Abstract Background Association of HLA-B27 with spondyloarthritis (SpA) has been known for 50 years, but still remains unexplained. We recently showed that HLA-B27 expressed in wing imaginal disc from HLA-B27/human-β2 microglobulin (hβ2m) transgenic Drosophila deregulated bone morphogenetic protein (BMP) pathway by interacting physically with type I BMP receptor (BMPR1) Saxophone (Sax), leading to crossveinless phenotype. Methods Genetic interaction was studied between activin/transforming growth factor β (TGFβ) pathway and HLA-B27/hβ2m in transgenic Drosophila wings. The HLA-B27-bound peptidome was characterized in wing imaginal discs. In mesenteric lymph node (mLN) T cells from HLA-B27/hβ2m rat (B27 rat), physical interaction between HLA-B27 and activin receptor-like kinase-2 (ALK2), ALK3 and ALK5 BMPR1s, phosphorylation of small mothers against decapentaplegic (SMADs) and proteins of the non-canonical BMP/TGFβ pathways induced by its ligands, and the transcript level of target genes of the TGFβ pathway, were evaluated. Results In HLA-B27/hβ2m transgenic Drosophila, inappropriate signalling through the activin/TGFβ pathway, involving Baboon (Babo), the type I activin/TGFβ receptor, contributed to the crossveinless phenotype, in addition to deregulated BMP pathway. We identified peptides bound to HLA-B27 with the canonical binding motif in HLA-B27/hβ2m transgenic Drosophila wing imaginal disc. We demonstrated specific physical interaction, between HLA-B27/hβ2m and mammalian orthologs of Sax and Babo, i.e. ALK2 and ALK5 (i.e. TGFβ receptor I), in the mLN cells from B27 rat. The magnitude of phosphorylation of SMAD2/3 in response to TGFβ1 was increased in T cells from B27 rats, showing evidence for deregulated TGFβ pathway. Accordingly, expression of several target genes of the pathway was increased in T cells from B27 rats, in basal conditions and/or after TGFβ exposure, including Foxp3, Rorc, Runx1 and Maf. Interestingly, Tgfb1 expression was reduced in naive T cells from B27 rats, even premorbid, an observation consistent with a pro-inflammatory pattern. Conclusions This study shows that HLA-B27 alters the TGFβ pathways in Drosophila and B27 rat. Given the importance of this pathway in CD4 + T cells differentiation and regulation, its disturbance could contribute to the abnormal expansion of pro-inflammatory T helper 17 cells and altered regulatory T cell phenotype observed in B27 rats.

IntroductionIn spondyloarthritis (SpA), an increased type 3 immune response, including T helper cells (Th) 17 excess, is observed in both human and SpA animal models, such as the HLA-B27/human β2-microglobulin transgenic rat (B27-rat).MethodsTo investigate this unexplained Th17-biased differentiation, we focused on understanding the immunobiology of B27-rat naive CD4+ T cells (Tn). ResultsWe observed that neutrally stimulated B27-rat Tn developed heightened Th17 profile even before disease onset, suggesting an intrinsic proinflammatory predisposition. In parallel with this observation, transcriptomic and epigenomic analyses showed that B27-rat Tn exhibited a decreased expression of Interferon/Th1- and increased expression of Th17-related genes. This molecular signature was predicted to be related to an imbalance of STAT1/STAT3 transcription factors activity. Stat1 mRNA and STAT1 protein expression were decreased before disease onset in Tn, even in their thymic precursors, whereas Stat3/STAT3 expression increased upon disease establishment. Confirming the relevance of these results, STAT1 mRNA expression was also decreased in Tn from SpA patients, as compared with healthy controls and rheumatoid arthritis patients. Finally, stimulation of B27-rat Tn with a selective STAT1 activator abolished this preferential IL-17A expression, suggesting that STAT1-altered activity in B27-rats allows Th17 differentiation. DiscussionAltogether, B27-rat Tn harbor a STAT1 deficiency preceding disease onset, which may occur during their thymic differentiation, secondarily associated with a persistent Th17 bias, which is imprinted at the epigenomic level. This early molecular phenomenon might lead to the persistent proinflammatory skew of CD4+ T cells in SpA patients, thus offering new clues to better understand and treat SpA.

