The First Report of Erythroderma as the First Manifestation of Myelodysplastic Syndromes that responded to 5-azacytidine

Background: Erythroderma is an uncommon and severe dermatological manifestation of a variety of diseases, and identifying its potential cause is challenging. Additionally, erythroderma is exceedingly rare as the rst manifestation of myelodysplastic syndromes (MDS). We report the case of a 67-year-old male patient with MDS that initially presented with erythroderma. The patient was dependent upon steroid treatment to control the erythroderma when he was treated with decitabine. When we converted decitabine to 5-azacytidine, the patient achieved complete remission of both erythroderma and MDS and was relieved of his dependency on the steroid treatment. The patient continued to be steroid-independent 13 months after treatment with 5-azacytidine.

This is the rst report of erythroderma as the rst manifestation of MDS. When screening the potential causes of erythroderma, MDS should be considered in addition to common cutaneous T-cell lymphoma.
Based on our case report and a review of the published literature, 5-azacytidine appears to be a more effective treatment option for MDS-related autoimmune and in ammatory dermatoses. On the other hand, various cutaneous adverse events can be induced by 5-azacytidine. Since MDS-related autoimmune and in ammatory dermatoses may occur prior to the diagnosis of MDS, concomitantly with it or even during the illness, it is important to distinguish whether the dermatoses is MDS-related or 5azacitidine-induced. Background Erythroderma presents as widespread erythema with a variable degree of scaling, and is distributed over 90% of the body surface. It has multiple causes with the most common reasons being underlying dermatoses, medication, and underlying malignancy. The most common hematological system disease associated with the etiology of erythroderma is cutaneous T-cell lymphoma [1].
MDS is a heterogeneous and clonal disorder of hematopoietic stem cells marked by dysplasia in myeloid cells, ineffective hematopoiesis, and refractory hemocytopenia with a risk of leukemic transformation.
It is important to identify the cause of erythroderma in order to provide targeted treatment. Herein, we report the case of a patient with erythroderma as the rst manifestation of MDS prior to diagnosis. By switching the patient from decitabine to 5-azacytidine treatment, the patient achieved relief of erythroderma.

Case Presentation
A 67-year-old male patient with whole-body scaling erythema was diagnosed with general eczema and took cetirizine hydrochloride and rupatadine fumarate intermittently for about six months to control the itchy rash. However, his erythema became aggravated gradually and he was obsessed with the swelling of limbs and fever. He was hospitalized in the Department of Dermatology of the First A liated Hospital of China Medical University and was diagnosed with erythroderma by skin biopsy. The patient received intravenous administration of 40mg/d methylprednisolone for 12 days and continuous oral administration of 28mg/d methylprednisolone. His skin lesions improved gradually and the dose of methylprednisolone was tapered regularly.
Routine blood examination revealed anemia and thrombocytopenia (hemoglobin 99g/L, platelet 62*10^9/L). A bone marrow aspirate was performed and a diagnosis of unclassi able MDS (MDS-U) was made according to the 2016 WHO classi cation of MDS with normal karyotype. The results of a PCR screening assay for 41 recurrent fusion genes in acute leukemia were negative. Next generation sequencing (NGS) revealed gene mutations in ASXL1, DNMT3A, and TET2.
Based on the patient's low International Prognostic Scoring System (IPSS) risk score, the patient received supportive care, including thalidomide and erythropoietin. Thereafter, the patient's platelet levels declined progressively to 10*10^9/L and he received platelet transfusions twice a week in the emergency ward. As such, he was hospitalized in our department for further treatment. At that time, he was administered 18 mg/d methylprednisolone as the erythroderma was still covering his limbs (Fig. 1A) and he complained of aggravated erythroderma when the dose of methylprednisolone was reduced. To address the patient's condition, treatment with decitabine was started, and two cycles later, the patient's platelet level returned to 244*10^9/L. During the treatment, there were several events of infection due to agranulocytosis and methylprednisolone, so we attempted to reduce the dose of methylprednisolone. As expected, the patient's rash became aggravated when the dose of methylprednisolone was reduced to 8 mg/d (Fig. 1B).
Therefore, we altered his treatment from decitabine to 5-azacytidine, once a month. After two cycles of 5azacytidine, the patient's erythroderma was relieved (Fig. 1C), we ceased administration of methylprednisolone, and re-examination of the patient's bone marrow indicated complete remission. Just before the sixth cycle of 5-azacytidine, the patient's platelet levels decreased to 63*10^9/L and, according to the morphology and immunophenotype studies on bone marrow, his MDS-U progressed to MDS with excess blasts-1(MDS-EB-1)with no relapse of erythroderma. Two more cycles of 5-azacytidine were administrated and his platelet levels continued to decline progressively. Due to the in uence of the coronavirus disease 2019 outbreak, the patient had to suspend treatment for 3 months; when he returned to our hospital, his platelet level was 19*10^9/L and was accompanied with the relapse of erythroderma. Upon further examination, bone marrow aspirate indicated acute leukemia. Due to nancial reasons the patient rejected ongoing treatment with 5-azacytidine, so we prescribed decitabine and venetoclax.
Presently, his platelet levels have stabilized around 30*10^9/L and 4 mg/d methylprednisolone is needed to control the erythroderma.

