autoinflammatory and periodic febrile...

Autoinflammatory

and Periodic

Febrile Syndromes

John J. Cush, MD

Baylor Research Institute

Baylor University Medical Center

Dallas, Texas

Dr John Cush

@RheumNow

Disclosure Information

• Investigator—Amgen, Celgene, Novartis, Pfizer,

UCB

• Consultant—Abbott, BMS, Celgene,

Genentech, Janssen, Pfizer, Savient, UCB

Febrile Syndromes Defined

• Autoinflammatory syndromes: characterized by

attacks of inflammation unrelated to infection,

autoantibodies or Ag-specific T cells.

– Defines the innate immune system

– Typically seen in infants and children

• Periodic Fevers: subset of autoinflammatory syndr.

– Hereditary/monogenic or acquired

– Recurrent fever, inflammatory Sxs, Disease-free intervals

• FUO: fever >101oF for more than 2-3 wks,

documented on several occasions after

extensive evaluation (hospital x 1 week?)

Patterns of Fever Fever Patterns

◄Continuous: above baseline thru-out the day

(infection, sepsis, Typhoid fever, etc)

◄Continuous Fever (resp to antipyretics)

◄Remittant: rises but falls to an elevated

baseline (infection, SBE, abscess)

◄Quotidian: rises but falls to baseline daily

(malaria, SoJIA, AOSD)

◄Undulant (Pel-Epstein):Hodgkins lymphoma

◄Relapsing fever: typical of Borreliosis

Mackowiak P. Frontiers in Bioscience 9: 2297-2301

Fever in Rheumatic Disease

• HIGH GRADE FEVER – Still’s disease

– Macrophage activation syndrome

– Septic arthritis, opportunistic infections

– Polymyalgia rheumatica, Giant Cell arteritis

– Kikuchi-Fujimoto syndome

• LOW GRADE FEVER – Lupus

– Early onset of Rheumatoid arthritis

– Gout: often mistaken for acute septic arthritis

– Small Vessel Vasculitis (HSP, Sweets syndrome)

Carsons SE. Infect Dis Clin North Am. 1996 Mar;10(1):67-84

Periodic Fevers

ADOLESCENTS/ADULTS

• Adult-onset Still’s disease

• FMF

• Muckle-Wells syndrome

• Cyclic neutropenia

• Schnitzler syndrome

• Polymyalgia Rheumatica

• Giant Cell Arteritis

• Kikuchis syndrome

NEONATES/CHILDREN

• Systemic onset JIA

• TRAPS

• Familial Mediterranean Fever

• Cryopyrinopathies (CAPS)

– Familial Cold Auto- inflammatory

syndrome

– Muckle-Wells syndrome

– NOMID/CINCA

• PFAPA syndrome

• Blau Syndrome

Spectrum of Autoinflammatory Syndromes

Autosomal recessive

• Familial Mediterranean fever

• HyperIgD (HIDS)

• Deficiency IL-1Ra (DIRA)

• Deficiency IL -36R (DITRA)

• Familial pustular psoriasis

Majeed syndrome

Autosomal-dominant

• TRAPS

• FCAS

• Muckle-Wells syndrome

• NOMID/CINCA

• PAPA syndrome

Adapted from Haskes P. Pediatr Clin North Am. 2012 Apr;59(2):447-70

Granulomatous

• Blau syndrome

• Early onset sarcoidosis

Other, nongenetic

• Marshall (PFAPA) syndrome

• Systemic JIA / Adult Still’s

• Behçet syndrome

• Recurrent pericarditis

• Chronic recurrent multifocal

osteomyelitis (CRMO)

