Systemic lupus erythematosus …

Ricard Cervera MD PhD FRCP

Neuroimmunology

Updated 01.26.2024
Released 05.14.1996
Expires For CME 01.26.2027

Systemic lupus erythematosus

Author: Ricard Cervera MD PhD FRCP

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Editor: Francesc Graus MD PhD

Systemic lupus erythematosus

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Introduction

Overview

Systemic lupus erythematosus is one of the best-studied autoimmune diseases that may affect all systems, particularly the central and peripheral nervous systems. Therapies have improved, resulting in better quality of life and lower mortality rates. In this article, the author reviews the diagnostic, pathogenetic, and therapeutic issues of systemic lupus erythematosus, with an emphasis on neurologic and neuropsychiatric lupus. The most recent guidelines for diagnosis and management are presented.

Key points

	• The differential diagnosis of NPSLE from CNS infections, metabolic disturbances, primary neuropsychiatric disorders, and drug adverse reactions is important.
	• Neuroimaging studies and novel laboratory tests for autoantibodies may aid the diagnosis of neuropsychiatric systemic lupus erythematosus and provide clues for the underlying pathophysiology.
	• The prevalence of cognitive dysfunction in systemic lupus erythematosus has not been accurately determined due to lack of uniform criteria used in its definition and diagnostic tests.
	• The distinction between major and minor or nonspecific events in neurologic manifestations has a prognostic value because accrual of major neuropsychiatric events and CNS lesions is associated with increased mortality and morbidity.

Historical note and terminology

Even though the term lupus was first used by Rogerius in the 13th century (28), the systemic nature of the disease was established much later by Osler in 1904 (164). A number of laboratory findings have revolutionized the understanding and diagnosis of the disease. The false-positive test for syphilis was first described in lupus by Hauck and Reinhart in 1909. Hargraves and colleagues reported the lupus erythematosus cell in 1948, and Friou developed the fluorescent antinuclear antibody test in 1957. These discoveries established lupus as an autoimmune disease. Since then, defects in immune complex clearance, B-cell tolerance, and T-cell function have been demonstrated (165). The discovery of various autoantibodies and the recognition that the antiphospholipid syndrome (91) can coexist with systemic lupus erythematosus have been important milestones in understanding the disease process. Other landmark observations have included the recognition of drug-induced lupus in 1945 and the establishment of a mouse animal model in 1958.

Clinical manifestations

Presentation and course

	• Systemic lupus erythematosus usually presents with various manifestations due to the involvement of a number of organs.
	• All patients with systemic lupus erythematosus should be monitored for high blood pressure, serum creatinine levels, estimated glomerular filtration rate, proteinuria, urinary sediment (microscopic evaluation), serum C3/C4, and serum anti-dsDNA antibody levels.
	• Neurologic manifestations may involve both the central and peripheral nervous system.

Systemic lupus erythematosus is a chronic, relapsing-remitting systemic autoimmune disease. Diagnosis can be challenging because it presents with various manifestations due to the involvement of a number of organs. The criteria for classification and inclusion of patients into clinical studies updated by the European League Against Rheumatism and the American College of Rheumatology (14) are listed in Table 1.

Table 1. Criteria for Classification and Inclusion of Patients into Systemic Lupus Erythematosus Clinical Studies

Entry criterion. • Antinuclear antibodies (ANA) at a titer of ≥ 1:80 on HEp-2 cells or an equivalent positive test (ever).
• If absent, do not classify as systemic lupus erythematosus. • If present, apply additive criteria.
Additive criteria. • Do not count a criterion if there is a more likely explanation than systemic lupus erythematosus. • Occurrence of a criterion on at least one occasion is sufficient. • Systemic lupus erythematosus classification requires at least one clinical criterion and ≥ 10 points. • Criteria need not occur simultaneously. • Within each domain, only the highest weighted criterion is counted toward the total score.
Clinical domains and criteria	Weight	Immunology domains and criteria	Weight
Constitutional • Fever	2	Antiphospholipid antibodies • Anti-cardiolipin antibodies OR anti-β2GP1 antibodies OR lupus anticoagulant	2
Hematologic • Leukopenia • Thrombocytopenia • Autoimmune hemolysis	3 4 4	Complement proteins • Low C3 OR low C4 • Low C3 AND low C4	3 4
Neuropsychiatric • Delirium • Psychosis • Seizure	2 3 5	SLE-specific antibodies • Anti-dsDNA antibody* OR • Anti-Smith antibody	6
Mucocutaneous • Nonscarring alopecia • Oral ulcers • Subacute cutaneous OR discoid lupus • Acute cutaneous lupus	2 2 4 6
Serosal • Pleural or pericardial effusion • Acute pericarditis	5 6
Musculoskeletal • Joint involvement	6
Renal • Proteinuria > 0.5 g/24 h • Renal biopsy class II or V lupus nephritis • Renal biopsy class III or IV lupus nephritis	4 8 10
Total score: classify as systemic lupus erythematosus with a score of 10 or more if entry criterion fulfilled.

Clinical manifestations most relevant to neurology in the differential diagnosis and in understanding disease pathogenesis

Arthritis or arthralgia. Arthritis or arthralgia affects 85% to 90% of patients during the course of their illness. Arthritis may be acute or chronic, usually affecting small joints of the hands, wrists, and knees symmetrically but may be migratory and asymmetric. The soft tissues surrounding the joint are affected, leading sometimes to joint deformity without bony erosion, known as Jaccoud arthropathy. The spine is not usually involved (67). Complaints of muscle pain and muscle weakness may indicate myositis, another manifestation of lupus that needs to be excluded from the outset.

Skin manifestations. A wide variety of skin manifestations occurs in 70% to 80% of patients with systemic lupus (37). These can be divided broadly into three main groups: (1) cutaneous forms of systemic lupus erythematosus (so-called “systemic lupus erythematosus-specific skin diseases”), such as acute cutaneous lupus erythematosus characterized by the “butterfly rash,” subacute cutaneous, systemic lupus erythematosus, and chronic cutaneous systemic lupus erythematosus; (2) non-specific cutaneous manifestations (eg, livedo reticularis); and (3) cutaneous complications of drug treatment (128). Acute cutaneous lupus erythematosus (butterfly rash) is characterized by a scaly, erythematous, raised, painful lesion affecting the malar region (usually sparing the nasolabial folds) that occurs in 26% to 60% of patients (38; 37). In the MedLink Neurology article on dermatomyositis, Dr. Dalakas advises that these skin manifestations need to be distinguished from those occurring in dermatomyositis where the nasolabial folds are affected. Subacute cutaneous lupus erythematosus is a nonfixed, non-scarring erythematous lesion that may appear as psoriasiform (papulosquamous) or may occur in polycyclic or annular lesions. The rash usually occurs on sun-exposed surfaces. Discoid lesions may occur alone (discoid lupus erythematosus) or in the context of systemic lupus. The lesions are usually coin-shaped, chronic erythematous papules, or plaques. Follicular plugging and scarring are characteristic, and the lesion may become thickened, centrally hypopigmented, or centrally atrophic. Ultraviolet light appears to trigger cutaneous lesions in 70% to 90% of patients (photosensitivity) (128). Oral ulcers, vaginal ulcers, pharyngitis, and nasal septal erosions are relatively frequent. Vascular abnormalities manifest as splinter hemorrhages, digital ulcerations, Raynaud phenomenon, livedo reticularis, and urticaria (37).

