Cognitive dysfunction (CD) is a well-known and frequent complication of systemic lupus erythematosus (SLE) and it is one of the 19 SLE-associated neuropsychiatric manifestations.1 The American College of Rheumatology (ACR) defines cognitive dysfunction as a “significant deficit in any of the following cognitive functions: simple or complex attention – reasoning – executive skills – memory – visual-spatial processing – language and psychomotor speed”.2

Studies have shown that the prevalence of CD ranges from 3% to 80%.3–5 Methodological differences, diverse studies’ designs and different population ethnic backgrounds may account for some of this variability. This condition exerts a significant impact on patients’ lives, affecting their social relations, professional integration, family dynamics and even treatment adherence.6 Recognition and treatment of CD are essential for enhancing the individual's quality of life. Although CD is a major concern in SLE patients and considered one of the most frequent complaints among the neuropsychiatric manifestations of the disease, there is a poor understanding of the progression of this clinical manifestation. Some studies suggest a potential association between CD and the development of future dementia7,8; other studies have found that cognitive function remains stable for 5–10 years,9,10 while a third group of researchers argues that these individuals may even show improvements in their condition.11

There is limited data on long-term follow-up of patients with cognitive impairment in SLE and no studies specifically focusing on the Brazilian population in this context has been found. Therefore, the objective of this study was to examine the evolution of cognitive performance in a sample of Brazilian SLE patients for 2 years.

This prospective study was approved by the Institutional Research Ethics Committee under protocol 39920920.2.0000.0103. All participants signed an informed consent.

A total of fifty SLE patients were included in the study. In this sample 34/50 (68%) patients had cognitive impairment (all mild). Table 1 shows the description of the studied sample as well as the comparison between patients with and without cognitive impairment at baseline assessment. The results showed that age, sex, comorbidity, presence of autoantibodies, disease duration, SLICC ACR/DI, depression and cumulative glucocorticoid dose were not associated with cognitive impairment; but formal education was associated with a lower prevalence of CD. Considering the MoCA domains, SLE patients with CD had lower scores in visuospatial/executive, naming, attention and delayed recall areas compared to those without CD.

The reassessment occurred in a median of 2.1 (1.5–2.4) years. In this second assessment 37/50 (74%) had cognitive dysfunction (all mild). Table 2 shows the results of the follow-up assessment. The total MoCA score remained stable, but that the domain abstraction showed improvement. The sample also had higher levels of depression and higher cumulative damage index at the second assessment when compared to the first. None of the individuals who had SLICC worsening had new central nervous system damage. Regarding medication use, there was an increase in the use of mycophenolate mofetil and a reduction in glucocorticoid dose.

The correlation between delta in the MoCA scores (second score minus first score) and delta CES-D – delta SLEDAI 2K and delta SLICC/ACR DI did not show any statistical significance (all with p>0.05).

In the second assessment, six (12%) patients showed a decline cognitive function (went from normal to mild cognitive dysfunction), while 3 (6%) patients showed improvement in cognitive function (went from mild cognitive dysfunction to normal).

The comparative analysis between the sample that had a decline in cognitive function in relation to the sample that did not have a decline is shown in Table 3. None of the epidemiological findings, comorbidity, disease activity or damage index were able to identify individuals who had a decline in cognitive function.

The results of this study show that more than half of SLE patients had mild cognitive impairment and this percentage increased with time. Although improvement was noticed in 3 patients – suggesting that this is an ongoing process that requires periodic assessment. Cognitive rehabilitation and exercise training remain as important interventional approaches16 but there is currently no effective preventive pharmacological treatment, as the pathophysiology of this process is poorly understood. Some proposed mechanisms are autoantibodies, cytokine-mediated neuronal dysfunctions, vasculopathy, and coagulopathy.11 Nysted et al.16 conducted a study with 61 females with SLE and found that patients with and without neuropsychiatric involvement had changes in the functional connectivity of core resting state networks, which play a crucial role cognitive function. Chessa et al.17 found an association between serum levels of anti-P antibodies and brain network perturbation. However, no association was established between cognitive dysfunction and this autoantibody. Antiphospholipid antibodies have also been associated with neuronal dysfunction as a result of thrombosis of small vessels and the direct impact on neuronal cells – leading to changes their function.5 Nevertheless, the findings in this context are also controversial. A study of 131 SLE patients found an association between anticardiolipin IgM and cognitive dysfunction.18 This association was not found in the study conducted by Hanly et al.19 These latter authors considered that the blood-brain barrier leakage alone was associated with cognitive impairment, regardless of SLE related autoantibodies including antiphospholipids.19 In the present study, three patients had antiphospholipid antibody syndrome: two of them had normal MoCA values and one had mild cognitive dysfunction at baseline. None of them was in the group with deterioration of cognitive function; they were fully anticoagulated. Five additional patients tested positive for antiphospholipid antibodies without exhibiting clinical manifestations of antiphospholipid syndrome. Of these, three presented with mild cognitive impairment, and one was among those who showed improvement in cognitive function in the second evaluation.

