Welcome to the Clinical Center Grand Rounds, a weekly series of educational lectures for physicians and health care professionals broadcast from the Clinical Center at the National Institutes of Health in Bethesda, MD. The NIH Clinical Center is the world's largest hospital totally dedicated to investigational research and leads the global effort in training today's investigators and discovering tomorrow's cures. Learn more by visiting us online at http://clinicalcenter.nih.gov OUR SPEAKER IS DR. MARRIANA J. KAPLAN WHO IS SENIOR INVESTIGATOR AND CHIEF SYSTEMIC AUTOIMMUNITY BRANCH DEPUTY SCIENTIFIC DIRECTOR OF NIAMS. DR. KAPLAN OBTAINED HER MEDICAL DEGREE FROM THE UNIVERSITY OF NEW MEXICO AND COMPLETED INTERNAL MEDICAL RESIDENCY AT THE NATIONAL INSTITUTE OF SCIENCE AND NEW TRICIAN IN MEXICO CITY. SHE THEN COMPLETED A RHEUMATOLOGY FELLOWSHIP AND POST DOCTORAL TRAINING AT THE UNIVERSITY OF MICHIGAN WHERE SHE REMAINED FOR 15 YEARS AS A MEMBER OF THE FACULTY, RISING TO THE RANK OF PROFESSOR OF MEDICINE IN THE DIVISION OF RHEUMATOLOGY, AND SERVING AS AN ACTIVE MEMBER OF THEIR MULTIDISCIPLINARY LUPUS CLINIC, DR. KAPLAN'S RESEARCH HAS FOCUSED ON MECHANISMS OF ORGAN DAMAGE AND PREMATURE VASCULAR DISEASE AND AUTOIMMUNITY. SHE'S LED CLINICAL TRIALS TO IDENTIFY MECHANISMS THAT REDUCE BLOOD VESSEL DYSFUNCTION IN AUTOIMMUNE AND CHRONIC INFLAMMATORY DISORDERS. DR. KAPL,A N IS AN ASSOCIATED EDITOR OF THE JOURNAL OF CLINICAL ASSOCIATION AND DEPUTY DIRECTOR OF THE JOURNAL OF ARTHRITIS AND RHEUMATOLOGY. SHE SERVES ON THE SCIENTIFIC ADVISORY BOARD FOR THE LUPUS RESEARCH ALLIANCE AND FOR THE SCIENTIFIC ADVISORY COUNCIL OF THE LUPUS FOUNDATION OF AMERICA. --THE AMERICAN ASSOCIATION OF AMERICAN PHYSICIANS IN 2017. RECIPIENT OF NUMEROUS AWARDS INCLUDING THE AMERICAN COLLEGE OF RHEUMATOLOGY'S HENRY KONKLER AWARD FOR SIGNIFICANT CONTRIBUTIONS TO RHEUMATOLOGY RESEARCH, EDUCATION AND PATIENT CARE AND THE EVELYN B. HESS AWARD FROM THE LUPUS FOUNDATION OF AMERICA IN RECOGNITION OF HER SIGNIFICANT CONTRIBUTIONS TO LUPUS RESEARCH. THE TITLE OF HER PRESENTATION TODAY IS PREMATURE CARDIOVASCULAR DISEASE IN SYSTEMIC AUTOIMMUNITY: LESSONS LEARNED FROM LUPUS AND NOW LET'S GIVE A WARM VIRTUAL WELCOME TO DR. KAPLAN. >> THANK YOU VERY MUCH FOR INVITING ME TO GIVE THIS TALK THESE ARE MY DISCLOSURES FOR TODAY. AND I'M GOING TO START WITH A CLINICAL CASE OF PATIENT I SAW WHEN I WAS STILL AT THE UNIVERSITY OF MICHIGAN. BUT I THINK EXEMPLIFIES THE IMPACT THAT WHAT I WILL DISCUSS TODAY HAS IN PATIENTS WITH SYSTEMIC AUTOIMMUNITY AND IN PARTICULAR WITH LUPUS. SO, THIS WAS A 32 YEAR-OLD FEMALE HAD BEEN DIAGNOSED WITH LUPUS 4 YEARS PRIOR TO PRESENTING TO THE EMERGENCY ROOM WITH CHEST DISCOMFORT. AND 2 MONTHS PRIOR TO ADMISSION SHE STARTED DEVELOPING SHORTNESS OF BREATH ON EXERTION AS WELL AS CHEST DISCOMFORT WITH ACTIVITY. BUT DURING HER VISIT TO THE EMERGENCY ROOM SHE WAS FOUND TO HAVE ELEVATED CARDIAC ENZYMES CONSISTENT WITH AN M. I. SHE WAS ALSO TO FOUND TO HAVE 100% OCCLUSION OF THE N. A. D. WITH THE FRACTION BRANCH, HER FRACTION WAS 10% AND SHE REQUIRED STINTS AND SYSTEMIC SUPPORT, DESPITE ALL THAT SHE DEVELOPED CARDIO GENIC SHOCK, PULL MONITORARY EDEMA AND REQUIRED INTERNATIONAL CLASSIFICATION BATION,IARDIO SUPERVIEGZ AND PRESSURE SUPPORT. PAST MEDICAL HISTORY OF FAIRLY UNREMARKABLE EXCEPT FOR THE DIAGNOSIS OF LUPUS WHICH HAD MANIFESTED FAIRLY MILDED WITH RASH, FATIGUE. SHE WAS A VEGETARIAN, AVID RUNNER AND NO HISTORY OF SMOKING OR ALCOHOL USE AND HER FAMILY HISTORY WAS UNREMARKABLE INCLUDING NO EVIDENCE OF FAMILY HISTORY FOR CORONARY ARTERY DISEASE OR VASCULAR DISEASE OF ANY KIND THEN. DURING HER PHYSICAL EXAM, SHE WAS FEBRILE, HYPER TENSIVE, SHE LUPUS RASH AND EVIDENCE OF LUNG CONGESTION. HER LABS WERE REMARKABLE FOR ANEMIA. SHE HAD NORMAL LIPIDS, NORMAL SISSINE, AND SHE HAD DOUBLE STRANDED DNA AND ANTIBODIES WERE CONSISTENT WITH ACTIVE LUPUS AND HER ANEMIA WAS CONSISTENT WITH HEMALITTIA AND SHE HAD INFLAMMATORY MARKERS AND HER ENZYMES WERE ALSO ELEVATED. SO SINCE WE KNEW SHE HAD LUPUS WE TREATED WITH WITH IV AND HER RASH GOT BETTER AND HEMOGLOBIN IMPROVED, SHE WAS EXTRANSLATIONAL RESEARCH BAITED AND HEART FUNCTION IMPROVED AND SHE WAS DISCHARGED TO HOME ON A VARIOUS COMBINATION OF MEDS AND PREDNISOLONE, WE SAW HER A FEW MONTHS LATER AND WAS DOING WELL, SHE HAD MANAGED TO DECREASE HER CORTICO STEROID DOSE AND HER HEART FUNCTION HAD RETURNED TO NORMAL AND SHE ASKED THE FOLLOWING QUESTIONS, WHAT CAUSED MY HEART ATTACK? AND WHAT--[AUDIO CUTS OUT ]--THIS CASE EXEMPLIFIES SOMETHING THAT WE--WHILE IT MAKES UP QUITE DRAMATIC THAT SOMEONE 32 YEARS OLD WOULD DEVELOP A HEART ATTACK WITH NO HISTORY OF RISK FACTORS, I THINK THIS IS A GOOD EXAMPLE OF CASES THAT AS RHEUMATOLOGYSTS WE ENCOUNTER NOT THAT INFREQUENTLY. SO, THE OBJECTIVES OF MY TALK TODAY IS TO REVIEW CARDIOVASCULAR RISK IN LUPUS, EXPLORE POTENTIAL MECHANISMS INVOLVED IN THIS DAMAGE AND I WILL FOCUS ON SOME OF OUR WORK ON THE ROLE OF THE INNATE IMMUNE SYSTEM AND THEN I WILL REVIEW POTENTIAL INTERACTIONS THAT MITIGATE AND EMIT CARDIOVASCULAR ISSUES IN LUPUS. WE HAVE KNOWN FOR SEVERAL YEARS THAT ABNORMAL GLUCOSE TOLERANCELER O SCLEROSIS IS NOT JUST INFLAMMATION OF THE ARTERIES BUT IT'S IT'S A STRONG DRIVER. AND PART OF THIS EVIDENCE HAS COME