Autoinflammatory Syndromes: An Overview

Transcription

1 Autoinflammatory Syndromes: An Overview Dr. Elizabeth Stringer Pediatric Rheumatologist Presented at the Canadian CAPS Network Forum Fredericton, New Brunswick Sept 15, 2013

2 ObjecMves To have a broad understanding of the autoinflammatory syndromes and treatments for these condimons To highlight a few research studies of treatment of cryopyrin- associated periodic syndrome (CAPS)

3 History of autoinflammatory diseases 1997: InternaMonal and French FMF ConsorMa discovered the gene responsible for Familial Mediterranean Fever (FMF) 1999: The gene for tumor necrosis factor associated periodic syndrome (TRAPS) discovered These were VERY important discoveries in clinical medicine 1. RealizaMon that many other rare inflammatory syndromes will turn out to be autoinflammatory diseases, caused by a genemc abnormality 2. Has led to targeted treatments for autoinflammatory condimons 3. Led to be[er understanding of the immune system and how it plays a role in other condimons with inflammamon Goldbach- Mansky, Monogenic autoinflammatory diseases: concept and clinical manifestamons, Clinical Immunology 2013

4 Rapidly expanding field Recent review discussed 6 groups of autoinflammatory diseases with 17 individual condimons The NaMonal InsMtutes of Health Clinical Center in the US conmnues to enroll paments in a research study* seeking to comprehensively evaluate individuals with known and suspected autoinflammatory diseases A number of children in our clinic at the IWK with suspected autoinflammatory condimons have parmcipated in this research study Goldbach- Mansky, Monogenic autoinflammatory diseases: concept and clinical manifestamons, Clinical Immunology 2013 * Studies of the Natural History and Pathogenesis and Outcome of Neonatal Onset Mul:system Inflammatory disease (and other Undifferen:ated autoinflammatory diseases) ClinicalTrials.gov

5 SelecMon of AI diseases The classical Periodic Fever Syndromes Familial Mediterranean Fever (FMF) Tumor necrosis factor receptor associated periodic syndrome (TRAPS) Hyper IgD syndrome (HIDS) Cryopyrin- associated periodic syndromes (CAPS) Familial Cold Autoinflammatory Syndrome (FCAS) Muckle- Wells syndrome (MWS) Neonatal onset mulmsystem inflammatory disease (NOMID) Pustular skin rashes and episodic fever Deficiency of interleukin- 1 receptor antagonist (DIRA)

6 What Mes these condimons together? Seemingly unprovoked episodes of inflammamon followed by symptom- free periods of variable duramon Recurrent bouts of fever InflammaMon in a variety of organ systems ElevaMon of inflammamon proteins in the bloodstream A gene abnormality has been discovered that helps to understand why the disease occurs The genes involved are directly related to the control of inflammamon in the body Some have risk of a complicamon called amyloidosis

7 InflammaMon A normal process: the body s a[empt to protect itself against harm such as physical damage, irritants, and germs, with the aim of healing through this process Viral infecmon Ankle sprain Poison Ivy Cardinal Signs of inflammamon: PAIN REDNESS HEAT SWELLING LOSS OF FUNCTION

8 Autoinflammatory Auto means self Some people think of these condimons as a[acking self There is no harmful smmulus causing the inflammamon

9 InflammaMon and the immune system The immune system is an extremely complex system of molecules and cells that works together in a coordinated response to the introducmon of foreign substances The immune system has 2 main systems 1. Innate immune system (generic response) 2. AdapMve immune system (specialized response)

10 Innate and adapmve immunity INNATE IMMUNE SYSTEM First line of defense should react to all foreign substances Consists of physical barrier (skin), chemicals against germs (acid in stomach), immune cells like macrophages and neutrophils, blood proteins (Il- 1, TNF) that regulate cells of the immune system Rapid response (within 6-12 hours from infecmon) Should not react to self CAPS and other autoinflammatory syndromes OVERLAP ADAPTIVE IMMUNE SYSTEM Second line of defense very specific, recognizes individual germs, remembers germs for the next Mme allowing for more vigorous response with the next encounter Consists of specialized immune cells called lymphocytes and blood proteins (anmbodies) Occurs days aier infecmon Should not react to self Lupus, rheumatoid arthrims

11 GeneMcs of autoinflammatory diseases Genes contain the blue- print for each person for her or his specific traits Genes are passed down from our parents such that we have one copy from our mother and one from our father For example, our eye colour is determined by which eye colour genes we get from our mother and father What eye colour we have depends on whether the genes passed down are dominant or recessive

12 Eye color The gene for brown eyes is dominant Capital B Brown eye trait always dominates over blue The gene for blue eyes is recessive Lower case b The only way to have blue eyes is to have the blue eye trait passed down by each parent

