Successful Use of Ruxolitinib in Steroid-Refractory Chronic GvHD affecting Central Nervous System: A Case Report

Successful Use of Ruxolitinib in Steroid-Refractory Chronic GvHD affecting Central Nervous System: 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 Successful Use of Ruxolitinib in Steroid-Refractory Chronic GvHD affecting Central Nervous System: A Case Report Ewa Karakulska-Prystupiuk, Beata Zakrzewska-Pniewska, Agnieszka Tomaszewska, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8745448/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background Chronic graft-versus-host disease (cGvHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Beyond its classical manifestations, cGvHD may involve additional organs, including the central nervous system (CNS), where involvement remains poorly characterized, and therapeutic options are undefined, particularly in steroid-refractory cases. Case Presentation We report the case of a 50-year-old woman who underwent allo-HSCT for myelodysplastic syndrome and subsequently developed classical acute followed by chronic GvHD-overlap syndrome. At 2 years and 9 months post-transplant, she presented with progressive spastic paraparesis, and brain MRI revealed multifocal hyperintense white-matter lesions. A diagnosis of possible CNS-cGvHD was established. Due to poor response and intolerance to prolonged corticosteroid therapy, ruxolitinib was initiated at 10 mg/day and subsequently increased to 20 mg/day, with concomitant tapering of prednisone and immunoglobulin supplementation. Over 12 months, the patient demonstrated both clinical and radiological improvement, including significant functional recovery and marked regression of CNS lesions. Conclusion This case suggests that ruxolitinib may represent a potential therapeutic option for atypical CNS involvement in cGvHD. Although clinical improvement likely reflected combined treatments, the neurological and radiological response suggests meaningful contribution from JAK inhibition. Further studies are needed to better define the role of ruxolitinib in this rare manifestation of cGvHD. allogeneic hematopoietic stem cell transplantation (allo-HSCT) graft-versus-host disease (cGvHD) chronic graft-versus-host disease with central nervous system involvement (cGvHD with CNS involvement) ruxolitinib steroid-refractory GvHD Figures Figure 1 Background Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), arising from immune dysregulation and impaired regulatory mechanisms. Chronic GvHD (cGvHD) affects 30–70% of transplant recipients and is the leading cause of non-relapse mortality [1]. Classical cGvHD is evaluated across eight diagnostic target organs. Beyond these classical manifestations, cGvHD may involve additional "unclassified" organs, potentially causing irreversible dysfunction [2]. One such atypical and incompletely characterized manifestation is involvement of the central nervous system (CNS-cGvHD) [3]. While systemic corticosteroids are the standard first-line therapy for classical cGvHD and ruxolitinib is recommended for steroid-refractory cases, no specific therapeutic guidelines are available for atypical cGvHD presentations [4]. Here, we report a case of steroid-refractory CNS-cGvHD that responded clinically and radiologically to ruxolitinib. To our knowledge, no published data specifically describe the use of ruxolitinib for CNS involvement in cGvHD. Case Description A 50-year-old woman with Hashimoto’s disease and chronic hepatitis B (on entecavir) was diagnosed with myelodysplastic neoplasm type 2 (MDS-EB2) with marrow fibrosis. After 11 months of supportive care she was qualified for allo-HSCT from a 9/10 HLA-mismatched unrelated female donor (mismatch at locus A). Conditioning consisted of fludarabine, busulfan, and anti-thymocyte globulin (FluBu4ATG), and she received peripheral blood stem cells with standard GvHD prophylaxis (cyclosporine A and methotrexate). The early post-transplant course was complicated by grade III mucositis and an anaphylactic reaction during platelet transfusion, followed by detection of HPA-1b and anti-HLA class I antibodies. Acute skin GvHD, stage 1 by MAGIC criteria [5], was diagnosed on day +34 and treated topically. On day +39, complete donor chimerism was confirmed in peripheral blood. Ten days later, she developed grade 2 acute GvHD (skin stage 2; upper GI grade 1; lower GI grade 1), and systemic corticosteroids with methylprednisolone at 1 mg/kg were initiated despite a negative biopsy. Cyclosporine A was switched to tacrolimus. Remission was achieved; corticosteroids were discontinued by day +111, and tacrolimus was gradually tapered. On day +240, she developed moderate overlap chronic GvHD (NIH 2014: skin 1, eyes 