Search Results (288)

Background/Objectives: Degenerative processes of the hip joint increasingly affect not only the articular cartilage but also periarticular structures such as the joint capsule and acetabular labrum. This study aimed to investigate the structural and molecular changes occurring in these tissues during advanced hip osteoarthritis. Methods: A combined analysis using immunohistochemistry (IHC), scanning electron microscopy (SEM), and micro-computed tomography (microCT) was conducted on tissue samples from patients undergoing total hip arthroplasty and from controls with morphologically normal joints. Markers associated with proliferation (Ki67), inflammation (CD68), angiogenesis (CD31, ERG), chondrogenesis (SOX9), and lubrication (Lubricin) were evaluated. Results: The pathological group showed increased expression of Ki67, CD68, CD31, ERG, and SOX9, with a notable decrease in Lubricin. SEM analysis revealed ultrastructural disorganization, collagen fragmentation, and neovascular remodeling in degenerative samples. A significant correlation between structural damage and molecular expression was identified. Conclusions: These results suggest that joint capsule and acetabular labrum degeneration are interconnected and reflect a broader pathophysiological continuum, supporting the use of integrated IHC and SEM profiling for early detection and targeted intervention in hip joint disease. Full article

Introduction/Objectives: Osteoarthritis (OA) is a chronic systemic disease that affects the entire array of joint structures. It is one of the most common chronic, socially significant diseases, associated with a decline in the quality of life of patients and constantly increasing the cost of treatment. Clinical trial outcomes are largely inconclusive, and OA remains one of the few musculoskeletal diseases without an established disease-modifying therapy. One potential explanation is the use of ineffective tools for OA classification, patient stratification, and the assessment of disease progression. There is growing interest in musculoskeletal ultrasonography (MSK US), as it enables the dynamic visualization of the examined structures and gives information about both inflammatory and structural changes that have occurred. Determining the leading ultrasound phenotype, which depends on the most damaged tissue at a given time (bone, cartilage, synovial membrane, joint capsule, ligaments, tendons, menisci, etc.), can rationalize therapy use by selecting patients more suitable for specific treatments. This article aims to evaluate and summarize the potential of MSK US in the process of determining the clinical phenotype of OA and to emphasize the importance of this imaging modality in evaluating further therapeutic strategies. Method: A single-center prospective study conducted in the period of September 2023–June 2024 enrolled 259 consecutive patients with proven OA. The statistical program Minitab version 22.2.1 (2025) was used to analyze the data. The predominant and secondary phenotypes were tabulated for each OA localization and were presented numerically and as relative proportions (%). The rate of the most frequently occurring phenotypes was compared against that of the less frequent ones through paired z-tests. The initially acceptable type I error was set at 5%; it was further adjusted for the number of comparisons (Bonferroni). Results: The most frequent and predominant US phenotype for patients with knee OA was intra-articular effusion (n = 47, 37.90%). It was significantly higher compared to the rest of the US phenotypes: synovial proliferation (n = 22, 17.70%; p < 0.001), cartilage destruction (n = 26, 21%; p = 0.001), altered subchondral bone (n = 8, 6.50%; p < 0.001), extra-articular soft tissue changes (n = 12, 9.70%; p < 0.001), crystal deposits (n = 6, 4.8%; p < 0.001), and post-traumatic (n = 3, 2.40%; p < 0.001). The most common US phenotype for hip OA was altered subchondral bone (n = 32, 47.1%), with significant differences from intra-articular effusion (n = 12, 17.60%; p = 0.001), synovial proliferation (n = 5, 7.40; p = 0.001), cartilage destruction (n = 12, 17.60%; p = 0.001), extra-articular soft tissue changes (n = 3, 4.40%; p = 0.001), crystal deposits (n = 3, 4.40%; p = 0.001), and post-traumatic (n = 0). Altered subchondral bone was also the leading US phenotype for hand OA (n = 31, 55.40%), with significant differences compared to intra-articular effusion (n = 1, 1.80%; p < 0.001), synovial proliferation (n = 7, 12.50%; p < 0.001), cartilage destruction (n = 11, 19.60%; p < 0.001), extra-articular soft tissue changes (n = 2, 3.60%; p < 0.001), crystal deposits (n = 3, 5.40%; p < 0.001), and post-traumatic (n = 1, 1.80%, p < 0.001). For shoulder OA, extra-articular soft tissue changes were the most frequent (n = 8, 46.20%), followed by post-traumatic (n = 4, 30.70%), as the rate of both phenotypes was significantly higher compared to that of intra-articular effusion (n = 0), synovial proliferation (n = 0), cartilage destruction (n = 1, 7.70%; p = 0.003), and crystal deposits (n = 0). Conclusions: The therapeutic approach for OA is a dynamic and intricate process, for which the type of affected joint and the underlying pathogenetic mechanism at a specific stage of the disease’s evolution is essential. MSK US is one of the options for the clinical phenotyping of OA. Some of the suggested ultrasound subtypes may serve as the rationale for selecting a particular treatment. Full article

