Neuropsychiatric lupus – two faces of one disease (two case reports)

Introduction: Neuropsychiatric lupus (neuropsychiatric systemic lupus erythematosus – NPSLE) is a form of a systemic autoimmune disease – systemic lupus erythematosus (SLE), with dominant central and peripheral nervous system involvement. Nuclear magnetic resonance imaging (NMRI) of the brain is considered the gold standard for diagnosing patients with NPSLE. Treatment of NPSLE includes the following: high doses of corticosteroids, methylprednisolone pulse therapy, intravenous immunoglobulins, plasmapheresis, immunosuppressants (cyclophosphamide, azathioprine, mycophenolate mofetil), and biological therapy – rituximab.

Case reports: In this paper, we present two patients diagnosed with neuropsychiatric lupus, with different clinical manifestations of the disease, as well as the diagnostics performed, and the good clinical outcomes of immunosuppressive therapy achieved in both patients.

Conclusion: The pathogenesis of NPSLE involves neuroinflammatory (autoimmune) and ischemic mechanisms. Neuroimaging has shown good results in differentiating patients with SLE from controls. The goal of SLE treatment is to achieve remission or low disease activity and to prevent episodes of exacerbation. Treatment with intravenous cyclophosphamide as well as with systemic corticosteroids has shown significantly positive results in patients with NPSLE. There is great need, in the future, for new biomarkers in the serum and cerebrospinal fluid (CSF), as well as for more innovative radiological procedures. Additional clinical trials that would lead to new therapeutic options for the treatment of NPSLE are necessary.

INTRODUCTION

Neuropsychiatric lupus (neuropsychiatric systemic lupus erythematosus – NPSLE) is a form of systemic autoimmune disease – systemic lupus erythematosus (SLE), with dominant involvement of the central and peripheral nervous system [1]. About 50% of patients develop neuropsychiatric symptoms of SLE within one year of the onset of systemic lupus erythematosus [2]. NPSLE includes a number of neurological and psychiatric symptoms that affect the quality of life of patients, as well as the prognosis of the disease [3]. In patients with SLE, mortality from NPSLE is second only to lupus nephritis [4]. The prevalence of NPSLE varies between 37% and 95%. This result is affected by different diagnostic criteria, study designs, different populations and races of patients, follow-up of different cohorts of patients, as well as the types and severity of the clinical presentation of the disease [1]. Nuclear magnetic resonance imaging (NMRI) of the brain is considered the gold standard for the diagnosis of patients with NPSLE [5]. Treatment of NPSLE includes the following: high doses of corticosteroids, pulse therapy with methylprednisolone, intravenous immunoglobulins, plasmapheresis, immunosuppressants (cyclophosphamide, azathioprine, mycophenolate mofetil), and biological therapy – rituximab [2].

The aim of this study is to present two completely different manifestations of neuropsychiatric lupus, the challenges in their diagnosis, as well as the favorable response to immunosuppressive therapy.

TWO CASE REPORTS

Case report I

The first case is a 65-year-old female patient. The diagnosis of systemic lupus erythematosus (SLE) was established in this patient in 1991, based on skin changes, photosensitivity, polyarthralgia, sores in the mouth and nose, polyserositis, bicytopenia, + antinuclear antibodies (ANAs), + anti-Smith antibodies (anti- Sm at), decreased values of the complement component 4 (C4), and inflammatory syndrome. At the same time, a diagnosis of secondary Sjögren’s syndrome was made, which was confirmed by the pathohistological findings of a small salivary gland biopsy.

Initial treatment, which achieved a satisfactory effect included the use of parenteral (methylprednisolone 1 mg/kg) and per os (prednisone – maintenance dose of 10 mg/day) glucocorticosteroid (GCS) therapy, together with an antimalarial drug – hydroxychloroquine at a dose of 200 mg/day. Over time, there were occasional exacerbations, in the form of polyserositis and cutaneous discoid lupus with a good response to pulse therapy with methylprednisolone.

