Hot Hot Hot

Autoinflammatory Diseases

Lori B. Tucker, MD

Clinical Professor in Pediatrics

Division of Rheumatology

BC Children’s Hospital

BC Children’s Hospital Research Institute

Vancouver, BC Canada

Objectives

• Explore the challenges in diagnosis of auto inflammatory diseases.

• Present an approach to the diagnosis of auto-inflammatory disease.

CM: 13 yr old girl

• Fever episodes since age 4 yrs.

– 3-5 days every 5-6 wks……every 3 weeks

– Abdominal pain and vomiting.

– Red papular rash.

– Fatigue, myalgia.

– Occ sore throat, headache.

• Mild developmental delay and learning issues.

• FH- fraternal twin normal, no fever episodes

• Scottish/Irish/English

• PE: microcephaly; 15%tile height and weight

– Otherwise normal.

CM: Treatment

• Had a tonsillectomy at some point.

• Trial colchicine….no response.

• Gene testing done: HyperIgD syndrome/Mevalonate

Kinase Deficiency– P.VAL377Ile (most common pathogenic variant)

– P.TRP188Ter

• Time to diagnosis: 9 years!

• Treatment: Anakinra (anti IL 1)

– No further fever episodes

– Patient reports she is GREAT and has better concentration

– Persistent behavior and learning issues

What did I learn from this patient?

• Lack of general awareness of periodic fever disorders in

the community.

– Diagnosis delay……..possible worse neurodevelopmental

outcomes in this patient.

• Spectrum of HIDS/MVK is broad.

• Treatment trial is worth undertaking.

LK: 5 yr old girl

• Fever episodes since age 1 ½ yrs old

– Every 4-6 weeks

– Lasts 4-5 days

– Accompanied by abdominal pain and vomiting

• PMH, FH all negative.

• Japanese Canadian background

• Lab testing:

– CRP 62

• Gene testing:

– Negative for FMF, TRAPS, MVK

• Treatment trial:

– Colchicine…..episodes resolved, CRP negative

– What is this disease?

Autoinflammatory Diseases are Challenging

• Debilitating for patient.

• Stressful and difficult for the family.

• Limited availability of diagnostic genetic testing.

• Monogenic diseases are RARE.

• Significant # of patients with ‘undifferentiated’

AID.

– No gene mutation

– Variants of uncertain significance….VOUS

• Treatment may require trial and error

❑ Group of rare disorders characterized by recurrent seemingly unprovoked inflammatory attacks.

❑ Includes monogenic disorders and more complex multifactorial disorders.

❑ Many begin early in childhood…….but not all!

❑ Frequent clinical features:❑ Fever ❑ Rash❑ Organ system involvement: abdominal pain, joint pain, headache

common.

❑ Outcomes are variable: remission, relapsing, or severe disability/disease with renal failure, developmental disability or death.

What are Auto inflammatory Diseases

Autoimmune-Autoinflammatory Disease Axis

Park et al 2012 Nat Rev Immunol 12:570

Familial HLH

Atypical HUS

1997-Causative gene mutations reported for FMF and TRAPS

MEFV and FMF

APLAID (Autoinflammation and PLCG2-associated Antibody deficiency and Immune Dysregulation) Behçet disease Blau

syndrome/Early-onset sarcoidosis CANDLE (Chronic Atypical Neutrophilic Dermatosis with

Lipodystrophy and Elevated temperature) or JMP/NSS (Joint contractures, Muscle atrophy, microcytic

anemia and Panniculitis-induced lipodystrophy) CAPS (Cryopyrin-Associated Periodic fever Syndromes) CINCA (Chronic

Infantile Neurological, Cutaneous and Articular Syndrome) CRMO (Chronic recurrent multifocal osteomyelitis)

DIRA (Deficiency of the interleukin-1 Receptor Antagonist) DITRA (Deficiency of the interleukin-36 Receptor Antagonist)

Erdheim-Chester disease FCAS (Familial Cold-induced Autoinflammatory Syndrome) FMF (Familial Mediterranean

Fever) HIDS (Hyperimmunoglobulin D Syndrome) HOIL-1 deficiency Idiopathic recurrent pericarditis

