Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these ...events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management.
First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed.
The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies.
These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.
Tremendous opportunities for health research have been unlocked by the recent expansion of big data and artificial intelligence. However, this is an emergent area where recommendations for optimal ...use and implementation are needed. The objective of these European League Against Rheumatism (EULAR) points to consider is to guide the collection, analysis and use of big data in rheumatic and musculoskeletal disorders (RMDs).
A multidisciplinary task force of 14 international experts was assembled with expertise from a range of disciplines including computer science and artificial intelligence. Based on a literature review of the current status of big data in RMDs and in other fields of medicine, points to consider were formulated. Levels of evidence and strengths of recommendations were allocated and mean levels of agreement of the task force members were calculated.
Three overarching principles and 10 points to consider were formulated. The overarching principles address ethical and general principles for dealing with big data in RMDs. The points to consider cover aspects of data sources and data collection, privacy by design, data platforms, data sharing and data analyses, in particular through artificial intelligence and machine learning. Furthermore, the points to consider state that big data is a moving field in need of adequate reporting of methods and benchmarking, careful data interpretation and implementation in clinical practice.
These EULAR points to consider discuss essential issues and provide a framework for the use of big data in RMDs.
Objective
To predict response to anti–tumor necrosis factor (anti‐TNF) prior to treatment in patients with rheumatoid arthritis (RA), and to comprehensively understand the mechanism of how different ...RA patients respond differently to anti‐TNF treatment.
Methods
Gene expression and/or DNA methylation profiling on peripheral blood mononuclear cells (PBMCs), monocytes, and CD4+ T cells obtained from 80 RA patients before they began either adalimumab (ADA) or etanercept (ETN) therapy was studied. After 6 months, treatment response was evaluated according to the European League Against Rheumatism criteria for disease response. Differential expression and methylation analyses were performed to identify the response‐associated transcription and epigenetic signatures. Using these signatures, machine learning models were built by random forest algorithm to predict response prior to anti‐TNF treatment, and were further validated by a follow‐up study.
Results
Transcription signatures in ADA and ETN responders were divergent in PBMCs, and this phenomenon was reproduced in monocytes and CD4+ T cells. The genes up‐regulated in CD4+ T cells from ADA responders were enriched in the TNF signaling pathway, while very few pathways were differential in monocytes. Differentially methylated positions (DMPs) were strongly hypermethylated in responders to ETN but not to ADA. The machine learning models for the prediction of response to ADA and ETN using differential genes reached an overall accuracy of 85.9% and 79%, respectively. The models using DMPs reached an overall accuracy of 84.7% and 88% for ADA and ETN, respectively. A follow‐up study validated the high performance of these models.
Conclusion
Our findings indicate that machine learning models based on molecular signatures accurately predict response before ADA and ETN treatment, paving the path toward personalized anti‐TNF treatment.
CSF-1 or IL-34 stimulation of CSF1R promotes macrophage differentiation, activation and osteoclastogenesis, and pharmacological inhibition of CSF1R is beneficial in animal models of arthritis. The ...objective of this study was to determine the relative contributions of CSF-1 and IL-34 signaling to CSF1R in RA.
CSF-1 and IL-34 were detected by immunohistochemical and digital image analysis in synovial tissue from 15 biological-naïve rheumatoid arthritis (RA) , 15 psoriatic arthritis (PsA) and 7 osteoarthritis (OA) patients . Gene expression in CSF-1- and IL-34-differentiated human macrophages was assessed by FACS analysis and quantitative PCR. RA synovial explants were incubated with CSF-1, IL-34, control antibody (Ab), or neutralizing/blocking Abs targeting CSF-1, IL-34, or CSF1R. The effect of a CSF1R-blocking Ab was examined in murine collagen-induced arthritis (CIA).
CSF-1 (also known as M-CSF) and IL-34 expression was similar in RA and PsA synovial tissue, but lower in controls (P < 0.05). CSF-1 expression was observed in the synovial sublining, and IL-34 in the sublining and the intimal lining layer. CSF-1 and IL-34 differentially regulated the expression of 17 of 336 inflammation-associated genes in macrophages, including chemokines, extra-cellular matrix components, and matrix metalloproteinases. Exogenous CSF-1 or IL-34, or their independent neutralization, had no effect on RA synovial explant IL-6 production. Anti-CSF1R Ab significantly reduced IL-6 and other inflammatory mediator production in RA synovial explants, and paw swelling and joint destruction in CIA.
