Rare Case of Rituximab Related Osteonecrosis of the Maxilla; A Case Report and Literature Review

Rare Case of Rituximab Related Osteonecrosis of the Maxilla; A Case Report and Literature Review | 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 of Rituximab Related Osteonecrosis of the Maxilla; A Case Report and Literature Review Arya Rao, Jason Tong, Gary Brierly, Emilija Jensen, Martin Batstone This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7626424/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 Medication-related osteonecrosis of the jaw (MRONJ) is a known adverse effect of antiresorptive and antiangiogenic therapies. However, reports of osteonecrosis linked to rituximab, a CD20 targeting monoclonal antibody, are exceedingly rare. We present a unique case of extensive maxillary MRONJ in a male 38 years of age with a background of multiple sclerosis receiving rituximab therapy. An initial presentation of acute sinusitis, progressed to bilateral maxillary bone destruction despite conservative management, multiple surgical interventions, and hyperbaric oxygen therapy. No other established MRONJ risk factors were identified including anti-resorptive use, antiangiogenic use, dento-alveolar surgery or dento-alveolar trauma. The extent of destruction, reaching the orbit and cranial base, is unprecedented in rituximab related cases. This report adds to the growing literature on rituximab associated MRONJ and emphasizes the need for increased awareness and understanding of this monoclonal antibody being a potential risk factor for MRONJ. Osteonecrosis Jaw Antibodies Monoclonal Risk Factors Case Reports Figures Figure 1 Figure 2 1. Introduction Osteonecrosis of the jaw secondary to medications was first described in individuals treated with bisphosphonates in the early 2000s and was reported by Marx [ 1 ]. The first case of a medication asides from bisphosphonates causing osteonecrosis of the jaws was described in a case report by Taylor et. al in 2010 [ 2 ] with denosumab, a receptor activator of nuclear factor- Kappa B ligand inhibitor. Various other drugs have been linked to this disease process since, and the nomenclature of this condition was changed to MRONJ [ 3 ]. Rituximab is a monoclonal antibody (MAB) that targets the CD20 molecule on B-lymphocytes and reduces humoral immunity [ 4 ]. In Australia, rituximab been approved by the Therapeutic Goods Administration for the management of rheumatoid arthritis, non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, granulomatosis with polyangiitis and microscopic polyangiitis [ 5 ]. Rituximab is also used as an off-label therapy for multiple sclerosis (MS), with the largest real-world study of rituximab in MS to date providing level 4 evidence that rituximab is safe and effective for treating MS for up to 2 years. Strong clinical efficacy was observed through reduction in disease relapse and radiological efficacy through reduction in contrast enhancing lesions on magnetic resonance imaging, along with a favourable safety profile [ 6 ]. There is limited evidence that rituximab has been associated with MRONJ. Here we report a rare case of MRONJ associated with rituximab therapy in a male with MS, adding to the growing literature associating rituximab and MRONJ. 2. Case Report A male, 38 years of age, was initially diagnosed with tumefactive MS in 2016 and was treated at this time with intravenous methylprednisolone and oral prednisolone with the intent of reducing cerebral oedema. The patient was subsequently trialled on intermittent high dose rituximab therapy with 6-month dosing intervals. At the age of 40, the 6 monthly dose of rituximab was reduced due to good disease stability. There were no other medical comorbidities present including previous head and neck radiation therapy or, previous cigarette use. The patient’s dental history revealed an uncomplicated dental maxillary implant placed 8 years prior with no other outstanding dental issues. At 41 years of age, the patient initially presented to the emergency department with dental pain in the left maxillary region and no clear cause for his symptoms. The patient was referred on for subsequent dental review and orthopantomogram study which demonstrated no odontogenic cause for the reported pain. Imaging was escalated to a computed tomography (CT) scan which suggested acute sinusitis and the initial therapy provided was a 5-day oral course of amoxicillin and clavulanate antibiotics. Due to ongoing odontogenic and sinusitis symptoms despite oral antibiotic therapy, the patient re-presented to the emergency department and was admitted by the ears, nose and throat (ENT) surgical department for management of acute sinusitis. Antibiotic therapy was escalated to intravenous amoxicillin and clavulanate, along with the addition of intravenous dexamethasone steroid therapy. The first surgical intervention performed was a functional endoscopic sinus surgery (FESS), providing findings consistent with acute sinusitis of the left maxillary sinus. Following this intervention the patient developed new onset severe right midfacial pain, prompting consultation with neurology and maxillofacial surgery. A clinical assessment revealed an acute onset of intraoral vesicular lesions on the left upper buccal gingiva and hard palate which tested positive for herpes simplex virus 1. Otherwise, the intra-oral and extra-oral examination was normal at this post-surgical review. It was decided that a repeat FESS would be undergone due to worsening right facial pain out of proportion to exam findings, treatment and investigations. Findings on this second FESS demonstrated a normal right maxillary antrum but, purulent discharge from the left middle accessory antrum and necrotic tissue in the left maxilla. Bilateral middle meatal antrostomies were performed with lavage of both sinuses and a right anterior ethmoidectomy and the patient was discharged with oral valacyclovir and analgesia. The patient however, presented for further consultation due to ongoing bilateral midfacial pain