Objectives: We wished to evaluate the safety profile of the Janus kinase (JAK) inhibitors used in the Spanish population; to study the onset of major adverse cardiovascular events (MACEs) and thrombotic events (arterial and venous); and to analyze the factors associated with the onset of these events. Methods: We conducted a retrospective observational study of a cohort of patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA) included in the biological therapy registry of the Rheumatology Department of Virgen Macarena University Hospital (HUVM), Seville, Spain, who started targeted treatment between 2019 and late 2024. We collected data on disease activity, traditional cardiovascular risk factors, the Charlson comorbidity index, previous synthetic or biologic drug therapy, the use of corticosteroids (and their dose), severity data (structural damage, extra-articular manifestations), and adverse events at the end of follow-up (e.g., MACEs, infections, neoplasms, and herpes zoster). We performed a descriptive bivariate analysis and a multivariate logistic regression analysis (dependent variable: MACEs) to identify factors that were independently associated with MACEs. Results: The study population comprised 137 patients (110 with RA, 18 with PsA, and 9 with SpA) who were followed up for a mean of 3.9 (2.6) years. Most patients had received JAK inhibitors as their second-line or subsequent treatment. At the end of the follow-up, 82 patients (66.7%) continued their treatment. Nine patients (6.6%) experienced a MACE, and five experienced a heart attack. All of these patients had RA. We found no differences between JAK inhibitors in terms of the incidence of the adverse events studied. Patients who experienced MACEs were more often male and smokers (current or former) and more often had hypertension and diabetes. No significant differences were found in the association with disease activity or previous or concomitant treatment. The factors that were independently associated with MACEs were a previous cardiovascular event (OR, 10.74; 95%CI, 1.05–113.7; p = 0.036), male sex (OR, 9.7; 95%CI, 1.6–76.5; p = 0.016), diabetes mellitus (OR, 10.3; 95%CI, 1.75–83; p = 0.013), and the duration of treatment with JAK inhibitors (OR, 1.47; 95%CI, 1.13–2.01; p = 0.005). Conclusions: We found no differences in the onset of adverse events, specifically MACEs, between the different JAK inhibitors analyzed. These events are more common in patients who already have cardiovascular risk factors, such as diabetes mellitus, or who have already experienced a cardiovascular event. JAK inhibitors broadly suppress cytokines in patients whose disease is refractory to other treatments. However, we must continue to evaluate their long-term safety in real-world studies. Full article

Background/Objectives: Recombinant Fc proteins have been produced that have a protective effect in mouse models of arthritis, such as the K/BxN rheumatoid arthritis model. We have previously shown that a recombinant human IgG1 Fc with a point mutation at position 309, replacing a leucine with a cysteine, fused to the human IgM tailpiece to form a human IgG1 Fc hexamer, rFc-µTP-L309C, effectively prevents neutrophil infiltration into the joints and ameliorates arthritis in the K/BxN serum transfer model and in the endogenous chronic arthritis K/BxN model. We have now investigated the effect of rFc-µTP-L309C on T-cells in the K/BxN chronic arthritis mouse model. Methods: PBMCs were isolated from the spleen, lymph nodes and joint synovial fluid from K/BxN mice having severe chronic arthritis that had been treated with 200 mg/kg rFc-µTP-L309C or human serum albumin (HSA). Flow cytometry was used to isolate the activated CD4⁺CD44⁺ T-cells and T-regulatory cells (Tregs). Intracellular staining was used to identify Th1 and Th17 T-cell subsets, and CD4⁺CD25⁺FoxP3⁺ Tregs. ELISA was used to measure levels of IL-10 and TGF-β in synovial fluid. Results: We find that amelioration of the arthritis occurs after treatment with rFc-µTP-L309C and results in a decrease in Th1 cells’ production of IFNγ and Th17 cells’ production of IL-17. Amelioration also results in decreased production of GM-CSF. Moreover, amelioration results in increased Tregs and IL-10 production in the synovial fluid. Conclusions: rFc-µTP-L309C reduces the inflammatory T-cells and increases the regulatory anti-inflammatory T-cells in the chronic arthritis K/BxN mouse model. This effect explains, in part, the ability of rFc-µTP-L309C to ameliorate the arthritis and reduce damage on the articular cartilage of K/BxN mice. Full article

