Long-term efficacy and safety of subcutaneous tocilizumab in clinical trials of polyarticular or systemic juvenile idiopathic arthritis.

OBJECTIVE: To investigate the safety and efficacy of subcutaneous tocilizumab (SC-TCZ) treatment in a long-term extension (LTE) of clinical trials in polyarticular or systemic juvenile idiopathic arthritis (pJIA or sJIA). METHODS: Patients with pJIA or sJIA from two open-label, 52-week phase 1b core trials of SC-TCZ who had adequate response per investigator assessment entered the LTE and continued SC-TCZ treatment according to body weight-based dosing regimens until commercial availability or up to 5 years. Pharmacokinetics, pharmacodynamics, and efficacy were assessed for up to 3 years, and safety for up to 5 years in the LTE. RESULTS: Forty-four patients with pJIA and 38 patients with sJIA entered the LTE. Tocilizumab trough concentrations were maintained within the range expected to provide clinical benefit (mean values: pJIA, ∼10 µg/ml; sJIA, ∼75 µg/ml over 3 years). Pharmacodynamic parameters (interleukin-6, soluble interleukin-6 receptor, erythrocyte sedimentation rate, C-reactive protein) were maintained throughout the LTE at levels achieved in the core trials. Inactive disease per American College of Rheumatology provisional criteria was reported for 90% (17/19) and 53% (8/15) of patients with pJIA and 91% (10/11) and 92% (12/13) of patients with sJIA in the <30 and ≥30 kg body weight groups, respectively. Serious adverse events in the LTE were reported in six patients with pJIA (13.6%; five serious infections) and five patients with sJIA (13.2%; one serious infection). CONCLUSION: Patients with pJIA or sJIA experienced long-term disease control with SC-TCZ treatment. Long-term safety was consistent with the known tocilizumab safety profile. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, NCT02165345.

Similarities and differences between systemic juvenile idiopathic arthritis and adult-onset Still's disease: a multicenter Spanish study.

To describe the characteristics of systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD), compare their presentation and evolution, and analyse possible complication predictors. Multicenter study. Data were retrieved from a hospital-based study of patients with a diagnosis or suspected diagnosis of sJIA or AOSD according to the responsible physician and followed-up for at least one year. Descriptive variables (classification criteria, clinical manifestations, complications, family, and personal history) were collected at disease onset and during follow-up. We present the clinical characteristics of 326 patients, 67% of whom had a diagnosis of sJIA and 33% of AOSD. Clinical manifestation frequencies were similar between the two groups, except for odynophagia, which was significantly more frequent in AOSD than in sJIA (78.4% vs. 25.5%; p < 0.0001). Among the complications, macrophage activation syndrome (MAS) was significantly more common in sJIA than in AOSD (24.4% vs. 9.5%; p = 0.002), to the extent that an sJIA diagnosis significantly increased the risk of MAS, together with serositis presence, and the need for biological therapy. Patients with sJIA and AOSD showed similar characteristics, supporting the idea that they are both part of Still's disease, but are expressed at different ages. Differences in manifestations and complications might be due to different management between diseases and immune response maturity.

Clinical outcome of SARS-CoV-2 infection in immunosuppressed children in Spain.

Limited information is available regarding SARS-CoV-2 infections in children with underlying diseases. A retrospective study of children less than 15 years old with primary or secondary immunosuppression infected with SARS-CoV-2 during March 2020 was performed. In this series, 8 immunocompromised patients with COVID-19 disease are reported, accounting for 15% of the positive cases detected in children in a reference hospital. The severity of the symptoms was mild-moderate in the majority with a predominance of febrile syndrome, with mild radiological involvement and in some cases with mild respiratory distress that required oxygen therapy. The rational and prudent management of these patients is discussed, evaluating possible treatments and options for hospitalization or outpatient follow-up.Conclusion: In our experience, monitoring of children with immunosuppression and COVID-19 disease can be performed as outpatients if close monitoring is possible. Hospitalization should be assessed when high fever, radiological involvement, and/or respiratory distress are present. What is Known: • SARS-CoV-2 infection is usually mild in children. What is New: • Outcome of immunosuppressed children with COVID-19 is generally good, with a mild-moderate course.

