Outcome of neuropsychiatric systemic lupus erythematosus within a defined Swedish population: increased morbidity but low mortality

A. Jönsen, A. A. Bengtsson, O. Nived, B. Ryberg1 and G. Sturfelt

Department of Rheumatology and
1 Department of Neurology, University Hospital of Lund, Lund, Sweden


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To investigate the outcome of neuropsychiatric involvement in systemic lupus erythematosus patients (NPSLE) recruited from a defined population.

Methods. All cases of adult SLE diagnosed during 1981–1995 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 2.06–6.96), whereas mortality was not increased (standardized mortality rate 1.4, 95% confidence interval 0.5–3.0).

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.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Systemic lupus erythematosus (SLE) is a complex multi-system disease characterized by hyperactive autoreactive B and T cells and inflammation induced by immune complexes. Disease manifestations involve many organ systems, such as the skin, joints, kidneys and nervous system. Symptoms in the nervous system can be very varied, ranging from peripheral neuropathy to seizures, cerebrovascular incidents and organic brain syndrome. The frequency of neuropsychiatric involvement in SLE (NPSLE) is reported to range between 14 and 75%. NPSLE was shown by Jonsson et al. [1] to be a predictor of a high frequency of flares and to be a major cause of longstanding functional impairment as well as being associated with a high mortality rate. In another study, by Swaak et al. [2], increased mortality was seen among patients with NPSLE, thus confirming NPSLE as a potentially serious manifestation of disease.

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.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
All patients (above 16 yr of age) with SLE within Lund-Orup Health Care District (mean adult population during 1981–1995, 187 000 individuals) diagnosed during 1981–1995 were included in the study. The patients were enrolled in an ongoing prospective follow-up programme for SLE [1]. The completeness of the methods of retrieval used has been validated by the capture–recapture technique [4]. On 1 January 1998, the total number of SLE patients in the study group was 117, of which 111 patients fulfilled four or more of the ACR classification criteria [5]. The other six patients, with a clinical diagnosis of SLE, fulfilled three ACR criteria and had multi-system disease with an immunological disorder (i.e. they were positive for ANA and/or anti-DNA antibodies) [1]. All patients but one, a Chinese woman, were Caucasians. The study group consisted of 100 female and 17 male patients with a mean age at diagnosis of 50 yr (range 16–88). The mean disease duration in January 1998 from diagnosis was 9.9 yr (range 2–17) among patients with NPSLE and 8.4 yr (range 1–17) (P=0.076) in patients without NPSLE. Age at diagnosis was similar in the two groups. Nineteen of 117 patients died during the follow-up time (1981–1998) and two patients moved out of the area. Patients with SLE who moved into the district and patients living outside the district who were referred to the Department of Rheumatology in Lund during this period were not included in this study.

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 1986–1999, 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 21–62) and 48.5 yr (range 31–64) 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 Mann–Whitney 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.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Neuropsychiatric manifestations
Forty-four patients (38%) developed NPSLE during the study period. A high percentage of the patients developed NPSLE early in the disease course, with a total of 24/44 (55%) within 1 yr of SLE-diagnosis. However, the presence of neuropsychiatric involvement early in the disease course (<2 yr from diagnosis) was not associated with a worse outcome at the study end-point, as measured by the SLICC/ACR-DI and mortality rate, compared with later-onset NPSLE.

The frequency of different neuropsychiatric manifestations is shown in Table 1Go. 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).


View this table:
[in this window]
[in a new window]
 
TABLE 1. Neurological manifestations in 44 NPSLE patients

 

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 0–0.55) and 0.09 in the non-NPSLE group (range 0–0.19). 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 1.8–4.6). The corresponding figure for NPSLE was 4.0 (95% CI 2.1–7.0) and for non-NPSLE 2.1 (95% CI 0.9–4.2). 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 1.07–2.77) compared with the population in the recruitment area. Further analysis revealed a significantly increased SMR of 2.1 (95% CI 1.1–3.5) for the non-NPSLE group, but not for the NPSLE patients (SMR 1.4, 95% CI 0.5–3.0). 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 0.3–2.6).


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Most published data on NPSLE are based on investigations of hospitalized patients or patients in very selected series [8]. We performed an epidemiologically based study of the long-term prognosis of neuropsychiatric manifestations in a defined group of SLE patients. Previous reports from the same area have shown that patients with NPSLE are at risk of severe disease, with frequent flares and increased mortality [1]. In the present study, the increased rate of organ damage and a tendency to increased working incapacity among patients with NPSLE compared with non-NPSLE patients illustrates the important clinical impact of neuropsychiatric manifestations, albeit the mortality in the NPSLE group did not differ significantly from that in the non-NPSLE group.

