Periodic fever syndromes
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.1–7
Fever
Rash
Arthralgia
Myalgia
Increased inflammatory markers (SAA, CRP, ESR, leucocytosis)
Impairment of QOL with limitations on daily activities and education
Sustained inflammation can lead to severe long-term complications such as amyloidosis and hearing loss
The underlying mechanism of PFS involves the activation and overproduction of IL-1β, which is an essential mediator of the inflammatory response in periodic fever syndromes.8,9
Find out more about the periodic fever syndromes below.
Rare, hereditary autoinflammatory disease characterised by:10
Length of typical attack is 1–3 days10
Frequency of attacks ranges from days to years11
Hereditary metabolic inflammatory disease caused by mutations in MVK, which affect the mevalonate pathway1,6
Symptoms include:
Median age of the first attack is 6 months7
Frequency of attacks decreases with age; however, 50% of patients over the age of 20 still have ≥6 attacks per year7
The disease is characterised by recurrent fever attacks which tend to last 3–7 days12
Episodes generally occur every 2–8 weeks but the length of time between episodes can vary from person to person12,13
Amyloidosis is a rare but serious long-term complication of the disease7
Hereditary autoinflammatory disease caused by mutations in TNFRSF1A1,6
The disease is characterised by:1
Length of attack is typically up to 3 weeks12,14
Frequency of attacks is 6 weeks to every few years14
Amyloidosis can be a long-term complication of the disease3,4
Spectrum of rare, lifelong genetic autoinflammatory diseases with significant morbidity15–17
Overproduction of IL-1β in CAPS patients elicits inflammatory responses17
CAPS comprise three phenotypes with increasing severity:9,15,16
Facts about FMF
Recurrent short-term fever attacks
With peritonitis (95%)
With arthritis (>50%)
With pleuritis (40%)
Find out more about manifestations of FMF, who it affects and what the long-term implications are.
Facts about HIDS/MKD
Fever attacks
Abdominal pain
Lymphadenopathy
Arthralgia
Diarrhoea & vomiting
Skin lesions
Aphthous ulcers
Facts about TRAPS
Recurrent fever attacks
Abdominal pain
Myalgia
Arthralgia
Facts about CAPS
Treatment goals for periodic fever syndromes
The goals of treatment include early as possible, rapid and sustained control of disease activity to prevent amyloidosis or other long-term complications.1,2,5,18
Overarching principles for the management of FMF, HIDS/MKD, TRAPS and CAPS1,2,5,18
Early as possible, rapid and sustained control of disease activity
Prevention of disease- and treatment-related organ damage
Early participation in daily activities and improved HRQoL
View the treatment goals for specific syndromes below.
Early use of colchicine is recommended to control recurrent attacks and prevent amyloidosis21
EULAR recommendations and the literature state that treatment with IL-1-blocking biologics may be a valid therapeutic option for these patients2,4,21
NSAIDs may provide symptom relief during inflammatory attacks
Short-term glucocorticosteroids, with or without NSAIDs, may be effective for alleviating inflammatory attacks
Short-term IL-1 blockade may be effective for terminating inflammatory attacks and should be considered to limit or prevent steroid side effects
Maintenance therapy with IL-1 blockade or etanercept† is recommended and may limit corticosteroid exposure
A switch to another IL-1 blocking agent or another biological agent† should be considered
NSAIDs may provide symptom relief during inflammatory attacks
Short-term glucocorticosteroids, with or without NSAIDs, may be effective for alleviating inflammatory attacks
IL-1 blockade is beneficial in the majority of patients with TRAPS
Etanercept‡ can be effective in some patients, but the effect might decline over time
Maintenance therapy with IL-1 blockade or etanercept‡ is recommended and may limit corticosteroid exposure
If one IL-1 blocking agent at adequate dose is ineffective or intolerable, a switch to etanercept‡ or another IL-1 blocking agent should be considered. Likewise, if etanercept‡ is ineffective or intolerable, a switch to an IL-1 blocking agent should be considered
IL-1 inhibition is indicated for the whole spectrum of CAPS, at any age
To prevent organ damage, long-term IL-1 inhibition should be started as early as possible in patients with active disease
There is no evidence for the efficacy of DMARDs or biological therapy other than IL-1 blockade in CAPS
For symptomatic adjunctive therapy, short courses of NSAIDs and corticosteroids may be used, but they should not be used for primary maintenance therapy
Colchicine alone may not be effective in treating FMF18
Colchicine resistance is defined as either recurrent clinical attacks (average ≥1 attacks per month over a three-month period) or persistently elevated CRP or SAA in between attacks.*19 An estimated 5–10% of patients continue to experience attacks despite a maximal dose of colchicine.20
In some cases, the optimal colchicine dose cannot be reached due to intolerance (cramping, abdominal pain, hyperperistalsis, diarrhoea or vomiting).*21 An estimated further 5–10% of patients experience serious side effects with colchicine.20
Amyloidosis develops as a consequence of persistent inflammation, which may be a manifestation of colchicine resistance.*19
EULAR recommendations for FMF
If resistant or intolerant to colchicine or experience only a partial response22,23
*Colchicine is recommended by EULAR as a first-line treatment but is not licensed to treat FMF within its current UK marketing authorisation.21
SHARE recommendations for HIDS/MKD1
If frequent attacks and/or subclinical inflammation between attacks
If chosen biological agent is ineffective or intolerable
†TNF inhibitors, including etanercept, are not licensed for the treatment of HIDS/MKD.
SHARE recommendations for TRAPS1
If frequent attacks and/or subclinical inflammation between attacks
If chosen biological agent is ineffective or intolerable
‡TNF inhibitors, including etanercept, are not licensed for the treatment of TRAPS.
SHARE recommendations for CAPS1
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; PFS, periodic fever syndromes; QoL, quality of life; SAA, serum amyloid A; TNF, tumour necrosis factor; TRAPS, tumour necrosis factor receptor-associated periodic syndrome.
References
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de Moraes MPM, et al. Brain Sci 2023;13(9):1351.
National Organization for Rare Disorders. Mevalonate Kinase Deficiency. Available at: https://rarediseases.org/rare-diseases/hyper-igd-syndrome/ [Accessed March 2025].
Genetics Home Reference. Tumor necrosis factor receptor-associated periodic syndrome. Available at: https://medlineplus.gov/genetics/condition/tumor-necrosis-factor-recepto... [Accessed March 2025].
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Özen S, et al. Semin Arthritis Rheum 2017;47(1):115–120.
Özen S, et al. Pediatric Rheumatology 2019;17(Suppl 1):18. Abstract 008. 10th Congress of International Society of Systemic Auto-Inflammatory Diseases (ISSAID).
Kacar M, et al. J Inflamm Res 2020;13:141–149.
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UK | March 2025 | FA-11324196
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Welcome to Pro.Novartis.com
The Novartis portal for UK healthcare professionals (HCPs) and other relevant decision makers* is where you can find promotional information about Novartis products, therapy area materials and professional resources.
*Other relevant decision makers particularly includes those with an NHS role who could influence in any way the administration, consumption, prescription, purchase, recommendation, sale, supply or use of any medicine but who are not health professionals.
This website is designed to be viewed on desktop.