ANA and autoantibodies

Using the defined cut-off of >20 ELISA units (EU), 615 individuals out of the 1,159 tested were ANA positive. For the subset of 401 HC, the average ANA was 19.5 EU and 101 individuals were in the positive range. This rate of 25% HC positivity is very close to what we have reported previously [1]. Healthy FDRs had a slightly higher overall average ANA (24.4 EU) and a prevalence of ANA positivity of 34%. These values were not significantly different than in the HCs (P >0.07 for both). For the overall group, ANA values were significantly higher in females than in males (Figure ​(Figure1)1) and no males had values >240 EU while 3.2% of females had values in this range (P = 0.0030). When the analysis was limited to HC, females again showed significantly higher ANA levels than males (21.4 vs. 15.6 EU; P = 0.033) and ANA positivity was also more prevalent in HC females (29%) than in HC males (17%; P = 0.014). This corresponds to a relative risk of ANA positivity in healthy females vs. males of 1.21 (95% confidence interval = 1.059 to 1.390). The highest ANA levels were seen almost exclusively in non-Hispanic females (data not shown), although the overall mean values for Hispanic and non-Hispanic females were not significantly different (P = 0.7). African-American (AA) HC (n = 32) had a higher mean ANA value than non-AAs (27.47 ± 5.8 EU vs. 18.1 ± 5.8 EU), but the difference did not reach statistical significance (P = 0.064). Within each gender, AA individuals also had higher values than non-AA individuals (females: 30.38 ± 8.12 EU vs. 20.59 ± 1.80 EU; males 21.09 ± 5.55 EU vs. 15.17 ± 1.31 EU); these differences were also not significant (P >0.1 for each). However, the results are highly suggestive of higher ANA values in AA HC, and the differences might achieve significance in a larger sample size. Patients with SLE did not show gender differences in overall ANA values, although the very highest ANA values were again seen exclusively in females (Figure ​(Figure11).

We compared these findings to another autoimmune disease, RA, which is associated with the CCP autoantibody. While RA patients showed significantly higher ANA levels in females than in males (Figure ​(Figure2),2), antibodies to CCP did not show gender differences in either the control population represented by the Dallas Heart Study or in RA patients from DRADR (Figure ​(Figure2).2). These findings suggest that female gender is a general risk factor for ANA but is not necessarily a correlate with other autoimmune disease-specific antibodies.

Age was not related to ANA positivity in HCs; high values were scattered throughout the age spectrum (R2 = 0.01). The high ANA levels in HC also were not explained by overall increases in total IgG as the two measures were not significantly correlated (R2 = 0.11; P = 0.2).

To further understand high ANA levels in HC, a subgroup analysis was done using HC subjects with ANA values greater than 40 EU as the index group. This value is approximately one standard deviation greater than the overall mean ANA for HC. A total of 18 of the 401 HC, or about 4%, fit this definition of high ANA. Two comparator groups, HC with negative ANA (ANA values <12 EU) and SLE patients with high ANA (>100 EU) were generally matched for demographic features including gender, race and ethnicity (Table ​(Table1).1). Autoantibodies on the ENA panel were generally not elevated in the high ANA HC group. Only 3 of the 18 individuals showed positive ENA results, and in all three the lone positive specificity was anti-chromatin.

The three study groups were then compared using the autoantigen array for both IgG and IgM autoantibodies (Figures ​(Figures33 and ​and4).4). Two major IgM clusters showed a tendency for the SLE patients to cluster together, but this was not statistically significant (P = 0.08); the high ANA HC individuals had a similar tendency to be in the non-SLE cluster (P = 0.06; Figure ​Figure3).3). For IgG, two primary IgG clusters were identified, and all of the SLE patients were in one of these clusters (P = 0.009; Figure ​Figure44).

Antibodies detected on the arrays were then examined for specificities appearing in HC that were lupus-like. This was defined as overall mean values for a given specificity showing no difference between the high ANA HC and SLE groups (P >0.1) while at the same time having lower values in the low ANA HC group compared to SLE (P <0.1). The antibodies in these groups were examined to choose those with stepwise increases in the groups (low ANA HC <High ANA HC <SLE) and to exclude any with distributions that were highly skewed by one or two individuals. This analysis yielded 14 IgGs; 9 of these with the most significant P-values (Kruskal-Wallis test) are shown (Figure ​(Figure5).5). Four of the nine specificities are directed against autoantigens found in skin tissues (DSG4, MMP1, recombinant human collagen, integrinα6β4) [8-10]. Others are associated with autoimmune kidney disease (GBM), thyroid disorders (thyroglobulin), scleroderma (PM/Scl100), and inflammatory arthritis (proteoglycan) [11]. A search for autoantibodies that might be associated with a lowered risk of lupus was carried out by choosing specificities that were elevated in high ANA HC but were not high in SLE patients. The ratio of the mean values for the high ANA HC group to the corresponding SLE group mean was calculated, and three specificities had IgG ratios greater than 4.0: Jurkat T cells, gliadin and SK-N-SH (Figure ​(Figure6).6). In each of these, a subset of the high ANA HC individuals showed strong reactivity while SLE patients did not have high values. For gliadin, an autoantigen associated with celiac disease, and Jurkat, a measure of anti-T cell and thymocyte antibodies, the distributions were significantly different for the three groups (P = 0.042 and 0.033, respectively). Although the antineuronal antibodies measured by SKNSH reactivity did not show significant differences across groups by ANOVA, a dichotomized analysis showed values greater than 400 MFI units were present only in the high ANA HC group (P = 0.0242). The four highest values for each of these different autoantibodies represented the same individuals.

An independent ELISA assay was carried out for thyroglobulin (TG) autoantibodies to compare with the findings on the array. Anti-TG levels of the IgG class measured by the two techniques were significantly correlated (P = 0.007) and values were significantly higher in the HC high ANA group (1.18 ± 0.23 EU) than the HC low ANA group (0.60 ± 0.07 EU; P = 0.030), consistent with the array results.

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