DISCLAIMER: This publication is aimed at health professionals. The information is meant to provide updates on medication safety issues, and not as a substitute for clinical judgement. While reasonable care has been taken to verify the accuracy of the information at the time of publication, NPRA shall not be held liable for any loss whatsoever arising from the use of or reliance on this publication.

 

Overview of Products

Rituximab is a monoclonal antibody that targets the cluster of differentiation 20 antigen (CD20) expressed on the surfaces of both normal and malignant B cells.^1-3 By binding to CD20, rituximab induces antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis in B-lymphocytes, thereby depleting B cells and impairing humoral immunity (antibody-mediated immune response).^2-4 Rituximab is effective in the treatment of lymphocytic malignancies of the B-cell origin. In addition, it is indicated for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis.¹ In Malaysia, there are currently 7 products containing rituximab registered with the Drug Control Authority (DCA), all in the form of injectables.⁵

 

Overview of Safety Concerns

Enteroviral meningoencephalitis is a serious and potentially fatal central nervous system (CNS) infection characterised by inflammation of both the meninges and brain tissue.^6.7 It is caused by enteroviruses, a group of positive single-stranded RNA viruses from the Picornaviridae family. These viruses are typically transmitted through the intestinal tract and usually cause mild, self-limited infections in immunocompetent individuals.^6-8 However, in immunocompromised individuals, enterovirus infections can progress to CNS involvement, leading to life-threatening enteroviral meningoencephalitis and severe neurological complications.

Serologic tests rely on detecting the presence of specific antibodies in the blood to identify certain diseases.^9,10 False-negative serologic results (i.e., incorrectly indicating the absence of antibodies even when infection is present) pose a diagnostic challenge in immunocompromised patients who are unable to mount adequate antibody responses or have received cell-depleting therapies.¹⁰ This may complicate microbiologic testing used to identify the causative pathogen(s) or to rule out infection.

 

Source of Safety Issue

The National Pharmaceutical Regulatory Agency (NPRA) learned from the European Medicines Agency (EMA) about the risk of enteroviral meningoencephalitis and false-negative serologic testing of infections associated with the use of rituximab.^11,12 Based on available data from the literature and spontaneous reports regarding enteroviral meningoencephalitis and false-negative serologic testing, along with a plausible mechanism of action, the EMA considers a causal relationship between rituximab and these adverse effects to be at least a reasonable possibility.¹² As a result, the EMA has recommended updating the product information for rituximab-containing products to reflect these risks.

 

Background of the Safety Issue

The pathophysiology underlying both risks of enteroviral meningoencephalitis and false-negative serologic testing with rituximab stems from its suppressive impact on the humoral immune response.^2-4,7,8,13 Rituximab induces profound and prolonged B-cell depletion, resulting in hypogammaglobulinemia (low levels of antibodies). This increases susceptibility to opportunistic infections such as enteroviruses. Simultaneously, it compromises the body’s ability to mount detectable antibody responses, potentially resulting in false-negative serological test results in individuals receiving rituximab, which lead to delays in the diagnosis of infections.^4,10

 

Risk of Enteroviral Meningoencephalitis

Cases of enteroviral meningoencephalitis or meningitis, including fatalities, have been reported following the use of rituximab in post-marketing surveillance and literature.^{1-3,7,8,12-16} The onset of rituximab-related enteroviral meningoencephalitis varies widely, occurring from immediately after, during, or even months to years after treatment.^{2,3,7,8,14-16} Symptoms are diverse and often non-specific, including neurological and systemic manifestations, which can lead to a low index of suspicion and delayed diagnosis. Moreover, viral load in the cerebrospinal fluid (CSF) may be low early in the disease course, making detection difficult.^8,14

Management of enteroviral meningoencephalitis generally involves prompt diagnosis, intravenous immunoglobulin (IVIG) therapy to replenish neutralising antibodies, and supportive care.^{2,3,7,8,13-16} Some cases reported recovery with complete resolution or neurological improvement; however, there have been reports of severe permanent neurological deficits, behavioural problems, and death.^{2,3,7,8,14-16}  

 

Risk of False-Negative Serologic Testing of Infections

Cases have been reported in which patients receiving rituximab developed rare infectious diseases such as West Nile virus infection and neuroborreliosis (Lyme disease), but had persistently negative serologic results across multiple tests.^4,17 There were also cases where initial false-negative serologic test results led to delayed diagnosis of secondary syphilis, as well as a prolonged course of COVID-19 requiring extended hospitalisation.^18-20

Given the risk of false-negative serologic testing, alternative diagnostic tools should be considered for patients on rituximab who present with symptoms indicative of infections.^1,4,17,18

 

Local Adverse Drug Reaction Reports²¹

To date, the NPRA has received a total of 422 reports with 1,011 adverse events suspected to be related to rituximab-containing products. The most frequently reported adverse events were dyspnoea (50 reports), chills (48), and pruritus (41). No reports of enteroviral meningoencephalitis or false-negative results in serologic tests for any infections have been received locally.

