Autoinflammatory Diseases: Familial Mediterranean Fever and Beyond

1. Autoinflammatory Diseases:Familial Mediterranean Fever and Beyond Mary Beth Humphrey, MD, PhD Associate Professor University of Oklahoma Health Sciences Center Modified from original work of Kenneth H. Fye, MD, FACP, FACR at UCSF

2. The Systemic Autoinflammatory Diseases • Episodes of seemingly unprovoked inflammation • Absence of high titer autoantibodies • Innate immune responses are prominently involved in the pathophysiology

3. Growing Family of Autoinflammatory Diseases • Hereditary Periodic Fever Syndromes • Familial Mediterranean Fever • TNF receptor-associated periodic syndrome (TRAPS) • Familial cold autoinflammatory syndrome • Muckle-Wells • Neonatal-onset multisystem inflammatory disease (NOMID)

4. Diseases Associated with Excessive Activation of the Inflammasome • Familial Mediterranean Fever Pyrin mutations • Muckle Wells Cryopyrin mutations • Familial Cold-induced urticariaCryopyrin mutations • Gout Monosodium Urate • Pseudogout Calcium pyrophosphate dehydrate • Alzheimer disease β-Amyloid • Asbestosis Asbestos • Silicosis Silica • Blau syndrome NOD2

5. Biology IL-1β: Production Is Sensitive and Rapid Uric acid crystal Injury LPS Receptor • Macrophage key producer in response to triggers such as • Bacterial toxins, eg, lipopolysaccharide (LPS) • MSU, CPPD, silica, amyloid • IL-1β, other cytokines • Stress factors • Genetic mutations in the inflammasome may result in increased production • Inflammasome: protein complex that regulates processing of IL-1β precursor SIGNAL Nucleus IL-1β PROCESSING Pro IL-1β Pro IL-1β IL-1β SYNTHESIS IL-1β Inflammasome IL-1β SECRETION IL-1β

6. Inflammasome = IL-1 Production

7. 1 2 3 1 5 2 4 3 4 5 Biology IL-1β: Tight Regulation Maintains Homeostasis Production Regulated at multiple steps of synthesis and processing Secretion regulated by multiple ionic, enzymatic events Signaling IL-1Ra: dominant endogenous regulator Inactive “decoy” IL-1RII Soluble IL-1 receptors IL-1RII “Decoy” IL-1Ra IL-1β IL-1β Soluble Receptor

8. Muckle-Wells & Cold Induced Urticaria Crohn’s FMF

9. Cryopyrin- Associated Periodic Syndromes (CAPS) • Familial Cold-induced Urticaria • Muckle-Wells • Neonatal Onset Multisystem Inflammatory Disease (NOMID)

10. Case 1 • 34 year old woman presented with a history of recurrent fevers, arthritis, cold-induced urticaria, conjunctivitis, lymphadenopathy, intermittent diarrhea, and sensorineural deafness that began before she was 4 months old. • Past therapies had included NSAIDs and corticosteroids. Prednisone had helped, but she had never taken it chronically.

11. Case 1 • Physical exam was normal except for decreased hearing (she used bilateral hearing aids), bilateral conjunctivitis, synovitis of the left wrist, and urticaria. • CBC was normal except for an Hct of 30.4%. ESR was 45, and CRP was 28.1. UA was (thankfully) normal. Autoimmune serologies were all negative. • Skin biopsy revealed urticarial vasculitis.

12. Case 1 • What is the diagnosis? • What is the definitive diagnostic test? • What is the therapy?

13. Case 1 • Diagnosis – Muckle-Wells syndrome. • Autosomal dominant disorder. • Mutation at CIAS1 (cold induced autoinflammatory syndrome 1) gene on 1q44. • Codes for cryopyrin, important as a platform for apoptosis and down regulating signaling pathways. • Defective cryopyrin leads to increased production of IL1-beta and TNF-alpha= inflammation and fever

14. Muckle-Wells & Cold Induced Urticaria IL1-β

15. Muckle-Wells • Inflammatory episodes • Limb pain/arthritis • Fever • Urticarial rash • Conjunctivitis • Sensorineural hearing loss • Systemic amyloidosis

16. Case 1 • Definitive test – genetic typing (buccal swab) to identify specific genetic polymorhisms of the CIAS1 (cold induced autoinflammatory syndrome 1)gene. • Over 20 defects in the CIAS1 (also known as NALP3 or PYPAF1) locus that lead to abnormalities in cryopyrin function.