13 GeneMcs of autoinflammatory diseases Result from a modificamon of a single gene occurring in all cells of the body The single- gene diseases can be categorized as Recessive (example: familial Mediterranean fever) Dominant (example: cryopyrin- associated period syndromes) Sporadic (not inherited, new gene modificamon, example: NOMID)

14 Recessive inheritance Example: Familial Mediterranean Fever

15 Dominant inheritance Example: CAPS

16 A few examples of autoinflammatory syndromes

17 Familial Mediterranean Fever Most prevalent single- gene autoinflammatory disease > people are affected world- wide Need two copies of the abnormal gene (MEFV) Over 50 different kinds of abnormalimes have been found to date Most people develop their symptoms before their 30 s Treated with a medicamon called colchicine

18 Signs and symptoms of FMF Fever a[acks for 1-3 days ArthriMs a[acks Rash that can be mistaken for skin infecmon Abdominal a[acks that can be mistaken for appendicims

19 Tumour necrosis factor receptor associated periodic syndrome (TRAPS) Second most common autoinflammatory disease Need just one copy of the abnormal gene (TNFRSF1A) Over 100 different abnormalimes in the gene have been discovered to date Usually presents in childhood Treated with biologics both anm- TNF (etanercept) and anm- Il1 (anakinra, canakinumab)

20 Signs and symptoms of TRAPS Fever a[acks for 2 weeks + Abdominal a[acks ArthriMs Painful Rash and Muscles Eye swelling Neurologic symptoms

21 Cryopyrin associated periodic syndromes (CAPS) Comprises a clinical conmnuum of three previously defined condimons: Familial Cold Autoinflammatory Syndrome (FCAS) Muckle- Wells Syndrome (MWS) Neonatal onset mulmsystem inflammatory disease (NOMID) or Chronic infanmle, neurological, cutaneous and armcular syndrome (CINCA) Have neutrophilic urmcaria in common

22 Cryopyrin associated periodic syndromes (CAPS) FCAS and MWS are dominantly inherited Sporadic (new gene mutamon) in NOMID Over 130 mutamons have been found in the gene (NLRP3) causing CAPS

23 How does this abnormal gene lead to the signs/symptoms of CAPS? Fever IL- 1β Neutrophil A protein that causes inflammamon The body makes it early in response to infecmon and Mssue injury by cells of the innate immune system TNF- α Il- 6 Orchestrates more inflammamon through acmvamng the immune system

24 How does this abnormal gene lead to the signs/symptoms of CAPS? IL- 1β Tight regulamon of Il- 1β is required in the body The appropriate amount will help in the process to fight off an infecmon and repair Mssues Too much Il- 1β can have detrimental effects on the body

25 CAPS gene mutamon IL- 1β NLRP3 is an important regulator of Il1- β producmon In CAPS, NLRP3 is abnormal leading to over producmon of Il1- β Leading to the signs and symptoms of CAPS

26 What we smll don t understand. What triggers a[acks? How do these triggers operate? (e.g. cold?) Why are only certain Mssues and organs affected? Why are some gene abnormalimes associated with very severe disease?

27 Signs and symptoms of CAPS NOMID Symptoms might be present at birth Can be sick all the Mme with conmnuous low- grade fever, rash, severe joint disease, irritability, headache, seizures, strokes If untreated, permanent damage can occur Photo from Round 26: The Expanding Spectrum of Systemic Autoinflammatory Diseases: Misadventures in the genomics of inflammamon by Dr. D Kastner

28 Muckle- Wells Syndrome Usually presents in childhood UrMcarial rash (hives), low grade fever, joint pain and arthrims, eye inflammamon Hearing loss sets this condimon apart from FCAS as well as the risk of amyloidosis Photo from

29 Amyloidosis A disease that occurs when substances called amyloid proteins build up in your organs Can affect heart, kidneys, liver, spleen, nervous system and gastrointesmnal system In autoinflammatory diseases, a protein called Serum Amyloid A (SAA) goes up with inflammamon Some people with AI diseases can develop amyloidosis if their inflammamon isn t well- controlled

30 Familial Cold Autoinflammatory Recurrent Flares Syndrome (FCAS) Low- grade fever triggered by cold exposure Sore joints and urmcarial rash that start aier 1-2 hours aier cold exposure and lasts hours Other symptoms: eye inflammamon, sweamng, dizziness, headache, nausea and excessive thirst Amyloidosis as a complicamon is quite rare

31 Treatment IL- 1β The best treatment of CAPS is inhibimng or blocking Il- 1

32 Il- 1 inhibitors Canakinumab InjecMon every 8 weeks 100K per year *Approved in Canada for CAPS Anakinra Daily injecmon 41$/injecMon 15K per year *Approved in Canada for RA Rilonocept InjecMon weekly 6K per 220 mg vial *Not found in Drug Product Database References for cost esmmates: Canakinumab: approved- for- JIA- 272.php, Anakinra: cepmg.gc.ca, Rilonocept: Kapur S, Rilonocept, an Interleukin- 1 Trap for the Treatment of CAPS. Pharmacy and TherapeuMcs 2009 *Drug Product Database, sc.gc.ca