and newly exposed maxillary alveolar bone, along with mobile maxillary teeth. A repeat CT scan demonstrated sinonasal disease and bony destruction. Advice from multiple specialties including maxillofacial surgery, infectious diseases, neurology, immunopathology and endodontics was sought. Further investigations were performed including multiple blood tests, dental reviews and sensibility testing. This prompted a third FESS to be undergone by ENT surgery, along with multiple biopsies of the sinuses, soft tissue and bone to identify the cause of the progressing symptoms and disease. A private oral surgeon also completed multiple maxillary extractions. Despite these investigations and interventions, subsequent CT findings showed progressive bony destruction. Hyperbaric oxygen therapy (HBOT) was commenced for the preliminary diagnosis of chronic osteonecrosis of the maxilla from an unknown cause. The diagnosis of rituximab related osteonecrosis was considered, and rituximab was withheld even though limited cases were reported in the literature. Progression of disease occurred despite 10 dives of HBOT and amoxicillin and clavulanate oral antibiotic therapy, with exposed maxillary bone bilaterally in the molar regions. This prompted an urgent CT scan, which showed advanced disease in previous areas with new erosions in inferomedial walls of both maxillary sinuses, cribriform plate, and crista galli [Figure 1 a-d]. Due to aggressive progression of the disease, the patient was discussed in a multidisciplinary meeting and planned for a total maxillectomy [Figure 2 a-d] and debridement of other facial bones with potential for a second stage vascularized free flap. A maxillectomy was undertaken by the maxillofacial surgery department and removed all the necrotic bone. The final histopathology of the specimen showed osteonecrosis with secondary areas of osteomyelitis. After a subsequent period without reconstruction and no resumption of the disease process, a total maxillary reconstruction was also undertaken by maxillofacial surgery in the form of a fibula free flap. The patient proceeded to have osseointegrated implants and dental rehabilitation with good success. There have been no further episodes of necrotic bone, and no further treatment with rituximab. The patient remains well after 5 years with no recurrence of osteonecrosis and stable dental rehabilitation. 3. Discussion MRONJ can occur spontaneously, however, majority of presentations are precipitated by trauma such as dental extractions. In the present case, it was hypothesized that an acute sinus infection caused the initial insult, which led to osteonecrosis. Systemic and local oral infection and inflammation have been implicated in the pathophysiology of MRONJ [ 7 ]. Whether sinusitis triggered osteonecrosis or was secondary to the osteonecrosis is difficult to ascertain but, exacerbation from the sinus disease is postulated. Distribution of the disease isolated to the maxilla makes this theory plausible but, in our case, the initial development of bilateral maxillary facial pain, which was more severe on the right, showed no evidence of right maxillary sinusitis on FESS initially. The patient also did undergo multiple periods of steroid therapy however, steroid use is predominantly believed to be a co-risk factor in the development of MRONJ as opposed to a causative risk factor [ 3 ] and is unlikely to have caused osteonecrosis in an otherwise fit and healthy 38-year-old. Iatrogenic rituximab related osteonecrosis of the jaw is another hypothesis. Osteonecrosis related to rituximab is rare with only 5 cases reported previously in the literature [ 4 , 8 , 9 , 10 , 11 ] as illustrated [Table 1 ]. Baur et al [ 11 ] described the first case of rituximab related MRONJ in the mandible of an individual with large B-cell lymphoma during chemotherapy treatment. Table 1 Reported Cases of Rituximab Related Osteonecrosis of the Jaw Case Report Age Co-morbidities Previous Anti-Resorptive Use Immunosuppression Duration of Rituximab Prior to Initial Symptoms MRONJ Distribution Preceding Dental Procedures Initial Symptoms Present Case 38 M Multiple sclerosis No No 41 months Maxilla up to orbit and base of skull No Pain in left maxilla Javelot et al, 2019 [ 8 ] 69 F Rheumatoid arthritis Osteoporosis Risedronate Hydroxychloroquine Methotrexate Infliximab Prednisolone Leflunomide 1 month Maxilla Mandible No Oral lesions suggestive of acute herpetic gingivostomatitis Aghaloo, et al, 2017 [ 9 ] 52 F Non-Hodgkin lymphoma Stem cell transplant Osteoporosis Smoker (15-pack-year history) No Chemotherapy, including steroids 12 months Maxilla No Deep periodontal pocket Keribin et al, 2017 [ 10 ] 69 M Renal transplantation PTLD No Tacrolimus Prednisone 17 months Maxilla Mandible No Persistent oral ulcers and mobile teeth Allegra et al, 2014 [ 4 ] 56 M Lymphoplasmacytic lymphoma No Cyclophosphamide Vincristine Prednisone 14 months Mandible Tooth extraction Mucosal ulceration Baur et al, 2012 [ 11 ] 58 M Large B-cell lymphoma T2DM Hypertension Hyperlipidaemia Bronchitis Dilated cardiomyopathy Ex-smoker (Previous 100-pack-year history) No Cyclophosphamide Doxorubicin Vincristine Prednisone 12 months Mandible Oral biopsy Pain in left mandible Hypertension (HTN), Type 2 Diabetes Mellitus (T2DM), post-transplantation lymphoproliferative disorder (PTLD), medication-related osteonecrosis of the jaw (MRONJ) The direct cause of osteonecrosis related to rituximab is unclear but the proposed actions on angiogenesis and bone turnover have been suggested. Allegra et al [ 4 ] hypothesized rituximab had a negative action on angiogenesis based on the anti-CD 20 antibody action on CD 20-positive B cell proliferation and the associated minor role of B cells as a precursor for angiogenesis. Another theory by Wheater et al [ 12 ] proposed that osteonecrosis of the jaw might be initiated or increased by the rituximab induced depletion of B-cells, which was related to suppression of bone turn over. An alternative hypothesis of rituximab induced MRONJ relates to immune