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\begin{document}

\title{Protein A Immunoadsorption combination with Immunosuppressive Therapy
Improve Neuropsychiatric Systemic Lupus Erythematosus: A Case Report}



\author[1]{Feng  Wen}%
\author[2]{Xiaoling  Wu}%
\author[3]{ Ruyi Liao}%
\author[4]{Zhonglin  Feng}%
\author[4]{Zhilian  Li}%
\author[3]{Xia  Fu}%
\author[3]{Lei  Fu}%
\author[3]{Sijia  Li}%
\author[3]{Zhuo  Li}%
\author[3]{Sheng  Li}%
\author[4]{Wenjian  Wang}%
\author[3]{Biao  Huang}%
\author[5]{Chaosheng  He}%
\author[5]{Wei  Shi}%
\author[5]{Xinling  Liang}%
\author[6]{shuangxin liu}%
\affil[1]{Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences}%
\affil[2]{Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences}%
\affil[3]{Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, }%
\affil[4]{ Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, }%
\affil[5]{ Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences,}%
\affil[6]{Affiliation not available}%


\vspace{-1em}



  
  \date{June 01, 2024}


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\selectlanguage{english}
\begin{abstract}
Neuropsychiatric systemic lupus erythematosus (NPSLE) is usually
associated with a worse prognosis. However, there are few effective
treatments for NPSLE. We described protein A immunoadsorption treatment
for a patient with NPSLE. The patient's brain lesions was improved
rapidly after two sessions of protein A immunoadsorption combination
with immunosuppressive agent treatment.%
\end{abstract}%



\sloppy


\textbf{Running title: Protein A Immunoadsorption and Systemic Lupus
Erythematosus}

\textbf{Title: Protein A Immunoadsorption combination with
Immunosuppressive Therapy Improve Neuropsychiatric Systemic Lupus
Erythematosus: A Case Report}

Feng Wen M. D. \textsuperscript{1,\textbf{\#}} , Xiaoling Wu M.
D.\textsuperscript{2,3,\textbf{\#}} , Ruyi Liao M.
D.\textsuperscript{1,\textbf{\#}} , Zhonglin Feng M.
D.\textsuperscript{1}, Zhilian Li M. D.\textsuperscript{1}, Xia Fu M.
D.\textsuperscript{1}, Lei Fu, M. D.\textsuperscript{1}, Sijia Li M.
D.\textsuperscript{1}, Zhuo Li M. D.\textsuperscript{1}, Sheng Li M.
D.\textsuperscript{1}, Wenjian Wang, M. D.\textsuperscript{1}, Biao
Huang M. D. \textsuperscript{2,3}, Chaosheng He M.
D.\textsuperscript{1}, Shi Wei M. D.\textsuperscript{1},Xinling Liang M.
D.\textsuperscript{1,2,\&}, Shuangxin Liu M. D.\textsuperscript{1,2,\&}

\textsuperscript{1} Department of Nephrology, Guangdong Provincial
People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou,
510080, China.

\textsuperscript{2} Medical School, South China University of
Technology, Guangzhou, 510080, China.

\textsuperscript{3}Department of Radiology, Guangdong Provincial
People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou,
510080, China.

\textsuperscript{\#}The authors contributed equally to this work.

\textsuperscript{\&} The authors are co-correspondence authors.

\textbf{Manuscript information:} 49 words in Abstract and 1343 words in
Main text

1 Figure (1 black \& white figure) and 1 Table.

\textbf{Correspondence authors}

Xinling Liang, Department of Nephrology, Guangdong Provincial People's
Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080,
People's Republic of China

Phone: +8613808819770; Fax: (86)20-83827812-62027;
E-mail:xinlingliang\_ggh@163.com

Shuangxin Liu, Department of Nephrology, Guangdong Provincial People's
Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080,
People's Republic of China

Phone: +8613543456446; Fax: (86)20-83827812-62027;
E-mail:13543456446@163.com

Abstract

Neuropsychiatric systemic lupus erythematosus (NPSLE) is usually
associated with a worse prognosis. However, there are few effective
treatments for NPSLE. We described protein A immunoadsorption treatment
for a patient with NPSLE. The patient's brain lesions was improved
rapidly after two sessions of protein A immunoadsorption combination
with immunosuppressive agent treatment.

