Patients with a rheumatological diagnosis in a psychiatrist's office - neuropsychiatric lupus

Introduction: Systemic lupus erythematosus is an autoimmune disease affecting up to 210 per 100,000 people in Europe, more often among women. The inflammatory process in lupus causes changes in various organs. However, somatic changes are not the only effects of lupus. The neuropsychiatric manifestations of this disease have been given a separate name – neuropsychiatric lupus. Material and methods: A review of the literature available on the PubMed platform in the period of 1987-2023 was performed using the key words: neuropsychiatric systemic lupus erythematosus, mental disorders, mood disorders, sleep disorders, systemic lupus erythematosus. Original studies, review works, meta-analyses and Internet sources were analyzed. Results: Psychotic disorders in lupus occur with a frequency of up to 3%. Risk factors include young age, male gender and glucocorticoids treatment. Mood disorders occur in several to several dozen percent of lupus patients, including depression affecting up to ⅓ of patients. Belimumab, psychotherapy and improving the quality of sleep, the disturbance of which is observed in most patients with lupus, have potential in treatment. Anxiety disorders are seen primarily in the teenage age group, where social phobia predominates – the fear of rejection due to the disease – and they worsen and are exacerbated by rheumatic disease. Cognitive dysfunctions occur in up to 80% of lupus patients. They are probably related to enzymes of metabolic pathways, dyslipidemia and thyroid dysfunction. Conclusions: Mental disorders develop more often in patients with lupus than in the general population and they predispose to autoimmune diseases. Comprehensive diagnosis and psychiatric care of patients with lupus are necessary.


Introduction
Systemic lupus erythematous (SLE) is a systemic autoimmune disease.During its course, it can lead to pathological changes in many regions of the body, leading to a various symptoms, ranging from mild skin manifestations to organ failure.Possible clinical manifestations included in the SLE classification criteria are presented in Table 1 [1].The occurrence rate of SLE ranges from 29.3 to 210 per 100,000 people in Europe, while in North America it ranges from 48 to 366.6 per 100,000 people [2].It is estimated that 9 out of 10 people with SLE in Europe are women [3][4][5].Differences depending on gender are also observed in the peak incidence of SLE, which in women falls on the reproductive period, and in men -at the age of 50-70 years [4,6].A metaanalysis by Lee et al. [7], including over 26,000 patients with SLE, showed that their standardized mortality ratio (SMR) was 2.6 times higher than the general population.The death causes significantly associated with increased SMR included kidney diseases, cardiovascular diseases and infections, with no significant relationship between cancer and increased SMR [7].
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a term covering neuropsychiatric manifestations associated with SLE.These syndromes and symptoms may occur as primary, secondary or consequences of the treatment.The causes of NPSLE are considered to be processes leading to abnormalities mainly in two areas: inflammatory and ischemic [8].The causes of these disorders are not fully specified, but it is believed that genetic and environmental factors, e.g.exposure to ultraviolet radiation, stress and endogenous retroviruses, play an important role [9].
In 1999, the research committee of The American College of Rheumatology distinguished 19 possible manifestations of NPSLE, including: acute confusional state, psychosis, mood disorders, anxiety disorders and cognitive disorders (Table 2) [10].Of the 19 identified, the most common are cognitive disorders, headache, and mood disorders [11].Table 3. presents the prevalence of the mental manifestations of SLE discussed in this work [11][12][13][14][15][16][17][18][19].The listed symptoms of NPSLE are not specific to SLE, and some of them may occur in the course of other diseases or independently, as separate conditions.The heterogeneity of the forms of NPSLE and the differences in time in relation to the onset of SLE symptoms make it difficult to make a correct diagnosis.Additionally, specific biochemical markers or changes in imaging tests of the nervous system that could direct the diagnostic process towards NPSLE have not yet been identified.The link between SLE and neuropsychiatric symptoms is therefore established by excluding other causes.This is problematic in clinical practice, especially among patients whose neuropsychiatric manifestations precede the diagnosis of SLE [8].

