ANA-arthritis: clinical and biomarker characterization of a population for basket trials.

OBJECTIVES: ANA-associated RMDs (ANA-RMDs-SLE, pSS, scleroderma, inflammatory myositis, mixed connective tissue disease (MCTD) and undifferentiated connective tissue disease) are a disease spectrum with overlapping clinical and immunological features. Musculoskeletal inflammation is common and impactful across ANA-RMDs. We evaluated musculoskeletal inflammation (ANA-arthritis) prevalence in a multi-disease ANA-RMD study, assessed its clinical impact across ANA-RMD diagnoses, proposed new basket groupings of patients and evaluated immunological profiles in legacy and new basket contexts. METHODS: An observational study enrolled ANA-RMD patients. Demographic variables, comorbidities, therapies, disease activity instruments (BILAG, SLEDAI, ESSDAI, physician-VAS), patient-reported outcomes (SF36, FACIT-Fatigue, EQ5D, ICECAP-A, WPAI, patient-VAS) and biomarker profile (6 gene expression scores, flow cytometry, autoantibody profile) were analysed. Reclustering utilized Gaussian Mixture Modelling (GMM). Clinical and immune features of new and legacy clusters were compared. RESULTS: Inflammatory MSK symptoms were prevalent across ANA-RMDs, in 213/294 patients. In ANA-arthritis patients, most variables did not differ between diagnoses, excluding EQ5D-5L index and mobility domains (lower in MCTD/pSS, both p< 0.05). Fibromyalgia and osteoarthritis prevalence were similar across diagnoses. Therapy use differed significantly, biologic use being greatest in SLE (p< 0.05).GMM yielded two multi-disease clusters; High-MSK disease activity (n = 89) and Low-MSK disease activity (n = 124). High-MSK disease activity contained all patients with active joint swelling and had significantly higher prednisolone usage, PGA and Sm/RNP/SmRNP/Chromatin positivity, Tetherin-MFI and Interferon Score-A activity; with numerically lower fibromyalgia and osteoarthritis prevalence. CONCLUSION: We define ANA-Arthritis, a more clinically and immunologically homogeneous population than existing RMDs for trials, and a more prevalent population for therapies in the clinic.

Stiff-person syndrome in association with Hashimoto's thyroiditis: a case report.

Stiff-person syndrome (SPS) is a rare neurological disorder characterized by chronic and progressive axial muscle rigidity and paroxysmal painful muscle spasms. The present case study described an SPS patient (increased anti-GAD65 antibody in serum and cerebrospinal fluid) with co-occurring Hashimoto's thyroiditis and decreased C3 complement levels. The clinical presentation, diagnostic approach, and treatment employed for this unique case were comprehensively described in detail. In this case, we comprehensively presented a case of SPS with co-occurring Hashimoto's thyroiditis and an associated decrease in serum C3 complement, as well as a discussion on the current data on this topic.

Meeting report: patient and caregiver recommendations for a mobile health application for paediatric systemic lupus erythematosus.

Paediatric systemic lupus erythematosus (pSLE) management and research could be enhanced by a mobile health application (app); however, no app designed for pSLE is currently available. A development and design committee comprising of patients, parents/caregivers and other stakeholders met to inform development and design of an app specific for pSLE. This meeting report summarises the group's discussions and recommendations that could help create a useful and desirable app or mobile health tool for the pSLE community.

Hypokalemic quadriplegia in Sjogren's syndrome: A case report.

Key Clinical Message: In managing Sjogren's syndrome, a thorough patient history, proper lab tests, and imaging are crucial. Clinicians should prioritize checking electrolyte levels in cases of muscle weakness, as early detection of hypokalemia can prevent severe complications. Proactive monitoring can avert renal tubular acidosis and improve patient outcomes. Abstract: Distal renal tubular acidosis (dRTA) occurs in approximately one-third of patients with Sjogren's syndrome, a systemic autoimmune disorder characterized by lymphocytic infiltration of exocrine glands, leading to dryness of mucous membranes. Hypokalemic paralysis, a well-documented but rare complication of dRTA, typically manifests as symmetric proximal muscle weakness of the extremities. We present the case of a 38-year-old woman with a history of Sjogren's syndrome diagnosed 3 years prior, who ceased her medication without medical supervision. She presented with quadriplegia, initially beginning unilaterally. This particular presentation is seldom documented in the literature. Laboratory investigations revealed hypokalemia and normal anion gap metabolic acidosis, consistent with dRTA-induced hypokalemic paralysis. Intravenous potassium chloride was administered, resulting in complete recovery of muscle strength. Hypokalemic paralysis associated with dRTA is typically reversible; however, delays in diagnosis and treatment can lead to life-threatening complications such as respiratory failure and arrhythmias. Therefore, clinicians should maintain a high index of suspicion for this condition in patients presenting with muscle weakness. Prompt and precise history takingand screening, and initiating appropriate management to prevent adverse outcomes.

