Autoinflammatory diseases (AIDs) are heterogeneous disorders characterized by dysregulation in the inflammasome, a large intracellular multiprotein platform, leading to overproduction of ...interleukin-1(IL-1)β that plays a predominant pathogenic role in such diseases. Appropriate treatment is crucial, also considering that AIDs may persist into adulthood with negative consequences on patients' quality of life. IL-1β blockade results in a sustained reduction of disease severity in most AIDs. A growing experience with the human IL-1 receptor antagonist, Anakinra (ANA), and the monoclonal anti IL-1β antibody, Canakinumab (CANA), has also been engendered, highlighting their efficacy upon protean clinical manifestations of AIDs. Safety and tolerability have been confirmed by several clinical trials and observational studies on both large and small cohorts of AID patients. The same treatment has been proposed in refractory Kawasaki disease, an acute inflammatory vasculitis occurring in children before 5 years, which has been postulated to be autoinflammatory for its phenotypical and immunological similarity with systemic juvenile idiopathic arthritis. Nevertheless, minor concerns about IL-1 antagonists have been raised regarding their employment in children, and the development of novel pharmacological formulations is aimed at minimizing side effects that may affect adherence to treatment. The present review summarizes current findings on the efficacy, safety, and tolerability of ANA and CANA for treatment of AIDs and Kawasaki vasculitis with a specific focus on the pediatric setting.
Abstract
Objectives
Only a third of patients with eosinophilic granulomatosis with polyangiitis (EGPA) are ANCA-positive, mainly directed against MPO. ANCA directed against PR3 are rarely found in ...EGPA. We aimed to examine the significance of PR3-ANCA in EGPA.
Methods
We set up a retrospective European multicentre cohort including 845 patients. Baseline characteristics and outcomes were analysed and compared according to ANCA status.
Results
ANCA status was available for 734 patients: 508 (69.2%) ANCA-negative, 210 (28.6%) MPO-ANCA and 16 (2.2%) PR3-ANCA. At baseline, PR3-ANCA patients, compared with those with MPO-ANCA and ANCA-negative, less frequently had active asthma (69% vs 91% and 93%, P = 0.003, respectively) and peripheral neuropathy (31% vs 71% and 47%, P < 0.0001), more frequently had cutaneous manifestations (63% vs 38% and 34%, P = 0.03) and pulmonary nodules (25% vs 10% and 8%, P = 0.046), and lower median eosinophil count (1450 vs 5400 and 3224/mm3, P < 0.0001). Vasculitis relapse-free survival was shorter for PR3-ANCA (hazard ratio 6.05, P = 0.005) and MPO-ANCA patients (hazard ratio 1.88, P = 0.0002) compared with ANCA-negative patients.
Conclusion
PR3-ANCA EGPA patients differ from those with MPO-ANCA and negative ANCA, and share clinical features with granulomatosis with polyangiitis. This suggests that PR3-ANCA EGPA could be a particular form of PR3-ANCA-associated vasculitis.
Inferential statistical methods failed in identifying reliable biomarkers and risk factors for relapsing giant cell arteritis (GCA) after glucocorticoids (GCs) tapering. A ML approach allows to ...handle complex non-linear relationships between patient attributes that are hard to model with traditional statistical methods, merging them to output a forecast or a probability for a given outcome.
The objective of the study was to assess whether ML algorithms can predict GCA relapse after GCs tapering.
GCA patients who underwent GCs therapy and regular follow-up visits for at least 12 months, were retrospectively analyzed and used for implementing 3 ML algorithms, namely, Logistic Regression (LR), Decision Tree (DT), and Random Forest (RF). The outcome of interest was disease relapse within 3 months during GCs tapering. After a ML variable selection method, based on a XGBoost wrapper, an attribute core set was used to train and test each algorithm using 5-fold cross-validation. The performance of each algorithm in both phases was assessed in terms of accuracy and area under receiver operating characteristic curve (AUROC).