Compassionate use of remdesivir in children with COVID-19.

Children represent a minority of total COVID-19 cases, but studies have reported severe disease and death in pediatric patients. Remdesivir (RDV) has recently demonstrated promising results in adults with COVID-19, but few data have been reported to date in children.A nationwide multicenter observational study was conducted on children with confirmed SARS-CoV-2 receiving compassionate treatment with RDV in Spain. Eight patients were included in the study, four infants and four older children [median age 5 years old; IQR 4 months-11.6 years old]. Half of them had complex underlying medical conditions, and the rest were mostly infants (3/4). Six out of eight children needed Pediatric Intensive Care Unit Admission. No RDV-related adverse outcomes were observed in our patients. Seven have reached successful clinical outcome, but one patient with serious clinical status died due to complications. However, she received RDV very late after the first COVID-19 symptom.Conclusions: In our cohort, most of the patients achieved successful clinical outcome, without observing adverse events. Clinical trials of RDV therapy for children with COVID-19 are urgently needed, to assess the safety, tolerability, efficacy, and pharmacokinetics of RDV in children, as this could be an effective treatment in severe cases. What is Known: • Remdesivir has not been approved to treat COVID-19 in children under 12 years old, although the drug is currently being prescribed in critically ill children. • Remdesivir has recently demonstrated promising results in adults with COVID-19, but few data have been reported to date in paediatric population. What is New: • We report a multicentre cohort of children with confirmed SARS-CoV-2 and severe COVID-19 disease receiving remdesivir during the first month of the pandemic in Spain. • No remdesivir-related adverse outcomes were observed in most of the cases. Seven patients reached successful clinical outcome, and one died due to complications (bacterial sepsis).

Unexpected relevant role of gene mosaicism in patients with primary immunodeficiency diseases.

BACKGROUND: Postzygotic de novo mutations lead to the phenomenon of gene mosaicism. The 3 main types are called somatic, gonadal, and gonosomal mosaicism, which differ in terms of the body distribution of postzygotic mutations. Mosaicism has been reported occasionally in patients with primary immunodeficiency diseases (PIDs) since the early 1990s, but its real involvement has not been systematically addressed. OBJECTIVE: We sought to investigate the incidence of gene mosaicism in patients with PIDs. METHODS: The amplicon-based deep sequencing method was used in the 3 parts of the study that establish (1) the allele frequency of germline variants (n = 100), (2) the incidence of parental gonosomal mosaicism in families with PIDs with de novo mutations (n = 92), and (3) the incidence of mosaicism in families with PIDs with moderate-to-high suspicion of gene mosaicism (n = 36). Additional investigations evaluated body distribution of postzygotic mutations, their stability over time, and their characteristics. RESULTS: The range of allele frequency (44.1% to 55.6%) was established for germline variants. Those with minor allele frequencies of less than 44.1% were assumed to be postzygotic. Mosaicism was detected in 30 (23.4%) of 128 families with PIDs, with a variable minor allele frequency (0.8% to 40.5%). Parental gonosomal mosaicism was detected in 6 (6.5%) of 92 families with de novo mutations, and a high incidence of mosaicism (63.9%) was detected among families with moderate-to-high suspicion of gene mosaicism. In most analyzed cases mosaicism was found to be both uniformly distributed and stable over time. CONCLUSION: This study represents the largest performed to date to investigate mosaicism in patients with PIDs, revealing that it affects approximately 25% of enrolled families. Our results might have serious consequences regarding treatment and genetic counseling and reinforce the use of next-generation sequencing-based methods in the routine analyses of PIDs.

Outpatients with acute osteoarticular infections had favourable outcomes when they received just oral antibiotics without intravenous antibiotics.

