Cryptococcal meningitis in a patient with VEXAS syndrome: a case report

Cryptococcal meningitis in a patient with VEXAS syndrome: a case report | 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 Cryptococcal meningitis in a patient with VEXAS syndrome: a case report Michelle Chun-Ping Lin, Thomas Day, Syed Basharat Ali This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7582383/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background Vacuoles, E1 enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome is a recently described multisystem disease. Opportunistic infections in VEXAS syndrome are increasingly being recognized, with multiple factors including immune dysregulation due to aberrant ubiquitination pathway, secondary effects from chronic immunosuppressive treatments and underlying comorbidities contributing. Given lack of consensus guidelines on antimicrobial prophylaxis, clinical practice is heterogenous with varying treatment outcomes. Case presentation: Herein, we report a rare case of cryptococcal meningitis in a patient with treatment refractory VEXAS syndrome, on chronic moderate-dose corticosteroid (average 20mg per day) and ruxolitinib. The patient initially presented with acute confusion and fevers, with elevated inflammatory markers and worsening cytopaenia. The differential diagnoses included an acute flare of VEXAS syndrome and intercurrent infection. Further testing revealed presence of Cryptococcus neoformans in the cerebrospinal fluid. Thereafter, antifungal therapy was initiated, however the patient suffered from irreversible functional decline despite successful antimicrobial clearance. Conclusion The case raises important considerations, firstly regarding antimicrobial - particularly antifungal - prophylaxis given paucity of guidelines, secondly prompt diagnosis and treatment of cryptococcal infections, and finally regular interval screening for opportunistic infections in this vulnerable patient cohort. A multidisciplinary approach to care is required to improve morbidity and mortality from atypical infections in VEXAS syndrome. VEXAS infection cryptococcus invasive fungal infection immune dysregulation Figures Figure 1 Figure 2 Figure 3 Background Vacuoles, E1 enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome is a recently described multisystem disease arising from a somatic mutation in the UBA1 gene ( 1 ). The estimated prevalence is rare, occurring in 1 in 13591 individuals across all age groups( 2 ). The UBA1 gene encodes for a vital protein in the ubiquitination pathway and mutation leads to impairment in protein degradation and cellular signalling resulting in profound cellular stress and inflammation( 3 ). As ubiquitination is essential in many cell lines, clinical presentation of VEXAS syndrome is heterogenous and involves multiple organ systems. Of these, bone marrow involvement is most common with multilineage cytopenia ensuing, and some patients with concurrent myelodysplastic syndrome (MDS), further contributing to morbidity and mortality. The persistent proinflammatory state requires immunosuppressive treatment. Unfortunately, the disease is often refractory to several lines of therapies. As patients with VEXAS syndrome are older with accompanying comorbidities, which compounded by cytopenia and immunosuppressive therapies, increases their overall risk of opportunistic infections. Furthermore, it is being increasingly recognized that immune dysregulation in VEXAS syndrome may also play a role( 4 ). For example, invasive fungal infections (IFI) and legionella infections have been reported independent of immunosuppressive treatments ( 5 ). In the absence of clear guidelines on prophylaxis, along with treatment refractory nature of the disease, clinicians must be vigilant for infection in patients with VEXAS syndrome. To date, several opportunistic viral, bacterial and fungal infections have been reported with a recent systematic review identifying that these infections are common and heterogenous ( 6 ). Herein, we report a rare case of cryptococcal meningitis, in a patient with treatment refractory VEXAS syndrome without concurrent MDS. The case provides important considerations on prophylaxis, recognition, and management. Case Presentation A 69-year-old male was managed in the immunology clinic for polyarteritis nodosa (PAN) with per oral (p.o.) mycophenolate 1g twice daily (BD) and prednisolone 15mg daily. His other background history included ankylosing spondylitis, with recent switch to subcutaneous (s.c.) etanercept after limited improvement on s.c. secukinumab. A year after commencing treatment for PAN, he developed breathlessness and cough over several months. Etanercept was withheld, however he continued to have symptoms leading to hospitalization. On admission, he had macrocytic anemia and type 1 respiratory failure, and imaging demonstrated extensive ground glass opacities without evidence of concurrent infective, autoimmune or vascular aetiologies. Higher dose prednisolone resulted in improvement of respiratory symptoms over the following fortnight; however, macrocytic anemia persisted with hemoglobin of 72 g/L (135–175 g/L) and mean cell volume (MCV) 102 fL (80–98 fL). Evaluation of hematinics and hemolysis screens were unremarkable. A bone marrow biopsy was reported as normal. Over the following 12 months, systemic symptoms with PAN persisted which included lower limb paraesthesia and weakness. A positron emission tomography (PET) scan suggested features of vasculitis in the popliteal arteries. Intravenous (i.v.) tocilizumab treatment was initiated thereafter; however he continued to have symptoms leading to treatment cessation after four months. Prednisolone dosing remained at 15mg, and trimethoprim/sulfamethoxazole 160mg/800mg (TMP-SMX) half tablet daily was initiated for Pneumocystis prophylaxis. In the following weeks, he developed bilateral left lower limb oedema and a doppler ultrasound revealed extensive bilateral deep venous thrombosis (DVT). Apixaban therapy was initiated and in the subsequent months, follow up scans showed persistence in thrombus. On a routine outpatient follow up, bloods demonstrated a trilineage cytopenia with Hb 125 g/L, white cell count (WCC) of 3.13 x10 9 /L (4.00–11.00 x10 9 /L) and platelets (PLT) of 99 x10 9 /L (150–450 x10 9 /L) which did not resolve on withholding mycophenolate. The combination of persistent cytopenia with macrocytosis, PAN and DVT in an older male led to the consideration of VEXAS syndrome given its recent description (Fig. 1 ). Peripheral blood testing confirmed a somatic mutation in the UBA1 gene; c.121A > G p.