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Yimaitong edited and sorted, please do not reprint
without authorization.
NPSLE is one of
the leading causes of morbidity and mortality in patients with SLE.
Its clinical manifestations are complex, neuropsychiatric events often overlap with non-lupus-related neuropsychiatric events, and the current understanding of neural tissue is limited, so the potential pathogenesis of NPSLE is still unclear and management optimization is limited
.
This article will review the latest progress in the pathogenesis and management of NPSLE, and discuss new ideas and new directions in treatment1
.
This review was recently published in the journal J.
Zhang Shangzhu, deputy chief physician of the Department of Rheumatology and Immunology of Peking Union Medical College Hospital, and others.
Clin.
Med.
。
Pathogenesis of NPSLE
The pathogenesis of NPSLE is complex and unclear
.
Ischemia and autoimmune-mediated neuroinflammatory pathways are thought to be the two main and potentially complementary pathogenesis leading to NPSLE (Figure 1).
Figure 1 Pathogenesis of diffuse NPSLE
Ischemic pathway
Antiphospholipid (aPL) antibodies, immune complexes, and complement activation-mediated ischemic injury of large and small vessels can lead to focal (e.
g.
,
g.
, cognitive dysfunction) neuropsychiatric manifestations
.
Among them, aPL antibodies play a leading role in intravascular thrombosis, and may also increase the risk of subclinical
.
In addition, complement activation is associated
with focal NPSLE, psychosis, and cognitive dysfunction.
Neuroinflammatory pathways
Complement activation of autoimmune-mediated neuroinflammatory pathways, increased blood-brain barrier (BBB) permeability, intrathecal migration of neuronal autoantibodies, local production of pro-inflammatory cytokines, and other inflammatory mediators are associated with most diffuse neuropsychiatric manifestations, such as psychosis, mood disorders, and cognitive dysfunction
.
Management of NPSLE
The pathogenesis of NPSLE is complex, difficult to diagnose, and there is a lack of relevant clinical trials, making its management challenging
.
Current treatment regimens for NPSLE are usually derived from observational studies or from experience with other SLE subtypes
.
Therefore, for better management of NPSLE, it is critical to develop practical treatment strategies to determine whether the cause of neurological disorders is SLE or non-SLE, or both
.
The 2019 European Union Against Rheumatism (EULAR) guidelines for the management of systemic lupus erythematosus2 states that the identification of neuropsychiatric manifestations in relation to SLE requires a combination of neuroimaging, cerebrospinal fluid testing, risk factors (type of neuropsychiatric manifestations, presence or absence of SLE onset, age of the patient, extraneurological lupus activity, presence of aPL antibodies), and exclusion of other confounding factors
.
The management goals of NPSLE should meet two criteria, the first being symptomatic treatment
.
The 2021
for the treatment of neuropsychiatric symptoms such as
Second, treatment should be selected based on whether the patient's pathogenesis is primarily related to inflammation or ischaemic pathways (Figure 2).
Figure 2 Treatment of NPSLE
Treatment targeting inflammatory pathways
Glucocorticoids are the cornerstone of NPSLE therapy, particularly NPSLE
associated with the immuno-inflammatory pathogenesis.
High-dose corticosteroids have been reported to be effective
in therapy with
However, there is evidence that glucocorticoid use is associated with accumulation of organ damage and psychiatric symptoms in SLE, so alternative agents
need to be sought.
There is a lack of high-level clinical evidence for the optimization of NPSLE therapy, and only two agents (oral
.
In addition, after 6 months of oral cyclophosphamide treatment, maintenance therapy with azathioprine was more
effective.
is needed.
The 2020 Chinese Guidelines for the Diagnosis and Treatment of Systemic Lupus Erythematosus4 proposed that for patients with severe NPSLE, it is recommended to first undergo hormonal shock therapy, and cyclophosphamide
can be added when the effect is not good.
In patients with severe NPSLE, high-dose pulse methylprednisolone therapy with intravenous cyclophosphamide improves psychiatric symptoms and is better than
.
The 2021 APLAR Consensus Statement also recommends that rituximab may be considered for the treatment of inflame-induced refractory NPSLE.
