Anti-aquaporin 4 IgG Is Not Associated With Any Clinical Disease Characteristics in Neuromyelitis Optica Spectrum Disorder

Abstract

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a clinically defined, inflammatory central nervous system (CNS) disease of unknown cause, associated with humoral autoimmune findings such as anti-aquaporin 4 (AQP4)-IgG. Recent clinical trials showed a benefit of anti-B cell and anti-complement-antibodies in NMOSD, suggesting relevance of anti-AQP4-IgG in disease pathogenesis.Objective: AQP4-IgG in NMOSD is clearly defined, yet up to 40% of the patients are negative for AQP4-IgG. This may indicate that AQP4-IgG is not disease-driving in NMOSD or defines a distinct patient endotype.Methods: We established a biobank of 63 clinically well-characterized NMOSD patients with an extensive annotation of 351 symptoms, patient characteristics, laboratory results and clinical scores. We used phylogenetic clustering, heatmaps, principal component and longitudinal causal interference analyses to test for the relevance of anti-AQP4-IgG.Results: Anti-AQP4-IgG was undetectable in 29 (46%) of the 63 NMOSD patients. Within anti-AQP4-IgG-positive patients, anti-AQP4-IgG titers did not correlate with clinical disease activity. Comparing anti-AQP4-IgG-positive vs. -negative patients did not delineate any clinically defined subgroup. However, anti-AQP4-IgG positive patients had a significantly (p = 0.022) higher rate of additional autoimmune diagnoses.Conclusion: Our results challenge the assumption that anti-AQP4-IgG alone plays a disease-driving role in NMOSD. Anti-AQP4-IgG might represent an epiphenomenon associated with NMOSD, may represent one of several immune mechanisms that collectively contribute to the pathogenesis of this disease or indeed, anti-AQP4-IgG might be the relevant factor in only a subgroup of patients.

Frequency of NMOSD misdiagnosis in a cohort from Latin America: Impact and evaluation of different contributors

“…Although MOGAD patients can meet the 2015 NMOSD clinical diagnosis, differentiating both central nervous system (CNS) immune-mediated conditions is critical, as treatment and prognosis may differ. 9,28–30 In addition, separating AQP4-Ab-negative NMOSD from MS in borderline cases is extremely challenging. Classifying overlap syndromes at presentation is a major unmet need, where even the experts have difficulty to the diagnostic and in whom recognizing this is important for making treatment decisions.…”

Granulocyte activation markers in cerebrospinal fluid differentiate acute neuromyelitis spectrum disorder from multiple sclerosis

“…However, 20%-40% of patients eventually fulfilling NMOSD criteria remain aAQP4 − which makes it even more difficult to establish the accurate diagnosis. [2][3][4][5] Furthermore, the presence or the titre of aAQP4 is not related to clinical disease characteristics. 4 Several biomarkers tend to be more highly elevated in NMOSD than in MS, for example, glial fibrillary acidic protein (GFAP), and S100B (both markers of astrocyte damage), 6 7 neurofilament light chain (NfL, a marker of neuroaxonal injury), 6 8 chemokine (C-X-C motif) ligand 13 (CXCL13, a B-cell attractant), [9][10][11] intercellular adhesion molecule-1 (ICAM-1) and vascular cellular adhesion molecule-1 (VCAM-1) (both leucocyte adhesion molecules) 12 and matrix metalloproteinase-9 (MMP-9, a matrix remodelling gelatinase).…”

Neuromyelitis Optica Spectrum Disorder: From Basic Research to Clinical Perspectives

“…Evidence shows that AQP-4 IgG antibodies are not strongly associated with clinical indices, such as the EDSS, risk of relapse, or visual prognosis in NMOSD [ 17 ]. On the other hand, there are data suggesting that the activation of complements, cytokines, and chemokines contributes to the complex pathogenesis of the disorder [ 104 , 105 ].…”

“…AQP4-IgG antibody titers seem to be linked to clinical presentation and immune response, with higher titers associated with worse visual function and more extensive cerebral involvement on MRI [ 16 ]. On the other hand, AQP4-IgG antibodies might represent a byproduct resulting from complex immunoinflammatory processes in NMOSD, with no significant variations in antibody titers between different disease stages [ 17 ]. Beyond autoantibodies, the clinical presentation and demographic features may be more reliable in terms of prognosis prediction [ 18 ].…”