Paediatric Rheumatology International Trials Organisation Research Articles

Overlap of International League of Associations for Rheumatology and Preliminary Pediatric Rheumatology International Trials Organization Classification Criteria for Nonsystemic Juvenile Idiopathic Arthritis in an Established UK Multicentre Inception Cohort.

The goal was to assess the degree of overlap between existing International League of Associations for Rheumatology (ILAR) and preliminary Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria for juvenile idiopathic arthritis (JIA). Participants from the Childhood Arthritis Prospective Study, a multicenter UK JIA inception cohort, were classified using the PRINTO and ILAR classification criteria into distinct categories. Systemic JIA was excluded because several classification items were not collected in this cohort. Adaptations to PRINTO criteria were required to apply to a UK health care setting, including limiting the number of blood biomarker tests required. The overlap between categories under the two systems was determined, and any differences in characteristics between groups were described. A total of 1,223 children and young people with a physician's diagnosis of JIA were included. Using PRINTO criteria, the majority of the patients had "other JIA" (69.5%). There was a high degree of overlap (91%) between the PRINTO enthesitis/spondylitis- and ILAR enthesitis-related JIA categories. The PRINTO rheumatoid factor (RF)-positive category was composed of 48% ILAR RF-positive polyarthritis and 52% undifferentiated JIA. The early-onset antinuclear antibodies-positive PRINTO category was largely composed of ILAR oligoarthritis (50%), RF-negative polyarthritis (24%), and undifferentiated JIA (23%). A few patients were unclassified under PRINTO (n=3) and would previously have been classified as enthesitis-related JIA (n=1) and undifferentiated JIA (n=2) under ILAR. Under the preliminary PRINTO classification criteria for childhood arthritis, most children are not yet classified into a named category. These data can help support further delineation of the PRINTO criteria to ensure homogenous groups of children can be identified.

Application of the new PRINTO classification criteria for juvenile idiopathic arthritis in a sample of Portuguese patients.

The International League of Associations for Rheumatology (ILAR) classification system for juvenile idiopathic arthritis (JIA) does not depict homogenous subgroups of disease. As to unify our language with the adult rheumatic diseases, the Pediatric Rheumatology International Trials Organization (PRINTO) is attempting to revise these criteria. To reclassify a JIA sample according to the new provisional PRINTO subsets: systemic JIA (sJIA), RF-positive JIA (RF-JIA), early-onset ANA-positive JIA (eoANA-JIA), enthesitis/spondylitis-related JIA (ESR-JIA), "other JIA" and "unclassified JIA". Retrospective study including JIA patients followed in a Pediatric Rheumatology Unit at a university hospital. Medical records were reviewed, and patients were reclassified as per the provisional PRINTO criteria. Of a total of 104 patients, 41 (39.4%) were reclassified as "other JIA", 36 (34.6%) as eoANA-JIA, 15 (14.4%) as ESR-JIA, 8 (7.7%) as sJIA and 4 (3.8%) as RF-JIA. More than 90% of the oligoarticular JIA were reclassified into either eoANA-JIA or "other JIA". Only one negative RF polyarticular JIA converted to RF-JIA due to the presence of a positive anti-citrulinated peptide antibody (ACPA). The psoriatic arthritis (PsA) subgroup disappeared into eoANA-JIA (25%), ESR-JIA (25%) or "other JIA" (50%). There were significant differences in age of onset, but not on the gender ratio or uveitis presence. Antinuclear antibody was more frequent in females (p=0.035) and younger patients (p<0.001). The number of affected joints and PsA features elapsed in favour of laboratory RF, ACPA and ANA traits. PsA and oligoarticular JIA were abolished. The "other JIA" entity is heterogenous and prevalent, claiming reformulation.

Defining criteria for disease activity states in juvenile dermatomyositis based on the Juvenile Dermatomyositis Activity Index

ObjectivesTo develop and validate the cut-offs in the Juvenile DermatoMyositis Activity Index (JDMAI) to distinguish the states of inactive disease (ID), low disease activity (LDA), moderate disease activity (MDA) and...