AIM: The traditional approach for acute paediatric osteoarticular infections (OAI) has comprised initial intravenous antibiotics followed by prompt oral antibiotics. We assessed how providing just oral antibiotics compared to the traditional two-step approach. METHODS: This prospective study was performed at the Hospital La Paz, Madrid, Spain, from September 2015 to September 2016. We compared 25 outpatients, with good general health and a mean age of 25 months who received just oral antibiotics, with 228 hospitalised children of a similar age who received intravenous and oral antibiotics from other hospitals in the Spanish Network of Osteoarticular Infections. RESULTS: The groups were comparable in terms of age, sex, fever, erythrocyte sedimentation rate value, C-reactive protein and diagnosis. The oral group comprised 15 with osteomyelitis, seven with septic arthritis, two with osteoarthritis and one with spondylodiscitis. This group had a lower percentage of Staphylococcus aureus (8% vs 26%, p = 0.06) and higher proportion of Kingella kingae (24% vs 9%, p = 0.017) than the intravenous group. There were complications (24%) and follow-up sequelae (6%) in the intravenous group, but none in the oral group. CONCLUSION: Outpatients with OAI who were in good general health had favourable outcomes when they received oral antibiotics without intravenous antibiotics.

Clinical Utility of a Multiplex PCR Panel (BioFire Joint Infection®) in the Adjustment of Empiric Antimicrobial Therapy: Experience in Pediatric Osteoarticular Infections.

BACKGROUND/OBJECTIVES: This study aims to evaluate the impact of the PCR multiplex panel (BioFire JI®) on the diagnosis and management of pediatric osteoarticular infections. METHODS: This retrospective study analyzed data from pediatric patients diagnosed with osteoarticular infections between January 2023 and April 2024. The effectiveness of the PCR multiplex panel in identifying pathogens was compared with traditional culture methods. RESULTS: In total, 50 patients were identified (66.6% male, 74% under 3 years of age). They were diagnosed as follows: septic arthritis in 46%, osteomyelitis in 26%, and septic osteoarthritis in 22%. An identifiable agent was isolated by conventional culture in 22 cases (44%). Kingella kingae was the predominant pathogen identified, accounting for 50% of cases (11/22), followed by Staphylococcus aureus (9/22). The BioFire JI® Panel PCR demonstrated a sensitivity of 93%, with a specificity of 63% when evaluated against synovial fluid culture as the reference standard. The panel identified seven additional pathogens not detected by conventional culture methods: 2/9 MSSA (22%), 1/1 S. pyogenes (100%), and 4/11 K. kingae (37%), increasing the yield by 14%. The rapid identification of pathogens facilitated timely and targeted therapeutic interventions. CONCLUSIONS: The PCR multiplex panel (BioFire JI®) improved the diagnosis of pediatric osteoarticular infections.

Sedation for intra-articular corticosteroid injections in juvenile idiopathic arthritis: the views of patients and their parents.

UNLABELLED: Intra-articular corticosteroid injections (IACI) are one of the mainstays of treatment for children with juvenile idiopathic arthritis. The most important disadvantage of IACI is the pain associated with the procedure. Little is known about the children or parents' perception of this pain. This study was undertaken to determine whether patients and their parents prefer sedation to receive IACI or not and why. A survey form was presented to patients and/or their parents from January to March 2010 to evaluate their choice of anesthesiologist-controlled deep sedation (with sevoflurane) vs. no sedation-no local anesthesia and the reasons for it. All participants had experienced the two options. In addition, there were two visual analog scales (VAS) to evaluate pain associated with blood draws and IACI, respectively. A total of 45 patients and their parents filled out the survey form. There were 34 females; the median age was 10.6 years, and the median duration of the disease was 6.4 years. Median VAS score was 1.3 for pain associated with blood draws, and 6, for IACI. Most children preferred sedation for IACI (26 vs. 15), although four did not show preference for either method. Children who preferred sedation for IACI were younger (p = 0.03) and had a shorter course of disease (p = 0.04). CONCLUSIONS: While most children prefer to receive IACI under sedation, a majority of parents prefer to avoid its risks. Children who prefer IACI without sedation are significantly older and have a longer course of disease.

Severe Thrombocytopenia as the Main Manifestation of Childhood-Onset Systemic Lupus Erythematosus.

Thrombocytopenia is a common hematologic abnormality of childhood-onset systemic lupus erythematosus (cSLE). Although in most cases thrombocytopenia is mild, severe thrombocytopenia with bleeding complications might occur, and is further correlated with disease activity and a worse prognosis. We report two female patients with severe thrombocytopenia as the initial manifestation of cSLE, which were successfully treated by intensive immunosuppression including several high-dose methylprednisolone pulses and IV cyclophosphamide. Both patients were initially diagnosed with idiopathic thrombopenic purpura (ITP) refractory to conventional treatment and complicated with haemorrhagic manifestations. For this matter, patients with ITP should be assessed for the presence of ANA, anti-dsDNA antibodies, and complement levels, since they are at high risk to develop cSLE.