(Met41Val). Bone marrow biopsy was repeated and confirmed characteristic cytoplasmic vacuolation. The histopathology department re-reviewed the previous bone marrow biopsy performed 18 months prior and confirmed vacuolation. Following prolonged and protracted symptoms over years, a unifying diagnosis of VEXAS syndrome was reached (Fig. 1 ). Prednisolone treatment was increased to 20mg daily, and a 6-month trial of anakinra was completed before compassionate access to p.o. ruxolitinib at 10mg twice daily was approved. He continued TMP-SMX and was commenced on p.o. valaciclovir 500mg daily for infection prophylaxis. His immunizations were up to date. His functional status at this time was equivalent to an Eastern Cooperative Oncology Group (ECOG) score of 1. His CD4 count was 270 cells/mm 3 (500–1500 cells/mm 3 ) and his C-reactive protein (CRP) was 3 mg/L (0.0–8.0 mg/L). Over the next few months, cytopenia persisted and was refractory to prednisolone dosage below 17.5mg daily. Importantly, CRP remained normal. He developed complications of long-term corticosteroid therapy including Cushingoid facies, increased interscapular fat pad, proximal myopathy and osteopenia (Fig. 2). His HbA1c was 6.4% (≤ 7%). Around 12 months later, he developed acute onset of fevers, malaise, headache and vomiting. On presentation, he was febrile (39°C) with Glasgow coma scale (GCS) 13 (E3, V4, M6), hypoxic with unilateral lower limb swelling. Investigations revealed worsening cytopenia: Hb 80 g/L, WCC 2.05 x10 9 /L (including neutrophil count 1.10 x109/L [1.80–7.50 x109/L]) and PLT 67x10 9 /L. Inflammatory markers were both elevated: CRP 253.4 mg/L and erythrocyte sedimentation rate (ESR) > 120 mm (1–15 mm). Imaging for venous thromboembolism demonstrated stable appearance of chronic thrombus. Magnetic resonance imaging (MRI) brain with gadolinium contrast identified subtle multifocal punctate enhancing foci in both cerebellar hemispheres, suggestive of early changes of rhombencephalitis. A lumbar puncture revealed elevated opening pressure of 27 cmH 2 O and the following cerebrospinal fluid (CSF) assessment: protein 0.89 g/L (0.15–0.45 g/L), glucose 3.8 mmol/L (2.2–5.5 mmol/L), 3 polymorphonuclear cells, 44 mononuclear cells and 10 erythrocytes. A multidisciplinary approach involving immunology, haematology and infectious diseases specialists led to consensus opinion to concurrently treat suspected VEXAS syndrome flare with pulse methylprednisolone, cover for meningoencephalitis with i.v. benzylpenicillin, i.v. ceftriaxone and i.v. acyclovir. Three days later, CSF cryptococcal antigen (CrAg) returned strongly positive at a titre of 1:512 with C. neoformans identified on fungal culture. A diagnosis of cryptococcal meningitis was made and induction therapy commenced (Fig. 3 ) with 2 weeks of i.v. liposomal amphotericin B (L-AMB) 300mg daily with p.o. flucytosine 2g 6-hourly. Due to concerns for L-AMB toxicity with rising creatinine to 193 µmol/L (60–110 µmol/L), L-AMB was ceased and switched to i.v. fluconazole 400mg daily, and flucytosine adjusted for renal function to 12 hourly intervals. Ruxolitinib dose was reduced to 5mg BD while prednisolone dose was reduced to 50mg with weaning following pulse methylprednisolone. TMP-SMX and valaciclovir were continued. A repeat lumbar puncture 2 weeks later showed persistently elevated opening pressure at 27.5 cmH 2 O and raised CSF protein of 0.67 but reduction in CrAg titre to 1:32. Dual antifungal consolidative therapy was completed for a month, followed by p.o. fluconazole monotherapy at 800mg daily for a further 8 weeks, then 200mg daily thereafter. Ruxolitinib therapy was ceased given lack of overall efficacy and prednisolone monotherapy was continued (Fig. 3 ). Whilst the headaches and fevers resolved, he had a significant decline in function despite prolonged inpatient rehabilitation. He was discharged to a residential care facility, with ECOG status of 3. Given significant decline in function, a haematology consensus was reached for consideration of low dose azacitadine over haematopoetic stem cell transplantation. Discussion This report describes a rare case of cryptococcal meningitis in a patient with VEXAS syndrome without concurrent MDS. Treatment with numerous lines of immunosuppressive therapies including chronic corticosteroids and VEXAS-related immune dysregulation, collectively predispose patients to serious opportunistic infections ( 7 ). Such infections, particularly disseminated to the central nervous system (CNS) have additionally pronounced impact on patient function and overall quality of life ( 4 , 8 ). Therefore, clinicians need to be vigilant in screening, diagnosing and consolidating guidelines for infection prophylaxis in this vulnerable patient cohort to improve treatment outcomes. Although there are no specific guidelines, early institution of antifungals, in addition to Pneumocystis, herpes simplex virus (HSV) and varicella zoster virus (VZV) prophylaxis is a key learning point from this case. To date, only one case of cryptococcal meningitis in VEXAS syndrome has been reported ( 5 ). Cryptococcus is one of the most common non-viral causes of meningitis in the immunocompromised host, with considerable mortality associated given its insidious presentation that often results in delays in diagnosis and treatment ( 9 ). Historically, patients with acquired immunodeficiency syndrome (AIDS) from human immunodeficiency virus (HIV) were most susceptible, however the rise in immunomodulatory therapies have led to an epidemiologic shift in affected patient cohorts ( 9 , 10 ). In non-HIV cohorts, risk factors include prolonged neutropenia, extended course of high dose glucocorticoids (although the exact dose and duration remains unclear) and several immunosuppressive therapies ( 11 , 12 ). These include calcineurin inhibitors (e.g. tacrolimus) and mammalian target of rapamycin (mTOR) inhibitors (e.g. sirolimus) in solid organ transplant recipients and rare cases described with anti-tumour necrosis factor alpha, sphingosine-1-phosphate receptor, anti-CD52 and anti-Bruton’s tyrosine kinase inhibitors ( 9 , 11 , 13 ). There are also specific patient cohorts with increased risk, and these include inborn errors of immunity as well as sarcoidosis ( 9 , 13 , 14 ). Interestingly, rates of IFI were rare amongst stem-cell transplant recipients, which has been attributed to routine anti-fungal prophylaxis in this cohort ( 14 – 16 ). Multiple factors contribute to infection risk in VEXAS syndrome, including intrinsic immune dysregulation from the disease itself and extrinsic effects from immunosuppressive therapy ( 4 , 8 ). This was described in a cohort of 813 patients with VEXAS, noting that opportunistic infections occurred even in patients not on immunosuppressive therapy ( 17 ). On a cellular level, in vitro studies have demonstrated evidence of monocyte exhaustion with diminished counts and aberrant chemokine receptor expression, alongside dysfunctional upregulation of proinflammatory cytokines such as IL-1β and IL-18 suggestive of inflammasome activation ( 4 , 8 ). It is thus imperative that infection be considered in the management of VEXAS patients irrespective of immunosuppression. Our patient was refractory to a range of biologic disease modifying antirheumatic drugs (DMARDs), frequently requiring steroid up titration to prevent worsening cytopenia. On review, his cumulative steroid burden equated to an annual prednisolone dose of 1300mg, averaging 25mg/day. The immunosuppressive effects of glucocorticoids are well documented, affecting the whole gamut of innate and adaptive immune system by, e.g. impeding neutrophil phagocytic activity, dampening macrophage, monocyte and natural killer cytotoxicity through downregulation of cytokine production and also by impairing toll-like receptor signalling ( 11 , 12 ). In addition, treatment with ruxolitinib, a JAK1/2 inhibitor of the JAK/STAT pathway, further predisposes to viral reactivation by interfering with natural killer (NK) cell maturation and has secondary effects blocking dendritic cell