In November 2015, for the first time since the onset of the disease, the first grand mal epileptic seizure occurred. Epileptiform changes with paroxysmal spikes and sharp waves were recorded on the electroencephalogram (EEG). Valproic acid and sodium valproate were introduced as a part of the therapy. In January 2016, an NMRI of the endocranium was performed recording supratentorial multiple microangiopathic white matter lesions of suspected vasculitis etiology, with cortical reductive changes. In the same month, the patient had another grand mal seizure. There were no clinical or laboratory criteria for the diagnosis of secondary antiphospholipid syndrome. In consultation with a neurologist, the diagnosis of NPSLE was established.

In early 2016, cyclophosphamide pulse therapy (500 mg/m² body surface area (BSA)) was started, with two pulses of methylprednisolone – 500 mg each. After one month, the patient had her third and final grand mal seizure. The patient received a total of 12 cycles of cyclophosphamide therapy, with a cumulative dose of 10 grams. After the end of the therapy, no epileptiform changes were described on the follow-up EEG, while the follow-up NMRI of the endocranium was without significant changes, as compared to the beginning of the disease. After the end of treatment with cyclophosphamide, in addition to prednisone at a dose of 10 mg/ day and hydroxychloroquine at a dose of 200 mg/day, azathioprine at a dose of 100 mg/day was also introduced into the therapy. On several occasions during treatment with cyclophosphamide, asymptomatic urinary infections with mild hypogammaglobulinemia were detected, which, in addition to antibiotic therapy, were also treated with the use of human intravenous immunoglobulins (IVIGs).

Case report II

The second case is a 53-year-old female patient. In 2016, she was diagnosed with Sjögren’s syndrome, based on a positive ANA test, elevated anti-SSA antibodies (anti-SSA at), dry eye syndrome (keratoconjunctivitis sicca – KC sicca), a pathological finding of salivary gland scintigraphy proving reduced accumulation and excretory capacity of the salivary glands, the PH finding of salivary gland biopsy with foci of lymphocytic infiltration, xerophthalmia, xerostomia, and polyarthralgia.

The patient was initially treated with prednisone at a dose of 1 mg/kg, which was gradually reduced to 15 mg/day, as well as with hydroxychloroquine at a dose of 300 mg/day. After several months, acute confusional state with cognitive dysfunction occurred. The patient was examined by a neurologist, and Alzheimer’s disease was initially suspected. NMRI of the endocranium was performed and punctiform microangiopathic lesions were registered, fronto-parietally, bilaterally, with cortical reductive changes.

In March 2017, during the patient’s first hospital stay at the Clinic of Allergology and Immunology of the University Clinical Center of Serbia (UCCS), a diagnosis of neuropsychiatric lupus was made, based on photosensitivity, polyarthralgia, + ANA, + lupus anticoagulant test (LA), bicytopenia, and neuropsychiatric manifestations. A psychiatrist diagnosed anxiety-depressive syndrome and selective serotonin reuptake inhibitor (SSRI) – sertraline, at a dose of 50 mg/day, was introduced as a part of the therapy. The electromyoneurography (EMNG) finding ruled out polyneuropathy (PNP). An examination by a neurologist revealed right-sided weakness with broad-based gait.

In July 2017, the patient was started on immunosuppressive therapy with cyclophosphamide at a dose of 500 mg/m² of body surface area, and a total of 12 cycles were prescribed with a cumulative dose of 7.2 grams, with methylprednisolone pulses of 1,000 mg per cycle. Since the diagnosis, in addition to prednisone and antimalarial drugs, the therapy included acetylsalicylic acid at a daily dose of 100 mg, due to + lupus anticoagulant (LA). After completing 12 cycles of cyclophosphamide therapy, a follow-up NMRI of the endocranium was performed, and the findings were significantly unchanged, as compared to the previous one, performed before the beginning of therapy.

