Primary central nervous system lymphoma in a patient with neuropsychiatric systemic lupus erythematosus receiving mycophenolate mofetil: A case ...
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Modern Rheumatology Case Reports, 00, 2021, 1–5
DOI: https://doi.org/10.1093/mrcr/rxab012
Case Report
Primary central nervous system lymphoma in a patient
with neuropsychiatric systemic lupus erythematosus
receiving mycophenolate mofetil: A case report and
Downloaded from https://academic.oup.com/mrcr/advance-article/doi/10.1093/mrcr/rxab012/6348229 by guest on 15 October 2021
literature review
Toru Sakairia,* , Masao Nakasatomia , Mitsuharu Watanabea , Hiroko Hamatania ,
Hidekazu Ikeuchia , Yoriaki Kanekoa , Hiroshi Handab and Keiju Hiromuraa
a
Department of Nephrology and Rheumatology, Gunma University Graduate School of Medicine, Gunma, Japan
b
Department of Hematology, Gunma University Graduate School of Medicine, Gunma, Japan
*Correspondence: Toru Sakairi; sakairit@gunma-u.ac.jp; Department of Hematology, Gunma University Graduate School of Medicine, 3-39-22 Showa, Maebashi,
Gunma 371-8511, Japan.
ABSTRACT
A 41-year-old woman with a 14-month history of systemic lupus erythematosus (SLE) presented with headache, aphasia, and agraphia. A lab-
oratory examination revealed mild proteinuria, hypocomplementemia, and elevated anti-double-stranded DNA antibody levels. A cerebrospinal
fluid analysis demonstrated elevated protein and interleukin-6 levels. Magnetic resonance imaging (MRI) of the brain identified multiple lesions
suggestive of brain edemas and small haemorrhages. She was diagnosed as having neuropsychiatric lupus and lupus nephritis and received
remission induction therapy with high-dose corticosteroid and intravenous cyclophosphamide. She achieved a complete remission, and treat-
ment with mycophenolate mofetil (MMF) was initiated 3 months thereafter for remission maintenance. At 13 months after the exacerbation of
SLE, she complained of headache and nausea. A gadolinium-enhanced MRI of the brain revealed a low-signal-intensity tumour with marginal
ring enhancement of 50 mm in the left frontal lobe. The tumour was excised, and the histological diagnosis was diffuse large B-cell lymphoma
with positive Epstein–Barr virus (EBV). MMF was discontinued. Remission induction therapy with rituximab, high-dose methotrexate, procar-
bazine, and vincristine was administered, and she achieved remission. Previous reports suggest that use of MMF is associated with primary
central nervous system (CNS) lymphoma (PCNSL) in patients with lupus nephritis or other autoimmune diseases or in post-transplant patients.
Our observation that PCNSL occurred after CNS involvement of SLE suggests that EBV and CNS inflammation arising from SLE might have
contributed to the development of PCNSL.
KEYWORDS: Systemic lupus erythematosus; Epstein–Barr virus; primary central nervous system lymphoma; mycophenolate mofetil
Introduction SLE with CNS involvement. We also provide a review of the
Primary central nervous system (CNS) lymphoma (PCNSL), literature regarding PCNSL in SLE patients receiving MMF.
a subtype of non-Hodgkin lymphoma (NHL), is a rare dis-
ease that accounts for 3–4% of primary CNS tumours [1].
