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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.
FACTS ABOUT FMF
- Rare, hereditary autoinflammatory disease characterised by:10
Recurrent short-term fever attacks
With peritonitis (95%)
With arthritis (>50%)
With pleuritis (40%)
- Length of typical attack is 1–3 days10
- Frequency of attacks ranges from days to years11
Find out more about manifestations of FMF, who it affects and what the long-term implications are:
FACTS ABOUT HIDS/MKD
- Hereditary metabolic inflammatory disease caused by mutations in MVK, which affect the mevalonate pathway1,6
- Symptoms include:
Fever attacks
Abdominal pain
Lymphadenopathy
Arthralgia
Diarrhoea & vomiting
Skin lesions
Aphthous ulcers
- Median age of the first attack is 6 months
- Frequency of attacks decreases with age; however, 50% of patients over the age of 20 still have ≥6 attacks per year7
- Length of typical attack is 3–7 days12
- Episodes generally occur once a month, however, the length of time between episodes can range from days to years11
- Amyloidosis is a rare but serious long-term complication of the disease7
FACTS ABOUT TRAPS
- Hereditary autoinflammatory disease caused by mutations in TNFRSF1A1,6
- The disease is characterised by:1
Recurrent fever attacks
Abdominal pain
Myalgia
Arthralgia
- Length of typical attack is 3 weeks13
- Frequency of attacks is 6 weeks to every few years14
- Amyloidosis can be a long-term complication of the disease3,4
FACTS ABOUT CAPS
- 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
Treatment goals for periodic fever syndromes
The goals of treatment include early, rapid and sustained control of disease activity to prevent amyloidosis or other long-term complications.1,2,5,18
View the treatment goals for specific syndromes below.
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 (abdominal cramps, 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
- Early use of colchicine is recommended to control recurrent attacks and prevent amyloidosis21
If resistant or intolerant to colchicine or experience only a partial response22,23
- EULAR recommendations and the literature state that treatment with an IL-1-blocking biologic is a valid therapeutic option for these patients2,4,21
SHARE recommendations for HIDS/MKD1
- 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
If frequent attacks and/or subclinical inflammation between attacks
- Maintenance therapy with IL-1 blockade or etanercept† is recommended and may limit corticosteroid exposure
If chosen biological agent is ineffective or intolerable
- A switch to another IL-1 blocking agent or another biological agent† should be considered
SHARE recommendations for TRAPS1
- 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
If frequent attacks and/or subclinical inflammation between attacks
- Maintenance therapy with IL-1 blockade or etanercept‡ is recommended and may limit corticosteroid exposure
If chosen biological agent is ineffective or intolerable
- 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
SHARE recommendations for CAPS1
- 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 is recommended by EULAR as a first-line treatment but is not licensed to treat FMF within its current UK marketing authorisation.18
†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; 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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- Genetics Home Reference. Familial Mediterranean fever. Available at: https://ghr.nlm.nih.gov/condition/familial-mediterranean-fever [Accessed August 2022].
- Living with Periodic Fevers. HIDS: Hyperimmunoglobulinemia D syndrome. Available at: https://www.periodicfevers.com/thescience/hids/ [Accessed August 2022].
- Living with Periodic Fevers. TRAPS: Tumor necrosis factor receptor associated periodic syndrome. Available at: https://www.periodicfevers.com/thescience/traps/ [Accessed August 2022].
- Genetics Home Reference. Tumor necrosis factor receptor-associated periodic syndrome. Available at: https://medlineplus.gov/genetics/condition/tumor-necrosis-factor-recepto... [Accessed August 2022].
- Kuemmerle-Deschner JB, et al. Ann Rheum Dis 2011;70(12):2095–2102.
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- Lachmann HJ, et al. Arthritis Rheum 2011;63(2):314–324.
- 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.
- Özen S, et al. Ann Rheum Dis 2016;75(4):644–651.
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- Eroglu FK, et al. Rheumatol Int 2015;35(10):1733–1737.