Introduction Spondylarthritis (SpA) development in HLA-B27/human β2-microglobulin transgenic rat (B27-rat) is correlated with altered conventional dendritic cell (cDC) function that promotes an inflammatory pattern of CD4+T cells, including a biased expansion of pro-inflammatory Th17 population and imbalance of regulatory T cells cytokine profile. Transcriptomic analysis revealed that cDCs from B27-rats under express IL-27, an anti-inflammatory cytokine which induces the differentiation of IL-10+ regulatory T cells and inhibits Th17 cells. Methods Here, we first investigated whether in vitro addition of exogenous IL-27 could reverse the inflammatory pattern observed in CD4+ T cells. Next, we performed preclinical assay using IL-27 to investigate whether in vivo treatment could prevent SpA development in B27-rats. Results in vitro addition of IL-27 to cocultures of cDCs and CD4+ T cell subsets from B27-rats reduced IL-17 and enhanced IL-10 production by T cells. Likewise, IL-27 inhibited the production of IL-17 by CD4+ T cells from SpA patients. Interestingly, in vivo treatment with recombinant IL-27 starting before SpA onset, inhibited SpA development in B27-rats through the suppression of IL-17/TNF producing CD4+ T cells. Discussion Overall, our results reveal a potent inhibitory effect of IL-27 and highlight this cytokine as a promising new therapeutic target in SpA, especially for SpA patients non responders to currently approved biotherapies.

Introduction: Axial spondyloarthritis (AxSpA) is an inflammatory disorder that affects the joints, entheses, and bone tissues and is sometimes associated with psoriasis, anterior uveitis, and gut inflammation. Its pathogenesis is not wholly understood and treatment strategies require optimization. Data concerning AxSpA pathogenesis support a critical role of abnormal CD4(+) T cell differentiation and exacerbated type 3 immune response. This knowledge boosted the development of interleukin (IL)-17 and Janus kinase inhibitors for AxSpA treatment beyond tumor necrosis factor-alpha inhibition. Areas covered: Emerging drug targets in animal and cellular models and with phase-II clinical trials have been evaluated. We also reflect on key issues for preclinical and clinical research going forward. Expert opinion: Some of the most promising approaches include: (i) modulation of transforming growth factor-beta family that could exert a specific role on bone formation; (ii) blockade of granulocyte-macrophage colony-stimulating factor that could reduce type 3 immune responses, and (iii) rebalancing of biased immune response by cytokines such as IL-2 or IL-27 that could favor anti-inflammatory response and sustained drug-free remission. Multiomics tools and artificial intelligence could contribute to identification of optimal targets and help stratify patients for the most appropriate treatment options.

Objective To better define the clinical distinctions between the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related paediatric inflammatory multisystem syndrome (PIMS) and Kawasaki disease (KD). Methods We compared three groups of patients: group 1, cases from our national historic KD database (KD-HIS), before the SARS-CoV-2 pandemic; group 2, patients with KD admitted to an intensive care unit (KD-ICU) from both our original cohort and the literature, before the SARS-CoV-2 pandemic; and group 3, patients with PIMS from the literature. Results KD-HIS included 425 patients [male:female ratio 1.3, mean age 2.8 years (s.d. 2.4)], KD-ICU 176 patients [male:female ratio 1.3, mean age 3.5 years (s.d. 3.1)] and PIMS 404 patients [male:female ratio 1.4, mean age 8.8 years (s.d. 3.7)]. As compared with KD-HIS patients, KD-ICU and PIMS patients had a higher proportion of cardiac failure, digestive and neurological signs. KD-ICU and PIMS patients also had a lower frequency of typical KD-mucocutaneous signs, lower platelet count, higher CRP and lower sodium level. As compared with KD-HIS and KD-ICU patients, PIMS patients were older and more frequently had myocarditis; they also had fewer coronary abnormalities and lower sodium levels. Unresponsiveness to IVIG was more frequent in KD-ICU than KD-HIS and PIMS patients. Conclusion On clinical grounds, KD-HIS, KD-ICU and PIMS might belong to a common spectrum of non-specific pathogen-triggered hyperinflammatory states. The causes of increasing inflammation severity within the three entities and the different effects on the heart remain to be determined.

La spondyloarthrite (SpA) est un rhumatisme inflammatoire chronique d’étiologie inconnue dont la survenue résulte de l’interaction de facteurs de prédisposition environnementaux et génétiques. Malgré des avancées récentes, une large fraction de la prédisposition génétique à la SpA demeure inexpliquée. Plusieurs mécanismes ont été proposés pour expliquer cette part d’héritabilité manquante, tels que l’épigénétique, qui peut jouer un rôle à l’interface entre facteurs génétiques et environnementaux de susceptibilité. L’épigénétique se réfère aux variations de l’expression génique qui n’impliquent aucun changement de la séquence d’ADN. Les mécanismes épigénétiques comprennent principalement la méthylation de l’ADN, les modifications des histones et les ARN non codants. La perturbation de l’un de ces systèmes peut conduire à une altération de l’expression génique susceptible de favoriser le développement de la maladie. Grâce aux récents progrès technologiques, on observe un intérêt croissant pour le domaine de l’épigénétique dans le contexte des maladies complexes comme la SpA. Cependant, les études épigénétiques sont confrontées à des obstacles méthodologiques qui limitent l’interprétation de leurs résultats : petite taille des échantillons, absence de confirmation des résultats, choix inapproprié des témoins, choix inadéquat du type cellulaire/tissulaire. Dans le futur, l’association de l’épigénétique aux autres données « -omiques » permettra de mieux comprendre la pathogénie de la SpA. Ces problématiques doivent être résolues avant d’envisager l’utilisation des marques épigénétiques en routine clinique, en tant que biomarqueurs ou cibles médicamenteuses.