Renal involvement. Renal involvement occurs in 50% to 60% of patients with systemic lupus erythematosus during the first decade of disease. The clinical indicators of renal involvement are proteinuria or casts, which may be red cell, hemoglobin, granular, tubular, or mixed (88). Nephritis is one of the most serious complications, increasing the risks for cardiovascular disease and renal failure and, therefore, reducing the 10-year survival from 92% to 88% in the systemic lupus erythematosus population. Renal biopsy should be performed at the first signs of renal involvement, such as reproducible proteinuria greater than or equal to 0.5 g/24 hours, especially with glomerular hematuria or cellular casts. The 2018 revised International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification system is helpful in assessing active and chronic glomerular and tubulointerstitial changes as well as vascular lesions associated with antiphospholipid syndrome (18). In addition, a study demonstrated a predictive model to assess the risk for a severe lupus nephritis subtype. Young age, musculoskeletal manifestations, new-onset hypertension, anti-dsDNA antibodies, increased number of leucocytes and cellular casts in urine, increased serum creatinine, and absence of nephrotic-range proteinuria are highly associated with proliferative LN (class III/IV), whereas older age, malar rash, nephritic-range proteinuria, normal C3, and hematuria are highly associated with membranous class V lupus nephritis (120). Although such an algorithmic model can hardly be a substitute for renal biopsy, it could be useful whenever a biopsy cannot be performed in a high-risk patient.

All patients with systemic lupus erythematosus should be monitored for high blood pressure, serum creatinine levels, estimated glomerular filtration rate, proteinuria, urinary sediment (microscopic evaluation), serum C3/C4, and serum anti-dsDNA antibody levels; those with previous or current renal involvement need more careful monitoring. Spot urine protein/creatinine ratio measured on the first morning void urine sample is a valid and repeatable alternative to 24-hour urine collections and can be used for measuring proteinuria and monitoring within-patient changes (25; 74). Reappearance of urine cellular casts has greater than 80% sensitivity and specificity for renal flares (86). In the MedLink Neurology article titled “renal failure: neurologic complications,” Dr. Garg explains that when renal involvement is severe, neurologic manifestations of renal failure may be seen.

Serositis. Serositis, a common finding, may manifest as pleuritis, with or without pulmonary effusion (45% to 60% of patients), pericarditis (47% to 83% of patients), or peritonitis (26; 103). New pulmonary effusions should be evaluated using diagnostic thoracentesis. With clearing of the fluid, there is usually minimal residual pleural thickening. Rapid and unpredictable exacerbation or regression of effusions is more frequent in patients who have combinations of pleural, cardiac, or pulmonary involvement than with isolated pleural involvement (103). Pericarditis is often clinically silent but may present as precordial chest pain and a pericardial rub (67; 139). Constrictive pericarditis and cardiac tamponade are rare, despite the common occurrence of pericarditis and effusion.

Pulmonary manifestations. Pulmonary manifestations include interstitial pneumonitis, pulmonary embolism, pulmonary hemorrhage, pulmonary hypertension, and shrinking lung syndrome (103). Acute lupus pneumonitis occurs in 1% to 4% of patients and presents with dyspnea, cough, pleuritic pain, hypoxemia, fever, and infiltrate on chest x-ray (139). It must be carefully differentiated from infection and other manifestations of lupus. Chronic interstitial lung disease may develop after repeated bouts of acute pneumonitis or de novo, and it is symptomatic in 1% to 6% of patients. Pulmonary hemorrhage is rare but may be life threatening. Hemorrhage usually occurs in the context of systemically active lupus. The clinical presentation overlaps that of acute pneumonitis; however, infiltrates clear rapidly once bleeding is stopped (103). Shrinking lung syndrome refers to progressive volume loss with high diaphragms and restrictive pulmonary function in the absence of interstitial or pleural disease. The syndrome has been attributed to weak respiratory or diaphragm musculature or phrenic nerve dysfunction, but this remains controversial (139). Pulmonary thrombotic events are also common in patients with lupus (168).

Cardiac disease. Cardiac disease in systemic lupus erythematosus includes pericarditis, myocarditis, endocarditis, and coronary artery disease. Myocarditis may manifest as tachycardia, cardiac enlargement, congestive heart failure, or arrhythmia. These symptoms may also occur as a result of anemia, uncontrolled hypertension, systemic infection, or fluid retention secondary to renal disease and steroid use, making myocarditis difficult to diagnose (67). The classic nonbacterial verrucous vegetations, as described by Libman and Sacks in 1924, may occur on any valve and can rarely cause hemodynamic changes or emboli in the brain, resulting in strokes. The frequency of these lesions has decreased since the introduction of steroids, according to autopsy studies. Studies conducted using ultrasound techniques reported the incidence to be less than 15% (114). Valvular heart disease may also occur in association with antiphospholipid syndrome (175). Bacterial endocarditis is a complication in approximately 1% of patients. Valvular disease is implicated in the etiology of stroke in lupus.

Cardiovascular disease. A high incidence of atherosclerosis appears to be present in patients with systemic lupus erythematosus and frequently affects premenopausal women (33; 118). Premature cardiovascular disease is now one of the leading causes of death in systemic lupus erythematosus (118). The incidence of myocardial infarction and stroke may be higher in patients with systemic lupus erythematosus, even after controlling for traditional risk factors. Disease activity is related to the risk of stroke (126). This suggests that systemic lupus erythematosus and treatment complications are both major causes of cardiovascular and cerebrovascular disease. Studies have shown that there is a baseline alteration in the vasomotor function of young patients with systemic lupus (87). The etiology of atherosclerotic vascular disease in systemic lupus erythematosus is related to a combination of numerous risk factors, as in patients without systemic lupus erythematosus. Chronic inflammation, endothelial cell injury, immune complex deposition, aberrant CD40 ligand interactions, and autoantibodies have all been implicated (124). An adverse effect of glucocorticoid therapy on lipid profile is an additional factor. Much is still unknown about the pathogenesis of premature atherosclerosis in systemic lupus erythematosus. Certainly, an aggressive approach in treating traditional cardiovascular health risks is important. However, better therapies that address the immune and inflammatory contributions in the development of atherosclerosis in patients with systemic lupus erythematosus is also likely to be necessary (118; 43). Patients with lupus need to be knowledgeable concerning their cardiovascular risks, and this knowledge can have a positive impact on their disease (159).

Hematologic abnormalities. Hematologic abnormalities in lupus include anemia, leukopenia, lymphopenia, and thrombocytopenia (88). An autoimmune hemolytic anemia occurs as a result of antibodies to red blood cells in about 3% of patients (38). Thrombocytopenia may mirror disease activity or can persist chronically with occasional fluctuations.

Antiphospholipid syndrome. Approximately 25% to 40% of patients with lupus have features of antiphospholipid syndrome, which is defined as repeated episodes of arterial or venous thrombosis (including cerebrovascular events), recurrent spontaneous abortions, or thrombocytopenia in patients with antiphospholipid antibodies, in addition to the cognitive dysfunction already described.

Neurologic involvement

Neurologic involvement in systemic lupus erythematosus is an important component of the disease. Of note, the presence of delirium, psychosis, or seizures is part of the current European League Against Rheumatism and American College of Rheumatology criteria for a classification of systemic lupus erythematosus. A broad range of neurologic manifestations affecting the central and the peripheral nervous system are encountered in patients with systemic lupus erythematosus. It is not always clear whether all the symptoms are directly related to the disease or are secondary to multisystem involvement as described above. Until the late 1990s, there was no standard nomenclature for the classification of systemic lupus erythematosus neurologic manifestations. In 1999, the American College of Rheumatology formulated a nomenclature system that provided definitions for 19 neuropsychiatric lupus syndromes, including recommendations for laboratory and imaging tests (09) (Table 2).

Table 2. Neuropsychiatric Lupus Syndromes

Central nervous system	Peripheral nervous system
Aseptic meningitis Cerebrovascular disease Demyelinating syndrome Headache Movement disorders (chorea) Myelopathy Epileptic seizures Acute confusional state Anxiety disorders Cognitive dysfunction Mood disorders Psychosis	Guillain-Barré syndrome Autonomic disorder Mononeuropathy, simple or multiplex Myasthenia gravis Cranial neuropathy Plexopathy Polyneuropathy

Although these definitions have refined the description and classification of neuropsychiatric systemic lupus erythematosus, there are limitations in their specificity and application in daily practice. “Minor” and nonspecific events, such as headache, mild depression, anxiety, subclinical cognitive dysfunction, and electrophysiologically normal polyneuropathy, are frequently seen in other systemic autoimmune diseases and, therefore, are not specific to systemic lupus erythematosus populations; this has increased the specificity of the ACR criteria from 46% to 93% (05; 06). In addition, statistical models attributing such nonspecific symptomatology to systemic lupus erythematosus have falsely inflated the incidence of neuropsychiatric manifestations (79). The European League Against Rheumatism (EULAR) published a revised version of the ACR criteria that focused on the incidence of clinically important neurologic events that seem to be most directly attributed to the disease, such as strokes, seizures, myelopathy, neuropathy, and cognitive dysfunction (24).

