Rare case report: A man with rheumatoid arthritis developed membranous nephropathy and ANCA- associated vasculitis successively

Rare case report: A man with rheumatoid arthritis developed membranous nephropathy and ANCA- associated vasculitis successively | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Rare case report: A man with rheumatoid arthritis developed membranous nephropathy and ANCA- associated vasculitis successively Daorina Bao, Zhuan Cui, Yao Yao, Min Lu, Danxia Zheng, Yue Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7245429/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Nov, 2025 Read the published version in BMC Nephrology → Version 1 posted 19 You are reading this latest preprint version Abstract Background Renal involvement in rheumatoid arthritis (RA) is relatively common, which may be due to the RA itself or may be associated with the use of nephrotoxic drugs. The widespread use of biological agents has ledto an increasing number of reports of RA-related nephropathy. Case presentation We report a rare case of sequential membranous nephropathy (MN) and ANCA-associated vasculitis (AAV) in a 74-year-old male with seropositive rheumatoid arthritis (RF 389 IU/mL, anti-CCP 360 U/mL). One month after initiating etanercept (25 mgtwice weekly), he developed nephrotic syndrome (proteinuria 5.42 g/day, albumin 19.9 g/L) and elevated anti-PLA2R (33.78 RU/mL). Renal biopsy revealed stage I MN with granular IgG/C3 deposits. Despite rituximab therapy (cumulative 1600 mg) improving proteinuria to 1.81 g/day, the patient presented with acute kidney injury (SCr 1016 μmol/L), hematuria, and positive MPO-ANCA (169.8 RU/mL)six months later, which wasconsistent with AAV. Immunosuppression with methylprednisolone and cyclophosphamide reduced the SCr level to 583 μmol/L, although dialysis dependence persisted. Conclusion To our knowledge, this represents the first documented case of sequential MN and AAV in an RA patient who received etanercept and rituximab therapy during the clinical course. While direct causality remains unproven, this case underscores the need for vigilance regarding complex renal complications in RA patients managed with biologics, irrespective of etiological determinants. Membranous nephropathy ANCA-associated vasculitis rheumatoid arthritis biologic drugs anti-TNF-alpha Figures Figure 1 Figure 2 Background Rheumatoid arthritis (RA) is a chronic inflammatory disorder of unknown etiology that primarily targets synovial joints and leads to cartilage destruction. Approximately 50% of patients develop extra-articular manifestations, with renal involvement being a clinically significant complication. While renal pathology in RA has been attributed primarily to the nephrotoxic effects of older generations of disease-modifying antirheumatic drugs (DMARDs), such as gold agents and D-penicillamine[ 1 , 2 ], biological agents such as antitumor necrosis factor-α (TNF-α)-blocking agents (e.g., etanercept) have been reported, with emerging evidence suggesting an association with autoimmune renal complications. The spectrum of RA-associated renal pathology predominantly includes mesangial proliferative glomerulonephritis, followed by amyloidosis, membranous nephropathy (MN), focal proliferative glomerulonephritis, minimal change nephropathy, and interstitial nephritis, but ANCA-associated vasculitis (AAV) is rarely mentioned[ 3 ]. Recently, anti-TNF-α therapy has been implicated in promoting autoantibodies (e.g., ANCA) and contributing to renal involvement[ 4 ]. We herein describe a rare case of a seropositive RA patient who developed primary MN after treatment with etanercept for 1 month, followed by AAV within six months of Rituximab therapy. To our knowledge, this represents the first reported instance of sequential MN and AAV in an RA patient under such therapeutic regimens. Case Report A 74-year-old Chinese man presented with a two-year history of inflammatory pain and swelling in the metacarpophalangeal and interphalangeal joints of both hands. Serological evaluation confirmed rheumatoid arthritis (RA) with strongly positive immunologic markers (rheumatoid factor (RF) titer of 389 IU/ml [normal range < 20 IU/ml] and anti-cyclic citrullinated peptide (anti-CCP) titer of 360 U/ml [normal range < 17 U/ml]). He was irregularly treated with methotrexate (MTX), leflunomide and nonsteroidal anti-inflammatory drugs (NSAIDs). The patient was treated with etanercept (designated Month 0) for severe polyarthritis at a dose of 25 mg via subcutaneous injection twice a week. Bilateral lower limb edema emerged one month after the injection. Laboratory findings after the 8th injection (month 1) revealed proteinuria (5.42 g/24 h), hypoalbuminemia (19.9 g/L), and normal renal function (serum creatinine 0.75 mg/dL; normal range: 0.70–1.30 mg/dL). The serologic workup excluded viral hepatitis (negative HBsAg, anti-HCV), lupus (negative ANA, anti-dsDNA, and anti-Sm antibodies), and vasculitis (negative ANCA, anti-GBM antibody) but pointed to primary membranous nephropathy (PMN) with anti-phospholipase A2 receptor (PLA2R) antibody at a titer of 7.61 RU/mL. Concurrently, the patient tested positive for COVID-19 during hospitalization but was discharged without nephrotic syndrome-specific therapy. MTX (7.5 mg daily) was reintroduced for moderate RA activity. Persistent proteinuria (2.51 g/24 h) and hypoalbuminemia (21.2 g/L) prompted a renal biopsy at Month 2 (suspended etanercept for one month). Light microscopic examination revealed 14 glomeruli and marked capillary basement membrane vacuolization with mild mesangial hypercellularity (Fig. 1 ). Masson-silver staining revealed tiny subepithelial fuchsinophilic deposits. Tubulointerstitial changes included epithelial vacuolization and small focal atrophy, alongside small arterial intimal fibrosis. Immunofluorescence demonstrated granular deposition of IgG (3+), C3 (3+), κ (3+), and λ (3+) along capillary walls, which was consistent with stage I membranous nephropathy (MN). Unfortunately, electron microscopy yielded no glomeruli samples. An angiotensin receptor blocker (losartan 25 mg per day p.o.) was initiated, but proteinuria remained (2.40 g/24 h) by Month 5. The