Advances in the study of ferroptosis and its relationship to autoimmune diseases.

Ferroptosis represents a novel mode of programmed cell death characterized by the intracellular accumulation of iron and lipid peroxidation, culminating in oxidative stress and subsequent cell demise. Mounting evidence demonstrates that ferroptosis contributes significantly to the onset and progression of diverse pathological conditions and diseases, including infections, neurodegenerative disorders, tissue ischemia-reperfusion injury, and immune dysregulation. Recent investigations have underscored the pivotal role of ferroptosis in the pathogenesis of rheumatoid arthritis, ulcerative colitis, systemic lupus erythematosus, and asthma. This review provides a comprehensive overview of the current understanding of the regulatory mechanisms governing ferroptosis, particularly its interplay with iron, lipid, and amino acid metabolism. Furthermore, we explore the implications of ferroptosis in autoimmune diseases and deliberate on its potential as a promising therapeutic target for diverse autoimmune disorders.

A pathologically expanded, clonal lineage of IL-21-producing CD4+ T cells drives inflammatory neuropathy.

Inflammatory neuropathies, which include chronic inflammatory demyelinating polyneuropathy (CIDP) and Guillain Barré syndrome (GBS), result from autoimmune destruction of the PNS and are characterized by progressive weakness and sensory loss. CD4+ T cells play a key role in the autoimmune destruction of the PNS. Yet, key properties of pathogenic CD4+ T cells remain incompletely understood. Here, we used paired single-cell RNA-Seq (scRNA-Seq) and single-cell T cell receptor-sequencing (scTCR-Seq) of peripheral nerves from an inflammatory neuropathy mouse model to identify IL-21-expressing CD4+ T cells that were clonally expanded and multifunctional. These IL-21-expressing CD4+ T cells consisted of 2 transcriptionally distinct expanded cell populations, which expressed genes associated with T follicular helper (Tfh) and T peripheral helper (Tph) cell subsets. Remarkably, TCR clonotypes were shared between these 2 IL-21-expressing cell populations, suggesting a common lineage differentiation pathway. Finally, we demonstrated that IL-21 receptor-KO (IL-21R-KO) mice were protected from neuropathy development and had decreased immune infiltration into peripheral nerves. IL-21 signaling upregulated CXCR6, a chemokine receptor that promotes CD4+ T cell localization in peripheral nerves. Together, these findings point to IL-21 signaling, Tfh/Tph differentiation, and CXCR6-mediated cellular localization as potential therapeutic targets in inflammatory neuropathies.

The causal relationship between autoimmune diseases and rhinosinusitis, and the mediating role of inflammatory proteins: a Mendelian randomization study.

Observational studies have linked autoimmune diseases (ADs) with rhinosinusitis (RS) manifestations. To establish a causal relationship between ADs and RS, and to explore the potential mediating role of inflammatory mediators between ADs and RS, we utilized Mendelian randomization (MR) analysis. Using a two-sample MR methodology, we examined the causality between multiple sclerosis (MS), rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis (PsO), type 1 diabetes (T1D), Sjogren's syndrome (SS), celiac disease (CeD), Crohn's disease (CD), hypothyroidism (HT), Graves' disease (GD), and Hashimoto's thyroiditis and their association with chronic and acute rhinosinusitis (CRS and ARS, respectively).To achieve this, we employed three distinct MR techniques: inverse variance weighting (IVW), MR-Egger, and the weighted median method. Our analysis also included a variety of sensitivity assessments, such as Cochran's Q test, leave-one-out analysis, MR-Egger intercept, and MR-PRESSO, to ensure the robustness of our findings. Additionally, the study explored the role of inflammation proteins as a mediator in these relationships through a comprehensive two-step MR analysis. Among the ADs, MS, RA, T1D, CeD, and HT were determined as risk factors for CRS. Only CeD exhibited a causal relationship with ARS. Subsequent analyses identified interleukin-10 (IL-10) as a potential mediator for the association of MS, RA and HT with CRS, respectively., while C-X-C motif chemokine 10 levels (CXCL10) and T-cell surface glycoprotein CD6 isoform levels (CD6) were found to influence HT's effect on CRS. Our findings demonstrate a causative link between specific autoimmune diseases and rhinosinusitis, highlighting IL-10, CXCL10, and CD6 as potential mediators in this association.

