Background: Lupus osteoarthritis is a disabling complication of systemic lupus erythematosus (SLE) caused by persistent inflammation and biomechanical factors. The complex pathogenesis and heterogeneous clinical course pose management challenges. 

Purpose: To review the etiology, clinical features, treatment, and prognosis of lupus osteoarthritis.

Main body: Lupus osteoarthritis stems from immune complex deposition, autoantibodies, and cytokines that damage joint tissues. Mechanical insultscoupled with altered joint biomechanics accelerate degeneration. The hands, wrists, and knees are most frequently involved, causing pain, stiffness, and reduced mobility. Radiographic hallmarks include joint space narrowing, periarticular osteopenia, and erosions. Composite tools like SLEDAI are used to quantify disease activity. Cardiovascular disease, osteoporosis, and infections are common comorbidities. Despite improved therapies, many patients develop disabling erosive arthritis within years of lupus diagnosis. Treatment entails lifestyle modification, analgesics, antimalarials, corticosteroids, immunosuppressants, injections, and surgery as needed. Emerging biologics, regenerative strategies, and precision medicine approaches tailored to molecular profiling offer promising directions to improve long-term outcomes. However, more research is required to halt joint damage and restore mobility in this challenging complication of SLE.

Conclusion: Lupus osteoarthritis remains a major contributor to morbidity in SLE warranting further research into pathogenetic mechanisms, predictive biomarkers, and personalized therapies to prevent irreversible joint damage.

Lupus osteoarthritis is a type of secondary osteoarthritis caused by systemic lupus erythematosus (SLE). SLE is an autoimmune disease that can damage multiple organ systems, including the joints. The prevalence of lupus osteoarthritis varies globally, with rates ranging from 0.2% in Caucasian populations to 6.1% in Chinese populations. Women are 9 times more likely to develop lupus osteoarthritis compared to men. Onset is typically between ages 20-40 [1, 2]. Several risk factors for developing lupus osteoarthritis have been identified as depicted in table 1. Having a longstanding history of SLE significantly increases risk, as ongoing inflammation can damage joint tissues. The use of corticosteroids to treat SLE also elevates risk. Joint trauma, obesity, and older age are additional risk factors. Genetic factors may also play a role, as lupus osteoarthritis disproportionately affects non-Caucasian racial groups [3-5]. Lupus osteoarthritis imposes a substantial burden on patients and healthcare systems. Pain, stiffness, deformity, and disability are common consequences and negatively impact quality of life. Depressive symptoms are also more prevalent in those with lupus arthritis compared to healthy controls or even those with non-lupus arthritis. Estimates suggest 20-30% of lupus patients will develop erosive arthritis. Treatment costs for lupus osteoarthritis remain high due to medications and surgeries required to manage symptoms [6].

Table 1: Risk factors for developing lupus osteoarthritis.

II. Pathogenesis 

The underlying mechanisms driving the development of lupus osteoarthritis are complex and involve both inflammatory and biomechanical factors. Persistent inflammation stemming from systemic lupus erythematosus (SLE) is central to the pathogenesis. SLE leads to increased production of autoantibodies and cytokines that damage joint tissues, activating degradative enzymes and hindering cartilage repair [7-9]. 

Autoantibodies implicated in lupus osteoarthritis pathogenesis include anti-dsDNA, anti-collagen, anti-C1q, and rheumatoid factor. These can form immune complexes that deposit in the synovium and cartilage, triggering inflammatory cascades. Cytokines shown to have destructive effects in lupus arthritis include TNF-alpha, IL-1beta, IL-6, and IL-17. The resulting inflammation disrupts cartilage homeostasis and accelerate breakdown [10].

Abnormal joint mechanics also contribute by increasing stresses on damaged joint surfaces. Tendon ruptures and ligamentous laxity from corticosteroid use alter joint biomechanics. Muscle weakness and joint deformities like subluxation further disturb normal mechanics. These mechanical insults coupled with inflammation drive rapid joint deterioration [11]. Advances in systems biology and omics methodologies are providing new insights into disease mechanisms. Genomics, epigenomics, and proteomics are identifying molecular signatures and networks specific to lupus osteoarthritis. Integrative analyses will help delineate complex interactions between inflammatory mediators, biomechanical factors, and joint tissues that lead to irreversible damage. This knowledge promises to uncover new therapeutic targets and personalized strategies.