imbalance and a proinflammatory state due to CD20 positive B cell depletion. B cells can function as antigen presenting cells for T cells. Specifically, in vitro studies provide evidence for B cells presenting to regulatory Th17 (Treg17) cells [ 13 ]. Eliminating the induction of anti-inflammatory Treg17 cells tips the balance in favour of proinflammatory Th17 cells [ 14 ]. In the present case, the cause of the MRONJ is likely multifactorial with either rituximab inciting the disease sub clinically or, potentiation of the process initiated by the sinusitis. The disease was exacerbated by subsequent FESS procedures, the use of steroids, and dentoalveolar surgery. There were no preceding risk factors. Due to the scarcity of previous reports linking rituximab to MRONJ, no staging was reported since it was not considered in the initial differential diagnosis. However, as the clinical condition progressed within a few weeks, it became clear his disease pattern was consistent with MRONJ and a diagnosis of stage 3 MRONJ was made using the American Association of Oral & Maxillofacial Surgeon’s staging system [ 3 ]. This was due to exposed necrotic bone extending beyond the region of alveolar bone and osteolysis extending to the inferior border of the sinus floor. Progression of the MRONJ occurred despite conservative management. Medication related osteonecrosis of the jaws predominantly affects the mandible in 73% of cases, the maxilla in 22.5% cases and both jaws in 4.5% of cases [ 3 ]. This finding has been attributed to the greater blood supply of the maxilla. This case is unique in the aspect that MRONJ related to rituximab has never been extensive enough to involve the orbit and base of the skull. Beyond classical antiresorptive drugs, several other agents and systemic conditions have been implicated in the pathogenesis of MRONJ. Isolated case reports describe MRONJ in patients receiving long-term statin therapy, particularly high-dose simvastatin, suggesting that inhibition of the mevalonate pathway may impair osteoclast function in a manner analogous to bisphosphonates [ 15 ]. Other monoclonal antibodies have also been linked, including bevacizumab and romosozumab, albeit with evidence largely limited to small case series and pharmacovigilance signals [ 3 ]. Several medical comorbidities have been implicated in increasing susceptibility to MRONJ [ 3 ]. These include malignancy, diabetes mellitus, and anaemia, as well as systemic factors such as immunosuppression and lifestyle habits like smoking. Such conditions are thought to contribute by impairing wound healing, altering immune function, or compounding the effects of antiresorptive and antiangiogenic therapies [ 3 ]. Recognition of these comorbidities is essential in contextualizing MRONJ risk and guiding preventive and therapeutic strategies. Clinicians should maintain a high suspicion of medications, especially the ever-developing monoclonal antibodies, causing MRONJ in symptomatic individuals. With the growing number of case reports describing the possibility of rituximab contributing to the pathogenesis of MRONJ, the consideration of this agent as an additional risk factor and/or iatrogenic cause should be considered. Declarations Clinical Trial Number Not applicable Ethics approval This case report was made in accordance with the guidelines of Metro North Health Queensland, the operating body for Royal Brisbane and Women’s Hospital. Patient consent was obtained for publication and ethics review was not required for an individual case report. Consent to participate Informed consent was obtained from the patient described in this report. Consent to publish Written informed consent for publication of clinical details and accompanying images was obtained from the patient. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Author Contribution The conception of this case report is credited to M.B. along with the initial documentation of findings. M.B. and J.T. acquired patient consent, photographs, radiographs and extracted information from medical records. A.R. and J.T. are responsible for creation of the initial manuscript. Review and editing of the manuscript is credited to M.B., G.B. and E.J. with all three reviewers providing substantial input to the final report. All authors read and approved the final manuscript. Acknowledgements The authors have no acknowledgements to declare. References Marx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg. 2003;61(9):1115–7. https://doi.org/10.1016/S0278-2391(03)00720-1 Taylor KH, Middlefell LS, Mizen KD. Osteonecrosis of the jaws induced by anti-RANK ligand therapy. Br J Oral Maxillofac Surg. 2010;48(3):221–3. https://doi.org/10.1016/j.bjoms.2009.08.030 Ruggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw—2014 update. J Oral Maxillofac Surg. 2014;72(10):1938–56. https://doi.org/10.1016/j.joms.2014.04.031 Allegra A, Oteri G, Alonci A, Bacci F, Penna G, Minardi V, et al. Association of osteonecrosis of the jaws and POEMS syndrome in a patient assuming rituximab. J Craniomaxillofac Surg. 2014;42(4):279–82. https://doi.org/10.1016/j.jcms.2013.05.014 Therapeutic Goods Administration. Australian Public Assessment Report for Rituximab (Ruxience). Sydney: Pfizer Australia Pty Ltd; 2021 Apr. Report No.: PM-2020-00593-1-6. Available from: https://www.tga.gov.au/product-information-pi [accessed 13 July 2025] Salzer J, Svenningsson R, Alping P, Novakova L, Björck A, Fink K, et al. Rituximab in multiple sclerosis: a retrospective observational study on safety and efficacy. 