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Introduction Systemic sclerosis (SSc) is characterized by extensive fibrosis, microvasculopathy, and the presence of many autoantibodies (autoAbs). Many autoAbs are detected in SSc, including disease-specific autoAbs, such as anti-topoisomerase I (ATA), anticentromere abs (ACA) and anti-RNA polymerase III (RNAP3), which are generally associated with distinct clinical subsets of SSc, and their detection usually reflects specific pathogenic pathways. The presence of two or more SSc-specific autoAbs in the same patient is considered rare, as these antibodies are typically mutually exclusive. However, occasional reports of coexisting autoantibodies do exist, and when identified, they may pose challenges in clinical interpretation.Material and Methods We present the case of a 42-year-old female patient diagnosed with SSc in 2003. At disease onset, she presented with Raynaud’s phenomenon, sclerodactyly, gastroesophageal reflux disease and exertional dyspnea. High-resolution imaging of the lungs revealed ground-glass opacities. Serological testing revealed a positive antinuclear antibody (ANA) with speckle pattern on immunofluorescence at high titer (1:640), positive ACA and negative ATA and RNAP3 by Enzyme-Linked Immunosorbent Assay (ELISA). The same serologic profile was confirmed one year later. The patient received immunosuppressive therapy with D-penicillamine for seven years, after which she was lost of follow-up.Results In 2025, the patient presented to the hospital with digital ulcers. Her skin and pulmonary involvement remained stable. Repeat serological testing revealed ANA positivity at a titer of 1:1280 with a centromere pattern, as well as positivity for ACA (>200IU/ml, normal<20), ATA (113IU/ml, normal<20) and positive RNAP3 (56IU/ml, normal<20). The simultaneous presence of all three classic SSc-related antibodies (ACA, ATA, RNAP3) was confirmed on three separate occasions using both ELISA and immunoblot assay.Conclusions This case highlights the rare occurrence of simultaneous positivity for all three major SSc-specific autoantibodies—ACA, ATA, and RNAP3—in a patient with longstanding SSc. While these autoAbs are typically considered mutually exclusive and associated with distinct clinical subsets and prognoses, their co-expression raises important questions about disease pathogenesis, immunological evolution, and the utility of sequential serological testing in selected cases. The shift in serologic profile over time in this patient—confirmed with both ELISA and immunoblot assays—underscores the need for cautious interpretation of autoantibody results and may suggest dynamic autoimmunity in certain individuals. Further studies are warranted to determine the clinical implications and prognostic relevance of such atypical serological presentations in SSc.