• Schnitzler syndrome

• Gout

INFEVERS

http://fmf.igh.cnrs.fr/ISSAID/infevers/

Febrile Disorders in Adults

Autoinflammatory % adult

• Schnitzler >80%

• DITRA > 80%

• Cyclic

Neutropenia 50%

• AOSD ~33%

• TRAPS <30%

• FMF <20%

• Muckle-Wells <20%

Rheumatic FUO adults

• AOSD

• Gout

• PMR/GCA/Vasculitis

• Hemophagocytic syndr

• Crohns colitis

• Sweets syndrome

• Kikuchi-Fujimoto syndr

• Lymphoma/leukemia

Understanding Autoinflammatory Syndromes

• Age

• Fever

– duration, magnitude, periodicity

• Cutaneous features

• Organ specific

– CNS

– Serositis

• Complications

– Amyloid

– Waldenstroms

Organization of the Immune System

Immune Responses

Immunity Innate Adaptive

Role 1st line Defense

(prime adaptive)

Recognition of self

from non-self

Response Minutes/Hrs

nonspecific

Days/Weeks

Ag-specific, Memory

Cells Epithelial, PMNs,

macrophages T, B, dendritic cells

Cytokines IL-1, IL-6, TNF, IL-8 IFN, IFN, IL-2, IL10

Provoked? stress, immunization or trauma Non-self, drugs

Disorders

Autoinflammatory :

innate responses w/o

AutoAbs

Autoimmune :

w/ auto-reactive T&B

cells, Ab

Prototypic Dz CAPS Lupus

Innate Immune Response

Tissue Damage

Microbes

DAMPs PAMPs

Pattern Recognition Receptors

TLR NLR CLR

, MSU, crystals, silica,asbestos

, hyaluron, ATP, HMGB-1

NLRP3

Inflammasome

NLR NOD like receptors TLR: Toll-like receptors CLR: C-type lectin receptor

IL-1

, Bacterial LPS,

PGN, flagellin,

zymosan,toxin

Inflammasome

http://flipper.diff.org/app/items/info/4713

Joint Pain and Fever

• 36 yr old Moroccan male w/ 5 yrs of intermittent

swelling/pain/warmth wrist, dorsum hand, elbow

• Episodes last x 3 days, fever, pink eye, CP

• Meds: On hydroxychloroquine x 1 yr (+ benefit?)

• Prior negative evaluation: included labs,

serologies, CXR, EKG, SF crystal negative

• Denies abdominal pain, LBP, heel pain, rash, hives

• +PPD 16 mm and 13cm Spleen on abdominal US

What is the most likely diagnosis for this

patient w/ episodes of fever, arthritis,

conjunctivitis?

1. Tuberculosis

2. Reactive arthritis

3. TRAPS

4. Adult-onset Still’s disease

5. Familial Mediterranean Fever

Familial Mediterranean Fever • Linked to Mediterranean Ancestry

• Ancestry should not exclude consideration

Samuels Medicine 1998;77:268-97.

Sephardic Jews,

Armenians, Turks,

North Africans,

Arabs,

Moroccans,

Italians, Greeks,

Japanese

United States:

uncommon in

Ashkenazi Jews.

Familial Mediterranean Fever - I

• Triad: Fever>38oC, Painful Serositis or Erythema

• Sephardic Jews, Armenians, Turks, N.Africans,

Arabs, Italians, Morrocans

• Bouts/Fever: lasts 1-3 d remit; variable periodicity

• 120K worldwide

• Onset:

childhood or

adolescents

• < 20 yrs in 80%

• MEFV gene

mutations

Padeh S. Rheum Dis Clin N Am 33 (2007) 585–623

Familial Mediterranean Fever - II

• Arthritis: recurrent monarthritis (chronic in 5% hip/SI)

– Peritonitis > Pleuritis > Pericarditis

– Skin: BLE erysipelas-like rash (painful)

– Myalgias, orchitis, aseptic meningitis, HSP, PAN

• Labs: high WBC, ESR, CRP during attacks

• Amyloidosis: manifest as proteinuria/nephrotic syndr.

• Dx made by rectal or BM Bx

• >100 missense mutations of MEFV

– 5 most common genotypes~80% of cases – (M694V, M6941, M680I, V726A, E148Q).