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Osteonecrosis of the jaw in a patient presenting with post-transplantation lymphoproliferative disorder treated with rituximab: a case report. J Oral Maxillofac Surg. 2017;75(12):2599–605. https://doi.org/10.1016/j.joms.2017.05.016 Baur DA, Weber JM, Collette DC, Dhaliwal H, Quereshy F. Osteonecrosis of the jaws unrelated to bisphosphonate exposure: a series of 4 cases. J Oral Maxillofac Surg. 2012;70(12):2802–8. https://doi.org/10.1016/j.joms.2012.02.019 Wheater G, Hogan VE, Teng YK, Tekstra J, Lafeber FP, Huizinga TW, et al. Suppression of bone turnover by B-cell depletion in patients with rheumatoid arthritis. Osteoporos Int. 2011;22(12):3067–72. https://doi.org/10.1007/s00198-011-1607-0 Shao TY, Hsu LH, Chien CH, Chiang BL. Novel Foxp3(-) IL-10(-) regulatory T-cells induced by B-cells alleviate intestinal inflammation in vivo. Sci Rep. 2016;6:32415. https://doi.org/10.1038/srep32415 Singh B, Summers KL, Kerfoot SM. Novel regulatory Th17 cells and regulatory B cells in modulating autoimmune diseases. Cell Immunol. 2019;339:29–32. https://doi.org/10.1016/j.cellimm.2019.03.001 Giladi HZ, Gabay E, Machtei EE. Medication-Related Osteonecrosis of the Jaw in Patients Taking High-Dose Simvastatin. J Oral Maxillofac Surg . 2020;78(6):862-863 https://doi.org/10.1016/j.joms.2020.01.009 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. We do this by developing innovative software and high quality services for the global research community. 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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-7626424","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":530668474,"identity":"bae5a7ea-9143-4ea9-9a02-a45a5ad17a0a","order_by":0,"name":"Arya 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1","display":"","copyAsset":false,"role":"figure","size":1001001,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea, b\u003c/strong\u003e: Axial computed tomographic images of the maxilla. Arrows demonstrating the marked moth-eaten appearance of the maxilla consistent with osteonecrosis of the jaws. \u003cstrong\u003eFig 1\u003c/strong\u003e \u003cstrong\u003ec, d\u003c/strong\u003e: \u0026nbsp;Coronal computed tomographic images of the facial bones. Arrows demonstrating the maxillary lesions consistent with osteonecrosis and asterisk demonstrating purulent bilateral maxillary sinusitis.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7626424/v1/abe7a39c84ed24db71ed3430.jpeg"},{"id":93775678,"identity":"77b922f7-2a9a-4805-a35c-3ba49296f624","added_by":"auto","created_at":"2025-10-17 12:32:30","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1321613,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea:\u003c/strong\u003eClinical photo of the intact maxillary palatal mucosa with exposed bone buccal to the upper right premolar tooth in keeping with osteonecrosis of the maxilla. \u0026nbsp;\u003cstrong\u003eFig. 2b\u003c/strong\u003e: Intraoral view of the reflected palatal mucosal flap in approaching the maxillary bone revealing the extent of the osteonecrosis of the jaw involvement. \u003cstrong\u003eFig. 2c:\u003c/strong\u003e Resected specimen showing the degree of necrotic maxilla with associated dentition affected by rituximab associated osteonecrosis of the jaw. \u003cstrong\u003eFig. 2d:\u003c/strong\u003e Intraoral closure of healthy intact mucosa post first stage excision of surgical specimen.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7626424/v1/4230aa62c0f7a82dd6fcab93.jpeg"},{"id":107900188,"identity":"2d613d82-136e-4441-ae23-e8a5580adc75","added_by":"auto","created_at":"2026-04-27 11:27:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2528539,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7626424/v1/85d38d3a-9d49-4b7f-87d0-4c8df150adf5.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Rare Case of Rituximab Related Osteonecrosis of the Maxilla; A Case Report and Literature Review","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eOsteonecrosis of the jaw secondary to medications was first described in individuals treated with bisphosphonates in the early 2000s and was reported by Marx [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The first case of a medication asides from bisphosphonates causing osteonecrosis of the jaws was described in a case report by Taylor et. al in 2010 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] with denosumab, a receptor activator of nuclear factor- Kappa B ligand inhibitor. Various other drugs have been linked to this disease process since, and the nomenclature of this condition was changed to MRONJ [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRituximab is a monoclonal antibody (MAB) that targets the CD20 molecule on B-lymphocytes and reduces humoral immunity [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In Australia, rituximab been approved by the Therapeutic Goods Administration for the management of rheumatoid arthritis, non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, granulomatosis with polyangiitis and microscopic polyangiitis [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Rituximab is also used as an off-label therapy for multiple sclerosis (MS), with the largest real-world study of rituximab in MS to date providing level 4 evidence that rituximab is safe and effective for treating MS for up to 2 years. Strong clinical efficacy was observed through reduction in disease relapse and radiological efficacy through reduction in contrast enhancing lesions on magnetic resonance imaging, along with a favourable safety profile [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThere is limited evidence that rituximab has been associated with MRONJ. Here we report a rare case of MRONJ associated with rituximab therapy in a male with MS, adding to the growing literature associating rituximab and MRONJ.\u003c/p\u003e"},{"header":"2. Case Report","content":"\u003cp\u003eA male, 38 years of age, was initially diagnosed with tumefactive MS in 2016 and was treated at this time with intravenous methylprednisolone and oral prednisolone with the intent of reducing cerebral oedema. The patient was subsequently trialled on intermittent high dose rituximab therapy with 6-month dosing intervals. At the age of 40, the 6 monthly dose of rituximab was reduced due to good disease stability. There were no other medical comorbidities present including previous head and neck radiation therapy or, previous cigarette use. The patient\u0026rsquo;s dental history revealed an uncomplicated dental maxillary implant placed 8 years prior with no other outstanding dental issues.