The value of measuring ANCA during follow-up to predict a relapse is controversial. On the basis of recently obtained pathophysiologic insights, we postulated that measuring ANCA is useful in patients with renal involvement but is less valuable in patients with nonrenal disease. One hundred sixty-six consecutive patients with ANCA-associated vasculitis, positive for either proteinase 3 (PR3)-ANCA or myeloperoxidase (MPO)-ANCA, were included in our study, followed at regular intervals, and tested for PR3-ANCA and MPO-ANCA. In this cohort, 104 patients had renal involvement (72 with PR3-ANCA, 32 with MPO-ANCA) and 62 patients had nonrenal disease (36 with PR3-ANCA, 26 with MPO-ANCA). During an average (6SD) follow-up of 49633 months and 18614 ANCA measurements, 89 ANCA rises and 74 relapses were recorded. ANCA rises correlated with relapses in patients who presented with renal involvement (hazard ratio [HR], 11.09; 95% confidence interval [95% CI], 5.01 to 24.55), but in comparison, associated only weakly with relapses in patients who presented with nonrenal disease (HR, 2.79; 95% CI, 1.30 to 5.98). In conclusion, longitudinal ANCA measurements may be useful in patients with renal involvement but is less valuable in patients with nonrenal disease.
We have evaluated the performance of a novel line-blot immunoassay (LIA; Mikrogen) and compared results with those obtained by CIE (in-house), ELISA (Pharmacia Diagnostics), and FEIA (Pharmacia Diagnostics). Sera from systemic lupus erythematosus (SLE) patients (n = 123), systemic sclerosis patients (n = 25), and healthy controls (n = 40) were analyzed for the presence of antibodies to RNP, Sm, SSA, SSB, CENP-B, Scl-70, and Jo-1. Reading of LIA results, as compared with a cutoff control, was performed by automatic analysis of the test strips. Because LIA enables recognition of separate subunits of RNP (68, A, and C), Sm (B and D), and SSA (52 and 60), at least two of the RNP antigens and either one of the Sm or SSA antigens should be detected for considering the test RNP, Sm, or SSA-positive, respectively. LIA had the highest sensitivity in patients with autoimmune connective tissue diseases: 131 specificities (not PO, PCNA, or histones), as compared with ELISA (121), FEIA (119), and CIE (80). However, LIA revealed three positive reactions in healthy controls; other assays were completely negative. LIA is better than CIE, but similar to ELISA and FEIA, in terms of detecting systemic sclerosis-associated antibodies (CENP-B and Scl-70). Furthermore, LIA had the highest sensitivity (17.9%) for the SLE-specific anti-Sm antibodies, as compared with ELISA (11.4%), CIE (8.1%), and FEIA (5.7%). Finally, anti-SSA antibodies were far more prevalent by LIA in the systemic sclerosis samples because of anti-SSA52 reactivity. The clinical relevance of the latter finding remains to be determined. In conclusion, LIA is suitable for routine evaluation of autoantibodies to extractable nuclear antigens.
For the diagnosis of systemic autoimmune rheumatic diseases (SARD), patients are screened for anti-nuclear antibodies (ANA). ANA, as assessed by indirect immunofluorescence (IIF), have a poor specificity. This hampers interpretation of positive results in clinical settings with low pretest probability of SARD. We hypothesized that the utility of positive ANA IIF results increases from primary to tertiary care. We retrospectively determined ANA, anti-ENA, and anti-dsDNA antibody prevalence in patient cohorts from primary (n = 1453), secondary (n = 1621), and tertiary (n = 1168) care settings. Results reveal that from primary care to tertiary care, ANA prevalence increases (6.2, 10.8, and 16.0%, resp.). Moreover, in primary care low titres (70% versus 51% and 52% in secondary and tertiary care, resp.) are more frequent and anti-ENA/dsDNA reactivities are less prevalent (21% versus 39% in secondary care). Typically, in tertiary care the prevalence of anti-ENA/dsDNA reactivities (21%) is lower than expected. From this descriptive study we conclude that positive ANA IIF results are more prone to false interpretation in clinical settings with low pretest probabilities for SARD, as in primary care. Whether alternative approaches, that is, immunoadsorption of anti-DFS70 antibodies or implementation of anti-ENA screen assays, perform better, needs to be determined.
The ANCA consensus prescribes screening by indirect immunofluorescence on neutrophils. We evaluated the first automated ANCA-pattern recognition system. C-ANCA (n = 39) and P-ANCA (n = 40) samples were selected from patients with ANCA-associated vasculitis (AAV). Non-AAV controls included sera from healthy controls (n = 40), sera with possible interfering antibodies (n = 46), or miscellaneous ANCA reactivity (n = 31). ANCA slides were analysed by AKLIDES and routine fluorescence microscopy. The C-ANCA pattern was recognized by routine microscopy in 92% and 97% on ethanol- and formalin-fixed slides, respectively. AKLIDES reported C-ANCA in 74% and 95%, respectively. P-ANCA was recognized by routine microscopy on ethanol-fixed neutrophils in 90%, while AKLIDES reported P-ANCA in 80%. Typically, only 65% and 33% of these samples showed the expected C-ANCA on formalin-fixed neutrophils by routine microscopy and AKLIDES, respectively. A C- or P-ANCA pattern was observed on ethanol-fixed neutrophils in 28% and 23% of the controls by routine microscopy and AKLIDES, respectively. Only 5% of the controls revealed C-ANCA on formalin-fixed neutrophils by routine microscopy and AKLIDES. Altogether, automated ANCA-pattern recognition by AKLIDES is promising. Distinction of C- and P-ANCA is good, but sensitivity on ethanol-fixed neutrophils needs improvement. When optimized, pattern recognition software may play an important role in AAV diagnostics.
Both celiac disease and inflammatory bowel disease (IBD) are characterized by chronic diarrhea and the presence of distinct (auto)antibodies. In the present study we wanted to determine the prevalence of serological markers for inflammatory bowel disease, i.e., perinuclear antineutrophil cytoplasmic antibodies (pANCA) and/or anti-Saccharomyces cerevisiae antibodies (ASCA), in 37 patients with biopsy-confirmed celiac disease (Marsh IIIb/c). The majority of the patients was positive for IgA (auto)antibodies typically associated with celiac disease, i.e., antiendomysium antibodies (EMA) (86.5%), antigliadin antibodies (AGA) (73%), and antirecombinant human tissue transglutaminase antibodies (rh-tTGA) (86.5%). Four patients with selective IgA deficiency could be identified by analyzing EMA, AGA, and rh-tTGA for the IgG isotype. The prevalence of pANCA and ASCA, markers that are used for IBD, was unexpectedly high in our cohort of patients with celiac disease: 8 patients were positive for pANCA (IgG) and 16 patients were positive for ASCA (IgG and/or IgA). These results indicate that the presence of pANCA or ASCA in the serum of patients with chronic diarrhea does not exclude celiac disease. A prospective study is required to determine whether pANCA and/or ASCA identify patients at risk for developing secondary autoimmune disease.
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