Papa R, Rusmini M, Volpi S, Caorsi R, Picco P , et al.
Rheumatology (Oxford, England) •
The number of innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased in recent years. More than 70% of patients with clinical manifestations of SAID did not receive a molecular diagnosis, thus being classed as so-called undifferentiated or undefined SAID (uSAID). The aim of the present study was to evaluate a next-generation sequencing (NGS)-based clinically oriented protocol in patients with uSAID. We designed a NGS panel that included 41 genes clustered in seven subpanels. Patients with uSAID were classified into different groups according to their clinical features and sequenced for the coding portions of the 41 genes. Fifty patients were enrolled in the study. Thirty-four patients (72%) displayed recurrent fevers not consistent with a PFAPA phenotype. Sixteen patients displayed a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0-6), a quarter of which affected suspected genes. Mutations with a definitive diagnostic impact were detected in two patients. Patients with genetically negative recurrent fevers displayed a prevalent gastrointestinal, skin and articular involvement. Patients responded to steroids on demands (94%) and colchicine, with a response rate of 78%. Even with a low molecular diagnostic rate, a NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients with evident cost-effectiveness. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine.
Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F , et al.
Annals of the rheumatic diseases •
Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA. Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria. The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98). Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
Konukbay D, Gattorno M, Yildiz D, Frenkel J, Acikel C , et al.
Clinical and experimental rheumatology •
To develop and test a new multidimensional questionnaire for assessment of children with auto-inflammatory disease (AID) such as FMF, PFAPA, HIDS, TRAPS in standard clinical care. The juvenile auto-inflammatory disease multidimensional assessment report (JAIMAR) includes 16 parent or patient-centered measures and four dimensions that assess functional status, pain, therapeutic compliance and health-related quality of life (physical, social, school, emotional status) with disease outcome. It is proposed for use as both a proxy-report and a patient self-report, with the suggested age range of 8-18 years for use as a self-report. 250 children with FMF were included in the study. Total of 179 forms were filled up by parents and patients, and 71 forms were filled up by parents having children less than 8 years. Completing and scoring the JAIMAR can be done in 15 minutes. For the JAIMAR's dimensions, the Cronbach's alpha coefficient for internal consistency was between 0.507-0.998. There was a significant and a positive correlation between the test-retest scale scores (ICC=0.607-0.966). Concerning construct validity, all factors loadings were above 0.30. For the criterion validity, the correlation level between each dimension and the related scale ranged from medium (r=0.329, p<0.0001) to large (r=0.894, p<0.0001). The parents' proxy-reported and children's self-reported data were outstandingly concordant (r=0.770-0.989). The development of the JAIMAR introduces a new and multi-dimensional approach in paediatric rheumatology practice. It is a new tool for children with auto-inflammatory dis-ease and it may help enhance their quality of care.
Federici S, Sormani MP, Ozen S, Lachmann HJ, Amaryan G , et al.
Annals of the rheumatic diseases •
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.
Burton MJ, Pollard AJ, Ramsden JD, Chong LY, Venekamp RP
The Cochrane database of systematic reviews •
Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome is a rare clinical syndrome of unknown cause usually identified in children. Tonsillectomy is considered a potential treatment option for this syndrome. This is an update of a Cochrane review first published in 2010. To assess the effectiveness and safety of tonsillectomy (with or without adenoidectomy) in children with PFAPA. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 30 October 2013. Randomised controlled trials comparing tonsillectomy (with or without adenoidectomy) with non-surgical treatment in children with PFAPA. Two authors independently assessed trial quality and extracted data. We used the standard methodological procedures expected by The Cochrane Collaboration. Two trials were included with a total of 67 children randomised (65 analysed); we judged both to be at low risk of bias.One trial of 39 participants recruited children with PFAPA syndrome diagnosed according to rigid, standard criteria. The trial compared adenotonsillectomy to watchful waiting and followed up patients for 18 months. A smaller trial of 28 children applied less stringent criteria for diagnosing PFAPA and probably also included participants with alternative types of recurrent pharyngitis. This trial compared tonsillectomy alone to no treatment and followed up patients for six months.Combining the trial results suggests that patients with PFAPA experience less fever and less severe episodes after surgery compared to those receiving no surgery. The risk ratio (RR) for immediate resolution of symptoms after surgery that persisted until the end of follow-up was 4.38 (95% confidence interval (CI) 0.64 to 30.11); number needed to treat to