2; MAGIC lower GI grade 1) [6,7]. Methylprednisolone was restarted at a reduced dose due to mood disturbances, insomnia, cataracts, and osteopenia. Attempts to increase tacrolimus were limited by neurotoxicity (tremor, dizziness, polyneuropathy). CNS MRI and extracranial arteries Doppler ultrasound were normal. Extracorporeal photopheresis (ECP) achieved disease control after 10 sessions; however, the patient subsequently discontinued follow-up, leading to cessation of immunosuppression. At 2 years and 9 months post-transplant, she was admitted to the department of neurology for progressive lower-limb weakness and urinary urgency progressing over several weeks. Neurological examination revealed severe, symmetrical spastic paraparesis. CSF analysis showed normal protein and glucose concentration, and normal cytosis (2 cells/µL). The meningitis/encephalitis PCR, Lyme disease testing, and JCV DNA PCR were negative. Electromyography was normal. A broad antineuronal antibody panel (anti-AMPA, anti-GABA-B, anti-NMDA, anti-DPPX, anti-CASPR2, and anti-LGI1) was negative. ANA was 1:160, while MPO- and PR3-ANCA were negative. Brain MRI revealed multifocal hyperintense white-matter lesions in both frontal lobes, the largest measuring > 20 mm in the right frontal region (Figure 1A). Figure 1. Axial brain MRI FLAIR images acquired on a 3.0-T GE Architect scanner. (A) Baseline image showing patchy hyperintense lesions in the white matter of the frontal lobes and left occipital lobe. (B) Follow-up image obtained seven months after ruxolitinib initiation demonstrating marked regression of the previously observed lesions. A diagnosis of CNS demyelinating disease, possibly related to GvHD was made. The patient received intravenous methylprednisolone 1 g/day for 5 days, followed by oral prednisone 1 mg/kg for six months. Corticosteroid tolerance was poor due to previously described complications, so doses were gradually tapered. In the fourth month of therapy, she sustained a complex right humeral fracture, which required surgical stabilization with a Weber band. At 3 years and 5 months post-HSCT, she returned to our center. On neurological examination severe spastic paraparesis was observed as well as urinary urgences and incontinence. She could stand with assistance and walk a few steps with bilateral support. CT imaging (MRI was contraindicated due to Weber fixation rod) showed small, ill-defined hypodense lesions in both hemispheres. Steroid-resistant, atypical CNS-cGvHD was diagnosed and ruxolitinib was initiated at 5 mg twice daily and increased to 15 mg daily ( with dose adjustment due to concomitant posaconazole therapy and financial considerations ), while prednisone was gradually tapered. Due to hypogammaglobulinemia, subcutaneous immunoglobulins were administered twice at a dose of 0.5 g/kg. After three months of ruxolitinib therapy, the patient reported subjective neurological improvement : lover limbs spastic paresis was markedly reduced and she was able to walk with a walker. Subsequent follow-up at a regional neurology center revealed only mild lower limbs weakness with decreased spasticity. The patient walked with a walker, displaying a cautious gait. After seven months of ruxolitinib therapy, continued neurological improvement was observed , and she was able to walk with unilateral support. Follow-up MRI showed regression of post-inflammatory demyelinating lesions in the frontal lobes (Figure 1B). In the ninth month, she entered a nationwide program providing free access to ruxolitinib, allowing the dose to increase to 20 mg daily (alternating with 10 mg). By the eleventh month, she was able to walk independently into the outpatient consultation room for the first time, although support was still required for longer distances. At one year of ruxolitinib, MRI demonstrated marked regression of CNS lesions and further neurological improvement. Functional tests showed substantial improvement: Berg Balance Scale increased from 22 to 41 points, and Timed Up and Go (TUG) time decreased from 30 to 17 seconds. Discussion We present a rare case of atypical chronic GvHD affecting the central nervous system (CNS) , diagnosed by exclusion, which responded favourably to ruxolitinib therapy. To our knowledge, there are no currently published data specifically evaluating the efficacy of ruxolitinib for CNS- GvHD. The patient had multiple risk factors for chronic GvHD, including transplantation from an HLA-mismatched unrelated female donor, prior alloimmunization, and previous acute GvHD [1,6-7]. The diagnoses of classic acute GvHD followed by an overlap syndrome, both steroid-sensitive, were based on clinical features without histopathological confirmation. Early immunosuppressive