Silvia Federici

Persistent efficacy of anakinra in patients with tumor necrosis factor receptor–associated periodic syndrome

OBJECTIVE To evaluate the efficacy and safety of treatment with the interleukin-1 receptor antagonist anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) requiring high cumulative doses of steroids. METHODS Four children (mean age 9.1 years [range 4-13 years]) and 1 adult (age 33 years) with TRAPS were enrolled in the study. The 3 children with cysteine mutations (C52Y, C55Y, C43R) had prolonged and frequent attacks of fever. One child with the R92Q mutation and the adult patient with the C43R mutation displayed a more chronic disease course, with fluctuating, nearly continuous symptoms and persistent elevation of acute-phase reactant levels (including serum amyloid A [SAA]). All patients were treated with anakinra (1.5 mg/kg/day). RESULTS All of the patients had a prompt response to anakinra, with disappearance of symptoms and normalization of acute-phase reactant levels, including SAA. In all pediatric patients, anakinra was withdrawn after 15 days of treatment. After a few days (mean 5.6 days [range 3-8]) a disease relapse occurred, which dramatically responded to reintroduction of anakinra. During the following period of observation (mean 11.4 months [range 4-20 months]), the patients did not experience episodes of fever or other disease-related clinical manifestations. Levels of acute-phase reactants remained in the normal range. No major adverse reactions or severe infections were observed. CONCLUSION Continuous treatment with anakinra effectively controlled both the clinical and laboratory manifestations in patients with TRAPS and prevented disease relapses.

A Diagnostic Score for Molecular Analysis of Hereditary Autoinflammatory Syndromes With Periodic Fever in Children

OBJECTIVE To identify a set of clinical parameters that can predict the probability of carrying mutations in one of the genes associated with hereditary autoinflammatory syndromes. METHODS A total of 228 consecutive patients with a clinical history of periodic fever were screened for mutations in the MVK, TNFRSF1A, and MEFV genes, and detailed clinical information was collected. A diagnostic score was formulated based on univariate and multivariate analyses in genetically positive and negative patients (training set). The diagnostic score was validated in an independent set of 77 patients (validation set). RESULTS Young age at onset (odds ratio [OR] 0.94, P = 0.003), positive family history of periodic fever (OR 4.1, P = 0.039), thoracic pain (OR 4.6, P = 0.05), abdominal pain (OR 33.1, P < 0.001), diarrhea (OR 3.3, P = 0.028), and oral aphthosis (OR 0.2, P = 0.007) were found to be independently correlated with a positive genetic test result. These variables were combined in a linear score whose ability to predict a positive result on genetic testing was validated in an independent data set. In this latter set, the diagnostic score revealed high sensitivity (82%) and specificity (72%) for discriminating patients who were genetically positive from those who were negative. In patients with a high probability of having a positive result on genetic testing, a regression tree analysis provided the most reasonable order in which the genes should be screened. CONCLUSION The proposed approach in patients with periodic fever will increase the probability of obtaining positive results on genetic testing, with good specificity and sensitivity. Our results further help to optimize the molecular analysis by suggesting the order in which the genes should be screened.

Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers

The objective of this work was to develop and validate a set of clinical criteria for the classification of patients affected by periodic fevers. Patients with inherited periodic fevers (familial Mediterranean fever (FMF); mevalonate kinase deficiency (MKD); tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS); cryopyrin-associated periodic syndromes (CAPS)) enrolled in the Eurofever Registry up until March 2013 were evaluated. Patients with periodic fever, aphthosis, pharyngitis and adenitis (PFAPA) syndrome were used as negative controls. For each genetic disease, patients were considered to be ‘gold standard’ on the basis of the presence of a confirmatory genetic analysis. Clinical criteria were formulated on the basis of univariate and multivariate analysis in an initial group of patients (training set) and validated in an independent set of patients (validation set). A total of 1215 consecutive patients with periodic fevers were identified, and 518 gold standard patients (291 FMF, 74 MKD, 86 TRAPS, 67 CAPS) and 199 patients with PFAPA as disease controls were evaluated. The univariate and multivariate analyses identified a number of clinical variables that correlated independently with each disease, and four provisional classification scores were created. Cut-off values of the classification scores were chosen using receiver operating characteristic curve analysis as those giving the highest sensitivity and specificity. The classification scores were then tested in an independent set of patients (validation set) with an area under the curve of 0.98 for FMF, 0.95 for TRAPS, 0.96 for MKD, and 0.99 for CAPS. In conclusion, evidence-based provisional clinical criteria with high sensitivity and specificity for the clinical classification of patients with inherited periodic fevers have been developed.

