AUTOINFLAMMATORY DISEASES

Monogenic Diseases

Most Periodic Fever Syndromes (PFS) Are Autoinflammatory Diseases Driven by an Excess of Proinflammatory Cytokines, Including IL-1β^1,2

Many PFS are monogenic diseases including FMF, HIDS/MKD, TRAPS, CAPS (FCAS, MWS, NOMID). These PFS may be rare and impact specific ethnic groups, may be associated with specific mutations, often appear in infancy and early childhood, and may take a decade or more to diagnose due to overlap with other conditions.

Many PFS present with the following^3,4:

Episodic high fever
A wide spectrum of skin rashes
Systemic inflammation commonly accompanied by arthralgia/arthritis

A spike in inflammatory markers (CRP, ESR, and SAA)
Fatigue

Symptoms of PFS can be physically debilitating and can lead to long-term health consequences, such as joint and organ damage^5-7
Patients with PFS and other autoinflammatory diseases can often experience health-related quality-of-life burdens and inability to participate in normal daily activities⁸

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Characteristics of 6 Types of Monogenic PFS

Review characteristics of 6 types of PFS below.

Review characteristics of 6 types of PFS below. Tap each header to expand or collapse the table for easier reading.

Predominant ethnic distribution⁹

Turkish, Armenian, Arab, Jewish, Italian

Worldwide prevalence or number of cases¹⁰

1 to 5 in 10,000

Gene mutation⁴

MEFV, autosomal recessive inheritance

Typical age at onset⁴

<20 years, with 60% appearing <10 years

Mean delay in diagnosis¹⁴

Can be 10 years

Duration of attacks⁹

12 hours to 3 days

Frequency of attacks¹⁸

Irregular; once per week to once every 5 to 10 years

Cutaneous findings⁷

Erysipelas-like erythema
Characterized by red, warm, and swollen areas
Lesions are tender to the touch, can be 10 cm to 15 cm in diameter, and usually occur below the knee on the anterior leg or top of foot

Other select clinical features^1,4

Abdominal pain
Peritonitis
Constipation > diarrhea
Chest pain
Arthritis/monoarthritis
Myalgia

Predominant ethnic distribution⁹

Dutch or Northern European

Worldwide prevalence or number of cases¹¹

>180

Gene mutation⁴

MVK, autosomal recessive inheritance

Typical age at onset⁴

<1 year

Median delay in diagnosis^15†

Can be 10 years

Duration of attacks⁹

3 to 7 days

Frequency of attacks¹⁹

Irregular; 2- to 8-week intervals

Cutaneous findings³

Diffuse maculopapular eruption often extending to the palms and soles, or nodular, urticarial, or morbilliform
Erythematous macules that are sometimes painful can occur

Other select clinical features^1,3,4

Abdominal pain
Vomiting
Diarrhea > constipation
Cervical lymphadenopathy
Aphthous ulcers
Rarely peritonitis
Arthralgia/polyarthritis

Predominant ethnic distribution⁹

All ethnicities

Worldwide prevalence or number of cases¹²

>1000

Gene mutation⁴

TNFRSF1A, autosomal dominant inheritance

Typical age at onset^4,13

Varies; <3 years to <20 years

Median delay in diagnosis^16†

Can be >10 years

Duration of attacks¹⁷

7 to 28 days; nearly continuous in one-third of patients

Frequency of attacks²⁰

Irregular; 5 weeks to months or years

Cutaneous findings⁶

Erythematous, migratory rash
Often overlies an area of myalgia and migrates together in a centrifugal pattern
Often found on the torso or extremity

Other select clinical features^1,3

Abdominal pain
Arthralgia
Arthritis in large joints
Peritonitis
Diarrhea
Constipation
Musculoskeletal pain
Eye manifestations, such as periorbital edema
Migratory myalgia and erythema

Predominant ethnic distribution⁹

Mostly European

Worldwide prevalence or number of cases¹⁰*

<1 in 1,000,000

Gene mutation⁴

NLRP3, autosomal dominant inheritance

Typical age at onset⁴

<1 year

Median delay in diagnosis^21†

Can be >10 years (FCAS & MWS)