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 83–93% [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.


    Acknowledgments
 
This work was supported by grants from the Swedish National Association Against Rheumatism, the Swedish Medical Research Council (grant 13489), the Medical Faculty of the University of Lund, Alfred Österlunds Stiftelse, Crafoords Stiftelse, Greta och Johan Kocks Stiftelser, Konung Gustaf V 80 års fond, Lunds Sjukvårdsdistrikt and Prof. Nanna Svartz Stiftelse.


    Notes
 
Correspondence to: A. Jönsen, Department of Rheumatology, University Hospital of Lund, S-221 85 Lund, Sweden. Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Jonsson H, Nived O, Sturfelt G. Outcome in systemic lupus erythematosus: A prospective study of patients from a defined population. Medicine (Baltimore)1989;68:141–50.[ISI][Medline]
  2. Swaak AJG, Nossent JC, Bronsveld W et al. Systemic lupus erythematosus. I. Outcome and survival: Dutch experience with 110 patients studied prospectively. Ann Rheum Dis1989;48:447–54.[Abstract]
  3. Gladman D, Ginzler E, Goldsmith C et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum1996;39:363–9.[ISI][Medline]
  4. Jonsson H, Nived O, Sturfelt G, Silman A. Estimating the incidence of systemic lupus erythematosus in a defined population using multiple sources of retrieval. Br J Rheumatol1990;29:185–8.[ISI][Medline]
  5. Tan EM, Cohen AS, Fries JF et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1982;25:1271–7.[ISI][Medline]
  6. How A, Dent PB, Liao SK, Denburg JA. Antineuronal antibodies in neuropsychiatric systemic lupus erythematosus. Arthritis Rheum1985;28:789–95.[ISI][Medline]
  7. ACR Ad Hoc Committee on Neuropsychiatric Lupus Nomenclature. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum1999;42:599–608.[ISI][Medline]
  8. Adelman DC, Saltiel E, Klinenberg JR. The neuropsychiatric manifestations of systemic lupus erythematosus: an overview. Semin Arthritis Rheum1986;15:185–99.[ISI][Medline]
  9. Calabrese LV, Stern TA. Neuropsychiatric manifestations of systemic lupus erythematosus. Psychosomatics1995;36:344–59.[Abstract]
  10. Sabbadini MG, Manfredi AA, Bozzolo E et al. Central nervous system involvement in systemic lupus erythematosus patients without overt neuropsychiatric manifestations. Lupus1999;8:11–9.[ISI][Medline]
  11. Lindahl E, Thorlacius, Steinsson K, Stefansson JG. Psychiatric disorders among subjects with systemic lupus erythematosus in an unselected population. Scand J Rheumatol1995;24:346–51.[ISI][Medline]
  12. Rahman P, Gladman DD, Urowitz MB, Halett D, Tam LS. Early damage as measured by the SLICC/ACR damage index is a predictor of mortality in systemic lupus erythematosus. Lupus2001;10:93–6.[ISI][Medline]
  13. Nived O, Jönsen A, Bengtsson A, Sturfelt G. High predictive value of Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for survival in systemic lupus erythematosus. J Rheumatol2002;29:1398–400.[ISI][Medline]
  14. Stoll T, Sutcliffe N, Klaghofer R, Isenberg DA. Do present damage and health perception in patients with systemic lupus erythematosus predict the extent of future damage? A prospective study. Ann Rheum Dis2000;59:832–5.[Abstract/Free Full Text]
  15. 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 Rheumatol1997;24:1061–5.[ISI][Medline]
  16. Pistiner M, Wallace DJ, Nessim S, Metzger AL, Klinenberg JR. Lupus erythematosus in the 1980s: A survey of 570 patients. Semin Arthritis Rheum1991;21:55–64.[ISI][Medline]
  17. Gripenberg M, Helve T. Outcome of systemic lupus erythematosus: a study of 66 patients over 7 years with special reference to the predictive value of anti-DNA antibody determinations. Scand J Rheumatol1991;20:104–9.[ISI][Medline]
  18. Ståhl-Hallengren C, Jönsen A, Nived O, Sturfelt G. Incidence studies of systemic lupus erythematosus in southern Sweden: Increasing age, decreasing frequency of renal manifestations and good prognosis. J Rheumatol2000;27:685–91.[ISI][Medline]
Submitted 14 December 2001; Accepted 26 April 2002