Int J Clin Lab Res 22: 190-195, 1992
9 Springer-Verlag 1992
Reviews
Systemic lupus erythematosus A.J.G. Swaak ~, J.C. Nossent ~, and R.J.T. Smeenk 2 1 Department of Rheumatology, Dr. Daniel den Hoed Clinic, Groene Hilkdijk 301, 3075 EA Rotterdam, The Netherlands -" Department of Autoimmune Diseases, C.L.B., Amsterdam, The Netherlands
Summary. The reported change in the incidence of systemic lupus erythematosus (SLE) is mainly due to a greater awareness of the disease, and to the introduction of serological detection methods such as the LE cell assay and subsequently a variety of other antinuclear antibody assays. SLE is seldom preceded by rheumatoid arthritis, nor does SLE often develop in patients with rheumatoid arthritis. In a substantial proportion of our SLE patients, discoid LE occurred first. On analyzing the literature no evidence could be found that nowadays less severe SLE is diagnosed. Also, in the last three decades no change has been observed in the prevalence of clinical features in large groups of patients with SLE. These data indicate that there has been no change in the expression or prognosis of SLE in recent decades. Key words: Systematic lupus erythematosus - Incidence Diagnosis - Prognosis
Introduction In this review different aspects of systemic lupus erythematosus (SLE) are discussed. We focus on the change in incidence, the postulated shift from rheumatoid arthritis (RA) or discoid lupus erythematosus (DLE) to SLE, the change in prognosis and the change in clinical features during the disease course. Increased incidence of SLE has been reported in recent decades, but the question remains of whether this might not simply reflect greater awareness of the disease. An overlap between RA, D L E and SLE is presumed on the basis of their common features. Shifts from one disease to another have also been described. The general concept about the prognosis of SLE has changed dramatically. The old view of a relatively unremitting disease course ending with death within a few years has been replaced by a new one, in which remission Correspondence to: A. J. G. Swaak
to some degree occurs. It remains unclear whether the old view or the new one is more accurate. Often it is stated that nowadays less severe SLE is more easily recognized, which influences the disease course and the survival rate.
The change in incidence: historical background of lupus erythematosus How the term lupus entered the medical literature is unclear. Its first use is attributed to Herbernus of Tours, who in 916 A.D. described " . . . the miraculous healing of Eraclius, bishop of Liege, who was seriously afflicted and almost brought to death by this disease called lupus ..." [34]. The term lupus was then used to describe various cutaneous disorders which were all reminiscent of the gnawing and ravaging of flesh by a wolf [33]. Discoid lupus erythematosus was described under various names, ' b u t it was the paper by Cazenave in 1851 that proposed the name lupus erythematosus [7]. In this paper the skin afflictions hitherto named lupus were divided into tuberculous lupus ("lupus vulgaris"), lupus with hypertrophy, ulcerating lupus and lupus erythematosus. From then on, lupus erythematosus became an accepted term in the medical vocabulary. Near the end of the last century the concept of LE as a disease with the potential for systemic complications emerged. Kaposi distinguished in 1872 between a discoid form of the disease and a form he called "lupus erythematosus discretus et aggregatus". This form was associated with arthritis and lymphadenopathy and ran a course in which "in a period of 2 - 3 weeks death ensues, preceded by increased mental disturbance and pleuropneumonia" [26]. This proposed scheme was supported by a number of other reports on systemic complications in patients with LE [4, 20]. Sir William Osler also published three papers between 1895 and 1904 concerning systemic diseases which afflicted the skin. His total series contained 29 patients of which two were (in retrospect) clear-cut cases of SLE, but (even though one of the two patients had the initials LE) Sir William did not reach this diagnosis [31].
A. J. G. Swaak et al.: Systemic lupus erythematosus
191
The first half of the present century brought two main developments with regard to disease recognition and treatment: first, the description and subsequent introduction of the LE cell test by Hargrave [21], allowing more rapid and widespread recognition o f the disease; second, the introduction of cortisone and antibiotics, causing a decrease in serum sickness owing to less use of antiserum and, more important, a decline in rheumatic fever. From this time on the incidence of SLE rose markedly. Another relevant factor was the increased medical interest in the so-called "collagen diseases". In retrospect many of the cases reported before the description of the LE cell can be classified as atypical rheumatic fever, RA, idiopathic pleuritis, nephrotic syndrome o f u n k n o w n etiology and other clinical entities [10], but also from this time on large groups of SLE variants were described, such as discoid lupus and RA with LE cells. Because the LE cell was also tbund in rheumatoid arthritis, a relationship between the two diseases was presumed. Often cases of RA characterized by a positive LE cell assay were described as SLE variants and/or mild SLE.
