Rheumatology 2001; 40: 424-431
© 2001 British Society for Rheumatology
Decreased serum erythropoietin and its relation to anti-erythropoietin antibodies in anaemia of systemic lupus erythematosus
Division of Rheumatology, Department of Internal Medicine III,
1 Division of Hematology and
2 Division of Infectious Diseases, Department of Internal Medicine I,
3 Clinic of Anesthesia and Intensive Care and
4 Department of Laboratory Medicine, Central Laboratory Unit, University of Vienna Medical School, Vienna, Austria
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Abstract |
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Objective. This study was performed to assess erythropoietin levels and anti-erythropoietin antibodies in patients with systemic lupus erythematosus (SLE).
Methods. The sera of 100 patients with SLE were investigated for serum erythropoietin levels and the presence of anti-erythropoietin antibodies by ELISA. Routine laboratory parameters such as peripheral blood count, relevant parameters of blood chemistry, and immunological parameters of SLE were recorded.
Results. Erythropoietin levels were significantly decreased in SLE patients when related to individual haemoglobin and haematocrit values (P<0.001), suggesting an inadequate erythropoietin response in SLE. Anti-erythropoietin antibodies were found in 46% of SLE patients, and erythropoietin levels (but not haemoglobin or haematocrit values) were significantly decreased in these patients compared with patients without anti-erythropoietin antibodies. Serum erythropoietin concentration as determined by ELISA was reduced in the presence of anti-erythropoietin antibodies. Furthermore, anti-erythropoietin antibodies also correlated with younger age, decreased serum levels of complement factors C3 and C4 and elevated anti-double-stranded DNA antibodies.
Conclusions. We conclude that the anaemia of SLE is characterized by an inadequate erythropoietin response. Anti-erythropoietin antibodies are frequently present in SLE and interfere with the measurement of serum erythropoietin level. However, these antibodies are not associated with increased severity of SLE-associated anaemia.
KEY WORDS: SLE, Anaemia, Erythropoietin, Anti-erythropoietin antibodies.
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Introduction |
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The production of erythropoietin (EPO) in human renal peritubular fibroblasts is regulated by arterial oxygen tension via a mechanism that is not fully understood but is known to involve oxygen-dependent conformational changes of the haem molecule [1–3]. An intact EPO response is necessary for the maintainance of adequate production and maturation of red cells and a stable haematocrit level in human blood [4]. The damage to the EPO-producing apparatus that occurs in renal disease leads to inadequate EPO production followed by a fall in haematocrit, which is commonly known as renal anaemia [5, 6]. In healthy individuals and patients with haematological disorders, a drop in haematocrit, e.g. after haemorrhage, leads to a rise in serum EPO levels [5, 7]. This functional EPO response is the basis of the inverse correlation of haematocrit and the serum EPO level. The normal range of serum EPO depends on the underlying haematocrit level, with a high EPO concentration in individuals with low haematocrit and vice versa. In contrast, an inadequate or blunted EPO response with inappropriate elevation of serum EPO level in response to anaemia is found not only in renal disease but also in the anaemia of chronic disease [8–14]. The mechanism of inhibition of the EPO axis in the anaemia of chronic disease has not yet been unravelled, but an inhibitory effect of proinflammatory cytokines, such as tumour necrosis factor
, interleukin 1 and 
-interferon, is suspected [15, 16]. Thus, an inadequate EPO response has been observed in a variety of disorders, such as rheumatoid arthritis, tumours, inflammatory bowel disease and acquired immunodeficiency syndrome [8–14]. Several different pathogenetic factors may influence the cycle of life of erythrocytes in SLE [17, 18]. Haemolytic and renal anaemia, due to autoimmune pathology and renal organ involvement respectively, are found in a subgroup of SLE patients [2], but do not convincingly explain the high incidence of anaemia in SLE. Interestingly, to our knowledge serum EPO levels have not yet been assessed in a significant number of SLE patients, and the question of whether the EPO response in SLE is adequate, and thus whether the EPO level is elevated in SLE patients with anaemia or is inadequate, is unanswered. This is even more surprising, as occasional reports have been published favouring substitution with the recombinant hormone as a therapy for anaemia associated with SLE [19], while others report EPO resistance in patients with high disease activity [20]. Furthermore, autoantibodies against human EPO have recently been described in SLE and are found at a higher frequency in SLE patients with anaemia [21]. The presence of such antibodies may lead to an alteration in the serum EPO level, or at least interference with the measurement of serum EPO levels, but could also inhibit the physiological activity of EPO in SLE.