\u003c/p\u003e\u003cp\u003eAt 41 years of age, the patient initially presented to the emergency department with dental pain in the left maxillary region and no clear cause for his symptoms. The patient was referred on for subsequent dental review and orthopantomogram study which demonstrated no odontogenic cause for the reported pain. Imaging was escalated to a computed tomography (CT) scan which suggested acute sinusitis and the initial therapy provided was a 5-day oral course of amoxicillin and clavulanate antibiotics. Due to ongoing odontogenic and sinusitis symptoms despite oral antibiotic therapy, the patient re-presented to the emergency department and was admitted by the ears, nose and throat (ENT) surgical department for management of acute sinusitis. Antibiotic therapy was escalated to intravenous amoxicillin and clavulanate, along with the addition of intravenous dexamethasone steroid therapy.\u003c/p\u003e\u003cp\u003eThe first surgical intervention performed was a functional endoscopic sinus surgery (FESS), providing findings consistent with acute sinusitis of the left maxillary sinus. Following this intervention the patient developed new onset severe right midfacial pain, prompting consultation with neurology and maxillofacial surgery. A clinical assessment revealed an acute onset of intraoral vesicular lesions on the left upper buccal gingiva and hard palate which tested positive for herpes simplex virus 1. Otherwise, the intra-oral and extra-oral examination was normal at this post-surgical review. It was decided that a repeat FESS would be undergone due to worsening right facial pain out of proportion to exam findings, treatment and investigations. Findings on this second FESS demonstrated a normal right maxillary antrum but, purulent discharge from the left middle accessory antrum and necrotic tissue in the left maxilla. Bilateral middle meatal antrostomies were performed with lavage of both sinuses and a right anterior ethmoidectomy and the patient was discharged with oral valacyclovir and analgesia.\u003c/p\u003e\u003cp\u003eThe patient however, presented for further consultation due to ongoing bilateral midfacial pain and newly exposed maxillary alveolar bone, along with mobile maxillary teeth. A repeat CT scan demonstrated sinonasal disease and bony destruction. Advice from multiple specialties including maxillofacial surgery, infectious diseases, neurology, immunopathology and endodontics was sought. Further investigations were performed including multiple blood tests, dental reviews and sensibility testing. This prompted a third FESS to be undergone by ENT surgery, along with multiple biopsies of the sinuses, soft tissue and bone to identify the cause of the progressing symptoms and disease. A private oral surgeon also completed multiple maxillary extractions. Despite these investigations and interventions, subsequent CT findings showed progressive bony destruction.\u003c/p\u003e\u003cp\u003eHyperbaric oxygen therapy (HBOT) was commenced for the preliminary diagnosis of chronic osteonecrosis of the maxilla from an unknown cause. The diagnosis of rituximab related osteonecrosis was considered, and rituximab was withheld even though limited cases were reported in the literature. Progression of disease occurred despite 10 dives of HBOT and amoxicillin and clavulanate oral antibiotic therapy, with exposed maxillary bone bilaterally in the molar regions. This prompted an urgent CT scan, which showed advanced disease in previous areas with new erosions in inferomedial walls of both maxillary sinuses, cribriform plate, and crista galli [Figure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea-d]. Due to aggressive progression of the disease, the patient was discussed in a multidisciplinary meeting and planned for a total maxillectomy [Figure \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea-d] and debridement of other facial bones with potential for a second stage vascularized free flap.\u003c/p\u003e\u003cp\u003eA maxillectomy was undertaken by the maxillofacial surgery department and removed all the necrotic bone. The final histopathology of the specimen showed osteonecrosis with secondary areas of osteomyelitis. After a subsequent period without reconstruction and no resumption of the disease process, a total maxillary reconstruction was also undertaken by maxillofacial surgery in the form of a fibula free flap. The patient proceeded to have osseointegrated implants and dental rehabilitation with good success. There have been no further episodes of necrotic bone, and no further treatment with rituximab. The patient remains well after 5 years with no recurrence of osteonecrosis and stable dental rehabilitation.\u003c/p\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eMRONJ can occur spontaneously, however, majority of presentations are precipitated by trauma such as dental extractions. In the present case, it was hypothesized that an acute sinus infection caused the initial insult, which led to osteonecrosis. Systemic and local oral infection and inflammation have been implicated in the pathophysiology of MRONJ [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Whether sinusitis triggered osteonecrosis or was secondary to the osteonecrosis is difficult to ascertain but, exacerbation from the sinus disease is postulated. Distribution of the disease isolated to the maxilla makes this theory plausible but, in our case, the initial development of bilateral maxillary facial pain, which was more severe on the right, showed no evidence of right maxillary sinusitis on FESS initially.\u003c/p\u003e\u003cp\u003eThe patient also did undergo multiple periods of steroid therapy however, steroid use is predominantly believed to be a co-risk factor in the development of MRONJ as opposed to a causative risk factor [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] and is unlikely to have caused osteonecrosis in an otherwise fit and healthy 38-year-old.