The only MoCA domain that exhibited a statistically significant difference in the follow-up period was “abstraction”, with some degree of improvement. Abstraction refers to the extent to which processing/representation is connected to or disconnected from particular instances and the prefrontal cortex plays an important role in this cognitive ability.20 This item accounts for only 2 points out of the total 30 points in the MoCA instrument. This minor contribution to the final result may explain why abstraction improved, but the median value of the total MoCA score remained the same. This ability can be trained by engaging in practices that focus information filtering, identifying similarities, and mapping problem structure.21 The observed improvement in this study may be attributed to certain stimuli that individuals were intentionally or unintentionally exposed to in their daily lives. It also possible that the increase in abstractive capacity in the sample might be biased, given that patients took the MoCA test twice throughout the trial and may have retained their responses from the first administration.

Another finding of the present study was that there was no correlation between disease activity, measured by SLEDAI 2K, or depression and changes in cognitive function. Our sample had a very low median SLEDAI, which may have prevented the detection of positive findings. Previous studies have already reported a lack of association between cognitive dysfunction and the disease's clinical activity.10–13 Moreover, Raghunath et al.22 could not associate cognitive dysfunction with anti dsDNA presence or with interferon gene signature but found an association with cumulative damage mainly in the neuropsychiatric domain.

We could not associate changes of CES-D values with changes in the MoCA results. Touma et al.,23 studying the trajectories of cognitive function and depressive symptoms during 7 years in 755 SLE patients, found that in 9% of their patients the cognitive impairment was associated with depression status. Trends of depression in persons with SLE over time have not been consistently reported in literature, despite of this symptom being very common.24 The interplay between cognition and depression may be difficult to interpret. Raghunath et al.25 found that mood disorders were more consistently associated with patient-reported cognitive symptoms than with objective cognitive dysfunction, and Vogel et al.26 demonstrated that affective status may influence subjective experience of cognitive functions even more than cognitive functioning itself. Furthermore, subclinical depression is not always easily recognized but still may contribute to cognitive dysfunction.27

Regarding the treatments administered, baseline results revealed that none of the medications – including the cumulative prednisone dose, exerted any measurable influence. It has been shown that glucocorticoid administration can impact cognitive functions, particularly memory. In animal research, acute glucocorticoid exposure impairs working memory by interacting with the β-adrenoceptor-cAMP signaling pathway, increasing PKA activity in the prefrontal cortex.28 In lupus patients, prednisone doses >9mg/day were independently associated with diminished mathematical processing abilities, an indicator of poorer working memory.29 Conversely, in another study, a short course of prednisone in mild lupus cases enhanced cognition and mood.30 Lim et al.31 observed that the total cumulative corticosteroid dose did not correlate with cognitive performance, echoing our current findings. Among the five patients who experienced cognitive changes during the study, only one – who exhibited cognitive decline – increased their prednisone dosage by 5mg/day; the remaining patients were not on glucocorticoids during either evaluation.

This study is limited by its small sample size and relatively short follow-up period. The limited number of participants may have reduced the statistical power, potentially hindering the detection of significant associations or effects. Future studies with larger sample sizes, with controls and extended follow-up durations are warranted to enhance the validity and generalizability of the findings. Additional potential contributors to cognitive dysfunction – such as sleep disorders and associated fibromyalgia – were not explored currently and warrant further investigation. Another limitation of our study is the lack of information on any cognitive abilities training the patients might have received during this period, although it is known that none underwent formal training. Nevertheless, it should be noted that patients may become familiar with the MoCA during the initial administration, potentially affecting their performance in subsequent evaluations. Including a control group would clarify changes due to aging alone versus those from aging combined with lupus. Additionally, the changes observed in the SLEDAI scores were minimal, as most patients had well-controlled disease activity; greater fluctuations could better demonstrate their influence on cognition. Furthermore, the ACR recommends conducting a comprehensive test battery (ACR-SLE battery) to assess neuropsychological function in SLE, which was not utilized in this study.2 Image studies such as MRI could offer additional information. However, these tests are costly, time-consuming, and often not feasible in real-world settings. MoCA is widely considered a practical and reliable tool for assessing cognitive decline or improvement in clinical practice.32,33

In conclusion, the follow-up of two years in cognitive function in SLE patients showed that this is a dynamic process and it was not associated with disease activity, disease damage or depression in the studied sample.

Idea/concept: Design: ESD, JHTV, EAB, TS and RN. Control/supervision: TS and RN. Data collection and/or processing: ESD, JHTV, MHF, TAGS. Analysis and/or interpretation: ESD, JHTV, EAB, TAGS, TS and RN. Literature review: ESD, JHTV, EAB. Writing the article: TS and RN. Critical review: All the authors.

A written informed consent was obtained from each patient.

This is a prospective study approved by the Institutional Research Ethics Committee (CAAE: 68969823.7.0000.0103) under protocol 39920920.2.0000.0103. The study was conducted in accordance with the principles of the Declaration of Helsinki.

The authors received no financial support for the research and/or authorship of this article.

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

The data that support the findings of this study are available from the corresponding author upon reasonable request.