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Rheumatology Advance Access published online on January 3, 2008
Rheumatology, doi:10.1093/rheumatology/kem318
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© Published by Oxford University Press on behalf of the British Society for Rheumatology 2007.

New CIAS1 mutation and anakinra efficacy in overlapping of Muckle–Wells and familial cold autoinflammatory syndromes

L. Maksimovic1, J. Stirnemann1, F. Caux1,2, N. Ravet3, S. Rouaghe1, L. Cuisset4, E. Letellier1, G. Grateau3, A.-S. Morin1 and O. Fain1

1Service de Médecine Interne, Hôpital Jean Verdier, Assistance Publique-Hôpitaux de Paris, Université Paris 13, 2Service de Dermatologie, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Université Paris 13, 3Service de Médecine Interne, Hôpital Tenon, Assistance Publique-Hôpitaux de Paris, Université Paris 6 and 4Laboratoire de Biochimie Génétique, Hôpital Cochin, Université Paris 5, Paris, France.

Correspondence to: N. Ravet, Service de Médecine Interne, Hôpital Tenon, 4 Rue de la Chine, 75020 Paris, France. E-mail: ravetnathalie73{at}yahoo.fr


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. Muckle–Wells syndrome (MWS) and familial cold autoinflammatory syndrome (FCAS) are rare periodic fevers associated with CIAS1 mutations. A third entity, the chronic infantile neurological, cutaneous, articular (CINCA) syndrome was also recently associated with mutation in the same gene. A phenotypic and genotypic continuum seems to exist from the most benign (FCAS) to the most severe forms (CINCA). Although a CIAS1 mutation can be associated with two different phenotypes.

Methods. We report a family of three patients exhibiting the MWS and FCAS phenotypes. These phenotypes were associated with a novel missense mutation in CIAS1.

Results. Anakinra controlled inflammatory flares in the three patients.

Conclusions. FCAS, MWS and CINCA could be different phenotype expressions of the same disease.

KEY WORDS: Muckle–Wells syndrome (MWS), Familial cold autoinflammatory syndrome (FCAS), CIAS1, Anakinra, Cryopyrin-associated periodic syndromes (CAPS)


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Muckle–Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and chronic infantile neurological, cutaneous, articular (CINCA) syndrome are dominantly inherited auto-inflammatory diseases associated with CIAS1 mutations and form a part of the hereditary periodic fever. They are defined by recurrent attacks of generalized inflammation lasting 2–3 days, induced by a variety of factors. MWS is characterized by urticaria, fever, arthralgia and progressive sensorineural hearing loss. Amyloidosis is rare and represents the principal complication [1].

The FCAS is characterized by intermittent urticaria, arthralgia, fever and conjunctivitis triggered by exposure to cold [1, 2]. MWS and FCAS are associated with heterozygous mutations in the CIAS1/NALP3/PYPAF1 gene that encodes a protein known as NALP3 or cryopyrin, which is a member of the recently characterized pyrin superfamily of death domain-fold proteins [3]. The CINCA syndrome has been associated with CIAS1 mutation too [4, 5].


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
We report a novel CIAS1 mutation (V262G), clinical overlap in three family members and the efficacy of anakinra.

A 48-yr-old man (Patient III-2, Fig. 1) was referred to our internal medicine unit for crisis of chronic urticaria and arthralgia. Clinical manifestations started at 6 months of age and were associated with recurrent fever, non-destructive polyarthritis, conjunctivitis and urticarial eruptions after exposure to cold, occurring every few days. An audiogram showed bilateral sensorineural deafness.


Figure 1
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  		FIG. 1. French family with a hereditary autoinflammatory disorder. Open circle, female; open square, male; shaded, affected; slashed, decreased.

 
His 16-yr-old son (Patient IV-1, Fig. 1) had clinical manifestations triggered by exposure to cold, lasting 12 h every day. He mainly had chronic urticaria and arthralgias rarely accompanied by fever and conjunctivitis since the age of 6 months.

