Behet146sDisease - PDF document

Behet’sDisease DisclosuresNo personal disclosures relevant to this talkSupport for the VF Symposium provided by CelgeneWill be discussing Apremilast Description of 3 patients in 1937Triad:AphthaeGenital ulcersHypopyon uveitisEarlier descriptionHippocrates Centu

ry BCTan SY et al. Singapore Med J 2016;57(7):408Springer JM, Hajjali R (2013). Behçet’sNetter’s Internal Medicine: Part III, section 5(3rd Edition ed., pp. plate 561). Worldwide Prevalence of Behcet’sCho SB et al. Yonsei Med J2012;53(1):3542. Diseas

e of the Silk Roads http://www.orexca.com/silk_road.html Chapel Hill Consensus Conference 2013Comparison to other forms of Vasculitis Demographics:Median age of onset in 3rddecade of lifeRare to start in childhood or � 50 years oldMales equally as effected a

s femalesMore severe course in young malesClinical courseCourse can have cycles of exacerbations and remissionsFor some, symptoms can disappear over timeStrongest Genetic AssociationHLAB51Quick facts: Limited information on etiopathogenesis Cho SB et al. Yonsei Med

J2012;53(1):3542. ManifestationsMucocutaneous (Skin, oral, genital)EyeMusculoskeletal (muscles/joints)Vascular/CardiacCentral Nervous SystemGastrointestinal Other, less common Springer JM, Hajjali R (2013). Behçet’sNetter’s Internal Medicine: Part III, se

ction 5(3rd Edition ed., pp. plate 561).Mucocutaneous: Oral soresMost commonly minor aphthous ulcers0mm85%Typically multiple at a timePainfulIndistinguishable from other causes Oral ulcers: Other causesImportant things to think about:Herpes simplex virusVitamin defi

ciencies (e.g. Zinc and Vitamin C)Iron, B12, folate deficienciesSystemic Lupus ErythematosusANCA associated vasculitisInflammatory bowel disease (i.e. Crohn’s and Ulcerative Colitis)Celiac diseaseHIVStress/diet induced YaziciY et al. Behcet’sSyndrome; Infl

ammatory Diseases of Blood Vessels. 2012, Blackwell Publishing. 289 Mucocutaneous: Genital ulcersMalesTypically on scrotumLess commonly on other sitesNot the urethraFemalesMajor or minor labiaMost commonly heal in about 24 weeksLarge ulcers may scar YaziciY et al. B

ehcet’sSyndrome; Inflammatory Diseases of Blood Vessels. 2012, Blackwell Publishing. 289Mucocutaneous: Skin80% of patientsAcnelike lesionsFace, upper chest, upper back, legs, Papulopustular lesionsErythema nodosum (left picture)Superficial Thrombophlebitis (rig

ht picture)Usually subsides in 26 weeksHyperpigmentation possibleUlceration possible https://www.mayoclinic.org/diseasesconditions/thrombophlebitis/symptomscauses/syc Mucocutaneous: Pathergy (Test)Springer JM, Hajjali R (2013). Behçet’sNetter’s Internal M

edicine: Part III, section 5(3rd Edition ed., pp. plate 561).YaziciY et al. Behcet’sSyndrome; Inflammatory Diseases of Blood Vessels. 2012, Blackwell Publishing. 289 Eye Involvement 50% of patientsMore frequent/severe in males and younger patientsUsually w/n 3

years of disease onsetVision threateningUveitis (inflammation within eyes)Retinal occlusive vasculitisConjunctivitis (rare)Concerning symptoms:Redness, pain, light sensitivity, blurred vision, dark floating spots in visionNetter’s Internal Medicine: Part III, s

ection 5(3rd Edition ed.). Musculoskeletal 50% of patientsGenerally effects only 1 or few joints at a timeNot deformingMost frequent joints include:KneesAnklesWristsElbowsEnthesitis(inflammation at the attachment of tendon to bone)Association with acne lesions Vascu

