Rheumato

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease with a complex pathogenesis, primarily affecting women. SLE is associated with the presence of autoantibodies, chronic inflammation, and multi-organ dysfunction. Increasing evidence suggests that SLE is linked to a higher risk of malignancies, compared to the general population, though the mechanism behind this phenomenon remains unclear. Malignant tumors are the fourth most common cause of death in SLE patients. SLE is associated with an elevated risk of hematological cancers, as well as cancers of the lungs, thyroid, liver, and bile ducts. The aim of this paper is to review the latest literature on the pathogenesis, epidemiology, and risk factors for malignancies in SLE patients. The mechanisms of oncogenesis in SLE are still not fully understood, and the pathophysiology includes such risk factors as chronic inflammation, immune disorders, therapies used, overlap syndromes of connective tissue diseases, viral infections, and traditional cancer risk factors. Evaluating these factors and understanding the process of oncogenesis are crucial for prevention. Systemic lupus erythematosus may be an independent risk factor for the development of malignancies. It is important to raise awareness among SLE patients about the increased risk of malignancies. Further research is needed to establish guidelines for prevention, including screening recommendations. Full article

Early diagnosis and therapy in axial spondyloarthritis, axSpA, is known to reduce long-term morbidity. However, the time from symptom onset to diagnosis is typically delayed by several years, and this situation has not improved in recent years despite greater clinical awareness and better imaging. This narrative review discusses the underlying causes for axSpA diagnostic delay. It is proposed that to reduce axSpA diagnostic delay, a better understanding of the axSpA subclinical inflammatory process is required, together with machine learning-enabled inflammation/repair biomarkers such as lipocalin 2 and lipocalin 2-matrix metalloprotease 9, developed through extensive clinical domain knowledge. Full article

Background: Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy characterized by a variety of clinical manifestations, mainly affecting joints and entheses, but also skin, nails, the eye, and the intestine. Objectives: In this review, we describe the essential characteristics of both synovial membranes and synovial fluid (SF) in PsA. Similarly to other inflammatory arthritis, the histological peculiarities in PsA synovitis are lining hyperplasia, neoangiogenesis, and sublining infiltration by immune cells and inflammatory mediators. Synovial effusions are frequent in PsA patients and SF analysis allows us to determine the pathological process occurring in the joint. Routine examinations help clinicians in defining the inflammatory status and possibly the detection of specific cell subsets. In addition, pathogenic crystals including monosodium urate and calcium pyrophosphate may be found in PsA SF. Conclusions: SF represents a potential substrate to identify the biomarkers that are useful to predict disease progression and response to medications in PsA patients, thus guiding the choice of appropriate and tailored pharmacological treatment. Full article

Background/Objectives: Accurate detection and classification of nodules in medical images, particularly rheumatoid nodules, are critical due to the varying nature of these nodules, where their specific type is often unknown before analysis. This study addresses the challenges of multi-class prediction in nodule detection, with a specific focus on rheumatoid nodules, by employing a comprehensive approach to feature extraction and classification. We utilized a diverse dataset of nodules, including rheumatoid nodules sourced from the DermNet dataset and local rheumatologists. Method: This study integrates 62 features, combining traditional image characteristics with advanced graph-based features derived from a superpixel graph constructed through Delaunay triangulation. The key steps include image preprocessing with anisotropic diffusion and Retinex enhancement, superpixel segmentation using SLIC, and graph-based feature extraction. Texture analysis was performed using Gray-Level Co-occurrence Matrix (GLCM) metrics, while shape analysis was conducted with Fourier descriptors. Vascular pattern recognition, crucial for identifying rheumatoid nodules, was enhanced using the Frangi filter. A Hybrid CNN–Transformer model was employed for feature fusion, and feature selection and hyperparameter tuning were optimized using Gray Wolf Optimization (GWO) and Particle Swarm Optimization (PSO). Feature importance was assessed using SHAP values. Results: The proposed methodology achieved an accuracy of 85%, with a precision of 0.85, a recall of 0.89, and an F1 measure of 0.87, demonstrating the effectiveness of the approach in detecting and classifying rheumatoid nodules in both binary and multi-class classification scenarios. Conclusions: This study presents a robust tool for the detection and classification of nodules, particularly rheumatoid nodules, in medical imaging, offering significant potential for improving diagnostic accuracy and aiding in the early identification of rheumatoid conditions. Full article

