Department of Rheumatology and
1 Department of Neurology, University Hospital of Lund, Lund, Sweden
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Abstract |
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Methods. All cases of adult SLE diagnosed during 19811995 within the Lund-Orup Health Care District were followed prospectively and neuropsychiatric manifestations were recorded. The SLICC/ACR (Systemic Lupus International Collaborating Clinics/American College of Rheumatology) Damage Index, mortality and working incapacity were recorded as measures of outcome.
Results. NPSLE manifestations developed in 38% (44/117) of the patients. A high rate of organ damage (SLICC/ACR Damage Index) was recorded in the NPSLE patients (P<0.001). Compared with patients without neuropsychiatric involvement, NPSLE patients were treated more intensively, with glucocorticoids (P<0.01) and cytostatic drugs (P<0.01). When compared with the normal population in the same area, the NPSLE patients had a higher rate of working incapacity (relative risk 4.0, 95% confidence interval 2.066.96), whereas mortality was not increased (standardized mortality rate 1.4, 95% confidence interval 0.53.0).
Conclusions. SLE patients with neuropsychiatric involvement have an increased rate of organ damage and a high degree of working incapacity, which illustrates the severity of disease in this subgroup.
KEY WORDS: SLE, SLICC/ACR Damage Index, Damage, Neuropsychiatric, NPSLE, Outcome, Mortality, Working incapacity, Morbidity, Disability.
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Introduction |
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In this study we investigated the prognosis and consequences of neuropsychiatric involvement in SLE during long-term follow-up of a defined SLE population. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR-DI) [3], mortality and working incapacity were recorded as measures of outcome, and the predictive value of early neuropsychiatric involvement was investigated.
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Patients and methods |
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A specialist in neurology (BR) assessed the patients with suspected neuropsychiatric involvement and classification was done according to the NPSLE criteria developed by How et al. [6], in which major or minor neurological and psychiatric symptoms are defined. For the definition of individual NPSLE items we used the proposed ACR nomenclature and case definitions for neuropsychiatric lupus syndromes [7]. Organ damage was determined according to the SLICC/ACR-DI [3]. Treatment with glucocorticoids and cytostatic drugs since the time of diagnosis was recorded, as were findings on magnetic resonance imaging (MRI) and computed tomography (CT) of the brain. Autoantibodies were measured by standard methods at the Department of Clinical Immunology, University Hospital Lund.
For the period 19861999, all patients aged <65 yr were assessed for continuous working incapacity, i.e. partial or full-time, temporary or permanent disability pension, during their fifth year with SLE. Patients with a disease duration <5 yr were excluded. This group consisted of 70 patients, 65 women and five men, of whom 28 had NPSLE. The ages of the non-NPSLE and NPSLE patients were similar, with means of 47.3 (range 2162) and 48.5 yr (range 3164) respectively. The observed number of patients drawing disability pension was compared with the expected frequency of individuals on a disability pension in the population, matched for age and gender, in a larger area (Scania) in southern Sweden during 1986 and 1999, obtained from the Regional Social Insurance Office.
Statistics
Comparisons between groups were done with Fisher's exact test and the MannWhitney U test. Exact 95% confidence intervals (CI) for standardized mortality ratios (SMR) were calculated by treating the observed number as a Poisson variable. The expected mortality was determined from death rates for county, gender, calendar year and 5-yr specific age groups. Direct comparison of mortality (mortality rate ratio) between the two groups was performed by Poisson regression analysis.
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Results |
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The frequency of different neuropsychiatric manifestations is shown in Table 1. Focal motor or sensory deficits, including disorders of movement or gait, transverse myelitis and focal, peripheral and cranial neuropathy, were most common, followed by headache. In addition, in 21 of the 73 (29%) non-NPSLE patients, minor neuropsychiatric complaints were recorded. These patients presented with headache, paraesthesiae or reactive depression, but, in accordance with the How criteria, they were not included in the NPSLE group. Of the 44 NPSLE patients, 21 had only one neurological manifestation. They had a shorter disease duration than patients with several neuropsychiatric manifestations (P<0.01).
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MRI and CT
Of the 44 NPSLE patients, 25 had undergone CT scanning or MRI of the brain. In nine of these 25 patients focal lesions were found, indicating infarctions of varying age; three patients displayed other abnormalities (haematoma, atrophy) and 14 (56%) were normal. One patient had both atrophy and evidence of an infarction.
Treatment
The mean duration of treatment with low-dose glucocorticoids (<20 mg prednisolone/day) was 54.0 months for NPSLE patients and 26.9 months for patients without NPSLE (P<0.01 when adjusted for disease duration). The total time on antimalarial drugs was similar in the two groups (adjusted for disease duration). As expected, treatment with cytostatic drugs (P<0.01) and high-dose glucocorticoids (20 mg prednisolone/day) was significantly (P<0.01) more common among patients in the NPSLE group than among the non-NPSLE patients (adjusted for disease duration).
