Cover Page
The handle http://hdl.handle.net/1887/31686 holds various files of this Leiden University dissertation
Author: Zirkzee, Els
Title: Care for patients with (neuropsychiatric) SLE
Issue Date: 2015-02-03
Chapter 1
General introduction
GENERAL INTRODUCTION
Systemic Lupus Erythematosus (SLE)
Epidemiology and clinical symptoms
Systemic lupus erythematosus (SLE) is an autoimmune disease, which can af- fect several organs. Most commonly involved are the joints, skin and kidneys, but the bone marrow, heart, lungs, gut and central and peripheral nervous system can also become diseased. SLE is a chronic condition, characterized by flares of disease activity and quiescent periods.
The usual age of onset is approximately from 15 to 40 years and few cases of new-onset SLE are described in the elderly (1). Up to 90% of SLE patients are female. SLE occurs more frequently in patients of Asian or African ancestry, in these groups SLE also tends to be more severe. The estimated prevalence varies per ethnic group, from 40 cases per 100.000 persons for Northern Europeans to more than 200 cases per 100.000 persons in blacks.
Although some patients suffer from mild forms of SLE, in general it leads to substantial morbidity and mortality. The standardized mortality ratio (SMR) of SLE is three, which means that patients have a threefold increased risk of death compared to their age and sex matched peers in the general population (2;3).
Next to disease activity and infections as causes of death, cardiovascular dis- ease and accumulated damage became increasingly important. Socioeconomic status and to a lesser extent race are patient related characteristics associated with an increased mortality(4;5), whereas with age and gender conflicting re- sults have been reported (5-7). Disease related characteristics associated with an increased mortality are the time between symptom onset and diagnosis, disease activity, therapy, accrued damage and the presence of specific disease manifestations (8-10).
Since SLE can affect many organs it can also mimic many other conditions, therefore diagnosing SLE can be difficult. In 1971 the American College of Rheumatology (ACR) established preliminary classification criteria for SLE, which have been revised in 1982 and last updated in 1997 leading to the fol- lowing list of criteria (11;12):
1. Malar rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Arthritis 6. Serositis
7. Renal disorder 8. Neurologic disorder 9. Hematologic disorder 10. Immunologic disorder 11. Antinuclear antibody
Following the criteria, SLE is diagnosed when four of the eleven criteria are met at some time during the course of the disease. Recently, in 2012, the Sys- temic Lupus International Collaborating Clinics (SLICC) have presented a new set of classification criteria, incorporating new immunological knowledge (13).
As well as in the above-mentioned ACR-criteria, four criteria must be met for a diagnosis of SLE. The criteria itself are somewhat different than the older criteria and the patient must meet a serological as well as a clinical criterion.
The neurologic symptoms that can contribute to establish a diagnosis of SLE have been expanded, with the addition of mononeuritis multiplex, transverse myelitis, peripheral and cranial neuropathy and acute confusional state. Next to that, a patient with biopsy proven lupus nephritis in the presence of anti- nuclear antibodies or anti-double stranded DNA antibodies is also classified as SLE. Although the SLICC-criteria claim to have greater sensitivity and seem clinically relevant, up to now their incorporation in scientific papers is scarce.
Pathogenesis
Since SLE is an autoimmune disease, it is caused by inaccurate reactions of the immune system, directed at host tissue. Specific for SLE, several autoantibod- ies are directed at components of the nucleus of the cell, e.g. double-stranded DNA. Defects in the clearance of apoptotic cells have been described, leading to the exposal of nuclear components and subsequently their uptake by anti- gen presenting cells. The presentation of these host components to the immune system leads to autoreactive B and T cells. The production, stimulation and survival of autoreactive B cells are important pathways in developing SLE (14). In the activation and prolongation of the aberrant immune reaction, many cytokines are involved, most notably interferon alpha. This immune reaction directed against host tissue leads to inflammation and finally to damage of the tissue.
Therapy
Frequently used medications in the treatment of SLE are nonsteroidal anti-in- flammatory drugs (NSAIDs), antimalarials and corticosteroids (e.g. predniso- lone). Also immunosuppressive agents such as azathioprine, methotrexate and
mycophenolate mofetil are utilized. In the most severe cases cyclophospha- mide, an alkylating agent with immunosuppressive properties, in concordance with high doses of corticosteroids, is applied. The disadvantages of prolonged corticosteroid therapy, such as osteoporosis, obesity and hypertension, have been known for decades. Nevertheless, the awareness of the harmful effects of low dose corticosteroids (prednisolone >7.5mg/day) in the long term is only slowly increasing. On the other hand the beneficial effects of antimalarials are sometimes disregarded (15). In SLE patients, morbidity and mortality due to therapy is substantial, leading to infections, toxicity and cardiovascular dis- ease.
Since 2000 several reports on the therapeutic effect of biological agents in the treatment of SLE have been published. Rituximab, a monoclonal antibody directed at CD20+ B cells, was the first biologic agent described in the treatment of SLE. And although this therapeutic approach seems sensible from a theoreti- cal viewpoint, clinical trials failed to show its effectiveness (16;17). Nonetheless many case and cohort studies described a remarkable positive outcome of its usage, especially in refractory cases (18).
Thereafter clinical trials also failed to show effectiveness of co-stimulation blocker abatacept (19). However, in 2012 the results of the BLISS-52 and 76 clinical trials showed the first beneficial effects of a biological agent, namely belimumab (20;21). This anti-B cell stimulator antibody was shown to prevent flares in SLE patients. The use of biologic agents in SLE progresses slowly, due to several reasons, most importantly lack of sound evidence for its effective- ness, uncertainty when to start therapy and its financial endorsement. At this moment several other biologic agents are being developed and tested, most of them directed at B cell function or stimulation, and the type-1 interferon pathway (22).