\u003c/p\u003e\u003cp\u003eIatrogenic rituximab related osteonecrosis of the jaw is another hypothesis. Osteonecrosis related to rituximab is rare with only 5 cases reported previously in the literature [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] as illustrated [Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e]. Baur et al [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] described the first case of rituximab related MRONJ in the mandible of an individual with large B-cell lymphoma during chemotherapy treatment.\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\u003eReported Cases of Rituximab Related Osteonecrosis of the Jaw\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"9\"\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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCase Report\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCo-morbidities\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePrevious Anti-Resorptive Use\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eImmunosuppression\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDuration of Rituximab Prior to Initial Symptoms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMRONJ\u003c/p\u003e\u003cp\u003eDistribution\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003ePreceding\u003c/p\u003e\u003cp\u003eDental\u003c/p\u003e\u003cp\u003eProcedures\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eInitial\u003c/p\u003e\u003cp\u003eSymptoms\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePresent Case\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38 M\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMultiple sclerosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e41 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaxilla up to orbit and base of skull\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePain in left maxilla\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eJavelot et al, 2019 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e69 F\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRheumatoid arthritis\u003c/p\u003e\u003cp\u003eOsteoporosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eRisedronate\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHydroxychloroquine\u003c/p\u003e\u003cp\u003eMethotrexate\u003c/p\u003e\u003cp\u003eInfliximab\u003c/p\u003e\u003cp\u003ePrednisolone\u003c/p\u003e\u003cp\u003eLeflunomide\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1 month\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaxilla\u003c/p\u003e\u003cp\u003eMandible\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eOral lesions suggestive of acute herpetic gingivostomatitis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAghaloo, et al, 2017 [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e52 F\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNon-Hodgkin lymphoma\u003c/p\u003e\u003cp\u003eStem cell transplant\u003c/p\u003e\u003cp\u003eOsteoporosis\u003c/p\u003e\u003cp\u003eSmoker (15-pack-year history)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eChemotherapy, including steroids\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaxilla\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eDeep periodontal pocket\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKeribin et al, 2017 [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e69 M\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRenal transplantation\u003c/p\u003e\u003cp\u003ePTLD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTacrolimus\u003c/p\u003e\u003cp\u003ePrednisone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e17 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMaxilla\u003c/p\u003e\u003cp\u003eMandible\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePersistent oral ulcers and mobile teeth\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAllegra et al, 2014 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e56 M\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLymphoplasmacytic lymphoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCyclophosphamide\u003c/p\u003e\u003cp\u003eVincristine\u003c/p\u003e\u003cp\u003ePrednisone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e14 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMandible\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eTooth extraction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMucosal ulceration\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBaur et al, 2012 [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e58 M\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eLarge B-cell lymphoma\u003c/p\u003e\u003cp\u003eT2DM\u003c/p\u003e\u003cp\u003eHypertension\u003c/p\u003e\u003cp\u003eHyperlipidaemia\u003c/p\u003e\u003cp\u003eBronchitis\u003c/p\u003e\u003cp\u003eDilated cardiomyopathy\u003c/p\u003e\u003cp\u003eEx-smoker (Previous 100-pack-year history)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCyclophosphamide\u003c/p\u003e\u003cp\u003eDoxorubicin\u003c/p\u003e\u003cp\u003eVincristine\u003c/p\u003e\u003cp\u003ePrednisone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e12 months\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMandible\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOral biopsy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePain in left mandible\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"9\"\u003eHypertension (HTN), Type 2 Diabetes Mellitus (T2DM), post-transplantation lymphoproliferative disorder (PTLD), medication-related osteonecrosis of the jaw (MRONJ)\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe direct cause of osteonecrosis related to rituximab is unclear but the proposed actions on angiogenesis and bone turnover have been suggested. Allegra et al [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] hypothesized rituximab had a negative action on angiogenesis based on the anti-CD 20 antibody action on CD 20-positive B cell proliferation and the associated minor role of B cells as a precursor for angiogenesis. Another theory by Wheater et al [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e] proposed that osteonecrosis of the jaw might be initiated or increased by the rituximab induced depletion of B-cells, which was related to suppression of bone turn over.