FROM THE REALIZE FROM EPIDEMIOLOGIC STUDIES AND ALSO CLINICAL OBSERVATIONS THAT PEOPLE THAT HAVE SYSTEM TEMMIC AUTOIMMUNE DISORDER HAVE HIGHER RISK TO DEVELOP CARDIOVASCULAR COMPLICATION SUCH AS MY O CARDIAL INFECTION AND STROKE. AND THIS HAS BEEN WELL OBSERVED IN THE CASE OF LIEWP ISOTOPE, ARTHRITIS AND PSORIASIS, AND CONDITIONS THAT ARE LESS PREVALENT AND THAT'S WHY IT'S MORE DIFFICULT TO KNOW THE EXACT INCIDENTS AND PREVALENCE OF ABNORMAL GLUCOSE TOLERANCE CLER O SCLEROSIS AND WE ALSO SEE INCREASED CARDIOVASCULAR RISK AND THIS SHOWS SJOGREN'S SYNDROME, ET CETERA. SO WHAT LESSONS CAN WE LEARN FROM AUTOIMMUNE DISEASES AND 1 QUESTION IS ARE THERE COMMON MEDIATORS THAT THIS IS IN AUTOIMMUNITY. IS IT ALL SYSTEMIC INFLAMMATION, HIGH CARP, OR MEDIATORS THAT CAUSE ATHEROSCLEROSIS SPECIFIC TO THE VARIOUS CONDITIONS AND CAN WE LEARN THERE ARE DIFFERENT WAYS BY WHICH ATHEROSCLEROSIS MAY DEVELOP IN PEOPLE WITH OUT AUTOIMMUNITY BUT ALSO IN THE GENERAL POPULATION. SO LUPUS IS A PRIME EXAMPLE, THIS IS AN AUTOIMMUNE SYNDROME, MAINLY WOMEN OF CHILD BEARING AGE AND MINORITIES. IT HAS A PROFOUND CLINICAL HETEROGENEITY BECAUSE THIS IS REALLY A SYNDROME AND NOT JUST 1 DISEASE AND IT IS MANIFESTED BY PERIODS OF CLINICAL FLARE FOLLOWED BY SOMETIMES LONG PERIODS OF REMISSION THAT THEN LEAD TO ANOTHER FLARE. AND THEREFORE PATIENTS ARE EXPOSED TO CHRONIC IMMUNE DISREGULATION FOR EXTENDED PERIODS OF TIME AS YOU KNOW THIS REQUIRES THE USE OF IMMUNOSUPPRESSIVE DRUGS THAT MAY ALSO IMPACT CHRONIC COMPLICATIONS AND DESPITE EVIDENCE THAT WE'RE DOING A BETTER JOB AT MANAGING LUPUS, OUR PATIENTS ARE MANAGING TO LIVE LONGER THAN THEY DID 50 YEARS AGO, WOMEN STILL HAVE A SIGNATURES HAD 95 CANTILY HIGH RISK OF DYING COMPARED TO WOMEN WITHOUT LUPUS AND AS THEY ACCRUE DAMAGE AND AS TIME GOES BY, THEIR MORTALITY SIGNIFICANTLY HIGHER THAN IN WOMEN WITHOUT THE DISEASE. SO THIS IS JUST TO SHOW YOU THAT BOTH IN KAWITATION POPULATION BUT MORE IN MINORITIES THAT HEAR SUCH AS AFRICAN AMERICAN AS TIME GOES BY AND PATIENTS ACCRUE MORE DAMAGE AND WHEN YOU START THINKING OF OUR YEARS SINCE LUPUS DIAGNOSIS THERE IS A SIGNIFICANT CUMULATIVE MORTALITY IF YOU ARE THINKING THAT THESE ARE YOUNG WOMEN SO THAT AN AFRICAN AMERICAN WOMEN 14 YEARS AFTER DIAGNOSIS COULD HAVE MORTALITY THAT IS HIGHER THAN 30%. AND THIS IS ASSOCIATED TO WHAT WE NOW KNOW IS A COMMUNITY IMPACT OF ATHEROSCLEROSIS IN VARIOUS TERRITORIES. AND THE FIGURE ON THE RIGHT SHOWS THE PREVALENCE OF CAROTID PLAQUE IN WOMEN WITH OR WITHOUT LUPUS AND YOU CAN SEE THAT EVEN IT STARTED VERY EARLY DURING THEIR LIFETIME WHEN WOMEN THAT ARE THEIR 30S OR HAVE A VERY SIGNIFICANT INCREASE IN THE PREVALENCE OF CAROTID PLAQUE COMPARED TO WOMEN WITHOUT LUPUS AND OF COURSE AGING DOESN'T MAKE THINGS BETTER AND IF YOU CAN SEE THE PREVALENCE OF CAROTID PLAQUE THAT MAY BE ASYMPTOMATIC WITH WOMEN WITH LIEWP ISOTOPE IN THEIR 50S AND 60S, IT IS QUITE DRAMATIC THE INCREASE. SO WE NOW KNOW THAT VASCULAR EVENTS CONTRIBUTE--[AUDIO CUTS OUT--] AND THIS VASCULAR DAMAGE IS FOR THE MOST PART COMING FROM ACCELERATED ABNORMAL ERATED ATHEROSCLEROS IS, WE ALSO KNOW THAT SMOKING, DIABETES, DISLIP DEEMIA ONLY PARTIALLY EXPLAIN THE INCREASE OF LUPUS SO EVEN AFTER ADJUSTING WITH THE FRAMING OF THIS QUESTION, WE STILL SEE SIGNIFICANT INCREASE IN CARDIOVASCULAR RISK. WOMEN WITH LUPUS ARE MORE LIKELY TO DIE FOLLOWING THEIR FIRST MY O CARDIAL INFECTION FOR PATIENTS WITH DIABETES AND THE AVERAGE WOMEN OF WOMEN IN M. I. WITH LUPUS IS MORE THAN 10 YEARS YOUNGER THAT YOU MAY EXPECT IN WOMEN WITHOUT LUPUS AND THESE VASC LOPATHY THAT MAY COME FROM ATHEROSCLEROSIS, IT'S SUCH A PROMINENT FEATURE IN LUPUS THAT IT'S NOT ONLY THE DEVELOPMENT OF THE ABNORMAL GLUCOSE TOLERANCELER O SCLEROSIS TO STROKE AND LEADING TO OTHER TYPES OF DISEASE WITH THE CNS WITH NEUROLOGIC MANIFESTATIONS, PREGNANCY COMPLICATIONS SUCH AS CLAMPSIA AND PREECLAMPSIA FOR WOMEN WITH LUPUS AND MORE CHILDHOOD ONSET LUPUS. WE KNOW KIDS, TEENAGERS ALREADY HAVE ACCRUED SIGNIFICANT VASCULAR DAMAGE AND SHOW EVIDENCE OF SUBCLINICAL CORONARY AND CAROTID ATHEROSCLEROSIS. SO THE PROBLEM IS SO STRIKING THAT IF YOU SCREEN A HUNDRED LUPUS PATIENTS THAT HAVE NO HISTORY OF PRIOR VASCULAR EVENT, YOU WILL FIND A SIGNIFICANT PROPORTION OF THEM HAVE PREVALENCE OF CLINICAL VASCULAR DYSFUNCTION AND ATHEROSCLEROSIS AND THIS CAN BE MEASURED BY LOOKING AT THE FUNCTION OF THE ARTERIES IN VARIOUS VASCULAR TERRITORIES BY SEEING HOW STRICT THE ARTERIES ARE BY LOOKING AT MIRROR IMAGEEE CARDIAL PROFUSION ABNORMALITIES AND BY LOOKING AT EVIDENCE OF PLAQUE IN BOTH THE CAROTID AND CORONARIES AND ALL OF THESE HAVE BEEN FOUND TO 8 HOURS SIEVE 95 CANTILY NORMAL AND THERE IS MUCH HIGHER THAN THE ACTUAL AGE OF THE INDIVIDUAL. SO WHAT IS UNUSUAL ABOUT THIS DEVELOPMENT OF THIS IN LUPUS? SO FIRST, MOAFORT IMPORTANT IS THAT THIS DISEASE LUPUS EFFECTS PRIMARILY YOUNG WOMEN AND WE DON'T THINK ABOUT HEART ATTACKS AND STROKES IN YOUNG WOMEN BUT AS YOU SAW WITH THE EXAMPLE OF THE PATIENT, I SAW YEARS AGO, THIS HAPPENS AND HAPPENS IN DRAMATIC WAYS. FURTHER MORE WHAT WE CALL THE CLASSICAL INFLAMMATORY BURDEN ASSOCIATE WIDE ATHEROSCLEROSIS, HIGH SENSITIVITY, ELEVATED HIGH SENSITIVITY CRP AND ASSOCIATE WIDE HIGH LDLs WHICH IS ASSOCIATE WIDE CARDIOVASCULAR EVENTS, WE TYPICALLY