The most common clinical manifestation of hyperlipidemia is the formation of xanthomas, which are most often localized subcutaneously, sometimes involving tendons and ligaments, and are usually asymptomatic. A fairly rare manifestation of hyperlipidemia is hypercholesterolemic arthritis caused by cholesterol crystals. In this article, we present a case of atypical xanthoma formation in a patient in the area of the first metatarsophalangeal joint, which resembled a gouty tophus. Taking into account the presence of hyperuricemia in the blood and the “classic” lesion of the first metatarsophalangeal joint, gout was primarily suspected in the patient. The diagnosis of arthritis associated with cholesterol crystals was confirmed using the “gold standard” diagnosis of microcrystalline arthritis—crystal detection using polarization microscopy. This case gives a clear idea of how important it is not to rely solely on the clinical picture when diagnosing gout.

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Antioxidant and anti-inflammatory compound whose biological properties have been linked to modulation of oxidative stress, cytokine signaling, and bone metabolism. Given the central role of oxidative and inflammatory mechanisms in rheumatic diseases, lycopene has emerged as a potential nutraceutical adjunct. This narrative review summarizes current evidence regarding lycopene supplementation and its effects on rheumatic and musculoskeletal disorders, integrating clinical, preclinical, and mechanistic data into a single comprehensive synthesis. A literature search was conducted in PubMed, SciELO, and LILACS up to July 2024, focusing on studies evaluating lycopene in rheumatic or musculoskeletal contexts. Three human studies met the inclusion criteria, all conducted in postmenopausal women, and demonstrated beneficial effects on bone metabolism and oxidative stress markers without adverse effects. Additional experimental evidence supports lycopene’s antioxidant, anti-inflammatory, and bone-protective actions, reinforcing its potential biological relevance in rheumatology. Overall, the available evidence suggests that lycopene may represent a promising, safe, and accessible adjunct for oxidative stress modulation and bone preservation, particularly in osteoporosis. However, the magnitude and durability of these effects remain to be clarified in larger, well-designed randomized trials, especially in inflammatory rheumatic diseases.

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Scleroderma, also known as systemic sclerosis, is a rare connective tissue disorder with an unclear and poorly understood pathogenesis. While it primarily affects the skin and internal organs through mechanisms involving vascular dysfunction, immune dysregulation, and fibrosis, its effects on the peripheral nervous system may also be substantial. We report the case of a 36-year-old male with a known history of scleroderma who presented with chronic, diffuse burning pain throughout the body. His symptoms included daily asthenia, dizziness, nausea, headaches, and limb pain exacerbated by cold, compression, or stretching. Diagnostic ultrasound confirmed multiple peripheral nerve entrapments, which were treated with ultrasound-guided 5% dextrose hydrodissection. This intervention provided significant relief of pain, paresthesia, and motor symptoms, which improved his quality of life. This case highlights the potential of dextrose hydrodissection as a safe, minimally invasive, and cost-effective symptomatic treatment for peripheral neuropathies in patients with scleroderma. Further studies are warranted to establish its broader therapeutic role in treating scleroderma-related neuropathies.

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Adhesive capsulitis, or frozen shoulder, is characterized by pain and progressive restriction of both active and passive shoulder range of motion. The pathophysiology involves an initial inflammatory phase with elevated cytokines, followed by pathological fibrosis, capsular thickening, and contracture involving both intra- and extra-articular structures, including the coracohumeral ligament and rotator cuff interval. Diagnosis is primarily clinical. The traditional three-stage model, freezing, frozen, and thawing, has been challenged by recent evidence showing that spontaneous recovery is uncommon and that many patients do not fully regain shoulder function without active treatment. This paradigm change emphasizes the necessity of early and focused interventions to maximize functional recovery. While physiotherapy remains the mainstay of management, interventional procedures have gained prominence for their ability to reduce pain and facilitate rehabilitation. Interventional options include intra-articular corticosteroid injections, hydrodilatation, and suprascapular nerve blocks. This narrative review summarizes current evidence on interventional procedures for adhesive capsulitis, highlighting their mechanisms, techniques, and comparative efficacy.

