Journal of the Neurological Sciences 353 (2015) 155–157

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Short communication

Rituximab treatment did not aggravate ongoing progressive multifocal leukoencephalopathy in a patient with multiple sclerosis F. Asztely a,⁎, E. Gilland a, M.P. Wattjes b, J. Lycke a a b

Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden Department of Radiology & Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands

a r t i c l e

i n f o

Article history: Received 2 March 2015 Received in revised form 1 April 2015 Accepted 8 April 2015 Available online 16 April 2015 Keywords: Multiple sclerosis Natalizumab Rituximab Progressive multifocal leukoencephalopathy JC virus MRI

a b s t r a c t A multiple sclerosis (MS) patient developed progressive multifocal leukoencephalopathy (PML) after 43 months of natalizumab treatment. New clinical and magnetic resonance imaging (MRI) findings were initially misinterpreted as breakthrough MS disease activity and natalizumab treatment was replaced by rituximab treatment. The patient had a single infusion of rituximab 1000 mg before a definite PML diagnosis was confirmed. Despite undetectable levels of B-cells, JC virus DNA became undetectable in the cerebrospinal fluid by quantitative polymerase chain reaction. The patient partially recovered without any clinical or MRI signs of new MS activity. These findings suggest that B-cell depletion in a non-immune compromised individual did not prevent the patient from clearing the JC virus infection. © 2015 Elsevier B.V. All rights reserved.

1. Introduction

1.1. Case report

Progressive multifocal leukoencephalopathy (PML), an opportunistic infection based on JC virus replication and neuroinvasion, is a serious but relatively rare side effect of natalizumab, an approved drug for the treatment of relapsing multiple sclerosis (MS) (https// medinfo.biogenidec.com, assessed January 2015). Therefore, pharmacovigilance with special regard to safety monitoring is essential during natalizumab treatment and after treatment discontinuation [1]. Rituximab, a chimeric monoclonal antibody depleting B-cells, is currently used off-label in several autoimmune neurological diseases, including MS. Although the estimate of the risk of PML in rituximab-treated patients is complicated due to confounders such as concomitant/preceding immune suppressive therapy, or the underlying disease it has been estimated to be approximately 4/100,000, with a case-fatality rate of 90% [2,3]. However, there have not been any reports of PML during rituximab treatment of MS. In the present case, natalizumab was switched to rituximab treatment during ongoing PML. Although, severe B-cell depletion was accomplished, the patient partially recovered, suggesting that B-cell-depleting therapies do not aggravate PML in MS.

A 42-year-old woman was diagnosed with MS in the summer of 2009. She presented with a high lesion load on brain MRI and a rather severe disease course, which led to the initiation of natalizumab treatment in July 2009. No clinical relapses were recorded during the following years. In December 2011, the patient's JC virus serostatus converted to positive (Stratify JCV, Unilabs, Copenhagen). Brain MRI performed in February 2012 (Fig. 1A–E) did not show any lesions suggestive of active MS inflammation or PML; natalizumab treatment was continued. In November 2012, after having received 43 infusions of natalizumab, she experienced double vision. The clinical examination showed left abducens nerve palsy, and a new brain MRI demonstrated multifocal new subcortical T2 lesions in the right parietal and temporal lobes. In addition, new small focal lesions were observed in the pons and mesencephalon; some of these lesions showed subtle contrast enhancement (Fig. 1F–J). At that time, PML was not suspected because of the origin of the clinical relapse and the lack of progressive neurological deterioration. The event was misinterpreted as breakthrough MS disease activity, and natalizumab treatment was switched (last infusion December 2012) to rituximab. The patient received a single infusion of rituximab 1000 mg i.v. in January 2013. Thereafter, the CD19 and CD20 count (b0.01 × 109/L) remained at undetectable levels for the next 15 months.

⁎ Corresponding author at: Institute of Neuroscience and Physiology, Department of Clinical Neuroscience and Rehabilitation, Sahlgrenska Academy at the University of Gothenburg, SE 413 45 Gothenburg, Sweden. Tel.: +46 704 883151. E-mail address: [email protected] (F. Asztely).

http://dx.doi.org/10.1016/j.jns.2015.04.010 0022-510X/© 2015 Elsevier B.V. All rights reserved.

