JAK inhibitors in refractory juvenile rheumatic diseases: Efficacy, tolerance and type-I interferon profiling, a single center retrospective study.

OBJECTIVES: - Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases. This study aimed to describe the safety and effectiveness of JAKi in these diseases, with a focus on longitudinal interferon-stimulated genes (ISG) assessment. METHODS: - We present a single-center retrospective study of children with refractory pediatric rheumatic diseases including connective tissue diseases, monogenic type I interferonopathies or juvenile idiopathic arthritis, receiving JAKi. According to physicians' assessment, treatment effectiveness was classified at 12 months as a complete response in the total absence of disease activity, partial response in case of significant (>50%) but incomplete improvement or no response in the case of non-response or improvement of less than 50% of the clinical and biological parameters. ISG were monitored longitudinally using Nanostring technology. RESULTS: - 22 children were retrospectively included in this study, treated either by baricitinib or ruxolitinib. Complete response was achieved at 12 months in 9/22 (41%) patients. 6/22 (27%) patients were non-responders and treatment had been discontinued in five of them. Within the interferon (IFN)-related diseases group, ISG-score was significantly reduced 12 months after JAKi onset (p = 0.0068). At 12 months, daily glucocorticoid doses had been reduced with a median dose of 0.16 mg/kg/day (IQR 0.11; 0.33) (p = 0.0425). 7/22 (32%) patients had experienced side effects, infections being the most common. Increase of the body mass index was also recorded in children in the first 6 months of treatment. CONCLUSION: - JAKi represent a promising treatment of immune-mediated pediatric diseases, enabling to decrease type-I IFN transcriptomic signature in responding patients, especially in the context of juvenile dermatomyositis. JAKi represent steroid-sparing drugs but they induce metabolic changes linked to weight gain, posing a concern in the treatment of young patients and teenagers. More data are required to define the efficacy and safety of JAKi in the management of refractory pediatric rheumatic diseases.

Extra-osseous manifestations in chronic recurrent multifocal osteomyelitis: a retrospective study.

OBJECTIVES: Extra-osseous (EO) manifestations are poorly characterized in chronic recurrent multifocal osteomyelitis (CRMO). This study aimed to further define the frequency, characteristics and treatment of EO events in CRMO and whether different phenotypes can be distinguished and benefit from special management. METHODS: This multicentre retrospective study included CRMO patients followed in several paediatric rheumatology departments in France, between 2015 and 2022. EO manifestations were defined as skin lesions, gastrointestinal manifestations, arthritis, enthesitis, sacroiliitis, uveitis, vasculitis, and fever. At the last visit, the physician defined CRMO as active in the presence of clinical manifestations including both osseous and EO symptoms. RESULTS: We included 133 patients; 87 (65.4%) were girls; the median age at first symptoms was 9.0 years (interquartile range 7.0-10.0). EO manifestations were described in 90 (67.7%) patients, with a predominance of skin lesions (n = 51/90; 56.7%), followed by sacroiliitis (n = 38/90; 42.2%), enthesitis (n = 21/90; 23.3%), arthritis (n = 14/90, 15.6%) and gastrointestinal manifestations (n = 6/90, 6.7%). The use of non-steroidal anti-inflammatory drugs and bisphosphonates did not differ by presence or not of EO manifestations. Biologics were taken more frequently by patients with than without EO manifestations (p< 0.001); tumour necrosis factor inhibitors were used in 33 (36.7%) EO+ patients. Under this treatment, 18 (54.5%) patients achieved complete remission of osseous and EO manifestations. At the last visit, more EO-positive than EO-negative patients were on treatment (p= 0.009), with active disease in 58 (64.4%) patients. CONCLUSION: The analysis of EO manifestations in CRMO delineates 2 groups of patients in terms of severity and treatments used. Our study opens up new pathophysiological leads that may underlie the wide range of CRMO phenotypes.

Canakinumab in patients with systemic juvenile idiopathic arthritis and active systemic features: results from the 5-year long-term extension of the phase III pivotal trials.

