IT IS MY GREAT PLEASURE TO INTRODUCE DR. NEHAL MEHTA, AN NIH LASKER SCHOLAR SENIOR INVESTIGATOR AT NHLBI AND OUR VERY FIRST NIH DIRECTOR SPEAKER OF THE 2021, 22 SEASON. NEHAL MEHTA WAS ENROLLED IN ACCELERATED MEDICAL PROGRAM AT GEORGE WASHINGTON UNIVERSITY AND COMPLETED HIS BA AND M.D. IN SEVEN YEARS. HE ALSO RECEIVED HE IS MSCE GENETIC EPIDEMIOLOGY FROM THE UNIVERSITY OF PENNSYLVANIA IN 2009. HE DID HIS INTERNSHIP AND RESIDENCY INCLUDING A CHIEF MEDICAL RESIDENCY AND A FELLOWSHIP IN CARDIOVASCULAR MEDICINE AT HOSPITAL OF THE UNIVERSITY OF PENNSYLVANIA, PRIOR O HIS POST-DOCTORAL RESEARCH IN GENETIC EPIDEMIOLOGY. AFTER A FEW YEARS ON THE UNIVERSITY OF PENNSYLVANIA FACULTY, DR. MEHTA JOINED THE NIH AS THE INAUGURAL NIH LASKER SCHOLAR AND INDEED HE BEGAN HIS WONDERFUL PROGRAM FOR OUR SCHOLARS. AND HE WAS TENURED LAST YEAR. HE'S ALSO AN ADJUNCT PROFESSOR OF MEDICINE GEORGE WASHINGTON UNIVERSITY. HIS WORK ON THE ROLE OF INFLAMMATION AND DEVELOPMENT MAINTENANCE AND CLINICAL COMPLICATIONS OF ATHEROSCLEROTIC VASCULAR DISEASE IS RECOGNIZED BY MANY AWARDS, INCLUDING ELECTION AS A FELLOW OF THE AMERICAN COLLEGE OF PHYSICIANS, AND THE AMERICAN HEART ASSOCIATION. HE'S ON SEVERAL EDITORIAL BOARDS AND ADVISORY COMMITTEES, AN ELECTED MEMBER OF THE ASCI AND HAS BEEN INVITED TO GIVE NUMEROUS NAMED LECTURES. MOST IMPORTANT OF ALL HIS CV INCLUDES AN EAGLE SCOUTS OF AMERICA AWARD. HIS DETAILED STUDIES HOW INFLAMMATION AND IN PARTICULAR INFLAMMATION RESULTING FROM ACTIVE PSORIASIS AND ACCELERATED CARDIOVASCULAR DISEASE CREATED AD NEW PARADIGM UNDERSTANDING AND TREATING ATHEROSCLEROTIC HEART DISEASE. WE ARE DELIGHTED TO HAVE HIM HERE TODAY TO GIVE A TALK ENTITLED PSORIASIS AS A MODEL, TO STUDY INFLAMMATION AND CARDIOMETABOLIC DISEASE IN HUMANS. NEHAL, STAGE IS YOURS. >> DR. GOTTESMAN, THANK YOU FOR THE OPPORTUNITY TO PRESENT MY WORK HERE TODAY. IT IS ABSOLUTELY AN HONOR AND PLEASURE TO HAVE THIS HOUR TO REVIEW TEN YEARS OF OUR WORK HERE AT NIH. IT IS TOUGH TIMES THAT WE ARE GOING THROUGH THESE DAYS AND I ALWAYS START MY TALKS WITH A THANKS TO EVERYBODY WHO HAS MADE ALL THE WORK POSSIBLE THAT I'M ABOUT TO TALK ABOUT. IT 'ALLY DOES START ALL THE WAY FROM THE LASKER PROGRAM AT THE NIH AND ALL WAY DOWN TO EXTRAMURAL COLLABORATORS WORLD WIDE AS WELL AS WITHIN THE U.S.. AND AS I ALWAYS SAY, THIS WHOLE JOURNEY IS NOT POSSIBLE BY MANY PEOPLE WHO COULDN'T -- I COULDN'T LIST ON THIS SLIDE BUT A WAY FOR ME TO SAY THANK YOU BEFORE I BEGIN. I WILL BEGIN BY SPEAKING ABOUT WHAT CARDIOMETABOLIC DISEASE IS. IT IS THE PRESENCE OF ANY OF THE FOLLOWING: THIS USED TO BE CALLED METABOLIC SYNDROME BUT WHAT WE HAVE REALIZED IS THAT A CLUSTERING OF THESE ABNORMALITIES ACTUALLY IS TOO LONG TO WAIT BEFORE DIAGNOSING ANY ONE OF THEM SO IT IS DISEASES OF ATHEROSCLEROSIS WHETHER CLINICAL OR SUB CLINICAL, INSULIN RESISTANCE SENSITIVITY ABOUT NORMALITIES. OBESITY OR SHEER PRESENCE OF AD POSE DYSFUNCTION OR HIGH CHOLESTEROL, DISLIPIDEMIA. I WILL START WITH A CASE WE HAVE ACTIVE RECRUITING PROTOCOL HERE AT THE NIH CLINICAL CENTER AS WELL AS TWO OTHER CENTERS THAT WE SEE PATIENTS WITH PSORIASIS AND OTHER CHRONIC INFLAMMATORY DISEASES FOR CARDIOVASCULAR RISK ASSESSMENT. HERE IS THE STORY OF A 44-YEAR-OLD FEMALE WHO PRESENTED ON HER OWN FOR A GENERAL EVALUATION. SHE HAD NO COMPLAINTS, SHE JUST FELT THAT HER BORDERLINE HYPERTENSION AND UNTREATED PSORIASIS SHOULD BE REVIEWED AND CONSIDERED FOR TREATMENT. HER FAMILY HISTORY WAS SIGNIFICANT FOR MOTHER WITH TYPE TWO DIABETES AND FATHER WITH MYOCARDIAL INFARCTION. THIS IS COMMON IN PATIENTS WITH PSORIASIS TO HAVE FAMILY HISTORY OF CARDIOMETABOLIC DISEASE. SHE SMOKED HALF A PACK PER DAY OF TOBACCO. SHE HAD NO GENERAL MEDICAL COMPLAINTS. HER PHYSICAL EXAM SHOWN HERE, IN RED YOU WILL SEE SOME ABNORMALITIES THAT I POINTED OUT. NUMBER BUN, THE PRESENCE OF A BLOOD PRESSURE OF 144 OVER 89. TOO HIGH FOR A 44-YEAR-OLD. THE DIASTOLIC PRESSURE IS NEAR STAGE 1 HYPERTENSION. HER BODY MASS INDEX IS 32 PUTTING HER IN OBESE CATEGORY AN WASTE TO HIP RATIO SOMEONE WHICH PUTS HER AT HOLDING A LOT OF HER WEIGHT IN THE CENTER OF THE BODY. SHE HAD NINE PERCENT OF HER BODY COVERED CAN THICK PLAQUE PSORIASIS AND THAT IS ABOUT NINE PALMS OF DISEASE OF ACTIVE INFLAMMATION IN HER SKIN. HER LABORATORY EXAMS SHOWED THAT SHE HAD A TOTAL CHOLESTEROL OF 210, LDL OF 159 TRIGLYCERIDES OF 200 HDL 40 AND SUGAR 116. I WOULD EXPECT THAT HER HDL WOULD BE HIGHER TRIGLYCERIDES WOULD BE LOWER AND LDL DEPENDING ON CARDIO VAS QUEUE ALREADY RISK SCORE -- CARDIO VAS QUEUE ALREADY RISK SCORE WOULD BE APPROPRIATE. THE FASTK SUGAR OF 116 IS FAR TOO HIGH FOR A 44-YEAR-OLD FEMALE, FASTING SUGAR OF 126 IS DIAGNOSIS OF DIABETES. SHE HAS TOBACCO USE AND FAMILY HISTORY OF C ASHESD, HIGH BLOOD PRESSURE, OBESE AND SHE HAS A GLUCOSE CONSISTENT WITH PRE-DIABETES. SO VERY COMMON QUESTION I GET IS WHAT IS MY CARDIOVASCULAR RISK? WHAT IS HER RISK? SO VERY QUICKLY MOST HEALTHCARE PROVIDERS WILL USE THE ACCAHA LIFETIME RISK CALCULATOR, BUT HERE TO ILLUSTRATE A POINT, I CALCULATED A FRAMINGHAM RISK SCORE BASED ON AGE LIPIDS DIABETES AND SMOKING PRESENCE. ONE WILL FIND THAT HER CARDIOVASCULAR RISK SCORE IS 9%, 9% CHANCE HAVING HEART ATTACK OVER TEN YEARS AND SOMEONE MIGHT LOOK AND SAY WHAT DOES THAT MEAN? WHAT THAT MEANS IS THAT SHE BE DEEMED LOW RISK FOR CARDIOVASCULAR DISEASE BASED ON THIS FLAMING HAM RISK SCORE. BUT WHAT ARE WE MISSING? THE INFLAMMATION ASSOCIATED WITH PSORIASIS. SO THIS IS DATA TWO DECADES OLD NOW DEMONSTRATENING THE WOMEN'S HEALTH STUDY 20,000 WOMEN FOLLOWED FOR TEN YEARS WHO HAD AN ELEVATED CRP HAD A POWER FOLD RATE OF CARDIOVASCULAR EVENTS. HIGH SENSITIVITY, C REACTIVE PROTEIN IS A MONOSPECIFIC MARKER MEASURED IN