REVIEW

The genetic background of tumour necrosis factorreceptor-associated periodic syndrome and othersystemic autoinflammatory disorders

S Stjernberg-Salmela1,2, A Ranki1, L Karenko1, T Pettersson2

Departments of 1Dermatology and 2Medicine, Helsinki University Central Hospital, Helsinki, Finland

Systemic autoinflammatory disorders are hereditary diseases with symptoms of acute inflammation and a rise inserum acute phase proteins as a consequence, but with no signs of autoimmunity. By the end of the 1990s, four

types of hereditary periodic fever had been described in the medical literature: familial Mediterranean fever,

hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), tumour necrosis factor receptor-associated

periodic fever syndrome (TRAPS) and Muckle-Wells syndrome. Since then, the number of diseases classified as

systemic autoinflammatory disorders has increased to eight. In patients of Nordic descent, cases of HIDS and

TRAPS have been reported. We provide an overview of the genetic background and main clinical aspects of the

different autoinflammatory disorders, with an emphasis on TRAPS.

The systemic autoinflammatory disorders have been

identified in the medical literature as familial

Mediterranean fever (FMF), hyperimmunoglobuli-

nemia D with periodic fever syndrome (HIDS),

tumour necrosis factor (TNF) receptor-associated

periodic syndrome (TRAPS) and Muckle – Wells

syndrome (MWS) (1). FMF and HIDS have anautosomal recessive mode of inheritance, whereas

TRAPS and MWS are autosomally dominantly

inherited. Today, four additional hereditary syn-

dromes are classified as autoinflammatory disorders:

familial cold autoinflammatory syndrome (FCAS),

formerly known as familial cold urticaria (FCU),

chronic infantile neurological cutaneous and articu-

lar (CINCA) syndrome (also called neonatal-onsetmultisystem inflammatory disorder, NOMID), pyo-

genic sterile arthritis in combination with pyoderma

gangrenosum and acne (PAPA), and Blau syndrome

or familial granulomatous arthritis (2). All these four

disorders are inherited dominantly in the autosome.

Despite differences in the clinical picture, all

autoinflammatory disorders are characterized by:

. Recurring attacks of fever

. Inflammation of serosal membranes

. Muscular and articular involvement

. Different types of rash.

. Particularly in FMF, TRAPS and MWS amyloi-

dosis may occur as a sequel of the disease

(Table 1).

The absence of autoantibody elevation, or antigen

specific T-cell activation distinguishes the auto-

inflammatory disorders from the autoimmune diseases(2, 3).

Familial Mediterranean fever

The most thoroughly studied of the autoinflamma-

tory disorders is FMF, which is common among

non-Ashkenazi Jews, Armenians, Turks, and Arabs.

It was, therefore, not surprising that the first

mutation behind an autoinflammatory disorder to

be identified was in the gene responsible for FMF,

the Mediterranean fever gene (MEFV), located onchromosome 16p13.3 (4, 5). Most mutations are

missense mutations located in exons 2 and 10, but

mutations in exons 3, 5, and 9 have also been

identified (6). The majority (70%) of the mutations

are present on both alleles. Even in the presence of

clinically overt symptoms, a mutation is not always

found and in v30% of cases only one mutation is

detected. Typical symptoms in FMF are periodicallyoccurring attacks of fever with abdominal pain and

Tom Pettersson, Department of Medicine, Helsinki University

Central Hospital, Haartmaninkatu 4, PO Box 340, FIN-00290

Helsinki, Finland.

E-mail: tom.pettersson@hus.fi

Received 18 July 2003

Accepted 2 December 2003

Scand J Rheumatol 2004;33:133–139 133

www.scandjrheumatol.dk

# 2004 Taylor & Francis on license from Scandinavian Rheumatology Research Foundation

DOI: 10.1080/03009740310004900

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arthralgia (Table 1). The duration of the attacks is

usually 2 – 3 days, and cutaneous involvement is

common in form of erysipeloid erythema. Otherclinical manifestations include myalgia associated

with physical exercise, splenomegaly, pleuritis, and,

in rare cases, pericarditis (6). The most important

complication of FMF is the development of AA

amyloidosis, mainly of the kidneys.