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F. Asztely et al. / Journal of the Neurological Sciences 353 (2015) 155–157

Fig. 1. Axial T2-weighted (A–C, F–H, K–M) and contrast-enhanced T1-weighted (D, E, I, J, N, O) MR Images (17-12-2012, middle row) demonstrating new lesions compared to a reference scan (10-02-2012, upper row) in the subcortical white matter (closed head arrows) and small focal contrast-enhancing lesions in the mesencephalon and pons (open head arrows). The lesions are highly suggestive of PML. However, they were misinterpreted as new and active MS lesions. Both non-enhancing lesions (closed head) and enhancing-lesions (open head arrows), showed PML progression over time as demonstrated on the follow-up MRI obtained on 18-3-2013 (bottom row).

In March 2013, the patient rapidly deteriorated. She experienced dysphagia, dysarthria, walking difficulties, and severe anxiety. Brain MRI showed progression of the earlier described lesions (Fig. 1K–O). In particular, the lesions in the temporal and parietal lobes became confluent. New small ‘satellite lesions’ highly suggestive of PML were identified. However, two separate subsequent PCRs for JCV DNA in CSF were negative, as described in other natalizumab-associated PML cases [4]. At admission to a tertiary neurology department (Sahlgrenska University Hospital), her condition had progressed further (EDSS 7.5). PML with an immune reconstitution inflammatory syndrome (IRIS) was suspected, and methylprednisolone (1000 mg i.v. daily for 3 days) was administered. A new lumbar puncture and qPCR for JCV showed 630 copies/mL (Laboratory of molecular medicine and neuroscience/ NINDS), and a diagnosis of definite PML according to the AAN criteria was confirmed. Sequential qPCR showed a low number of copies (13–19/mL) in CSF. No JCV DNA had been detected since December 2013. The patient slowly recovered without any clinical or MRI signs of new MS activity. The severity and course of PML was followed by repeated analysis of CSF biomarkers of axonal damage and astrogliosis (Table 1). At 21 months after the PML diagnosis, the patient is able to walk short distances with bilateral support (EDSS 6.5), is dependent on some support but takes care of most daily activities, and is still without any disease-modifying therapy. 2. Discussion This case emphasizes the importance of continued surveillance for PML after the termination of natalizumab treatment [1] and suggests

that B cells may be less important for viral clearance and recovery from already manifest PML. This patient had an increased risk of PML, and the possibility of PML at an earlier stage should have been considered. However, the onset of brain stem symptoms and the MRI findings were misinterpreted as breakthrough MS disease activity. It has been

Table 1 Monitoring PML after 1000 mg rituximab: lymphocyte count, JC virus DNA expression, and CSF biomarkers. March 2013

June September December April October 2013 2013 2013 2014 2014

IRIS Gradual clinical recovery reaction CSF-lymphocytes,/μL PB-lymphocytes, ×109/L IgG index Albumin ratio GFAP, ng/L NFL, ng/L IgG OB, n Tau, ng/L CD19, ×109/L CD20, ×109/L qPCR JCV DNA/mL

7 1.0

b3 0.6

b3 1.1

b3 1.2

b3 1.2

b3 1.1

0.60 8.5 300 4570 4–5 227 u.d. u.d. 630

0.59 10.0 540 9600 2–3 301 u.d. u.d. 100

0.60 6.7 920 9760 4–5 221 u.d. u.d. 19

0.57 5.6 1210 8510 3 270 u.d. u.d. 0

0.77 4.2 1030 5450 4–5 109 0.02 0.03 0

0.61 5.0 970 3090 4–5 117 0.07 0.08 0

IRIS: immune reconstitution inflammatory syndrome; CSF: cerebrospinal fluid; PB: periphera blood (normal 3.5–8.8 × 109/L); u.d.: undetectable (i.e. below 0.01 × 109/L); OB: oligoclonal bands; qPCR JCV DNA: quantitative polymerase chain reaction of JC virus DNA; GFAP: glial fibrillary acidic protein (normal b 750 ng/L); NFL: neurofilament light protein (normal b 890 ng/L); Tau (normal b 400 ng/L); IgG index (normal b 0.63); albumin ratio (normal b10.2)

