Anti–RNA Polymerase II Antibodies in a US Cohort of Systemic Sclerosis Patients: Comment on the Article by Hamaguchi et al

To the Editor: We read with great interest the recent article by Hamaguchi et al (Hamaguchi Y, Kodera M, Matsushita T, Hasegawa M, Inaba Y, Usuda T, et al. Clinical and immunologic predictors of scleroderma renal crisis in Japanese systemic sclerosis patients with anti–RNA polymerase III autoantibodies. Arthritis Rheumatol 2015;67:1045–52). The authors report that systemic sclerosis (SSc) patients with the combination of anti–RNA polymerase II/III (anti-RNAP II/III) have an increased incidence of scleroderma renal crisis (SRC) compared to those who are positive for anti–RNAP III only. We used a similar methodology to that used by Hamaguchi and colleagues, specifically immunoprecipitation, for determining RNAP I/II/III antibody status in 209 SSc patients enrolled in the Genetics versus Environment in Scleroderma Outcome Study. All patients fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc (Van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/ European League Against Rheumatism collaborative initiative. Arthritis Rheum 2013;65:2737–47). In this cohort, 48 patients (23%) were positive for RNAP III antibodies and 13 (6.2%) were positive for anti–RNAP II in addition to anti–RNAP III. Among 98 white patients with SSc, 20 (20.4%) had anti–RNAP III, of whom 6 (6.1%) also had anti–RNAP II. Among 111 nonwhite patients, there were 28 (25.2%) with anti–RNAP III, of whom 7 (6.3%) also had anti–RNAP II. Of note, of the anti– RNAP III–positive patients, all but 1 also had RNAP I antibodies, and no patient in the cohort was positive for anti–RNAP II but negative for anti–RNAP III. Table 1 shows a comparison of the baseline demographic and clinical features in patients who were positive for anti–RNAP III but not RNAP II versus those with anti–RNAP II/III. There was a trend toward shorter disease duration among the patients with anti–RNAP II/III, but this was not significant. After a mean followup of 6.8 years, 6 patients in the anti–RNAP III–positive only group (17.1%) and 4 patients in the anti–RNAP II/III–positive group (30.8%) had developed SRC. Similar to the study by Hamaguchi et al, we compared the frequency of SRC development between patients with anti–RNAP II/III and patients with anti–RNAP III alone. Although the presence of RNAP II/III antibodies was not significantly associated with SRC (P 5 0.302), the proportion of patients with SRC was higher in the RNAP II/III group than in the group with anti–RNAP III alone (odds ratio [OR] 2.15, 95% confidence interval [95% CI] 0.49–9.34). A comparison of patients with only RNAP III or those with RNAP II/III to the remainder of patients in the overall cohort showed that both antibodies were associated with the occurrence of SRC (OR 5.34, 95% CI 1.61–17.73, P 5 0.006 for anti–RNAP III only; OR 11.48, 95% CI 2.74–48.1, P 5 0.001 for anti–RNAP II/III). Our data indicate that the frequency of RNAP II antibodies is higher in US SSc patient populations than in Japanese cohorts (6.2% in our study, versus 2.9% [17 of 583] in the study by Hamiguchi and colleges; P 5 0.015). Although the frequency of SRC was numerically higher among patients with RNAP II/ III antibodies than in those with only RNAP III antibodies, the difference was not statistically significant. Moreover, RNAP II antibody determination is cumbersome as it requires immunoprecipitation, whereas RNAP III can be identified with a commercially available enzyme-linked immunosorbent assay.