926883

review-article2020
JSO0010.1177/2397198320926883Journal of Scleroderma and Related DisordersSimopoulou et al.

JSRD Journal of
Scleroderma and
Related
Case Report Disorders

Journal of Scleroderma and

Progressive multifocal
Related Disorders
2020, Vol. 5(3) NP1­–NP6
© The Author(s) 2020
leukoencephalopathy in a patient Article reuse guidelines:
sagepub.com/journals-permissions

with systemic sclerosis treated https://doi.org/10.1177/2397198320926883

DOI: 10.1177/2397198320926883
journals.sagepub.com/home/jso

with methotrexate: A case report

and literature review

Theodora Simopoulou1 , Vana Tsimourtou2, Christina Katsiari1,

Marianna Vlychou3, Dimitrios P Bogdanos1 and Lazaros I Sakkas1

Abstract
Reactivation of viruses occurs in autoimmune disorders in the setting of certain immunosuppressive drugs. We describe
a 54-year-old female with systemic sclerosis and extensive cutaneous calcinosis who had been treated with methotrexate
for 18 months and presented with headache and neurological deficits. She was diagnosed with progressive multifocal
leukoencephalopathy, a rare disease caused by JC virus. Methotrexate was discontinued and mirtazapine plus mefloquine
were added. The patient showed a slow recovery and five years later she had complete resolution of progressive
multifocal leukoencephalopathy clinical manifestations. Calcinosis had a limited response to various agents and severely
affected daily activities of the patient. This case report, highlights the importance of clinical suspicion for progressive
multifocal leukoencephalopathy in every patient with immune-mediated disease, even on weak immunosuppressant,
who presents with central nervous system manifestations and also the unmet therapeutic need for systemic sclerosis-
associated calcinosis.

Keywords
Progressive multifocal leukoencephalopathy, JC virus, methotrexate, systemic sclerosis, calcinosis