differentiation and antigen presentation. A systematic review identified herpes zoster infection (1336 total patients affected per year, OR 5.20 [1.27, 21.18]) as the most common ruxolitinib-associated infective complication in MDS patients, for which anti-viral prophylaxis can be considered ( 18 ). Moreover, the risk of hepatitis B virus and latent tuberculosis reactivation with JAK inhibitors (JAKi) have also been raised, and pre-treatment screening is recommended for at risk groups ( 19 ). There are no guidelines on pre-treatment anti-fungal prophylaxis for JAKi. Cases of ruxolitinib-associated IFI are rare in comparison to herpes zoster infections with only twelve reported cases of cryptococcosis in MDS patients receiving ruxolitinib, one of which had a diagnosis of chronic myelomonocytic leukaemia on combination azacitidine and cytarabine ( 13 ). MDS disease severity should be considered as severe disease with splenomegaly and splenic dysfunction may further contribute to infection risk independent of Ruxolitinib ( 20 , 21 ). Patients with VEXAS syndrome are at risk of developing MDS which with neutropenia and neutrophil dysfunction may predispose to opportunistic infection ( 2 ). Bacteria are the most common cause of infection in MDS patients treated with azacitidine ( 22 ). Moreover, comorbidities with advanced age in MDS patients likely add to their susceptibility to infection ( 16 , 23 ). Interestingly, a recent case series of seventy-four VEXAS syndrome patients did not find MDS an independent predictor of serious infection, but identified advanced age at diagnosis (> 75 years), p.Met41Val mutation, arthralgia and treatment with JAK inhibition as significant risk factors instead ( 5 ). Importantly, the greater association with MDS, transfusion dependency despite less chondritis amongst p.Met41Val mutated patients portends worse prognosis ( 24 , 25 ). Current screening and prevention guidelines for opportunistic infections are well established for immunocompromised patients in rheumatology, haematology, oncology, and transplant medicine ( 15 , 26 , 27 ). For example, the 2023 EULAR recommendation to screen for latent tuberculosis, hepatitis B and C virus, and HIV infection prior to initiating DMARD, glucocorticoid therapy or other immunosuppressants is robust, and has transpired across other fields ( 27 ). In addition, Pneumocystis jirovecii prophylaxis in patients on prolonged glucocorticoids (i.e. >15–30 mg prednisolone equivalent dose for > 2–4 weeks) is well documented in Rheumatology, and was certainly factored in for our patient who received TMP-SMX for this reason ( 27 ). Guidelines to prevent fungal infections is also well established in HIV-AIDS patients with low CD4 cell count < 200 cells/mm 3 and in haematological malignancies or stem cell transplant recipients ( 12 , 15 , 28 ). For solid organ transplant recipients, the screening for and prevention of cytomegalovirus and Epstein-Barr virus infection is of paramount importance to optimize graft function ( 29 ). Unfortunately, there are no equivalent recommendations for the prevention of IFI in other immunocompromised patients such as VEXAS syndrome, likely due to the comparative rarity of cases and heterogeneity of affected patients. This is further complicated by antifungal drug interactions and insidious nature of the disease, making both diagnosis and management difficult ( 30 ). Perhaps existing benchmarks for IFI prophylaxis in other specialties could help guide decisions in preventing opportunistic infections for at-risk VEXAS patients. While our case has exemplified a rare infective complication in VEXAS syndrome, there are a few limitations. Regarding, antifungal prophylaxis, earlier institution may have prevented such a complication, however the paucity on guidelines and understanding of side effects from multiple concurrent immunosuppressive and immunomodulatory treatment were possible barriers. Given the novelty of VEXAS syndrome, treatment options were limited by available evidence and clinical experience. Although azacitidine and transplant were raised as possible options much earlier in his disease course, these were not proceeded due to risk versus benefit evaluation at the time, considering his declining functional status, concern for infection risk, cost and experience at this centre. Previously, azacitidine showed promise with variable efficacy, but recently have been demonstrated to be effective regardless of MDS status ( 31 , 32 ). The patient has since been initiated on low dose azacitidine and is tolerating well (Fig. 3 ). Transplant is also an emerging treatment option, though infections have also been reported in this context ( 33 ). Conclusion In summary, we present a rare case of cryptococcal meningitis in a patient with treatment refractory VEXAS syndrome without concurrent MDS. Given the significant morbidity and mortality associated with opportunistic infections, particularly cryptococcus infection, this case raises several important clinical practice points. Firstly, a multidisciplinary approach amongst specialties, including infectious diseases and haematology specialists, is required on deciding initiation of antifungal therapies in patients with VEXAS syndrome. Secondly, addition of such therapy needs to be considered on balance with risks benefit profile, with close monitoring of drug-drug interactions with antifungals, degree of cytopenia, patient comorbidities and cumulative corticosteroid exposure. Finally, a growing need for a best practice consensus guideline on preventing opportunistic infections in VEXAS syndrome is urgently required to prevent irreversible sequelae. Abbreviations BD: twice daily C. neoformans: Cryptococcus neoformans CrAg: cryptococcal antigen CRP: C-reactive protein CSF: cerebrospinal fluid DMARD: Disease modifying antirheumatic drug DVT: deep venous thrombosis ECOG: Eastern Cooperative Oncology Group GCS: glasgow coma scale HIV-AIDS: human immunodeficiency virus acquired immunodeficiency syndrome HSV: herpes simplex virus IFI: invasive fungal infections i.v.: intravenous JAKi: Janus kinase inhibitors L-AMB: liposomal amphotericin MCV: mean cell volume MDS: Myelodysplastic syndrome MRI: magnetic resonance imaging mTOR: mammalian target of rapamycin inhibitor PAN: polyarteritis nodosa PET: positron emission tomography PLT: platelets p.o.: per oral s.c.: subcutaneous TMP-SMX: trimethoprim/sulfamethoxazole VEXAS: Vacuoles, E1 enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome VZV: varicella zoster virus WCC: white cell count Declarations Ethics approval: Ethical approval for this case report was obtained from the Southern Adelaide Clinical Human Research Ethics Committee (SAC HREC) on 30 th July 2025. Consent: The authors confirm that written informed consent was obtained from the patient for the publication of this manuscript and accompanying images. Availability of data: Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. Competing interests: The authors declare that they have no competing interests Funding statement: There was no funding received for the preparation of this manuscript. Authors’ contributions: S.A. conceived the idea for this case report and provided overall supervision of the project. M.L. conducted the literature review and drafted the initial manuscript. S.A. critically revised the manuscript. T.D. read and approved the final draft for submission. M.L. prepared figures 1-3. All authors have read and agreed to the published version of the manuscript. Acknowledgments: The authors would like to thank the patient for providing us with an ongoing opportunity to learn about this complex and rare disease. 