A novel use and dramatic efficacy of ofatumumab for the treatment of anti-N-methyl-D-aspartate receptor encephalitis: a report of two cases

Abstract

Ofatumumab (OFA), a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B-cells. The purpose of this study was to report the therapeutic effect and safety of OFA in two refractory anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis cases which were nonresponsive to first-line immunotherapies. Two severely affected anti-NMDAR encephalitis patients (mRS score: 5) with resistance to standard immunotherapies (corticosteroids, IV immunoglobulins) were treated with OFA (3 subcutaneous injections of 20 mg on days 1, 7, 14). The patients’ guardians declined plasma exchange (PE) and RTX. The clinical outcome of the patients was followed up for 6 months after the administration of OFA. Treatment with OFA led to rapid clinical improvement accompanied by the enhancement of neuropsychiatric function, disappearance of brain MRI lesions, and decline in partial NMDAR antibody titer. The CD20-positive B-cells were completely depleted in both patients. Moreover, the therapy was well tolerated with no adverse effects. The patients were discharged without clinical deficits and with significantly improved cognition. OFA appeared to be highly effective in the two presented cases despite the limited first-line therapy without PE, which suggests good potential for the application of OFA in this field. However, the lingering effects of previously administered corticosteroids and IV immunoglobulins cannot be excluded.

Keywords

anti-NMDAR encephalitis ofatumumab

Introduction

Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder involving the production of antibodies against NMDARs in the central nervous system which leads to neurological or psychiatric dysfunction.¹ B lymphocytes play important roles in the pathogenesis of this disease.² Intensive treatments with plasma exchange (PE) and subsequent anti-CD20 therapy are usually needed for refractory cases. Rituximab (RTX), a B lymphocyte–depleting monoclonal antibody directed against CD20, was shown to be effective in anti-NMDAR encephalitis.³ However, the intravenous use of B lymphocyte–depleting agents can be limited by infusion-related adverse events and/or inefficacy.⁴

Ofatumumab (OFA) is the first fully human anti-CD20 antibody with a lower risk of anti-drug antibody production and a decreased risk of infection.⁵ It can bind to a region distinct from that of other anti-CD20 antibodies, including the smaller and larger loops of CD20 receptors.⁶ This results in a high binding affinity and slow off-rate between OFA and the CD20 receptor in B-cells. These features allow for efficient B-cell lysis mediated by antibody-dependent and complement-dependent cytotoxicity.⁷ OFA can be self-administered subcutaneously by the patient himself after initial doses are given under medical supervision.⁸ Experimental models have also shown that subcutaneous administration of OFA may have more direct access to lymph nodes through the lymphatic system than intravenous infusion of other anti-CD20 antibodies.⁹ Therefore, despite potential pathophysiological differences between intravenous and subcutaneous injection methods as well as potentially incomplete B-cell depletion, subcutaneous administration is at least as effective as intravenous administration. OFA was recently approved for the treatment of relapsing remitting multiple sclerosis in China and has shown efficacy in treating aquaporin 4-IgG neuromyelitis optica.^8,10 However, there are no reports of its use in the field of anti-NMDAR encephalitis.

Two severe anti-NMDAR encephalitis patients with a modified Rankin scale (mRS) score of 5 and a Clinical Assessment Scale in Autoimmune Encephalitis score of more than 20 failed to respond to first-line immunotherapies. The patient’s guardians refused to use PE or second-line immunotherapies such as RTX and cyclophosphamide due to fear of the invasive procedure and the potential for adverse effects. After considering the risks and benefits of providing off-label OFA treatment, the two refractory NMDAR encephalitis patients received directly anti-CD20 with OFA. Herein, we report the use of OFA in anti-NMDAR encephalitis for the first time.

Report of cases

Written consent was provided before OFA treatment by the mother of the first patient and the wife of the second patient since the two patients had significant cognitive deficits and psychosis. Written informed consents were obtained from the patients for publication of medical data and images. The Sichuan University Review Board of the West China Hospital waived the need for ethics approval.