• Rx: Colchicine, Anakinra

Padeh S. Rheum Dis Clin N Am 33 (2007) 585–623

Crocus (Colchicum autumnale)

• Autosomal recessive MEFV mutation on gene 16p13

• MEFV (stands for MEditerranean FeVer)

– Encodes 781 AA protein Pyrin (AKA marenostrin)

– Pyrin: binds & inhibits caspase-1 • negative regulator of inflammasome function

– Defective pyrin (in PMNs) leads to unregulated Caspase-1 ( IL-1, IFNγ, TNFα, IL-6, IL-8)

• Over 100, mostly missense, mutations of MEFV

– 5 most common genotypes ~80% of cases

– (M694V, M6941, M680I, V726A, E148Q).

• Zygosity and mutation type determines the severity of the disorder and age of onset

Familial Mediterranean Fever

Sporadic Fevers

• 19 yr old Belgian male onset of febrile episodes

lasting 5-15 days, occurring 2-3 x yearly

– Assoc. w/ abdominal pain, LBP, arthralgia, T 40-41C

– Reponds to steroids

• Dx w/ AOSD, given HCQ, MTX without benefit

• At age 31 he develops new features of diarrhea,

proteinuria and creatinine = 2.3 mg/dl

• A diagnostic test was done

What Diagnostic Test Was Done?

1. ANA, dsDNA serologies

2. Ferritin

3. cANCA (PR3 Ab)

4. Colonoscopy w/ biopsies

5. Renal biopsy

Jadoul Kidney International (2001) 59, 1677–1682

TRAPS (AKA Hibernian Fever)

• 1945: 1st described in Irish, Scottish, Austrian, N. European

• Autosomal dominant; Missense mutations in genes encod-

ing for type I p55 TNF receptor (TNF-RI) (TNFRSF1A).

• 75% onset by age 10 yrs (mean 3 yrs; adults described)

• Characterized by arthralgia, myalgia, painful migratory rash,

abdominal pain, conjunctivitis, oral ulcers, scrotal swelling

• Febrile attacks that last 1-3 weeks

• Effective Rx: NSAID, Steroid (not colchicine)

– Rx:etanercept (anakinra in some) – Reports of worsening with infliximab

Haskes P. Pediatr Clin North Am. 2012 Apr;59(2):447-70

Arthritis & Rheumatism 2012; 64:908 ETN in 14 TRAPS pts

[----ETN-----] [ none ]

CAPS

Cryopyrin Associated Periodic Syndromes (also known as the Cryopyrinopathies)

• Autosomal dominant disorders

• Gain of function mutations of NACHT domain

of NLRP3 (includes the cold-induced

autoinflammatory syndrome-1 [CIAS1] gene)

• Cryopyrin(pyrin) expressed PMNs monocytes.

• FCAS, Muckle-Wells syndrome & NOMID

• Features: fever, urticarial-like rash,

conjunctivitis, bone and joint symptoms, and

elevated inflammatory markers such as CRP.

• CAPS patients respond well to IL-1 inhibition


Muckle-Wells Syndrome (MWS)

• 1st reported 1962

• Autosomal dominant CIAS-1 defect (lifelong)

• ~90% before age 20yrs; ~60% before 10yrs.

• Triad: rash, nerve deafness, amyloid nephropathy

• Urticarial rash, arthralgia, fever/chills 1/3,

abdominal pains 20%, conjunctivitis 10%

• 50-60% sensorineural hearing loss

• 25% develop amyloidosis

• Labs: elevated WBC, ESR, CRP

• Rx: IL-1 inhibition


Schnitzler Syndrome

• Rare, acquired autoinflammatory Dz in Adults

• Chronic nonpruritic urticaria & IgM gammopathy.

PLUS:

– Periodic fever <104F, arthalgia/itis, bone pain,

hepatosplenomegaly, lymphadenopathy,

increased WBC, ESR or anemia

• Other Sxs:lymphadenopathy, wt. loss, pancreatitis

• Complications: Disabling skin rash, fever, bone

involvement. Anemia or lymphoplasmacytic

malignancy (Waldenstroms in ~15% of pts.)

• Treatment: anakinra

Besada E. Clin Rheumatol. 2010 May;29(5):567-71 Lipsker D Medicine 2001; 80(1): 37-44.