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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-7582383","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":515164990,"identity":"530f81a6-3eb6-448d-8a26-5aa34d7f61ee","order_by":0,"name":"Michelle Chun-Ping Lin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYDACZgY2BoYCCwYGdsYGhg/EazGQADIYGxhnEGkPTAsQ8RCjXred+dmDDwYScgzMzG2Pbf7YMci79xgw/GzDrcXsMJu54QwDCWOgw9qNc9uSGQzPnDFg7MWrhYdNmsdAIrGBmbFNOreBmcFwRloCAy8hLX8MJOrBWiz+1IO1MP4lpAXo/QQGkBYGtsMM8hLJB5jx28JmJtljIGHYBtQi2dt2nMeA5/CBwzLn8Gg5f/iZxI8KG3l+9nYg40+1nHx7Y+PDN2W4tcABG5TmMTjAwHCACA1IQL6BNPWjYBSMglEw/AEAniJA0fPGRywAAAAASUVORK5CYII=","orcid":"","institution":"Flinders Medical Centre","correspondingAuthor":true,"prefix":"","firstName":"Michelle","middleName":"Chun-Ping","lastName":"Lin","suffix":""},{"id":515164991,"identity":"c7075c23-2878-4e3a-9141-12b90c809647","order_by":1,"name":"Thomas Day","email":"","orcid":"","institution":"Flinders Medical Centre","correspondingAuthor":false,"prefix":"","firstName":"Thomas","middleName":"","lastName":"Day","suffix":""},{"id":515164992,"identity":"8f15c0ab-3559-4445-89a5-fae19d847e59","order_by":2,"name":"Syed Basharat Ali","email":"","orcid":"","institution":"Flinders Medical Centre","correspondingAuthor":false,"prefix":"","firstName":"Syed","middleName":"Basharat","lastName":"Ali","suffix":""}],"badges":[],"createdAt":"2025-09-10 11:23:35","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7582383/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7582383/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91954467,"identity":"c1482bed-7da8-48c6-bca2-6d9d6086aef2","added_by":"auto","created_at":"2025-09-23 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07:15:50","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":85969,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7582383/v1/0d007fb9a6d5b8d7bba646db.html"},{"id":91954457,"identity":"fdd35bbe-e2e2-45c2-94cd-46919f843839","added_by":"auto","created_at":"2025-09-23 07:07:50","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":232878,"visible":true,"origin":"","legend":"\u003cp\u003eTimeline of events leading to VEXAS syndrome diagnosis.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7582383/v1/c4e0197f456cb4d43a760406.png"},{"id":91956499,"identity":"f37377c3-6184-4ea3-9c46-fb0ace34663e","added_by":"auto","created_at":"2025-09-23 07:15:50","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":205952,"visible":true,"origin":"","legend":"\u003cp\u003eSpectrum of clinical features predating diagnosis of VEXAS syndrome. GGO, ground glass opacity; PAN: polyarteritis nodosa; DVTs, deep vein thrombosis\u003c/p\u003e\n\u003cp\u003eGGO, ground glass opacity; PAN: polyarteritis nodosa; DVTs, deep vein thrombosis\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7582383/v1/5a211f217f22d02c2520ef7c.png"},{"id":91954459,"identity":"078ba848-1b55-4152-946f-76a0185ff42e","added_by":"auto","created_at":"2025-09-23 07:07:50","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":161765,"visible":true,"origin":"","legend":"\u003cp\u003eTreatment timeline in relation to symptom onset, VEXAS syndrome and cryptococcal meningitis diagnosis.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7582383/v1/e774e74ec2b85d1688720417.png"},{"id":91958048,"identity":"af443c81-9a79-41fc-8d43-f5fbc6444c5b","added_by":"auto","created_at":"2025-09-23 07:31:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1006352,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7582383/v1/c6744652-026b-4100-827d-e93facfdff23.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cryptococcal meningitis in a patient with VEXAS syndrome: a case report","fulltext":[{"header":"Background","content":"\u003cp\u003eVacuoles, E1 enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome is a recently described multisystem disease arising from a somatic mutation in the \u003cem\u003eUBA1\u003c/em\u003e gene (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The estimated prevalence is rare, occurring in 1 in 13591 individuals across all age groups(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The \u003cem\u003eUBA1\u003c/em\u003e gene encodes for a vital protein in the ubiquitination pathway and mutation leads to impairment in protein degradation and cellular signalling resulting in profound cellular stress and inflammation(\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). As ubiquitination is essential in many cell lines, clinical presentation of VEXAS syndrome is heterogenous and involves multiple organ systems. Of these, bone marrow involvement is most common with multilineage cytopenia ensuing, and some patients with concurrent myelodysplastic syndrome (MDS), further contributing to morbidity and mortality.\u003c/p\u003e\u003cp\u003eThe persistent proinflammatory state requires immunosuppressive treatment. Unfortunately, the disease is often refractory to several lines of therapies. As patients with VEXAS syndrome are older with accompanying comorbidities, which compounded by cytopenia and immunosuppressive therapies, increases their overall risk of opportunistic infections. Furthermore, it is being increasingly recognized that immune dysregulation in VEXAS syndrome may also play a role(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). For example, invasive fungal infections (IFI) and legionella infections have been reported independent of immunosuppressive treatments (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn the absence of clear guidelines on prophylaxis, along with treatment refractory nature of the disease, clinicians must be vigilant for infection in patients with VEXAS syndrome. To date, several opportunistic viral, bacterial and fungal infections have been reported with a recent systematic review identifying that these infections are common and heterogenous (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eHerein, we report a rare case of cryptococcal meningitis, in a patient with treatment refractory VEXAS syndrome without concurrent MDS. The case provides important considerations on prophylaxis, recognition, and management.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eA 69-year-old male was managed in the immunology clinic for polyarteritis nodosa (PAN) with per oral (p.o.) mycophenolate 1g twice daily (BD) and prednisolone 15mg daily. His other background history included ankylosing spondylitis, with recent switch to subcutaneous (s.c.) etanercept after limited improvement on s.c. secukinumab.\u003c/p\u003e\n\u003cp\u003eA year after commencing treatment for PAN, he developed breathlessness and cough over several months. Etanercept was withheld, however he continued to have symptoms leading to hospitalization. On admission, he had macrocytic anemia and type 1 respiratory failure, and imaging demonstrated extensive ground glass opacities without evidence of concurrent infective, autoimmune or vascular aetiologies. Higher dose prednisolone resulted in improvement of respiratory symptoms over the following fortnight; however, macrocytic anemia persisted with hemoglobin of 72 g/L (135\u0026ndash;175 g/L) and mean cell volume (MCV) 102 fL (80\u0026ndash;98 fL). Evaluation of hematinics and hemolysis screens were unremarkable. A bone marrow biopsy was reported as normal.