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OBJECTIVES: Conflicting results about clinical and subclinical atherosclerosis in systemic sclerosis (SSc) and the associated risk factors have been reported. Hence, we aimed to determine the prevalence of clinical and subclinical atherosclerosis in a large number of Italian SSc patients and the associated risk factors. METHODS: This study included 613 SSc patients from 11 Italian tertiary Rheumatologic Units. All patients underwent full history taking, clinical examination, and relevant laboratory and radiological investigations. Doppler ultrasonography (US) of the common carotid and upper and lower limbs was performed to measure carotid and femoral intima-media thickness (cIMT and fIMT), and carotid and peripheral atheroma plaques. Doppler US of the brachial artery was performed to measure flow-mediated dilatation (FMD). RESULTS: Patients were mostly women (91.4%) with a median age of 61 years (range, 20-100); a median disease duration of 14 years (range, 0-77) from the onset of the first non-Raynaud's phenomenon (RP); 9.3% had a history of clinical atherosclerosis (9 stable/unstable angina, 21 myocardial infarctions, 24 heart failure, 3 strokes, 8 transient ischaemic attack, 6 intermittent claudication, 10 atrial thrombo-embolism). In 37.1% of patients, subclinical atherosclerosis was detected, after excluding those with a history of clinical atherosclerosis. The prevalence of clinical and subclinical atherosclerosis was higher than that reported by the European Society of Cardiology and observational studies that enrolled Italian healthy individuals as a control group, respectively. CONCLUSIONS: A higher prevalence of clinical and subclinical atherosclerosis was detected in SSc Italian patients and correlated with traditional and SSc-related risk factors.
Subject(s)
Atherosclerosis , Carotid Intima-Media Thickness , Scleroderma, Systemic , Humans , Female , Scleroderma, Systemic/epidemiology , Scleroderma, Systemic/complications , Male , Middle Aged , Italy/epidemiology , Aged , Adult , Prevalence , Atherosclerosis/epidemiology , Atherosclerosis/diagnostic imaging , Atherosclerosis/etiology , Risk Factors , Aged, 80 and over , Young Adult , Ultrasonography, Doppler , Asymptomatic Diseases , Carotid Artery Diseases/epidemiology , Carotid Artery Diseases/diagnostic imaging , Plaque, Atherosclerotic/diagnostic imaging , Plaque, Atherosclerotic/epidemiologyABSTRACT
Inflammatory rheumatic diseases are different pathologic conditions associated with a deregulated immune response, codified along a spectrum of disorders, with autoinflammatory and autoimmune diseases as two-end phenotypes of this continuum. Despite pathogenic differences, inflammatory rheumatic diseases are commonly managed with a limited number of immunosuppressive drugs, sometimes with partial evidence or transferring physicians' knowledge in different patients. In addition, several randomized clinical trials, enrolling these patients, did not meet the primary pre-established outcomes and these findings could be linked to the underlying molecular diversities along the spectrum of inflammatory rheumatic disorders. In fact, the resulting patient heterogeneity may be driven by differences in underlying molecular pathology also resulting in variable responses to immunosuppressive drugs. Thus, the identification of different clinical subsets may possibly overcome the major obstacles that limit the development more effective therapeutic strategies for these patients with inflammatory rheumatic diseases. This clinical heterogeneity could require a diverse therapeutic management to improve patient outcomes and increase the frequency of clinical remission. Therefore, the importance of better patient stratification and characterization is increasingly pointed out according to the precision medicine principles, also suggesting a new approach for disease treatment. In fact, based on a better proposed patient profiling, clinicians could more appropriately balance the therapeutic management. On these bases, we synthetized and discussed the available literature about the patient profiling in regard to therapy in the context of inflammatory rheumatic diseases, mainly focusing on randomized clinical trials. We provided an overview of the importance of a better stratification and characterization of the clinical heterogeneity of patients with inflammatory rheumatic diseases identifying this point as crucial in improving the management of these patients.
