Presentation on theme: "Gina Lacuesta, MD FRCPC Allergy and Clinical Immunology"— Presentation transcript:
1C1 inhibitor Deficiency: Why does it happen and what does it look like? Gina Lacuesta, MD FRCPCAllergy and Clinical ImmunologyAssistant Professor, Dalhousie UniversityNov 29,2014
2Disclosure and Thank You CSL Behring -Berinert® Shire-Firazyr ® and Cinryze® -attended advisory boards, international meetings and worked with sales and medical representatives Board Member of CHAEN
3objectiveReview the definition and causes of angioedema – why are your doctors confused about this condition?Review the pathophysiology of C1 inhibitor deficiency – today you are a medical student!Review the clinical presentation of C1 inhibitor deficiency – does this sound like you?
4Angioedema ANGIO – vessel EDEMA – swelling Soft tissue swelling usually located around the eyes, lips, face, ears, tongue, hands, feetUsually asymmetricalIn C1 inhibitor deficiency, intestinal angioedema is common with abdominal pain and urinary difficultiesLaryngeal edema can be life threatening
5As opposed to….EDEMASwelling in dependant areas, ie feet, ankles, even sacral swelling, scrotal swelling, at end of day and around the eyes first thing in the morningRelated to fluid shifts/fluid retention/salt and water balanceStrongly associated with heart disease, liver disease, malnutrition, severe illness, ‘hormonal’ fluctuations
7Non HAE Angioedema – causes AllergyCause is easily identifiableFood, drug, stingCan be life threateningOften associated with hivesOften easy to figure out the allergic culpritWith avoidance, most patients can live ‘normal’ livesResponds to epinephrine, antihistamines and steroids
8Non HAE Angioedema - causes DRUGSAspirin/NSAIDs/anti-inflammatoriesACE- inhibitorsWell described phenomena; often forgotten aboutQuinke’s edemaUvula swelling only, repeatedlyOften as a rebound reaction to dryness in the throatOccasionally, surgery used to correct
9Non HAE Angioedema - causes InfectionMostly, viral relatedCommon, 1:10 will experience hives or angioedema, unexplained at least once in their lifetimeUsually short lived, ie lasting a few months maximum, most often benign
10Non HAE Angioedema - causes Chronic spontaneous/autoimmuneOften associated with hivesCan happen daily for months/yearsDiagnosis of exclusion, ie. No other cause foundBenign, most easily managed with well tolerated medications, ie antihistaminesNewer treatments: Xolair ®, rarely immunosuppressantsCommon condition
11Angioedema- why are your doctors confused Compared to the previous, C1 inhibitor deficiency is very rare, and rarely, if at all taught in medical school Doctors ARE aware of the other causes, and are AFRAID of the other causes EVERYONE wants the angioedema to be managed by steroids/antihistamines/epinephrine and AVOIDANCE of food!…but it doesn’t work that way
12Why is diagnosing C1 inhibitor deficiency an issue? Documented failure to recognize and diagnose HAE-22 year delay in survey by Frank et. al.(Ann Int Med. 1976;84:580)Delay still observed in recent surveyAge at diagnosis: 16.8 yrs (range 1-42 yrs)Age when sx began: 7.8 yrs (range 1-18 yrs)Delay in diagnosis: 9.1 yrs (range 0-32 yrs)Failure to diagnose dramatically increases the riskof significant M&M
14What is complement? Part of our INNATE immune system Present in everyone as a PRIMITIVE defense mechanism against infectionAs opposed to our ACQUIRED immune system which adapts based on our exposures, either via infection or vaccinationCOMPLEMENT helps our ACQUIRED immune system do its job, therefore, the term COMPLEMENT
16Importance of C1 inhibitor Controls bradykinin formationBradykinin causes blood vessels to dilate and become permeable, ie leak fluid into the soft tissues, thus, swellingIf bradykinin is allowed to produce repeatedly, if it does not get broken down and destroyed, and if its receptor is not blocked….there will be increased chances of swelling, inflammation and pain
21HAE nomenclatureHAE Type 1 – HAE due to C1 deficiency with low levels and functional assayHAE Type 2 – HAE due to C1 dysfunction with normal levels and low functional assayHAE Type 3 – HAE with normal C1 levels and functional assay
22HAE type 1 and 21:50,000Autosomal dominant; mutations of the SERPING1 gene25% de novo mutation rateBradykinin is the main mediator of swellingBradykinin produced when kallikrein cleaves HMW kininogen.Kallikrein activated by factor XIIKallikrein and factor XII both normally inhibited by C1 inhibitor.