Antiphospholipid syndrome
SLE can be complicated by venous and arterial thrombosis, especially in the case of a concomitant antiphospholipid syndrome (23). This syndrome is characterized by the presence of specific autoantibodies (anticardiolipin and anti-β2 glycoprotein 1 antibodies) and/or lupus anticoagulant, a venous or arterial thrombosis and/or obstetric complications. The classification criteria of the syndrome are based on both serological and clinical markers (24). The syndrome can be either primary or secondary to another autoimmune disease, most importantly SLE. Primary antiphospholipid syndrome is associated with increased morbidity and has a SMR of 1.8 (25). In around 1 per cent of cases an extremely lethal condition arises, characterised by microthrombi in multiple
organs, the so-called catastrophic antiphospholipid syndrome. Management of antiphospholipid syndrome has been a matter of debate mostly due to lack of unequivocal data (26). However experts in the field recently stated recommendations involving indefinite antithrombotic treatment in thrombotic antiphospholipid syndrome and primary prophylaxis in SLE patients carrying antiphosholipid antibodies with hydroxychloroquine and, although supported with less evidence, antiplatelet therapy (27).
Health care aspects
Research in health care over the past years has been mainly focused on the development and evaluation of clinically effective interventions, i.e. trials concerning a specific medication. Nowadays, more and more attention is being paid to the implementation of (cost) effective treatments in clinical practice. It is now generally acknowledged that for that purpose, apart from traditional clinical (cost) effectiveness studies, additional knowledge is needed.
This knowledge pertains to current health care delivery and its evaluation by its users as well as the needs and preferences of all stakeholders. Concern- ing stakeholder involvement, the perspective of the patients is of utmost importance. In this respect, the quote “The patient is the center of the medical universe around which all our works revolve and towards which all our efforts tend” (J.B. Murphy, professor of surgery (1857–1916)) should still guide all our research efforts.
The above mentioned aspects of health care are a relatively new area of research and methods are still in development (28). In the process of improv- ing health care delivery and incorporating the patient’s views, the following aspects are considered important: 1. Actual health care usage 2. Patients’ evalu- ation of health care provision; and 3. Patients’ preferences for (future) health care delivery. Actual health care usage can be determined in different ways, including review of medical records, records of health insurance companies and/or patient surveys. A question in such a survey could be: “How many times have you seen the rheumatologist in the past 12 months?”. An example of the second element can be “Rate your level of satisfaction with the last visit to your rheumatologist on a scale from 0 to 10?” and an example of the third element “If you would be able to contact your rheumatologist by means of e-mail, how likely is it that you would do that (scale 0-10)?” (28;29).
Concerning health care usage, not only its extent and its clinical outcomes and costs are interesting, but its organizational characteristics (structure and processes) as well. Interestingly, in studies regarding health care delivery in another chronic disease, for instance rheumatoid arthritis, the process and
structure of health care delivery were reported to have greater influence on the patient’s satisfaction than the medical outcome (30). The only modifiable aspect reported in SLE patients to improve patient’s satisfaction with health care delivery is to improve trust in and agreement on goals with the physician (31;32).
The organization and content of health care provision for SLE patients may be even more relevant than in other patients with a chronic disease, because of the clinical complexity of SLE. It is not unusual for a SLE patient to visit several medical specialists, the general practitioner and other health profes- sionals (e.g. a physical therapist) all for the same illness. The involvement of several health care providers has been reported to lead to miscommunication and uncertainty within the patient to choose to right health care provider for a specific question or problem (33). In literature the rheumatologist is the physi- cian that is involved in the treatment of the majority of SLE patients (34;35), therefore perhaps rheumatologists should take the initiative to improve care for this group of patients.
An important element of health care processes in patients with chronic diseases pertains to the delivery of information and education to patients. According to the chronic care model, patients need to mobilize or develop their own abilities and/or skills to cope with the physical, psychological and social demands of their disease. For example, in order to be able to obtain helpful medical care, make shared decisions and adhere to complex medication regimens, patients need to be educated on specific subjects (36). And although patient education is recommended by field experts (37), up to now it is not formally stated in disease- management guidelines (38;39), possibly due to lack of standardisation.
Gaps in knowledge on health care aspects
In the Netherlands, with regards to SLE patients, all of the following informa- tion is unavailable:
• Extent of health care usage
• Patient satisfaction with the structure, process and outcomes of health care (including patient education)
• Patient preferences regarding future health care delivery (including patient education)
Data on the extent of health care usage in SLE patients is available for patients from the United States, Canada and the United Kingdom. However, these data cannot be extrapolated to the situation in the Netherlands due to differences in population, local differences in health insurance and logistics of care. Next to that, there could be a difference in the policy of local health professionals with
regard to treating SLE, leading to different ‘standards of care’. These ‘standards of care’ could be unique to a country or even to a region, and result in health care needs that are not met with the current health care delivery.
Quantitative data on satisfaction and preferences in SLE patients are not available worldwide and few studies provide qualitative insights (33). Fur- thermore, at this moment a validated tool to examine educational needs in SLE patients is lacking.
Neuropsychiatric Systemic Lupus Erythematosus (NPSLE)
As mentioned before, in patients with SLE the disease can also affect the pe- ripheral and central nervous system. This can lead to an array of symptoms and complaints, which can be either neurological or psychiatric. In order to specify these symptoms the ACR published a nomenclature and case definition system for neuropsychiatric lupus syndromes. This is a list of nineteen syndromes, with recommendations for a minimally warranted diagnostic work-up (40).