DON'T SEE THAT IN LUPUS. MANY LUPUS PATIENTS DO NOT MOUNT A HIGH CRP RESPONSE AND WHEN WE ELEVATE THESE IN LUPUS WE SUSPECT INFECTIONS RATHER THAN THESE BEING FROM ACTIVE--LUPUS DISEASE ACTIVITY AND THEIR LDL LEVELS CAN BE HIGH, THEY'RE NOT WHAT CHARACTERIZES LIPID PANEL IN LUPUS THE MOST AND I WILL TALK ABOUT THESE A BIT MORE LATER DURING MY TALK. AS I MENTIONED THE ENHANCED CARDIOVASCULAR RISK IS NOT EXPLAINED BY THE LUPUS EQUATION OR BY MEDICATION EMPLOY YOU WILL STILL HEAR THAT MANY PHYSICIANS THINK THIS IS DUE TO THE USE OF COTTERRIC O STEROIDS, AND I THINK YEAH, THEY CAN BE BE WHEN USED FOR PROLONGED PERIODS OF TIME AND HIGH DOSES BUT THIS IS NOT THE MAIN REASON WHY MAISHTS WITH LUPUS OR PATIENTS WITH RHEUMATIC DISEASES DEVELOP ATHEROSCLEROSIS. FINALLY AT THIS POINT WE DON'T HAVE GOOD EVIDENCE THAT THE STATINS BY THEMSELVES CAN DO A GOOD JOB IN CARDIOVASCULAR PREVENTION IN LUPUS. NOT THAT THEY SHOULDN'T BE USED, THEY HAVE A ROLE BUT THE STATIN TRIAL SO FAR, ALBEIT SMALL HAVE BEEN INCONCLUSIVE. SO AT THE CLINICAL CENTER, WE HAVE ESTABLISHED CARDIOVASCULAR LUPUS COHORT, WHERE WE'RE TRYING TO BETTER UNDERSAND WHY CARDIOVASCULAR DISEASE DEVELOPS NATURALLY IN LUPUS. WHAT CAN BE EARLY BIOMARKERS OF THINGS WE MAY IDENTIFY AND CAN WE COME UP WITH GOOD INTERVENTIONS TO PREVENT THIS COMPLICATION, SO PATIENTS COME TO THE CLINICAL CENTER AND WE DRAW BLOOD AND THEY UNDERGO A VARIETY OF BIOMARKER ASSESSMENTS AND WE ALSO BIOBANK SOME OF THE BLOOD AND CELLS. WE ALSO PERFORM MULTIFUNCTIONAL ASSESSMENT OF THEIR VASCULATURE LOOKING AT SMALL MEDIUM AND SMALL LARGE VASCULAR TERRITORIES, WE IN COLLABORATION WITH [INDISCERNIBLE] GROUP AT NHLBI, WE HAVE BEEN LOOKING AT VASCULAR INFLAMMATION AND WHAT IS THE--CT ANCHLIO GRAMS TO LOOK AT THE QUANTITY AND QUALITY OF THE COROWNARY PLAQUE AND AS I MENTIONED HERE, IT'S TO UNDERSTAND THE NATURAL HISTORY OF CARDIOVASCULAR DISEASES IN LUPUS AND COMPARE WITH OTHER INFLAMMATORY DISEASES AND ALSO WE HAVE STARTED SEVERAL CLINICAL TRIALS THAT SOME OF THEM HAVE BEEN COMPLETED THAT HAVE US EITHER PRIMARY OR SECONDARY OUTCOMES, CARDIOVASCULAR FUNCTION, CARDIO METABOLIC RISK AND TALK ABOUT A COUPLE OF THESE TRIALS LATER DURING MY TALK. I HAVE TO SHOW YOU HERE HOW PROGRAMMATIC THIS CAN BE, THIS IS JUST REPRESENTATIVE IMAGE OF THE [INDISCERNIBLE] CT SCAN OF A HEALTHY CONTROL AND A LUPUS PATIENT, BOTH IN THE EARLY 40S AND IN RED AND YELLOW, YOU SEE EVIDENCE OF ENHANCED VASCULAR INFLAMMATION, YOU CAN SEE THAT A HEALTHY WOMAN IN HER 40S DOESN'T HAVE MUCH BUT AS YOU CAN SEE THIS PATIENT WHO HAD NO PREVIOUS HISTORY OF CLINICAL VASCULAR DISEASE HAS SIGNIFICANTLY ENHANCED VASCULAR INFLAMMATION AND THIS IS ASSOCIATED WITH EVIDENCE OF ACCELERATED OR INCREASED CORONARY PLAQUE THAT IN MANY LUPUS PATIENTS IS NOT KALINGSIFIED AND YOU CAN SEE HERE--CALCIFIED AND YOU SEE HOW THE CORONARY LOOKED IN A HEALTHY INDIVIDUAL, PRETTY STRAIGHT AND SMOOTH, THEN WE START IDENTIFYING HERE WHERE THE ARROWS ARE AREAS OF PLAQUE THE POSITION IN THE LUPUS PATIENTS AND THIS IS SIGNIFICANTLY ENHANCED IN LUPUS AND ALSO ASSOCIATED WITH THE EVIDENCE THAT THE ARTERIES IN IN PATIENTS ARE MUCH STIFFER AND APPEAR TO LOOK MORE LIKE THE ARTERIES YOU MAY SEE IN A 60 YEAR-OLD MAN WITH RESPECT TO CORONARY ARTERY DISEASE, NOT IN A 30-40 YEAR-OLD PATIENT WITH LUPUS. SO THIS IS JUST TO EXEMPLIFY THE VASCULAR PHENOTYPE OF THESE LUPUS PATIENT SYSTEM SIGNIFICANTLY ABNORMAL. SO WHAT DO WE KNOW ABOUT THE NATURAL HISTORY OF LUPUS THAT MAY GIVE US SOME CLUES ABOUT WHY LUPUS PATIENTS DEVELOP PREMATURE CARDIOVASCULAR ATROPHY AND WHAT CAN WE UNDERSTAND FROM THE IMMUNE REGULATION THAT THESE PATIENTS DEVELOP THAT HELP US COME UP WITH THERAPEUTIC STRATEGIES AND PREVEBTIVE STRATEGIC PLAN KNOWLEDGEYS. SO THE WAY WE UNDERSTAND LUPUS WHICH IS THE CASE WITH MANY CHRONIC INFLAMMATORY DISEASES IS THIS REPRESENTS A MULTISTEP PROCESS WHERE BOTH GENETIC AND ENVIRONMENTAL FACTORS PLAY KEY ROLES IN BREAKING IMMUNE TOLERANCE AND THERE ARE PROLONGED PRECLINICAL PHASES THAT MAY HAPPEN DECADES BEFORE PATIENTS DEVELOP CLINICAL EVIDENCE OF AUTOIMMUNE DISEASES WHERE YOU MAY SEE SIGNIFICANT ABNORMALITIES IN BOTH INNATE AND ADAPTIVE IMMUNE CELLS AND IN LUPUS THIS IS QUITE STRIKING, ALMOST EVERY CELL TYPE IS EFFECTED IN LUPUS AND EEIVETTUALLY WHAT WE KNOW IS THAT THROUGH ENVIRONMENTAL FACTORS, THROUGH STOIKASTIC MODEL CASTIC EVENTS, THERE IS A MOMENT WHERE PATIENTS START DEVELOPING AUTOANTIBODIES THAT ARE DIRECTED TO INTRA CELLULAR AND EXTRA CELLULAR ANTIGENS AND IN THE CASE OF LUPUS MOST OF YOU KNOW TO [INDISCERNIBLE] ANTIGENS AND AT SOME POINT THERE'S A SECOND OR THIRD OR FOURTH HIT THAT WILL LEAD TO THE ACUTE DEVELOPMENT OF MANIFESTATIONS OF LUPUS, FOLLOWED BY PERIODS OF INFLAMMATION OR FLARE EITHER FROM SPONTANEOUS OR MEDICATIONS AND AS PATIENTS LIVE LONGER WE NOW SEE MORE AND MORE THE CHRONIC COMPLICATIONS, CHARACTERISTICS OF PROLONGED SHORTOXIDATIVE STRESS AND IMMUNE DISREGULATION INCLUDING CARDIOVASCULAR DISEASE. AND SOMETHING I WANT TO MENTION REGARDING PATHOGENESIS OF LUPUS IS THAT WE NOW KNOW FROM MANY GROUPS BOTH IN MOUSE MODELS BOTH IN HUMANS THAT TYPE 1 INTERFERONS, THAT AS YOU KNOW ARE POTENT ANTIVIRAL PROTEINS, PLAY IMPORTANT ROLES IN LUPUS PATHOGENESIS, BOTH FROM GENETIC PREDISPOSITION AND FROM POORLY