23Features of HAE-Normal C1INH Compared to HAE-C1INH Deficiency – Bork 2007 Normal C1INH protein level and activityPredominantly women clinically affectedSymptom onset in adulthood more common, rarelyaffects childrenLess frequent symptoms with longer symptom-freeIntervalsFacial and lip swelling more frequentRecurrent tongue swelling a cardinal symptomMany patients have only skin swellingAbdominal attacks less frequentAsphyxiation due to airway involvement occursNo erythema marginatum; hemorrhages into skinswelling has been observed
26How patients presentAngioedema without urticaria, can have non-pruritic serpiginous rashAngioedema mostly face, limbs, gutCan have profound pain syndromes, vomiting, diarrhea, voiding difficultiesAttacks prolonged but do not occur daily; latency period“Average” untreated patient will swell q10-14 days, lasting 48-72hEnormous range of severity between patientsSubstantial morbidity seen in patient surveysRisk of death from laryngeal angioedema, mortality rate of 30% if left untreated
27Most attacks affect the skin or abdomen Angioedema most commonly involves the abdomen⁴, face, extremities, genitals, and larynx.¹Skin attacks are the most common and usually manifest as disfiguring, nonpitting, and sometimes painful skin swelling affecting most commonly the extremities, face, and genitals.²Abdominal attacks occur in 70%-80% of patients with recurrent abdominal pain caused by edema in the stomach or intestinal wall and free fluid in the peritoneal cavity.³Laryngeal attacks occur at least once in a patient’s lifetime in 50% of the cases. These attacks are usually classified as severe—as airway obstruction could be fatal—with mortality rates as high as 30% if left untreated or undiagnosed.2, 4The probability that a given attack will involve the skin or abdomen is nearly 50% each. All other attack locations, including genitourinary and laryngeal attacks, account for only 3.6% of attacks.⁴1. Khan D A, Allergy Asthma Proc 2011; 32:1-10; 2. Banerji A,Allergy Asthma Proc 2011; 32: ; 3. Caballero T, J Investig Allergol Clin Immunol 2011;21(5): 333 ; 4. Bork K. et al. Am J Med 2006; 119:267-74
28Frequency of HAE Attacks Attack frequency, severity, and course vary among patients, and even for a single patient depending on stage of life1,2,3Less than one attack per year to more than 26 attacks per yearMean of 27 attacks /yearMedian 12 attacks/ year per patientIn some rare cases, patients can experience more than 100 attacks per yearNo evident correlation between:Attack frequency and plasma levels of C1-INHNumber of attacks from one year and the nextFrequency of attacks in family membersAlthough precipitated by known factors, attacks may occur without obvious trigger1,3The frequency at which HAE attacks occur spans a broad range among patients and may also vary in the same patient during different stages of life. Reported rates range from <1 attack per year to >26 attacks per year. A recent study in 457 patients with HAE in the United States found that patients experienced an average of 27 attacks per year.In some cases, patients can experience >100 attacks per year. A survey of untreated patients with HAE in Italy found that nearly one-third had >1 attack per month, 40% had 6 to 11 attacks per year, and the remaining 30% had either no or infrequent attacks.[Agostoni 2004, p S57b; Levy 2006, p 6a]1 Gompels MM, et al. Clin Exper Immunol ;139(3): Kaplan AP. J Allergy Clin Immunol. 2010;126(5): Frank MM Ann Intern Med. 1976;84:580ñ593
29C1 inhibitor deficiency- acquired form AAE-symptoms the same no family historylater onset, usually after age 60often associated with hematological malignancies, ie lymphoma, monoclonal gammopathy, or autoimmune diseasesOften with low C1q levelsMechanism felt to be autoimmune, increased metabolism of C1 inhibitor, unknownMainstay is to treat the underlying condition, but also to be aware of usual C1 inhibitor treatment, can become resistant to treatment, requiring increasing doses of C1 inh replacementRarer than HAE
