Abstract
Neuromyelitis optica spectrum disorder is an autoimmune astrocytopathy that primarily affects the optic nerves and spinal cord. Its association with rheumatoid arthritis is remarkably rare, with only 15 documented cases reported globally to date. This report describes the unique case of a 34-years-old woman with rheumatoid arthritis who developed concurrent aquaporin 4-immunoglobulin G-positive relapsing neuromyelitis optica spectrum disorder. The case underscores the substantial risk of initial misdiagnosis as stroke in patients with autoimmune diseases presenting with acute or atypical neurological deficits. We explored the potential shared immunopathological mechanisms between the two disorders and propose integrated therapeutic strategies for concurrent management. Importantly, this report strongly advocates prompt magnetic resonance imaging of the brain and spinal cord, along with aquaporin 4-immunoglobulin G serological testing, in rheumatoid arthritis patients presenting with optic neuritis, a critical omission in current rheumatological guidelines.
Keywords
Introduction
Neuromyelitis optica spectrum disorder (NMOSD) is an immune-mediated inflammatory demyelinating disorder of the central nervous system (CNS), predominantly targeting the optic nerves and spinal cord. 1 Clinically, it manifests as severe optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM), with up to 40% of patients exhibiting concurrent systemic autoimmune diseases such as Sjögren’s syndrome and systemic lupus erythematosus (SLE).2,3 However, the co-occurrence of rheumatoid arthritis (RA), a chronic inflammatory joint disorder driven by synovial hyperplasia and autoantibody production, with NMOSD is exceedingly rare. We summarized globally published literature and found that only 15 such comorbid cases have been reported to date. Detailed case summaries are presented in Table 1. The pathophysiological interplay between NMOSD and RA remains poorly understood, limited by both scarcity of reported cases and absence of specific biomarkers for early detection. Although T helper 17 (Th17)/interleukin-6 (IL-6) axis hyperactivity and B-cell dysregulation have been proposed as shared immunopathological mechanisms contributing to damage in both articular and CNSs,1,12 no established diagnostic or therapeutic guidelines currently exist for this clinical overlap. Consequently, diagnostic delays or misdiagnosis frequently occur in clinical practice. Furthermore, conventional immunosuppressive therapies are associated with various limitations, necessitating further scientific evaluation.13,14 Herein, we report the case of a patient with aquaporin 4 (AQP4)-immunoglobulin G-positive (IgG+) NMOSD and a 25-year history of RA. Following treatment, the patient showed marked clinical improvement. The clinical features, timing of relapse, and therapeutic response in this case stand in sharp contrast to previously reported instances of concurrent RA and NMOSD. This study was performed with the aim of offering valuable insights to inform clinical decision-making.
Worldwide literature review of NMOSD cases associated with rheumatoid arthritis.
NMOSD: neuromyelitis optica spectrum disorder; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; RF: rheumatoid factor; anti-CCP: anti-cyclic citrullinated peptide antibody; AQP4-IgG+: aquaporin 4-immunoglobulin G-positive; MRI: magnetic resonance imaging; MTX: methotrexate; IVIG: intravenous immunoglobulin; AKA: anti-keratin antibodies; APF: antiperinuclear factor.
Case report
A 34-years-old Han Chinese woman presented to our hospital in mid-2022 with progressive left limb weakness (since 1 month) and right hemibody numbness (since 20 days). Symptoms began insidiously as left-sided functional decline (manual dexterity loss, gait instability) in early July 2022; she was initially diagnosed with stroke in the outpatient setting and treated with antiplatelet agents, statins, and butylphthalide without significant improvement. She was subsequently hospitalized in mid-July for further management after she developed right hypoesthesia.
Neurological examination revealed left visual acuity reduction and terminal convergence tremor (10-cm amplitude); visual acuity was 0.5 in the left eye and 0.8 in the right eye. Both eyes demonstrated full, pain-free rotation. There was left hemiparesis (Medical Research Council (MRC) grade 3/5), right superficial sensory deficit, left Babinski sign, and restricted left ankle dorsiflexion (10 limitation). The patient had a 25-year history of RA, initially presenting as migratory polyarthralgia and progressively evolving to joint deformities. In 2009, she was diagnosed with left ON. Pulsed corticosteroid therapy led to partial clinical improvement; however, residual left visual impairment persisted. Her current RA treatment includes methotrexate (10 mg weekly) and sulfasalazine (1 g twice daily).