UNDERSTOOD ENVIRONMENTAL FACTORS WE KNOW THAT LEVELS OR TYPES OF INTERFERONS ARE INCREASED IN LUPUS PATIENTS IN THE ABSENCE OF VIRAL INFECTIONS THEY ARE CHRONICALLY INCREASED SO PATIENTS ARE EXPOSED TO HIGH LEVELS OF TYPE 1 INTERFERONS FOR LONG PERIODS OF TIME AND ALSO THE LUPUS CELLS ARE MORE SENSITIVE TO THE EFFECTS OF TYPE 1 INTERFERON, SO THESE PHENOMENON APPEARS TO BE INVOLVED IN THE IMMUNE DISREGULATIONULATION CHARACERISTIC OF LUPUS, BUT AS I'LL MENTION IN THE NEXT SLIDES WE NOW THINK THAT TYPE 1 INTERFERONS HAVE PROFOUND EFFECTS IN THE VASCULATURE THAT MAY DRIVE AT LEAST IN PART PRETTY MUCH THE VASCULAR DAMAGE. AND TALKING A BIT ABOUT GENETIC FACTORS, WE NOW KNOW THAT THE MORE GENETIC RISK FACTORS YOU HAVE FOR THE DEVELOPMENT OF LUPUS SO YOUR GENETIC RISK SCORE, NOT ONLY YOU WILL DEVELOP LUPUS AT AN EARLY AGE--LUPUS IF YOUR GENETIC RISK IS HIGHER SO WE DO KNOW THAT GENETIC FACTORS PLAYS A ROLE AND THIS MAY BE RELAILTED TO HOW GENETIC RISK CONFIRMS AND HAS ABILITY TO PRODUCE TYPE 1 INTERFERONS OR TYPE 1 INTERFERON BUT THERE MAY BE OTHER FACTORS. SO IT IS DIFFICULT TO PINPOINT AT WHAT EXACTLY PROMOTES CARDIOVASCULAR DISEASE IN LUPUS AND OF COURSE THERE ARE LUPUS SPECIFIC MECHANISMS THAT MAY BE INVOLVED, PATIENTS WITH LUPUS MAKE A VARIETY EVER AND THOSE CAN DAMAGE THE VASCULATURE AND THEY HAVE COMPLEMENT ACTIVATION AND CONSUMPTION, THAT I PRODUCE A LARGE VARIETY OF PROINFLAMMATORY CYTOKINES AND THEY HAVE THIS REGULATION OF MANY CELL TYPES. LUPUS PATIENTS ALSO HAVE METABOLIC DISTURBANCES THAT ARE NOT LUPUS-SPECIFIC BUT ARE HIGH PREVALENCE AND QUITE PROFOUND AND THIS INVOLVES A VARIETY OF LIPID ABNORMALITIES THAT ARE DISCUSSED IN MY TALK BUT ALSO HIGHER INCIDENCE OF RENAL DISEASE AND HYPER TENSION AND AS WITH OTHER INFLAMMATORY DISEASES THERE IS HIGH PREVALENCE OF INSULIN RESISTANCE. --WE KNOW THE LEVELS OF CYTOKINES INCREASE WHEN PATIENTS ARE MORE SICK, SHOW MORE DISEASE ACTIVITY AND THERE IS PLENTY OF ANECDOTA EVIDENCE THAT IF YOU GIVE A HEALTHY INDIVIDUALS EXOGENOUS INTERFERONS FOR A VARIETY OF TREATMENTS FOR OTHER CONDITIONS, YOU MIGHT SEE DEVELOPMENT OF LUPUS OR EXACERBATION AND THERE ARE A NUMBER OF ONGOING CLINICAL TRIALS ARE TRYING TO TARGET THIS PATHWAY, WITH SOME PROMISING RESULTS. BUT WE ALSO KNOW FROM OLD LITERATURE THAT TYPE 1 INTERFERONS HAVE TYPE 1 ANGIOGENIC EFFECTS AND WE START TO STUDY THIS IN THE CONTEXT OF LUPUS AND WE HAVE MULTIPLE CANCER LINES BUT WHAT WE FOUND WAS THAT THIS CHRONIC ELEVATION OF TYPE 1 INTERFERONS WAS ACTUALLY PROMOTING A STRONG ANGIOGENIC PHENOTYPE IN THE LUPUS PATIENTS SO THE VASCULAR MECHANISMS WERE SIGNIFICANTLY PRETURBED FOR THE CHRONIC ELEVATION OF TYPE 1 INTERFERONS AND THROUGH A VARIETY OF MODELS AND ALSO STUDIES IN PATIENT CELLS WE FOUND THAT THIS--THIS MAY BE CRUCIAL NOT ONLY IN THE PROMOTION OR INITIATION OF VASCULAR DAMAGE IN LUPUS BUT AS I MENTIONED THAT THIS WAS ALSO LEADING TO AN ANGIOGENIC RESPONSE THAT WAS PROMOTING LOSS OF RENAL FUNCTION AND MAYBE ALSO CONTRIBUTING TO PREECLAMPSIA. SO JUST TO SUMMARIZE WORK IN FROM MANY YEARS AND OTHERS WE HAVE FOUND THAT TYPE 1 INTERFERONS HAVE PLEOTROAPIC EFFECTS IN THE VASCULATURE THAT MAY SIGNIFICANTLY ENHANCE THE DEVELOPMENT OF ATHEROSCLEROSIS. SO NOT ONLY TYPE 1 INTERFERONS PROMOTE THE DYSFUNCTION OF CELLS THAT INVOLVED IN VASCULAR REPAIR AND ANY VASCULAR FROM THE IMMUNE SYSTEM MAY NOT BE PROPERLY PREPARED BUT THIS MAY HAVE DIRECT EFFECTS ON THE MATURE AND FETAL CELLS AND LEAD TO ENDOTHELIAL DYSFUNCTION THAT MAY ALSO BE CONDUCIVE TO ATHEROSCLEROSIS. TYPE 1 INTERFERONS CAN MODULATE FUNCTION AND LEAD THEM TO BECOME HOME CELLS AND THERE IS QUITE A BIT OF EVIDENCE SUGGESTING THAT TYPE 1 INTERFERONS CAN MODULATE THE TRANSCRIPT OHM AND PROMOTE AND ACTIVATE A PLATE TO THE PHENOTYPE THAT MAY LEAD TO THROMBOSIS ENHANCEMENT AND DEVELOPMENT OF ACUTE CORONARY SYNDROMES AND FINALLY THERE HAS BEEN RECENT EVIDENCE BY VARIOUS GROUPS SHOWING EFFECTS FROM TYPE 1 INTERFERONS ON METABOLISM AND THERE IS EVIDENCE THAT THEY CAN IMPACT LIVER IMMUNE RESPONSES AND LEAD TO THE DEVELOPMENT OF INSULIN RESISTANCE AND METABOLIC SYNDROME. SO 1 COULD ENVISION THAT IN PATIENTS THAT HAVE CHRONICALLY RELATED LEVELS OF THESE CYTOKINES AS OPPOSE TO SOMEONE THAT JUST HAS A VIRAL INFECTION THAT IS CLEARED AND THE LEVELS GO DOWN, MAY OVER THE YEARS DEVELOP VASC LOPATHY AND THIS COULD POTENTIALLY LEAD TO THE DEVELOPMENT OF ATHEROSCLEROSIS. SO WE HAVE TESTED THIS IN A VARIETY OF MOUSE MODELS, THAT HAVE CONFIRMED THAT IF WE BLOCK TYPE 1 INTERFERONS IN MOT MODELS WITH LUPUS WE CAN SIGNIFICANTLY IMPROVE THE LUPUS RADICK LOPATHY AND AS WELL AS ATHEROSCLEROSIS AND WE STUDIED YEARS AGO IN A LUPUS ON COHORT, IF YOU FOLLOW THESE PATIENTS AND LOOK AT THEIR DEVELOPMENT OF ENDOTHELIAL DYSFUNCTION, CAROTID PLAQUE OR SEVERITY OF CORONARY FINDINGS, WITH THIS ABNORMALITIES, AFTER CONTROL BEING FOR FRAMING AND RISK FACTORS AND IN TURN WHAT WE FOUND IN THOSE STUDY SYSTEM THAT IF YOU WERE A LUPUS PATIENT THAT HAD LOWER TYPE 1 INTERFERON RESPONSES, YOU WERE LESS LIKELY TO PROGRESS IN YOUR CORONARY FINDINGS OVER A PERIOD OF TIME AND YOU STARTED WITH HIGH LEVELS OF TYPE 1 INTERFERON, SO THIS HAD SOME IMPLICATIONS FOR LONGITUDINAL FOLLOW UP. SO NOW I WILL TELL YOU ABOUT ANOTHER ASPECT OF THE INNATE SYSTEM THAT WE THINK