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In the double-blind, placebo-controlled phase 2 ARGO trial, patients with active psoriatic arthritis treated with a nanobody targeting IL-17A and IL-17F showed substantially better disease response rates compared with those receiving placebo treatment.

In a case series of six patients with multidrug-resistant rheumatoid arthritis, the CD19xCD3-targeting bispecific T cell engager blinatumomab reduced disease activity and led to reductions in autoantibodies.

Discerning which mediators drive pathogenesis in chronic inflammatory diseases can be complex: immune cells can release various pathogenic cytokines, and numerous cytokines may either cause one specific disease or many. Human validation and mechanistic studies will be necessary to identify the key immune cells and cytokines for a given inflammatory disorder and to pinpoint which cytokine might be the appropriate target for tackling each disease. In 'Bedside to Bench', Georg Schett et al. discuss how human trials targeting different cytokines suggest the existence of a hierarchical framework of cytokines that defines groups of chronic inflamatory diseases rather differently from the homogenous molecular disease pattern previously assumed. In 'Bench to Bedside', Vijay Kuchroo and Dominique Baeten peruse the role of interleukin-17A as drug target in several autoimmune diseases to highlight how success in the clinic will need understanding of pathogenic pathways and the immunological and tissue context of each inflammatory disease.

In this second in a series of three Reviews on Wnt–β-catenin signaling, Prof. Schett and colleagues discuss the molecular regulation of joint remodeling associated with chronic arthritis and the role of Wnt proteins in determining the differences in clinical presentation of inflammatory arthropathies, as well as implications for future therapy.

Results from a study of five patients with refractory systemic lupus erythematosus, who were treated with anti-CD19 CAR T cell therapy under a compassionate-use program, demonstrate remission of SLE disease with follow-up of up to 17 months.

In 2012, several new concepts emerged that widen our view of the regulation of bone mass in health and disease. Three key studies outline these discoveries, which affect our understanding of the skeletal system, particularly its physiological function and the changes it undergoes during inflammatory disease.

Cytokine storm seems to be a common feature of severe COVID-19 pathology. Here, the authors show a reduced rate of SARS-CoV2 positivity in a large population of patients with immune-mediated inflammatory diseases if they are already being treated with cytokine or JAK inhibitors, indicating these treatments are safe to continue and are possibly protective against COVID19.

Type 2 immune responses are viewed as opposites of Type 1 and 17 responses. Here the authors show that activation of Type 2 immunity by helminth infection counteracts the development of inflammatory arthritis, a type 17-mediated pathology, via IL-4/IL-13- STAT6 signalling and eosinophil activation.

Glucocorticoids reprogram the mitochondrial metabolism of macrophages, resulting in increased and sustained production of the anti-inflammatory metabolite itaconate and, as a consequence, inhibition of the inflammatory response.

The link between chronic inflammation and bone loss has been the subject of intense research over the past decade. This has led to the identification of key molecules that bridge the gap between immune function and bone turnover, including receptor activator of NFκB ligand, which represents a potential therapeutic target for patients with chronic inflammatory arthritis, and is the subject of this review.

In a patient with treatment-refractory idiopathic inflammatory myositis, reinfusion of CD19 CAR T cells following disease relapse led to the development of T cells targeting the CD19 CAR and no clinical improvement, with drug-free remission induced again after treatment with BCMA CAR T cells.

In this article, the authors critically appraise the current model of opinion-based academia–industry interactions, and advocate for a realignment towards partnerships that foster innovation and knowledge.

Psoriasis is a partially heritable skin disorder, the genetic basis of which is not fully understood. Here, the authors use genome-wide association meta-analysis to discover psoriasis susceptibility loci and genes, which encode existing and potential new drug targets.

Here, the authors identify interleukin-3 as a predictive marker for severity and outcome of SARS-CoV-2 infection in a multi-center, prospective study and find that patients with severe COVID-19 have reduced circulating plasmacytoid dendritic cell levels compared to non-severe COVID-19 patients.

Immunoglobulin A (IgA) has two subclasses, IgA1 and IgA2, but differential effects on inflammation are unclear. Here the authors show that IgA2, when compared with IgA1, has stronger pro-inflammatory functions associated with changed glycosylation and higher disease scores in patients with rheumatoid arthritis.

Anaemia as a result of chronic inflammation is common in patients with rheumatic disease. In this Review, Weiss and Schett provide a broad overview of the topic, covering the pathogenesis, diagnosis, treatment and management of anaemia in inflammatory rheumatic disease, offering practical guidance for clinicians.

In this Review, the authors summarize the substantial progress that has been made in understanding the pathophysiology of bone erosions and discuss the improvements in the diagnosis, monitoring and treatment of such lesions.

The IgG sugar moiety modulates the binding of immune complexes to their Fcγ receptors resulting in pro- or anti-inflammatory response. This study shows that IgG sialylation also affects osteoclastogenesis and bone mass in mice and humans, identifying a new link between bone and the immune system.

Stefan Kiechl and colleagues show that blockade of receptor activator of nuclear factor-κB (RANKL) signaling in hepatocytes by cell type–specific genetic deletion of its receptor promotes greater insulin sensitivity in both a genetic and a nutritional model of type 2 diabetes. They also show epidemiological evidence that elevated serum concentrations of soluble RANKL are a risk factor for the development of this disease.