Duration of attacks⁹

12 to 24 hours

Frequency of attacks²²

Variable; triggered by generalized cold exposure

Cutaneous findings^22,24

Urticaria-like appearance
Typically raised, erythematous, maculopapular, usually nonpruritic
Described by patients as feeling painful, tight, and/or warm
Severity worsening in the evening
Usually appears on the trunk and limbs with individual migratory lesions

Other select clinical features^3,4

Headache
Arthralgia
Fatigue
Myalgia
Conjunctivitis
Nausea

Predominant ethnic distribution⁹

Mostly European

Worldwide prevalence or number of cases¹⁰*

<1 in 1,000,000

Gene mutation⁴

NLRP3, autosomal dominant inheritance

Typical age at onset⁴

<20 years

Median delay in diagnosis^21†

Can be >10 years (FCAS & MWS)

Duration of attacks⁹

2 to 3 days

Frequency of attacks²²

Variable; triggered by cold, fatigue, and stress

Cutaneous findings^22,24

Urticaria-like appearance
Typically raised, erythematous, maculopapular, usually nonpruritic
Described by patients as feeling painful, tight, and/or warm
Severity worsening in the evening
Usually appears on the trunk and limbs with individual migratory lesions

Other select clinical features^3,4

Occasional abdominal pain
Headache
Arthralgia
Fatigue
Conjunctivitis
Sensorineural hearing loss

Predominant ethnic distribution⁹

All ethnicities

Worldwide prevalence or number of cases¹⁰*

<1 in 1,000,000

Gene mutation^4,10

NLRP3, autosomal dominant inheritance

Typical age at onset¹⁰

<1 year

Median delay in diagnosis^21†

Can be 2 years

Duration and frequency of attacks²³

Periodicity of the attacks is lost and, instead, there is a low-level continuous disease activity, with an occasional disease flare-up

Cutaneous findings⁵

Neutrophilic urticarial skin lesions

Other select clinical features^5,9

Most severe end of CAPS spectrum
Neurological involvement is a diagnostic feature; chronic aseptic neutrophilic meningitis with chronic irritability, headache, and seizures
Sensorineural hearing loss
Progressive vision loss
Conjunctivitis
“Typical facies” with frontal bossing, large cephalic perimeter, and the appearance of a “saddleback nose” in patients with hydrocephalus
Chronic aseptic meningitis
Cognitive delay

Image Sources: (FMF) Reproduced with permission from Arch Dermatol. 1976. 112(3):364-366. Copyright©(1976) American Medical Association. All rights reserved. (HIDS/MKD) Reprinted from Am J Kidney Dis, 48, Rainer Siewert, Jörg Ferber, Rolf Dieter Horstmann, Christof Specker, Peter Julius Heering, Christian Timmann, Hereditary periodic fever with systemic amyloidosis: is hyper-IgD syndrome really a benign disease?, e41-e45, Copyright (2006), with Permission from American Journal of Kidney Diseases. Reprinted from The Lancet, 48, Rainer Siewert, Jörg Ferber, Rolf Dieter Horstmann, Christof Specker, Peter Julius Heering, Christian Timmann, Hereditary periodic fever with systemic amyloidosis: is hyper-IgD syndrome really a benign disease?, e41-e45, Copyright (2006), with permission from Elsevier. (TRAPS) Reprinted with permission from The Journal of Rheumatology, Krelenbaum M, et al. J Rheumatol 2010;37(8):1780-1782. All rights reserved. (CAPS: FCAS) Reprinted from Textbook of Pediatric Rheumatology, 6, Karyl Barron, Balu Athreya, Daniel Kastner, Periodic Fever Syndromes And Other Inherited Autoinflammatory Diseases, 642-660, Copyright (2011), with permission from Elsevier. Reprinted from The Lancet, 6, Karyl Barron, Balu Athreya, Daniel Kastner, Periodic Fever Syndromes And Other Inherited Autoinflammatory Diseases, 642-660, Copyright (2011), with permission from Elsevier. (CAPS: MWS) Reprinted from Textbook of Pediatric Rheumatology, 6, Karyl Barron, Balu Athreya, Daniel Kastner, Periodic Fever Syndromes And Other Inherited Autoinflammatory Diseases, 642-660, Copyright (2011), with permission from Elsevier. Reprinted from The Lancet, 6, Karyl Barron, Balu Athreya, Daniel Kastner, Periodic Fever Syndromes And Other Inherited Autoinflammatory Diseases, 642-660, Copyright (2011), with permission from Elsevier. (CAPS: NOMID) Reprinted from Textbook of Pediatric Rheumatology, 6, Karyl Barron, Balu Athreya, Daniel Kastner, Periodic Fever Syndromes And Other Inherited Autoinflammatory Diseases, 642-660, Copyright (2011), with permission from Elsevier. Reprinted from The Lancet, 6, Karyl Barron, Balu Athreya, Daniel Kastner, Periodic Fever Syndromes And Other Inherited Autoinflammatory Diseases, 642-660, Copyright (2011), with permission from Elsevier.

