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 >> GRAND ROUNDS EMBEDDED IN THE CLINICAL CENTER GRANDS ROUNDS WHICH HAS A MAJOR EDUCATIONAL ROLE BY PRESENTING INTERESTING CASES OF THE CLINICAL LEVEL DIAGNOSTIC AND PATHOLOGICAL LEVEL. SO AT THE SAME TIME HIGHLIGHTING CLINICAL PROGRAMS HERE AT THE CLINICAL CENTER THAT REALLY SHOW WHAT WE DO IN THIS HOSPITAL WHICH IS BOTH CLINICAL CARE AT THE SAME TIME TRANSLATIONAL RESEARCH THAT CAN AFFECT PATIENTS' LIVES. SO I THINK TODAY'S PRESENTATION IS A GREAT EXAMPLE OF THIS. SO FIRST WE'LL HEAR AT THE CLINICAL LEVEL TWO PATIENTS PRESENTED BY DR. MONTEALEGRE WHO DESPITE A RECENT ACCIDENT AND SURGERY SHE'S THAT MOTIVATED THAT SHE CAME TO PRESENT. [APPLAUSE] >> FOLLOWED BY THE PATHOLOGICAL AND RADIO GRAPHIC FEATURES BY DR. MONTEALEGRE AND DR. LEE. THEN MOVING TO THE TRANSLATIONAL RESEARCH COMPONENT OF THE TALK WE WILL HEAR FROM DR. DEJESUS ABOUT THE KINETICS AND HOW THE RESEARCH CENTER IN THESE PATIENTS LED TO DEVELOPING TARGETED THERAPEUTIC INTERVENTIONS AND HAVE A POSITIVE OUTCOME. SO WE'RE GOING TO TALK ABOUT THE DISEASE CALLED CANDLE, COOL NAME. AND WITH NO FURTHER ADIEU, GINA. >> GOOD AFTERNOON. THANK YOU FOR THE INVITATION AND THE OPPORTUNITY TO PRESENT OUR PATIENT AND OUR DATA. I'M GOING TO START WITH TWO CASES. THESE ARE OUR DISCLOSURES. THE OBJECTIVES OF OUR LECTURE. I'M GOING TO START WITH TWO CASES, THESE WERE TWO PEDIATRIC CASES WHO CAME TO OUR CLINIC FOR GRADUATION OF UNDIFFERENTIATED (INAUDIBLE) DISEASE. THE FIRST IS A TEN MONTH OLD CAUCASIAN BOY WITH FEVER THRUSH IT WAS A FULL TERM PREGNANCY 39 WEEKS GESTATIONAL AGE BORN VIA C-SECTION DUE TO FAILURE TO PROGRESS. THE PREGNANCY WAS JUST COMPLICATED FOR GESTATIONAL GUIDANCE DIABETES. HE WAS ASYMPTOMATIC UNTIL AGE 2. WHEN HE DEVELOPED TESTIFY RAISED THRUSH IN HIS RIGHT UPPER ARM AND THEN IT SPREAD THROUGH HIS FOREHEAD AND THROUGH ALL HIS BODY. THE MANIFESTATIONS WERE THE ONLY SYMPTOM UNTIL TEN MONTHS OF AGE, BY 11 MONTHS HE WAS SUBMITTED TO THE HOSPITAL FOR PERSISTENT FEVER, HIS HIGHEST TEMPERATURE WAS 103 AND FEVERS WERE ASSOCIATED WITH ELEVATED ACUTE PHASE 3 REACTANTS AND SPLENOMEGALY. ON DIAGNOSIS HE WAS TRANSFER FOR FROM THE HOSPITAL, NOT UNCOMMONND READMITTED A MONTH LATER WHEN WHOLE BODY MRI SHOWED MYOSITIS IN ALL HIS MUSCLES AND ARTHRITIS IN THE ELBOW AND KNEE. WITHOUT A CLEAR DIAGNOSIS AND AFTER INFECTIONS HE WAS GIVEN A TRIAL OF PREDNISONE, HE WAS STARTED ON PREDNISONE 15-MILLIGRAMS A DAY. MULTIPLE ATTEMPTS TO -- WERE ASSOCIATED WITH CONTINUED -- REPRESENTED BY FEVERS, JOINT PAIN,MYALGIA AND HEADACHES. REASON FOR THAT HE WAS STARTED ON ONE MILLION GRAM TWICE A DAY. BY 34 MONTHS OF AGE WE HAVE NEW CLINICAL FEATURES REPRESENTED BY THE PRESENCE OF THROMBO CYTOPENIA AND SORE AT THIS TENTLY ELEVATED CK, A REFLECTION OF ONGOING INFLAMMATION. THIS WILL TAKE TOWS THE -- HIS VISIT -- TAKE US TO THE VISIT AT THE NIH. HIS SOCIAL HISTORY WAS UNREMARKABLE, THERE WAS NO HISTORY OF ANY INFLAMMATORY OR RULE TO LOGICAL CONDITION. THERE WAS NO CONCERN WITH REPORT AND THE ONLY FAMILY HISTORY THAT IT WAS POSITIVE WAS MATERNAL OBESITY, HE WAS THE ONLY CHILD. THE PHYSICAL EXAM LET ME WALK YOU THROUGH IT. FIRST HIS HEIGHT WAS LESS THAN THE 5TH PERCENTILE, DUE TO THE RECENT USE OF STEROIDS HIS BLOOD PRESSURE WAS MODERATELY ELEVATED AT 107 OVER 59 WHICH REPRESENTS A 95 TO 97 PERCENTILE FOR HIS AGE AND HEIGHT. PHYSICAL EXAMINATION WAS CONSISTENT WITH PERIORBITAL ADEEM AS YOU CAN SEE, POPULAR RASH ON HIS CHIN UPPER PEST CHEST AND BACK AND AREAS OF LIPODYSTROPHY NOTED P ON HIS FACE AND UPPER EXTREMITIES. LATER ON WE LEARN THAT THE LIPODYSTROPHY WERE CHARACTERISTICS OF THIS DISEASE. SO IF YOU FLOE ME YOU WILL SEE IS THE AIR AIAS ARE AROUND TEMPORAL AREAS, THE NEXT SLIDE WILL SHOW THIS BETTER. THE EXAMINATION WAS CONSISTENT WITH ARTHRITIS OF THE SMALL JOINTS AND LEFT KNEE, THE SMALL JOINTS REPRESENTED BY SWELLING ON THE META TARSAL FRANKIAL JOINTS AND PIP JOINTS. SWELLING OF LEFT KNEE AND CHRONIC ARTHRITIS LED TO JOINT CONTRACTURES HERE REPRESENTED BY LACK OF FULL EXTENSION OF THE LEFT ELBOW AND ACTUALLY OF THE LEFT KNEE. LABORATORY REPORTS WERE CONSISTENT WITH THROMBO CYTOPENIA, ELEVATED LDH AND POSITIVE ANTIBODIES, IT'S IMPORTANT TO NOTICE DESPITE HIS CLINICAL ACTIVITY HIS H ACUTE PHASE THREE REACTANTS WERE NORMAL. AFTER HIS NIH VISIT WE TRIED TO ADJUST HIS DOSING, THE DOSE WAS INCREASED TO 4-MILLIGRAMS A DAY, BID BUT UNSUCCESSFUL IN WINNING WITH STEROIDS. REASON WHY IL 6 INHIBITOR WAS ADDED TO THE TREATMENT WITHOUT ANY SUCCESS. DESPITE ALL THESE TREATMENTS HE DIAGNOSE WITH HYPERTENSION WAS CONFIRMED BY 15 MONTHS OF AGE, REQUIRING TREATMENT WITH AN ACE INHIBITOR AND LATER ON BY 17 MONTHS OF AGE HE WAS DIAGNOSED WITH HYPERTRIGLYCERIDEEMIA REQUIRING THYROID. BY 17 MONTHS OF AGE PRIOR TONE ROLEMENT IN THE TREATMENT STUDY THE PATIENT CONTINUED WITH THE DISEASE ACTIVITY REMITTED BY MONTHLY EPISODE OF FEVERS,MYALGIA, HEADACHES THROMBO CYTOPENIA, ELEVATED ACCUSE 3 REACTANTS AND HYPERTRIGLYCERIDEEMIA. PRIOR TO H NIH HL WAS WITH SEPTIC LYMPHOCYTIC MEN ANYONE EYETIS. HERE IS TO SHOW THE AWED -- MENINGITIS. HERE IS THE RIGHT UP PER PANEL YOU WILL SEE PHOTOGRAPHS TAKEN FROM FEBRUARY OF 2009 TO JULY OF 2012. YOU WILL SEE HOW THE PREVIOUS LIPODYSTROPHY IN THE PREVIOUS PICTURES IS MORE EVIDENT, MOSTLY AROUND THE BONE TEMPORAL AREA AND BELOW THE SINKOMATIC