Aim and methods
The aim of the study was to review the literature and present the characteristics of mental disorders occurring in the course of SLE.The selection of the discussed units was guided by the division of NPSLE manifestations distinguished in 1999 by the American College of Rheumatology research committee.The focus was on psychosis, mood disorders, anxiety disorders and cognitive disorders associated with SLE.In addition, due to particularly frequent occurrence, the review included studies on sleep disorders in patients with SLE.The literature available on the PubMed platform in the period of 1987-2023 was reviewed using the following keywords: neuropsychiatric systemic lupus erythematosus, mental disorders, mood disorders, sleep disorders, systemic lupus erythematosus.

Psychosis
Psychoses in SLE are among the rarest mental disorders occurring in SLE patients (Table 3) [12,13,20,21].In most patients, the disorder occurred only once and had a good prognosis.They appeared shortly after the diagnosis of SLE -usually within 1-3 years of diagnosis [20,21].A case report of a 22-year-old patient indicates that psychosis may also be one of the first symptoms of SLE [22].Psychotic disorders in the course of SLE are mainly manifested by hallucinations (visual and auditory) and delusions (grandiose and persecutory) [23].
To make a diagnosis, it is necessary to exclude another cause of psychotic disorders, and a temporal relationship between SLE and psychotic disorders is also necessary [24].The literature describes rare cases of SLE patients whose psychotic disorders were caused by mental disorders (e.g.bipolar disorder, BD) preceding SLE [25].
The causes of psychosis in SLE patients are not fully understood.There are few clinical studies on this topic.They may be caused by the impact of a systemic disease on the brain [25].A multicenter cohort study involving 1 826 SLE patients reports the following factors as increasing the risk of psychotic disorders in SLE patients: patient age (the risk is higher among younger people), African origin (especially from outside the USA), male sex, and probably also the use of corticosteroids (here the most important factor was the dose, the higher, the greater the risk) [20].Psychotic disorders may be associated, although inconsistently, with anti-ribosome P antibodies [13,20,[26][27][28].The prognosis for patients was good [20].The average remission time was 120 months [21].
Treatment options include: prednisone, cyclophosphamide, azathioprine, methotrexate and mycophenolate mofetil, and also antipsychotic drugs -most often chlorpromazine and haloperidol.Some patients required plasmapheresis [20,21].Research suggests that patients with the most severe psychotic symptoms achieved complete remission by treatment with intravenous methylprednisolone [21].Tokunaga et al., in a study on 10 patients, observed significant improvement in SLE-induced psychosis after administration of rituximab [29].