THE BLOOD THAT REFLECTS IL 6 AND,L 1 BETA DRIVEN INFLAMMATION. SO INFLAMMATION MATTERS IN THE GENERAL POPULATION. BUT WHAT ABOUT IN PSORIASIS? PSORIASIS IS A CHRONIC COMMON INFLAMMATORY SKIN DISEASE WITH A LOT OF UNDIAGNOSED CASES AND LOOKING AT THE PICTURE IN THE UPPER RIGHT THERE'S THICK SCALEY PLAQUES AND OVER A BILLION IMMUNE CELLS ACTIVATED IN THE BODY DURING A SU PSORIASIS FLAIR. ONE HI IT IS IF THE SKIN DISEASE WAS DRIVING CARDIOVASCULAR DISEASE, CBD WOULD BE MORE PRESENT IN PSORIASIS. BEFORE I ARRIVED TO THE NIH I SPENT TIME UNDERSTANDING EPIDEMIOLOGICAL LINK WORKING WITH DR. JOE GELFIN. IN CONJUNCTION WITH HIS LAB WE SHOW THERE HAD IS A 50% INCREASE RISK OF MORTALITY AND IF ONE LOOKS AT THIS FIVE YEARS OF LIFE LOST THESE CURVES ON THE RIGHT THE ONE IN BLUE WHICH IS PSORIASIS SHIFTED LEFT. THIS FIVE YEARS OF LIFE LOST IN PSORIASIS IS DUE TO INFECTION, CANCER, AND CARDIOVASCULAR DISEASE. BY FAR AND AWAY CBD IS HIGHER TWOFOLD BY NEXT NUMBER TWO KILLER. SECONDLY, WHEN ONE LOOKS AT THE YOUR HONOR POPULATION PATIENTS WITH PSORIASIS BETWEEN AGE 40 AND 50, ONE SEES A TWOFOLD ELEVATION IN FIRST HEART ATTACK. THAT AGE INTERACTION WAS WHAT SET OFF THE IDEA THAT INFLAMMATION AT A YOUNG AGE CAN SIT -- CAN DRIVE FUTURE CARDIOMETABOLIC RISK. WHEN ONE LOOKS AT ADJUSTED MODELS FOR RISK FACTORS ONE FINDS A 43 TO 58% INCREASE RISK OF STROKE, MYOCARDIAL INFARCTION, CARDIOVASCULAR DEATH AND MAJOR CARDIOVASCULAR EVENTS THEREFORE WE CONSIDER PSORIASIS TO PROVIDE A HUMAN MODEL TO STUDY IN ATHEROGENESIS IN CARDIOMETABOLIC DISEASE. SHOWN HERE IS A SEVERE PSORIASIS PATIENT. THROUGH IMMUNE ACTIVATION SYSTEMIC INFLAMMATION AND LIPOPROTEIN DYSFUNCTION, ACCELERATES THAT FIRST MYOCARDIAL INFARCTION. HOW WE HAVE APPROACHED THIS AT THE NATIONAL INSTITUTES OF HEALTH IS THROUGH USE OF HUMAN PROTOCOLS ENROLLING AT THE NIH CLINICAL CENTER AN I'M GOING TO WALK YOU THROUGH TWO SUCH PROTOCOLS THIS MORNING. THE FIRST PROTOCOL OUR 13H 0065 PROTOCOL, USES DEEP PHENOTYPING TO STUDY PSORIASIS AND WILL BRING PATIENTS IN AT ZERO, ONE AND FOUR YEARS. IN THIS CARTOON IMAGING VISITS ARE SHOWN IN GREEN. THEY COME BACK FOR HNP AS WELL AS YEARS TWO AND THREE AN THESE DATA ARE NOW BEING COMPARED ACROSS PET CT PET MRI CORONARY CTA FOR IMAGING VASCULAR TERRITORIES, BLOOD FOR ISOLATION OF LIPIDS AS WELL AS OTHER INFLAMMATORY CYTOKINES AND CHEMOKINES, WE ALSO HAVE A VERY ROBUST FLOW CYTOMETRY PROGRAM. THEN TISSUE, SKIN AND AD POSE OBTAINED IN ONE IN THREE PATIENTS. WE THEN ALSO HAVE A PARALLEL PROTOCOL WHICH HAS NOW BEEN APPROVED TO HAVE FOLLOW-UP VISITS AS WELL. WITH HEALTHY DIABETIC AND CORONARY DISEASE PATIENTS BEING FOLLOWED FIRST AT BASELINE AND THEN AT ONE YEAR, TO UNDERSTAND WHAT THE EXPOSURE OPEN OF OF PSORIASIS OVER TIME IS DOING TO VASCULAR PARAMETERS. FIRST, THESE ARE DATA THAT DEMONSTRATE WHEN ONE HAS PSORIASIS IT IS SYSTEMIC INFLAMMATORY DISEASE AND IT IS AS INFLAMMATORY AS HAVING AN ACUTE CORONARY SYNDROME. ACUTE CORONARY SYNDROME IS DEFINED AS HAVING A HEART ATTACK. MYOCARDIAL INFARCTION OR NEW CHEST PAIN WITH EKG PROVEN AND TROPONIN PROVEN CHANGES. SO HERE THIS WAS 120 PSORIASIS PATIENT, 100 ACS OR ACUTE CORONARY SYNDROME PATIENTS AND 30 WITH CHEST PAIN THAT TURNED OUT TO BE NON-CARDIAC. WHAT THESE DATA DEMONSTRATE IS PSORIASIS HAS A NINE FOLD ELEVATION COMPARED TO ACUTE CORONARY SYNDROME OF TNF ALPHA, FIVE FOLD ELEVATION OF IL 1 BETA INFLAMMASOME ACTIVATION AND COMPARED TO THOSE WITH NON-CORONARY OR NON-ACUTE CORONARY SYNDROME THESE CHANGES WERE EVEN HIGHER. THIS IS 120 PATIENTS WHO WALKED INTO OUR PSORIASIS CLINIC. AND THEY ARE MORE INFLAMED THAN THOSE WHO ARE HAVING ACUTE CORONARY SYNDROME. SECOND, THESE ARE DATA WHEN YOU LOOK AT NMR SPECTROSCOPY SHINE BASICALLY A LIGHT TO UNDERSTAND WHAT THE LIPID COMPOSITION IS OF YOUR LIPOPROTEINS, ONE FINDS THAT ON THE LEFT WHEN LOOK AT THE DRIBS OF CONTROL COMPARE TO PSORIASIS IN PSORIASIS THERE IS APOE LIPOPROTEIN B. @THREE GENIC LIPOPROTEIN. THERE'S MORE INTERMEDIATE DENSE LIPOPROTEIN, MORE SMALL LDL, THE LDL STAYS LONGER IS OXIDIZED THAT SMALL DENSE LDL WILL COME BACK UP WHEN WE TALK ABOUT THE LIPID RICH NECROTIC PORE. FINALLY THIS IS A PROCESS MY FORMER LAB HAD PIONEERED AND ELUCIDATED A PROCESS CALLED REVERSE CHOLESTEROL TRANSPORT. SO WHY HDL IS A BENEFICIAL ACTOR IN THIS GAME, IS THAT HDL CAN GO TO A LOADED CHOLESTEROL MACROPHAGE AND PULL OUT THE FREE CHOLESTEROL VIA ABCA 1, STEER PHI THE L CAT TURN TO MATURE HLD AN VIA SRV 1 RECEPTOR IN LIVER EXCRETE OUT EXCESS CHOLESTEROL AS BILE. THAT PROCESS OF REVERSE CHOLESTEROL RESPECT PREVENTS OUR BODIES FROM BECOMING CONSTIPATED WITH EXTRA CHOLESTEROL. WHEN ONE LOOKS AT PSORIASIS VERSUS THOSE WITHOUT PSORIASIS THERE IS 12% DECKMENT IN THIS REVERSE CHOLESTEROL TRANSPORT, MAY NOT SOUND LIKE A LOT, MAY NOT LOOK LIKE A LOT ACCORDING TO THE GRAPHS. BUT IF I TWO ENDS 160 MILLIGRAMS OF CHOLESTEROL, I WILL LIKELY EXCRETE 158 MILLIGRAMS OF THAT CHOLESTEROL. SOMEONE WITH PSORIASIS MAY ONLY EXCRETE 140 MILLIGRAMS. THAT EXTRA 20 MILLION GRAMS OF CHOLESTEROL ON A DAILY BASIS, THE CROWNICITY OF THAT, LEADS TO EARLY VASCULAR DISEASE ACROSS THE BODY AS WELL AS LIKELY INCREASE SKIN DISEASE SEVERITY. SO THEREFORE BY ROUNDING OUT IN THIS PRESENTATION I LIKE TO REMIND THE CROWD THAT PSORIASIS IS A MODEL TO STUDY THIS INFLAMMATORY INDUCED ATHEROSCLEROSIS AS WELL AS CARDIOMETABOLIC DISORDER. AND IT IS A COMMON DISEASE THAT HAS A WAXING AND WANING FORCE. THERE IS A YOUNG AGE FOR DEVELOPMENT CBD AND THE IMMUNE ACTIVATION IS TARGETED BY SINGLE CYTOKINE INHIBITION SO I WILL GO THROUGH THE BIOLOGIC THERAPY. FURTHERMORE, WHEN ONE LOOKS AT YOUNG AGE FOR DEVELOPMENT OF CBD SOME OF THE DATA WE DON'T WANT TO WAIT FOR CARDIOVASCULAR