therapy, including a calcineurin inhibitor, was associated with transient neurotoxicity; h owever, the subsequent development of spastic paraparesis and demyelinating MRI lesions approximately one year post transplant makes a causal link with prior calcineurin inhibitor therapy unlikely. According to the 2010 Consensus Conference criteria, this case fulfills the definition of possible CNS-cGvHD [8]. Both mandatory criteria (i.e. cGvHD involvement of other organs and neurological signs unexplained by alternative causes ) and two of six facultative criteria (corresponding MRI abnormalities, and a favourable response to immunosuppressive therapy, confirmed retrospectively) were met. Notably, the CNS-GvHD Study Group does not currently consider chronic GvHD in other organs mandatory for CNS- GvHD diagnosis [9]. Published data suggest that one-year overall survival after CNS-cGvHD is approximately 41%, with a median overall survival of 196 days [9]. Therapeutic response remains poorly characterized. In the CNS-cGvHD Study Group analysis, corticosteroids were used in 91% of patients, resulting in complete remission in 27% and partial improvement in 47%. Although ruxolitinib was administered in some cases, its specific efficacy for CNS involvement was not analyzed in detail [9]. Ruxolitinib therapy was initiated following protocols for classical cGvHD, considering the limited efficacy and adverse effects of prolonged corticosteroid therapy. The observed improvement likely reflects the drug’s immunomodulatory effects on the pathophysiology of CNS-GvHD [10-15]. T-cell infiltration of the CNS during GvHD differs between acute and chronic phases. In acute CNS-GvHD, infiltration is initially dominated by CD8⁺ T cells and associated with cytokine production (predominantly TNF and IL-6) by host microglial cells. In contrast, chronic CNS-GvHD is characterized by a shift toward CD4⁺ T-cell infiltration and recruitment of donor bone marrow–derived macrophages expressing major histocompatibility complex (MHC) class II, leading to increased INF-γ production as a key mediator. Th1 and Th17 lymphocyte subsets, important to GvHD immunopathology, are also implicated in CNS-directed autoimmunity, including experimental autoimmune encephalomyelitis and animal models of multiple sclerosis [1,3,8–9,16–19]. Ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, blocks downstream signaling of multiple cytokines involved in GvHD pathogenesis. In allo-HCT recipients, ruxolitinib increases regulatory T-cell (Treg) frequencies, decreases Th17 populations, and reduces MHC class II expression on antigen-presenting cells, thereby exerting broad anti-inflammatory and immunomodulatory effects [17–18,20–21]. The role of JAK/STAT signalling in neuroinflammation has also been demonstrated in cPIIRS (cryptococcal post-infectious inflammatory response syndrome) [22]. Hargarten et al. showed that JAK/STAT-dependent pathways drive hypercytokinemia and sustain inflammatory and cytotoxic immune cells at post-inflammatory foci in the brain, resulting in progressive neuronal damage. All of these processes were effectively suppressed by ruxolitinib, leading to marked clinical improvement and enhanced quality of life in six patients with suboptimal corticosteroid response [22] . This case suggests that ruxolitinib may represent a potential therapeutic option in atypical CNS involvement of chronic GvHD. While clinical improvement likely reflects the combined effects of corticosteroids, immunoglobulin supplementation, and ruxolitinib,the observed neurological and radiological responses indicate a meaningful contribution from JAK inhibition. Given the rarity of CNS-cGvHD and the absence of specific therapeutic guidelines, JAK inhibition may be considered in selected patients, and prospective studies are needed to better define optimal management strategies for this challenging manifestation of cGvHD. Declarations Acknowledgements This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We sincerely thank the patient for her consent to publish this case and for her cooperation during the diagnostic evaluation and treatment. Funding The authors did not receive support from any organization for the submitted work. Conflicts of interest Financial interests: Authors declare no financial interests. Availability of data and material All patient data was collected based on available medical records. All of the data was analyzed anonymously. Code availability Not applicable. Authors’ contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ewa Karakulska-Prystupiuk. The first draft of the manuscript was written by Ewa Karakulska-Prystupiuk and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Conceptualization: Ewa