Spondyloarthritis (SpA) is a chronic inflammatory disorder resulting from a combination of genetic predisposition and environmental factors. Despite recent advances, a substantial fraction of its genetic basis remains poorly understood. Several mechanisms have been proposed to account for this unexplained heritability, including epigenetics which can play a role at the interface between genetic and environmental susceptibility factors. Epigenetics refers to changes in gene expression that are not encoded in the DNA sequence itself. Such mechanisms may include DNA methylation, histone modifications and non-coding RNAs. Disruption of one of these systems can lead to inappropriate gene expression, which in turn might favour the development of disease. Thanks to recent technological progress, there has been a growing interest in the field of epigenetics in complex diseases, including SpA. However, epigenetic studies face some methodological limitations that hamper interpretation of their results: small sample size, absence of biological replication, lack of adequate controls for potential confounders, studies not performed in the most relevant cell/tissues. In the future, integration of epigenetics with other "omics" data will probably be necessary to improve our understanding of SpA pathogenesis. These issues need to be addressed before considering the use of epigenetic marks in clinical routine, as biomarkers or as drug targets.

Objective Anakinra has been shown to be successful in preventing and treating cardiovascular lesions both in experimental murine models of Kawasaki disease (KD) and in several studies on intravenous immunoglobulin (IVIG)– and steroid‐resistant patients with KD. This study was undertaken to determine the safety of blocking interleukin‐1 in patients with IVIG‐resistant KD. Methods Sixteen patients were included in the present study. Patients with KD who were not responsive to 1 or more courses of 2 mg/kg of IVIG received anakinra by subcutaneous daily injections. Starting doses were 2 mg/kg of IVIG (4 mg/kg in patients who were age <8 months and who weighed ≥5 kilograms), and the dose was increased up to 6 mg/kg every 24 hours if the patient’s body temperature remained >38°C, indicative of a fever. Treatment duration was 14 days. The last visit was on day 45. Primary outcome was abatement of fever. Secondary measures included disease activity, coronary artery Z score, and C‐reactive protein (CRP) levels. Results Seventy‐five percent of patients in the intention‐to‐treat group and 87.5% in the per‐protocol group became afebrile within 48 hours of the last escalation dose of anakinra. Reduction of disease activity by 50% was indicated on 93.3% (95% confidence interval [95% CI] 68.1–99.8%) of physician evaluations and on 100% (95% CI 73.5–100%) of parent evaluations. CRP values normalized by day 30. At the initial screening, 12 of 16 patients had a maximum coronary artery Z score of >2, and 10 of 16 patients had a maximum Z score of >2.5. At day 45, 5 of 10 patients (50% [95% CI 18.7–81.3%]) and 6 of 12 patients (50% [95% CI 21.1–78.9%]) had achieved coronary artery Z scores of <2.5 and <2, respectively. Five serious adverse events were observed in 3 patients, but no serious infections or deaths occurred. Conclusion Anakinra was well tolerated in the study patients and may have some efficacy in reducing fever, markers of systemic inflammation, and coronary artery dilatation in individuals with IVIG‐refractory KD.