Systemic lupus erythematosus (SLE) is a chronic autoim- Case presentation
mune disease that affects multiple organs, including the skin, A 41-year-old woman was referred to our hospital from a
joints, kidneys, and nervous system. Previous studies indicate local rheumatology clinic presenting with a month history of
that Epstein–Barr virus (EBV) is involved in the pathogene- aphasia and agraphia. She was diagnosed with SLE 14 months
sis of SLE [2–4]. EBV also contributes to the development ago based on arthritis, malar rush, photosensitivity, lym-
of lymphoma in immunocompromised patients such as post- phocytopenia and positive anti-nuclear antigen antibody and
transplant, human immunodeficiency virus (HIV)-infected, anti-double-stranded DNA antibody, and started 30 mg/day
and autoimmune disease patients. The incidence of lymphoma prednisolone at that time. Her SLE recurred with arthri-
in SLE patients is higher than that in the general popula- tis 8 months ago, which was relieved with an increase in
tion [5, 6]. This collective evidence suggests that EBV con- prednisolone to 30 mg and an initiation of azathioprine; aza-
tributes to both disease flares and lymphoma complications in thioprine was switched to tacrolimus due to stomach dis-
SLE patients. Recent reports suggest an association between comfort 1 month thereafter. Two months ago, she had a
PCSNL and the use of mycophenolate mofetil (MMF) in second SLE recurrence with arthritis and received intravenous
patients with autoimmune diseases, including SLE, and in methylprednisolone at 250 mg for 3 days, followed by pred-
post-transplant patients [7–20]. Here, we report a case of nisolone 30 mg/day; tacrolimus was discontinued due to ele-
EBV-associated PCNSL developed under the use of MMF in vated serum transaminases. One month ago, just before onset
Received 3 March 2021; Accepted 5 July 2021
© Japan College of Rheumatology 2021. Published by Oxford University Press. All rights reserved.
For permissions, please e-mail: journals.permissions@oup.com2 Sakairi et al.
of the neural symptoms, she was pointed out proteinuria. At herpes simplex virus-1 and tuberculosis DNA were nega-
the time of referral, she was on prednisolone 20 mg/day and tive. Magnetic resonance imaging (MRI) demonstrated multi-
oral cyclophosphamide 50 mg/day which was started 2 weeks ple high-signal-intensity lesions on fluid-attenuated inversion
ago. recovery images [Figure 1(a,b)] and small low-signal-intensity
On admission, she complained of headache, and a phys- lesions on T2-star images, each suggestive of brain edema
ical examination revealed mild alopecia, non-fluent aphasia, and small haemorrhages. She was diagnosed as having an
and agraphia. A laboratory examination showed mild pro- SLE flare with neuropsychiatric lupus, which was classi-
teinuria of 0.5 g/g creatinine; serum CH50, C3, and C4 levels fied to diffuse manifestations/cognitive dysfunction according
were low at 17.4 U/ml (reference value, 30–46), 37 mg/dL
(reference value, 65–135), and 8 mg/dL (reference value, 13–
Downloaded from https://academic.oup.com/mrcr/advance-article/doi/10.1093/mrcr/rxab012/6348229 by guest on 15 October 2021
35), respectively; serum anti-double-stranded DNA antibody
level was high at 85 IU/ml (reference value, 0–12); serum
anti-U1-RNP antibody was positive; serum anti-Smith, anti-
SS-A/Ro, anti-SS-B/La, anti-cardiolipin immunoglobulin G
(IgG), and anti-β 2 glycoprotein I antibodies were negative.
Dry eye or dry mouth, suggesting a co-morbidity of Sjögren’s
syndrome, was absent. A cerebrospinal fluid analysis demon-
strated an elevation in a protein level of 310 mg/dl and an
interleukin-6 level of 23 pg/ml; cell counts were within the
normal range; a culture was negative for bacteria and fungi;
Figure 1. Brain MRI findings. (a, b) Fluid-attenuated inversion recovery
(FLAIR) images obtained at the onset of neuropsychiatric lupus (NPSLE).
(c, d) FLAIR images obtained during the remission phase of NPSLE. (e, f) Figure 2. Histological findings of excised brain tumour. (a)
T1-weighted images with gadolinium enhancement obtained at the time Haematoxylin–eosin staining. (b) Immunostaining for CD20. (c) In situ
of the diagnosis of central nervous system lymphoma. hybridisation staining for EBV-encoded small RNAs.Primary central nervous system lymphoma in SLE 3
to American College of Rheumatology nomenclature sys- usually observed in cases of symptomatic EBV infections such
tem [21], and nephritis. We administrated 500 mg of intra- as lymphoproliferative disorders or chronic active EBV infec-
venous cyclophosphamide (IVCY) and 500 mg of intravenous tions [23]. Serum anti-EBV virus capsid antigen (VCA) IgG
methylprednisolone for 3 days, followed by 70 mg (equiv- and anti-EBV nuclear antigen IgG were positive, and anti-EBV
alent to 1 mg/kg body weight) of oral prednisolone; her early antigen IgG and anti-EBV VCA IgM were negative; the
neural symptoms and the brain MRI findings improved serum-soluble interleukin-2 receptor level was normal.