Karakulska-Prystupiuk, Methodology: Ewa Karakulska-Prystupiuk, Beata Zakrzewska-Pniewska, Marta Hałaburda- Rola. Formal analysis and investigation: Ewa Karakulska-Prystupiuk Writing - original draft preparation: Ewa Karakulska-Prystupiuk, Writing - review and editing: Ewa Karakulska-Prystupiuk, Beata Zakrzewska-Pniewska, Agnieszka Tomaszewska, Marta Hałaburda- Rola, Wiesław Wiktor Jędrzejczak, Grzegorz Władysław Basak Funding acquisition: - Resources: Agnieszka Tomaszewska, Wiesław Wiktor Jędrzejczak, Grzegorz Władysław Basak Supervision: Wiesław Wiktor Jędrzejczak, Grzegorz Władysław Basak Ethics approval The ethical consent was approved by Medical University of Warsaw, Bioethical Commission. Consent to participate This is a retrospective analysis of anonymous data contained in medical records. Consent for publication Written consent for publication was obtained from the patient. 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Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 16 Mar, 2026 Reviews received at journal 15 Mar, 2026 Reviews received at journal 11 Mar, 2026 Reviewers agreed at journal 07 Mar, 2026 Reviewers agreed at journal 26 Feb, 2026 Reviewers invited by journal 12 Feb, 2026 Editor assigned by journal 12 Feb, 2026 Submission checks completed at journal 12 Feb, 2026 First submitted to journal 30 Jan, 2026 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-8745448","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":595236620,"identity":"4d7f008d-a0b6-4f5f-a097-2cefde60a81d","order_by":0,"name":"Ewa Karakulska-Prystupiuk","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABY0lEQVRIie3Rv2rCQBzA8TuEuiS146Wp9BUSBFvoH1/ljoBZUltw6SAlEMiUOt8h9RniUhxPBLPoLghtpEMXC0rBUXtJWxtFpGMp+UJyR44PXPgBkJb2R4O2eCGQsePNVwigrL06hnwrgSsSrYJI/Of4N0R8QXgrySEjhLT2dKxQ4sxoDVROqPn6IrdPCWOT4uEQnOd9LvMEUWhZg36vqjcQcRW/B6pHQ0t35D4iDdUqqhYoF3y+jxNEG2ENhnsYNgURmyWhyIKO7CLSVK8eBekSn0tagpRG5hSGC1wSxJmFCyCIOf4kyiAiy02iqZYGWy4m4mK20nIjgvWYNJAcEb5J0PPkpsPq2GDe2FVYHVSRNNHZQx8VmHf9fmZpRoF11/4l5wWtsTfHFzQwujNvDiooa4bTt/ZdngY9MrJuL/P14L4Trs9lbUwYHODvycQ3F09GArvCIMeTJG43SUtLS/vvfQAniY4O+ZmKtAAAAABJRU5ErkJggg==","orcid":"","institution":"Medical University of Warsaw","correspondingAuthor":true,"prefix":"","firstName":"Ewa","middleName":"","lastName":"Karakulska-Prystupiuk","suffix":""},{"id":595236621,"identity":"9a9bcd17-4b35-46a8-b5e7-c76ee85b4333","order_by":1,"name":"Beata Zakrzewska-Pniewska","email":"","orcid":"","institution":"Medical University of Warsaw","correspondingAuthor":false,"prefix":"","firstName":"Beata","middleName":"","lastName":"Zakrzewska-Pniewska","suffix":""},{"id":595236622,"identity":"c949dd64-d271-43d2-993f-7edb7d5ce555","order_by":2,"name":"Agnieszka Tomaszewska","email":"","orcid":"","institution":"Medical University of Warsaw","correspondingAuthor":false,"prefix":"","firstName":"Agnieszka","middleName":"","lastName":"Tomaszewska","suffix":""},{"id":595236623,"identity":"aaa55b40-eec3-4a36-8b99-79577b189891","order_by":3,"name":"Marta Hałaburda-Rola","email":"","orcid":"","institution":"Medical University of Warsaw","correspondingAuthor":false,"prefix":"","firstName":"Marta","middleName":"","lastName":"Hałaburda-Rola","suffix":""},{"id":595236624,"identity":"05e3e56f-415f-4ffc-ba6b-0dd1e2ebaf51","order_by":4,"name":"Wiesław Wiktor Jędrzejczak","email":"","orcid":"","institution":"Medical University of Warsaw","correspondingAuthor":false,"prefix":"","firstName":"Wiesław","middleName":"Wiktor","lastName":"Jędrzejczak","suffix":""},{"id":595236625,"identity":"26fe2ffd-4d1f-4956-b4ef-aee8c57c65cc","order_by":5,"name":"Grzegorz Władysław Basak","email":"","orcid":"","institution":"Medical University of Warsaw","correspondingAuthor":false,"prefix":"","firstName":"Grzegorz","middleName":"Władysław","lastName":"Basak","suffix":""}],"badges":[],"createdAt":"2026-01-31 00:23:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8745448/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8745448/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103563121,"identity":"c21a24b7-ed1c-41e7-879b-70970ce862dc","added_by":"auto","created_at":"2026-02-27 06:28:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":219872,"visible":true,"origin":"","legend":"\u003cp\u003eAxial brain MRI FLAIR images acquired on a 3.0-T GE Architect scanner.\u003cbr\u003e\n \u003cstrong\u003e(A)\u003c/strong\u003e Baseline image showing patchy hyperintense lesions in the white matter of the frontal lobes and left occipital lobe. \u003cstrong\u003e(B)\u003c/strong\u003eFollow-up image obtained seven months after ruxolitinib initiation demonstrating marked regression of the previously observed lesions.