lar/Cardiac InvolvementVeins or arteriesVarious size blood vesselsMore common in males Venous (Vein) Involvement33% develop thrombophlebitis (clotinflammation of veins) of either superficial (near skin) or deep (larger veins)Deep vein thrombosis (DVT):Different from

regular DVTs:Lower risk of thromboembolism (traveling to other organs such as lungs)Adheres to vein wallRequires immunosuppressionBuddChiari SyndromeInvolvement of veins around liver (suprahepatic veins) Artery InvolvementLess than 5%Pulmonary artery aneurysm **Can

have hemoptysis coughing blood3cm or larger life threateningCT or MRI can confirmOther areas of aneurysm/occlusionAbdominal aortaCarotid arteriesFemoral arteriesPopliteal arteries(rarely) coronary arteries YaziciY et al. Behcet’sSyndrome; Inflammatory Diseases

of Blood Vessels. 2012, Blackwell Publishing. 289 Heart InvolvementValvular lesionsMyocarditis (upper picture)Endomyocardial fibrosis scarring on inner part of heartPericarditis (lower picture)Intracardiac thrombosis clot in heartCoronary vasculitisVentricular aneu

rysms http://www.secondscount.org/pediatriccenterhttps://medlineplus.gov Central Nervous System Involvement10% of individualsParenchymal brain involvement (80%)Brain itselfNonparenchymal brain involvement (20%)Vascular system of brainDural vein thrombosis Intracrani

al hypertensionPossible symptoms:Cognitive changes, behavioral changes, headaches, vision changes, loss of control of bowel/bladder, sensory loss https://www.osteopathwest.co.uk/whatcentralsensitization/ https://www.sciencedirect.com/topics/neuroscience/greatcerebra

lvein Gastrointestinal InvolvementMucosal ulcerationsCommon areas: Ileum, cecum, colonDifficult to distinguish from inflammatory bowel disease (i.e. Crohn’s and ulcerative colitis)Symptoms:Anorexia, vomiting, abdominal pain, diarrhea, blood or dark tarry stools

https://myhealth.alberta.ca/Health/pages/conditions.aspx?hwid=tp10133 Other featuresGlomerulonephritis (kidney) is uncommonAmyloidosisDeposition of abnormal proteins in tissueEpididymitisInflammation around testis in males Disease ClustersDeep vein thrombosis & Dur

al sinus thrombosisAcne & Arthritis & EnthesitisGI predominant diseaseCould there be more then 1 disease mechanism? Regional DifferenceGastrointestinal ManifestationsMore frequent in Far EastLess frequent in TurkeyPathergyMore frequent in Turkey, Mediterranean, Japa

nLess frequent in Northern Europe and USAB51 associationMost pronounced in Middle and Far East Treatment PrinciplesIn many patients, Behcet’sgoes into remission with timeIn nonsevere manifestations (e.g. mucocutaneous disease) treatment is conservativeConsider

topical therapies for oral and genital ulcersAggressive treatment of eye disease and organ threatening manifestationsCurrently only 1015% vision loss with eye involvement compared to around 75% 2030 years agoMales and younger patients are more likely to have more se

vere diseaseUnfortunately, there are limited studies Treatments: ColchicineIn trials, shown to be effective:Females: genital ulcers, erythema nodosum and arthritisMales: arthritis only Tablet generally taking 12 times dailyCaution in those with kidney or liver probl

emsPossible side effects:Diarrhea and other GI symptomsNeuropathyLow blood countsYurdakulS. et al. Arthritis Rheum2001;44:2686 Treatments: DapsoneIn trials, shown to be effective:Oral/genital ulcers, skin involvementOralConsider screening for glucosephosphate dehydr

ogenase (G6PD) deficiencyMonitor for anemia and liver function testsAvoid if Sulfa allergicPossible side effects:AnemiaLow white blood cell countSkin reactions (occasionally severe)LiverPeripheral neuropathy Treatments: AzathioprineIn trials, shown to be effective:E