EVENTS SO WE NEED TO UNDERSTAND HOW WE ARE GOING TO DECODE IF YOU WILL, THE PSORIASIS ATHEROSCLEROTIC PUZZLE. SO ONE OF THE DRIVING FORCES OF COMING TO THE NATIONAL INSTITUTES OF HEALTH, IN 2012 WAS THE ADVENT OF FDG PET MR ONE OF THE FIRST CENTERS MANY THE WORLD TO HAVE ONE AS WELL AS PDG PET CT. I PUT TOGETHER A MULTI-MODAL IMAGING PROGRAM ON THE RIGHT TWO STUDIES USE RADIO LABELED GLUCOSE NUCLEAR GLUCOSE AND GO INTO INFLAMMATORY CELLS AND THEY ESTIMATE THE INFLAMMATORY BURDEN IN THE AORTA AS WELL AS THE FUNCTIONAL CONSEQUENCE. SO YOU CAN LOOK FOR VASCULAR INFLAMMATION AS WELL AS AORTIC DISTENTIONIBILITY AND WALL THICKNESS. HEART ATTACKS ARE CAUSED BY CORONARY DISEASE SO WE ALSO IMAGE THE CORONARIES USING CORONARY CD ANGIOGRAPHY AND THAT ALLOW US TO -- WILL ALLOW US TO ESTIMATE PLAQUE BURDEN BEFORE THE HEART ATTACK OCCURS. SO I'M GOING TO COVER A LITTLE BIT OF THE FTD PET CT AND THEN SPEND REST OF OUR TIME GOING THROUGH CORONARY CTA. SO THIS IMAGE IS THE FIRST IMAGE THAT I WILL SHOW YOU THAT DEMONSTRATES THAT FROM AN IMAGING STANDPOINT PSORIASIS IS A SYSTEMIC INFLAMMATORY DISEASE. AND IT IS ASSOCIATED WITH VASCULAR INFLAMMATION. SO SHOWN HERE IS AN FDG AND NORMAL HEALTHY CONTROL AND WHAT WE FIND IS THAT THERE IS EXCRETION IN THE KIDNEY AND BLADDER, THERE'S HOMOGENOUS UPTAKE THROUGHOUT THE BODY. CONTRAST TO A PATIENT WITH PSORIASIS WHERE ONE FINDS FOUR CARDINAL FINDINGS. FIRST ONE FINDS UPTAKE IN THE SKIN PSORIATIC PLAQUES CD 68 POSITIVE MACROPHAGES ARE TAKING UP THE GLUCOSE. NUMBER TWO, WE FIND THAT THERE IS A TREMENDOUS AMOUNT OF UPTAKE IN THE JOINTS SPACE CONSISTENT WITH PSORIATIC ARTHRITIS IN A PATIENT IN A PATIENT WITHOUT CHOREATIC ARTHRITIS. WE FIND AN EXTREME AMOUNT OF FDG CONCENTRATED IN LIVER, THAT CONCEPT OF PSORIATIC LIVER BEING HYPERMETABOLIC AND ACTIVE, THE RETICULAR ENDOTHELIAL SYSTEM FILTERING CONTANTTANTLY THE SKIN CELLS FROM THE BODY. THE RELATIVELY LET GENIUS DIFFUSE UPTAKE TURN AORTIC VASCULAR UPTAKE OF FDG. WHEN WHEN YOU KNOW LOOKS AT THAT UPTAKE OF FDG IN SAGITTAL, PSORIASIS VERSUS CONTROL THE AORTIC TARGET TO BACKGROUND RATIO IN VOXELS IS DIRECTLY RELATED IN FRAMING HAM ADJUSTED MODELS TO THE AMOUNT OF SKIN DISEASE SEVERITY. SO WHAT YOU SEE ON THE OUTSIDE IS WHAT YOU GET ON THE INSIDE. THIS IS A BIG MOVE FORWARD FOR THE FIELD DEMONSTRATING PSORIASIS IS A SYSTEMIC INFLAMMATORY DISEASE ASSOCIATED WITH DIFFUSE VASCULAR INFLAMMATION. IT WAS AROUND THAT TIME THAT WE ALSO STARTED STUDYING THOSE WHO HAD JUST HAD A HEART ATTACK, HERE ARE SHOWN A PATIENT WHO CAME INTO OUR POST MI STUDY AND THAT SAME PATTERN OF VASCULAR INFLAMMATION THAT WAS NOTED IN PSORIASIS WAS ALSO OBSERVED IN MYOCARDIAL INFARCTION. THAT LED US TO THE QUESTION, IF PSORIASIS AND CARDIOVASCULAR DISEASE SHARE INFLAMMATORY PATHWAYS, MIGHT THE CORONARY ARTERY DISEASE ITSELF BE DETECTABLE AND EFFECTED BEFORE WE SEE THESE EVENTS? IN APPROXIMATELY 2014 OR 15 WE WERE LUCKY TO GROW OUR CT SCANS BY ONE THANKS TO THE STRONG COLLABORATION WE HAVE WITH DR. MARCUS CHEN AS WELL AS DR. DAVID BLOOMKY. THE CORONARY CTA HERE IS ON A 320, SO 320 SLICES THERE IS A SCAN OF LESS THAN 1.5 MILISIEVERTS, RESPONSE OF COUPLE OF CHEST CTs. WHEN ONE LOOKS AT ACC AHA MODEL YOU FIND THE LUMIN IN BLUE GETS ISOLATED AND LOOKED AT IN FOUR VIEWS I SHOW ON THE RIGHT. SO ONE CAN SEE A PROXIMAL MIX CALCIFIED PLAQUE HERE, GOING DOWN, THERE IS SMALLER MIX CALCIFIED PLAQUE. ONE SEES THIS INNER LYM LUMEN, INNER BORDER AND OUTER BORDER WHERE PLAQUE STARTS SO SHOWN IN CARTOON WE CAN SUBTRACT THE LUMEN VOLUME AND WE ARE LEFT WITH A PLAQUE VOLUME. SO ATHEROSCLEROSIS IS A DISEASE OF THE WALL. NOT OF THE LUMEN. IF IT GETS TO THE LUMEN WE WAITED TOO LONG. SO ATHEROSCLEROSIS IS A DISEASE OF THE WALL AND THE PLAQUE VOLUME ALONG THE LENGTH OF THE SEGMENT WE INDEX AND WE GET SOMETHING CALLED A PLAQUE INDEX. THEREFORE, WE ARE DETECTING DISEASE BEFORE IT MANIFESTS ON CLINICAL PLAQUE ANALYSES. SO THIS NONEQUALS FIED BURRND THE PORTION OF PLAQUE BEFORE IT BECOMES PLAQUE AS A PLAQUE INDEX IS WHAT I FOCUS ON THE NEXT SEVERAL SLIDES. OUR FIRST OBSERVATON IN 2017 RESOLVED AROUND THE FACT HEN YOU LOOK AT PSORIASIS COMPARED TO AGE GENDER HEALTHY MATCHED VOLUNTEERS THERE IS INCREASE OF 20% OF TOTAL PLAQUE BURDEN IN CORONARY SO 20% THICKER CORONARY WALLS. WHEN ONE LOOKED AT THE IMPACT OF PSORIASIS ON NON-CALCIFIED BURDEN, IN FULLY ADJUSTED MODELS THIS WAS ABOUT AFTER 15% INCREASE BY THE SHEER PRESENCE OF ANY PSORIASIS, THIS WAS NOT SEVERE ONLY, THIS WAS ANY COMMERCE, I REMIND YOU THAT THAT NON-CALCIFIED PLAQUE ALSO IS THE MOST COMMON CAUSE OF MYOCARDIAL INFARCTION. IF IT IS THE MOST COMMON CAUSE OF MYOCARDIAL INFARCTION COULD IT BE THE THE NON-CALCIFIED PLAQUE HAS OTHER ASSOCIATED FEATURES OF RUPTURE. SO WHEN WE LOOK AT FRANK CORONARY PLAQUE, WE SAY ALL PLAQUE IS NOT CREATED EQUAL. ONE CT SCAN ONE SEES POOCHING OF THE LUMEN OUTWARD. THIS POSITIVE REMODEL IS A STANDING ROOM ONLY PHENOMENON. THERE IS NOT ENOUGH ROOM ROOM IN THE ROOM, THE ROOM OPENS THE DOOR AND LETS PEOPLE POUCH OUT SO THIS POSITIVE REMODELS IS HIGHEST RISK FEATURES FOR FUTURE RUPTURE OF HEART ATTACK. FURTHER MORE, IF YOUR BODY IS CONSTIPATE OF THE LIPIDS CON FANTASTICTANTLY AND YOU HAVE LIPID YOU MAY DEVELOP A LOW ATTENUATION PLAQUE. AND THAT IS SHOWN HERE ON THE BOTTOM LEFT. A LOT OF LIPID BECOMES LOW ATTENUATION AND THE LIPID MAKES IT EASIER TORR THE PLAQUE TO RUPTURE. SO THESE TWO FEATURES OF POSITIVE REMODELING AND LOW ATTENUATION PLAQUE FOR THE NEXT QUESTIONS WE HAVE. SO WERE THESE TYPES OF PLAQUES PRESENT IN PSORIASIS PATIENTS? THEY WERE. I WILL SHOW YOU SET OF IMPACTS FROM A 38-YEAR-OLD LOCAL MAN WITH PSORIASIS, THIS IS IMAGE BETWEEN BASELINE AND ONE YEAR VISIT. BEFORE