anti-PLA2R antibody level increased to 33.78 RU/mL, suggesting the need for rituximab therapy (100 mg initial dose, followed by 500 mg each month×3; cumulative 1600 mg). Then, his proteinuria improved to 1.81 g/24 h, and his SCr stabilized at 0.88 mg/dL by month 8. However, the patient was lost to follow-up for more than six months. T he patient presented with fatigue, anorexia, and acute kidney injury (SCr 11.87 mg/dL, hyperkalemia) at month 16. The laboratory findings revealed proteinuria (1.51 g/24 h), hematuria (full-field view), and positive MPO-ANCA, with a titer of 169.8 RU/mL. The erythrocyte sedimentation rate was 32 mm/h, and the C-reactive protein concentration was 5.47 mg/dL. Complement levels (C3 0.846 g/L, normal range: 0.70–1.40 g/L; C4 0.322 g/L, normal range: 0.1– 0.4 g/L) and other autoantibodies (anti-dsDNA, anti-GBM) remained normal. Chest computed tomography (CT) revealed emphysema and fibrosis without infection or active hemorrhage. AAV was diagnosed on the basis of MPO-ANCA positivity and clinical features, and hemodialysis was performed immediately. However, the patient refused repeat renal biopsy and plasma exchange because of financial difficulties. Immunosuppression with intravenous methylprednisolone (0.5 g/day×3, tapered to 40 mg per day) and cyclophosphamide improved hematuria. His clinical course is shown in Fig. 2 . Despite the decrease in the SCr level to 6.60 mg/dL and improvement in the Hb level (increasing from 6.7 g/dL to 8.3 g/dL), the patient remained dialysis dependent at discharge. Discussion and Conclusions We present a complicated case of rheumatoid arthritis manifesting as sequential membranous nephropathy and ANCA-associated vasculitis during treatment with etanercept and rituximab. This complex presentation underscores diagnostic and therapeutic challenges in managing autoimmune renal complications. Below, we examine the interplay between RA, biologic therapies and renal pathology, emphasizing the need for vigilance regarding drug-induced autoimmunity. RA is a systemic autoimmune disorder characterized by chronic joint inflammation that results in progressive articular damage and significant physical disability. Extending beyond articular manifestations, RA frequently involves multiple organ systems, including the skin, lungs, cardiovascular system, and kidneys. Renal involvement represents a well-documented complication of RA, with a reported prevalence ranging from 8.8 to 15% across clinical studies[ 1 , 5 ]. This manifestation may arise either from the underlying autoimmune process or secondary to exposure to old nephrotoxic DMARDs. Membranous nephropathy (MN) in RA is believed predominantly to be attributed to nephrotoxic agents rather than the underlying autoimmune process. Makino et al. reported a 31.0% MN incidence among 100 RA patients, which appeared to be related to exposure to bucillamine, D-penicillamine, and gold sodium thiomalate[ 6 ]. Nevertheless, this perspective is challenged by contemporary evidence that MN may directly correlate with RA pathology, as reported in several studies and case reports[ 7 – 9 ]. Zhang et al. also presented findings in renal biopsy series where MN constituted 23.2% of lesions in 56 Chinese RA patients, second only to IgA nephropathy (48.2%)[ 1 ]. Notably, 38.5% (5/13) of these MN patients demonstrated serum anti-PLA2R positivity, a hallmark of primary MN. In addition, MN predominantly occurs in older patients as a renal manifestation of RA, with no clear association with the duration of RA. As the patient developed MN without nephrotoxic DMARDs exposure, the robust anti-PLA2R elevation in our patient supported primary MN pathogenesis, suggesting that the occurrence of MN could not be ruled out as being related to RA. Genetic and environmental factors have been implicated in the formation of anti-PLA2R, with the immune system playing a key role in stimulating antibody production and regulating the expression of PLA2R. The inflammation and cytokine network in RA are complex, with the tumor necrosis factor (TNF) superfamily playing a significant role. In particular, the TNF-like weak inducer of apoptosis (TWEAK) cytokine is present in high concentrations within the synovial tissue of patients with active RA[ 9 ]. Previous studies have shown that TWEAK can upregulate the expression of PLA2R in human podocytes and promote the cytotoxicity of anti-PLA2R[ 10 , 11 ]. Paradoxically, the temporal discordance between RA activity and nephrotic syndrome onset in our patient complicates the definitive attribution to RA-driven autoimmunity. The emergence of ANCA-associated vasculitis (AAV) following rituximab therapy for MN in this patient represents an unexpected progression. While AAV is rarely found in association with RA, it has been reported in only a few cases[ 12 ]. Biological DMARDs, particularly anti-TNF-α agents, may cause paradoxical autoimmune complications. TNF-α blockade (adalimumab, infliximab, etanercept) remains the cornerstone therapy for refractory RA, yet accumulating evidence links these agents to autoimmune renal injury, including AAV, lupus nephritis, and membranous nephropathy[ 4 , 13 – 16 ]. Critically, our patients’ prior etanercept exposure suggests potential drug-related pathogenesis. Piga et al. reviewed 26 cases of anti-TNF-α treatment-associated renal disorders associated with chronic inflammatory rheumatic diseases, among which 22 patients (84.6%) had RA. The analysis demonstrated that etanercept (ETN) was the most frequently implicated biologic agent in the development of renal disorders (15 cases, 51.7%). Histopathologic evaluation revealed 7 patients with AAV features, with detection of p-ANCA in 3 patients and c-ANCA in 4 patients, all of whom demonstrated biopsy-confirmed necrotizing crescentic glomerulonephritis. Additionally, membranous nephropathy was documented in 4 patients[ 17 ]. The pathogenic mechanism underlying anti-TNF-α-induced renal disorders remains incompletely understood, although several pathophysiological hypotheses exist. TNF-α blockade may provoke immune complex formation or induce inflammatory apoptosis, leading to the exposure of immunogenic antigens. Alternatively, TNF-α inhibitors exhibit