33 Provincial formularies PEI - doesn t appear that Anakinra or Canakinumab is covered NB not listed in regular formulary or for special authorizamon drugs NS Anakinra and Canakinumab ARE on the provincial formulary InformaMon as of September 2013

34 Highlights of research of anm- Il1 treatment for CAPS Spectrum of Clinical Features in MWS and Response to Anakinra Philip N. Hawkins et al. ArthriMs and RheumaMsm 2004

35 Highlights of research of anm- Il1 treatment for CAPS Anakinra for MWS members of a family with Muckle- Wells Syndrome were treated with Anakinra Each pament had fever, rashes, eye inflammamon, joint pain, deafness Bloodwork showed lots of inflammamon Treated for 3 months at 100 mg per day Within 4 hours of the dose of anakinra, all features of inflammamon resolved

36 Highlights of research of anm- Il1 treatment for CAPS Use of Anakinra in the Treatment of Familial Cold Autoinflammatory Syndrome with a 16- month Follow- up J Barrie Ross at al. Journal of Cutaneous Medicine and Surgery 2008

37 Highlights of research of anm- Il1 treatment for CAPS Anakinra for FCAS A local connecmon: study conducted in the MariMmes 8 individuals with FCAS All subjects had symptoms of FCAS during all seasons, at least 4 Mmes per week, interfering with ordinary daily acmvimes and normal life enjoyment Study Design 2 weeks No Treatment 4 weeks treatment 100 mg Anakinra daily 2 weeks No Treatment

38 Highlights of research of anm- Il1 treatment for CAPS Anakinra for FCAS 2 weeks No Treatment 4 weeks treatment 100 mg Anakinra daily 2 weeks No Treatment PaMents seen over these 3 periods PaMents given a cold exposure challenge in the morning and examined 2 hours later Symptoms recorded for up to 4 hours Completed daily diaries Inflammatory markers were checked including SAA

39 Highlights of research of anm- Il1 treatment for CAPS Anakinra for FCAS 2 weeks No Treatment 4 weeks treatment 100 mg Anakinra daily 2 weeks No Treatment All reported severe signs and symptoms of FCAS except for one who reported milder symptoms All signs and symptoms of FCAS resolved within 24 hours of the first dose of Anakinra. All remained symptom- free for the 4 week period of treatment All paments began to have symptoms within 36 hours of stopping treatment With cold exposure, all paments developed typical chills and characterismc discomfort within one hour of cold exposure. All had no symptoms during the treatment period. Blood inflammamon markers were elevated without treatment and normal during treatment

40 Highlights of research of anm- Il1 treatment for CAPS Anakinra for FCAS How effec4ve was this treatment? 100% of paments said it was completely effecmve Follow- up Ques4onnaire 5/8 conmnued to use Anakinra 3/8 would have liked to use Anakinra but couldn t access or finance the medicamon The frequency of use of Anakinra was variable

41 Highlights of research of anm- Il1 treatment for CAPS Two- year results from an open- label, mulmcentre, phase III study evaluamng the safety and efficacy of canakinumab in paments with CAPS across difference severity phenotypes. Keummerle- Deschner et al. Annals of RheumaMc Disease 2011

42 Highlights of research of anm- Il1 treatment for CAPS Canakinumab for CAPS 166 adult and pediatric CAPS paments 103 MWS, 30 FCAS, 32 NOMID Canakinumab 150 mg every 8 weeks, 2 years Some paments received higher doses if symptoms persisted Some paments had Canakinumab from other studies 109 had never had Canakinumab before this study

43 Highlights of research of anm- Il1 treatment for CAPS Canakinumab for CAPS RESULTS 78% had complete response, almost all within a week, the rest had some improvement 90% had no relapses All paments had normalizamon of inflammamon markers in their blood About 1/5 of paments required higher dosing, tended to be children and NOMID paments Reassuring safety profile However, more infecmons were reported in children

44 Canadian Pediatric Research Canadian Pediatric Society Surveillance Program, 2012 surveillance year 56 confirmed cases of Periodic Fever Syndromes PFS type Number of cases Average age Average number of fever aiacks/ year Undefined 28 6 years 12 PFAPA* 19 4 years 10 FMF *PFAPA syndrome = periodic fevers, aphthous stomamms (mouth sores), pharyngims (sore throat) adenims (swollen glands) Research led by Dr. Paul Dancey, Memorial University, Newfoundland

45 ObjecMves To have a broad understanding of the autoinflammatory syndromes and treatments for these condimons To highlight a few research studies of treatment of cryopyrin- associated periodic syndrome (CAPS)

46 Thank you