Neurologic manifestations

Seizures. Seizures occur in 2% to 10% of patients with lupus (95), with the majority single isolated events. Seizures can be tonic-clonic, complex partial, simple partial motor, and secondary tonic-clonic (69). Electroencephalographic abnormalities occur in 60% to 70% of patients, but only 24% to 50% of them present with typical epileptiform patterns predictive of a recurrence (12; 69). Risk factors for seizures include high disease activity (08; 82; 95), high cumulative damage (82), younger age of onset (95), recent disease onset (93; 69; 82), antiphospholipid antibodies, nephritis, and previous epileptic seizures (12; 95). Recurrence is observed in only 12% to 22% of seizure patients (24) and is associated with brain MRI structural abnormalities, focal neurologic signs, antiphospholipid antibodies, and epileptiform electroencephalographic activity (12; 69). According to the latest EULAR Recommendations, withholding of anti-epileptic treatment following recovery from the seizure should be considered in those cases without MRI lesions or EEG abnormalities. Long-term antiepileptic therapy should be administered for recurrent seizures (24).

Myelopathy. Myelopathy is relatively rare, occurring in 1% to 2% of patients with systemic lupus erythematosus (80). It usually occurs as an initial manifestation or within 5 years of diagnosis (106; 167; 50). Patients may present with acute flaccid weakness and hyporeflexia, often in association with high disease activity. Myelopathy can be inflammatory or autoimmune, when it presents as a rapidly evolving transverse myelitis, or it can be embolic or thrombotic. Longitudinal transverse myelitis, defined as involvement of four or more contiguous spinal cord segments, often presents in the context of the neuromyelitis spectrum of diseases, accounting for 21% to 48% of all myelitis cases (149). Presentation with slowly progressive spastic weakness and hyperreflexia is often related to lower systemic lupus erythematosus activity and antiphospholipid antibodies (27). The incidence of antiphospholipid antibodies seems to be generally higher in patients with systemic lupus erythematosus with myelopathy compared to the rest of the systemic lupus erythematosus population (55% to 74% vs. 30% to 50%) (106; 50).

Response to therapy with corticosteroids and cyclophosphamide (24), the most commonly used agents, is variable. Complete recovery is observed in 20% to 50%, partial recovery in 30% to 40%, and no improvement in 20% to 50% of patients; however, these numbers are based on reports prior to the use of monoclonal antibodies, such as rituximab (106; 24). Poor prognostic factors include extensive spinal cord MRI lesions, severely reduced muscle strength or sphincter dysfunction at presentation, and delay by more than 2 weeks in therapy initiation. The role of antiphospholipid antibodies as a poor prognostic factor and the merit of anticoagulation treatment remain contentious (99).

Cerebrovascular disease. The prevalence of cerebrovascular disease in systemic lupus erythematosus ranges from 2% to 10%; ischemic strokes or transient ischemic attacks are the commonest events, accounting for over 80% of the total cerebrovascular disease cases. Strong predictive factors for strokes are high disease activity; high cumulative systemic lupus erythematosus damage; persistently positive, moderate-to-high titers of antiphospholipid antibodies; heart valve disease; systemic hypertension; previous cerebrovascular events; and old age (70; 95).

Lupus psychosis. Lupus psychosis is rare and not well substantiated in various series, with an overall reported frequency less than 2.5% to 3.5% of the patients (177). Possible comorbidities and, most importantly, distinction from the autoantibody-mediated autoimmune encephalitides were not considered in these figures. True lupus psychosis seems to be an early manifestation of the disease and is usually associated with increased generalized disease activity (13; 145). Anti-ribosomal P antibodies have been reported by some as associated with lupus psychosis (176; 81); however, a meta-analysis questioned their role (97). Corticosteroid-induced psychiatric disease, also poorly substantiated, has been reported in up to 10% of patients treated with 1 mg/kg or greater of prednisone (42); however, these patients predominantly present with mood disorders rather than psychosis (13). The paradox is that true lupus psychosis is treated with corticosteroids, which on their own can cause psychotic symptomatology.

Chorea. Chorea, the best documented movement disorder in lupus, is a rare event, occurring in 0.6% of patients (177). It usually presents as a single episode early in the disease course, remitting within days to a few months (102). Chorea has been associated with antiphospholipid antibodies, ischemic cerebral lesions, and concomitant antiphospholipid syndrome (102; 17).

Headache. Headache as an isolated event is a frequent complaint occurring in up to 50% of patients with lupus (80). In spite of being considered part of neuropsychiatric systemic lupus erythematosus, it is not clearly related to systemic lupus erythematosus. A meta-analysis found no evidence of an increased prevalence of headaches in systemic lupus erythematosus, nor a unique type of headache associated with the disease (129). Several proposed models for the attribution of neuropsychiatric events to systemic lupus erythematosus have a priori excluded headache as a nonspecific manifestation (05; 78).

Aseptic meningitis. Aseptic meningitis may rarely develop in systemic lupus erythematosus, occasionally after the use of ibuprofen. Clinical manifestations vary, with headache and fever predominating. The illness is usually mild; however, some cases can be severe and life-threatening. Thickening and enhancement on brain MRI may rarely be seen (155).

Optic neuritis. Optic neuropathy is a distinct entity that includes inflammatory optic neuritis (relapsing or monophasic) and ischemic or thrombotic optic neuropathy. Diagnostic testing includes visual field examination, funduscopy, visual-evoked potentials, fluorescein angiography (when vasoocclusive retinopathy is suspected), and contrast-enhanced MRI. Funduscopy may reveal optic disc edema in only 30% to 40% of cases; MRI shows optic nerve enhancement in 60% to 70% with accompanying brain abnormalities in 67% (24). Optic neuritis can be a feature of the neuromyelitis optica spectrum disorders prompting a check for anti-aquaporin-4 antibody; however, the incidence remains to be determined.

Cognitive dysfunction. Mild cognitive dysfunction is reported in 10% to 20% of patients with systemic lupus erythematosus, and in 3% to 5% of them it is considered severe (173). The most commonly affected domains are attention, visual memory, verbal memory, executive function, and psychomotor speed. This profile is similar to that seen in frontal and subcortical dementias, such as Huntington and Parkinson disease, or the white matter dementias, such as those seen in multiple sclerosis and microangiopathy (108; 147). Cognitive impairment is reported in some series to occur early in the disease course, even in the absence of other neuropsychiatric manifestations (107; 147). The most common neuropsychological tests used include the American College of Rheumatology battery, which has demonstrated 80% sensitivity and 81% specificity, and the computer-based Automated Neuropsychological Assessment Metrics system (ANAM) (09; 96).

The severity of cognitive impairment correlates with multiple factors, attesting to its multifactorial etiology, including persistently elevated antiphospholipid antibodies, a high Systemic Lupus International Collaborating Clinics (SLICC)/ American College of Rheumatology Damage Index (SDI), consistent prednisone use, diabetes, hypertension, and low educational level (77; 123; 173). The estimated cognitive dysfunction seems to be related to the level of pain, fatigue, and depression (85), suggesting that the aforementioned figures are imprecise owing to inclusion of many nonspecific or secondary events.

Peripheral nervous system manifestations. Peripheral nervous system involvement in systemic lupus erythematosus can include chronic inflammatory demyelinating polyneuropathy, mononeuropathies, Guillain-Barré syndrome, plexopathy, cranial neuropathies, and autonomic dysfunction (171). The most common peripheral neuropathy is a small fiber sensory neuropathy followed by axonal polyneuropathy and mononeuropathy multiplex (2% to 5%) (138). Skin biopsy in patients presenting with neuropathic pains or fibromyalgia but without objective findings on neurologic examination has been found to be a useful tool to identify the presence of small-fiber sensory neuropathy (105).