The list is as follows:
Central nervous system aseptic meningitis cerebrovascular disease demyelinating syndrome
headache (including migraine and benign intracranial hypertension) movement disorder (chorea)
myelopathy seizure disorders acute confusional state anxiety disorder cognitive dysfunction mood disorder psychosis
Peripheral nervous system
acute inflammatory demyelinating polyradiculoneuropathy (Guillan-Barré syndrome)
autonomic disorder
mononeuropathy (single or multiplex) myasthenia gravis
neuropathy, cranial plexopathy
polyneuropathy
With these criteria the uniformity and transparency in establishing NPSLE diagnosis is ameliorated, however its usefulness in clinical practice is limited.
In the description of the NPSLE syndromes the elimination of all other possible diagnoses is noted, therefore it is important to keep in mind that SLE patients can also have a neurological or psychiatric disease apart from SLE. The at- tribution of neuropsychiatric symptoms to SLE, or in other words diagnosing NPSLE, can be a great challenge to the physician. This is also illustrated by the great discrepancy of the described prevalence of NPSLE in SLE patients, ranging from 15 to 91% in published data from diverse study methods (41-43).
From selected prospective cohort studies the estimated prevalence of NPSLE is approximately 50% (44).
Diagnostic process
In common practice, the diagnostic approach of neuropsychiatric symptoms in a patient with SLE consists of several tests. No single test is able to distinguish between neuropsychiatric symptoms attributed to SLE (NPSLE) or co-existent neuropsychiatric symptoms. Therefore the diagnosis of NPSLE is based on the (expert) opinion of the physician supported by a combination of diagnostic tests. Diagnostic tests employed in this process can be rheumatologic, car- diovascular, neurological, neuropsychological and psychiatric evaluations, serological markers and (advanced) imaging.
The rheumatologic assessment consists of the evaluation of current signs and symptoms, use of medication, medical history and family history. Also, a gen- eral physical examination with specific interest for lymphadenopathy, skin and joint symptoms is performed. The assessment should be specifically aimed at past and current manifestations of SLE disease activity and end organ damage due to SLE. All old and new criteria for SLE are scored and the activity of SLE should be assessed with a validated activity index. Several disease indices ex- ist, most importantly the Systemic Lupus Activity Measure (SLAM), Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), Lupus Activity Index (LAI), British Isles Lupus Assessment Group index (BILAG), and the European Consensus Lupus Activity Measure (ECLAM). Each index is a valid measure, and although SLEDAI is least sensitive to change it is very suitable for clinical practice and used in the studies in this thesis (45;46).
Furthermore symptoms of former and current vascular diseases should be assessed. Special attention is paid to symptoms of atherosclerotic disease, thrombotic events, vasculitis and cardiovascular risk factors including hyper- tension, dyslipidemia and diabetes. According to the SCORE risk stratifica- tions risk factors could be denominated as follows: hypertension if systolic
blood pressure is higher than 140 mmHg, obesity if body mass index exceeds 29.9, hypercholesterolemia if total cholesterol exceeds 6.5 mmol/l (47).
The neurological assessment is focused at the recognition of symptoms such as headache and signs of seizures, alertness, motor and sensory deficits and evaluation for co-existent, not SLE related neurological diseases. The neuro- logical physical examination includes fundoscopy, examination of cranial nerves, visual fields, strength of arm muscles and dexterity, observation of gait and ataxia, walking on toes and heels, tendon reflexes, Babinski reflex, sensory examination of gnostic and vital abilities, fingertip-nose test, muscle tone and muscle atrophy. Acute focal neurological deficits with a resolution within 24 hours are regarded as transient ischemic attacks (TIAs). Assessment of cerebral spinal fluid (CSF), electroencephalography (EEG) or electromyography (EMG) is performed according to the presenting symptoms. In case of recurrent TIA’s or cerebrovascular disease (CVD) SLE patients should be analyzed in the same manner as patients without SLE, including duplex of the carotids, electrocar- diography and ultrasound of the heart.
When the patient, or his/her relatives, or the physician suspects cognitive dysfunction, formal neuropsychological testing should be performed. An experienced neuropsychologist should conduct formal tests alongside history taking and clinical observation. In suspected NPSLE, specific focus is required on memory, executive functioning and psychomotor speed. In the 1999 ACR NPSLE nomenclature and case definition system appendix C a neuropsycho- logical test battery is recommended (40). The evaluation of cognitive deficits in highly educated patients may require additional neuropsychological testing, because deficits are harder to detect. Cognitive deficits are considered severe if they result in inability to function in daily life without (professional) help.
The psychiatric assessment includes a detailed psychiatric history and men- tal status examination assessing behavior, cognition, perception and thinking, as well as mood and affect in a standardized manner. Especially informative in clinical practice is a Neuropsychiatric Inventory (NPI), a 10-20 minute inter- view, which can be used for the evaluation of a wide range of neuropsychiatric symptoms (48). Psychopathology in SLE patients is based on the psychiatric history and mental status examination, following DSM IV classification (49).