F. Asztely et al. / Journal of the Neurological Sciences 353 (2015) 155–157

suggested previously that lesions in the brain stem with no mass effect and no Gd-contrast enhancement are less likely due to PML, even in the majority of natalizumab-associated PML cases. However, recent literature suggests that the MRI findings of natalizumab-associated PML are more heterogeneous and fluctuating [5]. Natalizumab-associated PML lesions do occur in the posterior fossa or temporal lobes, but in less than 10% of reported cases [5]. A definite PML diagnosis was made after steroid treatment of IRIS, and similar increases in CSF JCV load have been reported previously [6]. The onset of PML was initially misinterpreted as breakthrough relapses, and natalizumab was switched to rituximab [7]. Fingolimod was considered less efficacious [8], and alemtuzumab had not yet been approved. Thus, the patient had a single dose of rituximab during ongoing PML, which caused severe B-cell depletion lasting 15 months. This seemed not to influence the development of IRIS. In fact, the patient's condition gradually improved, contrast enhancement on MRI decreased, and CSF biomarkers of axonal damage and astrogliosis slowly decreased. It is interesting to note that, 21 months after her last natalizumab infusion, the patient has not developed any clinical or MRI findings suggesting re-appearance of MS activity. This is in contrast to several reports showing reactivation of MS within 15 months after the cessation of natalizumab treatment in 50% or more of cases [8,9]. Recently, indirect evidence of impaired B-cell function was claimed to influence the occurrence of PML in natalizumab-treated patients [10]. However, this case demonstrates that a patient with manifest PML can recover even after B-cell levels are rendered undetectable. JCV DNA also became undetectable on qPCR. B-cell depletion did not appear to influence the course of PML in MS, and this case indicates that rituximab may be an alternative treatment in the post-PML stage. Conflict of interest Dr. Asztely and Dr. Gilland have received honoraria from Genzyme. Dr. Wattjes serves as a consultant for Biogen Idec, Roche and Novartis. Dr. Lycke has received honoraria from Bayer Shering

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Pharma, BiogenIdec, Novartis and Sanofi-Aventis; has served on scientific advisory boards for Almirall, Teva, Biogen Idec and Genzyme/Sanofi-Aventis; serves on the editorial board of the Acta Neurologica Scandinavica, and has received unconditional research grants from BiogenIdec and Novartis. References [1] Fine AJ, Sorbello A, Kortepeter C, Scarazzini L. Progressive multifocal leukoencephalopathy after natalizumab discontinuation. Ann Neurol 2014;75(1): 108–15. [2] Bharat A, Xie F, Baddley JW, Beukelman T, Chen L, Calabrese L, et al. Incidence and risk factors for progressive multifocal leukoencephalopathy among patients with selected rheumatic diseases. Arthritis Care Res 2012;64(4):612–5. [3] Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIVnegative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 2009;113(20):4834–40. [4] Wattjes MP, Vennegoor A, van Mostert J, Oosten BW, Barkhof F, Killestein J. Diagnosis of asymptomatic natalizumab-associated PML: are we between a rock and a hard place? J Neurol 2014;261(6):1139–43. [5] Wattjes MP, Richert ND, de Killestein J, Vos M, Sanchez E, Snaebjornsson P, et al. The chameleon of neuroinflammation: magnetic resonance imaging characteristics of natalizumab-associated progressive multifocal leukoencephalopathy. Mult Scler 2013;19(14):1826–40. [6] Tan IL, McArthur JC, Clifford DB, Major EO, Nath A. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology 2011;77(11): 1061–7. [7] Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One 2013;8(7): e66308. [8] Rinaldi F, Seppi D, Calabrese M, Perini P, Gallo P. Switching therapy from natalizumab to fingolimod in relapsing-remitting multiple sclerosis: clinical and magnetic resonance imaging findings. Mult Scler 2012;18(11):1640–3. [9] Dahlhaus S, Hoepner R, Chan A, Kleiter I, Adams O, Lukas C, et al. Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients. J Neurol Neurosurg Psychiatry 2013; 84(10):1068–74. [10] Warnke C, Stettner M, Lehmensiek V, Dehmel T, Mausberg AK, von Geldern G, et al. Natalizumab exerts a suppressive effect on surrogates of B cell function in blood and CSF. Mult Scler 2014. http://dx.doi.org/10.1177/1352458514556296 [Epub ahead of print 2014].

Rituximab treatment did not aggravate ongoing progressive multifocal leukoencephalopathy in a patient with multiple sclerosis.

A multiple sclerosis (MS) patient developed progressive multifocal leukoencephalopathy (PML) after 43 months of natalizumab treatment. New clinical an...
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