Differentiating PFAPA syndrome from monogenic periodic fevers

OBJECTIVES: To analyze whether there were clinical differences between genetically positive and negative patients fulfilling periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria and to test the accuracy of the Gaslini diagnostic score for identifying patients with PFAPA syndrome with higher probabilities of carrying relevant mutations in genes associated with periodic fevers. METHODS: Complete clinical and genetic information was available for 393 children with periodic fever; 82 had positive genetic test results, 75 had incomplete genetic test results, and 236 had negative results for MVK, TNFRSF1A, and MEFV mutations. Current diagnostic criteria for PFAPA syndrome were applied. RESULTS: Of 393 children, 210 satisfied PFAPA syndrome criteria; 43 carried diagnostic mutations (mevalonate kinase deficiency: n = 33; tumor necrosis factor receptor-associated periodic syndrome: n = 3; familial Mediterranean fever: n = 7), 37 displayed low-penetrance mutations or incomplete genotypes, and 130 demonstrated negative genetic testing results. Genetically positive patients had higher frequencies of abdominal pain and diarrhea (P < .001), vomiting (P = .006), and cutaneous rash and arthralgia (P = .01). Genetically negative patients had a higher frequency of exudative pharyngitis (P = .010). Genetically undetermined patients showed the same pattern of symptom frequency as genetically negative patients. The Gaslini diagnostic score was able to identify 91% of genetically positive patients correctly, with a global accuracy of 66%. CONCLUSION: The Gaslini diagnostic score represents a useful tool to identify patients meeting PFAPA syndrome criteria and at low risk of carrying relevant mutations in genes associated with periodic fevers.

Role of IL-1 Beta in the Development of Human TH17 Cells: Lesson from NLPR3 Mutated Patients

Background T helper 17 cells (TH-17) represent a lineage of effector T cells critical in host defence and autoimmunity. In both mouse and human IL-1β has been indicated as a key cytokine for the commitment to TH-17 cells. Cryopyrin-associated periodic syndromes (CAPS) are a group of inflammatory diseases associated with mutations of the NLRP3 gene encoding the inflammasome component cryopyrin. In this work we asked whether the deregulated secretion of IL-1β secondary to mutations characterizing these patients could affect the IL-23/IL-17 axis. Methodology/Principal Findings A total of 11 CAPS, 26 systemic onset juvenile idiopathic arthritis (SoJIA) patients and 20 healthy controls were analyzed. Serum levels of IL-17 and IL-6 serum were assessed by ELISA assay. Frequency of TH17 cells was quantified upon staphylococcus enterotoxin B (SEB) stimulation. Secretion of IL-1β, IL-23 and IL-6 by monocyte derived dendritic cells (MoDCs), were quantified by ELISA assay. A total of 8 CAPS and 11 SoJIA patients were also analysed before and after treatment with IL-1β blockade. Untreated CAPS patients showed significantly increased IL-17 serum levels as well as a higher frequency of TH17 compared to control subjects. On the contrary, SoJIA patients displayed a frequency of TH17 similar to normal donors, but were found to have significantly increased serum level of IL-6 when compared to CAPS patients or healthy donors. Remarkably, decreased IL-17 serum levels and TH17 frequency were observed in CAPS patients following in vivo IL-1β blockade. On the same line, MoDCs from CAPS patients exhibited enhanced secretion of IL-1β and IL-23 upon TLRs stimulation, with a reduction after anti-IL-1 treatment. Conclusion/Significance These findings further support the central role of IL-1β in the differentiation of TH17 in human inflammatory conditions.