BONE AND HOW HIS METABOLIC PRESENTATION CHANGE WITH INCREASE ABDOMINAL CIRCUMFERENCE THAT LATER ON DR. MONTEALEGRE WILL EXPLAIN THAT IS REPRESENT IS INCREASED ABDOMINAL FAT. REALLY QUICK I WILL WALK YOU THROUGH THE SECOND CASE, THIS IS A 14-YEAR-OLD HISPANIC FEMALE WITH HISTORY OF FAILURE TO THRIVE, PANICLITIS, FEVER, INCREASE ABDOMINAL DISTENSION HER PREGNANCY WAS COMPLICATED BY LACK OF PRENEONATAL CARE AND HOME DELIVER RHODE ISLAND SHE PRESENTED WITH FAILURE TO THRIVE. AT FOUR MONTHS OF AGE, THAT SYMPTOM WAS ASSOCIATED WITH HISTORY OF MEDIA UNTIL AGE 17 MONTHS. BY 18 MONTHS OF AGE, SHE PRESENCED THE SAME RATE BUT ON THE FACE UP PER AND LOWER EXTREMITY ASSOCIATED WITH FEVER. SHE WAS BIOPSY CONSISTENT WITH NEUTRAPHYLIC DERMATOSIS THAT DR. LEE WILL EXPLAIN LATER ANKER ON AND BASED ON THAT SHE WAS GIVEN A TRIAL OF PREDNISONE. AFTER INITIATION OF PREDNISONE SHE DEVELOPED INCREASE INTRAABDOMINAL DISTENSION, 36 MONTHS OF AGE ARTHRITIS AT 48 MONTHS OF AGE. MULTIPLE ATTEMPTS WERE DONE TRYING TO WIN THE STEROIDS. FOR THIS REASON SHE WAS GIVEN A TRIAL OF CYCLOPHOSPHAMIDE FOR 12 MONTHS WITHOUT RESPONSE FOLLOWED BY TNF INHIBITOR WITHOUT RESPONSE, IN TWO YEARS AND IVID SIX DOSES. ALL OF THEM WITHOUT AN ADDED RESPONSE. AT THIS POINT WE HAD 72 MONTHS OLD GIRL WITH LONG TERM STEROID USE, ASSOCIATED WITH COMPLICATION SUCH AS CATARACTS REQUIRING SURGERY AND OSTEOPOROSIS LEADING TO FACTORS AND SEVERE GROWTH DELAY. PRIOR TO HER FIRST EVALUATION OF THE NIH, THERE WAS A TRIAL WITH ANNA KIN DR. IL-1 INHIBITOR WITHOUT RESPONSE. DESPITE ALL THESE TREATMENTS SHE CONTINUES TO DEVELOP JOINT CONTRACTURES, HYPERTRIGLYCERIDEMIA, AND LYMPHOPENIA. THERE WAS ONE CHRONIC CONCERN FROM THE MOTHER THAT WAS THE PRESENCE OF FATIGUE THAT LATER WAS NOTESSEDTOR ASSOCIATED WITH THE DISCOVERY OF PULMONARY HYPERTENSION IN THESE PATIENTS. THESE WILL TAKE HE TO HER FIRST VISIT TO THE NIH. HERE WE HAVE THE FAMILY HISTORY WAS CONSISTENT FOR -- THE FAMILY WAS FROM A SMALL TOWN IN MEXICO. THE PHYSICAL EXAM FOR WEIGHT AND HEIGHT LESS THAN THE 5 PERCENTILE, JUST TO TRY TO EXPLAIN THE AUDIENCE HOW SHORT SHE WAS, HER CHRONOLOGICAL AGE WAS 14 YEARS OF AGE AN BONE AGE WAS TWO YEARS. HER HEIGHT WAS 90-CENTIMETERS BASICALLY THE 5TH PERCENTILE FOR A TWO YEAR OLD. SHE HAD BILATERAL OCULAR LENSES AND THE PHYSICAL EXAM AS YOU CAN SEE YOU CAN SEE AGAIN MANY IN THE UPPER PICTURE THE PRESENCE OF THE LIPO ATROPHY BY BONE INCREASED FACIAL HAIR WITH ABDOMINAL DIGS TENSION WITH HE PATH SPLENOMEGALY ON THE THE FACE AND UPPER AND LOWER EXTREMITIES. ARTHRITIS LEADING TO JOINT CONTRACTURES AND LIPODYSTROPHY IN THE SOLE OF HER FEET THAT MAKE IT DIFFICULT TO AMBULATE. HERE IS THE BONE AGE OF A 14-YEAR-OLD THAT REPRESENTS A BONE AGE OF A 2-YEAR-OLD. LABORATORY REPORTS WERE REMARKABLE FOR ELEVATED ACUTE PHASE 3 REACTANTS. ANEMIA, TRANSAMINITIS, ELEVATED CK, LDH, HYPERTRIGLYCERIDE AND POSITIVE ANTIBODIES NOW I WILL INVITE TO REVIEW THE CO-FINDINGS FOR OUR PATIENTS. >> THANK YOU. SO THERE WERE SOME COMMON FINDINGS BETWEEN THESE TWO CASES THAT I'M GOING TO PRESENT THOSE FIRST AND THEN THERE ARE SOME UNIQUE FINDINGS FOR THE SECOND PATIENT THAT OUR PRESENT NEXT. ONE OF THE COMMON FINDINGS WERE LIPODYSTROPHY, THIS IS T-1 WEIGHTED IMAGE OF THE ABDOMEN. YOU CAN SEE THERE IS INCREASED FAT WITHIN THE ABDOMINAL CAVITY. DISPROPORTIONATE TO FAT SUBCUTANEOUS TISSUE THERE'S MINIMAL FAT THE SUBCUTANEOUS TISSUE. H THIS IS REALLY DISPROPORTIONATE DISTRIBUTION OF THE FAT COMPATIBLE WITH LIPODYSTROPHY. THIS IS A T-2 WEIGHTED IMAGE OF ABDOMEN, AS YOU CAN SEE HERE THERE IS SIGNIFICANT AMOUNT OF FAT WITHIN THE ABDOMINAL CAVITY, MORE THAN THE FIRST PATIENT AND MINIMAL AMOUNT OF FAT IN SUBCUTANEOUS TISSUE. AGAIN, COMPATIBLE WITH LIPODYSTROPHY. ANOTHER COMMON FINDING BETWEEN TWO ARE MYOSITIS. THESE ARE AXIAL STEREO IMAGES OF THE SIZE. THERE'S INCREASED SIGNAL SPENCETY WITHIN THE SUBCUTANEOUS TISSUE WHICH IS INDICATIVE OF EDEMA AND FLUID SIGNAL AND THERE ARE PATCHY AREAS OF STEREO SIGNAL HYPERINTENSITY WITHIN THE MUSCLE GROUPS OF THE THIGHS THAT IS RATHER SYMMETRIC. ANOTHER FINDING HERE IS INCREASE SIGNAL INTENSITY WITHIN THE DEEP FACTUAL PLANES OF POSTERIOR COMPARTMENT OF THE SIZE. BILATERALLY. THIS IS COMPATIBLE WITH MYOSITIS AND FABITIS. AFTER PARTICIPATING IN COMPASSIONATE CARE GENE WILL ELABORATE ON LATER, PATIENT -- THERE WAS DECREASED STEREO SIGNAL INTENSITY, ALMOST GONE WITHIN THE MUSCLE GROUPS OF THE THIGHS AND THEN THERE'S DECREASE SIGNAL INTENSITY EDEMA WITHIN THE SUBCUTANEOUS TISSUE. SIMILAR TO THE FIRST PATIENT, BUT MORE IMPRESSIVE IS OUR SECOND PATIENT, THESE ARE STEREO IMAGES, THERE ARE PATCHY SIGNALING WITHIN THE MUSCLE GROUPS, VERY IMPRESSIVE, MYOSITIS. AND AGAIN, AFTER TREATMENT WE HAVE THIS -- THESE STEREO IMAGES THAT SHOW ALMOST ALMOST COMPLETE RESOLUTION OF MYSITIS. IN THIS PATIENT. THERE WAS UNIQUE FINDINGS TO OUR SECOND PATIENT. THIS IS A T-1 WEIGHTED IMAGE OF THE LOWER EXTREMITIES, THIS IS A REGION OF THE THIGH. AS YOU CAN SEE THERE IS NO FAT WITHIN THE SUBCUTANEOUS TISSUE BUT WE HAVE THIS FAT SIGNAL WITHIN THE DEEP FACTUAL PLANES OF THE SIZE IN THE FIRST PATIENT WE DIDN'T REALLY HAVE THAT MUCH OF A PERIPHERAL LIPODYSTROPHY IN THE LOWER EXTREMITIES BUT IN THIS CASE WE HAD PERIPHERAL LIPODYSTROPHY AS SHOWN HERE ON THIS AXIAL T-1 WEIGHTED IMAGE. PULMONARY HYPERTENSION, IMAGE ON THE LEFT IS OUR LUNG