THANK YOU, EVERYBODY,
INTERESTING TO LISTEN TO SEZA
AND THIS WILL FOLLOW ALONG.
RAISE YOUR HAND IF YOU HAVE SEEN
A CASE OF FMF.
BEHCET?
A PLEA INSUFFICIENCY OF A 20.
OKAY.
THAT IS MY JOB TO TALK ABOUT NEW
AT THIS ORDER HAPLO
INSUFFICIENCY OF A 20.
THIS IS A FAMILY THAT I FIRST
SAW IN 1991.
THIS GIRL PRESENTED AT AROUND 15
MONTHS OF AGE WITH -- SHE HAD
STOPPED WALKING AND WAS ADMITTED
TO HOSPITAL, FOUND TO HAVE
MONOARTHRITIS OF THE RIGHT HIP
AND SHE ALSO HAD ASYMPTOMATIC OR
QUITE BAD UVEITIS.
WE KNOW YOUNG GIRLS WHO GET
ASYMPTOMATIC UVEITIS AND
ARTHRITIS HAVE THE DIAGNOSIS OF
POST ARTICULAR JIA.
OLIGOARTICULAR JIA AND THAT'S
NEVER INVOLVES THE HIP AT LEAST
AT THE BEGINNING.
WE KNEW THERE WAS SOMETHING
UNUSUAL ABOUT THIS GIRL.
HER ARTHRITIS WAS REASONABLY
EASY TO CONTROL, BUT NOT HER
UVEITIS.
A FEW YEARS LATER HER SISTER WAS
BORN AND YEAR OF AGE SISTER
DEVELOPED WIDESPREAD
POLYARTHRITIS AND QUITE
SIGNIFICANT UVEITIS DIFFICULT TO
CONTROL.
AS A RESULT I DID WHAT I OFTEN
DO WHEN I HAVE PATIENTS, I HAD
GREAT DIFFICULTY MANAGING, I
CONTACT MY FRIENDS AT THE NIH.
THIS WAS BEFORE THE
AUTOINFLAMMATORY DISEASE PROGRAM
WAS UP AND RUNNING SO THEY BOTH
WENT TO THE OCULAR PROGRAM WHERE
DR.
NUSSBLAT WAS WORKING HE CAME
UP WITH TREATMENT RECOMMENDATION
BUS NOTHING REGARDING DIAGNOSIS,
A FEW YEARS LATER I HAVE ALL
THIS PAIN, I'M HAVING GENITAL
ULCERS, TURNED OUT BOTH GIRLS
HAD RECURRENT ULCERS SO WE
THOUGHT IT WAS A CASE OF
FAMILIAL BEHCET.
THERE WAS ODD THINGS ABOUT THE
UVEITIS.
THEY HAD ARTHRITIS STARTING YEAR
OF AGE, SO WE THEN SENT THEM TO
NIH AND NIH DID WHAT THEY DO.
AND THEY FOUND GENE MUTATIONS.
THEY FOUND A MUTATION IN A GENE
CALLED TMOR NECROSIS FACTOR
ALPHA INDUCED PROTEIN 3 OR TNF
AIP.
IF YOU ARE SCRATCHING YOUR
HEADS, THAT'S WHAT I DID AND
STILL DO.
I WANT TO GIVE YOU A FEW FACTS,
IT CODES FOR A PROTEIN CALLED A
120 WHICH IS INVOLVED IN DEYOU
BICTYIZATION.
DR.
CAST NEAR TOLD US THE
IMPORTANCE OF THESE PROTEINS
THIS MORNING.
I HAS TWO ROLES IN
UBIQUITINATION PROCESS.
THERE'S
A GENE, THESE WERE FIRST GROUP
OF PATIENT WHERE IS MOST
MUTATIONS WERE FOUND ON IT WILL
SIDE OF THE GENE, ONLY ONE ON
ZINC FINGER.
THERE IS NO YET IDENTIFIED
GENOTYPE PHENOTYPE CORRELATION.
SO IF YOU HAVE A COMPLETE KNOCK
OUT OR FULL ABSENCE OF DISEASE
IN A MOUSE THAT'S LETHAL, IT'S
THOUGHT THIS DISEASE IS
APPROXIMATE PLEA INSUFFICIENCY
SO ONE OF THE MUTATIONS LEADS TO
DISREGULATION, CAUSED BY THE
PROTEIN LEADING TO CHANGES IN
ABILITY TO CONTROL NF KAPPA B.