Oral Versus Intravenous Antibiotics for Pediatric Osteoarticular Infection: When and to Whom?

BACKGROUND: Osteoarticular infections (OAIs) are typically treated initially with intravenous antibiotics. The objective of this study was to evaluate whether an exclusive oral treatment in selected children may be appropriate. METHODS: The Spanish Network of Osteoarticular Infections is a nationwide multicenter registry comprising 37 hospitals in Spain. The registry prospectively includes clinical characteristics and outcome of children with OAI. One of the hospitals from RioPed offers oral treatment to children meeting certain criteria. Patients were classified into 2 groups. Group 1: management with initial intravenous antibiotic therapy. Group 2: patients exclusively treated with oral antibiotics. A comparison between the 2 groups was performed. RESULTS: We compared 893 children who initially received intravenous antibiotics (group 1) with 64 children who received exclusively oral therapy (group 2). Patients from group 2 were younger (33.9 vs. 20.3 months; P = 0.001), had a lower percentage of Staphylococcus aureus (23.3% vs. 3.1%; P < 0.001), a higher proportion of Kingella kingae (12.1% vs. 28.1%; P = 0.001), higher erythrocyte sedimentation rate/C-reactive protein (CRP) ratio (1.4 interquartile range 0.6-3.6 vs. 3.3 interquartile range 1.7-5.7; P < 0.001) and showed lower rate of fever (63% vs. 48.8%; P = 0.024) than in group 1. Complications were not found in group 2. CONCLUSIONS: An exclusively oral administration could be a safe option in selected patients with OAI. Low-risk criteria are proposed: good general condition, no underlying disease, 6 months to 3 years old, appropriate oral tolerance, C-reactive protein <80 mg/L, erythrocyte sedimentation rate/C-reactive protein ratio ≥0.67, no skin injury, no recent surgery, no cervical spondylodiscitis and no local complications at onset.

Clinical course and seroprevalence of COVID-19 in children with rheumatic diseases-cross-sectional study from a reference centre in Spain.

SARS-CoV-2 infections in children are frequently asymptomatic or mild and can go unnoticed. This study aimed to describe the seroprevalence and clinical course of SARS-CoV-2 in a cohort of children with rheumatic diseases in a real-life setting and assess possible risk factors. A cross-sectional study was performed in a paediatric rheumatology unit (September 2020 to February 2021). At inclusion, a specific questionnaire was completed and SARS-CoV-2 serology was performed. Demographics, treatment and disease activity of patients with and without laboratory-confirmed SARS-CoV-2 infection were compared. A total of 105 children were included. SARS-CoV-2 infection was demonstrated in 27 patients (25.7%). The mean age was 11.8 years, and most patients were females (72.4%). The most frequent underlying condition was juvenile idiopathic arthritis (70.3%; 19/27). Patients received immunosuppressive treatment in 78% of cases (21/27). Overall, 44.4% (12/27) of infected patients were asymptomatic. A total of 66.7% (18/27) of patients did not require medical assistance. Three patients required hospital admission because of COVID-19. Children with confirmed SARS-CoV-2 infection were less frequently in remission (52% vs 72%; p 0.014). Moderate disease activity and treatment with oral corticosteroids were associated with higher risk for SARS-CoV-2 (OR 5.05; CI 95%: 1.56-16.3 and OR 4.2; CI 95%: 1.26-13.9, respectively). In a cohort of Spanish paediatric patients with rheumatic diseases, clinical course of COVID-19 was mild, with more than one third of asymptomatic cases. Higher disease activity and oral corticosteroids appear to be risk factors for SARS-CoV-2 infection. Key Points • We aimed to investigate the seroprevalence of SARS-CoV-2 infection in a cohort of Spanish paediatric patients with RD, testing both symptomatic and asymptomatic patients. We also compared treatment and disease activity of patients with and without laboratory-confirmed SARS-CoV-2 infection. • In our cohort of 105 paediatric patients with rheumatic diseases, the clinical course of COVID-19 was mild and 44% of cases were asymptomatic. Three cases required hospital admission with no complications. Seroprevalence was 20%. • No association was found between disease activity or treatment with corticosteroids and symptomatic or asymptomatic infection. Higher disease activity and treatment with oral corticosteroids appeared to be risk factors for laboratory-confirmed SARS-CoV-2 infection.