Mood disorders
Depression is one of the most common and most widely known mental disorders [31].It co-occurs with many somatic disorders, such as diabetes [32], chronic pain [33], cardiovascular diseases [34] and SLE [35].According to various studies, the percentage of people with SLE who suffer from depressive disorders is 24%-35% [14,15,35,36].This percentage is several times higher than in the general population.However, not all the people with SLE present symptoms of depression, and their occurrence is correlated with factors such as low physical activity [37] or poor socioeconomic status [38].The more frequent occurrence of depressive symptoms is also associated with a greater severity of skin lesions [39].Patients over 60 years of age, married people and those who have visited a primary care physician in the last year and were satisfied with the visit are at lower risk [40].In SLE patients with comorbid depression, the risk of other somatic diseases also increases.One study showed that women with SLE and depression have an increased risk of developing subclinical atherosclerosis -they experience greater carotid intima-medial thickness (CIMT) [41].Additionally, it has been shown that depressive and sleep disorders mediate the occurrence of pain and cognitive dysfunctions in SLE [42].The situation is similar with fatigue, which in SLE patients is more often associated with co-occurring depression than with the severity of inflammation [43].Describing a simple cause and effect relationship is difficult in this case because depressed mood also intensifies the inflammatory reaction in SLE [44].It is proven that in the case of depression in people with SLE, the production of various pro-inflammatory interleukins (Il-6, IL-17) and 16α-OHE1-A is increased [44].
Research is being conducted to determine the clinical and therapeutic significance of the co-occurrence of depression and SLE in patients.The results of metaanalyses and clinical trials conducted by Xie et al. and Zhang et al. indicate that belimumab is a drug that does not increase the risk of: developing depression, other mental disorders and suicide when used in patients with SLE [45,46].Research indicates the effectiveness of psychotherapy in reducing symptoms of anxiety and depression in comorbid SLE [47].The lack of such an effect was demonstrated for physical exercises [48,49], although they improved physical performance, which is reduced in the course of SLE [50].
Bipolar disorder (BD) is characterized by alternating symptoms of mania (or hypomania) and depression, separated (or not) by symptom-free periods.It is estimated that it occurs in 4% of people in the general population [51].However, BD is more prevalent in the SLE population.It is estimated that BD occurs in approximately 6% of SLE patients [52].There are also case reports in the literature indicating the possibility of lupus disguised as bipolar disorder [53,54].Treatment of bipolar disorder in SLE is difficult because the substances used to control the autoimmune process often affect patients' mood.Studies indicate good effectiveness of gabapentinit is well tolerated and effective in controlling depressive symptoms and reducing pain [55].
In the course of SLE, the incidence of manic episodes is approximately 3.3% [56].The cause of mania may be SLE or the treatment used in its course -steroid therapy [57].Case reports indicate that manic symptoms may be the first symptom of SLE [54,58,59], or appear even 10 years after its diagnosis [58].Patients most often improve their clinical condition after treatment with, among others, corticosteroids or chlorpromazine [54,58].

Anxiety disorders
Anxiety disorders are one of the most common (Table 3), but also the most difficult to define and study, psychiatric disorders in SLE.The etiology of these disorders is not yet known [60][61][62].There is a view that anxiety and mood disorders in SLE may result from psychosocial stress associated with living with a chronic, disabling, poorly understood and socially isolating condition with an unpredictable course [9,63].Patients with anxiety, like those with depression, have a more negative perception of the disease, which correlates with pain, functional impairment, inability to work, poor sleep quality, and non-use of medications, regardless of disease severity [60,64].Studies have shown that patients with SLE have a higher level of sensitivity to stress than people without SLE [65], as well as a greater risk of experiencing life-threatening situations, including: as receiving a diagnosis of a chronic disease or hospitalization [66].The activity of SLE disease is the primary cause of anxiety disorders and is directly proportional to them.Effective treatment can alleviate the severity of mood disorders [67,68].
SLE can be particularly severe in childhood.Neuropsychiatric tendencies in this disease, as well as medications taken, may lead to the occurrence of anxiety disorders, often related to the chronic disease process in pediatric patients [69,70].Children and adolescents are particularly susceptible to these problems due to chronic disease and often lack of acceptance of this condition by peers.These burdens may lead to chronic anxiety [70][71][72].Taken medications, including glucocorticosteroids, have many side effects.They may lead to low mood, which Curr Probl Psychiatry, Vol. 25 (2024) increases the risk of depression and anxiety disorders, which may also present as NPSLE [70,73].Another cause of anxiety disorders in this group of patients is chronic pain, which reduces the quality of life [70,74].The occurrence of SLE in childhood is also associated with numerous hospitalizations, which intensify the symptoms of anxiety [70,75].
A study by Quilter et al. from The Hospital for Sick Children in Toronto showed that the prevalence of anxiety disorders in children with SLE was 16.1%.A cohort of 56 patients with SLE, with an average age of 15.4, was subjected to psychiatric examination by completing special questionnaires.The most common anxiety disorder was social phobia (7.1%), followed by generalized anxiety disorder (5.3%) [70].These results are slightly higher than in children in the healthy population.It is likely that patients, out of fear of stigmatization by doctors or caregivers, provide incorrect data in surveys so that the test result suggests minor disorders [76,77].There is a clear need for further research on anxiety and mood disorders in NPSLE [60].There is a lack of research in the literature on anxiety disorders themselves, as they very often coexist with depression [70,78].These symptoms negatively affect the therapeutic process and compliance with recommendations.Paper by Daphne Lew et al. from the Washington University in St. Louis School of Medicine show that there is still a lack of research on the effectiveness of pharmacological and behavioral therapies in patients with SLE [67].

