Importance: Immune-mediated inflammatory diseases are rare but increasingly reported among patients with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML). Systemic lupus erythematosus (LE) and cutaneous LE associated with MDS/CMML have been rarely described, with atypical features and refractory disease.

Objective: To provide a comprehensive description of the phenotype and therapeutic responses of LE associated with MDS/CMML and to compare them with idiopathic LE.

Design, setting, and participants: This retrospective case-control study included nationwide, multicenter data from January 1975 to January 2023. Patients with MDS/CMML who either fulfilled classification criteria for systemic LE or had skin lesions diagnosed as cutaneous LE were included. For MDS/CMML systemic LE, a 2:1 case-control study was conducted with idiopathic systemic LE. Clinical features, centralized skin histopathology, and targeted next-generation sequencing were analyzed. Data were analyzed from May 2022 to June 2025.

Main outcomes and measures: The clinical, pathological, and molecular features of LE occurring in the setting of MDS or CMML compared with idiopathic LE.

Results: Of 24 included patients, 9 (38%) were female, 15 (63%) were male, and the median (range) age at diagnosis was 65 (32-85) years. A total of 19 were diagnosed with systemic LE and 5 with cutaneous LE. The median (range) follow-up was 4.5 (1-31) years. Cutaneous involvement was the most common manifestation of LE (17 [71%]). Chilblain lupus was the predominant subtype (6 [35%]). Compared with idiopathic systemic LE, patients with MDS/CMML-associated LE were older (median [range] age, 65 [32-85] years vs 23 [11-55] years; P < .001), more frequently male (10 [53%] vs 3 [8%]; P = .008), had less kidney involvement (2 [10%] vs 27 [71%]; P < .001), had less articular involvement (7 [36%] vs 37 [97%]; P < .001), and had reduced anti-double-stranded DNA positivity (6 [32%] vs 29 [76%]; P = .001). The underlying hematologic diseases included MDS (16 [66%]) and CMML (8 [34%]), with 22 (92%) classified as lower risk (Revised International Prognostic Scoring System score of 3.5 or less). Centralized histopathological review reclassified 6 skin biopsies (50%) as MDS/CMML cutis. Identical myeloid variants were detected in blood and skin in 6 of 8 patients, supporting a clonal inflammatory process. Standard LE therapies were often poorly effective, while clone-directed therapies (azacitidine or allogeneic hematopoietic stem cell transplant) led to parallel hematologic and LE responses in 5 of 7 patients.

Conclusions and relevance: In this study, MDS/CMML-associated lupuslike manifestations were a distinct entity mimicking systemic LE or cutaneous LE and characterized by clonal inflammation rather than classic autoimmunity in most cases. Early recognition is important, as treatment may require clone-targeting therapies rather than conventional LE therapy.