Colchicine is widely used to alleviate the symp-

toms in FMF and has been shown to be effective in

preventing the development of amyloidosis in FMFpatients. According to a recent report, treatment

with colchicine may, by preventing febrile attacks

and development of intra-abdominal adhesions,

promote fertility in female FMF patients (7).

Hyperimmunoglobulinaemia D with periodic feversyndrome

In another recessively inherited periodic fever syn-

drome, HIDS, a mutation in the mevalonate kinase

gene (MVK) was identified (8, 9). To date, 43different mutations of MVK have been reported (10).

Typical symptoms during febrile attacks are cervical

lymphadenopathy, abdominal pain, arthralgia and a

maculopapular rash (Table 1). High levels of serum

IgD are detected continuously, and often also high

levels of IgA (11, 12). A mutation of MVK causes

a deficiency in the action of the enzyme on the

biosynthesis of cholesterol, but the pathomechanismsof its pro-inflammatory action remains unclear. No

specific therapy is available, but the clinical symp-

toms can be alleviated by non-steroidal anti-

inflammatory drugs (NSAIDs).

The TNFRSF1B fusion protein etanercept has

been shown to have a favourable effect on the

symptoms in HIDS in two studies (13, 14).

Etanercept does not, however, affect the concentra-tion of serum IgD or the quantity of mevalonic acid

excreted in the urine.

TNF receptor-associated periodic syndrome

In 1982, Williamson and co-workers (15) reported a

large Irish/Scottish family with periodic fever and

inflammation, but with autosomal dominant inheri-

tance. The symptoms resembled those of FMF, but

there was a longer duration of the febrile attacks and

a good response to corticosteroids. This periodicsyndrome was named familial Hibernian fever

(FHF) because of the Irish/Scottish ancestry of the

study family. At that time, none of the patients had

developed amyloidosis, but a 14-year follow-up

study revealed amyloidosis in one of the 16 affected

family members (16). Through linkage analysis,

candidate genes for the autosomal dominant periodic

fever syndromes were located in a common region ofchromosome 12p13 (17).Ta

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134 S Stjernberg-Salmela et al

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An international research consortium discoveredthat the TNF-a-receptor type 1 gene (TNFRSF1A)

was responsible for the syndrome and reported

missense mutations in six different codons of this

gene in seven different families, one of which was

Finnish (18). With the discovery of the affected gene,

FHF was renamed TRAPS. To date, 44 different

TNFRSF1A mutations have been reported (10). Of

these, 33 are confirmed true mutations (Figure 1). Inaddition to the two Finnish families described by us

(18, 21, 22), a Swedish family with amyloidosis and

periodic fever, reported already in 1968 (23), as well

as a recently reported Danish family (20), and the

family described in this issue are the only TRAPS

patients reported from the Nordic countries.

Unlike in FMF and in HIDS, the symptoms in

TRAPS show a good response to corticosteroids.A more specific treatment is etanercept, which is

recommended in combination with corticosteroid

therapy, especially when prolonged courses or large

doses of corticosteroids are required (24).

The mutation in the Finnish family described in

1999 (18) was a C88Y (350 G-wA) mutation in

exon 4, resulting in the substitution of cysteine

with tyrosine. A second mutation in another Finnishfamily was identified in exon 4 of the third

extracellular domain of TNFRSF1A (22). This T-

wA missense mutation causes an amino acid

substitution (F112I) of phenylalanine with isoleu-

cine, close to a conserved cysteine at residue 114 and

a disulphide bond, and was the first to be reported in

the third extracellular domain. In all Finnish TRAPS

families studied, the patients have had lower levelsof soluble TNFRSF1A than healthy controls. A

shedding defect of the TNFRSF1A, after stimula-

tion by the metalloproteinase inducer phorbol myri-

state acetate (PMA), was observed in the affected

individuals from the two Finnish families studied.

Other dominantly inherited autoinflammatory disorders

Similar symptoms of fever, urticarial rash, and poly-

morphonuclear leukocyte infiltrations in skin bio-psies characterize the dominantly inherited MWS,

FCAS, and CINCA (25). Mutations in a common

gene, CIAS1 — the gene encoding cryopyrin and

located on chromosome 1q44, were reported as the

underlying cause of all three of these periodic fevers

(26, 27). Cryopyrin is known to both induce and

resolve inflammation by increasing processing and

secretion of the proinflammatory cytokine IL-1b

and by stimulating activation of the transcription

factor NF-kB, which has a dual function of

promoting and resolving inflammatory reactions

(28). Characteristic for FCAS is the appearance of

urticaria upon exposure to cold, whereas neurologi-

cal findings are typical in MWS and CINCA.