30Health-Related QOL Decreases in Patients With HAE Normative PopulationP<.0001P<.0001Patients With HAE49.6± 9.949.4± 9.86043.7± 10.242.6± 10.15040Mean SF-12 Score302010Physical Component SummaryMental Component SummaryIn a survey of 457 patients with HAE, patients reported significant reduction in health-related quality of life.One component of the survey, the 12-Item Short Form (SF-12) Health Survey, consisted of 12 questions about health-related functioning over the prior 4 weeks.Survey outcomes included two summary scores: a Mental Component Summary (MCS-12) and a Physical Component Summary (PCS-12). For each, a higher score represents higher functioning.Compared with population norms, patients with HAE had lower mean scores across all components of the SF-12 Health Survey.Patients with HAE had a mean overall PCS-12 score of 43.7 (SD ± 10.2, P<.0001) vs 49.6 (SD ± 9.9, P<.0001) for population norms.Up to 70% of patients with HAE reported that the disease had affected their educational and career goals, possibly due to elevated levels of anxiety and depression.Patients with HAE suffer activity impairment comparable with impairments suffered by patients with severe asthma and Crohn’s disease.ReferenceLumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Wilson DA, Horn PT. The humanistic burden of hereditary angioedema: impact of health-related quality of life, productivity, and depression. Allergy Asthma Proc.2010;31(5):Patients with HAE are also significantly more likely to experience symptoms of depression compared with population norms (P<.0001)Up to 70% of patients report that HAE has affected their educational and career goals and that they may be unable to realize their potential due to high levels of anxiety and depressionPatients with HAE experience a decline in productivity comparable with patients with severe asthma or Crohn’s diseaseQOL=quality of life; SF-12=Short Form Health Survey.Adapted from Lumry WR, et al. Allergy Asthma Proc. 2010;31(5):Shire Proprietary & Confidential Information
31Days Missed During Most Recent HAE Attackb HAE Attacks Adversely Impact Work, School, and Leisure ActivitiesPatients AffectedaDays Missed During Most Recent HAE AttackbWork Days (n=156)School Days (n=12)Leisure Days (n=271)Work Days (n=308)School Days (n=27)Leisure Days (n=457)3.3±14.41.9±0.82.7±3.051445910203040506070Patients Missing Days (%)246Mean Number of Days MissedIn a survey of 457 patients with HAE, patients reported that HAE significantly impacted their ability to work and gain an education.51% of employed patients missed at least 1 day of work due to their most recent HAE attack.44% of student patients missed at least 1 day of school due to their most recent HAE attack.59% of patient respondents reported that they missed at least 1 day of leisure activities due to their most recent HAE attack.Across all patients, the most recent HAE attack caused a mean number of 3.3 (SD ± 14.4) days of missed work, 1.9 (SD ± 0.8) days of missed school, and 2.7 (SD ± 3.0) missed leisure days.ReferenceLumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Wilson DA, Horn PT. The humanistic burden of hereditary angioedema: impact of health-related quality of life, productivity, and depression. Allergy Asthma Proc. 2010;31(5):aNumber of patients affected during most recent attack of HAE. bMean number of days missed during most recent attack of HAE.Lumry WR, et al. Allergy Asthma Proc. 2010;31(5):Shire Proprietary & Confidential Information
33Management of C1 inhibitor deficiency Gina Lacuesta, MD FRCPCAllergy and Clinical ImmunologyAssistant Professor, Faculty of MedicineDalhousie UniversityNov 29, 2014
34Objectives What are the goals of care? What did treatment look like BEFORE and what was the problem?What does treatment look like now?What can we do better?