In a diagnosis of SLE, serum autoantibodies play a pivotal role and are part of routine practice. However in the diagnostic process of NPSLE their role is far less evident. Conflicting but mainly positive data associates a rise in anti- dsDNA titre with general disease activity (50;51). However at this moment its predictive or affirmative role specifically in NPSLE is uncertain. Several clinical studies have been conducted on the association of antinuclear auto-
antibodies and NPSLE, but unfortunately until now most results have been conflicting (52). For example, anti-ribosomal P antibody was described to be associated with NPSLE, especially psychosis (53) but its role has been disputed because of a history of negative associations (54). Some reports reveal a role for anti-Sm antibodies in seizure disorder (55;56). Furthermore, positive and negative associations have been published on the role of anti-SSA antibodies (57;58). Only the role of antiphospholipid antibodies (and lupus anticoagulant) and their association with NPSLE has been consistent. Ischemic events in cere- brovascular disease are associated with these antibodies, but also less evident entities such as seizures and headache (53;56;59). In laboratory settings, the association and possible pathogenic role of other autoantibodies in NPSLE, namely anti-neuronal and anti-endothelial antibodies have been studied but this is not yet implacable in clinical practice (60).
In the diagnostic approach of NPSLE the standard of imaging is magnetic resonance imaging (MRI) of the brain (61). The recommended protocol for imaging of the brain is conventional T1/T2, FLAIR, DWI and gadolinium enhanced T1 sequences (62). As a first, the MRI scan is important to rule out other causes that explain the symptoms, for instance signs of infection or a tumour. Secondly, abnormalities possibly due to NPSLE can be visualized. In our retrospective cohort of NPSLE patients the following abnormalities were found on MRI scans of the brain: focal hyperintensities in the white matter (49% of patients) or in both the white and gray matter (5% of patients) sugges- tive of vasculopathy or vasculitis as the most important group. Furthermore, widespread, confluent hyperintensities in the white matter were observed, suggestive of chronic hypoperfusion due to the same mechanisms. And finally diffuse cortical gray matter lesions (12% of patients), which are compatible with an immune response to neuronal components or post seizure changes, were observed. However, in 42% of the patients no MRI abnormalities were found, despite their neuropsychiatric symptoms attributed to SLE (63). The absence of radiological findings in symptomatic NPSLE patients is also referred to as the clinical-radiological paradox. MR-angiography of the cerebral arteries and veins or MRI of the spine should be performed if indicated by the presenting symptoms.
In addition to the standard clinical sequences, several quantitative MRI sequence modalities are available, such as diffusion tensor MRI, MR spectros- copy, functional MRI and perfusion weighted imaging. An advanced imaging technique that was investigated in our center is magnetization transfer imaging (MTI). MTI is based on the exchange of protons between a pool of protons that is bound to macromolecules such as cholesterol (found in myelin in the central
nervous system) and a pool of free water protons that exist in biologic tissues (cellular water) (explanation adapted from thesis of G.M. Steup-Beekman).
Previous studies have shown that MTI is a valuable addition in diagnosing NPSLE, by correlating change in peak height to clinical activity of the disease (64). In our center MTI is used in clinical practice on an experimental basis.
Attribution of NP symptoms to SLE
As mentioned, the diagnosis NPSLE is a resultant of the discussed separate diagnostic entities. However, exactly when this resultant is reached is a mat- ter of discussion. Since the evaluation of neuropsychiatric symptoms in SLE patients is a challenge to physicians around the world, some efforts have been made with regards to aid the physician with the attribution of the neuropsy- chiatric symptoms to SLE and key symptoms and signs have been assigned.
Table 1 shows an overview of specific risk factors associated with a diagnosis of NPSLE derived from the EULAR recommendations for NPSLE (46).
Furthermore, Hanly published a decision rule with 2 stringencies (A most stringent and B least stringent). Factors considered in this decision rule in- clude: 1. Onset of NP event(s) prior to the diagnosis of SLE, 2. Concurrent non-SLE factor(s) identified from the ACR glossary for each NP syndrome and, 3. “Minor” NP events which are frequent in normal population controls as described by Ainiala (65). The latter includes all headaches, anxiety dis- orders, mild depression (mood disorders failing to meet criteria for “major depressive-like episodes”), mild cognitive impairment (deficits in less than 3 of the 8 specified cognitive domains) and polyneuropathy without electrophysi- ological confirmation.
If the following factors are fulfilled a diagnosis of NPSLE is established:
Decision rule A: only NP symptoms appearing after SLE diagnosis, the ab- sence of any non-SLE factor and only NP events not described as “minor” by Ainiala (65).
Decision rule B: all NP events whose onset was within 10 years prior to the diagnosis of SLE were attributed to SLE, and NP events for which only “as- sociation factors” but not “exclusion factors” were identified were attributed to SLE and only NP events not described as “minor” by Ainiala. When the decision rule was applied to an international inception cohort of SLE patients, the attribution of occurring NP events to SLE varied from 13% (model A) to 24% (model B) (66).
Finally, an Italian research group created an attribution-model which in- cludes several items that can point to an SLE-associated pathogenesis of NP manifestations. The model includes the following items: 1. time of onset and
type of the NP event, 2. confounding comorbidities and 3. favoring factors (young age; no familial history for seizures, migraine or psychiatric disorders;
abnormal neuroimaging; response to treatment; high disease activity; presence of antiphospholipid or anti-ribosomal P antibodies; and antecedent NPSLE events) (67).