Advances and Challenges in the Classification of Childhood Arthritis

The most appropriate classification of childhood arthritis remains controversial. Several efforts have been made over the years to devise classification systems that identify homogeneous subgroups within the disease spectrum. Although widely used, the International League of Associations for Rheumatology (ILAR) classification has shown major limitations as it was found to have failed its primary goal of identifying homogeneous disease categories. Furthermore, its use of the count of affected joints and of the presence of psoriatic features to define individual disease subsets has been criticized. A novel classification system has been proposed by the Pediatric Rheumatology International Trials Organization (PRINTO) through expert consensus. The preliminary scheme is currently being scrutinized by means a large-scale data collection aimed to formulate an evidence-based classification, whose results will likely be available in 2024. The development of a clinicobiologic classification has been tried in a proof-of-concept study by integrating meaningful biologic and clinical characteristics, including levels of proinflammatory cytokines and measures of disease activity, that defined indicators or composite variables capable of identifying homogeneous patient subgroups by cluster analysis. The current advance in biotechnology, especially genomics, proteomics and transcriptomics, may pave the way to the future identification of well-defined clusters of patients that will inform a biology-based and data-driven classification system. However, any attempt to defining biologic subtypes should be combined with precise clinical and prognostic data in order to devise a rational classification that facilitates the progress towards personalized management of children with JIA. Furthermore, the observed variability in the prevalence of disease subtypes across geographic areas and ethnic groups must be taken into account to develop a classification that is applicable on a global scale.

Advances in the Diagnosis and Treatment of Enthesitis-Related Arthritis.

Enthesitis-related arthritis (ERA) represents 5-30% of all cases of juvenile idiopathic arthritis (JIA) and belongs to the spectrum of the disorders included in the group of juvenile spondyloarthritis. In the last decade, there have been considerable advances in the classification, diagnosis, monitoring, and treatment of ERA. New provisional criteria for ERA have been recently proposed by the Paediatric Rheumatology INternational Trials Organisation, as part of a wider revision of the International League of Associations for Rheumatology criteria for JIA. The increased use of magnetic resonance imaging has shown that a high proportion of patients with ERA present a subclinical axial disease. Diverse instruments can be used to assess the disease activity of ERA. The therapeutic recommendations for ERA are comparable to those applied to other non-systemic JIA categories, unless axial disease and/or enthesitis are present. In such cases, the early use of a TNF-alpha inhibitor is recommended. Novel treatment agents are promising, including IL-17/IL-23 or JAK/STAT pathways blockers.

Welcome to the New Issue (Vol: 29, No: 3, 2023) and Current News of the European Journal of Therapeutics

Welcome to the New Issue (Vol: 29, No: 3, 2023) and Current News of the European Journal of Therapeutics

E08 Single center study of Systemic Juvenile Idiopathic Arthritis in Moroccan patients

Abstract Introduction Juvenile idiopathic arthritis (JIA) is the most common rheumatological disorder in childhood. About 10% to 20% of children with JIA have a rare and serious subtype called systemic juvenile idiopathic arthritis (SJIA). SJIA differs from other subtypes in that it’s the only one considered an autoinflammatory rather than autoimmune disease because of the association with systemic features and is therefore treated differently with anti-IL1 and anti-IL6. Objectives To describe epidemiological data of SJIA in Moroccan patients taking into account environmental conditions. To compare existing criteria (ILAR, Fautrel, Yamaguchi) to the new Pediatric Rheumatology International Trials Organization (PRINTO) classification currently in the process of validation. Patient and methods Retrospective prospective study conducted between January 2019 and December 2022. SJIA was diagnosed based on one of the four classification criteria ILAR, Fautrel, Yamaguchi or PRINTO Classification after ruling out infectious disease, immunodeficiency and malignancy whenever necessary. Complete remission was defined as the absence of clinical signs and inflammatory syndrome. Partial remission was defined as the absence of active clinical signs with persistence of inflammatory syndrome. Results Nine SIJA (44% male) patients were enrolled. The mean age at diagnosis was 4 years 8 months, the mean time to diagnosis was 4.8 months (range 1 – 24 months), the average follow up period was 16.4 months. At the time of diagnosis, the most common findings were typical fever (100%), arthritis (66%), skin rash (55%), 2 patients had pericarditis and one had macrophage activation syndrome (MAS), there was no renal or pulmonary involvement. Laboratory data showed in all patients, high level of C-reactive protein at mean value of 183 mg/l, increased erythrocyte sedimentation rate at mean of 88 mm first h, hyperleukocytosis at mean of 17 000 WBC/mm3 with high neutrophil counts at a mean of 12 297/mm3 and thrombocytosis at a mean of 625 000/mm3. To rule out other diagnosis, para clinical evaluation showed a positive antinuclear antibody in one patient without pathogenic significance, a bone marrow count performed in 3 patients, showed normal count in 2 patients and hemophagocytosis in one patient and immunoglobulins assay performed in 3 patients was normal. Of the 9 patients, 4 met all the criteria, 2 were diagnosed based on Yamaguchi criteria and one on Fautrel criteria, one fulfilled all criteria except ILAR and the last fulfilled only ILAR and new PRINTO classification. One patient was treated with corticosteroid pulse therapy for MAS and then oral corticosteroids with complete remission. Another received corticosteroids and biotherapy [tocilizumab (TCZ)] upfront due to late consultation and severe form with complete remission. Seven patients were treated with non-steroidal anti-inflammatory drugs (NSAIDs) of which one achieved partial remission with a delay of 2 months of follow up and 6 required adjunctions of another medication: corticosteroids (4), MTX (2), biotherapy (5) [anakinra (5), Switch TCZ (2)] with complete remission. The last patient reached complete remission under corticosteroids, Triamcinolone Hexacetonide knee infiltration and methotrexate. Anakinra was the most common first-line biologic treatment choice (n = 5), and 2 of them need switch to Tocilizumab to achieve remission. One of the 2 patients with pericarditis needed a rescue drainage. Outcome was favorable in all patients except one who had a relapse with final remission, and articular sequel in 3 patients. Discussion and conclusion SJIA is a rare but serious condition with high risk of morbidity related to arthritis and mortality from MAS and pericarditis. The latter features turn into a good prognosis with early diagnosis and treatment, as we have done. It can occur any time during childhood, but it most commonly starts at around the age of two years, unlike our patients who were older. No predominance ratio is reported as we have noted. SJIA is referred to as Still disease by some authors justifying the new PRINTO classification and the specific treatment. In our study, Yamaguchi criteria seem to be the most sensitive (7/9 fulfilled) followed by New PRINTO classification and Fautrel criteria (6/9 fulfilled), ILAR criteria are the less sensitive (5/9 fulfilled) what can delay diagnosis and treatment. Our study showed the benefit of biological agent, 66% of patients achieved remission with at least one biological agent and we concluded that Anti-IL1 drugs are mostly preferred for ongoing systemic inflammation. However Anti-IL-6 agents are very efficient in patients with a polyarticular course.