*Prevalence includes patients with FCAS, MWS, and NOMID.

^†Delay in diagnosis based off of a study.

Autoinflammatory Diseases Comparison Chart

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Treatment Goals for PFS

Timely diagnosis and effective treatment are imperative for patients with PFS²⁵

Due to the similarities and overlap among PFS symptoms with other diseases and conditions, it may take a long time for patients to be correctly diagnosed²⁶
A clinical, differential diagnosis of PFS can be made by excluding other diseases, determining inheritance patterns, and analyzing symptomatology specific to each disease. Genetic testing is not required²⁷
Even when there are no overt symptoms, some patients might experience ongoing, subclinical inflammation⁴

International Treatment Recommendations for HIDS/MKD, TRAPS, and CAPS^25‡

Rapid and early control of disease activity

Prevention of disease- and treatment-related damage

Enable or improve participation in daily activities

Improve health-related quality of life

^‡Per the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) taskforce.

Currently, no US-based treatment guidelines exist

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Read about Still’s disease, a rare polygenic disease, and the features that can aid in diagnosis

IDENTIFY STILL’S DISEASE

CAPS=cryopyrin-associated periodic syndromes; CRP=C-reactive protein; ESR=erythrocyte sedimentation rate; FCAS=familial cold autoinflammatory syndrome; FMF=familial Mediterranean fever; HIDS=hyperimmunoglobulin D syndrome; IL-1β=interleukin 1 beta; MKD=mevalonate kinase deficiency; MWS=Muckle-Wells syndrome; NOMID=neonatal-onset multisystem inflammatory disease; PFS=periodic fever syndromes; SAA=serum amyloid A; TRAPS=tumor necrosis factor receptor–associated periodic syndrome.