SYNERGIZES WITH TYPE 1 INTERFERON DISREGULATION TO ACCELERATE DAMAGING LUPUS AND THIS IS RELATED TO NUTRIFILLS. SO NUTRIFILLS AS YOU KNOW ARE VERY RELEVANT FOR ANTIMICROBIAL RESPONSES AND THEY CAN ATTACK THIS IN A VARIETY OF WAYS AND ABOUT 50 YEARS AGO A NEW ANTIMICROBIAL MECHANISM WAS DESCRIBED WHERE BY NUTRIFILLS UPON ENCOUNTER WITH THE VARIOUS MICROBES EXTRUDE THEIR DNA AND OTHER NUCLEAR MATERIAL BOUND TO PROTEIN GRANULES IN THIS MESH WORK OF CHROMATIN AND NUTRIFILL PROTEINS CALLED NUTRIFILL EXTRA CELLULAR TRAPS OR NETS AND THESE STRUCTURES ARE VERY GOOD AT TRAPPING MICROBES AND THEY'RE MORE RELAXING THEM SO THAT THE ANTIMICROBIAL MECHANISM FOR THE NUTRIFILLS CAN TAKE PLACE. NOW WE KNOW THAT FROM THE WORK FROM OUR GROUP AND OTHERS IS IN PATIENTS SUCH AS LUPUS SO LUPUS PATIENT CANS MAKE THESE NETS EVEN IN THE ABSENCE OF INFECTION AND THIS CAN BE A VERY STRIKING PHENOTYPE NUTRIFILL AND THIS IS PARTICULARLY THE CASE WE HAVE IN NUTRIFILLS IN THE PATIENTS WHEN YOU DO A DENSITY TEST TO THE BLOOD INSTEAD OF GOING TO THE BOTTOM, THESE CAN BE FOUND WHERE THE MONONUCLEAR CELLS ARE SO WE CALL THEM LOW DENSITY GRANULE SITES AND WE HAVE FOUND FROM WORK OVER MANY YEARS THAT THESE CELLS ARE ACTUALLY NOT JUST A PHENOMENON BUT THEY REPRESENT A DISTINCT DISTINCT PATHOGENIC SUBSET AND HAVE THE ABILITY TO FORM THESE NETS IN VERY HEIGHTENED WAYS EVEN IN THE ABSENCE OF ANY INFECTION, SO THEY'RE NETTING CONSTANTLY AND 1 OF THE CONSEQUENCES OF HAVING THIS INFORMATION IS THE IMPACT ON THE VASCULATURE AND WE KNOW THAT WE HAVE THAT FORMATION CAN LEAD TO ENDOTHELIAL CELL DEATH BUT THERE IS NOW EXTENSIVE WORK FROM OUR LAB AND OTHERS THAT THEY CAN HAVE DELETERIOUS EFFECTS ON THE VASCULATURE NOT ONLY IN PATIENTS WITH IMMUNITY BUT PLAY PROMULGATE NET ROLES WITH THE DEVELOPMENT OF ATHEROSCLEROSIS IN THE GENERAL POPULATION. SO NOT ONLY KILLING ENDOTHELIAL CELLS BUT ALSO IMPORTANT INDUCERS FOR PLATELET ACTIVATION AND ANTICOAGULATION FACTORS. THEY CAN THEMSELVES PRODUCE MORE SYNTHESIS AND OTHER PRO INFLAMMATORY PROCESSES I--DYSFUNCTIONAL AND THERE IS EVIDENCE NOW FROM A HUMAN STUDIES AND FROM AN AN ANIMAL MODELS THAT THEY ARE PROTOGENIC AND THAT DISRUPTING THIS CAN MITIGATE ATHEROSCLEROSIS. SO WHAT WE PROPOSE IS THAT BECAUSE BOTH TYPE 1 INTERFERON LEVELS AND RESPONSE TO THEM AND THE FORMATION OF NETS AND NUTRIFILL RESPONSES ARE REGULATED IN THROMBOSIS THIS MAY BE HAPPENING DURING ATHEROSCLEROSIS DEVELOPMENT EVEN IN THE GENERAL POPULATION WHERE YOU HAVE THE CONVERGENCE OF DISREGULATED DEVELOPMENT OF THE PLAQUE AND THEY PLAY A ROLE IN THE VARIETY OF PROCESSES AND IN THE ARTERY THAT LEAD TO PLAQUE FORMATION, ALONG WITH THIS INFILTRATING NETTING NUTRIFILLS THAT MAY BE HAVING THIS PATHOPHYSIOLOGIC CROSS TALK AND ECASSIGNEDDER BAITING PLAQUE AND PERHAP THIS IS IS WHY THEY DEVELOP SO EARLY IN PATIENTS WITH LUPUS AND OTHER CO-MORBIDITIES. SO THIS IS TO SHOW YOU IF WE TAKE THIS CARDIOVASCULAR LUPUS COHORT THAT I MENTIONED WE HAVE ESTABLISHED IN THE CLINICAL CENTER, AND WE--[AUDIO CUTS OUT ]--AND THE DEVELOPMENT OF VASCULAR INFORMATION AS MEASURED BY ACT, WE SEE THAT THOSE PATIENTS THAT HAVE HIGH PLAQUE OR HIGH VASCULAR INFORMATION VERY CHARACTERISTICALLY DEVELOP OR HAVE UPREGULATION OF GENES THAT ARE CONSISTENT WITH LOW DENSITY GRANULE GENE SIGNATURE, THE CELLS WE KNOW ARE FUNCTIONAL, THE NUTRIFILLS THAT MAKE THESE NETS AND IN FACT, THE NUMBER OF THESE LO DENSITY GRANULE SITE SIGNIFICANTLY SOCIETY WITH THE DEGREE OF NONCALCIFIED PLAQUE BURDEN THAT LUPUS PATIENTS DEVELOP. SO WE THINK THIS IS INDEED CONSISTENT WITH THE ROLE THAT THESE DYSFUNCTIONAL NUTRIFILLS MAY BE PLAYING IN PREMATURE VASCULAR DAMAGE AND IF ANYTHING THEY COULD POTENTIA WILY AND SOMETHING WE'RE STARTING SERVE AS A BIOMARKER FOR VASCULAR RISK. SO I'LL TELL YOU IN THE NEXT FEW MINUTES A LITTLE BIT ABOUT THE ROLE THAT PROTEIN--LIPO PROTEIN DISREGULATION MAY PLAY IN THE VASCULAR DAMAGE AND THE ROLE THE INNATE IMMUNE SYSTEM MAY PLAY IN INDUCING THIS LIPOPROTEIN DISREGULATION. SO THIS DISLIP DEEMIA IS COMMON IN LUPUS AND THIS PROBLEM HAS BEEN DESCRIBED HERE, I'M MENTIONING SOME OF THE ABNORMALITIES THAT HAVE BEEN FOUND. WHAT THE RESEARCH FROM VARIOUS GROUPS INCLUDING OURS HAS CONCLUDED OVER THE LAST FEW YEARS IS THAT THE MOST STRIKING ABNORMALITY IN LIPO TYPE OF PROTEINS IS REALLY IN THE HIGH DENSITY LIFE OF PROTEIN OR WHAT WE CALL THE GOOD CHOLESTEROL. SO WE KNOW THAT HDL HAS PLEOTROAPIC BENEFICIAL PROTECTIVE EFFECTS, ATHERO-EFFECTS AND THIS IS HAVING STRONG ANTIINFLAMMATORY EFFECTS AND ALSO PLAYING AN IMPORTANT ROLE IN PREVENTING CELL FORMATION THROUGH A MECHANISM CALLED MACROPHAGE CHOLESTEROL A-PLUGS WHERE CHOLESTEROL IS TAKEN OUT OF THE MACROPHAGE THROUGH HDL MEDIATED EEIVETS AND IN FACT, THESE INFLUX CAPACITY HAS BEEN FOUND TO HAVE PROTECTIVE EFFECTS SO WHEN YOU LOOK--THE CAPACITY OF THE HDL TO ACCEPT THESE FROM THE MACROPHAGES CAN ACTUALLY PREDICT THE HATFIELD BURDEN AND THE BETTER YOUR LOOKS, THE BETTER LOWER RISK FOR THE ATHEROSCLEROSIS IN THE GENERAL POPULATION. SO WHAT WE HAVE FOUND IS THAT CHOLESTEROL AFFLUX CAPACITY IS SIGNIFICANTLY DECREASED IN LUPUS PATIENTS, THE ABILITY TO REMOVE THE MA BEING ROUGH ATOM PHAGES IS IMPAIRED. AND THIS IMPAIRMENT BY THE LUPUS HDL IS SO, SO SIGNIFICANTLY ASSOCIATED WITH THIS NONCALCIFIED