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ID PMID Title PublicationDate abstract
32119470 Biochemistry, Substance P. 2022 Jan Substance P is a neuropeptide made up of 11 amino acids—an undecapeptide—and is a part of the tachykinin neuropeptide family. Its receptor, neurokinin type 1 (NK-1R), is a transmembrane bound receptor on many cell types in the body including the endothelium of the blood vessels and lymphatics, white blood cells (WBCs), fibroblasts, and neurons. Substance P's most well-known function is as a neurotransmitter and a modulator of pain perception by altering cellular signaling pathways. Additionally, substance P plays a role in gastrointestinal functioning, memory processing, angiogenesis, vasodilation, and cell growth and proliferation. Substance P works by altering cellular signaling pathways primarily through G-protein coupled receptors acting through both the inositol trisphosphate/diacylglycerol (IP3/DAG) and cyclic adenosine monophosphate (cAMP) second messenger systems, depending on the cell type. Clinically, research into substance P has led to the development of antiemetic medications called NK-1R/substance P antagonists. These are primarily used to control chemotherapy-induced vomiting by preventing the binding of substance P to NK1 receptors in the area postrema--the area in the brain that controls emesis. Substance P is also a key molecule in the neurogenic inflammation response, a critical interaction between the nervous system and the immune system. Additionally, the function of substance P is involved in the pathogenesis of various diseases including but not limited to cancer, diabetes, rheumatoid arthritis, myocarditis, heart failure, epilepsy, migraine, thrombosis, pruritus, depression, and anxiety.
35114021 Pyoderma gangrenosum: A systematic review of the molecular characteristics of disease. 2022 Apr Pyoderma gangrenosum is a painful recurrent ulcerative neutrophilic dermatosis in which the pathogenesis is incompletely defined. Current evidence suggests that PG is associated with dysregulation of components of both the innate and adaptive immune system with dysregulation of neutrophil function and contribution of the Th17 immune axis. PG can be present in numerous heterogeneous clinical presentations and be associated with multiple inflammatory conditions including rheumatoid arthritis, inflammatory bowel disease and hidradenitis suppurativa. However, no critical evaluation of the observed molecular characteristics in PG studies in association with their clinical findings has been assessed. Additionally, emerging evidence suggests a potential role for other cell types and immune pathways including B cells, macrophages, autoantibodies and the complement system in PG, although these have not yet been integrated into the pathogenesis of disease. This systematic review aims to critically evaluate the current molecular observations regarding the pathogenesis of PG and discuss associations with clinical characteristics as well as the evidence supporting novel cell types and immune pathways in PG.
35550114 Old drugs, new tricks: Emerging role of drug repurposing in the management of atopic derma 2022 Jun Atopic dermatitis is a chronic recurring pruritic inflammatory skin disease manifested by increased pro-inflammatory mediators which lead to dry, thickened, cracked, scaly skin. The current treatment options for atopic dermatitis management comprise drawbacks and leave unmet effective clinical needs. So, the approach for repurposing existing drugs for atopic dermatitis management may potentially overcome these unmet needs. Diseases that share the common pathophysiological pathways with atopic dermatitis can serve as a foundation for the repurposing of drugs. Drugs used in the management of cancer, rheumatoid arthritis, and other immune-mediated diseases such as psoriasis are under investigation to know the potential in atopic dermatitis management by utilizing repurposing strategies for a novel therapeutic indication. This review mainly envisages the probable repurposing of drugs for the management of atopic dermatitis disease; the barriers and regulatory aspects involved in the repurposing of existing drugs.