similar to that in patients without this serological abnormality. This demonstrates that the diagnosis of SLE should not be considered in a patient with a positive LE cell test in the absence of appropriate clinical findings. At the onset of disease, however the diagnosis of SLE may be difficult; arthralgia or arthritis with morning stiffness, the most c o m m o n manifestation of SLE often results in an initial diagnosis of RA [17]. Currently there are six patients attending our outpatient clinic of rheumatic diseases who originally fulfilled the ARA criteria for the diagnosis RA [3] and who have developed SLE in the past 10 years (Table 1). A rough estimate can be made that a shift from RA to SLE will take place in 0.2% of the patients newly referred to our outpatient clinic. (The diagnosis of RA is confirmed in 15% of the 2000 patients referred to our department annually.) It is still disputable, in retrospect, whether the diagnosis of RA at the onset of the disease was correct. It can be concluded that SLE seldom is preceded by RA, or, from the other viewpoint, that SLE rarely develops in patients previously diagnosed as having RA.
The shift of RA and D L E to S L E
Discoid lupus ervthematosus
Rheumatoid arthritis
Prior to 1872 [26] the diagnosis of lupus was used only to describe a chronic skin disorder. The concept of this disease changed dramatically with Kaposi's proposal to differentiate two clinical forms of lupus, a discoid form (DLE) and a systemic form (SLE). The discoid form was characterized by discoidal skin efflorescences mostly confined to the skin of the head or by more generalized skin efflorescences which consisted of smaller disseminated spots. Both descriptions concerned only the characteristic skin involvement. In the SLE form, besides the skin effloresences, various concomitant symptoms such as adenitis, fever, weight loss and anemia and several complications such as pleuritis, pericarditis and nephritis were mentioned. Kaposi considered the two types of lupus as variations of the same disease, and reported that in nearly one fourth of the SLE patients discoid lesions were the first sign [30, 43]. Attention was also drawn to the fact that dissemination seemed to be related to exposure to sun or other types of ultraviolet radiation, chronic infection or,
The "serological" overlap between RA and SLE is well recognized, with up to 20% of RA patients exhibiting LE cells. True coexistence of the two diseases is rare, however. Yet after the discovery of the LE cell a lot of RA patients with the LE cell were considered to have SLE or variants of LE. Longitudinal studies were started to discover whether patients with classical RA and LE cells would develop SLE. Patients with RA and LE cells were observed to have a higher incidence of extra-articular disease manifestations, a higher frequency of rheumatoid nodules and higher levels of rheumatoid factor than RA patients with negative LE cell assays [23]. Still, none of these selected LE cell-positive RA patients developed SLE during the course of the investigation. Most of the cases described as RA developing into SLE are explained by the fact that the two conditions share many features. Distinction between them, especially in the early stages of disease, may be difficult. Articular involvement is very c o m m o n in SLE and frequently resembles that of early RA. SLE patients can have a positive rheumatoid factor, usually in low titers, but in precisely these patients joint complaints can be prominent. Equally, the extra-articular features of RA may resemble SLE. In studying the diagnostic significance of the LE cell test, we selected 500 patients whose serum was sent to our laboratory for routine examination and had a positive LE cell test. These patients had not previously been known at our department of autoimmune diseases. The diagnosis of SLE, according to the criteria of the American Rheumatism Association (ARA) [8, 39], was confirmed in 19% of cases, but in the rest of the patients the diagnosis was RA. Furthermore, most RA patients characterized by a positive LE cell test can be expected to have a disease course
Table 1. Patients attending our Department of Rheumatology who
developed systemic lupus erythematosus Previous diagnosis
Discoid lupus Rheumatoid arthritis Hematological disease a
Number of patients
11 6 5
Age at onset of disease (:~_+SD)
Interval (years) from onset to diagnosis (.?_+SD)
31 _+9.2 30 + 4.6
8 _ 7.1 7 _+4.6
24 _+6
7_ 2
Two patients with hemolytic anemia, two patients with persistent leukocytopenia (
9 Springer-Verlag 1992
Reviews
Systemic lupus erythematosus A.J.G. Swaak ~, J.C. Nossent ~, and R.J.T. Smeenk 2 1 Department of Rheumatology, Dr. Daniel den Hoed Clinic, Groene Hilkdijk 301, 3075 EA Rotterdam, The Netherlands -" Department of Autoimmune Diseases, C.L.B., Amsterdam, The Netherlands