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Osteoporosis is a systemic skeletal disease characterized by low bone mineral density (BMD) and poor bone quality, leading to reduced bone strength and increased risk of fracture. In rheumatic and musculoskeletal diseases (RMD), including rheumatoid arthritis (RA) and spondyloarthritides (SpA), such as axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA), generalized bone loss associated with traumatic and non-traumatic fractures, such as insufficiency fractures (IF), is known to occur with the RANK-RANKL-osteoprotegerin axis and the Wnt-β-catenin signalling pathway playing a pathogenetic role. RA has been included in the Fracture Risk Assessment Tool (FRAX) system to be able to more precisely calculate the 10-year fracture risk associated with the disease. Various definitions for IF have been proposed; a recent paper by the EMA has defined fragility fractures as fractures occurring with low trauma at the hip, spine, pelvis, distal femur, proximal tibia, humerus, forearm, and multiple ribs. However, IF of the feet are currently not considered osteoporotic fractures. So-called stress fractures, which are known to often occur in athletes, have a similar MRI appearance. However, these are rather due to repetitive strain than to minor trauma. Also, based on recent data, this manuscript concentrates on the significance of fragility fractures in RMD.

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Immune checkpoint inhibitors (ICIs) have transformed cancer care, but their use is frequently complicated by immune-related adverse events (irAEs), including rheumatic manifestations such as arthritis. Distinguishing between inflammatory and non-inflammatory musculoskeletal symptoms is challenging, yet critical for appropriate management. Musculoskeletal ultrasound (MSKUS) provides unique advantages in this context by enabling the detection of subclinical synovitis, periarticular pathology, and crystal deposition, while also facilitating treatment decisions, including targeted corticosteroid injections. We present four cases that highlight the utility of MSKUS as a frontline tool in the evaluation of musculoskeletal irAEs.

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In the past decade, the metabolic syndrome has been recast as a chronic inflammatory disease whose mechanisms involve macrophage and neutrophil activation, initiation of the nod-like receptor protein 3 (NLRP3) inflammasome, and IL-1β secretion. Colchicine, an inhibitor of NLRP3, has been linked to the prevention or amelioration of diseases associated with the metabolic syndrome, including diabetes and cardiovascular disease. Its underlying therapeutic mechanisms extend beyond direct suppression of NLRP3, and include sirtuin and AMP-activated protein kinase (AMPK) pathway regulation, and downregulation of cellular stress signals, which promote atherosclerotic plaque rupture, insulin resistance, and obesity. Colchicine’s proven efficacy in preventing cardiovascular disease is a promising new development recognized by its inclusion in the 2023 American College of Cardiology treatment guidelines. As colchicine’s effects are better understood, along with a clearer understanding of metabolic syndrome’s pathophysiology, promising new applications and uses for this old drug may be on the horizon and are worthy of further investigation. In this review, we discuss colchicine’s pharmacology and explore its established and emerging anti-inflammatory mechanisms, and the role these could play in disrupting the chronic inflammation in metabolic syndrome and associated diseases.

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Gout is a chronic inflammatory arthritis driven by monosodium urate crystal deposition and the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome activation, leading to interleukin-1β (IL-1β)-mediated inflammation. Recent studies reveal that hyperuricemia induces a state of immunological memory in innate immune cells through persistent epigenetic and metabolic reprogramming of monocytes and macrophages. These alterations enhance the responsiveness of innate immune cells, leading to exaggerated inflammatory reactions upon subsequent stimulation. This review synthesizes recent studies that elucidate how metabolic shifts (e.g., increased glycolysis and fumarate accumulation) and epigenetic changes (e.g., altered histone methylation and DNA methylation) reinforce this pathogenic memory. Importantly, these mechanistic insights provide the rationale for emerging therapeutic strategies: IL-1β inhibitors aim to interrupt the central inflammatory axis; metabolic modulators (e.g., metformin, statins) seek to reverse the trained metabolic state; and epigenetic therapies [e.g., histone deacetylase (HDAC) or DNA methyltransferase (DNMT) inhibitors] hold potential to reset dysregulated immune programming. Collectively, this review argues that multi-layered intervention, such as cytokine blockade for acute control, coupled with metabolic or epigenetic remodeling for long-term reprogramming, could yield sustained disease suppression and reduced flare frequency in gout.