35260387 2021 EULAR recommendations regarding lifestyle behaviours and work participation to preven 2022 Mar 8 OBJECTIVES: A European League Against Rheumatism taskforce was convened to review the literature and develop recommendations on lifestyle behaviours for rheumatic and musculoskeletal diseases (RMDs). METHODS: Six lifestyle exposures (exercise, diet, weight, alcohol, smoking, work participation) and seven RMDs (osteoarthritis, rheumatoid arthritis, axial spondyloarthritis, psoriatic arthritis, systemic lupus erythematosus, systemic sclerosis, gout) were considered. The taskforce included health professionals in rheumatology, geriatricians, epidemiologists, public health experts, people with RMDs and exposure domain experts. Systematic reviews were conducted to gather available evidence, from which recommendations were developed. RESULTS: Five overarching principles and 18 specific recommendations were defined based on available evidence. The overarching principles define the importance of a healthy lifestyle, how lifestyle modifications should be implemented, and their role in relation to medical treatments. Exercise recommendations highlight the safety and benefits of exercise on pain and disability, particularly among people with osteoarthritis and axial spondyloarthritis. The diet recommendations emphasise the importance of a healthy, balanced diet for people with RMDs. People with RMDs and health professionals should work together to achieve and maintain a healthy weight. Small amounts of alcohol are unlikely to negatively affect the outcomes of people with RMDs, although people with rheumatoid arthritis and gout may be at risk of flares after moderate alcohol consumption. Smokers should be supported to quit. Work participation may have benefits on RMD outcomes and should be discussed in consultations. CONCLUSIONS: These recommendations cover a range of lifestyle behaviours and can guide shared decision making between people with RMDs and health professionals when developing and monitoring treatment plans.
35598995 Prognosis Prediction Using Magnetic Resonance Spectroscopy and Oligoclonal Bands in Centra 2022 May 21 Central nervous system methotrexate-associated lymphoproliferative disorder (CNS-MTX-LPD) is rare, but its spontaneous regression has been observed in some patients after withdrawal of agents. We herein report three cases of primary CNS-MTX-LPD that received oral MTX for rheumatoid arthritis. Epstein-Barr virus and oligoclonal bands (OCBs) were positive, while proton magnetic resonance spectroscopy ((1)H-MRS) showed an elevated lipid peak and slightly elevated choline/N-acetylaspartate ratio in common. After MTX withdrawal, brain lesions showed spontaneous regression in all cases. Our patient's (1)H-MRS findings and OCBs may reflect a non-monoclonal lymphoproliferative histology as benign-type lesions in CNS-MTX-LPD.
35384409 Genetic obstacles to developing and tolerizing human B cells. 2022 Apr 5 Early in development, B cells explosively diversify B-cell receptors (BCRs) to recognize a wide variety of microbial antigens. A variety of developmental and tolerance checkpoints are subsequently deployed at later developmental stages to purge useless or potentially dangerous autoreactive B-cell clones. Once B cells recognize cognate antigens within secondary lymphoid tissues, their BCRs are genetically modified to increase the specificity and strength of antigen binding. Identification and investigation of monogenic inborn errors of immunity (IEI) diseases demonstrate which specific molecules and pathways are essential for developing well-tolerized human B cells. Although rare, IEI patients have provided important mechanistic insights into, and therapeutic clues for, patients afflicted with more common autoantibody associated autoimmune diseases like lupus, rheumatoid arthritis, and type 1 diabetes. This article is categorized under: Immune System Diseases > Stem Cells and Development > Genetics/Genomics/Epigenetics.
35101714 Function of miRNA-145-5p in the pathogenesis of human disorders. 2022 Mar miR-145-5p is a microRNA whose role in diverse disorders has been verified. This miRNA is encoded by MIR145 gene on chromosome 5. This miRNA is mainly considered as a tumor suppressor miRNA in diverse types of cancers, including bladder cancer, breast cancer, cervical cancer, cholangiocarcinoma, renal cancer, and gastrointestinal cancers. However, few studies have reported up-regulation of this miRNA in some cancers. Moreover, it has been shown to affect pathogenesis of a number of non-malignant conditions such as aplastic anemia, asthma, cerebral ischemia/reperfusion injury, diabetic nephropathy, rheumatoid arthritis and Sjögren syndrome. In the current review, we summarize the available literature about the role of miR-145-5p in these conditions.
35358128 Racial Discrimination and Race-Based Biases on Orthopedic-Related Outcomes: An Integrative 2022 Mar Musculoskeletal diseases often lead to functional limitations and debility. The burden of these debilitating diseases is not balanced across race and ethnicity. The Institute of Medicine (now referred to as the National Academy of Medicine) identified racial discrimination as a substantive cause of race-based health disparities for racial and ethnic minority groups. The purpose of this integrative review is to summarize the evidence on the relationship among racial discrimination, race-based implicit biases and other types of biases (e.g., gender and appearance), and orthopaedic-related outcomes. Nine studies met inclusion criteria and were included in this review. The orthopaedic outcomes addressed across the nine studies were osteoarthritis, rheumatoid arthritis, low back pain, pain tolerance, disability, and likelihood of being recommended for a total knee arthroplasty. The results reveal that experiences of racial discrimination, race-based implicit biases, and other types of biases contribute to unsatisfactory orthopaedic-related outcomes for minority groups. Orthopaedic nurses can leverage their expertise to address these disparities in orthopaedic-related outcomes across minority groups.