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8745448/v1/9a2dc20e7a570fa5d17e3dd6.png"},{"id":104398291,"identity":"784f49e1-f9ba-41cc-893e-2d4215875d33","added_by":"auto","created_at":"2026-03-11 12:01:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1654232,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8745448/v1/24fc2ca5-282c-4c85-bf5d-997ea683cde1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Successful Use of Ruxolitinib in Steroid-Refractory Chronic GvHD affecting Central Nervous System: A Case Report","fulltext":[{"header":"Background","content":"\u003cp\u003eGraft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), arising from immune dysregulation and impaired regulatory mechanisms. Chronic GvHD (cGvHD) affects 30–70% of transplant recipients and is the leading cause of non-relapse mortality [1]. Classical cGvHD is evaluated across eight diagnostic target organs. Beyond these classical manifestations, cGvHD may involve additional \"unclassified\" organs, potentially causing irreversible dysfunction [2].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOne such atypical and incompletely characterized manifestation is involvement of the central nervous system (CNS-cGvHD) [3]. While systemic corticosteroids are the standard first-line therapy for classical cGvHD and ruxolitinib is recommended for steroid-refractory cases, no specific therapeutic guidelines are available for atypical cGvHD presentations [4].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHere, we report a case of steroid-refractory CNS-cGvHD that responded clinically and radiologically to ruxolitinib. To our knowledge, no published data specifically describe the use of ruxolitinib for CNS involvement in cGvHD.\u003c/p\u003e"},{"header":"Case Description","content":"\u003cp\u003eA 50-year-old woman with Hashimoto\u0026rsquo;s disease and chronic hepatitis B (on entecavir) was diagnosed with myelodysplastic neoplasm type 2 (MDS-EB2) with marrow fibrosis. After 11 months of supportive care she was qualified for allo-HSCT from a 9/10 HLA-mismatched unrelated female donor (mismatch at locus A). Conditioning consisted of fludarabine, busulfan, and anti-thymocyte globulin (FluBu4ATG), and she received peripheral blood stem cells with standard GvHD prophylaxis (cyclosporine A and methotrexate). The early post-transplant course was complicated by grade III mucositis and an anaphylactic reaction during platelet transfusion, followed by detection of HPA-1b and anti-HLA class I antibodies.\u003c/p\u003e\n\u003cp\u003eAcute skin GvHD, stage 1 by MAGIC criteria [5], was diagnosed on day +34 and treated topically. On day +39, complete donor chimerism was confirmed in peripheral blood. Ten days later, she developed grade 2 acute GvHD (skin stage 2; upper GI grade 1; lower GI grade 1), and systemic corticosteroids with methylprednisolone at 1 mg/kg were initiated despite a negative biopsy. Cyclosporine A was switched to tacrolimus. Remission was achieved; corticosteroids were discontinued by day +111, and tacrolimus was gradually tapered.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOn day +240, she developed moderate overlap chronic GvHD (NIH 2014: skin 1, eyes 2; MAGIC lower GI grade 1) [6,7]. Methylprednisolone was restarted at a reduced dose due to mood disturbances, insomnia, cataracts, and osteopenia. Attempts to increase tacrolimus were limited by neurotoxicity (tremor, dizziness, polyneuropathy). CNS MRI and extracranial arteries Doppler ultrasound were normal. Extracorporeal photopheresis (ECP) achieved disease control after 10 sessions; however, the patient subsequently discontinued follow-up, leading to cessation of immunosuppression.\u003c/p\u003e\n\u003cp\u003eAt 2 years and 9 months post-transplant, she was admitted to the department of neurology for progressive lower-limb weakness and urinary urgency progressing over several weeks. Neurological examination revealed severe, symmetrical spastic paraparesis. CSF analysis showed normal protein and glucose concentration, and normal cytosis (2 cells/\u0026micro;L). The meningitis/encephalitis PCR, Lyme disease testing, and JCV DNA PCR were negative. Electromyography was normal. A broad antineuronal antibody panel (anti-AMPA, anti-GABA-B, anti-NMDA, anti-DPPX, anti-CASPR2, and anti-LGI1) was negative. ANA was 1:160, while MPO- and PR3-ANCA were negative. Brain MRI revealed multifocal hyperintense white-matter lesions in both frontal lobes, the largest measuring \u0026gt; 20 mm in the right frontal region (Figure 1A).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 1.\u003c/strong\u003e Axial brain MRI FLAIR images acquired on a 3.0-T GE Architect scanner.