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- EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 updatePublication . Smolen, Josef S.; Landewé, Robert B. M.; Bergstra, Sytske Anne; Kerschbaumer, Andreas; Sepriano, Alexandre; Aletaha, Daniel; Caporali, Roberto; Edwards, Christopher John; Hyrich, Kimme L.; Pope, Janet E.; de Souza, Savia; Stamm, Tanja A.; Takeuchi, Tsutomu; Verschueren, Patrick; Winthrop, Kevin L.; Balsa, Alejandro; Bathon, Joan M.; Buch, Maya H.; Burmester, Gerd R.; Buttgereit, Frank; Cardiel, Mario Humberto; Chatzidionysiou, Katerina; Codreanu, Catalin; Cutolo, Maurizio; den Broeder, Alfons A.; El Aoufy, Khadija; Finckh, Axel; Fonseca, João Eurico; Gottenberg, Jacques-Eric; Haavardsholm, Espen A.; Iagnocco, Annamaria; Lauper, Kim; Li, Zhanguo; McInnes, Iain B.; Mysler, Eduardo F.; Nash, Peter; Poor, Gyula; Ristic, Gorica G.; Rivellese, Felice; Rubbert-Roth, Andrea; Schulze-Koops, Hendrik; Stoilov, Nikolay; Strangfeld, Anja; van der Helm-van Mil, Annette; van Duuren, Elsa; Vliet Vlieland, Theodora P. M.; Westhovens, René; van der Heijde, DésiréeObjectives: To provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field. Methods: An international task force was formed and solicited three systematic literature research activities on safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs). The new evidence was discussed in light of the last update from 2019. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned to and participants finally voted on the level of agreement with each item. Results: The task force agreed on 5 overarching principles and 11 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); GCs; biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab including biosimilars), abatacept, rituximab, tocilizumab, sarilumab and targeted synthetic (ts) DMARDs, namely the Janus kinase inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib. Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering in sustained clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were all considered. Initially, MTX plus GCs is recommended and on insufficient response to this therapy within 3-6 months, treatment should be based on stratification according to risk factors; With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD should be added to the csDMARD; after careful consideration of risks of MACEs, malignancies and/or thromboembolic events tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD (considering risks) is recommended. With sustained remission, DMARDs may be tapered but should not be stopped. Levels of evidence and levels of agreement were high for most recommendations. Conclusions: These updated EULAR recommendations provide consensus on RA management including safety, effectiveness and cost.
- Assessment of calcinosis in Portuguese patients with systemic sclerosis: a multicenter studyPublication . Samões, Beatriz; Guimarães da Fonseca, Diogo; Beirão, Tiago; Costa, Flávio; Vieira, Romana; Terroso, Georgina; Ferreira, Raquel Miriam; Nicolau, Rafaela; Saraiva, André; Salvador, Maria João; Duarte, Ana Catarina; Cordeiro, Ana; Vilas-Boas, João Paulo; Genrinho, Inês; Bento da Silva, Ana; Gago, Laura; Resende, Catarina; Martins, Patrícia; Madeira, Nathalie; Dinis, Sara; Couto, Maura; Santos, Inês; Araújo, Filipe; Mourão, Ana Filipa; Gomes Guerra, Miguel; Oliveira, Margarida; Daniel, Alexandra; Rodrigues, Marília; Dantas Soares, Catarina; Parente, Hugo; Furtado, Carolina; Fontes, Tomás; Abelha-Aleixo, JoanaIntroduction/objectives: The study aims to define the clinical and subclinical calcinosis prevalence, the sensitivity of radiographed site and clinical method for its diagnosis, and the phenotype of Portuguese systemic sclerosis (SSc) patients with calcinosis. Method: A cross-sectional multicenter study was conducted with SSc patients fulfilling Leroy/Medsger 2001 or ACR/EULAR 2013 classification criteria, registered in the Reuma.pt. Calcinosis was assessed through clinical examination and radiographs of hands, elbows, knees, and feet. Independent parametric or non-parametric tests, multivariate logistic regression, and sensitivity calculation of radiographed site and clinical method for calcinosis detection were performed. Results: We included 226 patients. Clinical calcinosis was described in 63 (28.1%) and