PLAQUE BURDEN, SO THE LOWERY REFLUX, THE LOWER PLAQUE YOU WILL HAVE IF YOU HAVE LUPUS AND WE FOUND THAT THIS IMPAIRMENT IN CHOLESTEROL CAPACITY WAS SIGNIFICANTLY ASSOCIATED WITH THE LEVELS OF LOW DENSITY GRANUE LOW SIGHTS AND THE NUMBER OF NETS WE CAN DETECT IN THE CIRCULATION OF THESE PATIENTS. SO WHY DO WE THINK THIS IS? WHAT ARE THE NUTRIFILLS DOING? SO SOMETHING THAT IF A VERY IMPORTANT INFORMATION ABOUT HDL IS THAT IT HAS STRONG ANTIINFLAMMATORY EFFECTS ON MACROPHAGES AND A FEW YEARS AGO, SOME WORK FROM A LAB GROUP SHOWED THAT MACROPHAGES THAT ARE EXPOSED TO DANGER SIGNALS SUCH AS A TLR LIGAND, IF THEY ARE ALSO ECPOSED TO HCL, THESE WOULD LEAD TO ABNORMALITIES BROIGATION OF THE PRO INFLAMMATORY SIGNALS THAT THESE MAY TRIGGER. SO IF YOU ARE EXPOSED, THE MACROPHAGES ARE EXPOSED, THIS COULD LEAD TO ACTIVATION OF PROINFLAMMATORY PATHWAYS AND SECRETION OF THESE CYTOKINES THAT MAY DRIVE INFLAMMATORY MACROPHAGES. IN THE PRESENCE OF HDL, NORMAL HDL, HEALTHY HDL THIS, IS ABROGATED. WHAT WE FOUND HAPPENS IN LUPUS IS THIS PHENOMENON IS DISRUPTED AND THIS IS WHAT WE THINK IS GOING ON BASED ON THE RESEARCH WE HAVE PERFORMED. BECAUSE LUPUS NUTRIFILLS MAKE ESPECIALLY LOW DENSITY MAKE MORE NETS, THESE NETS EXTERNALIZE POTENT END ZYMES SUCH AS MILE O PEROX DACE AND OTHER ENZYMES AND THAT MAY OXIDIZE COMPONENTS OF THE HCL. WHEN THE HCL BECOMES OXIDIZED NOT ONLY THIS IMPAIRS THE CLEFTERAL EPLUCKS CAPACITY BUT THIS HDL BINDS TO DIFFERENT RECEPTORS IN THE MA ROUGH ATOM PHAGES THAT IMPAIR THE ANTIINFLAMMATORY EFFECTS THAT NORMAL HDL COULD [INDISCERNIBLE] THE MACROPHAGES WITH. AND THESE MACROPHAGES BECOME POLARIZED INTO THE INFLAMMATORY MACROPHAGES THAT MAKE MORE INFLAMMATORY CYTOKINE AND THIS FURTHER PROMOTES CARDIOVASCULAR DISEASE. SO THESE DISEASES BY WHICH WE'RE LINKING INNATE IMMUNE RESPONSES TO ABNORMAL LIKE PROTEIN METABOLISM THAT WE THINK WILL BE 1 MECHANISM OF CARDIO VASC LEER DISEASE AND ILLNESS AND WHAT SOME OF THE TRIALS WERE DOING MAY TELL US ABOUT HOW TO MOVE FORWARD AND TRY TO DO SOMETHING FOR THESE DEVASTATING COMPLICATION, SO, CONTRARY TO WHAT WE KNOW FROM DIABETES, WE KNOW A LOT ABOUT CARDIOVASCULAR PREVENTION IN PATIENTS WITH DIABETES, THE GUIDANCE FOR CARD YE VASCULAR PREVENTION IN BAISHTS WITH SYSTEMIC AUTOIMMUNITY ARE STILL VERY UNCLEAR AND THERE HAVE BEEN SIGNIFICANT EFFORTS TO TRY TO MAKE THEM MORE CLEAR, BUT WE STILL DON'T KNOW HOW TO TREAT CERTAIN FINDINGS IN PATIENTS WITH AUTOIMMUNITY. FOR EXAMPLE, WHAT IS AN ACCEPTABLE LDL LEVEL IN A LUPUS PATIENT. WHEN DO WE START STUDY THANKSGIVING TREATMENT? IS LDL OF A HUNDRED LOW ENOUGH OR NOT? SO FAR WHAT WE DO KNOW IS THAT THE SAME AS WITH PATIENT WITHOUT LUPUS OR WITHOUT AUTOIMMUNITY WE SHOULD DO EARLY MONITORING OF RISK FACTORS BECAUSE EVEN IF THEY ARE NOT PLAYING THE ONLY ROLE IN DRIVING PREVASCULAR DISEASE, WE DO NEED TO CONTROL THEM. AND A QUESTION REMAINS IS LUPUS A CARDIOVASCULAR DISEASE EQUIVALENT AND HOW DO WE FOLLOW THESE LIPID MANAGEMENT AND THE ROLE OF STATINS REMAINS UNCLEAR. AND THIS RECENTLY PUBLISHED GUIDELINES ON PRIMARY PREVENTION OF CARDIOVASCULAR DISEASE, WE SEE NOW THAT THERE IS A MENTION THAT PATIENTS WITH AUTOIMMUNITY MAY NEED TO BE CONSIDERED HIGHER RISK, BUT IT'S STILL NOT SUFFICIENTLY DETAILED TO KNOW HOW DO WE MANAGE CARDIOVASCULAR RISK FACTORS COMPARED TO SOMEONE WITHOUT AUTOIMMUNITY. WE ALSO--THERE ARE ALWAYS QUESTIONS ABOUT HOW DO LUPUS MEDICATIONS SO MEDICATIONS WE COMMONLY USED TO TREAT LUPUS PROMOTE OR PREVENT CARDIOVASCULAR DISEASE? SO THERE'S STILL A WE DON'T KNOW. THERE IS SOME EVIDENCE THAT ANTIMALARIAL THAT HAVE RECEIVED A LOT OF PRESS RECENTLY AND THAT ARE VERY COMMONLY USED IN PATIENTS WITH LUPUS, THERE IS EVIDENCE THAT THEY USE THE ANTIMALARIALS REDUCES OVERALL MORTALITY IN LUPUS AND THE IDEA IS THAT THIS IS IN PART BECAUSE THEY MAY HAVE VASCULAR PROTECTIVE EFFECTS AND LIPIT PROFILES AND INTERESTINGLY ANTIMALARIALS CAN HAVE DECREASE TYPE 1 INTERFERON RESPONSES AND IT COULD BE THAT THIS DRUGS PLAY PLEOTROAPIC EFFECTS IN AND DECREASING VASCULAR DAMAGE. THE ROLE OF COTTER CO STEROIDS CONTINUES TO BE DEBATED AS I MENTIONED FOR MANY, MANY YEARS, THESE WERE THE MAIN CULPRITS AND CERTAINLY THERE ARE MANY METABELLIC EFFECTS FROM PROLONGED COTTER CO USE THAT SHOULD--THAT ARE IMPORTANT AND COULD PLAY A ROLL IN ATHEROSCLEROSIS BUT OF COURSE, LIMITING INFLAMMATION IN LUPUS IS KEY TO PREVENTING IMMUNE DISREGULATION AND SO WE RECOMMEND THAT THE LOWEST POSSIBLE DOSE FOR THE LEAST AMOUNT OF TIME BUT MAKING SURE THAT INFLAMMATION IS PROPERLY CONTROLLED. THERE IS ALSO EVIDENCE PRIMARILY FROM THE RHEUMATOID ARTHRITIS LITERATURE THAT MEX O TREKSATE COULD DECREASE RATE IN CARDIOVASCULAR MORTALITY, WE DON'T USE IT AS OFTEN IN LUPUS AS IN RHEUMATOID ARTHRITIS BUT IT HAS BEEN SHOWN TO DECREASE CARDIOVASCULAR MORTALITY AND FINALLY, MMF HAS BEEN SHOWN TO BE VASE KIEWL O PROTECTIVE IN SLE AND IT'S SOMETHING TO KEEP IN MIND AND THERE'S STILL QUESTIONS ABOUT THE STATINS OR ACE ININCREASE IN BODYITORS FOR--INHIB THORS IDENTITIORS FOR EXAMPLE AND THE ROLE THEY PLAY IN CARDIOVASCULAR AND LUPUS. I WILL TELL YOU A BIT ABOUT SOME OF THE NEWER TARGETS FOR CARDIO VASCLER PREVENTION IN LUPUS, THESE ARE SOME THAT HAVE BEEN MENTIONED BY VARIOUS GROUPS AND ON THE TOP IN RED I MENTION IN SOME OF THE 1S