Post-COVID-19 Syndrome Associated With Multiple Autoimmune Diseases (DM I-LADA, Chronic Autoimmune Thyroiditis and Pernicious Anemia): Case Report.

COVID-19, a global epidemic of infectious disease caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), not only initially refers to acute manifestations but also chronic symptoms known as Long COVID-19. Long COVID-19 represents a significant burden to healthcare systems worldwide. This syndrome encompasses a wide range of continuing health problems with variable durations and consequences for patients' everyday lives. A notable aspect of Long COVID-19 is the emergence of new-onset autoimmune diseases that could be triggered in predisposed patients with altered immune responses. Common autoimmune conditions that arise in post-COVID patients include autoimmune hemolytic anemia, immune thrombocytopenic purpura, autoimmune thyroid diseases, Kawasaki disease, Guillain-Barre syndrome, etc., but with unclear evidence of associated disease occurrence. We present a case of a female rheumatoid arthritis patient who developed autoimmune thyroid disease, latent autoimmune diabetes of adults (LADA), and pernicious anemia after SARS-CoV-2 infection.

Helminth derivative tuftsin-phopshorylcholine, to treat autoimmunity.

Autoimmune diseases (AIDs) affect 5-10% of the population . There are more than ~100 different autoimmune diseases. The AIDs are one of the top 10 causes of death in women under 65; 2nd highest cause of chronic illness; top cause of morbidity in women in the US. The NIH estimates annual direct healthcare costs for autoimmune diseases about $100 billion, in comparison, with cancers investment of $57 billion, heart and stroke cost of $200 billion. The current treatments for autoimmune diseases encompasses: steroids, chemotherapy, immunosuppressants, biological drugs, disease specific drugs (like acethylcholine-estherase for myasthenia gravis). The treatments for autooimmune diseases supress the patient immune network, which leads the patients to be more susceptible to infections. Hence, there is a need to develop immunomodulatory small molecules with minimal side effects to treat autoimmune diseases. The helminths developed secreting compounds which modulate the human defense pathways in order to develop tolerance and survive in the host environment. We have imitated the immunomodulatory activity of the helminth by using a derivative of the helminth secretory molecule. A bi-functional small molecule -tuftsin (T)-phosphorylcholine (PC), coined as TPC, was constructed . This chimeric molecule showed its immunomodulatory activity in 4 murine models of autoimmune diseases, attenuating the clinical score and the inflammatory response by immunomodutating the host immune system. Ex-vivo in human peripheral blood mononuclear cells (PBMCs) and biopsies originated from arteries of patients with giant cell arteritis. This paper decipher the mode of action of TPC immunomodulatory activity. Our data propose the potential for this small molecule to be a novel therapy for patients with autoimmune diseases.

Efficacy and safety of sequential therapy with subcutaneous belimumab and one cycle of rituximab in patients with systemic lupus erythematosus: the phase 3, randomised, placebo-controlled BLISS-BELIEVE study.