ye disease (RCT), oral/genital ulcers, arthritis, DVT preventionWeight based dosing Use for at least 3 monthsCaution with liver issuesDose adjustment with kidney disfunctionTPMT testing (blood test)Risk of side effectsPossible side effects:GI symptoms (nausea)Infect

ionsLow blood countsLiverMalignancy (lymphoma)Progressive multifocal leukoencephalopathy (PML)RareSevereReactivation of brain virus (JC)YaziciH et al. NEJM1990;322:281 Treatments: TNF inhibitorsIn trials, shown to be effective:Oral ulcers, nodular skin lesions, papu

lopustularskin lesions (Etanercept)Subcutaneous or intravenousUsed frequently in other autoimmune diseasesEtanercept, Infliximab, AdalimumabTB and viral hepatitis panel generally recommended priorPossible side effects:InfectionsInjection/infusions reactionsReactivat

ion of tuberculosisLupuslike reactionsCaution:History of congestive heart failureHistory of multiple sclerosis Treatments: MethylprednisoloneIn trials, shown to be effective:Erythema NodosumSubcutaneousSteroid (similar to prednisone)Short term useLong term use assoc

iated with multiple possible side effectsPossible side effects:Mood changesInsomniaOsteoporosisInfectionsCataracts/glaucomaHypertensionDiabetesWeight gainEasy bruisingOther Treatments: CyclosporineIn trials, shown to be effective:Eye and mucocutaneous lesionsOralQui

ck actingCaution in kidney and liver dysfunctionPossible side effects:Gingival hyperplasiaInfectionsLiverIncrease potassiumHypertension*Increased uric acidMalignancy (skin)Kidney dysfunction*Neurotoxicity*Thrombotic microangiopathy*close monitoring required Treatmen

ts: ThalidomideIn trials, shown to be effective:Treatment resistant oral/genital ulcers, papulopustularskin lesionsRecurrence usual when withdrawnOralDue to side effects, short duration useHigh pregnancy riskPossible side effects:Bone marrow suppressionLow heart rat

eCNS effectsSkin reactions (e.g. Steven Johnson’s syndrome)Hypersensitivity reactionsOrthostatic hypotensionConstipationHepatotoxicityNeuropathyMalignancySeizureThrombosis Treatments: InterferonIn trials, shown to be effective:Reducing frequency of oral ulcers,

genital ulcers, papulopustularlesionsExpert opinion:Effective in ocular diseaseSubcutaneousFrequent side effectsNot well toleratedPossible side effects:Flulike symptomsFeversJoint painsInjection site reactionsLow white blood cellsHair lossDepression Treatments: Cyc

lophosphamideNo large trialsEffective in severe forms of vasculitisUsed in organ/life threatening diseaseOral or intravenousClose monitoring of blood countsShort term use recommendedPossible side effects:InfectionsBone marrow suppressionCardiotoxicityInfertilityHepa

totoxicityPulmonary toxicityImpaired wound healingHemorrhagic cystitisMalignancies (e.g. bladder cancer)Risk based on lifetime dose ApremilastCauli A et al. ImmunoTargets and Therapy2014;3:91 Apremilast: Phase II study Hatemiet al. NEJM2015;372:1510 Treatments: Apre

milastPhase III study ongoingBest evidence in oral lesionsOral Does not suppress immune system (i.e. does not increase risk of infection)Possible side effects:Gastrointestinal (e.g. nausea, diarrhea)Mood (e.g. depression)Weight loss Behcet’s: The FutureNeeds:Mo

re randomized treatment studiesClarification: One disease or multiple diseases? Wide regional and sex differencesBetter tests for diagnosisApremilastphase III preliminary results encouragingPossible FDA approval (? This month) SummaryHighest prevalence in Mediterran

ean and Far EastMucocutaneous symptoms are the most common manifestationsTopical therapies can be effective for oral and genital lesionsEye disease is one of the most serious manifestations, requiring treatmentDeep vein thrombosis requires immunosuppressive treatmen