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OBJECTIVE: Tissue-resident memory cells (Trm) are a subset of T cells residing persistently and long-term within specific tissues that contribute to persistent inflammation and tissue damage. We characterised the phenotype and function of Trm and the role of CD103 in primary Sjogren's syndrome (pSS). METHODS: In both pSS and non-pSS sicca syndrome patients, we examined Trm frequency, cytokine production in salivary glands (SG) and peripheral blood (PB). We also analysed Trm-related gene expression in SG biopsies through bulk and single-cell RNA sequencing (scRNAseq). Additionally, we investigated Trm properties in an immunisation-induced animal model of pSS (experimental SS, ESS) mouse model and assessed the effects of Trm inhibition via intraglandular anti-CD103 monoclonal antibody administration. RESULTS: Transcriptomic pSS SG showed an upregulation of genes associated with tissue recruitment and long-term survival of Trm cells, confirmed by a higher frequency of CD8+CD103+CD69+ cells in pSS SG, compared with non-specific sialadenitis (nSS). In SG, CD8+ CD103+ Trm contributed to the secretion of granzyme-B and interferon-γ, CD8+ Trm cells were localised within inflammatory infiltrates, where PD1+CD8+ T cells were also increased compared with nSS and MALT lymphoma. scRNAseq of PB and pSS SG T cells confirmed expression of CD69, ITGAE, GZMB, GZMK and HLA-DRB1 among CD3+CD8+ SG T cells. In the SG of ESS, CD8+CD69+CD103+ Trm producing Granzyme B progressively expanded. However, intraglandular blockade of CD103 in ESS reduced Trm, reduced glandular damage and improved salivary flow. CONCLUSIONS: CD103+CD8+Trm cells are expanded in the SG of pSS and ESS, participate in tissue inflammation and can be therapeutically targeted.
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Emotion recognition and the resulting responses are important for survival and social functioning. However, how socially derived information is processed for reliable emotion recognition is incompletely understood. Here, we reveal an evolutionarily conserved long-range inhibitory/excitatory brain network mediating these socio-cognitive processes. Anatomical tracing in mice revealed the existence of a subpopulation of somatostatin (SOM) GABAergic neurons projecting from the medial prefrontal cortex (mPFC) to the retrosplenial cortex (RSC). Through optogenetic manipulations and Ca2+ imaging fiber photometry in mice and functional imaging in humans, we demonstrate the specific participation of these long-range SOM projections from the mPFC to the RSC, and an excitatory feedback loop from the RSC to the mPFC, in emotion recognition. Notably, we show that mPFC-to-RSC SOM projections are dysfunctional in mouse models relevant to psychiatric vulnerability and can be targeted to rescue emotion recognition deficits in these mice. Our findings demonstrate a cortico-cortical circuit underlying emotion recognition.
Subject(s)
Emotions , Prefrontal Cortex , Animals , Emotions/physiology , Prefrontal Cortex/physiology , Mice , Male , Humans , GABAergic Neurons/physiology , Neural Pathways/physiology , Somatostatin/metabolism , Recognition, Psychology/physiology , Mice, Inbred C57BL , Optogenetics , Female , Gyrus Cinguli/physiologyABSTRACT
OBJECTIVE: To evaluate the short-term effectiveness of guselkumab in patients with psoriatic arthritis (PsA) and suggestive features of axial involvement in a prospective "real-life" multicentre cohort. METHODS: Between June 2022 and June 2023, PsA patients with axial involvement were evaluated if treated at least for 4 months with guselkumab. The effectiveness was evaluated by BASDAI, ASDAS, DAPSA, and achievement of BASDAI ≤ 4, also exploiting predictive factors. In a group of patients, MRI findings on sacroiliac joints were assessed before and after guselkumab administration. RESULTS: Sixty-seven patients with PsA and suggestive features of axial involvement (age 53.4 ± 11.2 years, male sex 26.9%) were treated with guselkumab. After 4 months, a significant reduction of BASDAI, ASDAS, and DAPSA was observed. A ΔBASDAI of -2.11 ± 0.43 was estimated assessing the mean difference values before and after guselkumab administration and 52.2% of patients reached a BASDAI ≤ 4. In 27 patients, MRI findings on sacroiliac joints were assessed before and after guselkumab administration. A reduction of 0.80 or larger of the sacroiliac joint lesion score was observed in the majority of patients (70.3%) based on MRI improvements, paralleling with the clinical response.No life-threatening side effects were recorded; 17.9% of patients reported minor adverse events mainly injection site reactions. CONCLUSIONS: The short-term effectiveness of guselkumab in patients with PsA and suggestive features of axial involvement was shown. Although further studies are needed, our multicentre "real-life" study may suggest the clinical usability of guselkumab in this context.