35Previous goals of care Make the right diagnosis! Recognize that the condition is hereditary and screen the familyKeep the patients ALIVEKeep the patients out of the ER
36New goals of care Improving quality of life Treatment should aim to maximize patient health byAborting acute attacks to prevent morbidity and mortalityMinimize significant side effectsAvoid disruption of normal life, ie school, work, family life
40In Canada: June 2010 : Berinert® fully approved for use in HAE 2012: Cinryze® approved in Canada, still waiting for its full release2014: Firazry® approved in Canada
41In Maritimes: 2011First patient on prophylactic Berinert, early Spring 20114 patients being arrangedIn Hospital treatment only…thus far
42In Maritimes: 2013NS: 5 patients on prophylaxis( 4 self infusion/1 in hospital )NB: 1 patient on prophylaxis( line in place, home)PEI: 1 patient on prophylaxis (line in place, in hosp)NS: 1 patient on demand(self), 1 due to be taughtNB: 1 patient on demand (self)
43In Maritimes: 2013Still some patients on oral medications for on demand and prophylaxis and this works well for them5 acquired C1 inhibitor deficiency patients, 1 of which is on prophylaxis.
44In Maritimes: 2014 NS: 8 patients on Prophylaxis with Berinert NB: 1 patient on Prophylaxis with BerinertPEI: 1 patient on prophylaxis with Berinert10 others On Demand Berinert treatment, or prophylaxis with medications6 with Firazyr On Demand, a few others in the works for approval
47C1 inhibitor –eliminates the underlying cause by replacing the deficient protein Berinert®-CSL BehringCinryze®- Shire20U/kg, slow IV push<50kg 1000U, >50kg 1500UIndicated for acute attacksHalf life 32-47hWell toleratedOff label use with high doses in neonates resulted in thrombotic events1000U, slow IV push, not based on weightIndicated for long term, routine preventionHalf life 48+/- 10hWell tolerated
48IMPACT2- International Multicenter Prospective Angioedema C1 inhib Craig, T. et al, Allergy, 2011 57 patients, 975 HAE attacksOpen label extension of placebo controlled IMPACT1 trialMedian time to onset of symptom relief of 15min for laryngeal attacks, 20 min for abdominal attacks, 28 min for facial attacks and 31 minutes for peripheral attacks
49Nanofiltered C1 inhibitor in HAE- Zuraw, et al, Am J Med, 2012 Open label multi center extension study, 146 patients with HAE treated for 2.6y with prophylaxis Cinryze® 1000U every 3-7 days93.7% reduction in attacks compared with historical rate of attacks87.7% had 1 attack or less per month34.9% had no attacksTwice weekly seemed to have the best control, though sub group responded to once a week, no predictors found
50C1 inhibitor self infusion-Maritimes Currently, all teaching has been done by hemophilia nursing, with follow up and support as neededBerinert® does come with option to be taught by private nursing??Cinryze® to have a comprehensive training program established, based on education and training practices already used in the US, My PathTM, with ongoing support
52Characteristics of Icatibant Synthetic decapeptide with structure similar to bradykininIndicated for the treatment of acute attacks of HAE in adults with C1-esterase inhibitor deficiencyDelivered by subcutaneous (SC) injection in the abdomenProvided in a single-use, pre-filled syringe containing 30 mg (10 mg/mL) that can be stored at room temperatureH2NOSC3nShire Human Genetic Therapies (Canada) Inc. Firazyr Product Monograph. June 4, 2014.Shire Proprietary & Confidential Information
