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Periodic fevers and autoinflammatory conditions
SYMPOSIUM: INFECTION (& IMMUNITY)
Periodic fevers and autoinflammatory conditions
1:3 to 1:5, most AIS are rare. Less than 200 families have been reported with tumour necrosis factor (TNF) receptor associated periodic syndrome (TRAPS) worldwide, 100 cases of Familial cold autoinflammatory syndrome (FCAS) and MuckleeWells Syndrome (MWS) have been reported mainly in Europe and North America. There are less than 10 families reported to have Majeed syndrome mostly arising from Jordan.
Jyoti Bakshi Nick Wilkinson
Pathogenesis
Abstract
In contrast to autoimmune diseases, which are generally regarded as being mediated by the adaptive immune system, AIS are disorders of the innate immune system. Innate immunity not only serves to discriminate between “self” from “non-self” but serves as a system for sensing threat, by detecting specific danger signals, such as lipopolysaccharide or peptidoglycan, presented by pathogenic microbes or host derived molecules of cellular stress such as extracellular ATP. The small molecular motifs expressed by microbes are highly conserved through evolution and now known as PAMPs (Pathogen Associated Molecular Patterns). These are detected by intracellular pattern-recognition receptors (PRRs) such as Toll like receptors (TLRs) and nucleotide-binding oligomerization domain receptors, in short NOD-like receptors (NLRs), which are expressed by front line cells of the innate host defence including macrophages, monocytes, neutrophils and also lymphocytes of the adaptive immune system. This typically forms the first line of defence against infection. These receptors converge on a common set of signalling transcription factors that drive proinflammatory cytokine production. It is disruption of these pathways that result in AIS and increased levels of proinflammatory cytokines. Examples of such disruption to the innate immune system includes mutations of the NOD2 gene associated with Crohn’s disease and Blau syndrome, a sarcoid-like illness presenting in early childhood. Disruption of a molecular platform called the “inflammasome” which comprises NLRs, pyrin and CARDs (caspase activation and recruitment domain) results in gout and another form of AIS called cryopyrin-associated period syndrome (CAPS). This disruption results in excess interleukin-1b (IL-1b), a key proinflammatory cytokine.
Autoinflammatory syndromes (AIS) are a spectrum of immune-mediated disorders that typically present in childhood with recurrent fevers, high inflammatory markers and systemic involvement. The quintessential periodic fever is familial Mediterranean fever, which is relatively common in Middle Eastern populations, but in general, these conditions are rare and diagnostically challenging. As a group of conditions they are typified by a delay in diagnosis of several years with repeated hospital visits, unnecessary investigations and treatment, impact on quality of life and an increased risk of the most severe complication of systemic AA amyloidosis. The purpose of this review is to help clinicians suspect and diagnose AIS in children presenting with (recurrent) fevers or multisystem inflammation of unknown aetiology after common causes such as infection and autoimmune diseases have been excluded. We will identify when to consider AIS through a systematic approach of pattern recognition. We will discuss the presentation and differential diagnosis of recurrent fevers in neonates (the cryopyrinopathies), in childhood (hereditary periodic fevers) and pathognomonic rashes associated with AIS. Although, by no means exhaustive, we will also discuss other forms of AIS and provide an overview of the principles of treatment of AIS.
Keywords autoinflammatory syndromes; childhood; inflammasome; multisystem inflammation; recurrent fever
Introduction AIS are rare monogenetic childhood-onset disorders caused by mutations of genes coding for proteins that play a pivotal role in immune regulation especially of the innate immune system. The spectrum of recognised disorders and their gene defect can be found in Table 1. Most, when untreated, are characterised by lifelong, spontaneously relapsing bouts of fever and systemic inflammation with symptom-free intervals. Recurrent episodes of fever are associated with systemic inflammation typically affecting skin, joints, GI system or serous membranes. A diagnosis of AIS is suspected when a child presents with recurrent fevers of unknown aetiology and requires the exclusion of an underlying infection, neoplastic or autoimmune cause.
Assessment of possible AIS in a child with recurrent fever The salient features in the history of a child presenting with AIS would include recurrent self-limiting unexplained fevers often accompanied by a rash and possibly abdominal or limb pain. Family history, ethnicity, early onset of fever within first year of life and concomitant manifestations are also important clues to AIS. A thorough systemic examination including skin, joints and eyes during febrile periods is essential. High inflammatory markers (ESR/CRP) and a neutrophilia are typical during febrile episodes and normalise during disease free intervals. Blood and urine cultures are important to exclude an infectious cause. A urinalysis should be requested to screen for proteinuria which raises the possibility of secondary AA amyloidosis. Confirmation of AIS should be sought with genetic testing. However, it is important to remember that over 50% of AIS patients presenting with typical features have negative genetic results. Genetic tests are sent to a specialist centre for analysis. In the UK this is the National Amyloidosis centre at University College Hospital
Epidemiology Whereas the prototypical AIS, familial Mediterranean fever (FMF), has a carrier frequency in Middle Eastern populations of Jyoti Bakshi BSc MBBS MRCP is Rheumatology Registrar in the Rheumatology Department at the Nuffield Orthopedic Centre, Oxford, UK. Conflicts of interest: none. Nick Wilkinson MBChB MRCP MRCPCH DM is a Consultant Paediatrician and Paediatric Rheumatologist in the Rheumatology Department at Nuffield Orthopedic Centre, Oxford, UK. Conflicts of interest: none.
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Ó 2014 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INFECTION (& IMMUNITY)
The autoinflammatory syndromes Disease
Gene/Chromosome
Protein
Periodic fevers
FMF MKD TRAPS
MEFV/16p13.3 MVK/12q24 TNFRSF1A/12p13
Pyrin Mevalonate kinase p55 TNF receptor
Cryopyrinopathies
FCAS, MWS, CINCA
NLRP3
Cryopyrin
Granulomatous
Blau’s syndrome
CARD15/NOD2/16q12
CARD15
Pyogenic disorders
PAPA syndrome Majeed’s syndrome CROMO
PSTPIP1/15q24-q25.1 LPIN2/18p PSTP1P2/18p
PSTPIP1 LPIN2 PSTPIP2
Inflammatory bowel disease (IBD)
IBD 25 IBD 28
IL 10RB/21q22.11 IL 10RA/11q23.3
Interleukin 10 receptor beta Interleukin 10 receptor alpha
Note: FMF – familial Mediterranean fever; TRAPS – TNF receptor-associated periodic syndrome; MKD – mevalonate kinase deficiency; FCAS – familial cold autoinflammatory syndrome; MWS – Muckle-Wells syndrome; CINCA – chronic infantile neurologic cutaneous articular syndrome; PAPA – pyogenic arthritis pyoderma grangrenosa acne syndrome; CRMO – chronic recurrent multifocal osteomyelitis; IBD – inflammatory bowel disease.