The Effect of Clinical and Genetic Variables of Familial Mediterranean Fever Patients: Real Life Data.

The Eurofever/the Pediatric Rheumatology International Trials Organization (PRINTO) classification criteria for familial Mediterranean fever (FMF) include a combination of clinical symptoms and genotype. The pathogenicity of gene variants associated with FMF is categorized by the International Study Group for Systemic Autoinflammatory Diseases (INSAID) classification criteria. The aim of this study was to evaluate the real-life impact and usefulness of the Eurofever/PRINTO classification criteria and the INSAID classification criteria in patients with FMF and their impact on treatment management. In this medical records review study, the files of FMF patients who met the Eurofever/PRINTO classification criteria were reviewed. The MEFV (MEditerranean FeVer) variants were grouped according to the INSAID classification criteria. Of the 1062 patients, the female-to-male ratio was 1:1.01. In group 1, there were 150 patients (14.1%) who met the clinical criteria. Group 2 consisted of 912 patients (85.9%) who met the criteria according to genetic variants. The mean ages at symptom onset in groups 1 and 2 were 5.6 ± 3.8 and 1.5 ± 1.2 years, respectively ( p = 0.024). Whereas the mean annual attack frequency was 2.7 ± 3.1/year in group 1, it was 4.1 ± 2.3/year in group 2 ( p = 0.04). The pathogenic variant was higher in the colchicine-resistant group compared with the responders ( p = 0.12). The Eurofever/PRINTO classification criteria may provide a new perspective on the diagnosis and clinical follow-up of FMF patients. Patients with a pathogenic variant who meet the Eurofever/PRINTO classification criteria including genetic variables have earlier onset of disease and more frequent attacks than those who meet the criteria including clinical variables. These patients need regular and closer follow-ups in terms of attack frequency, colchicine dose adjustment, and colchicine resistance.

Improvement in Disease Activity in Refractory Juvenile Dermatomyositis Following Abatacept Therapy.

