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Biotechnological monoclonal antibodies and receptor antagonists capable of targeting specific inflammatory actors, such as cytokines, cytokines receptors, co-stimulatory molecules or leukocyte populations, have emerged as an alternative to conventional therapies for treating systemic inflammatory diseases with immune pathogenesis. However, there is no doubt that, with a frequency that is not exceptionally high but also not negligible, immunotherapies can favour the development of systemic and organ-specific immune-mediated disorders. It has become increasingly evident that interference with a specific immune pathway may favour the activation of opposing compensatory signalling, which may exacerbate underlying subclinical disorders or cause immune-mediated diseases completely different from the underlying disease. The 'compensatory immunological switch' has emerged primarily in patients treated with tumor necrosis factor (TNF) -α inhibitors, the first biological drugs approved for treating systemic inflammatory diseases with immune pathogenesis. In this Review, we describe the clinical features and predisposing factors of the main TNF-α inhibitor-related autoimmune disorders, organising them into subclinical serological autoimmunity, autoimmune disorders other than those for which TNF-α inhibitors are indicated, and paradoxical reactions. We also discuss the underlying pathogenetic mechanisms and precautions for use in the therapeutic management of these patients. Better understanding of the complex phenomenon of the 'compensatory immunological switch', which TNF-α inhibitors and other biological drugs might trigger, can help not only appropriately managing immune-mediated disorders, but also better interpreting the heterogeneity of the pathogenetic mechanisms underlying certain chronic inflammatory conditions that, although different from each other, are arbitrarily placed in the context of overly generic nosological entities., Competing Interests: Declaration of Competing Interest CM reports grant/research support from AbbVie, Eli Lilly, Roche and Novartis, and personal fees from AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galapagos, MSD, Novartis, Pfizer, Roche, Janssen. SB reports grant/research support from Pfizer and personal fees from AbbVie, Bristol-Myers Squibb, Eli Lilly, Galapagos, Pfizer and Novartis. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Serena Bugatti, Carlomaurizio Montecucco reports a relationship with AbbVie Inc. that includes: consulting or advisory and speaking and lecture fees. Serena Bugatti, Carlomaurizio Montecucco reports a relationship with Bristol-Myers Squibb Company that includes: consulting or advisory and speaking and lecture fees. Serena Bugatti, Carlomaurizio Montecucco reports a relationship with Eli Lilly and Company that includes: consulting or advisory and speaking and lecture fees. Serena Bugatti, Carlomaurizio Montecucco reports a relationship with Galapagos that includes: consulting or advisory and speaking and lecture fees. Serena Bugatti, Carlomaurizio Montecucco reports a relationship with Janssen Pharmaceuticals Inc. that includes: consulting or advisory and speaking and lecture fees. Serena Bugatti, Carlomaurizio Montecucco reports a relationship with Novartis that includes: consulting or advisory and speaking and lecture fees. Serena Bugatti, Carlomaurizio Montecucco reports a relationship with Pfizer that includes: consulting or advisory and speaking and lecture fees., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Autoimmune diseases (AID) are increasingly prevalent conditions which comprise more than 100 distinct clinical entities that are responsible for a great disease burden worldwide. The early recognition of these diseases is key for preventing their complications and for tailoring proper management. In most cases, autoantibodies, regardless of their potential pathogenetic role, can be detected in the serum of patients with AID, helping clinicians in making a definitive diagnosis and allowing screening strategies for early -and sometimes pre-clinical- diagnosis. Despite their undoubted crucial role, in a minority of cases, patients with AID may not show any autoantibody, a condition that is referred to as seronegative AID. Suboptimal accuracy of the available laboratory tests, antibody absorption, immunosuppressive therapy, immunodeficiencies, antigen exhaustion, and immunosenescence are the main possible determinants of seronegative AID. Indeed, in seronegative AID, the diagnosis is more challenging and must rely on clinical features and on other available tests, often including histopathological evaluation and radiological diagnostic tests. In this review, we critically dissect, in a narrative fashion, the possible causes of seronegativity, as well as the diagnostic and management implications, in several AID including autoimmune gastritis, celiac disease, autoimmune liver disease, rheumatoid arthritis, autoimmune encephalitis, myasthenia gravis, Sjögren's syndrome, antiphospholipid syndrome, and autoimmune thyroid diseases., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The development of rheumatoid arthritis (RA), at least in its autoantibody-positive subset, evolves through a series of events starting well before the appearance of synovitis. The distinction between 'early' and 'established' RA is, therefore, an evolving concept. In routine practice, however, the management of RA still starts with the occurrence of clinically detectable synovitis. As such, the synovial membrane remains a major target for the exploitation of possible stage-specific drivers of the disease. The recognition of a 'window of opportunity', in which treatment is more likely to succeed, raises the hypothesis that there might be a period in which the biological processes of RA are less mature and potentially reversible. The present review aims to provide a general picture of the modifications occurring in RA synovium, analysing the contribution of both infiltrating immune cells and stromal cells. When available, differences between early and established RA will be discussed., Competing Interests: Declaration of Competing Interest None to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Advances in our understanding of the key mediators of chronic inflammation and tissue damage in rheumatoid arthritis (RA) have fostered the development of targeted therapies and greatly expanded the available treatment options. Abatacept, a soluble human fusion protein that selectively modulates the co-stimulatory signal required for full T-cell activation, is approved for the treatment of moderate to severe RA in the United States, Canada, and the European Union. This review summarises the data on efficacy (disease activity, quality of life, prevention of structural damage) and safety from randomised clinical trials of abatacept plus methotrexate in patients with: i) active RA and an inadequate response to methotrexate who are naïve to biological disease-modifying anti-rheumatic drugs; and ii) methotrexate-naïve early RA with poor prognostic factors. Novel imaging outcomes and biological changes induced by abatacept treatment are also briefly reviewed. Optimal use of abatacept as a first-line biological therapy is discussed in light of the current recommendations and guidelines., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Abatacept is a selective T cell co-stimulation modulator that was first approved by the Italian Medicines Agency and reimbursed by the Italian National Health Service when used to treat active rheumatoid arthritis "not sufficiently responsive to other disease-modifying anti-rheumatic drugs (DMARDs) including at least one TNF inhibitor", and is now also approved as a first line biological agent. The aim of this review is to summarise the safety data collected in clinical trials and observational studies., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.autrev.2013.06.008. The duplicate article has therefore been withdrawn., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The early diagnosis of new-onset rheumatoid arthritis (RA) has become a major objective for rheumatologists in order to identify a management strategy able to change the natural history of the disease and to prevent joint damage and functional impairment. Emergent evidence emphasizes the benefits of early aggressive therapy of RA. By the nineties, early arthritis cohorts have been collected throughout the world with the aim to increase the early referral of patients with early onset disease by the general practitioners and to collect data on the development of full-blown RA. The frequency of undifferentiated arthritis (UA) ranged from 23% to 81% in these early cohorts with most of them reporting a rate of 30%. The transition rate from UA to RA was between 13% and 54%. A percentage of 20-60% of patients with UA had a self-limiting disease. Our article deals with the controversy existing in the management of UA. Should every patient with UA be treated? Could patients with a favorable disease course be exposed to unnecessary risk with initiation of aggressive therapy with synthetic disease-modifying anti-rheumatic drugs (DMARDs) or biologic agents? The pros and cons of treating patients with UA are examined., (Copyright © 2011. Published by Elsevier B.V.)