\u003c/p\u003e\n\u003cp\u003eOver the following 12 months, systemic symptoms with PAN persisted which included lower limb paraesthesia and weakness. A positron emission tomography (PET) scan suggested features of vasculitis in the popliteal arteries. Intravenous (i.v.) tocilizumab treatment was initiated thereafter; however he continued to have symptoms leading to treatment cessation after four months. Prednisolone dosing remained at 15mg, and trimethoprim/sulfamethoxazole 160mg/800mg (TMP-SMX) half tablet daily was initiated for Pneumocystis prophylaxis.\u003c/p\u003e\n\u003cp\u003eIn the following weeks, he developed bilateral left lower limb oedema and a doppler ultrasound revealed extensive bilateral deep venous thrombosis (DVT). Apixaban therapy was initiated and in the subsequent months, follow up scans showed persistence in thrombus. On a routine outpatient follow up, bloods demonstrated a trilineage cytopenia with Hb 125 g/L, white cell count (WCC) of 3.13 x10\u003csup\u003e9\u003c/sup\u003e/L (4.00\u0026ndash;11.00 x10\u003csup\u003e9\u003c/sup\u003e/L) and platelets (PLT) of 99 x10\u003csup\u003e9\u003c/sup\u003e/L (150\u0026ndash;450 x10\u003csup\u003e9\u003c/sup\u003e/L) which did not resolve on withholding mycophenolate.\u003c/p\u003e\n\u003cp\u003eThe combination of persistent cytopenia with macrocytosis, PAN and DVT in an older male led to the consideration of VEXAS syndrome given its recent description (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Peripheral blood testing confirmed a somatic mutation in the UBA1 gene; c.121A\u0026thinsp;\u0026gt;\u0026thinsp;G \u003cem\u003ep.(Met41Val).\u003c/em\u003e Bone marrow biopsy was repeated and confirmed characteristic cytoplasmic vacuolation. The histopathology department re-reviewed the previous bone marrow biopsy performed 18 months prior and confirmed vacuolation. Following prolonged and protracted symptoms over years, a unifying diagnosis of VEXAS syndrome was reached (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003ePrednisolone treatment was increased to 20mg daily, and a 6-month trial of anakinra was completed before compassionate access to p.o. ruxolitinib at 10mg twice daily was approved. He continued TMP-SMX and was commenced on p.o. valaciclovir 500mg daily for infection prophylaxis. His immunizations were up to date. His functional status at this time was equivalent to an Eastern Cooperative Oncology Group (ECOG) score of 1. His CD4 count was 270 cells/mm\u003csup\u003e3\u003c/sup\u003e (500\u0026ndash;1500 cells/mm\u003csup\u003e3\u003c/sup\u003e) and his C-reactive protein (CRP) was 3 mg/L (0.0\u0026ndash;8.0 mg/L).\u003c/p\u003e\n\u003cp\u003eOver the next few months, cytopenia persisted and was refractory to prednisolone dosage below 17.5mg daily. Importantly, CRP remained normal. He developed complications of long-term corticosteroid therapy including Cushingoid facies, increased interscapular fat pad, proximal myopathy and osteopenia (Fig. 2). His HbA1c was 6.4% (\u0026le;\u0026thinsp;7%).\u003c/p\u003e\n\u003cp\u003eAround 12 months later, he developed acute onset of fevers, malaise, headache and vomiting. On presentation, he was febrile (39\u0026deg;C) with Glasgow coma scale (GCS) 13 (E3, V4, M6), hypoxic with unilateral lower limb swelling. Investigations revealed worsening cytopenia: Hb 80 g/L, WCC 2.05 x10\u003csup\u003e9\u003c/sup\u003e/L (including neutrophil count 1.10 x109/L [1.80\u0026ndash;7.50 x109/L]) and PLT 67x10\u003csup\u003e9\u003c/sup\u003e/L. Inflammatory markers were both elevated: CRP 253.4 mg/L and erythrocyte sedimentation rate (ESR)\u0026thinsp;\u0026gt;\u0026thinsp;120 mm (1\u0026ndash;15 mm). Imaging for venous thromboembolism demonstrated stable appearance of chronic thrombus. Magnetic resonance imaging (MRI) brain with gadolinium contrast identified subtle multifocal punctate enhancing foci in both cerebellar hemispheres, suggestive of early changes of rhombencephalitis. A lumbar puncture revealed elevated opening pressure of 27 cmH\u003csub\u003e2\u003c/sub\u003eO and the following cerebrospinal fluid (CSF) assessment: protein 0.89 g/L (0.15\u0026ndash;0.45 g/L), glucose 3.8 mmol/L (2.2\u0026ndash;5.5 mmol/L), 3 polymorphonuclear cells, 44 mononuclear cells and 10 erythrocytes.\u003c/p\u003e\n\u003cp\u003eA multidisciplinary approach involving immunology, haematology and infectious diseases specialists led to consensus opinion to concurrently treat suspected VEXAS syndrome flare with pulse methylprednisolone, cover for meningoencephalitis with i.v. benzylpenicillin, i.v. ceftriaxone and i.v. acyclovir. Three days later, CSF cryptococcal antigen (CrAg) returned strongly positive at a titre of 1:512 with \u003cem\u003eC. neoformans\u003c/em\u003e identified on fungal culture.\u003c/p\u003e\n\u003cp\u003eA diagnosis of cryptococcal meningitis was made and induction therapy commenced (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e) with 2 weeks of i.v. liposomal amphotericin B (L-AMB) 300mg daily with p.o. flucytosine 2g 6-hourly. Due to concerns for L-AMB toxicity with rising creatinine to 193 \u0026micro;mol/L (60\u0026ndash;110 \u0026micro;mol/L), L-AMB was ceased and switched to i.v. fluconazole 400mg daily, and flucytosine adjusted for renal function to 12 hourly intervals. Ruxolitinib dose was reduced to 5mg BD while prednisolone dose was reduced to 50mg with weaning following pulse methylprednisolone. TMP-SMX and valaciclovir were continued.\u003c/p\u003e\n\u003cp\u003eA repeat lumbar puncture 2 weeks later showed persistently elevated opening pressure at 27.5 cmH\u003csub\u003e2\u003c/sub\u003eO and raised CSF protein of 0.67 but reduction in CrAg titre to 1:32. Dual antifungal consolidative therapy was completed for a month, followed by p.o. fluconazole monotherapy at 800mg daily for a further 8 weeks, then 200mg daily thereafter. Ruxolitinib therapy was ceased given lack of overall efficacy and prednisolone monotherapy was continued (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eWhilst the headaches and fevers resolved, he had a significant decline in function despite prolonged inpatient rehabilitation. He was discharged to a residential care facility, with ECOG status of 3. Given significant decline in function, a haematology consensus was reached for consideration of low dose azacitadine over haematopoetic stem cell transplantation.