[Figure 1(c,d)], and the proteinuria disappeared. After two MMF was discontinued, and five cycles of R-MPV ther-
more doses of monthly IVCY (800 mg/dose), MMF was ini- apy (rituximab, high-dose methotrexate, procarbazine, and
tiated at 1000 mg/day, which was gradually increased to vincristine) were administered, followed by whole-brain radi-
2000 mg/day. ation and high-dose cytarabine; complete remission was
Downloaded from https://academic.oup.com/mrcr/advance-article/doi/10.1093/mrcr/rxab012/6348229 by guest on 15 October 2021
At 13 months after the exacerbation of SLE, while receiving achieved. Her SLE has also been in remission, and she con-
maintenance therapy with prednisolone 8 mg/day, hydroxy- tinues to receive low-dose prednisolone and hydroxychloro-
chloroquine 200 mg/day, and MMF 2000 mg/day, she com- quine.
plained of headache and nausea. No other neurological
symptoms were observed. A brain MRI demonstrated a
large, low-signal-intensity tumour of approximately 50 mm in
the left frontal lobe with ring enhancement on T1-weighted Discussion
images with gadolinium enhancement [Figure 1(e,f)]. The The EBV viral load in SLE patients is higher than in con-
tumour was excised, and the pathological diagnosis was trol subjects [2]. Serological reactivation of EBV is associated
diffuse large B-cell lymphoma (DLBCL), nongerminal cen- with the occurrence of SLE in SLE relatives [3]. CD8+ cyto-
ter type, with positive CD20 immunostaining and positive toxic T-cells reacting to EBV are reduced in SLE patients,
in situ hybridisation for EBV-encoded small RNAs (EBER) possibly resulting in higher viral loads and the reactiva-
[Figure 2(a–c)]. This case was classified as ‘other iatro- tion of EBV [2]. EBV nuclear antigen2-dependent human
genic immunodeficiency-associated lymphoproliferative dis- transcriptional factors bind risk loci of SLE [4], by which
order’ according to the World Health Organization (WHO) EBV may trigger a flare of SLE. This collective evidence
classification because of the long-term use of immunosuppres- indicates the involvement of EBV in the pathogenesis of
sive agents [22]. No tumours other than the brain lesion were SLE.
identified using fluorodeoxyglucose-positron emission tomog- Previous studies have demonstrated increased risks of
raphy/CT, and a bone marrow aspirate was normal. The haematological malignancies in SLE patients, especially NHL
EBV-DNA level in the blood was 77 copy/µg peripheral blood [5]. A meta-analysis of 16 studies showed the relative risk
mononuclear cell DNA, which was much lower than the levels of NHL to be 5.4 [6]. The possible underlying mechanisms
Table 1. Clinical and pathological findings of previous 10 cases of PCNSL in SLE patient under MMF use and our case.
Organ Duration Neurological
Case manifestation of MMF symptoms by Pathology
No. Author (Ref. No.) Age, Sex of SLE use PCNSL of PCNSL EBER ISH Blood EBV
1 Finelli et al. (Ref. 42, F Nephritis 6 years Vertigo, hemi- DLBCL Positiveb NA
[9]) paresis, and
double vision
2 Dasgupta et al. 58, F Nephritis (WHO 1 year Headache and DLBCL Positive NA
(Ref. [10]) class III+V) confusion
3 Tsang et al. (Ref. 43,F Nephritis (WHO 8 years Hemiparesis DLBCL Positive NA
[11]) class IV)
4 Lai et al. (Ref. [12]) 20, F Nephritis NA Seizure NA NA NA
5 Svobodova et al. 41, F Nephritis 20 years Gait instability, DLBCL Negative NA
(Ref. [13]) nausea, and
headache
6 Tse et al. (Ref. [14]) 28, F Post-renal 11 years Hemiparesis and DLBCL Positive NA
transplantation memory loss
7 Balci et al. (Ref. 62, F Nephritis (class 2 years Headache and DLBCL Negative NA
[15]) IV) hemiparesis
8 Boddu et al.a (Ref. 57, F Nephritis (Class NA Headache, DLBCL NA NA
[16]) IIIA + V) dysarthria,
and tremor
9 Su et al. (Ref. [17]) 39, F Nephritis 1.5 years Headache and DLBCL Positive NA
nausea
10 Ichikawa et al. 34, F NPSLE, nephritis 7 years Impaired con- DLBCL Positive NA
(Ref. [18]) (class III), and sciousness and
enteritis seizures
11 Our case 42, F NPSLE and 10 months Headache DLBCL Positive Not
nephritis elevated
a
The second case of three cases.