HIS FOLLOW-UP WE WERE TOLD CAPTURED THAT HE HAD A MYOCARDIAL INFARCTION RIGHT POSTERIOR LATERAL BRANCH OF THE CORONARY ARTERY WHEN WE LOOK BACK AT ZERO BASELINE SCAN WE FOUND IN FACT THAT THERE WAS LOW ATTENUATION AND POSITIVE REMODELING FOUND IN THE PLAQUE THAT RUPTURED. WHEN WE AGGRAVATED THE DATA WE FOUND -- AGGREGATED THE DATA WE FOUND PSORIASIS HAS THE SAME AMOUNT OF RISK PRESENT AND COMES 14 YEARS EARLIER SO ANOTHER STUDY ON THE RIGHT WHICH IS A GROUP OF HEALTHY VOLUNTEER WHOSE ARE DIAGNOSED WITH HYPERLIPIDEMIA AND ON STATIN THERAPY, BEFORE THEIR STATIN THERAPY STARTS WE IMAGED THEM AND WHEN ONE LOOKS AT TOTAL PLAQUE BURDEN OF 60-YEAR-OLD COMPARED TO PSORIASIS, IT HAS JUST ABOUT THE SAME AMOUNT OF PLAQUE BURDEN JUST A LITTLE MORE NON-CALCIFIED BURDEN WHICH IS SIGNIFICANT AND SAME AMOUNT OF HIGH RISK PLAQUE. SO IT IS THESE DATA I TRY TO SHARE WITH YOUNGER PATIENTS NEWLY DIAGNOSED WITH THIS DISEASE TO REMIND THEM THAT THE DISEASE ITSELF IS DRIVING SOME OF THESE ABNORMALITIES. AND ONE OF THE MOST COMMON QUESTIONS THAT I GET BACK IS BUT IF THAT IS THE CASE, WHAT IF YOU TREAT ACTUAL SKIN DISEASE? SO IT WAS AROUND THAT TIME IF YOU LOOK AT THE SLIDE UNPUBLISHED DATA 2017 IT WAS AT THAT TIME WE GET A CALL FROM A COUPLE OF OUR GREAT COLLEAGUES DOWN MT. CT ROOM SAYING HEY WHAT ARE YOU DO US UP THERE AT THE CLINIC, THAT 30% SHAGGY PLAQUE ON THE LEFT HAS NOW GONE AWAY. WHAT IS GOING ON? SO WE SCRATCHED OUR HEADS AND WE SAID WHAT IS THIS REDUCTION IN LIPID RICH NECROTIC CORONARY PLAQUE? WHAT IS GOING ON HERE? WE ASKED THE SIMPLE QUESTION AND ANSWERED IN THREE WAYS DOES THE TREATMENT OF CHRONIC INFLAMMATION MODERATE CORONARY ARTERY CHARACTERISTICS. FIRST AND ALL DATA I WILL SHOW YOU COME FROM A CORE GROUP OF INDIVIDUALS IN OUR COHORT STUDY, UP TO 400 PATIENTS, THERE ARE PATIENTS WHO NOW COME IN WITH MODERATE TO SEVERE DISEASE JUST ABOUT TO START BIOLOGIC THERAPY SO ANTI-IL 17, ANTI-IL 1223, ANTI-TNF, ANTI-23, AND WE COMPARED THOSE TO PATIENTS WHO DECIDED NOT TO, SO WE ARE NOT CHOOSING THESE TREATMENTS THEE ARE REFERRED IN BUT WE SEE THEM BEFORE THEY START THERAPY. WE HAVE A NATURAL EXPERIMENT HERE THE SAME SOURCE POPULATION HAS 32 PEOPLE THAT CHOSE NOT TO GO ON BIOLOGIC THERAPY. WE FOLLOW THEM ONE YEAR AND OBTAIN BASELINE CT OR BASELINE N OF 1. THE POINT OF THE SLIDE IS TO REMIND YOU IN THOSE WHO WENT ON BIOLOGIC THERAPY, THERE WAS NO CHANGE IN BLOOD PRESSURE, GLUCOSE OR LIPIDS. THERE WAS A CHANGE IN SYSTEMIC INFLAMMATION ASSESSED BY C REACTIVE PROTEIN. ABOUT A 33% CHANGE IN ONE YEAR. VERY SIGNIFICANT. THE BIOLOGIC THERAPY ARE ANTI-TNF AND ANTI-IL 17. SO THEORETICALLY THIS OPEN LABEL OBSERVATIONAL STUDY IS COMPARING 90 ON BIOLOGIC THERAPY FOR A YEAR VERSUS 30 THAT DON'T. THE ONLY THICK THAT THEORETICALLY CHANGE WAS AMOUNT OF SKIN DISEASE. THE SKIN DISEASE. SO CORONARY PLAQUE IMPROVE FOLLOWING BIOLOGIC THERAPY. AND WHAT I SHOW YOU HERE IN ROW A VERSUS ROW B IS THE PRE-TREATMENT IN A AND POST TREATMENT IN B. A SHOWS THIS LIPID RICH NECROTIC PORE WITH THIS SMALL CALCIFIED FIBROFATTY BURDEN PLAQUE, IT IS DEFINITELY LUMEN, GETTING TO THE LUMEN, THE LUMEN IS PRESERVED BUT IT IS OUT POUCHING AND WHAT ONE FINDS AFTER A YEAR IS THAT THERE IS AN ABSENCE OF LIPID RICH NECROTIC PORE. THERE IS INCREASE IN A TOTAL CALCIFICATION. THERE IS A DECREASE IN THE FIBROFATTY BURDEN. SO TREATMENT OF SKIN DISEASE LED TO IMPROVEMENT IN THEIR CORONARY PLAQUE. LOOK AT NUMERICALLY IF YOU WENT ON BIOLOGIC THERAPY WE TREAT EACH ARTERY AS A SINGLE OBSERVATION. ONE FOUND THAT THERE IS A DECREASE IN FIVE TO SEVEN PERCENT OF CORONARY PLAQUE. COMPARE TO THOSE HON BIOLOGIC THERAPY WE SAW NO CHANGE OR EVEN MAYBE A LITTLE BIT WORSE. FURTHERMORE WHEN ONE LOOK AT THE HIGH RISK PLAQUE FEATURES I SHOWED YOU, ONE FOUND A DECREASE OF 55 AND 57%, IN THE FIBER FATTY BURDEN IN NECROTIC CORE WHEREAS THOSE UNOPPOSED INFLAMMATION FOR A YEAR FOUND THEY HAD AN INCREASE IN FIBROFATTY BURDEN AND INCREASE IN THEIR LIPID RICH NECROTIC PORE SUGGESTING ONE YEAR OF UNOPPOSED THERAPY OR EXCUSE ME ONE ON UNOPPOSED INFLAMMATION WITHOUT THERAPY IS ACTUALLY QUITE DANGEROUS FOR VASCULAR HEALTH. FINALLY, ALTHOUGH UNDERPOWER WE DID LOOK AT SUBGROUP ANALYSES, WHAT BIOLOGIC DID WHAT. AND WHEN ONE LOOK AT ANTI-TNF THERAPY ONE FOUND A REDUCTION IN NONEQUALS FIED AND TOTAL PLAQUE. AND WHEN ONE LOOK AT ANTI-IL 17 THERAPY, THERE IS A GREATER REDUCTION STATISTICALLY SIGNIFICANT SUGGESTING IL 17 THERAPY MAYBE BENEFICIAL AND NOT ONLY TREATING THE SKIN DISEASE BUT MAY HAVE SOME VASCULAR PROTECTIVE EFFECT. I WOULD NOT CONCLUDE THAT FROM THESE DATA, GIVEN THIS WAS AN OPEN LABEL OBSERVATIONAL STUDY. HOWEVER, IT IS HYPOTHESIS GENERATING EXAMPLE HOW THESE TRULY SMALL PROOF OF CONCEPT MECHANISTIC STUDIES CAN LEAD TO LARGER CLINICAL TRIALS. SECOND EFFECT OF TREATING PSORIASIS ON VASCULAR DISEASE. SO ONE LOOKS AT THIS CORONARY ON THE LEFT AND FINDS A LUMEN HERE A LARGE CALCIFIED NO DUAL AND TWO AREAS OF LIPID RICH NECROTIC PORE. HISTOPATHOLOGICALLY IMAGE VALIDATED VALIDATION TO QUANTIFY THE RICH NECROTIC PORE AND DO IT WITH CERTAINTY BECAUSE THANKS TO COLLEAGUES UP THE ROAD, ANDY BUTLER AND GROUP HAVE DONE THIS IN OVER 700 SPECIMENS OF CAROTID AND GIVEN HIGH RESOLUTION OF THE LIPID RICH NECROTIC PORE SO SHOWN HERE WE TAKE OUR CT SCANS CT DATA AND IDENTIFY AREAS OF LIPID RICH NECROTIC CORE BEFORE AND AFTER THERAPY. WHAT I SHOW YOU HERE IS LOOKING AT THE SOFTWARE, ONE WILL FIND THAT THERE IS A AN AREA IN THE LEFT ANTERIOR DESCENDING ARTERY WITH TREMENDOUS AMOUNT OF LIPID RICH NECROTIC PORE IN THE PLAQUE. WHAT ONE FINDS IS AFTER ONE YEAR, IN THIS CASE THIS WAS IL 17 THERAPY AS WELL, WITH ONE YEAR OF IL 17 THERAPY, ONE FINDS THAT THERE IS A REDUCTION OF