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis report describes a rare case of cryptococcal meningitis in a patient with VEXAS syndrome without concurrent MDS. Treatment with numerous lines of immunosuppressive therapies including chronic corticosteroids and VEXAS-related immune dysregulation, collectively predispose patients to serious opportunistic infections (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Such infections, particularly disseminated to the central nervous system (CNS) have additionally pronounced impact on patient function and overall quality of life (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Therefore, clinicians need to be vigilant in screening, diagnosing and consolidating guidelines for infection prophylaxis in this vulnerable patient cohort to improve treatment outcomes. Although there are no specific guidelines, early institution of antifungals, in addition to Pneumocystis, herpes simplex virus (HSV) and varicella zoster virus (VZV) prophylaxis is a key learning point from this case. To date, only one case of cryptococcal meningitis in VEXAS syndrome has been reported (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eCryptococcus is one of the most common non-viral causes of meningitis in the immunocompromised host, with considerable mortality associated given its insidious presentation that often results in delays in diagnosis and treatment (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Historically, patients with acquired immunodeficiency syndrome (AIDS) from human immunodeficiency virus (HIV) were most susceptible, however the rise in immunomodulatory therapies have led to an epidemiologic shift in affected patient cohorts (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). In non-HIV cohorts, risk factors include prolonged neutropenia, extended course of high dose glucocorticoids (although the exact dose and duration remains unclear) and several immunosuppressive therapies (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). These include calcineurin inhibitors (e.g. tacrolimus) and mammalian target of rapamycin (mTOR) inhibitors (e.g. sirolimus) in solid organ transplant recipients and rare cases described with anti-tumour necrosis factor alpha, sphingosine-1-phosphate receptor, anti-CD52 and anti-Bruton\u0026rsquo;s tyrosine kinase inhibitors (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). There are also specific patient cohorts with increased risk, and these include inborn errors of immunity as well as sarcoidosis (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Interestingly, rates of IFI were rare amongst stem-cell transplant recipients, which has been attributed to routine anti-fungal prophylaxis in this cohort (\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eMultiple factors contribute to infection risk in VEXAS syndrome, including intrinsic immune dysregulation from the disease itself and extrinsic effects from immunosuppressive therapy (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). This was described in a cohort of 813 patients with VEXAS, noting that opportunistic infections occurred even in patients not on immunosuppressive therapy (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). On a cellular level, in \u003cem\u003evitro\u003c/em\u003e studies have demonstrated evidence of monocyte exhaustion with diminished counts and aberrant chemokine receptor expression, alongside dysfunctional upregulation of proinflammatory cytokines such as IL-1β and IL-18 suggestive of inflammasome activation (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). It is thus imperative that infection be considered in the management of VEXAS patients irrespective of immunosuppression.\u003c/p\u003e\u003cp\u003eOur patient was refractory to a range of biologic disease modifying antirheumatic drugs (DMARDs), frequently requiring steroid up titration to prevent worsening cytopenia. On review, his cumulative steroid burden equated to an annual prednisolone dose of 1300mg, averaging 25mg/day. The immunosuppressive effects of glucocorticoids are well documented, affecting the whole gamut of innate and adaptive immune system by, e.g. impeding neutrophil phagocytic activity, dampening macrophage, monocyte and natural killer cytotoxicity through downregulation of cytokine production and also by impairing toll-like receptor signalling (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In addition, treatment with ruxolitinib, a JAK1/2 inhibitor of the JAK/STAT pathway, further predisposes to viral reactivation by interfering with natural killer (NK) cell maturation and has secondary effects blocking dendritic cell differentiation and antigen presentation. A systematic review identified herpes zoster infection (1336 total patients affected per year, OR 5.20 [1.27, 21.18]) as the most common ruxolitinib-associated infective complication in MDS patients, for which anti-viral prophylaxis can be considered (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). Moreover, the risk of hepatitis B virus and latent tuberculosis reactivation with JAK inhibitors (JAKi) have also been raised, and pre-treatment screening is recommended for at risk groups (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). There are no guidelines on pre-treatment anti-fungal prophylaxis for JAKi. Cases of ruxolitinib-associated IFI are rare in comparison to herpes zoster infections with only twelve reported cases of cryptococcosis in MDS patients receiving ruxolitinib, one of which had a diagnosis of chronic myelomonocytic leukaemia on combination azacitidine and cytarabine (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). MDS disease severity should be considered as severe disease with splenomegaly and splenic dysfunction may further contribute to infection risk independent of Ruxolitinib (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePatients with VEXAS syndrome are at risk of developing MDS which with neutropenia and neutrophil dysfunction may predispose to opportunistic infection (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Bacteria are the most common cause of infection in MDS patients treated with azacitidine (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Moreover, comorbidities with advanced age in MDS patients likely add to their susceptibility to infection (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). Interestingly, a recent case series of seventy-four VEXAS syndrome patients did not find MDS an independent predictor of serious infection, but identified advanced age at diagnosis (\u0026gt;\u0026thinsp;75 years), \u003cem\u003ep.Met41Val\u003c/em\u003e mutation, arthralgia and treatment with JAK inhibition as significant risk factors instead (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Importantly, the greater association with MDS, transfusion dependency despite less chondritis amongst \u003cem\u003ep.Met41Val\u003c/em\u003e mutated patients portends worse prognosis (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eCurrent screening and prevention guidelines for opportunistic infections are well established for immunocompromised patients in rheumatology, haematology, oncology, and transplant medicine (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). For example, the 2023 EULAR recommendation to screen for latent tuberculosis, hepatitis B and C virus, and HIV infection prior to initiating DMARD, glucocorticoid therapy or other immunosuppressants is robust, and has transpired across other fields (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). In addition, \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e prophylaxis in patients on prolonged glucocorticoids (i.e. \u0026gt;15\u0026ndash;30 mg prednisolone equivalent dose for \u0026gt;\u0026thinsp;2\u0026ndash;4 weeks) is well documented in Rheumatology, and was certainly factored in for our patient who received TMP-SMX for this reason (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Guidelines to prevent fungal infections is also well established in HIV-AIDS patients with low CD4 cell count\u0026thinsp;\u0026lt;\u0026thinsp;200 cells/mm\u003csup\u003e3\u003c/sup\u003e and in haematological malignancies or stem cell transplant recipients (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). For solid organ transplant recipients, the screening for and prevention of cytomegalovirus and Epstein-Barr virus infection is of paramount importance to optimize graft function (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Unfortunately, there are no equivalent recommendations for the prevention of IFI in other immunocompromised patients such as VEXAS syndrome, likely due to the comparative rarity of cases and heterogeneity of affected patients. This is further complicated by antifungal drug interactions and insidious nature of the disease, making both diagnosis and management difficult (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Perhaps existing benchmarks for IFI prophylaxis in other specialties could help guide decisions in preventing opportunistic infections for at-risk VEXAS patients.