Papa R, Bovis F, Federici S, Palmeri S, Bustaffa M , et al.
Arthritis & rheumatology (Hoboken, N.J.) β’
To develop evidence-based criteria to classify patients with syndrome of undifferentiated recurrent fevers (SURF). One hundred twelve patients with SURF observed in a single tertiary referral center were analyzed. Patients with genetically confirmed hereditary recurrent fever (HRF) or with periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome already analyzed for the Eurofever classification criteria were used as disease controls. A decision tree approach was tested by randomly splitting the available data in a training set and in an internal test set. An alternative model using a classical regression model was also analyzed. An external validation for both approaches was performed on 123 patients recruited from four other centers. The decision tree model integrating clinical and genetic data identified 91% of patients with SURF. A decision tree model based solely on clinical variables identified up to 88% of patients with SURF. The logistic regression model including genetic tests exhibited an overall accuracy of 89.2% (95% confidence interval [CI] 81.1-94.7). In contrast, the logistic regression model exclusively based on clinical manifestations displayed an overall accuracy of 66.7% (95% CI 56.1-76.1). When the classification criteria including genetic tests were applied to the external validation cohort, the model demonstrated a strong discriminative power, with areas under the receiver operating characteristic curve of 96.3% using the decision tree model and 88.0% with the logistic regression model. The study shows the possibility of achieving evidence-based criteria that can classify SURF at least with respect to the main HRF and PFAPA syndrome and may be considered as a preliminary tool for the enrollment of more homogeneous cohorts of patients in future studies.
Zhao Y, Oliver MS, Schnabel A, Wu EY, Wang Z , et al.
Annals of the rheumatic diseases β’
To develop and validate classification criteria for paediatric chronic nonbacterial osteomyelitis (CNO) jointly supported by the European Alliance of Associations for Rheumatology (EULAR) and the American College of Rheumatology (ACR). This international initiative had 4 phases: (1) candidate items were proposed in a survey of paediatric rheumatologists, (2) criteria definition and reduction by Delphi and nominal group technique exercises, (3) criteria weighting using multicriteria decision analysis, and (4) refinement of weights and threshold score in a development cohort of 441 patients and validation in another cohort of 514 patients. The new EULAR/ACR classification criteria for CNO require typical radiographic or magnetic resonance imaging findings and bone pain as an obligatory entry criterion and exclusion criteria of malignancy, infection, vitamin C deficiency, and hypophosphatasia, followed by additive weighted criteria in 5 clinical (site of bone lesions, pattern of bone lesions, age at onset, coexisting conditions, fever) and 4 pathology/laboratory domains (bone biopsy findings if done, anaemia, C-reactive protein level, and erythrocyte sedimentation rate). A total score β₯55 is required for classification as CNO. The new criteria had a sensitivity of 82% and specificity of 98% in the validation cohort. These new classification criteria for paediatric CNO developed with international input reflect current views about CNO, have high specificity and good sensitivity, and provide a key foundation for future CNO research.
Palmeri S, Ponzano M, Recchi G, Conti C, La Bella S , et al.
RMD open β’
Syndrome of undifferentiated recurrent fever (SURF) refers to a group of recurrent fevers without a clear monogenic cause. Clinical spectrum, treatment response predictors and management strategies remain unclear. This study aims to longitudinally analyse a homogeneously selected cohort of 101 SURF patients, to identify factors associated with colchicine resistance and to evaluate the efficacy of interleukin-1 (IL-1) inhibitors. Patients were enrolled in the Eurofever Registry, carefully excluding those with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA); familial Mediterranean fever and other known monogenic recurrent fevers. Demographic, clinical and treatment data were analysed to identify predictors of colchicine resistance and define subgroups through cluster analysis. Common symptoms included fever, arthralgia, abdominal pain and myalgia, with PFAPA-like features (lymphadenopathy, tonsillitis, oral aphthae) observed in one-third of cases, sporadically. Colchicine efficacy, assessed in 77 patients, revealed complete response in the majority of patients (61%). Univariable analysis identified PFAPA-like features, including aphthous stomatitis (p=0.001), cervical lymphadenopathy (p=0.012) and exudative tonsillitis (p=0.004), as associated with colchicine resistance. Multivariable analysis confirmed aphthous stomatitis as an independent predictor of resistance (p=0.014). Tonsillectomy was ineffective. IL-1 inhibitors (anakinra, canakinumab) were beneficial in refractory cases. Cluster analysis revealed three distinct subgroups with varying symptoms and colchicine responses. These findings provide new insights into SURF, identifying predictors of colchicine resistance and supporting the efficacy of IL-1 blockade. Cluster analysis suggests the heterogeneity within SURF, reinforcing the need for refined diagnostic criteria and personalised treatment strategies.