Here the authors use positron emission tomography to visualize fibroblasts in patients with arthritis and combined with spatial transcriptomic data show that these cells undergo a phenotypic shift upon resolution of inflammation. A CD200⁺DKK3⁺ fibroblast subset promotes this resolution by inhibiting tumor necrosis factor and interleukin-17A.

The IL-23–IL-17 signalling pathway has paradoxical effects on bone remodelling in psoriatic arthritis and ankylosing spondylitis. In this Review, Gravallese and Schett examine the evidence for and outline the reasons behind this paradox.

Eosinophils are traditional immune effectors involved in tissue homeostasis. In this study, eosinophils emerge as key regulators of bone homeostasis by interacting with osteoclasts, inhibiting their differentiation and pathological bone loss.

Immune-mediated inflammatory diseases are often treated with cytokine blocking therapy. This comment discusses whether such therapies may pose a risk — or even a benefit — in the context of the current COVID-19 pandemic.

Bone marrow-derived cells can rapidly enter the systemic circulation, but how this is achieved is unclear. Grüneboom et al. identify tiny capillaries, termed trans-cortical vessels (TCVs), that connect the bone marrow cavity to the systemic vasculature, and show that the majority of blood in long bones passes through TCVs.

Uncontrolled activation of fibroblasts contributes to tissue fibrosis and organ dysfunction. Here the authors demonstrate that the epigenetic control of autophagy is disturbed by a TGFβ-dependent downregulation of MYST1 in systemic sclerosis patients. Restoration of the epigenetic control of autophagy reduces fibroblast activation and ameliorates fibrotic tissue remodeling.

Members of the IL-1 family of cytokines have been implicated in several autoimmune diseases, including rare hereditary syndromes and more frequent diseases such as gout. Once processed and activated, IL-1α and IL-1β promote inflammation, monocyte and neutrophil infiltration and, ultimately, tissue damage and stress. Therapies that target IL-1 have already shown clinical efficacy, and are enabling a better understanding of the biology of this cytokine family.

Transferrin receptor 2 (Trf2) is known to regulate iron homeostasis through its action in the liver. Here the authors report a previously unrecognised role of Trf2 in regulating bone homeostasis mediated by modulation of BMP signalling specifically on osteoblasts.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disorder characterised by asthma, eosinophilia and vasculitis. Here, the authors describe a genome-wide association study of EGPA that reveals clinical and genetic differences between subgroups stratified by autoantibody status (ANCA).

This article provides an overview of the pathophysiology of enthesitis, from induction and inflammation to tissue proliferation and bone formation. Building on these pathophysiological concepts, the clinical presentation, assessment and treatment of enthesitis are also discussed.

The transcription factor PU.1 is an essential regulator of the pro-fibrotic gene expression program in fibroblasts; PU.1 expression is upregulated in various fibrotic diseases, whereas inactivation of PU.1 induces regression of fibrosis in a number of organs.

Short-chain fatty acids (SCFA) are a main class of metabolites derived from fermentation of dietary fibre in the intestine. Here, the authors show that dietary administration of SCFA is associated with inhibition of osteoclast differentiation, increased bone mass, and reduced pathological bone loss in mice.

Krönke and colleagues show that the cytokine IL-23 controls the glycosylation profile and inflammatory activity of autoantibodies through control of sialyltransferase activity in plasma cells mediated by the T_H17 subset of helper T cells.

Pancreatitis often develops as a consequence of ductal obstruction. Here, the authors show that bicarbonate ions initiate the release of neutrophil extracellular traps (NETs) that form pancreatic ductal aggregates and occlude the ducts, thereby driving pancreatitis in mice and humans.

Aberrant activation of the TGF-β pathway leads to fibrotic disease. Distler and colleagues show that TGF-β-mediated fibrosis requires the decrease of Dickkopf-1, an antagonist of canonical Wnt signalling, suggesting that the two pathways interact for the manifestation of this disease.

CAR T cell therapy shows promise for achieving long-term drug-free remission in various autoimmune diseases. This Review discusses the ongoing challenges and unanswered questions of CAR T cell therapy in autoimmune diseases, including pre-procedural, procedural and post-procedural considerations.

B cells are important for antigen presentation and antibody production in humoral immunity, but are also increasingly recognized for their immune regulatory functions. Here the authors show that HIF-1α, a hypoxia-induced transcription factor, is important for controlling IL-10 induction in and immune-suppressive activity of B cells.

This Perspective article explores similarities in the inflammatory processes underlying coronavirus disease 2019 (COVID-19) and rheumatoid arthritis, including the role of pro-inflammatory cytokines and the potential of anti-cytokine therapies to treat COVID-19, as well as the effect of the COVID-19 pandemic on rheumatology.

Intestinal dysbiosis is associated with an ever-growing list of autoimmune diseases. Here the authors show that both mice and humans with autoimmune arthritis can have dysbiosis and barrier leakiness prior to major signs of inflammatory arthritis, and treatment of mice with a zonulin antagonist can limit collagen-induced arthritis.