b
EBV was identified by immunostaining for latent membrane protein 1.
NA: not available.4 Sakairi et al.
include dysregulation of the immune system, chronic inflam- Conflict of interest
mation, and EBV activation caused by immunosuppressive K.H. has received speaking fees and/or honoraria from Astel-
therapy. An association between lymphoma and the use las, Ono, and Sanofi and has received research grants from
of cyclophosphamide or high-dose corticosteroids has been Astellas, Bayer, Chugai, Kyowa-Kirin, and Ono. M.W. has
suggested in SLE patients [24]. received research grants from GlaxoSmithKline. H.H. has
A substantial number of cases have been reported in which received honoraria from Takeda, Janssen, Celgene, BMS,
PCNSL was diagnosed while a patient was receiving treat- Ono, and Sanofi; advisory fees from Takeda, and Janssen; and
ment with MMF for autoimmune diseases, including SLE research grants from Kyowa-Kirin, Takeda, Chugai, Dai-ich
[9–12, 15–17, 19, 20]. Furthermore, both the use of MMF Sankyo, MSD, and Ezai.
and the lack of calcineurin inhibitors (CNIs) are independent
Downloaded from https://academic.oup.com/mrcr/advance-article/doi/10.1093/mrcr/rxab012/6348229 by guest on 15 October 2021
risk factors for primary CNS lymphoproliferative disorder
in post-transplant subjects [7, 8]. The possible mechanisms Funding
for the protective action of CNIs include the inhibition of
None declared.
EBV lytic cycle activation [25] and the suppression of tran-
scription factor nuclear factor of activated T cells, which is
thought to be involved in the pathogenesis of DLBCL [26]. Patient consent
Although not proven, this evidence suggests that the use of
MMF in patients with SLE is associated with the occurrence Written informed consent was obtained from the patient
of PCNSL. We note that several cases have been reported in described in this case report.
which PCNSL occurred during the use of azathioprine for the
treatment of SLE [27, 28] and other autoimmune diseases
Ethical approval
[20, 29–31] and acknowledge that immunosuppressants other
than MMF (such as cyclophosphamide or azathioprine) may Not applicable.
also be involved in the development of PCNSL in our case.
Table 1 summarises 10 previously reported cases of PCNSL
found in SLE patients during MMF treatment plus our case References
[9–18]. The median age at the time of PCNSL onset was [1] Villano JL, Koshy M, Shaikh H et al. Age, gender, and racial dif-
42 years (range, 20–61 years). In our case, the duration of ferences in incidence and survival in primary CNS lymphoma. Br
MMF use was 10 months, which was shorter compared than J Cancer 2011;105:1414–8.
those in the previously reported cases (range, 1–8 years). The [2] Kang I, Quan T, Nolasco H et al. Defective control of latent
Epstein-Barr virus infection in systemic lupus erythematosus. J
histological diagnosis was DLBCL in all 10 cases in which
Immunol 2004;172:1287–94.
the histological diagnosis was described. EBV was identified [3] Jog NR, Young KA, Munroe ME et al. Association of Epstein-
in tumour specimens from seven of the nine cases in which Barr virus serological reactivation with transitioning to systemic
the presence of EBV was analysed. Ten cases had nephri- lupus erythematosus in at-risk individuals. Ann Rheum Dis
tis prior to MMF use, and the remaining one case was a 2019;78:1235–41.