radiological calcinosis in 91 (40.3%) patients, of which 37 (40.7%) were subclinical. The most sensitive location to detect calcinosis was the hand (74.7%). Sensitivity of the clinical method was 58.2%. Calcinosis patients were more often female (p = 0.008) and older (p < 0.001) and had more frequently longer disease duration (p < 0.001), limited SSc (p = 0.017), telangiectasia (p = 0.039), digital ulcers (p = 0.001), esophageal (p < 0.001) and intestinal (p = 0.003) involvements, osteoporosis (p = 0.028), and late capillaroscopic pattern (p < 0.001). In multivariate analysis, digital ulcers (OR 2.63, 95% CI 1.02-6.78, p = 0.045) predicted overall calcinosis, esophageal involvement (OR 3.52, 95% CI 1.28-9.67, p = 0.015) and osteoporosis (OR 4.1, 95% CI 1.2-14.2, p = 0.027) predicted hand calcinosis, and late capillaroscopic pattern (OR 7.6, 95% CI 1.7-34.9, p = 0.009) predicted knee calcinosis. Anti-nuclear antibody positivity was associated with less knee calcinosis (OR 0.021, 95% CI 0.001-0477, p = 0.015). Conclusions: Subclinical calcinosis high prevalence suggests that calcinosis is underdiagnosed and radiographic screening might be relevant. Multifactorial pathogenesis may explain calcinosis predictors' variability. Key Points • Prevalence of subclinical calcinosis in SSc patients is substantial. • Hand radiographs are more sensitive to detect calcinosis than other locations or clinical method. • Digital ulcers were associated with overall calcinosis, esophageal involvement and osteoporosis were associated with hand calcinosis, and late sclerodermic pattern in nailfold capillaroscopy was associated with knee calcinosis. • Anti-nuclear antibody positivity may be a protective factor for knee calcinosis.
- EULAR study group on MHC-I-opathy: identifying disease-overarching mechanisms across disciplines and bordersPublication . Kuiper, Jonas J. W.; Prinz, Jörg C.; Stratikos, Efstratios; Kuśnierczyk, Piotr; Arakawa, Akiko; Springer, Sebastian; Mintoff, Dillon; Padjen, Ivan; Shumnalieva, Russka; Vural, Seçil; Kötter, Ina; van de Sande, Marleen G.; Boyvat, Ayşe; de Boer, Joke H.; Bertsias, George; de Vries, Niek; Krieckaert, Charlotte L. M.; Leal, Ines; Vidovič Valentinčič, Nataša; Tugal-Tutkun, Ilknur; el Khaldi Ahanach, Hanane; Costantino, Félicie; Glatigny, Simon; Mrazovac Zimak, Danijela; Lötscher, Fabian; Kerstens, Floor G.; Bakula, Marija; Vieira De Sousa, Elsa Cristina; Böhm, Peter; Bosman, Kees; Kenna, Tony J.; Powis, Simon J.; Breban, Maxime; Gul, Ahmet; Bowes, John; Lories, Rik J. U.; Nowatzky, Johannes; Wolbink, Gerrit Jan; McGonagle, Dennis G.; Turkstra, FranktienThe 'MHC-I (major histocompatibility complex class I)-opathy' concept describes a family of inflammatory conditions with overlapping clinical manifestations and a strong genetic link to the MHC-I antigen presentation pathway. Classical MHC-I-opathies such as spondyloarthritis, Behçet's disease, psoriasis and birdshot uveitis are widely recognised for their strong association with certain MHC-I alleles and gene variants of the antigen processing aminopeptidases ERAP1 and ERAP2 that implicates altered MHC-I peptide presentation to CD8+T cells in the pathogenesis. Progress in understanding the cause and treatment of these disorders is hampered by patient phenotypic heterogeneity and lack of systematic investigation of the MHC-I pathway.Here, we discuss new insights into the biology of MHC-I-opathies that strongly advocate for disease-overarching and integrated molecular and clinical investigation to decipher underlying disease mechanisms. Because this requires transformative multidisciplinary collaboration, we introduce the EULAR study group on MHC-I-opathies to unite clinical expertise in rheumatology, dermatology and ophthalmology, with fundamental and translational researchers from multiple disciplines such as immunology, genomics and proteomics, alongside patient partners. We prioritise standardisation of disease phenotypes and scientific nomenclature and propose interdisciplinary genetic and translational studies to exploit emerging therapeutic strategies to understand MHC-I-mediated disease mechanisms. These collaborative efforts are required to address outstanding questions in the etiopathogenesis of MHC-I-opathies towards improving patient treatment and prognostication.