17. Case 1 • Her gene sequencing revealed a heterozygous cytosine to thiamine substitution in exon 3 CIAS1, leading to a methionine for threonine substitution at amino acid position 348 in the cryopyrin protein. • Defect shared by Muckle-Wells and familial cold-induced urticaria.

18. Other disorders associated with defects in Cryopyrin • Familial cold-induced urticaria • Hives occur after cold exposure (breeze on sweaty skin, swimming, cold weather, air conditioning, etc.) • Cold foods can lead to tongue and throat swelling • Anaphylaxis/hypotension can occur • Treat with anti-histamines and avoidance of cold

19. Other disorders associated with defects in cryopyrin • Neonatal-onset multisystem inflammatory disease (NOMID) (very severe, from birth) • Chronic infantile neurologic, cutaneous, articular syndrome (CINCA) (very severe, from birth)

20. Characteristics of Cyropyrinopathies Neven B et al. (2008) Cryopyrinopathies: update on pathogenesis and treatment Nat Clin Pract Rheumatol doi:10.1038/ncprheum0874

21. Overgrowth arthropathy in a patient with CINCA or NOMID Neven B et al. (2008) Cryopyrinopathies: update on pathogenesis and treatment Nat Clin Pract Rheumatol doi:10.1038/ncprheum0874

22. Case 1: Therapy • Therapy: targeted at excessive IL-1 • Prednisone-mild cases • Arcalyst (Rilonacept): IL-1 trap; weekly injection (FDA approved for CAPS) • Anakinra (not FDA approved): IL1-ra (decoy receptor that binds to IL-1) • Canakinumab (monoclonal IL-1B antibody in phase III trials)

23. Case 1 • After 3 months of fighting, her insurance company finally agreed to pay for anakinra (IL1-ra) therapy (prior to Arcalyst FDA apporval). • After 1 week, all of her symptoms had disappeared. She stated: “Most people don’t remember when they were born. I remember the exact day. With the first shot I left my old life behind and started my new one.”

24. NOMID; before and after anakinra

25. Prognosis of CAPS • Prior to anti-IL-1 therapy prognosis was poor • Now patients can stop steroids and have symptoms controlled • Unclear if anti-IL-1 therapy will prevent the occurrence of AA amyloidosis that accompanies the disease

26. Case 2 • 52 year old male presented with a history of recurrent fevers, abdominal pain, arthralgias, and myalgias of 40 years duration. Each episode lasted for about 3 days and, although incapacitating, resolved spontaneously. • Family history was significant in that his father was an Iranian Sephardic Jew with a similar syndrome, and his mother was an Ashkenazi Jew.

27. Case 2 • Physical examination was normal at presentation. • No abnormal labs.

28. Case 2 • What is diagnosis? • What is the definitive test? • What is the therapy?

29. Case 2 • Diagnosis – Familial Mediterranean Fever. • Defect in the MEFV gene on chromosome 16p13.3 that codes for pyrin/marenostrin. • At least 35 mutations so far identified. M694V most common among various ethnic groups (Sephardic Jews, Arabs, Armenians, Turks). • V726A, mainly in Ashkenazi and Iraqi Jews, Druses, and Armenians, tends to be associated with milder disease, but amyloidosis does occur.