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OBJECTIVE: We aimed to evaluate the clinical usefulness of the systemic score in the prediction of life-threatening evolution in Still disease. We also aimed to assess the clinical relevance of each component of the systemic score in predicting life-threatening evolution and to derive patient subsets accordingly. METHODS: A multicenter, observational, prospective study was designed including patients included in the Gruppo Italiano Di Ricerca in Reumatologia Clinica e Sperimentale Adult-Onset Still Disease Study Group and the Autoinflammatory Disease Alliance Network Still Disease Registry. Patients were assessed to see if the variables to derive the systemic score were available. The life-threatening evolution was defined as mortality, whatever the clinical course, and/or macrophage activation syndrome, a secondary hemophagocytic lymphohistiocytosis associated with a poor prognosis. RESULTS: A total of 597 patients with Still disease were assessed (mean ± SD age 36.6 ± 17.3 years; male 44.4%). The systemic score, assessed as a continuous variable, significantly predicted the life-threatening evolution (odds ratio [OR] 1.24; 95% confidence interval [CI] 1.07-1.42; P = 0.004). A systemic score ≥7 also significantly predicted the likelihood of a patient experiencing life-threatening evolution (OR 3.36; 95% CI 1.81-6.25; P < 0.001). Assessing the clinical relevance of each component of the systemic score, liver involvement (OR 1.68; 95% CI 1.48-2.67; P = 0.031) and lung disease (OR 2.12; 95% CI 1.14-4.49; P = 0.042) both significantly predicted life-threatening evolution. The clinical characteristics of patients with liver involvement and lung disease were derived, highlighting their relevance in multiorgan disease manifestations. CONCLUSION: The clinical utility of the systemic score was shown in identifying Still disease at a higher risk of life-threatening evolution in a large cohort. Furthermore, the clinical relevance of liver involvement and lung disease was highlighted.
Subject(s)
Registries , Still's Disease, Adult-Onset , Humans , Male , Female , Adult , Prospective Studies , Middle Aged , Still's Disease, Adult-Onset/diagnosis , Still's Disease, Adult-Onset/complications , Young Adult , Severity of Illness Index , Prognosis , Disease Progression , Macrophage Activation Syndrome/diagnosisABSTRACT
OBJECTIVES: To investigate the mechanism by which intestinal epithelial cell (IEC) death induces arthritis. METHODS: IEC death was assessed by staining for necroptosis and apoptosis markers and fluorescence in situ hybridisation at different time points during collagen-induced arthritis (CIA). During the development of CIA, messenger RNA (mRNA) sequencing was performed, followed by Gene Ontology enrichment analysis of differentially expressed genes. Mice deficient for hypoxia-inducible factor 1α (Hif1a) in IECs (Hif1a ∆IEC) were generated and induced for arthritis. mRNA sequencing, chromatin immunoprecipitated (ChIP) DNA sequencing and ChIP-qualitative PCR were performed on IECs from Hif1a ∆IEC mice and littermate controls. Effects of HIF1α stabilisation by inhibition of prolyl hydroxylase domain-containing enzymes and treatment with the inhibitor of receptor-interacting protein kinase-3 (RIPK3) were tested in intestinal organoids and in CIA. RESULTS: IEC underwent apoptotic and necroptotic cell death at the onset of arthritis, leading to impaired gut barrier function. HIF1α was identified as one of the most upregulated genes in IECs during the onset of arthritis. Deletion of Hif1a in IEC enhanced IEC necroptosis, triggered intestinal inflammation and exacerbated arthritis. HIF1α was found to be a key transcriptional repressor for the necroptosis-inducing factor RIPK3. Enhanced RIPK3 expression, indicating necroptosis, was also found in the intestinal epithelium of patients with new-onset rheumatoid arthritis. Therapeutic stabilisation of HIF1α as well as small-molecule-based RIPK3 inhibition rescued intestinal necroptosis in vitro and in vivo and suppressed the development of arthritis. CONCLUSION: Our results identify IEC necroptosis as a critical link between the gut and the development of arthritis.