35028161 Will 14-3-3η Be a New Diagnostic and Prognostic Biomarker in Rheumatoid Arthritis? A Pros 2022 RESULTS: Serum14-3-3η levels were significantly higher in all RA patients than in controls (P < 0.001), its sensitivity was 86.7% and 88.3% in early and established RA patients with a significant difference with RF and ACCP at early disease, and the specificity was 96.7%. There was a significant reduction of 14-3-3η levels 6 months after treatment in the first group (p=0.004), and there was a significant positive correlation between serum 14-3-3η levels and parameters of disease activity and severity. CONCLUSION: 14-3-3η could be a novel, potent, and efficacious diagnostic, and prognostic marker for RA with high sensitivity, that may become a new therapeutic target for RA.
34928185 The role of PCSK9 in inflammation, immunity, and autoimmune diseases. 2022 Jan INTRODUCTION: Statins have pleiotropic effects, being both anti-inflammatory and immunomodulatory. Proprotein convertase subtilisin kexin 9 (PCSK9) targets the low-density lipoprotein receptor (LDLR), which increases LDL levels due to the lower expression of LDLR. AREAS COVERED: Inhibition of PCSK9 by the use of antibodies represents a novel principle to lower LDL levels. LDL may have other properties than being a cholesterol carrier but is well established as a risk factor for cardiovascular disease and atherosclerosis. In atherosclerosis, the plaques are characterized by activated T cells and dendritic cells (DCs), dead cells, and OxLDL. The latter may be an important cause of the inflammation typical of atherosclerosis, by promoting a proinflammatory immune activation. This is inhibited by PCSK9 inhibition, and an anti-inflammatory type of immune activation is induced. OxLDL is raised in systemic lupus erythematosus (SLE), where both CVD and atherosclerosis are much increased compared to the general population. PCSK9 is reported to be associated with disease activity and complications in SLE. Also in other rheumatoid arthritis, PCSK9 may play a role. EXPERT OPINION: PCSK9 has pleiotropic effects, being implicated in inflammation and immunity. Inhibition of PCSK9 is therefore interesting to study further as a potential therapy against inflammation and autoimmunity.
35242136 Proteus mirabilis Vesicles Induce Mitochondrial Apoptosis by Regulating miR96-5p/Abca1 to 2022 Bone loss due to an increased osteoclast activity is common in osteoporosis and rheumatoid arthritis. For the first time, we observed an inhibition of osteoclast formation and bone resorption by outer-membrane vesicles (OMVs) from a Gram-negative, pathogenic bacterium, Proteus mirabilis (P.M). Gene ontogeny and KEGG enrichment analyses of miRNA and mRNA sequencing data demonstrated a significant effect of P.M OMVs on mitochondrial functions and apoptotic pathways. OMVs induced mitochondrial dysfunction through an increased level of intracellular ROS, collapse of mitochondrial membrane potential (ΔΨm), and modulation of Bax, Bcl-2, caspase-3, and cytochrome c expression. In addition, P.M OMVs strongly inhibited miR-96-5p expression, which caused an upregulation of ATP binding cassette subfamily A member 1 (Abca1) in osteoclasts leading to an increased level of mitochondria-dependent apoptosis. Moreover, treatment with P.M but not Escherichia coli OMVs attenuated bone loss in experimental osteoporosis and collagen-induced arthritis. Collectively, we demonstrated osteoprotective functions of OMVs from Proteus mirabilis, which downregulated miR-96-5p causing an increased Abca1 expression and mitochondria-dependent apoptosis.