Background: Interleukin-11 (IL-11) is increased in patients with systemic sclerosis (SSc) and is thought to play a role in fibrosis. Many studies have reported decreased fibrosis when IL-11 is blocked, but few have examined factors that induce IL-11 expression. Because fibrosis has been linked to activated inflammasomes driving caspase-1 maturation and the secretion of IL-1β, we set out to determine if IL-11 expression was dependent on caspase-1 activity. Methods: Primary lung fibroblast cell lines derived from patients with SSc, IPF (fibrotic control), and healthy individuals were cultured at low passage. Gene expression for IL-11 and the IL-11 receptor (IL-11Rα1) was analyzed using qPCR and normalized to the control, and collagen production was measured using Sirius Red. Results: SSc and IPF fibroblasts expressed significantly more IL-11 transcripts than normal cells (3.35-fold and 9.97-fold more, p = 0.0396 and p = 0.0023, respectively). IL-11Rα1 was expressed 2.32-fold and 2.27-fold more in SSc and IPF (p = 0.0004 and p = 0.0032, respectively) than in normal cells. In SSc fibroblasts, inhibition of caspase-1 with YVAD decreased IL-11 expression by 49.59% (p = 0.0016) but did not affect IL-11Rα1 expression (p > 0.05). IL-11 expression was increased 2.97-fold with TGF-β1 (p = 0.0030) and 22.24-fold with IL-1β (p < 0.0001), while the expression of IL-11Rα1 was not induced with these two cytokines. LPS increased IL-11 expression in normal fibroblasts 1.52-fold (p = 0.0042), which was abolished with YVAD (p < 0.0001). IL-11Rα1 gene transcripts were also increased with LPS 1.50-fold (p = 0.0132), but YVAD did not inhibit this expression. In these studies, we were unable to detect IL-11 protein nor were we able to induce COL1A1 expression or increase the total amount of collagen secreted by fibroblasts with human recombinant IL-11. Conclusions: IL-11 and its receptor, IL-11Rα1, are both elevated in fibrosis. IL-11 expression is dependent on inflammasome activation of caspase-1 and the downstream cytokines TGF-β1 and IL-1β, while IL-11Rα1 was only dependent on NF-kB. Full article

Sjogren’s Disease (SjD) is associated with an increased risk of lymphoma. We investigated the prevalence of lymphoma in a retrospective case series of patients with SjD and reported on the clinical presentation, treatment, response, and outcome. A retrospective review of 132 patients diagnosed with Sjogren’s Disease was conducted at our institution from June 2000 to November 2023, and 10 cases of malignant lymphoma were identified. Clinical and biological markers known to be predictors of lymphoma, as well as lymphoma characteristics, were examined. The most common predictive lab findings were hypergammaglobulinemia, the rheumatoid factor, and lymphopenia. Persistent parotid gland enlargement was also found in greater than 50% of patients. The majority of patients were Caucasian females, and the average time between the diagnosis of SjD and lymphoma was 14.3 years. The median age at lymphoma diagnosis was 59.5 years, with 9 out of 10 lymphomas identified as non-Hodgkin lymphoma, the majority of cases being mucosa-associated lymphoid tissue (MALT) lymphoma. We identified similarities in our series, such as laboratory markers and clinical symptoms, to those previously identified as possible predictors of lymphoma development. These factors may be useful in determining the risk of malignancy development and justify the need for long-term monitoring, as well as provider education and awareness. Full article