Prognosis and complications

Survival in systemic lupus erythematosus has increased over the last 30 years (49). Most studies report a 10-year survival rate of 80% to 95% (38; 180). There is poorer long-term prognosis among men with systemic lupus erythematosus, which appears to be a result of their more rapid progression, particularly early in the course of the disease (07).

The main causes of mortality are cardiovascular events, thrombosis (153), organ failure, and sepsis (38; 40; 180). Ten-year damage accrual is reported to be approximately 50% and is mainly due to the neuropsychiatric, renal, and musculoskeletal manifestations (40).

Generalized systemic lupus erythematosus disease activity or damage, documented by validated indices, is associated with an increased risk for neuropsychiatric events (125; 95), especially seizures and severe cognitive dysfunction (173; 08). However, neuropsychiatric manifestations can also occur during periods with no disease activity outside the nervous system (27). Strokes and seizures seem to occur more frequently in patients who have had similar events in the past or are positive for antiphospholipid antibodies (98). Seizures are more often associated with concurrent cerebrovascular disease and psychosis (34; 12; 127).

Other cerebrovascular risk factors indirectly related to neuropsychiatric lupus include hypertension, an elderly age, smoking, contraceptives, and higher cumulative doses of glucocorticoids (70; 142).

Clinical vignette

A 17-year-old Caucasian woman was first diagnosed with systemic lupus erythematosus at the age of 13 on the basis of a malar rash, arthritis, diarrhea, and positive antinuclear and anti-dsDNA antibodies.

At the age of 16 years, she presented with edema of the lower extremities and increased fatigue. At that time, she received no medications and was free of symptoms for a 3-year period of time. Clinical and laboratory testing revealed anemia, hypoalbuminemia and low complement levels, nephrotic range proteinuria (3 gr 24-hour urine protein), and red blood cell casts. A renal biopsy was performed, and the patient was diagnosed with lupus nephritis.

During her hospitalization, she suffered a first episode of generalized tonic-clonic seizures and was started on intravenous methylprednisolone and cyclophosphamide. The seizures continued, and despite the addition of intravenous levetiracetam 30 mg/kg she developed status epilepticus, requiring additional treatment and intubation.

MRI of the brain revealed multiple contrast-enhancing white matter lesions in the frontal, temporal, and parietal lobes that were accompanied by angiogenic edema, a picture characteristic of CNS vasculitis. Her EEG was highly dysrhythmic with dominant delta and theta waves bilaterally, mainly in the frontal lobes as well as triphasic waves and epileptiform discharges. CSF analysis was normal. After 2 weeks in the intensive care unit, she started to improve with control of the seizures and resolution of proteinuria. A repeat MRI revealed substantial improvement of the diffuse vasculitic lesions.

She was discharged after 1 month of hospitalization on 80 mg of oral glucocorticoids, which was gradually tapered over the next 6 months to a low-daily dose of 5 mg prednisolone. She received six monthly intravenous pulses of 1 gr cyclophosphamide.

Her neurologic disease is now under control, and the main disease manifestation is persistent proteinuria (500 mg to 1 gr), despite receiving intravenous cyclophosphamide for 6 months and mycophenolate mofetil thereafter. Her medications include prednisolone 5 mg, mycophenolate mofetil 500 mg twice daily, phenytoin 100 mg three times daily, and a tapering dose of levetiracetam.

Biological basis

	• The etiology of systemic lupus erythematosus is not known.
	• The pathogenesis for each neurologic manifestation are multiple and involves both inflammatory and thrombotic mechanisms.

The pathogenesis of systemic lupus remains unclear, but compelling evidence suggests dysfunction of multiple immunological elements, such as altered antigen presentation, abnormalities in B cell responses, autoantibody production and immune-complex-mediated organ damage, increased function of T-helper cells, abnormal cytokine production, and loss of regulatory T cells or B cells (16).

Etiology

The etiology of systemic lupus erythematosus is not known. The disease is multifactorial and seems to be the result of interplay between a susceptible genetic profile and an environmental trigger (55).

Among the proposed, but never proven, environmental factors are infectious agents that could act as molecular mimics (ie, shared antigens between the pathogen and the host’s normal tissue) or as a means of breaking tolerance, leading to immune dysregulation. For example, a number of investigations, including studies with animal models, have implicated Epstein-Barr virus as a pathogen that leads to the development of systemic lupus erythematosus (166; 72). Epstein-Barr virus infection is more prevalent in patients with systemic lupus erythematosus, many of whom develop antibodies against a proline-rich epitope in the ribonucleoprotein Sm B/B that is similar to an epitope in EBNA-1, a major nuclear antigen of Epstein-Barr virus. Furthermore, immunization of mice against EBNA-1 protein leads to the production of anti-Sm and anti-dsDNA antibodies (166). Hormones have been also implicated in causing mild and moderate flares, especially after hormone replacement therapy (36). Stress and physical agents, including sun exposure, drugs, and various toxins, such as silica, mercury, and pesticides (46; 49), have also been proposed as possible triggering factors in the pathogenesis of the disease.

Genetics. The increased occurrence of the disease in a patient's family, and especially in twins, has suggested that a genetic predisposition may play a role in systemic lupus erythematosus. Abundant research indicates that the disease is multigenic (47). Some of the genes involved are associated with human leukocyte antigens (HLA) that differ among ethnic groups. Human leukocyte antigen class 2 genes, specifically DR2, DR3, and DQ, seem to be the ones most frequently associated with systemic lupus erythematosus (152). Genome-wide association studies have revealed many single nucleotide polymorphisms in the major histocompatibility complex region, possibly associated with the risk of systemic lupus erythematosus. Some of the polymorphisms are also strongly associated with the production of certain autoantibodies including anti-dsDNA, anti-Ro/SSA, anti-La/SSB, anti-SM, anti-RNP, and antiphospholipid antibodies (152).

Other genes with a potential association include those related to: complement components (C1q, C1r, C1s, C2, and C4) (152; 29); interferon type I-related genes, such as IRF5 and seven haplotypes (71; 104); single nucleotide polymorphisms in the FcR genes (29); other genes related to innate immunity, including toll-like receptors, tyrosine kinase genes, and STAT4 (104).

Potential genetic associations with neuropsychiatric manifestations have also been proposed, including TNF-alpha polymorphisms (121), the HLA-DRB104 genotype, the STAT4rs1018165 single nucleotide polymorphism and single nucleotide polymorphisms in the TREX1 gene (59).

Pathogenesis and pathophysiology

It has been proposed that the trigger of the disease is an exogenous immunogen that induces autoantibodies via a mechanism of molecular mimicry. Despite significant efforts, however, no infectious agent has been convincingly associated with the disease. Another prominent theory is that inadequate removal of apoptotic or necrotic material may lead to immune system activation with self-antigens (53) (104). A defect in the clearance of apoptotic cells in systemic lupus erythematosus could lead to aberrant uptake of material by macrophages, which could then present antigens to T and B cells, thus, driving the autoimmune process (133). This mechanism is also linked to increased interferon type I production, through the endocytosis of preformed immune complexes by plasmacytoid dendritic cells (pDCs), which in turn produce high amounts of interferon alpha and induce proinflammatory responses (49). Lastly, a study in lupus-prone mice suggested that apoptotic microvesicles with altered chromatin could lead to increased activation of dendritic cells and excess IL-6 production (54).

Pathological findings in various tissues reflect the effect of complement-fixing autoantibodies. Vasculitis, bland vasculopathy, and immune complex deposition are widespread and appear to be the basis of the immune dysfunction. Venous and arterial thromboses are commonly seen in association with antiphospholipid antibodies, though the mechanism of thrombosis is not known. Classic lesions include periarterial fibrosis of the spleen and the verrucous, nonbacterial vegetations of Libman-Sacks. Nephritis is common and displays subendothelial immune complex deposition and varying degrees of inflammation and proliferative change. Skin biopsies during active disease demonstrate immune complexes and complement in a bandlike pattern at the dermal and epidermal junction as well as associated inflammation and degeneration.

