Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry.

OBJECTIVE: To evaluate genetic, demographic and clinical features in patients with cryopyrin-associated periodic syndrome (CAPS) from the Eurofever Registry, with a focus on genotype-phenotype correlations and predictive disease severity markers. METHODS: A web-based registry retrospectively collected data on patients with CAPS. Experts in the disease independently validated all cases. Patients carrying NLRP3 variants and germline-mutation-negative patients were included. RESULTS: 136 patients were analysed. The median age at disease onset was 9 months, and the median duration of follow-up was 15 years. Skin rash, musculoskeletal involvement and fever were the most prevalent features. Neurological involvement (including severe complications) was noted in 40% and 12% of the patients, respectively, with ophthalmological involvement in 71%, and neurosensory hearing loss in 42%. 133 patients carried a heterozygous, germline mutation, and 3 patients were mutation-negative (despite complete NLRP3 gene screening). Thirty-one different NLRP3 mutations were recorded; 7 accounted for 78% of the patients, whereas 24 rare variants were found in 27 cases. The latter were significantly associated with early disease onset, neurological complications (including severe complications) and severe musculoskeletal involvement. The T348M variant was associated with early disease onset, chronic course and hearing loss. Neurological involvement was less strongly associated with V198M, E311 K and A439 V alleles. Early onset was predictive of severe neurological complications and hearing loss. CONCLUSIONS: Patients carrying rare NLRP3 variants are at risk of severe CAPS; onset before the age of 6 months is associated with more severe neurological involvement and hearing loss. These findings may have an impact on treatment decisions.

The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry.

OBJECTIVE: To evaluate the genetic findings, demographic features and clinical presentation of tumour necrosis factor receptor-associated autoinflammatory syndrome (TRAPS) in patients from the Eurofever/EUROTRAPS international registry. METHODS: A web-based registry collected retrospective data on patients with TNFRSF1A sequence variants and inflammatory symptoms. Participating hospitals included paediatric rheumatology centres and adult centres with a specific interest in autoinflammatory diseases. Cases were independently validated by experts in the disease. RESULTS: Complete information on 158 validated patients was available. The most common TNFRSF1A variant was R92Q (34% of cases), followed by T50M (10%). Cysteine residues were disrupted in 27% of cases, accounting for 39% of sequence variants. A family history was present in 19% of patients with R92Q and 64% of those with other variants. The median age at which symptoms began was 4.3 years but 9.1% of patients presented after 30 years of age. Attacks were recurrent in 88% and the commonest features associated with the pathogenic variants were fever (88%), limb pain (85%), abdominal pain (74%), rash (63%) and eye manifestations (45%). Disease associated with R92Q presented slightly later at a median of 5.7 years with significantly less rash or eye signs and more headaches. Children were more likely than adults to present with lymphadenopathy, periorbital oedema and abdominal pains. AA amyloidosis has developed in 16 (10%) patients at a median age of 43 years. CONCLUSIONS: In this, the largest reported case series to date, the genetic heterogeneity of TRAPS is accompanied by a variable phenotype at presentation. Patients had a median 70 symptomatic days a year, with fever, limb and abdominal pain and rash the commonest symptoms. Overall, there is little evidence of a significant effect of age or genotype on disease features at presentation.

Widening the Neuroimaging Features of Adenosine Deaminase 2 Deficiency.

Adenosine deaminase 2 deficiency (OMIM #615688) is an autosomal recessive disorder characterized by a wide clinical spectrum, including small- and medium-sized vessel vasculopathies, but data focusing on the associated neuroimaging features are still scarce in the literature. Here, we describe the clinical neuroimaging features of 12 patients with genetically proven adenosine deaminase 2 deficiency (6 males; median age at disease onset, 1.3 years; median age at genetic diagnosis, 15.5 years). Our findings expand the neuroimaging phenotype of this condition demonstrating, in addition to multiple, recurrent brain lacunar ischemic and/or hemorrhagic strokes, spinal infarcts, and intracranial aneurysms, also cerebral microbleeds and a peculiar, likely inflammatory, perivascular tissue in the basal and peripontine cisterns. Together with early clinical onset, positive family history, inflammatory flares and systemic abnormalities, these findings should raise the suspicion of adenosine deaminase 2 deficiency, thus prompting genetic evaluation and institution of tumor necrosis factor inhibitors, with a potential great impact on neurologic outcome.

Macrophage migration inhibitory factor (MIF) and oligoarticular juvenile idiopathic arthritis (o-JIA): association of MIF promoter polymorphisms with response to intra-articular glucocorticoids.

OBJECTIVES: To address the clinical relevance of macrophage migration inhibitory factor (MIF) promoter polymorphisms in oligoarticular juvenile idiopathic arthritis (o-JIA) by evaluating their associations with serum and SF MIF levels, with response to intra-articular glucocorticoid injections and with outcome of the disease. METHODS: Seventy-five Caucasian patients with o-JIA were studied. Alleles of the -794 CATT variable number of tandem repeats (VNTR) and of the -173 G/C single nucleotide polymorphism (SNP) were identified by capillary electrophoresis following fluorescently labelled PCR and by allelic discrimination assay, respectively. MIF levels were measured by ELISA. The association of MIF promoter polymorphisms with polyarticular extension, Childhood Health Assessment Questionnaire (CHAQ) score at the last follow-up visit and occurrence of chronic anterior uveitis was evaluated only in patients with a follow up > 5 years. RESULTS: Neither of the MIF promoter polymorphisms was associated with serum MIF levels, nor with the long-term outcome of o-JIA. The -173 G/C SNP was significantly associated with both SF MIF levels and duration of response to intra-articular glucocorticoid injection. Carriers of a MIF -173 C allele were 4 times more likely to relapse within 3 months. No association was found between the different MIF CATT alleles and both SF MIF levels and duration of response to intra-articular glucocorticoids. CONCLUSION: Our study shows the clinical relevance of the MIF -173 G/C SNP in o-JIA and suggests that the -173 C allele may represent a predictor of poor response to intra-articular glucocorticoid treatment.

Herpes Virus Infections During Treatment With Etanercept in Juvenile Idiopathic Arthritis.

Incidence rates for varicella and herpes zoster were similar in patients with juvenile idiopathic arthritis receiving etanercept/methotrexate (n = 85, 184.9 patient-years [PY]) or methotrexate alone (n = 71, 199.4 PY); no complicated varicella or herpes zoster cases were reported; herpes labialis incidence was higher in patients receiving etanercept/methotrexate versus methotrexate alone (0.38 vs. 0.24 PY).

Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM.

CD40 is a member of the tumor necrosis factor receptor superfamily, expressed on a wide range of cell types including B cells, macrophages, and dendritic cells. CD40 is the receptor for CD40 ligand (CD40L), a molecule predominantly expressed by activated CD4(+) T cells. CD40/CD40L interaction induces the formation of memory B lymphocytes and promotes Ig isotype switching, as demonstrated in mice knocked-out for either CD40L or CD40 gene, and in patients with X-linked hyper IgM syndrome, a disease caused by CD40L/TNFSF5 gene mutations. In the present study, we have identified three patients with an autosomal recessive form of hyper IgM who fail to express CD40 on the cell surface. Sequence analysis of CD40 genomic DNA showed that one patient carried a homozygous silent mutation at the fifth base pair position of exon 5, involving an exonic splicing enhancer and leading to exon skipping and premature termination; the other two patients showed a homozygous point mutation in exon 3, resulting in a cysteine to arginine substitution. These findings show that mutations of the CD40 gene cause an autosomal recessive form of hyper IgM, which is immunologically and clinically undistinguishable from the X-linked form.