Background/Purpose: RNA-binding region containing 3 (RNPC3) protein acts as a molecular bridge, promoting U11/U12 RNP complex formation. In previous studies, systemic sclerosis (SSc) patients who expressed anti-RNPC3 autoantibodies (aAbs) had an increased risk of interstitial lung disease (ILD), severe gastrointestinal (GI) disease and a closer temporal relationship between SSc onset and cancer diagnosis. The aim of this study was to compare phenotypic features of Mixed Connective Tissue Disease (MCTD) patients with and without anti-RNPC3 aAbs.

Methods: Anti-U1RNP+ MCTD patients from a previously clinically and serologically described retrospective cohort were studied. Patients were included if they fulfilled ≥ 1 MCTD classification criteria of either Alarcon-Segovia, Kasukawa, Kahn and/or Tanaka. An addressable laser bead immunoassay was used to detect specific anti-RNPC3 aAbs with normal reference range of < 1000 mean fluorescence intensity (MFI) to classify 1000-2,999 MFI as low-titer and ≥ 3000 MFI as high-titer positivity.

Cumulative clinical features were assessed for the presence of ACR/EULAR and non ACR/EULAR features of SSc, systemic lupus erythematous (SLE), Sjögren syndrome (SS) and myositis. ILD was defined on pulmonary imaging studies and GI involvement was defined as esophageal dysmotility/dilation and/or gastroesophageal reflux and/or pneumatosis and/or pseudo-obstruction and/or small intestine bacterial overgrowth. Cancer occurrence within 5 years of MCTD diagnosis was collected. Comparisons between anti-RNPC3+ and anti-RNPC3– subgroups were performed using Fisher two-tailed exact test, Wilcoxon rank sum test and logistic regression, where applicable.

Results: Sixty-six MCTD patients were included, 58 (88%) were females and mean (SD) age at MCTD diagnosis was 41.1 (13.5) years. Fifteen of 66 (23%) patients were positive for anti-RNPC3 aAbs: 13 (87%) had low-titer and 2 (13%) had high-titer, based on highest available titer during follow-up. Median follow-up duration was shorter in the anti-RNPC3+ group compared to the anti-RNPC3– group (5.0 vs 14.5 years, p=0.004).

The presence of anti-RNPC3 aAbs was associated with a higher frequency of sclerodactyly during the disease course (anti-RNPC3+ vs anti-RNPC3–: 100% vs 67%, p=0.007). Twelve of 15 (80%) and 3 of 15 (20%) anti-RNPC3+ patients displayed limited and diffuse SSc skin involvement, respectively. The frequency of ILD and GI involvement was not significantly different in anti-RNPC3+ compared to anti-RNPC3– patients (4/12, 33% vs 18/44, 41% p=0.73; and 13/14, 93% vs 43/46, 93% p=0.91). Anti-RNPC3 aAbs were not associated with any other SLE, SS or myositis manifestations. Cancer was found in 3 of 15 (20%) anti-RNPC3+ patients compared to 3 of 51 (6%) anti-RNPC3– patients (p=0.13). A trend towards a higher risk of cancer within 5 years was observed among patients with high-titer anti-RNPC3 compared to anti-RNPC3– patients (unadjusted OR 16.00, 95% CI: 0.54-484.28, p=0.07).

Conclusion: Anti-RNPC3 aAbs were associated with a higher frequency of SSc skin involvement in MCTD patients. Further studies are needed to clarify whether MCTD patients with high-titer anti-RNPC3 aAbs are at higher risk of cancer.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-rnpc3-autoantibodies-in-mixed-connective-tissue-disease-are-associated-with-systemic-sclerosis-skin-involvement/