\u003cbr\u003e\u003cstrong\u003e(A)\u003c/strong\u003e Baseline image showing patchy hyperintense lesions in the white matter of the frontal lobes and left occipital lobe. \u003cstrong\u003e(B)\u003c/strong\u003e Follow-up image obtained seven months after ruxolitinib initiation demonstrating marked regression of the previously observed lesions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA diagnosis of CNS demyelinating disease, possibly related to GvHD was made. The patient received intravenous methylprednisolone 1 g/day for 5 days, followed by oral prednisone 1 mg/kg for six months. Corticosteroid tolerance was poor due to previously described complications, so doses were gradually tapered. In the fourth month of therapy, she sustained a complex right humeral fracture, \u003cstrong\u003ewhich required surgical stabilization\u003c/strong\u003e with a Weber band.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt 3 years and 5 months post-HSCT, she returned to our center. On neurological examination severe spastic paraparesis was observed as well as urinary urgences and incontinence. She could stand with assistance and walk a few steps with bilateral support. CT imaging (MRI was contraindicated due to Weber fixation rod) showed small, ill-defined hypodense lesions in both hemispheres. Steroid-resistant, atypical CNS-cGvHD was diagnosed and ruxolitinib was initiated at 5 mg twice daily and increased to 15 mg daily (\u003cstrong\u003ewith dose adjustment due to concomitant posaconazole therapy and financial considerations\u003c/strong\u003e), while prednisone was gradually tapered. Due to hypogammaglobulinemia, subcutaneous immunoglobulins were administered twice at \u003cstrong\u003ea dose of\u003c/strong\u003e 0.5 g/kg.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter three months of ruxolitinib therapy, the patient reported \u003cstrong\u003esubjective neurological improvement\u003c/strong\u003e: lover limbs spastic paresis was markedly reduced and she was able to walk with a walker. Subsequent follow-up at a regional neurology center revealed only mild lower limbs weakness with decreased spasticity. The patient walked with a walker, displaying a cautious gait. After seven months of ruxolitinib therapy, \u003cstrong\u003econtinued neurological improvement was observed\u003c/strong\u003e, and she was able to walk with unilateral support. Follow-up MRI showed regression of post-inflammatory demyelinating lesions in the frontal lobes (Figure 1B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the ninth month, she entered a nationwide program providing free access to ruxolitinib, allowing the dose to increase to 20 mg daily (alternating with 10 mg). By the eleventh month, she was able to walk independently into the outpatient consultation room for the first time, although support was still required for longer distances. At one year of ruxolitinib, MRI demonstrated marked regression of CNS lesions and further neurological improvement. Functional tests showed substantial improvement: Berg Balance Scale increased from 22 to 41 points, and Timed Up and Go (TUG) time decreased from 30 to 17 seconds.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe present a rare case of \u003cstrong\u003eatypical chronic GvHD affecting the central nervous system (CNS)\u003c/strong\u003e, diagnosed by exclusion, which responded favourably to ruxolitinib therapy. To our knowledge, there are no currently published data specifically evaluating the efficacy of ruxolitinib for CNS- GvHD. The patient had multiple risk factors for chronic GvHD, including transplantation from an \u003cstrong\u003eHLA-mismatched unrelated female donor, prior alloimmunization, and previous acute GvHD [1,6-7]. The diagnoses of classic acute GvHD followed by an overlap syndrome, both steroid-sensitive, were based on clinical features without histopathological confirmation. Early immunosuppressive therapy, including a calcineurin inhibitor, was associated with transient neurotoxicity; h\u003c/strong\u003eowever, the subsequent development of spastic paraparesis and demyelinating MRI lesions approximately one year post transplant makes a causal link with prior calcineurin inhibitor therapy unlikely.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAccording to the 2010 Consensus Conference criteria, this case fulfills the definition of possible CNS-cGvHD [8]. Both mandatory criteria (i.e. cGvHD involvement of other organs and neurological signs unexplained by alternative causes ) and two of six facultative criteria (corresponding MRI abnormalities, and a favourable response to immunosuppressive therapy, confirmed retrospectively) were met. Notably, the CNS-GvHD Study Group does not currently consider chronic GvHD in other organs mandatory for CNS- GvHD diagnosis [9].