Infantile onset panniculitis with uveitis and systematic granulomatosis JMP/NSS (above with CANDLE) Majeed

syndrome MVKD (Mevalonic Kinase Deficiency) MWS (Muckle-Wells Syndrome) NALP12-related recurrent

fever Neutrophilic dermatosis NOMID (Neonatal-onset multisystem inflammatory disease) PAPA (Pyogenic Arthritis, Pyoderma

gangrenosum and Acne ) PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis,

Syndrome) SAPHO (Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis ) SAVI (STING-associated vasculopathy with

onset in infancy) Schnitzler syndrome TRAPS (Tumour necrosis factor Receptor Associated Periodic Syndrome)

Unclassified or Unexplained periodic fever / inflammatory syndrome Vitiligo-

associated autoimmune disease CAMPS (CARD14 mediated pustular psoriasis) HA20 (Haploinsufficiency of

A20) SAVI (STING) DADA 2 NLRC4 related autoinflammatory syndromes

An even larger family of clinically defined syndromes

Concern for autoinflammatory periodic fever syndrome? • ≥ 3 episodes of fever >38.0°C (any method including oral, rectal tympanic or axillary) over a period of 6 months, occuring at least 7 days apart AND•acute phase reactants (ex ESR, CRP) during or within 4 days of febrile episode AND •Normal clinical and laboratory features in between attacks

Have other causes of recurring or prolonged fever (ex: malignancy, infection, immunodeficiency, other rheumatic diseases) been excluded? Suggested investigations to consider:• Complete blood count and differential, peripheral smear • ESR and CRP• Consider blood culture, throat culture• Urinalysis, urine culture• Chest radiograph• Tuberculin skin testing• Serum electrolytes, BUN, creatinine, hepatic enzymes• ANA, ANCA (if history suggestive of classic rheumatic condition) • Viral studies (EBV, CMV, HIV, others as suggested by clinical findings)• Uric acid, LDH • Serum immunoglobulins• Other investigations as directed by patient history/physical exam

How to get started with evaluation for suspected AID

There always has to be exceptions….

• Some patients don’t have discrete episodes of illness.

• Not all of these disorders have fever.

• Patterns of symptoms can be variable…in the same

disease, in the same family.

• Pattern of disease suggesting INFLAMMATION without

other explanation.

• Family history of similar inflammatory phenotype.

You have to be a bit of a detective………

Take a careful history…the clues are there

• Careful documentation of symptoms with episodes.

– Age at onset

– Growth delay, neurodevelopmental disturbance, hearing loss

– Fever pattern- # days/frequency

– Symptoms associated with episodes: rash, GI symptoms, headache and other neurologic complaints, MSK complaints, fatigue; swelling around the eyes

– Triggering factors- immunizations, stress, menstruation, virus

• Ethnic background (both parents), ? consanguinity.

• Complete family history.

– Similarly affected individuals

– kidney transplant or early ESRD

– Deafness

SA and LA: 5 yr old twins

• Fever episodes since age 1 ½ yrs old.– Every 2-3 mo

– 3 days

– Lethargic but no other symptoms

• Diagnosed with T1D age 2 ½ yrs old.

• FH: T1D mat aunt, Graves disease mat aunt, dad deaf in one ear.

• Mom Scottish; Dad Egyptian/Turkish

• Exam: normal. Cute. Normal development.

• Labs: CRP 45 at time of episode

• Gene testing:– Heterozygous MEFV p.Val1726Ala

– Diagnosis: FMF

FMF: what you should know

• Can present in adulthood.

– 90% have onset <20 yrs of age.

• Most common in Turkish, Armenian, North African, Jewish, Arab

– But also identified in Japanese and other ethnic groups

• Mutation in MEFV (pyrin)

– >100 mutations identified….not all pathogenic.