\u003c/p\u003e\u003cp\u003eWhile our case has exemplified a rare infective complication in VEXAS syndrome, there are a few limitations. Regarding, antifungal prophylaxis, earlier institution may have prevented such a complication, however the paucity on guidelines and understanding of side effects from multiple concurrent immunosuppressive and immunomodulatory treatment were possible barriers. Given the novelty of VEXAS syndrome, treatment options were limited by available evidence and clinical experience. Although azacitidine and transplant were raised as possible options much earlier in his disease course, these were not proceeded due to risk versus benefit evaluation at the time, considering his declining functional status, concern for infection risk, cost and experience at this centre. Previously, azacitidine showed promise with variable efficacy, but recently have been demonstrated to be effective regardless of MDS status (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). The patient has since been initiated on low dose azacitidine and is tolerating well (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Transplant is also an emerging treatment option, though infections have also been reported in this context (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, we present a rare case of cryptococcal meningitis in a patient with treatment refractory VEXAS syndrome without concurrent MDS. Given the significant morbidity and mortality associated with opportunistic infections, particularly cryptococcus infection, this case raises several important clinical practice points. Firstly, a multidisciplinary approach amongst specialties, including infectious diseases and haematology specialists, is required on deciding initiation of antifungal therapies in patients with VEXAS syndrome. Secondly, addition of such therapy needs to be considered on balance with risks benefit profile, with close monitoring of drug-drug interactions with antifungals, degree of cytopenia, patient comorbidities and cumulative corticosteroid exposure. Finally, a growing need for a best practice consensus guideline on preventing opportunistic infections in VEXAS syndrome is urgently required to prevent irreversible sequelae.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBD: twice daily\u003c/p\u003e\n\u003cp\u003eC. neoformans: Cryptococcus neoformans\u003c/p\u003e\n\u003cp\u003eCrAg: cryptococcal antigen\u003c/p\u003e\n\u003cp\u003eCRP: C-reactive protein\u003c/p\u003e\n\u003cp\u003eCSF: cerebrospinal fluid\u003c/p\u003e\n\u003cp\u003eDMARD: Disease modifying antirheumatic drug\u003c/p\u003e\n\u003cp\u003eDVT: deep venous thrombosis\u003c/p\u003e\n\u003cp\u003eECOG: Eastern Cooperative Oncology Group\u003c/p\u003e\n\u003cp\u003eGCS: glasgow coma scale\u003c/p\u003e\n\u003cp\u003eHIV-AIDS: human immunodeficiency virus acquired immunodeficiency syndrome\u003c/p\u003e\n\u003cp\u003eHSV: herpes simplex virus\u003c/p\u003e\n\u003cp\u003eIFI: invasive fungal infections\u003c/p\u003e\n\u003cp\u003ei.v.: intravenous\u003c/p\u003e\n\u003cp\u003eJAKi: Janus kinase inhibitors\u003c/p\u003e\n\u003cp\u003eL-AMB: liposomal amphotericin\u003c/p\u003e\n\u003cp\u003eMCV: mean cell volume\u003c/p\u003e\n\u003cp\u003eMDS: Myelodysplastic syndrome\u003c/p\u003e\n\u003cp\u003eMRI: magnetic resonance imaging\u003c/p\u003e\n\u003cp\u003emTOR: mammalian target of rapamycin inhibitor\u003c/p\u003e\n\u003cp\u003ePAN: polyarteritis nodosa\u003c/p\u003e\n\u003cp\u003ePET: positron emission tomography\u003c/p\u003e\n\u003cp\u003ePLT: platelets\u003c/p\u003e\n\u003cp\u003ep.o.: per oral\u003c/p\u003e\n\u003cp\u003es.c.: subcutaneous\u003c/p\u003e\n\u003cp\u003eTMP-SMX: trimethoprim/sulfamethoxazole\u003c/p\u003e\n\u003cp\u003eVEXAS: Vacuoles, E1 enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome\u003c/p\u003e\n\u003cp\u003eVZV: varicella zoster virus\u003c/p\u003e\n\u003cp\u003eWCC: white cell count\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval:\u003c/strong\u003e Ethical approval for this case report was obtained from the Southern Adelaide Clinical Human Research Ethics Committee (SAC HREC) on 30\u003csup\u003eth\u003c/sup\u003e July 2025.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent:\u003c/strong\u003e The authors confirm that written informed consent was obtained from the patient for the publication of this manuscript and accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data:\u003c/strong\u003e Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement:\u003c/strong\u003e There was no funding received for the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions:\u003c/strong\u003e S.A. conceived the idea for this case report and provided overall supervision of the project. M.L. conducted the literature review and drafted the initial manuscript. S.A. critically revised the manuscript. T.D. read and approved the final draft for submission. M.L. prepared figures 1-3. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e The authors would like to thank the patient for providing us with an ongoing opportunity to learn about this complex and rare disease.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBeck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W, et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med. 2020;383(27):2628-38.\u003c/li\u003e\n\u003cli\u003eBeck DB, Bodian DL, Shah V, Mirshahi UL, Kim J, Ding Y, et al. Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population. 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The Lancet Rheumatology. 2025.\u003c/li\u003e\n\u003cli\u003eLussana F, Cattaneo M, Rambaldi A, Squizzato A. Ruxolitinib‐associated infections: a systematic review and meta‐analysis. American journal of hematology. 2018;93(3):339-47.\u003c/li\u003e\n\u003cli\u003eSant\u0026rsquo;Antonio E, Bonifacio M, Breccia M, Rumi E. A journey through infectious risk associated with ruxolitinib. British Journal of Haematology. 2019;187(3):286-95.\u003c/li\u003e\n\u003cli\u003eChiu CY, John TM, Matsuo T, Wurster S, Hicklen RS, Khattak RR, et al. Disseminated Histoplasmosis in a Patient with Myelofibrosis on Ruxolitinib: A Case Report and Review of the Literature on Ruxolitinib-Associated Invasive Fungal Infections. J Fungi (Basel). 2024;10(4).