Irritable bowel syndrome (IBS) is common in ankylosing spondylitis (AS) and may be associated with the disease. We aimed to determine the prevalence of IBS in AS patients and its association with clinical and demographic patient characteristics and with macroscopic and microscopic gut lesions. Sixty consecutive AS patients were included in this study. Disease activity was assessed with the BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and functional status with the BASFI (Bath Ankylosing Spondylitis Functional Index). The ROME III criteria were used to diagnose IBS. Macroscopic lesions were graded during colonoscopies. Biopsy specimens were taken from the terminal ileum, colon (ascending, transverse and descending) and rectum. Histological samples were scored with Cuvelier grading. The prevalence of IBS was 23.3% (14/60). The mean age of 14 IBS subjects (10 male) was 32 ± 8.50., with a higher BASDAI (p = 0.046). Macroscopic lesions were more frequent in IBS cases in the terminal ileum (46.2% vs. 34.9%), ascending colon (21.4% vs. 2.2%) and rectum (21.4% vs. 17.4%), with Grade 2 significantly more prevalent in the ascending colon (p = 0.03). Microscopic lesions did not differ among the IBS-present and -absent groups. In conclusion, the prevalence of IBS was high in AS patients and associated with higher disease activity. Grade 2 macroscopic lesions were more frequent in the ascending colon. Full article

Systemic lupus erythematosus (SLE) is a chronic, autoimmune, immune complex-mediated disease affecting mainly females at a young age. The disease etiology is still unknown, and different genetic and epigenetic factors related to disease onset and manifestations are being explored. The standard treatment regimen for SLE includes the long-term use of corticosteroids and non-specific immunosuppressive agents, often limited by co-morbidities or related side effects. However, recent advances in disease pathogenesis clarifying the role of inflammatory cytokines, chemokines, immune cells, and co-stimulation molecules have made a more practical, targeted approach possible, leading to personalized treatment strategies. This review summarizes current knowledge about SLE-targeted therapies in clinical practice. Full article

Lyme disease is a zoonotic infectious disease. Increased public interest in Lyme disease has caused increased efforts by researchers for its surveillance and control. The main concept for this paper is to determine the mammalian species composition of areas at high risk for Lyme disease utilizing GIS-based (Geographic Information Systems) techniques coupled with k-means clustering, random forest, and multinomial logistic regression. Cluster analysis results were similar to previous work involving maps that display areas where people are at high risk for developing Lyme disease. There were differences in which mammal species presence had associations with Lyme disease risk observed at the two different scales within this analysis, with some overlap observed between the national scale and the smaller regions, as well as some overlap between the Rocky Mountain and Southeast regions that was not found at the national scale. This is an investigative analysis to determine which species are needed for habitat suitability analyses in efforts to prioritize vaccine deployment locations. There has been limited research on vaccine deployment for Lyme disease. Increasing our understanding of not only the vaccine but also the interactions between the components of disease transmission is necessary to control this infectious disease successfully. Full article

The spectrum of disorders/phenomena encompassed in the practice of rheumatology is quite broad. In addition, our expertise is typically sought whenever other physicians encounter phenomena outside their knowledge base. While skin alterations typically prompt referrals to dermatology practices, alterations underlying the skin (e.g., subcutaneous) may well represent localization in “no man’s land” or an orphaned localization, with rheumatology thus referred as to the specialty of last resort—one of the roles that rheumatology has fulfilled for more than half a century. The current review addresses the cacophony of disorders producing or associated with variouslysized subcutaneous nodules. Their classifications, while necessarily artificial, encompass the full spectrum of pathologic processes. They are delineated in the current style to facilitate the consideration required to distinguish among them and to facilitate recognize the underlying processes for which we as rheumatologists are renowned. Full article

This work aimed to investigate a potential link between serum IL-1β levels in patients with giant cell arteritis (GCA) and their responsiveness to combined anti-IL-6 receptor (IL-6R) and glucocorticoid (GC) treatments within the context of two separate clinical trials. IL-1β levels were analyzed in serum samples of two prospective clinical trials investigating tocilizumab in GCA patients using quantitative Polymerase Chain Reaction (qPCR) based Proximity Ligation Assays (PLA). In the phase II randomized controlled trial, serum samples from five patients were quantified at two critical time points: the commencement of the trial (Week 2) and the conclusion of the trial (Week 52). In the GUSTO trial, serum samples from nine patients were similarly analyzed using PLA at Day 0 and Week 52. Furthermore, for the GUSTO trial, serum samples from 18 patients were assessed for IL-1β and IL-1RN at six time points: days 0, 3, and 10, weeks 4, 24, and 52 by a second assay (Proximity Extension Assay, PEA). PLA results from both studies indicated that IL-1β levels were below 1 pg/mL in most of the patients, resulting in notable signal deviations within the same samples. In the analysis of the GUSTO trial, both PLA and PEA exhibited similar trends in IL-1β variations among patients from day 0 to week 52. Notably, the PEA analysis did not show significant variation over time. Furthermore, we did not find a correlation of IL-1β levels with active disease as compared to remission, but interestingly, the measurement of IL-1β receptor antagonist (IL-1RN) revealed a substantial decrease over time. Our study shows that IL-1RN but not IL-1β concentration in serum samples could be directly related to anti-IL-6R treatment in patients diagnosed with GCA. Full article