Table 1. Overview of specific risk factors associated with a diagnosis of NPSLE NPSLE syndrome Risk factor (SLE-specific) Risk factor (general)
CVD · SLE disease activity · Hypertension
· Antiphospholipid antibodies · Dyslipidemia
· Heart valve disease · Age
· Previous CVD · Male gender
· Hyperhomocysteinemia Seizure disorder · SLE disease activity
· SLE damage
· Antiphospholipid antibodies
· Major NPSLE
· Anti-Sm antibodies
· Younger age
· Ethnicity
Cognitive dysfunction · SLE disease activity · Age
· SLE damage · Education level
· Major NPSLE history · Hypertension
· Antiphospholipid antibodies · Psychiatric disease
· Heart valve disease
Movement disorders · Antiphospholipid antibodies Acute confusional state · SLE disease activity
· Major NPSLE history Psychiatric disorders · SLE disease activity
· Major NPSLE history
· Psychological distress
· Anti-ENA
Myelopathy · Antiphospholipid antibodies Cranial neuropathy · Antiphospholipid antibodies Peripheral neuropathy · Anti-ENA
· Major NPSLE history
Therapy
As a very welcome guide in the clinic, in 2010 the European league against Rheumatism (EULAR) published recommendations for the management of NPSLE (62).
The treatment of NPSLE can be solely symptomatic, especially in mild cases.
Specifically, anxiety and mood disorders can be targeted with psychiatric med- ication, like benzodiazepines or antidepressants. In more severe cases, such as psychosis or seizures, respectively antipsychotic and antiepileptic drugs can be used to relieve symptoms, mostly in concordance with medication that targets the suspected underlying cause.
Treatment of the suspected underlying cause can be directed at inflammation with immunosuppressive medication or at ischemia and thrombotic events with anticoagulation or antiplatelet therapy. In some cases a differentiation cannot be made or both processes act simultaneously, in tthis case both thera- pies should be started.
In the case of CVD, thrombolytic therapy (ischemic stroke) or surgical therapy (hemorrhagic stroke) should be applied according to the same indications as patients who do not suffer from (NP)SLE. In the same perspective, patients with ischemic stroke should be treated with antiplatelet agents promptly. In the case of a cardio-embolic source or recurrent ischemic stroke with persistent antiphospholipid antibodies long-term anticoagulation therapy is warranted for secondary prevention. Though whether the benefits of high-intensity war- farin (INR 3.1-4.0) over moderate-intensity warfarin (INR 2.0-3.0) outweigh the disadvantages (bleeding events) is a matter of debate (68), the high-intensity regimen can also be considered in the case of recurrent ischemic episodes.
Immunosuppressive therapy starts with corticosteroids, alone or in combi- nation with other immunosuppressive agents. Evidence for the indication and dosage of corticosteroids for specific symptoms is not available since studies evaluating its effects in NPSLE are lacking. The dosing of corticosteroids is chosen according to the severity of the symptom based on expert opinion, however overall consensus exists that 1mg/kg/day orally is appropriate for moderate symptoms and initial treatment with 1 gram of methylprednisolone for 3 consecutive days intravenously followed by high dose corticosteroids orally for severe symptoms (69).
The immunosuppressive therapy with the soundest evidence for efficacy in NPSLE is cyclophosphamide. This is the only agent in NPSLE studied in a randomized clinical trial, although it only includes 32 patients (70). It describes the effect of cyclophosphamide combined with corticosteroids opposed to cor- ticosteroids alone, resulting in an improvement in 18 out of 19 patients treated
with cyclophosphamide versus 7 out of 13 patients treated with corticosteroids alone (p<0.03), which results in a number needed to treat of 3 (71).
Furthermore in all cases of NPSLE, but especially in the case of arterial events and cognitive dysfunction, aggressive control of cardiovascular risk factors is recommended. This includes the cessation of tobacco smoking, aggressive control of hypertension, hyperglycemia and dyslipidemia, weight control and adequate physical activity. Next to that, antimalarial therapy should be administered to all (NP)SLE patients if not contra-indicated, for instance in the case of pre-existent retinopathy (15).
Gaps in current knowledge in NPSLE
All data and every discussion on NPSLE are hampered by the diagnostic dif- ficulties of establishing the diagnosis. This is illustrated by the great variance in its reported prevalence and lack of data on clinical outcomes. Despite the efforts mentioned above, an objective “gold standard” for the attribution of NP symptoms to SLE is non-existent. Therefore a diagnosis of NPSLE based on expert opinion is still the international standard in research.
Symptoms of NPSLE can be mild but on the other side of the spectrum, they can also be life threatening. However the actual survival of NPSLE patients is not well known. Data on the prognosis of milder symptoms is also not readily available.
Probably the greatest caveat in NPSLE is data on the effect of treatment. At this moment, only one randomized controlled clinical trial was executed in NPSLE patients, all other knowledge of treatments is either based on research of less epidemiological quality or extrapolated from either other symptoms of SLE or other diseases.
Aim and outline of thesis
From the preceding paragraphs it can be concluded that several aspects of SLE need to be investigated and studied further. This thesis consists of two parts.
In PART I we describe vacant health care aspects of SLE patients in the Nether- lands and explore enhancements of the provision of health care. In PART II we describe novel insights into the diagnostic approach of NPSLE and the clinical outcome of our cohort.
Part I Health care aspects in SLE
Apart from disease activity SLE patients suffer from the effects of accrued damage, leading to dysfunction of various organs and functional disability.
Consequently, many different health care providers are involved in the care for SLE patients. In Chapter 2 we describe the health care usage of Dutch SLE patients and its determinants.
In order to be able to improve health care provision in a patient-centered manner we investigated the patients’ opinion. In Chapter 3 we describe Dutch SLE patients’ satisfaction with current health care provision, unmet needs and preferences for the future.
Up to date no validated tool is available to assess the educational needs of SLE patients. In Chapter 4 we describe the educational needs of SLE patients as measured with a recently validated Dutch version of the educational needs assessment tool (D-ENAT), which was developed for rheumatic diseases in general.