intrinsic immunogenicity that potentially alters lymphocyte function and cytokine production, shifting immune polarization from a Th-1 to Th-2 dominant profile. This immunological shift can increase the production of antibodies, including ANA, anti-dsDNA, and ANCA, in genetically susceptible individuals[ 17 – 19 ]. Moreover, TNF-α antagonists may increase infection susceptibility, potentially triggering autoimmune reactions through bystander activation or molecular mimicry[ 19 ]. In agreement with this hypothesis is the finding of infection prior to the onset of autoimmune-related renal disease in six cases identified in the aforementioned study[ 17 ]. Notably, our patient’s concurrent COVID-19 may have contributed to this process, as viral superantigens could activate autoreactive T-cell clones. In conclusion, we documented a rare co-occurrence of membranous nephropathy and ANCA-associated vasculitis in a patient with rheumatoid arthritis. While a direct causal link between these renal pathologies, rheumatoid arthritis disease, and anti-TNF-α therapy remains unverified owing to the lack of serial histological data, recognition of this potentially severe complication associated with widely prescribed antirheumatic agents is imperative. Further studies should prioritize both systemic case aggregation and mechanistic investigations to elucidate the underlying pathogenic pathways of this complex nephropathy. Abbreviations AAV ANCA-associated vasculitis ANA antinuclear antibody ANCA anti-neutrophil cytoplasmic antibody CCP cyclic citrullinated peptide COVID-19 corona virus disease 2019 CT computed tomography DMARDs disease-modifying anti-rheumatic drugs dsDNA double-stranded DNA HBsAg hepatitis B surface antigen HCV hepatitis C virus GBM glomerular basement membrane MN membranous nephropathy MPO myeloperoxidase MTX methotrexate PLA2R phospholipase A2 receptor PMN primary membranous nephropathy RA rheumatoid arthritis RF rheumatoid factor SCr serum creatinine Sm smith TNF tumor necrosis factor TWEAK TNF-like weak inducer of apoptosis Declarations Ethics approval and consent to participat e The studies involving human participants were approved by Peking University Third Hospital and performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from the individuals to participate in this study. Consent to publication Written informed consent was obtained from the individuals for the publication of any potentially identifiable images or data included in this article. Availability of data and materials The original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding author. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest. Funding No Funding. Authors’ contributions DB and ZC analyzed and interpreted the patient data and were major contributors to writing the manuscript. ML and YY interpreted the pathological data. DZ and YW interpreted the clinical data and substantively revised it. All the authors contributed to the article and approved the submitted version. Acknowledgments Not available. References Zhang T, Liang S, Feng X, Li M, Zhou H, Zeng C, Zhang J, Cheng Z: Spectrum and prognosis of renal histopathological lesions in 56 Chinese patients with rheumatoid arthritis with renal involvement . Clin Exp Med 2020, 20 (2):191-197. Iida A, Wada Y, Hayashi J, Tachibana S, Inaba T, Iyoda M, Honda K, Shibata T: Membranous nephropathy caused by rheumatoid arthritis . CEN Case Rep 2019, 8 (4):233-238. Helin HJ, Korpela MM, Mustonen JT, Pasternack AI: Renal biopsy findings and clinicopathologic correlations in rheumatoid arthritis . Arthritis Rheum 1995, 38 (2):242-247. Simms R, Kipgen D, Dahill S, Marshall D, Rodger RS: ANCA-associated renal vasculitis following anti-tumor necrosis factor alpha therapy . Am J Kidney Dis 2008, 51 (3):e11-14. Wang Q, Ruiz JP, Hart PD: Case report: a man with untreated rheumatoid arthritis, cryoglobulinemic vasculitis, membranous nephropathy and pulmonary sarcoidosis . BMC Nephrol 2020, 21 (1):496. Makino H, Yoshinaga Y, Yamasaki Y, Morita Y, Hashimoto H, Yamamura M: Renal involvement in rheumatoid arthritis: analysis of renal biopsy specimens from 100 patients . Mod Rheumatol 2002, 12 (2):148-154. Ichikawa K, Konta T, Sato H, Ueda Y, Yokoyama H: The clinical and pathological characteristics of nephropathies in connective tissue diseases in the Japan Renal Biopsy Registry (J-RBR) . Clin Exp Nephrol 2017, 21 (6):1024-1029. Kronbichler A, Mayer G: Renal involvement in autoimmune connective tissue diseases . BMC Med 2013, 11 :95. Perea-Ortega L, Munoz-Sanchez A, Leon-Fradejas M, Rojas RT, Ruiz-Esteban P, Lopez-Jimenez V: Rheumatoid arthritis and PLA2R-associated mebranous nephropathy. Cause or coincidence? Clin Case Rep 2024, 12 (12):e9516. Cuarental L, Valino-Rivas L, Mendonca L, Saleem M, Mezzano S, Sanz AB, Ortiz A, Sanchez-Nino MD: Tacrolimus Prevents TWEAK-Induced PLA2R Expression in Cultured Human Podocytes . J Clin Med 2020, 9 (7). Rojas-Rivera JE, Ortiz Arduan A: Primary membranous nephropathy in the era of autoantibodies and biological therapies . Med Clin (Barc) 2021, 157 (3):121-129. Draibe J, Salama AD: Association of ANCA associated vasculitis and rheumatoid arthritis: a lesser recognized overlap syndrome . Springerplus 2015, 4 :50. Ginsberg S, Rosner I, Slobodin G, Boulman N, Rozenbaum M, Kaly L, Beyar OK, Rimar D: Etanercept treatment-related c-ANCA-associated large vessel vasculitis . Clin Rheumatol 2016, 35 (1):271-273. Hirohama D, Hoshino J, Hasegawa E, Yamanouchi M, Hayami N, Suwabe T, Sawa N, Takemoto F, Ubara Y, Hara S et al: Development of myeloperoxidase-antineutrophil cytoplasmic antibody-associated renal vasculitis in a patient receiving treatment with anti-tumor necrosis factor-alpha . Mod Rheumatol 2010, 20 (6):602-605. Maruotti N, Corrado A, Gaudio A, Cantatore FP: Membranous nephropathy in rheumatoid arthritis: a case report . Clin Exp Rheumatol 2009, 27 (5):840-842. Lopetuso LR, Cuomo C, Mignini I, Gasbarrini A, Papa A: Focus on Anti-Tumor Necrosis Factor (TNF)-alpha-Related Autoimmune Diseases . Int J Mol Sci 2023, 24 (9). Piga M, Chessa E, Ibba V, Mura V, Floris A, Cauli A, Mathieu A: Biologics-induced autoimmune renal disorders in chronic inflammatory rheumatic diseases: systematic literature review and analysis of a monocentric cohort . Autoimmun Rev 2014, 13 (8):873-879. Chessa E, Piga M, Floris A, Congia M, Cangemi I, Mathieu A, Cauli A: Biologics and Targeted Synthetic Drugs Can Induce Immune-Mediated Glomerular Disorders in Patients with Rheumatic Diseases: An Updated Systematic Literature Review . BioDrugs 2021, 35 (2):175-186. Prinz JC: Autoimmune-like syndromes during TNF blockade: does infection have a role? Nat Rev Rheumatol 2011, 7 (7):429-434. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 30 Nov, 2025 Read the published version in BMC Nephrology → Version 1 posted Editorial decision: Revision requested 02 Sep, 2025 Reviews received at journal 01 Sep, 2025 Reviews received at journal 31 Aug, 2025 Reviews received at journal 27 Aug, 2025 Reviewers agreed at journal 22 Aug, 2025 Reviewers agreed at journal 22 Aug, 2025 Reviewers agreed at journal 21 Aug, 2025 Reviewers agreed at journal 21 Aug, 2025 Reviewers agreed at journal 20 Aug, 2025 Reviewers agreed at journal 20 Aug, 2025 Reviews received at journal 19 Aug, 2025 Reviews received at journal 18 Aug, 2025 Reviewers agreed at journal 12 Aug, 2025 Reviewers agreed at journal 11 Aug, 2025 Reviewers invited by journal 08 Aug, 2025 Editor invited by journal 05 Aug, 2025 Editor assigned by journal 04 Aug, 2025 Submission checks completed at journal 04 Aug, 2025 First submitted to journal 29 Jul, 2025 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. 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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-7245429","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":499567928,"identity":"8dc49716-49fc-410d-bf70-ef20633c078a","order_by":0,"name":"Daorina Bao","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Daorina","middleName":"","lastName":"Bao","suffix":""},{"id":499567929,"identity":"8456ee15-cb20-4db9-a8fc-3e237cc0f518","order_by":1,"name":"Zhuan Cui","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Zhuan","middleName":"","lastName":"Cui","suffix":""},{"id":499567930,"identity":"56de0f9d-ebca-4783-a01d-516f9fc0a266","order_by":2,"name":"Yao Yao","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yao","middleName":"","lastName":"Yao","suffix":""},{"id":499567931,"identity":"81751736-4136-47d2-a482-2558968a7b4f","order_by":3,"name":"Min Lu","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Min","middleName":"","lastName":"Lu","suffix":""},{"id":499567932,"identity":"e481e239-4dd6-434e-aa01-b876cf14acca","order_by":4,"name":"Danxia Zheng","email":"","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":false,"prefix":"","firstName":"Danxia","middleName":"","lastName":"Zheng","suffix":""},{"id":499567933,"identity":"d7a74a35-93a1-420a-a166-d57cebf13b06","order_by":5,"name":"Yue Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYBACA4YDUBZ7A5xJrBaeA0RrgQGJBOLcxWDOeMbwc8Gvw4n9ks8fHi6oYZDnFyNgmWXDGWPpmX2HE2fOzjE4POMYg+HM2QSsMzhwdoM0b8/hxA23cxgO87AxJBjcJqxl82+Qlv03jz84zPOPOC3bpHl+AG2RYDA4zNtGhBbLhvPfrHkb0o1nnAH6hbdPgrBfzCWOJd/m+WMt299+/PFnnm828vzSBLQwSBxgYGBsa4ZzCSgHAf4GIPGnjgiVo2AUjIJRMGIBALNnTR6Fb+LxAAAAAElFTkSuQmCC","orcid":"","institution":"Peking University Third Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yue","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2025-07-29 16:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7245429/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7245429/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12882-025-04646-7","type":"published","date":"2025-12-01T00:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":89230958,"identity":"2074657d-3416-4458-99d6-4913c9bb8c16","added_by":"auto","created_at":"2025-08-17 14:16:25","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":5118550,"visible":true,"origin":"","legend":"\u003cp\u003eRenal biopsy findings in this patient. A-B. Mild segmental thickening with extensive vacuolar degeneration of capillary basement membranes was observed. Mild mesangial hypercellularity and matrix expansion (A for H\u0026amp;E, original magnification ×200; B for periodic acid–Schiff–methenaminesilver stain, original magnification ×200). C. Subepithelial fuchsinophilic deposits (Masson’s trichrome stain, original magnification ×200). D. Periodic acid–Schiff staining of glomeruli; original magnification ×200. E. Tubular epithelial vacuolization and granular degeneration (H\u0026amp;E, original magnification ×200). F. The smallartery shows fibrointimal thickening (periodic acid Schiff stain, original magnification×200). G-H. Immunofluorescence microscopy showing granular capillary loop staining for IgG and C3 (original magnification ×200).\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7245429/v1/40ad547d04c80cf847d8179c.jpg"},{"id":89230952,"identity":"3504dfa8-130d-4221-a67f-9c6ee431a8c2","added_by":"auto","created_at":"2025-08-17 14:16:25","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":346107,"visible":true,"origin":"","legend":"\u003cp\u003eClinical course of the patient. Alb: albumin;anti-PLA2R: anti-phospholipase A2 receptor; CyS: cyclophosphamide; ETN: etanercept; MP: methylprednisolone; MPO-ANCA: myeloperoxidase antineutrophilcytoplasmic antibody; RTX: rituximab; SCr: serum creatinine; UTP: total protein in the urine.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7245429/v1/0417c5ca78782968f7c4b4ff.jpg"},{"id":97207183,"identity":"334a492f-cf29-4d00-84ac-f5ff6c873b8e","added_by":"auto","created_at":"2025-12-02 03:08:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6682248,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7245429/v1/7dcfcbe8-07af-4c95-b655-82abec6ab903.