We performed a cross-sectional study in 100 SLE patients to analyse (i) serum EPO levels, (ii) autoantibody reactivity to human EPO, and (iii) a possible association of EPO with anti-EPO antibodies (AEA) in SLE. Furthermore, EPO and AEA levels were studied in relation to a number of clinical features and standard laboratory variables.
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Materials and methods |
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Characteristics of patients
One hundred Caucasian patients with SLE were included in this study. All patients were from the city of Vienna or surrounding areas; nine were male and 91 were female and their age ranged from 15 to 75 yr (mean 37.5 yr). All patients were diagnosed and followed at the Division of Rheumatology of the Vienna General Hospital and fulfilled the American College of Rheumatology criteria for the classification of SLE [22]. Informed consent was obtained from all patients. None of these patients were receiving therapy with recombinant EPO or had ever received EPO therapy. We recorded the use of non-steroidal anti-inflammatory drugs (NSAIDs), steroids and immunosuppressive drugs and the clinical features of all patients. European Consensus Lupus Activity Measure (ECLAM) scores were calculated for each of the patients [23].
Routine laboratory tests
The following laboratory variables were analysed: haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), white blood count (WBC), thrombocyte count, lactate dehydrogenase (LDH), serum creatinine, urinalysis including daily protein excretion, C-reactive protein (CRP), fibrinogen, erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA), ANA subsets anti-SS-A/Ro, anti-SS-B/La, anti-U1-RNP and anti-Sm, antibodies to double-stranded DNA (dsDNA), and serum levels of complement factors C3 and C4.
Determination of serum EPO levels
Serum samples from SLE patients were collected and stored at -70°C before use. Quantification of serum EPO levels was performed by an ELISA [24] for human EPO (Quantikine IVD, R&D Systems, Minneapolis, MN, USA) according to the manufacturer's instructions. In short, polystyrene microtitre plates coated with a murine monoclonal antibody to human EPO were incubated with SLE sera (dilution 1.25 v/v) for 1 h at room temperature. A rabbit polyclonal antibody to human EPO conjugated with horseradish peroxidase (HRP) was added for 1 h and the reaction was detected by addition of 0.4 g/l tetramethylbenzidine/0.02% hydrogen peroxide. Optical density (OD) was assessed at 450 nm after 15 min with an automated ELISA reader and reference measurement was performed at 600 nm. A standard curve was created by plotting the mean absorbance of each of four different standards, and individual EPO levels were then determined.
Since EPO levels increase exponentially as the haematocrit decreases, EPO must be expressed in relation to the haematocrit value [25]. Therefore, for each of the patients an expected EPO level based on the individual haematocrit had to be calculated (EpoExp). An exponential regression line based on the association of haematocrit and EPO in a reference cohort was used to determine the expected EPO levels [25].
Determination of AEA
ELISA testing for antibodies to human EPO was performed according to a previously described protocol with slight modifications [21]. Recombinant EPO (R&D Systems) was dissolved in phosphate-buffered saline (PBS), pH 7.2, and polystyrene microtitre plates (Costar, Cambridge, UK) were coated with 10 µg EPO per well. After incubation overnight at 4°C, plates were washed with 0.1% Tween 20/PBS to remove unbound material and blocked with 5% bovine serum albumin (BSA)-PBS for 1 h. Diluted serum samples (1:25) were then added to the wells in duplicate and incubated for 1 h. For detection, an HRP-conjugated rabbit anti-human IgG (1:400) was added to the plates, and after a final washing step the reaction was visualized by addition of the substrates hydrogen peroxide and 2,2'-azino-bis 3-ethylbenzthiazoline-6-sulphonic acid (ABTS; Sigma, Munich, Germany). The OD of the samples was measured after 30 min at 410 nm (reference 630 nm) with a programmed ELISA reader. Each plate contained 10 samples of normal human serum as a reference for baseline absorption, and in total 20 control subjects were analysed; none of them showed a significant AEA response. The threshold for positive titres was OD 0.6 (corresponding to >3 standard deviations of the mean value of the control samples) and values were corrected for serum -globulin content.