19 yr. old autistic Nigerian male w/

recurrent urticaria, fever, pericarditis

• History began 9 mos ago with recurrent Urticaria

on Trunk, back, arms. 3-7 days fever 101-102F

• C/O occasional arthralgias, limping

• CP, pericarditis pericardial window 4 mos ago

• No response to HCQ, great response to steroids

• Hx: Autism, tympanostomies, congenital Ptosis

• Currently afebrile, no synovitis, nl HEENT

• Labs W 14.6, Hct 40, CRP 21.4 mg/dl, ESR53,

ACE 81, Ferritin 463, borderline +PR3 Ab

19 yr. old autistic Nigerian male w/

recurrent urticaria, fever, pericarditis

• What diagnostic treatment or test should you

order?

1.Trial of colchicine 0.6 mg bid

2.Trial of anakinra 100 mg sc qhs

3.TNF-R1 gene test for TRAPs

4.MEVF gene test for FMF

5.CIAS-1 gene test for CAPS

< 1 day FCAS IL-1 inhibitor CIAS-1

NLRP3

1-3 days

FMF Colchicine

Anakinra MEFV

MWS IL-1 inhibitor CIAS-1

NLRP3

3-7 days

HIDS Anakinra MVK

PFAPA Tonsillectomy

Steroids

Anakinra

7-21 days TRAPS Etanercept TNF-R1

Daily Fevers >39oC

SoJIA AOSD

Schnitzler

Anakinra

Tocilizumab

<16yr

16-35y

Algorithm for Undiagnosed Periodic Fever > 38oC

Fever Duration Dx Consideration Diagnostic Test/Intervention

NA

NA

<1 yr

Distinguishing Features of Autoinflammatory Dz

Adapted from Haskes P. Pediatr Clin North Am. 2012 Apr;59(2):447-70

Aphthous ulcers: PFAPA, HIDS, TRAPS,

Cyclic neutropenia

Pustulosis: PAPA, DIRA, DITRA, PASH

Arthritis: NOMID, Still’s, MWS, PAPA, DIRA

Conjunctivitis: TRAPS, MWS, FMF, Schnitzler,

DITRA, Cyclic Neutropenia

Common: Fever, serositis, arthralgia, myalgia (low PPV)

Amyloidosis: FMF, TRAPS, MWS, NOMID

CNS: MWS,

NOMID

Urticaria: CAPS/MWS, AOSD, SoJIA, Schnitzler

Italian Gal w/ Fever, sore throat, rash,

arthritis, serositis, lymphadenopathy, HSM

• 23 yr. WF admitted to hospital with 6wk hx of

fevers of 104F, rash, and a sore throat.

• C/O myalgias, BL wrist pain, abdominal pain, and

rash over the trunk, neck & extremities.

• PMHx: rheumatic fever at 9 yrs, FUO, hepatitis.

• Review of systems was otherwise negative.

• Hospital course (20d) was notable for pleuritis,

pericarditis, lymphadenopathy, splenomegaly,

WBC= 40K, and increased hepatic enzymes

What is the most likely diagnosis for this patient w/

prolonged fevers, arthritis, rash, serositis and

organomegaly?

1. Rheumatic fever

2. TRAPS

3. Adult-onset Still’s disease

4. Familial Mediterranean Fever

5. Schnitzlers syndrome

Still’s Disease

Systemic inflammatory disorder

Young adults (up to age 35yrs)

Quotidian fevers, evanescent rashes, arthritis, sore throat, serositis, organomegaly, leukocytosis and a marked acute phase response

No diagnostic or serologic tests

Syndrome = diagnosis of exclusion.

Systemic exacerbations and/or chronic arthritis, and disease-free intervals.