Summary. The reported change in the incidence of systemic lupus erythematosus (SLE) is mainly due to a greater awareness of the disease, and to the introduction of serological detection methods such as the LE cell assay and subsequently a variety of other antinuclear antibody assays. SLE is seldom preceded by rheumatoid arthritis, nor does SLE often develop in patients with rheumatoid arthritis. In a substantial proportion of our SLE patients, discoid LE occurred first. On analyzing the literature no evidence could be found that nowadays less severe SLE is diagnosed. Also, in the last three decades no change has been observed in the prevalence of clinical features in large groups of patients with SLE. These data indicate that there has been no change in the expression or prognosis of SLE in recent decades. Key words: Systematic lupus erythematosus - Incidence Diagnosis - Prognosis
Introduction In this review different aspects of systemic lupus erythematosus (SLE) are discussed. We focus on the change in incidence, the postulated shift from rheumatoid arthritis (RA) or discoid lupus erythematosus (DLE) to SLE, the change in prognosis and the change in clinical features during the disease course. Increased incidence of SLE has been reported in recent decades, but the question remains of whether this might not simply reflect greater awareness of the disease. An overlap between RA, D L E and SLE is presumed on the basis of their common features. Shifts from one disease to another have also been described. The general concept about the prognosis of SLE has changed dramatically. The old view of a relatively unremitting disease course ending with death within a few years has been replaced by a new one, in which remission Correspondence to: A. J. G. Swaak
to some degree occurs. It remains unclear whether the old view or the new one is more accurate. Often it is stated that nowadays less severe SLE is more easily recognized, which influences the disease course and the survival rate.
The change in incidence: historical background of lupus erythematosus How the term lupus entered the medical literature is unclear. Its first use is attributed to Herbernus of Tours, who in 916 A.D. described " . . . the miraculous healing of Eraclius, bishop of Liege, who was seriously afflicted and almost brought to death by this disease called lupus ..." [34]. The term lupus was then used to describe various cutaneous disorders which were all reminiscent of the gnawing and ravaging of flesh by a wolf [33]. Discoid lupus erythematosus was described under various names, ' b u t it was the paper by Cazenave in 1851 that proposed the name lupus erythematosus [7]. In this paper the skin afflictions hitherto named lupus were divided into tuberculous lupus ("lupus vulgaris"), lupus with hypertrophy, ulcerating lupus and lupus erythematosus. From then on, lupus erythematosus became an accepted term in the medical vocabulary. Near the end of the last century the concept of LE as a disease with the potential for systemic complications emerged. Kaposi distinguished in 1872 between a discoid form of the disease and a form he called "lupus erythematosus discretus et aggregatus". This form was associated with arthritis and lymphadenopathy and ran a course in which "in a period of 2 - 3 weeks death ensues, preceded by increased mental disturbance and pleuropneumonia" [26]. This proposed scheme was supported by a number of other reports on systemic complications in patients with LE [4, 20]. Sir William Osler also published three papers between 1895 and 1904 concerning systemic diseases which afflicted the skin. His total series contained 29 patients of which two were (in retrospect) clear-cut cases of SLE, but (even though one of the two patients had the initials LE) Sir William did not reach this diagnosis [31].
A. J. G. Swaak et al.: Systemic lupus erythematosus
191
The first half of the present century brought two main developments with regard to disease recognition and treatment: first, the description and subsequent introduction of the LE cell test by Hargrave [21], allowing more rapid and widespread recognition o f the disease; second, the introduction of cortisone and antibiotics, causing a decrease in serum sickness owing to less use of antiserum and, more important, a decline in rheumatic fever. From this time on the incidence of SLE rose markedly. Another relevant factor was the increased medical interest in the so-called "collagen diseases". In retrospect many of the cases reported before the description of the LE cell can be classified as atypical rheumatic fever, RA, idiopathic pleuritis, nephrotic syndrome o f u n k n o w n etiology and other clinical entities [10], but also from this time on large groups of SLE variants were described, such as discoid lupus and RA with LE cells. Because the LE cell was also tbund in rheumatoid arthritis, a relationship between the two diseases was presumed. Often cases of RA characterized by a positive LE cell assay were described as SLE variants and/or mild SLE.