– 25% FMF patients have 1 MEFV mutation

– 10-15% FMF patients have NO mutation

• Diagnostic criteria:

Diagnosis of FMF should be suspected in individuals with the following:

• Recurrent febrile episodes accompanied by peritonitis, synovitis, or pleuritis

• Recurrent erysipelas-like erythema• Repeated laparotomies for "acute abdomen" with no

pathology found• Amyloidosis of the AA type that characteristically develops

after age 15 years in untreated individuals, even in those who do not have a history of recurrent inflammatory attacks

• Favorable response to continuous colchicine treatment• A first-degree relative with FMF• Membership in an at-risk ethnic group

D: a family affair

• 12 yr old Afro-Canadian girl referred with fever and joint

pain.

• Sudden hearing loss age 11 yrs.

• Fever episodes, arthralgia, rash, red eyes, oral ulcers.

• Abdominal pain, fatigue.

• 2 sisters, mother and 2 maternal aunts: all have acquired

hearing loss of unclear etiology, and other symptoms

(fever episodes, arthralgia, rash).

• Genetic testing: Cryopyrin associated periodic

syndrome (CAPS)- Muckle Wells syndrome

19

CAPS (Cyropyrin associated periodic syndromes):

spectrum of disease

Familial cold autoinflammatory

syndrome (FCAS)

• Autosomal dominant

• Cold-induced

– Rash

– Arthralgia

– Conjunctivitis

Muckle–Wells syndrome (MWS)

• Autosomal dominant

• Urticarial rash

• Sensorineural deafness

• AA amyloidosis (in 25% of patients) leading to renal failure

MILD SEVERE

NOMID/CINCA

▪ Sporadic

▪ Progressive chronic meningitis

▪ Deafness

▪ Visual and intellectual damage

▪ Destructive arthritis

Long-term sequelae

(MWS and NOMID/CINCA)

▪ Sensorineural deafness

▪ Visual loss

▪ Cognitive impairment

▪ Central nervous system damage

▪ Growth retardation

▪ Bone and joint deformities

▪ AA amyloidosis and renal failure

Figures courtesy of Raphaela Goldbach-Mansky

Clinical Presentation of CAPS

Diagnosing and treating CAPS

• Genetic testing for CAPS:

– NLRP 3

– NLRP 12 (FCAS)

• Appropriate treatment should be anti IL-1

therapy.

– Anakinra.

– Rilonacept.

– Canakinumab.

• Normal pregnancy, delivery and infancy

• Age 2- recurrent fever episodes. Felt to be ‘viral illnesses’.

• Age 3- admitted to community hospital with fever, cough, oral ulcers.

• Parents began to realize that a group of symptoms were occurring every

2 weeks.

– Fever 103-104 F

– Irritable and fatigued

– Sore red throat

– Oral ulcers

– Arthralgia

– Mild abdominal pain

Clues that this is more than a regular virus:

✓ Periodic timing

✓Cluster of similar symptoms each episode

Patient G, a 4 year old with fever every month

Thomas KT, et al, J Pediatr 1999;135: 15-21

1. Consistently recurring HIGH fevers from an early age, <5 yr

• Clocklike precision, every 28 d for 4-5d

2. Symptoms in the absence of upper respiratory tract infection with at least one of the following :

• aphthous stomatitis: canker sores

• cervical adenitis: swollen lymph nodes

• Pharyngitis: sore throat

3. Exclusion of cyclic neutropenia

4. Asymptomatic between febrile episodes

5. Normal growth and development

Marshall, et al, Pediatr Infect Dis J,

1989;8:658-9

PFAPA – diagnostic criteria

Treatment of PFAPA

• Observation only.

• Prednisone at onset of episodes.

• Tonsillectomy.

• Colchicine.

• Majority of patients have resolution by

age 6-8 yrs.

– BUT…..in some patients it recurs!

– Some patients develop PFAPA in pre-teen yrs.

Some other new diseases to know about

• DADA2 (deficiency of adenosine deaminase 2)

– CERC1 mutations

– Early onset PAN, with strokes

• SAVI (STING associated vasculopathy of infancy)

– Pustular, blistering rash

– Interstitial lung disease

• NLRC4 related autoinflammatory syndromes

– Fever, colitis, MAS, CAPS-like manifestations

• CANDLE (chronic atypical neutrophilic dermatosis with

lipodystrophy and elevated temperature)

– Fever, panniculitis, brain calcifications

HA20: haploinsufficiency of A20

• Early onset disease resembling Behcet disease

– Recurrent oral and/or genital ulcers

– GI symptoms

– Rash

– Fevers

• Mutation in TNFAIP3 gene (NFkBpathway)

• Variable clinical phenotype and age at presentation.

