High disease activity at baseline does not prevent a remission in patients with systemic lupus erythematosus

F. Formiga, I. Moga, M. Pac, F. Mitjavila, A. Rivera and R. Pujol

Internal Medicine Service, Hospital de Bellvitge Princeps d'Espanya, L'Hospitalet de Llobregat, Barcelona, Spain

Correspondence to: F. Formiga, Internal Medicine Service, c/ Feixa Llarga s/n, Hospital de Bellvitge Princeps d'Espanya, L'Hospitalet de Llobregat, Barcelona, Spain.


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To evaluate the utility of systemic lupus erythematosus (SLE) initial clinical manifestations and the SLE Disease Activity Index (SLEDAI) for identifying patients who will have a remission.

Methods. We studied 100 SLE patients (85 females, 15 males) and identified all patients who had remission (defined as at least one continuous year during which lack of disease activity permitted withdrawal of all treatment to suppress general lupus activity of a particular clinical manifestation). Changes in laboratory parameters without clinical activity, thus not requiring treatment, did not invalidate remission. We did not include any patient who had never required treatment. We evaluated the SLEDAI values and the main SLE manifestations at the time of diagnosis of SLE, and also every 3 months during the first year of disease.

Results. Twenty-four of the 100 SLE patients achieved remission that occurred a mean of 64 months after the diagnosis. They remained in remission for a mean of 55 months. There were no statistical differences in SLEDAI values and the initial manifestations (including renal and cerebral) between patients who reached remission and those who did not. The patients who have a higher SLEDAI score take longer to achieve remission.

Conclusion. SLE patients with severe initial clinical manifestations and higher SLEDAI values may achieve clinical remission.

KEY WORDS: Systemic lupus erythematosus, Remission, Flare.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
One contrast between animal and human forms of systemic lupus erythematosus (SLE) is that in humans the progression of disease is less predictable [1, 2]. The most common clinical patterns are chronic or intermittent disease, but a significant percentage of patients experience complete and sustained remissions, usually associated with therapy [36]. Patients with previous severe disease may also have remission [7]. Nevertheless, the frequency and duration of remissions, and the characteristics of patients in whom remissions are more likely to occur, have not been determined.

We analysed the utility of the averaged SLE Disease Activity Index (SLEDAI) [8] to identify patients who will have a clinical remission. We evaluated the SLEDAI values and the main SLE manifestations at the time of diagnosis of SLE, and also at three additional visits (every 3 months during the first year of disease).


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
At our hospital, we closely follow 170 Caucasian patients with SLE. They fulfil four or more of the 1982 revised American College of Rheumatology criteria for the classification of SLE [9].

In the present study, we included only those patients, controlled in our hospital at the time of diagnosis of SLE (with entire information to complete SLEDAI available in clinical records, according to a fixed protocol and observed by the same clinic), who required therapy with corticosteroids, immunosuppressors, antimalarials or any other form of treatment for control of disease severity. We did not include any patient whose disease was so mild that it had never required treatment or patients diagnosed in other hospitals.

The total cohort included in the present study was 100 patients. All of them were seen at 3 month intervals at the out-patient clinic. When disease activity and/or infection was present, they were assessed as frequently as clinically necessary. Clinical history, physical examination and standard laboratory procedures were performed at each visit.

The disease activity was measured initially and every 3 months using retrospectively the SLEDAI index by two independent physicians [8]. SLEDAI consists of 24 variables, grouped according to nine organ systems (including some immunological tests). The range of possible SLEDAI scores is 0–105. We also studied main initial SLE manifestations and the disease exacerbations, and analysed the following: central nervous system (CNS), renal, mucocutaneous, serositis and musculoskeletal involvement. Serological and haematological results were also collected.

All patients were treated using the same general treatment protocol. Corticosteroids in the equivalent daily prednisone dose, antimalarials, azathioprine and cyclophosphamide therapy were recorded for all patients at each visit.

We identified all patients who had remission: defined as at least one continuous year during which the lack of clinical manifestations considered as evidence of lupus activity permitted withdrawal of all treatment to suppress general lupus activity of a particular clinical manifestation. We excluded those patients who had become asymptomatic, but who were still taking treatment to control lupus disease. Remission started at the time that all medications were stopped. Changes in laboratory parameters without concurrent clinical evidence of disease activity, thus not requiring treatment, did not invalidate the criteria for remission.

The results were expressed as the mean±S.D. We used the Statistical Package for the Social Sciences (SPSS Inc., Chicago, IL, USA) for all conventional analyses. Grouped data were compared by t-test. A {chi}2 test with Yates' correction for small numbers, when appropriate, was used for comparison of variables. To assess correlations of study variables with the degree of disease activity (SLEDAI), Spearman's rank correlation coefficients were calculated. All statistical tests were two-tailed and only associations with P<0.05 were considered significant.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The mean age of the 100 (85 females and 15 males) SLE patients at diagnosis of SLE was 30.5±14 yr. The mean follow-up of all these patients was 116±63 months, and the mean of new flares during this period was 2±1.