\u003c/p\u003e\u003cp\u003eAn alternative hypothesis of rituximab induced MRONJ relates to immune imbalance and a proinflammatory state due to CD20 positive B cell depletion. B cells can function as antigen presenting cells for T cells. Specifically, \u003cem\u003ein vitro\u003c/em\u003e studies provide evidence for B cells presenting to regulatory Th17 (Treg17) cells [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Eliminating the induction of anti-inflammatory Treg17 cells tips the balance in favour of proinflammatory Th17 cells [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn the present case, the cause of the MRONJ is likely multifactorial with either rituximab inciting the disease sub clinically or, potentiation of the process initiated by the sinusitis. The disease was exacerbated by subsequent FESS procedures, the use of steroids, and dentoalveolar surgery. There were no preceding risk factors. Due to the scarcity of previous reports linking rituximab to MRONJ, no staging was reported since it was not considered in the initial differential diagnosis. However, as the clinical condition progressed within a few weeks, it became clear his disease pattern was consistent with MRONJ and a diagnosis of stage 3 MRONJ was made using the American Association of Oral \u0026amp; Maxillofacial Surgeon\u0026rsquo;s staging system [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This was due to exposed necrotic bone extending beyond the region of alveolar bone and osteolysis extending to the inferior border of the sinus floor. Progression of the MRONJ occurred despite conservative management.\u003c/p\u003e\u003cp\u003eMedication related osteonecrosis of the jaws predominantly affects the mandible in 73% of cases, the maxilla in 22.5% cases and both jaws in 4.5% of cases [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This finding has been attributed to the greater blood supply of the maxilla. This case is unique in the aspect that MRONJ related to rituximab has never been extensive enough to involve the orbit and base of the skull.\u003c/p\u003e\u003cp\u003eBeyond classical antiresorptive drugs, several other agents and systemic conditions have been implicated in the pathogenesis of MRONJ. Isolated case reports describe MRONJ in patients receiving long-term statin therapy, particularly high-dose simvastatin, suggesting that inhibition of the mevalonate pathway may impair osteoclast function in a manner analogous to bisphosphonates [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Other monoclonal antibodies have also been linked, including bevacizumab and romosozumab, albeit with evidence largely limited to small case series and pharmacovigilance signals [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSeveral medical comorbidities have been implicated in increasing susceptibility to MRONJ [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. These include malignancy, diabetes mellitus, and anaemia, as well as systemic factors such as immunosuppression and lifestyle habits like smoking. Such conditions are thought to contribute by impairing wound healing, altering immune function, or compounding the effects of antiresorptive and antiangiogenic therapies [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Recognition of these comorbidities is essential in contextualizing MRONJ risk and guiding preventive and therapeutic strategies.\u003c/p\u003e\u003cp\u003eClinicians should maintain a high suspicion of medications, especially the ever-developing monoclonal antibodies, causing MRONJ in symptomatic individuals. With the growing number of case reports describing the possibility of rituximab contributing to the pathogenesis of MRONJ, the consideration of this agent as an additional risk factor and/or iatrogenic cause should be considered.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eClinical Trial Number\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\u003cp\u003e\u003ch2\u003eEthics approval\u003c/h2\u003e\u003cp\u003eThis case report was made in accordance with the guidelines of Metro North Health Queensland, the operating body for Royal Brisbane and Women\u0026rsquo;s Hospital. Patient consent was obtained for publication and ethics review was not required for an individual case report.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eConsent to participate\u003c/h2\u003e\u003cp\u003eInformed consent was obtained from the patient described in this report.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConsent to publish\u003c/strong\u003e\u003cp\u003eWritten informed consent for publication of clinical details and accompanying images was obtained from the patient.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\u003cp\u003e\u003cem\u003eCompeting Interests\u003c/em\u003e\u003c/p\u003e\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eThe conception of this case report is credited to M.B. along with the initial documentation of findings. M.B. and J.T. acquired patient consent, photographs, radiographs and extracted information from medical records. A.R. and J.T. are responsible for creation of the initial manuscript. Review and editing of the manuscript is credited to M.B., G.B. and E.J. with all three reviewers providing substantial input to the final report. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eThe authors have no acknowledgements to declare.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMarx RE. Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. \u003cem\u003eJ Oral Maxillofac Surg.\u003c/em\u003e 2003;61(9):1115\u0026ndash;7. https://doi.org/10.1016/S0278-2391(03)00720-1\u003c/li\u003e\n\u003cli\u003eTaylor KH, Middlefell LS, Mizen KD. Osteonecrosis of the jaws induced by anti-RANK ligand therapy. \u003cem\u003eBr J Oral Maxillofac Surg.