INTRODUCTION

Anti–tumor necrosis factor (TNF) therapies were first approved for management of Crohn's disease (CD) in 1998 and remain widely used.1 These therapies bind to transmembrane and soluble TNF-α, inhibiting binding to TNF-α receptors and thereby blocking proinflammatory signals and molecules upregulated by TNF-α.1 Various adverse effects from anti-TNF therapies are well-established, particularly with infectious and malignant conditions, although a growing body of evidence has demonstrated associations between anti-TNFs and inflammatory central nervous system events.1,2 These events can be differentiated as demyelinating (ie, multiple sclerosis and optic neuritis) or nondemyelinating (ie, meningitis, central nervous system (CNS) vasculitis, and encephalitis), with the former occurring more frequently.2

Anti‐N‐methyl‐D (NMDA) receptor antibody autoimmune encephalitis (NMDAr-AE) is the most common cause of autoimmune encephalitis in young adults with an estimated prevalence of 0.6–0.7 per 100,000 persons.3 This condition is defined by the presence of autoantibodies directed against the NMDA receptor GluN1 subunit.4 Exposure to anti-TNF agents has been found to paradoxically induce various autoantibodies associated with systemic vasculitis and systemic lupus erythematosus.5 A study from 2005 concluded that, in patients with CD, autoantibodies induced by infliximab were limited to antinuclear and anti-dsDNA antibodies, although this study had a small sample size, examined only serum autoantibodies, and was completed before NMDAr-AE being defined as a clinical entity.6 In recent years, 5 case reports have been published describing cases of NMDAr-AE in patients being treated with anti-TNF therapies.7–11 The current article reports a case of NMDAr-AE in a patient with CD on long-term adalimumab therapy.

CASE REPORT

A 46-year-old woman with a history of fistulizing CD presented to a rural hospital with a 1-week history of bizarre behaviors, headaches, and reported auditory hallucinations. She underwent a lumbar puncture with cerebral spinal fluid analysis returning high-titer positive for NMDA receptor antibodies. Her cerebral spinal fluid also showed oligoclonal banding and an elevated IgG synthesis rate of 5.9 mg/dL and was negative for bacterial culture and herpes simplex virus, varicella-zoster virus, and enterovirus. Magnetic resonance angiogram imaging of the brain was unremarkable without evidence of vasculitis or intracranial abnormalities. She was diagnosed with NMDAr-AE and transferred to a quaternary hospital for management.

This patient was diagnosed with CD 16 years before this presentation. Her fistulizing disease had resulted in recurrent perianal fistulae and a rectovaginal fistula requiring surgical repair. Her extraintestinal manifestations of CD included ankylosing spondylitis and episodes of iritis. Her medical management until time of admission had included 5-ASA and multiple courses of corticosteroids to manage flares, azathioprine monotherapy, and eventually the introduction of anti-TNF agents (ie, adalimumab) 6 years before the relevant admission. She switched to an adalimumab biosimilar in 2020, 3 years before her presentation of NMDAr-AE, and her CD was in clinical remission with 40-mg subcutaneous doses every 2 weeks. She had no previous adverse effects noted on adalimumab over this 6-year period.

Her NMDAr-AE management consisted initially of methylprednisolone (1 g/kg daily for 5 days), and she received 2 doses of intravenous immune globulin (2 mg/kg). After this, she was maintained on a 50-mg daily dose of prednisone. There was no evidence of an ovarian teratoma on cross-sectional imaging. Her encephalitis symptoms persisted despite initial treatments, and her management was escalated to 6 plasmapheresis treatments followed by 2 doses of rituximab (375 mg/m2). This treatment escalation resulted in resolution of her NMDAr-AE symptoms and eventual discharge home over a total 8-week timeframe from time of diagnosis.

Gastroenterology was consulted during this admission as the patient was due for her regular scheduled adalimumab. On the basis of her clinical remission and an ongoing prednisone dose of 50 mg daily anticipated for multiple months, it was recommended that adalimumab be held. After a review of her case and available literature at a multidisciplinary rounds meeting, it was determined that discontinuation of adalimumab was warranted in the setting of NMDAr-AE with a plan coordinated for outpatient initiation of vedolizumab for ongoing CD management.