His 20-yr-old daughter (Patient IV-2) had clinical manifestations that began at 14 yrs of age with ankle and wrist arthralgia. She had acute episodes, lasting 3 days, of non-pruritic urticaria with fever and conjunctivitis evolving by flares induced by emotional stress, infection or fatigue. In the two children, audiograms did not present hearing loss. No clinical evidence of secondary amyloidosis was reported. No symptoms suggestive of CINCA syndrome were found in this family.

Peripheral blood was obtained from patients and genomic DNA was extracted as previously described [3]. The heterozygous mutation c.785T>G resulting in valine-to-glycine substitution at position 262 (V262G) was identified in the three patients who were tested [6].

The three subjects consented to undergo a treatment with anakinra, an interleukin-1β receptor antagonist (IL-1Ra). The drug was self-administered by subcutaneous injection using an initial dosing schedule of 100 mg/day.


   Results
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 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Responses to treatment were documented by clinical consultations at monthly intervals. Potential adverse effects of IL1-Ra were monitored according to the recommendations for patients with rheumatoid arthritis. Inflammatory attacks disappeared completely and immediately in all the three patients and never recurred for Patients III-2 and IV-1. After 10 days of treatment, IL1-Ra was stopped in Subject IV-2 because allergic papules appeared at the injection sites. After its withdrawal MWS reappeared. IL-1Ra was reintroduced 15 days later combined with prednisolone and antihistamine drugs for 1 month and no urticarial rash recurred.

After 6 months, IL1-Ra was reduced to 100 mg every other day and symptoms were controlled for all three patients. However, symptoms recurred when the regimen was further reduced to 100 mg every 3 days. An audiogram at 6 months showed that the father's deafness was unchanged.


   Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
We described an MWS phenotype in Patient IV-2 (absence of hearing loss may be explained by her young age), an FCAS in her brother (Patient IV-1) and an MWS–FCAS overlap in their father (Patient III-2). Overlap of MWS and CINCA clinical phenotypes or MWS–FCAS symptoms were described in the same patient [7, 8]. Different intrafamilial phenotypes resulting from the same CIAS1 mutation were recently described [6]. Finally, the same CIAS1 mutation was identified in the two families with MWS and two others with FCAS, of different ethnic origins, thereby demonstrating that a single CIAS1 mutation may be present in both syndromes [9]. All these observations suggest that FCAS, MWS and CINCA could be different phenotypic expressions of the same disease. The term cryopyrin-associated periodic syndromes (CAPS) was recently proposed to refer a group of heterogeneous clinical manifestations sharing CIAS1 mutations as a common molecular basis [10].

CIAS1 sequencing identified a previously unknown mutation involved in these CAPS. CIAS1 has been located in chromosomal region 1q44 [3]. To date, 65 sequence variations have been described and the majority are located in exon 3. The mutation found in our family and involving amino acid (AA) 262 (V262G) was never reported, but another mutation in the same codon (V262A) has. This patient presented the CINCA phenotype [4].

Although valine and glycine belong to the same AA class, several arguments support the responsibility of this mutation for the clinical manifestations. First, it is located in exon 3, as are all other CAPS mutations. Second, its position is close to AA264 and AA260, mutations previously associated with CAPS, like R260W, R260L and R260P. Indeed, R260W is one of the most frequent mutations found in CAPS, whereas L264H and L264R were detected in CINCA patients. These findings suggest that AA260, AA262 and AA264 might belong to a cryopyrin functional domain. Finally, the V262G variant was not found in 400 independent chromosomes, which makes it not very probable that this mutation represents a polymorphism. This gene is already the seat of a mutation located in an important area taking part in the structure of molecule CIAS1 according to a hexameric model. The remarkable efficacy of IL-1Ra should be addressed. Cryopyrin, encoded by CIAS1, regulates the production of pro-inflammatory cytokines like IL-1β [11]. IL-1β was up-regulated in unstimulated monocytes obtained from a patient with mutated CIAS1 [4]. IL-1 enhanced production of pro-inflammatory cytokines during the acute-phase response. IL-1Ra is a recombinant non-glycosylated homologue of human IL-1β that competitively inhibits the binding of IL-1{alpha} and IL-1β to membrane IL-1 receptor type 1. Treatment of MWS patients with IL-1Ra led to the rapid disappearance of their inflammatory symptoms [11, 12]. To date, its use as reported by some patients has demonstrated remarkable clinical and biological efficacy, with net regression of markers of inflammation, and sometimes reversal of hearing loss and amyloidosis [13–15].

