Arterial Thrombosis as an Uncommon Presentation of Granulomatosis with Polyangiitis: A Case Report.

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Mohammad Abul Kalam Azad, Akash Ahmed Alif, Md. Masudul Hassan, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7394281/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction: Granulomatosis with polyangiitis (GPA) is a primary vasculitis usually affect predominantly small vessels and also medium-sized blood vessels with diverse manifestation. The incidence of Granulomatosis with Polyangiitis (GPA) is estimated at 10–20 cases per million people in Europe and North America, with higher in the UK (11.3/million/year). It occurs in the aged 40–60 years with male predominance. It usually involves upper and lower respiratory with renal system. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is associated with a greater risk of developing venous and arterial thrombosis. GPA and Rheumatoid arthritis (RA) may overlap in some cases, which is also rare. Lower limb ischemia due to medium-sized arteries is a rare manifestation in GPA. This report in medical literature extremely rare that provides valuable in diagnosis, management. Case Summary: We present a case of a 33 years old male who presented with poly arthralgia, fever, purpuric skin rash, and hemoptysis for a few weeks and later presented with sudden onset limb claudication. Physical examination revealed a purpuric skin rash on both lower limbs and palms, joint tenderness, and absent pulsation on the popliteal, dorsalis pedis (ADP), and posterior tibial arteries of the left lower extremity. Investigations showed anemia with high ESR and CRP levels, microscopic hematuria, elevated D-dimer levels, and Rheumatoid factor (RF) positivity in high titers. CT of chest revealed cavitary lesions. C-ANCA and Anti-proteinase 3 (PR3) antibody titers were positive. Duplex ultrasound and computed tomography (CT) angiography of the left lower limb revealed absent arterial flow distal to the popliteal artery. So, the patient was diagnosed as organ threatening GPA and treated with steroids, heparin, and intravenous rituximab and was discharged with outpatient rheumatology follow-up. Conclusion This unusual presentation of GPA presenting with arterial thrombosis and high titers of RF positivity. The report contributes to clinical awareness, helps in earlier recognition of similar cases, and gives the importance of considering systemic vasculitis in unexplained arterial thrombosis. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Granulomatosis with polyangiitis (GPA), previously known as Wegener’s granulomatosis, is systemic, chronic autoimmune disease characterized by necrotizing granulomatous inflammation and primarily involving the respiratory tract and kidneys affecting mainly small but may also involve medium-sized blood vessels [ 1 ]. GPA is part of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) vasculitis and is driven primarily by neutrophil activation and vascular inflammation. While venous thromboembolism is increasingly recognized in AAV, arterial thrombotic events (ATEs) remain rare and usually underdiagnosed. The pathogenesis is involving widespread endothelial injury, complement activation, and a transient hypercoagulable state during periods of active disease [ 2 ]. The presence of rheumatoid factor (RF) in AAV is uncommon and has been considered a non-specific finding. However, emerging evidence suggests that RF positivity may correlate with heightened inflammatory activity and disease severity. In rare cases, it may also suggest an overlap with rheumatoid arthritis [ 3 ]. Case Presentation A 33-year-old Bangladeshi male, who was normotensive, non-diabetic, and an ex-smoker, presented with a history of fever and cough for 3 months, multiple joint pain for 2 months, and skin rashes for 2 months. According to the patient 's statement, 3 months ago, he developed low-grade, intermittent fever and blood-stained mucoid sputum (Fig. 1 ) not associated with night sweats, evening rise, or contact with smear-positive TB patients. Later, he developed acute-onset, symmetric inflammatory polyarthritis involving both small and large joints. Subsequently, he developed painless, maculopapular, erythematous skin rashes (Fig. 2 ) over both upper and lower limbs, predominantly on the lower limbs. On examination, the patient was found to be anemic. Maculopapular, erythematous, nontender skin rash was present on both the upper and lower limbs. Vitals were normal. Grade 2 tenderness present in Metacarpophalangeal, wrists, metatarsophalangeal joints. Other systemic examinations revealed no abnormalities. Yellow arrow indicates blood-stained sputum Fig.2: Maculopapular erythematous skin rash in both During hospital admission, he developed acute-onset pain in the left leg, along with calf muscle tenderness and pallor the next day. The pain was exacerbated by walking. On examination, pulses were absent in the dorsalis pedis, posterior tibial, and popliteal arteries in the left lower limb. D-dimer levels were elevated, and duplex ultrasound of the left lower limb revealed absent arterial flow in the left popliteal, anterior tibial, posterior tibial, and anterior distal popliteal arteries (Fig. 3 ). Ill-defined intraluminal echogenic materials suggestive of thrombotic occlusion. No features of deep vein thrombosis were observed, and the right-sided arterial flow remained normal. Therefore, he was treated with low molecular weight (LMW) heparin (60 mg BD) along with warfarin 5 mg daily. The pain improved within 2 days. After 5 