Part II Neuropsychiatric systemic lupus erythematosus (NPSLE)
In animal models an immune-mediated pathway has been demonstrated in the pathogenesis of NPSLE. In Chapter 5 we describe the patient characteris- tics and time of occurrence of neuropsychiatric symptoms in SLE patients in order to assess whether these features fit an immune-mediated pathogenesis of NPSLE in humans.
The diagnostic approach in NPSLE varies in daily practice and evidence for the selection of different therapies for NPSLE patients is largely lacking. There- fore in Chapter 6 we describe a standardized multidisciplinary diagnostic ap- proach for NPSLE and an algorithm of the most relevant diagnostic consider- ations based on the expert opinion of the consensus group. Furthermore three NPSLE phenotypes are described with an assumed different pathogenesis and subsequent treatment.
In response to a scientific comment made with regard to Chapter 6, we re- sponded in a letter described in Chapter 7.
Since autoantibodies are a hallmark of SLE and are part of all classifica- tion criteria, they could be of diagnostic value in NPSLE as well. Up to now conflicting results have been reported on several individual autoantibodies.
Therefore in Chapter 8 we describe the association of clusters of autoantibodies with NPSLE with focal and diffuse manifestations. The serum samples of our NPSLE patients were analysed with FIDIS connective profile kit (Theradiag, Paris), a novel semi-quantitative homogeneous fluorescent-based micropar- ticles immunoassay for the simultaneous detection of several autoantibodies.
SLE is associated with a three-fold increased risk of mortality. Specific dis- ease manifestations can worsen the prognosis, for example in case of renal
involvement the risk of mortality rises to six. In Chapter 9 we describe the risk of mortality in NPSLE and its positive and negative associations.
REFERENCES
(1) Boddaert J, Huong DL, Amoura Z, Wechsler B, Godeau P, Piette JC. Late-onset systemic lupus erythematosus: a personal series of 47 patients and pooled analysis of 714 cases in the literature. Medicine (Baltimore) 2004 Nov;83(6):348-59.
(2) Moss KE, Ioannou Y, Sultan SM, Haq I, Isenberg DA. Outcome of a cohort of 300 patients with systemic lupus erythematosus attending a dedicated clinic for over two decades. Ann Rheum Dis 2002 May;61(5):409-13.
(3) Urowitz MB, Gladman DD, Abu-Shakra M, Farewell VT. Mortality studies in systemic lupus erythematosus. Results from a single center. III. Improved survival over 24 years. J Rheumatol 1997 Jun;24(6):1061-5.
(4) Alarcon GS, McGwin G, Jr., Bastian HM, Roseman J, Lisse J, Fessler BJ, et al. Systemic lupus erythematosus in three ethnic groups. VII [correction of VIII]. Predictors of early mortality in the LUMINA cohort. LUMINA Study Group. Arthritis Rheum 2001 Apr;45(2):191-202.
(5) Reveille JD, Bartolucci A, Alarcon GS. Prognosis in systemic lupus erythematosus. Nega- tive impact of increasing age at onset, black race, and thrombocytopenia, as well as causes of death. Arthritis Rheum 1990 Jan;33(1):37-48.
(6) Abu-Shakra M, Urowitz MB, Gladman DD, Gough J. Mortality studies in systemic lupus erythematosus. Results from a single center. II. Predictor variables for mortality. J Rheuma- tol 1995 Jul;22(7):1265-70.
(7) Ginzler EM, Diamond HS, Weiner M, Schlesinger M, Fries JF, Wasner C, et al. A multicenter study of outcome in systemic lupus erythematosus. I. Entry variables as predictors of prognosis. Arthritis Rheum 1982 Jun;25(6):601-11.
(8) Chambers SA, Allen E, Rahman A, Isenberg D. Damage and mortality in a group of British patients with systemic lupus erythematosus followed up for over 10 years. Rheumatology (Oxford) 2009 Jun;48(6):673-5.
(9) Lopez R, Davidson JE, Beeby MD, Egger PJ, Isenberg DA. Lupus disease activity and the risk of subsequent organ damage and mortality in a large lupus cohort. Rheumatology (Oxford) 2012 Mar;51(3):491-8.
(10) Mak A, Cheung MW, Chiew HJ, Liu Y, Ho RC. Global trend of survival and damage of systemic lupus erythematosus: meta-analysis and meta-regression of observational studies from the 1950s to 2000s. Semin Arthritis Rheum 2012 Jun;41(6):830-9.
(11) Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997 Sep;40(9):1725.
(12) Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1982 Nov;25(11):1271-7.
(13) Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012 Aug;64(8):2677-86.
(14) Jacobi AM, Diamond B. Balancing diversity and tolerance: lessons from patients with systemic lupus erythematosus. J Exp Med 2005 Aug 1;202(3):341-4.
(15) Fangtham M, Petri M. 2013 update: Hopkins lupus cohort. Curr Rheumatol Rep 2013 Sep;15(9):360.
(16) Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus:
the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010 Jan;62(1):222-33.
(17) Rovin BH, Furie R, Latinis K, Looney RJ, Fervenza FC, Sanchez-Guerrero J, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012 Apr;64(4):1215-26.
(18) Ramos-Casals M, Soto MJ, Cuadrado MJ, Khamashta MA. Rituximab in systemic lupus erythematosus: A systematic review of off-label use in 188 cases. Lupus 2009 Aug;18(9):767- 76.
(19) Furie R, Nicholls K, Cheng TT, Houssiau F, Burgos-Vargas R, Chen SL, et al. Efficacy and safety of abatacept in lupus nephritis: a twelve-month, randomized, double-blind study.
Arthritis Rheumatol 2014 Feb;66(2):379-89.