Cognitive disorders
Patients with SLE often report problems with cognitive functioning [79].They significantly affect the quality of life and are one of the most common neuropsychiatric disorders observed in SLE [80][81][82].Cognitive deficits and "brain fog" are routinely reported [83].The literature states that the incidence of cognitive impairment in SLE ranges from several to several dozen percent (Table 3).Such a range of data is probably caused by different study cohorts and differences in the way cognitive disorders are classified [11].It is difficult to determine the cause of cognitive impairment in SLE, as it is a diffuse syndrome characterized by difficulties in measuring and determining the direct cause [82].Factors, such as mood disorders, medications, pain, fatigue, and sleep disorders are non-SLE-specific factors that affect cognitive functions [84][85][86].Specific processes involved in SLE, such as inflammation and disease activity, have been investigated to be associated with the development of cognitive impairment [84,86].It has been established that pro-inflammatory mediators, cytokines and metabolic factors are involved in the pathogenesis of the development of cognitive disorders in SLE.Autoantibodies, activation of the complement system and microglia mediate neurotoxicity, which results from disruption of the integrity of the blood-brain barrier [87].Autoantibodies and cytokines can have local or widespread effects on the central nervous system [88,89].Alternative theory says that Interferon-alpha (IFN-α) is the main factor in the pathogenesis of SLE.Its mechanism of action is the induction of the enzyme indoleamine 2,3-dioxygenase in the kynurenine/tryptophan (KYN/TRP) pathway.This process creates a neurotoxic imbalance of increased levels of quinolinic acid (QA) relative to kynurenic acid (KA).An increased ratio of these acids is a potential cause of the development of cognitive dysfunctions in SLE [90].
The study by Li Lu et al. confirmed that dyslipidemia and reduced thyroid hormone levels are the main risk factors for cognitive disorders in SLE.F-T3 and F-T4 levels have been shown to positively correlate with most cognitive functions.Patients with low cognitive ability had significantly lower F-T3 and F-T4 levels than patients with high cognitive ability.Moreover, lipid metabolism was significantly altered in SLE patients.The relationship between these factors results from the fact that thyroid hormones influence lipid metabolism.Scientists demonstrate the involvement of apolipoproteins in the development of neuroinflammation.The results of a Chinese study present a new perspective on thyroid hormones.It has been shown that F-T3 and F-T4 can be used as biomarkers of cognitive dysfunction in SLE patients, but this requires further research [91].
Cognitive symptoms are particularly common in patients with fibromyalgia and SLE and may include a subjective sense of memory loss, language problems, and disruptions in attention and/or executive functions.The study by Raghunath et al. shows that older age, low premorbid IQ and a history of cerebrovascular disease are significantly associated with cognitive dysfunction in univariate analysis [92].
It has been shown that cognitive symptoms reported by SLE patients correlate more with mood disorders than with objective cognitive deficits [93,94].
Research shows that the presence of cognitive dysfunctions in SLE may adversely affect daily functioning and professional work [93,94].For many SLE patients, cognitive symptoms are the most bothersome manifestation of their disease [81,95].In assessing cognitive disorders and their severity, an interview with the patient is extremely important.Particular attention should be paid to risk factors for vascular disease (such as hypertension and diabetes) and previous episodes of neurological disorders.The medications used are particularly important, as some of them reduce cognitive functions.The greatest influence is exerted by hypnotics and anti-anxiety drugs (mainly benzodiazepines), painkillers containing codeine, and anticholinergic drugs [87,96].
Cognitive dysfunction in SLE, despite its high incidence and clinical significance, is poorly understood and requires further research [97].

