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Is there a recommendation to screen for JC virus antibodies prior to administering Rituximab?
According to a review of available data, the incidence of Progressive Multifocal Leukoencephalopathy (PML) has been found to be associated with treatment using rituximab, albeit with a low likelihood of occurrence – the estimated incidence rate is one case per 32,000 patients1. The risk is still considered rare among individuals with rheumatological diseases receiving rituximab, with an estimated incidence rate of 2-5 cases per 100,000.
It is important to note that while the presence of serum John Cunningham Virus (JCV) antibodies can be used to stratify the risk of PML in certain diseases such as Multiple Sclerosis (MS), it has not been verified as an independent screening test, but rather as part of a risk stratification score base on other factors, such as age, relapse rate, and prior immunosuppression therapy14. Unlike in MS, where JCV antibodies are included as a parameter in an index used to conduct risk stratification of PML in patients receiving natalizumab3, there is currently no such tool available for monitoring PML risk in patients treated with rituximab. Furthermore, a positive result for the presence of JCV serum antibodies alone does not provide enough information to be used as a standalone clinical screening tool, as 50%-90% of the population are carriers of the virus2.
Neither the services nor the research report constitute medical advice of any kind and are not intended to be a substitute for professional medical advice.
Medical Meta Findings
- Is there a recommendation to screen for JC virus antibodies prior to administering Rituximab?
- Rheumatologic patients:
Progressive multifocal leukoencephalopathy in patients treated with rituximab: a 20-year review5 published in The Lancet Haematology in 2021 (Q1, Impact factor 30.15) meant to evaluate the risk of PML in patients treated with rituximab, based on several data sources such as clinical trials and registries. Regarding rheumatologic patients, the authors mention that according to their data, there are 0.2 cases of PML per 10,000 RA patients and 0.5 cases of PML per 10,000 granulomatous or microscopic polyangiitis patients.
- The Incidence and Predisposing Factors of JC Virus-Induced Progressive Multifocal Leukoencephalopathy in Southern Finland: a cross-sectional retrospective observational population-based study5 published in Open Forum Infectious Diseases journal (Q1, Impact factor 3.83) in 2019 aimed to assess the prevalence, incidence rate (IR), predisposing factors, survival rate, and diagnostic delay of progressive multifocal leukoencephalopathy (PML) across medical specialties. The researchers collected data from PML patients during 2004–2016 in the Finnish Capital Region and Southern Finland from various sources.
During those years, a total of 31 patients have diagnosed with PML, and 15 of them received monoclonal antibody treatment (rituximab, natalizumab). In addition, Rituximab therapy was associated with an increased prevalence of PML in RA patients (4 per 100,000). The rate of PML in the background population was 0.2 per 100,000 discharges.
The main limitations of the study are that it is single-centered and uses an observational retrospective method.
- Rituximab-Associated Progressive Multifocal Leukoencephalopathy in Rheumatoid Arthritis: a case study6 published in the JAMA Archives of Neurology journal (Q1, Impact factor 29.907) in 2011, evaluated the risk for rituximab-associated PML among RA patients treated with rituximab. The results showed an increased risk of 1 case per 25000 treated patients, but the researchers did not mention a need for integration of screening tests as part of rituximab treatment.
- Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a report7, published in the Journal of NeuroVirology (Q2, Impact factor 2.64) in 2018 assessed the risk of PML in patients treated with rituximab for indications of rheumatoid arthritis (RA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). The findings have shown that the occurrence of PML in the rituximab-treated RA/GPA/MPA populations is very rare – 2.56 per 100,000 for RA and less than 1 case per 100,000 in GPA/MPA. Additionally, in the RA population, the estimated reporting rate of PML has been decreasing since 2010 despite rising exposure to rituximab. The reduction and stabilization of PML may be attributed to rituximab use instead of other immunosuppressive therapies.
- Progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus: a systematic literature review8 published in Lupus journal (Q2, Impact factor 2.85) in 2017 evaluated the risk factors for PML in SLE patients, and understand how underlying disease or treatment for SLE may be associated with PML in this population. According to the results, which were analyzed from 29 case reports that described 35 cases, reported PML incidence rates among SLE patients based on observational studies ranged from 1.0 to 2.4 cases per 100,000 person-years, and only one patient was exposed to rituximab at PML diagnosis.