Subject(s)
Apoptosis , Arthritis, Experimental , Hypoxia-Inducible Factor 1, alpha Subunit , Intestinal Mucosa , Necroptosis , Receptor-Interacting Protein Serine-Threonine Kinases , Animals , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Arthritis, Experimental/metabolism , Arthritis, Experimental/pathology , Arthritis, Experimental/genetics , Mice , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Epithelial Cells/metabolism , HumansABSTRACT
OBJECTIVE: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA. METHODS: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined. RESULTS: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed. CONCLUSION: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.
Subject(s)
Antirheumatic Agents , Arthritis, Psoriatic , Arthritis, Psoriatic/drug therapy , Humans , Antirheumatic Agents/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Methotrexate/therapeutic use , Biological Products/therapeutic useABSTRACT
The TAM tyrosine kinases, Axl and MerTK, play an important role in rheumatoid arthritis (RA). Here, using a unique synovial tissue bioresource of patients with RA matched for disease stage and treatment exposure, we assessed how Axl and MerTK relate to synovial histopathology and disease activity, and their topographical expression and longitudinal modulation by targeted treatments. We show that in treatment-naive patients, high AXL levels are associated with pauci-immune histology and low disease activity and inversely correlate with the expression levels of pro-inflammatory genes. We define the location of Axl/MerTK in rheumatoid synovium using immunohistochemistry/fluorescence and digital spatial profiling and show that Axl is preferentially expressed in the lining layer. Moreover, its ectodomain, released in the synovial fluid, is associated with synovial histopathology. We also show that Toll-like-receptor 4-stimulated synovial fibroblasts from patients with RA modulate MerTK shedding by macrophages. Lastly, Axl/MerTK synovial expression is influenced by disease stage and therapeutic intervention, notably by IL-6 inhibition. These findings suggest that Axl/MerTK are a dynamic axis modulated by synovial cellular features, disease stage and treatment.
Subject(s)
Arthritis, Rheumatoid , Receptor Protein-Tyrosine Kinases , Humans , Axl Receptor Tyrosine Kinase , c-Mer Tyrosine Kinase/genetics , c-Mer Tyrosine Kinase/metabolism , Inflammation/metabolism , Interleukin-6/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Receptor Protein-Tyrosine Kinases/genetics , Receptor Protein-Tyrosine Kinases/metabolism , Synovial Membrane/metabolismABSTRACT
OBJECTIVES: We aimed to evaluate the drug retention rate (DRR) of secukinumab, an anti-IL-17A monoclonal antibody, in patients with psoriatic arthritis (PsA) in a real-life cohort, and to assess the impact of comorbidities and patient clinical characteristics on the DRR of secukinumab. METHODS: A retrospective study of prospective followed-up patients was performed to evaluate the DRR of secukinumab on patients with PsA attending the recruiting centres between January 2016 and June 2022. RESULTS: In 207 patients with PsA, a 60-month DRR of secukinumab of 57.0% was estimated (mean time of administration of 21.5±17.1 months). Male gender, age ≥65 years, disease duration ≥5 years and ≥10 years did not influence the DRR of secukinumab. The presence of comorbidities, considering any concomitant disorder, did not affect the DRR of secukinumab. In patients with cardiometabolic multimorbidity, a trend toward a better DRR of secukinumab was recorded. In fact, patients with high blood pressure, dyslipidaemia, and type 2 diabetes showed a trend toward an improved DRR of secukinumab. Furthermore, the presence of obesity did not influence the DRR of secukinumab. Different dosages, previous bDMARDs, and concomitant therapy with csDMARDs did not influence the DRR of secukinumab. CONCLUSIONS: A cumulative 60-month DRR of secukinumab of 57.0% in patients with PsA was retrieved. The presence of cardiometabolic multimorbidity could be associated with an improved DRR of secukinumab, whereas obesity did not affect this feature in our cohort. Previous bDMARDs, concomitant csDMARDs, and different drug dosages could not influence the DRR of secukinumab over time.