Gout is highly prevalent in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD), owing to impaired uric acid excretion. However, treating gout in this population is challenging due to concerns about medication safety and efficacy with reduced kidney function. This review examines the evidence of various pharmacologic and non-pharmacologic approaches to managing gout in CKD/ESRD. For acute gout flares, there is insufficient evidence to guide optimal dosing of NSAIDs, colchicine, and corticosteroids in advanced CKD. The risks generally outweigh the benefits of NSAIDs and colchicine. Corticosteroids appear safer but require individual risk-benefit assessments. Interleukin-1 inhibitors show promise, but larger studies are needed. For long-term urate lowering, xanthine oxidase inhibitors like allopurinol and febuxostat are preferred over probenecid and other uricosurics. However, studies specifically evaluating urate-lowering therapies in CKD are scarce, resulting in conflicting expert guidelines. Starting with low allopurinol doses and gradual titration can mitigate the risks. Higher allopurinol doses may be needed to reach urate targets in some CKD patients. Febuxostat’s safety in advanced CKD remains debated. Optimal gout management in dialysis patients is also unclear, including when to continue urate-lowering therapy. Overall, gout is often suboptimally treated in CKD/ESRD, highlighting the need for more research to guide therapy in this population. Improving management can significantly reduce the burden of these comorbid diseases. Full article

Anti-melanoma differentiation-associated gene 5 (MDA-5) dermatomyositis (DM) is noteworthy for its association with rapidly progressive interstitial lung disease (RP-ILD), vasculopathy, and distinctive cutaneous features. First identified in a Japanese cohort in 2005, MDA-5 DM carries a significant mortality risk, emphasizing the crucial need for early diagnosis. This review explores the pathogenesis, clinical presentation, diagnosis, management, and prognosis of MDA-5 DM and ILD and includes new research and recommendations regarding disease management. Full article

Objectives: The aim of this study was to investigate whether serum TNF-α and IL-1β levels are independent risk factors for depression in axSpA patients. Methods: All axSpA patients with BASDAI ≥4 were invited consecutively between March 2021 and August 2021 to participate. Depression was evaluated with the WHO-5 Well-Being scale. Disease activity was assessed using BASDAI (0–10), ASDAS-CRP (0.61–7.22), ASDAS-ESR (0.29–7.61), and health status by ASAS-HI (0–17). Serum TNF-α and IL-1β levels were measured by ELISA. An association between depression and cytokine levels was investigated with Spearman’s rank correlation coefficient test. Results: A total of 252 axSpA patients (155 men) could be included; of these, 123 (48.81%) were depressed, and of these, 75 were male. Serum TNF-α and IL-1β were not significantly associated with depression (r −0.041 and 0.110, respectively). Serum TNF-α levels were higher in depressed female axSpA patients (20.05 vs. 17.87; p = 0.03). Differences between depressed and non-depressed patients were respectively: TNF-α (19.7 vs.18.0; p= 0.84), IL-1β (32.3 vs. 21.2; p= 0.04), BASDAI (5.47 vs. 4.77; p = 0.000), ASDAS-CRP (4.17 vs. 3.78; p = 0.000), ASDAS-ESR (3.86 vs. 3.39; p = 0.000), CRP (48.43 vs. 37.93 mg/L; p = 0.000), and ASAS-HI (13.37 vs. 10.24; p = 0.000). Factors associated with depression were: peripheral joint involvement (OR = 1.073, 95% CI 1.012–1.138), BASDAI (OR = 1.534, 95% CI 1.011–2.335), and ASAS-HI (OR = 1.39, 95% CI 1.239–1.557). Only in depressed patients with peripheral SPA were higher IL-1β levels found, though the differences were probably not clinically relevant. Conclusions: Serum TNF-α and IL-1β were not independently related to depression in axSpA patients. Disease activity, peripheral joint involvement, and reduced health status showed the highest association with depression. Full article