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Arterial thoracic outlet syndrome (aTOS) is a rare condition, but it has an elevated incidence among athletes due to high mechanical demands placed on the upper extremities. Post-surgical rehabilitation guidelines for aTOS are not well defined, especially in high-performance populations. Mechanically loaded neurodynamics (MLND) is a novel technique that introduces controlled external load during neurodynamic movements to optimize neurovascular adaptation and musculoskeletal function. A 47-year-old professional long-distance cyclist presented with left upper extremity pain, paresthesia, and vascular symptoms three weeks after undergoing left first rib and cervical rib resection with scalenectomy for aTOS. The patient had significant scapular dyskinesis, thoracic spine hypomobility, glenohumeral joint stiffness, and posture-related thoracic outlet compression, alongside hyperalgesia and allodynia in the ulnar nerve distribution. A structured 11-week physical therapy protocol was implemented, including traditional and MLND techniques, progressive scapular and thoracic mobility training, and sport-specific strengthening. MLND was introduced to progressively load neural tissues in median, ulnar, and radial nerve distributions while addressing musculoskeletal impairments that contribute to thoracic outlet compression. The patient demonstrated a significant reduction in pain and neurological symptoms, resolution of allodynia, restoration of full active range of motion, ≥ 93% limb symmetry index in strength testing, and an improvement in DASH score from 86.7 to 2.5. The athlete returned to unrestricted cycling at her previous level within 3.5 months post-operation. No adverse effects were reported with MLND use. This case highlights the potential role of MLND in accelerating recovery following thoracic outlet surgery in athletic populations. The approach emphasizes progressive mechanical loading to stimulate neurovascular adaptation and addresses the underlying musculoskeletal impairments contributing to neurovascular compression. Given the absence of standardized protocols for aTOS rehabilitation, MLND may serve as a safe and effective intervention. Future research should further investigate its mechanophysiological effects and clinical efficacy through controlled trials.

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The dynamic organization of chromatin plays a critical role in regulating muscle cell differentiation. Among the molecular elements influencing chromatin architecture, long noncoding RNAs (lncRNAs) have emerged as important regulators due to their capacity to act as scaffolds, recruiters of chromatin-modifying proteins, or as transcriptional enhancers. This review aims to explore the mechanisms by which lncRNAs influence chromatin structure in the context of skeletal muscle differentiation. We classified the functional roles of lncRNAs into three main strategies: recruitment of epigenetic modifiers, assembly of transcriptional scaffolds, and regulation through enhancer-like activity. We provide specific examples of lncRNAs associated with these mechanisms and discuss their involvement in the control of myogenic gene expression. These findings highlight the complexity and specificity of lncRNA-mediated chromatin remodeling and suggest their potential as targets for therapeutic intervention in muscle-related disorders.

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Calcium pyrophosphate crystal deposition disease is a prevalent and impactful form of crystal arthropathy. It usually targets the large joints of the extremities, significantly affecting daily life. Progression of this disease, commonly observed in older individuals and often mistaken for septic arthritis, osteoarthritis, or several rheumatic conditions, remains poorly understood. The disease can present in various forms, from asymptomatic to severe joint deformity. The primary goal of treating this disease is to firmly control inflammation, prevent joint deformities, and decisively stop attacks. Medications used to treat the disease include anti-rheumatic drugs such as non-steroidal anti-inflammatory drugs, oral, intramuscular, or intra-articular steroids, hydroxychloroquine, colchicine, methotrexate, and interleukin-1 receptor antagonists. Radiosynovectomy is a radioactive technique that effectively targets and eliminates inflamed synovium. This article highlights the importance of awareness and early intervention to manage this condition effectively.

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Calcium pyrophosphate deposition (CPPD) disease represents a crystal-induced arthropathy characterized by the deposition of calcium pyrophosphate dihydrate crystals within the articular joints and adjacent soft tissues. The manifestation of CPPD can present in a variety of clinical forms, including acute pseudogout episodes, chronic inflammatory arthritis, a variant associated with osteoarthritis, and the “crowned dens” syndrome; alternatively, it may be identified incidentally during radiological assessments. The condition is predominantly observed in individuals aged over 60 years, with its incidence escalating in correlation with advancing age. The presence of CPP crystals activates the innate immune response, subsequently eliciting an inflammatory cascade. Among the mechanisms implicated in this inflammatory process are the activation of the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3 (NLRP3) inflammasome, and the secretion of matrix metalloproteinases. The elevation of pro-inflammatory cytokines such as IL-6, IL-8, TNF-α, and pro-IL-1β exacerbates the inflammatory state within the affected joint. Although there is a marginally higher prevalence of CPPD in females, this gender disparity is not deemed statistically significant. CPPD may also manifest in younger and middle-aged populations, necessitating vigilance regarding potential metabolic disorders or hereditary conditions in such cases. The diagnosis of CPPD is predominantly established through a combination of clinical assessment and imaging modalities. The definitive diagnostic criterion involves the identification of CPP crystals in synovial fluid utilizing polarized light microscopy. Clinically, CPPD can be misdiagnosed as rheumatoid arthritis (RA), polymyalgia rheumatica (PMR), infectious arthritis, and other crystal-related arthropathies. The recently developed classification criteria by ACR/EULAR in 2023 are intended to enhance the precision of diagnosis. This review seeks to encapsulate the pathophysiology, clinical presentation, and diagnostic approaches related to CPPD disease, informed by contemporary literature.