- The Mediterranean diet, and not dietary inflammatory index, is associated with rheumatoid arthritis disease activity, the impact of disease and functional disabilityPublication . Charneca, Sofia; Ferro, Margarida; Vasques, João; Carolino, Elisabete; Martins-Martinho, Joana; Duarte-Monteiro, Ana Margarida; Dourado, Eduardo; Fonseca, João Eurico; Guerreiro, Catarina SousaPurpose: To assess the relationship between adherence to the Mediterranean Diet (MD) /individual Dietary Inflammatory Index (DII) and disease activity, disease impact, and functional status in Rheumatoid Arthritis (RA) patients. Methods: RA patients followed at a hospital in Lisbon, Portugal, were recruited. DII was calculated using dietary intake data collected with a food frequency questionnaire (FFQ). Adherence to the MD was obtained using the 14-item Mediterranean Diet assessment tool. Disease Activity Score of 28 Joints (DAS28) and the DAS28 calculated with C-Reactive Protein (DAS28-CRP) were used to assess disease activity. Impact of disease and functional status were evaluated using the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire and the Health Assessment Questionnaire (HAQ), respectively. Results: 120 patients (73.3% female, 61.8 ± 10.1 years of age) were included. Patients with higher adherence to the MD had significantly lower DAS28-CRP (median 3.27(2.37) vs 2.77(1.49), p = 0.030), RAID (median 5.65(2.38) vs 3.51(4.51), p = 0.032) and HAQ (median 1.00(0.56) vs 0.56(1.03), p = 0.013) scores. Higher adherence to the MD reduced the odds of having a higher DAS28 by 70% (OR = 0.303, 95%CI = (0.261, 0.347), p = 0.003). Lower adherence to MD was associated with higher DAS28-CRP (β = - 0.164, p = 0.001), higher RAID (β = - 0.311, p < 0.0001), and higher HAQ scores (β = - 0.089, p = 0.001), irrespective of age, gender, BMI and pharmacological therapy. Mean DII of our cohort was not significantly different from the Portuguese population (0.00 ± 0.17 vs - 0.10 ± 1.46, p = 0.578). No associations between macronutrient intake or DII and RA outcomes were found. Conclusions: Higher adherence to the MD was associated with lower disease activity, lower impact of disease, and lower functional disability in RA patients.
- Atherosclerosis and bone loss in humans: results from deceased donors and from patients submitted to carotid endarterectomyPublication . Carmona-Fernandes, Diana; Barreira, Sofia; Leonardo, Natacha; Casimiro, Renata I.; Castro, Alice M.; Santos, Pedro Oliveira; Fernandes, António N.; Cortes-Figueiredo, Filipe; Gonçalves, Carolina A.; Cruz, Rafael Moiteiro Da; Fernandes, Mariana L.; Ivo, Margarida; Pedro, Luís M; Canhao, Helena; Fonseca, João Eurico; Santos, MariaBackground and Aims: Atherosclerosis and osteoporosis share common risk factors, as well as inflammatory mechanisms. Our aim was to understand how atherosclerotic lesions are related with disturbances in bone. Methods: Gene expression of pro-inflammatory and bone metabolism related proteins (IL-1β, IL-6, IL-17A, TNF, RANKL, OPG, COL1, CTSK, OCL, TRAP, CBFA1, DKK1, SOST, ADIPOQ, and ADIPOR1) were analyzed in arteries and bones from 45 deceased donors and adipose tissue was used as control. Additionally, in 139 patients with advanced atherosclerosis submitted to carotid endarterectomy we compared calcium content (Alizarin red) and plaque inflammatory scores (CD3+, CD68+, and adiponectin) of patients with normal bone mineral density (BMD) with those with low BMD and explored the associations between gene expression in atherosclerotic plaques and BMD. Serum levels of pro-inflammatory and bone related proteins were measured both in donors and patients. Associations were investigated by the Pearson or Spearman correlation tests, and multivariate regression analyzes were performed when justified. Results: Gene expression of bone remodeling and pro-inflammatory proteins correlated positively in bone and aorta, independently of age and sex of donors, but not in adipose tissue. The expression of bone formation genes was significantly higher in atheroma plaques from endarterectomized patients with normal vs. low BMD as well as inflammatory CD68+ scores, regardless of patients' age and sex, but not of body mass index. No relationship was observed between serum levels and gene expression levels of pro-inflammatory or bone remodeling proteins. Conclusions: Our results suggest that the relationship between bones and vessels in the context of atherosclerotic disease and osteoporosis may rely on the intrinsic connection between the tissues involved, independently of disease stage. Serum measurements of pro-inflammatory and bone-remodeling proteins do not accurately translate tissue pathologic processes.
