Novel evidences of atypical manifestations in cryopyrin-associated periodic syndromes.

OBJECTIVES: Cryopyrin-associated periodic syndromes (CAPS) usually start during infancy as an urticarial-like rash and a marked acute phase response, with additional manifestations appearing during its evolution. The aim of this study was to expand the clinical diversity of CAPS by the description of novel atypical features. METHODS: Clinical data were collected from patients' medical charts. Sanger sequencing analyzed NLRP3. Response to anti-IL-1 blockade was evaluated by clinical assessments and by measurements of laboratory parameters. RESULTS: Seventeen patients from two families (A and B), carrying the p.Ala439Thr and p.Arg260Trp NLRP3 mutations respectively, were enrolled. The disease was unexpectedly atypical in all members of Family A, with a 16-year-old asymptomatic carrier, and onset in adulthood associated with absence of skin lesions in four affected members. Surprisingly, one patient from each family suffered from severe haemorrhagic cystitis due to AA amyloidosis in the urinary bladder. Members of Family B displayed a classical phenotype, with two patients suffering from olfactive disorders. CONCLUSIONS: Our evidence suggests that CAPS may occasionally be presented as a late-onset, recurrent inflammatory disease without urticarial-like rash. In some patients, AA amyloidosis in strange locations like urinary bladder may complicate the clinical course. The response to IL-1 blockade in these atypical CAPS was similar to that described in classical forms. Consequently, we suggest that CAPS should be included in the differential diagnosis of adult patients with unexplained, recurrent inflammatory diseases, and once confirmed, the early initiation of anti-IL-1 blockade will probably prevent the development of life-threatening complications.

Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes.

UNLABELLED: : Familial cold autoinflammatory syndrome, Muckle-Wells syndrome (MWS), and chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome are dominantly inherited autoinflammatory diseases associated to gain-of-function NLRP3 mutations and included in the cryopyrin-associated periodic syndromes (CAPS). A variable degree of somatic NLRP3 mosaicism has been detected in ≈35% of patients with CINCA. However, no data are currently available regarding the relevance of this mechanism in other CAPS phenotypes. OBJECTIVE: To evaluate somatic NLRP3 mosaicism as the disease-causing mechanism in patients with clinical CAPS phenotypes other than CINCA and NLRP3 mutation-negative. METHODS: NLRP3 analyses were performed by Sanger sequencing and by massively parallel sequencing. Apoptosis-associated Speck-like protein containing a CARD (ASC)-dependent nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB) activation and transfection-induced THP-1 cell death assays determined the functional consequences of the detected variants. RESULTS: A variable degree (5.5-34.9%) of somatic NLRP3 mosaicism was detected in 12.5% of enrolled patients, all of them with a MWS phenotype. Six different missense variants, three novel (p.D303A, p.K355T and p.L411F), were identified. Bioinformatics and functional analyses confirmed that they were disease-causing, gain-of-function NLRP3 mutations. All patients treated with anti-interleukin1 drugs showed long-lasting positive responses. CONCLUSIONS: We herein show somatic NLRP3 mosaicism underlying MWS, probably representing a shared genetic mechanism in CAPS not restricted to CINCA syndrome. The data here described allowed definitive diagnoses of these patients, which had serious implications for gaining access to anti-interleukin 1 treatments under legal indication and for genetic counselling. The detection of somatic mosaicism is difficult when using conventional methods. Potential candidates should benefit from the use of modern genetic tools.

Aeroallergen sensitization influences quality of life and comorbidities in patients with nasal polyposis.

BACKGROUND: Nasal polyposis (NP) is a chronic inflammatory disease of unknown etiology that impairs quality of life (QoL). The role of atopy in NP is not established. The aim of this study was to describe the clinical characteristics and QoL in a broad sample of patients with NP and to evaluate the influence of allergy on this disease. METHODS: A multicenter, observational, cross-sectional study was conducted in 67 allergy units in Spain. NP and nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity were diagnosed following EP(3)OS guidelines. Rhinitis and asthma were classified following Allergic Rhinitis and Its Impact on Asthma and the Global Initiative for Asthma guidelines, respectively. Skin tests with a battery of aeroallergens were performed on all patients. A visual analog scale (VAS) and Short-Form 12 (SF-12) and 31-item Rhinosinusitis Outcome Measure (RSOM 31) questionnaires were completed by all the patients. RESULTS: Of the 671 patients included, 611 were evaluable. Mean age was 46 years and 50% of patients were men. Also, 50% were atopic. Asthma was present in 66% of patients and NSAID hypersensitivity was present in 26%. The most frequent symptoms were nasal congestion and rhinorrhea. Mean value of VAS was 58.6. Global health and bodily pain were the items most frequently identified in the SF-12 questionnaire and nasal and ocular symptoms in the RSOM-31 questionnaire. There was a good correlation between VAS score and QoL (p < 0.0001). Rhinitis was more severe in nonallergic patients. Asthma was more frequent in atopic patients, whereas ASA triad was more frequent in nonatopic patients. Atopic patients showed higher VAS scores and worse QoL. CONCLUSION: Atopic NP patients showed worse QoL, higher incidence of asthma and a less severe form of rhinitis than non-atopic patients.