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Rare case report: A man with rheumatoid arthritis developed membranous nephropathy and ANCA- associated vasculitis successively","fulltext":[{"header":"Background","content":"\u003cp\u003eRheumatoid arthritis (RA) is a chronic inflammatory disorder of unknown etiology that primarily targets synovial joints and leads to cartilage destruction. Approximately 50% of patients develop extra-articular manifestations, with renal involvement being a clinically significant complication. While renal pathology in RA has been attributed primarily to the nephrotoxic effects of older generations of disease-modifying antirheumatic drugs (DMARDs), such as gold agents and D-penicillamine[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], biological agents such as antitumor necrosis factor-α (TNF-α)-blocking agents (e.g., etanercept) have been reported, with emerging evidence suggesting an association with autoimmune renal complications. The spectrum of RA-associated renal pathology predominantly includes mesangial proliferative glomerulonephritis, followed by amyloidosis, membranous nephropathy (MN), focal proliferative glomerulonephritis, minimal change nephropathy, and interstitial nephritis, but ANCA-associated vasculitis (AAV) is rarely mentioned[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Recently, anti-TNF-α therapy has been implicated in promoting autoantibodies (e.g., ANCA) and contributing to renal involvement[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWe herein describe a rare case of a seropositive RA patient who developed primary MN after treatment with etanercept for 1 month, followed by AAV within six months of Rituximab therapy. To our knowledge, this represents the first reported instance of sequential MN and AAV in an RA patient under such therapeutic regimens.\u003c/p\u003e"},{"header":"Case Report","content":"\u003cp\u003eA 74-year-old Chinese man presented with a two-year history of inflammatory pain and swelling in the metacarpophalangeal and interphalangeal joints of both hands. Serological evaluation confirmed rheumatoid arthritis (RA) with strongly positive immunologic markers (rheumatoid factor (RF) titer of 389 IU/ml [normal range \u0026lt; 20 IU/ml] and anti-cyclic citrullinated peptide (anti-CCP) titer of 360 U/ml [normal range \u0026lt; 17 U/ml]). He was irregularly treated with methotrexate (MTX), leflunomide and nonsteroidal anti-inflammatory drugs (NSAIDs). The patient was treated with etanercept (designated Month 0) for severe polyarthritis at a dose of 25 mg via subcutaneous injection twice a week. Bilateral lower limb edema emerged one month after the injection. Laboratory findings after the 8th injection (month 1) revealed proteinuria (5.42 g/24 h), hypoalbuminemia (19.9 g/L), and normal renal function (serum creatinine 0.75 mg/dL; normal range: 0.70–1.30 mg/dL). The serologic workup excluded viral hepatitis (negative HBsAg, anti-HCV), lupus (negative ANA, anti-dsDNA, and anti-Sm antibodies), and vasculitis (negative ANCA, anti-GBM antibody) but pointed to primary membranous nephropathy (PMN) with anti-phospholipase A2 receptor (PLA2R) antibody at a titer of 7.61 RU/mL. Concurrently, the patient tested positive for COVID-19 during hospitalization but was discharged without nephrotic syndrome-specific therapy. MTX (7.5 mg daily) was reintroduced for moderate RA activity.\u003c/p\u003e\u003cp\u003ePersistent proteinuria (2.51 g/24 h) and hypoalbuminemia (21.2 g/L) prompted a renal biopsy at Month 2 (suspended etanercept for one month). Light microscopic examination revealed 14 glomeruli and marked capillary basement membrane vacuolization with mild mesangial hypercellularity (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Masson-silver staining revealed tiny subepithelial fuchsinophilic deposits. Tubulointerstitial changes included epithelial vacuolization and small focal atrophy, alongside small arterial intimal fibrosis. Immunofluorescence demonstrated granular deposition of IgG (3+), C3 (3+), κ (3+), and λ (3+) along capillary walls, which was consistent with stage I membranous nephropathy (MN). Unfortunately, electron microscopy yielded no glomeruli samples. An angiotensin receptor blocker (losartan 25 mg per day p.o.) was initiated, but proteinuria remained (2.40 g/24 h) by Month 5. The anti-PLA2R antibody level increased to 33.78 RU/mL, suggesting the need for rituximab therapy (100 mg initial dose, followed by 500 mg each month×3; cumulative 1600 mg). Then, his proteinuria improved to 1.81 g/24 h, and his SCr stabilized at 0.88 mg/dL by month 8. However, the patient was lost to follow-up for more than six months.\u003c/p\u003e\u003cp\u003e\u003cb\u003eT\u003c/b\u003ehe patient presented with fatigue, anorexia, and acute kidney injury (SCr 11.87 mg/dL, hyperkalemia) at month 16. The laboratory findings revealed proteinuria (1.51 g/24 h), hematuria (full-field view), and positive MPO-ANCA, with a titer of 169.8 RU/mL. The erythrocyte sedimentation rate was 32 mm/h, and the C-reactive protein concentration was 5.47 mg/dL. Complement levels (C3 0.846 g/L, normal range: 0.70–1.40 g/L; C4 0.322 g/L, normal range: 0.1– 0.4 g/L) and other autoantibodies (anti-dsDNA, anti-GBM) remained normal. Chest computed tomography (CT) revealed emphysema and fibrosis without infection or active hemorrhage. AAV was diagnosed on the basis of MPO-ANCA positivity and clinical features, and hemodialysis was performed immediately. However, the patient refused repeat renal biopsy and plasma exchange because of financial difficulties. Immunosuppression with intravenous methylprednisolone (0.5 g/day×3, tapered to 40 mg per day) and cyclophosphamide improved hematuria. His clinical course is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Despite the decrease in the SCr level to 6.60 mg/dL and improvement in the Hb level (increasing from 6.7 g/dL to 8.3 g/dL), the patient remained dialysis dependent at discharge.\u003c/p\u003e"},{"header":"Discussion and Conclusions","content":"\u003cp\u003eWe present a complicated case of rheumatoid arthritis manifesting as sequential membranous nephropathy and ANCA-associated vasculitis during treatment with etanercept and rituximab. This complex presentation underscores diagnostic and therapeutic challenges in managing autoimmune renal complications. Below, we examine the interplay between RA, biologic therapies and renal pathology, emphasizing the need for vigilance regarding drug-induced autoimmunity.