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Review | DOI: https://doi.org/10.31579/2694-0248/107
1Medical Laboratories Techniques Department, College of Technology and Health Sciences, AL-Mustaqbal University, 51001, Hillah, Babylon, Iraq.
2Department of Biochemistry, Science Faculty, Menoufia University, Menoufia, Egypt.
3New burg El-Arab Hospital, Ministry of Health, Alexandria, Egypt.
4American Society for Clinical Pathology (ASCP), Chicago, USA.
*Corresponding Author: Tamer A. Addissouky, Medical Laboratories Techniques Department, College of Technology and Health Sciences, AL-Mustaqbal University, 51001, Hillah, Babylon, Iraq - Science Faculty, Menoufia University, Egypt. - New Burg El-Arab Hospital, Ministry of Healt
Citation: Tamer A. Addissouky, (2024), Unraveling the Molecular Signatures of Lupus-Associated Osteoarthritis: A Comprehensive Review of Novel Biomarker Strategies, J. Clinical Orthopedics and Trauma Care, 6(6); DOI:10.31579/2694-0248/107
Copyright: © 2024, Tamer A. Addissouky. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 21 October 2024 | Accepted: 28 October 2024 | Published: 06 November 2024
Keywords: lupus-associated osteoarthritis; biomarkers; systemic lupus erythematosus; joint inflammation; cartilage degradation.
Background: Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease affecting multiple organs, including joints. The co-occurrence of osteoarthritis (OA) in SLE patients, termed lupus-associated osteoarthritis (LAO), presents unique challenges in diagnosis and management due to overlapping symptoms and accelerated joint degradation.
Purpose: This review aims to explore the emerging landscape of novel biomarkers for early detection and monitoring of LAO, addressing the limitations of current biomarkers in capturing the unique pathophysiology of this condition.
Main Body: The pathophysiology of LAO involves a complex interplay between autoimmune inflammation and degenerative processes. Key molecular pathways include pro-inflammatory cytokines (TNF-α, IL-1, IL-6), matrix metalloproteinases, and oxidative stress mechanisms. Current biomarkers for OA (e.g., CTX-II, COMP) and SLE (e.g., anti-dsDNA, complement proteins) lack specificity for LAO. Emerging biomarker strategies encompass genomics, proteomics, and metabolomics approaches, aiming to distinguish between inflammatory lupus arthritis, typical OA, and LAO. These novel biomarkers could potentially revolutionize early detection, disease progression tracking, and personalized therapeutic interventions.
Conclusion: The development of LAO-specific biomarkers is crucial for improving early diagnosis and monitoring. Future research should focus on validating these biomarkers and translating them into clinical practice, potentially transforming the management of LAO in SLE patients.
• LAO presents unique diagnostic challenges due to overlapping symptoms with SLE and OA
• Novel biomarkers may revolutionize early detection and monitoring of LAO in SLE patients
• Integration of genomics, proteomics, and metabolomics approaches shows promise for LAO management.
Graphical Abstract
A. Overview of Systemic Lupus Erythematosus (SLE) and Osteoarthritis (OA)
Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease marked by excessive immune activity, leading to widespread inflammation and tissue damage. It affects multiple organs, including the skin, kidneys, heart, and joints [1-2]. Globally, SLE has a prevalence of approximately 20–150 cases per 100,000 individuals, with higher rates in women, particularly those of childbearing age. Ethnic disparities are also noted, with increased prevalence in African American, Hispanic, and Asian populations. SLE's hallmark is its heterogeneity, meaning symptoms and disease progression vary widely among patients [3-8]. On the other hand, Osteoarthritis (OA) is the most common form of arthritis, characterized by progressive cartilage degeneration, subchondral bone remodeling, and synovial inflammation. It predominantly affects the knees, hips, hands, and spine. OA is a major cause of disability worldwide, with its prevalence increasing with age, obesity, and joint injury. The primary pathophysiological mechanisms in OA involve mechanical stress, inflammatory mediators, and a breakdown in the homeostasis of cartilage and bone tissues [9-10]. In patients with SLE, the co-occurrence of OA adds another layer of complexity. Lupus-associated osteoarthritis (LAO), though less studied, presents unique challenges. The inflammatory milieu in SLE may accelerate cartilage breakdown, making these patients more susceptible to OA. While OA is traditionally viewed as a "wear and tear" disease, its manifestation in SLE suggests a more inflammatory-driven process. The prevalence of OA in SLE patients varies, with some studies suggesting that up to 10–30% of SLE patients develop OA, a rate higher than that of the general population [11-12].