35081305 Janus Kinase and Tyrosine Kinase Inhibitors in Dermatology: A Review of Their Utilization, 2022 Jan Janus kinase inhibitors, also commonly referred to as JAK inhibitors, are a novel drug class that target and block cytokine signaling mediated by the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, thereby regulating immune response and cell growth. Although JAK inhibitors are mainly used for rheumatological conditions such as rheumatoid arthritis, their application in the field of dermatology is actively being investigated. Tofacitinib is US FDA-approved for psoriatic arthritis and showing promise for treating psoriasis. Most recently, regulatory approvals for the US were gained by ruxolitinib as a first-inclass, selective, topical therapy for atopic dermatitis and oral upadacitinib for active psoriatic psoriasis. Additionally, abrocitinib and upadacitinib have demonstrated efficacy in atopic dermatitis and are pending FDA approval for this indication. The therapeutic potential of JAK inhibitors in dermatological conditions such as alopecia areata, psoriasis, atopic dermatitis, vitiligo, and dermatomyositis are showing promising results in clinical trials. Adverse events for JAK inhibitors seem to be similar to that of biologic drugs. Common adverse effects include increased risk of infections and thromboembolic events. Further investigation is needed to not only better understand the safety profile of JAK inhibitors, but also their full utility within the field of dermatology.
35301943 Computer-Aided Drug Design of Anti-inflammatory Agents Targeting Microsomal Prostaglandin 2022 Mar 17 Inflammation is a natural process in response to external stimuli associated with organism protection. However, this reaction could be exaggerated, leading to severe damages related to physiopathological processes, such as rheumatoid arthritis, cancer, diabetes, allergies, infections, among others. Inflammation is mainly characterized by pain, increased temperature, flushing, and edema, which can be controlled using anti-inflammatory drugs. In this context, prostaglandin E2 (PGE2) inhibition has been targeted for designing new compounds with anti-inflammatory properties. It is a bioactive lipid overproduced during an inflammatory process, in which its increased production is carried out mainly by COX-1, COX-2, and microsomal prostaglandin E2 synthase-1 (mPGES-1). Recently, studies have demonstrated that mPGES-1 inhibition is a safe strategy to develop anti-inflammatory agents, which could protect against pain, acute inflammation, arthritis, autoimmune diseases, and different types of cancers. To decrease production costs and increase the probability of discovering active substances, computer-aided drug design (CADD) approaches have been increasingly used for designing new inhibitors. Thus, this review will cover all aspects involving high-throughput virtual screening, molecular docking, dynamics, fragment-based drug design, quantitative structure-activity relationship in seeking new promising mPGES-1 inhibitors.
35655028 The Non-medical Switch from Reference Adalimumab to Biosimilar Adalimumab is Highly Succes 2022 Jun 3 INTRODUCTION: The adalimumab biosimilar (ADAbio) Amgevita® has a similar efficacy and safety profile as the adalimumab reference (ADA) Humira®. We studied the clinical consequences of a non-medical switch from ADA to ADAbio in adult patients with mainly established rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthritis (SpA). METHODS: Patients that received treatment with ADA for at least three months were switched to ADAbio. Data was collected retrospectively from 1 year before the switch up to 6 months after. RESULTS: A total of 603 patients were switched from ADA to ADAbio (switch group). During a 1-year follow-up, over 93% of all patients underwent a successful transition in terms of disease activity and safety from ADA to biosimilar, supporting the bioequivalence of both drugs in patients with stable inflammatory rheumatic joint diseases. Forty patients (6.6%) switched back to ADA (re-switch group). There were no objective changes in disease activity score in 28 joints using C-reactive protein (DAS28-CRP), or adverse effects before and after the switch between both groups. CONCLUSIONS: In line with earlier reports, the transition to ADAbio went successful in the majority of patients with stable inflammatory rheumatic joint diseases. Patient-reported symptoms without objective signs that indicate a flare of disease activity after the switch to ADAbio are probably explained by nocebo effects. A pre-emptive approach to counteract nocebo effects and stimulate placebo response may have a positive impact on health outcomes for patients and preserve the economic benefits of cost savings that can be achieved by prescribing a biosimilar instead of the reference drug.
