The rs13075270 and rs13092160 polymorphisms of CCR1 and CCR3 genes on oral aphthous-like lesions in PFAPA syndrome

Fever is a common symptom of infection in children. Periodic fever syndromes are less common but more complex. One of these Periodic fever syndromes is PFAPA (periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis) syndrome which is known as the most benign syndromes. The cause of this disease is unknown. Various factors, including environmental and genetic factors, are involved in the development of this disease. In this study, the association of rs13075270 and rs13092160 polymorphisms were investigated in CCR1 and CCR3 genes with susceptibility to this syndrome in the Chinese population. In this regard, 38 patients with PFAPA syndrome and 100 healthy individuals were selected. After DNA sampling and extraction, polymorphisms of CCR1 and CCR3 receptor genes were examined by the PCR-RFLP method. Findings were analyzed using SPSS software version 22 with a significant level of P <0.05. The frequency of T/T genotype rs13092160 polymorphism in the patient and control groups was 78.95% and 83%, respectively, C/T genotype was 21.05% and 17% (P = 0.421). The frequency of the C/C genotype was 0 in both groups. Regarding rs13075270 polymorphism, the frequency of T/T genotype in patient and control groups was 15.79% and 81%, C/T genotype was 78.95% and 18% and C/C genotype was 5.26% and 1%, respectively (P<0.05). Thus, in rs13075270 polymorphism, the C/T genotype was associated with the risk of PFAPA syndrome (P<0.05), but rs13092160 polymorphism did not show a significant difference between individuals with PFAPA syndrome and controls.

Risk-stratification of febrile African children at risk of sepsis using sTREM-1 as basis for a rapid triage test

Identifying febrile children at risk of sepsis in low-resource settings can improve survival, but recognition triage tools are lacking. Here we test the hypothesis that measuring circulating markers of immune and endothelial activation may identify children with sepsis at risk of all-cause mortality. In a prospective cohort study of 2,502 children in Uganda, we show that Soluble Triggering Receptor Expressed on Myeloid cells-1 (sTREM-1) measured at first clinical presentation, had high predictive accuracy for subsequent in-hospital mortality. sTREM-1 had the best performance, versus 10 other markers, with an AUROC for discriminating children at risk of death of 0.893 in derivation (95% CI 0.843–0.944) and 0.901 in validation (95% CI 0.856–0.947) cohort. sTREM-1 cutoffs corresponding to a negative likelihood ratio (LR) of 0.10 and a positive LR of 10 classified children into low (1,306 children, 53.1%), intermediate (942, 38.3%) and high (212, 8.6%) risk zones. The estimated incidence of death was 0.5%, 3.9%, and 31.8%, respectively, suggesting sTREM-1 could be used to risk-stratify febrile children. These findings do not attempt to derive a risk prediction model, but rather define sTREM-1 cutoffs as the basis for rapid triage test for all cause fever syndromes in children in low-resource settings.

477. Increased Referrals for New PFAPA (Aphthous Stomatitis, Pharyngitis, Adenitis) Diagnosis During the COVID-19 Pandemic