53Endpoints Measure Onset and Resolution of Symptoms Symptom severity of a treated attackTimet=0Time course of a treated attackBeginning of attackAlmost complete symptom relief(All VAS < 10mm)Treatment administrationInitial symptom improvementearliest of 3 consecutive measuresOnset of symptom relief(VAS )Shire Proprietary & Confidential Information53
54FAST 2: Time to Onset of Primary Symptom Relief Primary endpoint 100%Median95% CIp-valueIcatibant2.0<0.001Tranexamic Acid12.090%80%70%60%Tranexamic Acid% of PatientsNot Achieving Symptom Relief50%40%30%20%In FAST-2, Icatibant was effective in the treatment of acute HAE with primary endpoint showing consistent onset of primary symptom relief in 2 hours compared to median time to onset of 10.1 hours with tranexamic acid, which was statistically significant.To show you consistency of response, let‘s look as some other measures...10%Icatibant0%12243648Hours After TreatmentPrimary symptom relief is defined as a reduction of at least 30% from pre-treatment in the score for primary VAS; has to sustain for 3 consecutive non-missing measurementsCicardi M, et al. N Engl J Med. 2010;363: Erratum in: N Engl J Med. 2010;363:1468.ITT non-laryngeal populationVASShire Proprietary & Confidential Information
55FAST-3: Study Design and Patient Disposition First eligible attack(n=98)Laryngeal attack(n=10)Abdominal and/or cutaneous attack(n=88)Moderate to severe attackMild to moderate attackSevere attackDouble-blind treatment:Icatibant vs placebo(n=43) (n=45)Double-blind treatment:Icatibant vs placebo(n=3) (n=2)Open-label treatment:icatibant(n=5)Treatment of subsequent attacks (cutaneous, abdominal, or laryngeal)Open-label extension phase Icatibant 30 mg SC up to 3 x per attack; no more than 8 injections per month(n=82 pts)Lumry W et al. Ann Allergy Asthma Immunol. 2011; 107:Shire Proprietary & Confidential Information55
56FAST-3: Time to Onset of Symptom Relief Primary endpoint 100%Median95% CIp-valueIcatibant2.01.5, 3.0<0.001Placebo19.86.1, 26.390%80%70%60%Placebo (n=45)% of PatientsNot Achieving Symptom Relief50%40%30%20%Icatibant (n=43)We have used Kaplan Meier Curves to show the progress of patients as they respond to treatment over time.This also allows you to see the response of every patient in the trial.The y- axis shows the percentage of patients who have not yet met the target endpoint.So as we move from the left to right, we are showing you each patient as they respond to therapy and hit the target endpoint.This Kaplan- Meier curve from the FAST 3 trial shows the primary endpoint of time to onset of symptom relief based on the composite VAS score, the VAS-3,It shows the rapid drop in the graph for the icatibant treated patients as each patient reaches the endpoint.Icatibant was significantly better than placebo in treatment of HAE attacks.In the analyses of these cutaneous and abdominal attacks, Icatibant patients had onset of symptom relief based on the composite VAS-3 in median 2 hrscompared to placebo patients where relief was not seen for median of 19.8 hr.Next, if you look at the Kaplan Meier curve for time to onset of symptom relief based on the primary single VAS……10%0%12243648Hours After TreatmentITT populationVAS 3(abdominal pain, skin pain, and skin swelling)Onset of symptom relief is defined as a 50% reduction from pre-treatment in VAS 3 score; has to sustain for 3 consecutive non-missing measuresLumry W et al. Ann Allergy Asthma Immunol. 2011; 107:Shire Human Genetic Therapies (Canada) Inc. Firazyr Product Monograph. June 4, 2014.Shire Proprietary & Confidential Information