OF NOTE, POLYMORPHISMS HAS BEEN
FOUND IN LOTS OF AUTOIMMUNE
DISEASE INCLUDING RHEUMATOID
LUPUS, PSORIASIS, DIABETES AND
ALSO POLYMORPHISMS ASSOCIATED
WITH LYMPHOMA, SO IT MAY PLAY A
ROLE IN TUMOR REGULATION AS
WELL.
SO THE BASIC POINT FOR
ESPECIALLY CLINICIANS IS THAT
MUTATIONS IN TNFAIP DISEASE 120
IS ASSOCIATED WITH DIG
REGULATION OF NF KAPPA B AND
ONCE ACTIVATED IT DOESN'T TURN
OFF PROPERLY, MUTATION HAVE ROLE
IN ACTIVATING NLRP INFLAMMASOME,
WE KNOW ABOUT THAT IN CAPS
DISEASE.
SOME EVIDENCE OF THAT WAS
DOCUMENTED BY THE NIH GROUP LED
BY KING JU IN INITIAL
PUBLICATION WHERE GENE WAS FOUND
WITH HIGH LEVELS OF INFLAMMATORY
CYTOKINES, SOME WERE
SIGNIFICANTLY ELEVATED OTHERS
NOT SIGNIFICANT BUT THE GENERAL
TAKE AWAY MESSAGE IS THAT
THERE'S DISREGULATION OF NF
KAPPA B, IMMUNE ACTIVATION, AND
UPREGULATION OF MANY
INFLAMMATORY CYTOKINES, WHICH
MAKES IT DIFFERENT FROM SOME OF
THE OTHER MONOGENIC DISEASES
EASY TO TARGET WITH SPECIFIC
THERAPY, YOU WILL SEE NO
SPECIFIC THERAPY HAS RESULTED TO
-- KNOWN TO BE EFFECTIVE IN THIS
GROUP OF DISEASES.
THEY ARE NOT VERY MANY PATIENTS
REPORTED, I AM GOING TO GO
THROUGH THE LITERATURE WHICH IS
JUST A YEAR AND A HALF OR TWO
OLD ON THIS DISEASE AND TELL YOU
THE KEY FEATURES.
SO WHAT WE DID IS LOOK AT THE
FIRST 15 THEN FOUND ONE OTHER
PATIENT FROM THIS STUDY OF
DR.
JU WITH THE NIH AND WE
DEVELOPED A CLINICAL PROTOCOL TO
EVALUATE THESE PATIENTS.
THEY LOOK LIKE BEHCET SO THEY
ALL HAD ULCERATIONS AFTER MUCOUS
MEMBRANES, 56% HAD
MUSCULOSKELETAL SYMPTOMS
SIMILARLY WITH GASTROINTESTINAL
SYMPTOMS.
DIFFERENT FROM BUCKET'S IS HALF
HAD RECURRENT FEVER.
THAT PUTS YOU MORE INTO THE
CATEGORY OF THE AUTOI BELIEVE
FLAMTORY DISEASE.
HALF HAD VARIETY OF SKIN RASHES,
ONLY THREE HAD OCULAR
MANIFESTATION BUT THEY WERE
SEVERE, THE TWO OF OUR GIRLS,
ONE OTHER PATIENT, AND THERE
WERE ALSO CARDIOVASCULAR
MANIFESTATIONS IN A FEW OF THE
FIRST 16 PATIENTS.
IN TERMS OF ULCER DISEASE
FOLLOWING THE ERKAN'S TALK, ALL
PATIENTS HAD ORAL ULCERS AND 94%
HAD GENITAL ULCERS AND OF THE
NINE PATIENTS WITH
GASTROINTESTINAL COMPLAINTS
TWO-THIRDS AT GICS ULCERS
ANYWHERE ALONG THE GI TRACT ON
ENDOSCOPY.
THEY CAME AND WENT, THEY USUALLY
LASTED SEVEN TO TEN DAYS, THEY
WERE NOT ALWAYS, THOUGH
SOMETIMES ASSOCIATED WITH
CONSTITUTIONAL FEATURES, AND
SOMETIMES THE LESIONS HEALED
WITH SCARRING.