Subject(s)
Antibodies, Monoclonal, Humanized , Arthritis, Psoriatic , Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Humans , Male , Aged , Arthritis, Psoriatic/diagnosis , Arthritis, Psoriatic/drug therapy , Antibodies, Monoclonal/therapeutic use , Prospective Studies , Retrospective Studies , ObesityABSTRACT
Axial spondyloarthritis (axSpA) is a chronic, inflammatory rheumatic disease that primarily affects the axial skeleton, often inflicting severe pain, diminished mobility, and a compromised quality of life. The advent of Assessment of SpondyloArthritis international Society (ASAS) classification criteria for spondyloarthritis (SpA) have enabled the classification of patients with axSpA in the non-radiographic stage but poorly perform if mistakenly used for diagnostic purposes. Despite notable progress in early diagnosis facilitated by referral strategies and extensive magnetic resonance imaging (MRI) utilization, diagnostic delays persist as a concerning issue. This underscores the urgency to narrow the diagnostic gap and highlights the critical role of early diagnosis in mitigating the long-term structural damage associated with this condition. Research into the impact of non-steroidal anti-inflammatory drugs (NSAIDs) and biologic disease-modifying antirheumatic drugs (bDMARDs) on inflammatory symptoms and radiographic progression has been extensive. A compelling body of evidence suggests that early intervention leads to superior disease outcomes. However, most of these studies have centered on patients with established diseases rather than those in the early stages. Consequently, findings from studies on early pharmacological intervention remain inconclusive, and the potential for modifying the disease trajectory is still debatable. Without precise data from clinical trials, insights from basic science regarding the pathogenic mechanisms might point toward potential targets that warrant early intervention in the disease process. This review underscores the urgency of early diagnosis and intervention in axSpA, highlighting ongoing research gaps and the need for further exploration to improve patient outcomes.
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BACKGROUND: Different patient clusters were preliminarily suggested to dissect the clinical heterogeneity in Still's disease. Thus, we aimed at deriving and validating disease clusters in a multicentre, observational, prospective study to stratify these patients. METHODS: Patients included in GIRRCS AOSD-study group and AIDA Network Still Disease Registry were assessed if variables for cluster analysis were available (age, systemic score, erythrocyte sedimentation rate (ESR), C reactive protein (CRP) and ferritin). K-means algorithm with Euclidean metric and Elbow plot were used to derive an adequate number of clusters. RESULTS: K-means clustering assessment provided four clusters based on means standardised according to z-scores on 349 patients. All clusters mainly presented fever, skin rash and joint involvement. Cluster 1 was composed by 115 patients distinguished by lower values of age and characterised by skin rash myalgia, sore throat and splenomegaly. Cluster 2 included 128 patients identified by lower levels of ESR, ferritin and systemic score; multiorgan manifestations were less frequently observed. Cluster 3 comprised 31 patients categorised by higher levels of CRP and ferritin, they were characterised by fever and joint involvement. Cluster 4 contained 75 patients derived by higher values of age and systemic score. Myalgia, sore throat, liver involvement and life-threatening complications, leading to a high mortality rate, were observed in these patients. CONCLUSIONS: Four patient clusters in Still's disease may be recognised by a multidimensional characterisation ('Juvenile/Transitional', 'Uncomplicated', 'Hyperferritinemic' and 'Catastrophic'). Of interest, cluster 4 was burdened by an increased rate of life-threatening complications and mortality, suggesting a more severe patient group.