Palmeri S, Penco F, Bertoni A, Bustaffa M, Matucci-Cerinic C , et al.
Journal of clinical immunology β’
Syndrome of undifferentiated recurrent fever (SURF) is characterized by recurrent fevers, a lack of confirmed molecular diagnosis, and a complete or partial response to colchicine. Despite the clinical similarities to familial Mediterranean fever (FMF), the underlying inflammatory mechanisms of SURF are not yet understood. We here analyzed the in vitro activation of the pyrin inflammasome in a cohort of SURF patients compared to FMF and PFAPA patients. Peripheral blood mononuclear cells (PBMC) were collected from SURF (both colchicine-treated and untreated), FMF, PFAPA patients, and healthy donors. PBMC were stimulated ex vivo with Clostridium difficile toxin A (TcdA) and a PKC inhibitor (UCN-01), in the presence or absence of colchicine. The assembly of the pyrin inflammasome was evaluated by measuring the presence of apoptosis-associated Speck-like protein containing caspase recruitment domain (ASC) specks in monocytes using flow cytometry. IL-1Ξ² secretion was quantified using an ELISA assay. No differences in TcdA-induced activation of pyrin inflammasome were observed among FMF, PFAPA, and healthy donors. Untreated SURF patients showed a reduced response to TcdA, which was normalized after colchicine treatment. In contrast to FMF, SURF patients, similar to PFAPA patients and healthy donors, did not exhibit pyrin inflammasome activation in response to UCN-01-mediated pyrin dephosphorylation. These data demonstrate that in vitro functional analysis of pyrin inflammasome activation can differentiate SURF from FMF and PFAPA patients, suggesting the involvement of the pyrin inflammasome in the pathophysiology of SURF.
Spagnolo A, Mileto V, Civino A, Maggio MC, Risso P , et al.
Frontiers in pediatrics β’
Periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome (PFAPA) is the most common cause of periodic fever in childhood. Although PFAPA is generally a self-limited condition, it can have negative impact on child's and parents' quality of life and family functioning. Our primary aim was to assess the potential effectiveness of Streptococcus Salivarius K12 (SSK12) in preventing febrile attacks in PFAPA patients. Secondary objectives included evaluating the effectiveness of SSK12 in mitigating the severity of febrile episodes seen as a statistically significant reduction in the episode duration, highest fever temperature reached during fever, in the frequency of each associated symptom, calculated in the six months before and after the start of therapy. A total of 117 patients with PFAPA were evaluated using Marshall's criteria, modified by Thomas et al. and according to Eurofever/PRINTO classification criteria, aged 6 months to 9 years, with a median age at the onset of the disease of 2 years, treated with SSK12, since January 2021 to January 2023. Data were collected retrospectively. Before using SS K12, febrile episodes recurred on average every 26.1βΒ±β11.5 days, with a febrile episode duration of 4.1βΒ±β1.4 days. The highest fever temperature during the episode was 39.8βΒ±β0.7βΒ°C. After six months of SS K12, febrile episodes recurred on average every 70βΒ±β53,1 days ( value <0.01), the mean lenght of febrile episodes was 3.3βΒ±β1.6 ( value <0.01) and the highest fever temperature reached during the febrile episode was 39.1βΒ±β1.1βΒ°C ( value <0.01). We also documented a reduction in the frequency of exudative pharyngotonsillitis present in 72 vs. 103 patients ( value <0.01), oral aphthosis present in 47 vs. 80 patients ( value <0.01), lateral cervical lymphadenopathy in 45 vs. 83 ( value <0.01). Erythematous pharyngotonsillitis decreased in frequency but it was not statistically significant. The results of our study indicate that the use of SS K12 could be beneficial in decreasing febrile episodes related to PFAPA syndrome and its associated symptoms, potentially improving the quality of life in pediatric patients and decreasing the need for additional pharmacological therapies.