LIPID RICH NECROTIC PORE, WHAT IS SO INTERESTING TO ME IS THESE ARE VALIDATION OF SOFTWARE THAT HAVE JUST BEEN DONE ON ANOTHER PLATFORM AND SHOWN THE SAME FINDINGS. THAT FOLLOWING BIOLOGIC THERAPY BY THE NON-CALCIFIED BURDEN AND LIPID RICH NECROTIC PORE FROM ANOTHER PLAQUE OF SOFTWARE WE POUND THE SAME REDUCTION IN LIPID RICH NECROTIC PORE WE DID WHEN LOOK AT HISTOPATHOLOGICALLY VALIDATED SOFTWARE. WHY WAIT UNTIL WE GET TO A PLAQUE THAT HAS LIPID RICH NECROTIC PORE? THIS LAST STORY I'M ABOUT TO SHARE WITH YOU AND CLOSE OUT THE TALK WITH SOME CLINICAL KNOWLEDGE AND CLINICAL PEARLS, THIS LAST BIT OF THE STORY ASKS THE QUESTION, WHAT IF YOU DON'T HAVE CORONARY PLAQUE? WHAT IF YOU ARE AT THE POINT YOU JUST HAVE NON-CALCIFIED BURDEN OF CORONARY THICKNESS, WHAT IF THERE IS A WAY WE CAN LOOK TO SEE WHETHER OR NOT THERE IS INFLAMMATION WITHIN THIS ARTERY? SO WITH OUR COLLEAGUES FROM OXFORD, WE HAVE BEEN COLLABORATING ON LOOKING AT WHAT THE IMPACT OF THE FAT AROUND THE HEART CALLED THE PERIVASCULAR FAT AS A SENSOR, AND WHAT THIS IS SHOWING YOU IS THAT IN A NON-INFLAMED ARTERY, YOU SEE NONE OF THE EFFECT ON THE RIGHT, BUT IN INFLAMED ARTERY ONE FINDS THAT THERE IS MORE LIPID GENESIS, MORE -- LESS ADIP GENESIS, MORE GLYCOLYSIS AND MORE EDEMA. AND WHEN ONE LOOKS AT THE EDEMA, ONE CAN FIND THIS CROSS HERE THAT YOU SEE, IS ALLOWING FOR A DIFFERENTIAL AMOUNT OF WATER DECKED THERE BY CHANGING THE SENSOR SO THIS SLIDE SHOWING IF YOU ARE ABLE TO DETECT THE IMPACT OF INFLAMED ARTERY WITH EARLY LIPID DEPOSIT, AND IT IS SENSING ALL THIS BECAUSE OF THE INFLAMMATION RIGHT UNDERNEATH THE ARTERY, AND ONE CAN LOOK AT THIS DISTANCE COMPOSITION, SEEING CHANGES ENABLES CORONARY ARTERY INFLAMMATION TO BE DETECTED WHAT WE ARE NOW ABLE TO DO IS USE THE FAT ATTENUATION INDEX, HOW IT FIELDS UNIT DENSITIES AND FIND THERE'S AREAS AROUND THE ARTERY THAT ARE MORE INFLAMED IN PATIENTS WHO HAVE CORONARY INFLAMMATION. SO SHOWN HERE WHEN ONE HAS NO LUMINAL PLAQUE IN EITHER CASE, BUT THERE IS A HIGH AMOUNT OF FAT ATTENUATION MEANING SO MUCH EDEMA IN THAT AREA, WE CAN TRACK THAT ATTENUATION WHAT OUR COLLEAGUES HAVE DONE AT OXFORD THE COMPARED TO OVER 14,000 BUY I DON'T KNOWSIS AND SHOWN WHEN THERE'S CORONARY INFLAMMATION, THESE FINDINGS ARE PRESENT, AND THAT THE ALGORITHM FOR DETECTING PERIVASCULAR FAT ATTENUATION IS SENSITIVE TO CHANGE. SOUND LIKE WE CAN TEST SOMETHING. WE APPLIED PERIVASCULAR FAT ATTENUATION INDEX SENSORS TO A PATIENT WITH PSORIASIS SO NOW I'M GIVING YOU ANOTHER EXAMPLE OF AN ANTI-TNF, NOT ANTI-IL 17 AS IN THE FIRST EXAMPLE BUT AN ANTI-TNF, YOU WILL SEE THE FIVE HERE IS HIGHLY INFLAMED ABSENCE OF LUMINAL DISEASE BUT A LOT OF CORONARY INFLAMMATION. SIMPLE TREATMENT WITH ANTI-TNF THERAPY FOR PSORIATIC DISEASE LED TO AN IMPROVEMENT TO NORMALIZATION IN THE LAD. OF THIS CORONARY INFLAMMATION. SUGGESTING THAT EVEN IF THERE IS NO PLAQUE THERE, WE CAN CALM DOWN CORONARY INFLAMMATION. WHEN ONE LOOKS A ALL COMERS THOSE COMING IN WHO DON'T GET BIOLOGIC THERAPY OR SYSTEMIC THERAPY, THERE'S NO CHANGE IN THEIR FAT ATTENUATION INDEX. WHEN ONE LOOKS AT THOSE WHO WENT ON BIOLOGIC THERAPY THERE IS AN IMPROVEMENT OF 10%, WHEN ONE LOOKS AT ANTI-TNF THERAPY OR ANTI-1223 OR 17 THERAPY, HIGHLY SIGNIFICANT. WE ARE TRYING TO FIND THE DISEASE BEFORE THE CARDIOVASCULAR EVENTS OKAY CURRENT WE SHOW YOU NON-CALCIFIED PLAQUE CAN GET IMPROVED WITH SKIN DISEASE TREATMENT THEN LIPID RICH NECROTIC PORE OF HIGH RISK PLAQUE WITH IMPROVE FOLLOWING THERAPY, SOMETHING EVEN A STEP BACK WHICH IS CORONARY INFLAMMATION, IS RESPONDING TO ANTI-PSORIATIC TREATMENT. SO WE ARE AT A POINT THAT WE ASK, WHY IS CHRONIC INFLAMMATION DRIVING EARLY LIPID RICH PLAQUE? OUR LAB HAS DISSECTED THIS WITH TWO COMPONENTS. WE HAVE THE COMPONENT OF CHRONIC INFLAMMATION PRESENCE. AND WE HAVE THE PRESENCE OF TOO MUCH LIPID. THE TOO MUCH LIPID IS PROBABLY DRIVING INTO THE CORONARY WALL THROUGH ENDOTHELIAL BREACH. SO IN THESE TWO COMPONENTS, WHAT I WOULD LIKE TO DO OVER THE LAST TEN MINUTES OR SO, IS I WOULD LIKE TO GO THROUGH HOW DO WE APPROACH THIS FOR THE PATIENT? HOW DO WE APPROACH THIS AS A FIELD? WHEN YOU LOOK IT'S THERE, WHEN YOU TREAT IT RESPONDS, IS IT JUST PSORIASIS? PLENTY OF PROGRAMS ON CAMPUS BETWEEN LUPUS PROGRAM, RHEUMATOID ARTHRITIS PROGRAM, WE HAVE THREE HIV PROGRAMS, OUR PROGRAMS WITH IBB TEXAS. THE CHRONIC INFLAMMATION IS DEFINITELY THERE IN ALL OF THOSE DISEASES, THE DIFFERENTIAL FACTOR IN MY OPINION IS PRESENCE OF LIPID ATHEROSCLEROSIS I BELIEVE STRONGLY IS DRIVEN BY THIS EXCESS DISLIPIDEMIA. SO IT WAS PLEASING TO ME THAT WE STARTED OUR FIRST PATIENT FIRST VISIT JANUARY 13, 2013, COMING ON EIGHTIERS OF THE STUDY, WE HAVE ENROLLED OVER 380 UNIQUE PATIENTS IN THE PSORIASIS PROTOCOL. OVER 175 PATIENTS INTO THE OTHER COMPETING CORONARY PROTOCOL. AS WELL AS DIABETES, HEALTHY VOLUNTEERS. WHAT I LEARNED IS THAT THE DATA MATTER, NUMBER OF PEOPLE MATTER. THE FOLLOW-UP MATTERS. WE HAVE SUCH LOW ATTRITION RATES IN OUR STUDY, THAT ONE OF THE THINGS I CAN SAY IS PROUDLY WE NOW HAVE 5,000 PATIENT YEARS OF FOLLOW-UP DATA SO THINK ABOUT THAT, THAT'S OVER FIVE YEAR PERIOD OF TIME WE FOLLOWED CLOSE TO A THOUSAND PATIENTS AT VARIOUS TIME POINT. WHAT WE LEARNED IS THAT THERE IS A HIGH PREVALENCE OF DISLIPIDEMIA, DISGLEE SEEMIA AND SYSTEMIC INFLAMMATION. THESE ARE MODIFIABLE WITH DIET AND EXERCISE. WHAT I DON'T UNDERSTAND IS WHY IF THIS WERE DISEASE OF NEGLECT, WHY IT WOULDN'T COMPLETELY GO AWAY ONCE EIGHTEENS WAS PAID TO IT SO THERE'S SOMETHING -- ONCE ATTENTION WAS PAID TO IT. SO MANAGE IS BEYOND THAT. WHAT I LIKE TO IMPART ON MY PATIENT, IF YOU LEAVE THESE UNADDRESSED ALL THE SYSTEMIC INFLAMMATION, FEW PLAQUES ON THE SKIN, OVER TIME, OUR 44-YEAR-OLD