Following the most recent clinical episode, brain and spinal magnetic resonance imaging (MRI) revealed findings consistent with longitudinally extensive myelitis and left optic neuropathy. A comprehensive etiological evaluation was subsequently performed and demonstrated positivity for anti-AQP4 antibodies, thereby confirming the diagnosis of NMOSD.
The laboratory results are detailed in Table 2, and radiographic findings are presented in Figure 1(a) to (g).
Results of laboratory investigations during patient hospitalization.
Anti-RNP: antibodies against ribonucleoprotein; CSF AQP4-IgG: cerebrospinal fluid aquaporin-4 immunoglobulin G; MOG-IgG: myelin oligodendrocyte glycoprotein immunoglobulin G; MBP-IgG: myelin basic protein immunoglobulin G; GFAP-IgG: glial fibrillary acidic protein immunoglobulin G; CNS: central nervous system; pANCA: perinuclear anti-neutrophil cytoplasmic antibodies.
(a) Axial T2-weighted imaging shows speckle FLAIR high signal (arrow) in the left parietal lobe. (b) Axial T1-weighted enhanced imaging shows mild thickening of the intraorbital segment of the left optic nerve (arrow). (c–d) Anteroposterior radiographs of both hands in the upright position reveal multiple bone and joint deformities of bilateral hands, and multiple carpal and radial fusion changes on both sides. (e) Longitudinal extensive transverse myelitis-sagittal T2-weighted imaging of the cervical spine shows that the T2 high signal in the cervical spinal cord extended from C1 to C6 (arrow). (f) Sagittal T1-weighted enhanced imaging shows mild rim enhancement at the edge of the lesion (arrow). (g) Autoantibody testing shows positive AQP4 IgG with a titer of 1:1000+. FLAIR: fluid-attenuated inversion recovery.
The patient was diagnosed with AQP4-IgG+ NMOSD comorbid with RA based on the relevant diagnostic criteria. According to the treatment regimen recommended in the guidelines, acute-phase treatment was administered, comprising intravenous methylprednisolone (500 mg once daily) and intravenous immunoglobulin (IVIG, 20 g once daily) for 5 days, resulting in significant neurological improvement. Maintenance immunotherapy included mycophenolate mofetil (MMF, 1.5 g once daily), sulfasalazine (1 g twice daily), and a tapering regimen of prednisone (initiated at 20 mg once daily). Complete neurological recovery was sustained at the 12-month follow-up. RA activity decreased from 5.8 to 2.1.
Discussion
Epidemiological studies indicate that approximately 25% of AQP4-IgG+ NMOSD patients have comorbid autoimmune diseases, such as Graves’ disease, granulomatosis with polyangiitis (GPA), Sjögren’s syndrome, and SLE.3,10,15 Nevertheless, the co-occurrence of NMOSD with RA remains poorly documented, with 15 reported cases globally.4–10 The epidemiological characteristics of these cases indicate that these patients are predominantly middle aged (33–61 years), and a significantly higher proportion of them are women. Clinically, they often present with systemic inflammatory manifestations (elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and anti-cyclic citrullinated peptide antibody (anti-CCP) levels; fatigue; and low-grade fever) and involvement of the CNS (e.g. bilateral ON or motor dysfunction) combined with polyarthritis. The presence of AQP4-IgG seropositivity, co-positivity for other autoimmune antibodies, and spinal cord lesions involving more than three segments are key multifaceted factors associated with a higher risk of relapse in NMOSD patients. 16 The interval between the first episode of ON and the initial myelitis episode can extend up to 349 months. Consequently, some patients experience multiple episodes of ON (up to eight) prior to the onset of their first myelitis episode.3,4,10,15,17 Herein, we report a case of AQP4-IgG+ NMOSD in a patient with a 25-year history of RA. The patient initially presented 12 years ago with acute unilateral ON, followed by a prolonged quiescent period. The present relapse was characterized by progressive left limb weakness and right hemibody numbness over weeks. Serological testing for autoimmune antibodies was negative—a finding that distinguishes this case from previous reports with similar presentations.
