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Indian J Dermatol
Indian J Dermatol
IJD
Indian J Dermatol
Indian Journal of Dermatology
0019-5154
1998-3611
Wolters Kluwer - Medknow India

IJD-69-355
10.4103/ijd.ijd_211_24
Correspondences
Dapagliflozin-Induced Cutaneous Vasculitis, a Hitherto Unreported Adverse Effect
Bhattacharyya Surjyamukhi
Ghosh Aparajita
From the Department of Dermatology, Venereology and Leprosy, KPC Medical College and Hospital, Kolkata, West Bengal, India E-mail: dr.aparajitaghosh@gmail.com
Jul-Aug 2024
19 8 2024
69 4 355357
3 2024
4 2024
Copyright: © 2024 Indian Journal of Dermatology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.
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pmcDear Editor,

Cutaneous small-vessel vasculitis (CSV) encompasses a group of diseases characterised by inflammation and fibrinoid necrosis of small dermal blood vessels. Drugs can often act as triggering factors though the true incidence of drug-induced vasculitis is unknown. A large retrospective study determined that drugs were implicated in almost 31% of cases of CSV.[1] Common causative drugs include antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), allopurinol and antiepileptic drugs. CSV due to sodium-glucose cotransporter-2 inhibitors (SGLT2i) have not yet been reported. Here, we discuss a case of CSV caused by dapagliflozin, a commonly prescribed, highly potent, selective and reversible SGLT2i used worldwide for the treatment of type 2 diabetes.

A 69-year-old diabetic man attended the dermatology outpatient department (OPD) with intensely itchy red rash over both the lower limbs for the last 10 days. There was no fever or malaise preceding or accompanying the rash. Arthralgia, abdominal pain or increased bleeding tendency was absent. On delving deeper into the history, it was revealed that he was started on dapagliflozin 10mg once a day 14 days back. His lesions started appearing 4 days later and were gradually progressing. Examination revealed multiple, erythematous to purpuric papules about 1 mm–2 mm in diameter distributed symmetrically over the legs with a few isolated lesions on the trunk. The papules were non-blanching, with a few showing central crusting [Figure 1]. The differentials considered were CSV, erythema multiforme, urticarial vasculitis and thrombocytopenic purpura. Other than a raised glycosylated haemoglobin of 7.2%, the rest of the investigations, such as routine haemogram, platelet count, liver enzymes and blood urea nitrogen, were normal. Routine and microscopic examination of the urine did not show proteinuria, red blood cells (RBCs) or casts. The test for antinuclear factor (ANF) and anti-neutrophilic cytoplasmic antibody (ANCA) in blood was negative. Histopathology of the lesion revealed leucocytoclastic vasculitis in the dermis characterised by vascular necrosis and extravasation of RBCs. The perivascular inflammatory infiltrate was composed largely of lymphocytes and neutrophils showing leucocytoclasia along with a significant number of eosinophils [Figure 2a and b]. On direct immunofluorescence, deposit of complement C3 in the vessel wall was noted [Figure 2c]. Thus, a diagnosis of ‘CSV without systemic involvement’ was established. Dapagliflozin was stopped, and the patient was treated symptomatically with oral antihistamine (levocetirizine) and emollients. The lesions resolved over a month, and there was no recurrence even after glimepiride was added to his anti-diabetic regimen, lending credence to the role of dapagliflozin as a causative agent for CSV in our patient, especially in the absence of any other systemic cause (Naranjo adverse drug reaction score = 6). As per the World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale, our patient belonged to the ‘probable/likely’ casualty category, and according to Hartwig’s Severity Assessment Scale, this was a level 2 adverse drug reaction.

Figure 1 Multiple, erythematous to purpuric papules, with central crusting in some, over the legs. Inset depicting non-polarised contact dermoscopic image of the lesion showing a central crust on a dull red background (non-blanching)

Figure 2 (a) Perivascular inflammatory infiltrate in the dermis (H & E stain, 40×) (b) Necrosis of blood vessel walls with extravasation of RBCs, perivascular lymphocytes and neutrophils showing leukocytoclasia alongwith eosinophils suggestive of vasculitis (H & E stain, 400×). (c) Granular deposit of complement- C3 in the vessel wall (DIF) (H & E stain, 400×)

As there are no investigations, which are specific to drug-induced vasculitis, it remains a diagnosis of exclusion. The presence of eosinophils in the inflammatory infiltrate on histology might be suggestive of drug-induced aetiology. The mechanism of dapagliflozin-induced CSV is unknown but the deposition of immune complexes in the vessel wall may be the causative reason as in many other cases of CSV. Hypersensitivity reactions to this drug appear to be uncommon. However, a large study assessing the post-marketing data regarding SGLT2i drugs from the international pharmacovigilance databases found 1136 cases of significant cutaneous adverse effects.[2] The most common is candidal infection of the female and male genital tract.[3] Several cases of Fournier’s gangrene, a life-threatening polymicrobial, necrotising fasciitis of the perineum have been reported.[4] The other cutaneous adverse effects reported include eczematous rash, fixed drug reaction, generalised pruritus and Sweet’s syndrome.[4] Literature search to study the relationship between SGLT2i and vasculitis showed only one previously reported case of empagliflozin-associated cutaneous polyarteritis nodosa, a type of medium vessel vasculitis.[5] No reports of vasculitis associated with dapagliflozin were found. This makes our case unique as it is the first documented case of CSV due to this drug.

There is a possibility that cases of SGLT2i-induced vasculitis remain undiagnosed in the absence of histopathology and immunofluorescence studies, emphasising the fact that patients presenting with rashes after initiation of dapagliflozin or related drugs must be thoroughly investigated.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.
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1 Ortiz-Sanjuán F Blanco R Hernández JL Pina T González-Vela MC Fernández-Llaca H Drug-associated cutaneous vasculitis: Study of 239 patients from a single referral center J Rheumatol 2014 4 2201 7
2 Raschi E Parisotto M Forcesi E La Placa M Marchesini G De Ponti F Adverse events with sodium-glucose co-transporter-2 inhibitors: A global analysis of international spontaneous reporting systems Nutr Metab Cardiovasc Dis 2017 27 1098 107 29174026
3 Yabe D Nishikino R Kaneko M Iwasaki M Seino Y Short-term impacts of sodium/glucose co-transporter 2 inhibitors in Japanese clinical practice: Considerations for their appropriate use to avoid serious adverse events Expert Opin Drug Saf 2015 14 795 800 25851664
4 Boccardi A Shubrook JH Cutaneous reactions to antidiabetic agents: A narrative review Diabetology 2022 3 97 107
5 Marchiori E Rodionov RN Peters F Magnussen C Nordanstig J Gombert A SGLT2 Inhibitors and peripheral vascular events: A review of the literature Heart Fail Clin 2022 18 609 23 36216490