Discussion
Erythroderma, or generalized exfoliative dermatitis, is a rare in ammatory disorder of the skin characterized by erythema with scaling on 90% or more of the body surface [3]. A study from India reported that the incidence of erythroderma is 35 per 100000 dermatologic outpatients [4], but the actual incidence worldwide is unclear. The etiology of erythroderma includes several general groups, including preexisting dermatoses, medication, malignancies, connective tissue diseases, and idiopathic disorders. Erythroderma can be urgent or even life-threatening and the response to therapy varies by the underlying etiology. As such, it is crucial to identify the cause of erythroderma in order to provide the proper treatment [5].
Malignancy-associated erythroderma may be more progressive [6]. The most common malignancy associated with erythroderma is cutaneous T-cell lymphoma. Other hematological system diseases associated with the etiology of erythroderma include acute and chronic leukemia, lymphoma, and MDS [7][8][9], as in the case reported in this study. Various cytokines, antibodies and immunocytes play an important role in the cause of paraneoplastic dermatoses associated with malignancy, rather than the direct invasion of the tumor cells [10]. Although paraneoplastic dermatoses are frequently seen in MDS, erythroderma was rst reported.
It has been reported that the prognosis of the malignancy and dermatosis progress in parallel; as the malignancy is treated successfully or recurs, the dermatosis follows a similar course. In our case, the patient was initially treated with methylprednisolone to control erythroderma. When the patient was diagnosed with MDS, decitabine was then administrated. However, methylprednisolone dependency caused the patient to develop repeated pulmonary infections. Since several studies reported that 5azacytidine was an effective treatment for MDS-related autoimmune and in ammatory dermatoses, especially Sweet's syndrome [11,12], we switched the patient from decitabine to 5-azacytidine. After two cycles of 5-azacytidine, the patient's erythroderma was relieved along with the cessation of methylprednisolone. While it is unclear why 5-azacytidine appears to be more effective for treating MDSrelated autoimmune and in ammatory dermatoses than decitabine, we hypothesize that erythroderma can be relieved by dealing with the potential malignancy. Interestingly, 5-azacytidine can also lead to cutaneous adverse events, such as Sweet's syndrome, maculopapular erythematous eruption, and urticarial rash [13]. Since MDS-related autoimmune and in ammatory dermatoses may occur prior to the diagnosis of MDS, concomitantly with it or even during the illness, it is important to distinguish whether the dermatoses is caused by 5-azacitidine. 5-azacitidine-induced cutaneous adverse events always follow each cycle of 5-azacitidine and can be relieved by corticosteroids and/or discontinuation of 5-azacitidine administration.

Conclusion
The most common causes of erythroderma are preexisting dermatoses and drugs use. When these causes have been excluded, careful screening for an underlying malignancy should be undertaken. In Figure 1 Changes in cutaneous symptoms during the treatment of the patient. A. Condition of the patient when he was admitted to our department and was treated with 18 mg/d methylprednisolone by oral. B. After two cycles of decitabine, the patient's rash aggravated after the dose of methylprednisolone was reduced to 8mg/d orally. C. After two cycles of 5-azacytidine the patient's cutaneous symptoms were relieved.