Case 1

A patient in her mid-20s was admitted with acute seizure, agitation, hallucination, and disturbance of consciousness. She denied any relevant family history. Neurological examination revealed significant memory loss, disorientation, inattention, disorganization, and fluctuating mental status consistent with delirium with no obvious motor deficits. Laboratory examinations further excluded differential diagnosis induced by central nervous system infectious diseases (Table 1). Chest radiograph and brain magnetic resonance imaging (MRI) revealed no abnormalities. Abdominal enhanced computed tomography (CT), abdominal color Doppler ultrasound, and endovaginal color Doppler were used to exclude teratoma. The cerebrospinal fluid protein and glucose levels, the results of cytologic tests, and the IgG index were normal. However, NMDAR IgG antibodies were detected in the serum (1:320) and cerebrospinal fluid (1:32) by using a cell-based assay (CBA), leading to the diagnosis of anti-NMDAR encephalitis. The tests for other onconeuronal or neuronal cell surface antibodies were negative using the CBA and dot immunobinding assay (Table 1).

Table 1.

Auxiliary examinations in the two patients.

Items	Case 1		Case 2
	Acute phase	Recovery phase	Acute phase	Recovery phase
	(CSF/serum)	(CSF/serum)	(CSF/serum)	(CSF/serum)
^aAnti-NMDAR	1:320/1:32	1:100/1:10	1:10/-	Normal
^bOther neuronal cell surface antibodies	Normal	Normal	Normal	Normal
^cOnconeuronal antibodies	Normal	Normal	Normal	Normal
Oligoclonal bands	Normal	Normal	Normal	Normal
^dDemyelinating antibody	Normal	Normal	Normal	Normal
Cerebrospinal fluid biochemical test
WBC number (×10⁶/L)	4	0	18	10
Glucose	Normal	Normal	Normal	Normal
Protein	Normal	Normal	Normal	Normal
Microbiological analyses	Normal	Normal	Normal	Normal
Hematologic test results
WBC (normal range < 9.5 × 109/L)	13.76 × 10⁹/L	8.17 × 10⁹/L	10.94 × 10⁹/L	7.95 × 10⁹/L
NEUT% (normal range < 75%)	84.5%	72.6%	76.1%	70.3%
LYMPH% (20% < normal range < 50%)	7.3%	12.4%	8.6%	14.8%
MONO% (3% < normal range < 10%)	3.2%	4.7%	3.6%	5.4%
EO% (0.4% < normal range < 8.0%)	6.74%	6.80%	4.33%	4.93%
BASO% (0 < normal range < 1%)	0.91%	0.73%	0.74%	0.63%
ESR (normal range < 21 mm/h)	34 mm/h	12 mm/h	26 mm/h	9 mm/h
CRP (normal range < 5 mg/L)	20 mg/L	4.2 mg/L	3.1 mg/L	1.8 mg/L
IL-6 (normal range < 7 pg/mL)	6.4 pg/mL	0.9 pg/mL	5.4 pg/mL	3.3 pg/mL
PCT (normal range < 0.046 ng/mL)	0.05 ng/mL	0.01 ng/mL	0.02 ng/mL	0.02 ng/mL
^eInfection tests	Normal	Normal	Normal	Normal
^fImmunological test results (serum)	Normal	Normal	Normal	Normal
^gThyroid profile (serum)	Normal	Normal	Normal	Normal
Abdominal enhanced CT	Normal	Normal	Normal	Normal
Abdominal color doppler ultrasound	Normal	Normal	Normal	Normal
Endovaginal color doppler	Normal	Normal	–	–
Brain MRI	Normal	Normal	Abnormal	Abnormal
Cervical MRI	Normal	Normal	Normal	Normal
Thoracal MRI	Normal	Normal	Normal	Normal

CT, computerized tomography; NMDAR, N-methyl-D-aspartate receptor; MRI, magnetic resonance imaging; WBC, white blood cells; CSF, cerebrospinal fluid; NEUT, neutrophils; LYMPH, lymphocyte; MONO, monocyte; EO, eosinophil; BASO, basophil; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; IL-6, interleukin-6; PCT, procalcitonin.

Other neuronal cell surface antibodies including: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antibody; leucine-rich glioma-inactivated protein 1 antibody; contactin-associated protein-like 2 antibody; gamma-aminobutyric acid-B receptor antibody; dipeptidyl-peptidase-like protein-6 antibody; glycine antibody; gamma-aminobutyric acid-A receptor antibody; metabotropic glutamate receptor 5 antibody; anti-Glutamic acid decarboxylase antibody.

Onconeuronal antibodies including: anti-neuronal nuclear antibodies type 1 antibody; anti-cytoplasmic purkinje cell antibodies antibody; anti-neuronal nuclear antibodies type 2 antibody.