SO TO GO THROUGH THESE SPECIFIC
MANIFESTATIONS GASTROINTESTINAL
COULD BE ANYTHING FROM MILE PAIN
TO VALVE PERFORATION.
THIS WAS A SMALL SERIES OF 16
PATIENTS, THERE WERE RECURRENT
BLOODY DIARRHEA THAT SOUND LIKE
BEHCET'S, ARTHRITIS WAS THE
INITIAL PRESENTATION, THE
PATIENTS DEVELOPED POLYARTHRITIS
THOUGH MIGHT BE AL GO DISEASE.
SKIN MANIFESTATION SIMILAR TO
BEHCET, I MENTION IN THREE
PATIENTS IN TERMS OF
CARDIOVASCULAR OR PERICARDIAL
INFUSION IN TWO AND
HYPERCOAGULATION AND ONE PATIENT
HAD SEVERE VASCULITIS, THAT WAS
THE PRESENTING MANIFESTATION FOR
THAT PATIENT.
THE LABORATORY ABNORMALITIES ARE
NON-SPECIFIC.
U YOU SEE ELEVATION OF ACUTE
PHASE REACTANTS, DIFFERENT FROM
OUR CLASSICAL AUTOINFLAMMATORY
DISEASE THAT IS THAT THERE ARE
FLUCTUATING LEVELS OF
AUTOANTIBODY, ANTI-DOUBLE
STRANDED DNA AND COAGULANT, ONE
PATIENT ONE FAMILY WITH -- HAD
IGG SUBCLASS DEFICIENCY AND BOTH
HAD RECURRENT INFECTIONS, MAYBE
THERE WAS EARLIER DIGENIC
DISEASE IN THAT FAMILY.
IN TERMS OF TREATMENT, NO MAGIC
BULLET ALL PATIENTS RECEIVE
STEROIDS AND THEY WERE
ASSOCIATED WITH MULTIPLE
COMPLICATIONS ALL WELL AWARE OF
WITH LONG TERM HIGH DOSE
CORTICOSTEROID TREATMENT, FOUR
WITH JULY COLCHICINE, A NUMBER
IMPROVED OF A COOK BOOK BIOLOGIC
TREATMENTS NON-AND THALIDOMIDE
AND ONE PATIENT HEMATOPOIETIC
STEM CELL TRANSPLANT WAS DONE IN
PATIENT I DESCRIBED WITH CNS
VASCULITIS WHO LOOKS LIKE SHE
HAD LUPUS AT THE BEGINNING.
TERMS OF OUTCOME OF PATIENTS THE
FIRST 16 THEY HAD RECURRENT
EPISODES OF UNPROPOKE VEHICLED
INFLAMMATION OR CHRONIC ONGOING
DISEASE, ONE PATIENT WHO HAD
HORRIBLE TONSILLAR ULCERATIONS
IN THE CAROTID ARTERY AND DIED
FROM BLEEDING AND THERE WERE
MULTIPLE COMPLICATIONS FROM LONG
TERM STEROID TREATMENT.
WE BASICALLY WROTE THIS IS A
DISEASE WHICH LOOKS LIKE
MONOGENIC BEHCET'S THERE'S HIGH
DEGREE OF PENETRANTS, NO
GENOTYPE PHENOTYPE CORRELATION,
AND PATIENTS HAVE FEATURES OF
BOTH AUTOINFLAMMATION AND
AUTO-IMMUNITY AND WE THOUGHT IT
WAS A SPECTRUM.
SOME HAD MILD ORAL ULCERS AND
SOME PATIENTS HAD SEVERE DISEASE
WITH FATAL DEATH AND BLINDNESS.
WE SUMMARIZE THAT IN A PAPER
HERE.
YOU WILL HAVE THIS SLIDE SO I'M
NOT GOING TO GO THROUGH THIS FOR
SAKE OF TIME.
I THINK I MENTIONED THE
IMPORTANT POINTS REGARDING THE
COHORTS.
THAT WAS IN JANUARY OF 2018 THE
PAPER WAS PUBLISHED, A FEW OTHER
OBSERVATIONS OVER THE LAST TWO
YEARS, I WILL COVER THOSE.
