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Background Despite an increasing number of targeted and biological disease-modifying anti-rheumatic drugs (ts or bDMARDs), a significant number of Rheumatoid Arthritis (RA) patients are refractory to multiple lines of treatments. The definition of Difficult-to-treat (D2T) RA patients has been proposed to harmonize research on this condition. While data on D2T in established RA are emerging, this is the first study to specifically address the evolution from early disease (ERA) to D2T-RA. To identify early clinical, laboratory, and radiographic predictors of progression from early rheumatoid arthritis to difficult-to-treat RA over a five-year follow-up. Methods This was a retrospective monocentric cohort study of DMARD-naïve ERA patients (symptom duration ≤ 12 months), enrolled between 2010 and 2019. Patients were followed for 5 years with data collection at baseline, 6, 12, 36, and 60 months. The primary outcome was the development of D2T-RA, defined according to EULAR 2021 criteria. Baseline analyzed variables included clinical features, serology, radiographic damage, disease activity scores, patient-reported outcomes (PROs) and demographic features. Associations between baseline variables and D2T status were evaluated using univariate and multivariate logistic regression analyses. Results We included 391 ERA patients [M/F 109/282, median age 48.2 years IQR (21.26)]. After 5 years, forty-one patients (10.5%) matched the D2T definition. A higher baseline radiographic damage, seropositivity, and baseline disease activity characterized these patients. Only radiographic damage was confirmed as an independent factor for progression to D2T-RA in a multivariate analysis [OR = 2.38 CI (1.09–5.54); p  = 0.03]. During the follow-up, disease activity was consistently higher in the D2T group. D2T patients were exposed to a higher dose of glucocorticoids and more commonly suffered from infections and osteoporosis. Conclusions Baseline radiographic damage, seropositivity, and high disease activity represent the major risk factors for the evolution from ERA to D2T-RA. Disease activity indices were consistently higher in D2T patients all along the five-year follow-up. In addition, D2T patients received higher GC doses and more commonly developed disease and treatment-related comorbidities.

Objective Rheumatoid Arthritis (RA) often exhibits suboptimal treatment response despite early diagnosis and treatment. This study aimed to analyze Early Rheumatoid Arthritis (ERA) synovial biopsies through histology and immunohistochemistry (IHC) to identify predictive factors for treatment response to Methotrexate (MTX). Methods 140 ERA patients from the UCLouvain Arthritis Cohort underwent synovial biopsy and were monitored after initiating Disease-Modifying Antirheumatic Drug (DMARD) therapy. Histological features [Synovial Hyperplasia, Fibrinoid Necrosis (FN), Hypervascularization and Inflammatory Infiltrate] and IHC (CD3, CD20, CD138, CD68) were each semi-quantitatively assessed on a 0–3 scale with 7 levels. Results A strong association was observed between synovial CD68 and Fibrinoid Necrosis scores [ r  = 0.44 (0.27 − 0.56); p  < 0.0001]. CD68 correlated with C-Reactive Protein (CRP), DAS28, SDAI and CDAI. Fibrinoid Necrosis score correlated with CRP and DAS28. Patients were then categorized as CD68Necrosis HIGH (CD68 + Necrosis ≥ 3) and CD68Necrosis LOW (CD68 + Necrosis < 3). CD68Necrosis HIGH exhibited higher pre-treatment disease activity [5.48 (1.6) versus 4.8 (1.7); p  = 0.03] and a greater fall in DAS28 [1.99 (2.06) versus 1.1 (2.27), p  = 0.03], SDAI [21.45 (IQR 23.3) versus 11.65 (IQR 17.5); p  = 0.003] and CDAI [16 [14.9] versus 10.5 (20.1), p  = 0.04]. CD68Necrosis HIGH patients had a higher EULAR Moderate/Good Response rate. CD68Necrosis score was incorporated into a probability matrix model together with clinical features (SJC44 and DAS28) to predict achieving a Moderate/Good EULAR Response Criteria at 3 months with a good performance (AUC 0.724). Conclusion FN and CD68 + in ERA synovial biopsies identify patients with higher disease activity and predict a better treatment response at three months. A model including synovial CD68 and fibrinoid necrosis with baseline clinical features predicts EULAR response at 3 months.