days of heparin treatment, it was discontinued, and warfarin was continued with INR monitoring. After a few days, CT angiography of the lower limbs was performed, which revealed near-total occlusion from the superficial femoral artery & popliteal artery up to its bifurcation and the presence of collateral circulation in Fig. 4 . Routine investigations and Rheumatological investigations are stated in Table 1 and Table 2 . Table 1 Routine investigations of the patients Name of the test Value Normal range Interpretation Hb (gm/dl) 8.1 15+/-2 Anemia ESR, mm in the 1st hour 127 0–10 High Total of WBC/ cu mm of blood 10,000 4-11000 Normal Neutrophil % 73 40–75 Normal Lymphocyte % 20 20–40 normal Eosinophil % 2 0–6 Normal Monocyte % 5 5–10 Normal Total of platelet / cu mm of blood 350,000 250,0000-500,000 Normal CRP (mg/L) 127 < 6 High Urine R/E Pus cell-2-4/HPF, RBC:20–25/HPF, Protein: (+) 2–4/HPF Pyuria Hematuria Serum creatinine (mg/dl) 0.94 0.7–1.3 Normal D-dimer % 4.4 < 0.5 High Blood & Urine C/S No growth No Growth Normal Protein C (%) 93.80 70–140 Normal Protein S (%) 75.30 70–125 Normal S. Homocysteine (µmol/L) 6.08 5–15 Normal HBsAg, Anti-HBc(T), Anti-HCV, Anti HIV1& 2 Negative Negative Normal HRCT of chest Pulmonary inflammatory lesions with cavitations in the left lung and post-inflammatory fibrosis in the right lung Normal Inflammatory changes with cavitation Duplex Study of both lower limbs Long segment non-visualization of the distal part of the superficial femoral and popliteal arteries up to their bifurcation into the Antero tibial and tibio-peroneal trunks. Multiple collateral vessels are developed at the site of near total occlusion Triphasic Suggestive of Vasculitis CT angiogram of both lower limb Long segment non-visualization of the distal part of the superficial femoral and popliteal arteries up to their bifurcation into the Antero tibial and tibio-peroneal trunks. Multiple collateral vessels are developed at the site of near total occlusion. Patent of the vessels Suggestive of Vasculitis Skin Biopsy It showed focal perivascular infiltration of neutrophils and macrophages. No granuloma. Suggestive of cutaneous vasculitis Normal Cutaneous vasculitis Table 2 Rheumatological investigations Name of the Test Value Normal range Interpretation Rheumatoid Factor (IU/ml) 513 < 5 Positive Anti-CCP (U/ml) 0.5 < 5 Negative ANA (ELISA) 0.2 < 1.0 Negative p-ANCA (AU/ML) 5 < 24 Negative c-ANCA (AU/ml) 387 < 24 Positive Anti- PR3 (AU/ml) 64 < 10 Positive Anti-MPO (AU/ml) 0.5 < 10 Negative Anti-GBM (AU/ml) 0.0 < 10 Negative Lupus anti-coagulant 1.14 0-1.2 Negative Anti- beta 2 GP1 (GPL U/mL) 19.6 < 40 Negative Anti-cardiolipin (GPL U/mL) 10.5 < 40 Negative Discussion Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis which include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). GPA is characterized by necrotizing inflammation of small vessels and the presence of ANCAs directed against specific antigens, particularly proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA). The disease predominantly affects small vessels in the lungs, kidneys, and upper respiratory tract. AAV is not typically associated with a high risk of arterial thrombotic events (ATEs) or venous thromboembolism (VTE), thrombotic complications may not be recognized. The prevalence of digital ischemia and gangrene in GPA is estimated to be less than 1% [ 4 ]. During active disease, serum levels of proinflammatory cytokines are elevated, and tumor necrosis factor-alpha (TNF-α) has been implicated as a significant contributor to atherothrombotic risk [ 5 ]. The pathogenesis of AAV involves injury to the endothelium of blood vessels. Neutrophil activation leads to the release of thrombogenic tissue factors, neutrophil extracellular traps (NETs), and microparticles that promote coagulation. Moreover, antiphospholipid antibodies (APL) have been reported in up to one-third of AAV patients, contributing further to thrombotic risk, although our patient had no laboratory features of antiphospholipid antibodies. Thrombolysis may also be impaired by antiplasminogen antibodies, leading to persistent clot formation [ 6 ]. Activation of the coagulation cascade has been observed in AAV patients without overt thrombotic events. Elevated plasma levels of D-dimer and prothrombin fragments are more common in active disease than in remission [ 7 ]. Furthermore, in situ thrombosis from active vasculitis may cause ischemia and gangrene, supported by angiographic and histopathological findings demonstrating arterial thrombi in affected tissues [ 8 ]. A recent study found that the incidence of ATE was highest during the early course of AAV, with approximately 31% of events occurring within the first year. Usually the patients who developed ATEs after AAV diagnosis had a significantly higher mortality rate than those without thrombotic complications [ 9 ]. Several case reports have documented arterial thrombosis and digital ischemia as early manifestations of GPA, often resulting in autoamputation or requiring surgical intervention, as summarized in Table 3 . Table 3 case reports have documented arterial thrombosis and digital ischemia as early manifestations of GPA Age/Sex Onset C-ANCA Other Organ Involvement Treatment Outcome Reference 39/F Arterial thrombosis Positive Hemoptysis, declining respiratory function, bilateral pulmonary infiltrates Cyclophosphamide, steroids, plasmapheresis Gangrene formation; surgical amputation; partial improvement of reversible ischemia Leung et al. [ 10 ] 26/M Arterial thrombosis Positive Lung nodules, maxillary sinus mucosal