The pathogenic role of lupus-specific autoantibodies and Interleukin-6 on demyelination of the brainstem and spinal cord in systemic lupus erythematosus

Abstract

Objectives

Demyelinating syndromes that result in brainstem and/or spinal cord lesions similar to those observed in neuromyelitis optica spectrum disorder (NMOSD) as neuropsychiatric syndromes in systemic lupus erythematosus (NPSLE) occasionally develop in patients with SLE. Cerebrospinal fluid (CSF) interleukin (IL)-6 is a known biomarker for NMOSD; however, its application in patients with SLE with brainstem and/or spinal cord lesions is unknown. Additionally, the breakdown of blood–brain barrier (BBB) integrity by autoantibodies is another mechanism of NMOSD; however, it is not elucidated in SLE. Therefore, this study was designed to clarify the use of CSF IL-6 and investigate whether autoantibodies contribute to BBB breaches and the development of brainstem and/or spinal cord lesions.

Methods

Data from patients with NPSLE who had NMOSD-like demyelinating lesions in the central nervous system (CNS), including brainstem and/or spinal cord lesions, were retrospectively analyzed. We retrospectively investigated the interval changes in CSF IL-6 and clinical and serological factors related to BBB permeability using CSF/serum albumin ratio (QAlb).

Results

Twelve patients with NPSLE who had demyelinating lesions in the brainstem and/or spinal cord were recruited. Before treatment, CSF IL-6 levels were 29.1 pg/mL and significantly decreased to 3.8 pg/mL by treatment (p = 0.008). Before treatment, CSF IL-6 was significantly correlated with the anti-dsDNA antibody titer (p = 0.027). Furthermore, before treatment, QAlb was significantly correlated with the serum anti-Smith antibody titer. In patients with atypical NMOSD who had specific lesions defined in the NMOSD diagnostic criteria but were negative for antiaquaporin four antibody, a significant correlation was observed between the serum anti-Smith antibody titer and CSF IL-6 (p = 0.025) and QAlb (p = 0.033) values before treatment.

Conclusion

CSF IL-6 could be a surrogating marker for disease activity, and serum anti-Smith antibody permeabilizes the BBB in patients with NPSLE, supporting the development of NMOSD-like CNS lesions.

Keywords

Systemic lupus erythematosus neuromyelitis optica spectrum disorder cerebrospinal fluid interleukin-6 autoantibody

Get full access to this article

View all access options for this article.

References

Tsokos

. Mechanisms of disease: systemic lupus erythematosus. N Engl J Med 2011; 365(1): 2110–2121.

Ad ACR Committee HOC Neuropsychiatric ON , et al. The American college of rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum 1999; 42: 599–608.

Wingerchuk

Banwell

Bennett

, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015; 85: 177–189.

Lennon

Kryzer

Pittock

, et al. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 2005; 202: 473–477.

Papadopoulos

Verkman

. Aquaporin 4 and neuromyelitis optica. Lancet Neurol 2012; 11: 535–544.

Shimizu

Takeshita

Hamamoto

, et al. GRP 78 antibodies are associated with clinical phenotype in neuromyelitis optica. Ann Clin Transl Neurol 2019; 6: 2079–2087.

Katsumata

Kawachi

Kawaguchi

, et al. Semiquantitative measurement of aquaporin-4 antibodies as a possible surrogate marker of neuromyelitis optica spectrum disorders with systemic autoimmune diseases. Mod Rheumatol 2012; 22: 676–684.

Piga

Chessa

Teresa Peltz

, et al. Demyelinating syndrome in SLE encompasses different subtypes: do we need new classification criteria? pooled results from systematic literature review and monocentric cohort analysis. Autoimmun Rev 2017; 16: 244–252.

X-Y

Xiao

H-B

, et al. Myelitis in systemic lupus erythematosus frequently manifests as longitudinal and sometimes occurs at low disease activity. Lupus 2014; 23: 1178–1186.

10.

Costallat

Ferreira

Costallat

LTL

, et al. Myelopathy in systemic lupus erythematosus: clinical, laboratory, radiological and progression findings in a cohort of 1, 193 patients. Rev Bras Reumatol Engl Ed May-Jun 2016; 56: 240–251.

11.

Mader

Jeganathan

Arinuma

, et al.

Understanding the antibody repertoire in neuropsychiatric systemic lupus erythematosus and neuromyelitis optica spectrum disorder: do they share common targets?

Arthritis Rheumatol 2018; 70: 277–286.

12.

Wang

Zhong

, et al. Notable increased cerebrospinal fluid levels of soluble interleukin-6 receptors in neuromyelitis optica. Neuroimmunomodulation 2012; 19: 304–308.

13.

Uzawa

Mori

Arai

, et al. Cytokine and chemokine profiles in neuromyelitis optica: significance of interleukin-6. Mult Scler 2010; 16: 1443–1452.

14.