Subject(s)
Arthritis, Juvenile , Exanthema , Pharyngitis , Still's Disease, Adult-Onset , Humans , Arthritis, Juvenile/complications , C-Reactive Protein/metabolism , Exanthema/complications , Ferritins , Fever , Myalgia/complications , Pharyngitis/complications , Prospective Studies , Still's Disease, Adult-Onset/complications , Still's Disease, Adult-Onset/diagnosis , Still's Disease, Adult-Onset/epidemiologyABSTRACT
Spondyloarthritis (SpA) is characterized by the infiltration of innate and adaptive immune cells into entheses and bone marrow. Molecular, cellular and imaging evidence demonstrates the presence of bone marrow inflammation, a hallmark of SpA. In the spine and the peripheral joints, bone marrow is critically involved in the pathogenesis of SpA. Evidence suggests that bone marrow inflammation is associated with enthesitis and that there are roles for mechano-inflammation and intestinal inflammation in bone marrow involvement in SpA. Specific cell types (including mesenchymal stem cells, innate lymphoid cells and γδ T cells) and mediators (Toll-like receptors and cytokines such as TNF, IL-17A, IL-22, IL-23, GM-CSF and TGFß) are involved in these processes. Using this evidence to demonstrate a bone marrow rather than an entheseal origin for SpA could change our understanding of the disease pathogenesis and the relevant therapeutic approach.
Subject(s)
Axial Spondyloarthritis , Spondylarthritis , Humans , Immunity, Innate , Bone Marrow/metabolism , Bone Marrow/pathology , Lymphocytes/pathology , InflammationABSTRACT
Butyrophilins are surface receptors belonging to the immunoglobulin superfamily. While several members of the butyrophilin family have been implicated in the development of unconventional T cells, butyrophilin 2a2 (Btn2a2) has been shown to inhibit conventional T cell activation. Here, we demonstrate that in steady state, the primary source of Btn2a2 are thymic epithelial cells (TEC). Absence of Btn2a2 alters thymic T cell maturation and bypasses central tolerance mechanisms. Furthermore, Btn2a2-/- mice develop spontaneous autoimmunity resembling human primary Sjögren's Syndrome (pSS), including formation of tertiary lymphoid structures (TLS) in target organs. Ligation of Btn2a2 on developing thymocytes is associated with reduced TCR signaling and CD5 levels, while absence of Btn2a2 results in increased TCR signaling and CD5 levels. These results define a novel role for Btn2a2 in promoting central tolerance by modulating TCR signaling strength and indicate a potential mechanism of pSS development.
Subject(s)
Autoimmune Diseases , Central Tolerance , Mice , Humans , Animals , Butyrophilins/genetics , Thymus Gland , Epithelial Cells , Receptors, Antigen, T-Cell/geneticsABSTRACT
INTRODUCTION: Sexual dysfunctions (SD) are frequently encountered in patients with rheumatologic diseases. In this scenario, a multidisciplinary approach to rheumatologic diseases is often mandatory. The aim of this survey was to assess whether Italian rheumatologists routinely explore sexual health of their patients, their knowledge on the topic, and the barriers to discussing SD in clinical practice. METHODS: A 32-items anonymous questionnaire was mailed to members of the Italian Society of Rheumatology (rheumatologists and residents in rheumatology training) in February 2023. The questionnaire aimed to determine attitudes, knowledge, and practice patterns regarding the discussion of SD with rheumatologic patients. A descriptive analysis of responses was performed. RESULTS: A total of 162 responses were received. Overall, 50.0% of respondents occasionally asked patients about SD related to their rheumatologic pathologies, while 37.1% never did so. Respondents declared that patients occasionally (82.3%) or never (16.1%) reported SD related to rheumatologic diseases. The main barriers to discussing sexual health were lack of time during medical examination (46.6%), patients' discomfort (44.8%), and lack of knowledge/experience (39.7%). Overall, 41.9% and 33.9% of respondents respectively totally and partially agreed that rheumatologists should routinely investigate patients' sexual health. Most of the respondents (79.0%) thought that discussing sexual health problems could help patients cope with their rheumatologic diseases. Of all respondents, 74.2% felt the need to broaden their personal knowledge about SD. Finally, 45.9% and 34.4% of respondents respectively partially and totally agreed that training courses for rheumatologists could be helpful in the management of sexual health in rheumatological patients. CONCLUSIONS: SD was not routinely discussed in rheumatology practice, still remaining a neglected issue. The most frequent explanations for the lack of attention toward SD were lack of time, patients' discomfort, and lack of knowledge/experience. Most of the respondents expressed the possible usefulness of attending SD courses to improve knowledge about these conditions.
