What are periodic fever syndromes?

Periodic fever syndromes, which include familial Mediterranean fever (FMF), hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndromes (CAPS), are rare autoinflammatory diseases that are characterised by unprovoked, periodic febrile episodes lasting from a few days to a few weeks.1–8

Disease characteristics2–8

  • Symptoms commonly include fever, rash, arthralgia and myalgia

  • Increased levels of inflammatory markers (SAA, CRP, ESR and leucocytosis)

  • Impairment of quality of life regarding physical and psychosocial activities, with limitations in education and daily activities

  • Sustained inflammation can lead to potentially severe long-term disease related complications, such as amyloidosis and hearing loss

IL-1β is an essential mediator of the inflammatory response in periodic fever syndromes. The underlying mechanism of these diseases involves the activation and overproduction of IL-1β.9,10

  • FMF is a rare, hereditary autoinflammatory disease characterised by recurrent, short-term fever attacks with peritonitis (95%), arthritis (>50%) and pleuritis (40%).11
  • Other manifestations include pericarditis, scrotal swelling, myalgia and erysipeloid skin rash.11
  • The disease is common among ethnic groups originating in the Mediterranean region.11
  • The first attack appears before the age of 20 in more than 85% of patients.11
  • Amyloid A amyloidosis is a long-term complication of the disease.11
Length of typical attack 1–3 days11
Frequency of attacks Varies from days to years12

Icons depicting the symptoms of FMF

 
  • HIDS/MKD is a hereditary metabolic inflammatory disease caused by mutations in MVK, which affect the mevalonate pathway.2,7
  • Symptoms include fever attacks, lymphadenopathy, abdominal pain, arthralgia, diarrhoea, vomiting, skin lesions and aphthous ulcers.8
  • The median age of the first attack is 6 months. The frequency of attacks decreases with age; however, 50% of patients over the age of 20 still have 6 or more attacksper year.8
  • Amyloidosis is a rare but serious long-term complication of the disease.8
Length of typical attack 3–7 days13
Frequency of attacks 2–8 weeks13

 Icons depicting the symptoms of HIDS/MKD

 
  • TRAPS is a hereditary autoinflammatory disease caused by mutations in TNFRSF1A.2,7
  • The disease is characterised by recurrent fever attacks, as well as symptoms such as arthralgia, myalgia and abdominal pain.2
  • Amyloidosis can be a long-term complication of the disease.4,5
Length of typical attack 3 weeks14
Frequency of attacks 6 weeks to every few years15

 Icons depicting the symptoms of TRAPS

 
  • CAPS are a spectrum of rare, lifelong genetic autoinflammatory diseases with significant morbidity.16–18
  • Overproduction of IL-1β in CAPS patients elicits inflammatory responses.18
  • CAPS comprise three phenotypes with increasing severity10,16,17:

 

Image showing the spectrum of CAPS phenotypes from mild to severe

Treatment goals for periodic fever syndromes

The goals of treatment include early, rapid and sustained control of disease activity to prevent amyloidosis or other complications.2,3,6,20

Diagram showing overarching principles for the management of FMF, HIDS/MKD, TRAPS and CAPS

Colchicine alone may not be effective in treating FMF20


Text reading 'Resistance' and an icon of a calendar

Colchicine resistance is defined as either recurrent clinical attacks (average one or more attacks per month over a three-month period) or persistently elevated CRP or SAA in between attacks.21* An estimated 5–10% of patients continue to experience attacks despite a maximal dose of colchicine.22

 

 

 

 

Text reading 'Intolerance' and an icon of the digestive systemIn some cases, the optimal colchicine dose cannot be reached due to intolerance (abdominal cramps, hyperperistalsis, diarrhoea or vomiting).19* An estimated further 5–10% of patients experience serious side effects with colchicine.22

 

 

 

 

Text reading 'Amyloidosis' and an icon of a flame

Amyloidosis develops as a consequence of persistent inflammation, which may be a manifestation of colchicine resistance.21*