Table 1
(www.ucl.ac.uk/amyloidosis) in London. Information about the latest genetic abnormalities is available on the In-Fever website at http://fmf.igh.cnrs.fr/ISSAID/infevers/.
Established AIS in the first year of life includes CINCA (chronic infantile neurological cutaneous and articular syndrome) a severe form of cryopyrin-associated periodic syndromes (CAPS), that are also known in the US as NOMID (neonatal-onset multisystem inflammatory disease). Other forms of AIS in infancy include Majeed syndrome, Blau syndrome and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Majeed syndrome is defined by the association of recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia, neutrophil dermatosis and recurrent fevers.
Neonatal and infantile fevers A fever in a neonate or infant will result in a comprehensive search for infection and prompt and appropriate treatment with antibiotics. This fever may be associated with recognisable patterns of rash, as with Streptococcal or viral infections. In circumstances where the rash is persistent or unusual, the fever unresponsive to antibiotics or recurrent and there are atypical features, such as bone oedema, alternative diagnoses should be considered. These should include alloimmune conditions such as neonatal lupus and autoimmune conditions in an infant such as Kawasaki Disease. Systemic onset juvenile idiopathic arthritis and Behc‚et’s disease can also present in the first year of life and are now thought to be on the spectrum of AIS.
Cryopyrin-associated periodic syndromes (CAPS) and the inflammasome CAPS are a group of AIS that share the same gene mutation but present at different ages with variations of roughly the same phenotype. They are all autosomal-dominant diseases with NLRP3 gene (nucleotide binding oligomerization domain, leucine rich-
Differential diagnoses of CAPS
Onset Fever duration Skin Articular Ocular Amyloidosis Distinctive features Other findings Treatment
CINCA
FCAS
MWS
Neonatal Continuous (with flares) Polymorphic urticaria-like rash Deforming knee osteo-arthropathy Anterior uveitis, optic disc changes and blindness 20% Aseptic meningitis and naturopathy Mental retardation Anakinra, rilonacept, canakinumab
Infancy to adulthood <24 hours Cold induced urticarial rash Arthralgias Conjunctivitis
Adolescence to adulthood 1e2 days Evanescent urticarial rash Non erosive transient polyarthritis Conjunctivitis and episcleritis
2e4% Cold induced urticarial rash Myalgias, headache and drowsiness Cold avoidance, Anakinra
25% Sensorineural hearing loss Myalgia, drowsiness Anakinra, rilonacept, canakinumab
Table 2
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SYMPOSIUM: INFECTION (& IMMUNITY)
MuckleeWells Syndrome MuckleeWells Syndrome (MWS) is characterised by recurrent episodes of urticaria and fever. Unlike FACS, MWS is not triggered by cold, but can be associated with the same clinical manifestations. The attacks last longer than FCAS, typically 1e2 days. Sensorineural deafness is common usually appearing in childhood or early adulthood.
repeat family, pyrin domain containing 3) mutations. The NLRP3 gene encodes the protein cryopyrin. Identification of this gene will confirm the diagnosis. Clinical features include a characteristic urticarial rash with a number of other clinical manifestations (Table 2). CINCA is associated with the most severe phenotype. Cryopyrin is a key component of the NLRP3 inflammasome (an intracellular multi-protein complex), which regulates the processing of IL-1b. The NLRP3 inflammasome is activated by a range of pathogen associated molecular patterns and host derived molecules from damaged cells. After activation, NLRP3 unfolds and interacts with other proteins to mediate capase-1 activation which results in the maturation and release of proinflammatory cytokines such as IL-1b. In CAPS mutations in NLRP3 causes tertiary structure disruption of cyropyrin. Consequently the NLRP3 inflammasome becomes hyperactive resulting in excessive production of IL-1b and subsequent inflammation. Patients with CAPS respond well to IL-1b antagonists (see section on Principles of treatment). In CINCA fevers are usually short but they may also be absent. An urticarial rash is commonly present in the first few weeks of life. The typical “facies” are characterised by frontal bossing, saddle back nose and midface hypoplasia. Bony overgrowth with time mainly involving the knees and distal extremities of hands and feet are characteristic. Distinctive radiological features occur in the metaphysis and epiphysis with overgrowth and irregular ossification. A chronic inflammatory polyarthritis may also be present. Most children have CNS and ophthalmic involvement.
Childhood periodic fevers When investigating a child with a PUO infection, malignancy and autoimmune diseases are important differentials that must be excluded foremost. In a case-series of children with pyrexia of unknown origin a diagnosis was established in just over 70%; infectious causes in 37.8%, autoimmune disease 12.9%, Kawasaki’s 6.4%, malignant disease 6.4% and other causes 8.1%. A very small proportion of the latter is accounted for by AIS and thus it remains a diagnosis of exclusion. MWS may present in this age group. Hereditary periodic fevers (Table 3) more commonly present in childhood. What tends to characterise the AIS subsequently is a pattern of fever commonly associated with a rash. Three different conditions belong to the hereditary periodic fevers group; familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD also known as hyper-IgD syndrome (HIDS)) and tumour necrosis factor (TNF) receptor associated periodic syndrome (TRAPS). The ethnicity of the family may give important clues to the likely cause. FMF is most common in nonAshkenazi Jews, Arabs, Turks and Armenian populations. MKD in more prevalent in Dutch and Northern-Europeans and TRAPS is also more prevalent in Northern-Europeans populations and was previously known as Hibernian fever for its Scottish and Irish descendants.
Familial cold autoinflammatory syndrome Familial cold autoinflammatory syndrome (FCAS) also known as familial cold urticaria presents at birth or within the first 6 months of life. Unlike CINCA, symptoms are precipitated by exposure to cold temperature with symptoms starting 1e2 hours after exposure. The duration of attacks are short lived less than 24 hours and consist of low-grade fever, urticarial rash and arthralgia.