Subject(s)
Arthritis, Rheumatoid , Rheumatic Diseases , Rheumatology , Sexual Dysfunction, Physiological , Humans , Rheumatology/methods , Sexual Dysfunction, Physiological/epidemiology , Sexual Dysfunction, Physiological/etiology , Surveys and Questionnaires , Rheumatic Diseases/complicationsABSTRACT
Patients with chronic Inflammatory Arthritis (IA), such as Rheumatoid Arthritis (RA) and Spondyloarthritis (SpA) are more likely to experience psychosocial impairment. Gastrointestinal (GI) symptoms are also present, especially in Spondyloarthritis. No data are available on the relationship between gut and brain manifestations and their impact on daily activities in this setting; thus, this study aimed to assess these symptoms in an IA population and identify potential associations. IA patients and a control group were enrolled. The Patient-Reported Outcome Measurement Instrument System (PROMIS®) questionnaire was used to evaluate GI and psychosocial domains. The study included 389 subjects (238 controls and 151 with IA); demographic and clinical data were collected for each participant. IA patients reported both higher psychosocial and GI impairment compared with controls. The logistic regression model revealed a strong association between depression and belly pain (p = 0.035), diarrhea (p = 0.017), bloating (p = 0.018), and reflux (p = 0.01); anxiety was associated with belly pain (p = 0.004), diarrhea (p = 0.019), swallowing alterations (p = 0.004), flatulence (p < 0.001) and reflux (p = 0.008). Moreover, fatigue, sleep disorders, and pain interference were associated with almost all GI symptoms, whereas high physical function scores and satisfaction in social roles decreased the odds of most GI symptoms. IA patients had more significant impairment in both dimensions compared with controls. To address reported symptoms and improve the overall quality of life in rheumatologic patients, a new holistic approach is required.
ABSTRACT
Ankylosing spondylitis (AS) is an inflammatory disease leading to spine ankylosis; however, the mechanisms behind new bone formation are still not fully understood. Single Nucleotide Polymorphisms (SNPs) in PTGER4, encoding for the receptor EP4 of prostaglandin E2 (PGE2), are associated with AS. Since the PGE2-EP4 axis participates in inflammation and bone metabolism, this work aims at investigating the influence of the prostaglandin-E2 axis on radiographic progression in AS. In 185 AS (97 progressors), baseline serum PGE2 predicted progression, and PTGER4 SNP rs6896969 was more frequent in progressors. Increased EP4/PTGER4 expression was observed in AS circulating immune cells, synovial tissue, and bone marrow. CD14highEP4 + cells frequency correlated with disease activity, and when monocytes were cocultured with mesenchymal stem cells, the PGE2/EP4 axis induced bone formation. In conclusion, the Prostaglandin E2 axis is involved in bone remodelling and may contribute to the radiographic progression in AS due to genetic and environmental upregulation.