Demyelinating antibody including: aquaporin 4-IgG; aquaporin 1-IgG; myelin oligodendrocyte glycoprotein antibody; anti-glial fibrillary acidic protein antibody; MBP antibody; Flotillin-1/2-IgG.

Infection tests including: novel coronavirus (nasopharyngeal swabs and serum), treponema pallidum (serum), herpes simplex virus 1/2 (secretions), human immunodeficiency virus (serum), mycobacteria (cerebrospinal fluid), Epstein–Barr virus (cerebrospinal fluid) anti-streptolysin O.

anti-nuclear antibody, anti-SS-A and SS-B, anti-dsDNA, anti-Smith antibodies, rheumatoid factor, anti-Jo-1, anti-Ro-52, anti-Scl-70. double-stranded deoxyribonucleic acid = dsDNA; Anti-SS-A(Ro) and anti-SS-B(La) autoantibodies = Anti-SS-A and SS-B; anti-aminoacyl tRNA synthetase antibodies = anti-Jo-1.

Triiodothyronine thyroxine, free thyroxine, free triiodothyronine, thyroid-stimulating hormone, thyroid globulin antibody, and thyroid peroxidase antibody.

The patient received intravenous methylprednisolone sodium succinate equivalent to 1000 mg/d methylprednisolone and 0.4 mg/kg/d intravenous immunoglobulin for 5 days. Then, mycophenolate mofetil (MMF) was administered at a dose of 1 g/day; this was later switched to daily prednisone, starting with 1 mg/kg body weight during the first 2 weeks and tapering to zero. After 1 month of follow-up, no clinical improvements had occurred, and the patient’s condition continued to deteriorate with increased symptoms of severe agitation and disturbance of consciousness (Figure 1(A); Supplemental Video S1; somnolence and agitation). After being fully informed about the risks and benefits of PE, cyclophosphamide, and RTX, the patient’s guardian refused to use these treatment methods due to fear of the invasiveness and adverse effects. Then, we informed the potential advantages of OFA treatment including higher safety, efficient B-cell lysis, and convenient way of injection compared with other immunotherapies to patient’ guardian. Informed consent for the off-label use of OFA was obtained from the legal guardians of the patient, and the drug was subsequently administered (three subcutaneous injections of 20 mg on days 1, 7, 14). Given the lack of efficacy of short-term MMF treatment and the increased side effects caused by the combination of two types of immunosuppressants, we stopped treatment with MMF before the OFA injection.

Figure 1.

Timeline of disease disability course and different treatment regimes. (A, B) Clinical course and treatment in (A) case 1 and (B) case 2. The x-axis indicates the number of days after disease onset. The y-axis indicates clinical course, which is documented by the modified Rankin Scale (mRS) score, activity of daily living (ADL) scale, and neuropsychiatric inventory (NPI) score. The right y-axis also indicated the CD20 cell percentage. (C) Representative brain magnetic resonance images from case 2. (a) Axial T2-weighted fluid-attenuated inversion recovery images and (b) T1 contrast enhancement demonstrate multifocal hyperintensity (arrowhead) at the onset of neurologic symptoms in case 2. (c, d) This abnormality resolved after treatment with ofatumumab OFA, with corresponding symptomatic improvement.

The patient improved substantially a few days after the first injection of OFA, with the mRS score changing from 5 to 4 and the Activity of Daily Living (ADL) score changing from 5 to 30. Her therapy was well tolerated with no adverse effects. In the following days, her condition improved rapidly and continuously (Figure 1(A); Supplemental Video S2). In addition, the clinical deficits and anti-NMDAR antibody titers markedly improved. The neuropsychiatric inventory (NPI) score changed from 35 to 0, and the mini–mental State Examination (MMSE) score changed from 0 to 30 (Figure 2(A)). At her last follow-up, the patient did not experience any relapse and was able to resume working.

Figure 2.

Results of neuropsychiatric inventory questionnaire over the course of ofatumumab treatment. The components of neuropsychiatric inventory questionnaire scores at different follow-up points are shown in (a) the first cases and (b) the second case with anti-NMDA receptor encephalitis.

Case 2

A patient in his mid-30s presented to our department with marked behavioral changes, hallucinations, speech disturbances, and confusion. The patient also had insomnia and vegetative symptoms such as hyperhidrosis and tachycardia. There was no other relevant medical history, and the patient was not taking medications. The patient’s family history was unremarkable. Neuropsychological examination revealed significant hallucination, delusion, agitation, indifference, and cognitive deficits.