The main initial manifestations for the 100 SLE patients were 74% musculoskeletal, 70% haematological, 64% mucocutaneous, 44% renal (biopsy proved), 29% serositis and 10% CNS. All the patients had antinuclear antibodies (ANA) at the time of diagnosis. The frequency of detection of anti-double-stranded (ds) DNA antibodies was 80%.

Twenty-four of the 100 SLE patients (20 women and four men) achieved treatment-free remission. The mean age at the time of clinical remission was 39±14 yr. The mean follow-up of this group was 140±75 months. They remained in remission for a mean of 55±40 months (range 16–156). Remission occurred a mean of 64±36 months after the time of starting therapy; the patients did not respond equally quickly to treatment and did not achieve low SLEDAI scores at the same time (range of remission 24–120 months). There were no statistically significant differences in the initial SLE manifestations (Table 1Go) and other clinical individual characteristics (age, sex, follow-up) between patients in remission and those without remission. Two (8%) of the patients who underwent remission had initial CNS manifestations and 10 (42%) had renal involvement (including three patients with focal and one patient with diffuse proliferative lupus nephritis).


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TABLE 1.  Major initial clinical manifestations of 100 systemic lupus erythematosus patients at the end of the first year of disease
 
Seven patients had one, two patients had two and one patient had three new episodes of clinical evidence of disease activity previously to achieving remission. The flares occurred after a transient improvement in SLE that was not sustained to allow treatment to be stopped. The 14 remaining patients did not have other lupus flares after the SLE diagnosis. Seventeen of the 24 patients (70%) remained (and are at present) in the initial remission. Seven patients had suffered some new flares that occurred after a mean of 49±19 months in remission.

All patients were initially treated with prednisone and 54% with chloroquine. Of the patients who went into remission, 3 (12%) were receiving azathioprine and only one patient (4%) took cyclophosphamide, prior to remission. No differences were found in treatment with respect to non-remission patients.

Three of the 24 patients (12%) at the time of remission had persistent seroconversion from positive to negative ANA.

Although the means of SLEDAI values are higher in patients who did not achieve remission, the differences were not statistically significant (Table 2Go). The temporal correlation between SLEDAI and remission is shown in Fig. 1Go.


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TABLE 2.  Mean of SLEDAI values in patients who achieve remission compared to those who do not achieve remission
 


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FIG. 1.  SLEDAI values at diagnosis and 3 month interval visits in the SLE patients according to whether they reached remission or not.

 
In the patients who achieved remission, we found a significant correlation between SLEDAI total values and the time to clinical remission (P=0.002, r=0.587). The patients with higher SLEDAI achieved remission later.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Considerable knowledge has been accumulated about the clinical and serological abnormalities in SLE, but controversy exists concerning the possibility of predicting evolution of the disease.

Many reports have attempted to describe the clinical course of SLE. According to Fries and Holman [10], the disease is frequently active for a few years only, then goes into a remission that may be permanent. According to other authors, SLE is a chronic disease. For instance, Halberg et al. [11] found that none of 148 SLE patients were in remission after 10 yr of observation.

Recently, Drenkard et al. [3] found that nearly a quarter of their 667 patients with SLE were in remission for at least 1 yr. We also found 24 of 100 SLE patients who achieved treatment-free remission. Seventeen of 24 patients where still in the initial remission at the time of the present study. Remission was not limited to patients with mild disease. Our results suggest that the patients with higher initial lupus activity will have a remission. Nevertheless, the numbers of patients with renal and neuropsychiatric manifestations who achieve remission are small.

SLEDAI is a validated index for measuring disease activity and so it does not evaluate severity of prognosis, it could be calculated retrospectively [8]. We tested its utility for predicting the SLE patients who will achieve remission. We found higher values of SLEDAI (total and in each control) in patients who did not achieve remission compared to those who achieve remission, although the differences did not achieve statistical significance. We found a negative correlation, in patients achieving remission, between the SLEDAI values and the months passed until the time of remission. The patients with higher SLEDAI values, during the first year of lupus disease, achieved remission later.

During periods of remission, patients usually complained of mild symptoms or showed persistent laboratory abnormalities. The production of ANA continues during clinical remission of SLE [12], despite some patients becoming seronegative. Heller and Schur [13] reported that 4% of 305 SLE patients at the time of clinical remission had seroconversion from positive to negative ANA. We detected 12% of ANA seroconversion in our patients in remission.

In SLE patients in remission, an improvement in the immunoregulatory factors occurs, although some abnormalities may persist [1418]. The significance of persistent abnormal serological tests in these patients without active clinical disease is unclear. Gladman et al. [6] reported a group of 14 SLE patients in clinical remission who had persistent immunological test abnormalities, but they remained untreated for >4 yr. A controversial subject was the predictive value of changes in the titres of anti-dsDNA antibodies, in the components of the complement system and in other laboratory tests for predicting flares in SLE patients [1922]. Asymptomatic SLE patients with the above-mentioned changes should be evaluated more frequently.