Date received: 19 February 2020; accepted: 14 April 2020

Introduction to effectively prevent viral reactivation.2 In the 1980s and

Reactivation of viruses is a well-recognized adverse
effect of biologicals used for the treatment of immune-
mediated diseases. Reactivation of viruses after conven-
tional synthetic disease-modifying antirheumatic drugs
(csDMARDs) is not well recognized. Reactivation of JC
polyomavirus (JCV), a ubiquitous small DNA virus,
occurs in the central nervous system (CNS) almost exclu-
sively in immunocompromised patients and causes pro-
gressive multifocal leukoencephalopathy (PML), a rare
demyelinating disease. Suppression of cell-mediated
immunity, associated either with diseases, such as human
immunodeficiency virus (HIV) disease and lymphopro-
liferative malignancies, or with immunomodulatory/
immunosuppressive therapeutic agents is believed to be
the sine qua non of PML.1 Both T- and B cells are required
1990s, the majority of PML cases occurred in HIV-
positive patients, representing the most common oppor-
tunistic infection in this group. HIV-negative patients
1
 epartment of Rheumatology and Clinical Immunology, Faculty of
D
Medicine, School of Health Sciences, University of Thessaly, Larissa,
Greece
2
Department of Neurology, Faculty of Medicine, School of Health
Sciences, University of Thessaly, Larissa, Greece
3
Department of Radiology, Faculty of Medicine, School of Health
Sciences, University of Thessaly, Larissa, Greece
Corresponding author:
Lazaros I Sakkas, Department of Rheumatology and Clinical
Immunology, Faculty of Medicine, School of Health Sciences, University
of Thessaly, Biopolis, 41 110 Larissa, Greece.
Email: lsakkas@med.uth.gr
NP2 Journal of Scleroderma and Related Disorders 5(3)
with PML almost exclusively occurred in patients treated
with biologic agents/monoclonal antibodies for malig-
nancies or autoimmune diseases that deplete lympho-
cytes or impede leukocyte trafficking into the CNS.3 Of
all rheumatic diseases, systemic lupus erythematosus
(SLE) has the highest relative risk for PML, partly drug-
related, but also linked to the disease itself.4 As there are
no characteristic neurological symptoms or signs, it may
be difficult to distinguish PML from neuroinflammatory
conditions, such as multiple sclerosis (MS), neuropsychi-
atric SLE and CNS vasculitis; thus, a high suspicion
index is required.
Herein, we report a woman with systemic sclerosis
(SSc) and extensive cutaneous calcinosis, who was
treated with methotrexate (MTX) and then was diag-
nosed with PML that gradually resolved. To our knowl-
edge, this case is the second report of PML in SSc and
one of few PML in MTX-treated patients with autoim-
mune rheumatic diseases.
Clinical case
A 49-year-old Caucasian woman, with no previous medi-
cal history, was diagnosed with SSc in 2014. She was first
admitted to our Rheumatology and Clinical Immunology
Clinic with skin infection after surgical removal of a hard,
subcutaneous nodule at the suprapatellar area of her right
knee.
She reported Raynaud’s for at least 5 years and gastroe-
sophageal reflux symptoms. Physical examination was
remarkable for sclerodactyly and reduced grip strength.
She had no digital ulcers or pits, or telangiectasias.
Antinuclear antibodies were positive at 1:160 titer (refer-
ence ⩽ 1:80) with speckled pattern, with no Topoisomerase
I, centromere, or RNA polymerase III specificity.
Pulmonary function tests and echocardiography were nor-
mal. The patient was initially treated with antibiotics, and
then she received MTX (15 mg/week) and diltiazem.
Within few months, a significant worsening of calcinosis
was noted and at the 12-month follow-up visit, she had
calcinosis over the patella, the buttocks and at the left
axilla. The patient complained of recurrent episodes of
acute pain and skin redness over calcinosis, sometimes
accompanied with fever. These local inflammatory epi-
sodes resulted in an excretion of sterile chalk-like liquid,
but, at times with secondary infection. These episodes
were managed with colchicine and low-dose steroids
(5 mg/day), whereas the infectious episodes were managed
with antibiotics. At the 18-month follow-up visit, the
patient presented with a subacute condition involving low-
grade fever, headache, blurred speech, clumsiness and
speech difficulties, mental and behavioral deficits. A neu-
rologic examination revealed the presence of left
Babinski’s sign, gait ataxia, dysphasia, ideokinetic apraxia,
apathy and short memory deficit.
Figure 1.  Brain MRI—Axial T2-weighted fluid-attenuated
inversion recovery (FLAIR) image showing high-signal intensity
lesions in the white matter, mainly of the right hemisphere.
MRI of the brain revealed patchy high-signal lesions on
T2-weighted images in the right frontal lobe, without gado-
linium enhancement and without diffusion restriction
(Figure 1). Full blood count showed total lymphocyte count
780/μL, with no anemia or thrombocytopenia. Her lympho-
cyte count two months before admission was 1.200/μL.
Biochemistry tests were unremarkable. IgG and IgA levels
were within normal limits (1040 mg/dL and 149 mg/dL
respectively), while IgM was reduced (45 mg/dL, reference,
64–249 mg/dL). Serum C-reactive protein was slightly ele-
vated at 3 mg/dL (upper limit of normal, 0.7). Serology was
negative for herpes simplex virus, cytomegalovirus,
Epstein–Barr virus, varicella-zoster virus, toxoplasmosis,
rubella, HIV and syphilis. CSF revealed 2 cells/mm3, and
normal levels of protein, glucose and lactate dehydrogenase
(LDH). CSF Gram stain and culture were negative, whereas
CSF PCR was positive for JCV (326 copies/mL; refer-