35592318 Selective Targeting of IL-15Rα Is Sufficient to Reduce Inflammation. 2022 Cytokines are crucial molecules for maintaining the proper functioning of the immune system. Nevertheless, a dysregulation of cytokine expression could be involved in the pathogenesis of autoimmune diseases. Interleukin (IL)-15 is a key factor for natural killer cells (NK) and CD8 T cells homeostasis, necessary to fight cancer and infections but could also be considered as a pro-inflammatory cytokine involved in autoimmune inflammatory disease, including rheumatoid arthritis, psoriasis, along with tumor necrosis factor alpha (TNF-α), IL-6, and IL-1β. The molecular mechanisms by which IL-15 exerts its inflammatory function in these diseases are still unclear. In this study, we generated an IL-15-derived molecule called NANTIL-15 (New ANTagonist of IL-15), designed to selectively inhibit the action of IL-15 through the high-affinity trimeric IL-15Rα/IL-2Rβ/γc receptor while leaving IL-15 signaling through the dimeric IL-2Rβ/γc receptor unaffected. Administrating of NANTIL-15 in healthy mice did not affect the IL-15-dependent cell populations such as NK and CD8 T cells. In contrast, we found that NANTIL-15 efficiently reduced signs of inflammation in a collagen-induced arthritis model. These observations demonstrate that the inflammatory properties of IL-15 are linked to its action through the trimeric IL-15Rα/IL-2Rβ/γc receptor, highlighting the interest of selectively targeting this receptor.
35341974 Lymphocyte activation gene-3 (LAG-3) regulatory T cells: An evolving biomarker for treatme 2022 Jun Regulatory T cells (Tregs) comprise a CD4(+)CD25(+)Foxp3(+) T cell subset for maintaining immune tolerance, and their deficits and/or dysfunction are observed in autoimmune diseases. The lymphocyte activation gene 3 (LAG-3, also known as CD223), which is an immunoglobulin superfamily member expressed on peripheral immune cells, is recognized as an inhibitory regulator of Tregs. LAG-3(+) T cells represent a novel protective Tregs subset that produces interleukin-10. Alterations in LAG-3(+) Tregs have been reported in several autoimmune diseases, suggesting their potential pathogenic role. Recent studies have indicated that LAG-3(+) Tregs may be associated not only with immunopathology but also with response to therapy in several autoimmune and autoinflammatory diseases, such as rheumatoid arthritis, psoriasis, psoriatic arthritis and others. We present a review of Tregs phenotypes and functions, with a focus on LAG-3(+) Tregs, and discuss their potential role as biomarkers for treatment response in autoimmune diseases.
35525391 Clinical implications of tristetraprolin (TTP) modulation in the treatment of inflammatory 2022 May 5 Abnormal regulation of pro-inflammatory cytokine and chemokine mediators can contribute to the excess inflammation characteristic of many autoimmune diseases, such as rheumatoid arthritis, psoriasis, Crohn's disease, type 1 diabetes, and many others. The tristetraprolin (TTP) family consists of a small group of related RNA-binding proteins that bind to preferred AU-rich binding sites within the 3'-untranslated regions of specific mRNAs to promote mRNA deadenylation and decay. TTP deficient mice develop a severe systemic inflammatory syndrome consisting of arthritis, myeloid hyperplasia, dermatitis, autoimmunity and cachexia, due at least in part to the excess accumulation of proinflammatory chemokine and cytokine mRNAs and their encoded proteins. To investigate the possibility that increased TTP expression or activity might have a beneficial effect on inflammatory diseases, at least two mouse models have been developed that provide proof of principle that increasing TTP activity can promote the decay of pro-inflammatory and other relevant transcripts, and decrease the severity of mouse models of inflammatory disease. Animal studies of this type are summarized here, and we briefly review the prospects for harnessing these insights for the development of TTP-based anti-inflammatory treatments in humans.
35311022 Down Syndrome-Associated Arthritis (DA): Diagnostic and Management Challenges. 2022 Down syndrome (DS) is one of the most common birth defects in the United States, the most common genomic disorder of intellectual disability, and results from trisomy 21. This chromosome disorder causes an extensive, heterogenous phenotype that results in a broad presentation of symptoms that includes atlantoaxial instability, congenital heart defects, muscle hypotonia, hypothyroidism, hematologic disorders, recurrent infections, and autoimmune diseases. The autoimmune diseases are caused by immune system dysregulation that results in increased pro-inflammatory cytokines, along with other innate and adaptive immune system dysregulation. This is the likely cause of the increased risk of inflammatory arthritis or Down syndrome-associated arthritis (DA) seen in individuals with DS. Most individuals with DA present with polyarticular (five or more joints with arthritis at presentation of disease), rheumatoid factor and anti-nuclear antibody negative disease that is aggressive with bone and joint damage at presentation. There is notable delay in diagnosis of DA as there are no formal guidelines on screening or monitoring for inflammatory arthritis in individuals with DS. Once diagnosed, and despite aggressive therapy with disease modifying antirheumatic drugs, disease burden is high for those with DA. Therapy can also be challenging for those with DA as many require second and third-line disease modifying therapies. Many also struggle with medication toxicity and ineffectiveness that further causes challenges with management and outcomes. The purpose of this current review is to provide an up-to-date summary of the literature related to DA in children and adolescents with focus on presentation, diagnosis, and management considerations, along with current barriers that inhibit optimal care.