The clinical presentation of lupus osteoarthritis is driven by progressive joint damage and inflammation. Patients typically experience pain, swelling, tenderness, and stiffness in affected joints. The hands, wrists, and knees are most commonly involved, but any diarthrodial joint can be impacted. Joint symptoms are often asymmetric. Morning stiffness lasting over 30 minutes and severe fatigue are also frequently reported. Various extra-articular manifestations may accompany the arthritis. Anemia, leukopenia, and thrombocytopenia are common hematologic abnormalities. Serositis, pulmonary disease, and neuropsychiatric symptoms can also occur as part of the underlying systemic lupus erythematosus [12-14]. Radiographic findings include periarticular osteopenia, marginal erosions, and progressive joint space narrowing as depicted in table 2. Advanced imaging like MRI reveals synovitis, tenosynovitis, and bone marrow lesions. Ultrasound can detect earlier erosive changes. Repeated imaging allows quantification of structural damage progression over time. Composite tools like the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) are used to assess current disease activity. Specific joint counts and serum biomarkers like ESR, CRP, and complement levels inform scoring [15, 16].

Table 2: Molecular Mediators of Synovial Inflammation in Knee OA.

IV. Comorbidities and complications 

Lupus osteoarthritis does not occur in isolation, but rather in the context of systemic lupus erythematosus (SLE) and associated comorbid conditions. Patients with lupus arthritis face elevated risks of cardiovascular disease, osteoporosis, and infections stemming from both the underlying lupus and its treatments. Multi-omics profiling techniques are being applied to disentangle the complex molecular interconnections between lupus, arthritis, and co-occurring conditions. Cardiovascular disease is a leading driver of early mortality in lupus. Accelerated atherosclerosis stems from overlapping risk factors and immune-mediated arterial damage. Chronic inflammation promotes endothelial dysfunction, while corticosteroid therapy compounds hyperlipidemia, diabetes, hypertension, and obesity. Antimalarials like hydroxychloroquine help reduce cardiovascular risk but many patients still suffer myocardial infarction, stroke, or peripheral vascular disease. Ongoing arthritis activity itself acts as an independent risk factor for atherosclerotic progression. Management requires vigilance for cardiovascular risk factors through regular EKG, lipid panel, and blood pressure monitoring [17-19]. Osteoporosis and increased fragility fracture risk also accompany lupus osteoarthritis. Underlying lupus can directly impair bone health, while corticosteroids induce further bone loss. Chronic arthritis limits mobility, decreasing bone strength over time. Damage to joint structures alters biomechanical forces, contributing to focal osteopenia adjacent to inflamed joints. Early detection of osteopenia using DEXA scanning guides treatment with calcium, vitamin D, and bisphosphonates if needed. Addressing risk factors including vitamin D deficiency, smoking, alcohol use, and low BMI helps mitigate complications. Due to immunosuppression, infections represent another major concern in lupus arthritis. Herpes zoster, urinary tract infections, respiratory infections, salmonella, and listeria disproportionately affect those with lupus receiving corticosteroids and other immunosuppressants. Septic arthritis can arise, especially with intraarticular injections. Screening and vaccination against influenza, pneumococcus, HPV, hepatitis B, and COVID-19 are recommended. Prompt antibiotic treatment of suspected infections is key. Biologic agents require special caution due to higher serious infection risks [20-22].  Multi-omics approaches can provide molecular insights into comorbidity development in lupus osteoarthritis. Genomic analyses uncover genetic variants linked to cardiovascular, skeletal, and infectious complications. Epigenomics reveals chromatin modifications driving aberrant gene expression. Transcriptomics identify cytokine, growth factor and microRNA profiles underlying comorbid conditions. Proteomics detects biomarkers like autoantibodies that mediate organ damage. Metabolomics quantifies metabolic shifts contributing to accelerated atherosclerosis and bone loss. Integrating multi-omics data through systems biology networks will further unravel the complex biology connecting lupus, arthritis, and co-occurring illnesses [23-28]. 