Chronic non-bacterial osteomyelitis (CNO) is caused by aseptic inflammation of bones, primarily driven by the innate immune system. CNO may display different clinical presentations (acute vs chronic, uni- vs multifocal) and is accompanied by other inflammatory disorders in up to a third of patients. Once considered a rare disorder, it has become clear that many patients were underdiagnosed. With increasing awareness and the development of total-body MRI protocols, CNO recognition and diagnosis have greatly improved. Our knowledge of the clinical manifestations and outcomes of CNO has been refined in recent years, especially thanks to the recruitment of large international series. Similarly, new insights into the pathogenesis have been gained by the development of mice models and identification of rare monogenic diseases that resemble CNO. Unfortunately, these advances have not been paralleled in the therapeutic management. In the absence of prospective controlled trials, therapeutic strategies still rely on low-level evidence studies. About half of the patients respond to first-line therapies, but a more refractory and/or chronic disease course requires additional treatments. This narrative review aims to provide the practicing physician with an update on CNO pathogenesis, clinical presentation, associated inflammatory conditions, and diagnostic investigations, and includes a concise summary of current therapeutic recommendations. Conclusion : While major progresses have been made in the recognition and management of CNO, significant challenges remain, in particular regarding the treatment of refractory patients, and those with associated inflammatory disorders. What is Known: • Many physicians caring for children will encounter patients suffering of (suspected) CNO. CNO diagnosis requires exclusion of numerous conditions included in the differential diagnosis, which may be challenging. What is New: • We provide an updated review of recent findings in the field CNO, including imaging and diagnostic strategies, associated inflammatory diseases and long-term outcomes data. • We focus particularly on the challenges encountered by clinicians in the diagnosis and treatment of these patients. • We highlight knowledge gaps in the understanding and treatment of CNO, that should stimulate future research.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease targeting the joints. Current treatment strategies are based on clinical, biological and radiological features, yet still fail to reach the goal of early low disease activity in a significant number of cases. Hence, there is a need for refining current treatment algorithms, using accurate markers of response to therapy. Because RA induces histological and molecular alterations in the synovium even before apparition of clinical symptoms, synovial biopsies are a promising tool in the search of such new biomarkers. Histological and molecular characteristics of RA synovitis are heterogeneous. Variations in synovial lining layer hyperplasia, in cellular infiltration of the sublining by immune cells of myeloid and lymphoid lineages, and in molecular triggers of these features are currently categorized using well-defined pathotypes: myeloid, lymphoid, fibroid and pauci-immune. Here, we first bring the plasticity of RA synovitis under scrutiny, i.e., how variations in synovial characteristics are associated with relevant clinical features (disease duration, disease activity, effects of therapies, disease severity). Primary response to a specific drug could be, at least theoretically, related to the representation of the molecular pathway targeted by the drug in the synovium. Alternatively, absence of primary response to a specific agent could be due to disease severity, i.e., overrepresentation of all synovial molecular pathways driving disease activity overwhelming the capacity of any drug to block them. Using this theoretical frame, we will highlight how the findings of previous studies trying to link response to therapy with synovial changes provide promising perspectives on bridging the gap to personalized medicine in RA.

ObjectivesTranscriptomic profiling of synovial tissue from patients with early, untreated rheumatoid arthritis (RA) was used to explore the ability of unbiased, data-driven approaches to define clinically relevant subgroups.MethodsRNASeq was performed on 74 samples, with disease activity data collected at inclusion. Principal components analysis (PCA) and unsupervised clustering were used to define patient clusters based on expression of the most variable genes, followed by pathway analysis and inference of relative abundance of immune cell subsets. Histological assessment and multiplex immunofluorescence (for CD45, CD68, CD206) were performed on paraffin sections.ResultsPCA on expression of the (n=894) most variable genes across this series did not divide samples into distinct groups, instead yielding a continuum correlated with baseline disease activity. Two patient clusters (PtC1, n=52; PtC2, n=22) were defined based on expression of these genes. PtC1, with significantly higher disease activity and probability of response to methotrexate therapy, showed upregulation of immune system genes; PtC2 showed upregulation of lipid metabolism genes, described to characterise tissue resident or M2-like macrophages. In keeping with these data, M2-like:M1-like macrophage ratios were inversely correlated with disease activity scores and were associated with lower synovial immune infiltration and the presence of thinner, M2-like macrophage-rich synovial lining layers.ConclusionIn this large series of early, untreated RA, we show that the synovial transcriptome closely mirrors clinical disease activity and correlates with synovial inflammation. Intriguingly, lower inflammation and disease activity are associated with higher ratios of M2:M1 macrophages, particularly striking in the synovial lining layer. This may point to a protective role for tissue resident macrophages in RA.

Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1 interferon pathway activation in patients with C1QDef. Twelve patients with genetically confirmed C1QDef were recruited through an international collaboration. Clinical, biological and radiological data were collected retrospectively. The expression of a standardized panel of interferon stimulated genes (ISGs) in peripheral blood was measured, and the level of interferon alpha (IFNα) protein in cerebrospinal fluid (CSF) determined using SIMOA technology. Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients, and severe infections recorded in 2/12 patients. Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients. Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy. To our knowledge, we report the largest original series of genetically confirmed C1QDef yet described. Additionally, we present a review of all previously described genetically confirmed cases of C1QDef. Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα.