Organ damage
The mean SLICC/ACR-DI score for the NPSLE patients was 2.3 compared with 0.9 for the non-NPSLE patients (P<0.001, adjusted for disease duration). There was no difference in age at diagnosis between the NPSLE and the non-NPSLE group. The annual SLICC/ACR-DI score was higher in the NPSLE group (P<0.002), with a mean of 0.18 points per patient and year in the NPSLE group (range 00.55) and 0.09 in the non-NPSLE group (range 00.19). However, when SLICC/ACR-DI points received for neurologically related damage were excluded and adjustment was made for disease duration, there was no significant difference between the two groups (P=0.10). Neuropsychiatric damage was the most common damage category, with 32/117 (28%) patients affected, followed by musculoskeletal, cardiovascular and ocular damage. Renal damage, on the other hand, was rare (3.4%).
The organ damage rate was high during the first year after diagnosis, with a mean SLICC/ACR-DI score per patient of 0.55 in the NPSLE group and 0.19 in the non-NPSLE group. Thereafter the annual incidence rate of organ damage was lower, with a mean score of 0.18 and 0.09 in the two groups respectively, and fairly stable. The presence of anti-DNA and anti-cardiolipin antibodies predicted neither focal nor non-focal neuropsychiatric damage. As expected, patients with disease onset at >50 yr had a higher SLICC/ACR-DI score compared with younger patients (data not shown). Level of education had no effect on damage scores after stratification for age at diagnosis (data not shown).
Working incapacity
In the NPSLE group, 43% (12/28) received disability pension compared with 19% (8/42) among the non-NPSLE patients (P=0.06). A comparison of all the SLE patients with the general population revealed an increased risk of working incapacity (relative risk 3.0, 95% CI 1.84.6). The corresponding figure for NPSLE was 4.0 (95% CI 2.17.0) and for non-NPSLE 2.1 (95% CI 0.94.2). The underlying cause of disability pension was SLE in 17 (94%) of the 18 patients from whom this information could be obtained.
Mortality
There were 13 deaths (five men, eight women) in the non-NPSLE group and six in the NPSLE group (no men, six women) during the follow-up time. Analysis of survival showed an increased SMR for the whole SLE group (SMR 1.78, 95% CI 1.072.77) compared with the population in the recruitment area. Further analysis revealed a significantly increased SMR of 2.1 (95% CI 1.13.5) for the non-NPSLE group, but not for the NPSLE patients (SMR 1.4, 95% CI 0.53.0). Five-year survival rate in the NPSLE group was 95% and 10-yr survival was 80%. In the non-NPSLE group the corresponding rates were 90 and 84% respectively, and for a matched control population in the same area the rates were 99 and 96%. There was no difference in survival when the NPSLE patients were compared with the non-NPSLE patients. The mortality rate ratio between these groups was 0.9 (95% CI 0.32.6).
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Discussion |
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The proportion of patients in this study who developed NPSLE was 38%, which is within the range of frequencies in other larger series [8]. Focal motor and sensory deficiencies were the most common manifestations. Seizures and headache [7] were other common problems among our patients, while, for example, minor psychiatric problems were less often reported. The spectrum of neuropsychiatric manifestations deviates somewhat from those in other reports, in which headache and minor psychiatric manifestations were present at higher frequencies [810]. In another epidemiologically based study from Iceland, the frequency of psychiatric manifestations among SLE patients was investigated with a structured interview, the Diagnostic Interview Schedule [11]. A low frequency of major psychiatric manifestations was found, while anancastic and phobic problems were common. In another study, Sabbadini et al. [10] reported mood or anxiety disorders in 32% of patients without NPSLE. A similar frequency of minor psychiatric symptoms (29%) could be seen among our patients who did not fulfil the How criteria for NPSLE. It should be emphasized that our diagnoses were based on clinical judgement and confirmed by consulting psychiatrists, while the Icelandic results were based on a sensitive, validated, structured interview. Diagnostic and classification problems, together with different methods of selection of patients for the studies might explain the discrepant findings. In this study we used the established classification proposed by How et al. [6] and for definitions of individual items we used the ACR case definitions for neuropsychiatric lupus syndromes [7]. In addition, the diagnosis of cognitive impairment was clinical and cognitive function tests were not performed regularly, which might have resulted in relatively few patients with this particular manifestation.
The development of the SLICC/ACR-DI [3] has made it possible to measure outcomes other than mortality in a validated manner. It has been shown that a high total SLICC/ACR-DI score during the first years of disease is a strong predictor of increased mortality rate [12, 13]. In another recent prospective study, by Stoll et al. [14], the initial SLICC/ACR-DI score predicted the damage score at 3 yr after inclusion. These studies, together with the present investigation, further support the utility of SLICC/ACR-DI as a tool for outcome measurement and for determining prognosis. In our study, both total time on glucocorticoids and treatment with high-dose glucocorticoids were more common in the NPSLE group. This could be one of several possible explanations for high damage scores in NPSLE.
In our study, mortality rate was not increased among the NPSLE patients compared with non-NPSLE patients and the normal population. This could be due to a too short follow-up time with a low total number of deaths in the study groups. Furthermore, overall survival rate has improved during recent decades [15] and in recent studies the 10 yr survival rate has been reported to be 8393% [2, 1618].
This long-term follow-up of unselected patients with SLE clearly underlines the severity of neuropsychiatric involvement in SLE, with an increased risk of organ damage and a high degree of working incapacity. However, our results might indicate that adequate treatment of flares in NPSLE appears to reduce mortality in these severely ill patients.
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Acknowledgments |
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Notes |
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References |
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