OBJECTIVES: Disease activity control in patients with systemic lupus erythematosus (SLE) with corticosteroid and immunosuppressant withdrawal is a treatment goal. We evaluated whether this could be attained with sequential subcutaneous belimumab (BEL) and one cycle of rituximab (RTX). METHODS: In this phase 3, double-blind BLISS-BELIEVE trial (GSK Study 205646), patients with active SLE initiating subcutaneous BEL 200 mg/week for 52 weeks were randomised to intravenous placebo (BEL/PBO) or intravenous RTX 1000 mg (BEL/RTX) at weeks 4 and 6 while stopping concomitant immunosuppressants/tapering corticosteroids; standard therapy for 104 weeks (BEL/ST; reference arm) was included. PRIMARY ENDPOINT: proportion of patients achieving disease control (SLE Disease Activity Index-2000 (SLEDAI-2K) ≤2; without immunosuppressants; prednisone equivalent ≤5 mg/day) at week 52 with BEL/RTX versus BEL/PBO. Major (alpha-controlled) secondary endpoints: proportion of patients with clinical remission (week 64; clinical SLEDAI-2K=0, without immunosuppressants/corticosteroids); proportion of patients with disease control (week 104). Other assessments: disease control duration, anti-dsDNA antibody, C3/C4 and B cells/B-cell subsets. RESULTS: The modified intention-to-treat population included 263 patients. Overall, 16.7% (12/72) of BEL/PBO and 19.4% (28/144) of BEL/RTX patients achieved disease control (OR (95% CI) 1.27 (0.60 to 2.71); p=0.5342) at week 52. For major secondary endpoints, differences between BEL/RTX and BEL/PBO were not statistically significant. Anti-dsDNA antibodies and most assessed B cells/B-cell subsets were lower with BEL/RTX versus BEL/PBO. Mean disease control duration through 52 weeks was significantly greater with BEL/RTX versus BEL/PBO. CONCLUSIONS: BEL/RTX showed no superiority over BEL/PBO for most endpoints analysed; however, it led to significant improvements in disease activity markers compared with BEL/PBO. Further investigation of combination treatment is warranted. TRIAL REGISTRATION NUMBER: NCT03312907.

Elafin level in lichen planus.

Lichen planus (LP) is a chronic, inflammatory, autoimmune disease that affects the skin, oral mucosa and genital mucosa. Elafin is an epithelial host-defense protein that is absent in normal skin but highly expressed in inflamed skin keratinocytes. Overexpression of Elafin has been reported in various infective, inflammatory skin disorders, such as cellulitis, psoriasis, Behçet's syndrome, and graft versus host disease. The aim of this case- control study is to map the level of Elafin in LP in order to investigate its role in the pathogenesis of LP. This study included 30 LP patients and 30 healthy controls. 10 cc blood samples were withdrawn from study participants to evaluate the serum level of Elafin using enzyme-linked immunosorbent assay (ELISA) technique. Serum Elafin level was significantly higher in LP patients as compared to healthy controls; the mean values were (32.56 vs. 5.60) in LP cases and healthy controls respectively with a statistically significant p-value < 0.001. We conclude that Elafin could be part of the inflammatory autoimmune process in LP.

Reflecting on a decade of the international consensus on ANA patterns (ICAP): Accomplishments and challenges from the perspective of the 7th ICAP workshop.

The International Consensus on ANA Patterns (ICAP) is an ongoing international initiative dedicated to harmonizing technical and interpretation aspects of the HEp-2 IFA test. Comprised of internationally recognized experts in autoimmunity and HEp-2 IFA testing, ICAP has operated for the last 10 years by promoting accurate reading, interpretation, and reporting of HEp-2 IFA images by professionals involved in various areas related to autoimmune diseases, such as clinical diagnostic laboratories, academic research, IVD industry, and patient care. ICAP operates through continuous information exchange with the international community and encourages the participation of younger experts from all over the world. The 7th ICAP workshop has addressed several aspects that originated from this interaction with the international community and has effectively established objective goals and tasks to be delivered over the next two years. Some of these are outlined in this article, including the planning of three audio-visual educational modules to be posted at the www.anapattern.org website, the classification of two novel HEp-2 IFA patterns, the implementation of a project dedicated to continuously updating the information on the clinical and immunologic relevance of the HEp-2 IFA patterns, and the launch of two additional branches of the HEp-2 Clinical and Immunological (HEp-2 CIC) project.

Computational insights into rational design and virtual screening of pyrazolopyrimidine derivatives targeting Janus kinase 3 (JAK3).

