The mitochondrion is an intracellular organelle thought to originate from endosymbiosis between an ancestral eukaryotic cell and an α-proteobacterium. Mitochondria are the powerhouses of the cell, and can control several important processes within the cell, such as cell death. Conversely, dysregulation of mitochondria possibly contributes to the pathophysiology of several autoimmune diseases. Defects in mitochondria can be caused by mutations in the mitochondrial genome or by chronic exposure to pro-inflammatory cytokines, including type I interferons. Following the release of intact mitochondria or mitochondrial components into the cytosol or the extracellular space, the bacteria-like molecular motifs of mitochondria can elicit pro-inflammatory responses by the innate immune system. Moreover, antibodies can target mitochondria in autoimmune diseases, suggesting an interplay between the adaptive immune system and mitochondria. In this Review, we discuss the roles of mitochondria in rheumatic diseases such as systemic lupus erythematosus, antiphospholipid syndrome and rheumatoid arthritis. An understanding of the different contributions of mitochondria to distinct rheumatic diseases or manifestations could permit the development of novel therapeutic strategies and the use of mitochondria-derived biomarkers to inform pathogenesis.

To evaluate the effect of MTX withdrawal on disease activity and remission rate in patients at target after treatment with biologic DMARDs (bDMARDs)/targeted synthetic DMARDs (tsDMARDs) plus MTX.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), that share features of pauci-immune small-vessel vasculitis and the positivity of ANCA targeting proteinase-3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). AAV syndromes are rare, complex diseases and their aetio-pathogenesis is mainly driven by the interaction between environmental and genetic factors. In patients with GPA and MPA, the genetic associations are stronger with ANCA specificity (PR3- versus MPO-ANCA) than with the clinical diagnosis, which, in keeping with the known clinical and prognostic differences between PR3-ANCA-positive and MPO-ANCA-positive patients, supports an ANCA-based re-classification of these disorders. EGPA is also made up of genetically distinct subsets, which can be stratified on ANCA-status (MPO ANCA-positive versus ANCA-negative); these subsets differ in clinical phenotype and possibly in their response to treatment. Interestingly, MPO-ANCA-positive patients with either MPA or EGPA have overlapping genetic determinants, thus strengthening the concept that this EGPA subset is closely related to the other AAV syndromes. The genetics of AAV provides us with essential information to understand its varied phenotype. This Review discusses the main findings of genetic association studies in AAV, their pathogenic implications and their potential effect on classification, management and prognosis.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that predominantly affects the axial skeleton, although it can affect peripheral joints, and extra-musculoskeletal manifestations also occur. Historically, axSpA was thought to be a disease predominantly seen in men, although with the advent of magnetic resonance imaging techniques and advances in research, this dogma has been challenged and refuted. Sex and gender are different concepts, and both can have a role in disease. In axSpA, consideration of the influence of sex and gender on the disease phenotype is necessary to predict outcomes and to enable the development of therapeutic approaches that are best suited to individual patients.

The IL-23 p19-subunit inhibitor guselkumab has been previously compared with other targeted therapies for PsA through network meta-analysis (NMA). The objective of this NMA update was to include new guselkumab COSMOS trial data, and two key comparators: the IL-23 inhibitor risankizumab and the Janus kinase (JAK) inhibitor upadacitinib.

To summarize evidence on the relationship between early treatment (definition based on symptom/disease duration or radiographic damage) and treatment clinical response in patients with SpA.

Type I interferons have been suspected for decades to have a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). Evidence has now overturned several long-held assumptions about how type I interferons are regulated and cause pathological conditions, providing a new view of SLE pathogenesis that resolves longstanding clinical dilemmas. This evidence includes data on interferons in relation to genetic predisposition and epigenetic regulation. Importantly, data are now available on the role of interferons in the early phases of the disease and the importance of non-haematopoietic cellular sources of type I interferons, such as keratinocytes, renal tubular cells, glial cells and synovial stromal cells, as well as local responses to type I interferons within these tissues. These local effects are found not only in inflamed target organs in established SLE, but also in histologically normal skin during asymptomatic preclinical phases, suggesting a role in disease initiation. In terms of clinical application, evidence relating to biomarkers to characterize the type I interferon system is complex, and, notably, interferon-blocking therapies are now licensed for the treatment of SLE. Collectively, the available data enable us to propose a model of disease pathogenesis that invokes the unique value of interferon-targeted therapies. Accordingly, future approaches in SLE involving disease reclassification and preventative strategies in preclinical phases should be investigated.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that predominantly affects the joints. The prevalence of RA varies globally, with generally a higher prevalence in industrialized countries, which may be explained by exposures to environmental risk factors, but also by genetic factors, differing demographics and under-reporting in other parts of the world. Over the past three decades, strong trends of the declining severity of RA probably reflect changes in treatment paradigms and overall better management of the disease. Other trends include increasing RA prevalence. Common risk factors for RA include both modifiable lifestyle-associated variables and non-modifiable features, such as genetics and sex. A better understanding of the natural history of RA, and of the factors that contribute to the development of RA in specific populations, might lead to the introduction of specific prevention strategies for this debilitating disease.