This open-label, 24-week study was conducted to evaluate the safety and efficacy of abatacept in patients with refractory juvenile dermatomyositis (DM). Ten patients ≥7 years of age with moderate disease activity were enrolled in a 24-week study to examine the safety of subcutaneous abatacept and patient responses to the treatment. The primary endpoint was the International Myositis Assessment and Clinical Studies (IMACS) group Definition Of Improvement (DOI). Secondary endpoints included safety, changes in the core set activity measures (CSMs) of the IMACS group and the Pediatric Rheumatology International Trials Organization, and improvements in disease activity based on the American College of Rheumatology (ACR)/EULAR response criteria for juvenile DM. Radiologists blinded with regard to participant data assessed magnetic resonance images (MRIs) of patient thigh muscles. Interferon (IFN)-regulated gene score was performed on whole-blood RNA samples using a NanoString assay, and cytokines were assessed using a Luminex assay. Five patients achieved DOI at week 12, and 9 patients achieved DOI at week 24, including 2 patients with minimal, 4 patients with moderate, and 3 patients with major improvement by the 2016 ACR/EULAR response criteria for juvenile DM when patients were assessed using the CSMs of the IMACS Group. Improvements from baseline were seen in all CSMs at weeks 12 and 24, except in muscle enzymes. Daily glucocorticoid doses decreased from a mean of 16.7 mg at baseline to 10.2 mg at week 24 (P=0.002). Average MRI muscle edema scores decreased from a mean baseline score of 5.3 to 2.3 at week 24 (P=0.01). Six patients had down-trending IFN-regulated gene scores and galectin-9 expression at week 24. Decreases in IFN-regulated gene scores and in levels of interferon-γ-inducible protein 10kDa, galectin-9, and interleukin-2 correlated with improvements in disease activity and in muscle edema shown on MRI. Eleven grade 2 or 3 treatment-emergent adverse events were observed. This open-label study demonstrated that abatacept may be beneficial for patients with treatment-refractory juvenile DM.

Adipokine profile in long-term juvenile dermatomyositis, and associations with adipose tissue distribution and cardiac function: a cross-sectional study

ObjectivesIn long-term juvenile dermatomyositis (JDM), altered adipose tissue distribution and subclinical cardiac dysfunction have been described. Our aims were to compare adipokine levels in patients with JDM after long-term disease...

Enthesitis-related arthritis: the clinical characteristics and factors related to MRI remission of sacroiliitis

BackgroundTo describe the clinical characteristics and explore the factors related to the MRI remission of sacroiliitis in patients with enthesitis-related arthritis (ERA).MethodsPatients with ERA from 2018–2022 in our medical center were retrospectively reviewed, which identified according to Pediatric Rheumatology International Trials Organization (PRINTO) criteria. Demographics, clinical characteristics, examinations, and treatments were described. Univariate and multivariate logistic regression models were used to analyze the factors related to MRI remission of sacroiliitis in ERA.ResultsThis retrospective study included 160 ERA patients (51.9% male) with a mean onset age of 9.2 ± 3.0 years. There were 144 cases (81.9%) with peripheral arthritis, and the hip, knee, and ankle joints were the most commonly involved joints. Enthesitis occurred in 48 cases (30.0%), and sacroiliitis occurred in 142 cases (88.5%) at diagnosis. Human leukocyte antigen (HLA)-B27 was positive in 33 cases (17.1%), and acute uveitis occurred in 3 cases (1.9%). The majority of patients (93.7%) were treated with disease-modifying anti-rheumatic drugs (DMARDs), and 60% with biologics. Among 62 patients with MRI-defined sacroiliitis, 27 (43.5%) cases showed improvement in the sacroiliac joint lesion after treatment. Multivariate logistic regression analysis showed that duration from onset to diagnosis of less than 3 months (OR = 3.609, 95% CI: 1.068–12.192) and active joints of more than 4 (OR = 4.916, 95% CI: 1.006–24.037) were independent factors.ConclusionWe highlighted differences in ERA clinical characteristics. Patients with a shorter diagnosis time and more joint involvement improved more significantly in sacroiliac joint lesions after treatment.

Looking for the best strategy to treat children with new onset juvenile idiopathic arthritis: presentation of the “comparison of STep-up and step-down therapeutic strategies in childhood ARthritiS” (STARS) trial

