B cell depletion with rituximab, a chimeric monoclonal antibody that selectively targets B cells by binding CD20, has been used off label in severe and resistant systemic lupus erythematosus (SLE) for over two decades. Several biological mechanisms limit the efficacy of rituximab, including immunological reactions towards the chimeric molecule, increased numbers of residual B cells, including plasmablasts and plasma cells, and a post-treatment surge in B cell-activating factor (BAFF) levels. Consequently, rituximab induces remission in only a proportion of patients, and safety issues limit its use. However, the use of rituximab has established the value of B cell depletion strategies in SLE and has guided the development of several improved B cell depletion therapies for SLE. These include enhanced monoclonal antibodies, modalities that redirect the specificity of patient T cells using chimeric antigen receptor T cells or bispecific T cell engagers, and combination treatment that simultaneously inhibits the BAFF pathway. In this Review, we consider evidence gathered from over two decades of using rituximab in SLE and examine how B cell depletion therapies could be further optimized to achieve immunological and clinical efficacy. In addition, we discuss the prospects of B cell depletion strategies for personalized treatment in SLE based on genetic research and studies in pre-symptomatic individuals.

Prognostic factors in rheumatoid arthritis relate to several aspects, such as prediction of joint damage and loss of function or prediction of response to a particular therapy. For many decades it has been well established that high disease activity, especially exemplified by swollen joint counts and acute phase reactants, is associated with progression of joint damage. In addition, rheumatoid factor (RF) positive patients, but not patients with anti-citrullinated peptide antibodies (ACPA) are particularly prone to high disease activity and joint destruction. Newer studies have looked at molecular markers, but they have either not shown better results than those seen with the long-established ones or have not been sufficiently validated. Most recent insights suggest that high C-reactive protein levels may predict a particularly good response to IL-6 blockade, but not to other therapies, and that high RF-levels may be associated with better responses to Fc-free monoclonal antibodies than molecules containing an Fc-region. It is hoped, however, that with newer techniques and better insight into RA pathogenesis research may come up with even better molecular markers than currently available to predict responses to specific drugs in the not-too-distant future.

Health disparities in rheumatic disease are well established and urgently need addressing. Obstacles to precision medicine equity span both the clinical and the research domains, with a focus placed on structural barriers limiting equitable health care access and inclusivity in research. Less articulated factors include the use of inaccurate population descriptors and the existence of research silos in rheumatology research, which creates a knowledge gap that precludes addressing the health disparities and fulfilling the goals of precision medicine to understand the 'full patient'. The biopsychosocial model is a research framework that intertwines layers of biological and environmental effects to understand disease. However, very limited rheumatology research bridges across molecular and epidemiological studies of environmental exposures, such as physical and social determinants of health. In this Review, we discuss clinical obstacles to health care equity, including access to health care and the use of inaccurate language when labelling population groups. We explore the goals and data needed for research under the biopsychosocial model. We describe results from a rheumatic disease literature search that highlights the paucity of studies investigating the molecular influences of systemic exposures. We conclude with a list of considerations and recommendations to help achieve equitable precision medicine.

The RF is a representative autoantibody against the crystallizable fragment (Fc) of denatured IgG that is primarily detected in patients with RA. Although five types of TNF inhibitors can be used to treat RA, no guidelines are available for selecting the appropriate inhibitor for treatment. High serum RF levels are associated with high disease activity, progressive joint destruction, life prognosis associated with organ damage, decreased treatment responsiveness to TNF inhibitors and other drugs and low treatment retention rates. Meanwhile, certolizumab pegol (CZP), a TNF inhibitor without the Fc region, remains at high concentrations in the blood. Unlike other antibody drugs with the Fc region, CZP maintains efficacy in patients with high serum RF levels. When serum IgM-RF levels are high, antibody drugs with the Fc region are more likely to bind to IgM-RF and be degraded. Thus, CZP without the Fc region may be more favourable for patients with high serum RF levels.

The specificity of US for enthesitis in PsA is unclear. The objective was to analyse the specificity of US enthesitis in Mode B and using power Doppler for the diagnosis of PsA through a systematic review with meta-analysis.

To summarize and evaluate Cochrane reviews of pharmacological therapies for adults with fibromyalgia syndrome (FMS) pain.

Imaging has transformed the understanding of inflammatory and degenerative arthritis in both peripheral and axial disease. In axial inflammation, fat suppression magnetic resonance imaging (MRI) has unravelled the role of sub-fibrocartilaginous osteitis in axial spondyloarthritis and the role of peri-entheseal vertebral body osteitis and subsequent spinal new bone formation. Established or late-stage axial psoriatic arthritis (PsA) cases often exhibit impressive para-marginal or chunky syndesmophytosis on conventional X-ray that pathologically represents entheseal soft tissue ossification. However, the spinal entheseal soft tissue and contiguous ligamentous tissues are poorly visualized on MRI in subjects with early inflammatory back pain including those with axial PsA. In this article, we highlight the need for imaging modalities to discern the crucial soft tissue "ligamentous" component of axial PsA towards diagnosis, prognosis and therapy validation. We issue a clarion call to focus advanced imaging methodology on spinal ligamentous soft tissue that represents the last hidden backwater of PsA immunopathology that needs visualization to fully decipher axial PsA pathogenesis. This in combination with the existing ability to visualize ligamentous bony anchorage site osteitis is needed to define a gold standard test for axial PsA.