OBJECTIVES: To evaluate the long-term efficacy and safety of canakinumab in patients with active systemic juvenile idiopathic arthritis (JIA). METHODS: Patients (2-19 years) entered two phase III studies and continued in the long-term extension (LTE) study. Efficacy assessments were performed every 3 months, including adapted JIA American College of Rheumatology (aJIA-ACR) criteria, Juvenile Arthritis Disease Activity Score (JADAS) and ACR clinical remission on medication criteria (CRACR). Efficacy analyses are reported as per the intent-to-treat population. RESULTS: 144 of the 177 patients (81%) enrolled in the core study entered the LTE. Overall, 75 patients (42%) completed and 102 (58%) discontinued mainly for inefficacy (63/102, 62%), with higher discontinuation rates noted in the late responders group (n=25/31, 81%) versus early responders (n=11/38, 29%). At 2 years, aJIA-ACR 50/70/90 response rates were 62%, 61% and 54%, respectively. CRACR was achieved by 20% of patients at month 6; 32% at 2 years. A JADAS low disease activity score was achieved by 49% of patients at 2 years. Efficacy results were maintained up to 5 years. Of the 128/177 (72.3%) patients on glucocorticoids, 20 (15.6%) discontinued and 28 (22%) tapered to 0.150 mg/kg/day. Seven patients discontinued canakinumab due to CR. There were 13 macrophage activation syndrome (three previously reported) and no additional deaths (three previously reported). No new safety findings were observed. CONCLUSION: Response to canakinumab treatment was sustained and associated with substantial glucocorticoid dose reduction or discontinuation and a relatively low retention-on-treatment rate. No new safety findings were observed on long-term use of canakinumab. TRIAL REGISTRATION NUMBERS: NCT00886769, NCT00889863, NCT00426218 and NCT00891046.

Familial Mediterranean fever mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome.

Objectives: FMF is the most frequent autoinflammatory disease and is associated in most patients with bi-allelic MEFV mutations. MEFV encodes Pyrin, an inflammasome sensor activated following RhoGTPase inhibition. The functional consequences of MEFV mutations on the ability of Pyrin variants to act as inflammasome sensors are largely unknown. The aim of this study was to assess whether MEFV mutations affect the ability of Pyrin to detect RhoGTPase inhibition and other inflammasome stimuli. Methods: IL-1ß and IL-18 released by monocytes from healthy donors (HDs) and FMF patients were measured upon specific engagement of the Pyrin, NLRP3 and NLRC4 inflammasomes. Cell death kinetics following Pyrin activation was monitored in real time. Results: Monocytes from FMF patients secreted significantly more IL-1ß and IL-18 and died significantly faster than HD monocytes in response to low concentrations of Clostridium difficile toxin B (TcdB), a Pyrin-activating stimulus. Monocytes from patients bearing two MEFV exon 10 pathogenic variants displayed an increased Pyrin inflammasome response compared with monocytes from patients with a single exon 10 pathogenic variant indicating a gene-dosage effect. Using a short priming step, the response of monocytes from FMF patients to NLRP3- and NLRC4-activating stimuli was normal indicating that MEFV mutations trigger a specific hypersensitivity of monocytes to low doses of a Pyrin-engaging stimulus. Conclusion: Contrary to the NLRP3 mutations described in cryopyrin-associated periodic syndrome, FMF-associated MEFV mutations do not lead to a constitutive activation of Pyrin. Rather, FMF-associated mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome without affecting other canonical inflammasomes.

Mycophenolate mofetil in juvenile dermatomyositis: a case series.