Sensorineural hearing loss occurs in both MWS

and CINCA, but the neurological manifestations are

more severe in CINCA, and include chronic

meningitis, mental retardation, cerebral atrophy,

and cerebral ventricular dilatation. Deficient carti-

lage growth is another important feature in CINCA.

The Blau syndrome is an autosomally dominantly

inherited disease characterized by joint inflamma-

tion, uveitis, rash, and flexion contraction of one or

more fingers (2). The genetic background of the Blau

syndrome is a mutation of the NBS domain of the

gene CARD15 or NOD2 located on chromosome

16q12.1 (29,30). CARD15/NOD2 encodes a protein

with two caspase recruitment domains (CARDs), a

nucleotide binding site (NBS), and a group of

leucine-rich repeats (LRRs), through which the

protein interacts with polysaccharides to induce

NF-kB activation (2).

Another autosomally dominantly inherited disorder

is the PAPA syndrome, the underlying genetic

deficiency of which is a mutation of the gene

encoding for CD2 binding protein-1 (CD2BP1),

located on chromosome 15q (31). Mutations of

CD2BP1 result in the hyperphosphorylation of the

protein, as a result of inadequate interactions with

phosphatases (2). As CD2BP1 interacts with pyrin, it

is believed that a mutation of CD2BP1 may cause an

inappropriate binding of CD2BP1 to pyrin, resulting

in a defect in the anti-apoptotic and anti-inflamma-

tory effects of pyrin.

8 9

2 3 4

10

5 6 I170N 7

C98YC96Y

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TNFRSFIA YRHYWSENLFQCFNCSLCL _ _ _ _ _ _ _ NG _ _ _ T _ VHLSCQEKQNTVC _ TCHAGFFLRE _ _ _ _ NECVSCSNC _ _ _ _ KKSLECTKLCLPQIENVKG

TNFRSFIA CPQGKYIHPQNNSICCTKCHKGTYLYNDCPGPGQDTDCREC _ ESGSFTASENHLR _ HCLSC _ SKCRKEMGQVEISS _ CTVDRDTVCGCRKNQ

Figure 1. The TNFRSF1A amino acid sequence showing the extracellular domains and the 33 confirmed true mutations reported

(2, 10, 19, 20), as well as the mutation reported in this issue. Disulphide bonds are numbered and represented by lines. The

TNFRSF1A amino acid sequence is based on the picture in the article reporting the original seven point mutations in TNFRSF1A

(18).

Systemic autoinflammatory disorders 135

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Functions of the affected genes in relation toinflammation

The mutations in each autoinflammatory disorder

affect genes involved in inflammatory response

transmission. A mutation in MEFV or CIAS1

affects the inflammatory reaction mediated by pyrin

and cryopyrin, respectively, but the pathway by

which this occurs is as yet uncertain.

Pyrin and cryopyrin contain a death domain (DD)

resembling pyrin domain (PyD), which interacts with

the adaptor protein, apoptosis speck-like protein

with a caspase recruitment domain (ASC), to form

an ‘inflammasome’ (32) (Figure 2). ASC induces

apoptosis and activates NF-kB, as well as caspase 5

and caspase 1, through pro-caspase 1-activation.

Caspase 1 then cleaves the interleukin-1b (IL-1b)

precursor to produce its activated form. NF-kB is

involved both in inducing and resolving inflamma-

tion (28), by acting as a transcription factor on

promoters of certain target genes (34). Recent data

also shows that pyrin interacts with ASC to inhibit

apoptosis and NF-kB activation (33).

Cryopyrin, on the other hand, appears to induce

NF-kB activation through its interaction with

ASC (28). Cryopyrin has a structure similar to the

NOD-proteins, which might suggest a functional

resemblance between the two (28). Whether or not

cryopyrin mediates apoptosis through ASC is still

unclear. Data suggesting that pyrin regulates inflam-

matory processes through interactions with the

leukocyte cytoskeleton have also been reported (36).