THIS WAS INTERESTING BECAUSE OF
THE WAY FIRST PATIENT PRESENTED
AND WAS FOUND PRESENTED AT THE
AGE OF SEVEN.
WITH ABDOMINAL PRESENTATION, AT
AGE 11 DEVELOP RECURRENT FEVERS
LEUKOPENIA, LOOKED MORE AUTO
IMMUNE LUPUS PATIENT WITH
POSITIVE ANA AND ANTI-RO
ANTIBODIES AND DID WELL WITH
STEROIDS AN MMF.
THE SIBLING PRESENTED TWO AND A
HALF YEARS OF AGE WITH FUO AND
POLYARTHRITIS AND WAS THOUGHT TV
SYSTEMIC ONSET JICSA AND
DEVELOPED MANIFESTATIONS WHICH
LOOKED LINE CROHN'S DISEASE.
THE FATHER BY HISTORY HAD
RECURRENT AN THRALL GEEIA AND
FISTULA WHICH STARTED AGE 7,
THOUGHT PROBABLY TO HAVE CROHN'S
DISEASE BUT MUTATIONS IN THE
GENE COHORT WITH IL AND NIL
PATIENTS SUGGESTING THIS FAMILY
WAS ANOTHER 20 FAMILY, SO I
TALKED AUTOINFLAMMATORY AND
BEHCET FEATURES, THEY LOOK
PURELY AUTOIMMUNE LIKE THIS
PATIENT WHO STARTED WITH TYPE
ONE DIABETES.
CYTOPENIA, INTERSTITIAL LUNG
DISEASE AND THIS IS ANOTHER
PATIENT WITH -- WHO NEEDED STEM
CELL TRANSPLANT AND DID WELL
WITH REFRACTORY FOR SIGNIFICANT
TREATMENTS.
THIS IS AN INTERESTING FAMILY AS
WELL WHO WAS THOUGHT TO HAVE
JUVENILE ONSET FAMILIAL BEHCET'S
DISEASE, I WANT TO HIGHLIGHT THE
PRESENTING FEATURES MAY NOT BE
WHAT YOU INITIALLY DIAGNOSE AS
BEHCET, THIS PATIENT HAD FEVER
AND POLYARTHRITIS AND WAS
THOUGHT TO HAVE A POLYFORM OF
SYSTEMIC JIA AND ARE WELL ONS TO
LIZ HAS BEEN BUT DEVELOPED
ARTHRALGIA RECURRENT ULCERS,
CONJUNCTIVAL ULCERS COLONIC
ULCERS AND DIAGNOSED AS BEHCET
AND DID WELL ON AD LIMB HAS
BEEN.
THE MOTHER NINE MONTHS OF AGE BY
HISTORY HAD A STORY OF RECURRENT
GI SYMPTOMS WITH RECURRENT ORAL
ULCERS AND AGE 33, DO ADEENAL
AND GENITAL ULCERS SO A
LISTENING PERIOD OF TIME WELL AS
DIAGNOSED BEHCET AND THE
GRANDFATHER HAD EARLY ONSET
DISEASE AND DIED FROM INTESTINAL
BLEEDING THOUGHT TO BE BEHCET
AND WHEN THEY WENT AND LOOKED AT
THIS FAMILY, ANOTHER FAMILY WITH
MUTATIONS IN TNF AIP OR HOT 20
SO THIS IS A SERIES FROM JAPAN
PUBLISHED IN I THINK IN RECENTLY
IN 2019 WHERE THEY HAD A COHORT
OF BEHCET, 12 FAMILIES LOOKING
AT 25 PATIENTS FROM THE 12
FAMILIES.
LOOK AT WHOLE EXOME SEQUENCING
TO SEE IF THEY COULD IDENTIFY
ANYTHING AND THEY FOUND TWO, ONE
WITH MUTATION, ONE WITH DELETION
IN TNF AIP.
THE CHARACTERISTICS WERE BOTH
FAMILIES HAD VERY HE WILL ONSET
DISEASE, AND DISEASE WAS
EXTREMELY HARD TO TREAT.
THEY COMPARED THOSE PATIENTS TO
THE 54 CASES THAT THEY FOUND IN
THE LITERATURE WITH 20 RELATIVE
TO 520 CASES OF BEHCET THEY HAVE
IN THEIR COHORT.