30. Case 2 • Definitive test – genetic typing. Our patient had heterozygous M694V. • The homozygous state is more severe and more likely to lead to renal amyloidosis. • High risk groups: Jewish, Armenian, Arab, Turkish, Italian

31. Silk Road Distribution of FMF

32. Familial Mediterranean fever (FMF) • Recurrent episodes of inflammation lasting 1-3 days • Serositis, pleuritis, pericarditis • Asceptic meningitis • PAN • Glomerulonephritis or proteinuria • Arthralgias/arthritis • Rash- erysipeloid erythema • Amyloidosis

33. FMF features differ with genetic background

34. Rashes of FMF Erythema marginatum-like

35. Case 2: Treatment • Therapy • Colchicine: needs higher dosing • 1.2-1.8mg/d. • 85% respond. • Treatment prevents amyloidosis • Prednisone • NSAIDs • Other • Azelastine (antihistamine/mast cell stabilizer)- case reports • Prazosin 3mg po BID (old literature) • TNF-alpha antagonists

36. Case 2 • In our patient we managed to get prior authorization for etanercept therapy, to be used at the outset of fever as he could not tolerate the higher dose colchicine. • He has had two flares that were both aborted with etanercept • Prognosis is uncertain and depends on the pyrin mutation

37. Case 3 • 47 year old woman with a 10 year history of recurrent fever, myalgias, arthralgias, conjunctivitis, oral ulcers, and abdominal pain. • High dose prednisone and cytotoxics had been used with moderate success, but she had developed unacceptable side effects. • Father died in his late 30s from renal disease

38. Case 3 • Physical exam: fever of 102 degrees, conjunctivitis, oral ulcers, livido reticularis, cervical lymphadenopathy, and abdominal tenderness without masses or organomegally. • Lab evaluation revealed an ESR consistently between 80 and 100 mm/hr and a moderate anemia. • RF, ANA, C’ levels, ANCA, cryos, HCV Ab, IEP, CPK, UA, APLS screen were all negative or WNL.

39. Case3 • What is the diagnosis? • What is the therapy? • What is the prognosis?

40. Case 3 • Diagnosis – TRAPS (TNF Receptor1 Associated Periodic Fever Syndrome) • an autosomal dominant disorder • due to a mutation of the TNFRSF1A gene that codes primarily for the extracellular domain of the p55 TNFa cell surface receptor. • Deficient TNFa receptor function leads to decreased release of surface receptor, increased levels of circulating TNFa and increased inflammatory cell activation. • No ethnic predilection

41. Failure to shed soluble TNFR1

42. TRAPS attacks are weeks long • Attacks of fever, serositis, arthritis and rash lastingweeks • Migratory rash, periorbital edema help distinguish TRAPS • Renal amyloidosis not uncommon • Unlike FMF, colchicine in NOT effective

43. Case 3 • Prednisone at doses higher than 20 mg per day will work, but the best therapy is a TNF-a antagonist. • Prognosis depends on whether AA amyloidosis develops. The incidence of amyloidosis depends on the specific defect in the TNFRSF1A gene.

44. Case3 • Patient was started on etanercept with dramatic improvement. • However, within 6 months she developed a peripheral demyelinating neuropathy (proven by sural nerve biopsy). • What was happening, and what was to be done?

45. Case 3: complication • Anti-TNF-alpha toxicity. • Infection (mycobacterial, staph, other). • Local injection site reactions. • Demyelinating neuropathy. • Marrow suppression. • Malignancy (non-Hodgkins lymphoma). • Autoantibody formation (lupus-like syndrome). • Congestive heart failure. • Exacerbation of rheumatoid nodules.

46. Case 3 • Diagnosis – demyelinating neuropathy (“Pseudo-multiple sclerosis”) of anti-TNFa therapy. • Treatment. • Etanercept discontinued. • High dose prednisone and IVIG initiated. • Response. • Good response (still with low grade fevers and arthralgias, but “pseudo-MS” resolved). • Still on IVIG and prednisone (5 mg qd).

47. Review

48. Muckle-Wells syndrome Rare to daily attacks, hearing loss occurs early Cryopyrin mutations Treat with IL-1 inhibitors

49. Attacks are incapacitating and lasting days Colchicine Prednisone Anti-TNF

50. TRAPS • Inflammatory attacks last WEEKS • MIGRATORY rash • Periorbital edema SEROSITIS Anti-TNF therapy