Familial Mediterranean fever FMF FMF is caused by a mutation of the Mediterranean fever (MEFV) gene which codes for pyrin. Pyrin is expressed in the cytoplasm of
Differential diagnosis of hereditary recurrent fevers
Onset Usual ethnicity Fever duration Abdominal distress Skin Articular Ocular Amyloidosis Distinctive features Other findings Treatment
FMF
MKD
TRAPS
Childhood or adolescence Non-Sephardic Jewish, Armenian, Arab, Turkish 1e4 days Very common (sterile peritonitis)
Infancy Dutch and other Northern European
3e20 years Northern European, any ethnicity
3e7 days Very common (abdominal pain, vomiting, diarrhoea) Polymorphic rash
Splenomegaly common during attacks
7e21 days Common (abdominal pain, diarrhoea, constipation) Painful migratory eruption, oedematous plaques Migratory arthralgias, non erosive arthritides Conjunctivitis, periorbital oedema Present (10%) Migratory myalgia and eruption of periorbital oedema Pleuritis and headaches
Anakinra, Simvastatin
Corticosteroids, etanercept, Anakinra
Erysipelas-like rash Monoarthritis (usually knees, ankles and hips) Uncommon Present (uncommon) Monoarthritis, peritonitis and erysipelas-like lesions Pleuritis, pericarditis and scrotal pain/ swelling Colchicine
Arthralgias Uncommon Rare (5%) Cervical LAD and aphthous ulcers
Table 3
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SYMPOSIUM: INFECTION (& IMMUNITY)
The cutaneous manifestations associated with recurrent fevers are also important diagnostic clues. Urticarial eruptions are prototypic skin lesions of AIS and can help to identify these diseases in their early stages. An urticarial rash occurs in almost all patients with CAPS. It may at first sight be indistinguishable from that of chronic urticaria, far more common and often mast cell mediated. Chronic urticarial rashes are usually asymmetric with itchy recurrent wheal and flare type skin reactions often with angioedema. The urticarial rash in AIS has a broader spectrum of lesions than chronic urticaria may be symmetrically distributed on the trunk and/or extremities and usually spares the head. It may also have purple raised lesions typical of urticarial vasculitis, which is fixed in shape for more than 24 hours. The presence of systemic symptoms, absence of angioedema, repeated elevated inflammatory markers and failure to respond to combinations of anti-histamines are characteristic for AIS but not chronic urticaria. Skin biopsy in urticaria predominantly shows dermal oedema with absent or sparse inflammatory infiltrates where as in AIS dense neutrophil-rich perivascular and interstitial infiltrates are often seen. Rare AIS characterised by the development of multiple sterile abscesses and recurrent fever and rash include PAPA syndrome, Chronic recurrent multifocal osteomyelitis (CRMO) syndrome and Majeed syndrome. PAPA syndrome is characterised by the rash of pyogenic gangrenosum, cystic acne and pyogenic sterile arthritis. CRMO syndrome is defined by multiple foci of chronic osteomyelitis which appear radiologically as a mixture of osteolysis/sclerosis. CRMO is variably associated with recurrent fevers. CRMO can be associated with specific skin conditions such as palmo-plantar pustulosis, psoriasis and acne Blau’s syndrome is an autosomal dominant AIS characterised by a non-caseating granulomatous inflammation affecting the joints, the skin and the uveal tract. A typical tancoloured scaly, ichthyosiform rash is seen in almost 90% of patients.
myeloid cell and regulates the inflammasome modulating caspase1 and IL-1b activation. Fever episodes have a short duration (1e3 days) accompanied by pathognomonic erythema marginatum-like lesions of the lower extremities, large joint arthritis, severe abdominal pain and pleurisy. The condition is very responsive to oral colchicine, which achieves remission in 65% of patients. AA Amyloid is the most severe complication of FMF and the use of colchicine has dramatically reduced its incidence. Tumour necrosis factor receptor-associated periodic syndromes (TRAPS) TRAPS is caused by mutations in the p55 tumour necrosis factor receptor 1 (TNFR1). Tumour necrosis factor (TNF) is a key mediator of inflammation. Fevers in TRAPS last longer than the other periodic fevers, lasting 1e3 weeks with organ-localisedinflammation (Table 3) and are spaced by variable periods of remission. Abdominal pain and pleuritis are frequent. Typical cutaneous lesions consist of a migratory, tender macular rash on the extremes and/or torso. Mevalonate kinase deficiency syndrome (MKD)/Hyper IgD syndrome (HIDS) MKD was originally identified in 1984 in six patients of Dutch ancestry with a long history of recurrent attacks of fever caused by high serum IgD level and was originally named hyper IgD or Dutch fever. It is caused by mutations in the mevalonate kinase (MVK) gene. Patients with MKD still have residual MVK activity. MVK is an enzyme essential in cholesterol biosynthesis involved in different cellular processes. The pathogenic mechanisms leading to autoinflammation are yet to be fully understood, although it is proposed that the absence of MVK activity results in temporary build up in end products (isoprenoid) of a diverted metabolic pathway. This in turn results in increased intracellular IL-1b expression. MKD usually starts in early childhood and typically presents with fevers lasting 3e7 days with lymphadenopathy, abdominal complaints including pain and diarrhoea, arthralgia, aphthous ulcers and polymorphic rash (Table 3). Increased serum IgD concentration (at levels greater than 100 IU/ml) during and between attacks supports the diagnosis. However the specificity of this finding is low, given that it is seen in other AIS. Urine excretion of mevalonic acid is increased during fever spikes. Molecular analysis of the MVK gene is used to confirm the diagnosis. Mevalonic aciduria (MVA) is a more complete or severe form of MKD, in which signs and symptoms are present at all times and not just during episodes of fever. Children with MVA have developmental delay, progressive ataxia, visual loss and failure to thrive.
Periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA) PFAPA is syndrome defined by recurrent episodes of fever, sore throat, mouth or lip ulcers and tender swelling of the cervical lymph nodes. The disease is a diagnosis of exclusion after viral infections and recurrent streptococcal illnesses have been looked for. There is much controversy as to whether the disease is autoinflammatory in nature. There is no documented genetic cause for PFAPA syndrome. The syndrome usually presents before the age of 5 years and is characterised by abrupt onset of fever spikes lasting 3e6 days with recurrent episodes every 2e6 weeks. Children appear well during fever spikes and the fever flare ups are usually preceded by chills. The aphthous ulcers are typically self-remitting, small and found on labial gingival. Enlarged lymph nodes are tender and normalise with resolution of fever attacks. Cervical lymphadenopathy is frequently observed. Acute phase reactants and neutrophils are elevated during attacks and settle back to normal during disease free periods. The disease course is usually benign and tends to spontaneously resolve during the second decade of life. A short course of steroids may be given when there are significant effects on quality of life and the first course may be enough to stop or greatly reduce future episodes.
Characterisation of fever and rash in AIS When evaluating a child with recurrent fevers characterisation of the duration and periodicity of fever is essential. This will not only be helpful for diagnosis but also determine disease burden and impact on quality of life. Systemic onset JIA commonly presents with a quotidian fever (spiking fevers occurring once or twice a day at the same time of the day, with return to normal between spikes), systemic involvement (arthritis, lymphadenopathy, serositis and hepato-splenomegaly) and typically a salmon pink erythematous rash.
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SYMPOSIUM: INFECTION (& IMMUNITY)
Principles of treatment
differentiate the individual syndromes. In a child who presents with recurrent fevers and multi-system manifestations the exclusion of infection and neoplasia is first and foremost. Autoimmune diseases are also common and must be considered before a diagnosis of AIS is made. AIS are rare and are often a diagnosis of exclusion. Salient clues to the diagnosis of AIS include a positive family history and the higher prevalence of individual syndromes in certain ethnic groups. It is important to characterise the duration and periodicity of fevers which may help differentiate between individual syndromes. A thorough systems examination is essential to define the nature of systemic involvement and identify associated pathognomonic rashes. Confirmation through genetic testing is recommended but may not be confirmatory. Our knowledge of AIS is expanding and a genetic cause cannot be found in over 50% of children with a very suggestive clinical picture of AIS. Research enhancing the quality of molecular tests, studying genome-wide associations and molecular mechanisms leading to inflammations will help shed further light and also enable the development of targeted immunotherapy.A
CAPS and anti-IL therapies Therapeutic management of CAPS has been limited and typically consisted of NSAIDs and corticosteroids. There have been anecdotal cases of benefit with anti-TNF treatment and thalidomide. New therapeutic strategies are promising and are based on targeting the IL-1 pathway. Anakinra, a recombinant form of human IL-1 receptor antagonist, blocks the activity of IL-1 by competitively binding to the IL-1 receptor. Rilonacept is a long acting IL-1 blocker that comprises of the extracellular domain of the human type 1 IL-1 receptor coupled to human IgG1 antibody. Canakinumab is a fully human IG1 anti-IL-1b monoclonal antibody. There has been an excellent high quality study of this and is now the main course of treatment in the UK by a national programme led through the UCH amyloidosis centre and Great Ormond Street Hospital. Both canakinumab and rilonacept are approved for use in CAPS. Anakinra has been used successfully but may not be funded. Capase 1 inhibition in CAPS: capase 1 is another potential target for therapy in CAPS. VX-765 is an orally active capase 1 inhibitor that was able to block IL-1b secretion in vitro in patients with FCAS. A limited open label study of this drug has been conducted in six patients with MWS and these patients showed partial clinical and biological improvement with treatment.
FURTHER READING 1 Rigante D. Autoinflammatory syndromes behind the scenes of recurrent fevers in children. Med Sci Monit 2009; 15: 179e87. 2 Gattorno M, Federici S, Pelagatti MA, et al. Diagnosis and management of autoinflammatory diseases in childhood. J Clin Immunol 2008; 28: S73e83. 3 Farasat S, Aksentijevich I, Toro JR. Autoinflammatory diseases: clinical and genetic advances. Arch Dermatol 2008; 144: 392e402. 4 Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140: 821e32. 5 Pasic S, Minic A, Djuric P, et al. Fever of unknown origin in 185 paediatric patients: a single-centre experience. Acta Paediatr 2006; 95: 463e6. 6 Kone-Paut I, Piram M. Targeting interleukin-1B in CAPS syndromes. What did we learn? Autoimmun Rev 2012; 12: 77e80. 7 Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep 2011; 11: 12e20. 8 Hoffman HM, Throne ML, Amar NJ, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum 2008; 58: 2443e52. 9 Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 2009; 360: 2416e25.
Periodic fevers and anti-IL therapy: in FMF colchicine is the treatment of choice with 65% of patients showing complete remission of fever and 20e30% experience significant improvement with a reduction in the severity and number of fever attacks. 5e10% of patients are non-responders. Treatment with IL1 inhibitors such as Anakinra has been proposed as an effective treatment in colchicine-resistant FMF patients. However the evidence for this is from small cases and not controlled trials. Fever attacks respond favourably to steroids (prednisolone 1 mg/day in a single dose) in both MKD and TRAPS. Steroid use is limited due to the long term adverse effects. Small studies have suggested a positive response to Simvastatin in adult patients with MKD. The use of biological therapy is anecdotal and controversial in both conditions. Anakinra has also been used successfully but in small numbers of patients. Larger controlled studies are required. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is caused by autosomal recessive mutations in genes encoding the proteasome subunits, mainly the subunit b type 8 gene (PSMB8). It has been shown that CANDLE patients present with increased expression of Interferon (IFN) regulated genes and unregulated stat1 phosphorylation on peripheral blood monocytes. Drugs inhibiting Janus kinases (JAKs), mediators of IFN signalling, might be used as a treatment in CANDLE. Small studies have suggested treatment with a JAK inhibitor is able to down regulate IFN induced genes as well as genes associated with the regulation of other inflammatory cytokines.
Practice points C C
C
Conclusion C
As with many rare conditions high levels of suspicion are required to diagnose periodic fever syndromes. To know when to consider them as a group of conditions will help before beginning to
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AIS are rare monogenetic childhood onset disorders. AIS are a diagnosis of exclusion and should be considered in children presenting with recurrent fevers and systemic manifestations after more common causes are excluded. The diagnosis of most AIS relies on clinical history, demonstration of an increased acute phase during attacks with normalisation during disease free periods and possibly genetic confirmation. Systemic AA amyloidosis may be a severe long term complication. Anti-IL-1 treatments are safe and effective in all CAPS patient phenotypes.
Ó 2014 Elsevier Ltd. All rights reserved.
