Introduction
Neuropsychiatric systemic lupus erythematosus (NPSLE) represents one of the most complex aspects of SLE. Distinction between neuropsychiatric manifestations related to SLE (primary NPSLE) and those with other causes (non SLE-related) is of the utmost importance and represents a primary aim in clinical practice.
The underlying pathogenesis, severity, and diversity of manifestations make management of primary NPSLE particularly challenging. Clinically, these manifestations are categorized as:
- diffuse NPSLE, such as psychosis, acute confusional state, or cognitive disorders, which is typically considered to result from an inflammatory process; or
- focal NPSLE, which includes stroke or seizures, and is the result of thrombotic processes, especially when in the presence of antiphospholipid antibodies (aPL).
Physician judgment remains the “gold standard” for correct attribution and diagnosis of primary NPSLE. Treatment of NPSLE depends on the presumed underlying process (ie, inflammatory versus thrombotic), although it is not always easy to distinguish between these two conditions in routine clinical practice. To this end, all available diagnostic information, including lumbar puncture, neuroimaging, and presence of risk factors, should be taken into account to support the clinical evaluation.
The question of attribution
The key question for a clinician facing a lupus patient with a neuropsychiatric manifestation is whether or not to attribute the manifestation to the disease. This is not only a theoretical matter of taxonomy, but also a determinant of the therapeutic plan.
First, other causes (non-SLE factors) such as infection, malignancy, metabolic disorders, and drug-related adverse events should be excluded through clinical examination, lab tests, and neuroimaging (magnetic resonance imaging); the initial work-up for a particular manifestation should be similar to that carried out in a patient without lupus.
Once non-SLE factors have been ruled out, favoring factors for primary NPSLE should be sought, which include:
- generalized SLE activity;
- past or synchronous major neuropsychiatric event; and
- aPL persistently positive at moderate-to-high titers.
The majority of neuropsychiatric manifestations tend to occur close to SLE diagnosis, or within the first 2 years following diagnosis.
To facilitate the process of attribution, a number of “attribution models” have been proposed, most recently by the Italian Study Group on NPSLE.
Management plan
The initial step in the management of NPSLE is to treat any secondary cause, if present, as well as to symptomatically treat neuropsychiatric manifestations with anticonvulsants, antidepressants, or antipsychotics. For patients with mild manifestations, such as mood or anxiety disorders, symptomatic treatment may suffice.
For moderate-to-severe forms of NPSLE, the two operant mechanisms (inflammation versus thrombosis) should be examined in order to determine optimal treatment. As mentioned above, an inflammatory process is usually involved in diffuse manifestations, such as refractory seizures, inflammatory optic neuritis, peripheral neuropathies, severe psychosis, aseptic meningitis, myelitis, and acute confusional state. In moderate cases, glucocorticoids with or without immunosuppressive therapy (cyclophosphamide/ azathioprine/ mycophenolate mofetil) should be administered. In severe refractory cases, rituximab, intravenous immunoglobulin, or plasma exchange have been tried with various responses.
In the case of a presumed thrombotic mechanism associated with aPL (antiphospholipid syndrome [APS]), anticoagulation therapy is recommended for secondary prevention. This is recommended in focal manifestations, such as strokes and transient ischemic attacks. Vitamin K antagonists are preferable when aPL are present.
Target international normalized ratio (INR) is still a field of controversy. Randomized controlled trials (RCTs) have shown no difference for secondary thromboprophylaxis between a target INR of 2–3 and 3–4, but have indicated a lower risk for minor bleeding in the first group. However, results of a systematic review suggest a target INR of 3–4 for secondary APS, without an increase in major bleeding risk. When a non-thrombotic manifestation is accompanied by the persistent presence of aPL antibodies at moderate-to-high titers, antiplatelet therapy only is sufficient. Both therapies have been used in refractory myelitis, aPL-associated optic neuropathy, and chorea, with various outcomes.
Unmet needs in the treatment of NPSLE
Despite our increased understanding of the clinical aspects of NPSLE, its management remains largely empiric. High-quality clinical trials to guide therapeutic decisions are lacking, owing to the rarity and heterogeneity of NPSLE; which ranges from mild to devastating manifestations. Thus, the treatment strategy with immunosuppressants is akin to treatment of SLE with major organ involvement (eg, nephritis). For optimization of the current approach, better biomarkers and clinical tools to improve attribution models and distinguish inflammatory- from thrombotic-mediated neuropsychiatric manifestations in real-life practice are needed. To this end, murine models represent our best resource to investigate pathogenesis of central nervous system (CNS) lupus, and potentially develop new drugs. However, lupus-prone mice exhibit exclusively subtle abnormalities (anxiety, depression, cognitive) and, thus, they model the human disease inadequately.
Evidence toward the development of new drugs: Lessons learned from animal studies
Current research has highlighted microglia as emerging determinants of NPSLE pathogenesis, and studies in mice have detected new potential targets for the development of new drugs or repositioning of already existing ones. Of note, lupus-prone mice who were depleted of microglial cells exhibited improvement in their depression-like behavioral deficit. In another study in mice, angiotensin-converting enzyme inhibitors prevented microglia activation and preserved cognitive status and neuronal function.
A breakthrough study demonstrated that type I interferon (IFN) activates microglia, which then engulf synaptic material, leading to cognitive impairment. In this study, mice treated with the type I IFN receptor-blocking antibody anifrolumab exhibited attenuation of CNS disease. In view of the promising effects of baricitinib (Janus kinase 1/2 inhibitor) and evobrutinib (Bruton's tyrosine kinase inhibitor [BTKi]) in SLE and multiple sclerosis, respectively, kinase inhibition may prove an auspicious target in NPSLE. This hypothesis is supported by a study conducted in lupus-prone mice, which showed that treatment with a BTKi attenuates the neuropsychiatric disease.
Conclusion
Great progress has been made in the field of NPSLE since the 1999 American College of Rheumatology nomenclature, despite the complexity and rarity of some neuropsychiatric syndromes. Nevertheless, there is still a long way to go.
Unmet needs include development of more accurate neuroimaging and laboratory biomarkers to support a correct diagnosis in daily practice, identification of the underlying pathophysiologic pathways to guide treatment, determination of prognosis, and ultimately exploration of new target molecules for drug development specific for NPSLE. Animal studies, well designed RCTs, and international collaborations between research groups will aid in this effort.
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