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Abstract
IntroductionSerum levels of C-reactive protein (CRP) seldom reflect disease activity in systemic lupus erythematosus (SLE). We have previously shown that autoantibodies against neo-epitopes of CRP often occur in SLE, but that this does not explain the modest CRP response seen in flares. However, we have repeatedly found that anti-CRP levels parallel lupus disease activity, with highest levels in patients with renal involvement; thus, we aimed to study anti-CRP in a material of well-characterized lupus nephritis patients.MethodsThirty-eight patients with lupus nephritis were included. Treatment with corticosteroids combined with cyclophosphamide, mycophenolate mofetil or rituximab was started after baseline kidney biopsy. A second biopsy was taken after ≥ 6 months. Serum creatinine, cystatin C, complement, anti-dsDNA, anti-CRP and urinalysis were done on both occasions. Biopsies were evaluated regarding World Health Organisation (WHO) class and indices of activity and chronicity. Renal disease activity was estimated using the British Isles Lupus Assessment Group (BILAG) index.ResultsAt baseline, 34/38 patients had renal BILAG-A; 4/38 had BILAG-B. Baseline biopsies showed WHO class III (n = 8), IV (n = 19), III to IV/V (n = 3) or V (n = 8) nephritis. Seventeen out of 38 patients were anti-CRP-positive at baseline, and six at follow-up. Overall, anti-CRP levels had dropped at follow-up (P < 0.0001) and anti-CRP levels correlated with renal BILAG (r = 0.29, P = 0.012). A positive anti-CRP test at baseline was superior to anti-dsDNA and C1q in predicting poor response to therapy as judged by renal BILAG. Baseline anti-CRP levels correlated with renal biopsy activity (r = 0.33, P = 0.045), but not with chronicity index. Anti-CRP levels were positively correlated with anti-dsDNA (fluorescence-enhanced immunoassay: r = 0.63, P = 0.0003; Crithidia luciliae immunofluorescence microscopy test: r = 0.44, P < 0.0001), and inversely with C3 (r = 0.35, P = 0.007) and C4 (r = 0.29, P = 0.02), but not with C1q (r = 0.14, P = 0.24). No associations with urinary components, creatinine, cystatin C or the glomerular filtration rate were found.ConclusionsIn the present study, we demonstrate a statistically significant correlation between anti-CRP levels and histopathological activity in lupus nephritis, whereas a baseline positive anti-CRP test predicted poor response to therapy. Our data also confirm previous findings of associations between anti-CRP and disease activity. This indicates that anti-CRP could be helpful to assess disease activity and response to therapy in SLE nephritis, and highlights the hypothesis of a pathogenetic role for anti-CRP antibodies in lupus nephritis.
Highlights
Introduction Serum levels ofC-reactive protein (CRP) seldom reflect disease activity in systemic lupus erythematosus (SLE)
Our data confirm previous findings of associations between anti-CRP and disease activity. This indicates that anti-CRP could be helpful to assess disease activity and response to therapy in SLE nephritis, and highlights the hypothesis of a pathogenetic role for anti-CRP antibodies in lupus nephritis
Anti-CRP antibody levels were more efficiently reduced in patients who responded to therapy as judged by renal histopathology, and baseline anti-CRP levels were significantly higher (P = 0.0097) in patients who did not reach a renal British Isles Lupus Assessment Group (BILAG) improvement of at least two grades (Figure 2)
Summary
C-reactive protein (CRP) seldom reflect disease activity in systemic lupus erythematosus (SLE). Autoantigens escaping physiological clearance may become excessively presented to the adaptive immune system, resulting in loss of peripheral tolerance and occurrence of a multitude of BILAG: British Isles Lupus Assessment Group; BSA: bovine serum albumin; CLIFT: Crithidia luciliae immunofluorescence microscopy test; CRP: Creactive protein; dsDNA: double-stranded DNA; ELISA: enzyme-linked immunosorbent assay; IFN: interferon; IL: interleukin; mCRP: monomeric Creactive protein; SLE: systemic lupus erythematosus; TNF: tumour necrosis factor; WHO: World Health Organisation. The circulating levels of anti-dsDNA often correlate with disease activity, and these autoantibodies are presumed to be of pathogenetic importance in lupus nephritis [4,5,6]. Despite raised levels of IL-6 and extensive systemic inflammation, serum CRP concentrations typically remain low in lupus flares [8], differences between certain disease manifestations [9] and conflicting data have been reported [10]. The novel in vitro finding that IFNα mediates suppression of IL-6-induced CRP expression in human hepatocytes, could possibly explain the weak CRP response in SLE flares [11]
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