\u003c/p\u003e\u003cp\u003eRA is a systemic autoimmune disorder characterized by chronic joint inflammation that results in progressive articular damage and significant physical disability. Extending beyond articular manifestations, RA frequently involves multiple organ systems, including the skin, lungs, cardiovascular system, and kidneys. Renal involvement represents a well-documented complication of RA, with a reported prevalence ranging from 8.8 to 15% across clinical studies[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This manifestation may arise either from the underlying autoimmune process or secondary to exposure to old nephrotoxic DMARDs.\u003c/p\u003e\u003cp\u003eMembranous nephropathy (MN) in RA is believed predominantly to be attributed to nephrotoxic agents rather than the underlying autoimmune process. Makino et al. reported a 31.0% MN incidence among 100 RA patients, which appeared to be related to exposure to bucillamine, D-penicillamine, and gold sodium thiomalate[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Nevertheless, this perspective is challenged by contemporary evidence that MN may directly correlate with RA pathology, as reported in several studies and case reports[\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e–\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Zhang et al. also presented findings in renal biopsy series where MN constituted 23.2% of lesions in 56 Chinese RA patients, second only to IgA nephropathy (48.2%)[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Notably, 38.5% (5/13) of these MN patients demonstrated serum anti-PLA2R positivity, a hallmark of primary MN. In addition, MN predominantly occurs in older patients as a renal manifestation of RA, with no clear association with the duration of RA. As the patient developed MN without nephrotoxic DMARDs exposure, the robust anti-PLA2R elevation in our patient supported primary MN pathogenesis, suggesting that the occurrence of MN could not be ruled out as being related to RA. Genetic and environmental factors have been implicated in the formation of anti-PLA2R, with the immune system playing a key role in stimulating antibody production and regulating the expression of PLA2R. The inflammation and cytokine network in RA are complex, with the tumor necrosis factor (TNF) superfamily playing a significant role. In particular, the TNF-like weak inducer of apoptosis (TWEAK) cytokine is present in high concentrations within the synovial tissue of patients with active RA[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Previous studies have shown that TWEAK can upregulate the expression of PLA2R in human podocytes and promote the cytotoxicity of anti-PLA2R[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Paradoxically, the temporal discordance between RA activity and nephrotic syndrome onset in our patient complicates the definitive attribution to RA-driven autoimmunity.\u003c/p\u003e\u003cp\u003eThe emergence of ANCA-associated vasculitis (AAV) following rituximab therapy for MN in this patient represents an unexpected progression. While AAV is rarely found in association with RA, it has been reported in only a few cases[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Biological DMARDs, particularly anti-TNF-α agents, may cause paradoxical autoimmune complications. TNF-α blockade (adalimumab, infliximab, etanercept) remains the cornerstone therapy for refractory RA, yet accumulating evidence links these agents to autoimmune renal injury, including AAV, lupus nephritis, and membranous nephropathy[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan additionalcitationids=\"CR14 CR15\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e–\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Critically, our patients’ prior etanercept exposure suggests potential drug-related pathogenesis. Piga et al. reviewed 26 cases of anti-TNF-α treatment-associated renal disorders associated with chronic inflammatory rheumatic diseases, among which 22 patients (84.6%) had RA. The analysis demonstrated that etanercept (ETN) was the most frequently implicated biologic agent in the development of renal disorders (15 cases, 51.7%). Histopathologic evaluation revealed 7 patients with AAV features, with detection of p-ANCA in 3 patients and c-ANCA in 4 patients, all of whom demonstrated biopsy-confirmed necrotizing crescentic glomerulonephritis. Additionally, membranous nephropathy was documented in 4 patients[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The pathogenic mechanism underlying anti-TNF-α-induced renal disorders remains incompletely understood, although several pathophysiological hypotheses exist. TNF-α blockade may provoke immune complex formation or induce inflammatory apoptosis, leading to the exposure of immunogenic antigens. Alternatively, TNF-α inhibitors exhibit intrinsic immunogenicity that potentially alters lymphocyte function and cytokine production, shifting immune polarization from a Th-1 to Th-2 dominant profile. This immunological shift can increase the production of antibodies, including ANA, anti-dsDNA, and ANCA, in genetically susceptible individuals[\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e–\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Moreover, TNF-α antagonists may increase infection susceptibility, potentially triggering autoimmune reactions through bystander activation or molecular mimicry[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In agreement with this hypothesis is the finding of infection prior to the onset of autoimmune-related renal disease in six cases identified in the aforementioned study[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Notably, our patient’s concurrent COVID-19 may have contributed to this process, as viral superantigens could activate autoreactive T-cell clones.\u003c/p\u003e\u003cp\u003eIn conclusion, we documented a rare co-occurrence of membranous nephropathy and ANCA-associated vasculitis in a patient with rheumatoid arthritis. While a direct causal link between these renal pathologies, rheumatoid arthritis disease, and anti-TNF-α therapy remains unverified owing to the lack of serial histological data, recognition of this potentially severe complication associated with widely prescribed antirheumatic agents is imperative. Further studies should prioritize both systemic case aggregation and mechanistic investigations to elucidate the underlying pathogenic pathways of this complex nephropathy.