Rheumatology

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Rheumatology 2000; 39: 1316-1319
© 2000 British Society for Rheumatology

Prognostic parameters for flare in systemic lupus erythematosus

M. J. Mirzayan, R. E. Schmidt and T. Witte

Abteilung Klinische Immunologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

 
Objective. To characterize prognostic parameters for systemic lupus erythematosus (SLE) flares.

Methods. In a prospective study, 120 SLE patients attending our out-patient clinic were evaluated every 3 months for 2 yr. At every visit clinical manifestations and laboratory parameters were assessed and the SLE disease activity index (SLEDAI) was determined. A correlation analysis of the number of flares in the first year and SLEDAI as a marker of disease activity after 1 and 2 yr with several parameters determined at the start of the study was performed.

Results. Flares were predicted by erythrocyte sedimentation rate (P=0.001), anaemia (P=0.006) and lymphopenia (P=0.005). The SLEDAI after 1 yr was predicted by the titre of antinuclear antibodies (P=0.009), antibodies against double-stranded DNA (P=0.007), lymphopenia (P=0.007), anaemia (P=0.0002) and SLEDAI determined at the start of the study (P=0.001).

Conclusions. Anaemia and lymphopenia predict both flares and SLEDAI within the next year of follow-up.

KEY WORDS: SLE, Flares, SLEDAI, Prognosis.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with an incidence of 7:100 000 [1]. The course of SLE is variable and characterized by recurrent disease exacerbations. For the laboratory follow-up of inflammatory activity, parameters such as anti-double-stranded DNA (dsDNA) antibodies, complement fixation and leucocytopenia have been described [2, 3]. Although the course of SLE is characterized by recurrent flares, the term ‘flare' has not been defined clearly. Most studies characterizing prognostic markers in SLE have therefore used survival or disability as parameters of outcome. Severe organ involvement, such as renal and neuropsychiatric lupus, have been identified as risk factors [4–6]. In the few studies on exacerbations in SLE, rather subjective definitions for flares, such as the physician's decision to augment immunosuppressive therapy, were used, or exacerbations of renal involvement only were evaluated [4, 7–10].

The SLE disease activity index (SLEDAI) has been shown to be reliable and reproducible [11]. The SLEDAI increases by an average of 3 points in a flare [9]. In order to establish predictors for flares, we defined the term as an increase in SLEDAI of at least 3 points compared with the previous visit. Several laboratory parameters measured at the start of the study were then correlated with the number of subsequent flares and, as an additional assessment, with the SLEDAI score after 1 and 2 yr. For this purpose we evaluated 120 SLE patients attending our out-patients clinic over 2 yr for signs of clinical and laboratory disease activity and evaluated the SLEDAI every 3 months.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

 
Patients
One hundred and twenty German Caucasian SLE patients attending the out-patients clinic who fulfilled at least four of the American College of Rheumatology criteria for the classification of SLE [12, 13] were included in the study after informed consent. The characteristics of the patients are summarized in Table 1. One hundred and six of the patients were female and 14 were male. The average age of the patients was 45.2 yr (range 18–69 yr). The diagnosis of SLE had been established in the patients 6 months to 25 yr (median 9 yr) before they were included in the study.

View this table: [in this window] [in a new window]   TABLE 1. Clinical and immunological findings in the 120 SLE patients at the start of the study

 
The patients were seen every 3 months, and in some cases additionally at the time of disease exacerbation, for 2 yr by the same doctor, who also evaluated the SLEDAI on the basis of clinical and laboratory parameters. A flare of SLE was defined as an increase in the SLEDAI of at least 3 points compared with the previous visit. The following laboratory parameters were evaluated at the start of the study and at each visit: peripheral blood haemoglobin; peripheral blood counts of leucocytes, lymphocytes and platelets; antibodies against dsDNA (radioimmunoassay; Johnson and Johnson, Neckargemund, Germany); end-titre of antinuclear antibodies (ANA) (Hep2-immunofluorescence); CH50; C4 (nephelometry, Behring, Marburg, Germany); erythrocyte sedimentation rate (ESR); IgG (nephelometry, Behring); and SLEDAI.

Statistical correlations
Non-parametric tests were used because SLEDAI clearly deviated from a Gaussian distribution. Correlations of SLEDAI and the 10 laboratory markers shown in Table 1 with the SLEDAI at the start of the study and 1 and 2 yr later and with the number of flares in the next year were determined with Spearman's test. Probabilities of association of less than 0.05 were regarded as statistically significant.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

 
Patients' characteristics
One hundred and twenty SLE patients were evaluated every 3 months for 2 yr. The clinical characteristics of these patients visiting the out-patient clinic are summarized in Table 1. At the start of the study all patients were in clinical remission. The average SLEDAI at the start was 5.8 and the average ESR in the first hour was 22.8 mm (data not shown).

Incidence of flares
In the first year of the study, flares were observed in 65.5% of the patients. A total of 149 flares occurred in the 120 patients in the first year. Thus, the incidence of flares per patient was 1.2 in the first patient-year of follow-up. During the flares, the SLEDAI score increased by between 3 and 14; the average increase was 6.3 points. The distribution of the increase in SLEDAI score is summarized in Table 2. The treatment was changed (increase in prednisone dose or addition of an immunosuppressive agent or hydroxychloroquine) in 88% of the flares.