Osteoarthritis (OA) is now widely recognized not merely as a cartilage-centric disease but as a multifactorial disorder affecting the entire joint as an organ, including the articular cartilage, subchondral bone, synovium, ligaments, menisci, and the innervating neural elements. This review explores the complex pathophysiology of OA with a focus on the emerging mechanisms of pain and inflammation that extend beyond articular cartilage degradation. Joint inflammation driven by immune activation in response to cellular stress signals promotes the release of pro-inflammatory mediators and catabolic enzymes. Key signaling pathways such as NF-κB, MAPKs, and JAK/STAT amplify these responses, and pain is sustained through peripheral and central sensitization, contributing to exacerbating symptoms even in the absence of visible joint damage. This review also integrates molecular and cellular mechanisms to highlight innovative therapies aimed at modifying both the structural damage and neurosensory drivers of pain. These approaches offer the potential to not only alleviate symptoms but also alter disease progression, signaling a move toward personalized, mechanism-based treatments. Given the intricate interactions among joint tissues, immune activation, and sensory processing, a comprehensive strategy that targets both structural degeneration and neuroinflammation is essential for the future of OA management. Emphasizing the joint as an integrated organ, we advocate for translational research linking molecular pathology with clinically meaningful outcomes. Full article

Articular cartilage is an avascular and aneural connective tissue that is frequently damaged due to trauma or degenerative joint diseases, often resulting in arthritis. Its limited intrinsic capacity for self-renewal poses a significant challenge to effective repair. Hence, the development of regenerative strategies is essential to enhance the poor intrinsic healing of cartilage tissue. Photobiomodulation (PBM) has gained increasing attention as a noninvasive, drug-free, and safe approach. PBM exerts photobiological effects that promote cellular responses and reduce inflammatory conditions, all of which are beneficial for cartilage repair. Nonetheless, the efficacy of PBM varies depending on treatment parameters and treated targets. This review first summarizes PBM parameter-dependent outcomes in cartilage regeneration studies. Reported data indicate frequent use of red lasers (600–660 nm, 0–10 J/cm²), GaAIAs lasers (800–880 nm, 10–50 J/cm²), and Nd:YAG lasers (1064 nm, up to 200 J/cm²) in in vitro, in vivo, and clinical studies. Moreover, PBM in conjunction with cartilage tissue engineering (CTE) has shown synergistic effects, enhancing scaffold-based repair outcomes. This review additionally explores PBM applications within CTE frameworks. The summarized findings aim to inform researchers and physicians by outlining optimized PBM strategies and highlighting PBM’s strong potential in promoting cartilage regeneration, both independently and in combination with CTE. Full article

Synovial inflammation is recognised as a pathological driver of osteoarthritis (OA), a degenerative joint disease involving cartilage degradation and joint pain. Since extracellular vesicles (EVs) have emerged as key mediators of cellular cross-talk, this study characterised synovial fluid EVs (SFEVs) in OA patients with varying disease severity and determined their functional effects on OA articular chondrocytes. Synovial fluid and articular cartilage were collected from patients undergoing knee surgery. SFEVs were isolated via ultracentrifugation and characterised by nanoparticle tracking analysis, ExoView, and Luminex analysis of protein cargo. Patients were stratified into mild/moderate- and severe-OA groups based on Oxford Knee Score and EQ5D. Chondrocytes were treated with SFEVs, and transcriptomic and secretome responses were analysed using RNA sequencing, Luminex, and ELISA. SFEVs from patients with severe OA were more abundant, smaller and exhibited increased tetraspanin expression. Synovial fluid and SFEVs induced distinct transcriptomic changes in chondrocytes. SFEVs from patients with severe OA promoted a pro-inflammatory and catabolic chondrocyte phenotype, with upregulation of CRTAC1, COL6A3, TNC, and CXCL5, greater secretion of IL-6, MMP1, MMP3 and MMP13, and pro-nociceptive mediators (NGF and Substance P). These findings suggest that SFEVs may contribute to OA progression by exacerbating cartilage damage and promoting pain sensitisation. Full article

