Multiple Sclerosis Research Studies (4)
Rheumatoid Arthritis Research and Therapies (3)
Autoimmune and Inflammatory Disorders Research (3)
Adolescent and Pediatric Healthcare (3)
HIV/AIDS Research and Interventions (2)
Papa R, Bovis F, Federici S, Palmeri S, Bustaffa M , et al.
Arthritis & rheumatology (Hoboken, N.J.) •
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.
Oliveira Mendonça L, Matucci-Cerinic C, Terranova P, Casabona F, Bovis F , et al.
Rheumatology (Oxford, England) •
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-TCRαβ+ 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 (n = 26); (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 TCRαβ+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 TCRαβ+B220+ lymphocytes. Oliveira's required criteria are useful for the early suspicion of ALPS. TCRαβ+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 •
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) •
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.