TNF is a cytokine with multiple functions, includ-

ing apoptotic and necrotic cell death induction,

inflammation, tumour genesis, and viral replication.

Its main function, however, is the regulation of

immune cells (37). Two types of cell-surface

receptors specific for TNF have been identified,

TNFR1 (CD120a, p55TNFR, TNFRSF1A) and

TNFR2 (CD120b, p75TNFR, TNFRSF1B). These

TNF receptor subtypes are single transmembrane

glycoproteins, both with four extracellular cysteine-

rich motifs, repeated in tandem. The extracellular

domains of each TNF receptor possess a pre-ligand-

binding assembly domain PLAD, which induces

trimerization of the receptors themselves upon

ligation of TNF. The intracellular sequences of

TNFRSF1A and TNFRSF1B have little homology,

but both contain sequences that interact with

adaptor proteins and TNF-receptor associating

factors (TRAFs), activating intracellular processes.

Figure 2. The assumed pathway through which pyrin interacts with apoptosis-associated speck-like protein with a caspase recruitment

domain (ASC) through pyrin domain (PyD) contact to inhibit apoptosis. By binding to ASC, pyrin inhibits the interaction between

ASC and caspase-8, which is the pro-apoptotic mediator in the protein cascade (33). The pathway through which pyrin and cryopyrin

are assumed to affect NF-kB activation and IL-1b-secretion are also represented in Figure 2. ASC interacts with pro-caspase-1 to yield

caspase-1. Caspase-1, caspase-5, ASC and NALP1 form an inflammasome, which initiates the proteolytic cleavage of proIL-1b(32), con-

verting it to its active form, IL-1b. ASC interacts with inhibitor of kB kinase (IKK)-complex directly through its pyrin, AIM, ASC and

death domain-like (PAAD) domain (34), or using an intermediate adaptor protein, such as the receptor-interacting protein (RIP)-like inter-

acting CARP kinase (RICK), or another kinase with homologous function (28). The kinase or intermediate region of RICK binds to

the inhibitor of kB kinase (IKK) c subunit in the IKK complex. The IKK complex activates neighbouring NF-kB by phosphorylating

an inhibitor of NF-kB, IkB, subsequently releasing NkB (33, 34). NF-kB acts as a transcription factor to induce or resolve inflamma-

tion, whereas IL-1b is involved in mediating inflammatory responses. Apoptosis may also be induced by ASC through caspase-1 path-

ways or IKK-complex activation (28, 35). It is still unclear whether cryopyrin, in similarity to pyrin, induces apoptosis.

136 S Stjernberg-Salmela et al

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The intracellular part of TNFRSF1A contains a

death domain (DD), which interacts with various

associating proteins and other molecules to induce

apoptosis (Figure 3). Caspase-activation, pro-

apoptotic ceramide production, as well as liga-

tion to certain adaptor proteins are specific for

TNFRSF1A and are made possible through its DD

motif (37). DD interacts with the adaptor protein

TNF receptor-associated DD-containing protein

(TRADD) to activate the inhibitor of kB kinase

(IKK) complex, with subsequent phosphorylation of

inhibitor of kB (IkB) and release of NF-kB. The

production of most pro-inflammatory cytokines

induced by TNF is initiated by the transcription

factor NF-kB (35).

TNFRSF1A is a cell-surface receptor, but it is also

located intracellularly at the perinuclear Golgi

complex (37). Soluble and membrane-bound TNF

(mTNF) activate TNFRSF1A equally well. Follow-

ing enzymatic cleavage of the receptor from the

cell surface by TNF-a converting enzyme (TACE)/

ADAM 17, belonging to the ‘a disintegrin and

metalloprotease’ (ADAM) family of proteins, solu-

ble TNFRSF1A is present in serum. Shedding of

TNFRSF1A from the cell membrane is stimulated

by proinflammatory cytokines.

TNFRSF1B is likewise a cell-surface receptor,

but its functions are not as well known as those

of TNFRSF1A. TNFRSF1B has a greater affinity

for TNF and a longer half-life of binding thandoes TNFRSF1A. TNFRSF1B is activated by

both mTNF and soluble TNF, but mTNF is much

more efficient in activating TNFRSF1B than is

soluble TNF, which acts rather like a partial

agonist of TNFRSF1B (39,40). No inherited muta-

tions have been detected in the gene coding for

TNFRSF1B.

