Findings of the present study suggest that anti-RNP antibody-positive pSS - despite sharing many common (especially pathological) features with anti-RNP antibody-negative pSS - constitutes a clinical subgroup distinct from other well-known pSS subgroups.Specifically, anti-RNP antibody-positive patients demonstrated significantly higher frequencies of extra-glandular manifestations more commonly associated with MCTD and SLE, including RP, and pulmonary, lymphatic system, mucocutaneous, and hematological involvement. Additionally, anti-RNP antibody-positive patients exhibited significantly higher ESSDAI scores.
In the present cohort, anti-RNP antibody positivity prevalence was approximately 12 %, which is consistent with that reported in a previous study. In an Israeli pSS cohort (N = 82), 13.41 % of patients exhibited anti-RNP antibody positivity [24]. However, in a pSS cohort of Hispanic descent (N = 402), anti-RNP antibody positivity prevalence was only 2.49 % [25], and a French pSS cohort (N = 467) exhibited 4.50 % anti-RNP antibody positivity prevalence [15]. This relatively broad range of prevalence is likely attributable to ethnicity-related genetic factors.
Although the presence of anti-RNP antibodies is not included in American-European Consensus Group 2002 classification criteria for pSS [4], they do seem to be associated with a specific subset of system involvements and disease activity. Notably, the present study demonstrated that such patients exhibited a higher frequency of RP, and that RP was independently predictive for anti-RNP antibody positivity. This is consistent with anti-RNP antibody positivity association with RP across a broad spectrum of connective tissue disorders (e.g., MCTD, SSc, SLE, and RA) [26, 27]. This is interesting considering that ANA, ACA, anti-RNP antibody, anti-Sm antibody, and anti-Scl-70 antibody status is apparently not of utility in elucidating the pathology underlying RP [28]. However, our previous research also suggested that pSS patients with RP represent a distinct subset characterized by more frequent presence of ACA or anti-RNP antibodies, and more frequent pulmonary involvement. Furthermore, it has been hypothesized that RP may be associated with antibodies targeting oxidized U1-70kDa (a common target of anti-RNP antibody-positive autoimmune sera), which may be generated due to the formation of reactive oxygen species during ischemia-reperfusion [29, 30].
Regarding pulmonary manifestations of pSS, anti-RNP antibody positivity is known to be associated with pulmonary hypertension and ILD. Pulmonary fibrosis is more prevalent in anti-RNP antibody-positive than in anti-RNP antibody-negative pSS (51.28 % versus 15.65%). Moreover, we previously demonstrated that pSS patients with ILD exhibited a significantly higher frequency of anti-RNP antibody positivity than those without ILD (i.e., that the presence of anti-RNP antibodies was significantly associated with the risk of ILD). This is consistent with other studies reporting a higher incidence of ILD in the anti-RNP antibody-positive pSS patient cluster. Within such a patient cohort (N = 188), 26 % who underwent a computed tomography (CT) scan of the chest had ILD [31]. Interestingly, ILD (one of the most common extramuscular features of myositis) occurs in 45 % of anti-U1-RNP antibody-positive myositis patients, but in significantly lower proportions of DM patients (13 %) and IMNM patients (6 %) (all: p < 0.01) [32]. It was hypothesized that anti-RNP antibodies may contribute to connective tissue disorder-associated ILD by recognizing pulmonary endothelial antigens and stimulating inflammatory cytokine production [33–36]. In contrast, a meta-analysis revisiting antisynthetase syndrome patients demonstrated a lower frequency of ILD in patients with anti-U1-RNP autoantibodies [37]. It is possible that anti-U1-RNP antibodies contribute to disease pathogenesis via distinct mechanisms in different types of connective tissue disorder [34, 38]. Considering the seriousness of pulmonary fibrosis (which is generally asymptomatic during its early stages), screening by means of pulmonary CT may be prudent in anti-RNP antibody-positive pSS. In contrast, the present study found no significant difference in pulmonary hypertension frequency (12.82 % versus 5.78 %, p = 0.16) on the basis of anti-RNP antibody status.
Anti-RNP antibody positivity also correlated with hematological involvement in the present study: the proportion of patients exhibiting leukocytopenia, lymphopenia, and thrombocytopenia was significantly higher in the anti-RNP antibody-positive group. It has previously been suggested that anti-Sm/RNP antibodies (but not anti-Sm antibodies) are strong correlates of hematological disorders in SLE patients of European-American and African-American (but not Hispanic) descent. Relatedly, autoantibodies targeting RNP (but not Sm) were independently enriched in SLE patients of Hispanic descent exhibiting lymphopenia [39]. There may be an inter-individual difference in mechanisms by which anti-RNP antibodies contribute to pSS pathology. However, mechanisms underlying the above associations require further elucidation. Regarding muscular involvement, anti-RNP antibody positivity is associated with more frequent muscular involvement in pSS patients [15]. However, the present study did not confirm the association between anti-RNP antibody positivity and myositis.
Several potential limitations of the present study are acknowledged. First, the retrospective nature of the study precluded inclusion of comprehensive patient clinical data. For example, electromyography and muscle biopsy findings were not available for all patients, thereby preventing conclusions regarding the true prevalence of myositis in this population. A longitudinal prospective study would address such shortcomings. Second, the proportion of anti-RNP antibody-positive pSS patients was small relative to that of anti-RNP antibody-negative pSS patients. However, it was large enough to facilitate conclusions regarding statistical significance of between-group differences. Third, an insufficient number of anti-RNP antibody-positive patients had long-term follow-up data available. Finally, we did not evaluate associations between the presence of anti-RNP antibodies and other autoantibodies commonly found in pSS patients. Larger, multicenter, prospective studies (including systematic evaluation of autoantibody profiles) are recommended to elucidate the mechanistic and clinical significance of autoantibodies in pSS.