C1q deficiency is a rare inborn error of immunity characterized by increased susceptibility to infections and autoimmune manifestations mimicking SLE, with an associated morbidity and mortality. Because C1q is synthesized by monocytes, to date, four patients treated with allogeneic HSCT have been reported, with a positive outcome in three. We conducted an international retrospective study to assess the outcome of HSCT in C1q deficiency. Eighteen patients, fourteen previously unreported, from eleven referral centres, were included. Two patients had two HSCTs, thus 20 HSCTs were performed in total, at a median age of 10 years (range 0.9—19). Indications for HSCT were autoimmune manifestations not controlled by ongoing treatment in seventeen, and early development of MALT lymphoma in one patient. Overall survival (OS) was 71% and event-free survival was 59% at two years (considering an event as acute GvHD ≥ grade III, disease recurrence and death). In eleven patients HSCT led to resolution of autoimmune features and discontinuation of immunosuppressive treatments (follow-up time range 3–84 months). Five patients died due to transplant-related complications. Patients with a severe autoimmune phenotype, defined as neurological and/or renal involvement, had the worst OS (40% vs 84%; p  = 0.034). Reviewing data of 69 genetically confirmed C1q deficient patients, we found that anti-Ro antibodies are associated with neurologic involvement, and anti-RNP and anti-DNA antibodies with renal involvement. In conclusion, HSCT may be a valid curative option for C1q deficiency, but careful selection of patients, with an accurate assessment of risk and benefit, is mandatory.

Objectives: To investigate the findings associated with juvenile polyarteritis nodosa (PAN) on F18-FluoroDeoxyglucose (FDG), positron emission tomography combined with computed tomography (PET-CT). Methods: Patients diagnosed with juvenile PAN (onset <18 years) who underwent a PET-CT at diagnosis (before therapy) were enrolled. PET-CT images were systematically analyzed to identify abnormal findings associated with PAN. In addition, a systematic literature review was performed to identify previously published cases. Results: Six patients with biopsy-confirmed PAN were identified (age at onset 10–17 years). PET-CT was abnormal in all patients. Patchy muscular and subcutaneous FDG uptake with a symmetric distribution in the lower limbs was present in 4/6 patients. Increased FDG uptake in large arteries was found in 1/6 patients. FDG-avid bone lesions were identified in 2/6; additional MRI and bone biopsy results were consistent with chronic non-infectious osteomyelitis (CNO). Unspecific inflammatory findings (medullar and lymphoid organs hypermetabolism) were present in 6/6; these were the only abnormalities present in 2/6 patients. We found this pattern of PET-CT muscular involvement to differ from juvenile dermatomyositis and septic emboli (n = 7 and 2 patients, respectively). In addition, we identified four previously published cases of juvenile PAN investigated with PET-CT: one with FDG-avid muscular and subcutaneous foci, one with increased uptake in large arteries, and two with nonspecific signs (lymphoid organs hypermetabolism). Conclusions: This is the first series of juvenile PAN investigated with PET-CT. Diffuse, patchy hypermetabolic foci in the muscular and subcutaneous tissue of the lower limbs were the most common findings. These features should lead to suspicion of PAN. Further research is needed to assess the diagnostic value of PET-CT in PAN.

Our goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: tocilizumab, rituximab, methotrexate, and adalimumab. Synovial tissue was obtained using ultrasound-guided biopsy from affected joints of 14 patients, before and 16 weeks after treatment with subcutaneous abatacept 125 mg weekly. Paraffin-sections were stained and scored for CD3 , CD20 , and CD68 cell infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix) and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape, and EnrichR. Gene expression analysis identified 304 transcripts modulated by abatacept in synovial tissue. Downregulated genes were significantly enriched for immune processes, strongly overlapping with our findings on other therapies. Data were pooled across these studies, revealing that genes downregulated by DMARDs are significantly enriched for both T-cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have coordinate effects on the two pathways, with a stronger impact in good responders to therapy as compared to moderate and non-responders. We provide evidence that the effects of five DMARDs on the RA synovium culminate in the same pathways. This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets.

We explored histological and transcriptomic profiles of paired synovial biopsies from rheumatoid arthritis (RA) patients, in order to assess homogeneity in synovial tissue at the individual level. Synovial biopsies were performed simultaneously in one small and one large joint per patient using needle-arthroscopy for the knee and ultrasound-guided biopsy for the hand or wrist. Synovium from individuals with osteoarthritis was used as controls. Paraffin-embedded samples were stained for CD3, CD20, and CD68. Total RNA was hybridized on high-density microarrays. variable sequences were obtained from synovial and blood RNA samples. Twenty paired biopsies from 10 RA patients with active disease were analyzed. Semi-quantification of histological markers showed a positive correlation for synovial hyperplasia, inflammatory infiltrates and CD3-positive T cells between pairs. Pairwise comparison of transcriptomic profiles showed similar expression of RA-related molecular pathways (TCR signaling, T cell costimulation and response to TNFα). T cells clonotypes were enriched in all but one joints compared to blood, regardless of the magnitude of T cell infiltration. Enriched clonotypes were shared between pairs (23-100%), but this was less the case in pairs of joints displaying weaker T cell signatures and more pronounced germinal center-like transcriptomic profiles. Cellular and molecular alterations in RA synovitis are similar between small and large joints from the same patient. Interindividual differences in magnitude of T cell infiltrates and distribution of enriched T cell clonotypes support the concept of distinct synovial pathotypes in RA that are associated with systemic versus local antigen-driven activation of T cells.