WINDOW, IN A CT WITHOUT CONTRAST AXIAL VIEW. AND AS YOU CAN SEE HERE, LUNG PARENCHYMA IS NORMAL LOOKING THERE'S NO INTERSTITIAL THICKENING, THERE IS NO REAL CONSOLIDATION HERE. ON THE RIGHT YOU SEE ENLARGEMENT OF THE PULMONARY ARTERY RELATIVE O THE AORTA. THE RATIO OF THESE TWO SHOULD BE ONE OR LESS. MEANING THAT AWE THE AORTA SHOULD BE EQUAL IN SIZE OR LARGER COMPARED TO THE MAIN PULMONARY ARTERY, THIS IS INDICATIVE OF PULMONARY HYPERTENSION. IN THIS CASE WITH NORMAL LUNG PARENCHYMA HIGHLY SUSPICIOUS FOR PRIMARY PULMONARY HYPE TENSION. HERE WE HAVE ANOTHER FINDENING THE SECOND PATIENT WHICH IS CALCIFICATION OF THE BASAL GANGLIA, IN THIS CASE PALADI, WE HAVE A T-1 WEIGHTED IMAGE ON THE LEFT. MR IMAGE AT THE REGION OF THE BASAL GANGLIA. AND WE HAVE A NON-CONTRAST CT, THERE IS -- ARTIFACT AT THE REGION OF -- WHICH IS CONFIRMED TO BE CALCIFICATION ON IMAGE ON THE RIGHT CT NON-CONTRAST OF THE BRAIN. WITH THAT I'LL GIVE THE PODIUM TO DR. LEE WHO WILL PRESENT PATHOLOGY FINDINGS. THANK YOU. >> SO I'M GOING TO PRESENT THE SCHEME BIOPSY FINDINGS IN PATIENT NUMBER 1. SO THE CUTANEOUS FINDINGS IN CANDLE SYNDROME INCLUDES DERMATITIS PENICLITIS AND LIPODYSTROPHY. THIS IS A SCHEME BIOPSY FROM PATIENT NUMBER 1 FROM 2012. HERE YOU CAN SEE AS SCANNING MAGNIFICATION THE EPIDERMIS APPEARS UNREMARKABLE. IN THE DERMIS THERE IS A PATCHY PERIVASCULAR AS WELL AS INTERSTITIAL INFLAMMATORY INFILTRATE. AT HIGHER MAGNIFICATION, THESE ARE PREDOMINANTLY PREDOMINANTLY MONONUCLEAR CELLS. CELLS RESEMBLE MATURE NEUTROPHILS AND LESS MATURE FORMS THAN NEUTROPHILS AND MYELOID CELLS. THE OTHER SUBSET OF CELLS ARE THE HISTIOSITES. THESE ARE MACROPHAGES, PATIENT MACROPHAGES. ON THE MYELOPEROXIDASE, IT'S HIGHLY EXPRESSED IN NEUTROPHILS SO YOU CAN SEE SCANNING MAGNIFICATION THERE ARE PATCHES OF INTENSE STAINING BY MYELOPEROXIDASE. ON CLOSEUP HERE YOU CAN SEE THE LARGE MONONUCLEAR CELLS WITH SOME WITH NUCLEAR ATP STAIN INTENSELY FOR MYELOPEROXIDASE, ALSO CARYO ACT TICK DEBRIS ARE STAINING POSITIVE. THERE ARE SUBSET OF CELLS THAT ARE NEGATIVE FOR MPLD LYMPHOCYTES AND PA CROW PHAGOS. THIS IS A SERIAL SECTION OF SKIN BIOPSY SHOWING THE HNE MYELOPEROXIDASE AND CD 163 WHICH HIGHLIGHTS MACROPHAGES AND MONOCYTES. SO HERE YOU CAN SEE DENSE STAINING WITH MYELOPEROXIDASE INDICATING THESE ARE NEUTROPHILS AND IMMATURE NEUTRAL CELLS MYELOID PRECURSORS BUT THERE'S ALSO COLOCALLIZATION OF THE MACROPHAGES. THESE ARE NOT THE SAME POPULATION CELLS THAT THEY CO-LOCALIZE TO THE GENERAL AREA. THIS IS A SKIN BIOPSY FROM PATIENT 1 OBTAINED IN 2009. EARLIER TIME POINTS. AGAIN YOU CAN SEE A REMARKABLE EPIDERMIS AND RELATIVE SPARING OF THIS SUPERFICIAL DERMIS. BUT IN THE DERMIS THERE IS A DENSE INTERSTITIAL AS WELL AS PERIVASCULAR INFLAMMATION, THAT ARE PREDOMINANTLY MYELOPEROXIDASE POSITIVE. THESE ARE NEUTROPHILS AN PRECURSORS. THE CD 3 HIGHLIGHTS WHERE THE T LYMPHOCYTES ARE, THIS IS A REACTIVE INFLAMMATORY PATTERN SHOWING THE INFLAMMATION COMPOSED OF LYMPHOCYTES. YOU CAN SEE THE INTERSTITIAL POPULATION ARE PREDOMINANTLY MYELOPEROXIDASE POSITIVE NEUTROPHILS WITH KARYOEXIS. THIS IS A BIOPSY FROM A PATIENT WITH CANDLE FROM AREA OF LIPODYSTROPHY, EPIDERMIS WITH A DENSE DERMAL AND SUBCUTANEOUS INFLAMMATION. THIS THIS PATTERN OF SUBCUTANEOUS INFLAMMATION IS A LOBULAR PENICLITIS PATTERN WHERE THE INFLAMMATION INVOLVES THE SUBUCUTANEOUS LOBULES POPESSED TO THIS. YOU CAN SEE LIPODYSTROPHY AS OPPOSED TO UNIFORM SIZE AND SHAPE OF ADIPCYTES. THERE IS A GREAT VARIATION, SOME HYPERTROPHY, SOME ATROPHY OF ADIPOSE CELLS. LIPODYSTROPHY AND THEN ANOTHER IMPORTANT FINDING WOULD BE THE DENSE INFLAMMATORY INFILTRATE COMPOSED OF SOME MATURE NEUTRAPHIL, MOSTLY MONONUCLEAR CELLS THAT ARE A MIXTURE OF NEUTROPHILS. AND ALSO MACROPHAGES. AGAIN, THERE IS INTERSTITIAL DERMAL INFLAMMATORY INFILTRATE. OF SIMILAR CELL TYPE. TO RECAP THE HISTOLOGIC FINDINGS, THE CHARACTERISTIC FEATURES SEEN IN CANDLE INCLUDE INTERSTITIAL AND PERIVASCULAR MONONUCLEAR INFILTRATES THROUGHOUT THE DERMIS. AND SOMETIMES SUBCUTE WITH KARYOREXIS AND THE LOBULAR PATTERN PENICLITIS WITH LIPODYSTROPHY AND ALSO THESE LESIONAL CELLS ARE POSITIVE FOR MYELOPEROXIDASE AND COLORASTRAGEN WHICH IS NARCKER FOR MYELOID DIFFERENTIATION. IN ADDITION TO THE FINDING THAT ARE CHARACTERISTIC BUT NOT SPECIFIC TO THE DIAGNOSIS OF CANDLE INCLUDE SUPERFICIAL AND DEEPER VASCULAR LYMPHOCYTIC INFILTRATE, THE UNAFFECTED EPIDERMIS AND RARE TO ABSCESS OF MATURE NEUTROPHILS. NOW I INVITE DR. DEJESUS TO APPEAR IN GENETICS >> BOTH PATIENTS HAVE A CLINICAL GENETIC DIAGNOSIS OF CHRONIC DETERMINE FOLLOWTOSIS LIPODYSTROPHY ELEVATED TEMPERATURE OR CANDLE SYNDROME P. CANDLE SYNDROME IS A HEREDITARY AUTOIMMUNE DISEASE CAUSED BY MUTATIONS THAT ENCODE THE PROTOSOMES TO THE NEONATES. THE PROTOSOME IS A HIGH HI CONSERVED TUBULAR STRUCTURE THAT HAS TWO ALPHA AND TWO BETA RINGS, EACH RING HAS A SEVEN SUBUNIT. THE PROTOSOME IS COMPONENT OF THE PROTOSOME SYSTEM AND IT FUNCTIONS AS A PROTEASE, VERY IMPORTANT FOR DEGRADATION OF MISFOLDED AND POLYUBIQUITINATED PROTEIN. IN 2011 IN COLLABORATION WITH DR. (INDISCERNIBLE) IN ISRAEL, OUR GROUP IDENTIFIED CANDLE IS CAUSED BY MUTATION IN PSNB WHICH ENCODES BETA 5I SUBUNIT. THIS FINDING WAS MADE BY HOMOZYGOSITY MAPPING AND SIMULTANEOUSLY WITH OTHER GROUPS. MORE RECENTLY IN COLLABORATION WITH DR. DANIEL CASTTHER AND DR. YVONNE (INDISCERNIBLE) GROUP, WE