B. Importance of Early Detection and Monitoring
Early diagnosis of OA in SLE patients is particularly challenging. The overlapping symptoms of joint pain, stiffness, and swelling in both SLE and OA can make differentiation difficult. Additionally, SLE patients often have a higher threshold for reporting joint symptoms due to their chronic disease burden. Timely intervention is crucial to prevent irreversible joint damage, reduce pain, and improve quality of life. Delays in diagnosis can lead to more aggressive disease progression, contributing to significant morbidity [13-16]. Biomarkers offer a promising avenue for improving early detection and monitoring of LAO. Identifying specific biomarkers that can distinguish between inflammatory lupus arthritis, typical OA, and lupus-associated OA could revolutionize clinical practice. Biomarkers could provide a non-invasive way to detect disease at earlier stages, track disease progression, and tailor therapeutic interventions more precisely [17-18].
C. Objectives of the Review
This review aims to explore the emerging landscape of novel biomarkers in the early detection and monitoring of lupus-associated osteoarthritis (LAO). By delving into recent advancements in genomics, proteomics, metabolomics, and other fields, the goal is to provide a comprehensive analysis of current and future biomarker strategies. Additionally, this review will discuss the potential clinical applications of these biomarkers, the challenges in their validation, and future directions for research in this critical area.
A. Mechanistic Overview
The pathophysiology of LAO is inherently tied to the autoimmune nature of SLE. In SLE, immune dysregulation leads to the production of autoantibodies and immune complexes, which deposit in tissues, including the joints. This results in synovial inflammation, a key driver of joint damage. The inflammation observed in lupus arthritis differs from that in OA, which is primarily driven by mechanical stress and aging [19]. In LAO, the combination of autoimmune inflammation and traditional OA degenerative processes accelerates cartilage breakdown. The synovium in SLE patients is often more inflamed than in primary OA, leading to a faster progression of joint destruction. Additionally, the immune complexes in SLE can activate complement pathways, further exacerbating inflammation and contributing to joint degradation [20-24].
B. Molecular Pathways Involved
Several molecular pathways are implicated in the pathogenesis of LAO. Pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6), play prominent roles. These cytokines promote cartilage breakdown by enhancing the activity of matrix metalloproteinases (MMPs), which degrade the extracellular matrix. Oxidative stress also contributes to joint degeneration in LAO. Inflammation leads to the production of reactive oxygen species (ROS), which can damage cartilage cells and further exacerbate joint degradation. Additionally, oxidative stress can impair the repair mechanisms of chondrocytes, the cells responsible for maintaining cartilage integrity [25-27].
A. Conventional Biomarkers in Osteoarthritis
In OA, several biomarkers are used to assess cartilage breakdown, synovial inflammation, and bone turnover. C-telopeptide of type II collagen (CTX-II) and cartilage oligomeric matrix protein (COMP) are widely recognized as markers of cartilage degradation as presented in Table 1. Elevated levels of hyaluronic acid (HA) and MMPs indicate synovial inflammation, while markers like serum osteocalcin and alkaline phosphatase reflect bone turnover [28-33].
| Biomarker Category | SLE Biomarkers | OA Biomarkers | LAO Biomarkers | Strengths | Limitations |
|---|---|---|---|---|---|
| Autoantibodies | Anti-dsDNA- Anti-Sm- Anti-RNP | - | Anti-dsDNA- Anti-Sm- Anti-RNP | High specificity for SLE- Useful for diagnosis | Limited correlation with joint damage |
| Inflammatory Markers | CRP- ESR | CRP- IL-6 | CRP- ESR- IL-6 | Reflect overall inflammation- Easy to measure | Non-specific- Can be elevated in various conditions |
| Cartilage Degradation | - | CTX-II- COMP | CTX-II- COMP | Direct indicators of cartilage breakdown | May not distinguish between OA and LAO |
| Synovial Inflammation | - | Hyaluronic Acid- MMPs | Hyaluronic Acid- MMPs | Reflect joint-specific inflammation | Can be elevated in both OA and LAO |
| Bone Turnover | - | Osteocalcin- Alkaline Phosphatase | Osteocalcin- Alkaline Phosphatase | Indicate bone remodeling | Not specific to joint pathology |
| Complement Proteins | C3- C4 | - | C3- C4 | Reflect SLE disease activity | May not correlate directly with joint involvement |
| Oxidative Stress | - | Malondialdehyde- 8-OHdG | Malondialdehyde- 8-OHdG | Indicate oxidative damage | Non-specific to joint pathology |
| Novel Biomarkers | miRNAs- Metabolomics profiles | miRNAs- Proteomics signatures | Integrated multi-omics profiles | Potential for high specificity and sensitivity | Still in research phase- Need further validation |
Table 1: Comparison of Biomarkers in SLE, OA, and LAO
B. Standard Biomarkers in SLE
In SLE, autoantibodies such as anti-double-stranded DNA (anti-dsDNA), anti-Smith, and anti-ribonucleoprotein (RNP) are commonly used in clinical practice. These autoantibodies are indicative of immune dysregulation in SLE. Complement proteins such as C3 and C4 are also measured, as their levels decrease during active disease. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are general markers of inflammation but are nonspecific [34-35].