In the management of rheumatic musculoskeletal disorders (RMDs), regular physical activity (PA) is an important recognized non-pharmacological intervention. This systematic review and meta-analysis aims to evaluate how the use of wearable devices (WDs) impacts physical activity in patients with noninflammatory and inflammatory rheumatic diseases.

Idiopathic multicentric Castleman disease (iMCD) is an infrequent and life-threatening disorder characterized by systemic inflammatory symptoms, generalized lymphadenopathy, polyclonal lymphocyte proliferation and organ dysfunction caused by a hyperinflammatory state. It accounts for one-third to one-half of all multicentric Castleman disease (MCD) cases. iMCD is often associated with autoimmune manifestations that may precede the iMCD diagnosis, be identified at the same time or follow it. In addition, iMCD may also coincide with a number of autoimmune diseases (such as psoriasis or myasthenia gravis) or autoinflammatory diseases (such as familial Mediterranean fever). Moreover, diverse inflammatory disorders, such as rheumatoid arthritis, systemic lupus erythematosus, adult-onset Still disease, systemic juvenile idiopathic arthritis, immunoglobulin (IgG4) related disease, or the recently described VEXAS syndrome, can present clinical features or lymphadenopathy with histopathological 'Castleman-like' findings compatible with those of iMCD. Given the iMCD clinical heterogeneity and the overlap with other autoimmune or autoinflammatory disorders, iMCD diagnosis can be challenging. In this review, we explore the overlap between iMCD and inflammatory diseases and provide practical guidance on iMCD diagnosis in order to avoid misdiagnosis and confusion with other autoimmune or autoinflammatory conditions.

Gout management involves two broad aspects: treatment of gout flares to provide rapid symptomatic relief and long-term urate-lowering therapy to lower serum urate sufficiently to prevent gout flares from occurring. All of the major rheumatology societies recommend a target serum urate of <5 mg/dl (<0.30 mmol/l) or <6 mg/dl (<0.36 mmol/l), both of which are below the point of saturation for urate and therefore lead to monosodium urate crystal dissolution. In this Review, we describe the rationale for treat-to-target urate approach in the long-term management of gout and the current evidence and controversy around the appropriate serum urate targets.

Chronic nonbacterial osteomyelitis (CNO) is a rare inflammatory bone disease. The distinct CNO subtype that affects the anterior chest wall is descriptively named sternocostoclavicular hyperostosis (SCCH) and mainly occurs in adults. Literature on CNO/SCCH is scattered and lacks diagnostic and therapeutic consensus.

In women with systemic autoimmune rheumatic diseases (SARDs), female sexual dysfunction (SD) remains underestimated. We aimed to explore the prevalence and correlates of SD in females with SARDs.

The field of rheumatology has advanced significantly in recent years to provide rheumatologists with an extensive array of medications to combat rheumatic joint conditions. In contrast to an older era, when NSAIDs and other nephrotoxic agents were the mainstay of treatment, modern DMARDs vary considerably in their nephrotoxic potential and their use is not always precluded in populations with pre-existing chronic kidney disease (CKD). This review will explore in detail the safety and efficacy profiles of medications used to treat rheumatologic disease, specifically in the setting of CKD. Specifically, we discuss both traditional agents used, i.e. NSAIDs, CSs and conventional synthetic DMARDs, as well as novel biologic DMARDs and targeted synthetic DMARDs. Anti-gout prescribing in CKD is also reviewed. We aim to provide practical guidance to rheumatologists, nephrologists and general physicians when prescribing these medications in the setting of CKD.