In late 2018, the patient’s psychiatrist discontinued antidepressant treatment, but continued treatment with benzodiazepine, as needed. As early as the first cycle with cyclophosphamide was completed, attacks of acute confusional state no longer occurred, while cognitive functions were significantly improved. In addition to prednisone at a dose of 10 mg/day, hydroxychloroquine at a dose of 200 mg/day, and acetylsalicylic acid at a dose of 100 mg/day, further maintenance therapy also included azathioprine at a dose of 100 mg/day.

DISCUSSION

The neuropsychiatric form of systemic lupus erythematosus has always been a challenge for clinicians, both at the diagnostic and at the therapeutic level [1]. NPSLE occurs more often in African and Asian populations, however, more severe forms of the disease have been observed as more common in Caucasians [5]. NPSLE has a wide spectrum and high heterogeneity of clinical phenotypes, including headache, epilepsy, stroke, peripheral neuropathy, cognitive impairment, memory loss, and psychiatric symptoms. [2],[4].

In 1999, the American College of Rheumatology (ACR) proposed 19 entities within NPSLE (12 with in the central nervous system (CNS) and 7 within the peripheral nervous system (PNS), with an additional distinction between diffuse and focal involvement of the nervous system (NS)), (Table 1) [1]. Cerebral manifestations of SLE are defined as focal and diffuse neurological deficits, whereby focal disorders are mainly due to thromboembolic events caused by the presence of antiphospholipid antibodies. The pathogenesis of diffuse disorders (affective and cognitive disorders) is significantly more complex and, as yet, insufficiently understood [3]. Most of the symptoms of NPSLE can occur within comorbidities or can be a consequence of glucocorticosteroid (GCS) therapy, which significantly complicates the diagnosis of this disease [4].

Table 1. Manifestations of neuropsychiatric SLE according to the American College of Rheumatology (ACR)

The pathogenesis of NPSLE involves neuroinflammatory (autoimmune) and ischemic mechanisms. The pathological mechanism in SLE involves the loss of immune tolerance to the cell nuclear antigen, production of autoantibodies, and build-up of immune complexes, leading to complement activation, tissue inflammation, and cell apoptosis. The activation of B and T cells, as well as the production of interferon type I, is altered. In most cases, both pathogenetic mechanisms coexist at the same time [5].

Dysfunction of the blood-brain barrier with consequent passage of antibodies into the cerebrospinal fluid, as well as intrathecal synthesis of antibodies, are disorders that occur as a part of NPSLE. The presence of antiphospholipid antibodies is primarily associated with the occurrence of thrombotic events, such as stroke, in NPSLE, but also with the occurrence of epileptic seizures, movement disorders, cognitive dysfunction, and myelopathy. Anti-aqua porin 4 antibodies are associated with the occurrence of transverse myelitis and neuromyelitis optica. Anti-P ribosomal antibodies are most often associated with the onset of psychosis. As a part of NPSLE, anti-N methyl D aspartate receptor antibodies also appear, and, together with anti-P ribosomal antibodies, participate in the pathophysiology of diffuse damage through toxic damage to neurons and the induction of apoptosis [1]. In diffuse forms of NPSLE with clinical presentation of acute confusional state, an elevated level of IL-6 in the cerebrospinal fluid has been observed. Due to the lack of specificity, the presence of this cytokine in the cerebrospinal fluid is not routinely tested for, as yet [1],[5].

Neuroimaging has shown good results in differentiating patients with SLE, as compared to the control group [3]. Neuroimaging is not specific for the diagnosis of NPSLE, but it is important for excluding other causes (infectious agents, neoplastic causes, aneurysms, and others) of neuropsychiatric symptoms in these patients [4]. A common finding of conventional NMRI brain imaging in patients with SLE includes hyperintense white matter changes as well as brain atrophy, but these changes are not specific [6].