OBSERVE CANDLE CAN BE CAUSED BY MUTATION IN OTHER PROTOSOME SUBUNITS, PSMPS 4 AND MPS 9. REMARKABLY IT HAS BEEN ALSO SHOWN THAT PATIENTS WITH CANDLE CAN HAVE A DIE GENIC NOT ONLY MONOGENIC BUT CAN HAVE A DIGENIC INHERITANCE AS PATIENTS WITH MUTATIONS IN BETA 7 AND BETA 1I ARE ALPHA 7 AND BETA 5I. HAVE BEEN IDENTIFIED. NOOSE OF THE PATIENTS WITH CANDLE REPORTED SO FAR ARE HOMOZYGOUS FOR MUTATIONS IN PSNB 8 GENES WHICH ENCODE BETA 5I SUBUNIT. FROM NINE PATIENTS REPORTED BY OUR GROUP INITIALLY, FIVE WERE HOMOZYGOUS FOR THESE MUTATION HERE IN EXOME 2 PSNBA GENE. P 7 TO 5M. PATIENTS WHO WHICH WERE BORN TO -- PARENTS WAS FOUND TO BE HOMOZYGOUS FROM 27 TO 25 MUTATION BY TARGETED SEQUENCING. HOWEVER, PATIENT 1 ALSO BY TARGETED SEQUENCING WERE FOUND HETEROZYGOUS FOR T-7 TO 5M MUTATION. SO IN ORDER TO TRY TO FINE A SECOND MUTATION FOR THIS PATIENT, HE WAS -- HE HAD WHOLE EXOME SEQUENCE IN PERFORMANCE. THEN BESIDES THE HETEROZYGOUS VARIANT IN PSNBA THIS PATIENT HAS A DE NOVO MUTATION IN -- WHICH ENCODES ALPHA 7 SUBUNIT. THIS MUTATION IS IN FRAME DELETION AT POSITION 233. SO HE LOST ONE AMINO ACID, AS YOU CAN SEE HERE THIS ARGININE IS HIGHLY CONSERVE ACROSS SPECIES. IN CONCLUSION FOR DIGENETIC FINDINGS PATIENTS WHO IS HOMOZYGOUS FOR PSNBH MUTATION T 7 TO 5M THE MOST COMMON ONE, PATIENT ONE IS DOUBLE HETEROZYGOUS, DIGENIC INHERITANCE, INHERITED FROM HIS FATHER, DE NOVO VARIANT THAT ARE NOT -- THAT WAS NOT PRESENT IN EITHER OF HIS PARENTS. THE FINDINGS -- IDENTIFICATION OF THE PROTOSOME MUTATION, DID NOT PROVIDE ANY INDICATION FOR DISEASE MECHANISM OR FOR A THERAPEUTIC TARGET THAT COULD BE USED IN CANDLE. IN ADDITION TO THAT, PROTOSOME KNOCK OUT MOUSE -- MICE, THEY HAVE NO SPONTANEOUS INFLAMMATORY PHENOTYPE. WE USE IMMUNOPHENOTYPING, TO CHARACTERIZE PATIENTS AND PATIENTS WITH CANDLE HAVE EXTREMELY HIGH LEVELS OF INTERFERON GAMMA INDUCIBLE CHEMOKINE CXXL 10. PATIENT ONE HAS HIGH LEVELS OF IP-10, ALSO PATIENT 2 IN COMPARISON WITH OTHER CANDLE PATIENTS, AND PATIENTS WITH GAIN OF FUNCTION MUTATIONS. ALL THIS GROUP HAVE MUCH HIGHER LEVELS OF IP 10 THAN FOR EXAMPLE PATIENTS WITH IL -- DISEASE. LATER ON DR. -- TALK ABOUT THESE OTHER TYPE 1 INTERFERON DISEASE. SO HIGH LEVELS OF IP-10 SUGGESTED THAT PATIENTS WITH CANDLE HAVE AN EXCESSIVE SIGNALING INTERFERON SIGNALING, THESE WERE COLLABORATEED BY WHOLE BLOOD TRANSCRIPTOME ANALYSIS BY RNA SEQ WHICH SHOW PATIENTS WITH CANDLE HAVE ENOUGH INTERFERON SIMULATED GENES AS YOU CAN SEE HERE IN THE TYPE INTERFERON HIS MAP IN COMPARISON WITH PATIENTS WITH DISEASE -- AND HEALTHY CONTROLS. PATIENT ONE IS REPRESENTED HERE BY THE FIRST COLUMN. MORE RECENTLY WE HAVE BEEN OBSESSING THE PRESENCE OF INTERFERON SIGNATURE BY NANOSTRING USING 25 GENE STANDARDIZED CORE. AS YOU CAN SEE IN THIS GRAPH PATIENT ONE HAS VERY HIGH SCORE AS WELL AS PATIENT 2 IN COMPARISON WITH OTHER CANDLE PATIENTS REPRESENTED HERE WITH PATIENTS WITH GAIN OF FUNCTION MUTATIONS. WITH IOM DISEASE, HEALTHY CONTROLS WHO DO NOT HAVE INTERFERON SIGNATURE. SO BECAUSE OF THIS HIGH STRONG INTERFERON SIGNATURE OBSERVE IN CANDLE PATIENTS THESE SUGGESTED THAT BLOCKING INTERFERON SIGNALING COULD BE A GOOD APPROACH TO IMPROVE THE DISEASE IN THESE PATIENTS, AS DR. MONTEALEGRE DESCRIBE, THEY ARE REFRACTORY SO ALL IMMUNOSUPPRESSION THERAPIES. SO AMONG THIS STRATEGY, THE POSSIBLE STRATEGIES TO BLOCK INTERFERON SIGNALING, THE ONLY ONE AVAILABLE AT THAT TIME WAS (INDISCERNIBLE) WITH JACK 2 INHIBITOR. ARE INTRACELLULAR TYROSINE KINASE THAT SIGNALING OF SEVERAL CYTOKINES VIA THE JACKS PATHWAY. BESIDES USE IN POLYEMIA FIBROSIS, THE JACK INHIBITORS ARE ON TRIAL UNAPPROVED FOR THE TREATMENT OF RHEUMATOID ARTHRITIS TO BLOCK IL-6. THOUGH THEY ARE NOT APPROVED FOR TREATMENT OF TYPE 1 INTERFERON MEDIATE DISEASE, THEY USE ALSO WORK IN THIS DISEASE BECAUSE THEY WOULD BLOCK TYPE 1 AND TYPE 2 INTERFERON SIGNALING. SO IN ORDER TO UNDERSTAND HOW JACK INHIBITORS WORK WE NEED TO UNDERSTAND HOW JACKS PATHWAY GETS ACTIVATED. SO WHEN A CYTOKINE ENGAGED RECEPTOR THIS LOSE TO CORRELATION OF JACK AND ALSO OF THE INTRACELLULAR TALE OF THE CYTOKINE RECEPTOR. THESE GENERATE DOCKING SITES FOR THIS PATH, THIS PATH GETS PHOSPHORYLATED, AND ACTIVATED, THEY DIMERIZE AND TRANSLOCATE TO THE NUCLEUS REGULATING GENE EXPRESSION, IN OUR CASE HERE, INTERFERON SIMULATED GENES INTERFERON GENES THEMSELVES. SO NOW DR. MONTEALEGRE WILL RETURN, WE RETURN TO TALK TO SHOW THE CLINICAL RESPONSE IN CANDLE PATIENTS TO THE JAK1 AND JACK 2 INHIBITOR BARASITNIB. >> SO BASED ON ALL THE INFORMATION THAT DR. DEJESUS SHARED WITH US, WITH THE SUPPORT FROM ELY LILLY WE DEVELOP A COMPASSIONATE USE TREATMENT PROTOCOL WITH A JAK1 JACK 2 INHIBITOR BY SITNIB IT'S IMPORTANT FOR THE AUDIENCE TO REMEMBER COMPASSIONATE USE IS A PROGRAM DEFINED TO MAKE AVAILABLE INVESTIGATIONAL MEDICATIONS FOR PATIENTS WHOM THEY HAVE NOT RESPONDED TO ANY TREATMENT THAT IS AVAILABLE AND THEY DO NOT HAVE ANY OTHER TREATMENT OPTIONS. COMPASSIONATE USE PROTOCOLS ARE NOT DESIGNED AT THE CLINICAL TRIALS TO EVALUATE FOR EFFICACY. SO WHICH PATIENTS WERE ACTUALLY ENTITLE OR AVAILABLE FOR THE STUDY, CANDLE PATIENTS GREATER THAN 17.5 MONTHS OF AGE OR GREATER THAN 8.5-KILOS WHO HAVE SIGNS OF ACTIVE DISEASE REFLECTED BY SCORE GREATER THAN .5. A SCORE IS BASICALLY A TWO WORD PATIENT SCORE EARLY SYMPTOMS AND THERE IS SCORE BASED ON SEVERITY FROM HERE TO