Oliveira Mendonça L, Matucci-Cerinic C, Terranova P, Casabona F, Bovis F , et al.
Rheumatology (Oxford, England) β’
To test the usefulness of an extended panel of lymphocyte subsets in combination with Oliveira's diagnostic criteria for the identification of autoimmune lymphoproliferative syndrome (ALPS) in children referred to a paediatric rheumatology centre. Patients referred from 2015 to 2018 to our rheumatology unit for an autoimmune or autoinflammatory condition were retrospectively analysed. Oliveira's required criteria [chronic lymphoproliferation and elevated double-negative T (DNT)] were applied as first screening. Flow cytometry study included double-negative CD4-CD8-TCRΞ±Ξ²+ T lymphocytes (DNT), CD25+CD3+, HLA-DR+CD3+ T cells, B220+ T cells and CD27+ B cells. Data were analysed with a univariate logistic regression analysis, followed by a multivariate analysis. Sensitivity and specificity of the Oliveira's required criteria were calculated. A total of 264 patients were included in the study and classified as: (i) autoimmune diseases (nβ=β26); (ii) juvenile idiopathic arthritis (JIA) (35); (iii) monogenic systemic autoinflammatory disease (27); (iv) periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (100); (v) systemic undefined recurrent fever (45); (vi) undetermined-systemic autoinflammatory disease (14); or (vii) ALPS (17). Oliveira's required criteria displayed a sensitivity of 100% and specificity of 79%. When compared with other diseases the TCRΞ±Ξ²+B220+ lymphocytes were significantly increased in ALPS patients. The multivariate analysis revealed five clinical/laboratory parameters positively associated to ALPS: splenomegaly, female gender, arthralgia, elevated DNT and TCRΞ±Ξ²+B220+ lymphocytes. Oliveira's required criteria are useful for the early suspicion of ALPS. TCRΞ±Ξ²+B220+ lymphocytes should be added in the diagnostic work-up of patients referred to the paediatric rheumatology unit for a suspected autoimmune or autoinflammatory condition, providing a relevant support in the early diagnosis of ALPS.
Sutera D, Bustaffa M, Papa R, Matucci-Cerinic C, Matarese S , et al.
Seminars in arthritis and rheumatism β’
To describe a homogeneous group of patients with undifferentiated recurrent fevers followed-up in a tertiary referral center for systemic autoinflammatory diseases (SAIDs). Patients with undifferentiated recurrent fevers seen at our Center from 2008 to 2021 and followed-up for at least one year were included in a retrospective study. Monogenic recurrent fevers, patients carrying variants of unknown origin and PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) syndrome were excluded. Fifty patients (34 male, 16 female) were included in the study. The median age at onset was 3 years, and the median follow-up was 3.3 years. At baseline, arthralgia (70%) and abdominal pain (65%) were the most frequent manifestations. NSAIDs or steroids on demand had a variable and transient effect. Tonsillectomy was ineffective in the 10 patients (20%) that underwent surgery. Forty-eight patients (96%) were treated with colchicine. A complete response (absence of fever) was achieved in 31 patients (64.6%). Nine patients (18%) showed a partial response, with a median reduction of fever episodes per year of 72%. Nine patients (16.7%) were considered resistant to colchicine. The presence of generalized lymphadenopathy and, to a lesser extent, exudative tonsillitis was associated with a lack of response to colchicine. We describe the largest series of patients with syndrome of undifferentiated recurrent fever (SURF) reported in the literature so far. SURF should be considered as a distinct clinical entity in the context of multifactorial autoinflammatory diseases.
Papa R, Rusmini M, Volpi S, Caorsi R, Picco P , et al.
Rheumatology (Oxford, England) β’
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 β’
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 β₯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.
Federici S, Sormani MP, Ozen S, Lachmann HJ, Amaryan G , et al.
Annals of the rheumatic diseases β’
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.
Pelagatti MA, Meini A, Caorsi R, Cattalini M, Federici S , et al.
Arthritis and rheumatism β’
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). 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). 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. 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.
Caorsi R, Pelagatti MA, Federici S, Finetti M, Martini A , et al.
Current opinion in rheumatology β’
Periodic 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. A 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. The 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.
Gattorno M, Caorsi R, Meini A, Cattalini M, Federici S , et al.
Pediatrics β’
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.