Are infections in children with juvenile idiopathic arthritis more frequent than in healthy children? A prospective multicenter observational study.

Background: Children with juvenile idiopathic arthritis (JIA) might be at a higher risk of infection. Our objectives are to describe and compare infection rates in patients with JIA vs. healthy patients. Methods: A prospective, multicenter observational study was performed in Spain from January 2017 to June 2019. Patients with JIA from 7 participating hospitals and children without JIA (siblings of patients with JIA, and non-JIA children from primary health centers) were followed up with quarterly questionnaires to record infection episodes. Tuberculosis, herpes zoster, and infections requiring hospital admission were considered severe infections. Rates of infection (episodes/patient/year) were compared using a generalized estimating equations model. Results: A total of 371 children (181 with and 190 without JIA) were included. The median age was 8.8 years (IQR 5.5-11.3); 75% of the patients with JIA received immunosuppressive treatment (24% methotrexate, 22% biologic, 26% both). A total of 667 infections were recorded; 15 (2.2%) were considered severe. The infection rate was 1.31 (95%CI 1.1-1.5) in JIA and 1.12 (95%CI 0.9-1.3) in non-JIA participants (p = 0.19). Age <4 years increased the infection rate by 2.5 times (2.72 vs. 1.12, p < 0.001) in both groups. The most frequent infection sites were upper respiratory (62.6% vs. 74.5%) and gastrointestinal (18.8% vs. 11.4%). There were no differences in severe infections (2.5% vs. 2%, p = 0.65) between the groups. In children with JIA, younger age and higher disease activity (JADAS71) were associated with a higher infection rate. Conclusion: We found no differences in the infection rate or infection severity between patients with and without JIA. Most infections were mild. An age younger than 4 years increased the infection risk in both groups. Higher disease activity was associated with a higher infection rate.

Anakinra in Patients With Systemic Juvenile Idiopathic Arthritis: Long-term Safety From the Pharmachild Registry.

OBJECTIVE: To evaluate the long-term safety profile of anakinra in patients with systemic juvenile idiopathic arthritis (sJIA). METHODS: Data from patients with sJIA enrolled in the Pharmachild registry (ClinicalTrials.gov: NCT03932344) prior to September 30, 2018, and treated with anakinra were analyzed. The study endpoints were the occurrence of non-serious adverse events (SAEs) of at least moderate severity and SAEs, including macrophage activation syndrome (MAS), and the duration of anakinra treatment with reasons for discontinuation. All endpoints were analyzed overall by 6-month time windows, and in different treatment sets represented by those patients treated continuously with anakinra for at least 12, 18, and 24 months (set-12, -18, and -24, respectively). RESULTS: Three hundred six patients were enrolled. Of these patients, 46%, 34%, and 28% had been treated for at least 12, 18, and 24 months, respectively. Two hundred and one AEs, mostly represented by infections, were reported for 509.3 patient-years (PY) with an overall incidence rate (IR) of 39.5 per 100 PY. Among 56 SAEs (IR 11.0/100 PY), 23.2% were infections and 19.6% MAS episodes. The IR of AEs was higher during the first 6 months of anakinra treatment, followed by decreasing IRs in the long-term treatment sets. Treatment discontinuation occurred in 76% of patients, most frequently in the first 6 months, because of inefficacy (43%), remission (31%), or AEs/intolerance (15%). No deaths or malignancies occurred during anakinra treatment. CONCLUSION: The results of the present study confirm the long-term safety profile of anakinra in patients with sJIA and demonstrate an overall decreasing incidence of AEs over time. [ClinicalTrials.gov: NCT01399281 and NCT03932344].

Biological therapy in refractory chronic nonbacterial osteomyelitis: A case series of 19 patients.