Cush JJ. Adult onset Still’s disease. Bull Rheum Dis 2000; 49(6):1-4

JIA Variants

JIA Variant % Age Sex ANA RF Features

Pauciarticular

Type 1 50 1-8 F <60% 0

<4 Joints

Uveitis

Pauciarticular

Type 2 10 9-16 M 0 0

Knee, Hip, Ankle

Juvenile Spondylitis

Polyarticular

RF+ 5 10-16 F <70% 100

RA in children

Erosive Dz >50%

Polyarticular

RF(-) 15 3-9 F 0 0

Symmetric polyarthritis

Erosive <15%

Systemic 20 5-16 F=M 0 0

Fever, rash, serositis,

organomegaly, incr.

WBC, ESR, CRP

AOSD - 17-35 F=M 0 0

Fever, rash, serositis,

organomegaly, incr.

WBC, ESR, CRP

Sir George Frederick Still (1868–1941)

“On a form of chronic joint disease in children”

1897

Farrow SJ. Rheumatology 2006; 45:777

Quotidian (Spiking) Fever

Patterns in AOSD Quotidian

Author/Yr #AOSD(%) Time (yrs) Source

Bywaters ‘71 14 20 Rheum. Dept

Goldman ‘80 13 4 Rheum. Dept

Del Paine ‘83 7 9 Rheum. Dept

Cush ‘85 21 15 Rheum. Dept

Nkoghe ’02 17 13 Infect. Dz Dept

Mert ’03 20(15%) 17 Infect. Dz. Dept

Bujak ‘73 10 (5%) 11 200 FUO pts

Aduan ‘79 21 (6%) 15 347 FUO pts

Larson ‘82 5 (5%) 10 109 FUO pts

Kazanjian ‘92 5 (6%) 6 86 FUO pts

Knockaert ‘92 4 (9%) 9 45 FUO pts

Tabak ’03 13 (11%) 17 117 FUO pts

Frequency of AOSD and FUO

1-2 per year in most hospitals; AOSD #1 Rheumatic cause of FUO

Rheumatoid or “Still’s” Rash

• Characteristically evanescent (esp. with fever)

• Salmon-pink (faint erythema) maculopapular

• Trunk, neck, and extremities

• Dermatographism

• Koebner phenomenon

Uncommon in AOSD: pruritus, urticaria, dermal

plaques, facial rash, alopecia, erythema

nodosum, Raynaud’s phenomena

LK: Carpal Ankylosis

8/72 3/73

Intercarpal Ankylosis

Cush JJ, et al. Arthritis Rheum; 30:186-94, 1987

Common Features

Sore throat 70%

Weight loss 65%

Myalgias 75%

Hepatosplenomegaly 40%

Hepatic dysfunction 70%

Lymphadenopathy 65%

Pleuritis 40%

Pericarditis 30%

Abdominal Pain 30%

Pneumonitis 20%

Myocarditis rare


Myocarditis

19yoLM w/ T 104, WBC 64k, Pleuro-

pericarditis, Myocarditis, Splenomegaly

Lab Abnormalities in AOSD

• Negative ANA & RF 95%

• Neutrophilic leukocytosis 90%

• Anemia chronic disease 75%

• ↑↑ESR, ↑CRP, ↑Platelets 90%

• Hypoalbuminemia 75%

• Hyperferritinemia 50%


Serum Ferritin in AOSD

* adapted from van Reeth 1994

Hemophagocytic syndrome

(Macrophage Activation Syndrome - MAS)

• Dx: Histiocytic erythrophagocytosis on BM Bx

• Dz: SLE, RA, AOSD, SoJIA, PAN, MCTD, PSS, Sjogrens,

Sarcoid, Bacterial/Viral Infx, TBC, NHL, renal transplant

• Familial: rare, autosomal recessive, perforin gene mutation

• Fever, hepatosplenomegaly, LFTs, pancytopenia, DIC

• Labs: Very low > high WBC, CRP but ESR

– Hyperferritinemia

• High mortality rate: 8.2 - 38.5%

– Assoc w/ corticosteroid dose and thrombocytopenia

• Rx: Steroids, CyA, IL-1 Inhibitors, Abx (underlying dz)

Dhote R, etal. Arthritis Rheum 2003; 49:633

Diagnostic Criteria Cush 2000

Major (2pts) Minor (1pt)

Quotidian fever > 39 C Onset age < 35 yrs.