Background COVID-19 pandemic caused by SARS-CoV-2 resulted in a global health crisis in 2020. Quarantining, wearing masks and physical distancing- key infection prevention strategies implemented to stop the spread of COVID-19, also led to dramatic decreases in rates of common respiratory viral infection seen in young children. Due to lack of school and daycare exposure, we evaluated a larger than usual number of patients with periodic fevers without any known infectious contacts. Based on this observation, we conducted an analysis of all suspected cases of periodic fevers seen at our institution during the COVID-19 lockdown compared to prior seasons. Methods The clinical charts were queried for all patients presenting to any Lurie Children’s Hospital outpatient specialty clinic or laboratory with ICD diagnosis code of MO4.1 and MO4.8 (all recurrent and periodic fever syndromes) from June 1, 2020 through September 30, 2020, and compared to similar months the previous 2 years (2018 and 2019). Each patient chart was reviewed by the lead investigator to verify all new diagnoses of PFAPA. The number of new patients with PFAPA diagnosis were tallied and analyzed. Statistical comparisons were made using Kruskal-Wallis tests for monthly distributions in different years. Results We noted a significant increase in patients with new PFAPA diagnosis between June through August 2020 compared to similar months in 2018 and 2019 (Figure1). Experienced pediatric infectious disease physicians and rheumatologists diagnosed majority of the cases. During these months, a monthly median (IQR) of 13 (11.5, 14.5) patients were diagnosed among different Lurie specialty clinics, which is more than 2.5 folds increase in new PFAPA patients from the previous two years which were about 5 (3.5, 6) (Figure 2). Number of Patients with New PFAPA Diagnosis There was a significant increase in number of new patients diagnosed with PFAPA between June through August 2020 compared to similar months in 2018 and 2019. Monthly Distribution Summary for New PFAPA Diagnosis Statistical comparisons were made using Kruskal- Wallis tests for monthly distributions in different years Conclusion We observed a significant increase in PFAPA patients referred to our institution soon after introduction of public health measures to slow spread of COVID-19. Given that most children were not in daycare, schools, or camps, we suspect that parents and pediatricians were able to recognize patterns of periodic fevers in children much quicker than preceding years, when fevers would typically be attributed to an infectious process. Disclosures Ravi Jhaveri, MD, AstraZeneca (Consultant)Dynavax (Consultant)Elsevier (Other Financial or Material Support, Editorial Stipend as Co-editor in Chief, Clinical Therapeutics)Seqirus (Consultant)

Reasons for canakinumab initiation among patients with periodic fever syndromes: a retrospective medical chart review from the United States

Background Although canakinumab has demonstrated efficacy in multiple trials in patients with periodic fever syndromes (PFS), the evidence on initiation of canakinumab among PFS patients in real world setting is not well understood. We aimed to characterize the reasons for canakinumab initiation among patients with PFS, specifically, cryopyrin-associated periodic syndrome (CAPS), hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD), TNF receptor-associated periodic syndrome (TRAPS) and familial Mediterranean fever (FMF). Methods Physicians retrospectively reviewed the medical charts of PFS patients prescribed canakinumab between 2016 and 2018. Information collected included patient clinical characteristics, reasons for previous treatment discontinuation and canakinumab initiation. The results were summarized for overall patients, and by children (< 18 years) and adults and by subtype of PFS. Results Fifty-eight physicians in the US (rheumatologists, 44.8 %; allergists/immunologists, 29.3 %; dermatologists, 25.9 %) abstracted information for 147 patients (children, 46.3 %; males, 57.1 %; CAPS, 36.7 %; TRAPS, 26.5 %; FMF, 26.5 %; HIDS/MKD, 6.8 %; Mixed, 3.4 %). Overall, most patients (90.5 %) received treatment directly preceding canakinumab (NSAIDs, 27.8 % [40.0 % in HIDS/MKD]; anakinra, 24.1 % [32.7 % in CAPS]; colchicine, 21.8 % [35.9 % in FMF]), which were discontinued due to lack of efficacy/effectiveness (39.5 %) and availability of a new treatment (36.1 %). The common reasons for canakinumab initiation were physician perceived efficacy/effectiveness (81.0 %; children, 75.0 %; adults, 86.1 %), lack of response to previous treatment (40.8 %; children, 38.2 %; adults, 43.0 %) and favorable safety profile/tolerability (40.1 %; children, 42.6 %; adults, 38.0 %). Within subtypes, efficacy/effectiveness was the most stated reason for canakinumab initiation in HIDS/MKD (90.9 %), lack of response to previous treatment in FMF (52.4 %) and convenience of administration/dosing in CAPS (27.1 %). Conclusions This study provided insights into how canakinumab is initiated in US clinical practice among PFS patients, with physician perceived efficacy/effectiveness of canakinumab, lack of response to previous treatment and favorable safety profile/tolerability of canakinumab being the dominant reasons for canakinumab initiation in all patients and in children and adults and PFS subtypes. Notably, the favorable safety profile/tolerability of canakinumab was more often the reason for initiation among children versus adults.

