Introduction
Immune-mediated inflammatory diseases (IMIDs) are increasingly recognized as rare but significant complications in patients with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Among these, systemic lupus erythematosus (LE) and cutaneous LE have been described, though often presenting with atypical clinical features and showing resistance to standard rheumatologic treatments. This case report and cohort analysis explores the distinct phenotype of lupuslike manifestations in the setting of myeloid malignancies.
Patient Information
This study analyzed 24 patients with MDS or CMML who presented with lupuslike manifestations. The demographic profile differed significantly from traditional idiopathic systemic lupus erythematosus (SLE). Of the 24 patients, 63% (n=15) were male, and the median age at diagnosis was 65 years (range 32-85). This contrasts sharply with idiopathic SLE, which predominantly affects younger females. The underlying hematologic conditions included MDS in 16 patients (66%) and CMML in 8 patients (34%). Most patients (92%) were classified as lower risk according to the Revised International Prognostic Scoring System (IPSS-R) score (3.5 or less).
Diagnosis
The diagnosis of lupuslike manifestations was based on either the fulfillment of classification criteria for systemic LE or a histopathological diagnosis of cutaneous LE.
Key diagnostic findings include:
- Cutaneous Involvement: Observed in 71% of patients (n=17).
- Predominant Subtype: Chilblain lupus was the most frequent cutaneous manifestation (35%).
- Serology: Anti-double-stranded DNA (anti-dsDNA) positivity was present in only 32% of the MDS/CMML-associated cases.
- Pathology: Centralized histopathological review was crucial; it reclassified 50% of skin biopsies (6 out of 12) originally diagnosed as LE into MDS/CMML cutis.
- Molecular Profiling: Targeted next-generation sequencing (NGS) identified identical myeloid variants in both the blood and skin of 6 out of 8 tested patients, suggesting a direct clonal link between the malignancy and the inflammatory lesions.
Differential Diagnosis
The primary differential diagnosis is idiopathic systemic lupus erythematosus (SLE). However, several factors distinguish MDS/CMML-associated lupuslike disease:
- Demographics: Older age and male predominance versus younger female predominance in idiopathic SLE.
- Organ Involvement: Patients with MDS/CMML had significantly less kidney involvement (10% vs 71%, P < .001) and less articular (joint) involvement (36% vs 97%, P < .001) than those with idiopathic SLE.
- Autoantibody Profile: Lower frequency of classic SLE markers such as anti-dsDNA.
- Pathological Nature: The condition is often a manifestation of “clonal inflammation” rather than classic B-cell-mediated autoimmunity.
Treatment and Management
Management of these patients revealed a significant divergence from standard LE protocols. Traditional therapies for LE, such as hydroxychloroquine or standard immunosuppressants, were frequently found to be poorly effective.
In contrast, clone-directed therapies aimed at the underlying hematologic malignancy showed promising results. Interventions included:
- Azacitidine: A hypomethylating agent used for MDS/CMML.
- Allogeneic Hematopoietic Stem Cell Transplant (HSCT): Used in refractory or high-risk cases.
Parallel hematologic and lupuslike responses were observed in 5 out of 7 patients who received these clone-directed treatments, suggesting that the resolution of the malignant clone directly impacts the inflammatory manifestations.
Outcome and Prognosis
The median follow-up period was 4.5 years. While the hematologic disease was often lower-risk (IPSS-R ≤ 3.5), the quality of life was frequently impacted by refractory cutaneous or systemic inflammatory symptoms. The prognosis for the inflammatory manifestations appears to be tied closely to the success of hematologic management rather than rheumatologic stabilization.
Discussion
This study establishes that lupuslike manifestations in MDS and CMML represent a distinct clinical and pathological entity. The presence of identical myeloid variants in skin lesions and peripheral blood strongly supports the hypothesis that these are not coincidental autoimmune diseases but are driven by the malignant myeloid clone itself. This is termed “clonal inflammation.”
The prevalence of chilblain lupus in this population is particularly noteworthy and should prompt clinicians to screen for underlying hematologic abnormalities when it occurs in older patients or males. The reclassification of 50% of skin biopsies as MDS/CMML cutis emphasizes the importance of expert dermatopathological review in this context.
The practical clinical takeaway is the shift in treatment philosophy. Because standard LE therapies often fail, early recognition of the underlying MDS/CMML is vital. Treatment should prioritize targeting the malignant clone, as this approach addresses the root cause of the inflammatory process. Future research should focus on the specific molecular pathways by which mutated myeloid cells induce lupuslike tissue damage.
References
Chauffier J, Jachiet V, Battistella M, et al. Lupuslike Manifestations in Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia. JAMA Dermatol. 2026;162(1):31-40. doi:10.1001/jamadermatol.2025.4586
