Neuropsychiatric (NP) involvement is one of the most complex and challenging features of systemic lupus erythematosus (SLE) encompassing the central (CNS), peripheral (PNS) and autonomous nervous system (ANS) as defined by the 1999 American College of Rheumatology standard nomenclature and case definitions. NPSLE has a negative impact on patient’s quality of life and is associated with increased morbidity and mortality. The full disease burden of NPSLE is not clearly known, because robust epidemiology studies are lacking or biased by different methodology design. A realistic estimate of the prevalence of NP involvement in SLE is around fifty percent of SLE patients.

The challenge of diagnosis: As none of the NP syndromes that occur in SLE have features that are specific for SLE, determination of the correct attribution of NP events in SLE patients is a challenging but critical step in the treatment of individual patients and in performing research studies. In fact, erroneous attribution can lead to suboptimal treatment and to incorrect designation of patient groups in research studies. Approximately 30% of all NP events are attributable to SLE (NPSLE) and present most frequently around the time of SLE onset. Modern and rapidly evolving neuroimaging technologies can help clinicians in both diagnosis and follow up. A multidisciplinary expert team represents the best strategy for NPSLE.

The challenge of treatment: The main proposed pathogenetic pathways include both ischemic and neuroinflammatory mechanisms with evidence for complement and microglia activation. Following diagnosis and causal attribution, the treatment of NPSLE should be tailored to the type of NP event, the predominant putative pathogenic mechanism, in addition to the history (acute or chronic), activity and severity of the clinical event. To treat NPSLE, in the absence of high-level evidence, it is necessary to develop pragmatic therapeutic strategies supported by expert opinion, published observational cohort data on NPSLE and extrapolation from experience with other organ system disease in SLE. To date, therapeutic options include symptomatic, anti-thrombotic and immunosuppressive agents. Therapeutic recommendations released by EULAR in 2010 and, more recently, by ACR/EULAR in 2019 are available.^1–5

Although neuropsychiatric manifestations of SLE have been recognised for over 100 years, unmet needs for patients with NPSLE still exist, including a lack of diagnostic biomarkers, lack of novel therapies and lack of clinical trials, which should be focused on future research agendas.

Learning Objectives

• Explain the diagnostic challenges in NPSLE with focus on the attribution and neuroimaging

• Discuss the current knowledge about the main pathogenetic mechanisms of NPSLE

• Explain the available and novel therapeutic options to treat NPSLE

• Describe unmet needs in the approach to the diagnosis and management of NPSLE

References

1. Govoni M, Bortoluzzi A, Padovan M, et al. The diagnosis and clinical management of the neuropsychiatric manifestations of lupus. J Autoimmun 2016;74:41–72.

2. Bortoluzzi A, Scirè CA, Bombardieri S, et al. Development and validation of a new algorithm for attribution of neuropsychiatric events in systemic lupus erythematosus. Rheumatology (Oxford) 2015;54(5):891–8.

3. Hanly JG, Kozora E, Beyea SD, et al. Review: Nervous System Disease in Systemic Lupus Erythematosus: Current Status and Future Directions. Arthritis Rheumatol 2019;71(1):33–42.

4. Nikolopoulos D, Fanouriakis A, Boumpas DT. Update on the pathogenesis of central nervous system lupus. Curr Opin Rheumatol 2019;31(6):669–77.

5. Schwartz N, Stock AD, Putterman C. Neuropsychiatric lupus: new mechanistic insights and future treatment directions. Nat Rev Rheumatol 2019;15(3):137–52.