Pathogenesis of neuropsychiatric lupus. Overall, the etiologies for each neurologic manifestation are multifaceted and may involve both inflammatory and thrombotic processes, such as autoantibody production, intrathecal production of proinflammatory cytokines, microangiopathy, and atherosclerosis. In general, focal neurologic manifestations and absence of concomitant high disease activity are related to a thrombotic process, whereas diffuse events and generalized disease activity are thought to be related to an inflammatory process (23). Experimental, histopathologic and neuroimaging studies suggest that the noninflammatory microvasculopathy is related to the thrombophilic state due to antiphospholipid antibodies and complement activation, which leads to endothelial dysfunction (76; 23). Contrary to common belief, true cerebral vasculitis is rarely found in lupus (92).

The commonest brain lesions in neuropsychiatric lupus are ischemic, ranging from multifocal microinfarcts to global ischemic changes or gross infarcts. Cortical atrophy, micro- and macrohemorrhages, demyelination, bland angiopathy, thrombotic angiopathy with platelet and fibrin thrombi, neuronal necrosis, and loss of axons and neurons as well as parenchymal edema have been observed histologically. Agreement between clinical and histopathological findings, however, occurs in less than 50% to 70% in most published studies (83; 31; 162).

Probably, the best association of neuropsychiatric lupus seems to be with several autoantibodies, which strongly correlate with certain neurologic symptoms. The autoantibodies include:

Anti-phospholipid antibodies. Anti-Phospholipid (aPL) antibodies are implicated in microvascular thrombotic, embolic, or endothelial damage events (142) in the context of strokes, seizures, chorea, myelopathy, cranial neuropathy, migraines, and cognitive dysfunction (77; 156; 12; 188; 27). Their target is anionic phospholipids and protein-phospholipid complexes. The aPL include anti-cardiolipin (aCL), lupus anticoagulant, and anti-beta2 glucoprotein antibodies. They upregulate soluble adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin), which lead to an enhanced inflammatory response and subsequent thromboembolic events (186).

Anti-ribosomal P antibodies. Anti-ribosomal P antibodies are found in up to 36% of patients with lupus. They have been linked to depression and psychosis (176; 01); however, this association has not been confirmed (73). These antibodies are directed against the P0, P1, and P2 proteins located on the large subunit of the eukaryotic ribosome (57). Their pathogenetic potential was postulated on the basis that they bind to a neuronal surface protein expressed in anatomical areas involved in memory and cognition, inducing neuronal apoptosis by intracellular Ca2+ influx (119). A meta-analysis demonstrated 27% sensitivity and 80% specificity, concluding that anti-ribosomal P antibodies are of limited diagnostic value in neuropsychiatric systemic lupus erythematosus (97).

Anti-aquaporin 4 antibodies. Anti-aquaporin 4 (anti-AQP4) antibodies are detected in patients with “neuromyelitis optica spectrum of diseases,” who most commonly present with myelopathy and optic neuritis (115; 149; 27). The antibodies are also found in demyelinating conditions accompanying other systemic autoimmune diseases. In systemic lupus erythematosus and Sjögren syndrome, NMO-IgG/anti-AQP4 antibodies are found in patients with longitudinal extensive transverse myelitis or recurrent optic neuritis (183; 182). It is still debatable whether NMO-IgG seropositivity in neuropsychiatric patients with lupus is a coexistence of two separate entities or represents a discrete neuropsychiatric lupus manifestation (149).

Anti-NR2 glutamate receptor antibodies. Anti-NR2 glutamate receptor antibodies are found in the serum or CSF in some patients with lupus (52). An association between anti-NR2 antibodies and diffuse neuropsychiatric lupus manifestations, such as cognitive impairment and depression, has been shown in several studies (11; 111; 185; 109). In these patients, MRI studies have also shown atrophy and abnormal diffusion in the hippocampus and the amygdala (11; 58). The pathogenicity or specificity of NR2 antibodies in inducing these clinical and pathological signs, however, remains uncertain.

Anti-membrane neuronal autoantibodies. It has been hypothesized that various specific symptoms of NPSLE (eg, seizures) could be attributed to anti-neuronal surface antibodies, similar to limbic encephalitis. One study, however, in a cohort of neuropsychiatric lupus cases, showed that seizures were not associated with a specific anti-neuronal antibody (94). Still, this remains an open question as larger cohorts of patients need to be screened and investigated for new autoantibodies.

Despite recent advances, the underlying pathomechanisms in neuropsychiatric lupus remain unclear. Most importantly, the field needs to be revisited because certain CNS manifestations labeled as neuropsychiatric lupus (especially lupus psychosis, depression, and new-onset epileptic seizures) may fall within the context of newly described autoimmune encephalitides.

Epidemiology

	• Systemic lupus erythematosus is a disease that affects predominantly females.
	• Most of the neurologic complications tend to appear early in the course of the disease.

Systemic lupus erythematosus is a disease with a worldwide distribution that affects predominantly females (female to male ratio: 9:1) and has a prevalence of 52.2/100,000 in the United States (49). The incidence peaks between the ages of 15 and 40 years, with a mean age of onset of 32 years in women and 40 years in men. A greater incidence and prevalence in people of African descent and Hispanics versus Caucasians has been found consistently but may be attributable to socioeconomic differences rather than race. Ten to 20% of patients have a first-degree or second-degree relative with the disease, indicating a significant genetic component in the pathogenesis (165).

The reported frequency of neurologic involvement in systemic lupus erythematosus varies widely due to differences in inclusion criteria, diagnostic approach, and patients’ baseline characteristics (23; 177). A meta-analysis reported an estimated prevalence of 56.3% (177), whereas a multicenter prospective study of 1206 patients found a 40.3% frequency, of which only 13% to 24.6% could be attributed with certainty to the disease (80). The most commonly reported manifestations (regardless of whether they are systemic lupus erythematosus-specific) are headaches (20% to 40%), mood disorders (10% to 20%), cognitive dysfunction (10% to 20%), seizures (7% to 10%), cerebrovascular events (7% to 10%), and peripheral nervous system involvement (3% to 8%) (78; 80; 177). However, the “minor” and nonspecific events are excluded, the most common neurologic abnormalities in systemic lupus erythematosus are cerebrovascular disorders and seizures with a cumulative incidence of 5% to 15%; other uncommon manifestations, accounting for 1% to 5%, are severe cognitive dysfunction, psychosis, and polyneuropathy (24).

In published series, most of the neurologic events tend to appear early in the course of the disease, with approximately 40% occurring before the clinical manifestations of lupus or at the time of systemic lupus erythematosus diagnosis and 63% occurring within the first year of diagnosis. Cognitive dysfunction and cerebrovascular disease, however, seem to correlate with older age and disease progression (80).

Differential diagnosis

A great number of diseases can share clinical features with systemic lupus erythematosus, including AIDS, Lyme disease, subacute bacterial endocarditis, vasculitis, syphilis, other atypical infections, polychondritis, Whipple disease, cryoglobulinemia, lymphoproliferative and myeloproliferative diseases, occult malignancy, depression, fibromyalgia, sarcoidosis, thrombotic thrombocytopenic purpura, glomerulonephritis, and others. A careful history, laboratory workup, and adherence to the diagnostic criteria of systemic lupus erythematosus should support the correct diagnosis in the majority of cases.

Systemic lupus erythematosus should also be differentiated from other systemic autoimmune diseases. A combination of clinical features and antibodies can clarify the diagnosis. In rheumatoid arthritis there is erosive arthritis, lack of kidney involvement, and often negative antinuclear antibodies. Swollen hands and anti-ribonucleoprotein antibodies are specific for mixed connective tissue disease. Antinuclear, anticentromere, anti-Scl 70 antibodies, and skin thickening indicate systemic sclerosis. Anti-Ro/SSA and anti-La/SSB are more common in Sjögren syndrome. The skin manifestations of systemic lupus erythematosus may overlap or be confused with dermatomyositis; however, there are distinguishing features, especially sparing of the nasolabial folds in lupus and the involvement of the eyelids in dermatomyositis with violaceous discoloration and edema; the presence of proximal muscle weakness and creatine kinase elevation may also help to distinguish the 2.