V. Management of lupus osteoarthritis 

Management of lupus osteoarthritis centers on relieving symptoms, maintaining function, and slowing joint damage identified as depicted in table 3. A multimodal approach is typically needed as no single treatment confers complete disease control. Initial management emphasizes lifestyle modifications and conservative therapies. Pharmacologic treatments, injections, surgery, and complementary medicine approaches may be utilized for patients with ongoing disease activity and progression. Emerging nanotechnology, regenerative medicine, precision medicine and pharmacogenomics strategies aim to repair joint structures and provide customized treatment based on biomarker profiles [29]. Lifestyle measures represent important foundations of lupus osteoarthritis management. Low-impact aerobic exercise helps maintain joint mobility and muscle strength without overloading damaged joints. Physical therapy under an occupational therapist or physiatrist can optimize exercise regimens. Weight loss reduces mechanical stress on weight-bearing joints. Assistive devices like splints, braces, and canes protect joints from further damage. Applying alternating heat and cold therapies and distraction techniques can alleviate pain during flares. Avoiding excess joint-straining activities, pacing activity throughout the day, and scheduling planned rest periods are also recommended [30-33]. If conservative lifestyle approaches prove inadequate for controlling symptoms, pharmacologic treatments are initiated. Non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen and naproxen help relieve pain and inflammation by inhibiting cyclooxygenase enzymes. NSAIDs carry gastrointestinal and cardiovascular side effect risks with long-term use. Selective COX-2 inhibitor NSAIDs like celecoxib offer slightly improved safety profiles. Analgesics like acetaminophen and narcotics can be used adjunctively for pain relief. Low-dose oral corticosteroids such as prednisone suppress inflammation but side effects include osteoporosis, diabetes, and susceptibility to infections. Antimalarials like hydroxychloroquine have immunomodulatory and anti-inflammatory effects. Hydroxychloroquine has demonstrated efficacy for controlling lupus arthritis symptoms and is considered an anchor treatment. Immunosuppressants like methotrexate, azathioprine, mycophenolate mofetil and cyclosporine may be prescribed for patients with resistant disease. Biologic response-modifiers that target specific inflammatory mediators are emerging options but require further study for lupus osteoarthritis [34-46]. Intraarticular corticosteroid injections provide localized anti-inflammatory effects but should be used judiciously to limit joint damage. Repeated injections spaced 3-4 months apart are sometimes utilized for persistent synovitis in larger joints like the knees, ankles and elbows. Hyaluronic acid injections may supplement pharmacological treatment by restoring the lubricating properties of synovial fluid, but evidence for efficacy in lupus arthritis is limited. Nutraceuticals like chondroitin, glucosamine and avocado-soybean unsaponifiables have demonstrated benefits for osteoarthritic pain and may have adjunctive effects [47-49]. When joint damage is severe and unresponsive to other measures, surgical interventions may be warranted. Synovectomy removes inflamed synovial tissue. Tendon repairs can address tendon rupture secondary to corticosteroid use. Osteotomies realign joints to shift loading forces away from damaged cartilage. Total joint replacements provide pain relief and restore function in end-stage arthritis but outcomes are best when inflammation is well-controlled pre-operatively. Due to high failure rates, joint replacement surgery is often delayed as long as possible in lupus patients [50-52]. Some patients utilize complementary and alternative medicine approaches for lupus osteoarthritis management. Acupuncture may alleviate pain but supporting evidence is limited. Herbal remedies like thunder god vine andTripterygium wilfordii have anti-inflammatory and immunosuppressive properties in early research. Components of Traditional Chinese Medicine formulations like Duhuo Jisheng Wan have shown chondroprotective effects in vitro but require further study. More research is needed to establish the safety and efficacy of these complementary modalities. Caution is warranted with herbal remedies due to potential toxicity and drug interactions [53-57].

New frontiers in nanomedicine and regenerative medicine aim to repair and regenerate damaged joint tissues. Hydrogels, nanoparticles, and scaffolds fabricated from natural and synthetic biomaterials show promise for localized drug delivery and tissue engineering but are still early in development. Stem cell therapies like mesenchymal stem cell injections may have immunomodulatory and cartilage regenerating effects. Platelet-rich plasma provides growth factors that could stimulate healing. These novel biological treatments offer exciting potential but currently lack sufficient supporting evidence. Their long-term impacts and ideal methods of application remain uncertain. Carefully conducted clinical trials are needed to evaluate efficacy and safety [58, 59]. Looking ahead, pharmacogenomics and precision medicine approaches tailored to individual genetic profiles and biomarkers could transform treatment. Gene expression patterns, autoantibody specificities, cytokine levels, and synovial pathobiology vary across lupus osteoarthritis patients and may predict response to therapies. Matching treatments to pathogenic mechanisms identified through molecular profiling promises improved outcomes while minimizing treatment burdens. As science uncovers more connections between genetic makeup and disease phenotype, treatments can become more targeted and personalized. While still largely aspirational, precision medicine strategies offer hope for the future.