C. Limitations of Current Biomarkers for Detecting LAO
Current biomarkers, while useful in detecting SLE or OA individually, lack specificity for lupus-associated OA. OA biomarkers do not account for the autoimmune-driven inflammation seen in SLE, while SLE biomarkers do not reflect the structural changes occurring in OA. This highlights the need for novel biomarkers that can capture the unique pathophysiology of LAO, particularly in the early stages when joint preservation is still possible [36-41].
A. Genomic Biomarkers
Single Nucleotide Polymorphisms (SNPs) have been identified as potential genetic markers for OA susceptibility, including in patients with SLE. SNPs in genes related to inflammation, cartilage metabolism, and immune regulation may predispose SLE patients to develop OA as presented in Table 2. Additionally, epigenetic modifications such as DNA methylation and histone acetylation are increasingly recognized as contributing to the pathogenesis of OA in SLE. These modifications can alter gene expression in response to environmental and inflammatory stimuli, influencing joint health [42-43].
| Biomarker Strategy | Description | Potential Advantages | Challenges | Future Directions |
|---|---|---|---|---|
| Genomics | Analysis of genetic variations (SNPs) and gene expression profiles associated with LAO | - Identification of genetic susceptibility- - Potential for early risk stratification- - Insights into disease mechanisms | - Large sample sizes required- - Complex data interpretation- - Genetic heterogeneity among populations | - Integration with epigenetic data- - Development of polygenic risk scores for LAO |
| Transcriptomics | Examination of RNA expression patterns in joint tissues and peripheral blood | - Dynamic reflection of disease activity- - Potential for identifying novel therapeutic targets | - Tissue-specific expression patterns- - RNA instability- - Need for standardized collection protocols | - Single-cell RNA sequencing for cell-specific profiles- - Long non-coding RNA exploration in LAO pathogenesis |
| Proteomics | Identification and quantification of proteins in synovial fluid, serum, or urine | - Direct reflection of disease processes- - Potential for identifying novel biomarkers | - Complex sample preparation- - Variability in protein abundance- - Need for sensitive detection methods | - Development of targeted proteomic assays for LAO- - Integration with other -omics data |
| Metabolomics | Analysis of small molecule metabolites in biological fluids | - Reflection of real-time metabolic state- - Potential for identifying novel pathways in LAO | - Metabolite instability- - Influence of external factors (diet, medication)- - Need for standardized protocols | - Longitudinal metabolomic profiling in LAO progression- - Integration with microbiome data |
| Epigenomics | Study of DNA methylation, histone modifications, and chromatin structure | - Insights into gene regulation in LAO- - Potential for identifying environmental influences | - Tissue-specific epigenetic patterns- - Technical challenges in sample processing- - Complex data interpretation | - Development of epigenetic risk scores for LAO- - Exploration of epigenetic therapeutic targets |
| microRNA Profiling | Analysis of circulating microRNAs associated with LAO | - Stable biomarkers in circulation- - Potential for non-invasive monitoring | - Low abundance in biological fluids- - Need for sensitive detection methods- - Functional validation required | - Development of microRNA panels specific to LAO- - Exploration of microRNA-based therapeutics |
| Glycomics | Study of glycan structures on proteins in LAO | - Reflection of post-translational modifications- - Potential for identifying novel disease mechanisms | - Complex analytical techniques required- - Limited understanding of glycan functions in LAO | - Development of glycan-based biomarker panels- - Exploration of glycan-modifying enzymes as therapeutic targets |
| Multi-omics Integration | Combination of multiple -omics approaches for comprehensive profiling | - Holistic view of LAO pathogenesis- - Potential for identifying novel interactions between biological systems | - Complex data integration and analysis- - Need for advanced bioinformatics tools- - Large sample sizes required | - Development of integrated biomarker panels for LAO- - Machine learning approaches for multi-omics data analysis |
Table 2: Emerging Biomarker Strategies for LAO Detection and Monitoring
B. Proteomic Biomarkers
Proteomic studies have identified differential expression of various cytokines, chemokines, and growth factors in patients with LAO compared to those with primary OA. For example, elevated levels of TNF-α, IL-1, and IL-6, as well as MMPs, have been observed in LAO patients, suggesting a heightened inflammatory state. Furthermore, novel insights into extracellular matrix (ECM)-related proteins, such as aggrecan fragments, have revealed their potential role in disease progression [44].