BackgroundAlthough a satisfactory disease control is nowadays achievable in most patients with JIA, a substantial proportion of them still do not respond adequately or reach long-term drug-free remission. According to current recommendations, treatment should be escalated in subsequent steps. A different approach is based on the assumption that the initial start of an aggressive therapy may take advantage of the “window of opportunity” and could alter the biology of the disease, leading to an improvement of long-term outcomes, including the prevention of cumulative joint damage.ObjectivesThis randomised clinical trial aims to compare the effectiveness of a conventional therapeutic regimen, based on treatment escalation and driven by the treat-to-target approach, with that of an early aggressive intervention based on the initial start of a combination of conventional and biological DMARDs.MethodsJIA patients with oligoarthritis or RF negative polyarthritis aged more than 2 years and with less than 4 months of disease course will be included in the study. Children will be randomised into two arms: patients in Step-up arm with less severe oligoarthritis will undergo an intra-articular corticosteroid injection (IACI) in all affected joints; patients with polyarthritis or severe oligoarthritis will receive IACI and methotrexate. Subsequent treatment will follow a standardised protocol based on the patients’ level of disease activity measured with the JADAS, according to a treat-to-target strategy. Patients in Step-down arm will receive a 6-month early combined treatment (methotrexate plus IACI for less severe oligoarthritis, methotrexate plus etanercept for severe oligoarthritis and polyarthritis). The primary endpoint is the frequency of achievement of the status of clinical remission (i.e. persistence of inactive disease for at least 6 months) at the 12-month visit. Safety events, physician-centred measures and parent/patient-reported outcomes will be collected through the Paediatric Rheumatology International Trials Organisation on line database.Expected resultsThe STARS trial aims to provide important evidence supporting the first-line treatment choices in the care of children with oligoarticular and polyarticular JIA. If the superiority of an early aggressive therapy will be demonstrated, this will demand further studies on the biological definition of the window of opportunity for JIA.Trial registrationThe Trial is registered on the ClinicalTrials.gov registry (NCT03728478) on the 31st October 2018 and EU Clinical Trials Register on the 14th May 2018 (EudraCT Number: 2018–001931-27).

A Comparison of International League of Associations for Rheumatology and Pediatric Rheumatology International Trials Organization Classification Systems for Juvenile Idiopathic Arthritis Among Children in a Canadian Arthritis Cohort.

The aim of the Paediatric Rheumatology International Trials Organisation (PRINTO) juvenile idiopathic arthritis (JIA) classification criteria, which is still in development, is to identify homogeneous groups of JIA patients. This study was undertaken to compare International League of Associations for Rheumatology (ILAR) JIA classification criteria and PRINTO JIA classification criteria using data from the ReACCh-Out (Research in Arthritis in Canadian Children, Emphasizing Outcomes) cohort. We used clinicobiologic data recorded within 7 months of diagnosis to assign a diagnosis of JIA and identify subcategories of JIA among 1,228 patients according to the 2 JIA classification systems. We compared the proportions of patients classified and the alignment of classification categories with clinicobiologic subtypes and adult arthritis types. The PRINTO criteria classified 244 patients (19.9%) as having early-onset antinuclear antibody-positive JIA, 157 (12.8%) as having enthesitis/spondylitis-related JIA, 38 (3.1%) as having systemic JIA, and 10 (0.8%) as having rheumatoid factor-positive JIA. A total of 12% of patients were unclassifiable using the ILAR criteria, while 63.3% were unclassifiable using the PRINTO criteria (777 with other JIA and 2 with unclassified JIA). In sensitivity analyses, >50% of patients remained unclassifiable using the PRINTO criteria. Compared to the PRINTO criteria, ILAR JIA categories aligned better with clinicobiologic subtypes in 131 patients (χ2 = 44, P = 0.005, versus χ2 = 15, P = 0.07 for PRINTO), and ILAR categories aligned better with adult types of arthritis in 389 evaluable patients. Currently identified PRINTO disorders can only be used to classify a minority of JIA patients, leaving a large proportion of JIA patients with other disorders requiring further characterization. Current PRINTO JIA classification criteria do not align better with clinicobiologic subtypes or adult forms of arthritis compared with the older ILAR classification system.

Efficacy and tolerance of corticosteroids and methotrexate in patients with juvenile dermatomyositis: a retrospective cohort study.

To assess the efficacy and tolerance of the conventional first-line treatment by MTX and CS in patients with JDM regardless of severity. We conducted a monocentric retrospective study of patients with newly diagnosed JDM treated with MTX and CS from 2012 to 2020. The proportion of clinically inactive disease (CID) within 6 months of MTX initiation was evaluated using both Paediatric Rheumatology International Trials Organisation (PRINTO) criteria (evaluating muscle inactive disease) and DAS (evaluating skin inactive disease). We compared responders and non-responders using univariate analyses. Forty-five patients with JDM, out of which 30 (67%) severe JDM, were included. After 6 months of treatment with MTX and CS, complete CID, muscle CID and skin CID were achieved in 14/45 (31%), 19/45 (42%) and 15/45 (33%) patients, respectively. The absence of myositis-specific (MSA) or myositis-associated autoantibodies (MAA) at diagnosis was associated with a better overall, cutaneous and muscular therapeutic response, compared with antibody-positive forms (P &lt; 0.01). Requirement for ICU (P = 0.029) and cutaneous ulcerations (P = 0.018) were associated with a less favourable muscle response. MTX was stopped due to intolerance in six patients (13%) before month 6. Conventional first-line treatment with MTX was not efficient in a large subset of JDM patients, especially in patients with MSA-positive forms, and in patients with severe JDM. Larger, multicentre cohorts are required to confirm these data and to identify new predictive biomarkers of MTX response, in order to treat patients with JDM as early as possible with appropriate targeted drugs.