Informed patient consent was obtained for case publication.

DISCUSSION

The association between NMDAr-AE and anti-TNF therapies was first posited by Noble and Lancaster in 2018, after a patient with CD developed NMDAr-AE within 6 months of starting adalimumab therapy.7Table 1 summarizes this case, as well as 5 additional case reports of autoimmune encephalitis in patients on anti-TNF therapies published to date.7–11 Most cases identified have occurred with patients on adalimumab, with NMDAr-AE occurring within 9 months of anti-TNF therapy. The case reported by Oh et al deviated from this trend with a patient who had been on infliximab for 9 years before developing NMDAr-AE.11 All 5 patients were reported to recover from their autoimmune encephalitis events, with reported time to discharge from hospital ranging from 15 days to 6+ weeks.7,8 Only Oh et al (2022) reported a time to a full neurological recovery at 12 months, which is largely in keeping with the often protracted recovery time from NMDAr-AE.11,12 The current patient case is unique in this area as our patient was on adalimumab for 6 years before developing NMDAr-AE. In keeping with the available literature, we opted to discontinue adalimumab.

Table 1. - Summary of literature reviewing NMDAr-AE and Anti-TNF therapies Author (year) Age (sex) Anti-TNF indication Anti-TNF (duration) NMDAr ab in CSF Treatment Time to discharge Change in biologic Noble and Lancaster7 (2018) 58 F CD Adalimumab (5 mo) + MP + IVIG → rituximab 15 d Yes (vedolizumab) Demarez et al8 (2020) 25 M Psoriasis Adalimumab (5 mo) + MP + PLEX → rituximab 6+ wk Yes (brodalumab) Fernández Álvarez et al9 (2021) 58 M CD Adalimumab (6 mo) − MP + IVIG NR Yes (discontinued) Martin et al10 (2021) 31 M Psoriasis Adalimumab (9 mo) + MP + PLEX → rituximab 3 wk Yes (discontinued) Oh et al11 (2022) 27 M CD Infliximab (9 y) + MP + IVIG → rituximab 6 wk Yes (ustekinumab) Current report 46 F CD Adalimumab (6 y) + MP + IVIG → PLEX → rituximab 8 wk Yes (vedolizumab)

CD, Crohn's disease, F, female; IVIG, intravenous immune globulin, M, male; MP, methylprednisolone; NMDAr Ab, anti‐N‐methyl‐D aspartate receptor antibody NMDAr-AE; anti‐N‐methyl‐D aspartate receptor antibody autoimmune encephalitis; NR, not reported; PLEX, plasmapheresis; TNF, tumor necrosis factor.

The mechanism by which anti-TNF therapy could predispose patients to NMDAr-AE is not fully known. Proposed mechanisms to date include TNF-α suppression allowing for priming and expansion of self-reactive B-cell populations within complex cytokine environments, resulting in the production of autoantibodies.7 Anti-TNF therapies also enhance antigen-presenting cell function, increase T-cell receptor signaling, and can decrease apoptosis of autoreactive T cells.13 These mechanisms, combined with the inability for anti-TNF therapies to cross the blood-brain barrier, may result in autoreactive T cells in the CNS facilitating abnormal B-cell activation and the production of autoantibodies such as NMDAr-Ab.11,13

With growing recognition of nondemyelinating inflammatory CNS events for patients on anti-TNF therapies, it is important for clinicians to factor the presence of autoimmune encephalitis into biologic therapy choices for patients with CD. The current precedent in the literature is to discontinue anti-TNF therapies in patients with CD who develop NMDAr-AE while on these therapies, provided alternative biologic therapies are not contraindicated.

DISCLOSURES

Author contributions: Both authors provided substantial contributions to the drafting and critical review of this case report and were in consensus regarding the final approval of this report to be submitted for publication. S. MacKay is the article guarantor.

Financial disclosure: None to report.

Informed consent was obtained for this case report.

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