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAAV ANCA-associated vasculitis\u003c/p\u003e\n\u003cp\u003eANA\u0026nbsp; antinuclear antibody\u003c/p\u003e\n\u003cp\u003eANCA\u0026nbsp; anti-neutrophil cytoplasmic antibody\u003c/p\u003e\n\u003cp\u003eCCP\u0026nbsp; cyclic citrullinated peptide\u003c/p\u003e\n\u003cp\u003eCOVID-19\u0026nbsp; corona virus disease 2019\u003c/p\u003e\n\u003cp\u003eCT\u0026nbsp; computed tomography\u003c/p\u003e\n\u003cp\u003eDMARDs\u0026nbsp; disease-modifying anti-rheumatic drugs\u003c/p\u003e\n\u003cp\u003edsDNA\u0026nbsp; double-stranded DNA\u003c/p\u003e\n\u003cp\u003eHBsAg\u0026nbsp; hepatitis B surface antigen\u003c/p\u003e\n\u003cp\u003eHCV\u0026nbsp; hepatitis C virus\u003c/p\u003e\n\u003cp\u003eGBM\u0026nbsp; glomerular basement membrane\u003c/p\u003e\n\u003cp\u003eMN\u0026nbsp; membranous nephropathy\u003c/p\u003e\n\u003cp\u003eMPO\u0026nbsp; myeloperoxidase\u003c/p\u003e\n\u003cp\u003eMTX\u0026nbsp; methotrexate\u003c/p\u003e\n\u003cp\u003ePLA2R\u0026nbsp; phospholipase A2 receptor\u003c/p\u003e\n\u003cp\u003ePMN\u0026nbsp;\u0026nbsp; primary membranous nephropathy\u003c/p\u003e\n\u003cp\u003eRA\u0026nbsp; rheumatoid arthritis\u003c/p\u003e\n\u003cp\u003eRF\u0026nbsp; rheumatoid factor\u003c/p\u003e\n\u003cp\u003eSCr\u0026nbsp; serum creatinine\u003c/p\u003e\n\u003cp\u003eSm\u0026nbsp; smith\u003c/p\u003e\n\u003cp\u003eTNF\u0026nbsp; tumor necrosis factor\u003c/p\u003e\n\u003cp\u003eTWEAK\u0026nbsp; TNF-like weak inducer of apoptosis\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participat\u003c/strong\u003e\u003cstrong\u003ee\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe studies involving human participants were approved by Peking University Third Hospital and performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from the individuals to participate in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the individuals for the publication of any potentially identifiable images or data included in this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are included in the article; further inquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo Funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDB and ZC analyzed and interpreted the patient data and were major contributors to writing the manuscript. ML and YY interpreted the pathological data. DZ and YW interpreted the clinical data and substantively revised it. All the authors contributed to the article and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot available.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZhang T, Liang S, Feng X, Li M, Zhou H, Zeng C, Zhang J, Cheng Z: \u003cstrong\u003eSpectrum and prognosis of renal histopathological lesions in 56 Chinese patients with rheumatoid arthritis with renal involvement\u003c/strong\u003e. \u003cem\u003eClin Exp Med \u003c/em\u003e2020, \u003cstrong\u003e20\u003c/strong\u003e(2):191-197.\u003c/li\u003e\n\u003cli\u003eIida A, Wada Y, Hayashi J, Tachibana S, Inaba T, Iyoda M, Honda K, Shibata T: \u003cstrong\u003eMembranous nephropathy caused by rheumatoid arthritis\u003c/strong\u003e. \u003cem\u003eCEN Case Rep \u003c/em\u003e2019, \u003cstrong\u003e8\u003c/strong\u003e(4):233-238.\u003c/li\u003e\n\u003cli\u003eHelin HJ, Korpela MM, Mustonen JT, Pasternack AI: \u003cstrong\u003eRenal biopsy findings and clinicopathologic correlations in rheumatoid arthritis\u003c/strong\u003e. \u003cem\u003eArthritis Rheum \u003c/em\u003e1995, \u003cstrong\u003e38\u003c/strong\u003e(2):242-247.\u003c/li\u003e\n\u003cli\u003eSimms R, Kipgen D, Dahill S, Marshall D, Rodger RS: \u003cstrong\u003eANCA-associated renal vasculitis following anti-tumor necrosis factor alpha therapy\u003c/strong\u003e. \u003cem\u003eAm J Kidney Dis \u003c/em\u003e2008, \u003cstrong\u003e51\u003c/strong\u003e(3):e11-14.\u003c/li\u003e\n\u003cli\u003eWang Q, Ruiz JP, Hart PD: \u003cstrong\u003eCase report: a man with untreated rheumatoid arthritis, cryoglobulinemic vasculitis, membranous nephropathy and pulmonary sarcoidosis\u003c/strong\u003e. \u003cem\u003eBMC Nephrol \u003c/em\u003e2020, \u003cstrong\u003e21\u003c/strong\u003e(1):496.\u003c/li\u003e\n\u003cli\u003eMakino H, Yoshinaga Y, Yamasaki Y, Morita Y, Hashimoto H, Yamamura M: \u003cstrong\u003eRenal involvement in rheumatoid arthritis: analysis of renal biopsy specimens from 100 patients\u003c/strong\u003e. \u003cem\u003eMod Rheumatol \u003c/em\u003e2002, \u003cstrong\u003e12\u003c/strong\u003e(2):148-154.\u003c/li\u003e\n\u003cli\u003eIchikawa K, Konta T, Sato H, Ueda Y, Yokoyama H: \u003cstrong\u003eThe clinical and pathological characteristics of nephropathies in connective tissue diseases in the Japan Renal Biopsy Registry (J-RBR)\u003c/strong\u003e. \u003cem\u003eClin Exp Nephrol \u003c/em\u003e2017, \u003cstrong\u003e21\u003c/strong\u003e(6):1024-1029.\u003c/li\u003e\n\u003cli\u003eKronbichler A, Mayer G: \u003cstrong\u003eRenal involvement in autoimmune connective tissue diseases\u003c/strong\u003e. \u003cem\u003eBMC Med \u003c/em\u003e2013, \u003cstrong\u003e11\u003c/strong\u003e:95.\u003c/li\u003e\n\u003cli\u003ePerea-Ortega L, Munoz-Sanchez A, Leon-Fradejas M, Rojas RT, Ruiz-Esteban P, Lopez-Jimenez V: \u003cstrong\u003eRheumatoid arthritis and PLA2R-associated mebranous nephropathy. Cause or coincidence?\u003c/strong\u003e \u003cem\u003eClin Case Rep \u003c/em\u003e2024, \u003cstrong\u003e12\u003c/strong\u003e(12):e9516.\u003c/li\u003e\n\u003cli\u003eCuarental L, Valino-Rivas L, Mendonca L, Saleem M, Mezzano S, Sanz AB, Ortiz A, Sanchez-Nino MD: \u003cstrong\u003eTacrolimus Prevents TWEAK-Induced PLA2R Expression in Cultured Human Podocytes\u003c/strong\u003e. \u003cem\u003eJ Clin Med \u003c/em\u003e2020, \u003cstrong\u003e9\u003c/strong\u003e(7).\u003c/li\u003e\n\u003cli\u003eRojas-Rivera JE, Ortiz Arduan A: \u003cstrong\u003ePrimary membranous nephropathy in the era of autoantibodies and biological therapies\u003c/strong\u003e. \u003cem\u003eMed Clin (Barc) \u003c/em\u003e2021, \u003cstrong\u003e157\u003c/strong\u003e(3):121-129.