FOUR. THE OTHER CRITERIA WAS THOSE PATIENT NEEDED TO BE ON DOSES OF STEROIDS GREATER THAN 0.15-MILLIGRAMS PER KILO PER DAY OR NEED TO HAVE ADIPOSE COURSE OF STEROIDS. WE WEREN'T ABLE TONE ROLE PATIENTS WITH ANY ACTIVE DISEASE PATIENTS WITH RENAL FAILURE OR RECENT OKAY POE SURE TO IMMUNOSUPPRESSIVE MEDICATION. SO WE SAID EVALUATED EFFICACY BUT HOW WE CAN TEST OR KNOW THOSE PATIENTS ARE RESPONDING. SO THE FIRST THING IS THE FIRST CAN WE REDUCE THE SCORE TO LESS THAN .5 AND THE OTHER QUESTION IS, WAS FOR THOSE PATIENTS ON STEROIDS AT BASELINE CAN WE REDUCE THE TOTAL DOSE OF STEROIDS TO DOSES LESS THAN 0.15-MILLIGRAM PER KILO PER DAY OR 50% FROM THE DOSES THAT WERE ON BASELINE. THESE COMPASSIONATE USE COME WITH SPECIFIC CHALLENGES, ONE IS HOW TO DOSE PEDIATRIC PATIENTS USING MEDICATION THAT UNTIL THEN HAS ONLY BEEN USED IN ADULT IN PATIENTS WITH RHEUMATOID ARTHRITIS. THE HALF LIFE THAT IT WAS REPORTED FOR THEM WAS BETWEEN 7.9 TO 8.4. AS YOU KNOW FOR CLINICAL TRIALS THIS MEDICATION HAS BEEN USED ONCE A DAY FOR PATIENTS WITH RHEUMATOID ARTHRITIS. THE AREA WAS COMPLETELY DIFFERENT FROM OUR PEDIATRIC PATIENTS IN WHOM HALF LIFE WAS ACTUALLY DEPENDENT IN BODY SURFACE AREA AND RANGES BETWEEN 1.6 HOURS TO 3.44. FOR THIS REASON OUR PATIENTS WERE DOSED UP TO FOUR TIMES A DAY, A SINGLE PATIENT WAS THOSE UP TO FIVE TIMES A DAY WITH THIS MEDICATION. GOING BACK TO OUR PATIENTS DO WE SEE RESPONSE? BACK TO PATIENT NUMBER ONE. WE HAVE SEEN SO FAR JANUARY 2016 THAT WE HAVE BEEN ABLE TO DECREASE THE DAILY SCORE BY GREATER THAN 50% HAVING A DIARY SCORE OF .2 AT HIS LAST CLINIC VISIT ASSOCIATED REDUCTION IN DAILY DOSE OF STEROID BY 70%. THE DAILY DOSE AT THIS POINT IS 3.5-MILLIGRAMS A DAY. IN THE LEFT LOWER PANEL YOU CAN SEE DOCUMENTATION OF PANICLITIS FROM PICTURES COMPARING SEPTEMBER 2012 TO JANUARY 2015 AND IN THE PICTURES ON THE RIGHT LOWER PANEL IN PERSON MYOSITIS AND REVIEW BY DR. MALEARY. WHAT ABOUT SAFETY THE DR. DEJESUS WAS COMMENDING ON, DESPITE JACK 2 AND HAVING LOCKING GROWTH THESE PATIENTS HAVE GROWN. THEY WERE IMPROVEMENT IN LINEAR GROWTH. IN CONTEXT OF GROWTH HORMONE. THESE PATIENTS GROWN FROM ONE CENTIMETERS IN SEPTEMBER, JULY JULY 2012 TO 124-CENTIMETERS BY HIS LAST VISIT IN JANUARY 2016. IF YOU REMEMBER, IN THE INITIAL PICTURE THAT I SHOWED FROM 2009 TO 2012 THE PATIENT DID NOT GROW AT ALL. WE HAVE SEEN TRENDS, SOME ACTUALLY BONES SIGNS OF BONES IMMUNOSUPPRESSION HAVE IMPROVED. FOR EXAMPLE HERE THE IMPROVEMENT OF THROMBO CYTOPENIA, BASELINE PLATELET 68 MOST RECENTLY THAT WAS 148. WITH IMPROVEMENT IN TRANSAMINITIS LPH AND ANTIBODIES ARE NEGATIVE. HOWEVER THIS PATIENT DEVELOPED ONE OF THE EXPECTED JACK 2 TOXICITIES THAT IS THE DEVELOPMENT OF ANEMIA. ACUTE PHASE 3 E REACTANTS CONTINUE TO FLIP TO 8. WHAT ABOUT FOR PATIENT NUMBER 2 SIMILAR RESPONSES, WE HAVE ACTUALLY SEEN, HER DIARY SCORE DROPPED BY 93% AND PREDNISONE DOSE WE HAVE DECREASED BY 83%. AS SHE ACTUALLY HAD IMPROVEMENT IN MYSITIS. HOWEVER IN THE CONTEXT OF RECENT VIRAL INFECTION SHE WAS REPRESENTED BY LAST SET OF SLIDES ON THE BOTTOM FROM SEPTEMBER 2015. AGAIN, SHE HAS SHOWN IMPROVEMENT IN LINEAR GROWTH, SHE HAS GONE FROM 90 TO 101 SEPTEMBER-METERS. THIS IS WITHOUT THE HELP OF THE -- CENTIMETERS WITHOUT HELP OF THE GROWTH HORMONE. HER ANEMIA IMPROVED FROM 9.6 TO 12.7, TRANSAMINITIS COMPLETELY RESOLVED. WE HAVE IMPROVEMENT IN CK VALUES, NORMAL LDH, ACUTE PHASE 3 REACTANTS FLUCTUATE, AND THE HYPERTRIGLYCERIDE I'M MA IMPROVED WITH DECREASE OF STEROIDS AND INITIATION OF JACK INHIBITOR. A QUICK SUMMARY FROM THE EFFICACY DATA FROM ALL THE PATIENTS SO FAR ENROLLED. WE HAVE ENROLLED 11 CANDLE PATIENTS OF WHOM NINE OF THEM ARE ACTUALLY ACTIVE. NINE HAVE ACHIEVE AUTOINFLAMMATORY DIARY SCORE LESS THAN .5, IT WAS ONE OF OUR MAIN MEASURES FOR EFFICACY. THE TIME OF THE LAST VISIT. TEN PATIENTS OUT OF 11 ON DOSES OF CORTICOSTEROIDS AT BASELINE FOR OUT OF THOSE TEN WE HAVE ACTUALLY BEEN ABLE TO DISCONTINUE PREDNISONE COMPLETELY. THE OTHER ONES WE HAVE BEEN ABLE TO DECREASE THE DOSE COMPARED TO BASELINE BY GREATER THAN 50%. SO ANALYSIS FROM SAFETY PARAMETERS, HAVE SHOWN THAT PATIENTS WITH ANEMIA LOW HEMOGLOBIN VALUES AT BASELINE HAVE IMPROVED, SIX OUT OF EVEN, ONLY PATIENT THAT REPRESENTED WITH UPPER GI BLEEDING IN CONTEXT OF UNDERLYING LIVER DISEASE. SIMILAR TRENDS HAVE BEEN SEEN IN IMPROVEMENT OF ARCLC OR LYMPHOCYTE COUNTS AND WITH THROMBO CYTOPENIA. HOWEVER, FOR THROMBO CYTOPENIA THERE IS NOT A STATISTICALLY SIGNIFICANT DIFFERENCE. FOR SAFETY DATA THE MOST COMMON ADVERSE EVENT HAS BEEN INFECTION. TWO DISCONTINUED FROM THE STUDY, ONE DUE TO LACK OF EFFICACY AND DEVELOPMENT OF MULTIFOCAL VASCULAR NECROSIS AND SECOND PATIENT DEVELOPED IN BK VIREMIA. THE LATER PATIENT UNFORTUNATELY DIED TWO MONTHS AFTER DISCONTINUATION OF VARISITNIB IN CONTEXT OF ANOTHER JACK INHIBITOR DUE TO SEVERITY OF DISEASE. WE NEEDED TWO REQUIRED TEMPORARY INTRAOPTION KNEW DEW TO NEUTROPENIA, HIS COUNTS IMPROVE AFTER RESTARTING THE MEDICATION. THREE PATIENTS HAVE ELECTIVE REDUCTION DUE TO PRESENCE OF BK VIREMIA. THE MOST COMMON ADVERSE EVENT HAS BEEN UPPER RESPIRATORY INFECTION. WITH THIS I CONCLUDE AND WILL PASS ON TO DR. GOLDBACH-MANSKY FOR OVERVIEW OF OUR PROGRAM. >> THANK YOU ALL FOR COMING. I HAVE TO USE THE RIGHT ONE. CANDLE IS A RARE DISEASE WITH LESS THAN 100 CASES REPORTED. THE FIRST CASES WERE THE SYNDROME