Disorders of consciousness
Acute confusional state is a diffuse neurological syndrome occurring in NPSLE with a frequency of 0.9-7% [18,98].It is characterized by a reduced level of awareness and attention [99].
The pathogenesis of consciousness disorders in lupus is not fully explained.It is probably based on two main and complementary pathogenetic pathways.Typically, an autoimmune neuroinflammatory pathway is associated with acute confusional state.Complement activation, increased blood-brain barrier (BBB) permeability, intrathecal migration of neuronal autoantibodies, local production of immune complexes and pro-inflammatory cytokines and other inflammatory mediators are the main processes occurring in this pathway [18,100].
In clinical diagnosis, the same tests should be performed as in patients without SLE to exclude other causes of consciousness disorders.A full neurological evaluation should be performed, focusing on additional symptoms, including headache, seizures, and motor and sensory deficits [11,98].The differential diagnosis should include at least: infections, metabolic imbalances, poisoning or withdrawal from drugs or psychoactive substances, or drug side effects [18].Imaging, laboratory and cerebrospinal fluid tests should be performed to exclude malignant tumors and other neurological diseases [11,98].
Research is being conducted to search for reliable laboratory and neuroimaging biomarkers in the diagnosis of NPSLE.It was noted that an increased level of IL-6 in the cerebrospinal fluid showed a positive correlation with acute confusional state [11,101,102].
In their research, E. Trysberg et al. used the measurement of IL-6 levels to support the diagnosis of acute confusional states and monitor the response to treatment.The study included 34 SLE patients, 17 of whom were diagnosed with NPSLE.In five of the patients successfully treated for CNS lupus, a profound reduction in the intrathecal level of IL-6 was observed compared to the state before therapy [103].
A study by T. Asano et al. showed that in NPSLE with acute confusional state, the level of IL-6 in the cerebrospinal fluid was increased compared to NPSLE not associated with acute confusional state.These results suggest that this is not the result of intrathecal IL-6 synthesis, but the result of damage to the blood-brain barrier and the associated flow of these substances [104].Similar results were obtained by S. Hirohata's team.Serum IL-6 and CSF IL-6 levels were compared between NPSLE patients and non-SLE controls.Among the examined subjects, it was significantly increased in patients with NPSLE in acute confusional state [105].
Acute confusion associated with active inflammation requires intravenous administration of corticosteroids in the form of pulses.In the treatment of acute confusional state, antipsychotic drugs are used, including low doses of haloperidol (<3.0 mg daily) and atypical antipsychotic drugs such as risperidone, risperidone, olanzapine, quetiapine.The next-line drugs are a combination of corticosteroids and classic immunosuppressive drugs, and in cases resistant to treatment, cyclophosphamide, rituximab, and immunoglobulins.Plasmapheresis can also be used, synchronized with intravenous cyclophosphamide administration [62,99,106].
Evidence for the effectiveness of biological therapies in NPSLE is based on few case reports and uncontrolled studies.Javier Narváez et al.'s review of rituximab in refractory NPSLE yielded positive results.The study included 35 cases and of them, 85% of patients achieved a complete or partial therapeutic response after 1 treatment cycle, while relapse occurred in 45% of patients [107].

