Keywords
neuromyelitis optica - tocilizumab - pediatric - AQP4 - interleukin-6 - plasmablasts
Introduction
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease of the
central nervous system that predominately affects the optic nerves and spinal cord.
Serum antibodies against the astrocytic aquaporin-4 antigen (AQP4-abs) are considered
important factors of pathogenesis. Acute treatment of relapses includes high-dose
intravenous methylprednisolone (IVMP), IV immunoglobulins (IVIG), and plasma exchange.
For long-term immunotherapy and relapse prophylaxis oral corticosteroids and immunosuppressive
drugs, such as azathioprine or mycophenolate mofetil have been proposed, yet, B cell
depletion with the chimeric anti-CD20-antibody rituximab is widely considered treatment
of choice. However, up to 30% of patients suffer from clinical relapses in spite of
complete B cell depletion as measured by flow cytometric analysis.[1]
[2]
[3] For those patients the treatment with the interleukin-(IL)-6-receptor blocking antibody
tocilizumab has been proposed as a viable alternative.[4] We report two female adolescents who were treated with tocilizumab after relapsing
under B cell depletion.
Case 1
A previously healthy 17-year-old girl presented with hypesthesia of both hands, proprioception
deficits in both legs, and urinary retention. Spinal magnetic resonance imaging (MRI)
showed longitudinally extensive transverse myelitis (LETM) from C1 to the conus; cranial
MRI revealed no abnormalities ([Fig. 1]). Cerebrospinal fluid (CSF) studies showed a mild pleocytosis with slightly increased
protein, decreased glucose, and negative oligoclonal bands. Symptoms remitted under
treatment with IVMP (30 mg/day for 5 days), acyclovir, and ceftriaxone. After 3 months
the patient presented with a relapse of urinary retention, this time hypesthesia extended
to multiple areas of the pelvis, soles, face, and inner thighs. In addition, significant
fatigue, bilateral vision field deficits, and pain on movement of both eyes (right
[R] > left [L]) was reported (expanded disability status scale [EDSS] 4.0). MRI showed
multiple new lesions in centrum semiovale and multiple new spinal lesions ([Fig. 1]) as well as optic nerve enlargement, T2 hyperintensity, and contrast enhancement
([Fig. 2]). Antibody testing revealed AQP4-abs in serum (1:20,480). The patient was successfully
treated with IVMP, IVIG, plasma exchange (PLEX, 10x) and oral prednisolone tapering.
Subsequently, therapy with rituximab (375 mg/m2 body surface are [BSA], 2 weeks interval) was initiated. Three months later the patient
presented with relapse of vision field deficits on the left side without changes in
visual acuity while under complete B cell depletion as measured by flow cytometric
analysis. The patient was treated with IVMP, IVIG, and PLEX (7x). Long-term therapy
with tocilizumab (8 mg/kg, monthly) was started, which led to clinical stabilization.
Optical coherence tomography (OCT) revealed atrophy of both optic nerves 4 months
later (L > R).
Fig. 1 MRI at onset, relapse, and follow-up in two pediatric NMOSD patients treated with
tocilizumab after relapse. Sagittal spinal T2 images of case 1 (A, B, C) showing resolution of LETM until follow-up. Axial cranial T2 images of case 1 (D, E) showing resolution of a T2-hyperintense lesion in the left centrum semiovale. Sagittal
spinal T2 images of case 2 (F, G, H) showing increase of LETM at relapse and subsequent resolution until follow-up. LETM,
longitudinally extensive transverse myelitis; MRI, magnetic resonance imaging; NMOSD,
neuromyelitis optica spectrum disorder.
Fig. 2 MRI at onset, relapse, and follow-up. Coronal T1 images of case 1 (A, B) showing resolution of contrast enhancing lesion in the left optic nerve. Axial spinal
T2 images of case 2 (C, D, E) showing increase of LETM at relapse and subsequent resolution until follow-up. LETM,
longitudinally extensive transverse myelitis; MRI, magnetic resonance imaging.
Despite the absence of clinical signs of an acute attack of optic neuritis (no ocular
pain, no acute/subacute onset), the patient reported a slowly progressive decrease
of visual acuity during the second year of treatment. Twenty-four months after initiation
of tocilizumab a decrease in visual acuity from 1.0 to 0.6 was noted in the left eye;
however, atrophy measured by OCT had remained stable. Follow-up MRI revealed atrophy
of both optic nerves ([Fig. 2]) and residual subcortical lesions; however, no new intracranial or intraspinal lesions
were found ([Fig. 1]). At the latest clinical follow-up, the patient had remained relapse-free for 36
months after initiation of tocilizumab (EDSS 2.0). PLEX had led to a significant decrease
of AQP4-ab titers (1:320, before initiation of tocilizumab) with subsequent gradual
increase over the following months (1:5,120, 12 months after initiation of tocilizumab).