Conclusions

The hereditary periodic autoinflammatory disorders

constitute a heterogeneous group of syndromes

where the underlying cause is a mutation in a genecoding for proteins with various functions in the

inflammatory processes. Identification of the gene

mutations responsible for each autoinflammatory

disorder has disclosed new information about basic

inflammatory mechanisms. All eight syndromes

described are characterized by an inappropriate

and prolonged inflammatory reaction, without

antigen-specific T-cell activation or the presence ofautoantibodies.

Figure 3. Some of the intracellular pathways through which TNF interacts with TNFRSF1A to activate intracellular pathways are

depicted in this figure. Activation of TNFRSF1A by ligation of TNF activates the TRADD-protein through DD interaction. TRADD

activates a number of adaptor proteins, including the Fas-associated death domain (FADD), which binds caspase-8 to induce apoptosis

(37). TRADD also interacts with TNF receptor-associating factors (TRAFs). TRAF2 is activated by TRADD, subsequently activating

a cytokine cascade. The activation of the cytokine cascade leads to the activation of the enzyme inhibitor of kB (IkB) kinase (IKK),

which consists of three subunits (a,b, and c) (38). IKK phosphorylates IkB, leading to the release of NF-kB, which acts as a trans-

cription factor for most pro-inflammatory cytokines (35). Recent data suggest that ASC causes a decrease in NF-kB activity, probably

through its pyrin, AIM, ASC, and DD-like (PAAD) domain interaction with IKK, when stimulated by TNF-a (34). A number of inhi-

bitory proteins, such as silencer of DD (SODD) and BRE, a stress-related protein expressed in the brain and reproductive organs,

interact with TNFRSF1A to down-regulate intracellular activation pathways (37). (A) represents the TNF-a activation pathways in a

healthy individual. A large proportion of the transmembrane receptors are cleaved upon stimuli by TNF, leaving only small amounts

of receptors in the cell membrane. (B) Represents the same TNF-a activation pathways in an individual with a TNFRSF1A mutation.

Low levels of soluble TNFRSF1A are detected, whereas a large proportion of the transmembrane receptors stay in the cell membrane.

Systemic autoinflammatory disorders 137

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It is believed that the pathomechanism behind

FMF is the activation of ASC by pyrin, whereas the

activation of ASC by cryopyrin appears to accountfor the clinical picture in MWS, FCAS and CINCA.

The pathomechanism of inflammation in TRAPS

is still incompletely understood, but intracellular

activation of NF-kB, resulting in transcription of

pro-inflammatory cytokines has been demon-

strated. All these mechanisms of inflammation were

unknown until only a few years ago.

Since 1997, when MEFV was discovered to be theunderlying gene in FMF, 72 MEFV mutations have

been reported in patients with Arabian, Armenian,

European, Greek, Indian, Japanese, Jewish, and

Turkish origin (10, 41). HIDS has been reported

in Dutch, French, and Spanish patients, as well

as in a Caucasian/Afro-Caribbean and an Irish/

Albanian patient (10, 14). After the identification of

TNFRSF1A as the gene behind TRAPS and theinitial description of mutations in that gene, TRAPS

has been reported in Australian, Belgian, British,

Czech, Danish, Dutch, French, German, Italian,

Japanese, Kabylian, Polish, Portuguese, Puerto-

Rican, Sardinian/Sicilian, Spanish, North-American,

including Afro – American, and Mexican, as well as

in Arab and Jewish patients (2, 10, 19, 20). In the

Nordic countries, TRAPS appears to be the mostprobable autoinflammatory disorder to keep in

mind when investigating patients with recurring

attacks of fever and inflammation, and with a

positive family history indicating a dominant mode

of inheritance.

Acknowledgements

This study was supported by grants from the Helsinki University

Central Hospital Research Funds, the Finska Lakaresallskapet

and the Finnish Medical Society Duodecim. We thank Dr Michael

F McDermott, MD, PhD (Queen Mary’s School of Medicine

and Dentistry, London, UK) for helpful discussions. We also

thank Seija Rusanen at Duodecim for her skillful assistance with

Figures 2 and 3.

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