POS1326 FAMILIAL PERIODIC FEVER, APHTHOUS STOMATITIS, PHARYNGITIS AND ADENITIS (PFAPA)SYNDROME; IS IT A SEPARATE DISEASE?

Background:Periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome (PFAPA) is the most common periodic fever syndrome in the pediatric population. Unlike other periodic fever syndromes, the pathogenesis and genetics of PFAPA is unknown. Until recently, PFAPA was believed to be a sporadic disease, yet family clustering has been widely observed and current research indicates that heredity is likely.Objectives:To identify demographic and clinical differences between patients with PFAPA who have a positive family history (FH+) compared to those with PFAPA with no family history (FH-) that can reveal if heritable and sporadic subtypes of this disorder exist.Methods:In a database comprising demographic and clinical data of 273 pediatric PFAPA patients treated at two tertiary centers in Israel, 31(14.3%) of patients were PFAPA FH+. Data from patients with FH+ for PFAPA was compared to data from those with FH- of the disorder. Furthermore, family members (FMs) of those with FH+ were contacted via telephone for more demography and clinical details.Results:FH+ group had more headaches (32% vs.2%; p= 0.016), myalgia (56% vs. 19%; p= 0.001), higher carrier frequency of M694V mutation (54% vs. 25%; p=0.053), greater family history of FMF (30% vs. 15%; p=0.096) and better outcomes with colchicine (82% vs. 52%; p=0.096) compared to those with FH-. FMs displayed almost identical characteristics to the FH+ group except for greater arthralgia during flares (64% vs. 23%; p=0.008) and compared to the FH- group, more oral aphthae (68% vs. 43%; p=0.002), myalgia/arthralgia (64% vs. 19%/16%; p<0.0001), and higher rates of FH of FMF (45% vs.15%; p=0.003).Conclusion:Our findings suggest that FH+ had probably different subset of disease with higher frequency of family history of FMF arthralgia, myalgia and better response to colchicine. Colchicine prophylaxis for PFAPA should be considered in FH+.Disclosure of Interests:None declared

MO961KIDNEY TRANSPLANTATION AS A TREATMENT OF CHOICE FOR AA AMYLOIDOSIS DUE TO PERIODIC FEVER SYNDROME

Background and Aims Renal AA amyloidosis is the most serious complication of periodic fever syndrome, which, inadequate suppression, due to persistent inflammation, leads to nephrotic syndrome and renal failure over several years. In most cases, periodic fever syndromes begin to manifest clinically in early childhood. Occurrence in adulthood is considered rare and is associated with a poorer clinical course. Kidney transplantation is an effective and safe treatment for end-stage chronic kidney disease (CKD) based on AA amyloidosis. Method We present cases of two patients after deceased donor kidney transplantation, who have been diagnosed with adult periodic fever syndrome. Conclusion Periodic fever syndromes are diseases beginning to manifest clinically in early childhood in 60–90% of cases, most often in the case of familial Mediterranean fever around 4 years of age, in the case of CAPS usually only a few months after birth. Occurrence in adulthood is considered rare and is associated with a poorer clinical course. Kidney transplantation is an effective and safe treatment of end-stage CKD based on AA amyloidosis associated with periodic fever syndrome. Adequate targeted treatment against IL-1 or TNF is important and appears to be safe during the post-transplant period, with regular monitoring of renal function, acute phase inflammatory reactants, and histological findings by protocol graft biopsies. It will be important and necessary to assess the development of diseases in the post-transplant period in the long term.