WE HAVE BEEN PARTICULARLY INTERESTED IN EXPLORING I WON'T HAVE TIME TO TALK ABOUT THE PPR AGANIST TRIALS WE HAVE COMPLETED BUT I WILL TELL YOU ABOUT SOME WHERE WE HAVE BEEN DOING ON TESTING WHETHER BLOCKING TYPE 1 INTERFERONS AND NUTRIFILL RESPONSES MAY--WAWE HAVE FOUND IN THE CONTEXT OF CARDIO METABOLIC RISK. SO BASICALLY WHAT I TOLD YOU IS THAT WE THINK THAT TYPE 1 INTERFERONS ARE IMPORTANT IN CARDIOVASCULAR PREVENTION, DO WE KNOW IF TARGETING THIS PATHWAY COULD LEAD TO IMPROVEMENTS IN CARDIO METABOLIC IMPROVEMENT IN LUPUS. SO THIS WAS COLLABORATIVE RESEARCH AGREEMENT ESTABLISHED WITH METAIMMUNE AZSTRENECA, FOR A NUMBER OF YEARS AND IT'S IT'S A MONOCLONAL ANTIBODY THAT TARGETS THE TIME 1 INTERFERON RECEPTOR SO THE RECEPTOR BY WHICH TYPE 1 SIGNALING CELLS AND PRODUCED TO THE DROWN STREAM EFFECT AND THESE--AND THIS TRIAL WHICH LOOK AT A VARIETY OF END POINTS DISEASE ACTIVITY USING 2 DIFFERENT DOSES FOR UP TO 1 YEAR. AND WE'VE UNFORTUNATELY BY THE TIME WE PARTNER WITH THEM TO LOOK INTO THESE, WE COULDN'T GET FRESH BLOOD OR DO ANY VASCULAR FUNCTION STUDIES BUT WE HAVE ACCESS TO PLASMA AND SERUM AND WE STUDIED THE GROUP, WE COMPARED THE PLACEBO GROUP TO THE GROUP THAT RECEIVED 200-MILLIGRAMS WHICH IS THE DOSE THE COMPANY IS MOVING FORWARD WITH. AND WE HAVE ACCESS TO SAMPLES THAT WERE OBTAINED AT BASE LINE AND AT 1 YEAR OF TREATMENT. SO BECAUSE WE ONLY HAD SERUM AND PLASMA WHAT WE THOUGHT WE WOULD START WITH IS SEEING, OKAY, WOULD INHIBITED TYPE 1 INTERFERONS LEAD TO A-A DECREASE IN NET FORMATION WHICH WE THINK INTERFERON MAY BE PRIMING NUTRIFILLS IN PART TO PRODUCE NETS AND WAS BLOCKING NORMAL LIPO PROTEIN METABOLISM AND FUNCTION IN LUPUS PATIENTS AS SURROGATES THAT PERHAPS THEY ARE MODIFYING CARDIOVASCULAR RESPONSES. SO WE KNOW THAT LUPUS PATIENTS HAVE HIGHER LEVELS OF [INDISCERNIBLE] CIRCULATION AND WE MEASURE THIS NETS CIRCULATION IN BOTH GROUPSA THE BASE LINE AND AT 1 YEAR AFTER TREATMENT AND THIS IS THE GROUP THAT RECEIVED THE DRUG AND THIS IS THE GROUP THAT RECEIVED PLACEBO DISP WHAT WE FOUND IS IF WE BLOCK TYPE 1 INTERFORONS, THE LEVEL OF NETS SIGNIFICANTLY DECREASE WHERE IN FACT THEY INENDED UP INCREASING THE GROUP, SO IT WOULD ALSO LEAD TO ABNORMALITIES BROIGATION OF NET LEVELS IN CIRCULATION, SO THESE 2, THIS MOTIVATION OF TYPE 1 INTERFERON NETS MAY BE GOOD FOR THE VASCULATURE, NOW AS I MENTIONED WE THINK THAT THESE NETS ARE OXIDIZING HCL AND SERVING HCL FUNCTION SO WE LOOKED AT BLOCKING TYPE 1 INTERFERON COULD IMPROVE THE CAPACITY SO THIS IS THE CAPACITY IN HEALTHY PEOPLE. YOU CAN SEE AT BASE LINE BOTH PEOPLE HAVE A MUCH LOWER CHOLESTEROL CAPACITY WHICH DID NOT SIGNIFICANTLY CHANGE AT 1 YEAR FOLLOW UP IN THE PLACEBO, BUT SHOW ALMOST A 20% IMPROVEMENT IN THE GROUP 1 ANIFROLUMAB, SO THIS COULD BLOCK TYPE 1 INTERFERENCE SO COULD WE TEST IN THIS A MORE SYSTEMIC WAY? AND CAN WE FIND OR THINK OF DRUGS THAT COULD MODULATE BOTH IN THE REGULATED NUTRIFILL FUNCTION AND TYPE 1 INTERFERON RESPONSES IN LUPUS PATIENTS, SO THE [INDISCERNIBLE] SIGNALING PATHWAY IS A FUNDAMENTAL PATHWAY BUT BY WHICH A NUMBER OF CYTOKINE SIGNALING CELLS AND THIS PATHWAY IS OF COURSE VERY, VERY EARLY ON IN THE CONTEXT OF TYPE 1 INTERFERONS USED TO THE PATHWAY TO SIGNAL IN TARGET CELLS BUT ALSO NUTRIFILL VS A VERY STRONG AND VERY FUNCTIONING [INDISCERNIBLE] PATH WITH WHICH IMPORTANT CYTOKINES THAT MODULATE NUTRIFILL FUNCTION SIGNAL. SO WE CONSIDER THAT BLOCKING THIS PATHWAY COULD HAVE BENEFICIAL EFFECTS NOT ONLY IN THE CONTEXT OF LUPUS AND THERE HAVE BEEN ALREADY SOME TRIALS WITH JACK INHIBITORS THAT HAVE SHOWN UP IN CLINICAL EFFECTS, BOTH BARICITINIB YEARS AGO AND ANOTHER JACK INHIBITOR BUT IN THIS CONTEXT WE WANTED TO ASSESS WHETHER WE COULD MODULATE CARDIO METABOLIC RISK. SO THIS WAS A STUDY THAT WAS - RECENTLY COMPLETED AND THE MANUSCRIPT IS RECENTLY UNDER REVIEW AND WE TESTED WHETHER TARGETING THE PATHWAY IN LUPUS USING TOPOCITINIB IN A B1 PHASE 2 A, IN THE CONTEXT OF THIS TALK WE WANTED TO ASSESS WHETHER IT DECREASE SO WE STARTED IT WITHC- LUPUS, AND THEY WERE ON PLACEBO FOR 8 WEEKS AND THE PATIENTS WERE RANDOMIZED WERE 20 PATIENTS WERE RANDOMIZED TO THE JAK INHIBITOR, HALF OF THIS PATIENT HAD A GENETIC RISK ALLELE THAT IS ASSOCIATED WITH IT ENHANCED RESPONSES TO TYPE 1 INTERFERONS AMONG OTHER THINGS AND MORE SEVERE LUPUS, WITH MORE SEVERE CARDIOVASCULAR DISEASE AND HALF OF THE PATIENTS WE STUDY ON THIS GROUP WERE NEGATIVE FOR THIS RISK ALLELE AND THEN WE HAVE 10 PATIENTS THAT WERE ON PLACEBO AND AGAIN HAVE HAD THE RISK ALLELE AND HALF DID NOT. AND THEN WE FOLLOW THE PATIENTS FOR WEEKS OF STUDY DRUG. AND JUST TO SUMMARIZE THE DRUG WAS OVERALL SAFE, I WILL FOCUS PRIMARILYOT CARDIOVASCULAR RISK PARAMETERS AND TO MENTION HERE WHAT WAS SURPRISING AND EXCITING TO US WAS THAT--I WOULD THINK ARE BAD FOR THE VASCULATURE WHEREAS IF ANYTHING THEY INCREASED IN THE PLACEBO GROUP AND THOSE PATIENTS THAT OTHER THAN POSITIVE FOR THE GENERATED THETIC RISK POLYMORPHISM THAT I MENTIONED, ALSO HAD DECREASED LEVELS OF NET WHEN IS THEY WERE ON [INDISCERNIBLE] COMPARED TO PLACEBO AND THIS WAS ASSOCIATED WITH SIGNIFICANT ENHANCEMENT IN THE LEVELS OF HDL IN THE TOPOCITINIB GROUP, AT DAY 56 WHICH WENT BACK TO LOWER LEVEL WHEN WE STOP THE DRUG, AND THERE WERE NO CHANGES IN THE PLACEBO GROUP AND NOT