References: 1. Jesus AA, Oliveira JB, Hilário MOE, et al. Pediatric hereditary autoinflammatory syndromes. J Pediatr (Rio J). 2010;86(5):353-366. doi:10.2223/JPED.2015 2. Church LD, Cook GP, McDermott MF. Primer: inflammasomes and interleukin 1β in inflammatory disorders. Nat Clin Pract Rheumatol. 2008;4(1):34-42. doi:10.1038/ncprheum0681 3. Barron KS, Kastner DL. Periodic fever syndromes and other inherited autoinflammatory diseases. In: Petty RE, Laxer RM, Lindsley CB, Wedderburn LR, eds. Textbook of Pediatric Rheumatology. 7th ed. Elsevier; 2016:609-626. 4. Hoffman HM, Simon A. Recurrent febrile syndromes—what a rheumatologist needs to know. Nat Rev Rheumatol. 2009;5(5):249-256. doi:10.1038/nrrheum.2009.40 5. Almeida de Jesus A, Goldbach-Mansky R. Monogenic autoinflammatory diseases: concept and clinical manifestations. Clin Immunol. 2013;147(3):155-174. doi:10.1016/j.clim.2013.03.016 6. Hull KM, Drewe E, Aksentijevich I, et al. The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder. Medicine (Baltimore). 2002;81(5):349-368. doi:10.1097/00005792-200209000-00002 7. Samuels J, Aksentijevich I, Torosyan Y, et al. Familial Mediterranean fever at the millennium clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore). 1998;77(4):268-297. doi:10.1097/00005792-199807000-00005 8. Erbis G, Sergiichuk T, Benseler SM, Hansmann S, Kuemmerle-Deschner J. Determinants of health-related quality of life in children and adults with autoinflammatory diseases. Pediatr Rheumatol. 2015;13(suppl 1):P174. doi:10.1186/1546-0096-13-S1-P174 9. Kastner DL. Hereditary periodic fever syndromes. Hematology Am Soc Hematol Educ Program. 2005:74-81. doi:10.1182/asheducation-2005.1.74 10. Ciccarelli F, De Martinis M, Ginaldi L. An update on autoinflammatory diseases. Curr Med Chem. 2014;21(3):261-269. doi:10.2174/09298673113206660303 11. Haas D, Hoffmann GF. Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome. Orphanet J Rare Dis. 2006;1:13. doi:10.1186/1750-1172-1-13 12. Genetics Home Reference. Tumor necrosis factor receptor-associated periodic syndrome. US National Library of Medicine; 2020. Accessed March 10, 2020. https://ghr.nlm.nih.gov/condition/tumor-necrosis-factor-receptor-associated-periodic-syndrome 13. Hausmann JS, Dedeoglu F. Autoinflammatory diseases in pediatrics. Dermatol Clin. 2013;31(3):481-494. doi:10.1016/j.det.2013.04.003 14. Lidar M, Livneh A. Familial Mediterranean fever: clinical, molecular and management advancements. Neth J Med. 2007;65(9):318-324. 15. van der Hilst JCH, Frenkel J. Hyperimmunoglobulin D syndrome in childhood. Curr Rheumatol Rep. 2010;12(2):101-107. doi:10.1007/s11926-010-0086-1 16. Lachmann HJ, Papa R, Gerhold K, et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis. 2014;73(12):2160-2167. doi:10.1136/annrheumdis-2013-204184 17. Lachmann HJ, Hawkins PN. Developments in the scientific and clinical understanding of autoinflammatory disorders. Arthritis Res Ther. 2009;11(1):212. doi:10.1186/ar2579 18. Zadeh N, Getzug T, Grody WW. Diagnosis and management of familial Mediterranean fever: integrating medical genetics in a dedicated interdisciplinary clinic. Genet Med. 2011;13(3):263-269. doi:10.1097/GIM.0b013e31820e27b1 19. van der Burgh R, ter Haar NM, Boes ML, Frenkel J. Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clin Immunol. 2013;147(3):197-206. doi:10.1016/j.clim.2012.09.011 20. Kimberley FC, Lobito AA, Siegel RM, Screaton GR. Falling into TRAPS — receptor misfolding in the TNF receptor 1-associated periodic fever syndrome. Arthritis Res Ther. 2007;9(4):217. doi:10.1186/ar2197 21. Mehr S, Allen R, Boros C, et al. Cryopyrin-associated periodic syndrome in Australian children and adults: epidemiological, clinical and treatment characteristics. J Paediatr Child Health. 2016;52(9):889-895. doi:10.1111/jpc.13270 22. Hoffman HM. Hereditary immunologic disorders caused by pyrin and cryopyrin. Curr Allergy Asthma Rep. 2007;7(5):323-330. doi:10.1007/s11882-007-0049-4 23. Church LD, Savic S, McDermott MF. Long term management of patients with cryopyrin-associated periodic syndromes (CAPS): focus on rilonacept (IL-1 Trap). Biologics. 2008;2(4):733-742. doi:10.2147/btt.s3167 24. Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep. 2011;11(1):12-20. doi:10.1007/s11882-010-1060-9 25. ter Haar NM, Oswald M, Jeyaratnam J, et al. Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis. 2015;74(9):1636-1644. doi:10.1136/annrheumdis-2015-207546 26. Marcuzzi A, Piscianz E, Kleiner G, et al. Clinical genetic testing of periodic fever syndromes. Biomed Res Int. 2013;2013:501305. doi:10.1155/2013/501305 27. Ozen S, Bilginer Y. A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol. 2014;10(3):135-147. doi:10.1038/nrrheum.2013.174