thickening Cyclophosphamide, steroids, azathioprine Gangrene formation with autoamputation Agarwal and Khan [ 11 ] 24/F Arterial Positive Pulmonary infiltrates, nodule, hemoptysis Cyclophosphamide, steroids, heparin, thrombectomy Gangrene formation; surgical amputation Bessias etal [ 8 ] Our patient also exhibited high titers of RF and a clinical history suggestive of RA-like polyarthritis. This raises the possibility of an overlap between RA and GPA. RF positivity is reported in 37–50% of AAV cases, but it is usually considered non-specific [ 12 ]. One study described six patients with a prior diagnosis of RA who later developed AAV after a median of 10.5 years (range: 4–43 years). These patients had typically been treated with an average of two disease-modifying anti-rheumatic drugs (DMARDs) later develop renal tract involvement. Half of them were RF-positive at the time of AAV diagnosis, and their ANCA status included MPO-ANCA (n = 3), PR3-ANCA (n = 1), and ANCA-negative vasculitis (n = 2) [ 13 ]. Shared genetic factors may explain the overlap between RA and AAV, especially changes in the HLA region and the PTPN22 gene, which are important in both diseases [ 13 – 14 ]. A study involving 47 AAV patients without clinical RA found that serum IgM RF levels were significantly correlated with the Birmingham Vasculitis Activity Score (BVAS), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). These findings suggest that RF positivity may be associated with heightened disease activity and could serve as a potential prognostic marker in AAV [ 3 ]. RF in AAV may represent low-titer of autoantibodies rather than RA-specific markers, particularly since immunosuppressive therapy may alter RF levels over time. Conclusions Arterial thrombosis is an extremely rare in GPA. It is a serious presentation of GPA. Early recognition of arterial thrombosis in GPA and urgent treatments is essential to prevent permanent limb loss. Rheumatoid factor (RF) is rarely seen in ANCA-associated vasculitis, especially in granulomatosis with polyangiitis (GPA), making this diagnostic overlap is unusual. This overlap can affect treatment choices and prognosis. Abbreviations GPA= Granulomatous poly angiitis, ANCA=Anti-neutrophil cytoplasmic antibody, AAV= ANCA Associated Vasculitis, ATE= arterial thrombotic events, VTE=Venous thrombotic events, MPO= myeloperoxidase, PR3= proteinase 3. Declarations Funding of the report No external funding was received for the preparation of this case report. Consent to Participate Written informed consent was obtained from the patient for publication and for the use of their medical information for research purposes. Consent for Publication Written informed consent was also obtained from the patient for the publication of this case report and any accompanying images. A copy of the consent form is available. Ethical Approval This case report was reviewed and approved by the technical committee of the department of Rheumatology of Bangladesh Medical University. Data Availability All data generated or analyzed during this study are included in this published article. Further details are available from the corresponding author. Author Contribution Akash Ahmed Alif: Conceptualization, Methodology, Writing – Original Draft, Data Curation.Md. Masudul Hassan Masud: Investigation, Formal Analysis, Validation, Writing – Review & Editing.Farhana Binty Rashid: Literature Review, Data Collection, Visualization, Writing – Review & Editing.Abul Khair Ahmedullah: Supervision, Project Administration, Methodology, Writing – Review & Editing.Nayan Kumar Mallik: Statistical Analysis, Software, Data Interpretation, Writing – Review & Editing.All authors have read and approved the final manuscript.Mohammad Abul Kalam Azad: Supervision, Funding Acquisition, Critical Review, Final Approval of Manuscript. References Jennette JC, Falk RJ, Bacon PA et al (2013) 2012 revised international Chapel Hill consensus conference nomenclature of vasculitis. Arthritis Rheum. 65:1–11. 10.1002/art.37715 Marozoff S, Mai A, Dehghan N et al (2022) Increased risk of venous thromboembolism in patients with granulomatosis with polyangiitis: a populationbased study. PLoS ONE 17:0270142. 10.1371/journal.pone.0270142 Watanabe S, Gono T, Nishina K et al (2017) Rheumatoid factor is correlated with disease activity and inflammatory markers in antineutrophil cytoplasmic antibodyassociated vasculitis. BMC Immunol 18:53. 10.1186/s12865-017-0234-8 Lau RA, Bains R, Suraweera D et al A rare case of digital ischemia and gangrene in ANCAassociated vasculitis with review of the literature. Case Rep Rheumatol. 2017:2421760. 10.1155/2017/2421760 Jennette JC, Falk RJ, Hu P, Xiao H (2013) Pathogenesis of antineutrophil cytoplasmic autoantibodyassociated small vessel vasculitis. Annu Rev Pathol 8:139–160. 10.1146/annurev-pathol-011811-132453 Jari M Thrombosis as the first manifestation of granulomatosis with polyangiitis disease in an adolescent. Case:2021–2021. 10.1155/2021/5520258 Misra DP, Thomas KN, Gasparyan AY et al (2021) Mechanisms of thrombosis in ANCAassociated vasculitis. Clin Rheumatol 40:4807–4815. 10.1007/s10067-021-05790-9 Bessias N, Moulakakis KG, Lioupis C et al (2005) Wegener’s granulomatosis presenting during pregnancy with acute limb ischemia. J Vasc Surg 42:800–804. 10.1016/j.jvs.2005.05.038 Kang A, Antonelou M, Wong NL et al (2019) High incidence of arterial and venous thrombosis in antineutrophil cytoplasmic antibody-associated vasculitis. J Rheumatol. 46:285–293. 10.3899/jrheum.170896 Leung A, Sung Agarwal A, Khan NA (2012) Multiple digital gangrene and polyuria. Mayo Clin Proc. 87:25. 