF THIS, BUT WE DID TRY TO UTE FILGOTANIB AS WELL IN THE DIFFERENT SETTING AND WE HAD NO LUCK BASICALLY, IT WAS VERY INSOLUBLE, KIND OF DIFFICULT FOR US TO WORK WITH. SO WE HAVEN’T TRIED YET ANY DRUGS TO BLOCK TRAFFICKING TO TRY AND INTERFERE WITH ANY OF THAT. I DON’T HAVE A GUESS, MAYBE YOU DO, ABOUT WHICH ONE OF THE JAKS MIGHT BE THE BEST TO THINK ABOUT THERE, BUT I HOPE THAT ONCE WE GET THE MICROBIOME STORY DEVELOPED, THAT WE CAN FIND SOME INTERSECTION BETWEEN THAT AND USING INHIBITORS THAT WILL GIVE US AGAIN A LITTLE MORE INSIGHT. NOTHING YET.>>CAN I HAVE LAST QUESTION?>>THERE’S GOING TO AB RECEPTION IN THE LIBRARY, SO WHOEVER WANTS TO JOIN ANGELA, YOU’RE MORE THAN WELCOME.>>OKAY.>>THANKS.>>OKAY. SO I UNDERSTAND YOUR RATIONALE OF STARTING WITH THE FDA APPROVED DOSE OF TOFA AND THEN GOING UP TO 10 MILLIGRAM TWICE A DAY. HOW ABOUT INSTEAD STARTING WITH 10 MILLIGRAM TWICE A DAY AND THEN MAINTAINING 5 MILLIGRAM ONCE A DAY SO THAT KIND OF DIMINISH POSSIBLE SIDE EFFECTS, HAVE YOU THOUGHT ABOUT DOING THAT? HAVE YOU TRIED TO DO THAT AT ALL?>>SO MANY OF THE SITES ARE DOING EXACTLY THAT. THEY’RE STARTING WITH 10, SOME EVEN HIGHER, 15, AND SORT OF THE THINKING IS TO GIVE THE HIGHEST DOSE FIRST, GET THINGS UNDER CONTROL, AND THEN MOVE TO A LOWER DOSE. SO THE LOWER DOSE IN MOST CASES HAS GONE TO 5 BID. SOME PATIENTS HAVE FLARED EVEN AT 5 BID SO THEY’VE HAD TO GO BACK UP TO 10 OR SO, SO THERE IS SOME TUNING THAT TAKES PLACE, BUT YES, I MEAN, WE DID THIS CAUTIOUSLY AT FIRST IN THE SETTING OF THE STUDY, BUT PRACTICALLY SPEAKING, MANY OF THE FOLKS USING THIS NOW ARE STARTING HIGH AND THEN REDUCING JUST AS YOU SAID, ONCE THEY START TO GET REGROWTH. I DON’T THINK YOU COULD EVER GO TO — AND JOHN WILL CORRECT ME — A SORT OF ONCE A WEEK DOSING BECAUSE YOU NEED TO KEEP THINGS — HALF-LIFE AND OTHER THINGS, BUT MAYBE A LOW CONSISTENT DOSE OVER TIME RATHER THAN INTERMITTENT. SO BUT YES, THAT’S BECOME THE WAY THAT FOLKS ARE TRYING IT NOW. EXACTLY RIGHT.>>ACTUALLY WHAT’S BEEN TRIED WITH THE DOGS AND IT WORKS VERY WELL FOR THE DOGS.>>THANK YOU.>>SO I WOULD LIKE TO FINISH INVITING YOU TO COME JOIN US FOR A RECEPTION IN THE LIBRARY AND TO THANK ONCE AGAIN DR. CHRISTIANO FOR HER TALK. [APPLAUSE]

7 Comments

  • silkhead44 says:

    berberine, curcumin, cordyseps, red yeast rice and salacia are all natural JAK1/3 inhibitors

  • silkhead44 says:

    Decreased levels of intracellular free Mg2+ have been linked to
    defective expression of the natural killer activating receptor NKG2D in
    both natural killer (NK) and CD8+ T cells

  • silkhead44 says:

    FDA is denying people the treatment and raising the price for topical ruxo with overcostly clinical trials

  • Osiris says:

    Could hydrogen peroxide cause this because I was cleaning out my ear with peroxide and it ran dowm to my neck under my chin and that's where it is mostly affected and i didn't have any patches until I got hydrogen peroxide on my chin/neck area?

  • J T says:

    I have a question, i have Sebhorreic Dermatitis on my scalp, and i happen to pick the scabs frequently. Today when i looked at my hair, i notice a very small bald spot, very smooth to the touch, completely bald…next to a scale on my head. Is that a form of Alopecia? Is it gonna get worse? Do they expand and get balder?

  • Manish Arora says:

    Alopecia, which commonly known as hair loss. It is a common problem nowadays. Everyone wants their hair healthy and full of volume. If you want this Use Hair Care Pack of "Planet Ayurveda". It is really very effective.

  • bartdude82 says:

    Functional Medicine practitioners have already pointed out how important the microbiome is to autoimmune disorders. All I'm getting from this presentation is that the main goal is to approve drugs that target and inhibit specific JAK pathways. But this is no different from steroid injections that treat the symptoms but not the root cause of the issue at hand. As seen in the results from the human studies in this presentation, relapse has occured and probably will always occur using drugs like these. It's not a permanent solution. What is causing immune cells and JAK pathways to go haywire in the first place? What factor triggered the genes to turn on and initiate self-inflicted disease? Diet? Stress? Past infections?

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