Periodic fevers and autoinflammatory conditions
1:3 to 1:5, most AIS are rare. Less than 200 families have been reported with tumour necrosis factor (TNF) receptor associated periodic syndrome (TRAPS) worldwide, 100 cases of Familial cold autoinflammatory syndrome (FCAS) and MuckleeWells Syndrome (MWS) have been reported mainly in Europe and North America. There are less than 10 families reported to have Majeed syndrome mostly arising from Jordan.
Jyoti Bakshi Nick Wilkinson
Pathogenesis
Abstract
In contrast to autoimmune diseases, which are generally regarded as being mediated by the adaptive immune system, AIS are disorders of the innate immune system. Innate immunity not only serves to discriminate between “self” from “non-self” but serves as a system for sensing threat, by detecting specific danger signals, such as lipopolysaccharide or peptidoglycan, presented by pathogenic microbes or host derived molecules of cellular stress such as extracellular ATP. The small molecular motifs expressed by microbes are highly conserved through evolution and now known as PAMPs (Pathogen Associated Molecular Patterns). These are detected by intracellular pattern-recognition receptors (PRRs) such as Toll like receptors (TLRs) and nucleotide-binding oligomerization domain receptors, in short NOD-like receptors (NLRs), which are expressed by front line cells of the innate host defence including macrophages, monocytes, neutrophils and also lymphocytes of the adaptive immune system. This typically forms the first line of defence against infection. These receptors converge on a common set of signalling transcription factors that drive proinflammatory cytokine production. It is disruption of these pathways that result in AIS and increased levels of proinflammatory cytokines. Examples of such disruption to the innate immune system includes mutations of the NOD2 gene associated with Crohn’s disease and Blau syndrome, a sarcoid-like illness presenting in early childhood. Disruption of a molecular platform called the “inflammasome” which comprises NLRs, pyrin and CARDs (caspase activation and recruitment domain) results in gout and another form of AIS called cryopyrin-associated period syndrome (CAPS). This disruption results in excess interleukin-1b (IL-1b), a key proinflammatory cytokine.
Autoinflammatory syndromes (AIS) are a spectrum of immune-mediated disorders that typically present in childhood with recurrent fevers, high inflammatory markers and systemic involvement. The quintessential periodic fever is familial Mediterranean fever, which is relatively common in Middle Eastern populations, but in general, these conditions are rare and diagnostically challenging. As a group of conditions they are typified by a delay in diagnosis of several years with repeated hospital visits, unnecessary investigations and treatment, impact on quality of life and an increased risk of the most severe complication of systemic AA amyloidosis. The purpose of this review is to help clinicians suspect and diagnose AIS in children presenting with (recurrent) fevers or multisystem inflammation of unknown aetiology after common causes such as infection and autoimmune diseases have been excluded. We will identify when to consider AIS through a systematic approach of pattern recognition. We will discuss the presentation and differential diagnosis of recurrent fevers in neonates (the cryopyrinopathies), in childhood (hereditary periodic fevers) and pathognomonic rashes associated with AIS. Although, by no means exhaustive, we will also discuss other forms of AIS and provide an overview of the principles of treatment of AIS.
Keywords autoinflammatory syndromes; childhood; inflammasome; multisystem inflammation; recurrent fever
Introduction AIS are rare monogenetic childhood-onset disorders caused by mutations of genes coding for proteins that play a pivotal role in immune regulation especially of the innate immune system. The spectrum of recognised disorders and their gene defect can be found in Table 1. Most, when untreated, are characterised by lifelong, spontaneously relapsing bouts of fever and systemic inflammation with symptom-free intervals. Recurrent episodes of fever are associated with systemic inflammation typically affecting skin, joints, GI system or serous membranes. A diagnosis of AIS is suspected when a child presents with recurrent fevers of unknown aetiology and requires the exclusion of an underlying infection, neoplastic or autoimmune cause.
Assessment of possible AIS in a child with recurrent fever The salient features in the history of a child presenting with AIS would include recurrent self-limiting unexplained fevers often accompanied by a rash and possibly abdominal or limb pain. Family history, ethnicity, early onset of fever within first year of life and concomitant manifestations are also important clues to AIS. A thorough systemic examination including skin, joints and eyes during febrile periods is essential. High inflammatory markers (ESR/CRP) and a neutrophilia are typical during febrile episodes and normalise during disease free intervals. Blood and urine cultures are important to exclude an infectious cause. A urinalysis should be requested to screen for proteinuria which raises the possibility of secondary AA amyloidosis. Confirmation of AIS should be sought with genetic testing. However, it is important to remember that over 50% of AIS patients presenting with typical features have negative genetic results. Genetic tests are sent to a specialist centre for analysis. In the UK this is the National Amyloidosis centre at University College Hospital
Epidemiology Whereas the prototypical AIS, familial Mediterranean fever (FMF), has a carrier frequency in Middle Eastern populations of Jyoti Bakshi BSc MBBS MRCP is Rheumatology Registrar in the Rheumatology Department at the Nuffield Orthopedic Centre, Oxford, UK. Conflicts of interest: none. Nick Wilkinson MBChB MRCP MRCPCH DM is a Consultant Paediatrician and Paediatric Rheumatologist in the Rheumatology Department at Nuffield Orthopedic Centre, Oxford, UK. Conflicts of interest: none.
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Ó 2014 Elsevier Ltd. All rights reserved.
SYMPOSIUM: INFECTION (& IMMUNITY)
The autoinflammatory syndromes Disease
Gene/Chromosome
Protein
Periodic fevers
FMF MKD TRAPS
MEFV/16p13.3 MVK/12q24 TNFRSF1A/12p13
Pyrin Mevalonate kinase p55 TNF receptor
Cryopyrinopathies
FCAS, MWS, CINCA
NLRP3
Cryopyrin
Granulomatous
Blau’s syndrome
CARD15/NOD2/16q12
CARD15
Pyogenic disorders
PAPA syndrome Majeed’s syndrome CROMO
PSTPIP1/15q24-q25.1 LPIN2/18p PSTP1P2/18p
PSTPIP1 LPIN2 PSTPIP2
Inflammatory bowel disease (IBD)
IBD 25 IBD 28
IL 10RB/21q22.11 IL 10RA/11q23.3
Interleukin 10 receptor beta Interleukin 10 receptor alpha
Note: FMF – familial Mediterranean fever; TRAPS – TNF receptor-associated periodic syndrome; MKD – mevalonate kinase deficiency; FCAS – familial cold autoinflammatory syndrome; MWS – Muckle-Wells syndrome; CINCA – chronic infantile neurologic cutaneous articular syndrome; PAPA – pyogenic arthritis pyoderma grangrenosa acne syndrome; CRMO – chronic recurrent multifocal osteomyelitis; IBD – inflammatory bowel disease.