10.1016/j.mayocp.2011.12.018 Pagnoux C, Seror R, Bérezné A et al (2010) Remittent nondestructive polysynovitis in PANCApositive vasculitis patients with antiCCP antibodies. Joint Bone Spine 77:604–607. 10.1016/j.jbspin.2010.02.013 Draibe J, Salama AD (2015) Association of ANCAassociated vasculitis and rheumatoid arthritis: a lesserrecognized overlap syndrome. SpringerPlus. 4:50. 10.1186/s40064-015-0835-8 Jagiello P, Aries P, Arning L et al (2005) The PTPN22 620W allele is a risk factor for Wegener’s granulomatosis. Arthritis Rheum 52:4039–4043. 10.1002/art.21408 Johansson M, Arlestig L, Hallmans G, RantapaaDahlqvist S (2006) PTPN22 polymorphism and anticyclic citrullinated peptide antibodies in combination strongly predicts future onset of rheumatoid arthritis and has a specificity of 100% for the disease. Arthritis Res Ther 8:19. 10.1186/ar1868 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7394281","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":506538102,"identity":"f6011ac1-1a93-4733-a92b-b827e2addc05","order_by":0,"name":"Mohammad Abul Kalam Azad","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA/UlEQVRIiWNgGAWjYDACHhDBxsBgf+DwMZiYAQNjAzNhLQwHj6WRquXwGTPitPD3HH784UfZHbvGtjPfHv7M2ZbYwN68TYJxhzVOLRJn2wwMe849S27mObvdmHfb7cQGnmNlEoxn0nE77DyDQQJv2+FkNomz26QZQVokcswkGNsO49Qhf579w8G/QC088m+eSf4EaZF/g1+Lwdkew2agLXYSDGfYJMAOk+DBr8XwzJliZplzzxIMGI6Zg/xi3MaTVmyRiMcvcmfSN398U3bH3oDh8LOHQIfJ9rMf3njjI54Qg4IDiQ0wJiiOGBIIaQBqsSesZhSMglEwCkYsAADOOmBau3N23AAAAABJRU5ErkJggg==","orcid":"","institution":"Bangabandhu Sheikh Mujib Medical University","correspondingAuthor":true,"prefix":"","firstName":"Mohammad","middleName":"Abul Kalam","lastName":"Azad","suffix":""},{"id":506538103,"identity":"528f4bbd-58e2-4429-b0de-a2f0204d8eaf","order_by":1,"name":"Akash Ahmed Alif","email":"","orcid":"","institution":"Bangabandhu Sheikh Mujib Medical University","correspondingAuthor":false,"prefix":"","firstName":"Akash","middleName":"Ahmed","lastName":"Alif","suffix":""},{"id":506538104,"identity":"410e204b-2e77-4c2f-90bf-e263b61e8326","order_by":2,"name":"Md. 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Blue arrow indicating absent arterial flow in the left popliteal, anterior tibial, posterior tibial, and anterior distal popliteal arteries.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-7394281/v1/58205b8d2f7b7c50972f5768.png"},{"id":90319686,"identity":"768414b0-9f6b-4ea0-947c-874859505c3b","added_by":"auto","created_at":"2025-09-01 10:40:20","extension":"jpeg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":116966,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCT angiogram of the lower limbs. \u003c/strong\u003eThe blue arrow indicates a long segment non-visualization of the distal part of the superficial femoral and popliteal arteries up to their bifurcation into Antero tibial and tibio-peroneal trunks. Multiple collateral vessels develop at the site of near-total occlusion. HRCT of chest shows A cavitary lesion in the apical region with thin wall in figure 5.\u003c/p\u003e","description":"","filename":"image4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7394281/v1/b2df11276517f4c498d4a637.jpeg"},{"id":90319685,"identity":"a63f9ba2-a7a4-47b6-8938-e33fc9ba7dee","added_by":"auto","created_at":"2025-09-01 10:40:20","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1092081,"visible":true,"origin":"","legend":"\u003cp\u003ePulmonary inflammatory lesions with cavitation in the apical part of the left lung and post-inflammatory fibrosis in the right lung. The yellow arrow indicates the cavitary lesion.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-7394281/v1/89cfa0714c42c570af24d681.png"},{"id":90320570,"identity":"5b6c8c1d-258a-4943-842b-1d2c9822d80b","added_by":"auto","created_at":"2025-09-01 10:48:22","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3066839,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7394281/v1/58d247e6-b24e-4b32-82b4-8e1abbaba559.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Arterial Thrombosis as an Uncommon Presentation of Granulomatosis with Polyangiitis: A Case Report.","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGranulomatosis with polyangiitis (GPA), previously known as Wegener\u0026rsquo;s granulomatosis, is systemic, chronic autoimmune disease characterized by necrotizing granulomatous inflammation and primarily involving the respiratory tract and kidneys affecting mainly small but may also involve medium-sized blood vessels [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. GPA is part of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) vasculitis and is driven primarily by neutrophil activation and vascular inflammation.\u003c/p\u003e\u003cp\u003eWhile venous thromboembolism is increasingly recognized in AAV, arterial thrombotic events (ATEs) remain rare and usually underdiagnosed. The pathogenesis is involving widespread endothelial injury, complement activation, and a transient hypercoagulable state during periods of active disease [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe presence of rheumatoid factor (RF) in AAV is uncommon and has been considered a non-specific finding. However, emerging evidence suggests that RF positivity may correlate with heightened inflammatory activity and disease severity. In rare cases, it may also suggest an overlap with rheumatoid arthritis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 33-year-old Bangladeshi male, who was normotensive, non-diabetic, and an ex-smoker, presented with a history of fever and cough for 3 months, multiple joint pain for 2 months, and skin rashes for 2 months. According to the patient 's statement, 3 months ago, he developed low-grade, intermittent fever and blood-stained mucoid sputum (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) not associated with night sweats, evening rise, or contact with smear-positive TB patients. Later, he developed acute-onset, symmetric inflammatory polyarthritis involving both small and large joints. Subsequently, he developed painless, maculopapular, erythematous skin rashes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) over both upper and lower limbs, predominantly on the lower limbs.