(20) Furie R, Petri M, Zamani O, Cervera R, Wallace DJ, Tegzova D, et al. A phase III, ran- domized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011 Dec;63(12):3918-30.
(21) Navarra SV, Guzman RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 2011 Feb 26;377(9767):721-31.
(22) Lauwerys BR, Ducreux J, Houssiau FA. Type I interferon blockade in systemic lupus erythe- matosus: where do we stand? Rheumatology (Oxford) 2013 Dec 15.
(23) Derksen RH, de Groot PG. Clinical consequences of antiphospholipid antibodies. Neth J Med 2004 Sep;62(8):273-8.
(24) Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006 Feb;4(2):295-306.
(25) Cervera R, Serrano R, Pons-Estel GJ, Ceberio-Hualde L, Shoenfeld Y, de RE, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2014 Jan 24.
(26) Derksen RH, de Groot PG. Towards evidence-based treatment of thrombotic antiphospho- lipid syndrome. Lupus 2010 Apr;19(4):470-4.
(27) Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, Brey R, Crowther M, Derksen R, et al.
Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus 2011 Feb;20(2):206-18.
(28) Wensing M, Elwyn G. Methods for incorporating patients’ views in health care. BMJ 2003 Apr 19;326(7394):877-9.
(29) Zicht op zorgprocessen. Oratie bij de aanvaarding van het ambt van bijzonder hoogleraar op het gebied van Doelmatigheid van Revalidatieprocessen. Vliet Vlieland TP, (Mar 21, 2014).
(30) Rademakers J, Delnoij D, de BD. Structure, process or outcome: which contributes most to patients’ overall assessment of healthcare quality? BMJ Qual Saf 2011 Apr;20(4):326-31.
(31) Bennett JK, Fuertes JN, Keitel M, Phillips R. The role of patient attachment and working alliance on patient adherence, satisfaction, and health-related quality of life in lupus treat- ment. Patient Educ Couns 2011 Oct;85(1):53-9.
(32) Da Costa D., Clarke AE, Dobkin PL, Senecal JL, Fortin PR, Danoff DS, et al. The relationship between health status, social support and satisfaction with medical care among patients with systemic lupus erythematosus. Int J Qual Health Care 1999 Jun;11(3):201-7.
(33) Hale ED, Treharne GJ, Lyons AC, Norton Y, Mole S, Mitton DL, et al. “Joining the dots” for patients with systemic lupus erythematosus: personal perspectives of health care from a qualitative study. Ann Rheum Dis 2006 May;65(5):585-9.
(34) Sutcliffe N, Clarke AE, Taylor R, Frost C, Isenberg DA. Total costs and predictors of costs in patients with systemic lupus erythematosus. Rheumatology (Oxford) 2001 Jan;40(1):37-47.
(35) Yazdany J, Gillis JZ, Trupin L, Katz P, Panopalis P, Criswell LA, et al. Association of socio- economic and demographic factors with utilization of rheumatology subspecialty care in systemic lupus erythematosus. Arthritis Rheum 2007 May 15;57(4):593-600.
(36) Wagner EH, Austin BT, Davis C, Hindmarsh M, Schaefer J, Bonomi A. Improving chronic illness care: translating evidence into action. Health Aff (Millwood ) 2001 Nov;20(6):64-78.
(37) Houssiau FA. Therapy of lupus nephritis: lessons learned from clinical research and daily care of patients. Arthritis Res Ther 2012;14(1):202.
(38) Bertsias G, Ioannidis JP, Boletis J, Bombardieri S, Cervera R, Dostal C, et al. EULAR recom- mendations for the management of systemic lupus erythematosus. Report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics.
Ann Rheum Dis 2008 Feb;67(2):195-205.
(39) Bertsias GK, Tektonidou M, Amoura Z, Aringer M, Bajema I, Berden JH, et al. Joint Eu- ropean League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012 Nov;71(11):1771-82.
(40) The American College of Rheumatology nomenclature and case definitions for neuropsy- chiatric lupus syndromes. Arthritis Rheum 1999 Apr;42(4):599-608.
(41) Ainiala H, Loukkola J, Peltola J, Korpela M, Hietaharju A. The prevalence of neuropsychi- atric syndromes in systemic lupus erythematosus. Neurology 2001 Aug 14;57(3):496-500.
(42) Brey RL, Holliday SL, Saklad AR, Navarrete MG, Hermosillo-Romo D, Stallworth CL, et al.
Neuropsychiatric syndromes in lupus: prevalence using standardized definitions. Neurol- ogy 2002 Apr 23;58(8):1214-20.
(43) Jennekens FG, Kater L. The central nervous system in systemic lupus erythematosus. Part 1.
Clinical syndromes: a literature investigation. Rheumatology (Oxford) 2002 Jun;41(6):605- 18.
(44) Unterman A, Nolte JE, Boaz M, Abady M, Shoenfeld Y, Zandman-Goddard G. Neuropsy- chiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin Arthritis Rheum 2011 Aug;41(1):1-11.
(45) Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI.
A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE.
Arthritis Rheum 1992 Jun;35(6):630-40.
(46) Ward MM, Marx AS, Barry NN. Comparison of the validity and sensitivity to change of 5 activity indices in systemic lupus erythematosus. J Rheumatol 2000 Mar;27(3):664-70.
(47) Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De BG, et al. Estimation of ten- year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J 2003 Jun;24(11):987-1003.
(48) Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia.
Neurology 1994 Dec;44(12):2308-14.
(49) American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders (4th ed. text revision). 2000.
(50) Kallenberg CG, Stegeman CA, Bootsma H, Bijl M, Limburg PC. Quantitation of autoanti- bodies in systemic autoimmune diseases: clinically useful? Lupus 2006;15(7):397-402.
