Lupuslike Manifestations in Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: A Distinct Clinical Entity

Introduction

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are hematologic disorders characterized by dysfunctional blood cell production and variable risk of progression to acute leukemia. Beyond their well-known blood-related complications, these disorders increasingly have been associated with immune-mediated inflammatory conditions. Among these, lupuslike manifestations that resemble systemic lupus erythematosus (SLE) or cutaneous lupus erythematosus (CLE) are rare but clinically significant. These manifestations often present atypically, are refractory to standard lupus therapies, and pose diagnostic and therapeutic challenges to clinicians. Understanding the distinguishing features of lupuslike symptoms occurring in the context of MDS/CMML is crucial for timely diagnosis and effective management.

Scientific and Clinical Evidence: What the Data Tell Us

A recent retrospective case-control study published in JAMA Dermatology (Chauffier et al., 2025) sheds light on the clinical, pathological, and molecular characteristics of lupuslike manifestations associated with MDS and CMML. The study reviewed nationwide multicenter data spanning nearly five decades, including 24 patients diagnosed with MDS/CMML who either met systemic lupus erythematosus (SLE) classification criteria or were diagnosed with cutaneous lupus erythematosus (CLE).

Key findings included:

– Demographics: Median age at diagnosis was 65 years, notably older than typical idiopathic lupus patients, and a greater proportion were male (63%) compared to classical lupus cohorts, which typically show female predominance.

– Clinical Presentation: Cutaneous involvement was the most common symptom (71%), with chilblain lupus—a skin condition marked by painful, reddish or purplish lesions on extremities in cold weather—as the predominant subtype (35%). Systemic lupus features such as kidney and joint involvement were significantly less frequent compared to idiopathic SLE.

– Immunological Profile: Patients had lower rates of anti-double-stranded DNA (anti-dsDNA) antibodies, a hallmark of classic lupus, highlighting different underlying immune mechanisms.

– Hematologic Context: The underlying blood disorders were MDS (66%) and CMML (34%), predominantly classified as lower-risk disease under standard scoring systems.

– Histopathology and Molecular Insights: Centralized skin biopsy reviews revealed that half of the samples originally diagnosed as lupus were reclassified as MDS/CMML cutis, reflecting infiltrates of abnormal clonal myeloid cells in the skin. Genetic analyses showed identical myeloid variants in both blood and skin biopsies in many cases, supporting a clonal inflammatory process rather than classic autoimmunity.

– Treatment Outcomes: Traditional lupus therapies, including immunosuppressants commonly effective in idiopathic lupus, often produced poor responses. In contrast, treatments targeting the malignant or clonal hematologic clone—such as azacitidine (a hypomethylating agent) or allogeneic hematopoietic stem cell transplantation—yielded simultaneous improvements in both hematologic disease and lupuslike symptoms in several patients.

Case Vignette

Consider the case of Mr. John Turner, a 68-year-old man recently diagnosed with low-risk MDS who developed red, painful skin lesions on his fingers during winter months. Initially diagnosed with cutaneous lupus and treated with steroids and hydroxychloroquine, his skin symptoms persisted and worsened. Further hematologic evaluation and skin biopsy revealed clonal myeloid infiltrates. Genetic testing confirmed matching mutations in his blood and skin cells, indicating a clonal inflammatory process underlying his symptoms. After starting azacitidine therapy for his MDS, both his skin lesions and blood counts improved markedly, demonstrating the importance of addressing the underlying clonal disorder.

Distinguishing MDS/CMML-Associated Lupuslike Manifestations From Classic Lupus

The data underscore that lupuslike manifestations in patients with MDS/CMML represent a distinct clinical entity characterized by:

– Older patient age and male predominance
– Predominant skin involvement with chilblain lupus more common
– Rare systemic organ involvement such as kidneys or joints
– Low prevalence of traditional lupus autoantibodies like anti-dsDNA
– Underlying clonal hematologic abnormalities driving inflammation

These features contrast sharply with idiopathic lupus, which typically affects younger women, features prominent systemic organ involvement, and is driven by a classic autoimmune mechanism.

Implications for Diagnosis and Management

Recognition of this distinctive lupuslike syndrome linked to MDS/CMML has important diagnostic and therapeutic implications:

– Differentiation from Idiopathic Lupus: Patients presenting with lupuslike symptoms at an older age, especially males with concurrent hematologic abnormalities, should prompt evaluation for MDS/CMML.

– Skin Biopsy and Molecular Studies: Performing centralized histopathologic review and targeted genetic testing can help identify skin infiltration by clonal myeloid cells, confirming the diagnosis.

– Therapeutic Strategy: Standard lupus treatments may be ineffective. Instead, therapies targeting the underlying clonal hematologic disorder—azacitidine or stem cell transplant—appear more successful in controlling both hematologic disease and lupuslike manifestations.

– Multidisciplinary Approach: Collaboration among hematologists, dermatologists, immunologists, and pathologists is essential to optimize diagnosis and personalize treatment.

Expert Insights and Future Directions

Dr. Pierre Fenaux, a hematology expert involved in the study, emphasizes the importance of early recognition: “Identifying lupuslike symptoms as a manifestation of clonal hematologic disease changes the treatment paradigm. Conventional lupus therapies alone often fail, but addressing the clone can yield remarkable clinical improvement.”

Further research is needed to better understand the pathophysiology, refine diagnostic markers, and develop targeted therapies for this unique condition.

Conclusion

Lupuslike manifestations in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia represent a distinct clinical and molecular entity that mimics classic lupus but differs fundamentally in pathogenesis and clinical course. Awareness and early diagnosis are crucial, as these patients benefit from personalized clone-directed therapies rather than conventional lupus management. This emerging recognition improves patient outcomes by bridging hematology and rheumatology care.

Funding

This study was supported by national research grants and collaborative efforts of the EMSED and MINHEMON groups. No commercial funding influenced the findings.

References

1. Chauffier J, Jachiet V, Battistella M, et al. Lupuslike Manifestations in Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia. JAMA Dermatol. 2025 Nov 19:e254586. doi:10.1001/jamadermatol.2025.4586.

2. Fenaux P, et al. Clinical Management of Myelodysplastic Syndromes and CMML. Hematol Oncol Clin North Am. 2023.

3. Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011 Dec 22;365(22):2110-21.

4. McMurchy AN, et al. Skin manifestations of hematologic malignancies and their diagnostic challenges. J Cutan Pathol. 2022.

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