\u0026nbsp;\u003c/strong\u003ePublished data suggest that one-year overall survival after CNS-cGvHD is approximately 41%, with a median overall survival of 196 days [9]. Therapeutic response remains poorly characterized. In the CNS-cGvHD Study Group analysis, corticosteroids were used in 91% of patients, resulting in complete remission in 27% and partial improvement in 47%. Although ruxolitinib was administered in some cases, its specific efficacy for CNS involvement was not analyzed in detail [9].\u003c/p\u003e\n\u003cp\u003eRuxolitinib therapy was initiated following protocols for classical cGvHD, considering the limited efficacy and adverse effects of prolonged corticosteroid therapy. The observed improvement likely reflects the drug’s immunomodulatory effects on the pathophysiology of CNS-GvHD [10-15].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eT-cell infiltration of the CNS during GvHD differs between acute and chronic phases. In acute CNS-GvHD, infiltration is initially dominated by CD8⁺ T cells and associated with cytokine production (predominantly TNF and IL-6) by host microglial cells. In contrast, chronic CNS-GvHD is characterized by a shift toward CD4⁺ T-cell infiltration and recruitment of donor bone marrow–derived macrophages expressing major histocompatibility complex (MHC) class II, leading to increased INF-γ production as a key mediator. Th1 and Th17 lymphocyte subsets, important to GvHD immunopathology, are also implicated in CNS-directed autoimmunity, including experimental autoimmune encephalomyelitis and animal models of multiple sclerosis\u003c/strong\u003e [1,3,8–9,16–19].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRuxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, blocks downstream signaling of multiple cytokines involved in GvHD pathogenesis. In allo-HCT recipients, ruxolitinib increases regulatory T-cell (Treg) frequencies, decreases Th17 populations, and reduces MHC class II expression on antigen-presenting cells, thereby exerting broad anti-inflammatory and immunomodulatory effects\u003c/strong\u003e [17–18,20–21].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe role of JAK/STAT signalling in neuroinflammation has also been demonstrated in cPIIRS (cryptococcal post-infectious inflammatory response syndrome) [22]. Hargarten et al. showed that JAK/STAT-dependent pathways drive hypercytokinemia and sustain inflammatory and cytotoxic immune cells at post-inflammatory foci in the brain, resulting in progressive neuronal damage. All of these processes were effectively suppressed by ruxolitinib, leading to \u003cstrong\u003emarked clinical improvement and enhanced quality of life\u003c/strong\u003e in six patients with suboptimal corticosteroid response \u003cstrong\u003e[22]\u003c/strong\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis case suggests that ruxolitinib may represent a potential therapeutic option in atypical CNS involvement of chronic GvHD. While clinical improvement likely reflects the combined effects of corticosteroids, immunoglobulin supplementation, and ruxolitinib,the observed neurological and radiological responses indicate a meaningful contribution from JAK inhibition. Given the rarity of CNS-cGvHD and the absence of specific therapeutic guidelines, JAK inhibition may be considered in selected patients, and prospective studies are needed to better define optimal management strategies for this challenging manifestation of cGvHD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe sincerely thank the patient for her consent to publish this case and for her cooperation during the diagnostic evaluation and treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors did not receive support from any organization for the submitted work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial interests:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthors declare no financial interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patient data was collected based on available medical records. All of the data was analyzed anonymously.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ewa Karakulska-Prystupiuk. The first draft of the manuscript was written by Ewa Karakulska-Prystupiuk and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eConceptualization: Ewa Karakulska-Prystupiuk,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethodology: Ewa Karakulska-Prystupiuk, Beata Zakrzewska-Pniewska, Marta Hałaburda- Rola.