post-renal transplant case. A very recent case reported by [4] Harley JB, Chen X, Pujato M et al. Transcription factors operate
Ichikawa et.al. had NPSLE [18]. Therefore, our case is the sec- across disease loci, with EBNA2 implicated in autoimmunity. Nat
ond reported case in which the CNS involvement of SLE was Genet 2018;50:699–707.
present before MMF use. The fact that SLE and lymphoma [5] Klein A, Polliack A, Gafter-Gvili A. Systemic lupus erythemato-
occurred in a common site, the brain, suggests that EBV in sus and lymphoma: incidence, pathogenesis and biology. Leuk Res
2018;75:45–9.
the brain might have been associated with both CNS involve-
[6] Scheurer M, Cao L, Tong H et al. Systemic lupus erythematous and
ment of SLE and PCNSL. Further, although not proven, it malignancy risk: a meta-analysis. PLoS One 2015;10:e0122964.
is suggested that increased permeability of blood–brain bar- [7] Crane GM, Powell H, Kostadinov R et al. Primary CNS lym-
rier and inflammation induced by pathogens could facilitate phoproliferative disease, mycophenolate and calcineurin inhibitor
the entry of B-cells into CNS, and the small numbers of B- usage. Oncotarget 2015;6:33849–66.
cells that remains after the end of immune response may [8] Velvet AJJ, Bhutani S, Papachristos S et al. A single-center expe-
later transform to lymphomas [32]. Based on this hypothe- rience of post-transplant lymphomas involving the central ner-
sis, the brain inflammation caused by SLE might have been vous system with a review of current literature. Oncotarget
involved in the development of PCNSL in our case. We note 2019;10:437–48.
that there is a case report of multiple sclerosis preceding [9] Finelli PF, Naik K, DiGiuseppe JA et al. Primary lymphoma of
CNS, mycophenolate mofetil and lupus. Lupus 2006;15:886–8.
CNS lymphoma [33]. The blood EBV level was not elevated
[10] Dasgupta N, Gelber AC, Racke F et al. Central nervous sys-
in the current case at the onset of lymphoma and was not
tem lymphoma associated with mycophenolate mofetil in lupus
described in the previous cases. Notably, the blood EBV
nephritis. Lupus 2005;14:910–3.
load is reportedly not useful for the early identification of [11] Tsang HH, Trendell-Smith NJ, Wu AK et al. Diffuse large B-
patients with PCNSL after transplantation or those with HIV cell lymphoma of the central nervous system in mycophenolate
[8, 34, 35]. mofetil-treated patients with systemic lupus erythematosus. Lupus
In conclusion, one should be aware of a possible associa- 2010;19:330–3.
tion between PCNSL and MMF use in SLE patients. The asso- [12] Lai GGY, Koo YX, Tao M et al. Use of rituximab in combination
ciation between PCNSL and a history of CNS involvement with high-dose methotrexate in the treatment of primary central
in SLE patients receiving MMF treatment requires further nervous system lymphoma in a mycophenolate mofetil treated
analysis. patient with lupus nephritis. Acta Oncol 2011;50:144–5.Primary central nervous system lymphoma in SLE 5
[13] Svobodova B, Hruskova Z, Rysava R et al. Brain diffuse large B- [24] Bernatsky S, Ramsey-Goldman R, Joseph L et al. Lymphoma risk
cell lymphoma in a systemic lupus erythematosus patient treated in systemic lupus: effects of disease activity versus treatment. Ann
with immunosuppressive agents including mycophenolate mofetil. Rheum Dis 2014;73:138–42.