WHERE REPORTED IN THE JAPANESE LITERATURE BY -- NICHIMORA IN THE 1930s AND 50s. IT WASN'T UNTIL DISCOVERY OF GENETIC MUTATIONS AND PSNBA THAT WE RECOGNIZE THAT THESE PREVIOUSLY REPORTED SYMPTOMS -- SYNDROMES AND CANDLE ARE IN FACT THE SAME DISEASE. THE MORTALITY OF THIS CONDITION IS HIGH, CHILDREN OF -- DUE SUDDENLY IN CHILDHOOD, OFTEN WHAT LOOKS LIKE A SYSTEMIC INFLAMMATORY RESPONSE SYNDROME, AND OFTEN PLOT CURVES ARE NEGATIVE BUT SOMETIMES IT SEEMS LIKE TRIVIAL INFECTIONS CAN CAUSE THIS IMMUNE DISREGULATORY SYNDROME. THE INFLAMMATORY MANIFESTATIONS OF CANDLE WERE REPORTED BY DR. MONTEALEGRE BUT I WOULD LIKE TO GO THROUGH PATIENTS DO PRESENT WITH SYSTEMIC INFLAMMATION, FEVER, ANEMIA AND ELEVATION OF ACUTE PHASE 3 REACTANTS AND THE ORGAN INFLAMMATION, THE INFLAMMATORY ORGAN MANIFESTATIONS IN THE SKIN, MUSCULOSKELETAL WITH MYOSITIS, THAT IS SHOWN HONEST CORONAL IMAGE. AND LYMPHOCYTIC MENINGITIS. THE CLINICAL MANIFESTATIONS OF CANDLE CHANGE IN MORE INFLAMMATORY IN YOUNG CHILDREN, AS CHRONIC INFLAMMATION LEADS TO ORGAN DAMAGE, OLDER PATIENTS PRESENT WITH SIGNIFICANT ORGAN DAMAGEMENT YOU CAN SEE ACTUALLY FAIRLY REGIONAL LIPO ATROPHY AND MUSCLE ATROPHY WITH SEVERE JOINT CONTRACTURE HERE REPORTED BY EXAMINE THE ENDOCRINE LOGIC MANIFESTATIONS OF THIS DISEASE, AS YOU CAN SEE HERE, SYSTEMIC INFLAMMATION TRANSLATES INTO ORGAN DAMAGE, GROWTH RETARDATION, OSTEOPOROSIS AND BONE MARROW SUPPRESSION, SOMETIMES CHRONIC DISEASE BUT ACTUALLY INVOLVE WHITE BLOOD CELLS, PANICLITIS AND LIPO DOS TROPHY, THIS IS INFLAMMATORY IN ORIGIN OR IF THERE IS DAMAGE TO THE ENDOTHELIAL CELLS BY PROTEASOME DISEASE MANIFESTATIONS HYPERTENSION, PULMONARY HYPERTENSION AND CALCIUMOSIS. THE MYOSITIS LEADS TO MUSCLE LOSS, THE NON-INSIGN VIE AT THIS TO JOINT CONTRACTURES THE METABOLIC MANIFESTATIONS ARE INTERESTING, YOU HEARD PRESENTATIONS BY DR. MONTEALEGRE, WE BELIEVE THE NON-INFLAMMATORY ARE MODELS OF PRIMARY PROTEOSOME DYSFUNCTION IN MICE, WHERE HEPATIC RESISTANCE AND HEPATIC STEREO TOSIS ARE INDUCED IN ABSENCE OF OBESITY. THE EXACT MECHANISMS ACTUALLY NEED TO BE EVALUATED. INTERESTINGLY THESE MANIFESTATIONS DO NOT RESPOND P TO JACK INHIBITION. LYMPHOCYTIC MENINGITIS WHETHER OR NOT IT CONTRIBUTES TO THE DEVELOPMENT OF BASAL GANGLION CALCIFICATION, BY WHICH MECHANISM REMAINS UNKNOWN. PATIENTS WITH CANDLE AND OTHER PATIENTS WITH UNDIFFERENTIATED DISEASE THAT PRESENT TO OUR PROGRAM, PRESENT A TREATMENT DILEMMA. OFTEN HIGH DOSES STEROIDS ARE USED TO TREAT THEIR INFLAMMATION AND THEN ATTEMPT TO IDENTIFY IMMUNOSUPPRESSIVE AGENTS ENSUE AND VERY OFTEN WHEN WE SEE PATIENTS THE RESPONSE TO TREATMENT IS INSUFFICIENT, YOU HAVE SEEN THE ENTIRE LIST OF DRUGS THAT THEY ACTUALLY EXPOSED TO. WHICH RESULT IN TREATMENT AND DAMAGE FROM THOSE TREATMENT AS WELL AS ORGAN DAMAGE FROM ONGOING INFLAMMATION. SO THE APPROACH WE USE TO EVALUATE PATIENTS IS A CLINICAL PHENOTYPING HISTOLOGY AND IMAGING APPROACH TO CHARACTERIZE THE INFLAMMATORY DISEASE MANIFESTATION. GENETIC APPROACH IMMUNOHISTOCHEMISTRY AND WE TRY TO MODEL ORGANISM SUMMATION IN SOME INSTANCES IN ORDER TO IDENTIFY CLUES THAT HELP TREATMENTS WITH TARGETED AGENTS. THERE IS INCREASING NUMBER OF TARGETED AGENTS THAT COMES FROM STUDY INFLAMMATION IN PATIENTS WITH RHEUMATOID ARTHRITIS AND OTHERS AS WELL AS FROM CANCER STUDIES OF IDENTIFYING INFLAMMATORY TARGETS IN CANCER TREATMENT. THESE THERAPIES CAN BE USED AND IN EFFECT ON THE CLINICAL MANIFESTATIONS CAN BE OBSERVED AND TO OBTAIN PROOF OF CONCEPT TARGETED THERAPY HAS IMPACT ON CLINICAL DISEASE PHENOTYPE. MANY KNOW IN AUTOINFLAMMATORY DISEASE MANIFESTATIONS ARE PHENOTYPES, ONE HAS PROMINENT ROLE DRIVING THE PHENOTYPE AND THAT HAS BEEN STUDIED IN THE (INAUDIBLE) FEVER SYNDROME IN DAN CASTNER'S LAB, GROUP AND MANY OTHERS AND INSTANCES IT IS THE USE OF TARGETED THERAPY OF IL-1 BLOCKING THERAPY THAT PROVIDE PROOF THAT THESE CONDITIONS ARE ACTUALLY SIGNIFICANTLY MEDIATED BY IL-1 DISREGULATION WITH IL-1 BLOCKING AGENTS WITH MAJOR DIFFERENCES TO THE LIFE OF THESE PATIENTS. LIFE SAVING. ANOTHER CONDITION DO NOT RESPOND TO IL-1 MEDIATED DISEASE OR PARTIALLY TO IL-16 MEDIATED DISEASE WHICH REALLY MAKES IMPORTANT TO IDENTIFY TARGETS FOR TREATMENT AND PATHWAYS THAT LEAD TO THESE SYSTEMIC IMMUNE DISREGULATED PHENOTYPES. CANDLE HAS BEEN THE FIRST CONDITION THAT'S GIVEN US A SUGGESTION OF TYPE 1 INTERFERON DISREGULATION. WHEN WE LOOK AT PATIENTS IN OUR COHORT, ABOUT A THIRD OF PATIENTS HAVE IL-1 MEDIATED DISEASE AND CAN BE GENETICALLY CHARACTERIZED AND CAN BE SUFFICIENTLY TREAT TREATED WITH IL-1 BLOCKING TREATMENT. BUT THERE ARE TWO-THIRDS WE COULDN'T TREAT AND IDENTIFICATION OF INTERFERON SIGNATURE ALLOWED US TO CHARACTERIZE THOSE PATIENTS WITH INTERFERON SIGNATURE AND RAISE Z THE QUESTION WHETHER TYPE ONE INTERFERON MAYBE A DRIVING MECHANISM OR EPIPHENOMENON IN THOSE CONDITIONS THAT REMAIN GENETICALLY UNCHARACTERIZED. SO BACK TO CANDLE, ADDITIONAL QUESTION OR INITIAL QUESTION THAT YOU INITIALLY EXAMINED WAS WHETHER OR NOT THE INTERFERON MEDIATED GENE EXPRESSION WAS DUE TO TYPE ONE INTERFERON STIMULATION OR TYPE TWO INTERFERON STIMULATION. AND USE A PROTEASOME INHIBITOR, APOXMYCIN AND INCREASING DOSES WHEN EXPOSED OR WHEN ACTUALLY CULTURED WITH PBMCs, LED TO THE INDUCTIONS OF TYPE 1 INTERFERON GENE TRANSCRIPTION BUT NOT INTERFERON GAMMA TRANSCRIPTION. AND THERE WAS NO IMPACT ON UP-REGULATION