ence < 50 copies/mL).
PML diagnosis was based on the compatible MRI brain
findings and positive PCR for JCV in the CSF. MTX was
discontinued and mirtazapine (30  mg/day) was added
along with mefloquine at a dose of 250 mg/day for three
days and then once a week.
The patient showed gradual improvement of her CNS
clinical manifestations. Four months later, MRI findings
were nearly unchanged, while PCR for JCV was positive
but with a lower viral burden (114 copies/mL). Her CNS
status slowly improved. On Addenbrooks ACE-R cogni-
tive examination, performed one year after PML diagno-
sis, the patient achieved a high score of 96/100, and lost
only four points from the fluency domain. Addenbrooks
ACE-R cognitive examination contains five subscores,
Simopoulou et al. NP3
Figure 2.  Radiographs of the right arm (a), right hand (b), pelvis (c) and knees (d) showing extensive calcifications.
each one representing a cognitive domain: attention/orien-
tation (max score 18), memory (max score 26), fluency
(max score 14), language (max score 26), visuospatial
(max score 16), adding up to a maximum score of 100.
Higher scores indicate better cognitive functioning.5
Presently, five years after the PML diagnosis, the patient
has fully recovered and is back to her work as a school
teacher.
Of note, multiple therapeutic agents were used for her
cutaneous calcinosis with limited success. These included
colchicine, warfarin, bisphosphonates, high-dose diltiazem.
At present, the patient has multiple calcified masses, affect-
ing her buttocks, knees, soles, right hand, arms and shoul-
ders (Figure 2(a)–(d)). Calcified masses cause significant
pain, and recurrent episodes of local inflammation resulting
in ulcerations with excretion of sterile chalk-like material
and occasional infection. The extensive cutaneous calcifica-
tion also causes functional limitation affecting daily activi-
ties, psychological distress and impaired quality of life.
Discussion
PML is a rare demyelinating disease of the CNS with an
incidence of < 0.3 cases per 100,000 person years,6 caused
by the reactivation of the JCV.
It has been estimated that 1%–2% of the population
becomes infected each year, while antibodies against the
virus are detected in 30%–70% of the general population.1,7
It is proposed that the virus enters the brain during the pri-
mary infection and is kept under control by T cells or per-
sists inside lymphocytes or other cells and via these cells
gets access to the brain.8 B cells also play a significant role
acting as vectors or viral reservoirs.9 In addition, plasma-
cytes affect T-cell inflammatory activity via immune check-
point pathways.10 The most significant high-risk groups for
PML are patients with HIV, hematologic malignancies and
those receiving immunomodulatory/immunosuppressive
treatments for MS and other autoimmune diseases.8 Among
primary immunodeficiency disorders, idiopathic
CD4+ T-cell cytopenia is the most common disorder asso-
ciated with PML.11
The monoclonal antibodies efalizumab and natali-
zumab that target cell adhesion molecules, and rituximab
that targets B cells have most commonly been associated
with PML. Efalizumab, a humanized monoclonal antibody
against the human CD11a subunit of the lymphocyte func-
tion-associated antigen 1 (LFA-1), used to treat severe
plaque psoriasis, has been withdrawn from the market due
to its high incidence of PML (1/500 cases).12 Natalizumab,
used for the relapsing form of MS, is also associated with
NP4 Journal of Scleroderma and Related Disorders 5(3)
PML. Natalizumab is a monoclonal antibody that binds to
the α4 subunit of the α4β1 integrin on lymphocytes, block-
ing their attachment to the endothelium. The risk of PML
development during natalizumab treatment is very high
(3.85/1000 patients).3 Rituximab (RTX), a chimeric mono-
clonal antibody against CD20, causing depletion of B cells
and it is widely used in hematology and rheumatology. The
incidence of PML in RTX-treated patients is estimated to
be one case per 32,00013 and it is higher in SLE (1/4000
cases) compared to rheumatoid arthritis (RA; 1/25,000
cases).14 It has been hypothesized that depletion of mature
B cells results in expansion of pre-B-cells harboring latent
JCV that can carry the virus across the blood–brain barrier
and infect oligodendrocytes.2 Other drugs commonly used
in rheumatic disease have been reported in patients with
PML including csDMARDs.15 Using measures of dispro-
portionality to analyze possible associations of immuno-
suppressants with PML, Schmedt et al.16 examined the
spontaneous reports of the US Adverse Event Reporting
System reported between 1 January 2004 and 30 September
2010. Twenty one out of 36 immunosuppressants were
reported with PML. Although a signal was found for efali-
zumab, natalizumab, rituximab, azathioprine, cyclo-
sporine, cyclophosphamide (CyP), MMF, leflunomide,
MTX, tacrolimus and sirolimus in the univariate analysis,
the signal disappeared for MTX, leflunomide and siroli-
mus in the multivariate analysis.16 This emphasizes the
importance of co-medications in the development of PML.
Since then, few case reports of RA patients treated with
MTX and prednisone or infliximab appeared.17–20 In a
recent systematic literature review of SLE patients pre-
senting with PML, 66% of patients were exposed to immu-
nosuppressants, with CyP being the most commonly
reported, while only one patient was on MTX monother-
apy.21 In our department, we had one patient with polymy-
ositis who was on MTX and developed PML with adverse
outcome (unpublished observation). There has been an