C. Metabolomic Biomarkers
Metabolomic profiling is an emerging field that examines metabolic byproducts in biofluids such as synovial fluid, serum, and urine. In LAO, aberrant levels of amino acids, lipids, and other metabolites have been detected. These metabolic alterations may reflect underlying changes in joint metabolism, inflammation, and tissue degradation, offering potential for early detection and disease stratification [45-50].
D. Microbiome-Related Biomarkers
The gut-joint axis is a novel area of research, suggesting that gut dysbiosis may contribute to inflammatory pathways relevant to OA in SLE. Changes in the gut microbiome can influence systemic inflammation, potentially exacerbating joint disease in SLE patients. Understanding the relationship between the microbiome and LAO may provide new avenues for biomarker discovery and therapeutic intervention [51-52].
A. Imaging Biomarkers
Advances in quantitative magnetic resonance imaging (MRI) and ultrasound have enabled the detection of early cartilage degeneration and synovial inflammation in LAO. Novel imaging techniques, such as T2 mapping and delayed gadolinium-enhanced MRI of cartilage (dGEMRIC), can assess biochemical changes in cartilage before structural damage occurs. Radiomics, the extraction of high-dimensional data from imaging, is also gaining attention as a means to correlate imaging findings with molecular biomarkers, offering a more comprehensive assessment of disease progression [53-58].
B. Circulating Molecular Biomarkers
Circulating microRNAs (miRNAs) have emerged as promising biomarkers for tracking OA progression in SLE. These small, non-coding RNAs regulate gene expression and can reflect underlying pathological processes in the joints. Several miRNAs have been identified as being dysregulated in OA and SLE, suggesting their potential as diagnostic and prognostic tools [59-61].
C. Synovial Fluid Biomarkers
Synovial fluid analysis provides direct insight into the joint microenvironment. Elevated levels of COMP, MMPs, and CTX-II in synovial fluid have been associated with increased disease activity in LAO. These biomarkers can offer a window into ongoing cartilage degradation and joint remodeling, making them valuable for monitoring disease progression [62-67].
A. Combining Genomic, Proteomic, and Metabolomic Data
The integration of data from genomic, proteomic, and metabolomic studies is paving the way for the development of biomarker panels that offer a more holistic view of disease processes. Multi-omics approaches combine information from different biological layers, providing a more comprehensive understanding of LAO pathophysiology. Machine learning algorithms can be applied to these datasets to identify patterns and predict disease risk, progression, and response to treatment in individual patients [68-69].
B. Personalized Medicine Approaches
Personalized medicine is the future of LAO management. By using biomarker profiles to stratify patients based on their risk of developing OA or their likely disease trajectory, clinicians can tailor therapeutic interventions accordingly. This approach holds the potential to improve outcomes by ensuring patients receive the most appropriate treatments at the right time [70-74].
C. Validation of Biomarkers in Clinical Trials
Several clinical trials are currently evaluating novel biomarkers for LAO. These trials aim to validate the specificity, sensitivity, and clinical utility of new biomarkers. However, challenges remain in ensuring the reproducibility of findings across different populations and settings. Additionally, the cost-effectiveness of these biomarkers needs to be addressed before they can be widely implemented in clinical practice [75].
A. Current Clinical Applications of Biomarkers in LAO
While biomarker research is advancing rapidly, the translation of these discoveries into clinical practice remains challenging. Current diagnostic tools for LAO rely heavily on imaging and clinical assessment, with limited integration of novel biomarkers. However, as new biomarkers are validated, there is potential for them to be incorporated into existing diagnostic algorithms, enhancing the accuracy and timeliness of diagnosis [76].