(51) Pan N, Amigues I, Lyman S, Duculan R, Aziz F, Crow M, et al. A surge in anti-dsDNA titer predicts a severe lupus flare within six months. Lupus 2014;23(3):293-8.
(52) Colasanti T, Delunardo F, Margutti P, Vacirca D, Piro E, Siracusano A, et al. Autoantibodies involved in neuropsychiatric manifestations associated with systemic lupus erythemato- sus. J Neuroimmunol 2009 Jul 25;212(1-2):3-9.
(53) Hanly JG, Urowitz MB, Siannis F, Farewell V, Gordon C, Bae SC, et al. Autoantibodies and neuropsychiatric events at the time of systemic lupus erythematosus diagnosis: results from an international inception cohort study. Arthritis Rheum 2008 Mar;58(3):843-53.
(54) Eber T, Chapman J, Shoenfeld Y. Anti-ribosomal P-protein and its role in psychiatric mani- festations of systemic lupus erythematosus: myth or reality? Lupus 2005;14(8):571-5.
(55) Hitchon CA, Peschken CA. Sm antibodies increase risk of death in systemic lupus erythe- matosus. Lupus 2007;16(3):186-94.
(56) Mikdashi J, Krumholz A, Handwerger B. Factors at diagnosis predict subsequent occur- rence of seizures in systemic lupus erythematosus. Neurology 2005 Jun 28;64(12):2102-7.
(57) Conti F, Alessandri C, Bompane D, Bombardieri M, Spinelli FR, Rusconi AC, et al. Autoan- tibody profile in systemic lupus erythematosus with psychiatric manifestations: a role for anti-endothelial-cell antibodies. Arthritis Res Ther 2004;6(4):R366-R372.
(58) Mikdashi J, Handwerger B. Predictors of neuropsychiatric damage in systemic lupus erythematosus: data from the Maryland lupus cohort. Rheumatology (Oxford) 2004 Dec;43(12):1555-60.
(59) Sanna G, Bertolaccini ML, Cuadrado MJ, Laing H, Khamashta MA, Mathieu A, et al. Neu- ropsychiatric manifestations in systemic lupus erythematosus: prevalence and association with antiphospholipid antibodies. J Rheumatol 2003 May;30(5):985-92.
(60) Faust TW, Chang EH, Kowal C, Berlin R, Gazaryan IG, Bertini E, et al. Neurotoxic lupus autoantibodies alter brain function through two distinct mechanisms. Proc Natl Acad Sci U S A 2010 Oct 26;107(43):18569-74.
(61) Sibbitt WL, Jr., Sibbitt RR, Griffey RH, Eckel C, Bankhurst AD. Magnetic resonance and computed tomographic imaging in the evaluation of acute neuropsychiatric disease in systemic lupus erythematosus. Ann Rheum Dis 1989 Dec;48(12):1014-22.
(62) Bertsias GK, Ioannidis JP, Aringer M, Bollen E, Bombardieri S, Bruce IN, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsy- chiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis 2010 Dec;69(12):2074-82.
(63) Luyendijk J, Steens SC, Ouwendijk WJ, Steup-Beekman GM, Bollen EL, van der Grond J, et al. Neuropsychiatric systemic lupus erythematosus: lessons learned from magnetic resonance imaging. Arthritis Rheum 2011 Mar;63(3):722-32.
(64) Emmer BJ, Steens SC, Steup-Beekman GM, van der Grond J, Admiraal-Behloul F, Olofsen H, et al. Detection of change in CNS involvement in neuropsychiatric SLE: a magnetization transfer study. J Magn Reson Imaging 2006 Oct;24(4):812-6.
(65) Ainiala H, Hietaharju A, Loukkola J, Peltola J, Korpela M, Metsanoja R, et al. Validity of the new American College of Rheumatology criteria for neuropsychiatric lupus syndromes: a population-based evaluation. Arthritis Rheum 2001 Oct;45(5):419-23.
(66) Hanly JG, Urowitz MB, Su L, Bae SC, Gordon C, Wallace DJ, et al. Prospective analysis of neuropsychiatric events in an international disease inception cohort of patients with systemic lupus erythematosus. Ann Rheum Dis 2010 Mar;69(3):529-35.
(67) Bortoluzzi A, Scire CA, Bombardieri S, Caniatti L, Conti F, De Vita S et al. Development and validation of a new algorithm for attribution of neuropsychiatric events in systemic lupus erythematosus. Rheumatology (Oxford) 2014 Oct 21 (Epub ahead of print)
(68) Cohen D, Berger SP, Steup-Beekman GM, Bloemenkamp KW, Bajema IM. Diagnosis and management of the antiphospholipid syndrome. BMJ 2010;340:c2541.
(69) Popescu A, Kao AH. Neuropsychiatric systemic lupus erythematosus. Curr Neuropharma- col 2011 Sep;9(3):449-57.
(70) Barile-Fabris L, Ariza-Andraca R, Olguin-Ortega L, Jara LJ, Fraga-Mouret A, Miranda-Limon JM, et al. Controlled clinical trial of IV cyclophosphamide versus IV methylprednisolone in severe neurological manifestations in systemic lupus erythematosus. Ann Rheum Dis 2005 Apr;64(4):620-5.
(71) Fernandes MT, V, Castro AA, Ferreira Neves NJ, Atallah AN. Cyclophosphamide versus methylprednisolone for treating neuropsychiatric involvement in systemic lupus erythe- matosus. Cochrane Database Syst Rev 2013;2:CD002265.
