Malar rash, arthritis, proteinuria, cellular casts, haemolytic anaemia and anti-dsDNA and anti-nRNP antibodies were all independently associated with the age of disease onset when comparing childhood-onset with adult-onset SLE (). Photosensensitivity, oral ulcers, pericarditis, proteinuria, cellular casts, seizures, thrombocytopenia and anti-dsDNA, anti-Sm, and anti-nRNP antibodies were all independently associated with the age of disease onset when comparing early and late-adult onset SLE ().
Univariable analyses comparing age at onset and the clinical and serological manifestations of SLE
After adjusting for gender, race and disease duration, the odds of having proteinuria, malar rash, anti-dsDNA antibodies, haemolytic anaemia, arthritis and leucopenia were all higher in childhood-onset than in adult-onset SLE (). The differences in the frequency of proteinuria, malar rash, anti-dsDNA antibodies and haemolytic anaemia survive a stringent Bonferroni corrected p value of <0.004. There was an interaction between the age of onset and gender when modelling for cellular casts. In male subjects, although not significant, the odds of having cellular casts were higher in adult-onset than in childhood-onset SLE. In female subjects, the odds of having cellular casts were higher in childhood-onset than in adult-onset SLE (p=0.0027).
Multivariable analysis comparing age at SLE onset and the clinical and serological manifestations with univariable analysis p values <0.20
The odds of having proteinuria, cellular casts, anti-nRNP antibody, anti-Sm antibody, anti-dsDNA antibody and seizures were higher in early adult-onset than in late adult-onset disease after adjusting for gender, race and disease duration, while late adult-onset patients with SLE had higher odds of developing photosensitivity than patients with early adult-onset disease (). The difference in the frequency of renal involvement in early adult-onset compared with late adult-onset disease, as indicated by the presence of proteinuria and cellular casts, survive a Bonferroni corrected p value of <0.004 ().
It should be noted that the serological data we used in this study are based on a single serum sample obtained at the time of patient enrolment in LFRR. Given possible fluctuation in autoantibody levels in lupus patients, data for autoantibody associations should be replicated to be considered confirmed.
Gender proportions are not equal across our population of patients with SLE (). Specifically, the proportion of male subjects is 10.0% higher in the group of patients with age of onset <18 years than in the 18–49-year-old age group (χ2=12.34, p=0.0004). The proportion of male subjects is 5.7% higher in the ≥50 age group than in the 18–49 year-old age group (χ2 =5.85, p=0.0156).
We next hypothesised that childhood-onset SLE is associated with higher genetic risk for the disease, which might explain a more severe disease than with adult-onset disease. We calculated the total number of SLE-risk alleles by genotyping 19 SNPs that represent 19 independent previously confirmed genetic susceptibility loci for SLE. PCA was used to identify outliers and then lupus genetic risk analysis was performed in each race separately. We found a significant difference in the number of carried SLE risk alleles between childhood-onset and adult-onset disease in Gullah and African-American lupus patients with odds ratios (95% CI) of 1.48 (1.07 to 2.04) and 1.25 (1.02 to 1.54), and p values of 0.018 and 0.032, respectively. These data indicate that for each additional risk allele carried, the odds of developing SLE during childhood (<18 years) increases by an average of 48% per risk allele in Gullah patients with SLE, and 25% in African-American patients. There was no association between the number of lupus risk alleles and age of disease onset in Hispanic patients, although a similar trend was observed (OR=1.21 (0.98 to 1.50), p=0.075). There was no association between the number of SLE risk alleles and age of disease onset in European-American lupus patients (, online supplementary table 1
). These findings were further confirmed using linear regression and modelling each race individually to test if the age at disease onset predicts the number of risk alleles present in female patients with SLE (, online supplementary table 2
Figure 1 Estimated probability of childhood-onset systemic lupus erythematosus (SLE) predicted by the number of risk alleles present. Logistic regression modelling depicting the probability of developing childhood-onset SLE based on the number of SLE susceptibility (more ...)
Figure 2 Estimated number of systemic lupus erythematosus (SLE) risk alleles present as predicted by the age of disease onset. Linear regression analysis showing significant reduction in the number of risk alleles needed to develop SLE with increase age at disease (more ...)