Interference in EPO measurement by SLE sera
In principle, a similar assay procedure was performed as described for the determination of EPO levels. Microtitre plates precoated with a murine monoclonal antibody to human EPO were preincubated with undiluted or serial dilutions (1:10 to 1:10 000) of 10 representative SLE sera, five with high anti-EPO antibody reactivity and five without such reactivity for 1 h at room temperature. After thorough washing, the plates were then incubated with a defined concentration of EPO (50 mIU/ml) for 1 h, and after another washing step rabbit polyclonal anti-human EPO antibody was used for detection. After addition of the substrate (tetramethylbenzidine/0.02% hydrogen peroxide), OD was assessed at 450 nm.
Statistical analysis
Spearman's correlation coefficient 
was calculated in order to compare each of the individual parameters. For comparison of SLE sera with and without AEA with respect to other parameters, the Mann–Whitney U-test was used. ANOVA (analysis of variance) regression analysis was used to compare measured with expected EPO levels and to correlate EPO levels with haemoglobin and haematocrit values.
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Results |
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Characteristics of SLE patients
The characteristics of the SLE patients are shown in Table 1
. Anaemia, as defined by a decrease in haematocrit level below 37% in females and 40% in males, was found in 56% of the patients. With respect to haemoglobin, 42% of the patients were defined as anaemic, showing a haemoglobin level below 12 g/dl in females and 13.5 g/dl in males. Microcytosis was present in 23% (MCV <84 fl in females, <85 fl in males), normocytosis in 74% (MCV 84/85–98 fl) and macrocytosis in 3% (MCV >98 fl). Hypochromatic erythrocytes were seen in 23% (MCH <28 pg), normochromatic in 76% (MCH 28–34 pg) and hyperchromatic in 1% (MCH >34 pg) of the patients. Levels of LDH were normal or slightly elevated in all patients, and no patient displayed signs of haemolysis at the time of presentation.
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Immunological assessment revealed antibodies against dsDNA to be present in 45% of the subjects (>10 U/l). ANA were found in almost all SLE patients and the subsets SS-A/Ro, SS-B/La, U1-RNP and Sm were present in 36, 15, 12 and 4% of the patients respectively. Serum levels of C3 were decreased in 25% (<50 mg/dl) and those of C4 in 22% of the patients at the time of presentation (<10 mg/dl).
Twenty-seven per cent of the subjects presented with rash, 15% with active renal disease, 13% with arthralgia/arthritis, 9% with neurological manifestation and 2% each with pulmonary and pericardial disease. Median ECLAM score was 2. Use of NSAID therapy was recorded in 13% of patients, steroid therapy was recorded in 65% of the patients, and immunomodulatory drugs were taken by 57% of the patients [mostly hydroxychloroquine (23%), but also azathioprine (12%), cyclosporin A (5%), cyclophosphamide (5%), methotrexate (2%) and combination therapy (10%)].
Levels of EPO and AEA in SLE patients
EPO levels were measured by sandwich ELISA in all SLE patients, and ranged from 0.5 to 250 mIU/ml. Median EPO concentration was 9.4 mIU/ml (Table 1
). The presence of anti-EPO reactivity was tested in 93 SLE patients by ELISA using 10 µg recombinant EPO. Forty-three of these patients (46%) showed antibody reactivity to EPO (AEA) and the median extinction value (OD410 nm) was 1315 in SLE patients with AEA (Table 1).
Based on the observation of a high frequency of AEA, SLE patients were divided into two groups, one group with and the other group without AEA reactivity. A comparative analysis of these two subgroups was then performed to investigate the effect of AEA on other features of SLE, including the EPO concentration and EPO response.
EPO levels and other laboratory variables in SLE patients with and without AEA
Medians and ranges of laboratory values for AEA-positive and AEA-negative patients are shown in Table 2. The Mann–Whitney U-test was used to compare the two groups. The most significant difference between the groups was due to the extremely low EPO level in AEA-positive subjects (P<0.001). In addition, AEA-positive patients were significantly younger than AEA-negative ones (P<0.01). Also, the levels of C3 and C4 were lower and those of anti-dsDNA antibodies higher in AEA-positive patients. In contrast, no differences were found regarding parameters of renal disease (serum creatinine, proteinuria), the levels of ANA and blood counts (leucocytes, thrombocytes, MCV, MCH). With respect to clinical symptoms of SLE and the use of NSAIDs, steroid and/or immunomodulatory drug therapy, no differences between the two groups were found (data not shown). Most strikingly, haemoglobin and haematocrit levels were not different in the two groups, despite the fact that the concentrations of EPO were significantly lower in AEA-positive subjects.