UNTREATED MODERATE PSORIASIS PATIENT HERE IS HER SCANS. I WILL REMIND YOU SHE IS 44, TOLL CHOLESTEROL OF 200 LDL 159 TRIGLYCERIDES OF 200. , HDL OF 40 AND GLUCOSE OF 116. WOULD HAVE BEEN THE RIGHT TIME FOR ME TO SHOW YOU SHE HAD POOR HDL FUNCTION, SHE HAD HIGH SYSTEMIC INFLAMMATION, HAS SCORE LEFT UNTREATED AND LOOK AT HER CORONARY. SO HERE WHAT ONE FINDS IS TOO HEAVILY CALCIFIED PLAQUE WHICH IS IS RARE NOISE DISEASE STATE, USUALLY NONEQUALS FIED PLAQUES BUT WHEN ONE LOOKS THEY ARE NONEQUALS FIED PLAQUES BEYOND INITIAL AND THERE'S SEQUENTIAL STENOSIS. ONE MIGHT FIND ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE AND WHAT WE HAVE SHOWN SOMEBODY WHO IS 44 HAS HAD PSORIASIS FOR ONLY NINE YEARS. BUT LEFT UNTREATED, HAS DRIVEN VASCULAR HEALTH GAGA NOT DONE WELL, SHE IS ALSO A SMOKER SO THIS ACCELERATED IT. SHE HAS DISLIPIDEMIA WHICH NEEDS TO BE ADDRESSED SO IN 2018 DECEMBER 18, 2018 THERE IS ONE OF MY PROUDEST PROFESSIONAL MOMENTS, AROUND THE TIME I GOT TEN YOUR BUT MORE FAR REACHING IS THE AMERICAN COLLEGE OF CARDIOLOGY AND AMERICAN HEART ASSOCIATION HAD ADDED THAT CHRONIC INFLAMMATORY CONDITIONS SUCH AS PSORIASIS WARRANT A DISCUSSION WITH YOUR PATIENTS ABOUT EARLY INITIATION STATIN THERAPY. TO ME THIS WAS A PERSONAL JOURNEY OF TEN YEARS TRYING TO EDUCATE MY COLLEAGUES IN CARDIOLOGY AND INTERNAL MEDICINE THAT LOOK, THIS IS BEYOND COSMESIS. THIS IS A DISEASE THAT HAS ROOTED IMPLICATIONS AND SYSTEMIC INFLAMMATION. JUST A SHORT YEAR LATER I WAS ON THE GUIDELINES COMMITTEE FOR AMERICAN ACADEMY OF DERMATOLOGY AS WELL AS NATIONAL PSORIASIS FOUNDATION. AND LOOKING AT THESE RECOMMENDATIONS THEY JUST REALLY TOUCHED MY HEART BECAUSE THIS WAS THE EFFORTS OF OUR COMMUNITY FOR THE LAST TEN YEARS TRYING TO IMPART AMOUNT OF RISK SEEN IN THESE PATIENTS. HOW I EXPLAIN I SAY CHECK THE THREE Bs, THEY ARE THE BODY MASS INDEX, THE BLOOD PRESSURE, AND THEN THE BLOOD FOR CHOLESTEROL AND GLUCOSE, I WILL SAY THAT AGAIN. BODY MASS INDEX, BLOOD PRESSURE AND THEN CHECK THE BLOOD GLUCOSE. DOESN'T HAVE TO BE FASTING. THE GUIDELINES SAY RISK ASSESSMENTS SHOULD START AT FIRST DIAGNOSIS OF PSORIASIS, MORE FREQUENTLY IF MORE SEVERE DISEASE, THEY ACTUALLY BRING UP A MULTIPLICATION FACTOR SO OUR PATIENT WHO IS A NINE PERCENT RISK MAYBE SHE SHOULD ACTUALLY BE CONSIDERED 13 1/2 PERCENT, I LIKE THAT. AND HEN THE OTHER PIECE IS, CARRY OUT ALL THE RISK FACTOR MODIFICATIONS, AS PER NATIONAL GUIDELINES. I CONCLUDE WITH THIS CONCLUSION SLIDE AND DO OUR PART IN THESE STATES. IN CONCLUSION THERE ARE MODELS THAT HAVE SHOWN US INFLAMMATION PRO SEEDS DEVELOPMENT OF CARDIOMETABOLIC DISEASE. PSORIASIS PROVIDES THIS MODEL TO TEST THE EFFECT OF CHRONIC INFLAMMATION IN VIVO. THE TRANSLATIONALHOLD PROVIDES FOUNDATION TO UNDERSTAND PATH WAYS TEST NOVEL THERAPEUTICS AND EXPOSURE ON VASCULAR DISEASE MOVING FORWARD. WHEN WE SEE AN AMERE YOUR RATION OF PLAQUE BURDEN WE ARE MORE LIKELY TO SEE IMPACT ON CARDIOVASCULAR EVENTS IF SIGNAL IS REAL SO BEFORE WE JUMP INTO LARGE EVENTS BASED TRIALS THIS MODEL AND THIS APPROACH MAYBE GENERALIZABLE TO OTHER DISEASE STATES. I HAD AN OPPORTUNITY TO WORK WITH THE NATIONAL PSORIASIS FOUNDATION, THIS IS NOW PUBLISHED AND THIS IS NOW BEING USED BY THE CENTER FOR DISEASE CONTROL, FOR CHRONIC DISEASE IMPACT ON QUALITY OF LIFE. SO I'M GOING TO SPEND THE LAST MINUTE WALKING US THROUGH UNDERSTANDING PSORIATIC DISEASE. I APOLOGIZE IF IT DOESN'T COME THROUGH AS WELL, IT WAS A LITTLE BIT COUPLE BEARSOME TO GET ON ONE SLIDE. SO THE HYPEKERATOSIS SCALY DISEASE PSORIASIS ROOTED IN SYSTEMIC INFLAMMATION, THE ROOT OF THIS IS DRIVING CAUSE MORBIDITIES SUCH AS CARDIOVASCULAR AND OBESITY SHOWN HERE AS A HEART AND AS A BEER BELLY, AS WELL AS MENTAL HEALTH ILLNESS AND CHOREATIC ARTHRITIS. ONE IN THREE PATIENTS WILL GET PSORIATIC ARTHRITIS. WHAT IS IMPORTANT HERE IS THAT REMIND PATIENTS TREATMENT GOALS ARE GET THE DISEASE TO NOT HAVE ACTIVE INFLAMMATION WITHIN THE PLAQUE. WHEN THERE IS ACTIVE INFLAMMATION IN THE PLAQUE THERE IS DIFFUSE SYSTEMIC INFLAMMATION AND THAT DIFFUSE SYSTEMIC INFLAMMATION THEN LEADS TO THE DELETERIOUS EFFECTS WE HAVE JUST SPOKEN OF SO IF ONE IMAGINES TREATING THIS DISEASE WITH PHOTOTHERAPY, WITH TOPICAL, WITH BIOLOGICS WHEN IT IS SEVERE, MAY ACTUALLY CUT THE ROOT CAUSE OF THE SYSTEMIC INFLAMMATION AND HERE THERE BY OBLITERATING AND IMPROVING CO-MORBID DISEASE. I HAVE BEEN FORTUNATE THESE DATA NOT ONLY HAVE JUST BEEN AWARDED A LARGE FOUNDATION GRANT FROM NATIONAL PSORIASIS FOUNDATION TO UNDERSTAND THE IMPACT OF STATIN THERAPY AND PSORIASIS, I'M WORKING ON DR. JOE GALFIN WITH THAT. THEY HAVE ALSO PROVIDED DATA FOR A LARGE CDC FUNDED EFFORT TO UNDERSTAND THE IMPACT OF CHRONIC DISEASES ON QUALITY OF LIFE. BEST YET, THIS PROVIDED US SUCH IN A PLATFORM TO INTRODUCE THE CONCEPT THAT CHRONIC INFLAMMATION WHEREVER IT IS IN THE BODY, WILL DRIVE INFLAMMATORY CARDIOMETABOLIC DISEASES OVER TIME. WITH THAT I ALWAYS CLOSE WITH THIS SLIDE TO REMIND YOU THAT THE VASCULAR HEALTH OF PATIENTS REALLY DOES DEPEND ON NOT ONLY EVERYTHING THAT I BROUGHT UP BUT CONTROLLING SYSTEMIC INFLAMMATION. I CAN BE FOLLOWED ON TWITTER, EMAILED AT NEHAL.MEHTA@NIH.GOV. HAPPY TO TAKE QUESTIONS, THANK YOU FOR THIS INCREDIBLE HONOR. >> NEHAL, THANK YOU SO MUCH. IF I CAN TAKE THE PREROGATIVE OF HOST AND ASKING A COUPLE OF REALLY BIG QUESTIONS TO START WITH. THE FIRST ONE IS WE TALK FREQUENTLY ABOUT PSORIATIC ARTHRITIS, A DISEASE WHICH ACCOMPANIES THE INFLAMMATION OF PSORIASIS AND YOU POINTED OUT IT CAN FREQUENTLY BE PRE-CLINICAL. SHOULD WE NOW TALK ABOUT PSORIATIC CORONARY ARTERY DISEASE? OR CEREBROVASCULAR DISEASE. YOU DIDN'T MENTION THAT BUT THAT MAYBE A COMPONENT. >> I FEEL TERRIBLE THAT THE CEREBROVASCULAR DISEASE