Neuroimaging and the presence of autoantibodies in neuropsychiatric lupus are helpful to exclude nonsystemic lupus erythematosus-related causes, such as adverse drug reactions, other systemic disorders, infections, and metabolic disturbances (122). An algorithm was developed to assess the possible relationship between neuropsychiatric events and systemic lupus erythematosus, but its validity and clinical utility need further documentation (30).

Two neurologic syndromes whose differential diagnosis from neuropsychiatric lupus is facilitated by imaging are progressive multifocal leukoencephalopathy and posterior reversible leukoencephalopathy syndrome. About 2% of progressive multifocal leukoencephalopathy cases occur in patients with autoimmune diseases following treatment with immunosuppressants, the usual history in patients who develop progressive multifocal leukoencephalopathy. In systemic lupus erythematosus, however, the prevalence of progressive multifocal leukoencephalopathy is increased, occurring in about four in 100,000 patients. As about half of them had only been on mild immunosuppressants, it suggests that systemic lupus erythematosus itself may confer an increased susceptibility to progressive multifocal leukoencephalopathy. A differentiation of progressive multifocal leukoencephalopathy from neuropsychiatric lupus can be based on T1- and T2-weighted MRI images and FLAIR MRI sequences with gadolinium (161). The identification of JC virus by PCR in the cerebrospinal fluid helps confirm the diagnosis (131; 143).

Reversible posterior leukoencephalopathy syndrome can occur in patients with autoimmune diseases, including lupus and systemic vasculitides, and its clinical and radiological presentation is similar to that reported in patients with nonsystemic lupus erythematosus (150; 64). In up to 76.5% of patients with systemic lupus erythematosus, the manifestations of posterior reversible leukoencephalopathy syndrome are associated with recent initiation or augmentation of immunosuppressive therapy (131). Because reversible posterior leukoencephalopathy syndrome can develop in the context of a lupus flare, two subtypes have been proposed: ‘‘hypertensive posterior reversible leukoencephalopathy syndrome” in patients with inactive systemic lupus erythematosus, which is reversible with antihypertensive and anticonvulsive treatment, and ‘‘immunologic posterior reversible leukoencephalopathy syndrome,” which occurs in the context of a lupus flare, requires immunosuppressive therapy, and is considered a neurologic manifestation of active lupus (64).

Diagnostic workup

The diagnosis of systemic lupus erythematosus requires a complete physical examination, including inspection of sun-exposed surfaces for rash and a search for mucocutaneous ulcers. Laboratory evaluation should include a complete blood count, chemistry profile of the kidney and liver, activated partial thromboplastin time, erythrocyte sedimentation rate, urinalysis, antinuclear antibodies, complement levels (C3, C4, and CH50), anti-dsDNA, anti-extractable nuclear antigen, and antiphospholipid antibodies.

Neurologic manifestations require more specific laboratory workup. If mental status changes are present, there is a need for lumbar puncture. The CSF IgG index is increased, and oligoclonal bands are often present during a central nervous system flare. Measures of CSF antineuronal antibodies and CSF IL-6 and IL-8 levels can also be abnormal in association with some central nervous system manifestations (174); however, their diagnostic value remains uncertain. As noted above, serum autoantibodies related to neuropsychiatric lupus include antiphospholipid antibodies, anti-AQP4 antibodies in cases of optic neuritis or transverse myelitis, and possibly the anti-ribosomal P and anti-NR2 antibodies (176; 149).

The most common finding on MRI is hyperintense white matter lesions (172; 157). In one study, 49% of patients during their first neuropsychiatric episode had focal, not-necessarily specific hyperintensities or glial abnormalities in the white matter. Other abnormalities include confluent hyperintensities in the white matter and diffuse cortical grey matter lesions (117). Small white matter lesions may not have prognostic significance; however, larger hyperintense lesions and infarcts, although less common, are more likely to be related to clinical outcome (02; 100). The nonspecific white matter lesions due to ischemia sometimes generate confusion with small chronic demyelinating lesions and, therefore, require clinicopathologic correlations. Cerebral atrophy is reported in as many as 32% of patients with NPSLE, especially those with longer disease duration, a history of cerebral ischemia, cognitive impairment, and a higher cumulative dose of corticosteroids (04; 68). Quantitation of T2 values may be helpful in distinguishing active from chronic lesions because T2 values are increased in the frontal grey matter of patients with active neurologic syndromes (148).

Although other neuroimaging techniques have been evaluated in NPSLE patients, their use in clinical practice has not been established (158). Magnetic resonance spectroscopy measures the neuronal marker N-acetyl aspartate, the creatine/phosphocreatine present in glial tissue and neurons and associated with phosphate transport systems, and total choline, a marker of cell membrane metabolism. In NPSLE, N-acetyl aspartate is reportedly reduced in normal-appearing white matter, grey matter, and in high-signal lesions whereas Cho/Cre ratios are elevated, particularly in active disease. These changes are not specific for NPSLE because they can be seen in demyelinating and degenerative brain diseases (163; 184; 146).

Single photon emission computed tomography seems to detect changes not evident on MRI and may serve as a useful supplement in the diagnosis of NPSLE. The most common SPECT abnormality is patchy diffuse hypoperfusion mainly seen in association with acute major neuropsychiatric events. However, the specificity and sensitivity of SPECT results have been controversial (75; 02), and this technique is not recommended.

Management

	• Therapy of systemic lupus erythematosus is divided into that used for acute flares of disease activity and the used for chronic maintenance.
	• The main medications include nonsteroidal anti-inflammatory drugs, glucocorticoids, antimalarials, and immunosuppressants.
	• The biological therapies rituximab, belimumab, and anifrolumab, and the calcineurin inhibitors voclosporin and tacrolimus, are also being introduced for the management of active lupus patients.

Systemic lupus erythematosus is a chronic, relapsing-remitting disease. For this reason, therapy is divided into the one used for acute flares of disease activity and the other used for chronic maintenance. The main medications include nonsteroidal anti-inflammatory drugs, glucocorticoids, antimalarials, and immunosuppressants, including cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil (135). Newer agents, such as the monoclonal antibodies rituximab, belimumab, and anifrolumab are also used, as described below. Therapy should be individually tailored for each patient and in accordance with the particular features and clinical manifestations of the disease. The 2023 update of the European League Against Rheumatism recommendations for the management of systemic lupus erythematosus provides physicians and patients with updated consensus guidance on the management of this disease, combining evidence-base and expert-opinion (60).

Antimalarials (mainly hydroxychloroquine at a target dose of 5 mg/kg real body weight/day) are recommended for all patients, unless contraindicated (60). They are used to treat mild active disease with musculoskeletal, cutaneous, and constitutional symptoms as well as mild leukopenia and anemia and mild pleurisy and pericarditis. They are also used as a maintenance therapy to prevent flares, minimize damage accrual, and to prevent thromboembolic events in patients with antiphospholipid antibodies (20).

Nonsteroidal anti-inflammatory drugs may be used for systemic complaints, such as fatigue and fever, as well as for musculoskeletal manifestations and serositis. Glucocorticoids remain the mainstay of lupus therapy, and many patients may require chronic administration to avoid disease activity. They are dosed based on the type and severity of organ involvement and should be reduced to a maintenance dose of 5 or fewer mg/day (prednisone equivalent) (60).

Chemotherapeutic agents are used in organ-threatening disease and cases of refractory nonmajor organ involvement (22). Cyclophosphamide has an important role as induction treatment for lupus nephritis (140; 25; 74); it is also used for the treatment of neuropsychiatric lupus, refractory cytopenias, and vasculitis (140).