The dataset consisted of 107 GCA patients (73 women, 68.2%) with mean age ( ± SD) 74.1 ( ± 8.5) years at presentation. GCA flare occurred in 40/107 patients (37.4%) within 3 months after GCs tapering. As a result of ML wrapper, the attribute core set with the least number of variables used for algorithm training included presence/absence of diabetes mellitus and concomitant polymyalgia rheumatica as well as erythrocyte sedimentation rate level at GCs baseline. RF showed the best performance, being significantly superior to other algorithms in accuracy (RF 71.4% vs LR 70.4% vs DT 62.9%). Consistently, RF precision (72.1%) was significantly greater than those of LR (62.6%) and DT (50.8%). Conversely, LR was superior to RF and DT in recall (RF 60% vs LR 62.5% vs DT 47.5%). Moreover, RF AUROC (0.76) was more significant compared to LR (0.73) and DT (0.65).
RF algorithm can predict GCA relapse after GCs tapering with sufficient accuracy. To date, this is one of the most accurate predictive modelings for such outcome. This ML method represents a reproducible tool, capable of supporting clinicians in GCA patient management.
Phenylketonuria (PKU) is a metabolic inherited disorder in which transition from infancy to adult care is particularly difficult and not sufficiently regulated. According to the scientific ...literature, only few medical centers offer healthcare assistance for adult patients with PKU that are therefore still treated in pediatric settings. This generates psychological, emotional, and organizational discomfort among patients, leading them to discontinue the follow-up. European guidelines and national consensus documents underline this unmet need and the lack of practical recommendations for a structured transitional pathway in PKU. The aim of this review and expert opinion is to propose good practices for managing the transition period of PKU patients, based on the literature and the experience of a panel of Italian experts in PKU. The consensus of the experts was obtained through the administration of three rounds of surveys and one structured interview. The result is the first proposal of a pathway for an efficient transition of PKU patients. Key steps of the proposed pathway are the “a priori” planning involving the pediatric and adult teams, the acceptance of the patient and his/her family to the process, the preliminary definition of appropriate spaces in the structure, the organization of meetings with the joint team, and the appointment of a transition coordinator. For the first time, the involvement of decision makers and patient associations is proposed.
ObjectiveTo describe pregnancy outcomes in patients with SLE treated with belimumab before and/or during pregnancy.MethodsData of prospectively-followed pregnancies (2014–2022) in 7 Italian centers ...were retrospectively collected.ResultsTwenty-four SLE pregnancies were included (median age at conception: 33 21–37 years; 15 primigravidae).Belimumab was stopped in 4 cases preconceptionally, in 10 at positive pregnancy test and in 10 during pregnancy (4 during the 1st trimester, 3 during the 2nd trimester and 3 during the 3rd trimester). The timing of discontinuation was planned with the patient during preconception counselling.Other medications includedprednisone (92%); antimalarials (83%); azathioprine (46%); calcineurin-inhibitors (25%); low-dose aspirin (88%); heparin (58%).At preconception, median SLEDAI was 4(2–4).One patient who discontinued belimumab at the 11th week had active nephritis from preconception.Three flares (cutaneous; pericarditis; hematologic) occurred during the 3rd trimester in the group of patients who discontinued belimumab at positive pregnancy test, while 1 flare (cutaneous + articular) occurred in the 1st trimester in the group of patients who continued belimumab.Live-birth rate was 87.5%. Two miscarriages and 1 intrauterine fetal death (37th week; fetus with 21-trisomy and atrio-ventricular defect) occurred. One perinatal death occurred (patient with thrombotic+obstetric APS and lupus nephritis who underwent heterologous assisted reproductive technology -embryodonation- and developed eclampsia with cerebral haemorrage at 25th week; an urgent cesarean section was performed; the newborn died after 3 days).Two cases of pre-eclampsia in patients with multiple risk factors were observed.Five newborns were hospitalized in Intensive Care Unit for: milk protein intolerance; desaturation; respiratory distress; prematurity (2 cases). One sepsis starting from urinary tract infection occurred in a 2-months-old infant with calico-pyelic and ureteral dilatation at birth. One newborn presented with interatrial defect and situs inversus (paternal 10 chromosome inversion).ConclusionsDespite our data do not allow definitive conclusions, the live birth rate and the exclusion of drug-related congenital defects are encouraging. SLE flares occurred more frequently after Belimumab discontinuation at positive pregnancy test. We suggest that women on good disease control while on belimumab could be offered to continue it and to discuss discontinuation timing according to their specific risk/benefit ratio.Acknowledgements‘Gender Medicine’ Study Group of the Italian Society for Rheumatology
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