Simultaneous inhibition of CSF1R interactions with both CSF-1 and IL-34 suppresses inflammatory activation of RA synovial tissue and pathology in CIA, suggesting a novel therapeutic strategy for RA.
This study aimed to evaluate whether profiles of several soluble mediators in synovial fluid and cartilage tissue are pathology-dependent and how their production is related to in vitro tissue ...formation by chondrocytes from diseased and healthy tissue.
Samples were obtained from donors without joint pathology (n = 39), with focal defects (n = 65) and osteoarthritis (n = 61). A multiplex bead assay (Luminex) was performed measuring up to 21 cytokines: Interleukin (IL)-1α, IL-1β, IL-1RA, IL-4, IL-6, IL-6Rα, IL-7, IL-8, IL-10, IL-13, tumor necrosis factor (TNF)α, Interferon (IFN)γ, oncostatin M (OSM), leukemia inhibitory factor (LIF), adiponectin, leptin, monocyte chemotactic factor (MCP)1, RANTES, basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), vascular growth factor (VEGF).
In synovial fluid of patients with cartilage pathology, IL-6, IL-13, IFNγ and OSM levels were higher than in donors without joint pathology (P ≤ 0.001). IL-13, IFNγ and OSM were also different between donors with cartilage defects and OA (P < 0.05). In cartilage tissue from debrided defects, VEGF was higher than in non-pathological or osteoarthritic joints (P ≤ 0.001). IL-1α, IL-6, TNFα and OSM concentrations (in ng/ml) were markedly higher in cartilage tissue than in synovial fluid (P <0.01). Culture of chondrocytes generally led to a massive induction of most cytokines (P < 0.001). Although the release of inflammatory cytokines was also here dependent on the pathological condition (P < 0.001) the actual profiles were different from tissue or synovial fluid and between non-expanded and expanded chondrocytes. Cartilage formation was lower by healthy unexpanded chondrocytes than by osteoarthritic or defect chondrocytes.
Several pro-inflammatory, pro-angiogenic and pro-repair cytokines were elevated in joints with symptomatic cartilage defects and/or osteoarthritis, although different cytokines were elevated in synovial fluid compared to tissue or cells. Hence a clear molecular profile was evident dependent on disease status of the joint, which however changed in composition depending on the biological sample analysed. These alterations did not affect in vitro tissue formation with these chondrocytes, as this was at least as effective or even better compared to healthy chondrocytes.
Histone deacetylase inhibitors (HDACi) suppress cytokine production in immune and stromal cells of patients with rheumatoid arthritis (RA). Here, we investigated the effects of the HDACi givinostat ...(ITF2357) on the transcriptional and post-transcriptional regulation of inflammatory markers in RA fibroblast-like synoviocytes (FLS).
The effects of ITF2357 on the expression and messenger RNA (mRNA) stability of IL-1β-inducible genes in FLS were analyzed using array-based qPCR and Luminex. The expression of primary and mature cytokine transcripts, the mRNA levels of tristetraprolin (TTP, or ZFP36) and other AU-rich element binding proteins (ARE-BP) and the cytokine profile of fibroblasts derived from ZFP36
and ZFP36
mice was measured by qPCR. ARE-BP silencing was performed by small interfering RNA (siRNA)-mediated knockdown, and TTP post-translational modifications were analyzed by immunoblotting.
ITF2357 reduced the expression of 85% of the analyzed IL-1β-inducible transcripts, including cytokines (IL6, IL8), chemokines (CXCL2, CXCL5, CXCL6, CXCL10), matrix-degrading enzymes (MMP1, ADAMTS1) and other inflammatory mediators. Analyses of mRNA stability demonstrated that ITF2357 accelerates IL6, IL8, PTGS2 and CXCL2 mRNA degradation, a phenomenon associated with the enhanced transcription of TTP, but not other ARE-BP, and the altered post-translational status of TTP protein. TTP knockdown potentiated cytokine production in RA FLS and murine fibroblasts, which in the latter case was insensitive to inhibition by ITF2357 treatment.
Our study identifies that regulation of cytokine mRNA stability is a predominant mechanism underlying ITF2357 anti-inflammatory properties, occurring via regulation of TTP. These results highlight the therapeutic potential of ITF2357 in the treatment of RA.