Hyperuricemia, induced by monosodium urate (MSU) crystals that accumulate in articular joints and periarticular soft tissues, can impair macrophages. Possible causes of macrophage injury include uric acid-induced oxidative stress or inflammation. This study examined the dried fruits of guava (DFG) as a complementary medicine with urate-lowering properties, utilizing THP-1 macrophages to determine if high uric acid-induced cellular damage could be mitigated through the reduction of oxidative stress and inflammation via treatment with a phytochemical extract. The active extract was prescreened using a xanthine oxidase (XO) inhibition assay coupled with fractionation and component analysis. The DFG extracts were used to identify, through an in vitro study of THP-1 cells. The results indicated that the DFG extracts with the highest total flavonoids (12.08 ± 0.81 mg/g DW) exhibited the XO inhibition activity. High-performance liquid chromatography–tandem mass spectrometry analysis showed that DFG extract contained 85.32% flavonoids, including quercetin and kaempferol derivatives. Furthermore, fractionation results of DFG extracts indicated a significant reduction in MSU-induced cytotoxicity in THP-1 cells obtained from the 75% ethanol-eluted fraction (Fr-75). Additionally, kaempferol, an active compound in Fr-75, effectively mitigated MSU-induced NF-κB and NLRP3 gene overexpression. These findings suggest that the prepared Fr-75 is a promising hyperuricemia therapeutic candidate. Full article

Objective: Joint injury precipitates post-traumatic osteoarthritis (PTOA) via chondrocyte mitochondrial oxidative damage. Carbon monoxide (CO) is a small molecule with potent antioxidant and mitochondrial benefits in other tissues that have not been explored in healthy chondrocytes. We hypothesized that CO would subvert the mitochondrial effects of articular cartilage injuries upon resident chondrocytes. Design: We evaluated intra-articular delivery of a novel carbon monoxide-containing foam (COF). We used in vitro impact injuries to explore mitochondrial and redox endpoints after CO exposure. We then applied intra-articular injections of COF or control room air foam (RAF) to assess safety, efficacy, and other intra-articular responses. Results: COF increased the expression of HO1 and mitofusin-1 within 1 h and this increase was sustained for 12 h in vitro. COF increased chondrocyte mitochondrial respiration by 40% and increased reduced (not oxidized) thiols by 50% following in vitro injury to osteochondral explants. After cartilage injury, COF prevented the formation of 3-nitrotyrosine and the loss of articular chondrocyte mitochondria. When injected intra-articularly, COF was retained for 24 h post-injection in mouse stifle joints. It increased HO1 in those joints, enhanced reduced thiol levels in rabbit stifle joints, and exhibited no toxicity 1 and 4 weeks after injection. Conclusions: This study supports the hypothesis that CO functions as an antioxidant for articular chondrocytes by supporting mitochondria and intracellular GSH in the presence or absence of cartilage injury. Challenges in delivering exogenous CO have limited its preclinical development, but new CO-releasing materials like COF may enable new examinations of this promising small molecule. Full article

Articular cartilage has limited regenerative potential due to its anatomical characteristics, making complete recovery from damage challenging. Microfracture (MFx) is a widely used technique to promote cartilage healing, often enhanced with scaffolds to improve outcomes. In this study, we compared the efficacy of bilayer atelocollagen and standard collagen scaffolds combined with MFx in treating osteochondral defects in a rabbit model. Three articular cartilage defects were created in the femoral condyle of each rabbit and treated with either MFx plus a bilayer atelocollagen scaffold (test group), MFx plus a standard collagen scaffold (positive group), or MFx alone (negative group). Macroscopic and histological assessments were performed at 3, 6, and 12 weeks. By week 12, macroscopic examination showed hyaline-like cartilage restoration in the test group, while the positive group exhibited restoration with some overgrowth, and the negative group showed no restoration. Histological analysis revealed significantly better restoration in the test group than in the negative group, with comparable outcomes between the test and positive groups. These findings suggest that bilayer atelocollagen scaffold implantation following MFx is a promising treatment for articular cartilage defects and may provide a viable therapeutic option for patients with cartilage damage. Full article