In the 2019 EULAR guidelines, rituximab may be considered for severe lupus nephritis, haematological involvement, and neuropsychiatric lupus if SLE endangers organ function and conventional immunosuppressants are ineffective, intolerable, or contraindicated, i.
e.
, rituximab can be considered as a second-line agent for severe
.
Treatment of ischemic pathways
It is now thought that the cerebral ischemic events caused by NPSLE are associated
with aPL antibodies.
Therefore, primary prevention of NPSLE cerebral ischemia is associated
with a reduced risk of prethrombosis.
However, current recommendations for treatment and treatment goals are inconsistent
.
The 2021 APLAR consensus statement states that patients with NPSLE have thrombosis and are positive for aPL antibodies, requiring anticoagulation
.
In patients at high risk of thrombosis with aPL antibodies,
.
Low-dose aspirin (75 to 100 mg/day) can be used as the mainstay to prevent thrombosis in patients at high risk of aPL antibodies
, regardless of the presence or absence of other atherosclerotic risk factors.
However, a previous review on primary prevention of
in patients with cardiovascular risk factors.
Also, the optimal target for the international normalized ratio (INR) is inconsistent in these patients, with the recommended INR target of 2.
5 to 3.
0 for patients with APS, and 3.
0 to 4.
0
for patients with thrombosis recurrence after warfarin therapy.
However, in controlled trials in patients with APS, there was no clear difference
between low-intensity (target INR 2.
0 to 3.
0) and high-intensity (target INR >3.
0) warfarin in preventing thrombotic recurrence.
Therefore, higher quality clinical trials are needed to address this issue
.
Current evidence is insufficient to recommend the direct use of novel oral anticoagulants for the prevention of aPL antibody-mediated thromboembolic events
.
Potential adjunctive therapies also include antimalarials and statins, particularly in patients with
recurrent arterial and venous thrombosis.
Statins prevent aPL antibodies secondary to endothelial cell activation, while antimalarials prevent thrombosis
in patients with SLE.
Potential targeted therapy for NPSLE
Experience with targeted therapy with NPSLE is limited, but based on current understanding of the pathogenesis of NPSLE, the reduction of neuropsychiatric symptoms in relevant animal models shows the potential of targeted therapy (Table 1).
Table 1 Potential targeted therapies for NPSLE
Note: BBB: blood-brain barrier, MMPs: matrix metalloproteinases, IFN:
conclusion
Neuropsychiatric events are common and heterogeneous in patients with SLE, and there is limited understanding of NPSLE and its clinical management, and most of the current treatment is empirical
.
In the future, further exploration and research are needed to enhance the understanding of the pathogenesis of NPSLE and improve the ability to
diagnose, predict and treat NPSLE.
References:
1.
Wang, M.
; Wang, Z.
; Zhang, S.
; Wu, Y .
; et al.
Progress in the Pathogenesis and Treatment of Neuropsychiatric Systemic Lupus Erythematosus[J].
J.
Clin.
Med.
2022, 11, 4955.
https://doi.
org/10.
3390/ jcm11174955
2.
Fanouriakis A, Kostopoulou M, Alunno A, et al.
2019 update of the EULAR recommendations for the management of systemic lupus erythematosus[J].
Ann Rheum Dis.
2019 Jun; 78(6):736-745.
doi: 10.
1136/annrheumdis-2019-215089.
Epub 2019 Mar 29.
PMID: 30926722.
3.
Chi Chiu Mok,Laniyati Hamijoyo,Nuntana Kasitanon,et al.
The Asia-Pacific League of Associations for Rheumatology consensus statements on the management of systemic lupus erythematosus[J].
Lancet Rheumatology.
2021; 3(7):e517-e531.
4.
2020 guidelines for the diagnosis and treatment of systemic lupus erythematosus in China[J].
Chinese Journal of Internal Medicine, 2020(03): 172-173-174-175-176-177-178-179-180-181-182-183-184-185.
5.
JI Lanlan, ZHANG Zhuoli.
The road to achieving the standard of systemic lupus erythematosus: interpretation of the 2019 European Union Against Rheumatism guidelines for the management of systemic lupus erythematosus[J].
Peking Union Medical Journal, 2020, 11(03):283-288.