\textbf{Key Words:} Protein A immunoadsorption, Neuropsychiatric
systemic lupus erythematosus,

\subsection*{Key Clinical Message}

{\label{key-clinical-message}}

We described firstly protein A immunoadsorption combination with
immunosuppressive treatment improved rapidly a patient with NPSLE.

\subsection*{1 INTRODUCTION}

{\label{introduction}}

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with
a broad spectrum of clinical presentations {[}1{]}. The neuropsychiatric
SLE (NPSLE) presents with heterogeneous symptoms, such as headache,
cognitive impairment, memory loss, seizure and stroke which contributes
considerably to morbidity and mortality. The development and
deterioration of NPSLE are associated with the formation of a large
number of auto-antibodies and circulating immune complexes in the body,
which could cause severe brain damage and even life-threatening {[}2{]}.
Inhibiting or removing pathogenic auto-antibodies could prevent their
pathological outcomes {[}1{]}. Severe NPSLE should be treated with
immunosuppressive and biological agents. However, some patients are not
sensitive to these drugs. Protein A immunoadsorption (IAS) has been
shown to improve disease activity and lower glucocorticoid dosages in
lupus nephritis {[}3{]}. Braun and colleague reported that protein A
immunoadsorption had effect on severe and therapy-resistant SLE, which
suggested IAS as a possible option when other therapies were ineffective
{[}4{]}. We presented a case of NPSLE, who received 3 sessions of IAS
treatment after poor responses to immunosuppressive agents. The
significant improvement of brain magnetic resonance imaging (MRI)
manifestations have been firstly reported after the comprehensive
treatments.

\textbf{2 CASE HISTORY}

A 20-year-old woman, who had fever and red rash on her face, and was
admitted firstly on April 2016. Plasma antinuclear antibody (ANA),
anti-dsDNA and proteinuria were increased. She was diagnosed as SLE and
lupus nephropathy (type II) by kidney biopsy. Oral methylprednisolone
(MP, 40mg daily) and hydroxychloroquine (HCQ, 100mg,~twice daily) were
prescribed. The rash fade and the proteinuria completely relieved after
2 months treatments. She regularly decreased the dosage of MP. On August
2018, when the MP was reduced to 4mg daily, the rash on face reappeared.
Two months later, her right eye presented with blurred vision. The blood
tests indicated an elevated of ANA titer to 1:1280, anti-dsDNA
concentration to 74.5 IU/ml. The blood IgG concentration was 18.1 g/L.
The plasma C3 level slightly declined and proteinuria stayed normal. HCQ
was stopped immediately and MP of 12mg daily was given. Although the
rash soon improved, the patient had fever, and the visual impairment
developed to both sides. The first cerebrospinal fluid (CSF) examination
showed a normal tension of 170 mmH\textsubscript{2}O, with an increased
protein concentration of 922 mg/L, a slightly elevation of IgG level and
leukocyte count. Pathogen examinations including bacterial, fungal
cultures and variety of viral antibodies were all negative in the CSF
and blood tests. In brain MRI scan, the axial fluid attenuated inversion
recovery (FLAIR) sequence showed hyper-intense in the right basal
ganglia and bilateral peri-ventricular white matter, without abnormal
enhancement (Figure 1 A-C). Ophthalmic examinations suggested retinal
vasculitis in both eyes. The patient was identified as NPSLE with a
disease activity score of 19 (brain damage, visual impairment, rash, and
fever). Intravenous MP (500mg daily for 3 days) and cyclophosphamide
(200mg every other day) were prescribed. Prednisolone of 45 mg daily was
given subsequently.