Our patients’ complete and rapid clinical responses to IL1-Ra were associated with good tolerance except for transient local allergic reactions in one. Our results are in accordance with those described for 15 patients by Leslie et al. [15] and confirm that IL-1β plays a fundamental role in the pathogenesis of inflammation associated with CIAS1 mutations [16].

Formula

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Hentgen V, Despert V, Lepretre AC, et al. Intrafamilial variable phenotypic expression of a CIAS1 mutation: from Muckle-Wells to chronic infantile neurological cutaneous and articular syndrome. J Rheumatol (2005) 32:747–51.[Abstract/Free Full Text]
  2. Hoffman HM, Wanderer AA, Broide DH. Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol (2001) 108:615–20.[CrossRef][Web of Science][Medline]
  3. Cuisset L, Drenth JP, Berthelot JM, et al. Genetic linkage of the Muckle-Wells syndrome to chromosome 1q44. Am J Hum Genet (1999) 65:1054–9.[CrossRef][Web of Science][Medline]
  4. Aksentijevich I, Putnam D, Remmers EF, et al. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum (2007) 56:1273–85.[CrossRef][Web of Science][Medline]
  5. Feldmann J, Prieur AM, Quartier P, et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet (2002) 71:198–203.[CrossRef][Web of Science][Medline]
  6. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet (2001) 29:301–5.[CrossRef][Web of Science][Medline]
  7. Granel B, Philip N, Serratrice J, et al. CIAS1 mutation in a patient with overlap between Muckle-Wells and chronic infantile neurological cutaneous and articular syndromes. Dermatology (2003) 206:257–9.[CrossRef][Web of Science][Medline]
  8. Aganna E, Martinon F, Hawkins PN, et al. Association of mutations in the NALP3/CIAS1/PYPAF1 gene with a broad phenotype including recurrent fever, cold sensitivity, sensorineural deafness, and AA amyloidosis. Arthritis Rheum (2002) 46:2445–52.[CrossRef][Web of Science][Medline]
  9. Dode C, Le Du N, Cuisset L, et al. New mutations of CIAS1 that are responsible for Muckle-Wells syndrome and familial cold urticaria: a novel mutation underlies both syndromes. Am J Hum Genet (2002) 70:1498–506.[CrossRef][Web of Science][Medline]
  10. Arostegui JI, Aldea A, Modesto C, et al. Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene. Arthritis Rheum (2004) 50:4045–50.[CrossRef][Web of Science][Medline]
  11. Hoffman HM, Rosengren S, Boyle DL, et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet (2004) 364:1779–85.[CrossRef][Web of Science][Medline]
  12. Hawkins PN, Lachmann HJ, Aganna E, McDermott MF. Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum (2004) 50:607–12.[CrossRef][Web of Science][Medline]
  13. Mirault T, Launay D, Cuisset L, et al. Recovery from deafness in a patient with Muckle-Wells syndrome treated with anakinra. Arthritis Rheum (2006) 54:1697–700.[CrossRef][Web of Science][Medline]
  14. Rynne M, Maclean C, Bybee A, McDermott MF, Emery P. Hearing improvement in a patient with variant Muckle-Wells syndrome in response to interleukin 1 receptor antagonism. Ann Rheum Dis (2006) 65:533–4.[Abstract/Free Full Text]
  15. Leslie KS, Lachmann HJ, Brunin E, et al. Phenotype, genotype, and sustained response to anakinra in 22 patients with autoinflammatory disease associated with CIAS-1/NALP3 mutations. Arch Dermatol (2006) 142:1591–7.[Abstract/Free Full Text]
  16. Goldbach-Mansky R, Dailey NJ, Scott W, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition. N Engl J Med (2006) 355:581–92.[Abstract/Free Full Text]
Submitted 19 June 2007; revised version accepted 31 October 2007.
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This Article
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