attempt to categorize immunosuppressants into risk
classes.22 Class 1 with the highest risk includes efalizumab
and natalizumab. Class 2 includes rituximab, belimumab,
CyP, MMF and azathioprine; and class 3 includes TNFα
blockers.22
Among rheumatic disease-associated PML, SLE
accounts for approximately two-thirds of the PML cases,
and may be an independent risk factor for PML irrespec-
tive of the degree of lymphopenia or the intensity of
immunosuppression.4,22–24 SSc does not appear to be a
risk factor for PML. Molloy and Calabrese reviewed 46
cases of PML among patients with rheumatic diseases (30
with SLE, 6 with myositis, 4 with granulomatosis with
polyangiitis, and the others with RA and Sjogren’s syn-
drome). There was only one SSc patient who also had
amyloidosis.23 A recent meta-analysis of 326 cases of
drug-associated PML identified 78 cases with autoim-
mune diseases and none with SSc.25
PML, affects oligodendrocytes and astrocytes of the
white matter, with a noninflammatory lytic infection lead-
ing to demyelination.8 However, recent studies have iden-
tified JCV-infected glial cells located at the gray–white
matter junction or within the gray matter, causing demyeli-
nation. Neurons can be affected in various areas of the
CNS.26–29
Clinical manifestations of PML depend on the affected
brain area and include subacute, diffuse and focal neuro-
logical deficits that are generally progressive. Motor defi-
cits, limb and gait ataxia, speech problems, and visual
symptoms, diplopia and hemianopia and behavioral and
cognitive deficits are within the most common manifesta-
tions.1 Seizures have also been reported. At the onset of
symptoms, PML may pose difficulties in distinguishing it
from neurological manifestations of SLE.4
Diagnosis of PML is based on neurological features,
MRI findings and the detection of JCV in the CSF.
Definitive diagnosis of PML requires histopathologic
demonstration of the typical triad, demyelination, bizarre
astrocytes and enlarged oligodendroglial nuclei, along
with the presence of JCV.1,30 However, the need of brain
biopsy has been questioned in the context of compatible
clinical manifestations, MRI imaging findings features
and JCV detection.30,31 CSF analysis, showing a small
increase in cell count (< 20 cells/µL),30 is required for JCV
detection by PCR (sensitivity 70%–80%, specificity
approaching 100%)32 as well as for the exclusion of other
alternative diagnoses. Brain MRI findings include bilat-
eral, asymmetric, predominantly subcortical lesions that
are hyperintense on T2-weighted images and FLAIR, and
hypointense on T1-weighted images, devoid of mass
effect.1,30,33 Enhancement of lesions following gadolinium
administration is rarely seen but its presence has been
associated with more favorable prognosis.34
To date, there is no effective therapy for PML nor specific
prophylactic treatment. The therapeutic strategy relies on
reversal of the immunosuppressive state, including discon-
tinuation of the associated drug. Case reports have described
efficacy of mirtazapine, a noradrenergic and specific sero-
tonergic antidepressant, which prevents the attachment of
JCV to the serotonin receptors in glial cells in vitro and
mefloquine, an antimalarial drug, which diminishes JCV
replication within infected cells.35,36 In natalizumab-associ-
ated PML, plasma exchange may be used to remove the
drug.37 In HIV patients treated with HAART and in patients
who discontinue natalizumab as a result of PML develop-
ment, there may be an exacerbation of symptoms with severe
neuroinflammation as part of immune reconstitution inflam-
matory syndrome (IRIS).1,2 Reconstitution of immune cells
leads to a massive infiltration of the lesions by inflammatory
T lymphocytes with subsequent worsening of the symp-
toms,2 which on MRI exhibit contrast enhancement.38–40
Treatment with high-dose steroids briefly for these patients
is beneficial.1,37 In patients with hematologic malignancies,
Simopoulou et al. NP5
pembrolizumab and nivolumab that block programmed cell
death 1 (PD1) has emerged as promising agents for PML.41–42
Our patient had a favorable outcome regarding PML, which
is infrequently reported in the literature.1,15
Cutaneous calcinosis in our patient deserves few com-
ments. Cutaneous calcinosis in SSc, although not attract-
ing much attention, can be very disturbing. In our patient it
was very extensive affecting all activities of everyday life,
and adversely affecting quality of life. It frequently caused
frequent local inflammatory episodes and at times second-
ary infection. Many agents have been tried in calcinosis
with limited success.43 In short, cutaneous calcinosis in
SSc is an unmet therapeutic need.
In conclusion, our case suggests that physicians should
have a high index of suspicion for PML in patients with
immune-mediated diseases, even on weak immunosup-
pression, if they develop unexplained progressive neuro-
logical symptoms/signs. Early detection and withdrawal
of immunosuppressive drugs provide the main therapeu-
tic approach that can improve outcome. This is particu-
larly important, considering that patients may be
misdiagnosed for a flare or neuroinflammatory manifes-
tation of underlying disease, and be at a risk of intensi-
fied immunosuppression.
Acknowledgements
We thank Dr. Efthymios Dardiotis for critical reading of the
manuscript
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
Informed consent
Informed consent was obtained from the patient who participated
in this article.
ORCID iD
Theodora Simopoulou https://orcid.org/0000-0003-2604-5090
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