Does age substantially affect the emergence of human immune-mediated arthritis? Children do not usually develop immune-mediated articular inflammation during their first year of life. In patients with juvenile idiopathic arthritis, this apparent 'immune privilege' disintegrates, and chronic inflammation is associated with variable autoantibody signatures and patterns of disease that resemble adult arthritis phenotypes. Numerous mechanisms might be involved in this shift, including genetic and epigenetic predisposing factors, maturation of the immune system with a progressive modulation of putative tolerogenic controls, parallel development of microbial dysbiosis, accumulation of a pro-inflammatory burden driven by environmental exposures (the exposome) and comorbidity-related drivers. By exploring these mechanisms, we expand the discussion of three (not mutually exclusive) hypotheses on how these factors can contribute to the differences and similarities between the loss of immune tolerance in children and the development of established immune-mediated arthritis in adults. These three hypotheses relate to a critical window in genetics and epigenetics, immune maturation, and the accumulation of burden. The varied manifestation of the underlying mechanisms among individuals is only beginning to be clarified, but the establishment of a framework can facilitate the development of an integrated understanding of the pathogenesis of arthritis across all ages.

An increased risk of adverse maternal and foetal pregnancy complications (including pre-eclampsia, intrauterine growth restriction, and small for gestational age) is well described in women with autoimmune rheumatic disease (ARD) compared with the general population (GenPop). It is less clear, however, whether this risk of adverse pregnancy outcome (APO) also exists in women with 'preclinical ARD' (pre-ARD) before they are diagnosed with an ARD many years post-partum. Therefore, we have undertaken a systematic review of the available evidence on APO in patients who subsequently were diagnosed with a rheumatic disease to identify whether there is an increased risk in pre-ARD.

Psoriatic arthritis (PsA) is an inflammatory musculoskeletal disease with a chronic, progressive course. Various aspects of PsA, including its clinical features, disease course and response to treatment, are influenced by sociodemographic characteristics of the patient. This includes patient sex, the biological attributes associated with being male or female, and gender, a sociocultural construct that comprises attitudes, traits and behaviours associated with being a man or a woman. An understanding of sex- and gender-related differences in PsA, as well as their underlying mechanisms, is therefore important for individualized care. In this narrative review, the influence of sex and gender on PsA manifestation and course, patient function and quality of life, and their association with comorbidities are described. Sex- and gender-related disparities in response to advanced therapies and their potential underlying mechanisms are delineated. Differences in pathophysiological mechanisms between male and female patients including genetics, immune and hormonal mechanisms are discussed. Finally, fertility and pregnancy outcomes in PsA are outlined. By adopting sex and gender lenses, this review is aimed at highlighting key differences between male and female patients with PsA and uncovering mechanisms underlying these differences, ultimately promoting individualized care of men and women with PsA and informing future research in this area.

The COVID-19 pandemic represents one of the biggest challenges of the 21st century. In addition to the general effect on society and health-care systems, patients with systemic sclerosis and their physicians face specific challenges related to the chronic nature of their disease, the involvement of multiple organs, and the use of immunosuppressive treatments. Data from registries and single centre cohorts indicate that the risk of contracting SARS-CoV-2 does not seem to increase substantially in people with systemic sclerosis; conversely, severe COVID-19 outcomes are seen more frequently in these patients than in the general population. Vaccination against SARS-CoV-2 is therefore highly recommended for patients with systemic sclerosis; however, no specific recommendations are available regarding the different vaccine platforms. Both patients and physicians should be aware that the effectiveness of vaccines might be reduced in patients taking immunosuppressive therapy, because antibody responses might be blunted, specifically in patients treated with rituximab and mycophenolate mofetil.

Flare is the dominant feature of gout and occurs because of inflammatory response to monosodium urate crystals; prevention of gout flares should be the major goal of gout care. However, a paradoxical increase in the risk of flare following initiation of urate-lowering therapy presents considerable challenges for proving the expected long-term benefits of flare prevention in clinical trials. Nevertheless, excluding from enumeration flares that occur in the initial post-randomization period (which can last several months to 1 year) can threaten the core benefits of randomization: the characteristics of the remaining participants can differ from those who were randomized, introducing potential bias from confounding (both measured and unmeasured); participants who drop out or die are excluded from the analysis, introducing potential selection bias; and, finally, ignoring initial flares underestimates participants' experience during the trial. This Perspective discusses these issues and recommends measures that will allow for high-level evidence that preserves the randomization principle, to satisfy methodological scrutiny and generate robust evidence-based guidelines for gout care.

SSc is an auto-immune disease characterized by life-threatening manifestations such as lung fibrosis or pulmonary arterial hypertension. Symptoms with a detrimental impact on quality of life are also reported and sicca syndrome (xerostomia, xeropthalmia) is present in up to 80% of patients with SSc. Sicca syndrome can occur in the absence of overlap with Sjögren's disease and recent studies highlight that fibrosis of minor and major salivary glands, directly linked to the pathogenesis of SSc, could be a major contributor of xerostomia in SSc. This narrative review provides an overview of the clinical presentation, diagnostic strategies, management and future perspectives on sicca syndrome in patients with SSc.