OF TRANSCRIPTION OF IL-1 BETA, 6 TRANSCRIPTION WAS ACTUALLY REDUCED CONSISTENT WITH EFFECT THAT IN SOME INSTANCES PROTEASOME INHIBITORS ARE USED TO TREAT INFLAMMATORY CONDITIONS. AND SECOND APPROACH WAS USED IN COLLABORATION WITH CRUDERS LAB WHERE HUMAN NIGH FIBROLASTS WERE TREATED WITH SI RNA TO KNOCK DOWN ONE OR TWO PROTEOSOME COMPONENTS AND WHEN TWO PROTEOSOME COMPONENTS WERE KNOCKED DOWN CRITICAL REDUCTION OF MORE THAN 50% OF PROTEASOME FUNCTION WAS ACHIEVED, WE HAVE SEEN TYPE 1 INTERFERON TRANSCRIPTION AND TRANSCRIPTION OF INTERFERON RESPONSE GENES BUT NOT OF IL-1 BETA PROVIDING FIRST EVIDENCE, THERE WAS ACTUAL NO GAMMA TRANSCRIPTION THIS WAS TRULY AN IL-1 INTERFERON BETA MEDIATED DISEASE. THAT LED TO THIS HYPOTHESIS, IT HAS BEEN KNOWN THAT STIMULATION OF PROTEOSOMES WITH TYPE 2 INTERFERON OR OF CELLS WITH TYPE 2 INTERFERON LEAD TO THE PRODUCTION OF INCREASED OXYGEN DAMAGE DEFECTIVE RIBOSOMAL PROTEINS OR MISFOLDED PROTEINS. AND UPREGULATION OF THE CAPACITY OF THE PROTEOSOME. IN PSNB 8 KNOCK OUT HOMIES UPREGULATION CAPACITY IS NOT ACHIEVED AND THE MICE ACTUALLY FORM AGGREGATES OF PROTEIN AGGREGATES OF THE CELLS ACTUALLY DEVELOP AGGREGATES AND DIE OF APOPTOSIS. SO WE THOUGHT THAT THE MUTATIONS THAT POINT TO A GLOBAL PROBLEM WITH PROTEOSOME UPREGULATION MAY LEAD TO THE ACCUMULATION OF PROTEOTOXIC STRESS OR PROTEOTOXIC PRODUCTS THAT INDUCE TYPE 1 INTERFERON PRODUCTIONS THROUGH MECHANISMS WE STILL DON'T KNOW. BUT WE FURTHER HYPOTHESIZE THAT THIS MAY GENERATE A VICIOUS CYCLE OR FEEDBACK, POSITIVE FEEDBACK LOOP OR AMPLIFICATION LOOP THAT COULD RESULT IN THE DISEASE MANIFESTATIONS OF CANDLE AND THUS BLOCKADED OF FEEDBACK LOOP MIGHT PROVIDE CLINICAL BENEFIT. GINA GINA MONTEALEGRE HAS SHOWED THE BENEFIT, SHE'S ALSO SHOWED YOU THAT SOME OF THE SAFETY CONCERNS WE HAD AS JACK INHIBITORS ALSO ERYTHROPOIETIN RECEPTOR AND GROWTH HORMONE RECEPTOR, AT LEAST AT THE LEVEL WE NEED TO SEE EFFICACY DON'T SEEM TO ACTUALLY BE MAJOR CONCERN IN OUR PATIENTS AS WE SEE GROWTH AND RESOLUTION OF DISEASE INDUCED ANEMIA. WE FURTHER WANTED TO SEE WHETHER IN FACT THE EFFICACY IN THOSE PATIENTS WAS CAUSED BY BLOCKADE OF INTERFERON SIGNALING. AND WE THUS LOOKED AT THE CHANGE IN THE 25 INTERFERON GENE SCORE OVER TIME. YOU CAN APPRECIATE OVER THE ONE YEAR TREATMENT OF PATIENTS WE CAN SEE REDUCTION IN INTERFERON SCORES AND MANY NORMALIZE IN THOSE PATIENTS SUGGESTING THAT IN FACT WE ARE HITTING THE INTERFERON SIGNALING TARGET. IN SERO MARKERS IP-10 MARKERS IN RESPONSE TO TREATMENT SIGNIFICANTLY DECREASE IN HERE SEVEN PATIENTS AND WHOM WE PERFORM ANALYSIS. GENETIC CONFIRMATION THAT TYPE 1 INTERFERON SIGNALING PLAYS A ROLE IN DRIVING THESE AUTOINFLAMMATORY PHENOTYPES OR DRIVING INFLAMMATORY PHENOTYPES CAME FROM THE EVALUATION WITH WHOLE EXOME SEQUENCING OF THIS PATIENT AND TARGETED SEQUENCING OF FIVE OTHER PATIENT WHOSE SHARED THE CLINICAL PRESENTATION OF FEVER AND THEN VASCULITIS IN COAL EXPOSED AREAS INCLUDING THE EAR LOBE, THE CHEEK, THE TIP OF THE NOSE, AND THE TOES, AND WHO ALSO PRESENTED WITH INTERSTITIAL LUNG DISEASE. THESE PATIENTS HAVE PROMINENT INTERFERON RESPONSE SIGNATURE IN DISTINGUISHABLE FROM CANDLE PATIENTS SUGGESTING CHRONIC INTERFERON SIGNALING. THESE PATIENTS HAVE ALL SIX PATIENTS HAD DE NOVO MUTATIONS IN DIMERIZATION REGION OF TMI MERCK WHICH ENCODES STING THAT ACTUALLY LED TO A GAIN OF FUNCTION OF THE PROTEIN. STING IS ER TRANSMEMBRANE PROTEIN THAT FUNCTION AS AN ADAPTER FOR VIRAL SENSOR SIGNALING C GUESS THAT RECOGNIZES DOUBLE STRANDED DNA. WILD TYPE STING IS ACTIVATED UPON ENGAGEMENT AND ACTIVATION OF CGEN (PHONETIC) BUT OUR PATIENTS HAVE CONSTITUTIVE STING ACTIVATION WHICH ACTUALLY LEADS TO CONSTITUTIVE TRANSCRIPTION OF INTERFERON BETA. IT'S RECENTLY BEEN SHOWN THAT STING ITSELF IS AN INTERFERON RESPONSE GENE, THERE IS A STAT 1 INTERACTION SITE AS TRANSCRIPTOR OF STING AND THEREFORE CAN LEAD -- STING IS UPREGULATED THROUGH INTERFERON AMPLIFICATION OR FEEDBACK LOOP. ALTHOUGH BLOCKING STING DIRECTLY WOULD BE THE PREFER TARGET FOR TREATMENT IN THOSE PATIENTS, THERE IS REASON TO BELIEVE OR HYPOTHESIZE BLOCKING THAT AMPLIFICATION LOOP MAY ACTUALLY PROVIDE BENEFIT AND WE SHOW YOU DATA BUT WE HAVE INVOLVED FOUR PATIENTS WITH SAVVY IN THE JACK INHIBITOR PROTOCOL. AS MENTIONED SAVVY PATIENTS HAVE CONSTITUTIVE OF STAT 1 PHOSPHORYLATION. THIS IS UNSTIMULATED T-CELLS AN B CELLS, AND INHIBITION WITH THE CURRENTLY AVAILABLE JACK INHIBITORS TO TO SITNIB ARE APPROVED. WE ACTUALLY SEE DOWN REGULATION OF STAT 1 PHOSPHORYLATION. WE HAVE A FEW MORE MINUTES AND AT THE END I WILL TRY TO PUT CANDLE IN CONTEXT OF INCREASING GROUP OF INTERFERON OPATHIES, THE TERM WAS COINED BY YANI CROWE WHO EXAMINED PATIENTS WITH -- WHO PRESENT IN INFANCY WITH A SEVERE ENCEPHALITIS THAT MIMICS VIRAL ENCEPHALITIS OR TORCH INFECTIONS. THESE PATIENTS ARE NOT SEEN BY US RHEUMATOLOGISTS. WE ARE TYPICALLY SEEN BY RHEUMATOLOGISTS BECAUSE OF WHITE MATTER DISEASE, THE SPASTIC QUADRAPLEGIC MENTAL COGNITIVE IMPAIRMENT THAT IS RESULT OF THE EARLY DEVASTATING INFLAMMATORY MANIFESTATION -- BRAIN CNS MANIFESTATION. FOR A LONG PERIOD OF TIME, ONE OF THE BIOLOGIC DIAGNOSTIC MARKERS OF CHARACTERIZING ICONIC SYNDROME IS PRESENCE OF HIGH LEVELS OF INTERFERON CSF. YANIC CROW PRETTY MUCH IDENTIFIED THE GENETIC CAUSE FOR THE ICONIC SYNDROME PATIENTS AND THEY ARE CAUSED BY GAIN OF FUNCTION MUTATIONS