Axial involvement in psoriatic arthritis (PsA) has been a major feature of the disease since the original description by Wright and Moll. However, despite over 50 years of study, there is still no accepted definition of axial PsA, nor validated classification criteria. Numerous observational studies have described a phenotype of axial involvement that differs from classical ankylosing spondylitis (AS or axial spondyloarthritis) both clinically and radiographically, and in the frequency of the HLA-B27 antigen. These differences are important clinically, as axial PsA may be less prominent than AS, and in terms of treatment. This short review discusses these issues and offers some clarification for clinicians.

This scoping review sought to summarize the current knowledge on the epidemiology, pathogenesis and clinical presentation of, and the investigations that may help characterize faecal incontinence (FI) in patients with SSc.

Antigen-specific therapies have a long history in the treatment of allergy but have not been successful in autoimmunity. However, in the past 20 years, advances in the definition of the self-antigens that promote autoimmunity and the growing understanding of the mechanisms that maintain tolerance in health but fail in autoimmunity have led to antigen-specific approaches being considered for the treatment of autoimmune diseases. The core goal of each antigen-specific treatment approach is to remove the immune response that promotes autoimmunity whilst sparing protective responses. Approaches to antigen-specific therapy range from targeted deletion of autoreactive lymphocytes to tolerization of autoreactive T cells and active inhibition of autoimmune responses. Technologies such as vaccines, nanoparticles, cell-based therapies and gene editing are being harnessed to achieve these goals. Remaining challenges include the selection of the best antigen to target, modality and timing of administration of these therapies and the disease in which the therapies are used; overcoming these challenges will be vital to move antigen-specific therapies forward. Once established, antigen-specific therapy has the potential to be applied broadly in the area of autoimmunity.

The aetiology of polymyalgia rheumatica (PMR) is unknown. Recently, reports on cases of PMR following the coronavirus disease 2019 (COVID-19) have revived the role of infection as an aetiological or triggering factor. It is estimated that patients with PMR have manifestations of giant cell arteritis (GCA) in < 20% of cases. To date, little is known on the potential role of infectious agents in facilitating this association. Given this background, we performed a review of published literature. Our first aim was to review and discuss the relationship between PMR and infective agents. Secondly, we compared data of PMR-only patients with PMR and overlapping GCA to seek any commonalities or differences regarding the type of infectious agent in these two subgroups.

Systemic autoinflammatory diseases caused by dysregulation of the innate immunity are a known cause of recurrent fevers. We present the molecular diagnosis results of 12 children with recurrent fever, analyzing the correlation between molecular findings and clinical symptoms. No pathogenic variants confirming autoinflammatory disease were found. One child was diagnosed with SRP54 deficiency, linked to congenital neutropenia with a cyclic pattern. Variants of uncertain significance were found in 6 patients in genes associated with autoinflammatory disorders, though two lacked clinical correlation. Variants of uncertain significance in the NLRC4 gene were detected in 2 patients with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome, in the PLSG2 gene in 1 child with systemic juvenile idiopathic arthritis, and in the MEFV gene in 1 patient with syndrome of uncertain recurrent fever. COVID-19 was identified as a triggering factor in 54.5% of cases. Further research is needed to clarify the role of genetic variants and environmental factors in recurrent fevers.

Nutritional disorders are significant but often underestimated complications in patients with systemic sclerosis (SSc). The most prevalent nutritional disorders in SSc are malnutrition, affecting up to 62.5% of patients, and sarcopenia, with a frequency of up to 42%. Thus, clinical vigilance is recommended for the detection of eating disorders in SSc patients, particularly those with gastrointestinal involvement, cardiopulmonary complications, an advanced disease stage, and high disease activity. Nutritional treatment should be carefully tailored to the patients' clinical condition to ensure that it effectively addresses their specific needs. Studies focusing on enteral nutrition in SSc patients demonstrate its effectiveness in stabilizing or improving nutritional status in malnourished patients. In severe cases, parenteral nutrition offers viable options to support patient health. The findings highlight the importance of early nutritional assessment and intervention in improving patient outcomes and suggest that individualized nutritional therapy can be a critical component of comprehensive care for SSc patients.

Among adults who develop coronavirus disease 2019 (COVID-19), those with rheumatic diseases (RDs) have similar hospitalization rates compared with those without RDs. Similar comparisons are lacking in children, due to the overall rarity of COVID-19-related hospitalization in this population. We aimed to examine the risk factors for COVID-19-related hospitalization in paediatric patients with RDs.