Table 1
(www.ucl.ac.uk/amyloidosis) in London. Information about the latest genetic abnormalities is available on the In-Fever website at http://fmf.igh.cnrs.fr/ISSAID/infevers/.
Established AIS in the first year of life includes CINCA (chronic infantile neurological cutaneous and articular syndrome) a severe form of cryopyrin-associated periodic syndromes (CAPS), that are also known in the US as NOMID (neonatal-onset multisystem inflammatory disease). Other forms of AIS in infancy include Majeed syndrome, Blau syndrome and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Majeed syndrome is defined by the association of recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia, neutrophil dermatosis and recurrent fevers.
Neonatal and infantile fevers A fever in a neonate or infant will result in a comprehensive search for infection and prompt and appropriate treatment with antibiotics. This fever may be associated with recognisable patterns of rash, as with Streptococcal or viral infections. In circumstances where the rash is persistent or unusual, the fever unresponsive to antibiotics or recurrent and there are atypical features, such as bone oedema, alternative diagnoses should be considered. These should include alloimmune conditions such as neonatal lupus and autoimmune conditions in an infant such as Kawasaki Disease. Systemic onset juvenile idiopathic arthritis and Behc‚et’s disease can also present in the first year of life and are now thought to be on the spectrum of AIS.
Cryopyrin-associated periodic syndromes (CAPS) and the inflammasome CAPS are a group of AIS that share the same gene mutation but present at different ages with variations of roughly the same phenotype. They are all autosomal-dominant diseases with NLRP3 gene (nucleotide binding oligomerization domain, leucine rich-
Differential diagnoses of CAPS
Onset Fever duration Skin Articular Ocular Amyloidosis Distinctive features Other findings Treatment
CINCA
FCAS
MWS
Neonatal Continuous (with flares) Polymorphic urticaria-like rash Deforming knee osteo-arthropathy Anterior uveitis, optic disc changes and blindness 20% Aseptic meningitis and naturopathy Mental retardation Anakinra, rilonacept, canakinumab
Infancy to adulthood <24 hours Cold induced urticarial rash Arthralgias Conjunctivitis
Adolescence to adulthood 1e2 days Evanescent urticarial rash Non erosive transient polyarthritis Conjunctivitis and episcleritis
2e4% Cold induced urticarial rash Myalgias, headache and drowsiness Cold avoidance, Anakinra
25% Sensorineural hearing loss Myalgia, drowsiness Anakinra, rilonacept, canakinumab
Table 2
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MuckleeWells Syndrome MuckleeWells Syndrome (MWS) is characterised by recurrent episodes of urticaria and fever. Unlike FACS, MWS is not triggered by cold, but can be associated with the same clinical manifestations. The attacks last longer than FCAS, typically 1e2 days. Sensorineural deafness is common usually appearing in childhood or early adulthood.
repeat family, pyrin domain containing 3) mutations. The NLRP3 gene encodes the protein cryopyrin. Identification of this gene will confirm the diagnosis. Clinical features include a characteristic urticarial rash with a number of other clinical manifestations (Table 2). CINCA is associated with the most severe phenotype. Cryopyrin is a key component of the NLRP3 inflammasome (an intracellular multi-protein complex), which regulates the processing of IL-1b. The NLRP3 inflammasome is activated by a range of pathogen associated molecular patterns and host derived molecules from damaged cells. After activation, NLRP3 unfolds and interacts with other proteins to mediate capase-1 activation which results in the maturation and release of proinflammatory cytokines such as IL-1b. In CAPS mutations in NLRP3 causes tertiary structure disruption of cyropyrin. Consequently the NLRP3 inflammasome becomes hyperactive resulting in excessive production of IL-1b and subsequent inflammation. Patients with CAPS respond well to IL-1b antagonists (see section on Principles of treatment). In CINCA fevers are usually short but they may also be absent. An urticarial rash is commonly present in the first few weeks of life. The typical “facies” are characterised by frontal bossing, saddle back nose and midface hypoplasia. Bony overgrowth with time mainly involving the knees and distal extremities of hands and feet are characteristic. Distinctive radiological features occur in the metaphysis and epiphysis with overgrowth and irregular ossification. A chronic inflammatory polyarthritis may also be present. Most children have CNS and ophthalmic involvement.
Childhood periodic fevers When investigating a child with a PUO infection, malignancy and autoimmune diseases are important differentials that must be excluded foremost. In a case-series of children with pyrexia of unknown origin a diagnosis was established in just over 70%; infectious causes in 37.8%, autoimmune disease 12.9%, Kawasaki’s 6.4%, malignant disease 6.4% and other causes 8.1%. A very small proportion of the latter is accounted for by AIS and thus it remains a diagnosis of exclusion. MWS may present in this age group. Hereditary periodic fevers (Table 3) more commonly present in childhood. What tends to characterise the AIS subsequently is a pattern of fever commonly associated with a rash. Three different conditions belong to the hereditary periodic fevers group; familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD also known as hyper-IgD syndrome (HIDS)) and tumour necrosis factor (TNF) receptor associated periodic syndrome (TRAPS). The ethnicity of the family may give important clues to the likely cause. FMF is most common in nonAshkenazi Jews, Arabs, Turks and Armenian populations. MKD in more prevalent in Dutch and Northern-Europeans and TRAPS is also more prevalent in Northern-Europeans populations and was previously known as Hibernian fever for its Scottish and Irish descendants.
Familial cold autoinflammatory syndrome Familial cold autoinflammatory syndrome (FCAS) also known as familial cold urticaria presents at birth or within the first 6 months of life. Unlike CINCA, symptoms are precipitated by exposure to cold temperature with symptoms starting 1e2 hours after exposure. The duration of attacks are short lived less than 24 hours and consist of low-grade fever, urticarial rash and arthralgia.