Azathioprine and methotrexate have been used in systemic lupus erythematosus not only to treat a variety of manifestations, such as skin lesions, pneumonitis, thrombocytopenia, or hemolytic anemia but also for their steroid-sparing effects; azathioprine is also used as a maintenance therapy for lupus nephritis (03; 25; 74). Mycophenolate mofetil has proved to be equally effective as intravenous cyclophosphamide in treating lupus nephritis (41; 10); it has also been effective in extrarenal manifestations, including mucocutaneous, musculoskeletal, and hematological manifestations as well as in overall reduction of systemic lupus erythematosus flares. Calcineurin inhibitors, especially voclosporin or tacrolimus, can also be considered for the treatment of lupus nephritis (60).

Rituximab, an anti-CD20 monoclonal antibody, is mainly used in refractory cases of systemic lupus erythematosus. A number of studies as well as a meta-analysis support the use of rituximab in severe lupus cases where conventional treatment has failed (116; 169; 56).

Belimumab, a monoclonal antibody against B lymphocyte stimulator (BlyS)/BAFF (181), was the first biological therapy approved by the FDA for the treatment of systemic lupus erythematosus. It has shown efficacy and safety in moderately active systemic lupus erythematosus in several phase III studies (65; 134). Efficacy of belimumab was greater in seropositive (antinuclear antibody and dsDNA positive) patients. The efficacy of belimumab in lupus nephritis has also been demonstrated (66). However, all these studies excluded patients with active neurologic disease.

Anifrolumab is a monoclonal antibody that binds to the type I interferon receptor, blocking the activity of type I interferons, such as interferon-alpha and interferon-beta. It has shown efficacy and safety in moderately active systemic lupus erythematosus in two phase III studies (132) and was approved for medical use in the United States in July 2021 and in the European Union in February 2022. However, all these studies also excluded patients with active neurologic disease.

Intravenous immunoglobulin can be used in particular cases of refractory systemic lupus erythematosus, including peripheral neuropathy, CNS involvement, lupus nephritis, hematological manifestations, and catastrophic antiphospholipid syndrome (187; 25).

Low-dose aspirin has been recommended for adult patients with lupus receiving corticosteroids, for those with antiphospholipid antibodies, and for those with at least one traditional risk factor for atherosclerotic disease. Anticoagulation is recommended for those with at least one previous thrombotic event (101; 178).

Immunizations for the prevention of infections (herpes zoster virus, human papillomavirus, influenza, COVID-19, and pneumococcus), management of bone health, nephroprotection and cardiovascular risk, and screening for malignancies, should be performed in lupus patients (60).

Treatment of neuropsychiatric lupus manifestations varies and depends on the clinical manifestation and the underlying pathophysiological mechanisms.

Anti-epileptic therapy is not needed in patients presenting with a single seizure except if there are persistent epileptiform EEG discharges and structural MRI lesions. Long-term antiepileptic treatment is recommended when recurrent seizures occur (69; 82). Immunosuppressive therapy is indicated for seizures when there is generalized systemic lupus erythematosus activity because the seizures are considered to represent an inflammatory event. Glucocorticoids alone or in combination with immunosuppressive therapy, such as cyclophosphamide, are the treatment of choice whereas hydroxychloroquine is thought to have a protective effect. Anticoagulation may be of benefit if antiphospholipid antibodies are present (19; 82).

For systemic lupus erythematosus-related myelitis, the combination of intravenous methylprednisolone and intravenous cyclophosphamide is the treatment of choice and must be applied promptly to minimize permanent disability. Relapses are common (50% to 60%) during corticosteroid dose reduction, making maintenance immunosuppressive therapy a necessity (106). Plasma exchange therapy and rituximab have been used in severe cases (106; 136; 19; 15). If myelitis is thrombotic in connection with antiphospholipid antibodies, anticoagulation may be considered (50).

Acute management of systemic lupus erythematosus-related strokes or transient ischemic attacks is similar to treatment of the general population. Secondary prevention includes tight control of cardiovascular risk factors and antiplatelet therapy. Glucocorticoids or immunosuppressive therapy should be considered in cases of high disease activity. In patients with persistently positive moderate-to-high titers of antiphospholipid antibodies, chronic oral anticoagulation therapy is suggested. However, the efficacy and adverse events of high (INR 3.0 to 4.0) versus moderate intensity warfarin treatment (INR 2.0 to 3.0) are still under study (101; 48; 61; 154; 45).

Symptomatic management of lupus psychosis involves antidepressants or antipsychotic agents; however, glucocorticoids and immunosuppressive therapy (cyclophosphamide, rituximab) should be considered in the presence of high disease activity (130; 170; 145). Most psychiatric episodes resolve within 2 to 4 weeks. Relapses may occur in up to 50% of cases whereas 20% to 30% of patients exhibit a mild chronic psychiatric disorder (145).

Treatment of chorea in patients with high NPSLE disease activity consists of symptomatic therapy with dopamine antagonists or glucocorticoids plus immunosuppressive agents (azathioprine, cyclophosphamide). Antiplatelet or anticoagulation therapy is administered in patients positive for antiphospholipid antibodies (141).

Pulse intravenous methylprednisolone, followed by intravenous cyclophosphamide, is recommended for acute optic neuritis in the setting of active disease (19). Patients with relapsing optic neuritis, without brain imaging abnormalities, require maintenance therapy with low-dose steroids or an immunosuppressant (Dalakas unpublished observations).

Management of cognitive dysfunction in patients with systemic lupus erythematosus includes treatment of potentially exacerbating causes or comorbidities, such as anxiety and depression, control of cardiovascular risk factors (24), and psycho-educational group interventions (84). Whether antiplatelet or anticoagulation therapy has efficacy in patients with antiphospholipid antibody remains unclear (90; 123).

Outcomes

Survival in systemic lupus erythematosus has increased over the last 30 years due to new regimens and targeted treatment protocols (49). The principle of treating-to-target has been successfully applied to many highly prevalent diseases (ie, diabetes mellitus and arterial hypertension) and to some autoimmune diseases, including systemic lupus erythematosus. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers. In systemic lupus erythematosus treat-to-target initiative, four overarching principles and 11 recommendations have been proposed, including targeting remission, preventing damage, and improving quality of life (179) (Table 3).

Table 3. Treat-to-Target in Systemic Lupus Erythematosus

	• Overarching principle 1: The management of systemic lupus erythematosus should be based on shared decisions between the informed patient and her/his physician(s).
	• Overarching principle 2: Treatment of systemic lupus erythematosus should aim at ensuring long-term survival, preventing organ damage, and optimizing health-related quality-of-life by controlling disease activity and minimizing comorbidities and drug toxicity.
	• Overarching principle 3: The management of systemic lupus erythematosus requires an understanding of its many aspects and manifestations, which may have to be targeted in a multidisciplinary manner.
	• Overarching principle 4: Patients with systemic lupus erythematosus need regular long-term monitoring and review or adjustment of therapy.

Recommendations

	(1) The treatment target of systemic lupus erythematosus should be remission of systemic symptoms and organ manifestations or, where remission cannot be reached, the lowest possible disease activity, measured by a validated lupus activity index or by organ-specific markers.
	(2) Prevention of flares (especially severe flares) is a realistic target in systemic lupus erythematosus and should be a therapeutic goal.
	(3) It is not recommended that the treatment in clinically asymptomatic patients be escalated based solely on stable or persistent serological activity.
	(4) Because damage predicts subsequent damage and death, prevention of damage accrual should be a major therapeutic goal in systemic lupus erythematosus.
	(5) Factors negatively influencing health-related quality of life, such as fatigue, pain, and depression should be addressed, in addition to control of disease activity and prevention of damage.
	(6) Early recognition and treatment of renal involvement in patients with lupus is strongly recommended.
	(7) For lupus nephritis, following induction therapy, at least 3 years of immunosuppressive maintenance treatment is recommended to optimize outcomes.
	(8) Lupus maintenance treatment should aim for the lowest glucocorticoid dosage needed to control disease, and if possible, glucocorticoids should be withdrawn completely.
	(9) Prevention and treatment of antiphospholipid syndrome-related morbidity should be a therapeutic goal in systemic lupus erythematosus; therapeutic recommendations do not differ from those in primary antiphospholipid syndrome.
	(10) Irrespective of the use of other treatments, serious consideration should be given to the use of antimalarials.
	(11) Relevant therapies adjunctive to any immunomodulation should be considered to control comorbidity in patients with systemic lupus erythematosus.