Chest radiograph revealed no abnormalities, while brain MRI demonstrated multifocal hyperintensity (bilateral parietal lobe and left temporal lobe cortex lesions) on T2-weighted fluid-attenuated inversion recovery images with T1 contrast enhancement (focal enhancement of bilateral temporal cortex) (Figure 1(C) (a) and (b). Multiple lesions located in the cerebral cortex and near the cortex suggested a differential diagnosis of other demyelinating diseases. It has been previously reported that the presence of oligoclonal bands is approximately 8.5-fold higher in patients with NMDAR encephalitis than in controls.¹¹ Therefore, we tested the oligoclonal bands, a panel of oligoclonal bands and demyelination antibodies (AQP-4, GFAP, MOG, etc.), via cervical and thoracal MRI to further exclude central nervous system inflammatory demyelinating diseases.

The patient underwent abdominal color Doppler ultrasound to exclude teratoma, and the result was negative. The test for central nervous system infectious diseases was negative (Table 1). Antibody against NMDAR were detected in the patient’s cerebrospinal fluid (titer: 1:10), and anti-NMDAR encephalitis was diagnosed. Additional broad autoimmune encephalitis antibody panel testing remained negative. (Table 1).

Over the course of one month, the patient remained unresponsive to methylprednisolone, and his condition further deteriorated with additional disturbance of consciousness (Supplemental Video S3). Owing to his persistent deterioration, we informed the patient’s guardian of various treatment options, including IVIg, PE, and RTX. However, the patient’s guardian declined these treatments due to their cost and adverse effect. We subsequently informed the advantages of OFA treatment to patient’ guardian. Therefore, the patient was treated with OFA (for dosing regimen, see case 1). The second day after the introduction of OFA, a marked improvement in the patient’s consciousness level (from light coma to lethargy) was observed. A significant improvement in the patient’s ADL score (from 10 to 50) was seen 4 days after OFA treatment. The patient could speak in sentences fluently and correctly and could be mobilized into the standing position (Supplemental Video S4). In the following days, he showed dramatic improvements with regard to speech disturbances, hallucinations, disorientation, and behavioral disorders (Figure 1(B)), accompanied by significant improvements as observed by cranial MRI (Figure 1(C) (c) and (d)). The patient showed good tolerance and no adverse reactions to the treatment. The patient’s CD20-positive B-cells were completely depleted, the patient’s NPI score changed from 58 to 0, and the patient’s MMSE score changed from 0 to 30 over the course of follow-up (Figure 2(B)). The cerebro spinal fluid (CSF) and serological follow-up examination revealed that the anti-NMDAR antibody titer was negative. At his last follow-up, the patient was stable and was no longer experiencing cognitive impairments or hallucinations.

Discussion

Herein, we reported the therapeutic effect and safety of OFA in the refractory course of anti-NMDAR encephalitis for the first time, and these cases suggest that OFA has good potential to treat anti-NMDAR encephalitis.

Compared with other immunotherapies, the prominent advantages of administration of OFA in patients with anti-NMDAR encephalitis include the following: (1) Potentially leads to faster improvement. The median time to improve the one-point mRS score was significantly shorter in patients treated with OFA (1 day) than in patients treated with intravenous immunoglobulin or high-dose corticosteroids (7–14 days).¹² Complete recovery (to mRS = 0) was obtained within 1–2 months in the two patients treated with OFA, similar to the effects observed in patients that respond well to RTX.¹³ The underlying mechanism may involve a faster occurrence of B-cell lysis in OFA.⁵ (2) Good tolerability. Injection-related reactions are commonly observed in RTX; however, these were not observed in either patient treated with OFA, suggesting that patients could benefit from the advantages of the fully humanized antibody. (3) More convenient administration. The subcutaneous method of administration allows for quick self-administration of OFA at home in patients who have been relatively stable. This could greatly reduce the length of hospital stays and accordingly reduce the economic burden caused by hospitalization.¹⁴ Currently, the dosage of OFA is independent of body weight and body surface area, but ongoing studies may lead to adaptive dosages in the future, thereby reducing the drug cost for overweight patients.

The main reason that we have stopped OFA after the third injection in both cases was based on anecdotal evidence from OFA treatments in patients with multiple sclerosis and animal models. It is known that three to four injections of OFA result in complete B-cell depletion and clinical improvement.⁵ Since multiple sclerosis is a highly recurrent disease, it is necessary to achieve long-term immunotherapy with one injection of OFA per month. In China, the relapse rate of anti-NMDAR encephalitis is relatively low; it is reported to occur in approximately 15% to 20% of cases.^15,16 Consequently, we did not perform long-term OFA injections.

