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. 2004 Sep;63(9):1096–1103. doi: 10.1136/ard.2003.018663

Inverse association between circulating APRIL levels and serological and clinical disease activity in patients with systemic lupus erythematosus

W Stohl 1, S Metyas 1, S Tan 1, G Cheema 1, B Oamar 1, V Roschke 1, Y Wu 1, K Baker 1, D Hilbert 1
PMCID: PMC1755113  PMID: 15308519

Abstract

Objective: To assess longitudinal expression of a proliferation-inducing ligand (APRIL) in patients with systemic lupus erythematosus (SLE) and its correlation with B lymphocyte stimulator (BLyS) expression, serum anti-dsDNA titres, and clinical disease activity.

Methods: Sixty eight patients with SLE were longitudinally followed up for a median of 369 days. At each visit the physician assessed disease activity by SLEDAI, and blood was collected for determination of serum APRIL and BLyS levels and of blood APRIL and BLyS mRNA levels. Fifteen normal control subjects underwent similar laboratory evaluation.

Results: Dysregulation of APRIL was not as great as that of BLyS. Changes in serum levels of APRIL and BLyS over time were usually discordant, whereas blood levels of APRIL and BLyS mRNA strongly paralleled each other. Serum APRIL levels modestly, but significantly, inversely correlated with serum anti-dsDNA titres in anti-dsDNA positive patients analysed in aggregate. Moreover, serum APRIL levels modestly, but significantly, inversely correlated with clinical disease activity in all patients analysed in aggregate.

Conclusion: Serum levels of APRIL and BLyS are differentially regulated. APRIL may serve as a down modulator of serological and/or clinical autoimmunity in patients with SLE. This may have important ramifications for BLyS targeted treatment, and it remains to be determined whether agents which neutralise only BLyS will be preferable to agents which neutralise both BLyS and APRIL.

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Figure 1.

Figure 1

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 Heterogeneity in serum APRIL phenotypes among patients with SLE and relation to disease activity. (A) Serum samples collected from three representative normal controls (circles, triangles, squares) were assayed for APRIL levels. By definition, the first serum samples were collected on day 0. The dashed lines indicate 2SD above and below the geometric mean of all the values (n = 86) obtained from the 15 control subjects and arbitrarily define the "normal" range. (B-E) Serum samples collected from individual patients with SLE were assayed for APRIL levels (circles). Disease activity was measured by SLEDAI (bars). Results for representative patients exhibiting the "persistently normal" serum APRIL phenotype (B), the "persistently low" serum APRIL phenotype (C), the "intermittently raised" serum APRIL phenotype (D), or the "persistently raised" serum APRIL phenotype (E) are illustrated. (F) Serum APRIL levels plotted against the corresponding SLEDAI scores for the 523 individual serum samples from the 68 patients with SLE for whom serum APRIL levels and SLEDAI scores were both determined.

Figure 2.

Figure 2

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 Relation between serum APRIL and serum BLyS levels. Serum samples collected from two representative normal controls (A, B) and four representative patients with SLE (C–F) were assayed for APRIL and BLyS levels. The dotted lines delineate the normal range for serum APRIL, and the dashed lines delineate the normal range for serum BLyS.15

Figure 3.

Figure 3

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 Insensitivity of serum APRIL levels to treatment with high dose corticosteroids. Nine patients with SLE were treated with short courses of high dose corticosteroids.15 BLyS levels in pretreatment (B-pre) and post-treatment (B-post) serum samples and APRIL levels in pretreatment (A-pre) and post-treatment (A-post) sera are plotted.

Figure 4.

Figure 4

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 Heterogeneity in blood APRIL mRNA phenotypes among patients with SLE. (A) Peripheral blood samples collected from the same three representative normal controls illustrated in fig 1A (circles, triangles, squares) were assayed for APRIL mRNA levels. By definition, the first blood samples were collected on day 0. The dashed lines indicate 2SD above and below the geometric mean of all the values (n = 88) obtained from the 15 control subjects and arbitrarily define the "normal" range. (B–E) Serum APRIL levels (filled circles) and blood APRIL mRNA levels (open squares) were measured. The dotted lines delineate the normal range for serum APRIL, and the dashed lines delineate the normal range for blood APRIL mRNA. In four patients, blood APRIL mRNA levels were markedly raised despite normal serum APRIL levels (B, C). In most patients, blood APRIL mRNA levels remained normal throughout the entire observation periods (D, E).

Figure 5.

Figure 5

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 Relation between blood APRIL mRNA levels and blood BLyS mRNA levels. (A–D) Blood collected from two representative normal controls (A, B) and two representative patients with SLE (C, D) were assayed for APRIL mRNA and BLyS mRNA. The dotted lines delineate the normal range for blood APRIL mRNA, and the dashed lines delineate the normal range for blood BLyS mRNA.15 (E) Blood BLyS mRNA levels plotted against blood APRIL mRNA levels for the 526 individual blood samples obtained from the 68 patients with SLE for whom both blood APRIL and BLyS mRNA levels were determined.

Figure 6.

Figure 6

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 Relation between serum APRIL levels and serum anti-dsDNA titres. (A, B) Serum APRIL levels (filled circles) and serum anti-dsDNA titres (open squares) were determined in two representative patients with SLE in whom changes in serum APRIL levels largely paralleled those in serum anti-dsDNA titres. (C, D) Serum APRIL levels and serum anti-dsDNA titres were determined in two representative patients with SLE in whom changes in serum APRIL levels were largely anti-parallel to those in serum anti-dsDNA titres. (E) Serum anti-dsDNA titres plotted against serum APRIL levels for the 275 individual serum samples obtained from the 34 anti-dsDNA positive patients with SLE.

Selected References

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