 

 

 

 

 

EULAR recommendations for FMF

Flow chart showing EULAR recommendations for the treatment of FMF

SHARE recommendations for HIDS/MKD2

Flow chart showing SHARE recommendations for the treatment of HIDS/MKD

SHARE recommendations for TRAPS2

Flow chart showing SHARE recommendations for the treatment of TRAPS

SHARE recommendations for CAPS2

Flow chart showing SHARE recommendations for the treatment of CAPS

TNF inhibitors, including etanercept, are not licensed for the treatment of HIDS/MKD.

TNF inhibitors, including etanercept, are not licensed for the treatment of TRAPS.

CAPS, cryopyrin-associated periodic syndromes; CRP, C-reactive protein; FMF, familial Mediterranean fever; ESR, erythrocyte sedimentation rate; EULAR, European League Against Rheumatism; HIDS, hyperimmunoglobulin D syndrome; HRQoL, health-related quality of life; IL, interleukin; MKD, mevalonate kinase deficiency; NSAID, non-steroidal anti-inflammatory drug; SAA, serum amyloid A; TRAPS, tumour necrosis factor receptor-associated periodic syndrome.

References     

  1. De Benedetti F et al. N Engl J Med 2018;378(20):1908–1919.
  2. ter Haar NM et al. Ann Rheum Dis 2015;74(9):1636–1644.
  3. Vitale A et al. Mediators Inflamm 2013;2013:939847.
  4. Samuels J, Ozen S. Curr Opin Rheumatol 2006;18(1):108–117.
  5. Ozen S, Bilginer Y. Nat Rev Rheumatol 2014;10(3):135–147.
  6. Shohat M, Halpern GJ. Genet Med. 2011;13(6):487–498.
  7. Rigante D et al. Clin Rheumatol 2014;33(9):1197–1207.
  8. van der Hilst JCH et al. Medicine 2008;87(6):301–310.
  9. Jesus AA, Goldbach-Mansky R. Annu Rev Med 2014;65:223–244.
  10. Toker O, Hashkes PJ. Biologics 2010;4:131–138.
  11. Wang DQH et al. J Genet Syndr Gene Ther 2014;5(5):1–11.
  12. Genetics Home Reference. Familial Mediterranean fever. Available at: https://ghr.nlm.nih.gov/condition/familial-mediterranean-fever[Accessed May 2020].
  13. Living with Periodic Fevers. HIDS: Hyperimmunoglobulinemia D syndrome. Available at: https://www.periodicfevers.com/thescience/hids/[Accessed May 2020].
  14. Living with Periodic Fevers. TRAPS: Tumor necrosis factor receptor associated periodic syndrome. Available at: https://www.periodicfevers.com/thescience/traps/ [Accessed May 2020].
  15. Genetics Home Reference. Tumor necrosis factor receptor-associated periodic syndrome. Available at: https://ghr.nlm.nih.gov/condition/tumor-necrosis-factor-receptor-associa... [Accessed May 2020].
  16. Kuemmerle-Deschner JB et al. Ann Rheum Dis 2011;70(12):2095–2102.
  17. Church LD, McDermott MF. Expert Rev Clin Immunol 2010;6(6):831–841.
  18. Lachmann HJ et al. Arthritis Rheum 2011;63(2):314–324.
  19. Ozen S et al. Ann Rheum Dis 2016;75(4):644–651.
  20. Ozen S et al. Semin Arthritis Rheum 2017;47(1):115–120.
  21. Ozen S et al. Pediatric Rheumatology 2019;17(Suppl 1):18. Abstract 008. 10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID).
  22. Kacar M et al. J Inflamm Res 2020;13:141–149.
  23. ter Haar N et al. Ann Rheum Dis 2013;72(5):678–685.
  24. Eroglu FK et al. Rheumatol Int 2015;35(10):1733–1737.
ILA20-C008c September 2020.
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