Diagnosis and Management of Autoinflammatory Diseases in Childhood

IntroductionAutoinflammatory diseases are a group monogenic inflammatory conditions characterized by an early onset during childhood.DiscussionUnder the term “periodic fevers” are gathered some monogenic diseases (familial Mediterranean fever, mevalonate kinase deficiency, and tumor necrosis factor receptor-associated syndrome) characterized by periodic or recurrent episodes of systemic inflammation causing fever often associated with rash, serositis (peritonitis, pleuritis), lymphadenopathy, arthritis, and other clinical manifestations. Systemic reactive (AA) amyloidosis may be a severe long-term complication. Cryopyrinopathies are a group of conditions associated to mutations of the gene Cryopyrin that are responsible for a spectrum of diseases (familial cold autoinflammatory syndrome, Muckle–Wells syndrome, and chronic infantile neurological cutaneous and articular syndrome) characterized by a chronic or recurrent systemic inflammation variably associated with a number of clinical features, such as urticarial-like rash, arthritis, sensorineural deafness, and central nervous system and bone involvement. Other disorders are dominated by the presence of sterile pyogen abscesses prevalently affecting the skin, joints, and bones (pyogenic disorders). These include pyogenic sterile arthritis, pyoderma gangrenosum, and acne syndrome, and Majeed syndrome. Finally, some diseases, such as Blau’s syndrome, are characterized by the appearance of typical noncaseating granulomatous inflammation affecting the joints, skin, and uveal tract (granulomatous disorders). In the present review, we will focus on the clinical presentation of these disorders in childhood and report on the available therapeutic strategies.

Long-Term Clinical Profile of Children With the Low-Penetrance R92Q Mutation of the TNFRSF1A Gene

Objective To analyze the long-term impact of the R92Q mutation of TNFRSF1A in children with periodic fever, in comparison with children with tumor necrosis factor receptor–associated periodic syndrome (TRAPS) with TNFRSF1A structural mutations and children with periodic fever of unknown origin fulfilling the criteria for periodic fever, aphthosis, pharyngitis, and adenitis syndrome (PFAPA). Methods The extracellular region of TNFRSF1A was analyzed in 720 consecutive children with periodic fever, using denaturing high-performance liquid chromatography and DNA sequencing. Followup data on 11 pediatric patients with TNFRSF1A structural mutations (cysteine or T50M), 23 pediatric patients with an R92Q substitution, and 64 pediatric patients with PFAPA were collected during routine clinic visits. The 50-item Child Health Questionnaire was used to assess health-related quality of life (HRQOL). Results The frequency of typical TRAPS-related clinical manifestations was significantly lower and the impact of the disease on HRQOL was significantly reduced in patients with the R92Q mutation compared with TRAPS patients carrying structural mutations of TNFRSF1A. Followup data on 11 TRAPS patients with TNFRSF1A structural mutations (mean followup 7.9 years), 16 patients with theR92Q substitution (mean followup 7.3 years), and 64 patients with PFAPA (mean followup 5.2 years) were available. Patients with R92Q mutations and patients with PFAPA displayed a higher rate of self-resolution or amelioration of the fever episodes than did TRAPS patients with structural mutations. Conclusion Although some cases may progress to a more chronic disease course, the majority of children with an R92Q mutation of the TNFRSFA1 gene show a milder disease course than that in children with TNFRSFA1 structural mutations and have a high rate of spontaneous resolution and amelioration of the recurrent fever episodes.