The goal of SLE treatment is to achieve remission or low disease activity, as well as to prevent episodes of exacerbation. In all patients with SLE, the administration of hydroxychloroquine at a dose not exceeding 5 mg/kg of body weight (BW) is recommended. The maintenance dose of prednisone should not exceed 7.5 mg/day, with a tendency to completely discontinue the drug, when the conditions for this are met. The use of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can shorten the time required to reduce the dose of GCSs or to completely exclude them from therapy. In all patients with positive antiphospholipid antibodies (aPL at), primary prophylaxis with low doses of acetylsalicylic acid is recommended. The use of anticoagulant therapy – low molecular weight heparins (low molecular weight heparins – LMWHs) is recommended, especially during pregnancy, as well as during postoperative recovery. Depending on the manifestation of the disease, symptomatic therapy is also necessary (antipsychotic drugs, anxiolytic drugs, etc.) [7]. Hydroxychloroquine is used as firstline treatment in patients with SLE without significant damage to organ systems. Its application has also been suggested for the primary prevention of NPSLE, especially for cerebrovascular events and epileptic seizures [2]. Therapy with intravenous cyclophosphamide, as well as with systemic corticosteroids, has shown significantly positive results in patients with NPSLE, and nowdays, in most cases, this is the therapeutic option of choice for forms of the disease that involve organ systems (kidneys, the central and peripheral nervous system) [5]. In randomized controlled trials, the use of cyclophosphamide was compared with pulsed doses of corticosteroids, and it was concluded that treatment with cyclophosphamide had a better effect. It has been shown that the use of azathioprine, as maintenance therapy, reduces disease relapses [2]. The use of mycophenolate mofetil has the same effect with an even safer therapeutic profile. Rituximab is an anti-CD20 IgG1 monoclonal antibody that destroys B lymphocytes by acting on CD20 molecules located on their surface [2]. There are limited data on the effectiveness of biological therapy in the treatment of NPSLE. The use of rituximab has shown favorable effects, but additional studies on efficacy are needed. Belimumab has shown a positive effect in patients with the mild form of the disease [5]. In case of exacerbation of the extrarenal form of the disease, belimumab can be used, while in the case of exacerbation and activity of SLE, with a potential threat to organ systems, rituximab can be used [7].

More recent findings have shown that pharmacological modulation of microglia can affect the alleviation of disease symptoms (immunomodulator fingolimod; modulator of the sphingosine 1 phosphate receptor, which acts on lymphocytes by sequestering them in lymph nodes and preventing their migration to the site of the autoimmune process) [3]. There is a need for new therapeutic options that would target the disruption of the blood-brain barrier, cytokines, and microglial cells [5].

Despite extensive clinical research, to date, no laboratory or neuroimaging biomarker has proven to be completely accurate in the diagnosis of NPSLE. There is great need for new biomarkers in the serum and CSF, as well as for more innovative radiological procedures in the future [5]. Additional clinical trials are necessary that would lead to new therapeutic options in the treatment of NPSLE.

LIST OF ABBREVIATIONS AND ACRONYMS

NPSLE - neuropsychiatric systemic lupus erythematosus
NMRI – nuclear magnetic resonance imaging
SLE – systemic lupus erythematosus
ANAs – antinuclear antibodies
Anti-Sm at – anti-Smith antibodies
GCSs – glucocorticosteroids
EEG – electroencephalogram
IVIGs – intravenous immunoglobulins
Anti-SSA at – anti-Sjogren syndrome A antigen

KC sicca – keratoconjunctivitis sicca
LA – lupus anticoagulant
SSRIs – selective serotonin reuptake inhibitors
EMNG – electromyoneurography
PNP – polyneuropathy
CNS – central nervous system
PNS – peripheral nervous system
IL-6 – interleukin-6
aPL at - antiphospholipid antibodies
LMWHs - low molecular weight heparins