View this table: [in this window] [in a new window]   TABLE 2. Distribution of increases in SLEDAI during flares as a percentage of the total number of flares during follow-up. The preference for even numbers in the SLEDAI is caused by the weighting of the parameters forming the score. Twenty-one parameters are weighted with even numbers but only three (fever, thrombocytopenia and leucopenia) with odd numbers

 

Risk factors for flares
A correlation analysis of the frequency of flares in the first year with marker values at the start of the study revealed an association with the ANA titre (P=0.023), ESR (P=0.001), anaemia (P=0.006) and lymphopenia (P=0.005), but not with antibodies against dsDNA or complement fixation titre (Table 3). The incidences of flares in the patients younger or older than the average age of 45.2 yr were not significantly different (data not shown).

View this table: [in this window] [in a new window]   TABLE 3. Association of laboratory and clinical markers (SLEDAI) with lupus flares in the subsequent year

 

Risk factors for increased SLEDAI after 1 and 2 yr
The SLEDAI at the start of the study correlated positively with ANA, anti-dsDNA antibodies, lymphocytopenia, and negatively with complement component C4 and CH50 (Table 4).

View this table: [in this window] [in a new window]   TABLE 4. Association of laboratory and clinical markers (SLEDAI) with SLEDAI at the start (SLEDAI 0), after 1 yr (SLEDAI 1) and after 2 yr (SLEDAI 2). SLEDAI 0 was negatively correlated with CH50 and complement component C4

 
After 1 and 2 yr, the average SLEDAI was 5.2 and 4.3 points, respectively. Correlation analysis of the laboratory parameters present at the onset of the study with SLEDAI after 1 and 2 yr revealed that a high SLEDAI after 1 yr was associated with ANA, lymphopenia, anaemia, dsDNA antibodies and SLEDAI at the start of the study (Table 4). The SLEDAI after 2 yr was correlated only with antibodies against dsDNA and SLEDAI itself (Table 4).

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

 
Although SLE is characterized by recurrent exacerbations, there are no generally accepted criteria for the term ‘flare’. Studies trying to define laboratory markers predicting lupus flares have therefore been difficult to perform and have yielded partly contradictory results. As it has been shown that exacerbations of SLE are paralleled by an increase in SLEDAI by a mean of 3 points [9], we regarded a flare as an increase in SLEDAI of at least 3 points compared with the previous examination. This definition has the advantage of being standardized, as the SLEDAI is a well-established and accepted disease activity score. Although minor flares with a lower increase in the SLEDAI will be missed, the incidence of flares using our definition is similar to that in other studies [4, 9, 10].

Consistent with other studies establishing haematological disease [14] and anaemia [15] as predictors of flares and survival, respectively, lymphocytopenia, anaemia and in addition ESR and ANA appeared to be the best predictors of flares in the next year of follow-up. The weak association of flares with the ANA titre (P=0.023) after Bonferroni's adjustment for multiple parameters tested has to be viewed cautiously.

The SLEDAI measured after 1 yr correlated with ANA titre, antibodies against dsDNA, lymphopenia, anaemia and SLEDAI at the start of the study. Only antibodies against dsDNA and SLEDAI at the start of the study correlated with SLEDAI after 2 yr. Antibodies against dsDNA contribute to the SLEDAI. If they stay above the cut-off point throughout the follow-up period, they will always add to the SLEDAI even if the patient is clinically in remission, and these antibodies are therefore expected to be correlated with a constantly elevated SLEDAI after 1 and 2 yr. In this case, such an elevated SLEDAI does not necessarily mean that the patient has a flare. dsDNA antibodies can therefore correlate with the SLEDAI but not with flares. Similarly, the SLEDAI measured at the start of the study is based on a variety of clinical and laboratory parameters which may persist and are not independent of the SLEDAI measured subsequently. Therefore, only lymphocytopenia, anaemia and ANA titre predicted the SLEDAI reliably after 1 yr.

Previous reports [7] suggested that the risk of exacerbations decreased with advancing age of the patients. In agreement with several other studies [4, 8], we did not find a correlation of the rate of flares with age. Previous studies [14, 16] yielded contradictory results about whether antibodies against dsDNA or complement fixation predicted flares. We did not find a correlation of elevated dsDNA antibodies with flares. In our study as well as other studies [14, 15], SLEDAI itself did not show an association with flares.

In conclusion, flares of SLE (i.e. an increase in SLEDAI) and SLEDAI after 1 yr of follow-up are both predicted by ANA, anaemia and lymphocytopenia. These markers can be measured routinely as prognostic parameters in SLE to characterize patients who are at risk and who should be followed more closely.

	Acknowledgments

 
This work was supported by BMFT-project 01VM8608/9, BMG-project FB2-43346-8/59 and DFG/SFB 244/A09.

	Notes

 
Correspondence to: T. Witte, Abteilung Klinische Immunologie, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany.

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Submitted 10 February 2000; revised version accepted 19 May 2000.
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