This journal for Rheumato(philes) has provided a vehicle for the interdisciplinary sharing of the challenges and interventions of our specialty. The provision of state-of-the-art information is not at the expense of the basics from which it has grown. From its initial status as a source of discomfort, a review of back pain diagnostics and therapeutics provides a background for facilitating contemporary practice. We have met the enemy in the form of COVID-19, addressing its many rheumatologic complications, and have been introduced to the vagaries of IgG4 disease. Our clinical skills are tested in recognition of primary hypertrophic osteoarthropathy. The relationship of dental health to rheumatoid arthritis and nutritional issues is currently undergoing scientific review. A unique feature, one we seldom seem to discuss, is the evaluation of disease manifestations when the customary tools are not available. The latter brings us full circle in the evolution of our field. When our colleagues found diagnostic or treatment approaches elusive, they did not call for Ghostbusters; they called for us. Full article

Fibroinflammatory diseases are a group of rare pathologies in which the hallmark is the exuberant deposition of fibrotic tissue and inflammatory cellular infiltrates, characteristic of the specific disease. A sclerotic mass develops within soft tissues and/or organs, damaging and replacing them, with effects ranging from asymptomatic to life-threatening clinical manifestations. The kidneys and urinary tract can be involved in some of these diseases, which can lead to acute kidney injury, chronic kidney disease, and even end-stage kidney disease. IgG4-related disease, retroperitoneal fibrosis, and Erdheim–Chester disease are the three fibroinflammatory disorders that can involve the kidneys. Only a timely and accurate collection of clinical, radiological, metabolic, laboratory, and histological data allows prompt diagnosis and targeted treatment of these pathologies, allowing the stoppage of the evolution of renal and systemic manifestations, which can lead to complete remission. The epidemiology, clinical and histological features, and management of these conditions are herein described in a narrative fashion. Full article

We experience life and interact with others in a multitude of ways. The term ‘neurodivergence’ refers to variations from what is considered typical or normal. Neurodivergence influences an individual’s behaviour in social situations and is associated with atypical emotional responses. This can precipitate inequity and rejection. Neurodivergent females are especially prone to many physical and psychological health issues, and musculoskeletal disorders account for a significant proportion of these. Research and education into neurodivergent conditions in females should inform the reassessment of clinicians’ present approach to those who present with multiple unexplained symptoms. Obtaining official confirmation of a neurodivergent condition improves access to support services and helps them and their family better understand themselves and the challenges they face. This commentary highlights the increased risk of developing rheumatological disease for females with neurodivergent conditions and suggests how clinicians might increase their awareness of this. Full article

The axial skeleton, with the exception of spondyloarthropathy, is the most neglected aspect of rheumatology training and, as a result, perhaps the most complex. The clinical “problem” of back/neck pain could be considered the “orphan child” of medicine, and our perspective as rheumatologists is often sought for such entities. Sources of back/neck pain are myriad, and not all phenomena affecting the back are symptomatic. Perhaps the one that has most concerned rheumatologists is the cervical instability associated with rheumatoid arthritis. The current review examines intrinsic and extrinsic alterations in axial skeletal components, providing a guide to discriminating the causes (e.g., Scheuermann’s disease versus osteoporotic compression and the various forms of axial joint ankylosis) and the implications of vertebral endplate alterations. The specificity and sensitivity (limitations) of radiologic findings are reviewed, with a reminder that vertebral body osteophytes do not represent osteoarthritis and are therefore unlikely to explain back or neck complaints and that it is our clinical examination which will likely suggest symptom origin. Full article