However, the vision did not improve after intravenous MP combined with
cyclophosphamide treatment. The second brain MRI scan showed that
lesions of abnormal hyper-intense were increased in the right lateral
temporal cortex, right thalamus bilateral basal ganglia, insular lobe
external capsule, and peri-ventricular white matter on FLAIR images.
Intravenous MP (500 mg daily for 3 days) were used again, and rituximab
(500mg) was prescribed twice. Intrathecal injections of methotrexate and
dexamethasone were performed weekly for a total of six times. Although
the patient was treated with intensive therapy, the CSF examinations
turned out to be a significantly increase of tension (218
mmH\textsubscript{2}O) and protein concentration (2187 mg/L), and area
of brain lesions still expanded by MRI scan (Figure 1 D-F). The
patient's consciousness become worse accompanied with dysphagia.

Because prednisolone and immunosuppressive agents had no effects on
retinal vasculitis and consciousness, protein A IAS (KONCHEN Biotech.
Co., Ltd., Guangzhou, China) was performed. Three protein A IAS sessions
were executed. Each session ran 6 circles and total volume of plasma
adsorption was 3600 ml. Her consciousness got better soon after the
first session. After the second session, examination of CSF showed a
normal tension of 165mmH\textsubscript{2}O and a decrease of protein
concentration to 547 mg/L. The brain lesions on MRI were found to be
significantly reduced (Figure 1 G-I). Plasma IgG decreased significantly
after each IAS sessions (Table 1).The protein A IAS was interrupted
because of catheter related deep vein thrombosis after the third
section. Two weeks later, the patient discharged with oral MP (40mg
daily). Her consciousness and strength completely recovered after one
month, but the vision has still not restored.

\textbf{3 DISCUSSION}

The patient became severe during the process of glucocorticoid
reduction, and her brain was involved in damage. Although the changes of
laboratory tests were mild, the neuropsychiatric symptoms and brain MRI
were progressive. The symptoms became worse, even if intensive
immunosuppressive and biological agents were prescribed. It was worthy
of note that, the brain MRI was rapidly improved after two sessions of
IAS were performed, together with intravenous cyclophosphamide and
immunosuppressive therapy.

Glucocorticoid combination with intravenous pulse cyclophosphamide is
the most classical strategy for SLE with major organs involved {[}5{]}.
It's effective in many case, but not all situations. When common
strategies are contraindicated or fail in life-threatened SLE,
extracorporeal treatments are performed. Although plasma exchange could
non-selectively remove the antibodies, it is reported to be not
effective in prospective trail {[}6{]}. In contrast, IAS can reduce
significantly the concentration of IgG in blood without loss of
coagulation factors and plasma albumin. Stummvoll and colleague found
that IAS improved significantly disease activity and lowered
glucocorticoid dosages in SLE patients {[}3,7{]}. These patients showed
benefits within 3 months of treatment and stabilization thereafter. IAS
might be used as an optional treatment when other therapies are not
effective in SLE {[}4{]}.

NPSLE is associated with a worse prognosis, and brain MRI scan is
recommended to evaluate brain lesions in patients {[}8{]}. The most
frequent MRI findings are focal lesions in subcortical white matter,
cortical atrophy, diffuse cortical grey matter changes, less brain and
corpus callosum volumes in patients with NPSLE {[}9,10{]}. The patient
showed abnormal hyper-intense in right basal ganglia at the beginning,
similar to cerebral infarction. When the disease progressed, atrophy of
the brain, diffuse white matter and multiple nuclear lesions were
identified. The formation of these manifestations contribute to
blood-brain barrier dysfunction, cerebrovascular disease, serum and CSF
autoantibody-mediated injury {[}11{]}. Microinfarcts may be responsible
to retinal vasculitis and basal ganglia lesions in this patient. The
auto-antibodies deposition in the brain play an important role in the
pathogenesis {[}12{]}. Some of them, such as antiphospholipid
antibodies, are reported more likely to be elevated in NPSLE {[}13{]}.
Besides, evidences suggest that these immunoglobulins and immune cells
could leak into brain tissue and cause immune responses.