The Janus kinase 3 (JAK3) family, particularly JAK3, is pivotal in initiating autoimmune diseases such as rheumatoid arthritis. Recent advancements have focused on developing antirheumatic drugs targeting JAK3, leading to the discovery of novel pyrazolopyrimidine-based compounds as potential inhibitors. This research employed covalent docking, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis, molecular dynamics modeling, and MM/GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy techniques to screen 41 in silico-designed pyrazolopyrimidine derivatives. Initially, 3D structures of the JAK3 enzyme were generated using SWISS-MODEL, followed by virtual screening and covalent docking via AutoDock4 (AD4). The selection process involved the AMES test, binding affinity assessment, and ADMET analysis, narrowing down the candidates to 27 compounds that passed the toxicity test. Further covalent docking identified compounds 21 and 41 as the most promising due to their high affinity and favourable ADMET profiles. Subsequent development led to the creation of nine potent molecules, with derivatives 43 and 46 showing exceptional affinity upon evaluation through molecular dynamics simulation and MM/GBSA calculations over 300 nanoseconds, comparable to tofacitinib, an approved RA drug. However, compounds L21 and L46 demonstrated stable performance, suggesting their effectiveness in treating rheumatoid arthritis and other autoimmune conditions associated with JAK3 inhibition.

Atypical Presentation of Thrombotic Thrombocytopenic Purpura (TTP) as an Initial Manifestation of Systemic Lupus Erythematosus (SLE) in a Young Male.

Thrombotic thrombocytopenic purpura (TTP) is a rare but life-threatening hematologic disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, renal impairment, and fever. The etiology of TTP often involves a severe deficiency in ADAMTS13 activity, resulting in the accumulation of ultra-large von Willebrand factor multimers and subsequent microvascular thrombosis. Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect multiple organ systems, and although the initial presentation of SLE with TTP is rare, it necessitates a comprehensive diagnostic and therapeutic approach. We present a case of a 27-year-old male with no significant past medical history who developed altered mental status, headache, and right-sided numbness, leading to the diagnosis of TTP and subsequent detection of SLE.

IL-17B alleviates the pathogenesis of systemic lupus erythematosus by inhibiting FASN-mediated differentiation of B cells.

The interleukin-17 (IL-17) family of cytokines has emerged as a critical player in autoimmune disease, including systemic lupus erythematosus (SLE). However, the role of IL-17B, a poorly understood cytokine, in the pathogenesis of SLE is still not clear. In this study, we investigated the role of IL-17B in the activation and differentiation of B cells, and the pathogenesis of SLE. Intriguingly, IL-17B deficiency aggravated disease in lupus-prone mice and promoted the activation of B cells and the differentiation of germinal center (GC) B cells and plasma cells, while recombinant mouse IL-17B (rmIL-17B) significantly alleviated disease in lupus-prone mice. Mechanistically, rmIL-17B inhibited the activation of the Toll-like receptor (TLR) and interferon (IFN) pathways in B cells by downregulating the FASN-mediated lipid metabolism. Loss of FASN significantly alleviated the disease in lupus-prone mice and inhibited the activation and differentiation of B cells. In addition, B cells had greater FASN expression and lower IL-17RB levels in patients with SLE than in healthy controls. Our study described the role of IL-17B in regulating B-cell activation and differentiation, and alleviating the onset of SLE. These findings will lay a theoretical foundation for further understanding of the pathogenesis of SLE.

The History of Macrophage Activation Syndrome in Autoimmune Diseases.

In 1979, it became recognized in the literature that what we call hemophagocytic lymphohistiocytosis (HLH) was a nonmalignant disease of histiocytes. Subsequently a familial form and a secondary form of HLH were differentiated. When HLH is secondary to an autoimmune disease, rheumatologists refer to this entity as macrophage activation syndrome (MAS) to differentiate it from HLH itself. Although the first cases of MAS likely appeared in the literature in the 1970s, it was not until 1985 that the term activated macrophages was used to describe patients with systemic juvenile idiopathic arthritis (sJIA) complicated by MAS and the term macrophage activation syndrome first appeared in the title of a paper in 1993.MAS is one of the many types of secondary HLH and should not be confused with primary HLH. Experience has taught that MAS secondary to different autoimmune diseases is not equal. In the 30 years since initial description in patients with sJIA, the clinical spectrum, diseases associated with MAS, therapy, and understanding the pathogenesis have all made significant gains. The diagnostic/classification criteria for MAS secondary to sJIA, SLE, RA, and KD differ based on the different laboratory abnormalities associated with each (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018). These examples include the thrombocytosis associated with sJIA, a chronic generalized activation of the immune system, leading to elevations of fibrinogen and sIL-2R, low platelet count associated with SLE, and more acute inflammation associated with KD. Therefore, individual diagnostic criteria are required, and they all differ from the diagnostic criteria for HLH, which are based on a previously non-activated immune system (Ahn et al., J Rheumatol 44:996-1003, 2017; Han et al., Ann Rheum Dis 75:e44, 2016; Ravelli et al., Ann Rheum Dis 75:481-489, 2016; Borgia et al., Arthritis Rheumatol 70:616-624, 2018; Henter et al., Pediatr Blood Cancer 48:124-131, 2007). This helps to explain why the HLH diagnostic criteria do not perform well in MAS.The initial treatment remains high-dose steroids and IVIG followed by the use of a calcineurin inhibitor for resistant cases. IVIG can be used if there is a concern about malignancy to wait for appropriate investigations or with steroids. Interluekin-1 inhibition is now the next therapy if there is a failure to respond to steroids and calcineurin inhibitors. Advances in understanding the mechanisms leading to MAS, which has been greatly aided by the use of mouse models of MAS and advances in genome sequencing, offer a bright future for more specific therapies. More recent therapies are directed to specific cytokines involved in the pathogenesis of MAS and can lead to decreases in the morbidity and mortality associated with MAS. These include therapies directed to inhibiting the JAK/STAT pathway and/or specific cytokines, interleukin-18 and gamma interferon, which are currently being studied in MAS. These more specific therapies may obviate the need for nonspecific immunosuppressive therapies including high-dose prolonged steroids, calcineurin inhibitors, and etoposide.