INTRODUCTION: Chronic non-bacterial osteomyelitis (CNO) represents an autoinflammatory bone disorder. Currently there are no standardized diagnostic or treatment guidelines. The objective of the study is to describe our experience with biological therapy in children with the disease. METHODS: Retrospective chart review of patients with CNO treated with biological therapy followed at two tertiary hospitals from January 2007 to April 2020. Biologicals were started in most patients due to persistent disease activity after receiving standard therapy with at least 2 drugs (NSAIDs and corticosteroids and/or pamidronate). RESULTS: Twenty-five patients were diagnosed with CNO. Out of those, 19 patients (15 females) failed conventional therapy. The mean age at diagnosis was 8.8±2.9 years and the mean diagnostic delay was 6.9±8.3 months. All patients presented with bone pain and 6/19 also had fever. The most frequently affected bones were femur (9 patients), followed by clavicle, tibia and vertebrae (6, 6 and 5 patients respectively). Nine children had skin lesions. C-reactive protein was elevated in 13/19 patients (mean 20.2mg/L±11.7) and ESR in 16/19 (mean 48mm/h±29). All patients received nonsteroidal anti-inflammatory drugs, 15/19 pamidronate, 10/19 corticosteroids and 19 anti-TNF-therapy. At the last follow-up visit, 10/19 patients were still on biological therapy (8 adalimumab, 2 infliximab) and 18 out of 19 remained asymptomatic. In regards to adverse effects, one patient receiving infliximab developed S. aureus osteomyelitis and another cutaneous leishmaniosis. CONCLUSIONS: This research emphasizes that anti-TNF-therapy represents an effective and safe alternative for patients with CNO refractory to conventional treatments.

Fatal outcome of anti-MDA5 juvenile dermatomyositis in a paediatric COVID-19 patient: a case report.

Anti-melanoma differentiation-associated gene 5 juvenile dermatomyositis (anti-MDA5 JDM) is associated with high risk of developing rapidly progressive interstitial lung disease (RP-ILD). Here we report an 11-year-old girl with anti-MDA5 JDM and RP-ILD which led to a fatal outcome, further aggravated by SARS-CoV-2 infection. She was referred to our hospital after being diagnosed with anti-MDA5 JDM and respiratory failure due to RP-ILD. On admission, fibrobronchoscopy with bronchoalveolar lavage (BAL) revealed Pneumocystis jirovecii infection so treatment with intravenous trimethoprim-sulfamethoxazole was initiated. Due to RP-ILD worsening, immunosuppressive therapy was intensified using methylprednisolone pulses, cyclophosphamide, tofacitinib and intravenous immunoglobulin without response. She developed severe hypoxemic respiratory failure, pneumomediastinum and pneumothorax, further complicated with severe RP-ILD and cervical subcutaneous emphysema. Three real-time RT-PCR for SARS-CoV-2 were made with a negative result. In addition, she was complicated with a secondary hemophagocytic lymphohistiocytosis and a fourth real-time PCR for SARS-CoV-2 performed in BAS sample was positive. Despite aggressive treatment of RP-ILD due to anti-MDA5 JDM, there was no improvement of respiratory failure in the following days and patient developed refractory septic shock and died. Anti-MDA5 JDM patients with RP-ILD have a poor prognosis with a high mortality rate. For this reason, intensive immunosuppressive therapy is essential including the use of promising drugs such as tofacitinib. COVID-19 in children with underlying health conditions like anti-MDA5 JDM may still be at risk for disease and severe complications.

Colchicine treatment in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: A multicenter study in Spain.