ONLY THE LEVELS OF HDL IMPROVED, BUT ALSO THE FUNCTION OF THE HDL WAS IMPROVED WHEN COMPARED TO PLACEBO AT DAY 56, SOPHISTICATEDY WOO WE WERE ABLE TO MODULATE PROTEIN NUMBER AND FUNCTION AND ESPECIALLY THE HDL. AND THEN NOT SURPRISINGLY, WE SAW A SIGNIFICANT DECREASE IN THE TYPE 1 INTERFERON SIGNATURE AND WHEN THE PATIENTS WERE ON TOPOCITINIB FOR COMPARED TO DAY 1 AND ALL THIS ASSOCIATED WITH IMPROVEMENT IN VASCULAR STIFFNESS COMPARED TO THE PLACEBO GROUP WHERE YOU CAN SEE IF ANYTHING THIS INCREASE IN THE PLACEBO GROUP AND THERE WAS A DECREASE IN VASCULAR STIFFNESS IN THE TOPOCITINIB GROUP, SO JUST OVER A SHORT COURSE OF TREATMENT WERE ABLE TO MODULATE NOT ONLY THE ABNORMAL INNATE IMMUNE RESPONSES THAT ARE ASSOCIATED WITH VASCULAR FUNCTION AND THIS ALSO TRANSLATED INTO IMPROVEMENTS IN THE VASCULAR PHENOTYPE. AND WHILE THESE STUDIES ARE PRELIMINARY, WE ARE HOPING TO FOLLOW TO HAVE A LONGER FOLLOW UP WHERE WE CAN LOOK MORE OF ANATOMICAL MODULATION OF ATHEROSCLEROSIS IN THE CONTEXT OF LUPUS. SO TO FINALIZE, THESE ARE SOME OF THE TAKE HOME POINTS I'M HOPING TO BRING, I HOPE I HAVE BEEN PERSUASIVE ABOUT TELLING YOU THAT THIS IS A BIG PROBLEM IN LUPUS AND IN OTHER AUTOIMMUNE DISEASES. THIS INCREASED CARDIOVASCULAR RISK, IT'S RELATED TO A COMBINATION OF BOTH TRADITIONAL AND MOST IMPORTANTLY NONTRADITIONAL RISK FACTORS, WHERE LONG-TERM SUPPRESSION OF IMMUNE DISREGULATIONULATION MAY INDEED LESSEN CARDIOVASCULAR RISK BUT WHICH IS STILL VERY VIGILANT OF TRADITIONAL RISK FACTORS AND COME UP WITH STRATEGIES TO REDUCE THEM. WE THINK THAT THERAPEUTIC STRATEGIES THAT TARGET IMMUNE DISREGULATION MAY RESULT IN CARDIOVASCULAR RECENT IMPROVEMENTS IN LUPUS AND WE'RE EXCITED TO CONTINUE TO DO THESE STUDIES HERE AT THE NIH AND SEE IF WE SEE CLINICAL BENEFITS, AND I WANT EMPHASIZE THAT DISEASE SPECIFIC DYED LINES ARE DESPERATELY NEEDED IN THE CONTEXT OF PATIENTS WITH AUTOIMMUNE DISEASES. AND LAST BUT NOT LEAST, I WOULD LIKE TO THANK MANY PEOPLE INVOLVED IN THESE STUDY, THE PEOPLE IN MY LAB CURRENT AND FORMER MEMBERS THAT I MENTIONED HERE, THERE WERE MORE DIRECTLY INVOLVED IN THE CARDIOVASCULAR STUDIES I MENTIONED. A BIG THANKS TO THE LUPUS CLINICAL TRIAL UNITS, THAT IS HEADED BY [INDISCERNIBLE] AND ALL THE MEMBERS OF THE GROUP THAT HAVE BEEN INSTRUMENTAL IN DRIVING THESE STUDIES BOTH THE CLINICAL, THE VASCULAR LONG NUDEINAL FOLLOW UP AS WELL AS A CLINICAL TRIALS I MENTIONED. MY BIG THANKS TO THE GREAT COLLABORATIONS WITH THE VICTORYS AT NHLBI AND PARTICULARLY [INDISCERNIBLE] AND ALSO ADAM [INDISCERNIBLE] WITH THE PROTEIN WORK, AND MY OTHER COLLABORATORS AT NIAMS, [INDISCERNIBLE] WHO WERE VERY INVOLVED IN THE JAK INHIBITOR STUDIES AND THEN VARIOUS COLLABORATORS AT OTHER INSTITUTIONS THAT HAVE INSTRUMENT FOR THIS WORK AND THANK YOU VERY MUCH FOR YOUR ATTENTION AND I WILL BE HAPPY TO TAKE ANY QUESTIONS. >> THANK YOU VERY MUCH FOR THAT STIMULATING TALK. IF WE HAVE QUESTIONS FROM THE AUDIENCE I WILL READ THEM BUT MY QUESTION IS RELATED TO WHERE IS ESTROUGH ATOM GEN IN THIS ENTIRE PICTURE? ALL OF THE INFORMATION YOU HAVE PROVIDED WAS REALLY FASCINATING IN TERMS OF THE UNIQUE INFLAMMATORY STATE, BUT IN GENERAL 1 WOULD EXPECT IN THE CONTEXT OF THE HIGH ESTROGEN ENVIRONMENT, THAT SHOULD BE IN SOME WAY EITHER COUNTER REGULATED OR BALANCED. SO WHAT IS GOING ON FROM YOUR PERSPECTIVE? >> YEAH THAT'S A FASCINATING QUESTION BUT WE THINK A LOT ABUT THIS, SO THAT'S WHAT'S SO STRIKING ABOUT THESE EFFECTS, WITH THE WOMEN YET THEY ARE NONAPOPTOTIC THE PROTECTED BY ESTROUGH ATOM GEN, I'M SORRY NOT PROTECTED BUT I THINK THE OVERWHELMING DISREGULATION WINS HERE AND THAT'S WHY WE START SEEING WHAT YOU MAY SEE IN MOST MENOPAUSAL WOMEN OCCURRING SIGNIFICANTLY EARLIER AND--CONTRACEPTIVES MAY PLAY IN THIS PATIENT. SO WE TYPICALLY--ALTHOUGH A LITTLE WORRIED ABOUT EXPLORE THAGOREAN WITH INTERVENTIONS BUT WE ALSO HAVE EVIDENCE FROM UNPUBLISHED WORK THAT WILL SOON BE PUBLISHED THAT ACTUALLY ESTROUGH ATOM GENS MAY ALSO HAVE AN ACTIVATING ROLE IN THE CONTEXT OF NUTRIFILLS AND SO, WHILE ESTROUGH ATOM GEN IN THEORY MAY BE GOOD IN THE CONTEXT OF VASCULAR PREVENTION, THEY COULD ALSO PROMOTE MORE IMMUNE DISREGULATION AND IT COULD BE THAT HERE IT'S A DOUBLE--KIND OF A DOUBLE EDGED SWORD BUT WE NEED TO INVESTIGATE THIS FURTHER. >> RIGHT. ARE YOU A BIT HAMPERED BY THE LACK OF INEFFECTIVE ANIMAL MODEL FOR LUPUS WITH RESPECT TO YOUR RESEARCH? >> YEAH, SO WE HAVE LEARNED A LOT FROM ANIMAL MODELS IN THE CONTEXT OF VASCULAR FUNCTION. MICE DON'T TYPICALLY GET ATHEROSCLEROSIS UNLESS THEY ARE A VERY SPECIFIC GENETIC BACKGROUNDS THAT ARE IN A WAY PRETTY ARTIFICIAL AND THEY'RE NOT, SO IT IS A LITTLE DIFFICULT TO LOOK AT PLAQUE FORMATION IN THAT CONTEXT AND LETS YOU DO VERY CONVOLUNTEERSUDED% [INDISCERNIBLE] BUT THAT'S WHAT WE'RE REALLY INTERESTED IN STUDYING THIS COHORT OF PATIENTS BECAUSE WE CAN LEARN A LOT FROM OUTSIDE, BUT WE CAN LEARN MORE IF WE IDENTIFY BIOMARKERS THAT ARE IMPORTANT IN THE DEVELOPMENT AND TEST POTENTIAL DRUGS THAT MAY BE ALSO SAFE BUT EFFECTIVE IN PREVENTION. >> VERY GOOD. OKAY, IT LOOKS LIKE WE DO NOT HAVE ANY ADDITIONAL QUESTIONS FROM THE AUDIENCE SO WE WANT TO THANK YOU FOR AN OUTSTANDING PRESENTATION AND WE WISH YOU THE BEST IN YOUR CONTINUING STUDY OF THIS IMPORTANT DISEASE. >> THANK YOU VERY MUCH.