- Elderly-onset rheumatoid arthritis is a unique disease subset associated with poor overall outcomes: response to the letter by Haroon and AyamerPublication . Romão, Vasco C.; Fonseca, João Eurico; Pitzalis, CostantinoWe thank Haroon and Ayamer for their interest in our study, and for reporting their data on the outcomes of elderly-onset rheumatoid arthritis (EORA). Their findings mostly overlap ours, in describing a population with greater male gender representation, similar frequency of seropositivity, and severe, rapidly-deforming disease, requiring more intensive disease-modifying anti-rheumatoid (DMARD) therapy, in comparison to its younger-onset RA (YORA) counterpart. Of note, long-term low dose glucocorticoid therapy was often needed in this subgroup of patients, with frequent flares observed following tapering. In line with this, a recent study also showed that patients with EORA, but not YORA, had a lower risk of biologic DMARD discontinuation if concurrently treated with glucocorticoids. Overall, these findings are in accordance with the concept that EORA is a unique subset characterized by poor prognosis at multiple levels. This contradicts a previously held view of EORA as a benign form of disease. In fact, recent studies — including our own in a cohort of untreated patients with early arthritis — have shown that EORA is associated with worse clinical and imaging outcomes. Moreover, we could demonstrate that the poor features of EORA were also mirrored at the synovial tissue level, with pathologically-resistant disease that was less responsive to promptly started immunosuppressive treatment.
- Health-related quality of life and disability in adults with juvenile idiopathic arthritis: comparison with adult-onset rheumatic diseasesPublication . Oliveira Ramos, Filipa; Rodrigues, Ana; Magalhaes Martins, Fernando; Melo, Ana Teresa; Aguiar, Francisca; Brites, Luisa; Azevedo, Soraia; Duarte, Ana Catarina; Furtado, Carolina; Mourão, Ana Filipa; Sequeira, Graça; Cunha, Inês; Figueira, Ricardo; Melo Gomes, Jose Antonio; Santos, Maria; Fonseca, João EuricoObjective: To compare physical disability, mental health, fatigue and health-related quality of life (HRQoL) across juvenile idiopathic arthritis (JIA) categories in adulthood and between JIA and adult-onset rheumatic diseases. Methods: Cross-sectional analysis nested in a cohort of adult patients with JIA registered in the Rheumatic Diseases Portuguese Register (Reuma.pt). Physical disability (Health Assessment Questionnaire-Disability Index), mental health symptoms (Hospital Anxiety and Depression Scale), fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F)) and HRQoL (EuroQol-5D (EQ5D) and Short Form (SF-36)) were compared across JIA categories. Patients with polyarticular JIA and enthesis-related arthritis (ERA) JIA were compared respectively to patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA), matched for gender and age, adjusted for disease duration and activity. Results: 585 adult patients with JIA were included. Comparison across JIA categories showed that persistent oligoarthritis and patients with ERA reported a higher score in EQ5D and SF-36 physical component when compared with other JIA categories.Polyarticular JIA reported less disability and fatigue than patients with RA (median Health Assessment Questionnaire of 0.25 vs 0.63; p<0.001 and median FACIT-F score 42 vs 40 ; p=0.041). Polyarticular JIA had also better scores on EQ5D and all domains of SF-36, than patients with RA. Patients with ERA reported less depression and anxiety symptoms (0% vs 14.8%; p=0.003% and 9% vs 21.3%; p=0.002) and less fatigue symptoms (45 vs 41; p=0.01) than patients with SpA. Conclusion: Persistent oligoarticular JIA and ERA are the JIA categories in adulthood with better HRQoL. Overall, adult polyarticular and patients with ERA JIA have lower functional impairment and better quality-of-life than patients with RA and SpA.