The performances of the ILAR, ASAS, and PRINTO classification criteria in ERA patients: a comparison study.

Enthesitis-related arthritis (ERA) could be considered the pediatric equivalent of ankylosing spondylitis in adults albeit with certain significant differences. We aim to evaluate the sensitivity and specificity of the International League of Associations for Rheumatology (ILAR), the Assessment of Spondyloarthritis International Society (ASAS), and the preliminary Pediatric Rheumatology International Trials Organization (PRINTO) classification criteria in ERA patients. The medical records of ERA patients who were followed up between January 2005 and September 2020 have been analyzed. The control group consisted of patients with oligoarticular JIA (n = 146), polyarticular JIA (n = 55), and psoriatic arthritis (n = 20). This retrospective study included 108 ERA (73.1% male) and 221 control patients (25.8% male). The median age at diagnosis for ERA and control patients were 12.5 and 4.0years, respectively (p < 0.001). Arthritis was observed more frequently in the control group at diagnosis and in the follow-up (p < 0.001 for both), while enthesitis, sacroiliac joint tenderness, and inflammatory back pain were more common in the ERA group both at diagnosis and in the follow-up (p < 0.001 for all). In sacroiliac imaging, 70.1% of ERA patients had positive findings suggestive of sacroiliitis at diagnosis and 78% in the follow-up. The sensitivities of ILAR, PRINTO, ASAS criteria for axial SpA, and peripheral SpA at diagnosis were 74.0%, 57.4%, 21.3%, and 85.1%, respectively which increased to 82.4%, 78.7%, 35.1%, and 92.5%, respectively at follow-up. The specificities were 100%, 100%, 99.1%, and 90.9%, respectively at both diagnosis and follow-up. The ASAS criteria for peripheral SpA were the most sensitive while ILAR and the preliminary PRINTO criteria were the most specific criteria for classifying ERA patients. The ASAS criteria for peripheral SpA were the most sensitive criteria for classifying ERA patients. The use of ASAS axial SpA criteria may provide early detection of axial involvement.

The analysis of genotype-phenotype correlation in familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease manifesting with phenotypic heterogeneity. It is a clinically diagnosed disease supported by Mediterranean fever gene mutation analysis. This medical record review study aimed to make a new interpretation of clinical features in FMF patients by grouping genetic results based on the classification proposed by the Eurofever/ Paediatric Rheumatology International Trials Organisation. The medical charts of pediatric FMF patients who were diagnosed and followed up regularly at the two pediatric rheumatology units were reviewed. Genetic analysis results were classified as confirmatory and nonconfirmatory as defined in the new Eurofever/ Paediatric Rheumatology International Trials Organisation classification criteria, and they were compared with clinical findings. A total of 216 FMF patients were involved in the study. Group 1 was composed of 133 (61.6%) patients with a confirmatory mutation and group 2 included 83 (38.4%) patients with a nonconfirmatory mutation. All clinical findings were compared, and in terms of fever (P = 0.027), abdominal pain (P = 0.016), arthritis (P = 0.008) and erysipelas-like erythema (ELE; P = 0.003) incidence, there was a significant difference between the two groups. The most common Mediterranean fever gene mutation patterns were homozygous (33.8%) and heterozygous (17.1%) mutations of M694V. The frequency of arthritis and ELE in patients with M694V homozygous mutations was significantly higher than in the other patients (P = 0.002 and P <0.001, respectively). The most frequently observed clinical features of FMF (i.e., fever and abdominal pain) are both observed in patients with confirmatory and nonconfirmatory mutations, ELE and arthritis are more commonly observed in patients with confirmatory mutations.

An Outbreak of Severe Kawasaki-Like Disease at the Italian Epicentre of the SARS-CoV-2 Epidemic: An Observational Cohort Study