IN VIRAL SENSORS OR LOSS OF FUNCTION MUTATIONS IN ENZYMES IN NUCLEASES THAT ARE WHOSE FUNCTION IS TO METABOLIZE NUCLEIC ACID. SO THE HYPOTHESIS IS THAT NUCLEIC ACID MAY ACCUMULATE AND ACTUALLY SIGNAL TO THE VIRAL SENSORS AN LEAD TO THE INTERFERON RESPONSE SIGNATURE, SOMEWHAT DIFFERENT MECHANISM FROM THE PROTEOTOXIC MECHANISM WE PROPOSE IN CANDLE BUT REGARDLESS, ON THE NEXT SLIDE I'M GOING TO SHOW YOU THAT THESE INTERFERON OPATHIES I SHOWED ON THE PREVIOUS SLIDE HERE, AS CLINICAL MANIFESTATION SHARE OVERLAPPING CLINICAL FEATURES. BASAL GANGLION CALCIFICATIONS IN CANDLE PATIENTS IN SYNDROME PATIENTS AND PATIENTS WHO ACTUALLY HAVE SPONDYLO SPONDYLOENDOBEYONDIAL DYSPLASIA CAUSED BY MUTATIONS IN ALKALINE PHOSPHATASE BUT HAS VERY -- HAVE A LOT OF INFLAMMATORY SIMILARITIES AND STRONG INTERFERON SIGNATURE, IS UNCLEAR BY WHICH MECHANISMS ARE NEUTRAFILL INC. DERMATOSIS AND PANICLITIS SEEN IN CANDLE AND NEUTRAPHYLIC INFILTRATES IN THE OTHER SKIN MANIFESTATIONS OF SAVVY AND SYNDROME PATIENTS. VASCULITIS AND VASCULOPOTHY IS VERY PROMINENT IN OUR SAVVY PATIENTS AS WELL AS IN PATIENTS WITH ICONIC DS SYNDROME, THE I PATIENTS AND VASCULOPOTHY WITH CALCIFICATIONS AS SEEN IN PATIENTS WITH A SYNDROME CALLED SINGLE MERCHANT DISEASE THAT PRESENTS WITH INTERFERON SIGNATURE. SO TO RECAP THE INTERFERON MEDIATED DISEASE MANIFESTATIONS ARE DIFFERENT FROM THOSE WE OBSERVE IN THE IL-1 MEDIATED DISEASE AND I'M JUST GOING TO POINT OUT A FEW IN THE INTEREST OF TIME. CRP VERY WELL CORRELATES WITH DISEASE ACTIVITY AND IL-1 MEDIATED DISEASE BUT NOT SO WELL IN THE INTERFERON MEDIATED DISEASE, GRANULOCYTOSIS AND LYMPHOPENIA, THE CNS DISEASE IS NEUTROPHILIC. THE IL ONE MEDIATED DISEASE THAT PRESENT WITH MENINGITIS AND LYMPHOCYTIC IN THE INTERFERON MEDIATED DISEASE INCLUDING CANDLE AND ICONIC DS SYNDROME, BASAL GANGLION CALCIFICATIONS ARE NOT IN THE IL-1 MEDIATED DISEASE T. LIPO ATROPHY, LIPO THROMBOTIC DISEASE ARE RARE IN THE IL-1 MEDIATED DISEASE, PULMONARY FIBROSIS INTERSTITIAL LUNG DISEASE AND PULMONARY HYPERTENSION ARE FEATURES OF OF IL-1 MEDIATED DISEASE. GLUE GLAUCOMA IS ALSO A PRESENTATION SEEN IN A NUMBER OF PATIENTS SO WE ACTUALLY IN THE NEXT USE INTERFERON SIGNATURE TO PROBE FOR INTERFERON MEDIATED AUTOINFLAMMATORY DISEASES, AND DR. DEJESUS LOOKED AT 52 PATIENTS FROM OUR COHORT AND SEPARATED THOSE WITH PROMINENT INTERFERON SIGNATURE FROM THOSE THAT DO NOT HAVE INTERFERON SIGNATURE AND LOOKED AT THE CLINICAL DISEASE MANIFESTATIONS, YOU CAN SEE THOSE PATIENTS WITH YET CLINICALLY UNCHARACTERIZED DISEASES SORRY, GENETICALLY UNCHARACTERIZED DISEASES THAT HAVE HIGH INTERFERON SCORES HAVE CLINICAL FEATURES THAT OVERLAP WITH THOSE OF OUR CANDLE AND SAVVY PATIENTS WHICH IS NOT SEEN IN THOSE PATIENTS WHO DON'T HAVE INTERFERON SIGNATURE THUS SUGGESTING THAT INTERFERONS MAY DRIVE A SET OF CLINICAL FEATURES INHIBITING INTERFERON SIGNALING OR AMPLIFICATION MIGHT BE A POSSIBLE TREATMENT FOR THOSE PATIENTS. SO IN SUMMARY EVALUATION OF PATIENTS WITH VERY RARE NOVEL OR RARE ULTRA RARE NOVEL AUTOINFLAMMATORY DISEASE CANDLE FINDINGS SUGGESTING A PROMINENT TYPE 1 INTERFERON DISREGULATION IN THE DISEASE PATHOGENESIS, AND PRELIMINARY RESPONSE DATA FROM OUR COMPASSIONATE USE PROGRAM WHETHER JACK INHIBITOR VARY SITNIB ENCOURAGING SUPPRESSION OF INTERFERON SIGNALING CAN BE -- IN CANDLE PATIENTS WITH QUITE -- IN SOME -- WITH IMPRESSIVE RESPONSES. THE PRESENCE OF INTERFERON SIGNATURE IN THE BLOOD AND CLINICAL PRESENTATIONS OVERLAPPING WITH CANDLE AND SAVVY IN A WIDER SPECTRUM OF AUTOINFLAMMATORY SYNDROME SUGGESTS THAT YET UNCHARACTERIZED IMMUNE DISORDERS MAYBE MEDIATED BY TYPE 1 INTERFERON AND THAT INHIBITING THIS POSSIBLE AMPLIFICATION FEEDBACK LOOP MIGHT PROVIDE USEFUL THERAPY FOR THOSE PATIENTS BUT LONG TERM SAFETY AND EFFICACY NEEDS TO BE ESTABLISHED IN THESE POPULATIONS. AND OVERALL, THE APPROACH WE AND OTHERS TAKE A PERSONALIZED APPROACH USING GENETICS AND MORE PHENOTYPING IN PATIENTS WITH THESE SEVERE IMMUNE DISREGULATORY FEED -- (LOST AUDIO) CANDLE PATIENTS AND PAUL HAS BEEN HELPING WITH THE PK ANALYSIS ON OUR PATIENTS. THANK YOU VERY MUCH. [APPLAUSE] >> THANK YOU ALL FOR A GREAT PRESENTATION. WE HAVE A FEW MINUTES FOR QUESTIONS. >> I HAVE A QUESTION. >> YES. >> SO CHRIS FROM DERMATOLOGY. THANK YOU FOR THE INSPIRING SESSION. SO IN SEARCH OF A TARGETED THERAPY, IT'S IMPORTANT TO FIND THE SOLE SOURCE OF TYPE 1 INTERFERON. DO YOU GUYS HAVE ANY IDEA, EPITHELIAL CELLS MAKE TYPE 1 INTERFERON WHEREAS SOME HEMATOPOIETIC CELLS MAKE -- >> WE ACTUALLY HAVE IN ANN BERNADETTE ISOLATED CELLS AND LOOKED FOR THE SOURCE OF INTERFERON. AND WE HAVE BEEN SURPRISED TO FIND THAT AS MANY MONOCYTES THAT MAKE THE TYPE 1, THE INTERFERON BETA, WE DO NOT FIND IT IN PLASMA CYTODENDRITIC CELLS. >> THAT WAS AS A I WAS LISTENING TO THIS LECTURE, I WAS THINKING MONOCYTE MACROPHAGE LINEAGE COULD LINK ALL THE SYMPTOMS TOGETHER EVEN IN THE BRAIN OR THE MICROGLIA. THE CELLS IN THE SKIN WHERE TISSUE MACROPHAGES ARE WHICH CAN BE REPLACED BY THOSE INFLAMMATORY MONOCYTES. >> VERY -- THANK YOU FOR YOUR COMMENT. >> ANY OTHER QUESTIONS? THANK YOU FOR BEING HERE. THIS IS NOT THE LAST CPC GRAND ROUNDS FOR THIS FISCAL YEAR. WE HAVE ONE FOR JUNE. IF YOU HAVE GREAT CASES YOU WOULD LIKE TO HIGHLIGHT SEND US YOUR SUGGESTIONS. AND WE'LL BE HAPPY TO CONSIDER AND PRESENT THEM. SO THANK YOU ALL FOR BEING HERE. [APPLAUSE]