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Measured and expected EPO levels in SLE patients with and without AEA
Measured EPO levels and EPO levels expected by calculation using the individual haematocrit value (EpoExp) were compared to investigate if the EPO response was intact in SLE. Considering the high frequency of anaemia, one could expect an activated EPO response in SLE, leading to an increased serum EPO level. The opposite was found: serum EPO levels were significantly lower than expected both in patients with AEA (P<0.001, Wilcoxon signed rank test) and in those without AEA (P<0.001, Wilcoxon signed rank test) (Fig. 1). The mean measured EPO level in AEA-negative patients was 36.6 mIU/ml, compared with the mean expected EPO concentration of 53.1 mIU/ml. In patients with AEA, serum EPO concentrations were extremely low (mean 8.5 mIU/ml) (Fig. 1B) compared with the expected EPO level (mean 42.1 mIU/ml) and with the EPO level of AEA-negative SLE patients (P<0.001, Wilcoxon signed rank test).
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Correlation of EPO levels with haematocrit and haemoglobin values
In normal subjects and in various pathological states, despite renal anaemia, serum EPO levels are inversely related to both haemoglobin and haematocrit. EPO levels were therefore plotted against haemoglobin and haematocrit values. Despite low EPO levels, SLE patients without AEA had an intact correlation of EPO with haemoglobin (P<0.001) or haematocrit (P<0.001) (ANOVA regression analysis) (Fig. 2A). Thus, the EPO response to anaemia was essentially intact, but at a low level. In contrast, in patients with AEA there was no correlation between EPO levels and haemoglobin (P<0.4) or haematocrit (P<0.8; ANOVA regression analysis) (Fig. 2B). As detailed in Fig. 1B, serum EPO was low in these patients and also randomly distributed when plotted against haemoglobin and haematocrit (Fig. 2B).
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Correlation of EPO and AEA with other laboratory and clinical variables of SLE
In the total study population, EPO levels were inversely correlated with haemoglobin levels, haematocrit levels and the presence of AEA, as shown by Spearman's correlation test (Table 3). Subanalysis of patients based on the presence of AEA revealed an inverse correlation of EPO levels with haemoglobin and haematocrit in patients without AEA, but not in patients with AEA, as described above. In addition, ECLAM scores were correlated with EPO levels in the subgroup of patients without AEA, but not in the total population or in the subgroup with AEA.
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In the total study population, AEA were strongly correlated with lower serum EPO levels, as described above, and also with younger age. In addition, a positive correlation to anti-dsDNA antibodies was observed (Table 3
). In the AEA-positive subgroup, the quantity of AEA was correlated to surrogate markers of disease activity (ESR, CRP, LDH, low C4 and anti-dsDNA). In contrast, the level of AEA was not correlated with a lower EPO value (and also not with lower age), indicating that even serum samples with relatively low AEA had low serum EPO levels. No other correlations of EPO and AEA were observed in our study. Interestingly, the levels of EPO and the presence of AEA were not related to a particular clinical symptom or the use of NSAIDs, steroid or immunomodulatory drug therapy (data not shown). Anaemia itself was strongly related (P<0.01) to parameters of disease activity, such as ECLAM score, dsDNA antibodies, CRP and ESP (data not shown).
Inhibition of EPO measurement by AEA
To assess a possible inhibitory effect of AEA on EPO measurement in human serum, five serum samples each from patients with AEA and without AEA were subjected to EPO ELISA with a defined EPO concentration. In the presence of sera with AEA, dose-dependent inhibition of EPO measurement was observed, whereas no effect was seen with AEA-negative sera (Fig. 3). The results were identical when serum and EPO were preincubated first and then added to the system and when the serum was added before addition of EPO, as shown in Fig. 3. This clearly indicates that AEA interferes in the measurement of EPO.
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Discussion |
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Haematological abnormalities affecting one or more blood cell lineages are frequently found in SLE, and anaemia is among the most common findings [17]. Because of the high prevalence of anaemia in SLE, one would expect elevated serum levels of EPO in SLE patients. On the other hand, anaemia in SLE may largely reflect the presence of anaemia in chronic disease, associated with inadequate production of EPO. Here we show that serum EPO levels are low in patients with SLE and that the serum EPO response is inadequate when correlated to the degree of anaemia. This suggests that inadequate secretion of EPO is a major contributor to the anaemia of SLE, which has similarities with other types of anaemia in chronic disease.