• Treatment: cytokine inhibitors (anti TNF, anti IL1)

Management of AID

• Management of patients with AID should ideally be guided by a multidisciplinary team in a tertiary centre with expertise in AID, with access to genetic counselling.

• The care of patients with AID should include shared patient-centered and family-centered decision-making with the multidisciplinary team.

• Aims of the treatment of AID include:• ▸ Early and rapid control of disease activity• ▸ Prevention of disease and treatment-related damage• ▸ Enabling participation in daily activities• ▸ Improvement of health-related quality of life• In patients with AID, psychosocial support is recommended as

appropriate.

Recommendations for the management of autoinflammatorydiseases. ter Haar NM, et al. Ann Rheum Dis 2015;74:1636–1644. doi:10.1136/annrheumdis-2015-207546

Pediatric Rheumatology AID Clinic

• All AID patients and new consults (Query AID).

• Patients are being asked to enter longitudinal patient

registry- CAN-Fever.

• Pediatric rheumatologist, nurse, PT/OT, social worker

• Ability to bring in genetics, immunology, ENT, ophtho, etc

• Families feel like someone knows about their child’s

disease, and are beginning to meet each other (coffee

room in clinic, annual Family Day)

• Collaborating in research across Canada and US

Can-Fever enrollment

PFAPA, 30

Unclassified or PFS-NYD, 39

FMF, 8HIDS, 3

TRAPS, 5

CAPS, 1

Bechet's, 8

Blau's, 1

CRMO, 30

Other , 4

Total 129 enrolled patients

Summary points

• Autoinflammatory diseases are disorders of the innate

immune system, often involving the inflammasome.

• Identification of AID is important to allow as early

treatment as possible to prevent long term sequelae

(renal failure, deafness) and to improve QoL.

• The spectrum of AID is expanding…new diseases, new

knowledge, and hopefully new treatments.

• http://www.nomidalliance.org/compchart.php

• https://www.printo.it/eurofever/

• https://infevers.umai-montpellier.fr/web/

Thank you!

Thanks to our patients and families,

Dr. Kelly Brown, Jenny Tekano, and

the Pediatric Rheumatology team

at BC Children’s Hospital.

Thank you to Novartis for an educational

grant to help establish the CAN-Fever

registry.

Some common diseases are autoinflammatory

Disease Gene

Gout Complex (SLC1A9, ABCG2)

Chrohn’s disease Complex (NOD2, ATC16L1, IRGM)

Pseudogout Complex

Type 2 DM Complex

Atypical HUS Complex

Familial HLH MUNC 13-4, perforin 1, syntaxin 11

Secondary HLH/MAS Complex

Kastner, Akentijevich, Goldback-Mansky Cell 2010; Ciccarelli et al Current Med Chem 2014; Oda, Kastner Rheum Dis Clin NA 2017

Causative gene mutations….a selection of common ones

Management of AID

• Dependant on the specific disease.

• Corticosteroids can be effective in aborting episodes.

• Colchicine for FMF (and some other disorders..PFAPA,

unclassified)

• Biologics:

– Anti IL 1 is gold standard of treatment for some disorders.

– Anti TNF- TRAPS.

– Disease control and prevention of long term morbidity.

What the heck is TRAPS?

• Tumor necrosis factor receptor-associated periodic

syndrome

• Dominant inheritance

• TNFRSF1A mutations…..affects the inflammasome

• Median onset 3 yrs (2 wks-53 yrs); M:F 3>2

• Fever episodes every 4-6 wks, last longer than 1 wk,

chest/abdo pain, arthralgia/myalgia, periorbital

edema/conjunctivitis

– Recurrent pericarditis

• Raised inflammatory markers with risk of amyloidosis

• Treat: prednisone, etanercept, anti-IL1