Table 3: Emerging treatments for lupus osteoarthritis

There is a critical need to identify distinct molecular subtypes through unbiased omics profiling and machine learning approaches. Gene expression profiling, proteomics, metabolomics, and synovial histopathology may reveal distinct subsets with unique biomarker signatures. These molecular subtypes could be linked to clinical trajectory and treatment response, facilitating precision medicine. Developing predictive multi-biomarker panels for prognosis, damage accrual, and comorbidities through integration of multi-omics and deep learning represents a key future priority. Novel therapeutics targeted to specific pathogenic pathways hold promise to transform lupus osteoarthritis treatment. Small molecule inhibitors, biologics, and nanotherapies targeting cytokines, B and T cells, osteoclasts, and angiogenesis pathways should be evaluated. Optimal treatment may require combination strategies based on an individual's molecular profile. To enable precision medicine, biomarkers and algorithms to predict therapeutic response must be refined through multi-omics screens and artificial intelligence. Additionally, new chemical entities discovered through computational drug design can be optimized using high throughput screening and structure-activity analyses [59-62].  Regenerative medicine and tissue engineering have potential to reverse existing joint damage in lupus osteoarthritis. Mesenchymal stem cells, growth factors, bio scaffolds and hydrogels could stimulate cartilage and bone regeneration. Optimizing scaffold biomechanics, cell sourcing, and bioactive compound delivery will be critical. Combining regenerative approaches with advanced gene editing tools like CRISPR could enable durable joint tissue restoration. Rigorous clinical trials are required to demonstrate safety, efficacy and long-term impacts of these emerging biologics. Monitoring repair tissue integration and mechanics using advanced imaging will provide valuable insights [63-66]. Human and animal model studies should further delineate interactions between biomechanical stress and inflammatory pathways in lupus osteoarthritis progression. Elucidating mechanisms by which altered joint kinematics and muscle forces impact synovial inflammation, cartilage breakdown, and periarticular bone loss remains an important goal. This knowledge promises to reveal new targets for interrupting degenerative pathways amplified by biomechanical forces. Developing personalized biomechanical models of joint loading through integration of musculoskeletal imaging, gait analysis, and finite element modeling represents a fruitful research direction [67-68]. Leveraging big data science, sensors, and digital health tools could enable improved disease monitoring, treatment adherence, patient education and self-management in lupus osteoarthritis. Wearable devices and smartphone apps that capture real-world disease activity data can be integrated with electronic health records and clinical decision support systems to optimize treatment. Machine learning applied to multimodal data sources may uncover new predictive and prognostic indicators. Telemedicine and mobile health technologies have potential to improve access and quality of multidisciplinary care. Further research should evaluate the impact of digital health technologies on patient-reported outcomes [69-72].

Lupus osteoarthritis is a severe complication of systemic lupus erythematosus associated with pain, disability, and reduced quality of life. The complex interplay between ongoing inflammation, altered joint mechanics, and tissue damage drives disease progression. While treatment has improved, many patients still develop erosive arthritis and accrue joint damage over time. A systems medicine approach leveraging multi-omics technologies and computational models holds promise to unravel disease heterogeneity, predictive biomarkers, and molecular targets for personalized therapy. Advances in tissue engineering, nanotechnology, and digital health innovation may transform future management. However, lupus osteoarthritis remains a challenging condition warranting further research to improve long-term outcomes and restore joint health.

Further studies should evaluate efficacy and safety of novel biologics and small molecule inhibitors targeting pathogenic pathways identified through omics profiling of synovial tissue and circulating cells. Combination treatment strategies matched to molecular disease signatures require exploration. Regenerative medicine therapies aimed at durable joint tissue restoration should be rigorously tested in progressively larger randomized controlled trials. Development of predictive algorithms integrating multi-omics data and machine learning may enable precision medicine approaches. Digital health technologies that enhance disease monitoring and patient self-management deserve evaluation in lupus osteoarthritis populations. Multidisciplinary care and patient support systems are crucial to optimize outcomes.

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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 authors hereby that they have no competing interests.

Corresponding author supplied all study materials. There was no further funding for this study.

The authors completed the study protocol and were the primary organizers of data collection and the manuscript's draft and revision process. Tamer A. Addissouky wrote the article and ensured its accuracy. All authors contributed to the discussion, assisted in designing the study and protocol and engaged in critical discussions of the draft manuscript.

The authors thank all the researchers, editors, reviewers, and the supported universities that have done great efforts on their studies. Moreover, we are grateful to the editors, reviewers, and reader of this journal.