The objective of this study was to report the use of Mycophenolate Mofetil (MMF) in Juvenile Dermatomyositis (JDM). A retrospective chart review of children diagnosed with JDM having received MMF was performed. Response was evaluated 3 months after the onset of MMF by comparing muscle strength and steroid dosage before and after treatment. A good response was defined by global improvement concerning weakness and fatigability as evaluated subjectively by the physician along with a gain of at least 4 points on each of 2 muscle testings (Manual Muscle Testing, MMT and Childhood Myositis Assessment Score, CMAS) and/or a decrease of >15% of the corticosteroid dosage. Eight patients were identified. Except for one, all had received MMF secondary to an initial therapy of conventional immunosuppressants. Six patients showed good response by our predefined criteria. Changes of muscle testing scores ranged between +0 to +21 points (mean = +10.6) for the MMT and between +3 and +11 (mean = +7) for the CMAS. Corticosteroid tapering varied from 0 to 50%, with a mean of 18%. In most cases, follow-up was available for many months (up to 26); overall, we observed only one complication: a transient neutropenia in a patient concurrently receiving another immunosuppressant. This small series is the first published report on the use of MMF in JDM and suggests it is safe. Prospective larger studies are required to further elucidate the use of MMF in JDM.

The Spectrum of Still's Disease: A Comparative Analysis of Phenotypic Forms in a Cohort of 238 Patients.

Still's disease (SD) is a heterogeneous autoinflammatory disorder for which several phenotypes have been described. We conducted a retrospective study to re-evaluate the dichotomous view of the disease, to compare the juvenile and adult forms, and to look for prognostic factors. We collected data from ten French centers, seeking patients with a diagnosis of adult-onset SD (AOSD) or systemic juvenile idiopathic arthritis (sJIA). We identified 238 patients, 152 (64%) of whom had AOSD while 86 (36%) had sJIA. The median age at SD onset was 26.6 years. In patients with identifiable patterns, the course of SD was systemic in 159 patients (74%), chronic in 55 (26%). Sore throat and myalgia were more frequent in patients with AOSD. Abnormal liver tests, serum ferritin and C-reactive protein levels were higher in AOSD group. Fever and skin rash were predictive of complete remission or recovery and high lactate dehydrogenase level was a poor prognosis factor. Symptoms such as splenomegaly, skin rash, high polymorphonuclear neutrophils count and macrophage activation syndrome were predictive of a systemic phenotype. Overall, there were no major differences between sJIA and AOSD. Our results are consistent with the "biphasic" model of an autoinflammatory disease that can progress to chronic arthritis if not treated early.

Detection and Prediction of Macrophage Activation Syndrome in Still's Disease.

Distinguishing between macrophage activation syndrome (MAS) and a simple flare of Still's disease (SD) may be challenging. We sought to clarify the clinical features and outcome of MAS in SD and to explore predictive factors of MAS development. Demographic and clinical data, treatments, and outcomes were recorded in a cohort of 206 SD patients. SD patients with and without MAS were compared. To explore predictive factors for the development of MAS, patients were compared at the time of SD diagnosis. Twenty (9.7%) patients experienced MAS, which was inaugural in 12 cases. Patients with MAS were more likely to have hepatomegaly (OR, 3.71; 95% CI, 1.14-11.2; p = 0.03) and neurological symptoms (OR, 4.43; 95% CI, 1.08-15.3; p = 0.04) than patients without MAS. Cytopenias, abnormal liver tests, and coagulation disorders were significantly more frequent in patients with MAS; lactate dehydrogenase and serum ferritin levels were significantly higher. An optimized threshold of 3500 µg/L for serum ferritin yielded a sensitivity (Se) of 85% and a negative predictive value (NPV) of 97% for identifying patients with/without MAS. Survival analysis showed that a high ferritin level at the time of SD diagnosis was predictive of MAS development (p < 0.001). Specific factors, including neurological symptoms, cytopenias, elevated LDH, and coagulopathy, may contribute to the early detection of MAS. Extreme hyperferritinemia at the onset of SD is a prognostic factor for the development of MAS.

Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients.