OBJECTIVE: To evaluate the efficacy of colchicine therapy in pediatric patients with PFAPA syndrome who present with an incomplete response to the standard treatment or with frequent episodes (an interval of less than 14 days between two disease flares). METHODS: A multicenter cohort study of children diagnosed with PFAPA syndrome and treated with colchicine was performed in three separate hospitals located in Spain. The patients clinical and laboratory data were reviewed by accessing their medical records. Response to colchicine was evaluated after 12 months of treatment for frequency, duration, and intensity of PFAPA episodes. RESULTS: A total of 13 children were included in our study, 43% of whom were boys. Median age of the colchicine therapy initiation was 6 years (interquartile range (IQR)=3-9.5). Following a 12-month period of colchicine therapy (median dosage of 0.02 mg/kg/day; IQR=0.02-0.03), a significant decrease in the median number of flares (median 8; IQR=7-14 vs 3; IQR=2-4; p=0.005) and the duration of disease episodes (median 4 days; IQR=3.25-5.125 vs 1 day; IQR=1-2; p=0.003) was observed. Furthermore, the highest degree of fever during disease flares was reduced from median 40ºC (IQR=39.5-40) to 38.5ºC (IQR=37.7-38.9) (p=0.002). CONCLUSION: Colchicine therapy decreased the frequency and intensity of PFAPA. The use of colchicine could be an effective treatment in pediatric patients with PFAPA syndrome who present with frequent or severe relapses.

INSAID Variant Classification and Eurofever Criteria Guide Optimal Treatment Strategy in Patients with TRAPS: Data from the Eurofever Registry.

BACKGROUND: TNF receptor-associated periodic syndrome (TRAPS) is a rare autoinflammatory disease caused by dominant mutation of the TNF super family receptor 1A (TNFRSF1A) gene. Data regarding long-term treatment outcomes are lacking. OBJECTIVE: To assess correlations of genotype-phenotypes in patients with TRAPS, as defined by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) classification and Eurofever criteria, with treatment responses. METHODS: Data from 226 patients with variants of the TNFRSF1A gene and enrolled in the Eurofever registry were classified according to the INSAID classification in groups A (pathogenic or likely pathogenic variants), B (variants of uncertain significance or not classified variants), and C (benign or likely benign variants) and screened for Eurofever criteria. RESULTS: In group A (127 of 226 patients, 56%), all fulfilled Eurofever criteria and 20 of 127 patients (16%) developed AA amyloidosis. In group B (78 of 226 patients, 35%), 40 of 78 patients (51%) did not fulfill Eurofever criteria, displaying a lower incidence of abdominal pain (P < .02) and higher efficacy rate of on-demand nonsteroidal anti-inflammatory drugs (P < .02) and colchicine (P < .001). Group C (21 of 226 patients, 9%) presented a milder disease (P < .02) and none fulfilled Eurofever criteria. Anti-IL-1 drugs were the most frequently used in patients fulfilling Eurofever criteria, with the highest efficacy rate (>85% complete response). No patients on anti-IL-1 treatments developed AA amyloidosis, and 7 women with a history of failure to conceive had successful pregnancies. CONCLUSION: Anti-IL-1 drugs are the best maintenance treatment in patients with TRAPS. The diagnosis of TRAPS should be considered very carefully in patients of group B not fulfilling Eurofever criteria and group C, and colchicine may be preferable as the first maintenance treatment.

Biallelic loss-of-function LACC1/FAMIN Mutations Presenting as Rheumatoid Factor-Negative Polyarticular Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is a complex rheumatic disease with both autoimmune and autoinflammatory components. Recently, familial cases of systemic-onset JIA have been attributed to mutations in LACC1/FAMIN. We describe three affected siblings from a Moroccan consanguineous family with an early-onset chronic, symmetric and erosive arthritis previously diagnosed as rheumatoid factor (RF)-negative polyarticular JIA. Autozygosity mapping identified four homozygous regions shared by all patients, located in chromosomes 3, 6 (n:2) and 13, containing over 330 genes. Subsequent whole exome sequencing identified two potential candidate variants within these regions (in FARS2 and LACC1/FAMIN). Genotyping of a cohort of healthy Moroccan individuals (n: 352) and bioinformatics analyses finally supported the frameshift c.128_129delGT mutation in the LACC1/FAMIN gene, leading to a truncated protein (p.Cys43Tyrfs*6), as the most probable causative gene defect. Additional targeted sequencing studies performed in patients with systemic-onset JIA (n:23) and RF-negative polyarticular JIA (n: 44) revealed no pathogenic LACC1/FAMIN mutations. Our findings support the homozygous genotype in the LACC1/FAMIN gene as the defect underlying the family here described with a recessively inherited severe inflammatory joint disease. Our evidences provide further support to the involvement of LACC1/FAMIN deficiency in different types of JIA in addition to the initially described systemic-onset JIA.