35429590 Statin Use for Primary Cardiovascular Disease Prevention is Low in Inflammatory Arthritis. 2022 Apr 13 BACKGROUND: Inflammatory arthritis (IA) patients are at high risk for atherosclerotic cardiovascular disease (ASCVD), yet dyslipidemia management is infrequently prioritized. We applied Canadian dyslipidemia guidelines to determine how many IA patients would be eligible for primary prevention with statins. METHODS: We conducted a cross-sectional study of IA patients in a cardio-rheumatology clinic, with no known CVD and without statin therapy at cohort entry. We stratified patients by Framingham Risk Score (FRS) and summarized the proportion meeting guideline statin-indicated criteria. Multivariable logistic regression analyses determined the association of variables with statin indication after adjustment for age, sex, traditional ASCVD risk factors and arthritis characteristics. RESULTS: Among 302 patients, most had rheumatoid arthritis (59%). Mean age was 58 years and 71% were female. Overall, 50% of the cohort was eligible for statin therapy. The majority was low FRS risk category (68%) and the most frequent qualifier for statins was an elevated apolipoprotein B (ApoB) level or low-density lipoprotein cholesterol (LDL-c) level. In the intermediate FRS group, 91% met criteria for statin therapy based on the presence of a coronary artery calcification (CAC) score >0 or an elevated high-sensitivity C-reactive protein. Male sex, hypertension, elevated ApoB and a CAC score >0 were the factors most strongly associated with indication for statin therapy. CONCLUSIONS: Statin therapy is suboptimal in IA despite a significant number of patients meeting indication based on lipoprotein thresholds and/or CAC scores. Understanding the barriers and potential facilitators of implementing and interpreting these CVD screening tools in IA is needed.
35449805 B Cells on the Stage of Inflammation in Juvenile Idiopathic Arthritis: Leading or Supporti 2022 Juvenile idiopathic arthritis (JIA) is a term that collectively refers to a group of chronic childhood arthritides, which together constitute the most common rheumatic condition in children. The International League of Associations for Rheumatology (ILAR) criteria define seven categories of JIA: oligoarticular, polyarticular rheumatoid factor (RF) negative (RF-), polyarticular RF positive (RF+), systemic, enthesitis-related arthritis, psoriatic arthritis, and undifferentiated arthritis. The ILAR classification includes persistent and extended oligoarthritis as subcategories of oligoarticular JIA, but not as distinct categories. JIA is characterized by a chronic inflammatory process affecting the synovia that begins before the age of 16 and persists at least 6 weeks. If not treated, JIA can cause significant disability and loss of quality of life. Treatment of JIA is adjusted according to the severity of the disease as combinations of non-steroidal anti-inflammatory drugs (NSAIDs), synthetic and/ or biological disease modifying anti-rheumatic drugs (DMARDs). Although the disease etiology is unknown, disturbances in innate and adaptive immune responses have been implicated in JIA development. B cells may have important roles in JIA pathogenesis through autoantibody production, antigen presentation, cytokine release and/ or T cell activation. The study of B cells has not been extensively explored in JIA, but evidence from the literature suggests that B cells might have indeed a relevant role in JIA pathophysiology. The detection of autoantibodies such as antinuclear antibodies (ANA), RF and anti-citrullinated protein antibodies (ACPA) in JIA patients supports a breakdown in B cell tolerance. Furthermore, alterations in B cell subpopulations have been documented in peripheral blood and synovial fluid from JIA patients. In fact, altered B cell homeostasis, B cell differentiation and B cell hyperactivity have been described in JIA. Of note, B cell depletion therapy with rituximab has been shown to be an effective and well-tolerated treatment in children with JIA, which further supports B cell intervention in disease development.