\u003c/p\u003e\u003cp\u003eOn examination, the patient was found to be anemic. Maculopapular, erythematous, nontender skin rash was present on both the upper and lower limbs. Vitals were normal. Grade 2 tenderness present in Metacarpophalangeal, wrists, metatarsophalangeal joints. Other systemic examinations revealed no abnormalities.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eYellow arrow indicates blood-stained sputum\u003c/p\u003e\u003cp\u003eFig.2: Maculopapular erythematous skin rash in both\u003c/p\u003e\u003cp\u003eDuring hospital admission, he developed acute-onset pain in the left leg, along with calf muscle tenderness and pallor the next day. The pain was exacerbated by walking. On examination, pulses were absent in the dorsalis pedis, posterior tibial, and popliteal arteries in the left lower limb. D-dimer levels were elevated, and duplex ultrasound of the left lower limb revealed absent arterial flow in the left popliteal, anterior tibial, posterior tibial, and anterior distal popliteal arteries (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eIll-defined intraluminal echogenic materials suggestive of thrombotic occlusion. No features of deep vein thrombosis were observed, and the right-sided arterial flow remained normal. Therefore, he was treated with low molecular weight (LMW) heparin (60 mg BD) along with warfarin 5 mg daily. The pain improved within 2 days. After 5 days of heparin treatment, it was discontinued, and warfarin was continued with INR monitoring. After a few days, CT angiography of the lower limbs was performed, which revealed near-total occlusion from the superficial femoral artery \u0026amp; popliteal artery up to its bifurcation and the presence of collateral circulation in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eRoutine investigations and Rheumatological investigations are stated in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eRoutine investigations of the patients\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eName of the test\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eValue\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNormal range\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eInterpretation\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHb (gm/dl)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15+/-2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAnemia\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eESR, mm in the 1st hour\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e127\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u0026ndash;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal of WBC/ cu mm of blood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10,000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4-11000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeutrophil %\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e73\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e40\u0026ndash;75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLymphocyte %\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20\u0026ndash;40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003enormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEosinophil %\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0\u0026ndash;6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMonocyte %\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5\u0026ndash;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal of platelet / cu mm of blood\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e350,000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e250,0000-500,000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRP (mg/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e127\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUrine R/E\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePus cell-2-4/HPF, RBC:20\u0026ndash;25/HPF, Protein: (+)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u0026ndash;4/HPF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePyuria Hematuria\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerum creatinine (mg/dl)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.7\u0026ndash;1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eD-dimer %\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHigh\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood \u0026amp; Urine C/S\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo growth\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo Growth\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProtein C (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e93.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e70\u0026ndash;140\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProtein S (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e75.