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFormal analysis and investigation: Ewa Karakulska-Prystupiuk\u003c/p\u003e\n\u003cp\u003eWriting - original draft preparation: Ewa Karakulska-Prystupiuk,\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWriting - review and editing: Ewa Karakulska-Prystupiuk, Beata Zakrzewska-Pniewska, Agnieszka Tomaszewska, Marta Hałaburda- Rola, Wiesław Wiktor Jędrzejczak, Grzegorz Władysław Basak\u003c/p\u003e\n\u003cp\u003eFunding acquisition: -\u003c/p\u003e\n\u003cp\u003eResources: Agnieszka Tomaszewska, Wiesław Wiktor Jędrzejczak, Grzegorz Władysław Basak\u003c/p\u003e\n\u003cp\u003eSupervision: Wiesław Wiktor Jędrzejczak, Grzegorz Władysław Basak\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ethical consent was approved by Medical University of Warsaw, Bioethical Commission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is a retrospective analysis of anonymous data contained in medical records.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten consent for publication was obtained from the patient.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLee SJ, Williams KM, Sarantopoulos S, Kitko CL, Cutler C, Pidala J, Hill GR, DeFilipp Z, Greinix HT, Wolff D, Paczesny S, Cuvelier GDE, Schultz KR, Pavletic SZ (2025) NIH Chronic Graft-Versus-Host Disease Consensus Conference 2025 Update. 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PMID: 40117367; PMCID: PMC11927619\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":true,"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":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"allogeneic hematopoietic stem cell transplantation (allo-HSCT), graft-versus-host disease (cGvHD), chronic graft-versus-host disease with central nervous system involvement (cGvHD with CNS involvement), ruxolitinib, steroid-refractory GvHD","lastPublishedDoi":"10.21203/rs.3.rs-8745448/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8745448/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eChronic graft-versus-host disease (cGvHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Beyond its classical manifestations, cGvHD may involve additional organs, including the central nervous system (CNS), where involvement remains poorly characterized, and therapeutic options are undefined, particularly in steroid-refractory cases.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCase Presentation\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWe report the case of a 50-year-old woman who underwent allo-HSCT for myelodysplastic syndrome and subsequently developed classical acute followed by chronic GvHD-overlap syndrome. At 2 years and 9 months post-transplant, she presented with progressive spastic paraparesis, and brain MRI revealed multifocal hyperintense white-matter lesions. A diagnosis of possible CNS-cGvHD was established. Due to poor response and intolerance to prolonged corticosteroid therapy, ruxolitinib was initiated at 10 mg/day and subsequently increased to 20 mg/day, with concomitant tapering of prednisone and immunoglobulin supplementation. Over 12 months, the patient demonstrated both clinical and radiological improvement, including significant functional recovery and marked regression of CNS lesions.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis case suggests that ruxolitinib may represent a potential therapeutic option for atypical CNS involvement in cGvHD. Although clinical improvement likely reflected combined treatments, the neurological and radiological response suggests meaningful contribution from JAK inhibition. Further studies are needed to better define the role of ruxolitinib in this rare manifestation of cGvHD.\u003c/p\u003e","manuscriptTitle":"Successful Use of Ruxolitinib in Steroid-Refractory Chronic GvHD affecting Central Nervous System: A Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-27 06:28:49","doi":"10.21203/rs.3.rs-8745448/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-16T07:15:49+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-15T08:43:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-11T23:33:07+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"295352318034050191926724341346658429721","date":"2026-03-07T21:53:36+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"128097855194740207574675532160497006198","date":"2026-02-26T08:11:55+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-12T21:10:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-12T10:36:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-12T10:26:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2026-01-31T00:12:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3c6fd165-8a53-4069-9045-38db912d39ed","owner":[],"postedDate":"February 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T18:23:11+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-27 06:28:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8745448","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8745448","identity":"rs-8745448","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}