\u003c/li\u003e\n\u003cli\u003eSafdar A, Armstrong D. Infections in Patients With Hematologic Neoplasms and Hematopoietic Stem Cell Transplantation: Neutropenia, Humoral, and Splenic Defects. Clinical Infectious Diseases. 2011;53(8):798-806.\u003c/li\u003e\n\u003cli\u003eTrubiano JA, Dickinson M, Thursky KA, Spelman T, Seymour JF, Slavin MA, Worth LJ. Incidence, etiology and timing of infections following azacitidine therapy for myelodysplastic syndromes. Leuk Lymphoma. 2017;58(10):2379-86.\u003c/li\u003e\n\u003cli\u003eOntiveros-Austria J, Rodriguez-Rodriguez S, Demichelis R, Lara MFG, Chavez EIA. Risk Factors Associated to Severe Episodes of Infection in Myelodysplastic Syndromes. Blood. 2023;142:6493.\u003c/li\u003e\n\u003cli\u003eFerrada MA, Savic S, Cardona DO, Collins JC, Alessi H, Gutierrez-Rodrigues F, et al. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis. Blood, The Journal of the American Society of Hematology. 2022;140(13):1496-506.\u003c/li\u003e\n\u003cli\u003eGeorgin‐Lavialle S, Terrier B, Guedon A, Heiblig M, Comont T, Lazaro E, et al. Further characterization of clinical and laboratory features in VEXAS syndrome: large‐scale analysis of a multicentre case series of 116 French patients. British Journal of Dermatology. 2022;186(3):564-74.\u003c/li\u003e\n\u003cli\u003eCooley L, Dendle C, Wolf J, Teh BW, Chen SC, Boutlis C, Thursky KA. Consensus guidelines for diagnosis, prophylaxis and management of Pneumocystis jirovecii pneumonia in patients with haematological and solid malignancies, 2014. Internal Medicine Journal. 2014;44(12b):1350-63.\u003c/li\u003e\n\u003cli\u003eFragoulis GE, Nikiphorou E, Dey M, Zhao SS, Courvoisier DS, Arnaud L, et al. 2022 EULAR recommendations for screening and prophylaxis of chronic and opportunistic infections in adults with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2023;82(6):742-53.\u003c/li\u003e\n\u003cli\u003eAwotiwon AA, Johnson S, Rutherford GW, Meintjes G, Eshun-Wilson I. Primary antifungal prophylaxis for cryptococcal disease in HIV-positive people. Cochrane Database Syst Rev. 2018;8(8):Cd004773.\u003c/li\u003e\n\u003cli\u003eTSANZ. Clinical guidelines for organ transplantation from deceased donors. Canberra, Australia: Transplantation Society of Australia New Zealand. Organ and Tissue Authority; 2021.\u003c/li\u003e\n\u003cli\u003ePapon N, Nevez G, Le Gal S, Vigneau C, Robert-Gangneux F, Bouchara J-P, et al. Fungal infections in transplant recipients: pros and cons of immunosuppressive and antimicrobial treatment. The Lancet Microbe. 2021;2(1):e6-e8.\u003c/li\u003e\n\u003cli\u003eComont T, Heiblig M, Rivi\u0026egrave;re E, Terriou L, Rossignol J, Bouscary D, et al. Azacitidine for patients with Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome (VEXAS) and myelodysplastic syndrome: data from the French VEXAS registry. Br J Haematol. 2022;196(4):969-74.\u003c/li\u003e\n\u003cli\u003eJachiet V, Kosmider O, Beydon M, Hadjadj J, Zhao LP, Grobost V, et al. Efficacy and safety of azacitidine for VEXAS syndrome: a large-scale retrospective study from the FRENVEX group. Blood. 2025.\u003c/li\u003e\n\u003cli\u003eAli SB, Gurnari C. Allogenic haematopoietic stem cell transplantation in VEXAS: A review of 33 patients. Clin Rheumatol. 2024;43(11):3565-75.\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-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brhm","sideBox":"Learn more about [BMC Rheumatology](http://bmcrheumatol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/brhm/default.aspx","title":"BMC Rheumatology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"VEXAS, infection, cryptococcus, invasive fungal infection, immune dysregulation","lastPublishedDoi":"10.21203/rs.3.rs-7582383/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7582383/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eVacuoles, E1 enzyme, X-linked, autoinflammatory somatic (VEXAS) syndrome is a recently described multisystem disease. Opportunistic infections in VEXAS syndrome are increasingly being recognized, with multiple factors including immune dysregulation due to aberrant ubiquitination pathway, secondary effects from chronic immunosuppressive treatments and underlying comorbidities contributing. Given lack of consensus guidelines on antimicrobial prophylaxis, clinical practice is heterogenous with varying treatment outcomes.\u003c/p\u003e\u003ch2\u003eCase presentation:\u003c/h2\u003e\u003cp\u003eHerein, we report a rare case of cryptococcal meningitis in a patient with treatment refractory VEXAS syndrome, on chronic moderate-dose corticosteroid (average 20mg per day) and ruxolitinib. The patient initially presented with acute confusion and fevers, with elevated inflammatory markers and worsening cytopaenia. The differential diagnoses included an acute flare of VEXAS syndrome and intercurrent infection. Further testing revealed presence of \u003cem\u003eCryptococcus neoformans\u003c/em\u003e in the cerebrospinal fluid. Thereafter, antifungal therapy was initiated, however the patient suffered from irreversible functional decline despite successful antimicrobial clearance.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eThe case raises important considerations, firstly regarding antimicrobial - particularly antifungal - prophylaxis given paucity of guidelines, secondly prompt diagnosis and treatment of cryptococcal infections, and finally regular interval screening for opportunistic infections in this vulnerable patient cohort. A multidisciplinary approach to care is required to improve morbidity and mortality from atypical infections in VEXAS syndrome.\u003c/p\u003e","manuscriptTitle":"Cryptococcal meningitis in a patient with VEXAS syndrome: a case report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 07:07:45","doi":"10.21203/rs.3.rs-7582383/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-01-05T06:18:07+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-30T15:17:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"303046774692596491658748628630098840193","date":"2025-12-22T15:02:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"241987750998264254952816793212975950301","date":"2025-12-17T10:09:29+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-14T12:19:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"185182909461083149896967325823614875526","date":"2025-10-13T15:55:13+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-14T07:06:37+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-09-12T19:17:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-11T02:42:17+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-11T02:41:53+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Rheumatology","date":"2025-09-10T11:21:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-rheumatology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brhm","sideBox":"Learn more about [BMC Rheumatology](http://bmcrheumatol.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/brhm/default.aspx","title":"BMC Rheumatology","twitterHandle":"@BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"28669581-fb6a-4649-9eb7-7e7f2546f4c1","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-04-22T18:54:15+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-23 07:07:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7582383","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7582383","identity":"rs-7582383","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}