- Synovial tissue: turning the page to precision medicine in arthritis?Publication . Orr, Carl Kieran; Humby, Frances; Fonseca, João EuricoIt is with great pleasure that we present in this article collection, a timely overview of the rapidly developing field of synovial tissue analysis. Some of the most prominent protagonists in the field have contributed, and the collection walks the reader through everything from the history of the field’s development, to technical aspects of sampling, providing an update on the science and clinical applications, as well as discussing potential future perspectives. A broad consensus exists amongst clinicians and scientists, that a patient-centred, precision medicine approach holds the most promise to improve patient outcomes. The relevance of synovial biopsies in achieving this end is a major theme of this article collection. We are currently at an exciting juncture in this important field. This collection not only discusses the enormous potential of synovial tissue as a research and clinical tool, but also the many challenges in advancing its role in translational and clinical applications. Several key advancements concerning synovial biopsies over the last number of years have together contributed to the rheumatology community discussing in earnest how such sampling can contribute to precision medicine in arthritis.
- Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodiesPublication . Cavagna, Lorenzo; Meloni, Federica; Meyer, Alain; Sambataro, Gianluca; Belliato, Mirko; De Langhe, Ellen; Cavazzana, Ilaria; Pipitone, Nicolò; Triantafyllias, Konstantinos; Mosca, Marta; Barsotti, Simone; Zampogna, Giuseppe; Biglia, Alessandro; Emmi, Giacomo; De Visser, Marianne; Van Der Kooi, Anneke; Parronchi, Paola; Hirschi, Sandrine; da Silva, Jose Antonio Pereira; Scirè, Carlo Alberto; Furini, Federica; Giannini, Margherita; Martinez Gonzalez, Olga; Damian, Laura; Piette, Yves; Smith, Vanessa; Mera-Valera, Antonio; Bachiller-Corral, Javier; Cabezas Rodriguez, Ivan; Brandy-Garcia, Anahy M.; Maurier, François; Perrin, Julie; Gonzalez-Moreno, Juan; Drott, Ulrich; Delbruck, Christiane; Schwarting, Andreas; Arrigoni, Eugenio; Sebastiani, Gian Domenico; Iuliano, Annamaria; Nannini, Carlotta; Quartuccio, Luca; Rodriguez Cambron, Ana B.; Blázquez Cañamero, Maria Á.; Villa Blanco, Ignacio; Cagnotto, Giovanni; Pesci, Alberto; Luppi, Francesco; Dei, Giulia; Romero Bueno, Fredeswinda Isabel; Franceschini, Franco; Chiapparoli, Ilaria; Zanframundo, Giovanni; Lettieri, Sara; De Stefano, Ludovico; Cutolo, Maurizio; Mathieu, Alessandro; Piga, Matteo; Prieto-González, Sergio; Moraes-Fontes, Maria Francisca; Fonseca, João Eurico; Jovani, Vega; Riccieri, Valeria; Santaniello, Alessandro; Montfort, Stephen; Bilocca, David; Erre, Gian Luca; Bartoloni, Elena; Gerli, Roberto; Monti, M. Cristina; Lorenz, Hanns M.; Sambataro, Domenico; Bellando Randone, Silvia; Schneider, Udo; Valenzuela, Claudia; Lopez-Mejias, Raquel; Cifrian, Jose; Mejia, Mayra; Gonzalez Perez, Monserrat-Ixchel; Wendel, Sarah; Fornaro, Marco; De Luca, Giacomo; Orsolini, Giovanni; Rossini, Maurizio; Dieude, Philippe; Knitza, Johannes; Castañeda, Santos; Voll, Reinhard E.; Rojas-Serrano, Jorge; Valentini, Adele; Vancheri, Carlo; Matucci-Cerinic, Marco; Feist, Eugen; Codullo, Veronica; Iannone, Florenzo; Distler, Jorg H.; Montecucco, Carlomaurizio; Gonzalez-Gay, Miguel A.Objectives: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. Methods: We conducted a multicentre, international, retrospective cohort study. Results: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. Conclusions: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.
- B cells on the stage of inflammation in juvenile idiopathic arthritis: leading or supporting actors in disease pathogenesis?Publication . Moura, Rita; Fonseca, João EuricoJuvenile 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.