Because of the autoimmune pathogenesis of SLE, the relationship between haematocrit and EPO level is likely to be complex in this disease. Beside numerous autoantibody reactivities to predominantly nuclear antigenic structures [26], antibodies to the various types of peripheral blood cells have been described in SLE; serum inhibitors to erythropoiesis have also been reported to occur but have not yet been characterized in detail [27–29]. Recently, autoantibodies to human EPO have been described in SLE [21]. These antibodies were found at higher frequencies in SLE patients with a low haemoglobin level, although no direct correlation between haemoglobin or haematocrit and autoantibody levels to EPO was described. In addition, these antibodies were correlated with disease activity and with low levels of serum C4. Antibodies to EPO have been described to occur rarely after EPO therapy in patients with renal anaemia, a finding that can be explained by sensitization against the exogenous recombinant hormone [30]; such antibodies have also been described in Castleman disease [31]. A detailed investigation of AEA has been performed in patients with pure red cell aplasia, in which IgG autoantibodies to the polypeptide structures but not the carbohydrate residues of human EPO were found [32]. These antibodies were functionally active, leading to severe anaemia with low serum EPO levels, and inhibited both the proliferation of erythropoietic precursor cells, as measured by colony forming units-erythrocytes (CFU-E) growth, and the binding of EPO to its receptor. Thus, AEA in pure red cell aplasia led to clearance of the functional hormone from circulation, mimicking renal anaemia.
In our study, the presence of AEA was associated with very low serum EPO levels but not with low haemoglobin or haematocrit. This is indirect evidence that at least a significant proportion of AEA in SLE are not functionally active, because anaemia was not more pronounced in the subgroup of SLE patients with AEA. However, because serum EPO levels were extremely low in the subgroup of SLE patients with AEA but haemoglobin and haematocrit levels were similar in the two subgroups of SLE patients, interference by AEA with the measurement of serum EPO levels was a possible explanation for this discrepancy. Indeed, the addition of AEA-containing SLE sera reduced EPO measurements in a dose-dependent manner, whereas SLE sera without AEA did not influence the test. The physiological inverse correlations of haematocrit and haemoglobin with serum EPO levels were lowered and blunted in SLE patients without AEA; this clearly demonstrates an inadequate EPO response, which was maintained at lower level in these patients. The presence of AEA led to the complete abolition of this correlation, providing another piece of evidence for interference by AEA in the measurement of EPO.
The presence of AEA was associated with lower levels of serum complement factors C3 and C4, as well as elevated autoantibodies to dsDNA, which are considered to be surrogate markers of SLE disease activity. This finding is in line with earlier data showing a link between AEA and elevated SLE disease activity scores and lower levels of serum complement factors C4 [21]. However, in our study we were not able to find a difference in ECLAM score between SLE patients with and without AEA, making a relationship of AEA with the overall disease activity of SLE unlikely. On the other hand, ECLAM score was positively related to EPO, at least in patients without AEA, which reflects (i) the strong association of anaemia with disease activity, and (ii) the functional, although blunted, EPO response in SLE patients without AEA.
In conclusion, we have shown a blunted EPO response in patients with SLE. This inadequate EPO response may be a leading factor in anaemia in SLE. Furthermore, autoantibodies to human EPO were frequently found in SLE and interfere with the measurement of serum EPO levels; this may lead to underestimation of EPO concentrations in SLE patients. Because haemoglobin and haematocrit levels were not lower in SLE patients with AEA than in those without AEA, anti-EPO antibodies do not appear to inhibit EPO function. Further studies will be needed to analyse the effect of these antibodies on EPO receptor binding and the proliferation of red cell precursors.
With respect to the therapeutic administration of EPO in SLE, it should be borne in mind that (i) the anaemia of SLE is characterized by inadequate EPO production regardless of renal disease; (ii) the anaemia of SLE, like other types of anaemia, such as infection- or inflammation-associated anaemia, may prove to be EPO-resistant; and (iii) AEA may be present in SLE patients, leading to underestimation of EPO levels.
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Correspondence to: G. Schett, Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Währinger Gürtel 18-20, A-1180 Vienna, Austria
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