Classic regulatory T (Treg) cells expressing CD4 and the hallmark transcription factor FOXP3 are integral to the prevention of multi-system autoimmunity. However, immune-mediated arthritis is often associated with increased numbers of Treg cells in the inflamed joints. To understand these seemingly conflicting observations, which we collectively describe as 'the Treg paradox', we provide an overview of Treg cell biology with a focus on Treg cell heterogeneity, function and dysfunction in arthritis. We discuss how the inflamed environment constrains the immunosuppressive activity of Treg cells while also promoting the differentiation of TH17-like Treg cell, exTreg cell (effector T cells that were formerly Treg cells), and osteoclastogenic Treg cell subsets that mediate tissue injury. We present a new framework to understand Treg cells in joint inflammation and define potential strategies for Treg cell-directed interventions in human inflammatory arthritis.

HLA-B*27 confers a strong risk of developing spondyloarthritis (SpA), which includes axial SpA with or without peripheral arthritis, enthesitis, acute anterior uveitis and gastrointestinal inflammation. Although no definitive mechanism has been established to explain the role of this HLA class I protein in the pathogenesis of SpA, three main hypotheses have emerged. First is the idea that self-peptides displayed by HLA-B27 resemble microorganism-derived peptides, leading to the expansion of autoreactive CD8+ T cells that trigger disease. The second and third hypotheses focus on aberrant properties of HLA-B27, including its tendency to form cell-surface dimers that can activate innate killer immunoglobulin-like receptors on CD4+ T helper 17 cells, triggering the production of pathogenic cytokines. HLA-B27 also misfolds in the endoplasmic reticulum, which can activate the unfolded protein response, increasing IL-23 expression and thereby promoting the production of type 17 cytokines. HLA-B27 misfolding in mesenchymal stem cells has also been linked to enhanced bone formation by mesenchymal stem cell-derived osteoblasts, which could contribute to structural damage in axial SpA. In this Review we summarize prevailing ideas about the role of HLA-B27 in SpA, discuss the latest developments as well as the gaps in current knowledge, and provide recommendations for future research to address these unmet needs.

Over the past two decades, the number of genetically defined autoinflammatory interferonopathies has steadily increased. Aicardi-Goutières syndrome and proteasome-associated autoinflammatory syndromes (PRAAS, also known as CANDLE) are caused by genetic defects that impair homeostatic intracellular nucleic acid and protein processing respectively. Research into these genetic defects revealed intracellular sensors that activate type I interferon production. In SAVI and COPA syndrome, genetic defects that cause chronic activation of the dinucleotide sensor stimulator of interferon genes (STING) share features of lung inflammation and fibrosis; and selected mutations that amplify interferon-α/β receptor signalling cause central nervous system manifestations resembling Aicardi-Goutières syndrome. Research into the monogenic causes of childhood-onset systemic lupus erythematosus (SLE) demonstrates the pathogenic role of autoantibodies to particle-bound extracellular nucleic acids that distinguishes monogenic SLE from the autoinflammatory interferonopathies. This Review introduces a classification for autoinflammatory interferonopathies and discusses the divergent and shared pathomechanisms of interferon production and signalling in these diseases. Early success with drugs that block type I interferon signalling, new insights into the roles of cytoplasmic DNA or RNA sensors, pathways in type I interferon production and organ-specific pathology of the autoinflammatory interferonopathies and monogenic SLE, reveal novel drug targets that could personalize treatment approaches.

Myositis-specific autoantibodies (MSAs) have become pivotal biomarkers for idiopathic inflammatory myopathies and have revolutionized understanding of the heterogeneous disease spectrum that affects both adults and children. The discovery and characterization of MSAs have substantially enhanced patient stratification based on clinical phenotype, thereby facilitating more precise diagnosis and ultimately improving management strategies. Advances in immunoassay technologies in the past 20 years have further propelled the field forward, enabling the detection of a growing repertoire of autoantibodies with high specificity and sensitivity; however, evolving research over the past decade has revealed that even within antibody-defined subsets, considerable clinical diversity exists, suggesting a broader spectrum of disease manifestations than previously acknowledged. Challenges persist, particularly among patients who are seronegative, where the failure to identify certain rare MSAs stems from the use of diverse detection methodologies and inadequate consensus-guided standardization and validation protocols. Bridging these diagnostic gaps is crucial for optimizing patient care and refining prognostic stratification in idiopathic inflammatory myopathies.

Psoriasis is a chronic inflammatory skin disease that often precedes the development of psoriatic arthritis. Advances over the past 10 years have deepened our understanding of the transition from skin inflammation to joint inflammation, revealing various phases during which genetic, environmental, and immunological factors can affect this transition. In 2023, a European Alliance of Associations for Rheumatology task force outlined key considerations for identifying individuals with subclinical disease from those with clinically stabilised disease. Discerning between subclinical psoriatic arthritis and very early disease is crucial and raises doubts and questions about when an individual transitions from being at risk to having established psoriatic arthritis. Labelling this stage as very early psoriatic arthritis rather than subclinical disease might have substantial clinical and therapeutic implications. This Viewpoint highlights the importance of precisely identifying the different stages of progression of psoriatic arthritis for timely interventions and better outcomes for patients.

To assess the association of aPL and diffuse alveolar haemorrhage (DAH) in patients with SLE by performing a systematic review and meta-analysis.