Background: An increasing number of total elbow arthroplasty (TEA) procedures are performed in trauma patients every year through a variety of approaches. We have devised the Anconeus-reflected Triceps tongue (ARTT) approach for TEA, which optimizes soft tissue management and implant placement, particularly in post-trauma patients, where extensive scar tissue and/or marked bone deformity hamper joint exposure and carry a risk of component malposition. We describe the ARTT surgical technique, discuss its advantages, and report its preliminary results. Methods: Six consecutive patients with malunion of the articular elbow surfaces with severe soft tissue retraction and multiple previous surgeries underwent TEA using the ARTT approach, which spares the triceps tendon insertion on the olecranon and reflects the anconeus and triceps muscles as one. Results: At a mean follow-up of 29 months, the Mayo Elbow Performance Score had increased from 39 to 95 points, whereas the visual analog score for pain had fallen from 7.5 to 1. None of the patients had insufficiency or secondary detachment of the triceps tendon and all achieved grade 4 or 5 on the Medical Research Council scale. Discussion: The ARTT approach provides enhanced joint exposure, resulting in the preservation of the triceps tendon insertion on the olecranon and enabling earlier active rehabilitation. Our preliminary results indicate that it is a viable alternative to traditional techniques, particularly in post-trauma patients with severe elbow dysfunction, who often suffer from extensive scarring, soft tissue damage, and bone deformity. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammation that primarily affects the joints but can also involve extra-articular organs. Its multifactorial etiology remains incompletely understood, necessitating further investigation into its underlying mechanisms. The primary therapeutic goal in RA management is to achieve disease remission or maintain low RA activity to prevent long-term morbidity. RA therapies aim to mitigate joint damage, reduce disability, and prevent systemic complications such as cardiovascular diseases. In addition to pharmacological treatments, non-pharmacological interventions—including physiotherapy, occupational therapy, and lifestyle modifications such as smoking cessation, regular exercise, and adherence to a balanced diet—play a crucial role in managing the disease. Beyond joint inflammation, RA has been strongly associated with an increased risk of thrombosis, contributing significantly to both morbidity and mortality. The link between RA and thrombotic events arises from a complex interplay of inflammatory pathways, endothelial dysfunction, and coagulation abnormalities. This review provides an in-depth analysis of the mechanisms driving the association between thrombo-inflammatory manifestations and the incidence of RA, the impact of RA treatment on thrombosis prevalence, and potential therapeutic strategies for managing both conditions concurrently. By integrating recent advancements in rheumatoid arthritis (RA) pathophysiology and thrombo-inflammatory research, this paper provides a comprehensive resource on the inflammatory link between RA and thrombosis while discussing and comparing current and emerging treatment approaches. Further investigation into these mechanisms could facilitate the development of targeted therapies that reduce the risk of thrombosis in patients with RA. Full article

Background: Venous malformations (VMs) are congenital vascular abnormalities characterized by tortuosity, slow blood flow, and gradual growth. Intra-articular venous malformations (IAVMs) of the knee are rare and often present with symptoms similar to juvenile idiopathic arthritis (JIA) or late sequelae of trauma. VM in children is commonly misdiagnosed as hemangioma. This study aims to analyze the clinical and MRI features of IAVM in the knee joint. Methods: This retrospective study analyzed patients from a reference unit for the treatment of vascular malformations in the Pediatric Surgery Department. The group was collected starting from the year 2014 until the 100th patient was identified in the year 2018, all with MRI-confirmed VM based on a predefined protocol. From this group, 19 patients with lower limb symptoms were identified, and 9 patients with VM involving the knee joint were selected for further analysis. Results: The most common symptoms in IAVM patients were pain and swelling, chronic in five (55%) and intermittent in four (45%). Four (45%) reported worsening pain during or after physical activity. A history of intra-articular bleeding was noted in five (55%), leading to mild knee contracture (10° reduction in extension) and decreased mobility. Limb deformities were observed in eight (89%). Diffuse VMs, affecting both intra- and extra-articular tissues, were present in eight (89%), involving the thigh in seven (78%), crus in five (56%), gluteal muscles in three (33%), and foot tissues in one (11%). The suprapatellar recess and Hoffa’s fat pad were involved in all patients (100%). Conclusions: IAVMs are rare causes of knee dysfunction in children and young adults, particularly in cases of unexplained pain, swelling, or instability. They should be considered in the differential diagnosis of hemophilic arthropathy, JIA, or late post-traumatic sequelae. Untreated IAVMs can lead to intra-articular bleeding, cartilage degeneration, and disability. Early diagnosis via MRI and ultrasound is crucial to identifying IAVMs and preventing joint degeneration. Timely treatment helps avoid further damage and long-term disability. Full article