B cells play an important role in the pathogenesis of rheumatoid arthritis (RA). Rituximab is a chimeric monoclonal antibody that depletes B-cells by binding to the CD20 surface antigen that has been approved for the treatment of RA. Its efficacy has been clearly demonstrated by different clinical trials and, recently, in long-term observational studies. The use of rituximab in clinical practice has highlighted its efficacy and safety over more than 5 years of treatment, as well as to try to understand the timing for retreatment of patients relapsing after a good initial response.

Though its etiology remains unknown thus far, the role that autoimmune processes play in rheumatoid arthritis (RA) pathogenesis has been widely proven. Given the easier accessibility of humoral components, the first feature of this contribution to be recognized has been the occurrence of the so-called rheumatoid factor in a large proportion of RA patients. This antibody recognizes the Fc portion of human IgG. By investigating RA pathologic processes and also through experimental models where immune complexes play a fundamental role, many other autoantibodies have then come to our knowledge to be associated with the disease. Their presence and persistence implies that clones of autoreactive B cells survive and proliferate in RA patients under a continuous stimulation. Whether this is a mechanism of disease initiation or just an epiphenomenon is still unclear but no doubt exists that autoantibodies represent a very useful tool in both diagnostic and prognostic terms. Being much more than simple autoantibody producers, B cells are able to secrete many important cytokines and to efficiently present antigens to T lymphocytes in the synovial environment. All of these functions are essential in the development of RA, and lately have claimed attention as B cell depletion has become a common and effective strategy of treatment in RA.

CCL21 is a homeostatic lymphoid chemokine instrumental in the recruitment and organization of T cells and dendritic cells into lymphoid T areas. In human secondary lymphoid organs (SLOs), CCL21 is produced by cells distributed throughout the T zone, whereas high endothelial venules (HEVs) lack CCL21 mRNA. A critical question remains whether the development of ectopic lymphoid tissue (ELT) in chronic inflammation recapitulates the features of SLOs. Thus, we systematically investigated in situ the cellular sources of CCL21 in SLOs and ELTs in several human diseases characterized by lymphoid neogenesis. By in situ hybridization and the use of combinatorial cell markers, we show that CCL21-producing vessels in inflamed tissues systematically display typical markers of lymphatic vessels, whereas, as in SLOs, ectopic HEVs do not synthesize detectable levels of CCL21. We also provide first-time evidence that a common pattern of CCL21 expression by CD45-negative myofibroblast-like cells localized in extra-HEV position and organized in a fibroblastic reticular network similarly characterizes human SLOs and organized ELTs. Altogether, our results demonstrate that in humans the pattern of CCL21 production in SLOs is maintained during inflammation and that the phenotypic and functional properties of stromal cells, found in SLO T-cell areas, are reproduced at ectopic sites.

Though its etiology remains unknown thus far, the role that autoimmune processes play in rheumatoid arthritis (RA) pathogenesis has been widely proven. Given the easier accessibility of humoral components, the first feature of this contribution to be recognized has been the occurrence of the so-called rheumatoid factor in a large proportion of RA patients. This antibody recognizes the Fc portion of human IgG. By investigating RA pathologic processes and also through experimental models where immune complexes play a fundamental role, many other autoantibodies have then come to our knowledge to be associated with the disease. Their presence and persistence implies that clones of autoreactive B cells survive and proliferate in RA patients under a continuous stimulation. Whether this is a mechanism of disease initiation or just an epiphenomenon is still unclear but no doubt exists that autoantibodies represent a very useful tool in both diagnostic and prognostic terms. Being much more than simple autoantibody producers, B cells are able to secrete many important cytokines and to efficiently present antigens to T lymphocytes in the synovial environment. All of these functions are essential in the development of RA, and lately have claimed attention as B cell depletion has become a common and effective strategy of treatment in RA.