Familial Mediterranean fever FMF FMF is caused by a mutation of the Mediterranean fever (MEFV) gene which codes for pyrin. Pyrin is expressed in the cytoplasm of
Differential diagnosis of hereditary recurrent fevers
Onset Usual ethnicity Fever duration Abdominal distress Skin Articular Ocular Amyloidosis Distinctive features Other findings Treatment
FMF
MKD
TRAPS
Childhood or adolescence Non-Sephardic Jewish, Armenian, Arab, Turkish 1e4 days Very common (sterile peritonitis)
Infancy Dutch and other Northern European
3e20 years Northern European, any ethnicity
3e7 days Very common (abdominal pain, vomiting, diarrhoea) Polymorphic rash
Splenomegaly common during attacks
7e21 days Common (abdominal pain, diarrhoea, constipation) Painful migratory eruption, oedematous plaques Migratory arthralgias, non erosive arthritides Conjunctivitis, periorbital oedema Present (10%) Migratory myalgia and eruption of periorbital oedema Pleuritis and headaches
Anakinra, Simvastatin
Corticosteroids, etanercept, Anakinra
Erysipelas-like rash Monoarthritis (usually knees, ankles and hips) Uncommon Present (uncommon) Monoarthritis, peritonitis and erysipelas-like lesions Pleuritis, pericarditis and scrotal pain/ swelling Colchicine
Arthralgias Uncommon Rare (5%) Cervical LAD and aphthous ulcers
Table 3
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The cutaneous manifestations associated with recurrent fevers are also important diagnostic clues. Urticarial eruptions are prototypic skin lesions of AIS and can help to identify these diseases in their early stages. An urticarial rash occurs in almost all patients with CAPS. It may at first sight be indistinguishable from that of chronic urticaria, far more common and often mast cell mediated. Chronic urticarial rashes are usually asymmetric with itchy recurrent wheal and flare type skin reactions often with angioedema. The urticarial rash in AIS has a broader spectrum of lesions than chronic urticaria may be symmetrically distributed on the trunk and/or extremities and usually spares the head. It may also have purple raised lesions typical of urticarial vasculitis, which is fixed in shape for more than 24 hours. The presence of systemic symptoms, absence of angioedema, repeated elevated inflammatory markers and failure to respond to combinations of anti-histamines are characteristic for AIS but not chronic urticaria. Skin biopsy in urticaria predominantly shows dermal oedema with absent or sparse inflammatory infiltrates where as in AIS dense neutrophil-rich perivascular and interstitial infiltrates are often seen. Rare AIS characterised by the development of multiple sterile abscesses and recurrent fever and rash include PAPA syndrome, Chronic recurrent multifocal osteomyelitis (CRMO) syndrome and Majeed syndrome. PAPA syndrome is characterised by the rash of pyogenic gangrenosum, cystic acne and pyogenic sterile arthritis. CRMO syndrome is defined by multiple foci of chronic osteomyelitis which appear radiologically as a mixture of osteolysis/sclerosis. CRMO is variably associated with recurrent fevers. CRMO can be associated with specific skin conditions such as palmo-plantar pustulosis, psoriasis and acne Blau’s syndrome is an autosomal dominant AIS characterised by a non-caseating granulomatous inflammation affecting the joints, the skin and the uveal tract. A typical tancoloured scaly, ichthyosiform rash is seen in almost 90% of patients.
myeloid cell and regulates the inflammasome modulating caspase1 and IL-1b activation. Fever episodes have a short duration (1e3 days) accompanied by pathognomonic erythema marginatum-like lesions of the lower extremities, large joint arthritis, severe abdominal pain and pleurisy. The condition is very responsive to oral colchicine, which achieves remission in 65% of patients. AA Amyloid is the most severe complication of FMF and the use of colchicine has dramatically reduced its incidence. Tumour necrosis factor receptor-associated periodic syndromes (TRAPS) TRAPS is caused by mutations in the p55 tumour necrosis factor receptor 1 (TNFR1). Tumour necrosis factor (TNF) is a key mediator of inflammation. Fevers in TRAPS last longer than the other periodic fevers, lasting 1e3 weeks with organ-localisedinflammation (Table 3) and are spaced by variable periods of remission. Abdominal pain and pleuritis are frequent. Typical cutaneous lesions consist of a migratory, tender macular rash on the extremes and/or torso. Mevalonate kinase deficiency syndrome (MKD)/Hyper IgD syndrome (HIDS) MKD was originally identified in 1984 in six patients of Dutch ancestry with a long history of recurrent attacks of fever caused by high serum IgD level and was originally named hyper IgD or Dutch fever. It is caused by mutations in the mevalonate kinase (MVK) gene. Patients with MKD still have residual MVK activity. MVK is an enzyme essential in cholesterol biosynthesis involved in different cellular processes. The pathogenic mechanisms leading to autoinflammation are yet to be fully understood, although it is proposed that the absence of MVK activity results in temporary build up in end products (isoprenoid) of a diverted metabolic pathway. This in turn results in increased intracellular IL-1b expression. MKD usually starts in early childhood and typically presents with fevers lasting 3e7 days with lymphadenopathy, abdominal complaints including pain and diarrhoea, arthralgia, aphthous ulcers and polymorphic rash (Table 3). Increased serum IgD concentration (at levels greater than 100 IU/ml) during and between attacks supports the diagnosis. However the specificity of this finding is low, given that it is seen in other AIS. Urine excretion of mevalonic acid is increased during fever spikes. Molecular analysis of the MVK gene is used to confirm the diagnosis. Mevalonic aciduria (MVA) is a more complete or severe form of MKD, in which signs and symptoms are present at all times and not just during episodes of fever. Children with MVA have developmental delay, progressive ataxia, visual loss and failure to thrive.
Periodic fever, aphthous stomatitis, pharyngitis, adenitis syndrome (PFAPA) PFAPA is syndrome defined by recurrent episodes of fever, sore throat, mouth or lip ulcers and tender swelling of the cervical lymph nodes. The disease is a diagnosis of exclusion after viral infections and recurrent streptococcal illnesses have been looked for. There is much controversy as to whether the disease is autoinflammatory in nature. There is no documented genetic cause for PFAPA syndrome. The syndrome usually presents before the age of 5 years and is characterised by abrupt onset of fever spikes lasting 3e6 days with recurrent episodes every 2e6 weeks. Children appear well during fever spikes and the fever flare ups are usually preceded by chills. The aphthous ulcers are typically self-remitting, small and found on labial gingival. Enlarged lymph nodes are tender and normalise with resolution of fever attacks. Cervical lymphadenopathy is frequently observed. Acute phase reactants and neutrophils are elevated during attacks and settle back to normal during disease free periods. The disease course is usually benign and tends to spontaneously resolve during the second decade of life. A short course of steroids may be given when there are significant effects on quality of life and the first course may be enough to stop or greatly reduce future episodes.