Lupus 2011;20:1452–4. [25] Goldfeld AE, Liu P, Liu S et al. Cyclosporin A and FK506
[14] Tse TP, Chan AN, Chan TK et al. Post-transplantation primary block induction of the Epstein-Barr virus lytic cycle by anti-
central nervous system lymphoma in a patient with systemic lupus immunoglobulin. Virology 1995;209:225–9.
erythematosus and prolonged use of immunosuppressant. Hong [26] Pham LV, Tamayo AT, Li C et al. An epigenetic chromatin remod-
Kong Med J 2014;20:541–4. eling role for NFATc1 in transcriptional regulation of growth
[15] Balci MA, Pamuk GE, Unlu E et al. Development of primary cen- and survival genes in diffuse large B-cell lymphomas. Blood
tral nervous system lymphoma in a systemic lupus erythematosus 2010;116:3899–906.
patient after treatment with mycophenolate mofetil and review of [27] Woolf AS, Conway G. Systemic lupus erythematosus and primary
Downloaded from https://academic.oup.com/mrcr/advance-article/doi/10.1093/mrcr/rxab012/6348229 by guest on 15 October 2021
the literature. Lupus 2017;26:1224–7. cerebral lymphoma. Postgrad Med J 1987;63:569–71.
[16] Boddu P, Mohammed AS, Annem C et al. SLE and non-Hodgkin’s [28] Steckley JL, Tartaglia MC, Reddy H et al. Systemic lupus erythe-
lymphoma: a case series and review of the literature. Case Rep matosus and right leg weakness. Can J Neurol Sci 2009;36:98–
Rheumatol 2017;2017:1658473. 101.
[17] Su L, Ding ML, Chen LL et al. Primary central nervous system lym- [29] Finelli PF. Primary CNS lymphoma in myasthenic on long-term
phoma in a patient with systemic lupus erythematosus mimicking azathioprine. J Neurooncol 2005;74:91–2.
high-grade glioma a case report and review of literature. Medicine [30] Henkenberens C, Franzke A, Raab P et al. Primary EBV-positive
2018;97:e11072. Hodgkin’s lymphoma of the CNS under azathioprine treatment.
[18] Ichikawa T, Shimojima Y, Kishida D et al. Primary central nervous Strahlenther Onkol 2014;190:847–52.
system lymphoma in neuropsychiatric systemic lupus erythemato- [31] Uneda A, Hirashita K, Kanda T et al. Primary central
sus: case-based review. Rheumatol Int 2021;41:1009-17. nervous system methotrexate-associated lymphoprolifera-
[19] O’Neill BP, Vernino S, Dogan A et al. EBV-associated lymphopro- tive disorder in a patient with rheumatoid arthritis: case
liferative disorder of CNS associated with the use of mycopheno- report and review of literature. NMC Case Rep J 2020;7:
late mofetil. Neuro-Oncology 2007;9:364–9. 121–7.
[20] Kleinschmidt-DeMasters BK, Damek DM, Lillehei KO et al. [32] Deckert M, Engert A, Bruck W et al. Modern concepts in the
Epstein Barr virus-associated primary CNS lymphomas in elderly biology, diagnosis, differential diagnosis and treatment of pri-
patients on immunosuppressive medications. J Neuropathol Exp mary central nervous system lymphoma. Leukemia 2011;25:
Neurol 2008;67:1103–11. 1797–807.
[21] The American College of Rheumatology nomenclature and case [33] Yang JH, Wu SL. Multiple sclerosis preceding CNS lymphoma: a
definitions for neuropsychiatric lupus syndromes. Arthritis Rheum case report. Acta Neurol Taiwan 2007;16:92–7.
1999;42:599–608. [34] Bossolasco S, Cinque P, Ponzoni M et al. Epstein-Barr virus
[22] Swerdlow SH, Campo E, Harris NL et al. Who Classification DNA load in cerebrospinal fluid and plasma of patients with
of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: AIDS-related lymphoma. J Neurovirol 2002;8:432–8.
International Agency for Research on Cancer, 2017. [35] Shimizu H, Saitoh T, Koya H et al. Discrepancy in EBV-DNA load
[23] Kimura H, Morita M, Yabuta Y et al. Quantitative analysis of between peripheral blood and cerebrospinal fluid in a patient with
Epstein-Barr virus load by using a real-time PCR assay. J Clin isolated CNS post-transplant lymphoproliferative disorder. Int J
Microbiol 1999;37:132–6. Hematol 2011;94:495–8.You can also read