Still’s rash Arthritis

WBC & ESR Sore throat

Negative RF & ANA RES or LFTs

Carpal Ankylosis Serositis

Cervical/tarsal ankylosis

Definite AOSD: 10 points + 6 mos. observation

Probable AOSD: 10 points + 6 weeks observation

AOSD: Keys to Diagnosis

• Daily Fevers > 39oC

• Circadian illness: Temps same time EVERY

night or later afternoon (not 7AM!)

• “Still’s rash” - evanescent

• Confirm using Cush or Yamaguchi Criteria

• Diagnostic response to IL-1 inhibition?

AOSDTreatment Paradigm

Steroids

NSAIDs

MTX w/

Prednisone

OR

IL-1 Inhibitor

Role of IL-1 vs IL-6

inhibition in Still’s

IL-1 Inhibitors

Kineret (anakinra)

Ilaris (canakinumab)

Arcalyst (rilonacept)

IL-6 inhibitor

Actemra

Past

Approach

Effects of IL1, IL6, and TNF

Clinical Feature IL-1 IL-6 TNF

Fever > 39C + + +

Exanthem + 0 +

Myalgias + +/- +

Arthralgias/itis + + +

Weight loss + + ++

Leukocytosis + ++ +

Acute Phase Rxn + ++ +

Biologic Therapies in AOSD

• TNF inhibitors

– Effective in polyarthritis

– Less so for systemic disease (Infliximab?)

• Anti-IL-6 Tocilizumab

– Studied in SoJIA and AOSD

• Anti-IL-1 Anakinra

– Systemic and articular disease

• IL-18 as a Target?

Tocilizumab in AOSD

• 36 pts w/ OL TCZ – 8mg q 2-4 weeks in

MTX/DMARD-IR pts (42% prev Rx anakinra)

• Joints more refractory than systemic Sxs Ortiz-Sanjuan etal. Arthritis Rheumatol. 2014 Feb

WBC CRP

Ferritin Pred

Anakinra: Time to Response in SoJIA/AOSD

Ann Rheum Dis. 2008 Mar;67(3):302-8

http://www.ncbi.nlm.nih.gov/pubmed/17947302

Anakinra: Time to Response in AOSD

Laskari et al. Arthritis Res Ther. 2011; 13(3): R91.

Overall 7/25 Nonresponders

BL/AOSD: 55 WM, w/ ST, pleuritic CP, fever

104F, 65# wt loss, WBC 50k, Ferritin 28,000

Anakinra 100mg/d

Prednisone 20 mg/d Methotrexate 12.5-20 mg/wk

Leflunomide 20 mg/d Infliximab Singulair, colchicine

Anakinra

Microarrays pattern of inflammation that improves w/ Anakinra Rx

Cost of Therapies

Generic Dose Given Annual

Cost

Methotrexate 15-20 mg po Weekly $600

Etanercept 50 mg sc Weekly $35000

Anakinra 100 mg sc Daily $47000

Canaknumab 180 mg sc Every 8

wks $114,000

Rilonacept 150 mg sc Every 2

weeks $288,000

Tocilizumab 4-8 mg/kg IV Every

month $22-44,000

Injection Site Reactions

• Anakinra ISR may occur in 1st 28 days

• Frequency of ISR

– Anakinra 71% (RA)

– Canakinumab 9% (CAPS)

– Rilonacept 48% (CAPS)

Data from Package inserts: anakinra, canakinumab, rilonacept Photos courtesy J. Cush, MD

Understanding Febrile Syndromes

• Adults: Stills, Schnitzler, TRAPs, FMF

• Fever: 1-3 FMF, 7-21 TRAPS, qd AOSD

• Cutaneous features

– Hives: MWS, Still’s

– Pustular: PAPA, DIRA, DITRA, PASH

• Organ specific

– CNS - MWS

– Serositis: AOSD, TRAPs, FMF

• Complications: MAS

– Amyloid: FMF, TRAPS, CAPS

– Waldenstroms, gammopathy; Schnitzlers

Questions?

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