A Case of Ixazomib-Induced Histiocytoid Sweet Syndrome in a Patient With Multiple Myeloma

Sweet syndrome (SS), also known as acute febrile neutrophilic dermatosis, is characterized by erythematous, edematous, well-demarcated, tender plaques.¹ These plaques are asymmetrically distributed, often involving the face, neck, and upper extremities.² On histology, SS is characterized by intense dermal, neutrophilic infiltrates.¹

Three well-documented types of SS exist: classical or idiopathic, malignancy-associated, and drug-induced.¹ Idiopathic SS is associated with inflammatory bowel disease and pregnancy, among other diseases, and is usually preceded by an upper respiratory or gastrointestinal infection.^1,3 SS may also arise in the setting of malignancy as a paraneoplastic phenomenon, most frequently with hematologic malignancies.¹ Common classes of medications that have been reported to cause SS include all-transretinoic acid proteasome inhibitors, hypomethylating agents, tyrosine kinase inhibitors, and lenalidomide.¹ While the etiology of SS is still unclear, cytokine-mediated hypersensitivity reaction seems to play a role in the pathogenesis, followed by neutrophilic infiltration.² Elevated granulocyte colony-stimulating factor and IL-6 support the proinflammatory pathogenesis behind SS.^4,5 Treatment of SS includes systemic corticosteroids in addition to stopping the of- fending agent in cases of drug-induced SS.¹

Histiocytoid sweet syndrome (HSS) is a rare variant of SS first described in 2005 by Requena et al⁶ in a series of 41 patients. It is characterized by an immature myeloid precursor dominant infiltrate that resembles histiocytes.^6,7 This variant has been reported in cases of patients with previously diagnosed multiple myeloma and myelodysplastic syndrome.^3,8 In this article, we discuss the presentation and treatment of a patient with a 3-month history of multiple myeloma who presented with drug-induced HSS, likely due to the proteasome inhibitor ixazomib, and review the clinical features of HSS.

Case Presentation

A 73-year-old man presented with a 1-month history of a tender rash that started in the groin and subsequently spread to involve his face, chest, back, and arms. He was recently diagnosed with multiple myeloma 3 months prior to presentation and was treated with ixazomib, lenalidomide, and dexamethasone, all of which were started 5 weeks prior to the start of the rash. Review of systems was negative for systemic symptoms.

Physical examination revealed multiple erythematous, edematous papules and plaques scattered on the face, chest, back, abdomen, and upper extremities. Several plaques revealed dark, necrotic-appearing centers (Figure 1). At a follow-up visit 1 week later, his rash had spread with more than 30 lesions on his chest, back, and upper extremities (Figures 2, 3).

Skin biopsies were performed at his initial visit and follow-up. Initial biopsy showed superficial and deep perivascular mixed infiltrate with lymphocytes, eosinophils, and neutrophils with focal necrosis. The second biopsy showed moderate perivascular inflammation, this time with lymphohistiocytic infiltrate, basal layer vacuolization, and rare dyskeratosis (Figure 4). Acid-fast bacillus, FITE, Grocott methenamine silver, periodic acid–Schiff, and kappa and lambda stains were negative. Tissue culture had no growth. Laboratory results revealed a lactate dehydrogenase level elevated to 277 U/L (normal range, 135 U/L to 225 U/L), and there were no other abnormal labs on presentation.

The patient stopped his multiple myeloma therapy (ixazomib, lenalidomide, and dexamethasone) due to concern for a possible drug eruption. He was started on triamcinolone ointment 0.1% applied twice a day. The patient’s rash resolved within 4 weeks after the initial presentation. After resolution of the rash, the patient was restarted on lenalidomide and dexamethasone, but ixazomib was held due to the concern of drug- induced HSS. The rash did not recur on this regimen.

Discussion
Drug-induced HSS was the likely diagnosis given recent re- ports of proteasome inhibitors, such as bortezomib and ixazomib, triggering SS. Both the more typical neutrophilic SS (NSS) and HSS have been associated with bortezomib in patients with multiple myeloma.^9-12 Lenalidomide and ixazomib have been re- ported with NSS but not HSS.^{5, 13-15} In our patient, because the rash resolved after discontinuation of ixazomib, we believe his HSS was drug-induced rather than secondary to his underlying multiple myeloma, a commonly described cause of HSS.⁸

Diagnosis of SS is made through meeting two of the major criteria (abrupt onset of painful, erythematous plaques, and histologic compatibility) as well as two of the minor criteria (association with a known trigger, pyrexia, abnormal inflammatory markers, and response to systemic corticosteroids or potassium iodide).¹⁶ However, the diagnosis of drug-induced SS is made through meeting all five of the criteria outlined in the Table.¹⁷ No fever was measured in our patient, although it could have been masked by the use of immunosuppressive medications. As the patient’s malignancy is well controlled on lenalidomide and dexamethasone, it was not in the patient’s best interest to do a rechallenge to confirm that ixazomib was the cause of the patient’s rash.

The patient’s rash improved 4 weeks after starting him on topical corticosteroids. This is interesting, as the standard treatment for both SS variants has been oral corticosteroids.³ Topical corticosteroids have previously been reported as treatment of ixazomib-induced SS, indicating this may play a role as first-line therapy in such cases.¹⁵

Despite the different histologic appearances, both HSS and NSS share a similar presentation of fever, leukocytosis, and rash consisting of macules, papules, or ulcers mainly on the face, trunk, or upper extremities.³ HSS and NSS are both associated with conditions of upper respiratory tract infections, solid malignances, and inflammatory conditions such as rheumatoid arthritis and Crohn disease; however, HSS is more likely associated with malignancy, in particular hematologic malignancies, such as myelodysplastic syndromes.^3,8,18-25 Compared with NSS, a recent systematic review found that HSS has fewer systemic symptoms and does not have the female predominance seen in NSS.⁸

Conclusion
In summary, we present a case of 73-year-old man with a 3-month history of multiple myeloma on chemotherapy who presented with a new eruption that was diagnosed as drug- induced HSS, a rare variant of SS. Consistent with previously reported treatment of ixazomib-induced SS, the rash resolved with topical instead of oral steroids, highlighting the benefit of topical treatment before, perhaps, systemic therapy. This case also may help dermatologists recognize the unique variant of HSS, which can present with fewer systemic symptoms.

Ms Al Shabeeb is a fourth-year medical student at the School of Medicine and Health Sciences at The George Washington University, Washington, DC. Dr Fong is the chief resident in the department of dermatology at School of Medicine and Health Sciences at The George Washington University. Dr Khera is assistant professor in the department of dermatology at School of Medicine and Health Sciences at The George Washington University. Dr Maiberger is assistant professor in the department of dermatology at School of Medicine and Health Sciences at The George Washington University and chief of dermatology at the Veterans Affairs Medical Center in Washington, DC.

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