Le sindromi autoinfiammatorie: quando non è solo PFAPA

PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis and Adenitis) is the most common self-inflammatory disorder in children. The diagnosis of PFAPA is easy, based on Thomas criteria, and the prognosis is good. Differential diagnosis with hereditary periodic fever syndromes (Familial Mediterranean Fever, Mevalonate Kinase Deficiency, TRAPS and CAPS) should be considered only in the presence of red flags such as early onset, severe abdominal complaints, arthritis and severe rashes. Some patients may present distinct clinical entities with periodic fevers that neither meet PFAPA criteria nor hereditary periodic fever syndromes genotypes. Subjects with these “Undifferentiated Periodic Fever” may respond to glucocorticoids or colchicines or to anakinra in the most severe cases and still have an undetermined prognosis.

Atypical Familial Mediterranean Fever in a Japanese Boy with Heterozygous MEFV p.Ser503Cys Exon 5 Variant

Periodic fever syndromes are heterogeneous diseases. Familial Mediterranean fever (FMF) is one of the hereditary periodic fever diseases caused by a Mediterranean fever (MEFV) gene abnormality. FMF can be categorized as typical or atypical, based on clinical findings and genetic screening. Atypical FMF has a wide variation of clinical findings and disease-causing mutations of MEFV. Therefore, it is sometimes difficult to diagnose an unknown fever as FMF. To date, a large number of various typical and atypical FMF cases have been reported in Japan. Here, we describe a Japanese boy with heterozygous MEFV p.Ser503Cys exon 5 variant who developed periodic fever. He was treated with colchicine; a complete eradication of his fever and various accompanying symptoms have been subsequently achieved for more than a year. Given that there have been a few reports about patients with this variant, little is known about the genetic and phenotypic role of heterozygous MEFV p.Ser503Cys exon 5 variant. It is therefore imperative to consider atypical FMF as a differential diagnosis when a periodic fever is encountered. Furthermore, we suggest that it is worthwhile to integrate MEFV gene analysis with the potential effects of colchicine treatment in patients with periodic fever.

IL-1 Inhibitors in the Treatment of Monogenic Periodic Fever Syndromes: From the Past to the Future Perspectives

Autoinflammatory diseases (AIDs) represent a rare and heterogeneous group of disorders characterized by recurrent episodes of inflammation and a broad range of clinical manifestations. The most common symptoms involve recurrent fevers, musculoskeletal symptoms, and serositis; however, AIDs can also lead to life-threatening complications, such as macrophage activation syndrome (MAS) and systemic AA amyloidosis. Typical monogenic periodic fever syndromes include cryopyrin-associated periodic fever syndrome (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyper IgD syndrome (MKD/HIDS), and familial Mediterranean fever (FMF). However, a number of other clinical entities, such as systemic juvenile idiopathic arthritis (sJIA), adult-onset Still’s disease (AOSD), Kawasaki disease (KD) and idiopathic recurrent pericarditis (IRP), display similar phenotypical and immunological features to AIDs. All these diseases are pathophysiologicaly characterized by dysregulation of the innate immune system and the central pathogenic role is attributed to the IL-1 cytokine family (IL-1α, IL-1β, IL-1Ra, IL-18, IL-36Ra, IL-36α, IL-37, IL-36β, IL-36g, IL-38, and IL-33). Therefore, reasonable therapeutic approaches aim to inhibit these cytokines and their pathways. To date, several anti-IL-1 therapies have evolved. Each drug differs in structure, mechanism of action, efficacy for the treatment of selected diseases, and side effects. Most of the available data regarding the efficacy and safety of IL-1 inhibitors are related to anakinra, canakinumab, and rilonacept. Other promising therapeutics, such as gevokizumab, tadekinig alfa, and tranilast are currently undergoing clinical trials. In this review, we provide sophisticated and up-to-date insight into the therapeutic uses of different IL-1 inhibitors in monogenic periodic fever syndromes.