57FAST-3: Time to Almost Complete Symptom Relief Secondary endpoint 100%Median95% CIp-valueIcatibant8.05.0, 42.50.012Placebo36.029.0, 50.990%80%Placebo70%60%% of PatientsNot Achieving Symptom Relief50%40%Icatibant30%20%Icatibant accelerated resolution of attacks as measured by almost complete symptom relief at a median of 8 hr compared to placebo (median 36.0 h) as shown on this Kaplan-Meier that has now been extended to 120 hours on the x-axis.This faster time to near resolution of attacks reduced the amount of time that patients experienced the debilitating symptoms of HAE.Now that we have looked at the most recently completed and definitive trial,10%0%102030405060708090100110120Hours After TreatmentITT populationVAS 3(abdominal pain, skin pain, and skin swelling)Almost complete symptom relief is defined as all VAS scores ≤ 10 mm; has to sustain for 3 consecutive non-missing measurementsLumry W et al. Ann Allergy Asthma Immunol. 2011; 107:Shire Human Genetic Therapies (Canada) Inc. Firazyr Product Monograph. June 4, 2014.Shire Proprietary & Confidential Information
58Events including open label extension trial FAST-3: Icatibant Laryngeal Attack Efficacy Comparable to Abdominal or CutaneousLaryngeal TreatedEvents including open label extension trialIcatibant(N=27attacks)Median time to onset of symptom relief as measured by VAS-5; hours (95% CI)2.2(1.5, 3.5)Median time to onset of primary symptom relief; hours (95% CI)Median time to almost complete symptom relief; hours (95% CI)6.2(3.0, 24.3)Shire Proprietary & Confidential Information
59Laryngeal Attacks: Time to Initial Symptom Improvement % of PatientsNot Achieving Symptom ReliefFirst laryngeal attackISE Table 11.5Shire Proprietary & Confidential Information
60FAST OLE: Analysis of HAE Attacks Requiring Reinjection of Icatibant More than 90% of HAE attacks were treated with a single icatibant injection regardless of location.Icatibant reinjection was infrequent and appeared to be independent of patient age, patient sex, HAE type, and initial attack severity.0.5%0.9%90.4%8%91.8%7.3%1.1%All attacksLaryngeal AttacksAnalysis of pooled data from all FAST OLE studies.Total # pts in FAST OLE: 225. Total # of attacks treated: 1149Total # pts with laryngeal attacks in FAST OLE: 52. Total # of attacks treated: 1101 injection2 injections3 injections injection + other acute HAE treatmentBernstein JA, et al. Poster presented at: American College of Allergy, Asthma and Immunology (ACAAI) 2013 Annual Scientific Meeting; November 7-11, 2013; Baltimore, MD. Poster P90. Berstein et al. Poster presented at AAAAI 2014
61Safety ProfileShire Human Genetic Therapies (Canada) Inc. Firazyr (icatibant) Product Monograph. June 4, 2014.
62Safety ProfileThe overall incidence of serious adverse events (SAEs) was low in the clinical development programIn the Phase I and II studies, only 2 SAEs were reported within 14 days of FIRAZYR treatment (manic episode, HAE); these were judged as not related/probably not related to treatment.In the controlled part of the three Phase III studies, only one SAE (cystitis) was reported within 14 days of dosing with FIRAZYR. This event was judged as not related to treatment.In the repeated treatment part of the Phase III studies, safety was evaluated for up to 15 FIRAZYR-treated attacks for patients. Sixteen patients experienced a total of 22 SAEs that occurred within 14 days of FIRAZYR administration. The only SAE that occurred in more than one patient was worsening or recurrence of HAE. Two SAEs were considered by the investigator as related to FIRAZYR treatment (events of arrhythmia and noncardiac chest pain).Shire Human Genetic Therapies (Canada) Inc. Firazyr (icatibant) Product Monograph. June 4, 2014.