 

Regulatory Actions

The NPRA has completed a review of the potential risk of enteroviral meningoencephalitis and false-negative serologic testing of infections associated with rituximab. On 9 May 2025, a directive [Ruj. Kami: NPRA.600-1/9/13 (55) Jld. 1] was issued for all registration holders of injectable products containing rituximab to update the local package inserts to reflect this safety information.

 

Advice for Healthcare Professionals

Risk of Enteroviral Meningoencephalitis

• Be aware that cases of enteroviral meningoencephalitis or meningitis, including severe and potentially fatal complications, have been reported following the use of rituximab, regardless of the indication (e.g., autoimmune diseases or hematologic malignancies).
• Advise patients to seek immediate medical attention if they develop signs and symptoms suggestive of a serious brain infection (e.g., unexplained fever, headache, stiff neck, incoordination, personality change, hallucinations, altered consciousness, seizures or coma). These may occur during or even months or years after rituximab treatment.
• Given the diagnosis challenges and potential for severe complications, it is important to maintain a high index of suspicion for enteroviral meningoencephalitis in patients receiving rituximab and manage appropriately.

Risk of False-Negative Serologic Testing of Infections

• Recognise that false-negative serologic test results for infections have been reported following the use of rituximab.
• Remain vigilant when managing patients on rituximab, as they may exhibit clinical signs of infection despite initially negative serologic test results. In such cases, consider alternative diagnostic methods to prevent potential risks associated with delayed diagnosis and treatment.
  
  
• Report all adverse events suspected to be related to the use of rituximab-containing products to the NPRA.

 

References:

1. National Pharmaceutical Regulatory Agency (NPRA). MABTHERA (rituximab) [Package Insert]. QUEST3+ Product Search. 2024 May [cited 2024 Jul 22]. Available from: http://www.npra.gov.my.
2. Cook SG, Ford AW, Lindholm DA, Scott J. Enteroviral Meningoencephalitis as a Complication of Rituximab Therapy for Rheumatoid Arthritis. Cureus. 2021 Sep 22;13(9):e18189. Available from: https://doi.org/10.7759/cureus.18189
3. Givens P, Velez AP, Sandin RL, Quilitz RE, Greene JN. Development of enteroviral aseptic meningitis after rituximab treatment of non-hodgkin lymphoma. Infectious Diseases in Clinical Practice. 2012 Jul 1;20(4):291-3. Available from: https://doi.org/10.1097/IPC.0b013e3182506ea0
4. Tavakolpour S, Alesaeidi S, Darvishi M, GhasemiAdl M, Darabi-Monadi S, Akhlaghdoust M, Elikaei Behjati S, Jafarieh A. A comprehensive review of rituximab therapy in rheumatoid arthritis patients. Clinical rheumatology. 2019 Nov;38:2977-94. Available from: https://doi.org/10.1007/s10067-019-04699-8
5. National Pharmaceutical Regulatory Agency (NPRA). QUEST3+ Product Search [Internet]. 2025 [cited 2025 Jan 7]. Available from: https://www.npra.gov.my
6. Ellerington A, Duncan C. Enterovirus encephalitis. Encephalitis International [Internet]. 2025 Mar 17 [cited 2025 Jun 6]. Available from: https://www.encephalitis.info/types-of-encephalitis/infectious-encephalitis/enterovirus-encephalitis/
7. Tellez R, Lastinger AM, Hogg JP. Chronic enteroviral meningoencephalitis in a patient on rituximab for the treatment of psoriatic arthritis: A case report and brief literature review. IDCases. 2019 May 9;17:e00558. Available from: https://doi.org/10.1016/j.idcr.2019.e00558
8. Kiani-Alikhan S, Skoulidis F, Barroso A, Nuovo G, Ushiro-Lumb I, Breuer J, Lister A, Mattes F. Enterovirus infection of neuronal cells post-Rituximab. Br J Haematol. 2009 Aug;146(3):333-5. Available from: https://doi.org/10.1111/j.1365-2141.2009.07748.x
9. Antibody serology tests [Internet]. 2024 Sep 30 [cited 2025 Jan 9]. Available from: https://medlineplus.gov/lab-tests/antibody-serology-tests/
10. Casto AM, Fredricks DN, Hill JA. Diagnosis of infectious diseases in immunocompromised hosts using metagenomic next generation sequencing-based diagnostics. Blood Rev. 2022 May;53:100906. Available from: https://doi.org/10.1016/j.blre.2021.100906
11. European Medicines Agency (EMA). Pharmacovigilance Risk Assessment Committee (PRAC) Minutes of PRAC meeting on 05-08 June 2023 [Internet]. 2023 Aug 25 [cited 2025 May 16]. Available from: https://www.ema.europa.eu/en/documents/minutes/minutes-prac-meeting-5-8-june-2023_en.pdf
12. European Medicines Agency (EMA). Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s): Rituximab [Internet]. 2023 Jun [cited 2025 May 16]. Available from: https://www.ema.europa.eu/en/documents/scientific-conclusion/mabthera-h-c-psusa-00002652-202211-epar-scientific-conclusions-and-grounds-variation-terms-marketing-authorisation_en.pdf
13. Martin de Frémont G, Chabrolles H, Mirand A, L'Honneur AS, Mélé N, Dunogue B, Boutboul D, Farhat M, Hachulla E, Lazrek M, Rieu V, Mathian A, Chaussade H, Ruet A, Burrel S, Coury-Lucas F, Schuffenecker I, Lemaignen A, Stefic K, le Besnerais M, Carrette M, Mouthon L, Avettand-Fenoel V, Terrier B, Hadjadj J. Severe enterovirus infections in patients with immune-mediated inflammatory diseases receiving anti-CD20 monoclonal antibodies. RMD Open. 2024 May 20;10(2):e004036. https://doi.org/10.1136/rmdopen-2023-004036
14. Dineen J, Smyth S. Centerovirus encephalitis complicating rituximab treatment: a treatable condition. J Neurol Neurosurg Psychiatry. 2013;84(11):e2.50-e2. Available from: https://doi.org/10.1136/jnnp-2013-306573.143
15. Grisariu S, Vaxman I, Gatt M, Elias S, Avni B, Arad A, Pasvolsky O, Raanani P, Paltiel O. Enteroviral infection in patients treated with rituximab for non-Hodgkin lymphoma: a case series and review of the literature. Hematol Oncol. 2017 Dec;35(4):591-598. Available from: https://doi.org/10.1002/hon.2365
16. Jacksch C, Dargvainiene J, Böttcher S, Diedrich S, Leypoldt F, Stürner K, Berg D, Schäffer E. Chronic Enterovirus Meningoencephalitis in Prolonged B-Cell Depletion After Rituximab Therapy: Case Report. Neurol Neuroimmunol Neuroinflamm. 2023 Oct 9;10(6):e200171. Available from: https://doi.org/10.1212/NXI.0000000000200171
17. Wagemakers A, Visser MC, de Wever B, Hovius JW, van de Donk NWCJ, Hendriks EJ, Peferoen L, Muller FF, Ang CW. Case report: persistently seronegative neuroborreliosis in an immunocompromised patient. BMC Infect Dis. 2018 Aug 2;18(1):362. Available from: https://doi.org/10.1186/s12879-018-3273-8
18. Lefeuvre C, Croué A, Abgueguen P, Letzelter M, Ducancelle A, Grange P, Benhaddou N, Dupin N, Le Guillou-Guillemette H, Le Clec'h C. Serological diagnosis of secondary syphilis in a Rituximab-treated patient: an emerging diagnostic challenge? J Eur Acad Dermatol Venereol. 2021 May;35(5):e350-e352. Available from: https://doi.org/10.1111/jdv.17126
19. Maillart E, Papeix C, Lubetzki C, Roux T, Pourcher V, Louapre C. Beyond COVID-19: DO MS/NMO-SD patients treated with anti-CD20 therapies develop SARS-CoV2 antibodies? Mult Scler Relat Disord. 2020 Nov;46:102482. Available from: https://doi.org/10.1016/j.msard.2020.102482
20. Kos I, Balensiefer B, Roth S, Ahlgrimm M, Sester M, Schmidt T, Thurner L, Bewarder M, Bals R, Lammert F, Stilgenbauer S, Kaddu-Mulindwa D. Prolonged Course of COVID-19-Associated Pneumonia in a B-Cell Depleted Patient After Rituximab. Front Oncol. 2020 Sep 2;10:1578. Available from: https://doi.org/10.3389/fonc.2020.01578
21. National Pharmaceutical Regulatory Agency (NPRA). The Malaysian National ADR Database (QUEST) [Internet]. 2025 [cited 2025 Jan 7]. Available from: https://www.npra.gov.my (access restricted)

 

Written by: Wo Wee Kee
Reviewed/Edited by: Choo Sim Mei, Dr. Rema Panickar, Noor'ain Shamsuddin, Norleen Mohamed Ali