Sleep disorders
Sleep disorders are a broad group that includes abnormalities in the quantity and quality of sleep [108].Various types of sleep disorders occur in many diseases, primarily in neurological (Parkinson's disease, Alzheimer's disease) [109,110], psychiatric (schizophrenia, depression) [111,112] and endocrine [113].These are not the only diseases in which there is an increased percentage of patients with sleep disorders.Research shows that SLE is also a disease in which sleep disorders occur more often than in the general population -from 55% to 85% of lupus patients struggle with them [19].Sleep quality is reduced in SLE patients.In addition, it depends on, among other things, the breed and the duration of the disease.Sleep disorders are not observed in patients with newly diagnosed SLE, just as there are no differences in prolactin and melatonin concentrations [114,115].Research shows that poorer sleep quality in SLE patients is also correlated with higher pain intensity and more severe depressive symptoms [116].Additionally, the presence of comorbidities and drug side effects have been indicated as factors influencing the sleep quality of SLE patients [117].A study conducted by Young et al. shows that sleep disorders may also be one of the causes of SLE, and not only a result of the disease.People who slept less than 7 hours a day were more likely to be diagnosed with lupus within approximately 6 years than other subjects [118].
Curr Probl Psychiatry, Vol. 25 (2024) There are limited data on the treatment of insomnia in SLE.An important recommendation for patients is regular physical activity and weight reduction to BMI <25 kg/m2 [119,120].Additionally, it has been shown that doctors assess the condition of SLE patients too optimistically (compared to the assessment of the patients themselves) when they ignore, among other things, the aspect of insomnia [121].This indicates an important role of the treatment of sleep disorders in improving the quality of life of SLE patients.

Summary
Among the discussed manifestations of NPSLE, the most common include mood disorders (above all, depressive disorders), cognitive disorders, and anxiety disorders.Psychotic disorders are reported much less frequently and may be a complication of steroid therapy for SLE, while similarly rare disorders of consciousness are most likely caused by the passage of inflammatory proteins into the cerebrospinal fluid.Studies show that there is a correlation between the occurrence of specific psychiatric disorders in the course of SLE and the age of patients.Older age predisposes to the development of cognitive disorders, while psychotic disorders appear more often in young SLE patients.The coexistence of anxiety, depression and sleep disorders with SLE affects the patient's negative perception of the course of the disease.In addition to unfavorable subjective self-assessment, depressive and anxiety disorders are associated with more severe forms of skin lesions in the course of SLE.In addition, patients with SLE report a higher perceived intensity of pain if they co-exist with depression, anxiety and sleep disorders.Moreover, depression contributes to the development of further somatic changes in SLE patients, such as CIMT.
The diagnosis of psychiatric manifestations of SLE is made by excluding other potential causes.Due to the suspected neuroinflammatory pathogenesis of NPSLE, in order to improve the diagnosis, research focuses on inflammatory markers such as cytokines, IFN-α or components of the complement system.Endocrine factors are also taken into account, such as thyroid hormones in the case of cognitive disorders.However, due to the insufficient number of tests performed, there are no laboratory indicators that can lead to the diagnosis of NPSLE.
In the treatment of psychiatric disorders such as NPSLE, research indicates the effectiveness of psychotherapeutic and pharmacological interventions.The effectiveness of psychotherapy has been confirmed in the presence of depressive and anxiety disorders.Moreover, regular physical activity improves the condition of patients.However, it is suggested that the benefit in the case of mood disorders may come mainly from the improvement of physical performance, which is reduced in the course of SLE.Therapeutics used to treat SLE may lead to the development of neuropsychiatric symptoms.For example, side effects of glucocorticosteroids used systemically include depression, mood changes and insomnia.The latest research suggests that monoclonal antibodies, such as belimumab or rituximab, are a treatment for SLE that does not worsen the mental condition or even improves it.It should be noted, however, that the number of studies focusing on the safety of treatment in terms of neuropsychiatric symptoms is still small.NPSLE symptoms, such as anxiety, mood disorders and cognitive disorders, have a negative impact on the therapeutic process and compliance with medical recommendations.
Despite estimates that neuropsychiatric manifestations occur in more than half of SLE patients, this issue is not thoroughly understood.Due to the systemic nature of SLE and the lack of specific markers, making a correct diagnosis is difficult, especially if psychiatric symptoms precede the diagnosis of SLE by rheumatologists.Despite its relatively frequent occurrence, a small amount of research is devoted to this issue, also in Poland, where these are mainly clinical case studies [122,123].This indicates the need to conduct further work in this field.The need to provide psychiatric care to a patient with an apparently rheumatological diagnosis is important.
W 1999 roku komitet badawczy The American

Table 3 .
The prevalence of selected mental disorders occurring in people with SLE .