La fièvre méditerranéenne familiale peut se présenter sous la forme d’atteintes musculo-squelettiques, ce qui peut la rendre difficile à différencier d'une spondylarthrite juvénile. La survenue conjointe des deux pathologies étant rarement décrite en pédiatrie, l’objectif de ce travail était de préciser l’existence d’une association ou d’un chevauchement entre fièvre méditerranéenne familiale et spondylarthrite juvénile en France. Trois cohortes d’enfants, atteints de fièvre méditerranéenne familiale, ou atteints de spondylarthrite juvénile, ou ayant des critères pour les deux pathologies, ont été identifiées rétrospectivement dans le centre de référence français des maladies auto-inflammatoires et des amyloses inflammatoires du CHU de Bicêtre. La fièvre méditerranéenne familiale était définie selon les critères de Tel Hashomer ou les critères pédiatriques turcs et la présence d’au moins un variant de l’exon 10 du gène MEFV. La spondylarthrite juvénile était définie selon les critères de l’ILAR. Les patients atteints de fièvre méditerranéenne familiale ou de spondylarthrite juvénile ont été comparés à ceux présentant des critères pour les deux pathologies. Seize enfants atteints de spondylarthrite juvénile associée à la fièvre méditerranéenne familiale ont été identifiés. Le ratio garçon/fille était de 0,6 et l’âge médian à l’apparition de la spondylarthrite de 7,5 ans (3-16 ans). Tous présentaient au moins un variant M694V sur le gène MEFV et 16,7 % étaient porteurs de l’antigène HLA-B27. Comparativement à 83 patients atteints de fièvre méditerranéenne familiale, ceux atteints de spondylarthrite juvénile associée à la fièvre méditerranéenne familiale présentaient : moins de fièvre (p < 0,01), plus fréquemment des arthrites (p < 0,05), d'enthésites (p < 0,001), de rachialgies inflammatoires (p < 0,001) ; avec une efficacité moindre de la colchicine (p < 0,05). Comparativement aux 20 patients atteints de spondylarthrite juvénile, les patients présentant des critères pour les deux pathologies étaient moins souvent traités par anti-inflammatoires non stéroïdiens (p < 0,01) ou anti-TNF (p < 0,001). La fièvre méditerranéenne familiale peut être associée à un tableau classique de la spondylarthrite juvénile. Chez les enfants porteurs d’une fièvre méditerranéenne familiale associée à une spondylarthrite juvénile, qui répondent moins bien à la colchicine, le diagnostic de spondylarthrite doit être posé plus précocement pour introduire au besoin des anti-inflammatoires non stéroïdiens ou des anti-TNF.

Response to: 'Standard dose of ustekinumab for childhood-onset deficiency of interleukin-36 receptor antagonist' by Cherqaoui et alThe case reported by Cherqaoui et al 1 on ustekinumab in the treatment of deficiency of interleukin-36 receptor antagonist (DITRA) is interesting in several aspects.The authors describe intrathecal elevation of proinflammatory cytokines, which is a novel and intriguing finding.The mutation in their case is identical to that of the Dutch/Moroccan patient we described.The total absence of any clinical disease activity in a genetically affected younger sister of the patient further supports the variable expression of identical IL36RN mutations as reported by Cherqaoui et al.As observed in our cases, the patient was treated with several drugs with an absent or only transient improvement. 2 At variance with our previous experience, the use of ustekinumab at standard dose in monotherapy was able to completely control the clinical picture, without the need for any topical steroids.These observations underline the clinical spectrum of disease severity associated with DITRA.In our previous experience, both patients displayed an initial response at standard doses but displayed a tendency to mild/ moderate relapses in proximity to the scheduled doses.According to the few cases so far described, it is therefore conceivable that ustekinumab should be considered among the first-line treatments for this severe condition.As suggested by Cherqaoui et al, a standard dose of 0.75 mg/ kg every 12 weeks could be sufficient to completely control disease flares and should therefore be used as an initial approach.However, higher doses at more frequent intervals could be necessary to achieve a complete remission in patients with a partial clinical response, with a good safety profile.

Objectives: Children with Familial Mediterranean fever may suffer from musculoskeletal involvement, somewhat difficult to distinguish from juvenile spondyloarthritis. The association of these two diseases has been scarcely reported in children. Objective of this work was to define the association of familial Mediterranean fever and juvenile spondyloarthritis in France. Methods: Three cohorts of children with familial Mediterranean fever, juvenile spondyloarthritis, familial Mediterranean fever related juvenile spondyloarthritis, were retrospectively identified in the French reference center of auto-inflammatory diseases. Familial Mediterranean fever was defined according to Tel-Hashomer or Turkish pediatric criteria with at least one exon-10 MEW-gene mutation. Juvenile spondyloarthritis was defined according to ILAR criteria. Patients with familial Mediterranean fever or juvenile spondyloarthritis were respectively compared to familial Mediterranean fever related juvenile spondyloarthritis patients. Results: Sixteen children were identified as having familial Mediterranean fever related juvenile spondyloarthritis. The male/female-ratio was 0.6, with median age at spondyloarthritis onset of 7.5 years (3-16 years). All carried at least one M694V variant in MEW gene; 16.7% were HLA-B27-carriers. Compared to 83 familial Mediterranean fever patients, familial Mediterranean fever related juvenile spondyloarthritis patients had less frequently fever (P< 0.01) and more frequently arthritis (P < 0.05), enthesitis (P < 0.001), inflammatory back pain (P < 0.001), inadequate response to colchicine (P < 0.05). Compared to 20 juvenile spondyloarthritis patients, familial Mediterranean fever related juvenile spondyloarthritis patients less often received non-steroidal anti-inflammatory drugs (P < 0.01) and anti-tumor necrosis factor drugs (P < 0.001). Conclusions: Familial Mediterranean fever may be associated with typical pattern of juvenile spondyloarthritis. These patients, with less response to colchicine, should be diagnosed earlier and treated as for jSpA. (C) 2018 Societe francaise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.