Serological profiling revealed the following key pathological mechanisms. Strongly positive AQP4-IgG (serum titer 1:1000+ and cerebrospinal fluid (CSF) positivity) provided definitive evidence of NMOSD, while concomitant B-cell dysregulation (CD19+ 20.92%) and markedly elevated κ/λ light chains (κ 1960 mg/dL, λ 1180 mg/dL) suggested sustained B-cell hyperactivity within the chronic inflammatory milieu of RA, potentially driving CNS-specific autoimmunity. Elevated IL-6 (8.4 pg/mL) and aberrant B-cell activity further supported the involvement of Th17-mediated pathways, consistent with the “autoimmune breakthrough” hypothesis.13,17
Imaging findings included left parietal fluid-attenuated inversion recovery (FLAIR) hyperintensity on brain MRI (Figure 1(a)), nodular enhancement along the left optic nerve on orbital MRI (Figure 1(b)), and bilateral hand radiographs showing bone deformities and carpal fusion consistent with advanced RA (Figure 1(c) and (d)). Cervical spine MRI revealed a longitudinally extensive T2 hyperintense lesion extending from C1 to C6 (Figure 1(e) and (f)), characteristic of NMOSD. Although CSF analysis showed a normal cell count (4 cells/μL), a diagnosis of NMOSD was definitively established based on characteristic serological and radiological findings.
Literature review indicates that AQP4 antibody-positive NMOSD patients are predominantly female and more frequently present with comorbid autoimmune diseases. Clinically, such patients often exhibit isolated ON as the initial manifestation (68/117 cases), typically accompanied with severe visual impairment, along with longer intervals from onset to relapse and diagnosis. In contrast, AQP4 antibody-negative patients demonstrate a higher incidence of bilateral ON at disease onset. In the present case, the patient experienced acute onset in 2009 characterized by severe isolated ON, followed by a relapse 12 years later—a clinical course consistent with AQP4 antibody-positive NMOSD. As AQP4 antibody testing was not widely available at the time of initial onset, it is postulated based on her clinical manifestations and disease progression that the patient had AQP4 antibody-positive NMOSD in the setting of RA.3,4,10,15,17
The treatment strategy targeted both neurological and articular manifestations. Acute-phase management consisted of high-dose methylprednisolone (500 mg/day) combined with IVIG (20 g/day), resulting in rapid symptom remission through antibody neutralization and complement inhibition. This combination therapy is associated with a lower relapse risk in overlap syndromes compared with steroid monotherapy. 18 For maintenance, MMF was selected due to azathioprine resistance (genotype: GG AA wild-type homozygous, normal metabolizer), supplemented with sulfasalazine for articular control. Methotrexate was avoided despite its role as first-line RA therapy, owing to poor CNS penetration and limited efficacy in NMOSD relapse prevention. 19 Although eculizumab—which has shown to reduce the relapse risk by 89% in AQP4-IgG+ NMOSD in phase III trials20,21—was not used here, it remains an important option in refractory cases.
This case highlights that neurological symptoms in patients with long-standing RA should raise a suspicion for NMOSD rather than be attributed solely to vascular complications or articular involvement. Diagnosis necessitates AQP4-IgG serology and whole-spine MRI, even in the presence of normal CSF findings. Differentiation from multiple sclerosis (MS) is essential to avoid harmful MS-specific therapies such as interferon-β, which can exacerbate NMOSD. 6 A collaborative neuro-rheumatological approach is critical for tailoring immunosuppressive strategies to control both CNS and articular disease. Nevertheless, these insights are derived from a single case and require further validation in larger prospective studies.
Footnotes
Acknowledgments
We gratefully acknowledge the patient for providing informed consent for the publication of this case report. Our sincere thanks extend to the multidisciplinary teams from the Departments of Neurology and Cardiovascular Medicine at Taicang Affiliated Hospital of Nanjing University of Traditional Chinese Medicine for their dedicated clinical collaboration in diagnosis and management. We also recognize the contributions of the clinical laboratory team for performing pharmacogenetic analyses, which critically informed therapeutic strategies. Finally, we thank the editors and reviewers for their valuable insights.
Author contributions
XC-J: Writing the first draft of the manuscript (conception and editing).
JH-C: Writing the first draft of the manuscript (tissue preparation, staining, and imaging)
JF-Z: conception, organization, Review of the manuscript.
Y-W: Material preparation, Review
L-Y: Material preparation, Review
All authors contributed to the article and approved the submitted version.
Data availability statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
Declaration of conflicting interests
The authors have no conflicts of interest to disclose.
Ethics statement and informed consent
Written informed consent for both treatment and publication were obtained directly from the patient. Ethical approval was not required because this was a case report.
Funding
This work was supported by research grants from the Taicang Municipal Bureau of Science and Technology and the Suzhou Municipal Bureau of Science and Technology. Funding details are included below:
2022 Suzhou Science and Technology Development Plan Project (SKY2022028) 2022 Taicang Science and Technology Plan Project (TC2022JCYL17) 2020 Suzhou Science and Technology Development Plan Project (SYSD2020200) 2023 Taicang Science and Technology Plan Project (TC2023JCYL10)