63Injection Site Reactions are Common but Transient and Self-resolving Photos courtesy of Dr M Bas, Klinikum Rechts der Isar der TechnischenUniversität München, Munich, GermanyRepresents moderate severity reaction63Shire Proprietary & Confidential Information
64Icatibant Safety Profile in Open-Label Use AEs in open-label extension of phase III controlled trials (N=225) were similar in frequency and nature to those observed in the controlled / blinded phase of the trialsRash, nausea, headache, worsening or recurrence of HAESelf-administered icatibant (N=98) displayed a safety profile similar to that of HCP-administered icatibantNo hypersensitivity or anaphylactic reactions were reported in clinical trialsNo association between anti-icatibant antibodies and efficacy was observedShire Human Genetic Therapies (Canada) Inc. Firazyr Product Monograph. June 4, 2014.64CONFIDENTIAL64
66Kallikrein inhibitorInhibits cleavage of HMW kininogen to bradykinin and therefore prevents progression of angioedema attackEcallantide- Kalbitor®- Dyax.30mg sc injection, half life 1-2hoursHas had reported anaphylaxis
67Attenuated Androgens Danazol, stanazolol, oxandrolone Contraindicated in pregnancy, lactation, cancer, hepatitis, childhoodSignificant side effects of virilization, weight gain, acne, hair growth, altered libido, voice deepening, decreased breast size, menstrual irregularities, HTN, atherosclerosis, increased liver enzymes, cholestasis, HCCDose varies from 100mg EOD, to 200mg TID, adjusting to clinical responseMore effective than antifibrinolytic agents
68Antifibrinolytic agents Used in more in pediatric population, as a safer alternative to androgens, but evidence of efficacy lackingSide effects mostly GI, theoretical risk of increased thrombosisDosing 30-50mg/kg in divided doses 2-3 times /day to max of 6g
75Short term/preprocedural prophylaxis Evidence is lacking, but generally considered to be a strong recommendationDental/intraoral surgery, any procedure requiring intubation, with upper airway or pharynx manipulation, bronchoscopy or endoscopyHistory of frequent swellings, swelling after a similar procedure in the pastStressful periods, concurrent infectionsC1 inhibitor U/kg 1-6 hours before procedure, with on demand treatment available alsoOther options: Androgens or tranexamic acid
77Long term prophylaxisUse of regular medication to prevent episodes of angioedemaTakes into consideration severity of disease, frequency of attacks, patients' quality of life, availability of resources, failure to achieve adequate control with on demand therapyIf more than 1 severe attack occurs per month, or treatment for severe attack is not sufficiently effectiveChoice between C1 inhibitor replacement, androgens, antifibrinolytic agents
83Management Counseling about their disease, genetics Refer to patient support HAE groupsCarry letters identifying them as a C1 inhibitor deficiency patient, urgency and how to treatBaseline viral studies and liver function studies; Hepatitis A and B vaccine, influenza vaccine
86ManagementDepending on long term drug treatment- labs and radiology to monitor side effectsEducation regarding MEDS to avoid ( ACE inhibitors for blood pressure, estrogen supplements/birth control), potentially exacerbating situations(fatigue, stress, dental work, surgery, infection, etoh, menses etc)
87Management C1 inhibitor to be stocked at home hospital Patients educated to be vigilant about keeping relations with blood bank, especially in remote areas
88Long term care for HAE patients procedurestimingDevelop action planProvide with HAE emergency cardProvide with 2 doses of on demand therapyScreen familyHep B, C HIV screeningAssessment by HAE specialistInfluenza vaccineIf androgens used:LFT,CBC,Lipids, UACardiac RFU/S liverAt diagnosis and annuallyAt diagnosisAt diagnosis, annually if using blood productAnnuallyStart and q 6 monthsStart and q6 monthsStart and q 12 monthsCraig, et al, WAO Journal, Dec 2012
91Pediatric populationAttacks usually occur during school age years, in 50% of cases between age 5-11Upper airway is rarely the initial presentationErythema marginatum is more frequent and often mistaken for urticariaPre-natal testing is not recommendedTesting at birth is not recommended, due to false negative testing