A newly developed low disease activity index (LLDAS) suggests that patients who achieved a low disease activity score for a longer time period are less likely to develop higher cumulative damage (62). With further validation, the application of such activity indices in everyday clinical practice may help minimize the risk for permanent organ damage. However, treatment has its own share of potential complications. For example, infections, cardiovascular disease, and avascular necrosis may result from glucocorticoid therapy (40). Drug-related myopathy, secondary to steroids or antimalarials, usually resolves when the medication is withdrawn. Retinopathy may occur with hydroxychloroquine. Cyclophosphamide is associated with a higher incidence of transitional bladder cancer, gynecologic cancer (151), and non-Hodgkin lymphoma.

Special considerations

Pregnancy

Although the majority of lupus pregnancies have good outcomes, pregnancy in women with systemic lupus erythematosus remains a high-risk situation. Maternal complications include risk of maternal death, preeclampsia, preterm delivery, thrombosis, and hematological complications. Moreover, a higher risk for fetal loss, spontaneous miscarriage, and intrauterine growth restriction (IUGR) has been reported (49; 22; 44).

Risk factors for higher morbidity and mortality include high disease activity, lupus nephritis, presence of antiphospholipid antibodies, low complement levels, thrombocytopenia, and nonsystemic lupus erythematosus-related factors, such as a previous personal or family history of preeclampsia, pre-existing hypertension or diabetes mellitus, and obesity (39; 110; 113). Furthermore, the accrual of significant abnormalities from systemic lupus erythematosus, including pulmonary hypertension or fibrosis, renal insufficiency, and heart failure, can affect the outcome of pregnancy (112; 113).

Systemic lupus erythematosus flares during pregnancy range between 25% to 65%, and the majority are mild to moderate (49). Disease can remit for at least 6 months before conception and also are facilitated by tight disease control from frequent clinical and laboratory testing throughout pregnancy. Hydroxychloroquine should not be discontinued, and administration of low-dose aspirin and heparin is indicated for antiphospholipid-positive patients (113).

Physicians should be alert in distinguishing lupus flares from normal pregnancy changes. Of note, pre-eclampsia, a high-risk condition, may be difficult to differentiate from lupus nephritis flares because both can present with increasing proteinuria, deteriorating renal function, hypertension, and thrombocytopenia (113). Only a few medications that are generally used to treat systemic lupus erythematosus are safe during pregnancy; these include low corticosteroid doses, hydroxychloroquine, azathioprine, and low-dose aspirin (22).

Neonatal lupus is a discrete syndrome associated with maternal circulating anti-Ro/ SSA and anti-La/ SSB antibodies. Noncardiac manifestations in the neonate, which include rash, hepatic abnormalities, neutropenia, and thrombocytopenia, are transient and resolve within months. These contrast with cardiac abnormalities that may be permanent, including conduction abnormalities, myocarditis, cardiomyopathy, and congestive heart failure. Congenital heart block affects 2% of children born to primigravida with anti-Ro/ anti-La antibodies and 16% to 20% of children whose mothers had a previously affected child. First- and second-degree heart block may fluctuate in severity whereas third-degree block is irreversible. Monitoring by fetal Doppler echocardiography is recommended weekly between 16 and 26 weeks of gestation and biweekly thereafter (32; 35; 89; 113). Prophylactic treatment with fluorinated corticosteroids is administered in cases with a persistently prolonged PR interval and can improve fetal survival, whereas intravenous immunoglobulin or other regimens have shown conflicting results (63).

Anesthesia

Management of the systemic lupus erythematosus patient should include extensive preanesthetic assessment. Patients should be assessed for acute flares and organ damage. Nonurgent surgery should be delayed until disease is in remission. Other factors to be considered include pulmonary and renal dysfunction, cardiac valvular abnormalities, pericarditis, pleural effusions, interstitial lung disease, thrombocytopenia, anemia, and clotting abnormalities (21).

Perioperative immunosuppression and steroid replacement should be adjusted to an appropriate level. Adrenal suppression resulting from long-term corticosteroid therapy usually imposes the need for a “stress dose” perioperatively. The remote potential of drug interactions with immunosuppressants should be taken into account during selection of the anesthetic agent (137).

In the presence of antiphospholipid antibodies, thromboprophylaxis is indicated, especially in procedures with a significant risk of thrombotic complications, such as orthopedic or vascular surgery. If the patient is receiving anticoagulation, regional techniques may be contraindicated. Finally, appropriate prophylactic antibiotic treatment should be considered to minimize infection risk (21).

Conclusions: controversies for NPSLE

	• Differentiating NPSLE from infection, metabolic disturbances, primary neuropsychiatric disorders, and drug adverse reactions is of importance.
	• The distinction between major, minor, and nonspecific neuropsychiatric events is important because damage to the CNS and mortality have been mainly related to the major neuropsychiatric manifestations of the disease.
	• Neuroimaging studies are not currently sufficiently specific to diagnose systemic lupus erythematosus-related entities with certainty and cannot determine the exact underlying pathophysiology; they are, however, useful to exclude other conditions, such as multiple sclerosis.
	• The role and exact prevalence of cognitive dysfunction in systemic lupus erythematosus are still uncertain due to the variety of screening measures and discrepancies between studies.
	• New autoantibodies have been identified, and their potential relevance to specific neurologic manifestations is under continuing study. For example, NMO-IgG antibody in the context of neuromyelitis optica spectrum disorders can be present in patients with systemic lupus erythematosus with myelitis and optic neuritis. The value of anti-NR2 antibodies, which appears to be associated with depression and memory impairment, remains still uncertain.

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Ricard Cervera MD PhD FRCP

Dr. Cervera of University of Barcelona received consulting fees from AstraZeneca, GlaxoSmithKline, Eli Lilly, and Rubió as a member of an advisory committee.
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Editor

Francesc Graus MD PhD

Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.
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Former Authors

David Hermosillo-Romo PhD, Robin L Brey MD, Margaret E Burnett MD, Lori B Siegel MD, Eleni I Kampylafka MD, Harry Alexopoulos Dphil, and Marinos C Dalakas MD

Patient Profile

Age range of presentation: 0 month to 65+ years
Sex preponderance: female>male, >9:1
Heredity: heredity may be a factor
Population groups selectively affected: Hispanics

People of African descent
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-9: Systemic lupus erythematosus: 710.0
ICD-10: Systemic lupus erythematosus, unspecified: M32.9
OMIM: Systemic lupus erythematosus: #152700

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Systemic lupus erythematosus

Associated Disorders

Antiphospholipid syndrome
Autoimmune hemolytic anemia
Chronic active hepatitis
Raynaud phenomenon
Scleroderma
- Sjögren syndrome
- Thyroiditis

Differential Diagnosis

AIDS
Lyme disease
subacute bacterial endocarditis
vasculitis
syphilis
- polychondritis
- Whipple disease
- Cryoglobulinemia
- Lymphoproliferative and myeloproliferative diseases
- occult malignancy
- depression
- fibromyalgia
- sarcoidosis
- thrombotic thrombocytopenic purpura
- glomerulonephritis
- rheumatoid arthritis
- scleroderma
- Sjögren syndrome
- Dermatomyositis
- adverse drug reactions
- metabolic disturbance
- progressive multifocal leukoencephalopathy
- reversible posterior leukoencephalopathy syndrome

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Systemic lupus erythematosus

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Table 1. Criteria for Classification and Inclusion of Patients into Systemic Lupus Erythematosus Clinical Studies

Table 2. Neuropsychiatric Lupus Syndromes

Prognosis and complications

Clinical vignette

Biological basis

Etiology

Pathogenesis and pathophysiology

Epidemiology

Prevention

Differential diagnosis

Diagnostic workup

Management

Outcomes

Table 3. Treat-to-Target in Systemic Lupus Erythematosus

Recommendations

Special considerations

Pregnancy

Anesthesia

Conclusions: controversies for NPSLE

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

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