Approaches based on miRNAs in Behçet's Disease: Unveiling pathogenic mechanisms, diagnostic strategies, and therapeutic applications.

Behçet's Disease (BD) is an intricate medical puzzle, captivating researchers with its enigmatic pathogenesis. This complex ailment, distinguished by recurrent mouth and genital lesions, eye irritation, and skin injuries, presents a substantial obstacle to therapeutic research. This review explores the complex interaction of microRNAs (miRNAs) with BD, highlighting their crucial involvement in the disease's pathophysiology. miRNAs, recognized for regulatory influence in diverse biological processes, hold a pivotal position in the molecular mechanisms of autoimmune diseases, such as BD. The exploration begins with examining miRNA biogenic pathways and functions, establishing a foundational understanding of their regulatory mechanisms. Shifting to the molecular landscape governing BD, the review highlights miRNA-mediated impacts on critical signaling pathways like Notch, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and protein kinase B (AKT)/mammalian target of rapamycin (mTOR), offering insights into intricate pathophysiological mechanisms. Dissecting the immunological landscape reveals the profound influence of miRNAs on BD, shedding light on the intricate modulation of immune responses and offering novel perspectives on disease etiology and progression. Beyond molecular intricacies, the review explores the clinical relevance of miRNAs in BD, emphasizing their potential as diagnostic and prognostic indicators. The discussion extends to the promising realm of miRNA-based therapeutic interventions, highlighting their potential in alleviating symptoms and altering disease progression. This comprehensive review, serving as a valuable resource for researchers, clinicians, and stakeholders, aims to decipher the intricate molecular tapestry of BD and explore the therapeutic potential of miRNAs.

Repurposing anti-osteoporosis drugs for autoimmune diseases: A two-sample Mendelian randomization study.

Background: Despite the increasing availability of therapeutic drugs for autoimmune diseases, many patients still struggle to achieve their treatment goals. Our aim was to identify whether drugs originally used to treat bone density could be applied to the treatment of autoimmune diseases through Mendelian randomization (MR). Methods: Using summary statistics from genome-wide association studies, we used a two-sample MR design to estimate the correlation between autoimmune diseases and BMD-related drug targets. Data from the DrugBank and ChEMBL databases were used to identify the drug targets of anti-osteoporosis medications. The Wald ratio test or inverse-variance weighting method was used to assess the impact of genetic variation in drug target(s) on autoimmune disease therapy. Results: Through our analysis, we discovered a negative correlation between genetic variability in a specific gene (ESR1) in raloxifene/colecalciferol and various autoimmune disorders such as ankylosing spondylitis, endometriosis, IgA nephropathy, rheumatoid arthritis, sarcoidosis, systemic lupus erythematosus, and type 1 diabetes. Conclusion: These results indicate a possible link between genetic differences in the drug targeting ESR1 and susceptibility to autoimmune disorders. Hence, our study offers significant support for the possible use of drugs targeting ESR1 for the management of autoimmune disorders. MR and drug repurposing are utilized to investigate the relationship between autoimmune diseases and bone mineral density, with a focus on ESR1.