Matsushita

Tateishi

Isobe

, et al. Characteristic cerebrospinal fluid cytokine/chemokine profiles in neuromyelitis optica, relapsing remitting or primary progressive multiple sclerosis. PloS One 2013; 8: 2–9.

15.

Hochberg

. Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40: 1725.

16.

Gladman

Ibañez

Urowltz

. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002; 29: 288–291.

17.

Nagai

Arinuma

Yanagida

, et al. Anti-ribosomal P protein antibody in human systemic lupus erythematosus up-regulates the expression of proinflammatory cytokines by human peripheral blood monocytes. Arthritis Rheum 2005; 52: 847–855.

18.

Arinuma

Yanagida

Hirohata

. Association of cerebrospinal fluid anti-NR2 glutamate receptor antibodies with diffuse neuropsychiatric systemic lupus erythematosus. Arthritis Rheum 2008; 58: 1130–1135.

19.

Hirohata

Sakuma

Yanagida

, et al. Association of cerebrospinal fluid anti-Sm antibodies with acute confusional state in systemic lupus erythematosus. Arthritis Res Ther 2014; 16: 450.

20.

Winfield

Shaw

Silverman

, et al. Intrathecal IgG synthesis and blood–brain barrier impairment in patients with systemic lupus erythematosus and central nervous system dysfunction. Am J Med 1983; 74: 837–844.

21.

Fominykh

Vorobyeva

Onufriev

, et al.

Interleukin-6, S-nitrosothiols, and neurodegeneration in different central nervous system demyelinating disorders: is there a relationship?

J Clin Neurol 2018; 14: 327–332.

22.

Tono

Nagai

Hoshiyama

, et al. Transverse myelitis extended to disseminated encephalitis in systemic lupus erythematosus: histological evidence for vasculitis. Mod Rheumatol 2016; 26: 958–962.

23.

Chiganer

Hryb

Carnero Contentti

. Myelitis and lupus: clinical manifestations, diagnosis and treatment. Reumatol Clín (English) 2017; 13: 344–348.

24.

Xiao

Pai

. Myelitis in systemic lupus erythematosus. J Clin Neurosci 2017; 44: 18–22.

25.

Yoshio

Okamoto

Kurasawa

, et al. IL-6, IL-8, IP-10, MCP-1 and G-CSF are significantly increased in cerebrospinal fluid but not in sera of patients with central neuropsychiatric lupus erythematosus. Lupus 2016 Aug; 25(9): 997–1003.

26.

Yoshio

Okamoto

Hirohata

, et al. Anti-NR2 glutamate receptor auto-IgG antibodies from patients with systemic lupus erythematosus activate endothelial cells. Arthritis Rheum 2013; 65: 457–463.

27.

Shimizu

Schaller

Owens

, et al. Glucose-regulated protein 78 autoantibody associates with blood–brain barrier disruption in neuromyelitis optica. Sci Transl Med 2017; 9: eaai9111.

28.

Shimizu

Nishihara

Kanda

. Blood–brain barrier dysfunction in andom-mediated neurological diseases. Immunol Med 2018; 41: 120–128.

29.

Matsueda

Arinuma

Nagai

, et al. Elevation of serum anti-glucose-regulated protein 78 antibodies in neuropsychiatric systemic lupus erythematosus. Lupus Sci Med 2018; 105: e000281.

30.

Hirohata

Sakuma

Matsueda

, et al. Role of serum autoantibodies in blood–brain barrier damages in neuropsychiatric systemic lupus erythematosus. Clin Exp Rheumatol 2018; 36: 1003–1007.

31.

Arinuma

. What are the latest clinical findings regarding the association of neurotoxic brain antibodies found in the cerebrospinal fluid in patients with autoimmune disorders? Curr Opin Neurol 2020; 33: 347–352.

32.

Arinuma

Yamaoka

. Developmental process in diffuse psychological/neuropsychiatric manifestations of neuropsychiatric systemic lupus erythematosus. Immunol Med 2021; 44: 16–22.

33.

Andersson

Alvarez-Cermeno

Bernardi

, et al. Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry 1994; 57: 897–902.

34.

Castellazzi

Morotti

Tamborino

, et al. Increased age and male sex are independently associated with higher frequency of blood-cerebrospinal fluid barrier dysfunction using the albumin quotient. Fluids Barriers CNS 2020; 17: 14.

35.

Hirohata

Kikuchi

. Role of serum IL-6 in neuropsychiatric systemic lupus erythematosus. ACR Open Rheumatol 2021; 3: 42–49.

36.

Yamamura

Kleiter

Fujihara

, et al. Trial of satralizumab in neuromyelitis optica spectrum disorder. N Engl J Med 2019; 381: 2114–2124.

37.

Traboulsee

Greenberg

Bennett

, et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: a randomized, double-blind, multicentre, placebo-controlled phase 3 trial. Lancet Neurol 2020; 19: 402–412.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.49 MB