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Biologics are complex protein-based medications derived from living organisms, used primarily to treat immune-related diseases. Unlike small-molecule drugs synthesized from chemicals, biologics are produced using advanced biotechnology, making their replication difficult. Biosimilars are nearly identical alternatives to biologics, and they offer a cost-effective option that produces equivalent safety or efficacy outcomes as their reference biologics. Biosimilars are not classified as generic drugs and have a unique regulatory pathway. While biosimilars must demonstrate structural, functional, and clinical similarity to reference biologics, regulatory requirements vary across the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the World Health Organization (WHO). The FDA used to mandate clinical studies for interchangeability status, while the EMA and WHO had more flexible approval pathways that enable broader biosimilar adoption. However, the FDA’s approach is evolving, and they may grant interchangeability with scientific justification without separate switching studies. Regulatory inconsistencies extend beyond biosimilars, as batch-to-batch variability in brand-name biologics does not face the same scrutiny as biosimilar approvals. Addressing these regulatory disparities and greater alignment among the FDA, EMA, and WHO may enhance biosimilar adoption. Acceptance of biosimilars may expand treatment accessibility, reduce healthcare costs, and maintain standards of safety and efficacy in managing musculoskeletal diseases.

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Systemic inflammatory rheumatic disorders are associated with an increased risk of malignancy. The mechanism linking malignancy and rheumatic diseases is complex and multidirectional, and is only partially understood. This review focused on the incidence of neoplastic diseases in patients with the most common systemic rheumatic disorders. Rheumatoid arthritis is associated with a risk of malignancy that is about 10% higher than in the general population, and this is more related to the disease itself than to medication. Systemic lupus erythematosus is associated with an increased risk of neoplasms, particularly haematological malignancies such as non-Hodgkin lymphoma. The risk increases with long-lasting active disease. Systemic sclerosis is associated with an increased risk of lung and liver cancer, as well as malignancies of the haematological system. Men and patients with RNA polymerase III antibodies are at a higher risk. Dermatomyositis and polymyositis are subgroups of idiopathic inflammatory myopathy associated with a high risk of malignancy. Male gender and old age are additional risk factors. Other rheumatic diseases are also thought to be associated with an increased risk of cancer. Currently, the data are insufficient for a clear distinction to be made between subgroups at risk. Most patients with systemic autoimmune disorders are at enhanced risk of malignancy to some degree. The management of these patients should include procedures for the early detection of age- and population-specific malignancies, as well as those which are more prevalent in the patient population suffering from the individual rheumatic disease. It is important to note that an atypical disease course or increased treatment resistance for a rheumatic disorder may indicate that the observed changes are an expression of a paraneoplastic syndrome or that a new neoplasm is modifying the clinical course of an already diagnosed rheumatic disease.

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Commercialized non-autologous biologics are produced from a variety of human tissues and are intended to treat a wide range of musculoskeletal pathologies. This survey focuses on non-autologous biologic products that are delivered via the topical or percutaneous (i.e., injected) routes. The regulatory framework established in the USA will be reviewed, including an assessment of specific categories of non-autologous biologics with their intended uses, since regulatory compliance of a specific composition or physical form of a non-autologous biologic is tightly linked to its advertised use. Guidance is provided on how to manage emerging products whose regulatory status might be unclear. Clinical safety and efficacy for non-autologous biologics for wound and burn care, including minimally processed placental products in sheet form as well as bio-engineered viable cell composite products, are well established, although efficacy tends to be wound type-specific. Micronized placental tissue products have been investigated in treating osteoarthritis of the knee and hip, and for plantar fasciitis, but require large-scale clinical studies and remain to be approved by the United States Food and Drug Administration (USFDA). Several emerging types (secretomes, exosomes) of non-autologous biologics are well documented in pre-clinical studies, but human studies are lacking. There are no Phase 3 studies reported on a secretome-based product, while there is just one Phase 3 clinical trial on-going for a bone marrow progenitor cell derived exosome product that is being used to treat acute respiratory distress syndrome. There has been substantial progress in the commercialization of exosome-based products, with studies in treating musculoskeletal pathologies a priority. Progress has been made in assessing the treatment of osteoarthritic knees and discogenic low back pain with cultured progenitor cells. However, utility and safety of these investigational products remains to be determined.

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