Case 2
A previously healthy 17-year-old girl presented with acute onset of paresthesia of
both legs that increased with exercise. Three days later she described an additional
severe pruritus on the back. Initial MRI showed LETM, but no intracranial abnormalities
([Fig. 1]). CSF analysis revealed a mild pleocytosis with negative oligoclonal bands. In serum,
AQP4-abs (1:10,240) were detected using live cell-based assays. Treatment with IVMP
(30 mg/kg; 3 days) was initiated which led to resolution of pruritus and paresthesia.
In the following days, the patient started suffering from anesthesia of the abdomen
and the front of both thighs that resolved without treatment within 3 weeks. One month
later the patient relapsed with paresthesia of chest and both legs as well as cramps
of the right leg that increased on movement (EDSS 2.0). No visual deficits were noted.
Treatment with IVMP, PLEX (8x), oral prednisolone tapering, and rituximab (375 mg/m2 BSA, 4 weeks interval) was started which led to improvement of symptoms. One month
later the patient relapsed with paresthesia and pruritus of the left chest and shoulder
while under complete B cell depletion as measured by flow cytometric methods. Spinal
MRI showed significant disease progression with multiple new intramedullary lesions
([Figs. 1] and [2]). After additional PLEX (4x), therapy with tocilizumab (8 mg/kg, monthly) was started
which led to clinical stabilization. Follow-up MRI revealed residual signal changes,
but no new lesions ([Figs. 1] and [2]). At the latest clinical follow-up, the patient had remained relapse-free for 18
months after initiation of tocilizumab (EDSS 1.0). The AQP4-ab titers had not changed
significantly.
Discussion
We report two female adolescents with AQP4-abs positive NMOSD who clinically stabilized
after switching treatment from rituximab to monthly administrations of tocilizumab.
Despite the efficacy of rituximab, up to 30% of patients suffer from clinical relapses
in spite of complete B cell depletion.[1]
[2]
[3] Pathophysiologically, CD20-depletion resistant plasmablasts have been proposed as
origin of AQP4-abs in rituximab therapy resistant cases. Chihara et al identified
CD19intCD27highCD38highCD18− plasmablasts in NMOSD that secrete AQP4-abs in an IL-6 dependent manner.[5] In addition, they reported increased levels of IL-6 in NMOSD relapses. Therefore,
targeted therapy with the IL-6-blocking antibody tocilizumab has been suggested as
an alternative to standard treatment.[5]
The escalation of therapy in case of rituximab therapy refractory NMOSD is a matter
of debate. Our two patients were switched to tocilizumab 1 and 3 months, respectively,
after initiation of rituximab treatment and confirmed B cell depletion. Some authors
have described a time lag between B-cell depletion and clinical stabilization of NMOSD
patients treated with rituximab. In such cases, a bridging therapy with, for example,
low-dose corticosteroids has been proposed.[6] Another option would be to switch to one of the widely used steroid-sparing drugs
mycophenolate mofetil or azathioprine. A multicenter study comparing treatment efficacy
of rituximab, azathioprine, and mycophenolate mofetil in NMOSD showed the highest
reduction of relapse rate in patients treated with rituximab.[7] In case of treatment failure switching to either azathioprine or mycophenolate mofetil
led to a significant reduction in relapse rate.[7] Mycophenolate mofetil and azathioprine are known to show a delay in clinical efficacy
of several months. Due to the high clinical and paraclinical disease activity in both
patients, the risk of further disabling relapses was considered high. Therefore, we
decided to switch to tozilizumab.
Clinical data on tocilizumab treatment in NMOSD is sparse and has only been reported
in adults in small case series and case reports. A current clinical trial (NCT02028884),
including patients from 12 years of age aims at evaluating the efficacy and safety
of satralizumab (SA237), another IL-6-blocking antibody, as add-on in the treatment
of NMOSD. In terms of pediatric populations, only a single case of a 14-year-old male
patient suffering from Sjögren's syndrome and NMOSD has been reported who became relapse-free
after switching to tocilizumab.[8]
While previous reports in adults have shown mild recurrence in some patients, no relapses
were seen in our two cases. This might be due to adaptation of administration frequency
and dosing to recommendations published in a recent report[9] (4 weekly infusions and 8 mg/kg, respectively). However, one of our patients showed
slowly progressive decrease in visual acuity during treatment without clinical signs
of acute attack or further deterioration of OCT. In terms of safety, no severe adverse
effects or increased frequency of infections have been noted in our patients.
We conclude that early switching to tocilizumab might pose a viable treatment option
in B cell-depletion resistant pediatric NMOSD. Larger studies are necessary to reliably
evaluate efficacy and safety and define the patient groups who will profit most from
this treatment.