Subject(s)
Dinoprostone , Spondylitis, Ankylosing , Humans , Receptors, Prostaglandin E, EP4 Subtype/genetics , Receptors, Prostaglandin E, EP4 Subtype/metabolism , Spondylitis, Ankylosing/diagnostic imaging , Spondylitis, Ankylosing/geneticsABSTRACT
OBJECTIVES: To evaluate the impact of obesity in patients with adult-onset Still's disease (AOSD) and to assess their clinical characteristics and disease outcomes. METHODS: The clinical features of AOSD patients with a body mass index (BMI)≥30 were assessed among those included in the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort. RESULTS: Out of 139 AOSD patients, who had BMI registered in our database, 26 (18.7%) had a BMI≥30. A lower rate of sore throat (P<0.05), pericarditis (P<0.05), and pleuritis (P<0.05) was shown in obese patients. Additionally, obese patients showed higher values of C-reactive protein (CRP) (P<0.05) and ferritin (P<0.05) than others. Furthermore, obese patients were characterised by biologic disease-modifying antirheumatic drug (bDMARD) failure in subsequent follow-up (P<0.05). They also presented higher rate of comorbidity than non-obese patients (P<0.05). Finally, obesity predicted the presence of a chronic disease course in both univariate (HR: 1.72, 95%CI: 1.03-2.51, P<0.05) and multivariate analyses (HR: 1.85, 95%CI: 1.45-2.89, P<0.05). Obesity was also a significant predictor of bDMARD failure in AOSD patients in both univariate (HR: 3.03, 95%CI: 1.42-6.45, P<0.01) and multivariate analyses (HR: 3.59, 95%CI: 1.55-8.27, P<0.01). CONCLUSION: Obese patients at the time of diagnosis of the disease were characterised by a lower prevalence of sore throat, serositis, as well as by higher values of CRP and ferritin. Obesity was also a predictive factor for a chronic disease course and bDMARD failure, thus highlighting a subset of patients with AOSD to be carefully managed.
Subject(s)
Antirheumatic Agents , Still's Disease, Adult-Onset , Adult , Humans , Still's Disease, Adult-Onset/complications , Still's Disease, Adult-Onset/diagnosis , Still's Disease, Adult-Onset/epidemiology , Antirheumatic Agents/therapeutic use , C-Reactive Protein/metabolism , Obesity/complications , Obesity/epidemiology , Disease Progression , FerritinsABSTRACT
In the past 20 years, earlier diagnosis and more intensive management have considerably improved the prognosis of rheumatoid arthritis (RA), with milder disease course achieved in particular in seropositive patients. In contrast, seronegative RA has remained largely neglected, and continues to be surrounded by uncertainties regarding its correct diagnosis, clinical phenotype, optimal treatment strategies and relevant outcomes.The purpose of this review is to summarise new insights about the pathogenic, clinical and prognostic peculiarities of seronegative RA that emerged during 2022, and that make this disease subset at least partially different from its seropositive counterpart.
Subject(s)
Arthritis, Rheumatoid , Rheumatoid Factor , Humans , Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/drug therapy , Prognosis , Disease ProgressionABSTRACT
Both TLR7 and NF-κB hyperactivity are known to contribute to pathogenesis in Systemic Lupus Erythematosus (SLE), driving a pro-interferon response, autoreactive B cell expansion and autoantibody production. UBE2L3 is an SLE susceptibility gene which drives plasmablast/plasma cell expansion in SLE, but its role in TLR7 signalling has not been elucidated. We aimed to investigate the role of UBE2L3 in TLR7-mediated NF-κB activation, and the effect of UBE2L3 inhibition by Dimethyl Fumarate (DMF) on SLE B cell differentiation in vitro. Our data demonstrate that UBE2L3 is critical for activation of NF-κB downstream of TLR7 stimulation, via interaction with LUBAC. DMF, which directly inhibits UBE2L3, significantly inhibited TLR7-induced NF-κB activation, differentiation of memory B cells and plasmablasts, and autoantibody secretion in SLE. DMF also downregulated interferon signature genes and plasma cell transcriptional programmes. These results demonstrate that UBE2L3 inhibition could potentially be used as a therapy in SLE through repurposing of DMF, thus preventing TLR7-driven autoreactive B cell maturation.