similar to that in patients without this serological abnormality. This demonstrates that the diagnosis of SLE should not be considered in a patient with a positive LE cell test in the absence of appropriate clinical findings. At the onset of disease, however the diagnosis of SLE may be difficult; arthralgia or arthritis with morning stiffness, the most c o m m o n manifestation of SLE often results in an initial diagnosis of RA [17]. Currently there are six patients attending our outpatient clinic of rheumatic diseases who originally fulfilled the ARA criteria for the diagnosis RA [3] and who have developed SLE in the past 10 years (Table 1). A rough estimate can be made that a shift from RA to SLE will take place in 0.2% of the patients newly referred to our outpatient clinic. (The diagnosis of RA is confirmed in 15% of the 2000 patients referred to our department annually.) It is still disputable, in retrospect, whether the diagnosis of RA at the onset of the disease was correct. It can be concluded that SLE seldom is preceded by RA, or, from the other viewpoint, that SLE rarely develops in patients previously diagnosed as having RA.
The shift of RA and D L E to S L E
Discoid lupus ervthematosus
Rheumatoid arthritis
Prior to 1872 [26] the diagnosis of lupus was used only to describe a chronic skin disorder. The concept of this disease changed dramatically with Kaposi's proposal to differentiate two clinical forms of lupus, a discoid form (DLE) and a systemic form (SLE). The discoid form was characterized by discoidal skin efflorescences mostly confined to the skin of the head or by more generalized skin efflorescences which consisted of smaller disseminated spots. Both descriptions concerned only the characteristic skin involvement. In the SLE form, besides the skin effloresences, various concomitant symptoms such as adenitis, fever, weight loss and anemia and several complications such as pleuritis, pericarditis and nephritis were mentioned. Kaposi considered the two types of lupus as variations of the same disease, and reported that in nearly one fourth of the SLE patients discoid lesions were the first sign [30, 43]. Attention was also drawn to the fact that dissemination seemed to be related to exposure to sun or other types of ultraviolet radiation, chronic infection or,
The "serological" overlap between RA and SLE is well recognized, with up to 20% of RA patients exhibiting LE cells. True coexistence of the two diseases is rare, however. Yet after the discovery of the LE cell a lot of RA patients with the LE cell were considered to have SLE or variants of LE. Longitudinal studies were started to discover whether patients with classical RA and LE cells would develop SLE. Patients with RA and LE cells were observed to have a higher incidence of extra-articular disease manifestations, a higher frequency of rheumatoid nodules and higher levels of rheumatoid factor than RA patients with negative LE cell assays [23]. Still, none of these selected LE cell-positive RA patients developed SLE during the course of the investigation. Most of the cases described as RA developing into SLE are explained by the fact that the two conditions share many features. Distinction between them, especially in the early stages of disease, may be difficult. Articular involvement is very c o m m o n in SLE and frequently resembles that of early RA. SLE patients can have a positive rheumatoid factor, usually in low titers, but in precisely these patients joint complaints can be prominent. Equally, the extra-articular features of RA may resemble SLE. In studying the diagnostic significance of the LE cell test, we selected 500 patients whose serum was sent to our laboratory for routine examination and had a positive LE cell test. These patients had not previously been known at our department of autoimmune diseases. The diagnosis of SLE, according to the criteria of the American Rheumatism Association (ARA) [8, 39], was confirmed in 19% of cases, but in the rest of the patients the diagnosis was RA. Furthermore, most RA patients characterized by a positive LE cell test can be expected to have a disease course
Table 1. Patients attending our Department of Rheumatology who
developed systemic lupus erythematosus Previous diagnosis
Discoid lupus Rheumatoid arthritis Hematological disease a
Number of patients
11 6 5
Age at onset of disease (:~_+SD)
Interval (years) from onset to diagnosis (.?_+SD)
31 _+9.2 30 + 4.6
8 _ 7.1 7 _+4.6
24 _+6
7_ 2
Two patients with hemolytic anemia, two patients with persistent leukocytopenia (