Although obvious curative effects have been observed, a full understanding of the role of OFA in the long-term prognosis and recurrence of anti-NMDAR encephalitis requires further follow-up. In addition, based on the limitations of case reports, the exact effect of OFA on anti-NMDAR encephalitis should be further studied. Especially for patients with teratomas, further observation is necessary to determine whether OFA is effective for this more critical type. Another important limitation in our two cases was that both patients did not receive a second lumbar puncture to verify their CSF antibody titers. This was especially pertinent for the second patient who had a lower titer of NMDAR antibody in the CSF (1:10) which suggested the possibility of a false-positive titer. Finally, we could not completely rule out the possibility of long-term efficacy of first-line drugs in the two patients. However, the rapid clinical inflection point of the patients following the administration of OFA supports the main (if not the only) role played by the drug. Further extending the follow-up time of the two patients may be of value and interest. No observable relapses after 1–2 years would represent an important new observation. Further randomized controlled studies are required to address these concerns.

Footnotes

Acknowledgements

The authors thank all participants for their participation in our study.

Declarations

ORCID iDs

Dong Zhou

Zhen Hong

Supplemental material

Supplemental material for this article is available online.

References

Dalmau

Gleichman

Hughes

, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol 2008; 7: 1091–1098.

Martinez-Hernandez

Horvath

Shiloh-Malawsky

, et al. Analysis of complement and plasma cells in the brain of patients with anti-NMDAR encephalitis. Neurology 2011; 77: 589–593.

Thaler

Zimmermann

Kammermeier

, et al. Rituximab treatment and long-term outcome of patients with autoimmune encephalitis: real-world evidence from the GENERATE registry. Neurol Neuroimmunol Neuroinflamm 2021; 8: e1088.

Wincup

Menon

Smith

, et al. Presence of anti-rituximab antibodies predicts infusion-related reactions in patients with systemic lupus erythematosus. Ann Rheum Dis 2019; 78: 1140–1142.

Hauser

Bar-Or

Cohen

, et al. Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med 2020; 383: 546–557.

Lin

TS.

Ofatumumab: a novel monoclonal anti-CD20 antibody. Pharmgenomics Pers Med 2010; 3: 51–59.

Semple

Gonzaléz

Zarr

, et al. Evaluation of the ability of immune humanized mice to demonstrate CD20-specific cytotoxicity induced by ofatumumab. Clin Transl Sci 2019; 12: 283–290.

Bar-Or

Grove

Austin

, et al. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: the MIRROR study. Neurology 2018; 90: e1805–e1814.

Kähäri

Fair-Mäkelä

Auvinen

, et al. Transcytosis route mediates rapid delivery of intact antibodies to draining lymph nodes. J Clin Invest 2019; 129: 3086–3102.

10.

Maillart

Renaldo

Papeix

, et al. Dramatic efficacy of ofatumumab in refractory pediatric-onset AQP4-IgG neuromyelitis optica spectrum disorder. Neurol Neuroimmunol Neuroinflamm 2020; 7: e683.

11.

Malter

Elger

Surges

Diagnostic value of CSF findings in antibody-associated limbic and anti-NMDAR-encephalitis. Seizure 2013; 22: 136–140.

12.

Gong

Luo

Liu

, et al. Efficacy and tolerability of intravenous immunoglobulin versus intravenous methylprednisolone treatment in anti-N-methyl-D-aspartate receptor encephalitis. Eur J Neurol 2022; 29: 1117–1127.

13.

Nosadini

Eyre

Molteni

, et al. Use and safety of immunotherapeutic management of N-methyl-D-aspartate receptor antibody encephalitis: a meta-analysis. JAMA Neurol 2021; 78: 1333–1344.

14.

Gong

Guo

, et al. Direct economic burden of patients with autoimmune encephalitis in Western China. Neurol Neuroimmunol Neuroinflamm 2020; 7: e891.

15.

Titulaer

McCracken

Gabilondo

, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013; 12: 157–165.

16.

Gong

Chen

Liu

, et al. Long-term functional outcomes and relapse of anti-NMDA receptor encephalitis: a cohort study in Western China. Neurol Neuroimmunol Neuroinflamm 2021; 8: e958.

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