Biologic drugs in autoinflammatory syndromes

PURPOSE OF THE REVIEW Inherited autoinflammatory syndromes are conditions caused by mutations of proteins playing a pivotal role in the regulation of the innate immunity leading to an uncontrolled inflammation. The understanding of the molecular pathways involved in these disorders has shed a new light on the pattern of activation and maintenance of the inflammatory response and disclosed new molecular therapeutic targets. In this review we give a start of the art of the use of biologics in these disorders. MAIN TOPICS The dramatic response to anti IL-1 drugs in cryopyrin-associated periodic syndromes represents the brightest example of the possibility to completely dampen inflammation in these severe disorders with the selective blockade of a single pivotal cytokine. Periodic fevers are characterized by recurrent episodes of fever, usually treated with on demand steroids. However the increasing frequency of fever episodes or the development of a chronic disease course may require a continuous long-term treatment, with anti-TNF or IL-1 blockers in mevalonate kinase deficiency and TNF-receptor associated periodic syndrome. Anti-IL-1 treatment is also effective in FMF patients resistant or partially responsive to colchicine. The deficiency of the interleukin-1-receptor antagonist (DIRA) is caused by mutations in the gene encoding for the interleukin-1 receptor antagonist (IL-1Ra). In this case t he recombinant IL-1Ra (anakinra) is the treatment of choice. Due to their extreme rarity the response to the available biologic drugs in other autoinflammatory diseases is still largely anecdotal.

Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population

Objective To evaluate the actual impact of MEFV mutations on clinical manifestations associated with fever attacks in Caucasian children with periodic fever. Methods 113 children carrying MEFV mutations (44 with mutations in two alleles, 69 heterozygous) and 205 children negative for mutations in genes associated with periodic fevers were analysed. The following groups of patients were considered: patients carrying two high penetrance mutations (M694V, M694I, M680I); one high, one low penetrance mutation; two low penetrance mutations; one high penetrance mutation; one low penetrance mutation; genetically negative patients. Results Patients with two MEFV mutations displayed a shorter duration of fever attacks and higher prevalence of a positive family history than patients carrying one MEFV mutation and genetically negative patients. Severe abdominal pain, chest pain and pleurisy were also more frequent in patients with two MEFV mutations compared with children with one MEFV mutation and genetically negative patients. Conversely, a higher frequency of exudative and erythematous pharyngitis, enlargement of cervical lymph nodes, aphthous stomatitis and non-specific skin rash was observed in genetically negative patients and, to a lesser extent, in patients with one MEFV mutation. The frequency of ‘familial Mediterranean fever (FMF)-like symptoms’ decreases from patients carrying two high penetrance mutations towards patients with a single low penetrance mutation with an opposite trend for ‘periodic fever, aphthous stomatitis, pharyngitis, adenitis-like symptoms’. Conclusions This clinical observation supports recent findings contrasting the notion of FMF being a pure autosomal recessive disorder associated with recurrence of mutations leading to loss of protein function. A dosage effect could be invoked, giving rise to symptom onset even in the presence of one wild-type allele.

Periodic fever, apthous stomatitis, pharyngitis and adenitis syndrome

Purpose of reviewPeriodic fever, apthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome is the most common cause of periodic fever of unknown origin in childhood. During the last years a number of studies on large series of patients have shed more light on the actual clinical characterization, long-term outcome and response to treatment. Current PFAPA criteria have low specificity since they are positive in a considerable proportion of patients with inherited periodic fevers. We report on the findings coming from the analysis of large cohorts of PFAPA patients and the possible implication for the differential diagnosis. An update on the efficacy of possible prophylactic treatments and tonsillectomy is given. Recent findingsA diagnostic score developed in a large series of children identifies patients meeting PFAPA criteria and at higher risk to carry relevant mutations of genes associated with periodic fevers. Randomized studies on the efficacy of tonsillectomy give a more evidence-based justification to this possible therapeutic approach. SummaryThe findings coming from the recent literature give new information to clinicians for the correct diagnostic approach to pediatric and adult patients presenting periodic fever of unknown origin and provide an updated overview on the therapeutic possibilities for patients presenting a persistence of fever attacks.