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.

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:

Learn more

FACTS ABOUT HIDS/MKD

Hereditary metabolic inflammatory disease caused by mutations in MVK, which affect the mevalonate pathway^1,6
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 TNFRSF1A^1,6
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 disease^3,4

FACTS ABOUT CAPS

Spectrum of rare, lifelong genetic autoinflammatory diseases with significant morbidity^15–17
Overproduction of IL-1β in CAPS patients elicits inflammatory responses¹⁷
CAPS comprise three phenotypes with increasing severity:^9,15,16

Diagram 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 long-term complications.^1,2,5,18

Diagram representing the overarching principles for the management of FMF, HIDS/MKD, TRAPS and CAPS. Early, rapid and sustained control of disease activity, prevention of disease- and treatment-related organ damage and early participation in daily activities and improved HRQoL

View the treatment goals for specific syndromes below.

Colchicine alone may not be effective in treating FMF¹⁸

Image representing Colchicine resistance. Icon of a calendar and text reading 'Resistance'.

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

Image representing Amyloidosis. Icon of a flame and text reading 'Amyloidosis'

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 response^22,23

Flow chart downward arrow.

EULAR recommendations and the literature state that treatment with an IL-1-blocking biologic is a valid therapeutic option for these patients^2,4,21

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

Flow chart downward arrow.

Maintenance therapy with IL-1 blockade or etanercept^† is recommended and may limit corticosteroid exposure

If chosen biological agent is ineffective or intolerable

Flow chart downward arrow.

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

Flow chart downward arrow.

Maintenance therapy with IL-1 blockade or etanercept^‡ is recommended and may limit corticosteroid exposure

If chosen biological agent is ineffective or intolerable

Flow chart downward arrow.

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.

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UK | August 2022 | 223196

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