An outbreak of Kawasaki disease was noted in 2020 in Italy during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. The authors’ objectives in which to evaluate the incidence and features of patients with Kawasaki-like disease diagnosed during the SARS-CoV-2 epidemic. They looked at cases of hemodynamic instability during the acute phase of the disease (Kawasaki disease shock syndrome [KDSS]) and those that might fulfill the criteria of macrophage activation syndrome (MAS).All patients diagnosed with Kawasaki or Kawasaki-like disease who presented over the past 5 years (January 1, 2015, and April 20, 2020) before the COVID pandemic at this institution (Bergamo, Italy) were reviewed and compared with those who were diagnosed after the onset of the pandemic (February 18 to April 20, 2020).Patients with Kawasaki-like presentations were defined according to the 2017 criteria of the American Heart Association, including both classic type and incomplete types. KDSS was defined as Kawasaki disease accompanied by systolic arterial hypotension, a decrease from baseline systolic blood pressure of at least 20%, or the appearance of peripheral hypoperfusion. MAS was defined by using the Pediatric Rheumatology International Trials Organization criteria used in systemic juvenile idiopathic arthritis and commonly used for other systemic autoinflammatory diseases (Kawasaki disease and pediatric systemic lupus erythematosus). Data reviewed from medical records included demographic data, presenting symptoms and treatments, contact with confirmed or suspected cases of coronavirus disease 2019, vital signs, laboratory data (white blood cell count, lymphocyte count, erythrocyte sedimentation rate, C-reactive protein, procalcitonin, ferritin, fibrinogen, pro B-type natriuretic peptide, troponin I, natural killer activity, and interleukin 6 concentrations), electrocardiogram, and echocardiogram data. Current or previous infection with SARS-CoV-2 was obtained by reverse-transcriptase quantitative polymerase chain reaction in nasopharyngeal and oropharyngeal swabs and by serological testing for SARS-CoV-2 immunoglobulin M and immunoglobulin G. Patients were treated with 2 g/kg of intravenous immunoglobulin and aspirin dosed on the basis of Kobayashi score with 2-week methylprednisolone taper.Group 1 (pre–coronavirus disease) comprised 19 patients (7 boys and 12 girls; mean age: 3 years old) and group 2 (during coronavirus disease) included 10 patients (7 boys and 3 girls; mean age: 7.5 years old). A total 8 of 10 patients in group 2 were positive for SARS-CoV-2 immunoglobulin G or immunoglobulin M or both. A total of 5 presented with classic Kawasaki, and 5 presented with incomplete form. Comparing the 2 groups (group 1 versus group 2), there was a significant difference in disease incidence (0.3 patients per month versus 10 patients per month), mean age (3.0 vs 7.5 years), cardiac involvement (2 of 19 vs 6 of 10), KDSS (0 of 19 vs 5 of 10), MAS (0 of 19 vs 5 of 10), and need for adjunctive steroid treatment (3 of 19 vs 8 of 10; all P < .01).A 30-fold increased incidence of Kawasaki-like disease was seen at this institution. Children diagnosed with Kawasaki disease after the SARS-CoV-2 epidemic onset showed evidence of an immune response to the virus, were older, had a higher rate of cardiac involvement, had respiratory and gastrointestinal symptoms, were more resistant to intravenous immunoglobulin treatment, had more severe disease, and had features of MAS.Within the past year, multisystem inflammatory syndrome in children has been diagnosed around the world. Some of these children will fulfill criteria for complete and incomplete Kawasaki. Affected children tend to be older, and there is disproportionate number of Hispanic and African American children. They present with fever, gastrointestinal symptoms, rash, conjunctivitis, mucous membrane involvement, neurocognitive symptoms, lymphadenopathy, and respiratory symptoms. Clinicians should be aware of this syndrome to ensure proper care of patients.

Performance of recent PRINTO criteria versus current ILAR criteria for systemic juvenile idiopathic arthritis: A single-centre experience.

The purpose of this study is to evaluate the performances of recently proposed Pediatric Rheumatology International Trials Organization criteria versus current International League of Associations for Rheumatology criteria for systemic juvenile idiopathic arthritis (sJIA). The study was performed at the Department of Pediatric Rheumatology in Istanbul Faculty of Medicine with a retrospective design, covering the date range 2010-2021. Patients diagnosed with sJIA, Kawasaki disease and common autoinflammatory diseases were included. Both the International League of Associations for Rheumatology and Pediatric Rheumatology International Trials Organization classification criteria were applied to each patient and cross-checked with expert rheumatologist diagnosis. Eighty-two patients with sJIA were compared against 189 (74 Kawasaki disease, 83 familial Mediterranean fever, 16 mevalonate kinase deficiency, 10 cryopyrin-associated periodic syndromes, and 6 tumour necrosis factor receptor-associated periodic syndrome) patients. The Pediatric Rheumatology International Trials Organization criteria demonstrated higher sensitivity (62.2% vs 80.5%, P =.003) but comparable specificity (90.5% vs 91%) as regards the International League of Associations for Rheumatology criteria. The revised criteria appear to enhance the ability to provide early recognition and pertinent classification of sJIA. No superiority was observed in segregating sJIA from common autoinflammatory diseases and Kawasaki disease, namely in terms of specificity.