- PML and Rituximab: What Rheumatologists Should Know: an expert opinion published9 on the Rheumatology Network website in 2013 by Leonard Calabrese from Cleveland Clinic Ohio meant to address the main points of PML risk in rheumatologic patients. The writer mentions that in terms of risk, PML remains a very rare complication in rheumatic diseases in general and in RA in particular. For RA patients treated with rituximab, the risk is extremely low, with recent incidence estimates in the range of 5/100,000 patients exposed to the drug.
As a result, given the difference in levels of risk just described, he does not believe that risk-mitigation strategies (such as serologic testing for underlying JC infection, being used to stratify risk in MS), can be justified for patients with rheumatic diseases.
- Progressive multifocal leukoencephalopathy in patients treated with rituximab: a 20-year review4 published in The Lancet Haematology in 2021 (Q1, Impact factor 30.15) meant to evaluate the risk of PML in patients treated with rituximab, based on several data sources such as clinical trials and registries. Regarding oncologic patients, the writers mention that conclude that, since RADAR’s initial case series report of 52 cases of rituximab-associated PML among patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia mentioned below, updated and diligent pharmacovigilance efforts have provided reassurance that this fatal toxicity is a rare clinical event. In addition, the researchers do not mention a need for integration of screening in oncologic cases too.
- A large systematic review10 published in Blood journal in 2009 reported 57 patients who developed PML after receiving rituximab therapy between 1997 to 2008. Overall, 52 patients had lymphoproliferative disorders, 2 with SLE, 1 with RA, 1 with idiopathic autoimmune pancytopenia, and 1 with immune thrombocytopenia.
Of the 59 PML patients who had not undergone prior transplantation procedures, prior medications included purine analogs (46%), alkylating agents (81%), and corticosteroids (75%) – full patient characteristics are available in the attached article. A median of 6 rituximab doses preceded PML, the median time from the first dose to PML diagnosis was 16 months, and a median of 5.5 months from the last dose.
The authors concluded that rituximab therapy may increase the risk of developing PML, although the absolute risk probably remains low. Additionally, they highlight the importance of raising awareness of rituximab-associated PML potential as well as the need for early diagnosis which can improve the survival rates.
3. Neurologic patients:
- Reduction in JCV antibody titers in multiple sclerosis patients treated with rituximab: a study11 published in the Neurology Journal (Q1, Impact factor 11.36) in 2017, evaluated the reduction of anti-JCV antibodies in 68 patients diagnosed with multiple sclerosis and treated with rituximab. The results showed a reduction in antibody titers in 76.2% of the patients receiving 1000mg every 6 months, 66.7% of the patients receiving 500mg every 6 months, and no reduction in the group of patients receiving 100mg every 6 months. The overall seropositive prevalence was found to be 76% and fell to 69.7% after treatment as two patients experienced seroconversion.
Anti-JC virus antibodies in rituximab-treated patients with neuromyelitis optica spectrum disorder: another study12, published in the Journal of Neurology (Q1, Impact factor 6.68) in 2015, has also shown a decrease in anti-JCV antibodies seroprevalence among 78 Korean patients with Neuromyelitis Optica Spectrum Disorder (NMOSD). Six (11%) of the 54 initially seropositive patients have experienced seroconversion over a mean period of 4 years of repeated treatment with rituximab. The authors have concluded that those findings may support the relative safety of long-term rituximab treatment in patients with NMOSD7.
- Zhai S, Brew BJ. Progressive multifocal leukoencephalopathy. Handb Clin Neurol. 2018;152:123-137. doi: 10.1016/B978-0-444-63849-6.00010-4. PMID: 29604971.
- Paz SPC, Branco L, Pereira MAC, Spessotto C, Fragoso YD. Systematic review of the published data on the worldwide prevalence of John Cunningham virus in patients with multiple sclerosis and neuromyelitis optica. Epidemiol Health. 2018 Jan 5;40:e2018001. doi: 10.4178/epih.e2018001. PMID: 29370683; PMCID: PMC5900441.
- Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S, Schlain B, Campagnolo D, Belachew S, Ticho B. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol. 2014 Dec;76(6):802-12. doi: 10.1002/ana.24286. Epub 2014 Oct 24. PMID: 25273271; PMCID: PMC4282070.
- Bennett CL, Focosi D, Socal MP, Bian JC, Nabhan C, Hrushesky WJ, Bennett AC, Schoen MW, Berger JR, Armitage JO; Southern Network on Adverse Reactions. Progressive multifocal leukoencephalopathy in patients treated with rituximab: a 20-year review from the Southern Network on Adverse Reactions. Lancet Haematol. 2021 Aug;8(8):e593-e604. doi: 10.1016/S2352-3026(21)00167-8. PMID: 34329579.