Characterisation of fever and rash in AIS When evaluating a child with recurrent fevers characterisation of the duration and periodicity of fever is essential. This will not only be helpful for diagnosis but also determine disease burden and impact on quality of life. Systemic onset JIA commonly presents with a quotidian fever (spiking fevers occurring once or twice a day at the same time of the day, with return to normal between spikes), systemic involvement (arthritis, lymphadenopathy, serositis and hepato-splenomegaly) and typically a salmon pink erythematous rash.
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Principles of treatment
differentiate the individual syndromes. In a child who presents with recurrent fevers and multi-system manifestations the exclusion of infection and neoplasia is first and foremost. Autoimmune diseases are also common and must be considered before a diagnosis of AIS is made. AIS are rare and are often a diagnosis of exclusion. Salient clues to the diagnosis of AIS include a positive family history and the higher prevalence of individual syndromes in certain ethnic groups. It is important to characterise the duration and periodicity of fevers which may help differentiate between individual syndromes. A thorough systems examination is essential to define the nature of systemic involvement and identify associated pathognomonic rashes. Confirmation through genetic testing is recommended but may not be confirmatory. Our knowledge of AIS is expanding and a genetic cause cannot be found in over 50% of children with a very suggestive clinical picture of AIS. Research enhancing the quality of molecular tests, studying genome-wide associations and molecular mechanisms leading to inflammations will help shed further light and also enable the development of targeted immunotherapy.A
CAPS and anti-IL therapies Therapeutic management of CAPS has been limited and typically consisted of NSAIDs and corticosteroids. There have been anecdotal cases of benefit with anti-TNF treatment and thalidomide. New therapeutic strategies are promising and are based on targeting the IL-1 pathway. Anakinra, a recombinant form of human IL-1 receptor antagonist, blocks the activity of IL-1 by competitively binding to the IL-1 receptor. Rilonacept is a long acting IL-1 blocker that comprises of the extracellular domain of the human type 1 IL-1 receptor coupled to human IgG1 antibody. Canakinumab is a fully human IG1 anti-IL-1b monoclonal antibody. There has been an excellent high quality study of this and is now the main course of treatment in the UK by a national programme led through the UCH amyloidosis centre and Great Ormond Street Hospital. Both canakinumab and rilonacept are approved for use in CAPS. Anakinra has been used successfully but may not be funded. Capase 1 inhibition in CAPS: capase 1 is another potential target for therapy in CAPS. VX-765 is an orally active capase 1 inhibitor that was able to block IL-1b secretion in vitro in patients with FCAS. A limited open label study of this drug has been conducted in six patients with MWS and these patients showed partial clinical and biological improvement with treatment.
FURTHER READING 1 Rigante D. Autoinflammatory syndromes behind the scenes of recurrent fevers in children. Med Sci Monit 2009; 15: 179e87. 2 Gattorno M, Federici S, Pelagatti MA, et al. Diagnosis and management of autoinflammatory diseases in childhood. J Clin Immunol 2008; 28: S73e83. 3 Farasat S, Aksentijevich I, Toro JR. Autoinflammatory diseases: clinical and genetic advances. Arch Dermatol 2008; 144: 392e402. 4 Schroder K, Tschopp J. The inflammasomes. Cell 2010; 140: 821e32. 5 Pasic S, Minic A, Djuric P, et al. Fever of unknown origin in 185 paediatric patients: a single-centre experience. Acta Paediatr 2006; 95: 463e6. 6 Kone-Paut I, Piram M. Targeting interleukin-1B in CAPS syndromes. What did we learn? Autoimmun Rev 2012; 12: 77e80. 7 Yu JR, Leslie KS. Cryopyrin-associated periodic syndrome: an update on diagnosis and treatment response. Curr Allergy Asthma Rep 2011; 11: 12e20. 8 Hoffman HM, Throne ML, Amar NJ, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum 2008; 58: 2443e52. 9 Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 2009; 360: 2416e25.
Periodic fevers and anti-IL therapy: in FMF colchicine is the treatment of choice with 65% of patients showing complete remission of fever and 20e30% experience significant improvement with a reduction in the severity and number of fever attacks. 5e10% of patients are non-responders. Treatment with IL1 inhibitors such as Anakinra has been proposed as an effective treatment in colchicine-resistant FMF patients. However the evidence for this is from small cases and not controlled trials. Fever attacks respond favourably to steroids (prednisolone 1 mg/day in a single dose) in both MKD and TRAPS. Steroid use is limited due to the long term adverse effects. Small studies have suggested a positive response to Simvastatin in adult patients with MKD. The use of biological therapy is anecdotal and controversial in both conditions. Anakinra has also been used successfully but in small numbers of patients. Larger controlled studies are required. Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is caused by autosomal recessive mutations in genes encoding the proteasome subunits, mainly the subunit b type 8 gene (PSMB8). It has been shown that CANDLE patients present with increased expression of Interferon (IFN) regulated genes and unregulated stat1 phosphorylation on peripheral blood monocytes. Drugs inhibiting Janus kinases (JAKs), mediators of IFN signalling, might be used as a treatment in CANDLE. Small studies have suggested treatment with a JAK inhibitor is able to down regulate IFN induced genes as well as genes associated with the regulation of other inflammatory cytokines.
Practice points C C
C
Conclusion C
As with many rare conditions high levels of suspicion are required to diagnose periodic fever syndromes. To know when to consider them as a group of conditions will help before beginning to
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AIS are rare monogenetic childhood onset disorders. AIS are a diagnosis of exclusion and should be considered in children presenting with recurrent fevers and systemic manifestations after more common causes are excluded. The diagnosis of most AIS relies on clinical history, demonstration of an increased acute phase during attacks with normalisation during disease free periods and possibly genetic confirmation. Systemic AA amyloidosis may be a severe long term complication. Anti-IL-1 treatments are safe and effective in all CAPS patient phenotypes.
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