The ability of elimination of circulating complexes by protein A IAS was
confirmed in several autoimmune diseases {[}14-16{]}. Braun and
colleague reported the elimination kinetics of IgGs and circulating
immune complexes in vivo during the treatment of severe SLE {[}17{]}. It
showed that all IgG subclasses were removed from the patient's plasma.
The half time of IgG elimination is 4.8 days during intermittent
therapy. Protein A IAS decreases IgG levels in the blood, leads to a
reduction IgG in cerebrospinal fluid, and then improves the clinical
symptoms of NPSLE. The immunosuppressive treatment could reduce the
recomposition and redistribution. Thus the treatment of adsorption could
be better, when immunosuppressive agents are prescribed. Because of
competition for protein A binding sites, intravenous immunoglobulin
prevents the rapid decline of IgG in the patients,which is suggested to
be avoided during protein A IAS treatment{[}17{]}.

\textbf{4 CONCLUSION}

In summary, we firstly reported a case of NPSLE with severe brain
damage, who was improved rapidly after protein A IAS combination with
immunosuppressive treatment. Although IAS treatment is effective in the
patient with NPSLE, we need to do more~~studies to verify the
effectiveness of protein A immunoadsorption in future.

\textbf{Abbreviations}

SLE, systemic lupus erythematosus; NPSLE, neuropsychiatric systemic
lupus erythematosus; IAS, immunoadsorption; MRI, magnetic resonance
imaging; ANA, antinuclear antibody; MP, methylprednisolone; HCQ,
hydroxychloroquine; CSF, cerebrospinal fluid; FLAIR, fluid attenuated
inversion recovery.

\textbf{Acknowledgements}

We acknowledge Guobiao Hong and Li Song in the blood purification center
of Guangdong Provincial People's Hospital for operating and providing
medical care during the patient's protein A immunoadsorption treatments.

\textbf{Funding}

This study was supported by National Natural Science Foundation of China
(81670656,81870508, funder SXL), China Postdoctoral Science Foundation
(2017M612624, funder RYL),Natural Science Foundation of Guangdong
Province (2014A030313544, funder CSH), Guangdong Science and Technology
Fund (2014A020209001, funder CSH),Guangdong Medical Science and
Technology Research Fund (A2017564, funder RYL), Guangzhou City Science
and Technology Project (201707010009, funder SXL). These funding support
part treatment fee.

\textbf{Availability of data and material s}

The clinical data regarding this case is stored in hospital medical
records.

\textbf{Authors' contributions}

All authors have read and approved the manuscript.

FW and RYL collected the clinical data of the patient, performed the
literature search and drafted the manuscript. XLW provided and evaluated
the MR image and drafted part of the manuscript. ZLF and ZLL
participated in the data collection. XF, SJL, ZL, SL, WJW, CSH, and WS
established the diagnosis and agreed the patient's management plan. BH
participated in preparation the results of the MR images. XLL and SXL
supervised and drafted the manuscript.

\textbf{Ethics approval and consent to participate}

Because it is a case report, this study was exempted from research
ethics committee review (Ethics committee of Guangdong Provincial
People's Hospital). The patient has gave consent for publication.

.

\textbf{Consent for publication}

Written informed consent was obtained from the patient for publication
of this case report. A copy of the consent form is available for review
and can be provided on request.

\textbf{Competing interests}

The authors declare no competing interests.

\textbf{References}

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\textbf{Legends}

\textbf{Figure 1} . The changes of brain lesions in patient's MR scan
during treatment.

The abnormal signals could be found in axial fluid-attenuated inversion
recovery (FLAIR) sequences. Patients' first MRI showed diffuse and
symmetric hyper-intense areas in the bilateral peri-ventricular white
matter, basal ganglia and insula (A-C). Compared with first MR scan, the
area of brain lesions expanded obviously before protein A
immunoadsorptions treatment (D-F). After two sessions of protein A
immunoadsorptions, FLAIR images of MRI decreased significantly area of
lesions (G-I).

\textbf{Table 1.} Changes of blood immune indicators before and after
immunoadsorption sessions.\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/Figure-1Ai-Qi-Yi-/Figure-1Ai-Qi-Yi-}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/319232/articles/448978-protein-a-immunoadsorption-combination-with-immunosuppressive-therapy-improve-neuropsychiatric-systemic-lupus-erythematosus-a-case-report}

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