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e70\u0026ndash;125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eS. Homocysteine (\u0026micro;mol/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5\u0026ndash;15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHBsAg, Anti-HBc(T), Anti-HCV, Anti HIV1\u0026amp; 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHRCT of chest\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePulmonary inflammatory lesions with cavitations in the left lung and post-inflammatory fibrosis in the right lung\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eInflammatory changes with cavitation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDuplex Study of both lower limbs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLong segment non-visualization of the distal part of the superficial femoral and popliteal arteries up to their bifurcation into the Antero tibial and tibio-peroneal trunks. Multiple collateral vessels are developed at the site of near total occlusion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTriphasic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSuggestive of Vasculitis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCT angiogram of both lower limb\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLong segment non-visualization of the distal part of the superficial femoral and popliteal arteries up to their bifurcation into the Antero tibial and tibio-peroneal trunks. Multiple collateral vessels are developed at the site of near total occlusion.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePatent of the vessels\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSuggestive of Vasculitis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSkin Biopsy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIt showed focal perivascular infiltration of neutrophils and macrophages. No granuloma. Suggestive of cutaneous vasculitis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNormal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCutaneous vasculitis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eRheumatological investigations\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eName of the Test\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eValue\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNormal range\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eInterpretation\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRheumatoid Factor (IU/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e513\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnti-CCP (U/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eANA (ELISA)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;1.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ep-ANCA (AU/ML)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ec-ANCA (AU/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e387\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnti- PR3 (AU/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e64\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnti-MPO (AU/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnti-GBM (AU/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLupus anti-coagulant\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0-1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnti- beta 2 GP1 (GPL U/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAnti-cardiolipin (GPL U/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNegative\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis which include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). GPA is characterized by necrotizing inflammation of small vessels and the presence of ANCAs directed against specific antigens, particularly proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA). The disease predominantly affects small vessels in the lungs, kidneys, and upper respiratory tract.\u003c/p\u003e\u003cp\u003eAAV is not typically associated with a high risk of arterial thrombotic events (ATEs) or venous thromboembolism (VTE), thrombotic complications may not be recognized. The prevalence of digital ischemia and gangrene in GPA is estimated to be less than 1% [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. During active disease, serum levels of proinflammatory cytokines are elevated, and tumor necrosis factor-alpha (TNF-α) has been implicated as a significant contributor to atherothrombotic risk [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe pathogenesis of AAV involves injury to the endothelium of blood vessels. Neutrophil activation leads to the release of thrombogenic tissue factors, neutrophil extracellular traps (NETs), and microparticles that promote coagulation. Moreover, antiphospholipid antibodies (APL) have been reported in up to one-third of AAV patients, contributing further to thrombotic risk, although our patient had no laboratory features of antiphospholipid antibodies. Thrombolysis may also be impaired by antiplasminogen antibodies, leading to persistent clot formation [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eActivation of the coagulation cascade has been observed in AAV patients without overt thrombotic events. Elevated plasma levels of D-dimer and prothrombin fragments are more common in active disease than in remission [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Furthermore, in situ thrombosis from active vasculitis may cause ischemia and gangrene, supported by angiographic and histopathological findings demonstrating arterial thrombi in affected tissues [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eA recent