92Pediatric populationIf symptomatic, still need a treatment plan and on demand therapyEcallantide and icatibant are not licensed for use in childrenC1 inhibitor best choice for on demand therapyAntifibrinolytics(20-40mg/kg) chosen over androgens because of side effect profile.Common triggers include infection and mechanical traumaVaccination recommended to reduce infectionAvoid use of oral estrogen contraceptionEducate all caregivers
93PregnancyCan either mitigate, worsen or not change the frequency of attacks at allC1 inhibitor replacement is the recommended first line therapy.Short term prophylaxis is recommended during any procedures including amniocentesis, chorionic villus sampling, surgical abortion.Not necessary with uncomplicated natural delivery, but should be available for 72hours port partum
94Pregnancy C1 inhib should be given prophylactically if: HAE is known to be severeFrequent swellings in 3rd trimesterHistory of vaginal edema with mechanical traumaIf intubation necessaryWith forceps or vacuum extraction neededC- sectionAndrogens not recommended in pregnancy due to effects on the fetus, also not recommended during breastfeedingTranexamic acid can be used if C1 inhibitor not available
95AAE managementEssentially the same principles, except treatment for underlying condition plays an important roleMay have some benefit from antihistamines, steroids as can also have an autoimmune histamine mediated angioedema along with AAECan use either Icatibant or C1 inhibitor -On Demand, though not formally studiedIf prophylaxis required, can become “resistant” to C1 inhibitor replacement of may need higher than usual dosing
96After these presentations, you should be able to: Define and classify HAEKnow what tests are ordered to diagnose HAE/AAE. Know what other conditions your drs are thinking about and how to differentiate from themDiscuss management strategies, ie on-demand, short term and long term prophylaxisHow the appropriate medications and replacement are prescribedWhat information is important to patients and primary physicians about follow up, meds to avoid, when to be vigilantDiscuss special circumstances, ie pediatric population, pregnancyAcquired angioedemaRecognize and refer to international and national guidelinesBe an EXPERT in HAE
97What else can we do? 2011: Train and recruit more immunologists Educate local physicians/ER/nursesMaintain good working relationships with blood banksSet up self treatment programIf not a candidate for self treatment program, have a plan for treatment of acute swelling attacks….stay on top of C1 stock in local hospitals2013:Consider participating in upcoming trialsNow there is CHOICE in effective, safe treatments…how do we make those choices?Be responsible with the products that we use
98What else can we do? EDUCATE, EDUCATE, EDUCATE Lobby for coverage and access for all patientsComprehensive care clinicsLook forward to more sc products, ? Oral products
99questionsHow soon into an HAE attack do I take the first Firazyr injection?If I take the first injection early enough, should it stop the attack from worsening?In order to judge if Firazyr is going to be an effective treatment in decreasing an attack, would I have to use it during a couple of HAE attacks to assess the results? I used it once and I was still not well for 2-3 days afterwards.
100questionsIf the Firazyr did not decrease my swelling after the first dose, how long should I wait before I go to the hospital?Can I take Berinert between the first dose of Firazry and the second dose of Firazyr when the first dose did not stop or decrease my swelling?If I have to try the second dose of Firazyr before taking berinert, how long do I have to wait after I take the second Firazyr to take Berinert?
101questionsDoes Firazyr have the same drug components/ingredients in it as Berinert?I keep Firazyr in the fridge at a temperature above 2 degrees. What temperature should it be at when I administer it? For example, should I let it sit out of the fridge for a little while before I use it?
102questionsWhat is the experience of patients who have taken Firazyr ? for example how long did it for them to feel the swelling decreasing? How long did it take for the swelling to be gone completely? Have they had any side effects from it? If so what were they?For patients who took long term Danazol and is now off it, are there any tests as follow up that they should have done ?
103Canadian websites HAE Canada's Physician Website: www.chaen-rcah.ca