\u003c/em\u003e 2010;48(3):221\u0026ndash;3. https://doi.org/10.1016/j.bjoms.2009.08.030\u003c/li\u003e\n\u003cli\u003eRuggiero SL, Dodson TB, Fantasia J, Goodday R, Aghaloo T, Mehrotra B, et al. American Association of Oral and Maxillofacial Surgeons position paper on medication-related osteonecrosis of the jaw\u0026mdash;2014 update. \u003cem\u003eJ Oral Maxillofac Surg.\u003c/em\u003e 2014;72(10):1938\u0026ndash;56. https://doi.org/10.1016/j.joms.2014.04.031\u003c/li\u003e\n\u003cli\u003eAllegra A, Oteri G, Alonci A, Bacci F, Penna G, Minardi V, et al. Association of osteonecrosis of the jaws and POEMS syndrome in a patient assuming rituximab. \u003cem\u003eJ Craniomaxillofac Surg.\u003c/em\u003e 2014;42(4):279\u0026ndash;82. https://doi.org/10.1016/j.jcms.2013.05.014\u003c/li\u003e\n\u003cli\u003eTherapeutic Goods Administration. Australian Public Assessment Report for Rituximab (Ruxience). Sydney: Pfizer Australia Pty Ltd; 2021 Apr. Report No.: PM-2020-00593-1-6. Available from: https://www.tga.gov.au/product-information-pi [accessed 13 July 2025]\u003c/li\u003e\n\u003cli\u003eSalzer J, Svenningsson R, Alping P, Novakova L, Bj\u0026ouml;rck A, Fink K, et al. Rituximab in multiple sclerosis: a retrospective observational study on safety and efficacy. \u003cem\u003eNeurology.\u003c/em\u003e 2016;87(20):2074\u0026ndash;81. https://doi.org/10.1212/wnl.0000000000003331\u003c/li\u003e\n\u003cli\u003eKhan AA, Morrison A, Hanley DA, Felsenberg D, McCauley LK, O\u0026apos;Ryan F, et al. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. \u003cem\u003eJ Bone Miner Res.\u003c/em\u003e 2015;30(1):3\u0026ndash;23. https://doi.org/10.1002/jbmr.2405\u003c/li\u003e\n\u003cli\u003eJavelot MJ, Sergheraert J, Agbo-Godeau S, Levy-Weil F, Laurence S, Goudot P, et al. Rituximab as a trigger factor of medication-related osteonecrosis of the jaw: a case report. \u003cem\u003eJ Stomatol Oral Maxillofac Surg.\u003c/em\u003e 2019;120(6):583\u0026ndash;6. https://doi.org/10.1016/j.jormas.2019.06.009\u003c/li\u003e\n\u003cli\u003eAghaloo TL, Tetradis S. Osteonecrosis of the jaw in the absence of antiresorptive or antiangiogenic exposure: a series of 6 cases. \u003cem\u003eJ Oral Maxillofac Surg.\u003c/em\u003e 2017;75(1):129\u0026ndash;42. https://doi.org/10.1016/j.joms.2016.07.019\u003c/li\u003e\n\u003cli\u003eKeribin P, Guerrot D, Jardin F, Moizan H. Osteonecrosis of the jaw in a patient presenting with post-transplantation lymphoproliferative disorder treated with rituximab: a case report. \u003cem\u003eJ Oral Maxillofac Surg.\u003c/em\u003e 2017;75(12):2599\u0026ndash;605. https://doi.org/10.1016/j.joms.2017.05.016\u003c/li\u003e\n\u003cli\u003eBaur DA, Weber JM, Collette DC, Dhaliwal H, Quereshy F. Osteonecrosis of the jaws unrelated to bisphosphonate exposure: a series of 4 cases. \u003cem\u003eJ Oral Maxillofac Surg.\u003c/em\u003e 2012;70(12):2802\u0026ndash;8. https://doi.org/10.1016/j.joms.2012.02.019\u003c/li\u003e\n\u003cli\u003eWheater G, Hogan VE, Teng YK, Tekstra J, Lafeber FP, Huizinga TW, et al. Suppression of bone turnover by B-cell depletion in patients with rheumatoid arthritis. \u003cem\u003eOsteoporos Int.\u003c/em\u003e 2011;22(12):3067\u0026ndash;72. https://doi.org/10.1007/s00198-011-1607-0\u003c/li\u003e\n\u003cli\u003eShao TY, Hsu LH, Chien CH, Chiang BL. Novel Foxp3(-) IL-10(-) regulatory T-cells induced by B-cells alleviate intestinal inflammation in vivo. \u003cem\u003eSci Rep.\u003c/em\u003e 2016;6:32415. https://doi.org/10.1038/srep32415\u003c/li\u003e\n\u003cli\u003eSingh B, Summers KL, Kerfoot SM. Novel regulatory Th17 cells and regulatory B cells in modulating autoimmune diseases. \u003cem\u003eCell Immunol.\u003c/em\u003e 2019;339:29\u0026ndash;32. https://doi.org/10.1016/j.cellimm.2019.03.001\u003c/li\u003e\n\u003cli\u003eGiladi HZ, Gabay E, Machtei EE. Medication-Related Osteonecrosis of the Jaw in Patients Taking High-Dose Simvastatin. \u003cem\u003eJ Oral Maxillofac Surg\u003c/em\u003e. 2020;78(6):862-863 https://doi.org/10.1016/j.joms.2020.01.009\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"Osteonecrosis; Jaw; Antibodies, Monoclonal, Risk Factors, Case Reports","lastPublishedDoi":"10.21203/rs.3.rs-7626424/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7626424/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMedication-related osteonecrosis of the jaw (MRONJ) is a known adverse effect of antiresorptive and antiangiogenic therapies. However, reports of osteonecrosis linked to rituximab, a CD20 targeting monoclonal antibody, are exceedingly rare. We present a unique case of extensive maxillary MRONJ in a male 38 years of age with a background of multiple sclerosis receiving rituximab therapy. An initial presentation of acute sinusitis, progressed to bilateral maxillary bone destruction despite conservative management, multiple surgical interventions, and hyperbaric oxygen therapy. No other established MRONJ risk factors were identified including anti-resorptive use, antiangiogenic use, dento-alveolar surgery or dento-alveolar trauma. The extent of destruction, reaching the orbit and cranial base, is unprecedented in rituximab related cases. This report adds to the growing literature on rituximab associated MRONJ and emphasizes the need for increased awareness and understanding of this monoclonal antibody being a potential risk factor for MRONJ.\u003c/p\u003e","manuscriptTitle":"Rare Case of Rituximab Related Osteonecrosis of the Maxilla; A Case Report and Literature Review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-17 12:32:26","doi":"10.21203/rs.3.rs-7626424/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":"3afad53b-ce6b-48ec-99a2-421b6882f075","owner":[],"postedDate":"October 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-27T11:27:08+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-17 12:32:26","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7626424","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7626424","identity":"rs-7626424","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}