DIDN'T MAKE IT IN THIS BECAUSE THERE IS A SLIDE THAT I COVER ON HOW STROKE ITSELF RIGHT AFTER THE ORIGINAL PAPER ON MYOCARDIAL INFARCTION STROKE ITSELF IS INDEPENDENTLY ASSOCIATED WITH THIS DISEASE. SO GREAT QUESTION, DR. GOTTESMAN. I WOULD SAY WE DO NEED TO SOMEHOW -- THE NUMBER THAT GETS PATIENTS, ACTUALLY NUMBERS GET PATIENTS WE ARE AT AN INFORMATION AGE SO WHAT I DO SAY ONE IN THREE WILL GET PSORIATIC ARTHRITIS. NOW WHAT I WILL SAY IS ONE IN FOUR WILL DEVELOP SOME FORM OF INFLAMMATORY VASCULAR DISEASE. SO THAT COULD BE AN ARTLITIS, IT COULD BE A STREAK, COULD BE A HEART ATTACK. BUT I THINK I'M UNDERCUTTING THE DATA. ITY IT IS HIGHER THAN ONE IN FOUR, AND COMES FROM THE POPULATION BASED STUDIES A. CXFC I DO THINK WE NEED THIS ACROSS MULTIPLE OTHER INFLAMMATORY DISEASES FOR IT TO GAIN TRACTION. I KNOW THAT DR. KAPLAN AND I WORK CLOSELY IN LUPUS ASSOCIATED DISEASE BUT THIS IS STILL SOMETHING THAT IS NOT AS WELL ACCEPTED AS INFLAMMATION PLAYS A ROLE IN HEART DISEASE. THERE'S STILL NOT THE FULL BUY IN THAT IT DRIVES VASCULAR HEALTH ABNORMALITIES BUT AFTER TEN YEARS OF WATCHING THESE PATIENTS I DO BELIEVE WE CAN SAY THERE IS A PSORIATIC ATHEROSCLEROTIC COMPONENT TO THIS FOR SURE. >> MY OTHER BIG QUESTION IS, IN THE ABSENCE OF SYMPTOMATIC INFLAMMATORY DISEASE, ARE YOU CONVINCED THAT ENOUGH OF THE CORONARY ARTERY DISEASE IS DUE TO INFLAMMATION THAT WE MIGHT BE CONSIDERING ANTI-INFLAMMATORY TREATMENT FOR PATIENTS WITH THAT DISEASE? IN THE ABSENCE OF OBVIOUS DISEASE LIKE LUPUS. >> YEAH. I THINK NOW THAT I HAVE HAD THE PRIVILEGE OF BEING HERE TENURED THINKING ABOUT THAT, YES, IN FACT I THINK THAT'S THE NATURAL NEXT STEP TO THINK ABOUT. I'M GOING TO REPHRASE THE WAY YOU ASK THAT QUESTION BECAUSE I ACTUALLY HAVE THOUGHT ABOUT IT AS WHEN I GET A PATIENT WITH PSORIASIS DOWN TO ZERO SKIN DISEASE, PASI 100 IF YOU WILL AND I HAD THEIR DISEASE CHECK THEY HAD THEIR COLONS CHECKED NOT INFLAMED, THERE'S STILL SOMETIMES PERSISTENT SOURCE OF INFLAMMATION. WHEN ONE LOOKS AT THEIR SCANS IN FACT THAT SOURCE OF INFLAMMATION IS VASCULATURE. SO ATHEROSCLEROSIS ITSELF MAYBE ENOUGH TO HAVE INFLAMMATORY CONSEQUENCES SO IF THAT IS THE LOGIC NATURALLY SHORT CUTTING THAT CYCLE WITH SOME CULTURE SCENE OR SHORT CIRCUITING THAT CYCLE WITH BIOLOGIC THERAPY, I THINK WHERE WE ARE RIGHT NOW IS TRYING TO BALANCE WE ARE IN AN ERA OF INJECTABLE MEDICINES, TRYING TO BALANCE DO I FORESEE IN MY 50s SHOOTING AN ANTI-TNF AS PART OF A ONCE A YEAR ANTI-INFLAMMATORY CADRE TO PREVENT DIABETES OR HEART DISEASE? I BELIEVE THAT THE THERAPY NEEDS TO BE SAFE WHICH ANTI-TNFs ARE, IT HAS TO BE EASY TO TAKE WHICH YOU COULD SAY INJECTABLE MEDS PLUS MINUS BUT WE ARE EVIDENCE FILLED ENOUGH TO TREAT INFLAMMATION AS RISK FACTOR. HOW WE WILL DO THAT THE LOWEST HANGING FRUIT DR. GOTTESMAN IS POST MI. I WAS HAVING A DISCUSSION YESTERDAY THAT IF WE LOOK AT THAT'S WHO ARE INFLAMED AND MI POST MI IS THE BIGGEST PREDICTOR OF ANOTHER MI SO IMAGINE IF YOU SHORT CIRCUIT THAT POST MI INFLAMMATION, THAT'S LEDOCO THAT'S COLCOT, SO THE CULTURE SCENE STUDY VERSUS SHOWN US PRETTY STRONG PROOF OF CONCEPT THAT WE CAN DO THIS. COULD CHAI SCENE WHAT WILL IT GET TO TAKE OUT TO DO IT? LARGER LONGER TERM CONFIRMATORY STUDIES. >> OKAY. I'M GOING TO TURN THE QUESTIONS OVER TO JESSICA. I'M SURE SHE HAS A LONG LIST OF THINGS PEOPLE ARE INTERESTING IN HEARING ABOUT JESSICA. >> THANK YOU, DR. GOTTESMAN. >> THANK YOU, DR. GOTTESMAN. WE ARE HAVING A LOT OF INCOMING QUESTIONS AND THEY AMAZING COMMENTS COMING IN SO I WILL FORWARD YOU THOSE AS WELL. SOME ADJECTIVES ARE FASCINATING, AMAZING, AWESOME, NOBEL LEVEL WORK. GOOD JOB ON THE TALK. SO FOR THE FIRST QUESTION WE HAVE A QUESTION THAT SAYS WITH THE RECENT CHANGES IN RECOMMENDING STATINS, HOW MIGHT YOU RECOMMEND MEDICAL DOCTORS KEEP THIS IN MIND FOR THEIR PSORIASIS PATIENTS? >> WE ARE ALSO IN AN ERA OF PATERNALISTIC MEDICINE. LIKE BEING A COLLEAGUE AND A ALMOST A PARTNER IN MEDICAL CARE SO I ASK THE PATIENT NOW I SAY WE PARTICIPATED IN GUIDELINES I DON'T ENDORSE NOR REFUTE THEM. I'M ASKING YOU WOULD YOU LIKE TO GO ON STATIN AND THE GUIDELINES SIMPLY SAY YOU HAVE TO HAVE THAT DISCUSSION BECAUSE AFTER THE SECOND OR THIRD TIME, THE PATIENT BECOMES RECEPTIVE SO WHAT I'M TELLING MY GENERAL MED CONTROL DOCTORS IS SIMPLY MENTION IF YOU HAVE A PATIENT WITH PSORIASIS SAY ARE YOU AWARE YOU HAVE A HIGH RISK OF DEVELOPING DIABETES HIGH BLOOD PRESSURE AND HIGH CHOLESTEROL. AND IN FACT GUIDELINES RECOMMEND THAT YOU TAKE A STATIN NOW, WOULD YOU LIKE TO? YOU WOULD BE SURPRISED I WOULD SAY OVER 60 TO 70% OF PATIENTS WHO ARE REALLY TAKING THEIR HEALTH INTO THEIR HANDS THEY WILL GO ON IT AND GO ON IT MODERATE INTENSITY AND STAY ON IT. >> NEXT QUESTION, YOU SHOW DATA THAT USE OF BIOLOGICS REVERSES MALIGNANT PLAQUE CHARACTERISTICS. IS THERE ANY SIGNAL DATA THIS TRANSLATE TO A REDUCTION IN MAY? >> GREAT QUESTION. YES, NOT DIRECT DATA SO I CAN'T -- I CAN'T EMPHATICALLY AGREE THERE WILL BE AN EVENT RATE LOWER BUG THERE'S THREE LINES OF EVIDENCE THAT WHEN ONE LOOKS AT EFFECT OF BIOLOGICKINGS ON MACE YOU CAN DO IT A COUPLE OF WAYS. THE BEST IS IF WE HAD A BILLION DOLLARS, IF WE HAD A BILLION DOLLARS WE WOULD RANDOMLY ASSIGN SEVERE PSORIASIS TO BIOLOGICS VERSUS PHOTOTHERAPY STANDARD OF CARE OR SYSTEM OTHER THERAPY. AND YOU WOULD FOLLOW THEM AND DO FIVE YEAR, SEVEN YEAR EVENT RATE. THE PROBLEM WITH THAT IS THE EVENT RATES ARE SO EXCEEDINGLY LOW IT WOULD BE ABOUT 20 YEAR STUDY HENCE THE BILLION DOLLARS. THREE LINES OF EVIDENCE FAIRLY I WOULD SAY WELL ACCEPTED THAT WHEN ONE LOOKS AT REGISTRY DATA IF YOU LOOK AT WHEN TIME ONE PATIENT GOES ON BIOLOGIC AND YOU FOLLOW 10, 12,000 PATIENTS OVER 10 YEARS THOSE ON ANTI-TNF THERAPY HAD LOWER