B. Potential for Novel Therapeutic Targets
Biomarkers not only serve diagnostic purposes but could also help identify novel therapeutic targets. For example, targeting specific cytokines or MMPs involved in cartilage degradation may offer new avenues for treatment. By monitoring biomarkers during treatment, clinicians can also better assess therapeutic efficacy and make timely adjustments to therapy [77].
C. Regulatory and Ethical Considerations
The regulatory approval process for biomarkers is complex. Challenges include ensuring biomarkers are both specific and sensitive enough for clinical use, in addition to cost-effective. Ethical considerations must also be addressed, particularly when it comes to the use of biomarkers in vulnerable populations such as SLE patients, who may face additional health disparities [78-79].
D. Future Research Directions
There are still significant gaps in knowledge regarding the pathophysiology of LAO and the development of effective biomarkers. Future research should focus on identifying biomarkers that are not only specific to LAO but also capable of detecting the disease at its earliest stages. Artificial intelligence and big data analytics hold great promise in accelerating biomarker discovery and validation. Cross-disciplinary collaborations between rheumatologists, immunologists, bioinformaticians, and data scientists will be essential to drive progress in this field [80-82].
This comprehensive review underscores the critical need for novel biomarkers in the early detection and monitoring of lupus-associated osteoarthritis (LAO). The complex interplay between autoimmune inflammation in SLE and degenerative processes in OA necessitates a nuanced approach to biomarker development. Emerging strategies in genomics, proteomics, and metabolomics offer promising avenues for identifying LAO-specific biomarkers that can distinguish between inflammatory lupus arthritis, typical OA, and LAO. These advancements have the potential to revolutionize clinical practice by enabling earlier intervention, more precise disease tracking, and personalized treatment strategies. However, the field faces significant challenges in biomarker validation and translation to clinical practice. Future research should focus on large-scale, longitudinal studies to validate candidate biomarkers and assess their predictive value in diverse patient populations. The integration of these novel biomarkers with advanced imaging techniques and clinical assessments could lead to a more comprehensive understanding of LAO pathogenesis and progression.
To advance the field of LAO biomarker research and clinical application, we recommend the following: 1) Establish international collaborations to create standardized protocols for biomarker discovery, validation, and implementation; 2) Develop multi-omics approaches that combine genomic, proteomic, and metabolomic data to capture the full complexity of LAO pathophysiology; 3) Invest in longitudinal studies that track biomarker changes from early SLE diagnosis through the development and progression of LAO; 4) Explore the potential of artificial intelligence and machine learning algorithms to integrate biomarker data with clinical and imaging findings for improved diagnostic accuracy; 5) Investigate the role of emerging technologies, such as liquid biopsies and microRNA profiling, in non-invasive LAO detection and monitoring; 6) Foster partnerships between academia, industry, and regulatory bodies to accelerate the translation of promising biomarkers into clinical practice; and 7) Prioritize the development of point-of-care testing for validated biomarkers to enhance accessibility and facilitate timely interventions in diverse healthcare settings.
List of Abbreviations:
SLE - Systemic Lupus Erythematosus
OA - Osteoarthritis
LAO - Lupus-Associated Osteoarthritis
TNF-α - Tumor Necrosis Factor-alpha
IL-1 - Interleukin-1
IL-6 - Interleukin-6
MMPs - Matrix Metalloproteinases
ROS - Reactive Oxygen Species
CTX-II - C-telopeptide of type II collagen
COMP - Cartilage Oligomeric Matrix Protein
HA - Hyaluronic Acid
anti-dsDNA - Anti-double-stranded DNA
RNP - Ribonucleoprotein
CRP - C-Reactive Protein
ESR - Erythrocyte Sedimentation Rate
Declarations:
Ethical approval and consent to participate: Not Applicable
Clinical trial number: not applicable.
Consent for publication: Not Applicable
Availability of data and materials: all data are available and sharing is available as well as publication.
Competing interests: The author hereby that they have no competing interests.
Funding: Corresponding author supplied all study materials. There was no further funding for this study.
Authors' contributions: The Corresponding author completed the study protocol and was the primary organizer of data collection and the manuscript's draft and revision process. The corresponding author wrote the article and ensured its accuracy.
Acknowledgements: The author thanks all the researchers who have made great efforts in their studies. Moreover, we are grateful to this journal's editors, reviewers, and readers.
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