- Kartau M, Verkkoniemi-Ahola A, Paetau A, Palomäki M, Janes R, Ristola M, Lappalainen M, Anttila VJ. The Incidence and Predisposing Factors of John Cunningham Virus-Induced Progressive Multifocal Leukoencephalopathy in Southern Finland: A Population-Based Study. Open Forum Infect Dis. 2019 Feb 22;6(2):ofz024. doi: 10.1093/ofid/ofz024. PMID: 30815501; PMCID: PMC6386113.
- Clifford DB, Ances B, Costello C, Rosen-Schmidt S, Andersson M, Parks D, Perry A, Yerra R, Schmidt R, Alvarez E, Tyler KL. Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch Neurol. 2011 Sep;68(9):1156-64. doi: 10.1001/archneurol.2011.103. Epub 2011 May 9. PMID: 21555606; PMCID: PMC3428054.
- Berger JR, Malik V, Lacey S, Brunetta P, Lehane PB. Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event. J Neurovirol. 2018 Jun;24(3):323-331. doi: 10.1007/s13365-018-0615-7. Epub 2018 Mar 5. Erratum in: J Neurovirol. 2018 Apr 10;: PMID: 29508305; PMCID: PMC5992248.
- Henegar CE, Eudy AM, Kharat V, Hill DD, Bennett D, Haight B. Progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus: a systematic literature review. Lupus. 2016 May;25(6):617-26. doi: 10.1177/0961203315622819. Epub 2016 Jan 6. PMID: 26743322.
- Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, Laubach J, Bawn SD, Gordon LI, Winter JN, Furman RR, Vose JM, Zelenetz AD, Mamtani R, Raisch DW, Dorshimer GW, Rosen ST, Muro K, Gottardi-Littell NR, Talley RL, Sartor O, Green D, Major EO, Bennett CL. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009 May 14;113(20):4834-40. doi: 10.1182/blood-2008-10-186999. Epub 2009 Mar 5. PMID: 19264918; PMCID: PMC2686134.
- Baber U, Bouley A, Egnor E, Sloane JA. Anti-JC virus antibody index changes in rituximab-treated multiple sclerosis patients. J Neurol. 2018 Oct;265(10):2342-2345. doi: 10.1007/s00415-018-8996-3. Epub 2018 Aug 14. PMID: 30109480.
- Kim SH, Hyun JW, Jeong IH, Joung A, Yeon JL, Dehmel T, Adams O, Kieseier BC, Kim HJ. Anti-JC virus antibodies in rituximab-treated patients with neuromyelitis optica spectrum disorder. J Neurol. 2015 Mar;262(3):696-700. doi: 10.1007/s00415-014-7629-8. Epub 2015 Jan 6. PMID: 25559683.
- Salmen A, von Ahsen N, Trampe AK, Hoepner R, Plavina T, Subramanyam M, Kuesters G, Gold R, Chan A. Longitudinal analyses of anti-JCV antibody index for risk assessment of progressive multifocal leukoencephalopathy. Mult Scler J Exp Transl Clin. 2016 Feb 8;2:2055217316630008. doi: 10.1177/2055217316630008. PMID: 28607714; PMCID: PMC5433507.
- Toboso I, Tejeda-Velarde A, Alvarez-Lafuente R, Arroyo R, Hegen H, Deisenhammer F, Sainz de la Maza S, Alvarez-Cermeño JC, Izquierdo G, Paramo D, Oliva P, Casanova B, Agüera-Morales E, Franciotta D, Gastaldi M, Fernández O, Urbaneja P, Garcia-Dominguez JM, Romero F, Laroni A, Uccelli A, Perez-Sempere A, Saiz A, Blanco Y, Galimberti D, Scarpini E, Espejo C, Montalban X, Rasche L, Paul F, González I, Álvarez E, Ramo C, Caminero AB, Aladro Y, Calles C, Eguía P, Belenguer-Benavides A, Ramió-Torrentà L, Quintana E, Martínez-Rodríguez JE, Oterino A, López de Silanes C, Casanova LI, Landete L, Frederiksen J, Bsteh G, Mulero P, Comabella M, Hernández MA, Espiño M, Prieto JM, Pérez D, Otano M, Padilla F, García-Merino JA, Navarro L, Muriel A, Frossard LC, Villar LM. New Algorithms Improving PML Risk Stratification in MS Patients Treated With Natalizumab. Front Neurol. 2020 Dec 17;11:579438. doi: 10.3389/fneur.2020.579438. PMID: 33408681; PMCID: PMC7780851
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