Tofacitinib in juvenile idiopathic arthritis: a double-blind, placebo-controlled, withdrawal phase 3 randomised trial

Tofacitinib is an oral Janus kinase inhibitor. This trial assessed the efficacy and safety of tofacitinib versus placebo in patients with polyarticular course juvenile idiopathic arthritis (JIA). This double-blind, withdrawal phase 3 trial enrolled patients with polyarticular course JIA (extended oligoarthritis, rheumatoid factor-positive or rheumatoid factor-negative polyarthritis, or systemic JIA without active systemic features) aged 2 years to younger than 18 years, and was done at 64 centres of the Paediatric Rheumatology International Trials Organisation and Pediatric Rheumatology Collaborative Study Group networks in 14 countries. Patients with psoriatic arthritis or enthesitis-related arthritis were enrolled for exploratory endpoints. During part 1 of the study, patients received oral open-label tofacitinib (weight-based doses; 5 mg twice daily or lower) for 18 weeks. Patients achieving at least JIA/American College of Rheumatology 30 response were randomly assigned (1:1) using an Interactive Response Technology system to continue tofacitinib or switch to placebo in part 2 of the study for 26 weeks. The primary endpoint was JIA flare rate by week 44 in part 2 in patients with polyarticular course JIA; the intention-to-treat principle was applied. Safety was evaluated throughout part 1 and part 2 of the study in all patients who received one dose or more of study medication. This trial is registered with ClinicalTrials.gov, NCT02592434. Between June 10, 2016, and May 16, 2019, of 225 patients enrolled, 184 (82%) patients had polyarticular course JIA, 20 (9%) had psoriatic arthritis, and 21 (9%) had enthesitis-related arthritis. 147 (65%) of 225 patients received concomitant methotrexate. In part 2, 142 patients with polyarticular course JIA were assigned to tofacitinib (n=72) or placebo (n=70). Flare rate by week 44 was significantly lower with tofacitinib (21 [29%] of 72 patients) than with placebo (37 [53%] of 70 patients; hazard ratio 0·46, 95% CI 0·27-0·79; p=0·0031). In part 2 of the study, adverse events occurred in 68 (77%) of 88 patients receiving tofacitinib and 63 (74%) of 85 in the placebo group. Serious adverse events occurred in one (1%) and two (2%), respectively. In the entire tofacitinib exposure period, 107 (48%) of 225 patients had infections or infestations. There were no deaths during this study. The results of this pivotal trial show that tofacitinib is an effective treatment in patients with polyarticular course JIA. New oral therapies are particularly relevant for children and adolescents, who might prefer to avoid injections. Pfizer.

Differentiating children with familial Mediterranean fever from other recurrent fever syndromes: The utility of new Eurofever/PRINTO classification criteria.

Objectives In this study, we aimed to investigate the performance of Eurofever Registry and the Paediatric Rheumatology International Trials Organisation (PRINTO) classification criteria in pediatric patients with familial Mediterranean fever (FMF).Patients and methods This retrospective, cross-sectional study included a total of 130 pediatric FMF patients (67 males, 63 females; mean age: 12.4±3.6 years; range, 2.5 to 17.7 years) with at least one M694V mutation in MEFV gene between July 2010 and July 2019. Demographic features and disease characteristics were recorded. The control group was consisted of 41 patients (19 males, 22 females; mean age: 7.8±4.0 years; range, 2.1 to 17.8 years) with other hereditary autoinflammatory diseases (AIDs), including periodic fevers with aphthous stomatitis, pharyngitis, and adenitis syndrome (n=30), mevalonate kinase deficiency (n=9), and tumor necrosis factor receptor-associated periodic syndrome (n=2). Sensitivity and specificity of the Eurofever/PRINTO classification criteria were calculated.Results The sensitivity and specificity were 97.7% and 56.1% for Yalcinkaya-Ozen criteria, respectively and 93.1% and 90.2% for Tel Hashomer criteria, respectively. The Eurofever/PRINTO classification criteria reached a sensitivity and specificity of 94.6% and 82.9% and 93.1% and 80.5%, respectively, when genetic plus clinical criteria and clinical-only criteria were applied.Conclusion The Eurofever/PRINTO classification criteria have a comparable sensitivity for avoidance of FMF underdiagnosis in childhood. The Yalcinkaya-Ozen criteria have the highest sensitivity without a significant specificity. The Tel Hashomer criteria and Eurofever/PRINTO classification criteria were superior to Yalcinkaya-Ozen criteria to differentiate FMF from other AIDs, thus leading to less complications relevant to underdiagnosis of other AIDs.