benefit (NNTB) = 2, calculated based on an estimate that 156 in 1000 untreated children have a resolution).There was a large overall reduction in the average number of episodes over the total length of follow-up in these studies (rate ratio 0.08, 95% CI 0.05 to 0.13), reducing the average frequency of PFAPA episodes from one every two months to slightly less than one every two years. The severity, as indicated by the length of PFAPA symptoms during these episodes, was also reduced. One study reported that the average number of days per PFAPA episode was 1.7 days after receiving surgery, compared to 3.5 days in the control group. The proportion of patients requiring corticosteroids was also lower in the surgery group compared to those receiving no surgery (RR 0.58, 95% CI 0.37 to 0.92).Both trials reported that there were no complications of surgery. However, the numbers of patients randomly allocated to surgery (19 and 14 patients respectively) were too small to detect potentially important complications such as haemorrhage. Other outcomes such as quality of life, number of days with pain after surgery and absence from school were not measured or reported. The evidence for the effectiveness of tonsillectomy in children with PFAPA syndrome is derived from two small randomised controlled trials. These trials reported significant beneficial effects of surgery compared to no surgery on immediate and complete symptom resolution (NNTB = 2) and a substantial reduction in the frequency and severity (length of episode) of any further symptoms experienced. However, the evidence is of moderate quality (further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate) due to the relatively small sample sizes of the studies and some concerns about the applicability of the results. Therefore, the parents and carers of children with PFAPA syndrome must weigh the risks and consequences of surgery against the alternative of using medications. It is well established that children with PFAPA syndrome recover spontaneously and medication can be administered to try and reduce the severity of individual episodes. It is uncertain whether adenoidectomy combined with tonsillectomy adds any additional benefit to tonsillectomy alone.
Ter Haar N, Lachmann H, Özen S, Woo P, Uziel Y , et al.
Annals of the rheumatic diseases •
To evaluate the response to treatment of autoinflammatory diseases from an international registry and an up-to-date literature review. The response to treatment was studied in a web-based registry in which clinical information on anonymised patients with autoinflammatory diseases was collected retrospectively as part of the Eurofever initiative. Participating hospitals included paediatric rheumatology centres of the Paediatric Rheumatology International Trial Organisation network and adult centres with a specific interest in autoinflammatory diseases. The following diseases were included: familial Mediterranean fever (FMF), cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF)-receptor associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), pyogenic arthritis pustulosis acne (PAPA) syndrome, deficiency of interleukin-1 receptor antagonist (DIRA), NLRP12-related periodic fever and periodic fever aphthosis pharyngitis adenitis (PFAPA) syndrome. Cases were independently validated by experts for each disease. A literature search regarding treatment of the abovementioned diseases was also performed using Medline and Embase. 22 months from the beginning of the enrolment, complete information on 496 validated patients was available. Data from the registry in combination with evidence from the literature confirmed that colchicine is the treatment of choice for FMF and IL-1 blockade for DIRA and CAPS. Corticosteroids on demand probably represent a valid therapeutic strategy for PFAPA, but also for MKD and TRAPS. Patients with poorly controlled MKD, TRAPS, PAPA or FMF may benefit from IL-1 blockade; anti-TNF treatment may represent a possible valuable alternative. In the absence of high-grade evidence, these results could serve as a basis for therapeutic guidelines and to identify candidate drugs for future therapeutic trials.
Gattorno M, Caorsi R, Meini A, Cattalini M, Federici S , et al.
Pediatrics •
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. 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. 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%. 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.
Identification of the genes involved in hereditary periodic fever syndromes has led to the recognition of a new pathophysiological category, the autoinflammatory disorders. The main non-hereditary autoinflammatory disease in childhood is systemic juvenile idiopathic arthritis (sJIA), others being the chronic infantile neurological cutaneous arthropathy (CINCA) syndrome and the periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome. Familial Mediterranean fever (FMF) has been traced to mutations in the MEFV gene. Mutations in the MVK gene, encoding the enzyme mevalonate kinase, cause the hyper-IgD periodic fever syndrome (HIDS). The tumour necrosis factor(TNF)-receptor-associated periodic syndromes (TRAPS) have been linked to mutations in theTNFRSF1A gene, encoding a TNF-alpha receptor, and the CIAS1 gene is mutated in familial cold autoinflammatory syndrome. We discuss how this knowledge has influenced diagnosis and treatment of these rare genetic disorders and how it might change our approach to the more common rheumatic diseases.