Objective
Patients with definite systemic sclerosis (SSc) who lack fibrotic features can be stratified into an intermediate stage of disease severity between preclinical/early SSc (EaSSc) and ...fibrotic subsets (limited cutaneous SSc lcSSc and diffuse cutaneous SSc dcSSc). The aim of the present study was to molecularly characterize nonfibrotic SSc and EaSSc on the basis of a broad panel of serum markers of inflammation and tissue damage, in order to increase the knowledge of the pathophysiologic mechanisms underlying SSc progression before the development of fibrosis.
Methods
An 88‐plex immunoassay was performed in serum samples from a discovery cohort composed of 21 patients with EaSSc (meeting the LeRoy and Medsger criteria), 15 with nonfibrotic SSc (meeting the American College of Rheumatology/European League Against Rheumatism 2013 classification criteria, without skin or lung fibrosis), and 11 healthy controls. Analyte concentrations that were consistently significantly different at the exploratory P value threshold of 0.1 were selected for replication analysis in a larger group composed of 47 patients with EaSSc, 48 with nonfibrotic SSc, and 43 healthy controls, as well as 51 patients with lcSSc and 35 with dcSSc. The value of the replicated molecules in predicting SSc progression (at a family‐wise error rate of 0.05) was tested.
Results
Based on the results of the explorative analysis, 16 molecules were selected for testing in the replication set. The results showed that CXCL10, CXCL11, tumor necrosis factor receptor type II (TNFRII), and chitinase 3–like protein 1 levels were significantly increased in patients with EaSSc and those with nonfibrotic SSc as compared to healthy controls. The disease in patients with high concentrations of CXCL10 and TNFRII was also characterized by a faster rate of progression from EaSSc and from nonfibrotic SSc to worse disease stages.
Conclusion
SSc patients with preclinical/early SSc and those with established, yet nonfibrotic, disease exhibit clear molecular alterations that are associated with faster rates of disease evolution. These data open novel avenues for disease interception in SSc.
Gout is the most common inflammatory arthritis worldwide, and patients experience a heavy burden of cardiovascular and metabolic diseases. The inflammation is caused by the deposition of monosodium ...urate (MSU) crystals in tissues, especially in the joints, triggering immune cells to mount an inflammatory reaction. Recently, it was shown that MSU crystals can induce mechanistic target of rapamycin (mTOR) signalling in monocytes encountering these crystals in vitro. The mTOR pathway is strongly implicated in cardiovascular and metabolic disease. We hypothesised that inhibiting this pathway in gout might be a novel avenue of treatment in these patients, targeting both inflammation and comorbidities.
We used a translational approach starting from ex vivo to in vitro and back to in vivo.
We show that ex vivo immune cells from patients with gout exhibit higher expression of the mTOR pathway, which we can mimic in vitro by stimulating healthy immune cells (B lymphocytes, monocytes, T lymphocytes) with MSU crystals. Monocytes are the most prominent
expressers. By using live imaging, we demonstrate that monocytes, on encountering MSU crystals, initiate cell death and release a wide array of proinflammatory cytokines. By inhibiting
signalling with metformin or rapamycin, a reduction of cell death and release of inflammatory mediators was observed. Consistent with this, we show that patients with gout who are treated with the mTOR inhibitor metformin have a lower frequency of gout attacks.
We propose mTOR inhibition as a novel therapeutic target of interest in gout treatment.
Systemic sclerosis (SSc) is a complex autoimmune disease of unclear aetiology. A multitude of genetic studies, ranging from candidate-gene studies to genome-wide association studies, have identified ...a large number of genetic susceptibility factors for SSc and its clinical phenotypes, but the contribution of these factors to disease susceptibility is only modest. However, in an endeavour to explore how the environment might affect genetic susceptibility, epigenetic research into SSc is rapidly expanding. Orchestrated by environmental factors, epigenetic modifications can drive genetically predisposed individuals to develop autoimmunity, and are thought to represent the crossroads between the environment and genetics in SSc. Therefore, in addition to providing a comprehensive description of the current understanding of genetic susceptibility underlying SSc, this Review describes the involvement of epigenetic phenomena, including DNA methylation patterns, histone modifications and microRNAs, in SSc.
PDF