Familial Mediterranean fever (FMF) is the most frequent hereditary systemic autoinflammatory syndrome. FMF is usually caused by biallelic mutations in the MEFV gene, encoding Pyrin. Conclusive genetic evidence lacks for about 30% of patients diagnosed with clinical FMF. Pyrin is an inflammasome sensor maintained inactive by two kinases (PKN1/2). The consequences of MEFV mutations on inflammasome activation are still poorly understood. Here, we demonstrate that PKC superfamily inhibitors trigger inflammasome activation in monocytes from FMF patients while they trigger a delayed apoptosis in monocytes from healthy donors. The expression of the pathogenic p.M694V MEFV allele is necessary and sufficient for PKC inhibitors (or mutations precluding Pyrin phosphorylation) to trigger caspase-1- and gasdermin D-mediated pyroptosis. In line with colchicine efficacy in patients, colchicine fully blocks this response in FMF patients' monocytes. These results indicate that Pyrin inflammasome activation is solely controlled by Pyrin (de)phosphorylation in FMF patients while a second control mechanism restricts its activation in healthy donors/non-FMF patients. This study paves the way toward a functional characterization of MEFV variants and a functional test to diagnose FMF.

MISS questionnaire in French version: a good tool for children and parents to assess methotrexate intolerance.

The aim of this study was to assess the relevance for children and parents to use the French-validated version of the methotrexate intolerance severity score (MISS), a measure of methotrexate intolerance for children suffering from juvenile idiopathic arthritis. The French-version MISS was developed following the "Guidelines for the process of cross-cultural adaptation of self-report measures." The new version was tested in families of children with juvenile idiopathic arthritis who completed the questionnaire twice at a 2-week interval. Item correlations, Cronbach's alpha, and kappa coefficients were computed to evaluate acceptability, internal consistency, and reproducibility. A culturally acceptable version to French was obtained. A total of 71 individuals were included from May 2015 to November 2015. The results show very good acceptability: good response rate (80%), few missing data (<1%) and good understanding of parents and children. The inter-item, dimension-item, and inter-dimension correlations were satisfactory (except for "vomiting" items-other items correlation). Cronbach's alpha coefficient was well higher than the usually recommended value of 0.6. The results of validity of internal and external consistencies were satisfactory. We also found good agreement between the test-retest for every family. The empirical discriminative cut-off point of 3 showed a sensitivity of 86% and a specificity of 83%. The MISS questionnaire is quick to complete, easy to use. It can be completed by children or their parents with no significant difference. This validated French-version MISS can help study prevalence and risk factors of methotrexate intolerance, better detect this intolerance, and provide better support for patients on long-term treatment.

Tocilizumab in the treatment of mixed connective tissue disease and overlap syndrome in children.

Arthritis is one of the main manifestations of mixed connective tissue disease (MCTD) and overlap syndrome in children and can be responsible for functional disability. We report on 2 children with arthritis that were dramatically improved by a treatment with interleukin-6 (IL-6) blockers in the context of connective tissue disease. However, in both cases, other systemic autoimmune symptoms were not modified by the treatment and autoantibodies tend to increase, suggesting a differential effect of IL-6 inhibition on articular inflammation and systemic autoimmunity.

Takayasu arteritis in children.

Takayasu arteritis (TA) is a large vessel vasculitis that usually affects young female patients during the second and third decades of life, but has been reported in children as young as 24 months of age. Aim of this report was to describe four children (two girls) with TA, as well as summarizing main published studies. The mean age at presentation of our cases was 11 years (range 8-15). Three patients were Caucasians and one Asian. Arterial hypertension was the commonest mode of presentation followed by systemic symptoms. Other related symptoms were due to ischemia and consisted of abdomen, chest, and limb pain. An abdominal bruit was noted in only one patient. Inflammation markers were always abnormal. Angiography was performed in all cases; left subclavian artery and common carotid artery were more frequently involved. Renal artery stenosis was observed in two patients. One boy was diagnosed as having an associated immune deficiency (Wiskott-Aldrich syndrome). Treatment modalities included prednisone (n = 4), methotrexate (n = 3), and mycophenolate mofetil (MMF) (n = 1). Surgery was required in two patients. Follow-up ranged from 3 to 10 years since diagnosis. In three cases antihypertensive drugs and methotrexate were stopped, and prednisone was reduced to 7.5 mg/day.