SIMILAR TO WHAT WE SUMMARIZE IN
OUR PAPER KEY FEATURES WERE
EARLY ONSET OF DISEASE, FAMILIAL
NATURE OF THE DISEASE, PRESENCE
OF RECURRENT FEVER, MUCH HIGHER
INCIDENCE OF GI INVOLVEMENT, AND
MUCH LESS OCULAR INVOLVEMENT.
WHEN YOU ARE COMPARING THE
TUSHISH TO THE U.S. COHORT,
WHETHER A LOT OF PATIENTS MIGHT
HAVE 20 BECAUSE YOU WERE PART OF
THE SERIES WITH SEZA ONE, TWO
TURKISH FAMILIES IN THAT GROUP
SO PROBABLY A HIGHER CARRIAGE
RATE IN THAT POPULATION.
BE INTERESTING TO LOOK.
LAST PAPER TO COVER IS THIS
SYSTEMATIC REVIEW BY BERTO WHO
LOOKED AT 19 FAMILIES.
I THINK THERE WERE 54 PATIENTS
OR SOMETHING JUST TO SUMMARIZE.
IT HAS A WORLDWIDE DISTRIBUTION,
PENETRANTS OF DISEASE IS VERY
HIGH.
EARLY ONSET 70% LOOKED LIKE THEY
HAD BEHCET, ALMOST ALL HAD ORAL
ULCERS AND TWO-THIRDS HAD
GENITAL ULCERS.
THERE WERE A VARYING FREQUENCY
OF OTHER MANIFESTATIONS.
13% HAD ONLY EYE DISEASE.
SO YOU HAVE TO KEEP THIS IN
MIND.
VERY RARE DIAGNOSE THUS FAR BUT
IF WE LOOK WE ARE GOING TO FIND.
KEY DIFFERENTIAL DIAGNOSIS,
THINK OF THOSE DISEASES WHICH
GIVE EARLY ONSET ULCER ATIVE
DISEASE, BEHCET, HYPERIGD
SYNDROME, CYCLIC NEUTROPENIA ARE
THINGS TO THINK ABOUT.
BECAUSE THERE HAVE BEEN SOME
PATIENTS WITH TYPICAL
AUTO-IMMUNITY I WILL INCLUDE
MONOGENIC LUPUS IN THAT GROUP.
IF YOU HAVE FAMILIAL BEHCET,
HARD TO TREAT BEHCET ASSOCIATED
WITH RECURRENT FEVER SEVERE GI
INVOLVEMENT, YOUNG ONSET AND
MAYBE PATIENTS WITH ONSET
AUTOIMMUNE DISEASE YOU CONSIDER
THIS.
NOT MUCH TO TELL YOU ABOUT
MANAGEMENT, PATIENTS MILD SIDE
SEEM TO DO FINE WITH COLCHICINE.
OTHER WIDE END UP WITH
CORTICOSTEROID TOXICITY.
MANAGE THE IMPORTANT
MANIFESTATION, YOU DO IT AS
POLYJIA.
IF AUTOIMMUNE DISEASE YOU MANAGE
LUPUS PATIENT,s ASK LATE
BIOLOGICS FOR OTHER FEATURES.
JUST TO BRIEFLY TELL YOU ONE
PATIENT FROM THE INITIAL COHORT
WHO WAS ON PREDNISONE AND SFI
AND DOING SO, SO, WENT ON TO YOU
SEE HERE THE CRP RESULTS ON --
BEFORE TREATMENT, ON
200 MILLIGRAMS OF ANA KINRA
ESCALATE TO 400-MILLIGRAMS,
ACUTE FACE REACTANTS CAME DOWN,
HAD A BLIP, 500 SO PATIENT IS
STABLE WITH NORMALIZATION OF THE
ESR AND CRP ON THAT DOSE OF ANA
KINRA.
THAT'S A WHIRLWIND.
I AM WITHIN MY TIME.
I'M GOING TO STOP THERE AND SAY
THANK YOU TO OUR FELLOW AND PUT
THE INITIAL COHORT TOGETHER, THE
FANTASTIC AMAZING TEAM FROM THE
NIH WHO HELPED EACH AND EVERY
ONE OF US, AND OUR PATIENTS AND
TO THE INDEX FAMILY AND OTHERS
WHO PARTICIPATE IN CLINICAL
RESEARCH.
THANK YOU.