Traumatic or degenerative defects of articular cartilage impair joint function, and the treatment of articular cartilage damage remains a challenge. By mimicking the cartilage extracellular matrix (ECM), exosome-seeded cryogels may enhance cell proliferation and chondral repair. ECM-based cryogels were cryopolymerized with gelatin, chondroitin sulfate, and various concentrations (0%, 0.3%, 0.5%, and 1%) of hyaluronic acid (HA), and their water content, swelling ratio, porosity, mechanical properties, and effects on cell viability were evaluated. The regenerative effects of bone marrow-derived mesenchymal stem cell (BM-MSC)-derived exosome (at a concentration of 10⁶ particles/mL)-seeded 0.3% HA cryogels were assessed in vitro and in surgically induced male New Zealand rabbit cartilage defects in vivo. The water content, swelling ratio, and porosity of the cryogels significantly (p < 0.05) increased and the Young’s modulus values of the cryogels decreased with increasing HA concentrations. MTT assays revealed that the developed biomaterials had no cytotoxic effects. The optimal cryogel composition was 0.3% HA, and the resulting cryogel had favorable properties and suitable mechanical strength. Exosomes alone and exosome-seeded cryogels promoted chondrocyte proliferation (with cell optical densities that were 58% and 51% greater than that of the control). The cryogel alone and the exosome-seeded cryogel facilitated ECM deposition and sulfated glycosaminoglycan synthesis. Although we observed cartilage repair via Alcian blue staining with both the cryogel alone and the exosome-seeded cryogel, the layered arrangement of the chondrocytes was superior to that of the control chondrocytes when exosome-seeded cryogels were used. This study revealed the potential value of using BM-MSC-derived exosome-seeded ECM-based cryogels for cartilage tissue engineering to treat cartilage injury. Full article

Background: Ozone therapy is used for its immunomodulatory, antioxidant, and analgesic properties in several fields. It can be useful in the rehabilitation of musculoskeletal disorders. Studies showed that O₂-O₃ therapy can reduce pain and improve functioning in patients affected by low back pain and knee osteoarthritis. Only a few studies have been published about the efficacy of this treatment in upper limb disease. Objective: The aim of this study is to investigate the use of ozone therapy in upper limb pathologies, evaluating its quantity, quality, and reported results in upper limb musculoskeletal disease, supraspinatus tendinopathy, shoulder impingement, adhesive capsulitis, chronic epicondylitis, and carpal tunnel syndrome. O₂-O₃ reduces inflammation by stimulating anti-inflammatory cytokines and inactivating pro-inflammatory molecules, relieves pain by interacting with pain receptors and improving blood circulation, promotes the regeneration of damaged tissues by stimulating growth factors and improving vascularization, and, finally, activates endogenous antioxidant defense systems by protecting cells from oxidative damage. Methods: A comprehensive search was conducted on PubMed and Scopus using the following MeSH terms: ozone therapy, infiltration joint, musculoskeletal disease, rehabilitation, upper limb, shoulder, wrist, hand, elbow, including English papers published in the last five years. Results: Five papers have been selected: four randomized controlled trials and one retrospective cohort study. The RCTs compared the effectiveness of intra-articular ozone injection with steroid injection alone or with other conservative treatments in shoulder diseases; one paper studied the effectiveness of ozone injection and orthoses in carpal tunnel syndrome compared to orthoses alone; one paper used ozone injections compared with steroid injection in patients with chronic lateral epicondylitis. A total of 218 patients were studied in these trials. Conclusions: Ozone treatment seemed to improve pain and function as well as other therapies in upper limb musculoskeletal disease. However, the trials’ protocols and the upper limb areas treated are different. Further studies are needed to define the effectiveness of ozone therapy in upper limb diseases in rehabilitation fields. Full article