\u003c/li\u003e\n\u003cli\u003eDraibe J, Salama AD: \u003cstrong\u003eAssociation of ANCA associated vasculitis and rheumatoid arthritis: a lesser recognized overlap syndrome\u003c/strong\u003e. \u003cem\u003eSpringerplus 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arthritis: a case report\u003c/strong\u003e. \u003cem\u003eClin Exp Rheumatol \u003c/em\u003e2009, \u003cstrong\u003e27\u003c/strong\u003e(5):840-842.\u003c/li\u003e\n\u003cli\u003eLopetuso LR, Cuomo C, Mignini I, Gasbarrini A, Papa A: \u003cstrong\u003eFocus on Anti-Tumor Necrosis Factor (TNF)-alpha-Related Autoimmune Diseases\u003c/strong\u003e. \u003cem\u003eInt J Mol Sci \u003c/em\u003e2023, \u003cstrong\u003e24\u003c/strong\u003e(9).\u003c/li\u003e\n\u003cli\u003ePiga M, Chessa E, Ibba V, Mura V, Floris A, Cauli A, Mathieu A: \u003cstrong\u003eBiologics-induced autoimmune renal disorders in chronic inflammatory rheumatic diseases: systematic literature review and analysis of a monocentric cohort\u003c/strong\u003e. \u003cem\u003eAutoimmun Rev \u003c/em\u003e2014, \u003cstrong\u003e13\u003c/strong\u003e(8):873-879.\u003c/li\u003e\n\u003cli\u003eChessa E, Piga M, Floris A, Congia M, Cangemi I, Mathieu A, Cauli A: \u003cstrong\u003eBiologics and Targeted Synthetic Drugs Can Induce Immune-Mediated Glomerular Disorders in Patients with Rheumatic Diseases: An Updated Systematic Literature Review\u003c/strong\u003e. \u003cem\u003eBioDrugs \u003c/em\u003e2021, \u003cstrong\u003e35\u003c/strong\u003e(2):175-186.\u003c/li\u003e\n\u003cli\u003ePrinz JC: \u003cstrong\u003eAutoimmune-like syndromes during TNF blockade: does infection have a role?\u003c/strong\u003e \u003cem\u003eNat Rev Rheumatol \u003c/em\u003e2011, \u003cstrong\u003e7\u003c/strong\u003e(7):429-434.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Membranous nephropathy, ANCA-associated vasculitis, rheumatoid arthritis, biologic drugs, anti-TNF-alpha","lastPublishedDoi":"10.21203/rs.3.rs-7245429/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7245429/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRenal involvement in rheumatoid arthritis (RA) is relatively common, which may be due to the RA itself or may be associated with the use of nephrotoxic drugs. The widespread use of biological agents has ledto an increasing number of reports of RA-related nephropathy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe report a rare case of sequential membranous nephropathy (MN) and ANCA-associated vasculitis (AAV) in a 74-year-old male with seropositive rheumatoid arthritis (RF 389 IU/mL, anti-CCP 360 U/mL). One month after initiating etanercept (25 mgtwice weekly), he developed nephrotic syndrome (proteinuria 5.42 g/day, albumin 19.9 g/L) and elevated anti-PLA2R (33.78 RU/mL). Renal biopsy revealed stage I MN with granular IgG/C3 deposits. Despite rituximab therapy (cumulative 1600 mg) improving proteinuria to 1.81 g/day, the patient presented with acute kidney injury (SCr 1016 μmol/L), hematuria, and positive MPO-ANCA (169.8 RU/mL)six months later, which wasconsistent with AAV. Immunosuppression with methylprednisolone and cyclophosphamide reduced the SCr level to 583 μmol/L, although dialysis dependence persisted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion \u003c/strong\u003eTo our knowledge, this represents the first documented case of sequential MN and AAV in an RA patient who received etanercept and rituximab therapy during the clinical course. While direct causality remains unproven, this case underscores the need for vigilance regarding complex renal complications in RA patients managed with biologics, irrespective of etiological determinants.\u003c/p\u003e","manuscriptTitle":"Rare case report: A man with rheumatoid arthritis developed membranous nephropathy and ANCA- associated vasculitis successively","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-17 14:16:20","doi":"10.21203/rs.3.rs-7245429/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-02T07:14:42+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-01T11:39:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-31T10:10:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-27T12:38:20+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"323450911433559582907932623338364388734","date":"2025-08-22T12:08:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"119541692663005107560586373543503475170","date":"2025-08-22T05:00:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"318851385505063816029273951127436539950","date":"2025-08-21T14:05:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"164501553142063085914598531390079400353","date":"2025-08-21T10:15:02+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"17320514134010233300675529323962672292","date":"2025-08-20T12:37:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"41125219775358491262513310505238420366","date":"2025-08-20T06:16:40+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-19T18:41:09+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-18T09:04:43+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"11118990485299347851572349000370536707","date":"2025-08-12T16:04:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"141030428583089072269018875381183492488","date":"2025-08-11T17:45:03+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-08T14:53:15+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-05T12:14:33+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-04T12:56:23+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-04T12:55:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Nephrology","date":"2025-07-29T16:25:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fbd5c03b-4a39-45df-9dac-6d73cdc383be","owner":[],"postedDate":"August 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-12-02T03:08:28+00:00","versionOfRecord":{"articleIdentity":"rs-7245429","link":"https://doi.org/10.1186/s12882-025-04646-7","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2025-12-01 00:00:00","publishedOnDateReadable":"December 1st, 2025"},"versionCreatedAt":"2025-08-17 14:16:20","video":"","vorDoi":"10.1186/s12882-025-04646-7","vorDoiUrl":"https://doi.org/10.1186/s12882-025-04646-7","workflowStages":[]},"version":"v1","identity":"rs-7245429","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7245429","identity":"rs-7245429","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}