In conclusion, patients with severe initial SLE clinical manifestations and higher SLEDAI values may achieve remission, permitting withdrawal of therapy.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1.  Krause G, Martin L, Fritzler M, Hart DA. Influence of Corynebacterium parvum-PER on disease progression in the NZB/W model of systemic lupus erythematosus. Int J Immunopharmacol 1992;14:35–41.[ISI][Medline]
  2.  Hart DA, Garlepp M, Fritzler M. Plasma proteinase regulation during disease progression in murine models of SLE. J Clin Lab Immunol 1989;30:27–34.[ISI][Medline]
  3.  Drenkard C, Villa AR, Garcia-Padilla A, Pérez-Vazquez ME, Alarcón-Segovia D. Remission of systemic lupus erythematosus. Medicine (Baltimore) 1996;75:88–99.[ISI][Medline]
  4.  Dubois EL. Systemic lupus erythematosus: Recent advances in its diagnosis and treatment. Ann Intern Med 1956;45:163–84.[ISI][Medline]
  5.  Ropes MW. Observation on the natural course of disseminated lupus erythematosus. Medicine (Baltimore) 1964;43:387–91.[ISI][Medline]
  6.  Gladman DD, Urowitz MB, Keystone EC. Serologically active clinically quiescent systemic lupus erythematosus. A discordance between clinical and serologic features. Am J Med 1979;66:210–5.[ISI][Medline]
  7.  Tozman EC, Urowitz MB, Gladman DD. Prolonged complete remission in previously severe SLE. Ann Rheum Dis 1982;41:39–40.[Abstract]
  8.  Bombardier C, Gladman DD, Urowitz MB, Karon D, Chang CH, Committee on Prognosis Studies in SLE. Derivation of SLEDAI: a disease activity index for lupus patients. Arthritis Rheum 1992;35:630–40.[ISI][Medline]
  9.  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;25:1271–7.[ISI][Medline]
  10. Fries JF, Holman HR. In: Systemic lupus erythematosus. A clinical analysis. Vol. VI. Philadelphia: WB Saunders, 1975:127–33.
  11. Halberg P, Alsbjorn B, Trolle Balslov J, Gerstoft J, Lorenzen I, Ullman S et al. Systemic lupus erythematosus: Follow-up study of 148 patients I: Classification, clinical and laboratory finding, course and outcome. Clin Rheumatol 1987;6:13–21.[ISI][Medline]
  12. Meyer O, Molta C, Bourgeois P, Haim T, Kahn MF. Profil des anticorps antinucleaires dans 14 cas de lupus erythemateux systemiques eteints depuis plus de trois ans. Rev Rhum Mal Osteoartic 1990;57:599–603.[Medline]
  13. Heller CA, Schur PH. Serological and clinical remission in systemic lupus erythematosus. J Rheumatol 1985;12: 916–8.[ISI][Medline]
  14. Alvarado C, Alcocer-Varela J, Llorente L, Richaud-Patin I, Cerbon M, Alarcón-Segovia D. Effect of CD28 antibody on T cells from patients with systemic lupus erythematosus. J Autoimmun 1994;7:763–73.[ISI][Medline]
  15. López-Karpovich X, Cardiel M, Cárdenas R, Piedras J, Alarcón-Segovia D. Circulating-colony-forming units of granulocytes and monocytes/macrophages in systemic lupus erythematosus. Clin Exp Immunol 1989;77:43–6.[ISI][Medline]
  16. Markeljevic J, Batinic D, Uzarevic B, Bozikov J, Cikes N, Babic-Naglic D et al. Peripheral blood CD5+ B cell subset in the remission phase of systemic connective tissue diseases. J Rheumatol 1994;21:2225–30.[ISI][Medline]
  17. Koide J, Takano M, Takeuchi T, Hosono O, Amano K, Homma M et al. Direct demonstration of immunoregulatory T-cell defects in patients with systemic lupus erythematosus. Scand J Immunol 1986;23:449–59.[ISI][Medline]
  18. Alcocer-Valera J, Alarcón-Segovia D. Decreased production of and response to interleukin-2 by cultured lymphocytes from patients with systemic lupus erythematosus. J Clin Invest 1982;69:1388–92.[ISI][Medline]
  19. ter Borg EJ, Horst G, Hummel EJ, Limburg PC, Kallenber CGM. Predictive value of rises in anti-double stranded DNA antibody levels for disease exacerbation in systemic lupus erythematosus: a longterm prospective study. Arthritis Rheum 1990;33:634–43.[ISI][Medline]
  20. Swaak AJG, Groenwold J, Bronsveld W. Predictive value of complement profiles and anti-dsDNA in systemic lupus erythematosus. Ann Rheum Dis 1986;45:359–66.[Abstract]
  21. Esdaile JM, Joseph L, Abrahamowicz M, Li Y, Danoff D, Clarke AE. Routine immunologic test in systemic lupus erythematosus: is there a need for more studies? J Rheumatol 1996;23:1891–6.[ISI][Medline]
  22. Swaak AJG, Smeenk RJT. Following the disease course in systemic lupus erythematosus: are serologic variables of any use. J Rheumatol 1996;23:1842–4.[ISI][Medline]
Submitted 27 October 1998; revised version accepted 5 March 1999.



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