study found that the incidence of ATE was highest during the early course of AAV, with approximately 31% of events occurring within the first year. Usually the patients who developed ATEs after AAV diagnosis had a significantly higher mortality rate than those without thrombotic complications [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Several case reports have documented arterial thrombosis and digital ischemia as early manifestations of GPA, often resulting in autoamputation or requiring surgical intervention, as summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ecase reports have documented arterial thrombosis and digital ischemia as early manifestations of GPA\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge/Sex\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOnset\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eC-ANCA\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOther Organ Involvement\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTreatment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOutcome\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eReference\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e39/F\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eArterial thrombosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eHemoptysis, declining respiratory function, bilateral pulmonary infiltrates\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCyclophosphamide, steroids, plasmapheresis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGangrene formation; surgical amputation; partial improvement of reversible ischemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e\u003cb\u003eLeung et al.\u003c/b\u003e\u0026nbsp;[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e26/M\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eArterial thrombosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLung nodules, maxillary sinus mucosal thickening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCyclophosphamide, steroids, azathioprine\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGangrene formation with autoamputation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eAgarwal and Khan\u0026nbsp;[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e24/F\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eArterial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePositive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePulmonary infiltrates, nodule, hemoptysis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCyclophosphamide, steroids, heparin, thrombectomy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGangrene formation; surgical amputation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eBessias etal\u0026nbsp;[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eOur patient also exhibited high titers of RF and a clinical history suggestive of RA-like polyarthritis. This raises the possibility of an overlap between RA and GPA. RF positivity is reported in 37\u0026ndash;50% of AAV cases, but it is usually considered non-specific [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. One study described six patients with a prior diagnosis of RA who later developed AAV after a median of 10.5 years (range: 4\u0026ndash;43 years). These patients had typically been treated with an average of two disease-modifying anti-rheumatic drugs (DMARDs) later develop renal tract involvement. Half of them were RF-positive at the time of AAV diagnosis, and their ANCA status included MPO-ANCA (n\u0026thinsp;=\u0026thinsp;3), PR3-ANCA (n\u0026thinsp;=\u0026thinsp;1), and ANCA-negative vasculitis (n\u0026thinsp;=\u0026thinsp;2) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Shared genetic factors may explain the overlap between RA and AAV, especially changes in the HLA region and the PTPN22 gene, which are important in both diseases [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. A study involving 47 AAV patients without clinical RA found that serum IgM RF levels were significantly correlated with the Birmingham Vasculitis Activity Score (BVAS), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). These findings suggest that RF positivity may be associated with heightened disease activity and could serve as a potential prognostic marker in AAV [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. RF in AAV may represent low-titer of autoantibodies rather than RA-specific markers, particularly since immunosuppressive therapy may alter RF levels over time.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eArterial thrombosis is an extremely rare in GPA. It is a serious presentation of GPA. Early recognition of arterial thrombosis in GPA and urgent treatments is essential to prevent permanent limb loss. Rheumatoid factor (RF) is rarely seen in ANCA-associated vasculitis, especially in granulomatosis with polyangiitis (GPA), making this diagnostic overlap is unusual. This overlap can affect treatment choices and prognosis.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eGPA= Granulomatous poly angiitis, ANCA=Anti-neutrophil cytoplasmic antibody, AAV= ANCA Associated Vasculitis, ATE= arterial thrombotic events, VTE=Venous thrombotic events, MPO= myeloperoxidase, PR3= proteinase 3.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding of the report\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo external funding was received for the preparation of this case report.