MI AND LOWER MACE, AS A MARKET SCAN DATABASE ANALYSIS, IT'S RECONFIRMED IN DENMARK, THE INDUSTRY HAS SHOWN THAT THE BIODERM DATABASE BIOLOGICS IMPROVE MACE BUT NEVER BEEN DONE, WHAT WE ARE SHOWING OF VASCULAR CHANGES OVER ONE AND SOON FOUR YEARS WE WILL BE DOING FOUR YEAR ANALYSES SOON SO VASCULAR CHANGES WE ARE SEEING 0 TO 1 YEAR. WE WOULD LOVE TO BE ABLE TO INDEX THAT INTO DOES IT TRANSLATE TO EVENTS. WE ARE NOW THANK YOU TO THE NIH WE ARE NOW OPEN FOR TEN YEAR FOLLOW-UP SO GAIN SOFT OF THESE DATA AND WHAT OUR HOPE OUR GOAL WOULD BE IS TO A PSORIATIC SPECIFIC FRAMINGHAM TYPE RISK SCORE, AND THEN THE SECOND ONE, WE WOULD HOPE THAT WE WOULD HAVE TEN YEAR FOLLOW-UP DATA TO ADJUDICATE EVENTS. ONE UNPUBLISHED ANALYSIS THAT I FEEL COMFORTABLE SHARING WHEN WE LOOK AT 5,000 PERSON YEAR DATA ONE STRONGEST PREDICTOR OF HAVING INCIDENT EVENT WAS HIGHER NCB SO THE DATA THAT WE ARE SHOWING THIS NCB BEING BAD, HIGH AND GETTING BETTER, WE DO HAVE INTERNAL DATA THAT HIGH END CB IS BIGGEST PREDICTOR OF THE 11 EVENTS IN OUR COHORT. >> THANK YOU. THE NEXT QUESTION IS, WHAT ABOUT THE EFFECT OF THIS CHRONIC INFLAMMATION ON CANCER? >> SUCH A GREAT IMPORTANT TOPIC FOR US AS A COMMUNITY TO HEAR AND EMBRACE. IF YOU WILL ONCO LOGIC INFLAMMATION. CANCER INFLAMMATION. SO THE SECOND MOST COMMON CAUSE OF DEATH BEHIND CBD IN PSORIASIS IS CANCER. THOSE CANCERS MOST COMMONLY ORDER ARE LYMPHOMAS LEUKEMIA AND SOLID TUMORS. CTCL HAS A VERY HIGH PREVALENCE NINE FOLD ELEVATION OR SOMETHING LIKE THAT. THE INFLAMMATION IN OUR MODELS WE HAVE ACTUALLY WORKED WITH A FEW CANCER DOCTORS AND GROUPS FROM AROUND THE COUNTRY LOOKING AT DEVELOPMENT OF SOLID NO DUALS IN PSORIASIS. WE HAVEN'T PUBLISHED IT IN OUR GROUP WE WORKED WITH THE PIN GROUP AND FOUND THERE IS A HIGHER AMOUNT OF INCIDENTAL AN IMAGING FINDING THAT WASN'T SUPPOSED TO BE FOUND AND THE INCIDENT TALL LOMA RATE MOST COMMONLY ARE MUSCULOSKELETAL ABSCESSES, THEY CAN BECOME SARCOMAS, A LOT OF UTERINE AND LUNG NODULES WHICH CAN BECOME CARCINOMAS SO I THINK THERE IS A HUGE NEED TO UNDERSTAND THOSE BETTER. I ALWAYS MADE THE JOKE MUCH TO CHAGRIN OF CARDIOVASCULAR COLLEAGUES, ONCA IS DEN YEARS AHEAD OF US SO THEY ARE NOW LEARNING ABOUT THE INFLAMMATION PIECE, I DO INVITE STRONG COLLABORATORS TO COME IN AND FIGURE OUT HOW WE CAN DO THIS TOGETHER. THE HARDEST PART OF MY COHORT JUST TO KIND OF PUT A PERSONAL TOUCH TO THIS, THE HARDEST PART, I CAN'T FORGET TO THANK MY CLINICAL TEAM JUSTIN, ANDREW TONYA AND ALL THE FOLKS THAT DO THE WORK, WE HAVE ENOUGH INCIDENTAL CANCER DIAGNOSIS IT REALLY DOES BREAK MY HEART TO HAVE THAT DISCUSSION. SO WE NEED TO FIGURE THIS OUT. IT HAPPENS MORE IN THOSE NOT ON TREATMENT THOUGH PEOPLE WANT TO SAY IT IS THE BIOLOGIC THAT DID IT. WE HAVEN'T SEEN THAT IN OUR COHORT. BUT WE NEED TO REALLY TEAM UP AND GET THIS DOWN BECAUSE I KNOW CHRIS'S WORK SHOWING KEY PIECE OF IN >> MATION DRIVING ACUTE LEUKEMIA RECURRENCE AS WELL AS CHANGES IN CHIP AS WELL AS AXEL 2. SO THERE IS SOMETHING HERE IN BROADBAND MALIGNANCY, SOLID MALIGNANCY AS WELL AS PROLIFERATION IN GENERAL. >> I THINK WE HAVE TIME FOR ONE MORE QUESTION. THIS QUESTION ASKS HAVE YOU LOOKED AT SEX DIFFERENCES IN YOUR PSORIASIS PATIENTS? >> YES, WE HAVE. I'M GLAD THAT QUESTION HAS COME UP. FOR THE FIRST TIME WE HAVE THE POWER TO DETECT DIFFERENCES IN BINARY GROUPS BECAUSE WE HAVE HIT ABOUT 300 PATIENTS AT ONE AND SEE AND ONE YEAR FOLLOW-UP. WE PUT OUT A PAPER THAT DEMONSTRATED IN FACT MEN DEVELOP CORONARY DISEASE IN A PATTERN THAT IS SIMILAR TO GARDEN VARIETY ATHEROSCLEROSIS, SO THEY DEVELOP IT BUT THE DIFFERENCE BETWEEN MEN AND WOMEN IS MEN COMPARED TO WOMEN HAVE DIFFERENT AMOUNT OF FIBROFATTY AND LIPID DEPOSITION SO THIS AGAIN VARIED BY SEX BUT NOT BY HORMONAL STATUS SO WE LOOK AT PRE-MENOPAUSE VERSUS POST MEN PAUSE. POST MEN PAUSE BEHAVE LIKE MEN WITH ADVANCED CORONARY DISEASE. THESE ARE PUBLISHED IN JACK IMAGING IN 2021, AND WHAT WE HINTED IN THERE WAS THERE ARE HORMONAL DIFFERENCES ON THE VASCULAR WALL AS WELL AS LIPID BIOLOGY DRIVING SUBTLY FIBROFATTY BURDEN DIFFERENCES. WE HAVE NOT PUT OUT A LONGITUDINAL ANALYSIS BUT I FEEL COMFORTABLE SHARING THAT WE ARE NOW LOOKING AT OVER ONE YEAR,BACK DR. GOTTESMAN'S QUESTION THAT OVER A YEAR IF YOU LOOK AT IMPACT OF PSA ON PLAQUE WE ARE DOING THAT ANALYSIS NOW. IF YOU LOOK AT THE IMPACT OF SEX ON PLAQUE, WE HAVE DONE THAT ANALYSIS. IT IS INCREDIBLY IMPORTANT PEOPLE HEAR WHETHER YOU ARE A MAN OR WOMAN, THE BIGGEST PREDICTOR OF YOU HAVING IMPROVEMENT IN VASCULAR HEALTH IS YOUR PASI SCORE SO NEED TO TREAT ACTUAL DISEASE. THAT IS REASSURING. THE SECOND PIECE ABOUT THE SEX DIFFERENCES THAT I THINK IS VERY IMPORTANT WORK BY HEATHER TEAGUE IN MY LAB ARE DEMON INVESTIGATING AGE DIFFERENCES BY SEX AND HDL FUNCTION DIFFERENCES BY BIOLOGIC THERAPY SO WE MAY SEE FUTURE STUDIES LOOKING AT GENDER SEX EXCUSE ME, BIOLOGIC USE INTERACTIONS, AND THEN FINALLY THE THIRD PIECE, AGE MATTERS. ATHEROSCLEROSIS IS A DISEASE OF AGING, 80% OF US BY 80 WILL HAVE IT SO WE NEED TO FIND THESE PEOPLE EARLIER ON AND THAT'S WHY I HAVE LEFT IN A SCREEN SHARE ON BECAUSE IF ANY OF THIS RESONATES WITH YOU AS YOU CAN TELL I'M VERY HIGHLY MOTIVATED FOR COLLABORATION. >> WONDERFUL. THANK YOU. THANK YOU, VERY MUCH, NEHAL. BACK TO YOU MICHAEL. >> >> IT IS OVERWHELMING TO SEE HOW MUCH YOU ACCOMPLISHED IN YOUR TIME AT THE NIH AND IT IS REALLY QUITE FORTUNATE FOR US THAT YOU WERE THE FIRST OF THE LASKER SCHOLARS YOU SET A TONE AND THE PACE AND ORIGINALITY DISCOVERY THAT IS GOING TO BE VERY HARD TO MATCH. AS YOU KNOW, THE OTHER LASKER SCHOLARS ARE DOING QUITE WELL INDEED. THANK YOU SO MUCH FOR THIS LECTURE. WE LOOK FORWARD TO CONTINUING DISCUSSIONS ABOUT YOUR SCIENCE. TAKE CARE.