AUTOINFLAMMATORY DISEASES

Monogenic Diseases

Most Periodic Fever Syndromes (PFS) Are Autoinflammatory Diseases Driven by an Excess of Proinflammatory Cytokines, Including IL-1β1,2

Characteristics of 6 Types of Monogenic PFS

Skin Manifestations

Predominant ethnic distribution9

Worldwide prevalence or number of cases10

Gene mutation4

Typical age at onset4

Mean delay in diagnosis14

Duration of attacks9

Frequency of attacks18

Cutaneous findings7

Other select clinical features1,4

Skin Manifestations

Predominant ethnic distribution9

Worldwide prevalence or number of cases11

Gene mutation4

Typical age at onset4

Median delay in diagnosis15†

Duration of attacks9

Frequency of attacks19

Cutaneous findings3

Other select clinical features1,3,4

Skin Manifestations

Predominant ethnic distribution9

Worldwide prevalence or number of cases12

Gene mutation4

Typical age at onset4,13

Median delay in diagnosis16†

Duration of attacks17

Frequency of attacks20

Cutaneous findings6

Other select clinical features1,3

Skin Manifestations

Predominant ethnic distribution9

Worldwide prevalence or number of cases10*

Gene mutation4

Typical age at onset4

Median delay in diagnosis21†

Duration of attacks9

Frequency of attacks22

Cutaneous findings22,24

Other select clinical features3,4

Skin Manifestations

Predominant ethnic distribution9

Worldwide prevalence or number of cases10*

Gene mutation4

Typical age at onset4

Median delay in diagnosis21†

Duration of attacks9

Frequency of attacks22

Cutaneous findings22,24

Other select clinical features3,4

Skin Manifestations

Predominant ethnic distribution9

Worldwide prevalence or number of cases10*

Gene mutation4,10

Typical age at onset10

Median delay in diagnosis21†

Duration and frequency of attacks23

Cutaneous findings5

Other select clinical features5,9

Treatment Goals for PFS

Timely diagnosis and effective treatment are imperative for patients with PFS25

International Treatment Recommendations for HIDS/MKD, TRAPS, and CAPS25‡

Most Periodic Fever Syndromes (PFS) Are Autoinflammatory Diseases Driven by an Excess of Proinflammatory Cytokines, Including IL-1β^1,2

Predominant ethnic distribution⁹

Worldwide prevalence or number of cases¹⁰

Gene mutation⁴

Typical age at onset⁴

Mean delay in diagnosis¹⁴

Duration of attacks⁹

Frequency of attacks¹⁸

Cutaneous findings⁷

Other select clinical features^1,4

Predominant ethnic distribution⁹

Worldwide prevalence or number of cases¹¹

Gene mutation⁴

Typical age at onset⁴

Median delay in diagnosis^15†

Duration of attacks⁹

Frequency of attacks¹⁹

Cutaneous findings³

Other select clinical features^1,3,4

Predominant ethnic distribution⁹

Worldwide prevalence or number of cases¹²

Gene mutation⁴

Typical age at onset^4,13

Median delay in diagnosis^16†

Duration of attacks¹⁷

Frequency of attacks²⁰

Cutaneous findings⁶

Other select clinical features^1,3

Predominant ethnic distribution⁹

Worldwide prevalence or number of cases¹⁰*

Gene mutation⁴

Typical age at onset⁴

Median delay in diagnosis^21†

Duration of attacks⁹

Frequency of attacks²²

Cutaneous findings^22,24

Other select clinical features^3,4

Predominant ethnic distribution⁹

Worldwide prevalence or number of cases¹⁰*

Gene mutation⁴

Typical age at onset⁴

Median delay in diagnosis^21†

Duration of attacks⁹

Frequency of attacks²²

Cutaneous findings^22,24

Other select clinical features^3,4

Predominant ethnic distribution⁹

Worldwide prevalence or number of cases¹⁰*

Gene mutation^4,10

Typical age at onset¹⁰

Median delay in diagnosis^21†

Duration and frequency of attacks²³

Cutaneous findings⁵

Other select clinical features^5,9

Timely diagnosis and effective treatment are imperative for patients with PFS²⁵

International Treatment Recommendations for HIDS/MKD, TRAPS, and CAPS^25‡