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication and for the use of their medical information for research purposes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was also obtained from the patient for the publication of this case report and any accompanying images. A copy of the consent form is available.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis case report was reviewed and approved by the technical committee of the department of Rheumatology of Bangladesh Medical University.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article. Further details are available from the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAkash Ahmed Alif: Conceptualization, Methodology, Writing \u0026ndash; Original Draft, Data Curation.Md. Masudul Hassan Masud: Investigation, Formal Analysis, Validation, Writing \u0026ndash; Review \u0026amp; Editing.Farhana Binty Rashid: Literature Review, Data Collection, Visualization, Writing \u0026ndash; Review \u0026amp; Editing.Abul Khair Ahmedullah: Supervision, Project Administration, Methodology, Writing \u0026ndash; Review \u0026amp; Editing.Nayan Kumar Mallik: Statistical Analysis, Software, Data Interpretation, Writing \u0026ndash; Review \u0026amp; Editing.All authors have read and approved the final manuscript.Mohammad Abul Kalam Azad: Supervision, Funding Acquisition, Critical Review, Final Approval of Manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eJennette JC, Falk RJ, Bacon PA et al (2013) 2012 revised international Chapel Hill consensus conference nomenclature of vasculitis. Arthritis Rheum. 65:1\u0026ndash;11. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1002/art.37715\u003c/span\u003e\u003cspan address=\"10.1002/art.37715\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMarozoff S, Mai A, Dehghan N et al (2022) Increased risk of venous thromboembolism in patients with granulomatosis with polyangiitis: a populationbased study. PLoS ONE 17:0270142. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1371/journal.pone.0270142\u003c/span\u003e\u003cspan address=\"10.1371/journal.pone.0270142\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWatanabe S, Gono T, Nishina K et al (2017) Rheumatoid factor is correlated with disease activity and inflammatory markers in antineutrophil cytoplasmic antibodyassociated vasculitis. 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Arthritis Res Ther 8:19. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/ar1868\u003c/span\u003e\u003cspan address=\"10.1186/ar1868\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7394281/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7394281/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eIntroduction:\u003c/h2\u003e\u003cp\u003eGranulomatosis with polyangiitis (GPA) is a primary vasculitis usually affect predominantly small vessels and also medium-sized blood vessels with diverse manifestation. The incidence of Granulomatosis with Polyangiitis (GPA) is estimated at 10\u0026ndash;20 cases per million people in Europe and North America, with higher in the UK (11.3/million/year). It occurs in the aged 40\u0026ndash;60 years with male predominance. It usually involves upper and lower respiratory with renal system. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is associated with a greater risk of developing venous and arterial thrombosis. GPA and Rheumatoid arthritis (RA) may overlap in some cases, which is also rare. Lower limb ischemia due to medium-sized arteries is a rare manifestation in GPA. This report in medical literature extremely rare that provides valuable in diagnosis, management.\u003c/p\u003e\u003ch2\u003eCase Summary:\u003c/h2\u003e\u003cp\u003eWe present a case of a 33 years old male who presented with poly arthralgia, fever, purpuric skin rash, and hemoptysis for a few weeks and later presented with sudden onset limb claudication. Physical examination revealed a purpuric skin rash on both lower limbs and palms, joint tenderness, and absent pulsation on the popliteal, dorsalis pedis (ADP), and posterior tibial arteries of the left lower extremity. Investigations showed anemia with high ESR and CRP levels, microscopic hematuria, elevated D-dimer levels, and Rheumatoid factor (RF) positivity in high titers. CT of chest revealed cavitary lesions. C-ANCA and Anti-proteinase 3 (PR3) antibody titers were positive. Duplex ultrasound and computed tomography (CT) angiography of the left lower limb revealed absent arterial flow distal to the popliteal artery. So, the patient was diagnosed as organ threatening GPA and treated with steroids, heparin, and intravenous rituximab and was discharged with outpatient rheumatology follow-up.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThis unusual presentation of GPA presenting with arterial thrombosis and high titers of RF positivity. The report contributes to clinical awareness, helps in earlier recognition of similar cases, and gives the importance of considering systemic vasculitis in unexplained arterial thrombosis.\u003c/p\u003e","manuscriptTitle":"Arterial Thrombosis as an Uncommon Presentation of Granulomatosis with Polyangiitis: A Case Report.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-01 10:40:16","doi":"10.21203/rs.3.rs-7394281/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ac4cac83-e1a4-4ab7-80c5-5538189cc52d","owner":[],"postedDate":"September 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-01T10:40:16+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-01 10:40:16","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7394281","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7394281","identity":"rs-7394281","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}